FINAL Pathology topics Flashcards
Hodgkin’s lymphoma. Molecular biology. Morphology and classification. Clinical stages of HD.
HODGKIN LYMPHOMAS
Any lymphoma that has Reed Sternberg cells or its variants.
RS cell release various cytokines and chemotactic agents, attracting many different kind of cells which eventually forms a mass - lymphoma
Presence of them differentiates it from Non-Hodgkins Lymphomas since Non-Hodgkin has no RS cells
The presence of these cells is not enough for diagnosis since they are present in other conditions too
Reed-Sternberg cells have an owl eyes appearance
- Large cells
- 2 mirror image nuclei (or 1 nucleus with 2 lobes)
- CD30, CD15
The variants of RS cells
- Lacunar cell [Reed Sternberg cells in a big lake-like space]
- Popcorn cell [Reed Sternberg cells with Multilobed nuclei, looks like a popcorn]
RS cells and their variants are derived from B lymphocytes. They do not show the typical surface markers so the proof is presence of Ig Heavy chains
In 70% of cases it is the EBV that’s associated with the malignant transformation of the B lymphocyte into an RS cell or one of its variants.
EBV produces viral proteins → stimulate the cell to synthesize NFkB → NFkB both stimulates the cell to proliferate and inhibits apoptosis
In the rest of cases it is a mutation in the IkB gene (which usually inhibits NFkB synthesis) that elevated NFkB levels, leading to increased cell proliferation without check
SUBTYPES OF HODGKIN LYMPHOMA
♥Nodular sclerosis Hodgkin lymphoma
- Most common form. Equally occurring in males and females (young adults)
- Good prognosis
- Many lacunar cells [unique to Nodular Sclerosis type]
- Collagenous bands divide the lymphoid tissue into nodules
- Cellular component – macrophages, eosinophils, lymphocytes
♥Mixed-cellularity Hodgkin lymphoma
- Affects patients >50 years old, predominant in males.
- Better prognosis than other types
- Cellular component - small macrophages, eosinophils, plasma cells, lymphocytes [mix of granulocytes, macrophages and lymphocytes]
- RS cell secretes IL5 which attracts Eosinophils, not present in other subtypes of Hodgkins Lymphoma
♥Lymphocyte-predominance Hodgkin lymphoma
- few RS cells (if any) → good prognosis
- Many popcorn cells
- Large number of lymphocytes [as the name suggests]
♥Lymphocyte-rich Hodgkin lymphoma
- More common in older persons
- Best prognosis
- No popcorn cells
- Many lymphocytes
♥Lymphocyte-depleted Hodgkin lymphoma
- Worst prognosis
- Few or no lymphocytes [meaning RS cells are not secreting cytokines or chemotactic agents, and may have transformed into a worst cancer cell]
All Hodgkin lymphoma are slow growing, so usually easy to diagnose and treatable
Hodgkins Lymphoma classically presents with:
B symptoms
1. Fever
2. Night sweats (because of increased number of cytokines)
3. Weight loss (more than 10% of body weight in a 6-month period)
Extranodal lymphomas (lymphomas of the MALT, cutaneous lymphomas, CNS lymphoma)
EXTRA-NODAL LYMPHOMAS
Mature B cell tumors, most commonly arise in MALT (salivary glands, small intestine, large intestine, lungs), and in non-mucosal sites (orbit, breast).
Tend to develop in the setting of autoimmune diseases or chronic bacterial infections (Helicobacter pylori - Chronic Gastritis - MALT Lymphoma, Campylobacter jejuni).
MALT LYMPHOMA
MALT lymphoma originates in B cells of MALT of the GI tract.
May arise anywhere in the gut, but most commonly occur in the stomach, usually due to chronic gastritis caused by H. pylori bacterium.
The infection leads to polyclonal B cell hyperplasia and eventually to monoclonal B cell neoplasm.
Translocation between chromosomes 11 and 18 is common => creates a fusion gene between the apoptosis inhibitor BCL2 gene (chromosome 11), and the MLT gene (chromosome 18).
~50% of gastric lymphomas can regress with antibiotic treatment since the main causative agent is Helicobacter pylori
CUTANEOUS LYMPHOMA
There are 2 classes of cutaneous lymphoma affecting the skin:
- B cell cutaneous lymphoma
- T cell cutaneous lymphoma
T cell cutaneous lymphoma
Several forms, most common is Mycosis fungoides
- Caused by mutation of cytotoxic T cells that infiltrate the epidermis and upper dermis, characterized by infolding of the nuclear membrane
- At later stage => Sezary syndrome, characterized by erythroderma (inflammatory skin disease), and by tumor cells whose nucleus looks like a brain - cerebri form nuclei also known as Sezary cell
B cell cutaneous lymphoma
Constitute a group of diseases, characterized by B cells similar to those found in germinal centers => diffuse large B cell lymphoma, primary cutaneous follicular lymphoma, intravascular large B cell lymphoma
CNS LYMPHOMA
- Intracranial tumor that appears mostly in patients with severe immunosuppression.
- Highly associated with EBV infections in immunosuppressed patients, but rarely so in immunocompitant patients.
- Most CNS lymphomas are diffuse large B cell lymphoma metastasis or primary tumour
- Symptoms include:
–Dislopia (double vision).
–Dysphagia (difficulty in swallowing).
–Dementia.
–Systemic symptoms (fever, night sweat, weight loss).
Physiological T-cell reactions. Peripheral T cell lymphomas
Recall NORMAL T cell formation and maturation process
Understand WHAT peripheral T cell lymphomas do
PHYSIOLOGICAL T-CELL REACTIONS
- The precursors of T lymphocytes are originated from bone marrow-derived multipotent stem cells
- Via the blood stream these precursors migrate into the thymus, the site of T cell development
- Once T cells have completed their developmental program, they leave the thymus and circulate between the blood and the lymph, passing through many secondary lymphoid organs/ tissues
- Mature circulating T cells that have not recognized antigens yet
are in a resting state and defined as naive T cells - The activation of naive T cells occurs in the secondary lymphoid organs/ tissues where they interact with professional APCs (mainly
with DCs): - DC finds a pathogen in the periphery and phogocytoses it → transports it to the lymph nodes add presents it to a T cell → T cell able to recognize this specific surface MHC-I -peptide complex (special ability) → T cell activation (naïve helper/cytotoxic T cell to effector helper/cytotoxic T cell)
- Effector T cells eave the lymphoid tissue, enter the blood circulation and migrate into the sites of infection or inflammation in peripheral (non-lymphoid) tissues
- All effector T cell functions are initiated by recognition of a peptide antigen presented by MHC-I or MHC-II molecules on the surface of target cell by TCR
- T helper cells (CD4) help their target fight against the pathogens ➔ Bind to MHC-II on APCs ➔ Secrete cytokines that attract other cells of the immune system => B cells, macrophages
- T killer cells (CD8) induce their target to die (inducing apoptosis OR using perforin granzyme) ➔ Bind to MHC-I on all nucleated cells ➔ Directly kill infected cells.
T cells also present CD28 marker, which helps them to bind to APCs
PERIPHERAL T-CELL LYMPHOMA
Whether a lymphoma is of a B, T or NK can be determined by B/T/NK cell markers (CDs, receptors, enzymes). Whether it is precursor or peripheral depends on the stage where the malignant
transformation occurs
Peripheral
- lymphocytic cells (smaller, more cytoplasm, more condensed chromatin)
- low rate of proliferation
- more differentiated
- Aggressive tumors that respond poorly to therapy
- Types:
o Lymphoepitheloid lymphoma (Lennert’s lymphoma)
o Angioimmunoblastic lymphadenopathy – like T – lymphoma.
o T – zone lymphoma.
o Pleomorphic T-cell lymphoma.
o Large cell anaplastic lymphoma.
Lymphoepitheloid lymphoma (Lennert’s kymphoma)
o Is small cell (lymphocytic) infiltrate intermingled with high amount of epitheloid cells and some blasts.
o Resembles lymphocyte predominant Hodgkin disease but RS cells are missing.
Angioimmunoblastic lymphadenopathy – like T – lymphoma
o Mixed infiltrate of small, medium and large immunoblastic cells.
o Resembles mixed cellularity of Hodgkin disease.
o Neoplastic cells show clear cytoplasm and wrinkled nucleus.
o Proliferation of dendritic reticulum cells are the hallmark of this
disease (CD23 positive)
o There is also proliferation of HEV infection
T-zone lymphoma
o Spread within the T-cell areas.
o Lymph node follicles with germinal centers are preserved.
o Follicular hyperplasia with CD4 positive T-cells.
Pleomorphic T-cell lymphoma
o Strong nuclear pleomorphism of small, medium and large lymphoid
cells
o Clear cells are also present.
Large cell anaplastic lymphoma [Anaplastic means not resembling any normal surrounding tissue - usually sign of high, bad malignant cancer cell]
o T-cells are CD30 positive.
o Shows cohesive spreading.
o Found primarily within sinuses of lymph nodes.
o Often mistaken for carcinomas, malignant melanomas or malignant
histiocytosis (DD: malignant histiocytosis shows CD68 positive)
o Translocation t(2:5) will cause increase in tyrosine kinase.
o Some case of Hodgkin disease and peripheral T-cell lymphoma may
evolve into secondary large cell anaplsatic lymphoma.
o Multinucleated tumor giant cells may be present
The plasma cell reaction. Plasmocytic neoplasms.
PLASMA CELL REACTION
A group of disorders characterized by plasma cell dysfunctions [mature B cell that produces antibodies]
The cause is gain of function mutations of protooncogenes or loss of function mutation of\tumor suppression genes → abnormal proliferation in bone marrow
- Usually abnormally proliferating cells lose their function but in the case of plasma cell dysfunction , plasma cells are still able to secrete “M components; monoclonal antibodies or parts of them
1.Complete monoclonal antibodies
2.Monoclonal antibodies + light chains
3.Heavy chains only [heavy chain disease]
4.Light chains only [light chain disease]
Monoclonal: all secreted antibodies are exactly the same (both heavy and light chains) and have NO variation in its antigen recognition
They are non-specific and are secreted WITHOUT a real stimulation
Polyclonal: this is what happens in a physiological immune reaction. Different plasma cells secrete different antibodies with different heavy chains (α IgA, ɤ IgG, μ IgM) and different
light chains (κ, λ).
Disorders:
» Multiple myeloma (plasma cell myeloma)
» Monoclonal gammopathy of undetermined significance
» lymphoplasmacytic lymphoma
» Heavy-chain disease
» Primary or immunocyte-associated amyloidosis
MULTIPLE MYELOMA
- Causes: t(11,14) Cyclin D protooncogene fuses with Heavy chain region. Deletion of tumor suppression genes on chromosome 13
- Blood→ Primary AL amyloidosis- any protein when can aggregate into rigid, linear non-branching fibrils with a beta pleated sheet arrangement
- Urine→ Protein urea- “Bence-Jones protein”; light chains in urine
- Marrow plasma cytosis (>30% of cellularity) →crowding out of other cells → fatigue, bleeding, infections (number 1 cause of death in
these patients because other plasma cells do not produce antibodies). -
M spike in protein electrophoresis (ɤ curve higher than curve of albumin which is higher) →
many proteins in plasma → interfere with charges → clusters of RBCs - The plasma cells secrete** IL-6**, positively stimulating themselves to proliferate and to secrete cytokines, which activate osteoclasts and inhibit osteoblasts functions → formation of painful lytic lesions in bones; flat bones- vertebrae, ribs, skull, and in shafts of long bones.
- The lytic lesions will appear radiolucent in x-rays→ mobilization of Ca2+ into blood → hypercalcemia → Ca2+ can deposit in kidneys, CNS abdominal SM cells and calcify →
- Renal failure (number 2 cause of death)
- Main antibody is IgG, second is IgA
- Immunophenotype:
MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE
An isolated M spike with none of the other findings of multiple myeloma. Can develop into multiple myeloma.
HEAVY CHAIN DISEASE
Two main forms:
- α HCD - neoplastic cells in small intestine respiratory system
- ɤ HCD- liver, spleen, lymph nodes
- No Bence Jones protein
PRIMARY AMYLOIDOSIS
Over production of immunoglobulin light chains, forming aggregations => AL protein.
Diffuse large B-cell lymphoma, Burkitt lymphoma
DIFFUSE LARGE B-CELL LYMPHOMA
A type of non-Hodgkin lymphoma, constitute 50% of NHLs.
Aggressive
Cause:
*Mutations / rearrangements of Bcl6 gene on chromosome 3 → overexpression of Bcl6 →
increased proliferation of centroblasts
*30% t(14,18); follicular lymphoma which developed into DLBL
*unknown
Features
*+ for B cells markers (not 10)
*BCR
Clinical features – aggressive tumors that are rapidly fatal if not treated; can affect
virtually any organ
BURKITT LYMPHOMA
Highly aggressive
Cause:
*t(8, 14)- chromosomal translocation; MYC gene translocates from chromosome 18 next to
the Ig gene for heavy chain on chromosome 14 → MYC gene becomes hyperactive → MYC
becomes hyperactive → increased proliferation of centroblasts
Two types:
*Endemic “African type”; 100% associated with EBV. Manifests in mandible and maxilla.
*Sporadic “American type”; 20 associated with EBV. Manifests in abdominal and pelvic
cavities.
*Both are histopathologically identical “starry sky appearance”
Dark background- neoplastic cells which are dark because of the high amount of chromatin
(high rate of proliferation, also death)
Lighter regions- non-neoplastic macrophages with pale cytoplasm and small nuclei
Mantle cell lymphoma, marginal zone lymphoma
MANTLE CELL LYMPHOMA
A type of non-Hodgkin lymphoma, constitute 4% of NHLs. Aggressive.
Cause:
*t(11, 14)- chromosomal translocation; Cyclin D1 gene translocates from chromosome 11
next to the Ig gene for heavy chain on chromosome 14 → Cyclin D1 gene becomes
hyperactive → increased proliferation of naïve B cells → accumulation in the mantle zone
Features:
*+ for B cells markers
*+ for CD5 (T cell marker)
Clinical features – nonspecific symptoms (fatigue, fever, weight loss), lymphadenopathy,
generalized disease involving the liver, spleen, bone marrow and GI tract.
MARGINAL CELL LYMPHOMA
Indolent.
There are 3 types of marginal zone lymphomas:
♥MALT lymphoma – most common form, occurs most frequently in the stomach (also
called extra-nodal marginal zone lymphoma).
♥Nodal marginal zone lymphoma – in lymphatic follicles of lymph nodes.
♥Splenic marginal zone lymphoma – B cells replace the normal resident cells of the white
pulp of the spleen (T cells, macrophages).
Extra nodal characteristics:
* They often arise within tissues involved by chronic inflammatory disorders of autoimmune
or infectious etiology;
Sjögren disease → overstimulation lymphocytes of parotid gland
Helicobacter specific T cells produce growth factors which support the formation of a tumor.
*They may regress if the inciting agent (e.g., Helicobacter pylori) is eradicated.
Cause:
*t (1,14) chromosomal translocation; Bcl10 gene translocates from chromosome 1 next to
the Ig gene for heavy chain on chromosome 14 → Bcl10 gene becomes hyperactive → Bcl10
becomes hyperactive → increased proliferation of lymphocytes
Features:
*+ for B cells markers (not 10)
*BCR
Physiological B-cell maturation (role of germinal centers). Follicular lymphoma
B-CELL MATURATION
Peripheral lymph node is composed of a cortex and a medulla => the cortex contains lymphocytic nodules (follicles).
The lymph follicle contains mainly B cells, and can be either primary (not activated) or secondary (met with an antigen).
Upon activation, B cells start to proliferate and differentiate, creating the germinal center of the lymph follicle.
Process of B cell differentiation:
In the germinal center, the differentiating and proliferating B cells undergo:
Somatic hypermutation – rearrangement of DNA of the variable region genes to form variations of antibodies.
Class switching – rearrangement of the heavy chain genes to switch the class of the antibody.
FOLLICULAR LYMPHOMA
A type of non-hodgkin lymphoma, constitute 40% of NHLs.
Immunophenotype – B cell markers CD10, CD19, CD20; cells show somatic hypermutation.
Karyotype – characteristic translocation of BCL2 gene from chromosome 18 to the loci of IgH gene on chromosome 14, resulting in the overexpression of BCL2 gene, which produces anti-apoptotic proteins (prevent release of cytochrome C => no apoptosis).
Clinical features – painless lymphadenopathy, bone marrow contains lymphoma (RBC , WBC , platelets ), poor response to chemotherapy.
Follicular lymphoma may progress to a diffuse large B cell lymphoma.
Treatment is reserved lot patients who are symptomatic and involves low-dose
chemotherapy or rituximab (anti-CD20 antibody).
Precursor lymphoblastic lymphomas and leukemias
Whether a lymphoma / leukemia is precursor or peripheral depends on the stage where the
malignant transformation occurs;
In precursor lymphoblastic lymphomas / leukemias
*lymphoblast cells (bigger, less cytoplasm, less condensed chromatin)
*high rate of proliferation
*less differentiated
→ Acute leukemia / aggressive lymphoma;
after the first clinical sign manifests in the patient, deterioration is relatively very fast (death
after 6-12 months).
*Occur mainly in children / young adults
Whether a leukemia/lymphoma is lymphoid / myeloid
Whether a leukemia/lymphoma is of a B, T or NK can be determined by cell markers (CDs,
receptors, enzymes).
*B cell- CD 10, 19, 20, 21, 22
*T cell- CD 2, 3 (expressed by all T cells) , 4, 7, 8
*NK cell- CD 16, 56
Pre-B cell neoplasms occur in the BM while pre-T cell neoplasms occur in the thymus.
B ALL is a lot more common (85%) and usually affects children while T cell ALL is a lot less
common (10-15%) and usually affects adolescents. NK ALL is extremely rare.
PATHOGENESIS
Mutation → chromosomal abnormality → abnormal TF → malignant transformation
The mutation can occur due to radiation, chemical
substances like benzine, it can be genetic (Li–Fraumeni
syndrome), or it can occur spontaneously.
Chromosomal abnormalities can be:
*Numerical (hyper/hypoploidy/trisomy..)
*Structural (deletion / translocation)
1. Hyperploidy
2. Hypoploidy
3. t(12,21) balanced
4. t(9,22) balanced; the resultant chromosome 22 is
referred to as “Philadelphia chromosome”
RELATED DISEASES
1. Crowding out of normal cells (>25% of BM cellularity)
♥Anemia → fatigue
♥Thrombocytopenia → bleeding (epistaxis, petechia, ecchymosis…)
♥Neutropenia → infections
2. Hyper-cellular BM → expansion of MB → detachment of periosteum → pain & arthralgia
*Also starry night appearance like in Burkitt lymphoma.
3. Leukostasis in microcirculation (eyes, kidneys…) → thrombi
4.Tumor lysis syndrome; neoplastic cells release their content into the plasma (uric acid↑,
phosphate↑, H+↑, Na+↑, Ca2+↓ (forms complexes with phosphate).
PROGNOSIS- likelihood of survival
Classification of malignant lymphomas (WHO classification)
Lymphomas
Solid cohesive neoplasms (tumors) of
the immune system, which mostly
originate from lymphoid tissues (BM,
thymus, lymph nodes..)
*CNS in AIDS
Accumulation of mutations
↓
loss of ability to remain cohesive
↓
transfer into blood (leukemia)
Always lymphoid!
Leukemias
Malignancies of either lymphoid
or myeloid origin, which primarily
involves the bone marrow with
spillage of neoplastic cells into
the blood.
.
Sometimes they enter lymphoid
tissues and aggregate there
(lymphomas)
Can be: Lymphoid leukemia
Myeloid leukemia (RBCs, PLTs and
all other WBCs except for
lymphocytes)
WHO CLASSIFICATION
A system that defines lymphoid tumors according to
several features: morphology (follicular / diffused), cell of
origin (T/B/NK/myeloid…), clinical features and genotype
(as mentioned before).
The classification divides lymphomas into 3 categories:
- Tumor of B cells
♥Precursor B cell neoplasms (B cell ALL)
♥Peripheral B cell neoplasms (mantle cell lymphomas,
follicular lymphoma, Burkitt lymphoma) - Tumor of T cells and NK cells
♥Precursor T cell neoplasms (T cell ALL)
♥Peripheral T/NK cell neoplasms (NK cell leukemia, mycosis fungoides) - Hodgkin lymphomas
♥Classical Hodgkin lymphoma
♥NLPHL- nodular lymphocyte predominance Hodgkin lymphoma
Whether a leukemia/lymphoma is of a B, T or NK can be determined by B/T/NK cell markers (CDs,
receptors, enzymes). Whether it is precursor or peripheral depends on the stage where the malignant
transformation occurs;
Precursor
*lympho/myeloBLASTIC cells (bigger, less cytoplasm, less condensed chromatin)
*high rate of proliferation
*less differentiated
→ Acute leukemia / aggressive lymphoma;
after the first clinical sign manifests in the patient, deterioration is relatively very fast (death after 6-12
months).
*Occur mainly in children / young adults
*Pre-B cell neoplasms occur in the BM while
pre-T cell neoplasms occur in the thymus
Peripheral
*lympho/myeloCYTIC cells (smaller, more cytoplasm, more condensed chromatin)
*low rate of proliferation
*more differentiated
→ Chronic leukemia / indolent lymphoma
NON-HODGKIN LYMPHOMAS
Generally indolent tumors progress slower but are harder to treat and appear in elderly
patients. On the contrast, aggressive tumors progress very fast but are easier to treat and
appear in younger patients.
♥SLL (small lymphocytic lymphoma) / CLL (chronic lymphocytic leukemia)
Indolent
Cause:
*Trisomy of chromosome 12 (protooncogene) or
*deletion of chromosome 11/13 (tumor suppressor gene)
This interferes with the BCRs → naïve B lymphocytes stop maturing and die too slowly →
accumulation of naïve lymphocytes in the BM and transfer into the blood and from there to
various tissues;
*BM
*liver, spleen → hepatosplenomegaly
*Lymph node → lymphadenopathy (swelling of the lymph node) → accumulation into
masses → lymphoma
This “crowds out” the healthy B cells, suppressing their normal function and often resulting
in anemia, thrombocytopenia and neutropenia
The reduced function of the B cells may result in;
*autoimmune hemolytic anemia (antibodies are produced against the patients own RBCs)
*Hypo-ɤ-globulinemia (abnormally low concentration of globulins in the plasma)
*Richter syndrome- when a cell enters a lymph node and proliferates there progressing to
DLBL.
Features (problem with a naïve lymphocyte in the circulation):
*+ for B cells markers
*+ for CD5 (T cell marker)
Morphology
The circulating tumor cells are fragile and during the preparation of smears frequently are
disrupted, producing characteristic smudge cells
Reactive lymphadenopathies (acute lymphadenitis, follicular and paracortical hyperplasia, sinus histiocytosis, toxoplasma lymphadenitis, mononucleosis, dermatopathic lymphadenopthy)
Dermatopathic lymphadenopathy – inflammation of lymph nodes due to drainage of
REACTIVE LYMPHADENITIS
Enlargement of a lymph node. Can be:
♥Acute, painful- when a lymph node drains a region with an acute infection.
*Confined to a local group of nodes draining the area of infection (can also be generalized
in case of systemic infection).
Characterized by large germinal centers containing numerous mitotic figures.
♥Chronic, painless- depending on the causative agent, the following areas of the lymph
node can be enlarged:
- Follicular hyperplasia
(enlargement of the follicles); can
be caused by chronic disorders
like RA and early stages of HIV
infections. - Paracortical hyperplasia
(enlargement of the paracortex);
can be cause by viral infections
like EBV (Burkitt lymphoma),
certain vaccinations (smallpox)… - Sinus histiocytosis
(enlargement of the sinuses of the medulla); can be caused by draining of cancers like
breast cancer.
Toxoplasma lymphadenitis – caused by parasitic disease due to infection by the
protozoan Toxoplasma gandii.
infected area of the skin; characterized by the presence of melanin-filled macrophages,
eosinophils and plasma cells.
Chronic myeloproliferative diseases (chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis)
CHRONIC MYELOPROLIFERATIVE DISEASES
Neoplastic proliferation of mature cells of the myeloid lineage, commonly associated with
mutated tyrosine kinases.
The disorders include:
♥Chronic myeloid leukemia (CML).
♥Polycythemia vera (PCV).
♥Primary myelofibrosis
♥Essential thrombocythemia.
They are named after the predominant cell (all of them increase in number).
Myeloproliferative diseases result in high WBC counts (neutrophils > 100,000 cell/µL) and in
hypercellular BM.
CHRONIC MYELOID LEUKEMIA
Increased proliferation of mature myeloid cells, especially granulocytes.
Affects adults between 25 and 60 years of age
Cause:
t(9,22) balanced; the resultant chromosome 22 is referred to as “Philadelphia chromosome”
Neutrophils counts are high both in CML and when there is an inflammation. So what
features are characteristic for CML?
1.Basophilia
2.LAP- leukocyte alkaline phosphate
3.t(9,22)
Treatment
Imatinib → blocks tyrosine kinase activity
POLYCYTHEMIA VERA
Increased proliferation of mature myeloid cells, especially erythrocytes.
Cause:
Mutation in JAK2, a tyrosine kinase → hypersensitivity of the cells to EPO
Clinical signs:
*RBCs mass↑ → ɳ↑ → stasis→ blurry vision, flushed face…thrombosis (Budd-Chiari
syndrome) – hepatic vein thrombus → infarcts
*Serum EPO levels↓
*Itching after bathing (high nr. of basophils).
Treatment
Phlebotomy
Without treatment death will usually occur within a one-year period
PRIMARY MYELOFIBROSIS
Increased proliferation of mature myeloid cells, especially megakaryocytes.
Cause:
Mutation in JAK2, a tyrosine kinase → megakaryocytes overproduce PDGF → fibroblasts
deposit collagen→ marrow fibrosis
Clinical signs:
hematopoiesis can NOT longer take place in the BM → shift to the liver and spleen →
*hepatosplenomegaly
*leucoerythroblastic smear (no reticulin gate to prevent immature cells from entering the
circulation)
*fatigue, infections, thrombosis (not enough cells are produced)
*tear-drop cells (little hematopoiesis will still take place in BM but because it is fibrosed, the
RBCs will get squeezed while trying to leave to the circulation)
ESSENTIAL THROMBOCYTHEMIA
Increased proliferation of mature myeloid cells, especially platelets.
Cause:
Mutation in JAK2, a tyrosine kinase → unknown → abnormal PLTs → bleeding / thrombosis
Clinical signs:
Usually asymptomatic
*No significant risk for hyperuricemia or gout
Definition of leukemia. Acute myeloid leukemias. Myelo-dysplastic syndromes (WHO classification)
Pre-leukemic condition with increased chance to develop AML.
GENERAL FEATURES OF LEUKEMIAS
Leukemia – a group of malignancies of either lymphoid or myeloid origin, which primarily
involves the bone marrow with spillage of neoplastic cells into the blood.
*Leukemic cells may go through circulation to lymphoid tissues and make a solid mass =>
lymphoma.
Leukemia can be either acute or chronic:
» Acute leukemia – characterized by rapid increase in the number of immature
blood cells (blasts >20%); their accumulation within the bone marrow
suppresses the normal hematopoietic stem cells, resulting in the decreased
number of WBCs, RBCs and platelets.
» Chronic leukemia – characterized by the excessive build up of relatively mature,
but abnormal, leukocytes, and by slow progression
General features of acute leukemia:
*lympho/myeloBLASTIC cells (bigger, less cytoplasm, less condensed chromatin)
*high rate of proliferation
*less differentiated
*Pre-B cell neoplasms occur in the BM while pre-T cell neoplasms occur in the thymus
*Occur mainly in children / young adults
*Rapidly growing tumors- after the first clinical sign manifests in the patient, deterioration is
relatively very fast (death after 6-12 months).
Acute leukemias can be classified according to their lineage, either AML (acute myeloid
leukemia), or ALL (acute lymphoid leukemia).
ACUTE MYELOID LEUKEMIA
Usually affects adults (>50 y)
We already talked about the meaning of; acute and leukemia.
But how can we determine whether the neoplastic cell is of a myeloid or a lymphoid
lineage? See topic 58
*The clinical signs and symptoms closely resemble those produced by ALL.
1→ Associated with acquired mutations in TFs that inhibit normal myeloid differentiation,
leading to accumulation of cells at earlier stages of development.
Acute promyelocytic leukemia
t(15,17) → fusion of the retinoic acid receptor α (RAR α) gene on chromosome 17 and the
PML gene on chromosome 15 → PML/RARα fusion protein → blocks myelocyte
differentiation → promyelocyte unable to mature → accumulates
*Promyelocytic cells contain large numbers of Auer rods → increased risk of coagulation →
DIC (medical emergency)
*Treatment; ATRA; all trans retinoic acid receptor (vitamin A derivative) → binds to RAR →
promyelocyte matures into neutrophil → neutrophils die → decreased leukemic burden
More recently, it has been noted that the combination of ATRA and arsenic trioxide, a salt
that induces the degradation of the PML/RARA fusion protein, is even more effective than
ATRA alone, producing cures in more than 80% of patients.
II→ when CML or other dysplastic syndromes progresses into AML
IV→
*Surface markers: CD 13, 14, 15
*Cell type:
♥Erythroblast AML
♥Megakaryoblast AML
Megakaryoblstic leukemia- NO myeloperoxidase!
Associated with down syndrome below the age of 5.
♥Monoblast AML
Acute monocytic leukemia- NO myeloperoxidase! Infiltrated gums.
MYELODYSPLASTIC SYNDROMES
# The bone marrow is replaced by clonal progeny of mutant multipotent stem cell that
retains its capacity to differentiate into RBCs, granulocytes or platelets => all are
defective (mainly megaloblastoid erythroid precursor)
# The abnormal stem cell clone is genetically unstable => additional mutations occur,
and transformation into AML develops in 10%-40% of the cases.
# Karyotype abnormalities include loss of chromosome 5 or 7, or deletion of their long
arm, and trisomy 8.
# Response to chemotherapy is poor.
Anemias of reduced erythropoiesis (iron deficiency anemia, megaloblastic anemias, aplastic anemia, anemias of chronic disease)
IRON DEFICIENCY ANEMIA
The most common form of nutritional deficiency anemia.
Total body iron content => women 2.5g, men 3.5g.
~80% of functional iron is found in hemoglobin.
The rest (~20%) is found in myoglobin and iron-containing enzymes.
Iron storage pool is represented by hemosiderin and ferritin-bound iron, found mainly in the liver, spleen, bone marrow and skeletal muscle.
Serum ferritin => indicator of body iron stores. (33% ~)
Iron is absorbed in the duodenum:
The transfer between transferring receptor and ferritin expression is regulated by hepcidin, which is synthesized in the liver and secreted in an iron-dependent fashion (iron => hepcidin ).
Hepcidin binds to ferroportin and induces its internalization, thus less iron is transported out of the enterocytes to plasma transferring.
Negative iron balance can be caused by:
Low dietary intake, especially vegetarians.
Malabsorption due to celiac disease (an autoimmune disease that causes inflammation of the small intestine).
Increased demands of iron, not met by normal dietary intake, like during pregnancy and infancy.
Chronic blood loss may occur from GI tract (ulcer, colonic cancer, and hemorrhoids), or from the female genital tract (menorrhagia, metrorrhagia, and cancer).
Morphology –
RBCs are microcytic (small cells), and hypochromic (paler than usual) => MCV , MCHC
Iron deficiency is accompanied by increase in platelet count.
Erythropoietin level increases due to hypoxia (results from reduced number of RBCs), but the bone marrow cannot meet the demands of RBC production because of iron deficiency.
Clinical course – in most cases asymptomatic, but manifestations such as weakness and pallor (paleness) may appear; pica is characteristic (consumption of non-foodstuff such as dirt or clay).
Diagnostic criteria – anemia, microcytic and hypochromic RBCs, ferritin in serum, iron in serum, transferring saturation , good response to iron treatment.
ANEMIA OF CHRONIC DISEASE
Originates from inflammation-induced depletion of iron, such as chronic microbial infections (osteomyelitis, bacterial endocarditis etc.), chronic immune disorders (rheumatoid arthritis), and neplasms (Hodgkin lymphoma, carcinomas).
Characterized by low serum iron level, and RBCs that are either normocytic and normochromic, or microcytic and hypochromic.
Associated with increased storage of iron in the bone marrow, high serum ferritin level and reduced iron-binding capacity.
Major cause of these findings is high level of hepcidin, resulting from the presence of cytokines produced during inflammation (IL-6).
Effective treatment of the underlying condition can cure the anemia.
MEGALOBLASTIC ANEMIA
Caused by folate deficiency and vitamin B12 deficiency, both are required for DNA synthesis.
Pathogenesis –
Enlargement of erythroid precursors (megaloblasts), which give rise to abnormally large RBCs (macrocytes).
Granulocyte precursors are also enlarged (giant metamyelocytes), which give rise to hyper-segmented neutrophils.
The cellular gigantism is caused by impairment of DNA synthesis resulting in the delay of cell division, BUT the synthesis of RNA and cytoplasmic elements proceeds as normal, thus outpaces that of the nucleus => nuclear-cytoplasmic asynchrony.
Some megaloblasts undergo apoptosis in the bone marrow (ineffective hematopoiesis), others are released into the blood stream, but have shorter than usual lifespan.
Morphology – hypercellular bone marrow, nuclear-cytoplasmic asynchrony of megaloblasts and granulocyte precursors; in peripheral blood => hyper-segmented neutrophils (>5 lobes), and macrocytes (giant RBCs).
Folate Deficiency Anemia
Not common cause for megaloblastic anemia
Poor diet or increased metabolic need (pregnant woman)
Absorption be block by drug (Phenytoin) or by malabsorptive disorders (Celiac disease)
Metabolism can be block by drugs (Methotrexate – used in chemotherapy, and autoimmune disease)
Tetrahydrofolate (created from Dihydrofolate using the enzyme Dihydrofolate reductase) act as donor or acceptor of carbon in purines synthesis
Clinical features – same as B12 deficiency but NO neurological abnormalities
Vitamin B12 Deficiency (Cobalamin) Anemia (Pernicious Anemia)
Same as Folate but also cause demyelinating disorder of peripheral nerves and spinal cords.
absorption through intrinsic factor (parietal cells of fundus mucosa) in the ileum
delivery to the liver by transcobalamins
malabsorption due to gastric mucosal atrophy
autoimmune reaction against
parietal cells
intrinsic factor
malabsorption in the distal ileum (Crohn, Whipple)
APLASTIC ANEMIA
A disorder in which multipotent myeloid stem cells are suppressed, leading to marrow failure and pancytopenia.
In most cases, aplastic anemia is idiopathic; in other cases, it is caused by exposure to myelotoxic agents (drugs and chemicals).
Pathogenesis –
It seems that autoreactive T cells play an important role.
The events that trigger the T cell attack are unclear.
Rare genetic conditions that may predispose for aplastic anemia have inherited defects in telomerase (needed for maintenance and stability of chromosomes).
Morphology – the bone marrow is HYPOcellular, more than 90% of inter-trabecular spaces are occupied by fat.
Clinical course –
Affects persons of all ages and both sexes.
It is a slowly progressive anemia causing weakness, pallor and dyspnea.
Thrombocytopenia and granulocytopenia may occur.
NO splenomegaly.
General features of anemia. Blood loss anemia. Hemolytic anemias.
GENERAL FEATURES OF ANEMIA
Anemia – the reduction of oxygen transport capacity of the blood, resulting from decrease in number of RBCs (bleeding, increased destrucrion/decreased production), or reduced concentration of hemoglobin.
Decreased tissue ox tension triggers increased production of erythropoietin from specialized cells in kidney 🡪 compensatory hyperplasia of erythroid precursors in BM and, in severe anemias, the appearance of extramedullary hematopoiesis within secondary hematopoietic organs (liver, spleen, lymph nodes). Reticulocytes can be detected in peripheral blood (anemias due to decreased production are associated with reticulocytopenia).
Anemias can be also classified on the basis of RBC morphology:
Microcytic (iron def, thalassemia)
Macrocytic (folate/B12 def)
Normocytic with abnormal shape (hereditary sherocytosis, sickle cell)
and by color (normo/hyper/hypo-chromic)
Possible tests:
iron (anemia due to iron def/chronic disease/thalassemia)
plasma unconjugated bilirubin, LDH, haptoglobin (hemolytic anemias)
folate/b12 cc (low in megaloblastic anemias)
Hb electrophoresis
Coombs test (immunohemolytic anemia)
In case anemia occurs along thrombocytopenia/granulocytopenia, likely to be associated with BM aplasia/infiltration – BM examination
Clinical consequence are determined its by severity, rapidity of onset and underlying pathogenic mechanism.
If onset is slow, compensatory mechanism by increase plasma volume, CO, respiratory rate, level of red cell 2,3-diphosphoglycerate (enhance release of O2 from Hb).
Pallor, fatigue are common to all forms of anemia. Anemias that result from ineffective hematopoiesis are associated with inappropriate increase in iron abs, damage to endocrine and heart.
The lowered oxygen content of the circulating blood leads to dyspnea on mild exertion. Hypoxia can cause fatty change in the liver, myocardium, and kidney.
myocardial hypoxia manifests as angina pectoris, particularly when complicated by pre-existing coronary artery disease. With acute blood loss and shock. Central nervous system hypoxia can cause headache, dimness of vision, and faintness.
BLOOD LOSS ANEMIA
Acute (>20% of blood volume)
Immediate threat => hypovolemic shock.
The anemia is normocytic and normochromic.
Characterized by elevated erythropoietin level, which stimulates RBCs production. (5-7 days)
If the bleeding is sufficiently massive to cause a decrease in blood pressure, the compensatory release of adrenergic hormones mobilizes granulocytes and results in leukocytosis
Chronic
induces anemia only when the rate of loss exceeds the regenerative capacity of the marrow or when iron reserves are depleted and iron deficiency anemia appears
Iron is needed for heme synthesis and effective erythropoiesis.
Iron deficiency leads to chronic anemia of underproduction of RBCs.
The anemia is microcytic and hypochromic.
HEMOLYTIC ANEMIA
Anemia that is associated with accelerated destruction of RBCs.
Destruction can be caused by either inherent defects (intra-corpuscular), which are usually inherited, or by external factor (extra-corpuscular), which are usually acquired.
All hemolytic anemias are characterized by:
Increased rate of RBCs destruction.
Compensatory increase in erythropoiesis that results in reticulocytosis.
Retention of the products of RBCs destruction (iron – hemosiderosis)
Hemolytic anemias are associated with erythroid hyperplasia within the bone marrow, and an increased reticulocyte count in peripheral blood.
Hemolysis can occur in:
Intravascular (within vascular compartments)
Caused by mechanical trauma (cardiac valves, thrombotic narrowing of microcirc.
Biochemical or physical agents that damage the membrane (parasite/toxins)
Leads to hemoglobinemia, hemoglobinuria, and hemosiderinuria
Heam🡪bilirubin results in unconjugated hyperbilirubinemia and jaundice.
massive hemolysis may lead to acute tubular necrosis
Haptoglobin (clears free hb) is depleted from plasma, high levels of LDH. Free hemoglobin oxidizes to methemoglobin, which is brown in color, some passes out in the urine, imparting a red brown color.
Extravascular (within phagocytic cells)
More common
Occurs in spleen and liver
Phagocytes remove damaged cells from circulation
Leads to systemic hemosiderosis
Not associated with hemoglobinemia/hemoglobinuria, yet produces jaundice, if long-lasting leads to formation of bilirubin-rich gallstones.
Haptoglobin is decreased (some hb escapes macrophage to plasma), LDH elevated
Reactive hyperplasia of mononuclear phagocytes🡪splenomegaly
Intra-corpuscular hemolytic anemias:
Hereditary membrane defects
Hereditary spherocytosis
Hemoglobin synthesis defects
Sickle cell anemia
Thalassemias
Enzyme deficiency of RBCs
G6PD deficiency
Acquired membrane defects
Paroxysmal nocturnal hemoglobinuria
Extra-corpuscular anemias
Immunohemolytic anemias
Warm antibody immunohemolytic anemia
Cold antibody immunohemolytic anemia
Erythrocytosis fetalis
Mechanical trauma to RBCs
Infections
Mechanical damage
INTRA-CORPUSCULAR HEMOLYTIC ANEMIAS
Hereditary membrane defects
Abnormality of spectrin and ankrin, proteins of the RBC skeleton, which reduces membrane stability.
In circulation, the cells are exposed to circulatory stress, making them lose membrane fragments.
This reduces membrane surface area, forces the cells to assume spherical shape.
These spherical cells cannot leave the cords of the spleen (cannot undergo deformation like discoid RBCs), and eventually are destroyed.
Morphology – small spheric RBCs, splenomegaly, hyperplasia of red cell progenitor cells, increased number of macrophages in splenic cords.
Hemoglobin synthesis defects
Sickle cell anemia
Characterized by mutation in β-globin chain, glutamate is replaced by valine at the 6th position, creating hemoglobin S (HbS).
Upon deoxygenation, RBC shifts to sickle form, oxygenation transforms it back to normal; eventually, irreversible change to sickle shape.
The sickling of RBCs is affected by the presence of other hemoglonib types, the concentration of HbS, and the amount of time RBCs are exposed to O2.
Morphology – splenomegaly at early stage, splenic scarring and shrinkage at later stage; capillary stasis => ischemia, infarction fatty change and hemolysis.
Thalassemias – autosomal dominant
Enzyme deficiency of RBCs
G6PD deficiency => X-linked.
RBCs are vulnerable to injury by oxidants, which are usually inactivated by reduced glutathione (GSH).
G6PD produces NADPH needed for reduction of GSH (if GSH is not reduced, it cannot inactivate oxidants).
No symptoms unless RBCs are subjected to oxidants injury.
Oxidative stress => hemoglobin oxidation and denaturation => intracellular precipitations (Heinz bodies) => cell membrane flexibility decreases => hemolysis.
Acquired membrane defects
Paroxysmal nocturnal hemoglobinuria – caused by membrane defects due to mutation in myeloid stem cells.
The mutation occurs in proteins that block complement activation, resulting in spontaneous activation and hemolysis.
EXTRA-CORPUSCULAR ANEMIA
Immunohemolytic anemias
Warm antibody immunohemolytic anemia
Caused by IgG (rarely by IgA), active at 37oC
Primary in most cases, but can be secondary (associated with a disease affecting the immune system)
Hemolysis results from the opsonization of RBCs => phagocytosis in the spleen
Cells become spheroidal due to failed phagocytosis
Cold antibody immunohemolytic anemia
Caused by IgM, active only at 30oC (distal parts of the body)
IgM fixes complement system components, BUT the cells are not lysed at this temperature
The opsonized RBCs travel to warmer places where IgM is released, complement becomes active and causes phagocytosis
Erythroblastosis fetalis
Hemolysis induced by antibodies in newborns
Antigens of fetal RBCs enter maternal circulation during labor, thus sensitize the mother => increases the risk of harmful outcomes during next pregnancies (Rh incompetability, ABO incompetability)
Mechanical trauma to RBCs
Infections (Malaria)
Multiplies within liver cells, enters RBCs and goes through reproduction for 48 hours
Newly formed organisms escape RBCs by destroying them
Mechanical damage
Cardiac valve prosthesis => turbulent flow => cell damage
Vessels obstruction due to fibrin deposition => cells are destroyed when passing through
Decreased RBCs production:
Hematopoietic cell damage.
Deficiency of factors needed for heme synthesis (iron), or DNA synthesis (vitamin B12, folic acid).
Increased RBCs loss:
External blood loss (hemorrhage).
RBC destruction (hemolytic anemia).
Can be caused by:
α-thalassemia => deletion of α-globin genes.
β-thalassemia => deletion of β-globin genes.
Sickle cell anemia => base point mutation, resulting in the replacement of glutamine by valine.
G6PD deficiency => failure of erythrocytes under oxidative stress.
Large-vessel vasculitis (Giant-cell arteritis, Takayashu’s arteritis). Infectious vasculitis.
LARGE VESSEL VASCULITIDES
♥Giant cell arteritis
The most common vasculitis
>50 years, more common in females
Effects arteries of head, especially temporal arteries → headache
in the ophthalmic artery → visual disturbances
in arteries supplying the jaw (maxillary) → pain when chewing “claudication”
Etiology; Immunologic mechanisms
*Antibodies against endothelial cells
*cell mediated (autoreactive T cells)
Clinical features:
↑↑ESR
Biopsy: giant cells (which are actually granulomas) embedded in the internal elastic lamina
*Because temporal arteritis is extremely segmental, adequate biopsy requires at least a 2- to
3-cm length of artery; even
then, a negative biopsy
result does not exclude the
diagnosis.
Treatment; corticosteroids (to treat inflammation)
♥Takayasu arteritis
Mostly seen in Asian women <40
Affects the aorta and arteries branching from the aortic
arch (elastic arteries)
*branches serving the upper extremities: weak or nonexistent pulse (loss of function- cannot accommodate
systolic volume and coil back)
*branches serving the head: visual and neurological
symptoms, dizziness etc.
*corneal ostial stenosis
*aortic stenosis
Clinical features: same as giant cell arthritis except for segmentation.
Treatment; same as giant cell arthritis
Infectious Vasculitis
♥Direct- direct invasion of an infectious agent; fungi but mainly bacteria (Aspergillus and
Mucor spp)- they released exotoxins for example.
♥Indirect- a bacteria causes inflammation and endothelial cells are damaged because of
the many harmful cytokines etc.
Example: molecular mimicry; streptococcus causes endocarditis → vasculitis
Medium vessel vasculitis (polyarteriitis nodosa, Kawasaki’s disease, Buerger’s disease)
MEDIUM VESSEL VASCULITIDES
Typically effect a large variety of muscular arteries that supply organs
♥Kawasaki disease
<5 years old
effects the coronary arteries (transmural); may lead to MI
Clinical features:
Conjunctivitis
Rash
Adenopathy
Strawberry tongue
Hands and feet are swollen & rash
♥Polyarthritis Nodosa
Seen in young adults primarily
Multiple visceral arteries (mainly renal NOT pulmonary!)
Molecular mimicry; endothelium confused with HBV
Segmental (appears like beads on angiogram).
Causes transmural inflammation (tunica intima, media and adventitia are all infected).
treatment; corticosteroids (to treat inflammation)
NOT associated with ANCA!
Frequently accompanied by fibrinoid necrosis.
♥Buerger’s disease
Men 20-40 years old, tobacco might be the cause endothelium is attacked
Notorious for causing blood clots in tiny arteries in the fingers and toes (mainly tibial
and radial arteries) → dead tissue → autoamputation
spreads to adjacent veins and nerves.
Segmental.
Small-vessel (microscopic polyangitis, Churg-Strauss syndrome, granulomatosis with polyangiitis)
SMALL VESSEL VASCULITIDES
Effect arterioles, capillaries and venules
B cells produce antibodies ANCA (anti neutrophilic cytoplasmic antibodies, mainly IgG)
against granules made by self-neutrophils
♥Wegner’s granulomatosis
Middle aged males. Affects vessels in the:
*nasopharynx:
sinusitis → chronic pain
ulcers → bloody mucous
Saddle nose deformity
*Can spread to ear → otitis media
*lungs
difficulty breathing
ulcers → bloody cough
*kidneys
glomeruli die → urine production↓ & BP↑
cANCA (c for cytoplasmic) bind to a specific neutrophil granule; proteinase 3 → neutrophil
releases free radicals → nearby endothelium damaged
RELAPSES
treatment; corticosteroids (to treat inflammation) & cyclophosphamide (immunosuppressor)
*If untreated, death within one year
♥Microscopic polyangiitis
Very similar to Wegner’s granulomatosis but:
Only affects blood vessels of lungs and kidneys, NOT nasopharynx
No granulomas
Characterized by presence of pANCA myeloperoxidase instead of proteinase 3
Same treatment, also relapses
♥Churg-strauss syndrome
PANCA
similar symptoms: sinusitis, lung, kidney damage but ALSO GI, skin, nerve and heart
damage like some medium vessel vasculitis diseases
Granulomas can form
Eosinophils↑ + symptoms → mistaken with allergy
Vasculitides. Definition, pathogenesis, classification. Leuko-cytoclastic vasculitis.
Inflammation of vessel walls of virtually any type of vessel.
Vasculitides usually occur because of
1. Immunologic mechanisms (auto immune diseases)
*Immune complex deposition
type III hypersensitivity; SLE
*ANCA mediated (anti neutrophil cytoplasmic antibodies)
cANCA (cytoplasmic)- target proteinase 3 & pANCA (perinuclear) target myeloperoxidase
Proteinase 3 and myeloperoxidase are expressed on the cell surface of irritated neutrophils
but ALSO macrophages and endothelial cells! (so no ANCAs produced when there is no
inflammation)
*Antibodies against endothelial cells
*cell mediated (autoreactive T cells)
2. Infectious mechanisms
Direct invasion by infectious pathogens like varicella zoster virus and some fungi.
- Physical / chemical injuries
*Distinguishing between the different etiologies is extremely important when choosing the
treatment! Corticosteroids will be useful fighting the infection when immunologic
mechanisms are the cause of vasculitis, but they will be harmful when infectious
mechanisms are the cause!.
Damaged endothelium leads to: - weakening of BV → aneurysm → rupture of small vessels→ microhemorrhage (purpura)
- exposed underlying collagen and TF→ coagulation
- healing → fibrin deposition → vessel stiffness
→ reduced lumen diameter → organ ischemia
Systemic symptoms of vasculitis (only in severe cases of vasculitides).
Severe inflammation → many inflammatory cells activated → high amount of cytokines in
the body reach receptor in the hypothalamus; Fever, fatigue and weight loss
Cytokine R on hepatocytes → CRP (APC) produced → CRP stick to RBCs → sticky → ESR↑
*Specific symptoms depend on the organ supplied by the pathological BV
Vasculitides are characterized by the size of the BVs they affect:
Large, medium and small
Definition of dysplasia. Precancerous lesions.
DEFINITION OF DYSPLASIA
Disordered, non-neoplastic, cellular growth
Often arises from longstanding pathologic hyperplasia (e.g., endometrial hyperplasia) or
metaplasia (e.g., Barrett esophagus).
Dysplasia is reversible, in theory, with alleviation of inciting stress. If stress persists, dysplasia
progresses to carcinoma (irreversible).
The term dysplasia is typically used when the cellular abnormality is restricted to the
originating tissue.
For example; epithelial dysplasia of the cervix consists of an increased population of
immature cells which are restricted to the mucosal surface, and have not invaded through
the BM to the deeper soft tissues.
If the dysplastic cells span the entire thickness of the epithelium the lesion is referred to
carcinoma in situ.
Myelodysplastic syndromes, or dysplasia of blood-forming cells, show increased numbers of
immature cells in the bone marrow, and a decrease in mature, functional cells in the blood.
PRECANCEROUS LESIONS
Abnormalities that with time, have an increased risk of developing into cancer.
Early
removal may prevent the development of a cancer.
These consist of genetically and phenotypically altered cells that exhibit a higher risk to
develop to malignant tumors.
Arise in the setting of chronic tissue injury or inflammation, which may increase the
likelihood of malignancy by stimulating continuing regenerative proliferation or by exposing
cells to byproducts of inflammation, both of which can lead to somatic mutations
These lesions include:
» Squamous metaplasia and dysplasia of the bronchial mucosa, seen in
habitual smokers - a risk factor for lung cancer
» Endometrial hyperplasia and dysplasia, seen in women with unopposed
estrogenic stimulation - a risk factor for endometrial carcinoma
» Leukoplakia of the oral cavity, vulva, or penis, which may progress to
squamous cell carcinoma
» Villous adenomas of the colon, associated with a high risk of transformation
to colorectal carcinoma
Systemic effects of neoplasia (para-neoplastic syndromes, immunosuppression, cachexia)
Both malignant and benign tumors can cause morbidity and mortality.
SYSTEMIC EFFECT OF NEOPLASIA
# Clinical features:
» Location and impingement on adjacent structures
- Small tumor in the pituitary gland, either malignant or benign, may
compress and destroy the gland. (hypopituitarism)
- Leiomyoma in the renal artery may lead to ischemia and hypertension.
» Functional activity (e.g: hormone synthesis/paraneoplastic syndrome)
- Seen in neoplasms of endocrine glands.
- Adenoma/carcinoma in beta cells of the pancreatic islets of Langerhans
can cause hyperinsulinism
- Adenoma/carcinoma of adrenal cortex can affect aldosterne secretion
(Na retention), hypertension, hypokalemia
» Ulceration
- Tumors may cause ulceration through a surface, leading to bleeding and
infection.
» Cancer cachexia
- Loss of body fat, wasting, profound weakness.
» Rupture/infraction
PARANEOPLASTIC SYNDROMES
# Refers to symptoms that are not directly related to the spread of the tumor or to
hypersecretion of hormones caused by the tumor. (ectopic secretions)
# Paraneoplastic (10-15% of patients) syndromes are important because:
1) They may represent early manifestations of neoplasm.
2) They may cause significant clinical problems, and may be lethal.
3) They may mimic metastatic disease, confounding treatment
♥Cushing syndrome cortisol ACTH small cell lung / pancreatic carcinoma
*hypercalcemia
*hypertension
*obesity
*moon facies
♥Hypercalcemia PTH squamous cells carcinoma of lung / breast cancer
♥Hyponatremia ADH small cell lung carcinoma
♥Dehydration and diherria VIP GI tumor
♥Non-bacterial thrombotic endocarditis
CACHEXIA “wasting syndrome”
# Progressive loss of body fat accompanied by profound weakness and anemia.
# Occurs in 50% of cancer patients. Accounts for 20% of cancer-deaths.
# Cachexia is NOT caused by nutritional demands of the tumor, but it is caused by the
action of cytokines produced by the tumor.
# In cancer patients, calorie expenditure and BMR are high, despite reduced food intake.
# The basis of these metabolic abnormalities is unknown, but it is suspected that TNF
(also commonly referred to as cachectin) and IL-1 produced by macrophages in
response to tumor cells (or by the tumor itself), may mediate cachexia;
*TNF inhibits NPY → no signal sent to feeding center in hypothalamus
*TNF inhibits lipoprotein lipase → no release of FFAs from lipoproteins.
# Mobilizing factor – proteolysis-inducing factor, which causes breakdown on skeletal
muscle protein has been detected in the serum of cancer patients.
IMMUNOSUPRESSION
# Bone marrow suppression by tumor factors (leukemia? Monoclonal expansion of AB?)
# Toxicity of chemotherapy, irradiation of BM
# Malnutrition, anorexia
Laboratory diagnosis of cancer (histopathology, cytopathology and molecular methods)
Specimen evaluation and classification
MORPHOLOGIC METHODS
In order to determine whether a tumor is benign or malignant, it is usually enough to
examine the general characteristics; rate of growth, invasiveness, presence or lack of
metastasis, clinical features etc. But some benign tumors express malignant characteristics
and vice versa.
Therefore, in order to classify a tumor with certainty, histopathological
examinations are required.
Sampling techniques
» Excision or biopsy – removal of the tumor with margin, or of a large mass of
the tumor, preserve in fixation and microscopically analyzed.
» Frozen section – a sample is quick frozen and sectioned, permits immediate
histologic evaluation.
» Fine-needle aspiration – used with palpable lesions (breast, thyroid, lymph
nodes, salivary glands); involves aspiration of cells from a mass, followed by
cytologic examination of the smear.
» Cytologic smears – neoplastic cells are less adhesive and shed into fluids or
secretions; these cells are then evaluated for anaplastic features.
Verifying whether the tumor is benign or malignant using pleomorphism
Determining the TYPE of cell using Immunocytochemistry – detection of characteristic
proteins by specific monoclonal antibodies, labeled with peroxidase. Cells the have the
antigen and that react with the specific antibody will be stained in brown.
IHC for keratin → keratin + → epithelial cells
IHC for vimentin → vimentin + → mesenchymal cells
IHC for desmin → desmin + → muscle cells
We can also use immunohistochemistry to determine from which TISSUE the cell originated;
IHC for PSA → PSA + → prostate
IHC for estrogen receptor → ER + → breasts
*Flow cytometry – used in classification of leukemias and lymphomas; a method in which
antibodies against cell surface molecules and against differentiation markers are labeled
with fluorescence dye, and are used to obtain the phenotype of malignant cells.
TUMOR MARKERS
Substances produced by the tumor or by the host in response to the tumor, and present in
tissues or are released into the serum or body fluids.
They have low sensitivity and specificity and are also produced in non-neoplastic conditions,
so they CANNOT be used for definitive cancer diagnosis, but contribute to determination of
therapy effectiveness or recurrent appearance. Therefore, a biopsy is always needed!
Common markers are:
♥PSA (prostate specific antigen)
Screen for prostatic adenocarcinoma
♥CEA (carcino-embryonic antigen)
Increases in cancers of colon, pancreas, breast and stomach
♥AFP (alpha-fetoprotein)
Produced by hepatocellular carcinoma, and yolk sac remnants in gonads
Elevated in cancers of testes, ovary, pancreas and stomach
Clonality in neoplasia. Genetic progression in cancer. Tumor cell hetero-geneity
Tumor progression – the ability of the tumor to become more aggressive and acquire
Carcinogenesis is the process by which normal cells are transformed into cancer cells.
Tumors arise from monoclonal growth of a progenitor cell that have inflicted non-lethal
mutations in one or more of the following 4 classes of genes:
» Growth-promoting proto-oncogenes
*a mutation in one of the allele is enough
» Growth-inhibiting tumor suppressor genes
*both alleles must be mutated in order to lose the cell function
» Genes that regulate apoptosis.
» Genes involved in DNA repair.
GENETIC PROGRESSION IN CANCER
greater malignant potential; at the molecular level, tumor progression results from
mutations that accumulate independently in different cells, generating sub-clones with
different characteristics.
Explain about the features of malignant tumors (cancers)
TUMOR CELL HETEROGENEITY
# Malignant tumors are monoclonal in origin, but become extremely heterogenous by
the time they are clinically evident.
# Heterogeneity results from continuous multiple mutations that accumulate in different
cells, generating new sub-clones.
These new sub-clones are subjected to host defenses (immune and non-immune);
some will be destroyed, and some will survive and become “experts” in survival, growth,
invasion and metastasis.
Heredity in cancer. Cancer syndromes.
HEREDITY IN CANCER
Hereditary forms of cancer can be divided into three categories based on their pattern of
inheritance
- Autosomal dominant
Mutation in protooncogenes, transforming into oncogenes.
One hit hypothesis- a mutation in one of the alleles is enough for malignant
transformation. Inheritance of a single mutant gene greatly increases the risk of developing
a tumor.
Retinoblastoma is cancer of the retina. It can be sporadic (60%) or familial; autosomal
recessive- RB is a tumor suppressor gene (40%), but it presents clinically as autosomal
dominant (the risk of developing a mutation in the other allele and developing a tumor is
90%).
Unlike sporadic RB, familial RB develop bilateral tumors, appear at a younger age and are
at high risk of developing a secondary cancers (osteosarcoma)
- Autosomal recessive syndromes
Mutation of tumor suppressor genes or DNA repair genes. Two hit hypothesis- both alleles
must be mutated in order for a malignant transformation to occur.
Greatly increases the predisposition to environmental carcinogens (for example, xeroderma
pigmentosum).
*P53 mutation in 50 % of cancers
3. Familial cancers of uncertain inheritance – A condition that tends to occur more often in
family members than is expected by chance alone.
» Transmission pattern is not clear.
» Carcinomas of colon, breast, ovary, and brain.
CANCER SYNDROMES
In addition to genetic influences, some clinical conditions may predispose to development of
malignant neoplasms;
PRENEOPLASTIC DISORDERS
Chief predisposing conditions:
*Liver cirrhosis → Hepatocellular carcinomas
*Smoking → squamous metaplasia and dysplasia of the bronchial mucosa → lung cancer
*Unopposed estrogenic stimulation → endometrial hyperplasia and dysplasia →
endometrial carcinoma
* Leukoplakia of the oral cavity, vulva, or penis → squamous cell carcinoma
*Benign tumors are usually not precancerous, but exceptions exists; as adenomas of the
colon enlarge, they can undergo malignant transformation in 50% of cases
Mechanisms of local and distant spread. Molecular basics of metastases. Staging of cancer.
LOCAL SPREAD- Invasion
- Loosening; dissociation of a cell from its neighbors (by
downregulation of E-cadherins) - Attachment to laminin of BM
- Destruction of BM (by themselves (production of type IV
collagenase) or induce stromal cells like fibroblasts and to
elaborate proteases. - Attachment to fibronectin in ECM
- Locomotion; propelling tumor cells through the degraded BM
and zones of matrix proteolysi s
DISTAL SPREAD- Metastasis - Vascular Dissemination and Homing of Tumor Cells
Most tumor cells circulate as single cells but some tumor cells form emboli by aggregating and
adhering to circulating WBC, mainly platelets – thus achieve protection from anti-tumor host effector
cells.
Extravasation of free tumor cells or tumor emboli involves adhesion to the vascular endothelium,
followed by egress through the BM into the organ parenchyma by mechanisms similar to those
involved in invasion.
*The site of extravasation and the organ distribution of metastases generally can be predicted by the
location of the primary tumor and its vascular or lymphatic drainage.
Some tumors (lung cancer) tend to involve a specific distal tissue (adrenals), they do so by:
- Expression of adhesion molecules whose ligands are expressed preferentially on endothel of
target cells - Expression of chemokines and their receptors. For example, breast cancer express high levels of
CXCR4/7 chemokine receptors, the ligand of these receptors (CXCR12/21) are expressed only on
those organs to which the cancer metastasize. - Once reaching the target, the stroma must supply the growth demands of the tumor. In some
cases, the tissue may be a nonresponsive environment – for example skeletal muscle are rarely
site of metastases.
*carcinomas tend to spread via lymphatics to regional lymph nodes (breast cancer spread via the
lymphatics to the axillary lymph nodes)
*sarcomas tend to spread through the blood (lungs are characteristic site of spread)
Exceptions:
*Renal cell carcinoma- invades the renal vein
*Hepatocellular carcinoma- hepatic vain
*Follicular carcinoma of the thyroid
*Choriocarcinoma (malignancy of trophoblasts in placental tissue)
*Ovarian carcinoma spreads via body cavities, usually via the omentum.
MOLECULAR BASIS OF METASTASIS
- As tumors grow, individual cells randomly accumulate mutations, creating subclones with
distinct combinations of mutations. - Metastasis, according to this view, is not dependent on the stochastic generation of metastatic
sub clones during tumor progression, but is an intrinsic property of the tumor developed during
carcinogenesis. - A third idea that combines the two above supposes that the metastatic signature is necessary
but not sufficient for metastasis, and that additional mutations are needed for metastasis to
occur. - Candidates for metastasis oncogenes which could promote/suppress metastases are SNAIL and
TWIST, which promote epithelial-to-mesenchymal transition (EMT). In EMT, carcinoma cells
downregulate certain epithelial markers (e.g., E-cadherin) and upregulate certain mesenchymal
markers (e.g. smooth muscle actin).
These changes are believed to favor the development of a
promigratory phenotype that is essential for metastasis.
STAGING
Based on the size of the primary lesion, its extent of spread to regional lymph nodes, and the presence
or absence of bloodborne metastases.
The major staging system uses a classification called the TNM system:
T; primary tumor
The primary lesion is characterized as T1 to T4 based on increasing size
T0 is used to indicate an in-situ lesion.
N; regional lymph node involvement
N0 would mean no nodal involvement.
N1 to N3 would denote involvement of an increasing number and range of nodes.
M; metastases
M0 signifies no distant metastases
M1 or sometimes M2 indicates the presence of metastases and some judgment as to their number.
Local invasion in malignancy. Role of stroma. Angiogenesis.
Other GFs involved in angiogenesis:
LOCAL INVASION IN MALIGNANCY
The translocation on neoplastic cells across tissue barriers. Can be within the same organ of
from an organ to the adjacent tissue.
*See steps in next topic.
ROLL OF STROMA
♥Carrying blood supply, crucial to the growth of the tumor.
♥Determine the consistency of the neoplasm; certain cancers induce a dense, abundant
fibrous stroma(desmoplasia)
♥Encapsulation; in benign tumors
ANGIOGENESIS
Blood vessels are formed in 2 processes:
♥Vasculogenesis – the formation of primitive vascular system from angioblasts during
embryonic development.
♥Angiogenesis- new blood vessel development from existing vessels, primarily venules
Steps of angiogenesis:
1. Vasodilation and increased permeability induced by NO and VEGF, respectively.
- Tip cell selection (the single cell which bind the largest amount of VEGF with its receptor)
This binding will induce formation of filopodia on these cells, on which more such receptors
are found.
Also, they secrete proteolytic enzymes which help them break the BM and
surrounding matrix.
- Migration of tip cells toward the angiogenic center (hypoxic cell f.ex.) along with
proliferation of endothelial cells “stalk cells” (no gaps left behind) - Tubulogenesis; remodeling into capillary tubes (vacuoles fused)
- Fusion of two stalks
- Suppression of endothelial proliferation and migration and deposition of the BM
- Recruitment of peri-endothelial cells (pericytes for small capillaries and fibroblasts for
larger vessels) to form the mature vessel
» Angiopoietins 1 & 2, PDGF, TGFβ – participate in the stabilization of the newly
formed vessels by recruitment of pericytes and SM cells and deposition of CT.
» FGF2 – stimulates the proliferation of endothelial cells, promotes the migration
of macrophages and fibroblasts to the damaged area, and stimulates epithelial
cells migration to cover epidermal wounds.
Growing cancers stimulate angiogenesis. Neovascularization has a dual effect on tumor
growth:
1. Perfusion supplies needed nutrients and oxygen
2. Stimulate the growth of adjacent tumor cells by secretion of GFs such as insulin-like
growth factors (IGFs) and PDGF from newly formed endothelial cells.
These newly-formed vessels are leaky (incompletely formed inter-endothelial junctions, and
due to the presence of VEGF), permitting tumor cells and contributing to metastasis.
The cell cycle. Cell proliferation in neoplasia. Growth factors, receptors and signaling pathways.
The sequence of events that take place in the cell, leading to its replication and division
THE CELL CYCLE
(proliferation), to form copies of itself.
# Phases of cell cycle:
» Presynthetic growth phase 1 (G1) – during which the biosynthetic activities of
the cell resume at a high rate, mainly production of proteins necessary for DNA
replication.
» DNA synthesis phase (S) – during which the DNA is replicated, forming two
sister chromatids for each chromosome (one for the parental copy, and one for
the maternal copy of the chromosome).
» Premitotic growth phase 2 (G2) – continuation of protein production needed for
division.
» Mitosis (M) – a brief phase consists of nuclear division (karyokinesis), organelles
distribution and cytoplasm division (cytokinesis).
Stages of mitosis:
» Prophase – chromatin is condensed into distinct chromosomes and their sister
chromatids, bound at the centromere by cohesion protein complex;
centrosomes and microtubules appear next to the nucleus.
» Metaphase – nuclear membrane disintegrates; formation of kinetochores at the
centromere, to which microtubules attach, and the chromosomes are convened
along the equatorial plane.
» Anaphase – sister chromatids are separated, and pulled apart by the
microtubules connected to the kinetochore.
» Telophase – formation of nuclear membrane, appearance of nucleoli,
chromosomes “relax” and decondense to form chromatin.
Non-dividing cells can be found in either cell cycle arrest at G1, or they exit the cycle to
enter a phase called G0 => resting phase.
The progression of cell cycle through the different stages depends on the ability of the
cell to perform an intrinsic quality control => cell cycle checkpoints, thus preventing the
replication of damaged DNA, or the mitosis of abnormal cells (arrest cell cycle to allow
repair, or induce apoptosis).
The regulation and transition between stages of cell cycle are done by proteins called
cyclins; these protein complexes bind to CDKs (cyclin-dependent kinases), which
promote the mitotic process.
# CDKs are inhibited by CDIs (cyclin-dependent kinase inhibitors).
The transition between cell cycle stages depends on the amount of CDKs and cyclins of
the specific stage (G1/S transition => cyclin D/CDK4).
BIOLOGY OF TUMOR CELL GROWTH
# Carcinogenesis is the process by which normal
cells are transformed into cancer cells.
# Tumors arise from clonal growth of cells that have
inflicted mutations in 4 classes of genes:
» Growth-promoting proto-oncogenes.
» Growth-inhibiting tumor suppressor genes.
» Genes that regulate apoptosis.
» Genes involved in DNA repair.
These mutations are caused by carcinogens;
Radiation
Chemicals
Oncogenic viruses etc.
Protooncogenes
Genes essential for cell growth and differentiation. A gain of function
mutation to a protooncogene will transform it into an oncogene and
lead to unregulated cell growth.
Each of the steps in the picture involve protooncogenes.
The key categories of protooncogenes;
1. Growth factors
♥PDGF- brain tumors like astrocytoma
PDGF is overexpressed → binds to its receptor in an autocrine fashion
→ increased cell division
- Growth factor receptors
♥HER2/NEU epidermal GF R → breast cancer - Signal transducers
♥RAS- active when bound to GTP. A mutation in GAP which blocks the hydrolysis of GTP to
GDP leading to access signals to reach the nucleus.
♥ABL- its activity is unregulated when the ABL gene is translocated from chromosome 9 to
chromosome 22 where is fuses with part of the breakpoint cluster region (BCR), resulting in
the production of a hybrid protein with unregulated tyrosine kinase activity. - Transcription factors
♥MYC- translocation of this gene t(8,14) leads to its over expression and increased cell
proliferation. - Cell-cycle regulators (cyclins, CDKs and CKIs)
♥Cyclin D1- translocation of this gene t(11,14) leads to its over expression and increased cell
proliferation.
Tumor suppressor genes
Have a damping effect on the cell cycle and or promote apoptosis. A loss of function
mutation to a tumor suppressor gene will lead to unregulated cell growth.
*Both copies of the gene must be lost for tumor development.
♥Retinoblastoma gene – RB is in its active state (hypo-phosphorylated) and inhibits E2F
transcription factor by binding it, thus preventing the transcription of cyclin E (required for
G1/S transition => cyclin E-CDK2 complex).
GF signaling leads to cyclin D expression, activation of cyclin D-CDK4/6 complex and the
inactivation of RB by phosphorylation => mutations in RB gene render it nonfunctional.
♥P53 gene – arrest cell cycle (P21-CKI) / repair mechanisms (GAD45) / induce apoptosis
(puma, noxa)
♥TGFβ pathway – inhibits proliferation by activating growth-inhibiting genes (CDIs), and
suppression of growth-promoting genes (MYC, cyclins); compromising its function leads to
cancer.
* Limitless replicative potential – in normal (somatic) cells, telomerase enzyme is not
expressed, and the telomere regions of the chromosomes are shortened until they activate
cell cycle checkpoints, leading to the limitation of cell division; in cancerous cells, telomerase
prevents the activation of apoptosis by adding DNA sequences to the telomere region, thus
preventing activation of checkpoints.
*Development of sustained angiogenesis – tumors require blood supply, and trigger the
formation of new blood vessels (sprouts) from existing blood vessels in a process of
angiogenesis, usually due to hypoxia
Hypoxia → activation of hypoxia-induced factor 1α (HIF1α) → transcription of VEGF
In normal cells, VHL protein binds to HIF1α and leads to its destruction, while in cancerous
cells, HIF1α is not destroyed, leading to transcription of VEGF (vascular endothelial growth
factor), and angiogenesis.
PROLIFERATIVE POTENTIAL IN NEOPLASIA
# Dividing cells – continuously proliferate to replace cells that eventually die.
! Hematopoietic cells in bone marrow, cells of surface epithelia (skin, oral cavity,
vagina, GI tract).
# Quiescent cells – dividing cells found in G0 state; these cells may enter cell cycle in
response to stimulus.
! Parenchymal cells of most solid glandular tissues (liver, kidneys, pancreas).
# Non-dividing cells – cannot undergo division in post-natal life (neurons, skeletal and
cardiac muscle)
Differentiation and anaplasia. Pleomorphism. Grading of cancer.
Refers to parenchymal cells that constitute the neoplasm.
DIFFERENTIATION
# Differentiation of parenchymal cells is the extent to which they resemble their
normal cells of origin, both morphologically and functionally.
# The stroma carrying the blood supply is crucial to the growth of tumors, but has
no role in differentiation between benign and malignant tumors.
# The amount of stromal tissue determines the consistency of the neoplasm =>
certain cancers induce the formation of a dense, abundant fibrous stroma
(desmoplasia), thus the tumor is hard (scirrhous tumor).
BENIGN TUMORS
- Well differentiated cells that
resemble the normal tissue
Lipoma => made of mature fat
cells filled with lipid vacuoles
Chondroma => made of
mature chondrocytes that
synthesize cartilage matrix
- Low mitotic figures (in normal
configuration!!)
MALIGNANT TUMORS
- Wide range of parenchymal
differentiation, from well defined
cells to completely
undifferentiated cells
- Resemble primitive undesignated
cells
The better the differentiation of the cell, the more it retains the functional
capabilities of its normal cell of origin.
# The more rapidly growing and the more undifferentiated a tumor is, the less
likely it is to have specialized functional activity.
ANAPLASIA
# It is the abnormal lack of differentiation of cells, refers to the reversal in cell
differentiation or to the failure of cells to differentiate in the first place.
# Anaplasia is the characteristic of malignant tumors, and implies loss of the
structural and functional differentiation of normal cells.
# Anaplastic cells display pleomorphism
PLEOMORPHISM
# Variations in the size and shape of cells throughout the tumor.
# In anaplastic cells:
» Nucleus/cytoplasm ratio approaches 1:1 instead of the normal 1:4 or 1:6.
» The nucleus is very large and hyperchromatic (darkly stained); there can
be either enormous nucleus or several nuclei.
» Chromatin appears rough and clumped.
» Numerous and atypical mitotic figures.
» Loss of normal cell polarity (the organization and orientation of a certain
cell type in comparison with its neighboring cells).
» Large nucleoli may appear.
# Dysplasia – describes disorderly but non-neoplastic proliferation, and is the loss
in the uniformity of individual cells and in their architectural orientation; usually
appears in epithelium.
Display pleomorphosm
! Carcinoma in situ (CIN-III) => when dysplastic changes involve the entire
thickness of the epithelium.
GRADING OF CANCER
# Attempts to estimate the aggressiveness, or level of malignancy of the tumor,
based on:
» Cytologic differentiation of tumor cells.
» Number of mitoses within the tumor cells.
# Grading is in order of increasing anaplasia
I (benign) => well-differentiated (low grade)
II => moderately differentiated (intermediate grade)
III => poorly differentiated (high grade)
IV (malignant) => undifferentiated (high grade)
# Grading varies with each form of neoplasia:
» Gleason system – used to grade adenocarcinoma cells in prostate cancer.
» Bloom-Richardson system – for breast cancer.
» Fuhrman system – for kidney cancer.
LOW GRADE TUMOR
- Low mitotic rate
- Less aggressive => less mitotic
figures, reduced metastaltic
capability
- Bad prognosis => more difficult to
treat (chemotherapy works on
dividing cells)
- Well differentiated (minimal
pleomorphism)
- Less favorable => usually non
curable
HIGH GRADE TUMOR
- High mitotic rate => lots of mitotic
figures, little differentiation,
increased pleomorphism
- Very aggressive => spreads very
fast
- Good prognosis => dividing cells
are more easily destroyed, fast
treatment results
- More favorable => even that it is
more violent and dangerous, it is
evaluated better and can be cured
faster and easier
Definition of neoplasia. Nomenclature. Growth characteristics of benign and malignant tumors.
Literally means “new growth” – an abnormal mass of tissue, its growth is faster and
NEOPLASIA new growth
uncoordinated with that of a normal tissue.
# Growth persists even after the stimulation ceases, and is independent of regulatory
signals; therefore, these cells have some degree of autonomy.
# Nevertheless, neoplasias depend on blood supply and some on endocrine support from
the host.
*Hyperplasia is coordinated, growth does NOT persist after stimulation ceases, and the cells
resemble normal cells. It is polyclonal.
TUMOR
Can be categorized according to:
♥Tissue of origin
1.Parenchyma – made up of transformed cells, or neoplastic cells, from which the tumor
originates; determines the biologic behavior of the neoplasm (blood supply)
2.Stroma – supporting, non-neoplastic c. tissue of the host, which is crucial to the growth of
the neoplasm since it carries blood vessels (acts as a framework)
♥Clinical course
*Both are monoclonal.
Malignant neoplasm spread in one of three ways:
* Seeding within body cavities (ovary)
* Lymphatic spread (carcinoma)
* Hematogenous spread (sarcomas, liver & lung are most involved
secondary site)
*Malignant; Often contains central area of ischemic necrosis because the tumor’s blood
supply fails to keep up with the rate of growth.
NOMENCLATURE
♥Benign- names usually end with the suffix “-oma
Mesenchymal origin; “-oma” attached to the name of the cell type from which the tumor
arises.
fibroma- fibroblasts
chondroma- chondroblasts
osteoma- osteoblasts
Epithelial origin; based on their histogenesis and architecture
adenoma- glandular origin, may or may not be glandular in structure OR epithelial origin
with glandular structure
papilloma- microscopic finger-like projections beyond the surface
cyst adenoma- cystic structure
polyp- macroscopic finger-like projections into a lumen
♥Malignant – follows that of benign tumors, with certain additions and exceptions:
Mesenchymal origin; end with the suffix “-sarcoma”
fibrosarcoma
chondrosarcoma
Leukemia/Lymphoma – malignant neoplasms arising from mesenchymal cells of the blood
Epithelial origin; end with the suffix “-carcinoma”, derive from all germ-cell layers
(endoderm, mesoderm, ectoderm)
adenocarcinoma (cancer of glandular epithelium)
squamous cell carcinoma
# Mixed tumors – derived from one germ-cell layer that differentiates into more than one
cell type => mixed tumor of salivary glands contains epithelial cells as well as stroma
and cartilage-like tissue (pleomorphic adenoma), fibroadenoma (female breast, mixed
tumor)
# Teratoma – special type of mixed tumor, derived from totipotent germ cells, originating
from all germ-cell layers; has the capacity to differentiate into any cell type at any
location.
# Choristoma – congenital anomality in which perfectly functional cells belonging to a
certain organ, are found in the wrong place => nodule of well-developed pancreatic
tissue is found in the submucosa of the stomach.
# Hamartoma – disorganized masses of mature tissue, with characteristic differentiation
of the normal surrounding tissue => disorganized hepatic cells, blood vessels and bile
ducts are found within the liver.
Pathomechanisms of congential malformations (genetic and patho-anatomical causes, teratogenic effects)
Genetic causes – chromosomal syndromes, single gene mutations etc.
CONGENITAL ABNORMALITIES
Defects affecting the structure and or function of organs, that are present at birth.
♥Malformation
Primary errors of morphogenesis that occur due to multifactorial gene defects
Can be abnormally formed, partially formed or not formed at all (agenesis).
Example: neural tube defects, atresia of the esophagus.
♥Deformation
A change in the normal shape or size of normally forming structures, usually due to
mechanical effects.
Example: the presence of too little amniotic fluid oligohydramnios → restricts the
movements of the fetus → micrognathia (a small jaw).
♥Disruption
When outer/extrinsic influences cause defects in organs that were previously normally
developing.
Example: diabetes → increased amount of insulin crossing the placenta → macrosomia
(excessive birth weight of the fetus).
♥Dysplasia
Abnormal organization of cells in a tissue.
Example: osteogenesis imperfecta.
*Sequence – single major anomality alters the subsequent development of other structures.
Example: posterior urethral valves defect → obstruction of flow of urine into the bladder and
hence into the amniotic fluid → oligohydramnios → micrognathia
*Associations- abnormalities that occur together more frequently than expected by chance
alone.
Example: congenital abnormalities of the spine are consistently associated with
characteristic types of urinary tract malformation.
ETIOLOGY
# Environmental influences – viral infections, drugs, irradiation to which the mother is
exposed during pregnancy1
.
*Most important virus is CMV; can cause vision problems, hearing loss, developmental
delay.
# Multifactorial inheritance – the combination of environmental influence on the
expression of 2 or more genes.
PATHOGENESIS
# The timing of the prenatal defect –
*first 3 weeks, injurious agents can damage enough cells to cause an abortion, or just a
few cells from which the embryo can recover.
*3
rd
-9
th
weeks the embryo is extremely susceptible to injuries since organs are being
crafted out of germ cells layers.
*after the 9th
week, fetal period starts. Characterized by growth and maturation of
organs, less susceptible to injuries, but more sensitive to growth retardation.
# Genes that regulate morphogenesis – these genes are responsible for normal growth
and development of the fetus.
o Valproic acid is an antiepileptic disrupts expression of HOX genes (control
the body plan of an embryo along the head-tail axis); leading to
abnormalities
o The vitamin A (retinol) derivative all-trans-retinoic acid is essential for
normal development and differentiation (cleft lip and cleft palate)
Cytogenetic disorders. Down syndrome.
Chromosomal abnormalities that reflect an atypical number of chromosomes, or a
CYTOGENETIC DISORDERS
structural abnormality in one or more chromosomes.
# These chromosomal abnormalities usually occur when there is an error in cell division
following mitosis or meiosis.
# Karyotype – a photographic representation of a stained metaphase stage, in which
chromosomes are arranged in order of decreasing length.
DOWN SYNDROME
# Caused by the presence of a 3rd copy of chromosome 21, or part of it.
# The presence of an extra chromosome 21 can be caused by:
♥95% Non-disjunction during meiosis.
*Non-disjunction of a homologous pair of chromosomes at the 1st meiotic division.
*Non-disjunction of sister chromatids during the 2nd meiotic division.
The gametes formed this way have either an extra chromosome, or one less chromosome.
Fertilization of such gametes by normal gametes will result in 2 types of zygotes: trisomic (3
copies of the chromosome), and monosomic (1 copy of the chromosome).
These translocations are much more common than reciprocal translocations and are
estimated to occur in approximately 1 in 1,000 live births. They occur only in the acrocentric
chromosomes (13, 14, 15, 21, and 22) and involve the loss of the short arms of two of the
chromosomes and subsequent fusion of the long arms. An example of a Robertsonian
translocation involving chromosomes 14 and 21
Some patients can be mosaic => their cells consist of a mixture of cells, either with 46
or 47 chromosomes.
# Clinical features – flat facial profile, mental retardation, cardiac malformations.
» Approximately 40% of the patients have congenital heart disease, most
commonly defects of the endocardial
» Children with trisomy 21 have a 10- to 20-fold increased risk of developing acute
leukemia. Both acute lymphoblastic leukemias and acute myeloid leukemias
occur
» Virtually all patients with trisomy 21 older than age 40 develop neuropathologic
changes characteristic of Alzheimer disease
» Patients with Down syndrome demonstrate abnormal immune responses that
predispose them to serious infections, particularly of the lungs, and to thyroid
autoimmunity
Reciprocal translocations occur when genetic
material is exchanged between any two
nonhomologous chromosomes.
» Isochromosome – when the centromere divides horizontally rather than
vertically, resulting in the loss of one arm.
» Deletion – a portion of the chromosome is removed.
» Inversion – a portion of the chromosome has broken off, turned upside down
and reattached.
» Insertion – a portion of DNA was inserted in the chromosome.
X-linked inheritance. Polygenic inheritance. Multifactorial diseases. Gout.
Recessive X-linked inheritance
X-LINKED DISORDERS
» Transmitted by heterozygous female carriers only to sons, who are
hemizygous.
» Males will express the disorder, while females will be carriers, and will only
express the disorder if they are homozygous to the defected X chromosome.
» Affected males will not transmit the disorder to sons, but all daughters will be
carriers.
» Examples:
♥Duchenne muscular dystrophyMutation in dystrophin gene → no dystrophin protein AT ALL → muscle
weakness
*Nerves of NMJ are fine, unlike in neuropathies where both the nerve and the
muscle are effected.
♥HemophiliaA (factor VIII) / B (factor IX) → impaired hemostasis → bleeding
♥SCIDMutated ɤ chain of receptors of different cytokines → impaired humeral and
cellular immunity.
*Can be X-linked (T-, B+, NK-) or autosomal recessive
♥Hunter syndromeMucopolysaccharidosis type 2
♥Lesch-Nyhan syndromeHGPRT efficiency → blocked purine synthesis → hyperuricemia
Dominant X-linked inheritance
» Rare variant of inheritance.
» Transmission of the disease to 50% of the sons and daughters of heterozygous
females.
» An affected male cannot transmit the disease to sons, but all daughters will be
affected.
» Examples: Rett syndrome, vitamin D resistant rickets.
POLYGENIC INHERITANCE
# Refers to inheritance of phenotypic trait, attributed to 2 or more genes, and may be
affected by the environment (height, skin color…)
# Polygenic inheritance is characterized by:
» The risk of expressing a polygenic (multifactorial) disorder depends on the
number of mutant genes inherited.
» The rate of recurrence of a disorder in first degree relatives is the same as of
the affected individual => the risk is always 2%-7% that parents with an
affected child will have another affected child.
# This form of inheritance is characteristic for diabetes mellitus, hypertension, gout,
schizophrenia and bipolar disorders.
GOUT
Increased consumption of purine rich foods like meat / increased production / increased
degradation on cells (chemotherapy) → Purine↑↑↑ → hyperuricemia (high blood uric acid
levels) → formation of sharp crystals in places with slow circulation (joints & kidney tubules)
→ inflammation & tissues destruction → arthritis f.ex.
# There are two forms of gout:
» Primary – accounts for 90% of the cases, in which the enzymatic defect is
unknown (common), or it is due to a metabolic defect causing hyperuricemia,
e.g., partial HGPRT deficiency. (Rare).
» Secondary –in which the cause of hyperuricemia is known, but gout is NOT the
main clinical disorder. e.g.
Lesch-Nyhan syndrome – an X-linked disorder in which the enzyme HGPRT is deficient,
results in hyperuricemia, severe neurologic disorder and self mutilation; as a result,
purine synthesis via the salvage pathway is blocked.
# Gout is more common in men, and includes 4 stages:
1) Asymptomatic hyperuricemia.
2) Acute arthritis.
3) Asymptomatic inter-critical period (no attacks during this time).
4) Chronic tophaceous gout.
Lysosomal storage diseases (Tay-sachs disease. Niemann-Pick disease. Gaucher disease. Mucopolysaccharidoses). Glycogen storage diseases.
A group of autosomal recessive metabolic diseases that result from the defect in
LYSOSOMAL STORAGE DISEASES
lysosomal function.
# When a lysosomal enzyme malfunctions, it will lead to accumulation of the partially
degraded insoluble metabolites within the lysosome.
# Many disorders have been identified, each resulted from the functional absence of a
specific lysosomal enzyme, or proteins involved in their function.
TAY-SACHS DISEASE
# Deficiency1
in hexoaminidase A enzyme, responsible for breakdown of phospholipids
found in neurons, named gangliosides.
# When hexoaminidase A is malfunctioning, gangliosides are stored within lysosomes of
neurons and glial cells throughout the CNS.
# The disease is categorized to several forms according to the onset age:
» Infantile – for the first 6 months, infants appear to develop normally; as
neurons become swollen due to gangliosides accumulation, a mental and
physical deterioration occurs, and the infant becomes blind, deaf, unable to
swallow and paralytic => death before the age of 4.
» Juvenile – rare, seen in children 2-10 years of age; develop cognitive and motor
skill deterioration, motor speech disorder (dysarthria), swallowing difficulties
(dysphagia), and lack of coordination (ataxia) => death between 5-15 years
old.
» Adult (late onset) – first symptoms appear during 30s and 40s; usually not fatal
since progress can be stopped, characterized by loss of walking coordination
and neurological deterioration, dysphagia, dysarthria, cognitive decline and
psychiatric illnesses.
NIEMANN-PICK DISEASES
# A group of metabolic disorders caused by mutations in SMPD1 gene (types A and B),
and NPC1/2 gene (type C). *sphingomyelin phosphodiesterase.
# They are considered as lipid storage diseases in which lipids are accumulated in the
liver, spleen, lungs, bone marrow and brain.
# “zebra” bodies - lamellated myelin figures seen in electron microscopy
# Niemann-Pick type A & B – characterized by deficiency of acid sphingomyelinase, and
as a result accumulation of sphingomyelin.
» Type A – severe deficiency in sphingomyelinase, and the accumulation of
sphingomyelin in neurons and phagocytic cells; due to their high content of
phagocytic cells, the organs most affected are spleen, liver, bone marrow,
lymph nodes and lungs, resulting in massive visceromegaly and severe
neurologic deterioration => death by the age of 3.
» Type B – suffer from visceromegaly but no neurologic deterioration.
# Niemann-Pick type C – caused by defect in lipid transport; affected cells accumulate
cholesterol and gangliosides.
» marked by ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria,
and psychomotor regression.
GAUCHER DISEASE
# Results from mutations in the gene encoding for glucocerebrosidase (a glucosylceramidase activity) found on chromosome 1, resulting in accumulation of glucosylceramide in phagocytic cells => Gaucher cells.
# Classification of Gaucher disease:
» Type I –(99% of cases) symptoms include enlarged liver and spleen
(hepatosplenomegaly), skeletal weakness, bone disease, NO CNS
INVOLVEMENT.
» Type II – (Acute) begins within 6 months of birth, symptoms include liver and
spleen enlargement, extensive brain damage, spasticity, and limb rigidity =>
death by the age of 2.
» Type III – (chronic) characterized by slowly progressive, but milder neurologic
symptoms, including enlarged spleen and/or liver, anemia, and respiratory
problems.
MUCOPOLYSACCHARIDOSES
# Characterized by defective degradation of mucopolysaccharides (GAGs) in various
tissues.
# Mucopolysaccharides are part of ground substance, and are synthesized by fibroblasts.
# Accumulation (of Heparan/Dermatan/Keratan Sulfate) results in roughness of facial
features, clouding of cornea, joint stiffness, and mental retardation.
# MPS is classified from 1 to 7, all of which are autosomal recessive, except type 2 (Hunter
syndrome) which is X-linked.
GLYCOGEN STORAGE DISEASES
# Results from deficiency of any of the enzymes involved in glycogen synthesis or
degradation => lead to accumulation of glycogen or abnormal form of glycogen.
# Glycogen is most often stored in the cytoplasm, and sometimes within nuclei.
# Glycogen storage diseases can be categorized:
» Hepatic type – the liver contains enzymes that synthesize glycogen, and also
enzymes that break it down; this type of disease is characterized by liver
enlargement due to accumulation of glycogen, and by hypoglycemia due to
failure of glucose production.
! Von Gierke disease => lack of G-6-phosphatase
» Myopathic type – (McArdle syndrome – defected muscle phosphorylase)
glycogen is an important energy source in skeletal muscles, so when glycolytic
enzymes are defected, glycogen is accumulated, resulting in muscle weakness;
characterized by cramps after exercise and failure to produce lactate during
exercise.
» Pompe disease – caused by deficiency of lysosomal acid maltase and
associated with deposition of glycogen in different organs, but cardiomegaly is
most prominent.
» Brancher disease – deposition of abnormal glycogen
Autosomal recessive inheritance. Cystic fibrosis.
Occurs when both alleles at a given locus are mutants.
AUTOSOMAL RECESSIVE INHERITANCE
# Recessive disorders are characterized by:
» Parents are usually not affected, siblings may show the disease.
» Siblings have 25% chance of being affected.
» If the mutant gene occurs at low frequency in the population, it is most likely
that the affected patient was born as a result of relatives’ marriage.
# Most autosomal recessive disorders have the following features:
1) The expression of the defect tends to be more uniform.
2) Complete penetration is common.
3) Onset of the disease is usually at an early age.
4) Although new mutations for recessive disorders occur, they are rarely detected
clinically.
5) In many cases, enzyme proteins are affected.
CYSTIC FIBROSIS
# Widespread disorder of epithelial transport characterized by abnormal transport of Clacross epithelium, leading to thick viscous secretions.
# This disorder affects most critically the lungs, but also the GI tract, exocrine glands (like
the pancreas) and reproductive system.
# Pathogenesis – the primary defect of CF is the abnormal function of an epithelial Clchannel protein encoded by CF transmembrane conductance regulator (CFTR-cystic
fibrosis transmembrane conductance regulator) gene, located on chromosome 7;
# The most common severe CFTR mutation is a deletion of three nucleotides coding for
phenylalanine at amino acid position 508 (ΔF508). This causes misfolding so that the
CFTR is unable to translocate into the plasma membrane.
# mutations in this gene
leave the epithelium
relatively impermeable
to Cl-
ions, and
consequently
formation of more
viscous secretions
The impact of this defect is tissue specific:
» Sweat glands –hypertonic sweat (increased concentration of salt).
» Respiratory and intestinal epithelium – more mucous secretion → defective
mucociliary action → accumulation of concentrated secretions that obstruct air
passage.
» Pancreas – abnormalities are present in 85%-90% of patients.
In mild cases => accumulation of mucous in the small ducts with some
dilation of the exocrine glands.
In advanced cases => the ducts are completely plugged, causing atrophy of
the exocrine glands and progressive fibrosis → pancreatic enzymes do not
reach duodenum → defective absorption of lipids and proteins →
steatorrhea (fatty stool)
» Intestine – meconium ileus => thick viscid plugs of mucous obstruct the small
intestine of infants.
» Pulmonary changes – viscous mucous secretion of the submucosal glands of
the respiratory tree; bronchioles are distended and blocked due to this
secretion, associated with hyperplasia and hypertrophy of mucous-secreting
cells (superimposed infections give rise to chronic bronchitis).
» Liver – bile canaliculi are plugged; hepatic steatosis1
is common, and may
develop into cirrhosis.
» Vas deference – absent, or obstructed by thick secretion.
Autosomal dominant mendelian inheritance. Marfan syndrome. Ehlers-Danlos syndrome.
Dominance is a relationship between alleles of a gene in which one allele masks
AUTOSOMAL DOMINANT INHERITANCE
the expression (phenotype) of another allele at the same locus.
# Autosomal dominant inheritance affects both males and females, expressed in
heterozygote.
# Autosomal dominant diseases may include the following features:
» Some patients do not have affected parents => new mutations occurred in
the egg or sperm; their siblings are not affected.
» Some individuals inherit the mutant gene but are phenotypically normal
=> REDUCED PENETRANCE
» Some individuals may inherit the same mutant gene, but they expressed
differently => VARIABLE EXPRESSIVITY.
» Age of onset is delayed.
» 50% reduction in the normal gene product is associated with clinical
symptoms.
# Reduction of 50% in enzymatic activity can be compensated; therefore the
involved genes usually do not encode enzyme proteins.
# Two major categories of non-enzymes proteins are affected:
1) Regulatory proteins – involved in regulation of complex metabolic
pathways, such as membrane receptors and transport proteins.
2) Structural proteins – such as collagen and cytoskeletal components.
# Dominant negative – when a mutated allele impairs the function of the normal
allele => when the gene encoding one subunit of a multimeric protein, the
product of one mutant allele can interfere with the assembly of a functional
normal multimer.
MARFAN SYNDROME
# Autosomal dominant disorder of c. tissue, affecting
fibrillin-1.
# Fibrillin-1 is a glycoprotein secreted by fibroblasts and
is the major component of microfibrils found in ECM.
# Microfibrils serve as scaffoldings for the deposition of
elastic fibers.
# Fibrillin-1 is encoded by FBN1 gene found on
chromosome 15.
Mutant FBN1 gene acts as a dominant negative by preventing the assembly of
normal microfibrils.
In addition to FBN1 mutation, dysregulation of TGFβ production occurs, which
results in similar features to Marfan syndrome.
# Most cases of Marfan syndrome are familial (75%), the rest are sporadic (arising
from mutations in germ cells).
Morphology:
» Skeletal abnormalities – patients are tall and thin with abnormally long
legs, arms and fingers (arachnodactyly), high arch palate, hyper-extensible
joints, and spinal and chest deformities.
» Ocular changes – bilateral dislocation of the lens (weak suspensory
ligaments).
» Cardiovascular system – fragmentation of elastic fibers in tunica media of
the aorta, leading to aneurysm and death due to aortic rupture; cardiac
valves, mainly the mitral, may be extensively distended and result in
regurgitation.
EHLER-DANLOS SYNDROME
Characterized by defects in collagen synthesis or
structure; all are single gene disorders, and can be
inherited as autosomal recessive, autosomal
dominant or X-linked.
# Tissues affected are rich in collagen (skin, joints,
ligaments etc.).
Morphology:
» Skin is hyper-extensible, extremely fragile and lacks the normal tensile
strength.
» Joints are hyper-mobile and prone to dislocations.
» Internal organs may rupture (colon, large vessels), cornea may rupture.
# Classification of EDSs divides them into 6 groups.
# The molecular bases of three of the most common EDS are:
1) Deficiency of lysyl hydroxylase – kyphoscoliosis (type VI)
Hydroxylasion of lysyl residues decreases in collagen types I & III,
interferes with normal cross-links of collagen molecules; inherited as
autosomal recessive disorder.
2) Deficient synthesis of type III collagen – vascular (type IV)
Resulting from mutations affecting COL3A1 gene (structural); inherited
as an autosomal dominant disorder, characterized by weakness of vessels
and intestinal wall
3) Deficient synthesis of type V collagen due to mutations in
COL5A1 and COL5A2 is inherited as an autosomal dominant
disorder and results in classical EDS..
AIDS- Acquired immuno-deficiency syndrome (AIDS)
Sexual transmission – HIV is found in semen and in vaginal and cervical fluids.
AIDS
It is caused by the human immunodeficiency virus (HIV) which targets the cells of the
immune system (macrophages, DCs and T helper cells) → profound immunosuppression →
increased risk of opportunistic infections and tumors that a healthy immune system would
have been able to fend off.
Transmission
This mode of transmission accounts for over 75% of cases, especially male to male
transmission.
It is aided by other STDs that cause genital ulceration (syphilis, herpes simplex).
# Parenteral transmission – intravenous drug abuse.
# Mother-to-child transmission MTCT – in the uterus (transplacental), during delivery or
via ingestion of contaminated breast milk.
Structure:
♥Lipid envelope- originates from the host cell membrane,
contains transmembrane glycoproteins;
*gp-120- for the 1ry attachment of the virus to the CD4
molecule of the host cell
*gp-41- for the fusion with the host cell membrane.
♥Matrix protein- gp-17
♥Capsid protein- gp-24
♥Nucleocapsid protein- gp-7 (encloses the nucleic acid)
♥2 copies of (+)SSRNA
♥Viral enzymes (RIP);
*Reverse transcriptase
*Integrase
*Protease
The 2 types of HIV
1. HIV type 1 – more common type associated with AIDS in US, Europe and Central Africa.
*M (major); more common, and are further divided into subtypes (A-J), which differ in their
geographic distribution and their mode of transmission.
*O (outlier)
2. HIV type 2 – cause similar disease principally in West Africa and Southern Asia.
*Both types are genetically different, but antigenically similar.
Pathogenesis
→gp120 binds CD4, resulting in a conformational change and exposure
of new recognition sites for CCR5 and CXCR4 (cell surface chemokines),
which serve as co-receptors.
The active site for T helper cells is CXCR4 and CCR5 for other CD4+ cells
(macrophages, DCs…).
→gp41 undergoes a conformational change that allows it to be inserted
into the target cell membrane.
→Once internalized, the viral genome undergoes reverse transcription, leading to the
formation of complementary DNA (cDNA) that may stay in the cytoplasm or transfer into
the nucleus to be integrated into the host genome (in dividing T cells).
*After integration, the viral DNA may remain non-transcribed for months or years, and the
infection becomes latent; transcription and formation of viral particles will eventually lead to
cell death.
*Maraviroc- post exposure prophylaxis (within 72 hours)
Progression of HIV infection
1. Acute phase
The R5 strain will bind to the CCR5
co-receptor of DCs in the epithelial
or mucosal tissues.
*Initially it only has affinity for this
co-receptor, later it acquires
affinity for the CXCR4 co-receptor
on T helper cells.
The DC captures the virus and
migrates to the lymph nodes,
where it presents it to other CD4+
cells.
This leads to a large spike in the virus replication → viremia; increased amounts of viral
particles found in blood
Viremia is accompanied by a variety of non-specific symptoms (sore throat, fever, rash etc.).
2. Chronic phase
→ The immune system remains competent at handling most opportunistic infections =>
CLINICAL LATENCY PERIOD
→Destruction of CD4+ T cells steadily progresses, and their number steadily declines.
→No symptoms detectable
- Crisis phase
→ Low CD4+ T cells count (<500 cells/μL).
→Patients develop serious opportunistic infections, secondary neoplasms, and neurologic
manifestations.
CLINICAL FEATURES
# Opportunistic infections – pneumonia, herpes, tuberculosis, influenza.
# Neoplasms – Kaposi sarcoma, non-Hodgkin lymphoma, cervical cancer.
# CNS involvement – aseptic meningitis, vascular myelopathy, progressive
encephalopathy
Congenital and acquired immunodeficiencies ( Bruton’s agamma-globulinaemia, isolated IgA deficiency, DiGeroge’s syndrome, SCID)
(check the note, lots of diagrams)
BRUTON’S DISEASE – X-LINKED AGAMMAGLOBULINEMIA
X-linked disease, characterized by the failure of pre-B cells to differentiate into B cells,
resulting in the absence of γ-globulins in the blood
mmature B cells have a BCR (a membrane-bund antibody).
Pre B cells have “pre B cell receptors” which are composed of two heavy chains only.
The BTK gene (Bruton’s tyrosine kinase) plays an important role in the further assembly of
this receptor, and it is found on the X chromosome.
In XLA there is a mutation in this gene → B cell maturation stopped at pre B cell stage →
no B cells leave the bone marrow → far fever/complete lack of circulating plasma cells →
far fever/complete lack of circulating antibodies.
Because this disease is X-linked recessive it almost exclusively manifested as a disease in
men (one X and one Y chromosome). Women with a mutation in this gene in one x
chromosome only are carriers only.
*Sometimes XLA can develop sporadically rather than being inherited from a parent
→6 months- supply on Igs supplied through the placenta runs out
Although B cell and antibody mediated immune is compromised, T cell mediated immunity
remains intact so that some infection can be cleared
Treatment;
Life-long intravenous infusion of immunoglobulins from a variety of individuals (passive
immunity). Antibiotic in current infections.
ISOLATED IgA DEFICIENCY
A congenital B cell immunodeficiency in which the terminal differentiation of IgA-secreting B
cells to plasma cells is blocked.
IgA antibodies provide protection against microbes that multiply in body secretions
(tears , saliva , sweat , colostrum and secretions from the GI tract, the genitourinary
tract , prostate and respiratory epithelium).
Without them, the mucosal antigen exposure increases and the body makes more IgE
antibodies against inhalants and foodstuff → hyper allergy
*Usually asymptomatic but symptoms are generally diherria and pulmonary infections
DIGEORGE SYNDROME / 22q11.2 DELETION SYNDROME
A small portion of chromosome 22 is deleted (22q11.2) → developmental abnormalities.
This deletion is referred to as a microdeletion because
this small portion contains 30 genes (less than 5 million).
One of these genes is TBX1, which is involved in the
normal development of the 3rd and 4th pharyngeal
pouches.
(partial/complete) Digeorge syndrome → (mild to moderate/severe) thymic dysfunction →
(not fatal/fatal) deficiency in mature T cells.
* B cells and serum immunoglobulins are unaffected.
The 22q11.2 region encodes genes which can affect other organs and tissues.
Symptoms include:
» Cardiac abnormalities.
» Facial abnormalities (cleft palate, feces-long face/small teeth…)
» Mental disorders
SEVERE COMBINED IMMUNODEFICIENCY (SCID)
A genetic disorder in which both humoral (antibodies, complement proteins…) and cellmediated immunities are impaired, caused by mutations in the gene encoding the common
γ-chain of the receptors for different cytokines (IL-2, 4, 7, 9, 15).
*IL-7 is very important since it is responsible for stimulating the survival and expansion of
immature B cells and T cells precursors.
SCID can be:
♥X-linked
(T- B+ NK-)
♥Autosomal recessive
*Adenosine deaminase (ADA) deficiency is the most common.
Mutation in the enzyme → accumulation of adenosine → inhibits DNA synthesis →
immune cells are not able to mature (T- B- NK-)
*MHC-II gene mutation (T- B+ NK+) → CD4+ T-cell defect
*RAG gene mutation (T- B- NK+) → DNA Rearrangement defect
Treatment: bone marrow transplantation and gene therapy.
Sjogren’s syndrome. Systemic sclerosis. Myositis.
An autoimmune disease characterized by excessive fibrosis throughout the body,
THE SYNDROME
A chronic systemic autoimmune disease in which there is a destruction of the exocrine
glands:
*Lacrimal → dry eyes “keratoconjunctivitis sicca”
*Salivary → dry mouth “xerostomia” → increased risk of CARIES!
*Sweat → dry skin “xerosis”
*Mucous → dry vagina and pain during intercourse “dyspareunia”
dry nose and decrease in smell sensation
Sjogren’s syndrome is most common in middle aged women
Has 2 forms:
1. Primary – known as sicca syndrome, occurs as an isolated disorder where autoantibodies
are produced against 2 nuclear antigens => SS-A (Ro) and SS-B (La) (Sjogren’s syndrome
antigen A/B, which are ribonucleoproteins)
2. Secondary – associated with another autoimmune disease (RA most commonly).
* High risk of develop non-Hodgkin B cell lymphoma (Marginal zone)- unilateral
enlargement of the parotid gland.
PATHOGENESIS
Loss of tolerance in the helper T cells population to ductal epithelial cells of exocrine glands
→ duct obstruction → atrophy
SYSTEMIC SCLEROSIS
including the skin, GI tract, lungs, kidneys, heart and skeletal muscle.
# Can be classified into 2 groups:
» Diffuse scleroderma – initial widespread skin involvement, with rapid
progression and early visceral involvement.
» Limited scleroderma – mild skin involvement (fingers, face), relatively
benign course with late visceral involvement; also called CREST
syndrome.
Calcinosis => calcification of fingertips
Raynaud syndrome => vasospastic disorder causing fingers
discoloration
Esophageal dysmotility => acid reflux
Sclerodactyly => claw hands
Telangiectasia => dilation of superficial vessels
PATHOGENESIS
# Fibroblasts activation with excessive fibrosis.
# Helper T cells are activated by an unknown trigger => accumulate in the skin and
release cytokines that activate mast cells and macrophages => release fibrogenic
cytokines (IL-1, PDGF, TGFβ, FGF).
# B cells are also activated => indicated by the presence of
hypergammaglobulinemia and ANAs.
# 2 types of ANAs are produced:
» Anti-DNA topoisomerase I (anti-Scl70) – highly specific for diffuse
scleroderma, present in 70% of patients.
» Anti-centromere antibodies – highly specific for limited scleroderma
(CERST), present in 90% of patients.
# Microvascular disease is present early in the course of systemic sclerosis, caused
by local T cells reaction, followed by platelets aggregation and release of platelet
factors that trigger fibrosis of the adventitia, thus narrowing the microvasculature.
MORPHOLOGY
# Skin
Diffuse sclerotic atrophy with edema (doughy consistency); with progression,
replaced by fibrosis of the dermis tightly boubd to subcutaneous structures
Increase in compact collagen in the dermis along with thinning of the
epidermis.
Small vessels show thickening of basement membrane, endothelial cell
damage and partial occlusion; arterioles also thicken.
GI tract
Progressive atrophy, collagenous replacement of the muscular layers (most
severe in esophagus) => dysfunction of the esophageal sphincter resulting in
gastric reflux
Ulceration of the mucosa, excessive collagenization of lamina propria and
submucosa
Loss of microvilli and villi in small intestine => malabsorption
# Musculoskeletal system
Synovial hyperplasia and inflammation
At later stage => fibrosis
# Lungs
Fibrosis of small pulmonary vessels => pulmonary hypertension
Pulmonary vascular endothelial dusfunction
# Kidneys
Thickened wall of intertubular arteries => cell proliferation with deposition of
glycoproteins and mucopolysaccharides
Hypertension not always occur, but when it does, it is associated with fibrinoid
necrosis, thrombosis and infarction of arterioles
No glomerular change
Heart
Patchy myocardial fibrosis
Thickening of intramyocardial arterioles, caused by microvascular injury
Changes in lungs result in right ventricular hypertrophy and failure
CLINICAL COURSE
# SS affects woman x3 then man (peak btw 50-60)
# Distinctive feature of SS is the striking cutaneous involvement
# Almost all patient exhibit Raynaud phenomenon
Rheumatoid arthritis.
Histologically, the affected joints show chronic synovitis, characterized by:
RHEUMATOID ARTHRITIS
A systemic, chronic inflammatory disease affecting primarily the synovial joints.
Usually 5 or more joints are affected symmetrically; firstly, the small joints (MCP, MTP) and
as it worsens, bigger joints (shoulders, elbows, knees and ankles).
Extra articular involvement develops in the skin, heart, blood vessels, muscles and lungs.
PATHOGENESIS
Interplay of:
*environmental factors
e.g. infection, smoking → citrullination
*genetic factors (susceptibility genes)-
* Associated with HLA-DR4, and polymorphism in PTPN22 gene.
APCs do not recognize those antigens as self-antigens and carry them to the lymph nodes,
where they are presented to TH1 and TH17→
TH cells stimulate B cells to mature into plasma cells and secrete specific antibodies →
Antibodies and T helper cells reach synovial joints via the circulation;
1. T-cells (picture)
- Antibodies bind to citrullinated antigens → formation of immune complexes → chronic
inflammation and cell injury → angiogenesis → more immune cells
Over time the PANNUS can damage the
cartilage (synovial cells secrete
proteases), other soft tissues and also
erode bone.
Eventually, the pannus fills the joint
space → fibrosis and calcification result
in permanent ankylosis (stiff joint).
*Destruction of tendons, ligaments and joint capsules produce the characteristic deformities
=> radial deviation of the wrist, ulnar deviation of the fingers, bending of fingers…
MORPHOLOGY
» Synovial cell hyperplasia and proliferation.
» Infiltration of inflammatory cells, forming lymphoid follicles in the synivium
composed of helper T cells, plasma cells and macrophages.
» Increased vascularity due to angiogenesis.
» Aggregates of fibrin on synovial surface.
» Increased osteoclasts activity.
CLINICAL COURSE
# Weakness, fever, malaise (a feeling of general discomfort, uneasiness or pain).
# Swelling of joints; limiting movements, stiffness especially in the morning.
Systemic lupus erythematosus.
Acute necrotizing vasculitis – affects small arteries and arterioles; characterized by
SLE
A multisystem autoimmune disease that can affect any part of the body, but mostly affects
the skin, kidneys, serosal membranes, joints and heart.
The diagnosis is established if the patient shows at least 4 symptoms:
➔ Malar rash (butterfly)
➔ Discoid rash
➔ Photosensitivity
➔ Oral ulcers
➔ Serositis (pleuritis, pericarditis…)
➔ Neurological disorders
➔ Renal disorders
➔ Arthritis
➔ Hematologic disorders (anemia, thrombocytopenia, leukopenia…)
➔ ANA
PATHOMECHANISM
the pathogenesis of SLE involves a combination of environmental factors (UV, smoking,
medication, estrogen…) and genetic factors (less effective clearance of nuclear antigens
released from apoptotic cells, and failure of T cells and B cells tolerance to those selfantigens).
The major defect in SLE is the failure to maintain self-tolerance.
Tissue damage occurs in 2 pathways:
1) Deposition of antigen-antibody complexes (type III hypersensitivity).
2) Production of large number of autoantibodies, mainly ANA (type II
hypersensitivity).
*See topic 21
Spectrum of antibodies:
» Anti-nuclear antibodies (ANAs) – produced against nuclear antigens (DNA =>
Smith antibodies, histones, non-histone proteins, nucleolar antigens).
» Anti-phospholipid antibodies – directed against phospholipids of cell
membrane, but also disturb coagulation process, since phospholipids are
important in the formation of blood clots (“lupus antibodies”).
» Antibodies against blood cells – RBCs => hemolytic anemia, platelets =>
thrombocytopenia, lymphocytes => lymphopenia.
MORPHOLOGY
necrosis and fibrinous depositions within vessel walls, resulting in fibrous thickening and
lumen narrowing.
# Joint involvement – swelling and non-specific mononuclear cell infiltration in synovial
membranes.
# Skin involvement – malar rash (butterfly pattern), worsened by UV light
(photosensitivity) due to liquefactive degeneration of basement membrane and edema
in dermis-epidermis junction.
# CNS involvement – focal neurologic deficits, often related to vascular lesions causing
focal cerebral microinfarctions.
# Spleen – moderately enlarged with capsular fibrous thickening and follicular
hyperplasia.
# Serous membranes – pericardium and pleura show inflammatory changes from serous
effusions to fibrous exudation.
# Heart – manifested in the form of endocarditis, myocarditis and valvular lesions
(Libman-Sacks endocarditis which are vegetations formed on the mitral valve).
# Kidney involvement – most important clinical feature of SLE, causing renal failure which
is the most common; the pathogenesis of all forms of glomerulonephritis in SLE involve
deposition of antigen-antibody complexes within the glomeruli:
» Class I (5%) – rare, looks normal by light, electron and immunoflorescence
microscopy (no histological signs of inflammation).
» Class II – mesangial lupus glomerulonephritis (10%-25%) – immune complexes
are deposited in the mesangium (increased mesangial matrix).
» Class III – focal proliferative glomerulonephritis (20%-35%) – in an otherwise
normal glomerulus, 1-2 areas show swelling and proliferation of endothelial
and mesangial cells, with neutrophils infiltration and fibrinoid deposits;
associated with hemturia and proteinuria.
» Class IV – diffuse proliferative glomerulonephritis (35%-60%) – most severe
form, most glomeruli show endothelial and mesangial proliferation affecting
the entire glomerulus; subendothelial immune complexes deposition; patients
suffer from hemturia, proteinuria, hypertension, and renal insufficiency.
» Class V – membranous glomerulonephritis (10%-15%) – characterized by
widespread thickening of the capillary wall caused by deposition of basement
membrane like material, and accumulation of immune complexes; patients
have severe proteinuria.
Self-tolerance. Pathomechanisms of autoimmune disease.
SELF-TOLERANCE
Immunological tolerance – the lack of response of the immune system to an antigen.
ANTIGEN SPECIFIC! Unlike immunosuppression.
Self-tolerance – the immune system of an individual does not develop an immune response
toward self-antigens.
Failure of self-tolerance results in autoimmunity.
During development of B and T lymphocytes, antigen receptors are produced, some of them
are a match to the body’s own antigens. In order to eliminate self-reactive lymphocytes, 2
groups of mechanisms arise:
- Central tolerance
The elimination of self-reactive B and T cells during their maturation in the 1ry lymphoid
organs (bone marrow & thymus). Use AID (antigen-induced death)
♥BM:
Non-autoreactive immature B cells can leave the bone
marrow and finish the differentiation process. B cells
that bind membrane bound antigens will be retained
in the bone marrow. They will undergo “receptor
editing” until they are unable to bind self-antigens. If
they are not able to produce a non-autoreactive BCR,
they are eliminated by apoptosis.
- Not all self-antigens present in the bone marrow are
capable of crosslinking the antigen receptors of
autoreactive B cells. Monovalent self-antigens
(containing one copy of a given epitope) induce an
anergic state in developing immature B cells. Anergic
autoreactive B cells can leave the bone marrow, but
remain inactive and die within a few days in the
circulation.
♥Thymus:
Self antigens are processed and presented by APCs (AIRE gene – autoimmune regulator),
and any developing T cell that expresses a receptor to those antigens is negatively selected
and eliminated by apoptosis.
- Peripheral tolerance
The mechanisms of central tolerance are effective, yet some autoreactive clones still reach
the peripheral tissues. Autoreactive T and B cell clones escaping central tolerance
mechanisms in the primary lymphoid organs are eliminated or inhibited by the so-called
peripheral tolerance mechanisms.
♥B cells
First activation signal; Ag-mediated crosslinking of BCR. PAMPS
Second activation signal; binding of BCR to Ag presented on MHC-II & CD40-CD40 ligand
Third activation signal; cytokines secreted by T helper cell (IL-4, IL-5)
If all activation signals are present, B cells will proliferate and mature into plasma cells. If a
signal is lacking, the B cell will become anergic.
♥T cells
Anergy-functional inactivation
Negative / lack of co-stimulation.
Suppression (by regulatory T cells)
S ecretion of immunosuppressive cytokines (IL-10, TGFβ)
Expression of IL-2 R ( CD25), consuming IL-2, and not
producing it.
Induce expression of CTLA4 on effector T cells.
Break down DAMPs (ATP, ADP..) to adenosine; a
suppressive mediator
Deletion
T cells that recognize self-antigens with high affinity in
the absence of co-stimulation will undergo apoptosis:
Intrinsic mitochondrial pathway / extrinsic death
receptor pathway
MECHANISMS OF AUTOIMMUNE DISEASE
→Gene mutations
Autoimmune diseases have a tendency to run in families.
Several autoimmune diseases are linked with mutations in the HLA locus (genes that code
for MHC proteins) on chromosome 6.
The role of MHC genes in autoimmunity is still not clear, especially because they do not
distinguish between self and foreign peptide antigens.
Several non-HLA genes also confer susceptibility to type I diabetes, including polymorphisms
within the gene encoding insulin itself, as well as CTLA4 and PTPN22 (protein tyrosine
phosphatase) both are thought to inhibit T cell responses → over responsiveness
*Type I diabetes mellites- loss of self-tolerance of T cells → destruction of pancreatic β cells
→ NO insulin production → blood glucose↑
*Multiple sclerosis- loss of self-tolerance to myelin proteins → demyelination of neurons in
the CNS → neurologic deficits
*Rheumatoid arthritis- a systemic, chronic inflammatory disease affecting many tissues but
principally attacking the joints to produce a nonsuppurative proliferative synovitis that
frequently progresses to destroy articular cartilage and underlying bone with resulting
disabling arthritis.
→Infections
Some pathogens that invade cells express proteins which are very similar in structure to
self-antigens. When the infected cell will present the pathogenic antigen, the immune
system will be triggered, and Plasma cells will start producing antibodies specific to those
antigens. BUT these antibodies will also bind to the similar self-antigens, marking healthy
cells for attack.
*Rheumatic heart disease- streptococcal infections can produce antigens which are similar
to self-antigens found in the heart
→Privileged sites
Certain parts of the body like the cornea are out of reach of most leukocytes because they
contain virtually no BVs or lymphatics.
Physical damage to these sites will cause self-antigens, which have not yet to be
encountered by the immune system, to enter the circulation and be recognized as foreign
antigens and destroyed.
→Modification of an antigen – in drug induced situations, the drug metabolites initiate
conformational change of the antigen.
→Epitope spreading – in the thymus, T cells are not exposed to all self-antigens, each
antigen has several epitopes, and only the most dominant ones are presented to T cells in
the thymus; this, T cells are reactive to the less dominant epitopes are NOT eliminated.
→Failure of T cell suppression – insufficient production of IL-10.
→Lack of AICD – defect in the interaction of Fas and Fas ligand → SLE
Opportunistic infections (viruses, bacteria, fungi) and pre-disposing conditions.
Opportunistic infections – Definition:
* An infection by a microorganism that normally does not cause disease but becomes pathogenic when the
body’s immune system is impaired and unable to fight off infection.
* account for the majority of deaths in AIDS and in other diseases with immunosuppression.
Major opportunistic infections:
Fungal infections:
Fungi may cause superficial or deep infections:
* Superficial infections involve the skin, hair and nails. They are called dermatophytes.
* Deep fungal infections can spread systematically and invade tissues, destroying vital organs in
immunocompromised hosts.
Fungi are divided into endemic and opportunistic species:
* Endemic are invasive species that are limited to particular geographic region.
* Opportunistic fungi (e.g. Candida, Aspergilus, Mucor, Cryptococcus) they either colonize
individuals or are encountered from environmenta sources. In immunodeficient individuals
opportunistic fungi give rise to life threatening invasive infections characterized by tissue
necrosis, hemorrhage ect.. patiants with AIDS often are infected by opportunistic fungus
Pneomocystis jiroveci (=carinii).
Examples:
* Pneumocystosis:
❖ caused by P. jiroveci
❖ pneumonia or disseminated disease
❖ OI that causes most often death in AIDS
❖ treatable; prophylaxis possible
❖ transmission: via respiratory tract
* Candidiasis (’Thrush’)
❖ caused by C. albicans
❖ oral cavity, trachea, lung, oesophagus
* Cryptococcosis
❖ caused by cryptococci (fungi!)
❖ enters via respiratory tract / lung
❖ spreads to lepromeninges -> meningitis
❖ may also affect skin, skeletal system, urinary tract
❖ high mortality
❖ can be treated
* Histoplasmosis
❖ caused by H. Capsulatum
❖ by inhalation (birds, bat ‘dropping’)
❖ intracellular parasite in macrophages
❖ epitheloid cell granulomas with necrosis; later fibrosis, calcification; yeasts detectable by silver
impregnation
❖ Diff. Dg: TB, sarcoidosis, coccidioidomycosis
❖ in fulminant (imunosuppressed): no granulomas, macrophages filled with fungal yeasts throughout the
body.
Bacterial infections:
* Mycobacteriosis
❖ TB – pulmonary or extrapulmonary. M. tuberculosis block the fusion of of the phagolysosome
allowing the bacteria to proliferate unchecked within the macrophage.
❖ ‘atypical’: M. avium intracellulare – often disseminated
Usual pathogens
* S. aureus, S. pneumoniae, H. influenzae, Salmonella
* pneumonia; entiritis; meningitis; disseminated (sepsis)
Viral infections:
* Viruses are obligate intracellular.
* Cytomegalovirus (CMV)- infected cells are enlarged and show a large eosinophilic nuclear inclusion
and smaller basophilic cytoplasmic inclusion.
❖ very common, most people had CMV by 40y; stays dormant
❖ via saliva, blood, semen
❖ throat, lung, GI, meningoencephalitis, retinitis
* Herpes simplex virus (HSV 1,2)- large nuclear inclusion surrounded by a clear halo.
❖ very common
❖ gingivostomatitis (HSV-1); genital herpes (HSV-2)
❖ keratitis, encephalitis, hepatitis, pneumonia
❖ disseminated to viscera
* KSHV/HHV-8
❖ Kaposi sarcoma
* EBV
❖ B-cell lymphomas (e.g. Burkitt lymphoma)
* Varicella Zoster Virus (VZV)
❖ cause of chickenpox and shingles
❖ in immunosuppressed: encephalitis, transverse myelitis, necrotising visceral lesions
Tuberculosis.
A chronic granulomatous disease caused by various strains of Mycobacteria, mainly Mycobacterium
TUBERCULOSIS
tuberculosis.
# Typically attacks the lungs; air-borne, chronic granulomatous disease.
# Typically, the centers of tubercular granulomas undergo caseous necrosis.
# Two forms of tuberculosis
PULMONARY FORM
Spreads by inhalation of droplets
containing the organism
(Mycobacterium tuberculosis)
=> Tubercle bacillus
NON-PULMONARY FORM
Most often is caused by ingestion of
infected milk (Mycobacterium
bovis).
Mycobacteria species are obligate aerobes, slowly growing; growth is inhibited by low pH (<6.5) and
by long chain fatty acids.
# It is important that infection be differentiated from disease. Infection may or may not cause clinically
tissue damage. Such people are infected but do not have active disease and therefore cannot transmit
to others.
# The Mantoux test (DHR)- a positive tuberculin skin test signifies cell mediated hypersensitivitiy to
tubercular antigens. It does not differentiate btw infection and disease. False negative may be
produce by viral infection, Hodgkin lymphoma ect.
# Only a small fraction of those who contract an infection develop active disease.
PRIMARY TUBERCULOSIS
# Develops in previously unexposed, and therefore unsensitized, persons.
# Inhaled bacilli in distal airspaces of the middle portion of the lung, close to the pleura.
# As sensitization develops, an area of 1-1.5 cm of gray-white inflammatory dense mass appears =>
Ghon focus, its center usually undergoes caseous necrosis.
The bacilli then drain into regional lymph nodes => Ghon complex – the combination of
parenchymal lesion and nodal involvement.
Ghon complex undergoes progressive fibrosis, followed by calcification => Ranke complex.
Histologicall appearance – granulomatous inflammation, with the presence of giant cells and
epitheloid histiocytes.
The major consequences of primary TB:
» Induces hypersensitivity (DTH).
» The foci (locations) of scarring may harbor viable bacilli for years, and serve as a source for
reactivation (when host defenses are compromised).
» Progressive primary TB – occurs in individuals who are immunocompramised (AIDS),
elderly people or malnourished children.
SECONDARY TUBERCULOSIS (reactivation tuberculosis)
# Arises in a previously sensitized host, by activating Ghon complexes, with spread to a new
pulmonary or extra pulmonary site or by exogenous reinfection.
Secondary pulmonary tuberculosis is classically localized to the apex of one or both upper lobes.
Due to pre-existing hypersensitivity, the bacilli excite a large tissue response that tends to wall off the
focus => regional lymph nodes are less involved.
Cavitations occur more frequently, resulting in dissemination along the airways.
Increased risk of TB exists in all stages of HIV, the manifeatation differ depending on the degree of
immunosuppression:
» Less severe immunosuppression(CD4+ count>300 cells/mm3
) present with “usual” secondary
TB => apical disease with cavitations.
» Advanced immunosuppression (DC4+ count<200 cells/mm3
) present with symptoms similar
to primary TB => middle lobes, lymph nodes involvement.
Morphology –
» Small focus of solid mass, ~2cm, next to apical pleura.
» Sharply defined, firm, gray-white to yellow areas that have a variable amount of central
caseous necrosis and peripheral fibrosis.
» Histologically, granulomatous inflammation can be seen.
Secondary TB (localized, apical) may heal either spontaneously or after therapy, or it may progress
along several pathways:
» Progressive pulmonary TB – the apical lesion enlarges with expansion of the area of
cessation; erosion into a bronchus allows the evacuation of the caseous center, creating an
irregular cavity lined by caseous material, and the erosion of blood vessels results in
hemoptysis (coughing out blood).
» Military pulmonary disease – occurs when organisms drain through the lymph vessels that
drain into lymphatic ducts and from there to the venous system => right side of the heart =>
pulmonary arteries; small, yellow-white solid masses are scattered through the lung
parenchyma.
With progressive pulmonary TB, the pleural cavity is involved and serous
pleural effusions, tuberculous empyema (pus) or fibrous pleuritis may develop.
» Systemic miliary TB – when infective foci in the lung spread through pulmonary veins to the
left heart and to systemic circulation (liver, BM, spleen ect..)
» Isolated-organ TB – usually involves the meninges, kidneys, adrenal glands, bones and
fallopian tubes; in vertebrae it is called Pott disease.
» Lymphadenitis – most frequent form of extra pulmonary TB, usually occurring in the
cervical region.
» Intestinal TB – by drinking of contaminated milk; organisms are trapped in the lymphoid
tissue of large and small intestine.
PATHOGENESIS
# The Mycobacteria are ingested by macrophages, but inhibit their normal bactericidal responses by
manipulation of endosomal pH => impaired phagolysosome formation.
# The bacteria proliferate within the alveolar macrophages, resulting in bacteremia and seeding in
multiple sites. Despite the bateremia, most persons at this stage are asymptomatic or have a mild flu
like illness. [ in some people with NRAMPI gene- natural resistance ssociated macrophage protein I,
the disease may progress from this point without immune response].
# After 3 weeks, cell-mediated immunity develops (tissue hypersensitivity) => bacterial antigens reach
the lymph nodes, and presented bound to MHC-II by DCs to CD4+ T-cells.
# Under the influence of IL-12 (secreted by macrophages), CD4+ T-cells proliferate into TH1 subset,
capable of secreting IFNγ => activating macrophages.
# Activated macrophages release mediators such as TNF (recruitment of monocytes which go through
activation and differentiate into “epitheloid histiocytes” that characterize the granulomas response),
NO (by inducible nitric oxide synthase- antibacterial), and reactive oxygen species.
# Immunity to a tubercular infection is primarly mediated by THI cells, which stimulate
macrophage to kill bacteria!
CLINICAL COURSE
# Onset is asymptomatic.
# Systemic symptoms related to cytokine release (TNF, IL-1) by activated macrophages, include
malaise (nausea), anorexia, weight loss and fever.
With progression of the disease => increasing amount of sputum (first mucoid, later purulent); when
cavitations appear, the sputum will contain tubercle bacilli.
Some degree of hemoptysis.
# Pleuritic pain when the infection reaches pleural surface.
Extrapulmonary manifestation depend on the organ.
# Amyloidosis may develop in persistent cases.
Transplant rejection. Graft versus host reaction.
Occurs when immunologically competent T cells are transplanted into immunologically
TRANSPLANT REJECTION
All patients have some form of an immunological reaction to a transplanted tissue; except
for in the case of identical twins or autograft (Tissue transplanted from one part of the body
to another in the same individual).
Important term to define first: allograft- the transplant of an organ or tissue from one
individual to another of the same species.
Rejection of allografts is an immunologic reaction to the MHC molecules present on the cells
of the donor’s organ, which are highly polymorphic (no 2 individuals are likely to express the
same set of MHC).
*Tissue typing- a procedure in which the tissues of a prospective donor and recipient are
tested for compatibility prior to transplantation.
There are 2 main mechanisms by which the host immune system recognizes and responds
to grafts:
- Direct recognition – APCs in the graft is recognized by T-cells of the recipient, which are
stimulated by direct interaction with MHC molecules expressed on the graft. - Indirect recognition– the APCs of the host pick up the MHC molecules of the donor,
process and present them to T-helper cells of the recipient; in this case, cytotoxic T cells are
not involved in killing the graft, but production of antibodies occur
The rejection of the graft is made by:
T-cell mediated rejection – cytotoxic T cells directly kill cells of the grafted tissue; helper T
cells secrete cytokines that trigger DTH reaction, with increased vascular permeability and
local accumulation of lymphocytes and macrophages.
Antibody-mediated rejection – the antibodies of the host are directed against graft MHC
and activate complement as well as recruitment of leukocytes.
Categories of graft rejection:
♥Hyperacute rejection – occurs within minutes to a few hours after transplantation due to
pre-existing humoral immunity (antibodies); the graft is characterized by acute arteritis,
vessel thrombosis and ischemic necrosis.
♥Acute rejection – may occur within days to weeks after transplantation in a nonimmunosuppressed host; it is caused by both cellular and humoral immunity:
*Acute cellular rejection – extensive interstitial infiltration of helper and cytotoxic T cells,
accompanied by edema and mild hemorrhage, and renal failure.
*Acute humoral rejection – characterized by necrotizing vasculitis with endothelial cell
necrosis, deposition of antibodies, complement and fibron.
♥Chronic rejection – occurs late after transplantation with increased creatinine in serum
(indicates renal dysfunction), dominated by vascular changes, interstitial fibrosis and loss of
renal parenchyma.
GRAFT VS. HOST REACTION
compromised recipients during bone marrow transplantation, or solid organs rich in
lymphoid tissue.
# The host cannot reject the graft, but the T cells of the donor recognize the tissues of the
recipient as foreign and react against them.
# There are 2 types of GVHD:
Acute – occurs days to weeks after transplantation, causes epithelial cell necrosis in the
liver, skin and gut => destruction of small bile ducts (results in jaundice), mucosal
ulcerations (results in bloody diarrhea), and generalized rash.
Chronic – may follow the acute form or may occur on its own; patients develop skin
lesions and manifestations mimicking other autoimmune diseases.
*GVHD is a potentially lethal complication that can be minimized by MHC matching or by
depletion of donor T cells before transplantation.
*Immunosuppression
Interfere with protein synthesis or DNA replication thus suppressing the immune system,
preventing rejection of the transplanted organ. But a simple infection like the flu will be
dangerous. Also, higher chance to get cancer (T cells usually fight off).
Type III hypersensitivity (immune complex mediated). Type IV hypersensitivity (cell mediated)
TYPE III HYPERSENSITIVITY
An accumulation of immune complexes that have not been adequately cleared by innate
immune cells deposit in BV walls, causing inflammation and
tissue damage.
Damaged cell (necrosis f.ex.) → DNA is released →
autoreactive B cell binds the Ag → specific T helper cell
recognizes the Ag presented by the B cell → release of
cytokines → B cell activation → secretion of antibodies →
binding of antibodies to Ags → formation of small soluble,
less immunogenic complexes → float longer in blood→
complexes are deposited into BMs of blood vessels (+
charged DNA attracted to – charged BM) → activation of the
complement system
*C3a, C4a, C5a are:
*anaphylatoxins → permeability of BV↑ → edema
*chemokines → degranulation of neutrophils →
vasculitis → damaged cell (+ loop)
Here LARGE amounts of complement proteins
are used, in contrast to type II hypersensitivity,
where SMALL amounts are used. (detection in
blood).
Examples:
♥Systemic lupus erythematosus SLE
♥Glomerulonephritis- deposition in the BVs of the glomeruli
♥Arthritis (blood filtered to synovial fluid)
♥Serum sickness- Antibodies are produced against antibodies which are produced as a
reaction to venom Ags f.ex.).
♥Farmer’s lung- Interaction of IgG with large particles of inhaled allergens; the resulting
inflammation compromises gas exchange by the lung.
TYPE IV HYPERSENSITIVITY
Unlike the other types, it is not antibody-mediated but rather is a type of cell-mediated
response by:
1. T helper cells “delayed type hypersensitivity”
Called delayed because it takes 48-72 hrs to recruit TH1 cells.
♥The tuberculin test is a classic example – a
small amount of protein antigen, extracted
from Mycobacterium TB, is injected to the
dermis → DCs recognize and transport the
tuberculin Ag to the lymph nodes where they
present it to naïve T helper cells on MHCII
molecules → DC secrete IL-12 → naive T
helper cell differentiates into TH1 cell → TH1
cell secretes IFN-γ & TGF-β → inflammation
*DTH can also develop in response to contact
sensitizing agent, such as nickel or poison ivy (urushiol-causing dermatitis).
2. Cytotoxic T cells “direct cell cytotoxicity”
DCs present the Ag on MHC-I molecules → naïve T cell differentiates into cytotoxic T cell →
secretion of perforin & granzymes→ destruction of target cell
♥Type I diabetes mellitus – destruction of
pancreatic β cells.
♥Rheumatoid arthritis RA – WBCs infiltrate
synovial joints and produce antibodies
against the constant region of human IgG.
*The amount of antigen required to elicit a reaction is much greater than in antibodymediated (type II) hypersensitivity.
Immune mechanisms of tissue injury. Type I hypersensitivity (anaphylactic type). Type II hypersensitivity (antibody dependent)
The reactions produced by the normal immune system, which may cause tissue injury.
HYPERSENSITIVITY REACTIONS
# Hypersensitivity reactions are caused by:
♥autoimmune diseases
♥excessive reaction against microbes
♥immune response against common environmental substances.
TYPE II HYPERSENSITIVITY “tissue-specific / cytotoxic hypersensitivity”
Antibody-mediated reaction, caused by antibodies produced against antigens found on the
patient’s own cell surface (tissue specific).
These molecules can be intrinsic to the cell surface, and undergo configuration alterations,
or they can be exogenous (drug metabolites like penicillin)
Subtypes
1. Target cell depletion/destruction WITHOUT inflammation
The antibodies bind the cell surface antigens,
and their constant region serves as a ligand
for receptors found on macrophages,
neutrophils and NK cells; thus, the antibodies
“bridge” the interaction of these cells and
promote phagocytosis, or they lead to the
production on an opsonizing molecule.
*Opsonized cells are usually eliminated in
spleen – splenectomy may be beneficial
Examples:
*hemolytic anemia (warm type- Abs destroy
RBCs at body temp)
*thrombocytopenia
*ABO incompatibility
*erythroblastosis fetalis
- Complement / Fc R mediated INFLAMMATION
The antibodies bind to cell
surface antigens and activate the
complement system through the
classical pathway – recruit
neutrophils and macrophages
another example: acute
rheumatic fever. - Antibody mediated cell DYSFUNCTION
The antibodies bind to cell surface
antigens, thus block the binding site
of their normal ligand and interfere
with signal transduction of the cell.
Myasthenia gravis => antibodies are
directed against AchR of the motor
units, this inhibiting neuromuscular
transmission, which result in muscle
weakness.
Tissue reconstruction. Wound healing.
Cannot be accomplished by regeneration alone, but involves replacement of the
PROLIFERTAIVE CAPACITIES OF TISSUES
The ability of tissues to repair themselves is critically influenced by their intrinsic
proliferative capacity. Tissues of the body are divided to 3 groups:
* Labile (continuously dividing) tissues – cells are continuously replaced by
maturation of stem cells. Include hematopoietic cells in BM and majority of
surface epithelia (skin, oral cavity, vagina ,cervix, ducts of exocrine organs, GI
and urinary tract)
* Stable tissues- minimal replacative activity in normal state, yet can
proliferate in response to injury/loss of tissue mass. Can reconstruct
parenchyma of liver, kidney and pancreas
* Permanent tissues – cells of these tissues are permanently differentiated and
nonproliferative, such as neurons and cardiac muscle.
REPAIR BY CONNECTIVE TISSUE
non-regenerated cells with CT
# Stages of repair:
» Repair begins within 24 hours of injury by emigration of fibroblasts and
their induction, as well as endothelial cell proliferation.
» 3-5 days: granulation tissue is apparent
» Granulation tissue accumulates CT matrix, resulting in scar formation.
# There are 4 components of CT repair:
1) Angiogenesis – formation of new blood vessels; endothelial precursor
cells migrate from bone marrow to areas of injury.
2) Migration and proliferation of fibroblasts.
3) Scar formation – deposition of CT – together with vassels and leukocytes
is called granulation tissue.
4) Maturation and reorganization of the fibrous tissue.
ANGIOGENESIS (topic 41)
# Steps of blood vessel formation:
» Vasodilation by NO and permeability of existing blood vessels by VEGF
(vascular endothelial growth factor).
» Migration of endothelial cells to the site of injury.
» Proliferation and remodeling of endothelial cells => tube formation.
» Recruitment of pericytes and smooth muscle cells to form mature vessel.
# Newly formed vessel is leaky during angiogenesis since the interendothelial
junctions are not completely formed, and because VEGF increases permeability.
# Structural ECM proteins participate in the process by interactions with
endothelial cells through integrin receptors.
ACTIVATION OF FIBROBLASTS AND DEPOSITION OF CT
# Scar formation (deposition of CT) occurs in 2 steps:
1) Migration of fibroblasts into the site of injury and their proliferation
there.
2) Deposition of ECM produced by these cells.
# The recruitment and stimulation of fibroblasts are driven by growth factors:
» PDGF – platelet derived growth factor; promotes proliferation of
fibroblasts and smooth muscle cells.
» FGF2 – fibroblast growth factor.
» TGFβ – transforming growth factor; controls proliferation and
differentiation.
# Macrophages are important cellular components of granulation tissue that clear
the tissue debris, and also secrete mediators that induce fibroblast proliferation
and ECM production
ECM DEPOSITION
# Collagen synthesis by fibroblasts at day 3-5 from the onset of injury.
# The same GFs that induce fibroblasts proliferation, mediate collagen synthesis.
# Net collagen accumulation depends on increased synthesis along diminished
degradation of collagen.
# The granulation tissue evolves into a scar composed of inactive, spindle-shaped
fibroblasts, dense collagen and ECM components.
# As the scar matures, there is progressive vascular regression, which transforms
the vascularized granulation tissue into a pale, avascularized scar.
TISSUE REMODELING
# Transition from granulation tissue into scar tissue involves a shift in composition
of the ECM.
# Collagen and ECM components are degraded by metalloproteins (MMPs) that
are dependent on zinc ions for their activity.
# MMPs are produced by many cell types => fibroblasts, macrophages,
neutrophils.
! Production is inhibited by TGFβ or by steroids.
WOUND HEALING
# Involves both epithelial regeneration and the formation of c. tissue scar.
# Based on the nature of the wound, healing can occur by 1st or 2nd intention.
HEALING BY FIRST INTENTION => clean, uninfected surgical incision
# Incision causes only minor disruption of epithelial basement membrane
continuity, and death of relatively few epithelial and c. tissue cells => epithelial
regeneration predominates over fibrosis => small scar is formed.
# Day 1
Incision is filled with fibrin-clotted blood, followed by infiltration of
neutrophils.
Increased mitotic activity is seen in basal cells at the cut edge of the
epidermis.
# Day 2
Epithelial cells from both edges begin to migrate and proliferate along the
dermis, depositing basement membrane components as they go.
The cells meet in the midline, giving a thin, continuous epithelial layer.
# Day 3
Neutrophils are replaced by macrophages.
The granulation tissue invades the incision space.
Collagen fibers are vertically oriented => DO NOT bridge over the incision.
Proliferation of epithelial cells continues => thickened epidermal covering.
# Day 5
Maximal blood vessel formation (neovascularization).
Granulation tissue fills the incisial space.
Collagen fibers start to bridge the incision.
Epidermis recovers its normal thickness.
# Week 2
Continued collagen accumulation and fibroblast proliferation.
Diminish of WBC infiltration, edema and vascularity.
Increased collagen deposition and regression of vascular channels.
# Week 4
The scar comprises cellular c. tissue devoid of inflammatory cells, and
covered by normal epidermis.
HEALING BY SECOND INTENTION => tissue loss is more extensive (large wound,
abscess, ulceration, ischemic necross)
# The inflammatory reaction is more intense => necrotic exudate
# Abundant development of granulation tissue
# Wound contraction by action of myofibroblasts.
# Differences between 1st and 2nd intention:
1) At the surface of the wound, a larger clot will be formed, rich in fibrin
and fibronectin.
2) Intense inflammation due to greater volume of necrotic debris, exudate
and fibrin that must be removed.
3) Larger amount of granulation tissue is formed.
4) 2
nd intention involves wound contraction, due to myofibroblasts
WOUND STRENGTH
# Sutures give wounds up to 70% of the strength of unwounded skin due to their
location.
# When sutures are removed, the wound strength is 10% of the strength of
unwounded skin, but increases rapidly as wound healing continues.
# The recovery of tensile strength results from collagen synthesis exceeding its
degradation, and from structural modifications of collagen.
# Wound strength reaches up to 70%-80% of the strength of unwounded skin.
Outcomes of acute inflammation, abscess formation. Morphologic patterns of chronic inflammation.
Granulomatous inflammation
Although the consequences of acute inflammation are modified by the nature and intensity
of the injury, the site and tissue affected, and the ability of the host to mount a response,
acute inflammation generally has one of three outcomes:
1. Resolution
» When injury is limited with minimal damage, and the tissue is capable of
replacing irreversibly injured cells, the outcome is restoration of the tissue to
normal structure and function.
» Termination of acute inflammation has to occur in order for resolution to take
place:
*Decay (short half-life) or enzymatic degradation of chemical mediators.
*Normalization of vascular permeability.
*Cessation of leukocyte emigration with subsequent death (by apoptosis) of
extravasated neutrophils.
*Leukocytes produce inhibitory mediators => limit inflammation reaction.
*Lymphatic drainage and macrophage ingestion clear debris of necrotic cells, edema
fluid, inflammatory cells etc.
» Leukocyte secrete cytokines that initiate repair process –
*blood vessels grow into injured tissue to supply nutrients
*fibroblasts lay down collagen to fill defects
*residual tissue cells proliferate to restore structural integrity
2. Scarring (fibrosis)
» Occurs after substantial tissue destruction.
» The tissue is not able to regenerate itself.
» Extensive CT deposition occurs in attempt to heal damage or as consequence
of chronic inflammation.
» Outcome is fibrosis
3. Chronic inflammation
Inflammation of prolonged duration (weeks to years) in which continuing
inflammation, tissue injury, and healing, often by fibrosis, proceed simultaneously.
» Occurs if:
♥Persistent infections by microbes -microbes which are hard to eradicate like
mycobacterium tuberculosis
♥Prolonged exposure to toxic agents – non-degradable exogenous agents
(silica particles→silicosis), or endogenous (cholesterol crystals→atherosclerosis).
♥Hypersensitivity diseases – caused by excessive and inappropriate activation
of the immune system.
» May be followed by normal restoration/scarring
» Characterized by infiltration of mononuclear cells, consist of macrophages,
lymphocytes (both T and B), and plasma cells.
» Mediated by cytokines produced by macrophages (TNF, IL-1) and by
lymphocytes (mainly T cells => INFγ).
» Often includes proliferation of fibroblasts and new blood vessels, with resultant
fibrosis and disturbance of architecture.
CHRONIC INFLAMMATION
A circumscribed tiny lesion (1mm), characterized by aggregations of activated
macrophages with scattered lymphocytes.
It is a protective defense mechanism of the body which leads to tissue destruction.
» Granulomas are formed as a response of:
! Persistant T-cell response to certain microbes (TB/fungi). T-cell
derived cytokines are responsible for chronic macrophage activation
! Immune mediated disease (chron)
! Disease of unknown etiology – sarcoidosis, foreign body
granulomas
Macrophage engulfs a pathogen and transports it to the lymph node where it presents it to
a T helper cell → the T helper cell releases the following cytokines:
*IL-1 &IL-2: T cell proliferation
*TNF-α: fibroblast proliferation (fibrosis)
*IFN-ɤ: macrophage activation → macrophage becomes epitheloid cell → epitheloid cells
group together to form multinucleated giant cells
* multinucleated giant cells= Langerhans cells in TB
# Morphology of chronic inflammation:
» Epitheloid cells in granulomas => pink granular
cytoplasm with indistinct cell boundaries.
» Aggregations of epitheloid macrophages are
surrounded by a collar of lymphocytes, which
secrete cytokines that continuously activate macrophages.
» Older granulomas may have a rim of fibroblasts and CT
» Multinucleated giant cells (40-50μm) can be found in granulomas, consist of
large mass of cytoplasm and many nuclei.
! They are derived from the fusion of over 20 macrophages.
» In granulomas that are associated with certain infectious organisms, hypoxia
and free radical injuries lead to a central zone of necrosis, with a granular
cheesy appearance => CASEOUS NECROSIS
» The granulomas associated with Crohn disease, sarcoidosis, and foreign body
reactions tend to not have necrotic centers and are said to be “noncaseating.”
» Microscopically => amorphous, structureless, granular debris with complete
loss of cellular details.
Morphologic patterns in acute inflammation.
Outpouring of watery, protein-poor fluid = transudate.
SEROUS INFLAMMATION
# Fluid derived from:
*serum
*secretions of mesothelial cells lining serous cavities (peritoneum, pericardium, pleura).
* Fluid in a serous cavity is called effusion
# Example: skin blister – fluid accumulates beneath or within the epidermis.
FIBROUS INFLAMMATION
# A consequence of more serious injuries
# Greater vascular permeability → larger molecules, such as fibrinogen, cross the
endothelial barrier.
# Fibrinous exudate => characteristic of inflammation in the lining of body cavities
(meninges, pericardium, pleura).
# The fibrinous exudate may undergo degradation by fibrinolysis, and cell debris are
removed by macrophages → RESOLUTION (restoration of normal tissue structure).
# Failure to completely remove fibrin → ORGANIZATION (replacement by ingrowth of
fibroblasts and blood vessels) → scar tissue formation
# Example: organization of fibrinous pericardial exudate results in fibrous scar tissue that
obliterates the pericardial space and restricts myocardial function.
PURULENT/SUPPURATIVE INFLAMMATION
# Characterized by presence of pus (purulent exudate), containing neutrophils, fibrin,
necrotic cells, edema fluid, cell debris and bacteria.
# Organisms that are more likely to induce pus formation are called pyogenic
(staphylococci).
# Abscess – focal collections of pus caused by seeding of pyogenic organisms into the
tissue; usually composed of central necrotic region and a peripheral region of preserved
neutrophils, surrounded by dilated vessels and fibroblastic proliferation.
# With time abscess will be replaced by CT.
# Usual outcome: scarring
ULCERATIVE INFLAMMATION
# Local defect on the surface of an organ, produced by necrosis of cells and shedding of
inflammatory necrotic tissue.
# Most commonly seen in:
» Inflammatory necrosis of mucosa of the mouth, stomach, intestine and
urogenital tract.
» Tissue necrosis and subcutaneous inflammation of lower extremities in older
patients who have circulatory disturbances.
# Can be acute or chronic:
» Acute – intense PMN infiltration and vascular dilation in the margins of the
defect.
» Chronic – margins and base of the ulcer develop scarring with accumulation of
lymphocytes, macrophages and plasma cells.
Acute inflammation- cellular and vascular changes.
Stimuli for acute inflammation: mnemonic: HIT FT
ACUTE INFLAMMATION
A protective response intended to:
*eliminate the initial cause of cell injury (microbes f.ex)
*eliminate necrotic cells and tissues resulting from the original insult
Side effect- injury of normal tissues.
Acute inflammation is rapid in onset and of short duration, lasting from a few minutes to as
long as a few days, and is characterized by fluid and plasma protein exudation and a
predominantly neutrophilic leukocyte accumulation.
5 cardinal signs:
heat (calor), redness (rubor), swelling (tumor), pain (dolor) and loss of function (functio laesa).
1) Infections by pathogens – bacteria, viruses, fungi, parasites.
2) Trauma – thermal injury (burn), irradiation, toxic chemicals..
3) Tissue necrosis- like MI (ischemia)
4) Foreign bodies- sutures..
5) Hypersensitivity reactions
Acute inflammation has two major components:
1. Vascular changes
♥Changes in vascular caliber and flow (vasodilation)
Short lasting vasoconstriction (few seconds), then arteriolar vasodilation → increased local
blood flow → fluid moves to extravascular tissues (transudate) → [RBCs]↑→ viscosity↑ →
flow↓→ stasis → margination (accumulation of leukocytes, mainly neutrophils, along the
endothelial wall).
♥Increased vascular permeabilit
Immediate transient response:
Contraction of endothelial cells- by chemical mediators (histamine, bradykinin and leukotrienes)
Then, TNF and IL-1 cause further retraction of the endothelium due to changes in the
cytoskeleton.
Also Integrins!!! They induce signaling cascade → changes in cytoskeleton
*Immediate sustained response:
Direct endothelial injury- direct injury to endothelial cells is usually seen after severe injuries
(e.g., burns, microbes, toxins..).
In most cases leakage begins immediately after the injury and persists for several hours or days
until the damaged vessels are thrombosed or repaired.
Endothelial injury due to leukocytes- may occur as a consequence of leukocyte accumulation
along the vessel wall (activated leukocytes release many toxic mediators).
Transcytosis-VEGF (vascular endothelial growth factor) induces channel formation (fusion of
intracellular vesicles) → increased transport of fluids and proteins through channels
Leakage from renewed blood vessels
!!All of the mentioned mechanisms will enable fluid rich in cells and proteins (exudate) to exit
from the blood vessel into the injured tissue, inducing edema.
♥Increased adhesion of leukocytes
Expression of selectins and integrins to promote extravasation.
- Cellular events
Recruitment and activation of leukocytes (mainly neutrophils (PMN), also macrophages..) →
emigration from the vascular lumen to the extravascular space and accumulation in the focus of
injury.
Free floating
↓
Margination and rolling- Macrophages recognize pathogen → secrete IL-1&TNF) →
endothelium starts expressing E selectin receptors
Histamine, thrombin.. → endothelium starts expressing P selectin receptors
E&P selectin receptors bind to L selectins (selectin ligands), which are expresses constitutively on
leukocytes.
↓
Firm adhesion- endothelium starts expressing integrin ligands mainly ICAM, VCAM (due to
IL-1, TNF) which bind to integrin receptors (LFA-1) on leukocytes.
↓
Extravasation (diapedesis)
Mediated by CD31 (PECAM-1), on both leukocytes and endothelium.
Leukocytes squeeze between cells at intercellular junctions, through the basement membrane
(by secretion of collagenases).
↓
Invasion (chemotaxis)
Leukocytes migrate toward the site of inflammation along a chemical gradient of chemokines
(bacterial products, cytokines, components of complement sys – C5)
Leukocyte activation
Once leukocytes have been recruited to the site of infection or tissue necrosis, they must be
activated to perform their functions.
Stimuli for activation include microbes, products of necrotic cells, and several mediators.
Leukocytes use various receptors to sense these, inducing a number of responses:
♥Phagocytosis
*Recognition and attachment
*Engulfment
♥Intracellular destruction of phagocytosed microbes and dead cellsin phagolysosomes containing reactive oxygen and nitrogen species and lysosomal enzymes.
♥Liberation of substances that destroy extracellular microbes and dead tissues by NETosisa framework of nuclear chromatin with embedded antimicrobial peptides and enzymes
which prevents the spread of the microbes by trapping them.
♥Amplification of the inflammatory reaction- by production of mediators like arachidonic acid
metabolites and cytokines, recruiting and activating more leukocytes
*Leukocytes also cause injury to normal cells.
↓
Termination
# Decay (short half-life) or enzymatic degradation of chemical mediators.
# Normalization of vascular permeability.
# Cessation of leukocyte emigration with subsequent death (by apoptosis) of extravasated
neutrophils.
# Leukocytes produce inhibitory mediators => limit inflammation reaction.
# Lymphatic drainage and macrophage ingestion clear debris of necrotic cells, edema fluid,
inflammatory cells etc.
*Recognition of microbes, necrotic cells and foreign substances are accomplished by PRRs
MEDIATORS OF INFLAMMATION
# Vasoactive amines
Histamine => permeability , epithelial cells contraction
Serotonin => similar to histamine, derived from platelets
# Amino acids metabolites
COX pathway => thromboxane A2 – vasoconstrictor, platelet aggregator;
prostaglandins – vasodilator, platelet inhibitor
LOX pathway => leukotrienes
# Cytokines
Soluble proteins, signaling molecules
Macrophages secrete TNF, IL-1
# Kinin system
Factor XII links kinin, coagulation, plasminogen, complement
# Complement system
C3a and C5a => anaphylatoxins – mediate degranulation
C3b => opsonization
The definition and causes of shock. Morphological and functional changes.
Non-progressive stage = compensatory mechanisms
CATEGORIES OF SHOCK
1. Cardiogenic shock – due to severe CO↓ (failure of pump in LV).
Caused by:
➔ Myocardial infarction
➔ Ventricular arrhythmias
➔ Cardiac tamponade- fluid in the pericardium
builds up, resulting in compression of the heart.
➔ Outflow obstruction
- Hypovolemic shock – results from loss of blood or plasma volume.
Caused by:
➔ Hemorrhage
➔ Severe burns
➔ Trauma
➔ Vomit, diarrhea
- Vasodilative shock-
♥Septic shock – caused by microbial infection, usually G(+) followed by G(-) and fungi.
♥Neurogenic shock – anesthetic accident or spinal injury => loss of vascular tone.
♥Anaphylactic shock – systemic vasodilation and increased vascular permeability caused by
type I hypersensitivity reaction (IgE).
STAGES OF SHOCK
Body can still compensate for the loss of blood and decreased MAP by:
*short term changes: SNS↑ → CO=HR↑∙SV → CO↑ → MAP↑
*long term changes: RAS↑, ADH↑, ANP↓(volume↑)
# Progressive stage – compensatory mechanisms are no longer adequate.
» Anaerobic metabolism → lactic acidosis AND not enough ATP
» Confusion, consciousness
# Irreversible stage
» Tissue and organ damage cannot be repaired => death
» NO increased synthesis worsen myocardial contraction
» Lysosomal enzyme leakage
MORPHOLOGY
# Although any organ can be affected, brain, heart, kidneys, adrenals and GI tract are
most commonly involved.
Tissue changes occur as a result of hypoxic cell injury.
Brain => ischemic encephalopathy
Liver => fatty change, nutmeg liver (liver dysfunction due to venous congestion)
Kidney => tubular ischemic injury – electrolyte imbalance, fibrin thrombi
Adrenals => cortical cell lipid depletion – decrease in cortical production, lead to
decreased perfusion
GI => focal mucosal hemorrhage and necrosis
Heart => areas of ischemic coagulative necrosis
*Except for neuronal and cardiomyocyte loss, affected tissues can recover
completely if the patient survives.
Embolism types and consequences.
An intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant
from its point of origin.
The vast majority of emboli derive from a dislodged thrombus—hence the term
thromboembolism. Less common types of emboli include fat droplets, bubbles of air or
nitrogen, atherosclerotic debris (cholesterol emboli), tumor fragments, bits of bone marrow,
and amniotic fluid.
Inevitably, emboli lodge in vessels too small to permit further passage, resulting in partial
or complete vascular occlusion; depending on the site of origin, emboli can lodge anywhere
in the vascular tree. The primary consequence of systemic embolization is ischemic necrosis
(infarction) of downstream tissues, while embolization in the pulmonary circulation leads to
hypoxia, hypotension, and right-sided heart failure.
TYPES OF EMBOLISM
♥ Pulmonary thromboembolism
» Originates from DVT, above the knee level.
» Passes through the right side of the heart into the pulmonary circulation.
» Depending on size, may cause the occlusion of:
» Most pulmonary emboli (60% to 80%) are small and clinically silent, but a large
embolus that blocks a major pulmonary artery can cause sudden death.
➔ Main pulmonary artery
➔ Impact across the bifurcation of right and
left pulmonary arteries => saddle embolus
➔ arterioles
» Most pulmonary emboli (60% to 80%) are small and clinically silent, but a large
embolus that blocks a major pulmonary artery can cause sudden death.
» Consequences of occlusion:
1. Effect on the cardiovascular system:
*Left side of the heart will also be affected:
- Effect on lungs:
→ respiratory alkalosis
*Rarely, an embolus passes through an atrial or ventricular defect and enters the systemic
circulation (paradoxical embolism).
♥ Systemic thromboembolism
» Emboli in the systemic circulation, most of them arise from intracardial mural
thrombi.
» Most associated with left ventricular wall infarcts.
» The major sites for embolization are lower extremities and CNS, and to lesser
extent the kidneys, intestine and spleen.
♥ Fat embolism
» Caused by fractures of long bones (contain fatty marrow), or by soft tissue
trauma.
» Involves
*mechanical obstruction
Occlude pulmonary and cerebral vasculature – directly and by platelet
aggregation
*biochemical injury
rupture of marrow vasculature → fat enters circulation → FFA released from
the fat globules → local toxic injury to endothelium.
» Fat embolism syndrome (10%):
- Pulmonary insufficiency
- Neurologic symptoms
- Anemia
- Thrombocytopenia
=>
Appear after 1-3 days after injury with sudden onset of
tachypnea (rapid breathing), dyspnea (shortness of
breathing), tachycardia (rapid HR).
♥ Gas (air) embolism
» Gas bubbles in circulation physically obstruct vascular flow.
» Air => 100ml are required to produce clinical effects, caused by penetrating
chest injury or during obstetric procedures.
» Nitrogen (decompression sickness) => occurs when deep sea divers ascend
rapidly, thus exposed to sudden change in atmospheric pressure.
when air is breathed in high pressure, increased amounts of gas (mainly
nitrogen) become soluble and dissolve on blood; if sudden pressure change
occurs, insoluble nitrogen bubbles are formed.
♥ Amniotic fluid embolism
» An uncommon, grave complication of labor and the immediate postpartum
period.
» The mortality rate approaches 80%, making it the most common cause of
maternal death in the developed world.
» Escape of amniotic fluid into maternal circulation. Amniotic fluid contains large
amount of TF, and may induce coagulation cascade (causes DIC).
» Sudden severe dyspnea (shortness of breath), cyanosis (bluish or purplish
discoloration of the skin or mucous membranes due to low oxygen
saturation) and hypotensive shock.
» Pulmonary edema develops.
Thrombogenesis. Morphology of thrombi. Fate of the thrombus. Disseminated intravascular coagulation.
The pathologic form of hemostasis, involves the formation of an intravascular blood
THROMBOSIS
clot (thrombus) in an uninjured vessel, or thrombotic occlusion of a vessel after
relatively minor injury.
The three risk factors of thrombosis (Virchow’s triad):
➔ Endothelial injury
➔ Stasis/turbulence of blood flow
➔ Blood hypercoagulability
# Endothelium –
Injured endothelium will not be able to:
*Be a physical barrier, separating the blood from the subendothelial collagen (VWF
comes in contact with collagen it undergoes a conformational change, enabling it to
bind PLTs) and underlying TF (binds and activates factor VII, forming the extrinsic
tenase complex).
*Release substances that have an antithrombotic effect: NO, PGI2, ecto-ADPase (ADP
needed for recruitment)
Release substances that have an anticoagulant effect: TFPI, TPA, HLm.
*Endothel may be dysfunctional (not only damaged) and create an imbalance between the
anticoagulant and procoagulant activities of the endothelium may induce thrombosis =>
hypertension, bacterial endotoxins, vasculitis.
# Turbulence – any alterations in the laminar blood flow that causes endothelial
injury/dysfunction, as well as forming countercurrents and local pockets of stasis (the
flow stops allowing platelets and leukocytes to come in contact with endothel) =>
▪ aneurysm (arterial dilation)
▪ acute myocardial infraction (blood flow decreases or stops to a part of the
heart)
▪ bed-care patients
▪ hyper-viscosity syndromes (polycythemia)
▪ sickle cell anemia
▪ ulcerated atherosclerosis
▪ mitral valve stenosis (after RA) results in atrial dilation
# Hypercoagulability – when the balance between the pro and anticoagulant proteins is
upset.
Primary => inherited
▪ Factor V Leiden
▪ Less common, mutations in anticoagulant genes of AT III, proteins C&S.
Secondary => acquired
▪ Heparin-induced thrombocytopenia (HIT): autoantibodies that bind
complexes of heparin and platelets (platelet factor-4). Platelet binding
activates them and agg them.
▪ Antiphospholipid antibody syndrome: manifestations are recurrent
thrombosis and miscarriages and thrombocytopenia. Caused by
antibodies to phospholipids of cell membrane which induce endothel
injury. Some patients may have secondary Antiphospholipid syndrome
due to another autoimmune disease (SLE), patients without an underlying
autoimmune disease are classified as primary.
▪ Oral contraceptives: contain estrogen, stimulate the liver to produce
plasma proteins, including coagulation factors and reduced syn of AT III;
upon smoking, the contained compounds may induce endothelial wall
injury => collagen exposure => promotion of coagulation cascade.
▪ Age: increased platelet agg and PGI2
MORPHOLOGY OF THROMBI
# Thrombi can develop anywhere in the cardiovascular system.
# The size and shape of the thrombus depends on the site of origin and the cause:
Arterial/cardiac thrombi – begin at the sites of endothelial injury or turbulence.
Venous thrombi – occur at sites of stasis.
# Thrombi are attached to the vascular surface:
Arterial – grows in a retrograde direction
from the point of attachment.
Venous – extends in the direction of blood
flow.
The propagation portion of the thrombus tends to be poorly attached to the surface,
and therefore prone to fragmentation, generating an embolus.
# Lines of Zahn – laminations on the thrombi (gross or microscopical), representing pale
platelet & fibrin layers alternating with darker erythrocyte-rich layers => help
distinguish antemortem thrombosis from postmortem state (no laminations after
death). Also, postmortem blood clots are not attached to the vessel wall.
# Types of thrombi:
» Mural thrombi – occur in heart chambers or aortic lumen, caused by abnormal
myocardial contraction1
or endomyocardial injury2
. Non-occlusive.
» Arterial thrombi – occlusive, develop due to endothelial injury. Composed of
mainly PLT but also fibrin, erythrocytes and leukocytes.
» Venous thrombi (phlebothrombosis) – occlusive, caused by activation of
coagulation cascade and platelets (minor role), contain more erythrocytes and
are called red/stasis thrombi.
» Postmortem clots – gelatinous composition, with a dark red portion (red cells
have settles by gravity), and a yellow “chicken fat” portion; usually, they are not
attached to the vessel surface.
» Vegetations – thrombi on heart valves due to damage caused by bacterial or
fungal infections3
.
*Venous and postmortem thrombi are sometimes mixed but venous thrombi are firm,
focally attached to the vessel wall and contain gray strands of deposited fibrin.
FATE OF THE THROMBUS
# Propagation – thrombus enlarges due to accumulation of more platelets and fibrin
increasing odds of obstruction/embolism.
# Embolization – the thrombi are fragmented and transported elsewhere in the
vasculature.
# Dissolution – thrombi are removed by fibrinolytic activity. In older thrombi, lysis is
inefficient.
# Organization and recanalization – older thrombi become organized by the ingrowth of
endothelial cells, smooth muscle cell and fibroblasts. In time, capillary channels are
formed reestablishing the continuity of the lumen.
recanalization may occur without organization due to enzymatic digestion due to
entrapped WBC.
DISSEMINATED INTRAVASCULAR COAGULATION
» DIC is the sudden onset of widespread thrombosis within the microcirculation.
The thrombi are generally microscopic in size, yet so numerous that they often
lead to ischemia, particularly in the brain, lungs, heart, and kidneys and to
hemolysis (RBCs are traumatized while passing through vessels narrowed by
thrombi).
To complicate matters, the widespread microvascular thrombosis consumes
PLT & clotting factors (hence the synonym consumption coagulopathy). Thus,
other parts of the body start to bleed with even the slightest damage to the BV
walls.
*DIC is NOT a primary disease but rather a potential complication of numerous
conditions associated with widespread activation of thrombin, ranging from
obstetric complications (The release of TF or thromboplastic substances into the
circulation from the placenta) to advanced malignancy.
In G(-) and G(+) sepsis, endo- or exotoxins cause increased synthesis and release of TF
from monocytes release IL-1 and TNF, both increase the expression of TF and decrease
the expression of thrombomodulin (anticoagulator, activates protein C) => activation
of extrinsic coagulation pathway.
Hyperemia and congestion. Hemorrhage.
Active process of increased blood flow to different tissues due to arteriolar vasodilation,
The terms hyperemia and congestion both indicate a local increased volume of blood in a
tissue.
HYPEREMIA
as occurs in inflammation/exercising skeletal muscle.
# Redder than normal due to accumulation of oxygenated blood
# Hyperemia occurs when a tissue increases its activity, thus utilizing certain substances
and releasing metabolites => pO2 , pCO2 , pH , temperature , utilization of glucose,
FAs and other nutrients.
# The presence of certain metabolites (CO2, adenosine) will initiate vasodilation in order
to increase the blood flow; thus, waste products are cleared from the tissue, and new
blood, rich in oxygen and nutrients, supplies the tissue.
# Vasodilation can also be caused by
➔ Sympathetic tone
➔ Vasodilators (histamine, bradykinin)
➔ inflammation
CONGESTION
# Passive process refers to impaired venous flow out of the tissue, usually occurs when
the heart is unable to provide sufficient pump action to distribute the blood
(=>systemic), or when there is an obstruction of the vein (=>local).
# The tissue becomes cyanotic due to accumulation of deoxygenated blood.
# Congestion can be acute or chronic.
# In chronic congestion hypoxia may lead to parenchymal death and 20
tissue fibrosis.
Intravascular pressure may cause edema/vessel rupture – focal hemorrhage
HEMORRHAGE
# Extravasation of blood from the vessels into the extravascular space.
# Caused by:
➔ Trauma (most common cause)
➔ Atherosclerosis
➔ Inflammatory or neoplastic erosion of vessel wall
➔ Chronic congestion
Hemorrhage can be external to the tissue or confined within it (hematoma).
# Sizes of hemorrhages:
Petechia => minute (1-2 mm) hemorrhage into skin, mucous membrane or serosal
surface, associated with thrombocytopenia, defective platelet function and loss of
vascular wall support – vitamin C deficiency.
Purpura => 3-5 mm, can occur with trauma, vasculitis, vascular fragility.
Ecchymoses => 1-2 cm subcutaneous hematoma; RBCs are phagocytosed and
degraded by macrophages: Hb (red-blue) bilirubin (blue-green)
hemosiderin (golden brown).
# Large accumulations of blood in a body cavity are named according to the cavity:
hemothorax, hemopericardium, hemoperitoneum, hemarthrosis (joints).
# Patients with extensive hemorrhage may develop jaundice due to [bilirubin] .
# Recurrent external bleedings (ulcers, menstruation) can lead to iron loss and to iron
deficiency anemia.
# Blood loss of over 20% may cause hemorrhagic shock
Edema.
The abnormal accumulation of fluids in the interstitium, characterized by tissue
EDEMA
swelling.
# Extravascular fluids can accumulate in body cavities (hydrothorax,
hydropericardiun, hydroperitoneum/ascites).
# Ansarca – severe edema, selling of subcutaneous tissue and fluid accumulation in
body cavities
# Edematous fluid can be either transudate or exudates:
» Trabsudate – results from increased hydrostatic or decreased oncotic
pressure of plasma; non-inflammatory fluid with low protein content,
specific gravity<1.012.
» Exudates – results from increased permeability of blood vessels caused by
inflammation; viscous, yellowish-white fluid with high protein content
and inflammatory leukocytes, specific gravity>1.012.
EDEMA FORMATION
Increased hydrostatic pressure
Systemic edema mostly due to congestive heart failure :
CO => renal perfusion => activation of RAS => retention of Na+
, water =>
heart cannot increase CO (due to failure) => extra fluid will increase
hydrostatic pressure in veins => edema. Treated with anti-aldosteron/diuretics
Venous obstruction (example: thrombosis) will result in local edema distal to
the site of thrombus (Pc => absorption is impaired).
Decreased plasma oncotic pressure
Albumin is the serum protein most responsible for maintaining intravascular
oncotic pressure.
Reduced synthesis of albumin/albumin is lost decreases oncotic pressure of the
plasma, which leads to net movement of fluid from the plasma into the
interstitium.
Causes of albumin loss
➔ Nephritic syndrome (glomerular permeability ).
➔ Diffuse liver diseases, such as cirrhosis (synthesis ).
➔ Protein malnutrition.
Reduced intravascular volume => same manifestations as congestive heart
failure (20
hyperaldosteronism, renal hypoperfusion)
Lymphatic obstruction
Impaired lymphatic drainage => localized lymphoedema.
Can be cause by
➔ Inflammatory or neoplastic obstruction (parasites =>
fibrosis of lymphatics and lymph nodes).
➔ Surgical removal of lymph nodes (as therapy for breast
cancer) => arm edema.
Na+
and water retention
Primary => associated with renal dysfunction.
Water accompany Na+
Increased hydrostatic pressure due to intravascular expansion
Decreased oncotic pressure (within the vessels)
Secondary => due to congestive heart failure.
MORPHOLOGY OF EDEMA
Microscopically => appears as a clearing and separation of ECM elements
with cell swelling.
Edema is most commonly encountered in subcutaneous tissues, lungs and
brain.
# Subcutaneous edema – in regions with high hydrostatic pressure.
» Dependent edema => a gravity-dependent distribution, also a prominent
feature of cardiac failure, appears mostly on legs.
» Edema due to renal dysfunction is more severe than cardiac edema, and
affects body parts equally.
» Pitting edema => finger pressure over edematous subcutaneous tissue
displaces the fluid and creates a finger-shape depression.
# Pulmonary edema – most frequently seen in left ventricular failure, with lungs
weigh 2-3 times their normal weight.
# Brain edema – may be localized to site of injury (infarct, abscess, neoplasm), or
generalized1
(encephalitis, obstruction of venous outflow).
Amyloidosis.
A condition in which misfolded proteins (usually have a beta pleated sheet
AMYLOIDOSIS
configuration), which are soluble in their normal configuration, aggregate and form
abnormal fibrils. These deposit in the extracellular space predominantly (tends to be
localized around BVs), causing tissue damage and functional compromise.
*Usually proteins are degraded
*IC- (proteasome pathway)
*EC- (macrophages)
# Amyloid – an insoluble fibrous protein, formed by aggregation of over 20 different
misfolded proteins, which has some characteristics of starch (amylase).
» Composed of non-branching fibrils, each has β-pleated sheet configuration.
» Amorphous eosinophilic appearance in H&E.
» Staining with Congo red dye will give apple-green birefringence coloration in
polarized light.
# They are made of 95% Fibrillar proteins which are bound to the rest 5% of P proteins
(PG, GAG (heparin/dermatan sulfate) and serum amyloid P component (SAP)).
3 distinct forms of amyloid proteins:
» AL protein (Amyloid Light-chain)
▪ Produced by plasma cells.
▪ Composed of immunoglobulin light chains (defective degradation of
light chain)
▪ Associated with some forms of monoclonal B-cell proliferation
(multiple myeloma).
» AA protein (Amyloid-Associated)
▪ Derived from a serum precursor SAA => serum amyloid-associated.
▪ SAA id synthesized in the liver, and increased during acute phase
response (under influence of IL-1, IL-6).
▪ Associated with chronic inflammatory disorders.
▪ Defective proteolysis of SAA leads to its aggregation as AA fibrils.
» Aβ amyloid
▪ Derived from TM GP amyloid precursor protein (APP)
▪ Found in cerebral lesions of Alzheimer disease
▪ Deposits in cerebral blood vessels
# Other proteins associated with amyloid deposits:
» Transthyretin (TTR) – related to familial amyloid polyneuropathies, deposits
in the heart of aged people
» β2-MG – component of MHC-I, identified as amyloid fibril subunit (Aβ2m) –
high cc in patoents with renal disease
- SYSTEMIC AMYLOIDOSIS
When the amyloids are deposited systemically. In this case, the damaged organs CANNOT
be removed and therefore must be transplanted!
A biopsy can be taken from the abdominal fat pad or from the mucosa of the rectum.
# Primary = associated with monoclonal plasma cell proliferation
» Plasma cell dyscrasias: overproduction of light chain → leakage to blood →
misfolding and aggregation → AL type amyloid → deposition into tissues.
» Most common form.
» Monoclonal plasma cell prolif (5-15% in patients with multiple myeloma)
» Syn of abnormal ampunt of Ig (monoclonal gammaopathy), producing M
protein.
» Plasma cells may also produce either the λ (lambda) or κ (kappa) light chains
=> BENCE JONES PROTEINS.
» Deposition of AL in kidneys, heart, PNS, GI tract. (?)
# Secondary = complication of an underlying chronic inflammatory process
» Inflammation → macrophages produce IL-1, IL-6 → SAA (acute phase protein)
is secreted by the liver → AA amyloid is derived from it.
» Deposition occurs due to association with:
▪ inflammatory condition tuberculosis, bronchiatitis, chronic
osteomyelitis
▪ autoimmune state – RA, bowel disease
▪ renal carcinoma, Hodgkin lymphoma
# Hemodialysis-associated
beta 2 microglobulin is a structural component of MHC-I, which isn’t filtered from
the blood during dialysis and is thus deposited in joints. - LOCALIZED AMYLOIDOSIS
Amyloid deposition is limited to a single organ => produce nodular masses.
Affects mainly the lungs, larynx, skin, urinary bladder and tongue.
# Senile cerebral
Plaques containing αβ amyloid which is derived from β amyloid precursor protein, located
on chromosome 21. This explains why individuals with down syndrome have Alzheimer’s at
a relatively young age (40).
Endocrine amyloidosis – amyloid deposits in certain endocrine tumors
# Medullary carcinoma of thyroid
Tumor derived from C cells → overproduction of calcitonin → amyloid is derived from
calcitonin and deposited in the tumor.
# Type II diabetes
Insulin resistance of tissues → overproduction of insulin by pancreas → burn out of
pancreas → amylin1 is a byproduct → deposits in the pancreas => interferes with insulin
sensing by ȕ FHOOV.
- HEREDITARY AMYLOIDOSIS
# Familial Mediterranean fever:
» Autosomal recessive
» Pyrin (a gene) inhibits the function of neutrophils → acute inflammation →
gain-of-function mutation – overproduction of IL-1→ SAA (acute phase
protein) is secreted by the liver → AA amyloid is derived from it.
» This condition is characterized by periodic attacks of fever accompanied by
inflammation of serosal membranes (peritoneum, pleura).
# Familial amyloidotic polyneurophathies:
» Autosomal dominant.
» Deposition of amyloid in the peripheral and autonomic nerves.
» Amyloid deposition – mutant TTR (transthyretin, a plasma protein).
# Senile systemic amyloidosis (amyloid of aging):
» Systemic deposition of amyloid in elderly people.
» Usually involves the heart.
» The amyloid is composed of normal TTR molecules.
MORPHOLOGY
# No distinctive pattern of organ distribution, but generalizations can be made.
When amyloid is accumulated (always in EC) in large amount, the organ is frequently
enlarged, with firm consistency and gray in color.
Major organs involved:
Kidneys : Most common and severe involvement.
- Abnormally large, pale, gray and firm.
- Deposition mainly in glomeruli.
Spleen : Enlarged (200-800 gr).
- Deposits are limited to the splenic follicles, but may affect
the splenic sinusoids and extend to the splenic pulp.
- Firm, pale, gray, waxy appearance.
Liver : - Massive enlargement, up to 9 kg.
- Deposits first appear in the space of Disse, then on hepatic
parenchyma and sinusoids.
Heart: Minimal to moderate enlargement.
- Gray-pink subendocardial elevations, mainly between
myocardial fibers
Other organs : Most commonly in adrenal, thyroid and pituitary.
- Starts at epithelial cells and progresses to parenchyma.
- No disturbance of function
Pigments (hemoglobin and non-hemoglobin derived)
EXOGENOUS PIGMENTS
Carbon: Phagocytosed by alveolar macrophages, and transported to the
lymph nodes (tracheobronchial)
Anthracosis – blackening of the lymph nodes and pulmonary
parenchyma.
Heavy accumulation may indicate emphysema (destruction of
tissue responsible for maintaining physical shape of the alveoli and
lungs), or fibroblastic reaction (coal workers’ pneumonia).
ENDOGENOUS PIGMENTS
Lipofuscin : Brownish-yellow, insoluble pigment, derived from peroxidation of
lipids of membranes.
Mostly accumulates in elderly people, mainly in the heart, liver and
brain.
Not harmful to the cell.
Indication for past free radical injury.
Brown atrophy – large amount of lipofucsin in atrophied tissue.
Melanin: Brown-black pigment, produced in melanocytes in epidermis by
tyrosinase enzyme.
Once synthesized, melanin is transferred to keratinocytes, which
accumulate it (also macrophages).
Serves as a screen against harmful UV radiation.
Sun tanning will cause increased pigmentation; albinism and
vitiligo will cause decreased pigmentation.
Bilirubin: Yellowish pigment, end product of heme degradation.
When accumulated, stains mucous membranes, sclera and organs
(under pathological conditions) => JAUNDICE
Hemosiderin :
Golden-yellow to brown pigment, derived from Hb and contains
iron.
Consists of aggregates of ferritin (hemosiderin granules)
Identified by Purssian blue staining
Local excess of iron => hemosiderin results from hemorrhage
(example: common bruise)
Colors of the bruise reflect metabolism of Hb:
- Red-blue: hemoglobin, as a result of RBCs lysis.
- Green-blue: Hb is catabolized by lysosomes to
billiverdin (green-blue) and billirubin,
- Golden-yellow: hemosiderin (the iron of Hb).
Hemosiderosis => when there is systemic overload of iron,
hemosiderin is deposited in many organs (first seen in liver, bone
marrow, spleen, and lymph nodes).
Occurs due to:
1) Increased absorption of dietary iron.
2) Impaired utilization of iron.
3) Hemolytic anemia.
4) Transfusions.
Hereditary hemosiderosis => mutation in Hfe gene (chromosome 6)
“bronzed diabetes” – occurs in micronuclear cirrhosis,
diabetes mellitus and skin pigmentation
Pathologic calcification
The abnormal deposition of Ca2+ salts together with small amounts of other minerals,
PATHOLOGIC CALCIFICATION
such as iron and Mg2+ in a tissue.
# Two forms of calcification exist:
1) Dystrophic calcification – occurs in the absence of Ca2+ derangement (normal
level of serum Ca2+).
2) Metastatic calcification – deposition of Ca2+ salts due to hypercalcemia.
DYSTROPHIC CALCIFICATION
# The calcification occurring in dying/dead cells as a response to cell injury. (common in
caseous necrosis, but occurs in all types of necrosis).
# Ca2+ levels in the serum are NOT elevated.
# Pathogenesis – formation of crystalline Ca2+-phosphate
Initiation: Extracellular – occurs in membrane-bound vesicles, accumulating
Ca2+ and phosphate, derived from degenerating cells.
Intracellular – occurs in the mitochondria of cells that have lost
their ability to regulate IC Ca2+
.
» Propagation of crystal formation depends on [Ca2+] and [PO4-] in the
extracellular space, presence of mineral inhibitors, and rate of collagenization.
# Seen in aortic valves (aortic stenosis) and atherosclerosis.
METASTATIC CALCIFICATION
# Occurs due to hypercalcemia that can be caused by:
» Endocrine dysfunction – increased secretion of PTH due to tumors.
» Bone destruction – due to increased turnover (Paget’s disease), immobilization,
and tumors1
.
» Vitamin D related disorders – intoxification (hypervitaminosis), sarcoidosis
(macrophages that activate vitamin D precursors).
» Renal failure – phosphate retention leads to secondary hyperparathyroidism.
» Excess Ca2+ intake.
# Morphology – occurs throughout the body, mainly affecting kidneys2
, lungs3 and gastric mucosa.
Accumulation of proteins, lipids and carbohydrates.
Inadequate removal of the substance that is produced in a normal or increased rate
ABNORMAL INTRACELLULAR ACCUMULATIONS
(example: fatty change in liver).
# Genetic or acquired defects in folding, packaging, transport or secretion of a normal or
abnormal endogenous substance.
# Accumulation of an exogenous substance since the cell lacks the enzymatic machinery
to degrade it, or the ability to transport it out of the cell.
LIPID ACCUMULATION (fatty change – steatosis)
# Any abnormal accumulation of TAGs within parenchymal cells of organs of fat
metabolism, mainly in the liver, can also be seen in the heart, kidney and skeletal
muscle.
# May be caused by: toxins, malnutrition, diabetes mellitus, obesity or anoxia.
# FFAs are usually transported into hepatocytes, where they:
» Esterified into TAGs.
» Converted into cholesterol or phospholipids.
» Oxidized into ketone bodies.
# TAGs exit hepatocytes by forming complexes with apolipoproteins, creating the
lipoprotein complexes that can enter circulation; defects at any stage of this process
result in lipid accumulation:
» Hepatotxins (alcohol)
Alter mitochondrial and sER function
Inhibit FA oxidation
CCl4/protein malnutrition => Decreased synthesis of apoproteins
» Anoxia (extreme hypoxia) => Total decrease in oxygen level
Inhibit FA oxidation
Morphology => Appears as clear vacuoles within parenchymal cells, Can be visualized by special staining
- Sudan IV/oil red O => far appears orange-red
- PAS => glycogen appears red-violet
Liver appears yellow in color, enlarged (3-6 kg), and soft & greasy in consistency.
# In the heart, lipid deposition can appear in two forms:
» Specific => zebra-like pattern of yellow myocardium, alternated by bands of
healthy, red-brown myocytes; usually as a result of prolonged, moderate
hypoxia (anemia).
» Uniformly affected myocytes => produced due to profound hypoxia.
Cholesterol:
» Important component of cell membrane.
» Ensures synthesis of steroids, bile acids and vitamin D.
» When there is cholesterol overload, macrophages phagocytose the lipids, and
become filled with small lipid vacuoles to form FOAM CELLS.
» Xanthomas => clusters of foamy macrophages found in sub epithelial c. tissue
of the skin or in tendons.
» Atherosclerosis => smooth muscle cells and macrophages within the intimal
layer of the aorta and large arteries are filled with lipid vacuoles,
Such cells have a foamy appearance (foam cells). Some of these fat-laden
cells may rupture, releasing lipids into the extracellular space.
» Cholesterolosis => This refers to the focal accumulations of
cholesterol-laden macrophages in the lamina propria of the gallbladder.
» Niemann-Pick disease, type C. This lysosomal storage disease is caused by mutations affecting an enzyme involved in cholesterol trafficking.
PROTEIN ACCUMULATION
# usually appear as eosinophilic droplets of abnormal proteins deposit primarily in
extracellular spaces
# In the kidney, proteins like albumin, which are filtered through the glomerulus, are
normally reabsorbed by pinocytosis in the proximal tubule. In disorders with heavy
protein leakage across the glomerular filter there is increased reabsorption of the
protein into vesicles, and the protein appears as pink hyaline droplets within the
cytoplasm of the tubular cell.
# Accumulation of newly synthesized immunoglobulins that may occur in the RER of
some plasma cells, forming rounded, eosinophilic Russell bodies.
# Liver – Mallory bodies (“alcoholic hyaline”) => eosinophilic cytoplasmic inclusion
(crystals) in hepatocytes, composed of aggregated intermediate filaments that are
resistant to degradation.
# α1-antitrypsin deficiency results in the buildup of partially folded intermediates, which
aggregate in the ER of the liver and are not secreted. The resultant deficiency of the
circulating enzyme causes emphysema.
# Brain – Alzheimer’s disease => neurofibrillary compounds of aggregated proteins,
containing microtubule-associated proteins and neurofilaments.
CARBOHYDRATES ACCUMULATION
# Excessive IC deposits of glycogen due to abnormalities in glucose or glycogen
metabolism.
# Glycogen masses appear as clear vacuoles within the cytoplasm. Staining with
PAS reaction imparts a rose-to-violet color to the glycogen
# Glycogen storage disease – enzymatic defects in the synthesis or breakdown of
glycogen, result in massive storage with secondary cell injury and death.
# In untreated diabetes mellitus, glycogen accumulates in renal tubules, hepatocytes,
cardiac myocytes and pancreatic B cells.
The morphological forms of necrosis
Morphology:
NECROSIS
A form of cell injury that results in the pathologic premature death of cells in the living
tissue, which may lead to the death of the organ.
This type of cell death is characterized by loss of membrane integrity and leakage of cellular
contents → elicit inflammation
Necrosis is mediated by the following processes:
» Protein denaturation – due to low pH formed by hypoxia-induced glycolysis.
» Disruption of the plasma membrane
» Enzymatic digestion –
*Autolysis: by intracellular enzymes, derived from lysosomes
*Heterolysis: by enzymes derived from extrinsic sources (the dying cells induce
an inflammatory reaction, attracting leukocytes which release enzymes).
» Cytoplasmic changes: increased eosinophilia (loss of basophilic RNA,
attachment of eosin to denatured proteins)
» Nuclear changes: basophilia of chromatin may fade (karyolysis), nucleus may
shrink and increased basophilia (pyknosis), nucleus may undergo
fragmentation (karyorrhexis)
» Necrotic cells may be replaced by myelin which will be
phagocytosed/degraded to FA. FA may be calcified.
ORMS OF NECROSIS
1. Coagulative necrosis
Ischemia→ infarction=necrosis
Red (hemorrhagic) infarct
*loosely organized organ
reentry of blood
White infarct
*arterial occlusion
» Characteristic of ischemic infarcts in all solid organs EXCEPT THE BRAIN
» Tissue cells are dead, but the architecture is preserved (for several days).
» Firm texture.
» Denaturation of proteins predominates (of both structural proteins and
enzymes => NO PROTEOLYSIS => eosinophilia (eosin binds to denatured
proteins).
» Eventually cells are digested by leukocytes, cellular debris removed by
phagocytes
Gangrenous necrosis
» Usually affects lower limbs, initiated due to loss of blood supply, secondary to
coagulative necrosis (particularly in diabetics).
» Wet gangrene – in moist tissues => when bacterial infection develops
coagulative necrosis is modified by the liquefactive action of the bacteria.
» Dry gangrene – in lower extremities => caused by coagulative necrosis without
liquefaction.
Liquefactive necrosis
» Characteristic of bacterial/fungal infections => stimulates the accumulation of
inflammatory cells => enzymes of leukocytes digest “liquify” the tissue.
» Hypoxic death of cells in CNS evokes liquefactive necrosis (microglial cells which
contain hydrolytic enzymes). Also seen in abscesses (neutrophils) &
pancreatitis.
» Dead cells are completely digested, resulting in the transformation of the tissue
into a liquid viscous mass.
» Loss of basophilia due to degradation of proteins and RNA.
» If the process was initiated by acute inflammation => pus formation.
Caseous necrosis
» The tissue appears white and friable “cheese-like” consistency, because of
fungal infection, but mainly because of mycobacterium tuberculosis.
» Tissue architecture is completely obliterated, has amorphous granular
appearance (cells are not completely digested), cellular outlines cannot be
distinguished.
» enclosed within a distinctive inflammatory border. This appearance is
characteristic of a focus of inflammation known as a granuloma.
Granulomatous reaction – the necrotic area is composed of cellular decries
enclosed by multinucleated giant cells (fused macrophages); may also contain
epithelial cells, T cells and fibroblasts.
Fat necrosis
» Necrotic adipose tissue, caused by the release of activated pancreatic lipases
from acinar cells and ducts into the pancreatic tissue => pancreatitis =>
leakage of pancreatic enzymes to the peritoneal cavity, liquefying the
membranes of fat cells in the peritoneum
» Digestion of TAGs (in cell membrane) => FFAs are released (trauma/lipase)
and combine with Ca2+ => formation of grossly visible chalky white areas
(SAPONIFICATION).
» Characteristic of: Trauma to fat (car accident f.ex.) and pancreatitis mediated
damage of peripancreatic fat.
Fibrinoid necrosis
» Usually seen in immune reactions involving blood vessels damage.
» Complexes of antigen-antibody are deposited on the wall of the vessel,
together with fibrin (leaked out of the vessel due to increased permeability),
resulting in a bright pink and amorphous appearance in H&E stains, called
“fibrinoid”.
» Malignant hypertension and vasculitis result in the leaking of proteins into the
vessel wall.
The mechanisms of irreversible hypoxic cellular injury. The morphology of hypoxic necrosis.
It is the net result of degradation action of enzymes on lethally injured cells.
HYPOXIC CELL INJURY
# Causes of hypoxic cell injury:
» Ischemia – diminished blood flow to a tissue, usually due to obstruction of
arterial blood.
» Diminished O2 carrying capacity because of anemia (reduction in number of
RBCs or Hb molecules) or CO poisoning (due to affinity of CO to Hb).
» Decreased perfusion – in CHF (congestive heart failure), shock, hypertension.
» Poor oxygenation of blood – in pulmonary diseases.
Hypoxic cell injury eventually results in membrane damage:
» Mitochondrial membrane damage – reduction in ATP production, and release
of pro-apoptotic enzymes to the cytosol.
» Plasma membrane damage – loss of osmotic balance, influx of fluids and ions,
loss of cellular contents.
» Lysosomal membrane damage – leakage of digestive enzymes into the
cytoplasm
Hypoxia → Mitochondrial damage
*Formation of high conduction channels “mit. Permeability transition pores” →
membrane potential lost →
failure of oxidative phosphorylation → ATP depletion AND formation of ROS
leakage of proapoptotic molecules to cytosol AND
Diffusion of cyt-C to cytosol → stimulation of caspases → apoptosis
Reactive oxygen species (ROS) are produced normally in cells during mitochondrial
respiration and energy generation, but they are degraded and removed by cellular defense
systems. When the production of ROS increases or the scavenging systems are ineffective,
the result is an excess of these free radicals, leading to a condition called oxidative stress.
Mitochondrial damage → ATP depletion
Hypoxia / toxins (cyanide) / disrupted ETC (mit damage)→ ATP depletion:
*Anaerobic glycolysis → decrease in glycogen stores and lactic acidosis → pH↓ →
chromatin clumping AND decreased enzymatic activity
*Na+/K+ pump failure→ IC Na+ ↑ → water retention → cell & ER swelling → loss of
microvilli and detachment of ribosomes → reduced protein synthesis
=> damage to cellular components by activation 2+ *Ca2+ pump failure → Increased IC Ca
of enzymes (proteases, caspases, phospholipases).
CELL DEATH
# Occurs when severe injury or prolonged stimulus are applied.
» Swelling of mitochondria and lysosome.
» Extensive damage to plasma membrane.
» Massive Ca2+ influx.
IC enzymes are released from necrotic cells into the circulation due to loss of
membrane integrity:
» Myocardial enzymes
AST – aspartate aminotransferase
LDH – lactate dehydrogenase
CK – creatine kinase
troponin
» Liver enzyme
Alanine aminotransferase
Alkaline phosphatase(bile)
Gamma glutamyl transferase
The vulnerability of cells to hypoxic injury varies among different cell types:
» Neurons – 3-5 minutes; purkinje cells of cerebellum & hippocampus are much
more sensitive.
» Myocardial and hepatic cells – 1-2 hours.
» Skeletal muscle cells – several hours.
MORPHOLOGY OF HYPOXIC NECROSIS
# Hypoxic necrotic cells show increased eosinophilia => eosin binds to denatured
cytoplasmic proteins, loss of basophilia due to lack of RNA in cytoplasm.
# The cell may have a more glassy, homogenous appearance due to loss of glycogen
particles.
# When enzymes have digested the cytoplasmic organelles, the cytoplasm becomes
vaculated.
# Dead cells may be replaced by large masses of phospholipids => myelin figures,
derived from damaged cellular membranes.
# Eventually, dead cells may become calcified.
# By electron microscopy, necrotic cells are characterized by:
» Discontinuous membranes (plasma, organelles).
» Mitochondrial dilation.
» Lysosomal disruption.
» Cytoplasmic myelin figures.
» Nuclear changes:
1) Pyknosis – nuclear shrinkage and increased basophilia due to DNA
condensation.
2) Karyorrhexis – fragmentation of pyknotic nucleus.
3) Karyolysis – fading of chromatin basophilia due to DNAse activity.
Degeneration: pathomechanism and morphology of reversible celullar injury (cellular swelling, fatty change)
IC changes:
CELL INJURY
Occurs when the adaptive capability of the cell is exceeded.
Within a certain limit, cell injury is reversible, but a severe or persistent stress results in
irreversible injury and eventually cell death.
Cellular function may be long lost before cell death occurs, and morphologic changes of cell
injury lag far behind both (myocardial cells become noncontractile after 1-2min of ischemia,
die after 20-30min, appear dead after
2-3h at least).
The cellular response to injurious
stimuli depends on the type of injury,
its duration, and its severity. Thus, low
doses of toxins or a brief duration of
ischemia may lead to reversible cell
injury, whereas larger toxin doses or
longer ischemic intervals may result in
irreversible injury and cell death.
The consequences of an injurious
stimulus depend on the type, status,
adaptability, and genetic makeup of
the injured cell. The same injury has
vastly different outcomes depending on
the cell type; thus, striated skeletal muscle in the leg accommodates complete ischemia for 2
to 3 hours without irreversible injury, whereas cardiac muscle dies after only 20 to 30
minutes.
The nutritional (or hormonal) status can also be important; clearly, a glycogen-rich
hepatocyte will tolerate ischemia much better than one that has just burned its last glucose
molecule.
Genetically determined diversity in metabolic pathways can also be important. For
instance, when exposed to the same dose of a toxin, individuals who inherit variants in
genes encoding cytochrome P-450 may catabolize the toxin at different rates, leading to
different outcomes.
REVERSIBLE CELL INJURY
The cell can return to its normal state if the stress is removed.
This happens typically in the early stages/mild form of injury.
Significant structural/functional abnormalities may be present, there’s no severe membrane
damage/nuclear dissolution.
Types of reversible cell injury:
♥Cellular swelling / hydropic change/vacuolar degeneration
The failure of energy dependent ion pumps, leading to inability to maintain homeostasis:
ATP depletion → ion pump failure → failure of ionic and fluid hemostasis f.ex.:
IC Na+ increase → water retention → swelling
Cellular swelling is the first manifestation of almost all forms of injury to cells, but it
is difficult to appreciate it with the light microscope; it may be more obvious at the
level of the whole organ.
When it affects many cells in an organ it causes some pallor, increased turgor and increase
in weight of the organ. Microscopic examination may reveal small, clear vacuoles within the
cytoplasm (these are distended and pinched-off segments of the ER).
♥Fatty change (steatosis)
It is mainly seen in cells that are either involved or dependent on fat metabolism like
hepatocytes and cardiac myocytes.
Occurs in hypoxic injury and various forms of toxic or metabolic injury.
Fatty change is manifested by the appearance of lipid vacuoles in the cytoplasm of
parenchymal cells, which unite to form a large lipid droplet, displacing the nucleus to the
periphery.
Some cells may rapture, and their vacuoles unite to form fatty cysts.
Injured cells may show increased eosinophilic staining, which becomes more
pronounced as the cell progresses to necrosis.
The mechanism underlying fatty change is the inadequate removal of fat from the
cell.
Alcohol abuse and diabetes associated with obesity are the most common causes of
fatty change in the liver.
Free fatty acids from adipose tissue or from the food are normally transported into
hepatocytes, where they are esterified to triglycerides, converted into cholesterol,
phospholipids or oxidized into ketone bodies.
Some fatty acids are synthesized from
acetate. In order to leave the cell, triglycerides should form complexes with apoproteins to
form lipoproteins.
Excess accumulation of triglycerides may result from defects at any step
from fatty acid entry to lipoprotein exit
Hepatotoxins (e.g. alcohol) change the function of mitochondria and sER, and along with
anoxia they impair the oxidation of fatty acids;
Examples of fatty change:
*Mild fatty change in the liver may not affect the gross appearance.
With increasing accumulation, the liver enlarges and becomes yellow. It may reach 3-6 kg
and appear bright yellow, soft and greasy.
*In the heart, lipid is found in the form of small droplets, occurring in one of 2 patterns:
- Specific location – results from moderate, prolonged hypoxia, creating bands of yellow
myocardium alternating with bands of healthy tissue. - Uniformly affected myocytes – results from profound hypoxia or toxic injury.
sER is involved in the metabolism of various chemicals. Cells exposed to
these chemicals show hypertrophy of the ER. barbiturates are metabolizes in
liver by cytochrome P-450. Development of tolerance to the drug is due to this
hypertrophy and increased P-450 enzymatic activity. In addition, products
formed by the ox. metabolism include reactive ox. species(ROS) which may
injure the cell
» Plasma membrane alteration: blebbing, blunting, distortion of
microvilli, loosening of IC attachment.
» Mitochondrial changes: swelling and appearance of phospholipid-rich
densities.
» Dilation of ER with detachment of ribosomes and siddocoation of
polysomes
» Nuclear alteration with clumping of chromatin. Plasma may conatin
phospholipid masses – myelin figures – derived from damaged cellular
membranes
»
IRREVERSIBLE CELL INJURY
♥Inability to reverse mitochondrial damage
♥Profound membrane dysfunction
Can be necrosis or apoptosis
Necrosis- a spectrum of morphological changes that follow cell death in living tissues due to
progressive degradative action of enzymes on lethally induced cells. The enzymes can come
from the damaged cells itself “autolysis” (lysosomal f.ex.), from inflammatory cells
“heterolysis”. Morphology:
PATHOMECHANISM (causes) OF CELL INJURY
Cell injury results from functional and biochemical abnormalities in one or more of several
essential cellular components. The most important targets of injurious stimuli are
(1) mitochondria, the sites of ATP generation
(2) cell membranes, on which the ionic and osmotic homeostasis of the cell and its
organelles depend
(3) protein synthesis
(4) the cytoskeleton
(5) the DNA
1. Mitochondrial damage
Hypoxia / toxins / increased cytosolic Ca2+/ ROS / radiation → mit damage
*Formation of high conduction channels “mit. Permeability transition pores” →
membrane potential lost →
failure of oxidative phosphorylation → ATP depletion AND formation of ROS
leakage of proapoptotic molecules to cytosol AND
Diffusion of cyt-C to cytosol → stimulation of caspases → apoptosis
2. ATP depletion
Hypoxia / toxins (cyanide) / disrupted ETC (mit damage)→ ATP depletion:
*Anaerobic glycolysis → decrease in glycogen stores and lactic acidosis → pH↓ →
chromatin clumping AND decreased enzymatic activity
*Na+/K+ pump failure→ IC Na+ ↑ → water retention → cell & ER swelling → loss of
microvilli and detachment of ribosomes → reduced protein synthesis
*Ca2+ pump failure → Increased IC Ca2+ => damage to cellular components by activation
of enzymes (proteases, caspases, phospholipases).
3. Disturbance in Ca2+ hemostasis
Ischemia/toxin → release of sequestered Ca2+ from mit and SER → increased IC Ca2+
*increased mit. Permeability transition pores → apoptosis
*Activation of enzymes (ATPase, phospholipase, protease and endonuclease).
4. Membrane damage
*Ischemia/toxin/lytic complement components? → Damage to plasma and lysosomal
membranes
*Loss of osmotic balance (influx/efflux of fluid and ions) AND loss of cellular content.
5. Damage to DNA and misfolding of proteins
6. Oxidative stress
ROS are oxygen derived free radicals which are special molecules that have a single
unpaired electron in their outer orbit- not stable and thus very reactive. They can convert
proteins, carbs and lipids to free radicals themselves (chain reaction).
Examples- O2- (superoxide) H2O2 (hydrogen peroxide), OHReduction and oxidation reactions / Ionizing radiation / Inflammation reaction / transition
metals like iron and copper participate in “Fenton reactions”→ ROS → oxidative stress
*Oxidation of lipids → peroxidase formation in the different membranes
*Oxidation of proteins → enzymes lose function, abnormal folding
*DNA damage
Adaptation 2 : Hypertrophy. Hyperplasia. Metaplasia.
ADAPTATION
Reversible changes in the size, number, phenotype or function of the cell in response to
change in the environment, to achieve a new steady state and preserve its function.
PHYSIOLOGICAL
responses of the cell to normal
stimulation by hormones or
endogenous mediators => closing/opening of ion channels,
enlargement of the breast and
uterus during pregnancy
PATHOLOGICAL
responses of the cell to stress that
allows it to modulate its
structure, thus escape injury => atrophy, hypertrophy,
hyperplasia, metaplasia,
dysplasia
Adaptation 1: Atrophy, involution, programmed cell death (apoptosis, necroptosis, pyroptosis)
Caspase antagonist is a protein called FLIP. Some viruses produce a FLIP homolog and
ADAPTATION
Basic principles:
♥ An organ is in homeostasis with the physiologic stress placed on it.
♥ An increase, decrease, or change in stress on an organ can result in growth adaptations.
Adaptation
any response of a cell to stimuli (stress) to achieve a new steady state and preserve its
function.
PHYSIOLOGICAL
responses of the cell to normal
stimulation by hormones or
endogenous mediators => closing/opening of ion channels,
enlargement of the breast and
uterus during pregnancy
PATHOLOGICAL
responses of the cell to stress that
allows it to modulate its
structure, thus escape injury => atrophy, hypertrophy,
hyperplasia, metaplasia,
dysplasia
ATROPHY
A decrease in the size of an organ in response to a decrease in stress.
E.g.:
* Decreased hormonal stimulation (in menopause –physiologic)
* Disuse (immobilization of a limb to permit healing of a fracture)
* Decreased nutrient supply “cachexia”
* Decreased blood supply
* Denervation- pathologic
* Aging (senile atrophy)
Although some of these stimuli are physiologic and some are pathologic, the fundamental
cellular changes are identical. They represent a retreat by the cell to a smaller size at which
survival is still possible; a new equilibrium is achieved between cell size and diminished
blood supply, nutrition, or trophic stimulation.
*Decreased protein synthesis (due to reduced metabolic activity) and decreased protein
degradation
Mechanism- a decrease in the size and number of cells
♥ Decrease in cell number
Occurs via apoptosis (programmed cell death)
♥ Decrease in cell size
Occurs via
*Ubiquitin-proteasome degradation of the cytoskeleton
Intermediate filaments of the cytoskeleton are “tagged” with ubiquitin and destroyed by
proteasomes.
*Autophagy of cellular components- process in which the starved cell eats its own
components in an attempt to survive.
Generation of autophagic vacuoles with lysosomes whose hydrolytic enzymes breakdown
cellular components
APOPTOSIS
Cell death- The morphologic hallmark of cell death is loss of the nucleus, which occurs via
nuclear condensation (pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis),
leading the cytoplasm to become more eosinophilic.
The two mechanisms of cell death are necrosis and apoptosis.
Apoptosis: energy (ATP)-dependent, genetically programmed cell death, characterized by
nuclear dissolution without complete loss of membrane integrity. Apoptotic bodies fall from
the cell and are removed by macrophages; apoptosis is not followed by inflammation.
Whereas necrosis is always a pathologic process, apoptosis serves many normal functions.
Examples:
Physiological
1. Endometrial shedding during menstrual cycle
- Removal of cells during embryogenesis
- T cell-mediated killing of virally infected cells
- Cell loss in proliferating cell populations (intestinal crypt epithelia).
- Cells that have served their purpose (RBCs, neutrophils in an acute
.)inflammatory response – deprived of survival signals like GF - Elimination of potentially harmful self-reactive lymphocytes
Pathological
elimination of cells that are genetically altered or injured beyond repair,
keeping extent of tissue damage to a minimum
1) DNA damage that cannot be repaired – radiation, cytotoxic anticancer
drugs, extreme temp, hypoxia, directly/through free radicals
2) Misfolded proteins – accumulation of misfolded proteins causes ER
stress that induces apoptosis (unfolded protein response), part of
Alzheimer, Huntington, Parkinson.
3) Cell injury due to infections, mainly by viral infections.
4) Pathologic atrophy in parenchymal organs after duct obstruction
(pancreas, parotid gland, kidney)
Mechanism
Apoptosis is mediated by caspases that activate proteases (break down the cytoskeleton)
and endonucleases (break down DNA).
Caspases are activated by multiple pathways:
1. Intrinsic mitochondrial pathway
Loss of stimulation of growth factors/agents that damage DNA/acc of misfolded proteins →
Inactivation of antiapoptotic proteins (Bcl-2, Bcl-xL) and activation of pro-apoptotic proteins
Bax, Bak) →
Channels are formed in the mitochondrial membrane →
Cytochrome c leaks from the inner mitochondrial matrix into the cytoplasm →
Caspases are activated (cytochrome C + Apaf-1 activate caspase 9 →
Cytoskeletal and nuclear fragmentation
2. Extrinsic death receptor pathway
*FAS ligand binds FAS death receptor on the target cell, activating caspases (e.g., negative
selection of thymocytes in thymus).
*Tumor necrosis factor binds to receptor on the target cell, activating caspases.
3. Cytotoxic CD8+T cell-mediated pathway
*Perforins secreted by CD8+ T cell create pores in membrane of target cell.
*Granzyme from CD8+ T cell enters pores and activates caspases.
*CD8+ T-cell killing of virally infected cells is an example
Regulation of apoptosis is mediated by the Bcl-2 protein family, which includes both
pro- and anti-apoptotic proteins, and by p53 protein.
prevent cell apop
# When DNA is damaged, p53 accumulates in cell, arrests cell in G1 phase for repair, if
damage is too great, it triggers apop by activating Bax, Bak and increase synthesis of
pro-apop members of Bcl-2 family
INVOLUTION
Developmental loss
Examples of involution:
» Involution of the uterus – after birth the uterus returns from its hypertrophic
state to its normal size.
» Involution of the thymus – during puberty the gland begins to atrophy, and is
gradually replaced by fat.
The homeostasis of the cell. Physiological stress. The concept of adaptation and cellular injury.
Homeostasis – a process in which the cell regulates its internal environment by
HOMEOSTASIS OF THE CELL
continuous exchange of nutrients, fluids and temperature (heat) with the external
environment.
# Stress – any stimulus that interrupts with the homeostasis of the cell, which can be
physiological or pathological.
TYPES OF STRESS
mnemonic: higc pain
# Hypoxia – interferes with aerobic oxidative respiration; it can be caused by
*Ischemia- reduced arterial or venous blood flow (atherosclerosis…)
*Hypoxemia- reduced amount of oxygen in blood
PiO2 (inspired) → PAO2 (alveolar)→ PaO2 (arterial)→ SaO2 (RBC)
hypoventilation, high altitude → lack of lung perfusion, obstructive disease, lack of
surfactant… (pneumonia)
*Anemia/CO poisoning- reduction of the oxygen carrying capacity.
Infectious agents – viruses, bacteria, fungi etc.
# Genetic defects – congenital malformations (sickle cell), damaged DNA, misfolded
proteins.
# Chemical agents – substances that are osmotically active, such as glucose or salts,
which cause movement of fluids into or out of the cell, others: pollutants, co, asbestos,
high amount of ox.
# Physical agents – such as trauma, extreme temperatures, radiation, atmospheric
pressure etc.
# Aging – leads to alterations in the ability of the cell to replicate and repair itself.
# Immunologic reactions – autoimmune reactions, allergic reactions.
# Nutritional imbalance – when the diet lacks certain nutritional values (proteins,
vitamins).
THE CONCEPT OF ADAPTATION
An increase, decrease, or change in stress on an organ can result in growth adaptations.
# Reversible changes in the size, number, phenotype or function of the cell in response to
change in the environment, to achieve a new steady state and preserve its function.
The responses of the cell can be either physiological or pathological:
» Physiological adaptation – the responses of the cell to normal stimulation by
hormones or endogenous chemicals.
» Pathological adaptation – the responses of the cell to stress, allowing the cell to
modulate its structure and function to avoid cell injury.
These adaptations can be: hyperplasia, hypertrophy, metaplasia, atrophy and dysplasia.
CELLULAR INJURY
When the cell is exposed to severe stress that
exceeds its adaptive capability, cell injury may occur.
The injury can be acute or chronic, and these are
further subdivided as follows:
Acute
can be divided into: based on nature and severity of
stress AND basal cellular metabolism and nutrient
supply?
♥Reversible – the cell can return to its normal state
if the stress is removed.
Early stages/mild form of injury, Significant
structural/functional abnormalities may be present, there’s no severe membrane
damage/nuclear dissolution.
Morphological correlates:
1. Cellular swelling- failure of energy dependent ion pumps, leading to inability to maintain
homeostasis.
ATP depletion → ion pump failure → failure of ionic and fluid hemostasis f.ex.:
IC Na+ increase → water retention → swelling
→ loss of microvilli → absorption↓
→bulbes formation due to cytoskeletal failure
→ rER swelling → ribosomes detach → protein synthesis↓
2. Fatty change- occurs in hypoxic injury and in various forms of toxic/metabolic injury.
Manifested by lipid vacuoles in cytoplasm. Abnormal accumulation of TAGs within
parenchymal cells, observed most frequently in the liver (major organ of fat metabolism),
but also in the heart and kidney
♥Irreversible – the cell will eventually die. Necrosis (always pathological)/apoptosis (no GF,
DNA/proteins damage). Characterized by – inability to correct mitochondrial dysfunction,
and profound disturbance in membrane function.
The cell’s fate can be:
1. Necrosis
2. Apoptosis
Chronic:
The causes of injury are the various types of stress mentioned earlier, which induce
distinctive alterations that include only the organelles:
» Autophagy – lysosomal digestion of the cell’s own components, considered to
be a survival mechanism in nutrient deprived cells.
» Hypertrophy of sER – occurs in cells that are exposed to certain chemical
agents, such as barbiturates. (Hepatocytes detoxification).
» Mitochondrial alterations – change in the number, size and shape of
mitochondria.
» Cytoskeletal abnormalities – occur due to certain drugs that interfere with the
normal function of cytoskeleton (disrupt polymerization, cause accumulation of
fibrillar material, defective mobility of organelles).
Skin tumors of epithelial origin (epidermis, hair follicle, sebaceous and sweat gland tumors).
Benign epithelial neoplasms are very common properly develop from stem cells reside in the
BENIGN AND PREMALIGNANT EPITHELIAL LESIONS
epidermis and hair follicles.
They grow to a limited size and generally do not undergo malignant transformation.
SEBORRHEIC KERATOSIS
# Presents as raised round, discolored plaques on the extremities or face made of proliferating
basal epidermal cells Characterized by keratin pseudocysts on epidermis see also sometimes
hyperkeratosis
common tumor in the elderly Usually these lesions are of little clinical importance. In rare cases
see abundant such as lesions may appear as a paraneoplastic syndrome most common are the GI
tract carcinoma association which produce GF that stimulate epidermal proliferation.
# Pathogenesis – activating mutations in Fibroblast Growth Factor receptor .
ACTINIC KERATOSIS
# This lison usually a result of chronic exposure to sunlight, and is associated with hyperkeratosis
hence actinic keratosis.
Pathogenesis –. Mostly associated with TP53 mutation age fair skin n sun exposure (inducing
tp53 mutation). has the potential to become malignant (SSC) therefore must be removed .
# Morphology – Usually are less than 1 cm in diameter, brown or red in color, and rough.
Epidermis – show cytological atypia in lower part of epidermis; parakeratosis of stratum corneum
can also be seen .Dermis – actinic elastosis. Instead of collagen see elastic fibers become
homogenous appearance on HE …
SEBACEOUS ADENOMA
# Rear benign, self-limited growth, that appear in the head and neck region of older individuals.
Present as flesh-colored papules-elevated less than 5 mm lesion.
Pathophys Association with Muir-Torre syndrome, a rare autosomal dominant cancer syndrome,
and with internal malignancy, mainly colon carcinoma. Both cases are considered subtypes of
hereditary nonpolyposis colorectal carcinoma syndrome, characterized by loss of a DNA
mismatch repair protein.
Morphology – lobular proliferation of sebocytes that maintain an organoid appearance. with
expansion of germinative basaloid cell layers at periphery
MALIGNANT EPIDERMAL TUMORS
SQUAMOUS CELL CARCINOMA
# Malignant proliferation of squamous cells. Presents as an red scaling may ulcerate , nodular
mass, usually appear on sun-exposed sites in older people typically the face (classically
involving the lower lip) With higher incidence in men than in women.
Predisposing factors exposure to sunlight, albinism, and xeroderma pigmentosum. Additional
risk factors include immunosuppressive therapy, toxin exposure - arsenic exposure, and chronic
inflammation (e.g., scar from burn, chronic ulcers etc..)
Pathogenesis – Exposure to UV light Causes mutation in TP53, HRAS and loss of function in
Notch receptors, which regulates differentiation of normal squamous epithelia. Also has
Immunosuppressive effect on skin by impairing antigen presentation by Langerhans cells.
Morphology – Characterized by atypical cells at all levels of the epidermis Invasive tumors,
defined by penetration of the basement membrane.
Show variable degrees of differentiation,
ranging from tumors with cells arranged in orderly lobules that exhibit extensive keratinization
to neoplasms consisting of highly anaplastic cells with foci of necrosis and only abortive, singlecell
keratinization (dyskeratosis). See inflammatory reaction aroun nodules in dermis
Clinical features – Treatment is excision; rarely metastasize; the likelihood of metastasis is
related to the thickness of the lesion and degree of invasion into the sub cutis. Mucosal
squamous cell carcinoma (oral, pulmonary, esophageal) are much more aggressive
BASAL CELL CARCINOMA
# Malignant proliferation of the basal cells of the epidermis Most common cutaneous malignancyA
slow-growing tumor that Rarely metastasize
Pathogenesis – Tends to occur at sites subjected to chronic sun exposure associated with a
tumor suppressor mutation that regulates the Hedgehog pathway, causes familial basal cell
carcinoma and also in sporadic see mutations in hedgehok path. Mutations in p53 are also
common in familial or sporadic carcinomas.
Morphology – Presents as an elevated nodule with a central, ulcerated crater surrounded by
dilated (telangiectasia) vessels ‘pink, pearl-like papule’ Classic location is the upper lip. Tumor
cells resemble the epidermal basal cells from which they originate.
On histo see horizontal growth along-epithelodermaljunction and vertical growth into dermis crate island of malignant
cells may be bordered by palisading, around it see inflammation and it destroy surrounding
dermis as it replace it…
Clinical features – Should be radically removed extensive local invasion of bone or facial
sinuses may occur.
Actinic keratosis is a precursor lesion of squamous cell carcinoma and presents as a
hyperkeratotic, scaly plaque, often on the face, back, or neck.
Keratoacanthoma is well-differentiated squamous cell carcinoma that develops
rapidly and regresses spontaneously; presents as a cup-shaped tumor filled with
keratin debris
Melanocytic tumors of the skin.
A brown, uniformly pigmented, small (<5mm), solid regions of elevated skin (papules)
Melanocytes are responsible for skin pigmentation and are present in the basal layer
of the epidermis.
Derived from the neural crest.
Synthesize melanin in melanosomes using tyrosine as a precursor molecule Pass melanosomes to keratinocytes
Melanocytic nevus is the benign tumor of melanocytes Nevus = congenital.
Malignant melanoma is a malignant tumor of melanocytes
MELANOCYTIC NEVI
with well defined, rounded borders.
Initially composed of oval cells that grow in nests along the dermoepidermal junction
=> JUNCTIONAL NEVI
Most junctional nevi grow into the underlying dermis as nests or cords of cells =>
COMPOUND NEVI
In older lesions, the epidermal nests may be lost completely to leave pure
INTRADERMAL NEVI.
The majority of benign nevi show an activating mutation in BRAF, or less commonly
in RAS. BRAF – a gene encoding Ser/Thr kinase which is involved in directing cell
growth.
changes of morphology of cells as evidence of cellular senescence Superficial nevus
cells – larger and less mature, tend to produce melanin and grow in nests. Deeper nevus
cells – smaller and more mature, produce little to no pigment and grow in cords or
single cells; the deepest nevus cells grow n fascicles.
DYSPLASTIC NEVUS
Dysplastic nevi consist mainly of compound nevi and Marked by Cytological atypia
(consisting of irregular nuclei and hyperchromasia)
result from BRAF or RAS mutations May occur sporadically or in a familial form
(autosomal dominant inheritance).appearance of dysplastic nevi mainly Familial are
considered as markers for risk to develop melanoma .
Morphology – Larger than most acquired nevi (>5mm), may occur in large numbers
come as flat macules to slightly raised plaques, show variable pigmentation and
irregular borders.
accure on sun expose n non expose surfaces
Nevus cell nests within the epidermis may be enlarged and fusion with adjacent
nests.As a result, the nevus cells begin to replace the normal basal cells at the
dermoepidermal junction- lentiginous pattern
Dermal changes as host respond see Lymphocytic infiltration into the superficial
dermis. melanin phagocytosis by dermal macrophages Linear fibrosis surrounding
epidermal nests of melanocytes.
MELANOMA
# Malignant neoplasm of melanocytes; most common cause of death from skin cancer
# Pathogenesis – Sunlight exposure plays the important role - Most melanomas occur
sporadically also hereditary predisposition – dysplastic nevus syndrome (autosomal dominant
disorder characterized by formation of dysplastic nevi that may progress to melanoma).
Mutations in the gene of p16 gene that encodes a cyclin-dependent kinase inhibitor regulating
the G1-S transition; this mutation id found in 40% of familial melanomas and less commonly in
sporadic cases the gene is silenced by methylation.
Somatic activating mutations in the protooncogenes BRAF and NRAS are common in melanomas of bout kinds
Growth pattern- Radial growth is the initial tendency of a melanoma to grow horizontally within
the epidermis (in situ) and superficial dermal layers => during this stage no metastasizes, and do
not induce angiogenesis.
Vertical growth: the melanoma grows into the deeper dermal layers,
lacking cell maturation- with greater metastatic potential => metastases involves regional lymph
nodes, liver, lungs, brain etc.
Morphology –show large variation of pigmentation (black, brown, red etc..) The borders are
irregular and notched.
Malignant cells grow in poorly-formed nests or ad individual cells at all levels of the epidermis
Melanoma cells are larger than nevus cells, containing large nuclei with chromatin clumped at
the periphery of the nucleus, with prominent eosinophilic nucleoli (described as “cherry
red”).
Superficial spreading melanomas are associated with lymphocytic infiltrate.
Clinical features – Mostly arise in the skin, yet may also involve oral and anogenital mucosal
surfaces, esophagus, meninges, and the eye.
Signs of melanoma – ABCs of melanoma – Asymmetry, Border, Color, Diameter, Evolution
(change of an existing nevus).
Probability of metastasis is predicted by measuring the depth of invasion in mm of the vertical
growth phase nodule from the top of the granular call layer of the epidermis (Breslow thickness)
Classification and grading of soft tissue tumors. Tumors of adipose tissue. Tumors and tumorlike
lesions of fibrous tissue.
Sarcoma vs. Carcinoma : carcinoma easily will be separated into parenchyma &
CLASSIFICATION AND GRADING OF SOFT TISSUE TUMORS
Soft tissue – The bulk of the body is composed of the cells forming tissues that are
considered “soft” tissues or connective tissues.
(Any non-epithelial tissue except bone, cartilage, CNS, hematopoietic and lymphoid tissues).These embryological derived from the mesoderm. Hence, they are often called me-senchymal tissues.
Classification of soft tissue tumors:
stroma. In sarcoma both paranchyma & stroma are derived from the same origin =
cannot be separated.
Tumors of the peripheral nerves be-long here despite their derivation from the
neuroectoderm!
Currently we assume they originate from tissue-specific Mesenchymal stem cells and
not from malignant transformation of adult tissue cells .
MSCs, are multipotent stromal cells that can differentiate into a variety of cell types creating mesenchymal tissue MSCs
do not differentiate into hematopoietic cells got self-renewing asymmetric division and
found in body : placenta umbilical cord blood, adipose tissue, adult muscle, corneal
stroma or the dental pulp of deciduous baby teeth, but do not have the capacity to
reconstitute an entire organ.
Metaplasia is common in soft tissue tumors
Soft tissue tumors are rarely malignant (represent less than 1% of all invasive
malignancies), but they cause 2% of all cancer deaths, reflecting their lethal nature.
Soft tissue tumors can arise in any location, but 40% occur in the lower extremities.
Soft tissue sarcomas usually are treated with wide surgical excision (frequently limbsparing),
with irradiation and systemic therapy reserved for large high-grade tumors.
Prognosis of soft tissue:
Diagnostic classification- histology, immunohistochemistry, electron microscopy,
cytogenetics and molecular genetics are important in assigning the correct diagnosis.
Keeping in mind the high metaplastic appearance…
Histological diagnosis = pattern recognition help in estimate tumer type patterns apper
chrecteristicly with different tumers
Spindle cell/epitheloid/pleiomorphic/small blue cell /biphasic
Grading Differentiation! How well it resembles the origin cell. Staging = the stage!
Location.
# Staging- use TNM system as size and depth of invesion looked in T the N for nodal
involvement and the M for metastasis With tumors larger than 20 cm, metastases
develop in 80% of cases; by contrast, for tumors 5 cm or smaller, metastases occur in
only 30% of cases. It is rare for adult sarcomas to metastasize to lymph nodes.
Note that in STT the dipper ones more aggressive then superficial..
Grading- Grading based on a scale of I to III, relating to the degree of differentiation,
the mitotic activity and of the extent of necrosis.
- Differentiation (1-3 score) less diffrant. Higher score
- Mitotic count (1-3 score)
- Necrosis (1-3 score) higher score more necrosis
Total sum = from 1-3 by addition of scores in each category as 3 grade got higst summed up
score Grade help to indicate the probability of distant metastases and reaction to treatment…
TUMORS OF ADIPOSE TISSUE
LIPOMA
Benign tumors of fat.Most common soft tissue tumors in adult.
# Most lipomas are solitary lesions, mobile, slowly enlarging, painless masses (
Multiple lipomas may suggest the presence of rare heredity syndromes).
Can be classified based on their histologic features or chromosomal rearengment:
» Conventional lipoma- (the most common subtype) are soft, yellow, wellencapsulated
masses of mature adipocytes; they can vary considerably in
size and no pleomorphism.
» Myolipoma – a benign tumor that consists of fat cells with variable
number of muscle cells.
» Spindle cell lipoma – slow-growing subcutaneous tumors, mainly in the
back, neck and sholders of older men.
» Myelolipoma – a benign tumor composed of mature adipocytes and
hematopoietic cells.
» Pleomorphic lipoma – characterized by giant cells that resemble small
flowers, with overlapping nuclei.
» Angiolipoma – subcutaneous nodule with vascular structure; they are
commonly painful.
LIPOSARCOMA
Malignant neoplasms of adipocytes usually occur in 50-60 years old. Most
liposarcomas arise in deep soft tissues or in the retroperitoneum.
Can be sub classified:
» Well-differentiated liposarcoma – malignant lesions that arise in the
retroperitoneum, commonly associated with amplification of a region in
the long arm of chromosome 121
.
» Dedifferentiated liposarcoma – consists of a well-differentiated
liposarcoma adjacent to a more poorly differentiated tumor.
» Myxoid (round cell) liposarcoma – associated with translocation between
chromosomes 12 and 16, which affects the transcription factor that plays a
role in normal adipocyte differentiation. More aggressive pleomorphic
variant, which tend to recur after excision and metastasize to lungs.
Morphology – Well circumscribed lesion.
» Myxoid liposarcoma characterized by abundant, mucoid
extracellular matrix.
» Lipoblasts are present indicative of fatty differentiation.
They have cytoplasmic lipid vacuoles that scallop (צדפה (the nucleus
TUMORS AND TUMOR-LIKE LESIONS OF FIBROUS TISSUE
I. REACTIVE PROLIFERATIONS
# Nodular fasciitis –rapidly growing reactive lesion of self-limited fibroblastic
proliferation that probably resulted from trauma(Rarely recurs after excision)
and is superficial
» Morphology – Tightly woven uniform spindle cells and collagen are seen
(=stroiform arrangement) A few lymphocytes & vascular channels are
present.
» Can be up to several cm in diameter and appears nodular Typically occurs
in adults on the volar aspect of the forearm, chest or back
Myositis ossificans
» Distinguished from other types of fibroblastic proliferations by the
presence of metaplastic bone.
» Characterized by the ossification of muscle. Develops in the proximal
muscles of the extremities in athletic adolescents and young adults after
trauma.
» Initially, the involved area is swollen and painful, and eventually develops
into a hard, painless, well-demarcated mass. Critical to distinguish from
extra skeletal osteosarcoma.
II. FIBROMATOSES
# Benign soft tissue tumors the lesions are locally aggressive, but DO NOT metastasizes.
Many cases recur after surgical removal.
Can be divided into 2 groups:
» Superficial fibromatoses – arise in the superficial fascia2
, can be associated with
trisomy 3 & 8, but usually are harmless.
» Deep fibromatoses – include the desmoid tumor that arise in the abdominal wall and
mesentery, and muscles of the trunk and extremities, as isolated lesions or as a
component of Gardner syndrome3
; tend to grow in a locally aggressive manner,
Morphology –
» The tumors are gray-white, firm to rubbery, poorly demarcated, infiltrative masses (1-
15cm).
» histology consistent with : contain abundant dense collagen. with low cellularity , a
proliferation of well-differentiated fibroblasts that tend to grow in an infiltrative fashion
III. FIBROSARCOMA
# Malignant neoplasms composed of fibroblasts. Tend to grow slowly And Typically
found in the deep tissues of the thigh, knee and retroperitoneal area. Recur locally after
excision. (in 50% of cases) Can metastasize, usually to the lungs.
Morphology – soft, unencapsulated, infiltrative masses, usually with areas of
hemorrhage and necrosis. Histologic examination discloses all degree of
differentiation.
Tumors of skeletal muscle, smooth muscle, peripheral nerve and synovial origin.
Skeletal muscle neoplasms are almost all malignant.rheabdomyoma is rear bingeing skeletal
SKELETAL MUSCLE TUMORS
.m. tumor most often found in heart.
RHABDOMYOMA
# rear benign hamartomatous tumor of striated muscle. Can be cardiac or extra cardiac most
often found in the heart. Can be classified as adult type, fetal type and genital type. Very rear but
Most frequent primary tumor of the heart in infants and children
RHABDOMYOSARCOMA
# Skeletal muscle malignant neoplasm Usually appears in children and adolescents.
Occur most commonly in the head and neck region or the urogenital tract .
# often chromosomal translocation are found, mainly t(2,13)4
.
# Morphology – Can be sub classified into morphological types embryonal, alveolar and
pleomorphic variants.
Tumors that arise next to the bladder or vagina are soft, gelatinous, grape-like masses (sarcoma
botryoides); in other cases the tumor is poorly defined.
Rhabdomyoblast is the cell that appears in all types, and exhibits granular, eosinophilic
cytoplasm rich in thick and thin filaments. These cells can be round or elongated2 IHC: desmin,
aktin
Clink.: aggressive; chemotherapy often effective, especially in children (cure)
SMOOTH MUSCLE TUMORS
LEIOMYOMA
Benign smooth muscle tumors. Common, well-defined neoplasms that arise most commonly in
the uterus.
These tumors are monoclonal and are associated with chromosomal rearrangement of
chromosomes 6 and 12
Morphology – Very well-defined, gray-white masses with whorled cut surface. Can be
intramural (within the myometrium), submucosal (directly beneath the endometrium), or
subserosal5 (directly beneath the serosa).
Large neoplasms may develop ischemic necrosis with areas of hemorrhage and cystic
softening; after menopause, they may become collagenous and even calcified.
LEIOMYOSARCOMA
Occur in adults, more commonly in females. Usually exist as SOLITARY tumors, usually occur
in postmenopausal women (in contradiction to leiomyoma)
Present as firm, painless masses. Common sites of development are skin, deep soft tissues of the
extremities and retroperitoneum. Metastasize typically to the lungs.
Leiomyosarcoma of the uterus usually arise de novo from mesenchymal cells of the
myometrium, and NOT from pre-existing leiomyomas.
Morphology – Soft, hemorrhagic and necrotic. They show spindle cells with cigar-shaped nuclei
arranged in interwoven fascicles. Present cytological atypia and mitotic activity. Present a wide
range of cell differentiation, from close resemblance to leiomyoma to anaplastic tumors.
PERIPHERAL NERVE TUMORS
# In most tumors, the neoplastic cells show evidence of Schwann cell differentiation.
These tumpors usually occur in adults.They are frequently associated with familial tumor
syndromes neurofibromatosis type 1 (NF1) and type 2 (NF2)
SCHWANNOMA AND NEUROFIBROMATOSIS TYPE 2
# Schwannomas are benign encapsulated tumor composed of Schwann cells that may occur in
soft tissues, internal organs or spinal nerve roots
.Causing local compression of the involved
nerve, or the compression of adjacent structures
Most Schwannomas are sporadic; 10% inherited associated with NF2 or Schwannomatosis
.The presence of bilateral vestibular Schwannomas is the hallmark of NF2.
Affected patients carry a dominant loss-of-function mutation of the merlin8 gene on chromosome 22
Schwannomatosis is a familial condition associated with multiple Schwannomas in which
vestibular nerve is absent
Morphology – Well-defined, encapsulated Firm, gray masses. That are attached to the nerve, but
can be separated from it.
Histo-Biphasic tumor: Antoni A – dense areas; bland spindle cells arranged into intersecting
fascicles.Often align to produce nuclear palisading, resulting in alteration bands of nuclear and a
nuclear areas called Verocay bodies. Antoni B – loose meshwork of cells and stroma
Thick-walled hyalinized vessels often are present
NEUROFIBROMA
# Benign peripheral nerve sheath tumors.
# Subdivided into 3 types:
» Localized cutaneous neurofibroma – arise as superficial nodular or polypoid tumor. These occur
either as solitary sporadic lesions or as multiple lesions in the context of NF1
» Plexiform neurofibroma – grow diffusely within a nerve or a nerve plexus; associated with type 1
neurofobromatosis (NF1); may evolve to a malignant tumor; involve multiple fascicles of
individual affected nerves, residual axons are found embedded within the diffuse neoplastic
Schwann cell proliferation
» Diffuse neurofibromas – infiltrative proliferation; large subcutaneous masses. Often associated
with NF1; often found in the dermis and subcutis of the skin.
Morphology – not encapsulated (unlike Shwannomas). May appear circumscribed (localized
cutaneous neurofibroma) or diffuse.
In contrast with Schwannomas, neoplastic Schwann cells are mixed with other cell types (mast cells,
fibroblast-like cells and perineurial-like cells).
Stroma contains loose wavy collagen bundles/dense collagen
MALIGNANT PERIPHERAL NERVE SHEATH TUMOR
# Highly malignant sarcomas, which are locally invasive.
# Seen in adults, typically show evidence of Schwann cell derivation and sometimes arise from
transformation of a plexiform neurofibroma (50% arise from NF1)
Morphology –
» Large, poorly defined tumor masses.
» Tumors are highly cellular, exhibiting malignancy properties (anaplasia, necrosis, infiltrative
growth pattern, pleomorphism, high proliferative activity)
» Low power magnification shows alternating areas of high and low cellularity marble-like
appearance
NEUROFIBROMATOSIS TYPE 1
# Autosomal dominant disorder caused by mutation in the tumor suppressor neurofibromin found of
chromosome 17.
# Neurofibromin is a negative regulator of Ras.
Patients exhibit learning disabilities, seizures, skeletal abnormalities, vascular abnormalities with
arterial stenoses, pigmented nodules of the iris (Lisch nodules), pigmented skin lesions.
SYNOVIAL SARCOMA
The cell of origin is unclear (non-joint origin!!), but it is most certainly NOT cells of the
synovium; less than 10% are intra-articular.
Mostly affect persons in their 20-40 years
# Usually develop in deep soft tissues around the large joints of the extremities, mainly the knee
joint.
# Most synovial sarcomas show t(X, 18)9
.
# Morphology –
» The tumor can be monophasic (only one cell type – spindle cell), or biphasic (both cell types).
» Nonophasic tumors may be mistaken with fibrosarcomas or malignant peripheral nerve sheath
tumor, differential diagnosis is done by immunohistochemistry showing a positive test result
for keratin and epithelial membrane antigen.
» Tumor cells can be of two types:
1) Spindle cell (fibrous type cell) – arranged in cellular fascicles that surround the epithelial cells.
2) Epithelial-like cell – cuboidal to columnar, form glands or grow in solid cords or aggregates.
» Common metastatic site are the lungs, bones and regional lymph node
Tumors of skeletal muscle, smooth muscle, peripheral nerve and synovial origin.
Skeletal muscle neoplasms are almost all malignant.rheabdomyoma is rear bingeing skeletal
SKELETAL MUSCLE TUMORS
.m. tumor most often found in heart.
RHABDOMYOMA
# rear benign hamartomatous tumor of striated muscle. Can be cardiac or extra cardiac most
often found in the heart. Can be classified as adult type, fetal type and genital type. Very rear but
Most frequent primary tumor of the heart in infants and children
RHABDOMYOSARCOMA
# Skeletal muscle malignant neoplasm Usually appears in children and adolescents.
Occur most commonly in the head and neck region or the urogenital tract .
# often chromosomal translocation are found, mainly t(2,13)4
.
# Morphology – Can be sub classified into morphological types embryonal, alveolar and
pleomorphic variants.
Tumors that arise next to the bladder or vagina are soft, gelatinous, grape-like masses (sarcoma
botryoides); in other cases the tumor is poorly defined.
Rhabdomyoblast is the cell that appears in all types, and exhibits granular, eosinophilic
cytoplasm rich in thick and thin filaments. These cells can be round or elongated2 IHC: desmin,
aktin
Clink.: aggressive; chemotherapy often effective, especially in children (cure)
SMOOTH MUSCLE TUMORS
LEIOMYOMA
Benign smooth muscle tumors. Common, well-defined neoplasms that arise most commonly in
the uterus.
These tumors are monoclonal and are associated with chromosomal rearrangement of
chromosomes 6 and 12
Morphology – Very well-defined, gray-white masses with whorled cut surface. Can be
intramural (within the myometrium), submucosal (directly beneath the endometrium), or
subserosal5 (directly beneath the serosa).
Large neoplasms may develop ischemic necrosis with areas of hemorrhage and cystic
softening; after menopause, they may become collagenous and even calcified.
LEIOMYOSARCOMA
Occur in adults, more commonly in females. Usually exist as SOLITARY tumors, usually occur
in postmenopausal women (in contradiction to leiomyoma)
Present as firm, painless masses. Common sites of development are skin, deep soft tissues of the
extremities and retroperitoneum. Metastasize typically to the lungs.
Leiomyosarcoma of the uterus usually arise de novo from mesenchymal cells of the
myometrium, and NOT from pre-existing leiomyomas.
Morphology – Soft, hemorrhagic and necrotic. They show spindle cells with cigar-shaped nuclei
arranged in interwoven fascicles. Present cytological atypia and mitotic activity. Present a wide
range of cell differentiation, from close resemblance to leiomyoma to anaplastic tumors.
PERIPHERAL NERVE TUMORS
# In most tumors, the neoplastic cells show evidence of Schwann cell differentiation.
These tumpors usually occur in adults.They are frequently associated with familial tumor
syndromes neurofibromatosis type 1 (NF1) and type 2 (NF2)
SCHWANNOMA AND NEUROFIBROMATOSIS TYPE 2
# Schwannomas are benign encapsulated tumor composed of Schwann cells that may occur in
soft tissues, internal organs or spinal nerve roots
.Causing local compression of the involved
nerve, or the compression of adjacent structures
Most Schwannomas are sporadic; 10% inherited associated with NF2 or Schwannomatosis
.The presence of bilateral vestibular Schwannomas is the hallmark of NF2.
Affected patients carry a dominant loss-of-function mutation of the merlin8 gene on chromosome 22
Schwannomatosis is a familial condition associated with multiple Schwannomas in which
vestibular nerve is absent
Morphology – Well-defined, encapsulated Firm, gray masses. That are attached to the nerve, but
can be separated from it.
Histo-Biphasic tumor: Antoni A – dense areas; bland spindle cells arranged into intersecting
fascicles.Often align to produce nuclear palisading, resulting in alteration bands of nuclear and a
nuclear areas called Verocay bodies. Antoni B – loose meshwork of cells and stroma
Thick-walled hyalinized vessels often are present
NEUROFIBROMA
# Benign peripheral nerve sheath tumors.
# Subdivided into 3 types:
» Localized cutaneous neurofibroma – arise as superficial nodular or polypoid tumor. These occur
either as solitary sporadic lesions or as multiple lesions in the context of NF1
» Plexiform neurofibroma – grow diffusely within a nerve or a nerve plexus; associated with type 1
neurofobromatosis (NF1); may evolve to a malignant tumor; involve multiple fascicles of
individual affected nerves, residual axons are found embedded within the diffuse neoplastic
Schwann cell proliferation
» Diffuse neurofibromas – infiltrative proliferation; large subcutaneous masses. Often associated
with NF1; often found in the dermis and subcutis of the skin.
Morphology – not encapsulated (unlike Shwannomas). May appear circumscribed (localized
cutaneous neurofibroma) or diffuse.
In contrast with Schwannomas, neoplastic Schwann cells are mixed with other cell types (mast cells,
fibroblast-like cells and perineurial-like cells).
Stroma contains loose wavy collagen bundles/dense collagen
MALIGNANT PERIPHERAL NERVE SHEATH TUMOR
# Highly malignant sarcomas, which are locally invasive.
# Seen in adults, typically show evidence of Schwann cell derivation and sometimes arise from
transformation of a plexiform neurofibroma (50% arise from NF1)
Morphology –
» Large, poorly defined tumor masses.
» Tumors are highly cellular, exhibiting malignancy properties (anaplasia, necrosis, infiltrative
growth pattern, pleomorphism, high proliferative activity)
» Low power magnification shows alternating areas of high and low cellularity marble-like
appearance
NEUROFIBROMATOSIS TYPE 1
# Autosomal dominant disorder caused by mutation in the tumor suppressor neurofibromin found of
chromosome 17.
# Neurofibromin is a negative regulator of Ras.
Patients exhibit learning disabilities, seizures, skeletal abnormalities, vascular abnormalities with
arterial stenoses, pigmented nodules of the iris (Lisch nodules), pigmented skin lesions.
SYNOVIAL SARCOMA
The cell of origin is unclear (non-joint origin!!), but it is most certainly NOT cells of the
synovium; less than 10% are intra-articular.
Mostly affect persons in their 20-40 years
# Usually develop in deep soft tissues around the large joints of the extremities, mainly the knee
joint.
# Most synovial sarcomas show t(X, 18)9
.
# Morphology –
» The tumor can be monophasic (only one cell type – spindle cell), or biphasic (both cell types).
» Nonophasic tumors may be mistaken with fibrosarcomas or malignant peripheral nerve sheath
tumor, differential diagnosis is done by immunohistochemistry showing a positive test result
for keratin and epithelial membrane antigen.
» Tumor cells can be of two types:
1) Spindle cell (fibrous type cell) – arranged in cellular fascicles that surround the epithelial cells.
2) Epithelial-like cell – cuboidal to columnar, form glands or grow in solid cords or aggregates.
» Common metastatic site are the lungs, bones and regional lymph node
The patomechanism of glomerular kidney diseases.
The functional unit of the kidney is the nephron, which is composed of the glomerulus and a
STRUCTURE OF THE NEPHRON
tubular system, in which the filtered fluid is converted into urine.
The glomerular capillary wall is the filtration unit, and is composed of 3 layers:
1) Fenestrated endothelium – each pore is 70-100nm in diameter.
2) Glomerular basement membrane – consists of 3 sub layers => lamina rara interna and lamina
rara externa10, between them is the lamina densa
3) Visceral epithelium – composed of podocytes that possess interdigitating processes adherent to
the lamina rara externa create by their processes 20-30nm wide filtration slits that are covered
by a slit membrane. Podocyte slit diaphragm are an important diffusion barrier for plasma
proteins and synthesis of the GBM components.
The glomerular structure is supported by mesangial cells, lying between the capillaries, which
have contractile, proliferative abilities, laying down CT and secretion of active mediators.
# The selective permeability depends on the size of the molecule, the charge (cationic are more
permeable) of molecule
CLINICAL MANIFESTATION OF RENAL DISEASE
can be grouped into reasonably well-defined syndromes
Azotemia is an elevation of blood urea nitrogen and creatinine levels reflects a decreased
glomerular filtration rate (GFR) Prerenal azotemia is seen when there’s hypo perfusion of the
kidney -decrease in GFR Post renal azotemia – urine flow is obstructed below the level of the
kidney
Uremia when azotemia gives rise to clinical manifestations metabolic and endocrine alterations
incident to renal damage
Major syndromes:
* Nephritic syndrome: due to glomerular injury (most common - post streptococcal
glomerulonephritis); visible/microscopic hematuria, some level of oligouria and azotemia and
hypertension.
- Nephrotic syndrome: heavy proteinuria (>3.5g/day), hypoalbunemia, severe edema,
hyperlipidemia and lipiduria. - Asymptomatic hematuria: non-nephrotic proteinuria, usually due to mild glomerular
abnormalities. - Rapidly progressive glomerulonephritis: nephritic synd that progress to rena failure in weeks
to months - Acute kidney injury: dominated by acute oliguria or anuria and azotemia. May result from
glomerular injury, intestinal injury, vascular injury or acute tubular injury. - Chronic kidney disease: prolonged symptoms and signs of uremia, due to progressive
scarring in the kidney.
Urinary tract infection: characterized by bacteriuria and pyuria. May be symptomatic or
asymptomatic, may affect the kidney (pyelonephritis) or the bladder (cystitis) only.
- Nephrolithiasis (renal stones): manifested by renal colic-cherecter abd. Pain , hematuria
(without casts) and recurrent stone formation.
MECHANISM OF GLOMERULAR INJURY
Primary glomerular diseases- the kidney is the predominant organ involved (e.g minimal
change GN). In Secondary glomerular diseases- injury is caused by a systemic disease
(SLE, hypertension, diabetes mellitus, Alport syndrome).
Most types of primary glomerular diseases, and many of the secondary diseases, are caused by immune
reactions. Which come in 2 types :
1.antibody-associated
# Circulating immune complexes Injury resulting from deposition of soluble circulating
antigen-antibody complexes in the glomerulus.
Complexes are formed due to exposure to antigens that DO NOT originate in the
glomerulus. The deposition of these complexes produces injury through the activation of
the complement system and recruitment of leukocytes.
The glomerular lesions usually consist of leukocytes infiltration into glomeruli, and proliferation of endothelial,
mesangial and epithelial cells.
in situ immune complexes Injury by antibodies reacting in situ within the glomerulus,
either with glomerular antigens or with molecules planted within the glomerulus.
The antibodies react directly with antigens fixed or planted in the glomerulus.
Planted antigens include nucleosomal complexes in patients with SLE, bacterial products egendostroptosin
expressed by group A streptococci, IgG which tend to deposit in the
mesangium and the immune complexes themselves.
in most cases planted antigens induce a granular pattern under immunofluorescence microscopy.
Antibodies against glomerular cell components In anti-glomerular basement
membrane (GBM) glomerulonephritis, autoantibodies are produced against the
GBM14.Deposition of anti-GBM antibodies appears linear in immunoplerescence.
The GBM antigen responsible for the production of these antibodies is a domain in collagen
type IV of the GBM.
Constitute less than 1% of glomerulonephritis cases, its results include severe glomerular damage- with necrosis, crescents and rapidly progressive.
Anti-GBM may cross react with the basement membrane of the alveoli resulting in both
kidney and alveoli lesions known as Goodpasture syndrome.
2.cell-mediated Glomerular injury is caused by sensitized T cells, and may explain
incidents in which there were no deposits of antibodies or immune complexes.Even so, it
has been difficult to establish the exact role of T cells or cell-mediated immune response
in any form of glomerulonephritis.
Mediators of immune injury
# Complement-leukocyte mediated injury – activation of complement generates
chemotactic agents (mainly C5a) that help recruit neutrophils; the neutrophils
release proteases, oxygen-derived free radicals that cause cell damage and
arachidonic acid metabolites which contribute to reduction in GFR.
Complement dependent injury (when there are no neutrophils) – activation of the
membrane attack complex (C5-C9), which causes the creation of pores in the
GBM. And up-regulates TGF-β receptors on podocytes (stimulates synthesis of
ECM).
Monocytes and macrophages – infiltrate the glomerulus during the immune
response and release a vast number of biologically active molecules.
# Platelets – aggregate in the glomerulus during the immune response and release
prostaglandins and GF.
# Resident glomerular cells(mesangial,epithelial, endothelial) – can be stimulated
to secrete mediators
# thrombin – produces as a consequence of intraglomerular thrombosis cause
leukocytes infiltration and glomerular cell proliferation.
OTHER THEN IMMUNE MECHANISMS:
1) Podocyte injury:
# reflected by morphologic changes including; effacement of foot processes,
vacuolization, retraction ad detachment of cells from the GBM.
clinical signs: proteinuria ( mainly due to loss of the normal slit membrane).
2) Nephron loss:
# maladaption occurs in the remaining nephrons, for example: hypertrophy causig
an increase in the single nephron GFR, and capillary hypertention.
The remaining nephrons become maladaptive which leads to further endothelial
lesions and podocyte inury, increase in protein permeability and accumulation of
proteins and lipids in the mesangial matrix.
The final outcome is sclerosis of a portion (segmental) or complete sclerosis of the
glomeruli.
Diseases causing nephrotic syndrome
Characterize by proteinuria lead to hypoalbuminemia and edema. Glomerular disorders(in BM or
THE NEPHROTIC SYNDROME
podocyte) characterized by increased permeability to plasma proteins (mainly albumin)-
proteinuria (> 3.5 g/day) resulting in cherecter clinical manifestations:
1) Massive proteinuria – daily protein loss in the urine of 3.5g or more.
2) Hypoalbuminemia – serum albumin concentration of less than 3g/100 ml.
3) Generalized edema – also called anasarca, results from decreased plasma oncotic pressure.
Usually starts with periorbital edema, the edema is an character clinical manifestation
4) Hyperlipidemia and lipiduria – caused by increased hepatic lipoprotein synthesis. may be due to
hypoalbuminemia that triggers synthesis of lipoprotein or massive proteinuria causes loss of an
inhibitor of their synthesis.
5) Hypercoagulable state—due to loss of antithrombin III
Derangement of the capillary wall increased permeability leakage of plasma proteins into
filtrate proteinuria serum albumin hypoalbuminemia plasma ocnotic pressure
secretion of rennin by the renal juxtamedullary cells (due to decrease in intravascular volume)
angiotensin-aldosterone axis stimulation retention of salt & water by the kidney edema
# In children, nephritic syndrome is usually the primary illness , while in adults it is usually a
secondary manifestation to a systemic disease
May caused 2ndry to diabetes or systemic amyloidosis
MINIMAL-CHANGE DISEASE (lipoid nephrosis)
# Seen mainly in young children (also may be in adult) Most common cause of nephrotic syndrome
in children usually idiopathic (may be associated with Hodgkin lymphoma)
Pathogenesis – characterize by damage to podocyte layer of glomerular filtration apparatus lead
to proteinuria the damage caused by T-cell derived cytokines that damages the podocyte foot
processes.
Morphology – Characterized by glomeruli that have normal appearance (in light microscopy), but
show disappearance of podocytes foot processes (in electron microscopy) No immune complex
deposits; negative immunofluorescence.
The cells of the proximal convoluted tubules are heavily laden with protein droplets and lipids. The cytoplasm of the podocytes appears flattened; the
epithelial cells undergo vacuolization and occasional focal detachment.
Clinical features – leads to nephrotic syndrome, there’s no hypertension, and usually renal
function is preserved. Protein loss is usually confined to smaller proteins- selective proteinuria
(albumin); response to steroid therapy -corticosteroid treatment is used.
MEMBRANOUS NEPHROPATHY (membranous glomerulonephritis)
A progressive disease, most common for ages between 30-60 years Characterized by the presence
of sub epithelial immune complexes deposits along GBM in early stages, the glomeruli appear
normal, but later the show diffuse thickening of the capillary wall.
One of the major causes of nephrotic syndrome. In most cases it is an idiopathic (primary) disease.
Can be secondary to: Infections (chronic hepatitis B/C, syphilis). Solid Malignant tumors, mainly
melanoma, and carcinoma of lungs and colon. SLE and autoimmune conditions.
Drugs (penicilamine, non-steroidal anti-inflammatory agents).
Pathogenesis – a form of chromic immune complex glomerulonephritis, induced by antibodies
reacting with intrinsic or planted glomerular antigens; a podocyte antigen, the phospholipase A2
receptor, is the antigen that is most often recognized by the antibodies.
Morphology –Diffuse subepithelial immune deposits separate the GBM by small protrusions18,
resulting in thickening of the GBM H&E- LM. Due to immune complex sub epithelial deposition
along GBM see granular appearance in IF. in EM sub epithelial deposits, spike and dome pattern
the podocytes show effacement of foot processes
Clinical features – development of nephrotic syndrome (some may have a lesser degrees of
proteinuria)
Only 40% suffering from progressive disease will have renal failure after 2-20
years. Poor response to steroids
FOCAL & SEGMENTAL GLOMERULOSCLEROSIS
It is characterized by sclerosis affecting some, but not all glomeruli (focal involvement), and
involving only segments of each affected glomerulus (segmental involvement).
May be primary, accounts for 20%-30% of nephritic syndrome Usually idiopathic-May be
secondary to:
1) May be associated with HIV, heroin use, and sickle cell disease
2) As a maladaptation after nephron loss.
3) In inherited or congenital forms resulting from mutations affecting cytoskeletal or related proteins
expressed in podocytes (podocin).
Pathogenesis – The pathogenesis of primary FSGS is unknown, may be the progression of
minimal-change disease ,Injury to the podocytes is thought to be the initiating event of primary
FSGS. Deposition of hyaline masses in the glomeruli entrapment of plasma proteins and lipids
in foci of injury where sclerosis has developed.
Morphology –
» Light microscopy The affected glomeruli exhibit segmental increased mesangial matrix,
obliterated capillary lumens, and deposition of hyaline masses (hylinosis) and lipid droplets.
» Florescence No immune complex deposits but Nonspecific trapping of immunoglobulins, mainly
IgM, and complement proteins C3 in areas of hylinosis.
» Podocytes exhibit disappearance - effacement of foot processes.
» Progression of the disease leads to global sclerosis of the glomeruli with tubular atrophy and
interstitial fibrosis. Collapsing glomerulopathy – collapse of the entire glomerular tuft and
podocyte hyperplasia. May be in primary cases, or associated with HIV.
Clinical features – higher incidence of hematuria and hypertension, non-selective proteinuria, poor
response to corticosteroids therapy, development of end-stage renal failure (in 50% of the cases).
MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
Characterized by alterations in the GBM and mesangium result from proliferation of glomerular
cells. Patient may exhibit nephrotic or nephritic picture. Or sub nephrotic proteinuria
# Pathogenesis – There are two major types of MPGN (MPGN type 1 & Dense deposit disease
{once called type 2}), with type I more common (80%).
» Type I – sub endothelial deposit associated with HBV and HCV
» Type II – Type II (dense deposit disease)—intra membra no us; associated with C3 nephritic
Factor (autoantibody that stabilizes C3 convertase, leading to over activation of
Complement, inflammation, and low levels of circulating C3)
Morphology –
» Large glomeruli with lobular appearance. Proliferation of mesangial and endothelial cells. GBM
is thickened and glomerular capillary wall has a “tram track” appearance, this “splitting” of the
GBM is due to extension of processes of mesangial and inflammatory cells into the GBM and
deposition of mesangial matrix.
Type I more prominent train trak appearance then type 2
# Clinical features – Poor response to steroids; progresses to chronic renal failure
# Note membranous GN is the cause when you see lupus patient with nephrotic synd. but most
common lupus kidney is the membranous glomeruloproliferative nephritis comes with
nephritic synd.
Diseases causing nephritic syndrome.
Glomerular disorders cherectrize by glomerular inflamtion (damaging
THE NEPHRITIC SYNDROME
endothelium-GBM-mesangial cells) Main feature of syndrome include hematuria
oliguria & azotemia and hypertension
# Clinical manifestations include acute onset of:
1) Hematuria – with dysmorphic red cells and red cell casts in the urine This
inflammatory reaction injures the capillary walls permitting blood to pass into the
urine
2) some degree of oliguria and azotemia Oliguria (low output of urine).Azotemia
(high levels of nitrogen containing compounds). As result of reduced GFR
3) Hypertension result from fluid retention & sum release of renin from ischemic
kidneys.
4) +/- not severe proteinuria/edema(periorbital)
# Histologically
1. Proliferation of the cells within the glomeruli
2. Inflammatory leukocytes infiltrate
ACUTE POSTINFACTIOUS (POSTSTREPTOCOCCAL) GLOMERULONEPHRITIS
one of the more frequently occurring glomerular disorders This glomerulonephritis usually
develops following a streptococcal infection (beta-hemolytic, group A –nephritogenic strain
carry M protein).although may develop following other infections
usually seen in children but also may see in adult Children rarely (1%) progress to renal
failure.Some adults (25%) develop rapidly progressive glomerulonephritis (RPGN).
Pathogenesis- 1 to 4 weeks after the initial infection group A streptococcal nephritogenic
infection (localized to the pharynx or skin) see m Prot.
Molc mimicry result in autoreactive AB against glomerular components as GBM . glomerular deposition of immune complexes with activate the alternative complement pathway lead to infiltration of leukocytes (C5a attract
neutrophils etc.…) resulting in proliferation of and damage to glomerular cells pathogenesis
include streptococcal exotoxin B (Spe B) SpeB may induce immune-complex-mediated
glomerulonephritis as SpeB deposits colocalizes with complement and IgG and is present in the
sub epithelial humps that are the hallmark lesion of PSGN Nephritogenicity may be related to its
plasmin-binding activity of bough that would induce inflammatory reactivity and glomerular
basement membrane (GBM) degradation as, plasmin receptor of strep. co-localizes in
glomeruli mesangial cells with plasmin, but not with IgG or complement .bout SPEB70,
71 and
NAPlr72 are capable of inducing chemotactic (monocyte chemoattractant protein 1) and IL-6
moieties in mesangial cells
LM- diffuse increased cellularity - proliferation and swelling of endothelial and mesangial cells plus infiltrating
neutrophils and monocytes. sometimes there is necrosis of endothel cell and mass named crescents is visable in
part of glomeruli
IF -Granular IgG and C3c within the capillary walls +/- mesangial deposition
EM -Intramembranous or most often, subepithelial “humps”
and hypertension, BUT with gross hematuria cola urine color .Serum complement levels are low, streprococcal
antibodies may be detected.
IgA NEPHROPATHY
Characterized by the deposition of IgA in the mesangium. The most common cause of recurrent
microscopic/ gross hematuria appearance.
This condition usually affects children, and begins as an episode of gross/microscopic hematuria
within 1-2 days of a nonspecific upper respiratory tract infection.
Pathogenesis –In genetically susceptible individuals mucosal infection may lead to increased
IgA production21, some of which is abnormal, and deposition of IgA or IgA-containing immune
complexes in the mesangium activate complement (alternative) cause glomerular injury.
Also in liver disease defect in hepatobiliary clearance on IgA complexes (secondary IgA
nephropathy).
Morphology –
LM: vary considerably may see focal proliferative GN /mesangioproliferative GN /crescentic
GN
IF: mesangial deposition of IgA, often with C3
EM: electron-dense deposits in the mesangium
# Clinical- most often affects children and young adults50% present with gross hematuria after an
infection of the respiratory tract hematuria typically lasts for several days in recurrent episodes
over very long period of time there is risk to develop chronic renal failure -in 25% to 50% of
cases over a period of 20 years
HEREDITARY NEPHRITIS
A group of hereditary glomerular disease caused by mutation in the genes encoding for GBM
proteins.
Most common is the Alport syndrome, in which nephritis is accompanied by sensory hearing
loss and eye disorders22
Pathogenesis – the GBM is composed of type IV collagen; which is a heterotrimer composed of
α3, α4, α5 chains. Mutation in one of the α chains (crucial for lens, cochlea and glomerulus) will
cause Alport syndrome.
Morphology – glomeruli appear normal until late in course, when secondary sclerosis may
occur. In some cases, interstitial cells appear foamy as a result of accumulation of fats and
mucopolysaccharides (foam cells) as a reaction to proteinuria.
With progression, glomerulosclerosis; vascular sclerosis; tubuar atrophy and interstitial fibrosis are
typical changes.
GBM is thin at first, and late in course the GBM develops irregular foci of thickening with pronounced
splitting and lamination of the lamina densa basketweave appearance
# Clinical course – most common form of inheritance is X-linked (mutation in α5 chain) males are
affected more frequently and sevearly female carrier asymptomatic rarely, inheritance may be autosomal recessive/dominant (defects in α3/4 chains). At age of 5 to 20 see gross or microscopic hematuria and proteinuria renal failure develops between 20 and 50 years of age
Rapidly progressive glomerulonephritis.
Glomerulum-capillary network, glomeruli-corpuscle
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS
A clinical syndrome leading to renal failure in short time ~weeks and may arise from different types of
glomerulonephritis.
Characterized by:
» Progressive loss of renal function with Severe oliguria and azotemia
» Laboratory findings of nephritic syndrome
» Histologically, formations of crescents are seen between Bowman’s capsule and the glomerular capillary
network, due to proliferation of parietal epithelial cells
Etiology may be learned from immunofluorescence pattern:
ANTI-GLOMERULAR BASEMENT MEMBRANE CRESCENTIC GLOMERULONEPHRITIS
Characterized by linear deposits in immunofluorescent of IgG and C3 on the GBM.
May be idiopathic but in some cases see AB deposits on BM of alveolar capillaries if such as patient with
hematuria and hemoptysis its Goodpasture syndrome24. Classic seen in young adult male.
Morphology: Kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surface.
Glomeruli show segmental necrosis and crescents appearance In time, may undergo scarring
glomerulosclerosis develops
IMMUNECOMPLEX MEDIATED CRESCENTIC GLOMERULONEPHRITIS
Granular pattern of staining is characteristic finding in immunofluorescent
Rapid progressive GN with Crescents may be the complication of any immune-complex nephritides
most common associated with post streptococcal GN, diffused proliferative GN such as most common
SLE-kidney , IgA nephropathy and Henoch-Schonlein purpura
Morphology: Segmental necrosis and crescents are present. In contrast with Anti-GBM Crescentic
Glomerulonephritis, segments of glomeruli without necrosis show the underlying immune complex GN.
PAUCI-IMMUNE CRESCENTIC GLOMERULONEPHRITIS
Defined as no anti-GBM antibodies / immune complex deposition are detected not in IF nor EM.
Although Segmental necrosis and crescents are seen.
In many cases, the condition is limited to the kidney and is therefore called idiopathic.
Antineutrophil cytoplasmic antibodies (ANCA) typically are found in the serum in some cases crescentic GN is a
component of systemic vasculitis (e.g. microscopic polyagniitis pANCA or Wegener granulomatosiscANCA)
Chug Strauss got eosinophilia and asthma and granulomatous inflammation that polyangitis don’t have
even both come with pANCA
Acute and chronic pyelonephritis.
A purulent inflammation of the kidney and renal pelvis, caused by bacterial infection may origin
A group of inflammatory diseases that primarily involve the tubules and interstitium. The
glomeruli may be spared or affected only late in course.
» Pyelonephritis as you talk on bacterial infection of upper urinary tract prominently involving
The renal pelvis25 , most common form of TIN. The term interstitial nephritis relating to TIN
nonbacterial origin mostly results from drugs, metabolic disorders (hypokalemia), viral infection
and immune reaction.
ACUTE PYELONEPHRITIS
from lower part of UT or from blood hematogenous less common -molnar
Pathogenesis – Principal causative agents are enteric G(-) rods, mainly E.coli, but also Klebsiella,
Enterococcus faecalis. With outflow obstruction26 , bladder dysfunction- vesicoureteral reflux 3
,
catheter see infection may ascend…
# Morphology – Abscess with pus may be seen on cut surface, histo see mix inflammatory infiltrate
marked by neutrophils in tubular sys. Interstitum and b.v. -glomeruli are spared the affected areas
show abscess loss of parenchymal structures note it isn’t diffused .one complication is papillary
necrosis(ischemic and supportive); there are 3 predisposing conditions for this: diabetes, urinary
tract obstruction and analgesic abuse
Clinical features – Presents with fever, flank pain, and leukocytosis in addition to symptoms of
cystitis urgent frequent small amount of urine
CHRONIC PYELONEPHRITIS
In case of recurrent injury see morphology of chronic inflammation including scarring and
deformities of pelvic calycal system uneven interstitial fibrosis Chronic inflammatory infiltrate of
lymphocytes, plasma cells, and neutrophils. Dilation/contraction of tubules, with atrophy of the
lining epithelium. Dilated tubules contain colloid casts similar to thyroid appearance thyroidization.
#Can be divided into two forms:
1) Chronic obstructive pyelonephritis – recurrent infections superimposed on obstruction lesions,
leading to recurrent renal inflammation scarring, eventually causing chronic pyelonephritis.
2) Chronic reflux-associated pyelonephritis (reflux nephropathy) – results from superimposition of
UTI on congenital vesico-urethral reflux and intrarenal reflux.
The damage may cause
scarring/atrophy unilaterally or bilaterally
Clinical features – hypertension, asymmetrical contraction of the kidneys, polyuria eventually,
secondary glomerulosclerosis (with proteinuria)
UROCYSTITIS
Infection of the bladder Presents as dysuria(burning sensation), urinary frequency, urgency, and
suprapubic pain; systemic signs (e.g., fever) are usually absent.
Patho mechanisems:
o infections Principal causative agents are enteric G(-) rods, mainly E.coli, but also Klebsiella,
Staphylococcus saprophytics—increased incidence in young, sexually active women Proteus
mirabilis—alkaline urine with ammonia scent Enterococcus faecalis. Types may be : Acute
Chronic Granulomatous
o Vesico-ureteral reflux
o Urinary outflow disability- Causes include prostatic hyperplasia; bladder stones; tumors
neurologic disease, diabetic bladder
Fistula formation- Abnormal connection formed between the bladder and the surrounding
organs may create from Malignant tumors Postirradiating necrosis Crohn dissease Cervical
carcinoma /Rectum carcinoma
Laboratory findings1Urinalysis—cloudy
urine with pyuria > 10 WBCs/high power field (hpf)
2Dipstick—Positive leukocyte esterase (due to pyuria) and nitrites (bacteria convert nitrates to
nitrites)
- Culture—greater than 100,000 colony forming units (gold standard)
Note! Sterile pyuria is the presence of pyuria (> 10 WBCs/hpf and leukocyte esterase) with
negative urine culture.
Suggests urethritis due to Chlamydia trachomatis or Neisseria
gonorrhoeae (dominant presenting sign of urethritis is dysuria)
The pathogenesis of hypertension. Hypertensive vascular disease.
The blood pressure depends on the regulation of cardiac output-systolic (p) and total peripheral
HYPERTENSION
Hypertension – Increased blood pressure; may involve pulmonary or systemic circulation
,Systemic HTN is defined as pressure over 140/90 mm Hg (normal < 120/80 mm Hg) and its
Divided into primary or secondary types based on etiology
resistance-diastolicb.p. (regulated by arterioles ) hence Contributors to hypertension:
1) Reduced renal Na+ excretion – causes an obligatory increase in fluid volume and increased
cardiac output, resulting in elevated blood pressure.
2) Vascular change – vasoconstriction or structural changes in the vascular wall that result in
increased resistance( Aortic rigidity)
PATHOGENESIS OF HYPERTENSION
Primary (essential) hypertension- HTN of unknown etiology accunts for about 95% of cases,
although viewed as multifactorial condition involving inheritance and environment:
1) Risk factors include age, race (increased risk in African Americans, decreased risk in Asians)
2) Genetic factors – defects in the genes encoding components of RAS, familial history of
hypertensive disease .
3) Environmental factors – stress, obesity, smoking, physical inactivity and heavy consumption
of salt
# Secondary hypertension-It is secondary to a known underlying cause.
» Renal artery stenosis is a common cause, Stenosis decreases blood flow to glomerulus.
Responds by secreting renin, which converts Angiotensinogen to angiotensin .Angiotensin I is
converted to angiotensin 11 (ATII) by angiotensin converting enzyme ATII raises blood
pressure by (I) contracting arteriolar smooth muscle,increasing total peripheral resistance and
(2) promoting adrenal release of aldosterone, which increases resorption of sodium in the distal
convoluted tubule (expanding plasma volume).
Leads to HTN with increased plasma renin and
unilateral atrophy (due to low blood flow) of the affected kidney important causes of stenosis
include atherosclerosis (elderly males) and fibromuscular dysplasia (young females)
» Adrenals or other endocrine organ disorders:
1) Conn syndrome (primary hyperaldosteronism) – the overproduction of aldosterone, mainly due
to adrenal adenoma.
2) Cushing syndrome – excess production of cortisol that enhances the vasoconstrictive effect of
epinephrine.,hyperthyroidesiem
3) Diabetes mellitus – when complicated by diabetic glomerulonephritis
HYPERTENSIVE VASCULAR DISEASE
# Hypertension can cause cardiac hypertrophy and heart failure (hypertensive heart disease), aortic
dissection, renal failure and cerebrovascular hemorrhages-strokes. Hypertensive vascular disease,
induced by hypertension:
» In large to medium size .a. see increased tendency to atherogenesis plus risk to develop aortic
dissection and cerebrovascular hemorrhages
There are 2 form of small b.v. hypertension related diseases
» Hyaline arteriolosclerosis – homogenous, pink proteinaceous thickening of the walls of arterioles
with loss of underlying structural detail and narrowing of the lumen => plasma components leak
across the vascular endothelium,. Also seen in diabetic both lead to nephrosclerosis glomerular
scarring… link to bening HT
» Hyperplastic arteriolosclerosis – related to more acute blood pressure elevations, associated with
“onionskin”, concentric, laminated41 thickening of the walls of arterioles with luminal narrowing
=> the hyperplastic changes are accompanied by fibrinoid deposits and vessel wall necrosis.
Complications of hypertension
Progressive heart failure = left ventricular hypertrophy adaptation to pressure overload (left
ventricule) ↓ concentric (compensated) ↓ dilatative (decompensated)
Cerebrovascular stroke - atherosclerosis - reversible ischemic attack - haemorrhagic infarction
(encephalomalacia) - apoplexia (Pathology) sudden loss of consciousness, often followed by
paralysis, caused by rupture or occlusion of a blood vessel in the brain (primary hemorrhage)
Charcot–Bouchard aneurysms (also known as miliary aneurysms or microaneurysms) are
aneurysms of the brain vasculature which occur in small blood vessels (less than 300 micrometre
diameter).
Charcot–Bouchard aneurysms are most often located in the lenticulostriate vessels of
the basal ganglia and are associated with chronic hypertension.
Charcot–Bouchard aneurysms are a common cause of cerebral hemorrhage. cerebral haemorrhage and subarachnoid
haemorrhage due to ruptured berry aneurysms Berry aneurysm: A small aneurysm that looks like
a berry and classically occurs at the point at which a cerebral artery departs from the circular
artery (the circle of Willis) at the base of the brain. Berry aneurysms frequently rupture and bleed.
in patients with benign hypertension
Renal demage - nephrosclerosis - Hyperplastic arteriolosclerosis
Angina pectoris. Acute coronary syndrome.
ISCHEMIC HEART DISEASE
A group of related syndromes resulting from myocardial ischemia, most common cause for the
reduction in coronary blood flow is atherosclerotic disease. Hence risk to develop IHD are same as ones
of develop AS (age, gender, metabolic state, smoking etc.)
IDH can also be the result of increased demand (increased heart rate, hypertension), or of diminished
oxygen-carrying capacity (anemia, CO poisoning).
The clinical manifestations of IDH are angina pectoris, acute myocardial infarction, chronic IHD and
sudden cardiac death.
ANGINA PECTORIS
It is a periodic chest pain caused by reversible myocardial ischemia. Pressing retrosternal pain not
related to breading, no elevation in myocardial enzymes opposing to MI, character ECG changes may
seen (coronary/hyper acute t waves or ST alteration or both) and relief upon nitroglycerin
administration…
There are 3 variants of AP:
1) Typical (stable) AP
Episodic chest pain50 result of reversible injury to myocyte (swelling hallmark) associated with
increased myocardial oxygen demand (tachycardia, hypertension =exertion/emotional stress etc.)
Usually occurs due to fixed atherosclerotic narrowing (>70%) of one or more coronary arteries =>
myocardial oxygen supply is sufficient no stress , but cannot be increased to meet the adequate
demand.
Can be relieved by drugs that cause peripheral vasodilation, as nitroglycerin administration lead to
immediate relief- vasodilation of mainly veins as reduced preload thus o2 demand …
2) Prinzmetal (variant) AP
Episodic-less then 20 min chest pain unrelated to exertion, occurring at rest due to Short term
complete occlusion of blood supply like in coronary artery spasms/repeated complete obstructive
thrombus who partially lysed and reformed, usually take place near an existing atherosclerotic plaque,
although normal vessels can also be affected.
Can be relieved by vasodilators such as nitroglycerin and Ca2+ channel blockers. ECG ST elevation
transmural ischemia ,deadly may lead to arrhythmia and cardiac arrest. Main patient present it are
male smoker
3) Unstable AP (crescendo angina)
AP show also at rest from incomplete occlusion of coronary, It is associated with
atherosclerosis/plaque disruption and superimposed thrombosis, embolization… risk to progress to
potentially irreversible injury ischemia.- It is called pre-infarction angina
Characterized by increasing frequency of pain => episodes tend to be more intense and long lasting
than stable AP.
ACUTE CORONARY SYNDROME
Refers to any of the 3 catastrophic outcomes of IHD see picture upon coronary atherosclerosis and
typical AP may develop chronic ischemic heart diseas or progress to acute coronary syndrome.
- Unstable AP
- Acute MI-previously non major occlusive plaque build thrombose and see acute unset sever ischemia
- Sudden cardiac death-usually refer to sudden collapse of circulation as from arrhythmia without
prominent myocardial damage
Associated with coronary thrombosis/embolisem-acute pluqe changes,vasoconstriction such upon
agonist of epi ,platelet local realis, endothelin other vasoconstrictor realis upon endothelial imbalance
ext. endothelin and cocaine usage.
Symptoms include angina pectoris but sever, shortness of breath, nausea and sweating and sympathetic
dominance .
Congenital heart diseases.
Congenital heart diseases are abnormalities of the heart or great vessels that are
CONGENTIAL HEART DISEASE
present at birth, most of which arise during weeks 3-8 of gestation when major
cardiovascular structures develop…
» In most cases (~90%) the cause of the abnormality is unknown.
» Environmental factors – congenital rubella infection, teratogens exposure
etc..
Congenital rubella syndrome (CRS) can occur in a developing fetus of a
pregnant woman who has contracted rubella, usually in the first trimester
The classic triad for congenital rubella syndrome is:[4]
Sensorineural deafness (58% of patients)
Eye abnormalities—especially retinopathy, cataract,
and microphthalmia (43% of patients)
Congenital heart disease—especially pulmonary artery stenosis and patent
ductus arteriosus (50% of patients)
» Genetic factors – familial forms of congenital heart disease, and certain
chromosomal abnormalities (trisomy’s 13, 15, 18 & 21, and Turner
syndrome).
» Several congenital heart diseases are associated with mutation in
transcription factors => TBX560, NKX2.561
» Abnormal development of neural crest cells can cause defects in the
formation of the outflow tract => caused by deletions of a segment in the
long arm of chromosome 22.
1) Malformations causing a left-to-right shunt
2) Malformations causing a right-to-left shunt.
3) Malformations causing obstruction.
LEFT-TO-RIGHT SHUNTS
# Shunts permit the flow of blood from the left heart to the right heart.most
common CHD.
pulmonary blood flow, and expose the low pressure & low resistance
pulmonary circulation to increased pressure and volume, resulting in right
ventricular hypertrophy and eventually right-sided failure , but they are NOT
associated with cyanosis as an early feature.
- Atrial septal defects: abnormal fixed opening in atrial septum not closed by the
septum secundum, so a shunt exists across from left to right.
atrium in embryo life its open as valve closed on its left side by a flap of tissue
derived from the primary septum, which acts as a one way valve that allows
right-to-left blood flow keep embryo circulation. At the time of birth, pulmonary
vascular resistance drops and systemic arterial pressure rises, causing the pressure
in the left atrium to exceed those of the right atrium, resulting in the functional
closure of foramen ovale.
1) Ostium secundum ASD – the most common (90%), occurs when septum
secundum does not enlarge sufficiently to cover the ostium secundum. Significant
large lesion induce vol. overload so right atrial and ventricular dilation, right
ventricular hypertrophy, and dilation of the pulmonary artery.
2) Ostium premium ASD – less common (5%), occurs when the septum premium
and endocardial cushion fail to fuse; associated with other abnormalities in
structures derived from the endocardial cushion (AV valves malformations cleft
valves as antr leaflet mitral valve…).
3) Sinus venosus ASD – less common (5%), located near the entrance of SVC. often
accompanied by anomalous drainage of the pulmonary veins into the right atrium
or SVC.
openings do so but with time larger openings may end with pulmonary
hypertension with increased pulmonary arterial pressures that eventually led to
reversal and right-to-left shunt, resulting in marked right ventricular hypertrophy.
wall it develops present =Normally, the left atrial pressure keeps the foramen
closed, but if right atrial pressures rise with pulmonary hypertension (as with
pulmonary embolus), the foramen may open and even allow a thrombus to go
from right to left. This is a rare entity called “paradoxical embolus”……
- ventricular septal defects
# Incomplete closure of the ventricular septum. left-to-right shunts,
# The ventricular septum is formed by the fusion of an intraventricular muscular
ridge, and a thinner membranous portion that grows from the endocardial
cushion.
septum. Most VSDs close spontaneously in childhood.
» Size and location of defects are variable.
» In defects associated with significant left-to-right shunts, the right ventricle is
hypertrophied and often dilated.
» The diameter of the pulmonary artery is increased due to increased volume
ejected by the right ventricle.
severe left-to-right shunt, complicated by pulmonary hypertension and congestive
heart failure; progressive pulmonary hypertension results in reversal of the shunt
and cyanosis
- Patent ductus arteriosus
and a left-to-right shunt develops Ductal closure is delayed in infants with
hypoxia, resulting from respiratory distress or heart disease.
pulmonary artery to the aorta => bypass the unoxygenated lungs. After brith,
ductus arteriosus constrics and becomes ligamentum arteriosum.
the aorta just distal to the origin of the left subclavian artery.In PDAs, some of
the blood flowing out of the left ventricle is directed back to the lungs => volume
overload => dilation of proximal pulmonary arteries, left atrium and ventricle =>
pulmonary hypertension => right heart hypertrophy and dilation.
murmurs; large defects can lead to Eisenmenger syndrome with cyanosis and
congestive heart failure.
RIGHT-TO-LEFT SHUNTS
due to direct introduction of poorly oxygenated blood from the right side of the heart, into the
arterial circulation.
paradoxical embolism.
- Tetralogy of Fallot
The most common cause of cyanotic congenital heart disease. Results from abnormal
division into the pulmonary trunk and aortic root.
Pulmonic stenosis results in right ventricular hypertrophy and a right-to-left shunt across a
VSD, which also has an overriding aorta
Composed of 4 features:
1) VSD-near the membranous portion of the septum.
2) Obstruction to the right ventricular outflow tract- The proximal aorta is larger than normal
with diminished pulmonary trunk, pulmonary stenosis protects the lungs from overload and
pulmonary hypertension.
3) An aorta that overrides the VSD.
4) Right ventricular hypertrophy- The heart is large and “boot shaped” due to right ventricular
hypertrophy.
- Transposition of Great Vessels
aortopulmonary septa => aorta arises from the right
ventricle, and the pulmonary trunk originates from
the left ventricle. The atrium-to-ventricle connections
are normal.
systemic and pulmonary circulations, a condition
inadequate with postnatal life. A VSD, or ASD with
PDA, is needed for extra uterine survival. There is
right-to-left shunting.
cyanosis; the forecast of neonates with TGA depends
on the degree of shunting, the magnitude of tissue
hypoxia and the ability of the right ventricle to
maintain systemic pressure.
OBSTRUCTIVE LESION
# Congenital obstruction to blood flow that
occurs at the level of the heart valves, or
within a great vessel.
stenosis, and coarctation of the aorta.
Coarctation of the aorta
# The narrowing of the aorta. Males are affected twice as much as females but It
is common in girls who have Turner syndrome..
# There are 2 forms of aortic coarctation
Infantile –
» hypoplasia of the aortic arch narrowing of the aortic segment between
the left subclavian artery and ductus arteriosus just before it
Ductus arteriosus is usually patent and is the main source of blood
delivered to distal aorta.
The right side of the heart must supply the body (distal to the
narrowing), resulting in hypertrophy of the right ventricle.
Adult
- ridge-like in folding of the aorta, just opposite to ligamentum arteriosum sharp constriction of the aorta
- The constricted segment is made up of smooth muscle and elastic fibers that are continuous with the aortic media, lined by a thickened layer of intima
-Ductus arteriosus is closed
-Proximal to the contraction, the aortic arch and its branch vessels are dilated, and athersclrosed (in older patients).
-Hypertrophy of the left ventricle
Coarctation of the aorta may occur as a solitary defect, but in most cases (>50%) it is accompanied by a bicuspid aortic valve.
Chronic obstructive lung disease - chronic bronchitis and emphysema. Small airways disease
(SAD)
Pulmonary diseases can be classified as:
OBSTRUCTIVE VS. RESTRICTIVE
» Obstructive disease – characterized by limitation of airflow, Expiratory obstruction may result
from anatomic airway narrowing (asthma), or from loss of elastic recoil (emphysema) ,Includes 4
major diseases emphysema, chronic bronchitis, bronchiectasis, and asthma.
Spirometry changes: Decreased expiratory flow rate and decreased forced vital capacity
(FVC), with increased total lung capacity= tot. Amount of air in lung .
Most important FEV/FVC < 0.8 healthy (in COPD both decrease but FEV decrease a lot
from 4L/5L to 2L/4L=0.5)
» Restrictive disease – characterized by reduced expansion of lung parenchyma, accompanied by
decreased total lung capacity
FVC is reduced, and FEV is normal or proportionally reduced so FEV/FVC- near normal!
The restrictive defect occurs in:
severe obesity, diseases of pleura, and neuromuscular
CHRONIC OBSTRUCTIVE PULMONARY DISEASES (COPD)
bronchitis and emphysema both link to smoking and manifest together usually.
Unlike asthma also
an obstructive diseas in COPD the damage lead to IRREVERSIBLE airflow obstruction in asthma
there is REVERSIBLE airflow obstruction
EMPHYSEMA
from multiple small spaces a large air filled space is formed . With the loss of elastic tissue in the
surrounding alveolar septa, radial traction on the small airways is reduced. As a result, they tend to
collapse during expiration—an important cause of chronic airflow obstruction in severe emphysema
» Centriacinar emphysema Most commonly seen as a consequence of smoking in people with no
congenital deficiency of α1-antitrypsin The lesions are more common in the upper lobes
The proximal parts of the acini, formed by respiratory bronchioles, are affected (distal part spared) =>
both emphysematous and normal airspaces exist in the same acinus In severe cases, the distal acinus
also becomes involved
» Panacinar (panlobular) Associated with deficiency of α1-antitrypsin,
The acini are uniformly enlarged from the level of the terminal bronchiole to the alveoli
Tends to occur in lower lung areas
»Distal acinar (paraseptal) emphysema The proximal portion of the acinus is normal, but the distal part is
affected The emphysema is adjacent to the pleura, near areas of fibrosis, scarring or atelectasis * Cause is
unknown. Characterized by the presence of multiple enlarged airspaces (0.5mm-2cm) => may form cyst-like
structures referred to as bullae
»Irregular emphysema Clinically asymptomatic, and the most common form of emphysema.
The acinus is irregularly involved, this condition is almost always associated with scarring, such as in healed
inflammatory diseases.
Protease/antiprotease imbalance – always inhale some small particles (in-between 2-5 microns
less than 2 filter to lymph more than 5 cough out ) which stimulate inflammation
Exposure to toxic substances such as tobacco smoke and inhaled pollutants induce inflammation with
accumulation of neutrophils, macrophage & lymphocytes.
Neutrophils, the main source of cellular proteases, are found in peripheral capillaries (including those of the lungs), and gain access to the alveolar spaces. Release Elastase.
Exasseiv inflammation or lack of protease inhibitors result in emphysema:
- Exposure to toxic substances such as tobacco smoke and inhaled pollutants induce
inflammation with accumulation of neutrophils, macrophage & lymphocytes.
Smoking promotes accumulation of leukocytes, such as neutrophils and macrophages, in the alveoli,
and enhances the elastase activity of macrophages, which is NOT inhibited by α1-antitrypsin
- deficiency of α1-antitrypsin a major inhibitor of proteases (mainly elastase) encoded by
codominant genes The proteinase inhibitor allele (Pi) on chromosome 14- the most common
healthy allele is PiM , mutation as PiZ allele result in misfolding of it ; patients homozygous
to PiZ allele will present panacinar emphysema and may also manifest with liver cirrhosis
cause of accumulation of misfolded alpha 1 antitrypsin in the ER of hepatocytes ;
heterozygous patients are asymptomatic with lower levels of alpha 1 antitrypsin in blood ,
but upon smoking is a great risk for developing emphysema
- Oxidant-antioxidant imbalance – the lung contains antioxidants that keep oxidative damage
to a minimum => smoking increases the amount of free radicals, which deplete these
mechanisms; activated neutrophils also add oxygen species to the alveoli.
In general
- In emphysema there is loss of not only epithelial and endothelial cells but also mesenchymal cells, leading to
lack of extracellular matrix, the scaffolding upon which epithelial cells would have grown. Thus, emphysema
can be thought of as resulting from insufficient wound repair. By contrast, patients with fibrosing lung
diseases have excessive myofibroblastic or fibroblastic response to injury, leading to unchecked scarring.
enhanced volume, which often obscure the heart.Cantriacinar emphysema – lungs appear in deeper
pink, with less volume than in panacinar emphysema.
Micro -> Histologic examination reveals
destruction of alveolar walls without fibrosis, leading to enlarged air spaces.
lipes) weight loss, reduced FEV1, FEV1/FVC is reduced.
# Pink Puffer = Because of prominent dyspnea and adequate oxygenation of hemoglobin, these patients
sometimes are called “pink puffers.”
ASTHMA
respond following exposure to an allergen to which the person has been previously sensitized.
breathlessness, chest tightness, and cough. The hallmarks of the disease are:
Chronic bronchial
inflammation with eosinophils, Bronchial smooth muscle cell hypertrophy and hyperreactivity,
Increased mucus secretion.
1) Atopic (extrinsic) asthma Constitute ~70% of cases Patient has Genetic predisposition to type
I hypersensitivity (atopy) show family history of asthmatic or related hypersensitivity 1
reactions, clinically showed with Associated with other allergic diseases such as allergic rhinitis
and eczema. There is evidence for extrinsic allergen sensitization you can do skin test show
wheal and fler reaction immediate after exposure to this specific allergen.
2) Non-atopic (intrinsic) asthma- triggers are less clear there is negative skin test to common
inhalant allergens and normal serum concentrations of IgE. Caused by viral infections of the
respiratory tract /inhaled air pollutants. Characterized by increased bronchoconstriction response
due to increased airways reactivity Suspect that Viral inflammation of the respiratory mucosa
lowers the threshold of the sub epithelial vagal receptors to irritants.
3) Drug Induced Asthma- Several pharmacologic agents provoke asthma, aspirin being the most
striking example.Mechanism unknown. Maybe due to inhibition of COX pathway without
harming the lipoxygenase pathway shifting the balance toward leukotrines production that
causes bronchial spasm.
4) Occupational Asthma- Asthma attacks usually develop after repeated exposure to the inciting
antigen(s)
of asthma.Caused by IgE (type I hypersensitivity) and TH2-mediated70 immune responses to
environmental antigens (dust, pollens, animal hair, and food).
First exposure to allergen => TH2 cells activation => release of IL-4 & IL-5 => eosinophils recruitment
AND production of IgE (by plasma cells) => sensitization of mast cells (type I hypersensitivity)
reexposure to allergen => immediate reaction is triggered by sensitized mast cells => early reaction see
histamine realis increase primability of post capillary venoules and vasodilation of arteriole also realis
leukotrienes induce bronchoconstriction and vascular primability so initial see constriction and edema
late phase reaction initiated by recruited leukocytes that induce release of mediators from these cells,
and lead to epithelial damage e.g. eosinophils realis major basic protein damage epithel and maintain
bronchoconstriction Major basic protein induces mast cell and basophil degranulation, and is
implicated in peripheral nerve remodellin
# Macro
# Lungs are overdistended because of over inflation.
# Small area of atelectasis
# Bronchi and bronchioles are occluded by thick mucous plugs
# Shed epithelium = Curschmann spirals
eosinophil proteins)
# Air way Remodeling1)
Thickening of airway wall
2) Sub-basement membrane fibrosis
3) Increased vascularity in submucosa
4) An increase in size of the submucosal glands and goblet
Cell metaplasia of the airway epithelium
5) Hypertrophy and/or hyperplasia of the bronchial muscle
expiration.
The victim labors to get air into the lungs and then cannot get it out, so that there is
progressive hyperinflation of the lungs with air trapped distal to the bronchi, which are constricted and
filled with mucus and debris.
- Therapy, usually bronchodilators & corticosteroids.
CHRONIC BRONCHITIS
as a persistent productive cough for at least 3 consecutive months in at least 2
consecutive years.
» Simple chronic bronchitis – most common type, cough raises mucoid
sputum, but NO airway obstruction In the early stages of the disease.
» Chronic asthmatic bronchitis – hyper responsive airways with
bronchospasms => asthma episodes.
» Chronic obstructive bronchitis – heavy smokers that develop outflow
obstruction, usually with associated emphysema.
» Distinctive feature is hypersecretion of mucous.
Irritation (smoking, air pollutants) => hypertrophy & hyperplasia of
bronchial mucous glands, resulting in hyper secretion of mucous =>
increase in mucin-secreting goblet cells of smaller bronchi and
bronchioles
» Irritants also cause inflammation (cytotoxic T cells, macrophages and
neutrophils) *no Eosinophiles
» Whereas the defining feature of chronic bronchitis (mucus hypersecretion)
is primarily a reflection of large bronchial involvement, the morphologic
basis of airflow obstruction in chronic bronchitis is more peripheral and
results from (1) small airway disease, induced by goblet cell metaplasia
with mucous plugging of the bronchiolar lumen, inflammation, and
bronchiolar wall fibrosis, and (2) coexistent emphysema.
» Microbial infection often is present but has a 2ndry role, chiefly by
maintaining the inflammation and exacerbating symptoms.
» Macro = Mucosal lining is hyperemic and swollen by edema, covered by
mucinous or mucopurulent secretion.
» Micro = Enlargement of mucous secreting glands in the trachea and large
bronchi.
» Inflammatory infiltration of mononuclear cells
characterized by goblet cell metaplasia, fibrosis, inflammation, and mucous
plugging.
consequence of fibrosis (bronchiolitis obliterans). It is the submucosal fibrosis
that leads to luminal narrowing and airway obstruction. Changes of
emphysema often co-exist.
# Early stage = No obstruction, only productive cough, no ventilation
problems.
“Blue Bloaters”.
BRONCHIECTASIS
caused by loss of muscle and elastic tissue due to chronic necrotizing
infections. It can be congenital (children with cystic fibrosis, Kartagener
syndrome, immunodeficiency states) or acquired (post-infectious, systemic
autoimmune diseases, bronchial obstruction by foreign bodies or tumors),
most commonly located in the lower lobes, uni- or bilateral. Why obstructive?
Dilated airway impairs laminar air follow instead tubular flow and trapping of
air more force needed for expiration.
- Tumors/foreign bodies/ plugs of mucous. With these conditions, the
bronchiectasis is localized to the obstructed lung segment. - CF (causing wide spread bronchiectasis) due to secretion of abnormally viscid
mucous which predisposes to infections of the bronchia tree. - Immunodeficiency states => due to repeated bacterial infections.
- Kartagener syndrome => an autosomal recessive disorder causing immotile cilia
(dynein protein) and impaired mucociliary clearance infections. (The syndrome
also affects the mobility of the spermatozoa causing sterility in men, situs
inversus and sinusitis)./ Young syndrome: infertility caused by azoospermia, but
without ultrastructural ciliary abnormalities - Necrotizing or suppurative pneumonia (esp. staph. Aureus & spp. Klebsiella).
May predispose patient to later bronchiectasis development e.g. post tuberculosis
bronchiectasis
persistent infection => direct demage to wall or Obstruction => impairs the
clearance of the airways => secondary infection
The tissue is also damaged in part by the host response of neutrophilic proteases,
inflammatory cytokines, nitric oxide This results in damage to the muscular and
elastic components of the bronchial wall.
Additionally, peribronchial alveolar
tissue may be damaged, resulting in diffuse peribronchial fibrosis.
The result is abnormal bronchial dilatation with bronchial wall destruction and
transmural inflammation. The most important functional finding of altered airway
anatomy is severely impaired clearance of secretions from the bronchial tree.
Impaired clearance of secretions causes colonization and infection with
pathogenic organisms, The result is further bronchial damage and a vicious cycle
of bronchial damage.
involving a lobe, segment of the lung. Far less commonly, it may be a diffuse
process involving both lungs; these cases most often occur in association with
systemic illnesses, such as cystic fibrosis (CF) bronchiectasis.
Macroscopically,
the lung has an irregular surface in the affected area. On cut surface, there are
multiple cavities / cystic formations (dilated bronchi), round or oval, of varying
sizes, with a thick, fibrous, gray-whitish wall and muco-purulent content,
associated with changes of the adjacent lung parenchyma (areas of condensation
or fibrosis). With progression, the lung parenchyma can be fully replaced by
dysfunctional bronchial dilatation.
MICRO:
» Chronic inflammation, ulceration of bronchial wall, ossification of bronchial
cartilage.
» Intense inflammatory exudate within the walls of the bronchi and bronchioles and
shedding of the lining epithelium cause extensive areas of ulceration.
» Usually the injury is so severe that the epithelium lining the bronchial tree cannot
regenerate and after healing abnormal dilation and scarring persists as Fibrosis of
the bronchial and bronchiolar walls and peribronchial fibrosis develop in more
chronic cases.
sputum, which may contain blood.Hypoxemia, hypercapnia.
Chronic complications => pulmonary hypertension or cor pulmonale (though
rare).
Respiratory distress syndrome of the newborn. Sudden infant death syndrome.
A syndrome of premature infants caused by developmental insufficiency of
RESPIRATORY DISTRESS SYNDROME OF THE NEWBORN
surfactant production and structural immaturity of the lungs.
decreases with advancing gestational age.
section.
# The fundamental defect is the inability of the immature lung to synthesize
surfactant => in a healthy baby, surfactant is synthesized by type II
pneumocytes, and with first breath rapidly coats the surface of alveoli to
reduce surface tension.
requires greater effort to open alveoli => the infant rapidly tires, and
atelectasis develops.
leading to epithelial and endothelial
damage, and resulting in the
formation of hyaline membranes.
hormones => corticosteroids
stimulate the formation of surfactant
lipids, while high levels of insulin
suppress synthesis by counteracting
the effects of steroids.
» The lungs are of normal size, but
are heavy and relatively airless.
» Have a mottled purple color.
» The alveoli are poorly developed and collapsed.
» If the infant dies within a few hours => only necrotic cellular debris are
present in bronchioles.
» If the infant dies after a few days => Neonatal Respiratory Distress
Syndrome - NRDS (Hyaline membrane disease) is characterized by
collapsed alveoli alternating with hyperaerated alveoli, vascular
congestion and hyaline membranes (resulted from fibrin, cellular debris).
Hyaline membranes appear like an eosinophilic, amorphous material,
lining or filling the alveolar spaces and blocking the gases exchange.
Hyaline membrane is NEVER seen in stillborns or infants who die within
a few hours of birth.
weight of the infant; control of RDS focuses on prevention, either by delaying
labor until the fetal lung matures, or by inducing maturation of the lung.
oxygen for prolonged periods, however, is associated with two wellknown
complications: retrolental fibroplasia (also called retinopathy of
prematurity) in the eyes and bronchopulmonary dysplasia.
SUDDEN INFANT
DEATH SYNDROME
# Definition –
Sudden
unexpected
infant deaths in infants younger than 12 months of age that occur suddenly,
unexpectedly, and without obvious cause after a thorough investigation that
includes complete autopsy, examination of the death scene, and review of
clinical history.
# Pathogenesis – SIDS is a multifactorial condition of overlapping variables:
» A vulnerable infant – intrinsic developmental abnormalities in
cardiorespiratory control. Regions of the brain stem, particularly the
arcuate nucleus located in the ventral medullary surface, play a critical
role in the body’s arousal response to noxious stimuli such as hypercarbia,
hypoxia, and thermal stress encountered during sleep. In addition, these
areas regulate breathing, heart rate, and body temperature.
» A critical period in the development of homeostatic control
mechanisms– these factors may be attributed to the parents (young
mother, smoking during pregnancy, short intergestational intervals), or
to the infant (brain stem abnormalities, prematurity).
» An exogenous stressor – factors from the environment (prone sleep
position decres responsiveness to noxius stimultion, sleeping on soft
surface, hyperthermia).
# Morphology –
» Multiple petechiae present on the thymus, visceral and parietal pleura, and
epicardium.
» Lungs are congested Vascular engorgement (filled with blood), with or
without pulmonary edema.
» Hypoplasia of the arcuate nucleus.
Summary Sudden Infant death syndrome
SIDS is a disorder of unknown cause, defined as the sudden death of an infant younger than 1 year of age that remains unexplained after a thorough case investigation including performance of an autopsy. Most sids deaths occur between the ages of 2 anc 4 months.
The most likely basis for sids is a delayed development in arousal reflexes and cardiorespiratory control.
Numerous risk factors have been proposed, of which the prone sleeping position is best recognized, hence the success of the back to sleep program in reducing incidence of sids
Bacterial pneumonias. Lung abscess.
Pneumonia can be very broadly defined as any infection in the lung. Development of such as infection
(Check topic in diff note again)
is due to impairment of normal defense mechanisms or lowered host resistance
clearance (mucociliary action) and alveolar clearance (alveolar macrophages) Impairment is due to
primary or acquired immunosuppression, suppression of cough reflex (drugs, virus, coma, anesthesia),
injury to mucociliary apparatus (smoking, virus, Kartegeners syndrome), injury to macrophages
(tobacco, alcohol, anoxia), pulmonary congestion /
edema or accumulation of secretions (cystic fibrosis)
Note: viral pneumonia predisposes to bacterial pneumonia
1) Bronchopneumonia – (affects bronchioles and adjacent alveoli) patchy distribution of inflammation
around bronchioles often raise multifocal and bilateral- more than one lobe => results from initial
infection of bronchioles that extended into the alveoli.
2) Lobar pneumonia – the inflammation involve full segment are homogenously filled with exudates that
can be visualized as segmental or lobar consolidation
Consolidation: exudative solidification of lung=>
main causative agent is Streptococcus pneumoniae
Classic involve entire lobe with 4 gross phases of lobar pneumonia nowadays less seen thanks to
AB treatment options Lobar pneumonia:
Initially congestion edema heavy red lung with bacteria and few neutrophils;
Then red hepatization (grossly resembles liver harder consistency) with massive congestion,
neutrophils, fibrin in alveolar space;
Then gray hepatization with fibrinopurulent exudate in alveoli RBC got lysed;
Then resolution with resorption of exudate exudate enzyme digested debris cleaned by MQ
/cough out/reorganize by fibroblasts
3) Atypical interstitial pattern
BRONCHOPNEUMONIA
Staphylococcus aureus, Klebsiella, E. coli and Pseudomonas.
» Bronchopneumonia affects one or more lobes, being frequently bilateral and basal. Macroscopically,
one can identify multiple foci of condensation (1 - 3 cm diameter), white-yellowish, imprecisely
circumscribed, centered by bronchiole, separated by normal lung parenchyma Pleural involvement is
less common than in lobar pneumonia. . in severe cases usually seen In children, it has a tendency to
confluence, resulting in large condensation area (pseudo lobar pneumonia)
» Microscopy: foci of inflammatory condensation centered by a bronchiole with acute bronchiolitis
(suppurative exudate rich in neutrophils in the lumen, foci of ulceration of the epithelium and parietal
inflammation).
The alveolar lumens surrounding the bronchia are filled with neutrophils (“leukocytic
alveolitis”).
Capillaries in the alveolar walls show congestion. Inflammatory foci are separated by
normal, aerated parenchyma.
» Tissue destruction and necrosis => abscess formation.
» Accumulation of suppurative material in the pleural cavity => empyema.
» Organization of the intra-alveolar exudates that may convert areas of the lung into solid fibrous
tissue.
» Bacterial distribution (dissemination) can lead to meningitis, arthritis or infective endocarditis
Causes of lobar
Viral pneumonias. Pathology of COVID infection.
“Primary atypical pneumonia” is called primary because it develops independently of other diseases
Check diff note again
COMMUNITY-ACQUIRED ATYPICAL PNEUMONIAS
.”Atypical pneumonia” is atypical in that it is presentation with only moderate amounts of sputum,
absence of physical findings of consolidation, moderate elevation in WBC count, and lack of alveolar
exudates.
resistance Normal defense mechanisms are nasal clearance (sneezing, blowing, swallowing),
tracheobronchial clearance (mucociliary action) and alveolar clearance (alveolar macrophages)
Impairment is due to primary or acquired immunosuppression, suppression of cough reflex (drugs, virus,
coma, anesthesia), injury to mucociliary apparatus (smoking, virus, Kartegeners syndrome), injury to
macrophages (tobacco, alcohol, anoxia), pulmonary congestion / edema or accumulation of secretions
(cystic fibrosis)
Note: viral pneumonia predisposes to bacterial pneumonia
» Macroscopically – the affected areas are red-blue and congested.
» Histologically – inflammatory reaction is confined within the walls of the alveoli =interstitial
(inflammation affects the interstitial tissue, mainly the alveolar walls), with widened and edematous
septa; contain mononuclear infiltration of lymphocytes and histiocytes.
finding (interstitial inflammation just look a little clearer lung demarcations) mild to no fever
Lung carcinoma: histology and pathogenesis.
Lung cancer is 1st in cancer mortality in the us and 2nd in incidence in us 95% of lung cancer are
BRONCHIAL CARCINOMA
carcinomas and remaining 5% include: sarcomas, lymphomas and benign tumors as hamartoma’s.
cell carcinoma and small cell carcinoma
lung carcinoma (NSCLC) => SCLC metastasizes by the time of diagnosis surgery will not be helpful
but it is better treated by chemotherapy, while NSCLC are better treated by surgery
Now therapies are available that target specific mutated gene products present in the various
subtypes of NSCLC, mainly in adenocarcinomas. Thus, NSCLC must be sub- classified into histologic
and molecular subtypes.
» Carcinomas of the lungs arise due to the transformation of normal bronchial epithelium or
pneumocytes the alveolar epithelium into neoplastic cells. Exposure to carcinogens Dominantly
Cigarette smoking’s 85% of cancers are related (polycyclic aromatic hydrocarbons and arsenic –
squamous cell type especially associate) other environmental insults e.g. asbestos exposure (lung
cancer and to lesser extent mesothelioma) or radon (raise from uranium decay in soil as gas) are
the mainly responsible for the genetic changes that give rise to lung cancers.
» In smoking exposure mutation accumulation has an predictable order Inactivation of known
tumor suppressor genes ( short arm chromosome 3) occurs at an early stage and even found
at”healthy” smokers respiratory epithel , while p53 mutations occur at a later stage.
» There is a linear correlation between the intensity and duration of exposure to cigarette smoke
and the appearance of epithelial changes that begin with cell hyperplasia and squamous
metaplasia and progress to squamous dysplasia and carcinoma in situ, before culminating in
invasive cancer.
» Among the major histologic subtypes of lung cancer, squamous and small-cell carcinomas show
the strongest association with tobacco exposure. (remember S for Smoking)
» Carcinomas begin as firm, gray-white, small mucosal lesions.
» They may form intra luminal masses, invade the bronchial mucosa, or form large masses that are
pushed into adjacent lung parenchyma => some large masses might undergo cavitation due to
central necrosis, or develop focal areas of hemorrhage.
» Eventually, these tumors may invade the pleural cavity and chest wall.
» Carcinomas of the lung are silent lesions that extensively spread before any symptoms appear.
» Can produce cough, sputum, weight loss, dyspnea, bronchiectasis or pneumonia.
» NSCLCs have better prognosis than SCLC => if detected before metastasis occurs, cure is
possible by lobectomy or pneumonectomy.
» SCLCs are very sensitive to chemotherapy.
» Paraneoplastic syndromes include:
1) Hypercalcemia due to secretion of PTH related peptide.
2) Cushing syndrome from increased production of ACTH.
3) Syndrome of inappropriate secretion of ADH (SIADH).
4) Neuromuscular syndromes.
5) Clubbing of the finge
6) Thrombophlebitis, non-bacterial endocarditis, and DIC.
Squamous cell carcinoma Hypercalcemia most often is encountered
Adenocarcinoma = hematologic syndromes
Small cell carcinoma = The remaining syndromes
SMALL CELL CARCINOMA
treated by chemotherapy (with or without radiation).
# Consists of poorly differentiated, relatively SMALL cells
# It is thought to originate from neuroendocrine cells (APUD cells) in the bronchus called Feyrter cells.
Hence, they express a variety of neuroendocrine markers, and may lead to ectopic production of
hormones like ADH and ACTH that may result in paraneoplastic syndromes and Cushing’s syndrome.
involvement of hilar lymph nodes at an early stage.
Necrosis is present and may be extensive.
mutations and p53 mutations.
All the following Considered as non-small cell lung carcinoma (NSCLC); responds poorly to
chemotherapy, thus it is treated by surgery.
SQUAMOUS CELL CARCINOMA
epithelium => carcinoma in situ => well defined tumor mass obstructs the lumen of the bronchus =>
production of distal atelectasis and infection.
PEARLS and/or INTERCELLULAR BRIDGES, to poorly differentiated neoplasms.
# Most common tumor in NON SMOKERS and FEMALE. Tumer cells form glands that produce mucin,
usually forming smaller mass then other lung cancers growing slowly but metastise earlier then other
tumors
these are not the precursor lesions for this tumor.The precursor of peripheral adenocarcinomas is
thought to be atypical adenomatous hyperplasia (AAH)
Can progress to:
1.Adenocarcinoma in situ = Bronchioalveolar carcinoma name in past ,the initial progression from
hyperplasia less then 3 cm dimt.,grow alomg preexisting structures monolyer cuboidal tumor cells
not invading stroma and maintain alveolar architecture-named also lepidic growth.
2.Minimal invasive adenocarcinoma although less then 3cm got invasive component
3.Invasive adenocarcinoma = more the 5 mm depth.
papillary… acinar pattern –gland formation/papillary pattern-fibromuscular cores lined by glandular
tumor cells replacing normal alveolar lining(micropapillary no fibromuscular core but similar
papillary pattern )/mucinous-grow along alveolar septa not invasive in situ /solid type-see mucin
inside tumor cells may need special stain for recognizing, forming solid masses of cells.
The immuno histochemical profile can help differentiate between other various types of NSCLC. About 70% of
the Adenocarcinomas are positive for the thyroid transcription factor-1 (TTF-1).
BRONCHIOLOALVEOLAR CARCINOMA
parts of the lung, as a single nodule.
and preservation of alveolar architecture.
alveolar septa.
desmoplasia-no growth of fibros tissue
LARGE CELL CARCINOMA
treated by surgery.
# Composed of undifferentiated epithelial tumors that lack the cytologic features of small cell carcinoma,
show no glandular differentiation or mucin, and no keratin pearls or intercellular bridges.
CARCINOIDS TUMORS- BRONCHIAL
CARCINOIDS
neoplastic cells contain neurosecretory
granules in their cytoplasm, and may
secrete hormonally active peptides although
not usually manifest with paraneoplastic syndrome.
Tumor cells origin from the diffused
neuroendocrine system of the lung (korchinski cell) solid tumor with rich capillary network with Fine
delicate fibrovascularsepta inbt nests of cells Such as tumors morphology also seen in pancreas and
adrenal glands …
resectable and curable
Typical carcinoids (low grade) = These tumors are composed of nests of uniform cells that have
regular round nuclei with “salt and pepper” chromatin & central nucleoli. Less than 5mitotic figures
for HPF, no necrosis.
Atypical Carcinoids (Intermediate grade)= > 5 mitotic figures for HPF (40x objective) with/without
necrosis display a higher mitotic rate (but less than small or large cell carcinomas) and focal necrosis.
1) Expanding growth-Obstructing polypoid, spherical, intraluminal mass.
2) Invasing-Mucosal plaque that penetrates the bronchial wall to spread in the peribronchial tissue.
Cough, recurrent infections related to the intramural growth.
Rare- carcinoid syndrome characterized by attacks of diarrhea flushing and vomiting
Inflammatory bowel disease. Crohn disease. Ulcerative colitis.
Inflammatory bowel disease (IBD) is a chronic inflammatory condition resulting from
INFLAMMATORY BOWEL DISEASES
inappropriate mucosal immune activation.
- Ulcerative colitisinflammation is limited to the mucosa and submucosa and usually
extends to the distal colon and rectum. - Crohn disease transmural inflammation and usually found in the ileum and
proximal colon but has the potential to affect any part of the gastrointestinal tract
from mouth to anus.
common in western countries- North America Europe Ashkenazi Jews. .
colitis and Crohn disease.
» Genetic: There is a clear genetic predisposition for Crohn disease. First-degree
relatives have a 13-18% increase in incidence, and there are concordance rates of 50%
in monozygotic twins. Classic Mendelian inheritance is not seen, implying a
polygenic basis of the disease .
NOD2 is a susceptibility gene in Crohn disease. NOD2 encodes a protein that binds to
intracellular bacterial peptidoglycans and subsequently activates NF-κB Nuclear
factor kappa B (NF-κB) is an ubiquitous rapid response transcription factor in cells
involved in immune and inflammatory reactions, and exerts its effect by expressing
cytokines, chemokines, cell adhesion molecules…
» Mucosal immune response: Mechanism still uncertain, some combination that activate
mucosal immunity and suppress immunoregulation contribute to the development of
both disease.
Polarization of T cells to the T-helper cell type 1 (TH1) type is a well-recognized
feature of CD. Type 1 T helper (Th1) cells produce interferon-gamma, interleukin
(IL)-2, and tumor necrosis factor (TNF)-beta, which activate macrophages and are
responsible for cell-mediated immunity and phagocyte-dependent protective
responses.
Emerging data indicate that TH17 cells also contribute to disease pathogenesis,
whereas IL-23(an R involve in development and maintenance of Treg) receptor
polymorphisms may confer protection from CD and UC.
Only in ulcerative colitis = TH-2 is involved & polymorphism of IL-10 gene.
» Epithelial Defect: Defects in intestinal epithelial tight junction barrier function are
present in patients with Crohn disease such as defect result in more primableepithel so
inflammation stimulating material e.g. bacteria can come in. Paneth cell granulesgot
antimicrobial materials may alter microbe composition link to develop IBD.
» Microbiota: The precise contribute to IBD pathogenesis remains to be defined.
Possible mechanism: Transepithelial flux of luminal bacterial components activates
innate and adaptive immune responses –in genetic susceptible individual, TNF other
inflammatory cytokines stimulating the increase priamability of epithel more influx
more cytokine- circle end as IBD.
» Environmental factors - especially cigarette smoking and diet, are also clearly
involved in CD Tobacco smoking doubles the risk of both initial and recurrent Crohn
disease (CD), unlike the apparent protective effect of tobacco seen in ulcerative colitis
CROHN DISEASE
# transmural inflammation and usually found in the ileum and cecum (proximal colon)
but has the potential to affect any part of the gastrointestinal tract from mouth to
anus.may be accompanied by extra-intestinal complications of immune origin =>
uveitis (inflammation of uvea), sacroilitis, migratory polyarthritis, erythema nodosum,
bile duct inflammatory disorders, and obstructive uropathy.
» MACRO = the mucosal surface shows patchy lesional distribution with sharply
delineated areas of disease surrounded by normal mucosa.
» Transmural involvement of the bowel by an inflammatory process with thickening of
mucosal wall The intestinal wall is rubbery and thick as a result of edema,
inflammation, fibrosis, and hypertrophy of muscularis mucosae => causing the lumen
to become narrow, Cobblestone appearance upon granular appearance of surface
mucosa .
» “Creeping fat” => formation of granulation tissue within the fissure involves the
stricture of the fissure, which will pull up the fat of the mesentery.
» Ulceration => focal in early stages (aphthous ulcers), elongated linear ulcers (due to
fusion of ulcers) as disease progresses
» MICRO = Microscopically, Crohn disease is characterized by transmural
inflammation, inflammatory cells extend from mucosa through submucosa and
muscularis and appear as infiltrates on the serosal surface anther characteristic future
is the presence of non-caseating granulomas
Clusters of neutrophils within a crypt are referred to as a crypt abscess and often are
associated with crypt destruction destruction of normal epithelial mucosa.
Epithelial metaplasia = Pseudo pyloric metaplasia /Paneth cell metaplasia also may
occur in the left colon, where Paneth cells normally are absent.
(days-weeks), malabsorption with nutritional deficiency.
» Risk for Fistula formation to other segments of the bowel, urinary bladder, vagina
or perianal skin.
» Abdominal abscesses or peritonitis.
» Intestinal stricture or obstruction.
» Perforations and peritoneal abscesses are common.
» Increased risk for colonic adenocarcinoma.
ULCERATIVE COLITIS
limited to the mucosa and submucosa.Begins in the rectum and extends proximally
(=in retrograde manner), and may involve the entire colon. (=Pancolitis)
mucosal ulcers rarely extend beyond the submucosa. Unlike in Crohn disease, mural
thickening is absent, the serosal surface is normal, and strictures do not occur.
» Isolated islands of regenerating mucosa bulge upward => pseudopolyps.
» Inflammatory infiltrates, crypt abscesses, crypt distortion, and epithelial
metaplasia = similar to Crohn.
» Ulcer- extending to submucosa.
» No granulomas.
days/weeks/months, and then subsides only to recur after an asymptomatic
interval.
» Toxic megacolon = caused by inflammation and damage to the
muscularis propria = cause neuromuscular damage.
» High risk of carcinoma development!! Depends on the extent of colonic
involvement, and the duration of the disease.
The genetic basis of colorectal carcinoma.
Most common malignancy of GI as colorectal cancer is 3rd most common site of cancer and also 3rd in
cancer related death Incidence increases with age, and reaches its peak at age 60-70.
Both genetic and environmental factors contribute to the development of colorectal cancers:
» In young individuals => pre-existing ulcerative colitis or one of the polyposis syndromes.
» Individuals with hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome).
» Dietary factors => low content of fibers with high content of carbohydrates, high fat content, and
decreased intake of protective nutrients such as vitamins (A, C & E).
» Genetic factors => COX-2 is over expressed in colorectal cancer patients; inhibition by aspirin
and non-steroidal anti-inflammatory drugs may exert a protective effect against colon cancer.
Colorectal carcinogenesis – there are 2 major pathways for the development of colorectal cancer both
describe accumulation of mutations but involve different genes and different defected mechanism
leading to such as accumulation:
- APC/β-catenin pathway (adenoma-carcinoma sequence)
- Characterized by chromosomal instability associated with stepwise accumulation of
mutations in a number of oncogenes and tumor suppressor genes
- Initially there is localized epithelial proliferation, followed by the formation of small
adenomas that progressively enlarge, become more dysplastic and eventually develop
into invasive cancer
-Sequence of events:
- Loss of APC tumor suppressor gene – both copies of the gene must be lost may be part of
FAP syndrome one is already inherited or just acquired mutation in 2 copies; APC
protein bind and promotes the degradation of β-catenin in cytosol => if absent APC
accumulation of β-catenin, it translocate to nucleus bind TcF leads to transcription of
growth promoting genes such as cyclin D1 and MYC that promote cell
proliferation(usually such as thing happened upon WANT exposure hence path named
WANT pathway), more!
It cause gene expression of different repressors for E cadherin
and suppress contact inhibition of growth.
If APC is neutralized it related as mutation permissive for polyp development
- Mutation of K-RAS – the gene encodes signal transduction GTPase in pathway of GF
TKR receptors as PI3K/AKT or MEPK pathways. it alternates between activated GTP
bound state and inactivated GDP bound state => when mutated, the molecule remains
active constant growth signal to cell and lead to formation of adenomatous polyp. - loss of tumor suppressors allows the emergence of carcinoma. loss of tumor suppressor
genes SMAD2 and SMAD4, encoding components of the TGFβ pathway TGF-β
signaling normally inhibits the cell cycle by binding to TGFbeta receptor and inducing
CDKI molec expression as SMAD are signal transducers in this pathway , loss of these
genes may allow unrestrained cell proliferation . Also, loss of p53 – a tumor suppressor
gene that inhibits neoplastic formation by inducing apoptosis if lost neoplastic cell now
can evade death.
- Mismatch repair pathway (microsatellite instability)
In patients with DNA mismatch repair deficiency (due to loss of mismatch repair genes) mutations
accumulate in microsatellite repeats a condition referred to as microsatellite instability.
These mutated microsatellite seq.may disrupt the coding sequence of TGF-b receptor (Leads to
uncontrolled cell growth.) or of the pro-apoptotic protein BAX (enhances the survival of genetic
abnormal clones).
Other common DNA mismatch repair defects are Mutation in the oncogene BRAF & hyper
methylation of CpG islands. By contrast, KRAS and TP53 typically are not mutated. Thus, the
combination of microsatellite instability, BRAF mutation, and methylation of specific targets, such
as MLH1, is the signature of this pathway of carcinogenesis.
The morphology, staging and clinical features of colorectal carcinoma.
The vast majority of colorectal cancers are adenocarcinomas, tumors that arise from
the mucosa cells of the colon.
While most adenocarcinomas are well or moderately
differentiated, approximately 15% are poorly or undifferentiated tumors.
These tumors are associated with a poorer prognosis. Mucinous or colloid carcinomas, with
moderate to prodigious mucin production, are also associated with less favorable fiveyear survival rates.
THE MORPHOLOGY OF COLORECTAL CARCINOMA
# Morphologic patterns:
# Macro -> may occur anywhere along colon Both forms grow into the bowel wall
over time and may be palpable as firm masses.
» Proximal colon – tumors tend to grow as polypoid, exophytic mass that
extend along one wall of the cecum and ascending colon. but rarely cause
obstruction.
» Distal colon – carcinomas tend to encircle the lumen producing a
constrictive ring => narrowing of the lumen.
Micro -> composed of Tall columnar epithel with elongated, hyperchromatic
nuclei, increased size of nucleus.
Depending on glandular architecture, cellular
pleomorphism and mucosecretion of the predominant pattern, adenocarcinoma
may present 3 degrees of differentiation: well, moderate and poorly differentiate.
Well differentiated- The neoplastic glands are long and frond-like, similar to
those seen in a villous adenoma.
To more crowded gland appearance loss of
goblet cells and normal gland architecture….other character histo finding
include Necrotic debris in the gland lumen. And upon invasion of tumor cells
they induce Strong stromal desmoplastic response responsible for their
characteristic firm consistency even
May be composed of signet ring cells
that are similar to those in gastric cancer
The vast majority of colon carcinomas are adenocarcinomas, many of
which produce mucin. Cancers of the anus are most commonly squamous cell
carcinomas
CLINICAL FEATURES OF COLON CANCER
May Remain asymptomatic for years as symptoms develop gradually and slowly,
enhance the importance of screening from age 50/even younger at case of family
past:
» Cecal and right colonic cancers – appearance of fatigue, weakness and
iron deficiency anemia. In general Iron deficiency anemia in older men is
very suspicious for GI cancer until proven otherwise.
» Left-sided lesions – changes in bowel habits, left lower quadrant
discomfort, bleeding.
STAGING OF COLON CANCER
The two most important prognostic factors are depth of invasion and the presence
or absence of lymph node metastases.
For example tumors with muscularis
propria involvement is carrying much poor prognosis already compered to lesser depth of invasion also the occurrence of lymph node involvement much reduce
prognosis..
Colorectal tumors may spread by direct extension into adjacent structures, and by
metastasis through the lymph and blood vessels.
Sites of metastasis (in order of preference) => liver, regional lymph nodes, lungs,
bones. Note that The rectum does not drain by way of the portal circulation ->
usually doesn’t metastasize to the liver.
Staging of colorectal cancer refers to how far a cancer has spread on a scale from
0 to IV, with 0 meaning a cancer that has not begun to invade the colon wall and
IV describing cancer that has spread beyond the original site to other parts of the
body.
There is a close correlation between advancing stage and cancer mortality.
Tumor size does not appear to be important in terms of outcome.
The aggressiveness of colorectal cancer is based upon its ability to grow and invade
the colonic wall, lymphatic systeM
TNM Staging System -The TNM System, developed by the American Joint
Committee on Cancer (AJCC) is the most widely used, and is considered the
most precise and descriptive.
T stands for tumor and the depth to which it has
penetrated the colon wall, N stands for lymph node involvement, and M refers to
metastases, or whether the cancer has spread to other body parts Colorectal cancer most commonly spreads to the liver or the lungs
Detection and diagnosis is based on several test:
» Digital rectal examination.
» Fecal testing for presence of blood.
» Barium enema – barium sulfate fills the colon to give an X-ray picture.
» Sigmoidoscopy and colonoscopy.
» Biopsy for final confirmation.
» Radiographic studies (CT) to assess metastatic spread.
Acute and chronic liver failure. Cholestasis. Hepatic encephalopathy
The Liver –
The liver has the enormous task of maintaining the body’s metabolic homeostasis.
A healthy liver does the following:
1.It regulates the composition of blood, including the amounts of sugar (glucose), protein, and fat that
enters the bloodstream.
2.It removes bilirubin, ammonia, and other toxins from the blood.
3.It processes most of the nutrients absorbed by the intestines during digestion and converts those
nutrients into forms that can be used by the body.
The liver also stores some nutrients, such as vitamin
A, iron, and other minerals.
- It produces cholesterol and certain important proteins, such as albumin.
- It produces clotting factors, chemicals needed to help blood clot.
- It breaks down (metabolizes) alcohol and many drugs.
CLINICAL SYNDROMES
# The major clinical syndromes of liver disease are hepatic failure, cirrhosis, portal
hypertension, and cholestasis.
ACUTE AND CHRONIC HEPATIC FAILURE
Most severe outcome of liver disease that may develops as the end point of
progressive damage to the liver parenchyma or Less often, hepatic failure is the
result of sudden and massive destruction of hepatic tissue.
Note that Failure is almost certain when about 80%-90% of hepatic functioning tissue is lost
In many cases balance “tipped” toward dysfunction when increased stress exarted
on already injured liver such as systemic infections, electrolyte disturbances, surgery, heart failure and GI bleeding.
There are 3 categories of patterns of injury resulting in liver failure:
1) Acute liver failure with massive hepatic necrosis-
Characterized by massive hepatic necrosis, uncommon life threatening situation lead to
necessitates liver transplanted.
Most often Caused by drugs or viral hepatitis, in this type see Hepatic insufficiency that progresses into hepatic encephalopathy within 2-3 weeks.*subacute when ~3 month chain of events.
2) Chronic liver disease Most common route to hepatic failure represented
as end point of process inflicting chronic liver damage often manifest a cirrhosis.
The processes that initiate chronic damage to the liver can be
classified as:
1. Primarily hepatocytic (or parenchymal)
2. Biliary
3. Vascular
3) Hepatic dysfunction without overt necrosis -The hepatocytes are viable,
but cannot perform normal metabolic function Occurs in acute fatty liver
of pregnancy, toxicity, and Reye syndrome
Clinical features –
# In chronic liver failure
Jaundice a yellow discoloration of skin and sclerae (icterus), occurs
when systemic retention of bilirubin produces serum levels above 2.0 mg/dL.
Hypoalbuminemia => impaired synthesis of albumin; predisposes for peripheral edema.
Hyperammonemia => defective urea cycle function (takes place only in the liver)
Hyperestrogenemia => impaired estrogen metabolism; hypogonadism
and gynecomastia (in males)
Palmar erythema (a reflection of local vasodilatation)
Spider angiomas of the skin (v a central, pulsating, dilated arteriole from which small vessels radiate)
In acute liver failure May present as jaundice or encephalopathy, but
without the clinical signs of chronic liver failure (gynecomstia, spider angiomas etc.)
Complications –
# Accumulation of toxic metabolites Multiple organ systems failure
(respiratory/renal failure, pneumonia, sepsis, ).
# Coagulopathies due to impaired synthesis of blood coagulation factors
Massive GI bleeding.
CHOLESTASIS
# Bile congestion in liver result from condition in which bile cannot flow from
the liver to duodenum, decrease in bile flow may be due to impaired
secretion by hepatocytes or to obstruction of bile flow through intra-or
extrahepatic bile ducts.
Can be classified as:
# Obstruction – due to mechanical blockage in the duct system, such as
gallstone or malignancy or malformation.
# Metabolic/ intrahepatic cholestasis – due to disease of the
intrahepatic biliary tree or hepatocellular secretory failure cannot be
treated surgically.
# Morphology –may appear intracellular as bile brown pigment in
cytoplasem, also ext. cell in canaliculi system congested distant
canaliculi/filling space of disse etc.…
Symptoms include:
» Progressive fatigue
» Malabsorption of fat – no bile
» Jaundice- not always The presence of elevated serum concentration of
conjugated bilirubin is a principal sign of cholestasis. It results in
jaundice, which can be detected by scleral icterus at a concentration as
low as 2 mg/dL, and by dark urine. Pale stool (in obstructive
cholestasis)
» Elevated serum alkaline phosphatase
» Itchiness (pruritus)- unknown reason
» Skin xanthomas (accumulation of cholesterol)
HEPATIC ENCEPHALOPATHY
# Hepatic encephalopathy is a clinical syndrome of impaired brain function
occurring in patients with advanced liver failure=> manifests by the broad
spectrum of neuropsychiatric disturbances such as: behavioral abnormality,
confusion, deep coma and death
Associated with neurologic signs such as rigidity, hyperreflexia, EEG changes,
and seizures (rare).
Main characteristic is asterixis (flapping tremor) => non-rhythmic, rapid
extension-flexion movements of the head and extremities.
hyperammonemia is the main factor responsible for the brain abnormalities in
HE Two factors seem to be important in the genesis of this disorder:
» Severe loss of hepatocellular function - Nitrogenous compounds are
metabolized in liver urea cycle, resulting in the generation of urea which
is subsequently excreted through the urine
» Shunting of blood from portal to systemic circulation around the
chronically disease liver.
Exact patho mechanism is unclear but estimation: Ammonia bypasses the liver
and accumulates in the systemic circulation; it then crosses the blood-brain barrier
and is metabolized by astrocytes to synthesize glutamine Glutamine increases the
osmotic pressure within the astrocyte and is thought to cause mitochondrial
dysfunction the process of glutamine (Gln) synthesis from glutamate (Glu) and
ammonia, glutamate and as result GABA depletion
Ammonia influences also other mechanisms leading to development of hepatic
encephalopathy such as: impaired blood-brain barrier, changes in
neurotransmission, proinflammatory cytokines, and impaired cerebral blood flow
Acute setting -> elevation in blood ammonia -> impairs neuronal function
and promotes generalized brain edema.
Chronic settings -> Deranged neurotransmitter production -> neuronal dysfunction.
Hepatic bile formation serves two major functions:
Primary pathway for the
elimination of bilirubin, excess cholesterol and xenobiotics. Secreted bile salts
and phospholipid molecules promote emulsification of dietary fat in the lumen of
the gut.
In prhepatic see unconjugated bilirubin elevated in serum in hepatic see both and
in post hepatic see conjugated bilirubin elevated in serum.
Acute viral hepatitis. Pathomorphology, complications.
Hepatitis = A descriptor for specific histopathologic patterns of hepatocyte injury
associated with inflammation and, when chronic, with scarring.
Hence, Acute & chronic hepatitis = Distinguished in part by duration and in part by the pattern of
cell injury.
Causes: Hepatitis viruses A-E, Autoimmune, Drug- toxin- induced hepatitides
-> All share the same patterns of injury
MORPHOLOGY
» Mononuclear infiltrates predominate in all phases of most hepatitis
diseases because they all invoke T cell–mediated immunity.
» Distinction between acute and chronic hepatitis is based on the pattern of
cell injury and severity of inflammation.
» Acute hepatitis = less inflammation and more hepatocyte death than chronic hepatitis
Macro:
On gross inspection, liver involved by mild acute hepatitis appears normal or
slightly enlarged red liver; greenish if there is cholestasis.
At the other end of the spectrum, in massive hepatic necrosis the liver may shrink to 500to 700 g
and become transformed into a limp, red organ covered by a wrinkled, baggy capsule.
Micro:
Lobular disarray-loss of normal architecture
Hepatocyte injury-swelling (ballooning degeneration), in HCV: mild fatty
change of hepatocytes Hepatocyte necrosis isolated cells or clusters or apoptosis (shrinkage)
Inflammatory Influx- of mainly mononuclear cells into sinusoids inflammatory spillover into adjacent parenchyma When located in the
parenchyma away from portal tracts, these features are called lobular hepatitis, Kupffer cells undergo hyperplasia and Hypertrophy.
ACUTE VIRAL HEPATITIS
Infection of the liver caused by a small group of viruses’ initial infection and
following inflammation are the acute viral hepatitis in some cases it later may
progress to chronic infection yelling chronic viral hepatitis.
Acute hepatitis – less than 6 months of progression; initial features are
nonspecific flu-like symptoms with malaise (“feeling bad”), muscle and joint
pain, fever, nausea and vomiting => followed by jaundice and abdominal
discomfort.
Note that in viral hepatitis the Immune mediated mechanisms induce hepatocyte
damage in response to viral antigens.
Types of viruses:
1) Hepatitis A virus (HAV) and HEV:
both causing only acute form not progress to chronic infection hence
appearance of IgM noting acute infection while appearance of IgG signal
for resolution(note HAV got vaccine so IgG may link to immunized
individual).
Both Transmission by contaminated water and food Present in stool, got short incubation periods.
HEV infection associated with fuliment hepatitis (liver failure with massive liver necrosis)
2) Hepatitis B virus (HBV)
Causing acute hepatitis and in some caseas~20% may progress into chronic
case.
HBV-induced chronic liver disease is a precursor for development of hepatocellular carcinoma HBV-X is required for viral infectivity and may
have a role in the development of hepatocellular carcinoma by regulating p53 degradation and expression.
Prolonged incubation (4-26 weeks)
Transmission by blood and body fluids + vertical transmission from mother to
child It is NOT present in stool
Vaccine available= HBsAg
Serology:
o Hepatitis B core antigen (HBcAg) = retained in hepatocyte
o Hepatitis Be antigen (HBeAg) = Secreted to blood -> essential for infection
o Hepatitis B surface antigen (HBsAg) => produced & secreted to the blood in high amounts immunogenic.
1.acute infection – see HBsAg as initial serologic marker that rises denoting infection by virus, next in phase IgM against HBcAg
raise (in window period only one to appear in serum) in resolution
see IgG against both HBcAg and HBsAg providing protection
against future infections.
- Chronic infection- appearance of HBsAg longer than 6 months
as the mark of enter chronic state more in such patient no IgG
against HBsAg.
HBeAg or viral DNA as indicators that patient is
infective? there is IgG against HBcAg
- Patient who got vaccine or resolved the disease will have IgG against HBsAg (vaccine itself composed of viral surface AG)
3) Hepatitis C virus (HCV)
Transmission by blood and intravenous drug use
More likely to progress into chronic liver disease and eventual
cirrhosis
Incubation time 2-26 weeks
Acute hep. C is asymptomatic in 75% of cases
Persistent infection is the hallmark of HCV infection, occurring in
80% to 85% of patients with sub- clinical or asymptomatic acute
infection
Hepatitis C confers a significantly increased risk for hepatocellular carcinoma.
4) Hepatitis D virus (HDV)
Replication is dependent on HBV infection => replicates only when encapsulated by HBsAg.
Coinfection = infection by both HBV & HDV usually recover completely.
Superinfection = First HBV then HDV = acceleration of
hepatitis + more severe
Chronic hepatitis.
IgM anti-HDV antibody is the most reliable indicator of recent
HDV exposure
Clinical features & outcomes of viral hepatitis-
- Asymptomatic acute infection: serologic evidence only
- Acute hepatitis: anicteric or icteric
- Fulminant hepatitis: submassive to massive hepatic necrosis with acute liver failure.
- Chronic hepatitis: with or without progression to cirrhosis.
- Chronic carrier state: asymptomatic without apparent disease.
- HCV= development to chronic state is much more common then in HBV.
HCV= chronic.
PATHOMORPHOLOGY
Acute viral hepatitis can be caused by any of the hepatitis viruses.
# It is divided into 4 stages:
» Incubation period.
» Symptomatic pre-icteric phase – marked by nonspecific symptoms =>
fatigue, nausea, and loss of appetite.
» Symptomatic icteric phase – with jaundice and scleric icterus (=jaundice)
=> characterized by conjugated hyperbilirubinemia (causing dark colored
urine). Hepatocellular damage may occur (unconjugated
hyperbilirubinemia)
» Convalescence.
Alcoholic liver disease. Drug- and toxin-induced liver disease: different morphological forms of
injury.
Liver is the major detoxifying organ => subjected to injury by drugs and toxins. Metabolism of ethanol:
oxidation of ethanol to acetaldehyde by three different routes, and the generation of acetic acid.
Note that oxidation by alcohol dehydrogenase (ADH) takes place in the cytosol; the cytochrome P-450 system and its CYP2E1 isoform are located in the ER and catalase is located in peroxisomes.
Oxidation of acetaldehyde by
aldehyde dehydrogenase (ALDH) occurs in mitochondria.
The most common form of chronic liver diseas in the western world, manifest in 3 different forms
(collectively referred to as alcoholic liver disease)
» Hepatic steatosis (intra cellular fat accumulation)
Due to intake of ethanol (>60g/day) => Causes:
- Metabolism of ethanol by ADH produces NADH => signals the body it has enough
energy (although it doesn’t) stop glycosis + production of lipids
=> accumulation of these lipids in hepatocytes => steatosis!
Alcohol is oxidized by alcohol dehydrogenase which cause decrease in NAD+, and
increase NADH. NAD+ required for fatty acid oxidation in the liver, and by that
deficiency, fat accumulate in the liver of alcoholics
- Impaired assembly & secretion of lipoproteins.
- Increase peripheral catabolism of fat
Liver is enlarged (4-6kg), soft, yellow, and greasy micro see Fatty liver disease. steatosis
is most prominent around the central vein and extends outward to the portal tracts with
increasing severity.
The intracytoplasmic fat is seen as clear vacuoles smaller are microvasicles larger are macrovesicles may push nucleus aside..
Continued alcohol intake => fibrosis develops around the central veins and extends to
adjacent sinusoids (center to periphery)
Fatty change is a reversible state UNTIL fibrosis appears => by stopping alcohol
consumption
Clinical features – hepatomegaly with mild elevation of serum bilirubin and alkaline
phosphatase
Alcoholic hepatitis
» Usually associated with acute episode of excessive drinking it may stem from one or more of
the following toxic by products of ethanol and its metabolites: Acetaldehyde-disrupts
cytoskeleton and lipid membranes induce lipid peroxidation.
Alcohol-direct injury to cytoskeleton Mito and membrane fluidity
ROS-from ER metabolism & cytokine mediated inflammation (major cytokine TNF)-
stimulation for realis view ROS and alcohol stim.
Microbe of gut for endotoxin realis so
Kupffer cell realis cytokine
Ballooning = Swelling and necrosis => scattered cells undergo swelling due to
accumulation of fat, water and proteins, and then necrosis
Mallory dank bodies => scattered hepatocytes accumulate damaged intermediate
filaments, visible as eosinophilic cytoplasmic homogenous masses
Neutrophil infiltration => accumulate around degenerating hepatocytes; lymphocytes
and macrophages also enter the portal tracts and spill into the parenchyma
Steatohepatitis with Fibrosis => Generation of acetaldehyde and free radicals is
maximal in the centrilobular region this region is most susceptible to toxic injury
Pericellular fibrosis and sinusoidal fibrosis develop in this area of the lobule. Upon
repeated insult fibrosis become more prominent cirrhosis.
Clinical features – malaise, anorexia, presents with painful hepatomegaly and elevated
liver enzymes (AST > ALT) and fever; laboratory findings include hyperbilirubinemia,
elevated alkaline phosphate and neutrophilic leukocytosis
» Alcoholic cirrhosis
- Final and irreversible end stage organ form of alcoholic liver disease, ends as brown,
shrunken, non-fatty organ (<1kg) - For unknown reasons, cirrhosis develops in only a small fraction of chronic alcoholics.
- Concurrent viral hepatitis, particularly hepatitis C, is a major accelerator of liver disease
in alcoholics. The prevalence of hepatitis C among alcoholic is about 30% on other hand, - With complete abstinence, some regression of scar can be seen in all cases, and the
Micronodular liver transforms, with regeneration, into a macronodular - Cirrhotic organ;
- Characteristic diffuse nodularity of the surface is induced by the underlying fibrous
scarring. Small nodules with unorganized architecture are entrapped by fibrous tissue;
fatty accumulation is no longer
Seen in this “burned-out” stage. - Clinical features – Commonly, the first signs of cirrhosis relate to complications of
Portal hypertension (e.g., an abdomen grossly distended with ascites, wasted
extremities, and Caput medusa) alternatively, a patient may first present with lifethreatening variceal hemorrhage or hepatic encephalopathy. In other cases, cirrhosis
may be clinically silent, discovered only at autopsy or when stress such as infection or
trauma tips the balance toward hepatic insufficiency
Laboratory findings reflect
The developing hepatic disease, with elevated serum aminotransferase,
Hyperbilirubinemia, variable elevation of alkaline phosphatase, hypoproteinemia (globulins, albumin, and
clotting factors), and anemia. In chronic alcoholics, alcohol may become a major caloric source in the diet, displacing
Other nutrients and leading to malnutrition and vitamin deficiencies (e.g., thiamine, vitamin B12).
Among those with end-stage alcoholic liver disease, the immediate causes of death are:
- Hepatic failure
- Massive gastrointestinal hemorrhage
- Intercurrent infection (to which affected persons are predisposed)
- Hepatorenal syndrome
- Hepatocellular carcinoma in 3% to 6% of cases
NAFLD is condition in which fatty liver disease develops in persons who do not drink alcohol.
The liver Can show any of the three types of changes described earlier (steatosis, steatohepatitis, and cirrhosis).
NAFLD is associated with insulin resistance and Obesity.
DRUG- AND TOXIN-INDUCED LIVER DISEASE
# Liver is the major organ of detoxification; thus it is subjected to potential injury:
» Direct toxic damage to hepatocytes. (conversion of xenobiotic active toxin)
» Immune-mediated hepatocytes destruction. (acting as hapten)
Drug-induced liver disease is a common condition that may manifest as a mild reaction or, much more
seriously, as acute liver failure or chronic liver disease. The most important agent that produces toxic liver injury is alcohol.
Drug reactions may be classified as:
» Predictable – occur in anyone who accumulates a sufficient dose of the drug. E.g. Acetaminophen
toxicity = leading to acute failure & transplantation. The toxic agent is not acetaminophen itself,
but rather toxic metabolite produced by the cytochrome P-450 system in acinus zone 3 hepatocytes.
» Unpredictable – depends on the metabolic rate of the host and development of immune response to
the antigenic stimulus. (Individual variation) e.g. Chlorpromazine (an agent that causes cholestasis in
individuals who metabolize it slowly),
halothane (which can cause a fatal immune-mediated hepatitis in some persons exposed to this anesthetic on several occasions)
Morphology –
» Massive necrosis => the entire liver may be involved, or only random areas are affected; necrotic areas have red, may be depressed appearance. Upon Massive loss of hepatic substance => liver may shrink to 500-700g.
» Complete destruction of hepatocytes in continuous lobules leaves only reticulin framework and
preserved Drug/Toxin-Mediated Injury Mimicking Hepatitis
Clinically and histologically, drug-induced hepatitis cannot be distinguished from chronic viral hepatitis
or autoimmune hepatitis => serologic markers are critical for making a diagnosis.
» Acetaminophen toxicity = leading to acute failure & transplantation.
» Isoniazid = chronic hepatitis.
» Other drugs= induce autoimmune hepatitis.
Drug/Toxin-Mediated Injury with Steatosis
Fulminant liver failure and encephalopathy in children with viral illness who take aspirin
Presents with hypoglycemia, elevated liver enzymes, and nausea with vomiting; may Progress to coma and death Morphology: hepatocellular microvesicular steatosis. Cerebral edema
mitochondrial alternation in EM.
Metathroxate and corticosteroids induce steatosis
Amiodarone induce steattic hepatitis like alcohol
Acute pancreatitis. Chronic pancreatitis.
Pancreatitis- inflammation of pancreas range in severity from mild self-resolving to sever destructive event.
Acute pancreatitis
= function can return to normal if the underlying cause of inflammation is removed
Chronic pancreatitis is defined by irreversible destruction of exocrine pancreatic parenchyma.
ACUTE PANCREATITIS
Reversible relatively uncommon inflammatory
disorder that varies in severity,
Etiology: Most of cases are attributable to either
biliary tract disease or alcoholism.
Genetic mutation = mutation in gene PRSS1 = no
neg. feedback mechanism on trypsinogen =
hyperactivation of trypsin + other enzymes that
require trypsin cleavage for their activation.
20% idiopathic
Morphology
o The basic alterations in acute pancreatitis are:
(1) Microvascular leakage causing edema
(2) Necrosis of fat by lipases
(3) Acute inflammatory reaction
(4) Proteolytic destruction of pancreatic
parenchyma
(5) Destruction of blood vessels leading to interstitial hemorrhage.
o Mild form = Edema + Fat necrosis
Fat necrosis results from enzymatic destruction of fat cells; the released fatty acids
combine with calcium to form insoluble salts that precipitate in situ.
o Severe form (ex. acute necrotizing pancreatitis) necrosis of pancreatic parenchyma +
vascular damage (cause hemorrhage).
Macro = red-black hemorrhagic areas interspersed with foci of yellow-white, chalky
fat necrosis.
o Most severe form= hemorrhagic pancreatitis = extensive parenchymal necrosis is
accompanied by diffuse hemorrhage within the substance of the gland.
Pathogenesis
o Autodigestion of the pancreatic substance by inappropriately activated pancreatic enzymes.
Activation of trypsin is a critical triggering event in acute pancreatitis as it can activate itself
as well as other proenzymes (lots of pancreatic enzymes need cleavage for activation)
autodigestion.
Trypsin activates the kinin system activation of the clotting and complement systems.
3 pathways can cause enzyme activation:
- Pancreatic duct obstruction (gallstone, tumor) blockage of ductal flow=> increase
intraductal pressure => accumulation of enzyme rich interstitial fluid (containing active
lipase) => fat necrosis => inflammation => interstitial edema => edema compromises local
blood flow => ischemic injury to acinar cells.
- Primary acinar cell injury => ischemia, viral infections (e.g., mumps), drugs, and direct
trauma to the pancreas. - Defective transport of proenzymes within acinar cells in animal shown that metabolic
derangements contribute to abnormal transport of enzymes together with lysosomal
hydrolases result in activation.
Role of alcohol in acute pancreatitis:
1. Increases pancreatic exocrine secretion Increases contraction of sphincter of oddi.
- Direct toxic effect on acinar cells oxidative stress and membrane damage.
- Chronic ingestion results in secretion of protein rich fluid that causes obstruction of small
pancreatic ducts.
Clinical feature:
o Abdominal pain is the major manifestation of acute pancreatitis.
o Full-blown acute pancreatitis constitutes a medical emergency.
o The manifestations of severe acute pancreatitis are attributable to systemic release of
digestive enzymes and explosive activation of the inflammatory response: Leukocytosis,
DIC, ARDS (acute res. Distress syndrome) & diffuse fat necrosis.
o Can lead to shock
Pancreatic pseudocyst Liquefied areas of necrotic pancreatic tissue become walled off by fibrous
tissue to form a cystic space, lacking an epithelial lining
CHRONIC PANCREATITIS
Long-standing inflammation, fibrosis, and destruction of the exocrine pancreas. In late stages, the
endocrine parenchyma also is lost.
The chief distinction between acute and chronic pancreatitis is the irreversible impairment in
pancreatic function in the chronic state.
Etiology:
o The most common cause of chronic pancreatitis is long-term alcohol abuse.
o Less common:
Pancreatic duct obstruction (tumor/stone…)
Hereditary pancreatitis (PRRS1)
Associated with CFTR mutation => decreases bicarbonate secretion = > increase
viscosity of secretion => plugging.
Morphology:
o Parenchymal fibrosis, reduced number and size of acini, and variable dilation of the
pancreatic ducts. The ductal epithelium may be atrophied / hyperplastic .Islets of Langerhans
fused surrounded by sclerotic aggregates.
o Macro= the gland is hard, sometimes with extremely dilated ducts and visible calcified
concretions.
o Autoimmune pancreatitis (AIP)- distinct form of chronic pancreatitis:
Lymphoplasmacytic sclerosing pancreatitis-striking lymphocytes and plasma cells
infiltrate plus fibrosis
Idiopathic duct centric pancreatitis-mixed neutrophils and lymphcytic infiltrate
obliterating the duct epithel.
Pathogenesis:
Not well defined. Proposed hypotheses:
o Ductal obstruction: Alcohol => inc. protein conc. of secretion => plugs.
o Toxins: direct toxic effect injury to acinar cells and following inflammation /fibrosis.
o Oxidative stress: Alcohol generates ROS => membrane damage and chemokines expression
recruit inflammatory cells. (more oxidative stress assume to cause lysosomal and
proenzymes granules fusion subsequent enzyme activation and aggrevation of cell damage)
Clinical feature:
o Severe pancreatic exocrine insufficiency and chronic malabsorption may develop, as can
diabetes mellitus.
o Severe chronic pain may dominate the clinical picture
Acute pancreatitis. Chronic pancreatitis.
5
Pancreatic neoplasms. Tumors of the endocrine pancreas (islet-cell tumors)
Pancreatic exocrine neoplasm can be cystic or solid. They can be benign or malignant.
- Cystic neoplasm-5% OF ALL PANCREATIC TUMORS
a. Serous cystadenomas
i. Composed of glycogen rich cuboidal cells surrounding small cysts
containing clear’ strew-colored fluid.
ii. More common in females and in the seventh decade of life. Almost
uniformly benign and curable by removed surgically.
iii. Associated with somatic mutation of the von hipple-lindau tumor
suppressor gene which its product binds to hypoxia induced factor alpha-1
and results in its degradation.
b. Mucinous cystic neoplasm
i. Vest majority raise in women In the body or tail of pancreas Present as
painless, slow growing mass.
ii. Cyst space is large and filled with steaky-viscose mucin walls are lined by
columnar mucinous epithelium with an associated densely cellular stroma
(similar to ovary).
iii. Benign ones categorized by degree of dysplasia (cellular and architectural
abnormalities) into “mucinous cystic neoplasm with low-grade dysplasia,”
“mucinous cystic neoplasm with moderate dysplasia,” and “mucinous
cystic neoplasm with high-grade dysplasia.” These are all curable when
completely removed surgically.
iv. About a third of mucinous cystic neoplasms have progress to malignant
invasive type these are designated as “mucinous cystic neoplasm with an
associated invasive carcinoma.”
c. Intraductal papillary mucinous neoplasm
i. Intraductal papillary mucinous neoplasms are tumors (neoplasms) that
grow within the pancreatic ducts (intraductal) characterized by the
production of thick fluid by the tumor cells (mucinous).
ii. Arise in the main pancreatic duct or its major branches as papillary tumor
distending the lumen histologically look as Cyst containing mucin lack
the cellular stroma seen in mucinous cystic neoplasm
iii. Again if benign categoriesed by severity of dysplasia and malignant said
to be associated with adenocarcinoma component.
iv. Unlike other cystic tumor they More frequent in males and more
Frequently involved the head of pancreas(not tail as former
- Pancreatic neoplasma. adenocarcinoma arising from pancreatic ducts:
i. very high mortality rate
ii. Most common seen in older age around 70
iii. Risk factor- smoking (double the risk), chronic pancreatitis and diabetes
mellitus
b. Pathogenesis
i. As all cancers it’s a genetic disease arising as a consequence of inherited
and acquired mutations in cancer associated genes. There is a progressive
accumulation of genetic changes in pancreatic epithelium as it proceeds
from non-neoplastic, to noninvasive lesion in small ducts and ductules to
invasive carcinoma.
ii. Three morphologic forms of non-invasive pancreatic neoplasia have been
defined all may progress to carcinoma (pancreatic intraepithelial neoplasia
(PanIN), mucinous cystic neoplasm (MCN) and intraductal papillary
mucinous neoplasm (IPMN)). pancreatic intraepithelial neoplasia is the
most potent of these to do this progress.
Its an small papillary lesion ~1/2
cm raise in small pancreatic ducts, found next to carcinoma lesion and
share similar genes mutations with it (all such lesions has dramatic
telomerase shortening…)
iii. Four genes are most commonly affected by somatic mutation of this
neoplasm : K-RAS- GTPase found in vast majority of pancreatic cancers
,P16 , SMAD4 and P-53 also frequent involved genes.
iv.
The progression from normal ducts to pancreatic intraepithelial neoplasia
is associated with both architectural and cytological changes. In PanIN-1
the nuclei are uniform and basally oriented the nuclei in PanIN-2 are
slightly larger, more basophilic and there is some loss of nuclear polarity
the nuclear pleomorphism in PanIN-3 can be significant.
c. Presentation -signs and symptoms tend to appear only late in the course
i. Abdominal pain epigastric plus weight loss.
1. Diabetics – mainly if tumor in the body/tail where islets are
prominant
ii. Obstructive jaundice – Most carcinoma of the head obstructs the distal
common bile duct as it courses through the head of the pancreas.
iii. Pancreatitis
iv. ~10% may present with migratory thrombophlebitis (The Trousseau sign)
medical sign rare variant of venous thromboembolism (VTE) that is characterized by recurrent, migratory thrombosis in superficial veins and
in uncommon sites, such as the chest wall and arms.
This syndrome is
particularly associated with pancreatic and lung cancer.
d. Morphology
i. Site: pancreatic head (60%), body (15%), tail (5%), diffuse involves the
entire organ (20%) as hard greyish white masses poorly definde
ii. Pancreatic cancer highly invasive metastasize to nearby organs Distant
metastases to lung and bone
iii. Micro Seen as poorly formed glands surround by dens fibrotic stromadesmoplasia
iv. Less common variant of pancreatic cancer Adensquamous carcinomas
(with squamous cells) or Undifferentiated carcinoma with osteoclast-like
giant cell ( with monocyte linage cells)
e. Screening- endoscopic US and CT Treatment: surgical excision (whipple
procedure) Prognosis: very poor 1 year survival rate Tumor markers: CEA and
CA19-9 (not specific and not sensitive)
Pancreatic neuroendocrine tumors1. Pancreatic neuroendocrine tumors (also known as islet cell tumors or islet cell carcinoma)
are a type of neuroendocrine tumor found in the pancreas.
Only 2 percent of pancreatic
tumors arise in the islet cells. The vast majority of tumors found in the pancreas are
adenocarcinoma.
- All PanNET, except insulinoma, are regarded as having malignant potential. if they are
malignant, the liver is the most common site of metastasis Proliferative rate is one of the
best correlates to outcome - Genomic sequencing of sporadic PanNet has identified recurrent alteration genes
a. MEN1-(multiple endocrine neoplasia type 1)
b. Loss of function mutation in tumor suppressor genes such as PTEN which is a
negative regulators of oncogenic TOR signaling pathway - Insulinoma (b-cell tumor)
a. Most common type of islet cell tumor
b. Tumor produces insulin - major symptom is Hypoglycemia (which occurs when
plasma glucose level falls below 50 mg/dL) , sweating, hunger, confusion, insulin
come Lab: elevated insulin and C-peptides
c. As no malignant potential Most insulinomas are cured by surgical resection
d. Morphology
i. Majority are identified while they are small (less than 2 cm diameter) and
localized to the pancreas Most are solitary lesions
ii. Hitologically- Benign tumor looks like giant islets do not present much
evidence of anaplasia and they may be deceptively encapsulated.
- Deposition of amyloid (of amylin) in the EX tissue is a
characteristic feature - Under EM, neoplastic b-cells, like their normal counterparts,
display distinctive round granules.
Gastrinoma (g-cell tumor)
iii. Tumor produces gastrin and classicaly present as Zollinger-Ellison
syndrome
- Elevated serum gastrin
- Gastric hyperacidity
- Intractable peptic ulcer which may also occur in unusual locations
such as the jejunum
iv. May also arise outside the pancreas duodenum
v. Gastrinomas can occur as isolated, sporadic neoplasms or as multiple,
MEN-1 associated neoplasms
vi. Morphology
- Over half of gastrin-producing tumors are locally invasive or have
already metastasized at the time of the diagnosis. - Gastin producing tumors are histologically bland and rarely exhibit
marked anaplaisa
Glucagonoma (alpha-cell tumor)
vii. Glucagonomas are typically large and occur almost entirely within the
pancreas.
Glucagonomas secrete excessive amounts of glucagon, causing glucose
intolerance, weight loss, and a pathognomonic rash known as necrolytic
migratory erythema. Hyperglycemia (diabetes), anemia and skin rash
Somatostatinoma
viii. Tumor produces somatostatin Somatostatin inhibits
- Insulin secretion = diabetes
- Gastric secretion = hypochlorhydria
- Cholecystokinin secretion = gallstone and steatorrhea
VIPoma
ix. Tumor produces vasoactive intestinal peoptide
x. WDHA syndrome: watery diarrhea, hypokalemia and acholohydria
With respect to the digestive system, VIP seems to induce smooth muscle relaxation (lower
esophageal sphincter, stomach, and gallbladder),
stimulate secretion of water into pancreatic
juice and bile stimulating pancreatic bicarbonate secretion, and cause inhibiting gastrinstimulated gastric acid secretion also dilating peripheral blood vessels
Testicular neoplasias.
- Heterogeneous group of neoplasms may be divided into 2 major groups
a. Germ cell tumor - ~95% of cases all malignant, usually occur between 15-40years
of age
b. Sex cord- stromal tumor (Sertoli or Leydig cells) - uncommon usually benign.
- Cause of testicular neoplasm remains unknown. Risk Factor:
a. Cryptorchidism (3-5 fold increase)
b. Testicular dysgenesis (testicular feminization and Klinefelter syndrome)
c. Caucasians > African Americans
d. Family history
e. An isochromosome of the short arm of chromosome 12 is found in all germ cell
tumors.
f. Most testicular tumors in post pubertal males arise from the in-site lesion
intratubular germ cell neoplasm- Lesion can be found in grossly normal
testicular tissue adjacent to germ cell tumors in all cases
- Clinical presentation
Firm, painless testicular mass
Semonimas - Account for 50% of testicular neoplasm remain confined to the testis for a
long time Spread mainly to paraarotic nodes- distant spread is rare.
Non seminomatous – tumor Tend to spread earlier by both lymph and blood vessels
Treatment: Radical orchiectomy and Chemotherapy
- Germ cell tumors- although described separately As many as 60% of germ cell tumors
are mixed and contain more than one component, tumors arising from pluripotent
neoplastic germ cells.
a. Seminoma- most common testicular cancer, good prognosis late metastasis react
to treatment
i. Gross: Soft, well-demarcated, gray-white tumor cut surface is
homogenous no hemorrhage or necrosis
ii. Micro Large polygonal, uniform cells with distinct border Clear,
glycogen-rich cytoplasm Round nuclei and visible nucleoli (resembles
ovarian dysgerminoma)
Arranged in small lobules, which are separated by fibrous septae in it may
see Lymphocytic infiltrate
Variant; spermatocytic seminoma
a. affect older men lack lymphocytic infiltrate and
syncytiotrophoblasts
b. Not associated with intralobular germ cell neoplasm Do not
metastasize
iii. In 10% of cases, syncytiotrophoblast are present that are the source of
minimally elevated serum hCG concentration
b. Embryonal carcinoma more rear 2-3% poor prognosis early metastasis poor
reaction to treatment
- Common appear at Age 20-30,malignant tumor comprised of
immature, primitive cells. - Gross: mass with hemorrhage and necrosis
Micro: large primitive appearing cells with basophilic cytoplasm
Indistinct cell borders and large hyperchromatic nuclei with
prominent nucleoli. Pleomorphic cells in cords, sheets or gland like
arrangement. - Tumor markers: Negative (pure embryonal carcinoma) but in many
cases tumor is mixed with choriocarcinoma or yolk sac tumor cells,
so their markers may appear.
c. Choriocarcinoma
- Highly malignant with early hematogenous metastases most common
in the liver and the lung. - Common appear at age of 20-30 in tumor see trophoblastic linageplacenta forming cells.
- Gross: often small, non-palpable lesions with hemorrhage on cut
surface, in compare to large metastatic centers it creates in different
locations
Micro: proliferation of syncytiotrophoblasts large eosinophilic
multinucleated cells pleomorphic nucleus intermingle with small
cuboidal cytotrophoblasts.
- Tumor marker- hCG
d. Yolk sac tumor (endodermal sinus tumor)
- Most common germ cell tumor in children younger than 3. Good
prognosis in children In adults, it is often mixed with embryonic
carcinoma. - Marco: large and may be well demarcated
- Micro: Low cuboidal to columnar epithelial cells forming microcyst,
lacelike (reticular) patterns. schiller-Duval a developing glomerulus
resembling structure character for tumor - Tumor marker- alpha fetoprotein AFP
e. Teratoma
- Neoplastic germ cells differentiate along somatic cell line Majority
are malignant in male in female bening… - Gross: often cystic masses that may contain cartilage
- Micro:tumor composed of mature fetal tissue derived from two or
three embryonic layers(ectodermal, endodermal and mesodermal) in a
haphazard arrangement. E.g. cartilage plus neuron plus glandular
/squamous epithel. - They may occur at any age in young age more common and bening
old age rear and malignant. Rarely, nongerm cell tumor may arise in
Teratoma (teratoma with malignant transformation) - Tumor marker: 90% of patients have elevated hGC and AFP
- Scrotal squamous cell carcinoma is associated with exposure to soot (chimney sweeps)
SEXCORD-STROMALTUMORS
A. Tumors that origin from stromal tissues of the testicle usually benign
- Leydig cell tumor: are derived from normal Leydig cells that produce testosterone and are
located in the interstitium of the testis. usually produces androgen, causing precocious puberty in
Children or gynecomastia in adults Characteristic Reinke crystals (eosinophilic rod-shaped
cytoplasmic structures that are the most definitive light microscopic marker of Leydig cell
differentiation) may be seen on histology.
- Sertoli cell tumor: tumor derived from Sertoli cells, located within seminiferous tubules, which
help support spermatogenesis. Sertoli cell tumors are typically composed of solid tubules
containing Sertoli cells and is usually clinically silent.
IV. LYMPHOMA
A. Most common cause of a testicular mass in males > 60 years old; often bilateral
R. Usually of diffuse large B-cell type
Epithelial tumors of the ovary.
Tumors of the ovary are amazingly varied. This diversity is attributable to the presence of
three cell types hence 3 tumor groups plus metastasis, the multipotent surface (coelomic)
epithelium, the totipotent germ cells, and the sex cord–stromal cells
SURFACE EPITHELIAL TUMORS
Most common type of ovarian tumor (70% of cases) in woman above 40 age Surface
Epithelial Tumors Serous Tumors and Mucinous Tumors, less common Endometrioid
Tumors and Brenner Tumor.
Derived from coelomic epithelium that lines the ovary; coelomic epithelium
embryologically produces the epithelial lining of the fallopian tube (serous cells),
endometrium, and endocervix (mucinous cells).
Two most common subtypes of surface epithelial tumors are serous -full of watery fluid
and mucinous- full of mucus-like fluid both are usually cystic.
Benign lesions usually are cystic (cystadenoma) and may have an accompanying
stromal component (cystadenofibroma) – benign more common in pre-menopause
woman ~40.
Malignant tumors may also be cystic (cystadenocarcinoma) or solid (carcinoma) –
malignant more common to post menopause woman~70.
Borderline tumors have features in between benign and malignant tumors.
risk factors
1) nulliparity- higher incidence in unmarried women
2) family history
3) and germline mutations in certain tumor suppressor genes- 10-15% familial associated
with BRCA1,2
Prolonged use of oral contraceptives somewhat reduces the risk
Most common malignant ovarian tumor, Prognosis is generally poor for surface epithelial
carcinoma (worst prognosis of female genital tract cancers).
Epithelial carcinomas tend to spread locally, especially to the peritoneum. CA-125 is a
useful serum marker to monitor treatment response and screen for recurrence.
1) SEROUS TUMORS
The most common of the ovarian epithelial tumors most are benign but this category
account for highest frequency malignant tumor of ovary
two types of serous carcinomas:
- low-grade (KRAS, BRAF, or ERBB2 mutations)
- high-grade (96% of tumors have mutations in TP53)
morphology: MACRO=
- Most serous tumors are large, spherical to ovoid, cystic structures up to 30 to 40
cm in diameter, may have number of compartments.
- In the benign form, the wall is smooth cystadenocarcinoma shows nodular
irregularities as it infiltrates its surrounding Serosal penetration and solid areas of
growth are suggestive of malignancy.
- The cystic spaces usually are filled with a clear serous fluid.
MICRO=
- benign tumors contain a single layer of tall columnar epithelial cells that line the
cystor cysts. The cells may be ciliated.
- In carcinoma Papillary formations are complex and multilayered, nests or
undifferentiated sheets of malignant cells invade the axial fibrous tissue.
Metastasis along lymph node periartic and local. Psammoma bodies
(concentrically laminated calcified concretions)
- Tumors of low malignant potential-which exhibit less cytologic atypia and,
typically, little or no stromal invasion.
2) MUCINOUS TUMOR
Similar to serous tumors essential difference the neoplastic epithelium consists of
mucin-secreting cells 80% are benign
Morphology:
MACRO produce cystic masses with mucinous nature of the cystic contents. They are
more likely to be larger and multicystic the serous type.
Micro= the cysts are lined by mucin-producing epithelial cells
Compared with serous tumors, mucinous tumors are much less likely to be bilateral.
This feature is sometimes useful in differentiating mucinous tumors of the ovary from
Krukenberg tumor is a metastatic mucinous tumor that involves both ovaries; most
Commonly due to metastatic gastric carcinoma (diffuse type)
Implantation of mucinous tumor cells in the peritoneum with production of massive
amounts of mucin is called pseudomyxoma peritonei in most cases, this disorder is
caused by metastasis from the gastrointestinal tract, primarily the appendix to ovary
3) Endometrioid tumor
Endometrioid rumors are composed of endometrial-like glands and are usually malignant.
i. May arise from endometriosis
ii. 15% of endometrioid carcinomas of the ovary are associated with an
Independent endometrial carcinoma (endometrioid type). Have mutations in the PTEN
tumor suppressor gene (similar to endometroid endometrial tumor)
They are bilateral in about 30% of cases they are distinguished by the formation of
similar tubular glands to those of the endometrium within the lining of the cystic space.
4) Brenner Tumor
Brenner tumors are composed of bladder-like epithelium and are usually benign.
may arise from the surface epithelium or from urogenital epithelium trapped within the
germinal ridge
macro=solid, usually unilateral ovarian tumor smoothly encapsulated and gray-white on
cut section
Micro=abundant stroma containing nests of transitional-type epithelium resembling that
of the urinary tract
GERM CELL TUMORS
2nd most common type of ovarian tumor (15% of cases) usually occur in young women of
reproductive age.
4 major groups: Tumor subtypes mimic tissues normally produced by germ cells.
- Fetal tissue—cystic Teratoma and embryonal carcinoma
1) Benign (mature) cystic Teratoma (90% of germ tumor)
tumor composed of mature tissues derived from all three germ cell layers: ectoderm,
endoderm and mesoderm Most common germ cell tumor in females;
bilateral in 10% of cases with Cystic cavity On cut section, they often are filled with
sebaceous secretion and hair (ball) foci of bone and cartilage, nests of bronchial or
gastrointestinal epithelium, and other tissues also are present
Struma ovarii is a Teratoma composed primarily of thyroid tissue.
incidentally are discovered in young women as ovarian masses or are found on
abdominal radiographs or scans because they contain foci of calcification (tooth-like
structures)
Benign, but presence of immature tissue (usually neural) or somatic malignancy (Usually
squamous cell carcinoma of skin) indicates malignant potential.
Malignant(immature) teratomas (10%) are found early in life (18y) predominantly
solid on cut section, and punctuated by areas of necrosis Uncommonly cystic foci are
present that contain sebaceous secretion similar to those of mature teratomas
On microscopic examination presence of immature elements or minimally
differentiated
- Oocytes—dysgerminoma
Tumor composed of cells with clear cytoplasm and central nuclei (resemble oocytes);
Testicular counterpart is called seminoma (both result of gonadal dysgenesis)
Solid large to small gray masses Sheets or cords of large clear cells separated by scant
fibrous strands Stroma may contain lymphocytes and occasional granulomas
All malignant but Good prognosis; responds to radiotherapy
- Yolk sac—endodermal sinus tumor
Malignant tumor that mimics the yolk sac; most common germ cell tumor in Children
Serum AFP is often elevated.
Schiller-Duval bodies (glomerulus-like structures) are classically seen on Histology
- Placental tissue—choriocarcinoma
Malignant tumor composed of trophoblasts and syncytlotrophoblasts; mimics placental
tissue, but villi are absent (unlike mole)
Small, hemorrhagic tumor with early hematogenous spread create larger metastatic
masses than primary focus.
High beta-hCG is characteristic (produced by syncytiotrophoblasts)
poor respond to chemotherapy(unlike gestational related type)
SEX CORD STROMAL TUMORS
sex cord tumors are ones of stroma come from theca granulosa cells or from fibrocytes
really
Granulosa-theca cell tumor
Neoplastic proliferation of granulosa and theca cells Often produces estrogen; presents
with signs of estrogen excess
i. Prior to puberty—precocious puberty
ii. Reproductive age—menorrhagia or metrorrhagia
iii. Postmenopausal (most common setting granulosa-theca cell tumors) Endometrial
hyperplasia with postmenopausal uterine bleeding
Malignant, but minimal risk for metastasis
- Sertoli- leydig cell tumor
Composed of Sertoli cells that form tubules and Leydig cells (between tubules)
with characteristic Reinke crystals
May produce androgen; associated with hirsutism and virilization
- Fibroma
Benign tumor of fibroblast, solid gray tumor.
Associated with pleural effusions and ascites (Meigs syndrome); resolves with removal of
tumor.
Pathology of the infertility. Gestational trophoblastic disease and neoplasias. Ectopic
pregnancy
NORMAL HISTOLOGY REVIEW:
1) Membranes: The amnion lines the amniotic sac containing the fetus. The
amnion consists of a single layer of cuboidal epithelium, its basement membrane,
and a collagen layer.
The fibrous chorion lies deep to the amnion, chorion are fetal
in origin. Deep to it is the decidual layer (maternal in origin). This layer contains
decasualized maternal cells, vessels, fibrin, and often some degree of hemorrhage.
2) Umbilical cord: The outer surface of the umbilical cord is covered by amniotic
epithelium. Normally, 3 vessels (2 arteries and 1 vein) are embedded in (Wharton’s
jelly).
3) Placental disk: The chorionic plate (fetal surface) consists of a single layer of
cuboidal amniotic epithelium overlying a paucicellular collagenous matrix
(chorion) containing numerous large vessels of fetal origin.
Below this are the villi (large stem villi to small terminal villi) separated by clear or blood containing
spaces (the intervillous space) where the maternal blood circulates around the fetal
villi.
The villi consist of an outer layer of syncytiotrophoblasts deep to the
syncytial trophoblast cells is a single, discontinuous layer of cytotrophoblasts cells
(larger, cuboidal cells).
The cellular matrix consists of macrophages and fibroblasts with numerous vessels the resulting smaller and more highly branched terminal
villi increase the effective surface area in contact with the intervillous space thereby increasing gas and nutrient exchange without a significant increase in
placental mass.
The basal plate (maternal surface) consists of intermediate trophoblast cells, decasualized maternal cells and maternal vessels Normally, these
vessels are invaded by extravillous trophoblast cells, remodeled with elimination of
surrounding smooth muscle layers and enlarging the lumens leading into the
sinusoidal intervillous spaces.
PLACENTAL INFLAMMATIONS AND INFECTIONS
Infections may reach the placenta by either of two paths:
1) ascension through the birth canal
- more common in most instances, they are bacterial and are associated
with premature rupture of the fetal membranes.
- Major causative organism: Mycoplasma, Candida, and the numerous
bacteria of the vaginal flora.
- Micro = the chorioamnion shows neutrophilic infiltration associated with
edema and congestion (acute chorioamnionitis). - the infection may involve the umbilical cord and placental villi, resulting
in acute vasculitis of the cord (funisitis).
2) Hematogenous (transplacental) spread
- Micro = on histologic examination, placental villi are the most frequently
affected structures (villitis). - Causative agents: Syphilis, tuberculosis, listeriosis, toxoplasmosis, and
various viruses (rubella, cytomegalovirus, herpes simplex virus) all can
cause placental villitis. - Transplacental infections can affect the fetus and give rise to the socalled TORCH (toxoplasmosis, other infections, rubella,cytomegalovirus
infection, herpes) complex .
ECTOPIC PREGNANCY
Ectopic pregnancy is defined as implantation of a fertilized ovum in any site
other than the uterus.
In more than 90% of these cases, implantation occurs in the fallopian tube
(oviducts-tubal pregnancy);
other sites include the ovaries and the abdominal cavity Gestation within the
abdominal cavity occurs when the fertilized egg drops out of the fimbriated
end of the oviduct and implants on the peritoneum.
Any factor that retards passage of the ovum through the oviducts predisposes
to ectopic pregnancy slowed passage is attributable to chronic
inflammation and scarring, tumors and endometriosis etc.
MORPHOLOGY
- In all sites, early development of ectopic pregnancies proceeds normally,
with formation of placental tissue, the amniotic sac, and decidual changes.
- With tubal pregnancies, the invading placenta eventually burrows
through the wall of the oviduct, causing intratubal hematoma (hematosalpinx) The tube is usually distended by freshly clotted blood
containing bits of gray placental tissue and fetal parts. - intraperitoneal hemorrhage major risk see sudden intense abdominal
pain and blood loss. - Surgical emergency;
- The histologic diagnosis depends on visualization of placental villi or, rarely, of the embryo.
GESTATIONAL TROPHOBLASTIC DISEASE
Following conception instead of develop embryo develop trophoblastic tumor
have been divided on histopathologic grounds into three overlapping
morphologic categories: hydatidiform mole, invasive mole, and
choriocarcinoma. These demonstrate a range of aggressiveness from benign
hydatidiform moles to highly malignant choriocarcinomas.
All elaborate human chorionic gonadotropin (hCG), which can be detected in
the blood and urine at levels considerably higher than those found normally at
that stage of pregnancy.
1) Hydatidiform Mole: Complete and Partial
The typical hydatidiform mole is edematous swollen chorionic villi, appearing grossly as grapelike structures. The swollen villi are covered by varying
amounts of normal to highly atypical chorionic epithelium (proliferating
trophoblasts).
There are two distinctive subtypes of hydatidiform moles: complete and partial.
Invasive Mole
Invasive moles are complete moles that are more invasive locally but do not
have the aggressive metastatic potential of a choriocarcinoma.
An invasive mole retains hydropic villi, which penetrate the uterine wall
deeply, possibly causing rupture and sometimes life-threatening hemorrhage.
MICRO= the epithelium of the villi shows atypical changes, with
proliferation of both trophoblastic and syncytial components.
Hydropic villi may embolize to distant organs, such as lungs or brain Bout
invasive and hydatidform:
- Uterus expands as if a normal pregnancy is present, but the uterus is much larger
And hCG much higher than expected for date of gestation. - Classically presents in the second trimester as passage of grape-like masses
through the vaginal canal with prenatal care, moles are diagnosed by routine
ultrasound in the early first trimester. Fetal heart sounds are absent, and a
‘snowstorm’ appearance seen on ultrasound. - Treatment is curettage. Subsequent (3-hCG monitoring is important to ensure
adequate mole removal and to screen for the development of choriocarcinoma.
In invasive case sometime scraping not enough and see prolonged hCG elevation in
some cases chemotherapy needed
3) Gestational Choriocarcinoma
Choriocarcinoma, a very aggressive malignant tumor, arises either from
gestational chorionic epithelium or within the gonads as a germ cell tumor.
Approximately 50% of choriocarcinomas arise from complete hydatidform
moles; other arise after abortion/normal pregnancy and germ cell path…
MORPHOLOGY Choriocarcinomas usually appear as hemorrhagic, necrotic
uterine massesprimary lesion “self-destruct,” and only the metastases tell the
story. Very early invade myometrium and send metastasis.
In contrast with hydatidform moles and invasive moles, chorionic villi are not
formed; instead, the tumor is composed of anaplastic cuboidal cytotrophoblasts and syncytiotrophoblasts
In most cases, choriocarcinoma manifests with a bloody, brownish discharge In
general, the β-hCG titers are much higher than those associated with a mole.
widespread vascular spread usually has occurred to the lungs (50%), vagina
(30% to 40%), brain, liver, or kidneys.
these tumors are remarkably sensitive to chemotherapy Nearly 100% of
affected patients are cured. By contrast, response of ones that arise in the
gonads (ovary or testis) is relatively poor.
PREECLAMPSIAPregnancy-induced hypertension, proteinuria, and edema, usually arising in the
third trimester; seen in approximately 5% of pregnancies
Hypertension may be Due to abnormality of the maternal-fetal vascular interface in
the placenta; resolves with delivery
Eclampsia - is preeclampsia with seizures. HELLP is preeclampsia with thrombotic
microangiopathy involving the liver; characterized by Hemolysis, Elevated Liver
enzymes, and Low Platelets Both eclampsia and HELLP usually warrant immediate
delivery.
Non-neoplastic changes of the breast and benign breast tumors.
The designation fibrocystic is applied to a miscellany of changes in the female breast that consist
predominantly of cyst formation and fibrosis. (not neoplastic)
Overall, fibrocystic changes are the most common breast abnormality seen in premenopausal
women. The changes tend to arise during reproductive age and are most likely a consequence of the cyclic breast changes that occur normally in the menstrual cycle.
NON PROLIFERATIVE CHANGES
NON-PROLIFERATIVE FIBROCYSTIC CHANGE
Characterized by an increase in fibrous stroma associated with dilation of ducts and
formation of variably sized cysts primarily affects the terminal duct lobular unit, not the
large duct.
Macro: changes usually are multifocal and often bilateral. The cysts range from less than
1 cm and up to 5 cm in diameter. Unopened, they are brown to blue (blue dome cysts)
and are filled with watery, turbid fluid. The secretions within the cysts may calcify,
producing microcalcifications on mammograms.
Micro=epithelial lining that in larger cysts may be flattened or even totally atrophic
Apocrine metaplasia = a variant of non-proliferative fibrocystic change the lining cells
are large and polygonal with abundant granular, eosinophilic cytoplasm (apical secretory
granules) and small, round, deeply chromatic nuclei, do not increase risk for neoplastic
change!
The stroma surrounding all types of cysts usually consists of compressed fibrous tissue
that has lost the delicate, myxomatous appearance of normal breast stroma.
EPITHELIAL HYPERPLASIA
a variant of proliferative fibrocystic change in which fined more than the 2 normal
lining epithelial layers of the duct. Normal ducts and lobules of the breast are lined by
two layers of cells—a layer of luminal cells overlying a second layer of myoepithelial
cells.
MICRO= The ducts or lobules may be filled with orderly cuboidal cells within which
small gland patterns (called fenestrations)
The proliferating epithelium projects as multiple small papillary excrescences into the
ductal lumen ductal papillomatosis).
atypical ductal/lobular hyperplasia is used to describe hyperplasia’s that exhibit
changes that start to resemble ones of carcinoma in situ(see description next pic)
Both atypical ductal and lobular hyperplasia are associated with an increased risk of
invasive carcinoma.
SCLEROSING ADENOSIS
hyperplastic process involving an increased number of glandular components (number of
glands in one TDLU) =adenosis plus stromal proliferation that create hard palpable
mass=sclerosis
Less common but worth mentioning cause Its clinical and morphologic features may
mimic those of carcinoma.
MACRO= the lesion has a hard, rubbery consistency, similar to that of breast cancer.
MICRO= shows a characteristic: enlarged TDLU Preservation of luminal lining of
epithelium and myopithel layer (Help to distinguish from invasive ductal carcinoma)
with surrounding Dens Stromal fibrosis, which may compress and distort the
proliferating glands.
BENIGN BREAST TUMORS
E.
FIBROADENOMA
The most common benign neoplasm of the female breast. no increased risk of carcinoma
It is a biphasic slow growing tumor composed of fibroblastic stroma and epithelium-lined
glands = only the stromal cells are clonal and truly neoplastic.
They seen as solitary mobile masses firm consistency number of cm size mass.
Estrogen sensitive grows during pregnancy and may be painful during the menstrual
cycle also they peak in appearance in 3rd decade of life and after menopause, they may
regress and calcify.
A cut section shows a uniform grayish white color, punctuated by softer yellow-pink
specks representing the glandular areas.
MICRO: The epithelial proliferation appears as duct-like spaces of various shapes and
sizes surrounded by a loose fibroblastic stroma. Depending on the proportion and the
relationship between these two components, there are two main histological features:
intracanalicular and pericanalicular. Often, both types are found in the same tumor.
Intracanalicular fibroadenoma: stromal proliferation predominates and compresses the
ducts, which are irregular, reduced to slits.
Pericanalicular fibroadenoma: fibrous stroma
proliferates around the ductal spaces, so that they remain round or oval, on cross section.
The basement membrane is intact.
PHYLLODES TUMOR
Fibroadenoma-like tumor However, the stromal element of these tumors is more cellular
and abundant, often forming epithelium lined leaflike projections (phyllodes is Greek for
“leaflike”).
Less common than fibroadenomas arise de novo, not from preexisting fibroadenomas.
changes suggesting malignancy include increased stromal cellularity, anaplasia, high
mitotic activity, rapid increase in size, and infiltrative margins but most phyllodes
tumors remain localized and are cured by excision
INTRADUCTAL PAPILLOMA
Intraductal papilloma is a benign neoplastic papillary growth. Most often seen in
premenopausal women.
These lesions typically are solitary and found within the principal lactiferous ducts or
sinuses.
The clinical presentation may include
* Serous or bloody nipple discharge
* The presence of a small subareolar tumor a few millimeters in diameter
* Nipple retraction
MICRO= they are composed of multiple papillae, each having a connective tissue core
covered by epithelial cells that are double-layered, with an outer luminal layer overlying
a myoepithelial layer. The presence of a double-layered epithelium helps to distinguish
intraductal papilloma from intraductal papillary carcinoma.
Precancerous diseases of the breast. Breast carcinomas.
2nd to lung cancer in cancer related death among women The lifetime risk of developing breast cancer is
1 in 8 for women and 20-30% mortality rate in the United States.
risk factors for breast cancer:
1) Age. Risk increases after age of 30 , especially after menopause
2) Geographic Variations. The risk is significantly higher in North America and northern Europe than in
Asia and Africa. These differences seem to be environmental rather than genetic in origin.
3) Family history
4) Age at menopause greater than 55
5) 1st Pregnancy after age of 35/nulliparous
6) Benning breast diseas as proliferative atypical hyperplasia
7) Other Risk Factors.
- Prolonged exposure to exogenous estrogens postmenopausally, as occurs with hormone replacement
therapy/Oral contraceptives- no effect. - Ionizing radiation its age-period of time depended before age of 30 during breast development and
its dose depended also (therapy radiation increase risk but mammography not-smaller dose). - Less establish relation to: Obesity-alcohol consumption and a diet high in fat
pathogenesis:
three sets of influences seem to be important:
1) Genetic changes
Is overexpression of the HER2/NEU proto-oncogene, which undergoes amplification in ~ 30% of
invasive breast cancers. This gene is a member of the epidermal growth factor receptor family,
and its overexpression is associated with a poor prognosis. Also Amplification of RAS and MYC
genes also has been reported in some human breast cancers.
Gene expression profiling has demonstrated the presence of four molecular subtypes with
distinct natural histories and clinical behavior. these generally align with the presence or absence
of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor
receptor 2 (HER2):
(1) Luminal A (estrogen receptor–positive, HER2/NEU-negative);most common good
prognosis associated with age
(2) Luminal B (estrogen receptor–positive, HER2/NEU overexpressing); less good
prognosis
(3) HER2/ NEU positive (HER2/NEU over expressing, estrogen receptor– negative); less
common more aggressive appear at younger ages
(4) basal-like (estrogen receptor–negative and HER2/NEU-negative).also called triple
negative appear more in African American woman carry poor prognosis and appear at
younger age pre-menopausal.
~10% of cases are hereditary breast cancer specific related to one mutation, manifest as
premenopausal appearance see also in first degree relative and bilateral tumor/other related
tumor e.g. ovarian
Roughly one third of women with hereditary breast cancer have mutations in BRCA1 or
BRCA2 ).both BRCA1 an BRCA2 are believed to function in a common DNA repair pathway
BRCA1 and BRCA2 are classic tumor suppressor genes, in that cancer arises only when both
alleles are inactivated or defective—the first caused by a germline inherited mutation and the
second by a subsequent somatic mutation.
Less common genetic diseases associated with breast cancer are the Li-Fraumeni syndrome,
Cowden syndrome (caused by germline mutations in PTEN—mentioned earlier under
endometrial carcinoma) and the ataxia-telangiectasia gene carriers.
2) Hormonal Influences.
Estrogen excess = hormonal imbalance Estrogens stimulate the production of growth factors (such
as TGF-α, PDGF, and FGF) may promote tumor development through paracrine and autocrine
mechanisms.
3) Environmental Variables. See above geography treatments alcohol obesity etc.…
Morphology:
The most common location of tumors within the breast is in the upper outer quadrant (50%), followed
by the central portion (20%).
Breast cancers are classified according to whether they have or have not penetrated the limiting
basement membrane:
A. Noninvasive
1. Ductal carcinoma in situ (DCIS)
2. Lobular carcinoma in situ (LCIS)
B. Invasive (infiltrating)
1. Invasive ductal carcinoma (“not otherwise specified”), the most common subtype of invasive
carcinoma
2. Invasive lobular carcinoma
3. Medullary carcinoma
4. Colloid carcinoma (mucinous carcinoma)
5. Tubular carcinoma
6. Other types
Noninvasive (in situ) Carcinoma
include: DCIS and LCIS. both types usually arise from ductal epithelium of the terminal duct lobular
unit.
DCIS tends to fill and expand ductal lumen with proliferating ductal cells and necrosis, By contrast,
LCIS usually expands but does not alter the acini of lobules
PAGET DISEASE OF THE NIPPLE
is caused by the extension of DCIS up the lactiferous ducts and into the contiguous skin of the nipple, producing
a unilateral crusting exudate over the nipple and areolar skin.
In almost all cases, an underlying carcinoma is present, and approximately 50% of the time this
carcinoma is invasive.
Prognosis is based on the underlying carcinoma and is not affected by the presence of Paget disease.
Invasive (Infiltrating) Carcinoma
1) Invasive ductal carcinoma
- A majority (70% to 80%) of cancers fall into this group. type of cancer usually is associated with DCIS
and, rarely, LCIS.
- Most ductal carcinomas produce a desmoplastic response = which replaces normal breast fat (resulting
in a mammographic density) and forms a palpable mass - The microscopic appearance is quite heterogeneous, ranging from tumors with well-developed tubule
formation and low-grade nuclei to tumors consisting of sheets of anaplastic cells The tumor margins
typically are irregular - About two thirds express estrogen or progesterone receptors, and about one third overexpress
HER2/NEU.
2) Invasive lobular carcinoma
- Origen from lobule neoplastic cells morphologically identical to the cells of LCIS (monomorphic, mucin
vacuoles). Two thirds of the cases are associated with adjacent LCIS. - The cells invade individually into stroma and are often aligned in “single-file/indian file” strands or
chains. Associated with mutations in E cadherin - Most exhibit desmoplastic reaction so create palpable mass.
- Lobular carcinomas have a unique pattern of metastases among breast cancers; they more frequently
spread to cerebrospinal fluid, serosal surfaces, gastrointestinal tract, ovary, uterus, and bone marrow. - Almost all of these carcinomas express hormone receptors, whereas HER2/NEU overexpression is rare.
3) Inflammatory carcinoma
4) Medullary carcinoma
- is a rare subtype of carcinoma, create cohesive sheets of high pleomorphic cells with well
circumscribed, “pushing” borders, associated with prominent lymphocyte and plasma cells infiltration
- Medullary carcinomas occur with increased frequency in women with BRCA1 mutations And its triplenegative tumor.
5) Colloid (mucinous) carcinoma
- also is a rare subtype.The tumor cells produce abundant extracellular mucin into the surrounding stroma
Like medullary carcinomas, they often present as well-circumscribed masses and can be mistaken for
fibroadenomas.On gross evaluation, the tumors usually are soft and gelatinous.
- Most express hormone receptors
6) Tubular carcinomas
Common Features of Invasive Cancers
- Invasive cancers tend to become adherent and fixed to the pectoral muscles or deep fascia of the chest
wall and the overlying skin, with consequent retraction or dimpling of the skin or nipple.first indication
of malignancy. - Involvement of the lymphatic pathways may result in localized lymphedemaIn such cases, the skin
becomes thickened around exaggerated hair follicles, giving an appearance known as peau d’orange
(“orange peel”).
Clinical course:
At the time of clinical detection, the carcinoma typically is 2 to 3 cm in size, and involvement of the
regional lymph nodes (most often axillary) is already present in about 50% of patients.
Breast cancer spread occurs through lymphatic and hematogenous channels. Favored locations are the
lungs, skeleton, liver, adrenals, and (less commonly) brain, but no site is exempt.
Prognosis
tumor-node-metastasis (TNM) staging classification:
1) Tumor invasion and size. In situ carcinomas carry an excellent prognosis (5-year survival rate greater
than 90%), as do invasive carcinomas less than 2 cm in size (5-year survival rate of 87%).
2) Extent of lymph node involvement. With no axillary node involvement, the 5-year survival rate is close
to 80%.
Survival is inversely related to the number of involved lymph nodes and is less than 50% with 16 or
more involved nodes.
Sentinel node biopsy is currently the mainstay for staging the axila = This procedure identifies the
primary lymph node(s) that drain the breast parenchyma using dye or a radioactive tracer (or sometimes
both). Once identified, sentinel nodes are removed and examined microscopically.
3) Distant metastases. Patients who develop hematogenous spread are rarely curable
4) Histologic grade. The most common grading system for breast cancer evaluates tubule formation,
nuclear grade, and mitotic rate.
5) The histologic type of carcinoma. All specialized types of breast carcinoma (tubular, medullary, and
mucinous) are associated with a somewhat better prognosis than carcinomas of no special type (ductal
carcinomas). A major exception is inflammatory carcinoma, which has a poor prognosis.
6) The presence or absence of estrogen or progesterone receptors. The presence of hormone receptors
confers a slightly better prognosis.
Overexpression of HER2/NEU. Overexpression is associated with a
poorer prognosis. However, the clinical importance of evaluating HER2/NEU lies in predicting response
to trastuzumab (Herceptin), a monoclonal antibody that binds and inhibits the function of HER2/NEU.
Hyperpituitarism. Pituitary adenomas
- Pituitary gland
a. Small, bean shaped structures located at the base of the brain, on the sella turcica.
b. Connected to the hypothalamus by a stalk composed of axons and a rich venous plexuse.
c. Central role in regulation of other endocrine glands
d.Composed of two functionally and morphologically distinct components:
1.The anterior pituitary, or adenohypophysis, is composed of epithelial cells derived embryologically from the
developing oral cavity. In routine histologic sections, see array of cells containing basophilic cytoplasm,
eosinophilic cytoplasm, or poorly staining (chromophobic) cytoplasm the staining properties of these cells are
related to the presence of various trophic polypeptide hormones within their cytoplasm .
The pink acidophils secrete growth hormone (GH) and prolactin (PRL)
The dark purple basophils secrete corticotrophin (ACTH), thyroid stimulating hormone (TSH), and
gonadotrophins follicle stimulating hormone-luteinizing hormone (FSH and LH)
The pale staining chromophobes have few cytoplasmic granules, but may have secretory activity.
The release of trophic hormones is in turn under the control of factors produced in the hypothalamus; while most hypothalamic factors are stimulatory and
promote pituitary hormone release, others (e.g., somatostatin and dopamine) are inhibitory in their effects Rarely, signs and symptoms of pituitary disease may be caused
by excess or lack of the hypothalamic factors, rather than by a primary pituitary abnormality.
2.The neurohypophysis shown here resembles neural tissue, with glial cells, nerve fibers, nerve endings, and
intra-axonal neurosecretory granules. The hormones vasopressin (antidiuretic hormone, or ADH) and oxytocin
made in the hypothalamus (supraoptic and paraventricular nuclei) are transported into the intra-axonal
neurosecretory granules where they are released.
Diseases of the pituitary, accordingly, can be divided into those that primarily affect the anterior lobe and those that primarily affect the posterior lobe.
Hyperpituitarism and pituitary adenoma
Hyperpituitarism arises from excessive secretion of trophic hormones. It most often results from an anterior
pituitary adenoma but also may be caused by other pituitary and extrapituitary lesions .Causes of
hyperpituitarism:
a. Adenoma arising in anterior lobe (most common)
b. Hyperplasia and carcinoma of anterior lobe
c. Secretion of hormones by extrapituitary tumors
d. Hypothalamic disorders
Pituitary adenomas
Benign tumor of anterior lobe Found in adult 30-50 years old.
pituitary adenomas are usually composed of a single type of cell type and produce a single predominant
hormone.
Some adenomas secrete two hormones Most common combination- GH and prolactin
Plurihormonal adenomas- rare
May be functional (hormone producing and clinical sings), nonfunctional ( clinical silent) or hormone
negative
i. Nonfunctional and hormone negative (null cell) Likely to come to clinical attenation at a later stage
May cause hypopituitarism due to compression of the normal pituitary tissue
ii. Functional tumors represent with features based on the type of hormone produced.
Most adenomas occur as isolated lesion Microadenomas- less than 1 cm Macroadenoma- exceeds 1 cm in
diameter.
Most cases are sperodic but ~3% of adenomas are associated with multiple endocrine neoplasia.
Pathogenesis
One of most common mutations is Constitutive activation of a stimulatory G protein. A mutation in the alpha-subunit that interferes with its intrinsic GTPase activity Results in persistent generation of cAMP and
unchecked cellular proliferation Alpha subunit is encoded by GNAS1 gene
Pituitary adenomas that arise in the context of familial MEN-1 syndrome harbor mutation from MEN-1 gene
(interfer with check point regulation on p27) appear at younger age
Other abnormality is P53 mutation aggressive tumor.
Morphology
Usually well circumscribed, soft small lesion. Small tumors are confined by sella turcica, while larger lesions
typically extend into supracellar region, where they compress optic chiasm and adjacent structures.
Invasive adenomas- In 30% of cases, adenomas are grossly nonencapsulated and infiltrate adjacent bone,
dura and (uncommonly) bone.
Microscopically- mark by cellular monomorphism and absence of reticulin network.
Composed of relatively uniform, polygonal cells arrayed in sheets, cords or papillae Very little mitotic
activity Cytoplasm may be acidophilic, basophilic or chromophobic depending on type of secretory product.
Supportive CT-reticulin, is relatively absent accounting for soft consistency
Different adenomas subtypes
1. Prolactinoma
Most common type of pituitary adenoma Hyperprolactinemia due to Lactotroph cells secrete prolactin.
Hyperprolacinemia may be caused by other conditions than adenoma pregnancy, high dose estrogen
therapy/dopamine inhibiting drugs, renal failure, hypothalamic lesions or Stalk effect- any mass in the
suprasellar compartment that may disturb the normal inhibitory influence of hypothalamus on prolactin
secretion.
Clinical features
- Galactorrhea, amenorrhea and infertility
- Decreased libido and impotence
- Manifestation of hyperprolactinemia is more obvious in postmenopausal women.
- Growth hormone producing adenoma
GH producing , somatotroph cells, neoplasms are the second most common type of functional pituitary
adenoma Clinical manifestation may be subtle, so spmatotroph cell adenoma may be quite big by the time they
come to clinical attention
Microscopically Densely or sparsely granulated cells and GH within cytoplsm
Lab Elevated GH Elevated somatomedin C (IGF-1)
Giantism Occurs in children and adolescents prior to fusion of the growth plates Tall structure and long extremities
Acromegaly Occurs in adults after the growth plates have fused Prominent jaw Flat, broad forehead Enlarged
hands and feet The internal organs are typically enlarged
GH excess is also associated with a number of other disturbances Abnormal glucose and diabetes mellitus
Generalized muscle weakness Hypertension Arthritis Osteoporosis Congestive heart failure
- Corticotroph cell adenomas
Usually small at the time of diagnosis Usually stained positive with PAS as a result of the accumulation of
glycosylated ACTH proteins ACTH is synthesized as part of a larger prohormone that includes melanocyte
stimulating hormone, there may be hyperpigmentation.
May be clinically silent or may cause hypercortisolism (Cushing syndrome) because of stimulatory effect on
adrenal cortex.
Cushing disease- when hypercorticolism is caused by excessive production by pituitary gland
Nelson syndrome- aggressive corticotroph adeomona may develop after surgical removal of adrenal glands for treatment of cushing syndrome. Due to loss of the inhibitory effect of adrenal chorticoids on a preexisting corticotroph microadenoma
- Other anterior pituitary neoplasm
Gonadotroph (LH and FST-producing hormones) adenoma
Difficult to recognize
a. Secrete hormones inefficiently and variably
b. Secretory product do not cuase a recognizable clinical syndrome
Most frequent in middle age when tumor becomes large enough to cause neurological symptoms
Impaired vision Headaches Diplopia
FSH is usually the predominant secreted hormone.
Thyrotroph (TSH-produsing hormone) adenoma Rare cause of hyperthyroidism
Pituitary carcinoma Rare Local extension beyond the sella turcica Always distant metastases
Benign and malignant tumors of the thyroid gland.
Tóm tắt về U tuyến giáp và ung thư tuyến giáp
U tuyến giáp lành tính (Thyroid Adenoma)
a. Đặc điểm: Khối u lành tính từ biểu mô nang giáp, thường xuất hiện dưới dạng một nốt đơn lẻ.
b. Cơ chế bệnh sinh:
Trong các u độc, có đột biến trong con đường tín hiệu của thụ thể TSH dẫn đến việc tiết hormone tuyến giáp (TH) mà không cần TSH.
Một số u không chức năng có đột biến ở gene RAS hoặc PIK3CA, liên quan đến các loại ung thư nang giáp.
c. Hình thái:
Nốt đơn lẻ, có vỏ bọc rõ ràng.
Các tế bào sắp xếp thành nang đều, chứa chất keo, phân biệt tốt.
Nếu tế bào có bào tương ưa axit và nhân nhỏ, được gọi là tế bào Hurthle (u tuyến Hurthle).
d. Đặc điểm lâm sàng:
Thường không đau, nốt lớn có thể gây khó nuốt.
Đa số không chức năng, một số có thể sản xuất hormone giáp gây cường giáp.
Sau khi tiêm iod phóng xạ, các u thường hấp thu iod kém hơn so với mô giáp bình thường.
Ung thư tuyến giáp
a. Ung thư nhú giáp (Papillary Carcinoma)
Dịch tễ học: Phổ biến nhất (~85%), ung thư tuyến giáp chỉ chiếm khoảng 1% tổng số ca ung thư.
Cơ chế bệnh sinh:
Yếu tố môi trường: Tiếp xúc với bức xạ.
Yếu tố di truyền: Kích hoạt con đường MAP kinase thông qua đột biến RET hoặc NTRK1, hoặc đột biến ở gene RAF.
Hình thái:
Hiển vi: Nhân sáng “orphan annie eye”, mẫu hình nhú với lõi xơ mạch dày, có thể có thể có thể cát.
Đặc điểm lâm sàng:
Khối u không chức năng, có tỷ lệ sống sau 10 năm là 95%.
Biến thể thường gặp nhất là dạng nang.
b. Ung thư nang giáp (Follicular Carcinoma)
Dịch tễ học: Chiếm 15% ung thư giáp, nữ nhiều hơn nam, thường gặp ở tuổi 40-60.
Cơ chế bệnh sinh:
Yếu tố môi trường: Thiếu iod trong chế độ ăn.
Yếu tố di truyền: Đột biến trong con đường PI-3K/AKT hoặc gene PAX8/PPARG.
Hình thái:
Hiển vi: Tế bào đều, tạo thành các nang nhỏ chứa chất keo.
Thâm nhập bao vỏ và có thể thấy tế bào Hurthle.
Đặc điểm lâm sàng:
Xuất hiện dưới dạng nốt lạnh đơn lẻ, hiếm khi hoạt động.
c. Ung thư tủy giáp (Medullary Carcinoma)
Đặc điểm: U thần kinh nội tiết từ tế bào C, tiết calcitonin.
Cơ chế bệnh sinh:
Yếu tố di truyền: Đột biến RET, thường gặp ở hội chứng MEN 2A hoặc 2B.
Hình thái:
Hiển vi: Tế bào u hình đa giác trong mô đệm amyloid.
Đặc điểm lâm sàng:
Xuất hiện dưới dạng khối ở cổ, có thể gây khó nuốt và khàn tiếng.
d. Ung thư không biệt hóa (Anaplastic Carcinoma)
Đặc điểm: Thường gặp ở nữ, trên 60 tuổi, khối u lớn, dễ di căn.
Cơ chế bệnh sinh:
Đột biến RAS hoặc PIK3CA, mất chức năng TP53.
Hình thái:
Hiển vi: Tế bào lớn đa hình, tế bào hình thoi.
Tiên lượng: Rất xấu, tiến triển nhanh và gây tử vong.
- Thyroid Adenoma
a. Benign neoplasms derived from follicular epithelium appearing as solitary nodule.(multy
nodular pattern is for multinodular goiter)
b. Pathogenesis
In toxic adenomas one who produce TH see mutations in compartments of TSH receptor
signaling pathway Gain of thyroid autonomy (independ of TSH see TH secretion) such as
mutations in Gene encoding TSH receptor and less common in Alpha subunit of G protein as
signal trasducer part in signaling pathway of TSH receptor
In some of non-functional follicular adenoma exhibit mutations of RAS of PIK3CA which
shared with subsets of follicular carcinomas hence some of it may arise from adenoma…
c. Morphology
i. Solitary nodule compress non-neoplastic thyroid. Has well defined capsule
.(multinodular goiter no capsule multiple nodules no compression of parenchyma)
ii. Micro cells are arranged in uniform follicles that contain colloid-well differentiated.
If Neoplastic cells have bright eosinophilic granular cytoplasm and small nucleus
they called oxyphils/hurthle cells(and adenoma classified as hurthle cell adenoma)
May exhibit focal nuclear pleomorphism, atypia, and prominent nucleoli- endocrine
atypia.
Not infiltrate capsule its completely intact unlike in follicular carcinoma.
d. Clinical features
i. Usually painless nodules, large masses may produce local symptoms like difficulty in
swallowing.
ii. Vast majority are not functional but some may produce thyroid hormone and cause
hyperthyroidism (toxic adenoma)
iii. After injection of radioactive iodine, most adenomas take up iodine less avidly than
normal parenchyma. Therefore on radionuclide staining appears as cold nodules
relative to normal gland Toxic adenoma, however appears at warm nodules in the scan
- Carcinomas of the thyroid
All carcinomas on gross look as solitary nodule may be encapsuled or diffuse infiltrative marigin….
And all usually cold nodules.
Papillary carcinoma
- Epidemiology
a. Most common form of thyroid cancer(~85%) although thyroid cancer as itself is rear ~1% of
cancer cases..
b. Tumor may occur at any age
- Pathogenesis
a. Environmental- radiation exposure
b. Genetics- Activation of MAP kinase pathway featured in most of papillary subtypes, may done
by one of the two major mechanism - Rearrangements of RET or NTRK I (neuroytophic thyrosine kinse I) – encode for
tyrosine kinase receptor(fusion gene by usually non expressed in follicular epithel
RET(encode tyr kinas part of receptor) and PTC gene constantly expressed gene
(papillary thyroid carcinoma gene) so formed RET/PTC product gene and gain of
function to pathway) - Point mutation in gene of RAF protein , an intermediate signaling component in
the MAP kinase pathway - Gross May show as encapsulate or diffuse invasive form uni or multifocal Lesions may contain area of
fibrosis and calcification and often are cystic
Micro
a. Diagnostic essential feature is the appearance of Clear “orphan annie eye” nuclei
b. The tumor typically exhibits a papillary pattern with dense fibrovascular cores (true papilla) and
along rims see neoplastic cells pileup on each other.
c. Occasional psammoma bodies- concentrically calcified structure present in papillae
- Clinical features
a. Non-functional tumors
b. Indolent lesion with 10-year survival rate at 95% Over a dozen variant of papillary thyroid
carcinoma Most common- follicular variant Encapsulated Lower incidence of lymph node
metastases(if do so to cervical nodes)
c. Prognosis depends on age, extrathyroidal extension and present of distant metastases.
Follicular carcinoma
- Accounts for 15% of malignant thyroid tumors Female>male; age 40-60
- Pathogenesis
a. Environment- ionizing radiation and deficiency of dietary iodine more Frequent in areas with
dietary iodine deficiency
b. Genetics
i. Mutation in the PI-3K/AKT signaling pathway resulting in constant activation of
oncogenic pathway.
- Gain of function point mutation or Amplification of PI3K
- Loss of function mutation of PTEN (a tumor suppressor and a negative regulator
of the pathway)
ii. PAX8/PPARG fusion genes may impire the complete cell diffrantiation.
1. PAX8- homeobox gene that is important in thyroid development
- Peroxisome proliferator-activated receptor gene- gene which codes for a nuclear
hormone receptor - Morphologya. Microscopically-uniform cell appearance forming small follicles including colloid –not arranged
areas with back to back follicle irregular shape areas only tumor cells no CT or c cells etc..
Encapsulated but invade the capsule! And may see hurthle cells
b. Grossly may be widely invasive of minimally invasive minimally invasive carcinoma is sharply
demarcated and may be indistinguishable from follicular adenoma on gross examination
- Clinical features
a. Manifests as solitary cold thyroid nodules. In rare cases may be hyperfictional
b. Unlike carcinoma usually lymphatic spread it show Hematogenouse dissemination to lung, bone
and liver( which other carcinomas show it ? hepatocellular renal cell carcinoma and
choriocarcinomas )
Medullary carcinoma
- Neuroendocrine neoplasm arise from C cell (parfollicular cells) and secretes calcitonin. In some cases,
tumor cells elaborate other polypeptide hormones such as somatostatin, serotonin and VIP. - Majority are sporadic and minority are familial associated with MEN 2A or 2B syndromes or notassociated with MEN syndrome.
a. Sporadic and familial not associated with MEN- occur in adult. 50-60 yo
b. Familial associated with MEN- seen in younger patients including children.
- Pathogenesis
a. Genetics:
i. Familial medullary thyroid cancer occur in multiple endocrine neoplasia type 2 and are
associated with germline RET proto- oncogene mutation that leads to constitutive
activation of receptor
ii. RET mutations are also seen in sporadic cases.
b. Environment- ionizing radiation
- Morphology
a. May arise as a solitary nodule or as multiple lesions on both thyroid lobes.
b. Micro:
i. Nests of polygonal neoplastic cells in amyloid stroma derived from altered calcitonin
molecules.
ii. Calcitonin is demonstrated within the cytoplasm of tumor cells and in stroma
iii. EM reveleas variable number of intracytoplasmic membrane bound, electron-dense
granules
iv. Familial medullary carcinoma
- Multicentricity- large lesion contain areas of necrosis and hemorrhage and may
extend through the capsule of the gland - Multicentric C cell hyperplasia in the surrounding thyroid parenchyma
a. It is believed to be precursor lesions from which medullary carcinoma
arise.
- Clinical features
a. Manifests as a mass in the neck
i. Associated with compression effects such as dysphagia and hoarseness
b. In some cases manifests as secretion of peptide hormones
i. Diarrhea caused by VIP
c. Early detection of familial cases can be done by
i. Patient’s relatives for elevated calcitonin level
ii. RET mutations
Anaplastic carcinoma
- Presentation Females>males; age >60 years Firm, enlargeing, bulky mass Tendency for early
widespread metastasis and invasion of the trachea and esophagus
a. Risk factor- past history of well differentiated thyroid carcinoma
- Pathogenesis
a. De novo or more common as Dedifferentiation of well-differentiated papillary or follicular
carcinome
b. Genetics Molecular alteration seen in well differenatiated carcinoma (RAS or PIK3CA mutation)
Inactivation of TP53 is essentially restricted to anaplastic carcinoma
c. Environment- ionizing radiation
3. Micro: undifferentiated, anaplastic cells
a. large pleomorphic giant cells
b. spindle cells with sacromatous appearance
c. mixed spindle and giant cell lesions
4. Prognosis: very aggressive and rapidly fatal.
Tumors of the bone (osteoma, osteoid osteoma, osteoblastoma, osteosarcoma).
Các Khối U Xương Lành Tính và Ác Tính
Khối U Xương Lành Tính
- Osteoma
-
Đặc điểm:
- Khối u lành tính thường gặp ở đầu và cổ, bao gồm các xoang cận mũi.
- Xuất hiện ở tuổi trung niên dưới dạng các khối cứng, phát triển chậm trên bề mặt xương.
- Có thể gây ra các vấn đề cơ học tại chỗ (ví dụ, tắc nghẽn xoang) và biến dạng thẩm mỹ.
- Liên quan đến hội chứng Gardner: Xuất hiện nhiều khối u.
- Vi thể: Gồm hỗn hợp xương đan và xương vảy.
- Tiên lượng: Không xâm lấn tại chỗ và không chuyển sang ác tính.
- Osteoid Osteoma và Osteoblastoma
-
Đặc điểm:
- Khối u lành tính của tế bào tạo xương.
- Xuất hiện trong tuổi thiếu niên và 20 tuổi, phổ biến hơn ở nam giới.
- Osteoid osteomas nhỏ hơn 2 cm, thường gặp ở xương dài (xương đùi và xương chày), gây đau cục bộ, thường nặng hơn vào ban đêm và được giảm đau bằng aspirin.
- Osteoblastomas lớn hơn và thường gặp ở cột sống, gây đau khó khu trú và không đáp ứng với aspirin.
-
Hình thái học:
- Vi thể: Cả hai khối u có cấu trúc xương đan xen, bao quanh bởi các tế bào tạo xương và mô liên kết mạch máu lỏng lẻo chứa các tế bào khổng lồ.
- Đại thể: Khối u tròn đến oval, có mô tan màu nâu vàng.
- Tiên lượng: Hiếm khi chuyển sang ác tính trừ khi được điều trị bằng xạ trị.
Khối U Xương Ác Tính
- Osteosarcoma
-
Đặc điểm:
- Khối u ác tính sản xuất xương từ tế bào trung mô ác tính.
- Là khối u ác tính xương nguyên phát phổ biến nhất sau u tủy và u lympho, chiếm khoảng 20% các khối u xương nguyên phát.
- Thường gặp ở vùng metaphysis của xương dài, đặc biệt quanh đầu gối.
- Yếu tố nguy cơ: Bệnh Paget, đột biến RB gia đình, bức xạ. U xương tự phát xảy ra ở đột biến TP53.
-
Hình thái học:
- Đại thể: Khối u màu xám trắng, thường xuất huyết và thoái hóa nang. Khối u thường phá hủy lớp vỏ xương và tạo thành khối mô mềm xâm lấn.
- Vi thể: Tế bào u có kích thước và hình dạng đa dạng, thường có nhân lớn và không đều. Các tế bào ác tính sản xuất xương (osteoid) là tiêu chí chẩn đoán osteosarcoma.
-
Lâm sàng:
- Thường biểu hiện dưới dạng khối u đau, tăng kích thước.
- Hình ảnh X-quang thường cho thấy khối lớn, phá hủy, hỗn hợp giữa tiêu xương và tạo xương với viền xâm lấn không rõ ràng.
- Tam giác Codman (bóng tam giác giữa vỏ xương và màng xương nâng lên) đặc trưng của osteosarcoma.
- Osteosarcomas thường lan truyền qua đường máu, gây di căn phổi.
- Osteochondroma
-
Đặc điểm: Khối u xương có mũ sụn bên trên.
- Xuất hiện trong tuổi thiếu niên và trưởng thành sớm.
- Bệnh lý di truyền trội nhiễm sắc thể thường (đa u xương sụn).
- Liên quan đến đột biến gene EXT1 hoặc EXT2 ở tế bào sụn.
-
Hình thái học:
- Kích thước từ 1-20 cm, có mũ sụn hyaline.
-
Lâm sàng:
- Khối u phát triển chậm, có thể gây đau.
- Osteochondroma đơn lẻ hiếm khi chuyển thành chondrosarcoma hoặc các sarcoma khác, nhưng chuyển ác tính thường xảy ra ở bệnh nhân đa u xương sụn di truyền.
- Chondroma
-
Đặc điểm: Khối u lành tính của sụn hyaline.
- Khi xuất hiện trong tủy xương, gọi là enchondroma, thường ở vùng metaphysis của xương ngắn, đặc biệt là xương bàn tay và chân.
- Bệnh Ollier và hội chứng Maffucci có nhiều chondromas.
-
Hình thái học:
- Enchondromas là các nốt màu xám xanh, trong suốt, thường nhỏ hơn 5 cm.
- Vi thể: Gồm sụn hyaline có chondrocytes lành tính về mặt tế bào học.
-
Lâm sàng:
- Trên X-quang, nốt sụn chưa khoáng hóa tạo ra vùng mờ hình oval, bao quanh bởi viền xương đậm (dấu hiệu O-ring).
- Chondroma đơn lẻ hiếm khi chuyển thành ác tính, nhưng những khối u liên quan đến enchondromatoses có nguy cơ cao hơn.
Khối U Xương Ác Tính
- Chondrosarcoma
-
Đặc điểm: Khối u ác tính của mô liên kết sản xuất sụn.
- Thường xuất hiện ở bệnh nhân trên 40 tuổi, nam nhiều hơn nữ.
-
Hình thái học:
- Conventional chondrosarcoma: Xuất hiện trong tủy xương, tạo thành khối u mở rộng, sáng bóng, thường xói mòn vỏ xương.
- Vi thể: Gồm sụn hyaline ác tính và sụn nhầy.
-
Lâm sàng:
- Thường xuất hiện ở xương chậu, vai và xương sườn.
- Biểu hiện dưới dạng khối u đau, tăng kích thước.
- Metastasize qua đường máu đến phổi và xương.
Tổng kết
Các khối u xương có thể lành tính hoặc ác tính, với đặc điểm, hình thái học và lâm sàng khác nhau. Hiểu rõ các loại khối u này giúp chẩn đoán và điều trị hiệu quả, từ đó cải thiện chất lượng sống và tiên lượng cho bệnh nhân.
BENIGN
1) OSTEOMA
Osteomas are benign lesions most commonly encountered in the head and
neck, including the paranasal sinuses
They typically present in middle age as solitary, slowly growing, hard,
exophytic masses on a bone surface.
Multiple lesions are a feature of Gardner syndrome
MICRo = , osteomas recapitulate cortical type bone and are composed of a
mixture of woven and
lamellar bone.
Although they may cause local mechanical problems (e.g., obstruction of a
sinus cavity) and cosmetic deformities, they are not locally aggressive and
do not undergo malignant transformation.
2) OSTEOID OSTEOMA AND OSTEOBLASTOMA
Benign tumor of the osteoblast
Osteoid osteomas and osteoblastomas are benign neoplasms with very
similar histologic features.
appear during the teenage years and 20s, with a male predilection
They are distinguished from each other primarily by their size and clinical
presentation.
Osteoid osteomas arise most often beneath the periosteum or within the
cortex in the proximal femur and tibia or posterior spinal elements = mainly
long bones,and are by definition less than 2 cm in diameter, Localized pain,
most severe at night, is an almost universal complaint with osteoid osteomas,
and usually is relieved by aspirin.
osteoblastomas are larger and most often in the vertebral column. they also
cause pain, although it often is more difficult to localize and is not
responsive to aspirin.
. Malignant transformation is rare unless the lesion is treated with
irradiation.
Morphology:
MACRO = both lesions are round-to-oval masses of hemorrhagic, grittyappearing tan tissue.
A rim of sclerotic bone is present at the edge of both types of tumors = it is
much more conspicuous in osteoid osteomas.
MICRO = examination, both neoplasms are composed of interlacing
trabeculae of woven bone surrounded by osteoblasts
The intervening stroma is loose, vascular connective tissue containing
variable numbers of giant cells.
MALIGNANT
1) OSTEOSARCOMA
Osteosarcoma is a bone-producing malignant mesenchymal tumormalignant proliferation of osteoblast.
After myeloma and lymphoma, osteosarcoma is the most common
primary malignant tumor of bone, accounting for approximately 20%
of primary bone cancers;
Although any bone Can be involved, most tumors arise in the
metaphyseal region of the long bones of the extremities, with almost
60% occurring about the knee, 15% around the hip, 10% at the
shoulder, and 8% in the jaw.
Risk factores: paget disease, familial RB, radiation. Spontaneous
osteosarcoma occur in TP53 mutation.
Several subtypes of osteosarcoma are distinguished on the basis of the
site of involvement within the bone (e.g., medullary versus
cortical),degree of differentiation, number of involved sites, presence
of underlying disease, and histologic features;
the most common type of osteosarcoma is primary, solitary,
intramedullary, and poorly differentiated, producing a predominantly
bony matrix.
Morphology:
Macro = are gritty-appearing, gray-white tumors, often exhibiting
hemorrhage and cystic degeneration. Tumors frequently destroy the
surrounding ortices, producing soft tissue masses, Extensibly
infiltrating.
Micro = Tumor cells vary in size and shape and frequently have large
hyperchromatic nuclei; bizarre tumor giant cells are common, as are
mitotic figures.
The production of mineralized or unmineralized bone (osteoid) by
malignant cells is essential for diagnosis of osteosarcoma
When malignant cartilage is abundant, the tumor is called a
chondroblastic osteosarcoma.
Clinical :
- Osteosarcomas typically manifest as painful enlarging masses,
although a pathologic fracture can be the first sign.
- Radiographic imaging usually shows a large, destructive, mixed
lytic and blastic mass with indistinct infiltrating margins = The
tumor frequently breaks through the cortex and lifts the periosteum, resulting in reactive periosteal bone formation.
- A triangular shadow on the x-ray film between the cortex and
raised periosteum (Codman triangle) is characteristic of osteosarcomas. - Osteosarcomas typically spread hematogenously; ademonstrable
pulmonary metastases,
BENIGN
1) OSTEOCHONDROMA
Tumors of bone with overlying cartilage cap.
Solitary osteochondromas typically are first diagnosed in late
adolescence and early adulthood (
multiple osteochondromas become apparent during childhood, occurring
as multiple hereditary osteochondromas,autosomal dominant disorder.
Inactivation of both copies of the EXT1 or EXT2 genes through mutation
in chondrocytes is implicated in both sporadic and hereditary
osteochondromas
These tumor suppressor genes encode
glycosyltransferases essential for polymerization of heparin sulfate, an
important component of cartilage.
Osteochondromas develop only in bones of endochondral origin arising
at the metaphysis near the growth plate of long tubular bones, especially
about the knee
Occasionally they develop from bones of the pelvis, scapula, and ribs
and in these sites = long bones
Morphology:
- Range from 1-20 cm in size, and have a cartiligneous cup
- Hyaline cartilage
Clinical Features
- Osteochondromas are slow-growing masses that can be painful
- Solitary osteochondromas rarely progress to chondrosarcoma or
other sarcomas, but malignant transformation occurs more
frequently in those with multiple hereditary osteochondromas.
2) CHONDROMA
Chondromas are benign neoplasms of hyaline cartilage.
When they arise within the medulla, they are termed enchondromastypically are solitary and located in the metaphyseal region of tubular
bones, the favored sites being the short
tubular bones of the hands and feet.
Ollier disease is characterized by multiple chondromas preferentially
involving one side of the body, and Maffucci syndrome is characterized
by multiple chondromas associated with soft tissue spindle cell
hemangiomas.
when on the bone surface, they are called juxtacortical chondromas.
Pathogenesis:
- Enchondromas occurring in Ollier disease and Maffucci syndrome
frequently contain point mutations in either isocitrate
dehydrogenase I (IDH1) or IDH2 that create a new enzyme
activity. (The same IDH mutations occur as somatic mutations in
acute myeloid leukemias and gliomas), the mutations occurred
early during embryonic development, an example of genetic
mosaicism.
Morphology:
- Enchondromas are gray-blue, translucent nodules usually smaller
than 5 cm in greatest dimension.
- Micro = , they are well circumscribed and composed of hyaline
cartilage containing cytologically benign chondrocytes. - At the periphery, there is endochondral ossification, while the
center frequently calcifies and dies. I - in the hereditary multiple chondromatoses, the islands of cartilage
exhibit greater cellularity and atypia, making them more difficult
to distinguish from chondrosarcoma.
Clinical Features
- On x-ray imaging, the unmineralized nodules of cartilage produce
well-circumscribed oval lucencies surrounded by thin rims of radiodense bone (O-ring sign).
- Solitary chondromas rarely undergo malignant transformation, but
those associated with enchondromatoses are at increased risk for
such change. (Maffucci syndrome is associated with an increased
risk for development of other types of malignancies,
including ovarian carcinomas and brain gliomas.)
MALIGNANT
CHONDROSARCOMA
Chondrosarcoma is a malignant connective tissue tumor (sarcoma) whose
cells manufacture and secrete neoplastic cartilage matrix.
It is subclassified according to site (e.g., intramedullary versus juxtacortical)
and histologic variants
most patients are age 40 or older, with men >female.
MORPHOLOGY:
- Conventional chondrosarcoma, the most common variant,
arises within the medullary cavity of the bone to form an expansile
glistening mass that often erodes the cortex
It is composed of malignant hyaline and myxoid cartilage. - Myxoid chondrosarcomas are viscous and gelatinous in
consistency, and the matrix oozes from the cut surface.
The adjacent cortex is thickened or eroded, and the tumor grows
with broad pushing fronts into marrow spaces and the surrounding
soft tissue
- Tumor grade is determined by cellularity, degree of cytologic
atypia, and mitotic activity Low-grade tumors high grade - Approximately 10% of patients with conventional lowgrade
chondrosarcomas have a second high-grade poorly differentiated
component (dedifferentiated chondrosarcomas) - Other histologic variants include clear cell and mesenchymal
chondrosarcomas.
Clinical features:
- Chondrosarcomas commonly arise in the pelvis, shoulder, and ribs;
in contrast with enchondromas, chondrosarcomas rarely involve
the distal extremities. - They typically manifest as painful, progressively enlarging masses.
- the more radiolucent the tumor the greater the likelihood that it is
high grade. - Metastasize hematogenously to the lung and skeleton.
Brain parenchymal infections: Brain abscess. Viral encephalitides. Cerebral toxoplasmosis,
cysticercosis. Fungal encephalitis.
A parenchymal infection of the brain that is almost invariably associated with
VIRAL ENCEPHALITIS
meningeal inflammation –meningioencephalitis.
(i.e., involve the entire brain) or localized to a part of the brain.
#characteristic histologic features:
-perivascular and parenchymal mononuclear cell infiltrates
-microglial nodules
-neuronophagia
polio
immune mechanisms after systemic viral infections. Intrauterine viral infection may
cause congenital malformations, as occurs with rubella.
FUNGAL ENCEPHALITIS
Fungal infections usually produce parenchymal granulomas or abscesses, often
associated with meningitis.
The most common fungal infections have distinctive patterns:
Candida albicans usually produces multiple microabscesses, with or without
granuloma formation.
Mucormycosis is the term used to describe rhinocerebral infections caused by
several fungi belonging to the order Mucorales. It typically presents as an
infection of the nasal cavity or sinuses of a diabetic patient with ketoacidosis.
It may spread to the brain through vascular invasion or by direct extension
through the cribriform plate.
The proclivity of Mucor to invade the brain directly sets it apart from other fungi,
which tend to reach the brain by hematogenous dissemination from distant sites.
Aspergillus fumigatus tends to cause a distinctive pattern of widespread septic
hemorrhagic infarctions because of its marked predilection for blood vessel wall
invasion and subsequent thrombosis.
Cryptococcus neoformans can cause both meningitis and meningoencephalitis,
often in the setting of immunosuppression.
It can be fatal in as little as 2 weeks or may exhibit indolent behavior, evolving
over months or years. The CSF may have few cells but elevated protein, and the
mucoid encapsulated yeasts can
be visualized on India ink preparations. Extension into the brain follows vessels
in the Virchow-Robin spaces.
As organisms proliferate, these spaces expand, giving rise to a “soap bubble”–
like appearance.
In endemic areas, Histoplasma capsulatum, Coccidioides immitis, and
Blastomyces dermatitidis also can infect the CNS, especially in the setting of
immunosuppression
OTHER MENINGOENCEPHALITIDES
Cerebral Toxoplasmosis. Cerebral infection with the protozoan Toxoplasma
gondii can occur in immunosuppressed adults or in newborns who acquire the
organism transplacentally from a mother with an active infection.
In adults, the clinical symptoms are subacute, evolving during a 1- or 2-week
period, and may be both focal and diffuse. Due to inflammation and breakdown
of the blood-brain barrier at sites of infection, there’s edema around lesions (socalled
ring enhancing lesions).
In newborns who are infected in utero, the infection classically produces the triad
of chorioretinitis, hydrocephalus, and intracranial calcifications.
The CNS abnormalities are most severe when the infection occurs early in
gestation during critical stages of brain development.
Necrosis of periventricular lesions gives rise to secondary calcifications as well
as inflammation and gliosis, which can lead to obstruction of the aqueduct of
Sylvius and hydrocephalus.
Morphology
When the infection is acquired in immunosuppressed adults, the brain shows
abscesses, frequently multiple, most often involving the cerebral cortex (near the
gray-white junction)
and deep gray nuclei. Acute lesions consist of central foci of necrosis with
variable petechiae surrounded by acute and chronic inflammation, macrophage 33#
infiltration, and vascular proliferation. Both free tachyzoites and encysted
bradyzoites may be found at the periphery of the necrotic foci
Cysticercosis - is the consequence of an end-stage infection by the tapeworm
Tenia solium
If ingested larval organisms leave the lumen of the GI, where they would
otherwise develop into mature tapeworms, they encyst.
Common within the brain andsubarachnoid space. Cysticercosis typically
manifests as a mass lesion and can cause seizures. .
The organism is found within a cyst with a smooth lining. The body wall and
hooklets from mouth parts are most commonly recognized. If the encysted
organism has died, there can be an intense inflammatory infiltrate in the
surrounding brain, often including eosinophils, which may be associated with
marked gliosis.
Amebiasis - manifests with different clinical syndromes, depending on the
responsible pathogen.
Naegleria spp., associated with swimming in nonflowing warm fresh water,
cause a rapidly fatal necrotizing encephalitis.
Acanthamoeba causes a chronic granulomatous meningoencephalitis.
Brain parenchymal infections: Brain abscess. Viral encephalitides. Cerebral toxoplasmosis,
cysticercosis. Fungal encephalitis.
5
Cerebrovascular diseases, ischemic and hemorrhagic stroke (global cerebral ischemia, focal
cerebral ischemia, primary intraparenchymal hemorrhage).
clinical outcome: different upon different severity and duration of insult
CEREBROVASCULAR DISEASES
Brain disorders arise from pathologic processes involving blood vessels constitute a
major cause of death in the developed world. Most common the damage appear Due
to ischemia (85% of cases) but also can be the result of a hemorrhage (15% , out off
10% is intracerebral and 5%is subarachnoidal).
3 types of cerebrovascular pathologies :
(1) thrombotic occlusion of vessels
(2) embolic occlusion of vessels
(3) Vascular rupture.
“Stroke” is a clinical term for symptoms that arise from cerebrovascular problems,
particularly when symptoms begin acutely.
Thrombosis and embolism cause ischemic injury or infarction of specific regions of
the brain, depending on the vessel involved. A similar pattern of injury occurs
diffusely when there is complete loss of perfusion.
Hemorrhage accompanies rupture of vessels, leading to direct tissue damage as well
as secondary ischemic injury.
ISCHEMIC ENCEPHALOPATHY (global focal ischemia)
The brain tissue requires a constant delivery of glucose and oxygen from the blood.it
needs about 15% of cardiac output and responsible for 20% of body total oxygen
consumption Neurons are dependent on serum glucose as an essential energy source
and are
particularly susceptible to ischemia (undergo necrosis within 3 - 5 minutes).
Cerebral blood flow remains constant over a wide range of blood pressure and
intracranial pressure due to autoregulation of vascular resistance and it not influence
from regulatory mechanisms .
Ischemia is when no blood supply so bout sugar and o2 cant rich hypoxia when no o2
supply alone
o Functional hypoxia: cause by decrease partial pressure of O2 (e.g altitude),
impaired oxygen carrying capacity (e.g anemia) or inhibition of 02 by tissue
(e.g poisoning).
o Ischemia: either transient or permanent, due to tissue hypoperfusion (e.g
hypotension)
Such as injureis may be global or focal:
Global Cerebral Ischemia widespread ischemic/hypoxic injury to the brain . can occur
in the setting of sever systemic hypotension systolic pressures of less than 50mmHgsuch
as in cardiac arrest, shock, and severe hypotension
#main reasons:
-low perfusion (e.g due to atherosclerosis)
-acute decrease in blood flow (e.g cardiogenic shock)
-chronic hypoxia (e.g., anemia)
-repeated episodes of hypoglycemia.
In mild situations: transient confusional state, usually full recovery
In moderate situations: infracts in regions that are fed by the very end of the
circulation- watershed areas. Damage to highly vulnerable regions:
In severe situations: widespread neuronal death irrespective from regional
sensitivity , diffuse necrosis.
If such as patient survive he remain in persistent vegetative state . Other
patients meet the clinical criteria for “brain death,” including evidence of
diffuse cortical injury and brain stem damage, including absent reflexes and
respiratory drive.
#morphology:
Swollen brain , wide gyri and narrow sulci poor demarcated gray and white
zone.
The histopatho changes that accompany irreversible infury have 3 catagories:
1. 12-24 hours: early changes, acute neuronal change (red neurons).
- 24 hours-2 weeks: Subacute changes, include necrosis of tissue, influx of
macrophages, vascular proliferation, and reactive gliosis. - After 2 weeks: Repair,characterized by removal of all necrotic tissue, loss
of organized CNS structure, and gliosis . In the cerebral cortex the
neuronal loss and gliosis produce an uneven destruction of the neocortex.
VASCULAR DEMENTIA
B. 2nd most common cause of dementia as cerebrovascular diseas ie
hypertension atherosclerosis lead to modrate global ischemic demage to cortex
and hippocampus leading to dementia –treatment improve prognosis
Focal cerebral ischemia
Focal cerebral ischemia occurs when there is impierd blood flow in a
particular cerebral vessel so there is reduces blood flow to the particular brain
region, increasing the risk of cell death to that area And the development of
infarction.
cerebral arterial occlusion- mainly thromboembolism cardiac mural
thromboemboli.
branches or areas of stenosis.
#transiant ischemic attak when symptom last less then 24 hr if more its an
ischemic stroke=infarction
BRAIN INFRACTIONS
Cerebral infarction is focal brain necrosis due to complete and prolonged ischemia
that affects all tissue elements, neurons, glia, and vessels
# The majority of thrombotic occlusions causing cerebral infarctions are due to
atherosclerosis; the most common sites of primary thrombosis are the carotid
bifurcation, middle cerebral artery, and basilar artery.
# there are 2 types:
Non hemorrhagic- Thrombotic stroke is due to rupture of an atherosclerotic plaque.
Atherosclerosis usually develops at branch points (e.g., bifurcation of internal
Carotid and middle cerebral artery in the circle of Willis).Results in a pale infarct at
the periphery of the cortex Can be treated with thrombolytic therapy.
Hemorrhagic-result from reperfusion of ischemic tissue, . Hemorrhagic infarcts are
most common in embolism(common source of emboli is the left side of the heart e.g.,
atrial
Fibrillation). Blood leaks from collateral / occluding thrombus or embolus breaks up .
Most Usually involves the middle cerebral artery and
Results in a hemorrhagic
infarct at the periphery of the cortex.
Lacunar stroke occurs secondary to hyaline arteriolosderosis, a complication of
hypertension.
i. Most commonly involves lenliculostriale vessels, resulting in small cystic
areas of infarction
#morphology:
MACRO:
Macroscopically may not be detectable for 6‐12 hours
48‐72 hours Softening and disintegration of the infarcted region. May be oedema and
herniation.
Weeks to months: Cyst formation
MICRO:
Ischemic neuronal change –red neurons after about 12 hr initial microscopic finding
Initial influx of neutrophils from the blood stream enter the infarct through damaged
vessels about 48 hr. from unset .
Then in the following about 2 weeks macrophages
immigrate (They ingest the products of degradation of neurons and myelin and may
stay months to years in the lesion) also see at point core of infract disintegrate and
capillary in periphery proliferate
Astrocyte at edge of lesion enlarged divide and send network of glial cell processes
Results in formation of a fluid-filled cystic space surrounded by gliosis This is
completed in approximately 2 months the blood brain barrier is once again sealed
No scar formation!
INTRACRANIAL HEMORRHAGE
#Hemorrhage within the skull can occur in a variety of locations and be linked to
veraity of causes:
Epidural hematoma usually associated with trauma
Subdural hematoma
Subarachnoid hematoma- most commonly seen with aneurysms
Intracerebral (parenchymal) hemorrhage-link to hypertention about 15% of
death of chronic hypertention patient
Intraventricular hemorrhage, also known as hematocephalus internus.
Primary Brain Parenchymal Hemorrhage
#Spontaneous intraparenchymal hemorrhages occur most commonly in mid to late
adult life~60 years . Most are caused by rupture of a small intraparenchymal vessel.
occur in the basal ganglia, thalamus, pons, and cerebellum.
rim surrounding a cavity develops (neurons necrosis like in hemorrhagic infarction).
b.v. weakening the b.v. may lead to rupture (unlike hypertension related this one
manifested as lobar hemorrhage)
epidural hematoma
temporal bone with rupture of the middle meningeal artery; bleeding separates the
dura from the skull leading to formation of Lens-shaped lesion on CT
This sack is filling with blood in interval without any clinical sing may precede
eliciting neurologic signs even rapture put pressure on brain -Herniation is a lethal
complication.
subdural hematoma
#Subdural hemorrhage -Collection of blood underneath the dura;stems from
traumatically severed ‘‘bridging veins’’ that connect superficial cerebral veins and the
dural venous sinuses. This venous bleeding may stop on its own as soon as the
pressure outside the veins exceeds the pressure inside the vascular lumen. Increased
rate of occurrence in the elderly due to age-related cerebral atrophy,which stretches
the veins
Subarachnoid Hemorrhage and Saccular Aneurysms
berry aneurysm; other causes include AV malformations and an anticoagulated state
Present as a sudden headache with nuchal rigidity.LP show xanthochromia (yellowish
appearance of cerebrospinal fluid) - morphology: bleeding in the base of the brain.
a) Saccular aneurysms-(berry aneurysms) most common non traumatic cause, Berry
aneurysms are thin-walled saccular outpouching» that lack a media layer
, increasing the risk tor rupture.
Most frequently located in the anterior circle of Willis at branch points of the
anterior communicating artery
- Associated with Marfan syndrome and autosomal dominant polycystic kidney
disease
c) Charcot–Bouchard aneurysms (also known as miliary aneurysms or
microaneurysms) are aneurysms of the brain vasculature which occur in small blood
vessels (less than 300 micrometre diameter).
Charcot–Bouchard aneurysms are most
often located in the lenticulostriate vessels of the basal ganglia and are associated
with chronic hypertension.
[1] Charcot–Bouchard aneurysms are a common cause
of cerebral hemorrhage.
b) Traumatic
Meningeal neoplasms. Metastatic neoplasms of the brain.
Meningioma:
Predominantly Benign tumor of meningioepithelial cells of the arachnoid membrane.
Most common in adults more in female (the tumor express astrogen receptors!)
Multiple meningioma, especially in association with 8th nerve schwannomas or glial tumor
may indicate neruofibromatosis type 2. About half of meningiomas not associated with NF2
have acquired loss-of function mutations in the NF2 tumor suppressor gene on chromosome
22.
Imaging reveals a round mass attached to the dura. May present with seizures – due to
pressure on the cortex
Morphology: macro: masses that attach dura and compress the brain but DO NOT invade it.
micro: syncytial – whorled clusters of cells without cisible cell membranes, that sit in tight
groups.
The cells will show a unique pattern:
- maningiothelial cells in kind of onion skin whorled pattern. Some foci of dystrophic
calcification create psammoma bodies. - Fibroblastic component elongated cells and abundant collagen deposition btw them.
3.hence denoting features of no. 1 and 2 it’s an transitional tumor which shares features of
the syncytial and fibroblastic types
By Grading meningioma’s divide it into 3 categories: well differentiated benign slow
growing tumor as described in morphology, atypical WHO grade II/IV also bening and
recognized by the presence of certain histologic features increased cellularity higher mitotic
rate and tend to recurred, anaplastic WHO grade III/IV the highly aggressive malignant
variant.
METASTATIC TUMORS
Mostly carcinomas; The most common primary sites are lung, breast, skin (melanoma),
kidney, and gastrointestinal tract. Metastatic lesions, mostly carcinoma, account for quarter
to half of intracranial tumors Carcinomas are more commonly metastatic to the nervous
system than lymphoid malignancies.
Sarcomas infrequently metastasize to the brain.
Metastases form sharply demarcated masses, often at the gray-white junction, and elicit
edema. The boundary between tumor and brain parenchyma is sharp, with surrounding
reactive gliosis.
Beside local direct effect on brain may see evolvement of Paraneoplastic syndrome may involve the
peripheral and CNS, sometimes even preceding the clinical recognition of the malignant neoplasm.
Many but not all patients with PNS have antibodies against tumor antigens.
Manifestation of paraneoplastic syndrome:
Subacute cerebellar degeneration ataxia with destruction of purkinje cells, gliosis and mild
inflammation infiltrate.
Limbic encephalitis = causing sub-acute dementia and perivascular inflammatory cuffs, Microglial
nodules and some neuronal loss in the medial temporal lobe.
Subacute sensory neuropathy = altered pain sensation with loss of sensory neurons from dorsal
root ganglia.
Syndrome of rapid onset psychosis, catatonia, epilepsy and coma – associated with ovarian teratoma
and Ab against NMDA receptor
Multiple sclerosis and other demyelinating diseases. Leukodystrophies.
Within the CNS, axons are tightly ensheathed by myelin, an electrical insulator that allows
rapid propagation of neural impulses.
Myelin consists of multiple layers of specialized, plasma membranes that are assembled by
oligodendrocytes.
Although myelinated axons are present in all areas of the brain, they are the dominant
component in the white matter; therefore, most diseases of myelin are primarily white matter
disorders.
The myelin in peripheral nerves is similar to the myelin in the CNS but has several
important differences:
(1) made by Schwann cells; (2) each Schwann cell in a peripheral
nerve provides myelin for only one internode, while in the CNS, many internodes are
created by processes coming from a single oligodendrocyte;
and (3) the specialized proteins
and lipids are also different; Therefore, most diseases of CNS myelin do not involve the
peripheral nerves to any significant extent, and vice versa.
In general, diseases involving myelin are separated into two broad groups.
Demyelinating diseases -acquired conditions characterized by damage to previously
normal myelin. The most common diseases in this group result from immunemediated
injury, such as multiple sclerosis (MS); Other processes include viral
infection of oligodendrocytes, and injury caused by drugs and other toxic agents.
Dysmyelinating diseases, myelin is not formed properly or has abnormal turnover
kinetics. Associated with mutations that disrupt the function of proteins that are
required for the formation of normal myelin sheaths. The other general term for these
diseases is leukodystrophy
MULTIPLE SCLEROSIS
An autoimmune demyelinating disorder characterized by distinct episodes of neurologic
deficits, separated in time, attributable to white matter lesions that are separated in space.
It is the most common of the demyelinating disorders
The disease may become clinically apparent at any age, although onset in childhood or after
age 50 is relatively rare. Women are more than men.
In most patients, the illness shows relapsing and remitting episodes of neurologic
impairment.
Pathogenesis
Autoimmune diseases, caused by loss of tolerance to self proteins (myelin antigens).
A genetic risk factor is HLA-DR variants, the DR2 allele being the one that most
significantly increases the risk for developing MS.
Other genetic causes are polymorphisms in the genes encoding receptors for the
cytokines IL-2 and IL-7, which are known to control the activation and regulation of T
cell–mediated immune responses. Immune-mediated myelin destruction is thought to
have a central role in MS.
A central role for CD4+ T cells has been suggested, with an increase in TH17 and TH1
CD4+ cells thought to be a critical component of the injury to myelin.
There is also evidence for important contributions from CD8+ T cells and B cells.
Toxic effects of lymphocytes, macrophages, and their secreted molecules have been
implicated in initiating the process of axonal injury, sometimes even leading to neuronal
death.
Morphology
MS is primarily a white matter disease with affected areas showing multiple, wellcircumscribed,
depressed, gray, irregularly shaped lesions termed plaques.
These commonly arise near the ventricles. They also are frequent in the optic nerves and
chiasm, brain stem, ascending and descending fiber tracts, cerebellum, and spinal cord.
In an active plaque there is evidence of ongoing myelin breakdown with abundant
macrophages containing myelin debris.
Small active lesions often are centered on small veins.
Active plaques fall into four classes
Type I, which has macrophage infiltrates with sharp margins;
Type II, which is similar to type I but also shows complement deposition (suggesting an
antibody-mediated component);
Type III, with less welldefined borders and oligodendrocyte apoptosis;
Type IV, with nonapoptotic oligodendrocyte loss.
When plaques become quiescent (inactive plaques), the inflammation mostly disappears,
leaving behind little to no myelin. Instead, astrocytic proliferation and gliosis are
prominent.
Clinical features
The course of MS is variable, but commonly there are multiple relapses followed by
episodes of remission;
As a consequence, over time there is usually a gradual accumulation of neurologic
deficits.
Changes in cognitive function can be present, but are often much milder than the other
deficits.
The CSF shows a mildly elevated protein level with an increased proportion of
immunoglobulin; in one third of cases, there is moderate pleocytosis.
When the immunoglobulin is examined further, oligoclonal bands usually are identified.
These antibodies are directed against a variety of antigenic targets and can be used as
markers of disease activity.
OTHER ACQUIRED DEMYELINATING DISEASES
Immune-mediated demyelination can occur after a number of systemic infectious illnesses,
including relatively mild viral diseases.
It is believed that immune cells responding to pathogen-associated antigens are cross
reactive against myelin antigens, resulting in myelin damage.
There are two general patterns of postinfectious autoimmune reactions to myelin; they are
associated with acute-onset monophasic illnesses.
In acute disseminated encephalomyelitis, symptoms typically develop a week or two after an
antecedent infection and are nonlocalizing (headache, lethargy, and coma); Symptoms
progress rapidly, and the illness is fatal in as many as 20% of cases
Acute necrotizing hemorrhagic encephalomyelitis is a more devastating related disorder,
which typically affects young adults and children.
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease centered on the optic
nerves and spinal Cord; Antibodies to the water channel aquaporin-4 are both diagnostic and
pathogenic.
Central pontine myelinolysis is a nonimmune process characterized by loss of myelin
involving the center of the pons, most often after rapid correction of hyponatremia. May be
related to edema induced by sudden changes in osmotic pressure. It occurs in alcoholism and
severe electrolyte or osmolar imbalance.
Although the most characteristic lesion occurs in the pons, similar lesions can be found
elsewhere in the brain. Because of the involvement of fibers in the pons carrying signals to
motor neurons in the spinal cord, patients often present with rapidly evolving quadriplegia.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that occurs
after reactivation of JC virus in immunosuppressed patients.
LEUKODYSTROPHIES
Inherited dysmyelinating diseases in which the clinical symptoms derive from abnormal
myelin synthesis or turnover.
Some of these disorders involve lysosomal enzymes, while others involve peroxisomal
enzymes; a few are associated with mutations in myelin proteins.
Most are of autosomal recessive inheritance, although X-linked diseases also occur
Morphology
Most pathologic change are found in the white matter, which is diffusely abnormal in
color (gray
and translucent) and volume (decreased).
Early in their course, some diseases may show patchy involvement, while others have a
predilection for occipital lobe involvement; In the end, though, nearly all of the white
matter usually is affected.
With the loss of white matter, the brain becomes atrophic, the ventricles enlarge, and
secondary changes can be found in the gray matter.
Myelin loss leads to infiltration of macrophages, which often become stuffed with lipid.
Some of these diseases also show specific inclusions created by the accumulation of
particular lipids.
Clinical features
Affected children are normal at birth but begin to miss developmental milestones during
infancy and childhood.
Diffuse involvement of white matter leads to deterioration in motor skills, spasticity,
hypotonia, or ataxia.
In general, the earlier the age at onset, the more severe the deficiency and clinical course.
Peripheral neuropathies (primary axonal degeneration, segmental demyelination, GuillainBarré
syndrome, CIDP, diabetic peripheral neuropathy).
CLASSIFICATION OF MUSCLE DISEASES
A motor unit is made up of a motor neuron and the skeletal muscle fibers innervated by
that motor neuron’s axonal terminals hence muscle diseases may araise as :
Peripheral nerves consist of fascicles that contain myelinated and unmyelinated axons. .Myelin is a
spiral sheet of cell membrane wrapped around the axon. Unmyelinated axons are covered by
Schwann cell cytoplasm, but there is no spiraling.
Axonal neuropathies direct injury to the axon. The entire distal portion of an affected axon
degenerates atrophy of myofibers. The axon breaks down and secondary degrade of the
myelin (Wallerian degeneration).The morphological hallmark is decrease in the density of
the axons, which will lead to decrease in the strength of amplitude of nerve impulse. Causes
are may be diabetes or vascular disease…
Demyelinating neuropathies Schwann cell injury or myelin damage = slow nerve
conduction. Segmental demyelination –in individual myelin internodes* Remyelination may
occur (with shorter internodes & thin myelin) if repetitive process see “Onion bulb”
formations are concentric layers of Schwann cell processes and collagen around an axon
.later secondary axonal degeneration may also occur. May result from inflammatory diseases
like in topic or some tumors NFB schwannoma
Causes neuropathies include inflammatory neuropathies from SLE till 2 disease I talk about
these topic, metabolic disorder e.g. Diabetic (poly)neuropathy chronic axonal neuropathy with
some segmental demyelination, hereditary Charcot Mari tooth neuropathy, vascular such as
vasculitis One of the commonest and amyloid neuropathy, infectious-leprosy, neoplastic invasion
of peripheral nerves, toxin alcohol lead exogenous glucocorticoids etc. …
Patterns of peripheral neuropathies
Polyneuropathies usually affect peripheral nerves in a symmetric way Axonal loss is typically
diffuse and more pronounced in the distal segments of the longest nerves. Patients commonly
present with loss of sensation.
multiplex, in which the damage randomly affects portions of individual nerves, resulting in a right
radial nerve palsy and wrist drop together with loss of sensation in the left foot
A simple mononeuropathy involving only a single nerve most commonly is the result of traumatic
injury or entrapment (e.g., carpal tunnel syndrome).
DISORDERS ASSOCIATED WITH PERIPHERAL NERVE INJURY
Guillain-Barre syndrome
Acute autoimmune demyelinating peripheral neuropathy, It is a rapidly progressive disorder
affecting motor axons that results in ascending weakness that may lead to death from failure
of respiratory muscles over a period of only several days- One of the most common life
threatening diseases of the peripheral nervous system
It appears to be triggered by an infection or a vaccine that breaks down self-tolerance,
thereby leading to an autoimmune response.
Associated infectious agents include
Campylobacter jejuni, Epstein-Barr virus, cytomegalovirus, and human immunodeficiency
virus.
Antibodies and activated T-lymphocytes, reacting with antigens present on peripheral
nerves, elicit an inflammatory and macrophage reaction that destroys myelin and axons. The
strongest evidence of a humoral immune reaction in these neuropathies is that plasma
exchange results in significant clinical improvement.
Peripheral nerves show mononuclear
cell infiltrates rich in macrophages. , demyelination (myelin proteins are the source of
elevated CSF protein)..
Axonal damage, which accounts for the permanent deficits, is variable and may be severe. The pathology is most severe in nerve roots and proximal nerve
segments and less pronounced in more distal nerves. In the phase of recovery, the nerve
contains thin myelin sheaths, indicating myelin regeneration.
Treatments include plasmapheresis (to remove offending antibodies), intravenous
immunoglobulin infusions and supportive care, such as ventilator support.
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Typically manifests as a symmetric demyelinating disease. With similar immune pathomechanism
as GBS but unlike it CIDP follows a chronic, relapsing-remitting or progressive
course. occurs at increased frequency in patients with other immune disorders, such as systemic
lupus erythematosus and HIV infection.
The peripheral nerves show segments of demyelination and remyelination In long-standing
cases, chronically regenerating Schwann cells may concentrically wrap around axons in
multiple layers in an onion-skin pattern.
Both motor and sensory abnormalities are common, such as difficulty in walking, weakness,
numbness, and pain or tingling sensations. Some patients recover completely, but more often
recurrent bouts of symptomatic disease lead to permanent loss of nerve function.
Treatment includes plasmapheresis and administration of immunosuppressive agents.
Diseases of the skeletal muscles (dystrophinopathies, inflammatory myopathies). Diseases of
the neuromuscular junction (myasthenia gravis).
Muscle fiber types: 1. Slow twich, aerobic
= type I
2. fast twich, anaerobic = type II
Normal distribution of muscle fibers- checkboard pattern.
Muscle atrophy: abnormally small myofibers due to variety of disorders, for example
immobilization, exogenous glucocorticoids, Cushing syndrome.
Neurogenic atrophy:
Atrophy of muscle that results from damage to the nerve that stimulates the muscle. E.g: diabetic
neuropathy, spinal cord injuries and syndromes that cause nerve impingement.
Reminder: loss of a single neuron will affect all muscle fibers in a motor unit, then the adjacent
intact neurons send out sprouts to engage the NMJ which is injured. = now these fibers will have
the same innervating neuron. This process is called fiber type grouping.
Symptoms of neurogenic atrophy:
Stooped posture
Limited neck movement
Leg contractions
Heart failure (sometimes)
Disorders in the NMJ:
Produce functional abnormalities due to the disruption in the transmission of signals across the
NMJ- resulting in muscle weakness. Most common NMJ disorders:
- Myestenia gravis.
- Lambert – eaton syndrome
(Picture)
Therapy myestenia gravis:
- anti-choline esterase inhibitors.
- immunosuppression.
- Plasmapheresis
- Thymectomy (in patients with thymic lesion).
Lambert – Eaton syndrome:
Antibodies against presynaptic Ca2+ channels at the NMJ.
Arises as a paraneoplastic syndrome, most commonly due to small cell carcinoma.
Leads to impaired Ach release.
Proximal muscle weakness which improve with use.
Eyes are usually spared.
Muscular dystrophies:
Muscle dystrophy = inherited disporders of degeneration of muscle tissue with associated muscle
weakness and replacement of skeletal muscle by fibrofatty tissue.
Muscle dystrophy is due to primary inherited disease ( a muscle disease itself) in contrast to
muscle atrophy which is secondary due to loss of innervation, malnutrition etc.
- X linked MD (Duchenne and Becker MD)
Dystrophinopathies = Duchenne and Becker muscular dystrophy.
Dystrophinopathies are the most common form of muscular dystrophy.
Duchenne (DMD) and Becker (BMD) are the 2 most common examples, linked to
mutation in dystrophine gene. (DMD is more severe).
Both are X-linked MD associated with:
1. muscle wasting.
2. replacement of skeletal muscle by adipose tissue.
3. deletion of dystrophin (the mutation in the dystrophin gene is spontaneous!)
Dystrophin: plays a role of a “linker” protein btw the myofibrilar cytoskeleton to the
ECM.
Morphology: 1. Ongoing myofiber necrosis and regeneration.
2. replacement by fibrosis and fat.
3. micro level: in immunohistochemical method- complete absence of Membrane associated dystrophin.
Pathogenesis : loss of function mutation in the dystrophin gene located on the short arm of X chromosome.
Clinical features: progress to involve distal muscles (begins in pelvic => shoulders).
Calf pseudohypertrophy is characteristic finding, heart failure.
- Autosomal MD:
Several of the autosomal MD affect the proximal muscles (similar to X linked MD) and are
called limb girdle muscular dystrophy. It can be recessive or dominant. - Myotonic Dystrophy:
Myotonia = sustained involuntary contraction of a group of muscles.
Inherited as autosomal dominant, CTG trinucleotide repeat expansion on chromosome 19, which
will affect the synthesis of the intracellular protein kinase.
The disease will be present at late childhood with gait abnormalities, hands, wrist and facial muscles weakness.
Myopathy:
Myopathy = muscle disease. (such as the muscle dystrophy).
Primary myopathy should be distinguished from secondary neuropathic changes caused
by disorders that disrupt muscle innervation (even though both are associated with altered
muscle function but due to different reasons).
Myopathic condition are often associated with segmental necrosis and regeneration of
individual muscle fibers. Inflammatory infiltrate and intracellular inclusions may also be
present.
Congenital myopathies:
- ion channel myopathies: characterize by myotonia, relapsing episodes of hypotonic paralysis,
or both. Hyperkalemic periodic paralysis results from mutations in the gene for the skeletal
muscle sodium channel protein.
2.myopathies due to inborn errors of metabolism: disorders of glycogen synthesis and
degradation, lipid handling, carnitine transport.
- mitochondrial myopathies: mutations in mitochondrial or nuclear DNA that encodes
mitochondrial constituents. (will shoe maternal inheritance). These disorders will be present at
young adulthood with proximal muscle weakness and ocular musculature.
The most important pathological finding in skeletal muscle are irregular muscle fibers and
aggregates of abnormal mitochondria.
Acquires myopathies:
1.Toxic muscle injury: for example thyroxine myopathy: (intrinsic exposure). Either acute or
chronic proximal muscle weakness. The findings will include myofiber necrosis, regeneration
and interstitial lymphocytes. Examples for extrinsic exposure: ethanol, chloroquine.
- Inflammatory myopathies:
Dermatomyositis: Inflammatory disorders of the skin and skeletal muscle.
Unknown etiology, some cases are associated with carcinoma => paraneoplastic syndrome.
Clinical features: bilateral proximal weakness, distal involvement can develop, rush of
upper eyelids (helioptrope rash), malar rash, red papules on the elbows.
Micro: perivascular mononuclear cells infiltrate, myofiber damage, inflammation at the
perimysium => perifascicular atrophy (it helps to differentiate it from polymyositis which
shows endomysial inflammation)
Polymyositis: autoimmune disorder with increased expression of MHC I on myofibers.
Resemble dermatomyositis but skin is NOT involved.
Endomysial inflammation (CD8+) with necrotic muscle fibers.
- muscle infraction in the setting of diabetes.
