1st sem Flashcards
Hodgkin Lymphomas: Key Characteristics
Characterized by the presence of Reed Sternberg cell and its variants. These cells must be surrounded by inflammatory and reactive components to confirm Hodgkin Lymphoma. Usually originate from lymph nodes.
Non-Hodgkin Lymphomas: Key Characteristics
Non-Hodgkin Lymphomas: Key Characteristics
Reed sternberg cell characteristics
Large cells (15-45μm) with abundant eosinophilic cytoplasm, 2 mirror image nuclei (or 1 nucleus with 2 lobes), large eosinophilic nucleoli (1 in each nucleus), distinct nuclear membrane, CD30, CD15
Lacunar Cells: Characteristics
Large, retracted cytoplasm, multilobed nucleus, multiple nucleoli.
Popcorn Cells: Characteristics
Variant of Reed-Sternberg cells, derived from B lymphocytes but do not express typical surface markers.
Reed-Sternberg Cells: Genetic Evidence
Proof of origin found in genetic material showing Ig heavy chain genes rearranged and heavy chain variable region with signs of somatic hypermutation.
Hodgkin Lymphoma: EBV Association
In 70% of cases, EBV is associated with malignant transformation of B lymphocyte into Reed-Sternberg cell or its variants.
EBV Mechanism in Hodgkin Lymphoma
EBV produces viral proteins → stimulate the cell to synthesize the TF NFkB → NFkB stimulates proliferation and inhibits apoptos
EBV-Negative Hodgkin Lymphoma: Mechanism
Mutation in the IkB gene (which usually inhibits NFkB synthesis) elevates NFkB levels.
Nodular Sclerosis Hodgkin Lymphoma: Characteristics
Most common form, equally occurring in males and females (young adults). Few RS cells → good prognosis. Many lacunar cells, collagenous bands divide the lymphoid tissue into nodules. Cellular component – macrophages, eosinophils, lymphocytes.
Mixed-Cellularity Hodgkin Lymphoma: Characteristics
Affects patients >50 years old, predominantly males. Many RS cells → bad prognosis. Cellular component- small macrophages, eosinophils, plasma cells, lymphocytes. Diagnosed at advanced stage with systemic symptoms. Associated with EBV.
Lymphocyte-Predominance Hodgkin Lymphoma: Characteristics
Few RS cells (if any) → good prognosis. Many popcorn cells, large number of lymphocytes. Usually remains in cervical and axillary lymph nodes.
Lymphocyte-Rich Hodgkin Lymphoma: Characteristics
More common in males, older persons (40-50). Few RS cells → good prognosis. No popcorn cells, many lymphocytes.
Lymphocyte-Depleted Hodgkin Lymphoma: Characteristics
Many RS cells → very bad prognosis. Few lymphocytes.
B Symptoms in Hodgkin Lymphoma
Fever
Night sweats (due to increased number of cytokines)
Weight loss (more than 10% of body weight in a 6-month period)
Secondary Malignancies in Hodgkin Lymphoma
Tumors may come back after several years due to the therapy used to treat the first tumor.
Extra-nodal Lymphomas: Definition and Common Sites
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, Campylobacter jejuni).
MALT Lymphoma: Origin and Common Site
MALT lymphoma originates in B cells of MALT of the GI tract. It may arise anywhere in the gut but most commonly occurs in the stomach, usually due to chronic gastritis caused by H. pylori bacterium.
MALT Lymphoma: Pathogenesis
Infection with H. pylori leads to polyclonal B cell hyperplasia and eventually to monoclonal B cell neoplasm. MALT lymphoma cells are negative for CD5 and CD10 markers.
MALT Lymphoma: Genetic Abnormalities
Common translocation between chromosomes 11 and 18 creates a fusion gene between the apoptosis inhibitor BCL2 gene (chromosome 11) and the MLT gene (chromosome 18).
MALT Lymphoma: Treatment Response
Approximately 50% of gastric lymphomas can regress with antibiotic treatment.
Cutaneous Lymphoma: Classes
There are 2 classes of cutaneous lymphoma affecting the skin: B cell cutaneous lymphoma and T cell cutaneous lymphoma.
T Cell Cutaneous Lymphoma: Common Form and Cause
The most common form is Mycosis fungoides, caused by mutation of cytotoxic T cells that infiltrate the epidermis and upper dermis, characterized by infolding of the nuclear membrane.
T Cell Cutaneous Lymphoma: Advanced Stage
At a later stage, it progresses to Sezary syndrome, characterized by erythroderma (inflammatory skin disease) and by tumor cells in peripheral blood.
B Cell Cutaneous Lymphoma: Characteristics
Constitute a group of diseases, characterized by B cells similar to those found in germinal centers, such as diffuse large B cell lymphoma, primary cutaneous follicular lymphoma, intravascular large B cell lymphoma.
CNS Lymphoma: Association and Common Form
Intracranial tumor that appears mostly in patients with severe immunosuppression. Highly associated with Epstein-Barr virus infections in immunosuppressed patients but rarely so in immunocompetent patients. Most CNS lymphomas are diffuse large B cell lymphoma.
CNS Lymphoma: Symptoms
Symptoms include diplopia (double vision), dysphagia (difficulty swallowing), dementia, and systemic symptoms (fever, night sweats, weight loss).
Origin and Development of T Lymphocytes
The precursors of T lymphocytes originate from bone marrow-derived multipotent stem cells. They migrate into the thymus via the bloodstream, where they complete their developmental program. Once mature, they leave the thymus, circulating between blood and lymph, passing through many secondary lymphoid organs/tissues
Naive T Cells
Mature circulating T cells that have not recognized antigens yet are in a resting state and defined as naive T cells. Activation of naive T cells occurs in the secondary lymphoid organs/tissues where they interact with professional APCs (mainly DCs).
T Cell Activation Process
DCs find a pathogen, phagocytose it, transport it to lymph nodes, and present it to a T cell. The T cell recognizes the specific surface MHC-I-peptide complex, leading to T cell activation (naive helper/cytotoxic T cell to effector helper/cytotoxic T cell).
Effector T Cells Function
Effector T cells leave the lymphoid tissue, enter the blood circulation, and migrate to infection or inflammation sites in peripheral tissues. Their functions are initiated by recognizing a peptide antigen presented by MHC-I or MHC-II molecules on the target cell surface by TCR.
T Helper Cells (CD4)
T helper cells bind to MHC-II on APCs and secrete cytokines that attract other cells of the immune system, such as B cells and macrophages.
T Killer Cells (CD8)
T killer cells bind to MHC-I on all nucleated cells and directly kill infected cells by inducing apoptosis or using perforin granzyme. T cells also present the CD28 marker, which helps them bind to APCs.
Peripheral T-Cell Lymphoma: Determining Type
Whether a lymphoma is of a B, T, or NK cell origin can be determined by specific cell markers (CDs, receptors, enzymes). Whether it is precursor or peripheral depends on the stage of malignant transformation.
Characteristics of Peripheral T-Cell Lymphoma
Peripheral T-cell lymphomas are characterized by lymphocytic cells (smaller, more cytoplasm, more condensed chromatin), a low rate of proliferation, and more differentiation. These are aggressive tumors that respond poorly to therapy.
Types of Peripheral T-Cell Lymphoma
Types include:
Lymphoepitheloid lymphoma (Lennert’s lymphoma)
Angioimmunoblastic lymphadenopathy-like T-lymphoma
T-zone lymphoma
Pleomorphic T-cell lymphoma
Large cell anaplastic lymphoma
Lymphoepitheloid Lymphoma (Lennert’s Lymphoma)
Small cell (lymphocytic) infiltrate intermingled with a high amount of epithelioid cells and some blasts. Resembles lymphocyte-predominant Hodgkin disease but RS cells are missing.
Angioimmunoblastic Lymphadenopathy-Like T-Lymphoma
Mixed infiltrate of small, medium, and large immunoblastic cells. Resembles mixed cellularity Hodgkin disease. Neoplastic cells show clear cytoplasm and wrinkled nucleus. Immunoblasts and plasma cells are basophilic. Hallmarked by proliferation of dendritic reticulum cells (CD23 positive) and HEV.
T-Zone Lymphoma
Spreads within the T-cell areas. Lymph node follicles with germinal centers are preserved. Shows follicular hyperplasia with CD4 positive T-cells.
Pleomorphic T-Cell Lymphoma
Characterized by strong nuclear pleomorphism of small, medium, and large lymphoid cells. Clear cells are also present.
Large Cell Anaplastic Lymphoma
T-cells are CD30 positive. Shows cohesive spreading, primarily found within sinuses of lymph nodes. Often mistaken for carcinomas, malignant melanomas, or malignant histiocytosis. Translocation t(2:5) increases tyrosine kinase. May evolve into secondary large cell anaplastic lymphoma. Multinucleated tumor giant cells may be present.
Plasma Cell Reactions: Definition
A group of disorders characterized by plasma cell dysfunctions due to gain of function mutations of protooncogenes or loss of function mutations of tumor suppression genes, leading to abnormal proliferation in bone marrow.
Plasma Cell Dyscrasias: Antibody Secretion
Abnormally proliferating plasma cells in these disorders still secrete “M components”; monoclonal antibodies or parts of them:
Complete monoclonal antibodies
Monoclonal antibodies + excess light chains
Heavy chains only (heavy chain disease)
Light chains only (light chain disease)
Monoclonal vs Polyclonal Antibodies
Monoclonal: All secreted antibodies are exactly the same (both heavy and light chains), non-specific, secreted without real stimulation.
Polyclonal: Different plasma cells secrete different antibodies with different heavy chains (α IgA, ɤ IgG, μ IgM) and different light chains (κ, λ).
Disorders of Plasma Cell Dyscrasias
Multiple myeloma (plasma cell myeloma)
Monoclonal gammopathy of undetermined significance
Solitary plasmacytoma
Lymphoplasmacytic lymphoma
Heavy-chain disease
Primary or immunocyte-associated amyloidosis
Multiple Myeloma: Causes
t(11,14) Cyclin D protooncogene
Deletion of tumor suppression genes on chromosome 13
Multiple Myeloma: Symptoms
Primary AL amyloidosis
Proteinuria (Bence-Jones protein)
Marrow plasma cytosis (>30% of cellularity)
Fatigue, bleeding, infections
M spike in protein electrophoresis
Lytic bone lesions, hypercalcemia, renal failure, depression
Multiple Myeloma: Common Antibodies and Markers
Main antibody is IgG, second is IgA. Plasma cell tumors are positive for CD138 (syndecan-1) and often express CD56.
Monoclonal Gammopathy of Undetermined Significance (MGUS)
An isolated M spike with none of the other findings of multiple myeloma. Can develop into multiple myeloma.
Solitary Plasmacytoma: Types
Extraosseous (soft tissues) - mainly in upper respiratory tract, not very dangerous.
Intraosseous (bone marrow) - very dangerous, can develop into full multiple myeloma over 5-10 years.
Solitary Plasmacytoma: Characteristics
A single lesion
No Bence-Jones proteins
Moderate elevation of M proteins in some cases
Lymphoplasmacytic Lymphoma: Cell Types
Abnormal proliferation and infiltration of:
Lymphocytes
Immunoblasts (intermediate form of lymphocytes trying to convert to plasma cells)
Plasma cells
Lymphoplasmacytic Lymphoma: Symptoms
No multiple bony lytic lesions
Main antibody is IgM
Hyperviscosity syndrome “Waldenstrom’s macroglobulinemia”
Hepatosplenomegaly with generalized lymphadenopathy
No Bence-Jones proteins
Heavy Chain Disease: Main Forms
α HCD - neoplastic cells in small intestine and respiratory system
ɤ HCD - neoplastic cells in liver, spleen, and lymph nodes
No Bence-Jones proteins
Primary Amyloidosis: Cause
Overproduction of immunoglobulin light chains, forming aggregations known as AL protein.
Diffuse Large B-Cell Lymphoma (DLBCL): Definition and Prevalence
A type of non-Hodgkin lymphoma, constituting 50% of NHLs. Aggressive tumors that can affect virtually any organ and are rapidly fatal if not treated.
Diffuse Large B-Cell Lymphoma: Causes
Mutations/rearrangements of Bcl6 gene on chromosome 3 → overexpression of Bcl6 → increased proliferation of centroblasts.
30% t(14,18); follicular lymphoma which developed into DLBCL.
Unknown causes.
Diffuse Large B-Cell Lymphoma: Features
Positive for B cell markers (excluding CD10).
B-cell receptor (BCR) presence.
Burkitt Lymphoma: Definition and Aggressiveness
Highly aggressive non-Hodgkin lymphoma characterized by rapid growth and proliferation of centroblasts
Burkitt Lymphoma: Causes
t(8,14) - chromosomal translocation; MYC gene translocates from chromosome 8 next to the Ig gene for heavy chain on chromosome 14 → MYC gene becomes hyperactive → increased proliferation of centroblasts.
Burkitt Lymphoma: Types
Endemic “African type”; 100% associated with EBV, manifests in the mandible and maxilla.
Sporadic “American type”; 20% associated with EBV, manifests in abdominal and pelvic cavities.
Burkitt Lymphoma: Histopathological Appearance
“Starry sky appearance” with dark background of neoplastic cells (high chromatin content) and lighter regions of non-neoplastic macrophages with pale cytoplasm and small nuclei.
Mantle Cell Lymphoma (MCL): Definition and Prevalence
A type of non-Hodgkin lymphoma, constituting 4% of NHLs. It is aggressive.
Mantle Cell Lymphoma: Causes
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 naive B cells → accumulation in the mantle zone.
Mantle Cell Lymphoma: Features
Positive for B cell markers.
Positive for CD5 (T cell marker).
Mantle Cell Lymphoma: Clinical Features
Non-specific symptoms such as fatigue, fever, weight loss. Lymphadenopathy and generalized disease involving the liver, spleen, bone marrow, and GI tract.
Marginal Zone Lymphoma: Definition
An indolent type of lymphoma. 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 – occurs 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).
MALT Lymphoma: Characteristics
Often arises within tissues involved by chronic inflammatory disorders of autoimmune or infectious etiology, such as Sjögren disease or Helicobacter pylori infection. They may regress if the inciting agent (e.g., Helicobacter pylori) is eradicated.
Marginal Zone Lymphoma: Causes
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 → increased proliferation of lymphocytes.
Marginal Zone Lymphoma: Features
Positive for B cell markers (excluding CD10).
Presence of B-cell receptor (BCR).
MALT Lymphoma: Specific Pathogenesis
Helicobacter-specific T cells produce growth factors which support the formation of the tumor. It often occurs in the stomach due to chronic gastritis caused by H. pylori.
B-Cell Maturation: Peripheral Lymph Node Structure
The peripheral lymph node is composed of a cortex and a medulla. The cortex contains lymphocytic nodules (follicles), which primarily consist of B cells and can be either primary (not activated) or secondary (met with an antigen).
B-Cell Activation in Lymph Follicle
Upon activation by an antigen, B cells start to proliferate and differentiate, creating the germinal center of the lymph follicle.
B-Cell Differentiation Process
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: Definition and Prevalence
A type of non-Hodgkin lymphoma, constituting 40% of NHLs. It is characterized by painless lymphadenopathy and poor response to chemotherapy.
Follicular Lymphoma: Immunophenotype
B cell markers CD10, CD19, CD20. Cells show somatic hypermutation.
Follicular Lymphoma: 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. This produces anti-apoptotic proteins, preventing apoptosis.
Follicular Lymphoma: Clinical Features
Painless lymphadenopathy.
Bone marrow involvement (RBC, WBC, and platelet levels may be affected).
Poor response to chemotherapy.
Progression and Treatment of Follicular Lymphoma
Follicular lymphoma may progress to diffuse large B-cell lymphoma. Treatment is reserved for symptomatic patients and involves low-dose chemotherapy or rituximab (anti-CD20 antibody).
Determining Precursor vs. Peripheral Lymphoma/Leukemia
The classification depends on the stage where the malignant transformation occurs. Precursor lymphoblastic lymphomas/leukemias involve:
Lymphoblast cells (bigger, less cytoplasm, less condensed chromatin)
High rate of proliferation
Less differentiation
→ Results in acute leukemia/aggressive lymphoma with rapid deterioration (death after 6-12 months). Occurs mainly in children/young adults.
Determining Lymphoid vs. Myeloid Leukemia/Lymphoma
Whether a leukemia/lymphoma is lymphoid or myeloid can be determined by cell markers (CDs, receptors, enzymes).
B Cell Markers for Leukemia/Lymphoma
B cell markers include CD 10, 19, 20, 21, 22.
T Cell Markers for Leukemia/Lymphoma
T cell markers include CD 2, 3 (expressed by all T cells), 4, 7, 8.
NK Cell Markers for Leukemia/Lymphoma
NK cell markers include CD 16, 56.
Pre-B Cell Neoplasms vs. Pre-T Cell Neoplasms
Pre-B cell neoplasms occur in the bone marrow, while pre-T cell neoplasms occur in the thymus. B-ALL is more common (85%) and usually affects children, while T-ALL is less common (10-15%) and usually affects adolescents. NK-ALL is extremely rare.
Pathogenesis of Lymphoma/Leukemia
Mutation → chromosomal abnormality → abnormal transcription factor → malignant transformation. Causes include radiation, chemicals like benzene, genetic factors (e.g., Li-Fraumeni syndrome), or spontaneous mutations.
Types of Chromosomal Abnormalities in Leukemia
Chromosomal abnormalities can be numerical (hyperploidy, hypoploidy, trisomy) or structural (deletion, translocation).
Hyperploidy
Hypoploidy
t(12,21) balanced
t(9,22) balanced; the resultant chromosome 22 is referred to as the “Philadelphia chromosome”.
Related Diseases from Crowding Out Normal Cells
Anemia → fatigue
Thrombocytopenia → bleeding (epistaxis, petechia, ecchymosis)
Neutropenia → infections
Hyper-cellular Bone Marrow Effects
Expansion of bone marrow → detachment of periosteum → pain & arthralgia
Starry night appearance like in Burkitt lymphoma.
Leukostasis in Microcirculation
Leukostasis in microcirculation (eyes, kidneys) → thrombi formation.
Tumor Lysis Syndrome
: Neoplastic cells release their content into the plasma, resulting in:
Increased uric acid
Increased phosphate
Increased H+
Increased Na+
Decreased Ca2+ (forms complexes with phosphate)
Prognosis of Lymphoma/Leukemia
Prognosis depends on various factors including the type of chromosomal abnormalities, the stage of detection, and the effectiveness of the treatment plan. Likelihood of survival varies accordingly.
Lymphomas: Definition
Solid cohesive neoplasms (tumors) of the immune system, mostly originating from lymphoid tissues (bone marrow, thymus, lymph nodes, etc.). In AIDS, they can occur in the CNS. Accumulation of mutations leads to loss of cohesion and potential transition to leukemia.
Leukemias: Definition
Malignancies of either lymphoid or myeloid origin, primarily involving the bone marrow with spillage of neoplastic cells into the blood. Sometimes they enter lymphoid tissues and aggregate there, forming lymphomas.
Leukemia Types
Lymphoid leukemia
Myeloid leukemia (affecting RBCs, platelets, and all other WBCs except lymphocytes)
WHO Classification of Lymphoid Tumors
Defines lymphoid tumors based on morphology, cell of origin, clinical features, and genotype. Divides lymphomas into:
Tumors of B cells
Tumors of T cells and NK cells
Hodgkin lymphomas
Tumors of B Cells
Precursor B cell neoplasms (B cell ALL)
Peripheral B cell neoplasms (mantle cell lymphomas, follicular lymphoma, Burkitt lymphoma)
Tumors 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
Nodular lymphocyte predominance Hodgkin lymphoma (NLPHL)
Determining Lymphoma/Leukemia Cell Type
Identified by B/T/NK cell markers (CDs, receptors, enzymes). Whether it is precursor or peripheral depends on the stage of malignant transformation.
Characteristics of Precursor Lympho/MyeloBLASTIC Cells
Bigger cells with less cytoplasm and less condensed chromatin
High rate of proliferation
Less differentiation
→ Acute leukemia/aggressive lymphoma. Mainly occurs in children/young adults.
Characteristics of Peripheral Lympho/MyeloCYTIC Cells
Smaller cells with more cytoplasm and more condensed chromatin
Low rate of proliferation
More differentiation
→ Chronic leukemia/indolent lymphoma.
Non-Hodgkin Lymphomas: Indolent vs. Aggressive
Indolent tumors progress slower, are harder to treat, and appear in elderly patients. Aggressive tumors progress fast but are easier to treat and appear in younger patients.
SLL/CLL: Definition and Cause
Indolent lymphoma/leukemia caused by trisomy of chromosome 12 (protooncogene) or deletion of chromosome 11/13 (tumor suppressor gene). This interferes with BCRs, causing naive B lymphocytes to stop maturing and die slowly, leading to their accumulation in the bone marrow and transfer to various tissues.
SLL/CLL: Clinical Features
Bone marrow involvement
Hepatosplenomegaly (liver and spleen)
Lymphadenopathy (lymph nodes)
Anemia, thrombocytopenia, neutropenia
Autoimmune hemolytic anemia
Hypo-ɤ-globulinemia
Richter syndrome (progression to DLBL)
SLL/CLL: Features and Morphology
Positive for B cell markers
Positive for CD5 (T cell marker)
Circulating tumor cells are fragile, often disrupted in smears, producing characteristic smudge cells.
Reactive Lymphadenitis: Definition
Enlargement of a lymph node due to an immune response. It can be acute (painful) or chronic (painless), depending on the underlying cause.
Acute Reactive Lymphadenitis
Painful enlargement of a lymph node draining a region with an acute infection. It is often confined to a local group of nodes but can be generalized in the case of systemic infection. Characterized by large germinal centers with numerous mitotic figures.
Chronic Reactive Lymphadenitis: Characteristics
Painless enlargement of a lymph node. Depending on the causative agent, different areas of the lymph node can be enlarged, such as follicular hyperplasia, paracortical hyperplasia, or sinus histiocytosis.
Follicular Hyperplasia
Enlargement of the follicles, often caused by chronic disorders like rheumatoid arthritis (RA) and early stages of HIV infections.
Paracortical Hyperplasia
Enlargement of the paracortex, often caused by viral infections like EBV (Epstein-Barr Virus), certain vaccinations (e.g., smallpox), and sometimes by Burkitt lymphoma.
Sinus Histiocytosis
Enlargement of the sinuses of the medulla, often caused by draining of cancers like breast cancer. It is characterized by an increase in the number of histiocytes (macrophages).
Toxoplasma Lymphadenitis
Caused by infection with the protozoan Toxoplasma gondii. Characterized by the presence of melanin-filled macrophages, eosinophils, and plasma cells in the affected area of the lymph node.
Chronic Myeloproliferative Diseases: Definition
Neoplastic proliferation of mature cells of the myeloid lineage, commonly associated with mutated tyrosine kinases. Includes Chronic Myeloid Leukemia (CML), Polycythemia Vera (PCV), Primary Myelofibrosis, and Essential Thrombocythemia. These diseases result in high WBC counts (neutrophils > 100,000 cell/µL) and hypercellular bone marrow.
Chronic Myeloid Leukemia (CML): Definition and Affected Population
Increased proliferation of mature myeloid cells, especially granulocytes. Affects adults between 25 and 60 years of age.
CML: Cause
t(9,22) balanced translocation, resulting in the Philadelphia chromosome.
Features Characteristic of CML
Basophilia
Low leukocyte alkaline phosphatase (LAP)
Presence of t(9,22) translocation (Philadelphia chromosome)
CML: Treatment
Imatinib, which blocks tyrosine kinase activity.
Polycythemia Vera (PCV): Definition
Increased proliferation of mature myeloid cells, especially erythrocytes.
PCV: Cause
Mutation in JAK2, a tyrosine kinase, leading to hypersensitivity of cells to erythropoietin (EPO).
PCV: Clinical Signs
Increased RBC mass → increased blood viscosity → stasis → blurry vision, flushed face, thrombosis (e.g., Budd-Chiari syndrome)
Serum EPO levels decreased
Itching after bathing (due to high number of basophils)
PCV: Treatment
Phlebotomy. Without treatment, death typically occurs within a year.
Primary Myelofibrosis: Definition
Increased proliferation of mature myeloid cells, especially megakaryocytes.
Primary Myelofibrosis: Cause
Mutation in JAK2, a tyrosine kinase, leading to overproduction of PDGF by megakaryocytes, which stimulates fibroblasts to deposit collagen, causing marrow fibrosis.
Primary Myelofibrosis: Clinical Signs
Hepatosplenomegaly (due to extramedullary hematopoiesis)
Leucoerythroblastic smear (presence of immature cells in circulation)
Fatigue, infections, thrombosis (due to insufficient cell production)
Tear-drop cells (RBCs squeezed out of fibrosed marrow)
Essential Thrombocythemia: Definition
Increased proliferation of mature myeloid cells, especially platelets.
Essential Thrombocythemia: Cause
Mutation in JAK2, a tyrosine kinase, leading to abnormal platelet production, causing bleeding or thrombosis.
Essential Thrombocythemia: Clinical Signs
Usually asymptomatic. No significant risk for hyperuricemia or gout.
Acute vs. Chronic Leukemia
Acute Leukemia: Rapid increase in immature blood cells (blasts >20%), suppressing normal hematopoiesis and decreasing WBCs, RBCs, and platelets.
Chronic Leukemia: Slow progression with excessive buildup of relatively mature, but abnormal leukocytes.
General Features of Acute Leukemia
Lympho/myeloBLASTIC cells (bigger, less cytoplasm, less condensed chromatin)
High rate of proliferation
Less differentiation
Pre-B cell neoplasms occur in the bone marrow, pre-T cell neoplasms in the thymus
Occurs mainly in children/young adults
Rapid progression (death after 6-12 months if untreated)
Acute Myeloid Leukemia (AML): Definition and Affected Population
AML usually affects adults over 50 years old. Characterized by the accumulation of myeloid lineage cells at earlier stages of development.
Determining Lineage in Leukemia
Lineage is determined by cell markers and other characteristics. AML is identified by myeloid markers, while ALL is identified by lymphoid markers.
Pathogenesis of AML
Acquired mutations in transcription factors inhibit normal myeloid differentiation, leading to the accumulation of immature cells.
Examples include:
Acute promyelocytic leukemia (t(15,17) causing PML/RARα fusion protein, blocking differentiation)
Transformation from CML or other dysplastic syndromes to AML
Acute Promyelocytic Leukemia: Characteristics and Treatment
t(15,17) translocation leading to PML/RARα fusion protein
Promyelocytic cells contain Auer rods, increasing coagulation risk (DIC)
Treatment: ATRA (vitamin A derivative) promotes maturation into neutrophils; combination with arsenic trioxide is more effective.
Surface Markers and Cell Types in AML
Surface markers: CD 13, 14, 15
Cell types:
Erythroblast AML
Megakaryoblast AML (no myeloperoxidase, associated with Down syndrome under age 5)
Monoblast AML (acute monocytic leukemia, no myeloperoxidase, infiltrated gums)
Myelodysplastic Syndromes: Definition
Bone marrow is replaced by clonal progeny of mutant multipotent stem cells that differentiate into defective RBCs, granulocytes, or platelets. These syndromes are genetically unstable, often transforming into AML.
Myelodysplastic Syndromes: Characteristics
Defective megaloblastoid erythroid precursors
Transformation into AML in 10%-40% of cases
Karyotype abnormalities include loss of chromosome 5 or 7, deletion of their long arm, and trisomy 8
Poor response to chemotherapy
Iron Deficiency Anemia: Definition
The most common form of nutritional deficiency anemia, characterized by a decrease in total body iron content.
Iron Distribution in the Body
Women: 2.5g, Men: 3.5g
80% in hemoglobin
20% in myoglobin and iron-containing enzymes
Iron storage pool in hemosiderin and ferritin-bound iron (liver, spleen, bone marrow, skeletal muscle)
Iron Absorption and Regulation
Iron is absorbed in the duodenum. Hepcidin, synthesized in the liver, regulates iron transfer between transferrin receptor and ferritin expression by inducing internalization of ferroportin.
Causes of Negative Iron Balance
Low dietary intake (vegetarians)
Malabsorption (e.g., celiac disease)
Increased demands (pregnancy, infancy)
Chronic blood loss (GI tract ulcers, colonic cancer, female genital tract issues like menorrhagia)
Morphology of Iron Deficiency Anemia
RBCs are microcytic and hypochromic (low MCV, low MCHC)
Increased platelet count
Elevated erythropoietin levels due to hypoxia, but bone marrow cannot meet RBC production demands
Clinical Course of Iron Deficiency Anemia
Mostly asymptomatic but may include weakness, pallor, and pica (consumption of non-food items like dirt or clay).
Diagnostic Criteria for Iron Deficiency Anemia
Anemia with microcytic and hypochromic RBCs, low serum ferritin, low serum iron, low transferrin saturation, and a good response to iron treatment.
Anemia of Chronic Disease: Definition
Anemia resulting from inflammation-induced depletion of iron, commonly due to chronic infections, immune disorders, or neoplasms.
Characteristics of Anemia of Chronic Disease
Low serum iron level
RBCs are either normocytic and normochromic, or microcytic and hypochromic
Increased iron storage in bone marrow, high serum ferritin level, reduced iron-binding capacity
Major Cause of Anemia of Chronic Disease
High level of hepcidin due to cytokines produced during inflammation (e.g., IL-6).
Megaloblastic Anemia: Definition
Caused by deficiencies in folate or vitamin B12, both required for DNA synthesis, leading to enlarged erythroid precursors (megaloblasts) and abnormal RBCs (macrocytes).
Pathogenesis of Megaloblastic Anemia
Impaired DNA synthesis causes cell division delay, while RNA and cytoplasmic synthesis proceed normally, resulting in nuclear-cytoplasmic asynchrony.
Morphology of Megaloblastic Anemia
: Hypercellular bone marrow, nuclear-cytoplasmic asynchrony of megaloblasts and granulocyte precursors. In peripheral blood: hyper-segmented neutrophils and macrocytes.
Folate Deficiency Anemia: Causes
Poor diet or increased metabolic need (e.g., pregnancy)
Absorption blocked by drugs (e.g., Phenytoin) or malabsorptive disorders (e.g., Celiac disease)
Metabolism blocked by drugs (e.g., Methotrexate)
Folate Deficiency Anemia: Clinical Features
Same as vitamin B12 deficiency but without neurological abnormalities.
Vitamin B12 Deficiency (Pernicious Anemia): Clinical Features
Same as folate deficiency but also includes demyelinating disorders of peripheral nerves and spinal cord.
Vitamin B12 Absorption
Absorbed through intrinsic factor (produced by parietal cells in the fundus mucosa) in the ileum, and delivered to the liver by transcobalamins.
Causes of Vitamin B12 Deficiency
Malabsorption due to gastric mucosal atrophy
Autoimmune reaction against parietal cells or intrinsic factor
Malabsorption in the distal ileum (e.g., Crohn’s disease, Whipple disease)
Aplastic Anemia: Definition
A disorder where multipotent myeloid stem cells are suppressed, leading to marrow failure and pancytopenia. Most cases are idiopathic or caused by exposure to myelotoxic agents.
Pathogenesis of Aplastic Anemia
Autoreactive T cells attack the bone marrow. The trigger for the T cell attack is unclear, but may involve inherited defects in telomerase.
Morphology of Aplastic Anemia
Bone marrow is hypocellular, with more than 90% of inter-trabecular spaces occupied by fat.
Clinical Course of Aplastic Anemia
Affects all ages and sexes. Causes slow-progressing anemia with weakness, pallor, dyspnea, thrombocytopenia, and granulocytopenia. No splenomegaly.
Anemia: Definition
Reduction of oxygen transport capacity of the blood due to a decrease in RBC number or hemoglobin concentration. Causes include bleeding, increased destruction, decreased production, or reduced hemoglobin concentration.
Anemia: Compensatory Mechanisms
Decreased tissue oxygen tension triggers increased production of erythropoietin from kidney cells, leading to compensatory hyperplasia of erythroid precursors in the bone marrow and extramedullary hematopoiesis in severe cases.
Classification of Anemias Based on RBC Morphology
Microcytic (iron deficiency, thalassemia)
Macrocytic (folate/B12 deficiency)
Normocytic with abnormal shape (hereditary spherocytosis, sickle cell)
By color (normo/hypo/hyper-chromic)
Tests for Anemia Diagnosis
Iron levels (iron deficiency anemia, chronic disease anemia, thalassemia)
Plasma unconjugated bilirubin, LDH, haptoglobin (hemolytic anemias)
Folate/B12 levels (megaloblastic anemias)
Hemoglobin electrophoresis
Coombs test (immunohemolytic anemia)
Bone marrow examination (in case of associated thrombocytopenia/granulocytopenia)
Clinical Consequences of Anemia
Determined by severity, rapidity of onset, and underlying mechanism. Common symptoms include pallor, fatigue, and dyspnea. Severe anemia can lead to myocardial hypoxia, angina, CNS hypoxia, and systemic complications.
Blood Loss Anemia: Acute vs. Chronic
Acute: >20% blood volume loss, immediate threat of hypovolemic shock, normocytic and normochromic RBCs, elevated erythropoietin, leukocytosis.
Chronic: Anemia when loss exceeds marrow regenerative capacity or iron depletion, leading to microcytic and hypochromic RBCs.
Hemolytic Anemia: General Features
Characterized by accelerated RBC destruction, increased erythropoiesis (reticulocytosis), and retention of RBC destruction products (iron - hemosiderosis). Can be due to intra-corpuscular (inherited) or extra-corpuscular (acquired) defects.
Intravascular vs. Extravascular Hemolysis
Intravascular: Occurs within vascular compartments, caused by mechanical trauma, biochemical/physical agents, leading to hemoglobinemia, hemoglobinuria, hemosiderinuria.
Extravascular: Occurs within phagocytic cells (spleen/liver), more common, leads to systemic hemosiderosis, jaundice, and splenomegaly.
Intra-corpuscular Hemolytic Anemias
Includes hereditary membrane defects (spherocytosis), hemoglobin synthesis defects (sickle cell anemia, thalassemias), and enzyme deficiencies (G6PD deficiency).
Extra-corpuscular Hemolytic Anemias
Includes immunohemolytic anemias (warm/cold antibody), erythroblastosis fetalis, mechanical trauma to RBCs, and infections (malaria).
Iron Deficiency Anemia: Causes
Low dietary intake (especially in vegetarians)
Malabsorption (e.g., celiac disease)
Increased demands (e.g., pregnancy, infancy)
Chronic blood loss (e.g., GI tract ulcers, colonic cancer, menorrhagia)
Iron Deficiency Anemia: Morphology
RBCs are microcytic and hypochromic (low MCV, low MCHC). Increased platelet count, elevated erythropoietin levels, but bone marrow cannot meet RBC production demands.
Anemia of Chronic Disease: Characteristics
Low serum iron level, RBCs either normocytic/normochromic or microcytic/hypochromic. Increased iron storage in bone marrow, high serum ferritin, reduced iron-binding capacity. Caused by high levels of hepcidin from cytokines during inflammation.
Megaloblastic Anemia: Causes
Caused by deficiencies in folate or vitamin B12, necessary for DNA synthesis. Leads to enlargement of erythroid precursors (megaloblasts) and abnormal RBCs (macrocytes).
Aplastic Anemia: Definition and Causes
Disorder where multipotent myeloid stem cells are suppressed, leading to marrow failure and pancytopenia. Most cases are idiopathic or caused by exposure to myelotoxic agents.
Pathogenesis and Morphology of Aplastic Anemia
Autoreactive T cells attack the bone marrow, trigger unclear. Bone marrow is hypocellular with over 90% inter-trabecular spaces occupied by fat.
Clinical Course of Aplastic Anemia
Affects all ages and sexes, causes slow-progressing anemia with weakness, pallor, dyspnea, thrombocytopenia, and granulocytopenia. No splenomegaly.
Giant Cell Arteritis: General Features
The most common vasculitis, affecting individuals >50 years, more common in females. Primarily affects arteries of the head, especially temporal arteries.
Giant Cell Arteritis: Clinical Manifestations
Headache: Especially in the temporal arteries.
Visual disturbances: When ophthalmic artery is affected.
Jaw pain: Claudication in maxillary arteries.
Giant Cell Arteritis: Etiology
Immunologic mechanisms:
Antibodies against endothelial cells.
Cell-mediated (autoreactive T cells).
Giant Cell Arteritis: Clinical Features
Elevated ESR (erythrocyte sedimentation rate).
Biopsy: Presence of giant cells (granulomas) in the internal elastic lamina.
Giant Cell Arteritis: Biopsy Considerations
Segmental nature of the disease.
Requires at least a 2- to 3-cm length of artery for adequate biopsy.
Negative biopsy does not exclude the diagnosis
Giant Cell Arteritis: Treatment
Corticosteroids to treat inflammation.
Takayasu Arteritis: General Features
Mostly seen in Asian women <40. Affects the aorta and its branches, especially those from the aortic arch (elastic arteries).
Takayasu Arteritis: Clinical Manifestations
Weak or absent pulse in upper extremities due to affected branches.
Visual and neurological symptoms due to affected branches serving the head.
Corneal ostial stenosis.
Aortic stenosis
Takayasu Arteritis: Clinical Features and Treatment
Similar clinical features to giant cell arteritis, except for segmentation. Treatment is the same as giant cell arteritis (corticosteroids).
Infectious Vasculitis: Direct Invasion
Caused by direct invasion of an infectious agent, primarily bacteria (e.g., Aspergillus and Mucor spp.) which release exotoxins.
Infectious Vasculitis: Indirect Mechanism
Caused by bacteria-induced inflammation, damaging endothelial cells through harmful cytokines. Example: Molecular mimicry in streptococcus causing endocarditis and vasculitis.
Kawasaki Disease: General Features
Affects children <5 years old.
Primarily affects coronary arteries (transmural inflammation), which can lead to myocardial infarction.
Kawasaki Disease: Clinical Features
Conjunctivitis
Rash
Adenopathy (enlarged lymph nodes)
Strawberry tongue
Hands and feet are swollen with rash
Polyarteritis Nodosa (PAN): General Features
Primarily affects young adults.
Targets multiple visceral arteries (mainly renal, not pulmonary).
Segmental appearance (beads on angiogram).
Polyarteritis Nodosa: Pathogenesis and Clinical
Molecular mimicry: Endothelium confused with HBV (Hepatitis B Virus).
Causes transmural inflammation (affects tunica intima, media, and adventitia).
Frequently accompanied by fibrinoid necrosis.
Not associated with ANCA (antineutrophil cytoplasmic antibodies).
Polyarteritis Nodosa: Treatment
Corticosteroids to treat inflammation.
Buerger’s Disease: General Features
Affects men 20-40 years old, often associated with tobacco use.
Causes blood clots in small arteries, especially in the fingers and toes (mainly tibial and radial arteries).
Buerger’s Disease: Clinical Features
Leads to dead tissue and possible autoamputation.
Spreads to adjacent veins and nerves.
Segmental nature of the disease.
General Features of Small Vessel Vasculitides
Affect arterioles, capillaries, and venules.
B cells produce antibodies ANCA (anti-neutrophilic cytoplasmic antibodies, mainly IgG) against granules made by self-neutrophils.
Wegener’s Granulomatosis: General Features
Affects middle-aged males.
Involves vessels in the nasopharynx, lungs, and kidneys.
Associated with cANCA (cytoplasmic ANCA) which targets proteinase 3 in neutrophils.
Wegener’s Granulomatosis: Nasopharynx Symptoms
Sinusitis leading to chronic pain.
Ulcers causing bloody mucous.
Saddle nose deformity.
Can spread to the ear causing otitis media.
Wegener’s Granulomatosis: Lung and Kidney Symptoms
Lungs: Difficulty breathing, ulcers causing bloody cough.
Kidneys: Glomeruli damage leading to decreased urine production and increased blood pressure.
Wegener’s Granulomatosis: Treatment and Prognosis
Treatment: Corticosteroids and cyclophosphamide (immunosuppressor).
If untreated, death within one year.
Disease characterized by relapses.
Microscopic Polyangiitis: General Features
Similar to Wegener’s Granulomatosis but only affects blood vessels of lungs and kidneys.
Not associated with nasopharynx involvement.
No granulomas present.
Characterized by pANCA (perinuclear ANCA) which targets myeloperoxidase.
Microscopic Polyangiitis: Symptoms and Treatment
Symptoms: Lung and kidney damage.
Treatment: Corticosteroids and cyclophosphamide.
Disease characterized by relapses.
Churg-Strauss Syndrome: General Features
Associated with pANCA.
Involves symptoms similar to Wegener’s but also affects GI, skin, nerves, and heart.
Granulomas can form.
Increased eosinophils, often mistaken for an allergy.
Churg-Strauss Syndrome: Symptoms and Characteristics
Symptoms: Sinusitis, lung damage, kidney damage, GI issues, skin rashes, nerve damage, and heart problems.
Presence of granulomas and high eosinophil count.
General Definition of Vasculitides
Inflammation of vessel walls of virtually any type of vessel.
Etiologies of Vasculitides
Immunologic Mechanisms:
Immune Complex Deposition: Type III hypersensitivity; e.g., SLE.
ANCA Mediated:
cANCA: Target proteinase 3.
pANCA: Target myeloperoxidase.
Antibodies Against Endothelial Cells.
Cell-Mediated: Autoreactive T cells.
Infectious Mechanisms:
Direct invasion by infectious pathogens (e.g., varicella zoster virus, some fungi).
Physical / Chemical Injuries.
Significance of Etiology in Treatment
Distinguishing between etiologies is crucial for treatment.
Corticosteroids useful for immunologic causes but harmful for infectious causes.
Effects of Damaged Endothelium
Weakening of Blood Vessels:
Leads to aneurysm and rupture of small vessels → microhemorrhage (purpura).
Exposure of Underlying Collagen and TF:
Triggers coagulation.
Healing Process:
Fibrin deposition → vessel stiffness.
Reduced lumen diameter → organ ischemia.
Systemic Symptoms of Severe Vasculitis
Severe inflammation activates many inflammatory cells.
High cytokine levels affect the hypothalamus → fever, fatigue, and weight loss.
Cytokines affect hepatocytes → CRP production → sticky RBCs → increased ESR.
Large Vessel Vasculitides: Giant Cell Arteritis
Most common vasculitis, affects people >50 years, more common in females.
Affects arteries of the head, especially temporal arteries.
Symptoms: Headache, visual disturbances, jaw pain (claudication).
Immunologic mechanisms: Antibodies against endothelial cells, cell-mediated (autoreactive T cells).
Clinical features: ↑↑ESR, biopsy shows giant cells in internal elastic lamina.
Treatment: Corticosteroids.
Characteristics of Vasculitides Based on Vessel Size
Large Vessel Vasculitides.
Medium Vessel Vasculitides.
Small Vessel Vasculitides.
Large Vessel Vasculitides: Takayasu Arteritis
Mostly seen in Asian women <40.
Affects the aorta and its branches.
Symptoms: Weak pulse in upper extremities, visual/neurological symptoms, aortic stenosis.
Treatment: Same as giant cell arteritis.
Medium Vessel Vasculitides: Kawasaki Disease
Affects children <5 years old.
Primarily affects coronary arteries, may lead to MI.
Symptoms: Conjunctivitis, rash, adenopathy, strawberry tongue, swollen hands/feet.
Medium Vessel Vasculitides: Polyarteritis Nodosa
Primarily affects young adults.
Involves multiple visceral arteries, mainly renal (not pulmonary).
Cause: Molecular mimicry with HBV.
Segmental appearance, causes transmural inflammation.
Treatment: Corticosteroids.
Medium Vessel Vasculitides: Buerger’s Disease
Affects men 20-40 years old, associated with tobacco use.
Causes blood clots in tiny arteries, mainly in fingers/toes → tissue death → autoamputation.
Segmental spread to adjacent veins and nerves.
Small Vessel Vasculitides: Wegener’s Granulomatosis
Affects middle-aged males.
Involves vessels in the nasopharynx, lungs, and kidneys.
Symptoms: Sinusitis, bloody mucous, saddle nose deformity, otitis media, difficulty breathing, bloody cough, glomeruli damage.
Associated with cANCA targeting proteinase 3.
Treatment: Corticosteroids and cyclophosphamide.
Small Vessel Vasculitides: Microscopic Polyangiitis
Similar to Wegener’s but affects only lungs and kidneys.
No granulomas present.
Associated with pANCA targeting myeloperoxidase.
Treatment: Corticosteroids and cyclophosphamide.
