Other 13 Flashcards
CD34
Antigen/marker of HSC cells
CD45
leukocyte common antigen – found on all white cells
Hematopoietic stem cells
Pluripotent == can generate all mature blood cells
mature blood elements are terminally differentiated cells with finite life spans
One cell → all lineages
Capacity for self-renewal
Common origin of all formed blood elements
Myeloid: erythrocytes, granulocytes, monocytes, platelets
MMEG == Monocytes, megakaryocytes, erythrocytes, and granulocytes
this is how Putthoff refers to Myeloid derived cells
MPO (peroxidase) positive
Lymphoid: lymphocytes
TdT positive (pre-B and pre-T cell marker
HSC location
3rd week of development: transient in the yolk sac; definitive hematopoiesis in the mesoderm of the intraembryonic aorta/gonad/mesonephros region
3rd month of development: Migration to liver (also seen in placenta)
liver == chief sit of blood cell formation until shortly before birth
4th month of development: Migration to bone marrow (entire skeleton)
Puberty: Restricted to axial skeleton
Bone marrow sinusoids
Network of thin-walled sinusoids lined by a single layer of endothelial cells on top of a discontinuous basement membrane and adventitial cells
There are clusters of HSC and fat cells that sendoff differentiated cells via transcellular migration
Megakaryocytes lie next to sinusoids and extend out cytoplasmic processes that bud off into the blood stream to release platelets
RBC precursors surround macrophages (nurse cells) that provide the iron to make the hemoglobin
Extramedullary hematopoiesis
Extramedullary Hematopoiesis
In stress conditions, HSC migration occurs and tissues other than the bone marrow can provide adequate environment to allow hematopoiesis to occur
Liver and spleen
Erythropoietin
Regulates RBC progenitor cells Produced by peritubular capillary lining cells in the kidney Relative to the PO2 Released constantly at Hb > 10 Released logarithmically at Hb < 20
Leukoerythroblastosis
processes that distort the marrow architecture, such as deposition of metastatic cancer or granulomatous disorders, can cause the abnormal release of immature precursors into the peripheral blood
Marrow aspirate
Allows for the best assessment of the morphology of hematopoietic cells
immature precursors (-blasts) forms are identified with lineage-specific antibodies and histochemical markers
Mature marrow precursors are identified based on morphology alone
Normal adults: fat:hematopoietic elements = 1:1
Hypoplastic states: proportion of fat cells is greatly increased
Hyperplastic states: fat cells disappear
Normal % of T cells of lymphocytes in peripheral blood
80% are T cells
WBC disorders
Proliferative: expansion of leukocytes
Reactive (infection, inflammation) – fairly common
Neoplastic – much more important to recognize
Leukopenia: deficiency of leukocytes
Leukopenia
Abnormally low WBC count
Often a result of reduced neutrophils (so leukopenia is usually a neutropenia/granulocytopenia)
Lymphopenia is less common
If present, often due to HIV infection, after glucocorticoid or cytotoxic therapy, with autoimmune disorders, malnutrition, acute viral infections (redistribution of lymphocytes because type I IFNs lead to the sequestration of activated T cells in lymph nodes and increased adherence to endothelial cells
Neutropenia
Neutropenia: reduction in the number of neutrophils in the blood
Most common cause of agranulocytopenia is drug toxicity
Agranulocytosis
Agranulocytosis: clinically significant reduction in neutrophils
patients have increased susceptibility to bacterial and fungal infections
Most commonly due to drug toxicity: idiosyncratic and unpredictable due to metabolic polymorphisms or auto-antibodies (chloramphenicol, sulfa, chlorpromazine, thiouracil, phenylbutazone)
chloramphenicol == aplastic anemia and gray baby syndrome
Pathogenesis neutrophils
Pathogenesis
Inadequate or ineffective granulopoiesis
Suppression of HSC’s (aplastic anemia, infiltrative marrow disorders)
granulocytopenia, anemia, and thrombocytopenia
Suppression of committed granulocytic precursors due to drugs – most common cause
Disease states → ineffective hematopoiesis (megaloblastic anemia, myelodysplastic syndromes)
Congenital conditions (Kostmann syndrome: inherited defects in specific genes impair granulocytic differentiation)
Increased destruction or sequestration of neutrophils in the periphery
Immunologically mediated injury (idiopathic, related to autoimmune disorder, drug-related)
Splenomegaly → splenic enlargement leads to sequestration of neutrophils and modest neutropenia
associated with anemia and thrombocytopenia
Increased peripheral utilization (Overwhelming bacterial, fungal, or rickettsial infection)
Agranulocytosis morphology : hypocellularity in the bone marrow
Hypo- or hypercellularity in the bone marrow
Hyper: excessive destruction of the cells in the periphery, neutropenias caused by ineffective granulopoiesis (i.e. megaloblastic anemias and myelodysplastic syndromes)
Hypo: agents that suppress or destroy granulocytic precursors
Agranulocytosis morphology infections
Leads to infections with ulcerating necrotizing lesions of the oral cavity – agranulocytic angina
Deep lesions covered by dark necrotic membranes from which bacteria or fungi can be isolated
Infection can also occur in other locations
Increased risk of infection by Candida and Aspergillus
Clinical agranulocytosis
Signs and symptoms related to infection: Malaise, chills, fever followed by marked weakness and fatigability
Overwhelming infections can cause death within hours to days
Serious infections occur with a count < 500/mm3
Treatment agranulocytosis
Broad spectrum antibiotics
GCSF administration to stimulate production of granulocytes from marrow precursors
Leukocytosis
Increase in the number of WBCs in the blood
Common in inflammatory states
leukemoid reaction == elevated LAP
leukemia == normal LAP
Driven by production of cytokines (TNF, IL1), growth factors and adhesion molecules
May include d, eosinophilia, basophilia, monocytosis, lymphocytosis
Peripheral leukocyte count influences
Related to size of precursor in marrow pool, circulation and peripheral tissues
Rate of release of cells from the storage pools into the circulation
Proportion of cells adherent to the blood vessel walls (marginal pool)
Rate of extravasation of cells from the blood into tissues
Role of infection on leukocytosis
TNF and IL-1, if sustained, can cause there to be an egress of mature granulocytes out of the bone marrow and for there to be increased production of growth factors
IL5: Stimulates production of eosinophils
G-CSF: Stimulates production of granulocytes (neutrophils
Sepsis of severe inflammatory disease on leukocytosis
In sepsis or severe inflammatory diseases, can be accompanied by morphologic changes in neutrophils
Toxic granulations: coarser and darker, abnormal azurophilic (primary) neutrophilic granules
due to strong response to infection
Dohle bodies: patches of dilated endoplasmic reticulum seen as sky-blue cytoplasmic “puddles”
seen in neutrophils
due to strong response to infection
Leukomoid rection : many immature granulocytes
Leukemoid Reaction: many immature granulocytes appear in the blood due to an infection; looks like myeloid leukemia
LAP will be elevated in leukemoid reaction
LAP will be normal in leukemia
Lymphopenia causes
Decreased number of circulating lymphocytes
Immunodeficiency (Di George syndrome [chromosome 22q11 deletion])
High cortisol state (Cushing syndrome)
Autoimmune destruction (SLE)
Whole body radiation
Neutrophilic leukocyteis causes
Increased circulating neutrophils
Bacterial infection or tissue necrosis (left shift) with Decreased CD16 and Fc receptors
High cortisol state
Eosinophilic leukocytosis causes
Increased circulating eosinophils Allergic reactions (type I hypersensitivity) Parasitic infections Hodgkin lymphoma Drug reactions Some vasculitides *increased IL5 --> eosinophils
Basophils leukocytosis
Increased circulating basophils
CML (chronic myeloid leukemia)
Rare, except in CML ^^
Monocytosis causes
Increased circulating monocytes Chronic inflammatory states (autoimmune or infectious) TB, bacterial endocarditis, malaria Malignancy Collagen vascular disorders (SLE) Inflammatory bowel diseases
Lymphocytic lymphocytosis causes
Increased circulating lymphocytes Viral infections (HAV, CMV, EBV) Bordetella pertussis infection Chronic immunologic stimulation (TB, brucellosis) Often accompanies monocytosis
Germinal centers
Develop in lymph nodes within several days of antigenic stimulation
due to enlargement of primary follicles; pale staining
Highly dynamic structures where B cells acquire the capacity to make high-affinity antibodies against specific Antigens
Dark zone of proliferating centroblasts (blast like B cells)
Light zone of centrocytes (B cells with irregular or cleaved nuclear contours
Acute nonspecific lymphadenitis : localized
Localized: Direct microbiologic drainage (i.e. cervical region due to dental or tonsillar infection; axillary or inguinal regions due to infections in the extremities
Acute nonspecific lymphadenitis systemic
Systemic: Associated with bacteremia and viral infections (particularly in children
Mesenteric acute nonspecific lymphadenitis
Mesenteric: An infection that causes mesenteric lymph nodes to enlarge and become tender
Can look like appendicitis
Morphology acute nonspecific lymphadenitis
Large germinal centers with numerous mitotic figures
Nodes are swollen, gray-red and engorged
Presence of macrophages with particulate debris
In severe infections the entire lymph node can become necrotic or a bag of pus
Less severe infections have scattered infiltrates of neutrophils that accumulate in the lymphoid sinuses
Endothelial cell hyperplasia (lining the sinus
Calinical acute nonspecific lymphadenitis
Clinical
Affected nodes are enlarged and tender; may become fluctuant (moveable) when abscess formations is extensive; overlying skin is red
suppurative infections that penetrate the lymph node capsule & track to the skin –> draining sinuses –> scar
Chronic nonspecific lymphadenitis
Nontender lymph nodes without acute inflammation or tissue damage
Tender LAD == acute process (infection)
nontender LAD == chronic process (cancer)
Common in inguinal and axillary lymph nodes as they drain large areas of the body and are stimulated by trivial injury/infections of extremities
Tertiary lymphoid organs
chronic immune reactions can promote the appearance of organized collections of immune cells in nonlymphoid tissues
chronic gastritis caused by Helicobacter pylori infection –> peyer’s patch hyperplasia
can lead to MALToma (marginal cell lymphoma)
rheumatoid arthritis –> B-cell follicles appear in the inflamed synovium
can lead to MALToma (marginal cell lymphoma)
lymphotoxin is probably involved
Follicular hyperplasia
due to stimuli activating the humoral immune response
Presence of large oblong germinal centers (2° follicles) surrounded by a collar of small resting naive B cells (mantle zone)
Germinal centers contain centroblasts (dark) and centrocytes (light)
Dendritic cells and tingible-body macrophages are interspersed
tingible-body macrophages == macrophages that have phagocytosed the apoptotic B-cells
May be due to rheumatoid arthritis, toxoplasmosis, or early HIV – B cell responses
Tangible body macrophages
Tingible-body macrophages
Contain the nuclear debris of B cells
B cells undergo apoptosis if they fail to produce an antibody with a high affinity for antigen
Seen in ALL and Burkitt Lymphoma
tingible body == apoptotic B cells in a macrophage
Reactive follicular hyperplasia
Preservation of lymph node architecture – neoplastic means things are going awry
Marked variation in follicular shape and size
Frequent mitotic figures, phagocytic macrophages and recognizable light (-cyte) and dark (-blast) zones
Paracortical hyperplasia
due to stimuli triggering the T-cell mediated immune response (e.g. acute viral infection)
infectious mononucleosis (EBV)
In exuberant reactions, the T-cell zones (containing immunoblasts) may encroach on the B-cell follicles
Hypertrophy of sinusoidal and vascular endothelial cells
May be accompanied by infiltrating macrophages and eosinophils
Imunoblasts (dark staining)
Activated T cells 3-4 times the size of resting lymphocytes
Round nuclei, open chromatin, several prominent nucleoli, moderate amounts of pale cytoplasm
If numerous, exclude lymphoid neoplasm from differential diagnoses
Sinus histiocytosis
inus Histiocytes (aka reticular hyperplasia)
Increase in the number and size of cells that line lymphatic sinusoids
Nonspecific, but can be prominent in lymph nodes draining cancers such as carcinoma of the breast
lymphatic endothelial cells are markedly hypertrophied and significant increases in macrophages occurs
Expansion and distension of the sinuses
sinus histiocytosis does not mean metastatic cancer; these lymph nodes are reactive; sinus histiocytosis is a reactive phenomenon in a lymph node draining cancer
histiocytosis X is dendritic cell proliferation – what does the X stand for??
Hemophagocytic lymphohistiocytosis
Definition: macrophage activating syndrome
Reactive condition with cytopenias and signs and symptoms of systemic inflammation due to macrophage activation
Familial (early onset) and sporadic (any age
Pathogenesis hemophagocytic lymphohistiocytosis
Systemic activation of macrophage and CD8+ cytotoxic T-cells
macrophages phagocytose blood cell progenitors in the marrow and formed elements in peripheral tissues
Mediators released from macrophage and lymphocytes suppress hematopoiesis and produce signs and symptoms of systemic inflammation
“Cytokine storm” or SIRS can occur due to the cytopenias
SIRS criteria
Hyper/Hypo-thermia
Tachycardia
Tachypnea
Leukocytosis/leukopenia
Appear shock-like
unbridled HLH is associated with extremely high levels of inflammatory mediators such as IFNγ, TNFα, IL-6, and IL-12, as well as soluble IL-2 receptor
infection is the most common trigger for HLH, especially Epstein-Barr virus (EBV
Clinical hemophagocytic lymphohistiocytosis
patients present with acute febrile illness and hepatosplenomegaly
Hemophagocytosis may be seen on bone marrow exam – neither sufficient nor required to make diagnosis
Anemia, thrombocytopenia,
increased plasma ferritin and soluble IL-2 receptor (indicators of severe inflammation)
Elevated LFT’s and TGs (related to hepatitis)
coagulation studies may show evidence of DIC
Untreated = rapid progression to multiorgan failure, shock, death
Treatment HLH
Immunosuppressive drugs and “mild” chemotherapy
Germline mutations or persistent/resistant disease? HSC transplantation
Treated: 50% survive
May have significant sequelae (renal damage in adults, growth and mental retardation in children)
Untreated: grim prognosis, < 2 months survival if familial
Familial hemophagocytic lymphohistiocytosis
Mutations impact the ability of cytotoxic T cells and NK to properly form or deploy cytotoxic granules
Uncontrolled disease
Greatly increased IFNγ, TNFα, IL6, IL12 and soluble IL2 receptor
familial form is more severe
Leukocyte alkaline phosphatase (LAP)
Elevated in reactive WBC disorders
LAP will be high in reactive states, e.g. infection
Low in myeloproliferative and neoplastic WBC disorders
WBC neoplasma
WBC Neoplasms
Lymphoid
Myeloid
Histiocytoses
Lymphoid neoplasma
Neoplasm of B-cell, T-cell and NK-cell origin
Phenotype may resemble a particular stage of normal maturation – useful for diagnosis and classification
Myeloid neoplasma
Neoplasm of early hematopoietic progenitors
Tend to evolve over time to more aggressive forms of disease – clinically important
Acute myeloid leukemia
Immature progenitor cells (blasts) accumulate in the bone marrow suppressing normal hematopoiesis
Both myelodysplastic syndromes and myeloproliferative disorders can “transform” to this disease
Myelodysplastic syndromes
Ineffective hematopoiesis due to defective maturation of myeloid progenitors
Resultant peripheral blood cytopenias
more severe than myeloproliferative disorders
Chronic. Myeloproliferative disease
hronic Myeloproliferative Disease
Increased production of one or more terminally differentiated myeloid elements leads to elevated peripheral blood counts
Polycythemia Vera, Essential Thrombocytopenia, Primary Myelofibrosis, and CML
Histiocytosis
Uncommon proliferative lesions of macrophage and dendritic cells
Langerhans cell (special type of immature dendritic cell) gives rise to a spectrum of neoplastic disorders referred to as the Langerhans cell histiocytoses
look for cutaneous involvement; all are CD4 +ve
Factors influencing WBC neoplasia
Chromosomal translocations and other acquired mutations
Inherited genetic factors
acute leukemias: dominant negative oncogenic mutations involving transcription factors are often present that interfere with early stages of lymphoid or myeloid cell differentiation
Viruses
Chronic inflammation (i.e. Helicobacter Pylori)
Iatrogenic factors (radiation and some chemotherapy)
Smoking
oncogenic mutations occur most frequently in germinal center B cells during attempted antibody diversification
class switching == intragenic recombination event in which the IgM heavy-chain constant gene segment is replaced with a different constant gene
somatic hypermutation == point mutations within Ig genes that may increase antibody affinity for antigen
Translocations in WBC neoplasma
Translocations in WBC neoplasms
Most common nonrandom chromosomal abnormality seen in WBC neoplasms
WBC mutations
Play crucial roles in the development, growth or survival of the normal counterpart to the malignant cell (gain or loss of function)
Oncoproteins can block normal maturation, activate pro-growth signals or inhibit apoptosis
Protooncogenes may be activated during gene rearrangement and diversification
Activation induced cytosine deaminase and its role in neoplasia
This enzyme is upregulated after Antigen stimulation in germinal center B cells
Allows Ig class switching and somatic hypermutation to increased antibody affinity
May induce MYC/Ig translocations – AID creates lesions in DNA that lead to chromosomal breaks
Can activate protooncogenes (i.e. BCL6
V(D)J recombinant and its role in neoplasia
This enzyme cuts DNA at specific sites within the Ig and T-cell receptor loci
May go awry, leading to the joining of portions of other genes to Ag receptor gene regulatory elements
Unique to B and T cells
Leukemia and lymphoma can be influenced by
Leukemia & Lymphoma can be influenced by: Inherited genetic factors: Down syndrome (trisomy 21) associated with an increased risk of Acute Lymphoblastic Leukemia (ALL) in children < 5 years Bloom syndrome Fanconi anemia ataxia telangiectasia Type I neurofibromatosis
HTLV1
HTLV1: adult T-cell leukemia/lymphoma (ATLL
EBV
EBV: Burkitt lymphoma, Hodgkin lymphoma, other B-cell Lymphoma
EBV infects B cells in the cortex; response to EBV infection is a paracortical hyperplasia of T-cells
KSHV/HHV8
KSHV/HHV8: B-cell Lymphoma that presents as a malignant effusion in the pleural cavity
HIV
HIV: B-cell Lymphoma
Chronic inflammation leading to WBC neoplasia
Helicobacter pylori: Gastric B-cell Lymphomas
Gluten sensitive enteropathy: intestinal T-cell Lymphomas
Breast implants: T-cell Lymphoma
Iatrogenic factors leading to blood neoplasia
Iatrogenic factors leading to blood neoplasia
Radiation and chemo can affect the myeloid and lymphoid precursors to cause neoplasia
Smoking on blood neoplasia
Acute Myeloid Leukemia increased, especially due to benzene
Lymphocytic leukemia
(Lymphocytic) Leukemia: neoplasms that have wide spread involvement of the bone marrow and often (not always) the peripheral blood
signs and symptoms related to the suppression of normal hematopoiesis by tumor cells in the bone marrow
“acute” leukemia == most common leukemia of childhood (ALL)
infections –> thrombocytosis; leukemia –> thrombocytopenia
generally: acute means kids and are -blasts; chronic means adults and are -cytes
Lymphoma
Lymphoma: proliferations of lymphoid cells that arise as discrete tissue masses – involvement of the tissue makes it an “-oma” (“-oma” means mass)
2/3 of non-Hodgkin’s lymphomas and virtually all Hodgkin’s lymphomas present as enlarged, nontender lymph nodes; 1/3 of remaining non-Hodgkin’s lymphomas present with symptoms related to tissue/organ involvement
Leukemia vs lymphoma
Leukemia vs. Lymphoma
Lymphomas more commonly exhibit tissue involvement (“-oma” means mass)
leukemia and lymphoma reflect the usual tissue distribution of each disease at presentation
Immature B cells
Precursor B cell (-blasts) neoplasms
Mature B cells
Peripheral B cells (-cystes) neoplasma
Immature T cells
Precursor T cell neoplasma
Mature T cells and NK cells
Peripheral T cell neoplasms
Mature T cells and NK cells
Peripheral T cell and NK cell neoplasma
Reed sternberg cells and variants
Hodgkin lymphoma
Lymphoid neoplasms
Histological examination is required for diagnosis
Antigen receptor gene rearrangement precedes transformation of cells – all daughter cells derived from the malignant progenitor share the same antigen receptor gene configuration and sequence
Monoclonal: all daughter cells express the same configuration and sequence, synthesizing identical proteins (immunoglobulins or TCRs) – monoclonal means cancer, malignant
Polyclonal: means that they are immature and are reactive
Most resemble a recognizable stage of B or T cell differentiation (most are B cell neoplasms)
even though 80% of circulating lymphocytes are T-cells
Often associated with immune problems
Behavior resembles normal B and T-cells
most lymphoid tumors are widely disseminated at the time of diagnosis
Hodgkin lymphoma: sometimes restricted to one group of lymph nodes
marginal zone B-cell lymphomas: often restricted to sites of chronic inflammation
MALTomas that arise in the setting of chronic inflammation
t(11;18), t(14;18) or t(1;14)
HOdgkin
Hodgkin’s: spreads in an orderly fashion and staging is useful
distinctive pathologic features and is treated in a unique fashion
Non Hodgkin
Non-Hodgkin’s: spreads widely, and less predictably
Acute lymphoblastic
Neoplasm of immature lymphoblasts (most are B-ALL)
There is a lot of clinical overlap between B and T-ALL
Kids with a very low platelet count have ALL until proven otherwise – most common leukemia of childhood
Population ALL
Increased risk in Hispanics»whites > African Americans
Slight male predominance
Most common cancer of children (usually patients <15)
*Most common cancer of children
Pathogenesis ALL
Dysregulation of expression and function of transcription factors for normal B and T cell development
Disturb differentiation and promote arrest of maturation, inducing self-renewal
Mutations that drive cell growth (i.e. TK) are common
70% of T-ALLs have gain-of-function mutations in NOTCH1
majority of B-ALLs have loss-of-function mutations in PAX5, E2A, and RBF or a balanced t(12;21) involving the genes ETV6 and RUNX1
Numerical or structural chromosomal change: 90% (Translocations, altered ploidy)
Caused by relatively few mutations as compared to solid tumors
ALL morphology
Leukemic presentation: marrow is hypercellular and packed with lymphoblasts that replace the normal marrow elements
Scant basophilic cytoplasm with nuclei larger than small lymphocytes
Delicate, finely stippled nucleoli with a rim of condensed chromatin
Subdivided nuclear membrane (convoluted)
High mitotic rate
“Starry sky” due to macrophage ingestion of tumor cells
A bone marrow biopsy is performed and on microscopic examination shows nearly 100% cellularity with replacement by primitive cells that have large nuclei with delicate chromatin and indistinct nucleoli with scanty cytoplasm. These cells mark for CD10 (CALLA) antigen
Lymphoblasts (different features than myeloblasts
must differentiate ALL from AML because they differ in their response to chemotherapy
Acute lymphoblastic leukemia/lymphoma
More condensed chromatin
Less conspicuous nuclei
Smaller amounts of cytoplasm whihc lacks granules
MPO(-), PAS (+), TdT (+)
Abrupt; stormy onset”, within days to few weeks of first symptoms
Related to depression of marrow function; fatigue due to anemia; fever due to infection from neutropenia; bleeding due to thrombocytopenia;
More common in all; bone pain
More common in ALL ; HA, vomiting, nerve palsies from meningeal spread
Acute myeloid leukemia
MPO (+)
No nerve palsies
B and T cell antibody stain are required for definitive diagnosis of ALL or AML
Clinical
most common translocation == t(4;11) – ??? (Hubbard)
Normal hematopoiesis is suppressed due to physical crowding, growth factor competition, etc.
Abrupt, “stormy” onset in days to weeks of first signs and symptoms
Signs and symptoms related to depression of marrow function
Fatigue (anemia), fever (neutropenia → infection), bleeding (thrombocytopenia)
Mass effects due to neoplastic infiltration
Bone pain from marrow expansion and infiltration, LAD, HSM, testicular enlargement
neurological manifestations due to meningeal spread: headache, vomiting, nerve palsies; diplopia
With aggressive chemotherapy, 95% of children with ALL achieve complete remission, and 75-85% are cured
still leading cause of cancer deaths in children (most common cancer)
only 35-40% of adults are cured due to different molecular pathogenesis and inability to tolerate the necessary chemo regimen effective in children
Poor prognosis
Age < 2 (strong association of infantile ALL with translocation of MLL gene)
t(9:22) Philadelphia chromosome
Presentation in adolescence or adulthood
Peripheral blood blast count > 100,000 (high tumor burden likely)
Detection of residual disease after therapy
Favorable prognosis
Age between 2 and 10 years old Low white cell count Hyper-diploidy trisomy of chromosome 4, 7, 10 Presence of t(12:21) -- involves ETV6 and RUNX1 genes
B cell ALL
Acute childhood leukemia
Peak incidence at age 3
Extensive marrow and peripheral blood involvement
B-cell tumors present with cyclic tumors
Morphology B cell ALL
Marrow is hypercellular and packed with lymphoblasts
Pancytopenia
Genetics B cell ALL
loss-of-function mutations in PAX5, E2A, EBF or *t(12:21) ETV6/RUNX1
Hyperdiploidy and hypodiploidy may be present and are exclusive in B-ALL
Immunophenotype B cell all
TdT (+) (pre-B-cell marker) CD10, 19, 20 (+) Very immature neoplasm: CD10 (-) Mature neoplasm: IgM heavy chain (+) (μ chain) PAX5 (+) t(9:22) BCR/ABL protein
Treatment B cell all
Effectively treatment in children with chemotherapy
Prophylax scrotum and CSF
T cell all
Presents in adolescent male (teenagers) as thymic mass (mediastinal) “lymphomas”; and T-cells (thymocytes) – mnemonic == 3 T’s
May evolve to a leukemia
lymphadenopathy and splenomegaly
Signs and symptoms may include complications related to compression of vessels or airways in the mediastinum
Genetics T cell all
NOTCH1 gain-of-function mutations – T-cells are NOTCH1 GOF
Immunophenotype T cell ALL
TdT (+) – precursor lymphocyte (i.e. lymphoblast) markers
CD1 and CD8 positive
Immature: CD3, CD4, and CD8 negative
Chronic lymphocytic leukemia (CLL) & small lymphocytic lymphoma
only difference between CLL and SLL is the degree of peripheral blood lymphocytosis
Follicular lymphoma
lar lymphoma == efface the normal architecture of the lymph nodes
follicular hyperplasia does not
t(14;18
DLBCL
BCL6
Burkitt lymphoam
T(8;14)
Mantle cell lymphoma
T(11;14)
Marginal zone lymphoma MALToma
t(11;18), t(14;18), or t(1;14
Hairy cell leukemia
TRAP, BRAF
Chronic lymphocytic leukemia
Most common leukemia of adults in the Western world
*Morphologically, phenotypically and genotypically indistinguishable from SLL, differ only in the degree of peripheral blood lymphocytosis (absolute WBC count > 5000/mm3
Populations at risk CLL
Male 2:1
Age: 60yrs
More common in the West than Asian countries
Chromosomal anomalies CLL
Chromosomal translocations are rare
Deletions: 13q14.3(microRNAs 15a & 16-1), 11q, 17p
Trisomy 12q – “tr-elve,” and the mnemonic becomes “11, 12/trelve, 13, 14, 15, 16, and 17
Genetics CLL
Somatic hypermutation of immunoglobulin genes can occur indicating cell of origin may be post-germinal center memory B cell or naive B cell
Unmutated Ig segments = increased aggressive course
NOTCH1 receptor gain of function mutations – this is a poor prognostic factor
RNA splicing mutations
Tell growth CLL
Confined to proliferation centers
NFκB is stimulated by stromal cells = promotion of growth and survival
BCRs produce signals required for growth and survival via BTK (Bruton TK)
*BTK inhibitors have produced sustained response in many patients
Morphology CLL
Proliferation centers (pathognomonic): Larger lymphocytes gathered in loose aggregates that contain mitotically active cells
Smudge cells: Small round lymphocytes in the peripheral blood with scant cytoplasm, disrupted when making the smear
smudge cells are not characteristic of anything (non-specific)
lymph node architecture is effaced by small lymphocytes (6-12um) with round or slightly irregular nuclei, condensed chromatin and scant cytoplasm
Infiltrates seen in bone marrow, splenic pulp (white + red) and hepatic portal tracts
Immunophenotype CLL
CD 5, 19, 20, 23 (+)
B cell proliferation that is positive for CD5, think CLL
Low levels of surface Ig (IgM +/ IgD) are also seen
When lymph node involvement occurs this becomes known as Small Lymphocytic Lymphoma
only difference between CLL and SLL is the degree of peripheral blood lymphocytosis
Prolymphocytes are seen in lymph nodes
Clincial CLL
patients are often asymptomatic at diagnosis
Signs and symptoms appear as nonspecific: easy fatigability, weight loss, anorexia, generalized lymphadenopathy, hepatosplenomegaly
Variable leukocyte count
Leukopenia in SLL with marrow involvement
Leukocytosis in CLL with heavy tumor burden
Monoclonal Ig “spike” may be present in the blood – more indicative of multiple myeloma?
patients with monoclonal B cells < # than required for diagnosis can have similar genetic defects but only 1% progress to symptomatic disease
Median survival 4-6 years, 10 years in patients with decreased tumor burden at diagnosis
CLL effect on immune function
Hypogammaglobulinemia = bacterial infection
Neoplastic B cell auto-antibodies = hemolytic anemia or thrombocytopenia
Poor prognosis cll
11q, 17p deletions
Lack of somatic hypermutation
ZAP70 (+): augments immunoglobulin receptor signaling
NOTCH1 mutations
Richter syndrome: tendency of CLL/SLL to transform to a more aggressive tumor in the form of diffuse large B-cell lymphoma; transformation of CLL/SLL to an aggressive B-cell lymphoma
Rapidly enlarging mass within a lymph node or the spleen, likely due to additional acquired mutations
large cell transformation is BAD; survival < 1 yea
Treatment CLL symptomatic
Gentle chemotherapy
Immunotherapy with antibodies to surface proteins (CD20)
hematopoietic stem cell transplant is offered to young patients
BTK inhibitors
Follicular lymphoma
Tumor of lymph nodes that causes obliteration of the lymph node and loss of architecture
lymphoma (neoplastic) will efface lymph node architecture; hyperplasia (reactive) won’t
Most common form of indolent non-Hodgkin’s lymphoma in the US
Who gets follicular lymphoma
Less common in Europe
Rare in Asian population
Pathogenesis follicular lymphoma
Arises from germinal center cells
strongly associated with chromosomal translocations involving BCL2
t(14:18) BCL2/Ig heavy chain – seen in >90% of follicular lymphomas (characteristic translocation of follicular lymphoma)
IGH locus on chromosome 14
BCL2 locus on chromosome 18
BCL2 antagonizes apoptosis (promotes cell survival)
Overexpression of BCL2 inhibits apoptosis of B cells that fail somatic hypermutation
Devoid of apoptotic cells because BCL2 is anti-apoptotic
MLL2: histone methyltransferase (epigenetics!); mutated in >90% of follicular lymphomas
Neoplastic cells grown in lymph nodes in a network of reactive follicular dendritic cells, macrophages and T cells and their microenvironment determines treatment response
Morphology follicular lymphoma
Follicular (nodular) and diffuse proliferation of centrocytes (predominant) and centroblasts
Lymphocytosis in 10%, makes it more aggressive
Para-trabecular lymphoid aggregates in bone marrow (also seen in splenic white pulp and hepatic portal triads
Centrocytes follicular
Small cells with irregular or cleaved nuclear contours
Scant cytoplasm
Centroblasts cll
Large cells with open nuclear chromatin
Several nucleoli
Modest amounts of cytoplasm
Immunophenotype
CD 10, 19, 20 (+) CD5 (-) BCL6 (+) -- anti-apoptotic BCL2 (+) normal follicular cells are normally devoid of this marker Surface Ig (+)
Clinical follicular
Presents in middle age as painless, generalized lymphadenopathy
Extra-nodal site involvement is uncommon
Incurable with waxing-waning course; survival is 7-9 years not improved by aggressive therapy
palliate the patient with low dose chemotherapy or immunotherapy (anti-CD20 antibody)
Transformation in 30-50% to diffuse large B-cell Lymphoma (usually) or Burkitt Lymphoma
Diffuse large B cell lymphoma BAD: patient at risk
Most common form of non-Hodgkin’s lymphoma
Median age: 60 years old (may also occur in young adults and children
Pathogenesis DLBCL
3q27 mutation (translocation or acquired) involving BCL6
BCL6 is required for formation of normal germinal centers – dysregulation of BCL6 == DLBCL
Overexpression of BCL6 inhibits germinal center B-cell differentiation, growth arrest and apoptosis
Other potential mutations
t(14;18) involving BCL2 (anti-apoptotic)
tumors with BCL2 rearrangements usually lack BCL6 rearrangements
this translocation is characteristic/pathognomonic for follicular lymphoma
MYC mutation
myc dysregulation == Burkitt Lymphoma
Histone acetyltransferase mutations (p300, CREBP)
large, destructive masses; extranodal involvement
this is a mature B cell neoplasm
Morphology DLBCL
Large cells (4-5X > normal lymphocytes)
Diffuse pattern of growth
Substantial morphologic variation
Commonly has a round-oval nucleus (vesicular in appearance)
Multiple (2-3) nucleoli (or single and centrally placed)
Cytoplasm: moderately abundant and pale or basophilic
More anaplastic tumors may contain multinucleated cells with inclusion-like nucleoli
DLBCL immunophenotype
CD 19, 20 (+)
Variable expression of CD10 and BCL6
Most have surface immunoglobulin
DLBCL location
Rapidly enlarging mass at nodal or extranodal site
May arise anywhere in the body
commonly Waldeyer ring (oropharyngeal lymphoid tissue including the tonsils and adenoids)
DLBCL == Waldeyer ring
Liver and spleen involvement leads to destructive masses
Extranodal is common: GI, skin, bone, brain
Bone marrow involvement is rare (late course
DLBCL clincial
aggressive tumors that are rapidly fatal without treatment
Treated: 60-80% complete remission, 40-50% cured
Adjuvant treatment with anti-CD20 antibody –> improved initial response and improved outcomes
Limited disease has better outcome than widespread disease or those with bulky tumor masses
Inhibition of NFκB and B cell receptor pathways is beneficial
MYC translocations have worse outcome and may be best treated similar to Burkitt lymphoma
myc dyregulation == Burkitt Lymphoma
Immunodeficiency associated large B cell lymphoma
Occurs with severe T-cell immunodeficiency (HIV or allogenic bone marrow transplant)
EBV infection of neoplastic B cells
May regress with restoration of T cell immunity
Primary effusion lymphoma DLBCL
Malignant pleural or ascitic effusion
Most common in patients with advanced HIV or who are elderly
Tumor cells infected with KSHV/HHV8 which appears to have a causal role – always associated with Kaposi’s
Anaplastic tumor cells that do not express B or T cell markers
Possess clonal immunoglobulin heavy chain gene rearrangements
Burkitt lymphoma
Burkitt Lymphoma == “Burkitt is Burk-EIGHT” [t(8;14)]
Definition
Most commonly affect kids and young adults
Highly associated with MYC translocations on chromosome 8 that leads to high MYC protein levels
MYC increases genes for aerobic glycolysis (Warburg effect) allowing cells to biosynthesize building blocks for growth and cell division, if glucose and glutamine are available – this is important
Burkitt Lymphoma == dysregulation of c-MYC
Three variants: African (endemic), sporadic (nonendemic), HIV associated
histologically identical, but different in some clinical, genotypic, and virologic characteristics
not ALL Burkitt lymphomas are EBV positive; All African (endemic) Burkitt lymphomas are though
aka Diffuse Small Non-Cleaved Lymphoma (Hubbard)
Pathogenesis burkitt
t(8:14) MYC/Ig heavy chain
May also be t(2:8) or t(8:22) for the light chains
chromosome 2 == kappa
chromosome 22 == lambda
chromosome 8 == MYC
chromosome 14 == IgH
Induced by AID in germinal center B cells
MYC overexpression, increased activity
Fastest growing human tumor – doubles in size every 36 hours
Infection with EBV precedes transformation
Morphology burkitt
Diffuse infiltrate of intermediate sized lymphoid cells
Round/oval nuclei, coarse chromatin, several nucleoli, moderate amount of cytoplasm
High mitotic index
Numerous apoptotic B cells – tingible body macrophage
“Starry sky” pattern due to phagocytosis of nuclear remnants by macrophages
If bone marrow is involved, tumor cells exhibit clumped nuclear chromatin, 2-5 nucleoli and royal blue cytoplasm with clear cytoplasmic vacuoles
Immunophenotype burkitt
CD 10, 19, 20 (+) BCL6 (+) Surface IgM (+) BCL2 (-) MYC (+) -- Burkitt Lymphoma is dysregulation of c-MYC
Burkitt clincial
30% of childhood non-Hodgkin’s lymphoma in the USA
Aggressive lymphoma
Responds well to chemotherapy
Children and young adults are usually cured
Older adults have more guarded outcome
Burkitt sporadic
Burkitt Lymphoma: Sporadic (nonendemic)
t(8:14)
Breakpoint on IgH locus is in the class switch region
15-20% of patients are latently infected with EBV
Mass of ileocecum and peritoneum – just GI
Burkitt african endemic
Burkitt Lymphoma: African (endemic)
t(8:14)
Breakpoint on IgH locus is in the 5’ V(D)J sequence
All patients are latently infected with EBV
Mass of mandible/face and/or abdominal viscera (kidneys, ovaries, adrenals)
Bone marrow or peripheral blood involvement is rare
Burkitt lymphoma HIV
t(8;14)
25% of patients are latently infected with EBV
Plasma cell neoplasma(dyscrasias)
Most common plasma cell dyscrasia == Monoclonal Gammopathy of Uncertain Significance (MGUS)
most common plasma cell malignancy == multiple myeloma
Cells secrete monoclonal Ig (serve as tumor markers)
Will commonly see plasma cell clusters, they don’t normally present in clusters
M component: a monoclonal Ig in the blood
Restricted to plasma due to high molecular weight
not seen in urine unless glomerular damage has occurred
neoplastic plasma cells often synthesize excess light chains along with complete immunoglobulins
light chains are small in size and excreted in the urine (Bence-Jones proteins)
One light chain is increased others are low
15% of deaths due to lymphoid neoplasms
Monoclonal gammopathy
Monocolonal gammopathy
Heavy chain disease == rare monoclonal gammopathy that is seen in association with a diverse group of disorders including lymphoplasmacytic lymphoma and an unusual small bowel marginal zone lymphoma that occurs in malnourished populations (so-called Mediterranean lymphoma)
common feature == synthesis and secretion of free heavy chain fragments
Multiple myeloma
Multiple Myeloma (plasma cell myeloma) == the most common plasma cell neoplasm
Definition
causes bony destruction of the skeleton and often presents with pain due to pathologic fractures
Plasma cell neoplasm that commonly causes tumorous masses throughout the skeletal system
“moth eaten”
lytic bone lesions, hypercalcemia, renal failure, and acquired immune problems
Multiple myeloma patients
Male
African descent
Peak incidence: 65-70 years old – disease of older adults
Multiple myeloma variants
Solitary myeloma: single mass in bone or soft tissue
Smoldering myeloma: lack of signs and symptoms with high plasma M component
does not exhibit lytic bone lesions
Multiple myeloma pathogenesis
athogenesis Frequent IgH (heavy chain) rearrangements Translocated with cyclin D1 and D3: good prognosis Poorer prognosis Deletion of chromosome 13q Deletion of chromosome 17p (TP53) t(4;14) MYC acquisition NFκB promoting B-cell survival high levels of IL-6
Growth and survival multiple myeloma
Growth and survival
IL-6 is important for growth of plasma cells, produced by neoplastic plasma cells and resident marrow stromal cells (higher levels = poor prognosis)
Bone destruction is mediated by factors produced by neoplastic cells
MIP1α upregulates NFκB ligand (RANKL) activating osteoclasts
Osteoblasts are inhibited via Wnt pathway
increased bone resorption → hypercalcemia and pathologic fractures
Morphology multiple myeloma
Destructive plasma cell tumors (plasmacytomas) involving the axial skeleton
Vertebral column, ribs, skull, pelvis, femur, clavicle, scapula
Appear as 1-4cm punched-out defects radiographically
Soft, gelatinous, red tumor masses
Can also present as widespread myelomatous bone disease that causes diffuse demineralization (osteopenia) instead of focal defects (i.e. pathologic fractures
Morphology neoplastic plasma cells
Increased number of plasma cells in the marrow with perinuclear clearing due to large Golgi apparatus and odd placed nucleus
Rouleaux formation: high level of M proteins causes RBCs in blood smears to stick together linearly
characteristic/indicative but not specific – seen whenever immunoglobulin levels are elevated
Flame cells: intracellular accumulation of degraded protein with fiery red cytoplasm
Mott cells: multiple grapelike cytoplasmic droplets
Cells containing inclusions of fibrils, crystalline rods and globules
Globular inclusions: Russell bodies (cytoplasmic) or Dutcher bodies (nuclear)
Dutch == nuclear families
Immunophenotype multiple myeloma
CD138 (+) (aka syndecan-1)
May be CD56 (+)
Signs ANS symptoms multiple myeloma
Effects of plasma cell growth in tissues (bones)
Production of excess immunoglobulin
Suppression of normal humoral immunity
Clincial sequelae multiple myeloma
Pathologic fracture and chronic pain due to resorption
Hypercalcemia –> Neurologic signs and symptoms (confusion, weakness, lethargy)
stones, bones, groans, and psychiatric moans + shortened QT
Renal failure (second biggest cause of death after infections)
myeloma kidney
Acquired immune abnormalities
Recurrent bacterial infection (most common cause of death)
Cellular immunity is unaffected
Bence jones proteinuria
Excreted light chains are toxic to renal tubular epithelial cells –> myeloma kidney –> renal failure/insufficiency (second most common cause of death in multiple myeloma, after infection)
Some (λ3, λ6) may be prone to amyloidosis of the AL type
primary or immunocyte-associated amyloidosis results from a monoclonal proliferation of plasma cells secreting light chains (usually of the λ isotype) that are deposited as amyloid
Increased immunoglobulins (especially IgG) and/or light chains in the plasma & urine
most multiple myelomas are IgG with kappa light chains - ???
Monoclonal immunoglobulins M proteins: IgG (55%), IgA (25%)
Excessive production and aggregation of M proteins, especially IgA or IgG3 –> hyperviscosity
Waldenström macroglobulinemia == a syndrome in which high levels of IgM lead to symptoms related to hyperviscosity of the blood; occurs in older adults; associated with lymphoplasmacytic lymphoma
IgA or IgG3->hyperviscosity
Waldenström macroglobulinemia == a syndrome in which high levels of IgM lead to symptoms related to hyperviscosity of the blood; occurs in older adults; associated with lymphoplasmacytic lymphoma
Marrow involvement
Diagnosis requires bone marrow examination
Marrow involvement often gives rise to a normocytic, normochromic anemia +/- moderate leukopenia and thrombocytopenia
Treatment
survival is 4-7 years; no cure
Proteasome inhibitors: Degrade unwanted proteins (cells are prone to accumulation of misfolded, unpaired immunoglobulin chains). Induce cell death and retard bone resorption (through stromal cells)
also thalidomide
Bisphosphonates inhibit bone resorption; reduce the amount of pathologic fractures but can exacerbate renal complications of disease; ensure patient is adequately hydrated; follow creatinine
HSC transplant prolongs life but is not curative
Solitary myeloma
Solitary lesion of bone or soft tissue
Bone lesion in same locations as multiple myeloma → multiple myeloma in 10-20 years even if it is resected
solitary osseous plasmacytoma almost inevitably progresses to multiple myeloma
extraosseous lesions in lungs, oronasopharynx or nasal sinuses → cured by local resection
Modest increase in M proteins in blood or urine
Smoldering myeloma
Middle ground between multiple myeloma and Monoclonal Gammopathy of Uncertain Significance (MGUS)
Plasma cells are 10-30% of marrow cellularity
Elevated serum M protein > 3gm/dl (same level as in multiple myeloma, but no signs and symptoms)
patients are asymptomatic
75% progress (unpredictably) to multiple myeloma in 15 years
Monoclonal gammopathy of uncertain significance
Most common plasma cell disorder/dyscrasia
most common plasma cell neoplasm/malignancy == multiple myeloma
3% of people > 50
5% of people > 70
Asymptomatic patients with small to moderately large M components in their blood (< 3g/dl)
low but constant rate of transformation to symptomatic monoclonal gammopathies
most often multiple myeloma
1% of patients progress to symptomatic plasma cell neoplasm every year
May be a precursor to multiple myeloma as many of the same chromosomal aberrations are present (unpredictable)
monitor Bence-Jones Proteinuria and serum levels of M component to trend and predict transformation
Multiple myeloma
Elevated m component
Symptoms
Smoldering myeloma
Elevated m component
No sym[toms
MGUS
No m component
No symptoms
Lymphoblastic lymphoma
Definition
B-cell neoplasm of older adults (6-7th decade)
Substantial fraction of the tumor cells undergo terminal differentiation to plasma cells
how it differs from CLL/SLL
Can cause hyperviscosity (Waldenström macroglobulinemia)
Waldenström macroglobulinemia == a syndrome in which high levels of IgM lead to symptoms related to hyperviscosity of the blood; occurs in older adults; associated with lymphoplasmacytic lymphoma
Rarely does damage from secretion of light chains or bone destruction occur
Pathogenesis lymphoplasmacytic lymphoma
Acquired MYD88 mutation
Normally codes a protein that activates NFκB and augments signals downstream of the B-cell receptor (Ig) complex (aka it promotes the growth and survival of tumor cells
Morphology lymphoplasmacytic lymphoma
Marrow infiltrate of lymphocytes, plasma cells and plasmacytoid lymphocytes
Mast cell hyperplasia
Russell bodies: PAS (+) inclusions with Ig in the cytoplasm
Dutcher bodies: PAS (+) inclusions with Ig in the nucleus
Dutch == nuclear families
Dutcher and Russell bodies only seen in plasma cell dyscrasias
At diagnosis: tumor spread to lymph nodes, spleen and liver
Nerve Roots, meninges and brain may be affected with progression
Immunophenotype lymphoplasmacytic lymphoma
CD20 (+)
Surface Ig (+)
Plasma cells will secrete the same Ig that is expressed on the surface of the lymphoid cells
Usually IgM (may be IgG or IgA)
Clinical lymphoplasmacytic lymphoma
Nonspecific signs and symptoms: weakness, fatigue, weight loss
lymphadenopathy and hepatosplenomegaly in 50%
10% have autoimmune hemolysis due to cold agglutinins (IgM binding RBCs at T < 37°C)
No bone lesions
Waldenstrom macroglobunemia
Waldenström macroglobulinemia == a syndrome in which high levels of IgM lead to symptoms related to hyperviscosity of the blood; occurs in older adults; associated with lymphoplasmacytic lymphoma
IgM secreting tumors cause a hyperviscosity syndrome
retinopathy
neuro symptoms: HA to seizures and coma
spontaneous bleeding
Plasmapheresis alleviates signs and symptoms of increased IgM
Visual impairment due to venous congestion
Retinal vein tortuosity and distention +/- retinal hemorrhage and exudates
Neurological problems due to sluggish blood flow: headache, dizziness, deafness, and stupor
Bleeding due to macroglobulin-clotting factor complex formation and effects on platelet function
Cryoglobulinemia due to precipitation of macroglobulins at low Temperature == Raynaud phenomena and cold urticaria
cold agglutinin antibodies (IgM
Treatment
Incurable, progressive disease that rarely progresses to large cell lymphoma
Low dose chemotherapy and immunotherapy (antiCD20) may control tumor growth for a period of time
Median survival of 4 years
Mantle cell lymphoma
Uncommon non-Hodgkin’s lymphoma
tumor cells closely resemble the normal mantle zone B cells that surround germinal centers
Patients at risk mantle cell lymphoma
Presents in 5-6th decade
male predominance
Pathogenesis MCL
t(11:14) cyclin D1/IgH –> overexpression of cyclin D1 promotes G1 to S phase progression
IgH genes lack somatic hypermutation (== naïve B cell origin
MCL tumor location
Generalized painless lymphadenopathy, +/- peripheral blood involvement
Extranodal sites: bone marrow, spleen, liver, gut
Lymphomatoid polyposis: if mucosal involvement of the small bowel or colon → polyps (can be misdiagnosed as ulcerative colitis)
mantle cell lymphoma frequently presents in the GIT
Morphology MCL
Nodular appearance or diffusely efface the lymph node
Homogenous population of small lymphocytes with irregular/clefted (cleaved) nuclei
Condensed nuclear chromatin, inconspicuous nucleoli and scant cytoplasm
No centroblasts or proliferation centers (distinguished from CLL/SLL)
Requires immunophenotyping to distinguish blastoid variants from ALL
Can look like follicular lymphoma
Follicular lymphoma don’t have a germinal center
Mantel cell lymphoma will have a germinal center
MCL immunophenotype
Immunophenotype
Increased cyclin D1
CD 5, 19, 20 (+)
CD 23 (-) == distinguished from CLL/SLL
Elevated levels of surface Ig (usually IgM and IgD with κ or λ light chain)
IgH lacks somatic hypermutation (origin = naive B cell)
MCL clincal
Painless lymphadenopathy
Spleen and gut involvement are common – mantle cell lymphoma frequently presents in the GIT
Poor prognosis
Median survival: 3-4 years
COD: organ dysfunction due to lack of effective chemo and tumor infiltration
Blastoid variant and “proliferative” expression –> decreased survival
MCL treatment
Chemo is not helpful
HSC and proteasome inhibitors are now being used with potential
Marginal zone lymphoma
Heterogenous group of B-cell tumors in lymph nodes, spleen, or extranodal tissue
Tumor cells show evidence of somatic hypermutation (== memory B-cell origin)
marginal zone lymphoma and hairy cell leukemia are memory B-cell origin
Often referred to as MALTomas
Extranodal sites and 3 special characteristics
Arise in tissues affected by chronic inflammation (autoimmune or infectious)
i.e. Sjogren’s (salivary glands), Hashimotos (thyroid) and stomach (H. Pylori)
Remain localized for long periods of time, but may spread late in their course
May regress if the inciting agent (i.e. Helicobacter) is eliminated – cure cancer with antibiotics!
Lies on a spectrum of reactive lymphoid hyperplasia and full-blown lymphoma
Pathogenesis marginal zone lymphoma
Initially: polyclonal immune reaction that acquires mutations → B-cell clone that depends on Ag stimulated Th cells (eventually becomes monoclonal)
Withdrawal at this stage = involution of tumor
Additional mutations acquired over time renders growth and survival to be Ag independent
t(11:18), t(14:18) or t(1:14) which leads to activation of NFκB and promotes cell growth/survival
t(11:18), t(14:18) or t(1:14) are specific for extranodal marginal zone lymphomas (MALTomas)
upregulate the expression and function of BCL10 or MALT1 –> NFκB –> growth and survival
Further evolution = metastasis and transformation to large B-cell lymphoma
Hairy cell leukemia
Rare B-cell neoplasm that has hair-like projections coming out of the leukemic cells – hence, “hairy cell”
marginal zone lymphoma and hairy cell leukemia are memory B-cell origin
Patients at risk
Middle age (55), white males (males 5:1)
Pathogenesis
BRAF (serine/threonine kinase) activating mutation (valine → glutamate)
BRAF is positioned immediately downstream of RAS in the MAPK signaling cascade
Morphology hairy cell leukemia
Leukemic cells have fine, hair-like projections
Round, oblong or reniform (kidney shaped) nuclei
Moderate amounts of pale blue cytoplasm with bleb-like extensions
“Dry tap” because tumor cells are trapped in the ECM
Only seen on marrow biopsy
Heavily infiltrated splenic red pulp = obliteration of white pulp with a beefy red gross appearance
Hepatic portal triads may be involved
Hairy cell leukemia immunophenotype
CD 11c, 19, 20, 25, 103 (+)
annexin A1 (+)
Surface Ig (IgG) +ve
tartrate-resistant acid phosphatase (TRAP) +ve
Clincial hairy cell leukemia
Massive splenomegaly (hepatomegaly and lymphadenopathy are rare)
many patients will present with splenomegaly (dragging sensation in the LUQ)
Pancytopenia (from marrow involvement and splenic sequestration (hypersplenism)
1/3 have infection (often atypical mycobacterial)
increased susceptibility to mycobacterium kansasii
Exceptionally sensitive to gentle chemotherapy = long lasting remission
Relapse in 5 years but respond well to re-treatment with the same agents
BRAF inhibitors = excellent tumor response in patients who fail chemotherapy
Excellent prognosis
A 49-year-old man has had increasing fatigue for the past 4 months. On physical examination he has massive splenomegaly but no lymphadenopathy. Laboratory studies show a Hgb of 10.1 g/dL, Hct 30.3%, MCV 90 fL, WBC count 1600/microliter, and platelet count 48,000/microliter. Examination of his peripheral blood smear shows increased numbers of peripheral blood lymphocytes containing tartrate-resistant acid phosphatase (TRAP). Which of the following is the most likely diagnosis
Hairy cell leukemia is trap positive
Peripheral T cell lymphoma, unspecified
Derived from mature T cells so it has T-cell markers
diagnosis of exclusion
Immunophenotype peripheral T cell lymphoma
CD2+, CD3+, and CD5+
some may be CD4+ or CD8+
either αβ or γδ TCRs
requires immunophenotyping
Morphology peripheral T cell lymphoma
Tumors efface lymph nodes diffusely
Pleomorphic mix of variably sized malignant T-cells
Prominent infiltrate of reactive cells (eosinophils, macrophages) attracted by tumor cytokines
Neoangiogenesis may be seen
Clincial peripheral T cell lymphoma, unspecified
Present with general lymphadenopathy +/- pruritus, eosinophilia, fever, weight loss
Cure is rare, worse prognosis than comparably aggressive B cell neoplasms
Anaplastic large cell lymphoma
T-cell lymphoma with good prognosis
Pathogenesis ALK+ anaplastic large cell lymphoma
ALK rearrangement on chromosome 2p23 –> break the ALK locus and lead to formation of chimeric genes encoding ALK fusion proteins, constitutive active tyrosine kinases that trigger RAS and JAK/STAT pathways
ALK is not expressed in normal lymphocytes therefore the detection of ALK in tumor cells is a reliable indicator of an ALK gene rearrangement – presence of ALK is pathognomonic
Immunophenotype anaplastic large cell lymphoma alk+
CD30 positive
CD8 cell is anaplastic
Morphology anaplastic large cell lymphoma
Large anaplastic cells with horseshoe nuclei and voluminous cytoplasm (“hallmark cells”)
Tumor cells surround venules, infiltrating lymphoid sinuses (mimic metastatic carcinoma
Clinical anaplastic large cell lymphoma alk+
More common in children and young adults
Involve soft tissue == very good prognosis
Chemotherapeutic cure = 75-80%
ALK (-) tumors in older adults have a worse prognosis
Recombinant anti CD30 antibodies have produced promising responses in patients
Adult T cell leukemia/lymphoma atll
Neoplasm of CD4+ T-cells
patients are infected with HTLV-1
Common in Japan, West Africa and the Caribbean
Pathogenesis adult T cell leukemia/lymphoma atll
Virus produces Tax protein that activates NFκB
Morphology atll
Morphology
Cells have multi-lobulated nuclei (“cloverleaf” or “flower” cells) and contain clonal HTLV1 proteins
Clincial atll
Skin lesions, general lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, hypercalcemia
HTLV-1 can also cause a progressive demyelinating disease of the CNS and spinal cord
Prognosis atll
Rapidly progressive disease, fatal in months to 1 year despite aggressive chemotherapy
If only skin is involved (rare), disease has a more indolent course
My oasis fungoides
Tumor of CD4+ helper T-cells that homes to the skin
Cutaneous lesions progress through three phases: premycotic, plaque, and tumor
Epidermis and upper dermis are infiltrated by neoplastic T cells with a cerebriform appearance
due to nuclear membrane infolding
Late disease progresses extracutaneously, commonly to lymph nodes and bone marrow
Mycosis fungoides (with no relationship to fungi) is one form of cutaneous T-cell lymphoma. The abnormal CD4 cell proliferation is infiltrating the skin and producing erythroderma. If these neoplastic cells circulate, it is known as Sezary syndrome
Sezary syndrome
Tumor of CD4+ helper T-cells that homes to the skin
Rarely progresses to tumefaction
Generalized exfoliative erythroderma
Associated leukemia of cells with characteristic cerebriform nuclei
Mycosis fungoides and sezary syndrome==tumor of cd4 helper T cells that homes to the skin
CLA (+) *cutaneous leukocyte antigen
CCR4 and CCR10 (+) – chemokine receptors
Homes to skin
Tumor cells circulate through the blood, bone marrow, and lymph nodes
Indolent tumors
Median survival of 8-9 years
Occasionally transforms to aggressive T-cell lymphoma (terminal event)
Large granular lymphocytic leukemia variants and immunophenotype
T-cells variant (indolent): CD3 (+)
NK cells variant (subtler, common, aggressive): CD56 (
Morphology large granular lymphocytic leukemia
STAT3 mutation
Large lymphocytes with abundant blue cytoplasm and azurophilic granules
Sparse lymphocytic infiltrates in the marrow, spleen and liver
Clincial large granular lymphocytic leukemia
Clinical
Neutropenia and anemia dominate the clinical picture (despite low marrow involvement)
neutropenia –> striking decrease in late myeloid forms in the marrow
Mild-moderate lymphocytosis and splenomegaly of adults
No lymphadenopathy or hepatomegaly
Increased incidence of rheumatoid disorders – autoimmunity provoked by the tumor seems likely
Variable course based on cytopenias and their response to low dose chemo or steroids
Felty syndrome
Felty Syndrome == rheumatoid arthritis + Splenomegaly + Neutropenia
*associated with large granular lymphocytic leukemia as an underlying cause
Extranodal nk/t cell lymphoma
Extranodal NK/T-cell Lymphoma (nee lethal midline granuloma disorder)
Definition
Destructive nasopharyngeal mass
extra-nodal == extra-nosal
May also be seen in the testis and skin
Surrounds and invades small vessels = ischemic necrosis
More common in Asia
Tumor originates from a single *EBV-infected cell
Morphology extranodal nk/t cell lymphoma
Large azurophilic granules in tumor cell cytoplasm
small to large pyknotic cells cuffing and invading small vessels with ischemic necrosis
Immunophenotype extranodal nk/t cell
No CD21 (B-cell EBV receptor) implication is that EBV has other receptors associated with it that are not CD21 No CD3 No TCR rearrangements Express NK cell markers
Clincal extranodal nk/t cell lymphoma
Highly aggressive; respond well to radiation; resistant to chemotherapy
Poor prognosis in patients with advanced disease
Hodgkin lymphoma
Often localized to a single, axial group of lymph nodes (cervical, mediastinal, para-aortic, axillary, groin)
Hodgkin Lymphoma arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissues
Mesenteric lymph nodes and Waldeyer ring rarely involved
Extranodal presentation is rare
Presence of Reed-Sternberg cells: transformed B cells
fever!
Non Hodgkin lymphoma
non-Hodgkin Lymphoma vs Hodgkin Lymphoma
non-Hodgkin Lymphoma has:
Frequent involvement of multiple peripheral lymph nodes
Noncontiguous spread (not predictable)
Waldeyer ring and mesenteric lymph nodes commonly involved
Extranodal presentation common
Hodgkin
efinition
average age: 32
treated with radiation and chemotherapy, curable in most cases
Need to see Reed-Sternberg cells on a background of non-neoplastic inflammatory cells
5 subtypes of Hodgkin
Nodular sclerosis (classic) Mixed cellularity (classic) Lymphocyte rich (classic) Lymphocyte depleted (classic) Lymphocyte predominance: Reed-Sternberg cells have distinctive B-cell immunophenotype
Classical Hodgkin
Classical: frequently associated with acquired mutations that activate NFκB and with EBV infection
Lymphocyte Predominant: express B-cell markers and is not associated with EBV infection
Hodgkin lymphoma diagnosis
Di agnosis:
depends on the identification of Reed-Sternberg cells in a background of non-neoplastic inflammatory cells
Pathogenesis s
Pathogenesis
Ig genes have undergone V(D)J recombination and somatic hypermutation, but fail to be expressed
NFκB activation
NFKB activation hodgkin
EBV infection (or other mechanism promoting lymphocyte survival and proliferation) EBV+ cells have LMP1 = upregulation of NFκB Acquired loss-of-function mutations in IκB or A20 (both negative regulators of NFκB) Rescue of "crippled" germinal centers by EBV creates an environment of acquisition of other mutations --> Reed-Sternberg cells
Reed sternberg cells
Reed-Sternberg Cells == “Owl-Eyed Nuclei”
Definition
Derived from germinal center or post-germinal center B-cells
Reed-Sternberg cells are transformed B cells
despite having the genetic signature of a B-cell, the Reed-Sternberg cells of classical Hodgkin Lymphoma fail to express most B-cell specific genes, including the immunoglobulin genes
Release factors (cytokines, chemokines, etc.) inducing accumulation of reactive lymphocytes, macrophages, and granulocytes (> 90% of tumor cells)
Morphology reed sternberg cells
Large, aneuploid B cells with multiple nuclei or a single nucleus with multiple lobes and inclusion-like nucleolus == Owl-Eyed Nuclei
Clearing around the nucleoli; abundant cytoplasm is seen
background lymphocytes will be reactive
Immunophenotype
REL protooncogene (chromosome 2p) often gained that increase NFκB
CD15, CD30, and CD40 positivity (activated via eosinophils and T-cells)
Immunoglobulin (-)
Mononuclear variants
Contain a single round or oblong nucleus with large inclusion like-nucleolus
Lacunar variants
Seen in nodular sclerosis subtype
Delicate, folded or multilobate nuclei
Abundant pale cytoplasm that retracts during tissue processing = nucleus in an empty hole (a lacuna)
Seen in the nodular sclerosis type of Hodgkin Lymphoma
Mummification
Mummification: the process by which the Reed-Sternberg cells die
The cells shrink and become pyknotic
Lymphohistiocytosic variants
Lymphohistiocytic Variants (L&H cells) Polypoid (multilobed) nuclei Inconspicuous nucleoli Moderate cytoplasm "Popcorn cells" Seen in the lymphocyte predominant subtype of Hodgkin Lymphoma Express CD20, BCL6 No CD15 or CD30
HODGKIN LYMPHOMA CLASSIC immunophenotype
Classic Immunophenotype
PAX5 positive
CD15 and CD30 positive
except lymphocyte predominant
No other B-cell, T-cell markers, or CD45 (leukocyte common antigen)
Hodgkin Lymphoma does not present in extranodal locations
Hodgkin lymphoma nodular sclerosis subtype
Most common form of Hodgkin Lymphoma (65-70%)
Adolescents and young adults
Excellent prognosis
Morphology nodular sclerosis subtype
Lacunar variant Reed-Sternberg cells that are uncommonly found == lacunar cells
Deposition of collagen bands that divide lymph nodes into circumscribed nodules
Often involves cervical, supraclavicular and mediastinal lymph nodes
No EBV
Classic immunophenotype
PAX5 positive
CD15 and CD30 positive
No other B-cell, T-cell markers, or CD45 (leukocyte common antigen
Mixed cellularity subtype
Second most common subtype Male predominance Biphasic age distribution Signs and symptoms include night sweats and weight loss Commonly present in advanced tumor stage Prognosis is very good
Morphology hodgkin
Diagnostic Reed-Sternberg cells and mononuclear variants are plentiful
lymph nodes are diffusely effaced
70% of Reed-Sternberg cells are EBV+
Classic immunophenotype
PAX5 positive
CD15 and CD30 positive
No other B-cell, T-cell markers, or CD45 (leukocyte common antigen
Hodgkin lymphoma lymphocyte rich rubtype
Reactive lymphocytes make up the vast majority of the cellular infiltrate
Uncommon
lymph nodes are diffusely effaced with vague nodularity due to occasional residual B-cell follicles
Very good to excellent prognosis
Morphology lymphocyte rich subtype
Frequent mononuclear variants Diagnostic Reed-Sternberg cells 40% of cases are EBV+ Classic immunophenotype PAX5 positive CD15 and CD30 positive No other B-cell, T-cell markers, or CD45 (leukocyte common antigen
Definition lymphocyte depletion subtype
Least common form of Hodgkin Lymphoma
Elderly, HIV+ individuals, non-industrialized countries
Advanced stage and systemic signs and symptoms are frequent
Prognosis is less favorable than other subtypes
Morphology lymphocyte depletion subtype
Scarce lymphocytes
Abundant Reed-Sternberg cells or pleomorphic variants
EBV+ in 90% of cases
Classic immunophenotype
PAX5 positive
CD15 and CD30 positive
No other B-cell, T-cell markers, or CD45 (leukocyte common antigen)
Essential to do immunophenotype, as most tumors with lymphocyte depletion are actually large cell non-Hodgkin Lymphoma
Lymphocyte predominance subtype
Nonclassical Hodgkin Lymphoma subtype
Male < 35 years have cervical or axillary lymphadenopathy
Excellent prognosis, even though it is more likely to recur as compared to the other subtypes
lymph nodes are effaced with a nodular infiltrate of small lymphocytes and macrophages
Immunophenotype lymphocyte predominance subtype
munophenotype: L&H variants express B-cell markers in contrast to Reed-Sternberg cells from classical forms of Hodgkin Lymphoma
Express CD20, BCL6 (unique)
CD15 and CD30 negative
Morphology lymphocyte predominance subtypes
Not associated with EBV
IgH genes have ongoing somatic hypermutation – a feature found only in germinal centers
35% transform to diffuse large B-cell lymphoma due to expanded B-cell follicles
Classic Reed-Sternberg cells are difficult to find
L&H variant cells “popcorn cells” are seen
Eosinophils and plasma cells are scant or absent
Nodular sclerosis or lymphocyte predominant subtypes clincial
Typically stage I-II = free of systemic manifestations
90% cure rate
Mixed cellularity or lymphocyte depletion or disseminated disease clincial
Stage III-IV → constitutional signs and symptoms
5 year survival 60-70%
Anergy (cutaneous immune unresponsive)
TH1 suppression due to factors released by Reed-Sternberg cells
Hodgkin lymphoma progression
Generally presents as painless lymphadenopathy
spread is stereotyped: nodal disease → splenic disease → hepatic disease → marrow and other tissues
Prognosis hodgkin lymphoma
Tumor stage (not histology) is most important prognostic factor
Low stage 1st cured with involved field radiotherapy: increased risk of radiotherapy induced malignancies (lung cancer, melanoma, breast cancer)
2° tumors reduced by using minimal radiation and less genotoxic chemo without loss of therapeutic efficacy
AntiCD30 antibodies produce excellent response in patients failing conventional methods
wouldn’t work in Lymphocyte Predominant subtype as this is CD30 negative
Stage I
Hodgkin Lymphoma: Stage I
Involvement of a single lymph node region (I)
Involvement of a single extra-lymphatic organ or site (IE)
Hodgkin II
Hodgkin Lymphoma: Stage II
Involvement of 2+ lymph node regions on the same side of the diaphragm alone (II)
Localized involvement of an extra-lymphatic organ or site (IIE)
Hodgkin III
Hodgkin Lymphoma: Stage III
Involvement of lymph nodes on both sides of the diaphragm without (III) or with (IIIE) localized involvement of an extra-lymphatic organ or site
Hodgkin IV
Hodgkin Lymphoma: Stage IV
Diffuse involvement of one or more extra-lymphatic organs or sites +/- lymphatic involvement
Acute myeloid leukemia
a: accumulation of immature myeloid forms (blasts) in the bone marrow suppresses normal hematopoiesis
Myelodysplastic syndromes
D efective maturation of myeloid progenitors gives rise to ineffective hematopoiesis, leading to cytopenias; group of clonal stem cell disorders characterized by maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to AML
generally have a poor prognosis
Myeloproliferative disorders
Myeloproliferative disorders: there is usually increased production of one or more types of blood cells
AML
Definition
Accumulation of at least 20% or > immature myeloid blasts in the bone marrow due to acquired oncogenic mutations impeding differentiation
Causes marrow failure
Complications: anemia thrombocytopenia, neutropenia
Increased incidence throughout life, peak after 60 years old
Diagnosis is confirmed with myeloid specific antigen stains (i.e. MPO)
diagnosis of AML is based on the presence of at least 20% myeloid blasts in the bone marrow
Two most common chromosomal rearrangements == t(8:21) and inv(16)
t(8;21) == RUNX1 disrupted
inv(16) == CBFB disrupted
RUNX1 and CBFB normally bind one another to form a RUNX1/CBF1β transcription factor that is required for normal hematopoiesis
Class I
Genetic aberrations with favorable prognosis
t(8:21) == RUNX1 disrupted
inv(16) == CBFB disrupted
Normal cytogenetics, mutated NPM
Genetic aberrations with intermediate prognosis: t(15:17) – acute promyelocytic leukemia (subtype)
Genetic aberrations with poor prognosis: t(11:q23:v)
Class II
AML with MDS-like features (myelodysplastic syndrome) Prior MDS Multi-lineage dysplasia MDS-like cytogenic aberrations All have poor prognosis
Class III
AML that is therapy related
Post alkylating agent or radiation therapy = 2-8 year latency, MDS-like cytogenic aberrations
Post topoisomerase II inhibitor = 1-3 year latency, MLL translocations
Very poor prognosis
Class IV
ass IV
All AML’s that lack features of the other classes (NOS)
Classified based on degree of differentiation and lineage of leukemic blasts
Intermediate prognosis
AML FAB class MO
Minimally differentiated AML
2-3% of cases
Blasts lack cytologic and cytochemical markers of myeloblasts
Express myeloid lineage antigens and ultra-structurally resemble myeloblasts
AML FAB class M1
AML without maturation 20% of cases Very immature cells ≥ 3% are MPO (+) Few granules or Auer rods Little maturation past myeloblast stage
AML FAB class M2
AML with myelocytic maturation M2 == AML M3 == APL (P and 3) M4 = AMML (has four letters) 30-40% of cases Full range of myeloid maturation throughout granulocytes Auer rods present in most cases t(8:21
AML FAB class M3
Acute promyelocytic leukemia (APL) M2 == AML M3 == APL (P and 3) M4 = AMML (has four letters) 5-10% of cases Most cells are hypergranular promyelocytes Many Auer rods /cell Patients are younger (35-40 years old) increased incidence of DIC t(15:17) with Flt3
AML FAB class M4
AML: FAB Class M4
AML with MyeloMonocytic maturation (Acute MyeloMonocytic Leukemia (AMML)
M2 == AML
M3 == APL (P and 3)
M4 = AMML (has four letters)
15-20% of cases
Myelocytic and monocytic differentiation is evident
Myeloid elements with range of maturation
MPO positive
Monoblasts are positive for non-specific esterase
non-specific esterase is non-specific; positivity only tells you that there are monocytes present
diagnostic in the setting of AML; non-specific anywhere else
Inv(16
AML FAB class M5 a/b
AML with monocytic maturation (acute monocytic leukemia)
10% of cases
Monoblasts: MPO (-), non-specific esterase positive
Promonocytes
Older patients
High incidence of organomegaly, lymphadenopathy and tissue infiltration
AML FAB class M6 a/b
AML with erythroid maturation (acute erythroleukemia)
Dysplastic erythroid precursors (megaloblastoid or multiple nuclei) dominate
Nonerythroid cells = >30% myeloblasts
Elderly patients
*20% of therapy related AML
AML FAB class M7
AML with megakaryoblastic maturation (acute megakaryocytic leukemia)
Blasts of megakaryocytic lineage predominate
Blasts react with platelet specific antibodies (GPiib/iiia or vWF)
Myelofibrosis or increased reticulin
Pathogenesis
Genetic aberrations disrupt genes encoding transcription factors required for normal myeloid differentiation
t(8:21) RUNX1, inv(16) CBFB which lead to blocking of myeloid cell maturation
Mutations activating GF signaling pathways
t(15:17) → PML-RARα fusion protein interferes with terminal differentiation of granulocytes
treatment: all-trans retinoic acid or arsenic trioxide (chapter 7)
t(15;17) == acute promyelocytic leukemia subtype of AML
may exhibit early, significant, life-threatening bleeding
DIC, once established, is often fatal
also have frequent activating mutations of FLT3 mutation (receptor tyrosine kinase)
Epigenetic alterations: DNA methylation and posttranslational modification of histones is altered
Morphology
Diagnosis is made by > 20% myeloid blasts in the bone marrow
Myeloblasts
Monoblasts
Megakaryoblast
Erythroblast
*blasts may be entirely absent from the blood (aleukemic leukemia), hence a bone marrow examination is essential (especially in pancytopenic patients
Myeloblast morphology
Delicate nuclear chromatin
2-4 nucleoli
Voluminous cytoplasm (more than lymphoblasts)
Peroxidase (+) azurophilic granules
Auer rods: distinctive needle like azurophilic granules
particularly numerous in AML with the t(15:17) (acute promyelocytic leukemia)
Auer rods are formed of the cytoplasmic granules of the myeloid blasts of acute myelogenous leukemia (AML) and are a typical finding with AML. Myelodysplastic syndromes can precede development of AML, as can some cases of myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria, and chemotherapeutic regimens
Monoblast morphology
onoblast morphology Folded or lobulated nuclei Lack Auer rods Nonspecific esterase (+) Peroxidase (-)
Cytogenetics based on clincial scenario
Younger adults: Balanced translocations t(8:21), inv(16), and t(15:17)
Following MDS or chemo or radiation: Deletions or monosomy of chromosome 5 or 7 with a lack of translocations
Following topoisomerase II inhibitors: MLL translocation chromosome 11q23
Older adults: Worse aberrations (deletion of 5q, 7q)
Clincal presentation
Signs and symptoms very similar to ALL
Anemia, fatigue, neutropenia.
Fever due to opportunistic infections of oral cavity, skin, lungs, kidneys, bladder, colon (fungi, Pseudomonas, commensals)
Thrombocytopenia = spontaneous mucosal and cutaneous bleeding (gingiva, urinary tract); cutaneous petechiae and ecchymoses; exacerbated by procoagulants and fibrinolytics released by leukemic cells (especially in AML with the t(15;17
Tumor location
Signs and symptoms due to involvement of tissues other than bone marrow is less striking than in ALL
CNS involvement is less common
Often infiltrate the skin (leukemic cutis) and gingiva
May present as a localized soft-tissue mass (myeloblastoma, granulocytic sarcoma/chloroma)
Without systemic treatment these will progress to full-blown disease
Prognosis
60% remission with chemotherapy
5 years: 70-85% relapse
Molecular subtype targeted therapy improves outcomes
80% of t(15:17) are cured with all-trans retinoic acid and arsenic salts
t(8:21), inv(16) without KIT mutation = good prognosis with chemotherapy
AMLs that follow MDS or genotoxic therapy, in older adults, or returned AML = dismal prognosis
HSC transplant is performed with these “high-risk” disease
Myelodysplastic syndromes are more severe than myeloproliferative
MDS generally have a poor prognosis
Myelodysplastic syndromes
Clonal stem cell disorders with maturation defects associated with ineffective hematopoiesis
Increased risk of transformation to AML
Bone marrow is partly or wholly replaced by clonal progeny of a neoplastic multipotent stem cell with the capacity to differentiate (but does so ineffectively)
Peripheral blood *pancytopenias occur
primary MDS == idiopathic
t-MDS == secondary to previous genotoxic drug or radiation therapy (iatrogenic?)
More severe
Typically, older adults
myelodysplasias are characterized by thrombocytopenia
Cause MDS
May be primary or secondary to genotoxic drug or radiation (t-MDS) and appears 2-8 years after exposure
Transformation to AML occurs most rapidly and most frequently in t-MDS
Pathogenesis MDS
Mutations of epigenetic factors regulating DNA methylation and histone modifications
Mutations of RNA splicing factors involving the 3’ end of the RNA splicing machinery
Mutation of transcription factors for normal myelopoiesis
10% have TP53 loss-of-function mutations (poor outcome)
Monosomies 5 and 7; deletions of 5q, 7q, 20q; trisomy 8
MYC gene is on chromosome 8
Morphology
Hypercellular marrow is common, but can also be normal or hypocellular
Disordered differentiation of erythroid, granulocytic, monocytic and megakaryocytic lineages to varying degrees is the most characteristic finding
Erythroid lineage effects
Ring sideroblasts: erythroblasts with iron-laden mitochondria visible as perinuclear granules
seen with Prussian blue stain of aspirates or biopsies
Megaloblastoid maturation similar to B12 and folate deficiencies
Nuclear budding problems = misshapen nuclei (often with polypoid outlines
Granulocytes lineage effects
Neutrophils with decreased numbers of secondary granules, toxic granulations or Dohle bodies
Pseudo-Pelger-Hüet cells: Neutrophils with only two nuclear lobes
Hüet == Duet
Neutrophils lacking nuclear segmentation
Myeloblasts may be increased but account for < 20% of the overall marrow cellularity
recall: AML is when myeloblasts account for at least 20% of the marrow aspirate
Megakaryocytic lineage effects
Cells with single nuclear lobes or multiple separate nuclei (‘pawn ball’) are characteristic
Primary MDS clincial
Average age: 70 years
50% discovered incidentally on routine blood tests
Survive 9-29 months (up to 5+ years)
Signs and symptoms of weakness, infection, hemorrhage (due to pancytopenia)
Worse outcomes: higher blast counts, more severe cytopenias, multiple clonal chromosomal abnormalities
10-40% progress to AML (high rate of transformation to AML is in the definition)
cause of death: thrombocytopenia (bleeding) and neutropenia (infection
T-MDS clincial
Appears 2-8 years after treatment with genotoxic agents
Median survival of 4.8 months – terrible prognosis
Cytopenias are severe
Progression to AML is rapid
Treatment
HSC transplant in young patients
Older patients receive antibiotics and transfusions
Thalidomide-like drugs and DNA methylation inhibitors
Improve effectiveness of hematopoiesis and peripheral blood counts in some patients
FOUR Myeloproliferative Disorders == CML, polycythemia vera, essential thrombocytosis, and primary myelofibrosis
Mutated, constitutively active tyrosine kinases or other aberrations in signaling pathways → growth factor independence so there are lots of cells
tyrosine kinase inhibitors are a big deal here (e.g. Gleevec!)
Do not impair differentiation
Increased production of one or more mature blood elements – high counts of everything (pancytosis)
Originate in multipotent myeloid progenitors
Paradoxically, there is bleeding because the platelets are functionally abnormal, even though there are lots of them
Clinical
Increased proliferative drive in the bone marrow – tend to have thrombocytosis
Displace normal bone and suppress hematopoiesis
Homing of neoplastic stem cells to secondary hematopoietic organs → extramedullary hematopoiesis (liver)
Variable transformation to a spent phase with marrow fibrosis and peripheral blood cytopenias
Variable transformation to acute leukemia
Complications
Can either turn into AML (from the common myeloid progenitor) or go into a spent phase
A few will turn into an ALL and they have a terrible prognosis, even worse than if they turn into an AML
CML
Chimeric BCR-ABL gene driven by t(9:22), Philadelphia chromosome
Constitutive BCR-ABL tyrosine kinase activation driving growth factor independent proliferation and survival of bone marrow progenitors
Does not interfere with differentiation
Originates from pluripotent hematopoietic stem cell
Preferentially drives proliferation of granulocytic and megakaryocytic progenitors
Most common of the myeloproliferative disorders
Morphology CML
Hypercellular marrow from increased maturing granulocytic precursors
**Basophilia + eosinophilia
Increased megakaryocytes (small, dysplastic), increased platelets
Erythroid precursors are found at normal levels
Sea-blue histiocytes are a characteristic finding
Increased reticulin deposition
Sea blue histiocytes
Scattered macrophages with abundant wrinkled, green-blue cytoplasm
Seen in chronic myelogenous leukemia (CML)
Clincial CML
Primarily a disease of adults (5-6th decade) with insidious onset
Putthoff: male predominance
Huge spleen (extramedullary hematopoiesis) +/- infarcts, potential hepatomegaly, and lymphadenopathy
patients may present with fatigue, weight loss, anemia, anorexia and hyper-metabolism (increased cell turnover) or LUQ pain due to splenomegaly (dragging sensation) or splenic infarction
Much worse prognosis if they don’t have the Philadelphia chromosome
Gleevec treats the Philadelphia chromosome
Diagnose CML
BCR-ABL gene is detected via PCR or chromosome analysis
Leukocyte alkaline phosphatase (LAP) is low
LAP will be high in reactive states, e.g. infection
Blasts are < 10% of circulating cells (has to be less than 20% or else it’s an AML
Prognosis cml
Without treatment patients survive 3 years
“accelerated phase” == increased anemia and thrombocytopenia +/- basophilia
within 6-12 months, the accelerated phase terminates in a picture resembling acute leukemia (blast crisis)
70% are myeloid in origin, 30% are lymphoid in origin indicating the disease originates from a pluripotent stem cell with both myeloid and lymphoid potential
Treatment CML
90% of patients achieve remission with BCR-ABL inhibitors (Gleevec!)
Resistance has emerged due to mutations and are treated with 2nd and 3rd generation kinase inhibitors
hematopoietic stem cell transplant may be offered to young patients (75% cured)
Prognosis is less favorable when accelerated phase or blast crisis supervenes
Polycythemia Vera
Polycythemia Vera (PCV) == markedly increased red cell mass
Definition
Activating point mutation in JAK2 (tyrosine kinase)
Greatly increased RBCs (main source of signs and symptoms), slight increase in granulocytes and platelets
Pathogenesis PCV
Valine → phenylalanine at residue 617 – feels like a Dobson question
JAK2 then acts independently of growth factor
two mutated copies: higher WBC counts, more significant splenomegaly, pruritus and greater progression rate of the spent phase
Constitutively active JAK2 affects the JAK/STAT signaling pathway, downstream of the hematopoietic growth factor receptors
Decreased requirements for EPO (often suppressed
PCV morphology
Subtle increase in RBC progenitors with an associated increase in granulocytic precursors and megakaryocytes
Hypercellular marrow with residual fat
Increased reticulin fibers (10%)
Early phase: organomegaly due to congestion, and peripheral blood shows basophilia and large platelets
Spent phase pcv
Late in the course
Extensive marrow fibrosis that displaces hematopoietic cells, increased extramedullary hematopoiesis (hepatosplenomegaly)
1% transform to AML
Clincial pcv
Insidious, uncommon disease of adults
Signs and symptoms related to increased RBC mass and hematocrit (hyperviscosity) → abnormal blood flow
elevated hematocrit –> increased blood viscosity, + thrombocytosis and abnormal platelet function –> –> patients with PVC are prone to both thrombosis and bleeding
Venous circulation becomes congested and distended (patients are “plethoric” in the face (flushed))
pruritus after taking a hot shower
Deoxygenated blood remains in peripheral vessels longer → HA, dizziness, HTN, GI signs and symptoms
Sequelae pcv
Increased risk of thrombosis: DVT, hepatic vein (Budd-Chiari), portal vein, dural sinus thrombi
Pruritus due to basophil release of histamine, can also cause peptic ulcers
Hyperuricemia due to high cell turnover (gout
Lab findings pcv
Increased hemoglobin
Greatly increased hematocrit (>60%)
Iron deficiency due to chronic bleeding can suppress EPO, which decreases hematocrit to the normal range
Increased WBC (leukocytosis)
increased platelet count with morphologic abnormalities (giant with defective aggregation
Prognosis pcv
Untreated = death within months – not good
Phlebotomy, maintaining normal RBC mass extends survival to 10+ years
Evolves to a spent phase after this
2% transform to AML lacking JAK2 mutations
Disease is likely due to a progenitor mutation committed to myeloid differentiation
ALL transformation is rare (different from CML)
Spent phase pcv
15-20% of patients transition around 10 years into their disease (less common than other MPD)
Obliterative fibrosis of marrow (myelofibrosis)
Extensive medullary hematopoiesis (*spleen)
Massive splenomegaly
Essential thrombocytosis
Elevated platelet counts without polycythemia or marrow fibrosis
Increased megakaryocytes
Mild leukocytosis
Diagnosis of exclusion
Mutations essential thrombocytosis
mportant mutations
Activating JAK2 mutation (50%)
MPL (5-10%) [receptor tyrosine kinase normally activated by thrombopoietin]
Calreticulin
Clincial esssential thrombocytosis
Adults > 60 (signs and symptoms may resemble PCV)
Extramedullary hematopoiesis → organomegaly
Thrombosis and hemorrhage due to platelet dysfunction and increased number
DVT, portal and hepatic vein thrombosis, myocardial infarct
Thrombosis in patients with increased platelet counts and homozygous JAK2 mutations
Erythromelalgia: occlusion of small arterioles by platelet aggregates → burning and throbbing of hands and feet (may also be seen in PVC, peripheral neuropathy, peripheral vascular deficiency)
this is a non-specific finding
Prognosis et
Insidious: long asymptomatic phase with occasional thrombotic or hemorrhagic crises
Survival: 12-15 years
Treatment et
Treatment: gentle chemotherapy to suppress thrombopoiesis
Primary myelofibrosis
Development of obliterative marrow fibrosis due to non-neoplastic fibroblasts
Decreased bone marrow hematopoiesis → cytopenias and extramedullary hematopoiesis
Appears identical to the spent phase of other myeloproliferative disorders
Least common of the MPDs
chief pathologic feature == extensive deposition of collagen in the marrow by non-neoplastic fibroblasts
Mutations primary myelofibrosis
Activating JAK2 or MPL mutations (also calreticulin
Pathogenesis PM
Extensive deposition of collagen in the marrow by non-neoplastic fibroblasts
Displaces normal cells = marrow failure
Inappropriately released megakaryocyte factors: PDGF and TGFβ – both cause fibrosis and scarring
^^ bother are fibroblast mitogens
Extramedullary hematopoiesis takes over in spleen, liver and lymph node
Red cell production is impaired –> anemia
Morphology primary myelofibrosis
Marrow is hypercellular with large, dysplastic megakaryocytes that are abnormally clustered
Minimal fibrosis with leukocytosis and thrombocytosis
Myelofibrosis morphology late
Marrow becomes hypocellular and diffusely fibrotic
“Cloudlike” clusters of megakaryocytes
(spleen?) Sinusoids are markedly dilated
Osteosclerosis (fibrotic marrow → bone
Morphology spleen myelofibrosis
Marked splenomegaly, appearing red-gray and firm
Subcapsular infarcts occur
Initially hematopoiesis occurs in the sinusoids, but extends to the cords later
Liver and lymph nodes may also be involved in hematopoiesis (lymphadenopathy is uncommon)
Morphology blood myelofibrosis
Leukoerythroblastosis: Premature release of nucleated erythroid and early granulocyte precursors
DaCRYocytes: Tear drop shaped cells damaged during release from the fibrotic marrow
seen in pulmonary myelofibrosis, myelophthisic anemia, thalassemia, s/p splenomegaly
Abnormally large platelets
Basophilia
*these are also seen in other infiltrative disorders of the marrow (granulomatous disease and metastatic tumors
Clinical myelofibrosis
patients > 60 years old
Present with progressive anemia and LUQ “fullness”
Night sweats, fatigue and weight loss due to increased metabolism
Hyperuricemia and secondary gout due to high cell turnover
Diagnosis: bone marrow biopsy
Lab finding myelofibrosis
Normocytic, normochromic anemia with leukoerythroblastosis
WBC count is variable
Platelet count is variable, but thrombocytopenia will eventually show
Prognosis myelofibrosis
Prognosis
Survival: 3-5 years
Infection, thrombotic episodes, bleeding, transformation to AML (5-20%)
Treat myelofibrosis
JAK2 inhibitors for splenomegaly and signs and symptoms and HSC in young patients
Langerhans cell histiocytosis
Umbrella designation for a variety of proliferative disorders of dendritic cells or macrophages
considered neoplasms
Morphology langerhans histiocytosis
Abundant, vacuolated cytoplasm
Vesicular nuclei with linear grooves or folds
*Birbeck granules in the cytoplasm is characteristic: pantalaminar tubules with a dilated terminal end (“tennis racket” appearance) *contain langerin
Immunophenoty
Immunophenotype langerhans cell histiocytiosis
HLA-DR, S100, and CD1a positive
Mutations langerhans cell histiocytosis
BRAF activating mutation (600: valine → glutamate) as seen in hairy cell leukemia
Other mutations in tp53, RAS and MET (a tyrosine kinase
A 2-year-old boy has had a seborrheic eruption over the scalp and trunk over the past month. He then develops a right ear ache. On physical examination the right tympanic membrane is erythematous and bulging. He has hepatosplenomegaly and generalized lymphadenopathy. Laboratory studies show Hgb 9.5 g/dL, Hct 28.7%, MCV 90 fL, platelet count 58,000/microliter, and WBC count 3540/microliter. A bone marrow biopsy is performed and on microscopic examination shows 100% cellularity with extensive infiltration by cells resembling macrophages that express CD1a antigen and, by electron microscopy, have prominent HX bodies (Birbeck granules). Which of the following conditions is most likely to produce this boy’s findings
(D) CORRECT. The Langerhans cell histiocytoses include Letterer-Siwe disease (as in this case, it is typically a disseminated disease of children), and localized eosinophilic granuloma (often involving bone).
Multifocal Multisystem Langerhans Cell Histiocytosis (Letterer-Siwe Disease
Malignant proliferation of Langerhans cells
Mostly seen in kids <2 years old, but can be seen in adults
Clincial multifocal multisystem langerhans celll histiocytosis
Seborrheic eruption (rash) over the trunk and scalp HSM, LAD, pulmonary lesions and destructive osteolytic bone lesions Anemia, thrombocytopenia, recurrent infections (otitis media, mastoiditis) due to marrow involvement Anaplastic = Langerhans cell sarcoma
Prognosis treatment multifocal multisystem langerhans cell histiocytosis
Untreated = rapidly fatal
Treatment: intensive chemotherapy
5 year survival: 50%
Unifocal Unisystem Langerhans Cell Histiocytosis (eosinophilic granuloma
Benign proliferation of Langerhans cells in medullary cavity of bone typically in the calvarium, ribs, femur
Adolescents
Unifocal Unisystem Langerhans Cell Histiocytosis (eosinophilic granuloma) clincila
Pain, tenderness, pathologic fracture
Heal spontaneously, excised or radiated
Skin, lungs or stomach are uncommonly involved
Biopsy: Langerhans cells with mixed inflammatory cells (numerous eosinophils
Multifocal unisystem langerhans cell histiocytosis
Definition
Benign proliferation of Langerhans cells
Affects young children
Clincial multifocal unisystem langerhans cell histiocytosis
Multiple erosive bone masses
May extend into soft tissue
May involve posterior pituitary stalk = diabetes insipidus (50%)
Spontaneous regression or treatment with chemotherapy
Hand-Schuller-Christian Triad: Calvarial bone defects, diabetes insipidus, and exophthalmos – “probably should know that
Pulmonary langerhans cell histiocytosis
Reactive proliferation of Langerhans cells
Nodules and cysts in the middle and upper lobes
40% are associated with BRAF mutations and may be neoplastic in origin – as seen in hairy cell leukemia
Adult smokers (disease may regress with smoking cessation)
pulmonary disease associated with smoking, shocking
Immunophenotype of langerhans cell histiocytosis
Aberrant expression of chemokine receptors on Langerhans cells allows homing
Normally express CCR6
Neoplastic: CCR6 + CCR7 allowing cells to enter tissues in skin, bone, and lymphoid organs
Periarteriolar lymphatic sheath
Periarteriolar lymphatic sheath: an artery with an eccentric collar of T lymphocytes; at intervals this sheath expands to form lymphoid nodules composed mainly of B lymphocytes
Open circulation
open circulation: blood flows through capillaries into the cords and then squeezes through gaps in the discontinuous basement membrane of the endothelial linings to reach the sinusoids
cells are deformed when passing from cords to sinusoids
Closed circulation
closed circulation: blood passes rapidly and directly from the capillaries to the splenic veins
Spleen path
primary lesions to the spleen are rare; if they happen they are benign
metastatic disease to the spleen is rare
Splenic phagocytosis
phagocytosis of blood cells and particulate matter
conditions in which red cell deformability is decreased, more RBCs become trapped in the cords and phagocytosed by macrophages
macrophage are responsible for RBC “pitting:” process by which inclusions of Heinz bodies and Howell-jolly bodies are excised
Also remove particles (encapsulated bacteria
Splenic antibody production
Plasma cells within the sinuses of the red pulp
dendritic cells in periarteriolarl lymphatic sheaths present Antigens to T-lymphocytes
T & B cells interact at the edge of white pulp follicles –> plasma cells within the sinuses of the red pulp
Important production site against microbial polysaccharides and auto-antibodies to self-antigens
Splenic function hematopoiesis
Major site during fetal development, but disappears at birth
In chronic anemia, thalassemia, and patients with myeloproliferative disorders (CML, primary myelofibrosis) becomes an extramedullary site for production
Splenic sequesteration
Splenomegaly significantly increases the capacity from 30ml of RBCs
Normally contains 30-40% of the body’s platelets but can trap 80-90% of total platelet mass (in red pulp)
Thrombocytopenia and leukopenia can result when cells remain trapped in the spleen
Major manifestation of spleen
infections outside of the US
alcohol and disease in the US
Asplenia
Removal or dysfunction of this organ leads to increased susceptibility to sepsis caused by encapsulated bacteria
encapsulated bacteria == blood borne
Sickle Cell Patients –> increased autoinfarction of the spleen –> functionally asplenic (splenic insufficiency)
Decreased phagocytic capacity
Decreased antibody production
patients should be vaccinated against encapsulated bacteria: pneumococci, meningococci, and haemophilus influenzae
Dragging sensationin LUQ
Due to splenomegaly
Discomfort after eating due to pressure on the stomach
splenomegaly can cause hypersplenism: anemia, leukopenia, and thrombocytopenia either alone or in combination
Nonspecific acute splenitis
Reactive enlargement of the spleen that occurs due to blood borne infections (microbial agents and cytokines released due to immune response
Morphology nonspecific acute splenitis
Enlarged and soft spleen
Major feature: acute congestion of the red pulp that may encroach on and efface lymphoid follicles
White pulp follicles may undergo necrosis especially due to hemolytic streptococcus
Abscess formation rarely occurs
Congestive splenomeglay
Definition
Due to chronic venous outflow obstruction
Obstruction due to intrahepatic disorder affecting portal venous drainage
Causes congestive splenomegaly
Cirrhosis (ETOH, parasitic schistosomiasis, pigment)
Extrahepatic disorders impinging on portal or splenic veins
Spontaneous portal vein thrombosis, pyelophlebitis (inflammation of the portal vein), infiltrating tumors
Causes portal or splenic vein hypertension
Systemic congestion (CHF) may produce a moderately enlarged spleen
Morphology splenomegaly
Cut surface is gray-red to deep red
Firm
Thick, fibrous capsule
Red pulp: congested then fibrotic
Deposition of collagen in basement membrane of sinusoids that appear dilated (rigid walls) due to increased portal venous pressure
Hypersplenism (excess destruction) due to slow blood flow and increased exposure to macrophages
Splenic infarct
Common lesions; due to occlusion of major splenic artery or branches
Lack of collateral blood supply
Common in markedly enlarged spleens due to tenuous blood supply that is easily compromised
Common site of emboli (from the heart
Morphology splenic infarct
Bland: pale, wedge shaped, subcapsular, fibrous capsule
more common; splenic infarcts are usually bland
Septic: suppurative necrosis that leads to depressed scars
common in the setting of individuals with infective endocarditis of the mitral or aortic valves
Spleen neoplasms
Primary neoplastic involvement is rare; when it does happen it is benign
Lymphoid and myeloid tumors often cause splenomegaly
Benign fibromas, osteomas, chondromas, lymphangiomas, hemangiomas may arise; often cavernous in type
Spleen congenital anomalies
Complete absence is rare and associated with other anomalies (e.g. situs inversus and cardiac malformations)
Hypoplasia is more common
Accessory spleen (spleniculi): common; small, spherical structures histologically and functionally identical to the normal structure found anywhere in the abdominal cavity
very important to recognize in diseases with splenectomy as a treatment (i.e. hereditary spherocytosis and immune thrombocytopenia purpura
Splenic rupture
more commonly precipitated by blunt trauma
Spontaneous: never involves a truly normal organ, but likely involves an underlying condition
most common predisposing conditions: infectious mononucleosis, malaria, typhoid fever, lymphoid neoplasm
Splenomegaly with a thin, tense capsule susceptible to rupture
rupture causes intraperitoneal hemorrhage that must be treated with splenectomy
Chronically: unlikely to rupture due to reactive fibrosis of the capsule
Thymus
Derived from the 3rd and 4th pharyngeal pouches
Grows until puberty then involutes
Lobular structures contain
Thymic epithelial cells → Hassall corpuscles with keratinized cores
Immature T lymphocytes
Location of maturation of T cells
myoid cells (muscle-like cells) found in the thymus are thought to play some role in the development of myasthenia gravis (Myasthenia Gravisis an autoimmune disease which results in musclefatigability and weakness throughout the day. Symptoms improve with rest. Its main symptoms, which the ophthalmologist may encounter, areptosis, diplopia, variable extra-ocular muscle palsies or incomitant strabismus, and external ophthalmoplegia.)
fatigable ptosis
MOA: auto-antibodies against cholinesterase
Thymic hypoplasia/asplasia
Thymic Hypoplasia/Aplasia (DiGeorge Syndrome)
problem with the development of 3rd and 4th pharyngeal pouches
Severe defects in cell-mediated immunity
Variable anomalies of parathyroid development (hypoparathyroidism) –> hypocalcemia
Chromosome 22q11 deletion == CATCH-22
Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcemia (from hypoparathyroidism) resulting from 22q11 deletions
Thymic cysts
Uncommon, incidental finding
< 4 cm in diameter
Spherical or arborizing
Lined with stratified squamous to columnar epithelium
Fluid may be serous or mucinous
neoplastic thymic masses compress and distort adjacent normal thymus and sometimes cause cysts to form
presence of a thymic cyst in a symptomatic patient should invoke a search for adjacent neoplasm (lymphoma or thymoma
Thymic hyperplasia
Thymic (Follicular) Hyperplasia == B cell proliferation in the thymus
Appearance of B-cell germinal centers in the thymus (thymic follicular hyperplasia)
thymic hyperplasia is a B-cell lesion! (think about it)
Most common in myasthenia gravis 65-75% (or Graves disease, systemic lupus erythematous, scleroderma, rheumatoid arthritis, and other autoimmune disorders)
May be naturally large for a patient’s age and can be mistaken for a thymoma
True enlargement of the thymus is rare
Thymoma
hymoma == epithelial malignancy of squamous type cells
Definition
Tumor of thymic epithelial cells – these are squamous cells
thymoma is of squamous cell origin; this is an epithelial cancer; will not have abnormal peripheral blood smears (i.e. no blast count with a thymoma)
Typically contain benign immature T cells (thymocytes)
Adults > 40 years old; thymomas are rare in children
defined as either benign (proliferation of squamous cell component) or malignant (thymic epithelium)
look for cellular atypia to differentiate between benign and malignant
Three histologic subtypes of thymoma
Benign
Cytologically benign and noninvasive == thymoma
Malignant
Cytologically benign but invasive or metastatic == invasive thymoma
no cellular atypia
Cytologically malignant (thymic carcinoma) == malignant thymoma
cellular atypia
Location thymoma
Common in the anterior superior mediastinum (also a common location of some lymphomas)
May cause impingement of structures
Morphology thymoma
Morphology
Lobulated, firm, gray-white masses
+/- cystic necrosis and calcification
Most are encapsulated
20-25% of the tumors penetrate the capsule and infiltrate peri-thymic tissues
unremarkable thymic cortical and medullary regions; no atypia; whorled
Noninvasive Thomas
50% of all thymomas are mixed medullary type and cortical type epithelial cells
Tumors with substantial medullary epithelial cells are usually noninvasive
Medullary type epithelial cells: elongated/spindle shaped
Sparse infiltrate of thymocytes
Cortical type epithelial cells: polygonal
Malignant thymoma type I invasive
Invasive Thymoma (Type 1)
20-25% of all thymomas
Tumor that is cytologically bland but locally invasive
by definition, invasive thymomas penetrate through the capsule into surrounding structures
Cells are usually cortical with abundant cytoplasm and round, vesicular nuclei
The prognosis depends on how much the tumor has invaded surrounding structures
minimal invasion + complete excision –> 90% 5 year survival – good prognosis
extensive invasion –> 50% 5 year survival – not great
Thymic carcinoma type II malignant thymoma
5% of thymomas
Fleshy, invasive masses that metastasize (often to lungs)
Most are squamous cell carcinomas
second most common are lymphoepithelioma-like carcinoma
Sheets of cells with indistinct borders
Resemble nasopharyngeal carcinoma
EBV genomes are found in 50
Thymoma clincila
40% of patients present with signs and symptoms related to mediastinum impingement
30-45% of patients present with myasthenia gravis
other associated autoimmune disorders: hypogammaglobulinemia, pure red cell aplasia, Graves disease, pernicious anemia, dermatomyositis-polymyositis, and Cushing syndrome
thymocytes that arise within thymocytes give rise to long-lived CD4+ and CD8+ T cells, and cortical thymomas rich in thymocytes are more likely to be associated with autoimmune disease (statistically
Spleen
Periarteriolar lymphatic sheath: an artery with an eccentric collar of T lymphocytes; at intervals this sheath expands to form lymphoid nodules composed mainly of B lymphocytes
open circulation: blood flows through capillaries into the cords and then squeezes through gaps in the discontinuous basement membrane of the endothelial linings to reach the sinusoids
cells are deformed when passing from cords to sinusoids
closed circulation: blood passes rapidly and directly from the capillaries to the splenic veins
primary lesions to the spleen are rare; if they happen they are benign
metastatic disease to the spleen is rare
Splenic function : phagocytosis
phagocytosis of blood cells and particulate matter
conditions in which red cell deformability is decreased, more RBCs become trapped in the cords and phagocytosed by macrophages
macrophage are responsible for RBC “pitting:” process by which inclusions of Heinz bodies and Howell-jolly bodies are excised
Also remove particles (encapsulated bacteria*)
Splenic function: antibodies
Plasma cells within the sinuses of the red pulp
dendritic cells in periarteriolarl lymphatic sheaths present Antigens to T-lymphocytes
T & B cells interact at the edge of white pulp follicles –> plasma cells within the sinuses of the red pulp
Important production site against microbial polysaccharides and auto-antibodies to self-antigens
Splenic function hematopoiesis
Major site during fetal development, but disappears at birth
In chronic anemia, thalassemia, and patients with myeloproliferative disorders (CML, primary myelofibrosis) becomes an extramedullary site for production
Splenic function sequesteration
Splenomegaly significantly increases the capacity from 30ml of RBCs
Normally contains 30-40% of the body’s platelets but can trap 80-90% of total platelet mass (in red pulp)
Thrombocytopenia and leukopenia can result when cells remain trapped in the spleen
Splenomegaly
splenomegaly is the major manifestation of disorders of the spleen
infections outside of the US
alcohol and disease in the US
Asplenia
Removal or dysfunction of this organ leads to increased susceptibility to sepsis caused by encapsulated bacteria
encapsulated bacteria == blood borne
Sickle Cell Patients –> increased autoinfarction of the spleen –> functionally asplenic (splenic insufficiency)
Decreased phagocytic capacity
Decreased antibody production
patients should be vaccinated against encapsulated bacteria: pneumococci, meningococci, and haemophilus influenzae
Dragging sensation LUQ
Due to splenomegaly
Discomfort after eating due to pressure on the stomach
splenomegaly can cause hypersplenism: anemia, leukopenia, and thrombocytopenia either alone or in combination
Nonspecific acute splenitis
Reactive enlargement of the spleen that occurs due to blood borne infections (microbial agents and cytokines released due to immune response
Morphology acute splenitis
Enlarged and soft spleen
Major feature: acute congestion of the red pulp that may encroach on and efface lymphoid follicles
White pulp follicles may undergo necrosis especially due to hemolytic streptococcus
Abscess formation rarely occurs
Congestive splenomegaly
Due to chronic venous outflow obstruction
Obstruction due to intrahepatic disorder affecting portal venous drainage
Causes congestive splenomegaly
Cirrhosis (ETOH, parasitic schistosomiasis, pigment)
Extrahepatic disorders impinging on portal or splenic veins
Spontaneous portal vein thrombosis, pyelophlebitis (inflammation of the portal vein), infiltrating tumors
Causes portal or splenic vein hypertension
Systemic congestion (CHF) may produce a moderately enlarged
Morphology congestive splenomegaly
Cut surface is gray-red to deep red
Firm
Thick, fibrous capsule
Red pulp: congested then fibrotic
Deposition of collagen in basement membrane of sinusoids that appear dilated (rigid walls) due to increased portal venous pressure
Hypersplenism (excess destruction) due to slow blood flow and increased exposure to macrophages
Splenic infarct
Common lesions; due to occlusion of major splenic artery or branches
Lack of collateral blood supply
Common in markedly enlarged spleens due to tenuous blood supply that is easily compromised
Common site of emboli (from the heart
Morphology splenic infarct
Bland: pale, wedge shaped, subcapsular, fibrous capsule
more common; splenic infarcts are usually bland
Septic: suppurative necrosis that leads to depressed scars
common in the setting of individuals with infective endocarditis of the mitral or aortic valves
Spleen neoplasma
Primary neoplastic involvement is rare; when it does happen it is benign
Lymphoid and myeloid tumors often cause splenomegaly
Benign fibromas, osteomas, chondromas, lymphangiomas, hemangiomas may arise; often cavernous in type
Spleen congenital anomalies
n: Congenital Anomalies
Complete absence is rare and associated with other anomalies (e.g. situs inversus and cardiac malformations)
Hypoplasia is more common
Accessory spleen (spleniculi): common; small, spherical structures histologically and functionally identical to the normal structure found anywhere in the abdominal cavity
very important to recognize in diseases with splenectomy as a treatment (i.e. hereditary spherocytosis and immune thrombocytopenia purpura
Splenic rupture
more commonly precipitated by blunt trauma
Spontaneous: never involves a truly normal organ, but likely involves an underlying condition
most common predisposing conditions: infectious mononucleosis, malaria, typhoid fever, lymphoid neoplasm
Splenomegaly with a thin, tense capsule susceptible to rupture
rupture causes intraperitoneal hemorrhage that must be treated with splenectomy
Chronically: unlikely to rupture due to reactive fibrosis of the capsule
Thymus
Derived from the 3rd and 4th pharyngeal pouches
Grows until puberty then involutes
Lobular structures contain
Thymic epithelial cells → Hassall corpuscles with keratinized cores
Immature T lymphocytes
Location of maturation of T cells
myoid cells (muscle-like cells) found in the thymus are thought to play some role in the development of myasthenia gravis (Myasthenia Gravisis an autoimmune disease which results in musclefatigability and weakness throughout the day. Symptoms improve with rest. Its main symptoms, which the ophthalmologist may encounter, areptosis, diplopia, variable extra-ocular muscle palsies or incomitant strabismus, and external ophthalmoplegia.)
fatigable ptosis
MOA: auto-antibodies against cholinesterase
Digeorge
Thymic Hypoplasia/Aplasia (DiGeorge Syndrome)
problem with the development of 3rd and 4th pharyngeal pouches
Severe defects in cell-mediated immunity
Variable anomalies of parathyroid development (hypoparathyroidism) –> hypocalcemia
Chromosome 22q11 deletion == CATCH-22
Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcemia (from hypoparathyroidism) resulting from 22q11 deletions
Thymic Systems
Uncommon, incidental finding
< 4 cm in diameter
Spherical or arborizing
Lined with stratified squamous to columnar epithelium
Fluid may be serous or mucinous
neoplastic thymic masses compress and distort adjacent normal thymus and sometimes cause cysts to form
presence of a thymic cyst in a symptomatic patient should invoke a search for adjacent neoplasm (lymphoma or thymoma
Thymic follicular hyperplasia
Thymic (Follicular) Hyperplasia == B cell proliferation in the thymus
Appearance of B-cell germinal centers in the thymus (thymic follicular hyperplasia)
thymic hyperplasia is a B-cell lesion! (think about it)
Most common in myasthenia gravis 65-75% (or Graves disease, systemic lupus erythematous, scleroderma, rheumatoid arthritis, and other autoimmune disorders)
May be naturally large for a patient’s age and can be mistaken for a thymoma
True enlargement of the thymus is rare
Thymoma
Tumor of thymic epithelial cells – these are squamous cells
thymoma is of squamous cell origin; this is an epithelial cancer; will not have abnormal peripheral blood smears (i.e. no blast count with a thymoma)
Typically contain benign immature T cells (thymocytes)
Adults > 40 years old; thymomas are rare in children
defined as either benign (proliferation of squamous cell component) or malignant (thymic epithelium)
look for cellular atypia to differentiate between benign and malignant
Benign thymoma
Cytologically benign and noninvasive == thymoma
Malignant thymoma
Cytologically benign but invasive or metastatic == invasive thymoma
no cellular atypia
Cytologically malignant (thymic carcinoma) == malignant thymoma
cellular atypia
Location thymus tumor
Common in the anterior superior mediastinum (also a common location of some lymphomas)
May cause impingement of structures
Morphology thymic tumor
ocation of the tumor
Common in the anterior superior mediastinum (also a common location of some lymphomas)
May cause impingement of structures
Morphology
Lobulated, firm, gray-white masses
+/- cystic necrosis and calcification
Most are encapsulated
20-25% of the tumors penetrate the capsule and infiltrate peri-thymic tissues
unremarkable thymic cortical and medullary regions; no atypia; whorled
Noninvasive thymoma
50% of all thymomas are mixed medullary type and cortical type epithelial cells
Tumors with substantial medullary epithelial cells are usually noninvasive
Medullary type epithelial cells: elongated/spindle shaped
Sparse infiltrate of thymocytes
Cortical type epithelial cells: polygonal
Malignan thymoma : type 1
Invasive Thymoma (Type 1)
20-25% of all thymomas
Tumor that is cytologically bland but locally invasive
by definition, invasive thymomas penetrate through the capsule into surrounding structures
Cells are usually cortical with abundant cytoplasm and round, vesicular nuclei
The prognosis depends on how much the tumor has invaded surrounding structures
minimal invasion + complete excision –> 90% 5 year survival – good prognosis
extensive invasion –> 50% 5 year survival – not great
Malignant thymoma type 2
5% of thymomas
Fleshy, invasive masses that metastasize (often to lungs)
Most are squamous cell carcinomas
second most common are lymphoepithelioma-like carcinoma
Sheets of cells with indistinct borders
Resemble nasopharyngeal carcinoma
EBV genomes are found in 50%
Thymoma clinical
40% of patients present with signs and symptoms related to mediastinum impingement
30-45% of patients present with myasthenia gravis
other associated autoimmune disorders: hypogammaglobulinemia, pure red cell aplasia, Graves disease, pernicious anemia, dermatomyositis-polymyositis, and Cushing syndrome
thymocytes that arise within thymocytes give rise to long-lived CD4+ and CD8+ T cells, and cortical thymomas rich in thymocytes are more likely to be associated with autoimmune disease (statistically
