| What are components of hematopioetic system? | Myeloid Tissues (Bone marrow and cells derived from it)
Lymphoid Tissues (Thymus, Lymph nodes, Spleen)
Lymphoid Organs (Cells of the immune system are distributed through body in
1. blood, lymph, epithelial and connective tissues
2. lymphoid nodules
3. lymphoid organs (Lymph nodes, Spleen, Thymus, Bone marrow)
Mucosa-Associated Lymphoid Tissue (MALT) (Lungs, Peyer’s patches, Tonsils, Sites of IgA secretion to protect mucosal surfaces from infection)
Thymus
• Thymus is site of T-cell differentiation, into CD4+ or CD8+ T-cells, Thymic-blood barrier, with non-fenestrated endothelial cells, No afferent lymphatics |
| How is histology of lymph node? | . |
| How is benign lymph node enlargement? | Lymph nodes filter foreign particles, bacteria, and viruses,
out of the lymphatic fluid
• Most people will have had “swollen glands” at some time as a response to infection
• Also called lymphadenitis, and hyperplasia
• Can be acute (tender),or chronic (non-tender)
• Usually subside in less than 6 weeks
• Follicular hyperplasia is enlargement of the cortical 2nd
follicles and increase in number of the cortical 2nd follicles
• Sinus histiocytosis is prominence in medullary sinuses |
| How is bone marrow? | • It is made up of blood-forming stem cells, lymphoid
tissue, fat cells, and supporting tissues that aid the
growth of blood forming cells.
• All bones have active marrow at birth
• Adulthood - vertebrae, hip, shoulders, ribs, breast
and skull contain marrow. |
| How is humoral response histology? | • B-cells are activated by foreign proteins (antigens) and differentiate into plasma cells
• Plasma cells make immunoglobulin
• IgG: monomer, lots of it in plasma, neutralizes antigens
• IgM: pentamer, initial immune response, high levels in acute infection
• IgA: dimer, present in secretions (saliva, breast milk, tears), protects mucosal surfaces
• IgE: monomer, allergic and antiparasite responses
• IgD: monomer, small amount in plasma, triggers initial B-cell activation |
| How is cellular response histology? | . |
| What are hematopoietic malignancies? | • Lymphomas as clonal expansions of cells at certain
developmental stages
• Lymphocytic leukemia vs lymphoma Widespread involvement of the bone marrow and peripheral blood= “liquid” malignancies of either the lymphoid or the myeloid series. v/s hematopoietic solid malignancies |
| Figure of hematopoietic malignancies? | . |
| How is dx study for hematopoietic malignancy? | • Diagnosis should be biopsy-proven before treatment is initiated
• Need enough tissue to assess cells and architecture
– open bx v/s core needle bx v/s FNA
Labs (Lymph node biopsy, Bone marrow aspiration and biopsy, Immunohistochemistry, Flow cytometry, Molecular Genetic studies, FISH, Cytogenetics)
Protocol: Morphological evaluation then flow cytometry, immunostains, cytogenetics, molecular study (CD antigens) |
| How are CD antigens of different types of cells? | • T-Cell: 1,2, 3,4,5,7,8
• B-Cell: 19,20,79a
• Mono/Mac: 11c, 13, 14, 15, 33, 34
• Stem: 34
• RS: 15, 30
• All: 45 (Leukocyte Common Antigen)
• NK: (16, 56) |
| What are useful FISH analysis of parafinn embeded tissue sections in routine lymphoma labs? | • “Burkitt-like” lymphomas: Cases suggestive of Burkitt’s lymphoma but with atypical features should be analysed by the FISH technique for evidence of MYC translocation.
• MALT lymphomas with the t(11;18)(q32;q21) translocation: For many laboratories FISH analysis is more convenient than a PCR procedure for detecting such cases. |
| What are molecular cytogenetic tests in lymphoma? | • t(14;18) / Bcl2 - JH in follicular lymphoma
• t(11;14) / Bcl1 - JH in Mantle Zone lymphoma
• t(3;14) / Bcl6 - JH in Diffuse Large Cell lymphoma
• t(8;14) / cMyc - JH in Burkitt lymphoma
• t(2,5) / ALK-NPM in Anaplastic Large Cell Lymphoma |
| What are neoplastic proliferation types of WBCs? | Lymphoid neoplasms- B-cells, T-cells, NK cells origin
Myeloid neoplasms – Acute myeloid leukemias, myelodysplastic, myeloproliferative
Histiocytosis – macrophages, dendritic cells, Langerhans cells |
| How is classifications of lymphomas? | Usually classified by how the cells look under a
microscope and how quickly they grow and spread
– Aggressive lymphomas (high-grade lymphomas)
– Indolent Lymphomas (low-grade lymphomas)
Classification: NHL
• B-cell neoplasms
– precursor
– mature
• T-cell & NK-cell neoplasms
– precursor
– Mature
• Hodgkin lymphoma |
| What are etiologic and pathogenetic factors for lymphoma? | • Chromosome translocations and other acquired mutations
– Translocations +++
– Mutated genes often play critical roles in the development, growth, or survival
– Oncoproteins created by genomic aberrations
– Proto-oncogenes often activated by errors occurring during antigen receptor gene rearrangement and diversification
• Inherited genetic factors; Bloom, Fanconi, Down, ataxia
teleangectasia and type I NF
• Viruses; HTLV-1, EBV, HHV-8
• Chronic Immune stimulation (H. pylori, celiac, HIV)
• Iatrogenic factors (radiation therapy)
• Smoking (AML) |
| How is epidemiology of lymphoma? | • Males > females
• Incidence
– NHL increasing
– Hodgkin lymphoma stable
• NHL: 3rd most frequently diagnosed cancer in males
and 4th in females
• HL: 5th most frequently diagnosed cancer in males
and 10th in females |
| How is clinical manifestation of lymphoma? | • Variable( asymptomatic to severe symptoms, time course: evolution over weeks, months, or years)
• Systemic manifestations, fever, night sweats, weight loss, anorexia, pruritis)
• Local manifestations (lymphadenopathy, splenomegaly most common, any tissue potentially can be infiltrated)
Other complications:
• bone marrow failure (infiltration)
• CNS infiltration
• immune hemolysis or thrombocytopenia
• compression of structures (eg spinal cord, ureters)
• pleural/pericardial effusions, ascites |
| How is staging of NHL? | . |
| Table of T and B cell proliferations and lymphoma? | . |
| What is ALL? | • ALL is the most common cancer of childhood
• Must be distinguished from AML because of
differing responses to chemotherapy
• 90% have numerical or structural chromosomal
changes (hyperploidy)
• 85% 0f B-ALLs childhood acute leukemias
• T-ALLs less common, present as thymic
lymphomas in adolescent males (lymphadenopathy
and splenomegaly)
• Abrupt stormy onset, Symptoms related to bone
marrow suppression, CNS manifestations |
| How is proliferation in ALL? | • Proliferation of typically small to medium sized cells
• B and T cell precursors are morphologically
indistinguishable
• B-ALL / LBL
– CD19, CD79a, CD22, TdT, CD34, CD10 and PAX5
• T-ALL / LBL
– Typically TdT, CD34, CD99 and CD1a
– CD7 and cCD3 most commonly positive
– Variable expression of CD2, CD5,
• T-ALL often double positive for CD4 and CD8
– Only cytoplasmic CD3 considered lineage specific for T
cells
• Hypercellular, starry sky, TdT + |
| What are B-cell lymphoid proliferations and lymphoma? | . |
| How is follicular lymphoma? | • most common type of “indolent” lymphoma
• usually widespread at presentation
• not curable (some exceptions)
• despite “indolent” label, morbidity and mortality can
be considerable
• transformation to aggressive lymphoma can occur
• Partial or complete effacement of lymph node
• Neoplastic follicles:
– Similarly sized
– Nonpolarized
– Attenuated or absent mantle zones
– Lack tingible body macrophages
– Composed of centrocytes or centroblasts
– Infrequent mitoses (except grade 3) |
| How is mantle cell lymphoma? | Tumor cells closely resemble the normal mantle zone
B cells that surround germinal centers
Painless adenopathy
Small lymphocytes with cleaved contours
Express high levels of cyclin D1 t(11:14)
• Monotonous small to medium-sized cells, indented nuclei
• IHC: CD20+, CD5+, Cycline D1+ |
| How is marginal cell lymphoma? | • Maltomas
• Often arise in areas of chronic inflammation (H. pylori)
• Remain localized for prolonged periods
• May regress if inciting agent is eradicated
• Up regulations of BCL10/MALT1 |
| How is small lymphocytic lymphoma? | • Low grade B-cell malignancy, = chronic lymphocytic leukemia (CLL), Frequency ~ 4% of NHL, Most common leukemia of adults, Older age group (median, 60.5 years), Bone marrow involvement: Common, Indolent course
• Often asymptomatic at diagnosis
• Nonspecific –fatigue, weight loss, anorexia
• Generalized lymphadenopathy
• Hepatosplenomegaly
• Disrupts normal immune function through uncertain
mechanisms (hypogammaglobinemia, autoantibodes -> anemia, thrombocytopenia)
• Variable course and prognosis
• Tendency to transform to more aggressive tumors –
Prolymphocytic and large-cell transformations (latter = Richter syndrome) – poor prognosis
• Diffuse effacement of parenchyma by small, mature
lymphocytes
• Round nucleus, clumped chromatin with only small
nucleoli and scant cytoplasm
Proliferation centers pathognomic, immuno CD20, CD5, CD23 |
| What is richter syndrome? | Transformation of a CLL or SLL into an aggressive lymphoma, primarily diffuse large B cell lymphoma )DLBCL), or rarely into Hodgkin lymphoma
• Occurs in approximately 2 - 10% of patients with chronic lymphocytic leukemia
• May occur during various times after diagnosis
•Sudden clinical deterioration, Development of systemic symptoms (B symptoms), Rapid, asymmetrical lymph node growth |
| What is diffuse large B cell lymphoma? | • Most common form of NHL
• Tissue architecture is is partially or totally effaced by
medium-to-large sized lymphoid cells
• Large cell defined as having nucleus the same size or
larger than a macrophage nucleus, or more than twice
the size of a small lymphocyte nucleus
• Mature B cell phenotype
• Cytological features are diverse
– Centroblastic
– Immunoblastic
– Anaplastic
• t(14:18) in 25% of cases (40% in GCB-like DLBCL) |
| What are molecular subtypes of DLBCL? | • The activated B-cell-like type (ABC) of DLBCL, NOS
has an inferior outcome in response to standard
therapies when compared to the germinal centre Bcell group (GCB) in most but not all clinical cohorts.
• Gene expression profiling (GEP) is the gold standard
for cell of origin (COO) determination. Studies
comparing COO classification by gene expression
compared to the Hans criteria have shown that GEP
has superior performance in the prediction of overall
survival |
| What is Burkitt lymphoma? | • African (endemic)
• Sporadic (nonendemic)
• Aggressive subset in HIV
IG::MYC rearrangement: Translocations of the c-MYC gene on Chromosome 8 t(8,14)
Risk factors for endemic BL are Plasmodium falciparum
(malaria) and EBV infections. Essentially all endemic tumors
are infected with EBV
Clinical features: most present as tumor at extranodal site
- Endemic = mandible, abd viscera
- Sporadic = ileo-cecum, peritoneum |
| How is morphology of burkitt lymphoma? | • mature aggressive Bcell neoplasm
• monomorphic, medium-sized cells
• multiple small nucleoli,
• a germinal center B-cell phenotype,
• starry sky pattern
• high mitotic index
• numerous apoptotic cells
• CD20 and CD10 positivity.
• Absence or (rarely) weak expression of BCL2.
• Usually strong expression of MYC (in >80% of cells)
• a high proliferation index (Ki67 index >95%) |
| What is lymphoplasmacytic lymphoma? | • Lymphoplasmacytic lymphoma (LPL) is a neoplasm
comprising small B lymphocytes, plasmacytoid lymphocytes
and plasma cells, usually involving the bone marrow and
sometimes lymph nodes and spleen.
• Waldenström Macroglobulinemia (WM) is defined by the combination of LPL in the bone marrow with an IgM
monoclonal component in the blood. Plasma cell component secretes monoclonal IgM leading to hyperviscosity syndrome _ Waldenstrom macroglobulinemia
• Clinical features
– weakness, fatigue, weight loss,
– lymphadenopathy, hepatosplenomegaly
– Anemia, auto-immune hemolysis caused by cold agglutinins hyperviscosity syndrome
Seen by IgM monoclonal |
| How is labs of lymphoplasmacytic lymphoma? | • BM infiltration by > 10%; Spectrum of lymphocytes,
plasmacytoid lymphocytes and plasma cells
• Flow cytometry: monoclonal B cells with typical
immunophenotype and monoclonal plasma cells
• MYD88 L265P mutation present > 90% of cases |
| What are plasma cell neoplasms and related disorders? | • Plasmacytoma: solitary neoplasm of clonal plasma cells
without evidence of plasma cell (multiple) myeloma or
end-organ damage due to plasma cell neoplasia.
• Plasma cell myeloma is a bone marrow-based, multifocal neoplastic proliferation of plasma cells.
• Multiple myeloma is defined by the combination of :
– plasma cell myeloma,
– usually associated with a serum and/or urine monoclonal
immunoglobulin,
– and either evidence of organ damage related to the disease
– or in the absence of organ damage, laboratory or imaging findings that suggest a high risk of developing end-organ damage within 2 years |
| What is multiple myeloma? | Both criteria must be met:
1. Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma
2. Any one or more of the following myeloma defining events:
– Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
hypercalcemia >0.25 upper limit, anemia, renal insufficiency, bone lesions by PET
– Clonal bone marrow plasma cell percentage ≥60%
– Involved: uninvolved serum free light chain (FLC) ratio ≥100 (involved free light chain level must be ≥100 mg/L)
– >1 focal lesions on magnetic resonance imaging (MRI) studies (at least 5mm in size) |
| What are T cell and NK cell lymphoid proliferations? | . |
| What are peripheral T cell and NK cell neoplasms? | • Adult T-cell leukemia/lymphoma- CD4+cells, HTLV-1
(cloverleaf, flower cells)
• Mycosis fungoides/Sezary Syndrome
CD4+helper Tell tumor, homes to the skin, Sezary syndrome
• Extranodal NK/Tcell Lymphoma _ Destructive
nasopharyngeal mass, surrounds and invades blood vessels
leading to ischemic necrosis, associated with EBV |
| What is ALK+ anaplastic large cell lymphoma? | • CD30-positive mature T-cell lymphoma with aberrant expression of the Anaplastic Lymphoma Kinase (ALK) protein.
• Chromosomal rearrangements that fuse the 3’ portion of ALK on chromosome 2p23 and the 5’ portion of a partner gene that provides the promoter and leads to constitutive expression of the chimeric oncoprotein, as well as to to constitutive activation of the kinase function.
• There are over 20 partner genes involved in ALK
rearrangements. The predominant fusion partner is NPM1, which is involved in t(2;5)(p23;q35)
• Lymph nodes are commonly involved (90%), and extranodalinvolvement is frequent (60%)
• Median age of 30 years, usually present with advanced stage disease (stage III or IV), and systemic symptom |
| What are hallmarks of ALK+ anaplastic lymphoma? | • Characteristic “hallmark” cells that show eccentrically-placed, large, horse-shoe shaped nuclei with multiple nucleoli with abundant amphophilic cytoplasm.
• CD30, ALK
• CD2, and CD4 are most commonly expressed (40-70%)
• CD3 is negative in more than 75% of the cases
• CD45 can be negative |
| What is Hodgkins lymphonma? | • Cell of origin: germinal centre B-cell
• Reed-Sternberg cells (or RS variants) in the affected
tissues
• Most cells in affected lymph node are polyclonal
reactive lymphoid cells, not neoplastic cells
Epidemio: • less frequent than non-Hodgkin lymphoma
• overall M>F
• peak incidence in 3rd decade |
| How is presentation of HL? | • Nodular Sclerosis (most common subtype)
Collagen bands that divide lymph nodes into circumscribed
nodules Lacunar variant RS cells
• Mixed-cellularity T cells, eosinophils, plasma cells, macrophages, RS cells, EBV
• Lymphocyte-rich Reactive lymphocytes most of cellular infiltrate, EBV
• Lymphocyte depletion Paucity of lymphocytes, EBV
! Nodular lymphocyte-predominant Hodgkin
lymphoma (NLPHL) Non-classical RS cells- L&H variants
(popcorn cell)
Most important is RS cells |
