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  • Figure 2. Diagrammatic representation of B-cell differentiation
    and relationship to major B-cell neoplasms.
    B-cell neoplasms correspond to stages of B-cell maturation, even though the precise cell counterparts are not known in all instances.
    Precursor B cells that mature in the bone marrow may undergo apoptosis or
    develop into mature naive B cells that, following exposure to antigen and blast transformation, may develop into short-lived plasma cells or enter the germinal center (GC), where somatic hypermutation and heavy chain class-switching occur.
    Centroblasts, the transformed cells of the GC, either undergo apoptosis or develop into centrocytes. Post-GC cells include both long-lived plasma
    cells and memory/marginal zone B cells. Most B cells are activated within the GC, but T cell–independent activation can take place outside of the GC and also probably leads to memory-type B cells.
    Monocytoid B cells, many of which lack somatic hypermutation, are not illustrated.AG indicates antigen; and FDC, folllicular dendritic cell.
    Red bar represents immunoglobulin heavy chain gene (IGH@) rearrangement; blue bar, immunoglobulin light chain gene (IGL) rearrangement; and black insertions in the red and blue bars indicate somatic hypermutation.
  • Diagrammatic representation of T-cell differentiation and function. Lymphoid progenitors enter the thymus where precursor T cells develop into varied types of naive T cells.
    The cells of the innate immune system include NK cells, T cells, and NK-like T cells. These cells constitute a primitive type of immune response that lacks both specificity and memory.
    In the adaptive immune system, T cells leave the thymus, where, upon exposure to antigen, they may undergo blast transformation and develop further into CD4 and
    CD8 effector and memory T cells. T cells of the adaptive immune system are heterogeneous and functionally complex, and include naive, effector (regulatory
    and cytotoxic), and memory T cells. Another specific type of effector T cells is the follicular helper T-cell that is found in GCs (TFH).
    Upon antigenic stimulation, T-cell responses may occur independent of the GC, or in the context of a GC reaction.
    The lymphomas of the innate immune system are predominantly extranodal in presentation, mirroring the distribution of the functional components of this system. T-cell lymphomas of the adaptive immune system present primarily in adults, and are
    mainly nodal in origin.

    1. 1. Stephen Larsen 24th February, 2010 Lymphomas - classification and diagnosis
    2. 2. Two important references
    3. 3. $US122 $US104
    4. 4. Background
    5. 5. Thomas Hodgkin (1798-1866) Thomas Hodgkin published in 1832 the first description of lymphoma, specifically of the form named after him, Hodgkin's lymphoma. Name Hodgkin's Disease proposed in 1865 by Wiks.
    6. 6. History of Lymphoma Classification Since Thomas Hodgkin’s first description of lymphoma in 1832, many other forms of lymphoma have been described, grouped under several proposed classifications. 1956, 1966 Rappaport’s Classification of NHL 1966 Lukes-Butler (American) modern classification of HL Kiel classification: in 1974, Karl Lennert proposed a new system of classifying lymphomas based on cellular morphology and their relationship to cells of the normal peripheral lymphoid system.
    7. 7. The very popular 1982 Working formulation classification introduced the category Non- Hodgkin Lymphoma (NHL), itself divided into 16 different diseases. REAL classification: In 1994 the Revised European-American Lymphoma (REAL) Classification attempted to apply immunophenotypic and genetic features in identifying distinct clinico-pathologic NHL entities. The latest classification by the WHO (2001 updated in 2008) lists 43 different forms of lymphoma divided in four broad groups.
    8. 8. BLOOD, 1 DECEMBER 2008 VOLUME 112, NUMBER 12 p4384 Classification of lymphoid neoplasms: the microscope as a tool for disease discovery
    9. 9. A practical way to think of lymphoma Category Survival of untreated patients Curabilit y To treat or not to treat Non- Hodgkin lymphoma Indolent Years Generally not curable Generally defer Rx if asymptomatic Aggressive Months Curable in some Treat Very aggressive Weeks Curable in some Treat Hodgkin lymphoma All types Variable – months to years Curable in most Treat
    10. 10. Need for classification of Lymphomas Classification is a language of medicine: diseases must be described, defined and named before they can be diagnosed, treated and studied. A consensus on definitions and terminology is essential for both clinical practice and investigation. A classification should contain diseases that are clearly defined, clinically distinctive, non- overlapping and that together comprise all known entities.
    11. 11. WHO classification of tumours of the haematopoietic and lymphoid tissues 4th edition, 2008 – true worldwide consensus classification of haematological malignancies: WHO classification is based on the principles initially defined in REAL classification by the ILSG. Guiding principle of the REAL and WHO classification is the attempt to define “real diseases” that can be recognised by available techniques and that appear to be distinct clinical entities.
    12. 12. Three important components to the process of developing classification of Hematological Malignancies: First, recognising that the underlying causes of the neoplasm are often unknown and may vary. So, we use morphology, immunophenotype, genetic features, and clinical features to define diseases. Second principle is that classification relies on building a consensus among as many experts as possible on the definition and nomenclature of the disease. Third, while pathologists must take primary responsibility for developing a primary classification, involvement of clinicians is essential to ensure its usefulness and acceptance in daily practice.
    13. 13. There is no one “gold standard” by which all diseases are defined in the WHO classification. So: 1. Morphology is always important. 2. Immuno-phenotype and 3. Genetic features are an important part of the definition of haematologic tumors. Some diseases have a characteristic immunophenotype.  Similarly in some lymphoid a specific genetic abnormality is the key defining criteria, while others lack specific known genetic abnormality. Some genetic abnormalities serve as prognostic factors. Most of the diseases in WHO classification are considered to be distinct entities. However, some are not clearly defined and these are listed as provisional entities.
    14. 14. Conceptualizing lymphoma and its Classification neoplasms of lymphoid origin, typically causing lymphadenopathy leukemia vs lymphoma (extent of BM involvement) lymphomas as clonal expansions of cells at certain developmental stages
    15. 15. Clinically useful classification Diseases that have distinct • clinical features • natural history • prognosis • treatment Biologically rational classificationDiseases that have distinct • morphology • immunophenotype • genetic features • clinical features
    16. 16. stem cell lymphoid progenitor progenitor-B pre-B immature B-cell memory B-cell plasma cellplasma cell DLBCL, FL, HL ALL CLL MM germinalgerminal centercenter B-cellB-cell mature naive B-cell
    17. 17. Diagrammatic representation of B-cell differentiation and relationship to major B-cell neoplasms.
    18. 18. Diagrammatic representation of T-cell differentiation and function.
    19. 19. Main Groups in WHO Classification of Lymphoid Malignancies B Cell Neoplasms Precursor B Neoplasms Mature B Cell Neoplasms T Cell and NK Cell Neoplasms Precursor T Cell Neoplasms Mature T Cell and NK Neoplasms Hodgkins Lymphoma
    20. 20. Diagnosis Radiographic features • Ultrasound • Chest-x-ray film: the mediastinal lymphonodes • Computerized tomography(CT) • Chest • Abdomen, • Pelvis • Gallium-67 scintigraphy • Whole-body positron emission tomography(PET)
    21. 21. Diagnosis Biopsy----Pathological Diagnosis Histopathological classification Immunomarkers eg: NHL, diffused large cell, B cell Cytogenetic studies E.g; Mantle Cell Lymphoma Molecular Studies
    22. 22. Diagnosis depends on biopsy of lymph nodes or other involved organs Need enough tissue to assess cells and architecture open bx vs core needle bx vs FNA A fine needle biopsy is rarely sufficient! Peripheral blood: Blood involvement. Usually no changes in WBC and Platelet count BM: non-specific changes HD: R-S cell in smear and biopsy NHL: increased lymphocyte
    23. 23. Laboratory Findings Flow cytometry. Immunophenotyping of biopsy material is important in NHL.  Establish clonality  Pattern of surface protein expression can be diagnostic Immunological tests:  NHL: M-protein(+) Coombs’ test(+) hypoglobulinemia Other findings: ESR ↑ LDH ↑
    24. 24. Disorder Common Phenotype Comments/Variations Potentially Associated Genetic Abnormalities Chronic lymphocytic leukemia/small cell lymphocytic lymphoma DR, CD19, CD20, CD5, CD22(-), CD23, CD10(-), CD11c+/- , CD25+/- , CD43, clonal SIgM and SIgD weak CD20 dim Abnormalities of 13q, 14q, 11q BCL-2 overexpressed Bright SIg, CD20, FMC7 Mantle cell lymphoma DR, CD19, CD20, CD5, CD22, CD23(-), CD10(-), CD43, moderate clonal SIg (IgM > IgD) Cyclin D1 overexpressed t(11; 14) Follicular lymphoma DR, CD19, CD20, CD5(-), CD22, CD23+/- , CD10, CD11c(-), CD43(-), very bright clonal SIg CD10 negative <20% t(14; 18) Overexpression of BCL-2 Marginal zone and associated lymphomas DR, CD19, CD20, CD5(-), CD22, CD23(-), CD10(-), CD11c, CD25(-), CD103(-), moderate clonal SIg SIgD rare Trisomy 3 Hairy cell leukemia DR, CD19, CD20, CD5(-), CD22, CD23(-), CD10(-), CD11c, CD25, CD103, moderate clonal SIg SIgD common, very bright CD22 and CD11c No consistent alteration Plasma cell dyscrasias DR(-), CD19(-), CD20(-), CD22(-), CD38, CD45, clonal cIg, clonal SIg-/+ Two color bright CD38 and dim CD45 sensitive marker No consistent alteration
    25. 25. Laboratory Findings Chromosome changes in NHL:  t(14;18): Follicular lymphoma  t(8;14): Burkitt’s lymphoma  t(11;14): Mantle-cell lymphoma  t(2;5): Ki-1+ (CD30 + ) Anaplastic large-cell lymphoma  3q27: Diffuse large B-cell lymphoma
    26. 26. Laboratory Findings Molecular Biology changes in NHL • bcl-2 • TCR • IgH
    27. 27. Differential Diagnosis Lymph nodes enlargement Specific: TB Infection Non-specific: bacteria, virus, Maligancies: haematological (leukaemia,etc); solid tumor metastasis Connective tissue diseases  Kikuchi’s lymphadenitis in women with SLE Sarcoidosis Reactive!
    28. 28. Differential Diagnosis Fever Infection ( bacteria , virus, TB, etc ) Connective tissue disease Malignant tumors Malignancies in related organs Gastrointestinal tumors, liver cancer, etc
    29. 29. 30% 22%8% 7% 6% 6% 6% 2% 14% Large B-cell Follicular Marginal zone PTCL Mantle cell SLL/CLL Mediastinal Anaplastic L cell Hodgkin’s 2002 SEER database. O’Connor
    30. 30. Three most common lymphomas Follicular lymphoma Diffuse large B-cell lymphoma Hodgkin lymphoma
    31. 31. Follicular lymphoma most common type of “indolent” lymphoma usually widespread at presentation often asymptomatic not curable (some exceptions) associated with BCL-2 gene rearrangement [t(14;18)] cell of origin: germinal center B-cell
    32. 32. Follicular Lymphoma
    33. 33. defer treatment if asymptomatic (“watch- and-wait”) several chemotherapy options if symptomatic median survival: years despite “indolent” label, morbidity and mortality can be considerable transformation to aggressive lymphoma can occur
    34. 34. Diffuse large B-cell lymphoma most common type of “aggressive” lymphoma usually symptomatic extranodal involvement is common cell of origin: germinal center B-cell or activated B-like lymphoma treatment should be offered curable in ~ 40%
    35. 35. Diffuse Large B Cell Lymphoma
    36. 36. Hodgkin lymphoma Classical Hodgkin lymphomas: Nodular sclerosis Mixed cellularity Lymphocyte-rich Lymphocyte depleted or not depleted Nodular lymphocyte-predominant Hodgkin lymphoma
    37. 37. Hodgkin lymphoma 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
    38. 38. Reed-Sternberg cell
    39. 39. popcorn celllacunar cellclassic RS cell (mixed cellularity) (nodular sclerosis) (lymphocyte predominance)
    40. 40. germinal centre B cell transforming event(s) loss of apoptosis RS cell inflammatory response EBV? cytokines
    41. 41. Conclusion There are a large number of types of lymphoma. Therefore classification is important: a consensus on definitions and terminology is essential for both clinical practice and clinical studies. Classification has evolved as well learn more about the biology of distinct disorders. Diagnosis requires an adequate biopsy. There are differing roles of flow cytometry, cytogenetics and moelcular studies for different disorders.