Syed Z A Zaidi

1. Syed Z A Zaidi

2. HISTORY

4. HISTORY - IMPORTANT LAND MARKS 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. 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.

6. Need for classification of Lymphomas and Leukemia : 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.

7. WHO classification of tumours of the haematopoietic and lymphoid tissues 4th edition, 2008 – true worldwide consensus classification of hematological 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.

8. Three important components to the process of developing classification of Hema 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.

9. 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 hematologic tumors. Some diseases have a characteristic immunophenotype. Similarly in some lymphoid and many myeloid neoplasms a specific genetic abnormality is the key defining criteria, while others lack specific known genetic abnormality. Some genetic abnormalities serve as prognostic factors (such as TP53 mutations or FLT3 – ITD). 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. In July 2009, some more explanations have been published in Blood Journal (Blood.2009: Vol 114: 937-951).

10. Precursor B & T cell Neoplasms: Precursor B Lymphoblastic Leukemia/LBL, NOS Precursor B Lymphoblastic Leukemia/LBL with recurrent cytogenetic abnormalities B Lymphoblastic Leukemia/LBL with t(9;22) B Lymphoblastic Leukemia/LBL with t(v;11q23) B Lymphoblastic Leukemia/LBL with t(12;21) B Lymphoblastic Leukemia/LBL with Hyperdiploidy B Lymphoblastic Leukemia/LBL with Hypodiploidy B Lymphoblastic Leukemia/LBL with t(5;14) B Lymphoblastic Leukemia/LBL with t(1;19) Precursor T Lymphoblastic Leukemia/TLBL

19. 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

21. B-cell development

22. A practical way to think of lymphoma

23. Classification

24. WHO classification The WHO Classification, published in 2001 and updated in 2008, is the latest classification of lymphoma and is based upon the foundations laid within the “REAL” classification. This system attempts to group lymphomas by cell type (i.e. the normal cell type that most resembles the tumour) and defining phenotypic, molecular or cytogenetic characteristics. There are three large groups: the B cell, T cell, and natural killer cell tumors. Hodgkin's lymphoma, although considered separately within the WHO (and preceding) classifications, is now recognised as being a tumour of, albeit markedly abnormal, lymphocytes of mature B cell lineage.

43. A practical way to think of lymphoma

44. Three common lymphomas Follicular lymphoma Diffuse large B-cell lymphoma Hodgkin lymphoma

45. Relative frequencies of different lymphomas

46. 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

47. 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

48. Diffuse large B-cell lymphoma most common type of “aggressive” lymphoma usually symptomatic extranodal involvement is common cell of origin: germinal center B-cell treatment should be offered curable in ~ 40%

49. Hodgkin lymphoma Classical Hodgkin lymphomas: Nodular sclerosis Mixed cellularity Lymphocyte-rich Lymphocyte depleted or not depleted Nodular lymphocyte-predominant Hodgkin lymphoma

50. 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

51. Reed-Sternberg cell

52. RS cell and variants

53. A possible model of pathogenesis