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 Lymphoma : Malignancy of Lymphocytes

 Lymphoma : Malignancy of Lymphocytes.  Lymphocytes B-cells. T-cells NK-cells (Natural Killer Cells). Definition  The term "malignancy" refers to cancerous cells that have the ability to invade and destroy tissues, and / or to metastasize to

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 Lymphoma : Malignancy of Lymphocytes

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  1.  Lymphoma : Malignancy of Lymphocytes  Lymphocytes B-cells T-cells NK-cells (Natural Killer Cells)

  2. Definition The term "malignancy" refers to cancerous cells that have the ability to invade and destroy tissues, and / or to metastasize to other sites in the body. There may also be changes to the physiology of the organism. Malignant cells tend to have fast, uncontrolled growth due to changes in their genetic makeup.

  3. A malignant clone is a clone of cell that have genomic changes that leads to the malignant state. However not all genomic changes result in malignant clones.

  4. Clonal evolution is the further changes in the genome which may result in progression of disease relapse after treatment resistence to standard therapy.

  5. Lymphomas  10-20 new case per 100,000 per year  Deaths 8 per 100,000 per year Commonest: Diffuse Large B-cell lymphoma Follicular lymphoma CLL Mantle cell lymphoma

  6. Rappaport Lymphoma Classification  1966 Well-differentiated diffuse lymphocytic lymphoma Poorly differentiated diffuse lymphocytic lymphoma Well differentiated nodular lymphocytic lymphoma Poorly differentiated nodular lymphocytic lymphoma Nodular Histiocytic lymphoma (= large cell lymphoma) Diffuse Histiocytic lymphoma (=large cell lymphoma) Mixed cell lymphoma MORPHOLOGY ONLY

  7. Non-Hodgkin’s lymphoma  Lukes and Collins USA  Dorfman  Kiel (Lennert) Germany  WHO Geneva UK Hodgkin’s lymphoma  Lukes-Butler  Rye Nodular sclerotic Lymphocyte predominent Mixed cellularity Lymphocyte depleted

  8. Lukes and Collins (1974) Unidentified Cell Type I. T-cells Mycosis fungoides and Sezary, convoluted lymphocyte Immunoblastic sarcoma of T-cells. II. III. B-cells Small lymphocytic Plasmacytoid lymphocyte Follicular center cell (FCC types; follicular, diffuse, follicular and diffuse, sclerotic) small cleaved large cleaved small non-cleaved Large non-cleaved Immunoblastic IV Histiocytic type V Unclassifiable

  9. Updated Kiel B- cell Low Grade T-cell   Lymphocytic- CLL, prolymphocytic,hairy cell lymphoma Lymphoplasmacytic/lymphoplasmactoid Lymphocytic CLL, prolymphocytic Lymphoepitheloid   Medium Grade Plasmacytic Centrocytic Centroblastic/centroblastic Angioimmunoblastic T-zone Pleomorphic small cell Pleomorphic medium and large       High Grade Centroblastic Immunoblastic Large cell anaplastic Burkitt’s lymphoma Lymphoblastic  Immunoblastic Large cell naplastic      Lymphoblastic   Rare types Rare types  

  10. Working Formulation Low Grade  Malignant Lymphoma, small lymphocytic (chronic lymphocytic leukemia)  Malignant Lymphoma, follicular, predominantly small cleaved cell  Malignant Lymphoma, follicular, mixed (small cleaved and large cell) Intermediate grade  Malignant Lymphoma, follicular, predominantly large cell  Malignant Lymphoma, diffuse, small cleaved cell  Malignant Lymphoma, diffuse, mixed small and large cell  Malignant Lymphoma, diffuse, large cell High grade  Malignant Lymphoma, large cell, immunoblastic  Malignant Lymphoma, lymphoblastic  Malignant Lymphoma, small non-cleaved cells (Burkitt's lymphoma) Miscellaneous  Composite  Mycosis fungoides  Histiocytic  Extramedullary plasmacytoma  Unclassifiable    

  11. Immunophenotyping

  12. Cytogenetics Normal Karyotype

  13. t(9:22) Philadelphia chromosome

  14. Fluorescent In Situ Hybridisation (FISH)

  15. The Revised European American Lymphoma Classification (REAL) 1994 I. Precursor B-cell neoplasm: Precursor B-lymphoblastic leukemia/lymphoma II. Mature (peripheral) B-cell neoplasms B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes) Hairy cell leuekmia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type Nodal marginal zone lymphoma (+/- monocytoid B-cells) Follicle center lymphoma, follicular, Mantle cell lymphoma Diffuse large cell B-cell lymphoma Mediastinal large B-cell lymphoma Primary effusion lymphoma Burkitt's lymphoma/Burkitt's cell leukemia                  T-Cell and Natural Killer Cell Neoplasms I. Precursor T cell neoplasm: Precursor T-lymphoblastic lymphoma/leukemia II. Mature (peripheral) T cell and NK-cell neoplasms T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-Cell leukemia Adult T cell lymphoma/leukemia (HTLV1+) Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic gamma-delta T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sézary's syndrome Anaplastic large cell lymphoma, T/null cell, primary cutaneous type Peripheral T cell lymphoma, not otherwise characterized Angioimmunoblastic T cell lymphoma Anaplastic large cell lymphoma, T/null cell, primary systemic type                  Hodgkin lymphoma (Hodgkin Lymphoma) Nodular lymphocyte predominance Hodgkin's lymphoma Classical Hodgkin's lymphoma Nodular sclerosis Hodgkin's lymphoma Lymphocyte-rich classical Hodgkin's lymphoma Mixed cellularity Hodgkin's lymphoma Lymphocyte depletion Hodgkin's lymphoma       

  16. WHO classification 2002 Mature B cell neoplasms  Chronic lymphocytic leukemia/Small lymphocytic lymphoma  B-cell prolymphocytic leukemia  Lymphoplasmacytic lymphoma (such as Waldenström macroglobulinemia)  Hairy cell leukemia  Splenic marginal zone lymphoma  Extranodal marginal zone B cell lymphoma, also called MALT lymphoma  Nodal marginal zone B cell lymphoma (NMZL)  Follicular lymphoma  Mantle cell lymphoma  Diffuse large B cell lymphoma  Mediastinal (thymic) large B cell lymphoma  Intravascular large B cell lymphoma  Primary effusion lymphoma  Burkitt lymphoma/leukemia  Mature T cell and natural killer (NK) cell neoplasms  T cell prolymphocytic leukemia  T cell large granular lymphocytic leukemia  Aggressive NK cell leukemia  Adult T cell leukemia/lymphoma  Extranodal NK/T cell lymphoma, nasal type  Enteropathy-type T cell lymphoma  Hepatosplenic T cell lymphoma  Blastic NK cell lymphoma  Mycosis fungoides / Sezary syndrome  Primary cutaneous CD30-positive T cell lymphoproliferative disorders  Primary cutaneous anaplastic large cell lymphoma  Lymphomatoid papulosis  Angioimmunoblastic T cell lymphoma  Peripheral T cell lymphoma, unspecified  Anaplastic large cell lymphoma  Hodgkin lymphoma  Classical Hodgkin lymphomas: Nodular sclerosis Mixed cellularity Lymphocyte-rich Lymphocyte depleted or not depleted Nodular lymphocyte-predominant Hodgkin lymphoma       Immunodeficiency-associated lymphoproliferative disorders Associated with a primary immune disorder Associated with the Human Immunodeficiency Virus (HIV) Post-transplant Associated with methotrexate therapy Primary central nervous system lymphoma occurs most often in immuno-compromised patients, in particular those with AIDS, but it can occur in the immunocompetent as well. It has a poor prognosis, particularly in those with AIDS. Treatment can consist of corticosteroids, radiotherapy, and chemotherapy, often with methotrexate.      

  17. WHO Classification 2008 98 lymphoma entities

  18. Burkitt’s Lymphoma Endemic Sporadic

  19. c-myc oncogene Regulator of 15% of genes, some of which are involved in cell replication.

  20. Chronic Lymphocytic Leukemia Small lymphocytic lymphoma CD20 weak IgM weak FMC7 neg CD5 pos CD 23 pos CD 38 prognostic marker ZAP-70 prognostic marker

  21. CLL Staging Stage 0 (LOW RISK)  Lymphocytosis >5,000/mm3 without adenopathy (enlarged lymph nodes), hepatosplenomegaly (enlarged spleen), anemia (low red blood cells), or thrombocytopenia (low platelets).  Stage I (INTERMEDIATE RISK) lymphadenopathy  Stage II (INTERMEDIATE RISK) hepatomegaly or splenomegaly with or without lymphadenopathy  Stage III (HIGH RISK) Hb < 11.0 g/dL,  Stage IV (HIGH RISK) low platelets < 100,00/mcL 

  22. FISH 17 p- 11q- Normal 111 mths Trisomy 12 114 mths 13q- 6q-  14q32 Poor prognosis 32 mths 79 mths 133 mths Good prognosis

  23.  Low-risk CLL People in this group are often diagnosed based on a high lymphocyte count in the blood but otherwise have normal blood counts and do not have enlarged lymph nodes or organs. The prognosis (outlook) for people in this group is often very good, with long survival expected.  Most people can be observed with careful and frequent follow-up exams. Treatment is considered if there are signs that the leukemia is progressing or if a person develops bothersome symptoms. When needed, initial treatment is usually chemotherapy (chemo) often combined with a monoclonal antibody targeting CD20 like rituximab (Rituxan).

  24. Patients with high-risk CLL (stages III and IV) are more likely to need immediate treatment.  When treatment is needed, there are many options. What treatment is used will depend on factors like the patient's health, possible side effects, the reason treatment is needed, and any need for a rapid response. Commonly used treatments include:  ■FCR: fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab ■Bendamustine (sometimes with rituximab) ■FR: fludarabine and rituximab ■CVP: cyclophosphamide, vincristine, and prednisone (sometimes with rituximab) ■CHOP: cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone ■Chlorambucil ■PCR: pentostatin (Nipent), cyclophosphamide, and rituximab ■Alemtuzumab (Campath) Anti-CD52 ■Fludarabine (alone)

  25. Prolymphocytic leukemia FMC7 pos 

  26. Lymph node

  27. Mantle cell lymphoma CD5 +ve

  29. MC treatment CHOP (hyper VCAD) Proteosome inhibitors Stem cll transplant

  30. Follicular lymphoma WelI differentiated germinal centre lymphoma CD 5 –ve CD 10 +ve

  31. Bcl-2

  32. Lymphoma staging Ann Arbor A No symptoms B Symptoms Sweats, Unexplained fever Weight loss

  33. FL treatment CLL type combinations FMDR Fludarabine Mitoxanthrone Dexamethasone Rituxamab

  34. Diffuse Large B-cell Lymphoma  30% - 40% lymphomas  Poorly Differentiated Germinal Centre Lymphoma Bcl-6 +ve (Chr 3q.27) (Myc, Bcl-2, cyclin D2, CyclinD3,MUM-1)  Poorly differentiated non-germinal centre lymphomas May be cured by CHOP cyclophosphamide adriamycin vincristine prednisone     

  35. Marginal cell lymphomas  Mucosa-associated lymphoid tissue MALT-oma  Splenic marginal zone lymphoma  Nodal marginal zone lymphoma

  36. Gastric MALTOMA Helicobactor pylori nearly always present. Virulence factor CagA may be required for the continued growth of the lymphoma Japanese have shown triple antibiotic therapy for H. pylori will result in regression of the lymphoma. (amoxicillin, clarithromycin, omeprazole)

  37. Other Maltomas Associated with Autoimmune Disease  Thyroid Maltoma with Hashimoto’s thyroiditis  Lacrimal and Salivary gland Maltoma associated with Sjrogen’s disease.

  38. MALT FISH PANEL  t(11;18) in gastric Maltoma  t(14,18) in lacrimal/salivary gland Maltoma  t(3;14) in thyroid Maltoma  t(1;14) in lymph node marginal zone lymphomas

  39. Hairy cell leukemia  B memory cell  Red pulp of spleen Often bone marrow  Tartrate-resistent acid phosphatase positive  CD103 positive CD11c, CD25  DBA-44 positive in paraffin sections  Cures with α-interferon adenosine-deaminase inhibitors deoxycorfomycin 2-chlorodeoxyadenosine

  40. Immunoglobulin Secreting Disorders Primarily bone marrow diseases Lymphoplasmacytic lymphoma Waldenstom’s Macroglobulinaemia IgM > Hyperviscosity  1. MYD-88 L265P mutation 2013 2. Plasma cell IgG, IgA, (IgD, IgE rare)

  41. Plasma cell disorder WHO 2008 1. M-protein < 30g/L <10% plasma cells No symptoms = MGUS Monoclonal gammopathy of uncertain significance 2. M-protein > 30g/L and/or >10% plasma cells No symptoms = Smouldering multiple myeloma 3. M-protein and/or clonal plasma cells Symptoms CRAB hypercalcaemia renal impairment anaemia bone lesions = Multiple myeloma

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