1. Lymphoma

2. Haematological Neoplasia - Overview Leukemias: Leukemias: Acute & Chronic, Acute & Chronic, Myeloid & Lymphoid Myeloid & Lymphoid Lymphomas: Lymphomas: Hodgkins & Non-Hodgkins Hodgkins & Non-Hodgkins Premalignant: Premalignant: Myeloproliverative - MPS Myeloproliverative - MPS Myelodysplastic - MDS Myelodysplastic - MDS

3. It is primary malignant proliferative Tumour arising from the peripheral Lymphoreticular system ( nodal and extra nodal) Central lymphoreticuular system is thymus & BM

4. Hodgkin lymphoma Thomas Hodgkin (1798-1866)

5. Epidemiology of lymphomas 5 th most frequently diagnosed cancer overall for both males and females 5 th most frequently diagnosed cancer overall for both males and females males > females males > females incidence incidence NHL increasing over time NHL increasing over time Hodgkin lymphoma stable Hodgkin lymphoma stable less frequent than non-Hodgkin lymphoma less frequent than non-Hodgkin lymphoma overall M>F = 3 :1 overall M>F = 3 :1 peak incidence in 3rd decade peak incidence in 3rd decade

6. Associated (etiological?) factors EBV infection EBV infection smaller family size smaller family size higher socio-economic status higher socio-economic status caucasian > non-caucasian caucasian > non-caucasian possible genetic predisposition possible genetic predisposition other: HIV? occupation? herbicides? other: HIV? occupation? herbicides?

7. Hodgkin lymphoma cell of origin: germinal centre B-cell cell of origin: germinal centre B-cell Reed-Sternberg cells (or RS variants) in the affected tissues Reed-Sternberg cells (or RS variants) in the affected tissues most cells in affected lymph node are polyclonal reactive lymphoid cells, not neoplastic cells most cells in affected lymph node are polyclonal reactive lymphoid cells, not neoplastic cells

8. B-cell development stem cell lymphoid precursor progenitor-B pre-B immature B-cell mature naive B-cell germinal center B-cell memory B-cell plasma cell DLBCL, FL, BL, HL LBL, ALL CLL MCL MM MZL CLL

9. A possible model of pathogenesis germinal centre B cell transforming event(s) loss of apoptosis RS cell inflammatory response EBV? cytokines

10. Lymphoma - Gross

11. Hodgkins lymphoma

12. Reed-Sternberg cell

13. Hodgkins lymphoma cells

14. The Scream, 1893 Edvard Munch Reed-Sternberg cell

15. RS cell and variants popcorn celllacunar cellclassic RS cell (mixed cellularity)(nodular sclerosis) (lymphocyte predominance)

16. Hodgkins Lymphoma: Painless, firm lymphadenopathy, Painless, firm lymphadenopathy, Fever* Eosinophilia Fever* Eosinophilia Only Reed-Sternberg cells malignant (B cell) Only Reed-Sternberg cells malignant (B cell) Classification(WHO): Classic Hodgkins: Classification(WHO): Classic Hodgkins: Lymphocyte predominant. Lymphocyte predominant. Nodular Sclerosis. Nodular Sclerosis. Mixed cellularity. Mixed cellularity. Lymphocyte depleted. Lymphocyte depleted. Nodular lymph. predominant (non-classic) Nodular lymph. predominant (non-classic)

17. Hodgkin’s Disease Nodular Sclerosing < 80% < 80% Supraclavicular & mediastinal Supraclavicular & mediastinal Stage I&II b Stage I&II b From, Diagnostic Surgical Pathology of the Head and Neck, W.B.Saunders, p 750 & 764. Lymphocyte Predominant 5 % Cervical LN Stage I &II a

18. Hodgkin’s Disease Mixed Cellularity > 20 % > 20 % Retroperitoneal Retroperitoneal Stage II & III Stage II & III From, Diagnostic Surgical Pathology of the Head and Neck, W.B.Saunders, p 750. Lymphocyte Depleted < 5 % Extra nodal system Stage III & IV

19. Hodgkin’s Disease Presentation Presentation Asymmetric lymphadenopathy—90% Asymmetric lymphadenopathy—90% Firm, rubbery Firm, rubbery Supraclavicular fossa Supraclavicular fossa Spleen, liver (extranodal sites relatively uncommon except in advanced disease Spleen, liver (extranodal sites relatively uncommon except in advanced disease Constitutional symptoms—1/3 of cases Constitutional symptoms—1/3 of cases Fever, night sweats, anorexia, weakness, weight loss Fever, night sweats, anorexia, weakness, weight loss

20. Lymphadenopathy in HL Number one or two groups Site mostly cervical Size usually small Shape discrete Consistency india rubbery or firm Mobile No skin involvement No tenderness No fixation

21. Lymphadenopathy in NHL Number multiple Site mostly extra nodal Size usually large Shape matted Consistency hard & cystic Fixed skin stretched & red tender fixation

22. Lymphadenopathy in Lymphoma HL Number one or two groups Number one or two groups Site mostly cervical Site mostly cervical Size usually small Size usually small Shape discrete Shape discrete Consistency india rubbery or firm Consistency india rubbery or firm Mobile Mobile No skin involvement No skin involvement No tenderness No tenderness No fixation No fixation NHL Number multiple Site mostly extra nodal Size usually large Shape matted Consistency hard & cystic Fixed skin stretched & red tender fixation

23. (1) Cervical lymphadenopathy (2) Hilar LN bronchial compression which cause segmental atelectasis (3) Mediastinal (a)SVC compression --- dilated Neck veins (b) RLN ---hoarsness of voice (c) Trachea & bronchi--- cough& dyspnea (d) Lung--- Dyspnea & effusion(4) Splenomegally dt infiltration or hyperplasia (5) Hepatomegally--- Ascites dt Hepatic dysfunction Peritoneal invasion (6) jaundice Prehepatic hemolytic autoimmune hypersplenism Hepatic– cholestatic hepatitis Posthepatic – LN at porta hepatis (7) Stomach & bowel malabsorption syndromes (8) Bone deposites Sever pain Pathological fractures (9) Neurological cord compression Cranial nerve palsy Root pains (10) Skin nodules (11) Mycosis fungoids (12) Anaemia Hypersplenism BM infiltration Cytotoxic drugs Extranodal manifestations

24. The challenge of lymphoma classification Clinically useful classification Diseases that have distinct clinical features natural history prognosis treatment Biologically rational classification Diseases that have distinct morphology immunophenotype genetic features clinical features

25. Stage IStage IIStage IIIStage IV Staging of lymphoma A: absence of B symptoms B: fever, night sweats, weight loss

27. Hodgkin Disease

35. Lymphoma Row of enlarged lymph nodes

37. Diagnosis:

38. Hodgkin’s Disease Evaluation Evaluation H&P H&P Biopsy = Reed-Sternberg cells Biopsy = Reed-Sternberg cells Staging w/u Staging w/u Similar to NHL Similar to NHL Laparotomy Laparotomy Controversial Controversial From, Principles and Practice of Pediatric Oncology, Lippincott Williams & Wilkins, P 640.

39. Hodgkin’s Disease Localized disease Localized disease Extended field XRT Extended field XRT Disseminated disease Disseminated disease MOPP = nitrogen mustard, vinblastine, procarbazine, prednisone MOPP = nitrogen mustard, vinblastine, procarbazine, prednisone ABVD = adriamycin bleomycin, vincristine, dacarbazine ABVD = adriamycin bleomycin, vincristine, dacarbazine

40. Laboratory Diagnosis: Haematological: Haematological: Normocytic normochromic anemia, High ESR* Normocytic normochromic anemia, High ESR* Leucocytosis, Eosinophilia, lymphopenia Leucocytosis, Eosinophilia, lymphopenia Leukoerythroblastic picture - BM infiltration* Leukoerythroblastic picture - BM infiltration* Bone marrow: Bone marrow: Normal, or late involvement. Normal, or late involvement. Trephine biopsy- diffuse or follicular infiltration Trephine biopsy- diffuse or follicular infiltration Biochemical: Biochemical: High serum LDH – poor prognosis High serum LDH – poor prognosis Hypercalcemia, Alkaline phosphatase, Uric acid. Hypercalcemia, Alkaline phosphatase, Uric acid. Serum transaminases & Bilirubin – Liver Serum transaminases & Bilirubin – Liver

41. Laboratory Diagnosis: Haematological: Haematological: Normocytic normochromic anemia, High ESR* Normocytic normochromic anemia, High ESR* Leucocytosis, Eosinophilia, lymphopenia Leucocytosis, Eosinophilia, lymphopenia Leukoerythroblastic picture - BM infiltration* Leukoerythroblastic picture - BM infiltration* Bone marrow: Bone marrow: Normal, or late involvement. Normal, or late involvement. Trephine biopsy- diffuse or follicular infiltration Trephine biopsy- diffuse or follicular infiltration Biochemical: Biochemical: High serum LDH – poor prognosis High serum LDH – poor prognosis Hypercalcemia, Alkaline phosphatase, Uric acid. Hypercalcemia, Alkaline phosphatase, Uric acid. Serum transaminases & Bilirubin – Liver Serum transaminases & Bilirubin – Liver

42. Laboratory Diagnosis: Immunological: Immunological: Monoclonal gammopathy –B cell NHL, Myeloma Monoclonal gammopathy –B cell NHL, Myeloma Low normal gammaglobulins Low normal gammaglobulins Autoimmune hemolytic anemia – auto ab. Autoimmune hemolytic anemia – auto ab. Karyotypic/Genetic: Karyotypic/Genetic: t(14;18) – B cell follicular (14* heavy chain) t(14;18) – B cell follicular (14* heavy chain) t(11;14) – diffuse NHL t(11;14) – diffuse NHL

43. Radiological Chest x ray Chest x ray Bone scan Bone scan Bone x ray if +ve bone scan or bone pains Bone x ray if +ve bone scan or bone pains CT scan of chest & abdomen & pelvis CT scan of chest & abdomen & pelvis Ga 67 scan Ga 67 scan SPRCT SPRCT PET to evaluate residuals PET to evaluate residuals

44. Mediastinal Lymph nodes-NHL

45. LN biopsy Must whole LN as Must whole LN as destruction of the architecture is of diagnostic value and destruction of the architecture is of diagnostic value and also Reed Sternberg in HL id diagnostic also Reed Sternberg in HL id diagnostic

46. Additional work up in NHL Flow cytometry Flow cytometry Peripheral blood Peripheral blood Bone marrow detect haematological involvement Bone marrow detect haematological involvement Diagnostic spinal tab in Diagnostic spinal tab in Lymphoblastic lymphoma Lymphoblastic lymphoma Burkitt’s lymphoma Burkitt’s lymphoma Upper GIT& small bowel series & endoscopy in S&S of GIT Upper GIT& small bowel series & endoscopy in S&S of GIT

47. Diagnostic laparotomy Indicated only in HL stage I&IIa ( as supraclavicular enlargment = 40% abdominal involvement) Indicated only in HL stage I&IIa ( as supraclavicular enlargment = 40% abdominal involvement) Technique Technique 1. Systemic LN examination 2. Biopsy from suspicious LN 3. Splenectomy 4. Wedge biopsy from liver 5. Ovariopexy 6. Appendectomy 7. Putting silver clips at the site of involved LN

48. Hodgkin’s Disease Localized disease (Stage I & II) Localized disease (Stage I & II) Extended field XRT Extended field XRT Above diaphragm -------- Mantle Above diaphragm -------- Mantle below diaphragm --------Inverted Y below diaphragm --------Inverted Y Recently IFRT + new modality chemotherapy ABVD Recently IFRT + new modality chemotherapy ABVD Stage III a Stage III a Extended field RT Extended field RT IFRT + ABVD IFRT + ABVD Multi agent chemotherapy ABVD or MOPP Multi agent chemotherapy ABVD or MOPP Disseminated disease (Stage III b & IV ) Disseminated disease (Stage III b & IV ) MOPP = nitrogen mustard, vinblastine, procarbazine, prednisone MOPP = nitrogen mustard, vinblastine, procarbazine, prednisone ABVD = adriamycin bleomycin, vincristine, dacarbazine ABVD = adriamycin bleomycin, vincristine, dacarbazine

49. Radiotherapy

50. Treatment and Prognosis StageTreatment Failure- free survival Overall 5 year survival I,II ABVD x 4 & radiation 70-80%80-90% III,IV ABVD x 6 60-70%70-80%

51. Hodgkin’s Disease Survival Survival Stages I, II, and III = 90% Stages I, II, and III = 90% Stage IV = 75-80% Stage IV = 75-80%

52. Long term complications of treatment infertility infertility MOPP > ABVD; males > females MOPP > ABVD; males > females sperm banking should be discussed sperm banking should be discussed premature menopause premature menopause secondary malignancy secondary malignancy skin, AML, lung, MDS, NHL, thyroid, breast... skin, AML, lung, MDS, NHL, thyroid, breast... cardiac disease cardiac disease

53. Non-Hodgkins Lymphoma (NHL)

54. Mechanisms of lymphoma- genesis Genetic alterations Genetic alterations Infection Infection Antigen stimulation Antigen stimulation Immuno-suppression Immuno-suppression

55. NHL – Classification: According to cell type According to cell type T cell, B cell, Histiocytic & Misc. NHL T cell, B cell, Histiocytic & Misc. NHL According to Clinical grade According to Clinical grade Low grade, Intermediate & High grade NHL. Low grade, Intermediate & High grade NHL. Histopathological Histopathological Diffuse/Follicular NHL, Diffuse/Follicular NHL, Small, Intermediate & Large cell NHL Small, Intermediate & Large cell NHL Ex: Lennert’s lymphoma is a low grade T cell NHL. Burkitt’s lymphoma, a high grade B cell NHL Burkitt’s lymphoma, a high grade B cell NHL

56. Kiel Classification of NHL B Cell NHL: B Cell NHL: Low Grade: lymphocytic, plasmacytic, centrocytic, mixed centrocytic centroblastic. Low Grade: lymphocytic, plasmacytic, centrocytic, mixed centrocytic centroblastic. High Grade: Centroblastic, Immunoblastic, Burkitts, lymphoblastic. High Grade: Centroblastic, Immunoblastic, Burkitts, lymphoblastic. T Cell NHL: T Cell NHL: Low Grade: lymphocytic, mycosis, Lennerts Low Grade: lymphocytic, mycosis, Lennerts High Grade: immunoblastic, lymphoblastic etc. High Grade: immunoblastic, lymphoblastic etc. Rare types: Rare types:

57. NCI – Working Formulation Low-grade NHL: Low-grade NHL: Small lymphocytic Small lymphocytic Follicular small cleaved Follicular small cleaved Intermediate-grade NHL: Intermediate-grade NHL: Follicular large cell Follicular large cell Diffuse small cleaved Diffuse small cleaved High-grade NHL: High-grade NHL: Immunoblastic Immunoblastic Lymphoblastic Lymphoblastic Miscellaneous: Histiocytic, Mycosis etc. Miscellaneous: Histiocytic, Mycosis etc.

58. Non-Hodgkin lymphoma Incidence Diffuse large B-cell lymphoma Follicular lymphoma Other NHL

59. Follicular lymphoma most common type of “indolent” lymphoma most common type of “indolent” lymphoma usually widespread at presentation usually widespread at presentation often asymptomatic often asymptomatic not curable (some exceptions) not curable (some exceptions) associated with BCL-2 gene rearrangement [t(14;18)] associated with BCL-2 gene rearrangement [t(14;18)] cell of origin: germinal center B-cell cell of origin: germinal center B-cell

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

61. Diffuse - & - Follicular NHL- Histologic types

62. Small – Intermed. – Large NHL- Histologic types

63. Lymphoma classification (based on 2001 WHO) B-cell neoplasms B-cell neoplasms Precursor B-cell neoplasms (2 types) Precursor B-cell neoplasms (2 types) Mature B-cell neoplasms (19) Mature B-cell neoplasms (19) B-cell proliferations of uncertain malignant potential (2) B-cell proliferations of uncertain malignant potential (2) T-cell & NK-cell neoplasms T-cell & NK-cell neoplasms Precursor T-cell neoplasms (3) Precursor T-cell neoplasms (3) Mature T-cell and NK-cell neoplasms (14) Mature T-cell and NK-cell neoplasms (14) T-cell proliferation of uncertain malignant potential (1) T-cell proliferation of uncertain malignant potential (1) Hodgkin lymphoma Hodgkin lymphoma Classical Hodgkin lymphomas (4) Classical Hodgkin lymphomas (4) Nodular lymphocyte predominant Hodgkin lymphoma (1) Nodular lymphocyte predominant Hodgkin lymphoma (1)

64. Clinical manifestations Variable Variable severity: asymptomatic to extremely ill severity: asymptomatic to extremely ill time course: evolution over weeks, months, or years time course: evolution over weeks, months, or years Systemic manifestations Systemic manifestations fever, night sweats, weight loss, anorexia, pruritis fever, night sweats, weight loss, anorexia, pruritis Local manifestations Local manifestations lymphadenopathy, splenomegaly most common lymphadenopathy, splenomegaly most common any tissue potentially can be infiltrated any tissue potentially can be infiltrated

65. Lymphadenopathy in NHL Number multiple Site mostly extra nodal Size usually large Shape matted Consistency hard & cystic Fixed skin stretched & red tender fixation

66. (1) Cervical lymphadenopathy (2) Hilar LN bronchial compression which cause segmental atelectasis (3) Mediastinal (a)SVC compression --- dilated Neck veins (b) RLN ---hoarsness of voice (c) Trachea & bronchi--- cough& dyspnea (d) Lung--- Dyspnea & effusion(4) Splenomegally dt infiltration or hyperplasia (5) Hepatomegally--- Ascites dt Hepatic dysfunction Peritoneal invasion (6) jaundice Prehepatic hemolytic autoimmune hypersplenism Hepatic– cholestatic hepatitis Posthepatic – LN at porta hepatis (7) Stomach & bowel malabsorption syndromes (8) Bone deposites Sever pain Pathological fractures (9) Neurological cord compression Cranial nerve palsy Root pains (10) Skin nodules (11) Mycosis fungoids (12) Anaemia Hypersplenism BM infiltration Cytotoxic drugs Extranodal manifestations

67. Non Hodgkin

75. Lymphoma spread to Spleen

76. Lymphoma Intestine

77. A practical way to think of lymphoma CategorySurvival of untreated patients CurabilityTo treat or not to treat Non- Hodgkin lymphoma IndolentYearsGenerally not curable Generally defer Rx if asymptomatic AggressiveMonthsCurable in some Treat Very aggressive WeeksCurable in some Treat Hodgkin lymphoma All typesVariable – months to years Curable in most Treat

78. Staging of Lymphoma

79. Burkitt’s Lymphoma Unusual, B-Lymphoblastic high grade Unusual, B-Lymphoblastic high grade Young african children, jaw bones Young african children, jaw bones Isolated histiocytes, starry sky pattern Isolated histiocytes, starry sky pattern EBV infection related. t(8;14) EBV infection related. t(8;14) Chemotherapy – good response Chemotherapy – good response But relapse usual, 30% cure. But relapse usual, 30% cure.

81. Burkitt’s Lymphoma

83. Burkitt’s Lymphoma L.N.

84. Non specific LN

85. Tuberculosis of LN Tuberculosis of LN

90. Metastasis LN