LYMPHOMA: A MINI MULTIUNIVERSE OF CHANGES

Surgeons role is to give the pathologist and oncologists to make a perfect plan for the patient most of the time, unless there is no compromise in anatomical function throughout.
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1. LYMPHOMAS DR RESHMA CHANDRASEKARAN DNB GENERAL SURGERY RESIDENT

2. INTRODUCTION LYMPHOMA: A heterogenous group of malignancies characterized by proliferation of lymphoid tissue diverse in: Cellular origin Morphology Immunophenotype Cytogenic and molecular abnormalities Response to treatment and prognosis.

3. some facts: 80% of all lymphomas are NHL 80% of NHL are B cell origin 80% of Hodgkin are supra diaphragmatic 80% of Hodgkin are Nodular sclerosis type

4. IMMUNE SYSTEM

5. H ODGKIN S’ DISEASE Hodgkin disease (HD) is a potentially curable malignant lymphoma with distinct histology, biologic behavior, and clinical characteristics. Histologically, the picture is unique, with 1-2% of neoplastic cells ( Reed-Sternberg [RS] cells ) in a background of a variety of reactive mixed inflammatory cells consisting of lymphocytes, plasma cells, neutrophils, eosinophils, and histiocytes

6. HODGKIN’S DISEASE - in the beginning 1798-1866 First described in 1832 by Dr. Thomas Hodgkin Neoplasm of B lymphocytes – large pleomorphic prominent nucleolus in a halo - Hodgkin cells Reed-Sternberg cell – binucleate Hodgkin cell with owl eye appearance Classification: Classical Hodgkin’s Nodular sclerosis – low grade Mixed cellularity Lymphocyte rich Lymphocyte depleted. –high grade Nodular lymphocyte predominance Hodgkin’s

7. Epidemiology Bimodal age distribution first peak between 2 nd - 3 rd decade of life second peak between 5 th - 6 th decade of life Male and female ratio is 2:1 in kids, in adults almost equal M:F Mixed cellularity (MC) Hodgkin’s Disease is more common at younger ages More common in immune deficiency patients

8. Etiology The etiology of HD is unknown. Infectious agents : Epstein-Barr virus (EBV) may be involved in the pathogenesis of HD. Patients with HIV infection have a higher incidence of HD compared to the population without HIV infection. Genetic predisposition

9. Clinical History Asymptomatic lymphadenopathy (above the diaphragm in 80% of patients). Constitutional symptoms or B symptoms: ( unexplained weight loss , fever , night sweats ) are present in 40% of patients. Chest pain, cough and shortness of breath may be present due to a large mediastinal mass or lung involvement. Rarely, hemoptysis is observed.

10. Patients may present with pruritus. Alcohol-induced pain at sites of nodal disease is specific for HD and occurs in less than 10% of patients. Intermittent fever is observed in approximately 25% of cases. Infrequently, the classic Pel- Ebstein fever (high fever for 1-2 weeks followed by an afebrile period of 1-2 weeks) is observed.

11. Palpable painless lymphadenopathy, rubbery in consistency occurs in: cervical area (60-80%), axilla (6-20%), inguinal area (6-20%). CORE NEEDLE BIOPSY: Gross: bulging “fish-flesh appearance. Microscopic: Reed-Sternberg cells IHC: CD 15 +, CD 30 + Splenomegaly may be present.

12. investigations CBP : Anemia (normochromic/normocytic), eosinophilia, neutrophilia, lymphopenia ESR -raised LFT- (liver infiltration / obstruction at porta hepatis) RFT- prior to chemo/radiotherapy. LDH - adverse prognosis CXR- mediastinal mass CT thorax / abdomen / pelvis-for staging Other: Gallium scan, PET, Lymphangiography , Laparotomy

13. Lab studies Lactate dehydrogenase ( LDH ) may be increased. LDH may correlate with the bulk of disease. Alkaline phosphatase may be increased due to the presence of liver or bone involvement. Other uncommon laboratory findings include hypercalcemia, hypernatremia, and hypoglycemia (due to the presence of insulin autoantibodies). Beta-2-microglobulin correlate with tumor burden, systemic symptoms, and prognosis.

14. For Diagnosis Physical exam and CT. A histological diagnosis always is required. Excisional lymph node biopsy is recommended. Staging laparotomy includes splenectomy, needle and wedge biopsy of the liver, and biopsies of the para-aortic, mesenteric, portal, and splenic hilar lymph nodes. Bilateral bone marrow biopsies - because HD is seen as patchy infiltrates in the bone marrow, bilateral bone marrow biopsies are advised.

15. Bulky disease THYROID MASS THYMOMA TERATOMA TERRIBLE LYMPHOMA

16. HODGKINS LYMPHOMA TYPE FEATURES NODULAR LYMPHOCYTE PREDOMINANCE Good prognosis NODULAR SCLEROSIS F > M 70 % anterior mediastinal mass. Lacunar type RS cells Excellent prognosis LYMPHOCYTE-RICH Good prognosis MIXED CELLULARITY Elderly Eosinophils, Plasma cell histiocytes Abdominal LNs and Spleen LYMPHOCYTE DEPLETED Least common Most aggressive Poorest survival

17. ANN ARBOR STAGING SYSTEM B SYMPTOMS

18. Treatment Radiation therapy - is the use of high-energy x-rays (or sometimes other radiation) to kill cancer cells and shrink tumors. Conventional chemotherapy : High-dose chemotherapy with transplantation HDC at doses that ablate the bone marrow is feasible with reinfusion of the patient's previously collected hematopoietic stem cells ( autologous transplantation ) or infusion of stem cells from a donor source ( allogeneic transplantation ).

19. Irradiation fields used in Hodgkin’s Lymphoma

20. Complications Cardiac disease Pulmonary disease Myelodysplasia/leukemia Infertility Breast cancer Non-Hodgkin lymphoma Other solid tumors Infectious complications Hypothyroidism after neck/mediastinal radiotherapy Immunodeficiency after chemotherapy and/or radiation therapy

21. NON-HODGKIN LYMPHOMAS (NHL) MOST COMMON

22. NHL - E pidemiology Incidence varies with race; white people have a higher risk than black and Asian American people. Male-to-female ratio of approximately 1.4:1 .

23. NHL - E tiology Chromosomal translocations and molecular rearrangements play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype. Some viruses are implicated in the pathogenesis of NHL – EBV, HCV etc. Environmental factors linked to the development of NHL include chemicals, chemotherapy, and radiation exposure Congenital , acquired , and induced (eg, immunosuppression) immunodeficiency states are associated with increased incidence of NHL The chronic inflammation

24. TYPES CELL OF ORIGIN TRANSLOCATION IMMUNOPHENOTYPE FOLLICULAR Germinal centre 2 nd MC t(14;18) BCL-2 CD 5- CD 10+ CD 23- MANTLE CELL Mature B cell covering GC t(11;14) BCL-6 SOX11 CD 5+ CD 10- CD 23- MARGINAL ZONE Post GC B cell t(11;18) CD 5- CD 10- CD 23- BURRKITT’S GC MC in children t(2;8), t(8;14), t(8;22) c-MYC over expression CD 5- CD 10+ BCL 2- BCL 6+ DIFFUSE LARGE B-CELL GC MC BCL-6 > BCL-2 CD 5- CD 10+ CD 45+ HAIRY CELL GC Post GC B cells BRAF + TRAP+ ANNEXIN A1+

25. TYPES GRADE/ PROGNOSIS HISTOLOGY FOLLICULAR MC Indolent/low grade Centrocytes and centroblasts MANTLE CELL Intermediate grade Centrocytes MARGINAL ZONE Low grade Splenic: hairy projections. BURRKITT’S Aggressive Proliferative index 100% Starry sky appearance DIFFUSE LARGE B-CELL Aggressive Post transplant CNS lymphoma HAIRY CELL Low-moderate grade Honey comb bone marrow Hairy cells Fried egg appearance

26. TYPES CLINICAL FEATURES TREATMENT FOLLICULAR Painless generalised LAP. Extra-nodal spread + High chance of transformation to DLBCL R-CHOP MANTLE CELL LAP, Splenomegaly, Lymphomatoid polyposis R-CHOP with high dose CYTARABINE MARGINAL ZONE NODAL: SPLENIC: Hep C + (R/F) MALTOMA: h.Pylori etc a/w CHRONIC INFECTIONS ANTIBIOTICS, R-CHOP BURRKITT’S EBV 100% Jaw/ facial tumor Abdominal spread +, BM, CNS CODOX-M/IVAC regimen CNS prophylaxis DIFFUSE LARGE B-CELL LAP, lymphomatoid polyposis R-CHOP, Anti- CD19 CNS prophylaxis in high risk HAIRY CELL Splenomegaly, LAP -, Atypical MB, dry tap, involves red pulp of spleen. CLADRIBINE IFN-alpha, splenectomy

27. Gastric NHL

28. Intestinal NHL

29. Extranodal NHL SPLENIC NHL BONE NHL

30. TREATMENT: A. Indolent stage I and contiguous stage II NHL Involved-field radiation therapy may be the treatment of choice in patients with localized low-grade NHL, especially of the head and neck. For these patients, radiation therapy produces a 10-year failure-free survival (FFS) rate of 50-60%, with an overall survival (OS) rate of 60-80%. Adjuvant chemotherapy to selected patients with stage I-II NHL with unfavorable prognostic factors (eg, B symptoms, >2 nodal sites) and to those with follicular mixed histology.

31. B. Indolent stage II, III, and IV NHL Treatment for symptomatic patients includes (1) purine nucleoside analogues (i.e., fludarabine), which have significant antitumor activity in low-grade NHL; (2) oral alkylating agents with or without steroids (i.e., cyclophosphamide, chlorambucil); (3) combination chemotherapy using cyclophosphamide, vincristine, and prednisone (CVP) or cyclophosphamide, hydroxydaunomycin, Oncovin (vincristine), and prednisone (CHOP).

32. (4) intensive therapy with chemotherapy and total body irradiation (TBI) followed by autologous or allogeneic bone marrow or peripheral stem cell transplantation, especially for younger patients with poor prognostic factors, is under clinical investigation. (5) For patients who are unable to tolerate other options, anti-CD20 monoclonal antibody (rituximab) may be considered as the first-line therapy, either alone or with combination chemotherapy.

33. B. Aggressive noncontiguous stage II, III, and IV NHL The treatment of choice for these patients is combination chemotherapy, either alone or supplemented by involved field irradiation. Doxorubicin-based combination chemotherapy produces long-term disease-free survival (DFS) in 35-45% of patients. For intermediate-grade lymphomas, CHOP chemotherapy remains the standard of care at this time.

34. Autologous and allogeneic bone marrow or peripheral stem cell transplantation for patients at high risk of relapse are under clinical investigation. CNS prophylaxis, usually with 4-6 injections of methotrexate intrathecally, is recommended for patients with paranasal sinus or testicular involvement, Burkitt lymphoma, or lymphoblastic lymphoma.

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