LYMPHOMAS

1. LYMPHOMAS Dr. Marlene Hamilton

2. Objectives • What is lymphoma • Brief Overview of the history • How does it present clinically • How do we diagnose lymphoma • Hodgkin vs non-Hodgkin lymphoma • Principles of treatment

3. Lymphoma • cancer of lymphocytes • originate from T or B cells • relatively common maligancies • subdivided into Hodgkin and Non-Hodgkin Lymphoma (NHL)

4. Lymphoma History • First recognized by Thomas Hodgkin in 1832 • paper “On Some Morbid Appearances of the Absorbent Glands and Spleen” • recognized that enlarged lymph nodes could arise from primary disorder (vs infection or carcinoma) • in 1860’s Virchowdistinguished between leukemia “aleukmia” and “lymphosarcoma” • in 1871 Billroth coined term malignant lymphoma • about 1900 Reed and Sternberg identified cell classic for Hodgkin Lymphoma and pointed out importance of histopathology in the diagnosis of lymphoma

5. Lymphoma History • In 1920’s Brill described the pathologic features of Follicular lymphoma • 1956 Rappaport developed a morphologic classification of non-Hodgkin Lymphoma • in 1972 the immunologic origin discovered by finding monotypic Ig on surface of B cell lymphomas • In 1982 a morphologic classification of NHL developed called the Working Formulation • based on grade • in 1994 a Revised European-American Lymphoma Classification (REAL) developed which classified according to T of B cell lineage • current WHO classification

6. Which Tissues are Affected? • Lymph nodes • spleen • bone marrow • less common peripheral blood, solid organs, skin, CNS

7. Lymphadenopathy • Enlarged lymph nodes • usually greater than 1 cm • most infectious in etiology

8. Lymphadenopathy • Worrisome features for lymphoma • infectious work-up negative • persistent • growing • multiple sites • associated with fever • associated with night sweats • associated with weight loss

9. Lymphadenopathy • abnormal CBCD • abnormal renal or LFTs • Differential diagnosis of lymphadenopathy • infectious cause • lymphoma • carcinoma • other rarer causes

10. Lymphadenopathy • lymph nodes affected by lymphoma typically firm and may be rubbery • usually mobile, but may be fixed • lymph nodes often painless • lymph nodes affected by carcinoma more likely to be rock hard and fixed

11. Clinical presentation • LN • symptoms resulting from LN impact • ex SOB from mediatinal mass, ARF from ureteric obstruction • symptoms from bone marrow infiltration • ex bleeding from thrombocytopenia, infection from neutropenia, fatigue from anemia

12. Clinical presentation • Weight loss > 10% over 6 months • Fever >38*C • drenching night sweats • = “B” symptoms • May have associated autoimmune phenomena • ITP = immune thrombocytopenia purpura • AIHA = autoimmune hemolyic anemia May have no Symptoms

13. Clinical presentation • Hodgkin • younger (bimodal) • often above diaphragm • moves orderly to nodal groups • more often B symptoms (ex Pel- Ebstein fever) • NHL • often older • often disseminated • no orderly spread • often disseminated at diagnosis

14. Lymphadenopathy • To make diagnosis of lymphoma need an EXCISIONAL biopsy • pathologist needs sufficient tissue to view morphology and to perform immunostains • fine needle aspirate (FNA) insufficient • core biopsy may be acceptable • usually choose the largest lymph node to biopsy • disfavour inguinal lymph nodes • choose lymph node which is safe and accessible • if lymphadenopathy intra-abdominal may need to consider second best choice, U/S or CT guided core biopsy vs surgical excisional biopsy

15. Lymphoma Pathology • NHL • Hodgkin Lymphoma • Specific pathology and stage are important as they determine the treatment strategy • Ann Arbor Staging- applies to both NHL and Hodgkin

16. Lymphoma Staging • I single LN region/extranodal site • II 2/more LN regions on same side of diaphragm • III LN regions on both sides of the diaphragm • IV diffuse involvement of extralymphatic organs or sites • A no B symptoms • B • fever > 38 *C • weight loss >10% over 6 months • drenching night sweats • S spleen involvement • Bulky LN>10 cm • E extranodal

17. Lymphoma Extranodal Sites • Can be virtually anywhere • GIT • thyroid • parotid • breast • testicle • eye • skin • Bone • brain • sinuses • ...

18. Lymphoma Staging • History and physical • CT (neck), chest, abdomen and pelvis • Bone marrow biopsy • PET scan not routine • other in special situations (ex LP, CT head)

19. Lymphoma other tests • LDH (NHL) • ESR (HD)

20. NHL Lymphoma Classification • More than 40 entities • WHO subdivides into B and T or NK cell neoplasms • clinically subdivide into indolent, aggressive and very aggressive

21. NHL Lymphoma Classification • Resultant lymphoma dependent on site

22. NHL- Indolent B cell • Follicular lymphoma • Small Lymphocytic Lymphoma (SLL) or CLL • MALT • Splenic Marginal Zone • Marginal Zone • Waldenstrom’s Macroglobulinemia • Hairy Cell Leukemia • Follicular Lymphoma most common

23. Follicular Lymphoma • Follicular centre is the major site B lymphocyte differentiation and proliferation • low grade, but often widespread at diagnosis • often bone marrow is involved, even if CBCD is normal

24. Follicular Lymphoma • Follicular Lymphoma on lymph node biopsy

25. Follicular Lymphoma • Follicular Lymphoma on bone marrow (trephine) biopsy • Good test for confirming involvement, but difficult to make an initial diagnosis on

26. Follicular Lymphoma • BCL-2 molecular abnormality • t(14;18) • grades 1-3, with 3a and 3b • 3b considered aggressive disease

27. Follicular Lymphoma • Prognosis based on FLIPI score • age>60 years • stage III or IV disease • high LDH • Hg<120 • 5+ nodal sites • Indolent, but incurable (except in rare circumstance) • However highly sensitive to chemotherapy and radiotherapy

28. NHL- Aggressive B cell • Diffuse Large B cell (DLBC) Lymphoma • DLBCL, leg type • Primary Mediastinal DLBCL • Intravascular DLBCL • Plasmablastic lymphoma • High grade follicular lymphoma • Mantle cell lymphoma • DLBCL most common

29. DLCBL • Aggressive lymphoma • without treatment, fatal within weeks to months • bone marrow usually not involved, but if it is, it is associated with an increased incidence of CNS involvement • BCL-6 positive • Potentially curable with chemotherapy • chance of cure dependent on IPI prognostic features and stage

30. DLBCL • Diffuse effacement of the lymph node architecture, with little normal architecture remaining

31. DLBCL • Cells positive for staining anti-CD 20

32. DLBCL • Bone marrow involvement with DLBCL

33. DLBCL • IPI • increased LDH • stage III or IV disease • ECOG 2-4 • >1 extranodal site • age > 60 years • Limited stage disease with IPI = 0, 5 year progression free survival 94% • Advanced stage disease with high IPI, 4 year overall survival 55%

34. NHL- Very Aggressive B cell • Burkitt Lymphoma • Lymph node involved with Burkitt Lymphoma

35. NHL- Indolent T cell • Mycosis fungoides • primary cutaneous CD30+ • primary cutaneous CD30- • T cell LGL • Relatively uncommon

36. NHL- Indolent T cell • Mycosis fungoides • involves skin

37. NHL- Aggressive T cell • Peripheral T cell unspecified • angioimmunoblastic • T/NK cell, nasal type • enteropathy associated • hepatosplenic T cell • subcutaneous panniculitis-like • anaplastic large cell CD 30+, ALK + • anaplastic large cell CD 30+, ALK – • Relatively uncommon, thank goodness!

38. NHL- Aggressive T cell • Entropathy associated T cell lymphoma

39. NHL- Very Aggressive T cell • T Lymphoblastic Leukemia/Lymphoma • Adult T cell Leukemia/Lymphoma) ATLL (HTLV-1 associated) • Primary CNS Lymphoma (often HIV+) • Primary Effusion Lymphoma (HIV+) • Post-transplant lymphoproliferative disorder (PTLD)

40. Hodgkin Lymphoma • Classical • Nodular Sclerosis • Mixed cellularity • Lymphocyte Rich • lymphocyte depleted • Nodular lymphocyte predominant • Nodular Sclerosis most common • Quite potentially curable

41. Hodgkin Lymphoma • Classic histological feature = Reed Sternberg cell

42. Lymphoma Transformation • Lower grade lymphomas can “transform” into higher grade lymphomas • about 10% • ex DLBCL arising from follicular lymphoma • ex Hodgkin lymphoma arising from SLL • May have 2 pathologies on one surgical specimen • may have bone marrow discordance • If clinical behaviour of lymphoma changes or becomes more aggressive we will often repeat a LN biopsy, looking for transformation • Treat according to the most aggressive histology

43. Lymphoma Etiology • Often no cause identified • immunodeficiency states • HIV • EBV • Hepatitis C • other viruses • H pylori • systemic autoimmune disorders (ex SLE) • immunosuppression in transplant patients to prevent rejection • pesticides, herbicides, dioxins

44. Lymphoma Treatment Overview • Treatment is dependent on stage and pathology • If potentially curable we treat aggressively • If not, treatment is reserved for complications/symptoms

45. NHL Treatment- Indolent Lymphomas • Disease is often disseminated at diagnosis • disease slow growing • Only potential curative situation is when stage I A or contiguous IIA disease • can be encompassed within a radiation field--->IFRT • may prove to have had higher stage disease than detected if recurs elsewhere with time

46. NHL Treatment- Indolent Lymphomas • More advanced disease treat when: • symptoms • progressive/significant LN • moderate/severe splenomegaly • impending organ compromise • cytopenias • patient preference

47. NHL Treatment- Indolent Lymphomas • Upfront treatment does not currently improve overall survival • If no symptoms follow “wait and watch” treatment approach • If need to treat usually use chemotherapy, ex R-CVP • following chemotherapy patient may have maintenance treatment, depending on the pathology

48. NHL Treatment- Aggressive Lymphomas • Rapidly growing neoplasms • death if not treated, usually in the order of weeks to months • potentially curable • If early stage disease (I or IIA), treat with brief chemotherapy followed by IFRT • rationale for chemotherapy is to treat any “stray” disease beyond the radiation field • If advanced stage disease treat with chemotherapy alone in most cases • chemotherapy given IV, multidrug, with repeated cycles • if “bulky” disease will offer RT to site of bulk

49. NHL Treatment- Aggressive Lymphomas • If disease recurs after appropriate treatment and the patient is relatively young, they may be a candidate for an autologous stem cell transplant for salvage treatment • Otherwise recurrence ---> palliative

50. Hodgkin Lymphoma Treatment • Quite potentially curable • death if not treated, usually in the order of months • the lower the stage the increase chance of overall survival with therapy • Early stage disease (up to and including IIA) treat with abbreviated course of chemotherapy followed by IFRT • chemotherapy to irradiate potential disease outside of radiation field not detected by staging investigations