1. LYMPHOMA & MULTIPLE MYELOMA Arleigh McCurdy MD FRCPC

2. Objectives  Describe the genetic mechanisms involved in the development of lymphoma  Provide a classification system for lymphoma  Describe the clinical presentation of lymphoma  Differentiate between NHL and HL with respect to clinical presentation and prognosis  Describe the Ann Arbor staging system for lymphoma  Discuss the diagnosis, staging, and clinical presentation of multiple myeloma

4. Lymphoma

6.  Cancer derived from B cells, T cells, or rarely NK cells at various stages of maturation  Biologic features reflect “normal” counterparts  A cell of origin has been proposed for each type  Usually arise from lymph nodes, but any organ possible  Bone marrow can be involved, but not necessary

7. Lymphoma Hodgkin Lymphoma Non-Hodgkin Lymphoma Classical -Nodular sclerosis -Mixed cellularity -Lymphocyte rich -Lymphocyte depleted Nodular Lymphocyte Predominant B cell T cell Indolent Aggressive Indolent Aggressive Follicular SLL Mantle Cell Marginal zone Lymphoplasmacytic DLBCL Burkitt’s Lymphoblastic T cell LGL Mycosis fungoides Anaplastic large cell Peripheral T cell Lymphoblastic NK cell

8. Genetic Mechanisms in Lymphoma  Oncogenes become activated by chromosomal translocations that arise during normal gene rearrangement  Most common breakpoints are the Immunoglobulin (Ig) locus in B cell lymphoma and the T cell receptor (TCR) in T cell lymphoma  Some translocations are characteristic of specific lymphomas  t(14;18) in follicular lymphomas  t(8;14) in Burkitt’s lymphoma

10. Clinical Presentation  Highly variable  Aggressive: rapidly growing nodes/mass, fever, night sweats, weight loss, fatigue, cytopenias  Indolent: may be asymptomatic for years, slow growing nodes, splenomegaly, cytopenias

11. Hodgkin Clinical Presentation  Almost always arises in lymph nodes  70% present with painless mass  Usually in chest or neck, very rarely below diaphragm  Usually spreads in an orderly fashion to contiguous nodes  Risk of “B” symptoms increases with stage  Alcohol induced pain is very specific but not common  Most patients experience pruritis  10-15% at diagnosis

12. Lymphoma Diagnosis  Biopsy is required  “Tumor is the rumor, the issue is tissue, the answer might be cancer”  Excisional biopsy preferred, core biopsy can be adequate  Fine needle aspiration not useful

13. Hodgkin Diagnosis  Characterized by “Reed Sternberg cells”

14. Lymphoma Staging  Basic bloodwork  CBC, Electrolytes, Creatinine, Liver enzyme and function, lactate dehydrogenase, Calcium, Phosphate, uric acid, viral serology (HIV, Hep B, Hep C)  Imaging  CT scans of the neck, chest, abdomen, pelvis  PET scan may be useful depending on type  +/- Bone marrow biopsy

15. Lymph node regions

16. Ann Arbor Staging System Stage 1Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE) without nodal involvement. A single region can include one node or a group of adjascent nodes Stage IIInvolvement of two or more lymph nodes regions on the same side of the diaphragm alone (II) or involvement of limited, contiguous extralymphatic organ or tissue (IIE) Stage IIIInvolvement of lymph node regions or lymphoid structure on both side of the diaphragm Stage IVAdditional noncontiguous extralymphatic involvement, with or wiithout associated lymphatic involvement Cases are subclassified to indicate absence (A) or presence (B) of “B” symptoms: unexplained fevers (>38.3), drenching night sweats, unexplained weight loss (10% body weight in 6 months) Subscript “X” used for Bulky disease, subscript “E” used for limited extranodal extension

17. Lymphoma Treatment  Complex, varies widely depending on type  Chemotherapy is the backbone  Radiation and stem cell transplant have a role in some cases  Hodgkin lymphoma and Non hodgkin lymphoma are treated differently

18. Lymphoma Prognosis  Complex, varies widely depending on type  Aggressive lymphomas are often curable, whereas indolent lymphomas are not- referred to as “lymphoma paradox”  Hodgkin lymphoma is the most curable

19. Lymphoma Paradox 1 2 3 4 5 6 7 8 9 10 15 Survival in years 100 50 % of pts. alive Low grade lymphomas High grade lymphomas

20. Multiple Myeloma

22. Myeloma development

23. Pathobiology of MM  Step 1: Establishment of MGUS  Genetic/environmental predisposition  Cytogenetic abnormalities Translocations involving IgH locus (40%) Trisomies (40%)  Felt to be triggered by antigenic stimulation Mechanism unclear  Step 2: Progression to MM  Initial genetic changes appear to be necessary but not sufficient Rajkumar, 2014

24. Clinical Presentation  Bone pain and fractures  Fatigue  Recurrent infections  Renal failure  Hypercalcemia

25. Myeloma Diagnosis  Bloodwork- CBC, Creatinine, Calcium, Albumin, Total protein, beta 2 microglobulin, serum Protein electrophoresis and immunofixation, urine protein electrophoresis and immunifixation, serum free light chain assay  Bone marrow Biopsy  Imaging  Skeletal Survey  MRI in certain circumstances

26. WHO 2008  M-protein in serum or urine  Bone marrow clonal plasma cells or plasmacytoma  Related organ or tissue impairment  Hypercalcemia  Renal Insufficiency  Anemia  Bone lesions

27. Problems  Clinico-pathological definition  Serious organ damage required to make diagnosis  Prevents treatment at susceptible microenvironment dependent state  Treatment options have improved  Early intervention may well extend survival  Advances in laboratory and imaging technology

28. IMWG Diagnostic Criteria 2014  Clonal BM PCs >/= 10% or biopsy proven EM plasmacytoma and any one or more of:  Myeloma Defining Events End Organ Damage Hypercalcemia Renal insufficiency Anemia Bone lesions Biomarkers of Malignancy BM PCs >60% FLC ratio >100 >1 focal lesion on MRI Rajkumar et al (IMWG), Lancet 2014

29. Staging- Durie Salmon Stage 1All of the following: Hgb >100 g/L, IgG <50 g/L, IgA <30 g/L Normal serum calcium Urine monoclonal protein excretion <4 g/day No generalized lytic bone lesions Stage 2Not 1 or 3 Stage 3One of more of the following: Hgb 70 g/L, IgA > 50 g/L Serum calcium >12 mg/dL (3 mmol/L) Urine monoclonal protein excretion >12 g/d Advanced lytic bone lesions ACreatinine <177 umol/L BCreatinine >177 umol/L Durie & Salmon, Cancer 1975

30. Staging- ISS Griepp et al, JCO 2005

31. Risk Stratification - FISH www.msmart.org

32. Treatment  Very complicated & evolving  Take home points  Currently incurable  Chemotherapy +/- stem cell transplant are only effective options  Overall survival time has doubled in last decade

33. Summary  Lymphoma and Myeloma are lymphoproliferative disorders  Genetic mechanisms underlying both are multiple, but translocations play a large role  There are multiple subtypes that vary in clinical presentation, treatment, and prognosis  An adequate biopsy and accurate staging are essential for treatment planning