1. Lymphomas and Multiple Myeloma Elizabeth Bunting, MS, PA-C Clinical Medicine I April 8, 2011

2. Objectives For each of the following disorders, describe the pathophysiology, clinical presentation, significant historical and physical examination findings, diagnostic work-up, management, and prognosis: Hodgkin’s disease Non-Hodgkin’s lymphoma Multiple myeloma

4. B-cell Transformation

5. Lymphoma Non-Hodgkin’s disease All others Present at multiple sites in peripheral nodal groups Non contiguous spread to other nodal groups Hodgkin’s disease (HD) Reed-Sternberg cells Nontenderlymphadenopathy along central axis Contiguous spread to other nodal groups

6. Disease Classification Hodgkin’s Lymphocyte predominate Nodular sclerosing Mixed cellularity Lymphocyte depleted Prognosis dependent on stage and presence of ‘B symptoms’ Non-Hodgkin’s Mature or immature B-cell or T-cell Mature cell  less aggressive, disseminate earlier Immature cell more aggressive, disseminate later

7. Hodgkin’s Disease Essentials of diagnosis Painless lymphadenopathy +/- constitutional symptoms Pathologic diagnosis by lymph node biopsy (Reed-Sternberg cells)

8. Hodgkin’s Disease Epidemiology Bimodal peak 20’s 50’s Signs and symptoms Most patients present with a painless mass, usually in the neck Constitutional symptoms include fever, weight loss, night sweats

9. Hodgkin’s Disease Signs and symptoms Generalized pruritus Pain in an involved lymph node after EtOH ingestion Usually arises within a single lymph node area and spreads contiguously Late in the course, there may be widespread hematogenous dissemination

10. Hodgkin’s Disease Subtypes Lymphocyte predominance Nodular sclerosis Mixed cellularity Lymphocyte depletion Differential diagnosis Other lymphomas Reactive lymph nodes due to infections or drug reactions

11. Ann Arbor Staging for Hodgkin’s Disease Category A: patients are asymptomatic Category B: fever, night sweats, weight loss>10% of original body weight

12. Hodgkin’s Disease Treatment For stage IA and IIA  radiation therapy +/- limited chemotherapy For stage IIIB or IV  combination chemotherapy with ABVD or newer regimen (ABVD = Adriamycin (doxorubicin), bleomycin, vincristine, and dacarbazine)

13. Hodgkin’s Disease Prognosis Stage IA or IIA Excellent prognosis 10 year survival rate > 80% Stage IIIB or IV 5 year survival rate is 50-60% Poorer prognosis for increased age, bulky disease, mixed cellularity

14. Non-Hodgkin’s Lymphomas General information Heterogeneous group of cancers of lymphocytes Vary in clinical presentation and course Classification is controversial Best-studied pathology is Burkitt’s lymphoma, which has a translocation of chromosomes 8 and 14

15. Common Non-Hodgkin’s Lymphoma Subtypes Common Adult Follicular lymphoma Small lymphocytic lymphoma Diffuse large B-cell lymphoma Adult T-cell lymphoma Common Childhood and Adolescent Lymphoblastic lymphoma Burkitt’s lymphoma

16. WHO Classification of Non-Hodgkin’s Lymphomas Precursor B B cell lymphoblastic lymphoma Mature B Diffuse large B cell lymphoma Mediastinal large B cell lymphoma Follicular lymphoma Small lymphocytic lymphoma Lymphoplasmacytic lymphoma

17. WHO Classification of Non-Hodgkin’s Lymphomas Mature B Mantle cell lymphoma Burkitt’s lymphoma Marginal zone lymphoma MALT type Nodal Splenic Mucosal tissue associated

18. WHO Classification of Non-Hodgkin’s Lymphomas Precursor T T cell lymphoblastic lymphoma Mature T Anaplastic T cell lymphoma Peripheral T cell lymphoma

19. Non-Hodgkin’s Lymphomas Signs and symptoms Indolent lymphomas Painless lymphadenopathy May be isolated or widespread Retroperitoneum, mesentery, pelvis Usually disseminated at the time of diagnosis Frequent bone marrow involvement Fever, weight loss, night sweats Burkitt’s lymphoma – usually have abdominal pain or fullness

20. Non-Hodgkin’s Lymphomas Laboratory findings Peripheral smear usually normal Bone marrow shows paratrabecular lymphoid aggregates If meninges involved, there may be malignant cells in the CSF CXR may show mediastinal mass Serums LDH is a useful prognostic marker

21. Non-Hodgkin’s Lymphomas Laboratory findings Diagnosis made by tissue biopsy FNA may be suspicious, but node biopsy is required for definitive diagnosis and staging

22. Non-Hodgkin’s Disease Treatment Limited disease (1 abnormal lymph node) Localized radiation Treat for cure Indolent disseminated disease No clear consensus on treatment Rituximab +/- chemotherapy Allogeneic transplant

23. Non-Hodgkin’s Disease Treatment Intermediate grade lymphomas Treat for cure Chemotherapy (R-CHOP) +/- radiation Advanced disease Chemotherapy with R-CHOP Autologous stem cell transplant Burkitt’s lymphoma – intensive chemotherapy specifically tailored for Burkitt’s

24. Non-Hodgkin’s Disease Prognosis Median survival rate 6-8 years, but improving Poor prognostic factors Age > 60 years Elevated serum LDH Stage III or IV disease 0-1 risk factors = 80% response rate to chemo 2 risk factors = 70% response

25. Multiple Myeloma Essentials of diagnosis Bone pain, often in the back Monoclonal paraprotein found by serum and urine protein electrophoresis Replacement of bone marrow by malignant plasma cells General considerations Malignancy of plasma cells Malignant cells can cause tumors (plasmacytomas) that can compress the spinal cord

26. Multiple Myeloma General considerations Replacement of bone marrow  anemia  bone marrow failure Paraproteins (IgG or IgA) may cause hyperviscosity Immunoglobulins can lead to renal failure or be deposited in tissues as amyloid Patients are especially prone to infections with encapsulated organisms (Strep pneumoniae, Hib) Epidemiology Mean age = 65 years

27. Multiple Myeloma Signs and symptoms Most common presenting complaints are anemia, bone pain and infection Bone pain usually in back or ribs or due to pathologic fracture Renal failure Spinal cord compression Hyperviscosity (mucosal bleeding, vertigo, nausea, visual disturbance, changes in mental status)

28. Multiple Myeloma Signs and symptoms Incidental lab findings Hypercalcemia Proteinuria Increased sed rate Amyloidosis Pallor Bone tenderness Soft tissue masses

29. Multiple Myeloma Signs and symptoms Signs of spinal cord compression/neuropathy Enlarged tongue CHF Hepatomegaly Fever only with infection

30. Multiple Myeloma Laboratory findings Anemia with normal RBC morphology Rouleau formation is common Hallmark = paraprotein on serum protein electrophoresis (SPEP) Bone marrow infiltrated by plasma cells (20% to 100%) Lytic lesions seen on xrays (axial skeleton)

31. RouleauFormation of RBCs

32. Multiple Myeloma Differential diagnosis Monoclonal gammopathy of unknown significance (MGUS) More common than myeloma Progresses to malignant disease in 25% of cases Reactive polyclonal hypergammaglobulinemia Primary amyloidosis

33. Multiple Myeloma Treatment Observation for minimal disease Optimal treatment is in flux Previously combination chemotherapy Thalidomide + dexamethasone Velcade (bortezomib) Revlimid (lenalidomide) being investigated Autologous stem cell transplant

34. Multiple Myeloma Treatment Allogeneic transplantation is potentially curative, but has 40-50% mortality rate Localized radiation for palliation of bone pain Prognosis Median survival rate = 4-6 years Improving with new therapies

35. ThumbnailEpidemiology Non-Hodgkin’s lymphoma 75% of all lymphomas Mean age of onset = 42 Risk factors Radiation/benzene exposure EBV, HTLV-1 viral infections Autoimmune disease immunosuppresion Hodgkin’s lymphoma 25% of all lymphomas Bimodal distribution: 20s and >50s Men>Women Increased with HIV

36. ThumbnailPathophysiology Non-Hodgkin’s lymphoma Varied translocations affect cellular proliferation of lymphoid cells Hodgkin’s lymphoma Malignant Reed-Sternberg cells recruit inflammatory cells

37. ThumbnailClinical Presentation Non-Hodgkin’s lymphoma Non-tender, multiple, peripheral nodal groups Non contiguous spread to other nodes Extranodal lymphoid tissue involvement Pruritus B-symptoms Hodgkin’s lymphoma Nontender, single or nodal group Contiguous spread to adjacent nodes along central axis Mediastinal or abdominal LAD Generalized pruritus B-symptoms Clinical anergy

38. ThumbnailDiagnosis Non-Hodgkin’s lymphoma Lymph node/tissue biopsy Histologic examination Prognosis depends on grade Hodgkin’s lymphoma Reed-Sternberg cells found on node biopsy Prognosis depends on stage

39. ThumbnailTherapy Non-Hodgkin’s lymphoma Radiation treatment Chemotherapy Immunotherapy Stem cell transplant Hodgkin’s lymphoma Radiation therapy for stages I and II Combination therapy for stages III and IV

40. Key Points Lymphomas are solid tumors of lymphoid origin HD - Reed-Sternberg cells NHD – all others HD – central axis LAD with contiguous spread NHD – peripheral LAD with non-contiguous spread Plasma cell neoplasms hypersecrete IgM, IgG to produce serum hyperviscosity.

41. Case Study - HPI TL, a 59 yo female, presents with 5 days of fever and night sweats. She also noted a 20# unexplained weight loss in the last 3 months from her previous weight of 150#. She has had an intermittent cough with mild wheezing when lying on her right side. She has had no sick contacts nor symptoms suggesting infection. PPD negative 1 year ago and no risk factors for TB exposure. PMHx – Hashimoto’s thyroiditis during her 20s, now hypothyroid taking L-thyroxine. No history of smoking or drinking.

42. Case Study - PE T 38.6C BP 135/75 HR 85 RR 20 SaO2 98% Patient is thin and ill-appearing. Her exam is significant for positional wheezing audible anteriorly on the right middle chest when lying on the right side. Nontender lymphadenopathy consisting of two 2.5 cm rubbery nodules in the left axillary and right inguinal regions.

43. What Labs/Tests? CBC Chest X-ray

44. Case Conclusions Biopsies of the left axillary and right inguinal nodes reveal follicular lymphoma. Given that the patient presented with fever, night sweats and weight loss, she was thought to have more advanced disease and combination chemotherapy was initiated. She achieved complete remission, but relapsed in 2 years with histologic changes to diffuse large B-cell lymphoma.

45. Any Questions??