Lymphoma and Multiple Myeloma Terry Hayes, M.D., Ph.D.

Topics to be Covered Non-Hodgkin’s Lymphoma Hodgkin’s Disease Multiple Myeloma

Lymphoma and Multiple Myeloma 2004 U.S. Predicted Values Malignancy New Cases Deaths All Cancer s 1,368,030 563,700 Non-Hodgkin’s Lymphoma 54,370 19,410 Hodgkin’s Disease 7,880 1,320 Multiple Myeloma 15,270 11,070 CA Cancer J Clin 2004; 54:8-29

Non-Hodgkin’s Lymphoma

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Non-Hodgkin’s Lymphoma 6th most common cause of cancer death in United States. Increasing in incidence and mortality. Since 1970, the incidence of lymphoma has almost doubled.

Overview The types of non- Hodgkin’s lymphoma reflect the developmental stages of lymphocytes. Each type of lymphoma can be viewed as a lymphocyte arrested at a certain stage of development and transformed into a malignant cell. 85% B cell origin, the rest T or null cell.

B CELL DIFFERENTIATION Ig sIgM sIgM,D sIgM,G,A Cell Surface Markers CD19 CALLA (CD10) CD20 CD38 Precursor B Cell Leukemias CLL, B Cell Lymphomas Waldenström’s, Myeloma

MATURATION IN LYMPHOID FOLLICLE B D E C immunoblast B lympho- cyte F small non- cleaved large non- cleaved G small cleaved large H T lymphocyte plasma cell small lymphocyte

Follicular lymphoma Burkitt’s lymphoma Mantle zone lymphoma Sézary syndrome Mycosis fungoides Peripheral T cell lymphoma Chronic lymphocytic leukemia Small lymphocytic lymphoma Waldenström’s macroglobulinemia

Types of Lymphoma Indolent (low grade) Intermediate Life expectancy in years, untreated 85-90% present in Stage III or IV Incurable Intermediate Aggressive (high grade) Life expectancy in weeks, untreated Potentially curable

Commonly Used Classifications Working Formulation Low Grade Small lymphocytic Follicular small cleaved Follicular mixed Rappaport Diffuse well-differentiated lymphocytic (DWDL or WDLL) Nodular poorly differentiated lymphocytic (NPDL) Nodular mixed lymphocytic-histiocytic (NM)

Commonly Used Classifications Working Formulation Intermediate Grade Follicular large cell Diffuse small cleaved cell Diffuse mixed Diffuse large cell Rappaport Nodular histiocytic (NH) Diffuse poorly differentiated lymphocytic (DPDL) Diffuse mixed lymphocytic-histiocytic (DM) Diffuse histiocytic (DHL)

Commonly Used Classifications Working Formulation High Grade Large cell immunoblastic Lymphoblastic lymphoma Small noncleaved cell • Burkitt’s • Non-Burkitt’s Rappaport Diffuse histiocytic (DHL) Diffuse lymphoblastic Diffuse undifferentiated (DU)

Median Survival Histology (Years) DWDL 8-12 NPDL 5-8 NM 5-8 NH 1-3 DPDL 2-4 DM 1-3 DHL .5-1.5 DU .6- .7

Not Included in These Classifications Mycosis fungoides Marginal zone B cell lymphoma MALT lymphoma Mantle cell lymphoma Peripheral T cell lymphoma Angioimmunoblastic lymphoma

The REAL Classification (Revised European-American Lymphoma Classification) September, 1994

REAL Classification Precursor B-lymphoblastic lymphoma/leukemia B cell CLL/prolymphocytic leukemia/small lymphocytic leukemia Lymphoplasmacytoid lymphoma Mantle cell lymphoma Follicular center lymphoma, follicular Follicular center lymphoma, diffuse

REAL Classification Extranodal marginal zone B cell lymphoma (MALT type) Nodal marginal zone B cell lymphoma Splenic marginal zone B-cell lymphoma Hairy cell leukemia Plasmacytoma/myeloma

REAL Classification Diffuse large B cell lymphoma Primary mediastinal large B cell lymphoma Burkitt’s lymphoma High grade B cell lymphoma, Burkitt-like Precursor T lymphoblastic lymphoma/leukemia T cell CLL/prolymphocytic leukemia

REAL Classification Large cell granular lymphocytic leukemia: T cell type, NK cell type Mycosis fungoides/ Sézary syndrome Peripheral T cell lymphomas, unspecified Hepatosplenic g-d T cell lymphoma Angioimmunoblastic T cell lymphoma

WHO Classification

Types of Non-Hodgkin’s Lymphoma Small lymphocytic Immunoblastic Mantle cell Large Cell

Etiology of NHL Immune suppression DNA repair defects congenital (Wiskott-Aldrich) organ transplant (cyclosporine) AIDS increasing age DNA repair defects ataxia telangiectasia xeroderma pigmentosum

Etiology of NHL Chronic inflammation and antigenic stimulation Helicobacter pylori inflammation, stomach Chlamydia psittaci inflammation, ocular adnexal tissues Sjögren’s syndrome Viral causes EBV and Burkitt’s lymphoma HTLV-I and T cell leukemia-lymphoma HTLV-V and cutaneous T cell lymphoma Hepatitis C

Epidemiology Can occur at any age Overall incidence, and incidence of subtypes, varies with location: Burkitt’s in tropical Africa IPSID in Middle East Adult T cell leukemia-lymphoma in Japan and Caribbean

Epidemiology Indolent lymphomas are rare in young people and increase in incidence with age. Large cell lymphoma (DHL) is less age related, and is among most common cancers affecting the young. Burkitt’s and lymphoblastic lymphoma are common in adolescents. AIDS patients develop aggressive, high grade lymphomas.

Clinical Features Lymphadenopathy Cytopenias Systemic symptoms Hepatosplenomegaly Fever Night sweats

Clinical Features Lymphadenopathy may fluctuate or spontaneously remit, especially in low-grade lymphomas. B symptoms more common in high-grade lymphomas. Hematogenous spread of disease, with no predictable pattern.

Clinical Features Classic lymphoma: arises in lymph node or bone marrow. Extranodal primary more common in high-grade lymphoma. Waldeyer’s ring involvement frequent in GI lymphomas.

Diagnosis of NHL Excisional biopsy is preferred to show nodal architecture (follicular vs diffuse). Immunohistochemistry to confirm cells are lymphoid LCA (leukocyte common antigen) Monoclonal staining with Igk or Igl Flow cytometry: CD 19, CD20 for B cell lymphomas CD 3, CD 4, CD8 for T cell lymphomas

Diagnosis of NHL Chromosome changes 14;18 translocation in follicular lymphoma bcl-2 oncogene t(8;14), t(2;8), t(8;22) in Burkitt’s lymphoma c-myc oncogene t(11;14) in mantle cell lymphoma cyclin D1 gene

Staging Workup CBC, chemistries, urinalysis CT scans of chest, abdomen and pelvis Bone marrow biopsy and aspirate (Lumbar puncture) AIDS lymphoma T cell lymphoblastic lymphoma High grade lymphoma with positive marrow

Staging laparotomy and lymphangiogram are not indicated in non-Hodgkin’s lymphoma.

Staging: Ann Arbor I. 1 lymph node region or structure II. >1 lymph node region or structure, same side of diaphragm III. Both sides of diaphragm IV. Extranodal sites beyond “E” designation subscripts: A, B, E, S

Treatment Options: Indolent lymphomas WDLL, NPDL 10-15% in Stage I or II potentially curable local radiotherapy 85-90% Stage III or IV incurable treatment does not prolong survival

Reasons to Treat in Advanced Indolent Lymphomas Constitutional symptoms Anatomic obstruction Organ dysfunction Cosmetic considerations Painful lymph nodes Cytopenias

Treatment Options in Advanced Indolent Lymphomas Observation only. Radiotherapy to site of problem. Systemic chemotherapy oral agents: chlorambucil and prednisone IV agents: CHOP, COP, fludarabine, 2-CDA. Antibody against CD20: Rituxan, Bexxar, Zevalin. Stem cell or bone marrow transplant.

CHOP Chemotherapy Cyclophosphamide (Cytoxan) Hydroxydaunorubicin (Adriamycin) Oncovin (vincristine) Prednisone

Treatment Options: Aggressive Lymphomas Diffuse large cell lymphoma, large cell anaplastic lymphoma, peripheral T cell lymphoma. Very Aggressive Burkitt’s lymphoma and lymphoblastic lymphoma.

Treatment Options for Early Stage Aggressive Lymphomas Often in Stage I or II potentially curable disseminates through bloodstream early must use systemic chemotherapy CHOP x 6 cycles CHOP x 3 cycles followed by radiotherapy

Treatment Options for Advanced Stage Aggressive Lymphomas Systemic chemotherapy CHOP (± Rituxan for over 70 age group) ± Intrathecal chemotherapy AIDS patients and CNS involvement ± Radiotherapy Spinal cord compression, bulky disease

Lymphoblastic Lymphoma T cell malignancy. Male adolescents. Mediastinal mass. T cell variant of T cell acute lymphoblastic leukemia. Prognosis improving with intensive ALL regimens.

Burkitt’s Lymphoma African variety: jaw tumor, strongly linked to Epstein-Barr Virus infection. In U.S., about 50% EBV infection. May present as abdominal mass. Most rapidly growing human tumor. Typical chromosome abnormality: c-myc oncogene linked to one of the immunoglobulin genes.

Burkitt’s Lymphoma Treated with multidrug regimen similar to pediatric leukemia/lymphoma regimens.

Notable Subtypes of Lymphoma

Mycosis Fungoides Malignancy of helper T cells. Affinity for skin. Can be treated with electron beam radiation, ultraviolet light, or topical alkylating agents.

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Adult T Cell Leukemia-Lymphoma Associated with HTLV-I infection. Caribbean, southeastern U.S. Hepatosplenomegaly, leukocytosis, lymphadenopathy, skin involvement, lytic lesions of bone, hypercalcemia. May respond to AZT and interferon.

AIDS Lymphoma Aggressive lymphomas of B cell origin. Burkitt’s, Burkitt’s-like, and large cell immunoblastic. Treatment often limited by immune compromise of the patient. Prognosis improved with HAART therapy.

MALT Lymphoma Mucosa-Associated Lymphoid Tissue Chronic infection of the stomach by Helicobacter pylori. Localized to the stomach, indolent course. Can be cured in many cases by antibiotics against H. pylori.

Ocular Adnexal Lymphoma (OAL) A lymphoma affecting the tissues surrounding the eye that may arise after chronic inflammation.

Treatment May respond to antibiotic therapy against Chlamydia. One patient treated with doxycycline (100 mg bid for 3 weeks) had complete remission for more than 12 months, and another patient had minimal remission for more than 18 months. ASCO 2003, Abstract 2273

Hodgkin’s Disease

Thomas Hodgkin English pathologist, described the disease that bears his name in 1832.

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Hodgkin’s Disease One-seventh as common a snon-Hodgkin’s lymphoma. Highly treatable and curable, even when disseminated. Presence of Reed-Sternberg cell is necessary to make diagnosis.

Reed-Sternberg Cell

Subtypes of Hodgkin’s Disease Lymphocyte predominant Nodular sclerosis Mixed cellularity Lymphocyte depleted Unlike non-Hodgkin’s lymphoma, in Hodgkin’s Disease the histologic subtype does not determine how the disease is treated.

Etiology of Hodgkin’s Disease Reed-Sternberg cells are the malignant cells. Minor population in the malignant tissues many normal lymphocytes, eosinophils, other cells Cell of origin is unknown: T, B, both, neither. Some R-S cells contain EBV genomes.

Epidemiology In developed countries, bimodal distribution of patients. young adulthood after age 50 More common in affluent families with few siblings. In developing countries, more common in young children.

Signs and Symptoms Lymph node enlargement, usually cervical or mediastinal. Systemic “B” symptoms common. Pel-Ebstein fever. relapsing, high-grade fever that can reach 105-106°F, periodicity of 7-10 days. Fever spikes abrupt in onset and resolution Pain on drinking alcohol.

Pel-Ebstein Fever

Clinical Features T cell mediated immune deficiency, even in early stage disease. Prone to infections: Herpes zoster (“shingles”) in one fourth of patients Fungal or mycobacterial infections Immune defect may persist even after lymphoma is cured.

Clinical Features Predictable contiguous spread of disease: cervical nodes to mediastinum or axilla mediastinum to periaortic nodes or spleen, etc. Basis for staging and treatment decisions.

Diagnosis Excisional biopsy of a lymph node. Fine needle aspirate is not sufficient to make the diagnosis of Hodgkin’s disease.

Staging of Hodgkin’s Disease Same as for non-Hodgkin’s: H + P, labs, CT scans, bone marrow biopsy PLUS: Gallium scan Lymphangiogram or staging laparotomy ONLY if results would affect treatment decisions

Treatment by Stage

Chemotherapy Regimens MOPP Mechlorethamine, Oncovin, Procarbazine, Prednisone ABVD Adriamycin, Bleomycin, Vinblastine, Dacarbazine BEACOPP

Treatment Options Often, patients who relapse after radiotherapy can be cured by salvage chemotherapy. Combined chemotherapy and radiotherapy is given for bulky mediastinal masses. Chemotherapy now being tested for earlier stages of the disease.

Late Complications of Hodgkin’s Disease High incidence of second malignancies leukemia first 10 years, solid tumors over time. Leukemia in patients receiving alkylating agents or combined chemo/XRT. Lung cancer and breast cancer in patients receiving XRT to chest. Lung cancer especially high in smokers.

Late Complications of Hodgkin’s Disease Hypothyroidism after irradiation of the neck. Constrictive pericarditis after radiotherapy to the mediastinum. Infertility after use of alkylating agents. Heart failure after Adriamycin treatment.

Multiple Myeloma

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Overview of Multiple Myeloma Less common than non-Hodgkin’s lymphoma, more deadly. Average life expectancy 30 -36 months. Some patients develop a very indolent form and live for 10 years or more. Potentially curable with high dose chemotherapy (bone marrow or stem cell transplantation).

Overview of Multiple Myeloma Disease of malignant B-lymphocytes. Little similarity to lymphoma in presentation, age at diagnosis, treatment, or prognosis. Signs and symptoms of multiple myeloma are quite variable. Approximately 20% of patients have no symptoms.

Etiology of Multiple Myeloma Unknown. Suggested predisposing factors include: Viral infection with Human Herpesvirus 8 (HHV-8). MGUS (monoclonal gammopathy of undetermined significance).

Types of Plasma Cell Disorders Multiple Myeloma Indolent Myeloma Solitary Plasmacytoma Waldenström’s Macroglobulinemia Monoclonal Gammopathy of Undetermined Significance (MGUS)

Epidemiology Average age at presentation is about 65. Males are affected more often than females. Incidence in blacks is twice that of whites. Five-year survival is approximately 25-30%. Median survival 30-36 months.

Multiple Myeloma More than 15% plasma cells in the bone marrow. Monoclonal immunoglobulin peak on SPEP more than 3 gm/dL. Presence of Bence Jones protein in urine. Decreased levels of normal immunoglobulins.

Clinical Features Bone marrow failure - Anemia, thrombocytopenia, neutropenia Renal failure Bone disease with skeletal destruction lytic lesions generalized decrease in bone density Hypercalcemia

Clinical Features Hyperviscosity syndrome Recurrent infections Amyloidosis

Diagnosis of Multiple Myeloma Cell surface markers: CD38, plasma cell antigen, and cell surface immunoglobulins. Monoclonality can be demonstrated by immunoperoxidase staining with kappa and lambda antibodies.

Diagnosis and Staging Workup Bone marrow biopsy and aspirate Serum protein electrophoresis and immunofixation Skeletal survey Plain x-rays are better than bone scan. Lytic lesions do not show up well on bone scan. Quantitative immunoglobulins

Serum Protein Electrophoresis Total protein 7.2 a2 globulin 0.5 albumin 4.5 b globulins 0.7 a1 globulin 0.15 g globulin 1.4 Total protein 7.9 a2 globulin 0.6 albumin 3.9 b globulins 0.7 a1 globulin 0.19 g globulin 2.4 Normal Monoclonal Spike Alb. a1 a2 b g Alb. a1 a2 b g

Monoclonal Immunoglobulin Spike on Serum Protein Electrophoresis (SPEP) Multiple myeloma Non-Hodgkin’s lymphoma Monoclonal gammopathy of undetermined significance (MGUS). Not clinically significant unless present in high quantity (over 3 gm/dL).

Monoclonal Protein In Plasma Cell Neoplasms IgG 52 IgA 21 IgM 12 IgD 2 IgE <0.01 Light chain (k or l) 11 Heavy chains (g, a, or m) <1 Two or more monoclonal proteins <1 Nonsecretory myeloma 1

Lytic Bone Lesions in Multiple Myeloma http://140.251.5.102/Pathology_Images/ http://wheeless.orthoweb.be/o6/129.htm

Durie-Salmon Staging System for Multiple Myeloma Stage I Low myeloma cell mass Hemoglobin > 10 g/dL Normal bone, or solitary plasmacytoma Low immunoglobulin spike (M-component) IgG < 5 g/dL, IgA < 3 g/dL Bence-Jones protein < 4 g/24h

Durie-Salmon Staging System for Multiple Myeloma Stage III High myeloma cell mass Hemoglobin < 8.5 g/dL Serum calcium > 12 mg/dL Multiple lytic bone lesions on x-ray High M-component IgG > 7 g/dL, IgA > 5 g/dL Bence-Jones protein > 12 g/24h

Durie-Salmon Staging System for Multiple Myeloma Stage II Intermediate myeloma cell mass In between Stages I and III Subclassification A: Normal renal function - serum creatinine level < 2.0 mg/dL B: Abnormal renal function - serum creatinine level ³ 2.0 mg/dL

Treatment of Multiple Myeloma Standard Chemotherapy Melphalan and prednisone VAD (vincristine, adriamycin, dexamethasone) High Dose Chemotherapy Bone marrow transplant Peripheral stem cell transplant

Treatment of Multiple Myeloma Other Modalities Pulse dexamethasone Interferon Local radiotherapy to bony lesions Pamidronate and other bisphosphonates Thalidomide Velcade (Bortezomib, PS-341) Bendamustine

Prognostic Factors Poor prognosis: Age > 65 High tumor mass High b2 microglobulin Renal failure, hypercalcemia

Indolent Myeloma Hemoglobin > 10.5 gm/dL. Monoclonal immunoglobulin peak on SPEP (<4.5 gm/dL). Normal serum calcium level. Long life expectancy.

Indolent Myeloma Occurs in 20% of patients Associated with a low myeloma cell burden. Can be a very slowly developing disease. Treatment should be withheld until there is evidence of progression: lytic bone lesions rising immunoglobulins.

Solitary Plasmacytoma Solitary bone lesion due to plasma cell tumor. Normal bone marrow. No anemia, hypercalcemia, or renal disease. Normal levels of immunoglobulins. No other evidence of disseminated multiple myeloma.

Solitary Plasmacytoma Curable with radiotherapy.

Monoclonal Gammopathy of Undetermined Significance (MGUS) “Benign” monoclonal gammopathy Present in 1% of healthy adults at age 40, rises with age. One fourth of patients will go on to have multiple myeloma, amyloidosis, macroglobulinemia, non-Hodgkin’s lymphoma, or other diseases. Follow-up should be continued indefinitely.

Monoclonal Gammopathy of Undetermined Significance (MGUS) Monoclonal immunoglobulin level less than 3 gm/dL. Under 15% plasma cells in the bone marrow. No bone lesions or symptoms. Normal levels of immunoglobulins.

Waldenström’s Macroglobulinemia Uncommon, low-grade malignancy. Malignant plasmacytoid lymphocytes produce IgM. Lymphadenopathy and splenomegaly, hyperviscosity, cryoglobulinemia, neuropathy. Responds well to cladribine (2-CdA) or Rituxan.

Amyloidosis 10% of patients with multiple myeloma. Amyloid fibrils formed by light chain Ig molecules. Deposited in multiple organs, with severe organ dysfunction, often irreversible. Cardiomyopathy, hepatomegaly, nephrotic syndrome, neuropathy, carpal tunnel syndrome, periorbital purpura.

Conclusions: Lymphoma and Multiple Myeloma Malignancies of B cells. Sometimes preventable. Highly treatable and often curable. Study of these diseases have led to important advances in the understanding of the biology of lymphoid cells.