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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. MalignancyNew CasesDeaths All Cancers 1,368,030 563,700

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Lymphoma and Multiple Myeloma

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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 Myeloma2004 U.S. Predicted Values

MalignancyNew CasesDeaths

All Cancers 1,368,030 563,700


Lymphoma 54,37019,410

Hodgkin’s Disease 7,880 1,320

Multiple Myeloma 15,27011,070

CA Cancer J Clin 2004; 54:8-29

Non-Hodgkin’s Lymphoma

Jacqueline Kennedy Onassis

Former First Lady

King Hussein of Jordan

“Mr. T”

(Lawrence Tureaud)

Television star, The A-Team.

Sylvester Stallone's adversary in "Rocky III.”

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.


  • 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.

Precursor B Cell Leukemias

CLL, B Cell Lymphomas

Waldenström’s, Myeloma






Cell Surface Markers


































Follicular lymphoma

Burkitt’s lymphoma

Mantle zone


Sézary syndrome

Mycosis fungoides

Peripheral T cell


Chronic lymphocytic


Small lymphocytic lymphoma

Waldenström’s macroglobulinemia

Types of Lymphoma

  • Indolent (low grade)

    • 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


Low Grade

Small lymphocytic

Follicular small cleaved

Follicular mixed


Diffuse well-differentiated lymphocytic (DWDL or WDLL)

Nodular poorly differentiated lymphocytic (NPDL)

Nodular mixed lymphocytic-histiocytic (NM)

Commonly Used Classifications


Intermediate Grade

Follicular large cell

Diffuse small cleaved cell

Diffuse mixed

Diffuse large cell


Nodular histiocytic (NH)

Diffuse poorly differentiated lymphocytic (DPDL)

Diffuse mixed lymphocytic-histiocytic (DM)

Diffuse histiocytic (DHL)

Commonly Used Classifications


High Grade

Large cell immunoblastic

Lymphoblastic lymphoma

Small noncleaved cell

• Burkitt’s

• Non-Burkitt’s


Diffuse histiocytic (DHL)

Diffuse lymphoblastic

Diffuse undifferentiated (DU)

Commonly Used Classifications

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 inThese 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


Mantle cell

Large Cell

Etiology of NHL

  • Immune suppression

    • 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


  • 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


  • 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


  • 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 inAdvanced 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.

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.

A lymphoma affecting the tissues surrounding the eye that may arise after chronic inflammation.

Ocular Adnexal Lymphoma (OAL)


  • 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.

Paul Allen

Cofounded Microsoft with Bill Gates

Mario Lemieux

Top player in the US National Hockey League

Brandon Tartikoff

Youngest US television network president

(Cosby, Seinfeld)

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 ofHodgkin’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.


  • 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.


  • 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


  • 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


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 ofHodgkin’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 ofHodgkin’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

Ann Landers

Advice Columnist

Mark Lenard

Sarek (Spock’s father) on Star Trek

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).


  • 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 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

Alb. a1a2 bg

Alb. a1a2bg

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

Serum Protein Electrophoresis

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

    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


      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

    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.

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