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

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

3. Lymphoma and Multiple Myeloma 2004 U.S. Predicted Values
Malignancy New Cases Deaths
All Cancer s ,368, ,700
Non-Hodgkin’s
Lymphoma , ,410
Hodgkin’s Disease , ,320
Multiple Myeloma , ,070
CA Cancer J Clin 2004; 54:8-29

4. Non-Hodgkin’s Lymphoma

5. Jacqueline Kennedy Onassis
Former First Lady

6. King Hussein of Jordan

7. Television star, The A-Team.
“Mr. T”
(Lawrence Tureaud)
Television star, The A-Team.
Sylvester Stallone's adversary in "Rocky III.”

8. 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.

9. 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.

10. B CELL DIFFERENTIATIONIg
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

11. MATURATION IN LYMPHOID FOLLICLEB 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

12. 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

13. 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

14. 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)

15. 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)

16. 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)

17. Median Survival
Histology (Years)
DWDL
NPDL NM NH
DPDL DM
DHL DU

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

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

20. 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

21. 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

22. 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

23. 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

24. WHO Classification

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

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

27. 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

28. 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

29. 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.

30. Clinical Features Lymphadenopathy Cytopenias Systemic symptoms
Hepatosplenomegaly
Fever
Night sweats

33. 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.

34. 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.

35. 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

36. 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

37. 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

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

39. 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

40. 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

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

43. 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.

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

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

46. 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

47. 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

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

50. 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.

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

52. Notable Subtypes of Lymphoma

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

54. 3

55. 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.

56. 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.

57. 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.

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

60. 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

61. Hodgkin’s Disease

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

63. Cofounded Microsoft with Bill Gates
Paul Allen
Cofounded Microsoft with Bill Gates

64. Top player in the US National Hockey League
Mario Lemieux
Top player in the US National Hockey League

65. Youngest US television network president
Brandon Tartikoff
Youngest US television network president
(Cosby, Seinfeld)

66. 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.

67. Reed-Sternberg Cell

68. 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.

69. 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.

70. 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.

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

72. Pel-Ebstein Fever

73. 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.

74. 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.

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

76. 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

77. Treatment by Stage

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

79. 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.

80. 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.

81. 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.

82. Multiple Myeloma

83. Ann Landers
Advice Columnist

84. Mark Lenard
Sarek (Spock’s father) on Star Trek

85. Overview of Multiple Myeloma
Less common than non-Hodgkin’s lymphoma, more deadly.
Average life expectancy 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).

86. 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.

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

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

89. 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 months.

90. 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.

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

92. Clinical Features Hyperviscosity syndrome Recurrent infections
Amyloidosis

94. 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.

95. 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

96. Serum Protein Electrophoresis
Total protein a2 globulin 0.5
albumin b globulins 0.7
a1 globulin g globulin 1.4
Total protein a2 globulin 0.6
albumin b globulins 0.7
a1 globulin g globulin 2.4
Normal Monoclonal Spike
Alb. a1 a2 b g
Alb. a1 a2 b g

97. 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).

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

99. Lytic Bone Lesions in Multiple Myeloma

100. 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

101. 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

102. 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

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

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

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

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

108. 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.

109. 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.

110. Solitary Plasmacytoma
Curable with radiotherapy.

111. 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.

112. 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.

113. 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.

114. 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.

115. 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.