Lymphoma

Presentation and Diagnosis

Mark B. Juckett MD
Division of Hematology
University of Wisconsin
June 19, 2003
 Approach to Lymphadenopathy
• Palpable LAD in children – “the rule”
• LAD in adults
– < 1cm considered “normal” (< 2cm in groin)
• LAD is normal response to foreign antigens
– May include infections, allergens, autoimmune
targets
• Pathologic LAD due to proliferation or
infiltration
 Normal B cell Development
Pre B cell
IgM

B cell Follicles

Bone
Marrow Travel

Lymph Node
B cell finds “meaning”
“meaning”

B cell activation
Germinal Center
Formation
 Germinal Center Activity

Proliferation “Never die”

Signals Signals

Mutation
Survival Signals
Signals

Germinal Center
 Plasma Cells travel
back to bone marrow

Memory B cell

“Activated B cell”

Plasmacytoid Cell IgM

 Causes of LAD
• Infections
– Bacterial – pyogenic, cat-scratch, syphilis,
tularemia, plague
– Mycobacterial – tuberculosis, leprosy, MAI
– Fungal – histoplasmosis, coccidioidiomycosis
– Chlamydial – lymphogranuloma venereum
– Parasitic – toxo, trypanosomiasis, filariasis
– Viral – EBV, CMV, rubella, HIV, hepatitis C
 Causes of LAD (cont)
• Inflammatory disorders
– Autoimmune - Rheumatoid arthritis, SLE
– Drugs – serum sickness, phenytoin
– Castleman’s disease
– Histiocytic diseases (SHML, LH)
– Kawasaki syndrome
– Kimura’s disease
– Sarcoidosis
 Causes of LAD (cont)
• Storage diseases
– Gaucher’s, Neimann-Pick disease
– Amyloidosis
• Endocrinopathies
– Hyperthyroidism, adrenal insufficiency
• Cancer
– “Immune system” cancers
– Metastatic carcinoma
 Most Frequent Causes
• Unexplained (?)
• Infection
• Immune system disorders
• Immune system malignancies (Lymphoma)
• Metastatic carcinoma
• Other
 Approach to patient with LAD
• Does the patient have a known illness that
causes LAD? Treat and monitor
• Is there infection? Treat and monitor.
• Is the LAD large (> 3cm) or have unusual
characteristic (i.e. hard)? Biopsy.
• If none are true, monitor 2 to 6 weeks, if
persistent or large, biopsy.
Mortality Rate
by Cancer
1970 - 1994
•Males
•Age 50 - 74
Mortality Rate
by State
1970 - 1994

•NHL
•Males
•Age 50 - 74
Mortality Rate
by Year
1950 - 1994

•NHL
•All ages
Incidence Rate by Year
1973 - 2000

•NHL
•All ages
Incidence Rate by Age
1996 - 2000

•NHL
•M/F
 Classification of Lymphoma
• Past schemes: Rappaport, Kiel, Working
formulation, “R.E.A.L.”, others
• World Health Organization involved to
develop uniform classification
• Focus on defining distinct disease entities
• Classification defined 23 separate NHL and
5 Hodgkins lymphoma diagnoses.
General Comments on Diagnosis
• Initial diagnosis depends on tissue biopsy
– FNA rarely useful
• Fresh tissue important for path studies
– Flow cytometry and cytogenetics helpful
• Best imaging techniques: CT, PET scan
• Important labs: LDH, CBC
– Also LFT’s, Alb, Cr, uric acid, lytes
 WHO Lymphoma Types
Precursor T-lymphoblastic
Precursor B-lymphoblastic leukemia/lymphoma
leukemia/lymphoma T cell prolymphocytic leukemia
CLL / SLL T-cell granular lymphocytic leukemia
Prolymphocytic leukemia Aggressive NK-Cell leukemia
Lymphoplasmacytic lymphoma Adult T cell lymphoma/leukemia
Marginal zone B-cell lymphoma Extranodal NK/T-cell nasal type
Hairy cell leuekmia Enteropathy-type T-cell lymphoma
Follicle center lymphoma Hepatosplenic T-cell lymphoma
Mantle cell lymphoma Subcutaneous panniculitis-like T-cell
Diffuse large cell B-cell lymphoma Mycosis fungoides/Sézary's syndrome
Burkitt's lymphoma/Burkitt's cell Anaplastic large cell lymphoma
leukemia Peripheral T cell lymphoma
Angioimmunoblastic T cell lymphoma
General Comments on Prognosis
• Many lymphomas are curable
– Even after relapse
– The incurable NHL can be indolent
• International Prognostic Index
– Most important for most NHL
•Age over 60
•Stage 3 or 4 disease
•More than one extranodal site
•Elevated LDH
•Poor general health
 Most Common NHL Diagnoses
• Diffuse Large B-cell Lymphoma
• Follicular Lymphoma
• Small Lymphocytic Lymphoma
• Mantle Cell Lymphoma
• Peripheral T-cell Lymphoma

Armitage JCO 16:2780, 1998

Diffuse Large B-cell Lymphoma
• Present with symptoms from focal
disease
• Most common lymphoma
(30 – 40%)
• Aggressive behavior
• Median Age: 64 yo
• IPI predictive of response and
survival
• Standard treatment: CHOP ±
rituximab
• Curable with chemotherapy
 Prognosis of DLCL by IPI
Risk IPI Score CR rate 5y DFS 5y OS

Low 0–1 87% 70% 73%

Low/ 2 67% 50% 51%

Intermediate
High/ 3 55% 49% 43%
Intermediate

High 4–5 44% 40% 26%

NEJM 329:987, 1993

Follicular Lymphoma
• Asymptomatic LAD
• Median age: 59 yo
• Indolent behavior
– Median survival 10 years
• Stage III – IV disease 67%
• IPI predictive, few high risk
• Incurable with chemo
– Stage I curable with XRT
• Treatment based on symptoms
– No need to treat at diagnosis
• Characteristic t(14:18)
Small Lymphocytic Lymphoma
• Asymptomatic LAD
• Median Age 65
• “Solid” counterpart to CLL
• Indolent behavior
– Median survival 4 – 5 years
• Stage III – IV disease 91%
• Incurable with chemo
• Treatment based on symptoms
– No need to treat at diagnosis
• Treatment as for CLL
Mantle Cell Lymphoma
• Few symptoms at diagnosis
• Indolent behavior at diagnosis
– Relentless progression
– Median survival 2 yrs
• Male predominance 3:1
• Stage III – IV 80%
• GI/blood involvement common
• Poor overall response & survival
• Aggressive regimens may help
• Characteristic t(11:14)
 Peripheral T-cell Lymphoma
• Present with symptoms from focal disease
• Aggressive behavior
• Median Age: 61 yo
• IPI not predictive of response and survival
• Survival short: median 1 year
• Standard treatment (?) CHOP
• Few are cured with chemotherapy
• Novel approaches needed
 Treatment of NHL
• Most aggressive lymphomas
– CHOP – cyclophosphamide, vincristine,
doxorubicin, and prednisone
• Most indolent lymphomas
– Many need no treatment – only for symptoms
– Oral alkylators, CVP, CHOP, fludarabine,
rituximab (antibiotics for MALT)
• Relapse – many patients will benefit from
high dose chemotherapy (transplant)
High-dose Chemotherapy with
Stem Cell Rescue

Philip et al NEJM 333:1540, 1995

 Rituximab (Rituxan®)
• FDA Approved Indication
– “RITUXAN is indicated for the treatment of
patients with relapsed or refractory low-grade
or follicular, CD20 positive B-cell non-
Hodgkin’s lymphoma”
• IgG1 kappa chimeric murine/human
monoclonal antibody against CD20
• Application in B-cell malignancy and
autoimmunity
 Making Chimeric Antibody
Murine Anti-CD20 Ig gene
Human IgG1 gene
Clone Variable Region gene

Clone Constant Region gene

Mouse Human
Chimeric Gene

Cellular Producer
 Mechanisms of Activity for IgG1
Antibodies

Dendritic Cell

Complement

NK Cell
 New Agents/Approaches
• Rituximab
– Most commonly prescribed cancer drug
• Ibritumomab Tiuxetan (Zevalin®)
– Yittrium 90 labeled rituximab
• Iodine 131 Tositumomab (Bexxar®)
• Alemtuzumab (Campath 1H®)
• Pentostatin, Fludarabine, Cladribine
 Conclusion
• Persistent LAD in older pts needs biopsy
• Many with aggressive lymphoma will be
cured
• Many with indolent lymphoma will live
many years with disease
• Our ability to define NHL has outpaced our
knowledge of how to best treat
• Many new agents available (how to use?)