Transcript Lymphoma Presentation and Diagnosis

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
Bone
Marrow
Follicles
Travel
Lymph Node
B cell finds “meaning”
“meaning”
B cell activation
Germinal Center
Formation
Germinal Center Activity
Proliferation
Signals
“Never die”
Signals
Mutation
Signals
Survival
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
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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
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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
leukemia/lymphoma
Precursor B-lymphoblastic
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
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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/
Intermediate
2
67%
50%
51%
High/
Intermediate
3
55%
49%
43%
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
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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
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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
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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 nonHodgkin’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?)