Lymphoma Presentation and Diagnosis Mark B. Juckett MD Division of Hematology University of...

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

Travel

Lymph Node

Follicles

BoneMarrow

Pre B cellIgM

B cell

B cell finds “meaning”

B cell activation

Germinal CenterFormation

“meaning”

Germinal Center

Proliferation Signals

SurvivalSignals

“Never die”Signals

MutationSignals

Germinal Center Activity

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 Year1973 - 2000

•NHL

•All ages

Incidence Rate by Age1996 - 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 B-lymphoblastic leukemia/lymphoma

CLL / SLL Prolymphocytic leukemia Lymphoplasmacytic lymphoma Marginal zone B-cell lymphomaHairy cell leuekmia Follicle center lymphomaMantle cell lymphoma Diffuse large cell B-cell lymphomaBurkitt's lymphoma/Burkitt's cell

leukemia

Precursor T-lymphoblastic leukemia/lymphoma

T cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-Cell leukemia Adult T cell lymphoma/leukemiaExtranodal NK/T-cell nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cellMycosis fungoides/Sézary's syndrome Anaplastic large cell lymphomaPeripheral T cell lymphomaAngioimmunoblastic 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/

Intermediate2 67% 50% 51%

High/

Intermediate3 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• 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

Mouse HumanChimeric Gene

Clone Variable Region gene

Clone Constant Region gene

Cellular Producer

Mechanisms of Activity for IgG1 Antibodies

Complement

Dendritic Cell

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?)