Goals

• Understand the differences between Hodgkin Lymphoma and non-Hodgkin Lymphoma– Clinically and biologically

• Understand the differences between aggressive NHL and indolent NHL– Clinically and biologically

Definition of Lymphoma• Heterogeneous group of lymphoproliferative malignancies

– Results from clonal expansion of tumor cells derived from B, T, or NK cells

– 85%-90% in the US are derived from B cells

• Variable clinical presentations– Range from asymptomatic pick up on routine blood work to

painless adenopathy to an emergent medical problem• Pain, failure to thrive, organ failure

• Characterized by variable natural histories and therapeutic responses

C

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85

NHL

Hodgkin’s

~56,390 NHL cases/y~7,350 HD cases/y

Age at Diagnosis for Hodgkin’s andNon-Hodgkin’s Lymphoma

Data for diagnoses from 1997 to 2001.At: http://seer.cancer.gov. Accessed March 23, 2005.

Age at diagnosis (y)

Cas

es/1

00,0

00

Adapted from Greenlee et al. CA Cancer J Clin. 2001;51:15. Adapted from Jemal et al. CA Cancer J Clin. 2005;55:10.

United States

0

15,000

30,000

45,000

60,000

1980 1985 1990 1995 2000 2005

Estim

ated

ann

ual i

ncid

ence

Year

~4% compound annual increase in incidence

Non-Hodgkin’s Lymphoma:Epidemiology

Hodgkin’s Disease

Hodgkin Biology• RS is a “crippled” germinal center B cell

– does not have normal B cell surface antigens– micromanipulation of single RS followed by PCR demonstrates

clonally rearranged, but non functional immunoglobulin genes• somatic mutations result in stop codon (no sIg)• no apoptotic death malignant transformation

– unclear how this occurs; ? EBV– unclear how cells end up with RS phenotype

Hodgkin’s Disease

• Clinical features– Often seen in young adults– Wide variety of presentations

• B symptoms (fevers, night sweats, wt loss)• Pruritis• Cough/SOB• Pain• Painless adenopathy

Hodgkin’s Disease

• Approach to the Patient– staging evaluation

• H & P• CBC, diff, plts• ESR, LDH, albumin, LFT’s, Cr• CT scans chest/abd/pelvis• bone marrow evaluation• PET scan in selected cases

Ann Arbor Staging System for Hodgkin's Disease and Non-Hodgkin's Lymphoma

Stage I Stage II Stage III Stage IV

Reprinted with permission. Adapted from Skarin. Dana-Farber Cancer Institute Atlas

of Diagnostic Oncology. 1991.

Hodgkin’s Disease

• Typical staging results– Most often disease is localized to above the diaphragm– Common to have extensive mediastinal disease

• Tends to spread to contiguous nodal groups– Unlike NHL

Approach to the Patient

• Hodgkin’s Disease– approach dictated mainly by where the disease is

located rather (results of staging) than the exact histologic subtype

• NHL– approach is often dictated more by the histologic

subtype than the results of staging

Hodgkin Lymphoma: Treatment of limited stage disease

Hodgkin Lymphoma: Prognostic Factors

Hodgkins Disease Summary

• B cell lymphoma- several histologic subtypes

- Generally does not affect the approach to the patient– Reed-Sternberg Cells

• Tends to occur in young adults• Mediastinal disease common• Spreads to contiguous nodes• Common to have a “localized” presentation• Highly curable with current treatments

Non-Hodgkin’s Lymphoma• 30ish histologic subtypes

– B cell (85%), T cell, NK cell– Histologic subtype dictates the approach to the patient

• Median age at diagnosis 60• Often widespread disease at diagnosis• Wide variation in outcome

– Some cases rapidly fatal– Some cases readily curable– Some cases incurable but patient can live for many years with

good quality of life

WHO Classification:B-Cell Malignancies

Harris NL et al. J Clin Oncol. 1999;17:3835-3849.

Precursor B-cell neoplasm• Precursor B-lymphoblastic leukemia/lymphoma

Mature (peripheral) B-cell neoplasms• B-cell chronic lymphocytic leukemia/

small lymphocytic lymphoma • B-cell prolymphocytic leukemia • Lymphoplasmacytic lymphoma • Splenic marginal-zone B-cell lymphoma • Nodal marginal-zone lymphoma • Extranodal marginal-zone B-cell

lymphoma, mucosa-associated lymphoid tissue (MALT) type

• Hairy cell leukemia • Plasma-cell myeloma/

plasmacytoma • Follicular lymphoma • Mantle-cell lymphoma • Diffuse large B-cell lymphoma

(DLBCL) • Burkitt's lymphoma/Burkitt's cell

leukemia• Blastic NK-cell leukemia

WHO Classification:T-Cell MalignanciesPrecursor T-cell neoplasm• Precursor T-lymphoblastic leukemia/lymphoma

Mature (peripheral) T-cell neoplasms• T-cell prolymphocytic leukemia • T-cell granular lymphocytic leukemia • Aggressive NK-cell leukemia • Adult T-cell lymphoma/leukemia (HTLV1+) • Extranodal NK/T-cell lymphoma, nasal

type• Enteropathy-type T-cell lymphoma • Hepatosplenic gamma-delta T-cell

lymphoma

• Subcutaneous panniculitis-like T-cell lymphoma

• Mycosis fungoides/Sézary syndrome • Primary cutaneous anaplastic large cell

lymphoma, T/null cell • Peripheral T-cell lymphoma, unspecified • Angioimmunoblastic T-cell lymphoma • Primary systemic anaplastic large cell

lymphoma, T/null cell• Blastic NK lymphoma

Harris NL et al. J Clin Oncol. 1999;17:3835-3849.

B-Cell Development

MUM1

HLA-DR CD34

Stem cell

Pre-pre–B cell

Pre–B cell

Immature B cell

Mature B cell

HLA-DR CD19

HLA-DR CD19

HLA-DR

CD19CD20CD21

CD22CD79as-IgM

CD20

CD10

CD79a

s-IgM & IgD

CD19CD20

CD21CD22

HLA-DR

s-IgM/G/A

s-IgM/G/A

CD79a

CD19CD20CD21

CD22

HLA-DR

CD10

CD19CD20CD138±

CD22

HLA-DR

CD79a

CD79a CD138PCA-1

Follicle-center B cell

Immunoblast

Plasma cell

Precursor cellsVirgin (naïve) B cellsGerminal-center and post–germinal-center B cells

MUM1

TdT

TdTc-CD22c-CD79a

TdTc-CD22c-CD79a

c-

bcl6

c-Ig

c-Ig

Antigen Expression in B-Cell Lineage

Pre-B Early B Mature B Plasmacytoid B

Type of B cell lymphoma is a function of:

1) Where the cell was in development/maturation when it went “bad”

2) What molecular derangement occurred

PlasmaActivated BStem cell

Burkitts, FL, DLBCL WM MMMCL, CLLALL

Germinal center

Jaffe. In: Non-Hodgkin’s Lymphoma. 1997:84.

Models of Chromosomal Translocations in NHL

REG = regulatory sequence.Harris NL et al. Hematology (Am Soc Hematol Educ Program). 2001:194-220.

Proto-oncogene

Proto-oncogene

TRANSCRIPTIONALDEREGULATION

FUSIONPROTEIN

TRANSLOCATION TRANSLOCATION

REG

REG REG

REG

REG REGCODING CODING

COD

CODING CODING

CODING ING

Chromosomal Translocations Commonly Associated With Activation in B-Cell Malignancies

National Comprehensive Cancer Network. Practice Guidelines in Oncology. v.1.2005.

Oncogene Protein Translocation Disease

bcl-1 Cyclin D1 t(11;14) MCL

bcl-2 BCL2 (antiapoptosis) t(14;18) FL

myc Transcription factor t(8;14) Burkitt’s NHL

bcl-6 Zinc-finger transcription factor t(3;14) DLBCL (some

follicular NHL)

Lymphoma Biology• Aggressive NHL

– short natural history (patients die within months if untreated)

– disease of rapid cellular proliferation– Potentially curable with chemotherapy

• Indolent NHL– long natural history (patients can live for many years

untreated)– disease of slow cellular accumulation– Generally incurable with chemotherapy

NHL: Presentation and Staging

• Aggressive NHL– Patients likely to present with symptoms

• Indolent NHL– Patients likely to present with painless adenopathy

• Initial workup similar to Hodgkin Lymphoma

NHL: Approach to the Patient

• Approach dictated mainly by histology– reliable hematopathology crucial

• Aggressive NHL– Cure is often the goal

• Indolent NHL– Cure is rarely the goal– Control is the goal

Most Common NHLsCategory Frequency (%)Diffuse large B-cell 31

Follicular 22

Marginal-zone B-cell, MALT 8

Peripheral T-cell 7

Small B-lymphocytic/CLL 7

Mantle-cell lymphoma 6

Primary mediastinal large B-cell 2

Anaplastic large T/null cell 2

High-grade B-cell, Burkitt-like 2

Marginal-zone B-cell, nodal 2Precursor T-lymphoblastic lymphoma 2

Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795.

Follicular Lymphoma

Approach to Indolent NHL• Indolent NHL: guiding treatment principle

• immediate treatment does not prolong overall survival for many patients

– When to treat?• constitutional symptoms• compromise of a vital organ by compression or infiltration, particularly

the bone marrow• bulky adenopathy• rapid progression• evidence of transformation

• Will often begin with relatively non-toxic treatments and escalate the intensity of the therapy

Diffuse Large B Cell Lymphoma

Approach to Aggressive NHL

• Patients have the potential to be cured– Administer most effective therapy (no matter how

harsh) at diagnosis– If not cured, patients typically die within a few years of

diagnosis

International Prognostic Index for Age-Adjusted

Factor AdversePS ≥2LDH >NormalStage III-IV

Risk Group

Number of Factors Present

5-year DFSAge≤60

(%)

5-year OS Age≤60

(%)Low 0 86 83

Low-Intermediate 1 66 69

High-Intermediate 2 53 46

High 3 58 32

The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994.

DLBCL: Subtypes Revealed by Expression Array

Prob

abili

ty

Overall survival (years)0 2 4 6 8 10

Germinal-centerB-cell–like

ActivatedB-cell–like

P = 7.9 E-6

1.00.8

0.60.40.20.0

Alizadeh AA et al. Nature. 2000;403:503-511.

Single histology with multiple molecular

subtypes

…with different outcomes

Summary• NHL incidence increasing • Hodgkin incidence stable or decreasing• Hodgkin Lymphoma

– Characterized by the Reed-Sternberg Cells– Stage more important that histologic subtype– Often limited stage (stage I or II)– Spreads to contiguous nodes– Often affects younger patients– Very responsive to therapy– Cure rate quite high

Summary• NHL cure rate mediocre

– Many histologic subtypes• Often more important that the stage

– indolent vs. aggressive• Function of underlying biology

– indolent: • Often asymptomatic• Treatment: Less is more

– aggressive: • Often symptomatic• require aggressive treatment ASAP to achieve cure