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)

Ca

ses

/10

0,0

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

Est

imat

ed a

nn

ual

in

cid

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

CD19

CD20

CD21

CD22CD79a

s-IgM

CD20

CD10

CD79a

s-IgM & IgD

CD19CD20

CD21

CD22

HLA-DR

s-IgM/G/A

s-IgM/G/A

CD79a

CD19

CD20

CD21

CD22

HLA-DR

CD10

CD19

CD20

CD138±

CD22

HLA-DR

CD79a

CD79a CD138

PCA-1

Follicle-center B cell

Immunoblast

Plasma cell

Precursor cells

Virgin (naïve) B cells

Germinal-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-2BCL2

(antiapoptosis)t(14;18) FL

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

bcl-6Zinc-finger

transcription factort(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 NHLs

Category 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 2

Precursor 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 Adverse

PS ≥2

LDH >Normal

Stage 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

Pro

bab

ilit

y

Overall survival (years)

0 2 4 6 8 10

Germinal-centerB-cell–like

ActivatedB-cell–like

P = 7.9 E-6

1.0

0.8

0.6

0.4

0.2

0.0

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