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
C
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
Age at Diagnosis for Hodgkin’s and
Non-Hodgkin’s Lymphoma
120
~56,390 NHL cases/y
~7,350 HD cases/y
Cases/100,000
100
NHL
80
60
40
20
Hodgkin’s
0
0
5
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85
Age at diagnosis (y)
Data for diagnoses from 1997 to 2001.
At: http://seer.cancer.gov. Accessed March 23, 2005.
Estimated annual incidence
Non-Hodgkin’s Lymphoma:
Epidemiology
United States
60,000
45,000
30,000
~4% compound annual
increase in incidence
15,000
0
1980
1985
1990
Year
Adapted from Greenlee et al. CA Cancer J Clin. 2001;51:15.
Adapted from Jemal et al. CA Cancer J Clin. 2005;55:10.
1995
2000
2005
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 NonHodgkin'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
Precursor B-cell neoplasm
• Precursor B-lymphoblastic leukemia/lymphoma
Mature (peripheral) B-cell neoplasms
• B-cell chronic lymphocytic leukemia/
small lymphocytic lymphoma
• Hairy cell leukemia
• B-cell prolymphocytic leukemia
• Plasma-cell myeloma/
plasmacytoma
• Lymphoplasmacytic lymphoma
• Follicular lymphoma
• Splenic marginal-zone B-cell lymphoma
• Mantle-cell lymphoma
• Nodal marginal-zone lymphoma
• Diffuse large B-cell lymphoma
(DLBCL)
• Extranodal marginal-zone B-cell
lymphoma, mucosa-associated
lymphoid tissue (MALT) type
• Burkitt's lymphoma/Burkitt's cell
leukemia
• Blastic NK-cell leukemia
Harris NL et al. J Clin Oncol. 1999;17:3835-3849.
WHO Classification:
T-Cell Malignancies
Precursor T-cell neoplasm
• Precursor T-lymphoblastic leukemia/lymphoma
Mature (peripheral) T-cell neoplasms
• T-cell prolymphocytic leukemia
• T-cell granular lymphocytic leukemia
• Subcutaneous panniculitis-like T-cell
lymphoma
• Aggressive NK-cell leukemia
• Mycosis fungoides/Sézary syndrome
• Adult T-cell lymphoma/leukemia (HTLV1+)
• Primary cutaneous anaplastic large cell
lymphoma, T/null cell
• Extranodal NK/T-cell lymphoma, nasal type
• Enteropathy-type T-cell lymphoma
• Hepatosplenic gamma-delta T-cell
lymphoma
• 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
Stem cell
Immature B cell
s-IgM
CD79a
TdT
HLA-DR
HLA-DR
CD79a
CD22
CD21
CD20
CD34
Follicle-center B cell
s-IgM/G/A
CD22
CD10
bcl6
HLA-DR
CD21
CD20
CD19
CD19
Pre-pre–B cell
Immunoblast
s-IgM/G/A
TdT
c-CD22
c-CD79a
CD22
CD79a
Mature B cell
HLA-DR
CD19
CD20
CD79a
CD19
HLA-DR
MUM1
CD22
CD10
TdT
c-CD22
c-CD79a
c-m
HLA-DR
CD21
HLA-DR
Pre–B cell
CD138±
c-Ig
s-IgM & IgD
CD20
CD19
CD20
CD19
Plasma cell
CD79a
c-Ig
Precursor cells
Virgin (naïve) B cells
Germinal-center and post–germinal-center B cells
CD138
PCA-1
MUM1
Antigen Expression in BCell Lineage
ALL
Stem cell
MCL, CLL
Pre-B
Early B
Burkitts, FL, DLBCL
Mature B
Activated B
WM
Plasmacytoid B
Germinal center
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
Jaffe. In: Non-Hodgkin’s Lymphoma. 1997:84.
MM
Plasma
Models of Chromosomal
Translocations in NHL
REG
CODING
REG
CODING
REG
CODING
REG
Protooncogene
TRANSLOCATION
REG
CODING
TRANSCRIPTIONAL
DEREGULATION
CODING
Protooncogene
TRANSLOCATION
REG
CODING
FUSION
PROTEIN
REG = regulatory sequence.
Harris NL et al. Hematology (Am Soc Hematol Educ Program). 2001:194-220.
Chromosomal Translocations
Commonly Associated With
Activation in B-Cell Malignancies
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)
National Comprehensive Cancer Network. Practice Guidelines in Oncology. v.1.2005.
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
LDH
Stage
≥2
>Normal
III-IV
Number of
Factors
Present
5-year DFS
Age≤60
(%)
5-year OS
Age≤60
(%)
Low
0
86
83
Low-Intermediate
1
66
69
High-Intermediate
2
53
46
High
3
58
32
Risk Group
The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994.
DLBCL: Subtypes Revealed
by Expression Array
Probability
1.0
Germinal-center
B-cell–like
0.8
0.6
Activated
B-cell–like
0.4
0.2
P = 7.9 E-6
0.0
0
Single histology with
multiple molecular
subtypes
2
4
6
8
Overall survival (years)
10
…with different
outcomes
Alizadeh AA et al. Nature. 2000;403:503-511.
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