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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