Goals

1
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

2
Definition of Lymphoma
C

• 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

3
Age at Diagnosis for Hodgkins andNon-Hodgkins
Lymphoma
56,390 NHL cases/y
7,350 HD cases/y
NHL
Cases/100,000
Hodgkins
Age at diagnosis (y)
Data for diagnoses from 1997 to 2001. At
http//seer.cancer.gov. Accessed March 23, 2005.
4
Non-Hodgkins LymphomaEpidemiology
Estimated annual incidence
4 compound annual increase in incidence
Year
Adapted from Greenlee et al. CA Cancer J Clin.
20015115. Adapted from Jemal et al. CA Cancer
J Clin. 20055510.
5
Hodgkins Disease
6
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

7
Hodgkins 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

8
Hodgkins Disease

• Approach to the Patient
• staging evaluation
• H P
• CBC, diff, plts
• ESR, LDH, albumin, LFTs, Cr
• CT scans chest/abd/pelvis
• bone marrow evaluation
• PET scan in selected cases

9
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.
10
Hodgkins 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

11
Approach to the Patient

• Hodgkins 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

12
Hodgkin Lymphoma Treatment of limited stage
disease
13
Hodgkin Lymphoma Prognostic Factors
14
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

15
Non-Hodgkins 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

16
WHO ClassificationB-Cell Malignancies
Precursor B-cell neoplasm Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma Precursor B-lymphoblastic leukemia/lymphoma Precursor B-lymphoblastic leukemia/lymphoma
Mature (peripheral) B-cell neoplasms Mature (peripheral) B-cell neoplasms 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 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
Harris NL et al. J Clin Oncol. 1999173835-3849.
17
WHO ClassificationT-Cell Malignancies
Precursor T-cell neoplasm Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma Precursor T-lymphoblastic leukemia/lymphoma Precursor T-lymphoblastic leukemia/lymphoma
Mature (peripheral) T-cell neoplasms Mature (peripheral) T-cell neoplasms 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 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. 1999173835-3849.
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B-Cell Development
Stem cell
Immature B cell
Follicle-center B cell
s-IgM
s-IgM/G/A
CD79a
CD22
CD79a
TdT
CD22
CD10
CD21
bcl6
HLA-DR
CD21
HLA-DR
CD20
CD34
HLA-DR
CD20
CD19
CD19
Pre-preB cell
Immunoblast
s-IgM/G/A
TdTc-CD22c-CD79a
CD22
CD79a
Mature B cell
CD138
c-Ig
s-IgM IgD
CD20
CD19
HLA-DR
CD79a
CD19
HLA-DR
MUM1
CD22
CD21
HLA-DR
PreB cell
CD20
CD10
TdTc-CD22c-CD79ac-m
CD19
Plasma cell
CD20
CD79a
CD138
c-Ig
CD19
HLA-DR
PCA-1
MUM1
19
Antigen Expression in B-Cell Lineage
Jaffe. In Non-Hodgkins Lymphoma. 199784.
20
Models of Chromosomal Translocations in NHL
REG
REG
REG
REG
CODING
CODING
CODING
CODING
Proto-oncogene
Proto-oncogene
TRANSLOCATION
TRANSLOCATION
REG
REG
COD
ING
CODING
TRANSCRIPTIONALDEREGULATION
FUSIONPROTEIN
REG regulatory sequence. Harris NL et al.
Hematology (Am Soc Hematol Educ Program).
2001194-220.
21
Chromosomal Translocations Commonly Associated
With Activation in B-Cell Malignancies
Oncogene Oncogene Protein Translocation Translocation Disease
bcl-1 Cyclin D1 Cyclin D1 Cyclin D1 t(1114) MCL
bcl-2 BCL2 (antiapoptosis) BCL2 (antiapoptosis) BCL2 (antiapoptosis) t(1418) FL

myc Transcription factor Transcription factor Transcription factor t(814) Burkitts NHL
bcl-6 Zinc-finger transcription factor Zinc-finger transcription factor Zinc-finger transcription factor t(314) DLBCL (some follicular NHL)
National Comprehensive Cancer Network. Practice
Guidelines in Oncology. v.1.2005.
22
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

23
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

24
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

25
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.
1998162780-2795.
26
Follicular Lymphoma
27
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

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Diffuse Large B Cell Lymphoma
30
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

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International Prognostic Index for Age-Adjusted
Risk Group Number of Factors Present 5-year DFS Age60 () 5-year OS Age60 ()
Low 0 86 83
Low-Intermediate 1 66 69
High-Intermediate 2 53 46
High 3 58 32
Factor Adverse
PS 2
LDH gtNormal
Stage III-IV
The International Non-Hodgkin's Lymphoma
Prognostic Factors Project. N Engl J Med.
1993329987-994.
33
DLBCL Subtypes Revealed by Expression Array
1.0
Germinal-centerB-celllike
0.8
0.6
Probability
ActivatedB-celllike
0.4
0.2
P 7.9 E-6
0.0
0
2
4
6
8
10
Overall survival (years)
Single histology with multiple molecular subtypes
with different outcomes
Alizadeh AA et al. Nature. 2000403503-511.
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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

35
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