1. Lymphomas: The Basics Brad Kahl, MD Assistant Professor of Medicine
Director, UW Lymphoma Service

2. Lymphomas: NHL vs Hodgkin’s
EPIDEMIOLOGY
Biology
Classification
Approach to the Patient

3. Hodgkin’s Disease Epidemiology 14% of malignant lymphomas
0.5% of all malignancies
approximately 8000 new cases/yr in US
approximately 1500 deaths/yr
over past 30 years
age adjusted incidence rates declined appreciably
mortality rates declined substantially

4. Hodgkin’s Disease Epidemiology men > women
whites > blacks > Asians
no clear risk factors, several implicated
EBV (pathogen or passenger)
HIV
woodworking, farming
rare familial aggregations

5. NHL: Epidemiology Most common hematologic malignancy
60,000 new cases annually
6th leading cause of cancer death
incidence rising
overall incidence up by 73% since 1973
“epidemic”
2nd most rapidly rising malignancy

6. NHL: Epidemiology Why the increase? Other environmental factors?
Increase noted mostly in farming states
MN #1, WI #7 NHL incidence
possible role of herbicides, insecticides, etc.
Other environmental factors?

7. NHL: Epidemiology Other risk factors immunodeficiency states
AIDS, post-transplant, genetic
autoimmune diseases
Sjogrens
Sprue
infections
H. pylori, EBV, HHV-8

8. Epidemiology SEER 5 year survival data NHL Hodgkin’s
: %
: %
: % %

9. Hodgkin’s Disease Epidemiology BIOLOGY Classification
Approach to the Patient

10. Hodgkin’s Disease Background
first described in 1832 by Dr. Thomas Hodgkin
characterized by the presence of Reed-Sternberg cells
multinucleated giant cells
described by Sternberg in 1898 and Reed in 1902
classified as an infectious disease until 1950’s

11. Reed-Sternberg Cell

12. 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

13. Hodgkin’s Disease Epidemiology Biology CLASSIFICATION
APPROACH TO THE PATIENT

14. Hodgkin Lymphoma Classification
“Classic” Hodgkin’s Disease
nodular sclerosis
mixed cellularity
lymphocyte depleted (very rare)
classical lymphocyte rich
HRS cells CD30 and CD15 positive
nodular lymphocyte predominant
HRS cells (L&H cells) have B cell markers
CD 20 and surface Immunoglobulin

15. Classic Hodgkin Lymphoma

16. Nodular Sclerosing Hodgkin Lymphoma

17. 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 dictated mainly by the histologic subtype rather than the results of staging

18. 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 or gallium scan**
**lymphangiogram or laparotomy**

19. Ann Arbor Staging System
Stage I: single lymph node region (I) or single extralymphatic organ or site (IE)
Stage II: > 2 lymph node regions on same side of diaphragm (II) or with limited, contiguous extra lymphatic tissue involvement (IIE)
Stage III: both sides of diaphragm involved, may include spleen (IIIS) or local tissue involvement (IIIE)
Stage IV: multiple/disseminated foci involved with > 1 extralymphatic organs (i.e. bone marrow)
(A) or (B) designates absence/presence of “B” symptoms

20. Ann Arbor Staging System for Hodgkin's Disease and Non-Hodgkin's Lymphoma
Historically, this staging methodology was designed for Hodgkin’s disease but has been adapted to NHL. Staging defines the extent of a cancer along three axes: tumor (T); node (N); and metastasis (M). The rationale behind a staging system is to accomplish the following:
Plan treatment strategies
Help evaluate the treatment results
Standardize information to facilitate exchanges between health-care professionals and treatment centers
Formulate a more accurate prognosis
Promote the continuity of cancer investigation
The Ann Arbor Staging System is the most commonly used in NHL. It is divided into four stages (I to IV), according to nodal and extralymphatic involvement, and subclassified into A and B categories.
A designates the absence of the so-called B symptoms.
B signals their presence.
The B symptoms are as follows:
Unexplained loss of more than 10% of body weight in the 6 months before diagnosis
Unexplained fever with temperatures above 38o Celsius
Drenching night sweats
Skarin AT, ed. Dana-Farber Cancer Institute Atlas of Diagnostic Oncology. Philadelphia:
Lippincott; New York: Gower Medical Pub; 1991.
Available at Accessed 6/25/02.
Stage I Stage II Stage III Stage IV
Reprinted with permission. Adapted from Skarin. Dana-Farber Cancer Institute Atlas of Diagnostic Oncology

21. Modified Ann Arbor Staging
“E” designation for extranodal disease
B symptoms
recurrent drenching night sweats during previous month
unexplained, persistent, or recurrent fever with temps above 38 C during the previous month
unexplained weight loss of more than 10% of the body weight during the previous 6 months
Criteria for bulk
10 cm nodal mass
mediastinal mass > 1/3 thorax diameter

23. Hodgkin Lymphoma Treatment
approach depends upon stage, prognostic factors, and co-morbidities
Stage I-II
consider XRT, chemotherapy, or combined therapy
Bulky stage I-II
combined modality therapy
Stage III-IV
ABVD x 6-8 cycles gold standard

24. Hodgkin Lymphoma
Adverse prognostic features for stage I & II (EORTC data)
more than 3 nodal sites
bulky adenopathy
ESR > 50
B symptoms
invasion into critical organs
male
age > 40
MC or LD subtype
should probably not receive XRT alone if any of the above present (excessive relapse rate)

25. Hodgkin Lymphoma Independent adverse prognostic factors
advanced stage (III-IV)
male sex
age > 45
albumin < 4 gm/dl
HgB < 10.5 mg/dl
stage IV disease
WBC count > 15,000/mm3
lymphocyte count < 600/mm3
(Hasenclever et al, NEJM 339, ;1998)

26. Hodgkin’s Disease Role for Stem Cell Transplantation
clinical trials show benefit for patients who receive high dose chemotherapy followed by SCT for patients who have relapsed after initial therapy or for patients are primary refractory

27. Hodgkin’s Disease Results of Treatment stage 5 year overall survival
II 90%
III 80%
IV 65%

28. Hodgkin Lymphoma Late Complications
depends upon treatment modality utilized
XRT vs. MOPP vs. ABVD vs. CMT
issues depends upon the age of patient
relative risks higher in younger patients
absolute risks higher in older patients
major focus of current clinical trials to to maintain high cure rate while minimizing late complication
shorter courses of chemotherapy with lower radiation doses in smaller fields
elimination of radiotherapy

29. Hodgkin’s: future directions
Limited stage and good prognosis advanced stage
cure rate high
current goal is to minimize late complications
trials looking at CMT with less chemotherapy and less radiation
Advanced stage
cure rate around 50-70%
trial comparing ABVD to Stanford V
Clinical Trials

30. NHL
Epidemiology
BIOLOGY
Classification
Approach to the Patient

31. Lymphoma Biology Indolent vs. Aggressive NHL
key principle in understanding biology, and approach to the patient
Indolent = incurable
Aggressive = curable
WHY?
Chromosomal Abnormalities in NHL
frequent chromosomal translocations into Ig gene loci
t(8;14), t(2;8), t(8;22) Burkitt’s
t(14;18) follicular NHL

32. Lymphoma Biology Aggressive NHL Indolent NHL
short natural history (patients die within months if untreated)
disease of rapid cellular proliferation
Indolent NHL
long natural history (patients can live for many years untreated)
disease of slow cellular accumulation

33. NHL
Epidemiology
Biology
CLASSIFICATION
Approach to the Patient

34. NHL: Classification Historically- a mess 1940s Gail and Mallory
1950s Rappaport
1970s Lukes-Collins
1970s Kiel
1982 Working
1994 REAL
1999 WHO

36. NHL: Classification Key Points Principle
cell size: small cell vs. large cell
nodal architecture: follicular vs. diffuse
Principle
More aggressive: diffuse, large cell
More indolent: follicular, small cell

37. NHL: Classification Terminology (refers to natural history) Principle
low grade = indolent
intermediate grade = aggressive
high grade = aggressive
Principle
indolent: slow growing, incurable
aggressive: rapidly growing, curable

38. NHL
Epidemiology
Biology
Classification
APPROACH TO THE PATIENT

39. NHL: Approach to the Patient
Approach dictated mainly by histology
reliable hematopathology crucial
Approach also influenced by:
stage
prognostic factors
co-morbidities

40. NHL: Approach to the Patient
Staging evaluation
History and PE
Routine blood work
CBC, diff, plts, electrolytes, BUN, Cr, LFT’s, uric acid, LDH, B2M
CT scans chest/abd/pelvis
Bone marrow evaluation
Other studies as indicated (lumbar puncture, gallium, etc…)

42. NHL: Approach to the Patient
Indolent NHL: typical scenario
patient presents with painless adenopathy
otherwise asymptomatic
follicular small cell histology
average age 59
usually stage III-IV at diagnosis

45. NHL: Approach to the Patient
Indolent NHL: guiding treatment principle
early treatment does not prolong overall survival
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

46. NHL: Approach to the Patient
Indolent NHL: typical scenario
watchful waiting: 2-4 years
first remission length: 3-4 years
second remission: 2-3 years
third remission: 1-2 years
each subsequent remission shorter than prior
median survival 8-12 years for FLSC

47. NHL: Approach to the Patient
Indolent NHL: treatment options
watchful waiting
radiation to involved fields
single agent chemotherapy
chlorambucil + prednisone, fludarabine
combination chemotherapy
CVP, CF, FND, CHOP
chemotherapy + interferon
chemotherapy + monoclonal antibodies
monoclonal antibodies
radiolabeled monoclonal antibodies
stem cell transplantation

48. NHL: Approach to the Patient
Aggressive NHL: typical scenario
patients notes B symptoms of several weeks duration
work-up reveals pathologic adenopathy
histology: diffuse large cell lymphoma
about 50% patients stage I-II, 50% stage III-IV
average age 64
IPI score

51. NHL: Approach to the Patient
Aggressive NHL: treatment approach
Stage I-II: combined modality therapy
CHOP chemotherapy x 3 + IF radiotherapy
cure rate around 70%
Stage III-IV (also bulky stage II)
(R)CHOP chemotherapy x 6-8 cycles
cure rate around 40%
(R)CHOP is the standard

52. NHL: Approach to the Patient
International Prognostic Index
Risk Factors (0-5)
age > 60
two or more extranodal sites
performance status > 2
elevated LDH
stage III-IV
Age adjusted IPI (0-3)

53. CR and OS stratified by IPI

54. NHL: Approach to the Patient
Is CHOP the best we can do?
R-CHOP may be better
National Trials opening looking at alternative strategies in poor prognosis DLCL
age adjusted IPI > 2
CHOP vs. CHOP + SCT
Risk stratification is the current trend in NHL
Sorting out role for stem cell transplantation
Sorting out role for innovative combinations

55. NHL: Approach to the Patient
Role for Autologous Stem Cell Transplantation
Aggressive NHL
clear benefit when used for aggressive NHL in first relapse in appropriately selected patients
1/3 of these patients can be cured by SCT
Indolent NHL
no indication that patients are cured
no indication that OS is prolonged

56. NHL: future directions
Indolent
monoclonal antibodies (Rituximab)
radiolabeled monoclonal antibodies
chemotherapy combined with antibodies
antibodies combined with immunomodulators
Aggressive
risk stratification
CHOP vs. CHOP plus SCT
chemotherapy plus antibodies
Clinical Trials

57. Summary NHL incidence increasing, Hodgkin’s decreasing
Hodgkin’s cure rate quite high
approach is dictated mainly by disease stage
NHL cure rate mediocre
approach is dictated mainly by histologic subtype
indolent vs. aggressive
indolent: watchful waiting perfectly acceptable for asymptomatic patients
aggressive: require aggressive treatment ASAP to achieve cure

58. Lymphoma Clinic Multidisciplinary Emphasis on clinical trials
radiotherapy-Dr. Scott Tannehill
hematopathology-Dr. Catherine Leith
Emphasis on clinical trials
formal testing of promising new therapies
Every Wednesday
Clinic phone #: