4. Conceptualizing lymphoma
Lymphomas are malignant transformations of normal
lymphoid cells which reside predominantly in lymphoid
tissues
As clonal cell expansions at certain developmental
stages
Lymphatic system is our bodies main fight against
“foreigners”
Lymphocytes
Carried through our lymphatic system to help to fight
infection
Lymphocytes are carried through the lymph vessels as well as
the blood stream, so cancer can start in nodes and spread
anywhere throughout the body.
6. B-Cell Lymphoma (80%)
B-Cells help make antibodies, which are proteins that
attach to and help destroy antigens
Lymphomas are caused when a mutation arises
during the B-cell life cycle
Various different lymphomas can occur during
several different stages of the cycle
Follicular lymphoma, which is a type of B-cell lymphoma
is caused by a gene translocation which results in an over
expressed gene called BCL-2, which blocks apoptosis.
9. Germinal
Center
Mantle Zone
Pax-5
t(9;14)
Marginal Zone
Lympho-
plasmacytic
Mantle Cell
Lymphoma
Bcl-1
t(11;14)
Follicular
Lymphoma
p53
Bcl-2
t(14;18)
Bcl-6
t(2;3)
?
Diffuse Large
Cell Lymphoma
Burkitt’s
Lymphoma
p53, c-myc, EBV
t(8;14)
t(8;22)
t(2;8)
B-CLL
Small Lymphocytic
p53
Richter’s
Syndrome
Marginal Zone
Lymphoma (MALT)
Bcl-10
t(1;14)
CD5+
B Cells
CD5-
B Cells
?
Molecular pathogenesis of
B-cell lymphomas
HL
10. T-Cell Lymphoma (15%)
The T-cells are born from stem cells, similar to
that of B-cells, but mature in the thymus.
They help the immune system work in a
coordinated fashion.
These types of lymphomas are categorized by how
the cell is affected
Anaplastic Large cell Lymphoma, T-cell lymphoma
caused by a gene translocation in chromosome 5
11. Clinically useful
classification
Diseases that have distinct
• clinical features
• natural history
• prognosis
• treatment
Biologically rational
classification
Diseases that have distinct
• morphology
• immunophenotype
• genetic features
• clinical features
Lymphoma Classification
13. Clinically Rational Classification
Category Survival of
untreated
patients
Curability To treat or
not to treat
NHL Indolent Years Generally not
curable
Generally
In some
Aggressive Months Curable
in some
Treat
Very
aggressive
Weeks Curable
in some
Treat
HL All types Variable –
months to
years
Curable
in most
Treat
14. Epidemiology of Lymphoma
Hodgkin Lymphoma
14% of malignant lymphomas
0.5% of all malignancies
~ 8000 new cases/yr in US
~ 1500 deaths/yr
over past 30 years
age adjusted incidence rates declined appreciably
mortality rates declined substantially
15. Non-Hodgkin Lymphoma
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
Why the increase?
Increase noted in farming states (?? herbicides, insecticides. etc.)
immunodeficiency dis.(AIDS, post-transplant, genetic)
autoimmune diseases (Sjogrens, Sprue)
Infections (H. pylori, EBV)
16. Approach to Lymphoma Patient
HL
approach dictated mainly
by where the disease is
stage
the exact histologic
subtype
NHL
approach is dictated
mainly by the
histologic subtype
then staging
17. Diagnosis-Basics
As always a good H&P is priceless
CBC, diff, plts
ESR, LDH, albumin, LFT’s, Cr
CT scans Neck/chest/abd/pelvis
**PET or gallium scan**
Lymph node bx (again an entire intact LN is
preferable)
bone marrow bx whom?
**lymphangiogram or laparotomy**
18. Diagnosis requires an adequate
biopsy
Diagnosis should be biopsy-proven before
treatment is initiated
Need enough tissue to assess cells and
architecture
open (whole node) bx vs core needle bx vs FNA
19. Staging-Basics
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)
20. Modified Ann Arbor Staging
“E” designation for extra-lymphatic disease
B symptoms
recurrent drenching night sweats during previous month
unexplained weight loss of more than 10% of the body
weight during the previous 6 months
unexplained, persistent, or recurrent fever with temps
above 38 C during the previous month
Criteria for bulk
10 cm nodal mass
mediastinal mass > 1/3 thorax diameter
22. Radiation fields in Lymphoma
Extended-field radiation EFRT:
Radiation treatment volume includes the clinically involved nodes+
adjacent, clinically uninvolved sites (eg, mantle or inverted-Y field,
TNI, STNI).Radiation Therapy EFRT for lymphoma treatment
Involved-field radiation IFRT:
Radiation treatment volume encompasses all of the clinically
involved regions (eg, mediastinal plus low bilateral supraclavicular
field which covers the entire mediastinum)Radiation Therapy IFRT
for lymphoma threatment
Involved-node radiation INRT:
Radiation treatment volume includes pre- and post-chemotherapy
27. Clinical Presentation
Bimodal distribution: peak in 20’s and a second peak at 50’s
overall M>F
Most will present with asymptomatic lymphadenopathy
often in the neck
Can manifest as mediastinal mass on CXR. (can cause
cough, retrosternal cp or MS
contiguous spread
extranodal sites is uncommon except in advanced disease
“B” symptoms
28. Diagnosis
As always a good H&P is priceless
CBC, diff, plts
ESR, LDH, albumin, LFT’s, Cr
CT scans Neck/chest/abd/pelvis
**PET or gallium scan**
Lymph node bx (again an entire intact LN is
preferable)
bone marrow Bx if pt has
B symptoms,
clinical stage II-IV,
anemia, leukopenia or thrombocytopenia
**lymphangiogram or laparotomy**
29. Hodgkin lymphoma
Reed-Sternberg cells in the affected
tissues
RS is a “crippled” germinal center B cell
does not have normal B cell surface
antigens
most cells in affected lymph node are
polyclonal reactive lymphoid cells, not
neoplastic cells
30. Associated (etiological?) factors
EBV infection
smaller family size
higher socio-economic status
caucasian > non-caucasian
possible genetic predisposition
other: HIV? occupation? herbicides?
31. HL Histologic subtypes
1. Classical Hodgkin’s lymphoma:
*Reed-Sternberg Cells
*(CD30+/CD15+/CD45-/panB -panT antigen negative)
a. Lymphocyte-rich
b. Nodular sclerosis
c. Mixed cellularity
d. Lymphocyte depleted
2. Nodular Lymphocyte Predominant
*non-classical RS cells
*(CD30-/CD15-/pan-Bcell +)
32. 1.a Nodular Sclerosis Classical HL
Most common subtype
Most common in women, adolescents and young
adults
often will have a mediastinal mass, lower cervical,
supraclavicular L.N. w/ and orderly pattern of spread
Good Prognosis
33. 1.b Mixed Cellularity Classical HL
More common in males
More aggressive, but still curable
Pts usually older and more likely to have B
symptoms
More commonly in underdeveloped countries
34. 1.c Lymphocyte depleted Classical HL
Least common subtype
Older men and HIV infected pts
Less peripheral adenopathy, more abdominal
adenopathy.
BM often involved
35. 1.d Lymphocyte-rich Classical HL
Older patients usually
More frequently present w/ mediastinal mass
Late relapses less common, but more fatal
36. 2. Nodular Lymphocyte Predominant HL
Only 3-8% of HL
More common in adults (median age 34)
More often localized disease
More common in men
Slowly progressive w/ very favorable outcomes
Can progress to large B-cell NHL
*(CD30-/CD15-/pan-Bcell +)
*non-classical RS cells
37. Overview of Treatment
HL is highly curable even after relapse
Over the past century, HL has been converted
from a uniformly fatal disease to one that is
curable in greater than 75 %of patients worldwide
Stage and prognostic factors will determine high
vs. low risk disease and will drive treatment
choices
38. EVOLUTION OF "STANDARD"
TREATMENT
1960’s and early 1970’s:
Staging laparotomy
I-II RTH alone cured early stage(TNRT, EFRT, 40-44 Gy)
III-IV MOPP late 70’s ABVD
1980’s:
Trend to clinical staging (radiology)
ABVD
1990’s:
Only clinical staging
No more EFRT
Combined different CTH + Less RTH volume/dose
2000’s
ABVD ± IFRT less dose
radiotherapy is rarely, if ever, used currently as the sole treatment of
Hodgkin lymphoma
39. Chemotherapy regimens
MOPP (mechlorethamine, vincristine, procarbazine, and
prednisone) : first CTH regimen to establish the curability of
patients with advanced stage HL obsolete.
ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)
:the gold standard regimen
Stanford V (doxorubicin, vinblastine, mechlorethamine,
vincristine, bleomycin, etoposide, and prednisone) is a
combined modality treatment that incorporates RTH for the
great majority of patients.
Escalated or standard BEACOPP (bleomycin, etoposide,
doxorubicin, cyclophosphamide, vincristine, procarbazine, and
prednisone) is increasingly being used worldwide
05/05/2023
40. Adverse prognostic Factors
EORTC definitions
Adverse Px factors identified in CS I-II pts. Used to
define tx for CS I-II HD
Defined as follows:
Large mediastinal adenopathy
Age over 50
B symptoms
>4 LN regions involved
B Symptoms + ESR>30 or ESR >50 w/o B symptoms
41. Favorable CS Stage I-II
2-4 cycles ABVD IFRT
Stanford V for 8wks IFRT
Ongoing trials are attempting to identify newer regimens
and determine the optimal number of chemotherapy cycles
to administer to obtain the lowest relapse rate and improve
overall survival
42. Unfavorable Stage I-II
3 poor prognostic factors
4-6 cycles ABVD IFRT
Treat 2 cycles past maximum response as assessed
on imaging studies to max. 8 cycles
Stanford V for 12 wks followed by IFRT
43. Advanced Stage III-IV HL
6-8 cycles of ABVD most common regimen used
Hybrid regimens tested, but not better than ABVD
BEACOPP is alt. regimen
The role of IFRT after CTH for advanced stage
HL is controversial for bulky sites
Stanford V for 12 wks followed by IFRT
“essential part of the protocol” also being tested
45. Indication for RTH
IFRT
Following CTH in CR patients
Favourable CS I-II 30 Gy/ 15 f
Unfavourable CS I-II 36 Gy/18 f
Advanced CS IIIB-IV ?? Bulky sites
In PR – SD after 2nd line CTH
38-40 Gy/ 18-20f
Palliative RTH
40Gy/20f----5Gy x 4f
46. Relapsed/Refractory HL
Refractory (resistant) disease is defined as failure to
obtain an at least partial response with initial treatment (at
least 50 % decrease in lesion size with no new lesions.)
Relapse reappearance of HL > 3 ms after the
attainment of CR after initial treatment
Bx area of relapse to prove pt has truly relapsed and not
developed an infection/other malignancy
If tx w/ XRT only can still salvage w/ chemo
If late (>12mo) relapse after chemo, can use different
regimen or autologous transplant
47. HL
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
48. 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 maintain
high cure rate while minimizing late complication
shorter courses of chemotherapy with lower radiation
doses in smaller fields
elimination of radiotherapy
49. Long term
complications of treatment
depends upon treatment modality used RTH / MOPP/ ABVD/ CMT
infertility
MOPP > ABVD; males > females
sperm banking should be discussed
premature menopause
secondary malignancy
skin, AML, lung, MDS, NHL, thyroid, breast...
cardiac disease
radiation-induced hypothyroidism
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
51. Children with HL fare better than adults. OS ~85-
95%
Mediastinal mass is most common (search for)
Classic (NS-MC-LR-LD) vs LP(NLPHL)
NS (~40%)&LP(30%) most common (good prognosis),
LD (~5%) is the least common (poor prognosis).
Un-favourable prognostic factors:
B-symptoms
Bulky lymphadenopathy >6cm/ bulky mediastinum
>1/3 of intra-thoracic diameter.
>3 (4) sites of LN involvment
52. Staging is the same for adults.
80~85% I-III
25-30% B-symptoms
~20% bulky lymphadenopathy
ToCure with min. treatment-related toxicity:
Limit staging procedures.
Treatment is risk-adapted.
53. Hodgkin’s Lymphoma Treatment
Surgery
No Staging laparotomy
LN Bx
BM Bx for B ± III-IV
Oophoropexy (♀ pt. with pelvic LN why? How?
RTH or CTH alone should be avoided
54. Hodgkin’s Lymphoma Treatment
CTH:
MOPP is almost obsolete.
ABVD, ABVE-PC or OPPA/COP(P) are most commonly
used.
Localized (involved field) RTH
risk &CTH response adapted
IF: protocol specific, but generally = initially involved LN
region(s).
58. RTH Guidelines/advanced
After end of chemotherapy, patients have risk-adapted RTH (21 Gy)
The indications
RER
Initial bulky disease defined as
a contiguous nodal aggregate that measures > 6 cm
mediastinal mass with tumor diameter is > 1/3 maximal thoracic diameter
macroscopic splenic nodules.
Slow early responding (SER)
Bulky sites
FDG-PET scan residual avidity after the first 2 cycles of chemotherapy.
residual lesions ≥ 2.5 cm on CT scan after completion of all CTH even if FDG-
PET negative
parenchymal masses 2.5 cm or greater after 2 cycles of chemotherapy
59. Diagnostic tests
Lymph node biopsy
Preferably to have an entire lymph node over core bx
determine pattern of involvement (germ center/mantle/marginal)
allows for enough tissue for immunologic and molecular testing
Bone marrow bx for all pts
This is to determine stage
Controversial whether bilateral or unilateral bx’s
CBC, LDH, Uric acid, LFT, KFT
CT chest/abd/pelvis
PET scan
Aggressive is recommended
Indolent ????