LYMPHOMA
Dr Bruce Covell
Each year in the UK about about 1500 people
develop Hodgkin's disease, usually between 15-25
years of age. It can also develop later in life in
people over 60. In younger people the numbers of
men to women are about the same but overall
Hodgkin's affects more men.
Between 7000 and 7500 people develop nonHodgkin's lymphoma each year. It is more
common over the age of 60 and affects slightly
more men than women.
At present the cause of most lymphomas is
unknown.
Thomas Hodgkin
English physcian and pathologist,
born August 17, 1798, in
Pentonville, St. James Parish,
Middlesex; died April 5, 1866,
Jaffa, Palestine [now Tel AvivYafo, Israel].
members of "The Society of
Friends"
Defence against Infection
The castle walls-first line of defence is the skin
and the mucosa
The foot soldiers -macrophages Complement,
and other immune cells send out chemical
messengers to call for reinforcements.
The cavalry-neutrophils -small, short-lived
immune cells ,swallow the invaders and kill
them
The SAS-Antibodies recognise and stick to
foreign material.B lymphocytes exist to produce
antibodies. infection is over, most of the B cells
die, but some live on as memory cells.
The generals-T lymphocytes major
histocompatibility complex (MHC), Helper T
cells Cytotoxic T cells recognise cells with
foreign proteins attached to MHC on their
surface and destroy them directly.
Disease states correlate with stages in normal B-cell development
Diseases:
AML
Pro-B-ALL Pre-B-ALL
B-ALL
Lymphoid tumors that present as mature
B-cells
may have arisen as a result of the interplay
between genetic
lesions and normal processes that govern
lymphoid tolerance,
homeostasis and function
-B-CLL
-MGUS
-DLBCL
-Multiple Myeloma
-FLL
-Plasmacytoma
-BL
-Mantle Cell lymphoma
-Marginal Zone lymphoma
-MALT
-GALT
-Hodgkins (?)
A minimalist view of a T cell response
2. EFFECTOR PHASE
elimination of infection
T
1. EXPANSION
3. CONTRACTION
activation and proliferation
apoptosis and memory
T
Microbe
T
T
T
T
T
T
T
T
T
T
IMMUNODEFICIENCY
T
T
T
AUTOIMMUNITY
CANCER
T
Cancer “stem-cells”?!
CLASSIFICATION
“Nowhere in pathology has a chaos
of names clouded clear concepts as in
the subject of lymphoid tumors”
Willis R.A.: Pathology of tumors, Mosby 1948
Lymphomas
15%
Hodgkins
85%
Non Hodgkins
B Cells Nodular sclerosing 50%
Mixed cellularity –30-40%
T Cells
HODGKINS LYMHOMA
% Of
Lymphomas
Age of Incidence
Prognosis
Comment
With appropriate treatment, more than 80% of people with stage I or II Hodgkin's survive for at least 10 years. With
widespread disease, the treatment is more intense and the 5-year survival rate is about 60%.1.
Classical •
Nodular sclerosing -
50%
commonest of
all types of
Hodgkin's
lymphoma.
Commonest in
women in their
20’s and 30’s.
Mixed cellularity - .
30 – 40%-
Commonest in
older people.
•Lymphocyte depleted
rare
Lymphocyte-rich –
rare
2. Nodular lymphocyte
predominance
1%
less favourable
prognosis than the
lymphocyte
predominant
usually picked up
at an early stage
from enlarged
lymph nodes in the
neck.
worst prognosis
most favourable
prognosis
'popcorn' cells.
B Cell lymphoma
% Of Lymphomas
Age of Incidence
Prognosis
Comment
31%
mid-60s.
40% to 50% are cured
Follicular lymphoma
22%
60. rare in very young
5-year survival rate60%
to 70%.
fast growing
2 kinds Genetics One
serious
slow growing
can (transform) into a
fast growing diffuse Bcell lymphoma.
Chronic lymphocytic
leukemia (CLL)/small
lymphocytic lymphoma
(SLL):
Mantle cell lymphoma:
7%
live well over 10 years
not considered curable
6%
Extranodal marginal zone
B-cell lymphomas mucosa-associated
lymphoid tissue (MALT)
lymphomas
Nodal marginal zone B-cell
lymphoma:
8%
Men most often
affected. average age
63
average age about 60
very serious. 20% of
patients survive at least
5 years.
slow growing lymphoma
often curable in its early
stages.
Splenic marginal zone Bcell lymphoma
rare
often elderly and male
Primary mediastinal B-cell
lymphoma
2%
two thirds women. 30s.
Burkitt lymphoma:
2%
90% of patients are
male, and the average
age is about 30
Lymphoplasmocytic
lymphoma (Waldenstrom
macroglobulinemia
1%
Hairy cell leukemia:
rare
Patients are older in
general.
Primary central nervous
system (CNS) lymphoma:
rare
patients with AIDS
Diffuse large B-cell
lymphoma (DLBCL):
2%
are slow growing can
transform into a more
aggressive type of
lymphoma
stomach Helicobacter
pylori.
slow growing cured if
diagnosed in early
stages.
slow growing,
cells are small.
About half of patients
can be cured. fast
growing
half of patients are
cured by aggressive
chemotherapy.
not curable, most live
longer than 5 years.
mediastinum closely
related to Hodgkin
disease
medium size fast
growing African jaws d
US, abdomen,
slow growing Thick
blood Symptoms
slow growing, some
patients never need
treatment
poor. 30% 5 years.
called primary brain
lymphoma
% Of Lymphomas
Age of Incidence
Prognosis
Comment
Precursor T-lymphoblastic
lymphoma/leukaemia:
2%
(75%) men, average
age 25
No bone marrow cure
quite good. involve
bone marrow, 20%
cured.
lymphoma or
leukaemia. fast
growing,
Peripheral T-cell lymphomas:,
7%
There are several kinds of peripheral T-cell lymphomas
Cutaneous T-cell lymphoma
(mycosis fungoides, Sezary
syndrome):
1%
50s or 60s
T Cell Lymphoma
survival at 5 years
ranges 58% slowgrowing lymphomas
5% faster growing
ones
Skin Sezary
syndrome spread all
over the body OR
mushroom-like (so
first named mycosis
fungoides
Enteropathy type T-cell
lymphoma
outlook is poor
Coeliac disease
Subcutaneous panniculitis-like
T-cell lymphoma
cannot be cured
Angioimmunoblastic T-cell
lymphoma:
Extranodal natural killer/T-cell
lymphoma, nasal type
Anaplastic large T/null-cell
lymphoma
Unspecified:
2%
cured.
Hodgkin's Lymphoma
VS
Non-Hodgkin's Lymphomas
Age
Average age is 27.7 with two age peaks, the major one
between 15 and 24 with a lesser peak after age 55.
Average age is about 67.
Chance of getting in
all people over an
entire lifetime
Men 0.23%
Women 0.20%
Men 2.12%
Women 1.79%
Occurrence
About 15% of all lymphomas
About 85% of all lymphomas
Location
The disease occurs most often in lymph nodes above the
collar bone. In Hodgkin's it is also more likely to appear in the
chest cavity between the lungs (the mediastinum), particularly
in younger patients.
In NHL it is more likely to appear in the nodes in the
abdomen (called the mesenteric nodes).
Only about 15% to 20% of cases are found in areas below the
diaphragm.
The disease occurs in the chest cavity in less than 40%
of patients. (An exception, lymphoblastic lymphoma,
which is seen most often in young people, is likely to
first appear in the chest.)
Disease occurs outside the nodes in about 4% of cases.
Disease occurs outside the nodes in about 23% of
patients. Slow-growing lymphomas are common in the
liver and bone marrow.
Affected Lymph Cells
B-Lymphocytes
characterized by the Reed-Sternberg Cell
B-Lymphocytes, T-Lymphocytes or Natural Killer (NK)
Cells depending on the subtype
Symptoms
More likely than NHL (40%) to have systemic ("B") symptoms
(such as fever and night sweats) at the time of diagnosis.
Less likely than HL to have systemic ("B") symptoms
(27%) at the time of diagnosis.
Progression
Less likely than NHL to be diagnosed in stage IV (10%).
Hodgkin's disease usually progresses in an orderly way from
one lymph node region to the next. This process may be slow,
particularly in younger people, or very aggressive. The
disease typically spreads downward from the initial site. If it
spreads below the diaphragm, it usually reaches the spleen
first; the disease then may spread to the liver and bone
marrow. If the disease starts in the nodes in the middle of the
chest, it may spread outward to the chest wall and areas
around the heart and lungs.
More likely than HD to be diagnosed in stage IV (36%)
but this will vary by NHL subtype.
The Non-Hodgkin's lymphomas are less predictable in
their course than Hodgkin's and they are more apt to
spread.
Lymphoma Symptoms
(Hodgkin's Disease = HL, or a form of Non-Hodgkin's Lymphoma = NHL):
•Lymph node swelling, often in the upper body area but it can be in almost any node or
related organ. The node is usually NOT painful as opposed to infected lymph nodes which
are common and can be painful
(HL, NHL)
•A lack of energy, general fatigue. (HL, NHL)
•Weight loss - usually at least 10% over a short time (HL, NHL)
•Fevers which can come and go. This can be accompanied by chills or a feeling of
temperature swings (HL, NHL)
•Night sweats - unexplained sweating at night, often drenching (more often HL than NHL)
•Itching - itching without an apparent cause or rash, sometimes deep in the skin rather than
on the surface, sometimes on different parts of the body (more often HL than NHL)
Less Often:
•Some people have lower back pain that is unexplained (may be caused by expanding lymph
nodes pressing on nerves). (HL, NHL)
•Lymph nodes are possibly painful after alcohol consumption. (HL)
What now?
A good percentage of diagnoses are made during routine tests, x-rays, or even while
pregnant. This is how difficult it is to diagnose lymphoma based on external symptoms alone
Staging defines how widespread the
disease is and the locations of the
disease in the body.
Anne Arbor staging for Hodgkin's disease - Virginia.edu
Stage I - disease in single lymph node or lymph node region.
Stage II - disease in two or more lymph node regions on same
side of diaphragm.
Stage III - disease in lymph node regions on both sides of the
diaphragm are affected.
Stage IV - disease is wide spread, including multiple involvement at
one or more extranodal (beyond the lymph node) sites, such as the bone marrow
Extranodal notations
Extranodal means 'beyond nodal' - sites are
identified by the following notation:
ANN ARBOR notations
Ann Arbor staging further classifies patients with lymphoma into A or
B categories:
A = without symptoms
B = with symptoms including unexplained weight loss (10% in 6
months prior to diagnosis, unexplained fever, and drenching night
sweats.
Disease Staging may also be accompanied by local involvement of
an extranodal organ or site.
Example involving spleen and Ann Arbor notation: Stage IIIS A
Treatment
Lymphomas are usually treated by a
combination of chemotherapy,
radiation, surgery, and/or bone
marrow transplants. The cure rate
varies greatly depending on the type
of lymphoma and the progression of
the disease.
Current up-front treatment regimens for aggressive lymphomas
Regimen
Drugs
CHOP
Cyclophosphamide, Doxorubicin, Vincristine,
Prednisone
BACOP
Bleomycin, Doxorubicin, Cyclophosphamide,
Vincristine. Prednisone
M-BACOD
Methotrexate, Leucovorin, Bleomycin,
Cyclophosphamide, Vincristine, Dexamethasone
ProMACE/MOP
P
Prednisone, Methotrexate, Leucovin, Doxorubicin,
Cyclophosphamide, Etoposide
MACOP-B
Methotrexate, Leucovorin, Doxorubicin,
Cyclophosphamide, Vincristine, Bleomycin,
Prednisone, Trimethoprim-sulfamethoxazole
(Used at various doses, with, or without radiation)
Additional experimental therapies for B-cell lymphomas:
-CD20-specific antibodies (Rituximab, Bexxarr, Zevalin):
target a tetraspanin on the surface of all B-cells and ablates
the entire B-cell compartment for over 6 months. Mechanism
of action is unknown. Rarely used as up-front therapy.
-Clonotypic antibodies to individual lymphomas: pioneered
by Ron Levy and his colleagues at Stanford. Current success
rate is 1 patient in 15 years.
Evidence for a possible role of outside agent in lymphomagenesis:
-pristane-induced plasmacytomas in mice and rats (Andreson and Potter, 1969)
-Retroviral infection of mice elicits T-cell lymphomas only in those strains that could
mount an immune response to the virus (McGrath and Weissman, 1979, Lee and
Ihle, 1981)
-Infection with Helicobacter pylori correlates well with MALT lymphoma - antibiotic
treatment leads to remission in these patients (Casella et al, 2001).
-Long-term untreated chronic GVHD after transplantation (Gleichmann
and Gleichmann, 1971)
-Large B-cell lymphomas (DLBCL, FLL, BL) have been shown to express Ig
molecules on their surface, which bear the scars of affinity maturation; an
antigen-driven process (Klein et al, 1995, Chapman et al, 1995, Kuppers et al, 1997)
-The gene expression profiles of DLBCL cells resemble those of B-cells that
have mounted a response to antigen (Alizadeh et al, 2000).
These findings prompt the hypothesis that an antigenic stimulus may cooperate
with other tumorigenic influences in the genesis of lymphoid tumors
Autoimmunity and lymphoid neoplasia may represent different
parts of a single disease-spectrum:
-Patients who suffer from several autoimmune syndromes are
50-200 fold more likely to develop B-cell lymphomas
(Sjörgen’s syndrome, autoimmune thyroditis, autoimmune hemolytic
anemia, systemic lupus erythematosus, rheumatoid arthritis)
-Patients who develop the HTLV-1 associated tropical spastic parapesis
are also highly prone to develop T-cell lymphomas.
-Patients with NHL have been found to have high titers of
autoantibodies in their sera, and accompanying symptoms, such
as autoimmune hemolytic anemia.
-EBV infection correlates with some autoimmune diseases,
such as Hashimoto’s thyroditis.
Key differences: clonality of expanded population, disease grade, site of
anatomical presentation, FACS pattern, histopathology