LYMPHOMA

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LYMPHOMA

• Dr Bruce Covell

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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 non-Hodgkin'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.
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Thomas Hodgkin English physcian and pathologist,
born August 17, 1798, in Pentonville, St. James
Parish, Middlesex died April 5, 1866, Jaffa,
Palestine now Tel Aviv-Yafo, Israel. members of
"The Society of Friends"
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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.  
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Disease states correlate with stages in normal
B-cell development

• B-CLL
• DLBCL
• FLL
• BL
• Mantle Cell lymphoma
• Marginal Zone lymphoma
• MALT
• GALT
• Hodgkins (?)

• MGUS
• Multiple Myeloma
• Plasmacytoma

Pre-B-ALL
B-ALL
Pro-B-ALL
Diseases
AML
Lymphoid tumors that present as mature
B-cellsmay have arisen as a result of the
interplay between geneticlesions and normal
processes that govern lymphoid tolerance,homeosta
sis and function
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A minimalist view of a T cell response
2. EFFECTOR PHASE elimination of infection
1. EXPANSION activation and proliferation
3. CONTRACTION apoptosis and memory
Microbe
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Cancer stem-cells?!
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CLASSIFICATION
Nowhere in pathology has a chaos of names
clouded clear concepts as inthe subject of
lymphoid tumors Willis R.A. Pathology of
tumors, Mosby 1948
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Lymphomas
85
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Hodgkins
Non Hodgkins B Cells Nodular sclerosing
50 Mixed cellularity 30-40 T Cells
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B-Cell Lymphomas
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T Cell Lymphoma
T-Cell Lymphomas
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• 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
•  

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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
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Extranodal notations  Extranodal means 'beyond
nodal' -  sites are identified by the following
notation 
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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
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TreatmentLymphomas 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.
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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/MOPP 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)
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• Additional experimental therapies for B-cell
  lymphomas
• CD20-specific antibodies (Rituximab, Bexxarr,
  Zevalin)target a tetraspanin on the surface of
  all B-cells and ablatesthe entire B-cell
  compartment for over 6 months. Mechanismof
  action is unknown. Rarely used as up-front
  therapy.
• Clonotypic antibodies to individual lymphomas
  pioneeredby Ron Levy and his colleagues at
  Stanford. Current successrate is 1 patient in 15
  years.

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• 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 couldmount
  an immune response to the virus (McGrath and
  Weissman, 1979, Lee andIhle, 1981)
• Infection with Helicobacter pylori correlates
  well with MALT lymphoma - antibiotictreatment
  leads to remission in these patients (Casella et
  al, 2001).
• Long-term untreated chronic GVHD after
  transplantation (Gleichmannand Gleichmann, 1971)
• Large B-cell lymphomas (DLBCL, FLL, BL) have been
  shown to express Igmolecules on their surface,
  which bear the scars of affinity maturation
  anantigen-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 thathave mounted a
  response to antigen (Alizadeh et al, 2000).
• These findings prompt the hypothesis that an
  antigenic stimulus may cooperatewith other
  tumorigenic influences in the genesis of lymphoid
  tumors

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• Autoimmunity and lymphoid neoplasia may represent
  differentparts of a single disease-spectrum
• Patients who suffer from several autoimmune
  syndromes are50-200 fold more likely to develop
  B-cell lymphomas(Sjörgens syndrome, autoimmune
  thyroditis, autoimmune hemolyticanemia, systemic
  lupus erythematosus, rheumatoid arthritis)
• Patients who develop the HTLV-1 associated
  tropical spastic parapesisare 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 Hashimotos thyroditis.
• Key differences clonality of expanded
  population, disease grade, site ofanatomical
  presentation, FACS pattern, histopathology