Transcript Non-Hodgkin`s Lymphoma

LYMPHOMAS
H.A MWAKYOMA, MD
Normal lymphoid maturation
• Requires two major activities
– The production of a unique antigenic receptor on
it's surface
– The expression of several surface proteins
necessary for antigen recognition, cell activation,
cell-cell communication.
– Antigen receptors are generated through the
process of "genetic rearrangement"- the random
selection and juxtaposition of discontinuous
genetic segments encoding the antigen receptor
genes
Normal lymphoid maturation
– B cells
• Immunoglobulin receptor composed of two heavy and
two light chains
– Select specific heavy chain antigen recognition
sequence
– Select only one of two light chains, kappa or lambda
– T cells
• Select one of two heterodimeric receptors
– Alpha/Beta heterodimer T cell receptor
– Gamma/Delta heterodimer T cell receptor
Surface antigen production
• Immune cells require numerous surface molecules for effective
immune response, cell-cell communication and regulation
• Classified into B cell associated, T cell associated, activation
associated, cytokine receptors
• Expression occurs in an orderly sequence in lymphoid
maturation
• Antibodies to these molecules cataloged thru the CD - clusters
of differentiation - numerical system
– Initially developed to characterize monoclonal antibodies
detecting proteins whose function was unknown .
– Now up to CD166. You'll only be tested on 1-130 though (- a
joke for you paranoid types.)
STAGES IN LIFE CYCLE OF
B-LYMPHOCYTES
• Stage 1
– Maturation in bone marrow with
development of functional receptors
• Stage 2
– Testing for and elimination of selfreactive receptors
• Stage 3
– Mature naïve cells move to secondary
lymphoid tissues
Non-Hodgkin’s Lymphoma
Outlines
• Introduction of lymphoma
• Classification of lymphoma
i. Introduction
ii. Symptoms
iii.Signs
iv.Diagnosis
v.Staging
vi.Management
vii.Complication of treatment
viii.Prognosis
ix.Systemic involved
• non-hodgkin’s lymphoma
• Stem cell transplantation
Introduction of lymphoma
– The lymphomas are
malignant tumors of
lymphoid
tissue
,characterized by the
abnormal proliferation
B or T cells in lymphoid
tissue .
Non-Hodgkin’s Lymphoma
• Non-Hodgkin’s lymphomas (NHL) are a
heterogeneous group of malignant lymphomas.
• There are many different subtypes, every few
years the classification is updated.
• Today, morphology, immunophenotype,
molecular, cytogenetics, and other techniques are
used for diagnosis.
• Treatment generally depends on the
aggressiveness of the disease (indolent,
aggressive, or very aggressive)
Non-hodgkin’s lymphoma
• This is lymphoma without the presence of
Reed-Sternberg cell.
• B lymphocyte more than T lymphocyte.
• The extranodal involvement is
common,more than HL.
• Causes of it’s congenital and acquired
immunodeficiency e.g drugs , HIV infection,
H.pylori infection
Behaviour
• Lymphomas may be grouped by how quickly
they are likely to grow:
• Indolent (also called low-grade) lymphomas
grow slowly. They tend to cause few symptoms.
these lymphomas grow slowly.
 The majority of NHLs are considered indolent.
 Indolent lymphomas are generally considered
incurable with chemotherapy and/or radiation
therapy
Behaviour
• Aggressive (also called intermediate-grade
lymphomas)
 These lymphomas have a rapid growth
pattern.
They tend to cause severe symptoms.
 Over time, many indolent lymphomas
become aggressive lymphomas
This is the second most common form of
NHL and are curable with chemotherapy
Behaviour
• Very Aggressive – (also called High grade
lymphoma)
These lymphomas grow very rapidly.
They account for a small proportion of
NHLs and can be treated with
chemotherapy.
Unless treated rapidly, these lymphomas
can be life threatening.
Marginal Zone Lymphoma
• Indolent
• Accounts for ~10% of all lymphomas
• Subcategories
– MALT
– Nodal
– Extra Nodal
– Splenic
Mantle Cell Lymphoma
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Aggressive
Accounts for ~ 6% of all lymphomas
Considered “incurable” with traditional RX
Stem cell transplant is offered often as
front-line consolidation treatment in
“younger” patients
Primary CNS Lymphoma
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Aggressive
Accounts for ~ 1-2% of all lymphomas
Different chemotherapy treatments
Often requires radiation to the brain:
» Brain dysfunction in younger patients
» Dementia in older patients
Anaplastic Large Cell
Lymphoma (ALCL)
• Aggressive
• Accounts for ~ 2% of all lymphomas
– Two groups:
– ALCL ALK-1+ better prognosis, more common in younger
patients and children
– ALCL ALK-1-negative : as bad as any other T-cell
lymphoma
Peripheral T-cell Lymphoma
• Aggressive
• Accounts for ~ 7% of all lymphomas
• Worse prognosis, often associated with
extranodal presentation
• Often requiring salvage treatment and
transplant
Large Cell Lymphoma
• Very Aggressive
• Accounts for ~ 31% of all lymphomas
Classification of lymphomas
• Subtyping or classification within the two groupings necessary, because
different subtypes have
– Distinct clinical presentations
– Can require different therapy
– Have differing prognoses, reflecting different mechanisms of molecular
pathogenesis.
• Unfortunately, rarely unanimous acceptance of any one classification
scheme.
• Intermittent upgrading of classification, with new terminology, reflecting new
information and classifier bias
• Classification often lags behind advances in immunology, research
pathology
• Final result:
– Difficult area to teach
– Difficult to remember
– Job security for me
Classification of lymphoma
lymphoma
Hodgkin’s
lymphoma
Non
hodgkin’s
lymphoma
Histologic classification of nonHodgkin’s lymphomas
1. Rappaport
2. Lukes and Collins
3. Dorfman
4. Bennet et al.,
5. Lennert
6. WHO
7. Working Formulation
8. REAL
9. WHO
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1999
Working Formulation
• Divided into three "grades" of lymphoma- low, intermediate and
high.
– Low grade = indolent
– Intermediate and high = aggressive
• Limitations
– Purely morphologic classification mixed T and B cell
lymphomas together
– Lumped distinct subtypes of B cell lymphomas together
– Obscured the biologic, clinical and therapeutic differences
– Distorted interpretation of clinical trials
Histologic classification of nonHodgkin’s lymphomas - Working
Formulation (WF)
1. Low grade
2. Intermediate grade
3. High grade
Histologic classification of nonHodgkin’s lymphomas - Working
Formulation (WF)
Low grade non Hodgkin's lymphomas
• Small cell lymphocytic
• Follicular (it is the most common type of
lymphoma)
• Mantle cell
• Splenic marginal zone lymphoma
• MALT lymphoma
• Lymphoplasmacytic NHL
Histologic classification of nonHodgkin’s lymphomas - Working
Formulation (WF)
Intermediate grade
D. - Follicular, predominantly large
cell.
E. - Diffuse small cleaved cell.
F. - Diffuse mixed, small and large
cell.
G. - Diffuse large cell.
Histologic classification of nonHodgkin’s lymphomas - Working
Formulation (WF)
High grade
H. - Large cell immunoblastic.
I. - Lymphoblastic.
J. - Small noncleaved cell: Burkitt’s
Histologic classification of nonHodgkin’s lymphomas - Working
Formulation (WF)
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High grade non Hodgkin's lymphomas
Diffuse large B cell
Diffuse mixed cell lymphoma
Burkitt's lymphoma
Anaplastic large cell lymphoma
Diffuse mixed cell lymphoma
Non-Hodgkin’s lymphomas
/NHL/
- clinical features
Non-Hodgkin’s lymphomas-Clinical
features
1. Constitutional symptoms (fever, night sweats,
weight loss)
2. Lymphadenopathy
(cervical, supraclavicular, axillary, inguinal,
mediastinal, retroperitoneal, mesenteric, pelvic).
3. Mediastinal adenopathy (T cell lymphoma)
4. Extralymphatic involvement (gastrointestinal,
testicular masses, solitary bone lesions, CNS).
5. Unexplained anemia and thrombocytopenia (
bone marrow infiltration).
For the diagnosis of nonHodgkin’s lymphomas the
histological examination of a
lymph node is necessary!
Non-Hodgkin’s lymphomas histological classification
R.E.A.L./W.H.O. Classification
• WF replaced in 1994 by the Revised European
American Lymphoma (REAL) classification, now being
modified by the World Health Organization (WHO)
• REAL/WHO is a "disease” oriented rather than purely
morphology oriented classification, based on:
– Cell lineage: B v T v NK v Histiocytic
– Stage of maturation of the presumed normal
counterpart.
– Includes immunologic and molecular criteria in
addition to purely morphologic criteria of WF
R.E.A.L./W.H.O. Classification—
CONT-– Each disease entity may have differing grades
of aggressiveness
– Greatly expanded the list of entities; includes
leukemias of lymphoid origin
– Made teaching to medical students (and in
fact all physicians) even more difficult than
WF
• REAL contained a number of “provisional
entities” which have been clarified in the
upcoming W.H.O. revision.
REAL/WHO classificationbackbone
• B cell neoplasms
– Precursor B cells-related to acute leukemia
(acute lymphoblastic leukemia &
(lymphoblastic lymphoma)
– Peripheral B cell lymphomas- the majority of B cell
lymphomas
• T cell and Natural Killer cell neoplasms
– Precursor T cells
– Peripheral T cell and NK neoplasms
• Hodgkin’s lymphoma
REAL /Revised European-American
Lymphoma/-WHO classification of
non-Hodgkin’s lymphomas
• Peripheral B cell lymphomas
- Chronic lymphocytic leukemia/lymphocytic
lymphoma
- Chronic prolymphocytic leukemia
- Immunocytoma/lymphoplasmocytic lymphoma
- Mantle cell lumphoma
- Marginal zone lymphoma /MALT-type/
- Hairy cell leukemia
REAL /Revised European-American
Lymphoma/-WHO classification of
non-Hodgkin’s lymphomas
• Peripheral B cell lymphomas /continued/
- Follicle center cell lymphoma
- Plasma cell myeloma/plasmocytoma
- Diffuse large B cell lymphoma
- Burkitt’s lymphoma
- Splenic marginal zone B cell lymphoma
REAL /Revised European-American
Lymphoma/-WHO classification of
non-Hodgkin’s lymphomas
• Peripheral T cell lymphomas
– T cell chronic lymphocytic leukemia
– T cell chronic prolymphocytic leukemia
– Large granular lymphocyte leukemia /LGL/
– Mycosis fungoides /Sézary syndrome
– Peripheral T cell lymphomas, unspecified
REAL /Revised European-American
Lymphoma/-WHO classification of
non-Hodgkin’s lymphomas
• Peripheral T cell
lymphomas/continued/
– Angioimmunoblastic T cell lymphoma
– Angiocentric lymphoma
– Intestinal T cell lymphoma
– Adult T cell lymphoma/leukemia
– Anaplastic large cell lymphoma
Very aggressive non-Hodgkin’s
lymphomas
• B-, T-cell acute lymphoblastic
leukemia
• B-, T-cell lymphoblastic lymphomas
• Burkitt’s lymphoma
• Adult T cell lymphoma/leukemia
High risk aggressive nonHodgkin’s lymphomas
1. Age above 60 years.
2. Disease stage III and IV.
3. Extranodal involvement of more than 1
site.
4. Serum LDH concentration >1 x normal.
5. Performance status < 80%.
B cell neoplasms- Precursor B
• Precursor B cell lymphoblastic leukemia/lymphoma
– Frozen at lymphoblast cell stage of antigen
independent B cell differentiation- normally restricted
to bone marrow
– Usually present as acute leukemia +/- lymph node
involvement
– Can initially present as node or skin disease, with later
progression to bone marrow
– Treated as acute leukemia
• 80% cure rate in children
• 20-30% in adults because of "bad" cytogenetics:
frequent presence of Philadelphia chromosome
t(9;22)
Peripheral B-cell neoplasms
• Frozen at various stages of antigen dependent B cell
maturation and differentiation
– Small lymphocytic/CLL- the virgin B cell fresh from the
marrow
– Prolymphocytic leukemia- a more clinically aggressive
variant of above
– Lymphoplasmacytic lymphoma- the primary immune
response
– Mantle cell lymphoma- the mantle region surrounding the
follicle
– Follicular lymphoma- the follicle- grades 1-3
– Extranodal marginal zone lymphoma- cells at the periphery
of the follicle in extranodal sites of lymphoid tissueMucosal Associated Lymphoid tissue- such as G.I. tract
Peripheral B-cell neoplasms
– Nodal marginal zone lymphoma
– Splenic marginal zone lymphomaimmunologically distinct
– Hairy cell leukemia- pre-plasma cell
– Diffuse large B-cell lymphoma- this breaks the
ideal of specific cell stage but all represent
lymphomas with high replication rate
– Burkitt lymphoma- very aggressive
– Plasma cell myeloma- diffuse bone marrow
proliferation of plasma cells
– Plasmacytoma- solitary focus of monoclonal
plasma cells, with variable risk of progression to
myeloma, depending on site
Mantle cell lymphoma
• Clinical
– 6% lymphomas
– Disease of adults (median age 63)
– Usually widely disseminated
– Poor response to all attempted therapies,
– ? curable with transplant
– 5yr survival 27%
• Pathogenesis
– Due to t(11;14)
– Upregulates Bcl1 (cyclin D1), a cell cycle regulator
Mantle cell lymphoma
•
Pathology/Diagnosis
– Benign equivalent is lymphocyte of
inner mantle zone
– Cytology similar to cleaved cell, but
nuclear irregularities not as
prominent
– Nodal infiltration diffuse, vaguely
nodular or "mantle zone" around
residual benign follicles
– Large cell progression infrequent
– Immunophenotype:
• Positive: monoclonal light
chain, CD19, CD5, Bcl1 (and
Bcl2)
• Negative CD10, CD23
Follicular lymphoma
Mantle cell lymphoma
CyclinD1
Bcl2
T cell lymphomas-Precursor T
• Clinical
– Disease of teenagers; boys>girls
– Can present as acute leukemia or mediastinal
mass+/- marrow involvement
– Aggressive lymphoma/leukemia, but curable: ~70%
with appropriate multiagent chemotherapy
• Pathogenesis
– No single gene culprit, but frequently involve
translocation of (onco)genes to site of T cell receptor
genes, --> upregulation of proteins
T cell lymphomas-Precursor T
• Pathology
– Benign equivalent
immature T cells of
thymus
– Histology: Diffuse
infiltration of
thymus/adjacent lymph
nodes
– Cytology: “Blast cells”
of intermediate size with
oval to “convoluted”
nuclear profiles, fine
chromatin and 0-1
nucleolus
– Again need immunology
to distinguish from pre-B
Peripheral T cell lymphomas
• Predominantly leukemic/disseminated
– T-cell prolymphocytic leukemia
– T-cell large granular lymphocytic (LGL)
leukemia
– NK cell leukemia
– Adult T-cell leukemia/lymphoma
Peripheral T cell lymphomas
• Predominantly nodal
– Angioimmunoblastic T-cell lymphoma
– Peripheral T-cell lymphoma unspecified
– Anaplastic large cell lymphoma, T/null-cell
Peripheral T cell lymphomas
• Predominantly extranodal
– Mycosis fungoides
– Sezary syndrome
– Primary cutaneous CD30+ T-cell
lymphoproliferative disorders
– Subcutaneous panniculitis-like T-cell
lymphoma
– NK/T cell lymphoma, nasal and nasal-type
– Enteropathy-type intestinal T-cell lymphoma
– Hepatosplenic T-cell lymphoma
Key points regarding T cell
lymphomas
• Clinical
– Represent 20% all lymphomas
– More often extranodal than B
• Can involve skin, midline facial area, liver
• Very characteristic clinical presentations
– Most diseases bad: high stage, and poorer
response to therapy than B cell lymphomas of
all grades
Key points regarding T cell
lymphomas
• Pathogenesis:
– Characteristic cytogenetic findings associated
with several types
• Anaplastic large cell lymphoma- t(2;5): ALK1
gene
• Hepatosplenic T cell lymphomaIsochromosome 7
Key points regarding T cell
lymphomas
• Pathology
– Cytologic features not as predictive of
behavior as B cell lymphomas
• Anaplastic large cell lymphoma
-->
better prognosis than most indolent B cell
lymphomas- 77% 5 year survival
• Mycosis fungoides, indolent cutaneous
lymphoma, incurable, but with long clinical
course
Key points regarding T cell
lymphomas
– Immunophenotypic studies frequently
demonstrate
• Loss of normal T cell associated antigens
• Antigens associated with Natural Killer cell
function
• Immunology absolutely necessary to
recognize
Diagnosis
• BLOOD:
(FBC, Film, ESR, LFT, LDH, Urate , Ca.)
• Lymph node excision biopsy , image
guided needle biopsy.
• Chest X-ray, CT of thorax, abdominal,
pelvis
and bone marrow biopsy‫ـــــــ‬staging of HL
Immunologic Techniques
•
•
•
Flow cytometry-automated
fluorescent microscopy
Immunohistochemistry- in situ
immunologic detection
through the use of enzyme
substrate color deposition
Both utilize monoclonal
antibodies to detect clonality
and unique antigenic patterns
Immunologic Techniques
• Flow cytometry-automated fluorescent microscopy
• Immunohistochemistry- in situ detection through the use
of enzyme substrate color deposition
• Examples
– B cell small lymphocytic lymphoma• Monoclonal light chain, CD19, CD20, CD5, CD23
positive, CD10 negative
– B cell follicular lymphoma• Monoclonal light chain, CD19, CD20, CD10
positive, CD5 negative
Molecular techniques
• Detection of antigen receptor clonality
• Detection of unique cytogenetic
rearrangements/translocations
• Examples
– Clonal gene rearrangement by Southern blot
– Bcl2/JH rearrangement by polymerase chain
reaction
The End!