Dr. Manal El-Mahdy. MD
Professor of Pathology, Ain Shams University
Director of Pathology Lab., Nasser Institute
Head of Pathology Committee, BGICC
Lymph node anatomy
Lymph node histology
Malignant Lymphoma
•
A group of malignant tumors originated from lymph
nodes or other lymphatic tissues (tonsil, spleen,
bone marrow , ect).
•
Highly heterogeneous, both histologically and
clinically.
•
Tumours of mature and immature B cells, T
cells or NK cells.
• Annual incidence: 2-18 new cases per 100 000 persons
• 4% of new cancers each year
• Age distribution: middle-age elderly patients.
• Males are affected more often than females (1.5:1.0)
• Mature B-cell neoplasms comprise over 90% of
lymphomas worldwide
• The incidence of lymphomas is increasing wordwide
Pathogenesis.
• Viruses:
EBV : Burkitts Lymphoma, esp in endemic form (95%)
HTLV 1 : associated with Adult T cell leukemia/Lymphoma
• Helicobacter Pylori: MALT lymphoma
• Primary or secondary immunodeficiency (AIDS, PTLD,
chemotherapy)
Pathogenesis
Chromosomal translocations
• t(8:14) seen in Burkitts Lymphoma
• t(14:18) >80% of follicular NHL, leads to over
expression of ‘anti apoptotic gene’ bcl-2
• t(11:14) seen in almost all Mantle Cell
lymphomas.
Clinical Manifestations
• Enlargement of lymph nodes.
• Extra nodal infiltration:
- GI tract infiltration: small intestine( ileum), stomach, ect
- Hepatomegaly, splenomegaly, BM infiltration, CNS.
- Skin, Pulmonary infiltration, pleural effusion.
• Fever, weight loss, night sweating (B symptoms).
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Simplified schema of Hematopoetic Cancers
WBC
Acute and chronic
Hematopoetic
Stem Cell
RBC
Myeloid
Platelets
Myeloid
‘Leukemias’
B Cells
Lymphoid
Non Hodgkins lymphomas
T cells
B cell lympomas (90%)
T cell lymphomas
Stem
B
+TdT
+HLA-DR
Cell
T
T cell
B cell
Pro B
TdT+
CD19+
Pre
thymic
Bone Marrow
Cortical
Thymocyte
Precursor
Pre B
Bone
TdT+
CD19+ Marrow
TdT+ TCR
TCR
CD4+
CD22+
CD4- 

CD8+
CD20+/CD8Thymus
CD10+/Medullar Thymocyte
TdT+
CD4-  T
CD8-
CD20+
Mature
CD22+
B
CD19+
CD10+/-
Mature
Memory
Naive
Centroblast
Plasma
Centrocyte cell
TdT+
CD4+
TdT+
CD8+
Peripheral
Mature T cell
Blood &
2ry
Lymphoid
Organs
CD4CD8 T cell
CD4+
CD8+
Helper T
Cyto
toxic T
Fig. B and T cell MaturationPathway
Follicular
Lymphoma
Mantle Cell
Lymphoma
Lymphoplasmacytic
Richter’s
Syndrome
CD5B Cells
Pax-5
t(9;14)
B-CLL
Small Lymphocytic
p53
Bcl-1
t(11;1
4)
?
CD5+
B Cells
-2
Bcl ;18)
t(14
Mantle Zone
Bcl-6
t(2;3)
?
p5
Germinal
3,
c
Center
t(8 -my
t(8 ;14) c, EB
V
t(2 ;22)
;8)
p53
Diffuse Large
Cell Lymphoma
Burkitt’s
Lymphoma
Marginal Zone
Bc
t(1 l-10
;14
)
Marginal Zone
Lymphoma (MALT)
Molecular pathogenesis of
B-cell lymphomas
NHL Classification
Rappaport classification (1966)
Working Formulation (1982)
REAL classification (1994)
WHO 2000-2008
NCI Working Formulation
Low Grade
Small Lymphocytic
Follicular, small cleaved cell
Follicular, mixed small cleaved and large cell
Intermediate Grade
Follicular, large cell
Diffuse, small cleaved cell
Diffuse, mixed small cleaved and large cell
Diffuse, large cell(cleaved and non-cleaved)
High Grade
Large cell immunoblastic
Lymphoblastic
Small non-cleaved cell (Burkitt or non-Burkitt)
“REAL” Classification
Cell of origin
Cell morphology
Immunophenotyping
Genotyping
Clinical picture
Abandon the use of indolent – aggressive – highly aggressive
The WHO classification of lymphoid
neoplasms
The WHO classification of lymphoid
neoplasms (2008)
Basic principle: Classification for all neoplasms
based on:
Morphology and biologic features
Genetic
Immunophenotype
Clinical features
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WHO 2008: Peripheral B cell neoplasms
WHO 2008: Peripheral T cell neoplasms
Non Hodgkins Lymphoma
Indolent versus aggressive
Indolent
Aggressive
• Small lymphocytic lymphoma/CLL
• Lymphoplasmacytic lymphoma
• Follicular lymphoma
• Extranodal Marginal zone
lymphoma of MALT type
• Nodal marginal zone lymphoma
• Splenic marginal zone lymphoma
• Cutaneous T cell lymphoma
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•
•
•
•
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Diffuse Large B cell
lymphoma
Burkitt lymphoma
Mantle cell lymphoma
Anaplastic large cell
lymphoma
Prolymphocytic leukemia
All peripheral T cell
lymphomas
For the diagnosis of non-Hodgkin
lymphoma: the histological examination of
a lymph node is necessary!
Diagnosis
•
Total LN biopsy
•
Histopathological classification
• Immunophenotyping
- B-cell Lymphoma: CD20+,CD19
- T-cell Lymphoma: CD3+
•
Cytogenetic tests.
Immunophenotyping in B-lymphomas
Type/Ag
Bcl2
CD5
CD20
CD10
CD19
CD23
CD38
CD103
CLL/SLL
-
+
+
-
+
+
-
-
FL
+
-
+
+
+
-
-
-
MCL
-
+
+
-
+
-
-
-
DLCL
-
-
+
+
+
-
-
-
SMZL
-
-
+
-
+
-
-
-
HCL
-
-
+
-
+
-
-
+
MM
-
-
-/+
-
-
-
+
-
Non-Hogdkin lymphoma cytogenetics
Precursor B- and T- Cell neoplasms
• Immature B or T cells (lymphoblasts).
• 85% are B-ALLs, manifests as childhood acute
leukemias.
• T-ALLs tend to present in adolescent males as
thymic lymphomas.
• Aggressive clinical behavior.
• IPT: +ve terminal deoxynucleotidyl-transferase
(TdT)
• Pediatric ALL is one of the great success stories of
oncology.
Peripheral B cell lymphomas
Indolent
- Small lymphocytic lymphoma/CLL
- Lymphoplasmocytic lymphoma
- Marginal zone lymphoma /MALT-type
- Splenic marginal zone B cell lymphoma
- Follicular lymphoma, grade 1-3
Aggressive
- Diffuse large B cell lymphoma
- Mantle cell lymphoma
- Burkitt’s lymphoma
Small cell lymphoma/chronic
lymphocytic leukemia
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•
•
•
•
•
•
Indolent.
Adult (Median age: 60 years)
Male: Female: 2: 1.
Peripheral blood lymphocytosis.
Bone marrow is always involved.
Spleen and liver.
IHC:
Pan-B cell markers (CD 20)
CD5 &CD 23
• Only 5-10% progress to DLCL.
CLL/SLL
CLL/SLL
CD 5 + ve
Lymphoplasmacytic lymphoma
• Old adult (60 or 70 years)
• Resemble CLL/SLL.
• Plasma cell component which secrete Ig M.
• LN enlargement, hepatosplenomegaly
• Incurable progressive disease.
Follicular lymphoma
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•
•
•
•
•
•
•
•
•
•
Most common form of indolent NHL.
Usually middle age.
Male = Female.
Germinal center B cells.
Chromosomal translocations involving BCL2
Nodular morphology: small cleaved, and large cells
Grading: 1,2,3.
B.M involved in 85%.
- Lymphocytosis 10%
IPT: Pan-B (CD20), CD10, BCL2
Cytogenetics: BCL2 overexpression, t(14:18).
30-50% transform to DLCL.
Follicular lymphoma
Diffuse large cell lymphoma
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•
•
•
•
•
•
•
•
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Most common form of NHL.
Aggressive.
Slight male predominence.
Median age 60 years, but also occur in young adults and children.
Rapidly enlarging mass (nodal or extranodal).
Extranodal sites include GIT, skin, bone, brain, etc.
B.M. involvement is uncommon.
Diffuse large cells, and multinucleated cells (DD: RS cells in HD).
IPT: Pan-B markers (CD 20), CD 10, BCL6.
Cytogenetic: BCL 6, 10 to 20% t(14:18).
DLCL
CD 10 +ve
Burkitt΄s lymphoma
• 3 types: Histologically identical
but differ clinically, genetically and virology:
Endemic (African), Sporadic, Associating HIV.
• Highly aggressive.
• Children and young adults.
• Extra-nodal affection:
Endemic: Mandible. Sporadic: Ileocaecal.
• IPT: + ve CD 19, CD 20, CD10 and BCL6 (BCL2-ve).
• Cytogenetic: translocation of c- MYC gene.
Mantle cell lymphoma
• Uncommon 2.5 % of NHL in USA and 7% in Europe.
• Fifth to sixth decades of life.
• Male predominence.
• Nodular. DD: Follicular lymphoma.
• Generalized lymphadenopathy.
• Frequent site of extranodal involvement: BM, spleen, liver and gut.
• Mucosal inv. of small or large intestine (polyposis)
• IPT: Pan B markers, CD5, -ve BCL2.
• Cytogenetic: Cyclin D1, t (11:14)
• Poor prognosis. Median survival: 3 to 4 years.
Marginal zone lymphoma
• Heterogenous group can arise from LN, spleen
or extranodal tissues.
• Mucosa associated (Maltomas)
• Chronic inflammatory disorders: HP gastritis.
• Localized for prolonged peroid (Indolent).
• Cytogenetic: t (11:18), (14:18), (1:14).
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
• Angioimmunoblastic T cell lymphoma
• Angiocentric lymphoma
• Intestinal T cell lymphoma
• Adult T cell lymphoma/leukemia
• Anaplastic large cell lymphoma
Peripheral T cell lymphomas
Predominantly leukemic/disseminated
Predominantly extranodal
• T-cell prolymphocytic leukemia
• Mycosis fungoides
• T-cell large granular lymphocytic (LGL) leukemia • Sezary syndrome
• Primary cutaneous CD30+ T-cell
• NK cell leukemia
lymphoproliferative disorders
• Adult T-cell leukemia/lymphoma
• Subcutaneous panniculitis-like Tcell lymphoma
Predominantly nodal
• Angioimmunoblastic T-cell lymphoma
• Peripheral T-cell lymphoma unspecified
• Anaplastic large cell lymphoma, T/null-cell
• NK/T cell lymphoma, nasal and
nasal-type
• Enteropathy-type intestinal T-cell
lymphoma
• Hepatosplenic T-cell lymphoma
Adult T-cell leukemia/lymphoma
• Human T-cell leukemia retrovirus type 1 (HTLV-1)
• Skin lesions, generalized LNs, HSM.
• Rapidly progressive disease, fatal in less than one
year.
• IPT: CD3+
Mycosis Fungoides/Sezary syndrome
• Skin lesions:
1- Inflammatory premycotic phase.
2- Plaque phase.
3- Tumour phase.
• Then progress to LN and BM.
• Sezary syndrome is assoaciated with leukemia
of tumor cells (cerebriform nuclei).
• IPT: CD3+, CD4+, CD8 -
T cell marker
Anaplastic Large Cell Lymphoma
• Uncommon entity.
• Composed of anaplastic large cells.
• Aggressive.
• Cure rate with chemotherapy 75%.
• IPT: T cell marker CD3, and CD30.
Summary of types of NHLs
Summary of types of NHLs
Prognostic Indicators
• Histopathologic Type, grade (follicular)
• Clinical Parameters
Stage
International prognostic index
• Biology
Proliferation fraction
Oncogenes, tumor suppressor genes, MDR
International Prognostic Index (IPI)
1. Disease stage (I or II vs III or IV)
2. Age (60 vs >60)
3. Serum LDH concentration (<1 x normal vs >1
x normal)
4. ECOG performance status (2< vs 2)
Clinical Staining of NHL
(Ann Arbor classification)
Thank You