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

• 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.

Malignant Lymphoma

•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

• 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.

Pathogenesis

• 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).

Clinical Manifestations

9

Simplified schema of Hematopoetic Cancers

Hematopoetic

Stem Cell

Myeloid

Lymphoid

Acute and chronic

Myeloid

‘Leukemias’

Non Hodgkins lymphomas

WBC

RBC

Platelets

B Cells

T cells

B cell lympomas (90%)

T cell lymphomas

Stem

Cell +TdT

+HLA-DR

Pro B TdT+

CD19+

Pre B

CD19+

CD22+

CD20+/-

CD10+/-

Mature

B

CD20+

CD22+

CD19+

CD10+/-

Bone Marrow Pre

thymic

Cortical

Thymocyte

TCR

TCR

Medullar Thymocyte

TdT+

CD4-

CD8-

Bone

Marrow

Thymus

B cell T cell

Peripheral

Blood &

2ry

Lymphoid

Organs

TdT+

CD4-

CD8-

Mature T cell

TdT+

CD4+

TdT+

CD8+

TdT+

CD4+

CD8+

CD4+ CD8+

Helper T Cyto

toxic T

CD4-

CD8-

NaiveCentroblast Plasma

cell

T cell

T

Fig. B and T cell MaturationPathway

Centrocyte

Memory

Precursor

Mature

B T

Germinal

Center

Mantle Zone

Pax-5

t(9;14)

Marginal Zone

Lympho-

plasmacytic

Mantle Cell

Lymphoma

Bcl-1t(11;14)

Follicular

Lymphoma

p53Bcl-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

SyndromeMarginal Zone

Lymphoma (MALT)

Bcl-10t(1;14)

CD5+

B Cells

CD5-

B Cells

?

Molecular pathogenesis of

B-cell lymphomas

Rappaport classification (1966)

Working Formulation (1982)

REAL classification (1994)

WHO 2000-2008

NHL Classification

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)

NCI Working Formulation

Cell of origin

Cell morphology

Immunophenotyping

Genotyping

Clinical picture

“REAL” Classification

Abandon the use of indolent – aggressive – highly aggressive

The WHO classification of lymphoid neoplasms

Basic principle: Classification for all neoplasms based on:

Morphology and biologic features

Genetic

Immunophenotype

Clinical features

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The WHO classification of lymphoid neoplasms (2008)

WHO 2008: Peripheral B cell neoplasms

WHO 2008: Peripheral T cell neoplasms

Non Hodgkins Lymphoma

Indolent • 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

Indolent versus aggressive

Aggressive • 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!

• Total LN biopsy

• Histopathological classification

• Immunophenotyping

- B-cell Lymphoma: CD20+,CD19

- T-cell Lymphoma: CD3+

• Cytogenetic tests.

Diagnosis

Type/Ag Bcl2 CD5 CD20 CD10 CD19 CD23 CD38 CD103

CLL/SLL - + + - + + - -

FL + - + + + - - -

MCL - + + - + - - -

DLCL - - + + + - - -

SMZL - - + - + - - -

HCL - - + - + - - +

MM - - -/+ - - - + -

Immunophenotyping in B-lymphomas

Non-Hogdkin lymphoma cytogenetics

• 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.

Precursor B- and T- Cell neoplasms

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

Peripheral B cell lymphomas

Small cell lymphoma/chronic lymphocytic leukemia

• 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

• Old adult (60 or 70 years)

• Resemble CLL/SLL.

• Plasma cell component which secrete Ig M.

• LN enlargement, hepatosplenomegaly

• Incurable progressive disease.

Lymphoplasmacytic lymphoma

Follicular lymphoma • 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

• 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

• 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.

Burkitt΄s 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.

Mantle cell 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).

Marginal zone lymphoma

•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

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

Predominantly nodal

• Angioimmunoblastic T-cell lymphoma

• Peripheral T-cell lymphoma unspecified

• Anaplastic large cell lymphoma, T/null-cell

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

• 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+

Adult T-cell leukemia/lymphoma

• 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 -

Mycosis Fungoides/Sezary syndrome

T cell marker

• Uncommon entity.

• Composed of anaplastic large cells.

• Aggressive.

• Cure rate with chemotherapy 75%.

• IPT: T cell marker CD3, and CD30.

Anaplastic Large Cell Lymphoma

Summary of types of NHLs

Summary of types of NHLs

• Histopathologic Type, grade (follicular)

• Clinical Parameters

Stage

International prognostic index

• Biology

Proliferation fraction

Oncogenes, tumor suppressor genes, MDR

Prognostic Indicators

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)

International Prognostic Index (IPI)

Clinical Staining of NHL (Ann Arbor classification)

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