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). 9 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 17 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 • • • • • • 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 • • • • • • • 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 • • • • • • • • • • • 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 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
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