ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA

ANGIOIMMUNOBLASTIC TCELL LYMPHOMA October 29, 2004 Case presentation • • • • • • 71 year old male Rapid onset right cervical adenopathy Denies fever, sweats, weight loss, pruritis, skin rash PMH: Gastric ulcer, Trauma to right hand, UE fracture Meds: Ecotrin Habits: non-smoker, no excessive Etoh or illicit drug use SH: Retired maintenance man at Anheuser-Busch, married FH: One brother - A&W, no significant family history • • Case Presentation- Physical Exam • Well appearing, appears younger than stated age • Afebrile, VSS, Wt 156 lb • Half a dozen left cervical lymph nodes, 1-2cm in size, discrete, soft, rubbery • Right posterior cervical lymph nodes 1-2cm in size • Right supraclavicular node 2.5 x 2cm • Right jugulodigastric node 3cm • No inguinal/axillary adenopathy • No hepatosplenomegaly • No skin rashes Case Presentation- Data • • • • • WBC 6.5 Hgb 13.9 Plt 201 ALC 600 Chem WNL LDH 186 SPEP: no monoclonal protein CT Neck: 3 low density masses with enhancing rims along the right anterior cervical chain, 1-2cm in size • Right cervical lymph node biopsy - reactive lymphoid hyperplasia • Flow - No immunophenotypic abnormality Case Presentation • Repeat lymph node biopsy at BJH: Angioimmunoblastic T-cell lymphoma (AILT) Angioimmunoblastic T-cell Lymphoma • Clinical Syndrome initially described in 1970’s • Generalized lymphadenopathy, hepatosplenomegaly, anemia, hypergammaglobulinemia • Lymph node histology characterized by partial effacement by polymorphic inflammatory infiltrate and vascular proliferation • Immunoblastic lymphadenopathy, lymphogranulomatosis X, angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) Frizzera, G. (1974) Lancet, 1, 1070-107. Lukes, R.J.(1975) New England Journal of Medicine, 292, 1-8. Lennert, K. (1979) Deutsche Medizin Wochenschrift, 104, 1246-1247. Angioimmunoblastic T-cell Lymphoma • Initially thought premalignant, with a tendency to develop into lymphoma • Immunophenotyping and molecular techniques identified a monoclonal T-cell populations and clonal cytogenetic abnormalities • Much progress made over the last decade… WHO Classification • • • T-Cell and Natural Killer Cell Neoplasms I. Precursor T cell neoplasm: a. Precursor T-lymphoblastic lymphoma/leukemia b. Blastic NK lymphoma II. Mature (peripheral) T cell and NK-cell neoplasms a. T cell prolymphocytic leukemia b. T-cell granular lymphocytic leukemia c. Aggressive NK Cell leukemia d. Adult T cell lymphoma/leukemia (HTLV1+) e. Extranodal NK/T-cell lymphoma, nasal type f. Enteropathy-type T-cell lymphoma g. Hepatosplenic gamma-delta T-cell lymphoma h. Subcutaneous panniculitis-like T-cell lymphoma i. Mycosis fungoides/Sezary’s syndrome j. Primary Cutaneous Anaplastic large cell lymphoma T/null cell k. Peripheral T cell lymphoma, unspecified l.Angioimmunoblastic T-cell Lymphoma • m. Primary Systemic Anaplastic large cell lymphoma, T/null cell T-cell proliferation of uncertain malignant potential Jaffe et al, 2001 – Lymphomatoid papulosis Revised European-American Lymphoid Classification T-Cell Lineage 1. Indolent Lymphomas • Large Granular Lymphocytic Leukemia, T & NK cell types • • 2. • • Mycosis Fungoides/Sezary syndrome Smoldering and Chronic adult T-cell leukemia/lymphoma (HTLV-I) Prolymphocytic Leukemia Peripheral T-cell Lymphoma Aggressive Lymphomas • • • 3. • • Angioimmunoblastic Lymphoma Intestinal T-cell Lymphoma Anaplastic Large cell Lymphomas (T & null cell type) Precursor T-lymphoblastic Lymphoma/Leukemia Adult T-cell Lymphoma/Leukemia (HTLV-I) Harris et al, 1994 Very Aggressive Lymphomas Risk Factors and Etiology • History of Prescription drug Use – antibiotics • Infectious agents – Tuberculosis – Cryptococcus – Lymphotropic viruses • Epstein-Barr virus • Human Herpes virus 6 • Human immunodeficiency virus • Hepatitis C virus • Human Herpes Virus 8 Histological appearances of AITL (H + E). (A) Architecture partly preserved (B) Architecture is effaced by a polymorphic infiltrate with marked vascular proliferation (C) Depleted follicle surrounded by characteristic clear cells (D) High-power view of polymorphic infiltrate and prominent vessels (E) Large clear cells (F) FDC proliferation Dogan et al. British Journal of Haematology 121 (5), 681-691. Pathology • Good reproducibilty between expert hematopathologists • Differential diagnosis includes reactive lymphadenopathies, multicentric Castleman's disease, diffuse large Bcell lymphoma and classical Hodgkin's Disease Immunophenotype of AITL (immunohistochemistry) (A) (B) (C) (D) (E) (F) (G) (H) CD21 – low power CD21- high power CD3 CD4 - most CD3 cells also express CD4 CD10 Double-stained for CD20 in brown and CD10 in blue CD10 – low power CD10 – high power Dogan et al. British Journal of Haematology 121 (5), 681-691. Immunology • Substantial immune activation in lymph nodes and peripheral blood • Elevated serum soluble interleukin 2 receptor, tumor necrosis factor alpha, IL-1 beta, interferon gamma and other cytokines • BUT associated immunodeficiency: reduction in number of circulating T cells, inversion of CD4:CD8 ratio VEGF Wei-Li Zhao et al. Laboratory Investigation (2004) 84, 1512–1519 EBV Infection • EBV infected cells seen in over 95% of all patients • EBV infected cells are B cells, therefore unlikely to play a primary role in lymphomagenesis in AITL • Usually in the immunoblasts or RS-like cells • EBV protein expression pattern is consistent with latency EBER ISH Brauninger, A. Journal of Experimental Medicine, 194, 927-940. Zettl et al. Am J Clin Pathol. 2002 Mar;117(3):368-79 Clonality Dogan et al. British Journal of Haematology 121 (5), 681-691 Genetic Changes • 90% have cytogenetic alterations • Trisomy 3, trisomy 5 and gain of chromosome X • abnormal cytogenetic clones have been shown to reside in T cells • Only complex cytogenetic abnormalities have been shown to have any effect on clinical outcome • No mutations have been detected in p53 or bcl-6 in AITL Dogan et al. British Journal of Haematology 121 (5), 681-691 Clinical Features • Ederly individuals – 6th & 7th decades • Males = Females • Systemic illness Dogan et al. British Journal of Haematology 121 (5), 6 81-691 Clinical Features Dogan et al. British Journal of Haematology 121 (5), 681-691 Autoimmune phenomena • • • • • Autoimmune hemolytic anemia Vasculitis Polyarthritis Rheumatoid Arthritis Autoimmune thyroid disease Diagnosis • The diagnosis of AITL can only be achieved by biopsy and histological examination of one of the enlarged lymph nodes, where characteristic morphological features can be best appreciated. Clinical Outcome • Limited data • Retrospective data, small patient numbers, case reports • Outcomes dismal: – Median survival less than 36 months – 5 year survival 30-35% • Most patients die of infectious complications Treatment • Combination chemotherapy (CHOP, CVP, VAP, COPBLAM, IMVP-16) achieve CR in 50% • Relapse rates are high • Single Agent chemotherapy • Steroids • Cyclosporine • Thalidomide • Fludarabine • 2-chlorodeoxyadenosine • High dose chemotherapy followed by PBSCT Initial Combination Chemotherapy Johannes et al. Haematologica 2003; 88:1272-1278 Chemotherapy at Relapse Johannes et al. Haematologica 2003; 88:1272-1278 High Dose Chemotherapy Johannes et al. Haematologica 2003; 88:1272-1278 High Dose Chemotherapy Johannes et al. Haematologica 2003; 88:1272-1278 Our Patient 1. CHOP chemotherapy 2. Consideration of HDCT and PBSCT at relapse, if responds to salvage chemotherapy 3. OR Consider novel therapeutic approaches