ANGIOIMMUNOBLASTIC T-CELL 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.
• 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…
Angioimmunoblastic T-cell Lymphoma
• 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
– Lymphomatoid papulosis
WHO Classification
Jaffe et al, 2001
Revised European-American Lymphoid Classification
T-Cell Lineage1. Indolent Lymphomas
• Large Granular Lymphocytic Leukemia, T & NK cell types• Mycosis Fungoides/Sezary syndrome• Smoldering and Chronic adult T-cell leukemia/lymphoma (HTLV-I)
2. Aggressive Lymphomas• Prolymphocytic Leukemia• Peripheral T-cell Lymphoma
• Angioimmunoblastic Lymphoma• Intestinal T-cell Lymphoma• Anaplastic Large cell Lymphomas (T & null cell type)
3. Very Aggressive Lymphomas• Precursor T-lymphoblastic Lymphoma/Leukemia• Adult T-cell Lymphoma/Leukemia (HTLV-I)
Harris et al, 1994
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
Dogan et al. British Journal of Haematology 121 (5), 681-691.
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
Pathology
• Good reproducibilty between expert hematopathologists
• Differential diagnosis includes reactive lymphadenopathies, multicentric Castleman's disease, diffuse large B-cell lymphoma and classical Hodgkin's Disease
Dogan et al. British Journal of Haematology 121 (5), 681-691.
Immunophenotype of AITL
(immunohistochemistry)
(A) CD21 – low power
(B) CD21- high power
(C) CD3
(D) CD4 - most CD3 cells also express CD4
(E) CD10
(F) Double-stained for CD20 in brown and CD10 in blue
(G) CD10 – low power
(H) CD10 – high power
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
Brauninger, A. Journal of Experimental Medicine, 194, 927-940.
EBER ISH
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), 681-691
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 chemotherapy2. Consideration of HDCT and PBSCT at
relapse, if responds to salvage chemotherapy
3. OR Consider novel therapeutic approaches
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