angioimmunoblastic t-cell lymphoma

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


Clinical Features• Ederly individuals – 6th & 7th decades• Males = Females• Systemic illness


Clinical Features


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


High Dose Chemotherapy


Our Patient

1. CHOP chemotherapy2. Consideration of HDCT and PBSCT at

relapse, if responds to salvage chemotherapy

3. OR Consider novel therapeutic approaches

angioimmunoblastic t-cell lymphoma

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