ANGIOIMMUNOBLASTIC TCELL LYMPHOMA

1
ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA

• October 29, 2004

2
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 - AW, no significant family
  history

3
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

4
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

5
Case Presentation

• Repeat lymph node biopsy at BJH     
•         Angioimmunoblastic T-cell lymphoma
  (AILT)

6
Angioimmunoblastic T-cell Lymphoma

• Clinical Syndrome initially described in 1970s
• Generalized lymphadenopathy, hepatosplenomegaly,
  anemia, hypergammaglobulinemia
• Lymph node histology characterized by partial
  effacement by polymorphic inflammatory infiltrate
  and vascular proliferation
• Immunoblastic lymphadenopathy, lymphogranulomatosi
  s 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.
7
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

8
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
• T cell prolymphocytic leukemia
• T-cell granular lymphocytic leukemia
• Aggressive NK Cell leukemia
• Adult T cell lymphoma/leukemia (HTLV1)
• Extranodal NK/T-cell lymphoma, nasal type
• Enteropathy-type T-cell lymphoma
• Hepatosplenic gamma-delta T-cell lymphoma
• Subcutaneous panniculitis-like T-cell lymphoma
• Mycosis fungoides/Sezarys syndrome
• Primary Cutaneous Anaplastic large cell lymphoma
  T/null cell
• Peripheral T cell lymphoma, unspecified
• Angioimmunoblastic T-cell Lymphoma
• Primary Systemic Anaplastic large cell lymphoma,
  T/null cell
• T-cell proliferation of uncertain malignant
  potential 
•  Lymphomatoid papulosis

Jaffe et al, 2001
9
Revised European-American Lymphoid Classification

• T-Cell Lineage
• Indolent Lymphomas
• Large Granular Lymphocytic Leukemia, T NK cell
  types
• Mycosis Fungoides/Sezary syndrome
• Smoldering and Chronic adult T-cell
  leukemia/lymphoma (HTLV-I)
• Aggressive Lymphomas
• Prolymphocytic Leukemia
• Peripheral T-cell Lymphoma
• Angioimmunoblastic Lymphoma
• Intestinal T-cell Lymphoma
• Anaplastic Large cell Lymphomas (T null cell
  type)
• Very Aggressive Lymphomas
• Precursor T-lymphoblastic Lymphoma/Leukemia
• Adult T-cell Lymphoma/Leukemia (HTLV-I)

Harris et al, 1994
10
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

11

• Histological appearances of AITL (H  E).
• Architecture partly preserved
• Architecture is effaced by a polymorphic
  infiltrate with marked vascular proliferation
• Depleted follicle surrounded by characteristic
  clear cells
• High-power view of polymorphic infiltrate and
  prominent vessels
• Large clear cells
• FDC proliferation

Dogan et al. British Journal of Haematology 
121 (5), 681-691.
12
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

13

• Immunophenotype of AITL
• (immunohistochemistry)
• 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.
14
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
  CD4CD8 ratio

15
VEGF
Wei-Li Zhao et al. Laboratory Investigation
(2004) 84, 15121519
16
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.
17
Zettl et al. Am J Clin Pathol. 2002
Mar117(3)368-79
18
Clonality
Dogan et al. British Journal of Haematology 
121 (5), 681-691
19
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
20
Clinical Features

• Ederly individuals 6th 7th decades
• Males Females
• Systemic illness

Dogan et al. British Journal of Haematology 
121 (5), 681-691
21
Clinical Features
Dogan et al. British Journal of Haematology 
121 (5), 681-691
22
Autoimmune phenomena

• Autoimmune hemolytic anemia
• Vasculitis
• Polyarthritis
• Rheumatoid Arthritis
• Autoimmune thyroid disease

23
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.

24
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

25
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

26
Initial Combination Chemotherapy
Johannes et al. Haematologica 2003 881272-1278
27
Chemotherapy at Relapse
Johannes et al. Haematologica 2003 881272-1278
28
High Dose Chemotherapy
Johannes et al. Haematologica 2003 881272-1278
29
High Dose Chemotherapy
Johannes et al. Haematologica 2003 881272-1278
30
Our Patient

• CHOP chemotherapy
• Consideration of HDCT and PBSCT at relapse, if
  responds to salvage chemotherapy
• OR Consider novel therapeutic approaches