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Background

For many years since its original description as angioimmunoblastic lymphadenopathy, this disease was thought to be a reactive condition, usually referred to as AILD. Now, it is generally understood that cases diagnosed as AILD in the past are probably angioimmunoblastic T-cell lymphomas. If AILD does exist, it is very rare and characterized by a hypocellular lymphoid proliferation with arborizing venules which lacks clear cells and lacks definite cytologic atypia.

Patients with this lymphoma present with generalized lymphadenopathy, prominent systemic symptoms, fever, weight loss, skin rash, polyclonal gammopathy, circulating immune complexes and autoantibodies, and proneness to infection complication.

Outline

Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms
Internet Links

DISEASE ASSOCIATIONS CHARACTERIZATION
EPSTEIN-BARR VIRUS
 

Angioimmunoblastic T-cell lymphoma (angioimmunoblastic lymphadenopathy with dysproteinemia [AILD]-type T-cell lymphoma) followed by Hodgkin's disease associated with Epstein-Barr virus.

Nakamura S, Sasajima Y, Koshikawa T, Kitoh K, Koike K, Motoori T, Ueda R, Mori S, Suchi T.

Department of Pathology and Clinical Laboratories, Aichi Cancer Center Hospital, Nagoya, Japan.

Pathol Int 1995 Dec;45(12):958-64 Abstract quote

A patient is described with angioimmunoblastic T-cell lymphoma (AIL) (angioimmunoblastic lymphadenopathy with dysproteinemia [AILD]-type T-cell lymphoma), which was later followed by Hodgkin's disease.

At the time of the initial diagnosis, histological examination of a cervical lymph node showed a typical picture of AIL with abundant clear cells which were CD45RO+, CD43+, and CD20-, and there was no evidence of a monoclonal B-cell proliferation by immunohistochemical analysis. In situ hybridization for Epstein-Barr virus (EBV) was negative. Interposed by a bout of recurrence, the patient developed, 16 years later, a left subparotid mass which showed histologic features of Hodgkin's disease, mixed cellularity type. Diagnostic Reed-Sternberg cells and their variants were CD30+, CD15- and CD20+. Neither rearrangement of TCR beta and gamma chain genes nor of immunoglobulin heavy chain and kappa light chain genes was detected in DNA extract from fresh material. In situ hybridization showed the presence of EBV within the Reed-Sternberg cells.

The data show that EBV was not etiologically related to AIL in this case. Further, the deficit in cellular immunity that accompanied AIL conceivably permit primary EBV infection or reactivation of latent infection, which eventuated in development of Hodgkin's disease, but the exact pathogenesis remains uncertain.


Epstein-Barr virus-associated B-cell lymphoproliferative disorders in angloimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified.

Zettl A, Lee SS, Rudiger T, Starostik P, Marino M, Kirchner T, Ott M, Muller-Hermelink HK, Ott G.

Institute of Pathology, University of Wurzburg, Germany.

Am J Clin Pathol 2002 Mar;117(3):368-79 Abstract quote

Various patterns of Epstein-Barr virus (EBV)-associated B-cell lymphoproliferation occur in patients with immunodeficiency.

We studied 17 cases of T-cell lymphoma displaying extensive EBV-driven B-cell lymphoproliferation or simultaneous/subsequent EBV-associated B-cell lymphoma. In 10 cases of angioimmunoblastic T-cell lymphoma, an uncommonly prominent population of EBV+ atypical, activated, focally confluent large transformed B cells was found in the background of T-cell lymphoma. In 4 cases, an EBV-associated B-cell neoplasm (3 diffuse large B-cell lymphomas, 1 plasmacytoma) occurred in patients with T-cell lymphoma. Three cases were composite lymphomas of a peripheral T-cell lymphoma, unspecified, combined with EBV-associated diffuse large B-cell lymphoma. The transformed B-cell population displayed EBV latency types 2 and 3. Monoclonal and oligoclonal B-cell populations were detected in 5 and 6 cases, respectively.

Similar to other states of immunodeficiency, disease-related and therapy-induced immunosuppression in T-cell lymphoma may lead to a prominent EBV-associated B-cell lymphoproliferation and to EBV+ B-cell neoplasms.

 

PATHOGENESIS CHARACTERIZATION

Rearrangements on chromosomes 7 and 14 with breakpoints at 7q35 and 14q11 in angioimmunoblastic lymphadenopathy and IBL-like T-cell lymphoma.

Cosimi MF, Casagranda I, Ghiazza G, Rossi G, Galvani P.

Servizio di istologia e di anatomia patologica, Ospedale Civile (USSL 70) di Alessandria.

Pathologica 1990 Jul-Aug;82(1080):391-7 Abstract quote

In this report we discuss some cases of AILD and IBL-like T-cell lymphomas and attempt to clarify the cytogenetic relationship between these complex disease states. During the period 1980-1987 we have studied No. 6 patients affected with AILD, three of which showed final evolution into Immunoblastic T-cell lymphoma.

Cytogenetic studies, carried out on surgical lymphonodal material with histological diagnosis of AILD and leukemic cells obtained from the peripheral blood at the time of diagnosis, were analysed with IBAS 2000 for a computerized analysis, according to ISCA 1978 criteria. We have found similar translocations in three of our patients with AILD and terminal T-cell immunoblastic lymphoma, occurring between chromosomes 7 and 14 with breakpoints at 7q35 and 14q11. The arising of T-cell lymphoma in patients with AILD seems to be related to the presence of clonal cells with abnormal 7:14 translocation, which represent a very sensible marker of clonality desides of T-cell maturational lineage.

In our opinion, the forms of AILD with these cytogenetic aberrations are pre-lymphomatous lesions. On the contrary, the lack of such rearrangements is indicative of non-neoplastic patterns.

Analysis of T-cell subpopulations in T-cell non-Hodgkin's lymphoma of angioimmunoblastic lymphadenopathy with dysproteinemia type by single target gene amplification of T cell receptor- beta gene rearrangements.

Willenbrock K, Roers A, Seidl C, Wacker HH, Kuppers R, Hansmann ML.

Senckenberg Institute of Pathology, University of Frankfurt, Frankfurt am Main, Germany.

Am J Pathol 2001 May;158(5):1851-7 Abstract quote

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is defined in the current lymphoma classifications as a T-cell non-Hodgkin's lymphoma. However, in approximately one third of the cases of this lymphoproliferative disease rearrangements of T-cell receptor (TCR) genes indicating clonal expansion of T cells are not detectable. It is currently believed that these cases may represent early stages of a lymphoma with a minor oligoclonal T-cell population.

In the present study, 18 lymph nodes with the characteristic histology of AILD were investigated for clonal T-cell receptor gene rearrangements by analysis of DNA extracted from whole tissue sections. Dominant T-cell clones were detected in 12 of these cases. Single CD4(+) and CD8(+) T cells and proliferating Ki67(+) cells of seven cases were micromanipulated from frozen tissue sections. TCRbeta gene rearrangements were amplified from these cells by polymerase chain reaction and sequenced.

In all informative cases, the clonal gene rearrangements were only detected among CD4(+), and not among CD8(+) T cells, indicating that the tumor clones in AILD usually derive from CD4(+) T cells. Minor clonal T-cell populations in those cases in which no clone was found by whole-tissue DNA analysis were not detectable even at single cell resolution. T-cell clones in 4 of 10 cases were found to express similar TCRbeta chains, indicating a potential role of (super) antigen triggering in at least some cases of AILD.

LABORATORY/RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
RADIOLOGIC  
LABORATORY MARKERS  
Ig gene rearrangement Commonest type of PTCL that exhibits Ig gene rearrangement in 10-30% of cases in addition to TCR genes

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL Generalized lymphadenopathy
Skin rashes
Constitutional symptoms


Angioimmunoblastic T-cell lymphoma.

Ferry JA.

Adv Anat Pathol 2002 Sep;9(5):273-9 Abstract quote

Angioimmunoblastic T-cell lymphoma (AIL-TCL) is a rare subtype of lymphoma, making up only 1% to 2% of nonHodgkin's lymphomas; however, it accounts for a major subset of peripheral T-cell lymphomas.

Angioimmunoblastic T-cell lymphoma has clinical and pathologic features that set it apart from other B- and T-cell lymphomas. More recent studies have delineated the immunophenotypic and genetic features of this unusual lymphoma, and have tentatively identified the cell of origin of this neoplasm.

VARIANTS  
SKIN  

Cutaneous involvement by angioimmunoblastic T-cell lymphoma with remarkable heterogeneous Epstein-Barr virus expression.

Brown HA, Macon WR, Kurtin PJ, Gibson LE.

Department of Dermatology, Mayo Clinic, Rochester, Minnesota, USA.

J Cutan Pathol 2001 Sep;28(8):432-8 Abstract quote

INTRODUCTION: Initially described as an abnormal immune reaction, most cases of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)-like T-cell infiltrates are now regarded as a peripheral T-cell lymphoma (AILD T-NHL). AILD T-NHL is characterized clinically with constitutional symptoms, generalized lymphadenopathy, hepatosplenomegaly, skin rash, and polyclonal hypergammaglobulinemia. Epstein-Barr virus (EBV) is frequently detected in involved lymph nodes, but the presence of EBV in cutaneous infiltrates of AILD T-NHL has rarely been examined. We present a patient with AILD T-NHL with cutaneous involvement that shows marked heterogeneity of EBV expression in the lymph node and skin biopsies, and review the histological findings of AILD T-NHL in the skin.

METHODS: Two skin biopsies of a diffuse maculopapular rash and a lymph node were examined and immunophenotyped. In situ hybridization for detection of EBV in the lymph node and skin biopsies was utilized. In order to attempt to delineate which lymphocytes were EBV positive, skin biopsies were dual labeled with CD3, CD45RO, CD20 and EBV. The skin biopsies and lymph node were submitted for gene rearrangement studies by polymerase chain reaction (PCR). Capillary electrophoresis of fluorescently labeled PCR products was utilized for PCR product quantitation.

RESULTS: The histological features of the lymph node were diagnostic of AILD T-NHL and a T-cell clone was identified by PCR. The skin biopsies showed an atypical superficial and deep perivascular polymorphous infiltrate consistent with cutaneous involvement by AILD T-NHL. Both skin biopsies showed the same clonal T-cell receptor gene rearrangement as the lymph node. In situ hybridization of the lymph node and one skin biopsy showed a few scattered EBV-positive lymphocytes (<1% of the infiltrate). A second skin biopsy revealed 40-50% of the lymphocytes as EBV positive. Dual staining for CD20 and EBV identified a minority of EBV-infected lymphocytes as B-cells, but most of the EBV-positive cells lacked staining for CD3 and CD45RO.

CONCLUSIONS: In our patient, the same T-cell receptor gene rearrangGI ement was found by PCR in all three biopsy sites. Most cases of AILD T-NHL contain only a few EBV-positive cells, but in our patient the extent of EBV expression ranged from <1% to 40-50% of the AILD T-NHL cutaneous infiltrate. To our knowledge, this case is the most extensive and heterogeneous expression of EBV in cutaneous AILD T-NHL to date.

GI TRACT  

Peripheral T-cell lymphoma of AILD (angioimmunoblastic lymphadenopathy with dysproteinemia) type involving gastrointestinal tract. A morphologic, phenotypic and genotypic study.

Nakamura S, Takagi N, Kitoh K, Koshikawa T, Hayashi K, Yamamoto K, Suzuki H, Oyama A, Ueda R, Suchi T.

Department of Pathology and Clinical Laboratories, Aichi Cancer Center Hospital, Nagoya, Japan.

Acta Pathol Jpn 1992 Feb;42(2):141-9 Abstract quote

A case of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) which showed widespread involvement of the gastrointestinal tract is reported.

A lymph node biopsy specimen showed the characteristic histological features of AILD. During the progression of the illness, lymphomatous lesions developed in the gastrointestinal tract, complicated by cytomegalovirus infection. A double immunoenzymatic study using a combination of Ki-67 antibody and antibodies against surface antigens demonstrated that CD3+, CD4+, and/or T-cell receptor (TCR) beta+ cells were predominant (67-68%) among the population of proliferating Ki-67% cells, rather than CD8+ or CD22+ cells.

Clonal rearrangement of the TCR beta chain gene was also detected. These findings provide further evidence for the neoplastic nature of lesions of this type, and the diagnosis of peripheral T-cell lymphoma.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL Nodal architecture is effaced by a mixed cellular infiltrate
High endothelial venules are prominent
Mixed lymphoid infiltrate, including medium-sized cells with clear cytoplasm
Scattered very large cells resembling Reed-Sternberg cells
Interspersed irregular pale cells with eosinophilic foci comprising fascicles or whorls of plump spindly cells with abundant cytoplasm, representing extrafollicular follicular dendritic cells
VARIANTS  

Concomitant angioimmunoblastic T-cell lymphoma and low grade B-cell lymphoproliferative disorder.

Christopoulos C, Tassidou A, Golfinopoulou S, Anastasiadis G, Manetas S, Anagnostou D.

Second Department of Internal Medicine, Thriasio General Hospital, Athens, Greece; Department of Dermatology, Thriasio General Hospital, Athens, Greece; Department of Haematopathology, Evangelismos General Hospital, Athens, Greece.

Clin Lab Haematol 2001 Apr;23(2):139-42 Abstract quote

The presence of a rearranged immunoglobulin gene, in addition to the expected T-cell receptor gene rearrangement, is a frequent, albeit poorly understood, finding in the setting of angioimmunoblastic lymphadenopathy.

A case of an angioimmunoblastic T-cell lymphoma is presented, where this apparently paradoxical dual gene rearrangement could be ascribed to the coexistence of an occult B-cell lymphoproliferative disorder.

KIDNEY  

Proliferative glomerulonephritis with unusual, organized, cylindrical deposits associated with angioimmunoblastic lymphadenopathy-like T-cell lymphoma.

Duwaji MS, Shemin DG, Medeiros LJ, Esparza AR.

Department of Pathology, Rhode Island Hospital, Providence 02903, USA.

Arch Pathol Lab Med 1995 Apr;119(4):377-80 Abstract quote

We describe an elderly man who developed angioimmunoblastic lymphadenopathy-like T-cell lymphoma, followed by acute renal failure 2 months later.

Renal biopsy revealed proliferative glomerulonephritis, which was characterized by enlarged glomeruli with increased cellularity, thickened capillaries, intracapillary inflammatory cells, focal necrosis, and fibrin extravasation. Immunofluorescence studies revealed capillary and mesangial deposits of IgG, IgM, IgA, Ig kappa, Ig lambda, and C3.

Electron microscopy revealed unusual, organized, electron-dense deposits in the capillary walls and mesangium. The deposits occurred as accumulations of large rigid tubules or cylinders, which, in longitudinal section, were double-walled. In transverse section, the deposits were annular or horseshoe shaped and occasionally had a central filament. The morphologic characteristics of these deposits are different from those seen in cryoglobulinemia or fibrillary and immunotactoid glomerulopathies.

The significance of these deposits is uncertain; they may represent a cryoglobulin or an abnormal serum protein related to angioimmunoblastic lymphadenopathy-like T-cell lymphoma. The findings in this case expand the morphologic spectrum of glomerular lesions that may be associated with malignant lymphoproliferative disorders and, particularly, angioimmunoblastic lymphadenopathy-like T-cell lymphoma.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
SPECIAL STAINS Key features are positive CD10 and bcl-6
IMMUNOPEROXIDASE Major cell population:
CD20-
CD3+
CD5+
CD10+
CD30 -/+
CD15-
EBV LMP1-
Extrafollicular irregular meshworks of CD21+ follicular dendritic cells
  Interspersed large Reed-Sternberg-like cells:
CD20+/- (focal)
CD79a-
CD3-
CD30+
CD15-
EBV LMP1+

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
Follicular lymphoma  
Hodgkin's disease  
Peripheral T-cell lymphomas Angioimmunoblastic T-cell lymphoma has conspicuous irregular shaped extrafollicular meshworks of proliferated follicular dendritic cells
Reactive hyperplasia  
T-cell rich B-cell lymphoma  

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSTIC FACTORS  
TREATMENT  

Successful treatment with fludarabine in two cases of angioimmunoblastic lymphadenopathy with dysproteinemia.

Hast R, Jacobsson B, Petrescu A, Hjalmar V.

Department of Medicine, Danderyd Hospital, Stockholm, Sweden.

Leuk Lymphoma 1999 Aug;34(5-6):597-601 Abstract quote

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is today recognized as a T-cell lymphoma which in most cases runs an aggressive course. The diagnosis is often difficult because of the varying clinico-pathological picture. Less than a third of the patients can be expected to have long-term remissions even after multiagent chemotherapy. Complete remissions have been reported after the use of interferon-alpha, cyclosporin A, and recently purine analogues in a few patients.

We now report two cases of AILD that had unmaintained remissions for 32 and 10 months, respectively, after fludarabine therapy. In one of the patients fludarabine was used up-front and in the other after she had proved to be resistant to CHOP treatment. No severe infectious complications were noted. The use of purine analogues should be investigated further in AILD.

Successful treatment of immunoblastic lymphadenopathy-like T-cell lymphoma with cyclosporin A.

Takemori N, Kodaira J, Toyoshima N, Sato T, Sakurai H, Akakura N, Kimura S, Katagiri M.

Department of Internal Medicine, Asahikawa Kosei General Hospital, Japan.

Leuk Lymphoma 1999 Oct;35(3-4):389-95 Abstract quote

Immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma is considered to belong to peripheral T-cell lymphoma. Its prognosis is grave and effective treatments have not been established. Recently, we gave oral cyclosporin A (CsA) to a patient with IBL-like T-cell lymphoma, and succeeded in achieving dramatic remission.

In this case, serum levels of interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF alpha) were elevated and decreased or returned to normal after achieving remission. Since CsA is a potent suppressor of the immune system and most notably T-cells, the immunosuppression of T-cell function might have played an important role in achieving remission in this case, although the precise mechanism still remains to be elucidated.

The present case indicates that administration of CsA may be a very effective and safe selection of therapy for IBL-like T-cell lymphoma, as well as analogous disorders such as IBL and angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), thereby will contribute to improving the prognosis of patients with these diseases.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Taken from Chan JKC. Practical Lymphoma Diagnosis: A Simplified Approach. Presented at the 111th Semi-Annual California Tumor Tissue Registry. December 2001.


Commonly Used Terms

Peripheral T-cell lymphoma


Last Updated 9/13/2002

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