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

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
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
Morphologic and immunophenotypic analysis of angioimmunoblastic T-cell lymphoma: Emphasis on phenotypic aberrancies for early diagnosis. Merchant SH, Amin MB, Viswanatha DS. Department of Pathology, University of New Mexico, Albuquerque, NM, USA.	Am J Clin Pathol. 2006 Jul;126(1):29-38 Abstract quote.   The morphologic features and immunophenotype of diagnostic nodal and bone marrow biopsy specimens were reviewed in 29 well-established cases of angioimmunoblastic T-cell lymphoma (AILT). All cases showed a characteristic polymorphous lymphoid and inflammatory cell infiltrate along with stromal-vascular changes. Perivascular aggregation or clustering of neoplastic clear cells was seen in only 41% of cases. Unique architectural changes, including extranodal extension (83%), follicular dendritic cell proliferation (93%), and a distinctly marginalized distribution of residual B cells (67%) were observed. Subsets of T cells with immunophenotypic abnormalities (CD10 coexpression or loss of pan-T-cell antigens CD3 and CD7) were identified in a majority of cases (96%). Significantly, these morphologic and phenotypic features were seen irrespective of the presence of an overt lymphomatous pattern. Bone marrow involvement was present in 90% of patients with available biopsy specimens. Our results indicate that unique morphologic alterations and subsets of phenotypically aberrant T cells are present consistently in nearly all cases of AILT, including morphologically less definitive biopsy specimens.
The Role of the Perifollicular Sinus in Determining the Complex Immunoarchitecture of Angioimmunoblastic T-cell Lymphoma. Ottaviani G, Bueso-Ramos CE, Seilstad K, Medeiros LJ, Manning JT, Jones D. From the *Department of Hematopathology, University of Texas-MD Anderson Cancer Center, Houston TX; and the daggerInstitute of Pathology, University of Milan, Milan, Italy.	Am J Surg Pathol. 2004 Dec;28(12):1632-1640. Abstract quote   The growth of angioimmunoblastic T-cell lymphoma (AIL) in lymph node often produces complex patterns of neoplastic T cells and nonneoplastic B cells that complicate diagnosis. To understand better how these different patterns of B-cell expansion arise, we compared the microanatomic localization of B cells and T cells within the follicular, paracortical, and sinusoidal compartments in 30 patients with AIL (including 10 with multiple sequential samples) with that seen in 33 cases of other types of T-cell lymphoma. With early or partial nodal involvement in AIL, germinal center B-cell expansions were relatively undisturbed and often associated with a variably distended D2-40+ CD31+ perifollicular sinus that surrounded most of the follicular compartment. Identifiable tumor T cells resided mostly in the paracortex. In later stages of AIL with more complete nodal effacement, bcl-6+ follicular B-cell proliferations shifted to distorted FDC networks arrayed along patent trabecular sinuses and were more intermixed with tumor T cells. In both AIL and other T-cell lymphomas, the density and locations of follicular B cells as well as bcl-6-negative monocytoid B cells were largely related to the patency of adjacent sinuses, except in Epstein-Barr virus (EBV)+ and histiocyte-rich B-cell proliferations, which arose in paracortical locations. The prominence of the perifollicular sinus in early stages of AIL resembled that seen in reactive lymphadenitis during conditions of lymphatic engorgement and implicates cytokines within lymph fluid in maintaining both the normal and altered germinal center reactions. Patterns of sinus drainage largely explain the useful changes in B-cell distribution that occur in nodal T-cell lymphomas and represent an important tool in classification and diagnosis of these tumors.
VARIANTS
COMPOSITE
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.
Composite Angioimmunoblastic T-Cell Lymphoma and Diffuse Large B-Cell Lymphoma A Case Report and Review of the Literature Yin Xu, MD, PhD Robert W. McKenna, MD Mai P. Hoang, MD Robert H. Collins, MD Steven H. Kroft, MD	Am J Clin Pathol 2002;118:848-854 Abstract quote We report a rare case of composite angioimmunoblastic T-cell lymphoma (AILT) and diffuse large B-cell lymphoma occurring in a 48-year-old woman with generalized lymphadenopathy and hepatosplenomegaly. The patient initially sought care at a local hospital with a single enlarged left cervical lymph node. Histologic examination of the node was interpreted as an atypical immunoblastic proliferation. She developed generalized lymphadenopathy 10 months later and was referred to our institution for further evaluation. The recent biopsy of the cervical node showed typical features of AILT. Flow cytometric immunophenotyping identified an aberrant CD4+ T-cell population that lacked surface CD3. Polymerase chain reaction analysis of the T-cell receptor gamma gene revealed a clonal rearrangement. In addition to the AILT, the lymph node showed partial involvement by a diffuse large B-cell lymphoma. The B lymphoma cells and admixed immunoblasts and Reed-Sternberg–like B cells in the AILT were positive for Epstein-Barr virus (EBV) by in situ hybridization. Our findings raise the possibility that the EBV-associated large B-cell lymphoma is a secondary event in AILT via EBV infection or reactivation followed by clonal expansion of an immortalized EBV-infected B cell clone.
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+
CD10
CD10 and BCL6 expression in the diagnosis of angioimmunoblastic T-cell lymphoma: utility of detecting CD10(+) T cells by flow cytometry. Yuan CM, Vergilio JA, Zhao XF, Smith TK, Harris NL, Bagg A. Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.	Hum Pathol. 2005 Jul;36(7):784-91. Abstract quote   Angioimmunoblastic T-cell lymphoma (AITCL) is a histologically distinct and relatively common subtype of T-cell lymphoma. Although the putative normal cell counterpart is a mature CD4(+) T cell, the precise cell of origin remains elusive. We evaluated cases with a diagnosis of AITCL to determine the specificity and utility of CD10 coexpression, particularly by flow cytometry (FCM), in facilitating this diagnosis. Coexpression of BCL6 was also assessed. Eight AITCL cases were evaluated histologically, immunohistochemically, and by 4-color FCM. Four cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), were also analyzed. The lymphoma cells in all 8 AITCL cases were CD4(+), CD45RO(+) T cells, with classic extrafollicular meshworks of CD21/CD23/CD35(+) follicular dendritic cells. Furthermore, all cases of AITCL cases contained interfollicular CD10(+) cells by immunohistochemistry, and increased coexpression of CD10 on T cells was also detected in 6 of 8 cases by FCM. CD10 coexpression was not observed in all 4 PTCL-NOS cases. Although not specific for AITCL, increased numbers of BCL6(+) cells were seen in AITCL as compared with PTCL-NOS. Double immunohistochemistry performed on an AITCL case with high numbers of BCL6(+) cells highlighted coexpression of BCL6 and CD4 on the same cells. The finding suggests that AITCL may be a neoplasm of (possibly intrafollicular) CD10(+), BCL6(+), and CD4(+) memory T cells. Although our series is small, our results suggest that CD10 coexpression may be a useful discriminant, particularly if the differential diagnosis is PTCL-NOS, and demonstrate that this can be determined by FCM.
CD10 Expression in Extranodal Dissemination of Angioimmunoblastic T-cell Lymphoma. Attygalle AD, Diss TC, Munson P, Isaacson PG, Du MQ, Dogan A.	Am J Surg Pathol. 2004 Jan; 28(1): 54-61. Abstract quote   SUMMARY: Angioimmunoblastic T-cell lymphoma (AITL) is a systemic disease that often has evidence of extranodal involvement at presentation. In a recent study of lymph nodes in AITL, we showed that the neoplastic T cells in most cases can be identified by aberrant expression of CD10. The aim of this study was to investigate whether CD10 expression by the neoplastic T cells is maintained in extranodal sites. Ten cases of AITL with histologic and immunophenotypic evidence of extranodal dissemination were studied. Seven cases of peripheral T-cell lymphoma unspecified (PTLu), that included biopsies of involved extranodal sites, two cases of enteropathy type T-cell lymphoma (ETTL), and one case of extranodal NK/T lymphoma, nasal type were selected as controls. Diagnostic lymph node biopsies and biopsies of extranodal sites were reviewed. PCR for T-cell clonality and single layer immunostaining for CD3, CD20, CD10, and CD21 and double layer immunostaining for CD20/CD10 were performed. All 10 cases of AITL had characteristic histologic features and molecular evidence of the disease in lymph node biopsies. In these cases, aberrant CD10 expression was maintained in the lung, cecum, tonsil, nasopharynx, and one of six involved bone marrow trephines. In these extranodal biopsies, the distribution of CD10-positive tumor cells correlated with that of the follicular dendritic cell meshwork (FDC). The five bone marrow trephines that lacked aberrant CD10 expression were devoid of morphologic and immunohistochemical evidence of FDC. In these five cases, there was evidence of aberrant CD10 expression in other involved sites that had FDC. The neoplastic cells in PTLu, ETTL, and extranodal NK/T lymphoma, nasal type were CD10 negative. Our data show that aberrant CD10 expression is a useful phenotypic marker for diagnosis of AITL in most involved extranodal sites, except bone marrow, and suggest a possible role of FDC in the pathogenesis of AITL.
CXCL13
Expression of CXCL13 by Neoplastic Cells in Angioimmunoblastic T-Cell Lymphoma (AITL): A New Diagnostic Marker Providing Evidence That AITL Derives From Follicular Helper T Cells. Dupuis J, Boye K, Martin N, Copie-Bergman C, Plonquet A, Fabiani B, Baglin AC, Haioun C, Delfau-Larue MH, Gaulard P. Departments of *Hematology daggerPathology double daggerImmunology section signInserm U617, Hopital Henri Mondor, Creteil, France parallelDepartment of Pathology, Hopital Saint Antoine, Paris, France; and paragraph signHopital Foch, Suresnes, Suresnes, France.	Am J Surg Pathol. 2006 Apr;30(4):490-494. Abstract quote   Angioimmunoblastic T-cell lymphoma (AITL) represents a distinct entity among peripheral T-cell lymphomas (PTCLs). The cellular origin of AITL remains unknown, although a possible derivation from follicular helper T cells (TFH) has been suggested based on the CD4/Bcl-6 phenotype. It has been recently shown that expression of CXCL13, a chemokine critically involved in B-cell migration into germinal centers, is characteristic of TFH cells, as compared with other T helper subsets. We compared CXCL13 expression in 29 AITLs, 20 PTCLs, unspecified, 10 anaplastic large cell lymphomas (ALCL), and 4 other PTCLs. We showed that CXCL13 is expressed by AITL (29 of 29, 100%) and a subset of PTCL, unspecified (6 of 20, 30%), which all showed borderline features with AITL, but in only 1 of 10 (10%) ALCLs, and 0 of 4 other PTCLs. Two-color immunostainings further showed that CXCL13 was found in the cytoplasm of atypical CD5-positive T cells that expressed CD10. We conclude that CXCL13 expression is a common characteristic of AITL, which can help to delineate the morphologic spectrum of the disease, and further supports its derivation from TFH cells. CXCL13 expression may also provide an additional useful tool for the diagnosis of AITL.
PD-1
Programmed Death-1 (PD-1) is a Marker of Germinal Center-associated T Cells and Angioimmunoblastic T-Cell Lymphoma. Dorfman DM, Brown JA, Shahsafaei A, Freeman GJ. *Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; daggerDepartment of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA.	Am J Surg Pathol. 2006 Jul;30(7):802-810. Abstract quote   Programmed death-1 (PD-1), a member of the CD28 costimulatory receptor family, is expressed by germinal center-associated T cells in reactive lymphoid tissue. In a study of a wide range of lymphoproliferative disorders, neoplastic T cells in 23 cases of angioimmunoblastic lymphoma were immunoreactive for PD-1, but other subtypes of T cell and B cell non-Hodgkin lymphoma, as well as classic Hodgkin lymphoma, did not express PD-1. The pattern of PD-1 immunostaining of neoplastic cells in angioimmunoblastic lymphoma was similar to that reported for CD10, a recently described marker of neoplastic T cells in angioimmunoblastic lymphoma. Tumor-associated follicular dendritic cells in cases of angioimmunoblastic lymphoma were found to express PD-L1, the PD-1 ligand. In addition, PD-1-positive reactive T cells formed rosettes around neoplastic L&H cells in 14 cases of nodular lymphocyte predominant Hodgkin lymphoma studied. These findings, along with data from previous studies, suggest that angioimmunoblastic lymphoma is a neoplasm of germinal center-associated T cells and that there is an association of germinal center-associated T cells and neoplastic cells in nodular lymphocyte predominant Hodgkin lymphoma. PD-1 is a useful new marker for angioimmunoblastic lymphoma and lends further support to a model of T-cell lymphomagenesis in which specific subtypes of T cells may undergo neoplastic transformation and result in specific, distinct histologic, immunophenotypic, and clinical subtypes of T-cell neoplasia.

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
ADULT T-CELL LYMPHOMA/LEUKEMIA
Adult T-cell Lymphoma/Leukemia With Angioimmunoblastic T-cell Lymphomalike Features: Report of 11 Cases. Karube K, Suzumiya J, Okamoto M, Takeshita M, Maeda K, Sakaguchi M, Inada T, Tsushima H, Kikuchi M, Ohshima K. *Department of Pathology, School of Medicine, Kurume University, Kurume daggerJapan Society for the Promotion of Science (JSPS), Japan Departments of paragraph signPathology double daggerInternal Medicine, School of Medicine, Fukuoka University, Fukuoka section signDepartment of Internal Medicine, Fujita Health University School of Medicine, Toyoake parallelNational hospital organization Miyakonojo Hospital, Miyakonojo musical sharpSocial Insurance Yatsushiro General Hospital, Yatsushiro perpendicularHealth Insurance Amakusa Chuo General Hospital, Hondo **Department of Hematology, Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.	Am J Surg Pathol. 2007 Feb;31(2):216-223. Abstract quote In adult T-cell lymphoma/leukemia (ATLL), the neoplastic lymphoid cells are usually medium-sized to large, often with pronounced nuclear pleomorphism compatible with the diagnosis of diffuse pleomorphic peripheral T-cell lymphoma. We describe here 11 patients with the rare morphologic variant of ATLL, angioimmunoblastic T-cell lymphoma (AILT)-like type. The examined lymph nodes showed proliferation of high endothelial venules and presence of various infiltrating inflammatory cells including plasma cells and eosinophils. The lymphoma cells were medium-to-large size with clear cytoplasm. These findings were suggestive of AILT. However, immunohistochemical features of AILT, namely, CD10 and CXCL13 expression in lymphoma cells and proliferation of CD21-positive follicular dendritic cells, were not detected. Two cases were CXCR3-positive, whereas 9 expressed CCR4, which are usually positive in ATLL. All patients were positive for antiadult T-cell leukemia/lymphoma-associated antigen, which is a specific antibody for human T-cell lymphotropic virus type-I. Southern blot analysis revealed proviral DNA integration in lymphoma cells in 9 patients. The latter was not evident in the first biopsy of 2 patients but in the second biopsy obtained within several months after the first biopsy revealed definite proviral integration. Almost all patients showed aggressive clinical course and poor survival (median survival: 5 mo). This is the first report of ATLL with AILT-like morphologic 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.

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Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
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Taken from Chan JKC. Practical Lymphoma Diagnosis: A Simplified Approach. Presented at the 111th Semi-Annual California Tumor Tissue Registry. December 2001.

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