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Angioimmunoblastic T-cell lymphoma


1.1 Definition

Angioimmunoblastic T cell Lymphoma (AITL) is a rare neoplasia accounting for about 2% of all non Hodgkin’s lymphoma (NHL), but represents the most common subtype (15-20%) of peripheral T-cell lymphomas (PTCL). AITL is recognized as a distinct clinical and hystological entity by the WHO classification (Jaffe 2001). A CD4+ve T-cell subset homing in the lymph nodes germinal centers, the germinal centre T-helper cell (GC-th cell), has recently been suggested being the putative normal cell counter-part for AITL (Grogg 2005).

1.2 Risk factors and etiology

The aetiology and pathogenesis of AITL are unknown. In a high percentage of cases the diagnosis is preceded by allergic reactions, infections and/or exposure to drugs, particularly antibiotics (Freter 1993). All these features are more likely to be consequences of the severe immune derangement than putative risk factors. Biomolecular footprints of a wide array of viruses have been detected in affected lymph nodes, but not in the neoplastic cells. B-cell EBV genomes are detected by PCR and/or FISH analysis in up to 100% of AITL lymph nodes (Weiss 1992). However, EBV can be detected only in B-cells and making it unlikely to be somehow involved in the development of AITL (Brauningher 2001). Most of the large B-cells in the lymph node interfollicular area are EBV positive. Other Herpes viruses, HHV6 and HHV8, have been reported in AITL, but the expression is absent in the neoplastic T-cells (Luppi 1996).


2.1 Morphology

The nodal architecture is completely or partially effacted by an interfollicular infiltrate and regressed follicles can be evident. The neoplastic infiltrate, mostly confined to the paracortex often leaks beyond the nodal capsule. Peripheral sinuses are frequently preserved and dilated. The infiltrate is composed of small to medium-sized lymphocytes with clear cytoplasm and minimal cytological atypia, along with an inflammatory background composed of plasma cells, macrophages, eosinophyls, large lymphoid blasts, and rare Sternberg-Reed cells (Suchi 1987; Patsouris 1989). Other two prominent features, along with the polymorphous infiltrate, are a proliferation of small arborizing high endothelial venules (HEV), many of which show thickened or hyalinized PAS+ walls, and a coarse irregular extrafollicular meshwork of follicular dendritic cell (FDC). The latter surrounds the vessels and may have the appearance of “burn out” germinal centers (Feller 1988). This highly characteristic feature has been proposed as a crucial clue of help in the differential diagnosis. In near one half of cases, small clusters or even sheets of atypical immunoblasts are found, particularly in the perivascular areas. According to the presence of residual reactive hyperplastic B-cell follicles, degree of nodal architecture effacement and presence of cytological features of malignancies three different overlapping pattern have been described (Dogan 2003).

Figure 1:

Angioimmunoblastic T-cell lymphoma. A) Prominent blood vessels are evident among the lymphoid cells (arrows). B) CD4 immunostaining highlights neoplastic cells around the arborizing blood vessels. C) A conspicuous number of interfollicular CD10+ cells is detected in the context of the neoplastic infiltrate. D) A CD21+ meshwork of dendritic cells extends from the vessels resembling “burn-out” germinal centres.

2.2 Immunophenotype

Neoplastic cells account for a small fraction of the infiltrate, varying from 5% to 30%.The tumor clone in AITL derives from CD4+ T cells. Single-cell microdissection and molecular analysis have confirmed immunophenotypic studies suggesting that neoplastic cell have a T-helper cell phenotype expressing CD3,CD4 and frequently CD10 (Attygalle 2002). The neoplastic CD10+ cells show a striking cytoplasmic expression of CXCL13 (Grogg 2005), a chemokine that is over expressed by GC-Th cells (Kim 2004) and express Th1-cell cytokines (Tsuchiya 2004). The aberrant CD10 expression is a useful phenotypic marker for diagnosis of AITL also in most involved extranodal sites, except bone marrow (Attygalle 2004). In a recently reported large retrospective series, CD10 immunoreactivity was detected in 39% of AITL cases, suggesting that this marker is a useful but not absolute diagnostic tool in AITL (Went 2006). CXCL13 expression has been described in 29 of 29 AITL cases and in 30% of a subset of unspecified peripheral T-cell lymphomas with borderline features with AITL, while it was virtually absent in anaplastic large T-cell lymphomas and other unspecified peripheral T-cell lymphomas (Dupuis 2006). Two-colour immunostainings further showed CXCL13 immunoreactivity in the cytoplasm of atypical CD5-positive T cells that expressed CD10 (Dupuis 2006). CXCL13 immunoreactivity suggests a tumour derivation from follicular helper T-cells. Other markers for germinal centre T cells, such as SAP and PD-1, are expressed in 95% of AITL (Roncador 2007). Although further studies are needed, this distinct phenotype may prove to be a useful marker in the diagnosis of AITL. Non neoplastic CD8+ mature T cells are intermingled within the neoplastic infiltrate. Another characteristic is the dense meshwork of FDC highlighted with immunostaining with FDC markers, that is CD21, CD23 and CD35 (Figure 1) (Feller 1988; Weiss 1986). Interestingly, the neoplastic infiltrate is intimately associated to the FDC net. Most of the large immunoblasts, express B-cell markers, they may represent more than 25% of the cell population in up to 18% of cases (Lome-Maldonado 2002).
CD52 immunoreactivity is a relevant feature in some lymphoproliferative disorders where alemtuzumab (Mab-Campath), a humanized anti-CD52 monoclonal antibody, is being tested in prospective trials. In contrast with chronic lymphocytic leukaemia, CD52 expression is extremely variable among other haematological malignancies, mostly in T-cell lymphomas (Rodig 2006; Chang 2007; Piccaluga 2007). CD52 immunoreactivity was observed in 2 of 5 assessed cases of AITL (40%) (Rodig 2006). In situ hybridization for EBV EBER exhibits positive results in 50% of AILTs (Tan 2006). Cases with B-cell proliferations are more often EBV-positive and tend to show greater numbers of EBV-labelled cells. In cases with high numbers of EBV-labelled cells, the EBV staining pattern correlates with that of CD79a or CD20, consistent with an EBV-associated B-cell proliferation (Tan 2006). In cases with few numbers of labelled cells, the staining pattern for EBV is scattered and does not clearly correlate with that of B- or T-cell lineage markers.

Figure 1:

Angioimmunoblastic T-cell lymphoma. A) Prominent blood vessels are evident among the lymphoid cells (arrows). B) CD4 immunostaining highlights neoplastic cells around the arborizing blood vessels. C) A conspicuous number of interfollicular CD10+ cells is detected in the context of the neoplastic infiltrate. D) A CD21+ meshwork of dendritic cells extends from the vessels resembling “burn-out” germinal centres.

2.3 Genetic features

The presence of a monoclonal T-cell population can be confirmed in most but not all cases (Feller 1988; Kaneko 1988). Microdissection analysis have shown that clonal T-cell receptor genes (TCR) rearrangements are detected only among CD4+ cells, indicating that AILT derives from this population (Willenbrock 2001 ; Willenbrock 2005). In about 20% of cases, rearrangements of TCR are not detectable. It is unclear whether these cases lack clonal lymphocytic infiltrates, or whether they represent false negative results because of limited sensitivity of the Southern blot and/or PCR techniques applied. Another intriguing feature is the presence of an expanded monoclonal B-cell population in up to 30% of patients (Smith 2000). It is thought that these clones belong to EBV+ large B-immunoblasts that can be found in these patients (Weiss 1992; Anagnostopoulos 1992). In some cases, a B-cell clone can become dominant with the characteristics of the EBV driven lymphoprolipherations that are associated with immunosuppression. Chromosomal abnormalities are detected in the majority of AILT cases, 70% with conventional cytogenetics and 90% with FISH. Multiple different clones are found in up to 40% of cases. Trisomy 3 and 5 and an additional X chromosome are the most frequent cytogenetic abnormalities detected in AITL. There is a high incidence of individual metaphases with nonclonal abnormalities and of multiple, unrelated karyotipic clones (Schlegelberger 1990a; Schlegelberger 1990b; Schlegelberger 1996).
Recently reported studies on gene expression profiling strongly support that normal follicular helper T cells represent the normal counterpart of AITL, and suggest that the AITL spectrum may be wider than suspected, as a subset of CD30-negative unspecified peripheral T-cell lymphomas may derive from or be related to AITL (De leval 2007). The molecular profile of AITL is characterized by a strong microenvironment imprint (overexpression of B-cell- and follicular dendritic cell-related genes, chemokines, and genes related to extracellular matrix and vascular biology), and overexpression of several genes characteristic of normal follicular helper T cells, such as CXCL13, BCL6, PDCD1, CD40L, NFATC1. Overexpression of these genes was validated by immunohistochemistry in AITL (De leval 2007). A recent study showed that AILT and other unspecified peripheral T-cell lymphomas have rather similar gene expression profiling, possibly sharing common oncogenic pathways (Piccaluga 2007). AILT is closer to activated CD4(+), rather than to resting or CD8(+) lymphocytes, and several genes, including PDGFRA, REL, and vascular endothelial growth factor (VEGF), are deregulated in AILT. Interestingly, the VEGF is expressed not only by reactive cells, but also by neoplastic cells. These features provide new relevant information on AILT biology and new candidates for possible therapeutic targets such as PDGFRA (platelet-derived growth factor alpha) and VEGF (Piccaluga 2007).


3.1 Clinical presentation

AITL is a neoplasm of the elderly, the median patients age is 60-65 years, with an equal incidence in male and female. On diagnosis, almost all patients presents with advanced stage disease (stage III-IV). Rarely, the lymphoadenopathies are bulky; in about two-thirds of cases the most prominent manifestation of the disease is a combination of wide arrays of signs and symptoms suggesting a systemic disease: B-symptoms (70%), pruritus, skin rash (50%), hepatomegaly (50%) splenomegaly (79%), pleural effusion (37%), oedema (40%), ascites (25%) (Patsouris 1989; Frizzera 1974;Siegert 1995). In a significant proportion of patients autoimmune diseases can be detected, including: autoimmune hemolytic anemia, cold agglutinine anemia, vasculitis, polyarthritis, autoimmune thyroiditis (Dogan 2003). Among laboratory findings the most frequent on diagnosis are: anaemia, eosynophilia, hypergammaglobulinemia, autoantibodies, elevated lactate dehydrogenase serum levels, elevated eritrosedimentation rate, and bone marrow involvement.

3.2 Diagnostic criteria

The diagnosis of AITL is not always straightforward (Dogan 2003; Attygalle 2002). Clinical presentation can mimic infectious, inflammatory, autoimmune, or other lymphoid neoplasms, particularly Hodgkin’s disease. The diagnosis can only be achieved by lymph node biopsy and it should be underscored that the awareness of the clinical picture by the hemopathologist is of paramount importance. The lymph node architecture is often only partially effaced and there is not a single specific hallmark that can lead to the diagnosis. Histologically AITL may resemble a variety of disreactive or neoplastic conditions such as atypical T-zone hyperplasia, Castleman’s multicentric disease, Hodgkin’s lymphoma, large B-cell Lymphoma (Dogan 2003). Definite diagnosis is often difficult and can be tricky, particularly for a non experienced hematopathologist, leading to an error in initial diagnosis in about half of the cases (Attygalle 2002; Jaffe 1995). Therefore, fine needle aspiration or even a needle core biopsy do not constitute an appropriate diagnostic procedure when AILT is suspected. The recently reported aberrant expression of CD10 by the CD4 neoplastic clone may help the diagnosis (Yuan 2005). The expression of CXCL13 and PD1 in neoplastis cells could be helpful in differential diagnosis with some immunoreactive conditions like Still’s disease, where these molecules are expressed in normal CD4+ T-lymphocytes residing in the germinal centers. Molecular biology investigations are of value to monitor the minimal residual disease but their role for diagnosis is controversial. For instance, a TCR rearrangement cannot be demonstrated in up to 20% of AITL typical cases.


4.1 Staging procedures

The staging work-up for AITL requires total-body computerized tomography, bone marrow trephine biopsy and a thorough examination of all suspected extranodal sites. Ascitic or pleural effusion, present in up 40% of cases and all extranodal suspected lesions should be cytologically or histologically confirmed whenever it is possible. At present time, there are no data on the sensitivity and accuracy of positron emission tomography (PET) in the staging of AITL.

4.2 Restaging and analysis of minimal residual disease

Restaging should include all diagnostic procedures positive at the time of diagnosis and initial staging. Minimal residual disease in AITL is currently detected by PCR analyzing the rearrangement of TCR genes. PCR amplification and sequencing of immunoglobulin heavy chain genes is advisable because it detects a gene rearrangement in 10% of cases (Feller 1988; Kaneko 1988). There are no clues about the clinical and prognostic value of a molecular remission.


5.1 Natural history

AILT follows an aggressive clinical course and the results with the conventional chemotherapy are unsatisfactory. Although about two thirds of patients can achieve a complete remission, the median survival is less than three years and only 10-30% of patients are alive at five years from diagnosis. Patients often succumb to infectious complications. In addition, patients may develop expanded EBV-infected clones, that can lead to EBV-positive B-cell lymphomas in rare cases (Weiss 1992;Abruzzo 1993; Nathwani 1978). Actually, the overwhelming immune deregulations rather than tumor bulk is the leading problem and is responsible for most of the AILT-related mortality. Not surprisingly, there are many anedoctal reports of relapsed AILT patients who have responded to a variety of immunosuppressive therapy, such as low dose methotrexate/prednisone (Quintini 2001), cyclosporine, purine analogues (Ong 1996; Tsatalas 2001; Sallah 1996; Hast 1999), and thalidomide (Advani 1997; Takemori 1999; Dogan 2005).

5.2 Prognostic factors

Although AITL is a very aggressive neoplasm, the clinical outcome of the patients varies considerably, with rapid fatal course in some patients, and durable remission in others. A number of presenting clinical features, age, stage, B-symptoms, rush/pruritus, oedema, ascites, lactate dehydrogenase, haemoglobin (Siegert 1995) and cytogenetic findings (Schlegelberger 1996) have been reported to be significantly related to survival. However, the currently available staging systems and prognostic scores proved to be inadequate when applied to AITL cases. Up to 90% of AITL patients present an advanced stage and comprehensibly Ann Arbor staging system is insufficient in distinguishing different prognostic groups (Pautier 1999). The International Prognostic Index (IPI) failed in identifying groups with different prognosis (Lee 2003; Rudiger 2002). The PIT score, recently proposed for PTCL-NOS (Gallamini 2004), has not yet been applied to AITL series. Further, the presence or absence of TCR rearrangements or absence and presence focal or sheet-like proliferations of immunoblasts do not discriminate patients with different outcomes (Lome-Maldonado 2002; Lee 2003). Recently, in a small series of cases, it has been found that increased levels of vascular endothelial growth factor-A gene expression in both lymphoma cells and vascular cells, are related to the extranodal involvement and survival time (Zhao 2004).


6.1 Standard-dose anthracycline-containing chemotherapy

The standard therapeutic option for patients with AITL has not yet been clearly established. Randomized clinical trials that evaluate the effectiveness of different therapeutic modalities in AITL are lacking. There are only two trials focused on therapy of AITL, one prospective non-randomized and one retrospective. These studies accrued patients mostly before the 1990, and reflect the attitude of hematologist at that time of considering AITL a disreactive non neoplastic albeit often fatal disease. AITL patients showing stable disease received monotherapy with prednisone whereas those presenting with aggressive disease, or patients at release received combination chemotherapy. The remission rate was significantly higher in the chemotherapy group (29% vs. 64%) while no differences were detected in overall survival and disease-free survival, with a median overall survival of 15 months (Siegert 1992). In another trial, 33 patients received CHOP-like therapy (28 patients as first-line and 8 patients after prednisone). Sixty percent of patients achieved a complete remission but the outcome was poor with a relapse rate of 56% and a median overall survival of 36 months (Schetelig 2003).

6.2 High-dose therapy

An EBMT-base survey reported on the impact of high-dose chemotherapy (HDCT) and autologous hematopoietic stem-cell transplantation in patients with AITL. HDCT was given as part of 1st-line therapy in 48% of 29 cases and as 2nd/3rd-line in 52%. There was one treatment-related death; with a median follow-up of 5 years the overall survival and event-free survival was 44% showing that AITL is susceptible to HDCT and should be considered at least in selected cases (Schetelig 2003).

6.3 Other therapeutic approaches

Several case reports deal with the activity of immunosuppressive therapy or immunomodulatory drugs on AITL. Partial or even long lasting complete remissions have been described in patients who received as first-line or salvage therapy, interferon, cyclosporine, low-dose methotrexate and prednisone, thalidomide, 2-clorodeoxyadenosine, and fludarabine (Siegert 1991; Strupp 2002). The activity of thalidomide is intriguing in the light of its antiangiogenetic properties (Zhao 2004). Alemtuzumab (Mab-Campath), a humanized monoclonal antibody anti-CD52 antigen, with a substantial activity against T-cell lineage lymphomas, has recently been tested in a phase II trial (Gallamini 2007), in association with CHOP. The combination Campath-CHOP produces a high remission rate with considerable but manageable toxicity. In fact, complete remission was achieved in 17 (71%) of 24 treated patients. At a median follow-up of 16 months (5-42), 14 patients were alive, nine had died from progressive disease and one from pneumonia at day +198 while in remission. So far, 13 were disease-free, with an overall median duration of response of 11 months. The most frequent side effect were grade 4 neutropenia and CMV reactivation. Major infections were J-C virus reactivation, pulmonary invasive aspergillosis, Staphylococcus sepsis, and pneumonia (Gallamini 2007). CD52 expression variability (see item 2.2) suggests that target validation on a case-by-case basis will likely be necessary to guide the rational analysis of alemtuzumab therapy (Rodig 2006; Piccaluga 2007).

6.4 Which therapy outside a controlled trial?

Although it is difficult to establish firm guidelines regarding the optimal therapeutic regimen for AITL, it can be recommended that an anthracycline-containing regimen must be employed as first line therapy, on a type 3 level of evidence. High-dose chemotherapy can be offered to young fit AITL patients, as second- line therapy or as consolidation of the first remission, on a type 3 level of evidence. Prednisone and immunosuppressive or immunomodulatory drugs such as thalidomide, cyclosporine, or methotrexate can produce a very good palliation of the disease or even durable remission and must be considered, as suitable for individual clinical use, in patients unfit for standard therapy.


Abruzzo LV, Schmidt K, Weiss LM, Jaffe ES, Medeiros LJ, Sander CA, et al. B-cell lymphoma after angioimmunoblastic lymphadenopathy: a case with oligoclonal gene rearrangements associated with Epstein-Barr virus. Blood 1993; 82: 241-246 [Medline]

Advani R, Warnke R, Sikic BI, Horning S. Treatment of angioimmunoblastic T-cell lymphoma with cyclosporine. Ann Oncol 1997; 8: 601-603 [Medline]

Anagnostopoulos I, Hummel M, Finn T, Tiemann M, Korbjuhn P, Dimmler, et al. Heterogeneous Epstein-Barr virus infection patterns in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type. Blood 1992; 80: 1804-1812 [Medline]

Araki A, Taniguchi M, Mikata A. T cell receptor V beta repertoires of angioimmunoblastic lymphadenopathy-like T cell lymphoma. Leuk Lymphoma 1994; 16: 135-140 [Medline]

Attygalle A, Al Jehani R, Diss TC, Munson P, Liu H, Du MQ, et al. Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood 2002; 99: 627-633 [Medline]

Attygalle AD, Diss TC, Munson P, Isaacson PG, Du MQ, Dogan A. CD10 expression in extranodal dissemination of angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 2004; 28: 54-61 [Medline]

Banks PM. Incorporation of immunostaining data in anatomic pathology reports. American Journal of Surgical Pathology 1992; 16: 808 [Medline]

Brauninger A, Spieker T, Willenbrock K, Gaulard P, Wacker HH, Rajewsky K, et al. Survival and clonal expansion of mutating ‘quot;forbidden’quot; (immunoglobulin receptor-deficient) epstein-barr virus-infected b cells in angioimmunoblastic t cell lymphoma. J Exp Med 2001; 194: 927-940 [Medline]

Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 1971; 31: 1860-1861 [Medline]

Ch’ang HJ, Su IJ, Chen CL, Chiang IP, Chen YC, Wang CH, et al. Angioimmunoblastic lymphadenopathy with dysproteinemia–lack of a prognostic value of clear cell morphology. Oncology 1997; 54: 193-198 [Medline]

Chang ST, Lu CL, Chuang SS. CD52 expression in non-mycotic T- and NK/T-cell lymphomas. Leuk Lymphoma 2007; 48: 117-121 [Medline]

Cheng AL, Su IJ, Chen YC, Uen WC, Wang CH. Characteristic clinicopathologic features of Epstein-Barr virus- associated peripheral T-cell lymphoma. Cancer 1993; 72: 909-916 [Medline]

de Leval L, Rickman DS, Thielen C, Reynies A, Huang YL, Delsol G, et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 2007; 109: 4952-4963 [Medline]

Dogan A, Attygalle AD, Kyriakou C. Angioimmunoblastic T-cell lymphoma. Br J Haematol 2003; 121: 681-691 [Medline]

Dogan A, Ngu LS, Ng SH, Cervi PL. Pathology and clinical features of angioimmunoblastic T-cell lymphoma after successful treatment with thalidomide. Leukemia 2005; 19: 873-875 [Medline]

Dupuis J, Boye K, Martin N, Copie-Bergman C, Plonquet A, Fabiani B, et al. 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. Am J Surg Pathol 2006; 30: 490-494 [Medline]

Feller AC, Griesser H, Schilling CV, Wacker HH, Dallenbach F, Bartels H, et al. Clonal gene rearrangement patterns correlate with immunophenotype and clinical parameters in patients with angioimmunoblastic lymphadenopathy. Am J Pathol 1988; 133: 549-556 [Medline]

Foss HD, Anagnostopoulos I, Herbst H, Grebe M, Ziemann K, Hummel M, et al. Patterns of cytokine gene expression in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type. Blood 1995; 85: 2862-2869 [Medline]

Freter CE, Cossman J. Angioimmunoblastic lymphadenopathy with dysproteinemia. Semin Oncol 1993; 20: 627-635 [Medline]

Frizzera G, Moran EM, Rappaport H. Angio-immunoblastic lymphadenopathy with dysproteinaemia. Lancet 1974; 1: 1070-1073 [Medline]

Gallamini A, Stelitano C, Calvi R, Bellei M, Mattei D, Vitolo U, et al. Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study. Blood 2004; 103: 2474-2479 [Medline]

Gallamini A, Zaja F, Patti C, et al. Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL prospective multicentre trial. Blood 2007. In Press [Medline]

Grogg KL, Attygalle AD, Macon WR, Remstein ED, Kurtin PJ, Dogan A. Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells? Blood 2005; 106: 1501-1502 [Medline]

Hast R, Jacobsson B, Petrescu A, Hjalmar V. Successful treatment with fludarabine in two cases of angioimmunoblastic lymphadenopathy with dysproteinemia. Leuk Lymphoma 1999; 34: 597-601 [Medline]

Herman TS, Jones SE. Systematic re-staging in the management of non-Hodgkin’s lymphomas. Cancer Treat Rep 1977; 61: 1009-1015 [Medline]

Hsu SM, Waldron JAJ, Fink L, King C, Xie SS, Mansouri A, et al. Pathogenic significance of interleukin-6 in angioimmunoblastic lymphadenopathy-type T-cell lymphoma. Hum Pathol 1993; 24: 126-131 [Medline]

Jaffe ES, Harris NL, Stein H, Vardiman JW. Tumours of haematopoietic and lymphoid tissue. In: Jaffe ES, Harris, N.L., Stein, H., Vardiman, J.W., Editors. Pathology ‘amp; Genetics. Lyon: IRAC Press. 2001. p. 135-137. 2001 [Medline]

Jaffe ES. Angioimmunoblastic T-cell lymphoma: new insights, but the clinical challenge remains. Ann Oncol 1995; 6: 631-632 [Medline]

Kaneko Y, Maseki N, Sakurai M, Takayama S, Nanba K, Kikuchi M, et al. Characteristic karyotypic pattern in T-cell lymphoproliferative disorders with reactive “angioimmunoblastic lymphadenopathy with dysproteinemia-type” features. Blood 1988; 72: 413-421 [Medline]

Kanzaki Y, Eura M, Chikamatsu K, Yoshida M, Masuyama K, Nishimura H, et al. Angioimmunoblastic lymphadenopathy-like T-cell lymphoma. A case report and immunologic study. Auris Nasus Larynx 1997; 24: 199-206 [Medline]

Kanzaki Y, Eura M, Chikamatsu K, Yoshida M, Masuyama K, Nishimura H, et al. Angioimmunoblastic lymphadenopathy-like T-cell lymphoma. A case report and immunologic study. Auris Nasus Larynx 1997; 24: 199-206 [Medline]

Khan G, Norton AJ, Slavin G. Epstein-Barr virus in angioimmunoblastic T-cell lymphomas. Histopathology 1993; 22: 145-149 [Medline]

Kim CH, Lim HW, Kim JR, Rott L, Hillsamer P, Butcher EC. Unique gene expression program of human germinal center T helper cells. Blood 2004; 104: 1952-1960 [Medline]

Kon S, Sato T, Onodera K, Satoh M, Kikuchi K, Imai S, et al. Detection of Epstein-Barr virus DNA and EBV-determined nuclear antigen in angioimmunoblastic lymphadenopathy with dysproteinemia type T cell lymphoma. Pathol Res Pract 1993; 189: 1137-1144 [Medline]

Lee SS, Rudiger T, Odenwald T, Roth S, Starostik P, Muller-Hermelink HK. Angioimmunoblastic T cell lymphoma is derived from mature T-helper cells with varying expression and loss of detectable CD4. Int J Cancer 2003; 103: 12-20 [Medline]

Lennert K. Malignant lymphomas: other than Hodgkin’s disease: histology, cytology, ultrastructure, immunology. Berlin: Springer-Verlag. 1978 [Medline]

Lome-Maldonado C, Canioni D, Hermine O, Delabesse E, Damotte D, Raffoux E, et al. Angio-immunoblastic T cell lymphoma (AILD-TL) rich in large B cells and associated with Epstein-Barr virus infection. A different subtype of AILD-TL? Leukemia 2002; 16: 2134-2141 [Medline]

Lorenzen J, Li G, Zhao-Hohn M, Wintzer C, Fischer R, Hansmann ML. Angioimmunoblastic lymphadenopathy type of T-cell lymphoma and angioimmunoblastic lymphadenopathy: a clinicopathological and molecular biological study of 13 Chinese patients using polymerase chain reaction and paraffin-embedded tissues. Virchows Arch 1994; 424: 593-600 [Medline]

Luppi M, Torelli G. The new lymphotropic herpesviruses (HHV-6, HHV-7, HHV-8) and hepatitis C virus (HCV) in human lymphoproliferative diseases: an overview. Haematologica 1996; 81: 265-281 [Medline]

Nakamura S, Sasajima Y, Koshikawa T, Kitoh K, Koike K, Motoori T, et al. Angioimmunoblastic T-cell lymphoma (angioimmunoblastic lymphadenopathy with dysproteinemia [AILD]-type T-cell lymphoma) followed by Hodgkin’s disease associated with Epstein-Barr virus. Pathology International 1995; 45: 958-964 [Medline]

Nakamura S, Takagi N, Kitoh K, Koshikawa T, Hayashi K, Yamamoto K, et al. Peripheral T-cell lymphoma of AILD (angioimmunoblastic lymphadenopathy with dysproteinemia) type involving gastrointestinal tract. A morphologic, phenotypic and genotypic study. Acta Pathol Jpn 1992; 42: 141-149 [Medline]

Nathwani BN, Rappaport H, Moran EM, Pangalis GA, Kim H. Malignant lymphoma arising in angioimmunoblastic lymphadenopathy. Cancer 1978; 41: 578-606 [Medline]

Ohsaka A, Saito K, Sakai T, Mori S, Kobayashi Y, Amemiya Y, et al. Clinicopathologic and therapeutic aspects of angioimmunoblastic lymphadenopathy-related lesions. Cancer 1992; 69: 1259-1267 [Medline]

Ohshima K, Kikuchi M, Hashimoto M, Kozuru M, Uike N, Kobari S, et al. Genetic changes in atypical hyperplasia and lymphoma with angioimmunoblastic lymphadenopathy and dysproteinaemia in the same patients. Virchows Arch 1994b; 425: 25-32 [Medline]

Ohshima K, Takeo H, Kikuchi M, Kozuru M, Uike N, Masuda Y, et al. Heterogeneity of Epstein-Barr virus infection in angioimmunoblastic lymphadenopathy type T-cell lymphoma. Histopathology 1994a; 25: 569-579 [Medline]

Ong ST, Koeppen H, Larson RA, Olopade OI. Successful treatment of angioimmunoblastic lymphadenopathy with dysproteinemia with fludarabine. Blood 1996; 88: 2354-2355 [Medline]

Patsouris E, Noel H, Lennert K. Angioimmunoblastic lymphadenopathy–type of T-cell lymphoma with a high content of epithelioid cells. Histopathology and comparison with lymphoepithelioid cell lymphoma. Am J Surg Pathol 1989; 13: 262-275 [Medline]

Pautier P, Devidas A, Delmer A, Dombret H, Sutton L, Zini JM, et al. Angioimmunoblastic-like T-cell non Hodgkin’s lymphoma: outcome after chemotherapy in 33 patients and review of the literature. Leuk Lymphoma 1999; 32: 545-552 [Medline]

Piccaluga PP, Agostinelli C, Califano A, Carbone A, Fantoni L, Ferrari S, et al. Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. Cancer Res 2007; 67: 10703-10710 [Medline]

Piccaluga PP, Agostinelli C, Righi S, Zinzani PL, Pileri SA. Expression of CD52 in peripheral T-cell lymphoma. Haematologica 2007; 92: 566-567 [Medline]

Plank L, Hansmann ML, Fischer R. Monocytoid B-cell reaction associated with peripheral T-cell lymphomas. Pathol Res Pract 1995; 191: 1152-1158 [Medline]

Quintini G, Iannitto E, Barbera V, Turri D, Franco V, Florena AM, et al. Response to low-dose oral methotrexate and prednisone in two patients with angio-immunoblastic lymphadenopathy-type T-cell lymphoma. Hematol J 2001; 2: 393-395 [Medline]

Ree HJ, Kadin ME, Kikuchi M, Ko YH, Go JH, Suzumiya J, et al. Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers. Am J Surg Pathol 1998; 22: 643-655 [Medline]

Rodig SJ, Abramson JS, Pinkus GS, Treon SP, Dorfman DM, Dong HY, et al. Heterogeneous CD52 expression among hematologic neoplasms: implications for the use of alemtuzumab (CAMPATH-1H). Clin Cancer Res 2006; 12: 7174-7179 [Medline]

Roncador G, Garcia Verdes-Montenegro JF, Tedoldi S, Paterson JC, Klapper W, Ballabio E, et al. Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma. Haematologica 2007; 92: 1059-1066 [Medline]

Rosenberg SA. Validity of the Ann Arbor staging classification for the non-Hodgkin’s lymphomas. Cancer Treat Rep 1977; 61: 1023-1027 [Medline]

Rudiger T, Weisenburger DD, Anderson JR, Armitage JO, Diebold J, MacLennan KA, et al. Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin’s Lymphoma Classification Project. Ann Oncol 2002; 13: 140-149 [Medline]

Sallah AS, Bernard S. Treatment of angioimmunoblastic lymphadenopathy with dysproteinemia using 2-chlorodeoxyadenosine. Ann Hematol 1996; 73: 295-296 [Medline]

Schetelig J, Fetscher S, Reichle A, Berdel WE, Beguin Y, Brunet S, et al. Long-term disease-free survival in patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation. Haematologica 2003; 88: 1272-1278 [Medline]

Schlegelberger B, Feller A, Himmler A, Grote W. Inv(14)(q11q32) in one of four different clones in a case of angioimmunoblastic lymphadenopathy. Cancer Genet Cytogenet 1990a; 44: 77-81 [Medline]

Schlegelberger B, Nolle I, Feller AC, Bauer E, Grote W. Angioimmunoblastic lymphadenopathy with trisomy 3: the cells of the malignant clone are T cells. Hematol Pathol 1990b; 4: 179-183 [Medline]

Schlegelberger B, Zwingers T, Hohenadel K, Henne-Bruns D, Schmitz N, Haferlach T, et al. Significance of cytogenetic findings for the clinical outcome in patients with T-cell lymphoma of angioimmunoblastic lymphadenopathy type. J Clin Oncol 1996; 14: 593-599 [Medline]

Schmitz N, Prange E, Haferlach T, Griesser H, Sonnen R, Schlegelberger B, et al. High-dose chemotherapy and autologous bone marrow transplantation in relapsing angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). Bone Marrow Transplant 1991; 8: 503-506 [Medline]

Shipp MA. Prognostic factors in aggressive non-Hodgkin’s lymphoma: who has “high-risk” disease?. Blood 1994; 83: 1165-1173 [Medline]

Siegert W, Agthe A, Griesser H, Schwerdtfeger R, Brittinger G, Engelhard M, et al. Treatment of angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma using prednisone with or without the COPBLAM/IMVP-16 regimen. A multicenter study. Kiel Lymphoma Study Group. Ann Intern Med 1992; 117: 364-370 [Medline]

Siegert W, Nerl C, Agthe A, Engelhard M, Brittinger G, Tiemann M, et al. Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation. The Kiel Lymphoma Study Group. Ann Oncol 1995; 6: 659-664 [Medline]

Siegert W, Nerl C, Meuthen I, Zahn T, Brack N, Lennert K, et al. Recombinant human interferon-alpha in the treatment of angioimmunoblastic lymphadenopathy: results in 12 patients. Leukemia 1991; 5: 892-895 [Medline]

Smith JL, Hodges E, Quin CT, McCarthy KP, Wright DH. Frequent T and B cell oligoclones in histologically and immunophenotypically characterized angioimmunoblastic lymphadenopathy. Am J Pathol 2000; 156: 661-669 [Medline]

Strupp C, Aivado M, Germing U, Gattermann N, Haas R. Angioimmunoblastic lymphadenopathy (AILD) may respond to thalidomide treatment: two case reports. Leuk Lymphoma 2002; 43: 133-137 [Medline]

Suchi T, Lennert K, Tu LY, Kikuchi M, Sato E, Stansfeld AG, et al. Histopathology and immunohistochemistry of peripheral T cell lymphomas: a proposal for their classification. J Clin Pathol 1987; 40: 995-1015 [Medline]

Takemori N, Kodaira J, Toyoshima N, Sato T, Sakurai H, Akakura N, et al. Successful treatment of immunoblastic lymphadenopathy-like T-cell lymphoma with cyclosporin A. Leuk Lymphoma 1999; 35: 389-395 [Medline]

Tan BT, Warnke RA, Arber DA. The frequency of B- and T-cell gene rearrangements and epstein-barr virus in T-cell lymphomas: a comparison between angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified with and without associated B-cell proliferations. J Mol Diagn 2006; 8: 466-475 [Medline]

Tsatalas C, Margaritis D, Kaloutsi V, Martinis G, Kotsianidis I, Bourikas G. Successful treatment of angioimmunoblastic lymphadenopathy with dysproteinemia-type T-cell lymphoma with fludarabine. Acta Haematol 2001; 105: 106-108 [Medline]

Tsuchiya T, Ohshima K, Karube K, Yamaguchi T, Suefuji H, Hamasaki M, et al. Th1, Th2, and activated T-cell marker and clinical prognosis in peripheral T-cell lymphoma, unspecified: comparison with AILD, ALCL, lymphoblastic lymphoma, and ATLL. Blood 2004; 103: 236-241 [Medline]

Weiss LM, Jaffe ES, Liu XF, Chen YY, Shibata D, Medeiros LJ. Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma. Blood 1992; 79: 1789-1795 [Medline]

Weiss LM, Strickler JG, Dorfman RF, Horning SJ, Warnke RA, Sklar J. Clonal T-cell populations in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma. Am J Pathol 1986; 122: 392-397 [Medline]

Went P, Agostinelli C, Gallamini A, Piccaluga PP, Ascani S, Sabattini E, et al. Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol 2006; 24: 2472-2479 [Medline]

Willenbrock K, Renne C, Gaulard P, Hansmann ML. In angioimmunoblastic T-cell lymphoma, neoplastic T cells may be a minor cell population. A molecular single-cell and immunohistochemical study. Virchows Arch 2005; 446: 15-20 [Medline]

Willenbrock K, Roers A, Seidl C, Wacker HH, Kuppers R, Hansmann ML. 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. Am J Pathol 2001; 158: 1851-1857 [Medline]

Younes A. Cytogenetic findings in T-cell lymphoma of angioimmunoblastic lymphadenopathy. J Clin Oncol 1996; 14: 2188-2189 [Medline]

Yu RC, Schofield J, Alaibac M, Jones RR, Chu AC. Angioimmunoblastic lymphadenopathy with dysproteinemia and dermal T- cell lymphoma. Cancer 1994; 74: 1801-1807 [Medline]

Yuan CM, Vergilio JA, Zhao XF, Smith TK, Harris NL, Bagg A. CD10 and BCL6 expression in the diagnosis of angioimmunoblastic T-cell lymphoma: utility of detecting CD10+ T cells by flow cytometry. Hum Pathol 2005; 36: 784-791 [Medline]

Zhao WL, Mourah S, Mounier N, Leboeuf C, Daneshpouy ME, Legres L, et al. Vascular endothelial growth factor-A is expressed both on lymphoma cells and endothelial cells in angioimmunoblastic T-cell lymphoma and related to lymphoma progression. Lab Invest 2004; 84: 1512-1519 [Medline]

Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy

Dr. Emilio Iannitto (Author)
University of Palermo – Italy

Prof. Hans Kreipe (Reviewer)
Medizinischen Hochschule – Hannover, Germany
mail: Kreipe.Hans@MH-Hannover.DE