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Keywords:

  • angioimmunoblastic;
  • peripheral T-cell lymphoma;
  • follicular helper T cell;
  • pathobiology;
  • pathology;
  • treatment

Summary

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Clinical features
  5. Morphology and immunophenotype
  6. Molecular and genetic features
  7. Pathogenesis of AITL ()
  8. Issues in diagnosis and differential diagnosis
  9. Natural history and prognostic factors
  10. Therapeutic options
  11. Acknowledgement
  12. References

Angioimmunoblastic T-cell lymphoma (AITL) is a distinct peripheral T-cell lymphoma (PTCL) entity with peculiar clinical and pathological features. The recent identification of follicular helper T (TFH) cell as the cell of origin of this neoplasm represents a major step in our understanding of the pathobiological characteristics of the disease and should, in the future, clarify the diagnostic criteria for AITL and help to delineate its spectrum, especially from PTCL, not otherwise specified (PTCL, NOS). Deciphering the pathogenesis of the disease is needed to identify targets for new therapies that are expected to improve the poor outcome of AITL patients, when treated with conventional chemotherapy regimens. In this respect, efforts will be needed to evaluate promising innovative therapies in prospective clinical trials.


Historical perspective

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Clinical features
  5. Morphology and immunophenotype
  6. Molecular and genetic features
  7. Pathogenesis of AITL ()
  8. Issues in diagnosis and differential diagnosis
  9. Natural history and prognostic factors
  10. Therapeutic options
  11. Acknowledgement
  12. References

Angioimmunoblastic T-cell lymphoma (AITL) originally described in the 1970s as ‘angioimmunoblastic lymphadenopathy (AILD) with dysproteinaemia’(Frizzera et al, 1974), ‘immunoblastic lymphadenopathy’(Lukes & Tindle, 1975) or ‘lymphogranulomatosis X’.(Lennert, 1979), was initially reported as a non-neoplastic lymphoproliferation and believed to represent an abnormal ‘hyperimmune’ reaction of the B-cell system or an atypical lymphoid process, despite a clinical course characterized by multiple relapses and a fatal outcome in the majority of patients (Lukes & Tindle, 1975). Subsequently, the observation of morphological features of malignancy in cases with features of AILD, led to the designation ‘immunoblastic T-cell lymphoma’ (Shimoyama & Minato, 1979). In addition, later in the 1980s, the identification of clonal cytogenetic abnormalities and of clonal T-cell receptor (TCR) gene rearrangements definitively established the neoplastic nature of the disease (Weiss et al, 1986; Feller et al, 1988; Kaneko et al, 1988; Tobinai et al, 1988).

Thereafter, AITL was recognized as one of the most common forms of peripheral T-cell lymphoma (PTCL) in the REAL (revised European-American classification of lymphoid neoplasms) and World Health Organization classifications of haematological malignancies (Harris et al, 1994; Jaffe et al, 2001; Swerdlow et al, 2008). According to a recent survey, AITL represents the second most common form of PTCL, accounting for 18·5% of the cases worldwide. Interestingly, the disease is more common in Europe (representing 29% of cases) than in North America or Asia, where its prevalence is estimated at 16% and 18% of cases respectively (Rudiger et al, 2002; Armitage et al, 2008). This heterogenous geographic distribution might in part be explained by the overall low prevalence of T-cell neoplasms in western countries and a relative overrepresentation of other Natural Killer/T-cell lymphoma types in Asia, but true differences might exist. Yet, no risk factors or aetiological agent(s) have been identified, and no racial predisposition is recognized.

Clinical features

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Clinical features
  5. Morphology and immunophenotype
  6. Molecular and genetic features
  7. Pathogenesis of AITL ()
  8. Issues in diagnosis and differential diagnosis
  9. Natural history and prognostic factors
  10. Therapeutic options
  11. Acknowledgement
  12. References

AITL affects elderly adults in their 6th or 7th decades, at a median age ranging from 59 to 65 years in published series (Armitage et al, 2008; Mourad et al, 2008). A slight or marked male predominance is repeatedly reported. AITL is unique among lymphomas with respect to its peculiar clinical features. In typical cases, AITL presents as a subacute or acute systemic illness, which may manifest after administration of drugs (especially antibiotics) or after a viral infection. Several reports also mentioned an association with various bacterial or fungal infections, probably reflecting the consequences of immune deregulation in AITL patients, rather than a causal relationship. Generalized lymphadenopathy is almost constant, often accompanied by constitutional symptoms such as fever and weight loss (Frizzera et al, 1975). Lymph node enlargement is often mild to moderate (<1–3 cm), and usually affects peripheral drainage areas (Pautier et al, 1999; Lachenal et al, 2007). A high proportion of patients have hepatomegaly and/or splenomegaly. Bone marrow involvement has been reported in up to 70% of the cases and tends to correlate with a higher frequency of B symptoms, hepatosplenomegaly, laboratory abnormalities and with the presence of circulating tumour cells (Cho et al, 2009). Up to half of the patients have skin rash – either generalized or a predominantly truncular maculopapular eruption mimicking an inflammatory dermatosis – and/or pruritus, prior to or concurrent with the diagnosis of lymphoma, or at relapse. Nodular lesions, plaques, purpura and urticarial lesions can also be seen (Martel et al, 2000). Other clinical signs and symptoms (arthralgias or arthritis, pleural effusions, ascitis and/or oedema, lung involvement, neurological manifestations, gastrointestinal involvement) are less common, with a wide variation in their reported frequency (Table I) (Bradley et al, 1981; Kaneki et al, 1999; Tsochatzis et al, 2005; Kang et al, 2007; Lachenal, 2007; Mourad et al, 2008). Overall, most patients have concomitant extranodal disease, and the disease is stage III or IV in more than 80% of cases.

Table I.   Frequency of clinical and laboratory features in AITL patients. The data are summarized from 12 clinical series published between 1975 and 2009, comprising each 19–157 patients (total 670 subjects)(Frizzera et al, 1975; Kaneko et al, 1988; Tobinai et al, 1988 ; Patsouris et al, 1989; Nakamura & Suchi, 1991; Siegert et al, 1995 ; Ascani et al, 1997; Pautier et al, 1999; Lachenal et al, 2007; Mourad et al, 2008; Niitsu et al, 2008; Cho et al, 2009) Not all parameters were recorded for each patient.
  1. IPI, International Prognostic Index.

  2. *X-ray patterns showing diffuse patchy infiltrates or interstitial pneumonie.

  3. †various manifestatiosn reported: confusion, polyneuritis, loss of hearing or vision, apathy, regressive hemiparesis, cerebellar syndrome, tinnitus, aphasia.

  4. ‡lesions consist of mucosal ulcers which may resemble those of Crohn’s disease or tuberculous colitis, and manifest as bleeding and diarrhoea.

Sex ratio (male to female)0·7–6/1
Median age57–68 years
General clinical features
 Advanced stage (III/IV)68–94%
 Lactate dehydrogenase > normal46–86%
 Performance status > 140–57%
 B symptoms52–86%
 Bulky mass5–26%
 High-risk IPI (4–5)38%
Organ involvement
 Generalized lymphadenopathy84–100%
 Bone marrow involvement12–70%
 Hepatomegaly25–83%
 Splenomegaly51–73%
 Skin rash38–58%
 Effusion/oedema/ascites25–53%
 Polyarthritis/arthralgias16–18%
 Lung involvement*10%
 Neurological manifestations†10%
 Gastrointestinal involvement‡Rare
Laboratory tests
 Anaemia40–88%
 Positive Coombs’ test32–75%
 Lymphopenia17–52%
 Thrombocytopenia9–20%
 Hypereosinophilia32–50%
 Hypergammaglobulinaemia50–83%

Laboratory tests often disclose a variety of haematological, biochemical and/or immunological abnormalities. Anaemia (often haemolytic and Coombs-positive), polyclonal hypergammaglobulinaemia and hypereosinophilia are the most common alterations seen at diagnosis. Other common findings include lymphopenia, thrombocytopenia, and the presence of various autoantibodies (rheumatoid factor, anti-nuclear factor, anti-smooth muscle…), cryoglobulins or cold agglutinins.

Peripheral blood leucocytosis with lymphocytosis is rare; however, careful examination of blood smears can reveal a small population of atypical lymphoid cells in many patients, the presence of which is highlighted by flow cytometry disclosing an aberrant cell surface immunophenotype (most commonly CD10+ and/or sCD3 or dim, see below) (Baseggio et al, 2006).

Morphology and immunophenotype

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Clinical features
  5. Morphology and immunophenotype
  6. Molecular and genetic features
  7. Pathogenesis of AITL ()
  8. Issues in diagnosis and differential diagnosis
  9. Natural history and prognostic factors
  10. Therapeutic options
  11. Acknowledgement
  12. References

Lymph node involvement

In lymph nodes, AITL displays distinctive pathological features that may be categorized according to three overlapping architectural patterns, as described by Attygalle et al (2002). In typical cases (pattern III, AITL without follicles), AITL is characterized by complete loss of architecture, often with capsular and perinodal infiltration sparing the peripheral sinus, and absence of residual B-cell follicles (Fig 1A). The hallmark features of AITL are: (i) a diffuse polymorphous infiltrate including variable proportions of atypical neoplastic T cells, admixed with small lymphocytes, histiocytes or epithelioid cells, immunoblasts, eosinophils and plasma cells, (ii) prominent branching high endothelial venules, and (iii) irregular proliferation of follicular dendritic cells (FDCs) (Fig 1B–D).

image

Figure 1.  Typical morphology of angioimmunoblastic T-cell lymphoma. (A) Lymph node involvement characterized by a diffuse proliferation (pattern III) extending over the open peripheral sinus (original magnification ×25). (B) High magnification showing a polymorphous infiltrate including neoplastic clear cells in association with an abundant vasculature (original magnification ×200). (C) Follicular dendritic cell (FDC) proliferation appears as pale perivascular areas on haematoxylin and eosin sections (original magnification ×100). (D) CD21 immunostaining highlights perivascular FDC proliferation (original magnification ×200).

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The lymphoma cells are medium-sized cells with round or slightly irregular nuclei, abundant clear cytoplasm and tend to form small clusters around high endothelial venules (Willenbrock et al, 2005). In less typical cases, the neoplastic cells are smaller with only slight pleomorphism and atypia, and without striking clear cell components. These are mature αβ CD4+CD8 T-cells, which frequently show aberrant loss or reduced expression of CD7, surface CD3 and/or CD4 and may show partial CD30 expression in up to one-third of the cases (Willenbrock et al, 2001; Lee et al, 2003; Stacchini et al, 2007; Karube et al, 2008). The tumour cells are often outnumbered by reactive T cells, and usually the ratio of CD4 to CD8-positive cells is preserved (Merchant et al, 2006). Aberrant expression of CD10 by the neoplastic cells (Fig 2A) is observed in around 80% of the cases, but is often heterogeneous (detected on an often minor subset of the tumour cells, and of variable intensity) (Attygalle et al, 2002, 2007a; Yuan et al, 2005; Dorfman et al, 2006; Karube et al, 2008; Mourad et al, 2008). Since minor populations of CD3+/CD10+ have been detected in normal lymph nodes, the specificity and threshold for abnormal CD10+ T-cell populations remains, however, to be clarified (Cook et al, 2003; Dupuis et al, 2006; Stacchini et al, 2007). AITL tumour cells express several markers of follicular helper T cells (TFH), normally located in the light zone of reactive germinal centres (Fig 2B–D) (Vinuesa et al, 2005). Strikingly, cytoplasmic expression of the CXCL13 chemokine, a specific marker of normal TFH cells, is expressed in the neoplastic cells of virtually all AITL cases (Grogg et al, 2005; Dupuis et al, 2006). Additional TFH markers that have been demonstrated in AITL by immunohistochemistry include the cell surface molecules CXCR5, CD154, programmed death-1 (PD-1) (a member of the CD28 costimulatory receptor family resulting in negative regulation of T-cell activity), inducible costimulator (ICOS) (a CD28 homologue with costimulatory function in T-cell activation and expansion) and cytoplasmic SAP (SLAM-associated protein) (Dorfman et al, 2006; Krenacs et al, 2006; Roncador et al, 2007; Xerri et al, 2008; Rodriguez-Justo et al, 2009; Yu et al, 2009). Expression of BCL6, a transcription factor characteristic of the TFH subset of CD4+ cells, is another phenotypic marker of AITL tumour cells (Ree et al, 1999; Yuan et al, 2005). On tissue sections the distribution and intensity of the immunostains observed for the different TFH markers tend to correlate and, similar to CD10, show a relationship to the FDC meshwork. For diagnostic purposes, CXCL13, PD1, ICOS and BCL6 currently represent the most useful and robust immunohistochemical TFH markers.

image

Figure 2.  Immunohistochemical features of angioimmunoblastic T-cell lymphoma. (A) CD10 immunostaining typically produces variable membrane positivity in a subset of neoplastic cells. (B) In this case most tumour cells exhibit nuclear BCL6 staining. (C) CXCL13 usually produces intense cytoplasmic staining of most tumour cells. (D) PD1 is positive in most neoplastic cells. Panels A–D, immunoperoxidase, original magnification ×400.

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Expanded FDC meshworks, typically associated with vessels, can be seen by morphology alone when prominent and are best highlighted by immunohistochemistry using classical FDC markers (CD21, CD23, CNA.42 and/or CD35), among which CD21 appears to be the most sensitive (Fig 1D).(Leung et al, 1993; Troxell et al, 2005).

Varying numbers of small B cells and polytypical plasma cells are distributed randomly in single cells or as small clusters in association with FDC aggregates. In addition, a population of large B-blasts, which may sometimes mimic Reed-Sternberg cells, usually infected by Epstein-Barr virus (EBV), is almost invariably present (Anagnostopoulos et al, 1992; Weiss et al, 1992).

Morphological variants.  Besides the most common pattern III, two other patterns are recognized (Attygalle et al, 2002). In pattern I (AITL with hyperplastic follicles), the lymph node has a partially preserved architecture and contains hyperplastic follicles with poorly developed mantles, merging into the paracortex expanded by a polymorphous infiltrate that often comprises inconspicuous neoplastic cells, which tend to distribute around the follicles (Fig 3A) (Ree et al, 1998). In pattern II (AITL with depleted follicles) occasional depleted follicles are present (Fig 3B). In contrast with pattern III, FDC are normal or only minimally increased in patterns I and II (Attygalle et al, 2002). Patterns I to III have been documented in consecutive biopsies and are thought to represent progressive stages of the disease and to reflect morphological evolution rather than clinical progression, as patients with pattern I usually show advanced stage disease (Ree et al, 1998; Attygalle et al, 2002, 2007b; Rodriguez-Justo et al, 2009).

image

Figure 3.  Morphological variants of angioimmunoblastic T-cell lymphoma. (A) AITL pattern I showing a reactive hyperplastic follicle with an attenuated mantle zone and surrounded by a rim of neoplastic clear cells (original magnification ×100). (B) AITL pattern II showing an infiltrate of small neoplastic cells around a regressive (Castleman-like) follicle (original magnification ×100). (C) AITL rich in clear cells (original magnification ×400). (D) Epithelioid variant of AITL comprising an abundant histiocytic background (original magnification ×200). (E) AITL rich in B-cell blasts highlighted by CD20 immunostaining and (F) showing EBV infection (EBER in situ hybridization) (original magnification ×400).

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Other morphological variants are described according to cell content. The clear cell-rich variant of AITL designates a subset of cases comprising an overt lymphomatous proliferation of sheets of ‘clear’ neoplastic cells (Fig 3C) (Merchant et al, 2006). The epithelioid variant of AITL is characterized by a high content of epithelioid cells in small, poorly defined clusters (Fig 3D) (Patsouris et al, 1989). A subset of AITL contain a high proportion of large B-cell blasts (>25%) (B-cell-rich AITL), which are usually but not always infected by EBV (Fig 3E–F). In some cases, the proliferation of EBV-positive B-cell blasts may be so prominent that they form diffuse confluent sheets; in these cases a diagnosis of EBV-positive lymphoproliferation or EBV-positive diffuse large B-cell lymphoma may be rendered. This complication occurs most commonly during the evolution of the disease, but more rarely can be the presenting histological picture. EBV-negative large B-cell lymphoma or plasma cell proliferations can also occur occasionally (Zettl et al, 2002; Attygalle et al, 2007b; Willenbrock et al, 2007).

Extranodal organs.  Bone marrow involvement is often subtle, appearing as small single or multiple nodular or interstitial foci of infiltration in a paratrabecular or non-paratrabecular distribution. The infiltrates have a mixed composition of T and B cells, including atypical clear cells and are associated with blood vessel proliferation. Massive tumour replacement of hematopoietic tissues is exceptional (Sakai et al, 2007). In addition, secondary reactive marrow changes (polyclonal plasmacytosis, erythroid hyperplasia, eosinophilia, myelofibrosis, or haematophagocytosis) are frequently observed. They may obscure the lymphomatous foci and be misdiagnosed as other proliferative or reactive haematopoietic conditions (Grogg et al, 2007; Cho et al, 2009).

Different histopathological aspects can be seen in skin biopsies, ranging from subtle non-specific mild perivascular lymphocytic infiltrate to, more rarely, an overtly lymphomatous infiltration (Martel et al, 2000; Ortonne et al, 2007). In most instances, eosinophils, vascular hyperplasia and large immunoblasts are not obvious. EBV-positive cells are rarely demonstrated (Martel et al, 2000; Brown et al, 2001). A florid epithelioid or granulomatous reaction has been described in occasional cases, which may mimic sarcoidosis or an infectious process (Scarabello et al, 2002; Suarez-Vilela & Izquierdo-Garcia, 2003; Pujol et al, 2005; Jayaraman et al, 2006).

The distribution of the atypical lymphoid infiltrates in other organs is less well characterized. Tonsillar involvement may be subtle with preservation of reactive follicles, and may be difficult to demonstrate. Spleen involvement occurs in the form of nodules in the white and/or the red pulp. Not all symptomatic manifestations may result from direct tumour infiltration, for example, effusions are usually non-neoplastic in nature and their cause is poorly understood.

Molecular and genetic features

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Clinical features
  5. Morphology and immunophenotype
  6. Molecular and genetic features
  7. Pathogenesis of AITL ()
  8. Issues in diagnosis and differential diagnosis
  9. Natural history and prognostic factors
  10. Therapeutic options
  11. Acknowledgement
  12. References

Clonality analysis

The largest published molecular studies of clonality analysis of the T-cell receptor (TCR) and immunoglobulin (IG) genes in AITL are summarized in Table II (Weiss et al, 1986; Willenbrock et al, 2001; Attygalle et al, 2002, 2007a; Vrsalovic et al, 2004; Kawano et al, 2005; Tan et al, 2006; Bruggemann et al, 2007). Using sensitive polymerase chain reaction (PCR) techniques, the detection of monoclonal or oligoclonal rearrangement of the TCR is found in the vast majority of cases (95% in the series reported by the Biomed-2 consortium using multiplex strategies targeting TRB@, TRG@ and TRD@). In one recent study, sequence analysis of the rearranged TRB genes showed overrepresentation of the BV17S1 family compared to the use of other TRBV segments (Shah et al, 2009).

Table II.   Clonality studies in AITL.
StudyMethodPatients (n)Source of DNATCR clonalityBCR clonality
  1. F, frozen; FFPE, formalin-fixed paraffin-embedded; SB, Southern blotting; PCR, polymerase chain reaction.

  2. °Biomed-2 primers.

  3. *Includes oligoclonal and clonal patterns.

Weiss et al (1986)SB10F tissue8/10 (80%)0/10 (0%)
Feller et al (1988)SB24F tissue24/24 (100%)7/24 (29%)
Tobinai et al (1988)SB10F tissue8/10 (80%)0/10 (0%)
Kawano et al (2005)SB59F tissue15/50 (30%)2/50 (4%)
Smith et al (2000)PCR22FFPE tissue19/22* (TRB@ +TRG@) (86%)9/22 (CDR2-IGH) (41%)
Willenbrock et al (2001)PCR18FFPE or F tissue12/18 (TRB@) (66%)1/13 (CDR3-IGH) (8%)
Attygalle et al (2002)PCR30FFPE tissue29/30* (TRG@) (97%)6/30* (CDR3-IGH) (20%)
Vrsalovic et al (2004)PCR18FFPE tissue12/18 (TRG@) (66%)3/18 (CDR3-IGH) (17%)
Attygalle et al (2007a)PCR87FFPE tissue78/87* (TRG@) (90%)14/73* (CDR3-IGH) (19%)
Tan et al (2006)PCR°58FFPE tissue45/58 (TRG@) (78%)19/56 (IGH) (34%)
Bruggemann et al (2007)PCR°37F tissue33/37 (TRB@) (89%)11/37 (IGH) (30%)
34/37 (TRG@) (92%)11/37 (IGK) (30%)
13/37 (TRD@) (35%)2/37 (IGL) (5%)
35/37 (all TCR loci) (95%)12/37 (all IG loci) (32%)

In addition to TCR rearrangements, a clonal or oligoclonal rearrangement of the IG gene(s) is also found in up to one-third of patients. B-cell clonality tends to be evidenced in cases comprising increased numbers of B-cell blasts (Brauninger et al, 2001; Lome-Maldonado et al, 2002; Tan et al, 2006). Intriguingly, most EBV-infected B cells show ongoing mutational activity while carrying hypermutated IG genes with destructive mutations, suggesting that in AITL alternative pathways operate to allow the survival of these mutating « forbidden » (Ig-deficient) B cells (Brauninger et al, 2001).

Genetic features

By conventional cytogenetics, clonal aberrations are detected in up to 90% of the cases [reviewed in (de Leval et al, 2009)]. The most common recurrent abnormalities are trisomies of chromosomes 3, 5 and 21, gain of X and loss of 6q (Kaneko et al, 1988; Dogan et al, 2003; Nelson et al, 2008). Specific chromosomal abnormalities do not seem to be associated with survival, but complex karyotypes adversely impact the outcome (Schlegelberger et al, 1996; Nelson et al, 2008). Genetic heterogeneity manifested by unrelated clonal and non-clonal abnormalities in the same patient has been reported, possibly reflective of genetic instability (Schlegelberger et al, 1990), and also perhaps linked to genetic alterations in the EBV-positive B-cell blasts (Dogan et al, 2003). Intriguingly, whereas a high frequency of chromosomal imbalances was confirmed by matrix-based comparative genomic hybridization in a series of 39 AITL, with gains identified more commonly than losses, there was little overlap with classical cytogenetic data: trisomies 3 and 5 were infrequent and the most frequent gains were of 22q, 19 and 11p11-q14 and losses of 13q (Thorns et al, 2007).

Chromosomal breakpoints affecting the T-cell receptor gene loci are extremely rare (one of 54 AITLs analyzed in two recent studies using fluorescence in situ hybridization) (Gesk et al, 2003; Leich et al, 2007). The molecular alterations underlying the neoplastic transformation remain unknown. Mutations of TP53 are infrequent, and mutations in the 5′ region of BCL6 have not been detected (Kerl et al, 2001). A role for the c-maf transcription factor has been suggested, because its overexpression in transgenic mice induces the development of T-cell lymphomas, and high levels of c-maf have been detected in human AITL tissues (Murakami et al, 2007).

Gene expression signature

Critical insights into the understanding of AITL have been gained from recent molecular profiling analyses (de Leval et al, 2007; Piccaluga et al, 2007). In our study we firstly defined the global molecular signature of AITL in comparison to that of PTCL, NOS and secondly, given the availability of sorted tumour cell suspensions for profiling, distinguished the respective contributions of the tumour and non-tumour cells to the AITL signature (de Leval et al, 2007). In accordance with the known pathological features, the AITL molecular profile was dominated by a strong microenvironment imprint, including overexpression of B-cell- and FDC-related genes, chemokines and chemokine receptors, and genes related to extracellular matrix and vascular biology. Interestingly, the signature contributed by the neoplastic cells, albeit quantitatively minor, was enriched in genes normally expressed by TFH cells (Fig 4). This demonstration of molecular similarities between AITL tumour cells and TFH cells at a genome-wide level definitively established the cellular derivation of AITL from TFH cells, initially suspected on the basis of expression of single TFH markers in AITL tumour cells, in particular the CXCL13 chemokine (Grogg et al, 2005, 2006; Dupuis et al, 2006; Ortonne et al, 2007).

image

Figure 4.  Molecular signatures of AITL and PTCL, NOS by gene expression profiling analysis (adapted from (de Leval et al, 2007)). Expression data from two normal TFH cell populations, 2 AITL tumour cell suspension samples (arrows), 17 AITL tissue samples and 16 PTCL, NOS samples are shown. The genes represented in this heatmap include a set of 42 core genes representative of normal TFH cells, overexpressed in AITL (by comparison to PTCL, NOS) and overrepresented in sorted AITL tumour cells (arrows) in comparison to AITL tissues (as demonstrated by gene set enrichment analyses). Standardized expression ranges from −2·0 (blue) to 2·0 (red). This research was originally published in Blood. de Leval, L., Rickman, D.S., Thielen, C., Reynies, A., Huang, Y.L., Delsol, G., Lamant, L., Leroy, K., Briere, J., Molina, T., Berger, F., Gisselbrecht, C., Xerri, L. & Gaulard, P. 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. ©the American Society of Haematology.

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Pathogenesis of AITL (Fig 5)

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Clinical features
  5. Morphology and immunophenotype
  6. Molecular and genetic features
  7. Pathogenesis of AITL ()
  8. Issues in diagnosis and differential diagnosis
  9. Natural history and prognostic factors
  10. Therapeutic options
  11. Acknowledgement
  12. References
image

Figure 5.  Pathogenetic model of angioimmunoblastic T-cell lymphoma. In AITL, a complex network of interactions take place between the tumour cells and the various cellular components of the reactive microenvironment, the molecular mediators of which are partly deciphered. Different factors released by TFH cells are involved in B-cell recruitment, activation and differentiation (CXCL13), in the modulation of other T-cell subsets (IL21, IL10, TFGβ), or in promoting vascular proliferation (VEGF), and may also act as autocrine factors. EBV reactivation occurs in the context of a deregulated immune response, which also favours the expansion of both TFH cells and B cells. TGFβ is a mediator of FDC differentiation and proliferation, and FDC in turn are a source of CXCL13 and VEGF. B, B-cell; FDC, follicular dendritic cell; HEV, high endothelial venule; PC, plasma cell; TFH, follicular helper T cell.

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A tumour of follicular helper T cells

TFH cells constitute a minor subset of effector T cells with a specific microanatomic distribution and distinct gene signature and functions separable from the other known Th1, Th2, Th17 effector subsets (Vinuesa et al, 2005; Fazilleau et al, 2009). The cellular derivation of AITL from these TFH cells provides a rational model to explain several of the peculiar pathological and biological features inherent to this disease, i.e. the expansion of B cells, the intimate association with germinal centres in early disease stages and the striking proliferation of FDCs. Among the molecular mediators of TFH cells, CXCL13 probably plays a major role. This chemokine, critical in B-cell recruitment into germinal centres and for B-cell activation, probably promotes B-cell expansion, plasmacytic differentiation and hypergammaglobulinaemia. Interleukin (IL)-21, a TFH cytokine with important roles in germinal centre development and B-cell differentiation to Ig-producing cells, as well as in TFH development through an autocrine mechanism, might also contribute to several features of AITL (Fazilleau et al, 2009). New future insights in the precise functions of the network of mediators involved in the generation of TFH cells and their role in the immune system will certainly contribute to the better understanding of the pathogenesis of AITL.

Tumour microenvironment: functional alterations in AITL

Non-neoplastic cells typically represent a quantitatively major component of AITL and clinically, the manifestations of the disease mostly reflect a deregulated immune and/or inflammatory response rather than direct complications of tumour growth (Mourad et al, 2008), supporting the concept of a paraneoplastic immunological dysfunction. Moreover, AITL patients have defective T-cell responses, linked to both quantitative and qualitative perturbations of T-cell subsets (Pizzolo et al, 1987). Interestingly, normal TFH cells can suppress T-cell responses by inhibiting the proliferation and function of conventional CD4 T cells, especially through transforming growth factor-β (TGF-β) and IL-10 production (Marinova et al, 2007). The complex pathways and networks and the mediators linking the various cellular non-neoplastic and neoplastic components are only partly deciphered. Lymphotoxin β, demonstrated in AITL tumour cells (Foss et al, 1995) and potentially released by B cells under CXCL13 stimulation, might be involved in inducing FDC proliferation. Upregulation of several angiogenic mediators has been demonstrated in AITL. Vascular endothelial growth factor (VEGF) is overexpressed in AITL and probably acts as a key mediator of the prominent vascularization observed in the disease (de Leval et al, 2007; Piccaluga et al, 2007). By immunostaining, neoplastic cells and endothelial cells are positive for both VEGF and its receptor, suggesting the possibility of some paracrine and/or autocrine loop (Zhao et al, 2004; Piccaluga et al, 2007). Moreover, FDC represent another source of VEGF. The angiopoietin sytem may also play an important role as angiopoietin 1 is expressed by AITL neoplastic cells and FDCs (Konstantinou et al, 2009).

Infectious agents – viruses

EBV-positive cells are detected in most cases of AITL (Zhou et al, 2007), and as the infection targets B cells, the virus is unlikely to play a primary role in lymphomagenesis (Brauninger et al, 2001; Zhou et al, 2007). Higher EBV viral loads in tissues have been found to correlate with progression of histological patterns and with B-cell clonality (Zhou et al, 2007). The presence of human herpesvirus 6B (HHV6B) is also evidenced by PCR in almost half of the cases (Zhou et al, 2007). Although viral infection/reactivation probably occurs as a consequence of the underlying immune dysfunction, EBV and potentially also HHV6B, may, through the modulation of cytokines, chemokines and membrane receptors, play a role in the development of the tumour microenvironment, ultimately favouring disease progression. Interestingly, HHV6B also has immunosuppressive properties.

Issues in diagnosis and differential diagnosis

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Clinical features
  5. Morphology and immunophenotype
  6. Molecular and genetic features
  7. Pathogenesis of AITL ()
  8. Issues in diagnosis and differential diagnosis
  9. Natural history and prognostic factors
  10. Therapeutic options
  11. Acknowledgement
  12. References

Pathologically, the differential diagnosis of AITL encompasses several reactive conditions and lymphoma entities (Table III). The distinction between early involvement by AITL and reactive T-zone hyperplasia (in viral infections or dysimmune conditions) may be difficult. The presence of atypical clear cells positive for CD10 and/or TFH markers, minimal FDC expansion and clonal TCR (and IGH) gene rearrangements are criteria favouring AITL. Reactive lymphadenitis due to EBV comprises paracortical expansion and EBV-positive B cells, but the majority of T cells are CD8+ and polyclonal. There is some overlap between pattern II AITL and Castleman disease, but the expansion of the mantle zones seen in the latter is absent in the regressed follicles of AITL. The epithelioid variant of AITL can suggest a granulomatous disease but identification of atypical neoplastic T cells is the clue to the correct diagnosis.

Table III.   Differential diagnosis of AITL.
Clinical mimics
Infectious process
Systemic inflammatory disease
Pathological differential diagnosis
In lymph node biopsies
Reactive lymphoid hyperplasia
Hodgkin lymphoma
T-cell/histiocyte-rich large B-cell lymphoma
PTCL, NOS
Follicular PTCL
In extranodal sites
Reactive lymphoid infiltrates
Other PTCL subtypes

The B-blasts in AITL are often EBV-positive and CD30-positive, and may show Reed-Sternberg-like morphology and even partial CD15 expression in some cases, which is a source of confusion with classical Hodgkin lymphoma (cHL). However, in cHL, prominent branching venules and FDC expansion are absent and the T cells lack atypia, and are polyclonal.

The presence of scattered large B-cells in a background of T-cells and histiocytes is a feature common to AITL, especially the epithelioid variant and T-cell/histiocyte-rich large B-cell lymphoma; however, in the latter, the neoplastic B cells are EBV-negative, while the T cells lack atypia and are polyclonal. In elderly patients, however, the differential diagnosis is further compounded by possibility of an EBV-positive large B-cell lymphoma, which may comprise a T-cell rich background (Oyama et al, 2007).

The distinction between AITL and PTCL, NOS may be challenging but so far has no significant therapeutic implications. A subset of PTCL, NOS comprise small-to medium-sized cells with minimal atypia, and an inflammatory background. The presence of clear cells and an increased vasculature are variably present in PTCL, NOS. Features favouring AITL over PTCL, NOS include the perinodal extension of the lymphoproliferation over an open peripheral sinus, the proliferation of FDCs, the presence of CD10-positive clear cells and of EBV-infected large B-cells, but definitive categorization remains difficult in some cases (Attygalle et al, 2007a). Accordingly, a subset of cases routinely diagnosed as PTCL, NOS display a molecular signature that partly overlaps with that of AITL and/or show expression of TFH markers upon refined immunophenotypic analysis (Dupuis et al, 2006; de Leval et al, 2007; Rodriguez-Pinilla et al, 2009). Thus, a subset of PTCL, NOS cases may be related to or derived from AITL, and the spectrum of AITL may be broader than is currently thought (Attygalle et al, 2007a; de Leval et al, 2007, 2009). It remains to be defined which criteria should be used to define the borders of AITL entity. In that respect, whether clincial and/or laboratory symptoms should be taken into account in borderline cases requires further investigation. Among PTCLs with a TFH -like immunophenotype is the follicular variant PTCL, NOS, a rare and peculiar form whose designation refers to a pattern of growth intimately related to follicular structures, (de Leval et al, 2001; Macon et al, 1995; Rudiger et al, 2000; Uherova et al, 2002; Ikonomou et al, 2006; Huang et al, 2009). This follicular variant is derived from CD4+CD10+ T cells expressing an extensive TFH immunophenotype (BCL6+ CXCL13+ PD1+ ICOS+), and variably contains neoplastic clear cells and/or EBV-positive blasts (Bacon et al, 2008; Huang et al, 2009). Moreover, follicular PTCL and AITL have been occasionally reported in consecutive biospies in the same patients, suggesting that the two entities may be related (Bacon et al, 2008; Qubaja et al, 2009; Huang et al, 2009). Interestingly, however, a subset of follicular PTCLs harbour the t(5;9)(q33;q22) translocation (resulting in ITK-SYK fusion), which has not been found in AITL, suggesting distinct oncogenic pathways (Streubel et al, 2006).

The identification of AITL in extranodal localizations may be difficult because of the scarcity of neoplastic cells, especially in the absence of established diagnosis. Immunohistochemistry for CD10 and TFH markers is helpful to identify the neoplastic elements, and molecular genetic studies may demonstrate clonal TCR rearrangement.(Attygalle et al, 2004; Ortonne et al, 2007) In the bone marrow and skin infiltrates, CXCL13 may be more useful than CD10, which also stains the stroma and may be difficult to interpret. However, TFH markers are not entirely specific for AITL. Indeed, a BCL6+ PD1+ CXCL13+ immunophenotype has also been reported in primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (Rodriguez Pinilla et al, 2009).

Natural history and prognostic factors

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Clinical features
  5. Morphology and immunophenotype
  6. Molecular and genetic features
  7. Pathogenesis of AITL ()
  8. Issues in diagnosis and differential diagnosis
  9. Natural history and prognostic factors
  10. Therapeutic options
  11. Acknowledgement
  12. References

The course of AITL is variable, with occasional spontaneous remissions, but overall it portends a poor prognosis with a median survival <3 years in most studies, even when treated intensively. However, AITL is not always lethal, with 30% of cases being long-term survivors (Armitage et al, 2008; Mourad et al, 2008).

The prognostic significance of various other clinicobiological and pathological features was evaluated in a retrospective series of 157 AITL patients retrieved from the Goupe d’ Etude des Lmphomes de l’ Adulte (GELA) LNH87-LNH93 randomized trials (Mourad et al, 2008). Neither the architectural patterns nor the content in large cells appear to have a prognostic impact (Fig 6). In multivariate analysis, only male sex, mediastinal lymphadenopathy, and anaemia adversely affected overall survival. It was not possible to isolate a group with a better prognosis and both the International Prognostic Index (IPI) and Prognostic Index for PTCL (PIT) were of limited value.

image

Figure 6.  Overall survival (OS) of 157 AITL patients according to large cell content. The OS of patients with classic AITL versus AITL rich in large cell does not differ, according to (Mourad et al, 2008).

Download figure to PowerPoint

In general, successive biopsies harvested at relapses tend to show a stable histological picture, or, more rarely, a progression in histological pattern. Transformation into a T-cell lymphoma with a high content of large pleomorphic neoplastic T-cells resembling PTCL, NOS, is rare and does not seem to impact outcome (Lee et al, 2003; Attygalle et al, 2007b). Conversely, features of ‘high-grade’ lymphoma are usually represented by a secondary B-cell proliferation (Zettl et al, 2002; Attygalle et al, 2007b; Willenbrock et al, 2007). The incidence of this complication is poorly documented, and how to distinguish between B-cell-rich AITL and AITL with superimposed B-cell lymphoma is not established. Interestingly, whereas an increased large B-cell component does not seem to impact the clinical outcome (Lome-Maldonado et al, 2002; Mourad et al, 2008), the prognosis following the occurrence of overt diffuse large B-cell lymphoma or an EBV-positive lymphoproliferation is quite variable. From a therapeutic standpoint, in these circumstances the administration of Rituximab might be recommended. Rare cases of EBV-associated cHL have been reported (Nakamura et al, 1995; Attygalle et al, 2007b).

Therapeutic options

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Clinical features
  5. Morphology and immunophenotype
  6. Molecular and genetic features
  7. Pathogenesis of AITL ()
  8. Issues in diagnosis and differential diagnosis
  9. Natural history and prognostic factors
  10. Therapeutic options
  11. Acknowledgement
  12. References

The best approach for treating patients with AITL is still unknown. Various treatment strategies, which range from the watch-and-wait attitude to combinations of chemotherapeutic agents, have proved to be largely unsuccessful in curing the disease. The use of steroids has been recommended especially in elderly patients. Single-agent steroids, cytotoxic drugs, or combination chemotherapeutic regimens, such as cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP); and cyclophosphamide, vincristine, prednisolone, bleomycin, doxorubicin, procarbazine, ifosfamide, methotrexate and etoposide (COPBLAM/IMVP-16) (Siegert et al, 1992) have all failed to increase the long-term survival rate to more than 30%. When steroids are used as first line therapy, the duration of response is shorter than with chemotherapy and most patients have to be submitted to chemotherapy. Low-dose methotrexate together with steroids, (Gerlando et al, 2000; Quintini et al, 2001) fludarabine or 2-chlorodeoxyadenosine, (Sallah & Bernard, 1996; Bourgeois et al, 2000) interferon-α (Feremans & Khodadadi, 1987; Siegert et al, 1991) ciclosporin, (Murayama et al, 1992; Advani et al, 1997) or thalidomide (Strupp et al, 2002; Dogan et al, 2005) have been reported to have efficacy in AITL. These reports are often anecdotal or correspond to limited phase II trials with response rates averaging 30%, and there is no consensus whether any of these agents improve outcomes more than conventional treatment, even in combination.

Is more intensive conventional treatment better?

Several attempts have been made to find a better treatment than CHOP by increasing the dose or introducing other agents. A possible impact of more intensive regimen has been described with the addition of etoposide to CHOP (CHOEP), or the use of MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) (Karakas et al, 1996).

Only one GELA study has reported a statistical advantage for the subgroup of PTCL patients treated with ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) when compared to CHOP (Tilly et al, 2003). By contrast, a retrospective comparison of the outcome of 135 patients treated with various more or less intensive regimens at the MD Anderson failed to demonstrate a superiority of the most intensive treatment in 30 patients, with a 3-year survival of 49% vs. 43% for conventional treatment. (Escalon et al, 2005) Two GELA phase 2 studies yielded similar results.(Delmer et al 2003) Using prospectively an intensive combination regimen type Burkitt on 83 patients <60 years, the response rate was 52% with a median event-free survival at 6 months. Moreover, the ESHAP (etoposide, solumedrol, high dose cytarabine and platinum) regimen in 58 patients >60 years was associated with a very low complete response (CR) rate of 33%. According to this study, the use of anthracyclines is still recommended.

Is more intensive treatment with transplantation better?

More specifically, in the GELA study of AITL patients who had been submitted to various regimens according to the different protocols (Mourad et al, 2008), no positive impact of any treatment arm on survival was observed, even for patients submitted to a consolidation with autologous stem cell transplantation (ASCT), in agreement with a previous report on PTCLs (Mounier et al, 2004).

Nevertheless, the possible benefit of high dose chemotherapy with ASCT (HDT-ASCT) for AITL patients was initially suggested from case reports (Schmitz et al, 1991; Siegert et al, 1992; Rodriguez et al, 2001). A retrospective multicentre study of the European Group for Blood and Marrow Transplantation recently reported 146 AITL patients who received ASCT in different situations (relapse, refractory, first complete remission) (Kyriakou et al, 2008). After a median follow-up of 31 months, the actuarial overall survival (OS) was 67% at 24 months and 59% at 48 months. The estimated progression-free survival (PFS) rates were 70% and 56% at 24 and 48 months, respectively, for patients who received their transplants in CR; 42% and 30% for patients with chemotherapy-sensitive disease; and 23% at both time points for patients with chemotherapy-refractory disease.

Interestingly, a prospective study on PTCLs with upfront consolidation with ASCT suggests that long-term OS can be improved up to 71% (3-year OS) (Reimer et al, 2009). However, this procedure can only benefit less than half of the patients achieving complete or good partial response. Moreover, a recent study from the German High-Grade Non-Hodgkin Lymphoma Study Group sheds some doubt on the expectation that HDT-ASCT will significantly improve outcomes for PTCL patients, as dose-escalated CHOEP in this study appeared no better than other high-dose regimens (Nickelsen et al, 2009).

In young patients, data on allogeneic transplantation were encouraging, but patient cohorts were limited (Corradini et al, 2004; Le Gouill et al, 2008; Kyriakou et al, 2009) with PFS and OS rates of 66% and 64% at 3 years, respectively, with a relapse rate at 3 years estimated at 20%. However, whether allogeneic transplantation offers additional benefit over autologous transplantation to young patients remains to be determined.

What else is available for therapy?

The most commonly used treatment for PTCL is CHOP or variant regimens. However, the results with CHOP are inadequate and new approaches are needed. The activities of new drugs are being described in studies designed for PTCL patients, and attempts at novel combinations are emerging.

Several groups have piloted gemcitabine-based regimens with promising results (Zinzani et al, 1998) (Arkenau et al, 2007) (Kim et al, 2006).

Alemtuzumab, a monoclonal anti-CD52 antibody, has recently been added to CHOP for the treatment of PTCL. Twenty-four consecutive patients with newly diagnosed PTCL, including 6 AITL, enrolled in a prospective multicentre trial received a combination of alemtuzumab with CHOP (Gallamini et al, 2007). CR was observed in 17 of 24 (71%) patients. At a median follow-up of 16 months, 13/24 patients (54%) were disease-free with an estimated 2-year OS and failure-free survival of 53% and 48% respectively. Several Phase II trials with Alemtuzumab alone or combined with chemotherapy gave encouraging results for first line treatment, with manageable toxicities. However, caution should be taken to prevent complications related to immunodeficiency. The dose of Alemtuzumab should not exceed 60 mg per cycle. Alemtuzumab is now being tested in a phase III trial in association with CHOP.

A phase II study of CHOP with denileukin diftitox for 37 untreated PTCL, including 10 AITL, showed clinical activity with a 86% response rate (76% CR) and a 2-year PFS estimate of 41%, and only little added toxicity over CHOP (Foss et al, 2008).

Therapies targeting VEGF mediators have been proposed in relation to the expression of both VEGF and its receptor by neoplastic cells of AITL. Bevacizumab has shown anecdotal activity in PTCL, particularly AITL, and has been added to CHOP in an ongoing Eastern Cooperative Oncology Group (ECOG) trial for newly diagnosed patients with PTCL.

Pralatrexate, a novel antifolic drug, gave promising results in a Phase I-II trial where the first 4 PTCL patients achieved a CR (O’Connor et al, 2007). An expansion of this experience to 111 patients with relapsed and refractory PTCL including 13 AITL resulted in a 27% (19–36 95% CI) response rate, including 11 CR. Median duration of response was 9 months and, pralatrexate was reasonably well tolerated, overall. The dose- limiting toxicites were thrombocytopenia and stomatitis. This drug is now tested in combination with other agents (O’Connor et al, 2008).

Depsipeptide, a histone deacetylase inhibitor (HDACi), followed a similar pattern to pralatrexate with early activity seen in cutaneous T-cell lymphoma in a broad Phase I study. A National Cancer Institute Phase II study showed a 34% response rate in relapsed/refractory PTCL (Piekarz et al, 2009).

In addition to alemtuzumab, several novel monoclonal antibodies have shown some early promise in PTCL, such as Zanolimumab, a human monoclonal antibody targeting CD4 antigen expressed on neoplastic cells of AITL and of most PTCLs (d’Amore et al, 2007).

The addition of Bortezomib to ACVBP was recently tested in a phase 2 GELA study of 57 previously untreated PTCL patients. The observed CR rate (45%) was not higher than previously reported with ACVBP alone (Delmer et al, 2009). A specific study on AITL has been designed with the addition of rituximab to CHOP. The presence of large B-cell associated with EBV was the rational for a strategy of immune modulation in this specific disease (Joly et al, 2005).

Despite of various intensive regimens with an anthracycline-based chemotherapy, AITL, compared to other non-Hodgkin lymphomas, pursues an aggressive clinical course, and the optimal therapeutic regimen remains to be determined. AITL does not present any pertinent prognostic factor, except the achievement of a CR to therapy. Overall, novel strategies, including allograft with reduced intensity regimen in young patients as well as new agents, are needed. Consequently, in Europe, collaboration has been established among cooperative groups testing new approaches and new drugs.

References

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Clinical features
  5. Morphology and immunophenotype
  6. Molecular and genetic features
  7. Pathogenesis of AITL ()
  8. Issues in diagnosis and differential diagnosis
  9. Natural history and prognostic factors
  10. Therapeutic options
  11. Acknowledgement
  12. References
  • Advani, R., Warnke, R., Sikic, B.I. & Horning, S. (1997) Treatment of angioimmunoblastic T-cell lymphoma with cyclosporine. Annals of Oncology, 8, 601603.
  • D’Amore, C.F., Radford, J., Jerkeman, M., Relander, T., Tilly, H., Osterborg, A., Morschhauser, F., Gramatzki, M., Dreyling, M., Bang, B., Baadsgaard, O. & Hagberg, H. (2007) Zanolimumab (HuMax-CD4™), a Monoclonal, Fully Human Antibody: Efficacy & Safety in Patients with Relapsed or Treatment-Refractory Non-Cutaneous, CD4+ Lymphoma, T-Cell. Blood (Annual Meeting, ASH Abstracts), 110, 3409.
  • Anagnostopoulos, I., Hummel, M., Finn, T., Tiemann, M., Korbjuhn, P., Dimmler, C., Gatter, K., Dallenbach, F., Parwaresch, M. & Stein, H. (1992) Heterogeneous Epstein-Barr virus infection patterns in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type. Blood, 80, 18041812.
  • Arkenau, H.T., Chong, G., Cunningham, D., Watkins, D., Sirohi, B., Chau, I., Wotherspoon, A., Norman, A., Horwich, A. & Matutes, E. (2007) Gemcitabine, cisplatin and methylprednisolone for the treatment of patients with peripheral T-cell lymphoma: the Royal Marsden Hospital experience. Haematologica, 92, 271272.
  • Armitage, J., Vose, J. & Weisenburger, D. (2008) International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. Journal of Clinical Oncology, 26, 41244130.
  • Ascani, S., Zinzani, P.L., Gherlinzoni, F., Sabattini, E., Briskomatis, A., De Vivo, A., Piccioli, M., Fraternali Orcioni, G., Pieri, F., Goldoni, A., Piccaluga, P.P., Zallocco, D., Burnelli, R., Leoncini, L., Falini, B., Tura, S. & Pileri, S.A. (1997) Peripheral T-cell lymphomas. Clinico-pathologic study of 168 cases diagnosed according to the R.E.A.L. Classification. Annals of Oncology, 8, 583592.
  • Attygalle, A., Al-Jehani, R., Diss, T.C., Munson, P., Liu, H., Du, M.Q., Isaacson, P.G. & Dogan, A. (2002) Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood, 99, 627633.
  • Attygalle, A.D., Diss, T.C., Munson, P., Isaacson, P.G., Du, M.Q. & Dogan, A. (2004) CD10 expression in extranodal dissemination of angioimmunoblastic T-cell lymphoma. American Journal of Surgical Pathology, 28, 5461.
  • Attygalle, A.D., Chuang, S.S., Diss, T.C., Du, M.Q., Isaacson, P.G. & Dogan, A. (2007a) Distinguishing angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified, using morphology, immunophenotype and molecular genetics. Histopathology, 50, 498508.
  • Attygalle, A.D., Kyriakou, C., Dupuis, J., Grogg, K.L., Diss, T.C., Wotherspoon, A.C., Chuang, S.S., Cabecadas, J., Isaacson, P.G., Du, M.Q., Gaulard, P. & Dogan, A. (2007b) Histologic evolution of angioimmunoblastic T-cell lymphoma in consecutive biopsies: clinical correlation and insights into natural history and disease progression. American Journal of Surgical Pathology, 31, 10771088.
  • Bacon, C.M., Paterson, J.C., Liu, H., Payne, K., Munson, P., Du, M.Q. & Marafioti, T. (2008) Peripheral T-cell lymphoma with a follicular growth pattern: derivation from follicular helper T cells and relationship to angioimmunoblastic T-cell lymphoma. British Journal of Haematology, 143, 439441.
  • Baseggio, L., Berger, F., Morel, D., Delfau-Larue, M.H., Goedert, G., Salles, G., Magaud, J.P. & Felman, P. (2006) Identification of circulating CD10 positive T cells in angioimmunoblastic T-cell lymphoma. Leukemia, 20, 296303.
  • Bourgeois, E., Auxenfants, E., Jouffrey, C., Dubest, C., Mahieu, M. & Rose, C. (2000) [Efficacy of fludarabine in the treatment of angioimmunoblastic lymphoma (AIL)]. Annales de Medecine Interne (Paris), 151, 230231.
  • Bradley, S.L., Dines, D.E., Banks, P.M. & Hill, R.W. (1981) The lung in immunoblastic lymphadenopathy. Chest, 80, 312318.
  • Brauninger, A., Spieker, T., Willenbrock, K., Gaulard, P., Wacker, H.H., Rajewsky, K., Hansmann, M.L. & Kuppers, R. (2001) Survival and clonal expansion of mutating “forbidden” (immunoglobulin receptor-deficient) Epstein-Barr virus-infected B cells in angioimmunoblastic T-cell lymphoma. Journal of Experimental Medicine, 194, 927940.
  • Brown, H.A., Macon, W.R., Kurtin, P.J. & Gibson, L.E. (2001) Cutaneous involvement by angioimmunoblastic T-cell lymphoma with remarkable heterogeneous Epstein-Barr virus expression. Journal of Cutaneous Pathology, 28, 432438.
  • Bruggemann, M., White, H., Gaulard, P., Garcia-Sanz, R., Gameiro, P., Oeschger, S., Jasani, B., Ott, M., Delsol, G., Orfao, A., Tiemann, M., Herbst, H., Langerak, A.W., Spaargaren, M., Moreau, E., Groenen, P.J., Sambade, C., Foroni, L., Carter, G.I., Hummel, M., Bastard, C., Davi, F., Delfau-Larue, M.H., Kneba, M., Van Dongen, J.J., Beldjord, K. & Molina, T.J. (2007) Powerful strategy for polymerase chain reaction-based clonality assessment in T-cell malignancies Report of the BIOMED-2 Concerted Action BHM4 CT98-3936. Leukemia, 21, 215221.
  • Cho, Y.U., Chi, H.S., Park, C.J., Jang, S., Seo, E.J. & Huh, J. (2009) Distinct features of angioimmunoblastic T-cell lymphoma with bone marrow involvement. American Journal of Clinical Pathology, 131, 640646.
  • Cook, J.R., Craig, F.E. & Swerdlow, S.H. (2003) Benign CD10-positive T cells in reactive lymphoid proliferations and B-cell lymphomas. Modern Pathology, 16, 879885.
  • Corradini, P., Dodero, A., Zallio, F., Caracciolo, D., Casini, M., Bregni, M., Narni, F., Patriarca, F., Boccadoro, M., Benedetti, F., Rambaldi, A., Gianni, A.M. & Tarella, C. (2004) Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin’s lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. Journal of Clinical Oncology, 22, 21722176.
  • Delmer, A., Mounier, N., Gaulard, P., Bouabdallah, R., Hermine, O., Salles, G., Emile, JF., Casasnovas, O., Tilly, H., Gisselbrecht, C. & Groupe d’Etude des Lymphomes de l’Adulte. (2003) Intensified induction therapy with etoposide (VP16) and high-dose cytarabine (Ara-C) in patients aged less than 60 years with peripheral T cell/NK lymphoma: preliminary results of the phase II GELA study LNH98T7. Proceeding American Society of Clinical Oncolology, 22, Abstract 2375.
  • Delmer, A., Fitoussi, O., Gaulard, P., Laurent, G., Bordessoule, D., Morchhauser, F., Ferme, C., Tilly, H., Gisselbrecht, C. & Coiffier, B. (2009) A phase II study of bortezomib in combination with intensified CHOP-like regimen (ACVBP) in patients with previously untreated T-cell lymphoma: results of the GELA LNH05–1T trial. Journal of Clinical Oncolology (ASCO Meeting Abstracts), 27 (Suppl. 15), 8554.
  • Dogan, A., Attygalle, A.D. & Kyriakou, C. (2003) Angioimmunoblastic T-cell lymphoma. British Journal of Haematology, 121, 681691.
  • Dogan, A., Ngu, L.S., Ng, S.H. & Cervi, P.L. (2005) Pathology and clinical features of angioimmunoblastic T-cell lymphoma after successful treatment with thalidomide. Leukemia, 19, 873875.
  • Dorfman, D.M., Brown, J.A., Shahsafaei, A. & Freeman, G.J. (2006) Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. American Journal of Surgical Pathology, 30, 802810.
  • Dupuis, J., Boye, K., Martin, N., Copie-Bergman, C., Plonquet, A., Fabiani, B., Baglin, A.C., Haioun, C., Delfau-Larue, M.H. & Gaulard, P. (2006) 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. American Journal of Surgical Pathology, 30, 490494.
  • Escalon, M.P., Liu, N.S., Yang, Y., Hess, M., Walker, P.L., Smith, T.L. & Dang, N.H. (2005) Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M. D. Anderson Cancer Center experience. Cancer, 103, 20912098.
  • Fazilleau, N., Mark, L., McHeyzer-Williams, L.J. & McHeyzer-Williams, M.G. (2009) Follicular helper T cells: lineage and location. Immunity, 30, 324335.
  • Feller, A., Griesser, H., Schilling, C., Wacker, H., Dallenbach, F., Bartels, H., Kuse, R., Mak, T. & Lennert, K. (1988) Clonal gene rearrangement patterns correlate with immunophenotype and clinical parameters in patients with angioimmunoblastic lymphadenopathy. American Journal of Pathology, 133, 549556.
  • Feremans, W.W. & Khodadadi, E. (1987) Alpha-interferon therapy in refractory angioimmunoblastic lymphadenopathy. European Journal of Haematology, 39, 91.
  • Foss, H.D., Anagnostopoulos, I., Herbst, H., Grebe, M., Ziemann, K., Hummel, M. & Stein, H. (1995) Patterns of cytokine gene expression in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type. Blood, 85, 28622869.
  • Foss, F., Shak-Shie, N., Goy, A., Jacobson, E., Avandii, R., Komrokji, M., Pendergrass, K., Bolejack, V., Watts, K. & Acosta, M. (2008) Phase II study of Denileukin Diftitox with CHOP in PTCL. Annals of Oncology, 19(Suppl. 4), Abstract 096.
  • Frizzera, G., Moran, E. & Rappaport, H. (1974) Angio-immunoblastic lymphadenopathy with dysproteinemia. Lancet, i, 10701073.
  • Frizzera, G., Moran, E.M. & Rappaport, H. (1975) Angio-immunoblastic lymphadenopathy. Diagnosis and clinical course. American Journal of Medicine, 59, 803818.
  • Gallamini, A., Zaja, F., Patti, C., Billio, A., Specchia, M.R., Tucci, A., Levis, A., Manna, A., Secondo, V., Rigacci, L., Pinto, A., Iannitto, E., Zoli, V., Torchio, P., Pileri, S. & Tarella, C. (2007) Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood, 110, 23162323.
  • Gerlando, Q., Barbera, V., Ammatuna, E., Franco, V., Florena, A.M. & Mariani, G. (2000) Successful treatment of angioimmunoblastic lymphadenopathy with dysproteinemia-type T-cell lymphoma by combined methotrexate and prednisone. Haematologica, 85, 880881.
  • Gesk, S., Martin-Subero, J.I., Harder, L., Luhmann, B., Schlegelberger, B., Calasanz, M.J., Grote, W. & Siebert, R. (2003) Molecular cytogenetic detection of chromosomal breakpoints in T-cell receptor gene loci. Leukemia, 17, 738745.
  • Grogg, K.L., Attygalle, A.D., Macon, W.R., Remstein, E.D., Kurtin, P.J. & Dogan, A. (2005) Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells? Blood, 106, 15011502.
  • Grogg, K.L., Attygale, A.D., Macon, W.R., Remstein, E.D., Kurtin, P.J. & Dogan, A. (2006) Expression of CXCL13, a chemokine highly upregulated in germinal center T-helper cells, distinguishes angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified. Modern Pathology, 19, 11011107.
  • Grogg, K.L., Morice, W.G. & Macon, W.R. (2007) Spectrum of bone marrow findings in patients with angioimmunoblastic T-cell lymphoma. British Journal of Haematology, 137, 416422.
  • Harris, N.L., Jaffe, E.S., Stein, H., Banks, P.M., Chan, J.K., Cleary, M.L., Delsol, G., De Wolf-Peeters, C., Falini, B. & Gatter, K.C. (1994) A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood, 84, 13611392.
  • Huang, Y., Moreau, A., Dupuis, J., Streubel, B., Petit, B., Le Gouill, S., Martin-Garcia, N., Copie-Bergman, C., Gaillard, F., Qubaja, M., Fabiani, B., Roncador, G., Haioun, C., Delfau-Larue, M.H., Marafioti, T., Chott, A. & Gaulard, P. (2009) Peripheral T-cell lymphomas with a follicular growth pattern are derived from follicular helper T cells (TFH) and may show overlapping features with angioimmunoblastic T-cell lymphomas. American Journal of Surgical Pathology, 33, 682690.
  • Ikonomou, I.M., Tierens, A., Troen, G., Aamot, H.V., Heim, S., Lauritzsen, G.F., Valerhaugen, H. & Delabie, J. (2006) Peripheral T-cell lymphoma with involvement of the expanded mantle zone. Virchows Archiv, 449, 7887.
  • Jaffe, E., Harris, N., Stein, H. & Vardiman, J. (2001) Pathology and genetics. Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon.
  • Jayaraman, A.G., Cassarino, D., Advani, R., Kim, Y.H., Tsai, E. & Kohler, S. (2006) Cutaneous involvement by angioimmunoblastic T-cell lymphoma: a unique histologic presentation, mimicking an infectious etiology. Journal of Cutaneous Pathology, 33(Suppl. 2), 611.
  • Joly, B., Gaulard, P., Belhadj, K., Al Gnaoui, T., Dupuis, J., Divine, M., Rahmouni, A., Copie-Bergman, C., Delfau-Larue, M., Reyes, F. & Haioun, C. (2005) Rituximab in Combination with CHOP Regimen in Angioimmunoblastic T-Cell Lymphoma (AITL). Preliminary Results in 9 Patients Treated in a Single Institution. Blood, 106, 2686.
  • Kaneki, T., Kawashima, A., Akamatsu, T., Tanaka, N., Kubo, K., Koizumi, T., Sekiguchi, M., Hosaka, N., Honda, T., Koike, S. & Adachi, W. (1999) Immunoblastic lymphadenopathy-like T-cell lymphoma complicated by multiple gastrointestinal involvement. Journal of Gastroenterology, 34, 253259.
  • Kaneko, Y., Maseki, N., Sakurai, M., Takayama, S., Nanba, K., Kikuchi, M. & Frizzera, G. (1988) Characteristic karyotypic pattern in T-cell lymphoproliferative disorders with reactive “angioimmunoblastic lymphadenopathy with dysproteinemia-type” features. Blood, 72, 413421.
  • Kang, H.Y., Hwang, J.H., Park, Y.S., Bang, S.M., Lee, J.S., Chung, J.H. & Kim, H. (2007) Angioimmunoblastic T-cell lymphoma mimicking Crohn’s disease. Digestive Diseases and Sciences, 52, 27432747.
  • Karakas, T., Bergmann, L., Stutte, H.J., Jager, E., Knuth, A., Weidmann, E., Mitrou, P.S. & Hoelzer, D. (1996) Peripheral T-cell lymphomas respond well to vincristine, adriamycin, cyclophosphamide, prednisone and etoposide (VACPE) and have a similar outcome as high-grade B-cell lymphomas. Leukaemia & Lymphoma, 24, 121129.
  • Karube, K., Aoki, R., Nomura, Y., Yamamoto, K., Shimizu, K., Yoshida, S., Komatani, H., Sugita, Y. & Ohshima, K. (2008) Usefulness of flow cytometry for differential diagnosis of precursor and peripheral T-cell and NK-cell lymphomas: analysis of 490 cases. Pathology International, 58, 8997.
  • Kawano, R., Ohshima, K., Wakamatsu, S., Suzumiya, J., Kikuchi, M. & Tamura, K. (2005) Epstein-Barr virus genome level, T-cell clonality and the prognosis of angioimmunoblastic T-cell lymphoma. Haematologica, 90, 11921196.
  • Kerl, K., Vonlanthen, R., Nagy, M., Bolzonello, N.J., Gindre, P., Hurwitz, N., Gudat, F., Nador, R.G. & Borisch, B. (2001) Alterations on the 5′ noncoding region of the BCL-6 gene are not correlated with BCL-6 protein expression in T cell non-Hodgkin lymphomas. Laboratory Investigation, 81, 16931702.
  • Kim, J.G., Sohn, S.K., Chae, Y.S., Kim, D.H., Baek, J.H., Lee, K.B., Lee, J.J., Chung, I.J., Kim, H.J., Yang, D.H., Lee, W.S., Joo, Y.D. & Sohn, C.H. (2006) CHOP plus etoposide and gemcitabine (CHOP-EG) as front-line chemotherapy for patients with peripheral T cell lymphomas. Cancer Chemotherapy and Pharmacology, 58, 3539.
  • Konstantinou, K., Yamamoto, K., Ishibashi, F., Mizoguchi, Y., Kurata, M., Nakagawa, Y., Suzuki, K., Sawabe, M., Ohta, M., Miyakoshi, S., Crawley, J.T. & Kitagawa, M. (2009) Angiogenic mediators of the angiopoietin system are highly expressed by CD10-positive lymphoma cells in angioimmunoblastic T-cell lymphoma. British Journal of Haematology, 144, 696704.
  • Krenacs, L., Schaerli, P., Kis, G. & Bagdi, E. (2006) Phenotype of neoplastic cells in angioimmunoblastic T-cell lymphoma is consistent with activated follicular B helper T cells. Blood, 108, 11101111.
  • Kyriakou, C., Canals, C., Goldstone, A., Caballero, D., Metzner, B., Kobbe, G., Kolb, H.J., Kienast, J., Reimer, P., Finke, J., Oberg, G., Hunter, A., Theorin, N., Sureda, A. & Schmitz, N. (2008) High-dose therapy and autologous stem-cell transplantation in angioimmunoblastic lymphoma: complete remission at transplantation is the major determinant of Outcome-Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Journal of Clinical Oncology, 26, 218224.
  • Kyriakou, C., Canals, C., Finke, J., Kobbe, G., Harousseau, J.L., Kolb, H.J., Novitzky, N., Goldstone, A.H., Sureda, A. & Schmitz, N. (2009) Allogeneic stem cell transplantation is able to induce long-term remissions in angioimmunoblastic T-cell lymphoma: a retrospective study from the lymphoma working party of the European group for blood and marrow transplantation. Journal of Clinical Oncology, 27, 39513958.
  • Lachenal, F. (2007) [Angioimmunoblastic T-cell lymphoma]. Presse Medicale, 36, 16551662.
  • Lachenal, F., Berger, F., Ghesquieres, H., Biron, P., Hot, A., Callet-Bauchu, E., Chassagne, C., Coiffier, B., Durieu, I., Rousset, H. & Salles, G. (2007) Angioimmunoblastic T-cell lymphoma: clinical and laboratory features at diagnosis in 77 patients. Medicine (Baltimore), 86, 282292.
  • Le Gouill, S., Milpied, N., Buzyn, A., De Latour, R.P., Vernant, J.P., Mohty, M., Moles, M.P., Bouabdallah, K., Bulabois, C.E., Dupuis, J., Rio, B., Gratecos, N., Yakoub-Agha, I., Attal, M., Tournilhac, O., Decaudin, D., Bourhis, J.H., Blaise, D., Volteau, C. & Michallet, M. (2008) Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: a study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Journal of Clinical Oncology, 26, 22642271.
  • Lee, S.S., Rudiger, T., Odenwald, T., Roth, S., Starostik, P. & Muller-Hermelink, H.K. (2003) Angioimmunoblastic T cell lymphoma is derived from mature T-helper cells with varying expression and loss of detectable CD4. International Journal of Cancer, 103, 1220.
  • Leich, E., Haralambieva, E., Zettl, A., Chott, A., Rudiger, T., Holler, S., Muller-Hermelink, H.K., Ott, G. & Rosenwald, A. (2007) Tissue microarray-based screening for chromosomal breakpoints affecting the T-cell receptor gene loci in mature T-cell lymphomas. Journal of Pathology, 213, 99105.
  • Lennert, K. (1979) [Nature, prognosis and nomenclature of angioimmunoblastic (lymphadenopathy (lymphogranulomatosis X or T-zone lymphoma)]. Deutsche Medizinische Wochenschrift, 104, 12461247.
  • Leung, C.Y., Ho, F.C., Srivastava, G., Loke, S.L., Liu, Y.T. & Chan, A.C. (1993) Usefulness of follicular dendritic cell pattern in classification of peripheral T-cell lymphomas. Histopathology, 23, 433437.
  • De Leval, L., Savilo, E., Longtine, J., Ferry, J.A. & Harris, N.L. (2001) Peripheral T-cell lymphoma with follicular involvement and a CD4+/bcl-6+ phenotype. American Journal of Surgical Pathology, 25, 395400.
  • De Leval, L., Rickman, D.S., Thielen, C., Reynies, A., Huang, Y.L., Delsol, G., Lamant, L., Leroy, K., Briere, J., Molina, T., Berger, F., Gisselbrecht, C., Xerri, L. & Gaulard, P. (2007) 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, 109, 49524963.
  • De Leval, L., Bisig, B., Thielen, C., Boniver, J. & Gaulard, P. (2009) Molecular classification of T-cell lymphomas. Critical Reviews in Oncology/Hematology, 72, 125143.
  • Lome-Maldonado, C., Canioni, D., Hermine, O., Delabesse, E., Damotte, D., Raffoux, E., Gaulard, P., Macintyre, E. & Brousse, N. (2002) 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, 16, 21342141.
  • Lukes, R.J. & Tindle, B.H. (1975) Immunoblastic lymphadenopathy. A hyperimmune entity resembling Hodgkin’s disease. New England Journal of Medicine, 292, 18.
  • Macon, W.R., Williams, M.E., Greer, J.P. & Cousar, J.B. (1995) Paracortical nodular T-cell lymphoma. Identification of an unusual variant of peripheral T-cell lymphoma. American Journal of Surgical Pathology, 19, 297303.
  • Marinova, E., Han, S. & Zheng, B. (2007) Germinal center helper T cells are dual functional regulatory cells with suppressive activity to conventional CD4+ T cells. Journal of Immunology, 178, 50105017.
  • Martel, P., Laroche, L., Courville, P., Larroche, C., Wechsler, J., Lenormand, B., Delfau, M.H., Bodemer, C., Bagot, M. & Joly, P. (2000) Cutaneous involvement in patients with angioimmunoblastic lymphadenopathy with dysproteinemia: a clinical, immunohistological, and molecular analysis. Archives of Dermatology, 136, 881886.
  • Merchant, S.H., Amin, M.B. & Viswanatha, D.S. (2006) Morphologic and immunophenotypic analysis of angioimmunoblastic T-cell lymphoma: Emphasis on phenotypic aberrancies for early diagnosis. American Journal of Clinical Pathology, 126, 2938.
  • Mounier, N., Gisselbrecht, C., Briere, J., Haioun, C., Feugier, P., Offner, F., Recher, C., Stamatoullas, A., Morschhauser, F., Macro, M., Thieblemont, C., Sonet, A., Fabiani, B. & Reyes, F. (2004) All aggressive lymphoma subtypes do not share similar outcome after front-line autotransplantation: a matched-control analysis by the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Annals of Oncology, 15, 17901797.
  • Mourad, N., Mounier, N., Briere, J., Raffoux, E., Delmer, A., Feller, A., Meijer, C.J., Emile, J.F., Bouabdallah, R., Bosly, A., Diebold, J., Haioun, C., Coiffier, B., Gisselbrecht, C. & Gaulard, P. (2008) Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d’Etude des Lymphomes de l’Adulte (GELA) trials. Blood, 111, 44634470.
  • Murakami, Y.I., Yatabe, Y., Sakaguchi, T., Sasaki, E., Yamashita, Y., Morito, N., Yoh, K., Fujioka, Y., Matsuno, F., Hata, H., Mitsuya, H., Imagawa, S., Suzuki, A., Esumi, H., Sakai, M., Takahashi, S. & Mori, N. (2007) c-Maf expression in angioimmunoblastic T-cell lymphoma. American Journal of Surgical Pathology, 31, 16951702.
  • Murayama, T., Imoto, S., Takahashi, T., Ito, M., Matozaki, S. & Nakagawa, T. (1992) Successful treatment of angioimmunoblastic lymphadenopathy with dysproteinemia with cyclosporin A. Cancer, 69, 25672570.
  • Nakamura, S. & Suchi, T. (1991) A clinicopathologic study of node-based, low-grade, peripheral T-cell lymphoma. Angioimmunoblastic lymphoma, T-zone lymphoma, and lymphoepithelioid lymphoma. Cancer, 67, 25662578.
  • Nakamura, S., Sasajima, Y., Koshikawa, T., Kitoh, K., Koike, K., Motoori, T., Ueda, R., Mori, S. & Suchi, T. (1995) 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, 45, 958964.
  • Nelson, M., Horsman, D.E., Weisenburger, D.D., Gascoyne, R.D., Dave, B.J., Loberiza, F.R., Ludkovski, O., Savage, K.J., Armitage, J.O. & Sanger, W.G. (2008) Cytogenetic abnormalities and clinical correlations in peripheral T-cell lymphoma. British Journal of Haematology, 141, 461469.
  • Nickelsen, M., Ziepert, M., Zeynalova, S., Glass, B., Metzner, B., Leithaeuser, M., Mueller-Hermelink, H.K., Pfreundschuh, M. & Schmitz, N. (2009) High-dose CHOP plus etoposide (MegaCHOEP) in T-cell lymphoma: a comparative analysis of patients treated within trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Annals of Oncology, DOI:10.1093/annonc/mdp211.
  • Niitsu, N., Okamoto, M., Nakamine, H., Aoki, S., Motomura, S. & Hirano, M. (2008) Clinico-pathologic features and outcome of Japanese patients with peripheral T-cell lymphomas. Hematological Oncology, 26, 152158.
  • O’Connor, O.A., Hamlin, P.A., Portlock, C., Moskowitz, C.H., Noy, A., Straus, D.J., Macgregor-Cortelli, B., Neylon, E., Sarasohn, D., Dumetrescu, O., Mould, D.R., Fleischer, M., Zelenetz, A.D., Sirotnak, F. & Horwitz, S. (2007) Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma. British Journal of Haematology, 139, 425428.
  • O’Connor, O.P.C., Pinter-Brown, L., Popplewell, L., Barlett, N., Shustov, C., Lechowicz, M.J., Savage, K.J., Coiffier, B., Jacobsen, E., Zinzani, P.J., Goy, A., Zain, J., Wilroy, S., Patterson, M., Boyd, A., Saunders, M.E., Cagnoni, P. & Horwitz, S.M. (2008) PROPEL: A Multi-Center Phase 2 Open-Label Study of Pralatrexate (PDX) with Vitamin B12 and Folic Acid Supplementation in Patients with Replapsed or Refractory Peripheral T-Cell Lymphoma. Blood (ASH Annual Meeting Abstracts), 112, 261.
  • Ortonne, N., Dupuis, J., Plonquet, A., Martin, N., Copie-Bergman, C., Bagot, M., Delfau-Larue, M.H., Gaulier, A., Haioun, C., Wechsler, J. & Gaulard, P. (2007) Characterization of CXCL13+ neoplastic t cells in cutaneous lesions of angioimmunoblastic T-cell lymphoma (AITL). American Journal of Surgical Pathology, 31, 10681076.
  • Oyama, T., Yamamoto, K., Asano, N., Oshiro, A., Suzuki, R., Kagami, Y., Morishima, Y., Takeuchi, K., Izumo, T., Mori, S., Ohshima, K., Suzumiya, J., Nakamura, N., Abe, M., Ichimura, K., Sato, Y., Yoshino, T., Naoe, T., Shimoyama, Y., Kamiya, Y., Kinoshita, T. & Nakamura, S. (2007) Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clinical Cancer Research, 13, 51245132.
  • Patsouris, E., Noel, H. & Lennert, K. (1989) Angioimmunoblastic lymphadenopathy–type of T-cell lymphoma with a high content of epithelioid cells. Histopathology and comparison with lymphoepithelioid cell lymphoma. American Journal of Surgical Pathology, 13, 262275.
  • Pautier, P., Devidas, A., Delmer, A., Dombret, H., Sutton, L., Zini, J.M., Nedelec, G., Molina, T., Marolleau, J.P. & Brice, P. (1999) Angioimmunoblastic-like T-cell non Hodgkin’s lymphoma: outcome after chemotherapy in 33 patients and review of the literature. Leukaemia & Lymphoma, 32, 545552.
  • Piccaluga, P.P., Agostinelli, C., Califano, A., Carbone, A., Fantoni, L., Ferrari, S., Gazzola, A., Gloghini, A., Righi, S., Rossi, M., Tagliafico, E., Zinzani, P.L., Zupo, S., Baccarani, M. & Pileri, S.A. (2007) Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. Cancer Research, 67, 1070310710.
  • Piekarz, R.L., Frye, R., Turner, M., Wright, J.J., Allen, S.L., Kirschbaum, M.H., Zain, J., Prince, H.M., Leonard, J.P., Geskin, L.J., Reeder, C., Joske, D., Figg, W.D., Gardner, E.R., Steinberg, S.M., Jaffe, E.S., Stetler-Stevenson, M., Lade, S., Fojo, A.T. & Bates, S.E. (2009) Phase II Multi-Institutional Trial of the Histone Deacetylase Inhibitor Romidepsin As Monotherapy for Patients With Cutaneous T-Cell Lymphoma. Journal of Clinical Oncology, 27, 54105417.
  • Pizzolo, G., Vinante, F., Agostini, C., Zambello, R., Trentin, L., Masciarelli, M., Chilosi, M., Benedetti, F., Dazzi, F. & Todeschini, G. (1987) Immunologic abnormalities in angioimmunoblastic lymphadenopathy. Cancer, 60, 24122418.
  • Pujol, R.M., Gallardo, F., Servitje, O., Marti, R.M., Bordes, R., Garcia-Muret, M.P., Estrach, M.T. & Nomdedeu, J.F. (2005) Peripheral T-cell lymphoma with secondary epithelioid granulomatous cutaneous involvement: a clinicopathologic study of four cases. Journal of Dermatology, 32, 541548.
  • Qubaja, M., Audouin, J., Moulin, J.C., Molina, T.J., Le Tourneau, A., Gaulard, P., Straub, P., Audhuy, B. & Diebold, J. (2009) Nodal follicular helper T-cell lymphoma may present with different patterns. A case report.. Human Pathology, 40, 264269.
  • Quintini, G., Iannitto, E., Barbera, V., Turri, D., Franco, V., Florena, A.M. & Mariani, G. (2001) Response to low-dose oral methotrexate and prednisone in two patients with angio-immunoblastic lymphadenopathy-type T-cell lymphoma. The Hematology Journal, 2, 393395.
  • Ree, H.J., Kadin, M.E., Kikuchi, M., Ko, Y.H., Go, J.H., Suzumiya, J. & Kim, D.S. (1998) Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers. American Journal of Surgical Pathology, 22, 643655.
  • Ree, H.J., Kadin, M.E., Kikuchi, M., Ko, Y.H., Suzumiya, J. & Go, J.H. (1999) Bcl-6 expression in reactive follicular hyperplasia, follicular lymphoma, and angioimmunoblastic T-cell lymphoma with hyperplastic germinal centers: heterogeneity of intrafollicular T-cells and their altered distribution in the pathogenesis of angioimmunoblastic T-cell lymphoma. Human Pathology, 30, 403411.
  • Reimer, P., Rudiger, T., Geissinger, E., Weissinger, F., Nerl, C., Schmitz, N., Engert, A., Einsele, H., Muller-Hermelink, H.K. & Wilhelm, M. (2009) Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study. Journal of Clinical Oncology, 27, 106113.
  • Rodriguez Pinilla, S.M., Roncador, G., Rodriguez-Peralto, J.L., Mollejo, M., Garcia, J.F., Montes-Moreno, S., Camacho, F.I., Ortiz, P., Limeres-Gonzalez, M.A., Torres, A., Campo, E., Navarro-Conde, P. & Piris, M.A. (2009) Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma expresses follicular T-cell markers. American Journal of Surgical Pathology, 33, 8190.
  • Rodriguez, J., Munsell, M., Yazji, S., Hagemeister, F.B., Younes, A., Andersson, B., Giralt, S., Gajewski, J., De Lima, M., Couriel, D., Romaguera, J., Cabanillas, F.F., Champlin, R.E. & Khouri, I.F. (2001) Impact of high-dose chemotherapy on peripheral T-cell lymphomas. Journal of Clinical Oncology, 19, 37663770.
  • Rodriguez-Justo, M., Attygalle, A.D., Munson, P., Roncador, G., Marafioti, T. & Piris, M.A. (2009) Angioimmunoblastic T-cell lymphoma with hyperplastic germinal centres: a neoplasia with origin in the outer zone of the germinal centre? Clinicopathological and immunohistochemical study of 10 cases with follicular T-cell markers. Modern Pathology, 22, 753761.
  • Rodriguez-Pinilla, S.M., Atienza, L., Murillo, C., Perez-Rodriguez, A., Montes-Moreno, S., Roncador, G., Perez-Seoane, C., Dominguez, P., Camacho, F.I. & Piris, M.A. (2009) Peripheral T-cell Lymphoma With Follicular T-cell Markers. American Journal of Surgical Pathology, 33, 8190.
  • Roncador, G., Garcia Verdes-Montenegro, J.F., Tedoldi, S., Paterson, J.C., Klapper, W., Ballabio, E., Maestre, L., Pileri, S., Hansmann, M.L., Piris, M.A., Mason, D.Y. & Marafioti, T. (2007) Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma. Haematologica, 92, 10591066.
  • Rudiger, T., Ichinohasama, R., Ott, M.M., Muller-Deubert, S., Miura, I., Ott, G. & Muller-Hermelink, H.K. (2000) Peripheral T-cell lymphoma with distinct perifollicular growth pattern: a distinct subtype of T-cell lymphoma? American Journal of Surgical Pathology, 24, 117122.
  • Rudiger, T., Weisenburger, D.D., Anderson, J.R., Armitage, J.O., Diebold, J., MacLennan, K.A., Nathwani, B.N., Ullrich, F. & Muller-Hermelink, H.K. (2002) Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin’s Lymphoma Classification Project. Annals of Oncology, 13, 140149.
  • Sakai, H., Tanaka, H., Katsurada, T., Yoshida, Y., Okamoto, E. & Ohno, H. (2007) Angioimmunoblastic T-cell lymphoma initially presenting with replacement of bone marrow and peripheral plasmacytosis. Internal Medicine, 46, 419424.
  • Sallah, A.S. & Bernard, S. (1996) Treatment of angioimmunoblastic lymphadenopathy with dysproteinemia using 2-chlorodeoxyadenosine. Annals of Hematology, 73, 295296.
  • Scarabello, A., Leinweber, B., Ardigo, M., Rutten, A., Feller, A.C., Kerl, H. & Cerroni, L. (2002) Cutaneous lymphomas with prominent granulomatous reaction: a potential pitfall in the histopathologic diagnosis of cutaneous T- and B-cell lymphomas. American Journal of Surgical Pathology, 26, 12591268.
  • Schlegelberger, B., Feller, A., Godde, W. & Lennert, K. (1990) Stepwise development of chromosomal abnormalities in angioimmunoblastic lymphadenopathy. Cancer Genetics and Cytogenetics, 50, 1529.
  • Schlegelberger, B., Zwingers, T., Hohenadel, K., Henne-Bruns, D., Schmitz, N., Haferlach, T., Tirier, C., Bartels, H., Sonnen, R. & Kuse, R. (1996) Significance of cytogenetic findings for the clinical outcome in patients with T-cell lymphoma of angioimmunoblastic lymphadenopathy type. Journal of Clinical Oncology, 14, 593599.
  • Schmitz, N., Prange, E., Haferlach, T., Griesser, H., Sonnen, R., Schlegelberger, B., Claus, S. & Loffler, H. (1991) High-dose chemotherapy and autologous bone marrow transplantation in relapsing angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). Bone Marrow Transplantation, 8, 503506.
  • Shah, Z.H., Harris, S., Smith, J.L. & Hodges, E. (2009) Monoclonality and oligoclonality of T cell receptor beta gene in angioimmunoblastic T cell lymphoma. Journal of Clinical Pathology, 62, 177181.
  • Shimoyama, M. & Minato, K. (1979) [Clinical, cytological and immunological analysis of T-cell type lymphoid malignancies: a classification of T-cell type lymphoid malignancy (author’s transl)]. [Rinsho Ketsueki] The Japanese Journal of Clinical Hematology, 20, 10561069.
  • Siegert, W., Nerl, C., Meuthen, I., Zahn, T., Brack, N., Lennert, K. & Huhn, D. (1991) Recombinant human interferon-alpha in the treatment of angioimmunoblastic lymphadenopathy: results in 12 patients. Leukemia, 5, 892895.
  • Siegert, W., Agthe, A., Griesser, H., Schwerdtfeger, R., Brittinger, G., Engelhard, M., Kuse, R., Tiemann, M., Lennert, K. & Huhn, D. (1992) 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. Annals of Internal Medicine, 117, 364370.
  • Siegert, W., Nerl, C., Agthe, A., Engelhard, M., Brittinger, G., Tiemann, M., Lennert, K. & Huhn, D. (1995) Angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma: prognostic impact of clinical observations and laboratory findings at presentation. The Kiel Lymphoma Study Group. Annals of Oncology, 6, 659664.
  • Smith, J.L., Hodges, E., Quin, C.T., McCarthy, K.P. & Wright, D.H. (2000) Frequent T and B cell oligoclones in histologically and immunophenotypically characterized angioimmunoblastic lymphadenopathy. American Journal of Pathology, 156, 661669.
  • Stacchini, A., Demurtas, A., Aliberti, S., Francia di Celle, P., Godio, L., Palestro, G. & Novero, D. (2007) The usefulness of flow cytometric CD10 detection in the differential diagnosis of peripheral T-cell lymphomas. American Journal of Clinical Pathology, 128, 854864.
  • Streubel, B., Vinatzer, U., Willheim, M., Raderer, M. & Chott, A. (2006) Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia, 20, 313318.
  • Strupp, C., Aivado, M., Germing, U., Gattermann, N. & Haas, R. (2002) Angioimmunoblastic lymphadenopathy (AILD) may respond to thalidomide treatment: two case reports. Leukaemia & Lymphoma, 43, 133137.
  • Suarez-Vilela, D. & Izquierdo-Garcia, F.M. (2003) Angioimmunoblastic lymphadenopathy-like T-cell lymphoma: cutaneous clinical onset with prominent granulomatous reaction. American Journal of Surgical Pathology, 27, 699700.
  • Swerdlow, S., Campo, E., Harris, N., Jaffe, E., Pileri, S., Stein, H., Thiele, J. & Vardiman, J. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon.
  • Tan, B.T., Warnke, R.A. & Arber, D.A. (2006) 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. The Journal of Molecular Diagnostics, 8, 466475.
  • Thorns, C., Bastian, B., Pinkel, D., Roydasgupta, R., Fridlyand, J., Merz, H., Krokowski, M., Bernd, H.W. & Feller, A.C. (2007) Chromosomal aberrations in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma unspecified: A matrix-based CGH approach. Genes, Chromosomes and Cancer, 46, 3744.
  • Tilly, H., Lepage, E., Coiffier, B., Blanc, M., Herbrecht, R., Bosly, A., Attal, M., Fillet, G., Guettier, C., Molina, T.J., Gisselbrecht, C. & Reyes, F. (2003) Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood, 102, 42844289.
  • Tobinai, K., Minato, K., Ohtsu, T., Mukai, K., Kagami, Y., Miwa, M., Watanabe, S. & Shimoyama, M. (1988) Clinicopathologic, immunophenotypic, and immunogenotypic analyses of immunoblastic lymphadenopathy-like T-cell lymphoma. Blood, 72, 10001006.
  • Troxell, M.L., Schwartz, E.J., Van De Rijn, M., Ross, D.T., Warnke, R.A., Higgins, J.P. & Natkunam, Y. (2005) Follicular dendritic cell immunohistochemical markers in angioimmunoblastic T-cell lymphoma. Applied Immunohistochemistry & Molecular Morphology , 13, 297303.
  • Tsochatzis, E., Vassilopoulos, D., Deutsch, M., Filiotou, A., Tasidou, A. & Archimandritis, A.J. (2005) Angioimmunoblastic T-cell lymphoma-associated arthritis: case report and literature review. Journal of Clinical Rheumatology, 11, 326328.
  • Uherova, P., Ross, C.W., Finn, W.G., Singleton, T.P., Kansal, R. & Schnitzer, B. (2002) Peripheral T-cell lymphoma mimicking marginal zone B-cell lymphoma. Modern Pathology, 15, 420425.
  • Vinuesa, C.G., Tangye, S.G., Moser, B. & Mackay, C.R. (2005) Follicular B helper T cells in antibody responses and autoimmunity. Nature Reviews. Immunology, 5, 853865.
  • Vrsalovic, M.M., Korac, P., Dominis, M., Ostojic, S., Mannhalter, C. & Kusec, R. (2004) T- and B-cell clonality and frequency of human herpes viruses-6, -8 and Epstein Barr virus in angioimmunoblastic T-cell lymphoma. Hematological Oncology, 22, 169177.
  • Weiss, L., Strickler, J., Dorfman, R., Horning, S., Warnke, R. & Sklar, J. (1986) Clonal T-cell populations in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma. American Journal of Pathology, 122, 392397.
  • Weiss, L.M., Jaffe, E.S., Liu, X.F., Chen, Y.Y., Shibata, D. & Medeiros, L.J. (1992) Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma. Blood, 79, 17891795.
  • Willenbrock, K., Roers, A., Seidl, C., Wacker, H.H., Kuppers, R. & Hansmann, M.L. (2001) 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. American Journal of Pathology, 158, 18511857.
  • Willenbrock, K., Renne, C., Gaulard, P. & Hansmann, M.L. (2005) In angioimmunoblastic T-cell lymphoma, neoplastic T cells may be a minor cell population. A molecular single-cell and immunohistochemical study. Virchows Archiv, 446, 1520.
  • Willenbrock, K., Brauninger, A. & Hansmann, M.L. (2007) Frequent occurrence of B-cell lymphomas in angioimmunoblastic T-cell lymphoma and proliferation of Epstein-Barr virus-infected cells in early cases. British Journal of Haematology, 138, 733739.
  • Xerri, L., Chetaille, B., Seriari, N., Attias, C., Guillaume, Y., Arnoulet, C. & Olive, D. (2008) Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. Human Pathology, 39, 10501058.
  • Yu, H., Shahsafaei, A. & Dorfman, D.M. (2009) Germinal-center T-helper-cell markers PD-1 and CXCL13 are both expressed by neoplastic cells in angioimmunoblastic T-cell lymphoma. American Journal of Clinical Pathology, 131, 3341.
  • Yuan, C.M., Vergilio, J.A., Zhao, X.F., Smith, T.K., Harris, N.L. & Bagg, A. (2005) CD10 and BCL6 expression in the diagnosis of angioimmunoblastic T-cell lymphoma: utility of detecting CD10+ T cells by flow cytometry. Human Pathology, 36, 784791.
  • Zettl, A., Lee, S.S., Rudiger, T., Starostik, P., Marino, M., Kirchner, T., Ott, M., Muller-Hermelink, H.K. & Ott, G. (2002) Epstein-Barr virus-associated B-cell lymphoproliferative disorders in angloimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified. American Journal of Clinical Pathology, 117, 368379.
  • Zhao, W.L., Mourah, S., Mounier, N., Leboeuf, C., Daneshpouy, M.E., Legres, L., Meignin, V., Oksenhendler, E., Maignin, C.L., Calvo, F., Briere, J., Gisselbrecht, C. & Janin, A. (2004) Vascular endothelial growth factor-A is expressed both on lymphoma cells and endothelial cells in angioimmunoblastic T-cell lymphoma and related to lymphoma progression. Laboratory Investigation, 84, 15121519.
  • Zhou, Y., Attygalle, A.D., Chuang, S.S., Diss, T., Ye, H., Liu, H., Hamoudi, R.A., Munson, P., Bacon, C.M., Dogan, A. & Du, M.Q. (2007) Angioimmunoblastic T-cell lymphoma: histological progression associates with EBV and HHV6B viral load. British Journal of Haematology, 138, 4453.
  • Zinzani, P.L., Magagnoli, M., Bendandi, M., Orcioni, G.F., Gherlinzoni, F., Albertini, P., Pileri, S.A. & Tura, S. (1998) Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Annals of Oncology, 9, 13511353.