Follicular T-cell lymphoma: a member of an emerging family of follicular helper T-cell derived T-cell lymphomas

Human Pathology (2012) 43, 1789–1798

www.elsevier.com/locate/humpath

Progress in pathology

Follicular T-cell lymphoma: a member of an emerging family of follicular helper T-cell derived T-cell lymphomas Shimin Hu MD, PhD, Ken H. Young MD, PhD, Sergej N. Konoplev MD, PhD, L. Jeffrey Medeiros MD ⁎ Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Box 72, Houston, TX 77030, USA Received 13 March 2012; revised 30 April 2012; accepted 4 May 2012

Keywords: Follicular T-cell lymphoma; Follicular helper T-cells

Summary Unlike B-cell lymphomas, where knowledge of normal B-cell origin and differentiation has greatly contributed to their classification, the current classification of peripheral T-cell lymphomas is limited by a lack of understanding of their cellular origin. In the current World Health Organization classification of lymphomas, follicular T-cell lymphoma was formally recognized as a morphologic variant of peripheral T-cell lymphoma, not otherwise specified. There is growing evidence, however, that follicular T-cell lymphoma may be a unique clinicopathologic entity based on its morphologic features and derivation from follicular helper T-cells. In addition, there are abundant recent data supporting the concept that follicular helper T-cells can give rise to other types of T-cell lymphoma, including angioimmunoblastic T-cell lymphoma, primary cutaneous CD4 + small/medium T-cell lymphoma, and a subset of neoplasms, in addition to follicular T-cell lymphoma, currently classified as peripheral T-cell lymphoma, not otherwise specified. In this review, we focus primarily on the clinicopathologic, immunophenotypic, and molecular features of follicular T-cell lymphoma and discuss its potential relationship with other types of T-cell lymphoma thought to be derived from follicular helper T-cells. © 2012 Elsevier Inc. All rights reserved.

1. Introduction The current classification of B-cell lymphomas has been greatly aided by our extensive knowledge of B-cell origin and normal differentiation. In lymph nodes, normal B-cells form unique structures, such as germinal centers, mantle zones, and marginal zones, which can be recognized morphologically. A subset of B-cell lymphomas can exhibit morphologic patterns that correspond to these compartments. A follicular pattern, for example, is a common feature of follicular lymphomas. Assessment of the immunophenotype of normal B-cells in various compartments and correlation with B-cell lymphomas has allowed construction of normal ⁎ Corresponding author. E-mail address: [email protected] (L. J. Medeiros). 0046-8177/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.humpath.2012.05.002

B-cell differentiation stages and a putative cell of origin for most B-cell lymphomas. Recognition of consistent chromosomal translocations in B-cell lymphomas also has been helpful in understanding cell of origin and some chromosomal translocations are defining features of some types of B-cell lymphoma. In contrast, the current classification of T-cell neoplasms is largely based on a combination of clinical and pathologic features. Cases of T-cell lymphoma are grouped according to their anatomic sites of disease, in particular, leukemic/ disseminated, extranodal, cutaneous, and nodal [1]. T-cell lymphomas are further classified according to their morphologic features and the few cytogenetic or molecular abnormalities known to occur in these tumors. This approach has been taken, in part, because we know relatively little about normal T-cell differentiation. In normal lymph nodes,

1790 there are few T-cell compartments that can be recognized morphologically. Most T-cell lymphomas exhibit a diffuse pattern without clues to potential cellular origin or stage of differentiation. Based on what is known about T-cell subsets, others have attempted to classify T-cell lymphomas on the basis on CD4 versus CD8 expression, TH1 versus TH2 function, or presence or absence of a cytotoxic immunophenotype [1-5]. However, these attempts have failed to delineate clinically meaningful categories. Approximately 30% of all T-cell lymphomas worldwide, in part by default based on the issues already reviewed, fall into the category of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) [1,6]. The tumors in this category display a broad spectrum of cytologic features, from highly polymorphous to monomorphous, and with neoplastic cells that can be predominantly small, intermediate-sized, or large and pleomorphic [1]. These tumors can express T-cell markers corresponding to a variety of putative T-cell subsets [5]. Conventional cytogenetic analysis has shown a wide variety of cytogenetic abnormalities, often with complex karyotypes that correlate with inferior outcome [7-9], but very few of these abnormalities are consistent findings that can be used for T-cell lymphoma classification. Comparative genomic hybridization analysis and other high-throughput technologies have shown that virtually all PTCL-NOS cases harbor genetic imbalances, with gains commonly outnumbering losses [10-12]. There are no obvious genetic subgroups of PTCL-NOS that can be appreciated, however, further supporting the heterogeneity of this group of neoplasms. A major challenge for pathologists and researchers, therefore, is to tease out clinically and biologically meaningful subgroups from the category of PTCL-NOS, with the goal perhaps being the eventual elimination of PTCL-NOS all together. Peripheral T-cell lymphoma with a nodular/follicular pattern was first reported in 1988 [13]. The unusual morphologic pattern of this type of T-cell lymphoma was the first clue that these neoplasms may be distinctive. It was not until the fourth edition of the World Health Organization (WHO) classification was published in 2008, however, that this type of T-cell lymphoma was formally recognized, and considered as a morphologic variant of PTCL-NOS [1]. This was an important step forward, partly attributable to a flurry of case reports and small case series regarding this type of T-cell lymphoma during the past two decades [1332]. In the literature, a number of designations have been used for these tumors, including nodular T-cell lymphoma; follicular T-cell lymphoma (FTCL); peripheral T-cell lymphoma with a nodular, follicular, or perifollicular pattern; peripheral T-cell lymphoma with follicular involvement; and follicular variant of PTCL-NOS. Henceforth, we will use the term follicular T-cell lymphoma here to describe these tumors. Another important step forward is the recent progress in our understanding of the ontogeny of a distinct subset of CD4 + helper T-cells, known as follicular helper T-cells

S. Hu et al. (TFH), and their relationship with T-cell lymphomas, including FTCL [23-30,33-44]. Follicular helper T-cells normally have the capacity to home to germinal centers (GCs). This migration is facilitated by the interaction of one of their surface receptors, CXCR5, with the CXCL13 chemokine expressed by follicular dendritic cells in the light zone of GCs, where TFH cells support affinity maturation and isotype switching, leading to the generation of memory B-cells and long-lived plasma cells [35-39]. TFH cells express an array of molecules serving these functions, including cytokines and cytokine receptors (eg, interleukin21, CXCL13, CXCR5), immune-modulating receptors/ adhesion molecules (eg, programmed death-1 or PD-1, inducible co-stimulator [ICOS], CD57, CD154, CD200, signaling lymphocyte-activation molecule family), cytoplasmic signaling molecules (e.g., signaling lymphocyte-activation molecule–associating protein [SAP]), and transcriptional factors (eg, NF-ATc1 and c-Maf) [33-40]. Interestingly, the Bcl-6-MUM1/IRF4-BLIMP1 transcriptional axis, essential for GC B-cell differentiation, is also crucial for TFH cell identity [35,39,40]. Deregulation of TFH-cell functions is implicated in a variety of autoimmune disorders in both mouse models and humans [37]. Many of the molecules that support TFH cell functions have been used to identify these cells in lymph nodes and other sites using a variety of methods, and identification of TFH cells has had practical implications in the diagnosis of lymphomas [33,34,41-62]. These studies have shown that the TFH immunophenotype, although characteristic of FTCL, is not specific for this entity. Gene expression profiling studies of cases of angioimmunoblastic T-cell lymphoma (AITL) have shown over-expression of many genes characteristic of normal TFH cells, and the results of these studies have been validated at the protein level, suggesting that AITL arises from TFH cells [42-44]. These observations also provide a plausible explanation for the autoimmune phenomena and broad range of histopathologic features associated with AITL. In addition, a subset of nodal PTCLNOS cases other than FTCL have a TFH-cell immunophenotype, despite their apparently different morphologic appearances [5,23,29,30,63]. Adding to the complexity is the recent finding that cases of primary cutaneous CD4positive small/medium T-cell lymphoma also express many TFH cell markers [64,65]. These studies support the concept of an emerging family of TFH -cell derived PTCLs. In this review, we focus on FTCL, a rare neoplasm currently considered in the WHO classification to be a morphologic variant of PTCL-NOS. The data are compiled from a total 80 cases from 18 case reports or case series published in the English literature from 1988 to through 2011, as well as one previously unpublished case we have encountered (Figs. 1 and 2) [13-30]. Cases that have been reported more than once in different publications are combined correspondingly [20,24,25]. An additional 20 cases reported in the non-English literature without adequate clinical data are not included in this review [31,32].

Follicular T-cell lymphoma

1791

Fig. 1 A case of FTCL showing variably sized nodules composed of medium-sized lymphoid cells with moderately abundant pale eosinophilic cytoplasm (original magnification ×20 [A], × 1000 [B]) and with proliferation of high endothelial venules in the internodular areas (C; original magnification × 500). Nodules are highlighted by CD21 immunostain (D; original magnification × 20).

We also discuss the evidence supporting the origin of FTCL from TFH cells and the emerging family of TFH cellderived lymphomas.

2. Clinical features and laboratory findings Follicular T-cell lymphoma is a rare disease that represents 1%-2% of all PTCL-NOS cases [6]. This frequency may underestimate the overall incidence as this entity is challenging to recognize and cases can be missed [14,15,18,21]. These tumors mainly affect elderly patients, in the seventh decade, with a median and mean age of 62 years (Table 1) [13-29]. There is a wide age range, however, from 27 to 90 years. The male to female ratio is 1.2 to 1. Systemic (B-type) symptoms are observed in less than onethird of patients. Most patients (48/56, 86%) present with systemic lymphadenopathy that most commonly involves the cervical, axillary, or inguinal regions. Extranodal involvement has been reported. Hepatosplenomegaly and bone marrow involvement each occur in approximately one-fourth of patients. The tonsils, salivary glands and hard palate can be rarely involved [18]. A subset of patients (12/51, 23%) has skin lesions, either at time of diagnosis or at relapse, including erythema or papules, and occasionally patients can have isolated skin lesions [21,22,25,27]. Most patients (40/55, 73%) have clinical stage III or IV disease.

Laboratory tests reveal hematological, immunological, and/or biochemical abnormalities in a subset of patients with FTCL (Table 1). The most common findings include a positive Coombs’ test with or without autoimmune hemolytic anemia or thrombocytopenia (7/14, 50%), elevated serum lactate dehydrogenase level (13/29, 45%), and hypergammaglobulinemia (6/32, 19%). Two patients have been tested for serum soluble interleukin-2 receptor (sIL-2R) and human T-cell leukemia virus (HTLV); both patients had elevated sIL-2R levels and were negative for HTLV-1 [17,28]. Other rare laboratory findings reported in FTCL patients include hypereosinophilia and an elevated serum IgE level, reported in 2 and 1 patients, respectively [13,25].

3. Histopathology By definition, FTCL demonstrates a nodular growth pattern in lymph nodes (Fig. 1A). Depending on the morphologic pattern, lymph nodes can display minimal, partial, or total architectural effacement [13-29]. The peripheral sinuses are often spared [13,14,18,19]. Capsular fibrosis can be present [15,17]. Extranodal infiltration by tumor cells, frequently seen in AITL, is uncommon in FTCL [19,22]. In the WHO classification, 3 morphologic patterns in FTCL are recognized: follicular lymphoma (FL)–like, progressive transformation of germinal centers (PTGC)-like (also described

1792

S. Hu et al.

Fig. 2 Immunophenotype of a case of FTCL. The neoplastic lymphoid cells positive for CD3 (A; original magnification × 400), CD4 (B; original magnification ×400), CD20 dim (original magnification × 40 [D], × 400 [E]), CD10 (F; original magnification × 400), Bcl-6 (G; original magnification × 500), and PD-1 (H; original magnification × 500) and negative for CD8 (C; original magnification × 400). Rare cells positive for CXCL13 (I; original magnification ×500).

Table 1

Clinical features of patients with FTCL

General features Sex ratio (male:female) Age B-type constitutional symptoms Advanced stages (III/IV) Organ involvement Skin lesions Multiple lymphadenopathies Hepatomegaly Splenomegaly Bone marrow involvement Laboratory tests Elevated LDH Hypergammaglobulinemia AIHA/positive Coombs' test

1.2:1 (36:29) Mean: 62 Range: 27-90 29% (16/55) 73% (40/55) 23% 86% 23% 24% 26%

(12/51) (48/56) (6/26) (13/54) (6/23)

45% (13/29) 19% (6/32) 50% (7/14)

Abbreviations: LDH, lactate dehydrogenase; AIHA, autoimmune hemolytic anemia.

in the literature as nodular lymphocyte predominant Hodgkin lymphoma-like), and marginal zone lymphoma (MZL)–like. In cases with an FL-like pattern, representing approximately 20% of all FTCL cases, the tumor cells form intrafollicular aggregates or nodules that can closely resemble follicular lymphoma. The nodules can be surrounded by mantle zones, or mantle zones can be absent [19,20,23,26,30]. The nodules can be sharply demarcated [16,21,24,25,28]. In PTGC-like cases, representing approximately 50% of all FTCL cases, the tumor cells form large irregular or vague nodules that mimic progressively transformed germinal centers or nodules of nodular lymphocyte predominance Hodgkin lymphoma [13,16,17,21,22,24,25,27,28]. In cases that are MZL-like, representing approximately 30% of all FTCL cases, the neoplastic lymphoid cells show a perifollicular growth pattern or paracortical involvement that can mimic marginal zone lymphoma [14,15,18,20]. A mixture of FL-like and PTGC-like patterns are frequently seen in the same biopsy specimen.

Follicular T-cell lymphoma Although these patterns are grouped together in the WHO classification, these patterns are sufficiently different to suggest at least some differences in pathogenesis. In particular, cases of FTCL with a MZL-like pattern have some similarities with early phase AITL, so-called patterns I and II, as summarized by Attygalle et al [61]. The overall architecture is often minimally or partially effaced. The lymphoid follicles can be hyperplastic but, more often, are regressed or atretic. In advanced lesions with a perifollicular growth pattern, the neoplastic cells may extend into mantle zones and T-zone regions. Internodular or intranodular epithelioid histiocytes, rarely prominent, are often encountered [13,15,19,24]. Hodgkin-like cells and eosinophils are sometimes present. Proliferation of high-endothelial venules (HEV), an otherwise uncommon event in FTCL, is often seen in cases with MZL-like morphology [15]. However, in general cases of FTCL differ from AITL in that FTCL cases less often have a polymorphous reactive background, a proliferation of arborizing HEV, or expansion of follicular dentritic cell networks (Fig. 1C) [13,15-17,22,24]. Agostinelli et al reported 4 cases of FTCL involving lymph node in which the tumor nodules were not associated with follicular dendritic cell meshworks [29]. Although we have not reviewed these cases, their description seems similar to the MZL-like pattern of FTCL. All 4 cases expressed 3 to 6 TFH cell markers. However, most other cases of FTCL with MZL-like growth pattern have not been assessed for TFH cell markers because these studies were published before T FH cells were well-characterized [14,15,18,20]. Therefore, the true frequency of the MZLlike pattern may need to be re-evaluated. Cytologically, the neoplastic cells of FTCL involving lymph nodes have been described as medium or medium to large in size (58/80, 72.5%), small to medium-sized (16/ 80, 20%), or large (6/80, 7.5%) (Fig. 1B) [13-29]. The tumor cells tend to have round to slightly irregular or indented nuclear contours, vesicular to coarsely granular chromatin, and usually moderate or abundant clear or pale eosinophilic cytoplasm with indistinct cell borders. The nuclear features of FTCL cells can resemble centrocytes or centroblasts; the cytoplasm is helpful in their recognition as T-cells. Follicular T-cell lymphoma also has been reported to involve extranodal sites in a subset of patients, including bone marrow, liver, spleen, skin, tonsils, salivary glands, and hard palate, although as far as we are aware, descriptions of the histologic findings at every one of these sites are not available. The diagnosis of FTCL at an extranodal site can be highly challenging unless the diagnosis already has been established in lymph nodes. The pattern of bone marrow involvement by FTCL has been reported to be paratrabecular and/or interstitial [21,26]. At extranodal mucosal sites, FTCL can be associated with lymphoepithelial lesions similar to those of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) [18].

1793

4. Immunophenotype Follicular T-cell lymphoma is composed of lymphoid cells that express a variety of TFH cell markers (Fig. 2 and Table 2) [22-29]. PD-1/CD279 and ICOS are reported to be most sensitive, positive in all cases tested to date, 38 and 13 cases, respectively. PD-1 is a member of CD28/CTLA-4 co-receptor family that delivers inhibitory signals to T-cells, and ICOS is another member of the same coreceptor family that provides co-stimulation to T-cells. Most cases (35/40, 88%) of FTCL are positive for CXCL13. Cytoplasmic SAP and transcription factor NF-ATc1 have been positive in a few cases tested [23,29]. By contrast, CD10 and Bcl-6, 2 markers commonly expressed by both benign and malignant germinal center B-cells, are less sensitive markers of FTCL. CD10 and Bcl-6 have been expressed in 37/57 (65%) and 36/ 46 (78%) of FTCL cases, respectively. Down-regulation of Bcl-6 and CD10, which is frequently observed when neoplastic germinal center B-cells migrate out of the follicles in follicular lymphoma, has been observed in small numbers of FTCL cases reported [16,19,21]. It is important to remember that individual TFH markers can be expressed by other T-cell subsets, other types of T-cell lymphoma (eg, mycosis fungoides) and B-cell lymphoma (eg, chronic lymphocytic leukemia/small lymphocytic lymphoma) as well as in reactive conditions as reported by others [29,30,46,50,51,53,55,57,63,65-69]. Therefore, it has been suggested that a combination of markers be used, with an arbitrary minimum of three markers being positive to define the TFH immunophenotype [29,35,54]. Thirty-one cases of FTCL reported in the literature have been tested for expression of 4 to 6 TFH markers, with 29 (94%) positive for at least 3 markers supporting TFH cell lineage. The neoplastic cells of FTCL also express pan-T-cell antigens, including CD2, CD3, CD5, or CD7 (Fig. 2 and Table 2 a

Immunophenotype of FTCL

CD2 CD3 b CD4+CD8CD4+CD8+ CD4-CD8+ CD4-CD8CD5 CD7 CD43 CD45 CD56 TIA1/GraB

100% (56/56) 99% (74/75) 91% (67/74) 1%(1/73) 1%(1/73) 7% (5/73) 89% (59/66) 32% (17/53) 94% (15/16) 97% (32/33) 0% (0/22) 0% (0/31)

CD10 Bcl-6 PD-1 CXCL13 ICOS SAP CD57 NF-ATc1 CD25 CD30 CD31 Bcl-2

65% (37/57) 78% (36/46) 100% (38/38) 88% (35/40) 100% (13/13) 100% (3/3) 15% (7/47) 100% (1/1) 27% (3/11) 12% (4/34) 100% (2/2) 33% (3/9)

Abbreviations: GraB, granzyme B; PD-1, programmed cell death-1 ICOS, inducible costimulator; SAP, SLAM (signaling lymphocyteactivation molecule)-associated protein. a Including 1 case with partial loss of CD2 as positive [19]. b Including 2 cases with partial loss of CD3 and 4 cases with positive immunohistochemistry but negative flow cytometry as positive [14,18,19].

1794 Table 2) [13-29]. An aberrant T-cell immunophenotype or antigen “loss” is present in many cases. CD7 has been absent in FTCL most often (36/53, 68%), and CD5, in some cases (7/66, 11%). Partial loss of CD2, CD3, or CD4 has been reported in occasional cases. Most cases (67/74, 91%) of FTCL have a CD4+CD8− helper T-cell immunophenotype. A small subset (7%) of cases reported were CD4−CD8−. Aberrant expression of B-cell markers, such as CD79a or CD20, is rarely encountered (Fig. 2D and E) [22]. T-cell receptor expression has been infrequently assessed in FTCLs. Other markers seen in a small subset of cases include Bcl2 (3/9, 33%), CD25 (3/11, 27%), CD57 (7/47, 15%), and dim CD30 (4/34, 12%). CD31 expression has been observed in 2 cases tested [19,22]. They are negative for CD56 and cytotoxic antigens, such as TIA-1 and granzyme B. Scattered Epstein-Barr virus encoded RNA–positive B cells consistent with immunoblasts have been reported in 18 (41%) of 43 cases. Reactive follicular dendritic cell meshworks revealed by CD21, CD23, and CD35 immunostains can be expanded but within the nodular areas. The proliferation index, as assessed by Ki-67 immunoreactivity, is highly variable, ranging from 5% to 70%, with median and mean values of approximately 45%.

5. Molecular and genetic features Monoclonal rearrangement of the TCR (T-cell receptor) genes has been detected in 47 of 55 cases (85%) of FTCL assessed. An oligoclonal pattern was reported in 3 cases (5.5%), and 5 cases (9.5%) were polyclonal [13-29]. Most cases reported have been assessed by polymerase chain reaction methods, but 10 cases assessed by Southern blot analysis all showed monoclonal TCRβ chain gene rearrangements [13,14,18]. Monoclonal immunoglobulin (IgH) gene rearrangements are frequently observed in AITL [70,71]. However, no evidence of monoclonal IgH gene rearrangements has been detected in all 35 cases of FTCL tested; one case was reported as oligoclonal [25]. Using conventional cytogenetic analysis, 7 (39%) of 18 cases of FTCL reported had an abnormal and usually complex karyotype (Table 3) [15,20,21,28]. One case reported carried a t(5;9)(q33;q22) involving the fusion of 2 tyrosine kinases, ITK (IL-2-inducible T-cell kinase) and SYK (spleen tyrosine kinase), confirmed by fluorescence in situ hybridization [20]. Fluorescence in situ hybridization analysis for ITK-SYK has shown this fusion in 6 (21%) of 28 cases assessed, including 5 cases with a FL-like pattern and 1 case with a MZL-like pattern [20,25]. Interestingly, t(5;9)(q33;q22) also has been reported in 2 cases of PTCL-NOS with a diffuse growth pattern, one of which was examined for and had TFH cell immunophenotype [5,20]. The translocation was not found in AITL or anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma [20]. Thus, t(5;9) may be unique to FTCL and rare cases of PTCL-NOS with a TFH cell

S. Hu et al. Table 3

Karyotypes of 7 reported cases of FTCL

1. 46,XY,del(6)(q21)[3]/46,idem,add(17)(q25)[7]/46,XY[10] 2. 46,XX,t(5;9)(q33;q22)[2]/46,XX,t(5;9)(q33;q22), dup(17)(q21q24)[12]/46,XX[18] 3. 46,XX,del(6)(q15q25)[8]/46,XX,der(11)t(3;11)(q13;q25), der(13)t(X;13)(q22;p11)[6]/46,XX,der(9)t(1;9)(q21;p24), der(15;17)(q10;q10),+17[4] 4. 33~41,der(X)t(X;10)(q28;q24),Y,ins(1;22)(q31;q11q13), der(2)t(1;2)(q32;q37),der(3)t(3;17)(p21;q11),−4,der(5) t(4;5)(q11;p15),der(7)(qterp22::13q?::6p216pter),der(7) t(4;7)(q11:p22),−9,−10,t(13;15)(q22;q22),der(14)t(9;14) (q32;p11),der(14)(qter-p11::10q22–10q26::2q23-2qter)[cp7] 5. 45,XY,der(7)t(1;7)(q21;q32),add(12)(q24),+2mar,inc[9] 6. 47,XY,+add(X)(p22),+Y,add(1)(p34),−2,add(3)(q29), del(3)(q12q21),add(5)(q35),−6,del(6)(q15),+7,del(8)(q22), del(12)(q22),+add(12)(q24),−13,der(1;16)(q10;p10),+mar [10]/46,XY[5] 7. 45,XY,add(1)(q21),add (2)(p11.2),add (7)(p22), add(8)(p11.2),−9,add(10)(q22),−14,add (15)(q22),+mar1[18] NOTE. References [15,20,21,28].

immunophenotype[5,20]. Expression of ITK-SYK in mice induces lymphoma resembling human PTCL [72,73]. Overexpression of SYK, however, has been shown in a wide variety of T-cell lymphomas that lack t(5;9)/ITK-SYK [74]. The roles of BCL-2 and BC-L6, well known in B-cell lymphomas, are less clear in FTCLs. The Bcl-6 protein is known to be important for TFH cell differentiation [35-40]. In one case of FTCL that we observed recently, we showed amplification of both BCL-6 and BCL-2 by fluorescence in situ hybridization analysis (unpublished data). Aberrant somatic mutation of BCL-6 has not been identified in FTCLs [21]. To date, there are no reports of array-based global examination of genetic abnormalities or gene expression profiling in FTCL.

6. Therapy and prognosis Comprehensive studies on the prognosis and therapeutic options for patients with FTCL are not available in the literature, which is not surprising given the rarity of these tumors. Here, we have compiled data from case reports and small case series of FTCL patients that have been published [13-28]. Thirty-seven of 41 patients (90%) were treated with chemotherapy; 20 of 22 patients with available information regarding the treatment regimen received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, with or without other additional chemotherapeutic agents or therapeutic modalities. Six of these patients underwent autologous stem cell transplant [14,17,19-21,23,26,28]. After therapy, many patients had a complete or partial remission, but relapses were frequent. Clinical follow-up was available for 49 patients; 21 (43%) died after a median follow-up of 18 to 24 months (range, 1 week to 124 months) [14-16,18,20-23,25]. There are 28

Follicular T-cell lymphoma living patients at last follow-up, but only 16 were free of disease after median follow-up of 12 to 35 months (range, 9-124 months) [14-17,20,21,25,27,28].

7. Other TFH cell–derived T-cell lymphomas Other types of T-cell lymphoma that have a TFH cell immunophenotype are known, the best known of which is AITL, the first type of T-cell lymphoma shown to have a TFH cell immunophenotype. The morphologic findings of AITL have been divided into 3 patterns, arbitrarily designated as patterns I to III, which correlate with disease progression and loosely correlate with clinical progression and prognosis [61,75-77]. Cases of FTCL with an MZL-like pattern share some histological and clinicopathologic features with patterns I and II of AITL. It seems possible that FTCL with a MZL-like pattern and AITL are closely related or represent a spectrum of the same disease. Supporting this concept, rare cases of FTCL with coexistent AITL also have been reported [30]. In addition, Huang and colleagues reported that 4 patients were initially diagnosed with AITL but relapsed with biopsy specimens that resembled FTCL [25]. However, relapse of AITL as FTCL is rare as Attygalle et al followed up 30 patients with AITL and relapse as FTCL was not reported [75]. A subset of cases currently classified as PTCL-NOS also have been shown to express TFH cell markers suggesting a possible relationship with FTCL [5,29,30,42-44,46,50,53,55,63]. These cases have been identified by gene expression profiling or immunohistochemical analysis using TFHassociated markers. In gene expression profiling studies, approximately 20% to 25% of PTCL-NOS cases have a TFH gene signature [42-44]. Using immunohistochemistry, Rodriguez-Pinilla and colleagues [63] assessed for expression of CD10, Bcl-6, PD-1, and CXCL13 in 81 cases of PTCL-NOS; 16 cases (20%) expressed at least three TFH markers supporting a TFH cell immunophenotype. Zhan et al [30] also studied the same set of TFH cell markers in 81 cases of PTCL-NOS and found 4 cases (5%) that expressed 3 or more TFH markers. The explanation for the discrepancy between these 2 studies is unknown, but the results of Rodriguez-Pinilla and colleagues are more in line with the results of gene expression profiling studies [42-44]. It also appears that there are morphologic correlates associated with expression of TFH markers in PTCL-NOS. A subset of cases have some histologic features suggestive, although not diagnostic, of AITL [30,42,63]. It therefore seems likely that some cases of PTCL-NOS may be early cases of AITL, at a stage before the characteristic clinical or histologic features of AITL are present. In addition, cases of the lymphoepithelioid variant of PTCL (so-called Lennert lymphoma), T-zone variant PTCL, and rare cases of ALK-anaplastic large cell lymphoma, and truly unclassifiable cases of PTCL-NOS can express multiple TFH markers [29,30,63]. Importantly, there are definitional issues involved in classification. Is a TFH cell immunophe-

1795 notype adequate evidence to remove a tumor from the PTCL-NOS category and suggest another diagnosis, such as AITL? Primary cutaneous CD4-positive small/medium T-cell lymphoma (PCSMTCL) is another type of T-cell lymphoma recently shown to have a TFH cell immunophenotype [64,65]. PCSMTCL is a rare and indolent disease, currently listed as a provisional entity in the 2008 WHO classification [1,78]. These neoplasms have a predilection for the head/neck and upper trunk regions. Morphologically, PCSMTCL shows a diffuse or nodular dermal infiltrate that has a tendency to infiltrate the subcutis and can exhibit a minor component of epidermotropism. A reactive background is common. Aberrant T-cell immunophenotypes are uncommon and EBV infection is rare [64,78]. The TFH cell markers Bcl-6, PD-1 and CXCL13, but not CD10, are consistently expressed which help distinguish PCSMTCL from other types of cutaneous T-cell lymphoma and reactive conditions [64,65]. Le Tourneau et al reported 2 cases of FTCL occurring in head/neck and upper trunk [27]. These tumors exhibited a follicular dendritic cell (FDC) meshwork and were positive for CD10. It is not known whether these cases represent cutaneous FTCL or PCSMTCL with follicular pattern. Alternatively, PCSMTCL may represent a diffuse variant of FTCL. However, the indolent clinical behavior of PCSMTCL distinguishes this neoplasm from FTCL which is clinically more aggressive.

8. Conclusions There appears to be an emerging consensus that FTCL is a rare but distinctive type of T-cell lymphoma that arises from TFH cells, a normal T-cell subset located in the germinal centers of lymphoid follicles. A variety of morphologic patterns have been accepted in the WHO classification, but in our opinion, this heterogeneity raises the possibility that the criteria for diagnosis of FTCL need further refinement. A subset of FTCL is associated with a distinctive molecular abnormality, t(5;9)(q33;q22), involving SYK and TYK, further suggesting heterogeneity that will need to be addressed. Follicular T-cell lymphomas are clinically aggressive and often refractory to standard chemotherapy regimens such as CHOP. There is also emerging evidence that there is a family of Tcell lymphomas that have a TFH cell immunophenotype, including FTCL, AITL, the lymphoepithelioid (Lennert lymphoma) and T-zone variants of PTCL-NOS, and PCSMTCL. There are also case reports and small series of patients who have had FTCL and AITL or PTCL-NOS with a TFH immunophenotype, simultaneously or in sequential fashion. Whether these are examples of transformation from FTCL into another tumor type, or represent plasticity of TFH cell differentiation is unknown. It is essential to remember that many of these widely used TFH cell– associated markers are not entirely specific for TFH cells. As a result, the use of a single TFH cell marker for defining

1796 TFH cell immunophenotype is inadequate. There appears to be an emerging consensus that at least 3 TFH cell–associated markers being positive are needed to support a TFH cell immunophenotype[29,35,54]. Many questions remain to be answered. The paracortical or perifollicular location of the neoplastic cells in cases of FTCL with MZL-like pattern is difficult to reconcile with the GC location of TFH cells, the postulated cell of origin. As many cases of MZL-like FTCL were not assessed for TFH cells at the time they were published, perhaps considering these cases as FTCL needs to be evaluated. Alternatively, a recent study has identified a subset of non–germinal center T-cells with TFH cell immunophenotype [79]. These non-GC TFH cells induce the proliferation and differentiation of naïve, but not GC, B cells. There is also a quantitative difference in the expression of some of the TFH cell markers between these 2 subsets of TH cells [35,79,80]. Another recent development is the identification of TFH cell counterparts in the peripheral blood [81,82]. It is unknown whether these non-GC TFH cells are a completely different subset of TH cells, or they may represent a non-GC stage (precursor or memory stage) of GC TFH cells [35,36]. The identification of a family of T-cell lymphomas that arise from TFH cells or show TFH cell differentiation may have practical implications. Others have suggested that TFH cell–derived lymphomas have a broad spectrum and this raises the possibility of defining these neoplasms as a group in future lymphoma classification schemes. Although there are similarities between FTCL and AITL, the relationship between FTCL, AITL, PCSMTCL, and some cases of the lymphoepithelioid and T-zone variants of PTCL-NOS is unclear [25,29,30,62,63]. Should all of these lymphomas be classified as subtypes under the same umbrella term of TFH cell-derived lymphoma? In some ways, an analogy can be made with B-cell lymphomas that have a germinal center Bcell immunophenotype, a group that includes clinically indolent low-grade follicular lymphomas and clinically aggressive diffuse large B-cell lymphoma as well as Burkitt lymphoma. The umbrella term germinal center B-cell derived lymphoma has some academic value but certainly does not convey practical information in terms of guiding therapeutic decisions or predicting prognosis. At least for now, it may be premature to redefine T-cell lymphomas purely on the basis of a TFH cell immunophenotype.

9. Note in added proof After acceptance of this manuscript, Miyoshi et al reported 17 cases of FTCL [83]. In their study, the authors emphasize that FTCL shares many clinical and pathologic characteristics with AITL, as well as a TFH cell immunophenotype. The authors further suggest that FTCL and AITL belong to the same disease spectrum. The findings presented in this study are in keeping with some of the data we have presented in this review.

S. Hu et al.

References [1] Swerdlow SH, Campo E, Harris NL, et al, editors. WHO classification of tumors of hematopoietic and lymphoid tissue. 4th ed. Lyon, France: IARC Press; 2008. [2] de Leval L, Bisig B, Thielen C, Boniver J, Gaulard P. Molecular classification of T-cell lymphoma. Crit Rev Oncol Hematol 2009;72: 125-43. [3] Went P, Agostinelli C, Gallamini A, et al. Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol 2006;24:2472-9. [4] Rüdiger T, Geissinger E, Müller-Hermelink HK. ‘Normal counterparts' of nodal peripheral T-cell lymphoma. Hematol Oncol 2006;24: 175-80. [5] Matsumoto Y, Horiike S, Ohshiro M, et al. Expression of master regulators of helper T-cell differentiation in peripheral T-cell lymphoma, not otherwise specified, by immunohistochemical analysis. Am J Clin Pathol 2010;133:281-90. [6] Weisenburger DD, Savage KJ, Harris NL, et al. Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood 2011;117: 3402-8. [7] Lepretre S, Buchonnet G, Stamatoullas A, et al. Chromosome abnormalities in peripheral T-cell lymphoma. Cancer Genet Cytogenet 2000; 117:71-9. [8] Schlegelberger B, Himmler A, Godde E, Grote W, Feller AC, Lennert K. Cytogenetic findings in peripheral T-cell lymphomas as a basis for distinguishing low-grade and high-grade lymphomas. Blood 1994;83: 505-11. [9] Nelson M, Horsman DE, Weisenburger DD, et al. Cytogenetic abnormalities and clinical correlations in peripheral T-cell lymphoma. Br J Haematol 2008;141:461-9. [10] Zettl A, Rüdiger T, Konrad MA, et al. Genomic profiling of peripheral T-cell lymphoma, unspecified, and anaplastic large T-cell lymphoma delineates novel recurrent chromosomal alterations. Am J Pathol 2004;164:1837-48. [11] Meléndez B, Díaz-Uriarte R, Cuadros M, et al. Gene expression analysis of chromosomal regions with gain or loss of genetic material detected by comparative genomic hybridization. Genes Chromosomes Cancer 2004;41:353-65. [12] Thorns C, Bastian B, Pinkel D, et al. Chromosomal aberrations in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma unspecified: a matrix-based CGH approach. Genes Chromosomes Cancer 2007;46:37-44. [13] van den Oord JJ, de Wolf-Peeters C, O'Connor NT, de Vos R, Tricot G, Desmet VJ. Nodular T-cell lymphoma. Report of a case studied with morphologic, immunohistochemical, and DNA hybridization techniques. Arch Pathol Lab Med 1988;112:133-8. [14] Macon WR, Williams ME, Greer JP, Cousar JB. Paracortical nodular T-cell lymphoma. Identification of an unusual variant of peripheral T-cell lymphoma. Am J Surg Pathol 1995;19:297-303. [15] Rudiger T, Ichinohasama R, Ott MM, et al. Peripheral T-cell lymphoma with distinct perifollicular growth pattern: a distinct subtype of T-cell lymphoma? Am J Surg Pathol 2000;24:117-22. [16] de Leval L, Savilo E, Longtine J, Ferry JA, Harris NL. Peripheral Tcell lymphoma with follicular involvement and a CD4 +/bcl-6 + phenotype. Am J Surg Pathol 2001;25:395-400. [17] Hatano B, Fukushima T, Honda M, et al. Peripheral T-cell lymphoma with a nodular growth pattern. Pathol Int 2002;52:400-5. [18] Uherova P, Ross CW, Finn WG, Singleton TP, Kansal R, Schnitzer B. Peripheral T-cell lymphoma mimicking marginal zone B-cell lymphoma. Mod Pathol 2002;15:420-5. [19] Jiang L, Jones D, Medeiros LJ, Orduz YR, Bueso-Ramos CE. Peripheral T-cell lymphoma with a "follicular" pattern and the perifollicular sinus phenotype. Am J Clin Pathol 2005;123: 448-55.

Follicular T-cell lymphoma [20] Streubel B, Vinatzer U, Willheim M, Raderer M, Chott A. Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia 2006;20:313-8. [21] Ikonomou IM, Tierens A, Troen G, et al. Peripheral T-cell lymphoma with involvement of the expanded mantle zone. Virchows Arch 2006; 449:78-87. [22] Starkey CR, Corn AI, Porensky RS, Viswanatha D, Wilson CS. Peripheral T-cell lymphoma with extensive dendritic cell network mimicking follicular dendritic cell tumor: a case report with pathologic, immunophenotypic, and molecular findings. Am J Clin Pathol 2006;126:230-4. [23] Bacon CM, Paterson JC, Liu H, et al. Peripheral T-cell lymphoma with a follicular growth pattern: derivation from follicular helper T cells and relationship to angioimmunoblastic T-cell lymphoma. Br J Haematol 2008;143:439-41. [24] Qubaja M, Audouin J, Moulin JC, et al. Nodal follicular helper T-cell lymphoma may present with different patterns. A case report. HUM PATHOL 2009;40:264-9. [25] Huang Y, Moreau A, Dupuis J, et al. 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. Am J Surg Pathol 2009;33:682-90. [26] Ortiz-Muchotrigo N, Rodriguez-Pinilla SM, Ramos R, et al. Follicular T-cell lymphoma: description of a case with characteristic findings suggesting it is a different condition from AITL. Histopathology 2009; 54:902-4. [27] Le Tourneau A, Audouin J, Molina T, et al. Primary cutaneous follicular variant of peripheral T-cell lymphoma NOS. A report of two cases. Histopathology 2010;56:548-51. [28] Goto N, Tsurumi H, Sawada M, et al. Follicular variant of peripheral T-cell lymphoma mimicking follicular lymphoma: a case report with a review of the literature. Pathol Int 2011;61:326-30. [29] Agostinelli C, Hartmann S, Klapper W, et al. Peripheral T cell lymphomas with follicular T helper phenotype: a new basket or a distinct entity? Revising Karl Lennert's personal archive. Histopathology 2011;59:679-91. [30] Zhan HQ, Li XQ, Zhu XZ, Lu HF, Zhou XY, Chen Y. Expression of follicular helper T cell markers in nodal peripheral T cell lymphomas: a tissue microarray analysis of 162 cases. J Clin Pathol 2011;64:319-24. [31] Wang W, Ji FS, Chen HS, et al. Clinicopathologic features of peripheral T-cell lymphoma, unspecified with follicular pattern. Zhonghua Bing Li Xue Za Zhi 2009;38:248-52. [32] Zhan HQ, Zhu XZ, Li XQ, Zhou XY. Follicular variant of peripheral T-cell lymphoma: a clinicopathologic and genetic study of 2 cases. Zhonghua Bing Li Xue Za Zhi 2011;40:32-6. [33] 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;104:1952-60. [34] Chtanova T, Tangye SG, Newton R, et al. T follicular helper cells express a distinctive transcriptional profile, refecting their role as non– TH1/TH2 effector cells that provide helper for B cells. J Immunol 2004;173:68-78. [35] Yu D, Vinuesa CG. The elusive identity of T follicular helper cells. Trends Immunol 2010;31:377-83. [36] Fazilleau N, Mark L, McHeyzer-Williams LJ, McHeyzer-Williams MG. Follicular helper T cells: lineage and location. Immunity 2009;30: 324-35. [37] Yu D, Batten M, Mackay CR, King C. Lineage specification and heterogeneity of T follicular helper cells. Curr Opin Immunol 2009;21: 619-25. [38] King C. New insights into the differentiation and function of T follicular helper cells. Nat Rev Immunol 2009;9:757-66. [39] Nutt SL, Tarlinton DM. Germinal center B and follicular helper T cells: siblings, cousins or just good friends? Nat Immunol 2011;12: 472-7.

1797 [40] Crotty S, Johnston RJ, Schoenberger SP. Effectors and memories: Bcl6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol 2010;11:114-20. [41] Gaulard P, de Leval L. Follicular helper T cells: implications in neoplastic hematopathology. Semin Diagn Pathol 2011;28:202-13. [42] de Leval L, Rickman DS, Thielen C, 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;109:4952-63. [43] Piccaluga PP, Agostinelli C, Califano A, et al. Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. Cancer Res 2007;67:10703-10. [44] Iqbal J, Weisenburger DD, Greiner TC, et al. Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. Blood 2010;115:1026-36. [45] Grogg KL, Attygalle AD, Macon WR, Remstein ED, Kurtin PJ, Dogan A. Angioimmunoblastic T-cell lymphoma: a neoplasm of germinalcenter T-helper cells? Blood 2005;106:1501-12. [46] Dupuis J, Boye K, Martin N, 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;30:490-4. [47] Grogg KL, Attygalle AD, Macon WR, Remstein ED, Kurtin PJ, Dogan A. Expression of CXCL13, a chemokine highly upregulated in germinal center T-helper cells, distinguishes angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified. Mod Pathol 2006;19:1101-7. [48] Ortonne N, Dupuis J, Plonquet A, et al. Characterization of CXCL13 + neoplastic T cells in cutaneous lesions of angioimmunoblastic T-cell lymphoma (AITL). Am J Surg Pathol 2007;31:1068-76. [49] Dorfman DM, Brown JA, Shahsafaei A, Freeman GJ. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 2006;30: 802-10. [50] Roncador G. García Verdes-Montenegro JF, Tedoldi S, et al. Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma. Haematologica 2007;92:1059-66. [51] Xerri L, Chetaille B, Serriari N, et al. Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. HUM PATHOL 2008;39: 1050-8. [52] Yu H, Shahsafaei A, Dorfman DM. Germinal-center T-helper-cell markers PD-1 and CXCL13 are both expressed by neoplastic cells in angioimmunoblastic T-cell lymphoma. Am J Clin Pathol 2009;131: 33-41. [53] Krishnan C, Warnke RA, Arber DA, Natkunam Y. PD-1 expression in T-cell lymphomas and reactive lymphoid entities: potential overlap in staining patterns between lymphoma and viral lymphadenitis. Am J Surg Pathol 2010;34:178-89. [54] Laurent C, Fazilleau N, Brousset P. A novel subset of T-helper cells: follicular T-helper cells and their markers. Haematologica 2010;95: 356-68. [55] Marafioti T, Paterson JC, Ballabio E, et al. The inducible T-cell costimulator molecule is expressed on subsets of T cells and is a new marker of lymphomas of T follicular helper cell-derivation. Haematologica 2010;95:432-9. [56] Baseggio L, Traverse-Glehen A, Berger F, et al. CD10 and ICOS expression by multiparametric flow cytometry in angioimmunoblastic T-cell lymphoma. Mod Pathol 2011;24:993-1003. [57] Dorfman DM, Shahsafaei A. CD200 (OX-2 membrane glycoprotein) is expressed by follicular T helper cells and in angioimmunoblastic Tcell lymphoma. Am J Surg Pathol 2011;35:76-83. [58] Krenacs L, Schaerli P, Kis G, Bagdi E. Phenotype of neoplastic cells in angioimmunoblastic T-cell lymphoma is consistent with activated follicular B helper T cells. Blood 2006;108:1110-1.

1798 [59] 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;36:784-91. [60] Murakami YI, Yatabe Y, Sakaguchi T, et al. c-Maf expression in angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 2007;31: 1695-702. [61] Attygalle A, Al-Jehani R, Diss TC, et al. Neoplastic T cells in angioimmunoblastic T-cell lymphoma express CD10. Blood 2002;99: 627-33. [62] Warnke RA, Jones D, Hsi ED. Morphologic and immunophenotypic variants of nodal T-cell lymphomas and T-cell lymphoma mimics. Am J Clin Pathol 2007;127:511-27. [63] Rodriguez-Pinilla SM, Atienza L, Murillo C, et al. Peripheral T-cell lymphoma with follicular T-cell markers. Am J Surg Pathol 2008;32: 1787-99. [64] Rodriguez Pinilla SM, Roncador G, Rodriguez-Peralto JL, et al. Primary cutaneous CD4 + small/medium-sized pleomorphic T-cell lymphoma expresses follicular T-cell markers. Am J Surg Pathol 2009; 33:81-90. [65] Cetinozman F, Jansen PM, Willemze R. Expression of programmed death-1 in primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma, cutaneous pseudo–T-cell lymphoma, and other types of cutaneous T-cell lymphoma. Am J Surg Pathol 2012;36:109-16. [66] Kozako T, Yoshimitsu M, Fujiwara H, et al. PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients. Leukemia 2009;23:375-82. [67] Picchio MC, Scala E, Pomponi D, et al. CXCL13 is highly produced by Sézary cells and enhances their migratory ability via a synergistic mechanism involving CCL19 and CCL21 chemokines. Cancer Res 2008;68:7137-46. [68] Cook JR, Craig FE, Swerdlow SH. Benign CD10-positive T cells in reactive lymphoid proliferations and B-cell lymphomas. Mod Pathol 2003;16:879-85. [69] Chu PG, Chang KL, Weiss LM, Arber DA. Immunohistochemical detection of CD10 in paraffin sections of hematopoietic neoplasms: a comparison with flow cytometry detection in 56 cases. Appl Immunohistochem Mol Morphol 2000;8:257-62. [70] Zaki MA, Wada N, Kohara M, et al. Presence of B-cell clones in T-cell lymphoma. Eur J Haematol 2011;86:412-9. [71] Tan BT, Warnke RA, Arber DA. The frequency of B- and T-cell gene rearrangements and Epstein-Barr virus in T-cell lymphomas: a com-

S. Hu et al.

[72]

[73]

[74]

[75]

[76]

[77] [78]

[79]

[80]

[81] [82]

[83]

parison between angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified with and without associated B-cell proliferations. J Mol Diagn 2006;8:466-75. Pechloff K, Holch J, Ferch U, et al. The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma. J Exp Med 2010;207: 1031-44. Dierks C, Adrian F, Fisch P, et al. The ITK-SYK fusion oncogene induces a T-cell lymphoproliferative disease in mice mimicking human disease. Cancer Res 2010;70:6193-204. Feldman AL, Sun DX, Law ME, et al. Overexpression of Syk tyrosine kinase in peripheral T-cell lymphomas. Leukemia 2008;22: 1139-43. Attygalle AD, Kyriakou C, Dupuis J, et al. Histologic evolution of angioimmunoblastic T-cell lymphoma in consecutive biopsies: clinical correlation and insights into natural history and disease progression. Am J Surg Pathol 2007;31:1077-88. de Leval L, Gisselbrecht C, Gaulard P. Advances in the understanding and management of angioimmunoblastic T-cell lymphoma. Br J Haematol 2009;148:673-89. Dogan A, Attygalle AD, Kyriakou C. Angioimmunoblastic T-cell lymphoma. Br J Haematol 2003;121:681-91. Grogg KL, Jung S, Erickson LA, McClure RF, Dogan A. Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma: a clonal T-cell lymphoproliferative disorder with indolent behavior. Mod Pathol 2008;21:708-15. Bentebibel SE, Schmitt N, Banchereau J, Ueno H. Human tonsil B-cell lymphoma 6 (BCL6)-expressing CD4 + T-cell subset specialized for B-cell help outside germinal centers. Proc Natl Acad Sci U S A 2011;108:E488-97. McHeyzer-Williams LJ, Pelletier N, Mark L, Fazilleau N, McHeyzerWilliams MG. Follicular helper T cells as cognate regulators of B cell immunity. Curr Opin Immunol 2009;2:266-73. Vinuesa CG, Cook MC. Blood relatives of follicular helper T cells. Immunity 2011;34:10-2. Morita R, Schmitt N, Bentebibel SE, et al. Human blood CXCR5(+) CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 2011;34:108-21. Miyoshi H, Sato K, Niino D, et al. Clinicopathologic analysis of peripheral T-cell lymphoma, follicular variant, and comparison with angioimmunoblastic T-cell lymphoma. Am J Clin Pathol 2012;137: 879-89.