Pathology of Peripheral T-Cell Lymphomas: Where Do We Stand? Philippe Gaularda,b,c and Laurence de Levald Peripheral T-cell lymphomas (PTCLs) are heterogeneous and uncommon malignancies characterized by a usually aggressive clinical course. The current World Health Organization (WHO) classification delineates many entities grouped according to the clinical presentation as predominantly leukemic, cutaneous, extranodal, or nodal diseases. Yet, few genetic lesions serve as entity-defining markers. Using high-throughput methods, new recurrent genetic and molecular alterations are being discovered that are expected to refine the current classification and serve as diagnostic genetic markers and targets for novel therapies. There is increasing evidence that certain cellular subsets, in particular follicular helper T cells and gamma delta T cells, represent important defining markers and/or determinants of the biology of certain entities; nevertheless, the cellular derivation of many PTCL entities remains poorly characterized and there is evidence of plasticity in terms of cellular derivation (alpha-beta, gamma-delta, natural killer [NK]) especially in several extranodal entities with a cytotoxic profile. While most clonal NK/T-cell proliferations are in general highly malignant, some more indolent forms of NK or T-cell lymphoproliferations are being identified. Semin Hematol 51:5–16. C 2014 Elsevier Inc. All rights reserved.

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eripheral T-cell lymphomas (PTCLs)—encompassing all neoplasms derived from post-thymic T lymphocytes or mature natural killer (NK) cells —are overall rare but heterogeneous, representing less than 15% of all non-Hodgkin lymphomas worldwide. Strikingly, their epidemiology shows important geographic variations, partly overlapping with the endemy of certain viral infections and linked to the heterogeneous distribution of genetic backgrounds.1,2 Most entities are clinically aggressive with a dismal prognosis. The complexity of the biology of PTCLs is only partly deciphered. Here we will review the current status and discuss the issues and challenges relevant to pathological classification and diagnosis of PTCLs, with a focus on recent discoveries and novel molecular insights. Our review will be mostly restricted to T-cell neoplasms presenting as tissue infiltrates while the leukemic a

Department of Pathology, AP-HP, Groupe hospitalier Henri Mondor– Albert Chenevier, Créteil, France. b Université Paris-Est, Faculté de Médecine, Créteil, France. c Inserm U955, Institut Mondor de Recherche Biomédicale, Créteil, France. d Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. The authors have no financial disclosure or conflict of interest. Address correspondence to Philippe Gaulard, MD, Department of Pathology, Hôpital Henri Mondor, F-94010 Créteil, France. E-mail: [email protected] 0037-1963/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminhematol.2013.11.003

Seminars in Hematology, Vol 51, No 1, January 2014, pp 5–16

forms and the usual cutaneous T-cell lymphomas, like mycosis fungoides and Sézary syndrome, will be discussed only briefly and addressed essentially by synoptic summary tables.

T-CELL AND NK CELL SUBSETS Two classes of mature T cells are recognized: alphabeta, gamma-delta, both expressing CD3. Alpha-beta T cells comprise CD4þ (mainly helper) and CD8þ (mainly cytotoxic) subsets. Gamma-delta T cells (CD4-CD8- or CD4-CD8þ) comprise o5% of T cells and are preferentially distributed in the skin, mucosae, and to the splenic red pulp. NK cells are distinguished by the absence of T-cell receptor (TCR) rearrangement and membrane TCR expression. NK cells share some markers with T cells such as CD2, CD7, CD45RO, and cytoplasmic (but not surface) CD3. NK cells are usually CD4-CD8- but may be CD8þ, and they express one or several of the “NK-associated” antigens (CD11b, CD16, CD56, CD57, NK receptors), which are, however, not entirely specific. Both NK cells and activated cytotoxic T cells express cytotoxic proteins, T-cell intracellular antigen (TIA)-1 (a marker of cytotoxic cells in general), and perforin and granzyme B (both expressed upon activation and not in the resting stage). Functionally, the majority of αβT cells recognizing the antigen in a major histocompatibility complex (MHC)restricted fashion in the presence of an antigen-presenting cell, are part of the adaptative immune system that features 5

6

specificity and memory of the immunological response, whereas NK cells, a subset of the γδ T cells and a minor subset of αβ T cells are part of the innate immunity.

THE WHO CLASSIFICATION OF PTCLs The World Health Organization (WHO) principles of a multiparametric definition of lymphoma entities—based on morphologic, immunophenotypic, genetic, and clinical features, and putative normal cellular counterpart—have proven rather difficult for the delineation of NK/T-cell– derived neoplasms,2 somewhat reflecting the complexity of the T-cell system, with numerous functional subsets, and evidence of functional plasticity. The clinical features and disease localization are critical in defining NK/T-cell lymphoma entities (Table 1), which may present as disseminated (leukemic) (summarized in Table 2), predominantly extranodal or cutaneous, or predominantly nodal diseases (Figure 1).2 Some entities are relatively homogeneous and/or well defined, others have uncertain borders (typically PTCL not otherwise specified [NOS]), and some entities are provisional. In the light of recent findings there is increasing evidence that the cell of origin is a major determinant of PTCL biology; nevertheless, the cellular derivation of many PTCL entities remains poorly characterized or appears to be heterogeneous.3–5

P. Gaulard and L. de Leval

The tumor cells strongly express CD30, are by definition ALKþ, and usually coexpress the epithelial membrane antigen (EMA). They frequently exhibit so-called “null” immunophenotype with defective expression of the TCR/CD3 and of many T-cell antigens, despite a T-cell genotype.9,10 Most cases express cytotoxic-associated antigens. In vitro, constitutively activated NPM-ALK drives oncogenesis through engagement of multiple signaling pathways, including the JAK/STAT and the PI3K/Akt pathways. (for review, see Lai and Ingham11). No etiologic agent has been linked to ALCL, but there have been case reports of systemic ALKþ ALCL presenting with skin lesions occurring after an insect bite, suggesting the possible role of inflammatory mediators released upon the bite in eliciting lymphoma development.12

ALK-NEGATIVE ANAPLASTIC LARGE CELL LYMPHOMAS The WHO recognizes two other entities of ALCL, negative for ALK translocations and ALK expression, systemic ALK- ALCL, and primary cutaneous ALCL (Figure 1). Moreover, there have been recent reports of primary extranodal ALK- ALCL occurring in the vicinity of breast implants (breast implant-associated ALCL).

ANAPLASTIC LARGE CELL LYMPHOMA, ALK-POSITIVE

Systemic ALK-Negative ALCL

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is currently the sole PTCL entity defined by a genetic alteration, ie, rearrangement of the ALK gene @2p23. There is a variety of ALK translocations, the most common fusing ALK to the nucleophosmin gene (NPM) @5q35. All translocations induce formation of chimeric fusion proteins that induce constitutive ALK tyrosine kinase activation. ALKþ ALCL preferentially affects children and young adults. It usually presents with lymphadenopathy, but involvement of extranodal sites (skin, bone, soft tissues) is frequent. Systemic symptoms are common. Most patients present with stage III or IV disease. Overall ALKþ ALCLs are aggressive neoplasms with good response to therapy and survival significantly better than ALK- ALCL (perhaps as a result of the younger age of ALKþ ALCL patients) and other PTCLs.1,6,7 The type of translocation determines the subcellular distribution of ALK but has no prognostic significance. The morphology is variable. The classical form (common pattern) (75% of the cases) comprises sheets of large cells, showing a cohesive growth pattern and sinusoidal involvement composed of “hallmark cells,” showing an eccentric kidney- or horseshoe-shaped nucleus and a prominent Golgi region. The small cell and lymphohistiocytic variants (each accounting for o10% of the cases) are both associated with a less favorable outcome.8

This entity (provisional), is defined as a large cell lymphoma with comparable morphology to classical ALKþ ALCL, uniformly strongly positive for CD30 but lacking ALK expression.2 Compared to ALKþ ALCL, ALK- ALCL tends to occur in older individuals, and to have more preserved T-cell immunophenotype with less frequent expression of cytotoxic markers and of EMA.6 In the absence of consistent molecular marker for ALKALCL, a three-gene model has been proposed to distinguish ALK- ALCL from PTCL-NOS.13 Chromosomal aberrations differ from those of ALKþ ALCL.14 While distinct signatures have been derived from the comparison of ALKþ and ALK- ALCL,15 transcriptional profiling studies have also evidenced much commonality between ALKþ and ALK- ALCL, and between ALK- ALCL and a subset of PTCL-NOS with strong CD30 expression.10,16 Extra copies of PAX-5 are detected in a subset of ALK- ALCL.17 Rearrangements involving the 6p25.3 locus have been recently reported in approximately 20% of systemic and 30% of cutaneous ALKALCLs.18 The breaks @6p25.3 involve either IRF4 or DUSP22 (encoding a dual-specificity phosphatase that inhibits TCR signaling). The recurrent t(6;7)(p25.3; q32.3) translocation entails downregulation of DUSP22 and overexpression of MIR29, suggesting that DUSP22 might function as a tumour suppressor and MIR29 as an oncogene.19

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Table 1. Current WHO Classification and Worldwide Frequency of Peripheral T-Cell and NK Cell Lymphomas

PTCL Entities

Frequency Cellular Derivation (%)†

Disseminated/leukemic T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorders of NK cells* Aggressive NK cell leukemia Systemic EBV-positive T-cell lymphoproliferative disease of childhood Adult T-cell leukemia/lymphoma Extranodal Extranodal NK/T-cell lymphoma, nasal type (ENKTCL) Enteropathy-associated T-cell lymphoma (EATL) Hepatosplenic T-cell lymphoma (HSTL) Cutaneous Mycosis fungoides Sézary syndrome Primary cutaneous CD30þ T-cell lymphoproliferative disorders Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma Primary cutaneous γδ T-cell lymphoma Primary cutaneous CD8þ aggressive epidermotropic cytotoxic T-cell lymphoma* Primary cutaneous CD4þ small/medium T-cell lymphoma* Hydroa vacciniforme-like lymphoma

9.6 10.4 4.7 1.4

Phenotype

Tαβ Tαβ (more rarely Tγδ) NK

Non-cytotoxic Cytotoxic (A) Cytotoxic (A)

NK Tαβ

Cytotoxic (A) Cytotoxic (A)

Tαβ

T regulatory

NK (more rarely Tγδ or Tαβ) IEL, Tαβ (more rarely Tγδ) Tγδ (Vδ1) (more rarely Tαβ)

Cytotoxic (A) Cytotoxic (A) Cytotoxic (NA)

Tαβ (mostly CD4) Non-cytotoxic Tαβ (mostly CD4) Non-cytotoxic Tαβ (mostly CD4) 1.7

Tαβ (CD4)

Cytotoxic (A)

0.9

Tαβ (CD4) Tαβ (CD8)

Cytotoxic (A) Cytotoxic (A)

Tγδ (Vδ2) Tαβ (CD8)

Cytotoxic (A) Cytotoxic (A)

Tαβ (CD4, TFH)

TFH

Tαβ (rarely NK)

Cytotoxic (A)

Nodal Peripheral T-cell lymphoma, not otherwise 25.9 specified Angioimmunoblastic T-cell lymphoma 18.5 Anaplastic large-cell lymphoma, 6.6 ALK-positive 5.5 Anaplastic large-cell lymphoma, ALK-negative*

Tαβ (CD44CD8), Variable, a subset TFH, a rarely Tγδ small subset cytotoxic (A) TFH Tαβ (CD4, TFH) Tαβ (Th2?) Cytotoxic (A) Tαβ (Th2?)

Cytotoxic (A)

*Provisional entities. † Statistics are based on pathologic anatomy registries, with under-representation of leukemic and cutaneous entities. Abbreviations: ALK, anaplastic lymphoma kinase; EBV, Epstein-Barr virus; NK, natural killer; IEL, intestinal intraepithelial lymphocyte; TFH, follicular helper T cell. Cytotoxic (NA) ¼ non-activated (expression of TIA-1 only); (A) ¼ activated (expression of perforin and/or granzyme B in addition to TIA-1). Adapted from Swerdlow et al. 2

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Table 2. Major Distinguishing Features of NK/T-Cell Neoplasms With a Disseminated/Leukemic Presentation

Epidemiology

Clinical Features

Morphology Small/mediumsized mature lymphocytes, visible nucleolus, nongranular cytoplasm Large granular lymphocytes (2-20109/L)

Chronic lymphoproliferative disorder of NK cells

Adults No gender predominance

Asymptomatic or cytopenia, slight lymphocytosis, rare splenomegaly

Large granular lymphocytes (usually 42 x 109/L)

Adult T-cell lymphoma/ leukemia (ATLL)2

Adults (long latency) Endemic regions for HTLV1 Southwestern

Highly variable from leukemic variants to lymphoma forms (ADP, skin, spleen, gastrointestinal tract, lung)

Broad morphology (pleomorphic small to large cells), often

T-cell large granular lymphocytic leukemia (LGL)

Adults (median age 65 yr), rare

αβ T cells CD2þ, CD3þ, CD7þ, CD4þ, more rarely CD4þ/CD8þ or CD8þ TCL1þ Mostly αβ T cells, more rarely γδ T cells CD3þ, CD8þ (more rarely CD4-/CD8-), CD16þ, CD57þ, Activated cytotoxic (TIA1þ, GrBþ, Perfþ) NK lineage CD3eþ cyt, CD3-surface, TCR-, CD2þ, CD5-, often CD56þ, CD57-, CD8 variable TIA1þ, GrBþ, Perfþ αβ T cells with features of regulatory T cells (CD25þ, FoxP3þ)

Prognosis

Inv(14)(q11; Aggressive, q32.1), median t(14;14) (TCL1) or survival o1 yr t(X;14) (MTCP1) Resistance to conventional chemotherapy STAT3 mutations (20-30% of the cases)

Indolent Nonprogressive

STAT3 mutations Indolent (20%–30% of the Nonprogressive cases)

Monoclonal integration of HTLV1 (role of Tax)

Poor, mostly fatal, median survival o 3 mo in most studies

P. Gaulard and L. de Leval

Splenomegaly, hepatomegaly, skin (20%), generalized lymphadenopathy, Lymphocytosis (usually 4100 x 109/L) Adults Asymptomatic or Frequent context cytopenia, slight of auto-immune lymphocytosis, disorder (RA) moderate splenomegaly (50%)

T-cell prolymphocytic leukemia (T-PLL)2

Cell Derivation, Phenotype

Genetic and Molecular Features; Viral Association

NK lineage CD3eþ cytoplasm, CD3/TCR(surface) CD5-, CD56þ, CD4-/ CD8-, TIA1þ, GrBþ, Perfþ Variable pleomorphic medium to large atypical cells B symptoms, splenomegaly, cytopenia, leukemic cells, frequent hemophagocytic syndrome

Mostly CD4þ, polylobated ("flower" cells) rarely CD8þ, or CD4þ/CD8þ

EBV (clonal integration) 6q deletion,

Aggressive, fatal

Pathology of peripheral T-cell lymphomas

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Primary Cutaneous ALCL Primary cutaneous ALCL has overlapping clinical and pathological features with lymphomatoid papulosis, which together constitute the spectrum of primary CD30þ cutaneous lymphoproliferative diseases. Primary cutaneous ALCL presents as solitary skin nodules or tumors that may regress and recur, and usually carries a good prognosis. Cases with mucosal presentation in the head and neck have also been reported.20 Regional lymph node involvement may occur, but does not necessarily indicate an aggressive clinical course. The tumor comprises sheets of large anaplastic CD30þ cytotoxic T cells that are negative for EMA and ALK. Rearrangements of the 6p25.3 locus that occur in a subset of primary cutaneous ALCL are almost never found in lymphomatoid papulosis.21 ALK staining is required as skin-restricted ALKþ ALCLs, with a histopathological and clinical picture indistinguishable from that of primary cutaneous ALCL, have been recently reported in children.22

Breast Implant-Associated ALCL Numerous reports have documented the occurrence of ALK- ALCLs in association with saline or silicone breast implants. Breast implant-associated ALCL is overall rare. It commonly presents with an effusion (seroma) between the implant and the surrounding fibrous capsule, with or without capsular contracture, more rarely as a mass lesion. Breast implant-associated ALCLs have a morphology, cytokine profile, and biological behavior similar to those of primary cutaneous ALCLs.23 When presenting with an effusion alone, patients with breast implant-associated ALCLs have an excellent longterm survival, even in the absence of specific therapy other than implant removal. In contrast, presentation with a mass lesion is associated with a higher rate of relapse and may require more aggressive therapy.24

Aggressive NK cell leukemia

Japan, Caribbean islands, Central Africa) Teenager/young adult Slight male predominance Asians, Latin Americans

PTCLs WITH A FOLLICULAR HELPER PHENOTYPE T follicular helper (TFH) cells have recently emerged as a distinct functional subset of effector T-helper cells, of peculiar relevance to hematopathology since a significant proportion of T-cell neoplasms appear to derive from TFH cells (Figure 1) (for review see Gaulard et al25). TFH cells reside in germinal centers (GCs) and interact with GC B cells to promote B-cell survival and immunoglobulin classswitch recombination and somatic hypermutation, ultimately yielding high-affinity plasma cells and memory B cells. TFH differentiation is dependent upon the transcriptional repressor BCL6. The functions of TFH cells correlate with a specific secretory profile (expression of interleukin [IL]-21 and CXCL13 chemokine critical for Bcell recruitment into GCs and for B-cell activation) and a specific cell surface immunophenotype including the expression of CXCR5 (receptor to CXCL13, essential to

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P. Gaulard and L. de Leval

Figure 1. Putative cellular derivation and known oncogenic pathways for the main nodal and selected cutaneous PTCL entities.

localization of TFH cells to GCs) and co-stimulatory molecules such as ICOS, PD1, CD28, and CD40L that favor strong interactions with B cells.

Angioimmunoblastic T-Cell Lymphoma Angioimmunoblastic T-cell lymphoma (AITL) is the prototypic neoplasm derived from TFH cells3,26 and is one of the two most common PTCLs wordwide.1 The disease affects elderly adults, and usually manifests by generalized peripheral lymphadenopathy, systemic symptoms, rash, hypergammaglobulinemia, and autoimmune manifestations with a median survival o3 years (for review, see de Leval et al27). AITL comprises a diffuse polymorphous infiltrate including variable proportions of neoplastic T cells (atypical medium-sized with clear cytoplasm), admixed with small lymphocytes, histiocytes, immunoblasts, eosinophils, and plasma cells; a marked proliferation of arborizing high endothelial veinules; and a proliferation of follicular dendritic cells (FDCs). Other architectural patterns (AITL with hyperplastic or with depleted follicles) are seen less frequently. The neoplastic cells consist of clonal mature αβ CD4þ T cells expressing several markers of the TFH cells (CXCL13, PD1, ICOS, CD200, BCL6, SAP, cMAF), as well as, frequently, CD10.25,28 Overall, PD1 and ICOS are more sensitive than CXCL13 or CD10, which are conversely more specific, in identifying the neoplastic TFH

cells. The large blastic cells are B cells, sometimes resembling Hodgkin or Reed Sternberg cells, usually but not always infected by Epstein-Barr virus (EBV), most often scattered throughout the tissues, sometimes numerous (B-cell–rich AITL). The abundance of B cells correlates with the detection of B-cell clonality. A subset of patients go on to develop an EBV-associated B-cell lymphoproliferation, in most instances an EBV-positive diffuse large B-cell lymphoma, less commonly an EBVnegative B-cell or plasma cell neoplasm.29,30 The cellular derivation of AITL from TFH cells likely explains several of the peculiar pathological and biological features inherent to this disease, ie, the expansion of B cells, the proliferation of FDCs, hypergammaglobulinemia, and auto-immune manifestations, and CXCL13 probably is a key mediator of these effects. In addition, normal TFH cells can suppress T-cell responses, and may therefore contribute to defective T-cell responses in AITL. Interestingly, the microenvironment signature has been found of prognostic relevance in one study.26 The molecular alterations underlying the neoplastic transformation of TFH cells remain unknown. By cytogenetic analysis clonal aberrations—most commonly trisomies of chromosomes 3, 5, and 21, gain of X, and loss of 6q—are detected in up to 90% of the cases. Recent works have evidenced recurrent point mutations in TET2, IDH2, and DNMT3A—coding for enzymes involved in DNA methylation and epigenetic control of transcription —in about 50%, 30%–40%, and 10% of AITL cases,

Pathology of peripheral T-cell lymphomas respectively.31–33 TET2 mutations are associated with advanced-stage disease, high International Prognostic Index (IPI) scores, and a shorter progression-free survival. Finally, a recent study identified CD28-ICOS fusion transcripts in some cases of AITL, a finding of interest in view of the role of these costimulatory molecules in the interaction between TFH and B cells.34

Peripheral T-Cell Lymphoma, NOS, Follicular Variant This rare variant of PTCL, NOS comprises cases with a truly follicular pattern (F-PTCL), mimicking follicular lymphoma,35 and cases with a perifollicular growth pattern mimicking marginal zone lymphoma, or involving expanded mantle zones (progressive transformation of germinal centers-like). The neoplastic cells are CD3þ CD4þ αβ T cells strongly expressing TFH markers (PD1þ ICOSþ CXCL13þ BCL6þ CD10 þ/-, CD57-/þ).36 In addition, F-PTCL may present biological clinicopathological features overlapping with those of AITL, 36,37 therefore questioning its relationship to AITL, inasmuch as patients with F-PTCL may present with recurrent lesions as AITL and vice-versa. A chromosomal translocation t(5;9)(q33;q22), involving ITK and SYK tyrosine kinases, is found in about 20% of FPTCLs.38 ITK-SYK has transforming properties in vitro, and induces a T-cell lymphoproliferative disease in mice through a signal that mimics TCR activation.39

Primary Cutaneous CD4þ Small/Medium-Sized T-Cell Lymphoma This lymphoproliferation, delineated as a provisional lymphoma entity, presents as a solitary skin nodule in the head and neck region, and comprises a non-epidermotropic dermic infiltrate by atypical small/medium-sized cells, accompanied by plasma cells and histiocytes. The atypical cells are clonal CD4þ PD1þ CXCL13þ/- BCL6þ/- T cells usually negative for CD10.40 There is usually an abundant reactive component, including B cells, some of which are large and/or EBV-infected. A monoclonal TCR gene rearrangement is demonstrated in most cases. Most cases have features of lesions previously diagnosed as pseudolymphoma, and an indolent clinical course.41

Peripheral T-Cell Lymphoma, NOS Expressing TFH Markers In addition to the above-mentioned TFH-derived PTCL subtypes, a subset of cases classified as PTCL, NOS based on their pathological features, harbor imprints of the TFH signature and/or express TFH markers, and frequently exhibit some AITL-like clinical and/or pathological features, questioning whether they represent AITL evolving into PTCL, NOS-like tumors, and suggesting that the spectrum of AITL may be broader than is currently thought.3,42 It remains to be defined which

11

criteria should be used to define the borders of AITL entity.

PTCLs DERIVED FROM γδ T CELLS Reflecting the paucity and distribution of normal γδ T cells, γδ PTCLs comprise rare, mostly extranodal malignancies, with cytotoxic phenotype, an aggressive behavior, and poor outcome. The WHO classification comprises two lymphoma entities usually derived from γδ T cells, ie, hepatosplenic T-cell lymphoma, and primary cutaneous γδ T-cell lymphoma (for review, see Tipodo et al43). In addition minor subsets of other entities (T-cell large granular lymphocytic leukemia [T-LGL], ENKTCL, enteropathy-associated T-cell lymphoma [EATL]), as well as a small minority of PTCLs, NOS, also have a γδ phenotype. Until recently, expression of the γδ TCR in tissue samples could only be assessed by flow cytometry or frozen section immunohistochemistry. Monoclonal antibodies detecting the constant region of the TCRγ or TCRδ chain in paraffin sections have now been made available, and valuably assist in the characterization of T-cell lymphomas and the identification of γδ TCLs. These developments have also led to the recognition of a group of “silent TCR” PTCLs, indicating that a lack of TCRβ expression cannot be used to predict a γδ lineage.

Hepatosplenic T-Cell Lymphoma Hepatosplenic T-cell lymphoma (HSTL) is the prototype and the first entity initially defined by its γδ derivation (although there are rare cases with an αβ phenotype and similar clinicopathologic and molecular features).4 HSTL predominantly affects young male adults and may arise in the setting of chronic immune suppression or prolonged antigenic stimulation, particularly in solid organ transplant recipients or in children treated by azathioprine and infliximab for Crohn’s disease.44 The disease typically presents with hepatosplenomegaly, thrombocytopenia, and systemic symptoms, without lymphadenopathy or peripheral blood involvement. HSTL comprises a monotonous infiltrate of atypical medium-sized lymphoid cells, which infiltrate the cords and sinuses of the splenic red pulp, the sinusoids of the liver, and the bone marrow sinuses. HSTL is thought to derive from functionally immature cytotoxic γδ T cells of the splenic pool with vδ1 gene usage. The usual immunophenotype is CD3þ CD5 CD56þ CD4/CD8 TCRγδþ with a non-activated cytotoxic profile. The majority of the cases carry an isochromosome 7q. HSTL is a very aggressive disease with most patients dying from lymphoma within 2 years of diagnosis. The differential diagnosis include other T-cell lymphoma with a splenic presentation with or without cytopenias, mainly T-LGL leukemia (an indolent proliferation of αβ and uncommonly γδ T cells with an

12 activated cytotoxic phenotype, associated with STAT3 mutations in around one third of the cases) and aggressive NK-cell leukemia, which is EBV-associated (see Table 2).

Primary Cutaneous γδ T-Cell Lymphoma Primary cutaneous γδ T-cell lymphoma (PCGDTCL) (provisional entity) is very rare. The disease mostly occurs in adults (median age, 60 years) as deep plaques, patches, or tumors, often ulcerated, on the legs, trunk, and arms, with no lymphadenopathy or bone marrow involvement. A subset of patients have previous or concomitant autoimmunity, other lymphoproliferative disorders, visceral malignancies, or viral hepatitis. A hematophagocytic syndrome is common. The lymphoid infiltrate may feature a panniculitis-like pattern, or a predominantly dermal distribution with or without epidermotropism. The tumors cells are CD3þ CD5- CD4-/CD8- CD56þ βF1- TCRγδþ small- to largesized with an activated cytotoxic profile, typically featuring a vasculitic pattern, superficial necrosis and ulceration, fat necrosis, and karyorrhexis. Consistent with the prevalence of vδ2 γδ T cells residing in the skin, PCGDTCLs display vδ2 gene usage. EBV is negative. PCGDTCLs usually have an aggressive clinical course with an approximately 10% fiveyear overall survival. However, occasional cases have been reported with indolent clinical courses, and systematic TCR immunophenotyping of various primary cutaneous lymphomas has revealed that a small proportion of cases diagnosed as other lymphoma entities (ie, lymphomatoid papulosis, mycosis fungoides) exhibit a γδ immunophenotype, which does not appear to impart a worse outcome.45 The major differential diagnoses include subcutaneous panniculitis-like T-cell lymphoma (SPTCL) (entity restricted to cases of αβ derivation, showing selective infiltration of the subcutis by atypical CD8þ CD56- CD3þ cytotoxic T cells rimming subcutaneous adipocytes, of good prognosis), lupus panniculitis, and primary cutaneous epidermotropic CD8þ T-cell lymphoma.41

Non-hepatosplenic and Non-cutaneous γδ PTCLs There have been reports and series of other γδ TCLs presenting in other mainly extranodal (intestines, lung, orbit) or more rarely in nodal sites. A high proportion of type II EATLs is also derived from γδ T cells. The non-hepatosplenic γδ T-cell lymphomas, including those involving the skin, have been reported under the term “mucocutaneous γδ TCL.”46 In contrast with HSTL, non-hepatosplenic γδ PTCLs are heterogeneous clinically, morphologically, and at the molecular level, indicating that non-HSTL γδ TCL does not represent a single entity.5

EXTRANODAL NK/T-CELL LYMPHOMA Extranodal NK/T-cell lymphoma, nasal type (ENKTCL) represents the prototype of EBVþ NK cell, or more rarely,

P. Gaulard and L. de Leval

T-cell neoplasms. ENKTCL is not exceptional in western countries but predominantly affects middle-aged men in Asia, Mexico, and South America. It presents as tumors or destructive lesions in the nasal cavity, maxillary sinuses, or palate, and despite a localized presentation in most patients, tends to relapse locally or at other extranodal sites, such as the skin, and has an overall 40%–50% five-year survival rate. “Extranasal NK/T cell lymphomas” otherwise similar to the nasal NKTCL, may present in other localizations, especially in the skin, gastrointestinal tract, or testis, and tend to have a more adverse clinical outcome.47 ENKTCL ranges from monomorphic small/mediumsized to large cell lymphomas, and is characterized by frequent features of angioinvasion and angiocentrism, and common necrosis, accounting for frequent diagnostic difficulties on small biopsies. Neoplastic cells express cytoplasmic CD3 (CD3εþ), are CD2þ, CD5-, CD56þ, and have an activated cytotoxic profile. Most cases are derived from NK cells; however, up to 38% of the cases derive from clonal T cells with a γδ̣ or more rarely αβ TCR configuration. By definition, all cases are associated with EBV, best demonstrated by in situ hybridization.2 EBV is clonally present in an episomal form in the tumor cells and exerts oncogenic effects through the production of cytokines such as IL-9 and IL-10, and upregulation of IP10/MIP2 chemokines that may contribute to vascular damage and secondary necrosis,48 while TNF̃ α production may explain the common hematophagocytic syndrome. Partial deletion of chromosome 6 (6q21-25) is a recurrent aberration in ENKTCL. Several candidate tumor-suppressor genes, such as PRDM1, ATG5, AIM1, and HACE1, are mapping to that region and their inactivation by deletion and/or methylation might be involved in lymphomagenesis.49,50 The molecular signature of ENKTCL, irrespective of the cellular derivation, is distinct from that of other PTCLs, including overexpression of granzyme H. Compared to normal NK cells, ENKTCL is characterized by activation of plateletderived growth factor–derived receptor alpha (PDGFRA), and of the AKT, JAK/STAT, and nuclear factor-kappaB pathways.50,51 JAK3 somatic-activating mutations found in 20%–30% of ENKTCLs likely contribute to the constitutive activation of STAT3. Aggressive NK cell leukemia, also EBV-associated and derived from NK cells, is regarded as the systemic form of NKTCL (see Table 2).

ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA EATL defines an intestinal tumor derived from intestinal intraepithelial lymphocytes (IEL). It frequently presents as ulcerated jejunal lesions, often perforated, with frequent involvement of regional lymph nodes, and the disease carries a very dismal prognosis.52 EATL needs to be distinguished from clinically indolent

Pathology of peripheral T-cell lymphomas

13

lymphoproliferations of the gastrointestinal tract, ie, NK cell enteropathy and recently recognized CD8þ T-cell indolent lymphoproliferations.53

rarely in type II while gains of the MYC oncogene locus at 8q24 are frequent.56

EATL Type I

PERIPHERAL T-CELL LYMPHOMA, NOS

EATL type I occurs as a complication of glutensensitive enteropathy, and is most common in Nordic European countries with a high prevalence of celiac disease. In patients with symptomatic celiac disease, the development of EATL may be preceded by refractory celiac disease (characterized by monoclonal IEL with an aberrant immunophenotype) or chronic ulcerative jejunitis (multifocal ulcerated microlymphomas).54,55 In around half of the patients EATL represents the first manifestation of enteropathy. The majority of patients have celiacdisease HLA haplotypes (HLA-DQ2/8). EATL type I usually comprises pleomorphic cells, often with a predominance proportion of large or even anaplastic cells. Necrosis and admixed inflammation are common. The adjacent non-tumor mucosa usually shows enteropathic features (increase of IEL with or without villous atrophy). The neoplastic cells express the mucosal homing receptor CD103 characteristic of IEL, are usually CD3þ CD5- CD4- CD8- αβ T cells with an activated cytotoxic profile and frequent coexpression of CD30. Complex chromosomal gains at 9q31.3-qter or deletions of 16q21.1 are found in the majority of the cases, but gains or partial trisomy of 1q22-44 might be more specific.56

PTCL, NOS, reported as the most common PTCL entity, is defined by default for cases not fulfilling the criteria for more “specific” entities, and de facto the most heterogeneous entity. Presentation is usually nodal but can affect any site. The median age of patients is in the seventh decade, and 65% of the patients have stage IV disease. The patients have an overall poor outcome (20%–30% 5-year survival). Morphology is highly variable. PTCLs, NOS typically contain a mixture of small and large atypical pleomorphic cells expressing CD3 with frequent loss of CD7, more rarely CD5 and/or CD2. Most cases are CD4þCD8-. EBV has been recorded in up to 50% of the cases in bystander B cells and/or a variable fraction of the tumor cells, a finding correlated with a worse survival.60,61 The rare lymphoepithelioid variant of PTCL, NOS, characterized by an abundant background of histiocytes, consists of neoplastic small CD8þ cytotoxic T cells,62 and may be associated with better outcome. Attempts to subclassify PTCL, NOS according to immunological features (CD4 v CD8 subsets, Th1 v Th2 helper function, differentiation stage) have overall not proven meaningful. A molecular subgroup with features of cytotoxic T lymphocytes and a poor survival has been delineated in one microarray-based study,26 and accordingly expression of cytotoxic molecules in PTCL, NOS in general correlates with a poorer prognosis.63 Oncogenic alterations are poorly characterized (Figure 1). Expression and constitutive activation of PDGFRA and SYK tyrosine kinases appear to represent features common to many PTCLs, and although their role in lymphomagenesis remains poorly understood, they represent novel potential therapeutic targets.64 Recurrent abnormalities involving several p53-related genes have been recently evidenced in PTCLs. In particular, novel TP63 rearrangements encoding fusion proteins homologous to ΔNp63, a dominantnegative p63 isoform that inhibits the p53 pathway, are seen in approximately 6% of PTCLs and are associated with inferior overall survival.65

EATL Type II Type II EATL, also termed “monomorphic CD56þ intestinal T-cell lymphoma,” is overall very rare.57 Typically, it comprises a monomorphic proliferation of medium-sized cells, without necrosis and inflammation.58 Although this remains controversial, most studies suggest the lack of association with celiac disease in the majority of the cases.57 The neoplastic cells are usually CD3þ CD5- CD7þ CD4-/CD8þ CD56þ, with an activated cytotoxic immunophenotype. Aberrant expression of CD20 and/or other B-cell markers may be seen in up to 25% of the cases. The megakaryocyte-associated tyrosine kinase (MATK) has been documented as a novel marker of type II EATL. EATL type II appears heterogeneous in terms of TCR expression, in a study from Hong Kong, 78% of the cases were of γδ̣origin, therefore reflecting again plasticity in terms of cell derivation in many extranodal cytotoxic PTCL entities.59 Increased IEL in distant mucosa have an immunophenotype that is either concordant or variably discordant with that of the invasive tumor.59 The genetic profile of EATL type II partly overlaps with that of type I, with 9q33-q34 gains and 16q21.1 deletions common to both types. However, gains in 1q and 5q (commonly found in type I EATL) occur only

CONCLUSION Despite insights in the determination of cell counterpart for several PTCL entities, plasticity observed in term of cell derivation especially in some extranodal entities, may lead to some confusion in the use of markers of cellular derivation for their definition. Novel genetic and molecular abnormalities are being described, and it is likely that the current classification will change in the future to incorporate these novel discoveries.

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REFERENCES 1. Armitage J, Vose J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008; 26:4124-30. 2. Swerdlow S, Campo E, Harris N, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2008. 3. 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. 4. Travert M, Huang Y, de Leval L, et al. Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets. Blood. 2012;119:5795-806. 5. Garcia-Herrera A, Song JY, Chuang SS, et al. Nonhepatosplenic gammadelta T-cell lymphomas represent a spectrum of aggressive cytotoxic T-cell lymphomas with a mainly extranodal presentation. Am J Surg Pathol. 2011;35: 1214-25. 6. Savage KJ, Harris NL, Vose JM, et al. ALK-negative anaplastic large-cell lymphoma (ALCL) is clinically and immunophenotypically different from both ALK-positive ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111:5496-504. 7. Sibon D, Fournier M, Briere J, et al. Long-term outcome of adults with systemic anaplastic large-cell lymphoma treated within the Groupe d'Etude des Lymphomes de l'Adulte trials. J Clin Oncol. 2012;30:3939-46. 8. Lamant L, McCarthy K, d'Amore E, et al. Prognostic impact of morphologic and phenotypic features of childhood ALKpositive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol. 2011;29:4669-76. 9. Geissinger E, Sadler P, Roth S, et al. Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30þ T-cell lymphoproliferations. Haematologica. 2010;10:1697-704. 10. Bisig B, de Reynies A, Bonnet C, et al. CD30-positive peripheral T-cell lymphomas share molecular and phenotypic features. Haematologica. 2013;98:1250-8. 11. Lai R, Ingham RJ. The pathobiology of the oncogenic tyrosine kinase NPM-ALK: a brief update. Ther Adv Hematol. 2013; 4:119-31. 12. Lamant L, Pileri S, Sabattini E, et al. Cutaneous presentation of ALK-positive anaplastic large cell lymphoma following insect bites: evidence for an association in five cases. Haematologica. 2010;95:449-55. 13. Agnelli L, Mereu E, Pellegrino E, et al. Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma. Blood. 2012;120:1274-81. 14. Salaverria I, Bea S, Lopez-Guillermo A, et al. Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas. Br J Haematol. 2008;140:516-26. 15. Lamant L, de Reynies A, Duplantier MM, et al. Geneexpression profiling of systemic anaplastic large-cell lymphoma reveals differences based on ALK status and two distinct morphologic ALKþ subtypes. Blood. 2007;109:2156-64.

P. Gaulard and L. de Leval

16. Piva R, Agnelli L, Pellegrino E, et al. Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms. J Clin Oncol. 2010;28:1583-90. 17. Feldman AL, Law ME, Inwards DJ, et al. PAX5-positive T-cell anaplastic large cell lymphomas associated with extra copies of the PAX5 gene locus. Mod Pathol. 2010;23: 593-602. 18. Feldman AL, Law M, Remstein ED, et al. Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas. Leukemia. 2009;23:574-80. 19. Feldman AL, Dogan A, Smith DI, et al. Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. Blood. 2011;117:915-9. 20. Sciallis AP, Law ME, Inwards DJ, et al. Mucosal CD30positive T-cell lymphoproliferations of the head and neck show a clinicopathologic spectrum similar to cutaneous CD30-positive T-cell lymphoproliferative disorders. Mod Pathol. 2012;25:983-92. 21. Wada DA, Law ME, Hsi ED, et al. Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies. Mod Pathol. 2010;24:596-605. 22. Oschlies I, Lisfeld J, Lamant L, et al. ALK-positive anaplastic large cell lymphoma limited to the skin: clinical, histopathological and molecular analysis of 6 pediatric cases. A report from the ALCL99 study. Haematologica. 2013;98:50-6. 23. Thompson PA, Lade S, Webster H, et al. Effusionassociated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinico-pathological entity. Haematologica. 2010;95:1977-9. 24. Aladily TN, Medeiros LJ, Amin MB, et al. Anaplastic large cell lymphoma associated with breast implants: a report of 13 cases. Am J Surg Pathol. 2012;36:1000-8. 25. Gaulard P, de Leval L. Follicular helper T cells: implications in neoplastic hematopathology. Semin Diagn Pathol. 2011; 28:202-13. 26. 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. 27. de Leval L, Gisselbrecht C, Gaulard P. Advances in the understanding and management of angioimmunoblastic T-cell lymphoma. Br J Haematol. 2010;148:673-89. 28. Bisig B, Thielen C, Herens C, et al. c-Maf expression in angioimmunoblastic T-cell lymphoma reflects follicular helper T-cell derivation rather than oncogenesis. Histopathology. 2012;60:371-6. 29. 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. 30. Nicolae A, Pittaluga S, Venkataraman G, et al. Peripheral T-cell lymphomas of follicular T-helper cell derivation with Hodgkin/Reed-Sternberg cells of B-cell lineage: both EBVpositive and EBV-negative variants exist. Am J Surg Pathol. 2013;37:816-26. 31. Lemonnier F, Couronne L, Parrens M, et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate

Pathology of peripheral T-cell lymphomas

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43. 44.

45.

46.

47.

48.

with TFH-like features and adverse clinical parameters. Blood. 2012;120:1466-9. Cairns RA, Iqbal J, Lemonnier F, et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood. 2012;119:1901-3. Couronne L, Bastard C, Bernard OA. TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med. 2012;366:95-6. Guo s, Kucuk C, Iqbal J, et al. Novel fusion transcripts identified in angioimmunoblastic T cell lymphoma. Mod Pathol. 2013;26:330A. de Leval L, Savilo E, Longtine J, et al. Peripheral T-cell lymphoma with follicular involvement and a CD4þ/bcl-6þ phenotype. Am J Surg Pathol. 2001;25:395-400. 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. Moroch J, Copie-Bergman C, de Leval L, et al. Follicular peripheral T-cell lymphoma expands the spectrum of classical Hodgkin lymphoma mimics. Am J Surg Pathol. 2012;36:1636-46. Streubel B, Vinatzer U, Willheim M, et al. Novel t(5;9) (q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia. 2006;20:313-8. Pechloff K, Holch J, Ferch U, et al. The fusion kinase ITKSYK 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. Rodriguez Pinilla SM, Roncador G, Rodriguez-Peralto JL, et al. Primary cutaneous CD4þ small/medium-sized pleomorphic T-cell lymphoma expresses follicular T-cell markers. Am J Surg Pathol. 2009;33:81-90. Quintanilla-Martinez L, Jansen PM, Kinney MC, et al. Non-mycosis fungoides cutaneous T-cell lymphomas: report of the 2011 Society for Hematopathology/European Association for Haematopathology workshop. Am J Clin Pathol. 2013;139:491-514. 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. Tripodo C, Iannitto E, Florena AM, et al. Gamma-delta T-cell lymphomas. Nat Rev Clin Oncol. 2009;6:707-17. Belhadj K, Reyes F, Farcet JP, et al. Hepatosplenic gammadelta T-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients. Blood. 2003;102:4261-9. Rodriguez-Pinilla SM, Ortiz-Romero PL, Monsalvez V, et al. TCR-gamma expression in primary cutaneous T-cell lymphomas. Am J Surg Pathol. 2013;37:375-84. Arnulf B, Copie-Bergman C, Delfau-Larue MH, et al. Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood. 1998;91:1723-31. Au WY, Weisenburger DD, Intragumtornchai T, et al. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. Blood. 2009;113:3931-7. Teruya-Feldstein J, Jaffe ES, Burd PR, et al. The role of Mig, the monokine induced by interferon-gamma, and

15

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

IP-10, the interferon-gamma-inducible protein-10, in tissue necrosis and vascular damage associated with Epstein-Barr virus-positive lymphoproliferative disease. Blood. 1997;90: 4099-105. Iqbal J, Kucuk C, Deleeuw RJ, et al. Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killercell malignancies. Leukemia. 2009;23:1139-51. Huang Y, de Reynies A, de Leval L, et al. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood. 2010;115:1226-37. Coppo P, Gouilleux-Gruart V, Huang Y, et al. STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma. Leukemia. 2009; 23:1667-78. Ferreri AJ, Zinzani PL, Govi S, et al. Enteropathy-associated T-cell lymphoma. Crit Rev Oncol Hematol. 2011;79: 84-90. Attygalle A, Cabeçadas J, Gaulard P, et al. Peripheral T- and NK-cell lymphomas and their mimics: taking a step forward —report on the Lymphoma Workshop of the XVI meeting of the European Association for Haematopathology in Lisbon 2012. Histopathology. 2014;64:971-99. Ashton-Key M, Diss TC, Pan L, et al. Molecular analysis of T-cell clonality in ulcerative jejunitis and enteropathyassociated T-cell lymphoma. Am J Pathol. 1997;151:493-8. Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. Lancet. 2000;356:203-8. Deleeuw RJ, Zettl A, Klinker E, et al. Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes. Gastroenterology. 2007;132:1902-11. Delabie J, Holte H, Vose JM, et al. Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-Cell Lymphoma Project. Blood. 2011;118:148-55. Chott A, Haedicke W, Mosberger I, et al. Most CD56þ intestinal lymphomas are CD8þCD5-T-cell lymphomas of monomorphic small to medium size histology. Am J Pathol. 1998;153:1483-90. Chan JK, Chan AC, Cheuk W, et al. Type II enteropathyassociated T-cell lymphoma: a distinct aggressive lymphoma with frequent gammadelta T-cell receptor expression. Am J Surg Pathol. 2011;35:1557-69. Quintanilla-Martinez L, Fend F, Moguel LR, et al. Peripheral T-cell lymphoma with Reed-Sternberg-like cells of B-cell phenotype and genotype associated with Epstein-Barr virus infection. Am J Surg Pathol. 1999;23: 1233-40. Dupuis J, Emile JF, Mounier N, et al. Prognostic significance of Epstein-Barr virus in nodal peripheral T-cell lymphoma, unspecified: a Groupe d'Etude des Lymphomes de l'Adulte (GELA) study. Blood. 2006;108:4163-9. Geissinger E, Odenwald T, Lee SS, et al. Nodal peripheral T-cell lymphomas and, in particular, their lymphoepithelioid (Lennert's) variant are often derived from CD8(þ) cytotoxic T-cells. Virchows Arch. 2004;445:334-43. Asano N, Suzuki R, Kagami Y, et al. Clinicopathologic and prognostic significance of cytotoxic molecule expression in

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nodal peripheral T-cell lymphoma, unspecified. Am J Surg Pathol. 2005;29:1284-93. 64. Bisig B, Gaulard P, de Leval L. New biomarkers in T-cell lymphomas. Best Pract Res Clin Haematol. 2012;25:13-28.

P. Gaulard and L. de Leval

65. Vasmatzis G, Johnson SH, Knudson RA, et al. Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas. Blood. 2012;120:2280-9.