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Pathology of Peripheral T-Cell Lymphomas: Where Do We Stand?

Seminars in Hematology, 1, 51, pages 5 - 16

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 lympho-proliferations are being identified.

Peripheral 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 and 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 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: alpha-beta, gamma-delta, both expressing CD3. Alpha-beta T cells comprise CD4+ (mainly helper) and CD8+ (mainly cytotoxic) subsets. Gamma-delta T cells (CD4-CD8- or CD4-CD8+) comprise <5% 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 CD8+, 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 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, 4, and 5

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

PTCL Entities Frequency (%) Cellular Derivation Phenotype
Disseminated/leukemic      
T-cell prolymphocytic leukemia   Tαβ Non-cytotoxic
T-cell large granular lymphocytic leukemia   Tαβ (more rarely Tγδ) Cytotoxic (A)
Chronic lymphoproliferative disorders of NK cells *   NK Cytotoxic (A)
Aggressive NK cell leukemia   NK Cytotoxic (A)
Systemic EBV-positive T-cell lymphoproliferative disease of childhood   Tαβ Cytotoxic (A)
Adult T-cell leukemia/lymphoma 9.6 Tαβ T regulatory
 
Extranodal      
Extranodal NK/T-cell lymphoma, nasal type (ENKTCL) 10.4 NK (more rarely Tγδ or Tαβ) Cytotoxic (A)
Enteropathy-associated T-cell lymphoma (EATL) 4.7 IEL, Tαβ (more rarely Tγδ) Cytotoxic (A)
Hepatosplenic T-cell lymphoma (HSTL) 1.4 Tγδ (Vδ1) (more rarely Tαβ) Cytotoxic (NA)
 
Cutaneous      
Mycosis fungoides   Tαβ (mostly CD4) Non-cytotoxic
Sézary syndrome   Tαβ (mostly CD4) Non-cytotoxic
Primary cutaneous CD30+ T-cell lymphoproliferative disorders   Tαβ (mostly CD4)  
Primary cutaneous anaplastic large cell lymphoma 1.7 Tαβ (CD4) Cytotoxic (A)
Lymphomatoid papulosis   Tαβ (CD4) Cytotoxic (A)
Subcutaneous panniculitis-like T-cell lymphoma 0.9 Tαβ (CD8) Cytotoxic (A)
Primary cutaneous γδ T-cell lymphoma   Tγδ (Vδ2) Cytotoxic (A)
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma *   Tαβ (CD8) Cytotoxic (A)
Primary cutaneous CD4+ small/medium T-cell lymphoma *   Tαβ (CD4, TFH) TFH
Hydroa vacciniforme-like lymphoma   Tαβ (rarely NK) Cytotoxic (A)
 
Nodal      
Peripheral T-cell lymphoma, not otherwise specified 25.9 Tαβ (CD4>CD8), rarely Tγδ Variable, a subset TFH, a small subset cytotoxic (A)
Angioimmunoblastic T-cell lymphoma 18.5 Tαβ (CD4, TFH) TFH
Anaplastic large-cell lymphoma, ALK-positive 6.6 Tαβ (Th2?) Cytotoxic (A)
Anaplastic large-cell lymphoma, ALK-negative * 5.5 Tαβ (Th2?) Cytotoxic (A)

lowast 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) = non-activated (expression of TIA-1 only); (A) = activated (expression of perforin and/or granzyme B in addition to TIA-1).

Adapted from Swerdlow et al. 2

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

  Epidemiology Clinical Features Morphology Cell Derivation, Phenotype Genetic and Molecular Features; Viral Association Prognosis
T-cell prolymphocytic leukemia (T-PLL) 2 Adults (median age 65 yr), rare Splenomegaly, hepatomegaly, skin (20%), generalized lymphadenopathy, Lymphocytosis (usually >100 x 109/L) Small/medium-sized mature lymphocytes, visible nucleolus, nongranular cytoplasm αβ T cells Inv(14)(q11;q32.1), t(14;14) (TCL1) or t(X;14) (MTCP1) Aggressive, median survival <1 yr
CD2+, CD3+, CD7+, CD4+, more rarely CD4+/CD8+ or CD8+
Resistance to conventional chemotherapy
TCL1+
T-cell large granular lymphocytic leukemia (LGL) Adults Asymptomatic or cytopenia, slight lymphocytosis, moderate splenomegaly (50%) Large granular lymphocytes (2-20×109/L) Mostly αβ T cells, more rarely γδ T cells STAT3 mutations (20-30% of the cases) Indolent
Frequent context of auto-immune disorder (RA) Nonprogressive
CD3+, CD8+ (more rarely CD4-/CD8-), CD16+, CD57+, Activated cytotoxic (TIA1+, GrB+, Perf+)
Chronic lymphoproliferative disorder of NK cells Adults Asymptomatic or cytopenia, slight lymphocytosis, rare splenomegaly Large granular lymphocytes (usually >2 x 109/L) NK lineage STAT3 mutations (20%–30% of the cases) Indolent
No gender predominance Nonprogressive
CD3e+ cyt, CD3-surface, TCR-, CD2+, CD5-, often CD56+, CD57-, CD8 variable
TIA1+, GrB+, Perf+
Adult T-cell lymphoma/leukemia (ATLL) 2 Adults (long latency) Highly variable from leukemic variants to lymphoma forms (ADP, skin, spleen, gastrointestinal tract, lung) Broad morphology (pleomorphic small to large cells), often polylobated ("flower" cells) αβ T cells with features of regulatory T cells (CD25+, FoxP3+) Monoclonal integration of HTLV1 (role of Tax) Poor, mostly fatal, median survival < 3 mo in most studies
Endemic regions for HTLV1 Southwestern Japan, Caribbean islands, Central Africa)
Mostly CD4+, rarely CD8+, or CD4+/CD8+
Aggressive NK cell leukemia Teenager/young adult B symptoms, splenomegaly, cytopenia, leukemic cells, frequent hemophagocytic syndrome Variable pleomorphic medium to large atypical cells NK lineageCD3e+ cytoplasm, CD3/TCR- (surface) CD5-, CD56+, CD4-/CD8-, TIA1+, GrB+, Perf+ EBV (clonal integration) Aggressive, fatal
Slight male predominance
6q deletion,
Asians, Latin Americans
gr1

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

Anaplastic Large Cell Lymphoma, Alk-Positive

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.

ALK+ 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 ALK+ 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 ALK+ ALCL patients) and other PTCLs.1, 6, and 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 <10% of the cases) are both associated with a less favorable outcome. 8

The tumor cells strongly express CD30, are by definition ALK+, 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 and 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 Ingham 11 ). No etiologic agent has been linked to ALCL, but there have been case reports of systemic ALK+ 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).

Systemic ALK-Negative ALCL

This entity (provisional), is defined as a large cell lymphoma with comparable morphology to classical ALK+ ALCL, uniformly strongly positive for CD30 but lacking ALK expression. 2 Compared to ALK+ 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 ALK- ALCL, a three-gene model has been proposed to distinguish ALK- ALCL from PTCL-NOS. 13

Chromosomal aberrations differ from those of ALK+ ALCL. 14 While distinct signatures have been derived from the comparison of ALK+ and ALK- ALCL, 15 transcriptional profiling studies have also evidenced much commonality between ALK+ and ALK- ALCL, and between ALK- ALCL and a subset of PTCL-NOS with strong CD30 expression.10 and 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 ALK- ALCLs. 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

Primary Cutaneous ALCL

Primary cutaneous ALCL has overlapping clinical and pathological features with lymphomatoid papulosis, which together constitute the spectrum of primary CD30+ 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 CD30+ 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 ALK+ 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 long-term 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

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 al 25 ). TFH cells reside in germinal centers (GCs) and interact with GC B cells to promote B-cell survival and immunoglobulin class-switch 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 B-cell recruitment into GCs and for B-cell activation) and a specific cell surface immunophenotype including the expression of CXCR5 (receptor to CXCL13, essential to 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 and 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 <3 years (for review, see de Leval et al 27 ).

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 CD4+ T cells expressing several markers of the TFH cells (CXCL13, PD1, ICOS, CD200, BCL6, SAP, cMAF), as well as, frequently, CD10.25 and 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 EBV-negative B-cell or plasma cell neoplasm.29 and 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, respectively.31, 32, and 33TET2 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 CD3+ CD4+ αβ T cells strongly expressing TFH markers (PD1+ ICOS+ CXCL13+ BCL6+ CD10 +/-, CD57-/+). 36 In addition, F-PTCL may present biological clinicopathological features overlapping with those of AITL, 36 and 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 F-PTCLs. 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 CD4+ 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 CD4+ PD1+ CXCL13+/- BCL6+/- 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 and 42 It remains to be defined which 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 al 43 ). 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 CD3+ CD5 CD56+ CD4/CD8 TCRγδ+ 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 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 CD3+ CD5- CD4-/CD8- CD56+ βF1- TCRγδ+ small- to large-sized 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% five-year 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 CD8+ CD56- CD3+ cytotoxic T cells rimming subcutaneous adipocytes, of good prognosis), lupus panniculitis, and primary cutaneous epidermotropic CD8+ 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 EBV+ NK cell, or more rarely, 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/medium-sized 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 (CD3ε+), are CD2+, CD5-, CD56+, 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 TNF̃α 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 and 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 platelet-derived growth factor–derived receptor alpha (PDGFRA), and of the AKT, JAK/STAT, and nuclear factor-kappaB pathways.50 and 51JAK3 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 lymphoproliferations of the gastrointestinal tract, ie, NK cell enteropathy and recently recognized CD8+ T-cell indolent lymphoproliferations. 53

EATL Type I

EATL type I occurs as a complication of gluten-sensitive 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 and 55 In around half of the patients EATL represents the first manifestation of enteropathy. The majority of patients have celiac-disease 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 CD3+ 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

EATL Type II

Type II EATL, also termed “monomorphic CD56+ 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 CD3+ CD5- CD7+ CD4-/CD8+ CD56+, 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 rarely in type II while gains of the MYC oncogene locus at 8q24 are frequent. 56

Peripheral T-Cell Lymphoma, Nos

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 CD4+CD8-. 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 and 61 The rare lymphoepithelioid variant of PTCL, NOS, characterized by an abundant background of histiocytes, consists of neoplastic small CD8+ 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 dominant-negative p63 isoform that inhibits the p53 pathway, are seen in approximately 6% of PTCLs and are associated with inferior overall survival. 65

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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Footnotes

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

lowast Address correspondence to Philippe Gaulard, MD, Department of Pathology, Hôpital Henri Mondor, F-94010 Créteil, France

The authors have no financial disclosure or conflict of interest.