Mature T-Cell and Natural Killer-Cell Neoplasms: Comparison
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Mature T- and Natural Killer (NK)-cell neoplasms are derived from mature, post-thymic T-cells and NK-cells and comprise a diverse group of rare neoplasms with a wide range of clinical behavior, including highly aggressive lymphomas. 

  • epidemiology
  • pediatric lymphoma
  • chronic lymphocytic leukemia
  • follicular lymphoma
  • Burkitt lymphoma
  • diffuse large B-cell lymphoma
  • mediastinal lymphoma
  • T-cells

1. Introduction

Mature T-cell and NK-cell neoplasms classified by WHO 2008 comprised 5–9% of all mature non-Hodgkin lymphomas, including ~4% peripheral T-cell lymphomas and ~1% mycosis fungoides [1]. Table 1 shows the new WHO-HAEM5 category named T-cell and NK-cell lymphoid proliferations and lymphomas, which includes benign tumor-like lesions with T-cell predominance, precursor T-cell neoplasms (not shown in this table), and the mature T-cell and NK-cell neoplasms, compared with mature T-cell and NK-cell neoplasms in the ICC [2][3][4]. The mature T- and NK-cell neoplasms are classified based on various variables, including the primary site of presentation in the peripheral blood and bone marrow (leukemic), skin (cutaneous), gastrointestinal tract (intestinal), and the liver and spleen (hepatosplenic)—all extranodal sites, as shown in Table 1. Of note, there is a marked geographic variation in these neoplasms, and the occurrence and frequency of specific neoplasms are dependent on the geographic regions [5].
Table 1. T- and NK-cell neoplasms in the fifth edition WHO 2022 and ICC [2][3][4].
Fifth edition WHO Classification 2022 [2][3] International Consensus Classification 2022 [4]
T-cell and NK-cell lymphoid proliferations and lymphomas

Tumor-like lesions with T-cell predominance a

   Kikuchi-Fujimoto disease a

   Autoimmune lymphoproliferative syndrome a

   Indolent T lymphoblastic proliferation a

Mature T-cell and NK-cell leukemias

   T-prolymphocytic leukaemia

   T-large granular lymphocytic leukaemia

   NK-large granular lymphocytic leukaemia

   Adult T-cell leukaemia/lymphoma

   Sezary syndrome

   Aggressive NK-cell leukaemia

Primary cutaneous T-cell lymphoid proliferations and lymphomas

   Primary cutaneous CD4-positive small or medium

   T-cell LPD

   Primary cutaneous acral CD8-positive T-cell LPD

   Mycosis fungoides

   Primary cutaneous CD30+ T-cell LPD: Lymphomatoid papulosis

   Primary cutaneous CD30+ T-cell LPD Primary cutaneous ALCL

   Subcutaneous panniculitis-like T-cell lymphoma

   Primary cutaneous gamma/delta T-cell lymphoma

   Primary cutaneous CD8+ aggressive epidermotropic

   cytotoxic T-cell lymphoma

   Primary cutaneous peripheral T-cell lymphoma,

   NOS a

Intestinal T-cell and NK-cell lymphoid proliferations and lymphomas

   Indolent T-cell lymphoma of the gastrointestinal

   tract a

   Indolent NK-cell LPD of the gastrointestinal tract

   Enteropathy-associated T-cell lymphoma

   Monomorphic epitheliotropic intestinal T-cell

   lymphoma

   Intestinal T-cell lymphoma, NOS

Hepatosplenic T-cell lymphoma

   Hepatosplenic T-cell lymphoma

Anaplastic large-cell lymphoma

   ALK-positive anaplastic large-cell lymphoma

   ALK-negative anaplastic large-cell lymphoma

   Breast implant-associated anaplastic large-cell

   lymphoma

Nodal T-follicular helper (TFH) cell lymphoma a

   Nodal TFH cell lymphoma, angioimmunoblastic-type

   Nodal TFH cell lymphoma, follicular-type

   Nodal TFH cell lymphoma, NOS

Other peripheral T-cell lymphomas

   Peripheral T-cell lymphoma, NOS

EBV+ NK-cell and T-cell lymphomas

   EBV+ nodal T- and NK-cell lymphoma a

   Extranodal NK/T-cell lymphoma

EBV+ T-cell and NK-cell lymphoid proliferations and lymphomas of childhood

   Severe mosquito bite allergy

   Hydroa vacciniforme lymphoproliferative disorder

   Systemic chronic active EBV disease

   Systemic EBV-positive T-cell lymphoma of childhood		 Mature T-cell and NK-cell neoplasms

T-cell prolymphocytic leukemia

T-cell large granular lymphocytic leukemia

Chronic lymphoproliferative disorder of NK-cells (provisional)

Adult T-cell leukemia/lymphoma

EBV+ T-cell/NK-cell lymphoproliferative disorders of childhood b

  Hydroa vacciniforme lymphoproliferative disorder

     Classic

     Systemic

  Severe mosquito bite allergy

  Chronic active EBV disease, systemic (T-cell and NK-cell

  phenotype)

  Systemic EBV+ T-cell lymphoma of childhood

Extranodal NK/T-cell lymphoma, nasal type

Aggressive NK-cell leukemia

Primary nodal EBV+ T-cell/NK-cell lymphoma b (provisional)

Enteropathy-associated T-cell lymphoma

  Type II refractory celiac disease b

Monomorphic epitheliotropic intestinal T-cell lymphoma

Intestinal T-cell lymphoma, NOS

Indolent clonal T-cell LPD of the gastrointestinal tract b

Indolent NK-cell LPD of the gastrointestinal tract b

Hepatosplenic T-cell lymphoma

Mycosis fungoides

Sézary syndrome

Primary cutaneous CD30+ T-cell lymphoproliferative disorders

  Lymphomatoid papulosis

  Primary cutaneous anaplastic large-cell lymphoma

Primary cutaneous small/medium CD4+ T-cell LPD

Subcutaneous panniculitis-like T-cell lymphoma

Primary cutaneous gamma-delta T-cell lymphoma

Primary cutaneous acral CD8+ T-cell LPD b

Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma

Peripheral T-cell lymphoma, NOS

Follicular helper T-cell lymphoma b

  Follicular helper T-cell lymphoma, angioimmunoblastic

  type (angioimmunoblastic T-cell lymphoma)

  Follicular helper T-cell lymphoma, follicular type

  Follicular helper T-cell lymphoma, NOS

Anaplastic large-cell lymphoma, ALK positive

Anaplastic large-cell lymphoma, ALK negative

Breast implant-associated anaplastic large-cell lymphoma
a New entities or names introduced in WHO-HAEM5; b changes in ICC from WHO 2016 classification; EBV, Epstein–Barr virus; LPD, lymphoproliferative disorder, ALCL, anaplastic large-cell lymphoma; NOS, not otherwise specified; TFH, T-follicular helper.

2. Name Changes in WHO-HAEM5 and ICC Compared with the WHO 2017 Classification

Table 2 shows the name changes in WHO-HAEM5 and the ICC compared with the WHO 2017 classification. Mature T-cell lymphomas involving lymph nodes are clinically aggressive neoplasms and included angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large-cell lymphoma (ALCL) as specific entities in WHO 2001, with peripheral T-cell lymphoma (PTCL), unspecified or not otherwise specified (PTCL NOS), as the remaining heterogeneous group of nodal mature T-cell lymphomas. In a large international study, PTCL NOS and AITL were the two most frequent mature T-cell neoplasms [5]. This section will briefly describe nodal T-follicular helper cell lymphomas, ALCL, EBV+ nodal T- and NK-cell lymphoma, and PTCL NOS, which remains a diagnosis of exclusion. ALCL consists of systemic (ALK+ and ALK-negative), breast-implant-associated, and cutaneous ALCL; cutaneous ALCL is not described as it is best described with cutaneous lymphoproliferative disorders.
Table 2. Name changes in WHO-HAEM5 and ICC compared with the revised fourth edition for mature T-cell and NK-cell lymphomas and Hodgkin lymphomas.
WHO Classification, Fifth Edition, 2022 [2][3] WHO Classification, Revised Fourth Edition, 2017 [6] International Consensus Classification, 2022 [4]
T-cell and NK-cell neoplasms
NK-large granular lymphocytic leukemia (LGLL)

Cutaneous T-cell lymphomas

  Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma;

  Primary cutaneous acral CD8+ T-cell lymphoproliferative disorder (LPD);

  Primary cutaneous CD4+ small or medium T-cell LPD

Indolent T-cell lymphoma of the GI tract

Indolent NK-cell LPD of the GI tract

Breast implant-associated ALCL

Nodal T follicular helper (TFH) cell lymphomas

  Nodal T-follicular helper (TFH) cell lymphoma, angioimmunoblastic-type

  Nodal T-follicular helper (TFH) cell lymphoma, follicular-type

  Nodal T-follicular helper (TFH) cell lymphoma, NOS

Hydroa vacciniforme LPD

Systemic chronic active EBV disease

(not recommended: chronic active EBV disease or infection)

EBV+ inflammatory FDC/fibroblastic reticular cell sarcoma		 Chronic LPD of NK-cells

Cutaneous T-cell lymphomas

  Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (provisional);

  Primary cutaneous acral CD8+ T-cell lymphoma (provisional);

  Primary cutaneous CD4+ small/medium T-cell LPD (provisional)

Indolent T-cell LPD of the GI tract (provisional)

(Not previously included)

Breast implant-associated ALCL (provisional)

Nodal lymphomas of TFH origin

  Angioimmunoblastic T-cell lymphoma

  Follicular T-cell lymphoma (provisional)

  Nodal peripheral T-cell lymphoma with TFH phenotype (provisional)

Hydroa vacciniforme-like LPD

Chronic active EBV infection

EBV+ inflammatory FDC/fibroblastic reticular cell sarcoma		 Chronic LPD of NK-cells (provisional)

Cutaneous T-cell lymphomas

  Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma;

  Primary cutaneous acral CD8+ T-cell lymphoproliferative disorder (LPD);

  Primary cutaneous CD4+ small/medium T-cell LPD

Indolent clonal T-cell LPD of the GI tract

Indolent NK-cell LPD of the GI tract

Breast implant-associated ALCL

Follicular helper T-cell (TFH) lymphoma

  Follicular helper T-cell lymphoma, angioimmunoblastic type

  Follicular helper T-cell lymphoma, follicular type

  Follicular helper T-cell lymphoma, NOS

Hydroa vacciniforme LPD

Chronic active EBV disease

EBV+ inflammatory FDC/fibroblastic reticular cell tumor
Hodgkin lymphoma
Nodular lymphocyte predominant Hodgkin lymphoma Nodular lymphocyte predominant Hodgkin lymphoma Nodular lymphocyte predominant B-cell lymphoma
LPD, lymphoproliferative disorder; GI, gastrointestinal; ALCL, anaplastic large-cell lymphoma; TFH, T-follicular helper; NOS, not otherwise specified; FDC, follicular dendritic cell.

3. Nodal T-Follicular Helper (TFH) Cell Lymphoma

Nodal follicular T-cell lymphoma is the new WHO-HAEM5 name unifying three entities of nodal T-cell lymphoma with the phenotype and gene expression signatures of T-follicular helper (TFH) cells [2][3][7]. AITL was included as a specific entity in the REAL classification in 1994 and comprised the most frequent (18.5%) specific type in a cohort of 1153 T- and NK-cell neoplasms [5]. The other two entities in this group, follicular type and not otherwise specified, were included provisionally in WHO 2017 after a subset of PTCL NOS cases showed TFH-associated markers similar to AITL [8][9]. While the features of AITL are well-defined, including variable occurrence in different geographic locations [10][11], the other two entities have not yet been studied as much as AITL, and there are overlapping morphologic, clinical, and genetic features between these lymphomas [12][13].
Notably, there are treatment implications for the nodal T-follicular helper cell lymphomas group. These lymphomas frequently harbor mutations in ten-eleven translocation-2 (TET2), DNA methyl transferase-3A (DNMT3A), and isocitrate dehydrogenase-2 (IDH2), which affect DNA methylation and silence tumor suppressor genes; therefore, effective treatment options include epigenetic modifying and hypomethylating agents [14][15][16].
Nodal follicular T-cell lymphoma, angioimmunoblastic type, abbreviated AITL for simplicity, is diagnosed by integrating clinical, laboratory, characteristic histopathologic, and immunophenotypic findings. Histologically, three patterns have been described with partial or complete obliteration of nodal architecture, expanded CD21+ (or CD23+) follicular dendritic cell (FDC) meshworks, prominent high endothelial venules (HEVs), and small to medium-sized TFH marker-positive lymphoma cells with clear cytoplasm admixed with polymorphous inflammatory cells; a tumor-cell rich pattern may lack HEVs [3][17][18]. The lymphoma cells express PD1 (CD279), ICOS, BCL6, CXCL13, and CD10 at varying levels of sensitivity and sensitivity. PD1 and ICOS are more sensitive than CD10 and CXCL13, while CD10 and CXCL13 are more specific than PD1 and ICOS. Strong PD1 staining is more specific [3]. AITL frequently harbors mutations in Ras Homolog Family Member A, RHOA (p.G17V), TET2, IDH2 (p.R172), DNMT3A, VAV1, and PLCG1 [3][13][19][20][21]. Mutations in RHOA and IDH2 appear to be specific to the TFH lymphomas and are absent in PTCL NOS [13][21]. RHOA p.G17V mutation analysis may be valuable in the early detection of AITL and PTCL with TFH features [22]. IDH2 p.R172-mutated AITL shows specific features, including medium- to large-sized neoplastic cells with clear cytoplasm and a TFH phenotype with CD10 and CXCL3 immunohistochemical positivity [23][24].
The essential WHO-HAEM5 diagnostic criteria for the diagnosis of typical patterns 2, 3, and tumor-rich AITL require the following:
(1)
 Nodal disease,
(2 ) 
CD4+, occasionally CD4-negative, CD8-negative atypical lymphoid cells,
(3) 
Extrafollicular FDC expansion, and
(4) HEV hyperplasia, which is mild in tumor-cell-rich cases.
The desirable criteria are expression of >2 TFH markers, including strong PD1, clonal T-cell receptor (TCR) gene rearrangement, mutation involving RHOA p.G17V (NP_001655.1) or IDH2 p.R172, or both clonally rearranged TCR and the mutations, and EBV+ B-cells [3].
The essential WHO-HAEM5 diagnostic criteria to diagnose partial nodal involvement (patterns 1–2) require (1) nodal disease, (2) perifollicular CD4+, occasionally CD4-negative, and CD8-negative atypical T-cells that express >2 TFH markers, including strong PD1, and (3) clonal TCR gene rearrangement, mutation involving RHOA p.G17V or IDH2 p.R172, or both clonally rearranged TCR and the mutations. If the diagnostic criteria are not fulfilled due to insufficient sampling, re-biopsy is recommended [3].
Nodal TFH cell lymphoma, follicular-type, may represent a morphologic pattern of the broader group of TFH lymphomas instead of a distinct entity [3][13]. The essential WHO-HAEM5 diagnostic criteria require a follicular growth pattern (follicular lymphoma-like or progressive transformation of germinal center (PTGC)-like), no (absent) extrafollicular FDC expansion, and CD4+, occasionally CD4-negative, and CD8-negative atypical T-cells that express >2 TFH markers, including strong PD1. The desirable WHO-HAEM5 criteria are lack of a polymorphous infiltrate, HEV hyperplasia, and clonal TCR gene rearrangement [3].
Nodal TFH lymphoma, NOS, shows overlap with the tumor-rich pattern of AITL but lacks a prominent polymorphous inflammatory background, HEV hyperplasia, and extrafollicular FDC expansion. The less TFH-specific markers, PD1 and ICOS, are more often positive in these cases. The essential WHO-HAEM5 diagnostic criteria for nodal TFH lymphoma NOS require (1) nodal disease with effaced architecture/T-zone pattern by a morphologically atypical, immunophenotypically aberrant atypical T-cell infiltrate that is CD4+ and CD8-negative and expresses at least two TFH markers, including strong PD1, or both morphologically atypical and immunophenotypically aberrant T-cell infiltrate; and (2) lack of extrafollicular FDC hyperplasia, perifollicular distribution of neoplastic T-cells, and follicular growth pattern. The desirable criteria are clonal TCR gene rearrangement, mutation involving RHOA p.G17V, or both [3].
The T-follicular helper (TFH) phenotype was defined by WHO 2017 by the expression of at least two or preferably three TFH markers. The ICC recommends a five-marker immunohistochemistry panel to identify the TFH phenotype since establishing a TFH phenotype is critical to diagnose the follicular and NOS types of TFH lymphomas [4]. An immunohistochemistry panel of five TFH markers, CD10, BCL6, PD1, CXCL13, and ICOS, reclassified 41% of PTCL NOS cases to PTCL with TFH phenotype [25].

4. Anaplastic Large-Cell Lymphoma

The monoclonal antibody, Ki-1, was found to be specific for HRS cells in all examined cases of Hodgkin lymphoma in 1982 [26]. Subsequently, ALCL was first described in 1985 after applying Ki-1 (CD30) to a series of non-neoplastic and lymphoma tissues. Ki-1 was strongly expressed in 45 cases of diffuse large-cell lymphoma previously diagnosed as malignant histiocytosis or carcinoma due to marked pleomorphism in tumor cells; 35 of those cases expressed T-cell antigens, including 9 with co-expressed B-cell antigens, 7 expressing only B-cell-related antigens, and three lacking T- and B-cell markers [26]. Ki-1 was also expressed in variable numbers of cells in all cases of lymphomatoid papulosis and angioimmunoblastic lymphadenopathy, later termed AILT, and in 28% of cases of PTCL. The neoplastic cells in these lymphoid neoplasms resembled HRS cells in CHL and consistently expressed lymphoid markers in the absence of markers of other lineages [27]. The nature of the neoplastic cells as lymphoid was further confirmed by clonal rearrangements of antigen receptor genes [27][28][29]. These lymphomas were then termed Ki-1-positive ALCL.
In the late 1980s, the t(2;5)(p23;q35) translocation was described in a subset of ALCLs. Subsequently, in 1994, the nucleolar phosphoprotein NPM gene located at 5q35 was shown to fuse with the previously unidentified gene at 2p23 that encodes for the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) [30]. The resulting chimeric NPM::ALK gene, formed in the t(2;5) translocation due to the ALK gene now under the control of the NPM promoter, is transcribed to produce an 80-kd chimeric protein causing constitutive activation of ALK [30], first detected by the ALK monoclonal antibody in 1997 [31]. Variant ALK translocations were recognized in ~15% of ALCL with only cytoplasmic ALK staining, occasionally with granular positivity, compared to nuclear and cytoplasmic staining in NPM::ALK translocations [30][31][32][33][34].
ALCL was introduced in the REAL classification as anaplastic large-cell lymphoma, CD30+, T-, and null-cell types. The WHO 2008 classification recognized ALK+ ALCL as a distinct entity and provisionally included ALK-negative ALCL, which was subsequently included as a separate entity by WHO 2017. In 2022, DUSP22-rearranged ALCL was recognized as a specific genetic type of ALK-negative ALCL by WHO-HAEM5 and ICC.
The chimeric ALK protein is present only in neoplastic cells. Of note, the presence of the chimeric ALK protein does not indicate that the neoplastic cell is lymphoid since ALK gene abnormalities also occur in many other non-lymphoid neoplasms. WHO-HAEM5 defines ALK-positive ALCL as a CD30+ mature T-cell lymphoma with aberrant expression of the ALK protein secondary to ALK gene rearrangements. The essential WHO-HAEM5 diagnostic criteria require ALK expression in lymphoma cells and a strong uniform expression of CD30 in lymphoma cells [3]. A characteristic sinusoidal pattern of nodal involvement by lymphoma cells is often present, as illustrated in reference [35].
The essential WHO-HAEM5 diagnostic criteria require the following:
(1)
 Complete or partial infiltration of lymph node or extranodal tissue by large pleomorphic cells with lobated nuclei, distinct nucleoli, including “hallmark cells,”
(2) 
Uniform strong expression of CD30,
(3)
 Absence of ALK protein expression or ALK rearrangement, and
(4)
 Negativity for EBV. The desirable criteria include expression of T-cell markers and cytotoxic markers, albeit with frequent losses, and clonal rearrangement of the TCR gene [3].
ALK-negative ALCL has a worse prognosis than ALK+ ALCL when treated by conventional chemotherapy, but it is better than that of PTCL NOS [36]. In 2014, ALK-negative ALCL was shown to be a genetically heterogeneous disease with varying outcomes after standard therapy. In that study, DUSP22-rearranged and TP53-rearranged types of ALK-negative ALCL comprised 30% and 8% of all ALK-negative ALCL, respectively [37]. Of note, the 5-year overall survival rates in that study were 90% for DUSP22-rearranged ALCL, 85% for ALK+ ALCL, 17% for TP63-rearranged ALCL, and 42% for ALCL cases lacking all three genetic markers (p < 0.0001) [37]. Although all ALCL share similar histologic growth patterns, DUSP22-rearranged ALCL is more likely to show doughnut-shaped cells, less likely to show pleomorphic cells, and very likely to show a sheet-like growth pattern [38].
Significantly, the genome of ALK+ ALCL is less complex than that of ALK-negative ALCL, which indicates the strong potential of the ALK chimeric fusion to cause lymphoma [35][39]. Indeed, in January 2021, the ALK inhibitor, crizotinib, was FDA-approved for pediatric patients aged ≥1 year and young adults with relapsed or refractory systemic ALK+ ALCL, which could potentially improve clinical outcomes [40].
Notably, gene expression profiling showed a similar signature of 14 genes expressed by ALK+ ALCL and ALK- ALCL, indicating a shared ALCL profile that also distinguished ALK-negative ALCL from PTCL NOS [41]. Subsequently, gene expression profiling was able to separate ALK+ ALCL from ALK-negative ALCL [42][43]. Interestingly, ALK+ ALCL were enriched for the expression of hypoxia-inducible factor 1 alpha (HIF1α) target genes, IL10-induced genes, and H-ras/K-ras-induced genes compared with ALK-negative ALCL [43]. ALK-negative ALCL expressed TNSFR8 (CD30), BATF3, and TMOD1 [42][43], and compared to PTCL NOS, ALK-negative ALCL were enriched for the expression of MYC, IRF4, and proliferation and mTOR pathway genes [43]. Clinically, the anti-CD30 antibody-drug conjugate, brentuximab vedotin, is effective as a single agent in treating relapsed or refractory systemic ALCL [44] and is being studied to treat patients with PTCL NOS [45].
Breast-implant-associated ALCL is a mature CD30+ T-cell lymphoma that arises in relation to a breast implant and is usually confined by a fibrous capsule [3]. It usually presents as an effusion-associated fibrous capsule surrounding the implant and, less frequently, as a mass [46]. Treatment with capsulectomy and implant removal results in remission in most patients with a fibrous capsule-limited disease. In contrast, the disease may be highly aggressive and even fatal in patients presenting with a mass [46]. Tumor spread beyond the capsule is associated with a higher risk of lymph node involvement, which is associated with decreased overall survival [47]. The essential WHO-HAEM5 diagnostic criteria include (1) the presence of breast implant, (2) CD30+ lymphoma cells with anaplastic features, and (3) proven T-cell lineage supported by expression of one or more T-lineage markers, clonal TCR gene rearrangement, or both. The desirable WHO-HAEM5 criterion is the identification of lymphoma cells on the luminal side of the capsule in correctly oriented sections [3]. Clonal TCR rearrangement is present in >80% of cases, and breast-implant-associated ALCL is consistently negative for gene rearrangements involving ALK (2p23), DUSP22 (6p25.3), and TP63 (3q28), all of which can be detected by FISH [3]. The differential diagnosis of breast-implant-associated ALCL includes systemic lymphomas involving the breast, with DLBCL and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue being the most common [48]. Rare cases of EBV+ fibrin-associated large B-cell lymphomas described around breast implants must also be excluded [3][49][50].

5. Epstein–Barr Virus (EBV)+ Nodal T- and NK-Cell Lymphoma

Epstein–Barr virus (EBV)+ nodal T- and NK-cell lymphoma was included as a variant of PTCL in WHO 2017 and is now included as a definite entity in WHO-HAEM5 and provisionally in ICC [2][3][4]. It is a rare lymphoma of EBV+ cytotoxic T- or NK-cells that occurs mainly in East Asia and typically presents with lymphadenopathy at an advanced stage in adults. Bone marrow and the liver may be involved. The lymphoma is composed of EBV+ monomorphous large centroblastoid cells with a cytotoxic phenotype, with T-cell more common than NK-cell lineage. This lymphoma is a systemic disease with an aggressive clinical course and a CD8+, CD56-negative immunophenotype distinct from extranodal NK/T-cell lymphoma and PTCL NOS [51]. In contrast with extranodal NK/T-cell lymphoma, there is a lack of nasopharyngeal involvement, lack of prominent angiocentric growth and necrosis, and less frequent extranodal involvement. The outcome is worse than NK/T-cell lymphoma and PTCL, with a median overall survival of 2.8 to 8 months compared with 26–76 months for extranodal NK-/T-cell lymphoma and 16–20 months for PTCL NOS [3][51].
The essential WHO-HAEM5 criteria require (1) a cytotoxic T-cell or NK-cell lymphoma, (2) EBV-encoded RNA (EBER) present in the majority of neoplastic cells, (3) tumor primarily localized within lymph nodes but may involve a limited number of extranodal sites; no nasal involvement, and (4) exclusion of immune-deficiency-associated T- and NK-cell lymphoproliferative diseases, extranodal NK/T-cell lymphoma, systemic EBV+ lymphoproliferative diseases of childhood, and aggressive NK-cell leukemia with progression or secondary involvement of lymph nodes [3].

6. Peripheral T-Cell Lymphoma, Not Otherwise Specified (PTCL NOS)

Peripheral T-cell lymphoma (PTCL) NOS is a mature T-cell lymphoma that cannot be assigned to any specific mature T-cell lymphoma entity. Therefore, it is a diagnosis of exclusion and shows heterogeneity in pathologic and genomic features. Clinically, it affects primarily adults and has an aggressive clinical course [5].
Two molecular groups were identified by gene expression profiling in 2014 before the non-AITL nodal TFH lymphomas were included in the WHO 2017 classification. These two groups were characterized by high expression of either GATA3 (33%; 40/121) or TBX21 (49%; 59/121); the remaining 22 PTCL NOS cases were unclassified [43]. GATA3 and TBX21 are master transcriptional regulators of T-helper 2 and T-helper 1/cytotoxic T-cell differentiation. The GATA3 subgroup showed marginal enrichment for mTOR- and MYC-related gene signatures, also seen in ALK-negative ALCL in this same study [43], and significant enrichment of phosphatidylinositol 3 kinase (PI3K)-induced gene signatures [43]. The TBX21 subgroup showed significant enrichment of IFN α/β/γ-regulated gene signatures, a CD8+ T-cell profile, and NFκB pathway signatures. In the TBX21 subgroup, a subset with cytotoxic profiles showed a poor prognosis [43]. The GATA3 subgroup was significantly associated with poor overall survival. In addition, high expression of cytotoxic gene signature within the TBX21 group showed poor clinical outcomes [43].
The study in 2019 [52] also showed the two molecular subgroups, with the GATA3 subgroup characterized by greater genomic complexity and frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53 axis and PTEN-PI3K pathways. As would be expected, loss of CDKN2A correlated with poor prognosis, which was seen in PTCL NOS and the GATA3 subgroup [52]. The GATA3 subgroup showed co-occurring gains or amplifications of STAT3 and MYC. Both subgroups showed copy number aberrations affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling [52].
TP53 mutations co-occurred with the loss of CDNK2A and were present in the DNA binding and tetramerization domains, including the hotspot TP53 p.R175H. The presence of TP53 mutations and copy number loss leading to aberrant TP53 signaling was significantly associated with the GATA3 subgroup of PTCL [52]. Both subgroups harbored mutations in other DNA repair or TP53 signaling genes, ATM and TRRAP [52]. As mentioned earlier, PTCL NOS are usually negative for RHOA p.G17V and IDH2 p.R172 mutations, which are often present in nodal TFH cell lymphomas. An immunohistochemical algorithm using antibodies against the transcriptional factors, GATA3, TBX21, and their target proteins, CCR4 and CXCR3, respectively, has been shown to correlate with the two molecular subgroups [3][53].
The histologic and cytologic features of PTCL NOS are highly variable. There is partial or complete effacement of the nodal architecture by a paracortical or diffuse infiltrate of medium- to large-sized lymphoma cells, often with an inflammatory background. HRS-like cells may be present. The inflammatory background is much more frequent in the TBX21 subtype than in the GATA3 subtype [3][53]. The lymphoma cells express pan T-cell antigens and are more often CD4+ than CD8+ and frequently show decreased expression of CD5 and CD7. The expression of a single TFH marker is acceptable for the diagnosis of PTCL NOS. However, cases with diffuse positivity for two or more TFH markers should be diagnosed as nodal TFH cell lymphoma. Scattered Epstein–Barr virus-encoded RNA (EBER)-positive B-cells may be present. CD30 is expressed in 25% of cases, but the positivity is non-uniform and variable, not strong like in ALCL. CD15 may be positive in ~5% of cases and may be co-expressed with CD30 [3]. The differential diagnosis of PTCL NOS may include non-neoplastic conditions such as Kikuchi’s lymphadenitis and other lymphomas, including CHL, T-cell rich large B-cell lymphoma, and nodal marginal zone lymphoma. Careful integration of the clinical, histopathologic, and immunophenotypic features usually resolves the diagnosis of lymphoma versus non-neoplastic states. In difficult cases or specific diagnostic situations, the molecular genetic analysis would be helpful for precise diagnosis.
The essential WHO-HAEM5 criteria for a diagnosis of PTCL NOS require the following:
(1) 
The presence of an abnormal T-cell infiltrate, which is morphologically or immunophenotypically aberrant, monoclonal by ancillary studies, or both;
(2)
 The tumor cells are negative or express only one TFH marker (to differentiate from nodal TFH cell lymphomas), and the neoplasm only shows EBER positivity in scattered B-cells (to differentiate from EBV+ nodal T- and NK-cell lymphoma);
(3)
 The exclusion of other nodal or extranodal mature T- and NK-cell lymphomas, i.e., ALK+ ALCL, ALK-negative ALCL, adult T-cell leukemia/lymphoma, extranodal NK/T-cell lymphoma.
The desirable WHO-HAEM5 criteria are the presence of clonal TCR gene rearrangements and establishing the biological designation of PTCL-TBX21 and PTCL-GATA3 [3].

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