Abstract
Peripheral T-cell lymphomas are a heterogeneous, and usually aggressive, group of mature T-cell neoplasms with overlapping clinical, morphologic and immunologic features. A large subset of these neoplasms remains unclassifiable with current diagnostic methods (“not otherwise specified”). Genetic profiling and other molecular tools have emerged as widely applied and transformative technologies for discerning the biology of lymphomas and other hematopoietic neoplasms. Although the application of these technologies to peripheral T-cell lymphomas has lagged behind B-cell lymphomas and other cancers, molecular profiling has provided novel prognostic and diagnostic markers as well as an opportunity to understand the biologic mechanisms involved in the pathogenesis of these neoplasms. Some biomarkers are more prevalent in specific T-cell lymphoma subsets and are being used currently in the diagnosis and/or risk stratification of patients with peripheral T-cell lymphomas. Other biomarkers, while promising, need to be validated in larger clinical studies. In this review, we present a summary of our current understanding of the molecular profiles of the major types of peripheral T-cell lymphoma. We particularly focus on the use of biomarkers, including those that can be detected by conventional immunohistochemical studies and those that contribute to the diagnosis, classification, or risk stratification of these neoplasms.
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Introduction
Peripheral T cell lymphomas (PTCLs) represent lymphoid malignancies derived from mature (peripheral or post-thymic) T cells and constitute ~10–15% of all non-Hodgkin lymphomas in Western countries. PTCLs are rare, with an age-adjusted incidence of less than 1 per 100,000 and fewer than 4000 total cases diagnosed annually in the United States1. PTCLs are more common in Asian nations.
In the current World Health Organization (WHO) classification of lymphomas, more than 30 established and provisional neoplastic T-cell entities are recognized, subdivided into four major groups based on clinical presentation and disease site: nodal, extranodal, leukemic and cutaneous2. Nodal PTCLs account for over 50% of all mature T-cell neoplasms, and include PTCL, not otherwise specified (PTCL-NOS), systemic ALK-positive (ALK+ ) and ALK-negative (ALK-) anaplastic large cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL) and related lymphomas with a T follicular helper (TFH) cell phenotype. Extranodal and leukemic subtypes include hepatosplenic T-cell lymphoma, extranodal NK/T-cell lymphoma, aggressive and indolent intestinal lymphomas, adult T-cell leukemia-lymphoma and Sezary syndrome among others. Mycosis fungoides (MF) is the most common form of primary cutaneous T cell lymphoma. Leukemic T-cell lymphomas, MF and other primary cutaneous T cell lymphomas, except primary cutaneous ALCL, will not be discussed here.
In most academic institutions, the diagnostic approach for most mature T-cell neoplasms is based mostly on a combination of clinical, morphologic and immunophenotypic findings3. Genetic profiling is a routine component of the diagnostic workup for an increasing number of neoplasms, and is used to predict clinical outcomes and responses to targeted therapies, e.g., in acute leukemias and myelodysplastic syndromes. Although the mutational and genetic landscape of most PTCLs have not been fully characterized and genetic profiling of T-cell neoplasms is not part of the routine work up at most centers, a growing body of research data from molecular studies is helping to refine the current classification and support the incorporation of additional entities to the current schema. In addition, these genetic and molecular studies contribute to refining prognostic models and facilitating novel treatment opportunities in some PTCL patients4.
In this paper, we summarize the current mutational and genetic landscape of PTCLs emphasizing biomarkers that have an established or potential role in the work-up of these neoplasms. A list of biomarkers with potential relevance in the work-up of mature T-cell lymphomas is listed in Table 1. Additional work is needed to confirm the utility of some of these biomarkers, to extend emerging biological findings to a biomarker-driven classification, and to improve the risk stratification and treatment of patients with these neoplasms.
Anaplastic large cell lymphomas (ALCL)
ALK-positive ALCL
ALK-positive ALCL is a systemic T-cell lymphoma defined by neoplastic cells with characteristic morphology (hallmark cells), uniform expression of CD30, and rearrangement of the ALK gene5,6. ALK-positive ALCL has a slight male predominance but, unlike most other T-cell neoplasms, has a peak incidence in the second decade of life. ALK-positive ALCL typically involves lymph nodes but involvement of extranodal sites, including skin, soft tissue, bones, lungs, and liver, is often seen. Several morphologic variants are recognized. Immunohistochemistry demonstrates the presence of CD30 and ALK. Aberrant loss of one or more T-cell markers is common. Most patients have a favorable prognosis. Treatment approaches include systemic combination chemotherapy, the CD30 antibody-drug conjugate brentuximab vedotin, and in some cases ALK small molecule inhibitors7,8.
Genetics and molecular profiling
ALK-positive ALCLs carry rearrangements of ALK on chromosome 2p23. The most common partner gene is NPM1 on chromosome 5q35.1, followed by TPM3, ATIC, and a variety of other rare partners5. The biological and clinical significance of the partner gene is unknown. ALK rearrangements result in gene fusions that encode ALK fusion proteins; these proteins homodimerize, leading to constitutive ALK activation and a wide array of oncogenic functions including JAK-STAT3 pathway activation9. Other chromosomal rearrangements have not been comprehensively studied, although concurrent MYC rearrangements may be associated with adverse outcomes. Recurrent chromosomal gains (e.g., 1q, 2, 7q, 8q, 11, 17q) and losses (e.g., 4, 6q, 13q, 17p) have been reported but are less common than in ALK-negative ALCL5,10,11. ALK-positive ALCL has a reproducible gene expression signature, in part attributable to JAK-STAT3 activation, expression of cytotoxic molecules, and Th17-like features12,13,14. The mutational landscape of ALK-positive ALCL has not been entirely characterized, but includes recurrent mutations of TP53, epigenetic modifying genes, and genes in the T-cell receptor and Notch signaling pathways15,16. Recurrent NOTCH1 T349P and T311P mutations may confer sensitivity to targeted therapy16.
ALK-negative ALCL
ALK-negative ALCL is a systemic T-cell lymphoma lacking ALK rearrangements but otherwise resembling ALK-positive ALCL, including the presence of hallmark cells and expression of CD306,17. Like ALK-positive ALCL, ALK-negative ALCL has a slight male predominance, but this disease is relatively more common in older adults with a peak incidence in the 6th decade.
ALK-negative ALCL typically involves lymph nodes; extranodal involvement occurs but is less common than in ALK-positive ALCL. Morphologic variants are not recognized. Aberrant T-cell antigen loss is common. Patients generally have a poorer prognosis than patients with ALK-positive ALCL, but prognosis also varies by genetic subtype (see below)18,19. Front-line treatment approaches include combination chemotherapy and BV, with or without consolidative autologous stem-cell transplantation7.
Genetics and molecular profiling
ALK-negative ALCLs, by definition, lack ALK rearrangements. Two recurrent chromosomal rearrangements with clinical significance have been identified. Rearrangements of DUSP22 on chromosome 6p25.3 occur in about 30% of ALK-negative ALCLs and can be detected by fluorescence in situ hybridization (FISH)19,20. About half of these cases have a non-genic partner locus on 7q32.3, whereas the partners in other cases have not been characterized. ALK-negative ALCLs with DUSP22 rearrangements have distinct features. Morphologically, these neoplasms are composed of a monotonous population of medium-sized cells, often with nuclear pseudoinclusions (doughnut cells)21. By immunohistochemistry, they generally express LEF1 and HLA-DR and lack expression of cytotoxic markers and phosphorylated STAT314,19. These neoplasms have a unique gene expression signature characterized by cancer-testis antigen expression and show global DNA hypomethylation14,22. Clinically, patients have a favorable prognosis, like patients with ALK-positive ALCL, although high-risk cases with aggressive disease have been described23.
A second group of ALK-negative ALCLs, about 8%, have rearrangements of TP63 on chromosome 3q28, most frequently resulting from an inversion involving TBLXR1 on 3q26.324. The rearrangement encodes a fusion protein that lacks the transactivation domain of TP63 analogous to oncogenic ΔNp63 isoforms. Patients with these neoplasms have extremely poor outcomes19. Occasional cases have co-existing DUSP22 rearrangements25. Other fusions seen recurrently in ALK-negative ALCL involve the tyrosine kinase genes TYK2 or ROS1 and contribute to JAK-STAT3 activation analogous to the role of ALK fusions in ALK-positive ALCL26,27.
Recurrent oncogenic truncation of ERBB4 also has been described28. Losses involving TP53 and/or PRDM1 occur more frequently in ALK-negative ALCL than in ALK-positive ALCL and have adverse prognostic significance11. Genes recurrently mutated in ALK-negative ALCL include TP53, JAK1, STAT3, PRDM1, KMT2D, KRAS, TET2, and NOTCH127. A single point mutation E116K of the basic helix-loop-helix gene MSC is highly recurrent in ALK-negative ALCL with DUSP22 rearrangements29.
Primary cutaneous ALCL
Primary cutaneous (pc) ALCL is a localized form of ALCL presenting in the skin and is part of a spectrum of primary cutaneous CD30-positive T-cell lymphoproliferative disorders that also includes lymphomatoid papulosis and borderline cases6,30. Patients with documented MF are excluded. The male:female ratio is 2-3:1 and the median age is 60 years. Morphologic and immunophenotypic features are similar to systemic ALCL, and hallmark cells are generally present. CD30 should be expressed in >75% of the lymphoma cells. Nearly all cases are ALK negative. Clinical staging is required to exclude cutaneous involvement by systemic ALCL. Although pcALCL may be locally destructive, the prognosis is generally favorable.31 Frontline treatment generally consists of surgical excision and/or radiotherapy, with BV and/or chemotherapy in more advanced cases32.
Genetics and molecular profiling
pcALCL lacks ALK rearrangements in most cases30. The classification of the few (~3%) cases with ALK rearrangements and expression of ALK remains unclear; at least some cases have a clinical course similar to that of typical pcALCL33. Other rearrangements seen in systemic ALK-negative ALCL are also seen in pcALCL, including those involving DUSP22, TP63, and TYK26,20,24,26. pcALCL shows copy number abnormalities distinct from mycosis fungoides and other cutaneous T-cell lymphomas34,35; however, molecular features distinguishing pcALCL from systemic ALCLs remain unclear. In a gene expression profiling study combining pcALCLs and systemic ALCLs, cases preferentially clustered by genetic subtype rather than by anatomic site of presentation14. Similarly, while the mutational landscape of pcALCL has not been completely elucidated, mutations seen in systemic ALK-negative ALCL are observed, including those involving JAK1 and STAT3 as well as MSC E116K in cases with DUSP22 rearrangements6,27,29.
Breast implant-associated ALCL
Breast implant-associated (BIA) -ALCL is a rare form of ALCL presenting in association with prosthetic breast implants placed for either cosmetic or reconstructive purposes6,17. Virtually all patients are women. The mean age at presentation is 50 years and the median interval after implant placement is 11 years. Early diagnosis may be established in cytology preparations from peri-implant seroma fluid. Tissue diagnosis is generally made in capsulectomy specimens and occasionally in locoregional lymph nodes or distant sites. Morphologic and phenotypic features are similar to other ALCL types. The neoplastic cells uniformly express CD30, are ALK negative and often show aberrant T-cell antigen loss. A TNM staging system has been proposed and invasion, the presence of a mass, and lymph node involvement are adverse prognostic features36,37,38. Localized disease may be managed with implant removal and capsulectomy alone, but systemic chemotherapy is required for patients with advanced stage disease39.
Genetics and molecular profiling
All cases studied to date have lacked rearrangements of ALK, DUSP22, and TP6340. Recurrent losses of chromosome 20 have been reported and are relatively specific for BIA-ALCL41. Recurrent gains of 9p24.1 associated with CD274 (PD-L1) expression have been reported42. BIA-ALCL has a unique gene expression profile that distinguishes it from other ALCL types and other T-cell lymphomas, including up-regulation of cell motility genes such as the tyrosine kinase MET and hypoxia-associated genes such as carbonic anhydrase IX (CA9)43,44. The levels of several proteins are elevated in seroma fluid from BIA-ALCL patients, including CD30, CA9, and cytokines such as IL10 and IL1344. Like other ALK-negative ALCLs, recurrent mutations of JAK1, JAK3, and STAT3 occur in BIA-ALCL6,40,45,46. The frequencies of mutations in epigenetic modifying genes, particularly KMT2C, CREBBP, and CHD2, appear higher than in other ALCL types46. Germline mutations of TP53 (Li-Fraumeni syndrome) and an increased prevalence of BRCA1 and BRCA2 mutations have been reported in women with BIA-ALCL47,48.
Current role of genetic testing in workup of ALCLs
Genetic findings and potential biomarkers in all types of ALCL are summarized in Table 1. Immunohistochemistry for ALK is necessary in the work-up of all cases; FISH or next-generation sequencing (NGS) studies to assess ALK rearrangements may be helpful in some cases. FISH for DUSP22 rearrangement should be performed in ALK-negative cases because of the prognostic implications and these patients may be considered for clinical algorithms used for patients with ALK-positive ALCL49. We also recommend FISH for TP63 rearrangement for prognostic purposes and to identify rare cases with co-existent DUSP22 and TP63 rearrangements. Currently, mutation testing of ALCL cases is not standard in routine clinical practice.
Peripheral T cell lymphoma, not otherwise specified
PTCL-NOS is one of the most common types of PTCL, accounting for 30–50% of all PTCL cases. By definition, PTCL-NOS does not represent a uniform entity but instead is a heterogeneous group of lymphomas that cannot be assigned to more specific PTCL entities. Therefore, the morphologic, immunophenotypic, cytogenetic, and molecular features of PTCL-NOS are variable.
Genetics and molecular profiling
Using gene expression profiling (GEP), two novel biological subgroups with different diagnostic signatures have been identified within the PTCL-NOS group13. One subgroup is characterized by high expression of GATA3 and its target genes (e.g., CCR4, IL18RA, CXCR7) and is associated with high MYC and proliferation signatures, lack of a prominent microenvironmental signature, and poor clinical outcome. The other subgroup is characterized by high expression of TBX21 and its target genes (e.g., EOMES, CXCR3, IL2RB, CCL3, IFNγ) and enrichment of the NF-kB pathway and is characterized by a more favorable outcome. In addition, these groups show differences in their copy number aberrations, with higher genomic complexity in the high GATA3 subgroup50. The different outcomes of these subgroups were subsequently observed in an independent study using immunohistochemistry to categorize both subgroups51. An immunohistochemistry algorithm has been proposed using four antibodies specific for GATA3, CCR4, TBX21, and CXCR3 to apply this classification to clinical practice51. Whereas the identification of the GATA3 and TBX21 groups currently has no impact on front-line treatment decisions, this classification may impact the clinical management of PTCL-NOS patients in the future, as these two subgroups may be amenable to different treatments.
Limited data are available regarding the mutational landscape of PTCL-NOS. In addition, it is difficult to appreciate the actual frequency of genomic abnormalities in PTCL-NOS, in part because the WHO classification in 2016 recognized nodal PTCL with TFH phenotype, and in older studies these neoplasms were included within the PTCL-NOS group. Only a few studies have evaluated the genomic landscape of PTCL-NOS using current WHO classification criteria50,52,53,54.
As in other hematologic neoplasms, mutations/deletions in tumor suppressor genes are frequently described in PTCL-NOS and are usually associated with a poorer prognosis. Aberrations in TP53 signaling (biallelic deletions/mutations) are primary seen in PTCL-GATA3 cases and are associated with deletions of PTEN and CDKN2A50. These aberrancies are relevant because are associated with a poorer prognosis. TP53 mutations occur in the DNA binding and tetramerization domains, including the hotspot TP53R175H50. Immunohistochemistry is useful in identifying mutations in TP53, and therefore has some clinical utility in the diagnostic setting. A subsequent study identified a distinct poor prognosis subgroup characterized by TP53/CDKN2A mutations and deletions, accompanied by chromosomal instability and mutations in IKZF2 and genes associated with immune escape (such as HLA-A and HLA-B, CIITA, CD274, and CD58)52. A whole genome sequencing study with subsequent FISH analysis showed that CDKN2A and PTEN deletions are frequently encountered in PTCL-NOS, 46% and 26% of cases, respectively, and similarly associated with a poorer prognosis55. Furthermore, coexisting co-deletion of CDKN2A and PTEN was reported to be a highly specific finding for PTCL-NOS as compared with AITL and ALK-negative and ALK-positive ALCL55.
Mutations in genes encoding DNA modifying enzymes such as TET2 and DNMT3A have been described in PTCL-NOS50,52,54,56,57. However, after separation of cases of PTCL with TFH phenotype from the PTCL-NOS group, it has become apparent that genetic aberrations in epigenetic regulators are less frequent in PTCL-NOS. DNMT3 mutations are rarely detected in PTCL-NOS without a TFH phenotype52,57. On the other hand, TET2 mutations occur in ~20% of cases of PTCL-NOS52,54,57. In one of these studies, TET2 mutations occurred predominantly in association with TP53/CDKN2A alterations52. Similar to other types of T-cell lymphoma, mutations in PLCG1 (~25%), CD28 (~20%), and VAV1 (~5%) are encountered in PTCL-NOS52,58. These mutations have been recently described in association with TP53/CDKN2A alterations, and rarely in PTCL-NOS without these abnormalities52. IDH2 R172 57,59 and RHOAG17V 57 mutations are usually not detected in PTCL-NOS cases. A targeted sequencing study identified recurrent mutations of FAT1 in a subset of PTCL-NOS cases53. FAT1 is a tumor suppressor gene that encodes a protein that binds to β-catenin and inhibits nuclear localization, thus inhibiting cell growth. Recurrent mutations in FAT1 were observed in 39% of cases of PTCL-NOS and were associated with inferior outcome.
A recent study has described JAK2 rearrangements in a small subset of PTCL cases expressing CD30 that have Hodgkin-like morphologic features. Five different fusion partners were identified: poly(A) binding factor 3 (ILF3), pericentriolar material 1 (PCM1) and microtubule associated protein 7 (MAP7)60. Recurrent fusion transcripts have been identified in a subset of PTCL-NOS cases including VAV1-MYOF, VAV1-THAP4, VAV1-S100A7, TBL1XR1-TP63, FYN-TRAF3IP2, KHDRBS1-LCK.24,61,62 FYN-TRAF3IP2 was also detected in some cases of nodal PTCL with TFH phenotype61.
Current role of genetic testing in workup of PTCL-NOS
Genetic findings and potential biomarkers in PTCL-NOS are summarized in Table 2. The immunohistochemical algorithm for PTCL-NOS is not required for diagnosis, but we suggest this algorithm be used based on its prognostic value and the possibility that it likely will become standard-of-care in the future. The role of gene mutations in PTCL-NOS is currently being defined. Data described above suggest that routine testing for TP53, CDKN2A, and PTEN in PTCL-NOS may be relevant for refining the prognosis of PTCL-NOS patients. However, larger studies are needed to propose testing of these genes in routine clinical practice. Gene mutation testing also can be helpful in excluding other categories of T-cell lymphoma, particularly nodal PTCL with a TFH phenotype.
Angioimmunoblastic T-cell lymphoma, nodal PTCL with a TFH phenotype and follicular T-cell lymphoma
Three nodal lymphomas express signatures typical for TFH cells: AITL and two related tumors, nodal PTCL with a TFH phenotype and follicular T-cell lymphoma (FTCL). The lymphoma cells have a TFH immunophenotype as shown by expression of TFH markers such as CD10, BCL-6, PD1/CD279, ICOS, and CXCL13.2 The WHO classification recommends that at least, 2 but ideally 3 or more TFH markers be expressed to support TFH lineage.
Angioimmunoblastic T-cell lymphoma
AITL is the second most common type of PTCL in Northern Europe and in our own experience at our own institution, representing 15 to 20% of all cases63. AITL is most frequent in middle-aged and elderly patients. Patients usually present with generalized lymphadenopathy (typically less than 3 cm), hepatosplenomegaly, constitutional symptoms, and skin rash and usually have evidence of immune dysregulation (e.g., coombs-positive hemolytic anemia, cold agglutinins, polyclonal hypergammaglobulinemia)64. The diagnosis of AITL is based on a combination of clinical, histologic and immunophenotypic features. Distinctive histologic features include expansion of B-cells, proliferation of arborizing high endothelial venules (HEV) surrounded by expanded networks of follicular dendritic cells (FDCs), numerous plasma cells, and scattered EBV + activated B-cells (in ~80% of cases).
Genetics and molecular profiling
AITL shows lower genomic complexity than other PTCLs, with frequent co-occurring gains of chromosomes 5 and 2150. Other chromosomal gains (e.g., 7q, 11, 19 or 22q) occur in less than 10% of the cases.57 AITL frequently has mutations in genes involved in epigenetic pathways such as TET2 (40–80%), IDH2R172 (20–45%) and DNMT3A (20–30%) as well as mutations in the small GTPase RHOAG17V (50–70%). Mutations in components of the T-cell receptor (TCR) signaling pathway such as PLCG1, CD28, FYN, and VAV1 are also seen. Mutations in RHOAG17V and IDH2R172 have been shown to correlate with some of the distinctive features of AITL. AITL with RHOAG17V mutations, in comparison with the RHOA wild-type cases, have higher blood vessel density, more FDC perivenular expansion and express a greater number of TFH markers65,66. AITL with IDH2R172 mutations are characterized by medium-sized to large tumor cells, some with clear cytoplasm, and strong CD10 and CXCL13 expression67. IDH2R172 mutated cases are also enriched for gains of chromosomes 5 and 2150. TET2 and DNMT3A mutations are not specific to AITL; however, different from other neoplasms, these two mutations frequently co-occur in AITL. Interestingly, TET2 and DNMT3A mutations are not restricted to T-cells, but also can be identified in the admixed B-cells and in hematopoietic stem cells of patients with AITL, whereas RHOAG17V and IDH2R172 mutations appear confined to the neoplastic T-cells68,69,70.
Nodal PTCL with a TFH phenotype
Some nodal CD4-positive TCLs that lack the diagnostic morphologic features of AITL nevertheless express several TFH markers and have a mutational and expression profiling similar to AITL, prompting the provisional category of nodal PTCL with a TFH immunophenotype in the WHO classification2. Nodal PTCL with a TFH immunophenotype is not a rare T-cell neoplasm, since ~40% of neoplasms once designated as PTCL-NOS express TFH markers.
Genetics and molecular profiling
The mutational profile of nodal PTCL with a TFH phenotype seems to be similar to AITL with mutations in TET2, DNMT3A, and RHOAG17V 57,71. However, IDH2R172 mutations seem to be restricted to AITL and TET2 mutations seem to be slightly more frequent in nodal PTCL with a TFH phenotype57. Both neoplasms also share mutations in genes of the TCR signaling pathway, except CD28 mutations that seem to be restricted to AITL71. The chromosomal copy number gains seen in AITL occur with similar frequencies in nodal PTCL with a TFH phenotype57.
Follicular T-cell lymphoma
FTCL has a follicular growth pattern, mimicking follicular lymphoma, with follicles populated by aberrant T cells that express TFH markers72. In FTCL, Hodgkin and Reed-Sternberg (HRS)-like cells are frequently noted. These HRS-like cells are of B-cell lineage, positive for CD30 and, in a subset of cases, positive for CD15 and EBER raising concern for classic Hodgkin lymphoma. In contrast to AITL, FTCL lacks proliferation of HEVs and perivenular expansion of FDCs.
Genetics and molecular profiling
The mutational profile of FTCL seems to be similar to AITL and nodal PTCL with a TFH phenotype with mutations in TET2, IDH2R172, DNMT3A, and RHOAG17V 73. TET2 mutations seem to be more frequent in FTCL than in AITL and nodal PTCL with a TFH phenotype. FTCLs harbor a characteristic t(5;9)(q33;q22) resulting in an ITK-SYK fusion in ~40% of cases74. The ITK-SYK fusion acts as a constitutively active SYK tyrosine kinase and drives lymphomagenesis by triggering antigen-independent activation of TCR signaling. Translocations involving FER and FES have been recently described including ITK-FER and RLTPR-FES that result in activation of STAT3 signaling73.
Current role of genetic testing in workup of T-cell lymphomas with TFH phenotype
Genetic findings and potential biomarkers in T-cell lymphomas with TFH phenotype are summarized in Table 3. Immunohistochemistry with an anti-IDH2R172K antibody is highly sensitive for the detection of AITL with IDH2R172 mutations75. This test could be used as a first step for diagnosing AITL with IDH2R172 mutations. In addition to its diagnostic relevance, the identification of patients with mutated IDH2 may be clinically relevant because specific IDH2 inhibitors are currently in clinical trials. Mutations in DNMT3A, TET2, IDH2R172, and in RHOAG17V are common in PTCLs with a TFH phenotype and are helpful in supporting the diagnosis. Early phase clinical trials with hypomethylating agents and histone deacetylase inhibitors show promise in T-cell lymphomas related to AITL, and there is interest in determining whether TFH-related lymphomas may preferentially respond to such agents76.
The t(5;9)(q33;q22)/ITK-SYK appears to be specific for FTCL and is only rarely reported in AITL77. Targeted therapy with SYK inhibitors may be helpful in patients with these neoplasms74,78. ITK-FER and RLTPR-FES seem to be specific for FTCL and also represent potential targets for inhibition.
Extranodal NK/T cell lymphoma, nasal type
Extranodal NK/T cell lymphoma (ENKTL) is an EBV-associated neoplasm that is most common in Asia or Central/South America, but also occurs uncommonly in industrialized nations. About two-thirds of these lesions are thought to be of natural killer (NK) -cell origin, but one third are of T-cell lineage. The NK- and T-cell forms of ENKTL are morphologically and clinically very similar, but they differ with respect to immunophenotype and genotype. The NK-cell lesions express CD2, CD56, and cytoplasmic CD3 and lack evidence of T-cell clonality, whereas the T-cell lesions express surface CD3 and carry monoclonal T-cell receptor gene rearrangements. There are also two “anatomic variants” of ENKTL, nasal and extra-nasal, which are associated with different clinical findings and outcomes, with the extra-nasal form having a worse prognosis3. Morphologically, ENKTL with nasal or extra-nasal presentation is frequently characterized by vascular damage, tissue destruction and necrosis.
Genetics and molecular profiling
The genetic composition of ENKTL is complex and overlaid by EBV infection and the associated immune environment79. There are genetic differences based on geographic location implying differences in genetic predisposition80. Two major genome-wide association studies in Asian populations have been published with epidemiologic data suggesting that genetic or environmental factors predispose some individuals to ENKTL81,82. These studies identified single nucleotide polymorphisms (SNPs) in IL118RAP on chromosome 2q12.1, HLA-DRB1 on chromosome 6p21.3, and HLA-DPB1 on chromosome 6 as being associated with increased risk of ENKTL81,82.
NK- and T-cell ENKTLs also show differences in genetic abnormalities83. It is important to clarify that primary EBV-positive nodal T-cell or NK-cell lymphomas are distinct and deserve to be classified separately from ENKTCL. Primary nodal cases are more common in elderly patients, lack nasal involvement, are of T-cell lineage and are currently referred to as EBV-positive nodal T-cell lymphoma or EBV-positive PTCL rather than ENKTL, although this entity may have been diagnosed as ENKTL in the past83.
Alterations of the JAK-STAT pathway have been identified in up to 35% of ENKTL cases, particularly mutations of JAK3, STAT3 and STAT5B. Mutations of tumor suppressor genes are also relatively frequent, such as BCOR (up to 32%), DDX3X (up to 50%) and TP53 (8–63%)80,84,85,86. There are some differences in the frequency of these mutations in ENKTLs based on geography; for example, BCOR and DDX3X mutations are more often seen in cases in Asia, whereas STAT3 mutations are more common in cases in Latin America80. In addition, mutations in STAT3, BCOR and DDX3X are usually mutually exclusive, and TP53 mutations only rarely overlap with DDX3X mutations80,85. The alterations in ENKTL cases can be grouped as those involving single genes (e.g., survivin, AURKA, MYC, EZH2, and RUNX3) and those involving signaling pathways (JAK-STAT, NF-kB, NOTCH1, and PDGFR). In general, ENKTL are characterized by activation of MYC and NF-kB and deregulation of P5387. Many copy number alterations have been shown in ENKTLs including loss of 1p36.11-p36.32, 6q21-q25, 6q26-q27, 7p15.3-p22.3, 9p21.3, 11q22.3-23.3 and gains in 1q22-q44, 2q22.2-q33.1, 6p21.3, 7q21.1-q36.3, 11q24.3, 13q14.2 and 17q21.2-q25.379,83,85,88,89. Del(6)(q21;q25) is one of the more frequent abnormalities; this region encodes a variety of tumor suppressor genes, such as PRDM1, FOXO3, AIM1, and ATG5, as well as PTPRK, a gene known to encode for an enzyme that dephosphorylates phospho-STAT3 (pSTAT3)79,85,88,89,90. Loss of 14q11.2 (TRA locus) is more often seen in T-cell ENKTL83.
Xiong et al.90 recently defined three ENKTL molecular subtypes: TSIM, MB and HEA. The TSIM-subtype is associated with JAK/STAT activation, NK-origin and PD-L1 overexpression. The MB-subtype shows MYC overexpression and poor outcome, and the HEA-subtype is characterized by epigenetic changes, NF-kB activation, and T-cell origin. These molecular subtypes differ significantly in progression-free survival (PFS) and overall survival (OS) and are sensitive to different targeted therapeutic strategies. The predicted 3-year OS rates for the TSIM, MB and HEA subtypes were 79.1%, 38,5%, and 91.7%, respectively.
EBV in ENKTL expresses LMP1 (latency II pattern), which functions as a CD40 ligand, thereby activating the NF-kB pathway91. Most cases of ENKTL in Asia (>90%) harbor EBV with a 30 bp deletion in LMP1, which is associated with more aggressive behavior. However, EBV with the del-LMP1 form is less frequent in Central and South America, ranging from 0% in Peru to 42% in Argentina80,92,93. EBV is hypothesized, through epigenetic mechanisms, to be involved in tumor pathogenesis94. Furthermore, in ENKTL EBV frequently shows alterations in latent (EBNAs, LMP1 and LMP2) and lytic (BBLF2/3, BPLF1, and BALF3) genes. BALF3 is thought to contribute to ENKTL pathogenesis by causing DNA damage leading to genomic instability. However, in comparison with EBV-associated nasopharyngeal and gastric carcinoma, ENKTLs exhibit lower transcription of EBV-associated genes and have more T-cell epitope alterations, suggesting that immune evasion plays a role in pathogenesis90,95. Recent evaluation of the ENKTL immune microenvironment by gene expression profiling and immunohistochemistry shows three different immune microenvironments termed immune tolerance, immune evasion and immune silenced that are associated with different expression levels of PD-L1 and response to PD-L1 inhibitors and outcome. These features highlight the interplay of EBV, the microenvironment, tumor pathogenesis and clinical behavior96.
Current role of genetic testing in workup of extranodal NK/T-cell lymphomas
Some of the genetic findings in ENKTLs are shown in Table 4. Currently, genetic testing is not required for the workup of ENKTLs, with the exception of T-cell receptor gene rearrangement studies to distinguish NK- from T-cell neoplasms. We believe that this situation is likely to change because many genetic alterations in ENKTL represent potential therapeutic targets. The activity associated with pSTAT3 may be abrogated by increasing the expression of PTPRK employing demethylating agents such as 5-azacytidine to demethylate its promoter. Other therapeutic agents such as the JAK inhibitors, ruxolitinib and tofacitinib, or a STAT3 inhibitor may be helpful. Other therapeutic agents under consideration to treat ENKTL patients include daratumumab (anti-CD38), brentuximab vedotin, bortezomib, EZH2 inhibitors and the PD1 inhibitor pembrolizumab.
Hepatosplenic T-cell lymphoma
Hepatosplenic T-cell lymphoma (HSTCL) is an aggressive T-cell neoplasm that tends to occur in young men and can arise in the setting of chronic immunosuppression. Patients present with hepatosplenomegaly, bone marrow involvement and cytopenias without lymphadenopathy. Although this neoplasm was initially thought to be derived from cells that express TCRγ/δ, a subset of HSTCL cases express TCRα/β97,98,99,100. Lesions that express TCRα/β occur more often in women and in older individuals99. Morphologically, the neoplastic cells are usually of intermediate-size; however, there is variability in the cytologic appearance, ranging from cells that have condensed chromatin and inconspicuous nucleoli to those that have finely dispersed chromatin and prominent nucleoli, reminiscent of blasts97,101.
Genetics and molecular profiling
The most consistent genetic finding in HSTCL is isochromosome 7q [i(7q)], which is present in 25–70% of cases using either conventional cytogenetics or FISH. Although i(7q) can be seen in other diseases, this abnormality is thought to be a primary lesion in HSTCL. Trisomy 8 is another frequent cytogenetic finding, usually seen in association with i(7q). Additional cytogenetic abnormalities often occur with disease progression97,98,100,102,103.
HSTCL is a monoclonal T cell neoplasm98,99,103,104,105. In most cases, the T-cells express TCR γ/δ97,100,103,104 and usually exhibit Vδ1 usage at both the DNA and protein level. Furthermore, this Vδ1 usage parallels that of normal TCRγ/δ cells in the spleen and correlates with CD56 expression by the neoplastic cells102,104.
GEP shows a clear separation of HSTCL cases from other T-cell lymphomas, including PTCL-NOS, AITL and ENKTL. The profile appears to be more similar to ENKTL than other PTCL types103. Upregulated genes include S1PR5, which is involved in NK-cell homing to the spleen, and ABCB1, which encodes p-glycoprotein multidrug transported (MDR1). Other overexpressed genes (in comparison with PTCL-NOS) include KIRS, NCAM1, and CD244103. Genes underexpressed in HSTCL compared with PTCL-NOS, include those encoding for TFH-associated proteins such as CXCL13 and ICOS, and genes encoding immune modulating proteins such as IL411, CD5 and the tumor suppressor gene AIM1. Genes associated with cytotoxic molecules, such as Granzyme B and Granzyme H are also underexpressed (consistent with lack of expression of these markers as assessed by immunohistochemistry). In comparison to normal TCRγ/δ cells, the neoplastic cells in HSTCL overexpress S1PR5 and the oncogenes FOS and VAV3103. Furthermore, many of the underexpressed- and overexpressed genes are involved in a variety of pathways, including the AP1 and WNT pathways, and thus are likely important in the pathogenesis of this disease.
Whole exome sequencing has identified a variety of recurrent mutations that can be grouped into three categories. Chromatin modifying genes, such as SETD2, ARID1B, INO80, TET3, and SMARCA2, are mutated in >60% of cases and constitute the largest category of genes mutated. SETD2, a tumor suppressor gene, is the most frequent mutated gene (~70%) in this category. A second group have frequently mutations, usually missense mutations, occurring in signaling pathway genes, most commonly in STAT5B (31%), STAT3 and PIK3CD100,106. STAT5B and STAT3 mutations are activating mutations which are usually mutually exclusive in HSTCL cases.100 The last group of mutations consists of mutations in other genes such as TP53, UBR5, and IDH2 (5–10% of cases)100,106,107.
A variety of epigenetic changes occur in HSTCL, including hypermethylation of AIM1, BCL11B, LTA, GIMAP7, SEPT9, CD5, and CXCR6, all of which have relevance in the pathogenesis of T-cell lymphomas. Furthermore, hypermethylation in HSTCL has been associated with lack of protein expression, suggesting a mechanism for the frequent lack of expression of many markers in this disease, such as CD5. In addition, hypomethylation in ADARB1, NFIC, NR1H2, and ST3GAL3 has been described. Overall, the methylation changes are seen preferentially in regulatory elements, such as enhancers103,105.
Current role of genetic testing in workup of HSTCL
Genetic findings and potential biomarkers in HSTCL are summarized in Table 5. As i(7q) is seen in many cases of HSTCL, conventional cytogenetic analysis is helpful for establishing the diagnosis. This cytogenetic abnormality can be seen by karyotyping; however, FISH is often more sensitive. Trisomy 8 is seen in many additional cases. TCR gene rearrangement analysis is helpful in proving the presence of a monoclonal T-cell population. Additional genetic studies including single gene mutation analysis, whole exome sequencing and epigenetic studies are not required for diagnosis or the planning of therapy at this time point, but mutations in STAT genes are potentially targetable.
Primary intestinal T-cell lymphomas
Enteropathy-associated T-cell lymphoma (EATL)
Enteropathy-associated T-cell lymphoma (EATL) is an aggressive neoplasm of intestinal intraepithelial T-lymphocytes that arises in patients with celiac disease or gluten sensitivity. Although rare, EATL is the most common intestinal T-cell lymphoma in the Western world, seen with greater frequency in regions with a higher prevalence of celiac disease. EATL is more common in men, typically presents in patients 50–60 years of age, and is associated with the presence of HLA-DQ2 and HLA-DQ8 alleles. The small intestine is the most commonly affected site, but other gastrointestinal (GI) tract sites can be involved as well as extraintestinal sites.
EATL is characterized by a proliferation of pleomorphic, variably sized atypical lymphocytes, sometimes with large cell or anaplastic morphology, in a background rich in histiocytes and eosinophils. Adjacent uninvolved small intestine typically shows features of celiac disease. The malignant lymphocytes are CD3+, CD103+ T-cells that express cytotoxic proteins, are negative for CD56, and usually lack expression of CD4 and CD8. The lymphoma cells show variable expression of CD30 and express TCRα/β more often than TCRγ/δ.
Genetics and molecular profiling
EATL exhibits monoclonal rearrangements of TRB and TRG genes108. Several recurrent genetic changes have been described in EATL, many of which are shared with monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) (see below). Using array comparative genomic hybridization (CGH), FISH, microsatellite markers, and qPCR, the most commonly identified abnormality is segmental amplification of 9q31.3-qter, encompassing NOTCH1 and ABCL1 and present in 70–80% of cases109,110,111. In addition, gains of 1q32-41, 5q, 6p21, 7q, 8q24, and 19q; and losses of 3p12, 3q26, 4q, 6p24, 7p21, 8p, 10p12-13, 11q14;-q23 13q22, 16q12, 17q23-25, 17p13.1, 18q22, and Xq have been reported. 9p31.3-qter gains and 16q12 losses occur in a seemingly mutually exclusive pattern112. Losses of 1q32-41 and 5q35 are reported more frequently in EATL (compared to MEITL) and gains of 8q24 are rare (unlike MEITL). 9p21 (CDKN2A/2B) loss is seen in ~55% of cases with concomitant loss of p16 protein expression by immunohistochemistry. Loss of 17p13 and/or TP53 mutation is rare in EATL, but p53 protein overexpression by immunohistochemistry is seen in virtually all cases113.
Targeted next-generation sequencing and whole exome sequencing have shown that the JAK/STAT pathway is most frequently altered with gene mutations identified in 68% of cases, including STAT5B, JAK3, JAK1, STAT3, SOCS3, SOCS1, and TYK2114. STAT5B and STAT3 mutations occur in a seemingly mutually exclusive pattern. MAP kinase pathway alterations are seen in about one quarter of EATL cases with mutations in KRAS, NRAS, and BRAF identified. Recurrent mutations of the tumor suppressor gene SETD2 occur in ~30% of cases. Recurrent mutations are also seen in TP53, TET2, TERT, EZH2, FYN, NOTCH1, and CD247. Mutations known to occur in other T-cell lymphomas, including IDH2, DNMT3A, RHOA, GNB1, PLCG1, CCR4, JAK2, IL7R, and CD130 have not been consistently observed. Gene expression profiling has also shown that EATL shows increased expression of STAT3, STAT5A, IRF1, IRF4, TGM2, and genes in the IFNγ pathway compared to MEITL115.
Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)
MEITL, formerly known as type II EATL, is another aggressive neoplasm derived from intestinal intraepithelial T-lymphocytes. In contrast to EATL, MEITL is not associated with celiac disease and occurs worldwide with a predilection for patients of Asian, Hispanic, and indigenous origin112. It is the most common intestinal T-cell lymphoma in Asia. MEITL is more common in men and is a disease of adults with a median age of 59 years (range, 23–89 years). The small intestine is the most frequently involved site, with the jejunum showing the highest rate of involvement. Mesenteric lymph node involvement is also common, but involvement of other gastrointestinal sites, such as stomach and colon is infrequent. Dissemination to other extra-intestinal sites including liver, lungs, bone marrow, central nervous system, and peripheral lymph nodes can occur116.
MEITL is characterized by a proliferation of monomorphic medium-sized lymphocytes. An inflammatory background is absent, and necrosis is uncommon, but granulomas may be seen. There is prominent epitheliotropism, but adjacent uninvolved small intestine does not show features of celiac disease. The neoplastic T cells are CD3+, CD8+, and CD56+, express cytotoxic proteins, are negative for CD4 and CD30; and show variable expression of CD103. The neoplastic cells express TCRγ/δ more often than TCR α/β. Most cases also show expression of megakaryocyte-associated tyrosine kinase (MATK), which distinguishes MEITL from EATL if expressed in >80% of cells117. Aberrant CD20 expression has been seen in about 25% of cases116.
Genetics and molecular profiling
MEITL exhibits monoclonal rearrangement of the T-cell receptor genes108. MEITL shows strong overlap and shares numerous genetic changes with EATL, albeit at different frequencies (see above). As in EATL, the most commonly encountered abnormalities in MEITL are gains of 9q31.3-qter and mutually exclusive losses of 16q12109,110. Gains in 8q24 (25–73%) are more common in MEITL, whereas losses of 1q32-41 and 5q35 are rare.
Targeted next-generation sequencing and whole exome sequencing studies115 have shown that the JAK/STAT pathway is frequently altered in MEITL (80%) with STAT5B and JAK3 mutations occurring more frequently than in EATL114. MAP kinase pathway alterations are also frequently identified in MEITL (32%). Alterations in the G-protein coupled receptor signaling pathways have been described with recurrent mutations of GNAI2 reported in 24% of cases in one series118. The tumor suppressor gene SETD2 which encoded a non-redundant H3K36-specific trimethyltransferase is altered in over 90% of western European cases, mainly by loss-of-function mutations and/or loss of the corresponding locus (3p21.31)119. SETD2 alterations are also reported in about 70% of cases in North America and also are highly prevalent in Japanese patients. SETD2 inactivation consistently correlates with defective H3K36 trimethylation and seems to be a critical event in facilitating both neoplastic initiation and progression through decreasing H3K36me3120. CREBBP mutations are also described, occurring in 30% of cases, however they always occur in association with STAT5B and/or JAK3 mutations, suggesting CREBBP mutations may not be initiating events118. Gene expression profiling115 has shown that MEITL shows increased expression of FASLG, SYK, TGBR1, and NCAM1 (encodes CD56), as well as the NK-like cytotoxicity pathway as compared with EATL. Despite the increased frequency of 8q24 gains, MYC expression is not increased in MEITL.
Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract (ITLPD)
ITLPD is a monoclonal T-cell lymphoproliferative disorder involving any part of the GI tract mucosa, most frequently the small intestine and colon. This neoplasm usually occurs in adults and affects men more often than women in a chronic relapsing pattern. Rarely, extra-intestinal sites including peripheral blood, bone marrow, and liver can be involved.
ITLPD is characterized by a non-destructive expansion of the lamina propria by a dense proliferation of monotonous small mature appearing lymphocytes without significant epitheliotropism. There is no significant inflammation or necrosis. The infiltrate is composed of CD3+ T-cells that express TCRα/β. The cells show variable expression of CD4 and CD8, with CD4+/CD8−, CD4−/CD8+ and CD4−/CD8− cases. CD8+ cases are usually positive for TIA1 and negative for granzyme B. All cases are negative for CD56 and CD30.
Genetics and molecular profiling
ITLPD exhibits monoclonal rearrangement of the TCR genes. Recurrent alterations involving the JAK/STAT pathway and epigenetic modifiers have been reported, including mutations of STAT3, TET2, DNMT3A, and KMT2D, as well as SOCS1 deletion and STAT3-JAK2 fusions121,122. CD4 + ITLPD are associated with STAT3-JAK2 fusions121. CD8+ ITLPD cases can show structural alterations involving the untranslated region of IL2122. Other copy number changes have been described using SNP array analysis123.
Current role of genetic testing in workup of intestinal lymphomas including ITLPD
There are no known genetic changes specific for EATL with wide overlap seen in the genetic landscape of EATL and MEITL (Table 6). The most common abnormality, 9q31.3-qter gain, is not associated with nodal T-cell lymphomas and may help distinguish primary intestinal lymphoma from intestinal involvement by nodal T-cell lymphoma. In addition, several recurrent genetic abnormalities identified in other T-cell lymphomas, including IDH2, DNMT3A, RHOA, GNB1, PLCG1, CCR4, JAK2, IL7R, and CD130 have not been identified in EATL and may aid in distinguishing primary intestinal lymphoma from extraintestinal disease. Distinguishing EATL from MEITL currently depends clinical, morphologic, and immunophenotypic findings. Currently, genetic testing is of limited utility in establishing the diagnosis or guiding therapy.
There is a currently limited role for genetic testing in the workup of MEITL cases. There are no known genetic changes specific for MEITL and the genetic workup is similar to that of EATL. No biomarkers are available for cases of aggressive intestinal lymphomas classified as intestinal T-cell lymphoma, NOS.
JAK2 rearrangements present in ITLPD are not present in reactive infiltrates and have not been described in other intestinal TCLs, and therefore may serve as a useful marker to establish the diagnosis of ITLPD. In addition, a STAT3-JAK2 fusion was identified in one of two patients with ITLPD that progressed to more aggressive lymphoma and could possibly serve as a poor prognostic marker121. This finding needs to be validated in larger series.
Adult T cell leukemia-lymphoma (ATLL)
ATLL is an aggressive T-cell neoplasm arising from post-thymic regulatory T cells and, caused by infection by the RNA retrovirus human T-cell leukemia virus 1 (HTLV-1). ATLL is the most frequent type of T-cell lymphoma/leukemia in Asia (25% of all T-cell cases) and is rare in North America (2%) and Europe (1%), where it affects primarily immigrants from endemic countries. ATLL is associated with four clinical subtypes (Shimoyama classification): two indolent (smoldering and chronic) and two aggressive (acute and lymphomatous)124.
HTLV-1 is transmitted primarily by breastfeeding and infects CD4+ mature T-cells and immature thymocytes in early infancy. The virus is oncogenic by its expression of two genes, TAX and HBZ. It seems that HBZ is important for tumor maintenance and TAX is essential for early proliferation and initiation of the neoplasm125. However, the long latency interval from infection to tumor onset clearly points to additional genetic and/or epigenetic events involved in pathogenesis.
Genetics and molecular profiling
Genomic alterations are detected in most patients and are clustered in five main signaling pathways.126,127 These pathways include TCR/NF-KB (~75%), CD28, PLCG1, PRKCB, CARD11, CBLB, IRF4, CSNK1A1, FYN, RHOA, and VAV1; T cell trafficking (~45%),CCR4, CCR7, and GP183; immune escape (~30%), FAS, HLA-B, B2M, and CD58; cell cycle regulation (~25%), TP53, POT1, and RB1; and JAK/STAT3, JAK3, STAT3, and PTPN1126,127.
Alterations in TCR/NF-KB signaling, or associated pathways, is a hallmark feature detected in most patients with ATLL resulting in enhanced activation of TCR/NF-KB signaling126. One of the most frequently mutated genes is PLCG1 (~33%), which encodes the phospholipase Cγ1, a key regulator of proximal TCR signaling126. This activating mutation enhances PLCγ1 activity. The second most frequently mutated gene is PRKCB, encoding a signaling molecule downstream of PLCγ1. CARD11 is another frequently mutated gene. CARD11 is a cytoplasmic scaffolding protein required for NF-KB activation induced by antigen receptor activation. In ATLL, mutations and deletions in CARD11 are clustered within its PKC-responsive inhibitory domain, which is implicated in the autoinhibition of CARD11128. Negative regulators of TCR/NF-KB signaling are also affected by frequent loss-of function mutations and deletions, including CBLB, TRAF3, TNFAIP3, NFKB1A, and PTPRC among others.
Approximately 10% of cases have in-frame fusions involving CTLA4-CD28 and ICOS-CD28. The expected consequence of these fusions is prolonged and continuous CD28 costimulatory signaling contributing to NF-KB activation126. Other mechanisms resulting in NF-KB activation include transcriptional repression of negative regulators of TCR signaling, e.g., loss of PTPN6 (SHP1) expression, which is mediated by the oncoprotein TAX via a transcriptional mechanism129.
C-C chemokine receptor 4 (CCR4) is highly expressed in ~90% of ATLL patients. Patients with CCR4-positive ATLL are more likely to experience skin infiltration and worse outcomes than patients with CCR4-negative ATLL. CCR4 is also a frequent mutation in ATLL (up to 38% in some series)126,127,130. In most cases, the mutation results in truncation of the C-terminal cytoplasmic domain, preventing the internalization of receptor upon ligand stimulation and resulting in increased surface CCR4 expression, enhanced ligand-induced chemotaxis and activation of PI3K/AKT pathway130,131. The humanized monoclonal antibody against CCR4 mogamulizumab has shown some effects in ATLL (in both relapsed/aggressive ATLL and in front-line settings)132.
IRF4 amplifications (25%) and CDKN2A deletions are characteristic copy number abnormalities in ATLL126. Highly expressed in ATLL, IRF4 drives cell proliferation and is associated with a poor prognosis and therapeutic resistance133,134.
Epigenetic alterations in ATLL are also key to understand the pathogenesis of the disease. More than a third of cases of ATLL show widespread hypermethylation of CpG islands which is associated with transcriptional silencing126.
Current role of genetic testing in the workup of ATLL
Genetic findings and potential biomarkers in ATLL are summarized in Table 7. Aside from identification of integrated HTLV-1 in isolated lymphoma cells or anti-HTLV1/2 antibodies in serum as an imperfect surrogate, there are no specific clinical, morphologic, immunophenotypic or molecular genetic features that are diagnostic of ATLL. In fact, without knowledge of viral infection, ATLL can be difficult to distinguish from other more common T-cell lymphomas135.
Targeted molecular assessment can be useful to identify two molecular ATLL subgroups with clinical relevance. Group 1 is enriched for alterations affecting distal components of TCR/NF-KB signaling pathway (such as CARD11, PRKCB, and IRF4) and immune-related molecules (HLA-A, HLA-B, and CD58), whereas group 2 is enriched for alterations in proximal regulators of TCR/NF-KB signaling (PLCG1, VAV1, and CD28) and a JAK/STAT signaling molecule (STAT3). Group 1 cases have a larger number of mutations and CNAs than cases in group 2. Clinically, most cases of the lymphomatous subtype were classified as group 1, whereas group 2 mainly consisted of leukemic cases. Moreover, patients in group 1 showed poorer overall survival than patients in group 2, independent of clinical subtype. Fig. 1.
Some of the available inhibitors are listed in red. Note that cerdulatinib is a dual SYK/JAK inhibitor. The gray boxes indicate specific vulnerabilities in distinct PTCL subtypes, and the oval circles contain some treatment related comments. ALK anaplastic lymphoma kinase, ALCL anaplastic large cell lymphoma, HSTL hepatosplenic T cell lymphoma, AILT angioimmunoblastic T cell lymphoma, DNMT DNA methyltransferase, HDAC histone deacetylase, ATLL adult T cell leukemia/lymphoma.
Patients with CCR4 mutations have better responses to mogamulizumab136. Decreased expression of CCR4 using an antibody against the C-terminal domain of CCR4 is associated with the presence of CCR4 mutations and predicts response to mogamulizumab137. This decrease in the expression signal is probably due to protein truncation generated by the mutation.
Molecular biomarkers reported to be associated with a poorer prognosis in ATLL patients include TP53 mutation and CDKN2A deletion. There is clinical interest in developing and testing PLCγ1 inhibitors for patients with ATLL. Therefore, determination of PLCγ1 activation could be clinically relevant.
In summary, we have briefly summarized the genetic landscape of PTCLs emphasizing some biomarkers that have an established or a potential role in the work-up of patients with T-cell lymphomas. Although we have achieved significant progress, additional work is needed to extend emerging biological findings and to develop a biomarker-driven classification of this group of neoplasms. Development of biomarkers also will provide additional prognostic and predictive therapeutic biomarkers that can be exploited for more effective therapies. Biomarkers and molecular pathways amenable to therapeutic intervention in PTCL are illustrated in the figure.
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A.L.F. receives research funding from Seattle Genetics, is an inventor of technology related to T-cell lymphoma for which Mayo Clinic holds unlicensed patents, and has intellectual property licensed to Zeno Pharmaceuticals. F.V. receives research funding from NCI, CRISP Therapeutics, Geron corporation and received in the last 3 years honoraria from i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, Society of Hematology Oncology. There are no other competing financial interests to declare.
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Vega, F., Amador, C., Chadburn, A. et al. Genetic profiling and biomarkers in peripheral T-cell lymphomas: current role in the diagnostic work-up. Mod Pathol 35, 306–318 (2022). https://doi.org/10.1038/s41379-021-00937-0
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DOI: https://doi.org/10.1038/s41379-021-00937-0
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