Comprehensive genomic analysis identifying heterogeneity in peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous entity generally with a poor prognosis. Recent genomic analyses have characterized genomic alterations and described gene expression profiling and epigenetic mechanisms in PTCL, leading to reveal molecular pathophysiology in detail. One of several important findings is that heterogeneities exist in both the disease and in individuals. Among PTCL subtypes, adult T-cell leukemia/lymphoma (ATLL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are common in Japan. ATLL is an incurable T-cell malignancy induced by human T-cell lymphotropic virus type 1 (HTLV-1). The global genomics of ATLL can be summarized as alterations involving T-cell receptor (TCR) signaling and immune escape mechanisms. This highlights the fact that ATLL is a viral-mediated T-cell malignancy. Interestingly, several previous studies have found that the genomics of ATLL differ according to geographical region and age at diagnosis, suggesting disease heterogeneity, though they share HTLV-1 infection as initial disease hit. Clonal expansion of the cells acquired by somatic mutations in ATLL-related genes is identified in a part of HTLV-1 carriers who developed ATLL later. The risk for ATLL may be updated based on findings in detail. PTCL-NOS is a heterogeneous disease type of T-cell lymphoma that does not correspond to any other type of PTCL. Several studies have stratified PTCL-NOS according to transcriptional, genomic, microenvironmental, and clinical aspects. These kinds of analysis from multiple aspects are useful to understand the heterogeneous group. These efforts will help guide suitable translational research to target PTCL.

Cutaneous lesions of angioimmunoblastic T-cell lymphoma: Clinical, pathological, and immunophenotypic features.

BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) is a systemic peripheral T-cell lymphoma with a follicular helper T-cell (TFH ) immunophenotype that frequently involves the skin. However, the histopathology of cutaneous involvement by AITL has not been fully established. METHODS: We reviewed the clinicopathological features of 19 patients seen at our institution with AITL involving the skin. Pan-T-cell and TFH marker expression was evaluated by immunohistochemistry. Epstein-Barr virus (EBV) was detected using in situ hybridization (ISH) for Epstein-Barr virus-encoded small RNA (EBER). T-cell receptor (TCR) gene rearrangement was evaluated by PCR. RESULTS: AITL affected both trunk and extremities in 15/19 cases (79%). Perivascular infiltration by small and/or medium-sized lymphocytes was seen in 18/19 (95%). Granulomatous inflammation was identified in 4/19 (21%). Aberrant loss of CD2, CD5, or CD7 was identified in 1/18 (6%), 2/18 (11%), or 7/19 (37%) cases, respectively. Seventeen of eighteen evaluable cases (95%) expressed 2 to 3 TFH markers: PD-1 in 19/19 (100%), BCL6 in 94% (17/18), and CD10 in 37% (7/19). EBV-positive cells were detected in 3/18 (17%) with varying density. Clonal TCR gene rearrangement was identified in 9/11 (82%). CONCLUSIONS: Cutaneous involvement by AITL shows relatively non-specific histopathological features. However, an immunohistochemical panel including TFH markers and EBER ISH is useful in differential diagnosis.

Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes.

The molecular biology of primary nodal T- and NK-cell lymphoma and its relationship with extranodal NK/T-cell lymphoma, nasal type is poorly understood. In this study, we assessed the relationship between nodal and extranodal Epstein-Barr virus-positive T/NK-cell lymphomas using gene expression profiling and copy number aberration analyses. We performed gene expression profiling and copy number aberration analysis on 66 cases of Epstein-Barr virus-associated T/NK-cell lymphoma from nodal and extranodal sites, and correlated the molecular signatures with clinicopathological features. Three distinct molecular clusters were identified with one enriched for nodal presentation and loss of 14q11.2 (TCRA loci). T/NK-cell lymphomas with a nodal presentation (nodal-group) were significantly associated with older age, lack of nasal involvement, and T-cell lineage compared to those with an extranodal presentation (extranodal-group). On multivariate analysis, nodal presentation was an independent factor associated with short survival. Comparing the molecular signatures of the nodal and extranodal groups it was seen that the former was characterized by upregulation of PD-L1 and T-cell-related genes, including CD2 and CD8, and downregulation of CD56, consistent with the CD8+/CD56-immunophenotype. PD-L1 and CD2 protein expression levels were validated using multiplexed immunofluorescence. Interestingly, nodal group lymphomas were associated with 14q11.2 loss which correlated with loss of TCR loci and T-cell origin. Overall, our results suggest that T/NK-cell lymphoma with nodal presentation is distinct and deserves to be classified separately from T/NK-cell lymphoma with extranodal presentation. Upregulation of PD-L1 indicates that it may be possible to use anti-PD1 immunotherapy in this distinctive entity. In addition, loss of 14q11.2 may be a potentially useful diagnostic marker of T-cell lineage.

Frequency and clinical correlates of elevated plasma Epstein-Barr virus DNA at diagnosis in peripheral T-cell lymphomas.

Epstein-Barr virus (EBV)-encoded RNAs (EBER) in tumor tissue and cell-free plasma EBV-DNA (pEBVd) are detected in EBV-associated lymphomas. Studies have suggested that EBER+ peripheral T-cell lymphomas (PTCL) have worse prognosis but the role of EBV in these neoplasms remains unclear. pEBVd is quantitative and more easily amenable to standardization than EBER, but frequency of pEBVd detection, clinical impact and agreement with EBER status in PTCL are unknown. We retrospectively assessed frequency of detectable pre-treatment pEBVd, presence of EBER in tumor tissue, and outcomes in 61 of 135 EBV-assessable PTCL patients. Fifteen of 61 patients (24.5%, 95% CI: 14-37%) were pre-treatment pEBVd+, with no significant differences in baseline characteristics or treatment between pEBVd+ and pEBVd- patients. EBER-ISH was performed on 10 pEBVd+ and 35 pEBVd- tumors. All 10 pEBVd+ patients were EBER+, but 9 pEBVd- patients were also EBER+. With median follow up of 24 months (range 1-96), overall survival (OS) was shorter in pEBVd+ compared to pEBVd- patients (13 vs. 72 months; p = 0.04). In our retrospective study, pre-treatment pEBVd was elevated in 25% of PTCL patients, was highly specific for EBER+ tumors, and was associated with shorter survival. pEBVd should be further explored as a prognostic variable and tumor biomarker in PTCL.

Primary hepatic Epstein-Barr virus-associated CD30-positive peripheral T-cell lymphoma of cytotoxic phenotype.

Primary hepatic peripheral T-cell lymphoma (PTCL) is exceedingly rare. We encountered such a case in a 58-year-old Hispanic female with a history of chronic sinusitis and hypothyroidism who presented with 4weeks of fever and weight loss. Laboratory studies showed altered liver function and mild pancytopenia. Hepatitis and HIV infection were excluded by negative serological tests. A computed tomography (CT) scan showed innumerable small low-density lesions throughout the liver without splenomegaly or lymphadenopathy. CT-guided liver core biopsy showed scattered small lymphoid aggregates located mainly in the portal tracts and periportal regions. Within the lymphoid aggregates, scattered large pleomorphic lymphoma cells were seen, admixed with smaller lymphoid cells and histiocytes. By immunohistochemistry, the lymphoma cells expressed CD2, CD3, CD8, CD30, CD43, CD45, granzyme B, TIA-1, and negative for CD4, CD5, CD7, CD56, ßF1, ALK-1, and B-cell markers. In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) was positive in some lymphoma cells. To our knowledge, this is the first reported case of primary hepatic Epstein-Barr virus-associated PTCL with CD30 expression.

Cutaneous Lymphoma at Injection Sites: Pathological, Immunophenotypical, and Molecular Characterization in 17 Cats.

Feline primary cutaneous lymphomas (FPCLs) account for 0.2% to 3% of all lymphomas in cats and are more frequently dermal nonepitheliotropic small T-cell tumors. Emergence of FPCL seems unrelated to feline leukemia virus (FeLV) serological positivity or to skin inflammation. A total of 17 cutaneous lymphomas with a history of vaccine injection at the site of tumor development were selected from 47 FPCLs. Clinical presentation, histology, immunophenotype, FeLV p27 and gp70 expression, and clonality were assessed. A majority of male (12/17), domestic short-haired (13/17) cats with a mean age of 11.3 years was reported. Postinjection time of development ranged from 15 days to approximately 9 years in 5 cats. At diagnosis, 11 of 17 cats had no evidence of internal disease. Lymphomas developed in interscapular (8/17), thoracic (8/17), and flank (1/17) cutaneous regions; lacked epitheliotropism; and were characterized by necrosis (16/17), angiocentricity (13/17), angioinvasion (9/17), angiodestruction (8/17), and peripheral inflammation composed of lymphoid aggregates (14/17). FeLV gp70 and/or p27 proteins were expressed in 10 of 17 tumors. By means of World Health Organization classification, immunophenotype, and clonality, the lesions were categorized as large B-cell lymphoma (11/17), anaplastic large T-cell lymphoma (3/17), natural killer cell-like (1/17) lymphoma, or peripheral T-cell lymphoma (1/17). Lineage remained uncertain in 1 case. Cutaneous lymphomas at injection sites (CLIS) shared some clinical and pathological features with feline injection site sarcomas and with lymphomas developing in the setting of subacute to chronic inflammation reported in human beings. Persistent inflammation induced by the injection and by reactivation of FeLV expression may have contributed to emergence of CLIS.

[Discordant lymphoma of duodenal EBV-positive peripheral T-cell lymphoma not otherwise specified and ileal diffuse large B-cell lymphoma].

A 79-year-old woman was admitted with a 5-kg weight loss and anorexia. Computed tomography showed diffuse lymphadenopathy, and thickening of the duodenal and ileal walls. The patient then underwent biopsy of these sites. Pathological examination revealed duodenal Epstein-Barr virus (EBV)-positive peripheral T cell lymphoma-not otherwise specified (PTCL-NOS) and EBV-negative ileal diffuse large B-cell lymphoma (DLBCL) to be present simultaneously. Combination chemotherapy including rituximab produced a reduction of the duodenal EBV-positive PTCL-NOS lesion, but had no effect on the EBV-negative ileal DLBCL lesion. Thereafter, new lymphadenopathy, high fever, and lactate dehydrogenase (LD) elevation developed, complicated by pneumonia. The patient died due to rapid deterioration of the lymphoma and pneumonia on day 108 after initiation of treatment. EBV-positive PTCL-NOS is reportedly rare and the prognosis is poor. Moreover, EBV-negative ileal DLBCL was diagnosed simultaneously. This case is considered to have had an extremely rare discordant lymphoma, although the exact etiology of its development remains unknown. We speculate that age-related disorders of the immune system and HCV infection may have been associated with the pathogenic mechanism of lymphomagenesis in this case.

Cytotoxic Molecule-positive Epstein-Barr Virus-associated Peripheral T-cell Lymphoma in a 20-Month-old Child: A Case Report and Review of the Literature.

Peripheral T-cell lymphoma (PTCL) is rare in children. Expression of cytotoxic molecules (CM) in nodal PTCL has unique clinicopathologic features, including an Epstein-Barr virus (EBV) association. However, CM+, EBV-associated PTCL is extremely rare in the childhood, with only 1 study having been reported to date, including both pediatric and adult patients. We report a case of CM+ PTCL in a 20-month-old boy with left neck lymphadenopathy as well as multiple visceral lesions. A biopsied lymph node was diffusely infiltrated by atypical lymphoid cells with a CD4/CD8, granzyme B+, perforin+, and TIA-1+ phenotype, and EBV positivity by in situ hybridization. Rearrangements of the TCR γ-chain and ß-chain genes were demonstrated by polymerase chain reaction. Ancillary genetic studies detected trisomy 2, trisomy 10, a structurally abnormal 6p, and additional copies of the IRF4 gene. Multiple bone marrow biopsies failed to show any evidence of tumor, histiocytic hyperplasia, or hemophagocytosis. This lesion was therefore diagnosed as "CM+, EBV-associated high-grade peripheral T-cell lymphoma." After 5 cycles of chemotherapy, the patient was in remission 8 months following initial diagnosis. To our knowledge, this represents the youngest child with this rare tumor in the published literature, and showing an unusually favorable initial response to therapy.

Characterization of spontaneous malignant lymphomas in Japanese macaques (Macaca fuscata).

Lymphomas are common spontaneous tumors in nonhuman primates but remain poorly characterized in Japanese macaques (Macaca fuscata). This study examined 5 cases of spontaneous malignant lymphoma in Japanese macaques, focusing on the immunophenotypes and presence of simian lymphocryptoviruses, which are Epstein-Barr virus-related herpesviruses in nonhuman primates. The macaques with lymphoma were 5 to 28 years old, indicating that lymphomas develop over a wide age range. The common macroscopic findings were splenomegaly and enlargement of lymph nodes. Histologic and immunohistochemical analyses revealed that all cases were non-Hodgkin type and exhibited a T-cell phenotype, positive for CD3 but negative for CD20 and CD79α. The lymphomas exhibited diverse cellular morphologies and were subdivided into 3 types according to the World Health Organization classification. These included 3 cases of peripheral T-cell lymphoma, not otherwise specified; 1 case of T-cell prolymphocytic leukemia; and 1 case of an unclassifiable T-cell lymphoma. Positive signals were detected by in situ hybridization in 2 of the 4 examined cases using probes for the Epstein-Barr virus-encoded small RNA (EBER). Furthermore, the presence of M. fuscata lymphocryptovirus 2, a macaque homolog of Epstein-Barr virus, was demonstrated in EBER-positive cases by polymerase chain reaction amplification followed by direct sequencing. Immunohistochemistry using antibody to the Epstein-Barr virus-encoded nuclear antigen 2 was negative, even in the EBER-positive cases. The present study suggests that T-cell lymphoma is more common than B-cell lymphoma in Japanese macaques and that M. fuscata lymphocryptovirus 2 is present in some cases.

Evaluation of the role of Epstein-Barr virus in cases of nodal or extranodal T- and NK-cell lymphoma using eber in situ hybridization.

Various racial and geographic differences have been observed in studies questioning the role of Epstein-Barr virus (EBV) infection in the etiology of T- and NK-cell lymphomas. The aim of this study was to evaluate the relationship of EBV with nodal or extranodal (skin excluded) T- and NK-cell lymphoma subtypes encountered in our geographic area. Sixty-two cases of peripheral T-cell lymphoma were included in the study. EBV-encoded early RNA (EBER) was detected by in situ hybridization. The distributions of T- and NK-cell lymphoma subtypes were as follows: 32 peripheral T-cell lymphomas, unspecified (PTCL, NOS), 13 anaplastic large-cell lymphomas (ALCL), 8 angioimmunoblastic T-cell lymphomas (AITCL), 4 extranodal NK/T-cell lymphomas, nasal type (NKTCL), 3 enteropathy-type T-cell lymphomas (ETTCL), 1 hepatosplenic T-cell lymphoma (HSTCL), and 1 subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Using a cut-off value of >25% of EBER-positive neoplastic lymphoid cells, EBV was positive in 22.6% of all cases. According to subtype, the neoplastic cells of 31.3% of PTCL, NOS and 100% of extranodal NKTCL, nasal type were EBER positive, whereas some cases of ALCL, AITCL, and ETTCL presented EBER-positive non­neoplastic cells, and all cells of HSTCL and SPTCL were EBV negative. Extranodal NKTCL, nasal type, presented the strongest association with EBV, followed by PTCL, NOS.

EBV+ nodal T/NK-cell lymphoma associated with clonal hematopoiesis and structural variations of the viral genome.

ABSTRACT: Epstein-Barr virus (EBV)-positive (EBV+) nodal T- and natural killer (NK)-cell lymphoma is a peripheral T-cell lymphoma (EBV+ nPTCL) that presents as a primary nodal disease with T-cell phenotype and EBV-harboring tumor cells. To date, the genetic aspect of EBV+ nPTCL has not been fully investigated. In this study, whole-exome and/or whole-genome sequencing was performed on 22 cases of EBV+ nPTCL. TET2 (68%) and DNMT3A (32%) were observed to be the most frequently mutated genes whose presence was associated with poor overall survival (P = .004). The RHOA p.Gly17Val mutation was identified in 2 patients who had TET2 and/or DNMT3A mutations. In 4 patients with TET2/DNMT3A alterations, blood cell-rich tissues (the bone marrow [BM] or spleen) were available as paired normal samples. Of 4 cases, 3 had at least 1 identical TET2/DNMT3A mutation in the BM or spleen. Additionally, the whole part of the EBV genome was sequenced and structural variations (SVs) were found frequent among the EBV genomes (63%). The most frequently identified type of SV was deletion. In 1 patient, 4 pieces of human chromosome 9, including programmed death-ligand 1 gene (PD-L1) were identified to be tandemly incorporated into the EBV genome. The 3' untranslated region of PD-L1 was truncated, causing a high-level of PD-L1 protein expression. Overall, the frequent TET2 and DNMT3A mutations in EBV+ nPTCL seem to be closely associated with clonal hematopoiesis and, together with the EBV genome deletions, may contribute to the pathogenesis of this intractable lymphoma.

Nodal cytotoxic molecule (CM)-positive Epstein-Barr virus (EBV)-associated peripheral T cell lymphoma (PTCL): a clinicopathological study of 26 cases.

AIMS: The clinicopathological distinctiveness of nodal cytotoxic molecule (CM)-positive Epstein-Barr virus (EBV)-associated peripheral T cell lymphoma (PTCL) remains to be clarified. We investigated 26 patients with this lymphoma compared to nodal CM(+) EBV(-) PTCL (n = 39) and extranasal natural killer/T cell lymphoma of nasal type (ENKTL, n = 44). METHODS AND RESULTS: Nodal CM(+) EBV(+) PTCL patients were more likely to have B symptoms (P = 0.019) and hepatic involvement (P = 0.026) than nodal CM(+) EBV(-) PTCL patients. The former also had more Stage III/IV disease (P = 0.025) but much less cutaneous involvement (P < 0.001) than ENKTL patients at diagnosis. This nodal EBV(+) lymphoma possessed a distinctive immunophenotype of high CD8(+), CD56(-) pattern with an aggressive clinical course (median, 6.6 months). Thrombocytopenia was present in 11 (50%) patients and found to be the strongest prognostic indicator (P = 0.001) in this nodal EBV(+) group. For all nodal CM(+) PTCL cases CD5 negativity, but not EBV positivity, was the significant adverse prognostic factor (P < 0.002) in a multivariate analysis, independent of prognostic index for PTCL (PIT) or International Prognostic Index (IPI) scores. CONCLUSIONS: Nodal CM(+) EBV(+) PTCL constitutes a unique group of lymphomas distinct from ENKTL. The data provide support for our assertion that nodal CM(+) PTCL should be distinguished in the 2008 WHO category of PTCL, not otherwise specified.

[Clinical and pathological analysis of three cases of childhood systemic EB virus positive T-cell lymphoproliferative disease].

OBJECTIVE: To explore the clinicopathologic features of systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood (EBV+TLPD). METHODS: Three cases of EBV+ TLPD of childhood were studied by analyzing the clinical features, morphology, immunophenotypings, EBER-1 in situ hybridization(ISH)and T-cell receptor (TCR)γ gene rearrangement. RESULTS: The age of onset of the three patients was 2, 7 and 10 years, respectively. They all presented with fever, hepatosplenomegaly and liver failure, accompanied by lymphadenopathy. Skin rash occurred in case 2. Laboratory tests confirmed EBV infection. Lymph node biopsy showed effacement of normal architecture. The residue T zone was significantly expanded, with marked proliferation of arborizing high endothelial venules and prominent infiltration of small to medium-sized atypical lymphocytes. The immunostaining showed cytotoxic T cell phenotypes, e.g. CD3, CD5, T-bet and TIA-1 were all positive, while granzyme B were positive in two cases; CD4 and CD8 were double positive in two cases, but double negative in one case; CD56, CD21and CXCL13 were negative in all the cases. EBER-1 could be detected in all the cases by ISH. Monoclonal rearrangement of TCRγ gene was detected in two cases by polymerase chain reaction (PCR). CONCLUSION: EBV+ TLPD of childhood is a rare type of peripheral T cell lymphoma. EBV detection by ISH and molecular cloning technique analysis could contribute to the diagnosis. The clinicopathologic characteristics of our cases are consistent with that reported in international literature.

Primary intestinal T-cell and NK-cell lymphomas: a clinicopathological and molecular study from China focused on type II enteropathy-associated T-cell lymphoma and primary intestinal NK-cell lymphoma.

In China, which is a non-endemic area for celiac disease, primary intestinal T-cell and NK-cell lymphomas might comprise heterogeneous subtypes. Both type II enteropathy-associated T-cell lymphoma and primary intestinal NK-cell lymphoma are rarely reported and poorly characterized in China. In this study, we examined the clinicopathological and molecular features of 38 cases of primary intestinal T-cell and NK-cell lymphoma in Chinese patients. Based on these findings, we first classified the patients into an NK-cell group (n=6) and a T-cell group (n=32). In the NK-cell group, the mean age was 37 years. All tumors of the NK-cell group were positive for Epstein-Barr virus encoded mRNA in the majority of tumor cells and were polyclonal according to the results of commercial BIOMED-2 T-cell receptor gene rearrangement assays. The survival in the NK-cell group was significantly worse than that of the T-cell group (P=0.0247). Next, 7 tumors of the T-cell group were considered type II enteropathy-associated T-cell lymphoma, while 24 were considered peripheral T-cell lymphoma, not otherwise specified (NOS). In the type II enteropathy-associated T-cell lymphoma group, the mean age was 55 years. Type II enteropathy-associated T-cell lymphoma tumor cells from all seven patients were monomorphic, medium sized. The survival in the type II enteropathy-associated T-cell lymphoma group was significantly worse than that of the peripheral T-cell lymphoma, NOS group (P=0.0181). Multivariate analysis identified NK-cell phenotype, male gender, and CD8 positivity as factors for poor prognosis in our series of primary intestinal T-cell and NK-cell lymphoma patients. In conclusion, most cases of primary intestinal T-cell and NK-cell lymphoma in China are not associated with celiac disease and could be classified to NK-cell group, type II enteropathy-associated T-cell lymphoma group, and peripheral T-cell lymphoma, NOS group. Each group has distinctive histopathological features with prognostic significance.

Epstein-Barr virus-positive systemic NK/T-cell lymphomas in children: report of six cases.

AIMS: The World Health Organization lymphoma classification recognizes two different Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorders of childhood: systemic EBV-positive T-cell lymphoproliferative disease of childhood, and hydroa vacciniforme-like lymphoma, which is more prevalent in Asia and Latin America. The aim of this study was to characterize six cases of paediatric EBV-positive peripheral T-cell lymphoma with distinct features. METHODS AND RESULTS: All cases were male, with a median patient age of 9 years (range: 5-17 years). Most of them presented suddenly with fever, weight loss, hepatosplenomegaly, peripheral lymphadenopathy, and high lactate dehydrogenase (LDH) levels. Moreover, gut, lung or soft tissues of the abdominal wall were also affected in four cases. Partial to total replacement of the lymph node by pleomorphic infiltration of atypical neoplastic cells was found in all cases. Vasculitis and geographical areas of necrosis were seen in three and four cases, respectively. Neoplastic cells showed expression of EBV-encoded RNA, T-cell markers (CD2 and CD3), and cytotoxic markers (TIA1, granzyme-B, and perforin). CD56 and T-cell receptor -γ were expressed in one case each. TCR-BF1, CD4, CD8 and anaplastic lymphoma kinase were negative. In all cases, the disease progressed rapidly, causing death of the patient, with a median survival of 7.1 months (range: 1-13 months). CONCLUSIONS: These cases probably represent a solid form of systemic EBV-positive T-cell lymphoproliferative disease of childhood, which requires identification and the development of appropriate therapy.

Peripheral T cell lymphomas with follicular T helper phenotype: a new basket or a distinct entity? Revising Karl Lennert's personal archive.

AIMS: To revise 25 cases selected from Karl Lennert's personal archive (21) and Bologna and Frankfurt Registries (four) because of cytological similarities. METHODS AND RESULTS: All cases were provided with paraffin blocks and studied by immunohistochemistry and molecular techniques. While phenotyping was very informative, among molecular studies only EBER in situ-hybridization (ISH) was successful. Twenty-two cases were concluded as peripheral T cell lymphomas (PTCL). Of these, six were reclassified as angioimmunoblastic T cell lymphoma (AITL), 13 as PTCL, not otherwise specified (NOS), including four follicular variants and one tumour with T-zone pattern, and three as borderline tumours between AITL and PTCL/NOS. All these cases consisted homogeneously of small/medium-sized elements with mild nuclear atypia and an evident rim of clear/pale cytoplasm. On immunohistochemistry, they regularly expressed three to six follicular helper T cell (FTH)-associated markers. EBER-ISH revealed scattered EBV-infected B cells in all tumours except those with 'follicular' growth pattern. The content of follicular dendritic cells and high-endothelial venules varied significantly depending on the histotype. CONCLUSIONS: This study shows that: (i) historical material can be still employed usefully, and (ii) the FTH-phenotype corresponds to a broad spectrum of PTCLs that might form a new category to be validated in future molecular and clinicopathological analyses.