Molecular understanding of peripheral T-cell lymphomas, not otherwise specified (PTCL, NOS): A complex disease category.

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) includes various diseases. Attempts have been made to identify distinct properties of disease within the PTCL, NOS classification and evaluate their significance to prognosis. Comprehensive gene expression analysis and evaluation of genomic abnormalities have successfully identified specific diseases from heterogeneous PTCL, NOS cases. For example, cases with properties of T follicular helper cells have been identified and classified as an entity resembling angioimmunoblastic T-cell lymphoma (AITL), based on both immunohistochemistry and genomic features. Here, we focus on the molecular pathology of PTCL, NOS and discuss recent changes relevant to its classification.

Strategies for aggressive T-cell lymphoma: divide and conquer.

The aggressive peripheral T-cell lymphomas (PTCLs) are a heterogenous group of uncommon lymphomas of mature T lymphocytes dominated by 3 subtypes: systemic anaplastic large-cell lymphoma, both anaplastic lymphoma kinase positive and negative; nodal PTCL with T-follicular helper phenotype; and PTCL, not otherwise specified. Although the accurate diagnosis of T-cell lymphoma and the subtyping of these lymphomas may be challenging, there is growing evidence that knowledge of the subtype of disease can aid in prognostication and in the selection of optimal treatments, in both the front-line and the relapsed or refractory setting. This report focuses on the 3 most common subtypes of aggressive PTCL, to learn how current knowledge may dictate choices of therapy and consultative referrals and inform rational targets and correlative studies in the development of future clinical trials. Finally, I note that clinical-pathologic correlation, especially in cases of T-cell lymphomas that may present with an extranodal component, is essential in the accurate diagnosis and subsequent treatment of our patients.

[Peripheral T cell lymphomas: diagnosis and treatment]. / Lymphomes T périphériques : diagnostic et prise en charge.

Peripheral T cell lymphomas are rare malignancies with aggressive course, with several different subtype described in the 2016 WHO classification. Their distribution across the world is heterogenous, with marked difference between Western and Asian country. Their clinical presentation often comprise extra-nodal involvement, B symptoms and immune system disorder which can lead to wrong diagnosis orientation. Make a right diagnosis need a experienced pathologist in close collaboration with clinical datas. Peripheral T cell lymphomas are in general associated with poor prognosis when treated with anthracyclines-based regimen, and several studies and trials focused on the use of intensified regimen or novel targeted agents, whose proper indication still remain to be clarified.

Nodal EBV+ cytotoxic T-cell lymphoma: A literature review based on the 2017 WHO classification.

Nodal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (CTL) is a primary nodal peripheral T-cell lymphoma (PTCL) characterized by a cytotoxic phenotype and EBV on the tumor cells. This disease reportedly accounts for 21% of PTCL not otherwise specified (NOS). However, few nodal EBV+ lymphomas have been documented in detail. Nodal EBV+ CTL and nasal-type NK/T-cell lymphoma (NKTL) both exhibit cytotoxic molecule expression and EBV positivity on the tumor cells; however, nodal EBV+ CTL is characterized as a systemic disease without nasopharyngeal involvement, and exhibits a CD8+/CD56- phenotype distinct from NKTL. The clinicopathological uniqueness of nodal EBV+ CTL is further supported by its T-cell origin in most reported cases. In the 2008 WHO classification, it was unclear whether nodal EBV+ CTL should be classified as PTCL or NKTL. However, based on additional data, the 2017 revision classifies nodal EBV+ CTL as PTCL. In the present review, we focus on the clinicopathological characteristics of nodal EBV+ CTL, discuss the relationship between chronic active EBV infection and nodal EBV+ lymphoma, and highlight future perspectives regarding the treatment of this disease.

Therapy of Peripheral T Cell Lymphoma: Focus on Nodal Subtypes.

PURPOSE OF REVIEW: Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas with inferior prognosis compared with their B cell counterparts characterized by frequent relapses, resulting in a median 5-year survival of approximately 30%. Their diverse clinicopathologic features challenge existing treatment paradigms that treat all patients uniformly. Here we review recent advances in the treatment of these diseases. RECENT FINDINGS: While current treatment still relies largely on combination chemotherapy, the introduction of more effective novel and targeted therapies has improved outcomes in certain subtypes. Increasing understanding of the underlying biology of PTCL has prompted further subclassification by genetic and molecular subgroups. Overall, the most significant advances in PTCL management have resulted from improved understanding and classification of the biology of PTCL. Ongoing development of subtype-specific targeted therapies will be essential to improve long-term outcomes of patients with these diseases.

The new biology of PTCL-NOS and AITL: current status and future clinical impact.

Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of aggressive lymphoproliferative disorders almost all of which are associated with poor clinical outcomes. Angioimmunoblastic T-cell lymphoma (AITL) and some peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) have similarities to normal CD4+ T-cell subsets in their gene expression profiles. A cell of origin model is, therefore, emerging and is likely to be refined in the future. Follicular helper (Tfh) T cells are now established as the cell of origin of AITL and about 20% of PTCL-NOS. Sequencing studies have identified recurrent genetic alterations in epigenetic modifiers, T-cell receptor signalling pathway intermediates or RHOA, most commonly a specific mutation leading to RHOA G17V. While PTCL-NOS remains a diagnosis of exclusion, advances in genomics have identified subgroups expressing transcription factors TBX 21 (Th1-like origin) and GATA3 (Th2-like origin). These findings suggest new biomarkers and new therapeutic avenues including the hypomethylating agent azacytidine, or inhibitors of proximal T-cell receptor (TCR) signalling and potentially certain monoclonal antibodies. The advances over the past few years, therefore, prompt stratified medicine approaches to test biologically based treatments and determine the clinical utility of the new disease classifications.

Application of a 5 Marker Panel to the Routine Diagnosis of Peripheral T-Cell Lymphoma With T-Follicular Helper Phenotype.

The 2017 World Health Organization update introduced a new category of nodal peripheral T-cell lymphoma with T-follicular helper phenotype (PTCL-TFH) defined by expression of at least 2 or 3 TFH markers. Our study assesses the utility of an immunohistochemical panel of 5 TFH markers (CD10, BCL6, PD-1, CXCL13, and ICOS) for identification of TFH phenotype in angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified (NOS). Immunohistochemical for the 5 markers was performed on 22 cases of AITL and 29 cases of PTCL-NOS. Cases were reviewed for morphologic features characteristic of AITL. All AITL cases showed expression of ≥2 TFH markers. This panel resulted in reclassification of 41% PTCL-NOS cases to PTCL-TFH. Positive percent agreement for the TFH phenotype is 97% for PD1, 94% for ICOS, 44% for CD10 and CXCL13, and 29% for BCL6. Negative percent agreement for TFH phenotype is 100% for CD10, BCL6, and CXCL13, 82% for ICOS and 71% for PD1. AITL cases were more likely than PTCL-TFH cases to contain expanded CD21-positive follicular dendritic cell meshworks, clear cell cytology and polymorphous inflammatory background; however, there was a significant (P<0.005) Kruskal-Wallis trend in all morphologic variables between the 3 groups suggesting a continuum from PTCL-NOS to PTCL-TFH to AITL. The median number of morphologic features of AITL also correlated significantly with number of TFH markers positive (Spearman coefficient ρ=0.759). In summary, the stain panel chosen will have an impact on cases classified as PTCL-TFH. This entity may exist along a spectrum between PTCL-NOS and AITL.

[Heterogeneity of genomic alterations and clinical aspects in peripheral T-cell lymphoma: future perspectives].

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphoid malignancies. Several recent comprehensive genomic studies characterize the genomic alterations of each PTCL type and reveal the complexity and heterogeneity. The updated World Health Organization classification has precisely distinguished "lymphoma" from "lymphoproliferative disorder" and has included a new entity based on the tumor phenotypes. Although establishing the classifications based on genomic alterations has been difficult because of heterogeneity, the genomic alterations may support the diagnosis. Establishing genomic alterations that act as predictive markers for clinical courses and/or therapeutic targets is needed in future studies using genomic alteration information. Since patients with PTCL generally have poor prognosis, establishing the target and standard therapies is one of the major issues to be addressed. In addition to clinicopathological and genomic analyses, patient-derived xenograft models can provide these therapeutic strategies. Integration of analyzed data is considered to promote future PTCL studies, leading to improved PTCL prognosis.

Aggressive T-cell lymphomas: 2019 updates on diagnosis, risk stratification, and management.

INTRODUCTION: Aggressive T-cell lymphomas continue to have a poor prognosis. There are over 27 different subtypes of peripheral T-cell lymphoma (PTCL) and we are now beginning to understand the differences between the various subtypes beyond histologic variations. MOLECULAR PATHOGENESIS OF VARIOUS SUBTYPES OF PTCL: Gene expression profiling can help in diagnosis and prognostication of various subtypes including PTCL-nos and anaplastic large cell lymphoma. In addition, mutational analysis is now being incorporated in clinical trials of novel agents to evaluate various biomarkers of response to allow better therapeutic choices for patients. TARGETED THERAPIES: There are many targeted agents currently in various stages of clinical trials for PTCL that take advantage of the differential expression of specific proteins or receptors in PTCL tumors. The most promising is the CD30 directed antibody drug conjugate brentuximab vedotin. This has recently been approved by the Food and Drug Administration for the upfront treatment of CD30 expressing PTCLs in combination with cyclophosphamide, doxorubicin, and prednisone chemotherapy. Other notable targets are CD25, CCR4 tag, PI3kinase inhibitors, and JAK/STAT inhibitors. Anaplastic lymphoma kinase (ALK) inhibitors are promising for ALK expressing tumors. IMMUNOTHERAPIES: The use of checkpoint inhibitors in the treatment of PTCL is still controversial. The most promising results have been seen in cases of extranodal natural killer cell/T-cell lymphomas and cutaneous T-cell lymphomas. For all other subtypes, immune checkpoint inhibitors should be used with extreme caution and only in the context of a clinical trial. Allogeneic stem cell transplant continues to be the curative therapy for most aggressive subtypes of PTCL.

Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A /B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2 R172 mutation. CN losses were enriched in genes regulating PI3K-AKT-mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.

Molecular Insights Into Pathogenesis of Peripheral T Cell Lymphoma: a Review.

PURPOSE OF REVIEW: Peripheral T cell lymphoma (PTCL) is a heterogeneous group of lymphoproliferative neoplasms, with at least 29 distinct entities described in current WHO classification. Using present diagnostic approaches, more than a third of PTCL cases cannot be classified, hence designated as PTCL-not otherwise specified (PTCL-NOS). Herein, we summarize the current genomic findings and their role in the molecular pathogenesis in different PTCL entities. RECENT FINDINGS: Gene expression profiling (GEP) studies have identified distinct molecular signatures for accurate diagnosis and elucidated oncogenic pathways enriched in major PTCL entities. Furthermore, genomic characterization has identified recurrent somatic mutations and potential therapeutic targets. Further efforts are underway to develop genetically faithful murine models. GEP studies have identified molecular subgroups of PTCL, characterized by distinct genetic and epigenetic alterations. Understanding the molecular mechanisms of T cell lymphomagenesis using in vivo model will help to reveal novel therapeutic targets.

Updates of Peripheral T Cell Lymphomas Based on the 2017 WHO Classification.

PURPOSE OF REVIEW: This review will describe and update the readers on the recent changes of the 2017 WHO classification in regard to peripheral T cell lymphomas. RECENT FINDINGS: Significant advances in molecular studies have resulted in revisions of the classification as well as introduction of provisional entities (such as breast implant-associated ALCL, nodal PTCL with TFH phenotype). Major advances in molecular and gene expression profiling have expanded our knowledge of T cell lymphomas, including updates in the diagnostic criteria and sub-classification which will facilitate in improving patient care and research.

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.

Autologous stem cell transplantation as frontline strategy for peripheral T-cell lymphoma: A single-centre experience.

Objective To determine the efficacy and prognosis of autologous hematopoietic stem cell transplantation (ASCT) as frontline treatment for peripheral T cell lymphoma (PTCL). Methods Clinical data from 46 PTCL patients who achieved complete (CR) or partial remission (PR) after ASCT from October 1996 to July 2014 were analysed retrospectively. Results Median patient age was 32 (range: 15-68) years. Disease types included PTCL, unspecified type, in 23 patients, anaplastic large cell lymphoma in eight, angioimmunoblastic lymphoma in eight, extranodal NK/T-cell lymphoma in five, and hepatosplenic T-cell lymphoma and enteropathy associated T-cell lymphoma in one each. Of these patients, 80% had Prognostic Index for Peripheral T-cell Lymphoma scores ≥1. Thirty-four patients had pre-transplantation CR and 12 had PR. Median follow up was 37 (6-176) months. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 77.1% and 61.9%, respectively. Multivariate analysis showed that pre-transplantation CR was an independent risk factor for survival, and CR was more common than PR (OS 81% vs 59.3%; PFS 71.8% vs 17.8%). Conclusion Frontline consolidation treatment with ASCT was associated with favourable outcomes in patients with PTCL. Pre-transplantation CR was a prognostic factor for survival, suggesting that ASCT may be favoured as front-line consolidation therapy after first complete remission.

Peripheral T-cell lymphoma, not otherwise specified.

Peripheral T-cell lymphoma, not otherwise specified, is a broad category of biologically and clinically heterogeneous diseases that cannot be further classified into any other of the existing entities defined by the World Health Organization classification. Anthracycline-containing regimens, namely cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), nowadays represent the standard first-line treatment; for patients who achieve a satisfactory response, a consolidation by means of autologous stem cell transplantation may offer a greater chance of long-term survival. Several patients, however, display treatment refractoriness or relapse soon after obtaining a response, and just a few of them are suitable transplant candidates. This is why several new agents, with innovative mechanisms of action, have been investigated in this context: pralatrexate, romidepsin, belinostat, and brentuximab vedotin have been approved for relapsed and refractory peripheral T-cell lymphomas based on their activity, although they do not significantly affect survival rates. The incorporation of such new drugs within a CHOP backbone is under investigation to enhance response rates, allow a higher proportion of patients to be transplanted in remission, and prolong survival.

Clinical features and treatment outcome of Epstein-Barr virus-positive nodal T-cell lymphoma.

The classification of mature NK-/T-cell lymphoma mainly originating from the T-cell lineage with predominantly nodal involvement and Epstein-Barr virus (EBV) positivity in a majority of tumor cells is unresolved. We analyzed the clinical features and treatment outcomes of such patients. Five patients with EBV-positive nodal T-cell lymphoma were surveyed during follow-up period. The median age was 53 years (range 33-88 years), and all patients showed nodal involvement. The patients mostly presented advanced clinical features, such as stage III or IV disease, elevated lactate dehydrogenase, and hemophagocytosis. Four patients received cyclophosphamide-containing chemotherapy at the time of diagnosis. However, three patients (75 %) showed disease progression during the early cycles of initial treatment. The median overall survival was 1.5 months (95 % CI 0.0-3.4 months). Patients with EBV-positive nodal T-cell lymphoma mainly show lymph node involvement, but also show aggressive clinical features and poor treatment outcomes, such as aggressive NK-cell leukemia. Therefore, we should consider EBV-positive nodal T-cell lymphoma to be a unique disease entity distinct from peripheral T-cell lymphoma not otherwise specified.

Subtype distribution of lymphomas in South of Iran, analysis of 1085 cases based on World Health Organization classification.

Lymphoma is one of the most common malignancies worldwide. Subtype distribution is different throughout the world. Some reports from the Middle East are in record. This article is trying to report the subtype distribution of lymphoma in Iran and compare it to that of Western, Far East Asian and Middle Eastern countries. A retrospective study was done on all lymphomas diagnosed in a large referral center in the South of Iran during a time period between 2009 and 2014. All diagnoses have been made according to 2008 WHO classification. A total number of 1085 cases with diagnoses of lymphoma retrieved. Twenty-nine cases (2.6 % of all) were precursor lymphoid neoplasm, 608 cases (56 % of all) were mature B cell neoplasm, 115 cases (10.5 % of all) were mature T and NK cell neoplasm, and 333 cases (30.6 % of all) were Hodgkin lymphoma. The six most frequent subtypes of mature B cell neoplasm were diffuse large B cell lymphoma, NOS (57 %), Burkitt lymphoma (7 %), small lymphocytic lymphoma (6.9 %), mantle cell lymphoma (5.7 %), extranodal marginal zone B cell lymphoma (5.2 %) and follicular lymphoma (3.6 %). Among mature T and NK cell neoplasm, mycosis fungoides was the most common type (43.4 %) followed by peripheral T cell lymphoma, NOS (20 %) and angioimmunoblastic T cell lymphoma (9.9 %). Of Hodgkin lymphoma cases, 90.6 % were classical type and 9.3 % were nodular lymphocyte predominant Hodgkin lymphoma. Extranodal involvement was seen in 42.2 % and GI tract was the most common site. Lymphoma frequencies were similar to that of Middle Eastern countries except for lower rate of follicular lymphoma and higher incidence of diffuse large B cell lymphoma, NOS and small lymphocytic lymphoma.

FoxP3-positive T cell lymphoma arising in non-HTLV1 carrier: clinicopathological analysis of 11 cases of PTCL-NOS and 2 cases of mycosis fungoides.

AIMS: Forkhead box protein 3-positive (FoxP3(+) ) T cell lymphoma, in the absence of human T cell lymphotrophic virus type 1 (HTLV-1) infection, is rare and its clinicopathological characteristics still remain unclear. The aim of this study was to elucidate its characteristics. METHODS AND RESULTS: We describe here 11 cases of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) and two cases of mycosis fingoides (MF) which were positive for FoxP3. The median age of the 11 PTCL-NOS cases was 65 years (range: 48-80 years), and all the patients were male. Eight patients (80%) showed stages III/IV disease, and six (60%) were categorized as high-intermediate/high-risk groups according to the International Prognostic Index. Two cases of MF were 57- and 59-year-old males. Both cases were categorized as stage IA, according to International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer (ISCL/EORTC) classification. Immunohistochemically, all the cases were negative for cytotoxic molecule marker, and nine (75%) were αß T cell type. Scattered Epstein-Barr virus (EBV)-infected cells were detected in four cases of PTCL-NOS, implying the reactivation of EBV caused by the immunodeficient status of the patients. CONCLUSIONS: FoxP3(+) PTCL-NOS constitute a minor phenotypical subtype with poor prognosis and EBV reactivation in some. Conversely, two cases of MF showed an indolent clinical course which was different from previously reported cutaneous T cell lymphoma (CTCL) cases.

[Molecular pathogenesis of peripheral T-cell lymphoma (1): angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified and anaplastic large cell lymphoma]. / Aspects moléculaires des lymphomes T périphériques (1) - Lymphome T angio-immunoblastique, lymphome T périphérique non spécifié et lymphome anaplasique à grandes cellules.

Peripheral T-cell lymphomas (PTCL) belong to the group of non-Hodgkin lymphoma and particularly that of mature T/NK cells lymphoproliferative neoplasms. The 2008 WHO classification describes different PTCL entities with varying prevalence. With the exception of the histological subtype "ALK positive anaplastic large cell lymphoma", PTCL are characterized by a poor prognosis. The mechanisms underlying the pathogenesis of these lymphomas are not yet fully understood, but development of genomic high-throughput analysis techniques now allows to extensively identify the molecular abnormalities present in tumor cells. This review aims to summarize the current knowledge and recent advances about the molecular events occurring at the origin or during the natural history of main entities of PTCL. It will be published in two parts : the first is focused on the three more frequent entities, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified, and anaplastic large cell lymphoma. The second (which will appear in the november issue) will describe other subtypes less frequent and of poor prognosis : extranodal NK/T-cell lymphoma, nasal type, adult T-cell leukemia/lymphoma, and enteropathy-associated T-cell lymphoma. T or NK cell lymphoproliferative disorders with leukemic presentation, primary cutaneous T-cell lymphoma and very rare subtypes of PTCL whose prevalence is less than 5% (hepatosplenic T-cell lymphoma and subcutaneous panniculitis-like T cell lymphoma) will not be discussed herein.

Follicular helper T-cell lymphoma: a B-cell-rich variant of T-cell lymphoma.

Follicular helper T-cell lymphoma is a recently described variant of T-cell lymphoma sharing the cell of origin with angioimmunoblastic T-cell lymphoma and with primary cutaneous CD4-positive small/medium T-cell lymphoma. To better characterize the morphologic and immunophenotypic features of follicular helper T-cell lymphoma, a series of 4 confidently diagnosed cases are analyzed. The overall morphologic pattern significantly overlaps with that of progressive transformation of germinal centers in 3 cases and with follicular hyperplasia in 1. Detection of large, clustered, atypical T-cells is an important feature differentiating follicular T-cell lymphoma from benign, reactive processes such as progressive transformation of germinal centers. The abnormal T-cells have an immunophenotype identical to that of follicular helper T-cells in all cases. Clonal T-cell populations are detected in all cases. A characteristic setting follicular T-cell lymphomas apart from most other T-cell lymphomas is the abundance of small, mature B-cells. Differences from angioimmunoblastic T-cell lymphoma include the absence of proliferating vessels or of Epstein-Barr virus-positive immunoblasts.