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.

Extranodal natural killer/T cell lymphoma, nasal type: a diagnostic challenge.

Extranodal natural killer/T cell lymphoma, nasal type (ENKL) is a rare and aggressive tumour that can, clinically and histologically, mimic infectious and inflammatory conditions, presenting a diagnostic challenge. The authors report the case of a 69-year-old Portuguese woman previously misdiagnosed with chronic recurrent sinusitis. Despite maximal medical and surgical treatments, the disease was refractory and progressed. The patient had undergone multiple biopsies when the histopathological diagnosis of ENKL was made, 5 months after the initial complaints. Multiagent chemotherapy was offered, but during the first cycle, the patient developed severe infection and pancytopenia, which culminated in her death. This case highlights the need to consider a neoplastic cause when faced with aggressive sinonasal disease not responsive to maximal treatment and the difficulties in establishing the diagnosis of ENKL, with multiples biopsies of deep-tissue usually being required.

Intestinal T-cell and NK/T-cell lymphomas: A clinicopathological study of 27 Chinese patients.

BACKGROUND: Intestinal T-cell and NK/T- cell lymphomas are rare and aggressive. The diagnosis is quite difficult, especial in biopsy specimens. This study investigates the clinicopathological features of intestinal T-cell and NK/T-cell lymphomas to aid their differential diagnosis. METHODS: Clinical data of 27 cases were collected. Including extranodal NK/T-cell lymphoma, nasal type (ENKTCL-N), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), anaplastic large-cell lymphoma, ALK+ (ALCL, ALK+) and angioimmunoblastic T-cell lymphoma (AITL). The histologic features, immunohistochemical findings, T-cell receptor gene rearrangement results, and follow-up data were analyzed, with review of literature. RESULTS: The age of the patients (N = 27) was 15-85 years (mean, 47.5 years), and male:female ratio, 3.5:1. Abdominal pain and B symptoms were the most common symptoms. Although 85.2% of the patients were in clinical stage I-II, 59.3% died within 1 year. MEITL showed certain distinctive clinic opathological features from ENKTCL-N. Compared to lesions at other sites, there were no differences in the morphological features, immunophenotype and TCR gene rearrangement of intestinal ENKTCL-N, PTCL, NOS, ALCL, ALK+ and AITL. CONCLUSION: Intestinal T-cell and NK/T-cell lymphomas are a heterogeneous group of lymphomas. They could be classified to 5 histological subtypes in our study. ENKTCL-N and MEITL formed the majority of the tumor types. Each subtype has distinctive pathological features, but most of them have diamal prognosis.

Distribution of lymphoid neoplasms in Northwest China: Analysis of 3244 cases according to WHO classification in a single institution.

To explore the distribution of lymphoid neoplasms in Northwest China, the clinical and pathological data of lymphoma patients from 2006 to 2014 were analyzed according to the WHO classification in Xijing Hospital. Of the 3244 cases, mature B-cell neoplasms occupied 60.7%, while mature T/NK-cell neoplasms and Hodgkin's lymphomas (HL) occupied 26.2% and 8.1%, respectively. The most common subtype of lymphoma was diffuse large B-cell lymphoma (35.0%), followed by extranodal NK/T-cell lymphoma, nasal type (ENKTCL) (12.9%) and marginal zone B-cell lymphoma (7.8%). Mixed cellularity (34.0%) was the most common subtype of HL. The especially high proportion of ENKTCL was the most outstanding feature of our study in comparison to previous reports. The mean age of all lymphoid neoplasms cases was 51years and most subtypes showed male predominance, with an average male-female ratio of 1.6. Extranodal lymphomas took up about 60% of all cases and gastrointestinal tract was the most frequently involved site. In conclusion, the distribution of lymphoid neoplasms of Northwest China showed some features similar to previous reports of China and other countries, but some subtypes presented distinct features.

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 and Allogeneic Hematopoietic Cell Transplantation in Peripheral T/NK-cell Lymphomas: A Histology-Specific Review.

Peripheral T-cell lymphoma and natural killer/T-cell lymphomas (PT/NKCL) make up a diverse subgroup of non-Hodgkin's lymphomas characterized by an aggressive clinical course. The use of hematopoietic stem cell transplantation (HSCT) in the treatment of PT/NKCL remains controversial because of the absence of randomized controlled trials. The best available data suggest that certain subtypes of PT/NKCL may benefit more from the application of HSCT than other subtypes and that this benefit results from their unique clinical characteristics and underlying biology. Ultimately, however, prospective randomized controlled trials are needed to clarify the optimal type and timing of HSCT in patients with PT/NKCL.

Pyoderma gangrenosum preceding the onset of extranodal natural killer/T-cell lymphoma: A case report.

INTRODUCTION: Pyoderma gangrenosum (PG) is a neutrophilic dermatosis that may be associated with systemic diseases. The association of PG with lymphoid malignancies has rarely been reported. Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare but aggressive entity with a poor prognosis. Here, we report the case of a patient who had idiopathic PG refractory to systemic steroids and subsequently developed ENKTL. CASE REPORT: A 70-year-old man presented with a 2-month history of intermittent fever and multifocal painful papules, plaques, and ulcerations on his extremities. The histological and culture results of the lesions were consistent with those of PG. A thorough work-up was performed and did not demonstrate any underlying systemic diseases including malignancy. The PG lesions were refractory to systemic steroid therapy. An enlarging nodule was observed over his right infraorbital area 4 months after the onset of the skin eruptions. The nodule was later biopsied and diagnosed as ENKTL by using histopathological and immunohistochemical studies. Fludeoxyglucose positron emission tomography/computed tomography revealed multiple intense fludeoxyglucose-avid masses in the bones and lungs, suggesting multiorgan metastases. The patient rejected chemotherapy and died 4 weeks after the diagnosis. CONCLUSION: The present case indicates that in any patient with idiopathic PG refractory to conventional therapy, the presence of any underlying disease or malignancy must be thoroughly evaluated. The present case serves as a reminder that when assessing patients with PG, clinicians should increase their awareness regarding the delayed association with malignancy, even in the absence of a concomitant systemic disease at presentation. Furthermore, the prompt evaluation of any suspicious lesions in the context of PG for the possibility of a malignant nature can improve the prognosis, particularly in cases of aggressive malignancy. Understanding the cutaneous spectrum of ENKTL is crucial because of its variable clinical appearance and aggressive nature. Our case demonstrates that PG can be a presenting sign of ENKTL.

[The understanding of Epstein-Barr virus associated lymphoproliferative disorder].

In recent years, there are increasing articles concerning Epstein-Barr virus associated lymphoproliferative disorder (EBV+ LPD), and the name of EBV+ LPD is used widely. However, the meaning of EBV+ LPD used is not the same, which triggered confusion of the understanding and obstacles of the communication. In order to solve this problem. Literature was reviewed with combination of our cases to clarify the concept of EBV+ LPD and to expound our understanding about it. In general, it is currently accepted that EBV+ LPD refers to a spectrum of lymphoid tissue diseases with EBV infection, including hyperplasia, borderline lesions, and neoplastic diseases. According to this concept, EBV+ LPD should not include infectious mononucleosis (IM) and severe acute EBV infection (EBV+ hemophagocytic lymphohistiocytosis, fatal IM, fulminant IM, fulminant T-cell LPD), and should not include the explicitly named EBV+ lymphomas (such as extranodal NK/T cell lymphoma, aggressive NK cell leukemia, Burkitt lymphoma, and Hodgkin lymphoma, etc.) either. EBV+ LPD should currently include: (1) EBV+ B cell-LPD: lymphomatoid granulomatosis, EBV + immunodeficiency related LPD, chronic active EBV infection-B cell type, senile EBV+ LPD, etc. (2) EBV+ T/NK cell-LPD: CAEBV-T/NK cell type, hydroa vacciniforme, hypersensitivity of mosquito bite, etc. In addition, EBV+ LPD is classified, based on the disease process, pathological and molecular data, as 3 grades: grade1, hyperplasia (polymorphic lesions with polyclonal cells); grade 2, borderline (polymorphic lesions with clonality); grade 3, neoplasm (monomorphic lesions with clonality). There are overlaps between EBV+ LPD and typical hyperplasia, as well as EBV+ LPD and typical lymphomas. However, the most important tasks are clinical vigilance, early identification of potential severe complications, and treating the patients in a timely manner to avoid serious complications, as well as the active treatment to save lives when the complications happened.

Gastrointestinal Lymphoma in Southwest China: Subtype Distribution of 1,010 Cases Using the WHO (2008) Classification in a Single Institution.

UNLABELLED: The gastrointestinal tract (GIT) is the most common anatomic site of extranodal non-Hodgkin lymphoma (NHL) involvement. The classification criteria of lymphoma have changed in recent decades, and few large-sample studies regarding subtype analysis of lymphoma have been performed in this site. AIM: Therefore, the present study was conducted to analyze the histological subtype distribution of the GIT. METHOD: All patients in a single institution with a diagnosis of primary NHL in the GIT were enrolled between January 2007 and April 2014. The patients were categorized according to the WHO (2008) classification of tumors of hematopoietic and lymphoid tissue. RESULT: A total of 1,010 eligible cases diagnosed as NHL were collected in this study. The male:female ratio was 1.7:1 and the median age was 55 years. The percent of patients with lymphoma involvement in the stomach was 52% (n = 522), and the remaining 48% (n = 484) had intestinal tract involvement. Histologically, diffuse large B cell lymphoma (DLBCL) was the most common subtype in all of the GIT lymphoma cases, and was also the most common subtype in cases involving the stomach (78%) and the intestinal tract (53%). The incidence of DLBCL and mucosa-associated lymphoid tissue lymphoma in the stomach was significantly higher than the incident in the intestinal tract (p < 0.01). T and NK cell lymphoma was significantly more common in the intestinal tract than in the stomach (p < 0.01). Extranodal NK/T cell lymphoma nasal type (ENKTL-N) was the most common subtype of T and NK cell lineage lymphoma in GIT and was also the second most common intestinal tract-involved lymphoma. CONCLUSION: DLBCL was the most frequent lymphoma in the stomach and in the intestinal tract. T and NK cell lineage lymphoma had a higher occurrence in the intestinal tract than in the stomach. ENKTL-N was the most frequent subtype of lymphoma derived from NK/T cell lineage, and was the second most common lymphoma among all intestinal tract lymphomas.

EBV associated lymphomas in 2008 WHO classification.

Epstein-Barr virus (EBV) is a ubiquitous γ-herpes virus that asymptomatically infects more than 90% of the world's population. The exact mechanism of EBV in oncogenesis is an area of active debate. However, EBV has been implicated in the pathogenesis of several kinds of lymphomas and lymphoproliferative disorders, including B-, T- and NK-cell derived. Subsequent studies have proven that the EBV gene expression product plays an activating and/or promoting role on lymphomagenesis, and paves the way for novel cellular therapies of EBV-associated lymphomas. This review concentrates on the pathology, morphology, treatment and prognosis of EBV-associated lymphomas in the 2008 WHO classification of tumors of hematopoietic and lymphoma tissues.

Pathobiology of T-cell and NK-cell lymphomas.

T-cell and NK-cell lymphomas are uncommon lymphomas with an aggressive clinical course. The causes and precise cellular origins of most T-cell lymphomas are still not well defined. The WHO classification utilizes morphologic and immunophenotypic features in conjunction with clinical aspects and in some instances genetics to delineate a prognostically and therapeutically meaningful categorization. The anatomic localization of neoplastic T-cells and NK-cells parallels in part their proposed normal cellular counterparts and functions. T-cells of the adaptive immune system are mainly based in lymph nodes and peripheral blood, whereas lymphomas derived from T-cells and NK-cells of the innate immune system are mainly extranodal. This approach allows for better understanding of some of the manifestations of the T-cell and NK-cell lymphomas, including their cellular distribution, some aspects of morphology and even associated clinical findings.

Primary extra nodal non Hodgkin lymphoma: a 5 year retrospective analysis.

BACKGROUND AND AIM: The incidence of extra nodal non Hodgkin lymphoma (ENL) is rising throughout the world. However, data regarding ENL as a group is limited. The aim was to study the epidemiological and histomorphological trends of primary ENL (pENL) in India. MATERIAL AND METHODS: The biopsy materials from sixty eight patients with pENL (45 male, 23 female, M:F= 1.9:1), diagnosed over a five year period (2005-2009), were analysed and pathologically reclassified according to the World Health Organization (WHO) classification, 2008 criteria. RESULTS: Primary extra nodal non Hodgkin lymphomas constituted 22.0% (68/308) of all non Hodgkin lymphomas (NHL). The mean age at presentation for pENL and primary nodal NHL was 43 years and 58 years, respectively with a male predilection (M: F=2:1). Central nervous system (CNS) constituted the most common extranodal site (20/68, 29.5%) followed by gastrointestinal tract (17/68, 25%), and nose/nasopharynx (8/68, 11.8%). Diffuse large B-cell lymphoma (DLBCL, not otherwise specified), extranodal marginal lymphoma of mucosa associated lymphoid tissue (MALT) type, and B cell NHL unclassified (U) were the three most common histological types observed. T-cell phenotype was rarely noted (4%). Follicular lymphomas and anaplastic large cell lymphoma, seen among nodal NHL, were absent at extra nodal sites. Majority (41/68, 60%) of the patients with pENL were immunocompetent and 55% were in stage I-II with favorable prognosis. CONCLUSION: Central nervous system was the most common site of ENL, followed by gastrointestinal tract. Majority of pENL occurred in immunocompetent hosts with a favorable prognosis.

Clinical heterogeneity of extranodal NK/T-cell lymphoma, nasal type: a national survey of the Korean Cancer Study Group.

BACKGROUND: This national survey was undertaken to propose the classification of extranodal natural killer (NK)/T-cell lymphoma (NTCL) subtypes and to clarify a clinical heterogeneity. PATIENTS AND METHODS: Two hundred and eighty patients newly diagnosed as NTCL were enrolled from 22 Korean medical centers. Two subsets were compared: one involving the upper aerodigestive tract (UAT) and another involving the non-upper aerodigestive tract (NUAT) region, which comprises the skin, gastrointestinal tract, and liver or soft tissues. Clinical prognostic factors, survival outcomes, and independent predictors for survival were compared between each subset. RESULTS: NUAT-NTCL (59 patients) had significantly higher proportions of disseminated disease, aggressive biologic features, and unfavorable host reactions compared with UAT-NTCL (221 patients). NUAT-NTCL had shortened 5-year overall survival (OS) (22% versus 41%, P = 0.001). Ann Arbor staging, the International Prognostic Index, and the NTCL prognostic index failed to predict the OS of NUAT-NTCL, but did predict the OS in UAT-NTCL. Independent predictors for OS by multivariate analyses differed between each subset. In the NUAT subset, extranodal sites and regional nodes predicted the OS, while Ann Arbor staging, age, performance status, and lactate dehydrogenase level predicted the OS in the UAT subset. CONCLUSION: NUAT-NTCL may represent a distinctive disease entity in terms of clinical factors, independent predictors, and survival outcomes.