Surgical treatment of Epstein-Barr virus-associated lymphoepithelioma-like carcinoma occurring in both the posterior mediastinum and liver: Case report.

RATIONALE: Lymphoepithelioma-like carcinoma (LELC) is a rare malignant tumor that can occur in many areas of the body. The pathogenesis of LELC remains unknown, but Epstein-Barr virus (EBV) has been shown to be strongly correlated with LELC at several anatomic sites, including the lungs and thymus. To the best of our knowledge, EBV-associated LELC has never been reported in both the posterior mediastinum and liver. Herein, we report the case of a 41-year-old female diagnosed with LELC in both the posterior mediastinum and liver and discuss whether it is beneficial to perform surgery on advanced LELC when resectable metastases are found. PATIENT CONCERNS: The patient was a 41-year-old woman who had been suffering from intermittent pain in the upper right quadrant for 3 months without obvious cause and was admitted to our hospital with occasional nausea without vomiting. DIAGNOSIS: Her cancer antigen 125 and cytokeratin 19 fragment levels were elevated, whereas alpha-fetoprotein and alanine aminotransferase were normal. Computed tomography (CT) and magnetic resonance imaging revealed a mass in the S6 segment of the liver. Whole-body positron emission tomography/computed tomography (PET/CT) revealed a 3.2-cm mass in the posterior mediastinum and a 6.7-cm mass on the right side of the liver. We made a diagnosis of LELC based on the histological and immunohistochemical findings of specimens obtained by operation. However, it was difficult to determine the primary origin of the tumor. INTERVENTIONS: The patient underwent mediastinal tumor resection, hepatectomy, and diaphragmatic repair. Thereafter, she was administered paclitaxel and cisplatin as adjuvant chemotherapy. OUTCOMES: The postoperative course was uneventful, and the patient was discharged 10 days later. Although she was administered paclitaxel and cisplatin as adjuvant chemotherapy, we noted recurrence during the 4-month follow-up examination. Then, the patient passed away 5 months after surgery. LESSONS: We present the first case of LELC found in both the posterior mediastinum and liver and describe the functionality of PET/CT for finding occult carcinomas and identifying their primary tumor origin. Additional studies are urgently needed to discover whether it is beneficial to perform surgery on advanced LELC when resectable metastases are revealed by PET/CT.

Utilizing multiple pathway cross-talk networks reveals hub pathways in primary mediastinal B-cell lymphoma.

OBJECTIVE: The objective of this paper was to reveal hub pathways in primary mediastinal B-cell lymphoma (PMBL) based on multiple pathway crosstalk networks (PCNs) and give insight for its pathological mechanism. MATERIALS AND METHODS: Based on gene expression data, pathway data and protein-protein interaction data, background PCN (BPCN) and tumor PCN (TPCN) of PMBL were constructed. The rank product algorithm was implemented to identify hub pathways of BPCN and TPCN. Finally, topological properties (degree, closeness, betweenness, and transitivity) of hub pathways were analyzed. RESULTS: For BPCN, there were three hundred nodes and 42,239 edges, and the pathway pairs had great overlaps. TPCN was composed of 281 nodes and 12,700 cross-talks. A total of five hub pathways were identified, nonalcoholic fatty liver disease (NAFLD), tuberculosis, human T-lymphotropic virus type-I (HTLV-I) infection, hepatitis B, and Epstein-Barr virus infection. The topological properties for them were different from each other, further between PMBL and normal controls. CONCLUSION: We have identified five hub pathways for PMBL, such as NAFLD, HTLV-I infection, and Hepatitis B, which might be potential biomarkers for target therapy for PMBL.

Prognostic Differences: Epstein-Barr Virus-Associated Primary Leiomyosarcoma of the Spine Versus Spinal Leiomyosarcoma Metastases.

OBJECTIVE: The authors studied 6 cases of osseous leiomyosarcoma of the spine. Two of these cases were of immunocompromised human immunodeficiency virus (HIV)-positive patients with Epstein-Barr virus (EBV)-associated primary vertebral leiomyosarcomas. The remaining 4 cases were of patients with leiomyosarcoma metastases to the spine. METHODS: Each patient underwent surgical resection of their vertebral mass; however, the patients with the EBV-associated tumors had the best postoperative prognosis. RESULTS: The HIV-positive patients have had no further local recurrence, while the other 4 patients had rapid local recurrences requiring multiple surgical interventions. Furthermore, the patients living with HIV have lived longer with fewer leiomyosarcoma-related health complications. CONCLUSIONS: These findings suggest that EBV-associated vertebral leiomyosarcoma is of a less aggressive variety than metastatic leiomyosarcoma of the spine.

Epstein-Barr virus-positive plasmacytoma in immunocompetent patients.

AIMS: Extramedullary plasmacytomas are often localized, clinically indolent neoplasms, and affected patients usually respond to radiation therapy or limited cycles of chemotherapy. In contrast, plasmablastic lymphomas are clinically aggressive neoplasms composed of immunoblastic or plasmablastic cells and associated with more mature plasma cells in some cases. Patients with plasmablastic lymphoma usually have a poor prognosis despite aggressive chemotherapy. Evidence of Epstein-Barr virus (EBV) infection is uncommon in plasmacytoma, but common in plasmablastic lymphoma, and is therefore helpful in differential diagnosis. The aim of this study is to describe four cases of plasmacytoma arising in immunocompetent individuals that were diffusely positive for Epstein-Barr virus-encoded small RNA as shown by in-situ hybridization. METHODS AND RESULTS: We describe the clinicopathological and immunophenotypic findings of four EBV-positive plasmacytomas arising in immunocompetent patients. These tumours were characterized by diffuse proliferation of mature-appearing plasma cells intermixed with a briskly reactive, CD8-positive, TIA-1-positive cytotoxic T-cell infiltrate. Long-term follow-up was available for all patients, and all were alive and free of disease at last follow-up (median 43.4 months). CONCLUSIONS: We suggest the term EBV-positive plasmacytoma in immunocompetent patients for these lesions. It is essential to distinguish these tumours from plasmablastic lymphoma, as the latter diagnosis is associated with a much poorer prognosis, and patients require much more aggressive therapy.

NK/T cell lymphoma involving mediastinum: report of a case and review of literature.

Extranodal natural killer (NK)/T-cell lymphoma is a very aggressive malignant neoplasia with a poor prognosis. Herein we reported a case of NK/T cell lymphoma involving mediastinum. It was a 28-year-old Chinese male patient. The tumor cells were medium-sized, had irregularly folded nuclei, and inconspicuous or small nucleoli with coagulative necrosis. The tumor cells were positive for CD3ε, TIA-1, but negative for CD56. In situ hybridization revealed that tumor cells also expressed Epstein-Barr virus encoded RNA. To our knowledge, this is the first case of NK/T cell lymphoma involving mediastinum.

[Comparative study between primary mediastinal B-cell lymphoma and non-mediastinal diffuse large B-cell lymphoma by immunoglobulin gene rearrangement and Epstein-Barr virus infection detection].

OBJECTIVE: To investigate the differences between primary mediastinal B-cell lymphoma (PMBCL) and non-mediastinal conventional diffuse large B-cell common lymphoma (DLBCL) in immunoglobulin gene rearrangement and EB virus infections. METHODS: Twenty cases of PMBCL and 30 cases of non-mediastinal DLBCL were collected from September, 2000 to May, 2011. Pathological data were retrospectively analysed. Immunoglobulin heavy chain and light chain gene rearrangements and EBER in-situ hybridization were performed. RESULTS: Six of 20 cases of PMBCL showed monoclonal gene rearrangement, all of which were weakly detected. Twenty-seven of 30 cases of ordinary diffuse large B-cell lymphoma showed monoclonal gene rearrangement, which were strongly detected (90.0%). Only 1 of 20 cases PMBCL and 2 of 30 cases of DLBCL were positive for EBER in-situ hybridization. CONCLUSIONS: The detection rate of immunoglobulin gene rearrangement is significantly lower in PMBCL than that of non-mediastinal DLBCL. However, EB virus infection rates are very low in both types of lymphomas.

Cell cycle characteristics and Epstein-Barr virus are differentially associated with aggressive and non-aggressive subsets of Hodgkin lymphoma in pediatric patients.

We investigated the correlation of tumor characteristics with clinico-biological markers of aggressive disease, evaluated by Ann Arbor stage, risk group, B-symptoms, number of involved anatomic areas, mediastinal mass, nodular sclerosis (NS) grade, and risk, in pediatric Hodgkin lymphoma (HL). Leukopenia and extranodal disease influenced event-free survival (p = 0.032 and p = 0.041). In multivariate analysis, extranodal disease was associated with high number of tumor-infiltrating eosinophils (p = 0.035) and Ki67 < 50% (p = 0.024); B-symptoms with Ki67 > or =75% (p = 0.027) and high LDH levels (p = 0.001); and mediastinal mass with leukopenia (p = 0.048), NS grade II (p = 0.025), and high-risk (p = 0.046). Furthermore, low stages correlated with Ki67 > or =50% (p = 0.005) and Epstein-Barr virus (EBV) (p = 0.065). Low-risk NS was associated with EBV (p = 0.014). Hierarchical cluster analysis identified two clusters, one composed of high-risk patients and cell cycle and apoptosis features, and the other including low-risk patients, EBV, and low-risk NS. Our results show the association of biological markers with disease aggressiveness in pediatric HL.

T-cell leukemia 1 expression in nodal Epstein-Barr virus-negative diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma.

The physiologic expression of the product of the proto-oncogene TCL1 (T-cell leukemia 1) is primarily restricted to early embryonic cells. In nonneoplastic B cells, the expression of TCL1 is determined by the differentiation step with silencing at the germinal center stage. TCL1 protein is overexpressed in a wide variety of human diseases. It has been shown that TCL1 is a powerful B-cell oncogene, which has been implicated in the pathogenesis of various types of mature B-cell lymphomas. There is no comparative information in the literature addressing the expression of TCL1 in pediatric and adult nodal diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma. We studied 55 cases of adult and pediatric diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma to analyze the phenotypic profile of these lymphomas, including TCL1 expression, and its relationship with clinical outcome in different age groups. The cases were analyzed by immunohistochemistry for the expression of TCL1, CD10, BCL-2, BCL-6, and MUM1. We also evaluated c-MYC translocation by fluorescence in situ hybridization. TCL1 was observed in 11 cases, 5 pediatric and 6 adult cases, all but one diffuse large B-cell lymphoma. Pediatric cases showed a significant association between TCL1 expression, high proliferative index, and presence of c-MYC translocation. TCL1 positivity was predominantly found in germinal center phenotype diffuse large B-cell lymphoma. Overall survival was worse in adult TCL1-positive cases than pediatric ones. Primary mediastinal large B-cell lymphomas infrequently expressed TCL1 in both age groups.

Thymic lymphoepitheliomalike carcinoma in children: clinicopathologic features and molecular analysis.

Thymic lymphoepitheliomalike carcinoma (LELC) in children is extremely rare and we report 2 such cases with molecular analysis of Epstein-Barr virus (EBV) and its encoded latent membrane protein-1 as well as a literature review. Both of our patients were male, presented with a huge anterior mediastinal mass, expired within a year after diagnosis despite treatment. There were altogether 9 cases of thymic LELC in children. Their common clinical features include a male predominance, large tumor size, advanced clinical stage, and poor clinical outcome. All cases were associated with EBV and nearly half developed concurrent hypertrophic osteoarthropathy (HOA). Thymic LELC in children is an aggressive EBV-associated malignant tumor frequently accompanied by HOA. We proposed that EBV might play a role in the development of HOA through the interactions of latent membrane protein-1, vascular endothelial growth factor, and cyclooxygenases-2.

Carcinoma positive for Epstein-Barr virus staining. Mediastinal lymph node origination?

A 44-year-old man undergoing radical excision of metastatic carcinoma of the mediastinal lymph node with unknown primary sites remains alive and disease-free 14 years after surgery. His cancer cells were positive for the Epstein-Barr virus, which may have been related to the oncogenesis of this tumor. This case is unique in the patient's long, disease-free survival and its positive presence of the Epstein-Barr virus.

MedB-1, a human tumor cell line derived from a primary mediastinal large B-cell lymphoma.

Primary mediastinal B-cell lymphoma is a locally highly aggressive but poorly disseminating tumor composed of medium sized or large cells most probably of thymic medullary origin. It has a mature B-cell phenotype, typically lacks immunoglobulin expression and has variable defects in expression of HLA-molecules. We present here a cell line, MedB-1, derived from such a tumor. As is frequently found in mediastinal B-cell lymphomas in situ, MedB-1 is CD10(-), CD19(+), CD21(-), CD22(+), CD23(+), CD25(-), CD37(+), CD38(-), CD39(+), CD40(+), CD54(+), CD95(+). Like the parental tumor, MedB-1 lacks HLA-A,B,C alpha-chains and beta(2)microglobulin and expresses HLA-D molecules at decreased levels. Both parental tumor and MedB-1 cells are clonally related as shown by immunoglobulin heavy chain gene rearrangement analysis. Unlike the parental tumor tissue, the MedB-1 cell line cytoplasmically expresses IgG/kappa in a very small subset of cells under standard culture conditions. MedB-1 does not contain any Epstein-Barr virus DNA. In a tissue adhesion assay MedB-1 cells showed an extensive binding to the medullary region of normal thymus. Altogether, MedB-1 is a suitable tool for functional and molecular analysis of this distinct lymphoma entity.

Aggressive natural killer cell lymphoma presenting as an anterior mediastinal mass in a patient with acquired immunodeficiency syndrome.

We report a case of aggressive natural killer cell lymphoma presenting as an anterior mediastinal mass in an African-American man with acquired immunodeficiency syndrome. Histologically, the anterior mediastinal mass showed a diffuse dense infiltrate of atypical intermediate-sized and large lymphoid cells, as well as scattered immunoblasts with angiocentric and angiodestructive growth and extensive zonal necrosis. Similar lymphoid infiltrates were present in the patient's lungs, spleen, and bone marrow, accompanied by extensive lymphophagocytosis. Electron microscopic and cytologic examinations showed the presence of dense cytoplasmic granules. Immunophenotyping by flow cytometry and by immunohistochemistry yielded surface markers consistent with a natural killer cell lymphoma. The Epstein-Barr virus genome and monoclonality were detected by in situ hybridization and Southern blot analysis. Polymerase chain reaction confirmed the presence of type A Epstein-Barr virus. T-cell receptor gene rearrangement could not be identified by Southern blot analysis or polymerase chain reaction. To the best of our knowledge, this is the first reported case of designated natural killer cell lymphoma from the mediastinum, as well as the first reported case of natural killer cell lymphoma in a patient with acquired immunodeficiency syndrome. This tumor disseminated early and pursued a highly aggressive course. Epstein-Barr virus may play a role in the pathogenesis of this disease.

Primary mediastinal large B-cell lymphoma. A clinicopathologic study of 141 cases compared with 916 nonmediastinal large B-cell lymphomas, a GELA ("Groupe d'Etude des Lymphomes de l'Adulte") study.

Among non-Hodgkin's lymphomas, primary mediastinal large B-cell lymphoma (PMLCL) has been considered a separate entity that has specific clinical and histological aspects and a poor prognosis. In this study, we reexamined the clinicopathologic features and the response to current treatment of 141 PMLCL and compare them with 916 nonmediastinal large B-cell lymphomas (NMLCL) recorded in the same period and treated with similar combined chemotherapy. The clinical features of PMLCL at diagnosis were largely homogeneous and distinct from NMLCL, with a predilection for young women (59% with a mean age of 37 years versus 42% with a mean age of 54 years), bulky tumor (77% versus 7%, p < 10(4)), high serum lactic dehydrogenase (LDH) level 76% versus 51%, p < 10(4)), and frequent intrathoracic extension to adjacent organs such as pleura, pericardium, and lung. By contrast, extrathoracic or hematologic dissemination was uncommon (2% of bone marrow involvement versus 17%). All patients had diffuse large B-cell nonimmunoblastic, nonanaplastic lymphomas. Histological analysis of the 141 PMLCL evaluated two common patterns: the presence of large cells with clear cytoplasm (found in 38% of cases) and the presence of fibrosis (marked in 25% of cases). The presence of clear cells or intense fibrosis did not constitute prognostic indicators. Immunologic and molecular analysis assessed the profile of bcl-2 expression and the presence of Epstein-Barr virus (EBV) in PMLCL: 30% expressed a high level of bcl-2 protein; EBER RNAs were detected by in situ hybridization in only two of the 41 cases tested. Monotypic light chain restriction could be demonstrated in seven of the 41 PMLCL tested on fixed-section. Treated with polychemotherapy regimens without radiotherapy, 79% of PMLCL patients achieved a complete remission compared with 68% in the NMLCL patient group (p = 0.01). Overall, 3-year survival rates were estimated at 66 and 61%, respectively (p = 0.05), and disease-free survival rates were not significantly different (61 versus 64%). Stratified analysis on the International Prognostic Index (based on age, tumor stage, serum LDH level, and performance status) showed no difference in the overall and disease-free survivals between the two lymphoma groups. In conclusion, PMLCL can be combined with other diffuse large B-cell lymphomas on morphologic grounds; it is not associated with EBV. It responds favorably to treatment and should be managed like other high-grade lymphomas of equivalent histology. However, the uncommon clinical presentation makes it a distinct entity.

Molecular characterization of primary mediastinal B cell lymphoma.

Primary mediastinal B cell lymphoma (PMBL) is a diffuse large B cell lymphoma (DLCL) postulated to arise from noncirculating thymic B lymphocytes. Because of its distinctive clinical and morphological features and putative unique cellular origin, PMBL is generally considered a distinct clinicopathological entity. Little is known, however, about the molecular characteristics of PMBL. Therefore, we analyzed 16 PMBLs for molecular alterations involving the bcl-1, bcl-2, bcl-6, c-myc, H-ras, K-ras, N-ras, and p53 genes and for Epstein-Barr virus infection, which are commonly involved in lymphoid neoplasia. Employing a combination of Southern blotting and/or polymerase chain reaction and single-strand conformation polymorphism assays, we detected genetic alterations in 7 of the 16 (44%) PMBLs. Whereas the bcl-6 gene is rearranged in up to 45% of DLCLs, rearrangement of the bcl-6 gene was detected in only 1 of these 16 (6%) PMBLS. Point mutations of the 5' noncoding region of the c-myc gene were demonstrated in 3 other cases (19%), although c-myc gene rearrangements were not seen by Southern blotting. Missense point mutations of the p53 gene were identified in 3 additional PMBLs (19%). Alterations of the bcl-1, bcl-2, or ras genes and evidence of Epstein-Barr virus infection were not observed. In conclusion, a variety of molecular lesions occur in PMBLs and may be involved in their pathogenesis. This molecular genetic pattern bears little resemblance to that known for other B cell malignancies, including DLCL. In particular, the infrequent occurrence of bcl-6 gene rearrangement in PMBLs distinguishes them from other DLCLs of B cell origin, suggesting that PMBLs do not represent a distinct subtype of DLCL.