Possible association between viral infection and poor survival of the corneal graft after penetrating keratoplasty in patients with congenital corneal opacity: a cohort study.

BACKGROUND: Congenital corneal opacity (CCO) is a rare disorder. Penetrating keratoplasty (PK) is the main surgical option for CCO, but many factors affect graft survival. Therefore, this study aimed to perform a virological examination of CCO specimens after PK to explore the relationship between virological factors and graft survival after PK. METHODS: This prospective study included consecutive patients (<6 months of age) diagnosed with CCO and treated with PK at Beijing Tongren Hospital from August 2017 to January 2018. Next-generation sequencing was used to detect viral DNA in the CCO specimens. The survival of the primary graft was analysed using the Kaplan-Meier method. RESULTS: Overall, 24 eyes of 24 infants were treated with PK during the study period. The mean age at surgery was 4.8±1.1 months. Epstein-Barr virus DNA was detected in two specimens, varicella-zoster virus DNA in one specimen, herpes simplex virus DNA in three specimens and cytomegalovirus DNA in one specimen. In the virus-positive group, only one (14.3%) graft remained clear during follow-up. In contrast, in the virus-negative group (n=17), 13 (76.5%) grafts were still clear at the last follow-up. The mean survival of the grafts in the virus-positive group was significantly shorter than in the virus-negative group (11.0±9.8 months vs 27.1±7.7, p<0.001). CONCLUSION: The presence of viral DNA in CCO specimens might be associated with poor graft survival after PK.

High-dose chemotherapy and autologous stem cell transplantation in primary lymphomatoid granulomatosis of the central nervous system.

Primary lymphomatoid granulomatosis of the CNS (CNS-LG) is a rare lymphoid neoplasia associated Epstein-Barr Virus (EBV) and often accompanied by immunodeficiencies. No treatment standards have been defined yet. However, due to often devastating neurologic sequelae and based on similarities to diffuse large B-cell lymphoma, curative treatment requires intensive therapy protocols resembling protocols applied in CNS lymphoma. Here, the clinical courses and treatments of four primary CNS-LG patients in analogy to aggressive CNS-lymphomas including methotrexate, thiotepa, cytarabine, carmustine, and rituximab are presented. This is the first report on high-dose chemotherapy with CNS-directed drugs and autologous blood stem cell transplantation in primary CNS-LG.

Short-term outcomes of three rare cases of intramucosal Epstein-Barr virus-associated gastric cancer treated with endoscopic submucosal dissection.

Epstein-Barr virus-associated gastric cancer (EBVaGC) is a subtype of gastric cancer morphologically characterized by massive lymphocyte infiltration. We herein report the short-term outcomes of three rare cases of intramucosal EBVaGC treated with endoscopic submucosal dissection (ESD). Histologically, the lesions exhibited poorly to moderately differentiated tubular adenocarcinoma without lymphovascular invasion, and in situ hybridization revealed EBV-encoded small RNA. Helicobacter pylori infection was not found in any of the lesions. During the 3 to 12 months of follow-up following ESD, none of the ESD-treated patients showed evidence of local recurrence or distant metastases. Essential characteristics of intramucosal EBVaGC may include lymphocyte infiltration into the mucosal stroma or cancer nests as well as the presence of a lace pattern. We believe that ESD might be a safe and suitable treatment method for intramucosal EBVaGC that avoids needless surgery, particularly in patients with severe comorbidities or a high operational risk.

Lymphoepithelial carcinoma in the sublingual gland.

Lymphoepithelial carcinoma is rare in the salivary glands, with an incidence of 0.4%. The most commonly affected site is the parotid gland, followed by the submandibular gland. Lymphoepithelial carcinoma in the sublingual gland has been reported only four times in the existing English-language literature. Such tumours are characterized by the presence of a poorly differentiated carcinoma that is surrounded and infiltrated by lymphocytes, and they are strongly associated with Epstein-Barr virus infection, patient ethnicity, and prominent radiosensitivity. Wide surgical excision combined with adjuvant therapy has been suggested as the first-choice therapeutic regimen. This report describes the case of a 34-year-old Indonesian woman who was evaluated and treated in Taipei Medical University Hospital. She had a tumour that presented as a painless swelling on the floor of the mouth. The diagnosis was confirmed by conducting an incisional biopsy, and a wide surgical excision with bilateral supraomohyoid neck dissection and free flap reconstruction was performed. The patient also underwent adjuvant chemoradiotherapy. No evidence of local recurrence or distant metastasis was detected during the 6 months of follow-up. Subsequently, the patient returned to her home country, and further follow-ups were not conducted.

Endoscopic endonasal approach to the cavernous sinus Epstein-Barr virus-positive B cell non-Hodgkin lymphoma in a child: case report.

Cavernous sinus (CS) lymphoma without paranasal sinuses involvement is extremely rare in pediatric population and remains a diagnostic challenge due to its similarity to other tumors located in this area. An 8-year-old boy presented with a 6-day history of gradually developing ptosis in the right eyelid. After admission, his symptoms progressed within 24 h to include right-sided ophthalmoplegia consisting of oculomotor and abducens nerve palsies. Endoscopic endonasal approach (EEA) was performed urgently to decompress the CS and to obtain a diagnosis. The postoperative course was uneventful, and there was no complication related to the surgical approach. No immunodeficiency was identified. The histopathological diagnosis was an Epstein-Barr virus (EBV)-positive high-grade mature B cell non-Hodgkin lymphoma. He was initiated chemotherapy according to COG ANHL01P1 protocol. Two months after surgery, the third and sixth nerve palsies had resolved completely. Currently, he is well and has no clinical or radiological recurrence. This is the first pediatric case with EBV-positive CS lymphoma that underwent EEA for the diagnosis and decompression. In the pediatric population, EEA enables minimally invasive access to the CS and can play an alternative role in the management of CS lesions, either through biopsy or debulking.

A 39-Year-Old Woman With Synchronous Endobronchial and Adrenal Tumors.

CASE PRESENTATION: A 39-year-old woman with systemic lupus erythematosus that was complicated by end-stage renal disease that had required a deceased donor renal transplant 16 years ago was referred for evaluation of chronic, nonproductive cough for 2 years. She was a lifetime nonsmoker whose condition was maintained on prednisone 5 mg daily, tacrolimus 3 mg twice day, mycophenolate mofetil 500 mg twice a day for her immunosuppression regimen, valacyclovir 500 mg twice a day for prophylaxis, and clonidine 0.1 mg daily and metoprolol succinate 100 mg twice daily for hypertension.

ARID1A deficiency in EBV-positive gastric cancer is partially regulated by EBV-encoded miRNAs, but not by DNA promotor hypermethylation.

AT-rich interactive domain 1A (ARID1A), which is a tumor suppressor gene, is frequently mutated in Epstein-Barr virus-positive gastric cancer [EBV (+) GC]. While most ARID1A mutations in GC are truncating mutations, leading to loss of ARID1A protein expression, epigenetic modifications appear to contribute to ARID1A deficiency in EBV (+) GC harboring wild-type ARID1A. Based on the significant role of epigenetic modifications in EBV (+) GC that contributes to ARID1A deficiency, the methylation status of ARID1A was evaluated in EBV-infected cells and GC patients using a publicly available microarray and the Cancer Genome Atlas (TCGA) database. EBV-encoded miRNAs that potentially target ARID1A were identified as an additional epigenetic modulator by computational prediction. In vitro experiments were conducted to evaluate how EBV-encoded miRNAs affected ARID1A mRNA and protein levels. In clinical GC samples, the expression of predicted miRNAs and ARID1A and the mutation status of ARID1A was evaluated. As results, ARID1A was not hypermethylated in EBV (+) GC samples or EBV-infected GC cells. EBV infection did not alter ARID1A mRNA levels, suggesting that ARID1A protein deficiency was caused by post-transcriptional gene silencing in ARID1A-WT EBV (+) GC. Overexpression of miR-BART11-3p and miR-BART12, which were identified as miRNAs that potentially bind ARID1A, suppressed ARID1A protein expression in MKN7 and NCI-N87 cells. Highly expressed miR-BART11-3p and miR-BART12 were correlated with decreased ARID1A levels in GC tumors which did not harbor ARID1A mutations. The present findings revealed that ARID1A expression was epigenetically regulated by miR-BART11-3p and miR-BART12 in EBV (+) GC.

Inflammatory Pseudotumor-Like Follicular/Fibroblastic Dendritic Cell Sarcomas of the Spleen Are EBV-Associated and Lack Other Commonly Identifiable Molecular Alterations.

Inflammatory pseudotumor-like follicular/fibroblastic dendritic cell sarcoma (IPT-like FFDCS) is a rare, indolent neoplasm that occurs in the spleen or liver and harbors Epstein-Barr virus (EBV) integrated into the host genome. The molecular genetic characteristics of IPT-like FFDCS have not been well studied and there are no established and actionable molecular features to guide treatment decisions or diagnosis beyond the recognition of viral genome integration. We subjected two cases of IPT-like FFDCS to a comprehensive next-generation sequencing analysis. Several variants of uncertain clinical significance were detected in both tumors. No variants of potential or strong clinical significance were detected within the targeted regions of the evaluated genes. Additionally, no fusion events were detected involving the genes in either tumor. The performed molecular analysis identified no genetic aberrations in IPT-like FFDCS and its genomic landscape remains, with the exception of a monoclonal EBV gene, largely undefined.

Brote severo de enfermedad inflamatoria intestinal vs. rara manifestación de úlcera mucocutánea Epstein-Barr positiva. Informe de caso / No disponible

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Can Epstein-Barr virus play a role in upper urinary tract urothelial carcinomas?

INTRODUCTION: Upper urinary tract urothelial carcinomas are very rare tumours with different biological behaviours. The Epstein-Barr virus, which is the first known oncogenic virus, is being investigated for various malignant tumours. It is known that this virus is associated with nasopharyngeal carcinoma, as well as multiple haematological malignancies, head and neck and gastric cancers. We aimed to determine the presence of the Epstein-Barr virus in upper urinary tract urothelial carcinomas using chromogenic in situ hybridisation (CISH). MATERIALS AND METHODS: A total of 44 upper urinary tract urothelial carcinomas from two different centres were included. Demographic data and survival rates were obtained from hospital records. One demonstrative paraffin block from each case was stained using Epstein-Barr encoded RNA (EBER) with an automated CISH procedure. The positivity of EBER was statistically analysed for prognostic factors. RESULTS: Among all patients, 38 were male and 6 were female. The mean age of the patients was 65.93 years. At the time of the study, 15 patients had died and 29 were alive. EBER-CISH positivity was found in 13 patients. Four showed strong EBER-CISH expression and nine showed weak expression. EBER-CISH positivity was not statistically related to any of the prognostic factors or to overall survival. DISCUSSION: Although EBER-CISH positivity showed no significant relation with prognostic factors, it was observed in one-third of all cases. Therefore, we think that the Epstein-Barr virus may have a role in the pathogenesis of upper urinary tract urothelial carcinomas. This finding needs to be supported by larger studies.

Intracranial Leiomyoma Associated with Epstein-Barr Virus: A Cerebellopontine Angle Mass Presenting with Trigeminal Neuralgia.

BACKGROUND: Primary intracranial leiomyoma is a rare smooth muscle tumor often associated with Epstein-Barr virus (EBV), with <30 cases reported worldwide. These tumors commonly occur in patients with immunocompromised status, especially those with human immunodeficiency virus. In the present report, we have described the case of an EBV-associated leiomyoma at the cerebellopontine angle. The patient had presented with trigeminal neuralgia, which, to the best of our knowledge, is the first reported anatomical location and presentation for this tumor type. CASE DESCRIPTION: A 41-year-old male patient had presented with right-sided facial pain in the V1 and V2 dermatomes and previous workup and imaging studies. The patient had undergone treatment of a presumed right-side cerebellopontine angle meningioma as determined by the magnetic resonance imaging characteristics (no biopsy). The patient subsequently underwent right-sided retrosigmoid craniotomy and gross total resection of the tumor. The postoperative period was uneventful with resolution of the trigeminal neuralgia. Histopathologic examination revealed spindle cell neoplasm with histopathologic and immunohistochemical features consistent with leiomyoma. The tumor cells were positive for smooth muscle actin and desmin and were negative for S100, SOX-10, epithelial membrane antigen, glial fibrillary acidic protein, progesterone receptor, CD31, CD34, and E-cadherin. CONCLUSIONS: Primary intracranial leiomyomas are rare tumors associated with EBV infection that occur in immunocompromised patients. These lesions should be considered in the differential diagnosis for patients with known immunocompromised status (e.g., human immunodeficiency virus), and tissue biopsy should be considered.

Synchronous Epstein-Barr virus-associated skull base and adrenal smooth-muscle tumors in an 8-year-old girl with recent Epstein-Barr virus infection.

Epstein-Barr virus-associated smooth-muscle tumors are rare tumors seen in immunocompromised patients. Most cases occur in the context of AIDS and organ transplantation, and very rarely in the setting of congenital immunodeficiency, with only 5 case reports of the latter published so far in the literature. The authors report the case of a previously healthy 8-year-old girl with headaches and precocious puberty who was found to have a large skull base lesion. There was a synchronous left adrenal lesion. She underwent resection of the skull base lesion and a left adrenalectomy. Thorough evaluation for immunodeficiency was negative for a known congenital immunodeficiency syndrome. She had a short course of intravenous immunoglobulin and has had no recurrence of disease or new lesions in the 17 months since presentation. Continued surveillance for the development of opportunistic infections and new or recurrent lesions is warranted in this case. Repeat surgery for surgically accessible tumors or chemoradiation would be recommended for any additional lesions.

Epstein-Barr virus positivity among surgically resected intramucosal gastric cancer.

Epstein-Barr virus-associated gastric cancer (EBV-GC) accounts for approximately 8% of gastric cancers. However, little is known regarding intramucosal EBV-GC. The present study aimed to evaluate endoscopic and clinicopathological characteristics of intramucosal EBV-GC. Pathological data of 172 patients with 173 intramucosal gastric cancers who received gastrectomy with lymph node dissection were obtained for review. EBV-encoded small RNA in situ hybridization (EBER-ISH) was carried out using a tissue microarray block. Eight intramucosal early gastric cancers (4.6%) were EBER-ISH positive in which no cases had any lymph node metastasis. Macroscopic types were either depressed or flat, dominant histology was mixed type of moderate and poorly differentiated adenocarcinoma. In detail, histological features of "lace pattern" or "lymphocyte infiltration into the stroma or cancer nests" were observed.

Clinical and pathological characterization of Epstein-Barr virus-associated gastric carcinomas in Portugal.

AIM: To determine the prevalence of Epstein-Barr virus (EBV)-associated gastric carcinomas in the North Region of Portugal and to study its clinicopathological characteristics. METHODS: We have performed a retrospective study including a total of 179 consecutive patients with gastric cancer (GC) submitted to gastrectomy during 2011 at the Portuguese Oncology Institute of Porto. Clinical and pathological data was collected from individual clinical records and inserted on a database with unique codification. Tumour tissues were collected from the institutional tumour bank. EBV was detected by in situ hybridization for the detection of EBV-encoded small RNAs (EBERs) and EBV latent proteins (LMP1 and LMP2A) were detected by immunohistochemistry. RESULTS: The analysis showed that EBV-associated gastric carcinomas (EBVaGC) represents 8.4% (15/179) of all GC cases, with a significant differential distribution among histological types (P < 0.001): 100% (3/3) of medullary carcinomas, 100% (1/1) of adenosquamous carcinoma, 8.7% (8/92) of tubular adenocarcinomas, 8.0% (2/25) of mixed carcinomas and 2% (1/51) in poorly cohesive carcinomas. The analysis revealed a higher predominance of EBVaGC in the upper third and middle (cardia, fundus and body) of the stomach (P = 0.041), a significant lower number of regional lymph nodes invasion (P = 0.025) and a tendency for better prognosis (P = 0.222). EBV latent protein expression revealed that all EBVaGC cases were LMP1-negative, nevertheless 6 cases (40%) expressed LPM2A, which reveals that these cases show a distinct EBV-Latency profile (latency II-like). CONCLUSION: EBVaGC represents 8.4% of all GC in the North Region of Portugal. The EBV-infected patients have specific clinic-pathological features that should be further explored to develop new strategies of management and treatment.

Successful Cord Blood Stem Cell Transplantation for an Adult Case of Chronic Active Epstein-Barr Virus Infection.

A 41-year-old man was referred to our hospital for treatment of anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Chronic active Epstein-Barr virus (CAEBV) was diagnosed based on the findings of elevated EBV antibody titers and positive EBV-DNA in the peripheral blood, and cord blood stem cell transplantation (CBT) was performed. The EBV-DNA levels in the blood fell below the limit of detection. His lymphoma relapsed on Day 165 with the appearance of eruptions, which disappeared after the withdrawal of tacrolimus. One year after transplantation, there were no signs of recurrence. This encouraging result suggests that CBT should be considered for adult cases of CAEBV with aggressive clinical manifestations.

Secondary neuroendocrine tumor after allogeneic bone marrow transplantation.

Here we report a case of aggressive neuroendocrine tumor (NET), which is an extremely rare secondary solid tumor that occurs after allogeneic hematopoietic cell transplantation (allo-HSCT). A patient with chronic active Epstein-Barr virus infection received allo-HSCT from an HLA-DR two allele-mismatched unrelated donor. Four years later, he developed NET with multiple metastases. He received thoraco-abdominal irradiation as a conditioning regimen, and developed repeated episodes of intestinal graft-versus-host disease, for which he received long-term immunosuppressive therapy. Although these factors may be potential contributing factors to the development of secondary NET, the exact pathogenesis remains unclear.