Collision of Epstein–Barr virus-positive and -negative gastric cancer, diagnosed by molecular analysis: a case report

Abstract

Background Epstein–Barr virus (EBV)-positive gastric carcinoma (GC) is defined by the proliferation of GC cells with EBV infection. The co-existence of EBV-positive and -negative components in a single GC is rare. We report a case of GC with the co-existence of EBV-positive and EBV-negative components, in which we performed—for the first time—various molecular analyses to elucidate their histogenesis. Case presentation An 81-year-old man was diagnosed with GC based on the results of endoscopy and a pathological examination of the biopsy specimen. Systemic chemotherapy was performed, since lymph node and lung metastases were diagnosed based on computed tomography. Total gastrectomy and lymph node dissection were performed after chemotherapy, after confirming that the size of the metastatic lymph nodes had decreased and that the lung metastasis had disappeared. Grossly, a type 3 tumor was located in the middle posterior part of the stomach body. At the cut section, the tumor consisted of a white and solid part on the anal side of the tumor and a flat and elevated part on the oral side. Histologically, the former part consisted of GC with lymphoid stroma and the latter part was composed of poorly differentiated adenocarcinoma without prominent lymphocytic infiltration. The two histopathological components were clearly separated from each other. On EBV-encoded small RNA (EBER)-in situ hybridization (ISH), the part with the lymphoid stroma component was positive, while the other part was negative. Immunohistochemistry revealed that both components showed the overexpression of p53. Sequencing of TP53 using DNA extracted from the two components was conducted, and revealed different patterns. Targeted next generation sequencing revealed MYC amplification in the EBV-positive component of the tumor and HER2 amplification in the EBV-negative part. Immunohistochemistry revealed that the EBV-positive part was C-MYC( +)/HER2(−) and the EBV-negative part was C-MYC(−)/HER2( +). Correspondingly, chromogenic ISH and dual-color ISH showed amplification of C-MYC and no amplification of HER2 in the EBV-positive part, and no amplification of C-MYC and amplification of HER2 in the EBV-negative part. Conclusion We presented a case of collision of two different GCs composed of EBER-ISH ( +)/C-MYC ( +) and EBER-ISH (−)/HER2 ( +) cells.

Deep learning based on hematoxylin–eosin staining outperforms immunohistochemistry in predicting molecular subtypes of gastric adenocarcinoma

“…The HER2 status of a tumor also varies at different sites [37], so it is also possible that different molecular subtypes exist within a tumor. In addition to our data suggesting that heterogeneity of molecular subtypes according to TCGA definition is a common phenomenon, there are already case reports in which intra‐tumoral heterogeneity has been observed for EBV [36,38] or MSI [39,40]. Although GC heterogeneity is known, its detection is still challenging in the laboratory and deep learning could help.…”

Gastric cancer with distinct Epstein–Barr virus-positive and -negative tumor components and their whole exome sequencing result: a case Report

“…Since the tumor had EBV- positive and -negative areas at each side with distinct histology and p53 immunostaining pattern, we first considered this case as EBV collision gastric cancer. EBV collision gastric cancers have been rarely reported in the scientific literature [ 6 – 9 ]. Intratumoral heterogeneity of EBVaGCs have been reported in a few previous studies [ 15 , 16 ].…”

“…However, EBV collision gastric cancer, unlike gastric cancer with heterogeneous EBV positivity, has distinct tumor components at the border that exhibit EBV positivity and negativity, rather than having two intermixed components. Miyabe et al suggested that EBV-positive and -negative collision gastric cancers have different histogenesis based on the result of TP53 sequencing, targeted next-generation sequencing, and HER2 and C-MYC fluorescence in situ hybridization (FISH) study [ 6 ].…”

“…Recently, we encountered an unusual case of gastric cancer with distinct EBV-positive and -negative tumor areas, which has been usually described in the literature as a collision tumor [ 6 – 9 ]. Furthermore, we performed whole exome sequencing (WES) on both EBV-positive and -negative tumor areas and investigated their molecular characteristics.…”

Landscape of EBV-positive gastric cancer

“…Another genetic feature of EBV (+) GC is lack of TP53 mutations. The TP53 tumor suppressor is the most recurrently mutated gene in GC; however, TP53 mutations are not frequent in EBV (+) GC among the GC subtypes classified by TCGA [1,23,24].…”