Case of the Month

Discussion

Lymphoepithelioma-like carcinoma (LLC) of the stomach is an uncommon and quite an unusual type of gastric carcinoma that is first described by Watanabe et al in 1976 as gastric carcinoma with a lymphoid stroma.  It constitutes about 4% of all gastric carcinomas and is associated with a comparatively better prognosis than other types of gastric carcinoma. In general, there are two subsets of gastric cancers which are associated with a lymphocyte-rich phenotype e.g. Epstein-Barr virus (EBV)-positive and microsatellite instability (MSI)-high cancers. More than 80% of lymphoepithelioma-like gastric carcinomas have been found to be associated with EBV infection and express only several EBV-latent genes as opposed to 6% and 7% of diffuse and intestinal-type adenocarcinomas respectively. The prevalence of MSI-high in gastric carcinomas ranges from 7% to 39% with geographic variability. The stroma consists of CD8- or CD4-positive T lymphocytes, and CD68-positive macrophages, in a ratio of 2:1:1 and EBV infection is observed only in a very limited number of these infiltrating lymphocytes. The reports in the literature with the synonyms undifferentiated carcinoma with lymphoid stroma, gastric lymphoepithelioma-like carcinoma, or medullary carcinoma all describe carcinomas with similar morphology.

As most type of gastric cancers, LLC is more prevalent in males and in the elderly population. Typically the EBV associated LLC involves the the cardia and middle portion of the stomach, while MSI-high associated gastric carcinomas are more common in the antrum. Patients generally present with vague abdominal pain, early satiety and loss of appetite however, also can present with upper gastrointestinal (GI) bleeding and weight loss as in our patient. Macroscopically, LLC is characterized by an ulcerating tumor, with well-delineated margins and pushing borders. Histopathologic findings from our case are similar to those found in all previously reported cases, including characteristics such as a syncytial growth pattern, round-to-large vesicular nuclei, and prominent nucleoli. The nests of epithelial tumor cells are associated with an intense and accentuated lymphoid infiltrate. There is a sharp demarcation between tumor nests and the nondesmoplastic lymphocyte-rich stroma. The lymphocytes can also infiltrate into cancer cell nests, and epithelioid granulomas are sometimes observed within the lymphoid stroma. Invariably, there are more infiltrating lymphocytes than tumor cells. Accurate diagnosis is aided by immunohistochemical staining for a panel of epithelial markers and common leukocyte antigens. Generally, immunohistochemical staining shows nests that are positive for cytokeratin, carcinoembryonic antigen, and epithelial membrane antigen, suggesting epithelial origin, and the interstitial lymphoid tissue, or T lymphocyte clones.  The in situ hybridization for EBV-encoded small RNAs (EBER-1 and 2) shows an intensive nuclear hybridization signal corresponding to the carcinoma cells. No EBV hybridization signal is evident in the adjacent non-neoplastic gastric mucosa, in the lymphocytes around the tumor cell or in the dissected lymph nodes.

The mechanism by which infection of the gastric epithelial cells occurs is also poorly understood. The EBV receptor, CD21, is not expressed on gastric mucosa, so that the virus may enter the cells through an alternative receptor or direct interaction of gastric epithelial cells with EBV-infected lymphocytes/ oropharyngeal epithelial cells i.e. fusion-mechanism between EBV-infected lymphocytes and epithelial cells. This has been also supported by the fact that co-cultivation of virus producing lymphocytes shows higher efficiency of infection (up to 800-fold) than cell-free infection, therefore, EBV-infected epithelial cells, probably in the neck zone of fundic glands, are likely to initiate clonal growth to develop EBV-associated gastric carcinoma. Atrophic gastritis might induce the infiltration of EBV-carrying lymphocytes to increase the chance of contact with epithelial cells, or the inflammation may produce a cytokine-rich milieu to support the clonal growth of EBV-infected epithelial cells.

EBV is not integrated into the host DNA, but maintains itself as an episomal circular form in the nuclei of infected cells without the production of viral particles. EBV replicates synchronously with the host chromosomes at cell division. The descendent carcinoma cells, therefore, take over EBV-DNA of initially infected cells even at the fully developed stage of carcinoma.

The role of EBV in oncogenesis differs according to the host cell type and the immune status of the host. EBV-associated LLC belongs to the Latency I neoplasms, in which latent gene products are restricted to EBV nuclear antigen I (EBNA1), EBV-encoded small RNA (EBER), latent membrane protein 2A (LMP2A), and BamHI-A rightward transcripts (BARTs).

The primary molecular abnormality in EBV associated LLC of the stomach is global and non-random CpG island methylation in the promoter region of many cancer-related genes (such as LOX, HRASLS, FLNC, HAND1, and THBD). Promoter methylation of the CpG islands, which are CpG dinucleotide-rich areas, 0.5 to 2 kb regions rich in cytosine-guanine dinucleotides and present in the 5 promoter region of approximately 60% of human genes, is usually associated with long-term, irreversible epigenetic silencing of X-linked and imprinted genes. E-cadherin is also an important protein in carcinogenesis of the stomach.  Studies have shown that the abnormality of E-cadherin expression caused by the aberrant methylation of the E-cadherin gene promotor is closely associated with the development of EBV-associated gastric carcinomas. Studies have also shown that p53 protein is overexpressed in in the tumor cells, suggestive of p53 mutations.

Our patient did present at a later tumor stage (T) at diagnosis (T3) and with lymph-vascular invasion, in contrast to that seen in most case reports. LLC rarely present with very advanced T stage such as T3 and T4, but more often present with greater than T1 stage (T2) and has less propensity to involve the lymph nodes. However, LLC is known to have a favorable prognosis compared with that of ordinary gastric adenocarcinoma with the five-year survival rate being 83%. Some authors believe this better prognosis is ascribed to the lymphoid reaction of the body because abundant lymphocyte infiltration may prevent spread of neoplastic cells through the gastric wall to lymph nodes or adjacent tissue. Surgical operation is considered to be an important treatment option for LLC. However, the operative procedure is inconsistent. Most cases are diagnosed as undifferentiated gastric cancers preoperatively, so the patient would receive subtotal or total gastrectomy with lymphadenectomy.

Our patient has been doing well since his surgery in 2014 and does not report of any abdominal problems so far.

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