November 2016 - Presented by Dr. Ananya Datta Mitra

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.

 

Selected sources

Watanabe H, Enjoji M, Imai T: Gastric carcinoma with lymphoid stroma: its morphologic characteristic and prognostic correlations. Cancer 1976, 38:232–243.

Torlakovic G, Snover DC, Torlakovic E: Simultaneous EBV-positive lymphoepithelioma-like carcinoma and EBV-negative intestinal type adenocarcinoma in a patient with Helicobacter pylori–associated chronic gastritis. Am J Clin Pathol 2004, 121:237–243.

Horiuchi K, Mishima K, Ohsawa M, et al: Carcinoma of stomach and breast with lymphoid stroma: localization of Epstein Barr virus. J Clin Pathol 1994, 47:538–540.

Corvalan A, Koriyama C, Akiba S, et al: Epstein-Barr virus in gastric carcinoma is associated with localization in the cardia and with a diffuse histology: a study in one area of Chile. Int J Canc 2001, 94:527–530.

Grogg KL, Lohse CM, Pankratz VS, et al: Lymphocyte-rich gastric cancer: association with Epstein-Barr virus, microsatellite instability, histology and survival. Mod Pathol 2003, 16:641–651.

Fukayama M, Ushiku T: Epstein-Barr virus-associated gastric carcinoma. Pathol Res Pract 2011, 207:529–537.

Takada K: Epstein-Barr virus and gastric carcinoma. Mol Pathol 2000, 53:255–261.
Hiroshi S, Akinori N, Masayuki K, et al: Oesophageal and gastric cancer.J Gastroenterol Hepatol 1999, 14:534–539.

Iishita A, Ueyama T, Yamada Y, et al: Clinicopathological study on medullary carcinoma with lymphoid stroma of the stomach. I to Cho (Stomach and Intestine) 1991, 10:1159–1166

Minamoto T, Mai M, Watanabe K, et al: Medullary carcinoma with lymphocytic infiltration of the stomach. Clinicopathologic study of the subpopulations of infiltrating lymphocytes in the tumor. Cancer 1990, 66:945–952.

Shibata D, Tokunaga M, Uemura Y, et al: Association of Epstein-Barr virus with undifferentiated gastric carcinomas with intense lymphoid infiltration, lymphoepithelioma-like carcinoma. Am J Pathol 1991, 139:469–474.

Beek JV, Hausen AZ, Kranenbarg EK, et al: EBV-positive gastric adenocarcinomas: a distinct clinicopathologic entity with a low frequency of lymph node involvement. J Clin Oncol 2004, 22:664–670.

Chang MS, Kim WH, Kim CW, et al: Epstein-Barr virus in gastric carcinomas with lymphoid stroma. Histopathology 2000, 37:309–315.

Kang GH, Lee S, Kim WH, et al: Epstein-Barr virus–positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. Am J Pathol 2002, 160:787–794.

Shibata D, Weiss LM: Epstein-Barr virus–associated gastric adenocarcinoma. Am J Pathol 1992, 140:769–774.

Uemura Y, Tokunaga M, Arikawa J, et al: A unique morphology of Epstein-Barr virus related early gastric carcinoma. Canc Epidemiol Biomarkers Prev 1994, 3:607–611.

Vo QN, Geradts J, Gulley ML, et al: Epstein-Barr virus in gastric adenocarcinomas: association with ethnicity and CDKN2A promoter methylation. J Clin Pathol 2002, 55:669–675.

Osato T, Imai S: Epstein-Barr virus and gastric carcinoma. Semin Canc Biol 1996, 7:175–182.

Kaneda A, Kaminishi M, Yanagihara K, et al: Identification of silencing of nine genes in human gastric cancers. Canc Res 2002, 62:6645–6650.

Hino R, Uozaki H, Murakami N, et al: Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Canc Res 2009, 69:2766–2774.

Chang MS, Uozaki H, Chong JM, et al: CpG island methylation status in gastric carcinoma with and without infection of Epstein-Barr virus. Clin Canc Res 2006, 12:2995–3002.

Lee JH, Park SJ, Abraham SC, et al: Frequent CpG island methylation in precursor lesion and early lesions and early gastric adenocarcinomas. Oncogene 2004, 23:4646–4654.

Chang MS, Lee HS, Kin CW, et al: Clinocopathologic characteristics of Epstein-Barr virus-incorporated gastric cancers in Korea. Pathol Res Pract 2001, 197:395–400.

Chong JM, Fukayama M, Hayashi Y, et al: Microsatellite instability in the progression of gastric carcinoma. Canc Res 1994, 54:4595–4597.

Leung SY, Yuen ST, Chung LP, et al: Microsatellite instability, Epstein Barr virus, mutation of type II transforming growth factor receptor and BAX in gastric carcinomas in Hong Kong Chinese. Br J Canc 1999, 79:582–588.

Ojima H, Fukuda T, Nakajima T, et al: Infrequent overexpression of p53 protein in Epstein-Barr virus–associated gastric carcinomas. Jpn J Canc Res 1997, 88:262–266.

Leung SY, Chau KY, Yuen ST, et al: p53 overexpression is different in Epstein-Barr virus–associated and Epstein-Barr virus–negative carcinoma.Histopathology 1998, 33:311–317.

Fukayama M, Chong JM, Kaizaki Y: Epstein-Barr virus and gastric carcinoma. Gastric Canc 1998, 1:104–114.

Kijima Y, Ishigami S, Hokita S, et al: The comparison of the prognosis between Epstein-Barr virus (EBV)–positive gastric carcinoma and EBV-negative ones. Canc Lett 2003, 200:33–40.

Beghelli S, de Manzoni G, Barbi S, et al: Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery 2006, 139:347–356.