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Neuroendocrine carcinomas of the uterine cervix are rare tumors with aggressive behavior. They comprise <4% of cervical carcinomas. They may coexist with both adenocarcinoma and squamous cell carcinoma of cervix. Signet ring carcinoma of cervix is a rarer entity and less than 20 cases have been described in the literature. We present a case of a 34-year-old female who presented with systemic thrombosis, splenic mass and a cervical mass which on biopsy showed divergent differentiation of primitive large cell neuroendocrine carcinoma with signet ring cells. The cervical tumor was positive for human papilloma virus 16/18 by in situ hybridization, confirming cervical origin of the tumor. This unusual presentation and morphology needs to be recognized and appropriately evaluated when patients present with tumors of unknown origin in metastatic sites.

Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features.

Small cell carcinomas of the uterine cervix are rare tumors with an aggressive behavior. Although these tumors can exhibit neuroendocrine differentiation, the criteria for neuroendocrine differentiation are subjective and not well defined. In this study, the authors tentatively defined small cell neuroendocrine carcinoma (SCNEC) as a tumor composed of small cells with at least two of the following: argyrophilic cytoplasm, chromogranin A immunoreactivity, and synaptophysin immunoreactivity. We found 10 cases fulfilling these requirements. Five of the 10 tumors were composed mainly of small ("oat") cells and 5 of mainly larger "intermediate" cells. The majority of both subtypes showed an insular pattern. Three of the 10 SCNECs were pure, whereas the other seven were mixed with adenocarcinoma and/or squamous cell carcinoma or cervical intraepithelial neoplasia. In addition to the definitional markers noted earlier, the tumors were immunoreactive for serotonin (6 cases), somatostatin, gastrin, glucagon, and pancreatic polypeptide. No tumors were immunoreactive for cytokeratin 20. Human papillomavirus (HPV)-18 was detected in all of the pure tumors and both the SCNEC and adenocarcinomatous components in four of the mixed tumors. No other types of HPV were detected. The tumors showed a relatively low frequency of loss of heterozygosity for representative tumor suppressor gene sites; p53 mutations were found in only one case.

Large cell neuroendocrine carcinomas (LCNECs), one of the four newly categorised endocrine tumors of the uterine cervix, are unusual and aggressive tumors. The present report describes a case of LCNEC diagnosed at an early stage and associated with cervical intraepithelial neoplasia (CIN). The LCNEC showed organoid and trabecular growth patterns and was positive for chromogranin and synaptophysin. The CIN lesion was of a high grade and was negative for these neuroendocrine markers. Polymerase chain reaction (PCR) using genomic DNA extracted from archival tissue demonstrated human papillomavirus (HPV) type 16 DNA in both the LCNEC and CIN lesions. These histological, immunohistochemical and PCR findings suggested that the LCNEC lesion was distinct from the CIN lesion and that both resulted from the carcinogenic field effect of HPV 16.