title: The mismatch repair protein status of colorectal small cell neuroendocrine carcinomas.
abstract: Small cell neuroendocrine carcinoma (SCNC) of the colorectum is a rare and highly aggressive malignancy. It can be associated with conventional-type adenocarcinoma, and an overlying adenoma can often be identified. A disproportionate number has been noted to arise in the right colon. Although some phenotypes (eg, mucinous adenocarcinoma) have been shown to be associated with deficient mismatch repair (MMR) and thus microsatellite instability (MSI), the MMR protein status of colorectal SCNCs has not been investigated. This study investigated the status of 3 MMR proteins, hMLH1, hMSH2, and hMSH6, in SCNCs of the colorectum. Fifteen SCNCs were identified on the basis of previous descriptions and the World Health Organization histologic criteria for the diagnosis of pulmonary small cell carcinoma and immunohistochemical evidence of epithelial and neuroendocrine differentiation. Patient age and sex and tumor size and location were recorded. Immunohistochemistry was performed with antibodies to pancytokeratin (cocktail), CD56, neuron specific enolase, synaptophysin, chromogranin, hMLH1, hMSH2, and hMSH6. Patients' ages ranged from 44 to 87 years (mean age = 73 y) and there were 9 men and 6 women. Tumors were located in the right colon (6), sigmoid colon (4), and rectum (3) (the locations of 2 cases were not recorded) and ranged in size from 0.4 to 15 cm in greatest dimension (mean = 6.6 cm). All tumors showed immunoreactivity with antibodies to pancytokeratin and with antibodies to at least 1 neuroendocrine antigen. MMR proteins were intact by immunohistochemistry in all but a single case that had neither an identifiable precursor lesion nor positive internal control (hMLH1 loss). Colorectal SCNCs are rare and are often right-sided. They are aggressive and tend to occur in older individuals. Most colorectal SCNCs have intact MMR proteins, suggesting that they develop secondary to chromosomal instability rather than MSI. Our single case showing potential MMR protein loss suggests that this phenotype may be independent of the developmental pathway (ie, chromosomal instability vs. MSI). This may explain the rare cases of SCNC that have been identified in patients with hereditary nonpolyposis colon cancer.
authors.affiliation: Robert E Fechner Surgical Pathology Laboratory, University of Virginia, Charlottesville, VA, USA. edstelow@yahoo.com
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stelow
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Moskaluk
authors.forename: Stacey E
authors.initials: SE
authors.lastname: Mills
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000096:biosynthesis*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein