Abstract
Lynch syndrome is an autosomal-dominant disorder caused by defective DNA mismatch repair (MMR) genes and is associated with increased risk of malignancies in multiple organs. Small-intestinal adenocarcinomas are common initial manifestations of Lynch syndrome. To define the incidence and characteristics of Lynch syndrome-related small-intestinal adenocarcinomas, meticulous familial and clinical histories were obtained from 195 patients with small-intestinal adenocarcinoma, and MMR protein immunohistochemistry, microsatellite instability, MLH1 methylation, and germline mutational analyses were performed. Lynch syndrome was confirmed in eight patients (4%), all of whom had synchronous/metachronous malignancies without noticeable familial histories. Small-intestinal adenocarcinomas were the first clinical manifestation in 37% (3/8) of Lynch syndrome patients, and second malignancies developed within 5 years in 63% (5/8). The patients with accompanying Lynch syndrome were younger (≤50 years; P=0.04) and more likely to have mucinous adenocarcinomas (P=0.003), and tended to survive longer (P=0.11) than those with sporadic cases. A meticulous patient history taking, MMR protein immunolabeling, and germline MMR gene mutational analysis are important for the diagnosis of Lynch syndrome-related small-intestinal adenocarcinomas. Identifying Lynch syndrome in patients with small-intestinal adenocarcinoma can be beneficial for the early detection and treatment of additional Lynch syndrome-related cancers, especially in patients who are young or have mucinous adenocarcinomas.
Highlights
RESULTSLynch syndrome (LS), which is known as hereditary non-polyposis colorectal cancer syndrome, is a clinically defined cancer-predisposing syndrome
Lynch syndrome is an autosomal-dominant disorder caused by defective DNA mismatch repair (MMR) genes and is associated with increased risk of malignancies in multiple organs
To define the incidence and characteristics of Lynch syndrome-related small-intestinal adenocarcinomas, meticulous familial and clinical histories were obtained from 195 patients with small-intestinal adenocarcinoma, and MMR protein immunohistochemistry, microsatellite instability, MLH1 methylation, and germline mutational analyses were performed
Summary
Lynch syndrome (LS), which is known as hereditary non-polyposis colorectal cancer syndrome, is a clinically defined cancer-predisposing syndrome. The other synchronous or metachronous tumors known to be unrelated to LS included four lung cancers (three adenocarcinomas and one small cell carcinoma), two uterine cervical squamous cell carcinomas, one appendiceal adenocarcinoma, one urinary bladder adenocarcinoma, one testicular tumor of unknown pathology, and one chondrosarcoma of the proximal humerus, as well as a lung adenocarcinoma and a gastric gastrointestinal stromal tumor in one patient After analyzing this information in the context of detailed family histories, 40 SIAC patients were identified with suspected LS based on the revised Bethesda guidelines. 15 cases demonstrated identical loss of MMR protein expression both in the SIAC and the matched synchronous or metachronous tumor. The histologic findings of the LSrelated SIACs were similar to those of the matched synchronous or metachronous colorectal carcinomas (three cases) or gastric cancers (one cases), with comparable histologic types and differentiation patterns.
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