Families containing two or more first- and/or second-degree relatives with EC are designated as showing "familial" cancer clustering. The term familial does not consider age of onset or extrauterine cancers, such as colorectal or ovarian cancer, which if found in combination with EC, are cardinal features of the Lynch syndrome (4). Subsets of familial EC, when pedigrees are more extensively studied, may, in fact, be found to be hereditary.
Hereditary EC, in contrast, is a more precise term that specifies a segregating model of EC transmission within a family pedigree, which is consistent with Mendelian autosomal dominant inheritance. Hereditary EC most commonly occurs in the Lynch syndrome, the cardinal features of which are shown in Table 1. Genetic susceptibility to EC in a specific family might be confirmed by identification of a cancer-associated germline mutation in a mismatch repair (MMR) gene, such as MSH2, MLH1, or MSH6 (2,3).
Hereditary site-specific occurrences of EC have been described (5). However, when diagnosing this so-called "genetic entity," one must constantly search for features of known hereditary syndromes. For example, Fig. 2 is the pedigree of a family in which EC has occurred in three generations (II-3, III-7, and III-10, as IV-5). But notice the later age of onset in the progenitor (II-3) and her sister (II-4), and also ovarian cancer in two individuals (III-4 and IV-8) and breast carcinoma in the proband (III-10).
• Earlier average age of CRC onset than in the general population; the average age of CRC onset in HNPCC is approx 45 years, whereas the average age of onset in sporadic CRC is approx 63 years
• Proximal colon involvement (70% of CRCs arise proximal to the splenic flexure)
• A significant excess of synchronous and metachronous CRCs (approx 25-30% among patients having a second primary CRC within 10 years of surgical resection for initial CRC, if the surgery was anything less than a subtotal colectomy)
• Autosomal dominant inheritance pattern
• Increased risk for malignancy at certain extracolonic sites, foremost of which is endometrial carcinoma, followed by carcinoma of the ovary, stomach, small bowel, hepatobiliary tract, pancreas, upper uro-epithelial tract, and brain
• CRC tumors in HNPCC are more often poorly differentiated, with an excess of mucoid and signet-cell features, show a Crohn's-like reaction, and contain a significant excess of infiltrating lymphocytes within the tumor. MSI is found in most CRC tumors in the Lynch syndrome
• Increased survival from CRC
• Accelerated carcinogenesis and interval CRC; a tiny adenoma may emerge into a carcinoma within 2-3 years, as opposed to 8-10 years in the general population
• Sebaceous adenomas, sebaceous carcinomas, and multiple keratoacanthomas in the Muir-Torre syndrome variant of Lynch syndrome
• The sine qua non, the identification of a germline MMR mutation segregating with syndrome-affected individuals in the family
This raises questions as to whether Lynch syndrome or another hereditary cancer disorder, such as the hereditary breast-ovarian cancer syndrome (6,7) can be dealt with.
EC may occur with other genital cancers, such as ovarian or tubal carcinomas, perhaps as a part of a Mullerian field effect. But with the exception of colorectal carcinomas (8) in the Lynch syndrome, the occurrence with any nongenital malignancy is distinctly uncommon. The lifetime risk of EC in carriers of a Lynch syndrome germline mutation is 40-60% (8,9), whereas Lynch syndrome-related hereditary ECs constitute an estimated 7% of the total number of endometrial malignancies (2,3). Other rare instances of hereditary ECs include Cowden's syndrome, linked to PTEN mutations in chromosome 10, and characterized by autosomal dominant inheritance, multiple hamar-tomatous lesions, and carcinomas of endometrium, breast, and ovaries (10-12). There has also been an anecdotal report of lymphomas with endometrial and ovarian cancers observed in two relatives in the direct genetic lineage (5).
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