Multiple Primary Cancers

Eighteen of the 80 women (22.5%), deemed to be at high risk for HNPCC who were diagnosed with ovarian cancers in the international collaborative study, also had synchronous ECs, and two further patients subsequently developed primary ECs after the diagnosis of ovarian cancer in this group (50). Multiple primary tumors are common findings with hereditary EC (44,48,54-56). Analysis of the NIH-SEER database showed that women with antedating endometrial or ovarian cancers diagnosed before

50 years of age had significantly increased risks for CRC (57). Registry-based studies in Canada also found that the first-degree relatives of women who were diagnosed with double primary CRC and EC younger than age 55, carried a very high relative risk (RR = 30.5, 95%CI = 18.8-46.6) for developing CRC before the age of 55 years (58).

In patients from known or suspected HNPCC kindreds, multiple primary tumors generally are neoplasms that characterize the spectrum of this syndrome, including (besides colorectal, endometrial, and ovarian cancers) especially upper gastrointestinal, hepatobiliary duct, renal pelvis, and ureteral cancers (4,48,59-63). Seventy-five of 113 (61%) EC cases collected from HNPCC registries in seven countries were associated with second primary cancers, 72% of which were CRCs; and in 18/113 (16%) of the EC patients, there were two or more primary cancers (44). When a second primary tumor followed CRC in 1113 patients from the Swedish Family-Cancer Database, 100% of the ECs came from patients that fulfilled the Bethesda criteria for HNPCC syndrome (64). After a previous CRC, the risk for EC was increased 257-fold among the 12 families that fulfilled the Amsterdam criteria for the HNPCC syndrome in this study from the Swedish database (64). Moreover, the first-degree relatives of MMR gene mutation carriers with both primary CRC and EC bore a high relative risk (RR = 23.8, 95%CI = 6.4-61) for EC (56). And, although the risk for EC was lower, it remained significant (RR = 5.4, 95%CI = 2-11.7) in the first-degree relatives of mutation negative probands with both primary CRC and EC (56).

Investigations of EC utilizing some 9.6 million individuals from the Swedish Family-Cancer Database (48), included a subset of 20,000 cases of EC, among which there were 76 families in which both the mother and daughter were affected. This consisted of a familial SIR of 3.19 for daughters and 2.78 for mothers. The risk was inversely related to the age at diagnosis, reaching a risk of almost 10 in daughters who were diagnosed before age of 50 years when their mothers were also diagnosed before that age. The discordant primary cancer site most associated with EC between the two generations was colon, with a SIR of 1.44-1.68. When the maternal EC was diagnosed before age of 50 years, increased SIRs were observed in daughters or sons for rectal, pancreatic, breast, ovarian, and nervous system cancers. Second primary cancers with the highest overall risks in females diagnosed with EC were ovarian and connective tissue cancers with CRCs, also clearly in excess.

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