Surveillance And Surgical Prophylaxis

An absolute identification of women at increased genetic risk for EC may be difficult in the absence of detailed pedigrees and molecular evidence of which the sine qua non is a cancer-linked MMR gene mutation. Clearly, patients from family pedigrees with tumor spectrums that match the characteristic criteria for HNPCC syndrome are at definably high risk of developing EC. However, unless a woman is delineated by analysis of her extended family cancer pedigree to be an obligatory carrier of the adverse autosomal dominant trait or by DNA testing she is confirmed to carry the known MMR gene mutation associated with cancer in her family, hereditary susceptibility to EC will be little more than a conjecture. Nonetheless, through observations from the forgoing review of the pertinent literature on the hereditary aspects of EC, certain management strategies for individuals known or expected to be at increased genetic risk for this disease can be counseled and recommended.

Besides individuals who are found to carry cancer-associated MMR gene mutations, and family members in a direct line of descent from HNPCC syndrome affected, women who have been diagnosed with CRC at younger ages, and those with multiple cases of colorectal, endometrial, and ovarian cancer in close relatives, should be considered at risk for EC (7). First-degree relatives of patients diagnosed with EC and CRC at younger than 50 years of age must be suspected to be at heightened risk for cancers of the HNPCC syndrome. As it has been seen from the discussion of pathology (supra vide), the typical EC associated with hereditary predisposition is a type I carcinoma, characterized by the presence of ERs and PRs and hyperplastic precursors. Recent studies have demonstrated rather frequent MSI positivity and loss of markers for MMR genes in endometrial hyperplasias and carcinomas, but not in normal endometrium from patients deemed to be at genetic risk for endometrial carcinoma (35,65-67). If these data are substantiated in further and expanded investigations, when practical tests become more commonly available to clinically examine endometrial hyperplasias for evidence of MSI and the loss of MMR gene markers, patients who are members of families with EC clusters may be considered for this testing.

Because of the very early ages at which endometrial and ovarian cancers have been manifested in patients with a proven or a likely increased hereditary risk for these diseases (4,44,45,50,68), it is believed that baseline studies and then interval transvaginal pelvis ultrasound scans and endometrial cytological and histological screening are appropriate, beginning in the fourth decade of life (69,70). Although, the mean and median ages at which endometrial and ovarian cancers have been diagnosed in women from HNPCC kindreds lie in the fifth decade of life (4,44,45,50,68), as long as the uterus and ovaries are retained, surveillance ought to continue with alertness to symptoms and signs and judicious screening well into the eighth decade and beyond because of the persisting risk for gynecological cancers (44,45,50,68). In the context of thorough cancer genetics counseling, prophylactic surgery will be an alternative chosen by some women with high genetic risk for EC (71-73).

Members of HNPCC syndrome kindreds who are shown through DNA testing to carry the deleterious mutations associated with cancer in their families, and those who are demonstrated by pedigree analysis to be obligate mutation carriers, should be offered the consideration of prophylactic surgery. Other women assessed to be at significantly increased risk for EC, by analysis of their pedigrees, and in the future women who may be found to have endometrial hyperplasia with MSI or abnormal MMR gene function may be considered for prophylactic surgery. It is believed that appropriate prophylactic surgery in these patients should include not only hysterectomy but also bilateral salpingo-oophorectomy, because of the high risk for ovarian carcinoma. Additionally, members of HNPCC syndrome kindreds who have already developed cancer of a target organ as young women are, candidates for prophylactic surgery. As it has been noted, besides EC in women, CRC is by far the most frequently encountered malignancy in the Lynch syndrome. Therefore, when CRC is diagnosed and surgically treated in women from HNPCC syndrome families, serious consideration should be given to combining this operation with hysterectomy-salpingo-oophorectomy, if childbearing has been completed or surely by the fifth decade of life. Certainly, no extirpative surgery for EC should be undertaken without a thorough preoperative work-up to rule-out CRC and other target organ cancers of HNPCC syndrome, particularly ovarian carcinoma.

Unless laparotomy is indicated for coexisting indications, when prophylactic hysterectomy-salpingo-oophorectomy is done in women at hereditary risk (71), it has been found that peritoneal exploration is maximized and complications are minimized by employing video-laparoscopic techniques (74,75). These procedures permit meticulous inspection of most of the peritoneal cavity and its organs, collection of fluid for cytology, biopsies of any suspicious lesions, visualization, and dissection of the ovaries and fallopian tubes, and removal of the adnexal organs en bloc with transvaginal hysterectomy (71,76).

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