Tumori eredofamiliari: sorveglianza di donne ad alto rischio 14/01/2018 Dott Matteo Generali AUSL Modena Carpi U.O. Ostetricia e Ginecologia
Screening for gynaecologic cancer in genetically predisposed women Female lower genital tract cancers are strongly linked to infection with carcinogenic papilloma viruses Cancers of the upper genital tract are linked to different risk factors, of which family history of related cancers or genetic risk is the strongest independent predictor Hereditary breast and ovarian cancer syndrome HBOC and hereditary nonpolyposis colon cancer syndrome HNPCC are the two most important syndromes responsible for inherited cancers in gynaecology. Genetic testing is available for both these syndromes Hereditary non-polyposis colon cancer syndrome can now be diagnosed more frequently with the use of immunohistochemistry.
Screening for gynaecologic cancer in genetically predisposed women In the early 1990s, the molecular etiology of several hereditary cancers became established One of the best examples of such a scientific discovery and increased awareness in gynecologic cancer has been the discovery of the BRCA1 and BRCA2 genes and identification of the molecular basis of Lynch syndrome (LS) Up to 15% of ovarian and uterine cancers are directly attributable to inherited mutations in high penetrance cancer predisposition genes If genetic risk factors are recognised and correctly managed, the chance of the individual developing and dying from cancer should be lowered
The diagnosis and management of families and individuals with cancer predisposition syndromes are complicated psychology cancer risk evaluation gynaecology clinical genetics counselling prevention and screening Management by a multi-disciplinary team skilled in all the above mentioned aspects is highly recommended Specialist genetic counselling services are not widely available in all parts of the world and, when available, it is often limited to large centres. Genetic testing is unaffordable for most people in the world.
All gynaecologists should have at least basic knowledge of the related cancer syndromes and of cancer risk-management strategies The two important syndromes responsible for most inherited cancers in the gynaecologic organs are: Hereditary breast and ovarian cancer (HBOC) syndrome Hereditary nonpolyposis colon cancer (HNPCC) syndrome, also named Lynch syndrome. The three most common genes involved are MLH1, MSH2 and MSH6, and mutations predispose mainly to gastrointestinal (e.g. colorectal, stomach, small bowel, pancreas), urogynaecologic (e.g. renal, endometrial, ovarian) and brain cancer. Importantly, in women from these families, the most common cancer is endometrial cancer (usually reported as uterine ) followed by colorectal cancer
Family History Markers of genetic predisposition
Disease History Markers of genetic predisposition
Woman with a BRCA1 mutation has approximately 40% risk of developing an ovarian cancer on average, and a woman with a BRCA2 mutation has 11 e 18% risk of developing ovarian cancer. The risk of ovarian cancer for BRCA1 or BRCA2 mutation carriers by age 40 is less than 3% but increases up to 10% by age 50. For women with breast cancer, the 10-year risk of developing a subsequent ovarian cancer is 12.7% for BRCA1 mutation carriers and 6.8% for BRCA2 mutation carriers
Management guideline for women with BRCA 1 or BRCA 2 mutations The three options available for hereditary disease
Ovarian cancer screening is currently usually based upon serum markers followed by imaging in those with abnormal values. Current strategies lack in specificity and have low positive predictive values. In many women, screen-detected cancer is already in stage III, and screening failed to down-stage the disease. Screening for ovarian cancer cannot prevent disease at all, will not detect fallopian tube or peritoneal carcinoma early and, for the reasons stated above, it is seriously doubted whether it will really improve survival significantly in women at high risk for the disease.
Oral contraceptives reduce the incidence of ovarian cancer in the general population. A meta analysis found that OCP halved the risk of ovarian cancer in BRCA1 or BRCA2 mutation carriers. They found no increase in the risk of breast cancer with use of the OCPs formulated after 1975 These data are reassuring for young women needing contraception but do not replace the recommendation for definitive surgical risk reduction at the appropriate age. Beral V, Lancet 2008;371(9609):303e14. Iodice S, Eur J Cancer 2010;46(12):2275e84.
RRSO reduces the risk of ovarian cancer by at least 80% and breast cancer by 50% although there is variation amongst studies suggesting that the risk reduction of ovarian cancer is much greater and the reduction in breast cancer risk may be less. National Comprehensive Cancer Network (NCCN) guidelines recommend: RRSO for BRCA1 mutation carriers between the ages of 35 and 40 or when child bearing is complete. The option of delaying RRSO until age 40-45 in women with BRCA2 mutations may be considered because there appears to be a later average age of onset (approximately 8-10 years) than in women with BRCA1 mutation carriers
Women at Population Risk Undergoing Surgery for Benign Disease, opportunistic bilateral salpingectomy
Management guidelines for the risk of gynecological cancer in Lynch syndrome Inherited endometrial cancer is most commonly associated with Lynch syndrome. The colon and uterus are often affected and, to a lesser extent, the ovaries and stomach. Cancer risk by organ varies by mutation. MLH1 and MSH2 mutation carriers are most susceptible to colon cancer, whereas those with the MSH6 mutation are most at risk for endometrial cancer. Incidences of endometrial and ovarian cancer range from 20% to 60% and 1% to 25%, respectively. The mean age of onset also varies considerably from 42 to 66 years. Furthermore, a woman s family and personal history significantly modifies this risk. As such, appropriate risk-reducing management plans vary greatly by individual
Management guidelines for the risk of gynecological cancer in Lynch syndrome The NCCN does not give a clear recommendation regarding prophylactic surgery in Lynch syndrome. They state only that hysterectomy and BSO should be individualized based on reproductive wishes menopause status, comorbidities, family history, and [affected] gene, as risks for ovarian cancer vary by mutated gene There is no clear evidence to support screening for endometrial cancer by annual pelvic examination and pelvic ultrasound, but annual endometrial sampling is an option. Similarly, screening for ovarian cancer by pelvic ultrasound and serum CA-125 are options. Conclusive benefits of screening for ovarian cancer in women at average and high risk have not been demonstrated; At this time, risk-reducing surgeries include hysterectomy and bilateral salpingooophorectomy followed by hormone replacement therapy and remain the recommendation for women with LS aged 40 years or after childbearing is completed, particularly if the patient is undergoing abdominal surgery for another reason.