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Wednesday, July 13, 2016

Surgical prevention of epithelial ovary cancer without oophorectomy: changing the future

Editorial (open access)

 Published online: 12 Jul 2016

 There is a need for prospective studies aimed at evaluating opportunistic bilateral salpingectomy in women without BRCA mutations, in order to obtain more evidence in this regard. In addition, the number of women to be treated with salpingectomy remains to be determined in order to prevent one sporadic EOC and assess its global impact on economic costs.
Ovarian cancer is an important oncologic cause of mortality in developed countries. This trend has been maintained during decades and, as life expectancy increases, the number of cases will also. The pivotal cause of such a negative scenario is related to the ease with which this entity disseminates into the abdominal cavity without presenting specific symptoms or complaints. Certain gene mutations, such as BRCA-1 and BRCA-2, have been related to an increased risk of both ovarian and breast cancer. These patients have classically been managed by bilateral salpingo-oophorectomy (to reduce ovarian cancer risk) and mastectomy (to reduce breast cancer risk). Adnexal specimens from asymptomatic women with germline BRCA mutations show the presence of early Fallopian tube carcinomas or serous tubal intraepithelial carcinomas (STICs)1. These tubal lesions have also been reported among incidental non-uterine carcinomas2, suggesting that STICs are precursors of extrauterine, high-grade, serous carcinomas (ovarian and peritoneal cancers). These STICs are preferentially located at the site of the Fallopian fimbriae, which is closely related to the ovarian surface.
An important issue in analysis is whether bilateral salpingectomy has better or worse global results in the management of women with BRCA mutations as compared to the conventional salpingo-oophorectomy. Harmsen and colleagues3 determined a small difference in cumulative ovarian cancer risk among women of various ages and carrying BRCA 1/2 mutations when risk-reducing salpingectomy with oophorectomy delayed for several years after (two-step procedure) was compared to one-step conventional risk-reducing salpingo-oophorectomy. On the other hand, the available evidence suggests that salpingo-oophorectomy after childbearing is likely also to reduce breast cancer risk despite short-term menopausal hormone therapy (MHT)4. The evidence regarding consequences of long-term MHT in this population is limited5. Nevertheless, prospective clinical trials are ongoing to evaluate the two-step procedure for preventing ovarian cancer6. This two-step approach seeks to avoid earlier estrogenic deficiency and MHT use in an attempt to reduce severe menopause-related symptoms, vaginal dryness, painful intercourse and future increased risk of osteoporosis and cardiovascular disease. At the same time, the presence of STICs in the Fallopian tubes, surgical complications, quality of life and patient satisfaction will also be assessed.
Non-BRCA-related (sporadic) ovarian cancer includes a wide variety of histological types of malignant diseases, although the most prevalent are epithelial ovarian cancers (EOCs). The majority of EOC cases occur in women without hereditary risk factors in their second half of life, and there are no effective screening procedures7. The lack of specific ovarian symptoms or vague symptoms – such as bloating, digestive symptoms or indigestion – are common, and are easily missed or misinterpreted as the results of an advanced peritoneal dissemination, even in the absence of significant ovarian tumor growth. Hence, women are usually diagnosed and treated during clinical stages III or IV when the outcome is associated with high mortality rates. A combination of ultrasound explorations and biochemical marker measurements (CA 125, HE4, serum folate receptor alpha, immunoglobulins and other proteins) has been proposed to improve early diagnosis among women with low ovarian cancer risk; despite this, these tests have not decreased the mortality rate and render too many false-positive results, which in turn lead to unnecessary surgeries8,9. Microarray methods and nanotechnology are also being explored in pilot studies and in small populations, using blood, uterine and Fallopian tube fluids for the early diagnosis and prognostic evaluation of ovarian cancer-related conditions. However, further studies are needed in this area.
There are some clinical circumstances which may reduce non-hereditary-related EOC risk, including the use of various contraceptive methods and/or surgical interventions. Oral contraceptives may reduce the risk of EOC10, perhaps by decreasing the amount of menstrual content which could stimulate Fallopian carcinogenesis. Fallopian tubal ligation and hysterectomy have also been associated with reduced ovarian cancer risk11. The results from two cohorts of the Nurses’ Health Study reported that tubal ligation reduces ovarian cancer risk, particularly non-serous cancer, when carried out before the age of 3512. A large prospective study reported that tubal ligation confers different degrees of benefits in the prevention of ovarian cancer according to histological types (serous, endometrioid, mucinous and clear cell). The prevention of ovarian cancer was greater for high-risk serous, endometrioid and clear-cell tumors while the effect was nil for mucinous type cancer13. The results from a population-based study suggest that salpingectomy may confer a higher reduction of ovarian cancer risk than other sterilization methods14.
Hysterectomy alone (retaining Fallopian tubes and ovaries) may also contribute to reducing future ovarian cancer risk11,12. Opportunistic bilateral salpingectomy during surgery for benign conditions of the genital tract (i.e. uterine myomata) or sterilization has emerged as a probable way of reducing future non-hereditary EOC risk15. Madsen and colleagues16, reporting on a Danish cohort, showed the beneficial effects of tubal salpingectomy in decreasing EOC risk, with the greatest reduction being for endometrioid cancer. Based on the new scenario that ovarian cancer may probably initiate at the Fallopian tubes, opportunistic bilateral salpingectomy in young women may confer the advantage of removing the possible site of origin of the cancer, while maintaining the ovaries, and hence decreasing the side-effects of oophorectomy. This approach may also reduce cases related to inflammatory conditions of the Fallopian tubes. Although the evidence is limited, it seems that opportunistic salpingectomy may reduce the prevalence of ovarian cancer; hence, it should be performed during surgery for benign pelvic or genital conditions, and also in women who do not expect to have further children, instead of just tubal ligation. Prophylactic salpingectomy during laparoscopic, laparotomic or vaginal hysterectomy does not increase morbidity or severity of menopausal symptoms17–19.
There is a need for prospective studies aimed at evaluating opportunistic bilateral salpingectomy in women without BRCA mutations, in order to obtain more evidence in this regard. In addition, the number of women to be treated with salpingectomy remains to be determined in order to prevent one sporadic EOC and assess its global impact on economic costs.

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.


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