“You’ve got to know when to hold ‘em, know when to fold ‘em”: ovarian cancer risk reduction in patients with endometriosis

Abstract

The great Kenny Rogers once sang, “You’ve got to know when to hold ‘em, know when to fold ‘em, know when to walk away, and know when to run.” Many find these lyrics to be an allegory for life’s dilemmas, and one place this message may hold particular relevance is in the operating room. Take endometriosis surgery, for example. Surgeons must decide when to offer surgery, what to do during the procedure, and when to end the case, all the while weighing the risks and benefits of each decision on the outcome for the patient. In the absence of data, these decisions can sometimes be made arbitrarily. But over time, as we accumulate data to fill the gaps in our knowledge, surgical management decisions are becoming more and more based on evidence and less on our gut instinct.In this issue of Fertility and Sterility, Hermens et al. help to fill one of these knowledge gaps by performing a retrospective nationwide cohort study using the Dutch registry of histopathology and cytopathology to evaluate the incidence of ovarian cancer in patients with histologically proven endometriosis after a bilateral salpingo-oophorectomy (BSO) against two comparator groups: women with histologically proven endometriosis who did not have a BSO (endometriosis control), and women with a diagnosis of benign dermal nevus to represent the general population of women included in the registry who did not have histologically proven endometriosis (nevus control) (1Hermens M. van Altena A.M. van Vliet H.A. Siebers A.G. Bekkers R.L. Ovarian cancer incidence after bilateral salpingo-oophorectomy in women with histological proven endometriosis.Fertil Steril. 2022; 117: 938-945Scopus (2) Google Scholar).Compared with the 1.3% lifetime risk of ovarian cancer in the general population, patients with endometriosis have a 2–3 times increased odds of developing epithelial ovarian cancer, particularly the low-grade serous (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.39–3.20), endometrioid (OR, 2.04; 95% CI, 1.67–2.48), and clear-cell (OR, 3.05; 95% CI, 2.43–3.84) subtypes (2Pearce C.L. Templeman C. Rossing M.A. Lee A. Near A.M. Webb P.M. et al.Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies.Lancet Oncol. 2012; 13: 385-394Abstract Full Text Full Text PDF PubMed Scopus (627) Google Scholar). When oophorectomy is considered in a patient with endometriosis, it is generally an attempt at definitive treatment for endometriosis symptoms. However, BSO has been suggested as a risk-reducing strategy to prevent epithelial ovarian and fallopian tube cancers in patients who are considered to be at high risk; it is typically reserved for patients with BRCA1/2 mutations, Lynch syndrome, or other gene mutations known to increase the risk of ovarian cancer. With this in mind, given the potential increase in the risk of ovarian cancer in patients with endometriosis, should BSO also be considered in these patients for reduction of cancer risk?Hermens et al. identified 7,984 women with histologically proven endometriosis who had undergone BSO, with a median follow-up of 16 years. Nine cases (0.1%) of extraovarian (peritoneal) cancer were observed, for a total of 7.28 cases per 100,000 person-years. The age-adjusted incident rate ratio was 0.34 (95% CI, 0.15–0.76) compared with the endometriosis control group (170 ovarian and extraovarian cancers among 42,633 patients [0.4%]), and the age-adjusted incident rate ratio was 0.38 (95% CI, 0.17–0.85) compared with the nevus control group (444 ovarian and extraovarian cancers among 132,535 patients [0.3%]). This resulted in a number of patients with endometriosis needed to treat with BSO to prevent one case of ovarian cancer of 351 (95% CI, 272–591) (1Hermens M. van Altena A.M. van Vliet H.A. Siebers A.G. Bekkers R.L. Ovarian cancer incidence after bilateral salpingo-oophorectomy in women with histological proven endometriosis.Fertil Steril. 2022; 117: 938-945Scopus (2) Google Scholar).It is critical to understand that BSO has long-term implications for overall health. In addition to the potential increase in surgical morbidity, which would be increased in patients with adhesive disease due to endometriosis, long-term health risks include increased risks of all-cause mortality, cardiovascular disease, stroke, chronic kidney disease, and dementia (3Parker W.H. Feskanich D. Broder M.S. Chang E. Shoupe D. Farquhar C.M. et al.Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study.Obstet Gynecol. 2013; 121: 709-716Crossref PubMed Scopus (299) Google Scholar). Based on the all-cause mortality risks, it was estimated that one premature death would occur for every 24 women who had a BSO. Putting this together with the number of endometriosis patients needed to treat with BSO to prevent ovarian cancer, approximately 15 premature deaths would be expected to occur in women with endometriosis who have a BSO to prevent one case of ovarian cancer.After BSO in premenopausal patients, there is good observational evidence that estrogen therapy postoperatively can mitigate many of the long-term health risks associated with surgical menopause (3Parker W.H. Feskanich D. Broder M.S. Chang E. Shoupe D. Farquhar C.M. et al.Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study.Obstet Gynecol. 2013; 121: 709-716Crossref PubMed Scopus (299) Google Scholar). In patients with endometriosis, there may be an increased risk of recurrence of endometriosis with hormone therapy after BSO; however, the risk remains low (3.5%) and should be weighed against the long-term health benefits of hormonal therapy after BSO and surgical menopause (4Matorras R. Elorriaga M.A. Pijoan J.I. Ramón O. Rodríguez-Escudero F.J. Recurrence of endometriosis in women with bilateral adnexectomy (with or without total hysterectomy) who received hormone replacement therapy.Fertil Steril. 2002; 77: 303-308Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar).Does this mean that there is no role for ovarian cancer risk reduction in patients with endometriosis without a negative impact on long-term health? Of course not, and in fact this is a population that is ideal for consideration of an opportunistic salpingectomy for this purpose. Any patient having pelvic surgery who no longer desires fertility is a candidate for an opportunistic salpingectomy. Patients with endometriosis have both an increased likelihood of having pelvic surgery and an increased lifetime risk of ovarian cancer, and surgeons should consider this option to reduce the risks of epithelial ovarian, fallopian tube, and peritoneal cancer in appropriate patients (5Hanley G.E. Pearce C.L. Talhouk A. Kwon J.S. Finlayson S.J. McAlpine J.N. et al.Outcomes From opportunistic salpingectomy for ovarian cancer prevention.JAMA Network Open. 2022; 5e2147343Crossref Scopus (8) Google Scholar). Although Hermens et al. did not evaluate the association between salpingectomy alone and ovarian cancer in this study cohort, it is reasonable to expect that some level of ovarian cancer risk reduction would occur after an opportunistic salpingectomy in this population, which has an increased lifetime risk of ovarian cancer.Overall, although BSO resulted in a reduced risk of ovarian cancer in patients with endometriosis, as would be expected, this study highlights that a large number of patients would need to be treated to prevent one case of ovarian cancer, making BSO an unreasonable strategy for ovarian cancer risk reduction in this population. The long-term health implications of such an intervention must be considered, and when BSO is necessary for disease control, hormone therapy should be discussed. In his ode from “The Gambler,” Kenny Rogers sings that “the secret to survivin’ is knowin’ what to throw away and knowin’ what to keep.” For ovarian cancer risk reduction in patients with endometriosis, surgeons should consider performing bilateral salpingectomy but retaining the ovaries when appropriate to balance cancer risk with overall long-term health. The great Kenny Rogers once sang, “You’ve got to know when to hold ‘em, know when to fold ‘em, know when to walk away, and know when to run.” Many find these lyrics to be an allegory for life’s dilemmas, and one place this message may hold particular relevance is in the operating room. Take endometriosis surgery, for example. Surgeons must decide when to offer surgery, what to do during the procedure, and when to end the case, all the while weighing the risks and benefits of each decision on the outcome for the patient. In the absence of data, these decisions can sometimes be made arbitrarily. But over time, as we accumulate data to fill the gaps in our knowledge, surgical management decisions are becoming more and more based on evidence and less on our gut instinct. In this issue of Fertility and Sterility, Hermens et al. help to fill one of these knowledge gaps by performing a retrospective nationwide cohort study using the Dutch registry of histopathology and cytopathology to evaluate the incidence of ovarian cancer in patients with histologically proven endometriosis after a bilateral salpingo-oophorectomy (BSO) against two comparator groups: women with histologically proven endometriosis who did not have a BSO (endometriosis control), and women with a diagnosis of benign dermal nevus to represent the general population of women included in the registry who did not have histologically proven endometriosis (nevus control) (1Hermens M. van Altena A.M. van Vliet H.A. Siebers A.G. Bekkers R.L. Ovarian cancer incidence after bilateral salpingo-oophorectomy in women with histological proven endometriosis.Fertil Steril. 2022; 117: 938-945Scopus (2) Google Scholar). Compared with the 1.3% lifetime risk of ovarian cancer in the general population, patients with endometriosis have a 2–3 times increased odds of developing epithelial ovarian cancer, particularly the low-grade serous (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.39–3.20), endometrioid (OR, 2.04; 95% CI, 1.67–2.48), and clear-cell (OR, 3.05; 95% CI, 2.43–3.84) subtypes (2Pearce C.L. Templeman C. Rossing M.A. Lee A. Near A.M. Webb P.M. et al.Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies.Lancet Oncol. 2012; 13: 385-394Abstract Full Text Full Text PDF PubMed Scopus (627) Google Scholar). When oophorectomy is considered in a patient with endometriosis, it is generally an attempt at definitive treatment for endometriosis symptoms. However, BSO has been suggested as a risk-reducing strategy to prevent epithelial ovarian and fallopian tube cancers in patients who are considered to be at high risk; it is typically reserved for patients with BRCA1/2 mutations, Lynch syndrome, or other gene mutations known to increase the risk of ovarian cancer. With this in mind, given the potential increase in the risk of ovarian cancer in patients with endometriosis, should BSO also be considered in these patients for reduction of cancer risk? Hermens et al. identified 7,984 women with histologically proven endometriosis who had undergone BSO, with a median follow-up of 16 years. Nine cases (0.1%) of extraovarian (peritoneal) cancer were observed, for a total of 7.28 cases per 100,000 person-years. The age-adjusted incident rate ratio was 0.34 (95% CI, 0.15–0.76) compared with the endometriosis control group (170 ovarian and extraovarian cancers among 42,633 patients [0.4%]), and the age-adjusted incident rate ratio was 0.38 (95% CI, 0.17–0.85) compared with the nevus control group (444 ovarian and extraovarian cancers among 132,535 patients [0.3%]). This resulted in a number of patients with endometriosis needed to treat with BSO to prevent one case of ovarian cancer of 351 (95% CI, 272–591) (1Hermens M. van Altena A.M. van Vliet H.A. Siebers A.G. Bekkers R.L. Ovarian cancer incidence after bilateral salpingo-oophorectomy in women with histological proven endometriosis.Fertil Steril. 2022; 117: 938-945Scopus (2) Google Scholar). It is critical to understand that BSO has long-term implications for overall health. In addition to the potential increase in surgical morbidity, which would be increased in patients with adhesive disease due to endometriosis, long-term health risks include increased risks of all-cause mortality, cardiovascular disease, stroke, chronic kidney disease, and dementia (3Parker W.H. Feskanich D. Broder M.S. Chang E. Shoupe D. Farquhar C.M. et al.Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study.Obstet Gynecol. 2013; 121: 709-716Crossref PubMed Scopus (299) Google Scholar). Based on the all-cause mortality risks, it was estimated that one premature death would occur for every 24 women who had a BSO. Putting this together with the number of endometriosis patients needed to treat with BSO to prevent ovarian cancer, approximately 15 premature deaths would be expected to occur in women with endometriosis who have a BSO to prevent one case of ovarian cancer. After BSO in premenopausal patients, there is good observational evidence that estrogen therapy postoperatively can mitigate many of the long-term health risks associated with surgical menopause (3Parker W.H. Feskanich D. Broder M.S. Chang E. Shoupe D. Farquhar C.M. et al.Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study.Obstet Gynecol. 2013; 121: 709-716Crossref PubMed Scopus (299) Google Scholar). In patients with endometriosis, there may be an increased risk of recurrence of endometriosis with hormone therapy after BSO; however, the risk remains low (3.5%) and should be weighed against the long-term health benefits of hormonal therapy after BSO and surgical menopause (4Matorras R. Elorriaga M.A. Pijoan J.I. Ramón O. Rodríguez-Escudero F.J. Recurrence of endometriosis in women with bilateral adnexectomy (with or without total hysterectomy) who received hormone replacement therapy.Fertil Steril. 2002; 77: 303-308Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Does this mean that there is no role for ovarian cancer risk reduction in patients with endometriosis without a negative impact on long-term health? Of course not, and in fact this is a population that is ideal for consideration of an opportunistic salpingectomy for this purpose. Any patient having pelvic surgery who no longer desires fertility is a candidate for an opportunistic salpingectomy. Patients with endometriosis have both an increased likelihood of having pelvic surgery and an increased lifetime risk of ovarian cancer, and surgeons should consider this option to reduce the risks of epithelial ovarian, fallopian tube, and peritoneal cancer in appropriate patients (5Hanley G.E. Pearce C.L. Talhouk A. Kwon J.S. Finlayson S.J. McAlpine J.N. et al.Outcomes From opportunistic salpingectomy for ovarian cancer prevention.JAMA Network Open. 2022; 5e2147343Crossref Scopus (8) Google Scholar). Although Hermens et al. did not evaluate the association between salpingectomy alone and ovarian cancer in this study cohort, it is reasonable to expect that some level of ovarian cancer risk reduction would occur after an opportunistic salpingectomy in this population, which has an increased lifetime risk of ovarian cancer. Overall, although BSO resulted in a reduced risk of ovarian cancer in patients with endometriosis, as would be expected, this study highlights that a large number of patients would need to be treated to prevent one case of ovarian cancer, making BSO an unreasonable strategy for ovarian cancer risk reduction in this population. The long-term health implications of such an intervention must be considered, and when BSO is necessary for disease control, hormone therapy should be discussed. In his ode from “The Gambler,” Kenny Rogers sings that “the secret to survivin’ is knowin’ what to throw away and knowin’ what to keep.” For ovarian cancer risk reduction in patients with endometriosis, surgeons should consider performing bilateral salpingectomy but retaining the ovaries when appropriate to balance cancer risk with overall long-term health. Incidence of ovarian cancer after bilateral salpingo-oophorectomy in women with histologically proven endometriosisFertility and SterilityVol. 117Issue 5PreviewTo assess the incidence of ovarian cancer in women with histologically proven endometriosis after bilateral salpingo-oophorectomy (BSO). Full-Text PDF