Prophylactic Surgery to Reduce the Risk of Gynecologic Cancers in the Lynch Syndrome
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《新英格兰医药杂志》
ABSTRACT
Background Women with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have a 40 to 60 percent lifetime risk of endometrial cancer and a 10 to 12 percent lifetime risk of ovarian cancer. The benefit of prophylactic gynecologic surgery for women with this syndrome has been uncertain. We designed this study to determine the reduction in the risk of gynecologic cancers associated with prophylactic hysterectomy and bilateral salpingo-oophorectomy in women with the Lynch syndrome.
Methods Three hundred fifteen women with documented germ-line mutations associated with the Lynch syndrome were identified. Women who had undergone prophylactic hysterectomy (61 women) and women who had undergone prophylactic bilateral salpingo-oophorectomy (47 women) were matched with mutation-positive women who had not undergone the procedure in question (210 women for the analysis of endometrial cancer and 223 for the analysis of ovarian cancer). Women who had undergone prophylactic surgery and their matched controls were followed from the date of the surgery until the occurrence of cancer or until the data were censored at the time of the last follow-up visit.
Results There were no occurrences of endometrial, ovarian, or primary peritoneal cancer among the women who had undergone prophylactic surgery. Endometrial cancer was diagnosed in 69 women in the control group (33 percent), for an incidence density of 0.045 per woman-year, yielding a prevented fraction (the proportion of potential new cancers prevented) of 100 percent (95 percent confidence interval, 90 to 100 percent). Ovarian cancer was diagnosed in 12 women in the control group (5 percent), for an incidence density of 0.005 per woman-year, yielding a prevented fraction of 100 percent (95 percent confidence interval, –62 to 100 percent).
Conclusions These findings suggest that prophylactic hysterectomy with bilateral salpingo-oophorectomy is an effective strategy for preventing endometrial and ovarian cancer in women with the Lynch syndrome.
The Lynch syndrome (hereditary nonpolyposis colorectal cancer) is an autosomal dominant cancer-susceptibility syndrome caused by a germ-line mutation in one of the DNA-mismatch repair genes.1,2,3,4 It is associated with an early onset of cancer and the development of multiple types of cancer, including cancer of the colon and rectum, endometrium, ovary, small bowel, ureter, and renal pelvis. The lifetime risk of endometrial cancer for women with the Lynch syndrome is 40 to 60 percent, which equals or exceeds their risk of colorectal cancer. In addition, they have a 10 to 12 percent lifetime risk of ovarian cancer.5,6
Up to the present, data have been lacking on the basis of which to evaluate the efficacy of gynecologic surgery performed to reduce the risk of cancer in women with the Lynch syndrome. In 1997, the Cancer Genetics Studies Consortium reviewed the available evidence regarding the efficacy of prophylactic hysterectomy and bilateral salpingo-oophorectomy and published a consensus statement concluding that there was insufficient evidence for it to recommend whether or not women with the Lynch syndrome should have prophylactic surgery to reduce the risk of gynecologic cancer.7 Despite the lack of evidence, several authors have suggested that hysterectomy with bilateral salpingo-oophorectomy is a reasonable preventive strategy for women with the Lynch syndrome, after they have completed childbearing.8,9,10 We conducted a study to determine whether the risk of gynecologic cancers among women with the Lynch syndrome was reduced after hysterectomy and bilateral salpingo-oophorectomy.
Methods
Study Patients
Approval for this study, with a waiver of informed consent, was obtained from the institutional review board at each of the participating institutions. The records of patients enrolled in hereditary-cancer registries from 1973 to 2004 were reviewed. We identified 380 women with documented MLH1, MSH2, or MSH6 germ-line mutations from registries at Creighton University (284 women), the University of Texas M.D. Anderson Cancer Center (72 women), and the University of California at San Francisco (24 women). Women with genetic variants of unknown functional significance were excluded. The study was based on the 315 women (83 percent of the total) for whom follow-up information was available.
Registry databases and patients' medical records were reviewed to obtain information on demographic characteristics, genetic testing results, and vital status. Surgical information and occurrences of cancer were verified by reviews of medical records, operative notes, and pathology reports.
Endometrial Cancer
To determine whether prophylactic surgery reduced the risk of endometrial cancer, we performed a retrospective cohort analysis of women with germ-line mutations. In this analysis, we compared the outcome among those who had undergone hysterectomy either to prevent cancer or to treat benign conditions with the outcome among women who had not undergone hysterectomy (controls). We matched each woman who had undergone hysterectomy with one or more control women by a method similar to that used by Rebbeck et al.11 Control women were of similar age to the women with whom they were matched (i.e., their dates of birth were within five years of each other), had been treated at the same institutions, and had been alive, with an intact uterus and no history of gynecologic cancer, at the time the women with whom they were matched underwent hysterectomy. Sixty-one women who had undergone hysterectomy, with or without salpingo-oophorectomy, were matched with 210 controls. Forty-four potential controls could not be matched with case women because their dates of birth did not fall within five years of that of any woman who had undergone hysterectomy, and therefore they were not included in the analysis.
Ovarian Cancer
We performed a similar analysis to evaluate the reduction in the risk of ovarian cancer after prophylactic surgery. Women who had undergone bilateral salpingo-oophorectomy for preventive reasons or to treat benign conditions were matched with one or more mutation-positive control women who were of similar age (date of birth within five years), had been treated at the same institution, had not undergone prophylactic bilateral salpingo-oophorectomy, and had been alive, with both ovaries intact and no history of gynecologic cancer, at the time the women with whom they were matched underwent bilateral salpingo-oophorectomy. On the basis of these criteria, 47 women who had undergone prophylactic bilateral salpingo-oophorectomy were matched with 223 controls. Forty-five potential controls could not be matched with case women because their dates of birth did not fall within five years of that of any woman who had undergone bilateral salpingo-oophorectomy, and therefore they were not included in the analysis.
Statistical Analysis
The women who had undergone prophylactic surgery and the controls were followed from the date of the prophylactic surgery until the occurrence of endometrial, ovarian, or primary peritoneal cancer or until the observations were censored as of the date of death or the date of the last contact. The primary end point was the development of endometrial, ovarian, or primary peritoneal cancer. The incidence density12 (the number of cancers divided by the number of years the women were at risk) was calculated for endometrial, ovarian, and primary peritoneal cancer in each group. The prevented fraction12 (÷), or the proportion of potential new cancers prevented, was estimated with the 95 percent confidence interval. The cumulative incidence of cancer was estimated by the method of Kaplan and Meier.13 All analyses were performed with Stata (version 8.0) and S-PLUS 2000 software.
Results
Of the 315 women with germ-line mutations, 61 (19 percent) underwent gynecologic surgery for preventive reasons or to treat benign conditions. Forty-seven of these women underwent both hysterectomy and bilateral salpingo-oophorectomy, and 14 women underwent hysterectomy only. None of the women in our study underwent bilateral salpingo-oophorectomy without hysterectomy. Thirty-eight percent had genetic testing before undergoing prophylactic surgery. The characteristics of the entire study population are shown in Table 1. There were no significant differences among the participating institutions in the proportion of women who underwent prophylactic surgery. There were also no significant differences in the proportions of women with MLH1, MSH2, or MSH6 mutations between the group of women who underwent prophylactic surgery and the group who did not. Eighty-five percent of the women who had undergone prophylactic surgery, and 82 percent of the women who had not, were parous.
Table 1. Characteristics of the 315 Women in the Study Population.
Endometrial Cancer
Of the women who underwent prophylactic hysterectomy, none subsequently had endometrial cancer, as compared with 69 women (33 percent) in the control group (Table 2). The incidence density was 0.000 per woman-year for the women who underwent prophylactic hysterectomy and 0.045 per woman-year for the controls (P<0.001), yielding a prevented fraction of 100 percent (95 percent confidence interval, 90 to 100 percent). The cumulative incidence of endometrial cancer for each group is illustrated in Figure 1. The median age at prophylactic hysterectomy was 41 years (range, 20 to 63), and the median age at the diagnosis of endometrial cancer was 46 years (range, 30 to 69). Four endometrial cancers (6 percent) were diagnosed in women under 35 years of age. The women who underwent prophylactic hysterectomy were followed for an average of 13.3 years (range, 0.5 to 38.0) after surgery, and the controls were followed for an average of 7.4 years (range, 0.1 to 35.0) after the time of the matched woman's surgery. The distribution of patients according to the stage of endometrial cancer at diagnosis is shown in Table 2.
Table 2. Reduction in the Risk of Endometrial Cancer after Prophylactic Hysterectomy.
Figure 1. Cumulative Incidence of Endometrial Cancer among Women with the Lynch Syndrome Who Underwent Prophylactic Hysterectomy and Those Who Did Not.
Among women who did not undergo prophylactic hysterectomy, endometrial cancer developed in 22 of those who had an MLH1 mutation (28 percent), 47 of those with an MSH2 mutation (37 percent), and none of those with an MSH6 mutation. The differences among these figures are not statistically significant. Ninety-two percent of the patients underwent genetic testing after receiving a diagnosis of endometrial cancer. Endometrial cancers were incidentally diagnosed in three women at the time of prophylactic hysterectomy. Two of the patients had stage I disease and one patient had stage II disease. They underwent surgery at 38, 58, and 48 years of age, respectively, and are currently alive, without any evidence of disease, 27, 2, and 4 years after surgery.
At the time of the analysis, 25 women (9 percent) had died. Twenty-two of these women (10 percent) were from the control group and three (5 percent) had undergone prophylactic surgery. The causes of death among the women in the control group were endometrial cancer (three women), ovarian and colon cancer (one woman), colon cancer (seven women), other Lynch syndrome–related cancers (four women), other cancers (two women), cardiac disease (one woman), and unknown (four women). The causes of death for the three women who underwent prophylactic surgery were colon cancer, brain cancer, and bladder cancer.
Ovarian Cancer
Of the 47 women who had undergone bilateral salpingo-oophorectomy at the time of their hysterectomy for cancer prevention or for benign conditions, none subsequently had ovarian cancer, as compared with 12 of the controls (5 percent) (Table 3). One of the women who had ovarian cancer had previously undergone hysterectomy for a benign condition without bilateral salpingo-oophorectomy. The incidence density was 0.000 per woman-year for the women who had undergone surgery and 0.005 per woman-year for the controls (P=0.09). The prevented fraction was 100 percent (95 percent confidence interval, –62 to 100 percent). The cumulative incidence of ovarian cancer for each group is illustrated in Figure 2.
Table 3. Reduction in the Risk of Ovarian Cancer after Prophylactic Bilateral Salpingo-Oophorectomy.
Figure 2. Cumulative Incidence of Ovarian Cancer among Women with the Lynch Syndrome Who Underwent Prophylactic Bilateral Salpingo-Oophorectomy (BSO) and Those Who Did Not.
The median age at prophylactic bilateral salpingo-oophorectomy was 41 years (range, 20 to 58), and the median age at the diagnosis of ovarian cancer was 42 years (range, 31 to 48). Two (17 percent) of the ovarian cancers were diagnosed in women before the age of 35. The average follow-up was 11.2 years (range, 0.5 to 38.0) after surgery among women who had undergone prophylactic bilateral salpingo-oophorectomy and 10.6 years (range, 0.1 to 41.0) after the time of the matched woman's surgery among the control women. The distribution of women according to the stage of ovarian cancer at diagnosis is shown in Table 3.
Among the women who did not undergo prophylactic bilateral salpingo-oophorectomy, ovarian cancer developed in five of those with an MLH1 mutation (6 percent), seven of those with an MSH2 mutation (5 percent), and none of those with an MSH6 mutation (P not significant). None of the women who underwent prophylactic hysterectomy with bilateral salpingo-oophorectomy subsequently had primary peritoneal cancer. Of the 12 cases of ovarian cancer, 3 (25 percent) were synchronous primary cancers of the ovary and endometrium according to the criteria of Scully et al.14 No cases of ovarian cancer were incidentally diagnosed at the time of prophylactic bilateral salpingo-oophorectomy.
Surgical Complications
Surgical complications were noted in 1 of the 61 women who underwent prophylactic surgery (1.6 percent). The patient was a 27-year-old woman who had received a diagnosis of rectal carcinoma two years previously and had been treated by rectosigmoid resection with colostomy and creation of a Hartmann's pouch, followed by radiation therapy. At the time of prophylactic abdominal hysterectomy with bilateral salpingo-oophorectomy, a ureteral injury occurred and was repaired. The patient subsequently had a ureterovaginal fistula as well as a ureteroenteral fistula to the Hartmann's pouch and underwent a ureteroneocystostomy. She later had a rectovaginal fistula, which she decided not to have repaired.
Metachronous Colorectal and Endometrial or Ovarian Cancer
In our cohort, 107 women (34 percent) received a diagnosis of colorectal cancer. Forty-one patients had synchronous (3 patients) or metachronous (38 patients) colorectal cancer and endometrial or ovarian cancer (32 and 9 patients, respectively). The median age at the diagnosis of colorectal cancer was 47 years (range, 26 to 77). Five of the 41 women (12 percent) were 35 years old or younger, 6 (15 percent) were 36 to 40 years of age, 5 (12 percent) were 41 to 45 years of age, and 25 (61 percent) were over the age of 45. Twenty-one of these 41 women (51 percent) received a diagnosis of gynecologic cancer after receiving a diagnosis of and undergoing surgery for colorectal cancer. The median time between the diagnoses of colon cancer and gynecologic cancer was 5 years (range, 1 to 25).
Discussion
This study provides evidence of a benefit of prophylactic hysterectomy and bilateral salpingo-oophorectomy in preventing gynecologic cancers in women with the Lynch syndrome. In our cohort, there were no new cases of endometrial or ovarian cancer among the women who underwent prophylactic surgery. The reduction in the number of cancer cases was statistically significant for endometrial cancer but not for ovarian cancer; however, the power of the latter comparison was limited by the small number of ovarian cancers diagnosed in our cohort.
The median age at diagnosis was 46 years for endometrial cancer and 42 years for ovarian cancer. These numbers are consistent with those in previous studies of women with the Lynch syndrome that have found a mean age at diagnosis of 48 to 49 years for endometrial cancer15,16 and 42 years for ovarian cancer,17 with the majority of cancers diagnosed in women after the age of 35. These findings support consideration of prophylactic hysterectomy and bilateral salpingo-oophorectomy in women with the Lynch syndrome after the age of 35, or once childbearing has been completed.
There is currently limited information on the efficacy of surveillance in reducing the risk of endometrial and ovarian cancer in women with the Lynch syndrome.18,19 Current screening guidelines for gynecologic cancer recommend annual pelvic examinations, transvaginal ultrasonography, endometrial biopsy, and measurements of serum CA-125 levels beginning at 25 to 35 years of age,7 but controlled studies are lacking to support these methods in young premenopausal women. Information regarding screening for endometrial and ovarian cancer was not available for our cohort. Further research is needed to determine the efficacy of these screening methods in comparison with prophylactic surgery in reducing morbidity and mortality from endometrial and ovarian cancer in women with the Lynch syndrome.
The disadvantages of prophylactic hysterectomy and bilateral salpingo-oophorectomy include surgical complications and premature menopause. The most common complications associated with hysterectomy and bilateral salpingo-oophorectomy are bleeding, infection, and injuries to the urinary tract and bowel. In our study, the surgical complication rate was 1.6 percent. This figure is consistent with previously published complication rates of 1 to 9 percent associated with hysterectomy and bilateral salpingo-oophorectomy for benign conditions.20,21,22 In premenopausal women, bilateral salpingo-oophorectomy results in premature menopause, with attendant symptoms (including hot flashes, vaginal dryness, sexual dysfunction, and sleep disturbances) and an increased risk of osteoporosis.23,24,25 Many of these conditions can usually be managed with hormonal or nonhormonal medications.26 Information regarding these side effects was not available for our cohort.
None of the women in our cohort received a diagnosis of primary peritoneal cancer after prophylactic bilateral salpingo-oophorectomy; however, our sample size and follow-up time were limited. Previous studies involving women with BRCA mutations have reported an incidence of primary peritoneal cancer after prophylactic bilateral salpingo-oophorectomy of 0.8 to 1.0 percent.11,27 The risk of primary peritoneal cancer among women with the Lynch syndrome after prophylactic bilateral salpingo-oophorectomy remains uncertain.
Three women who underwent prophylactic hysterectomy were found to have occult endometrial carcinomas at the time of surgery. This finding emphasizes the need to maintain a high index of suspicion during prophylactic surgery in women with the Lynch syndrome.28 Preoperative assessment with endometrial biopsy, transvaginal ultrasonography, and measurement of CA-125 levels should be considered. The uterus and ovaries should be carefully assessed at the time of surgery; the pathologist should be advised of the high risk of endometrial and ovarian cancer, and the specimens should be carefully examined intraoperatively, with frozen sections obtained if indicated. The surgeon should be prepared to perform a complete staging operation, if necessary.
In our cohort, 41 of 315 women (13 percent) received a diagnosis of synchronous or metachronous colorectal cancer and endometrial or ovarian cancer. Thirty-six of these women (88 percent) were older than 35 years at the time of their diagnosis of colorectal cancer. In 21 of these women, the gynecologic cancer was diagnosed after the woman had undergone treatment for colorectal cancer and could have been prevented if prophylactic hysterectomy and bilateral salpingo-oophorectomy had been performed at the time of surgery for colorectal cancer.
Vasen et al.15 evaluated the lifetime cancer risks associated with different gene mutations in 138 families in which the Lynch syndrome occurred. They found the risks of both endometrial cancer and ovarian cancer to be higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the differences were not statistically significant. Similarly, we did not detect significant differences in the incidence of endometrial or ovarian cancer among women with MLH1, MSH2, and MSH6 mutations, but the power of this analysis was limited by our small sample size.
A limitation of our study is that the data were collected retrospectively. Many of the women in our cohort underwent prophylactic surgery or received a diagnosis of cancer before they had undergone genetic testing. We did not have information on body-mass index or other risk factors for gynecologic cancers. In addition, we were unable to assess the effects of prophylactic surgery on survival and on deaths related to gynecologic cancer. Further studies with longer follow-up will be needed to assess the differences in survival between women who undergo prophylactic gynecologic surgery and those who do not.
In summary, this study provides evidence of the efficacy of prophylactic surgery in preventing gynecologic cancers in women with the Lynch syndrome. Preoperative counseling should address the trade-offs between the reduction in the risk of cancer and the risks and side effects of surgery, as well as the uncertainties regarding surveillance of gynecologic cancer as an alternative management approach.
Supported in part by a grant from the National Cancer Institute (N01-CN-05127).
No potential conflict of interest relevant to this article was reported.
We are indebted to Dr. Patrick M. Lynch, Dr. Russell R. Broaddus, and the Lynch syndrome registry at the University of Texas M.D. Anderson Cancer Center; to Mrs. Jane F. Lynch, Mr. William C. Dowart, and the Creighton University Lynch syndrome registry; and to Dr. Jonathan P. Terdiman, Ms. Amie M. Blanco, and the University of California at San Francisco Colorectal Cancer Prevention Program Familial Gastrointestinal Cancer Registry.
Source Information
From the Departments of Gynecologic Oncology (K.M.S., P.T.S., K.G.W., S.G.B.-R., C.C.S., B.M.S., D.M.G., K.H.L.), Biostatistics and Applied Mathematics (M.F.M.), and Clinical Cancer Genetics (M.S.D.), the University of Texas M.D. Anderson Cancer Center, Houston; the Department of Preventive Medicine, Creighton University, Omaha, Nebr. (H.T.L., M.B.C.); and the Departments of Gynecologic Oncology (L.C., K.Y.Y., M.M.R.) and Medicine (P.G.C.), University of California at San Francisco, San Francisco.
Address reprint requests to Dr. Lu at the Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, P.O. Box 301439, Unit 1362, Houston, TX 77230-1439, or at khlu@mdanderson.org.
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Bertagnolli MM. Surgical prevention of cancer. J Clin Oncol 2005;23:324-332.
Lynch HT, Watson P, Shaw TG, et al. Clinical impact of molecular genetic diagnosis, genetic counseling, and management of hereditary cancer. Part II: Hereditary nonpolyposis colorectal carcinoma as a model. Cancer 1999;86:Suppl 11:2457-2463.
Lu KH, Dinh M, Kohlmann W, et al. Gynecologic cancer as a "sentinel cancer" for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol 2005;105:569-574.
Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346:1616-1622.
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Vasen HF, Stormorken A, Menko FH, et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol 2001;19:4074-4080.
Boks DE, Trujillo AP, Voogd AC, Morreau H, Kenter GG, Vasen HF. Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. Int J Cancer 2002;102:198-200.
Watson P, Butzow R, Lynch HT, et al. The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2001;82:223-228.
Dove-Edwin I, Boks D, Goff S, et al. The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer 2002;94:1708-1712.
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Kovac SR. Hysterectomy outcomes in patients with similar indications. Obstet Gynecol 2000;95:787-793.
Weber AM, Lee JC. Use of alternative techniques of hysterectomy in Ohio, 1988-1994. N Engl J Med 1996;335:483-489.
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Prior JC, Vigna YM, Wark JD, et al. Premenopausal ovariectomy-related bone loss: a randomized, double-blind, one-year trial of conjugated estrogen or medroxyprogesterone acetate. J Bone Miner Res 1997;12:1851-1863.
Graziottin A, Basson R. Sexual dysfunction in women with premature menopause. Menopause 2004;11:766-777.
Menopause and the perimenopausal transition. In: Speroff L, Glass RH, Kase NG. Clinical gynecologic endocrinology and infertility. Baltimore: Lippincott Williams & Wilkins, 1999:662-7.
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Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002;346:1609-1615.
Chung L, Broaddus R, Crozier M, Luthraa R, Levenback C, Lu K. Unexpected endometrial cancer at prophylactic hysterectomy in a woman with hereditary nonpolyposis colon cancer. Obstet Gynecol 2003;102:1152-1155.(Kathleen M. Schmeler, M.D)
Background Women with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have a 40 to 60 percent lifetime risk of endometrial cancer and a 10 to 12 percent lifetime risk of ovarian cancer. The benefit of prophylactic gynecologic surgery for women with this syndrome has been uncertain. We designed this study to determine the reduction in the risk of gynecologic cancers associated with prophylactic hysterectomy and bilateral salpingo-oophorectomy in women with the Lynch syndrome.
Methods Three hundred fifteen women with documented germ-line mutations associated with the Lynch syndrome were identified. Women who had undergone prophylactic hysterectomy (61 women) and women who had undergone prophylactic bilateral salpingo-oophorectomy (47 women) were matched with mutation-positive women who had not undergone the procedure in question (210 women for the analysis of endometrial cancer and 223 for the analysis of ovarian cancer). Women who had undergone prophylactic surgery and their matched controls were followed from the date of the surgery until the occurrence of cancer or until the data were censored at the time of the last follow-up visit.
Results There were no occurrences of endometrial, ovarian, or primary peritoneal cancer among the women who had undergone prophylactic surgery. Endometrial cancer was diagnosed in 69 women in the control group (33 percent), for an incidence density of 0.045 per woman-year, yielding a prevented fraction (the proportion of potential new cancers prevented) of 100 percent (95 percent confidence interval, 90 to 100 percent). Ovarian cancer was diagnosed in 12 women in the control group (5 percent), for an incidence density of 0.005 per woman-year, yielding a prevented fraction of 100 percent (95 percent confidence interval, –62 to 100 percent).
Conclusions These findings suggest that prophylactic hysterectomy with bilateral salpingo-oophorectomy is an effective strategy for preventing endometrial and ovarian cancer in women with the Lynch syndrome.
The Lynch syndrome (hereditary nonpolyposis colorectal cancer) is an autosomal dominant cancer-susceptibility syndrome caused by a germ-line mutation in one of the DNA-mismatch repair genes.1,2,3,4 It is associated with an early onset of cancer and the development of multiple types of cancer, including cancer of the colon and rectum, endometrium, ovary, small bowel, ureter, and renal pelvis. The lifetime risk of endometrial cancer for women with the Lynch syndrome is 40 to 60 percent, which equals or exceeds their risk of colorectal cancer. In addition, they have a 10 to 12 percent lifetime risk of ovarian cancer.5,6
Up to the present, data have been lacking on the basis of which to evaluate the efficacy of gynecologic surgery performed to reduce the risk of cancer in women with the Lynch syndrome. In 1997, the Cancer Genetics Studies Consortium reviewed the available evidence regarding the efficacy of prophylactic hysterectomy and bilateral salpingo-oophorectomy and published a consensus statement concluding that there was insufficient evidence for it to recommend whether or not women with the Lynch syndrome should have prophylactic surgery to reduce the risk of gynecologic cancer.7 Despite the lack of evidence, several authors have suggested that hysterectomy with bilateral salpingo-oophorectomy is a reasonable preventive strategy for women with the Lynch syndrome, after they have completed childbearing.8,9,10 We conducted a study to determine whether the risk of gynecologic cancers among women with the Lynch syndrome was reduced after hysterectomy and bilateral salpingo-oophorectomy.
Methods
Study Patients
Approval for this study, with a waiver of informed consent, was obtained from the institutional review board at each of the participating institutions. The records of patients enrolled in hereditary-cancer registries from 1973 to 2004 were reviewed. We identified 380 women with documented MLH1, MSH2, or MSH6 germ-line mutations from registries at Creighton University (284 women), the University of Texas M.D. Anderson Cancer Center (72 women), and the University of California at San Francisco (24 women). Women with genetic variants of unknown functional significance were excluded. The study was based on the 315 women (83 percent of the total) for whom follow-up information was available.
Registry databases and patients' medical records were reviewed to obtain information on demographic characteristics, genetic testing results, and vital status. Surgical information and occurrences of cancer were verified by reviews of medical records, operative notes, and pathology reports.
Endometrial Cancer
To determine whether prophylactic surgery reduced the risk of endometrial cancer, we performed a retrospective cohort analysis of women with germ-line mutations. In this analysis, we compared the outcome among those who had undergone hysterectomy either to prevent cancer or to treat benign conditions with the outcome among women who had not undergone hysterectomy (controls). We matched each woman who had undergone hysterectomy with one or more control women by a method similar to that used by Rebbeck et al.11 Control women were of similar age to the women with whom they were matched (i.e., their dates of birth were within five years of each other), had been treated at the same institutions, and had been alive, with an intact uterus and no history of gynecologic cancer, at the time the women with whom they were matched underwent hysterectomy. Sixty-one women who had undergone hysterectomy, with or without salpingo-oophorectomy, were matched with 210 controls. Forty-four potential controls could not be matched with case women because their dates of birth did not fall within five years of that of any woman who had undergone hysterectomy, and therefore they were not included in the analysis.
Ovarian Cancer
We performed a similar analysis to evaluate the reduction in the risk of ovarian cancer after prophylactic surgery. Women who had undergone bilateral salpingo-oophorectomy for preventive reasons or to treat benign conditions were matched with one or more mutation-positive control women who were of similar age (date of birth within five years), had been treated at the same institution, had not undergone prophylactic bilateral salpingo-oophorectomy, and had been alive, with both ovaries intact and no history of gynecologic cancer, at the time the women with whom they were matched underwent bilateral salpingo-oophorectomy. On the basis of these criteria, 47 women who had undergone prophylactic bilateral salpingo-oophorectomy were matched with 223 controls. Forty-five potential controls could not be matched with case women because their dates of birth did not fall within five years of that of any woman who had undergone bilateral salpingo-oophorectomy, and therefore they were not included in the analysis.
Statistical Analysis
The women who had undergone prophylactic surgery and the controls were followed from the date of the prophylactic surgery until the occurrence of endometrial, ovarian, or primary peritoneal cancer or until the observations were censored as of the date of death or the date of the last contact. The primary end point was the development of endometrial, ovarian, or primary peritoneal cancer. The incidence density12 (the number of cancers divided by the number of years the women were at risk) was calculated for endometrial, ovarian, and primary peritoneal cancer in each group. The prevented fraction12 (÷), or the proportion of potential new cancers prevented, was estimated with the 95 percent confidence interval. The cumulative incidence of cancer was estimated by the method of Kaplan and Meier.13 All analyses were performed with Stata (version 8.0) and S-PLUS 2000 software.
Results
Of the 315 women with germ-line mutations, 61 (19 percent) underwent gynecologic surgery for preventive reasons or to treat benign conditions. Forty-seven of these women underwent both hysterectomy and bilateral salpingo-oophorectomy, and 14 women underwent hysterectomy only. None of the women in our study underwent bilateral salpingo-oophorectomy without hysterectomy. Thirty-eight percent had genetic testing before undergoing prophylactic surgery. The characteristics of the entire study population are shown in Table 1. There were no significant differences among the participating institutions in the proportion of women who underwent prophylactic surgery. There were also no significant differences in the proportions of women with MLH1, MSH2, or MSH6 mutations between the group of women who underwent prophylactic surgery and the group who did not. Eighty-five percent of the women who had undergone prophylactic surgery, and 82 percent of the women who had not, were parous.
Table 1. Characteristics of the 315 Women in the Study Population.
Endometrial Cancer
Of the women who underwent prophylactic hysterectomy, none subsequently had endometrial cancer, as compared with 69 women (33 percent) in the control group (Table 2). The incidence density was 0.000 per woman-year for the women who underwent prophylactic hysterectomy and 0.045 per woman-year for the controls (P<0.001), yielding a prevented fraction of 100 percent (95 percent confidence interval, 90 to 100 percent). The cumulative incidence of endometrial cancer for each group is illustrated in Figure 1. The median age at prophylactic hysterectomy was 41 years (range, 20 to 63), and the median age at the diagnosis of endometrial cancer was 46 years (range, 30 to 69). Four endometrial cancers (6 percent) were diagnosed in women under 35 years of age. The women who underwent prophylactic hysterectomy were followed for an average of 13.3 years (range, 0.5 to 38.0) after surgery, and the controls were followed for an average of 7.4 years (range, 0.1 to 35.0) after the time of the matched woman's surgery. The distribution of patients according to the stage of endometrial cancer at diagnosis is shown in Table 2.
Table 2. Reduction in the Risk of Endometrial Cancer after Prophylactic Hysterectomy.
Figure 1. Cumulative Incidence of Endometrial Cancer among Women with the Lynch Syndrome Who Underwent Prophylactic Hysterectomy and Those Who Did Not.
Among women who did not undergo prophylactic hysterectomy, endometrial cancer developed in 22 of those who had an MLH1 mutation (28 percent), 47 of those with an MSH2 mutation (37 percent), and none of those with an MSH6 mutation. The differences among these figures are not statistically significant. Ninety-two percent of the patients underwent genetic testing after receiving a diagnosis of endometrial cancer. Endometrial cancers were incidentally diagnosed in three women at the time of prophylactic hysterectomy. Two of the patients had stage I disease and one patient had stage II disease. They underwent surgery at 38, 58, and 48 years of age, respectively, and are currently alive, without any evidence of disease, 27, 2, and 4 years after surgery.
At the time of the analysis, 25 women (9 percent) had died. Twenty-two of these women (10 percent) were from the control group and three (5 percent) had undergone prophylactic surgery. The causes of death among the women in the control group were endometrial cancer (three women), ovarian and colon cancer (one woman), colon cancer (seven women), other Lynch syndrome–related cancers (four women), other cancers (two women), cardiac disease (one woman), and unknown (four women). The causes of death for the three women who underwent prophylactic surgery were colon cancer, brain cancer, and bladder cancer.
Ovarian Cancer
Of the 47 women who had undergone bilateral salpingo-oophorectomy at the time of their hysterectomy for cancer prevention or for benign conditions, none subsequently had ovarian cancer, as compared with 12 of the controls (5 percent) (Table 3). One of the women who had ovarian cancer had previously undergone hysterectomy for a benign condition without bilateral salpingo-oophorectomy. The incidence density was 0.000 per woman-year for the women who had undergone surgery and 0.005 per woman-year for the controls (P=0.09). The prevented fraction was 100 percent (95 percent confidence interval, –62 to 100 percent). The cumulative incidence of ovarian cancer for each group is illustrated in Figure 2.
Table 3. Reduction in the Risk of Ovarian Cancer after Prophylactic Bilateral Salpingo-Oophorectomy.
Figure 2. Cumulative Incidence of Ovarian Cancer among Women with the Lynch Syndrome Who Underwent Prophylactic Bilateral Salpingo-Oophorectomy (BSO) and Those Who Did Not.
The median age at prophylactic bilateral salpingo-oophorectomy was 41 years (range, 20 to 58), and the median age at the diagnosis of ovarian cancer was 42 years (range, 31 to 48). Two (17 percent) of the ovarian cancers were diagnosed in women before the age of 35. The average follow-up was 11.2 years (range, 0.5 to 38.0) after surgery among women who had undergone prophylactic bilateral salpingo-oophorectomy and 10.6 years (range, 0.1 to 41.0) after the time of the matched woman's surgery among the control women. The distribution of women according to the stage of ovarian cancer at diagnosis is shown in Table 3.
Among the women who did not undergo prophylactic bilateral salpingo-oophorectomy, ovarian cancer developed in five of those with an MLH1 mutation (6 percent), seven of those with an MSH2 mutation (5 percent), and none of those with an MSH6 mutation (P not significant). None of the women who underwent prophylactic hysterectomy with bilateral salpingo-oophorectomy subsequently had primary peritoneal cancer. Of the 12 cases of ovarian cancer, 3 (25 percent) were synchronous primary cancers of the ovary and endometrium according to the criteria of Scully et al.14 No cases of ovarian cancer were incidentally diagnosed at the time of prophylactic bilateral salpingo-oophorectomy.
Surgical Complications
Surgical complications were noted in 1 of the 61 women who underwent prophylactic surgery (1.6 percent). The patient was a 27-year-old woman who had received a diagnosis of rectal carcinoma two years previously and had been treated by rectosigmoid resection with colostomy and creation of a Hartmann's pouch, followed by radiation therapy. At the time of prophylactic abdominal hysterectomy with bilateral salpingo-oophorectomy, a ureteral injury occurred and was repaired. The patient subsequently had a ureterovaginal fistula as well as a ureteroenteral fistula to the Hartmann's pouch and underwent a ureteroneocystostomy. She later had a rectovaginal fistula, which she decided not to have repaired.
Metachronous Colorectal and Endometrial or Ovarian Cancer
In our cohort, 107 women (34 percent) received a diagnosis of colorectal cancer. Forty-one patients had synchronous (3 patients) or metachronous (38 patients) colorectal cancer and endometrial or ovarian cancer (32 and 9 patients, respectively). The median age at the diagnosis of colorectal cancer was 47 years (range, 26 to 77). Five of the 41 women (12 percent) were 35 years old or younger, 6 (15 percent) were 36 to 40 years of age, 5 (12 percent) were 41 to 45 years of age, and 25 (61 percent) were over the age of 45. Twenty-one of these 41 women (51 percent) received a diagnosis of gynecologic cancer after receiving a diagnosis of and undergoing surgery for colorectal cancer. The median time between the diagnoses of colon cancer and gynecologic cancer was 5 years (range, 1 to 25).
Discussion
This study provides evidence of a benefit of prophylactic hysterectomy and bilateral salpingo-oophorectomy in preventing gynecologic cancers in women with the Lynch syndrome. In our cohort, there were no new cases of endometrial or ovarian cancer among the women who underwent prophylactic surgery. The reduction in the number of cancer cases was statistically significant for endometrial cancer but not for ovarian cancer; however, the power of the latter comparison was limited by the small number of ovarian cancers diagnosed in our cohort.
The median age at diagnosis was 46 years for endometrial cancer and 42 years for ovarian cancer. These numbers are consistent with those in previous studies of women with the Lynch syndrome that have found a mean age at diagnosis of 48 to 49 years for endometrial cancer15,16 and 42 years for ovarian cancer,17 with the majority of cancers diagnosed in women after the age of 35. These findings support consideration of prophylactic hysterectomy and bilateral salpingo-oophorectomy in women with the Lynch syndrome after the age of 35, or once childbearing has been completed.
There is currently limited information on the efficacy of surveillance in reducing the risk of endometrial and ovarian cancer in women with the Lynch syndrome.18,19 Current screening guidelines for gynecologic cancer recommend annual pelvic examinations, transvaginal ultrasonography, endometrial biopsy, and measurements of serum CA-125 levels beginning at 25 to 35 years of age,7 but controlled studies are lacking to support these methods in young premenopausal women. Information regarding screening for endometrial and ovarian cancer was not available for our cohort. Further research is needed to determine the efficacy of these screening methods in comparison with prophylactic surgery in reducing morbidity and mortality from endometrial and ovarian cancer in women with the Lynch syndrome.
The disadvantages of prophylactic hysterectomy and bilateral salpingo-oophorectomy include surgical complications and premature menopause. The most common complications associated with hysterectomy and bilateral salpingo-oophorectomy are bleeding, infection, and injuries to the urinary tract and bowel. In our study, the surgical complication rate was 1.6 percent. This figure is consistent with previously published complication rates of 1 to 9 percent associated with hysterectomy and bilateral salpingo-oophorectomy for benign conditions.20,21,22 In premenopausal women, bilateral salpingo-oophorectomy results in premature menopause, with attendant symptoms (including hot flashes, vaginal dryness, sexual dysfunction, and sleep disturbances) and an increased risk of osteoporosis.23,24,25 Many of these conditions can usually be managed with hormonal or nonhormonal medications.26 Information regarding these side effects was not available for our cohort.
None of the women in our cohort received a diagnosis of primary peritoneal cancer after prophylactic bilateral salpingo-oophorectomy; however, our sample size and follow-up time were limited. Previous studies involving women with BRCA mutations have reported an incidence of primary peritoneal cancer after prophylactic bilateral salpingo-oophorectomy of 0.8 to 1.0 percent.11,27 The risk of primary peritoneal cancer among women with the Lynch syndrome after prophylactic bilateral salpingo-oophorectomy remains uncertain.
Three women who underwent prophylactic hysterectomy were found to have occult endometrial carcinomas at the time of surgery. This finding emphasizes the need to maintain a high index of suspicion during prophylactic surgery in women with the Lynch syndrome.28 Preoperative assessment with endometrial biopsy, transvaginal ultrasonography, and measurement of CA-125 levels should be considered. The uterus and ovaries should be carefully assessed at the time of surgery; the pathologist should be advised of the high risk of endometrial and ovarian cancer, and the specimens should be carefully examined intraoperatively, with frozen sections obtained if indicated. The surgeon should be prepared to perform a complete staging operation, if necessary.
In our cohort, 41 of 315 women (13 percent) received a diagnosis of synchronous or metachronous colorectal cancer and endometrial or ovarian cancer. Thirty-six of these women (88 percent) were older than 35 years at the time of their diagnosis of colorectal cancer. In 21 of these women, the gynecologic cancer was diagnosed after the woman had undergone treatment for colorectal cancer and could have been prevented if prophylactic hysterectomy and bilateral salpingo-oophorectomy had been performed at the time of surgery for colorectal cancer.
Vasen et al.15 evaluated the lifetime cancer risks associated with different gene mutations in 138 families in which the Lynch syndrome occurred. They found the risks of both endometrial cancer and ovarian cancer to be higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the differences were not statistically significant. Similarly, we did not detect significant differences in the incidence of endometrial or ovarian cancer among women with MLH1, MSH2, and MSH6 mutations, but the power of this analysis was limited by our small sample size.
A limitation of our study is that the data were collected retrospectively. Many of the women in our cohort underwent prophylactic surgery or received a diagnosis of cancer before they had undergone genetic testing. We did not have information on body-mass index or other risk factors for gynecologic cancers. In addition, we were unable to assess the effects of prophylactic surgery on survival and on deaths related to gynecologic cancer. Further studies with longer follow-up will be needed to assess the differences in survival between women who undergo prophylactic gynecologic surgery and those who do not.
In summary, this study provides evidence of the efficacy of prophylactic surgery in preventing gynecologic cancers in women with the Lynch syndrome. Preoperative counseling should address the trade-offs between the reduction in the risk of cancer and the risks and side effects of surgery, as well as the uncertainties regarding surveillance of gynecologic cancer as an alternative management approach.
Supported in part by a grant from the National Cancer Institute (N01-CN-05127).
No potential conflict of interest relevant to this article was reported.
We are indebted to Dr. Patrick M. Lynch, Dr. Russell R. Broaddus, and the Lynch syndrome registry at the University of Texas M.D. Anderson Cancer Center; to Mrs. Jane F. Lynch, Mr. William C. Dowart, and the Creighton University Lynch syndrome registry; and to Dr. Jonathan P. Terdiman, Ms. Amie M. Blanco, and the University of California at San Francisco Colorectal Cancer Prevention Program Familial Gastrointestinal Cancer Registry.
Source Information
From the Departments of Gynecologic Oncology (K.M.S., P.T.S., K.G.W., S.G.B.-R., C.C.S., B.M.S., D.M.G., K.H.L.), Biostatistics and Applied Mathematics (M.F.M.), and Clinical Cancer Genetics (M.S.D.), the University of Texas M.D. Anderson Cancer Center, Houston; the Department of Preventive Medicine, Creighton University, Omaha, Nebr. (H.T.L., M.B.C.); and the Departments of Gynecologic Oncology (L.C., K.Y.Y., M.M.R.) and Medicine (P.G.C.), University of California at San Francisco, San Francisco.
Address reprint requests to Dr. Lu at the Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, P.O. Box 301439, Unit 1362, Houston, TX 77230-1439, or at khlu@mdanderson.org.
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