Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer

INTRODUCTION — Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) refers to individuals and families with a pathogenic germline autosomal dominant mutation in one of the DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) or the EPCAM gene. These individuals are at increased risk for developing a variety of cancers, particularly colorectal, endometrial, and/or ovarian cancer, as shown in the table (table 1). The diagnosis of Lynch syndrome should be suspected in individuals who fulfill Amsterdam criteria (table 2). (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Family history-based criteria'.)

This topic will discuss the risks for endometrial and ovarian cancer in patients with Lynch syndrome, as well as issues related to screening and options for risk-reduction for these cancers. Other important issues related to Lynch syndrome, including clinical findings, diagnosis, identification of individuals at risk, and screening and prevention of cancers other than endometrial and ovarian cancer, are reviewed separately.

●(See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

●(See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management".)

●(See "Gene test interpretation: Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM)".)

RISK FOR ENDOMETRIAL AND OVARIAN CANCER

Risk for endometrial cancer — Lynch syndrome accounts for 2 to 5 percent of all endometrial carcinomas [1-3]. In patients with Lynch syndrome, the lifetime risk of endometrial cancer ranges from 17 to 71 percent for those with MLH1, MSH2, or MSH6 and 13 to 15 percent for those with PMS2, compared with 2 to 3 percent in the general population (table 1). The wide range in lifetime risk of endometrial cancer in Lynch syndrome patients is due, in part, to variation in risk by genotype (table 1). Traditional endogenous and exogenous hormonal risk factors also appear to play a role [4]. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Chronically increased estrogen levels or estrogenic activity'.)

Endometrial cancer is also diagnosed at a younger age in patients with Lynch syndrome [3,5]: in one report, the mean age range was 47 to 55 years for those with MLH1, MSH2, or MSH6 and 49 to 56 years for those with PMS2, compared with a mean age of 60 years in those without Lynch syndrome [5]. Although only 5 percent of endometrial cancer occurs in patients under 40 years of age, in a study of 69 patients with Lynch syndrome-associated endometrial cancer, 18 percent were diagnosed before age 40 years [6].

Clinical features and histology

●Signs and symptoms – As in patients without Lynch syndrome, abnormal uterine bleeding is the typical presenting symptom, and the majority of endometrial cancers are diagnosed at an early stage, with a similar favorable prognosis [6,7]. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Abnormal uterine bleeding' and "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Prognosis'.)

●Uterine location – The distribution of tumor location in the uterus appears to be slightly different in patients with Lynch syndrome. In most patients with endometrial cancer (with or without Lynch syndrome), the tumor arises in the uterine corpus; however, patients with Lynch syndrome appear to have a higher proportion of lower uterine segment tumors, which can be misdiagnosed as cervical adenocarcinoma.

In a series of 133 patients with lower uterine segment endometrial cancer, the prevalence of Lynch syndrome was severalfold higher than that in the overall endometrial cancer population or in young (age <50) endometrial cancer patients (approximately 29, 2, and 9 percent, respectively) [8]. The lower uterine segment tumors were higher grade and more invasive than corpus cancer.

●Histology – The majority of Lynch syndrome-associated endometrial cancers are of endometrioid histology, similar to sporadic endometrial cancer. However, nonendometrioid components, including serous carcinoma, clear cell carcinoma, dedifferentiated carcinoma, and malignant mixed müllerian tumors, have been reported in patients with Lynch syndrome [7,9-11]. (See "Endometrial cancer: Pathology and classification".)

Risk for ovarian cancer — In patients with Lynch syndrome, the lifetime risk of ovarian cancer ranges from 8 to 20 percent in those with MLH1, 12 to 38 percent in those with MSH2, and 1 to 11 percent in those with MSH6, compared with 1.3 percent in the general population (table 1). The wide range in reported lifetime risk is partly because there are fewer data regarding risk for ovarian cancer in patients with Lynch syndrome than for endometrial cancer and partly because there are only a small number of cases in which the mutation type is known.

Ovarian cancer is also diagnosed at a younger age in patients with Lynch syndrome (age 43 to 48 versus age 60) [5,12-16].

Clinical features and histology — Ovarian cancer typically presents in a subacute fashion with signs/symptoms such as pelvic or abdominal pain, bloating, early satiety, constipation, and/or urinary urgency or frequency. An adnexal mass may be discovered during pelvic examination or on imaging. (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis".)

Ovarian cancer in patients with Lynch syndrome differs from the disease in the general population in some ways [5,12-16]:

●It is more likely to be diagnosed at an early stage (stage I or II: 85 versus 30 percent).

●Invasive epithelial cancer is more likely to be well or moderately differentiated (70 versus 50 percent).

●Epithelial carcinoma is the most common histology, as in non-Lynch related ovarian cancer, with a similar distribution of histologic subtypes. However, Lynch syndrome patients show a trend toward an excess of the endometrioid subtype and a lower frequency of nonepithelial histology (approximately 6 versus 16 percent). (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Histopathology".)

●A synchronous or nonsynchronous (ie, metachronous cancer) is common. In a series of 80 patients with Lynch-associated ovarian cancer, 26 percent were diagnosed with endometrial cancer; 35 percent with colorectal cancer; and 7.5 percent with either gastric, small bowel, or urinary tract cancer [12].

The order of diagnosis of synchronous or metachronous cancers is unpredictable. In a series of 117 patients with Lynch syndrome and dual primary cancers, 16 (14 percent) had colorectal and gynecologic cancers (endometrial or ovarian) diagnosed simultaneously [16]. Among the remaining 101 patients, the order of cancer diagnoses was evenly split: 52 were diagnosed with gynecologic cancer before a colorectal cancer diagnosis, and 49 were diagnosed after.

SURVEILLANCE FOR ENDOMETRIAL AND OVARIAN CANCER

Endometrial cancer surveillance — We suggest the following:

●Patients with Lynch syndrome should be informed of their increased risk for endometrial cancer and counseled to promptly seek medical attention for abnormal uterine bleeding, which is the typical presentation for endometrial cancer in both premenopausal and postmenopausal patients.

Symptomatic patients should undergo an endometrial biopsy. (See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Clinical presentation'.)

●For asymptomatic patients, we suggest annual endometrial sampling beginning at age 30 to 35 or 5 to 10 years prior to the earliest age of first diagnosis of Lynch-associated cancer of any kind in the family.

National Comprehensive Cancer Network guidelines suggest consideration of endometrial biopsy every one to two years beginning at age 30 to 35 years [17]; this is consistent with the recommendation of the American College of Obstetricians and Gynecologists [18].

Surveillance is continued until risk-reducing hysterectomy is performed. (See 'Risk-reducing TH-BSO at completion of childbearing' below.)

Evidence — A mortality benefit from endometrial cancer screening is plausible and suggested by limited available data but has not been conclusively proven. Endometrial sampling is the most commonly used screening modality as it is highly sensitive and specific for diagnosis of premalignant and malignant endometrial lesions. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Endometrial biopsy'.)

Few data are available regarding use of endometrial sampling or other approaches to screening in patients with Lynch syndrome. The best available data come from a retrospective study of 175 patients with Lynch syndrome aged ≥35 who underwent surveillance for endometrial cancer [19]. In this study, 9 of the 14 patients who developed endometrial cancer were detected as a result of routine endometrial biopsy; the remaining patients were diagnosed as a result of symptoms at 3 and 31 months after a surveillance visit (n = 2), suspicious cervical cytology (n = 2) and/or thick endometrium on transvaginal ultrasound examination (TVUS) surveillance (n = 4), or prophylactic total hysterectomy at the time of colectomy for colon cancer (n = 1). Surveillance was associated with a nonstatistically significant trend toward diagnosis at an earlier stage and higher 10-year survival (100 versus 92 percent) compared with 83 Lynch syndrome patients with endometrial cancer in the same registry who did not undergo surveillance and were diagnosed after becoming symptomatic. A limitation of this study is that the methods used for surveillance varied among hospitals and clinics: Clinical examination was performed at every visit, TVUS at 94 percent, and endometrial biopsies at 74 percent.

Although endometrial sampling is a minor procedure, it is invasive. An outstanding question is whether TVUS measurement of endometrial thickness would be sufficient surveillance in asymptomatic postmenopausal patients with Lynch syndrome. In this and other observational studies, TVUS for measurement of endometrial thickness had both a high false-positive and false-negative rate, but premenopausal patients were included, and this test performs poorly before menopause since the normal thickness varies widely across the menstrual cycle [19-21]. (See "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Transvaginal ultrasound'.)

Another question is whether endometrial sampling should be combined with hysteroscopy to enhance screening performance [22,23]. Data from randomized trials or well-designed observational studies are needed to answer these questions and potentially alter the surveillance protocol suggested above.

Ovarian cancer surveillance — We consider ovarian cancer screening with an annual pelvic examination and TVUS, with or without cancer antigen (CA 125) every 6 to 12 months, a reasonable option in patients with Lynch syndrome, but not screening is also reasonable given that no screening strategy (CA 125, TVUS, or multimodal testing) has been shown to reduce mortality and all screening strategies are associated with a high rate of false-positive tests and a risk of harm from invasive testing [24-27].

If screening is performed, we suggest starting at age 30 to 35 years or 5 to 10 years prior to the earliest age of first diagnosis of Lynch-associated cancer of any kind in the family. Surveillance is continued indefinitely but varies depending on whether bilateral salpingo-oophorectomy is performed. (See 'Gynecologic follow-up after risk-reducing surgery' below.)

Patients with Lynch syndrome should be counseled about the early nonspecific symptoms of ovarian cancer, which include bloating, increased abdominal size, urinary urgency or frequency, difficulty eating or feeling full, and abdominal or pelvic pain. They are told to contact their clinician if these symptoms occur coexistent with other symptoms, occur almost daily, and/or are more severe than expected. (See "Early detection of epithelial ovarian cancer: Role of symptom recognition".)

Evidence — There are no data regarding the efficacy of ovarian cancer screening with the most common tests, TVUS and CA 125, in patients with Lynch syndrome. Ovarian cancer screening using these tests is not performed in the general population, and reports from surveillance programs using these tests to screen patients at high risk of ovarian cancer due to a genetic predisposition or family history have reported poor performance. Tests evaluated for screening have not detected ovarian cancer at a sufficiently early stage to reduce mortality and have led to unnecessary surgical procedures for false-positive results. These data are reviewed in detail separately. (See "Screening for ovarian cancer".)

STRATEGIES FOR CANCER RISK REDUCTION

Planning — The preferred strategy for prevention of endometrial and ovarian cancer is total hysterectomy with bilateral salpingo-oophorectomy (TH-BSO). This will result in sterility and premature menopause since the procedure is generally performed between ages 35 and 45 years or even sooner if a family member was diagnosed with cancer at a very young age. (See 'Timing' below.)

For this reason, patients with Lynch syndrome should be referred soon after diagnosis to clinicians with expertise in female reproductive endocrinology and gynecologic oncology for counseling regarding gynecologic cancer surveillance and cancer risk reduction, as well as normal fertility, options for fertility preservation, use of assisted reproductive technology and additional options for parenthood, preimplantation genetic testing to prevent implantation of an affected embryo or prenatal diagnosis to determine whether the fetus is affected, and the consequences and treatment of premature menopause [28]. (Refer to individual topic reviews on each subject.)

Risk-reducing TH-BSO at completion of childbearing — Hysterectomy is effective for preventing endometrial cancer in patients with Lynch syndrome. (See 'Evidence' below.)

Prophylactic BSO is generally recommended at the time of hysterectomy, regardless of mutation type. It should be noted that ovarian epithelial neoplasms have both ovarian and extraovarian sites of origin, primarily the fallopian tube, but also the peritoneum [29,30], which is the basis for prophylactic salpingectomy in addition to oophorectomy. (See 'Evidence' below.)

Although the risk for developing ovarian cancer is lower than that for endometrial cancer (table 1) and may be lower in PMS2 carriers, BSO is generally recommended because there is no reliable screening test for ovarian cancer and ovarian cancer is more likely than endometrial cancer to present at an advanced stage and have a poor prognosis. In premenopausal patients, counseling regarding prophylactic BSO should include a discussion of the limited available data regarding lifetime risk of ovarian cancer and risk with specific mutations, the risks associated with premature menopause, and the risks associated with use of hormone replacement therapy. (See "Elective oophorectomy or ovarian conservation at the time of hysterectomy", section on 'Consequences of elective oophorectomy'.)

Patients should also be informed that BSO does not eliminate the risk for peritoneal cancer, but this risk is much lower than for ovarian cancer [31-33]. There is one report of two cases of peritoneal cancer diagnosed 8 and 12 years following BSO in patients with Lynch syndrome [34]. (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer".)

Timing

●Several society guidelines recommend risk-reducing TH-BSO for patients with Lynch syndrome when childbearing is complete and/or by a certain age. Given that the mean age of diagnosis of endometrial cancer in Lynch syndrome is 46 to 54 years, it is reasonable to delay hysterectomy until childbearing is complete and utilize endometrial sampling until hysterectomy is performed [6,7,35,36]. (See 'Endometrial cancer surveillance' above.)

The American College of Obstetricians and Gynecologists, the Society of Gynecologic Oncology, and the American College of Gastroenterology suggest age 40 to 45 years [18,37]; the United States Multi-Society Task Force on Colorectal Cancer and the European Hereditary Tumour Group suggest age 40 years [38,39]; the American Society of Clinical Oncology and the European Society for Medical Oncology suggest age 35 years [40,41]. National Comprehensive Cancer Network guidelines advise that total hysterectomy be considered in patients with Lynch syndrome; no specific age is recommended, and the advice is to individualize decisions based on desire for childbearing, comorbidities, family history, and gene mutation [42].

●Patients with Lynch syndrome who undergo surgery for treatment of colorectal cancer should be offered concurrent prophylactic TH-BSO. However, this decision needs to be individualized, taking into account the patient's childbearing plans and prognosis.

Evidence — The recommendation for hysterectomy and BSO is based, in large part, on data from a large retrospective cohort study including 315 patients with Lynch syndrome that compared outcomes of 61 patients who had undergone prophylactic total hysterectomy and 47 patients who had undergone prophylactic BSO with the outcomes of over 400 mutation-positive patients who had not undergone a procedure (210 for the analysis of endometrial cancer and 223 for the analysis of ovarian cancer) [6]. Median age at surgery was 41 years (range 20 to 63 years), and mean follow-up was 13 years after surgery. The incidence of both endometrial and ovarian cancer was significantly lower in patients who had undergone risk-reducing surgery compared with those who had not.

●No patients who had a hysterectomy developed endometrial cancer, compared with a 33 percent incidence (69 of 210) among controls.

●No patients in the BSO group developed ovarian cancer, compared with a 5 percent incidence (12 of 233) among controls. One ovarian cancer was diagnosed in a patient who had undergone hysterectomy.

Serious surgical morbidity was low: one patient had a ureteral injury.

Cost-effectiveness analyses of risk-reducing strategies for patients with Lynch syndrome also support use of prophylactic surgery rather than surveillance-based approaches [43-45].

Other options

Chemoprevention before completion of childbearing — Patients with Lynch syndrome who have not completed childbearing but are not currently attempting to conceive may reduce their risk of developing endometrial and ovarian cancer by using hormonal contraception (table 3) in addition to ongoing surveillance [4,46-49]. Estrogen-progestin contraceptives reduce the risk of both endometrial and ovarian cancer; progestin-based contraceptives reduce the risk of endometrial cancer. We strongly recommend risk-reducing hysterectomy with BSO after completion of childbearing rather than continuation of hormonal therapy.

Data regarding chemoprevention for gynecologic malignancies specifically in patients with Lynch syndrome are limited. In a study from the Colon Cancer Family Registry including 1128 patients, ever use of hormonal contraception (oral, implant, or injection) for at least one year was associated with a 60 percent reduction in endometrial cancer risk (hazard ratio 0.39, 95% CI 0.23-0.64) [4].

No studies have examined the efficacy of chemoprevention of ovarian cancer specifically in patients with Lynch syndrome. In a meta-analysis of studies of premenopausal patients using oral contraceptive pills for prevention of pregnancy or ovarian cancer, the reduction in ovarian cancer attributable to their use, compared with never users, was approximately 23 to 57 percent [50]. A similar meta-analysis limited to high-risk patients (BRCA1/BRCA2 carriers or strong family history of ovarian cancer) reported a 42 percent risk reduction [51].

Risk-reducing hysterectomy with delayed or no BSO — At completion of childbearing, patients may desire hysterectomy to prevent endometrial cancer but may not want to undergo surgical menopause. These patients may opt to take an estrogen-progestin contraceptive until menopause to inhibit ovulation and then undergo BSO. They may also opt to avoid the morbidity, albeit low, of a second surgical procedure and choose to discontinue the contraceptive at menopause. If BSO is not performed, we would continue ovarian cancer surveillance because the risk of ovarian cancer continues after menopause despite cessation of ovulation.

SURGICAL PROCEDURE

Preoperative assessment — Preoperative assessment before prophylactic total hysterectomy with bilateral salpingo-oophorectomy (TH-BSO) should include the following to exclude occult cancer [6,52]:

●Endometrial biopsy

●Transvaginal ultrasound examination of uterus and adnexa

●Baseline cancer antigen 125 level

●Appropriate nongynecologic cancer screening (see "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management", section on 'Endometrial and ovarian cancer')

Intraoperative procedures — The route of hysterectomy is based on patient characteristics and the surgeon's preference. If possible, minimally invasive surgery should be performed to minimize morbidity. (See "Hysterectomy (benign indications): Selection of surgical route".)

The uterus, ovaries, and bowel should be carefully assessed for evidence of tumor. The pathologist should be advised of the high risk of endometrial and ovarian cancer and the specimens carefully examined intraoperatively, with frozen sections performed if indicated. The surgeon should be prepared to perform a complete staging operation in the case of occult carcinoma. (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer" and "Endometrial carcinoma: Staging and surgical treatment".)

Side effects and complications of surgery — In premenopausal patients, TH-BSO results in sterility and premature menopause. These side effects and the complications associated with the surgery are the same as in patients undergoing the same surgery for other indications and are reviewed separately. Hormone therapy is also reviewed separately.

●Side effects of hysterectomy

●Complications of hysterectomy

●Consequences of premature menopause and hormone therapy (see "Elective oophorectomy or ovarian conservation at the time of hysterectomy", section on 'Consequences of elective oophorectomy' and "Elective oophorectomy or ovarian conservation at the time of hysterectomy", section on 'Role of estrogen therapy after hysterectomy with oophorectomy')

GYNECOLOGIC FOLLOW-UP AFTER RISK-REDUCING SURGERY — Hysterectomy removes the need for endometrial cancer surveillance, but the development of ovarian, fallopian tube, and primary peritoneal cancer remains a concern.

●For patients who have undergone risk-reducing hysterectomy with bilateral salpingo-oophorectomy (BSO), we screen for the development of primary peritoneal cancer by performing an annual pelvic examination and checking a cancer antigen 125 (CA 125) level every 6 to 12 months indefinitely.

Not screening is also a reasonable option. Screening with CA 125, transvaginal ultrasound (TVUS), or multimodal testing has not been shown to reduce mortality and is associated with a high rate of false-positive tests and a risk of harm from invasive testing. (See "Screening for ovarian cancer".)

●For patients who have undergone a risk-reducing hysterectomy without BSO, we perform an annual pelvic examination and TVUS examination, and check CA 125 every 6 to 12 months.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine cancer".)

SUMMARY AND RECOMMENDATIONS

●Clinical significance – Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) is an autosomal dominant cancer susceptibility syndrome caused by a germline mutation in one of the DNA mismatch repair genes. Affected individuals are at increased risk of developing a variety of cancers, particularly colorectal, endometrial, and/or ovarian cancer (table 1). (See 'Introduction' above and 'Risk for endometrial and ovarian cancer' above.)

●Strategies for cancer risk reduction – For patients with Lynch syndrome who have completed childbearing, we suggest risk-reducing total hysterectomy with bilateral salpingo-oophorectomy (TH-BSO) rather than surveillance and/or chemoprevention (Grade 2C). (See 'Strategies for cancer risk reduction' above.)

●Endometrial cancer surveillance

•Before completion of childbearing, we suggest endometrial cancer surveillance (Grade 2C). We perform yearly endometrial sampling starting at age 30 to 35 or 5 to 10 years prior to the earliest age of Lynch-associated cancer of any kind in the family. (See 'Endometrial cancer surveillance' above.)

•We also perform ovarian cancer surveillance with an annual pelvic examination and transvaginal ultrasound (TVUS) examination, with or without cancer antigen 125 (CA 125) every 6 to 12 months, but not screening is also reasonable given that no screening strategy (CA 125, TVUS, or multimodal testing) has been shown to reduce mortality and all surveillance strategies are associated with a high rate of false-positive tests and a risk of harm from invasive testing. (See 'Ovarian cancer surveillance' above.)

●Role of chemoprevention – In addition to surveillance, in premenopausal patients not attempting to conceive, we suggest use of hormonal contraception for chemoprevention of both endometrial and ovarian cancer (Grade 2B). Estrogen-progestin contraceptives reduce the risk of both endometrial and ovarian cancer; progestin-based contraceptives reduce the risk of endometrial cancer (table 3). (See 'Chemoprevention before completion of childbearing' above.)

●Follow-up risk-reducing surgery – Gynecologic follow-up after risk-reducing surgery depends on the procedures performed. Hysterectomy removes the need for endometrial cancer surveillance. For patients who have had a risk-reducing BSO, we continue screening (with pelvic examination and CA 125 levels every 6 to 12 months) because of the risk of primary peritoneal cancer. Not screening is also reasonable given that no screening strategy has been shown to reduce mortality and all screening strategies are associated with a high rate of false-positive tests and a risk of harm from invasive testing. (See 'Gynecologic follow-up after risk-reducing surgery' above.)