Uterine Cancer: Early Detection
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Each year approximately 36,000 women in the United States are diagnosed with endometrial cancer. There are currently no routine screening techniques for endometrial cancer in the general population. It is predominantly a disease of affluent, obese, postmenopausal women of low parity. Over the last few decades, age-standardized incidence rates have risen in most countries and in urban populations. Developing countries and Japan have incidence rates four to five times lower than western industrialized nations, with the lowest rates being in India and south Asia. In the United States, black women have approximately a 40% lower risk for development of cancer of the corpus uteri, but approximately a 54% greater risk of dying of the disease, mainly because of late diagnosis (1). Endometrial carcinoma has a peak age of 55 years; 75% of cases are postmenopausal.
The purpose of this document is to understand the risks for and symptoms of endometrial cancer in order to detect the uterine cancer early. There are currently no routine screening techniques for endometrial cancer in the general population. The vast majority of women have early-stage disease at diagnosis owing to postmenopausal bleeding. The American Cancer Society (ACS) has recommended that at the time of menopause, the average-risk woman should be informed about the risks for symptoms of endometrial cancer and be strongly encouraged to report any unexpected bleeding or spotting to her gynecologist. When appropriate, genetic counseling and testing should be offered.
Screening of Asymptomatic Women:
The ideal method for outpatient sampling of the endometrium has not yet been devised, and no blood test of sufficient sensitivity and specificity has been developed. Therefore, mass screening of the population is not practical. However, screening for endometrial carcinoma or its precursors is justified for certain high-risk people. Any factor that increases exposure to unopposed estrogen (hormone replacement therapy, obesity, anovulatory cycles, estrogen-secreting tumors) increases the risk of endometrial cancer, whereas factors that decrease exposure to estrogens or increase progesterone levels (oral contraceptives or smoking) tend to be protective. A high index of suspicion also is needed to make an early diagnosis in women younger than 40 years of age. Occasionally, vaginal bleeding does not occur because of cervical stenosis, particularly in thin, elderly, estrogen-deficient patients.
Patients for whom screening for endometrial cancer is justified, and endometrial cancer should be excluded:
- Postmenopausal women on exogenous estrogens without progestins
- Women from families with hereditary non-polyposis colorectal cancer syndrome
- Premenopausal women with anovulatory cycles, such as those with polycystic ovarian disease
- All patients with postmenopausal bleeding
- Postmenopausal women with pyometra
- Asymptomatic postmenopausal women with endometrial cells on a Pap smear, particularly if they are atypical
- Perimenopausal patients with intermenstrual bleeding or increasingly heavy periods
- Premenopausal patients with abnormal uterine bleeding, particularly if there is a history of anovulation.
Endometrial Biopsy Sampling:
Endometrial biopsy sampling is the most common office-based invasive procedure performed today in gynecology, and is one of the principal means of diagnosing endometrial cancer. There is a false-positive rate of approximately 10%. A negative endometrial biopsy in a symptomatic patient must be followed. A diagnosis of endometrial hyperplasia on endometrial biopsy does not obviate the need for further investigation. The devices used for sampling endometrium are: Serrated Novak, Novak, Kevorkian, Explora (Mylex), and Pipelle (Unimar), Gyno Sampler, Vabra aspiration. With these devices, an endometrial smear may be made for cytologic evaluation, and a cell-block may be prepared for histologic examination. A meta-analysis reported that the Pipelle was the best device, with detection rates for endometrial cancer in postmenopausal and premenopausal women of 99.6% and 91%, respectively (2). The sensitivity for the detection of endometrial hyperplasia was 81%. The specificity for all devices was >98%.
Saline-wash Endometrial Cytology as an Adjuvant to Histology:
With the advent new monolayer techniques, the usefulness of endometrial cytology has been studied. With the saline-wash biopsy, both cytology and histology can be assessed using the cell-block method. A standard dry endometrial biopsy is first obtained without anesthesia using the Milex syringe sampler, and any tissue retrieved is placed in standard formalin. A 3 ml vial of sterile saline solution is then opened using sterile scissors. A second Milex endometrial sampler was used to draw up 1.5 ml of sterile saline from the vial. The endometrial sampler is then placed in the uterine fundus, and the saline solution is injected into the cavity. The syringe then reaspirates the solution as the sampler scrapes the lining of the endometrial cavity. The saline wash specimen is then injected into a Cytolyte fixative jar. The Cytolyte-fixed material is then processed using the ThinPrep 2000 system. In this study, saline-wash endometrial biopsy resulted in more samples sufficient for pathologic diagnosis (92% versus 67%, P <.05). Endometrial cytologic evaluation is a rapidly growing field, and new monolayer techniques are spurring resurgence in research on the benefits to clinicians (3). By performing a saline-wash endometrial biopsy, the clinician can obtain a histologic specimen by cell-block and a cytologic specimen by ThinPrep. This can add to the pathologic data, aiding the clinician in the patient's management. The need for further evaluation by expensive D&C or ultrasonography could be reduced from 33% to 9% by using a saline-wash endometrial biopsy.
Fractional D&C and Hysteroscopy:
All of these office techniques for endometrial sampling cause the patient some discomfort, and in approximately 8% of the patients, it is not possible to obtain a specimen because of a stenotic os. This failure rate increases to approximately 18% for women older than 70 years of age. Because there is a false-negative rate of approximately 10%, a negative endometrial biopsy in a symptomatic patient must be followed by a fractional dilatation & curettage (D&C) under anesthesia. Hysteroscopy may provide information on benign endometrial disease, but it has not been shown to increase the yield in the diagnosis of endometrial cancer, and it increases the cost of the initial evaluation. There has been speculation that fluid hysteroscopy may facilitate the abdominal dissemination of malignant cells, but there is no evidence that it has any impact on the disease-free survival (4).
Ultrasound in Endometrial Applications:
Initially ultrasound was a tool of the obstetricians. As equipment and resolution improved, the use of ultrasound in gynecology including evaluation of endometrium and ovaries in postmenopausal women began. The vaginal probe has opened new doors to the application of ultrasound to postmenopausal women. After the menopause the endometrium becomes thin and atrophic because there is no epithelial stimulation by estrogen. Normal postmenopausal endometrium is a thin "pencil-line" echogenicity.
In the past this was referred to as "senile endometritis". It is almost common cause of postmenopausal bleeding but obviously it must be distinguished from hyperplasia or adenocarcinoma. Because ultrasound will not yield a tissue diagnosis, it is important that it be appropriately performed and documented.
There has been tremendous confusion regarding the endometrial thickness. Acknowledging that an endometrial echo <4 mm to 5 mm in thickness in patients with bleeding seems uniformly associated with inactive, atrophic endometrial tissue on pathology. High negative predictive value is not nearly the same as saying that endometrial measurements >4 mm to 5 mm are pathologic, especially if they are found incidentally in a non-bleeding patient. Often fibroids, previous surgery, marked obesity, or an axial uterus may make visualization suboptimal. If so, it is perfectly acceptable and in fact appropriate to conclude "endometrial echo not well visualized". In these cases, the ultrasound cannot be relied upon to exclude pathology. The decisions about what to do with incidental unexpected findings should be made on a case-by-case basis depending on a multitude of factors. Saline infusion sonohysterography or hysteroscopy are both appropriate next steps in endometrial evaluation of such patients if such patient has a history of bleeding (5). A recent meta-analysis reported that 4% of endometrial cancers would be missed using transvaginal ultrasonography for the investigation of postmenopausal bleeding, with a false-positive rate as high as 50%.
In summary, in women with bleeding, transvaginal ultrasound (and sonohysterography when necessary) forms a simple inexpensive well tolerated office procedure to triage patients to: (a) no anatomic endometrial pathology (treated expectantly or hormonally); (b) globally thickened endometrial tissue (candidates for endometrial sampling); or (c) abnormally thickened focal tissue (including polyps and non-global pathology) in need of visually directed sampling.
Genetic Testing for Uterine Cancer:
Hereditary malignancies in women account for 5% to 10% of breast, ovarian, and colorectal cancers. By age 80, female carriers of BRCA 1 or BRCA 2 mutations have a risk of ovarian cancer that may be as high as 60% and a risk of breast cancer that approaches 87%. In patients with mutations in the DNA mismatch repair genes, by age 70 the risk of colon cancer approaches 80% and the risk of endometrial carcinoma approaches 60%. Patients with the hereditary non-polyposis colorectal cancer (HNPCC) syndrome have high rates of colon cancer, and their rates of endometrial cancer may be just as high. The risk of endometrial cancer in these patients is 40% to 60% by age 70 (as compared to 1.5% in the general population) (6). Endometrial cancers in DNA mismatch repair (MMR) mutation carriers have an increased tendency to occur before menopause. These cancers appear to have the same good prognosis that is seen with sporadic type I endometrial caner. Patients with family history of early-onset colon or endometrial cancer may benefit from genetic testing for mismatch repair (MMR) genes so they can be offered counseling and increased surveillance for gastrointestinal and endometrial carcinomas.
Tamoxifen and Uterine Cancer:
Tamoxifen, a non-steroidal antiestrogen agent is used widely as adjunctive therapy for women with breast cancer. Most studies have found the increased relative risk of development of endometrial cancer while taking tamoxifen to be 2 to 3 times higher than that of an age-matched population. Several approaches are being explored for screening asymptomatic women using tamoxifen for abnormal endometrial proliferation or endometrial cancer. Correlation may be poor between ultrasonographic measurements of endometrial thickness and abnormal pathology in asymptomatic tamoxifen users because of tamoxifen-induced subepithelial stromal hypertrophy (7). American College of Obstetricians and Gynecologists (ACOG) Committee Opinion, April 2000, recommends the following:
- Women taking tamoxifen should be monitored closely for symptoms of endometrial hyperplasia or cancer and should have a gynecologic examination at least once every year.
- Women taking tamoxifen should be educated about the risks of endometrial proliferation, endometrial hyperplasia, and endometrial cancer. Women should be encouraged to promptly report any abnormal vaginal symptoms, including bloody discharge, spotting, staining or leukorrhea.
- Any abnormal vaginal bleeding, bloody vaginal discharge, staining, or spotting should be investigated.
- Because screening tests have not been effective in increasing the early detection of endometrial cancer in women using tamoxifen and may lead to more invasive and costly diagnostic procedures, they are not recommended.
- Tamoxifen use should be limited to 5 years' duration because a benefit beyond this time has not been documented.
- If atypical endometrial hyperplasia develops, appropriate gynecologic management should be instituted, and the use of tamoxifen should be reassessed.
If tamoxifen therapy must be continued, hysterectomy should be considered in women with atypical endometrial hyperplasia. Tamoxifen use may be reinstituted following hysterectomy for endometrial carcinoma in consultation with physician responsible for woman's breast care.
Familial Endometrial Cancer:
There are numerous reports describing family history as a risk factor for endometrial cancer. Hereditary nonpolyposis colorectal cancer is associated with germline mutations in any one of six genes, PMS2 on chromosome 7, MLH1 on chromosome 3, and MSH6, MSH2, or PMS1 on chromosome 2. Mismatch repair failure leads to microsatellite instability. Hereditary nonpolyposis colorectal cancer increases the population risk of endometrial cancer from 0.2% to 20% by age 50 and from 1.5% to 60% by age 70. The lifetime risk for hereditary nonpolyposis colorectal cancer gene carriers can be as high as 30%. Endometrial cancers in the Lynch II syndrome can be of any grade or histology. Up to 35% of endometrial cancers in this syndrome may be of high stage or adverse histology. Because these women can develop colon cancer before age 50 years and disease may be commonly found in the proximal colon, colonoscopy should be performed every other year starting at age 20 years and annually after 35 years. Annual evaluation including transvaginal ultrasound, CA 125 examinations, and pelvic examination should commence at age 30 years. Endometrial biopsy should be performed if symptoms of irregular bleeding or menorrhagia develop. Prophylactic hysterectomy with bilateral salpingo-oophorectomy has been proposed as an effective strategy for preventing endometrial and ovarian cancer in women with the Lynch syndrome as a risk-reducing procedure after childbearing is completed (8). Most studies do not suggest that the BRCA1 or BRCA2 gene is associated with endometrioid endometrial cancer (9). Several reports suggest that the serous histologic subtype of endometrial cancer may be linked to BRCA mutations. There are several studies suggesting removing the uterus for prophylaxis in BRCA1- and BRCA2-positive women undergoing prophylactic salpingo-oophorectomy for ovarian cancer prevention to prevent serous papillary uterine cancer. Although much controversy exits regarding prophylactic hysterectomy, this information should be discussed with women contemplating prophylactic risk-reducing surgery for BRCA mutations.
The PTEN tumor-suppressor gene is expressed in endometrial cancer. PTEN mutations are more common in endometrioid carcinomas and rarely detected in type II serous carcinomas. These mutations have also been identified in hyperplasias. PTEN mutations may be involved in carcinogenesis for type I disease. Women with endometrial cancer remain at risk for breast and colorectal cancer, and their follow up should include secondary cancer prevention strategies to maximize long-term survivorship (10).
Intermenstrual bleeding or heavy prolonged bleeding in perimenopausal or anovulatory premenopausal women should arouse suspicion. The diagnosis may be delayed unnecessarily in these women because the bleeding is usually ascribed to "hormonal imbalance". A high index of suspicion also is needed to make an early diagnosis in women younger than 40 years of age. For women who are members of HNPCC kindreds, screening with transvaginal ultrasonography and endometrial biopsy is recommended annually, age at initiation of screening 25-35 years. Tamoxifen increases the risk of endometrial cancer two-fold to three-fold and produces a sonographically unique picture of an irregularly echogenic endometrium that is attributed to cystic glandular dilatation, stromal edema, and edema and hyperplasia of the adjacent myometrium. Patients taking tamoxifen should be informed of the increased risk of uterine cancer and any bleeding or spotting must be investigated by biopsy.
The Project is funded by the WHEC Initiative for Global Health.
- Jermal A, Tiwari RC, Murray T et al. Cancer Statistics, 2005. CA Cancer J Clin 2005;55:10-30. (Level II-3)
- Dijkhuizen FPH, Mol BWJ, Brolmann HAM et al. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia. Cancer 2000;89:1765-1772
- ACOG Practice Bulletin. Management of anovulatory bleeding. Number 14, March 2000
- Obermair O, Germou M. Impact of hysteroscopy on disease-free survival in clinically stage I endometrial cancer patients. Int. J Gynecol Cancer 2000;10:275-279
- Tabor A, Watt HC, Wald NJ. Endometrial thickness as a test for endometrial cancer in women with postmenopausal vaginal bleeding. Obstet Gynecol 2002;99:663-670
- Lipton LR, Johnson V, Cummings C et al. Refining the Amsterdam criteria and Bethesda guidelines: testing algorithms for the prediction of mismatch repair mutation status in the familial cancer clinic. J Clin Oncol 2004;22:4934-4943
- Trible CL. Atypical endometrial hyperplasia: a tough call. Int J Gynecol Cancer 2005;15:401
- Schmeler KM, Lynch HT, Chen LM et al. Prophylactic surgery to reduce the risk of gynecologic cancers n the Lynch syndrome. N Engl J Med 2006;354:261-269
- Sorosky JI. Endometrial Cancer. Obstet Gynecol 2008;111:439-447
- Kwon JS, Elit L, Saskin R et al. Secondary cancer prevention during follow-up for endometrial cancer. Obstet Gynecol 2009;113:790-795
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