Obstetrics and Gynecology

Endometrial Cancer - Surgery and staging

Endometrial, uterine, or uterine corpus cancer

1. What every clinician should know Are you sure your patient has Endometrial cancer? What should you expect to find?

Endometrial cancer is the most common gynecologic cancer in western countries. About 47,000 cases are diagnosed in the U.S. annually, resulting in about 8,000 deaths. The most common presenting symptom (90%) is postmenopausal bleeding, defined as any bleeding, even light spotting, occurring in a woman whose last known menstrual period was at least 12 months prior to the onset of current bleeding. About 10% of women with postmenopausal bleeding will be diagnosed with endometrial cancer.

Endometrial cancer includes two common histologic subtypes:

Type I (endometrioid) adenocarcinoma accounts for at least 75% of all cases of endometrial cancer and has a more favorable prognosis than type II histology. Adenocarcinoma with squamous differentiation or a mucinous pattern are not considered differently than pure endometrioid adenocarcinomas.

Type II adenocarcinoma is associated with distinct risk factors and genetic aberrations compared to type I. Type II histologies generally have a worse prognosis than type I and are divided into two categories: uterine serous carcinoma (the most common type II adenocarcinoma and associated with an increased risk of extrauterine disease) and clear cell carcinoma (frequently chemoresistant).

Endometrial hyperplasia is the precursor to type I endometrial cancer. Rates of progression to cancer are 1% for simple hyperplasia and 3% for complex hyperplasia. In contrast, 30% of patients with atypical hyperplasia will develop an invasive carcinoma. More importantly, 25% to 45% of patients with atypical hyperplasia on biopsy will demonstrate invasive cancer if subjected to hysterectomy. Therefore, patients with atypical hyperplasia must be managed as if they have a diagnosis of endometrial cancer.

Risk factors for type I endometrial cancer are shown below, the most common of which are obesity, diabetes, hypertension, and unopposed estrogen. However, only half of patients present with identifiable risk factors ( Table I).

Table I.

Risk Factors for Type I Endometrial Cancer.
Factors Influencing Risk Estimated Relative Risk
Older age 2-3
Residency in North America or Northern Europe 3-18
Higher level of education or income 1.5-2
White race 2
Nulliparity 2-3
History of infertility 2-3
Menstrual irregularities 1.5
Late age at natural menopause 2-3
Early age at menarche 1.5-2
Unopposed estrogen therapy 4-8
Long-term use of high dosages of combination oral contraceptives 0.3-0.5
Tamoxifen therapy 2-3
Obesity 3-10
Stein-Leventhal disease or estrogen-producing tumor >5
History of diabetes, hypertension, gallbladder disease, or thyroid disease 1.3-3
Cigarette smoking 0.5
Lynch II syndrome 20

Uterine sarcomas are encountered far less frequently (2% to 6% of uterine cancers) than the histologic subtypes discussed above. This category includes malignant mixed müllerian tumors (MMMT, or carcinosarcomas), leiomyosarcomas, and endometrial stromal sarcomas. Far less is known about risk factors, although the relative risk of developing a uterine sarcoma is at least fivefold higher after pelvic radiation. Compared to epithelial uterine cancers, outcomes are less favorable, in particular for high grade sarcomas.

2. Diagnosis and differential diagnosis

The most common presenting symptom of endometrial cancer (EC) is postmenopausal bleeding, defined as any bleeding, even light spotting, occurring in a woman whose last known menstrual period was at least 12 months prior to the onset of current bleeding. Although all women with postmenopausal bleeding should be considered to have endometrial cancer until proven otherwise, only about 10% will be diagnosed with endometrial cancer. Rarely patients may present with an enlarged uterus or pelvic mass in the absence of bleeding. It should also be noted that 25% of patients with endometrial cancer are premenopausal and about 5% are under the age of 40. Therefore, endometrial cancer should be considered in the differential diagnosis for patients with irregular or heavy menses. Lastly, women on unopposed estrogen or who have had prolonged periods of amenorrhea (such as patients with polycystic ovarian syndrome) should be investigated for endometrial cancer.

A thorough pelvic examination is the most important step in evaluation. The size and mobility of the uterus, and presence of adnexal or parametrial involvement, should be evaluated. Inspection of the gynecologic structures for gross lesions will identify nonuterine causes of bleeding, such as the vulva, vagina, or cervix.

Patients with an abnormal appearing cervix should not undergo pap smear testing, but should rather undergo colposcopic-directed biopsies to rule out a cervical cancer. Rarely bleeding will not be gynecologic in origin, and abnormalities of the urethra, bladder, or GI tract will be discovered with closer examination and a careful history. The patients should also be evaluated for a pelvic mass, ascites, or supraclavicular or inguinal lymphadenopathy.

Women with suspected endometrial cancer should undergo endometrial biopsy. This is the gold standard for diagnosis, is easily performed in the office, and has a negative predictive value (NPV) of 98%. Rarely (5%) patients will not tolerate the procedure or it will not be possible because of cervical stenosis. These patients should be evaluated in the operating room with a dilation and curettage (D&C) hysteroscopy to obtain a tissue diagnosis.

Another diagnostic option is pelvic ultrasound, which has an NPV of 96% if the endometrial stripe is 5 mm or less. However, the positive predictive value (PPV) is 69%, and tissue sampling is therefore required for definitive diagnosis. Pap smear testing should notbe used as the primary method of evaluation in a patient with suspected endometrial cancer because only 30% to 50% of patients with endometrial cancer will have an abnormal result.

Preoperative testing should include a type and screen, complete blood count, creatinine, fasting blood glucose, electrocardiogram, and chest radiograph. Patients with a diagnosis of low grade endometrial cancer do not require imaging. However, CT or MRI may be used if there is suspicion of extrauterine disease and for patients with high grade or type II histology. Findings suggestive of extrauterine disease may impact the surgeon's approach to surgery, favoring an open rather than minimally invasive approach.

CA125 testing may also be performed in this high-risk cohort. Although CA125 is insensitive, elevations (>35) may herald the presence of peritoneal disease and could be useful to diagnose recurrences in the future. More recently, HE4 has been described as a more sensitive marker for deep myometrial invasion and for advanced-stage disease. However, at this time the sensitivity and specificity is not well-documented and normal values are still being delineated.

Patients with a diagnosis of endometrial cancer should be referred to a gynecologic oncologist for expert evaluation and treatment. These patients will require subspecialized surgical care and may require treatment postoperatively with radiation and/or chemotherapy. Multiple investigations have demonstrated improved outcomes for patients treated by a gynecologic oncologist. Proper surgical treatment and staging will in many cases obviate the need for adjuvant treatment, reducing morbidity. Furthermore, patients with endometrial cancer commonly have multiple comorbidities and are likely to derive benefit from referral to a team equipped to care for complex patients.

Staging is based on surgical findings, summarized below (FIGO 2009):

  • Stage IA — Tumor limited to endometrium or invades less than one half of the myometrium

  • Stage IB — Tumor invades one half or more of the myometrium

  • Stage II — Tumor invades stromal connective tissue of the cervix but does not extend beyond uterus

  • Stage IIIA — Tumor involves serosa and/or adnexa (direct extension or metastasis)

  • Stage IIIB — Vaginal involvement (direct extension or metastasis) or parametrial involvement

  • Stage IIIC1 — Regional lymph node metastasis to pelvic lymph nodes

  • Stage IIIC2 — Regional lymph node metastasis to paraaortic lymph nodes, with or without positive pelvic lymph nodes

  • Stage IV — Tumor invades bladder mucosa and/or bowel mucosa

It is important to recognize that stage cannot be used in isolation to determine the need for postoperative treatment. For example, a patient with stage I EC may require no treatment, chemotherapy, or a combination of chemotherapy and radiation depending on the presence of other risk factors, including high tumor grade, depth of myometrial invasion, and lymph vascular space involvement. Peritoneal cytology is no longer required for staging and generally does not impact treatment recommendations, but should be collected and documented. The presence of deep myometrial invasion only impacts subcategorization of stage I, but may impact treatment recommendations and prognosis for the more advanced stages.

Genetic testing

Women with Lynch II syndrome harbor germline mutations in MLH1, MSH2, MSH6, PMS1, and PMS2 genes. These mutations are inherited in an autosomal dominant fashion with 80% to 85% penetrance. Patients show early age of onset of colon, uterine, ovarian, and other cancers; the lifetime risk of endometrial cancer is 30% to 60%, and the lifetime risk of ovarian cancer is 10% to 12%. The Amsterdam and Bethesda guidelines have been used to identify patients at risk for Lynch II syndrome, but unfortunately about 75% of patients with this syndrome will be missed using this strategy. In contrast 93% of patients will be identified using the SGO 5% to 10% guidelines, shown below. Patients suspected of having hereditary endometrial cancer should be referred to a geneticist for evaluation.

SGO guidelines for Lynch syndrome testing

  • Patients with endometrial or colorectal cancer diagnosed prior to age 50

  • Patients with any of the above characteristics should be offered testing of the endometrial tumor specimen for DNA mismatch repair (MMR). This includes testing for microsatellite instability (MSI) and/or mismatch repair (MMR) proteins by immunohistochemistry. Any patient with high MSI testing or aberrant expression of one or more MMR proteins should be referred to medical genetics. Because loss of MMR occurs in 15% of sporadic endometrial cancers, additional testing (including methylation analysis and/or gene sequencing) must be performed for a definitive diagnosis of Lynch syndrome (LS).

  • Patients with endometrial or ovarian cancer with a synchronous or metachronous colon or other LS-associated tumor at any age

  • Patients with endometrial or colorectal cancer and a first-degree relative with LS-associated tumor diagnosed prior to age 50

  • Patients with colorectal or endometrial carcinoma diagnosed at any age with two or more first- or second-degree relatives with LS-associated tumors regardless of age

3. Management

What therapies should you initiate immediately?

In the vast majority of cases, diagnosis of endometrial cancer does not necessitate immediate treatment. However, the testing described above should be pursued on an outpatient basis without delay to move toward definitive surgery.

Occasionally, patients will present with heavy bleeding and anemia requiring transfusion. These patients are often not amenable to an in-office endometrial biopsy, as the Pipelle will simply fill with clot rather than an endometrial sample, and D&C will be necessary to establish the diagnosis. In very rare instances, bleeding will be profuse and it may be necessary to proceed with an immediate hysterectomy or emergent radiation therapy for those who are not surgical candidates.

What should the initial definitive therapy for the cancer be?

It is universally agreed that treatment for endometrial cancer should include a hysterectomy and removal of adnexal structures. Beyond that, the concept of surgical staging remains controversial, with no standard of care with regards to performing a lymphadenectomy or if used, the extent of the lymphadenectomy. This is an important topic because identification of positive lymph nodes will result in the recommendation for chemotherapy and/or radiation postoperatively.

However, most patients have negative lymph nodes and lymphadenectomy is associated with additional cost and morbidity. Although two randomized trials have shown no benefit to lymphadenectomy, flaws in trial design, in particular the study of low-risk patients, have neither changed nor standardized surgical practice. Most gynecologic oncologists in the U.S. perform lymphadenectomy according to one or more of the following three paradigms for patients with type I endometrial cancer.

1. Pelvic and paraaortic lymphadenectomy for all patients with endometrial cancer. Advocates for this strategy feel that it is not possible to accurately identify patients at risk of lymph node metastases without a routine lymphadenectomy.

2. Sentinel lymph node dissection. Several groups have investigated this approach, although the false negative rate has yet to be defined in large studies. 1 cc of methylene blue is injected both superficially and 1 to 2 cm deep at 3 and 9 o'clock on the cervix (total of 4 cc) and sentinel nodes are identified prior to a hysterectomy. Criticism includes the fact that in most studies the cervix rather than the uterine lesion itself is injected with tracer for the purpose of convenience, uncertainty regarding the ability of this method to identify paraaortic metastases, the fact that 38% to 50% of patients will nevertheless require unilateral or even full lymphadenectomy when the sentinel node cannot be identified, and a small series suggesting that the false negative rate is over 35% in high-risk patients. As more data are collected, this approach may be used with increasing frequency.

3. Selective lymphadenectomy for patients at risk. This approach uses primary tumor diameter, grade, and depth of myometrial invasion to identify patients at negligible risk of lymph node metastases with a false negative rate of less than 0.5%. Using this approach over 30% of patients will not require lymphadenectomy (see Figure 1 from a theoretical group of 100 patients). As shown, the need for paraaortic lymphadenectomy is likewise determined based on pathologic factors including lymph vascular space involvement, positive pelvic nodes, and deep myometrial invasion. Note that if deep myometrial invasion alone is used, this method remains very predictive with a false negative rate less than 3%. Disadvantages of this method include the reliance on expert frozen section, which may not be reliable in low-resource settings. However, there is preliminary evidence that the use of preoperative grade together with intraoperative tumor diameter is equally predictive of lymph node metastases (grade 1 or 2 and a tumor diameter of 2 cm or less do not require a lymphadenectomy). Following a debate at the Society of Gynecologic Oncologists in 2013, membership in attendance were polled and approximately two thirds used selective lymphadenectomy to manage patients with endometrial cancer.

Figure 1.

Selective lymphadenectomy

It is important to note that the above discussion applies only to patients with type I EC. Patients with type II EC have a much higher rate of lymph node involvement and the pathologic factors described above are not informative. For this reason, both pelvic and paraaortic lymphadenectomy is generally performed in these patients. Others would argue that these patients do not require lymphadenectomy, because they will require postoperative chemotherapy regardless of lymph node status, thus highlighting the lack of surgical standard of care in this disease.

In parts of Europe, hysterectomy alone is routinely performed together with postoperative radiotherapy. This approach is not generally used in the U.S. as it is thought to add unnecessary cost and morbidity. However, a head to head comparison between hysterectomy with lymphadenectomy versus hysterectomy alone with radiation has not been performed.

Additional considerations

Most experts agree that if encountered, grossly positive nodes should be removed at the time of surgery.

A number of investigations have demonstrated improved survival rate for stage IV patients who undergo cytoreduction to microscopic disease, similar to what has been shown for patients with ovarian cancer.

Occasionally a patient may present with pulmonary, mediastinal, or extensive peritoneal disease. These patients often have type II endometrial cancer. While little data exists to support this approach, it has been our practice to administer neoadjuvant chemotherapy and perform interval cytoreduction if response is demonstrated, as has been described in patients with ovarian cancer,

For patients with low grade cancers who are otherwise unfit for surgery, either because of super-obesity, advanced age, or multiple medical comorbidities, alternate treatment approaches include oral progesterone or placement of a progesterone-containing IUD. Patients should understand that this is most commonly a temporary stopgap to definitive therapy. Radiation is an accepted alternative to a hysterectomy for this patient population, although inconvenient. In particular, morbidly obese patients may nevertheless require examination under anesthesia in order for the brachytherapy device to be correctly positioned due to an inadequate pelvic examination and altered anatomy.

Patients who wish to preserve fertility

Endometrial cancer is diagnosed in women of child-bearing age in 5% of cases. While conservative management is an accepted method of treatment, patients should understand that this therapy may fail, that there have been documented deaths from disease as a result of this approach, and that frequently conservative management often simply delays, rather than replaces, hysterectomy.

Only grade 1 patients should be considered candidates for conservative management. MRI should be performed and if there is evidence of myometrial invasion greater than 50% or evidence of extrauterine disease, patients should be counseled to undergo hysterectomy. Young patients with endometrial cancer appear to be at higher risk of ovarian malignancy and if there is evidence of a nonfollicular mass on MRI, the mass should be further investigated without delay. In the absence of a worrisome mass, patients who desire immediate pregnancy should be referred to a reproductive endocrinologist to expedite pregnancy after demonstration of response to progestational treatment, as described below.

Dosage and duration of treatment varies within the literature, with higher doses theoretically improving efficacy. However, there is no evidence to suggest high doses of progesterone are necessary and in fact side effects may reduce compliance.

We favor placement of a progesterone IUD or the use of 20 mg of medroxyprogesterone acetate daily. Dilatation and curettage is then performed after 3 months of therapy. If response is documented, patients should be resampled every 3 months until they become pregnant or undergo hysterectomy. However, if there is evidence of persistent endometrial cancer or atypical hyperplasia, another 3-month round of treatment may be undertaken.

If oral progesterone is used, the dose may be increased to 40 mg or higher daily. If invasive disease or atypical hyperplasia persists, preservation of fertility is not possible and a hysterectomy will be necessary.

Postoperative treatment

Patients with stage IA grade 1 or 2 tumors have an excellent prognosis and require no adjuvant therapy.

Patients with stage I disease, but with myometrial invasion greater than 50% (stage IB) have a 25% to 30% risk of hematogenous recurrence. There is evidence that this risk may be reduced with cytotoxic therapy.

For high-risk, early-stage endometrial cancer, vaginal brachytherapy is generally given to 21 Gy to 5 mm in three fractions. This therapy is well tolerated and associated with 98% to 100% vaginal control rates. Despite the excellent local control rate, this modality has not been shown to improve overall survival time. Nevertheless, risk factors associated with higher rates of vaginal recurrence including high grade, deep myometrial invasion, and the presence of lymph vascular space involvement are indications for vaginal brachytherapy in many centers.

Patients with uterine serous carcinomas are at high risk of recurrence even in the absence of extrauterine spread. For this reason most patients are recommended to undergo treatment with carboplatin and paclitaxel regardless of stage. Patients with advanced disease are treated similarly to patients with advanced endometrioid cancer.

Advanced disease

External beam pelvic radiation does not appear to impact outcome for patients with high-risk, stage I endometrial cancer. However, patients with stage IIIA and IIIC disease are likely to benefit from postoperative pelvic radiation with or without chemotherapy. Radiation appears to be particularly effective for patients with metastatic lymph nodes. The most common treatment for stage IIIC patients is the use of pelvic radiation (50.4 Gy) combined with carboplatin and paclitaxel chemotherapy.

Administration schedules vary, with many favoring a "sandwich" approach of three cycles of chemotherapy before and after pelvic radiotherapy is given. Ongoing trials are testing chemotherapy alone versus radiation therapy alone versus chemoradiation with sequential chemotherapy to understand the relative contribution of each modality and the associated morbidity.

Patients with stage IV endometrial cancer have high rates of lymphatic metastasis, but are at highest risk of failure in the peritoneal cavity. For this reason, although radiation may be effective in controlling recurrence in the lymph node basins, chemotherapy is the more critical modality in this scenario. Patients may be treated with chemotherapy alone, or a combination of chemotherapy and radiation as described for patients with stage IIIC disease.

Sarcomas

Endometrial stromal sarcomas are low grade by definition and up to 50% respond to progestational therapy, the preferred first-line therapy. Because this tumor is hormonally responsive, the ovaries should be removed in patients who do not wish to preserve fertility.

Patients with stage I leiomyosarcomas have a 50% risk of recurrence and would appear to be excellent candidates for adjuvant therapy. However, pelvic radiation has been shown to reduce pelvic recurrences, but not overall survival rates, and there is no evidence that adjuvant therapy improves outcomes, although NCCN guidelines suggest offering pelvic radiation therapy to patients with stage I leiomyosarcomas. Enrollment in clinical trials should be strongly considered. Six to eight cycles of Gemzar/docetaxel resulted in a 50% response rate for patients with unresectable or recurrent disease, although median time to progression was less than 6 months and 20% to 25% will have grade 3-4 toxicity.

Similar to other uterine histologies, the use of pelvic radiation for stage I carcinosarcomas (MMMT) is associated with a reduction in recurrence-free, but not overall survival. Although carcinosarcomas have both epithelial and sarcomatous elements, recurrences are almost always epithelial in origin. For this reason most patients receive cytotoxic chemotherapy with either ifosfamide/cisplatin or carboplatin/paclitaxel. A phase III trial is in progress to determine if the less toxic carboplatin/paclitaxel regimen is equally effective as ifosfamide/cisplatin (response rate 18-42%).

4. Complications

As reviewed above, the most common presenting symptom is bleeding. However, bleeding will rarely be significant enough to require transfusion with blood products or an emergent hysterectomy.

Rarely, endometrial tumors may prolapse through the cervical os and an ascending infection may result. This is an uncommon occurrence, but such patients may present with endomyometritis and sepsis. These patients should be admitted, treated with broad-spectrum antibiotics, and may require an emergent hysterectomy. Most commonly patients will harbor a high grade endometrial cancer, such as a carcinosarcoma.

By virtue of the risk factors for endometrial cancer, many patients will have multiple co-morbidities, including morbid obesity, advanced age, diabetes, and hypertension. These comorbidities contribute to many of the complications which occur in the course of medical and surgical treatment and should be treated by physicians adept at caring for high acuity patients.

Complications as consequence of management

Patients with high-risk endometrial cancer are often recommended to receive treatment with chemotherapy and/or radiation.

Side effects of treatment with carboplatin and paclitaxel include bone marrow suppression, allergic reactions, peripheral neuropathy, and renal failure. Please see the chapter on ovarian cancer for additional details regarding these specific agents.

The use of sequential chemotherapy with radiation is commonly used for patients with stage III or IV endometrial cancer, and is toxic. One third of patients will not complete treatment with chemotherapy due to toxicity and up to 88% of patients will have at least one grade 3-4 toxicity. Long term follow-up of patients who received whole pelvic irradiation have demonstrated a 20% absolute increase in incontinence, more diarrhea, fecal urgency and leakage leading to limitations of daily activities, worse sexual function for patients treated with either brachytherapy or pelvic radiation compared to controls, and nearly double the risk of developing a secondary malignancy. A rare complication is radiation enteritis, which may result in obstruction and necessitate long-term use of parenteral nutrition.

In a recent review, most surgical complications were low grade, consisting of wound infections or the need for a blood transfusion. However, 7% of patients experienced a grade 3 or higher complication including sepsis, organ failure, or a complication requiring an intervention under anesthesia, such as stent placement or repair of a perforated viscus. The 30-day mortality rate was 1%. Body mass index (BMI) greater than 50 was among the patient characteristics associated with a grade 3 or higher surgical complication.

Lower extremity lymphedema (LEL) is a delayed complication that may result from a lymphadenectomy and radiotherapy. More recent data have demonstrated that at least 1 in 5 patients who undergo a lymphadenectomy will develop LEL if followed long term; this diagnosis was associated with important reductions in quality of life. The risk of LEL is higher when radiotherapy is included in the treatment regimen. It should also be noted that women with endometrial cancer are at high risk of developing LEL even if they do not undergo lymphadenectomy by virtue of their co-morbid conditions, such as obesity and cardiovascular disease.

Other therapies helpful for reduction of complications

The most important strategy for reducing complications is the use of minimally invasive surgery (MIS). A number of studies have demonstrated equivalent oncologic outcomes with reduced blood loss, lower rates of perioperative complications, and shorter hospital stay when minimally invasive surgery is used. Most notably, the odds of surgical site infection in patients who undergo a laparotomy is 14 times higher than for patients who undergo MIS. Between 75% and 90% of unselected patients will be candidates for the laparoscopic, robotic, or vaginal approach. Laparotomy should be used only for patients with evidence of advanced disease or for the rare patient with a contraindication to laparoscopy.

In addition to reducing perioperative morbidity and hastening recovery, MIS may reduce complications from radiation for patients with high-risk disease. Although this has not been definitively demonstrated, adhesions are far less common following MIS. This may reduce the risk of small bowel loops becoming fixed in the pelvis and receiving radiation injury.

As reviewed above, most patients will not have metastatic involvement of lymph nodes, and lymphadenectomy is associated with increased cost and morbidity. Therefore, omitting lymphadenectomy in patients at low risk is an increasingly favored strategy and has been shown to reduce perioperative morbidity and development of LEL. Patients who undergo lymphadenectomy are likely to benefit from consultation with a lymphedema specialist to recognize the signs and symptoms of LEL. Early diagnosis and treatment may help reduce long-term sequelae and disability.

5. Prognosis and outcome

Type I

Most patients with endometrial cancer have an excellent prognosis by virtue of the fact that 70% will have disease confined to the uterine corpus.

Patients with low-risk endometrial cancer, as defined by grade 1 or 2, less than 50% myometrial invasion, and primary tumor diameter of 2 cm have a 5-year disease-specific survival rate of 99%. This group represents about one third of all patients with endometrial cancer. Disease-specific survival rate for stage IA patients who do not meet low-risk criteria is approximately 97%.

Patients with stage I disease, but with myometrial invasion greater than 50% (stage IB) have a 25% to 30% risk of hematogenous recurrence. There is evidence that this risk may be reduced with cytotoxic therapy as reviewed above.

Stage II patients (cervical involvement) have a recurrence rate of approximately 16%, but also tend to have larger, high grade tumors.

Stage IIIA is a heterogeneous cohort. Full-thickness myometrial invasion with serosal involvement has a very high rate of recurrence, up to 100% in some series. In contrast, disease recurs in 20% to 25% of patients with adnexal involvement.

Patients with positive lymph nodes have about a 50% risk of recurrence and clearly benefit from adjuvant radiotherapy and chemotherapy. Risk of recurrence is slightly higher for patients with positive paraaortic nodes.

Patients with stage IV EC have a 5-year survival rate of less than 20%. Although cytotoxic chemotherapy is effective, response rates are not durable and patients should be encouraged to enroll in clinical trials.

As described above, prognosis is difficult to delineate based on stage alone for patients with stage II-IV endometrial cancer. Other prognostic factors, including grade, myometrial invasion, tumor size, and disease burden, will impact the risk of recurrence.

Type II

In general, outcomes are less favorable for patients with serous histology.

5-year overall survival is 85% for stage I patients, although myometrial invasion is an important prognostic factor. The survival rate is 90% for stage IA patients and 60% for patients with greater than 50% myometrial invasion. The 5-year survival rate for stage IIIC and IV uterine serous cancer is 40% to 50% and less than 10%, respectively.

Endometrial or cervical cancer?

A patient may present with an adenocarcinoma of unclear origin. If there is obvious involvement of the cervix, this is frequently a primary cervical cancer, and a conization may be performed to help direct surgical management. If there is any doubt of the origin after conization, a radical hysterectomy should be performed in the absence of parametrial involvement to reduce the possibility of cut-through disease. HPV testing on the tumor may also be helpful to delineate its origin.

My patient is not a surgical candidate

Alternate treatment approaches include placement of a progesterone-containing IUD, oral progestational treatment, or primary radiation therapy. In morbidly obese patients medical management may be particularly useful if the patient is considering bariatric surgery. This will offer a stopgap until the patient proceeds with bariatric surgery at which time a combined procedure may be performed, or else surgery may be delayed until the patient has achieved significant weight loss, reducing the risk of complications.

A progesterone containing IUD is preferable, as there is preliminary evidence of superior efficacy compared to oral therapy. It is critical to perform repeat endometrial biopsy within 3 months to document regression. If this is not achievable, it will be necessary to proceed with either surgery or radiation therapy. Radiation therapy appears to be a viable option, but in practice placement of a brachytherapy device may be extremely difficult for patients with a BMI higher than 50 or 60, and these patients may need to undergo anesthesia even to receive radiation, reducing its advantages.

May the ovaries be preserved in young patients? Is estrogen replacement contraindicated?

Approximately 25% of patients with endometrial cancer are premenopausal at diagnosis. The issue of oophorectomy at the time of hysterectomy is an important consideration given increasing evidence of excess risk of death from all causes in patients who undergo oophorectomy prior to age 45 in the absence of estrogen replacement. If the adnexae are grossly normal in appearance and the patient has no evidence of hereditary ovarian cancer, ovarian preservation is an option given that in this scenario the risk of occult metastases is less than 1%. For the patient who undergoes oophorectomy, estrogen replacement is generally considered safe for patients with low grade, early-stage disease.

6. Follow-up surveillance and therapy management of recurrences

About one half of patients with recurrent endometrial cancer complain of symptoms, most commonly bleeding and/or pelvic pain; 75% to 80% of recurrences are detected initially on physical examination. Therefore, history and physical examination are the most efficacious and cost-effective methods of follow-up. Patients should be examined every 3 to 4 months (every 6 months if they meet low-risk criteria) during the first 2 years and every 6 months thereafter. The routine use of imaging or vaginal cytology should be avoided in the absence of symptoms or suspicious findings.

Almost one half of all asymptomatic recurrences are detected by chest x-ray, and this may be performed every 12 months if desired. Serum CA125 may also be obtained, although this appears most useful in patients with elevated values or known extrauterine disease at the time of diagnosis.

Treatment of recurrent disease is dependent on recurrence site

Approximately 50% of recurrences are local or regional in nature. Isolated vaginal recurrences are treated with a combination of external beam irradiation and vaginal brachytherapy, with reclamation rates as high as 80% depending on patient characteristics. Larger central recurrences may be treated with pelvic exenteration with survival rates of 30% to 50%. In contrast, extension to the pelvic sidewall is associated with poorer outcomes, varying from 0% to 23% survival with radiation therapy alone. If pelvic sidewall recurrences are isolated, patients may be candidates for treatment with radical surgical resection and intraoperative radiation therapy. Survival rates as high as 75% have been reported using this approach when complete resection is achieved.

Patients with advanced stage endometrial cancer or those with type II histology often develop peritoneal or distant recurrences. Secondary cytoreduction is an option in the fit patient with a long disease-free interval, but more commonly these patients are treated with combination chemotherapy. Options include doxorubicin and cisplatin; cyclophosphamide, doxorubicin, and cisplatin; paclitaxel and cisplatin with or without doxorubicin; and carboplatin and paclitaxel. Although response rates range from 38% to 76%, median survival is approximately 12 months.

Most patients with recurrent disease harbor high grade tumors. However, some may develop low grade recurrences in the peritoneal or pleural space, which may be treated with hormonal therapy in the event they express hormone receptors. Response rates in an unselected group of patients with recurrence was less than 15%, but as high as 70% in tumors expressing estrogen and progesterone receptors. Long disease free intervals have been reported.

7. What is the evidence for specific management and treatment recommendations?

The following references provide an overview of the pathologic and genomic characteristics of endometrial cancer:

Lax, SF. "Molecular genetic pathways in various types of endometrial carcinoma: from a phenotypical to a molecular-based classification". Virchows Arch. vol. 444. 2004. pp. 213-23.

Kandoth, C, Schultz, N. "Integrated genomic characterization of endometrial carcinoma". Nature. vol. 497. 2013. pp. 67-73.

Lancaster, JM, Powell, CB, Kauff, ND. "Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions". Gynecol Oncol. vol. 107. 2007. pp. 159-62.

(The SGO Education Committee statement on genetic testing for hereditary endometrial cancer is a useful reference to direct triage of patients to a geneticist for counseling.)

Nout, RA, Smit, VT, Putter, H. "Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomized trial". Lancet. vol. 375. 2010. pp. 816-23.

Dowdy, SC, Borah, BJ, Bakkum-Gamez, JN. "Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer". Gynecol Oncol;. vol. 127. pp. 5-10.

Barlin, JN, Khoury-Collado, F, Kim, CH. "The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes". Gynecol Oncol. vol. 125. pp. 531-5.

Ballester, M, Dubernard, G, Lécuru, F. "Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial cancer: a prospective multicentre study (SENTI-ENDO)". Lancet Oncol. vol. 12. pp. 469-76.

Walker, JL, Piedmonte, MR, Spirtos, NM. "Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2". J Clin Oncol. vol. 27. 2009. pp. 5331-6.

Dowdy, SC, Borah, BJ, Bakkum-Gamez, JN. "Factors predictive of postoperative morbidity and cost in patients with endometrial cancer". Obstet Gynecol. vol. 120. 2012. pp. 1419-27.

Nout, RA, van de Poll-Franse, LV, Lybeert, ML. "Long-term outcome and quality of life of patients with endometrial carcinoma treated with or without pelvic radiotherapy in the post operative radiation therapy in endometrial carcinoma 1 (PORTEC-1) trial". J Clin Oncol. vol. 29. 2011. pp. 1692-700.

"GOG 122 demonstrated the advantages of chemotherapy compared to whole abdominal irradiation for patients with advanced endometrial cancer".

Randall, ME, Filiaci, VL, Muss, H. "Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study". J Clin Oncol. vol. 24. 2006. pp. 36-44.

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