47 Cancer of the Uterine Corpus

Amelia M. Jernigan

Amanda Nickles Fader

Endometrial cancer is the fourth most common cancer in women and the most common gynecologic malignancy, accounting for 6% of all female cancers.

EPIDEMIOLOGY OF UTERINE CANCER

In the United States and other developed countries, 1 in 38 women will develop uterine cancer, making it the most common gynecologic malignancy in these settings. The American Cancer Society estimates that there will be 49,560 new cases and 8,190 deaths from uterine cancer in 2013. The incidence has increased 0.8% each year since 1998. Most commonly, these are endometrial cancers; only 2% of uterine cancers are sarcomas. Seventy-two percent of cases will be localized at the time of diagnosis because endometrial cancer often presents with postmenopausal or irregular bleeding.

Risk Factors for Uterine Cancer

• A woman's risk of endometrial cancer increases with age. The median age at diagnosis is 61 years, and the peak incidence occurs from ages 55 to 70 years. Women older than 50 years old account for 90% of the diagnoses of endometrial cancer and 5% develop disease before age 40 years.

• Other risk factors are based on increased estrogen exposure.

• Estrogen replacement without concomitant progesterone carries a relative risk of 4.5 to 8.0 and persists for 10 years after treatment is stopped (Table 47-1).

• Chronic anovulation states, such as seen in polycystic ovarian syndrome (PCOS), lead to constant estrogen stimulation of the endometrium and increase the risk of cancer due to the lack of a corpus luteum to produce progesterone.

• Obesity increases endogenous estrogen by peripheral conversion of androstenedione to estrogen by aromatase in adipose tissues. Nearly 70% of early-stage endometrial cancer patients are obese. The relative risk of death increases with increasing body mass index (BMI), and a BMI >30 kg/m² will triple the risk of endometrial cancer.

• Nulliparity (related to infertility) and diabetes mellitus are independent risk factors and have a relative risk of two or three for endometrial cancer, whereas the association of hypertension seems related to obesity.

• A woman taking tamoxifen has an annual risk of 2 in 1,000 of developing endometrial cancer and 40% of women will develop cancer more than 12 months after stopping therapy.

• Women with hereditary nonpolyposis colon cancer (HNPCC) syndrome have a 39% risk of developing endometrial cancer by age 70 years.

• Some factors can decrease the risk of endometrial cancer.

• Factors that decrease circulating estrogen, such as cigarette smoking and oral contraceptive pill (OCP) use, may be protective.

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TABLE 47-1 Risk Factors for Endometrial Cancer

From Barakat RR, Markman M, Randall ME, et al. Corpus: epithelial tumors. In Hoskins WJ, Perez CA, Young RC, eds. Principles and Practice of Gynecologic Oncology, 2nd ed. Philadelphia, PA: Lippincott-Raven Publishers, 1997:884.

• OCPs decrease endometrial cancer risk by 40%, even up to 15 years after discontinuation, and this protection increases with length of use. Four years of use reduces risk by 56%, 8 years decreases risk by 67%, and 12 years of use decreases risk by 72%.

• Hyperplasia appears to be the precursor lesion for most endometrial cancer.

• A recent study revealed that 43% of hysterectomies performed in community hospitals for complex atypical hyperplasia will have endometrial cancer on final pathology.

PRESENTATION, EVALUATION, AND DIAGNOSIS

Clinical Presentation

• Seventy-five percent to 90% of endometrial cancer cases present with postmenopausal bleeding. In one study of women with postmenopausal bleeding, 7% had cancer, 56% had atrophy, and 15% had endometrial hyperplasia.

• The likelihood that postmenopausal bleeding is due to cancer significantly increases with a woman's age. One study showed that 9% of women in their 50s with postmenopausal bleeding had endometrial cancer, whereas the rate was 16% for women in their 60s, 28% for women in their 70s, and 60% for women in their 80s.

• Although endometrial cancer is mostly a disease of postmenopausal women, 20% of cases are diagnosed before menopause. Perimenopausal menometrorrhagia, especially in women at high risk for endometrial cancer, should be investigated with endometrial biopsy.

• Abnormal cervical cytology can prompt the workup for and diagnosis of endometrial cancer. However, routine Pap smear screening will only detect half of endometrial cancer cases and is not a screening test. Workup should be considered with the following Pap smear results:

• Endometrial cells (remote from menstrual bleeding) in a woman older than 40 years

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• Atypical glandular cells of undetermined significance (the risk of endometrial cancer in women older than 35 years with this Pap result is 23%)

• Adenocarcinoma (consider endometrial and cervical sampling)

• Some cases of endometrial cancer are discovered incidentally at the time of hysterectomy. If this is the case, a surgeon skilled on endometrial cancer staging procedures should be involved if available.

• With a few exceptions, there are no guidelines or recommendations to screen for endometrial cancer.

Tamoxifen

• Women who are on tamoxifen have an increased risk of developing endometrial cancer.

• Routine screening with ultrasound or endometrial biopsies is not recommended in this setting.

• Use of ultrasound for screening is of limited use because tamoxifen causes subepithelial stromal hypertrophy and therefore increases the thickness of the endometrial stripe and may result in unnecessary surgical procedures.

• Women on tamoxifen should be counseled on warning signs and followed with yearly pelvic exams. Any episode of vaginal bleeding should trigger an evaluation.

Hereditary Nonpolyposis Colon Cancer

• HNPCC, or Lynch syndrome, is inherited in an autosomal dominant fashion, resulting from a germline mutation in one of the mismatch repair genes (MMR genes MLH1, MSH2, MSH6) and comprises the majority of inherited cases of endometrial cancer. It also increases risk of cancer of the colorectum, small intestine, ureter, renal pelvis, and ovary.

• Genetic assessment for HNPCC is strongly recommended in women with a 20% to 25% risk of HNPCC.

• This includes women with a family pedigree meeting Amsterdam criteria, patients with metachronous or synchronous colorectal and endometrial or ovarian cancers before age 50 years, or those with a first- or second-degree relative with a known germline mutation in an MMR gene.

• Women with HNPCC have a high risk of endometrial cancer (as high as 50% lifetime). A prophylactic hysterectomy should be considered.

• There is limited evidence regarding endometrial cancer screening in this population, but current recommendations advise women to undergo endometrial biopsies annually starting at the age of 30 to 35 years or 10 years before the age that first case appeared in the family and to undergo hysterectomy and bilateral salpingooophorectomy once childbearing is completed.

Evaluation and Diagnosis of Postmenopausal Bleeding

• The appropriate evaluation for postmenopausal bleeding is widely debated. Ultrasound and endometrial

biopsy are the two main tools available.

Ultrasound

• Pelvic ultrasound measurement of the endometrial stripe can be used with a minimum cutoff of 5 mm in thickness based on the Postmenopausal Estrogen/Progestins

P.614 Intervention (PEPI) trial. This trial showed that with a 5-mm cutoff, postmenopausal ultrasound has a positive predictive value of 9%, a negative predictive value of 99%, a sensitivity of 90%, and a specificity of 48% for endometrial cancer.

• Meta-analysis shows that the posttest probability of cancer following a pelvic ultrasound with a stripe 5 mm conveys a 32% posttest probability of cancer.

• Even with a thin stripe, if a woman persistently bleeds, sampling should be performed.

Biopsy

• Endometrial biopsy provides a cancer detection rate of 99.6% in premenopausal women and 91 % in postmenopausal women. Specificity is 98%, and sensitivity is 99%. The false-negative rate is between 5% and 15%.

• The posttest probability of endometrial cancer is 82% if the biopsy is positive and 0.9% if it is negative.

• However, a biopsy read as “insufficient sample” should trigger further evaluation because on further investigation, 20% of these women will have pathology and 3% will have cancer.

Further Workup

• No matter which method is used for initial evaluation, if bleeding persists or clinical suspicion is high, further evaluation with a dilation and curettage (D&C) should be pursued. The false-negative rate of a D&C is 2% to 6%.

• Hysteroscopy with D&C has a positive predictive value of 96%, a negative predictive value of 98%, a sensitivity of 98%, and a specificity of 95%.

• A recent Gynecology Oncology Group (GOG) prospective study demonstrated the difficulty in diagnosing complex atypical hyperplasia (CAH). One third of cases of CAH were deemed to be “less than” CAH by study pathologists, one third were deemed to be “greater than” CAH (i.e., endometrial cancer), and another third of the diagnoses were consistent with the original diagnosis of CAH.

STAGING AND PROGNOSIS

Pretreatment Evaluation

• Complete history, assessing for hereditary cancer syndromes

• Complete physical exam including comprehensive pelvic exam assessing the size and mobility of the uterus and assessment for metastasis (i.e., supraclavicular lymphadenopathy)

• Consider cancer antigen 125 (CA-125). Elevated CA-125 levels are associated with metastatic disease and can be used to follow the patient if it was elevated at diagnosis.

• Imaging: Chest imaging should be ordered. A plain film is reasonable. A computed tomography (CT) or magnetic resonance imaging (MRI) is not necessary if surgical staging is planned. If no surgery is planned, an MRI is the best modality to assess myometrial or cervical and lymph node involvement.

Surgical Staging Procedures

• Staging for endometrial cancer is performed surgically, and because many patients have early-stage disease at the time of diagnosis, this is often the only intervention necessary.

• Surgical staging most commonly involves a minimally invasive surgical approach for apparent early- stage disease. The procedure includes total extrafascial

P.615 hysterectomy, bilateral salpingo-oophorectomy, a pelvic and periaortic lymph node assessment/dissection, as well as cytoreduction of all visible disease.

ξ Peritoneal washings are not part of surgical staging, but if performed, they should be obtained as the first step once abdominal access has been achieved.

ξ Omentectomy should be performed if serous or clear cell histology is suspected.

• Current standard of care is minimally invasive surgery when possible. The Gynecologic Oncology Group Study LAP 2 (GOG LAP-2) randomized trial demonstrated that a laparoscopic approach to endometrial cancer staging was feasible and safe with similar intraoperative complications but fewer postoperative adverse events and a shorter hospital stay.

• Long-term follow-up data suggest similar recurrence rates and 5-year overall survival in the open and laparoscopic groups.

• The lymphatics of the uterine fundus drain to the aortic nodes; the lower uterine segment drains to the internal and external iliac lymph nodes; and the round ligaments can drain to the superficial inguinal lymph nodes.

• Pelvic and para-aortic lymph node dissection is required for complete surgical staging of endometrial cancer. Pelvic lymph node dissection involves the removal of nodal tissue from the distal half of each common iliac artery, the anterior and medial proximal of each external iliac artery, and vein and the distal half of the obturator fat pad anterior to the obturator nerve.

• Para-aortic lymph node dissection involves the removal of nodal tissue over the distal vena cava from the inferior mesenteric artery to the mid common iliac artery and between the aorta and ureter from the inferior mesenteric artery to the left mid common iliac artery.

• Morbid obesity may render a lymph node dissection more challenging, but it is still a required component of the procedure if indicated based on histologic and pathologic risk factors (see the following text).

• One pitfall of lymph node dissection is the occurrence of lymphedema (5% to 20%). The incidence increases with the removal of more nodes and administration of adjuvant radiation.

• Furthermore, the performance of lymph node dissection is not clearly associated with improved survival. Retrospective data supports improved survival with more extensive lymph node resection, especially in patients with high-risk features. However, Consolidated Standards of Reporting T rials (CONSORT) and Adjuvant External Beam Radiotherapy in the Treatment of Endometrial Cancer (ASTEC) are two prospective randomized trials which demonstrated no difference in survival when lymph node dissection was performed.

• Importantly, ASTEC did not require para-aortic lymphadenectomy and is criticized for including many patients who were low risk and would not have benefited from lymph node dissection in the first place as well as a low median number of lymph nodes resected. In the CONSORT trial, more nodes were removed (median = 30) but only 26% of patients in the lymphadenectomy group underwent paraaortic dissection. Therefore, it is difficult to generalize and state that a full lymph node dissection conveys no survival benefit. Furthermore, many would argue that it is the information gained from the dissection that helps guide adjuvant therapy and may convey a survival benefit, which was not adequately tested in these trials.

• The decision as to whether or not to proceed to lymph node dissection is often made in the operating room based on frozen section evaluation of the uterus for histologic cell type, tumor differentiation (grade), and depth of myometrial invasion.

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TABLE 47-2 Lymph Node Metastasis by Grade and Depth of Invasion of Endometrial Cancer

From Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987;60:2035-2041.

• Lymph node dissection, if deemed surgically possible, should be pursued in the following instances: the presence of invasion to the outer one half of the myometrium (any grade), high-grade differentiation with any myometrial invasion, clear cell histology, papillary serous histology, tumor size >2 cm in maximal diameter, lymph-vascular space invasion, cervical or lower uterine segment invasion, adnexal involvement, clinically bulky lymph nodes, or disease outside of the uterus.

• Women without any of these risk factors have 90% 5-year survival rate with a total abdominal hysterectomy bilateral salpingo-oophorectomy (TAH-BSO).

• However, with the presence of any of these risk factors, the risk of positive lymph nodes increases to >10% and 5-year survival rate decreases to 70% to 85% without further treatment (Table 47-2).

• More than half of patients with a preoperative diagnosis of CAH are found to have some myometrial invasion.

• Routine CT scan rarely alters management and is a poor predictor of nodal disease, and MRI has not been shown to have sufficient accuracy to predict myometrial invasion. Neither modality should be used to determine which patient should undergo lymphadenectomy.

• Approximately 50% of positive lymph nodes will be as an isolated result does not improve survival.

• Prognosis for the more aggressive histologic types is less favorable. Even without myometrial invasion, 36% of uterine papillary serous carcinoma cancers will have positive lymph nodes.

• Five-year survival for disease stages I to II is 36% and is unusual for more advanced disease.

• Clear cell cancer portends a 72% 5-year survival for stage I disease and a 60% 5-year survival for stage II disease.

• Overall 5-year survival for the aggressive histologic subtypes is 40%.

• Relapses tend to occur distally, often in the lungs, liver, or bones.

MANAGEMENT OF ENDOMETRIAL CANCER

Appropriate treatment is determined by stage, grade, histologic type, and the patient's ability to tolerate therapies (Table 47-3).

• Patients with low-risk endometrial cancer of endometrioid type require no further therapy beyond surgery, particularly patients with grade 1, stage 1 endometrial cancer and no risk factors.

Management of High-Risk Endometrial Cancer

• T reatment for women with higher risk disease is more controversial. Multiple studies have sought to define the appropriate role for adjuvant therapy.

Radiation Therapy

• The Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) study randomized women with stage IC grade 1, stage IB and stage IC grade 2, or stage IA grade 3 (under 1988 FIGO staging). All women were treated with TAHBSO without a lymph node dissection. These women were then randomized to receive or not receive pelvic radiation with 4,600 cGy.

• Local recurrence occurred in 4.2% of radiated women versus 13.7% of those not radiated. However, the rate of death from cancer was not statistically different between the two groups (9.2% vs. 6.0%, respectively).

• Additionally, radiation therapy for vaginal recurrence in the nonradiated group was successful in inducing a complete response in 89%, and 5-year survival of this salvage radiation group was 65%. Therefore, postoperative radiation can significantly increase local control but does not appear to impact survival. The authors concluded that postoperative radiation should be limited to women with two out of three risk factors: older than age 60 years, stage IC, or grade 3.

• One problem with the PORTEC data was the lack of full surgical staging. The GOG addressed this in a phase III trial of 392 intermediate-risk patients who underwent TAH-BSO and lymph node surgery followed by observation (12% recurrence and 86% 4-year survival) versus radiation therapy (3% recurrence and 92% 4-year survival) and found similar results to the PORTEC data.

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• GOG-99 randomized 448 women with stage IB to II disease (1988 FIGO staging) to postoperative radiation (50.4 Gy) versus no adjuvant treatment after hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy. Again, they showed a decreased recurrence rate but no improved overall survival with radiation. The lower recurrence rate with radiation was especially notable (2-year recurrence rate of 26% vs. 6%) in the “high intermediate risk” subgroup: (1) any age with poorly differentiated tumor, LVSI, or outer one third myometrial invasion; (2) 50 years or older with any two of the preceding risk factors; and (3) 70 years or older with any one of the preceding risk factors.

• A multicenter retrospective trial demonstrated an 81 % response rate to salvage radiation for isolated vaginal recurrences in surgical stage I patients who did not initially receive adjuvant radiation.

• In PORTEC-2, women with stage I or IIA endometrial cancer were randomized to postoperative external beam radiation therapy (46 Gy) or vaginal brachytherapy (21 Gy) after hysterectomy and bilateral salpingo- oophorectomy with pelvic and para-aortic lymph node sampling of suspicious nodes. There were no differences in 5-year vaginal or locoregional recurrence rates, distant metastases, and disease-free or overall survival. Patients in the vaginal brachytherapy group reported better social functioning and fewer gastrointestinal complaints.

Cytoreductive Surgery

• Stage II uterine cancer significantly increases the risk for vaginal recurrence. If cervical involvement is known preoperatively, a radical hysterectomy should be considered, which has been shown to result in a 75% 5­year survival rate. A combination of extrafascial hysterectomy followed by radiation is associated with a 5-year survival rate of 70%.

• If the diagnosis is made postoperatively, vaginal brachytherapy should be offered.

• These data may need to be updated in light of the new staging system.

• For stages III and IV cancers, optimal cytoreductive surgery has been shown to improve survival. Adjuvant therapy after cytoreduction is advised; however, the optimal mode of adjuvant therapy is unclear.

• Complete salvage cytoreduction for recurrent disease has been associated with a prolonged postrecurrence survival (39 months) versus patients with gross residual disease (13.5 months).

Chemotherapy

• Chemotherapy can also be used; however, the optimal chemotherapy regimen for endometrial cancer is unknown. Single-agent response rates are low. Multiple trials have been conducted with various regimens.

• Cisplatin and doxorubicin together have a 43% response rate. The addition of paclitaxel to the cisplatin and doxorubicin regimen (TAP) in a randomized trial (GOG-177) resulted in an increase in response rate and survival. There was a significantly higher rate of peripheral neuropathy in the group treated with paclitaxel. Preliminary data from GOG 209 suggest that carboplatin and paclitaxel may be noninferior and less toxic compared to TAP.

• Hormonal therapies (progesterones like Megace, selective estrogen receptor modulators like tamoxifen, and aromatase inhibitors) are largely more useful in the palliative setting and are not used with an intention to cure.

• Targeted therapies that act on the PI3K/AKT/mTOR pathway, angiogenesis, and epidermal growth factor receptors are experimental but promising.

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• Patients who fail first-line chemotherapy generally have a very poor prognosis, with a response rate to second- and third-line agents of mesodermal tumors) are very aggressive and are associated with previous pelvic radiation. They are often large and necrotic. Carcinosarcoma is an independent predictor of survival with a hazard ratio of 3:2 for recurrence compared to the other histologies. Thus, carcinosarcoma should be studied separately from high-risk endometrial cancers given the difference in behavior.

• These are no longer considered a sarcoma but are poorly differentiated endometrial cancer.

• The 5-year survival rate is 50% for stage I tumors and 20% for stage IV.

• Lymph node dissection has not been shown to be therapeutic for these tumors. Stage and mitotic grade are the most predictive of disease course.

• Chemotherapy regimens, including cisplatin, doxorubicin, ifosfamide, and paclitaxel, have been used for malignant mixed mullerian tumors. Chemotherapy with ifosfamide and paclitaxel resulted in an improved response rate, overall survival, and progression-free survival but also more neuropathy compared to ifosfamide alone.

• Pelvic radiation improves local control but not overall survival.

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Fertility Preservation

• Women with very early endometrial cancer who wish to preserve their fertility have been treated with progesterone rather than surgery. A review of 81 patients with stage IA1 endometrial cancer treated with progesterone revealed the following:

• Two thirds responded with median time to response of 12 weeks, and median duration of treatment was 24 weeks. Of those who responded, 24% recurred and median time to recurrence was 19 months.

• Forty-seven percent of the women who recurred were retreated, and 72% had a second complete response.

• A multicenter prospective study examined 28 women with endometrial carcinoma and 17 women with atypical hyperplasia who were treated with progesterone.

• Complete response was noted in 55% of the patients with carcinoma and 82% of those with atypical hyperplasia. The patients were followed for 3 years during which there were 12 pregnancies and a 47% recurrence rate.

• A recent prospective trial followed 105 women with endometrial hyperplasia treated with a levonorgestrel- releasing intrauterine device and showed a 90% regression rate after 2 years.

• Women who wish to retain their fertility should be counseled that risks are associated with such an approach, and a TAH-BSO is recommended after childbearing is completed.

• D&C should be done to confirm pathology. An MRI is recommended to assess for myometrial invasion. D&C should be repeated every 3 months to assess response.

Incomplete Surgical Staging

• T reatment depends on risk factors.

• Grade 1 or 2 tumors with 10% risk of positive pelvic lymph nodes, and 5-year survival is decreased to 70% to 85% without further treatment. Therefore, restaging or use of adjuvant radiation is appropriate. Laparoscopic node dissection can be used for patients who were incompletely staged at their initial surgery. Additionally, fluorodeoxyglucose positron emission tomography scanning may hold promise for evaluating lymphadenopathy but further study is needed.

Medical Contraindications to Surgery

• Women who are medically unable to undergo surgery can be treated with pelvic radiation alone. However, 5­year survival for clinical stage I disease is decreased to 69% with this approach versus 87% for surgery alone.

• It has been shown that for stage I disease with a preoperative CA-125 of 5 cm

IIA Tumor involves the adnexae.

IIB Tumor involves other pelvic tissues.

IIIA Tumor infiltrates abdominal tissues at one site.

IIIB Tumor infiltrates abdominal tissues at more than one site.

IIIC Metastasis to pelvic and/or para-aortic lymph nodes

IVA T umor invades bladder and/or rectum.

IVB

Distant metastases (beyond the adnexa, pelvic, and abdominal tissues)

^aCarcinosarcomas should be staged as endometrial carcinomas, not as a sarcoma.

^bStaging based on the 2009 FIGO guidelines as presented in the National Comprehensive Cancer Network Guidelines. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed July 21,2013.

Staging of Uterine Sarcoma

• In 2009, a staging system for uterine sarcomas was defined (Table 47-4).

Leiomyosarcoma

• Uterine LMS are an aggressive and rare subtype of uterine sarcoma. They usually arise in the myometrium and rarely in fibroids. Vaginal bleeding is the most common presenting symptom. Ten percent of patients will have lung metastases at the time of diagnosis. The typical picture is a postmenopausal woman with a rapidly enlarging fibroid.

• In a series of 1,432 patients who underwent a hysterectomy for a fibroid uterus, only 0.49% were found to have LMS. Another series of 1,332 patients who underwent hysterectomy for fibroids had a subset of patients with “rapidly growing fibroids” and only 0.2% were found to have LMS.

• These tumors appear like leiomyomas but have >10 mitoses per 10 high-power fields and diffuse nuclear atypia. Additionally, the presence of coagulative necrosis is suggestive of LMS.

• No benefit of adjuvant radiation has been noted.

• Fixed-dose-rate gemcitabine plus docetaxel have had promising response rates as first-line therapy for metastatic uterine LMS.

Endometrial Stromal Sarcoma

• Endometrial stromal sarcoma (ESS) arises from the endometrium and can be separated into low and high grade. They represent 10% of sarcomas. They are the least aggressive uterine sarcomas. However, even in low-grade ESS, 36% of patients will relapse and 10% will die from the disease.

• Low-grade ESS often responds to progestins and aromatase inhibitors. Higher grade ESS should be treated with surgery and pelvic radiation. Chemotherapy has not been shown to be beneficial; however, with metastatic disease, doxorubicin and ifosfamide have been used.

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Prognosis for Uterine Sarcoma

• A retrospective study including women with all forms of sarcoma showed a 3-year survival rate of 82%, 60%, and 20% for sarcomas with low-, medium-, and highgrade histology, respectively.

• Three-year survival was 56%, 45%, 33%, and 5% for stages I, II, III, and IV sarcomas. These data may need to be updated in light of the revised staging criteria.

• Survival rates of 77%, 60%, and 30% were seen for sarcomas treated with surgery and then pelvic radiation with vaginal brachytherapy, surgery with just pelvic radiation, and no adjuvant therapy, respectively.

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