b.  Simple or complex hyperplasia with atypia. Twenty-three percent of untreated atypical hyperplasia progress to endometrial cancer (8% for simple atypical and 29% for complex atypical hyperplasia) over 11 years. More importantly, there is a 13% to 43% rate of concurrent endometrial cancer with atypical hyperplasia. In a Gynecologic Oncology Group (GOG 167) prospective cohort study of women with atypical endometrial hyperplasia, the rate of concurrent endometrial cancer was 43% for analyzed specimens, with 31% of these demonstrating myometrial invasion, and 11% invading the outer 50% of the myometrium (Cancer 2006;106:812). Due to these findings, patients with atypical hyperplasia should undergo D&C with or without hysteroscopy to rule out the presence of invasive cancer in the unsampled endometrium.

                   i.  Patients desiring pregnancy. Progestational agents including megestrol acetate 80 to 160 mg/day and levonorgestrel IUD have been used for treatment. The goal of therapy is complete regression of disease and reversion to normal endometrium followed by ovulation induction or assisted reproductive techniques for pregnancy. Repeat sampling with biopsy or D&C is recommended after 3 months of therapy.

                   ii.  Patients not considering pregnancy. Medical treatment: Regression is up to 90% with progestational agents including oral medroxyprogesterone (40 mg PO per day) and megestrol acetate (160 to 320 mg PO per day in divided doses) as well as levonorgestrel IUD (Obstetric Gynecol 2012;120:1160). Repeat biopsy or D&C to check for persistence or progression is recommended every 3 to 6 months till regression. Surgical treatment: Extrafascial hysterectomy with gross inspection and frozen section of the endometrium for evidence of endometrial cancer.

          5.  Complications are rare and minor, usually related to surgical complications of D&C including risk of anesthesia, infection, hemorrhage, and uterine perforation. An underlying concern is inappropriate surgical management due to misdiagnosed cancer.

          6.  Follow-up. Medically managed patients should be resampled at regular intervals (3 to 12 months) until regression of endometrial pathology. Those with normal histology can then either be taken off therapy or be cycled with progestational agents and should undergo periodic endometrial sampling. Follow-up interval for patients after hysterectomy is not well-established, but annual examinations should be adequate.

          7.  Current focus. The current focus is on determining molecular markers that predict progression to endometrial cancer and important prognostic factors in fertility-sparing medical management.

      B.  Endometrial cancer

          1.  Background. Endometrial cancer is the most common gynecologic malignancy in the United States with a rising incidence over the last 5 years. There were approximately 49,560 new cases and 8,190 deaths due to endometrial cancer in 2013 (CA Cancer J Clin 2013;63:11). Five-year survival for localized disease is 96%, whereas relative survival for all stages is approximately 82%. There are two morphologically and molecularly distinct histologic subtypes: type I and type II. Risk factors for type I endometrial cancer include unopposed exogenous estrogenic stimulation (estrogens or tamoxifen), chronic anovulation, obesity, diabetes mellitus, nulliparity, and late age of menopause (older than 52 years). Type II histology tends to be more sporadic and is not associated with clinical and physical factors mentioned above.

          2.  Presentation. More than 90% of patients are first seen with abnormal uterine bleeding. Patients with any postmenopausal bleeding or discharge deserve evaluation. Patients with abnormal pre- or perimenopausal bleeding, especially those with history of anovulatory cycles, older than 35 years, or morbidly obese warrant evaluation as well. Pap tests with atypical glandular cells of undetermined significance (AGUS) in patients of any age should be evaluated with a colposcopy, endocervical curettage, and endometrial biopsy. Pap test with endometrial cells on a postmenopausal patient should also be evaluated.

Cytology is mentioned separately and does not change stage.

FIGO, International Federation of Gynecology and Obstetrics.

          3.  Workup and staging. An office endometrial biopsy (pipelle) is an extremely sensitive method of obtaining a tissue diagnosis. A meta-analysis of 39 studies involving 7,914 women demonstrated a detection rate for endometrial cancer of 91% and 99.6% in pre- and postmenopausal women, respectively (Cancer 2000;89:1765). Patients with a nondiagnostic office biopsy, persistent bleeding abnormality despite a normal office biopsy, or those unable to undergo an office biopsy should undergo a fractional D&C, with or without hysteroscopy. All patients should be screened for other malignancies as appropriate for age and family history (Pap test, ultrasound, mammogram, and colorectal cancer screening). Cystoscopy, proctoscopy, and radiologic imaging may be necessary, as clinically indicated, if advanced stage is suspected. Surgical staging of endometrial carcinoma was adopted by the International Federation of Gynecologists and Obstetricians (FIGO) in 1988 and then revised in 2009 (Table 24-2). All patients who are medically able should first undergo surgical exploration with appropriate staging. Extrafascial hysterectomy with bilateral salpingo-oophorectomy, collection of peritoneal cytology, pelvic and para-aortic lymph node dissection, and biopsy of any suspicious areas are necessary for staging, except in small well-differentiated tumors without myometrial invasion. Omentectomy or omental biopsy is also indicated for high grade tumors and type II histology.

          4.  Therapy and prognosis. The first step of treatment is hysterectomy and surgical staging (abdominal, laparoscopic, or robotic). Total laparoscopic staging is being performed with increasing frequency for suspected early-stage endometrial cancer, and lymph node count and survival appear similar when compared to laparotomy. Hysterectomy removes primary tumor and intraoperative findings like size of tumor, myometrial invasion, and grade can help estimate risk or lymph node involvement and need for adjuvant therapy. Removal of adnexa is important due to the risk of metastasis to the ovary, synchronous ovarian cancers, and risk of future recurrence or primary cancer in the ovary. Lymphadenectomy is somewhat more controversial. Lymph node status is prognostically important and is essential in the decision of postoperative adjuvant therapy. But since there are rare but substantial risks and complications associated with the procedure, the benefit of lymphadenectomy is controversial in patients with low risk of positive nodes, high risk of morbid complication, and in patients that will receive adjuvant therapy due to other findings. Historically, radiation therapy (RT) had been the preferred choice of adjuvant therapy for patients with high risk of recurrence. However, the role of chemotherapy in all stages of endometrial cancer is evolving. While low risk stage I disease can be treated with surgery alone, adjuvant treatment for other stages is variable and includes vaginal brachytherapy (VB), external beam pelvic radiation therapy (EBRT), and chemotherapy (Table 24-3).

RT, radiation therapy; VB, vaginal cuff brachytherapy; HIR, high–intermediate risk.

              a.  Early stage. Results from GOG 33 and GOG 99 helped define a high intermediate risk (HIR) category for patients with Stage I or II disease with a higher risk of recurrence (Gynecol Oncol 2004;92:744). GOG 99 and PORTEC-1 showed that EBRT compared to no adjuvant treatment decreased local recurrence in patients with HIR stage I or II disease, but survival benefit was not significant. PORTEC-2 compared EBRT to VB and showed both were comparable in local recurrence rate. Therefore, adjuvant radiation treatment is recommended based on HIR criteria and patient desires of further treatment to decrease risk of recurrence or treatment when recurrence occurs. The pooled data from two randomized controlled trials showed a significant decrease in progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) for HIR stage I and II patients treated with combination chemotherapy and pelvic RT compared to pelvic RT alone. Currently there are two randomized trials comparing concurrent chemoradiation followed by adjuvant chemotherapy (PORTEC-3) or VB followed by chemotherapy (GOG 249) to pelvic RT alone in the treatment of HIR early-stage endometrial cancer.

              b.  Advanced stage. Cytotoxic chemotherapy for advanced stage endometrial cancer includes the following agents (response rate): cisplatin (20% to 35%), carboplatin (30%), doxorubicin (Adriamycin; 20% to 35%), epirubicin (25%) and paclitaxel. The combination of doxorubicin (60 mg/m²) plus cisplatin (50 mg/m²) every 3 weeks showed an improved response rate of 42%, progression-free interval of 6 months, and median OS of 9 months in a randomized trial by the GOG (J Clin Oncol 2004;22:3902). Combination of doxorubicin (60 mg/m² × 7 cycles) and cisplatin (50 mg/m² × 8 cycles) (AC) was superior to whole abdominal radiation (WAI, 30 Gy in 20 fractions with a 15-Gy boost) in a phase III trial of 202 randomized patients with stage III/IV endometrial cancer optimally debulked to ≤2 cm of residual disease with PFS of 50% versus 38% and OS 55% versus 42%, respectively (J Clin Oncol 2006;24:36). In 2004, a GOG trial demonstrated improved survival in patients with advanced or recurrent endometrial cancer treated with TAP (paclitaxel, doxorubicin, cisplatin) as compared to cisplatin and doxorubicin alone, although with increased toxicity (J Clin Oncol 2004;22:2159). A phase III trial comparing TAP and PT (carboplatin/paclitaxel) is currently underway and preliminary results show that PT is non-inferior to TAP and has a more favorable toxicity profile. In GOG 184, patients with stage III/IV endometrial cancer were treated with pelvic RT followed by AC versus TAP. There was no patient outcome benefit by adding paclitaxel but the study showed that combination radiation and chemotherapy was a feasible treatment option with acceptable toxicity.

                     Treatment with chemotherapy, RT, and/or hormone therapy is acceptable in patients where surgical staging and debulking is not a medically feasible option. Hormone therapy is also often used for patients with advanced/recurrent disease who test positive for estrogen and progesterone receptors. Response rate with either medroxyprogesterone acetate, 200 mg daily, or megestrol acetate, 160 mg daily, is approximately 20%.

          5.  Complications. Complications of staging surgery include pain, hemorrhage, infection, and damage to surrounding structure including bowel, bladder, and blood vessels. Lymphocysts and lymphedema of the lower extremities are rare complications of lymphadenectomy. Immediate toxicities from chemotherapy include hematologic, GI, and infectious complications. Immediate and late effects of radiation are usually related to bowel and bladder dysfunction. Concurrent treatment with chemotherapy and radiation therapy is currently under investigation, and the toxicities of combination treatment remain a major concern.

          6.  Follow-up. Typically patients are evaluated with physical examination, Pap test, and pelvic examination every 3 months for the first year, every 3 to 4 months for the second year, every 6 months for third to fifth year, and then at 6 to 12 month intervals thereafter.

          7.  Current focus. Current efforts are directed toward elucidating molecular markers that are prognostic and important in understanding endometrial cancer tumorigenesis New advances focused on the etiologic heterogeneity and defects in molecular pathways has lead to better histologic classification and the identification of potential therapies targeting defects in these pathways. Therapies targeting aberrations P13K/AKT/mTOR pathways, tyrosine kinase pathways, and angiogenesis are being studied in preclinical and phase II trials. While single-agent treatment with these drugs have not shown promising results, combination treatment with currently used chemotherapy regimens are being evaluated. Improved prognosis in endometrial cancer patients being treated with metformin has been observed in retrospective studies. Research to identify the pathways associating metformin use with improved endometrial cancer prognosis is underway.

      C.  Sarcomas

          1.  Background. These are uncommon tumors arising from the mesenchymal components of the uterus and comprise of 3% to 8% of uterine tumors. The GOG has broadly classified them based on histology: (1) Non-epithelial neoplasms including endometrial stromal sarcoma (ESS), leiomyosarcoma (LMS), and smooth muscle tumor of uncertain malignant potential (STUMP) and (2) Mixed epithelial–nonepithelial tumors including adenosarcoma and carcinosarcoma. Homologous types contain sarcomatous components that are unique to uterine tissue, whereas heterologous types produce stromal components that are not native to the uterus.

FIGO, International Federation of Gynecology and Obstetrics.

          2.  Presentation varies depending on type of tumor. Carcinosarcomas usually present with postmenopausal bleeding, while ESS and LMS can present as abnormal bleeding, rapidly enlarging pelvic pain or pelvic pressure and pain. Uterine sarcomas are often incidental diagnoses on hysterectomy specimens, and reoperation for complete surgical staging is usually not recommended.

          3.  Workup and staging. Workup is similar to endometrial cancer and involves endometrial biopsy or core biopsy of any masses protruding through the cervix. Pelvic imaging can be performed to delineate the size and origin of protruding masses. Staging for LMS and ESS is summarized in Table 24-4, As more is discovered about the biology and activity of these rare cancers, uterine carcinosarcomas may be considered more closely related to poorly differentiated endometrial carcinomas, and therefore they are staged using the 2009 FIGO staging for endometrial cancer (Table 24-2). Patients should be treated primarily with surgical exploration with appropriate staging, as primary radiotherapy and chemotherapy have very disappointing results.

          4.  Therapy and prognosis. Although each histologic subtype of sarcoma behaves differently, in general, survival is poor, with more than half the number of patients dying of their disease. For stage I and II disease, adjuvant RT often improves local recurrences but has little impact on long-term survival. Cytotoxic chemotherapy may have a role in the adjuvant setting. Hormonal therapy with high dose progestin therapy (megestrol acetate, 240 to 360 mg p.o. daily) has shown activity against endometrial stromal sarcomas, especially those that are low grade. Advanced stage (III/IV) and recurrent disease have been treated with radiotherapy with minimal success. Chemotherapy is most often used in this setting since phase II trials have shown tolerable toxicities and improved response compared to historical data. Single agent doxorubicin (60 mg/m² IV q3 weeks) or ifosfamide (1.2 to 1.5 g/m² IV q.d. × 4 to 5 days) have shown activity against LMS with approximate response rates of 25% and 20%, respectively. Combination gemcitabine (900 mg/m² IV on day 1 and 8, q3 weeks) and docetaxel (75 mg/m² IV q3 weeks) showed favorable response rates for completely resected stage I–IV disease as well as advanced and recurrent disease (Gynecol Oncol 2009;112:563). For carcinosarcomas, ifosfamide plus MESNA, with or without cisplatin, showed response rates of 30% to 50% in patients with advanced, persistent, or recurrent disease (Gynecol Oncol 2000;79:147). The combination therapy produced higher response rates but greater toxicity and no survival advantage over single-agent ifosfamide (GOG117). This combination chemotherapy regimen had similar patient outcomes as WAI for stage I–IV disease in a phase III GOG trial (GOG 150). Survival in advanced disease patients was improved by the addition of paclitaxel (135 mg/m² IV q3 weeks up to 8 cycles to ifosfamide). A phase II trial also showed acceptable response rates with paclitaxel and carboplatin in the treatment of carcinosarcoma patients with advanced disease (J Clin Oncol 2010;28:2727). Surgical resection of recurrent sarcoma and chemotherapy has shown to be beneficial in other soft tissue sarcomas, and may provide a survival advantage in uterine sarcomas as well.

          5.  Current focus. Recent chemotherapy trials for advanced or recurrent LMS have included doxorubicin, 40 mg/m², mitomycin, 8 mg/m², and cisplatin, 60 mg/m² q3 weeks; liposomal doxorubicin (Doxil), 50 mg/m² IV q4 weeks; and paclitaxel, 175 mg/m² i.v. over a 3-hour period q3 weeks. Further studies are underway to establish the use of paclitaxel and carboplatin in the treatment of advanced carcinosarcoma. Determining risk factors, prognostic factors, and the tumorigenesis for uterine sarcomas is also a focus for current research.

      D.  Gestational trophoblastic disease (GTD)

          1.  Background. Abnormal growth of the human trophoblast is called GTD

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