Positive peritoneal cytology in patients with endometrial cancer: Continued controversy despite shift in staging

Abstract

Endometrial cancer remains the most common gynecologic malignancy in developed countries and the second most common in developing parts of the world.1 In the United States, an estimated 50,000 new cases and over 8000 deaths from the disease were reported in 2013.1 Endometrioid histology represents the most common subtype and generally presents at an early stage, with a favorable prognosis. Other histologic subtypes, including serous and clear cell, tend to be more aggressive and have been documented to have a poorer outcome. Endometrial carcinoma is surgically staged based on the joint 2010 International Federation of Gynecology and Obstetrics (FIGO)/TNM classification system. Treatment includes total hysterectomy and bilateral salpingo-oophorectomy. In tumors with certain high-risk features, pelvic and para-aortic lymph node dissection also is performed. These features include high-grade histology (grade 3 endometrioid, serous, or clear cell), deeply invasive tumors, cervical involvement, and primary tumors >2 cm in greatest dimension. Compared with laparotomy, laparoscopic staging and treatment of endometrial carcinoma is associated with lower perioperative morbidity and comparable treatment effectiveness. A meta-analysis of 4 randomized trials supports this minimally invasive approach. In a randomized trial conducted by the Gynecologic Oncology Group (GOG) of over 2600 patients with uterine malignancy randomized to laparoscopy or laparotomy, it was noted that laparoscopic surgery was feasible and safe.3 Complication, recurrence, and survival rates were similar between the 2 groups, supporting the laparoscopic approach as less morbid. Other minimally invasive approaches, such as robot-assisted and single-port or laparoendoscopic single-site surgery (LESS), are newer techniques used for endometrial carcinoma staging. LESS technology allows the surgeon to complete the hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection, if performed, through a single incision. All surgical instruments, including the camera, are inserted through a single surgical site that measures approximately 1.5 cm in greatest dimension, usually placed at the level of the umbilicus. The 2010 staging system continues to require the collection of peritoneal cytology. However, under this new system, positive pelvic washings are no longer formally considered part of the staging system and, consequently, do not alter staging. No clear explanation or rationale was offered in the new staging system to explain the continued request to collect cytology without its results altering or impacting clinical care. An estimated 11% of patients undergoing staging for endometrial cancer will have positive peritoneal cytology, most commonly in the presence of extra-uterine disease.2 The prognostic significance of isolated positive cytology in the absence of extra-uterine disease is controversial. In a systematic review of over 50 studies, the prognosis associated with positive cytology varied based on the presence of other factors.4 The presence of positive peritoneal cytology in patients with otherwise low-risk tumors (grade 1 or 2, myometrial invasion <50%, no cervical involvement, no lymphovascular space invasion) had a significantly lower rate of recurrence (4.1% vs 32%) compared with other patients who had positive cytology and high-risk tumors.4 However, in another study of 14,704 patients using data from the Surveillance, Epidemiology, and End Results (SEER) registry, positive peritoneal cytology was an independent predictor of mortality, regardless of histologic subtype, among women with early stage (stage I or II) endometrial carcinoma.5 In that study, patients with high-risk disease, such as grade 3 endometrioid, clear cell, or serous histology, were more likely to have positive cytology compared with those who did not have these high-risk factors (17.5% vs 7.5%, respectively; P < .0001).5 Positive cytology also predicted significantly poorer survival, irrespective of histology and tumor grade.5 The risk of death was significantly greater among patients who had positive cytology compared with that among patients who had negative peritoneal cytology and stage IA disease (hazard ratio, 4.6; 95% confidence interval, 3.79-5.66).5 We generally do not consider positive cytology alone as a high-risk tumor criterion in the formulation of adjuvant treatment planning of patients with endometrial cancer. Treatment decisions in women with endometrial cancer should be based on extent of disease, as determined by staging, and final pathologic tumor features. Marcela del Carmen, MD, MPH, is Associate Professor of Obstetrics, Gynecology, and Reproductive Biology at Harvard Medical School. She has served on the Ovarian Cancer Committee for the Gynecologic Oncology Group, is a member of the American Board of Obstetrics and Gynecology PROLOG Task Force, and serves as oral examiner for the American Board of Obstetrics and Gynecology for both general gynecology and gynecologic oncology. Dr. del Carmen is the recipient of numerous teaching and service awards, including the National Council on Resident Education in Obstetrics and Gynecology (CREOG) Award, the Howard Ulfelder Teaching Award, the CINE Golden Eagle Award, CBS Cares, and the McGovern Award for Clinical Excellence. Dr. del Carmen's research focuses on surgical treatment of ovarian cancer and innovation in the treatment of rare gynecologic tumors.