Faculty Bibliography

OBJECTIVE:To describe the clinical presentation of hydatidiform molar pregnancy in women under the age of 20 years. In addition, we sought to understand if this adolescent population manifests differences in clinical factors compared to an adult population that may affect outcome. STUDY DESIGN/METHODS:We used a database from the New England Trophoblastic Disease Center to analyze clinical data from all women followed for molar pregnancy between 1970 and 2009 with complete follow-up information. This population was stratified by age and clinical parameters including presenting signs, molar histology and development of gestational trophoblastic neoplasia (GTN). Univariable and multivariable logistic regression was employed to discern clinical factors that associated with adolescent age. The Partners Human Research Committee approved this study. RESULTS:We identified 1,494 women diagnosed with hydatidiform mole (HM), of which 220 (14.7%) were adolescents defined as age <20 years. The most common presenting clinical signs were vaginal bleeding and an enlarged uterus compared to dates. Median gestational age at diagnosis was 13.4 weeks, not different from that in the adult population. Similarly, no difference in presenting human chorionic gonadotropin was observed between the adult and adolescent populations. Adolescents presented with a significant overrepresentation of complete mole (86% vs. 75%, p < 0.001) compared to adults. Complete mole was associated with a heightened risk of developing GTN (OR 2.6, 95% CI 1.9-3.5), and despite the association of complete mole with young maternal age, univariable analysis showed no difference in the rate of GTN observed between adolescents and adults (24% vs. 30%, p = 0.08). Multivariable analysis controlling for molar histology demonstrated that adolescent age was associated with a decreased risk of GTN (hazard ratio 0.67, 95% CI 0.48-0.93). CONCLUSION/CONCLUSIONS:Adolescents account for a substantial proportion of the population with HM. They commonly present with vaginal bleeding. Though this population develops a complete mole with a higher frequency than adults, adolescents appear to have a significantly decreased risk of developing GTN.

OBJECTIVE:To evaluate the clinical outcomes in adolescents with gestational trophoblastic neoplasia (GTN) compared to adult women. STUDY DESIGN/METHODS:Patients with International Federation of Gynecology and Obstetrics criteria for GTN who underwent treatment between January 1, 1973, and December 31, 2010, were identified from the Donald P. Goldstein, M.D., Trophoblastic Tumor Registry of the New England Trophoblastic Disease Center. Adolescents included patients <20 years old at the time of diagnosis. Standard univariate analyses were performed, as were multivariate analyses with logistic regression to control for potential confounding variables. RESULTS:We identified 423 women with GTN; 50 (12%) patients were adolescents (<20 years old), and 373 (88%) were > or = 20 years old. Both groups had the same rate of low-risk GTN score (98% vs. 98%, p = 0.9). In the adolescent group 47 (94%) women had stage I GTN, and 3 (6%) had stage III. In the adult group 304 (81.5%) women had stage I GTN, 4 (1%) had stage II, 64 (17%) had stage III and only 1 (0.5%) had stage IV disease (p = 0.7). Adolescents at molar presentation had higher rates of anemia (30% vs. 14%, p = 0.001), vaginal bleeding (86% vs. 67%, p = 0.001), and a uterus with size greater than dates (42% vs. 24%, p = 0.007). Factors determined to significantly influence resistance to initial chemotherapeutic treatment on multivariate analysis were beta-hCG level at molar presentation > 100,000 mIU/mL, beta-hCG level at persistence >20,000 mIU/mL, the presence of metastasis, and duration of disease > 4 months. Age <20 years old was not a prognostic factor of resistance to initial chemotherapeutic treatment. CONCLUSION/CONCLUSIONS:There was no difference between adolescents and adult women in the rates of low-risk GTN, stage of GTN, and the frequency of resistance to initial chemotherapeutic treatment.

OBJECTIVE:To assess the influence of hydatidiform mole (HM) management setting (reference center versus other institutions) on gestational trophoblastic neoplasia (GTN) outcomes. METHODS:This cohort study included 270 HM patients attending Botucatu Trophoblastic Diseases Center (BTDC, São Paulo State University, Brazil) between January 1990 and December 2009 (204 undergoing evacuation and entire postmolar follow-up at BTDC and 66 from other institutions [OIs]). GTN characteristics and outcomes were analyzed and compared according to HM management setting. The confounding variables assessed included age, gravidity, parity, number of abortions and HM type (complete or partial). Postmolar GTN outcomes were compared using Mann-Whitney's test, chi2 test or Fisher's exact test. RESULTS:Postmolar GTN occurred in 34 (34/204 = 16.7%) BTDC patients and in 27 (27/66 = 40.9%) of those initially treated in other institutions. BTDC patients showed lower metastasis rate (5.8% vs. 48%, p = 0.003) and lower median FIGO (2002) score (2.00 [1.00, 3.00] vs. 4.00 [2.00, 7.00], p = 0.003]. Multiagent chemotherapy to treat postmolar GTN was required in 2 BTDC cases (5.9%) and in 8 OI cases (29.6%) (p = 0.017). Median time interval between molar evacuation and chemotherapy onset was shorter among BTDC patients (7.0 [6.0, 10.0] vs. 10.0 [7.0, 16.0], p = 0.040). CONCLUSION/CONCLUSIONS:BTDC patients showed GTN characteristics indicative of better prognosis. This underscores the importance of GTD specialist centers.

OBJECTIVE:This study aimed to examine the pattern of recurrence in patients with endometrioid endometrial cancer and to identify clinically important prognostic factors in the recurrent population. METHODS:With institutional review board approval, a retrospective review identified 1061 patients who underwent primary surgery and treatment of endometrioid endometrial cancer at our institution from 1994 to 2007. Of this cohort, 77 (7.2%) patients developed a recurrence. Clinical factors were recorded, and Spearman correlation coefficients and χ test were used to determine associations between groups. Kaplan-Meier survival estimates and Cox proportional-hazards model were used to determine how prognostic variables affected survival after recurrence (RS) and overall survival (OS). RESULTS:Of 77 patients, site of recurrence was not available in 5 patients. The distribution of recurrence in the remaining 72 patients was as follows: isolated vaginal 18% (13/72), nonvaginal pelvic 12% (9/72), distant 31% (22/72), abdominal 24% (17/72), and nodal 15% (11/72). There was an overrepresentation of advanced stage (P < 0.001) and high-grade (P < 0.003) at presentation in the recurrent group. Median OS was 3.4 years and median RS was 1.3 years. Low-grade tumors, early stage, and those with less than 50% myometrial invasion were associated with a significant OS and RS advantage. Age-adjusted isolated vaginal recurrence presented with a 1.2-year RS survival advantage (P < 0.03). An age-adjusted Cox proportional hazard ratio model incorporating significant prognostic variables demonstrated that the only independent variable associated with worse OS and RS was increased histologic grade with a hazard ratio of 2.31 (95% confidence interval, 1.25-3.97) for RS and 2.44 (95% confidence interval, 1.41-4.62) for OS. CONCLUSIONS:Those patients with high-grade histology at the time of initial diagnosis manifest a decreased OS and RS, suggesting that the intrinsic biology of the tumor has the greatest prognostic importance.

OBJECTIVE:We sought to examine the evolution of surgical care for early-stage endometrial cancers and factors affecting use of laparoscopy. STUDY DESIGN/METHODS:Women with surgically managed early-stage endometrial cancer were divided into 2 groups corresponding to before and after addition of faculty with formal fellowship training in laparoscopic staging and access to a robotic surgery platform. RESULTS:In all, 502 women were identified. Laparoscopic management increased from 24-69% between time periods (P < .0001). Performance of comprehensive surgical staging, and lymph node counts, increased (P < .0001) despite an increase in median body mass index (P = .001). A traditional "straight stick" technique was performed in 72% of laparoscopic cases during the later period. Laparoscopy patients had lower estimated blood losses and shorter hospital stays (each P < .0001) compared to laparotomy patients. CONCLUSION/CONCLUSIONS:Addition of faculty with formal fellowship training in laparoscopic staging and access to a robotic surgery platform shifted management of early-stage endometrial cancer toward laparoscopy.

OBJECTIVES/OBJECTIVE:Gynecologic carcinosarcoma is an aggressive malignancy that requires more effective treatment approaches. However, therapeutic implications regarding the specific gynecologic site of origin and the admixture of carcinomatous and sarcomatous elements that define this tumor remain uncertain. Therefore, broad genotyping was performed to identify tissue-specific somatic mutational profiles that may help direct targeted therapies in this complex neoplasia. METHODS:Genotyping was conducted on primary gynecologic carcinosarcomas arising from various disease sites (uterus, ovary, fallopian tube, vagina) and within isolated histological subcomponents. Nucleic acids extracted from diagnostic tissue were used in a genotyping platform that simultaneously queried >120 common mutations across 14 cancer genes. Mutational status was correlated with clinical variables using logistic regression and Kaplan-Meier survival estimates. RESULTS:Cancer gene mutations were identified in 46% of the 52 patient cohort and include TP53 (23%), PIK3CA (19%), KRAS (15%), CTNNB1 (4%) and NRAS (2%). Mutation in a single gene was observed in 31% of patient samples, while synchronous mutations involving 2 and 3 genes were noted in 13% and 2% of samples, respectively. Comparative evaluation of the carcinomatous and sarcomatous elements within a tumor demonstrated a similar mutation signature. Mutations in PIK3CA, KRAS and NRAS were exclusive to tumors of uterine origin and age-adjusted Cox proportional hazards modeling associated advanced age, stage and TP53 mutations with decreased survival in the uterine subset. CONCLUSION/CONCLUSIONS:While carcinosarcomas across gynecologic disease sites are histologically similar, therapeutically relevant mutations in the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways predominated in carcinosarcomas arising in the uterus.

INTRODUCTION/BACKGROUND:Carcinosarcoma of the ovary is a rare tumor with a grim prognosis. Chemotherapy for these tumors is chosen according to guidelines established for epithelial ovarian cancer (EOC). The purpose of this study is to compare response to chemotherapy and survival in patients with advanced stage carcinosarcoma of the ovary. METHODS:We identified women with advanced carcinosarcoma of the ovary who underwent first-line platinum and taxane-based chemotherapy. Each case was matched to two women with serous EOC. Cases and controls were matched by age, stage, and year of diagnosis. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the log-rank test and Cox proportional hazards model. RESULTS:Fifty women treated with first line platinum and taxane-based chemotherapy had advanced carcinosarcoma of the ovary and were selected as cases. The response rates to chemotherapy for cases and controls were 62% and 83% (P=0.03), respectively. Median progression-free survival was 11 months (95% CI, 8 to 14 months) versus 16 months (95% CI, 12 to 21 months; P=0.02) and median overall survival was 24 months (95% CI, 18 to 29 months) versus 41 months (95% CI, 33 to 49 months; P=0.002) for cases and controls, respectively. CONCLUSION/CONCLUSIONS:Patients with advanced carcinosarcoma of the ovary have a poorer response to platinum and taxane-based first-line chemotherapy and worse survival, compared to patients with serous EOC. Aggressive surgical treatment may play an important role. However, other alternative systemic therapeutic approaches should be sought for patients with carcinosarcoma of the ovary.

PURPOSE/OBJECTIVE:We sought to examine how splenectomy as part of up-front cytoreductive surgery in ovarian cancer influences the postoperative course and affects survival. METHODS:We reviewed cases of ovarian cancer diagnosed at Massachusetts General Hospital from 1994 to 2008 and found 44 patients who had a splenectomy as part of their up-front cytoreductive surgery. These were compared to 171 patients who did not undergo splenectomy. We evaluated age at diagnosis, estimated blood loss, percentage of patients whose disease was optimally cytoreduced (<1 cm), reason for splenectomy (oncologic vs. surgical), length of stay, time to first chemotherapy treatment, and survival. RESULTS:In the splenectomy cohort, the mean age at diagnosis was 64 (44-83) years. A total of 37 of 44 (84%) patients were optimally cytoreduced. Mean estimated blood loss was 1326 ml. The purpose of splenectomy was to accomplish an optimal cytoreduction (oncologic) in 82% of cases. Median length of stay was 13 (6-76) days. Median time to first chemotherapy was 13.5 (5-54) days. The median disease-free interval and overall survival of the splenectomy cohort were 8 and 30 months, respectively. The median overall survival for patients whose disease was optimally cytoreduced in the splenectomy cohort compared to the no-splenectomy group was 30 and 45 months (P < 0.045), respectively. CONCLUSIONS:The addition of splenectomy to up-front cytoreductive surgery was feasible and safe. However, it appears to carry with it a shortened survival that is unrelated to postoperative morbidity. Our data raise the questions that splenectomy is needed for optimal cytoreduction in more biologically aggressive disease and that splenectomy may be an independent prognostic factor related to depressed immune function.