SGO and the elephant that is still in the room: Wellness, burnout and gynecologic oncology.

OBJECTIVE: To measure wellness and burnout among gynecologic oncology clinicians and identify trends and at-risk populations to inform future interventions. METHODS: Gynecologic oncologist (GO) and advanced practice provider (APP) responses to the 2020 Society of Gynecologic Oncology State of the Society survey were analyzed. The Maslach Burnout Inventory criteria for burnout was used. Work-life balance was scored on a 5-point Likert scale. Chi-square tests were used to compare mental health factors and the prevalence of burnout. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for associations between burnout and gender. RESULTS: 543 survey responses were included for analysis. Most GO (54%) and all APP respondents were female. Female GOs were disproportionately affected by burnout particularly in the Northeast (female(F): 40.9% vs male(M): 19.1%, p = 0.007) and South (F: 42.5% vs M:22.9%, p = 0.01). Burnout in female GOs over 40 was 1.79 (CI: 1.13-2.83; p-value 0.01) times higher than similarly aged males. Females in non-private practice experienced burnout 1.66 times that of males in similar positions (CI: 1.18-2.94; p < 0.0001). Female GOs reported the worst work-life balance across all 5 domains. APPs and female GOs experienced more stress and feeling overwhelmed compared to men. GOs were more reluctant to see a mental health professional (p = 0.0003) or take medication (p = 0.009) than APPs. CONCLUSIONS: Burnout in gynecologic oncology persists in both genders and is felt most acutely by female GOs. APPs are not immune and would benefit from inclusion in future research to mitigate burnout in healthcare clinicians.

Long term follow up of BRCA1 and BRCA2 mutation carriers with unsuspected neoplasia identified at risk reducing salpingo-oophorectomy.

OBJECTIVES: The reported incidence of neoplasia identified at the time of risk-reducing salpingo-oophorectomy (RRSO) in germline BRCA1/2 mutation carriers ranges from 4 to 12% but long-term outcomes have not been described. We evaluated recurrence and survival outcomes of mutation carriers with neoplastic lesions identified at RRSO. METHODS: We identified BRCA1/2 mutation carriers with neoplasia at RRSO at three institutions. Data was collected on clinical variables, adjuvant treatment and follow-up. RESULTS: We identified 32 mutation carriers with invasive carcinomas (n=15) or high-grade intraepithelial neoplasia (n=17) that were not suspected prior to surgery. 26 occurred in BRCA1 and 6 in BRCA2 mutation carriers. Median and mean age for carcinomas were 50 years and 49.3 respectively, significantly younger than for intraepithelial neoplasm, median 53 years, and mean 55 years (p=0.04). For the 15 invasive carcinomas, median follow up was 88 months (range 45-172 months), 7 recurred (47%), median time to recurrence was 32.5 months and 3 have died of disease; 1 additional patient died of breast cancer. Overall survival was 73%, disease specific overall survival was 80% and disease free survival was 66%. For the 17 high-grade intraepithelial neoplasms, median follow up was 80 months (range 40-150), 4 were treated with chemotherapy. One recurred at 43 months and is currently not on therapy with a normal CA125, 16 months later. All patients with noninvasive neoplasia are alive. CONCLUSIONS: BRCA1 and BRCA2 mutation carriers with unsuspected invasive carcinoma at RRSO have a relatively high rate of recurrence despite predominantly early stage, small volume disease. High-grade intraepithelial neoplasms rarely recur as carcinoma and may not require adjuvant chemotherapy.

Hormone receptor expression in uterine sarcomas: prognostic and therapeutic roles.

OBJECTIVES.: The utility of hormone therapy in the management of uterine sarcomas is poorly defined. We hypothesize that estrogen receptor (ER) expression is common in uterine sarcomas, and carries prognostic significance. Further, we hypothesize that ER-positive uterine sarcomas respond to hormone therapy. METHODS.: We retrospectively reviewed charts of patients with uterine sarcomas. Stepwise Cox proportional hazards regression model was used to evaluate variables related to the risk of death: age, histology, stage, use of pelvic radiotherapy, and ER expression. In addition, we examined clinical outcomes in patients treated with aromatase inhibitors, megestrol acetate, depot medroxyprogesterone acetate, and tamoxifen. RESULTS.: Fifty-four patients underwent immunohistochemical staining, and 34 (63%) were ER-positive. Kaplan-Meier survival analysis and log-rank test indicated that patients with ER-positive sarcomas demonstrated improved overall survival when compared with ER-negative patients (median OS 36 vs. 16 months, p=0.004). Upon multivariate analysis, ER positivity retained significance as an independent predictor of survival (HR=0.32, CI 0.12-0.89, p=0.03). Four patients received hormonal treatment in the adjuvant setting and remained in remission (range of follow up: 18-68 months). Eighteen patients received hormone therapy in the setting of recurrent or progressive disease: fourteen (78%) demonstrated stable disease or complete or partial response (range of follow up: 6-124 months). CONCLUSIONS.: ER expression is common and is associated with improved overall survival in uterine sarcomas. Conducting immunohistochemical staining to ascertain ER status may aid with prognostication in this disease. Hormone therapy should be considered in patients with primary and recurrent ER-positive uterine sarcomas.

BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study.

There is a clear association between germ-line BRCA1 mutations and inherited ovarian cancer; however, the association between BRCA1 mutations and sporadic ovarian cancer remains ambiguous. The frequency of BRCA1 promoter hypermethylation as an epigenetic means of BRCA1 inactivation was determined for a large, population-based cohort of ovarian cancer patients. BRCA1 promoter hypermethylation was determined by methylation-specific restriction digestion of tumor DNA, followed by Southern blot analysis and confirmed by methylation-specific PCR. BRCA1 promoter hypermethylation was observed in 12 of 98 ovarian tumors. BRCA1 methylation status of the primary tumor was conserved in six recurrent tumors after interim chemotherapy. None of the 12 tumors with BRCA1 promoter hypermethylation demonstrated BRCA1 protein expression by immunohistochemistry. BRCA1 methylation was only seen in ovarian cancer patients without a family history suggestive of a breast/ ovarian cancer syndrome. Therefore, the 12 BRCA1 methylated tumors represented 15% (12 of 81) of the sporadic cancers analyzed in this study. Although the clinical significance of BRCA1 promoter hypermethylation is yet to be determined, promoter hypermethylation may be an alternative to mutation in causing the inactivation of the BRCA1 tumor suppressor gene in sporadic ovarian cancer.

A case of fatal pulmonary thromboembolism associated with the use of intravenous estrogen therapy.

OBJECTIVE: To report a case of fatal pulmonary embolism associated with the use of i.v. estrogen therapy for menometrorrhagia. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 52-year-old woman with fibroid uterus treated with GnRH analogues with add-back therapy who presented with excessive vaginal bleeding. INTERVENTION(S): Intravenous conjugated estrogens were administered for a total of six doses. MAIN OUTCOME MEASURE(S): Fatal thromboembolic event. RESULT(S): The day after i.v. conjugated estrogens were administered, the patient had only scant vaginal bleeding, but she experienced the sudden onset of respiratory distress, became comatose, and subsequently had ventricular fibrillation leading to asystole. All resuscitative efforts failed. Postmortem examination revealed bilateral pulmonary artery thromboembolism (saddle embolus). CONCLUSION(S): Intravenous conjugated estrogen therapy may be complicated by fatal thromboembolic events. This potential adverse effect must be considered in the use of such therapy for severe menometrorrhagia, especially when treating a patient at increased risk.

Identifying human papillomavirus subtypes in cervical biopsies with in situ DNA hybridization with biotinylated probes.

To test the utility of biotinylated DNA probes against various subtypes of human papillomavirus (HPV), we performed in situ DNA hybridization on routinely processed archival material from 30 patients with serial cervical biopsies including conization (group I) and a prospective group of 35 patients whose cervical biopsies showed various degrees of koilocytotic atypia and/or dysplasia (group II). Commercially available biotinylated probe cocktails against HPV types 6 and 11, 16 and 18, and 31, 35 and 51 were detected via the avidin-biotin horseradish peroxidase technique. Virus was found in 87% (26/30) of group I and 57% (20/35) of group II. Almost exclusively, viral types 16, 18, 31, 35 and 51 were detected in group I; 54% (19/35) of group II stained for types 16, 18 or 31, 35 and 51; 2.9% (1/35) stained for types 6 and 11. Nine percent of group II (3/35) showed coinfection with types 16, 18 and 31, 35 and 51. Three of six vulvar condylomata (50%) stained for types 6 and 11. In general, weaker staining was associated with greater dysplasia. In situ hybridization using biotinylated DNA probes is useful in identifying patients infected with dysplasia/carcinoma-associated HPV subtypes and can be performed easily on routine surgical specimens.

Molecular advances in gynecologic oncology.

Cancer is a genetic disease, and inherited or acquired genetic defects contribute to the initiation and progression of cancer. Improved molecular techniques have lead to the identification of many of these genetic mutations in gynecologic malignancies. The molecular characterization of cancer has provided a better understanding of tumor formation and the clinical behavior of different tumor types, with important implications for developing screening tests and prognostic markers. Applications of these findings have led to novel targeted gene therapies that correct the critical genetic defects seen in gynecologic cancers. Future research will focus on the clinical translation of these genetic alterations as targets of cancer prevention, screening, and treatment.

Effect of combination chemotherapy with cisplatin and cyclophosphamide on human immunodeficiency virus type-1 surrogate markers in a patient with advanced epithelial ovarian cancer.

This is the first report to evaluate the effects of combination chemotherapy on HIV-1 surrogate markers in an HIV-1-infected patient with an advanced epithelial ovarian cancer. Cisplatin combined with cyclophosphamide was well-tolerated, without significant changes in the HIV-1 p24 antigen, neopterin, beta 2-microglobulin, and CD4 values. The patient demonstrated a chemical and clinical response to therapy, without evidence of opportunistic infection or severe neutropenia. During the 6-month period of observation, treatment with cisplatin and cyclophosphamide did not significantly increase the risk of HIV-1 disease progression.

Malignant Brenner tumor mimicking a primary squamous cell carcinoma of the cervix.

An 86-year-old female presented with a necrotic cervical mass that was biopsy-proven squamous cell carcinoma. She had an elevated CA-125 and a pelvic mass. At surgery, this mass was found to be of adnexal origin and contiguous with the cervix. Histology showed a malignant Brenner tumor with abundant squamous differentiation eroding the cervix and simulating a primary cervical malignancy. We describe this case and review the literature on metastatic tumors to the cervix.

Pattern of lymph node metastases in clinically unilateral stage I invasive epithelial ovarian carcinomas.

PURPOSE: There is controversy regarding the pattern of lymphatic spread in unilateral stage I invasive ovarian carcinomas. The purpose of this study is to describe the incidence and distribution of lymph node (LN) metastases in ovarian carcinomas clinically confined to one ovary. METHODS: Ninety-six patients with disease visibly confined to one ovary were identified. Pathology reports were reviewed to identify metastatic LN involvement, number of involved nodes, and their locations. Patients with gross disease in the pelvis or abdomen or those who had grossly positive LNs removed for debulking were excluded from this review. RESULTS: Fourteen of ninety-six patients (15%) had microscopically positive LNs on pathologic review. All of these 14 patients had grade 3 tumors. Grade 3 tumors were more commonly seen in LN-positive versus LN-negative patients (P < 0.001). Pelvic nodes were positive in 7 patients (50%), paraaortic nodes in 5 patients (36%), and both in 2 patients (14%). Forty-two patients had LN sampling only on the side ipsilateral to the neoplastic ovary, 4 of whom (10%) had LN metastases. Fifty-four patients had bilateral sampling performed, 10 of whom (19%) had LN metastases. Of these 10 patients, isolated ipsilateral LN metastases were seen in 5 (50%) cases. Isolated contralateral LN metastases were seen in 3 (30%) cases, and bilateral metastases were seen in 2 (20%). CONCLUSIONS: In this cohort of patients with clinical stage I ovarian carcinoma with disease limited to one ovary, bilateral LN sampling increased the identification of nodal metastases. Ipsilateral sampling may result in the understaging of patients. Bilateral pelvic and paraaortic LN sampling is recommended to accurately stage ovarian carcinoma.

Combination chemotherapy with etoposide, cisplatin, and doxorubicin in mixed müllerian tumors of the adnexa.

Eleven patients with ovarian (9) or fallopian tube (2) mixed müllerian tumors who underwent primary surgery at Yale New Haven Medical Center between 1986 and 1994 were treated with etoposide, cisplatin, and doxorubicin. Responses were observed in three (60%) of five evaluable patients with two complete (40%) and one partial (20%) response. Median survival time was 17 months with an estimated 3-year survival of 18%. Survival may have been improved with earlier stage disease, but survival was not significantly improved with optimal surgical cytoreduction in patients with advanced disease. Four patients required dose reductions for myelosuppression and there was one treatment related death. Toxicity was comparable to other combination chemotherapy regimens. EPA has modest therapeutic activity in ovarian and fallopian tube MMT.

Allelotype of papillary serous peritoneal carcinomas.

OBJECTIVE: Papillary serous peritoneal carcinoma (PSPC) is histologically indistinguishable from papillary serous ovarian carcinoma (PSOC) with a similar clinical presentation, yet may differ in its carcinogenesis. The purpose of this study was to determine the incidence of allelic loss and the frequency of p53 mutation by p53 overexpression in PSPC compared to PSOC. METHODS: An allelotype analysis of 26 patients with PSPC was performed using 39 microsatellite markers from 25 chromosomal arms. Thirty-seven previously studied patients with PSOC served as the comparison. P53 mutations were detected by immunohistochemical protein overexpression. RESULTS: There was significantly less LOH in PSPC than PSOC. Both the number of chromosomes with LOH and the proportion of tumors with allelic loss were less frequent. Significant LOH, defined as >/=30% of informative tumors having loss at a chromosome locus, was seen on 4 chromosome arms in PSPC: 12p, 17p, 17q, and 18q, compared to 18 arms in PSOC: 4q, 5q, 6p, 6q, 9p, 9q, 12p, 12q, 13q, 15q, 16q, 17p, 17q, 18q, 19p, 19q, 22q, and Xq (P < 0.001). The median LOH frequency was higher in PSOC than PSPC, 43% versus 33%, respectively (P = 0.013), and more PSOC tumors had LOH than PSPC tumors, 91% versus 65% (P = 0.042). P53 overexpression was detected in 80% of PSPC tumors. CONCLUSIONS: LOH occurs less frequently in PSPC compared to PSOC. Chromosomal regions with high frequencies of LOH common to PSPC and PSOC, such as 12p, 17p, 17q, and 18q, may harbor tumor suppressor genes important in the carcinogenesis of both malignancies and likely include p53.