Clinical outcomes with utilization of high-potency topical steroids in patients with lichen sclerosus-associated vulvar cancer.

OBJECTIVES: To evaluate the impact of high-potency topical steroid use on risk of recurrence of lichen sclerosus-associated vulvar cancer. METHODS: This is a retrospective cohort study evaluating patients with lichen sclerosus (LS)- associated vulvar squamous cell cancer (VSCC). Demographic and clinical outcome data were compared between two comparison groups: patients who received steroids, mainly clobetasol, and patients who did not receive steroids following treatment of LS-related vulvar cancer. Categorical variables were compared using Fisher's exact test or chi-square test. Continuous variables were compared using a two-sided student's t-test. Time to recurrence (TTR) and overall survival (OS) were analyzed using Kaplan-Meier survival plot and compared using Mantel-Cox log rank test. Cox proportional hazard regression models were conducted to generate hazard ratios for both TTR and OS. A p value of <0.05 was considered statistically significant. RESULTS: A total of 49 patients were included, with 36 patients receiving steroid treatment and 13 patients in the expectant management group. The median age of diagnosis was 68. The average BMI was 31.7 +/- 7.0. The median length of follow up was 41 months. The majority of patients were diagnosed with stage I VSCC. There was no difference in demographics or oncologic management of vulvar cancer between the two cohorts. Overall recurrence was decreased among patients who received steroid treatment when compared to patients who did not, 12 patients (33.3%) versus 9 patients (69.2%) respectively (p = 0.048). CONCLUSIONS: High-potency topical steroid use following treatment of lichen sclerosus-associated vulvar squamous cell carcinoma is associated with decreased risk of recurrence and prolonged median time to recurrence.

Optimal overall treatment time for adjuvant therapy for women with completely resected, node-positive vulvar cancer.

INTRODUCTION: The optimal overall treatment time (OTT) from radical surgery to the end of adjuvant radiation therapy for some squamous cell carcinomas has been found to impact treatment outcomes. This study aims to identify the impact of OTT on overall survival (OS) for women with completely resected, node-positive squamous cell carcinomas of the vulva. MATERIALS AND METHODS: The National Cancer Data Base was queried for women with surgically resected, node-positive vulvar squamous cell carcinomas between 2004 and 2016 who were treated with adjuvant radiation therapy. Kaplan-Meier analysis with log-rank test and Cox proportional hazards tests were utilized for OS calculations. RESULTS: A total of 1500 women met inclusion criteria. The median OTT was 104 days. Shorter OTT was associated with age, facility volume, private insurance, and duration of post-operative hospitalization. Median OS with OTT ≤ 104 days was 56.1 months vs 45.4 months if ≥105 days (p = 0.015). On multivariable Cox analysis, OTT was independently associated with an increased risk of death of 0.4% per additional day (95%CI 1.001-1.007, p = 0.003), as were age at diagnosis (HR 1.031 [95%CI 1.024-1.037], p < 0.001), number of nodes positive (HR 1.031 [95%CI 1.024-1.037], p = 0.006), the use of concurrent chemotherapy (HR 0.815 [95%CI 0.693-0.960], p = 0.014) and increasing pT/pN stage. After propensity adjustment for factors predicting a shorter OTT, OTT continued to be associated with an increased risk of death per additional day (HR 1.004 [95%CI 1.001-1.007], p = 0.007). CONCLUSION: Overall treatment time is an independent risk factor for death in women being treated with adjuvant radiation therapy following complete resection of node-positive squamous cell carcinoma of the vulva.

Survival disparities in vulvar cancer patients in Commission on Cancer®-accredited facilities.

OBJECTIVES: To investigate survival disparities and prognostic factors in vulvar cancer by age at diagnosis. METHODS: Women who underwent surgery and were diagnosed with stage I-IV vulvar cancer from 2004 to 2014 in the National Cancer Database were eligible. Proportions were compared using Chi-Square test. Survival was evaluated using Cox analysis. RESULTS: There were 18,207 eligible women. Median age at diagnosis was 64 years, and 31% diagnosed ≥75 years old were categorized as elderly. Most vulvar cancers were diagnosed at stage I and with squamous histology. Diagnosis with higher stage or non-squamous histology was more common in elderly vs. non-elderly patients (P < 0.001). Survival was 3.5 times worse in the elderly than the non-elderly (P < 0.0001). Risk of death for each 5-year increment in age increased by 22% for non-elderly and 43% for elderly patients (P < 0.0001). The prognostic value of comorbidity score, stage, regional node assessment and histology was smaller in elderly vs. non-elderly women (each P < 0.05). Adjuvant chemoradiotherapy (CTRT) use in the elderly vs. non-elderly was rare for stage I-II disease (3% vs. 2%) and more common for stage III-IV disease (6% vs. 43%), respectively (P < 0.0001). The survival disadvantage for elderly patients persisted following no adjuvant therapy, radiotherapy or chemotherapy alone, or CTRT (P < 0.0001). In stage III-IV disease, survival was superior following CTRT vs. radiotherapy when diagnosed <75 years (HR = 0.80, 95% CI = 0.69-0.93) but not in the elderly (HR = 0.99, P > 0.05). CONCLUSIONS: Age-associated risk of death increased at different rates in vulvar cancer and was larger in elderly vs. non-elderly patients. The impact of other prognostic factors was smaller in elderly vs. non-elderly women. The survival benefit of CTRT over radiotherapy in stage III-IV did not extend to the elderly.

Race-driven survival differential in women diagnosed with endometrial cancers in the USA.

OBJECTIVE: African American women are increasingly being diagnosed with advanced and type II histology endometrial cancers. Outcomes have been observed to be worse in African American women, but whether or not race itself is a factor is unclear. We sought to evaluate the rates of diagnosis and outcomes on a stage-by-stage basis with respect to race using a large national cancer registry database. METHODS: The National Cancer Data Base was searched for patients with surgically staged non-metastatic endometrial cancer between 2004 and 2015. Women were excluded if surgical stage/histology was unknown, there was no follow-up, or no information on subsequent treatment. Pairwise comparison was used to determine temporal trends and Cox hazards tests with Bonferroni correction were used to determine overall survival. RESULTS: A total of 286 920 women were diagnosed with endometrial cancer and met the criteria for analysis. Median follow-up was 51 months (IQR 25.7-85.3). In multivariable models, in women with stage I disease, African American women had a higher risk of death than Caucasian women (HR 1.262, 95% CI 1.191 to 1.338, p<0.001) and Asian/Pacific Islander women had a lower risk of death than Caucasian women (HR 0.742, 95% CI 0.689 to 0.801, p<0.001). This held for African American women with stage II type I and type II disease (HR 1.26, 95% CI 1.109 to 1.444, p<0.001 and HR 1.235, 95% CI 1.098 to 1.388, p<0.001) but not for Asian/Pacific Islander women. African American women with stage IIIA-B disease also had a higher risk of death for type I and type II disease versus Caucasian women (HR 1.221, 95% CI 1.045 to 1.422, p=0.010 and HR 1.295, 95% CI 1.155 to 1.452, p<0.001). Asian/Pacific Islander women had a lower risk of death than Caucasian women with type I disease (HR 0.783, 95% CI 0.638 to 0.960, p=0.019) and type II disease (HR 0.790, 95% CI 0.624 to 0.999, p=0.05). African American women with stage IIIC1-2 had a higher risk of death with type I disease (HR 1.343, 95% CI 1.207 to 1.494, p<0.001) and type II disease (HR 1.141, 95% CI 1.055 to 1.233, p=0.001) whereas there was no significant difference between Caucasian women and Asian/Pacific Islander women. CONCLUSION: Race appears to play an independent role in survival from endometrial cancer in the USA, with African American women having worse survival on a stage-for-stage basis compared with Caucasian women.

Unplanned hospitalizations in a racially and ethnically diverse population of women receiving chemotherapy for epithelial ovarian cancer.

OBJECTIVES: Unplanned hospital admission following chemotherapy is a measure of quality cancer care. Large retrospective datasets have shown admission rates of 10-35% for women with ovarian cancer receiving chemotherapy. We sought to evaluate the prevalence and associated risk factors for hospital admission following chemotherapy in our racially diverse urban population. METHODS: After IRB approval, clinicopathologic and treatment data were abstracted from all patients with newly diagnosed epithelial ovarian cancer who received chemotherapy at our institution from 2005 to 2016. Two-sided statistical analyses and Cox regression analysis were performed using Stata. RESULTS: Of 217 evaluable patients, 87 (40%) had unplanned admissions following chemotherapy: adjuvant 64 (74%) and neoadjuvant 23(26%). Thirty (14%) had more than one admission. In total, there were 1314 days of hospitalization. The median readmission duration was 3 days. Body mass index and hypertension were predictive of readmission (p < 0.05). When comparing those readmitted more than once to those admitted once, both race and aspirin use were predictive of readmission (p < 0.05). Of those admitted more than once the self-identified race and ethnicity was 12 (40%) Hispanic, 8 (27%) White, 8 (27%) Black and 2 (7%) other. There was a significant difference in disease free (p = 0.01) and overall survival (p = 0.004) for patients with unplanned admission after chemotherapy as compared to those without admission. CONCLUSIONS: Readmission rates in our racially diverse patient population were higher than previously reported in the literature. Identifying patients at risk of readmission may play a role in chemotherapy decision-making, and resource allocation including patient care navigators.

Comparative Use of Napsin A and Glypican 3 to Distinguish Endometrial Clear Cell from Serous and Endometrioid Carcinomas.

OBJECTIVE: Diagnosis of endometrial clear cell carcinomas is difficult owing to the low reproducibility of histological cell type in high-grade endometrial cancers. Recently, immunoreactivity for napsin A and glypican 3 has been reported in clear cell cancers. We sought to evaluate the use of napsin A and glypican 3 staining to distinguish clear cell carcinoma from other high-grade endometrial cancers. METHODS/MATERIALS: Twenty cases of pure and mixed endometrial clear cell carcinoma were extracted from the 2000-2014 archival material in the Departments of Obstetrics & Gynecology and Pathology at Montefiore Medical Center and compared to serous and grade 3 endometrioid controls. Representative sections were stained with monoclonal antibodies to napsin A and glypican 3. Immunostains were independently reviewed by 2 pathologists to assess frequency and pattern of staining. Charts were reviewed for clinicopathologic and treatment data. RESULTS: Granular cytoplasmic positivity for napsin A was observed in 70% of endometrial clear cell carcinomas; only 25% showed cytoplasmic or membranous glypican 3 positivity. No serous or high-grade endometrioid tumors stained for either marker. No cases of clear cell carcinoma that stained negative for napsin A stained positive for glypican 3. No difference in the immunohistochemical profile was found between pure and mixed clear cell carcinomas and between early- and advanced-stage clear cell carcinomas. CONCLUSIONS: Napsin A is a more sensitive marker for endometrial clear cell carcinoma than glypican 3. In histologically ambiguous cases, napsin A and glypican 3 may help distinguish clear cell carcinoma from other high-grade histologies. Further investigation of endometrial clear cell carcinoma is needed to identify additional diagnostic tools for this rare histology. Correlation of a unique immunohistochemical profile and clinical outcomes is necessary.

Racial Differences in Survival From Epithelial Ovarian Cancer Are Associated With Stage at Diagnosis and Use of Neoadjuvant Therapy: A 10-Year Single-Institution Experience With a Racially Diverse Urban Population.

OBJECTIVE: The aim of this study was to evaluate the racial/ethnic disparities in ovarian cancer survival in a diverse population. METHODS: We performed a retrospective cohort study evaluating all patients with epithelial ovarian cancer who received primary treatment at Montefiore Medical Center from 2005 to 2015. Clinicopathologic and survival data were abstracted from medical records. Two-sided statistical analyses were performed using SAS 9.3. RESULTS: Three hundred forty-four evaluable patients were identified: 85 (25%) black, 107 (31%) white, 74 (21%) Hispanic, and 78 (23%) other. Black patients were more likely to present with stage IV disease (P = 0.01) and receive neoadjuvant chemotherapy (P < 0.01). By Kaplan-Meier survival analysis, black race was associated with worse recurrence-free survival (P = 0.01) when compared with white race. In multivariate Cox regression model including treatment and stage, race was no longer associated with survival. In a separate multivariate analysis, utilization of neoadjuvant chemotherapy was associated with black race (odds ratio 4.03; 95% confidence interval, 1.56-10.38; P < 0.01) and stage IV disease (odds ratio 3.44; 95% confidence interval, 1.66-7.12; P < 0.01). CONCLUSIONS: In a racially/ethnically diverse population with ovarian cancer, black women had poorer disease-free survival than whites, although this was statistically accounted for by stage at diagnosis and use of neoadjuvant therapy. Research is needed to determine how differences in access/utilization of care and genetic differences in tumor biology may impact late stage diagnosis and use of neoadjuvant chemotherapy among black ovarian cancer patients.

Adjuvant Pelvic Radiation "Sandwiched" Between Paclitaxel/Carboplatin Chemotherapy in Women With Completely Resected Uterine Serous Carcinoma: Long-term Follow-up of a Prospective Phase 2 Trial.

OBJECTIVE: We prospectively evaluated patients with completely resected uterine serous carcinoma (USC) treated with radiation "sandwiched" between carboplatin/paclitaxel (C/T). The primary objective was to determine the safety profile, and the secondary outcome was to evaluate progression-free and overall survival. METHODS: Surgically staged patients with completely resected USC were enrolled to receive 3 cycles of paclitaxel 175 mg/m and carboplatin (area under the curve, 6-7.5) every 21 days, followed by radiotherapy and an additional 3 cycles of T/C at area under the curve of 5-6 (6 cycles + radiotherapy). Toxicity was graded according to National Cancer Institute Common Toxicity Criteria, version 4.03. Kaplan-Meier and log-rank tests were used to compare survival probabilities. RESULTS: One hundred forty patients were enrolled, of which 132 were evaluable, completed at least 3 cycles of chemotherapy and radiation. One hundred seven (81%) completed 6 cycles of chemotherapy and radiation. Patients with early-stage (I/II) disease have survival probabilities of 0.96 and 0.81 at 2 and 5 years. Patients with stage I USC and lymphovascular invasion have considerably worse overall survival, with 2.7 times' higher risk of death than those without lymphovascular invasion. Patients with late-stage (III/IV) disease had overall survival probabilities of 0.64 and 0.18 at 2 and 5 years, which is far higher survival than what has been reported in single-modality trials. Interestingly, and different than what is reported in other studies, there is no difference in survival in African Americans versus whites/other races who were evaluable. Of the 779 cycles administered, 22% and 14% of cycles were associated with grades 3 and 4 hematologic toxicities, respectively. Grades 3 and 4 nonhematologic toxicities occurred in 6.9% of cycles. CONCLUSIONS: The long-term follow-up in this study demonstrates that "sandwich" therapy is an efficacious, well-tolerated treatment approach with acceptable toxicities. Lymphovascular invasion (LVSI) is a significantly poor prognostic factor in stage I USC. Multimodal "sandwich" therapy should be considered in all USC patients who have undergone complete surgical resection and staging.

Utilization of intraperitoneal chemotherapy for optimally cytoreduced advanced stage epithelial ovarian cancer: A 10-year single institution experience with a racially diverse urban population.

OBJECTIVES: The goal of our study was to define utilization and clinical results of intraperitoneal (IV/IP) compared to intravenous (IV) chemotherapy in a racially and ethnically diverse population with optimally debulked advanced stage epithelial ovarian cancer. METHODS: After IRB approval, all patients diagnosed with epithelial ovarian cancer that underwent primary cytoreductive surgery at our institution from 2005 to 2016 were identified. Death was verified by the National Social Security Death Index. Patients who received at least one IV/IP cycle were analyzed in the IV/IP cohort. Kaplan-Meier and Cox proportional hazards models were performed. RESULTS: 96 patients with advanced stage optimally cytoreduced epithelial ovarian cancer (median follow up 33months) were identified. 51% and 49% of patients received IV/IP and IV chemotherapy, respectively. 27%, 22%, and 39% of patients were of white, black, and other race. Compared with IV chemotherapy only, IV/IP chemotherapy was associated with longer OS (log rank <0.002) and IV/IP chemotherapy versus IV chemotherapy alone was associated with a lower risk of death (HR=0.31, 95% CI 0.16-0.62, P<0.001). The median overall survival for the IV/IP and IV groups was 76months (95% CI 62 - not estimated) and 38months (95% CI 30-55), respectively. There was a trend toward higher risk of death for patients who completed fewer than 6cycles of IV/IP chemotherapy compared to women who completed 6 IV/IP cycles (HR=3.2, 95% CI 0.98-9.27 (P=0.05). No differences in patient or tumor characteristics were identified between these two groups of patients. CONCLUSIONS: In our racially diverse urban patients, 50% of patients received IV/IP chemotherapy and it was associated with improved overall survival compared to IV chemotherapy alone. Further investigation is needed to identify barriers to use of IV/IP chemotherapy.

Invasive endometrial adenocarcinoma and missed abortion: A case report.

BACKGROUND: Endometrial cancer is the most common gynecologic cancer in the United States; however, reports of endometrial cancer diagnosed in the setting of intrauterine gestation are rare. CASE: We describe the case of a clinical stage IA grade 1 endometrioid endometrial adenocarcinoma diagnosed at the time of D&C performed for missed abortion in a gravida 1 para 0 female with no identifiable risk factors. Fertility-sparing treatment, with combined oral megestrol acetate and levonorgestrel intrauterine system, was used to manage this incidentally-diagnosed carcinoma with endometrial sampling every 3 months.

Utility of a custom designed next generation DNA sequencing gene panel to molecularly classify endometrial cancers according to The Cancer Genome Atlas subgroups.

BACKGROUND: The Cancer Genome Atlas identified four molecular subgroups of endometrial cancer with survival differences based on whole genome, transcriptomic, and proteomic characterization. Clinically accessible algorithms that reproduce this data are needed. Our aim was to determine if targeted sequencing alone allowed for molecular classification of endometrial cancer. METHODS: Using a custom-designed 156 gene panel, we analyzed 47 endometrial cancers and matching non-tumor tissue. Variants were annotated for pathogenicity and medical records were reviewed for the clinicopathologic variables. Using molecular characteristics, tumors were classified into four subgroups. Group 1 included patients with > 570 unfiltered somatic variants, > 9 cytosine to adenine nucleotide substitutions per sample, and < 1 cytosine to guanine nucleotide substitution per sample. Group 2 included patients with any somatic mutation in MSH2, MSH6, MLH1, PMS2. Group 3 included patients with TP53 mutations without mutation in mismatch repair genes. Remaining patients were classified as group 4. Analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, North Carolina, USA). RESULTS: Endometrioid endometrial cancers had more candidate variants of potential pathogenic interest (median 6 IQR 4.13 vs. 2 IQR 2.3; p < 0.01) than uterine serous cancers. PTEN (82% vs. 15%, p < 0.01) and PIK3CA (74% vs. 23%, p < 0.01) mutations were more frequent in endometrioid than serous carcinomas. TP53 (18% vs. 77%, p < 0.01) mutations were more frequent in serous carcinomas. Visual inspection of the number of unfiltered somatic variants per sample identified six grade 3 endometrioid samples with high tumor mutational burden, all of which demonstrated POLE mutations, most commonly P286R and V411L. Of the grade 3 endometrioid carcinomas, those with POLE mutations were less likely to have risk factors necessitating adjuvant treatment than those with low tumor mutational burden. Targeted sequencing was unable to assign samples to microsatellite unstable, copy number low, and copy number high subgroups. CONCLUSIONS: Targeted sequencing can predict the presence of POLE mutations based on the tumor mutational burden. However, targeted sequencing alone is inadequate to classify endometrial cancers into molecular subgroups identified by The Cancer Genome Atlas.

Association between diabetes mellitus and progression free survival in women with ovarian granulosa cell tumors.

•Diabetes mellitus confers worse survival in women with granulosa cell tumors.•Routine lymphadenectomy does not improve survival in women with granulosa cell tumors.•Women in this cohort had a high prevalence of concurrent breast cancer.•Further studies are needed to see if glycemic control improves survival outcomes.

Uterine sarcoma with ambiguous histomorphology: A case report.

BACKGROUND: Leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS) may display overlapping histomorphology, which may challenge diagnostic accuracy. Since LMS and ESS have vastly different clinical behavior and adjuvant therapy recommendations, accurate diagnosis is critical. CASE: We present the case of an 83-year-old female with postmenopausal bleeding who underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy for clinically atypical appearing leiomyomata. Histologically, dual populations of cells with morphologic features of low-grade ESS and high-grade spindle cell sarcoma were seen. Immunohistochemistry and molecular studies revealed the cells to be of smooth muscle derivation, rendering a diagnosis of high-grade LMS with heterogeneous morphology (stage IB). The patient received adjuvant gemcitabine plus docetaxel. She recurred 8 months after completion of chemotherapy and was transferred to hospice care. CONCLUSION: Ancillary studies, such as immunohistochemistry and molecular testing, aid in accurate subcategorization of uterine sarcomas with ambiguous histomorphology.

Development and validation of a targeted next generation DNA sequencing panel outperforming whole exome sequencing for the identification of clinically relevant genetic variants.

Next generation sequencing (NGS) technologies have revolutionized our approach to genomic research. The use of whole genome sequencing (WGS), whole exome sequencing (WES), transcriptome profiling, and targeted DNA sequencing has exponentially improved our understanding of the human genome and the genetic complexities underlying malignancy. Yet, WGS and WES clinical applications remain limited due to high costs and the large volume of data generated. When utilized to address biological questions in basic science studies, targeted sequencing panels have proven extremely valuable due to reduced costs and higher sequencing depth. However, the routine application of targeted sequencing to the clinical setting is limited to a few cancer subtypes. Some highly aggressive tumor types, like type 2 endometrial cancer (EC), could greatly benefit from routine genomic analysis using targeted sequencing. To explore the potential utility of a mid size panel (~150 genes) in the clinical setting, we developed and validated a custom panel against WGS, WES, and another commercially available targeted panel. Our results indicate that a mid size custom designed panel is as efficient as WGS and WES in mapping variants of biological and clinical relevance, rendering higher coverage, at a lower cost, with fewer variants of uncertain significance. Because of the much higher sequencing depth that could be achieved, our results demonstrate that targeted sequencing outperformed WGS and WES in the mapping of pathogenic variants in a breast cancer case, as well as a case of mixed serous and high-grade endometrioid EC, the most aggressive EC subtype.

Vesical clear cell adenocarcinoma arising from endometriosis: A mullerian tumor, indistinguishable from ovarian clear cell adenocarcinoma.

Endometriosis is associated with increased rates of ovarian, particularly clear cell, adenocarcinomas. Malignant transformation of ovarian endometriosis is most common but rare cases have been reported in the bladder, abdominal wall, diaphragm, and rectum. We present the case of a 44-year-old female with vesical clear cell adenocarcinoma arising in a background of endometriosis in the absence of other pelvic endometriosis. The malignancy was diagnosed on transurethral resection of bladder tumor and managed with radical surgery. Histology and immunohistochemical findings were consistent mullerian origin and indistinguishable from similar tumors arising in the female genital tract. Extrapolating from the gynecologic literature, the recommendation was made for adjuvant chemotherapy. Further studies are needed to clarify the optimal treatment paradigm for ovarian and bladder clear cell adenocarcinomas.