ChatGPT accurately performs genetic counseling for gynecologic cancers.

OBJECTIVE: Artificial Intelligence (AI) systems such as ChatGPT can take medical examinations and counsel patients regarding medical diagnosis. We aim to quantify the accuracy of the ChatGPT V3.4 in answering commonly asked questions pertaining to genetic testing and counseling for gynecologic cancers. METHODS: Forty questions were formulated in conjunction with gynecologic oncologists and adapted from professional society guidelines and ChatGPT version 3.5 was queried, the version that is readily available to the public. The two categories of questions were genetic counseling guidelines and questions pertaining to specific genetic disorders. The answers were scored by two attending Gynecologic Oncologists according to the following scale: 1) correct and comprehensive, 2) correct but not comprehensive, 3) some correct, some incorrect, and 4) completely incorrect. Scoring discrepancies were resolved by additional third reviewer. The proportion of responses earning each score were calculated overall and within each question category. RESULTS: ChatGPT provided correct and comprehensive answers to 33/40 (82.5%) questions, correct but not comprehensive answers to 6/40 (15%) questions, partially incorrect answers to 1/40 (2.5%) questions, and completely incorrect answers to 0/40 (0%) questions. The genetic counseling category of questions had the highest proportion of answers that were both correct and comprehensive with ChatGPT answering all 20/20 questions with 100% accuracy and were comprehensive in responses. ChatGPT performed equally in the specific genetic disorders category, with 88.2% (15/17) and 66.6% (2/3) correct and comprehensive answers to questions pertaining to hereditary breast and ovarian cancer and Lynch syndrome questions respectively. CONCLUSION: ChatGPT accurately answers questions about genetic syndromes, genetic testing, and counseling in majority of the studied questions. These data suggest this powerful tool can be utilized as a patient resource for genetic counseling questions, though more data input from gynecologic oncologists would be needed to educate patients on genetic syndromes.

Let's chat about cervical cancer: Assessing the accuracy of ChatGPT responses to cervical cancer questions.

OBJECTIVE: To quantify the accuracy of ChatGPT in answering commonly asked questions pertaining to cervical cancer prevention, diagnosis, treatment, and survivorship/quality-of-life (QOL). METHODS: ChatGPT was queried with 64 questions adapted from professional society websites and the authors' clinical experiences. The answers were scored by two attending Gynecologic Oncologists according to the following scale: 1) correct and comprehensive, 2) correct but not comprehensive, 3) some correct, some incorrect, and 4) completely incorrect. Scoring discrepancies were resolved by additional reviewers as needed. The proportion of responses earning each score were calculated overall and within each question category. RESULTS: ChatGPT provided correct and comprehensive answers to 34 (53.1%) questions, correct but not comprehensive answers to 19 (29.7%) questions, partially incorrect answers to 10 (15.6%) questions, and completely incorrect answers to 1 (1.6%) question. Prevention and survivorship/QOL had the highest proportion of "correct" scores (scores of 1 or 2) at 22/24 (91.7%) and 15/16 (93.8%), respectively. ChatGPT performed less well in the treatment category, with 15/21 (71.4%) correct scores. It performed the worst in the diagnosis category with only 1/3 (33.3%) correct scores. CONCLUSION: ChatGPT accurately answers questions about cervical cancer prevention, survivorship, and QOL. It performs less accurately for cervical cancer diagnosis and treatment. Further development of this immensely popular large language model should include physician input before it can be utilized as a tool for Gynecologists or recommended as a patient resource for information on cervical cancer diagnosis and treatment.

Barriers, facilitators, and recommendations for sexual orientation and gender identity data collection in community oncology practices.

BACKGROUND: Sexual orientation and gender identity (SOGI) data collection in community oncology practices is critical to identify and address cancer inequities, but less than 20% of NCI Community Oncology Research Program (NCORP)-affiliated practices regularly collect SOGI data despite widespread recommendations. We evaluated multilevel barriers and facilitators for SOGI data collection at NCORP practices. METHODS: We conducted 14 semi-structured interviews at seven purposefully sampled NCORP oncology practices. We interviewed one clinician (oncologist, advanced practice provider) and one clinic staff member per practice. Thematic analysis informed by the Consolidated Framework for Implementation Research (CFIR) was conducted to identify barriers and facilitators. RESULTS: Thematic saturation occurred after interviews at six practices and was confirmed with interviews at an additional practice. Participants highlighted multilevel barriers including low levels of understanding, information technology infrastructure, and perceived low relative priority. Not understanding the role of SOGI data in oncology care contributed to cis-heteronormative culture. At the clinic level, this culture coincided with a lack of processes and policies for collecting SOGI from all patients. At the care team level, perceived irrelevance to oncology care was related to discomfort asking SOGI, fear of patient discomfort, and limited awareness of SOGI in electronic health records. Suggested solutions included: normalizing asking SOGI questions, giving patients privacy to complete SOGI, and clarifying clinical relevance. CONCLUSIONS: SOGI data collection barriers stemmed from perceptions that SOGI disclosure does not influence care quality. Oncology teams may benefit from training on culturally sensitive SOGI collection, education on SOGI data relevance to oncology practices, and support for implementing SOGI data collection policies.

Survey of Clinical Providers and Allied Health Staff at a National Cancer Institute-Designated Comprehensive Cancer Center: Cultural Awareness in the Care of LGBTQ2S + Patients with Cancer.

To identify potential gaps in attitudes, knowledge, and practices towards LGBTQ2S + patients with a cancer diagnosis, a survey of clinical providers (CP) and allied health staff (AHS) was conducted to identify areas of improvement and guide development for future education and training. A previously published, validated survey was adapted at the direction of a LGBTQ2S + Patient and Family Advisory Council, and modified to include AHS. The survey was disseminated to all faculty and staff, and was adapted to the participants' self-identified level of patient interaction/care responsibilities. Subsections consisted of questions related to demographics, knowledge, attitudes, and practice behaviors towards participating in the care of LGBTQ2S + patients. Results were quantified using stratified analysis and an attitude summary measure. Of the 311 respondents, 179 self-identified as CPs and 132 as AHS. There was high agreement in comfort treating or assisting LGBTQ2S + patients by CP and AHS respondents, respectively. CPs possessed significantly higher knowledge regarding LGBTQ2S + health when compared to AHS; however, there remained high percentages of "neutral" and "do not know or prefer not to answer" responses regardless of clinical role. There was high agreement regarding the importance of knowing a patient's gender identity (GI) and pronouns (CP vs. AHS; 76.9% vs. 73.5% and 89.4% vs. 84.1%, respectively), whereas patient's sexual orientation and sex assigned at birth (CP vs. AHS; 51.1% vs. 53.5% and 58.6% vs. 62.9%, respectively) were viewed as less important. There was high interest in receiving education regarding the unique needs of LGBTQ2S + patients regardless of clinical role. Stratified analyses of CPs revealed early-career physicians (< 1-5 years from graduation) expressed higher interest in additional education and involvement with LGBTQ2S + -focused trainings when compared to mid- and late-career providers. This is the first study, to our knowledge, assessing the attitudes, knowledge, and practices of CPs and AHS regarding the care of LGBTQ2S + patients with cancer. Overall, there was high comfort treating/assisting LGBTQ2S + patients among CP and AHS respondents, respectively; yet, both groups possessed significant gaps in LGBTQ2S + -focused knowledge.

Genomic Determinants of Early Recurrences in Low-Stage, Low-Grade Endometrioid Endometrial Carcinoma.

Low-stage, low-grade endometrioid endometrial carcinoma (EEC), the most common histologic type of endometrial cancer, typically has a favorable prognosis. A subset of these cancers, however, displays an aggressive clinical course with early recurrences, including distant relapses. All statistical tests were 2-sided. Using a combination of whole-exome and targeted capture sequencing of 65 FIGO stage IA and IB grade 1 EECs treated with surgery alone, we demonstrate that chromosome 1q gain (odds ratio [OR] = 8.09, 95% confidence interval [CI] = 1.59 to 54.6; P = .02), PIK3CA mutation (OR = 9.16, 95% CI = 1.95 to 61.8; P = .01), and DNA mismatch repair-deficient molecular subtype (OR = 7.92, 95% CI = 1.44 to 87.6; P = .02) are independent predictors of early recurrences within 3 years in this patient population. Chromosome 1q gain was validated in an independent dataset of stage I grade 1 EECs subjected to whole-exome sequencing. Our findings expand on the repertoire of genomic parameters that should be considered in the evaluation of patients with low-stage, low-grade EEC.

Disparities in cancer screenings for sexual and gender minorities.

Sexual and gender minorities (SGM) include persons identifying as lesbian, gay, bisexual, transgender/non-binary, and queer experience a greater cancer burden than their heterosexual or cisgender counterparts. Access to cancer care includes prevention and early detection, however despite known increased risk for various malignancies among SGM individuals, cancer screening rates remain low. This commentary outlines disparities in cancer screening for SGM individuals and provides the current evidence-based screening guidelines for these patients.

Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies.

The lectin, galectin-3 (Gal3), has been implicated in a variety of inflammatory and oncogenic processes, including tumor growth, invasion, and metastasis. The interactions of Gal3 and MUC16 represent a potential targetable pathway for the treatment of MUC16-expressing malignancies. We found that the silencing of Gal3 in MUC16-expressing breast and ovarian cancer cells in vitro inhibited tumor cell invasion and led to attenuated tumor growth in murine models. We therefore developed an inhibitory murine monoclonal anti-Gal3 carbohydrate-binding domain antibody, 14D11, which bound human and mouse Gal3 but did not bind human Galectins-1, -7, -8 or -9. Competition studies and a docking model suggest that the 14D11 antibody competes with lactose for the carbohydrate binding pocket of Gal3. In MUC16-expressing cancer cells, 14D11 treatment blocked AKT and ERK1/2 phosphorylation, and led to inhibition of cancer cell Matrigel invasion. Finally, in experimental animal tumor models, 14D11 treatment led to prolongation of overall survival in animals bearing flank tumors, and retarded lung specific metastatic growth by MUC16 expressing breast cancer cells. Our results provide evidence that antibody based Gal3 blockade may be a viable therapeutic strategy in patients with MUC16-expressing tumors, supporting further development of human blocking antibodies against Gal3 as potential cancer therapeutics.

Case-scenario exploration of cancer disparities experienced by gender minority persons.

Transgender, non-binary, and gender non-conforming people, also referred to as gender minorities, have unique cancer prevention, treatment, and care needs and experience cancer health disparities compared to the cisgender population. We present four composite cases of the cancer care challenges experienced by gender minorities.

Genomic Alterations as Potential Therapeutic Targets in Extramammary Paget's Disease of the Vulva.

PURPOSE: To identify genomic alterations as potential therapeutic targets in extramammary Paget disease (EMPD) of the vulva. METHODS: We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. Microsatellite instability (MSI) was assessed by MSIscore. RESULTS: Tumors of 26 patients with EMPD underwent genomic sequencing. At diagnosis, all patients had noninvasive or microinvasive (< 1 mm) disease; invasive disease eventually developed in 2 patients. Primary treatment was surgery for 19 patients (73%) and imiquimod topical therapy for 7 (27%). Seven patients had ≥ 2 surgeries as part of clinical course (1 patient had 5 vulvar resections). Samples had a median of 2 coding mutations in the genes analyzed (range, 0-29). The most common mutations were in PIK3CA (n = 9; 35%), ERBB2 (4 mutations and 3 copy number alterations; 27%), and TP53 (n = 7; 27%). MSIscore was available for 23 samples; all were microsatellite stable. After tumor genomic profiling, a patient who was initially treated with multiple resections and imiquimod was found to have a PIK3CA p.E542K mutation. She underwent PI3K-inhibitor treatment for 18 months before disease progression. CONCLUSION: EMPD of the vulva has a chronic and relapsing course, often requiring multiple surgical resections. Effective topical treatments are lacking. We identified targetable mutations (PIK3CA or ERBB2) in > 25% of a real-world clinical cohort. Additional prospective research implementing targetable therapies for EMPD treatment is warranted.

Sexual harassment and gender discrimination in gynecologic oncology.

OBJECTIVE: To determine the prevalence of sexual harassment and perceptions of gender disparities affecting the careers of physicians in gynecologic oncology. METHODS: We conducted a survey of US physician members of the Society of Gynecologic Oncology. Participants were queried about demographics, sexual harassment experiences during training/practice, and perceptions of gender disparities in compensation and career advancement. Responses were categorized as "never" versus "ever" and compared using Fisher's exact test. RESULTS: The survey was sent to 1566 members-405 (255 females, 147 males, 3 other) responded (response rate 26%). Sixty-four percent reported having experienced sexual harassment during training/practice. Sexual harassment was experienced by 71% of females and 51% of males. Of these respondents, only 14.5% reported it. Reasons for not reporting included: "incident did not seem important enough" (40%); "did not think anything would be done about it" (37%); and "fear of reprisal" (34%). Female respondents were more likely to report gender affected their career advancement (34% vs. 10%; p ≤ .001) and compensation (64% vs. 19%; p ≤ .001); males were more likely to report no gender income disparity (91% vs. 57%; p ≤ .001). CONCLUSIONS: Sexual harassment during training/practice appears common among male and female gynecologic oncologists. Although most are aware of how to report an incident, few do so, mostly for fear of reprisal or concern nothing will be done. Despite practicing in a field defined by caring for women, female physicians more often perceive gender influences their compensation and career advancement. Awareness of these issues can lead to their elimination from our specialty.

Galectins and Ovarian Cancer.

Ovarian cancer is known for its aggressive pathological features, including the capacity to undergo epithelial to mesenchymal transition, promoting angiogenesis, metastatic potential, chemoresistance, inhibiting apoptosis, immunosuppression and promoting stem-like features. Galectins, a family of glycan-binding proteins defined by a conserved carbohydrate recognition domain, can modulate many of these processes, enabling them to contribute to the pathology of ovarian cancer. Our goal herein was to review specific galectin members identified in the context of ovarian cancer, with emphasis on their association with clinical and pathological features, implied functions, diagnostic or prognostic potential and strategies being developed to disrupt their negative actions.

Clinical patterns and genomic profiling of recurrent 'ultra-low risk' endometrial cancer.

OBJECTIVE: Despite good prognosis for patients with low-risk endometrial cancer, a small subset of women with low-grade/low-stage endometrial cancer experience disease recurrence and death. The aim of this study was to characterize clinical features and mutational profiles of recurrent, low-grade, non-myoinvasive, 'ultra-low risk' endometrioid endometrial adenocarcinomas. METHODS: We retrospectively identified patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA endometrioid endometrial cancers who underwent primary surgery at our institution, between January 2009 and February 2017, with follow-up of ≥12 months. 'Ultra-low risk' was defined as FIGO tumor grade 1, non-myoinvasive, and lacking lymphovascular space invasion. Tumor-normal profiling using massively parallel sequencing targeting 468 genes was performed. Microsatellite instability was assessed using MSIsensor. DNA mismatch repair (MMR) protein proficiency was determined by immunohistochemistry. RESULTS: A total of 486 patients with ultra-low risk endometrioid endometrial cancers were identified: 14 (2.9%) of 486 patients developed a recurrence. Median follow-up for non-recurrent endometrioid endometrial cancers: 34 (range 12-116) months; for recurrent endometrioid endometrial cancers: 50.5 (range 20-116) months. Patients with recurrent disease were older, had lower body mass index, and were most commonly non-White (p=0.025, p<0.001, and p<0.001, respectively). Other clinical characteristics did not differ. MMR immunohistochemistry was obtained for 211 (43%) tumors: 158 (75%) MMR-proficient and 53 (25%) MMR-deficient. Primary tumors of 9 recurrent and 27 non-recurrent endometrioid endometrial cancers underwent mutational profiling. Most were microsatellite stable (6/9, 67% recurrent; 25/27, 93% non-recurrent). Recurrent PTEN and PIK3CA mutations were present in both groups. Exon 3 CTNNB1 hotspot mutations were found in 4/9 (44%) recurrent and 8/27 (30%) non-recurrent (p=0.44). CONCLUSIONS: Patients diagnosed with ultra-low risk endometrioid endometrial cancers have an overall excellent prognosis. However, in our study, 2.9% of patients with no identifiable clinical or pathologic risk factors developed recurrence. Further work is warranted to elucidate the mechanism for recurrence in this population.

Clinical outcomes of patients with POLE mutated endometrioid endometrial cancer.

OBJECTIVES: Assess outcomes of a clinical cohort of patients with endometrioid endometrial cancer (EEC) harboring somatic POLE exonuclease domain mutations (EDMs). METHODS: Patients were consented to a protocol of tumor-normal massively parallel sequencing of 410-468 cancer related genes. EECs subjected to sequencing from 2014 to 2018 were reviewed. Tumors with somatic POLE EDMs were identified. EECs were assessed for microsatellite instability (MSI) using MSIsensor and immunohistochemical analysis for mismatch repair (MMR) proteins. RESULTS: Of the 451 EECs sequenced, 23 had a POLE EDM (5%): 20 primary and 3 recurrent tumors sequenced. Nineteen cases (83%) were stage I/II and 4 (17%) were stages III/IV. Thirteen EECs (57%) were of FIGO grades 1/2, 10 (43%) grade 3. All patients were treated with surgery and 17 (89%) received adjuvant therapy. Five (22%) demonstrated loss of DNA MMR protein expression, none were due to Lynch syndrome. MSIsensor scores were conclusive for 21 samples: 19 were microsatellite stable and 2 MSI-high. After median follow-up of 30 months, 4/23 (17%) developed recurrences: 3 with initial grade 3 stage I and 1 with grade 1 stage III disease. One patient with grade 2 stage IV EEC had progressive disease after treatment. CONCLUSIONS: Patients with POLE EDM EEC have been shown to have a favorable prognosis. In this real-world cohort of patients, de novo metastatic disease and recurrences in initially uterine-confined cases were observed. Further research is warranted before incorporating the presence of POLE EDM into decision-making regarding adjuvant therapy.

Fallopian Tube Carcinoma.

Primary fallopian tube carcinoma is a rare and difficult to cure disease. It is often grouped under the epithelial ovarian cancer umbrella, together with primary ovarian and peritoneal carcinomas. More recent evidence has suggested that epithelial ovarian cancers originate from a fallopian tube precursor. The mainstay of treatment is surgical cytoreduction and platinum-based chemotherapy. There is much debate over the best timing for surgery and the best approach to delivering the chemotherapy: traditional intravenous once every 3 weeks regimen, versus intraperitoneal, versus dose-dense intravenous regimens. Although these debates continue, novel targeted therapies, including bevacizumab and poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, have emerged. PARP inhibitors are particularly efficacious in patients with BRCA1/2 gene mutations, and their use has been shown to prolong patient survival. This article reviews the pathologic etiology; describes the heredity, treatment challenges, and controversies; and summarizes novel therapies in primary fallopian tube carcinoma.

Brain metastasis in epithelial ovarian cancer by BRCA1/2 mutation status.

OBJECTIVE: To evaluate clinical outcomes of patients with BRCA-associated ovarian cancer who developed brain metastases (BM). METHODS: Patients with epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC) and BM, treated at a single institution from 1/1/2008-7/1/2018, were identified from two institutional databases. Charts and medical records were retrospectively reviewed for clinical characteristics and germline BRCA mutation status. Appropriate statistics were used. RESULTS: Of 3649 patients with EOC, 91 had BM (2.5%). Germline mutation status was available for 63 (69%) cases; 21 (35%) of these harbored a BRCA1/2 mutation (15 BRCA1, 6 BRCA2). Clinical characteristics were similar between groups. BM were diagnosed at a median of 31 months (95% CI, 22.6-39.4) in BRCA-mutated (mBRCA) and 32 months (95% CI, 23.7-40.3) in wild-type BRCA (wtBRCA) (p = 0.78) patients. Brain metastases were the only evidence of disease at time of BM diagnoses in 48% (n = 10) mBRCA and 19% (n = 8) wtBRCA (p = 0.02) patients. There was no difference in treatment of BM by mutation status (p = 0.84). Survival from time of BM diagnosis was 29 months (95%CI, 15.5-42.5) in mBRCA and 9 months (95% CI, 5.5-12.5) in wtBRCA patients, with an adjusted hazard ratio (HR) of 0.53, p = 0.09; 95% CI, 0.25-1.11. HR was adjusted for presence of systemic disease at time of BM diagnosis. CONCLUSION: This is the largest study to date comparing outcomes in patients with EOC and BM by mutation status. mBRCA patients were more likely to have isolated BM, which may be a factor in their long survival. This supports the pursuit of aggressive treatment for mBRCA EOC patients with BM. Additional studies examining the correlation of BRCA mutational status with BM are warranted.

Brain metastases in patients with low-grade endometrial carcinoma.

OBJECTIVE: To report characteristics of patients with low-grade endometrioid endometrial carcinoma (EC) who develop brain metastases. METHODS: We retrospectively identified all patients treated at our institution for FIGO grades 1/2 EC from 1/2000-12/2016, who developed brain metastases. Electronic medical records were reviewed, data abstracted. Overall survival (OS) was determined from time of brain metastases to death or last follow-up. Appropriate statistical tests were used. RESULTS: Of 3052 patients, 23 (9, grade 1; 14, grade 2) developed brain metastases (incidence = 0.75%). Presentation at initial diagnosis: median age = 61.3 years (range, 41-81); median BMI = 29.8 kg/m2 (range, 20.3-42.6 kg/m2); distribution by stage: I, 15/23 (65%); II, 2/23 (8.7%); III, 3/23 (13.0%); IV, 3 (13.0%). None showed clinical evidence of brain metastases at presentation. Median time to diagnosis of brain metastases = 29.7 months (range, 6-145); median age = 64.6 years (range, 47.5-86.5). Brain metastases were the first, isolated site of recurrence in 2/23 (9%). All presented with neurological symptoms. Six (26%) had solitary brain lesions. Seventeen (74%) received treatment; 6 (28%), supportive care only. Median OS for patients receiving any treatment = 5.8 months (95% CI, 1.6-10.0), versus 2.4 months (95% CI, 1.5-3.3; p = .04) for best supportive care. CONCLUSION: Brain metastases in low-grade EC is rare, prognosis generally poor. Compared to supportive care only, any treatment results in more favorable outcomes.

Comparison of first-line chemotherapy regimens for ovarian carcinosarcoma: a single institution case series and review of the literature.

BACKGROUND: The optimal first-line chemotherapy for ovarian carcinosarcoma has not yet been determined. We therefore sought to determine the progression-free survival (PFS) and overall survival (OS) for patients with ovarian carcinosarcoma treated at our institution with different first-line chemotherapy regimens. METHODS: This single-institution, retrospective analysis included all patients with ovarian or primary peritoneal carcinosarcoma diagnosed from September 1996 to July 2017. Kaplan Meier analysis with a log-rank Mantel-Cox test was used to compare PFS and OS between treatment groups, and a p-value of < 0.05 was considered statistically significant. RESULTS: Thirty-one patients met inclusion criteria: two patients were stage IC, 5 were stage II, 21 were stage III, and 3 were stage IV. The median PFS and OS for all stages was 9.3 and 19.7 months respectively. Fifteen patients (48%) received carboplatin/paclitaxel as first therapy, 7 (23%) received ifosfamide/paclitaxel, 6 (19%) received a different regimen, and 3 (10%) did not receive chemotherapy. Patients treated with carboplatin/paclitaxel had a statistically significant longer PFS when compared to those receiving ifosfamide/paclitaxel (17.8 vs. 8.0 months, p = 0.025). OS was similar between all comparisons. CONCLUSIONS: In summary, in our cohort of ovarian carcinosarcoma patients, median PFS is longer in patients treated with carboplatin/paclitaxel compared to ifosfamide/paclitaxel. Overall survival was similar for all treatment groups, potentially due to subsequent treatment crossover. Given the rarity and aggressive nature of this tumor, further study into optimal first-line chemotherapy is warranted.

Gynecologic melanomas: A clinicopathologic and molecular analysis.

OBJECTIVE: Melanoma originating from gynecologic sites (MOGS), including the vulva, vagina, and cervix, is a rare and aggressive form of melanoma with poor long-term clinical outcome. The clinicopathologic features of vulvar and non-vulvar tumors remain relatively understudied, and in contrast to cutaneous melanomas at non-sun-exposed sites, MOGS typically do not harbor BRAF mutations. Thus, we sought to analyze the clinicopathologic and molecular features of MOGS. METHODS: A large retrospective cohort of patients with MOGS (n=59) at a single large academic institution over a 28-year period was identified. Associations among clinicopathologic characteristics were assessed via standard statistical approaches, and clinical outcome was examined using Cox regression analysis. Sanger sequencing was utilized to identify mutations in hotspot regions of BRAF, KIT, NRAS, and CTNNB1. RESULTS: Tumors involving the vagina and/or cervix (non-vulvar) are significantly associated with high-risk clinicopathologic features, including increased tumor thickness, ulceration, positive resection margins, lymph node metastasis, and poor long-term clinical outcome (with increased risk of death due to disease). The aggressive clinical behavior of non-vulvar tumors is independent of advanced clinical stage and lymph node metastasis in multivariate analysis. Targeted molecular analysis confirms an overall low rate of oncogenic mutations in our MOGS cohort, although KIT mutations (particularly in exon 11) are relatively enriched. CONCLUSIONS: Overall, our results show that non-vulvar MOGS are aggressive tumors with poor long-term clinical outcome and indicate that few targeted therapeutic options are currently available to patients with MOGS.