Background/Objectives: Melanoma is a malignant tumour of melanocytes. Cutaneous melanoma accounts for the vast majority of cases and has benefitted from advances in targeted and immune checkpoint inhibitor therapies, leading to substantial improvements in survival. In contrast, mucosal and vulvovaginal melanomas are rare, aggressive subtypes with distinct molecular and immune profiles and poor prognoses. This review synthesises evidence comparing cutaneous, mucosal, and vulvovaginal melanoma, with emphasis on biology, treatment, and outcomes Methods: A narrative comparative review was undertaken, examining the published literature on the epidemiology, molecular and immune characteristics, and treatment outcomes of cutaneous, mucosal, and vulvovaginal melanoma, including systemic therapies and surgical approaches. Results: Cutaneous melanoma demonstrates high tumour mutational burden and frequent BRAF and NRAS mutations, underpinning the success of targeted therapy and immunotherapy. Mucosal and vulvovaginal melanomas exhibit lower mutational burden, distinct mutation patterns, and reduced immunogenicity, correlating with poorer treatment responses. Surgery remains the mainstay of management, though optimal margins in vulvovaginal melanoma are unclear. Recurrence rates are high, and five-year survival remains poor. Evidence for systemic therapy is limited to small retrospective cohorts and subgroup analyses, showing lower response and survival rates compared with cutaneous melanoma. Chemotherapy has minimal benefit. Conclusions: Mucosal and vulvovaginal melanomas are biologically and clinically distinct from cutaneous melanoma and continue to have poor survival outcomes. Their rarity restricts high-quality evidence, highlighting the need for collaborative, innovative research to inform effective treatment strategies.

Primary presacral clear cell carcinoma (CCC) of Müllerian origin is extremely rare. Malignant transformation of endometriosis is a known phenomenon, though typically involving the ovaries or pelvic peritoneum. Retroperitoneal presentation, especially decades after definitive surgery, is exceedingly uncommon. A 60-year-old woman presented with a large retroperitoneal/presacral pelvic mass leading to hydronephrosis, 20 years after total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometriosis. MRI showed a cystic-solid mass with mural nodularity. Surgical exploration revealed dense retroperitoneal adhesions with involvement of the rectosigmoid and the appendix. En bloc resection was performed in posterior exenterative fashion. Histopathology confirmed clear cell carcinoma arising from endometriotic foci, fulfilling Sampson's criteria. Postoperative management included adjuvant paclitaxel-carboplatin chemotherapy. The patient recovered uneventfully and was scheduled for ileostomy reversal. This case illustrates the potential late malignant transformation of endometriosis into Müllerian CCC even decades after hysterectomy and oophorectomy. Endometriosis-associated carcinoma should be considered in the differential diagnosis of retroperitoneal pelvic masses, particularly in women with prior endometriosis.

Background/Objectives: To evaluate the clinicopathological features, treatment, and survival outcomes and to identify independent prognosticators for recurrence and mortality in patients with endometrioid ovarian cancer. Methods: The medical records of patients diagnosed with endometrioid ovarian carcinoma between January 2010 and December 2022 were reviewed retrospectively. Demographic and disease-related data were evaluated. Kaplan–Meier survival analysis using log rank test and Cox regression was performed. Results: Seventy-six patients were included in the study. The median age at diagnosis was 54 years (range 31–86). A total of 85.5% of the patients were diagnosed with early-stage disease and 88.1% of the tumours represented low-grade carcinomas. Synchronous endometrioid endometrial cancer was confirmed in 19.7% of the cases. All patients underwent surgical management and 65.8% received adjuvant chemotherapy. Median follow-up time was 67.5 months. The 5-year disease-free survival and overall survival were 92.1% and 93.4%, respectively. The risk of cancer-related death was higher in advanced stages (HR = 13.86; 95% CI 2.16–57.17; p < 0.001) and in the presence of residual disease (HR = 15.18; 95% CI 2.36–87.17; p < 0.002). Residual disease and advanced stages were also identified as independent risk factors for disease relapse with HR = 16.04 (95% CI 2.61–93.7; p < 0.002) and HR = 11.73 (95% CI 1.92–41.6; p < 0.001), respectively. Conclusions: Endometrioid ovarian carcinoma usually affects younger patients with the majority of the cases representing low-grade carcinomas diagnosed at early stages. Residual disease and advanced stages are independently associated with inferior survival outcomes. There was no significance of lymph node dissection and adjuvant chemotherapy in the overall and recurrence-free survival rates. Further research focusing on molecular profiling should aim to define the prevalence and the prognostic value of major molecular alterations and develop precise stratification models to plan personalised treatment for optimal care.

Background/Objectives: Cervical mesonephric adenocarcinomas (MNACs) are among the rarest neoplasms of the female genital tract. Unlike the majority of cervical cancers, which are predominantly squamous in origin and strongly associated with HPV seropositivity, MNACs are distinct in both histology and pathophysiology. Despite their unique characteristics, MNACs have historically been managed in parallel with squamous cell carcinomas, resulting in a lack of optimised, evidence-based treatment protocols. In this systematic review, we aim to evaluate the current management strategies for MNACs and their associated clinical outcomes. Additionally, we critically appraise existing surgical and adjuvant therapies and propose embryologically oriented surgical techniques to achieve optimal tumour resection. Methods: We performed a systematic search across the MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov databases from 1960 to June 2024. The search strategy employed a combination of keywords and MeSH terms, including "Uterine Cervical Neoplasms" [MeSH], "mesonephric tumour", "mesonephric neoplasm", and "mesonephric cancer". All relevant publications, including case reports and case series, were considered. Results: A total of 49 publications were finally included in the analysis, involving a thorough description of 91 MNAC cases. Most patients had stage I disease (70.8%) (n = 51). Hysterectomy was performed in 77 patients. The median follow-up was 29 months (range 1-199 months). Disease recurrence was observed in 35.2% (n = 25) of the cases, with the median disease-free survival (DFS) being 24 months (range 1-199). At the follow-up, 64.8% (n = 46) of patients remained in remission irrespective of the treatment modality, while 27.4% (n = 20) died due to disease progression. Conclusions: Mesonephric neoplasms of the uterine cervix are rare and clinically aggressive cancers that signify poor prognosis. Accurate identification and effective management can be challenging due to their particular anatomic and immunohistochemical characteristics. Therefore, a more tailored embryological-based approach should be considered for an optimal oncologic outcome.

OBJECTIVES:The aim of this study of this study was to evaluate preoperative radiology and histopathology findings in cervical cancer lymphadenopathy detection, allowing targeted frozen section examination (FSE). DESIGN:A retrospective analysis was conducted of 203 early-stage cervical cancer patients between 2010 and 2019 in a tertiary centre. PARTICIPANTS/MATERIALS, SETTING, AND METHODS:All patients had histologically confirmed cervical cancer and underwent magnetic resonance imaging (MRI) prior to intraoperative FSE. The primary objectives of the study were to determine the diagnostic accuracy of intraoperative FSE in the identification of lymph node metastases (LNM) in early-stage cervical cancer by correlation with final results obtained using standard histopathology techniques and to examine different preoperative, intraoperative, demographic, radiological, and histopathological factors that could identify those at greatest risk of nodal disease and hence predict those most likely to benefit from FSE, enabling more selective and targeted use. RESULTS:Nineteen patients were found to have LNM (9.36%) at FSE. Patients were at increased risk of LNM by 6-fold with positive LVSI, 3-fold with MRI lymphadenopathy, and 3.5-fold with MRI-visible disease. The presence of lymphadenopathy on MRI and positive LVSI in combination increased the risk of LNM by 19-fold. LIMITATIONS:We acknowledge that FSE is expensive and time intensive, exposing patients to increased surgery duration and associated risk. We also recognize that it may not be feasible for all patients. Finally, the analysis is limited by retrospective nature of the study. CONCLUSIONS:By application of the preoperative risk stratification algorithm, we may suggest that FSE can be a useful tool in high-risk patients.

Table S2. The QuPath classification results for the immunohistochemistry of CAPS in SOC tissue microarrays.

Introduction/BackgroundCervical cancer is the fourth gynaecological cancer amongst women worldwide with one third of new cases being women between 20 and 40 years old. Nowadays, the societal progress along with economic insecurity and pursuing of higher educational and career development have led to delayed childbearing.Hence, an increasing desire for fertility sparing options has emerged. Aim of our study was to evaluate the oncologic and obstetric outcomes of laparoscopic radical trachelectomy with pelvic lymph node assessment in women with cervical tumour size less than 4cm (IB1 FIGO 2009)MethodologyMedical records of women who underwent laparoscopic radical trachelectomy with pelvic lymphadenectomy for early-stage cervical carcinoma between March 2010 and March 2019 were reviewed retrospectively. Clinicopathological variables, oncologic and obstetric outcomes were evaluated.ResultsA total of 18 patients were included. The median age at initial diagnosis was 32 years (range 23–43). All patients had a FIGO stage Ib1 disease in the final histopathology examination and none them received adjuvant therapy. Median follow up was 87.5 months (range 44–120). One recurrence (5.5%) recorded 27 months after completion of initial treatment and no death was recorded during the time of the study. The overall survival rates were 100%. (95% CI, 97.6–99.7) Seven women attempted to conceive during the study period and they all achieved a clinical pregnancy. Among the patients who have attempted a pregnancy, the live birth rate was 71,4%.ConclusionOur study showed that laparoscopic radical trachelectomy seem to be favorable in meticulously selected patients who desire to preserve their fertility. Future research will hopefully provide further insight into more accurate selection criteria and minimally invasive surgical mode to achieve maximal obstetric outcomes without jeopardizing the oncologic outcomes.DisclosuresNo

Supplementary Figures and Tables

Objective: The ischiorectal fossa is a key anatomical location with boundaries and internal structures owing distinct contributions to function and quality of life. Methods: We highlight the importance of management of pathology in this deep anatomically complex location. Results: We present a ten-step multidisciplinary surgical approach; achieving en bloc radical excision with primary closure and reassuring outcomes. Schwannomas are benign slow-growing nerve sheath tumors. Conclusions: Pelvic schwannomas are rare with only 3 reported cases of the pudendal nerve. We also offer an overview of this rare pathology whilst acknowledging a paucity of recommendations regarding management of disease of the ischiorectal fossa.

AbstractPurpose: Using RNA sequencing, we recently developed the 52-gene–based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier. Experimental Design: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n = 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs. Results: We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition–high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P = 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P < 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors. Conclusions: The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.

Similar to tumor-initiating cells (TICs), minimal residual disease (MRD) is capable of reinitiating tumors and causing recurrence. However, the molecular characteristics of solid tumor MRD cells and drivers of their survival have remained elusive. Here we performed dense multiregion transcriptomics analysis of paired biopsies from 17 ovarian cancer patients before and after chemotherapy. We reveal that while MRD cells share important molecular signatures with TICs, they are also characterized by an adipocyte-like gene expression signature and a portion of them had undergone epithelial-mesenchymal transition (EMT). In a cell culture MRD model, MRD-mimic cells showed the same phenotype and were dependent on fatty acid oxidation (FAO) for survival and resistance to cytotoxic agents. These findings identify EMT and FAO as attractive targets to eradicate MRD in ovarian cancer and make a compelling case for the further testing of FAO inhibitors in treating MRD.

PURPOSE:Struma ovarii is rare, accounting for 0.3-1% of ovarian tumours. Malignant transformation may occur, most often into papillary thyroid carcinoma. There is a paucity of data pertaining to malignant struma ovarii. This paper shares a decade of experience of a single institution in the management of this rare ovarian cancer, exploring the characteristics of this tumour and suggesting a standardised approach to treatment and follow-up.METHODS:All patients treated for malignant struma ovarii within a large cancer centre over one decade were identified and data collected retrospectively on presentation, diagnosis, management, follow-up and survival outcomes. A literature review was also undertaken.RESULTS:Eleven cases of malignant struma ovarii were managed in the Oxford Cancer Centre between 2010 and 2019, 6 of which were of papillary thyroid carcinoma sub-type. No cases were correctly diagnosed pre-operatively. All patients had stage I disease and were managed surgically-but with variation in radicality. Patients identified as high-risk based on final histopathology underwent additional thyroidectomy and radio-active iodine ablation therapy. One case of synchronous malignancy of the thyroid gland proper was identified. No disease recurrence occurred.CONCLUSION:Malignant struma ovarii present a diagnostic challenge. Multi-disciplinary team (MDT) input is essential. Unilateral salpingo-oophrectomy may be adequate if stage I; reserving more radical surgery for advanced disease. Histopathological risk-stratification should be used to identify those most likely to benefit from adjuvant thyroid-targeting therapies. Patients require follow-up, anticipating an overall good prognosis.

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.

PurposeFresh-frozen (FF) tissue is the optimal source of DNA for whole-genome sequencing (WGS) of cancer patients. However, it is not always available, limiting the widespread application of WGS in clinical practice. We explored the viability of using formalin-fixed, paraffin-embedded (FFPE) tissues, available routinely for cancer patients, as a source of DNA for clinical WGS.MethodsWe conducted a prospective study using DNAs from matched FF, FFPE, and peripheral blood germ-line specimens collected from 52 cancer patients (156 samples) following routine diagnostic protocols. We compared somatic variants detected in FFPE and matching FF samples.ResultsWe found the single-nucleotide variant agreement reached 71% across the genome and somatic copy-number alterations (CNAs) detection from FFPE samples was suboptimal (0.44 median correlation with FF) due to nonuniform coverage. CNA detection was improved significantly with lower reverse crosslinking temperature in FFPE DNA extraction (80 °C or 65 °C depending on the methods). Our final data showed somatic variant detection from FFPE for clinical decision making is possible. We detected 98% of clinically actionable variants (including 30/31 CNAs).ConclusionWe present the first prospective WGS study of cancer patients using FFPE specimens collected in a routine clinical environment proving WGS can be applied in the clinic.

Received: October 15, 2018; Accepted: October 25, 2018; Published: October 29, 2018 Abbreviations: CT: Contrast Enhanced Computerised Tomography, EBRT: External Beam Radio Therapy, BRACHY: Brachytherapy Alone, LVS: Lymph Vascular Space, BSO: Hysterectomy and Bilateral SalpingoOophorectomy, Pe LA: Pelvic Lymphadenectomy, Pe N: Pelvic Nodes, FIGO: International Federation of Gynaecology and Obstetrics.

Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy.

Abstract In spite of excellent clinical response to primary chemotherapy, more than 70% of patients with high grade serous ovarian cancer (HGSOC) suffer from recurrence within 12 months of completion of treatment. Moreover, clinical and biochemical response are poor surrogates for survival outcomes: patients with complete clinical response following primary treatment usually suffer from recurrence, which can occur as early as within the first six months after treatment. The reason for this paradoxical disconnect between response and survival is unclear. Results from patients treated with neoadjuvant chemotherapy (NACT) suggest that, while complete clinical response following primary treatment is common, complete pathological response is highly unusual in HGSOC. The characterization of microscopic residual disease (MRD) following NACT is required to advance our understanding about the key mechanisms of primary chemotherapy resistance. Accurate and comprehensive characterization of MRD, however, has been very difficult because of the minute nature of these samples. Here we report our results from a prospective phase 0 translational clinical study (OXO-PCR) for the comprehensive genomic characterization of MRD. Twenty women with at least stage IIIC HGSOC were prospectively recruited to this study. All patients had paired samples collected at the time of diagnostic laparoscopy prior to chemotherapy and following at least three cycles of NACT. Chemotherapy response was evaluated using CT and CA125, while site-specific response was assessed through laparoscopy, which was conducted before and after chemotherapy. Laser capture microdissection was then used to obtain MRD which were analyzed through RNA-seq and whole genome sequencing. Our results show that, in contrast to sites where only partial clinical response was observed, complete clinical response and MRD are characterized by differential expression of specific gene signatures related to cell adhesion, actin binding and RNA processing. Most notably, MRD is characterized by the upregulation of a large number of ATP-binding cassette transporters (n = 12). For one patient, recurrence samples were also collected and analyzed: PCA of RNA-seq data from this patient shows that the recurrence resembles the pre-chemotherapy samples, suggesting that MRD represents a distinct cell state that is capable of resisting chemotherapy. Such state is lost following repopulation and emergence of recurrence. Our results show that the approach of comprehensive analysis of MRD is a powerful method for the early characterization of tumor resistance. This has important implications for future design of appropriate maintenance therapies to prevent recurrence. Citation Format: Mara Artibani, Garry Mallett, Dhar Sunanda, Mohammad KaramiNejadRanjbar, Matteo Morotti, Salma ElSahhar, Tatjana Sauka-Spengler, Ahmed A. Ahmed. The Oxford Ovarian Cancer Predict Chemotherapy Response (OXO-PCR) study: Understanding the genomic drivers of primary chemotherapy-resistant microscopic residual disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5373.

OBJECTIVE:In early-stage cervical cancer, single modality therapy is the main objective, to minimize patient morbidity while offering equivalent cure rates. Intraoperative frozen section examination (FSE) of lymph nodes (LNs) can facilitate this aim, ensuring that radical surgery is avoided in patients requiring adjuvant therapy for metastatic LN involvement. We aimed to evaluate the accuracy of routine intraoperative FSE of pelvic LNs during the surgical staging of early-stage cervical cancers and identify a group at low risk for nodal metastases.METHODS:A retrospective cohort study of 94 women aged 23 to 80 years who underwent primary surgery and planned intraoperative FSE of the pelvic LNs at the gynecological cancer center in Oxford was performed. The diagnostic value of FSE and the prediction of metastatic nodal disease were assessed by use of preoperative and intraoperative variables.RESULTS:A total of 1825 LNs were submitted for FSE. Of 94 women (13.8%), 13 had positive LNs at FSE. Two false-negative cases were reported with micrometastases but no false-positive cases. Frozen section examination as a diagnostic test reached a sensitivity of 86.7% and a specificity of 100%. A regression model including grade I to II and tumor size of less than 20 mm identified a low-risk group for LN involvement.CONCLUSIONS:In light of diverse practice patterns, FSE should be routinely offered to women with early-stage cervical cancer in a 1-step protocol. We equally devised a model to predict those patients at least risk of nodal disease, who may be spared of FSE.