Lynch syndrome–associated urothelial carcinoma (LS-UC) is a rare and undercharacterized clinical entity. While FGFR3 alterations are well described in sporadic urothelial carcinoma, their prevalence and clinical implications in LS-UC remain unclear. We aimed to provide a comprehensive clinical and molecular characterization of LS-UC. We conducted a retrospective single-center study including patients with Lynch syndrome (LS) and histologically confirmed urothelial carcinoma (UC). Clinical, pathological, treatment, and follow-up data were collected. Targeted next-generation sequencing was performed on available tumor samples to assess genomic alterations, with particular attention to FGFR3 mutations. A total of 27 patients with LS-UC were identified, with a predominance of upper urinary tract involvement (70
Genetic counselling for hereditary cancer predisposition has evolved substantially over more than three decades, driven by advances in genomic technologies and the growing use of tumour and germline testing. These developments have expanded access to hereditary cancer testing, treatment and prevention, while also introducing new clinical, psychosocial and system-level challenges. This review examines the transition from traditional specialist-led genetic counselling to mainstreamed testing pathways. Using Lynch syndrome as a paradigm, we explore how service redesign, personalised risk communication and patient experience intersect in contemporary hereditary cancer care. This invited review synthesises clinical, academic and patient perspectives on the evolution of hereditary cancer genetic counselling. Lived experiences of Lynch syndrome were incorporated through patient and public involvement contributors involved in manuscript development and interpretation. Mainstreamed testing has expanded access to genomic information and strengthened opportunities for cascade testing and prevention within families. However, it has also increased testing volumes, complexity of results interpretation and reliance on non-genetics clinicians. As a result, effective care requires close coordination between genetics and cancer services, alongside support for shared decision-making, family communication and psychosocial needs. This review uniquely integrates clinical evidence and lived experience to highlight how mainstreaming has transformed the delivery of hereditary cancer genetic counselling but not the need for specialist genetics expertise. Lynch syndrome illustrates how genomics can be integrated into routine cancer care while maintaining personalised counselling and family-centred follow-up. These principles are relevant across hereditary cancer predispositions and inform the future development of genetic counselling services.
Rare pathogenic variants affecting components of the evolutionary conserved cAMP/protein kinase A (PKA) signalling pathway are implicated in a spectrum of adrenocortical disorders. Germline inactivating PRKAR1A variants leading to constitutive PKA activation, underlie primary pigmented nodular adrenocortical disease (PPNAD) in Carney complex. More recently, several patients with PPNAD and other types of bilateral nodular adrenal disease (BNAD) have been diagnosed with rearrangements in chromosome 19 at band p13.12, resulting in copy number gains of the entire PRKACA gene. Here, we report the identification of a 19p13.12 rearrangement, resulting in a duplication of the PRKACA gene, in a 32-year-old female from whom the genetic aetiology remained unknown for 20 years. Furthermore, we provide an updated overview of patients with PRKACA germline copy number gains that have previously been reported in the literature.
Background Fertility preservation in ovarian tumours or advanced gynaecologic malignancies is often challenging. Traditional fertility preservation techniques, such as ovarian tissue cryopreservation or oocyte retrieval, may not always be suitable, especially in cases where immediate cancer treatment is necessary or where hormonal stimulation is contraindicated. Ex-vivo in-vitro maturation of ovarian tissue oocytes (OTO-IVM) offers a promising alternative in these women by enabling the retrieval and maturation of immature oocytes outside the body from the oophorectomy tissue specimen. Method We present a case series of four women with gynaecologic malignancies who underwent ex-vivo oocyte retrieval and in-vitro maturation at the time of their oncologic surgeries. Conclusion Evidence supporting live births following OTO-IVM remains limited, and as such, the technique is currently regarded as experimental. Nevertheless, for selected women in whom conventional fertility preservation is not feasible, OTO-IVM may provide the only opportunity for fertility preservation and warrants consideration.
Objective:Although molecular classification has been associated with outcomes in vulvar squamous cell carcinoma (vSCC), its relevance in patients with stage III disease is less well characterized. We evaluated the association between molecular subtype and oncologic outcomes among patients with 2021 FIGO stage III vSCC. Methods:We conducted a retrospective study of patients with primary stage III vSCC treated at a single institution from 2000 to 2021. Tumors were classified as HPV-associated (HPV+), HPV-independent/p53 wild-type (HPV-/p53wt), or HPV-independent/p53 mutant (HPV-/p53mut) using HPV RNA in situ hybridization and p16 immunohistochemistry (IHC) for HPV status and p53 IHC as a surrogate for TP53 mutation status. Primary outcomes were recurrence and disease-specific mortality within five years from primary treatment evaluated using Cox proportional hazards and Kaplan-Meier survival analysis. Results:Fifty-two patients had complete molecular data: 32.7% HPV+, 21.2% HPV-/p53wt, and 46.2% HPV-/p53mut. Smoking was associated with HPV+ tumors (p < 0.001). Within five years, 46.2% experienced recurrence (median 11 months, IQR 7.3-29.2). The highest proportion of recurrences occurred in the HPV-/p53mut group, and most groin recurrences occurred in HPV-independent tumors; however, HPV/p53 status was not significantly associated with five-year recurrence (p = 0.22). For disease-specific survival, HPV-/p53mut tumors were associated with a 5.7-fold increased risk of disease-specific death compared with HPV+ tumors (HR 5.70, 95% CI 1.66-19.62). Conclusions:Molecular classification distinguishes clinically meaningful subgroups in stage III vSCC. HPV-independent tumors, particularly those with TP53 mutation, are associated with worse disease-specific survival and supports further evaluation of molecularly informed risk stratification and treatment approaches.
Background:Postoperative lymphatic leakage is a challenging complication following radical surgery for gynecologic malignancies. Effective medical treatment for controlling lymphatic leakage is still lacking. This study analyzed the clinical efficacy and safety of intraperitoneal OK-432 perfusion for managing postoperative lymphatic leakage. Methods:We conducted a retrospective cohort study involving 9 patients who developed postoperative lymphatic leakage after pelvic lymph node dissection with or without para-aortic lymphadenectomy for gynecologic tumors. All patients received a single intraperitoneal perfusion of OK-432. Results:The mean age and BMI of the patients were 53.1 years old and 22.7. The primary site was endometrium, ovary, cervix and fallopian tube in 5, 1, 2, and 1 patient, respectively. Most patients had adenocarcinoma (6/9). The FIGO stages were I, II, and III in 3 patients each. The mean number of resected lymph nodes was 24.6 and 7 patients underwent para-aortic lymphadenectomy. Seven patients underwent robotic/laparoscopic surgery while open surgery was applied in 2 patients. In terms of efficacy, the median time to drainage tube removal was 4 days. Although pretreatment drainage volume was high, post-treatment drainage volume decreased remarkably. With a median follow-up of 2.7 years and 100% follow-up rate, no chronic pelvic pain, lower-limb lymphedema, persistent lymphoceles, or tumor recurrences were observed. Conclusion:Intraperitoneal OK-432 perfusion is a safe and effective treatment for postoperative lymphatic leakage following gynecologic tumor surgery. It may shorten drainage duration, avoids reoperation, and may offer a therapeutic alternative to current treatments for postoperative lymphatic leakage.
Background:Low-grade serous ovarian carcinoma (LGSOC) is an uncommon epithelial malignancy that typically arises in the setting of a serous borderline ovarian tumor (SBOT), with the majority of low-grade serous neoplasms harboring mutually exclusive mutations in KRAS, BRAF, or NRAS. The time to progression from SBOT to LGSOC is highly variable with a median of 10 years, with the longest previously reported interval of 39 years. LGSOC often presents at advanced stage with a high propensity for recurrence despite surgical intervention (the primary treatment modality) and systemic pharmacologic treatments. Case Presentation:Herein, we present the case of a 62-year-old patient with a diagnosis of advanced LGSOC that presented 39 years after her initial diagnosis and 35 years after last documented surgical resection of SBOT. Additionally, we describe the utilization of molecular testing for a BRAF V600E mutation in both the SBOT and LGSOC specimens, suggesting a clonal relationship between the two neoplasms in this case, and also providing an indication for targeted therapy to which this patient demonstrated a rapid and robust response. Conclusion:This case exemplifies the long-term natural history of low-grade serous neoplasia and highlights how the incorporation of molecular studies can improve diagnostic certainty and guide therapy selection for patients. Further, we provide a review of the literature on SBOT progression to LGSOC, including risk factors for progression and therapeutic options to treat recurrent/progressive disease.
Background Immune checkpoint inhibitor-induced bullous pemphigoid (ICI-BP) is a rare but recognized complication of immune checkpoint inhibitor therapy. Compared to conventional BP, ICI-BP can present atypically, leading to delayed diagnosis and treatment, which can devastate quality of life for cancer patients. Literature on the presentation, diagnosis, and management of ICI-BP in patients with gynecologic cancer is scarce. Case Presentation We report a case of ICI-BP presenting as erythema multiforme (EM)–like lesions in a woman in her early 60s with stage IVB uterine serous carcinoma. Upon diagnosis, the patient was treated with neoadjuvant carboplatin/paclitaxel followed by debulking surgery, adjuvant chemotherapy, and maintenance pembrolizumab immunotherapy. Pembrolizumab was discontinued after four cycles due to uveitis. Two months thereafter, she acutely developed painful oral mucosal erosions and a progressive palmoplantar eruption composed of targetoid and pseudo-targetoid plaques, leading to limited mobility and oral intake. Initial clinical evaluation favored EM, for which she began empiric antivirals and high-potency topical corticosteroids. Dermatology performed a skin biopsy which supported the diagnosis of ICI-BP with concomitant EM secondary to varicella zoster reactivation. The patient improved with systemic and topical corticosteroids followed by dupilumab as maintenance therapy. She was able to taper off systemic corticosteroids without recurrence of BP in eight weeks from rash onset. Conclusion This case report exemplifies a delayed-onset, atypically presenting instance of ICI-BP in a patient with uterine serous carcinoma, and substantiates the utility of dupilumab as a steroid-sparing option for ICI-BP.
Objective(s): To evaluate the association of the Prognostic Nutritional Index (PNI) and Nutritional Risk Index (NRI) with immune-related adverse events, immunotherapy response, and oncologic outcomes. Methods: This study is an IRB-approved retrospective, single-institution cohort study in patients with CC treated with IO from January 1, 2017 to January 1, 2023. Clinical, oncologic, and nutritional parameters were collected from patient charts. The NRI and the PNI are validated composite prognostic indices derived from routinely collected laboratory and anthropometric parameters to evaluate nutritional status. Factors associated with NRI and PNI were evaluated. Progression-free survival (PFS) was defined from the start date of IO until progression of disease, and overall survival (OS) from time of diagnosis to death, with censoring at last follow-up. Kaplan Meier methods were used to assess survival outcomes. Results: 71 patients with CC were treated with IO during the study period. 61% (n = 43) of patients met criteria for low-risk NRI prior to receiving IO, with the remaining 39% (n = 27) meeting criteria for high-risk NRI. Low-risk NRI scores were associated with lower ECOG scores, increased grade 3/4 immune-related adverse events (G3/4 irAEs), and an improvement in OS, p < 0.05. Low-risk post-IO NRI scores were associated with a significant improvement in PFS and OS, p < 0.05. High-risk PNI scores were associated with higher ECOG scores, fewer G3/4 irAEs, and increased hospitalizations during IO, p < 0.05. Low-risk PNI scores were associated with improved response to IO as well as prolonged PFS and OS, p < 0.05. Conclusion(s): In this cohort of CC patients treated with IO, approximately 39% and 55% of patients were categorized as high risk according to pre-treatment NRI and PNI, respectively. High-risk PNI and NRI classifications were associated with differences in irAEs, IO response, and oncologic outcomes.
Background:Mucinous endometrial carcinoma of gastric type (MCG) is a rare and aggressive malignancy with no established standard of care. Biomarkers of homologous recombination deficiency (HRD), including BRCA1/2 alterations and genomic signatures, are increasingly used to predict sensitivity to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), but their utility in rare gynecologic cancers remains unclear. Case presentation:We report a 52-year-old female with metastatic TP53-abnormal endometrial MCG. Whole-genome and transcriptome analysis identified a pathogenic germline BRCA1 mutation with somatic loss of heterozygosity (LOH), resulting in biallelic BRCA1 loss. A high HRDetect score (0.96) further supported an HRD phenotype. The patient achieved an initial partial response to frontline platinum-based chemotherapy. However, despite genomic evidence predicting PARPi sensitivity, she experienced rapid disease progression within three months of completion of platinum and starting maintenance niraparib. Retrospective copy-number signature analysis classified the tumor as a non-HRD signature characterized by high ploidy rather than classic BRCA-associated genomic scarring. To further investigate treatment response, a patient-derived xenograft (PDX) model was established. The model faithfully recapitulated the clinical phenotype, showing response to cisplatin but intrinsic resistance to the PARP inhibition. Conclusion:This case demonstrates a discordance between genomic HRD biomarkers and therapeutic response. Despite germline BRCA1 mutation, somatic LOH, and a high HRDetect score, platinum response was not durable and PARPi sensitivity was not observed. These findings highlight the limitations of current HRD biomarkers in rare gynecologic cancers and support integrating functional and genomic approaches to guide precision oncology.
Objective:To evaluate the prevalence and prognostic relevance of pretreatment computed tomography-defined sarcopenia in women with cervical cancer treated with definitive radiotherapy with or without concurrent chemotherapy. Methods:This retrospective cohort study included women aged 18 years or older with FIGO 2018 stage IB2 to IVA cervical cancer who initiated definitive radiotherapy, with or without radiosensitizing chemotherapy, between January 2016 and December 2018 at CAISM/UNICAMP, Campinas, Brazil. Follow-up continued through 2022 to ensure a minimum follow-up period to evaluate 5-year survival outcomes. Women with prior malignancy treated with chemotherapy or radiotherapy, unavailable or non-measurable pretreatment computed tomography, pregnancy, or death before treatment initiation were excluded. Pretreatment sarcopenia was defined as skeletal muscle index <38.9 cm2/m2 using bilateral psoas and paraspinal linear measurements at L3 on planning computed tomography. Treatment response followed World Health Organization response definitions. Progression-free survival and overall survival were estimated using Kaplan-Meier methods and compared with log-rank tests. Cox proportional hazards models and multivariable logistic regression were performed to estimate hazard ratios (HR), odds ratios (OR), and 95% confidence intervals. Results:Among 210 included women, 79 (37.6%) had pretreatment sarcopenia. Most patients had squamous histology (176/210, 83.8%), advanced FIGO stage III/IV disease (120/210, 57.1%), and received chemotherapy (177/210, 84.3%). Sarcopenia was more frequent among women aged <50 years, premenopausal women, women with body mass index <25 kg/m2, and women with anemia. Complete or stable response occurred in 100 patients, whereas progression or recurrence occurred in 110; sarcopenia was more common among patients with progression or recurrence. In univariable analysis, pretreatment sarcopenia was associated with worse progression-free survival (HR 1.70, 95% CI 1.15 to 2.51) and overall survival (HR 1.75, 95% CI 1.11 to 2.75). In multivariable Cox regression, complete response to treatment was the only factor independently associated with overall survival (HR 0.07, 95% CI 0.02 to 0.18, p < 0.0001). Multivariable logistic regression showed a trend for higher sarcopenia prevalence in women aged <50 years (OR 1.73, 95% CI 0.98 to 3.05, p = 0.057). Conclusion:Pretreatment CT-defined sarcopenia was common and associated with poorer survival outcomes in univariable analysis, although treatment response remained the strongest independent prognostic factor in women with cervical cancer treated with definitive chemoradiotherapy.
Background:Folate receptor alpha (FRα) is frequently expressed in ovarian high-grade serous carcinomas and is a clinically actionable biomarker targeted by FDA-approved mirvetuximab soravtansine (MIRV) for platinum-resistant disease with high expression (≥75% of tumor cells with ≥2+ staining). However, longitudinal variability in FRα expression remains poorly understood. We evaluated temporal FRα expression changes in paired ovarian cancer specimens. Methods:We performed a retrospective study of epithelial ovarian malignancies at Mayo Clinic Florida (2013-2025) in patients with ≥2 tumor specimens available. Tumors were classified as FRα-positive when ≥75% of viable tumor cells showed moderate-to-strong (2+ and/or 3+) staining and categorized as concordant or discordant based on changes in FRα status. Associations between clinicopathologic variables and FRα variability were evaluated using Fisher exact and Kruskal-Wallis tests. Results:Sixty-six patients (median age 66 years), most with advanced-stage high-grade serous carcinoma (65/66), had paired tumor specimens. FRα expression was concordant in 77.3% of cases and discordant in 22.7%. Negative-to-positive conversion occurred more frequently than positive-to-negative conversion (16.7% vs 6.1%). No significant associations were identified between FRα variability and clinicopathologic factors, including age, grade, stage, treatment setting, prior chemotherapy exposure, MIRV use, specimen type, sampling site, baseline FRα expression, or timing intervals. In patients treated with neoadjuvant chemotherapy, negative-to-positive conversion was numerically more frequent, although not statistically significant (25% vs 9%; p = 0.479). Conclusions:FRα expression in ovarian carcinomas is generally stable over time, with concordance observed in most paired specimens. However, discordance in approximately one-quarter of cases suggests spatial and/or temporal tumor heterogeneity.
Objectives:To evaluate temporal trends in estrogen replacement therapy (ERT) utilization among younger gynecologic cancer survivors. Methods:We conducted a cross-sectional study using the Merative MarketScan Research Database from January 1, 2013, through December 31, 2021. We included female patients aged 18-51 years with a diagnosis or history of gynecologic cancer. Annual prevalence of ERT use was calculated, and trends over time were assessed using annual percent change (APC) and 95% confidence intervals (CIs). Results were assessed across cancer types and age groups. Results:ERT utilization increased from 10.9% in 2013 to 14.1% in 2021 among all gynecologic cancer survivors (APC 3.41%, 95% CI 2.13-4.71%). Increasing ERT use was observed across all gynecologic cancer subgroups and age categories during the study period. Ovarian cancer survivors consistently had the greatest prevalence of ERT use, whereas uterine cancer survivors had the lowest prevalence across the study period. Among the age sub-groups, the 18-34 years old age group had the largest increase in ERT utilization, from 6.8% to 10.5% (APC 5.68%, 95% CI 3.1-8.33) over the study period. Conclusions:ERT utilization among younger gynecologic cancer survivors increased between 2013 and 2021. As ERT use continues to rise in this population, further research is needed to identify patient-, provider-, and system-level factors associated with prescribing and uptake and to evaluate gaps in menopausal survivorship care.
Colorectal cancer (CRC) development in Lynch syndrome (LS) has long been regarded to follow an adenoma-carcinoma sequence accelerated in comparison to microsatellite-stable (MSS) CRC development. Yet, several clinical observations challenged this hypothesis, most notably the persistently high CRC incidence under colonoscopy surveillance, a non-measurable benefit from shorter screening intervals, and substantial differences in cancer risk between carriers of the different mismatch repair (MMR) genes. Advances in the last decade have produced new hypotheses, highlighting the distinct biology of LS CRC and unravelling several co-existing pathways to cancer. Alongside the genomic heterogeneity, the immunogenic load created by the accumulation of frameshift mutations imposing selective pressure and leading to immune evasion, appears to be a critical step for cancer manifestation. We discuss potential clinical implications of these advances in understanding CRC pathogenesis for cancer prevention in LS and outline open questions that remain.
Genetic testing in ovarian carcinoma (OC) patients is very important for patients and their relatives. The Tumor-First workflow uses a tumor DNA test to stratify germline testing for hereditary cancer predisposition as well as treatment options with PARP inhibitors. This workflow is adopted and successfully implemented nationwide. Here, we evaluated recent tumor DNA testing rates in the Netherlands to identify untested OC patient groups and optimize tumor DNA testing rates. OC patients diagnosed in 2023 or 2024 were selected from the Netherlands Cancer Registry. We analyzed patient characteristics associated with the likelihood of tumor DNA testing using multivariable logistic regression. Tumor-First testing was performed for 1765 out of the 2221 (79
Background:Adult cervical embryonal rhabdomyosarcoma (ERMS) is an exceptionally rare malignant mesenchymal tumor, and evidence regarding its clinicopathologic characteristics, optimal management, and prognostic factors remains limited. We report an aggressive case of adult cervical ERMS and provide a contemporary review of the literature. Case presentation:A 50-year-old woman presented with abnormal vaginal bleeding and was diagnosed with cervical ERMS following histopathologic and immunohistochemical evaluation. She underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy followed by adjuvant vincristine, actinomycin D, and cyclophosphamide (VAC) chemotherapy. Despite multimodal treatment, she developed rapid pelvic recurrence, progressive disease, and recurrent vaginal bleeding requiring palliative radiotherapy and died 13 months after diagnosis. To better characterize adult cervical ERMS, we reviewed English-language reports published between 2015 and 2026. Forty-one previously reported adult cases with sufficient clinical information were identified. The median age at diagnosis was 38 years, and the median tumor size was 5 cm. Most patients presented with stage I disease and were treated with surgery combined with chemotherapy, most commonly VAC-based regimens. Overall outcomes were generally favorable. Uncommon clinical presentations and associated conditions included uterine inversion, pregnancy-associated disease, cerebral venous sinus thrombosis, melanoma, and DICER1-associated alterations. Conclusion:Adult cervical ERMS demonstrates substantial clinical heterogeneity. Although most reported patients achieve favorable outcomes with multimodal treatment, a subset may experience aggressive disease characterized by rapid recurrence and poor prognosis. Greater molecular characterization, particularly regarding DICER1-associated alterations, may improve risk stratification and support more individualized treatment strategies.
Background:Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with cytoreductive surgery has demonstrated survival benefits in advanced ovarian cancer. However, the safety of HIPEC administration in patients with indwelling ventriculoperitoneal (VP) shunts remains unknown, as no prior cases have been reported. Theoretical risks include shunt infection, chemical ventriculitis, and potential central nervous system (CNS) metastasis via retrograde flow through the shunt catheter. The absence of established management guidelines poses a significant challenge for clinicians treating ovarian cancer patients with concurrent VP shunts. Case Presentation:A 60-year-old G1P1 with a 6-year history of a programmable VP shunt for hydrocephalus secondary to cerebellar hemangioblastoma presented with high-grade serous ovarian carcinoma, FIGO stage IIIA2. Following neoadjuvant chemotherapy, she underwent interval debulking surgery with cisplatin-based HIPEC. A multidisciplinary approach was employed: neurosurgery externalized the VP shunt catheter from the peritoneal cavity and wrapped it in metronidazole-soaked gauze during HIPEC administration and the shunt was replaced at case completion. Postoperative vancomycin, cefepime, and metronidazole were provided for five days for meningitis prophylaxis. The patient experienced no shunt-related complications and was discharged on postoperative day 4. At 10-month follow-up, she demonstrated excellent oncologic response with CA-125 normalization and no evidence of shunt malfunction or CNS involvement. Conclusion:This case demonstrates that HIPEC can be safely performed in patients with indwelling VP shunts when a multidisciplinary strategy incorporating intraoperative shunt externalization and antimicrobial prophylaxis is utilized. This approach expands treatment options for ovarian cancer patients with VP shunts who may otherwise be excluded from potentially beneficial HIPEC therapy.
Background:Uterine leiomyosarcoma (uLMS) is an aggressive malignancy with limited advanced-stage treatments. Actionable molecular alterations like ALK fusions are extremely rare but present critical opportunities for targeted therapy. Case Presentation:A 59-year-old woman with stage IV uLMS, initially misdiagnosed as uterine fibroids, underwent a hysterectomy in 2008. Recurrence was confirmed in 2011. Over the following decade, she developed progressive pelvic disease requiring multiple debulking surgeries, arterial embolizations, and pembrolizumab, which was stopped due to progression and adrenal insufficiency. Her course was complicated by obstructive uropathy and bowel perforation. Next-generation sequencing identified an ALK-DCTN1 fusion. She was commenced on the ALK inhibitor ceritinib at 450 mg daily, later reduced to 300 mg due to transaminitis. Treatment yielded significant tumour regression and durable partial remission. A May 2025 PET-CT showed no FDG-avid disease and no evidence of new local recurrence or distant metastasis, consistent with a metabolic complete response, although stable residual pelvic lesions persisted. Conclusion:This case underscores the importance of comprehensive molecular profiling in advanced uLMS. It demonstrates that targeting rare ALK rearrangements with ceritinib can achieve sustained disease control after conventional therapies have failed or were poorly tolerated.
