International Journal of Gynecological Cancer最新文献

Neuroendocrine cervical carcinomas are rare, aggressive tumors with a high risk of early metastasis and poor survival outcomes. Despite existing therapies, over half of patients experience recurrence or progression after primary treatment, and survival after recurrence remains limited. Survival rates have not significantly improved over the past several decades, underscoring an urgent need for better therapeutic options. The rarity of neuroendocrine cervical carcinoma has precluded randomized trials, leaving treatment strategies to be guided by small retrospective studies or adapted from protocols for small cell lung cancer. However, as we gain a deeper understanding of its unique origin, genomic landscape, and biological characteristics, it has become clear that neuroendocrine cervical carcinoma requires distinct management strategies. Key questions in managing neuroendocrine cervical carcinoma remain unanswered: does adjuvant radiation therapy improve outcomes for early-stage disease? Should neoadjuvant chemotherapy be considered for patients with bulky, localized tumors? Can immunotherapy improve outcomes when added to chemoradiation in locally advanced cases? Should immunotherapy be a standard option for recurrent disease? Addressing these questions requires a thorough understanding of the unique molecular and biological characteristics of neuroendocrine cervical carcinoma and its clinical behavior. This review aims to provide an updated summary of the molecular landscape of neuroendocrine cervical carcinoma, highlighting features that distinguish it from small cell lung cancer and align with other types of cervical cancer. We discuss current treatment approaches, identify gaps in knowledge, and examine paradigm-shifting clinical trials that have significantly impacted survival outcomes in cervical cancer and small cell lung cancer, translating these insights into potential strategies for neuroendocrine cervical carcinoma. By focusing on the unique aspects of neuroendocrine cervical carcinoma, this review emphasizes the need for specialized treatment strategies for this challenging disease.

Mesonephric and mesonephric-like adenocarcinomas of the gynecologic tract are a rare subset of gynecologic tumors that are frequently associated with the presence of somatic KRAS mutations. Owing to their rare nature and ability to arise in different gynecologic sites, pathologic diagnosis is often challenging and under-represented. Immunohistochemistry and routine use of next-generation sequencing has allowed these cases to be more readily identified; however, there is still a paucity of clinical outcomes data, and the efficacy of treatment paradigms remains largely unknown. Historically, mesonephric and mesonephric-like adenocarcinomas were considered to be less responsive to systemic treatment, but response rates to first-line platinum-doublet chemotherapy for metastatic disease may be higher than initially suspected. Recurrent disease is often distant and located in the lungs, suggesting an important role of surveillance chest imaging. Given that most of these tumors are associated with somatic mitogen-activated protein kinase pathway mutations, a currently open phase II trial is assessing the dual RAF/MEK clamp avutometinib in combination with the FAK inhibitor defactinib in patients with recurrent mesonephric and mesonephric-like adenocarcinomas. Continued multi-institutional prospective trials are necessary to elucidate additional treatment options for these rare tumors.

Despite an oftentimes radical surgical approach when treating patients with early-stage vulvar cancer, local recurrence occurs in approximately 40% of cases. Surgery in this setting can result in significant morbidity; however, treatment failure is associated with high mortality rates. Historically, many guidelines recommended a tumor-free margin ≥8 mm in the surgical treatment of vulvar cancer, although this is largely consensus-based and supported by a few small retrospective case series. Recently, numerous retrospective studies have found no association between a tumor-free margin of <8 mm and locoregional recurrence. Emerging evidence suggests that the presence of differentiated vulvar intra-epithelial neoplasia and lichen sclerosis at the pathologic margin may also play a role in local recurrence; however, data are retrospective and heterogenous, and the definition of what a "safe" tumor-free margin is remains unclear. However, increasing evidence has failed to demonstrate the beneficial role of re-excision or adjuvant radiation in the setting of margins of <8 mm. These additional treatments are associated with significant morbidity and have a negative impact on patients' quality of life; thus, they should be reserved solely for patients with positive margins. One of the main challenges in finding the ideal tumor-free margin is that the rarity of vulvar cancer makes prospective and randomized controlled trials difficult to conduct. Therefore, it is imperative that we make a concerted effort as a field to collaborate across nations and institutions, promote centralization of care for rare tumors, and prioritize future work to better understand the nature of this disease.

Malignant ovarian germ cell tumors (MOGCT) are rare and often aggressive cancers that predominantly affect young women. Fortunately, combined surgery and chemotherapy results in high cure rates. In this review, we will consider some of the many controversies and poorly understood areas in the management of MOGCT that have arisen largely because of the lack of randomized trial data. This paucity of strong evidence is unsurprising, given the rarity of MOGCT and their multiple subtypes which differ biologically and in their clinical behavior. We will explore what is known about the biology and prognostic factors, and how the disease differs from its much more common and robust evidence-based male testicular counterpart. The type and extent of surgery, the value of surveillance in early-stage disease, and the role of neoadjuvant chemotherapy in advanced cases remain uncertain. In addition, optimizing outcomes in relapsed disease following initial chemotherapy is a key area for future development, as survival in this situation is worse than that in patients with testicular germ cell tumors. Fertility preservation remains of central importance, but the best way to achieve it remains debated. Finally, the type and duration of surveillance after treatment remain unclear. These and other controversies are discussed below.

Low-grade serous ovarian cancer has been recognized as a distinct oncologic entity for the last 20 years. Over the last 10 years, treatment strategies tailored to the biological and clinical characteristics of the disease have been tested and implemented. However, several key controversies remain. Here, we articulate the uncertainties surrounding the identification of the tissues of origin of low-grade serous ovarian cancer and its precursor lesion, the serous borderline tumor, the challenges in identifying molecular drivers of low-grade serous ovarian cancer, where a driver mutation in the mitogen-activated protein kinase pathway has not been identified, and discuss the phenomenon of co-existent low- and high-grade components in a tumor. In the clinical arena, we discuss the challenges surrounding fertility preservation in young patients, difficulties encountered in patients with unresectable disease, and the controversy surrounding the recommendation of adjuvant chemotherapy. We also discuss the role of secondary debulking surgery, how to order the administration of biological therapies, and the key issues in accelerating the discovery and development of new therapies. For many of these issues, the solution lies in improved international collaboration and cooperation. For each, we allude to how this might best be achieved.

Background: The standard treatment for advanced epithelial ovarian cancer is primary cytoreductive surgery, with the goal of achieving no residual disease. Neoadjuvant chemotherapy and interval cytoreductive surgery can be viable treatment options for patients with extensive disease that precludes complete tumor removal during initial surgery, or when significant comorbidities increase the surgical risk without adversely impacting overall survival rates. However, published studies mostly included patients with high-grade serous ovarian cancer, with an underrepresentation of non-high-grade serous epithelial and non-epithelial cancers. This review aimed to provide an overview of the available data on the outcomes of primary cytoreductive surgery versus interval cytoreduction in patients with rare ovarian cancer histotypes.

Methods: Published literature on primary versus interval cytoreductive surgery in non-high-grade serous ovarian cancers from 2004 to 2024 was searched using PubMed, EMBASE, and Google Scholar and reported for each histological subtype. The outcomes of patients with low-grade serous, endometrioid, clear-cell, and mucinous carcinomas after neoadjuvant chemotherapy were reviewed. Furthermore, the results following neoadjuvant chemotherapy in non-epithelial ovarian cancers, such as ovarian germ cell tumors, sex cord-stromal tumors, and small-cell carcinoma of the ovary, have also been reported. Most data were derived from retrospective studies, with heterogeneity in design.

Results & conclusions: Several ovarian cancer histotypes, including low-grade serous and mucinous carcinomas, may be less responsive than high-grade serous carcinomas to neoadjuvant chemotherapy. Consequently, primary cytoreduction with maximal surgical effort may confer a survival advantage. Other tumors responded well to neoadjuvant chemotherapy, allowing for interval fertility-sparing surgeries. Additional evidence is required because no prospective studies are currently available. Given the low incidence of these diseases, randomized controlled trials may not be feasible. However, national or international registries could play a pivotal role in determining the optimal approach for managing patients with these rare histotypes.

Ovarian sex cord-stromal tumors are rare and include adult granulosa cell tumors, juvenile granulosa cell tumors, and Sertoli-Leydig cell tumors. Adult granulosa cell tumors the most prevalent malignant ovarian sex cord stromal tumors are the focus of the review which synthesizes published data to highlight the diagnostic challenges and the controversies surrounding the management of adult granulosa cell tumors, juvenile granulosa cell tumors, and Sertoli-Leydig cell tumors. Adult granulosa cell tumors have frequently been misdiagnosed, with up to 30% of cases reassigned after a contemporary review of historical cases, which could affect the interpretation of older studies. Diagnostic accuracy improved in 2009 following the identification of a somatic FOXL2 c.402C>G missense point in almost all adult granulosa cell tumors. Surgery is the mainstay of treatment at diagnosis and recurrence, and fertility-sparing surgery is recommended for younger patients with stage 1 ovarian sex cord-stromal tumors. The role of adjuvant chemotherapy in stage I high-risk adult granulosa and Sertoli-Leydig cell tumors remains controversial, with guidelines providing varied and conflicting recommendations based on limited evidence. Surveillance strategies, including the frequency of follow-up, duration of surveillance, sensitivity, and specificity of tumor markers, and the timing and nature of imaging, are debatable. We reviewed the evolution of systemic therapy for ovarian sex cord-stromal tumors over the last 4 decades and raised questions regarding the choice of chemotherapy regimens and evidence to support adjuvant chemotherapy. The efficacy of endocrine therapy in adult granulosa cell tumors is contentious, and most studies are retrospective with variable criteria to define response and clinical benefit. The available data are discussed, including trials in progress. In conclusion, the management of ovarian sex cord-stromal tumors requires a nuanced understanding of their unique pathologic and biological characteristics and an appreciation of the limitations of the existing evidence. There is a high priority to encourage international collaboration through prospective data collection and randomized trials to provide the required evidence to support treatment guidelines and ultimately improve patient outcomes.

More than half of all gynecological cancers are classified as rare (annual incidence <6 per 100,000), and present significant challenges in diagnosis, management, and research. Rare cancers collectively comprise more than 20% of new cancer diagnoses and exceed the burden of individual common cancers. Their rarity complicates evidence-based guideline development, clinical trial design, and drug access, and is exacerbated by variations in epidemiology, histology, and biological behavior. Key controversies include the need for centralized pathological reviews and harmonized diagnostic criteria. Recent World Health Organization classification updates, such as the redefinition of ovarian and fallopian tube cancers, illustrate the impact of evolving guidelines on epidemiology and patient management. Variations in the classification among pathologists and limited access to molecular diagnostics further hinder effective management. Multidisciplinary care in expert centers improves outcomes; however, significant geographic and resource disparities persist. National and international collaborations including European Reference Network for rare adult solid tumors, Gynecologic Cancer Intergroup, Gynecologic Oncology Group, Asia-Pacific Gynecologic Oncology Trials Group, and European Network for Gynaecological Oncology Trials have made strides in standardizing care and advancing research. Novel trial designs, such as basket and umbrella trials, alongside synthetic control arms, are essential for addressing the small sample sizes typical of rare tumors. Emerging consortia, such as International Ovarian Tumor Tissue Analysis Consortium and International Consortium for Low-grade Serous Ovarian Cancer, provide robust platforms for translational research and biomarker validation. However, challenges remain in fostering cross-border collaboration, streamlining regulatory pathways, and ensuring equitable access to trials and therapy. To optimize outcomes, a comprehensive approach that integrates centralized care, innovative trial designs, and international networks is imperative. This paradigm fosters the harmonization of care, accelerates translational research, and bridges the gap between scientific innovation and patient benefits.

Clear cell ovarian and endometrial carcinomas are rare and aggressive gynecologic malignancies that present unique challenges owing to their underrepresentation in clinical trials and limited prospective data. In this report, we aimed to explore 3 major controversies in the management of clear cell ovarian and endometrial carcinomas, highlighting areas that require further investigation. First, we addressed the unique phenotypic characteristics of clear cell ovarian carcinoma and clear cell endometrial carcinoma and whether they should be considered a unified disease entity or a distinct disease. Recent trials grouped these carcinomas, potentially expanding their therapeutic options. However, emerging molecular data underscores the significant differences between clear cell ovarian carcinoma and clear cell endometrial carcinoma, raising questions regarding this combined approach. This distinction is critical in guiding tailored treatment strategies. Second, we examined the management of localized diseases. Although early-stage diagnoses are common in clear cell carcinomas, optimal surgical and adjuvant treatment strategies remain uncertain. Current practice often relies on data from broader studies with limited inclusion of clear cell histology. This review underscores the need for more specific evidence to refine treatment protocols and balance efficacy with the minimization of treatment-related morbidity. Third, we explored novel therapeutic strategies for the treatment of recurrent diseases. Advances in the understanding of the biology of clear cell carcinomas have identified potential targets in the immune microenvironment, cellular processes, and metabolism. Ongoing clinical trials are investigating these approaches, which hold promise in transforming the treatment landscape and outcomes. In conclusion, this review emphasizes the necessity for international collaboration and the inclusion of diverse patient populations to address the challenges posed by cell carcinomas. By focusing on these controversies, we aim to stimulate further research and support more evidence-based personalized approaches for the management of these rare but challenging cancers.

Low-grade endometrioid ovarian and endometrial tumors are unique clinical entities and their molecular characteristics affect their biology and clinical course. Although low-grade endometrioid ovarian tumors are rare, low-grade endometrioid endometrial carcinomas are common among uterine tumors. These tumors are often diagnosed at an early stage in women of childbearing age; thus, the selection of patients for conservative treatment is crucial. Synchronous tumors are not rare in this sub-group of patients and might represent a challenge for treatment. In the setting of advanced/recurrent disease, both these histologies are poorly represented in large randomized clinical trials; thus, their management is often based on evidence in the field of low-grade serous or high-grade endometrioid histology. The molecular characterization of these tumors has provided further patient stratification with relevant implications for clinical management. Given the paucity of available data, there are several controversies regarding the diagnosis and management of these tumors, from the correct identification of the primary tumor to the surgical approach and medical treatment of the recurrent/advanced disease. This review aims to provide an overview of the main controversial issues on this topic, along with the evidence currently available to guide clinical management, with particular interest in recent and future clinical trials.