Search Results (13)

 Background/Objectives: Extrapulmonary neuroendocrine carcinomas (EP-NECs) are rare, aggressive malignancies with no standardized treatment approach. Although platinum-based chemotherapy is considered the first-line therapy, overall survival (OS) and progression-free survival (PFS) remain limited. This study aims to evaluate the clinical and pathological characteristics of EP-NEC patients, their treatment responses, and survival outcomes. Methods: This retrospective observational study included 29 EP-NEC patients diagnosed and followed between 2015 and 2024. Clinical and demographic data, tumor localization, disease stage, administered treatments, and survival outcomes were analyzed. Kaplan–Meier survival analysis was used to assess OS and PFS, with subgroup comparisons performed via the log-rank test. Results: The most common primary tumor sites were the pancreas (21%), prostate (17%), and cervix (14%). At diagnosis, 55.2% of patients had metastatic disease. First-line platinum-based chemotherapy achieved an objective response rate of 82.1%, with a median PFS of 8.16 months and a median OS of 14.16 months. Surgical intervention significantly improved survival (p = 0.020), while a high Ki-67 proliferation index (>80%) was associated with worse PFS (p = 0.032). Other factors, including smoking status and liver-directed therapies, had no significant impact on survival. Conclusions: EP-NECs present with a poor prognosis despite platinum-based chemotherapy achieving high response rates. Surgical resection improves survival outcomes, whereas high Ki-67 expression is associated with a worse prognosis. These findings highlight the need for further research into novel therapeutic strategies for EP-NECs. Full article

Background and clinical significance: Large-cell neuroendocrine carcinoma (LCNEC) of the cervix is considered a rare type of cancer: it represents <1% of invasive cervical cancers. The optimal treatment protocol is not fully established because of its rarity and diagnostic challenges. Case Presentation: A 72-year-old Asian female presented to our outpatient clinic with postmenopausal vaginal spotting for 1 month. Vaginal sonography revealed a cervical tumor of 2.7 cm in diameter with hypervascularity. Tumor markers such as CA 125, CA 19-9, carcinoembryonic antigen, and squamous cell carcinoma antigen all showed no abnormality. Due to high suspicion of cervical cancer, a pap smear and endocervical curettage were performed and confirmed the diagnosis of LCNEC. A positron emission tomography–computed tomography scan demonstrated a glucose hypermetabolic lesion in the mid-pelvic region, localized to the uterus, consistent with LCNEC. Surgery with radical hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic lymph node dissection was performed. The patient was finally diagnosed with pT1b2N1mi, FIGO IIIC1. Immunohistochemical stain shows that the neoplastic cells were CK (+), p63 (−), p16 (−), CEA (−), vimentin (−), ER (−), WT-1 (−), p53 (−), and CD56 (+), with a high Ki67 index (75%). Concurrent chemotherapy with cisplatin and radiotherapy was performed. Four cycles of etoposide and cisplatin were planned. A 3-month follow-up of this patient revealed stable tumor marker levels. Conclusions: This case highlights the diagnostic challenges and aggressive nature of LCNEC of the cervix, emphasizing the need for a standardized treatment approach to improve patient outcomes. Full article

Small-cell neuroendocrine carcinoma of the cervix (SCNECC) is a rare cancer with poor prognosis, with limited data to guide its treatment. The objective of this study was to evaluate practice patterns in the management of SCNECC. A 23-question online survey on management of SCNECC was disseminated to Canadian gynecologic oncologists (GO), radiation oncologists (RO) and medical oncologists (MO). In total, 34 practitioners from eight provinces responded, including 17 GO, 13 RO and four MO. During staging and diagnosis, 74% of respondents used a trimodality imaging approach, and 85% tested for neuroendocrine markers. In early-stage (1A1-1B2) SCNECC, 87% of practitioners used a surgical-based approach with various adjuvant and neoadjuvant treatments. In locally advanced (1B3-IVA) SCNECC, 53% favored primary chemoradiation, with cisplatin and etoposide, with the remainder using surgical or radiation-based approaches. In metastatic and recurrent SCNECC, the most common first-line regimen was etoposide and platinum, and 63% of practitioners considered clinical trials in the first line setting or beyond. This survey highlights diverse practice patterns in the treatment of SCNECC. Interdisciplinary input is crucial to individualizing multimodality treatment, and there is a need for prospective trials and intergroup collaboration to define the optimal approach towards managing this rare cancer type. Full article

Small-cell neuroendocrine cervical carcinoma (SCNCC) is a rare yet aggressive gynecological malignancy associated with dismal clinical outcomes. Its rarity has led to a limited number of retrospective studies and an absence of prospective research, posing significant challenges for evidence-based treatment approaches. As a result, most gynecologic oncology centers have limited experience with this tumor, emphasizing the urgent need for a comprehensive review and summary. This article systematically reviews the pathogenesis, immunohistochemical and molecular characteristics, prognostic factors, and clinical management of gynecologic SCNCC. We specifically focused on reviewing the distinct genomic characteristics of SCNCC identified via next-generation sequencing technologies, including loss of heterozygosity (LOH), somatic mutations, structural variations (SVs), and microRNA alterations. The identification of these actionable genomic events offers promise for discovering new molecular targets for drug development and enhancing therapeutic outcomes. Additionally, we delve deeper into key clinical challenges, such as determining the optimal treatment modality between chemoradiation and surgery for International Federation of Gynecology and Obstetrics (FIGO) stage I phase patients within a precision stratification framework, as well as the role of targeted therapy within the homologous recombination (HR) pathway, immune checkpoint inhibitors (ICIs), and prophylactic cranial irradiation (PCI) in the management of SCNCC. Finally, we anticipate the utilization of multiple SCNCC models, including cancer tissue-originated spheroid (CTOS) lines and patient-derived xenografts (PDXs), to decipher driver events and develop individualized therapeutic strategies for clinical application. Full article

Introduction: Cervical cancer is the fourth most common malignancy in women and the fourth leading cause of death among women. The main histological types of cervical cancer are squamous cell carcinoma—75% of all cases; adenocarcinoma—10–25%; and all other rare variants including adenosquamous carcinoma and neuroendocrine carcinoma. Squamotransitional cervical cancer is an extremely rare and poorly studied subtype of squamous cell carcinoma. Case report: We present a case of a 64-year-old female patient with early-stage squamotransitional carcinoma. A metastasis was observed in the left ovary and the left fallopian tube and a benign Brenner tumor in the right ovary. Discussion: Although it is believed that this cervical cancer subtype shares the same risk factors and prognosis as squamous cell carcinoma, it is more likely to metastasize and recur. It is not unusual for spread to exist within nearby structures like the cervix and adnexa. It is impossible to tell which is the predominant focus from the immunoprofile of the lesions. Practically speaking, the best course of action in these situations is to rule out the presence of a primary tumor in the urinary tract before clarifying the condition of the cervix, uterus, and adnexal tissues. The presence of a Brenner tumor raises the possibility of a connection between the tumor’s differentiation from a cell population and potential urothelial differentiation. Conclusion: Squamotransitional cervical cancer is a rare tumor with a poorly studied clinical behavior. Despite a shortage of information in the literature, it should be regarded as a more aggressive variety of squamous cell carcinoma and, as such, should be treated and followed up more aggressively. This case is the first described with involvement of the cervix, endometrium, and adnexal structures and a concomitant Brenner tumor. Full article

The aim of the current study is to investigate the survival outcome of stage IVB SCNEC of the uterine cervix in comparison to major histological subtypes of cervical cancer. A population-based retrospective cohort study was conducted using the Osaka Cancer Registry data from 1994 to 2018. All FIGO 2009 stage IVB cervical cancer patients who displayed squamous cell carcinoma (SCC), adenocarcinoma (A), adenosquamous cell carcinoma (AS), or small-cell neuroendocrine carcinoma (SCNEC) were first identified. The patients were classified into groups according to the types of primary treatment. Then, their survival rates were examined using the Kaplan–Meier method. Overall, in a total of 1158 patients, clearly differential survival rates were observed according to the histological subtypes, and SCNEC was associated with shortest survival. When examined according to the types of primary treatments, SCNEC was associated with significantly decreased survival when compared to SCC or A/AS, except for those treated with surgery. In patients with FIGO 2009 stage IVB cervical cancer, SCNEC was associated with decreased survival when compared to SCC or A/AS. Although current treatments with either surgery, chemotherapy or radiotherapy have some therapeutic efficacies, to improve the prognosis, novel effective treatments specifically targeting cervical SCNEC need to be developed. Full article

Background: Combining traditional clinical parameters with neuroendocrine markers to construct a nomogram model to predict the postoperative recurrence of neuroendocrine carcinoma of cervix (NECC). Methods: A total of 257 patients were included in this study. Univariate and multivariate Cox regression analyses were used to establish a nomogram model in the training cohorts, which was further validated in the validation cohorts. The calibration curve was used to conduct the internal and external verification of the model. Results: Overall, 41 relapse cases were observed in the training (23 cases) and validation (18 cases) cohorts. The univariate analysis preliminarily showed that FIGO stage, stromal invasion, nerve invasion, lymph vascular space invasion, lymph node involvement, cervical–uterine junction invasion and CgA were correlated with NECC recurrence. The multivariate analysis further confirmed that FIGO stage (p = 0.023), stromal invasion (p = 0.002), lymph vascular space invasion (p = 0.039) and lymph node involvement (p = 0.00) were independent risk factors for NECC recurrence, which were ultimately included in the nomogram model. In addition, superior consistency indices were demonstrated in the training (0.863, 95% CI 0.784–0.942) and validation (0.884, 95% CI 0.758–1.010) cohorts. Conclusions: The established nomogram model combining traditional clinical parameters with neuroendocrine markers can reliably and accurately predict the recurrence risks in NECC patients. Full article

Background: Neuroendocrine carcinoma of the cervix (NECC) is an aggressive and rare type of cervical cancer. The five-year overall survival is low at 30% and there is no standardized therapy based on controlled trials for this type of tumour. Most are locally advanced or metastasized at the time of the diagnosis. Extracellular vesicles (EVs) could be a carrier of viral DNA/RNA, given their vital role in cellular communication. The content of EV derived from NECC cells has not been investigated due to the lack of cell line, and it is not known whether they contain human papillomaviruses (HPV) DNA/RNA or not. Methods: The presence of viral E7 DNA/RNA in EVs purified from a culture of a recently established NECC cell line, GUMC-395, was evaluated by using droplet digital polymerase chain reaction (ddPCR). These EVs were characterized using nanoparticle tracking analysis (NTA) for size distribution, transmission electron microscopy (TEM) for morphology, Western blot for CD63, and bioanalyser for RNA quantity and quality. Results: HPV16 viral-RNA, but not DNA, was detected in EVs from GUMC-395 using ddPCR. NTA identified EVs with a mean diameter of 105.0 nm, TEM confirmed normal morphological shape and size, and Western blot analysis confirmed the presence of EV-associated proteins CD63. The EVs were found to be enriched with small RNAs using a bioanalyser. Conclusions: HPV16 RNA is found in EVs from a neuroendocrine cervical cancer and could be involved in the pathogenesis of the disease and used as a diagnostic biomarker. Full article

Neuroendocrine carcinoma (NEC) of the female genital tract is a rare and aggressive subtype of cancer that is still poorly understood. Several recent studies reported that pulmonary and gastroenteropancreatic neuroendocrine neoplasms show significantly different patterns of metastasis compared to non-NECs of the same primary sites. The aim of this study was to evaluate the metastatic patterns of gynecologic NECs and to compare the metastatic patterns of NECs and non-NECs of the same primary sites. We retrieved and analyzed cervical, endometrial, and ovarian NEC cases from the Surveillance, Epidemiology, and End Results (SEER) database. To validate the results, we also retrieved and analyzed cervical NEC cases from an institutional database. Uterine cervical NEC was the most common NEC. The overall metastatic rate was significantly higher in the NEC group than in the non-NEC group for all three primary sites. All cervical, endometrial, and ovarian NECs showed a higher tendency for bone, brain, and liver organotrophic metastasis than non-NECs of the same primary sites. We demonstrated that gynecologic NECs show significantly different metastatic patterns compared to non-NECs of the same primary sites. These findings might help clinicians to better manage patients with gynecologic NECs. Full article

Gynecological tract neuroendocrine neoplasms (NEN) are rare, aggressive tumors from endocrine cells derived from the neuroectoderm, neural crest, and endoderm. The primary gynecologic NENs constitute 2% of gynecologic malignancies, and the cervix is the most common site of NEN in the gynecologic tract. The updated WHO classification of gynecologic NEN is based on the Ki-67 index, mitotic index, and tumor characteristics such as necrosis, and brings more uniformity in the terminology of NENs like other disease sites. Imaging plays a crucial role in the staging, triaging, restaging, and surveillance of NENs. The expression of the somatostatin receptors on the surface of neuroendocrine cells forms the basis of increasing evaluation with functional imaging modalities using traditional and new tracers, including ⁶⁸Ga-DOTA-Somatostatin Analog-PET/CT. Management of NENs involves a multidisciplinary approach. New targeted therapies could improve the paradigm of care for these rare malignancies. This article focuses on the updated staging classifications, clinicopathological characteristics, imaging, and management of gynecologic NENs of the cervix, ovary, endometrium, vagina, and vulva, emphasizing the relatively common cervical neuroendocrine carcinomas among these entities. Full article

Neuroendocrine neoplasms (NENs) are particularly rare in all sites of the gynecological tract and include a variety of neoplasms with variable prognosis, dependent on histologic subtype and site of origin. Following the expert consensus proposal of the International Agency for Research on Cancer (IARC), the approach in the latest World Health Organization (WHO) Classification System of the Female Genital Tumours is to use the same terminology for NENs at all body sites. The main concept of this novel classification framework is to align it to all other body sites and make a clear distinction between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The previous WHO Classification System of the Female Genital Tumours featured more or less the same principle, but used the terms ‘low-grade neuroendocrine tumor’ and ‘high-grade neuroendocrine carcinoma’. Regardless of the terminology used, each of these two main categories include two distinct morphological subtypes: NETs are represented by typical and atypical carcinoid and NEC are represented by small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). High-grade NECs, especially small cell neuroendocrine carcinoma tends to be more frequent in the uterine cervix, followed by the endometrium, while low-grade NETs usually occur in the ovary. NENs of the vulva, vagina and fallopian tube are exceptionally rare, with scattered case reports in the scientific literature. Full article

Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (PIK3CA, 32%; TP53, 24%) and distinct (SMAD4, 20%; RET, 16%; EGFR, 12%; APC, 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and RB1 mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies. Full article

Background. Gynecological neuroendocrine neoplasms (NENs) are extremely rare, accounting for 1.2–2.4% of the NENs. The aim of this study was to test cervical NENs for novel markers of potential utility for differential diagnosis and target therapy. Methods. All cases of our center (n = 16) were retrieved and tested by immunohistochemistry (IHC) for 12 markers including markers of neuroendocrine differentiation (chromogranin A, synaptophysin, CD56), transcription factors (CDX2 and TTF1), proteins p40, p63, p16INK4a, and p53, somatostatin receptors subtypes (SST2-SST5) and the proliferation marker Ki67 (MIB1). Results. All cases were poorly differentiated neuroendocrine carcinomas (NECs), 10 small cell types (small cell–neuroendocrine carcinomas, SCNECs) and 6 large cell types (large cell–neuroendocrine carcinomas, LCNECs); in 3 cases a predominant associated adenocarcinoma component was observed. Neuroendocrine cancer cells expressed at least 2 of the 3 tested neuroendocrine markers; p16 was intensely expressed in 14 (87.5%) cases; SST5 in 11 (56.25%, score 2–3, in 9 cases); SST2 in 8 (50%, score 2–3 in 8), CDX2 in 8 (50%), TTF1 in 5 (31.25%), and p53 in 1 case (0.06%). P63 and p40 expressions were negative, with the exception of one case that showed moderate expression for p63. Conclusions. P40 is a more useful marker for the differential diagnosis compared to squamous cell carcinoma. Neither CDX2 nor TTF1 expression may help the differential diagnosis versus potential cervical metastasis. P16 expression may suggest a cervical origin of NEC; however, it must be always integrated by clinical and instrumental data. The expression of SST2 and SST5 could support a role for SSAs (Somatostatin Analogues) in the diagnosis and therapy of patients with cervical NECs. Full article