Neuroendocrine Cervical Carcinoma Research Articles

HER2 mutations in advanced cervical neuroendocrine carcinoma: implications for trastuzumab deruxtecan therapy.

Recent clinical evidence shows that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) can successfully treat patients with advanced HER2-mutant non-small cell lung cancer (NSCLC). We aimed to characterize HER2 mutations in cervical neuroendocrine carcinoma (NEC) among Taiwanese women to provide the rationale for exploring T-DXd as a tumor-agnostic targeted therapy option. We analyzed 12 archived primary cervical NEC samples from Taiwanese patients. Tumor-rich areas were marked for microdissection on 10 μm unstained sections. DNA was extracted, and HER2 hotspots were sequenced using a targeted panel on the Illumina MiSeq. HER2 missense mutations were identified in 5 of 12 cases (41.7%). Of the 5 cases with mutations, 2 patients (40%) had a single mutation, while 3 patients (60%) had double mutations. We detected 4 substitutions outside the tyrosine kinase domain (non-TKD), which were p.P1170A, p.S305C, p.I655V, and a novel T328K alteration. No mutations were found within the tyrosine kinase domain (TKD). The 41.7% HER2 mutation rate warrants expanded screening and future clinical investigation of the T-DXd targeting HER2 mutations in cervical NEC patients. Overall, this study contributes to the molecular understanding of cervical NEC and lays the groundwork for developing more effective treatment strategies.

Advancements in the Understanding of Small-Cell Neuroendocrine Cervical Cancer: Where We Stand and What Lies Ahead.

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.

Impact of pelvic radiation therapy in patients with early neuroendocrine cervical carcinoma and no residual disease in the radical hysterectomy specimen: a NeCTuR study

ObjectiveThe impact of adjuvant pelvic radiation therapy on the rate and location of recurrences was evaluated in patients with early-stage (IA1–IB2) neuroendocrine cervical carcinoma who underwent prior conization or polypectomy...

Advances in Research, Diagnosis, and Treatment of Neuroendocrine Cervical Carcinoma: A Review.

Neuroendocrine neoplasms (NENs) were classified separately in the 5th edition (2020) of the World Health Organization (WHO) classification of female genital malignancies. Cervical neuroendocrine carcinoma (NEC) is distinguished by its low incidence, high invasiveness, early local dissemination, and distant metastases. The purpose of this review is to outline the achievements in pathology, diagnostics, gene sequencing, and multi-modality treatment of cervical NEC.

Whole exome sequencing identifies common mutational landscape of cervix and endometrium small cell neuroendocrine carcinoma.

Primary small cell neuroendocrine carcinomas of the cervix and endometrium are rare gynecological malignancies with limited treatment options. This study aimed to improve the understanding of the carcinogenesis process and identify potential therapeutic targets for these two tumor types by constructing the mutational landscape at the whole exome level. Primary tumor tissues and their matched blood samples were obtained from 10 patients with small cell cervical neuroendocrine carcinoma (NECC) and five patients with small cell endometrial neuroendocrine carcinoma (NECE). Whole exome sequencing was performed to construct the somatic mutation profiles. Mutational signature and recurrent mutated gene analysis were used to identify tumor subtypes and common carcinogenesis processes. Based on the burden of different mutational signatures, the NECCs in this work can be divided into two subtypes, including the mismatch repair deficiency like (dMMR-like) type (4/10) and the high spontaneous deamination type (6/10). Components of the PI3K/AKT signaling and RAS signaling were exclusively mutated in these two subtypes, respectively. The integration of human papillomavirus made a limited contribution to tumorigenesis in NECC (20%). The dysfunction of the mismatch repair system and microsatellite instability are the major features of NECE. PI3K/AKT, JAK/STAT signaling, and chromatin remodeling activity were the common mutated pathways in NECE. PIK3CA, WNK2, and KMT2B underwent mutations in both the dMMR-like subtype of NECC (50% - 75%) and in NECE (60% - 80%) specimens, while exhibiting infrequent mutational occurrences in publicly available data pertaining to neuroendocrine carcinomas of the lung or bladder (< 10%). We identified the two subtypes of NECC with distinct mutated pathways and potential therapy targets. The dMMR-like type NECC and NECE may share a similar carcinogenesis process that include dysfunction of PI3K/AKT signaling, cell cycle, antiapoptotic processes, and chromatin remodeling activity.

Clinicopathologic characteristics, oncologic outcomes, and prognostic factors in neuroendocrine cervical carcinoma: a Neuroendocrine Cervical Tumor Registry study

ObjectiveTo evaluate clinicopathologic features and oncologic outcomes of patients with neuroendocrine cervical carcinoma in an institutional neuroendocrine cervical tumor registry.MethodsRetrospective study including patients with neuroendocrine cervical carcinomas diagnosed between 1986...

Cervical neuroendocrine carcinoma in the third trimester: a rare case report and literature review

BackgroundThe incidence of cervical neuroendocrine carcinoma (CNECC) during pregnancy is extremely rare. Insufficient awareness of gynecological tumor screening, as well as atypical and insidious initial clinical symptoms, may result in diagnostic delays and misdiagnosis. There is no standardized treatment for cervical cancer in pregnancy. Herein, we present a case of cervical neuroendocrine carcinoma diagnosed in the third trimester of pregnancy.Case presentationA 26-year-old female at 30 1/7 weeks of gestation presented with lower back and sacroiliac joint pain, abdominal distension, and lower limb dyskinesia. A pelvic examination revealed a large fungating gray mass that encompassed the entire cervix, with cervical contact bleeding testing positive. Imaging studies showed a significant cervical mass, diffuse liver changes, and metastasis to multiple sites. Biopsy results revealed poorly differentiated cervical carcinoma exhibiting high-grade neuroendocrine features, consistent with a diagnosis of large cell neuroendocrine carcinoma. The patient was diagnosed with stage IVB CNECC with HPV18 (+), and due to the gestational age of the fetus and her deteriorating condition, she underwent cesarean section delivery after receiving fetal lung maturation therapy. Following surgery, eight cycles of neoadjuvant chemotherapy were applied. Unfortunately, she succumbed to multiple tumor metastases six months post-treatment. Despite this tragic outcome, the infant was discharged in a healthy condition.ConclusionsCNECC during pregnancy, particularly the large-cell type, is an ultra-rare condition with poor prognosis. This case highlights the importance of individualized treatment approach and the need for better screening, early detection, and treatment. Given the rarity of the disease, further research is warranted to determine the prognostic factors and develop effective treatment strategies for this ultra-rare and aggressive malignancy.

EXCEPTIONAL LONG-TERM SURVIVAL OF AN ELDERLY PATIENT WITH METASTATIC SMALL CELL NEUROENDOCRINE CARCINOMA OF THE CERVIX – A CASE REPORT

Small cell neuroendocrine cervical carcinoma (SCCC) is known for its aggressive nature and poor prognosis. There are no standard treatments so small cell lung cancer treatments are often referenced due to their similar morphology. Typical treatment options include a combination of external beam radiotherapy and brachytherapy for localised disease and palliative chemotherapy for advanced disease. The 5-year survival rate for patients presenting with advanced disease is dismal, around 0–14%. Here, we report a case of a 75-year-old woman who was diagnosed with small cell neuroendocrine cervical carcinoma (SCCC) in 2015. She presented with locally advanced SCCC with vaginal involvement, as well as solitary lung and peripancreatic metastases. She was treated with a combination of chemotherapy, chemoradiation and stereotactic radiotherapy, followed by maintenance etoposide, and achieved a very long-term survival. The patient continues to survive today.

Impacts of ovarian preservation on the prognosis of neuroendocrine cervical carcinoma: a retrospective analysis based on machine learning

BackgroundNeuroendocrine cervical carcinoma (NECC) is a rare but aggressive malignancy with younger patients compared to other common histology types. This study aimed to evaluate the impacts of ovarian preservation (OP) on the prognosis of NECC through machine learning.MethodsBetween 2013 and 2021, 116 NECC patients with a median age of 46 years received OP or bilateral salpingo-oophorectomy (BSO) and were enrolled in a retrospective analysis with a median follow-up of 41 months. The prognosis was estimated using Kaplan–Meier analysis. Random forest, LASSO, stepwise, and optimum subset prognostic models were constructed in training cohort (randomly selected 70 patients) and tested in 46 patients through receiver operator curves. Risk factors for ovarian metastasis were identified through univariate and multivariate regression analyses. All data processing was carried out in R 4.2.0 software.ResultsAmong 116 patients, 30 (25.9%) received OP and showed no significantly different OS compared with BSO group (p = 0.072) and got better DFS (p = 0.038). After construction of machine learning models, the safety of OP was validated in lower prognostic risk group (p > 0.05). In patients ≤ 46 years, no impacts of OP were shown for DFS (p = 0.58) or OS (p = 0.67), and OP had no impact on DFS in different relapse risk population (p > 0.05). In BSO group, regression analyses showed that later stage, para-aortic LNM, and parametrial involvement were associated with ovarian metastasis (p < 0.05).ConclusionsPreserving ovaries had no significant impact on prognosis in patients with NECC. OP should be considered cautiously in patients with ovarian metastasis risk factors.

Cervical Neuroendocrine Carcinomas: A Population-Based Analysis of Clinicopathologic Characteristics and Survival Outcomes in Comparison with Conventional Cervical Malignancies

Cervical Neuroendocrine Carcinomas: A Population-Based Analysis of Clinicopathologic Characteristics and Survival Outcomes in Comparison with Conventional Cervical Malignancies

PD-L1 expression and prognosis in definitive radiotherapy patients with neuroendocrine cervical carcinoma

PD-L1 expression and prognosis in definitive radiotherapy patients with neuroendocrine cervical carcinoma

RB1 alteration and poor prognosis in women with high-grade neuroendocrine carcinoma of the uterine cervix: a NeCTuR study.

To describe the gene alteration status in high-grade neuroendocrine cervical carcinoma (NECC) specimens and to explore the potential association of unique gene alterations with survival. Results from tumor-based molecular testing on specimens from women with high-grade NECC in the Neuroendocrine Cervical Tumor Registry were reviewed and analyzed. Tumor specimens could be from primary or metastatic sites and obtained at initial diagnosis, during treatment, or at recurrence. Molecular testing results were available for 109 women with high-grade NECC. The genes most frequently mutated were PIK3CA (mutated in 18.5% of patients), TP53 (17.4%), and MYC (14.5%). Other targetable alterations identified were alterations in KIT (7.3%), KRAS (7.3%), and PTEN (7.3%). Women with tumors having an RB1 alteration (6.4%) had a median overall survival (OS) of 13 months, compared to 26 months for women with tumors that did not have an RB1 alteration (p=0.003). None of the other genes evaluated were shown to be associated with OS. Although no individual alteration was found in a majority of tumor specimens from patients with high-grade NECC, a large proportion of women with this disease will have at least one targetable alteration. Treatments based on these gene alterations may offer additional targeted therapies for women with recurrent disease, who currently have very limited therapeutic options. Patients with tumors that harbor RB1 alterations have decreased OS.

Preliminary Investigation into Ultrasound and MRI Presentation of Large-Cell Neuroendocrine Carcinomas of the Uterine Cervix

Abstract Objective: The aim of this study was to analyze the ultrasound and MRI features of eight patients with cervical large-cell neuroendocrine carcinoma to improve awareness of this disease among sonographers, radiologists, and clinicians. Methods: Clinical data for eight patients with cervical large-cell neuroendocrine carcinoma confirmed by pathology at Sun Yat-sen Memorial Hospital of Sun Yat-sen University between February 2018 and April 2021 were retrospectively analyzed according to clinical, conventional ultrasound, contrast-enhanced ultrasound, and MRI characteristics. Results: Conventional ultrasound examination of the cervical large-cell neuroendocrine carcinoma lesions in the eight patients revealed two features: (1) irregular hypoechoic areas in the muscular layer, with slightly hyperechoic inlay streaks, and poorly delineated lesions, and (2) slightly abundant blood flow distribution in the lesions. The contrast-enhanced ultrasound showed a “fast-in and fast-out” mode; after subsidence, a “fence-like” change was observed, and the enhancement range was significantly greater than the range of two-dimensional ultrasound. In MRI, T1WI showed a low signal or isosignal; T2WI showed a high signal; DWI showed a high signal and low ADC value; and most of the enhanced MRI showed inhomogeneous hyperenhancement. Conclusion: Conventional ultrasound, contrast-enhanced ultrasound and MRI are complementary methods that provide additional imaging information for the diagnosis of cervical large-cell neuroendocrine carcinoma.

Comparison of Metastatic Patterns Among Neuroendocrine Tumors, Neuroendocrine Carcinomas, and Nonneuroendocrine Carcinomas of Various Primary Organs.

Both neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) exhibit neuroendocrine differentiation and are classified as neuroendocrine neoplasms (NENs). NECs and nonneuroendocrine neoplasms (non-NENs), such as adenocarcinoma, have similar mutational profiles. The purpose of this study was to identify differences in metastatic patterns and to identify the key factor causing these differences by simultaneously comparing the metastatic patterns of NETs, NECs and non-NENs from various primary organs. We retrieved data for 4,223 patients with NENs and 41,637 patients with non-NENs arising at various primary sites from an institutional database and then compared NET, NEC, and non-NEN metastatic patterns. NETs and NECs showed generally similar metastatic patterns. Most NEN patients had a higher liver organotrophic metastasis rate, lower lung organotrophic metastasis rate, and lower pleural/peritoneal organotrophic metastasis rate than non-NEN patients. Some differences were characteristics of specific organs. Some of these site-specific differences were not caused by NENs but by non-NENs, including a higher bone organotrophic metastasis rate for medullary thyroid carcinoma and a lower bone organotrophic metastasis rate for pulmonary NEN. Other differences were probably caused by NENs, including a higher bone organotrophic metastasis rate for colorectal NETs. Uterine cervical NEC showed unique patterns of metastasis compared to NEN from other sites. Significant differences between the metastatic patterns of NENs and non-NENs were detected. The multigene program that causes neuroendocrine differentiation might be associated with organotropic metastasis.

Neuroendocrine Carcinomas of the Uterine Cervix, Endometrium, and Ovary Show Higher Tendencies for Bone, Brain, and Liver Organotrophic Metastases.

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.

Distant organ metastasis patterns and prognosis of neuroendocrine cervical carcinoma: a population-based retrospective study.

BackgroundNeuroendocrine carcinoma of the cervix (NECC) is a rare pathological form of cervical cancer. The prognosis of NECC with distant organ metastases is unclear. In our study, the patterns and prognosis of distant organ metastasis of NECC were investigated.MethodsData were obtained from the surveillance epidemiology and end results (SEER) database from 2000 to 2018. Cox regression, Kaplan–Meier and log-rank analyses were conducted.ResultsNECC was prone to single and multi-site metastases. The median overall survival (OS) was greatly decreased in patients with distant metastasis (P < 0.0001). Other characteristics such as age ≥60 years, poorer grade, higher T stage, those without surgery, no radiotherapy, and no chemotherapy were predictors of poor prognosis.ConclusionsMetastasis is an independent prognostic factor for patients with NECC. Surgery, radiotherapy, and chemotherapy give an overall survival advantage for patients with distant organ metastases.

A variant of multiple endocrine neoplasia type 1 in a dog?

AbstractA 9‐year‐old male neutered Cockerpoo dog was presented with pyrexia and was diagnosed with sterile idiopathic panniculitis. During initial investigations, advanced imaging revealed a suspected left‐sided cervical paraganglioma and bilateral adrenal masses. The dog underwent immunosuppression and achieved remission of the sterile idiopathic panniculitis. Bilateral adrenalectomy and paraganglioma excision were then performed. Histopathology identified bilateral adrenocortical carcinoma and cervical neuroendocrine carcinoma. Three months later, the dog was diagnosed with primary hyperparathyroidism. Despite left total thyroidectomy and parathyroidectomy, mild hypercalcaemia persisted for several months. Eight months later the dog became persistently hypokalaemic refractory to potassium supplementation, with metabolic alkalosis and systemic hypertension. The dog was euthanised 5 months later due to clinical deterioration. On postmortem examination, right parathyroid hyperplasia and metastatic neuroendocrine carcinoma involving liver, jejunum, pancreas and tracheobronchial lymph node were identified. This is the first report describing the concurrent presence of these types of endocrine neoplasms in a dog.

Prevalence, Associated Factors, and Survival Outcomes of Small-Cell Neuroendocrine Carcinoma of the Gynecologic Tract: A Large Population-Based Analysis.

Small-cell carcinomas are highly malignant tumors with neuroendocrine function and which often occur in the lungs. Primary small-cell neuroendocrine carcinomas of the gynecologic tract are extremely rare. This study aimed to evaluate the prevalence of independent predictors related to the prognosis and overall survival of patients with small-cell neuroendocrine carcinomas of the gynecologic tract. Patients with gynecologic small-cell neuroendocrine carcinomas diagnosed between 1973 and 2015 were identified from the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox risk regression analyses were performed to determine the independent predictors of overall survival. Overall survival was calculated using the Kaplan–Meier method, and the log-rank test was used for comparison. We included 5,15,393 eligible carcinomas in the present study; the prevalence of gynecologic small-cell neuroendocrine carcinomas was 0.121% (N = 622). Multivariate analysis indicated that advanced age, stage III and IV cancer, and no chemotherapy treatment may be predictors of poor small-cell neuroendocrine cervical carcinoma prognosis. Stage III and IV cancer and lack of surgery, radiotherapy, or chemotherapy were identified as potential predictors of poor prognosis in patients with ovarian small-cell neuroendocrine carcinoma. Kaplan–Meier analysis suggested that the median survival was 19, 11, and 12 months for cervical, ovarian, and endometrial small-cell neuroendocrine carcinomas, respectively. The 1-, 3-, and 5-year overall survival rates were as follows: 58.8, 31.4, and 26.1%, respectively, for small-cell neuroendocrine cervical carcinoma; 46.3, 23.5, and 22.0%, respectively, for ovarian small-cell neuroendocrine carcinoma; and 49.4, 29.4, and 25.9%, respectively, for endometrial small-cell neuroendocrine carcinoma. Our findings indicate that comprehensive and individualized treatment of small-cell neuroendocrine carcinomas of the gynecologic tract may prolong patient survival, although further studies are required.

Neuroendocrine Neoplasms of the Gynecologic Tract.

Simple SummaryNeuroendocrine refers to the cells that synthesize and secrete messenger chemicals such as neuropeptides and amines. Neuroendocrine neoplasms (NENs) are aggressive tumors arising from neuroendocrine cells, with an annual incidence of 6.98/100,000 and a prevalence of 170,000 in the United States. Primary gynecologic NENs constitute ≤2% of female reproductive tumors. NENs of the gynecologic tract are associated with high recurrence rates and dismal prognosis, making their treatment challenging. This article focuses on the updated staging classifications, clinicopathological characteristics, imaging, and management of NENs of the gynecological tract.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.

Definitive pelvic radiation therapy improves survival in stage IVB neuroendocrine cervical carcinoma: A NeCTuR study

ObjectiveTo evaluate the survival impact of adding definitive pelvic radiation therapy (RT) to chemotherapy among patients with stage IVB neuroendocrine cervical carcinoma (NECC). MethodsWe retrospectively studied patients with FIGO 2018 stage IVB NECC diagnosed during 1998–2020 who received chemotherapy with or without definitive whole pelvic RT (concurrent or sequential). Demographic, oncologic, and treatment characteristics were summarized. Progression-free (PFS) and overall survival (OS) were plotted using the Kaplan-Meier method, and hazard ratios (HRs) were calculated using Cox regression. ResultsThe study included 71 patients. Median age was 43 years (range, 24–75). Fifty-nine patients (83%) had pure neuroendocrine histology, and 57 (80%) had pretreatment tumor size >4 cm. Fifty-six patients (79%) received chemotherapy alone with (n = 15) or without (n = 41) palliative pelvic RT, and 15 (21%) received chemotherapy and definitive pelvic RT (chemo+RT). Median follow-up time was 20.1 months (range, 11.3–170.3) for the chemo+RT group and 13.5 months (range, 0.9–73.6) for the chemotherapy-alone group. Median PFS was 10.3 months (95% CI, 7.5-∞) for the chemo+RT group vs 6.6 months (95% CI, 6.1–8.7) for the chemotherapy-alone group (p = 0.0097). At 24 months, the PFS rate was 24% for chemo+RT vs 7.8% for chemotherapy alone. Median OS was 20.3 months (95% CI, 18.5-∞) for the chemo+RT group vs 13.6 months (95% CI, 11.3–19.2) for the chemotherapy-alone group (p = 0.0013). At 24 months, the OS rate was 49.2% for chemo+RT vs 21.5% for chemotherapy alone. In a Cox regression model, definitive RT was associated with improved PFS (HR, 0.44; 95% CI, 0.23–0.83; p = 0.0119) and OS (HR, 0.31; 95% CI, 0.14–0.65; p = 0.0022). ConclusionsAddition of definitive pelvic RT to chemotherapy may improve survival in patients with stage IVB NECC.