Single-Cell Transcriptome Analysis of Small Cell Neuroendocrine Carcinoma of the Endometrium Reveals ISL1 as a Potential Biomarker for Diagnosis and Treatment.

BACKGROUND: As a dedifferentiated tumor, small cell endometrial neuroendocrine tumors (NETs) are rare and frequently diagnosed at an advanced stage with a poor prognosis. Current treatment recommendations are often extrapolated from histologically similar tumors in other sites or based on retrospective studies. The exploration for diagnostic and therapeutic markers in small cell NETs is of great significance. METHODS: In this study, we conducted single-cell RNA sequencing on a specimen obtained from a patient diagnosed with small cell endometrial neuroendocrine carcinoma (SCNEC) based on pathology. We revealed the cell map and intratumoral heterogeneity of the cancer cells through data analysis. Further, we validated the function of ISL LIM Homeobox 1 (ISL1) in vitro in an established neuroendocrine cell line. Finally, we examined the association between ISL1 and tumor staging in small cell lung cancer (SCLC) patient samples. RESULTS: We observed the significant upregulation of ISL1 expression in tumor cells that showed high expression of the neuroepithelial markers. Additionally, in vitro cell function experiments demonstrated that the high ISL1 expression group exhibited markedly higher cell proliferation and migration abilities compared to the low expression group. Finally, we showed that the expression level of ISL1 was correlated with SCLC stages. CONCLUSIONS: ISL1 protein in NETs shows promise as a potential biomarker for diagnosis and treatment.

Metastatic neuroendocrine carcinoma: Liver metastases presenting with diffuse nodular calcifications on CT.

We report a case of the 46-year-old female patient, who presented with diffuse nodular liver calcifications on computed tomography. Histopathology of the calcified nodules revealed neuroendocrine tumors (NETs). Calcified NET liver metastases are extremely rare and need to be considered in the differential diagnosis with other benign and malignant liver calcification.

Updates on Urinary Bladder Tumors With Neuroendocrine Features.

The most common neuroendocrine tumor in the urinary bladder is small cell carcinoma, which can be pure or mixed with components of urothelial or other histologic subtypes. Large cell neuroendocrine carcinoma of the bladder is rare and remains ill-defined but is increasingly recognized. Well-differentiated neuroendocrine tumor and paraganglioma can arise in the bladder but are very rare in this location. Recent advances in molecular characterization allowed for better classification and may offer improved stratification of these tumors.

Large Cell Neuroendocrine Carcinoma of Gallbladder: A Case Report.

Large cell neuroendocrine carcinoma of the gallbladder is an extremely rare tumour with aggressive behaviour and a bad prognosis. Here, we report a case of a 65-year-old lady suspected of carcinoma of the gallbladder and underwent extended cholecystectomy. The histopathology report revealed neuroendocrine carcinoma of a large cell type of gall bladder infiltrating the liver and three periportal and pericholedochal lymph nodes. She had an uneventful perioperative period and was doing good till 6 months of follow-up. The only potentially curative treatment for large cell neuroendocrine carcinoma of the gallbladder is aggressive surgical resection, owing to its aggressive behaviour and bad prognosis. Keywords: carcinoma; case reports; cholecystectomy; gallbladder.

[Practical application of immunohistochemistry in pancreatic neuroendocrine neoplasms : Tips and pitfalls]. / Praktische Anwendung von Immunhistochemie in pankreatischen neuroendokrinen Neoplasien : Tipps und Pitfalls.

Pancreatic neuroendocrine neoplasms (PanNEN) are rather rare entities. Morphology, combined with immunohistochemistry, allows typing and grading, thereby leading therapeutic decisions. Depending on tumor stage and differential diagnosis, a broad diagnostic panel may be required. The present work summarizes the minimal diagnostic, prognostic, and predictive markers in PanNEN.Markers of choice for defining a neuroendocrine phenotype are synaptophysin, chromogranin A, and INSM1. The proliferation fraction Ki67 is indispensable for grading, while p53 and Rb1 can help in the differentiation from neuroendocrine carcinoma (NEC). Transcription factors, such as cdx2, TTF­1, and Islet­1, can indicate the site of a primary tumor in the setting of a cancer of unknown primary (CUP). DAXX/ATRX immunohistochemistry has mainly prognostic value. Molecular pathology studies currently have little practical value in the diagnosis of PanNEN.An important pitfall in routine diagnostics is the wide spectrum of differential diagnoses mimicking neuroendocrine neoplasms. An expanded immunohistochemical panel is strongly recommended in case of doubt.

[Advances of pathological diagnosis and molecular pathology of lung neuroendocrine neoplasms].

The pathological classification and diagnostic criteria for lung neuroendocrine neoplasms (NENs) in the 2021 World Health Organization (WHO) lung tumor classification are similar to the prior classifications. However, the advances on the molecular studies of lung NENs have shown that both small cell lung carcinoma and large cell neuroendocrine carcinoma are highly heterogeneous tumors with neuroendocrine characteristics and can be subclassified based on the features of genomics or transcriptomics, which are valuable in the diagnosis of lung NENs subtypes and patient treatment. In addition, it is necessary to interpret emerging concepts such as "lung neuroendocrine tumor G3" and "histological transformation" from pathological perspectives, as well as to know the novel neuroendocrine biomarkers such as INSM1 and POU2F3. This article summarized the diagnostic changes and the advances of molecular pathology of lung NENs based on the latest WHO classification and molecular research.

Diagnosis and management of neuroendocrine prostate cancer.

BACKGROUND: Although most patients with prostate cancer (PC) respond to initial androgen deprivation therapy (ADT), castration-resistant disease invariably develops. Progression to treatment-emergent neuroendocrine PC (t-NEPC) represents a unique mechanism of resistance to androgen receptor (AR)-targeted therapy in which lineage plasticity and neuroendocrine differentiation induce a phenotypic switch from an AR-driven adenocarcinoma to an AR-independent NEPC. t-NEPC is characterized by an aggressive clinical course, increased resistance to AR-targeted therapies, and a poor overall prognosis. METHODS: This review provides an overview of our current knowledge of NEPC, with a focus on the unmet needs, diagnosis, and clinical management of t-NEPC. RESULTS: Evidence extrapolated from the literature on small cell lung cancer or data from metastatic castration-resistant PC (mCRPC) cohorts enriched for t-NEPC suggests an increased sensitivity to platinum-based chemotherapy. However, optimal strategies for managing t-NEPC have not been established, and prospective clinical trial data are limited. Intertumoral heterogeneity within a given patient, as well as the lack of robust molecular or clinical biomarkers for early detection, often lead to delays in diagnosis and prolonged treatment with suboptimal strategies (i.e., conventional chemohormonal therapies for mCRPC), which may further contribute to poor outcomes. CONCLUSIONS: Recent advances in genomic and molecular classification of NEPC and the development of novel biomarkers may facilitate an early diagnosis, help to identify promising therapeutic targets, and improve the selection of patients most likely to benefit from NEPC-targeted therapies.

Diagnostic Challenges and Long-term Outcomes of Neuroendocrine Carcinoma of the Cervix: A Case Series.

Neuroendocrine carcinomas (NECs) of the cervix are rare, aggressive malignancies that are challenging to diagnose and treat. They are high-grade lesions that often share features with poorly differentiated adenocarcinoma and squamous cell carcinoma. NECs are classified into large-cell or small-cell subtypes but can often have a mixed appearance or occur concurrently with a squamous or adenocarcinoma. Diagnosis is dependent on tissue sampling, histomorphology, and immunohistochemistry. Eight cases of NEC were retrieved from the Department of Pathology at our institution from 2008 to 2022. Tumor slides were reviewed and evaluated by 2 independent pathologists. Seven of 8 patients tested positive for neuroendocrine markers, including CD56, synaptophysin, and chromogranin. We discuss the diagnostic challenges, review the histopathology, and describe the treatment courses and clinical outcomes. This case series reveals that traditional markers, such as p16, p63, and p40, may be focally positive in NEC and should not be considered a confirmation of squamous cell carcinoma. Patient outcomes can be affected by delays in diagnosis, misdiagnosis, and inadequate treatment when NEC is not considered in the initial differential diagnosis.

[Exocrine meets neuroendocrine: mimickers of pancreatic neuroendocrine neoplasms]. / Exokrin trifft neuroendokrin: Mimickers neuroendokriner Neoplasien des Pankreas.

Neuroendocrine neoplasms (NENs) originate from various epithelial or neuroectodermal tissues, can occur in any organ, including the pancreas, and are characterized by the expression of the neuroendocrine markers synaptophysin and chromogranin A. Pancreatic neuroendocrine tumors (PanNETs) are well-differentiated epithelial neoplasms with morphological and immunohistochemical features of neuroendocrine differentiation of low, intermediate, or high grade. Pancreatic neuroendocrine carcinomas (PanNECs) are clinically aggressive, high-grade (poorly differentiated) carcinomas with morphologic features suggesting neuroendocrine differentiation, a high proliferative rate (> 20 mitoses per 2 mm2 and Ki67 index > 20%), and immunohistochemical labeling for neuroendocrine markers. They include the small cell neuroendocrine carcinoma and the large cell neuroendocrine carcinoma categories.Neuroendocrine-like morphology coupled with immunohistochemical markers of neuroendocrine differentiation are highly specific. However, neuroendocrine markers may also be expressed in non-neuroendocrine neoplasms, which can therefore be confused with NENs. Mimickers of pancreatic NENs comprise a number of important pitfall tumors, including epithelial and non-epithelial neoplasms, such as acinar cell carcinomas, solid pseudopapillary neoplasms (SPNs), or even non-neoplastic lesions. All of these lesions have the expression of neuroendocrine markers in common, such as synaptophysin and chromogranin A, and although they are comparatively rare, they can cause considerable diagnostic problems. This review article deals with some of the most important mimickers of pancreatic neuroendocrine neoplasms and even non-neoplastic lesions, such as islet aggregation. The similarities and differences between these entities and pancreatic neuroendocrine neoplasms are highlighted, and key findings that facilitate the correct diagnosis are discussed.

Real-World comprehensive genomic profiling data for diagnostic clarity in pulmonary Large-Cell neuroendocrine carcinoma.

BACKGROUND: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon subtype of lung cancer believed to represent a spectrum of tumors sharing characteristics of both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Other groups have proposed genomic LCNEC subtypes, including small cell-like, non-small cell-like, and carcinoid-like subtypes. The primary goal of this study was to better define the NSCLC-like subtype with comprehensive genomic profiling (CGP). METHODS: An institutional database was queried to identify tissue specimens (TBx, N = 1,426) and liquid biopsies (LBx, N = 39) submitted for CGP during routine clinical care (8/2014 - 7/2023) with a disease ontology of LCNEC. TBx were profiled with FoundationOne® (F1) or F1CDx, using hybrid-capture technology to detect genomic alterations (GAs). RESULTS: 1,426 LCNEC samples were genomically profiled. The presence of RB1 and TP53 genomic alterations (GAs) were used to define a SCLC-like subtype (n = 557). A carcinoid-like group was defined by the presence of MEN1 mutation in the absence of TP53 GAs (n = 25). The remaining 844 samples were compared to the SCLC-like group and GAs enriched relative to the SCLC-like samples with a false discovery rate (FDR) < 0.0001 were used to define a NSCLC-like group. These NSCLC-like subtype-defining GAs included SMARCA4, KRAS, FGF3/4/19, STK11, CDKN2A/B, MTAP, and CCND1. Under this schema, 530 samples were classified as NSCLC-like and 314 remained unclassified. CONCLUSIONS: Large-scale CGP can better characterize biologically distinct molecular subtypes in LCNEC. Further studies to define how these molecular subtypes may help inform treatment decisions in this complex and challenging malignancy are warranted.

A rare report of a metastatic lung large-cell neuroendocrine carcinoma in palatine tonsil.

INTRODUCTION: Neuroendocrine carcinoma is a rare form of cancer originating from neuroendocrine cells, with the lungs being the most common site of occurrence. These tumors have the potential to metastasize to the head and neck region. CASE REPORT: A 57-year-old man, with a smoking history of 74 pack-years, presented with complaints of hoarseness, dry cough, dysphagia, and significant weight loss over a two-month period. During oral examination, a submucosal nodule in the left palatine tonsil was discovered. Histological analysis confirmed a poorly differentiated tumor consisting of large cells with nuclear pleomorphism and abundant cytoplasm. The tumor tested positive for CD56, chromogranin, synaptophysin, and EMA. Further imaging revealed a substantial endobronchial lesion in the upper segment of the left lower lobe. Biopsy results from this lesion were morphologically and immunohistochemically consistent with those from the oral lesion. A diagnosis of metastatic large-cell neuroendocrine carcinoma originating from the lung and involving the oral mucosa was established. CONCLUSION: This case highlights the metastatic potential of pulmonary neuroendocrine carcinoma and its occurrence in atypical dissemination sites. Additionally, our findings underscore the importance of early detection of oral metastases to ensure accurate diagnosis and expedite appropriate treatment.

Early postoperative prediction of the risk of distant metastases in medullary thyroid cancer.

Purpose: The purpose of this study was to develop and validate a nomogram for estimating the risk of distant metastases (DM) in the early postoperative phase of medullary thyroid cancer (MTC). Patients and methods: We retrospectively reviewed cases of patients diagnosed with MTC from the Surveillance, Epidemiology, and End Results (SEER) database from 2007 to 2017. In addition, we gathered data on patients who diagnosed as MTC at Department of Thyroid Surgery in the First Hospital of Jilin University between 2009 and 2021. Four machine learning algorithms were used for modeling, including random forest classifier (RFC), gradient boosting decision tree (GBDT), logistic regression (LR), and support vector machine (SVM). The optimal model was selected based on accuracy, recall, specificity, receiver operating characteristic curve (ROC), and area under curve (AUC). After that, the Hosmer-Lemeshow goodness-of-fit test, the brier score (BS) and calibration curve were used for validation of the best model, which allowed us to measure the discrepancy between the projected value and the actual value. Results: Through feature selection, we finally clarified that the following four features are associated with distant metastases of MTC, which are age, surgery, primary tumor (T) and nodes (N). The AUC values of the four models in the internal test set were as follows: random forest: 0.8786 (95% CI, 0.8070-0.9503), GBDT: 0.8402 (95% CI, 0.7606-0.9199), logistic regression: 0.8670(95%CI,0.7927-0.9413), and SVM: 0.8673 (95% CI, 0.7931-0.9415). As can be shown, there was no statistically significant difference in their AUC values. The highest AUC value of the four models were chosen as the best model since. The model was evaluated on the internal test set, and the accuracy was 0.84, recall was 0.76, and specificity was 0.87. The ROC curve was drawn, and the AUC was 0.8786 (95% CI, 0.8070-0.9503), which was higher than the other three models. The model was visualized using the nomogram and its net benefit was shown in both the Decision Curve Analysis (DCA) and Clinical Impact Curve (CIC). Conclusion: Proposed model had good discrimination ability and could preliminarily screen high-risk patients for DM in the early postoperative period.

Neuroendocrine carcinoma of ovary: Hitherto rare entity in primary ovarian tumors.

Neuroendocrine neoplasms (NEN) of the female genital tract are extremely uncommon. These tumors can be broadly divided into well differentiated (carcinoid) and poorly differentiated NEN (small cell and large cell carcinomas). Occurrence of neuroendocrine carcinomas (NECs) in ovary has rarely been reported. These high-grade malignant tumors have a fulminant clinical course with a short period of survival, even when diagnosed at an early stage. We hereby report two cases of primary neuroendocrine carcinoma of the ovary.

Case series of ovarian neuroendocrine carcinoma: overview of clinicopathological features.

BACKGROUND: Ovarian neuroendocrine carcinoma (O-NEC) is a relatively uncommon neoplasm, and the current knowledge regarding its diagnosis and management is limited. In this series, our objective was to provide an overview of the clinicopathological characteristics of the disease by analyzing clinical case data to establish a theoretical foundation for the diagnosis and management of O-NEC. CASE PRESENTATION: We included three patients in the present case series, all of whom were diagnosed with primary O-NEC based on pathomorphological observation and immunohistochemistry. Patient 1 was a 62-year-old patient diagnosed with small cell carcinoma (SCC) of the pulmonary type. Post-surgery, the patient was diagnosed with stage II SCC of the ovary and underwent standardized chemotherapy; however, imaging examinations conducted at the 16-month follow-up revealed the existence of lymph node metastasis. Unfortunately, she passed away 21 months after the surgery. The other two patients were diagnosed with carcinoid tumors, one at age 39 and the other at age 71. Post-surgery, patient 2 was diagnosed with a carcinoid in the left ovary, whereas patient 3 was diagnosed with a carcinoid in her right ovary based on clinical evaluation. Neither of the cases received adjuvant therapy following surgery; however, they have both survived for 9 and 10 years, respectively, as of date. CONCLUSION: Primary O-NECs are rare and of diverse histological types, each of which has its own unique biological features and prognosis. SCC is a neoplasm characterized by high malignancy and a poor prognosis, whereas carcinoid tumors are of lesser malignancy and have a more favorable prognosis.

The Evolving Treatment Landscape of Medullary Thyroid Cancer.

OPINION STATEMENT: Genetic assessment is crucial to address the correct treatment for advanced medullary thyroid cancer (MTC). Multi tyrosine kinase inhibitors (mTKIs) cabozantinib and vandetanib are good first line options, even vandetanib prescription is currently limited to RET mutated patients. Selective RET inhibitors such as pralsetinib could be a preferred upfront treatment in case of RET mutated MTC presenting common or gatekeeper RET mutations (e.g. M918T; V804L/M). Selpercatinib, otherwise, can be prescribed as the second line after disease progression to mTKIs. The best option for subsequent lines is to consider inclusion in clinical trials or alternatively other mTKIs such as sunitinib, sorafenib, lenvatinib, or pazopanib could be evaluated. New perspectives include next-generation RET inhibitors able to overcome resistance mechanisms responsible for disease progression to standard mTKIs and RET inhibitors, and immunotherapy for MTC presenting with high tumor mutational burden.