Clinical characteristics and treatment management of combined large cell neuroendocrine carcinoma, a subtype of large cell neuroendocrine carcinoma.

Combined large cell neuroendocrine carcinoma (CLCNEC) is a rare neuroendocrine carcinoma, accounting for approximately 10% of large cell neuroendocrine carcinoma (LCNEC). Mainly composed of coexisting adenocarcinoma components, with strong invasiveness and poor prognosis. The treatment regimen for CLCNEC mainly refers to complete surgical resection as the first choice in the early stage, while patients with stage II or higher require adjuvant treatment. At present, research on CLCNEC is mostly small sample and retrospective, and there is no consensus on whether molecular typing and treatment should be carried out. There is considerable controversy over whether it should be managed as small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC). Therefore, in order to solve the problem of confusion in the selection of treatment regimens for CLCNEC, while also considering the therapeutic effects, this article summarizes and analyzes previous studies, fully seeks evidence, and boldly proposes new therapeutic insights: the etoposide-platinum (EP) regimen serves as the basis for adjuvant therapy; In addition, SCLC/NSCLC-CLCNEC can be distinguished based on presence of RB1 and TP53 co-mutation, and targeted therapy or NSCLC type chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) can be used in combination or sequentially for NSCLC-CLCNEC.

Large Cell Neuroendocrine Carcinoma With Acquired Hemophilia A Diagnosed by Endobronchial Biopsy: A Case Report.

Primary lung cancer with acquired hemophilia A is rare. We report a case of large cell neuroendocrine carcinoma (LCNEC) with acquired hemophilia A diagnosed by endobronchial biopsy. A 75-year-old male was admitted to our hospital due to severe anemia and multiple organ failure. Hematomas, prolonged activated partial thromboplastin time, decreased activity of factor VIII, and the presence of serum factor VIII inhibitors led to the diagnosis of acquired hemophilia A. Administration of recombinant activated factor VIII and steroid treatment resolved the coagulation abnormalities. Simultaneously, a CT scan showed a lung mass and an endobronchial biopsy confirmed the diagnosis of LCNEC. Although acquired hemophilia A can cause severe bleeding symptoms, a lung cancer diagnosis by bronchoscopy was possible under appropriate treatment of acquired hemophilia A.

A Rare Case of Large-Cell Neuroendocrine Carcinoma Metastasizing to the Brain: A Case Report.

Neuroendocrine tumors (NETs) encompass a diverse spectrum of neoplasms that can originate from various sites, including the gastrointestinal tract. Brain metastases from neuroendocrine tumors, while rare, present significant clinical challenges. In this case report, we present the unique instance of a 50-year-old female with a history of gastrointestinal neuroendocrine tumor who manifested left-sided weakness, tremors, and recurrent focal convulsions. Initial imaging scans revealed a lesion in the right parietal lobe, which was surgically excised and diagnosed as a metastatic large-cell neuroendocrine carcinoma. Post-surgery, the patient's condition stabilized, but she was subsequently advised to chemotherapy. This case underscores the infrequency of brain metastases in the context of gastrointestinal neuroendocrine tumors, underscoring the need for comprehensive screening in such scenarios. Given the aggressive nature of neuroendocrine carcinomas and their propensity to disseminate to the brain, early detection and intervention are crucial. Our rare case also underscores the importance of distinguishing high-grade neuroendocrine carcinomas, which necessitate intensive management, from less aggressive NETs and other metastatic neoplasms that have different treatment approaches.

First-line selpercatinib for a patient with RET fusion-positive pulmonary large cell neuroendocrine carcinoma.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an uncommon variant of non-small cell lung cancer (NSCLC), known for its aggressive behavior. This includes rapid progression, widespread metastases, and resistance to conventional chemotherapy, all of which contribute to a dismal prognosis. Consequently, managing pulmonary LCNEC remains a significant challenge. In this case report, we describe the successful use of selpercatinib, RET (rearranged during transfection) kinase inhibitor, as a first-line treatment in a patient with advanced pulmonary LCNEC harboring a RET fusion gene. Although RET fusion genes are exceedingly rare in pulmonary LCNEC, this case underscores the importance of early genetic testing in patients with pulmonary LCNEC to tailor targeted therapies effectively.

Large-cell neuroendocrine carcinoma of the bladder: A case report.

BACKGROUND: Bladder neuroendocrine tumors are few and exhibit a high degree of aggressiveness. The bladder is characterized by four distinct forms of neuroendocrine tumors. Among them, large-cell neuroendocrine carcinoma is the least prevalent, but has the highest level of aggressiveness. The 5-year survival rate for large-cell neuroendocrine carcinoma of the bladder is exceedingly poor. To date, only a few dozen cases have been reported. CASE SUMMARY: Here, we report the case of a 65-year-old man with large-cell neuroendocrine carcinoma of the bladder. The patient presented to the Department of Urology at our hospital due to the presence of painless hematuria without any identifiable etiology. During hospitalization, abdominal computed tomography revealed the presence of an irregular mass on the right anterior wall of the bladder. A cystoscopic non-radical resection of the bladder lesion was performed. The postoperative pathological examination revealed large-cell neuroendocrine bladder cancer. Previous reports on cases of large-cell neuroendocrine carcinoma cases were retrieved from PubMed, and the present paper discusses the currently recognized best diagnostic and treatment options for large-cell neuroendocrine carcinoma based on the latest research progress. CONCLUSION: Large-cell neuroendocrine carcinoma of the bladder is an uncommon malignancy with a highly unfavorable prognosis. Despite ongoing efforts to prolong patient survival through multidisciplinary therapy, the prognosis remains unfavorable. Large-cell neuroendocrine carcinoma continues to be a subject of uncertainty.

Molecular subtypes and prognostic factors of lung large cell neuroendocrine carcinoma.

Background: Lung large cell neuroendocrine carcinoma (LCNEC) is an aggressive disease with poor prognosis and short-term survival, which lacks effective prognostic indicators. The study aims to investigate the molecular subtypes and prognostic markers of lung LCNEC. Methods: Patients diagnosed with lung LCNEC at Sun Yat-sen University Cancer Center (SYSUCC) between November 2007 and January 2021 were screened. Baseline clinical data were collected and routine blood indexes including lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) were calculated. Immunohistochemistry (IHC) of ASCL1, NEUROD1, POU2F3, YAP1 were done to perform molecular subtyping, while CD56, Syn, CgA, CD3, CD8, CD20, CD68, and CD163 were also stained on tissue samples. Then prognostic factors of lung LCNEC were explored. Results: One hundred and fifty-one lung LCNEC patients were identified, 103 of whom had complete clinical information, available routine blood and biochemical indexes were eventually included in the present study. Tumor tissue specimens were available from 64 patients. Positive expression rates of ASCL1, NEUROD1, and YAP1 were 82.8%, 50.0%, and 28.1%, respectively. No POU2F3+ cases were detected. Forty (62.5%) patients co-expressed with two or three markers. High LMR (>3.3) was an independent predictor of favorable prognosis of disease-free survival (DFS) [hazard ratio (HR), 0.391; 95% confidence interval (CI): 0.161-0.948; P=0.04] and overall survival (OS) (HR, 0.201; 95% CI: 0.071-0.574; P=0.003). Notably, high LMR was correlated with higher intra-tumoral CD3+ (P=0.004), CD8+ (P=0.01), and CD68+ (P<0.001) immune cell infiltration compared to low LMR in lung LCNEC. Conclusions: Our study validated molecular subtypes by IHC in lung LCNEC, and co-expression was found among different subtypes, with no prognostic effect. High blood LMR level was associated with a favorable prognosis in lung LCNEC, which might partly reflect a hot tumor tissue immune microenvironment. Our findings may benefit clinical practice, and further studies are warranted.

Real-world efficacy of PD-1/PD-L1 inhibitors in patients with advanced pulmonary neuroendocrine carcinoma: a single-center analysis.

Background: Immunotherapy blocking programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) has revolutionized the treatment of extensive-stage small-cell lung cancer (SCLC), but only with limited real-world efficacy data; evidence from immunotherapy for other pulmonary neuroendocrine carcinoma (PNEC) is scarce. Objective: The purpose of this study is to evaluate the efficacy of receiving PD-1/PD-L1 inhibitors in patients with advanced PNEC and explore factors related to survival prognosis, providing clues for treatment for patients with advanced PNEC. Methods: In all, 203 patients with advanced PNEC who received PD-1/PD-L1 inhibitors between January 2019 and December 2021 were retrospectively analyzed. Kaplan-Meier curves were constructed for progression-free survival (PFS) and overall survival (OS). Results: For the 203 patients, the objective response rate (ORR) was 48.3%, the disease control rate (DCR) was 83.3%, the median PFS (mPFS) was 6.0 months, and the median OS (mOS) was 13.1 months. Among them, the histology was 166 SCLC, 13 large-cell neuroendocrine carcinoma, and 24 other unspecified PNEC. Histologically, no significant difference was observed in PFS (p = 0.240) or OS (p = 0.845). In first-line (1L) treatment (N = 125), patients received chemoimmunotherapy and had an ORR of 64.8%, DCR of 92.0%, mPFS of 6.6 months, and mOS of 14.9 months. In second-line (2L) or later-line setting, the ORR, DCR, mPFS, and mOS were 21.8%, 69.2%, 4.4, and 9.4 months; immunotherapy plus small-molecule antiangiogenic agents showed significantly greater PFS than immunotherapy monotherapy or chemoimmunotherapy (6.4 vs 1.4 vs 3.7 months, p = 0.041). Patients without liver metastasis had superior PFS (7.0 vs 5.1 months, p < 0.001) and OS (19.2 vs 9.6 months, p < 0.001) than those with liver metastasis. Conclusion: In clinical practice, PD-1/PD-L1 inhibitors are effective in patients with advanced PNEC, regardless of the pathological histology. The efficacy of 1L immunochemotherapy is worthy of recognition, and the addition of small-molecule antiangiogenic agents to immunotherapy in 2L or later-line treatment provides a better survival trend. Design: Retrospective study.

Therapeutic effects of an ALK inhibitor, brigatinib, on lung large cell neuroendocrine carcinoma with EML4-ALK fusion.

A 64-year-old light-smoking woman was clinically diagnosed with lung large-cell neuroendocrine carcinoma (LCNEC) with a metastatic brain tumor. An Oncomine Dx Targeted Test using metastatic brain tissue revealed that the patient's lung cancer cells had an EML4-ALK rearrangement. Patients with LCNEC and anaplastic lymphoma kinase (ALK) gene rearrangements are rare, and there is currently no standard treatment. Based on the genomic analysis, we treated the patient with brigatinib, an ALK inhibitor. We describe here a patient with LCNEC who responded significantly to brigatinib without serious adverse events.

Right Upper Lobe Large Cell Neuroendocrine Carcinoma with Atypical Carcinoid Features: Case Report.

Introduction: Large cell neuroendocrine carcinoma (LCNEC) and atypical carcinoid (AC) tumor are two distinct types of pulmonary neuroendocrine tumors (NETs) that are considered genetically unrelated. AC is categorized as a well-differentiated NET, while LCNEC is considered a poorly differentiated NET with a significantly poorer prognosis. Case Presentation: In this case report, we present an 83-year-old male who presented with 2-day history of hemoptysis and subsequently diagnosed with a right upper lobe carcinoid tumor on pre-excision biopsy. After evaluation of the entire excised specimen, the tumor was subsequently reclassified as LCNEC. This case is rare as the tumor displayed pathologic features of AC (areas with low mitotic activity and punctate necrosis) alternating with areas of LCNEC (high mitotic activity with sheets of necrosis). Subsequent molecular studies were more characteristic of AC, with no mutations detected in Rb1 or p53. The patient underwent surgical resection (right upper lobectomy with bronchoplasty and mediastinal lymph node dissection) to remove the tumor. Conclusion: This report outlines the clinical presentation and the underlying pathology of this rare case, which underscores the complex molecular landscape of neuroendocrine neoplasms and the need for nuanced molecular analyses in refining diagnostic approaches.

Unmasking Neuroendocrine Prostate Cancer with a Machine Learning-Driven 7-Gene Stemness Signature that Predicts Progression.

Prostate cancer (PCa) poses a significant global health challenge, particularly due to its progression into aggressive forms like neuroendocrine prostate cancer (NEPC). This study developed and validated a stemness-associated gene signature using advanced machine learning techniques, including Random Forest and Lasso regression, applied to large-scale transcriptomic datasets. The resulting 7-gene signature (KMT5C, MEN1, TYMS, IRF5, DNMT3B, CDC25B and DPP4) was validated across independent cohorts and patient-derived xenograft (PDX) models. The signature demonstrated strong prognostic value for progression-free, disease-free, relapse-free, metastasis-free, and overall survival. Importantly, the signature not only identified specific NEPC subtypes, such as large-cell neuroendocrine carcinoma, which is associated with very poor outcomes, but also predicted a poor prognosis for PCa cases that exhibit this molecular signature, even when they were not histopathologically classified as NEPC. This dual prognostic and classifier capability makes the 7-gene signature a robust tool for personalized medicine, providing a valuable resource for predicting disease progression and guiding treatment strategies in PCa management.

Tarlatamab for Large Cell Neuroendocrine Carcinoma in a Young Adult: A Case Report.

A 20-year-old man with metastatic large cell neuroendocrine carcinoma of the lung was treated with the delta-like ligand 3-targeting bispecific T cell engager, tarlatamab. Treatment was complicated by transient cytokine release syndrome but resulted in a partial response. Bispecific T cell engagers may offer a novel treatment approach for large cell neuroendocrine carcinoma of the lung.

Isolated Splenic Metastasis From Large-Cell Neuroendocrine Carcinoma of Lung: A Case Report.

Splenic malignancies are mostly primary and lymphocytic. Metastases to the spleen are rare and imply tumor dissemination. Limited cases were reporting isolated splenic metastasis from non-small cell cancer of the lung (NSCLC). We report the case of a 68-year-old male with mixed large-cell neuroendocrine carcinoma (LCNEC) and adenocarcinoma of the lung who presented with asymptomatic, synchronous, and isolated splenic metastasis. The patient refused adjuvant or neoadjuvant therapies. Surgical removal of both primary and metastatic lesions was achieved separately. In the scenario of isolated splenic metastasis, local consolidative therapy such as splenectomy appears to benefit survival by alleviating tumor burden. The patient is currently disease-free after one year of postoperative follow-up.

Unusual Association of Large Cell Neuroendocrine Carcinoma of the Bladder and Prostatic Adenocarcinoma Within a 76-Year-Old Man.

Large cell neuroendocrine carcinoma (LCNEC) is one of the rarest types of bladder cancer, with an aggressive course and a poor prognosis. We report a case of LCNEC of the bladder associated with a prostatic adenocarcinoma. A very rare association, to our knowledge, is described for the first time in the literature. The patient was a 76-year-old non-smoker male, who presented with intermittent hematuria and dysuria. Cystoscopy revealed a lesion on the right lateral bladder wall. Biopsy was in favor of a LCNEC with muscle invasion. The CT scan showed the presence of a second lesion in the prostate, confirmed by histological examination. The patient was treated by neoadjuvant chemotherapy of the cisplatin-etoposide type for large-cell bladder neuroendocrine carcinoma, and hormone therapy with luteinizing hormone-releasing hormone (LH-RH) analogs for prostatic adenocarcinoma, followed by radical surgery. Given the rarity of this tumor, LCNEC treatment lacks precision. Many cases are published with different therapeutic strategies. A literature review would be interesting to codify the therapeutic strategy for this rare tumor.

A Case of Rapidly Progressive De Novo Metastatic Small-Cell Neuroendocrine Prostate Cancer.

Introduction: Neuroendocrine/small-cell prostate cancer (NEPC) is a rare and aggressive subtype of prostate cancer, which typically develops after prolonged treatment for metastatic castration-resistant disease, but can, less commonly, occur de novo. Case Presentation: We describe a case of de novo NEPC in a tumor with mixed pathology including acinar adenocarcinoma and neuroendocrine/small-cell carcinoma with rapid progression of metastatic disease. Despite initiation of treatment with androgen deprivation therapy (ADT) and chemotherapy, the patient continued to exhibit progression leading to multiple complications including a large bowel obstruction and ultimately progressive hepatic metastases resulting in liver failure. Conclusion: This case illustrates the clinical presentation and highly aggressive nature of de novo NEPC. Recognizing atypical clinical progression in prostate cancer is critical for the detection of NEPC; however, despite early identification and initiation of treatment, the prognosis remains poor, thus highlighting the need for further study into NEPC biology and novel therapeutic approaches.

Perioperative serplulimab­based chemoimmunotherapy in stage IV large cell neuroendocrine carcinoma of the lung: A case report.

Large cell neuroendocrine carcinoma (LCNEC) is a rare and enigmatic tumor, characterized by neuroendocrine features and a poor prognosis similar to small cell lung cancer (SCLC). The present report details the case of a 45-year-old male with oligometastatic stage IV LCNEC who achieved clinical cure after undergoing perioperative immunochemotherapy. Despite the typical non-recommendation of surgery for stage IV cases, based on the insistence of the patient, the present study initiated three cycles of neoadjuvant therapy combining serplulimab (a programmed cell death protein 1 inhibitor) with chemotherapy, resulting in the radiological disappearance of the tumor. Pathological complete response was confirmed following resection of the primary tumor. The treatment continued with three cycles of adjuvant therapy using serplulimab and chemotherapy, followed by maintenance therapy with serplulimab alone. After 17 cycles of maintenance therapy, a positron emission tomography-computed tomography scan revealed a complete metabolic response of the metastasis, and radiological scans revealed no visible tumor or distant metastasis, indicating a clinical cure. Event-free survival has exceeded 11 months, and overall survival has exceeded 14 months. The present case highlights the efficacy of immunochemotherapy in treating advanced LCNEC.

[Advances of Treatment of Pulmonary Large Cell Neuroendocrine Carcinoma].

Large cell neuroendocrine carcinoma (LCNEC) of lung is a rare neuroendocrine carcinoma subtype with difficulty in early diagnosis and poor prognosis which is treated with standard strategies of small cell lung cancer and non-small cell lung cancer. In recent years, the precise types of LCNEC and its response to therapy have been identified by next-generation sequencing. Some researches have also found the correlation between different subtypes of LCNEC and the efficacy of chemotherapy regimens. However, there is no consensual agreement of its therapy. Recently, immune checkpoint inhibitors (ICIs) has provided a new option for LCNEC patients based on some retrospective research data and case reports. In this review, we aimed to summarize the epidemiological characteristics, standard therapy, the advances of molecular subtypes and clinical applications of ICIs of LCNEC, so as to provide optimal systemic clinical decision-making for LCNEC patients.
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Small Cell Bladder Cancer: Treatment Patterns for Local Disease and Associated Outcomes. A Retrospective Cohort Study.

BACKGROUND: Small cell bladder cancer (SCBC) is a rare histologic subtype with relative paucity of data regarding treatment response and outcomes. We reviewed 2 databases to compare outcomes in patients with localized SCBC treated with cystectomy versus concurrent chemoradiotherapy (CCRT). We hypothesized that survival would be similar with these therapy approaches. METHODS: We retrospectively reviewed our institutional and SEER-Medicare databases to identify patients with SCBC. Overall survival (OS) was determined from the date of diagnosis to last follow-up/death. For those with nonmetastatic disease, a multivariate Cox analysis was used to compare locoregional therapy with neoadjuvant chemotherapy (NAC) + cystectomy versus CCRT. RESULTS: We identified 53 patients in our institutional database and 1166 patients in SEER-Medicare with localized SCBC. Median OS (mOS) with NAC + cystectomy was 46 months (95% CI, 21-72) and 45 months (95% CI, 0-104) in the institutional and SEER-Medicare databases, respectively, whereas mOS with CCRT was 26 months (95% CI, 5-47) and 23 months (95% CI, 18-28) in the 2 series, respectively. In multivariate analysis, NAC followed by cystectomy was associated with an approximately 30% reduction in mortality compared to CCRT in both institutional and national databases but did not reach statistical significance (Institution HR 0.71, 95% CI, 0.22-2.4, P = .58; SEER HR 0.73, 95% CI, 0.49-1.08; P = .11). CONCLUSIONS: SCBC is very aggressive with limited survival observed in our institutional and SEER-Medicare datasets regardless of locoregional therapy used. There is an unmet need to define the optimal locoregional therapy for nonmetastatic stage and identify novel therapeutic targets.

Bronchoscopic Interventional Therapy Combined With Pembrolizumab in the Treatment of Pulmonary Large Cell Neuroendocrine Carcinoma: A Case Report.

This study reports a significant clinical outcome following the use of bronchoscopic interventional therapy combined with pembrolizumab for treating pulmonary large cell neuroendocrine carcinoma (LCNEC), showcasing a novel approach in managing this aggressive cancer.

Metabolomic Profiling of Pulmonary Neuroendocrine Neoplasms.

BACKGROUND/OBJECTIVES: Pulmonary neuroendocrine neoplasms (NENs) account for 20% of malignant lung tumors. Their management is challenging due to their diverse clinical features and aggressive nature. Currently, metabolomics offers a range of potential cancer biomarkers for diagnosis, monitoring tumor progression, and assessing therapeutic response. However, a specific metabolomic profile for early diagnosis of lung NENs has yet to be identified. This study aims to identify specific metabolomic profiles that can serve as biomarkers for early diagnosis of lung NENs. METHODS: We measured 153 metabolites using liquid chromatography combined with mass spectrometry (LC-MS) in the plasma of 120 NEN patients and compared them with those of 71 healthy individuals. Additionally, we compared these profiles with those of 466 patients with non-small-cell lung cancers (NSCLCs) to ensure clinical relevance. RESULTS: We identified 21 metabolites with consistently altered plasma concentrations in NENs. Compared to healthy controls, 18 metabolites were specific to carcinoid tumors, 5 to small-cell lung carcinomas (SCLCs), and 10 to large-cell neuroendocrine carcinomas (LCNECs). These findings revealed alterations in various metabolic pathways, such as fatty acid biosynthesis and beta-oxidation, the Warburg effect, and the citric acid cycle. CONCLUSIONS: Our study identified biomarker metabolites in the plasma of patients with each subtype of lung NENs and demonstrated significant alterations in several metabolic pathways. These metabolomic profiles could potentially serve as biomarkers for early diagnosis and better management of lung NENs.

Implementing machine learning to predict survival outcomes in patients with resected pulmonary large cell neuroendocrine carcinoma.

BACKGROUND: The post-surgical prognosis for Pulmonary Large Cell Neuroendocrine Carcinoma (PLCNEC) patients remains largely unexplored. Developing a precise prognostic model is vital to assist clinicians in patient counseling and creating effective treatment strategies. RESEARCH DESIGN AND METHODS: This retrospective study utilized the Surveillance, Epidemiology, and End Results database from 2000 to 2018 to identify key prognostic features for Overall Survival (OS) in PLCNEC using Boruta analysis. Predictive models employing XGBoost, Random Forest, Decision Trees, Elastic Net, and Support Vector Machine were constructed and evaluated based on Area Under the Receiver Operating Characteristic Curve (AUC), calibration plots, Brier scores, and Decision Curve Analysis (DCA). RESULTS: Analysis of 604 patients revealed eight significant predictors of OS. The Random Forest model outperformed others, with AUC values of 0.765 and 0.756 for 3 and 5-year survival predictions in the training set, and 0.739 and 0.706 in the validation set, respectively. Its superior validation cohort performance was confirmed by its AUC, calibration, and DCA metrics. CONCLUSIONS: This study introduces a novel machine learning-based prognostic model with a supportive web-based platform, offering valuable tools for healthcare professionals. These advancements facilitate more personalized clinical decision-making for PLCNEC patients following primary tumor resection.