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Background: Both small-cell carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) of the lung are often clinically dealt with as being in the same category as neuroendocrine carcinoma, and their clinical differences have not been adequately assessed. Methods: The postoperative prognosis was retrospectively analyzed using the data of 196 patients who underwent resection for SCLC or LCNEC. Results: Of the patients included, 99 (50.5%) had SCLC and 97 (49.5%) had LCNEC. The median duration of follow-up was 39 months (interquartile range [IQR] 21–76) and 56 months (IQR 21–87) for SCLC and LCNEC, respectively. The estimated 5-year overall survival (OS) probabilities were 53.7% and 62.7% (p = 0.133) for patients with SCLC and LCNEC, respectively. In the SCLC group, a multivariate analysis showed that adjuvant chemotherapy (hazard ratio 0.54, 95% confidence interval 0.30–0.99, p = 0.04) was the only factor that was significantly associated with OS. In the LCNEC group, univariate analyses demonstrated that pathologic stage I (p = 0.01) was the only factor that was associated with better OS after surgery. Conclusions: We found different clinical features in SCLC and LCNEC; in patients with SCLC, because OS could be expected to significantly improve with postoperative adjuvant chemotherapy, patients with resected SCLC of any pathologic stage should receive adjuvant chemotherapy. For patients with LCNEC, because pathologic stage I LCNEC is related to better prognosis than any other stages, a thorough clinical staging, including invasive staging, according to present guidelines should be performed to identify clinical stage I LCNEC with the highest certainty. [ABSTRACT FROM AUTHOR]

Background: This retrospective study aims to examine the patient demographics, survival rates, and treatment methods for small-cell neuroendocrine carcinoma (SCNEC) and large-cell neuroendocrine carcinoma (LCNEC) of prostate origin while also identifying the main differences between common types of prostate cancer with comparative analysis for survival. Methods: Our analysis utilized the Surveillance, Epidemiology, and End Results database (SEER), and data was collected from 2000–2020. Cox proportional hazards and chi-squared analysis were used for statistical analysis. Results: A total of 718 cases of prostate small and large neuroendocrine carcinoma were identified. The median age was 71.5 years, and the median follow-up was 11.0 years (95% confidence interval (95% CI) = 9.2–12.8). Most patients were over the age of 80 years (33.8%) and Caucasian (74.4%). The overall 5-year survival was 8.0% (95% CI = 6.8–9.2). The 5-year OS for Caucasians was 7.3% (95% C.I. 6.0–8.3). For Black Americans, the 5-year OS was 11.9% (95% C.I. 7.3–16.5). For Hispanics, the 5-year OS was 12.2% (95% C.I. 7.7–16.7). The 5-year cause-specific survival (CSS) was 16.2% (95% CI = 14.3–18.1). For treatment modality, the five-year survival for each were as follows: chemotherapy, 3.5% (95% CI = 2.1–4.9); surgery, 18.2% (95% CI = 13.6–22.8); multimodality therapy (surgery and chemotherapy), 4.8% (95% CI = 1.7–7.9); and combination (chemoradiation with surgery), 5.0% (95% CI = 1.0–9.0). The prognostic nomogram created to predict patient survivability matched the findings from the statistical analysis with a statistical difference found in race, income, housing, stage, and nodal status. The nomogram also indicated a slight increase in mortality with tumors of greater size. This analysis showed a slight increase in mortality for patients of Asian race. In addition, there was a significant increase in death for patients with stage 3 tumors, as well as patients who underwent surgery and radiation. Furthermore, we performed propensity score matching for survival differences, and no survival difference was found between SCNEC and LCNEC. Conclusions: Asian patients, larger tumor size, and distant disease were associated with worse long-term clinical outcomes. By leveraging insights from registry-based studies, clinicians can better strategize treatment options, improving patient outcomes in this challenging oncology arena. [ABSTRACT FROM AUTHOR]

Aims: Cytoplasmic p53 expression indicates a high frequency of TP53 abnormalities in gynaecological carcinoma. However, the implication of this expression in pulmonary neuroendocrine carcinoma (NEC) remains unclear. Thus, our study aimed to fill this research gap. Methods and results: Immunohistochemistry (IHC) of p53 was performed on 146 cases of resected small‐cell lung carcinoma and large‐cell NEC, and next‐generation sequencing was conducted on cases showing cytoplasmic and wild‐type p53 expression. IHC revealed overexpression in 57% of the cases (n = 83), complete absence in 31% (n = 45), cytoplasmic expression in 8% (n = 12) and wild‐type expression in 4% (n = 6) of the cases. TP53 mutations were identified in nine of the 13 cases with available genetic analysis. The TP53 mutation rates in cases with cytoplasmic and wild‐type p53 expression were 88% (seven of eight) and 40% (two of five), respectively. All seven cases showing cytoplasmic expression with TP53 mutations harboured loss‐of‐function type mutations: four had mutations in the DNA‐binding domain, two in the nuclear localisation domain and one in the tetramerisation domain. Clinically, cases with cytoplasmic p53 expression had a poor prognosis similar to that in cases with p53 overexpression or complete absence. Conclusions: Cytoplasmic p53 expression in patients with pulmonary NEC suggests a high TP53 mutation rate, which is associated with a poor prognosis similar to that in patients with p53 overexpression or complete absence. This cytoplasmic expression should not be misidentified as a wild‐type expression. This is the first report, to our knowledge, that demonstrates the implication of cytoplasmic p53 expression in pulmonary NEC. [ABSTRACT FROM AUTHOR]

Abstract Background With the widespread use of low-dose computed tomography for lung cancer screening, the detection rate of pulmonary lesions manifesting as ground-glass opacities (GGOs) has been increasing dramatically. The volume doubling time (VDT) has been introduced in clinical practice to monitor the potential growth rate of GGOs during long-term follow-up periods. Case presentation A 72-year-old never-smoker female diagnosed with mixed GGO manifested abruptly accelerated growth with sudden decreased VDT from 400 to 36 days. A thoracoscopic left lower lobectomy with mediastinal lymph node dissection was performed, and the diagnosis was stage IB large-cell neuroendocrine carcinoma (LCNEC). Next-generation sequencing of the tumor highlights an EML4-ALK gene fusion. Conclusions The LCNEC may present as GGO with longer VDT in the early stage. VDT should calculate by the whole size either on the entire tumor diameter or on consolidation diameter. It is recommended that meticulous long-term follow-up with dynamic VDT monitoring may help select high-risk GGOs performing timely semi-elective surgical resection in clinical practice.

Abstract Purpose This study aimed to investigate the prognostic significance of surgery in large-cell neuroendocrine carcinoma (LCNC) patients. Methods A total of 453 patients from the Surveillance, Epidemiology, and End Results database diagnosed with stage T1-4N0-2M0 LCNC from 2010 to 2015 were analyzed. The propensity-score matching analysis with a ratio of 1:1 was used to minimize the bias effect of other clinical characteristics, and 77 pairs of patients’ data were performed for subsequent statistical analysis. The Cox proportional hazards model, Kaplan-Meier analysis, and Log-rank test were used in the present study. The primary observational endpoint was cancer-specific survival (CSS). Results The 1-year, 3-year, and 5-year CSS rates were 60.0%, 45.0%, and 42.0% in those 453 LCNC patients. Compared with patients who underwent surgical resection, patients without surgery had a lower 5-year CSS rate (18.0% vs. 52.0%, P

Abstract Thymic neuroendocrine tumors associated with multiple endocrine neoplasia are only defined as carcinoid and are not associated with large‐cell neuroendocrine carcinoma (LCNEC). We report the case of a multiple endocrine neoplasia type 1 patient with atypical carcinoid tumors with elevated mitotic counts (AC‐h), an intermediate condition between carcinoid and LCNEC. A 27‐year‐old man underwent surgery for an anterior mediastinal mass and was diagnosed with thymic LCNEC. Fifteen years later, a mass appeared at the same site, which was determined to be a postoperative recurrence based on the pathological results of a needle biopsy and the clinical course. The patient's disease remained stable for 10 months on anti‐programmed death‐ligand 1 antibody and platinum‐containing chemotherapy. The needle biopsy specimen was submitted for next‐generation sequencing, which revealed a MEN1 gene mutation, and after further examination, a diagnosis of multiple endocrine neoplasia type 1 was made. A re‐examination of the surgical specimen from 15 years prior showed that it corresponded to AC‐h. Although thymic AC‐h is classified as thymic LCNEC according to the current definition, our data suggests that a search for multiple endocrine neoplasia is warranted in such patients.

Background: According to the 2019 World Health Organization (WHO) classification of gastric neuroendocrine neoplasms, gastric neuroendocrine carcinoma (GNEC) can be further divided into gastric large-cell neuroendocrine carcinoma (GLNEC) and gastric small-cell neuroendocrine carcinoma (GSNEC). Whether the prognoses of the two types have a discrepancy has long been disputed. Method: We collected patients diagnosed with GLNEC or GSNEC in the National Cancer Center of China between January 2000 and December 2020. The characteristics and survival outcomes were compared between the two groups. We further verified our conclusion using the SEER dataset. Results: A total of 114 GNEC patients, including 82 patients with GLNEC and 32 patients with GSNEC, have completed treatment in our hospital. Clinicopathologic differences were not observed between patients with GSNEC and GLNEC concerning the sex, age, body mass index, Charlson Comorbidity Index, tumor location, tumor size, stage, treatment received, the expression of neuroendocrine markers (CD56, Chromogranin A, synaptophysin), and score on the Ki-67 index. The 1-year, 3-year, and 5-year overall survival rates of GLNEC and GSNEC were 89.0%, 60.5%, and 52.4%, and 93.8%, 56.3%, and 52.7%, which showed no statistically significant differences. This result was confirmed further by using the SEER dataset after the inverse probability of treatment weighting. Conclusions: Although with different cell morphology, the comparison of prognosis between the GLNEC and GSNEC has no significant statistical difference. [ABSTRACT FROM AUTHOR]

Background: With the widespread use of low-dose computed tomography for lung cancer screening, the detection rate of pulmonary lesions manifesting as ground-glass opacities (GGOs) has been increasing dramatically. The volume doubling time (VDT) has been introduced in clinical practice to monitor the potential growth rate of GGOs during long-term follow-up periods. Case presentation: A 72-year-old never-smoker female diagnosed with mixed GGO manifested abruptly accelerated growth with sudden decreased VDT from 400 to 36 days. A thoracoscopic left lower lobectomy with mediastinal lymph node dissection was performed, and the diagnosis was stage IB large-cell neuroendocrine carcinoma (LCNEC). Next-generation sequencing of the tumor highlights an EML4-ALK gene fusion. Conclusions: The LCNEC may present as GGO with longer VDT in the early stage. VDT should calculate by the whole size either on the entire tumor diameter or on consolidation diameter. It is recommended that meticulous long-term follow-up with dynamic VDT monitoring may help select high-risk GGOs performing timely semi-elective surgical resection in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the prognostic significance of surgery in large-cell neuroendocrine carcinoma (LCNC) patients. Methods: A total of 453 patients from the Surveillance, Epidemiology, and End Results database diagnosed with stage T1-4N0-2M0 LCNC from 2010 to 2015 were analyzed. The propensity-score matching analysis with a ratio of 1:1 was used to minimize the bias effect of other clinical characteristics, and 77 pairs of patients' data were performed for subsequent statistical analysis. The Cox proportional hazards model, Kaplan-Meier analysis, and Log-rank test were used in the present study. The primary observational endpoint was cancer-specific survival (CSS). Results: The 1-year, 3-year, and 5-year CSS rates were 60.0%, 45.0%, and 42.0% in those 453 LCNC patients. Compared with patients who underwent surgical resection, patients without surgery had a lower 5-year CSS rate (18.0% vs. 52.0%, P < 0.001). After analyses of multivariable Cox regression, chemotherapy, T stage, N stage, and surgery were identified as independent prognostic indicators (all P < 0.05). In the cohort of old patients, the median survival time was longer in cases after surgery than those without surgery (13.0 months vs. NA, P < 0.001). Besides, in patients with different clinical characteristics, the receiving surgery was a protective prognostic factor (all hazard ratio < 1, all P < 0.05). In addition, for the cohort with stage T1-2N0-2M0, patients after the operation had more improved outcomes than patients without surgery (P < 0.001). Conclusions: We proposed that the surgery could improve the survival outcomes of LCNC patients with stage T1-4N0-2M0. Moreover, old patients could benefit from surgery. [ABSTRACT FROM AUTHOR]

Thymic neuroendocrine tumors associated with multiple endocrine neoplasia are only defined as carcinoid and are not associated with large‐cell neuroendocrine carcinoma (LCNEC). We report the case of a multiple endocrine neoplasia type 1 patient with atypical carcinoid tumors with elevated mitotic counts (AC‐h), an intermediate condition between carcinoid and LCNEC. A 27‐year‐old man underwent surgery for an anterior mediastinal mass and was diagnosed with thymic LCNEC. Fifteen years later, a mass appeared at the same site, which was determined to be a postoperative recurrence based on the pathological results of a needle biopsy and the clinical course. The patient's disease remained stable for 10 months on anti‐programmed death‐ligand 1 antibody and platinum‐containing chemotherapy. The needle biopsy specimen was submitted for next‐generation sequencing, which revealed a MEN1 gene mutation, and after further examination, a diagnosis of multiple endocrine neoplasia type 1 was made. A re‐examination of the surgical specimen from 15 years prior showed that it corresponded to AC‐h. Although thymic AC‐h is classified as thymic LCNEC according to the current definition, our data suggests that a search for multiple endocrine neoplasia is warranted in such patients. [ABSTRACT FROM AUTHOR]

Background: We aimed to assess the clinical behavior of gynecologic largecell neuroendocrine carcinoma (LCNEC) via a retrospective analysis of data from 469 patients. Methods: Patients diagnosed with gynecologic LCNEC from 1988 to 2015 were identified using the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox hazard regression analyses were performed to assess independent predictors of overall survival (OS) and cancer-specific survival (CSS). OS and CSS were also evaluated using the Kaplan-Meier method, and the effects of different treatment regimens on prognosis were compared according to disease stage. Results: Cervical, ovarian, and endometrial LCNEC were observed in 169, 219, and 79 patients, respectively. The 5-year OS rates for patients with cervical, ovarian, and endometrial LCNEC were 35.98%, 17.84%, and 23.21%, respectively, and the median duration of overall survival was 26, 11, and 11 months in each group. The 5-year CSS rates for the three groups were 45.23%, 19.23%, and 31.39%, respectively, and the median duration of CSS was 41, 12, and 11 months in each group. Multivariate analysis revealed that American Joint Committee on Cancer stage, lymph node metastasis, and chemotherapy were independent prognostic factors for OS and CSS in patients with cervical LCNEC. Lymph node metastasis, surgery, and chemotherapy were independent prognostic factors for OS and CSS in the ovarian group and for OS in the endometrial group. Lymph node metastasis and surgery were also independent prognostic factors for CSS in the endometrial group. Conclusion: Surgery alone may help to improve overall survival and CSS in patients with early-stage cervical LCNEC. In contrast, surgery+chemotherapy and surgery+radiotherapy may help to improve survival in those with earlystage ovarian and endometrial LCNEC, respectively. Regardless of subtype, comprehensive treatment involving surgery, CTX, and RT should be considered to improve prognosis in patients with advanced-stage gynecologic LCNEC. [ABSTRACT FROM AUTHOR]

Abstract Background We investigated whether adjuvant chemotherapy, extent of resection, and immunoistochemical neuroendocrine markers affected survival of patients with the early stage of large‐cell neuroendocrine cancer. Methods This was a retrospective multicenter study including consecutive patients undergoing resection of node negative large‐cell neuroendocrine carcinoma. Five‐year survival and disease‐free survival rate were evaluated by the Kaplan–Meier method and the log‐rank test in relation to adjuvant chemotherapy, extent of resection, and immunoistochemical neuroendocrine markers (synaptophysin, chromogranin A, and neuron‐specific enolase). Results Our study population included 117 patients; 47 (40%) of these received adjuvant chemotherapy. Patients treated with adjuvant chemotherapy had better survival (74% vs. 45%, p = 0.002) and disease‐free survival (79% vs. 40%, p = 0.001) in all cases except patients with tumor 20 mm.

Aims: Large‐cell neuroendocrine carcinoma (LCNEC) and small‐cell carcinoma (SCLC) of lung encompass high‐grade neuroendocrine tumour category and share several fundamental features. As both tumours may respond to different treatment modalities and show unique molecular alterations distinction between the two is clinically relevant, but can be challenging due to sampling and fixation issues and shared morphological features. Methods: Surgically resected primary SCLC (n = 129) and LCNEC (n = 27) were immunohistochemically stained with Rb1, cyclin D1 and p16 using tissue microarray (TMA), and expression patterns of the proteins were compared between the two to identify the discriminatory pattern. Results: All markers had high diagnostic accuracy; Rb1 was the highest followed by p16 and cyclin D1. The majority of SCLC had the pattern Rb1−/p16+/cyclin D1– and more than half of LCNEC had Rb1+/p16−/cyclin D1+. Overall, the expression pattern Rb1– and cyclin D1– was strongly associated with the diagnosis of SCLC, while the pattern Rb1+ and/or cyclin D1+ was strongly associated with LCNEC. The use of this simplified expression pattern leads to a diagnostic accuracy of 97.3%. p16 did not add to further discrimination. The heterogeneity in Rb1, cyclin D1 and p16 expression was insignificant in SCLCs compared with LCNECs. Conclusions: Use of Rb1, cyclin D1 and p16 immunohistochemistry can distinguish the two with high accuracy. Notably, the Rb1−/cyclin D1– pattern in given tumour sample would confirm the diagnosis of SCLC. Our results could be extrapolated and applied to routine diagnostic samples such as biopsies and cytology samples. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Yu et al.)

Small-cell lung cancers (SCLC) and large-cell neuroendocrine carcinomas (LCNEC) are two types of high-grade pulmonary neuroendocrine carcinomas (NECs). Diagnostic neuroendocrine markers commonly include synaptophysin, chromogranin A, CD56, and insulinoma-associated protein 1 (INSM1). In this study, the utility of secretagogin (SCGN) was examined in the context of pulmonary NEC diagnosis. The study included 71 pulmonary NEC cases (18 SCLCs, 13 combined-SCLCs, 23 LCNECs, and 17 combined-LCNECs). Immunohistochemical stains of SCGN, synaptophysin, chromogranin A, CD56, and INSM1 were performed on whole tumor sections. The stains were evaluated based on combined staining intensity and the proportion of positive tumor cells. At least mild staining intensity in at least 1% of the cells was considered positive. Bioinformatic studies showed specific SCGN expression in neuroendocrine cells and NECs. SCGN showed diffuse nuclear and cytoplasmic staining in NECs with intra-tumoral heterogeneity. The non-neuroendocrine components were negative. The sensitivity of SCGN was no better than the other established neuroendocrine markers based on all NECs combined or LCNECs/c-LCNECs only. However, the sensitivity of SCGN (71%) was higher than chromogranin A (68%) for SCLCs/c-SCLCs only. The average proportion of SCGN positive tumor cells was 8% higher than chromogranin A (22% versus 14%, P = 0.0332) in all NECs and 18% higher for SCLC and c-SCLC cases only (32% versus 13%, P = 0.0054). The above data showed that SCGN could be used as a supplemental neuroendocrine marker to diagnose SCLC. [ABSTRACT FROM AUTHOR]

Background: We investigated whether adjuvant chemotherapy, extent of resection, and immunoistochemical neuroendocrine markers affected survival of patients with the early stage of large‐cell neuroendocrine cancer. Methods: This was a retrospective multicenter study including consecutive patients undergoing resection of node negative large‐cell neuroendocrine carcinoma. Five‐year survival and disease‐free survival rate were evaluated by the Kaplan–Meier method and the log‐rank test in relation to adjuvant chemotherapy, extent of resection, and immunoistochemical neuroendocrine markers (synaptophysin, chromogranin A, and neuron‐specific enolase). Results: Our study population included 117 patients; 47 (40%) of these received adjuvant chemotherapy. Patients treated with adjuvant chemotherapy had better survival (74% vs. 45%, p = 0.002) and disease‐free survival (79% vs. 40%, p = 0.001) in all cases except patients with tumor <20 mm (79.5% vs. 57.4%, p = 0.43). Lobectomy compared to sublobar resection was associated with better survival (67% vs. 0.1%, p < 0.0001) and disease‐free survival (65% vs. 0.1%, p < 0.0001) also in patients with tumor <20 mm (79% vs. 28%, p = 0.001). Patients with triple‐positive neuroendocrine markers had better survival (79% vs. 35%, p = 0.0001) and disease‐free survival (69% vs. 42%, p = 0.0008). Regression analysis showed that tumor size <20 mm, lobectomy, adjuvant chemotherapy, and triple‐positive immunistochemical neuroendocrine markers were significant favorable prognostic factors for survival outcomes. Conclusions: Lobectomy seems to be the management of choice in patients with large‐cell neuroendocrine cancer <20 mm while adjuvant chemotherapy should be administered only in patients with tumor >20 mm. [ABSTRACT FROM AUTHOR]

Although precursor lesions of pulmonary squamous carcinoma, adenocarcinoma and carcinoid tumour are well known and accepted entities, precursor lesions of pulmonary neuroendocrine carcinomas, i.e. small‐cell lung carcinoma and large‐cell neuroendocrine carcinoma, have never been identified. A small body of literature documenting intraepithelial involvement in cases of pulmonary neuroendocrine carcinoma begs the question of whether the intraepithelial lesion represents de‐novo intraepithelial neoplasia or invasion by underlying tumour. In this article, the literature on cases of invasive neuroendocrine carcinomas with an intraepithelial component showing a neuroendocrine immunophenotype is thoroughly and critically reviewed. The authors of the publications of cases of coexisting invasive and intraepithelial neuroendocrine carcinoma generally favour invasion as the explanation for the intraepithelial component. However, in practice, it is difficult or impossible to determine the direction of migration of tumour cells when there is both an invasive component and an intraepithelial component. Pulmonary neuroendocrine carcinomas in situ have been produced in genetically engineered mouse models. On the basis of the illustrations in the literature of human cases and the production of pulmonary neuroendocrine carcinomas in situ in genetically engineered mice, it seems likely that these tumours also exist in humans. However, their existence and acceptance require definitive proof. Studies should be undertaken to identify bronchial and other lung biopsies with in‐situ carcinoma showing a neuroendocrine immunophenotype and a subsequent negative resection specimen and no follow‐up evidence of invasive carcinoma. Documenting such cases would provide definitive proof for the existence of pulmonary neuroendocrine carcinomas in situ in humans. [ABSTRACT FROM AUTHOR]

Purpose: Large cell neuroendocrine carcinoma (LCNEC) of the cervix represents a rare tumour entity associated with poor prognosis. Knowledge about carcinogenesis and therapeutic options is scarce, while novel therapeutic targeted approaches are limited.Methods: We performed a systematic review of four electronic databases from inception to June 2020. Eligible studies included all reports that addressed survival outcomes of women with LCNEC.Results: A total of 31 case studies including 87 LCNEC patients were identified. Median patients' age was 41 years (range: 21-81). Most women (76.3%) had FIGO stage I-II disease. Overall, 72.0% had surgery, 70.1% received chemotherapy and 50.7% received radiotherapy. Of 13 patients with known HPV-status, 15% were HPV negative. Median overall survival (OS) was 24 months (range: 0.5-151), with 3- and 5-year OS of 42% and 29%, respectively. In multivariate analyses, only surgery and lymphadenectomy significantly associated with survival (Surgery OS: HR 0.14; 95% C.I:0.03-0.71, p = 0.018 / Surgery PFS: HR 0.23, 95% C.I. 0.06, 0.92, p = 0.037 / Lymphadenectomy OS: HR 0.26, 95% C.I. 0.07-0.98, p = 0.046 / Lymphadenectomy PFS: HR 0.30, 95% C.I. 0.09-0.98, p = 0.046). Age, chemotherapy or radiotherapy did not significantly impact survival, but lower stage was associated with improved survival.Conclusion: Cervical LCNECs overall have a poor prognosis, despite their relatively early-stage initial presentation. Surgery and lymphadenectomy appear to significantly affect survival in contrast to chemotherapy and radiotherapy, which appear to have no significant effect on prognosis. Prospective multicentre cancer registries are warranted to improve treatment options for this rare disease. [ABSTRACT FROM AUTHOR]

Abstract Background Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is selective for both epidermal growth factor receptor tyrosine kinase inhibitor–sensitizing and T790M resistance mutations. Almost all patients who initially respond to an epidermal growth factor receptor tyrosine kinase inhibitor subsequently report disease progression. Epidermal growth factor receptor–dependent resistance mechanisms, bypass pathway activation, and histological transformation have been reported with osimertinib therapy. Case presentation We report a case of a 64-year-old Asian man with epidermal growth factor receptor T790M-positive adenocarcinoma that transformed to epidermal growth factor receptor T790M-negative large-cell neuroendocrine carcinoma after osimertinib therapy. A prompt rebiopsy revealed a rare mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitor, and subsequently treatment with carboplatin and etoposide was effective. Conclusions Despite the promising emergence of circulating tumoral DNA testing, this case report emphasizes the importance of rebiopsy of a progressive epidermal growth factor receptor–mutant tumor.

This work aimed to explore chest computed tomography (CT) image segmentation of patients with large-cell neuroendocrine carcinoma (LCNEC) based on deep learning, as well as the clinical manifestations and imaging and pathological features of LCNEC patients. Clinical data of 40 patients with LCNEC confirmed by pathological examination in the X Hospital from December 2015 to December 2017 were retrospectively selected. CT image data were segmented by TJ-1 model modified full convolutional neural network (FCNN) model. The accuracy and training time of TJ-1 FCNN model and classic deep learning segmentation network model AlexNet model were compared in terms of image segmentation. According to the image segmentation results by TJ-1 FCNN model, chest CT images of LCNEC patients, were reviewed, and the clinical manifestations, as well as the imaging and pathological features of the patients were reviewed, sorted, and summarized. The results showed that the image segmentation accuracy of TJ-1 network model (99.38%) was higher than that of AlexNet model. The iteration training time of TJ-1 network model for 30 times was 45 min, lower than that of AlexNet model (82 min). LCNEC was more likely to be found in elderly male with a long history of smoking. The clinical symptoms were cough, sputum, sputum blood, and chest pain with no significant specificity. CT imaging showed that peripheral mass was the most common manifestation (67.5%), both lungs were visible, the upper lobe was more likely with lesion (60%), the edge of the lesion was clear or smooth (57.5%), which was lobulated (70%). Under the light microscope, tumor cells were characterized by large volume, low nucleocytoplasmic ratio, high mitosis, and large area necrosis. The positive rates of immunohistochemical neuroendocrine markers were CD56 (62.5%), CgA (50%), and Syn (85%), among which Syn was with the highest positive rate. To sum up, LCNEC lacked clinical and radiological specificity manifestations, while chest CT image segmentation based on TJ-1 FCNN model can quickly mark the location of the lesion, providing technical support for the diagnosis and evaluation of LCNEC clinically. [ABSTRACT FROM AUTHOR]

Aims: To gather the best available evidence regarding Ki‐67% values in large‐cell neuroendocrine carcinoma (LCNEC) and determine whether certain cut‐off values could serve as a prognostic feature in LCNEC. Methods and results: Aperio ScanScope AT Turbo, eSlide Manager and ImageScope software (Leica Biosystems) were used to measure Ki‐67% in 77 resected LCNEC diagnosed by World Health Organisation (WHO) criteria. Cases were stratified into six classes by 10% Ki‐67 increments. Using the Kaplan–Meier method, overall (OS) and disease‐free survivals (DFS) were compared by AJCC stage, by six Ki‐67% classes and with Ki‐67% cut‐points ≥20% and ≥40%. Tumours were from 0.9 to 11.5 cm and pathological stages 1–3. The system measured Ki‐67% positivity using 4072–44 533 tumour nuclei per case (mean 16610 ± 8039). Ki‐67% ranged from 1 to 64% (mean = 26%; median = 26%). Only 16 (21%) tumours had Ki‐67% ≥40%. OS ranged from 1 to 298 months (median follow‐up = 25 months). DFS ranged from 1 to 276 months (median follow‐up = 9 months). OS and DFS differed across AJCC stage (overall log‐rank P = 0.038 and P = 0.037). However, neither OS nor DFS significantly correlated with Ki‐67% when six or two classes were used with either ≥20% Ki‐67 or ≥40% Ki‐67 as cut‐point. A literature review identified 14 reports meeting our inclusion criteria with ≥10 LCNEC. Reported Ki‐67% ranged from 2% to 100%. Problems contributing to variability in Ki‐67% measurements are discussed. Conclusion: Our findings caution against a blanket use of 20%, 40% or other Ki‐67% cut‐points for LCNEC diagnosis or prognostication. [ABSTRACT FROM AUTHOR]

Background: Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a rare tumor with an aggressive clinical course. However, there is limited knowledge of its treatment strategy. This retrospective study aimed to assess the efficacy and safety of anti-programed death-1 (PD-1) blockade monotherapy in previously treated advanced LCNEC. Methods: Eleven patients with previously treated advanced LCNEC who received immune checkpoint inhibitor monotherapy between January 2015 and November 2020 were retrospectively analyzed for efficacy and safety. Results: Of a total of 11 patients (median [range] age, 66 [37–79] years; 8 men [73%] and 3 women [27%]), 8 patients had performance status (PS) 0–1 [73%] and 3 patients had PS 2 [27%]; 9 patients received 1 prior chemotherapy [82%] and 2 patients received 2 prior chemotherapies [18%]. The median follow-up duration was 4.6 months. Although PD-1 blockade was administered at median cycles of 3 (range, 1–12), overall response rate, median progression-free survival, and median overall survival were 9.1%, 2.7 months, and 4.6 months, respectively. Any adverse events were observed in 9 patients (82%), including 1 patient with grade 3 pneumonitis as a serious adverse event. Conclusion: Anti-PD-1 blockade monotherapy as a subsequent line for previously treated advanced LCNEC exhibited usefulness and tolerability and was identified as a valid treatment option. [ABSTRACT FROM AUTHOR]

ObjectiveLarge-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of pulmonary cancer with poor survival. Optimal adjuvant chemotherapy for resected LCNEC is controversial till now; clinical features together with the prognostic factors in LCNEC should be clarified better.MethodsClinicopathological characteristics, driven genes’ status (EGFR, ALK, and ROS1), adjuvant chemotherapy strategy for 94 surgical resected LCNECs were extracted from digital database, tumor relapse or progression, and survival were analyzed with clinical profiles.ResultsDriven gene mutants were scarce in LCNEC, 8.3% (4/48) samples harbored EGFR mutations, 5.8% (3/52) with ALK positive, and none of ROS1 positive. A total of 44 patients suffered tumor relapse or progression during follow-up. Tumor/lymph node (N) stage, serum carcinoembryonic antigen (CEA) level before surgery, different adjuvant chemotherapies were associated with tumor relapse (P < 0.05); poorer disease-free survival (DFS) appeared in N2/stage III, serum CEA positive and pemetrexed based chemotherapy (P < 0.05); for overall survival (OS) analysis, the T/tumor stage, serum positive CEA/neuron-specific enolase (NSE) at baseline were associated with worse OS (P < 0.05). Moreover, in the multivariate analysis, N stage still acted as prognostic for DFS (P = 0.019); OS differed significantly in different T stages, chemotherapy selection and serum CEA levels after adjustment (P < 0.05).ConclusionClassical driven gene mutations were rare in LCNEC. Tumor N stage appeared as prognostic for DFS, while serum positive CEA, different adjuvant chemotherapy strategies, and T stage were independent prognostic factors for OS. Etoposide–platinum regime seemed to be a better choice which should be confirmed by further prospective investigations.

Objective: Large-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of pulmonary cancer with poor survival. Optimal adjuvant chemotherapy for resected LCNEC is controversial till now; clinical features together with the prognostic factors in LCNEC should be clarified better. Methods: Clinicopathological characteristics, driven genes' status (EGFR, ALK, and ROS1), adjuvant chemotherapy strategy for 94 surgical resected LCNECs were extracted from digital database, tumor relapse or progression, and survival were analyzed with clinical profiles. Results: Driven gene mutants were scarce in LCNEC, 8.3% (4/48) samples harbored EGFR mutations, 5.8% (3/52) with ALK positive, and none of ROS1 positive. A total of 44 patients suffered tumor relapse or progression during follow-up. Tumor/lymph node (N) stage, serum carcinoembryonic antigen (CEA) level before surgery, different adjuvant chemotherapies were associated with tumor relapse (P < 0.05); poorer disease-free survival (DFS) appeared in N2/stage III, serum CEA positive and pemetrexed based chemotherapy (P < 0.05); for overall survival (OS) analysis, the T/tumor stage, serum positive CEA/neuron-specific enolase (NSE) at baseline were associated with worse OS (P < 0.05). Moreover, in the multivariate analysis, N stage still acted as prognostic for DFS (P = 0.019); OS differed significantly in different T stages, chemotherapy selection and serum CEA levels after adjustment (P < 0.05). Conclusion: Classical driven gene mutations were rare in LCNEC. Tumor N stage appeared as prognostic for DFS, while serum positive CEA, different adjuvant chemotherapy strategies, and T stage were independent prognostic factors for OS. Etoposide–platinum regime seemed to be a better choice which should be confirmed by further prospective investigations. [ABSTRACT FROM AUTHOR]

Colorectal large-cell neuroendocrine carcinomas (NECs) are extremely rare and have very poor prognosis compared to adenocarcinomas. A 74-year-old man presented with abdominal pain, diarrhea and hematochezia. The histopathologic report of colonoscopic biopsy performed at a local clinic was a poorly differentiated carcinoma. An abdominopelvic computed scan revealed irregularly enhanced wall thickening at the sigmoid colon with regional fat stranding and lymphnode enlargement. He underwent a laparoscopic high anterior resection with selective peritonectomy for peritoneal carcinomatosis, intraoperative peritoneal irrigation chemotherapy, and early postoperative intraperitoneal chemotherapy for 5 days. The tumor had a high proliferation rate (mitotic count > 50/10 HPFs and 90% of the Ki-67 index) and lymph-node metastases had occurred. On immunohistochemistry, the tumor cells expressed CD56 and synaptophysin. Large-cell NEC was confirmed. Systemic chemotherapy with cisplatin/etoposide was done. The patient is still alive after 3 years with no evidence of recurrence.

Abstract Background The response to temozolomide (TMZ) treatment in small-cell lung cancer (SCLC) correlated with O(6)-methylguanine -DNA methyltransferase (MGMT) promoter methylation. 1p/19q co-deletion within oligodendroglioma is a responsive predictor for TMZ. Currently, the status of MGMT promoter methylation and 1p/19q co-deletion in pulmonary carcinoid (PC) and large-cell neuroendocrine carcinoma (LCNEC) is not reported. Methods Nine PC [two atypical carcinoids (AC), seven typical carcinoids (TC)] and six LCNEC patients were collected retrospectively. The pyrosequencing and fluorescence in situ hybridization were used to detect the MGMT promoter methylation and 1p/19q co-deletion in surgically resected specimens. Kaplan–Meier analysis was used to assess the rate of disease-free survival (DFS). Results MGMT promoter methylation was found in two (2/6, 15.3%) LCNEC patients but not in any PC patients. Three (3/6, 50%) 1p and two (2/6, 33.3%) 19q single deletions were found in LCNEC patients. One 1p single deletion was found in AC patients. One (1/7, 14.3%) 1p and two (2/7, 28.6%) 19q single deletions were found in TC patients. After a median follow-up of 38 months, three LCNEC patients developed distant metastasis and one patient died of LCNEC disease. The DFS of PC patients was much longer than LCNEC patients (χ 2 = 7.565, P = 0.006). Conclusions MGMT promoter methylation and 1p/19q co-deletion might not be the ideal biomarkers for TMZ treatment in TC/AC patients. Thus, the detection of MGMT promoter methylation and whether it can be used as a medication for TMZ in LCNEC patients necessitates investigation. Furthermore, 1p deletion could be a negative prognostic factor for LCNEC patients.

Background: Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is selective for both epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. Almost all patients who initially respond to an epidermal growth factor receptor tyrosine kinase inhibitor subsequently report disease progression. Epidermal growth factor receptor-dependent resistance mechanisms, bypass pathway activation, and histological transformation have been reported with osimertinib therapy.Case Presentation: We report a case of a 64-year-old Asian man with epidermal growth factor receptor T790M-positive adenocarcinoma that transformed to epidermal growth factor receptor T790M-negative large-cell neuroendocrine carcinoma after osimertinib therapy. A prompt rebiopsy revealed a rare mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitor, and subsequently treatment with carboplatin and etoposide was effective.Conclusions: Despite the promising emergence of circulating tumoral DNA testing, this case report emphasizes the importance of rebiopsy of a progressive epidermal growth factor receptor-mutant tumor. [ABSTRACT FROM AUTHOR]

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Early identification of acute pancreatitis etiology is essential for choosing the best therapeutic management. The main causes are cholelithiasis and alcohol consumption. Tumors that obstruct the main pancreatic duct are uncommon causes of acute pancreatitis. Duodenal neuroendocrine tumors are rare entities and may be exceptional causes of acute pancreatitis. A 57-year-old male, with associated severe cardiovascular pathology, was admitted with clinical and biological picture of acute pancreatitis. Biliary and alcoholic causes were excluded. Abdominal contrast-enhanced computed tomography scan identified circumferential wall thickening of the second segment of the duodenum with peri-ampullary and papillary nodular non-homogenous contrast enhancement aspect. Upper gastrointestinal endoscopy described irregular hypertrophic duodenal mucosal folds and biopsies were performed. The histopathological diagnosis after immunohistochemistry tests was duodenal large-cell neuroendocrine carcinoma. The patient was referred to the oncology clinic and palliative treatment was initiated. The evolution was marked by additional complications due to the tumor evolution - upper gastrointestinal bleeding and obstructive jaundice, conservatory treated and, respectively, by interventional radiology technique. This case illustrates that, although often obvious, etiological diagnosis approach of acute pancreatitis can be sometimes challenging. Tumor cause is infrequent and requires thorough work-up, as the treatment is different. Although extremely rare and sometimes with mild clinical presentation, duodenal neuroendocrine carcinomas may have dramatic onset and evolution, involving extensive therapeutic resources. [ABSTRACT FROM AUTHOR]

Primary neuroendocrine tumors of the genitourinary tract are rare and are comprised of a heterogeneous group of neoplasms. These include paraganglioma, well-differentiated neuroendocrine tumors or carcinoid tumors, small-cell neuroendocrine carcinoma, and large-cell neuroendocrine carcinoma. Personal experiences, in addition to the findings of an extensive literature search for pertinent publications, were used to compile the epidemiological data, clinical information, histopathological features, prognostic factors, and therapeutic approaches. We also include molecular alterations and targeted treatments of the various neuroendocrine tumors of the genitourinary tract. • Primary NETs in the GU tract are much rarer than in the lung or the GI tract. • This warrants diligent search for primaries outside the GU tract before rendering such diagnoses. Thus, collaboration between the pathologist and the urologist is essential. • Despite the advances in imaging techniques, serum marker studies, and molecular diagnostics, the diagnosis of these tumors continues to be challenging. The use of NE immunohistochemical markers can be a sensitive tool to detect NE differentiation, but not necessarily a specific one. • The outcome of these tumors varies, with paragangliomas and WDNETs having a better prognosis than high-grade NETs. • Due to the rarity of these cases, no treatment guidelines are available, and patients are usually managed using regimens extrapolated from NE tumors at other sites. [ABSTRACT FROM AUTHOR]

Aims: Pure large‐cell neuroendocrine carcinoma (LCNEC) is an uncommon but well‐recognised primary tumour of the colorectum. It is characterised by large cells organised in a discernible neuroendocrine pattern with >20 mitoses per 10 high‐power fields (HPFs), and/or a Ki67 index of >20%, and coagulative tumour necrosis is invariably present. These features are supplemented by positivity for neuroendocrine immunohistochemical markers. The aim of this study was to highlight three primary LCNECs of the colorectum. Methods and results: All three patients were elderly females, aged 79, 85 and 89 years, who presented with ascending colon (two) tumours and a rectal tumour. All three tumours were large, ulcerated, polypoid masses (85, 76 and 55 mm; average size 72 mm) and were pT3N2. Histologically, the tumours were composed of packets and nests of cells with rosettes; other areas were in sheets composed of large cells. The mitotic counts were 23/10 HPFs, 27/10 HPFs and 24/10 HPFs, respectively. There was no mucosal dysplasia, precursor adenoma or associated adenocarcinoma component. All cases contained mainly peritumoral lymphoid aggregates, with smaller numbers of intratumoral lymphocytes. Synaptophysin, chromogranin (less intensely) and epithelial markers were expressed in all cases in the majority of the tumour cells. The Ki67 proliferative indices were 95%, 100%, and 80%, respectively. Two patients survived for 48 and 72 months, whereas the third is alive after 12 months without evidence of recurrence. Conclusions: These unusual primary colorectal LCNECs with an accompanying lymphoid component are characterised by loss of MLH1/PMS2, BRAF mutation, microsatellite instability, and Epstein–Barr virus negativity. The patients also have better overall survival than those with LCNECs lacking an accompanying lymphoid component. [ABSTRACT FROM AUTHOR]

Highlights from the article: Patient who developed ILD after AC0010 treatment and was then successfully re-challenged 1st Biopsy Prior EGFRTKI 2nd Biopsy Subsequent therapy 3rd Biopsy Subsequent therapy Notes: *The patient was diagnosed with large-cell neuroendocrine carcinoma transformation after 1 month of osimertinib treatment, indicating that the transformation was a resistance mechanism of erlotinib rather than of.

Background: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is associated with poor prognosis, and its treatment strategy is still controversial, especially regarding chemotherapy regimens. Case report: We present the case of a 49-year-old Chinese male with primary pulmonary LCNEC treated with neoadjuvant and adjuvant chemotherapy with cisplatin plus pemetrexed. A suspected quasi-circular mass in the left lower pulmonary lobe and an enlarged mediastinal lymph node were found. The patient was diagnosed with adenocarcinoma with neuroendocrine differentiation based on computerized tomography-guided percutaneous lung biopsy. An EGFR gene mutation test showed negative results. Cisplatin and pemetrexed were administered as the neoadjuvant chemotherapy regimen. The primary lesion had reduced markedly, and the enlarged mediastinal lymph node had disappeared after two cycles of neoadjuvant chemotherapy. A left lower lobectomy and mediastinal lymph node dissection were performed. The lesion was confirmed as LCNEC based on postoperative histopathological analysis and immunohistochemical results. The patient underwent four cycles of adjuvant chemotherapy with cisplatin and pemetrexed for a month postoperatively, followed by postoperative adjuvant radiotherapy. The patient was still alive after a follow-up of 24 months, with no evidence of tumor recurrence. Conclusion: Cisplatin combined with pemetrexed is effective and safe for patients with pulmonary LCNEC. [ABSTRACT FROM AUTHOR]

Large-cell neuroendocrine carcinoma (LCNEC) of the endometrium is an extremely rare, high-grade malignant tumor. We herein report a case of a rapidly growing LCNEC arising in the endometrium. A 52-year-old woman was referred to Toyooka Hospital (Tooyoka, Japan) due to genital bleeding in February 2016. There had been no abnormalities on a regular gynecological and physical examination 3 months prior to the consultation. Imaging (computed tomography and magnetic resonance imaging) and a pelvic examination revealed a tumor sized 16.9x8.4x7.8 mm occupying the intrauterine cavity and extending into the vaginal cavity. Multiple metastatic pelvic and paraaortic lymph nodes were also identified. Continuous bleeding from the tumor was observed, and a blood examination revealed anemia, which was likely due to that bleeding. Biopsy of the tumor was performed, and large atypical cells were identified. The tumor cells were negative for cytokeratin AE1/AE3 and chromogranin A, but positive for CD56 and synaptophysin. There was also an abundance of Ki-67-positive cells in the tumor, altogether suggesting that the tumor was an LCNEC. The patient succumbed to the disease 36 days after the first consultation. Based on the findings of the present case and previously published cases, LCNECs arising in the endometrium may progress rapidly and are associated with an unfavourable outcome. LCNEC should be included in the differential diagnosis in cases of rapidly growing tumors of the uterine corpus. [ABSTRACT FROM AUTHOR]