Case Of Large Cell Neuroendocrine Carcinoma Research Articles

The role of immunotherapy in stage III large cell neuroendocrine carcinoma of the lung (LCNEC): A retrospective NCDB analysis.

e20568 Background: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare lung cancer subtype. Despite advances in understanding lung cancer biology, a consensus on the use of consolidation immunotherapy (IO) in patients with LCNEC is still lacking. Methods: Using National Cancer Database (NCDB), we reviewed stage III lung LCNEC cases diagnosed from 2017 through 2019 with a follow-up through 2020. Several variables were incorporated into the multivariate logistic regression analysis, including age, gender, race, Charlson-Deyo comorbidity score (CDCS), insurance status, and IO use. Survival distribution was examined using the Kaplan-Meier analysis and compared by the log-rank test. Results: A total of 956 cases with a male:female ratio of 1.2:1, and a median age (±SD, range) of 66.4 (±9.7, 37–90) years—baseline characteristics are shown in the Table. In the univariate analysis, IO use (n = 184) resulted in a superior median overall survival (mOS; 30.6 vs. 20.3 months, HR 0.76, 95% CI 0.62-0.96, p = 0.02, compared to no IO use). Results from multivariate analysis further demonstrated survival benefit with IO use (HR 0.79, 95% CI 0.63-0.98, p = 0.03, compared to no IO use). Additionally, in the multivariate analysis, the female gender was associated with improved survival (HR 0.84, 95% CI 0.71-0.99, p = 0.04); while notable factors associated with reduced survival were age ≥75 years (HR 1.45, 95% CI 1.08-1.95, p = 0.01, compared to 18-64 years age group), CDCS of ≥1 (HR 1.19, 95% CI 1.004-1.420, p = 0.04, compared to zero), and Medicaid (HR 1.46, 95% CI 1.05-2.05, p = 0.02, compared to private insurance). There was no statistical significance for OS noted with age group 65-74 years (HR 1.09, 95% CI 0.84-1.42, p = 0.49, compared to 18-64 years age group); and race (African American, HR 1.001, 95% CI 0.77-1.29, P = 0.99, compared to White). Conclusions: This study shows that IO improves survival in stage III LCNEC. Despite the inherent limitations of the database, our findings are intriguing and warrant further evaluation through prospective clinical trials in order to assess and optimize the benefit of IO in this patient population. [Table: see text]

NOL4 is a novel nuclear marker of small cell carcinoma and other neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) such as small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) have characteristic histologies, but immunohistochemistry using neuroendocrine markers is still desirable to confirm diagnosis. CD56 is the most sensitive marker, but also stains various normal tissues and other tumors. Recently, we reported that nucleolar protein 4 (NOL4) is present in the blood of SCLC patients and found it was stained in the SCLC nuclei. In this study, we compared expressions of NOL4 and CD56, using 64 cases of SCLC, 18 cases of LCNEC, 6 cases of atypical carcinoid tumor, 7 cases of typical carcinoid tumor, 68 cases of lung adenocarcinoma, and 62 cases of lung squamous cell carcinoma. For primary lung NENs, sensitivity, specificity, positive predictive value (PPV) and negative predictive value of NOL4 were 77.5%, 95.8%, 93.2%, and 85.1%, respectively, while those of CD56 were 92.1%, 93.3%, 91.1%, and 94.1%. The specificity and PPV of NOL4 were higher than those of CD56, although the differences were not statistically significant. However, NOL4 retains its nuclear immunoreactivity in areas of crush artifact or necrosis. Furthermore, NOL4 was not expressed in adjacent normal tissues including bronchial cells and pneumocytes. Therefore, a combination of NOL4 staining with other cytoplasmic or membranous neuroendocrine markers might enhance diagnostic utility for SCLC and other NENs.

Prognostic significance of YAP1 expression and its association with neuroendocrine markers in resected pulmonary large cell neuroendocrine carcinoma (LCNEC)

BackgroundYAP1 (Yes-associated protein 1), an important effector of the Hippo pathway, acts as an oncogene and is overexpressed in various malignant tumors. However, the function and expression pattern of YAP1 in pulmonary large cell neuroendocrine carcinoma (LCNEC) have not been systematically established. This study aimed to explore the relationship between YAP1 expression and neuroendocrine differentiation markers and their prognostic significance in LCNEC. Materials and methodsYAP1 protein and neuroendocrine markers (INSM1, NeuroD1 and DLL3) expression were examined by immunohistochemical (IHC) staining in 80 resected pulmonary LCNEC cases. The possible association between these markers and clinicopathological features was evaluated and survival analyses were performed. ResultsYAP1 was highly expressed in 25% LCNECs (20/80) , especially at a relatively higher T stage (p = 0.015). YAP1 expression was negatively correlated with INSM1 (χ2=11.53, p = 0.001) and DLL3(χ2=8.55, p = 0.004), but not with NeuroD1 (p = 0.482). For survival analyses, YAP1 expression was associated with worse disease-free survival (DFS) and overall survival (OS) (median DFS: 13 months vs. not reached (NR), p = 0.0096; median OS: not reached, NR vs. NR, p = 0.038), and was an unfavorable prognostic factor for DFS (HR:3.285; 95%CI: 1.526-7.071, p = 0.002) and OS (HR: 2.864, 95% CI: 0.932-8.796, p = 0.066). ConclusionsYAP1 was found to be conversely correlated with neuroendocrine markers and a prognostic factor for worse survival in resected LCNEC patients, and mechanisms need to be further investigated.

Molecular Subtypes of High-Grade Neuroendocrine Carcinoma (HGNEC): What is YAP1-Positive HGNEC?

Small cell lung cancer (SCLC) subtype classification, based on high-level expression of key transcriptional regulators; ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y), has recently been proposed. YAP1 (and POU2F3) has attracted attention as an important factor for non-neuroendocrine (non-NE) phenotypic subtyping of SCLC. However, subsequent studies reported that YAP1 expression alone cannot define a single group in primary SCLC, which makes it difficult to understand what SCLC-Y is by focusing only on SCLC. In this review, we concluded that YAP1 is an essential anti-neuroendocrine factor in both SCLC and non-small cell lung cancer (NSCLC) based on previous studies, including our own analysis of the cell lines and primary tumors of SCLC and NSCLC. The classification of SCLC-Y is a concept mainly established from the analysis of cell lines, and SCLC-Y cell lines correspond to "variant type" SCLC cell lines. Primary SCLC and large cell neuroendocrine carcinoma (LCNEC) are typically heterogeneous tumors composed mostly of NE-type cells, but they contain a small number of non-NE-type cells. Importantly, individual cells with NE features exhibit YAP1 loss, whereas the non-NE-type cells exhibit YAP1 expression. Although rare in primary SCLC, some cases of primary LCNEC have many YAP1-positive cells, which is correlated with chemotherapy resistance. YAP1 staining may be useful in the exclusion diagnosis of SCLC or in the selection of treatment for LCNEC.

68Ga-Tetraazacyclododecane Tetraacetic Acid-DPhe1-Tyr3-Octreotate Positron Emission Tomography/Computed Tomographic Findings of Large-Cell Neuroendocrine Carcinoma of the Lung in a Child.

Primary lung cancers in children are rare, and most children are diagnosed incidentally while being investigated for another medical problem. The diagnosis of primary lung tumors in children is very difficult because many children are asymptomatic until the advanced stages of the disease and nonspecific imaging findings. Although the usage of 68Ga-tetraazacyclododecane tetraacetic acid-DPhe1-Tyr3-octreotate (68Ga-DOTATATE) positron emission tomography/computed tomography (PET/CT) in adult patients is well known, it is a relatively new imaging modality for the pediatric patient group. Herein, we presented a unique case of large-cell neuroendocrine carcinoma of the lung in a child on 68Ga-DOTATATE PET/CT.

Expression of SATB2 in Neuroendocrine Carcinomas of the Lung: Frequent Immunopositivity of Large Cell Neuroendocrine Carcinoma with a Diagnostic Pitfall.

Small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC) are both classified as lung neuroendocrine carcinoma (NEC). It has recently been reported that the special AT-rich sequence-binding protein 2 (STAB2), known as a colorectal cancer marker, is also expressed in NECs occurring in various organs including the lung. However, few studies have examined any differences of SATB2 immunopositivity between SCLC and LCNEC. We investigated SATB2 expression in 45 SCLC and 14 LCNEC cases using immunohistochemistry as well as the expression of caudal-type homeobox 2 (CDX2) and keratin (KRT) 20. The LCNEC cases were more frequently positive for SATB2 (ten out of 14, 71%) than the SCLC ones (seventeen out of 45, 38%) with a statistically significance (P = 0.035). Furthermore, two LCNEC cases were positive for CDX2 while no positive findings were observed for any SCLC cases, the difference of which, however, was not statistically significant (P = 0.053). KRT20 was negative in all LCNEC and SCLC cases. These results require our attention when we use SATB2 and CDX2 as colorectal cancer markers because their expression in pulmonary NECs can lead to a misdiagnosis that the tumor is of metastatic colorectal adenocarcinoma, especially when the patient has a past history of colorectal cancer. Analyzing the relationship between the demographic/clinical variables and the SATB2 expression in the SCLC cases, just high Brinkman index (≥ 600) was significantly related to the positivity of SATB2 (P = 0.017), which is interesting considering the strong relationship between SCLC and smoking.

INTERESTING CASES OF LARGE CELL NEUROENDOCRINE LUNG CARCINOMA

TOPIC: Lung Cancer TYPE: Medical Student/Resident Case Reports INTRODUCTION: Large-cell neuroendocrine carcinoma (LCNEC) is a rare form of pulmonary tumors with features of small cell lung carcinoma and non-small cell lung cancer. Due to its rarity, there is little known about its presentation and prognosis. We review 2 cases of LCNEC with different outcomes which will help contribute to the current literature of LCNEC. CASE PRESENTATION: Patient A was a 76-year-old male who presented to the Emergency Department with chief complain of dyspnea and shortness of breath. Patient had a history of COPD with 4-5L of home oxygen, hypertension, and a right lung mass. Patient A is a current smoker with 100 pack-year history. He had reported a recent unintentional weight loss of 40 pounds. CT Chest demonstrated a right chest mass measuring 11.9cm. Patient B is a 43-year-old male with no prior smoking history who presented to the ED with complaints of myalgias, sore throat, fevers, and shortness of breath. Patient A also began having generalized weakness, unintentional weight loss of 20lbs, and hoarseness which increased over the past month. Chest CTA demonstrated a large multi-spatial mediastinal mass with confluent adenopathy extending to the left hilum. Both patients underwent endobronchial ultrasound-guided biopsy with bronchioalveolar lavage that demonstrated large cell neuroendocrine carcinoma of the lung. Patient A underwent diagnostic studies 4 month after the mass was detected and Patient B underwent diagnostic studies the following day after mass detection. Patient A experiences an extended stay in the medical intensive care unit and was ultimately admitted to hospice. Patient A expired 24 hours after admission to hospice. Patient B began systemic chemotherapy and radiation with and oncologist and is currently improving. DISCUSSION: Further studies are aimed towards finding similarities in symptoms or laboratory values in order to identify this aggressive carcinoma earlier in its course. Our case reports highlight the aggressive nature of LCNEC. It reveals that advanced age, pulmonary comorbidities and delayed diagnosis all feed into a poor prognosis for LCNEC. CONCLUSIONS: LCNEC is an aggressive cancer that warrants an expediated work-up and early treatment. With time as we analyze more cases of LCNEC, our understanding of the cancer will improve. This will pave the way for better treatment and better prognosis in patients suffering from LCNEC. REFERENCE #1: Berry, M. F. (2020). Approach to the adult patient with a mediastinal mass. UpToDate. https://www-uptodate-com.mwu.idm.oclc.org/contents/approach-to-the-adult-patient-with-a-mediastinal-mass?search=Approach%20to%20the%20adult%20pateint%20with%20a%20mediastinal%20mass&source=search_result&selectedTitle=1˜150&usage_type=default&display_rank=1 REFERENCE #2: Glisson, B. S. (2020). Large cell neuroendocrine carcinoma of the lung. UpToDate. https://www-uptodate-com.mwu.idm.oclc.org/contents/large-cell-neuroendocrine-carcinoma-of-the-lung?search=Large Cell Neuroendocrine Carcinoma of the Lung&source=search_result&selectedTitle=1˜16&usage_type=default&display_rank=1 REFERENCE #3: Tazelaar, H. D. (n.d.). Pathology of lung malignancies. UpToDate. https://www-uptodate-com.mwu.idm.oclc.org/contents/pathology-of-lung-malignancies?search=Pathology of lung malignancies&source=search_result&selectedTitle=1˜150&usage_type=default&display_rank=1 DISCLOSURES: No relevant relationships by Andriana Saric, source=Web Response

Genomic and immunologic characterization of large-cell neuroendocrine carcinoma of the lung.

8535 Background: Large-cell neuroendocrine carcinoma (LCNEC) is a rare type of lung cancer with a poor prognosis. Due to its rarity, molecular characterization of LCNEC is not well elucidated. We aim to understand the genomic and immunologic landscape of LCNEC to identify molecular alterations and relevant biological pathways with potential therapeutic value. Methods: Comprehensive profiling including whole exome sequencing (WES), next-generation sequencing (NGS), whole transcriptome sequencing (WTS), and immunohistochemistry (IHC) for PD-L1 was performed (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations. LCNEC was categorized as small cell lung cancer (SCLC)-like LCNEC ( TP53/ RB1 co-mutated) and non-small-cell lung cancer (NSCLC)-like LCNEC (wild type for one or both of TP53/ RB1). Molecular features of LCNEC were compared among the subgroups and with those of SCLC using the χ2 test with Benjamini & Hochberg correction. Results: A total of 467 cases of LCNEC were included. Commonly altered genes (≥ 5%) included TP53 (79.1%), RB1 (36.8%), SMARCA4 (10.4%), ARID1A (10.3%), KRAS (9.7%), KEAP1 (9.2%), KMT2D (8.7%), STK11 (8.4%), NF1 (7.1%), PTEN (6.1%), and CDKN2A (5.9%) . The prevalence of potentially actionable mutations was as follows: EGFR exon 19 deletion (0.48%), EGFR L858R (0.48%), ALK fusion (1.7%), KRAS G12C (2.9%). EGFR exon 19 deletion, EGFR L858R, and ALK fusion were exclusive to NSCLC-like LCNEC tumors. RET fusion, NTRK fusion and BRAFV600E were not detected. Copy number alterations (CNAs) were found in MYC (8.8%), ZNF703 (4.1%), FOXA1 (4.0%), FGFR1 (4.0%), ATK2 (3.9%), CCNE1 (3.7%), FGF19 (3.4%), TNFRSF14 (3.4%), and CCND1 (2.7%). Over-expression of cMET was noted in 10% and PD-L1 expression (by 22C3 pharmDx) of > 1% was noted in 21.5% of samples. WTS detected cMET exon 14 skipping mutations in 2.4% of samples. High tumor mutation burden (TMB; ≥ 10 Mut/MB) was seen in 40.6%. Among the 467 cases of LCNEC, 112 (24%) were SCLC-like LCNEC and 335 (76%) NSCLC-like LCNEC. Mutations in KRAS (12%), STK11 (11%), CDKN2A (9%), and SMARCA4 (14%) were more common in NSCLC-like LCNEC, compared with SCLC-like LCNEC (p value < 0.05). 442 cases of SCLC were compared with LCNEC tumors. SLFN11:SLFN12 fusion events, detected by WTS, were exclusively seen in SCLC and were not seen in any of the LCNEC cases. Gene expression profiles revealed that 1) B cell infiltration was higher in SCLC-like LCNEC, compared with SCLC, and 2) NK and T cell infiltration was lower, but B-cell infiltration was higher in NSCLC-like LCNEC, compared with SCLC. Conclusions: LCNEC displays a broad pattern of genomic alterations that overlap in the SCLC-like subset with the classic alterations in SCLC. The distinct genomic alterations and transcriptomic profiles present opportunities for therapeutic targeting and inform a future framework for development of therapeutics for LCNEC.

Improving differential diagnosis of pulmonary large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer via a transcriptomic, biological pathway-based ridge regression model.

3065 Background: In clinics, it can be challenging to make correct diagnosis of LCNEC, Small cell lung cancer (SCLC), if tissues, like needle biopsies, are insufficient or morphology was poorly preserved. In this study, a reliable classifier was constructed based on transcriptome data and machine learning (Ridge regression) to improve the diagnostic accuracy for LCNEC and SCLC. Methods: RNA-Seq data obtained from 3 public cohorts were collected as training set, including 60 NSCLC cases from The Cancer Genome Atlas (TCGA), 66 LCNEC cases from Julie George et al., Nature Communications 2018, and 33 SCLC cases from Julie George et al., Nature 2015. Another 80 NSCLC, 30 LCNEC and 15 SCLC cases published by Martin Peifer et al., Nature Genetics 2012 were used as validation set. Additionally, RNA-Seq data of 27 borderline samples which were hard to make diagnosis based on histology and Immunohistochemistry were used to test the accuracy of the prediction model. Results: 13,959 genes mapped to 186 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were included. Gene Set Variation Analysis (GSVA) algorithm was used to enrich and score each KEGG pathway. A prediction model based on GSVA score of each pathway was constructed via Ridge regression. This GSVA Score Model achieved ROC-AUC 0.949 and concordant rate of 0.75 for the entire prediction efficiency. Of the 27 borderline samples which were hard to make confirmed diagnosis, 17/27 (63.0%) were predicted as LCNEC, 7/27 were predicted as SCLC, and the remainder were predicted as NSCLC. While only 8 (29.6%) cases with LCNEC were diagnosed by pathologists, which was significantly lower than the results predicted by the model. Furthermore, cases with model predicted LCNEC had a significant longer disease-free survival than that with model predicted SCLC (median DFS,59 months for LCNEC vs 5 months for SCLC, p = 0.0043), which was in parallel with currently known prognostic difference of these two types of neuroendocrine tumors. Conclusions: This GSVA algorithm-based prediction model was able to make accurate diagnosis of LCNEC and SCLC. And it may provide valuable information for clinics to choose optimal therapeutic approach for patients with pulmonary neuroendocrine tumors.[Table: see text]

Role of Immunotherapy in Stage IV Large Cell Neuroendocrine Carcinoma of the Lung.

Background:Despite approvals of immune checkpoint inhibitors in both small cell and non-small cell lung cancers, the role of immunotherapy in large cell neuroendocrine carcinoma (LCNEC) in lung is undefined. Methods:Using the National Cancer Database (NCDB), Stage IV lung LCNEC cases diagnosed from 2014 to 2016 were analyzed. Information regarding cancer treatment was limited to first course of therapy, including surgery for primary lesion, radiation, chemotherapy, and immunotherapy. Survival analysis was performed using Kaplan-Meier curves and Log-rank tests. Cox proportional hazard model was used for multivariate analysis. Results:Among 661 eligible cases, 37 patients were treated with immunotherapy. No significant association between use of immunotherapy and clinical demographics was observed except for use of chemotherapy (p=0.0008). Chemotherapy was administered in 34 (92%) and 406 (65%) in immunotherapy and non-immunotherapy groups, respectively. Use of immunotherapy was associated with improved overall survival (Log-rank p=0.0018). Landmark analysis in the immunotherapy group showed 12 and 18-month survivals of 34.0% and 29.1%, respectively, whereas those in the non-immunotherapy group were 24.1% and 15.0%, respectively. Multivariate analysis demonstrated that female sex (HR=0.79, p=0.0063), liver metastases (HR=0.75, p=.0392), surgery (HR= 0.50, p<0.0001) use of chemotherapy (HR= 0.44, p<0.0001), and use of immunotherapy (HR=0.64, p=0.0164) had statistical significance. Propensity score matching in overall survival analysis showed a nonsignificant trend (p=0.0733) in favor of immunotherapy treatment. Conclusion:This retrospective study using NCDB suggests that use of immunotherapy may improve survival of LCNEC patients.

SMARCA4 (BRG1) and SMARCB1 (INI1) expression in TTF-1 negative neuroendocrine carcinomas including merkel cell carcinoma

SMARCA4 and SMARCB1 loss of function has been implicated in many different tumors. The objective of this study was to investigate the loss of BRG1 and INI1 expression in TTF-1 negative neuroendocrine carcinomas to see if they are analogous to small-cell carcinoma of the ovary, hypercalcemic type. The potential role of these tumor suppressor genes in high-grade neuroendocrine carcinoma largely remains unknown. Cases of previously diagnosed Small cell carcinoma (SmCC), Large cell neuroendocrine carcinoma (LCNEC) and Merkel cell carcinoma (MCC) were selected. Immunohistochemical expression patterns for BRG1 and INI1 were interpreted as: intact, hybrid and complete loss of nuclear staining. SmCC and LCNEC cases were divided as TTF-1 positive and TTF-1 negative subsets. One case of TTF-1 negative SmCC (lung) showed loss of SMARCA4(BRG1) expression. Amongst TTF-1 negative LCNEC, one case (lung) showed complete loss of SMARCA4(BRG1) and partial loss of SMARCB1(INI1) and one case (lymph node) had hybrid expression of SMARCA4(BRG1) with intact SMARCB1(INI1) expression. All TTF-1 positive cases and all MCC cases showed intact expression of SMARCA4(BRG1) and SMARCB1(INI1). Our study highlights that SMARCA4(BRG1) is deficient in a subset of NEC. Inactivation of SMARCA4 in a subset of TTF-1 negative neuroendocrine carcinomas especially of pulmonary site can be further studied for their therapeutic response to targeted therapy e.g. EZH2 inhibitors. In addition, our study is the first to show that BRG1 and INI1 expression are intact in MCC and hence the biology of MCC might be completely exclusive of these two tumor suppressor genes.

Outcomes for localized treatment of large cell neuroendocrine carcinoma of the lung in the United States.

BackgroundTreatment paradigms for large cell neuroendocrine carcinoma (LCNEC) of the lung are based largely upon small retrospective studies and smaller prospective trials. It is unclear if these tumors behave like non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). Data are lacking with regard to the role of radiotherapy (RT). U. S. guidelines recommend that LCNEC be treated as a NSCLC. We sought to perform a cross-sectional study of LCNEC cases to understand treatment paradigms and outcomes in this disease.MethodsThe Surveillance, Epidemiology and End Results database was queried for cases of stage I–III pulmonary LCNEC diagnosed 2004–2013. Treatment groups were defined as no surgery, RT alone, surgery alone, and surgery + RT. The Cox-proportional hazards regression model was used to compare overall survival and cause-specific survival (OS/CSS), stratified by AJCC 6th Staging. Factors that were significant on univariable analysis were included in multivariable analysis.ResultsWe identified 1,523 cases of LCNEC, with 748, 177, and 598 cases of stage I, II, and III disease, respectively. In stage I and II disease, RT was associated with improved survival for non-surgical patients, but not for those who underwent surgery. In stage I disease, the adjusted hazard ratios for OS for RT alone, surgery, and surgery + RT were 0.39, 0.21, and 0.22, respectively (P<0.001). In stage II disease, the adjusted hazard ratios for RT alone, surgery, and surgery + RT were 0.51 (P=0.15), 0.39 (P=0.004), and 0.38 (P=0.01), respectively. For patients with stage III disease, RT was associated with improved survival in surgical and non-surgical patients. The adjusted hazard ratios for RT alone, surgery, and surgery + RT were 0.49, 0.43, and 0.36, respectively (P<0.001).ConclusionsOur findings indicate that non-metastatic LCNEC may be treated as a NSCLC with respect to RT. Prospective studies are necessary to increase our understanding of optimal treatment regimens.

Five Cases of Large-cell Neuroendocrine Carcinoma of the Lung Treated with Nivolumab

Five Cases of Large-cell Neuroendocrine Carcinoma of the Lung Treated with Nivolumab

TTF-1 and c-MYC-defined Phenotypes of Large Cell Neuroendocrine Carcinoma and Delta-like Protein 3 Expression for Treatment Selection.

The standard treatment regimen has not yet been established for advanced pulmonary large cell neuroendocrine carcinoma (LCNEC) because of its rarity. LCNEC can be subdivided into 2 mutually exclusive molecular subgroups: STK11/KEAP1 and TP53 mutated with high neuroendocrine expression and transcriptional profile of ASCL1high/DLL3high/NOTCHlow (non–small cell lung carcinoma, NSCLC-like) or RB1 and TP53 mutated with reduced neuroendocrine markers and transcriptional pattern of ASCL1low/DLL3low/NOTCHhigh (small cell lung cancer, SCLC-like). Model-based clustering shows that SCLC has subdivided into 2 major proteomic subsets defined by either TTF-1high/c-MYClow or TTF-1low/c-MYChigh, which may correspond to 2 mutually exclusive molecular subgroups: NSCLC-like or SCLC-like, respectively. We herein investigated whether TTF-1 and c-MYC could be applied to LCNEC to identify distinct subsets immunohistochemically and assessed DLL3 expression in these subsets. The protein expression profile may be useful to select patients for potential efficacy of targeted therapies including aurora kinase inhibitors for MYC alterations or anti-DLL3 antibody-drug conjugates. TTF-1 and c-MYC expression was mutually exclusive in 25 of 27 (93%) cases; TTF-1+/c-MYC- in 10, TTF-1−/c-MYC+ in 15, and TTF-1+/c-MYC+ in 2. DLL3 expression was seen in 15 of 27 cases (56%). All 12 TTF-1+ LCNEC cases were positive for DLL3. Three of 15 (20%) TTF-1−/c-MYC+ cases showed DLL3 positivity. LCNEC could be separated into 2 subsets proteomically defined by TTF-1 and c-MYC expression, which may be suitable to guide treatment selection including aurora kinase inhibitors for c-MYC+ cases. TTF-1 positivity can serve as a surrogate marker for DLL3, but caution is necessary as 20% of TTF-1− cases showed DLL3 positivity.

Feasibility of a deep learning algorithm to distinguish large cell neuroendocrine from small cell lung carcinoma in cytology specimens.

Distinguishing small cell lung carcinoma (SCLC) from large cell neuroendocrine carcinoma (LCNEC) in cytology is challenging. Our aim was to design a deep learning algorithm for classifying high-grade neuroendocrine carcinomas in fine needle aspirations. Archival cytology cases of high-grade neuroendocrine carcinoma (17 small cell, 13 large cell, 10 mixed/unclassifiable) were retrieved. Each case included smears (Diff-Quik® and Papanicolaou stains) and cell block or concomitant core biopsies (haematoxylin and eosin [H&E] stain). All slides (n=114) were scanned at 40× magnification, randomised and split into training (11 large, nine small) and test (two large, eight small, 10 mixed) groups. Tumour was annotated using QuPath and exported as JPEG image tiles. Three distinct deep learning convolutional neural networks, one for each preparation/stain, were designed to classify each tile and provide an overall diagnosis for each slide. The H&E-trained algorithm correctly classified 7/8 (87.5%) SCLC cases and 2/2 (100%) LCNEC cases. The Papanicolaou stain algorithm correctly classified 6/7 (85.7%) SCLC. and 1/1 (100%) LCNEC cases. The algorithm trained on Diff-Quik® stained images correctly classified 7/8 (87.5%) SCLC and 1/1 (100%) LCNEC cases. Using open source software, it was feasible to design a deep learning algorithm to distinguish between SCLC and LCNEC. The algorithm showed high precision in distinguishing between these two categories on H&E sectioned material and direct smears. Although the dataset was limited, our deep learning models show promising results in the classification of LCNEC and SCLC. Additional work using a larger dataset is necessary to improve the algorithm's performance.

Role of immunotherapy in stage IV large cell neuroendocrine carcinoma of the lung.

9060 Background: Despite approvals of immune checkpoint inhibitors in both small cell and non-small cell lung cancers, role of immunotherapy in large cell neuroendocrine carcinoma (LCNEC) in lung is undefined. Methods: Using National Cancer Database (NCDB), Stage IV LCNEC cases diagnosed in 2014-2016 with at least 30-day follow up were analyzed. Clinical demographics included age (20-69 vs. 70+), sex (male vs. female), race (whites vs. others), insurance (uninsured vs. others), institution (academic vs. others), Charlson-Deyo score (0-1 vs. 2-3), brain metastasis (Yes vs. No), liver metastasis (Yes vs. No). Information regarding cancer treatment was limited to first course of therapy, including surgery for primary lesion (Yes vs. No), radiation (Yes vs. No), chemotherapy (Yes vs. No), and immunotherapy (Yes vs. No). Survival analysis was performed using Kaplan-Meier curves and Log-rank tests. Cox proportional hazard model was used for multivariate analyses. A two-sided p-value &lt; 0.05 was considered as significant. Results: Among 661 eligible cases, 37 patients were treated with immunotherapy. No significant association between use of immunotherapy and clinical demographics was observed except for use of chemotherapy (p = 0.0008). Chemotherapy was administered in 34 (92%) and 406 (65%) of cases in immunotherapy and non-immunotherapy groups, respectively. Use of immunotherapy was associated with improved overall survival (Log-rank p = 0.0168). Landmark analysis in the immunotherapy group showed 12 and 18-month survival of 34.0% and 29.1%, respectively, as compared with 24.1% and 15.0% in the non-immunotherapy group Multivariate analysis demonstrated that female sex, presence of liver metastases, surgery, use of chemotherapy and immunotherapy (HR = 0.64, p = 0.0164) had significantly improved survival. Propensity score matching in overall survival showed a nonsignificant trend (p = 0.0733) in favor of immunotherapy group. Conclusions: This retrospective study using one of the largest cancer databases suggests that use of immunotherapy may improve survival of LCNEC patients. Prospective studies are warranted for further validation.

Large cell neuroendocrine carcinoma of the lung that responded to nivolumab: A case report.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare type of lung cancer, accounting for 3% of all lung cancers. The prognosis is poor and the standard therapy has not been well established. Herein, we report a case of advanced LCNEC of the lung that responded to nivolumab. The patient was a 62-year old man with stage IVB LCNEC of the lung. The disease progressed following the administration of second-line chemotherapy, and he was treated with nivolumab 3 mg/kg as the third-line treatment. Although treatment was ceased after two cycles due to interstitial pneumonia, the disease remained stable for approximately six months under observation. There was no other adverse event related to nivolumab. Following patient mortality from tumor progression, PD-L1 expression was observed to be negative (tumor proportion score <1%) by a re-examination of the primary biopsy specimen. The case herein suggests that nivolumab may be a possible treatment option for LCNEC.

Outcomes of Patients with Clinical Stage I-IIIA Large-Cell Neuroendocrine Lung Cancer Treated with Resection.

Large-cell neuroendocrine carcinoma (LCNEC) is a rare malignancy with poor prognosis. The rationale of the study was to determine the survival of LCNEC patients in I–IIIA clinical stages who underwent resection. A total of 53 LCNEC (89%) and combined LCNEC (11%) patients in stages I–IIIA who underwent surgery with radical intent between 2002–2018 were included in the current study. Overall survival (OS) and time to recurrence (TTR) were estimated. Uni- and multivariable analyses were conducted using Cox-regression model. Patients were treated with surgery alone (51%), surgery with radiochemotherapy (4%), with radiotherapy (2%), with adjuvant chemotherapy (41%), or with neoadjuvant chemotherapy (2%). The median (95% Confidence Interval (CI)) OS and TTR was 52 months (20.1–102.1 months) and 20 months (7.0–75.6 months), respectively. Patients treated in clinical stage I showed better OS than patients in stages II–IIIA (p = 0.008). Patients with R0 resection margin (negative margin, no tumor at the margin) and without lymph node metastasis had significantly better TTR. In the multivariate analysis, age was an independent factor influencing OS. Recurrence within 1 year was noted in more than half cases of LCNEC. R0 resection margin and N0 status (no lymph node metastasis) were factors improving TTR. Age >64 years was observed as a main independent factor influencing OS.

Secretagogin, a marker for neuroendocrine cells, is more sensitive and specific in large cell neuroendocrine carcinoma compared with the markers CD56, CgA, Syn and Napsin A.

A common method to distinguish large cell neuroendocrine carcinoma (LCNEC) from non-neuroendocrine large cell carcinoma (non-NE LCC) is from using specific immunohistochemistry markers, such as CgA, Syn, CD56 and Napsin A, however, the results remain controversial using these markers. Secretagogin (SCGN) is a newly discovered biomarker of neuroendocrine cells. In the present study, the expression of SCGN in 33 cases of human lung large cell carcinoma (LCC), including 17 cases of LCNEC and 16 cases of non-neuroendocrine (NE) LCC and lung cancer cell lines (A549, H1650, H358, H292 and H661). The association between SCGN expression and the clinicopathological characteristics of patients, including sex, age, clinical stage and metastasis, was analyzed. The results revealed that the different lung cancer cell lines had different expression levels of SCGN, and the SCGN protein was localized in the nucleus and cytoplasm of A549 cells detected using immunofluorescence. A total of 54.5% (18/33) of specimens positively expressed the SCGN protein. Of the 17 patients with LCNEC, only 23.5% (4/17) of cases were CgA positive, 35.29% (6/17) were Syn positive, 41.2% (7/17) were CD56 positive, and 41.2% (7/17) were Napsin A positive. However, SCGN was positively detected in 94.1% (16/17) of patients with LCNEC, which was more frequent compared with that in CgA, Syn, CD56 and Napsin A. Analysis of the clinical characteristics indicated that SCGN expression was only significantly associated with pathological type in patients with lung cancer (P<0.001). Furthermore, a positive correlation was observed between SCGN expression and CgA, Syn, and CD56 expression in patients with LCNEC. SCGN was co-localized with the NE markers (CgA, Syn, and CD56) in A549 lung cancer cells and in LCNEC tissues. Thus, SCGN displayed more sensitivity and specificity in lung cancer cells with NE differentiation. A combined analysis of SCGN and other common NE markers may be a potential tool for diagnosing these tumors.

Large Cell Neuroendocrine Tumor of the Lung: A Diagnostic Challenge

Lung neuroendocrine carcinoma (NEC) is a rare heterogeneous carcinoma with NE cells in the pulmonary and bronchial epithelium as the site of origin. We describe a case of large cell NEC (LCNEC) in a 55-year-old male, smoker with 25 pack-years, who presented with cough, dyspnea, hemoptysis, and loss of appetite for 6 months. There was no diabetes, hypertension, asthma, chronic obstructive pulmonary disease, tuberculosis, or contact with tuberculosis or malignancy. The presence of a large homogenous mass lesion in the right chest on chest X-ray, further clearly defined on chest computed tomography scan (130/94/123 mm) was suggestive of huge mass. There was no mediastinal or pleural involvement. Possibility of LCNEC was suspected as the ultrasound-guided biopsy was indicating the presence of poorly differentiated carcinoma. Immunohistochemistry was negative for thyroid transcription factor, cytokeratin 7 but was positive for synaptophysin and P40, suggestive of high-grade LCNECs. It was in T4N0M0, stage 3A and treatment with combination chemotherapy was initiated.