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Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare but aggressive malignancy of the lung. Its nonspecific presentation and propensity for severe disease at the time of diagnosis create challenges in treatment. We report a case of an asymptomatic 61-year-old female who was incidentally found to have a pulmonary nodule after a fall. Upon further workup, she was found to have an aggressive LCNEC. The patient underwent a robotic-assisted left upper lobectomy, which was complicated by left lower lobe bronchus kinking and post-obstructive atelectasis, warranting further management by thoracic surgery. The patient additionally underwent video-assisted thoracoscopic surgery (VATS), open thoracotomy, pneumopexy, and bronchial stenting. This case highlights the need for strategies for early detection in at-risk populations. A multidisciplinary approach, which may involve both medical and surgical subspecialties, is essential in the management of this complex disease from the time of diagnosis to follow-up postoperatively to achieve the best clinical outcome.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) presents significant treatment challenges due to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC.
METHODS: In this non-randomized study, patients with metastatic LCNEC were prospectively enrolled and assigned to receive either standard chemotherapy plus atezolizumab followed by maintenance with atezolizumab or standard chemotherapy alone. The primary outcomes measured were 12- and 24-month survival rates, progression-free survival (PFS), and overall survival (OS) between the two groups.
RESULTS: Of the 22 patients screened, 17 met the inclusion criteria and received either atezolizumab plus platinum-based chemotherapy (n = 10) or chemotherapy alone (n = 7). After a median follow-up of 23.3 months, the 12-month survival rate was 57.1% (95% CI: 32.6-100%) and 14.3% (95% CI: 2.33-87.7%) for the atezolizumab and the chemotherapy-only groups, respectively. The survival benefit for the atezolizumab group was sustained at 24 months (45.7% vs. 14.3%). Overall survival was significantly higher for the atezolizumab group, and PFS was non-significantly associated with the addition of atezolizumab (log-rank p = 0.04 and 0.05, respectively).
CONCLUSIONS: This pilot study suggests that the addition of atezolizumab to standard platinum-based chemotherapy may provide a substantial survival benefit compared with chemotherapy alone in the first-line treatment of metastatic LCNEC.

Primary bladder large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive neoplasm with high recurrence rates and poor prognosis. Traditional management has heavily relied on radical cystectomy, which, despite its aggressiveness, often results in unsatisfactory outcomes. Emerging evidence suggests the potential for less invasive, bladder-sparing approaches, yet detailed reports and long-term outcomes remain scarce. We report a groundbreaking case of a 59-year-old male diagnosed with primary bladder LCNEC, managed through a pioneering bladder-sparing multimodal treatment. This novel strategy included transurethral resection followed by a tailored chemoradiation protocol, resulting in exceptional disease control and preservation of bladder function over a 20-month follow-up period, without evidence of recurrence. This case underscores the viability of bladder conservation strategies as a legitimate alternative to radical cystectomy for managing LCNEC, presenting a beacon of hope for patients wishing to preserve bladder functionality. It prompts a reevaluation of traditional treatment paradigms and advocates for further research into multimodal, organ-sparing approaches for this challenging malignancy.

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BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) represents an exceptionally aggressive and infrequent variant within the realm of non-small cell lung cancer, necessitating surgical intervention as the primary therapeutic approach. However, the postoperative management strategy for early-stage patients continues to be a subject of intense debate and uncertainty.
METHODS: A retrospective analysis was conducted on a cohort of patients diagnosed with LCNEC who underwent surgical resection at Shanghai Pulmonary Hospital between July 2018 and June 2022. Comprehensive assessments, encompassing univariate and multivariate analyses, were performed to evaluate the prognostic significance of these indicators in patient clinical profiles, overall survival (OS), and disease-free survival (DFS).
RESULTS: A comprehensive screening effort identified 171 patients with LCNEC, with 70 stage I patients meeting the criteria for inclusion in the final cohort. Of these, 11 patients (15.7%) presented with combined LCNEC, and 59 (84.3%) exhibited pure LCNEC. Univariate and multivariate analyses both unveiled that spread through air spaces (STAS) status emerged as an independent prognostic determinant for both DFS (P = .003) and OS (P = .013), whereas histologic subtype independently predicted OS (P = .011). Subgroup survival analyses further underscored that the advantageous effects of postoperative chemotherapy were significantly pronounced exclusively among STAS-positive patients, showcasing a statistically significant enhancement in DFS (P = .047) and OS (P = .018).
CONCLUSIONS: STAS may serve as an adverse prognostic factor in stage I LCNEC patients, potentially offering guidance for postoperative chemotherapy decisions.

Little is known as to whether there may be any pathogenetic link between pulmonary carcinoids and neuroendocrine carcinomas (NECs). A gene signature we previously found to cluster pulmonary carcinoids, large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), and which encompassed MEN1, MYC, MYCL1, RICTOR, RB1, SDHA, SRC and TP53 mutations or copy number variations (CNVs), was used to reclassify an independent cohort of 54 neuroendocrine neoplasms (NENs) [31 typical carcinoids (TC), 11 atypical carcinoids (AC) and 12 SCLC], by means of transcriptome and mutation data. Unsupervised clustering analysis identified two histology-independent clusters, namely CL1 and CL2, where 17/42 (40.5%) carcinoids and all the SCLC samples fell into the latter. CL2 carcinoids affected survival adversely, were enriched in T to G transversions or T > C/C > T transitions in the context of specific mutational signatures, presented with at least 1.5-fold change (FC) increase of gene mutations including TSC2, SMARCA2, SMARCA4, ERBB4 and PTPRZ1, differed for gene expression and showed epigenetic changes in charge of MYC and MTORC1 pathways, cellular senescence, inflammation, high-plasticity cell state and immune system exhaustion. Similar results were also found in two other independent validation sets comprising 101 lung NENs (24 carcinoids, 21 SCLC and 56 LCNEC) and 30 carcinoids, respectively. We herein confirmed an unexpected sharing of molecular traits along the spectrum of lung NENs, with a subset of genomically distinct aggressive carcinoids sharing molecular features of high-grade neuroendocrine neoplasms.

Background: Large Cell Neuroendocrine Carcinoma (LCNEC) is a high-grade malignancy with limited treatment options. Despite promising results of immunotherapy in non-small cell and small cell lung cancers, its benefit in LCNEC remains elusive. Methods: We included 24 patients diagnosed with stage IV LCNEC from the Moffitt Cancer Center database who received systemic therapy between January 2016 and May 2021. Group A comprised patients who received first-line CT and ICI (anti-PD-1 or anti-PD-L1 therapy for ICI, n = 11), and Group B received first-line CT only (n = 13). The collected data encompassed overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicities since treatment initiation. Results: Kaplan-Meier survival analysis revealed median OS was 56 weeks (95%CI = 22.2-89.8) and 28 weeks (95% CI=16.3-39.7) in groups A and B, respectively. Log-rank test showed the difference was statistically significant (p=0.029). Median PFS was 32 weeks (95%CI=14.7-49.3) in group A and 20 weeks (95% CI=13.8-26.2) in groups B, but the difference was not statistically significant (p= 0.136). Univariate Cox analysis confirmed that the addition of ICI to CT significantly improved OS in patients with stage IV LCNEC (HR=0.35, 95% CI=0.13-0.95, p = 0.039). The ORR (63.6% vs 45.4%, p= 0.670) and DCR (81.8% vs 63.6%, p= 0.635) tended to be higher in group A than in group B but the difference was not statistically significant. Importantly, the combined treatment demonstrated a satisfactory safety profile, with only two patients reporting grade 2 or higher adverse events. Conclusions: Our results suggest that the combination of immunotherapy with chemotherapy holds potential for improving outcomes in stage IV LCNEC. Despite the retrospective nature and limited sample size of our study, these preliminary findings provide a valuable insight into the potential of immunotherapy in LCNEC treatment and encourage further research through larger, prospective trials.

There is a clear need to expand the toolkit of adequate mouse models and cell lines available for preclinical studies of high-grade neuroendocrine lung carcinoma (small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC)). SCLC and LCNEC are two highly aggressive tumor types with dismal prognoses and few therapeutic options. Currently, there is an extreme paucity of material, particularly in the case of LCNEC. Given the lack of murine cell lines and transplant models of LCNEC, the need is imperative. In this study, we generated and examined new models of LCNEC and SCLC transplantable cell lines derived from our previously developed primary mouse LCNEC and SCLC tumors. RNA-seq analysis demonstrated that our cell lines and syngeneic tumors maintained the transcriptome program from the original transgenic primary tumor and displayed strong similarities to human SCLC or LCNEC. Importantly, the SCLC transplanted cell lines showed the ability to metastasize and mimic this characteristic of the human condition. In summary, we generated mouse cell line tools that allow further basic and translational research as well as preclinical testing of new treatment strategies for SCLC and LCNEC. These tools retain important features of their human counterparts and address the lack of LCNEC disease models.

BACKGROUND: Combined large cell neuroendocrine carcinoma (C-LCNEC) has a poor prognosis and there is no consensus about the treatment regimen for both LCNEC and C-LCNEC patients.
METHODS: The patient was a 47-year-old female who received surgical resection. The postoperative histology and staging of the tumor suggested C-LCNEC with adenocarcinoma and squamous cell carcinoma and T2aN0M0 stage IB. Next-generation sequencing test showed KIF5B/RET fusion mutation without EGFR, ALK, RB1, and TP53 alterations. Adjuvant chemotherapy with 4-cycle docetaxel plus carboplatin was given and brain metastasis occurred after 10 months.
CONCLUSIONS: C-LCNEC with adenocarcinoma and squamous cell carcinoma is rare and highly aggressive cancer. Surgical resection and adjuvant chemotherapy with SCLC regimen may improve the disease-free survival and overall survival. The accumulation of similar cases will clarify the profile and management of the disease.