Exploring the molecular features and genetic prognostic factors of pulmonary high-grade neuroendocrine carcinomas.

Molecular research on large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC) has progressed significantly. However, there are still fewer molecular markers related to prognostic/therapeutic strategies for these conditions compared to those for adenocarcinoma. We therefore investigated the molecular characteristics of neuroendocrine carcinomas (NECs). We enrolled patients surgically diagnosed with NECs between 2011 and 2019, with complete follow-up records. All were analyzed using whole exome sequencing and p53/Rb immunohistochemistry (IHC). A total of 92 cases, comprising 45 pure SCLC, 15 combined SCLC, 27 pure LCNEC, and 5 combined LCNEC, were included. TP53 (78.3%) and RB1 (34.8%) were the most common molecular alterations, followed by KMT2D, LRP1B, FAT3, NCOR2, SPTA1, and NOTCH1. The mutation frequency for EGFR was 10.9%. Sixteen patients with LCNEC who had TP53/RB1 co-alterations were SCLC-like, while the remaining were NSCLC-like. There was no statistically significant difference between the groups regarding overall survival (OS; p = 0.458) and progression-free survival (PFS; p = 0.157). The frequency of the loss of Rb expression by IHC in SCLC-like LCNEC was 100%. Significant pathway alterations unique to SCLC included Notch and AMPK, while HIF-1 was enriched exclusively in LCNEC. NCOR2 mutation was linked to worse OS (p = 0.029) and PFS (p = 0.015), while wild-type SPTA1 was associated with poor PFS (p = 0.018). IHC for Rb was reliable for predicting LCNEC molecular subtypes, indicating its clinical value. NCOR2 and SPTA1 alterations were identified as prognostic factors that may provide therapeutic targets for patients with NEC.

Pulmonary large cell neuroendocrine carcinoma (LCNEC): a population-based study addressing recent molecular-genetic advances and emerging therapeutic approaches.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) of the lung is a rare, aggressive cancer most commonly found in the lungs but not exclusively, with a worse prognosis than non-small cell lung carcinomas. Currently, LCNEC patients are treated using small cell and non-small cell protocols. This study aims to use the SEER database to identify demographic, clinical, pathological, and therapeutic factors affecting the prognosis and survival of patients with LCNEC of the lung. METHODS: Demographic, clinical, and management data of patients with lung LCNEC were extracted from the SEER database for the period 2000-2018. RESULTS: In the USA, LCNEC has a higher incidence in elderly white men: M:F ratio = 1.2:1, Caucasian: 83.3%, mean age: 67 ± 10.2 years. The most common treatment modality was chemotherapy only: 29.2%, followed by surgery: 21.5% (but in this group the statuses of chemotherapy were unknown), and combination surgery/chemotherapy: 8.8%. The overall and cause-specific 5-year survival was 17.5% (95% CI 16.3-18.8) and 21.9% (95% CI 20.5-23.4), respectively. By treatment, the best 5-year survival was for surgery alone (48%), followed by multimodality therapy (chemo + surgery + radiation) at 35% (95% CI 27-43). Age > 60 years, male gender, size > 7 cm, and nodal and liver metastasis were independent risk factors associated with increased mortality. CONCLUSION: Lung LCNEC is an aggressive neoplasm most common in older white males that presents at an advanced stage despite small primary tumors. Most patients die within 2 years. The best predictor of survival is surgery with chemotherapy. Given its dismal prognosis, new treatment guidelines are needed for this aggressive cancer.

Integrated pathological analysis to develop a Gal-9 based immune survival stratification to predict the outcome of lung large cell neuroendocrine carcinoma and its usefulness in immunotherapy.

This study aimed to integrate the cell spatial organization to develop a Gal-9-based immune survival stratification in the lung large cell neuroendocrine carcinoma (LCNEC) and investigate its potentials to immunotherapy. The expression of Gal-9 and other twelve immune markers were evaluated in 122 cases of surgical LCNEC samples from our center using immunohistochemistry. The Gal-9-based immune survival stratification risk score was constructed and its predictive performance was evaluated. Then, we thoroughly explored the effects of Gal-9 and immune risk score on LCNEC immune pathways, immune micro-environment and immunotherapy sensitivity in different cohort and platform, and made a validation in pathology images using Histology-based Digital-Staining (HDS). In 122 LCNEC samples, 43 cases were positive Gal-9 expression on tumor cells (Gal-9 TC). Increased Gal-9 TC predicted worse overall survival. Gal-9's interaction with other immune markers added to the immune suppression and immune tolerance in LCNEC. Immune protein marker-based risk score consisting of Gal-9, CD3, CD4, PD-L1, and PD-1 was developed and validated to robustly discriminate survival high-risk or low-risk in LCNEC patients. The high-risk group characterized by immune-desert tumor had less various T cells. The low-risk group featuring immune-inflamed tumor was more likely to respond to anti-PD1 immunotherapy. HDS in 122 LCNEC samples' 108,369 cells validated that the high-risk group had more tumor cells, less stromal cells, less lymphocytes, higher tumor cell nucleic solidity and lower stromal cells nucleic solidity. An integrated pathological analysis confirms the Gal-9 based immune survival stratification is distinctively related to micro-environment status involved in immune suppression and immune tolerance and could act as a combinatorial biomarker to predict the outcome of LCNEC. These findings may help effectively stratify LCNEC patients sensitive to immunotherapy.

Clinicopathological characteristics and survival outcomes of patients with large cell neuroendocrine carcinoma of the uterine cervix: A systematic review and meta-analysis.

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.

Large cell neuroendocrine lung carcinoma: consensus statement from The British Thoracic Oncology Group and the Association of Pulmonary Pathologists.

Over the past 10 years, lung cancer clinical and translational research has been characterised by exponential progress, exemplified by the introduction of molecularly targeted therapies, immunotherapy and chemo-immunotherapy combinations to stage III and IV non-small cell lung cancer. Along with squamous and small cell lung cancers, large cell neuroendocrine carcinoma (LCNEC) now represents an area of unmet need, particularly hampered by the lack of an encompassing pathological definition that can facilitate real-world and clinical trial progress. The steps we have proposed in this article represent an iterative and rational path forward towards clinical breakthroughs that can be modelled on success in other lung cancer pathologies.

Survival and prognosis of lung large cell neuroendocrine carcinoma.

INTRODUCTION: Only a few large-scale studies have focused on large cell neuroendocrine carcinoma, a rare type of pulmonary malignancy, and uniform diagnostic criteria and standardized treatments are lacking. This study aimed to assess the treatment outcomes and factors influencing patients' prognosis with large cell neuroendocrine carcinoma. METHODS: The data of 55 patients with pathologically confirmed large cell neuroendocrine carcinoma, treated at our hospital from January 2013 to January 2018, were collected. Relationships between clinical characteristics, diagnoses, treatment outcomes, and prognoses were retrospectively analyzed. RESULTS: Patients were followed for a median of 18.5 (0.5-41.0) months. Thirty-four patients died before the final follow-up, resulting in a median overall survival of 17.9 (0.5-36.0) months, with 1-, 2-, and 3-year survival rates of 69.1%, 23.6%, and 1.8%, respectively. Single-factor analysis identified gender (P=0.036), smoking history (P=0.008), obstructive atelectasis (P=0.032), regional lymph node metastasis (P=0.020), and treatment selection (P=0.000) as factors influencing overall survival. Multifactor analysis identified treatment selection as an independent survival prognostic factor. Particularly, significant differences were observed between the combination therapies (surgery+chemotherapy, surgery+radiotherapy, surgery+radiotherapy+chemotherapy, and concurrent chemoradiotherapy) and single-therapy approaches (chemotherapy or radiotherapy alone; P<0.001), but not among the combination therapies (P=0.216). DISCUSSION: Male patients with large cell neuroendocrine carcinoma with a history of smoking, obstructive atelectasis, and regional lymph node metastasis have a particularly poor prognosis. Our observation of the treatment approach as an independent survival prognostic factor suggests that combination therapies may yield survival benefits to patients.

Urinary Large Cell Neuroendocrine Carcinoma: A Clinicopathologic Analysis of 22 Cases.

Large cell neuroendocrine carcinoma (LCNEC) of the urinary tract is a rare disease. We present a relatively large retrospective cohort of urinary LCNEC, 20 from the urinary bladder, and 2 from the ureter, from a single institution. The patients included 16 men and 6 women with a median age of 74.5 years. Most LCNEC presented at an advanced stage with tumors invading the muscularis propria and beyond (21/22). Eight cases were pure LCNEC, while 14 cases were mixed with other histologic types, including conventional urothelial carcinoma (n=9), carcinoma in situ (n=7), small cell carcinoma (n=6), and urothelial carcinoma with glandular (n=3) features. Most LCNEC expressed neuroendocrine markers synaptophysin (22/22), chromogranin (13/16), CD56 (7/7), TTF1 (8/8), and INSM1 (2/3). They were negative for common urothelial markers including HMWCK (0/3), p40/p63 (0/6), CK20 (0/10), and had variable GATA3 staining (4/8). Ki-67 stained 25% to nearly 100% tumor cell nuclei. Patient survival was associated with cancer stage, and pure LCNEC showed worse survival than mixed LCNEC. Compared with small cell carcinoma at similar stages from a prior study, LCNEC had a worse prognosis only when patients developed metastatic disease. For organ-confined LCNEC, neoadjuvant chemotherapy followed by radical resection is the treatment option to achieve long-term survival.

Disparate outcomes in nonsmall cell lung cancer by immigration status.

OBJECTIVE: The purpose of this study was to evaluate overall survival (OS) outcomes by race, stratified by country of origin in patients diagnosed with NSCLC in California. METHODS: We performed a retrospective analysis of nonsmall cell lung cancer (NSCLC) patients diagnosed between 2000 and 2012. Race/ethnicity was defined as White (W), Black (B), Hispanic (H), and Asian (A) and stratified by country of origin (US vs. non-US [NUS]) creating the following patient cohorts: W-US, W-NUS, B-US, B-NUS, H-US, H-NUS, A-US, and A-NUS. Three multivariate models were created: model 1 adjusted for age, gender, stage, year of diagnosis and histology; model 2 included model 1 plus treatment modalities; and model 3 included model 2 with the addition of socioeconomic status, marital status, and insurance. RESULTS: A total of 68,232 patients were included. Median OS from highest to lowest were: A-NUS (15 months), W-NUS (14 months), A-US (13 months), B-NUS (13 months), H-US (11 months), W-US (11 months), H-NUS (10 months), and B-US (10 months) (p < 0.001). In model 1, B-US had worse OS, whereas A-US, W-NUS, B-NUS, H-NUS, and A-NUS had better OS when compared to W-US. In model 2 after adjusting for receipt of treatment, there was no difference in OS for B-US when compared to W-US. After adjusting for all variables (model 3), all race/ethnicity profiles had better OS when compared to W-US; B-NUS patients had similar OS to W-US. CONCLUSION: Foreign-born patients with NSCLC have decreased risk of mortality when compared to native-born patients in California after accounting for treatments received and socioeconomic differences.

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.

Primary Large Cell Neuroendocrine Carcinoma of the Parotid Gland. Report of a Rare Case.

Primary neuroendocrine carcinomas of the salivary glands are very rare neoplasms that present light microscopic, ultrastructural, and immunohistochemical features of neuroendocrine differentiation. Twelve cases have been published in the English language literature. We describe the pathologic features of a case of primary large cell neuroendocrine carcinoma of the parotid gland in a 91-year old male and summarize the immunophenotype of previously reported LCNECs of the major salivary glands. It is concluded that primary LCNEC of the salivary glands presents as a high-grade undifferentiated carcinoma, whose diagnosis may be hindered by its rarity and non-specific light microscopic features. A high level of awareness, immunohistochemical staining for neuroendocrine markers synaptophysin and CD56, and a thorough diagnostic work-up in order to exclude metastasis from a primary neuroendocrine carcinoma will allow its diagnosis.

Primary MiNEN of the urinary bladder: an hitherto undescribed entity composed of large cell neuroendocrine carcinoma and adenocarcinoma with a distinct clinical behavior : Description of a case and review of the pertinent literature.

Neuroendocrine carcinomas (NECs) of the urinary bladder are very rare and can be observed in the context of mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs), most frequently in association with urothelial carcinoma. Small cell NECs are far more common than large cell NECs (LCNECs), which are exceedingly rare. We describe a primary MiNEN of the urinary bladder, composed of a LCNEC and of an adenocarcinoma, in which the neuroendocrine component reached complete pathological regression after neoadjuvant M-VAC chemotherapy, whereas the non-neuroendocrine component of the tumor progressed to metastatic disease. Compared to mixed neuroendocrine/non-neuroendocrine neoplasms described in the literature until now, this appears to be a unique case that expands the spectrum of neuroendocrine neoplasia of the urinary bladder.

High-grade Neuroendocrine Carcinomas of the Vulva: A Clinicopathologic Study of 16 Cases.

Vulvar high-grade neuroendocrine carcinomas (HGNECs) are rare and primarily thought to represent Merkel cell carcinoma (MCC). We present the clinicopathologic features of 16 such cases, the largest series to date. Patients were most often White, postmenopausal, and symptomatic from a palpable vulvar mass/nodule. Tumors ranged from 0.7 to 6 cm and most commonly involved the labium majus. Majority of the cases were pure HGNECs (15/16) with small cell (SC) morphology (14/16); 2 were large cell neuroendocrine carcinomas, of which 1 was combined with moderately differentiated adenocarcinoma. All tumors expressed synaptophysin. Of the 14 HGNECs with SC morphology, 6 were CK20-positive MCCs with characteristic CAM5.2 and neurofilament (NF) expression. Five of these MCCs were positive for Merkel cell polyoma virus large T-antigen (MCPyVLTAg). In contrast, 6 HGNECs with SC morphology were negative for CK20, NF, and MCPyVLTAg and classified as SCNECs. High-risk human papilloma virus was positive in all SCNECs and negative in all MCCs. One case of HGNEC with SC morphology could not be entirely characterized due to lack of tissue for ancillary testing. Five of 12 (42%) cases had a discrepant diagnosis initially rendered. Most patients (10/15) presented with International Federation of Gynecology and Obstetrics stage III or IV disease. Usual sites of metastasis included inguinal lymph node, liver, bone, and lung. Twelve patients underwent surgery with adjuvant chemotherapy and/or radiation therapy, 1 received adjuvant immunotherapy, and 1 patient received neoadjuvant chemotherapy followed by surgery and adjuvant radiation therapy. Median overall survival was 24 months (range: 7 to 103 mo), and overall 5-year survival was 12% (95% confidence interval: 1% to 39%). In summary, vulvar HGNECs are rare, aggressive neoplasms that can be further subclassified into MCC, SCNEC, and large cell neuroendocrine carcinoma. CK20, CAM5.2, NF, TTF-1, MCPyVLTAg, and high-risk human papilloma virus facilitate the distinction of MCC from SCNEC. Proper identification of vulvar HGNECs is critical for patient management.

Neuroendocrine carcinoma of the endometrium: A very rare gynecologic malignancy.

OBJECTIVE: To investigate the clinicopathologic characteristics, prognostic factors, outcome, and treatment of the neuroendocrine carcinoma (NEC) of the endometrium. MATERIALS AND METHODS: We retrospectively reviewed the clinicopathologic and survival data of 10 patients who underwent surgery for NEC. The patients were collected between 1999 and 2017 from four referral centers in Turkey. RESULTS: The median age of patients was 67 years (range: 34-75 years). The NEC of endometrium consist of 9 cases with small cell carcinoma (SC) NEC (two with mixed histotypes), and one with a large cell (LC) NEC. According to FIGO 2009 criteria, 70 % (7/10) of patients had advanced stage (III and IV) disease. All patients except one underwent surgical staging, eight patients received platinum-based chemotherapy (CTX) and of 6 those were additionally treated with radiotherapy (RT). Four patients died of disease ranging from 2 to 10 months and six were alive 12-72 months with no evidence of disease. In addition, 4 SC NEC cases raised in polypoid features had no evidence of disease from 24 to 72 months. DISCUSSION: NEC of the endometrium is a rare disease with poor prognosis, which frequently diagnosed in advanced stages. The main treatment modality was the administration of platinum-based CTX as an adjuvant to surgery or surgery and RT. Our result suggests that the polypoid feature of the tumor might be one of the best predictors for the prognosis of SC NEC.

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.

Mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon: detailed molecular characterisation of two cases indicates a distinct colorectal cancer entity.

We present two rare cases of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon. A literature search revealed only three published cases with similar histology but none of these reports provided profound molecular and mutational analyses. Our two cases exhibited a distinct, colon-like immunophenotype with strong nuclear CDX2 and ß-catenin expression in more than 90% of the tumour cells of both components. We analysed the two carcinomas regarding microsatellite stability, RAS, BRAF and PD-L1 status. In addition, next-generation panel sequencing with Ion AmpliSeq™ Cancer Hotspot Panel v2 was performed. This approach revealed mutations in FBXW7, CTNNB1 and PIK3CA in the first case and FBXW7 and RB1 mutations in the second case. We looked for similar mutational patterns in three publicly available colorectal adenocarcinoma data sets, as well as in collections of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) and colorectal neuroendocrine carcinomas. This approach indicated that the FBXW7 point mutation, without being accompanied by classical adenoma-carcinoma sequence mutations, such as APC, KRAS and TP53, likely occurs at a relatively high frequency in mixed neuroendocrine and squamous cell carcinoma and therefore may be characteristic for this rare tumour type. FBXW7 codifies the substrate recognition element of an ubiquitin ligase, and inactivating FBXW7 mutations lead to an exceptional accumulation of its target ß-catenin which results in overactivation of the Wnt-signalling pathway. In line with previously described hypotheses of de-differentiation of colon cells by enhanced Wnt-signalling, our data indicate a crucial role for mutant FBXW7 in the unusual morphological switch that determines these rare neoplasms. Therefore, mixed large cell neuroendocrine and a squamous cell carcinoma can be considered as a distinct carcinoma entity in the colon, defined by morphology, immunophenotype and distinct molecular genetic alteration(s).

Prognostic impacts of extracranial metastasis on non-small cell lung cancer with brain metastasis: A retrospective study based on surveillance, epidemiology, and end results database.

This study was designed to investigate the prognostic value of the number and sites of extracranial metastasis (ECM) in NSCLC patients with BM. NSCLC patients with BM from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015 were enrolled in analysis. Patients from 2010 to 2013 were included in the training set and those from 2014 to 2015 in the validation set. ECM sites among different subtypes of NSCLC were compared by Chi-square tests. Kaplan-Meier methods and Cox regression models were performed to analyze survival data. Competing-risks analysis was used to predict cumulative incidence rates for CSS and non-CSS cause. We included 5974 patients in the training cohort and 3561 patients in the validation cohort. Most (nearly 80%) NSCLC patients with BM showed 0-1 involved extracranial organ, with the most and least common ECM organ being bone and distant lymph nodes (DLNs) among all subtypes of NSCLC, respectively. The number of involved extracranial organs was an independent prognostic factor for patients with BM from NSCLC (p < 0.001). Patients with 0-1 ECM had better survival than those with larger number of involved extracranial organs (p < 0.001). Cumulative incidence rates for CSS were increased with the number of ECM raising (p < 0.001). All involved extracranial organs were associated with worse survival (p < 0.05). In patients with single-organ ECM, we observed a better prognosis in lung and bone metastasis, while liver metastasis showed worst survival. But the difference in survival in these patient groups was relatively small. Patients with liver metastasis had higher cumulative incidence rates for CSS than that in patients with lung and bone metastasis (p < 0.05). More extracranial metastases were associated with poor prognosis in NSCLC patients with BM and ECM sites showed limited effect on survival. Tailored treatments would be reasonable for BM patients from NSCLC with different metastasis patterns.

Large cell neuroendocrine carcinoma of the lungs: case report and literature review.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare but destructive tumor type, accounting for approximately 1% of all lung cancers, associated with poor prognosis. LCNEC is challenging diagnosing using biopsy specimens. While current LCNEC therapies include surgery, radiotherapy, and chemotherapy, it has not yet proved its greatest treatment strategies. Immunotherapy is rapidly emerging as a possibility for lung cancer treatment. However, there are scant reports in the literature regarding LCNEC immunotherapy. Therefore, the author here reports a case of LCNEC by immunotherapy, and retrospective reviews the present research status and progress of LENCE and corresponding clinical treatment progress. This case will supply valuable information for the treatment options for LCNEC. A 64-year-old male smoker was treated for one month for blood in his sputum. Chest radiography and computed tomography revealed a 3-cm solitary tumor in the left upper lung. We treated the patient with thoracoscopic radical surgery for upper left lung cancer. Postoperative pathology shows pulmonary LCNEC. We performed postoperative chemotherapy with a double-drug regimen holding platinum. Then, bevacizumab, paclitaxel, and the PD-L1 checkpoint inhibitor nivolumab were applied, but the patient progressed rapidly. Immunotherapy is an ineffective treatment possibility for these patients, even if PD-L1 expression is positive. A possible contributing factor is the timing of immunotherapy too late.

Urinary Tract Large Cell Neuroendocrine Carcinoma: Diagnostic, Prognostic and Therapeutic Issues.

Large cell neuroendocrine carcinoma (LCNEC) of the urinary tract is a high-grade neuroendocrine tumor with distinct pathological features, usually portending an aggressive clinical behavior in comparison to conventional urothelial carcinoma. Due to its low prevalence, little is known about its clinical management and there is no current standard of care. The aim of this review was to summarize the current knowledge about LCNEC of the bladder, ureter and kidney, with relevance to diagnostic, prognostic and therapeutic issues, through a systematic analysis of clinical, pathological and outcome data retrieved from the literature.