Clinical characteristics, treatment, and outcome of patients with large cell neuroendocrine carcinoma of the lung and brain metastases - data from a tertiary care center.

Large cell neuroendocrine carcinoma (LCNEC) of the lung is an aggressive malignancy, with brain metastases (BM) occurring in approximately 20% of cases. There are currently no therapy guidelines for this population as only few data on the management of LCNEC and BM have been published. For this retrospective single center study, patients with LCNEC and BM were identified from the Vienna Brain Metastasis Registry. Data on clinicopathological features, BM-specific characteristics, treatment, and outcome were extracted. In total, 52/6083 (0.09%) patients in the dataset had a diagnosis of LCNEC and radiologically verified BM. Median age at diagnosis of LCNEC and BM was 59.1 and 60.1 years, respectively. Twenty-seven (51.9%) presented with single BM, while 12 (23%) exhibited > 3 BM initially. Neurologic symptoms due to BM were present in n = 40 (76.9%), encompassing neurologic deficits (n = 24), increased intracranial pressure (n = 18), and seizures (n = 6). Initial treatment of BM was resection (n = 13), whole brain radiation therapy (n = 19), and/or stereotactic radiosurgery (n = 25). Median overall survival (mOS) from LCNEC diagnosis was 16 months, and mOS after BM diagnosis was 7 months. Patients with synchronous BM had reduced mOS from LCNEC diagnosis versus patients with metachronous BM (11 versus 27 months, p = 0.003). Median OS after BM diagnosis did not differ between LCNEC patients and a control group of small cell lung cancer patients with BM (7 versus 6 months, p = 0.17). Patients with LCNEC and BM have a poor prognosis, particularly when synchronous BM are present. Prospective trials are required to define optimal therapeutic algorithms.

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

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

Large-cell Neuroendocrine Carcinoma of the Lung with Carcinoid Syndrome.

A 76-year-old woman was admitted to our hospital for refractory diarrhea with a poor antidiarrheal effect. Chest and abdominal computed tomography revealed a 24×22-mm mass in the left upper lobe of lung and multiple masses in the liver. Urine 5-Hydroxy indol acetic acid was markedly elevated. A liver biopsy revealed large-cell neuroendocrine carcinoma with serotonin production, suggestive of a lung origin, and a lung biopsy revealed combined large-cell neuroendocrine carcinoma and squamous cell carcinoma. Therefore, we made a definitive diagnosis of carcinoid syndrome caused by large-cell neuroendocrine carcinoma of the lung. Although chemotherapy was performed after diagnosis, the patient died 50 days postadmission.

Large cell neuroendocrine carcinoma of the lung controlled for 4 years by a single administration of pembrolizumab: A case report.

Large cell neuroendocrine carcinoma of the lung (LCNEC) is a rare and highly progressive tumor with a poor prognosis. Although immune checkpoint inhibitors have been approved for treatment of both small cell and non-small cell lung cancers, their role in the treatment of LCNEC is unclear. We describe a patient with postoperative recurrence of LCNEC who maintained complete remission for 4 years after a single administration of pembrolizumab. A 68-year-old Japanese man underwent thoracoscopic right lower lobectomy for LCNEC (pathological stage pT1bN0M0, stage IA2). Epidermal growth factor receptor and anaplastic lymphoma kinase were negative, and the programmed death ligand 1 expression rate in tumor cells was 5% (clone 22C3). Eight months later, the patient developed recurrence with mediastinal lymph node metastasis and pleural dissemination. Therefore, chemotherapy with cisplatin and etoposide was administered. However, relapse occurred 6 months later. Pembrolizumab was administered as second-line chemotherapy, which was discontinued after first dose because of interstitial pneumonia 1 month later. Thereafter, however, both the lymph node metastasis and pleural dissemination disappeared and did not relapse for 4 years. Pembrolizumab may be used as a treatment option for pulmonary LCNEC.

Effect of Adjuvant and Palliative Chemotherapy in Large Cell Neuroendocrine Carcinoma of the Lung: A Systematic Review and Meta-Analysis.

BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare subset of lung carcinoma with poor overall survival. METHODS: A systematic review following a meta-analysis of studies was performed to identify the effect of different selections of chemotherapy in LCNEC. Articles providing overall survival data for adjuvant chemotherapy or palliative chemotherapy for LCNEC were eligible. The odds ratio (OR) of mortality at one or two years after chemotherapy was evaluated. RESULTS: A total of 16 reports were finally included in the quantitative synthesis, involving a total of 5916 LCNEC patients. Adjuvant chemotherapy was administered to 1303 patients, and palliative chemotherapy was administered to 313 patients using either a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC) regimen. The OR for adjuvant chemotherapy was 0.73 (95% confidence interval (CI): 0.59 to 0.89, p = 0.002). The SCLC regimen showed an OR of 0.52 (95% CI: 0.11 to 2.38, p = 0.40) after one year, and 0.32 (95% CI: 0.11 to 0.89, p = 0.03) after two years, compared with the NSCLC regimen. CONCLUSIONS: Adjuvant chemotherapy for pulmonary large cell neuroendocrine carcinoma improved the outcome after surgery. The SCLC regimen showed better survival than the NSCLC regimen as palliative chemotherapy.

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

BACKGROUND: Treatment 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. METHODS: The 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. RESULTS: We 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). CONCLUSIONS: Our 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.

A Semiquantitative Scoring System May Allow Biopsy Diagnosis of Pulmonary Large Cell Neuroendocrine Carcinoma.

OBJECTIVES: The aim of this study was to devise reproducible biopsy criteria for distinguishing pulmonary large cell neuroendocrine carcinoma (LCNEC) from non-small cell lung carcinoma (NSCLC). METHODS: Tissue microarrays of LCNEC and NSCLC were generated from resection specimens and used as biopsy surrogates. They were stained for neuroendocrine markers, Ki-67, napsin-A, and p40, and independently analyzed by standardized morphologic criteria by four pathologists. Tumors were scored based on morphology, neuroendocrine marker expression, and Ki-67 proliferative index. RESULTS: The average total score for LCNEC was significantly higher than for NSCLC (5.65 vs 0.51, P < .0001). Utilizing a cutoff score of 4 or higher showed 100% sensitivity and 99% specificity for LCNEC diagnosis, with an excellent agreement among four pathologists (98%). CONCLUSIONS: The proposed semiquantitative approach based on a combination of specific morphologic and immunophenotypic features may be a useful tool for biopsy diagnosis of LCNEC.

Survival outcomes and incidence of brain recurrence in high-grade neuroendocrine carcinomas of the lung: Implications for clinical practice.

BACKGROUND: Among patients with advanced high-grade neuroendocrine carcinoma (HGNEC) of the lung, the optimal therapeutic management is much less established for large cell neuroendocrine carcinomas (LCNECs) than for small cell lung cancers (SCLCs). We evaluated the survival outcomes and incidence of brain recurrence of advanced LCNECs, and compared them with those of a population of SCLCs matched by stage. MATERIALS AND METHODS: Forty-eight unresected stage III HGNECs (16 LCNECs and 32 SCLCs) and 113 stage IV HGNECs (37 LCNECs and 76 SCLCs) were eligible for the analysis. The efficacy of platinum-etoposide chemotherapy with or without thoracic radiotherapy (TRT) and/or prophylactic cranial irradiation (PCI) was investigated. RESULTS: Overall response was significantly lower for LCNECs compared with SCLCs for both stage III (43.8% vs 90.6% respectively, P=0.004) and stage IV (43.3% vs 64.5%, respectively, P=0.04). Similarly, an inferior outcome was observed in terms of progression-free survival (PFS), and overall survival (OS) for LCNECs compared with SCLCs, which, however, reached significance only for stage III disease (median: 5.6 vs 8.9 months, P=0.06 and 10.4 vs 17.6 months, P=0.03 for PFS and OS, respectively). In the lack of PCI, LCNECs showed a high cumulative incidence of brain metastases, as 58% and 48% of still living stage III and IV patients, respectively, developed brain metastases at 18 months. CONCLUSION: Patients with advanced LCNECs are at high risk for brain recurrence. Unresected stage III LCNECs treated with platinum-etoposide with or without TRT bear a dismal prognosis, when compared indirectly with SCLC counterparts. Randomized trials should evaluate whether PCI could improve survival of advanced LCNECs.

Large cell neuroendocrine carcinoma of the lung: CT and FDG PET findings.

PURPOSE: To evaluate the CT and (18)fluorine FDG PET findings of large cell neuroendocrine carcinomas (LCNECs) of the lung and to evaluate whether CT and FDG PET findings can help predict the clinical outcome. MATERIAL AND METHODS: Thirty-one patients (Male:Female=29:2; mean age, 69 years) who underwent surgical resection of an LCNEC of the lung were included in this retrospective study. The tumours were assessed with respect to morphologic characteristics and the maximum standardised uptake value (SUVmax) on pre-operative CT and FDG PET. For patients undergoing curative resection (n=26), disease-free survival was evaluated using the Kaplan-Meier test. The prognostic significance was assessed using a multivariate Cox proportional hazards regression analysis. RESULTS: The mean tumour diameter was 3.8 ± 2.1cm. Eight tumours (25.8%) were located centrally in the lung, and 23 (74.2%) were located peripherally. The margins were lobulated in 29 patients (93.5%) and well defined in 20 (64.5%). The mean SUVmax was 9.0 ± 3.8. The five-year disease-free survival rate was 46.3%. The shorter disease-free survival was related to the TNM stage greater than stage I, no lobulated margin of a tumour, a SUVmax >12.9 of a tumour, a long diameter >5.6 cm of a tumour, or female gender (P=0.115, P=0.134, P=0.056, P=0.168, P=0.113, respectively). The multivariate analysis indicated that a long diameter >5.6 cm (hazard ratio, 9.265; 90% confidence interval (CI), 1.996-42.992; P=0.017), female gender (hazard ratio, 5.579; 90% CI, 1.398-22.264; P=0.041), no lobulated margin (hazard ratio, 9.955; 90% CI, 1.433-69.136; P=0.051), and SUVmax >12.9 (hazard ratio, 4.062; 90% CI, 1.235-13.368; P=0.053) were independent predictors of shorter disease-free survival. CONCLUSIONS: LCNECs of the lung more commonly occurred peripherally and exhibited well-defined and lobulated margins on CT. The mean SUVmax was consistent with malignant tumours. Female gender, a larger tumour diameter, no lobulated margin, and higher SUVmax were poor prognostic factors.