Large Cell Neuroendocrine Carcinoma of the Lung: Clinico-Pathologic Features, Treatment, and Outcomes

Abstract

Background: Large cell neuroendocrine carcinoma (LCNEC) accounts for approximately 3% of lung cancers. Pathologic classification and optimal therapies are debated. We report the clinicopathologic features, treatment and survival of a series of patients with stage IV LCNEC.

Materials and methods: Cases of pathologically-confirmed stage IV LCNEC evaluated at Memorial Sloan Kettering Cancer Center from 2006 to 2013 were identified. We collected demographic, treatment, and survival data. Available radiology was evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria.

Results: Forty-nine patients with stage IV LCNEC were identified. The median age was 64 years, 63% of patients were male, and 88% were smokers. Twenty-three patients (n = 23/49; 47%) had brain metastases, 17 at diagnosis and 6 during the disease course. Seventeen LCNEC patients (35%) had molecular testing, of which 24% had KRAS mutations (n = 4/17). Treatment data for first-line metastatic disease was available on 37 patients: 70% (n = 26) received platinum/etoposide and 30% (n = 11) received other regimens. RECIST was completed on 23 patients with available imaging; objective response rate was 37% (95% confidence interval, 16%-62%) with platinum/etoposide, while those treated with other first-line regimens did not achieve a response. Median overall survival was 10.2 months (95% confidence interval, 8.6-16.4 months) for the entire cohort.

Conclusion: Patients with stage IV LCNEC have a high incidence of brain metastases. KRAS mutations are common. Patients with stage IV LCNEC do not respond as well to platinum/etoposide compared with historic data for extensive stage small-cell lung cancer; however, the prognosis is similar. Prospective studies are needed to define optimum therapy for stage IV LCNEC.

Keywords: Brain metastases; KRAS mutation; Platinum-etoposide chemotherapy; Small cell lung carcinoma; Stage IV.

Figure 1. Microscopic Images of a Representative Case of LCNEC. (A) Low-Power and (B) High-Power Images of H&E-Stained Sections Demonstrating Classic LCNEC Morphology, Including Neuroendocrine Architecture (Nesting With Peripheral Palisading and Rosettes), High Mitotic Rate and Necrosis, and Non—Small-Cell Cytologic Features (Abundant Cytoplasm, Prominent Nucleoli). Immunohistochemistry for Synaptophysin (C) and CD56 (D) Shows Diffuse Labeling, Supporting Neuroendocrine Differentiation

Abbreviations: H&E = hematoxylin and eosin; LCNEC = large cell neuroendocrine carcinoma.

Figure 2. (A) Time to Progression for Patients With De Novo Stage LCNECs at Diagnosis (n = 21) Compared With Those With Recurrent, Metastatic Disease After Having Initially Presented With Stage I/II/III Disease (n = 9). (B) Time to Progression for Patients Who Received First-Line Chemotherapy Platinum/Etoposide (n = 20), Versus Those Who Received an Alternative Regimen (n = 10). (C) Overall Survival for Patients With De Novo Stage IV LCNECs at Diagnosis (n = 32) Compared With Those With Recurrent, Metastatic Disease After Having Initially Presented With Stage I/II/III Disease (n = 13). (D) Overall Survival for Patients Who Received First-Line Chemotherapy With Platinum/Etoposide (n = 26), Versus Those Who Received an Alternative Regimen (n = 11)

Abbreviations: E = etoposide; LCNEC = large cell neuroendocrine carcinoma; OS = overall survival; Plt/E = platinum/etoposide; TTP = time to progression.