New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management

Abstract

Carcinoids and large cell neuroendocrine carcinomas (LCNECs) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin-remodeling genes (e.g., menin 1 gene [MEN1]), and few affect genes of the phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin gene pathway. Aggressive disease has been related to chromothripsis, DNA-repair gene mutations, loss of orthopedia homeobox/CD44, and upregulation of ret proto-oncogene gene (RET) gene expression. In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with biallelic inactivation of tumor protein p53 gene (TP53) and retinoblastoma gene (RB1), a hallmark of SCLC; and the other one with biallelic inactivation of TP53 and serine/threonine kinase 11 gene (STK11)/kelch like ECH associated protein 1 gene (KEAP1), genes that are frequently mutated in NSCLC. These data, together with the identification of common mutations in the different components of combined LCNEC tumors, provide further evidence of the close molecular relation of LCNEC with other lung tumor types. In terms of therapeutic options, future studies should explore the association between mechanistic target of rapamycin pathway mutations and response to mechanistic target of rapamycin inhibitors in carcinoids. For LCNEC, preliminary data suggest that the two molecular subtypes might have a predictive value for chemotherapy response, but this observation needs to be validated in randomized prospective clinical trials. Finally, delta like Notch canonical ligand 3 inhibitors and immunotherapy may provide alternative options for patient-tailored therapy in LCNEC.

Clinicopathological characteristics and prognostic factors of pulmonary large cell neuroendocrine carcinoma: A large population‐based analysis

“…3,11 The incidence of LCNEC increased with time, which may be the result of new insights into the molecular characteristics of LCNEC and its reclassification. 3,4,12,13 Previous SCLC cases might be reclassified as LCNEC cases according to the new and comprehensive recognition of LCNEC. The baseline clinicopathological characteristics of LCNEC, except for marital status, were significantly different from those of ONSCLC in this study.…”

Is the sum of positive neuroendocrine immunohistochemical stains useful for diagnosis of large cell neuroendocrine carcinoma (LCNEC) on biopsy specimens?

“…The value of INSM1 in an algorithm of ≥2 neuroendocrine markers staining for biopsies to recognise LCNEC is unclear. Furthermore, recent studies have addressed the existence of different molecular subtypes of LCNEC . Proposed are the LCNEC‐SCLC with TP53/RB1 mutations recognised with IHC by loss of the RB1 protein and the LCNEC‐NSCLC subtype with STK11/KEAP/KRAS mutations and the presence of RB1 protein staining .…”

“…Furthermore, recent studies have addressed the existence of different molecular subtypes of LCNEC. 27,33,34 Proposed are the LCNEC-SCLC with TP53/RB1 mutations recognised with IHC by loss of the RB1 protein and the LCNEC-NSCLC subtype with STK11/KEAP/KRAS mutations and the presence of RB1 protein staining. 27,35 In the differential diagnosis of LCNEC versus SCLC, staining of RB1 IHC is indicative of a non-SCLC-like tumour.…”

Neuroendocrine marker staining pattern categorization of small‐sized pulmonary large cell neuroendocrine carcinoma

“…Histologically, these tumors have neuroendocrine morphologies, such as organoid nesting, rosette‐like structures, and peripheral palisading patterns. TC and AC are categorized as low‐ and intermediate‐grade malignancy, whereas, LCNEC and SCLC are categorized as high‐grade malignancies …”

“…TC and AC are categorized as low-and intermediate-grade malignancy, whereas, LCNEC and SCLC are categorized as high-grade malignancies. [1][2][3] LCNEC, first proposed by Travis et al in 1991, 4 is a rare tumor known to be associated with shorter survival than that of other non-small cell lung cancers (NSCLC), 5,6 whereas SCLC accounts for 13% of all lung carcinomas 7 and is the most aggressive lung cancer. SCLC metastasizes lymph nodes and distant organs even in the early stage.…”