Comprehensive analysis of mutational and clinicopathologic characteristics of poorly differentiated colorectal neuroendocrine carcinomas

Sun Mi Lee,Chang Ohk Sung

doi:10.1038/s41598-021-85593-9

Abstract

Poorly differentiated neuroendocrine carcinoma (NEC) is a rare subtype of colorectal cancer (CRC). This study aimed to investigate clinicopathologic characteristics of colorectal NECs and elucidate genomic differences and similarities between colorectal NECs and colorectal adenocarcinomas (ACs). A total of 30 colorectal NECs were screened for frequently identified CRC oncogenic driver genes by targeted next-generation sequencing of 382 genes. The median age of the patients was 67 years (range, 44 to 88 years). NECs occurred predominantly in the rectum (47%) and exhibited multiple adverse prognostic pathologic factors, including frequent lymphatic and vascular invasions, high rates of lymph node metastasis and distant metastasis and advanced TNM stage. The 1-, 3-, and 5-year overall survival rates of NEC patients were 46.7%, 36.4%, and 32.7%, respectively, with a median overall survival period of 11.5 months. In a molecular analysis, NECs showed high rates of BRAF mutation (23%), predominantly p.V600E (71%), and alterations in RB1 (47%), particularly deletion (57%). The frequencies and distributions of other genes, such as KRAS, APC, SMAD4, and PIK3CA, and microsatellite instability status were similar to those of ACs. These findings provide beneficial information for selecting therapeutic options, including targeted therapy, and a better understanding of the histogenesis of this tumour.

Highlights

Differentiated neuroendocrine carcinoma (NEC) is a rare subtype of colorectal cancer (CRC)
Several prior studies have investigated the genetics of colorectal NECs which have been reported to have frequent alterations in RB1 as well as in genes commonly identified in colorectal adenocarcinomas (ACs) including TP53, APC, KRAS, PIK3CA, BRAF etc[7,8,9,10]
With a median overall survival (OS) of 11.5 months, the findings demonstrate that poorly differentiated colorectal NEC has an aggressive biologic behaviour with a poor clinical outcome, in line with prior studies

Summary

Introduction

Differentiated neuroendocrine carcinoma (NEC) is a rare subtype of colorectal cancer (CRC). Well-differentiated neuroendocrine tumours with a high proliferation index are classified as “grade 3 tumours” according to the current WHO classification system, they show different molecular alterations and decreased response to platinum-based therapy compared with small-cell or largecell NECs5. Poorly differentiated NEC is considered a different disease entity that is distinct from welldifferentiated neuroendocrine tumours with a high proliferation index, WHO grade 3. Several prior studies have investigated the genetics of colorectal NECs which have been reported to have frequent alterations in RB1 as well as in genes commonly identified in colorectal adenocarcinomas (ACs) including TP53, APC, KRAS, PIK3CA, BRAF etc[7,8,9,10]. In a recent series of 25 colorectal NECs, Shamir et al found RB1 alterations in 14 tumours (56%), with TP53 being mutated in 12 (48%), similar to the frequencies of small-cell carcinoma of the lung[11]. Our study adds an additional 30 pure NEC cases to the previous literature, which helps to validate the prior molecular data of colorectal NECs

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