Original contributionMolecular characteristics of colorectal neuroendocrine carcinoma; similarities with adenocarcinoma rather than neuroendocrine tumor☆
Introduction
Colorectal neuroendocrine carcinomas (NECs) are rare but highly aggressive neoplasms [1], [2], [3], [4], [5], [6], [7]. A recent World Health Organization (WHO) classification [1] graded neuroendocrine neoplasms (NENs) into 3 groups of neuroendocrine tumors (NETs)—NET G1, NET G2, and NECs—simply based on tumor proliferative activity. Morphologically, colorectal NECs are a heterogeneous group ranging from small cell NECs (SCNECs) to large cell NECs (LCNECs). Some cases of LCNECs are difficult to distinguish from poorly differentiated adenocarcinomas (PDCs) with solid growth patterns [7].
The mechanisms of carcinogenesis and aggressiveness of colorectal NECs are still largely unknown. Although the expression of some biomarkers and the molecular features of NECs were previously analyzed, only a small number of colorectal NECs were included in most of those articles [8], [9], [10], [11], [12], [13].
There is a hypothesis that they are derived from preceding adenoma/adenocarcinomas. This is supported by combined cases with conventional adenoma/adenocarcinoma and NECs and some molecular features such as the identical loss of heterozygosity [12] or identical mutation [13] of some genes in both components.
Aberrant expression of p53 was observed in approximately 80% of colorectal NECs in the previous reports [5], [6]. The expression of other p53-related proteins, such as p21, cyclin E, and Bcl-2, has not been clearly described yet in colorectal NECs.
Disruption of the Rb-p16 pathway, which is another key role in the cell cycle checkpoint, was previously reported in pulmonary and gastrointestinal NECs [8], [14]. Overexpression of p16 was reported in gastrointestinal NECs, including 6 cases of colorectal NECs [8]. On the other hand, low expression of p16 and the methylation of the CDKN2A gene were reported to be associated with poorer prognosis in some NENs, including colorectal NECs [9].
The Wnt–β-catenin pathway and the expression of cyclin D1 in NENs of various organs have been investigated [8], [10], [15], [16], but colorectal NECs have not been the focus of attention.
In this study, we have attempted to sharpen our understanding of the molecular features of colorectal NECs systematically by analyzing a relatively large number of cases and by directly comparing the characteristics of colorectal NECs with those of NETs and PDCs.
Section snippets
Patient selection
We first searched the institutional database of the Department of Anatomic Pathology of Kyushu University (Fukuoka, Japan) and related facilities to identify cases diagnosed between 1986 and 2013 as colorectal “neuroendocrine carcinoma,” “endocrine cell carcinoma,” “small cell carcinoma,” and “carcinoma with neuroendocrine differentiation (or features).” We reviewed hematoxylin-eosin–stained sections of all the cases.
To correctly select NEC cases, we referred to the histologic criteria from the
Patient selection
We identified 25 cases of colorectal NECs (9 cases of SCNECs and 16 cases of LCNECs) (Fig. 1A-D). Twenty-three were surgically resected specimens, and 2 were biopsy specimens.
We also subclassified them, except for the 2 biopsy cases, into 8 combined NECs (Fig. 1C and D), which had additional adenoma and/or adenocarcinoma components, and 15 pure NECs. Among the combined NECs, 4 tumors fulfilled the criteria of mixed adenoneuroendocrine carcinoma defined by the WHO classification [1].
We also
Discussion
In this study, we sharpened our understanding of the molecular features of colorectal NECs by demonstrating their differences from, and similarities to, those of NETs and PDCs.
First, we demonstrated that NECs had certain similarities with PDCs in the immunostaining patterns of several biomarkers, including p53, cyclin E, and β-catenin. We demonstrated that NECs, but not NETs, had high frequencies of aberrant p53 expression, consistent with previous reports [5], [6]. For the first time, we
Supplementary data
The following is the Supplementary data to this article. . Antibodies used for immunohistochemistry. . Primers and condition for PCR amplification for the sequence analysis.
Acknowledgment
The English usage in this article was reviewed by KN International (http://www.kninter.com/).
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Disclosures: The authors declare that there are no conflicts of interest or funding disclosures to make.