Colorectal Poorly Differentiated Neuroendocrine Carcinomas and Mixed Adenoneuroendocrine Carcinomas

Abstract

Colorectal poorly differentiated neuroendocrine carcinomas (NECs) and mixed adenoneuroendocrine carcinomas (MANECs) are well-recognized entities generally known to be associated with biological aggressiveness and poor patient survival. However, a few published papers have highlighted the existence of a subgroup of tumors with a better survival than expected; however, to date, there are no established parameters that usefully identify this category. In the present study we have investigated the morphologic features, the CpG methylator phenotype (CIMP), microsatellite instability (MSI), and the immunohistochemical profile, including the expression of transcription factors (TTF1, ASH1, CDX2, and PAX5), stem cell markers (CD117 and CD34), and cytokeratins 7 and 20, in a series of 39 carcinomas (27 NECs and 12 MANECs) to better characterize such neoplasms and to search for prognostic indicators. No different patient survival was observed between NECs and MANECs. Neoplasms showed a heterogenous spectrum of morphologic and immunohistochemical features; however, only large-cell subtype, significant peritumoral lymphoid reaction, CD117 immunoreactivity, vascular invasion, and MSI/CIMP+ status were significantly correlated with prognosis on univariable analysis. Furthermore, vascular invasion and CD117 immunoreactivity were independent prognostic markers on multivariable analysis. In addition to these prognostic features, neoplasms showed different expression of transcription factors, stem cell markers, and cytokeratins that should be considered for diagnostic purposes and, especially, for discriminating among possible differential diagnoses.

Mixed Adenoneuroendocrine Carcinomas of the Gastrointestinal Tract: Targeted Next-Generation Sequencing Suggests a Monoclonal Origin of the Two Components

“…In the stomach, mixed tumors follow an intermediate behavior between pure large cell NEC, which is the most aggressive subgroup, and conventional gastric adenocarcinoma [25]. In the colon and rectum, the extent of the neuroendocrine component is not a predictor of behavior, and even a minor high-grade neuroendocrine cell population was found able to metastasize [24,26]. Very few cases of hepatobiliary MANEC have been reported so far, and clinical comparisons are still missing [6].…”

Prognostic Relevance of Aberrant DNA Methylation in G1 and G2 Pancreatic Neuroendocrine Tumors

“…As previously described, we fully validated the sensitivity and specificity of these MS-MLPA assays [24,25]. Aberrant methylation was scored as a categorical variable using a specific methylation ratio for each gene corresponding to the highest level of accuracy of the test [25].…”

Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity

“…Regardless of anatomic site, TP53 alterations have been found to be frequent in NECs (Dacic et al 2002, Furlan et al 2005, together with the impairment of the CDKN2A/p16-Rb pathway (Parwani et al 2003, Nassar et al 2005, Yachida et al 2012. Most GEP-NECs have high chromosomal instability (Furlan et al 2005, Lubensky & Zhuang 2007, while microsatellite instability (MSI) has rarely been observed (Ghimenti et al 1999, Nassar et al 2005, Stelow et al 2006, La Rosa et al 2012a and the role of other epigenetic mechanisms is still poorly understood.…”

“…Although GEP-NECs are generally aggressive cancers, showing ominous prognosis with a median survival (MS) ranging from 6 to 12 months (La Rosa & Sessa 2014), recent findings from a few published studies (Shia et al 2008, Power et al 2010, La Rosa et al 2012a and from anecdotal experience seem to suggest that there is a fraction of patients with GEP-NECs showing a better than expected survival rate. We have recently demonstrated that a subset of colorectal NECs exhibiting MSI and extensive gene hypermethylation showed a better prognosis than NECs without these features (La Rosa et al 2012a,b).…”