Mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon: detailed molecular characterisation of two cases indicates a distinct colorectal cancer entity

Abstract

We present two rare cases of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon. A literature search revealed only three published cases with similar histology but none of these reports provided profound molecular and mutational analyses. Our two cases exhibited a distinct, colon-like immunophenotype with strong nuclear CDX2 and β-catenin expression in more than 90% of the tumour cells of both components. We analysed the two carcinomas regarding microsatellite stability, RAS, BRAF and PD-L1 status. In addition, next-generation panel sequencing with Ion AmpliSeq™ Cancer Hotspot Panel v2 was performed. This approach revealed mutations in FBXW7, CTNNB1 and PIK3CA in the first case and FBXW7 and RB1 mutations in the second case. We looked for similar mutational patterns in three publicly available colorectal adenocarcinoma data sets, as well as in collections of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) and colorectal neuroendocrine carcinomas. This approach indicated that the FBXW7 point mutation, without being accompanied by classical adenoma-carcinoma sequence mutations, such as APC, KRAS and TP53, likely occurs at a relatively high frequency in mixed neuroendocrine and squamous cell carcinoma and therefore may be characteristic for this rare tumour type. FBXW7 codifies the substrate recognition element of an ubiquitin ligase, and inactivating FBXW7 mutations lead to an exceptional accumulation of its target β-catenin which results in overactivation of the Wnt-signalling pathway. In line with previously described hypotheses of dedifferentiation of colon cells by enhanced Wnt-signalling, our data indicate a crucial role for mutant FBXW7 in the unusual morphological switch that determines these rare neoplasms. Therefore, mixed large cell neuroendocrine and a squamous cell carcinoma can be considered as a distinct carcinoma entity in the colon, defined by morphology, immunophenotype and distinct molecular genetic alteration(s).

Mixed small cell neuroendocrine carcinoma and squamous cell carcinoma covered by tubulovillous adenoma in the rectum: a case report and detailed molecular analyses

“…Previously, only six cases of MiNENs with SCC component have been described in the colorectum [ 1 , 5 – 8 ], and only one tumor was histologically covered by tubulovillous adenoma like ours [ 7 ]. It is currently hypothesized that the adenocarcinoma component and NEC component of mixed adenoneuroendocrine carcinoma (MANEC, a subgroup of MiNEN [ 3 ]) arise from either multipotent stem cells or 2 similar but separate precursors.…”

“…Possible causes for squamous colonic carcinoma are malignant transformation of persistent ectopic embryonal nests of ectodermal cells, chronic inflammation, human papillomavirus, pelvic radiation exposure, etc. [ 1 , 2 ]. Some authors postulated that the non-neuroendocrine component might give rise to a neuroendocrine component through the trans-differentiation process and then acquire a more aggressive phenotype [ 9 ].…”

“…Neuroendocrine carcinomas (NEC) are highly aggressive tumors with poor clinical outcome, accounting for < 1% of all tumors of the colorectum [ 1 ]. Squamous cell carcinomas (SCC), which usually involve the esophagus or anal canal, are even more rare in the colorectum [ 2 ].…”

Combined large cell neuroendocrine carcinoma and squamous cell carcinoma of the oropharynx: A collision course of tumors

“…Munakata et al reported this rare case of colon cancer, although final pathologic examination suggested the primary lesion likely originated from the lung 26 . Conversely, Woischke et al present two cases of combined LCNEC and SCC of the colon with histologic and genetic evidence of local origin in the colon 27 . Furthermore, the authors present genetic evidence of mutations of the FBXW7 gene leading to upregulation of the Wnt‐signaling pathway, a possible pathophysiologic explanation for local tumorigenesis of this rare combined malignancy.…”

“…Outside of the H&N, a small number of case reports in the literature describe combined LCNEC and SCC in the gastrointestinal tract, specifically in the colon and rectum 26–29 26 .…”