Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors

October 13, 2021


Modern Pathology

Publication Date

October 13, 2021


Harms PW, Verhaegen ME, Hu K, Hrycaj SM, Chan MP, Liu CJ, Grachtchouk M, Patel RM, Udager AM, Dlugosz AA Summary

We have long suspected that sunlight-damaged skin cells can develop into either a squamous cell carcinoma (SCC) or much less often a Merkel cell carcinoma (MCC). This process does not involve the Merkel cell polyomavirus, and is relevant for about 20% of MCC cases in the US. We have long believed this is occurring because there are many cases reported in the literature in which heavily sun-damaged skin develops from a common central area into an MCC and an adjacent SCC. None of such cases have been positive for the Merkel polyomavirus, supporting the concept that these tumors are caused only by sunlight. An excellent team at University of Michigan led by Paul Harms and Anj Dlugosz have now provided a very detailed look at how this happens, including the fact that the two tumors (across multiple patient samples with both MCC & SCC) share many specific, identical, UV-induced mutations in genes that are well known to lead to cancer. These data clearly show a ‘shared evolution’ of SCC & MCC, and show that many gateway mutations can lead to either cancer. On the other hand, we certainly do not yet know which cell(s) in the skin are infected with the Merkel virus and lead to virus-positive MCC, though there are multiple possible target cells that are being explored.


Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma without a known dysplastic precursor. In some cases, MCC is associated with SCCIS in the overlying epidermis; however, the MCC and SCCIS populations display strikingly different morphologies, and thus far a relationship between these components has not been demonstrated. To better understand the relationship between these distinct tumor cell populations, we evaluated 7 pairs of MCC-SCCIS for overlapping genomic alterations by cancer profiling panel. A subset was further characterized by transcriptional profiling and immunohistochemistry. In 6 of 7 MCC-SCCIS pairs there was highly significant mutational overlap including shared TP53 and/or RB1 mutations. In some cases, oncogenic events previously implicated in MCC (MYCL gain, MDM4 gain, HRAS mutation) were detected in both components. Although FBXW7 mutations were enriched in MCC, no gene mutation was unique to the MCC component across all cases. Transcriptome analysis identified 2736 differentially expressed genes between MCC and SCCIS. Genes upregulated in the MCC component included Polycomb repressive complex targets; downregulated transcripts included epidermal markers, and immune genes such as HLA-A. Immunohistochemical studies revealed increased expression of SOX2 in the MCC component, with diminished H3K27Me3, Rb, and HLA-A expression. In summary, MCC-SCCIS pairs demonstrate clonal relatedness. The shift to neuroendocrine phenotype is associated with loss of Rb protein expression, decrease in global H3K27Me3, and increased expression of Merkel cell genes such as SOX2. Our findings suggest an epidermal origin of MCC in this setting, and to our knowledge provide the first molecular evidence that intraepithelial squamous dysplasia may represent a direct precursor for small cell carcinoma.

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