Abstract
Merkel cell carcinoma (MCC) is an aggressive poorly differentiated neuroendocrine cutaneous carcinoma associated with older age, immunodeficiency and Merkel cell polyomavirus (MCPyV) integrated within malignant cells. The presence of intra-tumoural CD8+ lymphocytes reportedly predicts better MCC-specific survival. In this study, the distribution of inflammatory cells and properties of CD8+ T lymphocytes within 20 primary MCC specimens were characterised using immunohistochemistry and multicolour immunofluorescent staining coupled to confocal microscopy. CD8+ cells and CD68+ macrophages were identified in 19/20 primary MCC. CD20+ B cells were present in 5/10, CD4+ cells in 10/10 and FoxP3+ cells in 7/10 specimens. Only two specimens had almost no inflammatory cells. Within specimens, inflammatory cells followed the same patchy distribution, focused at the edge of sheets and nodules and, in some cases, more intense in trabecular areas. CD8+ cells were outside vessels on the edge of tumour. Those few within malignant sheets typically lined up in fine septa not contacting MCC cells expressing MCPyV large T antigen. The homeostatic chemokine CXCL12 was expressed outside malignant nodules whereas its receptor CXCR4 was identified within tumour but not on CD8+ cells. CD8+ cells lacked CXCR3 and granzyme B expression irrespective of location within stroma versus malignant nodules or of the intensity of the intra-tumoural infiltrate. In summary, diverse inflammatory cells were organised around the margin of malignant deposits suggesting response to aberrant signaling, but were unable to penetrate the tumour microenvironment itself to enable an immune response against malignant cells or their polyomavirus.
Highlights
Merkel cell carcinoma (MCC) is a cutaneous high grade neuroendocrine carcinoma that is locally invasive with high metastatic potential [1]
High titre circulating IgG for either Merkel cell polyomavirus (MCPyV) Viral Protein (VP) 1 or Large T antigen (LTA) was detected for 7/9 patients: the two with negative titres had tumours negative for LTA on IHC but one patient with an LTA-negative tumour was serologically positive
In many cases MCC is loco-regionally aggressive and disseminated disease carries a poor outlook with no treatment established as inducing durable responses
Summary
Merkel cell carcinoma (MCC) is a cutaneous high grade neuroendocrine carcinoma that is locally invasive with high metastatic potential [1]. Over a 20 year period, the annual incidence rate in the United States has increased threefold, from 0.2 patients per 100,000 person-years (PY) in 1986, to 0.6 per 100,000 PY in 2006 [2]. The 10-year age standardised incidence rate of MCC in England has increased from 0.1 to 0.2 per 100,000 PY The mortality rate of MCC is more than twice that of melanoma, being 46% at 5 years [3]. The prognosis is related to the stage of the disease at presentation, with survival more than 90% for T1a or local disease. MCC is an aggressive tumour, and median survival for patients with distant metastases is only 9 months [4]. Palliation of loco-regional and distant disease is often difficult to achieve, and development of more effective treatments necessitates a better understanding of the underlying biology
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