The role of micrometastasis in high-risk skin cancers

Abstract

The propensity to metastasize is the most important prognostic indicator for solid cancers. New insights into the mechanisms of early carcinogenesis have revealed micrometastases are generated far earlier than previously thought. Evidence supports a synergistic relationship between vascular and lymphatic seeding which can occur before there is clinical evidence of a primary tumour. Early vascular seeding prepares distal sites for colonisation while regional lymphatics are co-opted to promote facilitative cancer cell mutations. In response, the host mounts a global inflammatory and immunomodulatory response towards these cells supporting the concept that cancer is a systemic disease. Cancer staging systems should be refined to better reflect cancer cell loads in various tissue compartments while clinical perspectives should be broadened to encompass this view when approaching high-risk cancers. Measured adjunctive therapies implemented earlier for low-volume, in-transit cancer offers the prospect of preventing advanced disease and the need for heroic therapeutic interventions. This review seeks to re-appraise how we view the metastatic process for solid cancers. It will explore in-transit metastasis in the context of high-risk skin cancer and how it dictates disease progression. It will also discuss how these implications will influence our current staging systems and its consequences on management.

Keywords: Merkel cell cancer (MCC); adjunctive radiotherapy (ART); adjuvant therapies; cancer seeding; carcinogenesis; circulating tumour cells (CTC); immunoassay; immunotherapy; in-transit metastases (ITM); intravital staining; liquid biopsy; loco-regional disease; lymphatic pathways; melanoma (MM); metastasis-initiating cells (MICs); occult cancer; regional radiotherapy; sentinel lymph node biopsy (SNLB); squamous cell cancer (SCC); total body tumour load (TBTL); tumour microenvironment (TME).