Dormancy of growth-stunted malignant melanoma. The sustainable and smoldering patterns

Abstract

The versatility of presentations of primary and metastatic cutaneous malignant melanoma (CMM) is large. Evidence increasingly indicates that single CMM cells spread to distant sites quite early during neoplastic progression. They are soon eliminated before they become clinically detectable. Late appearing bulky metastases possibly arise from some of the early disseminated neoplastic cells. It seems that local CMM single cell micrometastases commonly predict sentinel lymph node involvement, without firmly reflecting CMM progression to bulky visceral metastatic competence. The current understanding of mechanisms supporting two peculiar CMM presentations are revisited. First, an extended apparent disease-free interval corresponding to sustainable CMM dormancy sometimes precedes overt metastatic growth. Immunosurveillance possibly induces dormancy in single disseminated CMM cells by arresting their cell cycle of proliferation. Second, the so-called CMM smoldering phenomenon represents the regional CMM alternating progression and regression when metastases wax and wane for long periods of time over restricted skin areas. It is likely that a set of biological factors impacts the versatile CMM progression, including the activation of CMM stem cells, and the combined phenotypic heterogeneity and variability in proliferative amplification in clusters of CMM cells. In addition, adequate stimulation of the CMM immunosurveillance, combined with the induction of a privileged stromal structure and vascular response are required. In this concert, most early CMM tumors are in part controlled by lymphocyte-mediated responses before they become clinically detectable. It remains that the importance of immunosurveillance remains debated. The array of mechanisms underlying both the sustainable and smoldering CMM dormancies remain unsettled.