LESSONS FROM TUMOR PROGRESSION - THE INVASIVE RADIAL GROWTH-PHASE OF MELANOMA IS COMMON, INCAPABLE OF METASTASIS, AND INDOLENT

Primary melanoma generally evolves through three clinically and morphologically discernable tumor progression steps. Transformed melanocytes first proliferate above the epidermal basement membrane, then invade the papillary dermis (the in situ and invasive radial growth phases of melanoma), and subsequently develop the capacity to grow as a tumor (the vertical growth phase). Here, we address three aspects of the invasive radial growth phase that provide the rationale for viewing it as the critical lesion for melanoma detection and therapy. We determined the fraction of melanomas having this growth phase, tested its hypothesized incapacity to metastasize, and estimated its longevity. The high prevalence of this step in tumor progression was demonstrated in a data base of 624 patients, where at least 87% of melanomas exhibited a radial growth phase. The benignity of this lesion was evinced by the perfect metastasis-free survival of 161 patients treated for pure radial growth-phase melanomas and followed for a median of 13.7 years. Its indolence was evident in an analysis of the ages of 234 patients with superficial spreading melanomas without or with vertical growth phase: The cases with lesions having only radial growth phase were 4.3 years younger than those additionally having vertical growth phase (p < 0.05). These features of the invasive radial growth phase of primary melanoma, first described by Wallace H. Clark, make it a pivotal lesion in the evolutionary biology of melanocytic neoplasia and confirm its central place in public health programs to control melanoma mortality.