Hypoxia and apoptosis are core findings of Spitz morphology of combined melanocytic nevi

Background: The microvessel profile bases in cutaneous melanocytic lesions are poorly understood, in particular for combined Spitz tumors (CST). No study has correlated microvessel profile and HIF­1α expression with cell kinetics by topographic and phenotypic compartments in CST to date. Design: We selected combined Spitz tumor­conventional melanocytic nevi (44), and malignant melanomas (43, 23 radial growth phase MM­RGP and 20 vertical growth phase MM­VGP), the latter two groups used as controls. Immunostaining for Ki­67 and HIF­1α, and in situ end labeling (ISEL) of DNA fragments (using Klenow fragment of DNA polymerase I) were scored by topographic (junctional, dermal above 0.76 mm, and dermal below 0.76 mm) and phenotypic (conventional, ST) compartments, screening the whole compartment in each case. Appropriate controls were run in each sample. CD­31­stained slides were used to estimate microvessel density. The results were statistically compared using analysis of variance and Student t­test, and considered significant if P<0.05. Results: Superficial­to­deep gradient was maintained for Ki­67 in all lesions, but was significantly higher in MM. From junctional to deep dermal compartments, ST showed a progressive and statistically significant increase of ISEL indices (5.39%, 5.84%, 9.48%), a microvessel density (4.38, 4.39, 7.41 vessels/HPF), and no correlation between them. The Ki67/ISEL index increased in MM but keeping a superficial­deep gradient in MM­RGP only. Conclusion: Localized ischemic changes drive ST morphology of combined nevi (deep dermal upregulation of HIF­1α directly correlated with apoptosis), in contrast to the apoptosis independent HIF1 upregulation of vertical growth phase MM. This over­expression represents an additional mechanism of relatively inefficient neovascularization, which does not correlate directly with the vascular density level.