Deep VEGF up-regulation in atypical melanocytic lesions:Differential correlation with apoptosis in Spitz tumors and atypical melanocytic nevi

Background: The bases of the cell kinetics and microvessel profiles in cutaneous atypical melanocytic lesions (atypical melanocytic nevi, AMN, and Spitz tumors, ST) are poorly understood. No study has correlated cell kinetics, microvessel profile, and VEGF expression by topographic compartments in AMN and ST to date. Design: We selected low-grade AMN (93), high-grade AMN (31), ST (42), malignant melanomas (42, 15 radial growth phase MM-RGP and 27 vertical growth phase MM- VGP), and conventional melanocytic nevi (15 junctional, 20 compound), the latter two groups used as controls. Immunostaining for Ki-67 and VEGF, and in situ end labeling (ISEL) of DNA fragments (using Klenow fragment of DNA polymerase I) were scored by topographic compartments: junctional, superficial dermal (above 0.76 mm) and deep dermal (below 0.76 mm), screening the whole compartment in each case. Appropriate controls were run in each sample. CD-31-stained slides were used to estimate microvessel density. The results were statistically compared using analysis of variance and Student t- test, and considered significant if P&lt;0.05. Results: Superficial-to-deep gradient was maintained for Ki-67 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 (4.38%, 4.73%, 8.35%), which correlate directly with microvessel density (4.38, 4.39, 7.41 vessels/HPF). Dysplasia grading revealed an inverse correlation with apoptosis in AMN, but kept the superficial- deep gradient. VEGF expression by compartments appears in the Table. Junctional/ Superficial/ Deep Junctional Nevi/ 11.00/ --/ -- Compound Nevi/ 4.39/ 0.92/ 0.45 Spitz/ 29.04/ 34.85/ 42.82 LG-AMN/ 18.57/ 8.76/ 0.53 HG-AMN/ 16.74/ 7.20/ 5.56 MIS/ 5.52/ --/ -- MM-RGP/ 25.25/ 28.08/ 52.79<br>MM-VGP/ 39.65/ 55.21/ 43.83<br>Conclusion: Deep VEGF up-regulation characterizes the vascular reaction associated with high-grade AMN and inversely correlates with the apoptosis index. In contrast, VEGF expression in ST directly correlates with the microvessel density and apoptosis index and inversely with the proliferation index, suggesting that this distinctive blood vessel pattern is reactive to regressive cellular changes.