Deep dermal up-regulation of HIF-1A is directly correlated with apoptosis in Spitz tumors
Background: The microvessel profile bases in cutaneous atypical melanocytic lesions (atypical melanocytic nevi, AMN, and Spitz tumors, ST) are poorly understood. No study has correlated microvessel profile and HIF-1 expression with cell kinetics 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 HIF-1, 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<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%), and no correlation with microvessel density. Dysplasia grading revealed an inverse correlation with Ki67/ISEL index in AMN, but kept the superficial-deep gradient. HIF-1 expression by compartments appears in the Table.
Junctional Superficial Deep Junctional Nevi/ 2.48/ --/ -- Compound Nevi/ 2.59/ 2.41/ 0 Spitz/ 16.32/ 15.09/ 14.12 LG-AMN/ 2.59/ 0.86/ 0 HG-AMN/ 3.42/ 0.55/ 0
MIS/ 0.76/ --/ --
MM-RGP/ 5.81/ 11.63/ --
MM-VGP/ 10.58/ 18.78/ 18.08
Conclusion: Deep dermal upregulation of HIF-1 characterizes Spitz tumor and vertical growth phase MM, with preservation of the superficial-deep gradient and direct correlation with apoptosis in Spitz tumors only. This over-expression represents an additional mechanism of neovascularization, which does not correlate directly with the vascular density level.
