Microinvasive radial growth phase of cutaneous melanoma: a histopathological and immunohistochemical study with diagnostic implications

Cutaneous melanoma (M) can develop through two progression phases: the radial growth phase of M (RGPM) and the vertical one. This distinction has a practical relevance in defining lesions with potential for a metastatic course. We analyzed the morphological attributes (intraepidermal proliferation type, inflammatory infiltrate, mitogenicity, Breslow thickness, Clark level, ulceration) and the immunohistochemical profile (S100, Melan A, HMB45, p16INK4a, CD117, Ki67, Cyclin D1, E Cadherin, Podoplanin) of 12 microinvasive RGPMs in absence of regression, with almost 10 years of follow-up. Immunohistochemistry (IHC) revealed that S100, Melan A, and HMB45 maintain a high expression in M cells in both epidermal and dermal compartments. Interestingly, an overexpression of p16INK4a in the nests of dermal microinvasion has been ascertained in all our cases. On the other hand, we found an attenuation of expression for CD117, Ki67, Cyclin D1, and E Cadherin in the migration phase from the epidermis to dermis. Each phase in M progression appears characterized by a specific immunohistochemical profile, as a result of molecular alterations. The long-term follow-up of our case series showed that microinvasive RGPM without regression is not tumorigenic and is devoid of metastatic potential; therefore, its accurate categorization is important. Conversely, microinvasive RGPM with regression should be classified as melanocytic tumor with uncertain biological potential. IHC for p16INK4a can be helpful in the diagnosis of microinvasive M on challenging cutaneous biopsies. Moreover, it can be applied as an immunohistochemical discriminator to distinguish microinvasive RGPM from in situ RGPM and microinvasive RGPM from dysplastic nevi.