Recent Advances in Dermatopathology: Perineural Invasion, PRAME, and WHO Skin Tumor Updates

Conclusions

• Perineural invasion appears to worsen immunotherapy outcomes by inducing nerve injury, chronic interferon/IL-6 signaling, and an immunosuppressive tumor microenvironment.
• Blocking IL-6 signaling may help counter nerve-injury–associated resistance to anti-PD-1 therapy.
• PRAME is a useful adjunct marker for diagnosing melanoma when it shows strong, diffuse nuclear staining, especially in conventional, mucosal, nail unit, and acral melanoma.
• PRAME has important limitations because some benign or intermediate lesions can be positive, so it should not be used in isolation.
• PRAME is generally not very helpful in desmoplastic or uveal melanoma, and special caution is needed in certain sites and lesion types.
• The WHO fifth-edition update brings more molecular order to intermediate melanocytic lesions by reclassifying several entities based on defining genomic alterations.
• WNT-activated melanocytomas, including deep penetrating nevus and plexiform nevus/melanocytoma, are now grouped by beta-catenin pathway activation.
• Pigmented epithelioid melanocytoma is defined by PRKAR1 loss and can be further subclassified by associated mutations or fusions.
• TERT promoter mutations and p16 loss remain key molecular red flags that should raise concern for melanoma.
• Digital papillary adenocarcinoma is strongly linked to HPV42, making viral testing a useful diagnostic adjunct in this difficult entity.