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- Presentation
Recent Updates in Dermatopathology: Perineural Invasion, PRAME, and WHO Skin Tumor Classification
Description
Dr. Kenneth Tsai reviewed recent dermatopathology updates, focusing on three main areas: perineural invasion (PNI), PRAME immunostaining, and the WHO fifth edition skin tumor classification. He highlighted new mechanistic work showing that PNI can injure nearby nerves, trigger demyelination, chronic interferon and IL-6 signaling, promote immunosuppression, and reduce response to anti-PD-1 therapy; blocking IL-6 in models improved tumor viability, suggesting PNI is not only a poor prognostic sign but also biologically linked to immunotherapy resistance. He then discussed PRAME as a useful marker for melanocytic lesions, emphasizing that strong, diffuse nuclear staining supports melanoma, while several pitfalls exist, including positivity in a subset of dysplastic nevi and some non-melanocytic tumors, and poor utility in desmoplastic and uveal melanoma. PRAME was noted to be especially helpful in mucosal, nail unit, and acral lesions, but interpretation must be integrated with morphology and other markers such as SOX10. Finally, he summarized WHO updates that bring more molecular order to intermediate melanocytic proliferations, including Wnt-activated melanocytomas, PRKAR1A-loss pigmented epithelioid melanocytomas, and BAP1-inactivated melanocytomas, while stressing that TERT promoter mutations and p16 loss remain concerning features for melanoma. He ended with a note that digital papillary adenocarcinoma is strongly associated with HPV42, which can sometimes be detected through commercial low-risk HPV testing panels.
View moreConclusions
- Perineural invasion appears to injure nerves and create a chronic interferon/IL-6-driven immunosuppressive microenvironment that is associated with poorer anti-PD-1 response.
- Blocking IL-6 signaling in the setting of nerve injury may improve tumor control and help reverse resistance to immunotherapy.
- PRAME is a useful adjunct marker for diagnosing melanoma, especially in conventional cutaneous, mucosal, nail unit, and acral lesions, but it is not perfectly specific or universally sensitive.
- PRAME is less helpful in desmoplastic, uveal, and some other melanoma variants, so it should be interpreted with site- and subtype-specific caution.
- SOX10 remains a better screening or index marker for melanocytic proliferations, while PRAME functions more as a gauge of malignant concern than a stand-alone diagnostic test.
- Recent WHO updates bring more molecular order to intermediate melanocytic lesions by grouping them into biologically defined entities such as WNT-activated melanocytomas, PRKAR1A-deficient pigmented epithelioid melanocytomas, and BAP1-inactivated melanocytomas.
- For intermediate melanocytic lesions, molecular findings such as TERT promoter mutation and p16 loss should raise stronger concern for melanoma than morphology alone.
- Digital papillary adenocarcinoma is strongly linked to HPV42, and HPV testing can provide a practical diagnostic adjunct when histology is equivocal.
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