Utility of Combined Immunohistochemical Staining for AMBRA1 and Loricrin for Improving the Pathologic Diagnosis of High-Grade Dysplastic Nevi

Background: The diagnosis of high-grade dysplastic nevus (HGDNs) can present a challenge for a pathologist. The utility of combined AMBRA1 and loricrin staining for the diagnosis of HGDN was evaluated using preferentially expressed antigen in melanoma (PRAME) as a comparator.

Materials and methods: A cohort of 145 cases of HGDN was selected from a consecutive series of 409 dysplastic nevi ascertained in a single pathology service between 2015 and 2019. Combined immunohistochemistry for AMBRA1 and loricrin expression in the epidermis overlying the HGDN was consensus scored by 2 experienced pathologists. PRAME immunohistochemistry was also consensus scored in the melanocyte population using a five-point scale (0–4+).

Results: All HGDNs showed maintenance of either 1 or both AMBRA1 and loricrin epidermal expression with 3 exceptions. In 1 instance, a focus of melanocytes within the HGDN was associated with loss of both markers in the overlying epidermis and the melanocytes in the focus were strongly positive (4+) for PRAME. On expert review, the diagnosis was changed to thin melanoma. In the other 2 cases showing loss of both markers, the absence of staining was focal and restricted to mounds of parakeratosis. Most HGDN were negative for PRAME although 48% were positive to some degree and 4% showed a 4+ expression.

Observations: Clinical follow-up showed no evidence of progression or metastasis. We found that 23 patients (16%) had previous, concurrent, or subsequent early stage melanomas and 2 patients (1%) had previous melanoma in situ. One HGDN recurred after 3 years, and the further excision sample showed recurrent HGDN only.

We observed that mild epidermal hyperplasia and parakeratosis were often found in HGDNs, suggesting an active melanocyte–epidermal interaction in the lesions. We speculate that epidermal hyperplasia resulted in some of the HGDN showing single-cell loricrin gaps or thinning of the loricrin band. AMBRA1, loricrin, and PRAME staining was additionally performed on 39 benign melanocytic nevi covering a range of types for comparison. Epidermal hyperplasia was generally not seen and almost all cases showed maintenance of both epidermal AMBRA1 and loricrin, with loricrin gaps and thinning seen only in 3 Meyerson nevi where there was parakeratosis (3/5 Meyerson nevi).

Conclusion: This study suggests that AMBRA1 and loricrin staining is a useful biomarker to confirm the diagnosis and/or to signal low-risk behavior in HGDN, particularly in cases where 4+ PRAME staining could potentially point to a melanoma diagnosis.