The EORTC protocol for sentinel lymph node biopsy (SLNB) reveals a high number of nodal nevi and a strong association with nevus-associated melanoma

Cutaneous Melanomas: A Single Center Experience on the Usage of Immunohistochemistry Applied for the Diagnosis

“…An additional diagnostic field for HMB-45 is the differential diagnosis between nodal nevi (NN) (HMB45(-)) and MM (HMB45(+)) in the pathological evaluation of SLNB [ 53 ]. Nevertheless, according to the literature data, as well as in our experience, p16 and PRAME (NN: p16(+) and PRAME(-); MM: p16(-) and PRAME(+)) have much more sensibility and specificity than HMB-45 in this specific diagnostic set [ 53 , 54 , 55 , 56 ].…”

“…Besides, CDKN2A biallelic inactivation is recognized to be a late molecular step in the oncogenesis of cM, which is mainly involved in the advanced/metastatic stages (the percentage of metastatic cM p16(+) ranges between 0% and 41%); as result, p16 is not useful for the differential diagnosis of superficial lesions (superficial spreading cM and dysplastic cN), which represent the majority of routine diagnostic dilemmas [ 82 , 83 ]. In our experience, and in line with most of the literature data, the diagnostic scenarios in which p16 is mainly useful are the following: (1) the evaluation of dermal and/or nodular atypical melanocytic lesions/melanocytomas (the atypical Spitz tumor, atypical cellular blue tumor, and atypical proliferative nodule arising in congenital cN), where p16 loss reflects the biallelic inactivation of CDKN2A (also proved by molecular techniques) and represents strong criterion of malignancy; (2) the identification of a more aggressive phenotype is acquired by the primary cM, as p16 loss is characteristic of the advanced/metastatic cM; (3) differential diagnosis between NN and MM in the evaluation of SLNB [ 28 , 29 , 53 , 54 , 55 , 56 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. Although some studies showed that PRAME is superior to p16 for discriminating NN from MM, in our experience, p16 remains a reliable diagnostic tool in this diagnostic setting [ 53 , 54 , 55 , 56 , 83 , 84 ].…”

“…In our experience, and in line with most of the literature data, the diagnostic scenarios in which p16 is mainly useful are the following: (1) the evaluation of dermal and/or nodular atypical melanocytic lesions/melanocytomas (the atypical Spitz tumor, atypical cellular blue tumor, and atypical proliferative nodule arising in congenital cN), where p16 loss reflects the biallelic inactivation of CDKN2A (also proved by molecular techniques) and represents strong criterion of malignancy; (2) the identification of a more aggressive phenotype is acquired by the primary cM, as p16 loss is characteristic of the advanced/metastatic cM; (3) differential diagnosis between NN and MM in the evaluation of SLNB [ 28 , 29 , 53 , 54 , 55 , 56 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. Although some studies showed that PRAME is superior to p16 for discriminating NN from MM, in our experience, p16 remains a reliable diagnostic tool in this diagnostic setting [ 53 , 54 , 55 , 56 , 83 , 84 ]. Interestingly, we found very exceptional cases of cM that show a “paradoxical” diffusion and/or clonal overexpression of p16, representing a potential diagnostic pitfall and reflecting complex cell cycle deregulation, which results in the intracellular accumulation of p16 protein [ 85 ].…”

“…As previously clarified (Chapter 2.2.2. ), our working group has recently developed two DS combining PRAME (nuclear) with HMB-45 and MART-1 (cytoplasmatic) that showed very encouraging results and became part of the immunohistochemical panels routinely used in our laboratory [ 56 , 107 ]. In our experience, these DS (HMB-45/PRAME and MART-1/PRAME) are particularly useful in the following diagnostic scenarios: (1) lesions almost exclusively junctional/intraepithelial (allowing us to not evaluate keratinocytes); (2) lesions with a high inflammatory infiltrate (allowing us to not evaluate lymphocytes); (3) differential diagnosis between NN and MM, especially in SLNB; (4) metastasis of unknown primary tumor and/or primary cutaneous tumor with undifferentiated morphology, especially with limited available histological material.…”