Pigmented epithelioid melanocytoma (PEM) is a recently described entity comprising most cases previously described as "animal-type
melanoma" and epithelioid
blue nevus (EBN) occurring in patients with the multiple
neoplasia syndrome Carney complex (CNC). Mutations of the
protein kinase A regulatory subunit type 1alpha (R1alpha) (coded by the PRKAR1A gene) are found in more than half of CNC patients. In this study, we investigated whether PEM and EBN are related at the molecular level, and whether changes in the PRKAR1A gene status and the expression of the R1alpha
protein may be involved in the pathogenesis of PEM and other melanocytic lesions. Histologic analysis of
hematoxylin and
eosin-stained sections and immunohistochemistry (IHC) with R1alpha antibody were performed on 34 sporadic
PEMs, 8 CNC-associated
PEMs from patients with known PRKAR1A mutations, 297 benign and malignant melanocytic
tumors (127 conventional sections of 10 compound
nevi, 10 Spitz
nevi, 5 deep-penetrating
nevi, 5
blue nevi, 6
cellular blue nevi, 2 malignant
blue nevi, 3
lentigo maligna, and 86
melanomas of various types); in addition, 170 tissue microarray sections consisting of 35 benign
nevi, 60 primary
melanomas, and 75 metastatic
melanomas, and 5 equine dermal
melanomas, were examined. Histologic diagnoses were based on preexisting pathologic reports and were confirmed for this study.
DNA studies [loss of heterozygosity (LOH) for the 17q22-24 locus and the PRKAR1A gene sequencing] were performed on 60
melanomas and 7
PEMs. IHC showed that R1alpha was expressed in all but one core from tissue microarrays (169/170), and in all 127 melanocytic lesions evaluated in conventional sections. By contrast, R1alpha was not expressed in the 8 EBN from patients with CNC and PRKAR1A mutations. Expression of R1alpha was lost in 28 of 34
PEMs (82%). R1alpha was expressed in the 5 equine
melanomas studied.
DNA studies correlated with IHC findings: there were no PRKAR1A mutations in any of the
melanomas studied and the rate of LOH for 17q22-24 was less than 7%; 5 of the 7
PEMs showed extensive 17q22-24 LOH but no PRKAR1A mutations. The results support the concept that PEM is a distinct melanocytic
tumor occurring in a sporadic setting and in the context of CNC. They also suggest that PEM differs from
melanomas in equine melanotic disease, further arguing that the term animal-type
melanoma may be a misnomer for this group of lesions. Loss of expression of R1alpha offers a useful diagnostic test that helps to distinguish PEM from lesions that mimic it histologically.