Pigmented Epithelioid Melanocytoma

Pigmented epithelioid melanocytoma (PEM) is a rare melanocytic neoplasm composed of pigmented epithelioid and dendritic melanocytes with large vesicular nuclei. It was first described in patients with Carney complex under the rubric of epithelioid blue nevus. Carney complex is a rare familial cancer and lentiginous syndrome associated with mostly benign or indolent neoplasms, including myxomas, psammomatous melanotic schwannomas, and endocrine neoplasms. In spite of significant cytological atypia present in some cases ( Figs. 10.1 and 10.2 ), there was no evidence of aggressive behavior in Carney complex–associated pigmented lesions, which were considered to be a benign. Lesions similar in microscopic appearance to the epithelioid blue nevi reported by Carney were subsequently also described in patients without Carney complex.

Open full size image

Pigmented Epithelioid Melanocytoma from a Patient With Carney Complex.

(A) Low-power view showing epidermal hyperplasia. (B) Junctional component C. (C) Clusters of atypical large epithelioid cells in the center of the lesion.

Open full size image

Open full size image

Open full size image

Pigmented Epithelioid Melanocytoma from a Patient With Carney Complex.

(A) Low-power view. The less pigmented right half of the lesion is composed predominantly of large epithelioid cells, as shown in (D). (B) Dendritic cells, melanophages, and epithelioid cells at the infiltrating edge of the lesion. (C) Multinucleated large epithelioid cell. (D) Area consisting mainly of severely atypical large epithelioid cells.

Open full size image

Open full size image

Open full size image

Independently, studies into the nature of atypical heavily pigmented melanocytic lesions led to the concept of animal-type melanoma, pigment synthesizing melanocytic lesions that resemble malignant melanomas in animals, especially gray horses. These heterogeneous lesions were regarded as melanomas because they were able to metastasize to regional lymph nodes.

In 2004, Zembowicz, Carney, and Mihm suggested that a subset of lesions previously considered as animal-type melanoma were histologically indistinguishable from the epithelioid blue nevus of Carney complex. In spite of frequent tumor deposits in the sentinel lymph node, observed in 46% of cases, clinical follow-up indicated a favorable prognosis. Therefore Zembowicz and colleagues proposed that epithelioid blue nevus of Carney complex and cases diagnosed as animal-type melanoma should be considered as a unified histologic entity, which they designated PEM. Subsequent studies confirmed favorable outcome in PEM after 5 years of follow-up, with no local recurrence or metastases. A shared molecular pathway of at least some sporadic and Carney complex–associated PEMs was suggested by loss of expression in 80% of sporadic PEMs of protein kinase A regulatory subunit 1 alpha (PRKAR1A), a product of the PRKAR1A gene, which is mutated in 62% of families with Carney complex,

In 2004, the concept of PEM was controversial. The paradigm in melanoma pathology at that time was that melanocytic lesions were either benign or malignant and that lymph node metastasis was considered proof of malignancy. A number of lesions of PEM, whether occurring sporadically or in context with Carney complex, were found to have tumor deposits in sentinel lymph nodes, but distant spread was exceedingly rare. Such primary melanocytic neoplasms with tumor deposits in the regional lymph node but a subsequent indolent clinical course did not fit neatly into a binary tumor classification scheme. Thus the experience with PEM paralleled observations of several studies on atypical Spitz tumors that confirmed an indolent clinical course in most cases in spite of sentinel lymph node involvement.

Further similarities between spitzoid neoplasms and PEM were revealed by molecular studies. Spitzoid neoplasms are associated with gene fusions involving different kinases. Recently Cohen et al. showed that some PEMs also harbor gene fusions involving the protein kinase C alpha (PRKCA) gene. This gene has not thus far been implicated in Carney complex but is curiously located very close to PRKAR1A on chromosome 17. Another similarity exists with BAP1-deficient melanocytic neoplasms, which, like PEM, may occur in the setting of a familial cancer syndrome and also as sporadic lesions. The majority of BAP1-mutated melanocytic neoplasms harbor BRAFV600E mutations. Similarly, some PEMs that arise in conjunction with a precursor nevus were recently shown to harbor BRAFV600 mutation combined with aberrations of PRKAR1A gene. Finally, pure PEMs, lesions showing no evidence of a precursor lesion, have been shown to harbor mutations in MAP2K1 , a gene encoding MEK1, a protein kinase functioning downstream of BRAF in the MAP kinase cascade.

Historically, melanocytic neoplasms with morphologic features of PEM were considered to be members of the blue nevus family. This conclusion was based on the presence of dendritic cells reminiscent of dendritic cells of blue nevus, with heavy pigmentation. However, salient morphologic features of PEM and recent molecular data discussed further on argue against this notion and suggest that PEM lesions may be better grouped together with spitzoid neoplasms than with blue nevi.