The presented two cases of carcinoma ex PA showed immunohistochemical expression of melanocytic markers, mimicking MM and potentially representing a diagnostic challenge. In both cases, the histological diagnosis of myoepithelial/melanocytic overlapping differentiation in carcinoma ex PA was reached after complete surgical resection, based on the histological features of the entire lesions and the complete immunohistochemical profile. Besides, BRAF V600E was negative in both cases.
The presence of epithelial/myoepithelial markers allowed to exclude both metastatic and exceptionally rare primary MM of the salivary glands [
12,
13]. The most challenging aspect of the presented two cases and subject of numerous pathogenetic speculations is the widespread expression of multiple melanocytic markers, as well as the potential presence of melanin pigment in salivary gland tumors [
2‐
11]. Salivary glands tumors can be “colonized” by the melanocytes resident in the salivary glands [
2‐
8]. Melanocytes present in human oral mucosa and salivary glands of healthy patients can be activated and move to the adjacent tumor, injecting melanosomes in the neoplastic cells, similarly to what occurs with keratinocytes in the epidermis [
2‐
6]. Melanocytic colonization can justify the aberrant expression of some melanocytic markers (HMB45 and MART-1) by salivary gland tumors [
8‐
11]. Nevertheless, the present two cases did not show melanin pigment and/or cells with a clear-cut melanocytic morphology (large and dendritic cells, with an appearance similar to melanocytes found in the basal layer of the normal skin), but only an immunohistochemical melanocytic differentiation. In addition, positivity for markers related to melanosomes (MART-1 and HMB45) was associated with positivity for markers of melanocytic differentiation as SOX10 and MITF; furthermore, the positivity was so strong and widespread throughout the entire lesion to be difficultly explainable just by melanosomes presence in the neoplastic cells. The alternative pathogenetic theory is a myoepithelial/melanocytic overlapping differentiation, justified by a common neural crest origin and proved by numerous shared immunohistochemical markers such as S-100 [
7]. Myoepithelial cells are well-known for the potential acquisition of divergent phenotypes, as epithelioid, spindle, adipocytic, clear, plasmacytoid, squamous with or without keratin [
7,
10,
11].
Desai SS et al
. reported a case of adenoid cystic carcinoma with abundant melanin in the neoplastic myoepithelial cells, with no evidence of intratumoral cells resembling dendritic melanocytes [
7]. The authors interpreted this phenomenon as a demonstration that myoepithelial cells can acquire a melanocytic-like phenotype [
7]. As result, the melanocytic immunophenotype and the synthesis of melanin by myoepithelial cells should be considered as an alternative “phenotypic avatar” potentially shown by these plastic cells [
7]. Additional proof of the myoepithelial/melanocytic overlapping differentiation is the widespread SOX10 expression observed in salivary glands [
9,
10].
Ohtomo et al
. reported that in normal human salivary gland tissue, SOX10 expression was observed in the nuclei of acini and both luminal and abluminal cells of intercalated ducts [
10]. The same authors showed as SOX10 is expressed from the developmental stage to adulthood, associated with the presence of epithelial stem/progenitor cells from embryonic day 13.5 (E13.5) [
10]. In the neoplastic counterpart, SOX10 is observed in a broad group of tumors as acinic cell carcinomas, adenoid cystic carcinomas, epithelial-myoepithelial carcinomas, myoepithelial carcinomas, basal cell adenoma and pleomorphic adenoma [
9,
10]. These data suggest that a broad family of salivary glands tumors, regardless of a specific lineage, derive from neural crest stem cells (SOX-10 positive) and may display a plastic and hybrid phenotype not always clearly definable [
10]. For this reason,
Ohtomo et al
. proposed a revolutionary classification of salivary glands neoplasia in SOX10 + tumors (originating from neural crest stem cells) and SOX10 – ones (alternative origin) [
10]. Melanocytic differentiation has been reported also in metaplastic breast carcinoma and rare examples of soft tissue tumors with bi or multi-directional differentiation [
14‐
16]. It remains to be determined whether this apparently paradoxical differentiation is the result of the transformation of a cancer stem cell (histogenesis theory) rather than a trans-melanocytic differentiation occurring as a late-step change (dedifferentiation theory) [
14‐
16]. The cases of salivary gland tumors with melanin pigment and/or melanocytic phenotype reported in the literature are too few to obtain data on the possible prognostic impact of the myoepithelial/melanocytic overlapping differentiation [
2‐
11]. The reported cases were different in histological subtypes and AJCC clinical-pathological stages, which does not allow to obtain easily comparable data on the possible prognostic impact of this rare and intriguing phenomenon [
2‐
11]. Carcinoma ex PA could show a broad range of histological features and, as consequence, of clinical aggressivity and prognosis (Case#1 had a low-grade malignant component and a very short follow-up; Case#2 had a pleomorphic and high-grade malignant component and the patient died of widespread metastatic disease 7 months after the diagnosis); besides, Case#2 showed at onset multiple lesions in liver and lungs, radiologically suspicious for metastasis (IV AJCC clinical stage). As result, the present cases do not add specific prognostic information as we think that the different histology and AJCC clinical stage could justify the clinical course of the two patients, regardless of the co-expression of myoepithelial and melanocytic features. Future studies are needed to clarify if this this aberrant melanocytic phenotype could have clinical and prognostic relevance.