Secondary neoplasms involving the major salivary glands, including the parotid gland, account for a notable proportion of malignant neoplasms diagnosed by FNA of salivary glands. [1, 2, 3] Metastatic squamous cell carcinoma and malignant melanoma comprise the majority of cases, with the head and neck being the most common primary site. [1, 3] Cutaneous primaries are particularly frequent sources of metastasis to intra- and peri-glandular parotid lymph nodes. [3]

Cutaneous melanoma is a highly aggressive neoplasm known for its predilection to metastasize. Metastases are most frequently found in regional lymph nodes and skin, followed by distant visceral sites such as lungs, liver, the central nervous system, and bones. [4] Cytologically, melanoma exhibits a diverse spectrum of morphologies, with a discohesive pattern frequently observed in cases of melanoma with an epithelioid or plasmacytoid morphology, while fragments, three dimensional clusters, and syncytial groups are more commonly seen in cases with a spindle cell or mixed morphology. The most common morphological variants are epithelioid, plasmacytoid, and spindle cell, with rare variants including small, rhabdoid, signet-ring, myxoid, and balloon cell. [4]

Melanoma has been given the moniker “great mimicker” as it can resemble many diverse neoplasms and frequently poses diagnostic challenges. This is particularly true in very rare variants such as the myxoid variant of melanoma, which is additionally frequently negative for melanocytic markers such as Melan-A and HMB-45 [5]. The myxoid variant most frequently occurs as a metastasis, and the primary neoplasm commonly does not itself manifest a myxoid morphology.[5] Tissue sections show malignant melanocytic cells - which can exhibit a range of different morphologies, from spindled to large and polygonal - embedded in a basophilic matrix comprising acidic mucopolysaccharides, thought to be produced by stromal cells in response to tumor invasion 5,6]. The myxoid stroma can appear as a fibrillary matrix on FNA smears. [6]

The heterogeneity of melanoma cytomorphology underscores the necessity of maintaining a high index of suspicion, with close attention to the patient's clinical history, and ancillary studies, especially immunocytochemistry, to aid in accurate diagnosis. Melanocytic markers such as SOX10, S100, Melan-A, HMB45, and PRAME are typically employed to help distinguish melanoma from other neoplasms that may present overlapping cytologic features. [7]

Notably, in the context of lesions of the salivary gland, the highly sensitive but nonspecific melanocytic markers S100 and SOX10 are less helpful as they are also positive in many salivary gland neoplasms. In this context, markers such as Melan-A, HMB45, and PRAME are expected to be more helpful in making the diagnosis of melanoma. However, it is important to keep in mind that some melanomas do not exhibit positive staining for Melan-A, HMB45, and PRAME. [8] Given high clinical suspicion, a differential diagnosis of melanoma should therefore still be considered even when staining is negative for some of these latter markers in the setting of positivity for S100 and SOX10, which are the most sensitive markers for melanoma. [7] This is particularly true if there is negative or only focal/weak staining for markers which are expected to be positive in primary parotid neoplasms, such as pankeratin, CK7, p40, p63, calponin and SMA, as in the current case. In such challenging cases, molecular testing may be necessary to render the correct diagnosis.