Primary malignant melanoma can be found in about 3% of individuals during their lifetime. Whereas, metastatic melanoma is typically seen in only approximately 4% of the 3% of people diagnosed with melanoma. The most common sites of metastatic melanoma are lymph nodes, lungs, liver, bones, brain, and abdomen [1].

While melanoma is not an entirely uncommon finding in the mediastinum (about 5% of cases), this is not the first diagnosis considered when examining an inflamed mediastinal lymph node without apparent malignant tumor cells [2]. In fact, this diagnosis was mainly entertained due to the patient’s known history of cheek and abdominal skin melanoma with metastatic disease, combined with the imaging finding of multiple enlarged lymph nodes and pulmonary nodules (rather than a solitary nodule). Clinical history is essential to achieving an accurate diagnosis.

Mediastinal lymph nodes are located in the center of the thoracic cavity, and are surrounded by the heart, trachea, and esophagus [3]. Therefore, melanoma spreading to this region of the body is often associated with a poor prognosis. On FNA cytology, melanoma cells appear singly and can be seen in sheets but not in true groups. Cells may appear epithelioid or spindled, with hyperchromatic nuclei and prominent nucleoli. Binucleation and nuclear enlargement with eccentric nuclei can often be appreciated [4]. Cells often display pleomorphism, though they can sometimes be blander in appearance. Melanin pigment may be appreciated, but may be absent. Pigmented histiocytes may be present [5].

Immunohistochemistry, can aid in the diagnosis of melanoma which is typically positive for S-100, SOX-10, PRAME, HMB45 and MelanA. The use of these markers is essential for accurate diagnosis, to distinguish melanoma from other neoplasms with similar cytological features [6].

When examining mediastinal lymph nodes for malignant disease, most commonly, primary lung carcinomas must be considered. Morphologically, there can be overlap with small cell and non-small cell lung carcinomas, due to the heterogeneous nature of melanoma morphologies [7]. Therefore, immunohistochemistry can be the key to distinguishing these entities, as negative staining for pancytokeratins helps to rule out carcinomas [8]. Small cell carcinoma would additionally be positive for TTF1, Synaptophysin, ChromograninA and INSM1, whereas, adenocarcinoma would be positive for TTF1 and NapsinA (and negative for the neuroendocrine markers) [9]. Keratinizing squamous cell carcinoma can typically be distinguished due to the presence of keratin, however, there can occasionally be morphologic overlap and the use of P40 (or P63) and CK5/6 (positive) can help distinguish this entity from melanoma (negative for squamous markers) [10].

Another helpful ancillary test in malignant melanoma is molecular testing. In the case of our patient, a BRAF c.1799T>A, p.Val600Glu mutation was detected. BRAF v600E mutations are fairly common and are present in 50% of all melanomas. A BRAF v600E mutation is caused by substitution of valine (V) for glutamic acid (E). The patient will form a tumor due to the uncontrollable division of cells [11].