Answer: Mucosal melanoma

Histology: The surface epithelium demonstrates a pseudostratified ciliated columnar epithelium without evidence of metaplastic or dysplastic changes. A dense sheet-like cellular proliferation fills the submucosa. At high power, the cells have a primitive small round appearance with a high nuclear to cytoplasmic ratio. There are a few entrapped glands, but the tumor cells themselves do not show any specific differentiation in the form of rosettes, glands, melanin production or squamous pearls. Immunohistochemical studies were performed. The tumor cells are immunoreactive for S100 and HMB-45; and they are not immunoreactive for AE1:AE3, EMA, Chromogranin, SYN, CLA, or CD99.

Discussion: Melanocytes are normally present in the mucosa of the upper aerodigestive tract, and just like their cutaneous counterparts, these mucosal melanocytes can undergo malignant transformation. Even though cutaneous and mucosal melanomas arise from the same cell type – the neural crest derived melanocyte – these subgroups of melanoma are distinct. Mucosal melanomas of the head and neck are not associated with ultraviolet (UV) exposure, an important risk factor in the development of cutaneous melanomas. Mucosal melanomas tend to arise in an older age group compared to cutaneous melanomas. The onset of mucosal melanoma is typically two decades later than that of cutaneous melanoma. Mucosal melanomas and cutaneous melanomas appear distinct at the genetic level. For one example, activating mutations of the Braf oncogene are commonly encountered in cutaneous melanomas (about 80%), but are rarely detected in mucosal melanomas. Finally, mucosal melanomas are more aggressive than their cutaneous counterparts. They are characterized by advanced local growth, frequent local recurrences and distant dissemination, and exceedingly high fatality rates even in the setting of apparently complete tumor resection. Most mucosal melanomas of the head and neck involve the sinonasal tract, but melanomas of the oral cavity are well documented.

Mucosal melanoma of the head and neck is all too often misdiagnosed as some other neoplasm. One reason why sinonasal melanomas are so easily overlooked by the pathologist and surgeon alike is because they are entirely unexpected in this non-cutaneous site. Another reason why primary melanoma is often not considered in the differential diagnosis of sinonasal tumors is the infrequency with which they are encountered at this site. Less than 2% of all malignant melanomas arise from the mucosa of the upper respiratory tract. Mucosal melanomas sometimes elude detection because they lack several key features that are helpful in recognizing their true nature. Specifically, the majority of mucosal melanomas do not produce melanin pigment (i.e. they are amelanotic), and an in-situ component is usually not apparent. Perhaps the most significant factor contributing to the misdiagnosis of sinonasal melanomas has to do with their tendency to morphologically mimic a variety of other neoplasms. In the sinonasal tract, melanomas may have a spindle cell morphology and be confused with spindle cell sarcoma. Sinonasal mucosal melanomas may have an epithelioid appearance and be confused with poorly differentiated squamous cell carcinoma. As illustrated in the present case, sinonasal melanomas may be comprised of small blue cells and be confused other small round cell tumors.

The differential diagnosis of round cell tumors of the sinonasal cavity is quite extensive and includes rhabdomyosarcomas, lymphoma, small cell carcinoma, esthesioneuroblastoma, and PNET/EWING group tumor. Sorting through this differential diagnosis requires immunohistochemistry. As shown in the table below, mucosal melanomas have a characteristic immunohistochemical profile. They tend to be immunoreactive for S-100 protein and for other more specific markers of melanocytic differentiation including HMB-45, Melanin-A and MITF. Conversely, they are non-immunoreactive for epithelial markers (cytokeratin), lymphoid markers (common leukocyte antigen), and neuroendocrine markers (chromogranin, synaptophysin), or for CD99.