Sinonasal malignant melanoma

Sinonasal malignant melanoma is a rare, aggressive malignant neoplasm arising from melanocytes within the mucosal lining of the nasal cavity and paranasal sinuses.[1][2] It accounts for less than 1% of all melanomas and less than 5% of all sinonasal tract neoplasms.[2][3] The tumor exhibits high metastatic potential and carries a markedly worse prognosis than cutaneous melanoma, with a median overall survival of approximately 21 months for the airway/sinonasal subsite.[4] Pathogenesis remains incompletely understood; unlike cutaneous melanoma, ultraviolet radiation plays no role, though an association with inhaled carcinogens such as formaldehyde and polycyclic aromatic hydrocarbons has been suggested, as sinonasal melanocytes participate in the metabolization of these compounds.[5] On imaging, the hallmark finding is a sinonasal soft-tissue mass with aggressive bone destruction; on MRI, melanotic tumors characteristically demonstrate T1 hyperintensity due to the paramagnetic effect of melanin.[6] Treatment centers on surgical resection with adjuvant radiotherapy.[7]

The AJCC 8th edition (2017) recognizes a dedicated TNM staging system for mucosal melanoma of the head and neck, which is distinct from the staging system used for sinonasal carcinomas.[7] The accepted designation is sinonasal mucosal melanoma (SNMM); the term primary mucosal melanoma (PMM) is used broadly for mucosal melanomas at any site.[2] Older literature may use "nasal melanoma" or "melanoma of the paranasal sinuses" without distinguishing mucosal origin. The qualifier "malignant" is sometimes appended but is redundant, as all melanomas are malignant by definition. The term "amelanotic melanoma" applies to the clinically non-pigmented variant, which constitutes a substantial proportion of sinonasal cases.[5]

• Age: Median age at diagnosis is approximately 68–70 years.[4][8]
• Sex: A slight female predominance has been reported in large molecular series, though some population-based analyses show a more balanced distribution.[4][8]
• Ethnicity: Most common in Caucasians; an increased incidence has been noted in individuals of Japanese and African ancestry.[4][5]
• Anatomic distribution: The nasal cavity is the most common primary site, with the lateral nasal wall and nasal septum predominating; the lateral wall accounts for nearly half of nasal cavity cases. The maxillary sinus is the most commonly affected paranasal sinus, followed by the ethmoid sinus; frontal and sphenoid sinus involvement is rare. Nasal cavity melanomas are typically diagnosed at an earlier stage than paranasal sinus melanomas.[2][9][10]

Symptoms

Presenting symptoms are nonspecific and frequently mimic benign sinonasal disease, contributing to diagnostic delay (mean symptom duration approximately 6–7 months before diagnosis).[9] The most common complaints are:

• Unilateral nasal obstruction and epistaxis, occurring in combination in the vast majority of patients[9]
• Facial pain, headache, rhinorrhea, and hyposmia[5][9]

Examination findings

• Endoscopy typically reveals a polypoid or fleshy mass, most often dark brown or black, though color ranges from white to red in amelanotic variants. A substantial proportion of sinonasal mucosal melanomas are clinically amelanotic.[5][9][11]
• Pigmented mucosal patches (melanosis) adjacent to the primary mass may represent precursor lesions.[5]

Advanced disease

• Proptosis, diplopia, and orbital pain indicate orbital invasion.[2]
• Cranial nerve deficits, facial numbness, or neurological symptoms suggest skull base or intracranial extension.[2][12]
• Regional lymph node metastasis at presentation is uncommon in sinonasal melanoma compared with oral mucosal melanoma.[9]

Sinonasal malignant melanoma is not a primary jaw lesion, but maxillary sinus tumors and, less commonly, nasal cavity tumors may extend inferiorly to involve the alveolar process, hard palate, and adjacent teeth. Dental radiographic findings therefore reflect secondary invasion from the sinonasal compartment rather than a primary intraosseous process.

Location and distribution

• The tumor most commonly arises from the lateral nasal wall, nasal septum, or maxillary sinus mucosa. On panoramic radiography, the lesion may be detected as opacification of the maxillary sinus, loss of the antral cortical outline, or a soft-tissue density projecting into the sinus.[2]
• When the maxillary sinus floor is breached, the mass may extend into the posterior maxillary alveolus, presenting as an ill-defined radiolucency in the alveolar bone on periapical or panoramic images.[13]

Periphery and shape

• Margins are characteristically ill-defined and irregular, reflecting the aggressive, infiltrative growth pattern of the tumor.[14]
• Unlike benign or slow-growing sinonasal lesions that produce smooth bony remodeling, sinonasal melanoma causes lytic, destructive bone changes without a sclerotic border.[14]

Internal architecture

• The internal pattern is a homogeneous soft-tissue density without calcification or internal mineralization. No matrix production (osseous or chondroid) is expected.[15]
• On CT, the mass appears as a non-calcified, moderately enhancing soft-tissue density filling the involved sinus or nasal cavity.[15][16]

Effects on teeth and adjacent structures

• When the tumor invades the maxillary alveolar process, it may cause displacement or loosening of teeth, mimicking periodontal disease or a primary odontogenic process.[13][17]
• Root resorption of adjacent teeth may occur with direct tumor invasion of the alveolus.
• Loss of the lamina dura and widening of the periodontal ligament space adjacent to the tumor may be visible on periapical radiographs.
• Destruction of the hard palate can produce an oroantral communication.[18]

Extent and cortical involvement

• Aggressive cortical bone destruction is the hallmark radiographic finding. The walls of the maxillary sinus—particularly the medial, inferior (alveolar), and posterolateral walls—may be eroded or completely destroyed.[14][19]
• Extension through the orbital floor produces orbital soft-tissue involvement; erosion of the cribriform plate indicates anterior skull base invasion.[12]
• Infratemporal fossa erosion, when present, is specific for malignancy and distinguishes the process from chronic sinusitis.[19]
• CBCT is not useful in the workup of sinonasal masses because of its limited soft-tissue contrast resolution. However, when a sinonasal melanoma extends into the maxillary alveolus, CBCT acquired for dental indications may incidentally reveal the destructive bony changes—cortical perforation, sinus floor loss, and alveolar bone destruction—that should prompt urgent referral for medical CT and MRI.[14][20]

Variants

• Amelanotic tumors lack the melanin-related signal characteristics on MRI that aid diagnosis of melanotic variants and are indistinguishable from other sinonasal malignancies on dental radiographs alone.[5][6]
• Paranasal sinus primaries tend to present at a more advanced stage with more extensive bone destruction than nasal cavity primaries.[2][10]

MRI signal characteristics

MRI is the preferred modality for soft-tissue characterization and staging of sinonasal melanoma.[7][14] The signal behavior depends on melanin content:

• Melanotic tumors (the majority) demonstrate characteristic high signal intensity on T1-weighted images due to the paramagnetic effect of melanin, and intermediate to low signal on T2-weighted images. This combination is highly suggestive of melanoma among sinonasal masses.[2][6]
• Amelanotic tumors show intermediate T1 signal intensity, losing the diagnostic T1 hyperintensity and making them harder to distinguish from other malignancies.[6]
• A septate pattern on precontrast T1-weighted images—alternating hyperintense and hypointense striations reflecting uneven melanin and hemorrhage distribution—has high specificity (97%) for sinonasal melanoma and serves as a useful discriminator from other sinonasal malignancies.[21][22]
• Mild to moderate gadolinium enhancement is typical.[6]
• Diffusion-weighted imaging shows significantly lower ADC values in sinonasal melanoma compared with squamous cell carcinoma, aiding differentiation.[22]

Tumor extent and staging

• MRI is superior to CT for evaluating skull base invasion, dural and intracranial extension, orbital involvement, perineural tumor spread, and bone marrow infiltration.[7][16]
• MRI effectively distinguishes tumor from obstructed sinus secretions, which appear T2 hyperintense in contrast to the intermediate-to-low T2 signal of melanoma.[14][16]

CT for bone assessment

• Contrast-enhanced CT complements MRI by providing superior depiction of cortical bone erosion, bony destruction patterns, and foraminal widening that may indicate perineural spread.[16]

PET/CT

• Sinonasal mucosal melanomas are characteristically FDG-avid; FDG-PET/CT is valuable for initial staging to detect distant metastases and for surveillance of recurrence.[2][7]

Sinonasal melanoma must be distinguished from other aggressive sinonasal malignancies that present as destructive soft-tissue masses. The T1 hyperintensity and septate pattern on MRI, when present, are the strongest imaging discriminators; however, amelanotic variants and cases evaluated only with dental radiographs or CT require histopathologic confirmation.

The highest-risk diagnostic pitfall is the amelanotic variant, which lacks the characteristic MRI signal features and may be indistinguishable from squamous cell carcinoma or undifferentiated carcinoma on imaging alone. Biopsy with an immunohistochemical panel (S-100, HMB-45, Melan-A) is essential for definitive diagnosis.[1][7]

Microscopic features

• Sinonasal mucosal melanomas are characteristically pleomorphic, with the epithelioid cell type predominating; spindle cell, rhabdoid, and undifferentiated morphologies also occur.[1][5]
• An in situ component with junctional activity is identifiable in the majority of cases and supports mucosal origin.[25]
• Melanin pigment is present in a variable proportion of tumors; a substantial fraction are histologically amelanotic.[5]
• High mitotic rate and tumor necrosis are common and correlate with aggressive behavior.[26][27]

Immunohistochemistry

• Diagnosis requires a panel approach: S-100 (most sensitive), HMB-45, and Melan-A are the standard markers. SOX10 is an additional useful marker.[1][7]
• CD117 (c-Kit) expression is seen in approximately one-third of cases and correlates with tumoral pigmentation.[28]

Radiologic-pathologic correlation

• The T1 hyperintensity on MRI corresponds histologically to melanin-containing tumor cells; the septate pattern reflects alternating bands of melanin-rich tumor and fibrous stroma.[21]
• Amelanotic tumors lack this paramagnetic effect, explaining their intermediate T1 signal and the loss of the characteristic MRI appearance.[6]

Molecular profile

• NRAS mutations are the most frequent oncogenic alteration, identified in approximately 14–42% of cases depending on the series and sequencing methodology.[8][29][30]
• KIT mutations occur in approximately 5–22% and BRAF mutations in approximately 4–8%; BRAF V600E is rare.[8][29][30]
• A large proportion of sinonasal mucosal melanomas are wild-type for BRAF, NRAS, and KIT, distinguishing them molecularly from cutaneous melanoma and limiting targeted therapy options.[8][30]
• SF3B1 mutations, TERT promoter alterations, and SPRED1 mutations have been identified at lower frequencies.[8][28]
• Ki-67 proliferative index and the presence of brisk tumor-infiltrating lymphocytes are associated with survival outcomes and may inform prognosis.[26]

Staging

The AJCC 8th edition provides a dedicated staging system for mucosal melanoma of the head and neck. Notably, there is no T1 or T2 category; the minimum stage is T3 (tumor limited to mucosa and immediately underlying soft tissue), reflecting the inherently advanced nature of these tumors at diagnosis.[7] T4a denotes invasion of deep soft tissue, cartilage, bone, or overlying skin; T4b indicates involvement of brain, dura, skull base, lower cranial nerves, masticator space, carotid artery, or mediastinal