Mucosal Melanoma

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Diagnosis and reasoning

New-onset unilateral nasal complaints in an elderly person are highly suspicious for a sinonasal mass, especially when combined with extranasal features involving the ipsilateral orbit. Thus, anterior rhinoscopy is a good first step in the evaluation of this patient; this confirms the clinical suspicion by revealing a large, friable mass with contact bleeding in the affected nostril. Given his age, a neoplastic lesion is a very real concern; infectious and inflammatory etiologies are the other possibilty, but are clinically less likely given the absence of other supportive symptoms. With respect to neoplasms, while benign tumors are far more common, even at this age, the gross appearance of the tumor is worrisome of a malignancy. In turn, malignancies are most often epithelial in origin, including squamous cell carcinoma, adenocarcinoma, adenocystic carcinoma, or mucosal melanoma; malignant lymphoma is the most common nonepithelial malignancy. Given the histological diversity of the above possibilities, a biopsy is crucial to distinguish between them; here, histology confirms that the tumor is indeed malignant in nature. Furthermore, immunohistochemical staining reveals positivity for S-100, Melan-A, and HMB-45; this is diagnostic of a mucosal melanoma; thus, the tumor is a sinonasal mucosal melanoma (SMM). Similar to any other malignancy, staging should be the next step; imaging studies are essential to delineate local extension, with magnetic resonance imaging (MRI) being a suitable modality. Here, MRI reveals that the mass is large, with evidence of local invasion; the T1, T2, and contrast film findings are characteristic of SMM. While there is no evidence of regional lymph node involvement, distant spread in the absence of this is a well known phenomenon with this malignancy. The National Comprehensive Cancer Network (NCCN) recommends F-18 FDG PET/CT for the detection of distant metastasis; this shows that the liver and axial skeleton are indeed involved. The above findings show the tumor to be T4aN0M1, as per the American Joint Committee on Cancer (AJCC) clinical staging system for mucosal melanoma (mmTNM); he is thus in prognostic group IV-C. Unfortunately, this is an extremely advanced stage of disease; palliation is the only realistic option. Note that CYFRA 21-1 is a tumor marker used in the management of non-small cell lung cancer (NSCLC); it has no role here. Systemic chemotherapy is the only modality which appears to improve survival at this stage; radiotherapy, while not affecting survival, will help improve quality of life by facilitating with local and regional control. Given the stage of the disease, local resection is not an option now; immunotherapy has not been shown to affect survival.


Discussion

Mucosal melanoma (MM) is a rare but highly aggressive form of melanoma which is clinically and biologically distinct from cutaneous melanoma; it accounts for between 0.8% to 3.7% of all melanomas, and ~0.03% of all cancer diagnoses. Sinonasal mucosal melanomas (SMM) are the most common clinical subform of MM; as the name suggests, these involve the mucosa of the nose and paranasal sinuses. The remainder of this monograph pertains to this entity, although much of that information is applicable to MM in general. Given the rarity of SMM, statistics are limited; however, MM in general are predominantly encountered in the elderly, with a median age at diagnosis of 70 years, and a slight female predilection. The specific mechanisms underlying the malignant transformation of mucosal melanocytes are still unclear; however, alterations in the RAS-RAF-MEK pathway and the PI3K–AKT pathway (including PTEN-regulated signaling) are believed to play a key role. Note also that inhaled and ingested carcinogens (particularly products of smoking and formaldehyde), have been implicated in the pathogenesis of SMM. The disease typically demonstrates an insidious onset; due to the hidden location and nonspecific features, many patients only seek medical attention in the advanced stages. Typical symptoms include nasal pain, discharge, obstruction, or swelling; epistaxis; and the presence of a visible mass at the vestibule. Diplopia, epiphora, and proptosis are late features. Note also that SMM is highly aggressive, with lymph node spread and distant metastasis often occuring early in the course of the disease. Depending on the presentation, the nasal mass may be detected by endoscopic assessment, e.g. anterior rhinoscopy, or imaging studies such as computed tomography (CT) or magnetic resonance imaging (MRI). Tissue biopsy is essential to establish the diagnosis; this typically reveals heterogeneous epithelioid, spindle, or small cells, with an abundant eosinophilic cytoplasm, cytoplasmic pigment deposits, round pleomorphic nuclei, and prominent nucleoli. Immunohistochemical staining will reveal positivity for S-100 protein, mean-A, HMB-45, microphthalmia transcriptase factor (MITF), tyrosinase, vimentin, and cytokeratin. National Comprehensive Cancer Network (NCCN) guidelines recommend either CT or MRI for local staging; however, more recent research favors the latter, due its higher soft tissue resolution, and ability to easily detect melanin, which is paramagnetic. Fluorodeoxyglucose (FDG)-PET/CT is recommended for the detection of distant metastases, as the tumor cells show high avidity to this substance. Staging can be via either the American Joint Committee on Cancer (AJCC) system for carcinoma of the nasal cavity and sinuses (carTNM), or the system for head and neck primary MMs (mmTNM). While the former is more widely used, certain authorities favor the mmTNM, on the basis that it respects the oncologic premise that the behavior of MM is the same, regardless of the site of origin. The therapeutic consensus is for surgical excision where the disease is localized and complete resection is feasible; both open and endoscopic approaches are possible, with the latter becoming increasingly popular due to lower morbidity rates, shorter hospital stays, and better cosmesis. Chemotherapy is used in metastatic and late-stage disease, although there is only a limited impact on survival. Radiotherapy, immunotherapy, and biological therapy have been used as adjuvant modalities; however, their efficacy is yet to be clear established. While prognostic data for SMM is limited, MM in general has a poor prognosis, with five-year survival rates of between 22% to 46%; recurrences, both local and regional, tend to occur early on, and repeatedly.


Take home messages

  1. SMM is a disease of the elderly; the hidden location, and nonspecific symptoms and signs often result in a high diagnostic latency, and contribute to an overall poor prognosis.
  2. Distant metastasis may occur even in the absence of nodal spread, and even before the tumor is locally advanced.
  3. Local excision is the only curative therapy; where distant spread has occurred, chemotherapy is the only intervention know to improve survival, albeit only marginally.

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