*3.1.2 Primary mucosal melanomas of the oral cavity*

Primary mucosal melanomas of the oral cavity account for <1% of all melanomas, 0.5% of all oral malignancies, and 40% of all PMMs of the head and neck. The incidence of oral PMMs is higher in Asians, Africans, Hispanics, and Asian Indians [43–45].

Oral primary mucosal melanomas tend to present late as they are usually asymptomatic in the early stages and are often unnoticed by patients [11].

Compared to sinonasal disease, it may be diagnosed earlier due to the greater accessibility for inspection and oral examination.

Oral MM generally presents as a hyperpigmented lesion (**Figures 1** and **2**), with a wide range of colors varying from black, brown, gray to reddish or white. Interestingly, oral lesions may be amelanotic in up to 10–30% of cases; in these patients, diagnosis may be challenging. Amelanotic melanomas may simulate pyogenic granulomas [46, 47].

The tumors can be macular, nodular or plaque-like. Just like cutaneous melanomas, melanoma in the mouth may be asymmetric with irregular borders.

There can also be non-specific symptoms including bleeding, ulceration and pain, which is associated with the vertical growth of the lesion [48].

Macular lesions are flat, and up to one-third of patients have a long history of mucosal pigmentation (melanosis) [49, 50], which is considered the radial growth phase before invasion of underlying tissues (vertical growth phase). Nodular tumors, conversely, have an irregular surface and present as ulcerated, exophytic lesions.

**Figure 1.** *Aveolar ridge mucosal melanoma.*

**Figure 2.** *Hard palate mucosal melanoma.*

As with the sinonasal tract, it is also possible to observe satellite lesions in the oral cavity surrounding the primary lesion [49, 51].

The majority of oral melanomas occur in the maxillary alveolar ridge or the hard palate. Such locations favor early invasion of underlying bone, which may account for their poor prognosis. The buccal mucosa, lips, tongue, floor of the mouth, and uvula can also be affected as well [52].

The involvement of other subsites (floor of the mouth and tongue) is not commonly observed.

Tanaka et al. [52] featured oral MM into 5 types: pigmented, nodular type; non-pigmented, nodular type; pigmented, macular type; pigmented, mixed type; non-pigmented, mixed type. This classification was based in patterns of growth and presence of pigmentation.

25% of the patients with oral cavity melanomas present with lymph node metastases. The likelihood of cervical lymph node metastases increases when the tumor thickness is more than 5 mm [53, 54]. Wu et al. [52], on the other hand, found that MMs with a nodular pattern of growth have a higher risk of nodal involvement compared to macular melanomas.

#### *3.1.3 Primary mucosal melanomas of other head and neck sites*

Rare cases of laryngeal [55], oropharyngeal [56] and nasopharyngeal [50, 57] MM have been reported; these lesions are extremely rare, with only sixty cases reported in the literature. The tumors are most commonly located in the supraglottic region (62.2%) followed by the vocal cords (37.8%).

Clinical presentation does not generally differ from that typical of other primary tumors, mainly squamous cell carcinomas, arising in the same sites.

The symptoms of laryngeal MM are dysphagia, hoarseness, and painful sore throat [18, 19, 58].

Pharyngeal lesions may cause hemorrhage, dysphagia and/or dyspnea [19].

Symptoms of nasopharyngeal PMMs are similar to sinonasal PMMs; the tumors usually present with epistaxis, nasal obstruction, and obstruction of the Eustachian tube with serous otitis [19].

Notably, the risk of nodal (65.5%) and distant (59.3%) metastases in pharyngolaryngeal lesions is definitely higher than in other head and neck subsites [4].

As a general rule, the risk of nodal involvement in HNMM at presentation is higher in oral (25-43%) [47] than in sinonasal lesions (<10%) [35, 53].

The high rates of cervical node involvement at presentation is probably related to the size of primary lesions. 61% of nodal involvement occurs in lesions larger than 4 cm. Levels I (68%), II (68%) and III (23%) are the most commonly involved,

**73**

*Mucosal Melanoma of the Head and Neck: From Diagnosis to Treatment*

involvement may be detected in up to one-third of cases [53].

whereas the frequency of metastases at levels IV (12%) and V (2%) is much lower [44]. The occurrence of distant metastases at presentation is low (5-10%), with no significant difference between oral and sinonasal lesions [53, 59]. The brain and lungs are the preferential sites of distant localization, whereas multiple organ

Head and neck PMMs are usually diagnosed at advanced stages, thus presenting macroscopically as aggressive nodular neoplasms arising from the mucosa; few cases are detected in situ [60]. Histopathological diagnosis is straightforward when the tumor cells are melanin rich. About two thirds of mucosal melanomas contain some intracytoplasmic brown pigment, which has to be confirmed as melanin and can be

The histological features of HNMM can be as diverse as cutaneous melanomas [62], with variable mitotic activity and cell morphology [11]. Approximately 15 to 50% of cases presents with amelanotic lesions [63, 64]; as they can mimic another malignant neoplasms, including squamous cell carcinoma, this diagnosis has been

Histologically, mucosal melanoma is characterized by the proliferation of neoplastic melanocytes with variable phenotypes (epithelioid, spindle, and plasmacytoid cells without maturation and with nuclear changes, appearing as large and hyperchromatic nuclei with prominent nucleoli) that are arranged in a sheet-like, organoid, alveolar, solid, or desmoplastic architecture. They display high mitotic activity and show a pattern of invasion of the submucosa destroying the underlying

Tumors with mixed cell phenotypes are more related with vascular invasion and the development of metastasis. The neoplastic proliferation is commonly found along the junction between the epithelial and lamina propria, but this may be difficult to

Molecular studies have tried to find clinical predictors and immunohisto-

Immunohistochemical stains may help distinguish mucosal melanoma from

PMMs variously express S-100 protein and melanocytic markers, including MART-1/Melan-A, tyrosinase, HMB- 45, and MITF. 62 S-100 protein has greater sensitivity, but HMB-45 is probably more specific [42]. The absence or scarcity of melanin makes the diagnosis difficult and immunohistochemical techniques are required. The cells of amelanotic melanomas are positive for S-100 protein Melan-A, HMB-45, MITF and vimentin; and negative for cytokeratin [71].

One study assessed the expression of DNA mismatch repair and looked for the presence of microsatellite instability in HNMM. They showed that the cells had increased expression of mismatch repair proteins and increased microsatellite stability [72]. Besides these classical markers, the diagnostic potential of other molecules has been evaluated in Primary Oral Mucosal Melanoma (POMM), in particular several adhesion molecules. Integrin beta-3 and CD166 expression is correlated with extensive vascular invasion, while lower expression of CD54 is

The expression of BCL2 in POMM has an important correlation with a longer

The expression of podoplanin and CD13 in combination with S100 has been useful in the evaluation of lymph vessel and blood vessel invasion. Both markers are

chemical biomarkers to improve outcomes and survival rates.

challenging. These tumors frequently have a worse outcome [65, 66].

*DOI: http://dx.doi.org/10.5772/intechopen.93804*

found in tumor cells or macrophages [61].

detect in advanced and ulcerated lesions [70].

correlated with cell necrosis [73].

related to a poorer prognosis [75].

overall survival [74].

other malignancies and from cutaneous melanoma.

**3.2 Histological diagnosis**

tissues [67–69].

whereas the frequency of metastases at levels IV (12%) and V (2%) is much lower [44]. The occurrence of distant metastases at presentation is low (5-10%), with no significant difference between oral and sinonasal lesions [53, 59]. The brain and lungs are the preferential sites of distant localization, whereas multiple organ involvement may be detected in up to one-third of cases [53].
