State of the Art Oncology in EuropeFont: aaa

Mucosal melanoma of the head and neck – 2016



1.1 Incidence

Malignant melanomas of the mucosa (MM) are very rare cancers. In 2013, almost 850 newly diagnosed cases were estimated to occur in Europe, with an annual incidence rate of 1.5 per million (RARECAREnet). The most common sites are the head and neck (41%) (Mallone 2012). Incidence is slightly but significantly higher in women than men (1.0 vs. 1.2). The disease is unusual in people under the age of 65; in those over 65 years of age, the rate is 6.3 per million. There are geographical differences in the occurrence of melanoma of mucosa, with age-adjusted incidence highest in the North (2.2) and lowest in the East of Europe (0.7). During the period 1995-2007, incidence rates remained stable (RARECAREnet).

1.2 Survival

Melanoma of mucosa is an aggressive malignancy with a very poor prognosis. In Europe, according to the RARECAREnet project (RARECAREnet), where survival was calculated from 2,277 European cases diagnosed between 2000-2007, 1-, 3-, and 5-year survival were 63%, 30% and 20%, respectively.
Five-year survival was 23% in patients aged 25-64 years of age and 19% in patients >65 years of age. In Europe, during the period 1999-2007, 5-year survival remained stable. (RARECAREnet) Despite numerous technological developments in surgery and radiation therapy, as well as advances in systemic modalities, no increased survival advantage was seen for melanoma of mucosa (Lazarev 2014).

1.3 Risk factors

Sun radiation, a major risk factor for cutaneous melanoma, is unlikely to be implicated in mucosal melanomas, which occur on sun-shielded surfaces. For oral mucosal melanoma, cigarette smoking has been suggested as risk factor, because it has been demonstrated that pigmented oral lesions are more prevalent among smokers (Axell 1982). Exposure to formaldehyde was suggested to be a risk factor for sinonasal mucosal melanoma, since some cases were reported among workers subject to industrial or professional exposure to this substance (Holmstrom 1991). Association with viruses is unlikely, since several studies did not show a link between mucosal melanomas and human papilloma viruses, human herpes viruses, or polyomavirus (Holmstrom 1991; Lundberg 2006; Giraud 2008).


Mucosal malignant melanoma represents a rare group of tumours (0.2%-8% of all malignant melanoma), with different localizations in the body. Head and neck mucosal melanomas comprise less than 1% of all melanomas and the mucosa of nasal cavity, paranasal sinuses and oral cavity are the most common locations.
In contrast to cutaneous melanoma, the biology and pathogenesis of mucosal melanoma of the head and neck region is poorly understood. The latest experimental studies specifically address primary mucosal melanoma of the oral cavity (POMM).
Precursors of melanocytes arise from the neural crest, from where they migrate to their final destination through embryonic mesenchyme, along specific pathways (Dupin 2003). Most of the melanocytes are located in the epidermis and dermis of the skin, but it is not rare to find them in other body structures such as eyes and mucosal surface of the head and neck region, in particular in the sinonasal region (Patel 2002; Bachar 2008).
The presence and the function of melanocytes in the mucosal membrane are not yet clarified, although a few studies have supported the hypothesis of an antimicrobial and immunological function (Mackintosh 2001; Plonka 2009).
Several hypotheses have been put forward on POMM pathogenesis. Early studies supposed that POMM arose from pigmented nevi, pre-existing pigmented areas or de novo from an apparently normal mucosa (Rapini 1985). In 2005, Kahn et al suggested that POMM could arise from the transformation of a benign oral pigmentation (Kahn 2005).
As for the pathogenesis of other tumour entities, the existence of precursors cells that originate from stem/progenitor melanocytes has also been hypothesized for POMM. These melanocytes, following a series of molecular alterations, would have acquired a malignant phenotype (Bandarchi 2013). Another hypothesis suggested that precursor cells could develop as mature melanocytes remaining in the submucosa. As a result of specific molecular and cytogenetic alterations, they have then acquired a de-differentiated phenotype with the gain of a self-renewal capacity (Cramer 2009).
The pathogenesis of mucosal melanoma is under the control of several signalling pathways. The analyses of genetic profiling of mucosal melanoma have mainly identified the mitogen activated protein kinase (MAPK) pathway, with signalling cascade RAS/MEK/ERK, as involved in POMM development (Hsieh 2013).
Moreover, the phosphatidylinositol-3-kinase (PI3K)-PTEN pathway, along with the alteration of several other genes and proteins, also appears to be involved in POMM pathogenesis (Omholt 2011).
Microphthalmia transcription factor (MITF) is a leucine zipper transcription factor that plays an important role in the regulation of proliferation, differentiation, growth and survival of melanocytes. MITF expression has been found in 40 to 90% of POMM (Morris 2008).
c-KIT regulates MITF activity and its overexpression has been reported in all mucosal melanoma, frequently associated with c-KIT mutation (Rivera 2008) in about 14% of cases (Tacastacas 2014).
Mutations of c-kit are numerous and can involve exons 9, 11, 13 and 17. The most common are represented by point mutation L576P in exon 11 and K642E mutation in exon13 (Curtin 2006). Specifically, Lyu et al showed that in oral mucosal melanoma the most frequent mutations in cKIT gene are those in exon 13 (p.K642) and exon 17 (p.N822I), while no mutation in exon 9 has been detected (Lyu 2016).
Consequently, different inhibitors of mutated c-KIT for the treatment of metastatic mucosal melanomas are in the experimental phase of development (Minor 2012).
Unlike cutaneous melanoma, BRAF mutations are infrequent in mucosal melanoma. A recent study reported that only 5% of these tumours showed a BRAF mutation (Tacastacas 2014). Lyu et al found that only 3% of POMM patients had a BRAF mutation in exon 15, but not the renowned V600E mutation. The most frequent mutations are represented by a pD594N substitution and a p.T599T synonymous mutation (Lyu 2016).The contribution of these mutations to POMM pathogenesis needs to be clarified. Besides, the absence of BRAF V600E mutation suggests that vemurafenib would not be efficacious in the treatment of patients with mucosal melanoma.
NRAS is frequently mutated in melanoma. The main mutations are detected in codons 12, 13, and mostly in codon 61 (Berger 2009).
Oncogenic mutation in the NRAS gene is present in 19-28% of melanomas, but rarely it is described in POMM. However, the higher incidence of NRAS mutation is documented in sinosal mucosal melanoma compared to other types of head and neck mucosal melanoma (Zebary 2013). In sinosal melanoma NRAS mutations are located in exon2 (codon 12 and 13) and exon 3 (codon 61), with similar frequencies, in 14-22% of patients (Turri-Zanoni 2013).
Mutations in GNAQ/GNAII pathway are described as important triggers in melanoma pathogenesis. In particular a GNAQ/GNAII p.Q209L mutation has been found in 77% of primary uveal melanomas, but it is rare in POMM (Lyu 2016).
Cell cycle regulation molecules have been abundantly studied in melanoma pathogenesis. In particular it has been reported that dysregulation of G1/S phase and impairment of programmed cell death may play a role in pathogenesis of POMM. Accumulation of p53 protein occurs in 58% of POMM but no mutations are associated (Gwosdz 2006). BCL-2 overexpression and loss of p16 are described as early events in POMM (Prasad 2012).
Several cytogenetic aberrations are also associated with mucosal melanoma pathogenesis. Amplification of chromosome 4q12.7 was described in acral and mucosal melanoma (Curtin 2006). Cyclin D1 amplification was found in 10% of mucosal melanoma and Myc amplification was detected in 62.5% of the mucosal melanoma (Glatz-Krieger 2006).


3.1 Clinical signs and symptoms

Presenting symptoms of MM differ in relation to the site of origin. In the sinonasal tract, early signs and symptoms (nasal obstruction and discharge, epistaxis, facial pain) are similar to those encountered in inflammatory conditions and therefore may be overlooked for some time. Other complaints (exophthalmos, ophthalmoplegia, headache, skin infiltration and ulceration) are less frequently encountered and are commonly associated with advanced-stage disease. At endoscopy, MM may present as a polypoid, fleshy lesion with strict unilateral involvement in the majority of cases. Lesions may have different degrees of pigmentation, with the possibility of diversely pigmented areas within the same mass; completely amelanotic tumours are rare but not exceptional. Furthermore, not infrequently multiple lesions (i.e., satellite lesions) even centimetres away from the main tumour, with spreading occurring along the mucosal/submucosal planes, can be observed. The most frequently involved sites are the inferior turbinate/lateral nasal wall and nasal septum (43.1% and 24.2%, respectively) (Moreno 2010a). Paranasal sinus involvement is mainly due to lesions arising within the maxillary sinus and the ethmoid, whereas primary lesions of the sphenoid and frontal sinus are exceedingly rare (Moreno 2010a; López 2016).
Conversely, lesions arising in the oral cavity may be diagnosed earlier than their sinonasal counterparts due to the greater accessibility for inspection. Oral MM generally presents as a hyperpigmented lesion, with a wide range of colours varying from black, brown, grey to reddish or white (Penel 2006). Interestingly, in up to 10−30% of cases oral lesions may be amelanotic; in these patients, diagnosis may be challenging (Tomicic 2003; Tanaka 2004; Sun 2012).
Oral MM may have either a nodular or macular appearance (Tanaka 1994; Wu 2014). Macular lesions are flat, and up to one-third of patients have a long history of mucosal pigmentation (melanosis) (Warszawik-Hendzel 2014; Tacastacas 2014), which is considered the radial growth phase before invasion of underlying tissues (vertical growth phase). Nodular tumours, conversely, have an irregular surface and present as ulcerated, exophytic lesions. Haemorrhage and ulceration are usually a late occurrence, associated with the vertical growth of the lesion (Meleti 2007). As with the sinonasal tract, it is also possible to observe satellite lesions in the oral cavity (Hicks 2000; Tacastacas 2014). The most involved sites are the hard palate, maxillary gum and mandibular gum (Wu 2014; Sun 2012), whereas the involvement of other subsites (tongue, floor of the mouth) is exceedingly rare.
Tanaka et al. (Tanaka 1994) categorized oral MM into 5 types according to the pattern of growth the presence of pigmentation:

  • Pigmented, nodular type;
  • Non-pigmented, nodular type;
  • Pigmented, macular type;
  • Pigmented, mixed type:
  • Non-pigmented, mixed type.

Rare cases of laryngeal (Terada 2007; Zaghi 2013), oro-pharyngeal (Wagner 2008) and nasopharyngeal (Thompson 2003; Mardi 2014; Bekci 2014) MM have been reported; clinical presentation does not generally differ from that typical of other primary tumours, mainly squamous cell carcinomas, arising in the same sites. Laryngeal MM may cause hoarseness, sore throat, and dysphagia, whereas pharyngeal lesions may cause haemorrhage, dysphagia and/or dyspnoea (Lourenço 2014).
As a general rule, the risk of nodal involvement at presentation is higher in oral (25-43%) (Patel 2002; Wu 2014) than in sinonasal lesions (<10%) (Patel 2002; Moreno 2010a; Nakashima 2008). Analysing a large series of 254 patients with oral MM, Wu et al. (Wu 2014) found a 43% rate of cervical node involvement at presentation. However, this high value might be due to the high rate of primary lesions larger than 4 cm (61%). Levels I (68%), II (68%) and III (23%) are by far the most frequently involved, whereas the frequency of metastases at levels IV (12%) and V (2%) is much lower (Wu 2014). In oral lesions, this risk of regional metastasis is deemed higher in lesions with a depth of infiltration >5 mm (Patel 2002). Wu et al. (Wu 2014), on the other hand, found that MMs with a nodular pattern of growth have a higher risk of nodal involvement compared to macular melanomas. For this reason, they advocate elective neck dissection in patients with nodular or macular MM greater than 4 cm, whereas in nodular MM smaller than 4 cm close observation of the neck may be adequate. Notably, the risk of nodal (65.5%) and distant (59.3%) metastases in pharyngo-laryngeal lesions is definitely higher than in other head and neck subsites (Lourenço 2014).
The occurrence of distant metastases at presentation is low (5-10%), with no significant difference between oral and sinonasal lesions (Patel 2002; Bachar 2008) 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 (Patel 2002).

3.2 Histological diagnosis

Normally, mucosal melanoma can be easily diagnosed by a morphological analysis. Histologically, POMM is characterized by the proliferation of neoplastic melanocytes with variable phenotypes (epithelioid, spindle, and plasmacytoid tumour cells) that are arranged in a sheet-like, organoid, alveolar, solid, or desmoplastic architecture. Tumours with mixed cell phenotypes are more aggressive and are associated with a higher prevalence of vascular invasion and metastasis. Usually the neoplastic proliferation lies along the junction between the epithelial and lamina propria, but in advanced, ulcerated lesions, this might be difficult to detect (Coutinho-Camillo 2015).
Many molecules involved in POMM pathogenesis can be considered as useful immunohistochemical biomarkers for diagnosis and prognosis of this disease. Immunohistochemical stains may help distinguish mucosal melanomas from other malignancies and from cutaneous melanoma. They are likely to stain positively for S-100, vimentin, HMB-45, and Melan-A and negatively for cytokeratin and epithelial membrane antigen (Lourenço 2014) (Figure 1). These immunostainings are recommended on a Type C basis (General consensus).

Figure 1. Morphological  and  Immune-phenotypical features of mucosal melanoma: Hematoxylin/Eosin coloration, immune-positivity for S100, HMB45 and MITF (40X).

Figure 1. Morphological and Immune-phenotypical features of mucosal melanoma: Hematoxylin/Eosin coloration, immune-positivity for S100, HMB45 and MITF (40X).

Besides these classic markers, the diagnostic potential of other molecules has been evaluated in POMM, in particular several adhesion molecules. Integrin beta-3 and CD166 expression is correlated with extensive vascular invasion, while lower expression of CD54 is correlated with cell necrosis (Bologna 2013).
MITF protein expression has been reported as positive in 26% of POMM (Figure 1), while a different staining intensity has been detected in POMM for p75 and p53 markers (Alaeddini 2015). P75 is expressed at high levels in 43% of POMM, while p53 was detected in 14% of POMM (Tanaka 2001) especially in tumours of undifferentiated cells, compared to epithelioid or spindle cells (Prasad 2004a).
Moreover, positive staining has been found for Rb protein in 23% and for p16 in 53% of POMM (Tanaka 2001). However, p16 expression decreased from 32% in primary tumours, to 12% in recurrent and 15% in metastatic tumours (Prasad 2012).
A consistent expression of BCL2 has also been described in POMM with a significant correlation with a longer overall survival (Prasad 2012).
To verify the prognostic value of lymph vessel invasion (LVI) and blood vessel invasion (BVI) in POMM, the expression of podoplanin and CD13 in combination with S100 has been evaluated. The expression of both markers has been useful in the prognostic classification of POMM patients presenting a worse outcome (Wermker 2015).
Finally, as with cutaneous melanoma, mucosal melanoma can also be considered as a strongly immuno-modulated tumour. Several studies reported in POMM the aberrant expression of cancer-testis antigens (CT7, MAGE-A4 and NY-ESOI) in POMM, suggesting the potential use of CTA based immunotherapy (Prasad 2004a).
More recently, Curioni-Fontecedro et al. showed that MAGE-C1/CT7 and MAGE-C2/CT10, highly expressed in cutaneous melanoma in which they induce a specific cellular immune response, are also strongly expressed in mucosal melanoma. In particular, CT7 was present in 55% of primary and metastatic samples, and CT10 in 30% of samples (Curioni-Fontecedro 2015).
Programmed cell death ligand 1 (PDL-1) is known as a potent prognostic biomarker in several human tumours. A recent interesting study highlighted the strong prognostic value of PDL-1 also in POMM. Immunohistochemical expression of PDL-1 has been detected in 13% of POMM and it is directly correlated with longer recurrence-free survival (Thierauf 2015). Although this experimental evidence strongly supports the use of monoclonal antibodies targeting immune checkpoint proteins in mucosal melanoma and specifically in POMM (Lian 2014; Del Vecchio 2014), PDL-1 expression does not seem to be predictive of patient outcome, at least in melanoma (Fusi 2015).

3.3 Imaging of melanomas of the head and neck

Imaging of melanomas of the mucosa (MM) should preferably be obtained with MRI. The analysis of signals in the different sequences provides a pattern of information on the tumour, which is by and large more sophisticated than the analysis of CT densities. Similarly, the combination of high spatial and contrast resolution obtained with 3d MRI sequences allows a more accurate delineation of deep tumour extension.
MRI signal of MM is mainly influenced by the amount of melanotic pigment and haemorrhage within the lesion. The paramagnetic properties of melanin and of the free radicals produced by the metals ligated to the pigment itself account for a MRI pattern composed of T1 hyperintensity and T2 hypointensity (Kim 2000; Gomori 1986). According to Woodruff, however, a high T1 signal is more related to intratumoral haemorrhage (in particular to the paramagnetic effect of some blood by-products) (Woodruff 1987).
Although this pattern has been described in intraocular, skin, and intracranial metastatic melanomas, overall the evidence for MM are limited by its rarity which hinders the collection of large series of surgical specimens with documented radiological and pathological data. However, in a series of 6 MM, Yoshioka et al. found T1 hyperintensity in all highly melanotic tumours (>10% melanin-containing cells) and T1 isointensity in intermediate (<10% melanin-containing cells) lesions; no significant correlation was seen for T2 signal (Yoshioka 1998). In 11 patients, Kim et al. observed T1 hyperintensity in 6/11 MM: 5 were melanotic tumours while the sixth was an amelanotic MM with abundant haemorrhage; in this series, a low T2 signal was seen exclusively in amelanotic tumours (Kim 2000).
When the abovementioned pattern is absent, MM is in most cases indistinguishable from other histotypes. Linear signal voids within the lesion – that may represent vessels or fibrous septa – and contrast enhancement, generally heterogeneous, are poorly specific findings (Kim 2000) (Figure 2).

Figure 2. Patient 1: coronal TSE T2 (a) and axial SE T1 (b). Patient 2: coronal SE T1 (c) and post contrast 3d GE T1 on sagittal plane (d). Patient 1 exhibits the typical MRI pattern (T2 hypointensity and T1 hyperintensity), whereas the absence of melanotic pigment and /or hemorrhage (c) makes T1 signal in patient 2 rather nonspecific. Contrast enhancement (d) is only moderate, significantly lower than normal mucosa (asterisk); some linear hyperenhancing structures (arrows) may either represent fibrous septa or intratumoral vessels.

The apparent diffusion coefficient (ADC) measured with diffusion weighted (DWI) sequences is a finite parameter quantifying the mobility of water molecules within tissues. Although this parameter may be used to discriminate between benign and malignant lesions, the characterisation of malignant entities probably exceeds its potential. On the other hand, several preliminary reports have shown promising applications in head-and-neck cancers treated with chemoradiation both for prediction and monitoring of response to treatment (Thoeny 2012). Evidence for MM are limited to a series of 37 patients in which minimum ADC proved to be a prognostic factor for overall survival and distant metastasis-free survival (Jingu 2011).
In most cases, the MM manifests radiologically as an aggressive solid tumour eroding bone structures and invading adjacent soft tissues (Gilain 2014). Thus, pre-treatment tumour mapping requires definition of tumour relationships with all surrounding anatomic sites and subsites. For example, sinonasal MM requires careful scrutiny of the orbits, the anterior cranial fossa, the pterygopalatine fossa and the infratemporal fossa. Tumours arising in the nasopharynx or along the Eustachian tube may invade the skull base at the foramen lacerum or spread along the tube to potentially reach the middle ear. MM of the oral cavity typically occurs in the hard palate and maxillary gingival; tongue, mandibular, and oropharyngeal lesions are exceedingly rare. Key elements in the preoperative staging of MM of the oral cavity and oropharynx include depth of submucosal invasion, extension across the midline bone invasion and infiltration of deep space of the suprahyoid neck. Perineural spread should be carefully evaluated particularly when the neoplasm reaches key anatomic crossroads, such as the posterior third of the hard palate, the pterygopalatine fossa, and the foramen ovale.


A universal staging system for mucosal melanomas does not exist. There are several system according to each site. However, in the 7th edition of the American Joint Committee on Cancer (AJCC), classic TNM staging system is adopted for melanomas of head and neck, although it is still necessary to create appropriate staging systems for mucosal melanomas of other regions. This could facilitate comparisons of the results of different institutions, and help define the best therapy (AIOM 2014).
The TNM classification for nasal and paranasal sinus cancer was originally conceived for epithelial tumours, while a staging system specific for melanoma is available only for skin and ocular lesions. The first staging system specific for malignant melanoma (MM) dates to 1970 when Ballantyne (Ballantyne 1970) proposed a very simple classification for head and neck MM, by identifying three stages (Table 1):

Table 1. Ballantyne head and neck MM classification.
Stage Characteristics
I MM limited to the primary site
II MM with regional (neck lymph node) metastasis
III MM with distant metastasis

This system, as highlighted by López et al. (López 2016), is very easy and applies well to MMs of all head and neck subsites. The simplicity is also the inherent limit of this system, since the overwhelming majority of patients with MM, especially in the sinonasal tract, belong to Stage I and no further factors (i.e., local extension, depth of infiltration) may be used to stratify patients in terms of prognosis; moreover, the presence of nodal involvement without distant metastasis is quite rare.
Thompson et al. (Thompson 2003) found that patient outcome in sinonasal and nasopharyngeal MM was mainly affected by the presence of metastatic and/or multifocal disease. Consequently, they suggested a staging specific for sinonasal and nasopharyngeal MM (Table 2). The most relevant changes are that the T category identified in the Ballantyne system is sub-divided in T1 (tumour limited to a single anatomic site) and T2 (tumour involving more than one anatomic site including any extension into deep and/or surrounding structures and tissues) (Table 2). The T category can then be combined with N- and M-status into a staging group (Table 2) in the attempt to define a system more similar to the TNM classification than the Ballantyne system. By applying this staging system to their series of 115 cases, a statistically significant difference in treatment outcome was found between patients with Stage I-II and III-IV disease.

Table 2. Thompson et al. staging system for sinonasal tract and nasopharyngeal mucosal malignant melanoma.
Staging Characteristics
Primary tumour
T1 Single anatomic site
T2 Two or more anatomic sites
Regional lymph node
N1 Any lymph node metastasis
Distant Metastasis
M1 Distant metastasis
Stage grouping
Stage I T1; N0; M0
Stage II T2; N0; M0
Stage III Any T; N1; M0
Stage IV Any T; any N; M1

With the intention of better defining Ballantyne Stage I lesions, Prasad et al., subdivided this category into three sub-categories according to the depth of infiltration (Prasad 2004b) (Table 3):

Table 3. Prasad et al MM sub-categories.
Level Characteristics
1 in situ disease
2 infiltration limited to the lamina propria (limited invasion)
3 invasion of muscle, cartilage and/or bone (deep invasion)

The prognostic relevance of this system was confirmed by the statistically significant difference in 5-year disease specific survival (DSS) at different levels, showing decreased survival with increasing levels of invasion.
Head and neck MM can also be staged according to the AJCC TNM classification originally conceived for epithelial cancer (Greene 2002); its prognostic value has been demonstrated in both head and neck (Loree 1999) and sinonasal MM (Moreno 2010b).
In 2009, the UICC 7th TNM edition introduced a classification specific for MM of the upper aero-digestive tract (Sobin 2009). The most relevant difference is that, in order to emphasize the aggressiveness of the disease, Category T1-T2 and Stage I-II are omitted (Table 4). Similar to skin melanoma, the intent is to focus on depth of infiltration rather than involvement of single subsites. Moreover, this staging system is not site-dependent, thus confirming that MM is a very aggressive disease, regardless of the site of origin. At present, discordant data have been published: some reports (Michel 2014; Shuman 2011; Moreno 2010b) have demonstrated the superiority of the TNM classification for epithelial cancer over the Ballantyne, Prasad and/or the TNM specific for mucosal melanoma. Conversely, Koivunen et al. (Koivunen 2012) and Gal et al. (Gal 2011) found that the current UICC staging system gives reliable prognostic information and is very useful in routine clinical use.

Table 4. Classification of malignant melanoma of upper aero-digestive tract (7th edition of the UICC) (2009).
Tumour Characteristics
T3 Epithelium/submucosa (mucosal disease)
T4a Deep soft tissue, cartilage, bone, or overlying skin
T4b Brain, dura, skull base, lower cranial nerves, masticator space, carotid artery,
prevertebral space, mediastinal structures, cartilage, skeletal muscle, or bone
Staging group Tumour Node Metastases
III T3 N0 M0
IVA T3-T4a N1 M0
IVB T4b Any N M0
IVC Any T Any N M1


The prognosis of patients with head and neck MM remains dismal, since this tumour has a very high propensity to relapse, regardless of the radicality of resection and adjuvant treatment(s) administered. Local, regional, and distant failures are observed in up 81% of patients (Michel 2014) and they can be present in combination in a relevant number of cases (López 2016; Gavriel 2011). The frequency and nature of disease recurrence explain the poor survival rates, with 5-year OS generally less than 35% (López 2016).
Advanced T-category, positive surgical margins, deep infiltration, male gender and vascular invasion have frequently been associated with poorer prognosis (Shuman 2011; Patel 2002; Penel 2006; Jethanamest 2011; Jangard 2013) but this was not a consistent finding in the literature. Other factors that have been demonstrated to have a negative prognostic impact are the presence of nodal and distant metastasis, degree of pigmentation and Ki-67 score (Shuman 2011; Jethanamest 2011; Kim 2008; Wermker 2015).


6.1 Medical treatment

After decades of little progress, a host of new treatment options have been produced for patients with melanoma. Since 2011, several new treatments for advanced melanoma have been approved. In particular, targeted therapies and immunotherapies have effectively changed the treatment of cutaneous melanoma.
Targeted therapies include the BRAF inhibitors, dabrafenib (Tafinlar) and vemurafenib (Zelboraf), the MEK inhibitor trametinib (Mekinist) and KIT inhibitors. Vemurafenib, dabrafenib and trametinib are recommended on a type-1 evidence as standard option for the treatment of patients with a BRAF V600 mutation who have been diagnosed with unresectable or metastatic melanoma. The KIT gene is mutated or present in increased numbers in certain subtypes of melanoma, including mucosal melanoma. Drugs currently being tested in clinical trials for patients with stage IV, mutated KIT melanoma include imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna). Imatinib, dasatinib, and nilotinib are recommended on type 3 evidence as individualized option. Immunotherapy options include ipilimumab, a monoclonal antibody that targets cytotoxic T-lymphocyte associated molecule-4 (CTLA-4) and programmed death-1 (PD-1)/PD-ligand (PDL-1)-1 pathway inhibitors (nivolumab and pembrolizumab). Ipilimumab, nivolumab, and pembrolizumab are recommended on type-1 evidence as standard option for patients with unresectable or metastatic melanoma.
Compared with cutaneous and ocular melanoma, mucosal melanoma is associated with lower rates of 5-year survival. However, the recent revealing of the molecular changes that underlie the development of mucosal melanoma has offered new hope for the development of more effective systemic therapy.

6.1.1 Adjuvant treatment

Standard adjuvant therapy for mucosal melanoma has not been established. Some studies show clinical benefits of adjuvant chemotherapy while others do not (Agarwala 1998; Chang 1998; Chi 2011; Eggermont 2007; Garbe 2011; Patel 2002; Yang 2010; Yi 2011). High-dose interferon

Interferon is recommended in the adjuvant treatment of melanoma on type 1 evidence as individualized option either at high (Kirkwood 1996) or low (Garbe 2008) dosage. It is more than 15 years since the first study of adjuvant therapy of melanoma reported significant improvements in both recurrence-free survival (RFS) and overall survival (OS) in patients treated with high-dose interferon (IFN) α-2b (ECOG 1684) (Kirkwood 1996). In the first of two major meta-analyses of clinical studies for adjuvant IFN therapy of melanoma, Wheatley et al (Wheatley 2007) reviewed 13 randomized trials involving a total of 6067 patients and reported an absolute OS benefit of 3% (95% confidence interval [CI]: 1-5%), regardless of dose and duration of treatment. More recently, Mocellin et al. (Mocellin 2010) analysed 14 randomized clinical trials with a total of 8,122 patients and showed that IFN has a statistically meaningful impact on both 5-year disease-free survival (DFS) (18% relative risk reduction, hazard ratio [HR]: 0.82; 95%CI 0.77-0.87) and 5-year OS (11% relative risk reduction, HR: 0.89; 95%CI 0.83-0.96) in melanoma patients at high risk of recurrence. Based on these data, treatment with IFN is beneficial with regard to DFS and OS and, currently, there are no available alternative treatments that provide similar or better improvements in OS.
However, clinical trials of high-dose IFN as adjuvant therapy have included only a few mucosal melanoma patients, with efficacy in this subset not specified (Kirkwood 2001). A phase II study in patients with mucosal melanoma suggested that IFN might be less effective than chemotherapy as adjuvant therapy for this particular subgroup (Lian 2012). Patients with resected mucosal melanoma were randomized to observation, postoperative adjuvant IFN α-2b (15 MU/m2/day 5 days/week for 4 weeks followed by 9 MU/m2 three times/week for 48 weeks), or chemotherapy with temozolomide (200 mg/m2 on days 1-5 plus cisplatin 25 mg/m2 on days 1-3, repeated every 3 weeks for 6 cycles). A total of 189 patients were enrolled, of whom 184 were eligible for survival analysis. With a median follow-up of 26.8 months, the median RFS for the observation only, IFN and chemotherapy groups was 5.4, 9.4 and 20.8 months, respectively (p<0.001), while estimated median OS was 21.2, 41.1 and 49.6 months (p<0.001). Toxicities were generally mild to moderate. Thus, adjuvant chemotherapy appeared to significantly improve RFS and OS in mucosal melanoma patients compared with high-dose IFN or observation. This trial suggests mucosal melanoma may be more aggressive and that patients with this melanoma type may require a different adjuvant approach. However, this approach should be confirmed in larger phase III trial.
Some of the new metastatic melanoma treatments (e.g., vemurafenib, dabrefenib/trametenib combination, ipilimumab, nivolumab, pembrolizumab) may have potential as adjuvant therapy in the future. The placebo-controlled CA184-029 trial reported significantly improved RFS with adjuvant ipilimumab 10 mg/kg for up to 3 years in patients with completely resected stage III melanoma, although toxicity was a problem with around 40% of patients having discontinued treatment by the end of the initial dosing period (Eggermont 2015). However, this study excluded patients with mucosal melanoma, as have ongoing adjuvant trials of vemurafenib, dabrafenib plus trametinib, and pembrolizumab. At the moment ipilimumab does not have approval for the adjuvant treatment of melanoma.

6.1.2 Metastatic disease: targeted therapies

Evidence suggests that the biology of non-cutaneous melanoma significantly differs from that of cutaneous melanoma, which may affect therapeutic opportunities. In an analysis of 45 mucosal melanomas, c-KIT and NRAS mutations were detected in 16% and 25% of tumours, respectively. By contrast, no mutations were observed in the BRAF gene, which is commonly mutated in patients with cutaneous melanoma (Beadling 2008). However, in an analysis of another 20 mucosal melanomas, BRAF mutations were detected in 11% of tumours while NRAS mutations were less frequent, being reported in 5% of tumours (Curtin 2005). The use of appropriately targeted agents (i.e., inhibitors of c-KIT, NRAS/MEK or BRAF) is therefore one therapeutic strategy, although, because of the rarity of metastatic mucosal melanoma, clinical data are limited.
KIT, a receptor tyrosine kinase, triggers a cascade of downstream substrates leading to cell growth signalling. Mutations in or amplifications of the KIT gene are estimated to occur in approximately 39% of mucosal melanomas (Curtin 2006). However, a recent Swedish study of sinonasal mucosal melanomas identified KIT mutations in only 4% of tumours, suggesting that its occurrence differs between different sites of mucosal melanomas. Although rare in sinonasal mucosal melanomas, KIT mutation frequency appears to be much higher in vulvar melanomas, for example (Zebary 2013).
Numerous studies have shown that imatinib mesylate, a multi-targeted tyrosine kinase inhibitor with potent anti-KIT activity, induces major responses in gastrointestinal stromal tumour (GIST) and chronic myeloid leukaemia. Melanomas with specific genetic alterations may also respond to treatment with imatinib. A recent trial shows that imatinib therapy targeting c-KIT in patients with metastatic melanoma harbouring c-KIT mutations or amplifications is associated with a median PFS of 3.5 months, tumour regression in 41.9% of patients, and overall 1-year survival rate of 51.0%. Responses were largely observed in exon 11 or 13 mutant tumours (Guo 2011). In an open-label, phase II trial of patients with acral, mucosal, or chronically sun-damaged melanoma and KIT mutations or amplification treated with imatinib, durable responses were observed in 16% (95%CI 2%-30%) among 25 evaluable patients with all sustained for more than 1 year. These included two complete responses lasting 94 (ongoing) and 95 weeks, 2 durable partial responses lasting 53 and 89 (ongoing) weeks, and 2 transient partial responses lasting 12 and 18 weeks (Carvajal 2011). However, responses may be limited to tumours harbouring KIT alterations of proven functional relevance. More specifically, responses were observed in those patients whose tumours harboured the secondary KIT mutations, K642E and N822K.
In mucosal melanoma, Hodi and colleagues were the first to report a dramatic response to imatinib (Hodi 2013). In this multicentre phase II trial patients with mucosal, acral, or chronically sun-damaged melanoma with KIT amplifications and/or mutations received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Best overall response rate (BORR) was 29% (21% excluding non-confirmed responses) with a two-stage 95%CI of 13%-51%. There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated vs. 18% amplified).
The number of patients with the potential to benefit from imatinib is restricted by the relatively low proportion of patients with c-KIT mutated mucosal melanoma, as evidenced by slow recruitment to clinical trials.
It is possible that more potent and selective inhibitors could result in greater clinical activity. Nilotinib, a tyrosine kinase inhibitor that has a similar target profile to imatinib but which does not require an active transport mechanism to enter cells, is currently being compared with dacarbazine in a randomized trial in patients with certain c-KIT aberrations. In another trial of 25 patients, of whom 23 (92%) had tumours with KIT mutations, 5 (20%) with KIT amplifications, and 3 (12%) with both, nilotinib resulted in one complete response and 4 partial responses, with an ORR of 20% (95%CI 6.8-40.7) all in patients with KIT mutation. One-year overall survival was 68.3% (95%CI 46.5-1.00) (Lebbe 2014).
A recent study was conducted to detect and test the immunohistochemical expression of Sox10 and c-KIT in mucosal melanomas arising in the nasal cavities of Chinese patients. The authors demonstrated that Sox10 is a sensitive marker for sinonasal mucosal melanomas and it may possess diagnostic value in addition to that of S100 protein. The expression of c-KIT in the majority of mucosal melanomas suggests that it may be useful in the assessment of these tumours for potential treatment with tyrosine kinase inhibitors (Liu 2012).
The activity of BRAF and MEK inhibitors in patients with advanced cutaneous melanoma suggests they may also have utility in patients with BRAF- and NRAS-mutated mucosal melanoma, respectively. In BRAF V600 mutated patients vemurafenib showed a better ORR (48% vs. 5%), PFS (6.9 vs. 1.6), and increase of OS respect dacarbazine: median OS 13.6 months versus 9.7 months respectively with an HR of 0.70 (Chapman 2011; McArthur 2014). Also dabrafenib showed a similar impact on ORR (50% vs. 6%), and PFS (5.1 vs. 2.7; HR: 0.30) (Hauschild 2012).
In an open-label, phase 2 study, patients with NRAS-mutated or BRAF-mutated advanced melanoma were assigned to one of three treatment arms on the basis of mutation status. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response. MEK162 appears the first targeted therapy to show activity in patients with NRAS -mutated melanoma (Ascierto 2013).
Combi-V, Combi-D, and coBRIM studies provided clear evidence that combined BRAF and MEK inhibition results in improved clinical outcomes. The combination dabrafenib/trametinib compared to dabrafenib monotherapy (Combi-D) (Long 2014; Long 2015), or vemurafenib monotherapy (Combi-V) (Robert 2015) showed a significant 25% relative reduction in the risk of disease progression among patients with metastatic melanoma with BRAF V600E or V600K mutations who received first-line treatment with the combination as compared with dabrafenib alone, and a significantly improved overall survival (OS) compared to vemurafenib monotherapy, with a 31 % decrease in the risk of death for patients treated with the combination.
The combination of vemurafenib plus cobimetinib vs vemurafenib alone resulted in 49% reduction in risk for progression (Larkin 2014). However, mucosal melanoma patients were not allowed to be enrolled in all of these studies.

6.1.3 Immunotherapy Ipilimumab

Ipilimumab is a promising immunotherapy that has been shown to improve the overall survival of patients with cutaneous melanoma. The efficacy of ipilimumab in patients with mucosal melanoma, however, remains unknown.
Ipilimumab therapy was associated with survival of at least 2 years in approximately one-fifth of patients enrolled in the MDX010-20 study. A total of 676 patients with unresectable stage III or IV melanoma, previously treated, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). The 1-year OS rate was 44% and 46%, and the 2-year OS rate was of 22% and 24% in the two ipilimumab arms respectively. While primary ocular melanoma was excluded, mucosal melanoma was allowed but there is not an analysis of this subgroup at the moment (Hodi 2010).
In the CA 209-024 trial (Robert 2011) 502 patients with previously untreated metastatic melanoma were randomized in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo. Patients were ineligible if they had evidence of brain metastasis, primary ocular or mucosal melanoma. The median overall survival in the ipilimumab–dacarbazine group was 11.2 months (95%CI 9.4-13.6), as compared with 9.1 months (95%CI 7.8-10.5) in the dacarbazine group, with estimated survival rates in the two groups, of 47.3% and 36.3% at 1 year, 28.5% and 17.9% at 2 years, and 20.8% and 12.2% at 3 years respectively.
In a multicenter, retrospective analysis of 33 patients with unresectable or metastatic mucosal melanoma treated with ipilimumab, there was one complete response, one partial response, 6 patients with stable disease, and 22 with progressive disease according to immune-related response criteria among the 30 patients who underwent radiographic assessment after ipilimumab at approximately week 12. Durable responses to ipilimumab were observed, but the overall response rate was low (Postow 2013).
In the US extended access programme (EAP) with ipilimumab, 131 of 2155 patients had mucosal melanoma. One-year OS was 32% (95%CI 0.24 -0.41) for patients with mucosal melanoma versus 38% (95%CI 0.35-0.40) among all patients. Grade 3/4 drug-related adverse events were consistent with those observed in other melanoma subtypes (Lawrence 2012). In the Italian EAP, of the 855 patients who were treated with ipilimumab 3 mg/kg, 71 had mucosal melanoma, including patients with anal/rectal (No. 24), genitourinary (No. 2), gastric (No. 4) or nasal (No. 15) melanomas. Of 31 patients with mucosal melanoma tested for BRAF-mutation status, two (6%) were positive. Additionally, of 12 patients tested for the c-KIT mutation, two were positive (17%). Three patients were tested for NRAS mutations, but all were negative. Median OS and PFS were 6.4 and 4.3 months, respectively, and the 1-year OS rate was 35%. These results are similar to survival rates observed in the wider population of the EAP in Italy (Del Vecchio 2014). Anti PD1/PDL-1

The anti-PD-1s’ study with nivolumab and pembrolizumab in advanced melanoma patients allowed the enrollment of mucosal melanoma patients. However, specific data regarding this subgroup of patients were not reported.
Nivolumab was compared with investigator’s choice of chemotherapy (ICC) as a second-line therapy in a randomised, controlled, open-label, phase-III trial (CheckMate 037) (Weber 2015). Specifically, confirmed objective responses were reported in 38 (31.7%) of the first 120 patients in the nivolumab group versus five (10.6%) of 47 patients in the ICC group. Therefore, patients treated with nivolumab had greater objective response and fewer toxic effects than patients treated with alternative available chemotherapy regimens.
Data was recently reported from a randomized phase II study (KEYNOTE-002). This was a study with similar design to the checkmate 037, and enrolled 540 ipilimumab-refractory advanced melanoma patients. This study showed that pembrolizumab achieved the primary endpoint of progression-free survival (HR 0.57 and 0.50 for 2 mg/kg and 10 mg/kg every three week doses, respectively), compared to chemotherapy (p<0.0001 for both comparisons). At six months, the PFS rates for pembrolizumab were 34% at the dose of 2 mg/kg and 38% at the dose of 10 mg/kg, compared to 16% for chemotherapy (Ribas 2015).
In the randomized, phase 3 CA209-066 study, 418 previously untreated patients with metastatic melanoma without a BRAF mutation were randomized to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks). The median progression-free survival was 5.1 months in the nivolumab group and 2.2 months in the dacarbazine group. The overall survival rate at 1 year was 72.9% in the nivolumab group and 42.1% in the dacarbazine group (Robert 2015a).
KEYNOTE-006 is a randomized, phase III study where 834 patients with advanced melanoma were assigned in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg/kg body weight) every 2 weeks or every 3 weeks, or four doses of ipilimumab (at 3 mg/kg) every 3 weeks. It was demonstrated that pembrolizumab prolonged PFS and OS and had less high-grade toxicity than ipilimumab (Robert 2015a). Specifically, the estimated 6-month progression-free survival rate was 47.3% for patients receiving pembrolizumab every 2 weeks, 46.4% for those receiving pembrolizumab every 3 weeks, and 26.5% for those receiving ipilimumab. The benefit for progression-free survival was evident in all prespecified subgroups for the two pembrolizumab groups. The benefit of pembrolizumab over ipilimumab was observed in both PD-L1–positive and PD-L1–negative subgroups, as compared with ipilimumab. One-year estimates of survival were 74.1% for patients receiving pembrolizumab every 2 weeks (HR for death as compared with the ipilimumab group, 0.63; p <0.0005), 68.4% for those receiving pembrolizumab every 3 weeks (HR for death as compared with the ipilimumab group, 0.69; p = 0.0036), and 58.2% for those receiving ipilimumab.
Postow et al. conducted a randomized phase II study which compared the combination of ipilimumab/nivolumab with ipilimumab monotherapy in untreated patients with advanced melanoma (CA209 -069). In this double-blind, randomized study, the combination of nivolumab and ipilimumab resulted in a significantly higher objective response rate, more frequent complete responses, and significantly longer progression-free survival than obtained with ipilimumab alone. In the population with BRAF wild-type tumours, the median progression free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (HR = 0.40). Among patients with BRAF mutations, PFS was 8.5 months in the combination group and 2.7 months in the ipilimumab monotherapy group (HR: 0.38) (Postow 2015).
The CA-209-067 study was a randomized, double-blind, phase 3 study, where nivolumab alone or combined with ipilimumab was compared to ipilimumab alone in patients with untreated metastatic melanoma. The combination met its co-primary endpoint PFS: 11.5 months vs. 6.9 and 2.9 months of nivolumab and ipilimumab respectively (HR: 0.42 combination vs. ipilimumab, HR: 0.57 nivolumab vs ipilimumab). The ORR was of 57.6%, 43.7%, and 19% respectively for the combination, nivolumab, and ipilimumab. The data of PFS stratified according the PD-L1 status were very interesting: considering the cut-off of 5% for the positivity to the PD-L1, the PFS was 14 months for both the groups of patients treated with the combination and nivolumab alone, while for the ipilimumab group was of 3.9 months. In the PD-L1 negative population, the combination confirmed its superiority to the monotherapy: 11.2 months versus 5.3 months and 2.8 months respectively in the nivolumab and ipilimumab group. Data about OS are as yet unknown. The incidence of treatment-related adverse events of grade 3 or 4 was also higher in the nivolumab plus ipilimumab group (55.0%) than in either the nivolumab (16.3%) or ipilimumab (27.3%) groups.
The pembrolizumab compassionate use programme and the CA209-172 study, a nivolumab study designed to determine the rate and frequency of high-grade treatment-related adverse events in advanced melanoma patients who progressed after previous ipilimumab therapy, will generate more data in the setting of patients with mucosal melanoma.

6.1.4 Studies excluding mucosal melanoma Adjuvant

A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High Dose Interferon a-2b for Resected High Risk Melanoma is currently recruiting participants.
BRIM-8 is a multicentre, randomized, double blind, placebo-controlled study that evaluated the efficacy and safety of vemurafenib in patients with completely resected, cutaneous BRAF-mutation positive melanoma at high risk for recurrence. The study is currently recruiting participants. Mucosal melanoma patients were excluded.
COMBI AD is a trial to evaluate the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib in the adjuvant treatment of high-risk BRAF V600 mutation-positive melanoma after surgical resection. Mucosal melanoma was excluded. This trial is no longer recruiting patients and we await the results.
PD-1 and PD-L1 inhibition achieved durable responses in the metastatic setting, not only for melanoma, but in many other solid tumours and with an acceptable toxicity profile (Ott 2013).
KEYNOTE-054 is a study to assess whether post-resection adjuvant therapy with the anti PD-1 pembrolizumab improves recurrence-free survival (RFS) as compared to placebo for high-risk Stage III participants. Mucosal or ocular melanoma were exclusion criteria.
The purpose of the CA209-238 trial will be to determine whether nivolumab is better than ipilimumab in preventing recurrence of Stage IIIb/c or Stage IV Melanoma. This study has completed accrual. Ocular or uveal melanoma are excluded Metastatic disease: Targeted therapy

BRIM-3 was a phase III, randomized, clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated metastatic melanoma with the BRAF V600E mutation. Vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of tumour progression in patients with previously untreated, unresectable stage IIIC or stage IV melanoma with the BRAF V600E mutation, as compared with dacarbazine. The survival benefit in the vemurafenib group was observed in each prespecified subgroup, according to age, sex, ECOG performance status, tumour stage, lactate dehydrogenase level, and geographic region (Chapman 2011).
Break-3 was a multicentre, open-label, phase III randomised controlled trial. 250 patients were randomly assigned (3:1) to receive either dabrafenib or dacarbazine. The median progression-free survival for the dabrafenib group was 6.7 months and 2.9 months for the dacarbazine group. The benefit in progression-free survival was observed in all subgroups analysed (Hauschild 2012).
Break-MB was a multicentre, open-label, phase II trial which show that the BRAF inhibitor dabrafenib is active and has an acceptable safety profile in melanoma metastatic to the brain, whether they were untreated or have been previously treated but have progressed (Long 2012).
In the phase III COMBI-d study, a significant 25% relative reduction in the risk of disease progression was found among patients with metastatic melanoma with BRAF V600E or V600K mutations who received first-line treatment with a combination of dabrafenib and trametinib, as compared with dabrafenib alone. Mucosal melanomas were excluded (Long 2014).
COMBI-v was a phase III, randomised study comparing the combination of dabrafenib and trametinib to vemurafenib in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation-positive melanoma. Published results show that treatment with the combination of trametinib and dabrafenib significantly improved overall survival (OS) compared to vemurafenib monotherapy, with a 31% decrease in the risk of death for patients treated with the combination. Mucosal melanomas were excluded (Robert 2015b).

6.1.5 Conclusions

Despite the different biology, mucosal melanoma is currently treated the same as cutaneous melanoma. Considering that in most of recent clinical trials mucosal melanoma was excluded, we consequently missed a lot of information and need to generate more data in this setting. However, currently both targeted therapy and immunotherapy seem to provide good options for mucosal melanoma patients. The high response rate, duration of response and improvement in OS shown by anti-PD-1s (nivolumab and pembrolizumab recently approved by EMA in first and second line treatment for advanced melanoma) with a low incidence of side effects, suggest use of these compounds, on the basis of type 1 evidence, as standard first line for all patients. The combination of BRAF inhibitors and MEK inhibitors (dabrafenib/trametinib and vemurafenib /cobimetinib) were superior to the monotherapy with dabrafenib or vemurafenib and should be considered on the basis of type 1 evidences as standard for all BRAF V600 mutated patients. This combination can also be used in first line; however, the high probability of having a durable response and long-term survival with anti-PD-1s also recommends their use as first line for BRAF mutated patients. In cases of a symptomatic and/or a fast kinetics disease the use of targeted agents should be preferred in order to achieve the fast impact of these on the disease. In the countries where nivolumab or pembrolizumab are not available yet, ipilimumab can be recommended, on the basis of type 1 evidence, as standard in all patients. However, where anti-PD-1s are available, the place of ipilimumab in therapy will probably be after the progression from anti-PD-1 and/or combo BRAFi/MEKi. Another important role of ipilimumab will be in combination with nivolumab. Despite the toxicity, this regimen showed a dramatic impact on the disease in terms of response rate and PFS. This combination should be recommended in first line on the basis of type-1 evidence as standard for all patients in the near future.

6.2 Surgical treatment

Surgery is still considered the mainstay of treatment for most MMs of the head and neck region, despite the lack of prospective, randomized trials supporting this approach. The description of and indications for the individual surgical procedures and approaches are beyond the scope of this paper.
As a general rule, radical tumour excision with disease-free surgical margins should be the first goal of surgery in head and neck MM (Shuman 2011). Clear surgical margins, in fact, are considered as one of the most important prognostic factors in many reports on both head and neck (Lee 1994; Penel 2006; Shuman 2011) and sinonasal MM (Tajudeen 2014).
The importance of clear margins should, however, be balanced with several important adjunctive considerations. It is noteworthy that clear margins are difficult to obtain in a significant percentage of patients due to anatomical complexity of the region and proximity to vital structures (Bachar 2008; Moreno 2010a; Sun 2014). Moreover, despite radical surgery, a relevant proportion of patients with head and neck MM will suffer from recurrent disease, with various combinations of local, regional, and distant relapse. On one hand this confirms that head and neck MM is a very aggressive neoplasm with a high tendency to recur despite an adequate treatment and, on the other hand, that aggressive surgery does not automatically translate into better survival.

6.2.1 Surgical treatment of the primary lesion

The treatment of sinonasal tumours has dramatically evolved over the last decades due to the increasing application of transnasal endoscopic techniques; this paradigm shift has led to a decrease in the indications for “classic” or traditional external approaches, such as anterior craniofacial resection (Nicolai 2008). Endocoscopic transnasal approaches can nowadays be used to remove a significant number of nasoethmoidal lesions, whereas most tumours originating in the maxillary sinus still require a non-endoscopic approach.
Sinonasal MM is not an exception; until a few years ago, external surgical techniques with wide resections were considered the best option to treat most sinonasal MMs. In recent years, different authors have started to advocate excision of sinonasal MM by an endoscopic approach, either in an exclusive or combined setting, mainly because survival analyses have confirmed that mutilating procedures are not necessarily associated with better outcomes (Papaspyrou 2011; Hanna 2009; Clifton 2011; Lund 2012; Swegal 2014).
In a retrospective analysis of 58 patients, Moreno and Hanna (Moreno 2010a) found that oncologic outcomes in patients treated by a purely endoscopic approach were comparable with those obtained with open approaches. Clifton et al. (Clifton 2011) analysed 24 patients with sinonasal MM and confirmed that, despite the limitations related to the low number of patients, an endoscopic approach was at least as effective as other surgical approaches.
One of the most important publications in this area evaluated treatment outcomes in a cohort of 115 patients treated from 1963−2010 (Lund 2012); in this paper, a significantly better survival was clearly seen in patients treated by an endoscopic approach. Another study demonstrated that an endoscopic approach was not inferior to aggressive surgery, even in the treatment of recurrent sinonasal MM (Ledderose 2014).
One of the most intriguing speculations, as yet to be confirmed, to explain the favourable outcomes of endoscopic surgery was offered by Lund et al., who hypothesized that aggressive surgery might cause disturbances in immunobalance, thus promoting dramatic recurrence and/or rapid systemic dissemination (Lund 2012).
When dealing with maxillary MM, the surgical options encompass a variety of maxillectomies. An endoscopic approach should be limited to those lesions involving only the medial wall of the maxillary sinus, without any critical relationship with palate, orbit, and/or pterygopalatine fossa. In lesions limited to the alveolar process – hard palate, the treatment of choice should be an inferior maxillectomy by a transoral-sublabial approach with different reconstructive options according to the site and size of the defect (prosthetic obturator, local flap). In all cases involving the maxillary walls, with the exception of the medial one, a subtotal, total, or radical maxillectomy through a lateral rhinotomic approach, according to the local extension of the tumour, may be required. Orbit content removal, namely orbital clearance, should be performed only in the presence of neoplasms transgressing the periorbit, whereas excision should be extended to the pterygopalatine fossa for lesions extending in proximity or frankly involving the posterior wall of maxillary sinus.
In presence of MM involving the oral tongue and/or floor of the mouth, different approaches (transoral, “pull-through”, manibulotomy/mandibulectomy) tailored according to the site of origin and local extension of the lesion with different types of reconstruction are available. Umeda and Shimada (Umeda 1994) advanced a protocol for the treatment of oral MM advocating the excision of the primary lesion, preferably using an intraoral approach and involving at least 1.5 cm of healthy tissue.

6.2.2 Surgical treatment of the neck

In the presence of a clinically-positive neck, proper neck dissection (chosen according to the number of involved nodes and levels and possible extra-capsular extension) is mandatory in all cases of head and neck MM amenable to radical treatment of the primary tumour. In contrast, the role of elective treatment of the neck is more controversial. The higher prevalence of nodal involvement in oral than in sinonasal MM should dictate the need for elective neck treatment for lesions arising in the oral cavity. Medina et al. (Medina 2003) advocated elective neck dissection in oral MM; Krengli et al. (Krengli 2006) reinforced the role of prophylactic treatment of the neck due to the very high risk of regional recurrence (77%).
Wu et al. (Wu 2014), analysing a series of 254 patients with oral MM, stratified the risk of nodal metastasis in relation to appearance and size of lesions. They found that MMs with a nodular growth pattern have a higher risk of nodal involvement than macular lesions. Accordingly, they suggested that elective neck dissection should be performed in patients with nodular MM or macular MM with diameter greater than 4 cm, whereas in nodular MM with a size less than 4 cm a close observation of the neck may be adequate.
In view of the lack of a survival advantage in patients undergoing elective treatment of the neck (neck dissection and biochemotherapy), a wait and see policy has even been proposed (Wang 2012).
Another option in the decision-making process is to rely upon sentinel lymph node biopsy. Starek et al. (Starek 2006) should be credited with the first study on the feasibility of this technique in two cases of oral MM, and another preliminary study demonstrated its reliability in sinonasal MM (Baptista 2008). More recently, the combined use of the so-called triple technique (lymphoscintigraphy, patent-blue staining, and a gamma probe) together with fluorescence navigation using indocyanine green have been advocated for head and neck cutaneous and MM (Hayashi 2012). However, Moreno and Hanna (Moreno 2010a) highlighted that sentinel lymph node biopsy is currently used in the decision-making algorithm for MM arising in specific sites, such as the vagina and female genital tract, but not in the head and neck.

6.2.3 Surgical treatment of recurrent disease

A local relapse is amenable to surgical treatment in only a minority of cases (López 2016). First of all, local recurrence is associated with distant metastases in a relevant number of cases. Second, surgery can be considered a reliable option only if radical excision can be obtained, but this is particularly difficult due to the infiltrative and multilocular pattern of growth of the recurrence (Ledderose 2014). Finally the intrinsic morbidity of surgical excision may be unacceptable, especially in those lesions abutting or encroaching vital neurovascular structures.

6.3 Radiotherapy

6.3.1 Radiotherapy synthetic recommendation

Postoperative radiotherapy to the tumour bed is recommended on a type 3 basis as standard option in all patients.
Primary radiotherapy is recommended, on a type-3 basis, as standard option for patients who refuse surgery or who are suffering from an inoperable/unresectable tumour.
Exclusive radiotherapy with heavy particles (hadrontherapy) can be considered as experimental treatment within clinical trials, on a type R basis, even for operable patients.
Radiotherapy is recommended as individualized treatment on a type R basis for the salvage of local recurrence.
Palliative radiotherapy is recommended on a type R basis as standard treatment of symptomatic metastatic disease.

6.3.2 Operable loco-regional disease Indication for post operative RT

Despite the rarity of this disease, there is substantial amount of retrospective data. In the framework of the French GETTEC (Groupe d’Etude des Tumeurs de la Tête et du Cou) outcome of 160 patients with mucosal melanoma of the head and neck treated in several French institutions between 1980 and 2008 were analysed comparing retrospectively surgery alone or surgery + postoperative radiotherapy. Patients treated with postoperative RT had significantly less local failures (29.9% vs. 55.6%) but no difference in overall survival was detected (Benlyazid 2010). In a retrospective analysis of 38 patients treated in Italy and the Netherlands, the addition of postoperative RT was able to reduce local failures from 57.9% to 26.3% even though statistical significance was not reached (p=0.099). In this series patients treated with postoperative RT had a significantly worse 5-year overall survival compared with those treated with surgery alone. According to the authors’ interpretation of this finding, it may be due to the higher proportion of non-radical resection in the radiotherapy group (Meleti 2008). Similar results with post-operative radiotherapy, improving local control but not affecting survival, were found in a retrospective study within the rare cancer network. In this series of 59 patients, treated in various European hospitals between 1972 and 2002, local control at 3 years was 57% after surgery alone and 71% after surgery and radiotherapy (Krengli 2006). Also, in a series of 69 patients treated at Institut Gustave-Roussy (France) from 1979 to 1997 the addition of postoperative RT could improve local control (from 26% to 62%) and the advantage was present both for early and advanced stage tumours. No difference in survival was observed (Temam 2005). In 58 patents treated in MD Anderson cancer centre (USA) from 1993 to 2004 the addition of post-operative RT (at doses higher than 54 Gy) decreased local failures from 61% to 22% (p=0.0125) (Moreno 2010a). In a series of 48 patients treated between 1985 and 1998 at the University of Colorado the addition of post-operative RT could decrease local failure rate from 45% to 17%. This finding showed a trend toward statistical significance (p=0.13), but no difference in survival was detected (Owens 2003). In a series of 68 patient treated at Princess Margaret Hospital in Canada between 1958 and 1998 post-operative RT could increase 5-year local control rates from 17% to 30%. No statistically significant difference in survival was detected (Bachar 2008).
A series of 259 patient treated in the United Kingdom has been published; data were obtained from a single institution and from cancer registries of two counties. Treatment details were not very detailed and the authors do not specifically address the issue of adjuvant radiotherapy versus surgery alone. Even with these limits there are two interesting findings: radiotherapy as sole treatment modality does not provide any survival advantage over supportive care, whereas surgery as sole modality significantly improves survival; local recurrence in patient treated with surgery and radiotherapy were significantly reduced as compared with patients treated with either single modality. These indirect findings confirm the role of adjuvant radiotherapy in improving local control but not survival (Nandapalan 1998). Data from a series of 98 patients treated in Japan between 1998 and 2007 have been published. The role of post-operative RT has not been specifically investigated but the authors conclude that surgery plus radiation can achieve better local control than either modality alone (Shiga 2012).
In a report from the Memorial Sloan Kettering Cancer Center (USA) on 59 patients treated between 1978 and 1998, the use of post-operative radiotherapy was not related to improved local control. No details are available on the dose employed, and the authors interpret this finding as potentially due to a different proportion of oral cavity and sinonasal subsites among the groups (Patel 2002). Results from a series of 35 patients treated between 1978 and 2009 in Hong Kong have been published. Patients receiving post-operative RT had longer local recurrence free survival (55 months vs. 10 months); this finding did not reach statistical significance. No difference in overall survival was observed (Chan 2012) Considering the findings of 9 published series (statistically significant in 5 series, demonstrating a trend in 3 and not significant in the one study with the smallest sample size), the indirect confirmation from two more series, and the unclear results of the MSKCC data (that however do not contradict, since in the opinion of the authors of that paper, RT did improve local control), post-operative RT is advised on a type 3 basis as standard option for all patients. Technical aspects of RT Volumes

Irradiation of the tumour bed, positive resection margins, residual disease and non-resected lymph node metastases is recommended on a type C basis. It is not possible to make any definitive recommendation for the need of laterocervical lymph node irradiation after neck dissection or on elective neck irradiation (ENI). On a type R basis ENI may be indicated for selected patients with oral mucosal melanoma. Dose and fractionation

The role of high dose per fraction and of total dose (described as BED, biologically equivalent dose) is not well understood in cases of postoperative RT. High dose per fraction (>3 Gy) and high total dose (BED > 118 Gy) may be recommended on a type R basis in case of residual macroscopic disease (Wada 2004; Gilligan 1991; Overgaard 1986; Harwood 1982). Type of RT

Highly conformal irradiation (photons IMRT or hadrontherapy) is recommended on a type C basis for all patients. High linear energy transfer (LET) hadrontherapy with carbon ions is recommended on a type R basis in patients with macroscopic residual disease.

6.3.3 Unresectable/inoperable locoregional disease

In cases of unresectable/inoperable locoregional disease, radiotherapy has been used as radical treatment. In a series of 28 patients with mucosal melanoma of the nasal cavity and paranasal sinus, treated at the Christie Hospital, Manchester UK with radiotherapy as sole modality, a complete response was achieved in 79% of the patients which lasted at least 12 months in 74%. 3-years local disease free survival was 49% and 5-years overall survival was 17.9% (Gilligan 1991).
In a series of 28 patients with stage I/II melanoma of the upper jaw treated exclusively with radiotherapy at Tokyo Medical and Dental University (Japan) local relapse was observed in 1 out of 12 patients when brachytherapy was employed (oral mould or interstitial seed implantation), in 3 out of 9 patient treated with intra-oral electron beams and in 3 out of seven patients treated with external beams photon RT. Five year overall survival was 25% (Shibuya 1993).
In an older series of 24 patients, radiotherapy alone achieved complete remission in 72%. Long-term local control was not reported, but from the details given for each patient it is possible to recalculate a 2-year actuarial local control of 43% (Harwood 1982). The main limit of this series is the short median follow up of 12 months.
More recently, in a series of 8 patients treated at the University of Heidelberg with photons intensity-modulated radiotherapy (IMRT) at doses ranging from 60 to 68 Gy and conventional fractionation (1.8-2.2 Gy per fraction), a 3-year local progression free survival of 57% has been reported (Combs 2007).
Hadrontherapy allows delivery of high dose in hypofractionated schedules to complex volumes with acceptable toxicities. Carbon ion hadrontherapy has the additional advantage of higher efficacy against the relatively radioresistant melanoma cells thanks to its radiobiological characteristics.
In a series of 85 patients with inoperable disease, treated with carbon ion hadrontherapy as sole modality between 1997 and 2006 in NIRS (National Institute of Radiological Sciences, Chiba Japan) 5-year local control rate was 75%, with no grade-III late toxicity and minimal (<3%) grade-II late toxicity. Doses employed have ranged from 57.6 to 64 GyE in 16 fractions (Mizoe 2012; Yanagi 2009). In a series of 14 patients treated with proton hadrontherapy between 2004 and 2007 at the National Cancer Center Hospital East (Kashiwa, Japan) at doses of 60 GyE in 15 fractions 1-year local control rate was 85.7% (Zenda 2011).
Radiotherapy is recommended, for inoperable disease. If available, hadrontherapy with carbon ions or protons is to be preferred on a type 3 level of evidence as standard option. Technical aspects of radiotherapy Volumes

Irradiation of macroscopic disease, residual disease and non-resected lymph node metastases is recommended on a type C basis. It is not possible to make any definitive recommendation on the need of elective neck irradiation (ENI). On a type R basis, ENI may be indicated for selected patients with oral mucosal melanoma. Dose and fractionation

The role of high dose per fraction and of total dose (BED) is not well understood in cases of postoperative RT. High dose per fraction (>4 Gy [Relative Biological Effectiveness, RBE]) may be recommended on a type R basis. Special care is needed in case of carbon ion hadrontherapy as RBE weighted dose depends critically on the radiobiological model used. Doses published in the literature cannot be employed without conversion factors if different radiobiological models are used (Fossati 2012; Steinsträter 2012).

6.4 Exclusive hadrontherapy for operable disease

In a retrospective series of 62 patients treated between 2003 and 2011 with particle therapy at Hyogo in Japan (Demizu 2014) no apparent difference between proton (33 patients) and carbon ion (29 patients) was observed. Doses between 65 GyE and 70.2 GyE were delivered in 26 fractions. 2-year local control was 83% for the proton group and 59% for the carbon group (not statistically significant). 2-year overall survival was 58% for the proton group and 62% for the carbon group (not statistically significant). 8% of the patients experienced grade III/IV late toxicity. This series includes both operable and inoperable patients and the treatment was offered as alternative to surgery. In another retrospective series of 20 patients (operable and inoperable), with sinonasal melanoma, treated between 2006 and 2012 with proton therapy at Shizuoka in Japan (Fuji 2014) 5-year local control was 62% and 5-year overall survival was 51%. Delivered dose was 70 GyE in 20 fractions. 3% of the patient experienced grade-IV late toxicity.
Considering the complete lack of level 1 and 2 evidence for mucosal melanoma and the rarity of the disease, existing data is sufficient to recommend exclusive hadrontherapy for operable patients on a type R basis as experimental treatment to be carried out within prospective clinical trials. Exclusive hadrontherapy for operable patients can be offered on a type 3 level of evidence if the patient refuses surgery.

6.5 Local relapse

There is a complete lack of published data on the use of radiotherapy to treat local recurrence of mucosal malignant melanoma; that notwithstanding it is possible to recommend radiotherapy as individualized treatment on a type R basis for the salvage of local recurrence.

6.6 Metastatic disease

There is a complete lack of published data on the use of radiotherapy to treat distant metastases from mucosal malignant melanoma. It is possible, however, to recommend palliative radiotherapy as standard treatment on a type R basis as routinely done for metastasis from skin melanoma.


Considering the overall poor prognosis and the rarity of the disease, no specific data on late sequelae for MM are available; however, it is possible to extrapolate from the clinical experience with other head and neck tumours.
For further information, see the same paragraph in «Paranasal sinus cancer» chapter.


Frequency of the medical examination is not standardised, because subjects affected by melanoma can relapse up to 5 years after diagnosis; even relapses in the period exceeding 10 years after surgical intervention are documented (AIOM 2014).
The cost-benefit of an instrumental follow-up to evaluate the presence of occult metastases is not likely to be justified for every patient at 5 years after surgery. However, one specialised examination per year for the rest of a patient’s life in subject with a history of melanoma is justified, because of the risk of developing a further neoplasm. This risk is estimated to be between 4% and 8% (AIOM 2014).
The patient is invited to seek medical advice if any symptom resurfaces, re-accessing specialised care in cases of suspected disease (AIOM 2014) (Table 5).
Table 5 shows AIOM recommendations for cutaneous melanoma adapted for follow-up to mucosal melanomas.

Table 5. Analysis of the strength of follow-up clinical recommendations (Source: AIOM 2014).
Quality of evidence, SIGN Clinical recommendation Strength of clinical recommendation
D* In in situ melanoma, patients should undergo a periodical examination once every 12 months for epithelial lesions at risk together with an eye examination. In cases of patients with multiple common and/or atypical melanocytic nevi, an examination once every 6 months should be considered. Weak positive
D* In patients with melanoma with limited invasion (infiltration limited to the lamina propria):Clinical follow-up: should consist of a clinical examination focusing on possible local recurrence, on local lymph nodes, and on the presence of possible further melanomas. Clinical examination once every 3 months for 2 years according to the clinician, and once every 6 months between the 3rd and the 5th year are recommended. After 5 years, clinical examination every 12 months up to 10 years is recommended.Instrumental procedures: CT or PET/CT every 12 months until the 5th year; ultrasound scan of lymph nodes relating to the primary lesion and hepatic ultrasound scan (during every clinical examination). Weak positive
D* In patients with melanoma with deep invasion (invasion of muscle, cartilage, and/or bone):Clinical follow-up: clinical examination once every 3 months for 2 years, and once every 6 months between the 3rd and the 5th year is recommended. After 5 years, clinical examination every 12 months up to 10 years is recommended.Instrumental procedures (for the first 5 years): CT or PET/CT every 6-12 months for the first 3 years (the frequency is to be decided on the basis of the risk of relapse); then every 12 months until the 5th year; ultrasound scan of lymph nodes relating to the primary lesion and hepatic ultrasound scan (during every clinical examination). Weak positive
D* In inoperable stage III and stage IV melanomaThe staging should be carried out with a total body PET/CT, or other imaging techniques, if clinically indicated (NMR, bone scan, etc.). Mutational state of BRAF gene, NRAS gene, and c- KIT gene should be verified.Clinical follow-up: clinical examination once every 3 months for 2 years, once every 6 months between the 3rd and the 5th year. After 5 years, clinical examination every 12 months up to 10 years.Instrumental procedures (for the first 5 years): total body CT or PET/CT every 3-6 months; in cases of PET/CT, they should be accompanied by a brain CT or NMR. In cases of treatment with ipilimumab, considering the weak effect of the drug on objective response, an instrumental re-examination (CT/NMR) 16 weeks after the treatment is recommended. In cases of suspected PD, a confirming CT after 4 weeks is recommended. Weak positive



Agarwala SS, Kirkwood JM. Adjuvant therapy of melanoma. Semin Surg Oncol 1998; 14(4): 302-10. [Medline]

AIOM. Il follow up. Milano, AIOM, 2014.

Alaeddini M, Etemad-Moghadam S. Immunohistochemical profile of oral mucosal and head and neck cutaneous melanoma. J Oral Pathol Med 2015; 44(3): 234-8. [Medline]

Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 2013; 14(3): 249-56. [Medline]

Ascierto PA, Chiarion-Sileni V, Muggiano A, Mandalà M, Pimpinelli N, Del Vecchio M et al. Interferon alpha for the adjuvant treatment of melanoma: review of international literature and practical recommendations from an expert panel on the use of interferon. J Chemother 2014; 26(4): 193-201. [Medline]

Axell T, Hedin CA. Epidemiologic study of excessive oral melanin pigmentation with special reference to the influence of tobacco habits. Scand J Dental Res 1982; 90(6): 434-42. [Medline]

Bachar G, Loh KS, O’Sullivan B, Goldstein D, Wood S, Brown D et al. Mucosal melanomas of the head and neck: experience of the Princess Margaret Hospital. Head Neck 2008; 30(10): 1325-31. [Medline]

Ballantyne AJ. Malignant melanoma of the skin of the head and neck. An analysis of 405 cases. Am J Surg 1970; 120(4): 425-31. [Medline]

Bandarchi B, Jabbari CA, Vedadi A, Navab R. Molecular biology of normal melanocytes and melanoma cells. J Clin Pathol 2013; 66(8): 644-8. [Medline]

Baptista P, Garcia Velloso MJ, Salvinelli F, Casale M. Radioguided surgical strategy in mucosal melanoma of the nasal cavity. Clin Nucl Med 2008; 33(1): 14-8. [Medline]

Beadling C, Jacobson-Dunlop E, Hodi FS, Le C, Warrick A, Patterson J et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res 2008; 14(21): 6821-8. [Medline]

Bekci T, Aslan K, Günbey HP, Incesu L. Primary malignant mucosal melanoma of the nasopharynx: an unusual cause of unilateral hearing loss. J Craniofac Surg 2014; 25(6): e567-9. [Medline]

Benlyazid A, Thariat J, Temam S, Malard O, Florescu C, Choussy O et al. Postoperative radiotherapy in head and neck mucosal melanoma: a GETTEC study. Arch Otolaryngol Head Neck Surg 2010; 136(12): 1219-25. [Medline]

Berger MF, Garraway LA. Applications of genomics in melanoma oncogene discovery. Hematol Oncol Clin North Am 2009; 23(3): 397-414, vii. [Medline]

Bologna SB, Nico MM, Hsieh R, Coutinho-Camillo CM, Buim ME, Fernandes JD et al. Adhesion molecules in primary oral mucosal melanoma: study of claudins, integrins and immunoglobulins in a series of 35 cases. Am J Dermatopathol 2013; 35(5): 541-54. [Medline]

Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011; 305(22): 2327-34. [Medline]

Chan RC, Chan JY, Wei WI. Mucosal melanoma of the head and neck: 32-year experience in a tertiary referral hospital. Laryngoscope 2012; 122(12): 2749-53. [Medline]

Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998; 83(8): 1664-78. [Medline]

Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26): 2507-16. [Medline]

Chi Z, Li S, Sheng X, Si L, Cui C, Han M et al. Clinical presentation, histology, and prognoses of malignant melanoma in ethnic Chinese: a study of 522 consecutive cases. BMC Cancer 2011; 11: 85. [Medline]

Clifton N, Harrison L, Bradley PJ, Jones NS. Malignant melanoma of nasal cavity and paranasal sinuses: report of 24 patients and literature review. J Laryngol Otol 2011; 125(5): 479-85. [Medline]

Combs SE, Konkel S, Thilmann C, Debus J, Schulz-Ertner D. Local high-dose radiotherapy and sparing of normal tissue using intensity-modulated radiotherapy (IMRT) for mucosal melanoma of the nasal cavity and paranasal sinuses. Strahlenther Onkol 2007; 183(2): 63-8. [Medline]

Coutinho-Camillo CM, Lourenço SV, Soares FA. Head and Neck: Primary oral mucosal melanoma. Atlas Genet Cytogenet Oncol Haematol 2015; in press.

Cramer SF. Stem cells for epidermal melanocytes – a challenge for students of dermatopathology. Am J Dermatopathol 2009; 31(4): 331-41. [Medline]

Curioni-Fontecedro A, Pitocco R, Schoenewolf NL, Holzmann D, Soldini D, Dummer R et al. Intratumoral Heterogeneity of MAGE-C1/CT7 and MAGE-C2/CT10 Expression in Mucosal Melanoma. Biomed Res Int 2015; 2015: 432479. [Medline]

Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353(20): 2135-47. [Medline]

Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006; 24(26): 4340-6. [Medline]

Dahlgren L, Schedvins K, Kanter-Lewensohn L, Dalianis T, Ragnarsson-Olding BK. Human papilloma virus (HPV) is rarely detected in malignant melanomas of sun sheltered mucosal membranes. Acta Oncol 2005; 44(7): 694-9. [Medline]

Del Vecchio M, Di Guardo L, Ascierto PA, Grimaldi AM, Sileni VC, Pigozzo J et al. Efficacy and safety of ipilimumab 3mg/kg in patients with pretreated, metastatic, mucosal melanoma. Eur J Cancer 2014; 50(1): 121-7. [Medline]

Demizu Y, Fujii O, Terashima K, Mima M, Hashimoto N, Niwa Y et al. Particle therapy for mucosal melanoma of the head and neck. A single-institution retrospective comparison of proton and carbon ion therapy. Strahlenther Onkol 2014; 190(2): 186-91. [Medline]

Dupin E, Le Douarin NM. Development of melanocyte precursors from the vertebrate neural crest. Oncogene 2003; 22(20): 3016-23. [Medline]

Eggermont AM, Gore M. Randomized adjuvant therapy trials in melanoma: surgical and systemic. Semin Oncol 2007; 34(6): 509-15. [Medline]

Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H et al. Adjuvant ipilimumab versus placebo after complete resectionof high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 2015; 16(5): 522-30. [Medline]

Fossati P, Molinelli S, Matsufuji N, Ciocca M, Mirandola A, Mairani A et al. Dose prescription in carbon ion radiotherapy: a planning study to compare NIRS and LEM approaches with a clinically-oriented strategy. Phys Med Biol 2012; 57(22): 7543-54. [Medline]

Fuji H, Yoshikawa S, Kasami M, Murayama S, Onitsuka T, Kashiwagi H et al. High-dose proton beam therapy for sinonasal mucosal malignant melanoma. Radiat Oncol 2014; 9: 162. [Medline]

Fusi A, Festino L, Botti G, Masucci G, Melero I, Lorigan P et al. PD-L1 expression as a potential predictive biomarker. Lancet Oncol 2015; 16(13): 1285-7. [Medline]

Gal TJ, Silver N, Huang B. Demographics and treatment trends in sinonasal mucosal melanoma. Laryngoscope 2011; 121(9): 2026-33. [Medline]

Garbe C, Radny P, Linse R, Dummer R, Gutzmer R, Ulrich J et al. Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis. Ann Oncol 2008; 19(6): 1195-201. [Medline]

Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 2011; 16(1): 5-24. [Medline]

Gavriel H, McArthur G, Sizeland A, Henderson M. Review: mucosal melanoma of the head and neck. Melanoma Res 2011; 21(4): 257-66. [Medline]

Gilain L, Houette A, Montalban A, Mom T, Saroul N. Mucosal melanoma of the nasal cavity and paranasal sinuses. Eur Ann Otorhinolaryngol Head Neck Dis 2014; 131(6): 365-9. [Medline]

Gilligan D, Slevin NJ. Radical radiotherapy for 28 cases of mucosal melanoma in the nasal cavity and sinuses. Br J Radiol 1991; 64(768): 1147-50. [Medline]

Giraud G, Ramqvist T, Ragnarsson-Olding B, Dalianis T. DNA from BK virus and JC virus and from KI, WU, and MC polyomaviruses as well as from simian virus 40 is not detected in non-UV-light-associated primary malignant melanomas of mucous membranes. J Clin Microbiol 2008; 46(11): 3595-8. [Medline]

Glatz-Krieger K, Pache M, Tapia C, Fuchs A, Savic S, Glatz D et al. Anatomic site-specific patterns of gene copy number gains in skin, mucosal, and uveal melanomas detected by fluorescence in situ hybridization. Virchows Arch 2006; 449(3): 328-33. [Medline]

Gomori JM, Grossman RI, Shields JA, Augsburger JJ, Joseph PM, DeSimeone D. Choroidal melanomas: correlation of NMR spectroscopy and MR imaging. Radiology 1986; 158(2): 443-5. [Medline]

Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG et al (eds). AJCC Cancer Staging Manual. 6th Edition. New York, Springer, 2002.

Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification J Clin Oncol 2011; 29(21): 2904-9. [Medline]

Gwosdz C, Scheckenbach K, Lieven O, Reifenberger J, Knopf A, Bier H et al. Comprehensive analysis of the p53 status in mucosal and cutaneous melanomas. Int J Cancer 2006; 118(3): 577-82. [Medline]

Hanna E, DeMonte F, Ibrahim S, Roberts D, Levine N, Kupferman M. Endoscopic resection of sinonasal cancers with and without craniotomy: oncologic results. Arch Otolaryngol Head Neck Surg 2009; 135(12): 1219-24. [Medline]

Harwood AR, Cummings BJ. Radiotherapy for mucosal melanoma. Int J Radiat Oncol Biol Phys 1982; 8(7): 1121-6. [Medline]

Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380(9839): 358-65. [Medline]

Hayashi T, Furukawa H, Oyama A, Funayama E, Saito A, Yamao T et al. Sentinel lymph node biopsy using real-time fluorescence navigation with indocyanine green in cutaneous head and neck/lip mucosa melanomas. Head Neck 2012; 34(5): 758-61. [Medline]

Hicks MJ, Flaitz CM. Oral mucosal melanoma: epidemiology and pathobiology. Oral Oncol 2000; 36(2):152-69. [Medline]

Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711-23. [Medline]

Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol 2013; 31(26): 3182-90. [Medline]

Holmstrom M, Lund VJ. Malignant melanomas of the nasal cavity after occupational exposure to formaldehyde. Br J Ind Med 1991; 48(1): 9-11. [Medline]

Hsieh R, Nico MM, Coutinho-Camillo CM, Buim ME, Sangueza M, Lourenço SV. The CDKN2A and MAP kinase pathways: molecular roads to primary oral mucosal melanoma. Am J Dermatopathol 2013; 35(2): 167-75. [Medline]

Jangard M, Hansson J, Ragnarsson-Olding B. Primary sinonasal malignant melanoma: a nationwide study of the Swedish population, 1960-2000. Rhinology 2013; 51(1): 22-30. [Medline]

Jethanamest D, Vila PM, Sikora AG, Morris LG. Predictors of survival in mucosal melanoma of the head and neck. Ann Surg Oncol 2011; 18(10): 2748-56. [Medline]

Jingu K, Kishimoto R, Mizoe JE, Hasegawa A, Bessho H, Tsuji H et al. Malignant mucosal melanoma treated with carbon ion radiotherapy with concurrent chemotherapy: prognostic value of pretreatment apparent diffusion coefficient (ADC). Radiother Oncol 2011; 98(1): 68-73. [Medline]

Kahn MA, Weathers DR, Hoffman JG. Transformation of a benign oral pigmentation to primary oral melanoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005; 100(4): 454-9. [Medline]

Kim SS, Han MH, Kim JE, Lee CH, Chung HW, Lee JS et al. Malignant melanoma of the sinonasal cavity: explanation of magnetic resonance signal intensities with histopathologic characteristics. Am J Otolaryngol 2000; 21(6): 366-78. [Medline]

Kim DK, Kim DW, Kim SW, Kim DY, Lee CH, Rhee CS. Ki67 antigen as a predictive factor for prognosis of sinonasal mucosal melanoma. Clin Exp Otorhinolaryngol 2008; 1(4): 206-10. [Medline]

Kahn MA, Weathers DR, Hoffman JG. Transformation of a benign oral pigmentation to primary oral melanoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005; 100(4): 454-9. [Medline]

Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14(1): 7-17. [Medline]

Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 2001; 19(9): 2370-80. [Medline]

Koivunen P, Bäck L, Pukkila M, Laranne J, Kinnunen I, Grénman R et al. Accuracy of the current TNM classification in predicting survival in patients with sinonasal mucosal melanoma. Laryngoscope 2012; 122(8): 1734-8. [Medline]

Korabiowska M, Brinck U, Hoenig JF, Bartkowski SB, Mirecka J, Schauer A. An application of MIB antibody to the retrospective study of melanomas of oral mucosa and facial skin. J Cancer Res Clin Oncol 1994; 120(6): 365-8. [Medline]

Krengli M, Masini L, Kaanders JH, Maingon P, Oei SB, Zouhair A et al. Radiotherapy in the treatment of mucosal melanoma of the upper aerodigestive tract: analysis of 74 cases. A Rare Cancer Network study. Int J Radiat Oncol Biol Phys 2006; 65(3): 751-9. [Medline]

Krengli M, Masini L, Kaanders JH, Maingon P, Oei SB, Zouhair A et al. Radiotherapy in the treatment of mucosal melanoma of the upper aerodigestive tract: analysis of 74 cases. A Rare Cancer Network study. Int J Radiat Oncol Biol Phys 2006; 65(3): 751-9. [Medline]

Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014; 371(20): 1867-76. [Medline]

Lawrence D, McDermott D, Hamid O, Weber J, Wolchok J, Richards J et al. Ipilimumab (IPI) Expanded Access Program (EAP) for patients (pts) with Stage III/IV melanoma: safety data by subgroups. Ann Oncol 2012; 23 Suppl 9: abstr 1129P.

Lazarev S, Gupta V, Hu K, Harrison LB, Bakst R. Mucosal melanoma of the head and neck: a systematic review of the literature. Int J Radiat Oncol Biol Phys 2014; 90(5): 1108-18. [Medline]

Lebbe C, Chevret S, Jouary T, Dalac S, Dalle S, Guillot B et al. Phase II multicentric uncontrolled national trial assessing the efficacy of nilotinib in the treatment of advanced melanomas with c-KIT mutation or amplification. J Clin Oncol 2014; 32(5s) Suppl: abstr 9032.

Ledderose GJ, Leunig A. Surgical management of recurrent sinonasal mucosal melanoma: endoscopic or transfacial resection. Eur Arch Otorhinolaryngol 2014; 272(2): 351-6. [Medline]

Lee SP, Shimizu KT, Tran LM, Juillard G, Calcaterra TC. Mucosal melanoma of the head and neck: the impact of local control on survival. Laryngoscope 1994; 104(2):121-6. [Medline]

Lian B, Mao LL, Cui CL, Chi ZH, Si L, Sheng XN et al. Phase II randomized study of high-dose interferon alfa-2b (HDI) versus chemotherapy as adjuvant therapy in patients with resected mucosal melanoma. J Clin Oncol 2012; 30 Suppl: abstr 8506.

Lian B, Guo J. Checkpoint inhibitors in treatment of metastatic mucosal melanoma. Chin Clin Oncol 2014; 3(3): 37. [Medline]

Liu HG, Kong MX, Yao Q, Wang SY, Shibata R, Yee H et al. Expression of Sox10 and c-kit in sinonasal mucosal melanomas arising in the Chinese population. Head and Neck Pathol 2012; 6(4): 401-8. [Medline]

Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13(11): 1087-95. [Medline]

Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J et al. Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma. N Engl J Med 2014; 371(20): 1877-88. [Medline]

Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015; 386(9992): 444-51. [Medline]

López F, Rodrigo JP, Cardesa A, Triantafyllou A, Devaney KO, Mendenhall WM. Update on primary head and neck mucosal melanoma. Head Neck 2016; 38(1): 147-55. [Medline]

Loree TR, Mullins AP, Spellman J, North JH Jr, Hicks WL Jr. Head and neck mucosal melanoma: a 32-year review. Ear Nose Throat J 1999; 78(5):372-5. [Medline]

Lourenço SV, Fernandes JD, Hsieh R, Coutinho-Camillo CM, Bologna S, Sangueza M et al. Head and neck mucosal melanoma: a review. Am J Dermatopathol 2014; 36(7): 578-87. [Medline]

Lund VJ, Chisholm EJ, Howard DJ, Wei WI. Sinonasal malignant melanoma: an analysis of 115 cases assessing outcomes of surgery, postoperative radiotherapy and endoscopic resection. Rhinology 2012; 50(2): 203-10. [Medline]

Lundberg R, Brytting M, Dahlgren L, Kanter-Lewensohn L, Schloss L, Dalianis T et al. Human herpes virus DNA is rarely detected in non-UV light-associated primary malignant melanomas of mucous membranes. Anticancer Res 2006; 26(58): 3627-31. [Medline]

Lyu J, Wu Y, Li C, Wang R, Song H, Ren G et al. Mutation scanning of BRAF,NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma: a study of 57 cases. J Oral Pathol Med 2016; 45(4): 295-301. [Medline]

McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014; 15(3): 323-32. [Medline]

Mackintosh JA. The antimicrobial properties of melanocytes, melanosomes and melanin and the evolution of black skin. J Theor Biol 2001; 211(2): 101-13. [Medline]

Mallone S, De Vries E, Guzzo M, Midena E, Verne J, Coebergh JW et al. Descriptive epidemiology of malignant mucosal and uveal melanomas and adnexal skin carcinomas in Europe. Eur J Cancer 2012; 48(8): 1167-75. [Medline]

Mardi K. Primary mucosal malignant melanoma of nasopharynx: a rare case report. J Cancer Res Ther 2014; 10(2): 416-8. [Medline]

Medina JE, Ferlito A, Pellitteri PK, Shaha AR, Khafif A, Devaney KO et al. Current management of mucosal melanoma of the head and neck. J Surg Oncol 2003; 83(2): 116-22. [Medline]

Meleti M, Leemans CR, Mooi WJ, Vescovi P, van der Waal I. Oral malignant melanoma: the Amsterdam experience. J Oral Maxillofac Surg 2007; 65(11): 2181-6. [Medline]

Meleti M, Leemans CR, de Bree R, Vescovi P, Sesenna E, van der Waal I. Head and neck mucosal melanoma: experience with 42 patients, with emphasis on the role of postoperative radiotherapy. Head Neck 2008; 30(12): 1543-51. [Medline]

Michel J, Perret-Court A, Fakhry N, Braustein D, Monestier S, Richard MA et al. Sinonasal mucosal melanomas: the prognostic value of tumor classifications. Head Neck 2014; 36(3): 311-6. [Medline]

Minor DR, Kashani-Sabet M, Garrido M, O’Day SJ, Hamid O, Bastian BC. Sunitinib therapy for melanoma patients with KIT mutations. Clin Cancer Res 2012; 18(5): 1457-63. [Medline]

Mizoe JE, Hasegawa A, Jingu K, Takagi R, Bessyo H, Morikawa T et al. Results of carbon ion radiotherapy for head and neck cancer. Radiother Oncol 2012; 103(1): 32-7. [Medline]

Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2010; 102(7): 493-501. [Medline]

Moreno MA, Hanna EY. Management of mucosal melanomas of the head and neck: did we make any progress? Curr Opin Otolaryngol Head Neck Surg 2010a; 18(2): 101-6. [Medline]

Moreno MA, Roberts DB, Kupferman ME, DeMonte F, El-Naggar AK, Williams M et al. Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center. Cancer 2010b; 116(9): 2215-23. [Medline]

Morris LG, Wen YH, Nonaka D, DeLacure MD, Kutler DI, Huan Y et al. PNL2 melanocytic marker in immunohistochemical evaluation of primary mucosal melanoma of the head and neck. Head Neck 2008; 30(6): 771-5. [Medline]

Nakashima JP1, Viégas CM, Fassizoli AL, Rodrigues M, Chamon LA, Silva JH et al. Postoperative adjuvant radiation therapy in the treatment of primary head and neck mucosal melanomas. ORL J Otorhinolaryngol Relat Spec 2008; 80(6): 344-51. [Medline]

Nandapalan V, Roland NJ, Helliwell TR, Williams EM, Hamilton JW, Jones AS. Mucosal melanoma of the head and neck. Clin Otolaryngol Allied Sci 1998; 23(2): 107-16. [Medline]

Nicolai P, , Battaglia P, Bignami M, Bolzoni Villaret A, Delù G, Khrais T et al. Endoscopic surgery for malignant tumors of the sinonasal tract and adjacent skull base: a 10-year experience. Am J Rhinol 2008; 22(3): 308-16. [Medline]

Omholt K, Grafström E, Kanter-Lewensohn L, Hansson J, Ragnarsson-Olding BK. KIT pathway alterations in mucosal melanomas of the vulva and other sites. Clin Cancer Res 2011; 17(12): 3933-42. [Medline]

Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res 2013; 19(19): 5300-9. [Medline]

Overgaard J, Overgaard M, Hansen PV, von der Maase H. Some factors of importance in the radiation treatment of malignant melanoma. Radiother Oncol 1986; 5(3): 183-92. [Medline]

Owens JM, Roberts DB, Myers JN. The role of postoperative adjuvant radiation therapy in the treatment of mucosal melanomas of the head and neck region. Arch Otolaryngol Head Neck Surg 2003; 129(8): 864-8. [Medline]

Papaspyrou G, Garbe C, Schadendorf D, Werner JA, Hauschild A, Egberts F. Mucosal melanomas of the head and neck: new aspects of the clinical outcome, molecular pathology, and treatment with c-kit inhibitors. Melanoma Res 2011; 21(6): 475-82. [Medline]

Patel SG, Prasad ML, Escrig M, Singh B, Shaha AR, Kraus DH et al. Primary mucosal malignant melanoma of the head and neck. Head Neck 2002; 24(3): 247-57. [Medline]

Penel N, Mallet Y, Mirabel X, Van JT, Lefebvre JL. Primary mucosal melanoma of head and neck: prognostic value of clear margins. Laryngoscope 2006; 116(6): 993-5. [Medline]

Plonka PM, Passeron T, Brenner M, Tobin DJ, Shibahara S, Thomas A et al. What are melanocytes really doing all day long…? Exp Dermatol 2009; 18(9): 799-819. [Medline]

Postow MA, Luke JJ, Bluth MJ et al. Ipilimumab for patients with advanced mucosal melanoma. Oncologist 2013; 18(6): 726-32. [Medline]

Postow M, Chesney J, Pavlick AC et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372(21): 2006-17. [Medline]

Prasad ML, Jungbluth AA, Patel SG, Iversen K, Hoshaw-Woodard S, Busam KJ. Expression and significance of cancer testis antigens in primary mucosal melanoma of the head and neck. Head Neck 2004a; 26(12): 1053-7. [Medline]

Prasad ML, Patel SG, Huvos AG, Shah JP, Busam KJ. Primary mucosal melanoma of the head and neck: a proposal for microstaging localized, Stage I (lymph node-negative) tumors. Cancer 2004b; 100(8): 1657-64. [Medline]

Prasad ML, Patel SG, Shah JP, Hoshaw-Woodard S, Busam KJ. Prognostic significance of regulators of cell cycle and apoptosis, p16(INK4a), p53, and bcl-2 in primary mucosal melanomas of the head and neck. Head Neck Pathol 2012; 6(2): 184-90. [Medline]

Rapini RP, Golitz LE, Greer RO Jr, Krekorian EA, Poulson T. Primary malignant melanoma of the oral cavity. A review of 177 cases. Cancer 1985; 55(7): 1543-51. [Medline]

RARECAREnet – Information Network on Rare Cancers. Available at:

Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncology 2015; 16(8): 908-18. [Medline]

Rivera RS, Nagatsuka H, Gunduz M, Cengiz B, Gunduz E, Siar CH et al. C-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma. Virchows Arch 2008; 452(1): 27-32. [Medline]

Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364(26): 2517-26. [Medline]

Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372(1): 30-9. [Medline]

Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015a; 372(4): 320-30. [Medline]

Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015b; 372(1): 30-9. [Medline]

Shibuya H, Takeda M, Matsumoto S, Hoshina M, Suzuki S, Takagi M. The efficacy of radiation therapy for a malignant melanoma in the mucosa of the upper jaw: an analytic study. Int J Radiat Oncol Biol Phys 1993; 25(1): 35-9. [Medline]

Shiga K, Ogawa T, Kobayashi T, Ueda S, Kondo A, Nanba A et al. Malignant melanoma of the head and neck: A multi-institutional retrospective analysis of cases in Northern Japan. Head Neck 2012; 34(11): 1537-41. [Medline]

Shuman AG, Light E, Olsen SH, Pynnonen MA, Taylor JM, Johnson TM et al. Mucosal melanoma of the head and neck: predictors of prognosis. Arch Otolaryngol Head Neck Surg 2011; 137(4): 331-7. [Medline]

Sobin LH, Gospodarowicz MK, Wittekind C (eds). TNM Classification of malignant tumours. Wiley-Blackwell 2009.

Starek I, Koranda P, Benes P. Sentinel lymph node biopsy: A new perspective in head and neck mucosal melanoma? Melanoma Res 2006; 16(5): 423-7. [Medline]

Steinsträter O, Grün R, Scholz U, Friedrich T, Durante M, Scholz M. Mapping of RBE-weighted doses between HIMAC- and LEM-Based treatment planning systems for carbon ion therapy. Int J Radiat Oncol Biol Phys 2012; 84(3): 854-60. [Medline]

Sun C, Chen YF, Jiang YE, Hu ZD, Yang AK, Song M. Treatment and prognosis of oral mucosal melanoma. Oral Oncol 2012; 48(7): 647-52. [Medline]

Sun CZ, Li QL, Hu ZD, Jiang YE, Song M, Yang AK. Treatment and prognosis in sinonasal mucosal melanoma: A retrospective analysis of 65 patients from a single cancer center. Head Neck 2014; 36(5): 675-81. [Medline]

Swegal W, Koyfman S, Scharpf J, Sindwani R, Greskovich J, Borden E et al. Endoscopic and open surgical approaches to locally advanced sinonasal melanoma: comparing the therapeutic benefits. JAMA Otolaryngol Head Neck Surg 2014; 140(9): 840-5. [Medline]

Tacastacas JD, Bray J, Cohen YK, Arbesman J, Kim J, Koon HB et al. Update on primary mucosal melanoma. J Am Acad Dermatol 2014; 71(2): 366-75. [Medline]

Tajudeen BA, Vorasubin N, Sanaiha Y, Palma-Diaz MF, Suh JD, Wang MB. Sinonasal mucosal melanoma: 20-year experience at a tertiary referral center. Int Forum Allergy Rhinology 2014, 4(7): 592-7. [Medline]

Tanaka N, Amagasa T, Iwaki H, Shioda S, Takeda M, Ohashi K et al. Oral malignant melanoma in Japan. Oral Surg Oral Med Oral Pathol 1994; 78(1): 81-90. [Medline]

Tanaka N, Odajima T, Mimura M, Ogi K, Dehari H, Kimijima Y et al. Expression of Rb, pRb2/p130, p53, and p16 proteins in malignant melanoma of oral mucosa. Oral Oncol 2001; 37(3): 308-14. [Medline]

Tanaka N, Mimura M, Kimijima Y, Amagasa T. Clinical investigation of amelanotic malignant melanoma in the oral region. J Oral Maxillofac Surg 2004; 62(8): 911-7. [Medline]

Temam S, Mamelle G, Marandas P, Wibault P, Avril MF, Janot F et al. Postoperative radiotherapy for primary mucosal melanoma of the head and neck. Cancer 2005; 103(2): 313-9. [Medline]

Terada T, Saeki N, Toh K, Uwa N, Sagawa K, Mouri T et al. Primary malignant melanoma of the larynx: a case report and literature review. Auris Nasus Larynx 2007; 34(1): 105-110. [Medline]

Thierauf J, Veit JA, Affolter A, Bergmann C, Grünow J, Laban S et al. Identification and clinical relevance of PD-L1 expression in primary mucosal malignant melanoma of the head and neck. Melanoma Res 2015; 25(6): 503-9. [Medline]

Thoeny HC, De Keyzer F, King AD. Diffusion-weighted MR imaging in the head and neck. Radiology 2012; 263(1): 19-32. [Medline]

Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol 2003; 27(5): 594-611. [Medline]

Tomicic J, Wanebo HJ. Mucosal melanomas. Surg Clin North Am 2003; 83(2): 237-52. [Medline]

Turri-Zanoni M, Medicina D, Lombardi D, Ungari M, Balzarini P, Rossini C et al. Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases. Head Neck 2013; 35(8): 1066-77. [Medline]

Umeda M, Shimada K. Primary malignant melanoma of the oral cavity – its histological classification and treatment. Br J Oral Maxillofac Surg 1994; 32(1): 39-47. [Medline]

Wada H, Nemoto K, Ogawa Y, Hareyama M, Yoshida H, Takamura A et al. A multi-institutional retrospective analysis of external radiotherapy for mucosal melanoma of the head and neck in Northern Japan. Int J Radiat Oncol Biol Phys 2004; 59(2): 495-500. [Medline]

Wagner M, Morris CG, Werning JW, Mendenhall WM. Mucosal melanoma of the head and neck. Am J Clin Oncol 2008; 31(1): 43-8. [Medline]

Wang X, Wu HM, Ren GX, Tang J, Guo W. Primary oral mucosal melanoma: advocate a wait-and-see policy in the clinically N0 patient. J Oral Maxillofac Surg 2012; 70(5): 1192-8. [Medline]

Warszawik-Hendzel O, Słowińska M, Olszewska M, Rudnicka L. Melanoma of the oral cavity: pathogenesis, dermoscopy, clinical features, staging and management. J Dermatol Case Rep 2014; 8(3): 60-6. [Medline]

Weber JS, D’Angelo SP2, Minor D3, Hodi FS4, Gutzmer R5, Neyns B et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015; 16(4): 375-84. [Medline]

Wermker K, Brauckmann T, Klein M, Haßfeld S, Schulze HJ, Hallermann C. Prognostic value of S100/CD31 and S100/podoplanin double immunostaining in mucosal malignant melanoma of the head and neck. Head Neck 2015; 37(9): 1368-74. [Medline]

Wheatley K, Ives N, Eggermont A, Kirkwood J, Cascinelli N, Markovicet SN al. Interferon-α as adjuvant therapy for melanoma: an individual patient data meta-analysis of randomised trials. J Clin Oncol 2007; 25(18S): abstr 8526.

Woodruff WW, Djang WT, McLendon RE, Heinz ER, Voorhees DR. Intracerebral malignant melanoma: High-field-strength MR imaging. Radiology 1987; 165(1): 209-13. [Medline]

Wu Y, Zhong Y, Li C, Song H, Guo W, Ren G. Neck dissection for oral mucosal melanoma: caution of nodular lesion. Oral Oncol 2014; 50(4): 319-24. [Medline]

Yanagi T, Mizoe JE, Hasegawa A, Takagi R, Bessho H, Onda T et al. Mucosal malignant melanoma of the head and neck treated by carbon ion radiotherapy. Int J Radiat Oncol Biol Phys 2009; 74(1): 15-20. [Medline]

Yang X, Ren GX, Zhang CP, Zhou GY, Hu YJ, Yang WJ et al. Neck dissection and post-operative chemotherapy with dimethyl triazeno imidazole carboxamide and cisplatin protocol are useful for oral mucosal melanoma. BMC Cancer 2010; 10: 623. [Medline]

Yi JH, Yi SY, Lee HR, Lee SI, Lim do H, Kim JH et al. Dacarbazine-based chemotherapy as first-line treatment in noncutaneous metastatic melanoma: multicenter, retrospective analysis in Asia. Melanoma Res 2011; 21(3): 223-7. [Medline]

Yoshioka H, Kamada T, Kandatsu S, Koga M, Yoshikawa K, Matsuoka Y et al. MRI of mucosal malignant melanoma of the head and neck. J Comput Assist Tomogr 1998; 22(3): 492-7. [Medline]

Zaghi S, Pouldar D, Lai C, Chhetri DK. Subglottic presentation of a rare tumor: primary or metastatic? Primary mucosal melanoma of the subglottic larynx. JAMA Otolaryngol Head Neck Surg 2013; 139(7): 739-40. [Medline]

Zebary A, Jangard M, Omholt K, Ragnarsson-Olding B, Hansson J. KIT, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases. Br J Cancer 2013; 109(3): 559-64. [Medline]

Zenda S, Kawashima M, Nishio T, Kohno R, Nihei K, Onozawa M et al. Proton beam therapy as a nonsurgical approach to mucosal melanoma of the head and neck: a pilot study. Int J Radiat Oncol Biol Phys 2011; 81(1): 135-9. [Medline]

Remo Accorona (Author)
Department of Otorhinolaryngology, University of Brescia, Italy
email address:

Paolo Antonio Ascierto (Author and Editor)
Department Melanoma, Soft Tissues, Musculoskeletal and Head&Neck, Italian National Cancer Institute – IRCCS Pascale Foundation, Naples – Italy
email address:

Gerardo Botti (Author)
Department of Pathology and Cytopathology, Italian National Cancer Institute – IRCCS Pascale Foundation, Naples – Italy
email address:

Davide Farina (Author)
Department of Radiology, University of Brescia – Italy
email address:

Piero Fossati (Author)
Particle Therapy Cancer Research Institute, CNAO Foundation, Milan – Italy
email address:

Gemma Gatta (Author)
Italian National Cancer Institute – IRCCS Foundation, Milan – Italy
email address:

Helen Gogas (Reviewer)
First Department of Medicine, Laiko General Hospital, Athens – Greece
email address:

Davide Lombardi (Author)
Department of Otorhinolaryngology, University of Brescia – Italy
email address:

Roberto Maroldi (Author)
Department of Radiology, University of Brescia – Italy
email address:

Piero Nicolai (Author)
Department of Otorhinolaryngology, University of Brescia – Italy
email address:

Marco Ravanelli (Author)
Department of Radiology, University of Brescia – Italy
email address:

Vito Vanella (Author)
Department Melanoma, Soft Tissues, Musculoskeletal and Head&Neck, Italian National Cancer Institute – IRCCS Pascale Foundation, Naples – Italy
email address: