**3.2 Histological diagnosis**

*Melanoma*

**Figure 2.**

As with the sinonasal tract, it is also possible to observe satellite lesions in the

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

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

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

Rare cases of laryngeal [55], oropharyngeal [56] and nasopharyngeal [50, 57] MM have been reported; these lesions are extremely rare, with only sixty cases reported in the literature. The tumors are most commonly located in the supraglottic

Clinical presentation does not generally differ from that typical of other primary

The symptoms of laryngeal MM are dysphagia, hoarseness, and painful sore

Pharyngeal lesions may cause hemorrhage, dysphagia and/or dyspnea [19]. Symptoms of nasopharyngeal PMMs are similar to sinonasal PMMs; the tumors usually present with epistaxis, nasal obstruction, and obstruction of the Eustachian

Notably, the risk of nodal (65.5%) and distant (59.3%) metastases in pharyngo-

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

laryngeal lesions is definitely higher than in other head and neck subsites [4]. As a general rule, the risk of nodal involvement in HNMM at presentation is

higher in oral (25-43%) [47] than in sinonasal lesions (<10%) [35, 53].

The majority of oral melanomas occur in the maxillary alveolar ridge or the hard palate. Such locations favor early invasion of underlying bone, which may account for their poor prognosis. The buccal mucosa, lips, tongue, floor of the mouth, and

oral cavity surrounding the primary lesion [49, 51].

involvement compared to macular melanomas.

region (62.2%) followed by the vocal cords (37.8%).

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

tumors, mainly squamous cell carcinomas, arising in the same sites.

uvula can also be affected as well [52].

commonly observed.

*Hard palate mucosal melanoma.*

throat [18, 19, 58].

tube with serous otitis [19].

presence of pigmentation.

**72**

Head and neck PMMs are usually diagnosed at advanced stages, thus presenting macroscopically as aggressive nodular neoplasms arising from the mucosa; few cases are detected in situ [60]. Histopathological diagnosis is straightforward when the tumor cells are melanin rich. About two thirds of mucosal melanomas contain some intracytoplasmic brown pigment, which has to be confirmed as melanin and can be found in tumor cells or macrophages [61].

The histological features of HNMM can be as diverse as cutaneous melanomas [62], with variable mitotic activity and cell morphology [11]. Approximately 15 to 50% of cases presents with amelanotic lesions [63, 64]; as they can mimic another malignant neoplasms, including squamous cell carcinoma, this diagnosis has been challenging. These tumors frequently have a worse outcome [65, 66].

Histologically, mucosal melanoma is characterized by the proliferation of neoplastic melanocytes with variable phenotypes (epithelioid, spindle, and plasmacytoid cells without maturation and with nuclear changes, appearing as large and hyperchromatic nuclei with prominent nucleoli) that are arranged in a sheet-like, organoid, alveolar, solid, or desmoplastic architecture. They display high mitotic activity and show a pattern of invasion of the submucosa destroying the underlying tissues [67–69].

Tumors with mixed cell phenotypes are more related with vascular invasion and the development of metastasis. The neoplastic proliferation is commonly found along the junction between the epithelial and lamina propria, but this may be difficult to detect in advanced and ulcerated lesions [70].

Molecular studies have tried to find clinical predictors and immunohistochemical biomarkers to improve outcomes and survival rates.

Immunohistochemical stains may help distinguish mucosal melanoma from other malignancies and from cutaneous melanoma.

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

One study assessed the expression of DNA mismatch repair and looked for the presence of microsatellite instability in HNMM. They showed that the cells had increased expression of mismatch repair proteins and increased microsatellite stability [72]. Besides these classical markers, the diagnostic potential of other molecules has been evaluated in Primary Oral Mucosal Melanoma (POMM), in particular several adhesion molecules. Integrin beta-3 and CD166 expression is correlated with extensive vascular invasion, while lower expression of CD54 is correlated with cell necrosis [73].

The expression of BCL2 in POMM has an important correlation with a longer overall survival [74].

The expression of podoplanin and CD13 in combination with S100 has been useful in the evaluation of lymph vessel and blood vessel invasion. Both markers are related to a poorer prognosis [75].

#### *Melanoma*

Programmed cell death ligand 1 (PDL-1) is known as a potent prognostic biomarker in several human tumors. Although this experimental evidence strongly supports the use of monoclonal antibodies targeting immune checkpoint proteins in MM, PDL-1 expression does not seem to be predictive of patient outcome, at least in melanoma [76]. Indeed, although PDL-1 positive tumors achieve a better responses to immunotherapies, PDL-1 negative patients can also have good outcomes.

### **3.3 Imaging of melanomas of the head and neck**

When malignancy is suspected, computed tomography (CT) and magnetic resonance imaging (MRI) are valuable in defining the locoregional extent of the tumor, which is critical in determining resectability. For more accurate evaluation of MM, magnetic resonance imaging (MRI) is the modality of choice. This modality provide more information about the tumor, the localization, its relation to adjacent structures, and expansive or infiltrative characteristics. The analysis of signals in the different sequences is more.

sophisticated than the analysis of CT densities. The MRI signal of mucosal melanoma is influenced by the amount of melanotic pigment and hemorrhage within the lesion.

CT and MRI, when used together, can be complementary and define even better the invasion and destruction of structures of the skull base by soft-tissue masses.

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 [77].

MM usually manifests radiologically as an aggressive solid tumor with destructive characteristics related to compression or infiltration. The tumor causes bone destruction and invades adjacent soft tissues [13]. Thus, pre-treatment tumor mapping requires definition of tumor relationships with all surrounding anatomic sites and subsites. It is mandatory the accurate evaluation of involvement of intracranial structures and the surrounding vital structures such as cranial nerves or vessels, the anterior cranial fossa, the orbits, the pterygopalatine fossa and the infratemporal fossa.

Tumors arising along the Eustachian tube or in the nasopharynx can spread to the skull base at the foramen lacerum or along the tube to potentially reach the middle ear.

From a surgical point of view, key elements in the preoperative staging of mucosal melanoma 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 [77]. When the neoplasm reaches important anatomic crossroads, such as the posterior third of the hard palate, the pterygopalatine fossa, and the foramen ovale, perineural growth should be accurately evaluated.

MRI is the standard imaging modality for postoperative surveillance. Micrometastases may be radiologically occult. Because of the high fluorodeoxyglucose avidity of PMMs, FDG-positron emission tomography (PET)/CT may play an important role in the staging of PMM and in selecting the goals of therapy for patients with suspected metastasis or recurrence [78, 79].

#### **3.4 Staging**

Tumor staging for mucosal melanoma remains a challenge. Several staging systems have been suggested, including tumor-nodal-metastases (TNM) staging systems, but none are frequently used. TNM staging is only used for head and neck mucosal melanoma [11, 18].

**75**

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

melanomas in 1970, which continues to be largely used:

Level III (deeply invasive: muscle, bone or cartilage).

noted on pre-treatment imaging can be included.

The often concealed locations of mucosal melanoma result in frequent presen-

In addition, unique to these anatomic locations are vast vascular and lymphatic networks in close proximity to the primary tumor, allowing for diffuse spread, with approximately one third of patients having nodal involvement at

While different staging systems are in place for mucosal melanomas of different primary sites, Ballantyne described a three level staging system for classifying mucosal

Although its major advantage lies in its simplicity, this classification does not include depth of invasion or local tumor extension. The classification provides limited prognostic information as the majority of patients present with stage I

To overcome these limitations, the pattern of tumor invasion has been studied in depth by Prasad et al., who reported that progression of the invasion at the microscopic level is associated with clinical worsening and suggests increased aggression. They proposed microstaging as a prognostic marker, based on invasion of tissue

Level II (superficially invasive: melanoma invading up to the lamina propria)

The study evidenced a statistically significant difference in disease specific survival rates in levels I (75%), II (52%) and III (23%) respectively. However, this classification system is based on histological findings, the disadvantage is that it can only be used in evaluation of tissues following tumor excision, although invasion

The American Joint Committee on Cancer (AJCC) staging system for head and neck mucosal melanoma is often utilized, beginning at stage III. This focuses on the extent or size of the primary mucosal tumor using it as a predictor for outcome [82]. Mucosal melanomas are aggressive tumors, therefore T1 and T2 are omitted as are

T3: Tumor limited to the epithelium and/or submucosa (mucosal disease) T4a: Moderately advanced disease involving the deep soft tissue, bone, cartilage, or overlying skin T4b: Tumor invades any of the following: brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral

Stage II: regional nodal involvement (cervical lymph node metastases).

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

Stage I: clinically localized disease;

Stage III: distant metastatic involvement.

tations of advanced disease.

diagnosis [17, 21, 22, 24, 25, 29].

disease [80].

compartments [81]:

stages I and II.

Level I (in situ disease)

TNM Clinical Classification:

TX: Primary tumor cannot be assessed T0: No evidence of primary tumor

NX: regional lymph nodes cannot be assessed N0: no regional lymph node metastasis N1: regional lymph node metastasis

T – Primary Tumor

space, mediastinal structures N – regional lymph nodes.

> M – distant metastasis M0: no distant metastasis M1: distant metastasis Stage Grouping Stage III: T3 N0 M0 Stage IV A: T4a N0 M0

The often concealed locations of mucosal melanoma result in frequent presentations of advanced disease.

In addition, unique to these anatomic locations are vast vascular and lymphatic networks in close proximity to the primary tumor, allowing for diffuse spread, with approximately one third of patients having nodal involvement at diagnosis [17, 21, 22, 24, 25, 29].

While different staging systems are in place for mucosal melanomas of different primary sites, Ballantyne described a three level staging system for classifying mucosal melanomas in 1970, which continues to be largely used:

Stage I: clinically localized disease;

*Melanoma*

Programmed cell death ligand 1 (PDL-1) is known as a potent prognostic biomarker in several human tumors. Although this experimental evidence strongly supports the use of monoclonal antibodies targeting immune checkpoint proteins in MM, PDL-1 expression does not seem to be predictive of patient outcome, at least in melanoma [76]. Indeed, although PDL-1 positive tumors achieve a better responses

to immunotherapies, PDL-1 negative patients can also have good outcomes.

When malignancy is suspected, computed tomography (CT) and magnetic resonance imaging (MRI) are valuable in defining the locoregional extent of the tumor, which is critical in determining resectability. For more accurate evaluation of MM, magnetic resonance imaging (MRI) is the modality of choice. This modality provide more information about the tumor, the localization, its relation to adjacent structures, and expansive or infiltrative characteristics. The analysis of signals in

sophisticated than the analysis of CT densities. The MRI signal of mucosal melanoma is influenced by the amount of melanotic pigment and hemorrhage

CT and MRI, when used together, can be complementary and define even better the invasion and destruction of structures of the skull base by soft-tissue masses. 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

MM usually manifests radiologically as an aggressive solid tumor with destructive characteristics related to compression or infiltration. The tumor causes bone destruction and invades adjacent soft tissues [13]. Thus, pre-treatment tumor mapping requires definition of tumor relationships with all surrounding anatomic sites and subsites. It is mandatory the accurate evaluation of involvement of intracranial structures and the surrounding vital structures such as cranial nerves or vessels, the anterior cranial fossa, the orbits, the pterygopalatine fossa and the

Tumors arising along the Eustachian tube or in the nasopharynx can spread to the skull base at the foramen lacerum or along the tube to potentially reach the

From a surgical point of view, key elements in the preoperative staging of mucosal melanoma 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 [77]. When the neoplasm reaches important anatomic crossroads, such as the posterior third of the hard palate, the pterygopalatine fossa,

Tumor staging for mucosal melanoma remains a challenge. Several staging systems have been suggested, including tumor-nodal-metastases (TNM) staging systems, but none are frequently used. TNM staging is only used for head and neck

and the foramen ovale, perineural growth should be accurately evaluated. MRI is the standard imaging modality for postoperative surveillance. Micrometastases may be radiologically occult. Because of the high fluorodeoxyglucose avidity of PMMs, FDG-positron emission tomography (PET)/CT may play an important role in the staging of PMM and in selecting the goals of therapy for

patients with suspected metastasis or recurrence [78, 79].

**3.3 Imaging of melanomas of the head and neck**

the different sequences is more.

hyperintensity and T2 hypointensity [77].

within the lesion.

infratemporal fossa.

middle ear.

**3.4 Staging**

mucosal melanoma [11, 18].

**74**

Stage II: regional nodal involvement (cervical lymph node metastases). Stage III: distant metastatic involvement.

Although its major advantage lies in its simplicity, this classification does not include depth of invasion or local tumor extension. The classification provides limited prognostic information as the majority of patients present with stage I disease [80].

To overcome these limitations, the pattern of tumor invasion has been studied in depth by Prasad et al., who reported that progression of the invasion at the microscopic level is associated with clinical worsening and suggests increased aggression.

They proposed microstaging as a prognostic marker, based on invasion of tissue compartments [81]:

Level I (in situ disease)

Level II (superficially invasive: melanoma invading up to the lamina propria) Level III (deeply invasive: muscle, bone or cartilage).

The study evidenced a statistically significant difference in disease specific survival rates in levels I (75%), II (52%) and III (23%) respectively. However, this classification system is based on histological findings, the disadvantage is that it can only be used in evaluation of tissues following tumor excision, although invasion noted on pre-treatment imaging can be included.

The American Joint Committee on Cancer (AJCC) staging system for head and neck mucosal melanoma is often utilized, beginning at stage III. This focuses on the extent or size of the primary mucosal tumor using it as a predictor for outcome [82]. Mucosal melanomas are aggressive tumors, therefore T1 and T2 are omitted as are stages I and II.

TNM Clinical Classification:

T – Primary Tumor

TX: Primary tumor cannot be assessed

T0: No evidence of primary tumor

T3: Tumor limited to the epithelium and/or submucosa (mucosal disease)

T4a: Moderately advanced disease involving the deep soft tissue, bone, cartilage, or overlying skin T4b: Tumor invades any of the following: brain, dura, skull base, lower cranial nerves (IX, X, XI, XII), masticator space, carotid artery, prevertebral space, mediastinal structures

N – regional lymph nodes.

NX: regional lymph nodes cannot be assessed N0: no regional lymph node metastasis N1: regional lymph node metastasis M – distant metastasis M0: no distant metastasis M1: distant metastasis Stage Grouping Stage III: T3 N0 M0 Stage IV A: T4a N0 M0

T3 ou T4a, N1, M0 Stage IV B: T4b, Any N, M0 Stage IV C: Any T, Any N, M1

A staging system should be valid as a prognostic tool to target treatment in terms of overall survival, but this system is not yet identified. At this point, tumor thickness greater than 5 mm, more than 10 mitotic figures per high power fields and/or ulceration has been suggested as independent prognostic factors [11]. To develop a uniform staging system a more thorough understanding of the prognostic factors is required [17]. This could facilitate comparisons of the results of different institutions, and help define the best therapy.

## **4. Treatment/management**

There is no clear consensus on the management of head and neck mucosal melanoma, which reflects the rare nature of the disease and complexity of the anatomic site. The late diagnosis, frequently presenting at an advanced stage, denoting the aggressive nature of the disease. Currently, early detection and surgical excision is considered the primary method of treatment.

#### **4.1 Surgery**

Surgical treatment is the "gold standard" [80]. Wide excision with clear margins is the first goal in surgical management, once the complete surgical resection with negative margins significantly improves patient prognosis [83], whereas positive surgical margins have been associated with a higher rate of distant metastases, decreased survival measures, and a significantly higher risk of death compared to patients with negative surgical margins [84–86].

The incision depends on tumor site and size. Due to low rate of regional spread and the lack of effect on survival, elective neck dissection is not recommended. Neck dissection is mandatory only in cases of clinical or radiological positivity neck. Sentinel lymph node biopsy is not usually performed [80, 87, 88].

Surgical excision as a monotherapy should be reserved for patients with small tumors, localized disease and negative margins [89].

For sino-nasal mucosal melanomas, endoscopic techniques or external incision can be used [80, 90, 91]. In cases of oral mucosal tumors, a radical surgical resection with clear margins is the only curative option, and in cases of large masses, maxillectomy or marginal or segmental mandibulectomy is a possibility [11].

For laryngeal or pharyngeal melanomas, for complete resection is necessary total or partial laryngectomy or pharyngectomy [91]. The HNMM can be an aggressive disease and has high recurrences, demanding extensive resection surgery leading to disfigurement [80].

In most cases, complete resection is technically impossible without a destructive or disabling procedure, due to the proximity of the tumor to critical organs, but also because of the acceptable cosmetic result [36, 92], which frequently makes an adjuvant therapy necessary. Supplementary surgery can be executed for patients with recurrent disease and no evidence of distant disease [35, 90].

The National Comprehensive Cancer Network (NCCN, U.S.A.) guidelines emphasize that primary treatment should be surgical for stage III to IVA in the AJCC staging system but state that surgery is not recommended for stages IVB and IVC. These patients should be allocated in clinical trials or offered primary radiation therapy [93].

**77**

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

Radiotherapy (RT) is indicated to control local disease, positive surgical margins, or in case of palliative therapy. The addition of radiotherapy to surgery (adjuvant RT) may reduce the risk loco-regional recurrence without any impact on overall survival and disease-specific survival neither on the risk of distant

According to the NCCN, adjuvant RT is indicated for patients with resected melanoma with high-risk nodal disease with four or more positive lymph nodes, lymph nodes of ≥3 cm and macroscopic extranodal soft tissue extension [93]. There is no clear indication of the appropriate evidence and the best radia-

Particle-beam therapy has also been used to facilitate the delivery of high doses

Primary RT alone has been advocated in patients with non-operable disease or a

The role of chemotherapy is minor compared to the biological and immunological systemic therapies [102]. The paucity of association of chemotherapy alone with improve overall survival led to its discontinuation as the election treatment for patients with metastatic mucosal melanoma. Therefore, chemotherapy is nowadays used as an adjuvant therapy in combination with other immunothera-

The selective inhibitors of various targeted (targeted therapy) have been approved since 2011 and include the BRAF inhibitors, dabrafenib and vemurafenib, the MEK inhibitors, trametinib and binimetinib and c-KIT inhibitors, which provides an attractive opportunity for developing adjuvant therapies for HNMM,

Vemurafenib, dabrafenib and trametinib are options for patients with BRAF V600 mutations who have unresectable or metastatic melanoma, mostly in com-

The selective inhibition of c-KIT alteration with, for example, the tyrosine kinase inhibitor, imatinib mesylate, has been revealed significant outcomes in patients with the K642E c-KIT gene mutation [27] whereas dasatinib, showed promising results in clinical trials in patients with L576P c-KIT gene mutation, once the KIT gene is mutated or present in increased numbers in mucosal melanoma [28]. Nilotinib is another selective inhibitor of c-KIT that does not require an active transport mechanism to enter cells [3]. Sadly, target therapy for c-KIT-mutated mucosal melanoma does not attempt the clinical reliability detected with BRAF-

In clinical trials vemurafenib, a BRAF kinase inhibitor, has been showed greater

efficacy and tolerability when compared to the chemotherapeutic dacarbazine [105, 106], as well as binimetinib, a MEK inhibitor (MEK162), administrated before or after immunotherapy with better overall response, progression-free

mainly for patients with advanced locoregional or metastatic disease.

to the residual tumor while minimizing exposure to the surrounding normal tissues, avoiding severe adverse effect in patients with tumors proximal to critical

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

**4.2 Radiotherapy**

tion scheme.

metastasis [83, 87, 94–98].

anatomical structures [99–101].

poor performance status [91].

peutic and biological drugs [103, 104].

targeted treatment in cutaneous melanoma.

survival, and disease control [107, 108].

**4.4 Biological treatment**

bined therapy [3].

**4.3 Chemotherapy**

*Mucosal Melanoma of the Head and Neck: From Diagnosis to Treatment DOI: http://dx.doi.org/10.5772/intechopen.93804*

### **4.2 Radiotherapy**

*Melanoma*

T3 ou T4a, N1, M0

Stage IV B: T4b, Any N, M0 Stage IV C: Any T, Any N, M1

tions, and help define the best therapy.

considered the primary method of treatment.

patients with negative surgical margins [84–86].

tumors, localized disease and negative margins [89].

leading to disfigurement [80].

Sentinel lymph node biopsy is not usually performed [80, 87, 88].

with recurrent disease and no evidence of distant disease [35, 90].

**4. Treatment/management**

**4.1 Surgery**

A staging system should be valid as a prognostic tool to target treatment in terms of overall survival, but this system is not yet identified. At this point, tumor thickness greater than 5 mm, more than 10 mitotic figures per high power fields and/or ulceration has been suggested as independent prognostic factors [11]. To develop a uniform staging system a more thorough understanding of the prognostic factors is required [17]. This could facilitate comparisons of the results of different institu-

There is no clear consensus on the management of head and neck mucosal melanoma, which reflects the rare nature of the disease and complexity of the anatomic site. The late diagnosis, frequently presenting at an advanced stage, denoting the aggressive nature of the disease. Currently, early detection and surgical excision is

Surgical treatment is the "gold standard" [80]. Wide excision with clear margins is the first goal in surgical management, once the complete surgical resection with negative margins significantly improves patient prognosis [83], whereas positive surgical margins have been associated with a higher rate of distant metastases, decreased survival measures, and a significantly higher risk of death compared to

The incision depends on tumor site and size. Due to low rate of regional spread and the lack of effect on survival, elective neck dissection is not recommended. Neck dissection is mandatory only in cases of clinical or radiological positivity neck.

Surgical excision as a monotherapy should be reserved for patients with small

For sino-nasal mucosal melanomas, endoscopic techniques or external incision can be used [80, 90, 91]. In cases of oral mucosal tumors, a radical surgical resection with clear margins is the only curative option, and in cases of large masses, maxillectomy or marginal or segmental mandibulectomy is a possibility [11]. For laryngeal or pharyngeal melanomas, for complete resection is necessary total or partial laryngectomy or pharyngectomy [91]. The HNMM can be an

aggressive disease and has high recurrences, demanding extensive resection surgery

The National Comprehensive Cancer Network (NCCN, U.S.A.) guidelines emphasize that primary treatment should be surgical for stage III to IVA in the AJCC staging system but state that surgery is not recommended for stages IVB and IVC. These patients should be allocated in clinical trials or offered primary radiation

In most cases, complete resection is technically impossible without a destructive or disabling procedure, due to the proximity of the tumor to critical organs, but also because of the acceptable cosmetic result [36, 92], which frequently makes an adjuvant therapy necessary. Supplementary surgery can be executed for patients

**76**

therapy [93].

Radiotherapy (RT) is indicated to control local disease, positive surgical margins, or in case of palliative therapy. The addition of radiotherapy to surgery (adjuvant RT) may reduce the risk loco-regional recurrence without any impact on overall survival and disease-specific survival neither on the risk of distant metastasis [83, 87, 94–98].

According to the NCCN, adjuvant RT is indicated for patients with resected melanoma with high-risk nodal disease with four or more positive lymph nodes, lymph nodes of ≥3 cm and macroscopic extranodal soft tissue extension [93].

There is no clear indication of the appropriate evidence and the best radiation scheme.

Particle-beam therapy has also been used to facilitate the delivery of high doses to the residual tumor while minimizing exposure to the surrounding normal tissues, avoiding severe adverse effect in patients with tumors proximal to critical anatomical structures [99–101].

Primary RT alone has been advocated in patients with non-operable disease or a poor performance status [91].

#### **4.3 Chemotherapy**

The role of chemotherapy is minor compared to the biological and immunological systemic therapies [102]. The paucity of association of chemotherapy alone with improve overall survival led to its discontinuation as the election treatment for patients with metastatic mucosal melanoma. Therefore, chemotherapy is nowadays used as an adjuvant therapy in combination with other immunotherapeutic and biological drugs [103, 104].

#### **4.4 Biological treatment**

The selective inhibitors of various targeted (targeted therapy) have been approved since 2011 and include the BRAF inhibitors, dabrafenib and vemurafenib, the MEK inhibitors, trametinib and binimetinib and c-KIT inhibitors, which provides an attractive opportunity for developing adjuvant therapies for HNMM, mainly for patients with advanced locoregional or metastatic disease.

Vemurafenib, dabrafenib and trametinib are options for patients with BRAF V600 mutations who have unresectable or metastatic melanoma, mostly in combined therapy [3].

The selective inhibition of c-KIT alteration with, for example, the tyrosine kinase inhibitor, imatinib mesylate, has been revealed significant outcomes in patients with the K642E c-KIT gene mutation [27] whereas dasatinib, showed promising results in clinical trials in patients with L576P c-KIT gene mutation, once the KIT gene is mutated or present in increased numbers in mucosal melanoma [28]. Nilotinib is another selective inhibitor of c-KIT that does not require an active transport mechanism to enter cells [3]. Sadly, target therapy for c-KIT-mutated mucosal melanoma does not attempt the clinical reliability detected with BRAFtargeted treatment in cutaneous melanoma.

In clinical trials vemurafenib, a BRAF kinase inhibitor, has been showed greater efficacy and tolerability when compared to the chemotherapeutic dacarbazine [105, 106], as well as binimetinib, a MEK inhibitor (MEK162), administrated before or after immunotherapy with better overall response, progression-free survival, and disease control [107, 108].

#### **4.5 Immunotherapy**

A role for biologic treatment, as well as immunotherapy, has emerged over the last decade. Recent studies suggest that immunotherapy may confer survival benefit to patients with advanced disease.

Multiple prospective and retrospective studies support the use of the monoclonal antibody targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), ipilimumab, a promising immunotherapy [109], and the inhibitor of interactions of ligands PD-L1 and PD-L2 with its receptor, programmed death-1 receptor (PD-1), therefore blocking T-cell activation (anti-PD1 agents), nivolumab and pembrolizumab [110].

Nivolumab has been used as a promisor therapy in clinical trials. In patients with ipilimumab monotherapy-refractory or ipilimumab in combination with BRAF inhibitor-refractory metastatic melanoma, nivolumab showed a higher overall survival rate than standard chemotherapy [110, 111]. Furthermore, nivolumab in combination with ipilimumab has been shown a higher overall response rate then monotherapies [112].

Just like nivolumab, other checkpoint inhibitors, like pembrolizumab, have demonstrated more improvement in progression-free survival, toxicity, and overall survival than ipilimumab [113, 114].

Durvalumab and atezolizumab, other anti-PD-L1 antibody monotherapies, have not been very successful [115], whereas ipilimumab, nivolumab and pembrolizumab are standard options for unresectable or metastatic melanoma and may have potential as adjuvant therapy [3].
