**2. Pathology and biology**

Melanomas are malignant tumors arising from pigment cells - melanocytes. Tumors can either develop from stem melanocytes with cytogenetic variations or mature melanocytes with secondary cytogenetic alterations due to external stimuli [6]. Precursors of melanocytes migrate from the neural crest to their final destination through embryonic mesenchyme, along specific pathways, most of them ending up in the epidermis and dermis of the skin, while some of them can be found in other locations, such as the mucosal membranes of the respiratory, gastrointestinal, and genitourinary tract [2, 3]. Melanin, the main product of melanocytes, may be missing in rare cases (2 to 8%), resulting in a non-pigmented lesion, referred as amelanotic malignant melanoma [9]. The presence and the function of melanocytes in the mucosa remain unclear. A few studies have supported the hypothesis of anti-oxidative, antimicrobial and immunological functions [3, 6]. In the sinonasal region, melanocytes take part in the metabolization of polycyclic aromatic hydrocarbons, suggesting association between inhaled environmental and immune factors and the development of mucosal melanoma in this particular site [5].

The etiology and pathogenesis of mucosal melanoma of the head and neck is still not fully understood. Whether it is due to preexisting mucosal nevi or racial pigmentation affecting its site, no risk factors have been unequivocally linked to

**69**

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

those features. Despite the common association between cutaneous melanomas and sun exposure, mucosal melanomas are associated with embryology alterations (justifying the close proximity of commonly affected areas), inhaled and ingested carcinogens (e.g. smoking and formaldehyde exposure) and family history. Reports suggest that smoking patients have greater prevalence of pigmented oral lesions due to a hyper-production of melanocytes in the oral mucosa. Furthermore, 33% of oral cavity mucosal melanomas are preceded by pathological oral melanosis - increased number of normal or atypical melanocytes in the basal cell layer of the oral epithelium. Even though, conflicting data suggest oral melanosis should not be considered a pre-cancerous lesion [6]. Molecular studies of mucosal melanoma show several genetic changes in intracellular signaling cascades, which may constitute the distinct pathogenic mechanisms among these malignancies. Genomic hybridization studies have shown varied chromosomal aberrations - gains of 1q, 6p and 8q; gain of function mutations, such as K642E, L576P, D816H and V559A; amplifications of

Special attention is addressed to the high incidence of activating mutations in the c-KIT (CD117) oncogene, present in 80% of all primary mucosal melanomas, whereas it seems not to have pathogenic importance in cutaneous melanomas [2, 5, 11]. KIT is a transmembrane tyrosine kinase receptor, expressed on melanocytes, but also on hematopoietic progenitor cells, mast cells, primordial germ cells, and interstitial cells of Cajal. Activating mutations and amplifications generate activation of growth and proliferation pathways, which seem to be important and common in acral and mucosal melanoma, both tumors unrelated to sun exposure [8]. Screening for KIT aberrations may have diagnostic value, given the evidence of a possible pathogenic role of this gene in mucosal melanomas, as well as a possible a therapeutic target in these patients [12]. Therapeutic c-KIT blockade could be useful in the treatment of patients with activating KIT muta-

Along its signaling pathway, Microphthalmia-associated transcription factor (MITF) is referred to be involved in melanocyte development. The amplification of this gene is found in approximately 15-20% of primary mucosal melanomas. RAS-mitogen activated protein kinase related genes overexpression were found in up to 90% of primary mucosal melanomas [11]. Mutations in B-type Raf gene (proto-oncogene BRaf), present in up to 70% of cutaneous melanomas, have been detected in less than 10% of primary mucosal melanomas [2, 11]. Differently from the Human Papillomavirus (HPV) infection, which leads to p16/INK4a overexpression, loss of p16 expression, CDKN2A mutations, and loss of heterozygosity are observed in up to 50% of primary mucosal melanomas. GNAQ/11 mutations were observed in only 9.5% of the patients, who also presented shorter mean survival when compared to patients with wild type GNAQ/11. Programmed death-ligand 1 (PD-L1) expression seems to occur less frequently in patients with mucosal melanoma, which may lead to believe that mucosal melanomas are less immunogenic due to a lower mutational burden [2]. Primary sinonasal melanomas develop due to distinct genetic abnormalities, that lead to diffuse activation of the PI3K/Akt and RAS-MAPK pathways. These specific genetic pathway alterations,

tion [6]. New drugs, such as imatinib, work on this pathway [8].

however, are not associated with different prognosis [6].

to a future of more optimized target therapy [11].

The key molecular events that trigger the malignancy development and progression is still unknown, which makes it difficult to work on new specific or multimodal treatment for this disease [12]. We can observe that mucosal melanoma is one unique subgroup in a vast emerging molecular classification system of melanoma. The complete understanding of these mechanisms may hopefully lead

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

the 4q12 locus [11].

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

*Melanoma*

esophagus [3, 9].

this chapter [1].

**2. Pathology and biology**

mucosal melanoma in this particular site [5].

still not identified [5]. Mucosal melanomas represent 0.8 to 3.7% of all melanomas, 0.03% of all neoplasms [6] and occur most commonly in the head and neck (55%) [7], mainly in the nasal cavity (lateral wall and septum) and paranasal sinuses (ethmoid and maxillary sinuses) [6], followed by the oral cavity – approximately 80% in the mucosa of the upper jaws (maxillary anterior gingiva), in the keratinizing mucosa of the palate and alveolar gingivae [8] -, pharynx, larynx, and upper

To date there are no clearly established risk factors for the mucosal melanoma development [5]. Cigarette smoking seems to be a risk factor for the oral tumor, while exposure to formaldehyde has been suggested as risk factor for the sinonasal malignancy. Association with viruses, such as human papilloma viruses, human herpes viruses or polymavirus is unlikely. Although sun radiation is a well-established risk factor for cutaneous melanoma, there is no evidence of its implication in mucosal melanoma pathogenesis, since its common locations preclude exposure to UV light [3]. Another particularity of mucosal melanomas, divergent from the cutaneous ones, is the more hostile behavior and frequent neoplastic dissemination, which results in greater death rate [10]. The mucosal melanoma aggressive clinical course results in very poor prognosis, especially among old male patients, likely due to little understanding of this rare malignancy and delayed detection, given the lack of specific clinical features for diagnosis, a challenging scenario for clinicians and pathologists [4]. Studies made on European cases diagnosed between 2000 and 2007 showed survival rates in 1, 3 and 5 years of 63%, 30% and 20%, respectively, as well as high rates of locoregional recurrence and distant metastasis [3, 11]. Tumor arising from the respiratory mucosa (such as the nasal cavity) have different clinical and pathological features when compared to those involving oral mucosa, as melanomas originating from non-squamous mucosa behave differently than those originating from multilayered squamous mucosa [11], but still they share similar adverse outcomes and prognosis and, therefore, will be discussed further in

Melanomas are malignant tumors arising from pigment cells - melanocytes. Tumors can either develop from stem melanocytes with cytogenetic variations or mature melanocytes with secondary cytogenetic alterations due to external stimuli [6]. Precursors of melanocytes migrate from the neural crest to their final destination through embryonic mesenchyme, along specific pathways, most of them ending up in the epidermis and dermis of the skin, while some of them can be found in other locations, such as the mucosal membranes of the respiratory, gastrointestinal, and genitourinary tract [2, 3]. Melanin, the main product of melanocytes, may be missing in rare cases (2 to 8%), resulting in a non-pigmented lesion, referred as amelanotic malignant melanoma [9]. The presence and the function of melanocytes in the mucosa remain unclear. A few studies have supported the hypothesis of anti-oxidative, antimicrobial and immunological functions [3, 6]. In the sinonasal region, melanocytes take part in the metabolization of polycyclic aromatic hydrocarbons, suggesting association between inhaled environmental and immune factors and the development of

The etiology and pathogenesis of mucosal melanoma of the head and neck is still not fully understood. Whether it is due to preexisting mucosal nevi or racial pigmentation affecting its site, no risk factors have been unequivocally linked to

**68**

those features. Despite the common association between cutaneous melanomas and sun exposure, mucosal melanomas are associated with embryology alterations (justifying the close proximity of commonly affected areas), inhaled and ingested carcinogens (e.g. smoking and formaldehyde exposure) and family history. Reports suggest that smoking patients have greater prevalence of pigmented oral lesions due to a hyper-production of melanocytes in the oral mucosa. Furthermore, 33% of oral cavity mucosal melanomas are preceded by pathological oral melanosis - increased number of normal or atypical melanocytes in the basal cell layer of the oral epithelium. Even though, conflicting data suggest oral melanosis should not be considered a pre-cancerous lesion [6]. Molecular studies of mucosal melanoma show several genetic changes in intracellular signaling cascades, which may constitute the distinct pathogenic mechanisms among these malignancies. Genomic hybridization studies have shown varied chromosomal aberrations - gains of 1q, 6p and 8q; gain of function mutations, such as K642E, L576P, D816H and V559A; amplifications of the 4q12 locus [11].

Special attention is addressed to the high incidence of activating mutations in the c-KIT (CD117) oncogene, present in 80% of all primary mucosal melanomas, whereas it seems not to have pathogenic importance in cutaneous melanomas [2, 5, 11]. KIT is a transmembrane tyrosine kinase receptor, expressed on melanocytes, but also on hematopoietic progenitor cells, mast cells, primordial germ cells, and interstitial cells of Cajal. Activating mutations and amplifications generate activation of growth and proliferation pathways, which seem to be important and common in acral and mucosal melanoma, both tumors unrelated to sun exposure [8]. Screening for KIT aberrations may have diagnostic value, given the evidence of a possible pathogenic role of this gene in mucosal melanomas, as well as a possible a therapeutic target in these patients [12]. Therapeutic c-KIT blockade could be useful in the treatment of patients with activating KIT mutation [6]. New drugs, such as imatinib, work on this pathway [8].

Along its signaling pathway, Microphthalmia-associated transcription factor (MITF) is referred to be involved in melanocyte development. The amplification of this gene is found in approximately 15-20% of primary mucosal melanomas. RAS-mitogen activated protein kinase related genes overexpression were found in up to 90% of primary mucosal melanomas [11]. Mutations in B-type Raf gene (proto-oncogene BRaf), present in up to 70% of cutaneous melanomas, have been detected in less than 10% of primary mucosal melanomas [2, 11]. Differently from the Human Papillomavirus (HPV) infection, which leads to p16/INK4a overexpression, loss of p16 expression, CDKN2A mutations, and loss of heterozygosity are observed in up to 50% of primary mucosal melanomas. GNAQ/11 mutations were observed in only 9.5% of the patients, who also presented shorter mean survival when compared to patients with wild type GNAQ/11. Programmed death-ligand 1 (PD-L1) expression seems to occur less frequently in patients with mucosal melanoma, which may lead to believe that mucosal melanomas are less immunogenic due to a lower mutational burden [2]. Primary sinonasal melanomas develop due to distinct genetic abnormalities, that lead to diffuse activation of the PI3K/Akt and RAS-MAPK pathways. These specific genetic pathway alterations, however, are not associated with different prognosis [6].

The key molecular events that trigger the malignancy development and progression is still unknown, which makes it difficult to work on new specific or multimodal treatment for this disease [12]. We can observe that mucosal melanoma is one unique subgroup in a vast emerging molecular classification system of melanoma. The complete understanding of these mechanisms may hopefully lead to a future of more optimized target therapy [11].

## **3. Diagnosis**

Melanomas are malignant tumors arising from pigment cells—melanocytes. Melanocytes in mucosal membranes are distributed to the oral cavity, nasal cavity, paranasal sinuses, esophagus, larynx, vagina, cervix, rectum, and anus [13].

Mucosal melanoma of the head and neck (HNMM) region constitutes 55% of all mucosal melanomas, but <10% of all melanomas of the head and neck region. A majority of these tumors are found in the sinonasal regions (55%), while the rest are located in the oral cavity (25–40%) [13–16]. Mucosal melanomas generally present at a later stage, are more aggressive and carry a worse prognosis regardless of the stage at diagnosis [17–31].

Of all mucosal melanomas, paranasal sinus has the worst prognosis. The best prognosis locations are the nasal and oral cavity [15]. In contrast to cutaneous melanomas, mucosal melanomas more frequently are amelanotic and present in a multifocal fashion [17]. Early detection provides the best chance at survival but is often difficult due to anatomic location [17, 22, 27, 29]. Mucosal melanoma remains a challenge for several reasons: firstly, the clinical diagnosis often occurs relatively late, because it is not usually confirmed before the disease is symptomatic; secondly, traditional aspects of cutaneous melanoma clinical staging may not apply; and thirdly histological diagnosis can be difficult due to its rarity and variable appearance.

#### **3.1 Clinical signs and symptoms**

Presenting symptoms of mucosal melanomas differ in relation to the site of origin.

#### *3.1.1 Primary mucosal melanomas of the nose and paranasal sinuses*

Sinonasal primary mucosal melanomas (PMM) account for <1% of all melanomas and <5% of all sinonasal tract neoplasms [32].

In the sinonasal tract, early signs and symptoms are similar to those encountered in inflammatory benign conditions and therefore may be overlooked for some time [33].

The tumors can present with non-specific symptoms including nasal obstruction, facial pain, rhinorrhea and epistaxis [34]. In advanced stage primary tumors, symptoms such as diplopia, exophthalmos, ophthalmoplegia, headache, skin infiltration and ulceration, can occur [11].

At endoscopy, MM may present as a polypoid, with strict unilateral involvement in most cases. Lesions may have different degrees of pigmentation, with the possibility of diversely pigmented areas within the same mass. It can assume dark, brown, red, or pale white colors.

Compared with oral melanoma, completely amelanotic tumors are rare but when they do occur are associated with an even worse prognosis because of a more aggressive biology and greater difficulty in diagnosis [33]. Furthermore, multiple lesions (satellite lesions) can be frequently observed, even centimeters away from the main tumor, with spreading occurring along the mucosal/submucosal planes.

Among sinonasal cases, approximately 80% are located in the nasal cavity itself, most commonly the middle and inferior turbinates, lateral nasal wall and nasal septum, while 20% occur in the paranasal sinuses [13, 15, 16].

Concurrent nasal and paranasal lesions are infrequent.

The most frequently involved paranasal sinus is the maxillary sinus followed by the ethmoid, frontal and sphenoid sinuses respectively [11]. Primary lesions of the sphenoid and frontal sinus are exceedingly rare [11, 35].

**71**

**Figure 1.**

*Aveolar ridge mucosal melanoma.*

lesions.

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

malignant melanomas of the nasal cavity and paranal sinuses.

*3.1.2 Primary mucosal melanomas of the oral cavity*

accessibility for inspection and oral examination.

Indians [43–45].

pyogenic granulomas [46, 47].

Most of the patients with melanomas of the nasal cavity (75%) are diagnosed with clinically localized disease. That is the reason why patients with nasal melanoma have a more favorable prognosis when compared with melanoma arising from other head and neck sites. However, melanomas of the paranasal sinuses are usually advanced at presentation. PMMs of the ethmoid and maxillary sinuses have a worse prognosis than those arising from other sites. This is related to the higher T classification and late symptomatology. When occurs infiltration into the orbit, skull base, infratemporal fossa or facial soft tissue, the outcome is very poor [36–39]. At initial diagnosis, lymphatic metastases are present in 10% to 20% of patients with sinonasal PMMs, and <10% of patients have evidence of distant metastases [40]. 40% of cases will develop distant metastases in lungs, brain, bone, and liver, during the course of the disease [41]. Vascular and neural invasion is observed in approximately 40% of patients [42]. Early and repeated recurrences is frequently noticed in

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

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

Compared to sinonasal disease, it may be diagnosed earlier due to the greater

The tumors can be macular, nodular or plaque-like. Just like cutaneous melanomas,

There can also be non-specific symptoms including bleeding, ulceration and

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

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

melanoma in the mouth may be asymmetric with irregular borders.

pain, which is associated with the vertical growth of the lesion [48].

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

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

*Melanoma*

**3. Diagnosis**

stage at diagnosis [17–31].

variable appearance.

time [33].

**3.1 Clinical signs and symptoms**

and ulceration, can occur [11].

brown, red, or pale white colors.

and <5% of all sinonasal tract neoplasms [32].

Melanomas are malignant tumors arising from pigment cells—melanocytes. Melanocytes in mucosal membranes are distributed to the oral cavity, nasal cavity, paranasal sinuses, esophagus, larynx, vagina, cervix, rectum, and anus [13].

Mucosal melanoma of the head and neck (HNMM) region constitutes 55% of all mucosal melanomas, but <10% of all melanomas of the head and neck region. A majority of these tumors are found in the sinonasal regions (55%), while the rest are located in the oral cavity (25–40%) [13–16]. Mucosal melanomas generally present at a later stage, are more aggressive and carry a worse prognosis regardless of the

Of all mucosal melanomas, paranasal sinus has the worst prognosis. The best prognosis locations are the nasal and oral cavity [15]. In contrast to cutaneous melanomas, mucosal melanomas more frequently are amelanotic and present in a multifocal fashion [17]. Early detection provides the best chance at survival but is often difficult due to anatomic location [17, 22, 27, 29]. Mucosal melanoma remains a challenge for several reasons: firstly, the clinical diagnosis often occurs relatively late, because it is not usually confirmed before the disease is symptomatic; secondly, traditional aspects of cutaneous melanoma clinical staging may not apply; and thirdly histological diagnosis can be difficult due to its rarity and

Presenting symptoms of mucosal melanomas differ in relation to the site of origin.

Sinonasal primary mucosal melanomas (PMM) account for <1% of all melanomas

In the sinonasal tract, early signs and symptoms are similar to those encountered

The tumors can present with non-specific symptoms including nasal obstruction, facial pain, rhinorrhea and epistaxis [34]. In advanced stage primary tumors, symptoms such as diplopia, exophthalmos, ophthalmoplegia, headache, skin infiltration

At endoscopy, MM may present as a polypoid, with strict unilateral involvement in most cases. Lesions may have different degrees of pigmentation, with the possibility of diversely pigmented areas within the same mass. It can assume dark,

Compared with oral melanoma, completely amelanotic tumors are rare but when they do occur are associated with an even worse prognosis because of a more aggressive biology and greater difficulty in diagnosis [33]. Furthermore, multiple lesions (satellite lesions) can be frequently observed, even centimeters away from the main tumor, with spreading occurring along the mucosal/submucosal planes. Among sinonasal cases, approximately 80% are located in the nasal cavity itself,

most commonly the middle and inferior turbinates, lateral nasal wall and nasal

The most frequently involved paranasal sinus is the maxillary sinus followed by the ethmoid, frontal and sphenoid sinuses respectively [11]. Primary lesions of the

septum, while 20% occur in the paranasal sinuses [13, 15, 16]. Concurrent nasal and paranasal lesions are infrequent.

sphenoid and frontal sinus are exceedingly rare [11, 35].

in inflammatory benign conditions and therefore may be overlooked for some

*3.1.1 Primary mucosal melanomas of the nose and paranasal sinuses*

**70**

Most of the patients with melanomas of the nasal cavity (75%) are diagnosed with clinically localized disease. That is the reason why patients with nasal melanoma have a more favorable prognosis when compared with melanoma arising from other head and neck sites. However, melanomas of the paranasal sinuses are usually advanced at presentation. PMMs of the ethmoid and maxillary sinuses have a worse prognosis than those arising from other sites. This is related to the higher T classification and late symptomatology. When occurs infiltration into the orbit, skull base, infratemporal fossa or facial soft tissue, the outcome is very poor [36–39]. At initial diagnosis, lymphatic metastases are present in 10% to 20% of patients with sinonasal PMMs, and <10% of patients have evidence of distant metastases [40]. 40% of cases will develop distant metastases in lungs, brain, bone, and liver, during the course of the disease [41]. Vascular and neural invasion is observed in approximately 40% of patients [42]. Early and repeated recurrences is frequently noticed in malignant melanomas of the nasal cavity and paranal sinuses.
