Elsevier

Oral Oncology

Volume 36, Issue 2, March 2000, Pages 152-169
Oral Oncology

Review
Oral mucosal melanoma: epidemiology and pathobiology

https://doi.org/10.1016/S1368-8375(99)00085-8Get rights and content

Abstract

The vast majority of healthy individuals have some form of melanocytic lesions with most having several cutaneous melanocytic nevocellular nevi. The incidence of cutaneous melanoma, despite improved prevention and early diagnosis of precursor melanocytic lesions, is on the increase with a projection that one in 75 persons born in the year 2000 will develop cutaneous melanoma in his/her lifetime. With cutaneous melanoma, the number, location and type of nevi, sun exposure and inability to tan, and presence or absence of dysplastic nevi affect transformation to a malignant process. Certain familial factors, syndromes, cytogenetic abnormalities, and mutations in tumor suppressor genes also influence tumor formation.

In contrast, mucosal melanoma involving the oral cavity and head and neck regions is not as well understood or characterized. No doubt, this is due to the fact that this subtype of melanoma accounts for less than 1% of all cases. Mucosal melanomas tend to present at a higher stage, are more aggressive, and in a vertical growth phase of disease. A definitive precursor lesion for mucosal melanoma has not been identified; however, atypical melanocytic hyperplasia may represent a proliferative phase before overt tumorigenesis occurs. Melanoma-related antigens, growth factors, and proliferation markers have been identified in cutaneous melanoma, and allow for development of immunotherapy directed against melanoma-associated entities. It is currently possible to evaluate the cytogenetic make-up of precursor melanocytic lesions and frank melanoma, and the constitutional genetic background of individuals at risk for melanoma. No doubt, as concerted investigations of mucosal melanomas of the oral cavity and head and neck evolve, similar factors will be identified which will direct therapy and predict recurrence and survival. In the not too distant future, innovative retroviral transfection, antibodies against specific melanoma-associated factors, vaccination against melanoma, and gene therapy to repair cytogenetic abnormalities and tumor suppressor gene mutations may provide effective therapy and protection against melanomas.

Introduction

In contrast to well-established etiologic factors participating in melanoma evolution in the skin, such factors are either not a consideration (sun exposure, tendency to tan poorly) or have not been studied extensively (familial history, syndromes, cytogenetic defects) with mucosal melanomas of the oral cavity and head and neck region [1], [2], [3], [4], [5]. Probably the major reason for this lack of understanding regarding mucosal melanomas is the rarity of this malignancy (Table 1) [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. This contributes to difficulties in procuring a sufficient number of cases to evaluate on a scientific, standardized protocol. In fact, over 90% of melanomas occur on skin surfaces with slightly over 1% of melanomas arising from mucosal surfaces (Table 1) [7]. The most common sites for mucosal melanomas are the head and neck region (55%), followed by anal/rectal region (24%), female genital tract (18%), and urinary tract (3%). Head and neck mucosal melanomas account for less than 1% of all melanomas, with an incidence of four cases per 10 million population per year in the USA. With oral melanomas, the incidence is even lower at 1.2 cases per 10 million population per year. In the oronasal (Table 2) region, approximately one-half of melanomas occur in the oral cavity (48%), with the remaining proportion primarily found in the nasal cavity (44%) and a smaller portion in the sinuses (8%) [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. If one looks at the frequency of oral melanoma in comparison with other primary oral malignancies, squamous cell carcinoma is most common, representing 87% of all primary malignancies, whereas oral melanoma accounts for only 0.5% of oral malignancies [21]. This low prevalence of primary oral melanoma is in contrast to cutaneous melanoma which has been increasing by 4–6% per year since 1973, with 41,600 new cases diagnosed and 7200 melanoma-related deaths in 1998 in the USA [7], [26]. It has been estimated that one in 75 persons born in the year 2000 will develop cutaneous melanoma in his/her lifetime. The relative rarity of mucosal melanoma, and in particular head and neck mucosal melanoma, does not negate this serious and often fatal melanoma type.

Section snippets

Histogenesis from melanocytes to nevus cells to malignant melanoma cells

Melanocytes in skin provide a protective function against the harmful effects of sun exposure [27], [28], [29], [30]. The function of melanocytes in mucosa is not certain. In oral mucosa, melanocytes are located along the tips and peripheries of the rete pegs [16], [22], [23]. Melanocytes in single tissue sections are found in the gingiva with a ratio of one melanocyte to 15 keratinocytes. In contrast, various types of skin have differing concentrations of melanocytes to keratinocytes with a

Evolution of melanocytic nevi

With mucosal melanocytic nevi (Fig. 1, Fig. 1), the majority represent congenital nevi or melanocytic proliferation to unknown toxins, hormonal response, medications, or localized injury. Nevus formation commences with proliferation of melanocytes in a linear pattern along the epithelial basal cell layer with elongation of the rete ridges [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47]. The

Melanotic macule of the oral mucosa

These benign pigmented lesions (Fig. 1) are usually less than 1 cm in maximum dimension, solitary, well circumscribed, macular, and range in color from gray to brown to black [9], [15], [16], [22], [23], [38], [39], [40], [41]. These lesions are asymptomatic and most commonly found on the vermillion border of the lip (30%), the gingiva and alveolar ridge (23%), and the buccal (16%) or labial mucosa (9%). The hard palate is a less frequent site (7%). There is a female predilection (2:1), with

Oral mucosal nevus

Oral nevi (Fig. 1) are relatively rare with a prevalence of 0.1% in the general population [9], [15], [16], [22], [23], [42], [43], [44], [45]. Intramucosal lesions are most common (55%), followed by blue nevus (36%). Junctional nevi are infrequent (3%) with a female predilection (2:1), and are more common in black individuals. The mean age at excision is 35 years of age. Most are relatively small with an average diameter of 0.5 cm (range 0.1–3.0 cm). In fact, 80% are less than 1 cm in maximum

Melanoacanthoma

This benign entity (Fig. 1) may mimic oral mucosal melanoma due to its rapid increase in size with diameters of several centimeters being reached in just a few weeks [41], [46], [47], [48]. These lesions are more common in the third and fourth decades in primarily black females. The lesion is usually flat or slightly raised and most commonly occur on the buccal mucosa. Histopathologic examination of an incisional biopsy is indicated to rule out melanoma. The lesion is characterized by mild

Non-melanocytic pigmentations of oral mucosa

Blue-black discoloration of oral mucosa (Fig. 2) secondary to deposition of amalgam during restorative or surgical procedures is the most common reason for mucosal pigmentation in the oral cavity [9], [15], [16], [22], [23], [49], [50], [51], [52]. Amalgam tattoos (focal argyrosis) are twice as common as melanotic macules and 10 times more common than oral nevi. About 50% of these lesions are seen in the gingiva and alveolar mucosa with another 20% found in the buccal mucosa. The maximum

Oral melanoma and atypical melanocytic hyperplasia: histogenetic and clinical factors

In contrast to cutaneous melanoma, those involving head and neck mucosal surfaces typically present at a more aggressive vertical growth (nodular) phase with invasion of the underlying submucosa (Table 4) [5], [8], [9], [10], [13], [14], [15], [16], [18], [19], [20], [22], [23], [24], [25], [54]. Because of the advanced stage at discovery, the majority will not have an associated radial growth (superficial spreading) phase. Oral melanomas (Fig. 3, Fig. 4, Fig. 5, Fig. 5) do not fit well into

Histopathologic predictive factors of survival in cutaneous and oral melanoma

Numerous histopathologic parameters have been evaluated and several have predictive value in determining recurrence and survival in patients with cutaneous tumorigenic (vertical growth phase) melanomas at the time of primary tumor diagnosis [34], [54], [55], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68]. Two separate measures of tumor invasion have been employed. Clark's levels of melanoma invasion evaluate the depth of invasion based upon anatomical compartments of the skin.

Melanoma-related antigens, growth and proliferation factors

During the transformation process from a benign melanocytic nevus to the premalignant stage (atypical melanocytic hyperplasia/dysplastic nevus) to melanoma, several melanoma-associated antigens, cell-to-cell and cell matrix interacting antigens, signaling and transport function receptors and antigens, mutated tumor suppressor gene products, and proliferating antigens are expressed (Table 6) [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87]

Genetic abnormalities in familial and sporadic atypical nevi and melanoma

Cytogenetic and molecular analysis of FAMM kindred and sporadic melanoma have provided considerable insight into the process of malignant transformation (Table 7) [73], [74], [77], [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118]. Atypical (dysplastic nevi) moles and melanomas show recurring nonrandom karyotypic abnormalities [101], [102]. In early (thin) and late (thick) melanomas, defects in chromosomes 1, 6, 7

Survival in mucosal and cutaneous melanomas

The treatment of choice for melanoma is complete excision with adequate negative margins (Table 8) [7], [26]. The majority of cutaneous melanomas undergo surgery alone, with a small percentage undergoing conventional radiotherapy or chemotherapy, either alone or in combination with surgery. While many mucosal melanomas are treated with surgery alone, radiotherapy or chemotherapy are employed more frequently than with cutaneous melanomas. Overall survival for melanoma is quite encouraging with

Prevention of head and neck mucosal melanoma

Prevention and screening for mucosal melanomas of the head and neck involve annual evaluation for pigmented lesions in the oronasal and upper respiratory tract. Any pigmented lesion other than amalgam tattoo, racial pigmentation, or physiologic pigmentation due to localized injury, medications, or hormonal changes should be excised and submitted for histopathologic evaluation. The best likelihood for favorable outcome is early detection and excision of melanocytic mucosal lesions of the head

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