Oral mucosal melanoma: epidemiology and pathobiology

Oral Oncology 36 (2000) 152±169

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Review

Oral mucosal melanoma: epidemiology and pathobiology M.J. Hicksa,b,*, C.M. Flaitzb,c a

Director of Surgical and Ultrastructural Pathology, Department of Pathology, MC1-2261, Baylor College of Medicine, Texas Childrens Hospital, 6621 Fannin Street, Houston, TX 77030-2399, USA b Department of Pediatric Dentistry, University of Texas-Houston Health Science Center, Dental Branch, Houston, TX, USA c Department of Stomatology, Oral and Maxillofacial Pathology, University of Texas-Houston Health Science Center, Dental Branch, Houston, TX, USA Received 10 February 1999; accepted 22 February 1999

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 a€ect transformation to a malignant process. Certain familial factors, syndromes, cytogenetic abnormalities, and mutations in tumor suppressor genes also in¯uence 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 de®nitive precursor lesion for mucosal melanoma has not been identi®ed; however, atypical melanocytic hyperplasia may represent a proliferative phase before overt tumorigenesis occurs. Melanoma-related antigens, growth factors, and proliferation markers have been identi®ed 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 identi®ed which will direct therapy and predict recurrence and survival. In the not too distant future, innovative retroviral transfection, antibodies against speci®c melanoma-associated factors, vaccination against melanoma, and gene therapy to repair cytogenetic abnormalities and tumor suppressor gene mutations may provide e€ective therapy and protection against melanomas. # 2000 Elsevier Science Ltd. All rights reserved. Keywords: Melanoma; Oral mucosa; Oronasal; Pathology; Cytogenetics; Epidemiology

1. 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±5]. Probably the major reason for this lack of understanding regarding mucosal melanomas is the rarity of this malignancy (Table 1) [6±25]. * Corresponding author. Tel.: +1-713-770-1869/713-770-2250; fax: +1-713-770-1032. E-mail address: [email protected] (M.J. Hicks).

This contributes to diculties in procuring a sucient number of cases to evaluate on a scienti®c, 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

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M.J. Hicks, C.M. Flaitz / Oral Oncology 36 (2000) 152±169 Table 1 Epidemiology of melanomaa Site Cutaneous Mucous membranes Head and neck (55.4%) Female genital (18.0%) Anal/rectal (23.8%) Urinary (2.8%)

Table 2 Oral and sinonasal mucosal melanomasa 91.2% 1.3%

Ocular Uveal (85.0%) Conjunctival (4.8%) Other (10.2%)

5.3%

Unknown primary site Regional metastasis (43.0%) Distant metastasis (57.0%)

2.2%

Lymph node status All melanomas Head and neck Female genital tract Anal/rectal Urinary tract

Positive lymph nodes 40% 27% 23% 61% 11%

a

153

Data source: Refs. [7,26].

proportion primarily found in the nasal cavity (44%) and a smaller portion in the sinuses (8%) [8±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. 2. Histogenesis from melanocytes to nevus cells to malignant melanoma cells Melanocytes in skin provide a protective function against the harmful e€ects of sun exposure [27±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 di€ering concentrations of melanocytes to keratinocytes with a high proportion in the cheek (1:4) and a lesser proportion in the trunk

Oral mucosal melanomas (n=703) Palate, NOS (n=223) Hard palate (n=66) Soft palate (n=7)

32% 9% 1%

Alveolar gingiva, NOS Maxillary gingiva Mandibular gingiva

(n=37) (n=114) (n=50)

5% 16% 7%

Oral cavity, NOS

(n=82)

12%

Buccal mucosa Lip Tongue Floor of mouth Uvula

(n=46) (n=45) (n=18) (n=11) (n=4)

Sinonasal mucosal melanomas (n=770) Nasal (n=648) Nasal cavity, NOS (n=383) Septum (n=105) Lateral wall (n=45) Inferior turbinate (n=46) Middle turbinate (n=50) Turbinate, NOS (n=12) Floor of nose (n=7) Sinuses Maxillary sinus Ethmoid sinus Frontal sinus Sinus, NOS a

(n=122) (n=58) (n=20) (n=2) (n=42)

48%

7% 7% 3% 2% <1% 84% 50% 14% 6% 6% 6% 2% 1%

52%

16% 7% 3% <1% 5%

Data source: Refs. [8±25].

(1:14). Melanocytes are located along the basal layer of the epithelium and do not contact each other (contact inhibition); rather, these melanin-producing cells in skin are separated from each other by about 10 basal cells [27±34]. The keratinocytes of the epithelial±melanin unit come into contact with their melanocyte and induce `their' melanocyte to form dendritic processes for transfer of melanosomes by phagocytosis or direct deposition into the keratinocyte cytoplasm. The engulfed melanosomes are incorporated into keratinocyte lysosomes and impart protection against the e€ects of sun exposure, and toxic metabolites. The melanin is eventually shed from cutaneous and mucosal surfaces along with keratinaceous debris as melanin dust. Melanocytes are derived from the neural crest and during embryogenesis migrate to the skin, hair follicles, retina, and oronasal and upper respiratory tract mucosa [27±36]. Melanocytes are highly specialized cells that form a complex pigmented polymer, melanin (eumelanin, a brown-black pigment; pheomelanin, a red-yellow pigment). Melanin functions include: (1) absorption of ultraviolet light; (2) scavenger for cytotoxic intermediates; and (3) possible role in development of the nervous system. Melanin is packaged into spherical membrane-bound cytoplasmic vesicles, melanosomes

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[31]. With complete melanization, end-stage melanosomes have a uniform electron-dense appearance by electron microscopy, somewhat resembling lysosomes. Melanocytes, nevus cells and melanoma cells di€er markedly regarding their cytologic appearance, organization, and biologic characteristics [32±36]. Melanocytes are characterized by dendritic cytoplasm containing melanosomes, solitary cell arrangement without melanocyte to melanocyte contact, ready transfer of melanosomes without retention of these structures, location along the basal cell layer of the epithelium, small regular nuclei, and rare mitotic activity. While nevus cells have similar nuclear morphology to that described for melanocytes, nevus cells di€er from melanocytes in that their cell morphology is ovoid to spindle-shaped with absence of dendritic processes; contact inhibition has been lost with clusters of nevus cells in close apposition; melanosomes are retained and not transferred to adjacent keratinocytes; and the ability to migrate from the basal cell layer into the underlying submucosa occurs. Nevus cells lack cytologic atypia, pleomorphism, and rarely have mitotic activity. Melanoma cells retain some features of nevus cells, such as lack of dendritic processes, round-to spindled-shape, and loss of contact inhibition. These malignant cells possess considerable pleomorphism with large, irregular hyperchromatic nuclei and prominent nucleoli, and have readily detectable mitotic activity. Melanoma cells also possess the ability to invade the super®cial mucosa (Pagetoid spread), the underlying submucosa, as well as metastasize via lymphatic and vascular channels to the draining lymph node basin and to distant sites. 3. Evolution of melanocytic nevi With mucosal melanocytic nevi (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±47]. The nevus cells lose contact inhibition and retain melanin pigment. Melanin incontinence in the submucosa with phagocytosis by macrophages (melanophages) may be seen. This lesion (lentigo simplex) appears as a dark brown-black pigmented macule, usually of 1±2 mm in diameter. With further proliferation, nevus cell nests or theques form along the submucosal±mucosal junction with aggregation at the rete peg tips. This results in a nonpalpable tan-brown junctional nevus, usually <5 mm in diameter. The nevus cells continue to proliferate along the submucosal± mucosal junction, protrude into the submucosa while still surrounded by basement membrane material, and eventually become separated from the submucosal±

mucosal junction. Migration occurs across the entire lesional area, giving the lesion a raised appearance. This lesion is now a compound nevus, and is usually tanbrown and 5 mm or less in size. Over time, the junctional nests are lost, and the nevus cells become con®ned to the submucosa. Pigmentation fades with time and the lesion takes on a pink to ¯esh color (intramucosal nevus). Nevi do not induce a lymphoid in®ltrate, have only rare mitotic activity, lack cytologic and nuclear atypia, and undergo nevus cell maturation (neuralization). Several clinical and histologic variants of melanocytic nevi exist [31±45]. The variants that may be of importance, from a clinical standpoint, are those which may be confused with malignant melanoma. The epithelioid and spindle cell nevus (Spitz nevus, Fig. 1) may mimic melanoma, both clinically and histopathologically. Blue nevi (Fig. 1) are also of interest, because of the intense submucosal melanin pigment which often is associated with mucosal melanoma. Often it is necessary to perform a bleaching procedure on tissue sections to remove the melanin pigment and allow microscopic evaluation of the architectural and cytologic appearance of this lesion. Malignant blue and Spitz nevi do occur and this confounds the clinical and pathologic evaluation. 4. 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±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 most occurring in Caucasians and in young adults. There is no increase in melanocytes, but rather an increase in melanin deposition within the basal cell layer and submucosa/lamina propria of the oral mucosa (Fig. 1). Elongation of the rete ridges does not typically occur. Malignant transformation has not been reported. Excision of these lesions may be indicated to rule out other melanocytic neoplasms. 5. 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±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,

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Fig. 1. Benign mucosal melanocytic proliferations. (A,B) Melanotic macule involving the mucosa of the lip characterized clinically as a ¯at, nonelevated lesion and histologically as a basal cell epithelial layer which has uniform melanin accumulation without an increase in the density of melanocytes or the presence of nevus cells. (C±E) Melanocytic nevi involving (C) the mucosa of the lip and (D) the ¯oor of the mouth characterized as slightly raised pigmented lesions with uniform borders which on histologic examination (E) possess submucosal nevus cells which elevate the overlying mucosa. (F,G) Blue nevus involving the palatal mucosa imparting a bluish hue to the mucosa (F) and composed histologically (G) of dense deposits of melanin obscuring the submucosal nevus cells. (H) Melanoacanthoma involving the gingiva characterized by uniform pigmentation, slightly raised from surrounding gingiva, and possessing surface stippling similar to the adjacent nonpigmented gingiva. This lesion rapidly increases in size, reaching several centimeters in a few weeks. (I,J) Spitz nevus with (I) epithelioid and (J) spindle cell features: histopathologic appearance. This benign melanocytic nevus may be confused clinically and histologically with melanoma.

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Fig. 1. (continued).

80% are less than 1 cm in maximum dimension. Approximately 15% of oral nevi are nonpigmented. Two-thirds are raised, relatively well-circumscribed lesions. Although de®nitive transformation from typical nevi to melanoma has not been documented, oral nevi may represent precursor lesions to oral mucosal melanoma. Most oral nevi occur on the palate (38%), buccal and labial mucosa (31%) and gingiva (11%). The palate is the most common site for melanoma development (Table 2). The identi®cation of atypical melanocytic hyperplasia (similar to cutaneous atypical mole/dysplastic nevus) and an in situ component to oral mucosal melanoma implicates a melanocytic precursor lesion in some cases. Oral nevi may mimic mucosal melanomas clinically. Because of the uncertain nature of oral nevi and exposure to chronic irritation, excision of these melanocytic lesions is indicated usually. 6. 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±48]. These lesions are more common in the third and fourth decades in primarily black females. The

lesion is usually ¯at 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 acanthosis and spongiosis, with frequent dendritic melanocytes in the basal layer of the epithelium. The underlying submucosa contains a mild-to-moderate chronic in¯ammatory in®ltrate. The lesion is thought to be a reactive process and not related to melanocytic proliferations associated with nevus or melanoma formation. Following incisional biopsy, lesions have been reported which undergo spontaneous involution. Once melanoacanthoma (melanoacanthosis) is established as the diagnosis, no further treatment is necessary. 7. 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±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%

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157

tobacco usage, or as an aberrant drug reaction. Drugs which are commonly associated with oral mucosal pigmentation include clofaximine, ketoconazole, antimalarials, minocycline, estrogen, cyclophosphamide, busulfan, doxorubicin, 5-¯uorouracil, and azidothymidine. 8. Oral melanoma and atypical melanocytic hyperplasia: histogenetic and clinical factors

Fig. 2. Pigmented intraoral lesions mimicking melanocytic lesions. (A) Post-in¯ammatory pigmentation of the dorsal tongue in patient with lichen planus. (B) Amalgam tattoo in the buccal mucosa. (C) Tattoo of mandibular lip mucosa, adjacent to melaoncytic intraoral nevus (arrow).

found in the buccal mucosa. The maximum dimension ranges up to 2 cm with most being less than 6 mm. Radiographs may show tiny radiopaque particles, but this is found in less than one-third of lesions. Biopsy of suspicious lesions typically shows discrete black to dark brown granules of foreign material in the submucosa. Occasionally a chronic in¯ammatory reaction with foreign body giant cells may be present. Pigmentation may also occur as a post-in¯ammatory reaction with hemosiderin deposition in the submucosa, with heavy metals (arsenic, bismuth, platinum, lead, mercury), secondary to

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± 10,13±16,18±20,22±25,54]. Because of the advanced stage at discovery, the majority will not have an associated radial growth (super®cial spreading) phase. Oral melanomas (Figs. 3±5) do not ®t well into any speci®c cutaneous melanoma category; however, some have likened oral melanomas to acral lentigenous and nodular melanomas. At the 1995 WESTOP Ban€ Workshop [8] on oral melanomas, a nomenclature was proposed for this unique oral malignancy, as well as a review of various factors associated with primary oral melanomas collected from several oral and maxillofacial pathology biopsy services (Tables 2 and 3) [8±25]. The nomenclature employs a relatively simplistic system, whereby oral mucosal melanomas are classi®ed by histologic pattern as in situ (Fig. 4), invasive (Fig. 5), and combined in situ and invasive. In addition, the term atypical melanocytic hyperplasia was designated for oral mucosal lesions with equivocal histopathologic features, such as hyperchromatic and angulated nuclei with very infrequent mitotic activity (Fig. 3). This essentially represents an indeterminant to premalignant melanocytic lesion similar to that of the cutaneous atypical mole (dysplastic nevus). For comparison, the histopathologic criteria for the cutaneous atypical mole include [1± 4,6,32,53±63]: (1) architectural disorder with asymmetry; (2) subepidermal concentric eosinophilic and/or lamellar ®broplasia; and (3) lentigenous melanocytic hyperplasia with spindle or epithelioid melanocytes aggregating in variably sized nests forming bridges between adjacent rete ridges (Fig. 3). Melanocytic atypia may vary from mild to severe. A `shoulder' phenomenon may be present, and is characterized by intraepidermal nevus cells extending singly or as nests beyond the underlying dermal component. Atypical nevi are capable of Pagetoid spread into the epidermis, and inciting a lymphoid in®ltrate in the super®cial dermis. Mitoses are rare with this lesion. Atypical nevus is considered to be a marker for cutaneous melanoma in both sporadic and familial patterns, and warrants a thorough evaluation of the patient and his kindred for melanoma, as well as long-term follow-up. Similarly, atypical melanocytic hyperplasia in the oral cavity may

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Fig. 3. Atypical melanocytic hyperplasia (atypical mole or dysplastic mole): histopathologic features. Nevi with atypical melanocytic hyperplasia typically have a shoulder (A,B) due to elevation of the overlying epithelium by a proliferation of underlying atypical nevus cells. (A±D) Bridging of rete pegs and nests of nevus cells along the lateral sides of the rete pegs, as well as at the tips of the rete pegs are prominent features. Cytologic atypia is present, but migration of the atypical nevus cells into the overlying epithelium does not occur. Eosinophilic lamellar ®broplasia (arrow) within the superi®cial submucosa and dermis is also a common feature (D,E).

represent a precursor lesion to melanoma or an indication of increased risk for developing mucosal melanoma at other sites. The importance of designating a lesional category as atypical melanocytic hyperplasia in the oral cavity cannot be overlooked. With cutaneous melanoma, an inherited pattern that predisposes to melanoma development in virtually 100% of a€ected individuals has been de®ned as the Familial Atypical Mole and Melanoma

Syndrome (FAMM) [1±4,6,53±63]. This syndrome is found in 10-15% of all people with atypical (dysplastic) nevi. FAMM has been de®ned as: (1) melanoma history in one or more ®rst or second degree relatives; (2) >50 cutaneous melanocytic nevi, some of which may be atypical clinically and of variable size; and (3) nevi that have histopathologic features of atypical nevi. In contrast to the eventual development of melanoma in FAMM, the risk for melanoma for individuals with

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Fig. 4. In situ melanoma resembling super®cial spreading melanoma. (A,B) Poorly demarcated pigmented lesions at (A) commissure and (B) in maxillary labial mucosa (arrows) which proved to be intraoral melanoma resembling superi®cal spreading melanoma upon biopsy. (C) Migration of melanoma cells from the basal layer region into the mucosa (arrows). (D) Proliferation of melanoma cell nests along basal layer region; however, tumor nests are encased by basement membrane and not invading underlying submucosa.

sporadic atypical nevi varies from 3.8 to 6.3 times that for the general population. With designation of oral nevi as having atypical melanocytic hyperplasia, it may be possible to identify a subset of individuals at high risk for oral melanoma development. In fact, a preexisting melanocytic lesion is noted in about one-third of primary mucosal melanomas of the head and neck (Table 4) [8,10,15,16,18±20,23,24,54]. Perhaps, these lesions may represent the cutaneous equivalent of atypical nevus with a predisposition for transformation to melanoma. Several di€erent cell types comprise the tumor in oral mucosal melanoma (Table 3) [8,16,17]. Spindled, plasmacytoid and epithelioid tumor cells arranged in a sheet-like, organoid, alveolar, neurotropic or desmoplastic con®guration may be seen. Melanin pigment is noted in almost 90% of lesions. The lesions also vary clinically in color, shape and as to whether the lesions are macular, nodular or ulcerated. The preferred site for oral mucosal melanoma is the palate with over 40% occurring either on the hard or soft palate (Table 2, Figs. 4 and 5) [8±25]. Gingival melanomas represent almost one-third of melanomas.

Other sites include the buccal mucosa, lips, tongue, ¯oor of the mouth and even the uvula. The maxillary sinus represents less than 10% of sinonasal mucosal melanomas, but may be a potential biopsy site that the head and neck pathologist encounters. As noted previously, in contrast to cutaneous melanomas where the majority present in the radial growth phase, oral mucosal melanomas are found in a vertical growth phase (Table 3) [8,16,17]. Most lesions (85%) are invasive or have both an invasive and in situ pattern. Relatively few at diagnosis possess an in situ pattern at discovery. Despite the anatomic site of the oral mucosal melanoma, prognosis is quite poor (Table 4) [8,10,15,16,18± 20,23,24,54]. The 5-year survival is 15% for all oral melanomas compared with 18 and 11% for gingival and palatal tumors, respectively. Median survival is a€ected by whether there is lymph node involvement (18 months) or not (46 months). In general, median survival for all oral mucosal melanomas is slightly over 2 years from time of diagnosis. The poor prognosis may relate to the increased thickness of the tumors and the vertical growth phase of the tumors at diagnosis (Table 3) [8,16,17].

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9. 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±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. Although quite helpful, this is dependent upon the experience of the pathologist in assessing the anatomic location of the tumor within the skin. A more reproducible method of assessing invasion is based upon measuring tumor thickness (Breslow tumor thickness) from the super®cial aspect of the granular cell layer of the epidermis to the greatest depth of tumor cell penetration into the deep aspect of the skin. When ulceration is present, the measurement is made from the ulcerated surface to the greatest depth of the tumor. Extensive statistical analysis has shown that 5- and 8-year survival rates are related inversely to tumor thickness. In general, risk for development of metastatic disease with cutaneous melanoma is considered to be: (1) low for tumor thickness of 40.75 mm; (2) low to intermediate for tumor thickness of 0.76±1.49 mm; (3) intermediate to high for tumor thickness of 1.50±4.00 mm; and (4) de®nitely high for tumor thickness of >4.00 mm. In contrast to cutaneous melanoma (Table 4), a standardized correlation of histopathologic features and prognosis for mucosal melanomas of the head and neck has not been completed [5,8,9,13,15,16,19,20,22±24,54]. However, a comparison of the thickness of oral and cutaneous melanomas has been performed (Table 3) [8,16,17]. This comparative study indicated that the majority of oral melanomas present with a thickness of 54.0 mm at Stage I (70%) and Stage II (83%) disease. In contrast, signi®cantly fewer cutaneous melanomas at Stage I (10%) and Stage II (49%) present with a thickness of 54 mm. The 1995 WESTOP Ban€ Workshop [8] on oral melanomas emphasized that the prognostic histopathologic features in cutaneous melanoma should be assessed and reported with oral melanomas (Table 5) [6,8,68]. This will allow for retrospective and prospective studies in oral melanomas of the factors associated with favorable and unfavorable outcomes in cutaneous melanomas, and for determination of the prognostic signi®cance of these factors. Several diculties exist when dealing with mucosal head and neck melanomas, in particular oral melanomas (Table 4) [8,10,15,16,18±20,23,24,54] and these include: (1) architecture of the entire lesion may not be assessed due to small biopsy size; (2) possible unrepresentative sampling; and (3) late stage at presentation. Of particular

importance is determining whether an oral melanoma is a primary or metastatic lesion [8,16,22,69]. The most important features in de®ning a primary lesion from a metastatic lesion (Table 4) [8,10,15,16,18±20,23,24,54] are site of involvement, presence or absence of pigment, overlying mucosal ulceration, extension along salivary gland ducts, and vascular and perineural invasion. It is quite obvious that histopathologic evaluation in cutaneous and oral melanomas provides many factors which may predict the course of the patient's disease and survival at primary diagnosis. The histopathologic factors which should be included in a pathology report for cutaneous and mucosal melanomas are listed in Table 5 [6,8,68]. 10. 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±92]. Many of these are associated

Fig. 5. Melanoma with vertical growth phase (nodular melanoma). (A) Nodular melanoma of palate with mucosal ulceration with residual intact densely pigmented mucosa. (B) Invasion of the underlying submucosa with readily indentifed melanin pigment. (C,D) Marked cytologic pleomophism with prominent nucleoli, mitotic activity (arrow) and melanin incontinence. (E) Di€use cytoplasmic immunoreactivity of tumor cells with antibody to HMB-45. (F,G) Ultrastructural examination reveals premelanosomes/stage II melanosomes (arrows) and con®rms the diagnosis of melanoma.

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161

Fig. 5. (continued).

with various enzymes and factors associated with melanin production. Melanoma-associated antigens are HLA-restricted and not expressed in all individuals with melanoma, but are dependent upon the individual's HLA class. Many of these antigens have been targeted for vaccine and immune modulated therapy; however, it is quite apparent that the vaccine and immunotherapy needs to be tailored to the patient's HLA type to be e€ective. Recent clinical investigations in patients with metastatic melanoma have shown that peptide vaccines increase HLA binding to melanoma-associated antigens with generation of melanoma-reactive cytotoxic T lymphocytes. Objective tumor responses are reported in

over 40% of these individuals. Several studies have noted the infrequency of melanoma in HLA-B7 individuals. Cytotoxic T-cell function is improved via CD28 expression in HLA-B7 individuals, and probably allows immune surveillance to eliminate melanoma cells prior to tumor formation. Gene therapy to transform melanoma cells to HLA-B7 antigen expression is currently under investigation as a potential treatment. Many antigens associated with cell-to-cell and cell matrix interactions are found within tumorigenic melanomas (Table 6). Expression of these antigens enhances the ability of the malignant cells to invade the underlying tissue (local invasion), perineurium, and vascular structures

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Table 3 Characteristics of oral mucosal melanomasa Mean age (Range)

56 years (22±83 years)

Gender ratio

2.8 M:1.0 F

Symptoms

Pain, ulceration, bleeding, loose teeth, bone erosion

Appearances Color Shape Number Surface

Varies from black to gray to purple to white to red Asymmetric, irregular outline Multiple and satellitosis Macular to ulcerated to nodular

Di€erential diagnosis Melanoma, melanotic macule, smoking-associated melanosis, post-in¯ammatory pigmentation, medication melanosis, melanoacanthoma, nevus, amalgam tattoo, Kaposi's sarcoma Histologic patterns In situ pattern Invasive pattern Combined in situ and invasive pattern Atypical melanocytic hyperplasia

15% 30% 55% Not available

Melanotic Amelanotic

88% 12%

Cell types Architecture

Spindled, plasmacytoid and epithelioid Sheet-like, organoid, alveolar, neurotropic, desmoplastic

Thickness of melanoma

41.5 mm

1.5±4.0 mm

54.0 mm

Oral mucosal melanoma Stage I, localized Stage II, nodal involvement

0% 0%

30% 17%

70% 83%

Cutaneous melanoma Stage I, localized Stage II, nodal involvement

57% 11%

33% 40%

10% 49%

a

Data source: Refs. [8,16,17].

(metastasis). MUC-18 and gangliosides (GD3, GD2, GM2) are overexpressed and represent targets for immunotherapy. GD2, the predominant ganglioside in melanoma cells, and MAGE-3 are especially promising, because normal melanocytes express GM3 as their major ganglioside and do not express MAGE-3. Signaling and transport function receptors and antigens (Table 6) which participate in cell growth, regulation and proliferation are overexpressed in melanoma and may provide a mechanism to a€ect growth and proliferation by antibody-directed inactivation, or down regulation of these factors by gene therapy. For example [74], melanomas express high levels of basic ®broblast growth factor (bFGF) and ®broblast growth factor receptor-1 (FGF), in contradistinction to normal melanocytes. Liposomal gene transfer of antisense-oriented bFGF and FGF cDNA into tumor cells results in growth arrestment and regression along with intratumoral angiogenesis inhibition, and leads to tumor necrosis. Proliferation antigens (Table 6) are prominently displayed by melanoma cells, and allow

dysregulation of the cell growth cycle and tumor progression. In animal models, melanoma tumor regression occurs when antibodies to bcl-2 protein are introduced directly into tumor [75]. This therapy may also improve chemosensitivity in patients with melanoma, and improve treatment outcome and survival. Overexpression of p53 protein in cutaneous nevi and melanomas, and oral melanomas involving the head and neck region may prove to be helpful with diagnosis and prognosis [86,92]. Cutaneous nevi infrequently expressed p53 protein (seven of 25 cases) with a p53 index (% positive cells expressing p53) of less than 1% [92]. In contrast, cutaneous melanomas immunoreacted with p53 antibody in most cases (16 of 19) with a p53 index of slightly less than 6%. About two-thirds (11 of 17) of oral mucosal melanomas were positive for p53 with an index of slightly less than 4%. p53 antibody was very frequently expressed in melanoma metastatic to lymph nodes (23 of 25 cases) and distant sites (10 of 12 cases), with p53 indices of 6.6 and 7.7%, respectively. Of particular note was the fact that the p53 index was

M.J. Hicks, C.M. Flaitz / Oral Oncology 36 (2000) 152±169

Table 5 Histopathologic ®ndings in pathology reports for patient prognosis and staginga

Table 4 Considerations in oral mucosal melanomasa Diagnostic diculties with oral mucosal melanomas Small biopsy size Unrepresentative sampling Late stage lesion precludes interface evaluation Clinical data lacking Clinician and/or pathologist unable to recognize in situ lesions Metastatic versus primary mucosal melanomas of head and neck Primary mucosal melanoma Junctional activity Epithelial migration/invasion of epithelium Vascular and perineural invasion infrequent History of pre-existing melanocytic lesion in about one-third (37%) Palate and gingiva commonly involved Ulcerated mucosa Pigmented lesion more common (69%) Extension along minor salivary gland ducts Metastatic mucosal melanoma Lack junctional activity and invasion of epithelium Band-like lymphocytic in®ltrates Palatal and gingival sparing Base of tongue commonly involved Intact overlying mucosa Pigmented lesions less common (20%) Ð amelanotic Survival in oral mucosal melanoma 1 year Oral mucosal melanoma 75% Gingival melanoma 86% Palatal melanoma 75% Mean survival without nodal involvement Mean survival with nodal involvement a

5 years 15% 18% 11%

163

Median 25 mos 46 mos 22 mos 46 mos 18 mos

Data source: Refs. [8,10,15,16,18±20,23,24,54].

correlated ( p<0.05, Wilcoxon sample and Pearson correlation) with tumor thickness, survival and presence of metastatic disease for both oral and cutaneous melanomas. In melanomas with p53 expression, the mean p53 index for a 2.5-mm-thick lesion was 6.7% for cutaneous melanoma and 6.3% for oral melanoma. Lesions of less than 2.5 mm in thickness had mean p53 expression of 2.1 and 3.0% for cutaneous and oral melanomas, respectively. Greater than 48 months survival was associated with a p53 index of 3.9 and 2.8% for cutaneous and oral melanomas, respectively. In contrast, survival of less than 48 months had p53 indices of 7.1 and 5.3% for cutaneous and oral melanomas, respectively. Metastatic disease was found to have p53 indices of 8.2 and 7.5% for cutaneous and oral melanomas, respectively. When metastatic disease was not present, p53 indices were 3.1% for both cutaneous and oral melanomas. Another study [86] of 121 cutaneous melanomas from various anatomic locations found that the strongest predictors of p53 expression in melanoma were failure to tan [odds ratio (OR) 6.8], history of nonmelanoma cancer (OR 3.2), head and neck site (OR 2.7), and lower limb site (OR 2.1).

Tumor site Gender of patient (Head, neck, trunk, volar, subungal)b (Male)b Melanoma histogenetic subtype (Nodular, acral lentigenous)b

Clark's level of invasion (III, IV, V)b

Breslow tumor thickness (mm) (>1.70 mm)b

Growth pattern (Vertical)b

Overlying surface ulceration (present or absent) (Present)b

Mitotic index (>6.0 mitoses/mm2)b

Tumor regression (Absent)b

Angiolymphatic invasion (Present)b

Tumor in®ltrating lymphocytes (Absent)b

Microsatellitosis (Present)b

Tumor in transit (Present)b

Neurotropism (Present)b

Margins of resection (Involved)b

Precursor nevus/atypical nevus

Age (>60 years)b

Lymph nodes (Involved)b

DNA ploidy (Aneuploid)b

Proliferation index by ¯ow cytometry (Increased)b

Specialized laboratory tests (Cytogenetics, electron microscopy, immunocytochemisty, DNA analysis for ploidy and proliferative fraction [S+G2M]) a

Data source: Refs. [6,8,68]. Predictive factors associated with decreased survival in vertical growth phase melanoma. b

Recently, intermediate thickness (0.76±4.0 mm) primary melanomas have been analyzed for integrin expression and related to prognosis [93]. In 111 primary melanomas, beta-1 integrin was found in 52%, and beta-3 integrin was identi®ed in 64%. Relapse of disease was associated with beta-1 (53%) and beta-3 (58%) integrin-positive melanomas, compared with relapse rates of 30% for beta-1 negative integrin and 15% for beta-3 negative integrin melanomas. Of interest was the fact that individuals dying from their disease were considerably greater with tumors positive for beta-1 (43%) and beta-3 integrin (45%); whereas only 7.5% with beta-3 integrin negative melanomas and 19% of beta-1 negative integrin tumors died of disease. Similarly, both beta-1 and beta-3 integrin expression were associated with increased regional lymph node metastases (36 and 58%, respectively). This is in contrast to the fact that lymph node involvement occurred in 19% of beta-1 negative tumors, and in only 7% of beta-3 negative

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Table 6 Tumor-associated antigens in melanomaa Melanoma associated HLA-restricted antigens Glycoprotein (gp)100/HMB-45 (HLA-A2) TRP-1 and TRP-2/gp75 (HLA-A31) MAGE-1(HLA-A1, -Cw16) BAGE-3 (HLA-Cw16) p15 (HLA-A24) Beta-catenin (HLA-A24) CDK4 (HLA-A2)

MART-1/melanA (HLA-A2) Tyrosinase (HLA-A2,-B44,-A24,-DR4) MAGE-3 (HLA-A1, -A2) GAGE-1, GAGE-2 (HLA-Cw16) N-Acetylglucosaminyl-transferase-V (HLA-A2) MUM1 (HLA-A24)

Cell±cell and cell matrix interacting antigens ICAM-1 MUC-18 VCAM-1 CD44 HLA-DR CSPG (chondroitin sulfate proteoglycan, melanoma high molecular weight antigen)

Gangliosides (GM2, GD2, GD3, 9-O acetyl GD3) Tenascin VLA-2, VLA- 3, VLA-4 NCAM Integrins, beta-1 and beta-3

Signaling and transport function receptors and antigens EGF receptor TGF-beta-receptor GM-CSF receptor TNF receptor Melanotransferrin (p97)

NGF receptor IL-1 and IL-6 receptors FGF receptor bFGF receptor S-100 protein

Proliferation antigens bcl-2 Ki-67

Mutated p53 (late event) Proliferating cell nuclear antigen (PCNA)

a

Data source: Refs. [70±92].

melanomas. Lung metastases also correlated with beta-3 integrin expression, with 22 of 24 (92%) patients who developed pulmonary metastases possessing beta-3 integrin-positive primary melanomas. From this most interesting clinicopathologic study, beta-1 and beta-3 integrin analysis in primary intermediate thickness melanomas may prove to direct therapy and predict prognosis at the time of initial diagnosis. Immunotherapy against malignant melanoma has involved several di€erent approaches. Immunotherapy is based upon the possession of speci®c melanomaassociated antigens, and other overexpressed antigens described previously [70±85,87±91]. Whole cell vaccines (autologous irradiated cells or allogeneic cells), de®ned component vaccines (GM2, GD2, MAGE-1, MAGE3, BAGE-3, GAGE-1/2, tyrosinase, gp100/HMB-45, MART-1/MelanA), and gene-modi®ed vaccines (HLAB7 co-stimulator molecule, cytokines, HLA-B7 class I molecule) represent melanoma vaccine alternatives. Nonspeci®c immunotherapy has been directed toward treatment with interferon alpha-2, interleukin-2, and intralesional lymphokines [78±80,83±85,94±99]. The further understanding of unique melanoma-associated antigens and overexpression of other factors may lead to innovative therapy for those at particular risk for recurrent and metastatic disease. In the near future, it may be possible to analyze tumorigenic melanoma cells

from a patient to determine which therapeutic interventions would be e€ective in eradicating the tumor, and avoiding local recurrence and metastatic disease. Based upon polymerase chain reaction (PCR) and reverse transcriptase-PCR (RT-PCR) analyses, it is possible to determine if occult micrometastases are present in lymph nodes or other tissues, and if circulating melanoma cells are present in peripheral blood [87,100]. Analysis for tyrosinase, MUC-18, MAGE-3, and p97 (melanotransferrin) in sentinel lymph nodes from patients with melanomas of >0.76 mm in thickness revealed over one-third with occult micrometastases, compared with only 5% detection by histologic examination. Melanoma detection within sentinel lymph nodes is important because those individuals with negative nodes by both histology and PCR have a lower recurrence rate than those with negative histology, but positive PCR. Tumor thickness also correlates with PCR detection of tumor in lymph nodes. One-third of patients with lesion thickness of 0.76±1.5 mm had PCR detected nodal involvement, compared with 70% for individuals with tumors >4.0 mm in thickness. This technology may be applied to more accurately determine stage of disease and therapy in melanoma patients. In addition, serum can be monitored for circulating melanoma antigens to evaluate for `molecular' relapse and recurrence.

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11. 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±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 and 9 are found. Loss of heterozygosity (Table 7) is frequently identi®ed in sporadic melanomas, and several loci with loss of heterozygosity are tumor suppressor gene sites (FHIT on 3p; NM23 and NF1 on 17q; p53 on 17p) [101,102]. Loss of p53 heterozygosity or p53 mutation appears to be a late event in melanoma, and not an early transforming event. However, p53 mutation and loss of wildtype p53 function heralds more aggressive disease and the ability to metastasize. Molecular evaluation of kindred of individuals with FAMM has lead to the discovery of several cutaneous malignant melanoma susceptibility genes (CMM, Table 7) [101±118]. The ®rst cutaneous malignant melanoma

165

susceptibility gene (CMM1) is located on the short arm of chromosome 1 (1p36) near the Rh blood group locus. This mutation may involve the PITSLRE protein kinase gene which participates in apoptosis signaling and is a tumor suppressor gene. CMM1 has a high penetrance (82%) by the eighth decade and an autosomal dominant inheritance pattern. CMM2 is positioned on the short arm of chromosome 9 (9p21) and a€ects the CDKN2A gene which encodes for proteins p16INK4a and p19ARF. p16INK4a inhibits the growth promoting activity of cyclin/cyclin-dependent kinase complexes 4 (cdk4) and 6 (cdk6). CDKN2A, a tumor suppressor gene, participates in cell cycle regulation, and regulates the passage of cells from the G1 (growth) phase to S (DNA synthetic) phase in the cell cycle. This gene's protein (p16) is upstream from the retinoblastoma gene product (pRb) and is necessary to inhibit cdk4 and cdk6 in order for pRb tumor suppressor activity and DNA repair. The other gene product a€ected by the CDKN2A mutation at 9p21 is p19ARF. p19ARF inhibits proliferation by interacting with cell cycle regulators upstream from p53, allowing for regulated cell proliferation. Mutation of these tumor suppressor gene products (p16INK4a and p19ARF) in

Table 7 Cytogenetic abnormalities in melanomaa CMM1 (cutaneous malignant melanoma susceptibility gene) Unidenti®ed gene near Rh locus (Possibly mutated PITSLRE protein kinase, participates in apoptosis signaling: mutated tumor suppressor gene)

1p36

CMM2 (cutaneous malignant melanoma susceptibility gene) Mutated CDKN2a gene encodes for mutant protein p16INK4a and p19ARF Mutated p16INK4a interferes with inhibition of growth-promoting activity of cyclin/cyclin-dependent kinase complexes 4 and 6 (cdk4 and cdk6) Mutated p19ARF inhibits cell cycle regulators upstream from p53 Mutated tumor suppressor genes

9p21

CMM3 (cutaneous malignant melanoma susceptibility gene) Mutated CDK4 gene encodes a protein resistant to normal inhibition exerted by p16INK4a and leads to unregulated promotion of cell division and cell growth

12q14

Non-random frequent chromosomal abnormalities in melanoma 6q25 antioxidant manganese superoxide dismutase gene (tumor suppressor gene function in vitro) Polysomy 7 Extra copies of EGF receptor gene Extra copies of multidrug resistance gene (MDR1, PRP) Maps to 7q (increased copies in melanoma) Loss of chromosome 10 in 70% of melanomas and in malignant brain tumors (Deletion of potential tumor suppressor genes on 10q and 10p; 10q11 maps to RET proto-oncogene; 10q23-241 maps to Fas/APO gene; 10q24 maps to homeobox 11 gene; 10q24.3 maps to O-6-methylguanine-DNA methyltransferase gene) Loss of heterozygosity: frequency in sporadic malignant melanoma 1p 5% 9p 3p 19% 9q 3q 14% (FHIT)b 10q 6q 31% 11q a b

Data source: Refs. [101±118]. Tumor suppressor gene.

47% 19% 31% 17%

13q 17p 17q 22q

9% 16% (p53)b 4% (NM23, NF1)b 6%

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atypical nevi and melanoma results in unregulated cell proliferation. CMM2 has a relatively high penetrance (53%) by the ninth decade and an autosomal dominant, partial penetrance pattern. CMM3 is located on the long arm of chromosome 12 (12q14) and results in cdk4 gene mutation. Mutated cdk4 gene product is resistant to inhibition by wildtype p16INK4a, and inhibits pRb tumor suppressor function, leading to unregulated cell growth. CMM3 functions as a dominant gene and is not a mutated tumor suppressor gene. Similar cytogenetic and molecular mutations are considered to be operative in mucosal melanomas of the head and neck and at other sites. Several frequent nonrandom chromosomal abnormalities have been discovered in familial and sporadic atypical nevi and melanoma (Table 7) [101±112]. Defects in the long arm of chromosome 6 (6q25) are associated with a tumor suppressor gene, antioxidant manganese superoxide dismutase. This gene is necessary to reverse toxic damage to cells by oxidative injury that lead to DNA defects. Extra copies of epidermal growth factor receptor gene and multidrug resistance gene are found in melanoma and atypical nevi and this is ascribed to chromosome 7 polysomy. Chromosome 10 loss of heterozygosity occurs in melanomas and malignant brain tumors. Deletion of several potential tumor suppressor genes on chromosome 10 have been implicated in unregulated cell growth. Potential mutated tumor suppressor genes include: (1) RET proto-oncogene at 10q11; (2) Fas/APO gene at 10q23-24.1; (3) homeobox 11 gene at 10q24; and (4) O-6-methylguanine-DNA methyltransferase gene at 10q23.4.

The importance of tumor suppressor gene mutation and growth factor dysregulation in melanoma transformation is illustrated by cell culture studies comparing melanocytes, nevus cells and melanoma cells [101,102]. The number of cell generations to senescence with melanocytes and nevus cells is 50±60; while melanoma cells in culture usually do not reach senescence until >100 cell generations or are immortalized. Growth factor supplementation is necessary to maintain melanocytes and nevus cells in culture. In contrast, melanoma cells in culture do not require supplemental growth factors. The vast majority of melanoma cells in culture have the ability to invade agar gelatin; whereas less than 0.1% of melanocytes and nevus cells invade agar gelatin. These discrepant ®ndings between melanoma cells compared with melanocytes and nevus cells may be ascribed to the e€ects of mutated tumor suppressor genes and other mutated growth and proliferation factors. 12. 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 80% of individuals alive at

Table 8 Melanoma: treatment and survivala Treatment Surgery alone Radiotherapy Chemotherapy Surgery+radiotherapy Surgery+chemotherapy Radiotherapy+chemotherapy Surgery+radiotherapy+cheomtherapy No treatment 5-Year disease speci®c survival All melanomas Cutaneous Mucous membrane Head and neck Female genital Anal/rectal Lymph node positive Lymph node negative Survival (all melanomas) a

Data source: Refs. [7,26].

Cutaneous melanomas 92% <1% <1% 1% 1% <1% <1% 3% 1 year 93% 94% 74% 82% 68% 62% 62% 85% 10 year 80%

2 years 88% 89% 49% 54% 40% 44% 34% 56% 20 year 66%

Mucosal melanomas 56% 8% 2% 19% 2% 2% 3% 6% 3 years 84% 86% 38% 46% 26% 27% 26% 44%

4 years 81% 83% 30% 37% 21% 20% 16% 39%

5 years 79% 81% 25% 32% 11% 20% 16% 39%

M.J. Hicks, C.M. Flaitz / Oral Oncology 36 (2000) 152±169

5 years, and with as many as two-thirds alive at 20 years (Table 8). In contrast, mucosal melanomas of the head and neck, female genital tract, and anal/rectal region have a particular dismal 5-year survival rate ranging from 11 to 32% (Table 8). In fact, median survival for mucosal membrane melanomas is slightly less than 2 years. With oral melanomas, 5-year survival is 15% with a median survival of 25 months (Table 4) [5,7,10,15,16,18±20,23±26]. Gingival melanoma (18%) has a slightly greater 5-year survival than that for palatal melanoma (11%), with a considerably longer median survival period (46 months vs. 22 months). Nodal involvement with oral melanoma reduces median survival substantially from 46 months to only 18 months. No doubt this discrepancy in survival between cutaneous and mucosal melanoma is due to the vertical growth phase, higher stage at discovery of the malignancy, and the inability to adequately resect the lesions with negative margins. 13. 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 and neck. Perhaps, increasing the awareness of healthcare professionals and the general public for the need to detect head and neck mucosal melanocytic lesions and melanomas will help identify these lesions at an innocuous stage. With the incidence of melanoma on the increase and with the projection that the lifetime risk in the year 2000 will be one in 75, preventive practices and education of the general public in skin and head and neck selfexamination for avoidance of melanoma development cannot be over emphasized. In order to identify potential mucosal melanomas of the head and neck region, attention should be directed toward oral and nasal screening by quali®ed dental professionals, in addition to skin examination for pigmented lesions. References [1] Slade J, Marghoob AA, Salopek TG, Rigel DS, Kopf AW, Bart RS. Atypical mole syndrome: risk factor for cutaneous malignant melanoma and implications for management. J Am Acad Dermatol 1995;32:479±94. [2] Rigel DS. Malignant melanoma: incidence issues and their e€ect on diagnosis and treatment in the 1990s. Mayo Clin Proc 1997;72:367±71.

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