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Oral melanoma and other pigmented lesions of the oral cavity Drore Eisen, MD, DDS,* and John J. Voorhees, M D Ann Arbor, Michigan This article presents a review of oral malignant melanoma and other oral cavity pigmented lesions. The dismal prognosis for patients with oral malignant melanoma is partly due to patients' delayed recognition of signs of early disease and delayed diagnosis by physicians. Pigmented macules and plaques in the oral cavity, representing the radial growth phase of tumors, often go unrecognized for months or years before tumor invasion. Therefore, if early detection of thin oral melanomas is to be achieved, all pigmented oral cavity lesions should be viewed with suspicion. Biopsies of such lesions are indicated when the clinical diagnosis is uncertain. Prompt aggressive surgical treatment is essential in reducing the morbidity and mortality from oral melanomas. The differential diagnosis of oral melanomas includes nevi, oral melanotic macules, amalgam tattoos, Kaposi's sarcoma, oral melanoacanthoma, and physiologic pigmentation. (J AM ACAD DERMATOL1991;24:527-37.)

The dramatic increase in survival rates of patients with cutaneous melanoma in the past 20 years suggests that melanomas are being recognized and diagnosed early in the course of the disease. 1 In contrast, the prognosis for patients with oral melanoma is grave despite aggressive therapy and has not significantly changed since Chaudhry's review 2 of 105 cases in 1958. 36 Unfortunately, delayed detection by physicians and patients may well explain the poor prognosis] Surprisingly, the dermatologic literature is practically devoid of information on the subject of oral ORTHO The C ME articles are made possible through an ed ucational grant from the Dermatological Division, Ortho Pharmaceutical Corporation. From the Department of Dermatology, University of Michigan. Reprint requests: John J, Voorhees, MD, Department of Dermatology, University of Michigan Medical Center, 1910-0314 Taubman Center, Ann Arbor, Mf 48109. *Current address: Dermatology Associates of Cincinnati, 7691 Five Mile Rd., Cincinnati, OH 45230. 16/2/25508

melanoma. Furthermore, as public awareness of melanoma screening has risen because of the efforts of the medical community, there has not been a concomitant effort by physicians to stress the importance of oral cavity examinations, g Early detection of oral melanomas depends on the clinical recognition of all pigmented lesions of the oral cavity. This review article of oral melanoma emphasizes the potential benefits of early diagnosis. Oral lesions that may be confused clinically with melanoma include nevi, oral melanotic macules, amalgam tattoos, physiologic pigmentation, oral melanoacanthoma, and Kaposi's sarcoma. The clinical features of these entities will be presented. EXAMINATION OF PATIENTS One of the primary objectives of an oral cavity examination is to distinguish between oral tissue pigmentation in health and disease. Changes in color of the oral mucosa may result from a variety of causes, as outlined in Fig. 1. Most of these conditions

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Journal of the American Academy of Dermatology

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Pigmentation of the Oral C a v i t y Endogenous Origin

Exogenous Origin

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Fig. 1. Causes of pigmentation in oral mucosa. can usually be differentiated from oral malignant melanoma on the basis of a complete patient history and physical examination. Much of what is currently known about oral melanomas originates in the dental literature. This is most likely the result of the dental profession stressing oral cavity examinations. Other oral health care providers, including dermatologists and otoIaryngologists, should feel confident in their assessment of the oral cavity. A routine examination of the oral cavity minimizes the possibility of overlooking undiscovered or underrecognized lesions. As with cutaneous examinations, proper inspection, palpation, and illumination are essential. Table I provides a guide for a complete oral cavity examination.

ORAL MELANOMA Epidemiology Literature on the subject of oral melanoma consists of retrospective reviews and case reports beginning with the first recorded description of the entity by Weber 9 in 1859. In 1941, Baxter t~ published the first of many reviews of oral melanomas compiling data from 54 cases, and most recently, Rapini et al.l I reviewed 171 cases and added six new cases to the literature in 1985.1214 Oral melanomas are rare, as evidenced by the lack of a large series presented by a single institution. However, they have been reported to constitute a range as broad as 0.1% to 8% of all melanomas. 15, 16 The high percentage reported in some series may reflect a bias towards a high prevalence in small studies/5 Alternatively, racial, cultural, or geo-

graphic factors may predispose the subjects in any of these studies to the development of oral melanoma. For example, in Japan, the oral cavity represents a site of predilection for melanoma 13 and in Uganda, 8% of melanomas in a series of 125 cases occurred in the mouth. 17 Other racial characteristics include a high incidence of oral mucosal melanomas in southwestern American Indians 18 and Hispanics.19 A review of the relative frequency of oral melanom as in American and African black persons reveals that it is similar to white persons. 2~ Oral melanomas occur most frequently in the fourth through seventh decades of life and are exceedingly rare in persons younger than 20 years of age. 21,22 Most studies support equal sexual predilection or a slightly higher incidence in men. 1I, z3

Clinical characteristics There is general agreement that oral melanomas occur most commonly on the palate and maxillary gingivae. 24-26Together, these sites account for nearly two thirds of all cases with the palate the single most common site. 11 The mandibular gingiva, buccal mucosa, tongue, and lips are other sites of predilection for oral melanomas. Attempts have been made to explain the high incidence of melanomas on the palate, implicating trauma from ill-fitting dentures, chemical factors, (i.e., tobacco and alcohol), and poor oral hygie n e y 29 but these have been discounted by most authors. A more valid correlation exists between melanomas of the palate and preexisting pigmentation. Asymptomatic oral pigmentation at the site of oral

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Table I, A guide to the oral cavity examination

Materials needed: Patient position: Examination:

Tongue depressor, 4 X 4 inch gauze, gloves, light Seated or semireclined 1. A suggested sequence: inner surfaces of upper and lower lips, the buccal mucosa with its vestibular reflections, the gingiva, the dorsal and ventral aspects of the tongue, the floor of the mouth, the hard and soft palates, and the tonsillar pillars 2. A tongue depressor is used to fully retract the cheeks and depress the tongue (for examination of the oropharynx). 3. A 4 X 4 inch gauze is used to grasp and mobilize the tongue to examine its lateral and ventral surfaces. 4. Bimanual or bidigital palpation of intraoral structures may be done as necessary. 5. Palpation of the superficial and deep lymph nodes of the neck follows the intraoral examination. This is best accomplished with the physician positioned behind the patient.

melanoma was noted before diagnosis by approximately one third of patients in each of five large reviews.2. 10-13In the series of Liversedge,12 19 of 65 patients had observed the pigmentation for 4 to 20 years. This pigmentation, in most cases, is believed to represent the radial growth phase of the tumor that may precede tumor invasion by months to years.2, 11 The appearance of pigmentation in the oral cavity preceding invasive malignant melanoma underscores the necessity of routine oral examifi~tions and prompt diagnosis. Other than the radial growth phase of melanoma, causes of preexisting pigmentation potentially include oral nevi, oral melanotic macules, and physiologic pigmentation. Diffuse patches of pigmentation are commonly present in blacks and other dark-skinned persons in whom they are easily recognized on the palate and gingiva3~ (Fig. 2). Clinically, physiologic pigmentation consists of pigmerited macules of various configurations and sizes that have their onset in infancy or puberty. 32 Biopsies must be performed on all such patches that are of recent origin or those that have exhibited changing appearance. Oral melanomas have a variable presentation (Figs. 3 and 4). They may suddenly appear and rapidly enlarge, causing ulceration, bleeding, and pain. However, these features are uncommon in the early stages of the disease. 3 In fact, the absence of pain often causes patients considerable delay in seeking medical attention. Pigmented macules, patches, plaques, and nodules more commonly persist asymptomaticaUy for years. 21, 33 As tumors enlarge, patients may experience loosening of teeth as a result of bone destruction or ill-fitting dentures. 34' 35In a series of 42 oral melanomas reviewed by Trodahl and Sprague, 36 nearly one fourth was described

clinically as only an innocuous "pigmented spot," (thereby reinforcing the need to subject to biopsy all pigmented lesions of unknown origin). Clinical diagnosis is further complicated because 5% to 15% of oral melanomas are amelanotic or pink. 37-39 Classification

Cutaneous melanomas are classified into four clinical types: nodular melanoma (NM), superficial spreading melanoma (SSM), acral lentiginous melanoma (ALM), and lentigo maligna melanoma (LMM). 39-44 Similar classification of oral melanomas, although attempted by some authors, 45, 46 has been abandoned. Criteria used to categorize cutaneous melanomas are invalid for lesions in the mouth. For example, oral lesions may have ultrastructural features of L M M but lack the actinic origin and excellent prognosis described for these tumors of the skin.42 Regezi et al.47 recognized the distinction between oral melanomas with a radial growth phase and those exhibiting a vertical growth phase as a basis for classifying superficial melanoma and nodular melanomas, respectively. This classification has been accepted by other authors.ll Determination of the depth of invasion in millimeters has proved to be the single most important prognostic factor for cutaneous melanomas. 48,49 The usefulness of this standard with respect to oral melanomas is unclear because of the scarcity of such information in reports of cases. The few studies that have included measurement of depth of invasion have concluded a probable causative relation between tumor thickness and prognosis. 5~In a series of 74 mucosal melanomas of the head and neck including 23 with oral melanoma, a higher survival rate was observed in patients with tumors less than

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Fig. 2. Physiologicpigmentationofthemaxillarygingivacommonindark-sldnnedpersons. Fig. 3. Early superficial melanoma of the hard palate and maxillary alveolar ridge. (Courtesy Dr, Bela B. Toth, The University of Texas M. D. Anderson Cancer Center, Houston, Tex.) Fig. 4. Melanoma of the hard palate with nodular component detected at an advanced stage. (Courtesy Dr. Bela B. Toth, The University of Texas M. D. Anderson Cancer Center, Houston, Tex.) 0.5 m m deep than in those whose tumors exceeded 1 m m in depth. 51 Macintyre and Briggs 21 and Rapini et al. 11 reported the depth of invasion in a total of nine thick oral melanomas extending from 2.9 to I 0 mm. Four of the nine patients survived 1 year or less after diagnosis, two patients were alive but metastases developed within 3 years, and one patient (tumor thickness 5 m m ) died of metastatic disease after 11 years. The two remaining patients showed no evidence of disease at a 1-month and 1-year follow-up, although their long-term status was not reported. It is likely that the poorer prognosis of oral melanoma compared with that of cutaneous melanoma is due to the detection of oral melanomas with advanced depths of invasion. The prognostic value of levels of invasion as described by Clark et al. 4~ has been regarded as inapplicable to mucosal melanomas; the absence of papillary and reticular dermis

often prohibits the determination of invasive levels.7, 52

Histologie features Histologically, melanoma of the oral cavity is often indistinguishable from its cutaneous counterpart. 53 Tumors composed of spindle cells may be arranged in small nests or in a palisade fashion. 33 These may mimic sarcomas, squamous cell carcinomas, and, occasionally, adenocarcinomas. 54 Other tumors contain large round or polygonal cells resembling atypical epithelioid cells; mixed epithelioid and spindle cell tumors are frequent. 6' 55 In a series of 23 oral melanomas, Eneroth 6 histologically classified the tumors, reporting nine spindle cell-type tumors, nine rounded undifferentiated cell-type tumors, and five mixed cell tumors. The survival rate did not vary according to histologic features.

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Melanoma and other pigmented lesions of the oral cavity

Microscopic interpretation can be complicated by varied histomorphologic features as in amelanotic lesions, which are not uncommon. 36 The Fontana stain, dopa reaction, S-100 protein, and ultrastructural examination for the presence of premelanosomes and melanosomes may be helpful in establishing the diagnosis. 33 However, the presence of melanin and premelanosomes may occur in other tumors derived from the neural crest. Recently, antibody panels were found to be useful iri the diagnosis of mucosal melanomas even when enzyme histochemistry did not successfully support the diagnosis. 56

Prognosis Oral melanoma, with a median survival of 1 to 2 years after diagnosis, 6, 15, 52has a dismal prognosis in comparison with melanoma of the skin (Table II). Unfortunately, in many instances, there is a substantial delay in the diagnosis of oral melanoma. This may account for the high incidence of metastatic lesions detected at the time of diagnosis.la, 57, 58 In one group of 23 patients, a delay in diagnosis with a mean duration of 12 months occurred and more than 50% of patients had demonstrable metastases preoperatively. 6 Failure of patients to seek medical care was responsible for the delay observed in this study. However, physician error in recognizing oral malignant lesions is well documented.3,13, 59 Other factors contributing to the poor prognosis of oral melanoma include delayed development of symptoms and the difficulty of achieving wide radical excisions because of the anatomically imposed limitations of the oral cavity. 6~ In addition, the rich blood supply to the oral cavity may expedite hematogenous dissemination. 61 In seven of nine patients reviewed by Eneroth 6 and in six of seven patients studied by Ohya et al. 6z in whom radiographs were obtained on initial examination, bone destruction was already evident. This was associated with early hematogenous spread and decreased survival. 9

Therapy The treatment of choice for oral melanomas is radical surgery whenever feasible. 63, 64 Local recurrence of the primary tumor is common even when adequate surgical margins have been achieved. 65, 66 Prophylactic lymph node dissection in the absence of

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Table II. Prognosis of patients with oral melanoma Author(s}

Year

Chaudhry et at.z Trodahl and Sprague36 Eneroth 6 Liversedge~z Rapini et al.t

1958 1970 1975 197 5 1985

I No. of / Survivalrate r ($-~r) 24 29 19 64 101

13% 22% 16% 20% t3%

clinically involved lymph nodes is controversial. When the tumor exceeds 3 m m in thickness, radical neck dissection is preferred unless there is evidence of distant metastases. 14 Although oral melanomas are generally considered resistant to radiotherapy, 67-69 temporary regression of tumors treated with this modality has been reported. 3, 23, 62, 7o Postoperative irradiation is recommended when adequate surgical margins are unattainable; primary radiotherapy is an acceptable alternative to surgery in the elderly and medically compromised patients. 33 A wide variety of chemotherapeutic and immunotherapeutic regimens has been attempted with variable results, 7' 9, 71-73 but controlled studies are not available. Occasionally, patients have received limited benefit from repeated local measures such as cryotherapy, 74 electrodesiccation, 75 and conservative surgery. 76 Currently available therapy for oral melanomas is inadequate, further stressing the necessity of early diagnosis and prompt therapy at a potentially curable stage. ORAL NEVI Of all causes of intraoral pigmentation, oral nevi pose the greatest diagnostic challenge. 39 Intraoral nevi are rare; they occur in approximately 0.1% of the general population. 77 The total number of documented oral nevi in the literature now exceeds 200. The clinical significance of oral nevi lies in their predilection for the palate, a characteristic shared by oral melanomas. 78 Although oral nevi have been reported in all age groups, they are most frequently diagnosed during the third and fourth decades of life. 79 Clinically, more than 80% of intraoral nevi are less than 1 cm and almost half measure from 0.1 to 0.3 cm (Fig. 5). 8~ Approximately two thirds of nevi

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Fig. 5. Blue nevus of the hard palate, the most common location for this entity in the oral cavity. (Courtesy Dr, DeNs P. Lynch, The University of Texas Health Science Center, Houston, Tex.) Fig, 6. Well-circumscribed brown macule on lower lip characteristic of labial melanotic macule. Fig. 7. Amalgam tattoo of the buccal mucosa exhibits typical blue-gray pigmentation. Fig. 8. Kaposi's sarcoma of the hard palate in patient with AIDS. in the oral cavity are raised, a feature that aids in differentiating these from physiologic pigmentation, amalgam tattoos, and oral melanotic macules. 78 Approximately half of oral nevi are histologically of the intramucosal (intradermal) type and one third are common blue nevi. 31,78, 81 Junctional,SZ combined, s3 and congenital nevis4 have been reported infrequently. Oral nevi are typically pigmented and appear in shades of blue or black depending on the depth of the nevus cells. In the series of Buchner and Hansen, 78 13% of oral nevi were nonpigmented; most were of the intramucosal type. The potential for oral nevi to undergo malignant transformation has not been determined, yet the excision of a l l suspected oral nevi is justified for the following reasons 78, 80, 85, s6: (1) They cannot be clinically differentiated from other pigmented le-

sions including oral melanoma. (2) Oral nevi may represent precursor lesions of melanoma and may in some instances account for the pigmentation that commonly precedes the development of oral melanoma. This hypothesis is substantiated by the fact that the average age of patients at diagnosis of oral nevi is 20 years earlier than that of oral melanoma and that both occur most commonly on the palate. ORAL AND LABIAL MELANOTIC MACULES In 1976, Weathers et al. s7 originally described the "labial melanotic macule" and Page et al. ss subsequently described the "oral melanotic macule." These lesions are frequently encountered as dark spots on the lips and in the mouth and continue to be mistakenly diagnosed as lentigines or ephelides. Oral melanotic macule and labial melanotic macule are terms that now appear in standard oral pa-

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Melanoma and other pigmented lesions of the oral cavity

thology textbooks but have not been generally recognized by dermatologists, as evidenced by their scarcity in dermatologic journals and textbooks.89 Clinically, melanotic macules may be confused with oral melanomas. They are usually solitary, well circumscribed, black or brown macules that measure less than 1 cm (Fig. 6). These lesions are most commonly located on the vermilion border of the lower lip, followed by the gingiva, buccal mucosa, and palate. 9~ Approximately 80% occur in white persons. 9o Histologically, the oral and labial melanotic macules are similar. 91 Both are characterized by increased melanin in the basal cell layer, the lamina propria (mostly within melanophages), or in both locations. 9~ Sexton and Maize 91 reported an increased number of dendritic melanocytes along the basal cell layer in labial melanotic macules, but others have reported normal numbers of melanocytes. 87'89'90 In contrast to lentigines, melanotic macules do not exhibit elongation of rete ridges. The term melanotic macule of the oral mucosa encompasses a variety of clinical entities. Some labial melanotic macules are undoubtedly ephelides, because both are histologically identical, according to the majority of authors. 84' 89, 90 However, unlike ephelides, melanotic macules do not change in color in relation to sun exposure. 87 Although postinflammatory hyperpigmentation and melanotic macules are similar histologically, a history of trauma before the appearance of melanotic macules is rarely obtained, s9 Although some regard the oral and labial melanotic macules as distinct entities without cutaneous counterparts, histologically similar lesions have been reported on other mucosal and cutaneous surfaces. 92-95 Oral and labial melanotic macules are completely innocuous and have no malignant potential, 32,90 although many cannot be clinically differentiated from incipient melanomas and other causes of pigmentation. Some authors have recommended observation with frequent examinations for changes in color, size, or shape, 9~ whereas others have advocated excision.87, 88 For lesions on the palate, where oral melanomas are most prevalent, the decision to excise or subject to biopsy is well founded. AMALGAM TATTOOS Pigmented lesions of the oral cavity may commonly result from exogenous sources, as in the case

533

of amalgam tattoos. Blue-black discoloration of oral mucosa occurs during surgical or dental procedures when small amounts of filling material (amalgam) used in restorative dentistry are accidentally introduced into soft tissue. 96 Buchner and Hansen 97 reviewed the data on 268 amalgam tattoos and found almost half located on the gingiva and alveolar mucosa and more than 20% on the buccal mucosa. Clinically, amalgam tattoos are typically macular, asymptomatic, and range in size from 0.1 to 2.0 cm (Fig. 7). They appear blue, gray, or black depending on the depth at which the particles lodge.86 In most cases, amalgam pigmentation can be recognized clinically and the diagnosis supported by a dental history. Radiographically, amalgam tattoos may appear opaque, which confirms their diagnosis; however, this finding was present in only 10 of 37 cases in one series. 97 Histologically, amalgam may appear as discrete fine dark granules or as irregular solid fragments. Suspect lesions that are large, irregular, or of changing appearance cannot always be differentiated from other causes of oral pigmentation, including oral melanoma. In such instances, a biopsy should be performed to establish a definitive diagnosis. ORAL KAPOSI'S S A R C O M A

The cardinal features of the acquired immunodeficiency syndrome (AIDS) include opportunistic infections and the appearance of Kaposi's sarcoma. In contrast to the classic and African forms of Kaposi's sarcoma, intraoral involvement is frequent in AIDSrelated cases. 98 Kaposi's sarcoma has been reported to occur in approximately 20% to 30% of patients with AIDS99; in one study, oral involvement was present in 27 of 53 patients with AIDS-related Kaposi's sarcoma, loo The importance of recognizing these lesions is paramount because oral Kaposi's sarcoma may be the first sign of AIDS or may be clinically confused with oral tumors, including melanoma. In a series by Ficarra et al.] ~ the oral cavity was the initial site affected in 29 of 13 6 patients with Kaposi's sarcoma; oral lesions occurred concomitantly with skin lesions and/or visceral lesions in 45% of cases and after the appearance of skin lesions in one third. The frequency of Kaposi's sarcoma is highest in homosexual persons with a male/female ratio of

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20:1. t~ Oral Kaposi's sarcoma in intravenous drug users, kidney transplant patients, and other immunocompromised patients who do not have AIDS has been reported. 1~ 103 Clinically, oral tumors may appear as blue, red, or purple macules in the early stages and as darkly pigmented nodules and plaques in the advanced stages (Fig. 8). 1~ Tumors occur predominantly on the palate and gingiva, although any oral site may be involved. :05 Multiple lesions are commonly encountered and are a frequent source of pain and bleeding. Nonpigmented tumors of oral Kaposi's sarcoma and other atypical presentations have been reported. 1~ HistologicaUy, early macular lesions are composed of endothelium-lined vessels and late nodular lesions are dominated by spindle cells with interspersed blood-filled clefts. Recently, vascular origin of both endothelium-lined vessels and spindle cells has been demonstrated. 107 Treatment of intraoral Kaposi's sarcoma is aimed at alleviating pain, bleeding, and dysphagia. Commonly used therapeutic modalities include radiation, chemosurgery, laser, and surgical resection, l~ x09 ORAL MELANOACANTHOMA Intraoral melanoacanthomas are rare, with fewer than 25 eases reported in the literature. However, their clinical and histologic similarities to melanoma underscore their significance to clinicians and pathologists. Almost allcases have occurred in blacks at a mean age of 26 years (range 9 to 4 3 years ). l L0Females are three times as likely to be affected as males. Clinically, oral melanoacanthomas appear as darkly pigmented, unilateral, sharply demarcated patches or plaques with a rough irregular surface. 11~ Nodular as well as bilateral and diffuse lesions are rare variants. 1~1 In all cases, a biopsy is necessary to differentiate these lesions from melanoma and other causes of oral pigmentation. The cause of oral mdanoacanthomas is unknown; however, they are thought to represent a reactive phenomenon.ll0,111 This is supported by the location of the majority of lesions in areas subjected to oral trauma such as the buccal and labial mucosa as well as their sudden appearance varying from weeks to months. 11~ 111 Furthermore, many, but not all, cases have regressed after removal of irritants or performance of biopsy.112, 113There is no evidence to suggest that melanoacanthomas transform into melanomas.

Histologically, underlying a hyperplastic mucous membrane, numerous large dendritic melanocytes are uniformly distributed through all layers of the epithelium. 1~4 Melanoacanthomas exhibit no nuclear pleomorphism or mitoses. It is imperative to differentiate histologically oral melanoacanthomas from other entities that have been reported to be colonized with dendritic melanocytes. For instance, in acral lentiginous melanomas, dendritic melanocytes are eytoIogicalIy atypical and are grouped only at the base of the epithelium.115 Squamous cell carcinomas, t t5 salivary gland tumors, 116 and nevocellular nevi115 are entities reported to contain dendritic melanocytes, thereby necessitating careful differentiation. CONCLUSION The incidence of malignant melanoma has dramatically increased in the past decade. 116 Dermatologists have succeeded in raising public awareness of melanoma partly by promoting melanoma education to other physicians and the public.t17 Early detection and diagnosis of these tumors have resuited in fewer deaths. 118 Unfortunately, melanoma of the oral cavity has received little attention. The annual National Melanoma/Skin Cancer Prevention Campaign, sponsored and promoted by the American Academy of Dermatology, involves dermatologists performing complete skin examinations. The oral cavity screen, however, is excluded from this program. J19 Irorfitally, oral melanoma, a cancer that exhibits a detectable radial growth phase, is extremely conducive to visual screening. Visual inspection of the oral cavity, especially the hard palate where most melanomas are found, is rapid, painless, and noninvasive, and readily doable by dermatologists without dentistry training. As the concept of the dermatologic standard of care expands to include entire skin examinations for new patients presenting with a localized chief complaint 120.t~t it may be advisable to incorporate a thorough oral cavity screening into this practice. Dermatologists should share responsibility with otolaryngotogists, dentists, and other oral health care providers in identifying thin oral melanomas. All pigmented lesions of the oral cavity should be viewed with suspicion. Those that possess clinical features suggestive of melanoma or that lack an obvious cause must be subjected to biopsy. If the prognosis for patients with oral melanoma is to improve,

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Melanoma and other pigmented lesions of the oral cavity 535

early detection and p r o m p t surgical attention to these aggressive tumors must be achieved. REFERENCES

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