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Vol. 96 No. 4 October 2003

ORAL MEDICINE

Intraoral melanoma: Long-term follow-up and implication fordental clinicians. A case report and literature reviewGao Man Gu, DDS, PhD,a Joel B. Epstein, DMD, MSD, FRCD(C),b and Thomas H. MortonJr., DDS, MSD,c Seattle, Wash, and Chicago, IllUNIVERSITY OF WASHINGTON AND UNIVERSITY OF ILLINOIS AT CHICAGO

Primary intraoral melanoma is a rare neoplasm with a poor prognosis, accounting for 1% to 8% of allmelanoma in Europe and the United States. The incidence (12%) and 5-year survival rate (17.4%) are higher in Japan.We report a case of oral lentiginous melanoma in a Japanese-American man who survived disease-free for more than5 years after surgery, radiation therapy, and chemotherapy but developed chronic mucositis of the palate under thedenture in the primary radiated field. This lesion responded to antifungal therapy. Subsequent multiple biopsies ruledout the recurrence of melanoma but demonstrated prolonged melanocytic hyperplasia and focal epithelial atypia. Wereviewed clinical differences in oral melanoma reported in the United States and Japanese literature, and describe thewide variety of oral clinical features of postoperative radiation and chemotherapy, as well as the oral tissue changescaused by denture-induced mucositis and candidiasis in such patients. Dental clinicians should conduct a thoroughhead, neck, and oral follow-up with increased vigilance in patients with a history of prior cancer. (Oral Surg OralMed Oral Pathol Oral Radiol Endod 2003;96:404-13)

Malignant melanoma is the fifth most frequently occur-ring cancer in the United States, with a more rapidlyincreasing incidence than any other cancer despite im-proved prevention and early diagnosis of precursormelanocytic lesions. Cases of cutaneous melanomahave been increasing by 4% to 6% per year since 1973,with an incidence of 1 in every 250 US citizens by1980,1 1 in 150 by 1985,2 1 in 84 by 1997,3 and 1 in 75by 2000.4 However, primary melanoma of the oralcavity is a rare malignancy, accounting for 0.2% to 8%of all melanomas in Europe and the United States5-8

and 0.5% of all oral malignancies.9 Oral melanomaoccurs slightly more often in males (2.8:1 male-to-female ratio), and the age range is from 20 to 83 years

with an average age of 56 years.10 In a study by Rapiniet al,6 58% of 386 patients were males. Black Africans,Asians,11 Native Americans,12 and Hispanics13 aremore commonly affected. The most common site fororal melanoma is the palate (32%), followed by themaxillary gingiva (16%); other common sites are themandibular gingiva (7%), buccal mucosa (7%), lips(7%), and alveolar gingiva (5%).4

The etiologic factors for oral melanoma have notbeen studied extensively, although factors such as to-bacco use and formaldehyde exposure have been im-plicated.14 However, several etiologic factors havebeen associated with cutaneous melanoma, includingsun exposure, inability to tan, and the presence orabsence of dysplastic nevi. Familial history, syndromes(such as familial atypical mole and melanoma syn-drome), melanoma-related antigens (such as humanleukocyte antigen [HLA] restricted antigen), growthfactors and proliferation factors (such as bcl-2 andKi-67), and cytogenetic defects (such as CMM1, 2, and3 in chromosome 1, 6, 7, and 9, and mutated tumorsuppressor gene products p161NK4a and p19ARF) alsoinfluence tumor formation.4 The importance of tumorsuppressor gene mutation and growth factor dysregula-tion in melanoma transformation has been illustrated by

aResident, Department of Oral Medicine, School of Dentistry, Uni-versity of Washington, Seattle.bProfessor, Department of Oral Medicine and Diagnostic Sciences,College of Dentistry, University of Illinois at Chicago, Chicago.cProfessor, Department of Oral Biology, School of Dentistry, Uni-versity of Washington, Seattle.Received for publication Nov 18, 2002 ; returned for revision Feb 19,2003; accepted for publication Apr 28, 2003.© 2003, Mosby, Inc. All rights reserved.1079-2104/2003/$30.00 � 0doi:10.1016/S1079-2104(03)00320-2

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cell culture studies comparing melanocytes, nevuscells, and melanoma cells. The majority of melanomacells have the ability to invade agar gelatin, whereasless than 0.1% of melanocytes and nevus cells invadeagar gelatin. These discrepant findings between mela-noma cells and melanocytes and nevus cells may beascribed to the effects of mutated tumor suppressorgenes and other mutated growth and proliferation fac-tors.15,16

The presentation of oral melanoma varies. One thirdof the patients are asymptomatic at diagnosis. Thelesions may be incidentally observed by the patient orthe dentist.17 This tumor may present itself in 2 differ-ent patterns. In the first, there is a rapid appearance andenlargement of a pigmented lesion, whereas in thesecond, the tumor is preceded by a pigmented area fora variable period.18

There are 3 growth phases: (1) a macular phaseconsisting of proliferation of dendritic melanocyteswithout apparent atypia and with simple hyperpigmen-tation in the basal cell layer and melanin incontinence;(2) a pigmented plaque phase consisting of preinvasivetumor cell nests in the lower epithelial layers; and (3) anodular phase consisting of spindle-shaped or epithe-lioid tumor cells in the submucosa.19 The histopatho-logic classification of oral melanoma, however, doesnot fit well into specific cutaneous melanoma catego-ries, although some have linked oral melanoma to acrallentiginous and nodular melanomas. A nomenclaturewas proposed at the 1995 WESTOP Banff Workshop toclassify oral melanoma by histologic pattern as in situ,invasive, and combined in situ and invasive.10

The diagnosis of this neoplasm is not well estab-lished because of the rarity of oral melanoma. Previous

Fig 1. Incisional biopsy (04/1997) of asymptomatic pigmented lesion from hard palate was diagnosed as dysplastic lentiginousnevus, junctional type, with marked cytologic and architectural melanocytic atypia (A, hematoxylin-eosin, �100; B, hematoxylin-eosin, �200; and C, hematoxylin-eosin, �400). The lesion extended to the lateral surgical margins.

Gu, Epstein, and Morton 405ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGYVolume 96, Number 4

criteria for the diagnosis of primary oral melanoma weredescribed by Greene et al20 and included (1) demon-stration of melanoma in the mucosa; (2) presence ofjunctional activity; and (3) inability to demonstrateextraoral primary melanoma. Now cytogenetic and mo-lecular analyses have provided considerable insight intothe pathogenesis of melanoma and have facilitated di-agnosis. S-100 protein, HMB-45, NKI/C3, HLA-DR,PCNA, and cytokeratin (AE1/AE3) are demonstrated tobe the more sensitive markers in the diagnosis of oralmelanoma.21,22

The current treatment approach for oral melanoma issurgery and chemotherapy with or without immuno-therapy or radiation therapy. Although complete re-moval of the lesion is recommended, adjacent anatomymay make it impossible to resect widely, and incom-plete resection may contribute to the recurrence or

metastasis of the tumor and poor prognosis. Therapeu-tic neck dissections are recommended for patients withclinically palpable regional lymph nodes.3 Chemother-apy may be used to reduce the size of the tumorpreoperatively and to improve surgical management.The first line of chemotherapeutic agents are dime-thyltriazeno imidazole carboxamide alone11,23 or incombination with vincristine or dactinomycin.24 Immu-notherapy is based on the possession of specific mela-noma-related antigens. Immunotherapeutic drugs in-clude interferon (INF)-�,25 interleukin 2, andintralesional lymphokines.26 The use of INF-� andcimetidine in combination is believed to activate killerT-cells and inhibit suppressor T-cells, resulting in areduction of the size of the melanoma.11 Malignantmelanoma may be resistant to radiation, which is usedonly for adjunctive treatment when adequate margins

Fig 2. Excisional biopsy (05/1997) of the previous biopsy site was diagnosed as malignant melanoma, lentiginous type, Breslow’sthickness equivalent 1.1 mm, with low-to-moderate mitotic activity (A, hematoxylin-eosin, �100; B, hematoxylin-eosin, �200;and C, hematoxylin-eosin, �400). The tumor extended to the lateral margins.

406 Gu, Epstein, and Morton ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGYOctober 2003

are not obtained at surgery, and not as a single modal-ity.11,27

Oral melanoma is an aggressive malignancy with apoor prognosis because most lesions are locally inva-sive and may involve underlying bone or metastasize.The most common sites of metastasis are lymph nodes,lung, and liver.28,29 The overall 5-year survival rate is18% and 11% for gingival and palatal tumors respec-tively, with a 15% rate for all oral sites. Median sur-vival is 18 months with lymph node involvement and46 months when there is no evidence of lymph nodeinvolvement. The poor prognosis may relate to theincreased tumor thickness (�4 mm) and the amount ofvertical growth phase of the tumor at diagnosis.10,30,31

The rich vascular supply in the oral cavity may alsocontribute to dissemination of the melanoma. Immuno-

histochemically, the presence of pRb2/p13032 and thestaining intensity of S-10033 correlates inversely withthe survival of patients with oral melanoma.

CASE REPORT

Biopsy and surgeryA dentist found an irregular dark lesion on the hard palate

of his patient, a 54-year-old Japanese-American man, in Feb-ruary 1997. The diagnosis of an incisional biopsy (April1997) was dysplastic nevus (lentiginous nevus, junctionaltype) with marked cytologic melanocytic atypia (Fig 1). Be-cause the nevus extended to lateral surgical margins, anexcision of the entire pigmented lesion was performed (May1997) and the biopsy was diagnosed as mucosal melanoma,lentiginous type (Fig 2), with Breslow’s thickness equivalentto 1.1 mm and melanocytic tumor cells extending to the

Fig 3. Second excisional biopsy (06/1997) of residual melanoma of hard palate further demonstrated residual melanoma in situ.A (hematoxylin-eosin, �100) and B (hematoxylin-eosin, �200), Tumor cells within the epithelium forming nests. C (hematox-ylin-eosin, �400), Tumor cells with evidence of pleomorphic, hyperchromatic nuclei, mitotic activity, and melanin within theepithelium.


lateral margin of the excision. A subsequent re-excision of theresidual tumor (June 1997) confirmed residual malignant mel-anoma in situ, lentiginous type, with tumor extending close tothe posterior margin (0.1 mm) (Fig 3).

Radiotherapy and chemotherapyAfter surgery, the patient completed an initial 1-month

subcutaneous INF-� therapy with a high-dose regimen of 5million units/m2, 3 times a week, followed by hypofraction-ated photon radiotherapy (3000 cGy over 2.5 weeks in 5fractions) and then additional INF-� chemotherapy—5 mil-lion units/m2 for the first 5 months, reduced to 2.5 millionunits/m2 for the next 7 months because of the severe fatigue,weight loss, and depression that was related to the INF-�.

Oral findingsAfter the completion of chemotherapy (August 1998), a 3

� 3-mm area of hyperpigmentation posterior to the resection

site on the soft palate was noted. In May 1999, all residualmaxillary teeth were extracted because of severe generalizedperiodontal disease. At that time, a biopsy of the residualpigmented lesion was performed and melanocytic hyperplasiawas diagnosed; there was no evidence of melanoma (Fig 4).The patient received an immediate upper complete dentureafter extraction, and it was relined 3 months later (August1999). Because this denture did not have good retention, apermanent complete denture was constructed in January2000.

In September 2000, the patient reported irritation of thepalatal mucosa from his upper denture. Upon examination, asuperficial erosion of the hard palate was seen. Vitamin E 500IU twice a day and Trental 400 mg twice a day were pre-scribed, but the patient’s lesion did not respond to the med-ication. By July 2001, hyperpigmentation on the palate wasnot clinically present, but erythema of the palate persisted.

The patient was referred to the Department of Oral Medi-

Fig 4. Excisional biopsy of residual pigmented area 2 years after initial surgery (05/1999) resulted in a diagnosis of atypicalintraepithelial melanocytic hyperplasia. Pleomorphic and hyperchromatic nuclei, and mitotic figures were observed in the basallayer with melanin incontinence into the connective tissues (A, hematoxylin-eosin, �100; B, hematoxylin-eosin, �200; and C,hematoxylin-eosin, �400).


cine at the University of Washington (October 2001) formanagement of the erythematous changes. Other than thehistory of melanoma, the health history was noncontributory.The patient had never smoked but imbibed 2 cups of sakedaily. He denied a family history of melanoma.

Oral examination revealed a 2.5 � 1.5-cm area of erythemawith superficial erosion on the anterior hard palate (Fig 5).The palatal mucosa was not elevated. No clinically visiblebrown or black pigmentation was noted. The upper denturehad limited retention because of the atrophic posterior max-illary ridge. Saliva volumes were within normal limits (WRS:4.21g/5 min, WSS: 6.11g/5 min). No lymphadenopathy ormasses were identified in the submandibular, cervical, andsupraclavicular regions.

These initial findings were consistent with local tissueirritation in a field of past radiation therapy and with thepossibility of candidiasis. An oral culture was completed torule out fungal infection. In the meantime, patient was startedon antimicrobial treatments of Diflucan (by mouth 100 mg/day), a topical antifungal for the denture surface, and chlo-rhexidine rinse solution. At a 2-week follow-up visit, dra-matic reduction in tissue erythema and swelling was noted.The patient was asked to continue the Diflucan for another 2weeks; after that time he returned with subjective and clinicalimprovement (including the change from positive to negativefor culture results for Candida) that confirmed the clinicaldiagnosis of chronic erythematous and hyperplastic candidi-asis.

A 4-mm punch biopsy was conducted in November 2001because of persistent tissue erythema in the anterior palate;histopathologic examination ruled out the recurrence of mel-anoma but epithelia atypia was reported (Fig 6). Continuedsystemic antifungal regimen and palliative therapies for thefollowing 6 months failed to eliminate the palatal erythemacompletely, although the intensity of erythema had beenreduced.

The patient was followed up by his prosthodontist at3-month intervals for 3 years for both the erythematousmucosa under the denture and the denture retention. Thedenture he received in 2000 did not resolve the limiteddenture retention, and he used denture adhesive to help withthe retention.

A 4-mm punch biopsy was performed (April 2002) in anerythematous area of the anterior palate to assess for atypia orrecurrent melanoma. It showed atypical epithelial changeswith increased inflammation without evidence of melanoma(Fig 7). It was also negative for HMB45/50 and Melan-A, butimmunohistochemistry showed it S100-positive for dendriticcells. Systemic antifungal therapy was discontinued becausein both biopsies (November 2001 and April 2002) specificstains for fungus were negative. However, the patient contin-ued to be managed by topical antimicrobial agents and re-ceived regular care from the prosthodontist for the manage-ment of clinical erythema associated with the denture.

DISCUSSIONOral malignant melanoma is more prevalent in Japan

than in the United States and accounts for11% to12.4%of all malignant cancers, 7.5% of all malignant mela-noma, and 34.4% of all mucosal melanoma (Table). 7,34

The survival rate is also higher in Japan, with a 3-yearsurvival rate of 46.6% and a 5-year survival rate of16.6%.35 Many of the clinical features of the currentcase, including age, sex, site, race, and survival mirrorthe clinical presentation described in the literature.

Our patient’s original lesion had been managed sur-gically followed by radiotherapy and chemotherapywith 5 years of disease-free survival. However, closefollow-up and multiple biopsies were conducted be-cause of the risk of recurrence of melanoma indicated

Fig 5. Clinical presentation of palatal erythema when the patient was referred to the Department of Oral Medicine (10/2001).Irregular and extensive erythema with superficial erosion on anterior hard palate and right alveolar ridge.


by persistent mucosal erythema and the risk of progres-sion of his melanocytic hyperplasia and epithelialatypia. Melanocytic hyperplasia may be seen in inflam-matory or reactive epithelial hyperplasia (tobacco ker-atosis, denture irritation hyperplasia,and other chronictraumatic irritations) with or without cytologic atypia ordysplasia. In this patient, there was cytologic evidenceof epithelial atypia in subsequent biopsies. Thesechanges included large, pleomorphic and hyperchro-matic nuclei with mitotic activity in the basal layer(Figs 4, 6, and 7). Atypical epithelial changes mayrepresent early epithelial dysplasia, and atypical mela-nocytic hyperplasia may represent a precursor lesion to

melanoma or an indication of increased risk for devel-oping mucosal melanoma at other sites.4

Oral mucositis occurs in almost all patients withchemotherapy and radiotherapy for head and neck can-cers. The onset, intensity, and duration of mucositisdepend on accumulative dose, dose intensity, radiationfield size, fractionation schedules, smoking, alcoholconsumption habits, and infection.36 The pathogenesiscan be attributed to direct mucosal toxicity of cytotoxicagents and ionizing radiation and to indirect mucosaldamage caused by a concomitant inflammatory reactionexacerbated by the emergence of bacteria (gram-negative bacilli) and mycotic, fungal (Candida spe-

Fig 6. Incisional biopsy 4.5 years after initial surgery (11/2001). A, After a 5-week topical and systemic antifungal treatment,intensity of erythema remarkable reduced, with residual late radiation changes visible. A 4-mm punch biopsy from the residualerythema was performed to rule out the recurrence of malignant melanoma. B (hematoxylin-eosin, �200) and C (hematoxylin-eosin, �400), The diagnosis was mild epithelial atypia with acute and chronic mucositis. There was no evidence of recurrentmelanoma but there were large polymorphic and hyperchromatic nuclei, mitotic figures, and loss of cohesion within basal andparabasal layers. The underlying fibrous connective tissue was infiltrated by lymphocytes, plasma cells, a few eosinophils, and afew neutrophils. Some of the inflammatory cells extended into the epithelium.


cies), and viral infections of the damaged mucosa. Thepathologic process has (1) an initial inflammatory/vas-cular phase, in which proinflammatory cytokines arereleased; (2) an ulcerative/bacteriological phase, result-ing from the epithelial breakdown; and (3) a healingphase.37 In a standard 200 cGy daily protocol, mucosalerythema occurs within the first week, with mucositispeaking during the fourth to fifth week of therapy.These lesions heal within several weeks but may bepresent for up to several months, depending upon epi-thelial proliferation rate, hematopoietic recovery, re-establishment of the local microbial flora, and the ab-

sence of factors interfering with wound healing, such asinfection and mechanical irritation.38 However, the ef-fects of radiotherapy upon epithelial cells can be furtherenhanced by connective tissue damage.39

This patient received a total of 3000 cGy in 5 frac-tions within a 2.5-week period. This dose intensity of600 cGy/time may have resulted in severe damage ofthe epithelium and connective tissue, therefore delayinghealing. Vitamin E and Trental were applied with thegoal of improving the healing of the erosion by anti-oxidant and membrane stabilization, thus interferingwith the inflammatory damage caused by reactive ox-

Fig 7. Incisional biopsy 5 years after initial surgery (4/2002). A, Palliative therapies failed to eliminate the palatal erythema,although the overall intensity of erythema was clinically reduced. A 4-mm punch biopsy from an area of the erythema of theanterior hard palate was performed to assess any change in epithelial atypia. B (hematoxylin-eosin, �200) and C (hematoxylin-eosin, �400), The diagnosis was focal and mild epithelial atypia with chronic inflammation. The atypical epithelial changes werefewer than in previous biopsy. However, the underlying fibrous connective tissue contained a band-like infiltrate of lymphocytesand plasma cells.


ygen species and free radicals created in the course ofradiotherapy or chemotherapy,37 On the other hand, thepatient’s excellent salivary flow rate suggests that hissalivary gland function was not compromised by radio-therapy. His chronic mucositis could also be associatedwith the toxicity of his 1-year high-dose INF-� chemo-therapy. Prolonged or repetitive administration of cy-totoxic agents, as compared with bolus infusions, hasbeen associated with an increased risk for the develop-ment of oral mucositis. The toxicity of radiation ther-apy increases with prior or concurrent administration ofchemotherapeutic agents.40 Fatigue and weight losswere 2 other complications of INF-� chemotherapy forthis patient. Fatigue and weight loss have been shownin more than 70% of patients on IFN-�, and may alsobe associated with psychological and neuromuscularcomponents.41,42 Depression is generally categorized asa neuropsychiatric condition, which can occur in che-motherapy patients without predisposing factors or pasthistory of psychiatric problems.25

Other contributing factors in the chronic inflamma-tory changes may include irritation resulting from ill-fitting dentures, daily use of alcohol (sake), and sec-ondary fungal infection of the irradiated denture-bearing mucosa. Candidiasis is one of the mostcommon complications of chemotherapy and radiother-apy.43 In clinical terms, oral candidiasis is most oftencharacterized by pseudomembranes or erythema. In thiscase, the erythematous and inflammatory changes mayhave been initiated by the tumor therapies and compli-cated by local irritation. The complexity of chemother-apy- and radiotherapy-induced mucositis as a biologicalprocess suggests that this condition represents a se-quential interaction among oral mucosal cells and tis-sues, pro-inflammatory cytokines, and local factorssuch as mechanical irritation and oral microbiota.

A long-term follow-up and oral care regimen cannotbe overly emphasized to clinicians responsible for pa-tients experiencing mucositis as a sequela of cancertherapy. Oral care protocols must be developed to meetthe needs of patients and must be conducted by multi-disciplinary teams (including dentists, oncologists, ra-diotherapists, oral medicine specialists, and prosth-

odontists). An effective oral hygiene program, denturecare, the avoiding of alcohol, and appropriate antimi-crobial therapy are essential for the reduction of chronicoral mucositis in edentulous patients receiving tumori-cidal radiotherapy to the head and neck regions.Chronic mucositis may be associated with melanocytichyperplasia and epithelial atypia, and must be differen-tiated from the cytologic features of early melanoma orepithelial dysplasia. For patients experiencing chronicmucositis from oral cancer treatment, periodic biopsiesand resultant histopathologic findings may help to de-termine the appropriate treatment and prognosis.

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Table. Comparison of oral melanoma between US and Japanese patients

USA4 Japanese19

Incidence 0.2–8.0% 11–12.4%1%–8% of all malignant melanoma 7.5% of all malignant melanoma

Age 22–83 years, average of 56 years 32–82 years, average of 61 yearsSex M � F (2.8:1) F � M (4:10)Location Palate, maxillary gingiva Palate, maxillary gingiva3-year survival rate 46% 79.5% (cumulative), 46.6% (Kaplan-Meir)5-year survival rate 15% 63.6% (cumulative), 16.6% (Kaplan-Meir)


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Reprint requests:

Gao Man GuDepartment of Oral MedicineUniversity of Washington1959 Pacific StSeattle, WA [email protected]


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