Melanoma arising from the mucosal surfaces of the head and neck

Melanoma arising from the mucosal surfaces of the head and neck Meir Gorsky, DMD, a and Joel B. Epstein, DMD, MSD, b Vancouver, British Columbia, and Tel Aviv, Israel BRITISHCOLUMBIACANCERAGENCY,VANCOUVERHOSPITAL,UNIVERSITYOF BRITISHCOLUMBIA,AND TEL AVIVUNIVERSITY Oral mucosal malignant melanoma is a rare disease. We reviewed 30 years of data from a tumor registry and identified 65 patients who had head and neck melanomas. Two thirds (43) of the 65 patients were identified as male, with the mean age in the sixth decade. Of the 65 patients, only 6 had melanoma that arose from the oropharyngeal mucosa. Of the lesions involving the oral mucosa, each lesion manifested itself as a mass or was associated with symptoms of discomfort; only one third (2) of the lesions were pigmented. The clinician must carefully examine the head, neck, and oral cavity, and any pigmented lesion that is not recognized as a specific entity, such as amalgam tattoo, should be biopsied. The more common presentation of amelanotic malignant melanoma requires a high index of suspicion for masses identified in the mouth and requires biopsy for definitive diagnosis. The prognosis for oral mucosal malignant melanoma is poor. (Oral Surg Oral Med

Oral Pathol Oral Radiol Endod 1998;86:715-9)

Oral cancer accounts for approximately 3.5% of all human cancers, of which approximately 96% are carcinoma. Malignant melanoma (MM) that does not originate in the skin is a very rare tumor and is considered one of the most deadly of all human neoplasms. In searching the English literature of the last 15 years for head and neck melanomas, we found very few articles that describe case series limited to mucosa of the head and neck region. Hormia and Vuori 1 reported that mucosal melanomas represent only 0.009% of all malignant tumors in Finland. Others 2 report that only 6.3% of all melanomas in the head and neck region are of mucosal origin. According to Moore and Martin, 2 mucosal melanomas in the nasal and oral cavity account for only about 1.7% of all melanomas. Another study demonstrated that oral melanomas are very rare, accounting for only 1.6% of 7500 melanomas reported) Racial, cultural, or geographic factors may predispose subjects to the disease.4, 5 The mean age at diagnosis of patients with oral melanoma is 55 years (range, 40-70 years). 6 A recent literature review and description of 14 cases of mucosal melanoma of the head and neck 7 identified a total of approximately 1000 cases of head and neck melanoma. 7 Of 14 new cases aMaurice and GabrielaGoldschlegerSchool of Dental Medicine, Tel Aviv University. bBritish Columbia Cancer Agency, VancouverHospital, University of British Columbia. Received for publicationApr. 30, 1998; returned for revisionJune 8, 1998; acceptedfor publication July 22, 1998. Copyright © 1998 by Mosby, Inc. 1079-2104/98/$5.00 + 0 7/14/93890

reported, only 1 occurred in the oral mucosa. A high predilection was found for the palate and the maxillary gingiva, with 77% of the cases reported in those sites.3, 7 The oral cavity may be a site of predilection for melanomas in Japanese persons,4, 5 although it is very rare in the white population. 8 Melanoma of the skin is a neoplasm of dermal melanocytes, and its etiologic character is strongly related to sun exposure. Great progress has occurred in the management of skin melanomas in the last 3 decades, resulting in improved prognosis. 9 However, despite aggressive therapy in cases of mucosal melanoma, the prognosis remains poor. On review of the approximately 1000 cases reported, it was found that the 5-year survival rate was 17% and the 10-year survival rate was 5%. 7 The prognosis of oral melanoma is at least partially related to the time of detection of a suspected lesion) Buchner and Hansen 10 stressed that histologic diagnosis is required for most of the pigmented lesions in the mouth. The radial growth phase of the oral melanoma, which often lasts for an extended time before invasion of the tumor takes place, may serve as a guide for suspicion and may allow for earlier diagnosis of oral melanomas. 11 At a workshop recently held in Canada, I2 only 50 primary oral melanomas were retrieved from a biopsy service pool of a total of 712,000 oral biopsies from 14 institutes. These 50 biopsies account for a prevalence of 0.007%. The gender distribution was 74% male and 26% female, with a mean age of 56 years at diagnosis; 68% of the oral lesions were located in the palate and upper gingiva. A similar predilection for melanoma

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ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY December 1998

Table I. 66 patients with mucosal melanoma of head

that mucosal MM of the palatal-suprapalatal regions was twice as common in men as in women. Table III shows the profile of the patients whose sites of involvement were those under the direct responsibility of the dental professional. The palate and upper gingiva were involved in 4 patients (67%), 3 (75%) of whom were men. The mean age at diagnosis was 73.7 years, and the most prevalent clinical presentation was a mass. The existence of any pigmentation at the time of diagnosis was reported in only one third of the intraoral sites, all in the palate. The mean follow-up period for the oral melanoma patients was 5.6 years; followup time ranged from 2 months to 23 years. Four patients (67%) died within a mean of 7 years. One patient (patient 4) was alive for 23 years with multiple recurrences that were treated by surgery, radiation, and chemotherapy. If this patient were excluded from the calculation, the mean survival time would be 2 years. Only 1 patient with oral melanoma survived for more than 5 years, with multiple recurrences successfully controlled.

and neck Site

Gender M F

Non-oral Oral Totals

38 5 43

21 1 22

Age at diagnosis (y) Mean Range 65.8 73.7 66.5

23-92 59-90 23-92

Survival (y) 5 7 >10 8 2 10

5 1 6

3 1 4

M, Male; F, female.

occurrence in the palate and upper gingiva has been reported in the literature. 7 The aim of this article was to evaluate the prevalence of noncutaneous MMs of the head and neck in British Columbia (BC), with an emphasis on the clinical manifestations of melanomas that involve the oral cavity.

MATERIAL AND METHODS A total of 65 cases of melanomas of the head and neck were identified from the Tumor Registry and the computer files of the British Columbia Cancer Agency for the period from January 1969 through March 1997. The database was searched for melanoma involving the following regions: lip, oral cavity, salivary glands, pharynx, nasal cavity, and paranasal sinuses. The medical charts of 5 of the 6 oral melanoma cases were available, and the data were analyzed separately.

RESULTS The profile of the 65 patients (43 men and 22 women) with mucosal head and neck melanomas are presented in Table I. The mean age at diagnosis was 66.5 years; however, the mean age of patients with oral melanomas (73.7 years) was greater than the mean age of patients with melanomas in other head and neck sites (65.8 years). Only 10 patients (15.4%) survived for 5 years. Forty percent died within 2 years of diagnosis, and only 6% survived for more than 10 years. Information regarding ethnic origin was available for only 50% of the group. Ninety-four percent of these patients were Caucasian; 6% of the group originated in Asia. A total of 65 cases of mucosal melanoma that involved head and neck sites were studied (Table II). We found that in most of the patients (61; 93.8%) the palatal and suprapalatal (nasal) regions were involved. The leading site for head and neck mucosal melanoma was the nasal cavity, where the tumor was detected in 42 patients (64.6%); this was followed by the sinuses (14 patients; 21.5%) and the palate (3 patients; 4.6%). When the gender-site relation was studied, we found

DISCUSSION Approximately 450 cases of head and neck cancer are diagnosed in BC each year, which accounts for 3.2% of all cancers diagnosed in the province. MM of the head and neck accounts for 0.45% of total head and neck cancers in BC, and intraoral melanoma accounts for only 0.72 % of all oral cancers. The rate of new cases of MM in BC is approximately 0.56 per 100,000 persons. MM of the skin, which is highly linked to sun exposure, is a deadly disease. Sixty-five percent of the deaths casued by skin cancer are attributed to melanoma.13 A genetic component of this disease was demonstrated in family members with dysplastic nevus syndrome, in whom the risk was almost 17 times higher than in a control Caucasian population) 4 Depth of invasion and lymph node involvement are major criteria in the prognosis, whereas anatomic location is not. Fischer 15 studied 887 patients with head and neck cutaneous melanomas and found that indicators of poor prognosis include old age, male gender, large size, and nodular growth pattern. Unfortunately, research related to oral melanoma is limited, inasmuch as this disease is rare and there is a lack of large series of cases with long follow-up. The lack of research limits sources of information primarily to case reports. Mucosal melanoma occurs mainly between the fourth and seventh decades and most frequently in persons 50 to 60 years old. 7,16,17 It is not clear whether there is a higher prevalence in

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males.7,16,18 Conley 18 reported more men with mucosal melanoma (57%) than women with the condition (43%). We also found, consistent with findings in some of the literature, that there were more men (66%) than women and that the mean age was in the sixth decade. The poor prognosis of this disease has been reported in earlier studies. 7,18,19 We found that the 5-year survival rate was only 15% and that only 6% of patients survived for 10 years. The nasal cavity, paranasal sinuses, and oral cavity are the major sites for mucosal melanoma.7,19 Oral involvement is rare. In one study, 49% of melanomas of the mucosal membranes of the head and neck were detected in the oral cavity) 8 In another study, 17 oral involvement was described in 37% of 38 mucosal melanomas, and 4 (21%) of these had regional lymph node involvement at diagnosis. The palatal and suprapalatal region were the most common sites in our current study; only 6% of the mucosal melanoma lesions were other than paranasaly located. Other studies have shown similar site distribution in the head and neck.7,16, 2° We found that of the 6 oropharyngeal melanomas, 67% were in the palate and upper gingiva and only 33% included pigmentation. The first oral symptoms identified by Berthelsen et a117 were those of asymptomatic swelling and bleeding. Only 2 patients (14%) had pain, and pigmentation was observed in only 4 patients (29%). In 9 (64%) of the oral melanomas the tumor was located in the palate. 17 Because most of the mucosal melanotic lesions are painless in their early stages, the diagnosis is unfortunately often delayed until symptoms resulting from ulceration, growth, and/or bleeding are noted. 7 Because of the possibility of the development of oral melanoma within pigmented areas, 7a9 such areas should be biopsied. The oral lesions in our group were most frequently diagnosed after identification of a mass; only 40% of the patients complained of pain or discomfort. In clinical appearance, most of these lesions were described as nonpigmented, and they were diagnosed after discovery of a mass. Others have reported that pigmentation is present only in approximately one third of patients. 7,17 Biopsies should be performed on all pigmented lesions not consistent with amalgam tattoo or physiologic pigmentation that recently occurred or that are Suspected of undergoing changes in their clinical appearance. Though it has been mentioned that incisional biopsy may negatively affect the prognosis, it has also been stated that biopsy of melanoma does not increase the risk of metastasis and does not affect the prognosis. 21 Certainly biopsy is

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Table II. Sites involved with mucosal melanoma in 65 patients Site Non-oral Nasal cavity Sinuses Parotid Other Oral Palate U p p e r gingiva Tonsils

Male

Female

30 7 I --

12 7 1 1*

2 1 2

1 --

*Nasopharynx.

essential in suspected lesions and should not be delayed. Early detection of MM is further complicated when the lesion is not pigmented (amelanotic), which in some series is true of most of the lesions subsequently diagnosed as melanoma. In our oral cases, two thirds of the lesions were nonpigmented and all were palatal tumors. The presence of amelanotic melanoma makes diagnosis more difficult, inasmuch as most clinicians may consider melanoma only when confronted with a pigmented lesion. Therefore, any growing lesion, pigmented or nonpigmented, requires that a diagnosis be made, and it should be biopsied without delay. It may be appropriate to excise small masses, but large lesions should be sampled with incisional techniques. The prognosis of the mucosal melanoma is not influenced by the size of the primary lesion. Local multiple recurrences are the most common cause of failure, and recurrences are common even after long disease-free periods. 7 Therefore, even 5-year survival may not represent cure. However, the 5~year survival rate for mucosal melanoma of the head and neck is low. Even though some progress has been made in recent years (from 8% in 1972 to 26% in 198718), the survival rate is still much worse than that for cutaneous melanoma, which is reported to be between 73% and 81%. 22 In a study covering the years 1932 through 1987, only 78 (7.8%) of 995 melanomas of the head and neck were melanomas of the mucous membrane 18 and only 13% of the patients survived disease-free for 5 years. 18 Generally, survival from head and neck melanoma is reported as 17% at 5 years, 2,7,19 and the 10-year survival rate is 5%. 7 The prognosis in cases of oral melanoma is poor; reported 5-year survival rates range from 13% to 22%.2°, 23 Likewise, we show that only 17% of our patients with oral melanoma survived for more than 5 years. The poor prognosis may be related

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December 1998

Table Ill. Patients with oropharyngeal mucosal melanoma Patient no.

Age at diagnosis

Gender

1

85

M

Maxillaryridge

Site

Swelling ×2 y

Signs

Discomfort

Symptoms

2 3

90 70

M M

Hard and soft palate Hard palate

Black lump, 2 neck nodules, weight loss 4-cm mass x2 mo

Bleeding;no pain No pain

4

53

F

Hard palate

2-3-mm dark pigmented spots

No pain

5 6

86 59

M M

Tonsillararea Tonsillararea

4-cm fungiform mass (No data)

Sore throat x6 mo (No data)

M,Male; F,,female;MM, malignantmelanoma.

directly to patient or health care worker delay in diagnosis, but it is certainly related to the biologic behavior of this disease. It is interesting that the most prevalent site for head and neck melanomas (the nasal cavity) is in close anatomic proximity to the most c o m m o n site in the oral cavity (the palate). It is possible that this may represent the embryology of the region. It has been speculated that mucosal melanomas may arise from both pigmentproducing cells and Schwann cells found in the mucous membrane. 24 It has also been stated that melanomas are often preceded by pigmentation for several years.7, 25 However, this may not be the case in the oral cavity, where most lesions present themselves as nonpigmented masses. In 2 older studies, 26,27 the authors attempted to relate M M of the head and neck to smoking. It is possible that physical and/or chemical stimulation play a role in physiologic oral pigmentation. 28 In addition, in a laboratory study assessing the influence of cigarettes, Axell and Hedin 29 showed that chemical and physical stimulation caused hyperproduction of the melanocytes in the oral epithelium, which resulted in oral pigmented lesions. It is well established that people with light complexions are at greater risk for developing skin melanomas. These can in some ways be compared with hyperkeratotic lesions in nonkeratinized areas. Exposure to solar radiation stimulates the cellular activity of the melanocytes, which can perhaps be transformed into melanotic cellular proliferation and melanoma. Because these 2 sites (nasal cavity and palate) are continuously exposed to the air we breathe, it is possible that irritants and carcinogenic compounds in the air (such as components of tobacco smoke) may play a contributing role in the development of melanomas in these sites. The suspected signs of oral m e l a n o m a include swelling, ulceration, pigmentation, discomfort or

painful sensation, bleeding, and any combination of the above. The primary mode of treatment of mucosal melanoma is wide surgical resection.7,19 In a review of the outcome of primary mucosal melanomas treated only with radiation, 30 44% of patients survived for a period of 4.5 years of follow-up. Even though these results appear to be encouraging, radiation is most often used as a supplementary mode of treatment after surgery or after a failure of previous management. Local failure is c o m m o n and may indicate a risk of metastasis. Advances in surgical technique may allow more extensive resection and reconstruction. Consideration should be given to radiation therapy or combined therapy. Early diagnosis will be promoted by careful oral examination and early biopsy of pigmented and nonpigmented masses. Prognosis may be improved by early diagnosis and treatment. We acknowledge the assistance of Lisa Dykman and Norm Phillips in the computer searches and with epidemiologic support and of Karen McKay for editorial review. REFERENCES l. Hormia M, Vuori EJ. Mucosal melanomas of the head and neck. J Laryngol Otol 1969;83:349-59. 2. Moore ES, Martin H. Melanoma of the upper respiratory tract and oral cavity. Cancer 1955;8:1167-76. 3. Pliskin ME. Malignant melanoma of the oral cavity. In: Clark WH Jr, Goldman LI, Mastrangelo MJ. Human malignant melanoma. New York: Grune & Stallon; 1979. 4. TakagiM, IshikawaG, Mori W. Primarymalignant melanomaof the oral cavity in Japan: with special reference to mucosal melanosis. Cancer 1974;34:358-70. 5. Umeda M, Mishima Y, Teranobu O, Nakanishi K, Shimada K. Heterogeneity of primary malignant melanomas in oral mucosa: an analysis of 43 cases in Japan. Pathology 1988;20:234-41. 6. Macintyre DR, Briggs JC. Primary oral malignant melanoma. Int J Oral Surg 1984;13:160-5. 7. Anneroth G, Carlson GO, Eneroth CM, Moberger G. Primary melanoma in the oral mucous membrane. Swed Dent J 1973;66:27-37. 8. Manolidis S, Donald PJ. Malignant mucosal melanoma of the

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Histology (1) Pyogenic granuloma with underlying functional nevus/no evidence of malignancy; (2) Spindle cell MM MM MM MM H-E: nonlymphoid malignancy; S100: MM MM

9. 10.

11. 12.

13. 14.

15. 16. 17.

18. 19. 20.

Follow-up

Outcome status

Partial maxillectomy and postoperative radiation

Treatment

4.5 y

Alive; free of disease

Palliative radiation; no clinical response Maxillectomy and neck dissection; one submandibular node involved Surgery; later, radiation and chemotherapy for multiple recurrence Radiation (No data)

5 mo 2 mo 23 y

Died with disease Alive; radiation planned Died with disease

7 mo 5y

Died with disease Died with disease

head and neck: review of the literature and report of 14 patients. Cancer 1997;80:1373-86. Smith T. The Queensland melanoma project: an exercise in health education. BMJ 1979;1:253-4. Buchner A, Hansen LS. Pigmented nevi of the oral mucosa: a clinicopathologic study of 36 new cases and review of 155 cases from the literature, 2: analysis of 191 cases. Oral Surg Oral Med Oral Pathol 1987;63:676-82. Eisen D, Voorhees JJ. Oral melanoma and other pigmented lesions of the oral cavity. J Am Acad Dermatol 1991;24:527-37. Barker BF, Cat, enter WM, Daniels TE, Kahn MA, Leider AS, Lozada-Nur F, et al. Oral mucosal melanomas: the WESTOP Banff workshop proceedings. Oral Surg Oral Med Oral Pathol 1977;83:672-9. Elwood JM, Lee JAH. Recent data on the epidemiology of malignant melanoma. Semin Oncol 1975;2:149-54. Sober AJ, Fitzpatrick TB, Mihin MC Jr. Primary melanoma of the skin: recognition and management. J Am Acad Dermatology 1980;2:179-97. Fischer S. Cutaneous melanoma of the head and neck. Laryngoscope 1989;99:822-36. Conley J, Pack GT. Melanoma of the mucous membrane of the head and neck. Arch Otolaryngol 1974;99:315-9. Berthelsen A, Andersen AE Jensen TS, Hansen HS. Melanomas of the mucosa in the oral cavity and upper respiratory passages. Cancer 1984;54:907-12. Conley JJ. Melanomas of the mucous membrane of the head and neck. Laryngoscope 1989;99:1248-54. Snow GB, Van der Esch ER Van Slooten EM. Mucosal melanomas of the head and neck. Head Neck Surg 1978;1:24-30. Rapini RR Golitz LE, Greer RO, Krekorian EA, Poulson T. Primary malignant melanoma of the oral cavity: a review of 177 cases. Cancer 1985;55:1543-5.

21. Batsakis JG. Tumours of the head and neck: clinical and patho•logical considerations. 2nd ed. Baltimore: Williams and Wilkins; 1979. p. 431-47. 22. Mackie AM, Hole DJ. Incidence and thickness of primary tumors and survival of patients with cutaneous malignant melanoma in relation to the socioeconomic status. BMJ 1996;312:1125-8. 23. Trodahl JN, Sprague WG. Benign and malignant melanocytic lesions of the oral mucosa: an analysis of 135 cases. Cancer 1970;25:812-23. 24. Masson R My conception of cellular nevi. Cancer 1951;4:9-38. 25. Snow GB, Waal I. Mucosal melanoma of the head and neck. Otolaryngol Clin North Am 1986;19:537-47. 26. Prinz H. Pigmentation of the oral mucous membrane. Dental Cosmos 1932;74:554-65. 27. Sampat MB, Sirsat MV. Malignant melanoma of the skin and mucous membranes in Indians. Indian J Cancer 1966;3:228-54. 28. Gorsky M, Buchner A, Fundoianu-Dayan D, Aviv I. The physiologic pigmentation of the gingiva in Israeli Jews of different ethnic origin. Oral Surg Oral Med Oral Pathol 1984;58:506-9. 29. Axell T, Hedin CA. Epidemiologic study of excessive oral melanin pigmentation with special reference to the influence of tobacco habits. Scandinavian Journal of Dental Research 1982;90:434-42. 30. Harwood AR, Cummings BJ. Radiotherapy for mucosal melanomas. Int J Radiat Oncol Biol Phys 1982;8:1121-6.

Reprint requests: J. B. Epstein, DMD, MSD British Columbia Cancer Agency 600 West 10th Ave. Vancouver, BC Canada V5Z 4E6