(1) Servicio de Cirugía Oral y Maxilofacial. (Jefe de Servicio: Francisco J. Díaz González). 
Hospital Universitario de La Princesa (Universidad Autónoma) Madrid
(2) Servicio de Anatomía Patológica. Hospital Universitario La Princesa

Address:
Raúl González García
C/ Los Yébenes nº 35, 8º C
28047 - Madrid
Número de teléfono- + (34) 917191259
Número de Fax- + (34) 914702259
E-mail: raugg@mixmail.com

Received: 28-11-2004 Accepted: 9-01-2005

Melanoma of the oral mucosa is an extremely rare disease. It has been referred an incidence of 1.2 cases per 10 million inhabitants-year (1). It is included in the context of mucosal melanomas, in which incidence is situated slightly upper than that for all melanomas (1,2). In relation with cervicofacial region, the most common place for appearance of the melanoma is the conjunctiva, followed by the upper airway and the oral cavity (3,4). The palate and maxillary gingiva constitute the most frequent sites in this latter location (5,6). Some authors (1) refer a 48% of melanomas in the oral cavity, 44% in nasal cavity and 8% in paranasal sinuses. Other sites for appearance in the oral mucosa are the mandibular gingiva, buccal mucosa, tongue and the floor of the mouth. Generally, melanoma constitutes 0.5% of malignant tumors of the oral cavity (7,8). The mean age for the appearance of this entity has been referred at about 55 years, although it may appear in any age group (very uncommon in younger than 30 years) (3), with a men-women relation of 2:1 (9,10).

It is unknown if the worse prognosis of oral mucosal melanoma in comparison with cutaneous melanoma is due to differences in its histological behaviour or, in the other side, late diagnosis or anatomical features are the determinants of such differences. Otherwise, it has been referred lower survival rates for oral mucosal melanoma, although large clinical series are required.

Contrary to cutaneous melanoma, there is not a well-defined clinical and histological classification for oral mucosal melanoma, and the majority of the information is based upon series of cases. The purpose of this work is to present 2 new cases of primary melanoma of the oral mucosa and review the main literature about this entity.

CLINICAL CASES

A 49-year-old woman, ex-smoker of 1 packet of cigarettes/ day, consulted to us showing a pigmented lesion in the upper vestibular gingiva and palatal pre-maxillary gingiva. A histopathologic study was previously performed in other centre with the diagnosis of malignant mucosal melanoma. A 0.6 x 0.5 x 0.1 cm-pigmented lesion in the upper vestibular gingiva and two 1.5 x 1 and 0.9 x 0.6 cm-pigmented lesions in the palatal gingiva of the pre-maxillae were observed in the physical exploration. Moreover, small pigmented lesions were observed in the buccal mucosa, left upper lip, left lower gingiva and right lower gingiva.

With the suspected diagnosis of mucosal melanoma, a biopsy of the lesion located in the upper vestibular gingiva was performed, with the result of oral mucosal melanoma in situ. Under general anaesthesia, it was performed an excision of the vestibular gingiva and palate of premaxillae with wide margins and CO₂-LASER vaporization of the surgical defect. Histological study of the specimen showed an oral mucosal melanoma with superficial erosion, which infiltrated the superficial layer of the corion, with a maximum thickness of 1.10 mm, in the proximity to surgical borders in the upper gingiva. In the other side, the histological study of palatal mucosa was reported as melanoma in situ of the oral mucosa that did not infiltrate surgical margins, associated to oral mucosal melanosis (Fig.1). The other melanotic pigmentations were identified as oral mucosal melanosis with no signs of malignancy in buccal mucosa, left upper lip, left lower gingiva and right lower gingiva. Postoperatory was uneventful.

Seven months later, during the follow-up period, melanotic pigmentation in upper gingival and palatal mucosa was observed. A new biopsy confirmed the diagnosis of oral mucosal melanoma. Surgery intervention with partial maxillectomy including inserted gingiva, vestibular and palatal mucosa and dental pieces was performed. Reconstruction with a superiorly-based facial artery buccinator myomucosal flap and an anterior iliac crest bone graft was performed (Fig.2). Postoperatory evolution was favourable. Histopathological diagnosis was reported as gingival mucosa and underlying bone infiltrated by melanoma, with free surgical margins. Follow-up 12 months after the surgery did not demonstrate clinical or radilological (Computarized Tomography (CT) scan) signs of neither local-regional relapse nor distant metastasis. Buccinator myomucosal flap and anterior iliac crest bone graft remain viable.

Clinical Case 2

A 56-year-old man, active smoker of 2 packets of cigarretes/day, was remitted to our Department by the dentist showing a 4-months ulcer in right upper gingiva, with spontaneous bleeding and progressive increase in size. In the physical exploration it was observed a 1-cm non-melanotic erosive lesion in gingiva next to 17 and 18 dental pieces, with eritematous colouration, friable aspect, and with neither spontaneous bleeding nor after manipulation (Fig.3). An incisional biopsy of the lesion was performed. Immunohistochemical study revealed diffuse positivity for melanoma antigen, S-100 protein and vimentin, and negativity for low-molecular-weight keratins (Cam 5.2), keratins AE1 and AE3, carcinoembrionary antigen (CEA) and epithelial membrane antigen (EMA).

With the diagnosis of gingival melanoma, surgical intervention was performed, with resection of the gingival lesion, right maxillary alveolar process, exodontias of 16, 17 and 18 and reconstruction of the defect by means of a Bichat buccal fat pad flap (Fig.4). Resection was established with macroscopic free margins. Postoperatory recovery was uneventful.

Histopathological study of the specimen showed a pigmented area formed by grossly marked atypical melanocytes of variable nuclei size, hyperchromatic, with prominent nucleoli and numerous mitosis and great and clear cytoplasms, which extend deeply from the mucosa. Melanocytes infiltrated grossly the totality of submucosa and underlying bone to reach the surgical edge of the specimen. Focally, pagetoid ascent of tumoral melanocytes to the overlying epithelium, without radial extension of the tumor to the basal layer of the mucosal epithelium, was identified. Diagnosis was 11-mm-thickness gingival melanoma, with osseous infiltration and affectation of deep surgical block, and surgical mucous edges free of tumoral infiltration (Fig.5).

One month after the first surgery the patient was operated again, with enlargement of margins, bone resection to the sinus floor and maxillary tuberosity. Histopathologic study was described as maxillary fragment with chronic inflammation without evidence of infiltration.

Postoperative control CT-scan was performed one month later, with demonstration of an image corresponding to a 2 x 1-cm necrosed right yugulodigastric lymph node, suggestive of metastasis. Fine-needle-aspiration (FNA) showed positivity for melanoma. Modified type III radical neck dissection was performed, with the histological result of 3 of 17 infiltrated lymph nodes in right levels 2 and 3, with capsular spread in one of them. Postsurgical recovery was favourable.

After this, right lymph node chains were irradiated by means of lateral direct 18 and 15 MeV-electron fields, with administration of ten 5Gy/day sessions, 2 sessions in each week. Radiotherapic treatment was well-tolerated, although mucositis was presented in right oral cavity, which was solved by symptomatic treatment. Simultaneously, patient began with α-interpheron, which was extended during a year.

Patient has been followed for 6 years, without local-regional relapse or distant metastasis and acceptable functional situation.

DISCUSSION

In our series, location was maxillary palate and gingiva in both cases. In concordance with other authors, they are the most frequent sites for appearance of this entity (11,12). Symptoms of oral mucosal melanoma include bleeding and rarely pain, which use to appear in a late period. Moreover, bleeding has been referred as the most frequent sign at diagnosis (13), and the presence of melanotic pigmentation is presented in one third of the patients before diagnosis (11). In this sense, and probably related to a later diagnosis, a worse prognosis has been referred for amelanotic oral mucosa melanoma (14), such as our second case.

Oral mucosal melanoma usually extends in a uniform pattern, and no imflammatory response in the borders has been referred, so imflammatory response in the edges is minimal or absent (3). Deep extension, with or without bone invasion, is present in the diagnosis of numerous cases. However, it is possible a superficial dissemination previous to the vertical dissemination, as in our case. One third of the patients presented mucosal melanosis, present for years.

The exclusion of any other tumoral focus is essential in diagnosis of melanoma, so that mucous melanoma can not be explained by means of a metastatic origin. In relation with it and according with Greene et al. (15), we think that clinical and histological demonstration of the melanoma in the oral mucosa, the presence of tumoral activity in the lesion and the impossibility to demonstrate a melanoma in any other location, are conditions necessary to make an appropriate diagnosis. Delgado Azañero et al. (16) describe a method which consists in "rubbing a gauze" over the lesion to diagnose oral mucosal melanomas. They refer a sensibility of 84.6%, but a negative result does not exclude the possibility of melanoma in the histological study. We disagree with these authors in the availability of this technique, because it does not modify final diagnostic management. Firstly, an elevate percentage of mucosal melanomas shows no alterations in pigmentation. On the other side, it has been referred that cytology by means of scraping the lesion does not show reliable results (11).

Histologically, the presence of abnormalities of the junction, high density of melanocytes and atypical cells in the biopsy of melanotic lesions of the oral mucosa is suspicious for malignancy. The necessity of establishing the primary origin of the melanoma is clear in an attempt to make an effective control of the disease. In relation with it, there are some anatomoclinical considerations which are present more frequently in primary melanoma than in metastasis of melanoma in the oral mucosa, which are referred in table 1. In relation with immunohistochemistry, it has been referred a variable positivity for melanoma associated antigens NKFC3, S-100 protein, HMB-45 and vimentin. We demonstrated positivity for S-100, vimentin and melanoma antigen.

It is necessary a differential diagnosis with other malignant entities, such as poorly-differentiated carcinoma, large cells anaplastic lymphoma; with other melanotic lesions, such as melanotic macule, melanocytic nevi of the oral mucosa, blue nevi, melanoacanthoma, and nevi of Spitz; and with other non- melanotic lesions, such as those secondary to the deposit of dental restorations and those related with the use of heavy metals, tobacco and some drugs.

The most accepted treatment is surgical resection with wide margins, although disease is controlled in few cases. There is controversy with respect to the necessity of cervical dissection, between those who advocates for elective cervical dissection and those who advocates for cervical dissection in clinically positive necks (18). Adjuvant radiotherapy and immunochemotherapy may be associated to surgery. The former may be used as primary treatment in cases with very bad prognosis and those in which surgery is rejected, although its real value is unknown. Dacarbazine-DTIC and INF-alpha-2b have been described as chemotherapical and immunotherapical treatments, associated in different combinations to BCG and recombinant interleukin-2 (rIL-2) (12).

Rapidis et al. (3) describe the excision of the lesion with a 1.5-2 cm-width macroscopically healthy margin. In concordance with these authors, we think that surgery combined with immunochemotherapy constitutes the most effective treatment modality to control the disease, although addition of the last one does not increase long-term survival. In any case, existent comparative studies between different treatment modalities seem to award more local control and cure to radical surgery with wide margins. Apart from conventional surgical resection, it has been referred the Mohs micrographic surgery in fixed-tissue (5). Our group advocates for resection of the lesion with wide margins from the beginning, with subsequent reconstruction in the same surgical time if it was necessary.

Prognosis of melanoma is poor, with a 5-year-mean survival rate after resection of 5 to 38%, according with authors (3,5,11). Yii et al. (20) refer, over 89 head and neck mucosal melanomas, a 5-year survival of 26% when the lesion was confined to the primary site, while it descended to 0% when regional lymph node or distant metastasis existed. Prasad et al. (7), over 37 patients, documented metastasis in 64.5% of the cases, and specific and global 5-year survival rates of 36 and 42%, respectively. In general, this poor prognosis, lower than that assigned to cutaneous melanoma, may be explained by the difficulty in obtaining a wide resection due to the anatomy of the region, the major extension in depth in relation with cutaneous melanoma and the early haematogenous metastasis. In relation with it, some authors refer more unfavourable prognosis when lesion depth is greater (21,22), while others affirm that ulceration, tumoral thickness, histological type, number of mitosis, perineural invasion or depth of invasion does not seem to have as similar prognosis as that referred for cutaneous melanoma (7,23). In a similar manner, controversy exists with respect to regional lymph node affectation and, while some authors (21) refer this feature to have no special prognostic relevance, some others identify it as a clear prognostic factor (24). Due to the poor prognosis of this entity, it is necessary an early identification and biopsy of melanoma lesions. A near follow-up of patients with pigmented lesions of the oral mucosa is mandatory.

BIBLIOGRAFÍA         [ Links ]

2. Dematos P, Tyler D, Seigler HF. Malignant melanomas of the mucous membranes: a review of 119 cases. Am Surg Oncol 1998;5:733-42.         [ Links ]

3. Rapidis AD, Apostolidis C, Vilos G, Valsamis S. Primary malignant melanoma of the oral mucosa. J Oral Maxillofac Surg 2003; 61:1132-9.         [ Links ]

4. Landa S, Ereno C, Montes E, Santamaria J, Perez I. Metastatic malignant melanoma of intraparotid lymph nodes. Med Oral. 1997;2:49-52.         [ Links ]

5. Oriba HA, Stanley R, Snow SN, Mohs FE. Oral malignant melanoma treated with Mohs micrographic surgery by fixed-tissue technique. Arch Otolaryngol Head Neck Surg 1998;124:199-201.         [ Links ]

6. Cebrian Carretero JL, Chamorro Pons M, Montesdeoca N. Melanoma of the oral cavity. Review of the literature. Med Oral 2001;6:371-5.         [ Links ]

7. Prasad ML, Patel S, Hoshaw-Woodard S, Escrig M, Shah JP, Huvos AG, Busam KJ. Prognostic factors for malignant melanoma of the squamous mucosa of the head and neck. Am J Surg Pathol 2002;26:883-92.         [ Links ]

8. Ostman J, Anneroth G, Gustafson H, Tavelin B. malignant oral tumors in Sweden 1960-1989- an epidemiological study. Oral Oncol Eur J Cancer 1995;31:106-12.         [ Links ]

9. Berthelsen A, Andersen AP, Jensen TS, Hansen HS. Melanomas of the mucosa in the oral cavity and the upper respiratory passages. Cancer 1984;54:907-12.         [ Links ]

10. Rapini RP, Golitz LE, Greer Jr RO, Krekorian EA, Poulson T. Primary malignant melanoma of the oral cavity. A review of 177 cases. Cancer 1985;55:1543-51.         [ Links ]

11. Garzino-Demo P, Fasolis M, Maggiore GM, Pagano M, Berrone S. Oral mucosal melanoma: a series of case reports. J Craniomaxillofac Surg 2004;32:251-7.         [ Links ]

12. Takagi M, Ishikawa G, Mori W. Primary malignant melanoma of the oral cavity in Japan. With special reference to mucosal melanosis. Cancer 1974;34:358-70.         [ Links ]

13. López-Graniel CM, Ochoa-Carrillo FJ, Meneses-García A. Malignant melanoma of the oral cavity: diagnosis and treatment experience in a Mexican population. Oral Oncol 1999;35:425-30.         [ Links ]

14. Kotani K, Shindoh M, Yamazaki Y, et al. Amelanotic malignant melanomas of the oral mucosa. Br J Oral Maixllofac Surg 2002;40:195-200.        [ Links ]

15. Greene GW, Haynes JW, Dozier M, et al. Primary malignant melanoma of the oral mucosa. Oral Surg Oral Med Oral Pathol 1953;6:1435.        [ Links ]

16. Delgado Azañero WA, Mosqueda Taylor A. A practical method for clinical diagnosis of oral mucosal melanomas. Med Oral 2003;8:348-52.        [ Links ]

17. Villarreal PM, Junquera LM, Herreros M, Ferreras J, Rodriguez O. Maxillary undifferentiated carcinoma with rhabdoid features. Med Oral. 2001 Jan-Feb;6(1):31-5.         [ Links ]

18. Snow GB, van der Waal I. Mucosal melanomas of the head and neck. Otolaryngol Clin North Am 1986;19:537.        [ Links ]

19. Manolidis S, Donald PJ. Malignant mucosal melanoma of the head and neck: review of the literature and report of 14 patients. Cancer 1997;80:1373-86.         [ Links ]

20. Yii NW, Eisen MN, A´Hern R, Rhys-Evans P, Archer D, Henk JM, Gore ME. Mucosal malignant melanoma of the head and neck: the Marsden experience over half a century. Clin Oncol 2003;15:199-204.         [ Links ]

21. Shah JP, Huvos AG, Strong EW. Mucosal melanomas of the head and neck. Am J Surg 1977;134:531-5.         [ Links ]

22. Seigler HF. Mucosal melanoma. J Surg Oncol 2004;86:187-8.         [ Links ] 23. Liversedge RL. Oral malignant melanoma. Br J Oral Surg 1975;13:40.        [ Links ]

24. Umeda M, Shimada K. Primary malignant melanoma of the oral cavity: its histological classification and treatment. Br J Oral Maxillofac Surg 1994;32:39.        [ Links ]