ARTICLE IN PRESS Journal of Cranio-Maxillofacial Surgery (2004) 32, 251–257 r 2004 European Association for Cranio-Maxillofacial Surgery. doi:10.1016/S1010-5182(04)00047-2, available online at http://www.sciencedirect.com
Oral mucosal melanoma: a series of case reports Paolo Garzino-Demo1, Massimo Fasolis1, Gian Marco La Terra Maggiore1, Marco Pagano2, Sid Berrone1 1 2
Department of Maxillofacial Surgery (Director: Prof. S. Berrone), University of Turin, Italy; Department of Pathological-Anatomy (Director: Prof. G. Palestro), University of Turin, Italy
SUMMARY. Introduction: Due to the rarity of oral malignant melanomas case reports are a necessary source of
information. Ten new cases are reported with a minimum follow-up of 3 years. Patients and methods: Patients were treated during a period of 10 years. Clinical, demographic and pathologic findings were examined. Results: In 6 males (60%) and 4 females with a mean age of 64.3 years the tumour locations were: hard palate-maxillary gingiva (3 cases), maxillary gingiva (2), lower gingiva (2), tongue (2), hard/soft palate-buccal mucosa (1). Preexisting melanotic pigmentation had been present in 4 patients. Four patients were in stage I, 5 in stage II, and 1 in stage III. Surgical excision was the primary treatment in 9 cases. Five patients underwent simultaneous neck dissections. All patients received radiation and multimode adjuvant therapies. After a 3-year follow-up 3 patients are still alive (50% (2/4) of those presenting in stage I and 20% (1/5) in stage II). Conclusions: Due to the rarity of oral melanoma, individual experience is limited. The poor prognosis and the different treatments reflect this situation. r 2004 European Association for Cranio-Maxillofacial Surgery. Keywords: Oral melanoma; Head and neck melanoma
et al., 1985) showed a peak incidence between 41 and 60 years of age, and the male/female ratio is 2:1. Preferred sites in the oral mucosa include the hard palate and the alveolar crests (Takagi et al., 1974; Regezi et al., 1978; Pliskin, 1979; Manolidis and Donald, 1997). Other sites less frequently affected include the labial and buccal mucosa or the tongue. No risk factor for intraoral lesions has been clearly identified to date (Shaw, 1977; Manganaro et al., 1995). One-third of the patients are asymptomatic at the time of diagnosis and haemorrhage is the most common presenting symptom (Lopez-Graniel et al., 1999). Melanotic pigmentation prior to the diagnosis of melanoma is found in one-third of the patients. More rarely, the tumour is immediately manifest in the nodular, infiltrative stage on apparently healthy mucosa (Liversedge, 1975; Conley and Hamaker, 1977; Regezi et al., 1978; Berthelsen et al., 1984; Rapini et al., 1985; Batsakis et al., 1998). Oral melanomas have a poor prognosis because they tend to metastasise or locally invade the surrounding tissue more readily than squamous cell carcinomas. The most common sites of metastasis are lymph nodes, liver and lung, with widespread involvement occurring in advanced disease. These data were confirmed in the Workshop on Oral Malignant Melanoma (Barker et al., 1997), convened at the annual Western Society of Teachers of Oral Pathology in 1995. As this type of tumour is rare, data collection from case reports is considered to be the best source of information. The purpose of this paper is to report on
INTRODUCTION Primary malignant melanoma has been described in virtually all sites and organ systems into which neural crest cells migrate. Over 90% of melanomas occur on the skin with slightly over 1% of melanomas arising from mucosal surfaces (Allen and Spitz, 1953; Moore and Martin, 1955; Chaudry et al., 1958; Conley and Pack, 1974; Pliskin, 1979; Chang et al., 1998; Hicks and Flaitz, 2000). Chang et al., (1998) reviewing the characteristics, management, and outcomes of melanoma cases occurring in the US, stated that for mucosal melanoma, the distribution of head and neck, female genital tract, anal/rectal, and urinary tract sites was 55.4, 18.0, 23.8 and 2.8%, respectively. Among those in the head and neck area, oral mucosal melanoma is extremely rare. It accounts for only 0.5% of oral malignancies. In the oro-nasal region approximately one-half of melanomas occur in the oral cavity (48%) and the remaining portions are located in the nasal cavity (44%) and sinuses (8%) (Chang et al., 1998; Hicks and Flaitz, 2000). The various cutaneous forms of melanoma have been clearly defined (McGovern et al., 1973; Barnhill and Mihm, 1993) whilst, the variants of primary melanoma of the oral cavity are still not clear. There is a low incidence of this tumour in Europe but it is encountered more often in the Japanese (Umeda et al., 1998), African (Broomhall, 1967) and North American Indian populations (Soman and Sirsat, 1974; Black and Wiggins, 1985). Large series of patients reported (Berthelsen et al., 1984; Rapini 251
ARTICLE IN PRESS 252 Journal of Cranio-Maxillofacial Surgery
10 new cases of primary malignant melanoma of the oral cavity and to review the pertinent literature. Patients and methods Ten patients with the diagnosis of primary intraoral melanoma were seen and treated at the Department of Maxillo-Facial Surgery of the University of Turin during a period of 10 years. Their clinical and pathologic findings were reviewed.
RESULTS Age, sex and primary sites (Table 1) There were 6 males (60%) and 4 females (40%). The age range was from 35 to 80 years (mean 64.3 years) with one exception they were all older than 50 years. The sites were: hard palate and maxillary gingiva in 3 cases, maxillary gingiva alone in 2, mandibular gingiva in 2, tongue in 2 and hard/soft palate plus buccal mucosa in one case (Table 1). Initial symptoms, stage, course of disease (Table 1) Melanotic pigmentation prior to the diagnosis of melanoma was present in 4 patients. These preexisting lesions had been present for at least 12 months. The time period from onset to definitive diagnosis was from 1 to 30 months. Bleeding was the first symptom in 4 patients, whilst patient recognition of the presence of a lesion was the initial presentation in 6. In all cases no links have been established with denture wearing, chemical or physical trauma or tobacco use. The clinical colour varied from black to grey, from purple to red and white. In most patients, the size of the tumour was significant at the time of diagnosis: No lesion was smaller than 1 cm. The American Joint Committee on Cancer has not published guidelines for the staging of oral malignant melanomas. Like most practitioners do, the patients were classified according to general clinical stages: 4 patients were in stage I (localized disease), 5 in stage II (with regional lymph node metastases) and 1 patient was in stage III (metastatic
disease). Thus the frequency of loco-regional spread was higher than that of disseminated disease. In all cases brush cytology tests were performed first, but in the event of a negative result multiple incisional biopsies were performed. (In all cases an incisional biopsy has been taken.) Histological findings Six cases were described as the pigmented nodular type (Figs 2, 3, 5); 2 as pigmented, macular type (Fig. 1) and 2 as pigmented, mixed type (Fig. 4). Immunohistochemical tests revealed that there was intense and widespread positivity for NKFC3-associated melanoma antigens in all cases, in 8 cases S-100 protein and homatropine methylbromide (HMB-45) antigen positivity was seen, and focal positivity for vimentin and cytokeratin was evident in 3 cases. Microscopic findings in the nodular phase revealed the proliferation of atypical, spindleshaped or epithelioid tumour cells in the submucosa, with pigmented melanoma cells that invaded the deep layer. The pigmented macular type showed a lentiginous growth pattern with a proliferation of large and atypical melanocyte-like dendritic cells in the epithelio-stromal junction, with hyperpigmentation in the basal cell layer. In the mixed type, the macular and nodular characteristics were both present.
Fig. 1 – Female patient with extensive, black-pigmented and irregularly bordered macule in soft/hard palate and buccal mucosa (case no. 10).
Table 1 – Case data, clinical findings, staging Case
Age
Sex
Site
Macroscopic aspect
Pre-existing pigmentation
Stage
1 2 3 4 5 6 7 8 9 10
60 72 67 63 55 72 35 67 72 80
Female Male Female Male Male Male Female Male Female Male
Hard palate-maxillary gingiva Hard palate-maxillary gingiva Hard palate-maxillary gingiva Maxillary gingiva Maxillary gingiva Maxillary gingiva Mandibular gingiva Mandibular gingiva Tongue Hard/soft palate-buccal mucosa
Pigmented Pigmented Pigmented Pigmented Pigmented Pigmented Pigmented Pigmented Pigmented Pigmented
Yes No No No Yes Yes No No No Yes
II II I II II I II I III I
nodular nodular macular/nodular nodular nodular nodular macular/nodular macular nodular macular
ARTICLE IN PRESS Oral mucosal melanoma 253
Fig. 2 – Male patient with an ulcerated, blue–black–white, elevated lesion in the edentulous maxilla on the right side (case no. 2).
Fig. 3 – Female patient with an ulcerated, blue–black–white, elevated lesion in the lateral border of the tongue (case no. 9).
Fig. 5 – Male patient with an ulcerated, black, slightly elevated lesion in left maxilla (case no. 4).
stage II patients radical neck dissection or elective lymph node neck dissection was undertaken simultaneously with treatment of the primary site. In all cases presented, the surgical margins were considered to be microscopically free from disease. All patients received hyperfractionated radiotherapy to the primary location (betatron, 70–74 Gy for buccal or lingual and 50–54 Gy for palatal lesions). All neck dissections were followed by radiation (70 Gy). In addition, various, multimodal adjuvant therapies were applied in all cases (Table 2): drug therapy (dacarbazine-DTIC) and immunotherapy (IFN alpha-2b) trials have been applied in various combinations with many other vaccination and immunomodulation agents, such as bacille Calmette-Gue! rin (BCG) and recombinant interleukin-2 (rIL-2). Follow-up After a minimum follow-up of 3 years only 2 of the 4 patients in stage I have survived without evidence of primary or disseminated disease and only 1 out of 5 in stage II is still alive – however, with evidence of disseminated disease. The patient in stage III died 12 months after diagnosis, while from all the other patients in stages I or II who died, none survived longer than 2 years.
DISCUSSION
Fig. 4 – Female patient with black-pigmented and irregularly bordered macule in the mandibular gingiva (case no. 7).
Treatment results (Table 2) In 9 cases, a wide excision of the tumour was performed as the primary treatment, in the 10th case surgery was performed after radiotherapy. In the 5
While cutaneous melanomas are divided into clinically and pathologically well-defined varieties, (McGovern et al., 1973; Barnhill and Mihm, 1993), a definitive classification of oral malignant melanoma has not yet been drawn up. Its rarity has led to confusion both in clinical and histological terminology (Barker et al., 1997). Some authors (de Graciansky et al., 1967; Grinspan et al., 1969; Robinson and Hukill, 1970; Takagi et al., 1974) regarded lentigo maligna melanoma (LMM) as similar to oral melanoma clinically and pathologically.
ARTICLE IN PRESS 254 Journal of Cranio-Maxillofacial Surgery Table 2 – Treatment modality and survival Case
Site
Stage
Surgery
Adjuvant therapy
Survival (months)
1 2 3 4 5 6 7 8 9 10
Hard palate-maxillary gingiva Hard palate-maxillary gingiva Hard palate-maxillary gingiva Maxillary gingiva Maxillary gingiva Maxillary gingiva Mandibular gingiva Mandibular gingiva Tongue Hard/soft palate-buccal mucosa
II II I II II I II I III I
Maxillectomy-RND Maxillectomy Maxillectomy Maxillectomy Maxillectomy Maxillectomy Mandibulectomy-FND Mandibulectomy-RND Glossectomy-FND Composite resection-RND
XRT+DDP/rIL-2/a-IFN/TAM XRT+DDP/rIL-2/a-IFN/TAM XRT+CBDT/rIL-2/a-IFN XRT+CBDT/IL-2/a-IFN XRT+DDP/rIL-2/a-IFN/TAM XRT+BHD XRT+CBDT/rIL-2/a-IFN XRT+BHD XRT+DTIC/rIL-2/a-IFN/TAM XRT+DTIC /rIL-2/a-IFN/TAM
No (19) No (11) No (11) No (14) Yes Yes No (17) Yes No (9) No (18)
FND: Functional Neck Dissection. RND: Radial Neck Dissection. XRT: Radiation therapy. DDP Cisplatin, TAM Tamoxifene, DTIC Dacarbazine. CBDT=DDP Cisplatin, BCNU Carmustine, DTIC Dacarbazine, TAM Tamoxifen. BHD=BCNU Carmustine, Hydroxyurea, DTIC Dacarbazine. a-IFN Interferon alpha. rIL-2 Interleukin-2.
Lesions with the same characteristics as the precursors of LMM were described, namely lentigo maligna, melanosis circumscripta praeblastomatosa Dubreuilh, or Hutchinson’s melanotic freckle (McGovern et al., 1973, 1986; Buchner et al., 1991). In contrast, Regezi et al. (1978), Coleman et al. (1980), McDonald et al. (1983), Mishima and Nakanishi (1985) and Sutherland et al. (1993) are of the opinion that oral malignant melanoma was similar to acrolentiginous melanoma (ALM). Irrespective of these arguments, Kato et al. (1987) were the first to underline the fact that the prognosis of melanoma in this site is very poor compared with cutaneous melanomas. Moreover, in view of the difference in biological growth between the two sites, they felt it was appropriate to make a clear distinction between cutaneous and mucosal forms. Rapini (1997) considered it useless to try to classify oral melanoma and to use the terms ‘malignant melanoma in situ’ and ‘infiltrating melanoma’. During the Workshop on Oral Malignant Melanomas (Barker et al., 1997), convened at the annual Western Society of Teachers of Oral Pathology in 1995, the authors agreed on the fact that oral lesions should be considered separately from cutaneous forms. The terms ‘in situ OMM’, ‘invasive OMM’, ‘invasive with in situ component OMM’, and ‘atypical melanocytic proliferation’ (for an equivocal lesion) were considered to be preferable terms. Atypical melanocytic proliferation indicated an oral mucosal melanosis with equivocal histopathological features, such as hyperchromatic and angulated nuclei with very infrequent mitotic activity. Some epidemiological and diagnostic data from the literature seem to be confirmed by this report of cases with a male-to-female ratio of almost 2:1 (1.5:1 in our series); average age at diagnosis 56 years (64.3 years in our series). In this report, the hard palate and the maxillary gingiva were the preferred location (50%), this being similar to other reports: Pliskin (1979)
found that 77% of all OMM occurred in either the palate or the upper alveolus, Takagi et al. (1974) found 34% out of a total of 120 cases to be in the palate and 24% in the maxillary gingiva. Melanotic pigmentation prior to diagnosis of melanoma was present in 4 of our patients (40%). This confirms that more than a third of them develop within oral melanosis (Liversedge, 1975; Regezi et al., 1978; Berthelsen et al., 1984; Rapini et al., 1985; Batsakis et al., 1998). Rapini et al. (1985) stated that these melanotic patches probably represent the radial growth phase of the tumour which may last for 10–15 months. Oral melanoma colour varies (Ohashi et al., 1992; Smyth et al., 1993) and many pigmented lesions have to be considered for differential diagnosis (Manganaro et al., 1995). Cytological tests on brushed samples are not reliable, negative results were obtained in all our cases. Biopsy is essential even if this may theoretically risk spreading neoplastic cells. However, Batsakis (1979) stated that this possibility has not been clearly demonstrated. Junctional anomalies, an increased density of melanocytes, and atypical cells found in biopsies from pigmented lesions of the palate and gingiva are strongly suspicious (Greene et al., 1953); the neoplastic cells may appear as spindle shape, plasmocytoid or epithelioid, and may be amelanotic (Barker et al., 1997). Histopathological differential diagnosis includes poorly differentiated carcinoma and anaplastic large-cell lymphoma. This demands the use of immunohistochemical techniques to highlight intermediate filaments or antigens specific for a particular cell line. The positivity to S-100 protein and homatropine methylbromide antigen (HMB-45) is characteristic of, although not specific for, melanoma. S-100 protein is frequently used to highlight the spindled, more neural-appearing melanocytes, whereas HMB-45 is used to identify round cells. Melanomas, unlike epithelial lesions, are also positive for vimentin, a marker of mesenchymal cells.
ARTICLE IN PRESS Oral mucosal melanoma 255
Recently, microphthalmic transcription factor, tyrosinase, and melano-A immunostains have been used to highlight melanocytes. The inclusion of these in a panel of stains for melanoma should be beneficial. Studies by Gazit and Daniels (1994) showed a high immunoreactivity of oral melanoma to protein S-100 (46 cases out of 50) and HMB-45 (especially in the epithelioid variations). In our own series, all cases were intensely and widely positive to NKFC3associated melanoma antigens and in 8 cases to S-100 protein and homatropine methylbromide (HMB-45). There was focal positivity to vimentin and cytokeratin in 3 cases. In view of the histological differences between oral mucosa and skin, it is impossible to use Clark’s and Breslow’s classifications for prognosis (Breslow, 1970; Clark et al., 1975). Batsakis et al. (1982) and Patel et al. (2002) recently affirmed that, once invasion has exceeded a depth of 0.5 mm, there was a marked deterioration in prognosis for oral mucosal melanoma. The great problem is that there is still no consensus on the treatment. Patients have been treated with varying combinations of modalities (Manolidis and Donald, 1997; Pandey et al., 2002; Medina et al., 2003). The poor prognosis of our own patients and the different treatment modalities applied reflect this situation. In other series (Snow and van der Waal, 1986; Batsakis, 1979; Batsakis et al., 1982; Berthelsen et al., 1984; Rapini et al., 1985), life expectancy was also very low, the 5-year survival rate ranging between 15 and 38%. The poor prognosis may be related not only to the histotype but also to the difficulty of wide enough resection (palate and alveolar crest), the early haematogenous metastases and lastly by the age of the patients (Manolidis and Donald, 1997; Umeda and Shimada, 1994). These tumours are regarded as poorly radiosensitive (Catlin, 1967). However, a number of authors (Takagi et al., 1974; Eneroth and Lundberg, 1975; Rapini et al., 1985) report a slight regression of oral melanoma after a few cycles of radiotherapy. Trials show that external beam radiation may be valuable as an adjuvant therapy for melanoma. For patients with evidence of multiple positive lymph nodes or with extracapsular spread, post-operative radiation therapy after neck dissection seems to be appropriate. Radiation can also be used palliatively for metastatic disease. At present, the recommended treatment is surgery in combination with chemotherapy and, to a lesser extent, immunotherapy or irradiation therapy (Manganaro et al., 1995). Umeda and Shimada (1994) have adopted their own protocol with reasonable results: (1) excision of the primary lesion using an intraoral approach and involving at least 1.5 cm of healthy tissue; (2) excision of any lymph node metastases (Stage II); (3) chemotherapy using DTIC-ACNU-VCR.
Immunotherapy trials have shown encouraging results in the adjuvant treatment of melanoma (Schwipper, 2000); however, the long-term ramifications of IFN alpha-2b therapy are less well known (Kirkwood et al., 1993, 2000). Many other vaccination and immunomodulation agents, such as bacille Calmette-Gue! rin (BCG) and recombinant interleukin-2 (rIL-2), are currently under trial (Molife and Hancock, 2002). Surgery offers the best chance for long-term survival (Eneroth and Lundberg, 1975; Rapini et al., 1985; Snow and van der Waal, 1986; Andersen et al., 1992; Guzzo et al., 1993; Trotti and Peters, 1993; Lee et al., 1994; Umeda and Shimada, 1994; Rapini, 1997; Manolidis and Donald, 1997; Pandey et al., 2002; Medina et al., 2003). It is still not clear to what extent lymph node involvement may influence the prognosis: Shah et al. (1977) do not see a direct correlation, whereas Liversedge (1975) think that there may be an indirect relationship. There is an apparent correlation between the degree of invasion and incidence of lymph node metastasis (Umeda and Shimada, 1994). Decisions regarding a radical surgical approach need to be critically tempered in view of the rate of local failure and functional outcome (Manolidis and Donald, 1997). However, studies that made a comparison between various primary treatment modalities demonstrated that, at present, radical surgery offers the best probability of cure and local control of oral malignant melanoma (Andersen et al., 1992; Guzzo et al., 1993; Lee et al., 1994; Manolidis and Donald, 1997; Pandey et al., 2002; Medina et al., 2003).
CONCLUSION Some authors carried out a literature review grouping together all melanomas of the head and neck, but Medina et al. (2003) and Patel et al. (2002) have pointed out that oral melanomas are more prone to develop nodal metastases (26% of cases) than other head and neck melanomas, e.g. sinonasal (6%). The experience with malignant melanoma of the oral cavity is still too limited. The only well-known fact is the poor prognosis and the need for an evidencebased treatment protocol.
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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 20: 234–241, 1988 Umeda M, Shimada K: Primary malignant melanoma of the oral cavity—its histological classification and treatment. Br J Oral Maxillofac Surg 32: 39–47, 1994 Dr. Paolo Garzino Demo Department of Maxillofacial Surgery, University of Turin San Giovanni Battista Hospital C.so Dogliotti 14, 10126 Turin, Italy. Tel.: +39-011-6335471; Fax: +39-011-6335125 E-mail:
[email protected] Paper received 17 February 2003 Accepted 12 December 2003
