- Email: [email protected]
Tumor Size and Depth in Primary Malignant Melanoma in the Oral Cavity Influences Survival
J Oral Maxillofac Surg 67:1409-1415, 2009
Tumor Size and Depth in Primary Malignant Melanoma in the Oral Cavity Influences Survival Thomas Mücke, MD,* Frank Hölzle, MD, DDS, PhD,† Marco R. Kesting, MD, DDS,‡ Denys J. Loeffelbein, MD, DDS,§ Luisa K. Robitzky,储 Bettina Hohlweg-Majert, MD, DDS,¶ Andrea Tannapfel, PhD, MD,** and Klaus-Dietrich Wolff, MD, DDS, PhD†† Purpose: Primary oral malignant melanoma (OMM) is rare, and there are few studies examining the
impact of this disease. This study aims to assess the outcome of surgically treated patients with OMM treated at a single institution. Patients and Methods: Ten patients with OMM treated at the Department of Oral and Maxillofacial Surgery, Ruhr-University Bochum, Bochum, Germany, between 1992 and 2002 were analyzed retrospectively. Treatment included wide local excision with or without modified neck dissection, supplemented by radiotherapy and chemotherapy. Clinical and histologic data were analyzed by univariate analysis. Results: Five patients were diagnosed with stage I disease, 4 with stage II disease, and 1 with stage III disease at presentation. The alveolar arch (40%) and palate (30%) were the most frequently affected sites. The adjusted hazard ratio was 4.513 (95% confidence interval, 1.47-13.89) for size and 1.919 (95% confidence interval, 1.03-3.59) for depth, yielding a poor prognosis (P ⫽ .009 and P ⫽ .048, respectively). The mean survival rate of the patients succumbing to disease was 19 ⫾ 17 months. Conclusions: Primary OMM carries a poor prognosis. Early identification of OMM and its treatment by radical surgery comprise the single most important treatment strategy. Any pigmented lesion in the oral cavity not clearly clinically amenable to diagnosis should be excised for histologic confirmation. Analysis of the lymph node status, supplemented by sonography or other imaging, and postoperative histologic evaluation of the size and depth should be performed routinely. In cases in which the mucosal melanoma may not be the primary site, all potential primary sites should be examined. © 2009 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 67:1409-1415, 2009 *Resident, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany. †Senior Consultant, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany. ‡Consultant, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany. §Resident, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany. 储Graduate Student, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany.
¶Consultant, Department of Oral and Maxillofacial Surgery, Klinikum Rechts der Isar der Technischen, Universität München, München, Germany. **Professor and Head of Department, Institute of Pathology, University of Bochum, Bochum, Germany. ††Professor and Head of Department, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany. Address correspondence and reprint requests to Dr Mücke: Department of Oral and Maxillofacial Surgery, Klinikum Rechts der Isar der Technischen Universität München, Ismaninger Strasse 22, 81675 München, Germany; e-mail: [email protected] © 2009 American Association of Oral and Maxillofacial Surgeons
0278-2391/09/6707-0008$36.00/0 doi:10.1016/j.joms.2008.12.021
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1410 Malignant melanoma in the head and neck area is rare. Oral cavity primary malignant melanoma comprises 6.3% of all melanomas in the head and neck area.1 Only about 0.7% to 1.6% of all melanomas arise in the oral mucosa.1,2 The incidence of primary mucosal melanomas of the head and neck is approximately 4 per 10 million of the population per year.3 The most frequently affected oral sites are the palate and maxillary gingiva (Fig 1).3-5 It is generally accepted that the outcome of oral malignant melanoma (OMM) is worse compared with that of cutaneous and overall head and neck melanoma. The 5-year survival rate reported in the literature for oral melanomas varies from 0% to 20%,6-8 whereas the overall survival rate for head and neck melanomas ranges between 20% and 48%.9-12 Treatment modalities for primary oral melanoma include surgical resection with or without neck dissection. Adjunctive modalities such as immunotherapy, chemotherapy, and radiation therapy may offer a supportive but as-yet-noncurative role. The mainstay of curative treatment is surgery, mandating complete resection of the tumor with clear margins.7,13 Immunotherapy and chemotherapy are techniques that are principally the subject of controlled trials or palliation.14 The rarity of head and neck melanomas, particularly the small proportion of oral melanomas, means that, to date, no randomized clinical trial has been conducted to establish an evidence base in the literature to provide comparisons of treatment modalities. The efficacy of surgery with planned supplementary radiotherapy remains unresolved and continues to generate controversy.10 Because of the rarity of this disease, most reports accumulate over an extended period of time. The disadvantage of such studies is obvious; there is a lack of consistency in immunohistochemical confirmation
PRIMARY ORAL MALIGNANT MELANOMA
of the diagnosis, staging strategies, and treatment planning because diagnostic techniques and treatment have evolved over recent years. The purpose of this study is to analyze our experience in treating primary OMM and to identify clinical and histologic predictors of outcome.
Patients and Methods Between 1992 and 2002, 10 patients (6 men and 4 women) with primarily intraoral melanoma were treated at the Department of Oral and Maxillofacial Plastic Surgery, Ruhr-University Bochum, Bochum, Germany. In all cases the diagnosis of OMM was established by microscopic and immunohistochemical examinations (positivity for S-100 and HMB-45). The extent of the tumor, tumor spread in relation to the underlying and surrounding tissues, resection margins, tumor thickness, and vascular and neural invasion were observed and described clinically and histologically. Patients with stage I disease were reviewed for microstaging as described by Prasad et al:15 level I, pure melanoma in situ without invasion or only microinvasion; level II, invasion limited to lamina propria; and level III, deep invasion into surrounding tissues. According to Tanaka et al,16,17 the types of OMM were histologically subdivided into 1) in situ melanoma, which is limited to the epithelium; 2) pigmented nodular type; 3) nonpigmented nodular type; 4) pigmented macular type; 5) nonpigmented macular type; 6) pigmented mixed type; 7) nonpigmented mixed type; and 8) degenerated type. As described by Greene et al,18 the diagnosis of primarily OMM was also verified by computed tomography (CT) or magnetic resonance imaging (MRI), skeletal scintigraphic surveys, sonography, gastroscopy, and bronchoscopy; therefore the possibility of a primary malignant melanoma elsewhere in the body was excluded during initial staging, ensuring that these cases were, in fact, primary oral mucosal malignant melanoma and not metastatic deposits. CT or MRI was used to evaluate the neck for regional disease. Patients were staged according to the Union Internationale Contre le Cancer as follows: stage I, confined to the primary site; stage II, positive cervical lymph nodes; and stage III, distant metastases.8-12,14,15 Clinical and histologic data were analyzed regarding the impact of outcome by univariate analysis by use of the log rank test. Differences were considered to be statistically significant at P less than .05.
Results FIGURE 1. Intraoral view of nodular type malignant melanoma arising from palate. Mücke et al. Primary Oral Malignant Melanoma. J Oral Maxillofac Surg 2009.
This study included 4 women and 6 men; all were white. The primary location of the tumor and the stage are shown in Table 1. Stage-dependent overall
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Table 1. DISTRIBUTION OF STAGE AND TUMOR LOCATION
Stage
Tumor site Palate Alveolus Floor of mouth Buccal mucosa Total
I
II
III
1 2 0 2 5
2 2 0 0 4
0 0 1 0 1
P Value NS
Abbreviation: NS, not significant. Mücke et al. Primary Oral Malignant Melanoma. J Oral Maxillofac Surg 2009.
survival of the patients is presented in Figure 2. Surprisingly, the relation between patient outcome and clinical stage at presentation was not significant (P ⫽ .647). Patients ranged in age from 45 to 93 years (mean, 65 ⫾ 12 years), with a median of 64.5 years. Presenting symptoms were oral pigmentation (50%), ill-fitting dentures (20%), and ulcers (10%), whereas 20% were discovered opportunistically on oral examination. Of the cases, 30% involved the hard palate (Fig 1); 30%, the alveolar arch; 20%, the buccal mucosa; and 10%, both the floor of the mouth and the alveolar arch including the maxillary tuberosity. Five patients were diagnosed with stage I disease, 4 with stage II disease,
and 1 with stage III disease at presentation (Table 1). The patients with melanoma involving the hard palate had a high incidence of nodal metastases (66%) as well as the cases involving the alveolar arch (50%). No nodal metastases were observed in patients in whom the buccal mucosa was affected. In histologic terms, 3 OMMs were of the pigmented nodular type (Fig 1), 3 were of the pigmented macular type, 2 were of the nonpigmented nodular type, and 1 was of both the nonpigmented macular and degenerate type. In 1 patient lymph node metastasis of malignant melanoma cells showed the diagnosis of OMM. Univariate analysis of histologic features showed that the size of the tumor and tumor depth influenced survival, yielding a poor prognosis (P ⫽ .009 and P ⫽ .049, respectively) (Table 2). The adjusted hazard ratio was 4.513 (95% confidence interval, 1.47-13.89) for size and 1.919 (95% confidence interval, 1.033.59) for depth (Table 2). On review of the stage I patients, there were no patients with level I tumors. Of the tumors, 2 infiltrated into the lamina propria (level II) (40%), and 2 of 3 tumors at level III infiltrated into the bone and 1 infiltrated into the skeletal muscle (level III) (60%). The mean length of survival of patients with level II tumors was 102.5 months (180 and 25 months, respectively), whereas in patients with level III tumors, the mean length of survival was 47.7 months (133, 8, and 2 months, respectively). Univariate analysis showed that microstaging did not influ-
FIGURE 2. Survival of patients depending on tumor stage. Although, during initial survival, no differences can be found in both groups, stage I was associated with a better long-term outcome (not significant). (cum, cumulative.) Mücke et al. Primary Oral Malignant Melanoma. J Oral Maxillofac Surg 2009.
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PRIMARY ORAL MALIGNANT MELANOMA
Table 2. SIGNIFICANT HISTOLOGIC FEATURES FOR PREDICTION OF SURVIVAL
95% Confidence Interval
Histologic Criteria Size Depth
Mean
Lower
Higher
Hazard Ratio
P Value
2.85 cm2 1.34 cm
1.47 1.03
13.89 3.59
4.51 1.92
.009 .042
Mücke et al. Primary Oral Malignant Melanoma. J Oral Maxillofac Surg 2009.
ence prognosis significantly in this group. Age, gender, pigmentation, and primary tumor site were also not prognostic factors. Of the patients, 3 had local recurrences (30%), 3 had recurrences in the neck (30%) (Fig 3), and 6 had development of distant metastasis (60%). Two patients remained disease free at 154 and 155 months after primary diagnosis, and 3 patients survived for more than 5 years (30%). Of the 7 patients who died within the first 5 years, the mean length of survival was 19 ⫾ 17 months (median, 20 months).
Discussion Primary malignant melanomas affecting the mucosa represent a rare entity. Affected sites include the conjunctiva, upper respiratory tract, nasal cavity, paranasal sinuses, and oral cavity.5,14,15,19 The most affected areas in the oral cavity are the palate and the maxillary gingiva,3,4,10,20 both representing 80% of all melanomas in the oral cavity.5,8 Other affected locations are the mandibular gingiva, buccal mucosa, tongue, and floor of the mouth.3,4,8,10 In one of the largest studies, by Patel et al,10 a total of 24 OMMs were found with 37% involvement of the alveolus and 33% of the palate, which is in accordance with our findings. According to Greene et al,18 the criteria to verify the presence of a primary intraoral melanoma are as follows:
mary oral mucosal malignant melanoma is supported by the exclusion of other potential mucosal sites, for example, the respiratory and gastrointestinal tracts, which are more frequently found than OMMs.5,14,19 The age of the patients reported in the literature ranges from 20 to 80 years with a male preponderance.7 The incidence reported in Japan is higher than in Western countries.13 The mean age of the patients presented in this study was 65 years and is comparable to the literature, which ranged from 56 to 66.5 years.3,7,8,10,13,21 In an African population the mean age was 41 years (range, 18-60 years), which is very low.22 The etiology of oral melanoma is unknown. Some authors describe a pre-existing oral pigmentation for several months or years in one third of all patients with a primary malignant melanoma,6,7,23 although others found no correlation.24 The histologic spectrum of benign pigmentations is wide: macular hyperpigmentation caused by junctional proliferation with or without cellular atypical, melanocytic nevi, such as junctional, compound, subepithelial, blue, and combined nevi. Other causes of oral pigmentation include race; Peutz-Jeghers syndrome25; Laugier-Hunziker syndrome26; Addison disease27; patients with pulmonary diseases, especially lung cancer28; and hemosiderosis. Because of the high mortality rate from OMMs, excisional biopsy of small pigmented lesions should be made when other reasons for these pigmentations have been excluded.21,29 Although isolated oral pigmentation should be excised because the risk of dedifferentiation of pigmented lesions is still unclear,6,7,21,23,24,29 this can hardly be advised as a hard and fast rule in patients with widespread but not clinically characteristic pigmentation for purely pragmatic reasons. If an excision is not possible because of the size of the lesion or anatomic limitations, an
1. demonstration of clinical and microscopic tumor in the oral mucosa 2. presence of junctional activity in the lesion 3. inability to show any other primary site All patients presented in this study fulfilled these criteria. In addition to the standard staging procedure, patients in our department are further observed by means of sonography, gastroscopy, and bronchoscopy to exclude other potential primary sites and confirm by exclusion the diagnosis of primary oral mucosal malignant melanoma. We believe it valuable to ensure that the comparatively rare finding of pri-
FIGURE 3. Patient with OMM and lymph node involvement after neck dissection. The arrows show pigmentation of the malignant melanoma indicating recurrence at the neck. Mücke et al. Primary Oral Malignant Melanoma. J Oral Maxillofac Surg 2009.
MÜCKE ET AL
incisional biopsy has to be an alternative; however, on the basis of cutaneous melanoma, the risks of cutting into a melanoma during incisional biopsy causing accidental dissemination of malignant cells within the adjacent tissues or even into the blood or lymphatic stream may occur with probable devastating consequences.30,31 In a study by Kilpatrick et al32 all 3 patients were primarily misinterpreted as having desmoid tumor or squamous cell carcinoma after initial incisional biopsies of the malignant melanoma. In general, less is known about differences between incisional and excisional biopsy of OMMs because of the lack of studies on this topic. It may be appropriate to excise small pigmented lesions, but large tumors should be sampled with incisional techniques, excluding or confirming an OMM. Awareness of the morphologic diversity in OMM is important for diagnosis, which may be further compounded by frequent lack of melanin pigment.19 In this study, 30% of OMMs were nonpigmented. It should be kept in mind that epithelioid cell melanoma needs to be distinguished from undifferentiated carcinomas, such as poorly differentiated squamous cell carcinoma, desmoid tumors, and anaplastic large cell lymphoma.19 We identified 1 patient with OMM after metastases to lymph nodes, whereas the initial diagnosis of undifferentiated squamous cell carcinoma had been made. Early excision of disputed but suspicious lesions is advisable because of the higher risk associated with tumor size and depth as shown in this study. After we controlled for prognostic factors, patients with a 1-unit larger tumor had a 4.51-fold increased hazard rate for death. Deeper invasion of the malignant melanoma by 1 unit had a 1.92-fold increased hazard rate for death in this study. This is in keeping with other studies showing a correlation between the histologic depth of invasion and the prognosis of OMM.7,33 To our knowledge, a correlation between tumor size and prognosis has not yet been described. The increasing mortality risk created by increasing size and invasion supports early radical resection. Prasad et al15 showed a correlation between microstaging and survival of patients with malignant melanomas of the mucosa of the head and neck region. It is an easily interpretable system for tumors without lymph node involvement or distant metastases. In our series only 5 patients met the criteria for microstaging: 2 were at level II and 3 at level III. One patient in each group is still alive. Of the nonsurviving patients, metastases developed in all of them, and they showed a shorter length of survival after treatment at higher microstage levels (25 months at level II vs 2 and 8 months, respectively, at level III). Given the low number of patients with stage I disease in this study, the microstaging was statistically not
1413 found to be a significant predictor of survival, although this may simply reflect the available number of patients. The cumulative effect of tumor size, invasion, and microstaging on survival rates needs to be elucidated. Treatment of OMM remains controversial principally in relation to supportive therapy.17,34 Surgery is the mainstay of treatment followed by empirically based postoperative radiotherapy, particularly if adverse prognostic pathologic features such as a positive lymph node are present, even though OMMs are regarded as poorly radiosensitive.34 Tanaka et al17 observed a 5-year cumulative survival rate of 35.5% in patients treated by radiation alone. Although surgeryrelated outcome still remains poor in the literature,6-8 this has not been analyzed in a site- and stage-specific fashion. We have followed the protocol of Umeda and Shimada,13 carrying out a radical resection of the tumor in our patients as well as the excision of any probable lymph node metastasis. This showed a mean length of survival of 60 ⫾ 67.7 months and a longterm survival rate of 30% (Fig 2). Again, to confirm the most appropriate treatment modality, site- and stagespecific comparisons would be necessary, but our data seem to support the concept of radical surgical treatment. Resections in the head and neck area can be performed radically as long as vital parts are not affected and the possibility of reconstruction via microvascular tissue transfer exists. Large defects can be reconstructed immediately with the help of autologous tissue, and a collapse of structures in the oral cavity can be avoided with some retention of function. Umeda and Shimada13 recommended the following strategy: 1. excision of the primary lesion via an intraoral approach and involving at least 1.5 cm of healthy tissue 2. excision of any lymph node metastasis 3. consideration of chemotherapy The rationale for transoral excision is unclear, and it seems self-evident that any approach that allows 3-dimensional complete excision of the tumor with clear margins should be followed. Chemotherapy and systemic adjuvant therapies have not been supported for intraoral OMMs in recent trials14,35,36 but should be kept in mind for adjuvant and palliative purposes or the therapy of metastatic melanoma,13,20,35 provided that treatment does not further reduce the patient’s quality of life. Although we present a small sample of patients, our results are in accordance with reports with encouraging treatment results.6,13
1414 Controversy still remains on the issue of prophylactic neck dissection.20,37 Oral melanoma is more often associated with cervical lymph node metastasis than other regions.10,12,21 Some authors state that a neck dissection should be performed only when lymph nodes are palpable preoperatively.38,39 In this study, the proportion of patients presenting with lymph node metastasis was 50%, whereas in other studies the proportion is between approximately 13% and 21%.19 According to Tanaka et al,17 neck dissection should be reserved for cases with preoperatively unclear or confirmed lymph node metastases. The most practicable examination techniques of the regional lymph nodes are palpation and ultrasound.40 The status of the neck should be confirmed by multiple methods in accordance with local practice, such as CT or MRI with or without additional ultrasound scanning, which allows a more sensitive statement about the neck status in specifically trained hands.40,41 Early detection of subcutaneous and regional metastases in patients with oral melanoma may improve the outcome, because surgery can be performed without delay. Early identification of OMM and treatment by radical surgery with adjuvant treatment modalities, if considered relevant, are the most important strategies in dealing with this rare highly malignant disease. Histologic evaluation is important to assess the patient’s individual risk for metastasis and outcome. Preoperatively, dedicated analysis of the lymph node status should be performed by CT or MRI, supplemented by sonography to assess the stage of disease. The size and depth of the tumor should be routinely measured by pathologic examination as well as the microstaging system in stage I tumors to identify the histologic prognostic factors. In addition, early biopsy and close follow-up of any pigmented or unclear lesion in the oral cavity should be performed. More studies are needed to examine this kind of tumor, as well as its prognostic factors and influence on patient outcome.
References 1. Chang AE, Karnell LH, Menck HR: The National Cancer Data Base report on cutaneous and noncutaneous melanoma: A summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 83:1664, 1998 2. Moore ES, Martin H: Melanoma of the upper respiratory tract and oral cavity. Cancer 8:1167, 1955 3. Hicks MJ, Flaitz CM: Oral mucosal melanoma: Epidemiology and pathobiology. Oral Oncol 36:152, 2000 4. Barker BF, Carpenter WM, Daniels TE, et al: Oral mucosal melanomas: The WESTOP Banff workshop proceedings. Western Society of Teachers of Oral Pathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 83:672, 1997 5. Lee SP, Shimizu KT, Tran LM, et al: Mucosal melanoma of the head and neck: The impact of local control on survival. Laryngoscope 104:121, 1994
PRIMARY ORAL MALIGNANT MELANOMA 6. Liversedge RL: Oral malignant melanoma. Br J Oral Surg 13:40, 1975 7. Rapini RP, Golitz LE, Greer RO Jr, et al: Primary malignant melanoma of the oral cavity. A review of 177 cases. Cancer 55:1543, 1985 8. Rapidis AD, Apostolidis C, Vilos G, et al: Primary malignant melanoma of the oral mucosa. J Oral Maxillofac Surg 61:1132, 2003 9. Guzzo M, Grandi C, Licitra L, et al: Mucosal malignant melanoma of head and neck: Forty-eight cases treated at Istituto Nazionale Tumori of Milan. Eur J Surg Oncol 19:316, 1993 10. Patel SG, Prasad ML, Escrig M, et al: Primary mucosal malignant melanoma of the head and neck. Head Neck 24:247, 2002 11. Stern SJ, Guillamondegui OM: Mucosal melanoma of the head and neck. Head Neck 13:22, 1991 12. Temam S, Mamelle G, Marandas P, et al: Postoperative radiotherapy for primary mucosal melanoma of the head and neck. Cancer 103:313, 2005 13. Umeda M, Shimada K: Primary malignant melanoma of the oral cavity—Its histological classification and treatment. Br J Oral Maxillofac Surg 32:39, 1994 14. Mendenhall WM, Amdur RJ, Hinerman RW, et al: Head and neck mucosal melanoma. Am J Clin Oncol 28:626, 2005 15. Prasad ML, Patel SG, Huvos AG, et al: Primary mucosal melanoma of the head and neck: A proposal for microstaging localized, stage I (lymph node-negative) tumors. Cancer 100:1657, 2004 16. Tanaka N, Amagasa T, Iwaki H, et al: Oral malignant melanoma in Japan. Oral Surg Oral Med Oral Pathol 78:81, 1994 17. Tanaka N, Mimura M, Ogi K, et al: Primary malignant melanoma of the oral cavity: Assessment of outcome from the clinical records of 35 patients. Int J Oral Maxillofac Surg 33:761, 2004 18. Greene GW, Haynes JW, Dozier M, et al: Primary malignant melanoma of the oral mucosa. Oral Surg Oral Med Oral Pathol 6:1435, 1953 19. Prasad ML, Busam KJ, Patel SG, et al: Clinicopathologic differences in malignant melanoma arising in oral squamous and sinonasal respiratory mucosa of the upper aerodigestive tract. Arch Pathol Lab Med 127:997, 2003 20. Meleti M, Leemans CR, Mooi WJ, et al: Oral malignant melanoma: A review of the literature. Oral Oncol 43:116, 2007 21. Gorsky M, Epstein JB: Melanoma arising from the mucosal surfaces of the head and neck. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 86:715, 1998 22. Chidzonga MM, Mahomva L, Marimo C, et al: Primary malignant melanoma of the oral mucosa. J Oral Maxillofac Surg 65:1117, 2007 23. Chaudhry AP, Hampel A, Gorlin RJ: Primary malignant melanoma of the oral cavity: A review of 105 cases. Cancer 11:923, 1958 24. Meleti M, Mooi WJ, Casparie MK, et al: Melanocytic nevi of the oral mucosa—No evidence of increased risk for oral malignant melanoma: An analysis of 119 cases. Oral Oncol 43:976, 2007 25. Daley TD, Armstrong JE: Oral manifestations of gastrointestinal diseases. Can J Gastroenterol 21:241, 2007 26. Mowad CM, Shrager J, Elenitsas R: Oral pigmentation representing Laugier-Hunziker syndrome. Cutis 60:37, 1997 27. Lamey PJ, Carmichael F, Scully C: Oral pigmentation, Addison’s disease and the results of screening for adrenocortical insufficiency. Br Dent J 158:297, 1985 28. Merchant HW, Hayes LE, Ellison LT: Soft-palate pigmentation in lung disease, including cancer. Oral Surg Oral Med Oral Pathol 41:726, 1976 29. Anneroth G, Carlson GO, Eneroth CM, et al: Primary melanoma in the oral mucous membrane. Sven Tandlak Tidskr 66:27, 1973 30. Harter LP, Curtis JS, Ponto G, et al: Malignant seeding of the needle track during stereotaxic core needle breast biopsy. Radiology 185:713, 1992 31. Kusukawa J, Suefuji Y, Ryu F, et al: Dissemination of cancer cells into circulation occurs by incisional biopsy of oral squamous cell carcinoma. J Oral Pathol Med 29:303, 2000
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MÜCKE ET AL 32. Kilpatrick SE, White WL, Browne JD: Desmoplastic malignant melanoma of the oral mucosa. An underrecognized diagnostic pitfall. Cancer 78:383, 1996 33. Regezi JA, Hayward JR, Pickens TN: Superficial melanomas of oral mucous membranes. Oral Surg Oral Med Oral Pathol 45: 730, 1978 34. Medina JE, Ferlito A, Pellitteri PK, et al: Current management of mucosal melanoma of the head and neck. J Surg Oncol 83:116, 2003 35. Lengyel E, Gilde K, Remenar E, et al: Malignant mucosal melanoma of the head and neck. Pathol Oncol Res 9:7, 2003 36. Liarikos S, Rapidis AD, Roumeliotis A, et al: Secondary orbital melanomas: Analysis of 15 cases. J Craniomaxillofac Surg 28: 148, 2000 37. Gu GM, Epstein JB, Morton TH Jr: Intraoral melanoma: Longterm follow-up and implication for dental clinicians. A case
38. 39. 40.
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report and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 96:404, 2003 Snow GB, van der Esch EP, van Slooten EA: Mucosal melanomas of the head and neck. Head Neck Surg 1:24, 1978 Snow GB, van der Waal I: Mucosal melanomas of the head and neck. Otolaryngol Clin North Am 19:537, 1986 Blum A, Schlagenhauff B, Stroebel W, et al: Ultrasound examination of regional lymph nodes significantly improves early detection of locoregional metastases during the follow-up of patients with cutaneous melanoma: Results of a prospective study of 1288 patients. Cancer 88:2534, 2000 Blum A, Schmid-Wendtner MH, Mauss-Kiefer V, et al: Ultrasound mapping of lymph node and subcutaneous metastases in patients with cutaneous melanoma: Results of a prospective multicenter study. Dermatology 212:47, 2006
Tumor Size and Depth in Primary Malignant Melanoma in the Oral Cavity Influences Survival Thomas Mücke, MD,* Frank Hölzle, MD, DDS, PhD,† Marco R. Kesting, MD, DDS,‡ Denys J. Loeffelbein, MD, DDS,§ Luisa K. Robitzky,储 Bettina Hohlweg-Majert, MD, DDS,¶ Andrea Tannapfel, PhD, MD,** and Klaus-Dietrich Wolff, MD, DDS, PhD†† Purpose: Primary oral malignant melanoma (OMM) is rare, and there are few studies examining the
impact of this disease. This study aims to assess the outcome of surgically treated patients with OMM treated at a single institution. Patients and Methods: Ten patients with OMM treated at the Department of Oral and Maxillofacial Surgery, Ruhr-University Bochum, Bochum, Germany, between 1992 and 2002 were analyzed retrospectively. Treatment included wide local excision with or without modified neck dissection, supplemented by radiotherapy and chemotherapy. Clinical and histologic data were analyzed by univariate analysis. Results: Five patients were diagnosed with stage I disease, 4 with stage II disease, and 1 with stage III disease at presentation. The alveolar arch (40%) and palate (30%) were the most frequently affected sites. The adjusted hazard ratio was 4.513 (95% confidence interval, 1.47-13.89) for size and 1.919 (95% confidence interval, 1.03-3.59) for depth, yielding a poor prognosis (P ⫽ .009 and P ⫽ .048, respectively). The mean survival rate of the patients succumbing to disease was 19 ⫾ 17 months. Conclusions: Primary OMM carries a poor prognosis. Early identification of OMM and its treatment by radical surgery comprise the single most important treatment strategy. Any pigmented lesion in the oral cavity not clearly clinically amenable to diagnosis should be excised for histologic confirmation. Analysis of the lymph node status, supplemented by sonography or other imaging, and postoperative histologic evaluation of the size and depth should be performed routinely. In cases in which the mucosal melanoma may not be the primary site, all potential primary sites should be examined. © 2009 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 67:1409-1415, 2009 *Resident, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany. †Senior Consultant, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany. ‡Consultant, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany. §Resident, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany. 储Graduate Student, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany.
¶Consultant, Department of Oral and Maxillofacial Surgery, Klinikum Rechts der Isar der Technischen, Universität München, München, Germany. **Professor and Head of Department, Institute of Pathology, University of Bochum, Bochum, Germany. ††Professor and Head of Department, Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, München, and Department of Oral and Maxillofacial Plastic Surgery, University of Bochum, Bochum, Germany. Address correspondence and reprint requests to Dr Mücke: Department of Oral and Maxillofacial Surgery, Klinikum Rechts der Isar der Technischen Universität München, Ismaninger Strasse 22, 81675 München, Germany; e-mail: [email protected] © 2009 American Association of Oral and Maxillofacial Surgeons
0278-2391/09/6707-0008$36.00/0 doi:10.1016/j.joms.2008.12.021
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1410 Malignant melanoma in the head and neck area is rare. Oral cavity primary malignant melanoma comprises 6.3% of all melanomas in the head and neck area.1 Only about 0.7% to 1.6% of all melanomas arise in the oral mucosa.1,2 The incidence of primary mucosal melanomas of the head and neck is approximately 4 per 10 million of the population per year.3 The most frequently affected oral sites are the palate and maxillary gingiva (Fig 1).3-5 It is generally accepted that the outcome of oral malignant melanoma (OMM) is worse compared with that of cutaneous and overall head and neck melanoma. The 5-year survival rate reported in the literature for oral melanomas varies from 0% to 20%,6-8 whereas the overall survival rate for head and neck melanomas ranges between 20% and 48%.9-12 Treatment modalities for primary oral melanoma include surgical resection with or without neck dissection. Adjunctive modalities such as immunotherapy, chemotherapy, and radiation therapy may offer a supportive but as-yet-noncurative role. The mainstay of curative treatment is surgery, mandating complete resection of the tumor with clear margins.7,13 Immunotherapy and chemotherapy are techniques that are principally the subject of controlled trials or palliation.14 The rarity of head and neck melanomas, particularly the small proportion of oral melanomas, means that, to date, no randomized clinical trial has been conducted to establish an evidence base in the literature to provide comparisons of treatment modalities. The efficacy of surgery with planned supplementary radiotherapy remains unresolved and continues to generate controversy.10 Because of the rarity of this disease, most reports accumulate over an extended period of time. The disadvantage of such studies is obvious; there is a lack of consistency in immunohistochemical confirmation
PRIMARY ORAL MALIGNANT MELANOMA
of the diagnosis, staging strategies, and treatment planning because diagnostic techniques and treatment have evolved over recent years. The purpose of this study is to analyze our experience in treating primary OMM and to identify clinical and histologic predictors of outcome.
Patients and Methods Between 1992 and 2002, 10 patients (6 men and 4 women) with primarily intraoral melanoma were treated at the Department of Oral and Maxillofacial Plastic Surgery, Ruhr-University Bochum, Bochum, Germany. In all cases the diagnosis of OMM was established by microscopic and immunohistochemical examinations (positivity for S-100 and HMB-45). The extent of the tumor, tumor spread in relation to the underlying and surrounding tissues, resection margins, tumor thickness, and vascular and neural invasion were observed and described clinically and histologically. Patients with stage I disease were reviewed for microstaging as described by Prasad et al:15 level I, pure melanoma in situ without invasion or only microinvasion; level II, invasion limited to lamina propria; and level III, deep invasion into surrounding tissues. According to Tanaka et al,16,17 the types of OMM were histologically subdivided into 1) in situ melanoma, which is limited to the epithelium; 2) pigmented nodular type; 3) nonpigmented nodular type; 4) pigmented macular type; 5) nonpigmented macular type; 6) pigmented mixed type; 7) nonpigmented mixed type; and 8) degenerated type. As described by Greene et al,18 the diagnosis of primarily OMM was also verified by computed tomography (CT) or magnetic resonance imaging (MRI), skeletal scintigraphic surveys, sonography, gastroscopy, and bronchoscopy; therefore the possibility of a primary malignant melanoma elsewhere in the body was excluded during initial staging, ensuring that these cases were, in fact, primary oral mucosal malignant melanoma and not metastatic deposits. CT or MRI was used to evaluate the neck for regional disease. Patients were staged according to the Union Internationale Contre le Cancer as follows: stage I, confined to the primary site; stage II, positive cervical lymph nodes; and stage III, distant metastases.8-12,14,15 Clinical and histologic data were analyzed regarding the impact of outcome by univariate analysis by use of the log rank test. Differences were considered to be statistically significant at P less than .05.
Results FIGURE 1. Intraoral view of nodular type malignant melanoma arising from palate. Mücke et al. Primary Oral Malignant Melanoma. J Oral Maxillofac Surg 2009.
This study included 4 women and 6 men; all were white. The primary location of the tumor and the stage are shown in Table 1. Stage-dependent overall
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Table 1. DISTRIBUTION OF STAGE AND TUMOR LOCATION
Stage
Tumor site Palate Alveolus Floor of mouth Buccal mucosa Total
I
II
III
1 2 0 2 5
2 2 0 0 4
0 0 1 0 1
P Value NS
Abbreviation: NS, not significant. Mücke et al. Primary Oral Malignant Melanoma. J Oral Maxillofac Surg 2009.
survival of the patients is presented in Figure 2. Surprisingly, the relation between patient outcome and clinical stage at presentation was not significant (P ⫽ .647). Patients ranged in age from 45 to 93 years (mean, 65 ⫾ 12 years), with a median of 64.5 years. Presenting symptoms were oral pigmentation (50%), ill-fitting dentures (20%), and ulcers (10%), whereas 20% were discovered opportunistically on oral examination. Of the cases, 30% involved the hard palate (Fig 1); 30%, the alveolar arch; 20%, the buccal mucosa; and 10%, both the floor of the mouth and the alveolar arch including the maxillary tuberosity. Five patients were diagnosed with stage I disease, 4 with stage II disease,
and 1 with stage III disease at presentation (Table 1). The patients with melanoma involving the hard palate had a high incidence of nodal metastases (66%) as well as the cases involving the alveolar arch (50%). No nodal metastases were observed in patients in whom the buccal mucosa was affected. In histologic terms, 3 OMMs were of the pigmented nodular type (Fig 1), 3 were of the pigmented macular type, 2 were of the nonpigmented nodular type, and 1 was of both the nonpigmented macular and degenerate type. In 1 patient lymph node metastasis of malignant melanoma cells showed the diagnosis of OMM. Univariate analysis of histologic features showed that the size of the tumor and tumor depth influenced survival, yielding a poor prognosis (P ⫽ .009 and P ⫽ .049, respectively) (Table 2). The adjusted hazard ratio was 4.513 (95% confidence interval, 1.47-13.89) for size and 1.919 (95% confidence interval, 1.033.59) for depth (Table 2). On review of the stage I patients, there were no patients with level I tumors. Of the tumors, 2 infiltrated into the lamina propria (level II) (40%), and 2 of 3 tumors at level III infiltrated into the bone and 1 infiltrated into the skeletal muscle (level III) (60%). The mean length of survival of patients with level II tumors was 102.5 months (180 and 25 months, respectively), whereas in patients with level III tumors, the mean length of survival was 47.7 months (133, 8, and 2 months, respectively). Univariate analysis showed that microstaging did not influ-
FIGURE 2. Survival of patients depending on tumor stage. Although, during initial survival, no differences can be found in both groups, stage I was associated with a better long-term outcome (not significant). (cum, cumulative.) Mücke et al. Primary Oral Malignant Melanoma. J Oral Maxillofac Surg 2009.
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Table 2. SIGNIFICANT HISTOLOGIC FEATURES FOR PREDICTION OF SURVIVAL
95% Confidence Interval
Histologic Criteria Size Depth
Mean
Lower
Higher
Hazard Ratio
P Value
2.85 cm2 1.34 cm
1.47 1.03
13.89 3.59
4.51 1.92
.009 .042
Mücke et al. Primary Oral Malignant Melanoma. J Oral Maxillofac Surg 2009.
ence prognosis significantly in this group. Age, gender, pigmentation, and primary tumor site were also not prognostic factors. Of the patients, 3 had local recurrences (30%), 3 had recurrences in the neck (30%) (Fig 3), and 6 had development of distant metastasis (60%). Two patients remained disease free at 154 and 155 months after primary diagnosis, and 3 patients survived for more than 5 years (30%). Of the 7 patients who died within the first 5 years, the mean length of survival was 19 ⫾ 17 months (median, 20 months).
Discussion Primary malignant melanomas affecting the mucosa represent a rare entity. Affected sites include the conjunctiva, upper respiratory tract, nasal cavity, paranasal sinuses, and oral cavity.5,14,15,19 The most affected areas in the oral cavity are the palate and the maxillary gingiva,3,4,10,20 both representing 80% of all melanomas in the oral cavity.5,8 Other affected locations are the mandibular gingiva, buccal mucosa, tongue, and floor of the mouth.3,4,8,10 In one of the largest studies, by Patel et al,10 a total of 24 OMMs were found with 37% involvement of the alveolus and 33% of the palate, which is in accordance with our findings. According to Greene et al,18 the criteria to verify the presence of a primary intraoral melanoma are as follows:
mary oral mucosal malignant melanoma is supported by the exclusion of other potential mucosal sites, for example, the respiratory and gastrointestinal tracts, which are more frequently found than OMMs.5,14,19 The age of the patients reported in the literature ranges from 20 to 80 years with a male preponderance.7 The incidence reported in Japan is higher than in Western countries.13 The mean age of the patients presented in this study was 65 years and is comparable to the literature, which ranged from 56 to 66.5 years.3,7,8,10,13,21 In an African population the mean age was 41 years (range, 18-60 years), which is very low.22 The etiology of oral melanoma is unknown. Some authors describe a pre-existing oral pigmentation for several months or years in one third of all patients with a primary malignant melanoma,6,7,23 although others found no correlation.24 The histologic spectrum of benign pigmentations is wide: macular hyperpigmentation caused by junctional proliferation with or without cellular atypical, melanocytic nevi, such as junctional, compound, subepithelial, blue, and combined nevi. Other causes of oral pigmentation include race; Peutz-Jeghers syndrome25; Laugier-Hunziker syndrome26; Addison disease27; patients with pulmonary diseases, especially lung cancer28; and hemosiderosis. Because of the high mortality rate from OMMs, excisional biopsy of small pigmented lesions should be made when other reasons for these pigmentations have been excluded.21,29 Although isolated oral pigmentation should be excised because the risk of dedifferentiation of pigmented lesions is still unclear,6,7,21,23,24,29 this can hardly be advised as a hard and fast rule in patients with widespread but not clinically characteristic pigmentation for purely pragmatic reasons. If an excision is not possible because of the size of the lesion or anatomic limitations, an
1. demonstration of clinical and microscopic tumor in the oral mucosa 2. presence of junctional activity in the lesion 3. inability to show any other primary site All patients presented in this study fulfilled these criteria. In addition to the standard staging procedure, patients in our department are further observed by means of sonography, gastroscopy, and bronchoscopy to exclude other potential primary sites and confirm by exclusion the diagnosis of primary oral mucosal malignant melanoma. We believe it valuable to ensure that the comparatively rare finding of pri-
FIGURE 3. Patient with OMM and lymph node involvement after neck dissection. The arrows show pigmentation of the malignant melanoma indicating recurrence at the neck. Mücke et al. Primary Oral Malignant Melanoma. J Oral Maxillofac Surg 2009.
MÜCKE ET AL
incisional biopsy has to be an alternative; however, on the basis of cutaneous melanoma, the risks of cutting into a melanoma during incisional biopsy causing accidental dissemination of malignant cells within the adjacent tissues or even into the blood or lymphatic stream may occur with probable devastating consequences.30,31 In a study by Kilpatrick et al32 all 3 patients were primarily misinterpreted as having desmoid tumor or squamous cell carcinoma after initial incisional biopsies of the malignant melanoma. In general, less is known about differences between incisional and excisional biopsy of OMMs because of the lack of studies on this topic. It may be appropriate to excise small pigmented lesions, but large tumors should be sampled with incisional techniques, excluding or confirming an OMM. Awareness of the morphologic diversity in OMM is important for diagnosis, which may be further compounded by frequent lack of melanin pigment.19 In this study, 30% of OMMs were nonpigmented. It should be kept in mind that epithelioid cell melanoma needs to be distinguished from undifferentiated carcinomas, such as poorly differentiated squamous cell carcinoma, desmoid tumors, and anaplastic large cell lymphoma.19 We identified 1 patient with OMM after metastases to lymph nodes, whereas the initial diagnosis of undifferentiated squamous cell carcinoma had been made. Early excision of disputed but suspicious lesions is advisable because of the higher risk associated with tumor size and depth as shown in this study. After we controlled for prognostic factors, patients with a 1-unit larger tumor had a 4.51-fold increased hazard rate for death. Deeper invasion of the malignant melanoma by 1 unit had a 1.92-fold increased hazard rate for death in this study. This is in keeping with other studies showing a correlation between the histologic depth of invasion and the prognosis of OMM.7,33 To our knowledge, a correlation between tumor size and prognosis has not yet been described. The increasing mortality risk created by increasing size and invasion supports early radical resection. Prasad et al15 showed a correlation between microstaging and survival of patients with malignant melanomas of the mucosa of the head and neck region. It is an easily interpretable system for tumors without lymph node involvement or distant metastases. In our series only 5 patients met the criteria for microstaging: 2 were at level II and 3 at level III. One patient in each group is still alive. Of the nonsurviving patients, metastases developed in all of them, and they showed a shorter length of survival after treatment at higher microstage levels (25 months at level II vs 2 and 8 months, respectively, at level III). Given the low number of patients with stage I disease in this study, the microstaging was statistically not
1413 found to be a significant predictor of survival, although this may simply reflect the available number of patients. The cumulative effect of tumor size, invasion, and microstaging on survival rates needs to be elucidated. Treatment of OMM remains controversial principally in relation to supportive therapy.17,34 Surgery is the mainstay of treatment followed by empirically based postoperative radiotherapy, particularly if adverse prognostic pathologic features such as a positive lymph node are present, even though OMMs are regarded as poorly radiosensitive.34 Tanaka et al17 observed a 5-year cumulative survival rate of 35.5% in patients treated by radiation alone. Although surgeryrelated outcome still remains poor in the literature,6-8 this has not been analyzed in a site- and stage-specific fashion. We have followed the protocol of Umeda and Shimada,13 carrying out a radical resection of the tumor in our patients as well as the excision of any probable lymph node metastasis. This showed a mean length of survival of 60 ⫾ 67.7 months and a longterm survival rate of 30% (Fig 2). Again, to confirm the most appropriate treatment modality, site- and stagespecific comparisons would be necessary, but our data seem to support the concept of radical surgical treatment. Resections in the head and neck area can be performed radically as long as vital parts are not affected and the possibility of reconstruction via microvascular tissue transfer exists. Large defects can be reconstructed immediately with the help of autologous tissue, and a collapse of structures in the oral cavity can be avoided with some retention of function. Umeda and Shimada13 recommended the following strategy: 1. excision of the primary lesion via an intraoral approach and involving at least 1.5 cm of healthy tissue 2. excision of any lymph node metastasis 3. consideration of chemotherapy The rationale for transoral excision is unclear, and it seems self-evident that any approach that allows 3-dimensional complete excision of the tumor with clear margins should be followed. Chemotherapy and systemic adjuvant therapies have not been supported for intraoral OMMs in recent trials14,35,36 but should be kept in mind for adjuvant and palliative purposes or the therapy of metastatic melanoma,13,20,35 provided that treatment does not further reduce the patient’s quality of life. Although we present a small sample of patients, our results are in accordance with reports with encouraging treatment results.6,13
1414 Controversy still remains on the issue of prophylactic neck dissection.20,37 Oral melanoma is more often associated with cervical lymph node metastasis than other regions.10,12,21 Some authors state that a neck dissection should be performed only when lymph nodes are palpable preoperatively.38,39 In this study, the proportion of patients presenting with lymph node metastasis was 50%, whereas in other studies the proportion is between approximately 13% and 21%.19 According to Tanaka et al,17 neck dissection should be reserved for cases with preoperatively unclear or confirmed lymph node metastases. The most practicable examination techniques of the regional lymph nodes are palpation and ultrasound.40 The status of the neck should be confirmed by multiple methods in accordance with local practice, such as CT or MRI with or without additional ultrasound scanning, which allows a more sensitive statement about the neck status in specifically trained hands.40,41 Early detection of subcutaneous and regional metastases in patients with oral melanoma may improve the outcome, because surgery can be performed without delay. Early identification of OMM and treatment by radical surgery with adjuvant treatment modalities, if considered relevant, are the most important strategies in dealing with this rare highly malignant disease. Histologic evaluation is important to assess the patient’s individual risk for metastasis and outcome. Preoperatively, dedicated analysis of the lymph node status should be performed by CT or MRI, supplemented by sonography to assess the stage of disease. The size and depth of the tumor should be routinely measured by pathologic examination as well as the microstaging system in stage I tumors to identify the histologic prognostic factors. In addition, early biopsy and close follow-up of any pigmented or unclear lesion in the oral cavity should be performed. More studies are needed to examine this kind of tumor, as well as its prognostic factors and influence on patient outcome.
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