Introduction: Of all malignant processes of the oral mucosa, 0.5% are malignant melanomas. Because of late diagnosis, pattern of growth, close proximity to the bone (particularly in palatinal localizations), and the correlated infiltration, malignant melanomas have a bad prognosis. Patients and methods: In this retrospective study, six cases of patients with oral mucosal malignant melanoma are evaluated, and a critical review of the literature is presented. The female to male proportion was 1:1 with an average age of 60.2years; all patients were treated between January 1999 and July 2007. A neck dissection was performed on two patients because of clinically positive lymph nodes; one patient received interleukin 2 therapy, and three patients received postoperative radiotherapy. Two male patients died. Conclusions: We recommend biopsy on every growing lesion, pigmented or nonpigmented, for the required diagnosis and, in cases of malignant melanoma, wide excision as a second step. Neck dissections should be performed in patients with clinically positive lymph nodes. Concerning interleukin 2 therapy, further studies should be performed in order to evaluate a routine applicatio

Graetz, Klaus

Kruse, Astrid

Luebbers, Heinz-Theo

Riener, Marc

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ORIGINAL ARTICLEMucosal malignant melanomas in head and neck surgery:a retrospective study of six patients and reviewof the literatureAstrid L. D. Kruse & Marc O. Riener &Klaus W. Graetz & Heinz-Theo LuebbersPublished online: 12 March 2010# Springer-Verlag 2010AbstractIntroduction Of all malignant processes of the oral mucosa,0.5% are malignant melanomas. Because of late diagnosis,pattern of growth, close proximity to the bone (particularlyin palatinal localizations), and the correlated infiltration,malignant melanomas have a bad prognosis.Patients and methods In this retrospective study, six casesof patients with oral mucosal malignant melanoma areevaluated, and a critical review of the literature is presented.The female to male proportion was 1:1 with an average ageof 60.2 years; all patients were treated between January1999 and July 2007. A neck dissection was performed ontwo patients because of clinically positive lymph nodes;one patient received interleukin 2 therapy, and threepatients received postoperative radiotherapy. Two malepatients died.Conclusions We recommend biopsy on every growinglesion, pigmented or nonpigmented, for the requireddiagnosis and, in cases of malignant melanoma, wideexcision as a second step. Neck dissections should beperformed in patients with clinically positive lymph nodes.Concerning interleukin 2 therapy, further studies should beperformed in order to evaluate a routine application.Keywords Malignant melanoma . Oral mucosa . Head andneck oncologyIntroductionMelanoma of the mucosa is very rare, presenting in only1.3% of all melanomas [1], and it is especially rare inpatients below the age of 30 years [2]. The peak age isbetween 65 and 79 years [3]. No risk factors for intraorallesions have been clearly identified to date [4]. For mucosalmelanomas, distribution on the head and neck occurs in55.4% of cases, followed by anal/rectal (23.8%), femalegenital tract (18%), and urinary tract sites (2.8%) [1]. Themost frequently affected sites in the oral cavity are themaxillary gingival and the palate [5, 6], and they are morecommonly affected in Japan and Africa than in Westerncountries [2, 7, 8]. The development of oral malignantmelanomas (OMM) and the function of melanocytes in theoral mucosa have still not been clearly identified. Onereason for the rare appearance of OMM might be the lowconcentration of melanocytes in the oral mucosa. In singletissue sections of the gingiva, the ratio is one melanocyte to15 keratinocytes, whereas in the skin of the cheek, the ratiois 1:4 and in the trunk 1:14 [5]. Melanocytes migrate muchless frequently to endodermally derived mucosa—e.g.,nasopharynx, larynx, esophagus, or tracheobronchial tree;A. L. D. Kruse :K. W. Graetz :H.-T. Luebbers (*)Clinic for Craniomaxillofacial and Oral Surgery,University Hospital Zurich,Frauenklinikstr. 24,8091 Zürich, Switzerlande-mail: t.luebbers@gmail.comM. O. RienerDepartment of Pathology, University Hospital Zurich,Zurich, SwitzerlandOral Maxillofac Surg (2010) 14:143–147DOI 10.1007/s10006-010-0207-ztherefore, mucosal malignant melanomas are rare in theselocations [3]. Concerning the difference between oralmelanomas arising in the squamous or the respiratory(sinonasal) mucosa, the clinical outcome is slightly, but notsignificantly, worse in sinonasal melanomas. Prasad et al.[9] studied the difference in clinical behavior of 36 oralversus 59 sinonasal malignant melanoma. The latterdemonstrates more aggressive morphologic features, butprognosis remains similar in both groups. It is striking,however, that in the squamous mucosa men are affected 3.5times more frequently than women [9].Three criteria for the diagnosis of primary oral melano-ma were proposed by Greene et al. [10]: (1) demonstrationof malignant melanoma in the oral mucosa, (2) presence of“junctional activity” in the lesion, (3) and inability to showmalignant melanoma at another primary site. But junctionalactivity is now seen as an unreliable indicator that thelesion is primary because melanoma metastasis can alsoinvolve the epithelium junction.For determining the stage of cutaneous malignantmelanomas, Breslow’s depth of penetration and Clark’slevel of invasion, which correspond to the regional lymphnode status and presence/absence of metastasis, have beenused. Furthermore, two different growth patterns have beenmentioned: (1) a radial growth phase that tends not toinvade the underlying reticular corion but is associated withmetastasis and (2) the vertical growth pattern, invasive andgrowing before metastasis can occur [3]. For mucosalmalignant melanomas, Clark’s level of invasion cannot beapplied because of missing histological landmarks likepapillary and reticular dermis [11]; in addition, oralmalignant mucosas have a radial growth phase [2] withearly metastasis.Therefore, the purpose of this study was to determine theinitial symptoms, localization, stage, presence of regional ordistant metastases, and treatment.Patients and methodsThe records of all patients with mucosal malignantmelanoma from January 1999 to July 2007, six patients(three females, three males) treated at the Clinic forCraniomaxillofacial and Oral Surgery, University HospitalZurich, were systematically reviewed. Criteria for inclusionwere histologically proven primary malignant melanoma ofthe oral cavity. Criteria for exclusion were inadequateinformation, secondary oral malignant melanoma, andrecurrent disease. Data of site of tumor, histopathology,stage, presence of regional or distant metastases, treatment,recurrence, and outcome were analyzed.All patients had incisional biopsy performed beforedefinitive treatment.ResultsAge, sex, and primary sitesSubjects involved were three female and three male patientswith an average age of 60.2 years. All patients revealed anOMM of the maxilla. The initial clinical presentation islisted in Table 1.Initial symptoms, stages, and course of the diseaseThe primary symptoms were pigmentation in three casesand painless swelling in three cases (Fig. 1). No bleedingor pain as a first symptom was reported. In all patients, abiopsy was first performed, and wide excision followed asa second step. Two patients presented primary positivelymph nodes, so a neck dissection was immediatelyperformed.Histological findingsIn two (with clinical T1 status) out of the four patients, theprimary incisional biopsy was taken alio loco and a cleardetermination of infiltration depth was impossible, but inone of the two patients a superficial spreading growthpattern (patient 6 in Table 2) was observed. Concerningthe melanoma marker, HMB-45, S-100 protein, andtyrosinase were used. One case was an amelanoticmelanoma.The tumors consisted of highly atypical melano-cytes with partial pigmentation. They showed focalnecrosis and infiltration of the gnathic bones (Fig. 2a,Table 1 Initial clinical presentationGender Male 3Female 3Localization Lateral maxillary alveolus 4Anterior maxilla 2T status T1 2T2 1T3 0T4 3N status N0 5N1 0N2a 0N2b 0N2c 1N3 0Metastases M0 6M1 0144 Oral Maxillofac Surg (2010) 14:143–147b). Three of the cases were composed of spindle cellmelanomas.Treatment resultsTwo (male) patients out of six died because of themalignant melanoma. After 3 months, one of these twopatients had developed lung metastases; he receivedinterleukin 2 therapy after metastasis, but he died. Onemale patient had a recurrence.Three of the six patients underwent directly postsurgicalradiation therapy. None of the patients received chemother-apy (Table 2).DiscussionClinically, OMM can be divided into five types: (1)pigmented nodular, (2) nonpigmented nodular, (3) pig-mented macular, (4) pigmented mixed, and (5) nonpig-mented mixed type [12]. Differential diagnosis includedrug-, disease-, pregnancy-, or smoking-associated mela-nosis, oral melanotic maculae, Kaposi’s sarcoma, physio-logic pigmentation, melanoacanthoma, and nevus.OutcomeIt is generally accepted that the outcomes for oral malignantmelanomas are worse than those for the cutaneous form.About 10% of oral melanomas are amelanotic, and morethan 95% of the lesions are anti-S-100 antigen positive,with more specific markers including HMB 45, Melan-A,and antityrosinase [13]. These amelanotic malignant mela-nomas have a worse prognosis than other kinds because ofthe delays in establishing the correct diagnosis and alsobecause they are thought to be more aggressive thanpigmented melanomas [8]. One of the two patients thatdied had an amelanotic malignant melanoma (patient 2 inTable 2) and presented early lung metastases.Rogers et al. [14] reported that 50% of all patients withoral melanoma had regional lymph node metastases. In ourpatients, one with OMM revealed directly positive lymphnodes, so a neck dissection was performed. We did noelective neck dissection on N0 tumors. Lens et al. [15] did ameta-analysis of 1,522 cases and showed that there is noFig. 1 Painless swelling as a first symptomTable 2 Initial staging, treatment, and outcome of the presented patientsPatient Sex cTNM Treatment Local recurrence Metastases Survival Follow-up time(months)1 m T4N0M0 Resection, RT – Skin metastases DOD 12Recurrence (skin)Involvement of skull base2 m T3N2c0o Resection, bilat. neckdissection, RTLocal recurrence(17 months)Ileum metastases DOD 9Pulmonary and mesenterialmetastases3 f T4N0M0 Resection, RT – – Alive,tu-free324 f T1N0M0 Resection – Metastases lower eyelid Alive,tu-free425 f T4N0M0 Resection – Pulmonary metastasis Palliative 266 m T1N0M0 Resection – Contralateral cervical lymphnode metastasisPalliative 13Cheek metastasisCervical lymph nodemetastasisPulmonary, mediastinal, livermetastasesDOD dead of diseaseOral Maxillofac Surg (2010) 14:143–147 145significant overall survival benefit for patients undergoingelective neck dissections.There are different reasons for aggressive behavior inoral malignant melanomas. One reason is, on the one hand,the presence of the vertical more aggressive growth(nodular) with invasion of the underlying submucosa and,on the other hand, the radial growth (superficial spreading)phase that is characterized by early metastasis [5]. In thepresent study, one patient revealed a superficial spreadinggrowth pattern (patient 6 in Table 2) with primary T1 statusand early metastases. Furthermore, the diagnosis can bedelayed because most of the oral forms are painless in theearly stages and do not reveal ulceration like the oralsquamous cell carcinomas. In the present study, no patienthad ulceration, bleeding, or pain as a first symptom.However, the overall 5-year survival rate is <30% [16–18].Another important prognostic factor is the early metas-tasis in oral malignant melanomas because, in certainlocalizations like the palate, the tumor does not need toinvade very deeply before reaching the bone, and radiologicevidence of bony erosions has been associated with earlyhematogenous spread [2]. In our study population, allpatients had malignant melanomas in the upper jaw.In the oral cavity, wide excisions are limited because ofthe anatomical structures; therefore, surgical results cannotalways be compared between cutaneous and oral forms.The average age of patients with OMM in our studypopulation was 60.2 years of age; the age is, in general,higher in comparison to squamous cell carcinomas. Thehighest incidence in the group is between 40 and 70 yearsas reported [13, 19]. Therefore, the higher age also plays animportant role in the outcome.Bad prognostic factors, in general, correlate with tumorthickness and ulceration. Several studies also showed thatmale patients had a worse prognosis; the two patients that diedand the one patient with a recurrence were men. In general,malignant melanomas are found almost three times morefrequently in men than in women, though in the presentretrospective study the male–female distribution was 1:1.Gingival melanoma has a slightly greater 5-year survivalrate than that for palatinal melanoma, with a longer mediansurvival period (46 vs. 22 months). Nodal involvement withoral melanoma reduces median survival substantially from46 months to only 18 months [5]. In the literature, differentsurvival times are mentioned for OMM. Chang et al. [1]reported a 5-year disease-specific survival for OMM of 31.7%.Meleti et al. [7] reported a 5-year survival of only 15%.To sum up, the factors that are significant in lowerdisease-specific survival rates are primary high clinicalstage, tumor thickness greater than 5 mm, presence ofvascular invasion, absence of melanosis, and developmentof lymph node or distant metastases.Excisional versus incisional biopsyCytological tests on brushed samples seem not to bereliable [4] and are, like fine-needle aspiration, contra-indicated [3]. Concerning biopsies in malignant melano-mas, dissemination of malignant cells in the tissue, blood,or lymphatic stream is discussed. Bong et al. [20], in aretrospective study of 265 patients having an incisionalbiopsy of cutaneous melanoma and 496 control cases ofexcisional biopsy, reported no correlation of malignantspreading; and Lederman et al. [21] reported similar results.One patient had been lasered before because of pigmen-tation. We recommend that any growing lesion, pigmentedor nonpigmented, should be biopsied without delay for adiagnosis.TreatmentMost authors advocate wide local excision of the tumor [4,22]. Oral malignant melanomas are not very radiosensitive,but postoperative radiotherapy is generally recommended inFig. 2 a Melanoma infiltrating the maxillary bone (arrow), H&E, ×100. b Melanoma cells positive for HMB-45 (clone HMB-45, 1:50,DAKO, ×200)146 Oral Maxillofac Surg (2010) 14:143–147multiple positive nodes, in extranodal spread, and in poorprognostic pathologic features [7, 23].The goal of immunotherapy is an activation of immune-competent cells in the tumor defense when, for example,interferon or interleukin are administered [24]. Verma et al.[25] were able to show in a review that a high dose ofinterferon is associated with a significant improvement indisease-free survival and a reduction of 2-year mortality.Concerning interleukin 2 therapy, between 1985 and2006, Petrella et al. [26] reviewed noncomparative phase IItrials of high-dose, single-agent interleukin 2 with aresponse rate of 10–33% and with a complete responserate from 0% to 15%. The one patient that was treated withinterleukin 2 in the present study already had lungmetastasis and died. There is still a need for furtherinvestigations concerning immunotherapy in this particulargroup of malignancies.ConclusionEvery growing lesion, pigmented or nonpigmented,requires a diagnosis; therefore, we recommend biopsyand, because of anatomical limits, wide excision as asecond step. In cases of clinically positive lymph nodes,a neck dissection should be done immediately. Inpatients with negative lymph nodes, an elective neckdissection should not be offered directly. Despite theimprovement of surgical techniques and the introductionof new chemotherapeutic agents, prognosis of thismalignancy remains poor.Competing interests The authors declare that they have nocompeting interests.References1. 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Mucosal malignant melanomas in head and neck surgery: a retrospective study of six patients and review of the literature

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Mucosal malignant melanomas in head and neck surgery: a retrospective study of six patients and review of the literature

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