Primary malignant mucosal melanoma of the head and neck is a

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1 1373 Malignant Mucosal Melanoma of the Head and Neck Review of the Literature and Report of 14 Patients Spiros Manolidis, M.D., F.R.C.S.(C) 1 Paul J. Donald, M.D., F.R.C.S.(C), F.A.C.S. 2 1 Department of Otolaryngology Head and Neck Surgery and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts. 2 Department of Otolaryngology Head and Neck Surgery and Center for Skull Base Surgery, University of California, Davis Medical Center, Sacramento, California. BACKGROUND. Fortunately, primary malignant mucosal melanoma of the head and neck is a rare entity. A paucity of data elucidating the predictive factors as well as the unpredictable and aggressive biologic behavior of mucosal melanoma compound the vexing clinical situation. This review summarizes what the literature reveals about the epidemiology, patient survival, patterns of local recurrence, and local and distant metastasis of the disease. Over 1000 patients with this disease have been reported. Survivals at 5 and 10 years is 17% and 5%, respectively. Approximately 19% of patients present with lymph node metastasis and another 16% develop lymph node metastases after treatment, whereas 10% present with distant metastasis. Local metastasis does not affect survival; this is in sharp contrast with skin melanoma. Over 50% of patients experience local treatment failure, and salvage treatment is effective in only 25% of these cases. Local failure is the harbinger of distant metastases. Patients with nasal mucosal melanoma have a 31% 5-year survival rate, whereas sinus melanoma patients fare poorly, with a 0% rate of 5- year survival. METHODS. The authors conducted a retrospective review of 14 patients with characteristics similar to those in the literature in terms of outcome. RESULTS. The 5-year survival rate for these patients was 14%. Whole-body positron emission tomography was performed on 3 patients to detect metastatic disease. The patterns of local recurrence, distant metastasis, and survival for these patients were compared with the same data for patients described in the literature. CONCLUSIONS. Surgery appears to have the greatest efficacy in the management of mucosal melanoma, although radiation therapy may play an increasingly important role in the future. Cancer 1997;80: American Cancer Society. KEYWORDS: melanoma, mucosa, head and neck, review. Primary malignant mucosal melanoma of the head and neck is a rare entity. The paucity of data elucidating the predictive factors and the aggressive biologic behavior of this disease is a vexing clinical problem. Weber, in Germany in 1856, was the first to describe mucosal melanoma. 1 Lucke recognized it as a distinct clinical entity in 1869 on Presented at the Fourth International Head and Neck Cancer Meeting, Toronto, Ontario, Canada, resecting a melanotic sarcoma which arose from the nasal mucous August 2, membrane from a man age 52 years. 2 However, the literature commonly attributes the first case to Viennois, who in 1872 described a Address for reprints: Spiros Manolidis, M.D., similar case. 3 Lincoln, in 1885, was the first to report a mucosal mela- F.R.C.S.(C), Department of Pharmacology and noma of the head and neck in the U.S. 4 Ravid and Esteves, in the first Experimental Therapeutics, Tufts University comprehensive literature review of the topic, reported finding 117 School of Medicine, 136 Harrison Avenue, Boscases in their exhaustive worldwide search in In their review ton, MA of the topic, Batsakis et al. reported 531 cases in Since then, Received February 27, 1997; revision received several series have added approximately another 420 cases, bringing May 7, 1997; accepted May 7, the total number of reported cases to nearly American Cancer Society

2 1374 CANCER October 15, 1997 / Volume 80 / Number 8 TABLE 1 Patient Data Patient Melanoma DM at Local and regional Time no. site presentation recurrence Treatment DM after treatment Status (mos) 1 Nasal Regional 1 mo Surgery total Osseous, lung DOD 6 2 Nasal At 7 mos Surgery total, XRT Lung AwD 19 3 Nasal At 18 mos Surgery total AsD 30 4 Nasal Surgery total AsD 16 5 Oral cavity CNS, liver, lung Surgery total DOD 4 6 Nasal Surgery total DOC 32 7 Ethmoid Surgery subtotal DOD 4 8 Ethmoid At 4 mos Surgery total Liver, bone DOD 8 9 Maxillary Surgery total, XRT Lung AwD Nasal At 18, 30, 42 mos Surgery total Lung, bone AwD Nasal At 48 mos Surgery total Liver, lung DOD Nasal Liver, lung XRT DOD 4 13 Nasal Osseous No treatment DOD Nasal At 84, 128 mos Surgery total DOC 156 DM: distant metastases; DOD: dead of disease; AwD: alive with disease; DOC: dead of other causes; AsD: alive without disease; CNS: central nervous system; XRT: radiation therapy. In this article, 14 patients with this disease are Symptoms reported, and the literature is comprehensively reviewed. Twelve (86%) of the 14 patients presented with sympnoma toms related to the nose. The only oral cavity mela- patient presented with an asymptomatic mucosal MATERIALS AND METHODS lip lesion, and one patient presented with knee The records of all patients who presented with mela- pain as the only complaint related to an osseous metastasis noma between January 1985 and June 1995 at the University of a nasal melanoma. Six patients had only of California, Davis Medical Center, were re- one symptom at presentation (1 had obstruction and viewed. Of 377 melanoma cases that were treated at 5 had epistaxis); 3 of these patients were alive at short this institution during this period, 254 (67.4%) were follow-up (mean follow-up, 45.5 months). Three patients not head and neck, mucous membrane, eye, or urogenital presented with both obstruction and epistaxis; melanomas. Eighty-two cases (21.7%) were 2 were alive at short follow-up (mean follow-up, 35 head and neck, 16 (4.2%) were ocular (6 choroid, 4 months). Three patients presented with obstruction, ciliary body, 3 retinal, and 3 conjunctival), 10 (2.6%) epistaxis, and proptosis, indicating advanced disease; were urogenital (6 vaginal, 2 bladder, and 2 urethral), all 3 were dead at a mean of 5 months. and 1 (0.26%) was of unknown origin. Fourteen cases (3.7%) were mucosal melanomas of the head and neck Positron Emission Tomography and comprise the subject of this report. Three patients were investigated for distant metasta- For these 14 patients, the diagnosis of primary ses by whole body positron emission tomography mucosal melanoma of the head and neck was established (PET). In one, distant osseous metastases were found on histopathologic grounds and by ruling out and confirmed by computed tomography (CT) and by melanoma at another site. One patient presented with biopsy. In one, no distant metastases were found, and distant osseous metastases from a nasal mucosal mel- this patient was still free of metastasis on follow-up. anoma. The age range was years. The mean age The third patient had a false-positive PET scan; this was 70.7 years. There were seven males and seven result was confirmed by conventional CT and biopsy. females. Thirteen of these melanomas were sinonasal in origin and one was a lip melanoma. Of the nasal Follow-Up melanomas, five arose from the nasal cavity not otherwise Mean follow-up was 31.4 months, with a range of 4 specified, two arose from the nasopharynx, two months to 13 years. Five patients are alive today. Three from the inferior turbinate, and one from the nasal are alive with distant metastases at 19, 42, and 48 septum. There were three sinus melanomas, two eth- months. Two are alive without evidence of disease at moid and one maxillary. Data on the 14 patients is 16 and 30 months. Five-year survival was 14.3% (2 shown in Table 1. patients). One died of disease at 61 months and 1 died

3 Mucosal Melanoma of the Head and Neck/Manolidis et al of other causes at 13 years. Nine patients are dead, 2 advanced local disease as hypofractionated palliative of other causes (at 32 months and 13 years, respectively) treatment for local control, which it failed to achieve. and 7 of their disease (4 at 6, 8, 10, and 61 In the third instance, it was given as a hypofraction- months, respectively, and 3 at 4 months). For six of ated protocol to control local disease that was pre- the seven patients who died of their disease, the cause ceded by the development of lung metastases by 3 was distant metastases; in one, the cause was uncontrolled months. One patient was not treated, and in no in- local disease due to advanced presentation (tu- stances were chemotherapy or immunotherapy used. mor in frontal lobes by direct extension) and medical infirmity that limited surgical treatment to debulking. LITERATURE REVIEW Three of these seven patients presented with distant Incidence metastases (Stage III). Their survival was 4 months for Referral pattern bias makes it difficult to obtain an the patient with lip melanoma, 4 months for a patient accurate incidence of this malignancy. In addition, ra- with nasal melanoma treated with hypofractionated cial and possibly geographic differences in the incidence radiotherapy without response, and 10 months for a of mucosal melanoma of the head and neck woman whose first symptom was knee pain from osse- introduce a different type of bias. Nevertheless, a fairly ous metastasis and who did not receive any treatment. good assessment can be made if one studies the avail- able information. Local Recurrence Moore and Martin, in examining the cases of mel- Six patients (42.9%) experienced a local recurrence at anoma at the Memorial Sloan-Kettering Cancer Center some point during their follow-up. These recurrences from 1930 to 1948, found 26 cases of primary malig- occurred anywhere from 7 months to 7 years after nant mucosal melanoma of the head and neck. 7 These initial treatment. The only 2 patients to survive 5-years represented 1.7% of all melanoma cases and 6.3% of experienced local recurrences. One experienced a local all head and neck melanoma cases reviewed at this recurrence at 55 months, which preceded distant metastases institution. 7 Similarly, Pack et al. found the incidence by a few months and death at 61 months. The of melanoma of the mucous membranes of the head second 5-year survivor experienced 2 local recurrences, and neck to be 1.8% of all melanoma cases in their at 7 years and 10.8 years, and died of chronic series of 1190 cases. 8 Allen and Spitz found the inci- obstructive pulmonary disease (but was free of malignancy) dence of this type of melanoma in their series of 934 at 13 years. In both instances, recurrences were cases to be 1.05%. 9 From a different perspective, Holddence treated with aggressive surgery. craft and Gallagher found that sinonasal melanoma Of the remaining patients, 1 is alive and free of represented 3.6% of all sinonasal malignancies in the disease at 30 months after a local recurrence at 18 Armed Forces Institute of Pathology (AFIP) files. 10 In months. Two are alive with distant metastases, 1 at his series, Harrison reported that melanoma represented 3.5 years after 3 extensive resections. A second patient 12.5% of all the sinonasal malignancies he had with 3 local recurrences and pulmonary metastases is treated. 11 In 1990, Conley, in reviewing his extensive alive at 16 months. One died of disease at 8 months personal experience with head and neck melanoma, after local recurrence preceding the development of found the incidence of upper aerodigestive and sinonasal distant metastases at 4 months. melanoma to be 6.7% of head and neck melanodistant mas. 12 This was a revision of his previously published Regional Metastasis figure of 6%, which has been widely quoted in the Only one patient (7.1%) developed a regional metasta- literature. 13,14 Shah et al., in a review of the Memorial sis 1 month after initial therapy for nasal melanoma, Sloan-Kettering Cancer Center experience during the and this preceded the development of distant metasta- period , reported that approximately 20% ses by 4 months. of head and neck melanomas occurred in the mucous membranes. 15 This was a higher estimate than was Treatment given in the previous study conducted at the same Overall, 10 patients (71%) received full surgical treat- institution. 7 In 1976, Scotto et al. examined 432 noncutaneous ment with total macroscopic resection; in only 1 instance, melanomas only. He found that upper aerodiment surgery involved subtotal resection. Three pa- gestive tract and sinonasal melanomas accounted for tients received radiotherapy. In one instance, the radiotherapy 3.6% of these. 16 Hormia and Vuori, in a study of the was adjuvant treatment for a nasal Finnish cancer registry from 1953 to 1964, reported melanoma; that patient is alive with distant metastases that the ratio of head and neck mucosal melanoma to to the lung but with local control at 36 months. In the all malignancies was 1:11,626. In the same study, the second instance, it was administered to a patient with ratio of head and neck mucosal melanomas to head

4 1376 CANCER October 15, 1997 / Volume 80 / Number 8 and neck melanomas was 1: Andersen et al., who epithelia, compared with 800 melanocytes/mm 2 on reviewed data on a study population of 2.5 million in the abdomen and 2380 melanocytes/mm 2 on the skin Denmark, reported that mucosal melanomas of the of the penis. 33,34 He also found that the ratio of dopa head and neck represented 0.8% of all melanomas and positive melanocytes to keratinocytes was 1:15 in gin- 8% of head and neck melanomas. 18 givae as compared with 1:14 on the skin of the trunk and 1:4 on the skin of the cheek. 35 Soames, by using Racial Differences the same method of dopa positive melanocytes that There is a racial discrepancy in the incidence of this measures active melanin synthesizing melanocytes, disease. Tagaki et al. found 105 cases of oral cavity studied the maxillary and mandibular gingival epithe- melanoma from the period in Japan. 19 The lia in adults. 36 He found, as in the studies of skin melanocyte incidence of cutaneous malignant melanoma in Japan density, great interindividual variation in the was 0.07% of all malignancies, making this malignancy number of melanocytes. 36 Zak and Lawson demonstrated 10-fold less frequent among the Japanese than among melanocytes in the respiratory mucosa, mu- whites. 19 However, among the Japanese, oral mela- cous glands,and deep stroma of the nasal cavity epithelia. noma made up 7.5% of all melanomas and 35% of 30 Furthermore, they demonstrated the universal mucosal melanomas, as compared with 1%õ and presence of stromal melanocytes in both blacks and 3.6%, respectively, for whites. 6,19 22 In a study of melanoma whites. 30 These melanocytes were not demonstrated incidence among Ugandan Africans, Lewis et al. in the only black newborn infant they studied; this found that sinonasal melanomas accounted for 2.6% result supported the theory of migration. Intraepithe- of all melanomas (4 of 152 cases). When the oral cavity lial melanocytes were demonstrated only in blacks, was included, malignant mucosal melanoma of the and this was in agreement with the clinical observation head and neck accounted for 10% of all malignant of Lewis and Martin that 13.5% of their Ugandan African melanomas. 23 However, Milton and Lane-Brown, who patients demonstrated visible pigmentation. 37 In studied 457 cases of melanoma occurring in black peo- addition, Cove pointed out that these areas of ectopic ple, found 8 cases of oral cavity melanoma, for an pigmentation corresponded with the areas of the high- incidence of 1.7% (which was comparable to that in est incidence of melanoma. 38 The relationship of clinical whites). 24 Other studies of ethnic groups of Iranian or melanosis of racial origin or benign melanin conwhites). Indian background reported slight variations in the taining lesion to mucosal melanoma is still under scrutiny. incidence of mucosal melanoma. 25,26 It is difficult to For the oral cavity, several authors reported that ascertain from these studies whether the incidence of mucosal melanoma was preceded by oral melanosis this specific type of melanoma is higher among Asians in 30 37% of their cases ,30 It has been suggested and blacks or whether the ratio of mucosal melanoma that melanosis represents the radial phase of the to skin melanoma is different due to a lower incidence growth of the tumor and precedes the vertical compo- of cutaneous melanoma in these racial groups. nent by years. 22 No survival advantage has been demonstrated for these patients with preexisting melanosis. Etiology 22 The etiopathogenesis of this form of melanoma is Batsakis et al., in an excellent review of the pathology poorly understood. The literature alludes to factors of mucosal melanomas, classified the intraoral such as tobacco use and exposure to formaldehyde melanocytic lesions into four distinct categories that without any substantiation. 27 It is clear, however, ascribed to them their clinical importance. 6 that mucosal melanoma is derived from melanocytes present in the mucosa that have migrated as 1. Amalgam tattoo neuroectodermal derivatives in the ectodermally derived This is caused by iatrogenic deposit of dental amal- mucosa This explains the relative infre- gam. It is twice as common as melanotic macules and quency of mucosal melanoma in nonectodermally 10 times as common as intraoral melanocytic nevi. derived mucosa, such as mucosa of the nasophar- Most frequently, it is found in the gingival and alveolar ynx, larynx, tracheobronchial tree, and esophagus, mucosae. It should be recognized as a distinct entity as these epithelia are of endodermal origin. 31 Shanon for which no further action is required. et al., in an extensive review, accepted only 10 cases of laryngeal melanoma Racial pigmentation Quantitative studies of the number of melanocytes This is found in up to 87% of blacks and is considered in these epithelia are also available. Szabo, in studying benign. Excision in these cases is not indicated; besides, the distribution of human melanocytes in the integument, it is not feasible in most instances, as the area found 1500 melanocytes/mm 2 in nasal and oral of pigmentation is rather extensive.

5 Mucosal Melanoma of the Head and Neck/Manolidis et al Melanotic macules better prognosis in the very young. A less virulent form These lesions represent discrete areas of increased of melanoma or better immunosurveillance were basal cell layer pigmentation. There is no increase in among the explanations he offered. 11 the number of melanocytes. They are most frequently Oral cavity melanoma occurs at a younger age found on the vermilion border of the lower lip and than sinonasal mucosal melanoma. Rapini et al., in on the hard palate. Some authors recommend their their review of 332 cases, found that only 37% were excision in areas where oral mucosal melanomas are older than 60 years, whereas 82% were younger than commonly found, as they pose a problem in differential 40 years. However, oral cavity melanoma, like sinona- diagnosis. sal melanoma, is rare in the very young. 22 tically. 6,19 22,39 4. Nevi Gender According to Rapini et al., these lesions are exceedingly In the gender distribution of the series of mucosal rare. 22 Batsakis et al. believe that nevi are certainly melanoma patients surveyed in this study, a predomi- more common than melanoma and also more com- nance of males was observed. Only two small series mon than what other reports in the literature imply. 6 (Panje and Moran and Lee et al.) showed a female Tagaki et al. and Buchner and Hansen demonstrated preponderance. 42,43 The series in which only nasal mucosal the malignant potential of these lesions. 19,39 Intramucosal melanomas were examined reported a total of nevi account for 55% of all nevi, whereas blue 172 patients, of which 98 (57%) were male and 74 nevi account for 36% and junctional nevi for 3%. Of (43%) were female. 10,11,44 46 Similarly, in the review of these, the blue nevi are benign. However, the distinc- Rapini et al. of only oral cavity melanomas, 271 of 467 tion is not always possible on clinical grounds. In addition, patients (58%) were male and 196 (42%) were female. 22 some authors suggest that repeated mechanical Thus, in both oral cavity and sinonasal mucosal mela- trauma may lead to malignant transformation. Therefore, nomas, there is a slight male predominance. No pubder. it is suggested that these be excised prophylac- lished study has examined survival as it relates to gennomas, However, among the few long term survivors, there is no gender predilection. 7,10,11,13,15,17,18,22,41 51 Age Sinonasal mucosal melanoma is primarily a disease of Sites adults and the elderly. The onset is typically 2 decades In the oral cavity, the palate (in 188 of 445, 42.2%) and later than that of skin melanoma. Ravid and Esteves, the alveolus (in 143 of 445, 32.1%) account for the in their review of the world literature in 1959, reported majority of cases. Specifically, the hard palate and the an age range of 29 to 84 years. 5 In the AFIP series, the maxillary alveolus are the leading sites for mucosal mean age was 61 years and the range was 17 to 84 melanoma of the oral cavity. The soft palate, the years. 10 In the series reported by Conley and Pack, the tongue, and the floor of the mouth are rare sites for age range was years, with 73% of the patients mucosal melanoma of the upper aerodigestive tract. older than 50 years. 14 Similarly, 78% of Harrison s pa- Exceedingly rare cases of primary mucosal melanomas tients were older than 50 years. 11 Shah et al. reported of the pharynx, larynx, and esophagus do exist. 58% of their patients to be in this age group, whereas Most laryngeal melanomas occur in the supraglottic 54% in the series of Conley and Pack and 50% in the region. 7,14,15,18,22,40 43,51 Only 10 cases of primary larynseries of Snow et al. were in this age group. 14,15,40 Stern geal mucosal melanoma have been reported. 22 Sites and Guillamondegui at the M. D. Anderson Cancer of oral cavity and pharyngeal mucosal melanoma are Center reported that60% of their patients were ages listed in Table years. 41 For mucosal melanoma of the sinonasal tract, Mucosal melanoma of the head and neck in the few authors have reported the site of origin with very young is an extremely uncommon entity. The series accuracy. The exact origin is often difficult to ascer- of Shah et al. included a patient age 4 years, and tain due to anatomic limitations and, for older pa- Harrison described a patient age 7 years. 11,15 Ravid and tients, due to lack of fiberoptic endoscopy and ac- Esteves described a black girl age 8 months who was curate modern anatomic and radiologic diagnostic alive after treatment without evidence of disease at techniques. Advanced stage at presentation with age 4.5 years. 5 This is the youngest patient reported involvement of multiple subsites is another reason to date. Harrison s patient who was age 7 years was for the lack of accurate data. Of 328 cases for which also described as a long term survivor despite still hav- information was available, 63 (19%) occurred in the ing macroscopic disease left after resection. This sinuses and 265 (81%) were nasal. Accurate ana- prompted Harrison to speculate on the reasons for tomic data was reported for 190 patients. The nasal

6 1378 CANCER October 15, 1997 / Volume 80 / Number 8 TABLE 2 Oral Cavity and Pharyngeal Mucosal Melanoma Sites Site No. of cases % of cases TABLE 3 Sites of Sinusoidal Mucosal Melanomas Site No. of cases Lip Nasal NOS 159 Buccal mucosa Septum 44 Soft palate Lateral wall 44 Hard palate Inferior turbinate 12 Palate NOS Middle turbinate 7 Maxillary alveolus Turbinate NOS 12 Mandibular alveolus Floor of nose 5 Alveolus NOS Maxillary sinus 32 Tongue Ethmoid sinus 8 Floor of mouth Frontal sinus 2 Pharynx Sinus NOS 21 Larynx Esophagus Total 328 Oral cavity NOS NOS: not otherwise specified. Total NOS: not otherwise specified. a symptom by any of those patients. 18 In the series of Stern and Guillamondegui from the M. D. Anderson Cancer Center, 57% had obstruction, 52% had episeptum accounted for 44 (23%) of the cases, and staxis, and only 15% had other symptoms. 41 In the the lateral nasal wall and turbinates combined acseries of Lee et al., 51% had obstruction and 40% had counted for 75 (39%). Forty two (22%) of these 190 epistaxis; only 3 of 35 patients had diplopia and/or cases were found in the sinuses. 5,7,10,11,14,15,40 44,47,49,51 proptosis. Ravid and Esteves, in reviewing the topic of muco- 43 sal melanoma, first noted the relative rarity with The duration of symptoms varied from a few which melanoma presents in the middle turbinate, weeks to up to 2 years. Harrison stated that the diagnoas well as the virtual nonexistence of melanoma sis of his patients was commonly delayed, and misdi- higher up in the superior turbinate or even in the agnosis contributed to this on several occasions. 11 The olfactory region. 5 The data presented here concur mean number of months of symptoms to diagnosis with this observation, which in the past has been was noted by Freedman et al. 44 to be 3.5 months, made on qualitative grounds. The rarity of mucosal whereas Andersen et al. 18 noted this to be 5 months, melanomas of the ethmoid and frontal sinuses is and other authors, such as Stern and Guillamonde- also noteworthy. Batsakis et al. noted two frontal gui, 41 Lee et al., 43 and Hoyt et al., 49 noted it to be 8 sinus and eight ethmoid sinus melanomas. 6 Sites months, 3 months, and 2 months, respectively. Conley, of sinonasal mucosal melanomas are listed in in examining his series, noted that 50% of his patients Table 3. had symptoms for 1 5 months, 11% had symptoms for 6 12 months, and 14% had symptoms for more Symptoms than 12 months. 15 Similarly, for the 27 patients in the Unilateral obstruction and epistaxis accounted for 85 AFIP series, the time from the onset of symptoms to 90% of the symptoms encountered. 6 Pain and facial diagnosis was less than 1 month for 5 patients, 1 4 deformity in advanced cases were more frequent. In months for 14 patients, and 6 24 months for 8 pa- the AFIP series, 86% of the patients presented with tients. 10 epistaxis and/or obstruction. In the series of Freedman In the oral cavity, approximately 35 37% of patients et al., which comprised 56 sinonasal melanomas, 88% have preexisting melanomatosis. 22 Snow et al. found that of patients had this dyad of symptoms. 10,44 In the same in 5 of their 13 patients with oral melanoma, the malig- series, 16% presented with pain and 9% had facial nancy was preceded by benign melanosis. 40 Lee et al. deformity. 44 Of Harrison s 40 patients, only 2 (0.5%) noted that in many cases the lesion was predated by a had facial deformity, and virtually all presented with pigmented area that exhibited increased growth. 18,43 It obstruction or epistaxis; but none had pain. 11 In the is quite common for neck metastases to be the present- series of Andersen et al., 83% had obstruction and ing sign in oral cavity melanoma because the primary 67% had epistaxis, whereas pain was not recorded as lesion is most often asymptomatic.

7 Mucosal Melanoma of the Head and Neck/Manolidis et al Histopathology review of oral cavity melanomas, stated that these resembled Pathologic diagnosis of melanoma hinges on the identification acral lentiginous melanoma histologically of intracellular melanin. Estimates of de- and clinically. 22 monstrable melanin in these lesions range from 50% Other histopathologic features that have been to 70%. 6 The next step in the diagnosis is conventional studied include lymphoplasmacytic reaction to tumors, staining with stains such as the Fontana stain. Enzyme angioinvasiveness, as the size and thickness of immunohistochemistry significantly improves the ac- tumors. Eneroth and Lundberg, in their review of mucosal curacy of diagnosis. Using the dopa reaction to demonstrate melanomas, first noticed the conspicuous abcuracy tyrosinase activity requires fresh tissue, which sence of any lymphoplasmacytic reaction to mucosal can be a drawback. In addition, the results for amelanotic melanoma. 51 Batsakis et al. noted that like acral lentigimicroscopy melanomas are not always positive. 52 Electron nous melanomas, there was only a slight lymphoplas- can also be utilized and is very specific in macytic reaction with acellular fibroplasia. 6 This des- its demonstration of premelanosomes. However, it is moplastic reaction is observed in a variant of skin melanoma, not sensitive enough, as many melanomas will not desmoplastic neurotropic melanoma, which necessarily demonstrate this subcellular organelle. 11,52 has a particular propensity to occur in the head and Two types of premelanosomes are recognized based neck. This observation has been confirmed repeatedly on morphology. Wright et al. attempted to show that and is often cited as the primary reason for the uncontrolled tumors with type A melanosomes were more likely clinical and biologic behavior of this maligtumors to metastasize. 53 Finally, immunohistochemistry has nancy. 15 added tremendously to our ability to make a confident Angioinvasiveness is another feature of this malig- diagnosis of malignant mucosal melanoma in the head nancy that has been consistently observed. The propensity and neck In general, melanomas react positively for early metastatic spread to distant sites has with antivimentin and NKI/C-3 antibodies. 52 It reacts been attributed to this finding. strongly with S-100, which is a calcium-binding protein Depth of invasion has been studied by a number found in neural tissues, and oral mucosal mela- of authors, with conflicting results. Shah et al., in their noma stains specifically with antibodies against the series of 74 mucosal melanomas of the head and neck, alpha subunit of S ,57 It also reacts strongly with observed that when the depth of invasion was less HBM-45, which is specific to melanoma cells. 52 Neither than 0.5 cm, the survival was 30% (3 of 10 patients); antikeratin antibodies nor antileukocytic antigen this dropped to 18% (4 of 22 patients) when the depth antibodies react with melanoma cells. 52 On pathologic of invasion was 0.6 cm to 1 cm, and only 10% (1 of 10 grounds, the differential diagnosis of an amelanotic patients) survived if the depth of invasion was ú1 lesion may include poorly differentiated carcinoma, cm. 15 Several years later, Iversen and Robins con- small cell carcinoma, lymphoma, sarcomas (rhabdo- firmed this observation on a qualitative basis by comparing myosarcoma, neurosarcoma, or angiosarcoma, poorly survival in patients with thin versus thick lemyosarcoma, differentiated), and metastasis from a primary skin sions. 59 More recently, Lee et al. investigated this topic melanoma and found survival to be adversely correlated with a Based on cellular composition, 3 different types depth of invasion exceeding 7mm. 43 Snow et al. observed of malignant mucosal melanoma can be distinguished: that mucosal melanoma was rarely encounof spindle cell, polygonal cell, and mixed cell. These are tered when the depth of invasion was less than 3 mm. 40 encountered with varying frequency. Batsakis et al. The absence of dermal elements make a classification noted that the spindle variant is much less common system similar to the one utilized in skin melanoma in skin melanoma than in mucosal melanoma. In the inapplicable. 6 The size of a lesion has not been corre- AFIP series of 39 cases, there was one spindle cell type, lated with survival. 15 Multicentricity, however, is frequently 13 polygonal cell type, and 25 mixed cell types. 10 Eneroth present and has been cited as an important and Lundberg, on the other hand, found 19 spindle factor in the local failure of surgical treatment leading cell types with 3 polygonal cell types and 14 mixed cell to poor survival rates. 44 types. 51 Freedman et al. studied the mitotic figures in the Staging various cell types and found the average mitotic figure There were 13 series in the literature for which de- per high-power field in their series of 56 patients to tailed information was available on stage at presentation. be 0.9. The spindle cell variant showed a mitotic index Of 547 patients examined, 75.3% presented of 0.5, and the polygonal cell variant showed an index with localized disease (Stage I), 18.1% had metastases of In these studies, no correlation between cell to regional lymphatics (Stage II), and only 6.6% type and survival was established. Rapini et al., in their presented with distant metastatic disease (Stage

8 1380 CANCER October 15, 1997 / Volume 80 / Number 8 TABLE 4 Sites and Stages of Disease at Presentation Year/study/no. of cases Stage I Stage II Stage III 1994/Lee et al. 43 / /Stern and Guillamondegui 41 / /Andersen et al. 18 / /Guzzo et al. 50 / /Shah et al. 15 / /Harrison 11 / /Eneroth and Lundberg 51 / /Freedman et al. 44 / /Conley et al./ /Moore and Martin 7 / /Hoyt et al. 49 / /Berthelsen et al. 47 / /Gilligan and Slevin 46 / Total no. of cases: % of total 75.3% 18.1% 6.6% Stage I: local disease; Stage II: regional metastasis; Stage III: distant metastasis. evaluable cases). 10,11,14,15,27,40 44,47 49,51,60,61 III). 7,11,12,14,15,18,41,43,44,46,47,49,51 In three series that in- primary lesion is such that lymphatic metastases do cluded only sinonasal melanomas (Harrison, 11 not alter its course. The observations of lymph node Freedman et al., 44 and Gilligan and Slevin 46 ), which metastases in cases of mucosal melanoma are given represented a total of 124 patients, 107 (86.2%) presented in Table 5. in Stage I, whereas only 13 (10.4%) had lym- phatic metastases at presentation. At presentation, 2. Local failure there was a higher incidence of Stage II disease Failure at the primary site is a significant problem with among patients with oral cavity melanomas. Sites this malignancy. Many authors have commented on and stages of disease at presentation are given in the importance of this. The propensity of malignant Table 4. mucosal melanoma to fail at the primary site has dire consequences for the survival of the patient. 42 Stern 1. Lymphatic metastases and Guillamondegui showed that of their 10 patients Overall, in 18.7% of patients with malignant mucosal who survived, 9 had no relapse. 41 Andersen et al. noted melanoma of the head and neck, lymphatic metastasurvival this discrepancy between recurrence free and crude ses were evident on presentation, whereas in 16.4% at 5 years. 18 of patients (90 of 550 evaluable cases), these develmation Of 484 patients in 14 series in which specific infor- oped after treatment. The total number of patients about local control was provided, 258 patients with lymphatic metastases before and after treat- (53.3%) failed locally. Pooled data from 9 studies (on ment was 33.4% (240 of 610 evaluable cases). The patients) provided information about the salvage year survival of patients with lymphatic metastases rate in local failure. For 49 of these 196 patients, sal- was 21.4% (14 of 66 evaluable cases) versus 30% for vage therapy was successful after 2 or more attempts patients without lymphatic metastases (42 of 141 to control the disease surgically, for a mean salvage rate of 25% and a range of 0 75%. 11,14,15,18,40 45,47 49,51 Shah et al. concluded that lymphatic metastases Rates of local failure and salvage are given in Table 6. do not impact on the survival of patients with this type of malignancy. In their series, the 5-year survival was 3. Distant metastases 27% for lymph node negative patients and 19% for Pooled data from 11 series showed the average distant lymph node positive patients. In contrast, cutaneous metastatic rate at presentation to be 10% (44 of 437 melanoma patients with positive lymph nodes had a patients). In 12 studies, data were available for metas- 39% survival, as compared with an 80% survival for tases after treatment; this average was 51.5% (171 of patients without lymphatic metastases at 5 years. 15 It 332 patients). is likely that the severity of this disease due to the In 4 series, information was available regarding

9 Mucosal Melanoma of the Head and Neck/Manolidis et al TABLE 5 Lymph Node Metastases in Mucosal Melanoma Cases with Year/study/no. of cases positive LN LN / 5yr LN0 5yr 1994/Lee et al. 43 / /Stern and Guillamondegui 41 /42 7 2/7 12/ /Andersen et al. 18 / /Guzzo et al. 50 / /23 6/ /Panje and Moran 42 / /Snow et al. 40 / /11 9/ /Shah et al. 15 / /20 15/ /Harrison 11 / /8 1975/Eneroth and Lundberg 51 / /Freedman et al. 44 / /Conley 12 / /Holdcraft and Gallagher 10 / /Hormia and Vuori 17 /11 7 1/7 1989/Hoyt et al. 49 / /Blatchford et al. 48 / /Barton 61 / /Berthelsen et al. 47 /38 12 Total no. of cases 204/610 14/66 42/141 % of total 33.4% 21.2% 30% LN: lymph node; LN / 5 yr: 5-yr survival of lymph node positive patients; LN 0 5 yr: 5-yr survival of lymph node negative patients. TABLE 6 Mucosal Melanoma and Local Failure Year/study/no. of cases Failure Salvage % salvaged 1994/Lee et al. 43 / % 1991/Stern and Guillamondegui 41 / % 1992/Andersen et al. 18 / % 1993/Guzzo et al. 50 / % 1986/Panje and Moran 42 / % 1978/Snow et al. 40 / /Shah et al. 15 / % 1975/Eneroth and Lundberg 51 / /Freedman et al. 44 / % 1972/Conley/ % 1989/Hoyt et al. 49 / /Blatchford et al. 48 / % 1988/Matias et al. 45 / /Berthelsen et al. 47 /38 21 Total no. of cases: /196 % of total 53.5% 25% 25% local failure and distant metastasis. Ninety of 123 pa- Survival tients (73.1%) who failed their initial treatment and In 21 series of malignant mucosal melanoma (962 pa- had local recurrence developed distant metastases. tients), mean survival at 3 years was 39.2%; the range These data showed local failure to be a harbinger of was 7 65% (93 of 237 patients). At 5 years, mean surdistant metastasis. 7,10,11,14,15,17,18,40 45,47 49 Data on dis- vival was 17.1%, with a range of 0 48% (161 of 937 tant metastases at presentation, developing later, and patients). At 10 years, mean survival was 4.8%, with a in relation to local control are given in Table 7. range of % (22 of 453 patients). In 3 series for

10 1382 CANCER October 15, 1997 / Volume 80 / Number 8 TABLE 7 Distant Metastases at Presentation, Developing Later, and in Relation to Local Control Year/study/no. of cases DM at pr DM later DM total DM local failure 1994/Lee et al. 43 / / /Stern and Guillamondegui 41 / / /Andersen et al. 18 / /Guzzo et al. 50 / /Panje and Moran 42 / / /Snow et al. 40 / /Shah et al. 15 / / /Harrison 11 / /Eneroth and Lundberg 51 / /Conley et al./ /Holdcraft and Gallagher 10 / /Hormia and Vuori 17 / /Hoyt et al. 49 / /Matias et al. 9 / /Blatchford et al. 48 / /Barton 61 / /Berthelsen et al. 47 / Total no. of cases 44/ / /405 90/123 % of total 10% 51.5% 58.5% 73.1% DM at pr: distant metastases at presentation; DM later: distant metastases developing later; DM total: distant metastases at presentation and developing later. which data on more than 10 years of follow-up were in these patients is to decrease the tumor burden in available, the survival was 1.2% (1 of 82 patients). order to ease symptoms. 5,7,10,11,14,17,18,40 44,47 51,60,61 Eneroth and Lundberg Lee et al., in their study of 35 patients with this reported this 1 survivor at 20 years in their series of disease, made a comparison between primary treat- 41 patients. 51 Data on disease specific survival is given ment modalities. 43 Six of 15 patients treated with radical in Table 8. surgery had local control of disease, versus 1 of 11 There was a site specific difference in survival. patients treated with local resection and 0 of 8 patients Patients with nasal melanoma fared better than those treated with radiotherapy, chemotherapy, or a combiwith either oral cavity or pharyngeal melanoma. In nation of the two. Similarly, the M. D. Anderson experience pooled data from 5 series (203 patients), 5-year survival with 42 patients showed that patients treated for patients with nasal melanoma was 30.9% (30 with surgery do significantly better. 41 of 97); for those with sinus melanoma, it was 0% (0 of In the series of Andersen et al. from Denmark, all 27 patients). For patients with oral cavity melanoma, survivors were treated with surgery. Six patients treated 5-year survival was 12.3% (8 of 65 patients); for those with single modality radiation had either no response (4 with pharyngeal melanoma, it was 13.3% (2 of 15 pa- patients) or a short-lived response (2 patients). Another tients). 7,15,40,42,44 6 patients treated with chemotherapy also had no re- sponse. None of the 6 patients treated with adjuvant Treatment chemotherapy had a complete response; all progressed Surgery rapidly to death from uncontrollable disease. 18 In another Surgery currently offers the best probability for cure European study by Guzzo et al. (from Milan), none and local control of malignant mucosal melanoma of of 5 patients treated with chemotherapy, immunotherapy, the head and neck. Radiation therapy and chemotherapy and radiation became disease free; all progressed have been used alone or in combination with sur- to death rapidly. However, 42 of 43 patients treated with gery. The results of treatment with these modalities surgery became disease free for variable periods of time, have been consistently disappointing. although only 5 of these patients did not relapse and Although many patients eventually die of this disease, the 4-year survival in this study was a dismal 7% for those some can survive for prolonged periods of time who received surgery as therapy. 50 Of the 21 patients of with local and even metastatic disease in a relatively Panje and Moran, the only 3 survivors were treated with indolent state. 44 The aim of local surgical intervention surgery alone, and 3 who received chemotherapy died

11 Mucosal Melanoma of the Head and Neck/Manolidis et al TABLE 8 Disease Specific Survival of Patients with Mucosal Melanoma No. (%) of patients surviving Year/study/no. of cases 3 yrs 5 yrs 7 yrs 10 yrs ú10 yrs 1994/Lee et al. 43 /35 16 (45%) 1991/Stern and Guillamondegui 41 /42 27 (65%) 20 (48%) 10 (26%) 1992/Andersen et al. 18 /26 9 (35%) 3 (16%) 1 (4%) 0 (0%) 1993/Guzzo et al. 50 /48 3 (7%) 0 (0%) 1986/Panje and Moran 42 /16 7 (44%) 2 (13%) 1978/Snow et al. 40 /26 9 (38%) 1977/Shah et al. 15 /74 15 (20.3%) 1976/Harrison 11 /40 19 (47.4%) 11 (27.5%) 3 (7.5%) 1975/Eneroth and Lundberg 51 /41 7 (17%) 3 (7%) 1 (2%) 20 yrs 1973/Freedman et al. 44 /56 26 (46.2%) 17 (30.9%) 1972/Conley/52 12 (23%) 1 (2%) 1969/Holdcraft and Gallagher 10 /31 4 (13%) 2 (7.5%) 1969/Holdcraft and Gallagher/26 24 (11%) 1 (0.5%) 1967/Catlin et al. 60 /22 5 (22.7%) 1960/Ravid and Esteves 5 /117 7 (6%) 2 (1.7%) 1955/Moore and Martin 7 /26 1 (4.5%) 0 (0%) 1969/Hormia and Vuori 17 /11 3 (27.2%) 2 (18%) 1989/Hoyt et al. 49 /15 1 (6.6%) 1 (6.6%) 0 (0%) 1986/Blatchford et al. 48 /9 2 (22.2%) 0 (0%) 1969/Barton 61 /11 3 (27.2%) 1984/Berthelsen et al. 47 /38 4 (19.5%) Total no. of cases: / /937 7/200 22/453 1/82 % of total 39.2% 17.1% 3.5% 4.8% 1.2% without response to their treatment. 42 At the Memorial Steward noted only a transient response in 3 of 15 Sloan-Kettering Cancer Center, radiation was used as a patients treated with radium implants or external palliative measure alone. 15 Harrison did not use radiaa beam radiation. 62 In 1991, Gilligan and Slevin reported tion to treat any of his 40 patients and reported 27.5% crude survival of 17.9% in treating 28 cases of sinona- 5-year survival. 11 Freedman et al. found no survival adtheir sal melanomas. Local control was achieved in 61% of vantage for patients treated with combined surgery and cases. 46 However, their cases lacked immunohis- radiation at 3 years and 5 years (60.7% and 34.2%, reexcluded tochemical confirmation; in addition, 20 cases were spectively) versus those who were treated with surgery due to advanced local or metastatic disease. alone (75% and 61.3%, respectively). Of the 18 patients In the 4 most recent series in which radiation was who were treated with radiation alone, none survived to used as the primary treatment modality, local control 5 years. 44 In contradistinction, Holdcroft and Gallagher, ranged from 44% to 61%. 63 The authors of these studies in their review of the AFIP series, showed that patients stressed the use of hypofractionation in the treatment treated with surgery alone survived a mean of 31 months, of this disease. Ample clinical and basic scientific evi- versus 43 months for those treated with surgery and dence lends support to the theory that melanoma has radiation. 10 With his results, Conley supported extended a high capacity for sublethal damage repair, making local resection over local resection alone. It is notewor- it resistant to conventional fractionation schemes. 64,65 thy that he reported a case of cure with radiation alone More recently, cutaneous malignant melanoma has and a case with distant metastases and spontaneous been treated by neutron beam radiotherapy with good regression. 12,14 More recent studies have reported better results in controlling disease locally in patients with 5-year survival and attributed this to advancements in Stage III melanoma Whether these results can be surgical techniques and to intraoperative and postoperaremains to be seen and can certainly provide fertile extrapolated to the mucosal counterpart of this disease tive patient care that allowed more radical procedures. 43 ground for newer treatment approaches. Radiation therapy Several authors have reported their experience with radiation therapy as the primary treatment modality. Chemotherapy Results of chemotherapy in mucosal melanoma of the head and neck are difficult to evaluate objectively.

12 1384 CANCER October 15, 1997 / Volume 80 / Number 8 There has been no report of chemotherapy as the only three patients who presented with obstruction, epistaxis, modality of treatment. In several studies, chemotherapy and proptosis were dead of disease at an avermodality was utilized in a noncontrolled fashion as adjuvant age of 6 months. therapy, with consistently disappointing results. At Three (21.4%) of our patients presented with Stage best, the occasional patient receiving chemotherapy III disease, but distant metastases developed in another has shown a transient, short-lived response. A variety 5, for a rate of 57.1%. In the seven patients who of agents have been used alone and in combination. died of disease, the cause was distant metastases in 6 Andersen et al. treated 6 of his patients with adjuvant (85.7%). Our rate of distant metastasis at presentation chemotherapy, with no observed response; similarly, was higher than that of the collected series, and our Guzzo et al. treated 5 patients with no response; and subsequent metastatic rate was comparable to that in the series of Panje and Moran, 3 patients were seen in other series. 10,11,14,15,27,40 44,47 49,51,60,61 treated with chemotherapy, with no response. 18,42,50,69 Local failure in this group of patients occurred 42.9% of the time. This compared favorably with previous Immunotherapy reports. Both 5-year survivors experienced local Immunotherapy has been used in the form of a bacil- relapses, so our salvage rate based on 5-year survival lus Calmette-Guérin vaccine to treat mucosal melanoma, was 33%. Two patients had 3 local relapses with distant but always as adjunctive treatment in isolated metastases on last presentation. For two of our pa- cases. As such, it is difficult to evaluate. More recently, tients who are alive without disease, the follow-up for skin melanoma, improved survival has been noted time has been insufficient to draw conclusions. As others for patients with metastatic melanoma treated with have stated, local recurrence is the harbinger of a polyvalent melanoma vaccine, as compared with a distant metastasis. It is also important to note that historic group of patients with disease in a similar although local recurrence may be unavoidable in this stage. 70,71 Others have reported mixed results with disease with current treatment modalities, its further such treatments. There have been no reports of similar aggressive treatment leads to prolonged survival time studies with mucosal melanoma. and provides good palliation, as others have noted. CONCLUSIONS Mucosal melanoma of the head and neck is a highly malignant tumor. Few survive for prolonged periods of time. Some claim that cure of this disease is not possible; indeed, long term survival statistics could substantiate this claim. Of the categories of mucosal melanoma in the head and neck, the ones that occur in the sinuses are the most lethal, followed by oral cavity, pharyngeal, and intranasal. Local failure is a significant problem for most treated patients, and the adequacy of margins is difficult to evaluate in such an anatomic area. The ques- tion of adequacy of resection versus diffuse melanomatosis has not been elucidated. Most patients who experience local failure can be successfully treated with curative intent when they do not present with concurrent distant metastases. In more recent series, in which surgical treatment has been aggressive and prompt due to early detection, salvage rates have been acceptable. In addition, local failure can be treated multiple times and result in prolongation of disease free survival. It is unclear whether modern surgical techniques, with advancements in patient care that have allowed us to perform more radical surgery, have impacted on the survival or local control of these patients. The problem is compounded not only by nonuniform stan- DISCUSSION The age range was 52 to 85 years and the mean age 70 years in our group of patients. This was similar to what other authors have reported for patients with nasal mucosal melanoma, which is a disease of the elderly. Our series contained only one oral cavity melanoma, and this was insufficient to skew the mean age. When information about the origin of melanoma was available, it indicated that the disease most often arose from the inferior turbinate or the septum. Three cases of sinus melanomas accounted for 21% of the total. In the series of Friedman et al., which comprised 56 patients with sinonasal melanoma, 16 (32%) had melanomas arising in the sinuses. In the same study, there were no 5-year survivors among the patients with sinus melanomas, and only 16% of them were alive at 3 years. 44 Two of our patients with ethmoid sinus melanomas presented with advanced disease. For one, treatment was not possible; for the other, despite treatment, survival was limited to 8 months. Our third sinus melanoma patient is alive at 3 years with distant disease after combined treatment for a melanoma of the maxillary sinus. Sinus melanomas are asymptomatic in this anatomically silent area until invasion of adjacent structures is evident. In addition, symptoms of epistaxis or sinusitis are not specific to this disease in order to raise clinical suspicion. Multiple symptoms at presentation are an ominous sign. In our series, the