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Clinical and. pathologicprimary and metastaticthe head and neckdistinction betweenmucosal melanoma of

KATHLEEN R. BILLINGS, MD, MARILENE B. WANG, MD, JOEL A. SERCARZ, MD, an( ] YAO S. FU, MD,Los Angeles, California

Metas ta t i c mu cosa l me lan om a is ex t rem ely rare. Only 0 .6% to 9 .3% of pat ients w i th cutaneousmal ig nan t me lan om a wi l l have metas tases to the mucosa o f the upper aerod iges t i ve t rac t . Therecords o f a l l pa t ients w ith mucos a l m ela nom a of the hea d and neck a t the Universi ty o fCal i fornia, Los Angeles Medical Center dur ing the past 30 years were reviewed. Pat ients wi thpr imary tumors were separated f rom those w ith metas ta t i c invo lvem ent f rom a cutan eouspr imary s i te . These two groups were compared for d i f fe rences in c l in ica l symptoms, h is to-pa tho log ic f indings, t reatmen t, an d surv ival character ist ics. Frequent s ites of metas tat icinvo lvemen t inc luded the base o f tongue and nasa l cav i ty . These arose from a va r ie ty o fcutan eou s s i tes inclu ding the trunk and extremit ies and, in most instances, did n ot ar ise unt i l2 to 7 years a f ter the in i t ia l cu taneous lesion. Most o f those w ith metas tases to the head andneck muc osa had d isse minated d isease. The h is topatho log ic d is t inc t ion betwee n the twogroups is descr ibed w i th photomicrographs. Junc t iona l a c t i v i ty in the over ly ing or ad jac entmucosa d is tingu ishes pr imary mucosa l me lano ma f rom metas ta t i c d isease, in which theoverly in g mucos a is usual ly intact . This di f fere nce is useful in dete rmin ing wo rkup a ndt reatme nt opt ions . Aggress ive surg ica l resec t ion i s suggested in t reatmen t o f pr ima ry mela-nomas, whereas surgery is a t bes t pa l l i a t i ve in those w ith m etas ta t i c d isease. (OTOLARYNGOLHEADNECK SURG 1995;112:700-6,]

N o t u m o r d i s s e m i n a t e s m o r e w i d e l y o r i n v ol v e sm o r e o r g a n s t h a n m a l i g n a n t m e l a n o m a . 1 T h e m o s tf r e q u e n t s i te s o f m e t a s t a s e s f r o m c u t a n e o u s m e l a -noma are the reg iona l lymph nodes , lung , l iver , andb r a i n . 2 M e t a s t a s i s t o t h e m u c o s a o f t h e u p p e r a e r o -d iges t ive t rac t i s muc h l es s f requen t and i s o f t en no tapp rec ia te d c l inica lly . Au tops y s tud ies 1-3 have re -v e a l e d a n i n c i d e n c e o f m u c o s a l m e t a s t a s e s t o t h eh e a d a n d n e c k i n 2 % t o 9 . 3 % o f t h o se w i t h c u t a n e -o u s m a l i g n a n t m e l a n o m a . T h i s r e p o r t e v a l u a t e s 1 1p a t i e n t s i d e n t i f i e d w i t h m e t a s t a t i c m u c o s a l m e l a -n o m a t o t h e u p p e r a e r o d i g e s t i v e t r a c t . S p e c i a l a t -From the Division of Head and Neck Surgery (Drs. Billings,Wang, and Sercarz) and the Department of Pathology (Dr. Fu),University of California, Los A ngeles School of Medicine.Presented at the Annual Meeting of the American Academy ofOtolaryngology-Head an d N eck Surgery, San Diego, Calif.,Sept. 18-21, 1994.Receive d for publication Sept. 20, 1994; accepted De c. 30, 1994.Reprint requests: Marilene B. Wang, MD, Division of Head andNeck Surgery, UCL A Medica l Center, CH S 62-132, 10833 LeConte A ve., Los Angeles, CA 90024.Copyright 1995 by the Ame rican Acad emy of O tolaryngology-Head and N eck Surgery Foundation, Inc.0194-5998/95/$3.00 + 0 23/1/63069

ten t ion i s pa id to the c l in ica l cou rse , e f fec t on ou t -c o m e , a n d p a t h o l o g i c d i s t i n c t i o n b e t w e e n p r i m a r ya n d m e t a s t a t i c m u c o s a l d i s e a s e . P r i m a r y m u c o s a lm a l i g n a n t m e l a n o m a w a s t h e s u b j e c t o f a r e c e n ts t u d y c o n d u c t e d a t t h e U n i v e r s i ty o f C a l if o r n i a , L o sA n g e l e s M e d i c a l C e n t e r , f r o m w h i c h c o m p a r i s o n sare ma de in th i s s e r i es . 4METHODS AND PATIENTS

A c o m p u t e r s e a r c h o f t h e p a t h o l o g y r e c o r d s a t t h eU C L A M e d i c a l C e n t e r f r o m 1 9 6 3 t o 1 9 9 3 w a s c o n -d u c t e d t o i d e n ti f y t h o se p a t i e n t s w i t h m u c o s a l m e l a -n o m a o f t h e h e a d a n d n e c k . P a t i e n ts w i t h c u t a n e o u so r o c u l a r m e l a n o m a w e r e e x c l u d e d .

A n e x t e n s i v e c h a r t r e v i e w w a s d o n e t o s e p a r a t ep r i m a r y f r o m m e t a s t a t i c m u c o s a l d i s e a s e . A t o t a l o f11 p a t i e n t s h a d m e t a s t a t i c l e si o n s . D u r i n g t h is t i m ea s e a rc h b y t h e U C L A T u m o r R e g i s t r y re v e a l e d t h a t5 0 0 9 p a t i e n t s w i t h m a l i g n a n t m e l a n o m a w e r e s e e na t thi s in s t itu t ion , fo r an inc idence o f met as ta ses tot h e u p p e r a e r o d i g e s t i v e t r a c t o f 0 . 2 % ; a u t o p s y s t u d -i e s w e r e n o t i n c l u d ed . T e n p a t i e n t s w e r e f o l l o w e d u pa t U C L A f o r a n a v e r a g e o f 6 . 2 y e a r s ( r a n g e , 4m o n t h s t o 1 2 .6 y e a r s ) . O n e p a t i e n t n o t f o l l o w e d u p

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Table 1. Clinical characterisitics of patients with met astat ic muco sal me lan om a to the uppe raerodigestive tract

Patien t no./ Breslow's Site of Years to Trealm ent Years toag e (yr)/ Cutaneous Clark's depth mucosal mucosal of mucosal widespread Survivalsex origin leve l (mm ] metastasis metastasis metastasis metastasis status1/31/M Trunk II 0.9 Nasopharynx 5.0 Chemotherapy, BCG tumo r 7.3 DOD, 12.6 yrcell vaccine2/38/F Extremity IV 3.0 Floor of mou th 7.7 Excision 4.3 DO D, 8.9 yr3/47/M Extremity Ill 0.77 Posterior pharynx 0 NA 0 DOD, 4.0 mo4/67/F Trunk III 1.85 Base of tong ue 6.6 Excision, che moth erap y 3.1 DNED, 11.1 yr5/46/F Trunk III 1.0 Lateral tong ue 5.0 Excision, tumo r cell vaccine NA NA6/77/M Scalp IV 1.6 Base of tongu e 2.3 Excision 1.0 DOD, 2.3 yr7/46/F Trunk III 3.0 Nasopharynx 3.4 Excision NA DOD, 3.4 yr8/30/M Trunk IV NA Gingiva 8.3 Chemotherapy, radiation 7.3 DOD , 12.6 yrtherapy9/64/F Extremity NA NA Base of tong ue 7.3 Excision 4.0 DOD, 7.6 yr10/30/M Trunk NA NA Nasal cavity 3.4 Immunotherapy, radiation 3.8 DOD, 4.0 yr

therapy11/62/M Neck NA NA Nasal cavity 6.0 Interferon 5.3 DOD, 6.6 yrDOD,Dead of disease;DNED,dead with no evidence of disease;NA, data not available;BCG, bacillus Calmette-Gu&in.

at UCL A M edical Center was included in evaluationof the t ime of onset of metas ta t ic d isease .

The records of each pat ien t were evaluated forage, sex, location of Primary, location of head andneck mucosal metastasis , clinical course, treatment,and outcome. Slides , whenever available, were re-viewed by a senior pathologis t (Y. S. F.) to docu men this topathologic features useful in dis tinguishingmetas ta t ic f rom pr imary d isease . Specia l no te wasma de of junction al activity, epiderm al m igration,pigmentation, growth pattern, an d degre e of differ-entiation. Chi-squared analysis was performed todetermine whether the pathologic d i f ferences be-tween metastatic and primary lesions were s ignifi-cant. No t all s lides were available for review becauseof s ignificant earthqu ake damag e to the s toragefacility on Jan . 17, 1994.RESULTS

Of the 11 pat ien ts wi th metas ta t ic d isease to theupper aerodiges t ive t rac t mucosa , 5 were m en and 6were women (Table 1) . Average age at diagnosis ofcutan eous p rimary dise ase was 48.4 years (range, 30to 77 years ) . Three pat ien ts had metas ta t ic d iseaseto the base of tongue; 3 to oral cavity sites includingthe f loor of mouth, lateral tongue, and gingiva; 2 tothe nasopharynx; 2 to the nasal cavity; and 1 to theposterior pharynx. These arose from a variety ofcuta neou s s ites, including th e trun k in 6 of 11 (55%),extremities in 3 of 11 (27%), and head and neck in2 of 11 (18%).

Of these cutaneous lesions, information on

Clark 's level and Bres low's depth were docum entedin 8 of 11 patients . Seven of 11 (64%) patients inwhom metas ta t ic d isease subsequent ly developedhad Clark 's level III to IV lesions. Common symp-toms at diagnosis included bleeding (4 of 11), masslesion (3 of 11), pain (2 of 11), nasal obstruction (2of 11), and dysphagia (2 of 11).

Only one pat ien t had mucosal metas ta t ic d iseaseinitially, and on average, the remaining patients didnot have mucosal metastases until 5.5 years (range,2.3 to 8.3 years) after the cutaneous disease wasdiagnosed, as shown in Table 1. Some patients hadhad metastases to other areas before those involvingthe head and neck mucosa, including the regionallymph nodes (4), lung (2), skin (2), liver (1), andgastrointestinal tract (1) . Seven of 11 (64%) haddocumented ev idence of d is seminated metas taseswithin 4 years (range, 0 to 7.3 years) of initialdiagnosis. In two patients the p resenc e of metastaticdisease other than that to the upper aerodigestivetract mucosa was unknown. Those pat ien ts wi th baseof tongue or nasopharyngeal m etas tases mos t of ten~had multisystem involvement.

All patients u nderw ent w ide local excis ion of theirpr imary cu taneous les ion , and two had concomitan tregional lymph node dissection. Therapy for themetastatic disease varied from simple excis ion toimmuno therapy pro tocols and is d isp layed in Table1. Six patients underwent s imple excis ion of theirmucosa l m etastasis as initial treatme nt. Thre epat ien ts received chemotherapy , th ree immuno-therapy, and one bacillus Calmette-Gu6rin injec-


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Fig. 2. Primary mucosal mela nom a of the l ip demonstrating junctional activi ty in overlying mucosa(small arrow) as well as epide rmal migration (large arrow). (Hematoxylin an d eo sin stain; me diumpower.)

Fig. 3. Metastatic lesion of base of tongu e showing pred omin anc e of round, oval, and epithel ioidcel ls an d lack o f junctional activi ty in overlying mucosa. (Hematoxyl in and eosin stain; high power.]n o m a w h o d i e d o f t h e d i s e a s e w i th i n 2 y e a r s o fthe in i t i al d iagnos i s . My er e t a l . 5 desc r ibed then i n t h k n o w n c a se o f m e t a s t at i c m e l a n o m a t o t h etons i l in a pa t i en t wi th a C la rk ' s l eve l V l es ion on

the t runk . W i th in 3 years of in it i a l d iagnos is , thep a t i e n t h a d d i s s e m i n a t e d d i s e a s e a n d s u b s e q u e n t l yd i e d . T h e s e a n d o t h e r s i m i l a r c a s e s i l l u s t r a t e t h a t ,a l t h o u g h r a r e , m u c o s a l m e t a s t a s e s t o t h e h e a d a n d


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J u n e 1 9 9 5

neck are generally part of lethal widespread meta-static disease.In Henderson et al.'s series ~ of 8823 patient s withdisseminated malignant melanoma, mucosal me-tastases developed in 54, for an incidence of 0.6%.Sixty-two percent of these patients had evidence ofdisseminated'disease at the time of diagnosis of themucosal lesion. Autopsy studies of those with dis-seminated disease have reported an incidence of 2%to 9.3% with mucosal metastases to the head andneck. 13 The overall median survival has been re-ported at 3 to 6 months in patients with disseminateddisease. Patients with a shorter time to developmentof metastases have a decreased survival comparedwith those with longer times. 2'H'12 Isolated me-tastases in malignant melanoma represent less than1% of patients with metastatic disease and areassociated with a significantly bett er survival. 2The patient s described in this article are unusualin that only one patient initially had disseminateddisease including the mucosal metastasis. The re-mainder did not have mucosal metastases until 5.5years, on average, after the initial diagnosis. Sixty-four percent of the patients did have evidence ofdisseminated metastases at the time of diagnosis oftheir mucosal lesion, which concurs with the priorstudy. ~ Although a survival rate in this series aver-aging 7.0 years seems high, disseminated metastasesdid not develop until 4.0 years after primary diag-nosis. This lends support to increased length of timeto metastasis improving overall survival in patientswith cutaneous melanoma. Presence of a mucosalmetastases did not influence overall prognosis be-cause of the already uniformly fatal outcome asso-ciated with disseminated disease.Melanin cells can be found in respiratory epithe-lium, nasal glands, superficial and deep stroma ofthe septum, and middle and inferior turbinates) 3Rapini et al. 14 found that 37% of patients in whomprimary mucosal melanomas developed had preex-isting melanosis. The recent UCLA review of pri-mary mucosal melanoma4 identified 35 patients.Eighty percent of these primary lesions were locatedin the nasal cavity or paranasal sinuses, and 20% inthe ora l cavity and oropharynx. Common sites withinthe oral cavity included the palate and gingivalmucosa.Metastatic disease occurs in a variety of sitesincluding the tonsil, tongue, nasopharynx, larynx,and lip. In Henderson et al.'s series 1 the palate andgingiva appear to be spared by metastatic disease.The base of tongue and oral cavity were involvedmost frequently in our series. The gingiva was in-

volved in one case, marking this as another caselocated in this rare site. The larynx was not involvedin any of the cases, although laryngeal metastaseshave been reported.aS Of 22 cases of metastaticmucosal malignant melanoma to the larynx, thesupraglottic larynx was most commonly involved.This has been related to the more abundant vascularsupply and to the ease of invasion of the ossifiedcartilages by metastatic tumors. 8

The initial symptoms of those with primary andmetastatic lesions are similar and include nasal ob-struct ion, epistaxis, and a mass in the oral cavity.Diagnosis was made by physical examination orendoscopy. Radical surgical resection of primarymucosal melanomas is recommended, for a 5-yearsurvival of 45% in the UCL A s t u d y . 4 In contrast, inthe presence of widely disseminated disease, mostpatients in this study group received only local ex-cision, followed in a few cases by radiat ion therapy,chemotherapy, and immunotherapy.Despite the deadly nature of widespread me-tastases arising from cutaneous melanomas, primarymucosal melanomas are almost always more lethalthan their cutaneous counterpart, with a 5-yearsurvival from 10% to 38% and a relatively highrecurrence ra te despite early clinical stage at time ofdiagnosis.15 This may be rela ted to the lack of indu-ration or to patient delay due to failure to recognizethe nature and significance of pigmentation in thenasal and oral cavities, x6 Certain factors appear toworsen the prognosis, including ulceration, rapidgrowth, lymph node metastases, bone erosion, mul-ticentric origin, and absence of pigmentation. Likeprimary disease, metastati c disease is frequently notnoticed and may not be discovered until time ofautopsy.2,3 This suggests the need for a more thor-ough head and neck examination in those withdisseminated disease so that palliative therapy canbe offered for mucosal lesions.

Trodahl and Sprague 12 state tha t in de terminingprimary vs. metastatic mucosal disease the mainconsideration is involvement of the overlying epi-thelium. The changes in the junctional layer are thedominant features in the histogenesis of a melanomain the mucous membranes, as in the skin. 17 In meta-static mucosal disease, there is typically intact over-lying mucosa. 11

In this study distinct pathologic features weredemonstra ted that are useful in differentiating pri-mary and metastatic lesions. All metastatic lesionslacked evidence of junctional activity in the overly-ing mucosa and showed no epidermal migration.This is in contrast to primary lesions, in which 44%


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and 38% had junctional activity and epidermal mi-gration, respectively. Four of those that did notdemonstrate junctional activity had ulcerated sur-faces, making this feature difficult to delineate. Pig-menta tion was more commonly seen in the primary(69%) than in the metastat ic lesions (20%). Trodahland Sprague 12 found tha t metastases were pig-mented in all but one lesion they reported, but thenumber of cases has been too small to draw firmconclusions.

A mixture of cell types was found in bothprimary and metastatic mucosal disease, includinground, oval, and epithelioid- to spindle-shapedcells. This feature is therefore not as useful indistinguishing the two. A unique feature seen inthe primary lesions (25%) was the presence ofextension of the mela-notic pigment into the minor salivary glands. Thiswas not seen in any of the metastatic lesions. Whenprimary mucosal disease is considered, there ap-pears to be no correlation between size, location,or histologic appearance of the tumor and sur-vival. 18 In fact, Clark's classification does not applyto primary lesions because of the absence ofhistologic landmarks analogous to the papillary orreticular dermis in the mucosa. An attempt wasmade to correlate tumor thickness of primarymucosal lesions with 3-year survivaU9 This studyfound that 4 of 6 patients with lesions smaller than7 mm were disease free compared with 1 of 7 withlesions larger than 7 mm during this time period.Conley and Hamaker 2 noted that the verticalgrowth phase supervenes more quickly in mucosa,which may explain the frequent extension of mel-anosis into the minor salivary glands in this seriesof primary lesions. Conley and Pack 17 also foundthat the relative incidence of mucosal malignantmelanoma in proportion to benign nevi is higherthan on the skin and advised removing all pig-mented lesions of the mucosal surfaces for diag-nostic and prophylactic purposes.The thickness of the primary cutaneous lesion inthose with metastatic disease correlates with recur-rence rate and survival. 2~ All patients in this serieshad a Breslow's depth greater than 0.76 mm, whenreported. The poor survival rate was not surprisingin patients with metastases to the upper aerodiges-tive tract given that these lesions were rarely the solemetastasis. Palliative excision of these metastaticlesions was the most common treatment and isrecommended to provide relief of epistaxis, airwayobstruction, dysphagia, or other head and necksymptoms. Immunotherapy, chemotherapy, and ra-

diation therapy have all been used as palliativemeasures in those with disseminated disease, withlittle impact on overall survival.CONCLUSION

Metastatic malignant melanoma to the mucosalsurfaces of the upper aerodigestive tract is usuallypart of a widely disseminated disease process andtherefore has no impact on the overall survival andprognosis of these patients. Treatment of these le-sions is palliative in most instances, and survival isuniformly poor. Pathologic features, in particularthe lack of junctional activity in the overlying mu-cosa, allow the pathologis t to more easily distinguishprimary from metastati c disease. This is particularlyimportant in primary disease, in which aggressivesurgical resection can effect survival. Overa ll, themetastatic pattern of malignant melanoma is quitevariable, and no organ is immune from metastaticdisease.

We thank George S. Smith, MD, for assistance in thepathology search and Theodore Bell, PhD, for assistancein statistical analysis.REFERENCES

1. Einhorn LH, Burgess MA, Valle jos C, e t a l . Prognost iccorrela t ions and response to t reatment in advanced meta-static malignant melanoma. Cancer Res 1974;34:1995-2004.

2 . P ate l JK, Didolkar MS, Pickren JW, Moore RH. Metasta t icpat tern of malignant melanom a: a s tudy of 216 autopsy cases .Am J Surg 1978;135:807-10.

3 . Das Gupta T, Brasf ie ld R. Metasta t ic melanoma: a c l in ico-pathologic al study. Can cer 1964;17:1323-8.

4 . Lee SE Shimizu KT, Tran LM, Jui l l iard G, Calcaterra TC.Mucosal melanom a of the head and neck: the impact of localcontrol on survival. Laryngoscope 1994;104:121-6.

5 . Myer CM, Wood MD, Donegan JO. Me tas ta t i c me lanoma tothe palatine tonsil. Ear Nose Throat J 1983;62:62-4.

6 . Mosby EL, Sugg WE, Hiat t WR. Gingival and pharyngealmetastas is f rom a malignant melanoma: rep ort of a case . OralSurg Oral Med Oral Pathol 1973;36:6-10.

7 . El idan J , Sela M, Li jovetsky G, Wesh ler Z. M etasta t ic max-i l lary s inus melanoma treated by local excis ion and brach-therapy. J Otolaryngol 1989;18:293-6.8 . Fer l i to A, Caruso G. Secondary malignant melano ma of thelarynx. ORL J Otorhinolaryngol Relat Spec 1984;46:117-33.

9 . Free land AP, van Nos t r and AWE Jahn AF, M e tas tase s to thelarynx. J Otolaryngol 1979;8:448-56.

10. Henderson LT, Robbins KT, Weitzner S. Upper aerodiges-t ive t ract metastases in disseminated malignant melanoma.Arch Otolaryngol Head Neck Surg 1986;112:659-63.

11. Nambisan RN, Alexiou G, Reese PA, Karakousis CP. Earlymetasta t ic pat tern and survival in malignant melanoma.J Surg Oncol 1987;34:248-52.

12. Trodahl JN, Sprague WG. Benign and malignant melanocyticlesions of the oral mucosa. Cancer 1970;25:812-23.

13. Batsakis JG, Regezi JA, Soloman AR, Rice DH. The pathol-ogy of head and neck tumors: mucosal melanomas. XIII .Head Neck Surg 1982;4:404-18.


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14. Rapini RP, Golitz LE, Gr eer RO, Krekorian EA, Poulson T.Primary malignant melanoma of the oral cavity: a review of177 cases. Cancer 1985;55:1543-51.15. Blatchford SJ, Koopman CF, Coulthard SW. Mucosal mela-noma of the head and neck. Laryngoscope 1986;96:929-34.16. Snow GB, van der W aal I. Mucosal melanomas o f the headand neck. Otola ryngol Clin North A m 1986;19:537-47.17. Conley J, Pack GT. Melanoma o f the mucous mem branes ofthe head and neck. Arch Otolaryngol 1974;99:315-9.

18. Wenig BM. Atlas of head and neck pathology. Philadelphia:W.B. Saunders Co., 1993:67-72.19. Trapp TK , Fu YS, Calcaterra TC. Melanoma of the nasal andparanas al sinus mucosa. A rch O tolaryngol Hea d N eck Surg1987;113:1086-9.20. Conley J, Hamaker RC. Melanoma of the head and neck.Laryngoscope 1976;87:760-4.21. Breslow A. Thickness, cross-sectional area and depth ofinvasion in the prognosis of cutaneous melanoma. Ann Surg1970;172:902-8.

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