Nevus Ota and Nevus Ito in American Negroes* Yutaka Mishima, M.D

NEVUS OTA AND NEVUS ITO IN AMERICAN NEGROES* YUTAKA MISHIMA, M.D. AND BARUKH MEVORAH, M.D.t

Nevus fusco-caeruleus ophthalmo-maxillaris Clinical Aspects Ota is a congenital pigmentary disorder of the Case 1.A35 year old Negro woman has had, skin and mucous membranes, observed fre-since birth, pigmented spots on both cheeks, quently in the yellow race. In 1938 (1) and 1939shoulders and the back. There has been no change (2), this condition was first reported by Ota at ain the extent or intensity of the pigmentation. The patient noticed, however, that the spots on dermatological society meeting in Japan. Thethe face become somewhat darker during her following year, Ota's pupil Tanino (3), published a detailed description of 26 cases. According tomenstruation. The past medical history is non-contributory. this description, the pigmentation was usuallyThe patient is an alcoholic and was admitted to unilateral, being most pronounced on the eye-lidsthe hospital for cirrhosis of the liver and bilateral and fading away towards the zygomatic andparotid gland enlargement. The physical examina- maxillary regions. These areas are innervated bytion revealed on both cbeeks, the upper and lower the first and second branches of the trigeminalright eye-lids and the left lower lid a maeular nerve. The lesions were composed of brown andpigmentation composed of brownish and bluish, blue maeules the size of which varied from thatpartially confluent, lentigo-like lesions. The of a grain of rice to that of a lentil. The overallcentral part of the areas was more bluish while the periphery was rather brownish, and the overall pigment picture varied from deep purplish-blue to light brownish-blue. In 17 of these cases, therepigmentary picture resembled that of a powder- blast burn. (Fig. 1-A). was an associated melanosis oeuli, and in 3 eases One blue-gray 2 x 4 em. maeule was located the condition was bilateral. behind the left ear, while behind the right ear Later, Ito (4) (1954) described under the namethere was another one extending above the ear and of nevus fuseo-caeruleus aeromio-deltoideus aalso toward the lateral part of the neck. The right similar nevoid discoloration in a Japanese woman.scapular, part of the posterior deltoid and the This condition differed from the above easesaeromio-clavieular regions were involved with a mainly in its area of involvement which corre-diffuse and uniform bluish to slate pigmentation spond to the distribution of Nn. supraclavicu-which was darker than that on the face. There lares posteriores and N. eutaneus braehii lateralis.were a few, scattered, brownish, lentigo-like lesions in this area. A few small, ill-defined and He found some sweating dysfunction and an ab- scattered maeules were present on the left scapular normal histamin skin test in the lesions andregion; their color, although similar to that on proposed a homolateral neurogenic factor in thethe right shoulder, was definitely lighter. (Fig. pathogenesis of the dispigmentation. 1-B). Along the midline, from the gluteal region to the posterior neck, there were several persistent CASE REPOET5 Mongolian spots. The pigmentation in these areas was bluish-slate, diffuse and of uniform intensity; Three eases of nevus Ota, in American Negroes, there were no brownish lentigo-like lesions. will be described. In one of them nevus Ito was Melanosis oeuli was observed. There were associated, and in another one a glaucoma wasgrayish-blue, flat and irregular spots around the discovered. cornea on both sides; they were much more pronounced on the right side. According to the *Fromthe Departments of Dermatology, Wayne State University College of Medicine andophthalmologists, the eyegrounds as well as the Detroit Receiving Hospital (Hermann Pinkus,rest of the eye-status were within normal limits. M.D., Chairman) Detroit, Michigan. (Fig. 2). Supported in part by research grant RG-4435 and C-2072 from the National Institutes of Health, The hard palate showed, along the midline, U. S. Public Health Service, and in part by re-several 2 to 3 mm. sized, light bluish macules in search contract DA-49-007-MD-584 from the Re-streak-like appearance. On the left border of the search and Development Division, Office of thetongue there were two, 8 to 10 mm. sized, bluish Suregon General, Department of the Army. t Senior Postdoctoral Trainee under P. H. S.maeules. The rest of the otorhinolaryngologie Graduate Training Grant 2G-309. status was found within normal limits by the Received for publication June 15, 1960. department of otorhinolaryngology of the hospital 133 134 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

A B FIG. 1-A (Case 1). A bilateral bluish brown spotted pigmentation in a 36 year old American Negress. The overall pigment picture resembles somewhat a powderblast burn—nevus Ota, Type IV. FIG. 1-B (Case 1). A dense bluish to slate pigmentation with scattered brownish lentigo-lilce spots— nevus Ito.

Gale 2. A 45 year old Negro man has had, sincebluish discoloration. The white of the left eye as birth, a large pigmented area on the left side ofwell as its palpebral eonjunetiva showed spots the face. Apparently, no change in the extent ofof slate pigmentation. The mucous membranes and the pigmentation has been noticed. The patientthe eyes of the patient were examined by the remarked, however, that the involved regionDepartments of Otorhinolaryngology and Oph- becomes definitely darker in summer and lighterthalmology. in winter time. The physical examination revealed a macular,E.N.T. Findings: slate to black, pigmentation involving, on the 1. Ear: the outer part of the left external canal left side, the cheek, eye-lids, forehead and nose. showed .some slate discoloration. The pigmentation passed slightly to the right of 2. Nose: the mueosa of the left inferior turhinate the midline on the nose and forehead; it also was also somewhat slate in color. extended slightly behind the left ear. The pig- 3. Oral Mueosa: to the left of the midline, the mentation was of uniform intensity on the fore- hard palate showed some ill-defined bluish head. The involved areas below the forehead, pigmentation. however, had a spotted appearance and showed lighter and darker slate to dark-brown maeules.Ophthalmologic Findings: The overall pigment picture resembled somewhat a 1. Conjunctiva: both the bulbar and palpebral powder-blast burn, although the macules had a conjunetivae on the left side showed a spotty, denser distribution than in the first ease. (Fig. 3). bluish-gray pigmentation. On the middle part of the hard palate and to the 2. Cornea: the endothelium showed a grayish- left of the midline there was some ill-defined and white pigmentation (left side only). NEVUS OTA AND NEVTJS ITO IN AMERICAN NEGROES 135

LA k

FIG.2 (Case 1). Melanosis bulbi of nevus Ota. Bulbar Conjunetiva around cornea shows bluish-grey, fiat and irregular pigment spots.

3. Iris: on the left side it was deep brown andthe pigmentation involved the right cheek it did darker than that on the right side. not extend beyond the naso-lahial fold and did 4. TJveal Tract: definite increase in bluish-blacknot involve the mandibular region. pigmentation which showed through the This lack of pigmentation beyond the naso- selera (left side only). labial fold and on the mandibular region was a 5. Fundus: black pigmentation on the laminacommon finding in all three eases. cribrosa of the optic disc, (left side only). 6. Intraocular Tension: 30mm. of Hg. AlthoughOphthelmnologic Findings: a glaucoma was suspected, all other examinations failed to confirm its existence. 1. Conjunetiva: blotchy, bluish-gray pigmenta- Cese 3. This Negro, middle-aged male patient tion (right side only). was primarily seen by the Department of Oph- 2. Cornea: negative. thalmology. We were consulted for the pignienta- 3. Iris: slight increase of pigmentation on the tion on this patient's face and discovered that this right side. was a typical nevus Ota. 4. Uveal Tract: excess of bluish-black pigmenta- The pigmentation has been present on the right tion (right side only). side of the face since birth, and the patient could 5. Fundus: pigmentation of the optic disk in not remember any change in intensity or extent the lamina eribrosa (right side only). of the discoloration. The physical examination 6. Intraocular Tension: right side—50.6 mm. revealed on the right side a spotted bluish- of Hg, left side—16 mm. of Hg. This finding brown pigmentation involving both eye-lids, the as well as all other examinations confirmed periorbital region and the cheek; it extended the presence of glaucoma on the right side. toward, and involved the right ear lobe. Although (Fig. 4-A, B). 136 THEJOURNAL OF INVESTiGATIVE DERMATOLOGY

connected with each other. They were packed with brown pigment granules masking their nuclei. On close examination, however, one could see in the center of these cells ellipsoid nuclei. (Fig. 6). Kawamura (5) pointed out, in his study of Japanese cases, that histologically the brownish freckle-like lesions show an increase in junctional melanocytes and pigment deposition which is microscopically identical with nevus spilus. Ac- cording to his findings the bluish areas do not show these changes. Melanin and mclanocytes were not definitely increased in the epidermis of our sections. However, histologically, epidcrmal hyperpigmcntation in the Negro skin may not be as easy to determine as it is in the white or

lit yellow race. In the Mongolian spot, which is diffusely bluish in color, the melanocytes are located in the lower two thirds or the lower half of the corium (Bloch (6); Gans and Steigleder (7)). On the other hand, in nevus Ota the dermal melanocytes FIG. 3 (Case 2). Nevus Ota of 45 year old Ameri- arc located predominantly in the upper corium can Negro. tending to approach the epidermis in some areas, where they are seen in the subpapillary layer of MICROSCOPIC FINOINGS the dermis. This superficial location of the nevus Ota cells was described by Ota and Tanino (2, Several biopsy Specimens were taken from the3) and was also observed in our sections. It is areas of nevus Ota and nevus Ito in case 1. possible that part of the brownish color of the Microscopic sections were stained with: heina-lesions in our patient is due to the superficial toxylin-eosin, Dopa reaction, Masson's ammo-scat of the dermal melanocytcs. niated silver nitrate method, Liang's stain, Champy's stain and orcein-Giemsa. Dopa Reaction of Nevus Ota Cells The remarkable changes were in the upper Dopa positive granules were demonstrated in corium. There were heavily pigmented, slender,the scantily pigmented nevus Ota cells, while in fusiform melanocytes, most of which were seenthe heavily pigmented melanocytes a positive in the upper third of the pars reticularis. In ad-Dopa reaction was scarcely if at all observed. dition, some areas of our sections showed melano- Orcein-Stain for Elastic Fibers cytes in the subpapillary layer. A few melanocytes The elastic fibers in the upper corium were were found in the deeper dermis, sporadically around sebaceous glands, sweat ducts, sweatprominent. The general direction of the nevus Ota cells was parallel to that of the elastic fibers. glands, blood vessels and as far down as the fat They seemed to cling to the elastic fibers and the tissue. The melanocytes in the more superficialthin extensions of their finger-like ends were layers of the dermis were fusiform or stcllate while most of the deeply situated melanocytesdifficult to differentiate from the elastic fibers, were thread-like or fiber-like. even under oil immersion. (Fig. 7-A, B). Such a relationship was also observed in the sections The melanoctyes, referred to as nevus Ota cells, were somewhat wavy, and most of them hadfrom a Mongolian spot of an eight month old their long axis parallel to the skin surface. Al-human fetus (Fig. 7-C). though the general configuration of these cellsMelanocytes in Relation to Vessels and Eccrine was similar to that in a Mongolian spot, their Sweat Ducts average size and total number appeared larger. In some areas of the sections, melanocytes were Moreover, some of these melanocytes wereseen within vascular walls adjacent to the endo- NEVTJS OTA AND NEVUS ITO IN AMERICAN NEGROES 137

FiG. 4-A (Case 3). Right side fundus in nevus Ota. Pigmentation of the optic disk in the lamina eribrosa. Fia. 4-B (Case 3). Left side fundus in nevus Ota. No pigmentation was observed 138 THEJOURNAL OF INVESTIGATIVE DERMATOLOGY

A B Fin. 5-A. Type III (intensive type) of nevus Ota in a 27 year old Japanese woman FIG. 5-B. Melanosis bulbi in the same Japanese woman

—• .— .——--

—— 4c•' —• — — — — • I ' iet: 4-.., - 4.:.'

• - %. •e "I • S •. •'* ' II — • •_ -• • -s_i • I. '•a— • FIG. 6. Heavily pigmented, slender, fusiform nevus Ota cells, most of which are seen in the upper third of the corium. Section taken from the face and stained with hematoxylin and eosin. X 171. — •'

B as a

FIG. 7-A. Section of nevus Ota, stained with orcein to demonstrate elastic fibers. X 148. FIG. 7-B. X 880 enlargement showing the relationship between rievus Ota cells and elastic fibers. Section stained with orcein. FIG. 7-C. Section taken from the sacral region of an eight month old human fetus, showing Mongolian spot cells in close relationship with elastic fibers. Orcein. X 880. 139 $ S

B I'

FIG. 8-A. Fusiform, pigmented nevus Ota cells surrounding closely superficial blood vessels. ilema- toxylin and eosin. X 333. FIG. 8-B. X 990 enlargement, showing large, pigmented and well developed nevus Ota cells within and near the vessel wall. Hematoxylin and eosin. 140 NEVUS OTA AND NEVUS ITO IN AMERICAN NEGROES 141

a. Mild orbital b. Mild zygamatic

S r.

FIG. 0. Nevus Ota cells closely associated with Type Ill the peripheral cuboidal cells of uncoiled eccrine Intensive sweat ducts which normally do not contain any FIG.10.Classificationof nevus Ota according to melanin. Hematoxylin and eosin. X 560. the involved areas. thelial cells, as Becker (8) described recently. slate spotted pigmentation limited to the Most of these vessels were in the corium, although upper and lower eyelids. a few subcutaneous vessels were similarly in-Type lB. Mild Zygomatic Type: discrete brownish spots limited to the zygomatic region. volved (Fig. 8-A, B). In several sections nevus Ota cells were closelyType II. Moderate Type: deep slate to brown- associated with the peripheral cuboidal cells of purple, relatively densely spotted pigmentation the straight portion of sweat ducts which nor- on the eyelids, the zygomatic region and the mally do not contain any melanin. These melano- base of the nose. eytcs did not seem to enter the epithelial wall.Type III. Intensive Type: deep blue to bluish- (Fig. 9). purple, densely spotted or almost diffuse pigmentation on the eyelids, the zygomatic region, the base of the nose and the ala nasi, the fore- EEvIEw OF LITERATURE head, the external ear, the postauricular region Ota, Tanino (1, 2, 3,) were the first to recognize and the anterior part of the scalp. (Fig. 5-A, this entity and, in 1939, reported 26 cases out of B). 2300 patients examined in the dermatologicalType IV. Bilateral Type. department of Tokyo University. This repre- It was observed, in all types, that the pig- sented 0.84%. Tanino (3) classified his cases inmentation does not extend beyond the naso- four types. (Fig. 10): labial fold and does not involve the mandibular Type IA. Mild Orbital Type: light brown orregion. TABLE I Review of the European and American Literature on Nevus Ota and Nevus Ito

Color of No, of Race Color of Eye and Mucous Eye and Malignant Nature- Author Cases Sex Age of Onset Side Involved Skin Areas Skin Lesion Membranes Mucosal Changes & Author's Diagnosis Condition in Lesions Others Our Opinion

12 Hulke 1 White birth right eyelid, eyebrow deep sciera, fundus brown malignant melanosis nevus Ota 1860 F bronze (sciera) melanoma type I-a (fundus) 13 Schamberg 1 White birth left neck, chest, or- black- conjunctiva, black melanosis nevus Ota 1882 M bital area dark sciera, fundus type I-a violet 14 Schein 1 White birth left forehead, nose, slate conjunctiva, bluish melanosis nevus Ota 1905 M eyelid, cheek sciera, fundus type II 15 Kraemer 1 White birth right eyelid blue- conj unctiva, bluish melanosis nevus Ota . 1909 F black sclera type I-a 16 Coats 1 White birth bilat- cheek, nape, eye- conjunctiva melanosis nevus Ota 1912 F eral lid sclera, fundus type IV 17 Kestenbaum 1 White birth bilat- cheek, temple, brown conjunctiva, bluish glaucoma melanosis ? 1915 F eral eyelid, bridge to slate sclera, cornea, 88 mm. of nose, fore- iris, fundus Hg. (r.- head side) 18 Pusey 1 Clii- right nose, cheek, eye- brown conjunctiva, blue to pigmented nevus nevus Ota 1916 nese brow, temple, to black sclera slate type II M forehead, eye lid

19 Friedenthal, 1 White shortly bilat- eyelid slate to conjunctiva, bluish melanosis nevus Ota Friedenwald F after eral choc- sclera type IV 1925 birth late 20 Narducci 1 White right deltoid area slate ? melanosis nevus Ito 1926 F ? 21 Doherty Negro birth right cheek, nose, eye black conjunctiva, iris, bluish glaucoma melanosis nevus Ota 1927 F lid, forehead sciera, fundus, (r.-side) type II choroid 22 Ebert 1 White 20 year old left temple, eyelid bluish sciera bluish blue nevus? nevus Ota Nomland F (skin) grey black type I-b 1931 l5yearold (eye) 23 Goldschlag 1 White birth left eyelid, zygomatic steel- melanosis nevus Ota 1935 F region blue type I-a 24 O'Leary, 1 White 17 year old left temple, eyelid bluish benign melanosis, nevus Ota Montgomery, F metalic pig- type II? Brunsting mentation? 1935 25 . Cornell 1 White 25year old bilat- forehead, upper bluish sclera bluish blue nevus? nevus Ota 1937 F (skin) eral cheek black black argyria? type IV 16 year old (eye) 26 Jensen, 1 Clii- 20 year old right scalp, forehead, slate- nasal & oral mu- bluish progressive nevus Ota Haffly nese (skin) eyelid, cheek, grey cosa, conjun- to black melanosis oculi type III 1948 five year temple tiva, sciera, old (eye) iris, optic disk 27 Rothman, 1 Amer- birth (eye) right temple, cheek, bluish conjunctiva, bluish blue nevus (eye) nevus Ota Pinne (skin) ican 17 year old nose, periorbi- grey selera melanosis due to type II 1948 Jap- (skin) tal region contact (skin) anese F 28 Pariser, Beer- 1 White 20 year old bilateral forehead, scalp, deep sclera bluish blue patch nevus Ota mann F bridge of nose, blue type IV? 1949 cheek, forearm 29 Cole, Hubler- 1 Negro birth left forehead, orbital grayish sciera bluish persistent aber- nevus Ota Lung F region, cheek green rant Mongo- type III? 1950 han spot TABLE I—Continued

Color of Author Age of Onset Side Involved Skin Areas changes& Author's Conditiin a0e 1ace Skin Lesion EearoUS eCaflr Others Diagnosis Lesions our Opinion

1 White early child- upper back, neck slate- persistent aber- nevus Ito? M hood grey rant Mongo- lian spot 1 White birth (skin) bilateral eyelid, forehead, greyish conjunctiva bluish persistent aber- nevus Ota F childhood temple blue rant Mongo- type IV? han spot 30 Curtis 1 White 12 year old right temple, auricular dark sclera dark melanosis but- nevus Ota 1951 F area, eyelid col- col- borum, aher- type III ored ored rant Mongolian spots 31 Findlay, Rand 1 Negro two year bilateral forehead, cheek, deep, sclera bluish nevus Ota nevus Ota 1954 M old scalp, zygo- dusty type IV matic region greyish blue

1 Negro right forehead, nose, bluish selera bluish nevus Ota ncvus Ota M zygomatic re- type III gion 32 Jadassohn, 1 Negro right orbital area, bluish conjunctiva, bluish Mongolian spot nevus Ota Frances- M temple, maxil- to sclera type II chetti, Go- lary region, black lay lower part of 1954 ear 1 White bilateral eyelid, forehead, greyish sclera, iris, fun- bluish Mongolian spot nevus Ota M temple blue dus type IV 1 White after pu- tinilat- shoulder pigmen- Mongolian spot neVUS ItO F berty era! tation with black spot 33 Dorsey, Mont- 1 White birth left face conjunctiva, malignant nevus Ota nevus Ota gomery F sclera? (bilat- mela- (type?) 1954 eral) noma in area of nevus Ota 1 White birth right face bluish sclera, buccal bluish malignant nevus Ota nevus Ota M mucosa mela- (type?) noma arose in area of nevus Ota (zygomatic region) 34 Stuart 1 White 12 year old right temple, eyelid brown- nevus Ota nevus Ota ,_- 1955 M ish type II blue 35 Fitzpatrick, 1 Cauca- birth right eyelid, temple brown- sclera, fundus bluish nevus Ota nevus Ota Zeller, Ku- sian ish type II kita, Kita- F blue mura 1956 36 Helmick, 1 Negro birth right forehead, eyelid, bluish sclera bluish nevus Ota nevus Ota Pringle F ala nasi green type III 1956 1 White birth left cheek, forehead dark conjunctiva, bluish nevus Ota nevus Ota M brown sclera, iris type III 37 Kaminsky, 7 White birth (over unilat- forehead, cheek, brown- sciera slate nevus Ota nevus Ota Daitsch, (Ar- 50%) eral temple, eyelid ish blue (type?) Abulafia gen- 28 year old blue 1957 tin- (1 case) ian) 40 year old (1 case) TABLE I—Continued

Color of Malignant Nature- No. of Race Color of Eye and Mucous Eye and in Author Cases Sex Age of Onset Side Involved Skin Areas Skin Lesion Membranes Mucosal Changes & Author's Diagnosis Condition Lesions Others our Opinion

Mishima, 1 Negro birth bilateral cheek, eyelid, bluish conjunctiva, greyish nevus Ota nevus Ota Mevorah F auricular re- brown hard palate blue type IV type IV gion, bilateral shoulder slate nevus Ito nevus Ito — 1 Negro birth left forehead, eyelid, slate to conjunctiva, cor- slate to glaucoma? nevus Ota nevus Ota M cheek, nose, black flea, iris, uveal black (same type III type III auricular re- tract, fundus, side) 30 gion hard palate, mm. Hg. nasal rnucosa, ext. auditory canal Negro birth right periorbital re- bluish conjunctiva, bluish definite nevus Ota nevus Ota M gion, eyelid, brown iris, uveal to glau- type II type II cheek, ear tract, fundus black coma (same side) 50.6 m.m. Hg. NEVUS OTA AND NEVUS ITO IN AMERICAN NEGROES 147

Following the papers of Ota and Tanino, many TABLE TT case reports appeared in the Japanese literature.Mucous membrane and eye involvement in our cases Several Chinese and Korean cases were also of nevus Ota* reported. In 1952, Yoshida (9) reported 110 cases Number of cases which represented 0.4% of the patients seen in Locatioo the clinic of Tohoku University. Tn 1956, Kita- I II III mura and Furuya (10) reported 246 cases out of Hard Palate. ... ? 42,342 patients seen in the clinic of Tokyo Uni- + + Tongue + — versity (0.74%). In 1957, Hidano, Nomato andNasal Mueosa... — + ? Mishima (11) studied 61 cases of which 16.4%Pharynx — — ? were of type Ia, 18.0% of type Tb, 27.9% of typeConjunetiva. ... + + + II, 24.6% of type III and 13.1% of type TV. Cornea — + — In an attempt to evaluate the occurrence ofTris — + + this condition in the white race and the Negro,Uveal Tract — + + we reviewed the European, British and AmericanFundus — + + literature. (Table I) Ext. Audit. Canal — + — PIGMENTATION OF MUCOUs MEMBRANES ANO EYE Tympanum — — ? IN NEVUS OTA The pigmentation of the mucous membranes * Thegingival and bueeal mueosa were ex- and ocular structures in our cases is recorded included from this table because of their frequent pigmentation in the Negro. See disession. Table TI. According to a recent study of 61 Japanese eases of nevus Ota by Hidano, Nomato and Mishima (11), pigmentation of the tympa- In other normal appearing areas of the oral num was observed in 55% of the cases; pharynr—mueosa, such as the gingiva and hard palate, 24%; nasal mueosa—28 %; hard palate—iS %;Dopa positive junctional melanocytes have been So called physiologic pigmentation of the oraldemonstrated in Japanese persons and the dog. mueosa has been described by several authors.However, in the same studies, junctional melano- Mine (38) studied a group of 1425 Japanesecytes could not be demonstrated in the normal patients and found physiologic pigmentation ofappearing tongue mucosa by the Dopa reaction the oral mucosa in 32% of the eases, macro-and Masson's ammoniacal silver nitrate stain. seopieally. The areas involved in decreasing orderOn the other hand, numerous Dopa positive of frequency were: bueeal mneosa, gingiva,junctional melanocytes have been observed in palate and lip; there was only one ease in whichthe tongue of patients with Addison's disease the tongue was pigmented, and the patient had(Kitamura and Mishima (41)). In general, hemiplegia. Monash (39) reported what hepigment pathology of the mucous membranes considered physiologic macroscopic pigmentationhas not yet been studied thoroughly, and in our of the oral cavity mueosa in a group of 220opinion it is not always easy to decide what is American Negroes. The gum surface was pig-physiologic or unphysiologie when it comes to mented in 89% of the eases; bueeal mucosa—mucous membrane pigmentation. 40%; hard palate—38 %; tongue—33 %; lip Previously, one of us (Mishima (42)) did mueosa—3O %; soft palate—26 %.Healso ob-biopsy studies of hard palate pigmentation in served a definite correlation between the intensityJapanese eases of nevus Ota. The epithelium of the skin color and the distribution of theshowed a moderate number of junctional Dopa pigment in the oral mueosa, although he did notpositive melanoeytes. In the upper and middle mention whether any of the studied eases had, incorium there were numerous, elongated, bipolar, addition, pigmentary disorder of the skin. BeckerDopa positive pigment cells. They were identical (40) studied microscopically normal buecalwith the nevus Ota cells in the skin but consti- mueosa obtained from 53 cases of white, unse-tuted a denser infiltrate. (Fig. ii). Clinically, lected autopsy eases, and showed a slight degreethese biopsied areas showed, characteristically, of epithelial pigmentation in 74% of the eases.bluish-black, rounded, ill-defined macules or He also found chromatophores in 26%, andstreaks distributed along the midline. Unfortu- junctional melanoeytes in 70% of the cases. nately, we could not perform biopsy studies of 148 THEJOURNAL OF- INVESTIGATIVE DERMATOLOGY

Fso. 11. Large, well developed, elongated, nevusOta cells and junctional melanocytes showing a positive dopa reaction. X 968. the oral lesions in our eases, and it is impossibleBased on similar findings Yoshida (9) expressed to rule out completely their physiologic nature.the opinion that nevus Ota cells were derived However, their clinical appearance was similarfrom the perineurium or endoneurium of periph- to that of the oral lesions in the previouslyeral nerves. In Ito's (45) opinion, the cells of studied eases. In addition to the oral lesions,Mongolian spot and blue nevus have the same there was involvement of other mucous mem-origin. For these authors the perineurium and branes in our eases, such as the tympanum andendoneurium are of mesenchymal origin and nasal mucosa, and of ocular structures which aretherefore, the cells of nevus Ota, Mongolian spot known to be frequently involved in nevus Ota.and blue nevus are of mesenchymal derivation. Therefore, it seems that at least part of the From studies on embryonal nerves and experi- mucous membrane pigmentation in our cases ismental schwannomas, Masson (46) came to the of nevus Ota nature. conclusion that endoneurium and perineurium Fitzpatrick, Zeller, Kukita and Kitamura (35)are of neuro-ectodermal origin. On the other stressed the eye changes in nevus Ota and sug-hand, Kawamura (5) is of the opinion that gested the term of ocular and dermal melano-nevus Ota cells come from abnormal cells origi- eytosis. In our opinion a more appropriate namenating in the neural crest. Therefore, he pointed would be oculo-muco-dermal melanocytosis. out, one would expect a close relationship between nevus Ota cells and peripheral nerves both NERVES AND NEVUS OTA CELL5 of which have a common origin. In several sections stained with Champy and Masson (47) described a case of névrome Coujard's (43) osmium-iodide method andmyélinisé dermique associated with blue nevus Liang's (44) stain for nerves, nevus Ota cellsand supposed that this blue nevus developed were observed in close relationship with or amongfrom peripheral nerves and possibly from the the sheath cells of peripheral nerves (Figs. 12, 13).ehwannian sheath of myelinated nerves. Re- NEVIJS OTA AND NEVIJS ITO IN AMERICAN NEGROES 149

V 4

A13

FIG. 12. Nevus Ota cells in close association with the sheath cells of peripheral nerves. Dopa reaction and toluidine stain. x990. FIG. 13. Section stained with Liang's stain for nerves showing aevus Ota cells along peripheral nerves. X 720. cently we came across two cases of schwannomapigmented, Sehwann-cell bundles in cross section associated with blue nevus. The epidermis(Fig. 15). A few of the bundles were longitudi- covering the tumor was normal except for somenally sectioned. These cellular bundles showed hyperkeratosis. The periphery of the tumor wasnumerous elongated nuclei arranged in a composed of densely aggregated, typical, bluestreaming fashion. It is difficult to draw definite nevus cells (Fig. 14). They were pigmented andconclusions about the origin of these cells or were arranged in a stream-like pattern aroundnevus Ota cells from the above findings. How- the center of the tumor. Throughout the tumorever, these findings suggest at least the possibility there were scattered and distinctive, scarcelythat dermal melanocytes, such as blue nevus or r—t,Jv Th0

FIG. 14. Area of blue nevus cell proliferation in a case of schwannoina associated with blue nevus. Hematoxylin and eosin. X 570.

FIG. 15. Scattered distinctive, scarcely pigmented Schwann cell bundles in same section of Fig. 12. Hematoxylin and eosin. X 135. 150 NEVTJS OTA AND NEVUS ITO IN AMERICAN NEGROES 151

TABLEIII Differential Diagnosis Between Nevus Ota and Mongolian Spot

Nevus Ota Mongolian Spot.

1. Onset about 60% at birth, about 40% around usually at birth or soon altar birth puberty

2. Course persistent tends to disappear with age 3. Color brownish-blue with a powder-blast burnrather uniformly bluish, without a appearance brownish spotted component 4. Distribution limited to 1st and 2nd branches of tn- at random, although usually on the geminal nerve—does not extend be- sacral region yoad the naso-labial fold and toward the mandibular region 5. Melanosis Bulbiin about 50% of cases rarely if ever present

6. Pigmentation ofout of 29 cases rarely if ever present Mucous Mem- a) tympanum, 55% branes b) nasal mucosa, 28% c) pharynx, 24% d) palate, 18%

7. Histology elongated dermal melanocytes predomi- elongated dermal melanocytes in the nantly in the upper corium and fre- lower fiorlower half of the co- quently in the subpapillary layer of rium. No pigmentary changes in the corium. Areas of hyperpigmenta- the epidermis tion of the basal layer and increase in the number of junctional melanocytes nevus Ota cells, may derive from certain periph-aberrant and persistent Mongolian spot on the eral nerve sheath cells. face may pose a serious diagnostic problem, we believe that it is better to classify it as a separate DIFFERENTIAL DIAGNOSIS entity. The main differential point between nevus The main condition to be differentiated fromOta and Mongolian spot are listed in Table III. nevus Ota are: blue nevus and Mongolian spot. The blue nevus is a sharply circumscribed, CONJUNCTIVAL MELANOSIS TO BE DIFFERENTIATEn round or oval, soft nodule of bluish-black or FROM NEVU5 OTA slate-blue color which measures, as a rule, only a Various conjunctival melanoses were studied few millimeters in diameter. Although indi-by Reese (49) and others. The conjunctival vidually the cells of blue nevus are very much pigmentation in nevus Ota is more prevalent on like those of nevus Ota, their number is much the bulbar region of the lateral superior quadrant, greater in blue nevus. Also, they are grouped in irregular bundles which disturb the normaland less marked and less frequent in the medial structure of the dermis. The cells are Dopa-inferior quadrant. The pigmentation is macular positive in both conditions, while the tyrosinaseand of a gray to slate or slate-blue color. The reaction is positive only in blue nevus. This washistology and the slit-lamp examination show recently demonstrated by the autoradiographicsubconjunetival, stromal (dermal) melanocytes. technic of Fitzpatrick and Kukita (48). This stromal conjunctival melanosis is almost The differentiation between nevus Ota andalways accompanied by pigmentary changes on Mongolian spot is usually easy. Although anthe skin. In addition, there may be an involve- 152 THEJOURNAL OF INVESTIGATIVE DERMATOLOGY ment of other eye structures, such as the fundus,influence on the tyrosinase system were studied choroid, iris and sciera. by Mishima42. Diminution in the intensity of the pigmentation after the application of this 1. Melanosis Circumscripta Praecancerosa—- chemical, in a hydrophilic ointment base, has Dubreuilh been observed in Japanesc cases. This chemical This condition may be considered as a non-is used for the colorimetric detection of traces of nevoid prcmelanoma which is distinct fromcopper. Tyrosinase is a protein conjugated with junction nevus (1960 (50)). The lesion is non-copper. It was demonstrated that this chemical elevated and its pigmentation is not uniform ininhibits the tyrosinase and Dopa reactions, and density. The luster of the epithclium is disturbed,that it also produces a diminution in the pigment and usually a black punctate stippling can beof black goldfish and rat skin when injected seen over the surface. The average age at whichsubcutaneously. The above mentioned ointment this condition appears is 40 to 50, and the averageshould be applied to the involved region several length of time between its appearance and thetimes a day. One should start with a weak concen- malignant change is from 5 to 10 years. tration, namely 5%, and can go gradually up to 20%. Some patients may notice an improvement 2. Diffuse "Flat" Nevus of the Corijunctiva after several weeks of treatment, while others This lesion is always somewhat elevated andwill require much longer periods of time. A well demarcated. It is congenital, rarely becomesslight local irritation may be expected in some transformed into malignant melanoma, and thepatients but usually the treatment can be con- microscopic findings are conclusive because oftinued. In the series of patients treated with this the presence of ncvus cells. topical preparation, no lcukodcrma or serious toxic effects were observed so far. If the above 3. Congenital Conjunctival ilielanosis methods of treatment fail, skin grafting may be This lesion consists of a mottled and sometimestried. striated pigmcntation located at or near the limbus. The pigment is not accentuated at the SUMMARY limbus and on the cornea as it is commonly seen 1. Three cases of nevus Ota in American in acquired melanosis-Dubreuilh. The histologicNegro patients are presented. In one of them examination shows an increased pigment patternthere was an associated nevus Ito while in in the basal layer, as in lcntigo simplex of theanother one a glaucoma on the side of pigmenta- skin. tion was discovered. 2. Special reference is made to the changes of TEEATMENT the mucous membranes and eye accompanying Occurrence of malignant melanoma in the areathis entity. The following structures in our cases of nevus Ota has been reported in a few cases inor in cases from the literature were shown to be the European literature, but this has not yet beenpigmented: conjunctiva, cornea, sclcra, iris, observed in Japan where ncvus Ota is fairlyuveal tract, retina; palate, pharynx, nasal mu- common. We feel that, for practical purposes, thecosa, tympanum. The presence of nevus Ota cells problem in this condition is mainly of cosmeticin the pigmented part of mucous membranes was nature. demonstrated. For treatment, periodic applications of dry ice 3. The differential diagnosis of conditions which are recommended. The dry ice should be appliedmay be confused with nevus Ota is discussed, and to the lesion for about one second and withit was pointed out that nevus Ota, in our opinion, moderate pressure, once a week or every twohas to be separated from aberrant Mongolian weeks. Blistering should be avoided. After about 6 spot. months, a fair to significant diminution in the 4. In connection with the histogenesis of ncvus intensity of the pigment may be expected. How-Ota, two cases of schwannoma associated with ever, if the results have been minimal, a secondblue nevus are discussed. coursc of dry icc applications can be given. 5. Treatment of nevus Ota with application The therapeutic effects of sodium diethyldithio-of dry ice or sodium diethyldithiocarbamate carbamate [(C2H5)2NCS2Na] and its inhibitoryointment is mentioned. NEVUS OTA AND NEVUS ITO IN AMERICAN NEGROES 153

ACKNOWLEDGMENT 15. KRAMER, R.:Angeborene Pigmentanomalie. Ztschr. f. Augenheilk., 22: 79—80, 1909. We are indebted to Dr. Hermann Pinkus, who16. COATS, G.: Unilateral diffuse melanosis of the gave us frequent advice and consultation uvea with small elevations on the snrface of the iris. T. Ophth. Soc. U. Kingdom, 32: throughout this study. Dr. Fishman and Dr. 165—171, 1912. Anderson did the ophthalmologic examination of17. KE5TENBAUM, A.: Em Fall von doppelseitiger the patient. Miss R. Hunter, Miss D. Major Melanosis bulbi et facies. Zschr. f. Augen- heilk., 34: 317—319, 1915. and Miss J. Dudzinski gave technical assistance.18. PUsEY, W. A.: Facial pigmented nevus involving the sclera. Ophth. Rec., 25: 618-619, REFERENCES 1916. 1. OTA, M.: Nevus fusco-caeruleus ophthalmo-19. FEIRDENTHAL, H. AND FEIEDENWALD, J. S.: maxillaris. Jap. J. Dermat., 46: 369, 1939. Melanosis of the lids conjunctiva and selera 2. On, M. AND TANINO, H.: A variety of nevus, with wartlike growths on the iris. Arch. frequently encountered in Japan, nevus Ophth., 54: 51—54, 1925. fusco-caeruleus ophthalmomaxillaris and its20. NARDUccI, F.: Sulle chiazze mongoliche. Gior. relationship to pigmentary changes in the ital. di dermat. e sif., 67: 1476—1479, 1926. eye. Tokyo Med. J.,63: 1243—1244, 1939. 21. DOHERTY, W. B.: Cases of melanosis oculi 3. TANINO,H.: Uber eine in Japan haufig vor- with microscopic findings. Am. J. Ophth., kommende Nävusform: "Naevus fusco- 10: 1—8, 1927. caeruleus ophthalmo-maxillaris Ota", I.22. EBEET, M. H. AND NOMLAND, R.: Blue nevus? Mitteilung: Bcobachtung uber Lokalisa- Arch. Dermat. & Syph., 23: 1002—1003, 1931. tion, Verfkrbung, Anordnung und histo-23. CoLnsdnLAo, F.: Blaner Naevus. Zentralbl. f. logische Veranderung. Jap. J.Dermat.,46: Haut-u. Geschlechtskr., 51: 162, 1935. 107—111 and 435—451, 1939. II. Mitteilung: 24. O'LEARY, P. A., MONTGOMERY, H. AND Beobachtungen uber die Augenmelanose als BEUN5TING, L. A.: Benign melanosis; Komplikation dieses Naevus und seine metallic pigmentation? Arch. Dermat. & klinische Erscheinung. Jap. J. Dermat., 47: Syph., 31: 411—412, 1935. 51—53and 181, 1940. 25. CORNELL, V. A.: A case for diagnosis (Blue 4. (a) ITo, M.: Studies on melanin: XXII. Nevus Nevus ? Argyria ?) Arch. Dermat. & Syph., fusco-caeruleus acromiodeltoideus. Tohoku 36: 1261—1262, 1937. J.Exp.Med., 60: 10, 1954. (b) ITo, M.: On26. JENSEN, D. D. F. AND HAFFLY, C. N.: An naevus foscocaeruleus acromio-deltoideus. nnnsual case of progressive melanosis- Dermat. and Urolog. (Hifu to Hitunyo), 16: oculi. Am. J. Ophth., 31: 1476—1479, 1948. 322—324, 1954. 27. ROTUMAN, S. AND PINNE, G.: Blue nevus of 5. KAWAMUEA, T.: Japanese Handbook of the eye and melanosis of the temple (due to Dermatology, VII/2, p. 136—140. Tokyo, contact with telephone receiver?) Arch. Kanehara Shupan Co. 1957. Dermat. & Syph., 58: 550—551, 1948. 6. BLodu, B.: Das Pigment, in Jadassohn, J.:28. PAEI5EE, H. AND BEEEMAN, H.: Extensive Handbuch der Haut und Ceschlechtskrank- blue patchlike pigmentation. Ibid., 59: heiten, Vol. 1, Pt. 1, p. 434—541. Berlin, 396—404, 1949. Springer-Verlag 1933. 29. COLE, H. N., HURLER, W. R. AND LUND, H. 7. GAN5, 0. AND STEIGLEDEE, C.: Histologic der Z.: Persistent aberrant mongolian spots. Hautkrankheiten, 2nd Ed., Vol. 2, p. 263- Arch. Dermat. & Syph., 61: 244—260, 1950. 265. Berlin, Springer 1957. 30. CURTIs, A. C.: Melanosis bulborum and aber- 8. BEcKEE, S. W., Jrt.: Histologic study of nevus rant mongolian spots. A. M. A. Arch: of Ota. Jap. J. Dermat., 69: 251—253, 1959. Dermat. & Syph., 63: 521—522, 1951. 9. Yosmo.&, Y.: Nevus fusco-caeruleus ophthal-31. FINDLAY, C. H. AND RAND, W. W. : Mesodermal momaxillaris Ota. Tohoku J. Exp. Med., 55: melanosis of the face and sclera with ab- Supp. (I): 34—43, 1952. normalities of the cranium. South African 10. KITAMUEA, K. AND FUEUYA, T.: Uber Haut- J. Clin. Sc., 2: 281—287, 1951. geschwulste Naevi und Phakomatosen32.JADAS5ORN,W., FRANcE5CEETTi, A. AND Einteilung und statistische Beobachtungen. GOLAY, M.: Quelques observations cliniques Hautarzt, 7: 297—303, 1956. cocernant la pigmentation du derme. 11. HIDANO, A., NoMoTo, K. AND MI5HIMA, Y.: Dermatologica, 108: 225—234, 1954. Pigmentation des muqueuses dans Ic naevus33. DOESEY, C. S. AND MONTGOMERY, H.: Blue d'Ota. Bull. Soc. franc. de dermat. et syph., nevus and its distinction from mongolian 3: 287—288, 1957. spot and the nevus of ota. J. Invest. 12. RULKE, J. W.: A series of eases of carcinoma Dermat., 22: 225—236, 1954. of the eyeball. Ophthalmic Hosp. Reports,34. STUART, C.: Nevus of Ota. Brit. J. Dermat., III: 279—286, 1860—61. 67: 317, 1955. 13. ScIIAUMBEEG, D.: Missbildungen des Auges, 35.FITZPATRICK,T. B., ZELLEE, R., KUKITA, A. Diss. Marburg. 1882, Quoted from Bourquin, AND KITAMURA, K.: Ocular and dermal J.: Die angeborene Melanose des Auges. melanocytosis. A. M. A. Arch. Ophth., 56: Zschr. f. Augenheilk., 37: 129—174 and 294— 830—832, 1956. 311, 1917. 36.HELMICK,E. AND PEINGLE, R. W.: Oculocu- 14. ScriEn,: tiLer exzessive Pigmentierung am taneous melanosis or nevus of Ota.Ibid., 56: Mensehenauge. 1905, Qnoted from Bour- 833—838, 1956. quin, J.: Die angeborene Melanose des 37.KAMINSKY, A., DAITSCH, J. AND ABULAFIA, J.: Auges. Zschr. f. Augenheilk., 37:129—174 Dermo-ocular melanocytosis. Arch. argent. and 294—311, 1917. dermat., 7: 231—241, 1957. 154 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

38. MINE, M.: Pigmentation of oral mucosa in the46. MAssoN, P.: Tumcurs Humaines, 2nd Ed., p. Japanese. Jap. J. Dermat., 28: 325, 1928. 909—915. Paris, Maloninc 1956. 39. MONAsH, S.: Normal pigmentation of the oral 47. M.&ssoic, P.: Névromc myélinisé dcrmique mueosa. Arch. Dermat. & Syph., 26: 139— associé aunnacvus blcu. Schweiz. Mcd. 147, 1932. Wchnsch., 77: 1154—1155, 1947. 40. BECKER, S. W.: Melanin pigmentation: A48. FITZPATrnCK, T. B. AND KUKITA, A.: Tyro- systematic study of the pigment of the sinasc Activity in Vertebrate Melanocytes, human skin and upper mucous membranes in Pigment Cell Biology, p. 489—524. New with special consideration of pigmented York, Academic Press 1959. dendritic cells. Arch. Dermat. & Syph., 16:49a. REESE, A. B.: Precancerous mclanosis and 259—290, 1927. the resulting malignant melanoma (can- 41. KITAMURA, K. AND MI5HIMA, Y.: Zur Fragc cerous melanosis) of conjunctiva and skin der Zungcnpigmcntierung bei Morbus Añdi- of lids. Arch. Ophth., 29:737—746,1943. son. Hautarzt, 8: 484—486, 1957. 49b. REESE, A. B.: Pigmented tumors. Am. J. 42. MI5RIMA, Y.: Unpublished data. Ophth., 30: 537—565, 1947. 43. CHAMPY, C., COUJARD, H. AND COUJARD- 49c. RnsE, A. B.: Pigmented lesions of the con- CHAMPY, CII.: l'Innervation Sympathique junctiva. Trans. Ophth. Soci. Austr., XII: 56—58, 1952. des glandes. Acta Anat., 1: 233—283, 1945/49d. REEsE, A. B.: Precancerous and cancerous 1946. mclanosis of the conjunctiva. Am. J. Ophth., 44. LIANG, H.: A new method for staining nerves 39: 96—100, 1955. and their endings using the Schiff reaction.50. MI5HIMA, Y.: Mclanosis circumscripta prac- Anat. Eec., 99: 511—522, 1947. canccrosa (Dubrcuilh); A nonncvoid pre- 45. Pro, M.: Genesis of mongolian spot and blue melanoma distinct from junction ncvus. J. ncvus. Ibid. 55, Supp. (I): 21—29, 1952. Invest. Dermat., 34: 361, 1960.