Dermal melanocytosis: A clinical spectrum

Australasian Journal of Dermatology ii99Q) 37, 19-25

PERSONAL REVIEW

Dermal melanocytosis: A clinical spectrum Duncan G Stanford and Katherine E Georgouras The Dermatology Centre, Liverpool Hospital, Liverpool, New South Wales, Australia

Table 1. Classification ofthe circumscribed dermal melanocytoses"

SUMMARY While most dermal melanocytoses are congenital or have an onset in early childhood, there is a group which is clearly acquired, with an onset in adult life. While the Mongolian spot typically disappears in childhood, other dermal melanocytoses persist for life. A brief review of the clinical spectrum of the dermal melanocytoses is undertaken and three illustrative cases are described: a case of congenital naevus of Ota, a case of acquired bilateral naevus of Ota~like macules, and an unusual case of a congenital dermal melanocytotic lesion on the left hand which began to spread in adulthood. The possibilities regarding the pathogenesis of this intriguing group of disorders are considered. Key words: acquired, congenital, Horfs naevus, naevus of Ota, pathogenesis.

INTRODUCTION During evolution, melanocytes disappeared from their primary location in the dermis and became widely scattered throughout the body of lower vertebrates, to be found mainly in the epidermis and a few other sites in humans. Dermal melanocytes serve no obvious purpose in man, whereas a role has been attributed to them in sexual attraction for some other mammals and in background mimicry for lower vertebrates.' Melanocytes are embryologically derived from a stem population of melanoblasts that originate from the neural crest just after closure of the neural tube. In the human embryo, migration starts at 2.5 weeks gestation,^ and melanocytes have been demonstrated in the epidermis by 8 weeks on electron microscopy.^ Dermal melanocytes have been found throughout the integument in early fetal life but are restricted to a few localized areas after birth.* Dermal melanocytoses are usually localized, are especially common in Asians and are mostly developmental or heritable in origin.^ When a sufTicient number of melanin-containing Correspondence: Associate Professor Ratherine Georgouras. Director, Dermatology Centre, Liverpool Hospital. 45-47 Coulburn St, Liverpool, NSW 2170, Australia. Duncan G Stanford. MB. BS. Katherine E Georgouras. DDM. FACD. Received 24 June 1995; revised manuscript accepted 13 August 1995.

Congenital or naevoid

Acquired

Mongolian spot Naevus of Ota (naevus fuscocaeruleus ophthalmomaxillaris) Naevus of Ito (naevus fuscocaeruleus acromiodeltoideus) Blue naevus Common Cellular Atypical

Hori's naevus (acquired bilateral naevus of Ota-like macules) Blue macules in progressive systemic scleroderma

cells are present in the dermis, the various clinical forms arise (Table 1). The blue skin colour results from a decreased diffuse reflectance in the longer wavelength red region ofthe visible spectrum as compared to the surrounding normal skin.' Dermal melanocytes are 'continent' melanocytes that retain the melanosomes that they synthesize. They are spindle-shaped and contain melanosomes which are singly dispersed and mostly fully melanized.* They are surrounded by a basal lamina and basement membrane substance.' CASE 1 A 55 year old Vietnamese sewing machinist presented with a typical naevus of Ota. At birth the lesion was confined to the right eye; then at 5 years of age it started to spread over the right side of the face. Over the past 5 years, it had been spreading very slowly to involve the nose and an adjacent area on the left side of the face. The pigmentation was more noticeable after sunlight. Chemical peeling had been tried unsuccessfully in Vietnam. Her past medical history was unremarkable and she gave no family history of pigmentary disorders. On examination, there was mottled blue-black macular pigmentation affecting predominantly the right temple, zygomatic area and cheek, and the bridge and ala of the nose (Fig. 1). The right upper eyelid and left side of the face were involved to a lesser extent. On ophthalmological examination, there was bluish pigmentation ofthe right sclera and conjunctiva, heterochromia iridis and generalized pigmentation ofthe uveal tract. Oral and nasal mucosae and tympanic membranes were not involved. Histology revealed numerous elongated dendritic melanocytes scattered amongst the collagen bundles in the upper dermis (Fig. 2). Electron microscopy demonstrated large fully

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DG StanTord and KE Georgouras

melonizcd melanosomes within the dermal melanocytes and a well-developed extrarellular shenth (Fig. 3). This patient disguises the lesion successfully with cosmetic camouflage and uses a broad-spectrum SPF15+ sunscreen daily. CASE 2 A 52 year old Cambodian housewife presented with a 6 year history of facial hyperpigmentation. No external contactants were elicited and she had been taking no medications prior to the onset ofthe eruption. On examination, multiple dark bluish-brown macules in association with diffuse pale brown hyperpigmentation appeared bilaterally in the forehead, temple and malar areas (Fig. 4). There was no ocular, mucosal or tympanic membrane involvement. Skin biopsy demonstrated numerous elongated melanincontaining cells in the upper dermis forming an almost band-

Figure 3 Case 1. Electron microscopy demonstrating large hilly melanized melanosomes within the dermal melanocytes and a welldeveloped extracellular sbeatb (X 12500). Figure 1 Case 1. Naevus of Ota with mottled blue-black macules affecting mainly the right side of the face and the nose. (Copyright © The Medical Journal of Australia 1992; 156: 847-53. Reprinted witb permission.)

Figure 2 Case 1. Skin biopsy showing elongated dendritic melanocytes scattered amongst collagen bundles in the upper dermis (H&E, X4O).

Figure 4 Case 2. Hori's naevus affecting the face bilaterally with dark bluisb-brown macules associated with more diffuse pale brown pigmentation.

Dermal melanocytosis like infiltrate (Fig. 5). A few similar cells were seen in the deep dermis. There was no evidence of malignancy and immunofluorescence was negative. A diagnosis of acquired bilateral naevus of Ota-like macules was made. The patient was advised to use a broad-spectrum SPF15 + sunscreen and she was referred to a cosmetic camou' flage clinic. She is being regularly observed and at the most recent review only a slight extension of the pigmentation was noted.

CASE 3 A 22 year old Vietnamese woman presented with a pigmented lesion on her left hand. A dark blue lesion had been present at tbe base of the middle finger since birth. Pigmented lines had

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developed along the nails of tbe middle and ring Hngers 3 years previously. Over the past 2 years, paler bluish areas began to spread over the dorsum of the left hand then onto the palmar surface, where small dark areas had also appeared. The patient denied taking any medications prior to the spread of the pigmentation. This single trainee accountant had no significant past medical history and gave no family history of pigmentary lesions. On examination, a well-circumscribed bluish macule was present at the base of the left middle finger dorsally (Fig. 6). Diffuse paler pigmentation was apparent over an adjoining area on the dorsum of the hand and on the palmar surface at the base of the ring and middle fingers. Several small dark bluish macules were present in the distal palmar skin crease. Linear melanonychia was evident in the nails of the middle and ring fingers. There was no dyspigmentation elsewhere on the body. Skin hiopsies taken from the congenital lesion and the spreading pigmented area both showed elongated pigmented melanocytes in the upper and mid dermis with perivascular prominence (Fig. 7). Special stains confirmed tbat the pigment was not iron and there was no evidence of malignancy. Clinical features of the three cases are summarized in Table 2.

Figure 5 Case 2. Skin biopsy demonstrating a band-like pattern of elongated pigmented cells in the upper dermis (H&E. X 33).

Figure 6 Case 3. Well-circumscribed bluish macule at the base of the left middle finger dorsally with diffuse paler pigmentation over the adjoining dorsum of the hand.

Figure 7 Case 3. Skin biopsy showing elongated pigmented cells in the upper and mid-dermis with perivascular prominence (H&E, x 50).

DG Stanford and KE Georgouras Tnbic 2 Siimmury of cases

Diagnosis Age Sex

Country or origin Onset Course Site involved Appearance

Case 1

Case 2

Case 5

Naevus of Ota 35 years Fenfiale Vietnam Congenital Persistent Face; unilateral Ocular; no mucosal Blue-black macules

Hori's naevus 52 years Female Cambodia Acquired Persistent Face; bilateral No ocular; no mucosal Blue-brown macules; pale brown areas

Unusual circumscribed variant 22 years Female Vietnam Congenital Spread in adulthood Left band Bluisb maculei adjacent paler blue area; linear melanonychia

Table 5 Clinical spectrum of the dermal melanocytoses Mongolian spot*'^

Naevus of Ota' ^•^•"' Naevus of Ito^ '•"•"' Bluenaevus"-'-"'"

n u l l 0 IlaCVUa

Blue macules in progressive systemic scleroderma*' '*

Onset

Congenital

Course

Most disappear; 5-4% persist; malignancy not reported Most lumbosacral and buttocks; may occur anywbere

60% congenital; 60% congenital 2nd peak at puberty Most persist; Most persist; malignancy rare malignancy rare

Fourth and fiftb decades Not reported

About 4 years after onset of scleroderma Increasing area and intensity in one of the four cases

Site

Most unilateral; 1st and 2nd division of trigeminal nerve

Most unilateral; posterior supraclavicular and Lateral brachial cutaneous nerves

Appearance

Uniform blueblack macules

Bluish macules and small brown patches

More diffuse tban naevus of Ota

Histology

Scattered melanocytes in lower dermis

Scattered melanocytes in upper and lower dermis

Scattered melanocytes in upper dermis

Large singly dispersed fully melanized melanosomes Present (increase with age)

Large singly dispersed fully melanized melanosomes Present

Melanocyte Large singly ultra structure dispersed fuily melanized melanosomes Extracellular Present(decrease with age) sbeatb

DISCUSSION The clinical spectrum of the circumscribed dermal melanocytoses is summarized in Table 3 and the rarer clinical variants are described in Table 4. The major distinguishing features are the clinical course and the site involved. Typically. Mongolian spots are congenital and regress during childhood,'"^ while naevi of Ota and Ito appear from birth through to adolescence and persist.''"'''° That certain sites of predilection exist is suggested by the similar distribution of Hori's naevus to naevus of Ota and of the blue macules of progressive systemic sclero-

Most acquired

Most persist; occasional malignancy in cellular type Common type: Bilateral; as for most on dorsa of Ota except no bands and feet mucosal, ocular Cellular type: most or tympanic on buttocks and membrane sacral area invovlement Common type: Ota-like macules; blue-black papule less intense Cellular type; blue-black nodule Common type; Scattered groups of melanocytes in melanocytes in upper dermis lower dermis; stroma and melanophages admixed Cellular type; spindle-shaped cells also present Large variably Large singly melanized dispersed melanosomes melanized melanosomes Absent Present

Back, shoulder. upper arm

Blue macules consisting of linear streaks and small patches Scattered melanocytes in lower dermis

Large singly dispersed fully melanized melanosomes Present

derma to naevus of Ito. Melanocytes scattered in the upper dermis give a brownish-blue tint while those confined to the lower dermis appear more uniformly blue.^' Blue naevi have features which distinguish them from other forms of dermal melanocytosis."''*'^^ They are usually papulonodular rather than macular, dermal melanocytes appear in bundles rather than scattered amongst the collagen fibres, other cell types and/or stroma are admixed in these bundles, melanophages are usually seen, and melanosomes show greater variation in degree of melanization. The case presentations are summarized in Table 2 and

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Dermal melanocytosis Table i

Rare clinical variants or the dermal melanocytoses

Clinical variant

Onset

Course

Site

Appearance

Other features

Circumscribed variants Unusual case''

Childhood

Progressive

Right hand

Blue-grey macules

Adulthood

Progressive

Sural nerve course

Linear brown macules

Adulthood

Progressive

Right back

Grey-blue area

Scattered melanocyles and melanophages in lower dermis Scattered melanocytes in upper dermis; some associated with nerve fibres Scattered melanocytes in lower dermis

Congenital

Regressed in infancy

Generalized; sparing acral and genital areas

Blue-grey patches

Dermal melanocyte hamartoma'"

Congenital

Persistent

Grey-blue patch

Levene's syndrome*' (Carleton-Biggs)

Congenital

Slowly progressive; terminal metastatic melanoma from occult primary

Both buttocks: down right leg in dermatomal pattern Ocular then face and trunk; disseminated internally at autopsy

Acquired linear variant'*

Adult onset Mongolian spot'^ Diffuse variants Generalized variant'*

illustrate the clinical spectrum seen in dermal melanocytosis. While case 1 is congenital and unilateral, case 2 is acquired and bilateral. Case 3 is unique, presenting in adult life with recent spread from around a pre-existing congenital dermal melanocytotic lesion. Case 3 bears some resemblance to the unusual circumscribed variant (Table 4) described by Mevorah et al..}^ in which a spreading dermal melanocytosis was noted to occur from around a pre-existing lesion on the hand. However, there are some differences: first, the original lesion was not congenital, appearing at age 11 years; and second, the histology was more suggestive of a blue naevus, showing melanophages admixed with the dermal melanocytes. A persistent Mongolian spot is a differential diagnosis for case 3, which was considered. These have been noted on the dorsum of the hand in 0.5% of 480 Japanese children; however, adult-onset spread, as in case 3, has not been described.^' Following is an outline ofthe treatment options available for this group of disorders, although a detailed discussion of management is beyond the scope of this article. Sun protection advice is generally given to the patient as this may, at least theoretically, prevent darkening ofthe lesion due to the trigger-, ing of melanogenesis by ultraviolet light. Cosmetic camouflage is the most successful and safest option for most patients.^ Opaque cosmetics, such as Dermablend and Covermark, are used. Laser therapy has a promising new role in treating pigmentary disorders that involve the superficial dermis. Selective photothermolysis using a pulsed laser, such as the Qswitched ruby laser, has been used successfully to treat naevus of Ota. This avoids the scarring associated with using continuous wave lasers, such as the argon laser.'^* Cryotherapy is an option for very dark lesions, while a partial response can be achieved by aggressive cryotherapy. scarring and depigmentation limit its usefulness.'-* Surgical therapy with skin grafiing has been used only in the most extreme cases.*

Multiple bluish macules; cranial abnormality

Scattered melanocytes in lower dermis; poorly developed extracellular sheath Scattered melanocytes in upper dermis Widespread mixed melanocytic-melanophagic dermal melanosis at autopsy

The pathogenesis ofthe dermal melanocytoses is not known, although they are thought to result from the failure of melanocytes to reach the epidermis in their migration from the neural crest.^ Some authors suggest, however, that the blue naevus represents a benign neoplasm arising from an abnormal melanoblast.^^ Several mechanisms may play a role in pathogenesis: (1) Extracellular sheath. This is composed of fine filaments and granules^^ and has been found around melanocytes in all the macular forms of dermal melanocytosis.* A protective role for the sheath in the persistence of melanocytes within the dermis has been proposed.''* In the Mongolian spot, the sheath appears in a less developed form and then declines markedly with age as the cytolemma is disrupted and the lesion disappears clinically.^^ In the persistent forms of dermal melanocytosis, including persistent Mongolian spots, a highly developed sheath is present which shows no change with age." while in naevus of Ota the sheath thickens.^^ (2) Homeobox genes. These encode transcription factors that determine the fate of a cell during development of an organism and are regulated by the co-ordinated action of growth factors and cytokines.^^ From studies of white spotting in allophenic and transgenic mice. Mintz proposed a model for skin domains that contain melanoblasts descended from cloneinitiating progenitors arranged in a linear order along the anteroposterior axis of the embryo (white spots lack melanocytes and have been attributed to a defect in the genes that regulate the deployment and fate of melanoblasts during development). Interestingly, homeobox genes also specify regional domains along the body axes and display some functional overlap with these white spotting genes.^^ Cultured human fetal melanocytes express certain homeobox genes, some of which affect migration of neural crest derivatives when overexpressed in transgenic

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DG Stanford and KE Georgouras

(5) I'estigial remnonls. Melanocytes in the dermis and throuf^hout the body are common in lower vertebrates but increasingly disappear on moving up the phyla.' Thus in humans, their presence in a few localized sites may represent a vestigial remnant. Boissy' suggested that dermal melanocytes may derive from the separate population of large melanosomecontaining melanoblasts that are known to originate from the more caudal areas of the neural tube. He also proposed that a post-emigration contrdl point influences the development or suppression of the various subpopulations during embryogenesis. (4) Neural influen(*es. Given their common origin from the neural crest, it is not surprising that a close relationship between the nervous system and melanocytes exists. Several pigmentary disorders, especially genetic in origin, are associated with nervous system abnormalities including neurofihromatosis, lentiginoses, piebaldism and tuberous sclerosis.'*^ In several of the dermal melanocytoses, melanocytes are seen near cutaneous nerve fibre bundles."''^' The naevl of Ota and Ito*"^ and the acquired linear variant'^ are distributed in areas of cutaneous innervation. Nerve growth factor (NGF) is critical to the development and maintenance of the peripheral nervous system. Melanocytes have receptors for NGF which act as a chemotropic signal for melanocytes in tissue culture. As NGF is expressed in vitro by human keratinocytes and the homologous neurotrophin-3 by human dermal fibroblasts, a role for these neurotrophic factors in melanocyte migration during embryogenesis has been suggested." A defect in this mechanism could account for the failure of melanocytes to migrate into the epidermis in these disorders. With regard to the pathogenesis of the adult-onset group of dermal melanocytoses, Hori**'^ proposed two possible mechanisms: (i) migration from epidermal or hair bulb melanocytes; and (ii) reactivation of a latent dermal melanocytosis. Although no studies have been conducted to systematically look for dermal melanocytes by electron microscopy, there is some evidenee for the presence of latent melanocytes in the dermis. For instance, dermal melanocytes can be found by electron microscopy in the lumbosacral region in most Caucasian children but are not clinically visible as they contain incompletely melanized melanosomes.^ Dermal melanocytes may also persist throughout life after a Mongolian spot has disappeared clinically.' If latent dermal melanocytes are also present in the areas affected by the adult-onset dermal melanocytoses, then some trigger must activate the cells in order to produce the melanized melanosomes found in clinically apparent lesions. Ultraviolet radiation is well known to stimulate melanogenesis, and it is noteworthy that Hori's naevus spares the unexposed sites involved in the naevus of Ota." Cytokines released during inflammatory dermatoses or after ultraviolet radiation are known to affect melanocyte pigmentation, proliferation and differentiation.'' Inflammatory mediators may trigger the onset of the blue macules seen in progressive systemic sclerosis, as a large number of degranulated mast cells are seen in the affected dermis." A neural influence on melanogenesis in stromal melanocytes has been seen in animals," while in humans nerves have been found in close association with active melanocytes in hyperpigmented skin conditions induced

by ultraviolet radiation." In addition, neurotrophin-3 production by dermal fibroblasts is modulated by ultraviolet light." Hormonal changes may play a role, as the acquired naevus of Ota has a peak onset at puberty and a fluctuation in intensity of pigmentation with menstruation is commonly described." In Hori's naevus, the marked female preponderance (female to male ratio 50:1) and an onset around menopause'* may also relate to an hormonal effect. In summary, dermal melanoeytosis describes a spectrum of related disorders characterized by a persistence of melanocytes in the dermis after birth, and they are clinically apparent when these cells contain melanized melanosomes. While they are thought to result from the arrested migration of melanocytes during development, the adult-onset group is difTicult to explain on that basis alone. This group may arise when previously latent dermal melanocytes are switched on by some trigger.

ACKNOWLEDGEMENTS The authors are grateful to Dr Pam Brown for contributing Case 3. They would also like to thank Dr Phillip Baird for the histopathology and Dr Murray Rillingsworth for the electron microscopy.

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