Acquired dermal melanocytosis: Appearance during pregnancy

Acquired dermal melanocytosis: Appearance during pregnancy Adam I. Rubin, MD, S. Van Laborde, MD, and Matthew J. Stiller, MD New York, New York We report the first case of acquired dermal melanocytosis (ADM) appearing during pregnancy. A 23-year-old Hispanic woman presented to the Dermatology Clinic of Columbia-Presbyterian Medical Center during the second trimester of pregnancy with a nonpalpable blue-gray patch with interspersed discrete brown macules on the right lower extremity. It had appeared during the first trimester of pregnancy. Cutaneous biopsy specimens revealed dermal melanocytes. A review of all reported cases of this rare dermatosis in the international literature is presented. (J Am Acad Dermatol 2001;45:609-13.)

W

e report the first case of acquired dermal melanocytosis (ADM) occurring during pregnancy. Existing ADM lesions have reportedly darkened during pregnancy.1 ADM initially described by Mevorah, Frenk, and Delacretaz2 in 1977 has been reported on the face,3 upper extremities,3 wrist,4 back,5 left leg,6 and dorsal aspects of the hands7 and feet.6 During the first trimester of pregnancy, a 23-year-old Dominican woman experienced a nonpalpable blue-gray patch with interspersed discrete brown macules over her right buttock, posterior thigh, and calf with segmental sparing of flexural folds. Spindle-shaped melanocytes were seen in the dermis of cutaneous biopsy specimens. The pathogenesis of ADM is equivocal. Estrogen, progesterone, and sunlight may activate pre-existing immature dermal melanocytes.1 The initial appearance during pregnancy is consistent with the hypothesis of Japanese investigators that “female hormones” may lead to the onset of ADM.8 We propose that ADM be added to the already imposing list of dermatoses that initially present during pregnancy.

Fig 1. Blue-gray patches with superimposed brown macules extend over right buttock with segmental sparing of flexural folds.

CASE REPORT A 23-year-old Dominican woman was examined in the Dermatology Clinic of Columbia Presbyterian Medical Center (CPMC) late in the second trimester of her first pregnancy. Blue-gray patches with superFrom the Department of Dermatology, Columbia University, College of Physicians and Surgeons. Conflict of interest: None. Reprint requests: Matthew Stiller, MD, Associate Professor of Dermatology, Department of Dermatology, Columbia-Presbyterian Medical Center, 161 Fort Washington Ave, New York, NY 10032. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/91/114289 doi:10.1067/mjd.2001.114289

Fig 2. Posterior aspect of right leg affected by blue-gray patches with superimposed brown macules.

imposed brown macules extending over her right buttock and leg had all appeared during the first trimester of pregnancy (Figs 1 and 2). There was sparing of the flexural folds. The face, torso, mucosa, 609

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Table I. Summary of reported ADM cases Year

No. of patients

No. female

No. male

Ethnic group

F/M (ratio)

Age (y) at onset

Mevorah et al2 Pariser & Bluemink6 Hori et al9 Ono et al10 Sun et al11 Kaneko12 (in Japanese) Ono et al5 Ono et al13 (in Japanese) Hidano and Kaneko3

1977 1982 1984 1986 1987 1988 1991 1991 1991

1 1 22 1 110 39 7 1 4

1 1 21 1 102 35 0 0 3

0 0 1 0 8 4 7 1 1

W B J J CH J 6 J, 1 NM J 2 K, 2 J

1:0 1:0 21:1 1:0 12.8:1 9:1 0:7 0:1 3:1

Fukuda et al7 Carmichael et al14 Jimenez et al15 Shinohara et al16 (in Japanese) Kokutani17 (in Japanese) Kunachak et al8 Kuniyuki4 Mizoguchi et al1 Mizushima et al18

1993 1993 1994 1994 1995 1996 1997 1997 1998

1 1 1 1 1 320 1 34 2

0 0 0 0 0 320 0 33 1

1 1 1 1 1 0 1 1 1

0:1 0:1 1:0 0:1 0:1 320:0 0:1 33:1 1:1

Current report Totals

2000 2000

1 549

1 519

0 30

J A NM J J TH J J 1 K (F) 1 J (M) H

11 34 19-69 (avg) 36.3 65 Varied After 20 Varied 53 25 K,F; 20 K (F) 18 J (F) 17 J (M) 18 20 20 62 16 After age 20 45 8-51, avg 26.8 Teen (F) 18 (M) 23

Author(s)

1:0 17:1

A, Asian; ADM, acquired dermal melanocytosis; B, black; CE, chronic eczema; CH, Chinese; DM, diabetes mellitus; F, female; H, Hispanic; J, Japanese; K, Korean; L, left; M, male; NM, not mentioned; PLE, polymorphous light eruption; PV, psoriasis vulgaris; R, right; RA, rheumatoid arthritis; TH, study performed in Thailand, actual ethnicity not mentioned; W, white.

and eyes were not affected. Visualization of lesions was not enhanced during Wood’s light illumination. She was taking no medications, had no known allergies, and denied trauma. There was no family history of abnormal cutaneous pigmentation. Biopsy specimens from a blue-gray patch and from a brown macule showed scattered, darkly pigmented, spindle-shaped cells and dendritic cells containing abundant golden brown pigment in the dermis (Fig 3). The patient refused to undergo further biopsies for electron-microscopic examination.

DISCUSSION Histology in this case showed dermal melanocytes. The onset was after birth, giving the diagnosis of ADM. ADM comprises a variety of conditions characterized by abnormal cutaneous pigmentation. ADM can vary in color and has been described as graybrown or dark-brown,1 blue-black,4 and gray-blue.5 Table I lists all case reports and series of ADM in the international literature. A total of 549 cases have been reported, 94.5% of whom were women (ie, a male/female ratio of 1:17). A family history of ADM was reported in 13.9% of patients. Most patients are

Asian, with a high percentage from Japan. This is the first case of ADM reported in a Hispanic patient. The most common differential diagnoses, once a skin biopsy specimen has been obtained and dermal melanocytes found, are nevus of Ota, nevus of Ito, blue nevus, and Mongolian spot (Table II). The location of our patient’s lesion on the right lower extremity and buttock excludes a diagnosis of nevus of Ota, which is located unilaterally in the areas innervated by the first and second branches of the trigeminal nerve. Nevus of Ota can present with pigmentation of the eye, auditory canals, tympanic membranes, and mucous membranes of the nose, mouth, and throat. The nevus of Ito is also excluded in this patient. It occurs in the distribution of the posterior supraclavicular and lateral cutaneous brachial nerves and involves the shoulder, side of the neck, and supraclavicular areas. In histologic examination of blue nevi, a high concentration of melanocytes can be seen between collagen bundles in the dermis, causing dermal disarray. Mongolian spots are usually present at birth in the sacrococcygeal area, lumbar area, buttock, and back, and by 10 years of age virtually all Mongolian spots have cleared spontaneously.

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Family history

None NM NM NM 16.3% (18/110) 10.3% (4/39) NM No Yes Yes NM NM NM None NM NM NM NM NM 5.9% (2/34) NM NM None (26/187) 13.9%

Location

Associated event

R hand L leg, area of sural nerve innervation Face, bilaterally R parietal region Face, bilaterally in zygomatic region Face, symmetric; left wrist; thighs Upper back Face, upper extremities and trunk Face, extremities

None Blunt trauma NM Basal cell epithelioma None None Trauma, RA, DM, PV, CE, ADM ↑α-MSH and GH, ↑epidermal melanin None

R hand Loin, back, L anterior abdominal wall Dorsum of R wrist Hands and forearms Palms, soles, hands, feet Face Dorsum of R wrist Face, extremities Face, arms, dorsum of R hand, middle finger

None None Bruise PLE, contact dermatitis None “Female hormones” Weather, general condition Sunlight, estrogen/ progesterone NM None Pregnancy

R buttock, R leg

Mizoguchi et al1 postulated that the activation of pre-existing immature melanocytes could be caused by estrogen or progesterone. Patients older than 30 years have reported recent darkening of pigmentation, especially during pregnancy. Kunachak et al8 postulated that “female hormones” affect the occurrence of ADM because of the high percentage of women. Our case report supports the hypothesis that estrogen and progesterone may induce onset of ADM. Our patient’s lesion was first noticed during pregnancy. Further support for the theory that estrogen and progesterone activate melanocytes is found by observing melasma. It is characterized by circumscribed hypermelanosis of the face, neck, and forearms and may either occur initially or exacerbate during pregnancy and in women taking oral contraceptives.28 In melasma, melanin deposition is increased, but the number of melanocytes remains stable. In ADM, new melanocytes appear or are activated in the dermis. Mizoguchi et al1 proposed that sunlight could be a causal factor for ADM because of distribution of lesions on sun-exposed areas. Endothelin-1 secreted by keratinocytes exposed to ultraviolet radiation can

Age range at presentation

32 34 NM 67 1-61 12-53 61–75 53 33 31 26 21 22 26 60 62 26 28-50 50 21-66, avg 40.8 17 25 23 1-75

cause acceleration of melanogenesis in murine cKIT-positive immature cultured melanocytes.1 We believe sunlight was not a causative factor in our patient because of localization to nonexposed skin. Mizushima et al18 proposed that ADM lesions are composed of dormant melanocytes in which melaninsynthesizing pathways become activated. Biopsy specimens of uninvolved skin from 2 patients showed dermal melanocytes with fully melanized stage IV melanosomes. This indicates that these melanocytes were functional because melanin production is possible beginning with stage III melanosomes in which tyrosinase activity becomes positive, and melanization begins on the lamellae of the inner matrix. This suggests that inactive dermal melanocytes may be present but unnoticed. Mizushima suggests that dormant or inactive melanocytes are present in the dermis from birth, and the melanin synthesizing pathway is activated later by unknown factors. Dermal melanocytosis in our patient may have been the result of faulty migration of melanocytes from the neural crest to the hair bulb and epidermis. The misplaced dermal melanocytes were inactive until pregnancy when exposure to high estrogen and

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A

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B

Fig 3. Scattered darkly pigmented spindle-shaped melanocytes in upper half of dermis. (Hematoxylin-eosin stain; original magnification: A, ×40; B, ×100.)

Table II. Differential diagnosis of dermal melanocytosis Age at onset

Mongolian spot19

Congenital

Blue nevus20

Acquired or congenital

Nevus of Ota21

Nevus of Ito22

Usually congenital, but early childhood or young adulthood noted Same as nevus of Ota

ADM

1–75

Neurocristic cutaneous hamartoma23 Dermal melanocyte hamartoma24 Adult disseminated melanoma25 Nerve sheath myxoma26 Dermal melanocytosis within a primar cutaneous lesion of angiosarcoma27

Distribution

Form

Color

Usually lumbosacral skin or buttocks Dorsum of hands and feet most common, but can occur anywhere on body 1st and 2nd branches of trigeminal nerve

Macules

Blue-gray

Papule, nodule, or plaquelike aggregate

Blue, blue-gray, blue-black

Macules

Blue-black or slate-gray, with brown, small flat spots

Lateral supraclavicular and lateral brachial nerves Listed in Table I

Macules

Same as nevus of Ota

Macules

One case of 27-y-old

L side of scalp

Nodules

Grayish-brown, dark-brown, blue-black, gray-blue Unspecified

One case of 18-mo-old Adults

R leg

Macules

Gray-blue

Varies

Varies

One case of 44-y-old One case of 54-y-old

Lateral aspect of upper arm Dorsum of R foot

Plaque

Varies from gray to brown with a metallic tint Blue-black

Macule on a plaque, tumor

Dark blue, dark purple, reddish-purple

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progesterone levels caused ADM to become clinically apparent. Fukuda et al7 suggested that dermal melanocytes are present when melanocytes migrating from the neural crest fail to reach their proper location in the basal layer of the epidermis. Carmichael, Tan, and Abraham14 suggested that the protective extracellular sheath enclosing dermal melanocytes adds stability to these cells in adult life, leading to the onset of ADM. Mechanisms of ADM development proposed by Hori et al9 include dropping off of epidermal melanocytes, migration of hair bulb melanocytes, reactivation of preexisting dermal melanocytes, or manifestation of latent dermal melanocytosis triggered by dermal inflammation, and atrophy or degeneration of the epidermis or dermis by aging. Other postulated mechanisms include local abundance of melanocyte-stimulating growth factors or breakdown of a regulating mechanism of melanocyte proliferation in the epidermal melanin unit.15 Ultraviolet irradiation has been postulated to increase melanocytestimulating hormone or endothelins, thereby increasing tyrosinase activity and inducing melanogenesis, especially in sun-exposed areas.4 Therapeutic options discussed with our patient included use of the Q-switched ruby laser and the Q-switched neodymium:yttrium-aluminum-garnet laser (Nd:YAG), which destroy melanin by selective photothermolysis. Ogata29 reported that the Qswitched ruby laser was more effective in treatment of dermal melanocytosis than the Q-switched Nd:YAG laser because the former caused significantly greater melanosome expansion. ADM has been successfully treated by dermabrasion,8 but this has become a second-line therapy. Other treatment modalities that have been unsuccessful include bleaching, chemical peels, carbon dioxide laser vaporization, and electric cauterization.8 ADM is only one of the many disorders of ceruloderma,30 the term that denotes the biology of dermal pigmentation and the clinical syndromes with pigmentation in the dermis. A thorough discussion on the “blue” phenomenon in dermatologic disorders has been produced by Fitzpatrick et al.30 REFERENCES 1. Mizoguchi M, Murakami F, Ito M, Asano M, Baba T, Kawa Y, et al. Clinical, pathological, and etiologic aspects of acquired dermal melanocytosis. Pigment Cell Res 1997;10:176-83. 2. Mevorah B, Frenk E, Delacretaz J. Dermal melanocytosis: report of an unusual case. Dermatologica 1977;154:107-14. 3. Hidano A, Kaneko K. Acquired dermal melanocytosis of the face and extremities. Br J Dermatol 1991;124:96-9. 4. Kuniyuki S. Acquired dermal melanocytosis on the wrist. J Dermatol 1997;24:120-4. 5. Ono T, Egawa K, Kayashima K, Kitoh M. Late onset dermal melanocytosis: an upper back variant. J Dermatol 1991;18:97-103.

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6. Pariser RJ, Bluemink GG. Acquired linear dermal melanocytosis: nerve course distribution. Arch Dermatol 1982;118:125-8. 7. Fukuda M, Kitajima J, Fushida H, Hamada T. Acquired dermal melanocytosis of the hand: a new clinical type of dermal melanocytosis. J Dermatol 1993;20:561-5. 8. Kunachak S, Kunachakr S, Sirikulchayanonta V, Leelaudomniti P. Dermabrasion is an effective treatment for acquired bilateral nevus of ota-like macules. Am Soc Derm Surg 1996;22:559-62. 9. Hori Y, Kawashima M, Oohara K, Kukita A. Acquired, bilateral nevus of Ota-like macules. J Am Acad Dermatol 1984;10:961-4. 10. Ono T, Fallas V, Higo J. Basal cell epithelioma with dermal melanocytes: a case report. J Dermatol 1986;13:63-6. 11. Sun C, Lu Y, Lee E. Naevus fusco-caeruleus zygomaticus. Br J Dermatol 1987;117:545-53. 12. Kaneko K. [Acquired symmetrical dermal melanocytosis of the face.] Rinsho Dermatol 1988;30:1649-59. Japanese. 13. Ono S, Hori M, Yamashita K, Yamakawa M. [Generalized type of acquired dermal melanocytosis]. Nippon Hifuka Gakkai Zasshi 1991;101:965-71. Japanese. 14. Carmichael AJ, Tan CY, Abraham SM. Adult onset Mongolian spot. Clin Exp Dermatol 1993;18:72-4. 15. Jimenez E, Valle P, Villegas C, Roo E, Sanchez Yus E, Furio V. Unusual acquired dermal melanocytosis. J Am Acad Dermatol 1994;30:277-8. 16. Shinohara M, Matsushita T,Toriyama F,Yoshida H. [A case of dermal melanocytosis on the forearms and dorsal hands.] Nishinihon J Dermatol 1994;56:1097. Japanese. 17. Kakutani H, Kakutani T. [A case of acquired dermal melanocytosis on the extremities.] Rinsho Dermatol 1995;37:2068-9. Japanese. 18. Mizushima J, Nogita T, Higaki Y, Horikoshi T, Kawashima M. Dormant melanocytes in the dermis: do dermal melanocytes of acquired dermal melanocytosis exist from birth? [letter]. Br J Dermatol 1998;139:349-50. 19. Kikuchi I, Inoue S. Natural history of the Mongolian spot. J Dermatol 1980;7:449-50. 20. Dorsey C, Montgomery H. Blue nevus and its distinction from mongolian spot and nevus of Ota. J Invest Dermatol 1954;22: 225-36. 21. Ota M. Nevus fusco-caeruleus ophthalmo-maxillaris. Jpn J Dermatol 1939;46:369-74. 22. Ito M. Nevus fusco-caeruleus acromio-deltoideus. Tohoku J Exp Med 1954;60:10. 23. Mezebish D, Smith K, Williams J, Menon P, Crittenden J, Skelton H. Neurocristic cutaneous hamartoma: a distinctive dermal melanocytosis with an unknown malignant potential. Mod Pathol 1998;11:573-8. 24. Burkhart CG, Gohara A. Dermal melanocyte hamartoma: a distinctive new form of dermal melanocytosis. Arch Dermatol 1981;117:102-4. 25. Geerts ML, Elewaut A, Kint A, Speelman G. Generalized melanosis due to malignant melanoma. Arch Belg Dermatol Syphiligr 1972;28:395-403. 26. Misago N, Narisawa Y, Inoue T, Yonemitsu N. Unusually differentiating immature nerve sheath myxoma in association with dermal melanocytosis. Am J Dermatopathol 1999;21:55-62. 27. Akiyama M, Naka W, Harada T, Nishikawa T. Angiosarcoma with dermal melanocytosis. J Cutan Pathol 1989;16:149-53. 28. Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sanchez JL, Mihm MC. Melasma: a clinical, light microscopic, ultrastructural and immunofluorescence study. J Am Acad Dermatol 1981;4:698-710. 29. Ogata H. Evaluation of the effect of Q-switched ruby and Qswitched Nd-YAG laser irradiation on melanosomes in dermal melanocytosis. Keio J Med 1997;46:188-95. 30. Fitzpatrick TB, Kukita A, Morikawa F, Makoto S, Sober AJ, Toda K. Biology and diseases of dermal pigmentation.Tokyo: University of Tokyo Press; 1981. p. 3-4.