Progressive macular hypomelanosis in Singapore: a clinico-pathological study

doi: 10.1111/j.1365-4632.2006.02755.x

Report Oxford, UK International IJD Blackwell 1365-4632 45 Publishing, Publishing Journal Ltd, of Ltd. Dermatology 2005

Progressive macular hypomelanosis in Singapore: a clinico-pathological study Progressive macular Kumarasinghe Report et al. hypomelanosis

Sujith Prasad W. Kumarasinghe, MBBS, MD, FCCP, FAMS, Suat Hoon Tan, MBBS M Med, Steven Thng, MBBS, MRCP, Thomas Paulraj Thamboo, MB, ChB, Shen Liang, MSc, and Yoke Sun Lee, MBBS, MRCP, FRCPA, FCAP, FAMS

Form the National Skin Center, Singapore, Department of Pathology, Faculty of Medicine, National University of Singapore, Singapore, and Clinical Trials and Epidemiology Research Unit, National University Hospital, Singapore Correspondence S. P. W. Kumarasinghe, MD National Skin Center, Mandalay Rd. Singapore E-mail: [email protected]

Abstract Introduction Progressive macular hypomelanosis (PMH), a condition of uncertain etiology, is characterized by asymptomatic hypopigmented macules predominantly located on the trunk. To date, there are no reports from South-East Asia concerning this condition. We sought to record the clinical features of PMH in Asian patients, identify etiologic factors, and study the structural and ultrastructural features of melanocytes in this disorder. Methods Patients who presented to the National Skin Center with acquired, hypopigmented macules on the trunk, without a history of inflammation or infection, were recruited. Erythrocyte sedimentation rate (ESR), complete blood count, fasting blood glucose, liver function tests, skin scrapings for fungi, and skin biopsy specimens (from lesional and normal skin) were obtained. Biopsies were stained with hematoxylin and eosin (H&E), Fontana Masson, an immunohistochemical panel for identification of melanocyte differentiation antibodies (HMB 45, Melan A, and S100) and CD 68. Electron microscopy (EM) was also performed. The patients were evaluated every 3 months. Results During a 9 month period, eight patients (all Chinese) presented with hypopigmented, ill-defined, confluent macules involving the lower aspect of the trunk. There were four men and four women, and the mean age was 25.9 years (range 19 – 45 years). Skin scrapings were negative for fungi and laboratory tests were normal. Microscopic evaluation of skin biopsy speciments showed reduced pigmentation of lesional as compared with normal appearing skin, but H&E-stained sections revealed only minimal histologic differences between lesional and normal skin. EM demonstrated a statistically significant (P = 0.047, Wilcoxon Signed Rank Test, Wilcoxon 95% CI 0.02 – 0.62) higher ratio of stage IV and late stage III (dark) melanosomes in normal vs. lesional skin. Conclusions PMH may occur among young adults in Singapore. Its etiology is uncertain. The melanin content of lesional skin appears to be less than that in normal sites. EM shows a higher ratio of immature melanosomes in lesional vs. normal skin.

Introduction Progressive macular hypomelanosis (PMH), or progressive macular confluent hypomelanosis, is characterized by hypopigmented skin lesions of varying sizes and of normal sensation, which occur on the trunk and upper extremities without previous history of inflammation, infection, or injury.1–8 Lesions may be discrete or confluent. Histologic findings are usually nonspecific. By definition, the diagnosis may be made only after evidence of specific cutaneous diseases manifested as hypopigmented macules, such as pityriasis versicolor, leprosy, or mycosis fungoides, have been excluded. © 2006 The International Society of Dermatology

In 1987, Borelli1 described the same condition, but named it “cutis trunci variata.” The current term “progressive macular hypomelanosis” was coined by Guillet et al., following a study in the French West Indies,1 concerning this condition in Black adults of mixed ethnic origin. Subsequently, additional cases were reported from the Netherlands by Menke et al. and Westerhof et al.3,4,8 One of us observed PMH in young Asian adults, including those from Sri Lanka and Singapore. The etiology of this condition is uncertain, although Westerhof et al. recently incriminated Propionobacterium acnes.8 PMH appears to progress to some extent, over months to years, and then becomes relatively static. No consistently International Journal of Dermatology 2006, 45, 737 – 742

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effective therapy is known, but lesions may spontaneously be resolved. In patients with dark skin types, PMH may be distressing because the contrast between normal skin and hypopigmented macules makes the lesions appear more prominent and the patients feel socially awkward. To date, there are no published reports of this condition from the Asian region. The purpose of this study was to document the clinical features of PMH in Asian patients, to attempt identification of etiological factors and associated medical problems, to study the histologic and ultrastructural morphologies of melanocytes from lesions of PMH, and to determine if these findings might explain the development of hypopigmentation in this disorder.

Kumarasinghe et al.

according to the density of melanin deposition.10,11 Oval organelles with internal membranous or filamentous formations, without melanin deposition, were identified as stage II melanosomes. Organelles in which the interior structure was totally masked or obliterated by melanin deposition were identified as stage IV melanosomes. stage III melanosomes were identified as intermediate organelles with varying amounts of melanin deposition but without total obliteration of the internal structures. For the purpose of the present study, we subdivided stage III melanosomes into stage III light (mild–moderate) and stage III dark (heavy, but with some internal structures), according to the relative amounts of melanin deposition.

Results Methods Patients, who were at least 18 years old, presenting to the National Skin Center with acquired, hypopigmented, discrete or confluent macules larger than 1 cm in diameter, of normal sensation, consistent with the clinical features of PMH described by Gullet and Halenon,2 were selected. Patients were excluded if their hypopigmentation was associated with or the result of a specific disease at the site, such as pityriasis versicolor, hypopigmented macules of leprosy, hypopigmented mycosis fungoides, idiopathic guttate hypomelanosis, eczema, psoriasis, pityriasis lichenoides chronica, pityriasis rosea, injury, infection, congenital disorders of pigmentation such as piebaldism, nevus depigmentosus, ash leaf macules of tuberous sclerosis, pityriasis alba, and vitiligo. The Research Ethics Committee of the National Skin Center approved this study. Details of the history and examination were recorded. Patients were evaluated at 3-month intervals. Photographs taken at the first visit were compared with those obtained during follow-up evaluations. The following studies were performed on all study patients: erythrocyte sedimentation rate (ESR), complete blood count, fasting blood glucose, hepatic transaminase levels, blood urea, and skin scrapings for fungi. Two pairs of 3 mm punch biopsy specimens were obtained, from comparable anatomic sites of lesional and normal appearing skin, for histology and electron microscopy. Formalin-fixed, paraffin-embedded sections were evaluated after hematoxylin and eosin (H&E) staining. Masson–Fontana stain for melanin was obtained, as well as immunohistochemical stains for HMB45, Melan-A, S100, and CD68. Sources and dilutions of primary antibodies used were as follows: HMB45 (DAKO-HMB45, 1:100), Melan-A (Clone A103, Novocastra, 1:25), S100 (DAKO rabbit anti-cow S100, 1:2000), and CD68 (DAKO KP1, 1:200).9 Specimens from eight patients were processed for EM. In seven cases, we examined tissue from both lesional and normal skin, while one (Case 5) had EM evaluation only of lesional skin. Electron micrographs of melanocytes and melanosomes at various stages of melanin deposition were identified and counted with the aid of a magnifying lens, without knowledge of whether the section was lesional or control tissue. Melanosomes were classified International Journal of Dermatology 2006, 45, 737 – 742

Eight patients (four men, four women) with PMH were recruited over a 9 month period. All were of Chinese descent, with no history of racial mixing. Several patients with PMH were excluded from the study because they refused skin biopsy. The mean age was 25.9 years; seven patients were in the 19–25 years age range (inclusive) and one was age 45. The average time from the patients first noticing pigment change to presentation was 3.1 years (range 1–5 years). No patient had been exposed to potentially depigmenting chemicals, and none had a background of inflammatory, infectious, malignant, or traumatic cutaneous disorders that might be responsible for the hypopigmentation. The key clinical features are summarized in Table 1, and Fig. 1 shows the classical appearance of PMH. The patients presented with hypopigmented, ill-defined, discrete or confluent macules scattered around the lumbar region, abdominal wall, and the lower flanks. The lumbar region was involved in all cases. Occasionally, lesions were visible also on the buttocks, arms, and upper chest. All lesions had normal sensation, and the KOH mounts of skin scrapings were negative for Malassezia furfur. ESR, complete blood count, fasting blood glucose, liver enzymes, and blood urea were within normal limits in all patients. Normal and lesional skin biopsy specimens were available for comparison in seven of eight cases (one patient consented Table 1 Clinical features of PMH

Patient

Age (year)

Sex

Duration (year)

Anatomic sites of lesions

1 2 3 4 5 6 7 8

23 45 22 24 24 25 21 19

F F F F M M M M

4 5 3 4 1 3 1 4

Shoulders, lumbar, buttocks, thighs Lumbosacral Lumbar, abdomen Lumbar, abdomen, back Lumbar, abdomen, chest Lumbar, abdomen, back, buttocks Lumbar, abdomen, chest, buttocks Lumbar, back

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Figure 1 Ill-defined confluent hypopigmented macules without

textural change are noted in the lumbosacral region of this patient with PMH

Figure 3 HMB 45-stained sections of (a) normal and (b) lesional

skin (original magnifications × 400)

Figure 2 H&E-stained sections show slightly less melanin

pigment in lesional (b) as compared with normal (a) skin (original magnification × 200)

to lesional biopsy only). H&E-stained sections showed no significant difference between lesional and normal skin, except in two cases in which there was a subtle decrease in pigment intensity in lesional tissue (Fig. 2a,b). The proportion of © 2006 The International Society of Dermatology

melanocytes to basal cells was similar in lesional and normal skin. There was no significant inflammatory infiltrate or epidermotropism in any of the cases. Fontana–Masson-stained sections showed overall reduction in melanization of the basal cell layer of lesional skin. Melanocytes stained negative for HMB 45 and Melan A stains. The brown pigmentation seen was due to Melanin pigment (Fig. 3a,b). S100 staining did not detect any differences in the number of melanocytes, Langerhans cells, or dermal dendritic cells. Occasional melanophages were noted, in the dermis of both lesional and normal skin, on H&E and CD68 stained sections. Melanosomes of all stages were found in both lesional and nonlesional tissue. Lesional skin tended to have more melanosomes in earlier stages of melanization, while normal skin tended to have more mature melanosomes. Figure 4a,b shows the differences in melanosomes in a typical case. The distribution of melanosomes of different stages is shown in Table 2. When the ratios of (stages II + III light + III dark)/stage IV International Journal of Dermatology 2006, 45, 737 – 742

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Figure 4 Electron microscopy: lesional

skin (b) appears to be less densely pigmented and with less mature melanosomes than normal skin (a) from the same patient

Table 2 Analysis of melanosome maturation in lesional and

normal skin by electron microscopy Normal skin No. of melanocytes/specimen Median 7 Range 4 –12 Average stage II melanosomes Median 2.2 Range 0.25 –3.57 Average stage III (light) melanosomes Median 19.33 Range 12.75 –26.20 Average stage III (dark) melanosomes Median 20.60 Range 14.08 –26.50 Average stage IV melanosomes Median 5.75 Range 2.50 –23.00 Ratio of (II + III light + III dark)/IV Median 6.55 Range 2.00 –21.76 Ratio of (II + III light)/(III dark + IV) Median 0.83 Range 0.41–1.14

Lesional skin

8 5 –17 5.18 0.86 –12.20 20.71 14.40 –29.33 17.14 11.82–34.25 5.50 1.40 –13.60 9.84 3.66 –27.10 1.18 0.55 –1.55

melanosomes were compared, there was no significant difference between normal skin and lesional skin (P = 0.219, Wilcoxon signed-rank test, median difference 4.82, Wilcoxon 95% CI −5.77–15.01). However, when the ratios of (stages II + III light)/(stages III dark + IV) melanosomes were compared, there was a significant difference between normal skin and lesional skin (P = 0.047, Wilcoxon signed-rank test, median difference 0.34, Wilcoxon 95% CI 0.02– 0.62). International Journal of Dermatology 2006, 45, 737 – 742

Discussion Although initially described in 1988, PMH is not yet recognized as a distinct entity in many parts of the world, possibly because the initial publications on this subject were not in English. Multiple synonyms, including PMH, progressive macular confluent hypomelanosis, cutis trunci variata, progressive and confluent hypomelanosis of the melanodermic metis, Creole dyschromia, nummular and confluent hypomelanosis of the trunk, and idiopathic multiple large macules, add to the confusion.4,7 When occurring in dark-skinned individuals, PMH may be misdiagnosed as hypopigmentation associated with pityriasis versicolor, despite exclusion of Malassezia furfur. In areas where leprosy is endemic, tuberculoid or borderline tuberculoid leprosy may be considered, but there is no sensory impairment, no textural change, and no histologic evidence of granulomas in lesions of PMH. Hypopigmented mycosis fungoides differs from PMH in its asymmetrical distribution, poikiloderma, and textural changes. In endemic areas of visceral leishmaniasis (not Singapore), hypopigmented lesions of post-kala azar dermal leishmaniasis could also be considered in the differential diagnosis. The community prevalence of PMH in Singapore is unknown, but this is not a rare condition. In our institution, the total number of patients with PMH was greater than the number recruited for the study, because several refused skin biopsy. Also, during the same period, there were patients who had characteristic features of PMH who presented for unrelated conditions; they also were excluded. Therefore, PMH is not uncommon and patients may not be aware of the lesions. As previously reported, we found that PMH is a disorder of adolescents and young adults. Although our study did not © 2006 The International Society of Dermatology

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identify any definite causative factors, it was evident that exposure to sunlight (e.g., spending several hours in the tropical sun at the swimming pool) enhanced the visual demarcation between lesional and nonlesional skin, indicating that PMH lesions tan poorly. Use of sunscreens helped to reduce the contrast between lesional and nonlesional skin in patients who participated in outdoor sports. In contrast to our observation, temporary improvement in lesions after sun exposure has been reported.8 Long-term follow-up is necessary to determine the true effect of sun exposure on PMH. In some of our patients, there was slight regression of lesions within the follow-up period of up to 9 months. As noted in the literature, virtual absence of this condition in the elderly was a notable feature in our study, suggesting that PMH is not a progressive disorder. Westerhof et al. recently found gram-positive bacteria in the pilosebaceous ducts of lesional skin, and Propionobacterium acnes has been cultured from follicular lesional skin from patients with PMH; they postulate a causal relationship between P. acnes and PMH.8 This is a plausible explanation because PMH is a disease of young adults. However, as observed by Westerhof and others, there was no active acne in any of our patients. Their study showed a very strong female preponderance. However, in Singapore and Sri Lanka, we did not observe a predominant sex distribution. The patients in our study were relatively young and without other medical problems. None had parental consanguinity or parents of different ethnic groups as initially reported. The first author has seen many cases of PMH in Sri Lanka, in young persons of both sexes in whom there was no racial mixing. Thus, it is clear that PMH occurs in Mongoloid and Indian-type skin (i.e. in patients from India, Bangladesh, and Sri Lanka), and not only in mixed Negroid subjects as reported previously. Perhaps the type of minor pigmentary decrease that occurs in PMH (in contrast to the total depigmentation of vitiligo), also occurs in white-skinned subjects, but it may not be obvious enough to concern patients. In this study, histologic examination demonstrated decreased melanization of the basal layer in lesions of PMH as compared to normal skin. This difference was best illustrated with Fontana–Masson stain. Junctional melanocytes are preserved. A lack of inflammation is characteristic and melanophages are not present in significant numbers. Histologic evaluation is sometimes important to exclude hypopigmented mycosis fungoides, vitiligo, and postinflammatory pigmentary changes. The observation that there was no decrease in numbers of melanocytes but only a decrease in melanin content suggests that there is probably a functional defect in pigmentation or a problem in melanin distribution. Previously, Helenon et al. reported that melanocytes found in lesional skin had Caucasoid types of melanosomes (e.g. stage II). Our study appears to be the only one in which lesional and nonlesional electron microscopic features were blindly com© 2006 The International Society of Dermatology

Progressive macular hypomelanosis Report

pared. In addition, two pathologists independently evaluated all electron microscopic images. We found melanosomes of all stages in both lesional and normal skin in all cases studied; it was only the ratio of fully mature to immature melanosomes that was different in PMH and normal skin. While no statistical significance was seen in the ratios (stages II + III)/ stage IV melanosomes in lesional vs. normal skin, there was statistical significance when stage III (dark) melanosomes were grouped together with stage IV melanosomes. Because melanogenesis is a continuous process, the differentiation between stage III (dark) and stage IV is arbitrary. Our findings support the theory that the hypopigmentation in PMH is due, in part, to a decrease in melanin deposition in melanosomes. The reason for the decrease in melanin deposition is unknown. The role of keratinocytes in the development of hypopigmentation in PMH also is not clear. Our findings differ from those of Helenon et al. in that we found mature melanosomes in lesional as well as normal skin, although the proportion is less in lesional skin. The hypopigmented macules of PMH do not occur along Blaschko’s lines or in a dermatomal pattern and may be due to active inhibition of the melanogenesis, abnormal packaging or maturation of melanosomes in lesional skin, or a reduction in melanin production. Failure of lesions to tan with exposure to UV light tends to favor an inhibitory effect rather than a primary reduction in melanogenesis. The clinical observations that PMH fades over time and that it is not found in the elderly suggest that an inhibitory effect on melanogenesis is not permanent. Melanogenesis is known to be inhibited by factors such as IL-1, IL-6, and TGF-beta.11 It would be useful to study the presence and amount of these factors in lesional compared with normal skin. In a predominantly Chinese population, this study is particularly relevant because, clinically, early patch stage mycosis fungoides may resemble PMH. Hypopigmented mycosis fungoides is the most common type of mycosis fungoides found in Singapore.12 Careful examination in cases of hypopigmented mycosis fungoides should reveal atrophy of the skin with mild textural changes, features that are absent in PMH. In our opinion, the term “progressive” in PMH is erroneous, because the condition does not progress in most patients and regresses spontaneously after many years. However, because there are already too many terms for this condition, it may be prudent to keep the terminology “progressive macular hypomelanosis” until the etiology of this condition is established. Conclusions Progressive macular hypomelanosis is a benign pigmentary anomaly, of uncertain etiology, which may be found in young adults. This is the first documentation of PMH in Singapore. Exposure to sunlight appears to increase the contrast between lesional and normal skin in patients with PMH. No effective International Journal of Dermatology 2006, 45, 737 – 742

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treatment is known. Melanin content appears to be less in lesional than nonlesional skin, although there is no difference in the number of melanocytes. By EM, lesional skin shows a statistically significant, lower proportion of stage IV and late stage III melanosomes than normal skin.

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Acknowledgments This study was supported by research funds from the National Skin Center. We are grateful to Medical Director, Professor Chee Leok Goh for his support, Ms. Wong Bee Yin of the National Skin Center for her coordination of the study, and the laboratory staff of the National Skin Center and the Department of Pathology, National University of Singapore for their technical expertise.

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Pigmentary System: Physiology and Pathophysiology. New York: Oxford University Press, 1998: 686 – 688. Guillet G, Halenon R, Guillet MH, et al. Progressive and confluent hypomelanosis of the melanodermic metis. Ann Dermatol Venereol 1992; 119: 19 –24. Lesueur A, Gracia-Granel V, Halenon R, et al. Progressive macular confluent hypomelanosis in mixed ethnic melanodermic subjects: an epidemiologic study of 511 patients. Ann Dermatol Venereol 1994; 121: 880 – 883. Ortonne JP, Bahadoran P, Fitzpatrick TB, et al. Hypomelanosis and hypermelanosis. In: Freedburg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 2003: 836 – 881. Westerhof W, Relyveld GN, Kingswijk MM, et al. Propionobacterium acnes and the pathogenesis of progressive macular hypomelanosis. Arch Dermatol 2004; 140: 210 –214. Orchard GE. Comparison of immunohistochemical labelling of melanocyte differentiation antibodies melan-A, tyrosinase and HMB 45 with NKIC3 and S100 protein in the evaluation of benign naevi and malignant melanoma. Histochem J 2000; 32: 475– 481. Halaban R, Hebert DN, Fisher DE. Biology of melanocytes. In: Freedburg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 2003: 127–147. Chu DH, Haake AR, Holbrook K, et al. The structure and development of skin. In: Freedburg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th edn. New York: McGraw-Hill, 2003: 58 – 88. Tan E, Tay YK, Giam YC. Profile and outcome of childhood mycosis fungoides in Singapore. Paediatr Dermatol 2000; 17: 352–356.

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