|Year : 2014 | Volume
| Issue : 1 | Page : 17-22
Exogenous ochronosis in melasma: A study from South India
Sivashankari Kulandaisamy, Devinder Mohan Thappa, Divya Gupta
Department of Dermatology and STD, Jawaharlal Nehru Institute of Postgraduate Medical Education and Research, Puducherry, India
|Date of Web Publication||26-Jun-2014|
Devinder Mohan Thappa
Department of Dermatology and STD, Jawaharlal Nehru Institute of Postgraduate Medical Education and Research, Puducherry 605 006
Source of Support: None, Conflict of Interest: None
Background: Exogenous ochronosis (EO) can be associated with the prolonged application of hydroquinone (HQ) used for the treatment of melasma. Histopathological examination is required for a definite diagnosis. Dermoscopy can be used to avoid unnecessary biopsies from the face. Aims and Objectives: The aim was to characterize the clinical profile of melasma, to elicit the dermoscopic features of melasma and EO if any, and to histopathologically confirm any suspected cases of EO. Materials and Methods: This was a descriptive study spanning October 2011 to June 2013. With informed consent, a detailed history and examination was carried out along with details of skin lightening creams used if any. This was followed by cutaneous examination and dermoscopic evaluation. In those who had lesions suspicious of EO, consent for 3 mm punch biopsy was obtained and the samples were studied using hematoxylin and eosin stain for banana-shaped ochre colored fibers. Results: In 104 (94 females, 10 males), the mean age at onset and duration of melasma was 36.6 and 4.14 years, respectively. Past history of treatment for melasma was present in 30.8% patients. The most common clinical type of melasma was malar (51.9%). EO was suspected in five patients. In suspected cases, brown-blue globules were noted in addition to melasma features dermoscopically. Telangiectasias were noted in 37.5% of patients. Histopathological confirmation of EO was obtained in only one out of four patients who gave consent for biopsy. Conclusion: The frequency of EO in our study was found to be 0.9%. The incidence of EO in Indian population appears to be quite low, which might be due to under reporting, lack of awareness, irregular and infrequent use of HQ or population based difference in prevalence.
Keywords: Dermoscopy, exogenous ochronosis, hydroquinone, melasma
|How to cite this article:|
Kulandaisamy S, Thappa DM, Gupta D. Exogenous ochronosis in melasma: A study from South India. Pigment Int 2014;1:17-22
| Introduction|| |
Melasma is a symmetric progressive hyperpigmentation of the facial skin that has a predilection for darker skin phenotypes.  Exogenous ochronosis (EO) is an uncommon disorder characterized by the deposition of microscopic, ochre-colored pigment in the dermis, giving rise to a blue-black hue in the skin. It is often associated with the prolonged application of various topical depigmenting agents particularly hydroquinone (HQ).  EO can be clinically mistaken for other acquired facial melanosis, and this misdiagnosis of EO leads to further prescription of topical depigmenting agents resulting in a vicious cycle which further aggravates the hyperpigmentation. Although the use of topical depigmenting agents, including HQ, is widespread in India, the actual incidence of EO in Indian population is probably quite low, and its frequency is not known. Hence, we decided to investigate the prevalence of EO and correlate it with the clinical profile of melasma patients clinically and dermoscopically.
| Materials and Methods|| |
This was a descriptive study spanning over a period of 21 months from October 2011 to June 2013. Ethics Committee Clearance was obtained. All consenting consecutive patients of both genders attending the outpatient department (OPD) with melasma were included in the study. Patients who were on antimalarials within 2 years before the onset of study, patients with clinical history suggestive of alkaptonuria and patients who declined to give consent for biopsy of suspicious lesions suggestive of EO were excluded. After obtaining informed consent, history regarding onset and duration of melasma, sun exposure, exacerbating factors, chronic drug intake, family history, menstrual history, and presence of endocrine disorders, if any, was noted. History of application of skin lightening creams, their composition and duration of the application was also recorded. Pattern of distribution and melasma area severity index (MASI) were recorded. Skin type was assessed using visual examination of the skin color and enquiring about the tendency to tan or sunburn. Following this, Wood's lamp examination and dermoscopic evaluation was done. Skin biopsy was done in lesions suspected to be EO on dermoscopy. A photographic record was also maintained. All analysis was carried out at 5% level of significance, and a P < 0.05 was considered as significant. SPSS software version 15 was utilized to analyze the results.
| Results|| |
Clinical and dermoscopic characteristics of patients with melasma
A total of 104 consecutive patients with melasma were recruited for this study. Out of 104 melasma patients, 94 (90.4%) were females and 10 (9.6%) were males. The mean (standard deviation [±SD]) age at the onset of melasma was 36.67 ± 8.69 years and the mean (±SD) age at presentation of melasma to our OPD was 40.4 ± 9.3 years. The mean (±SD) duration of melasma in our study was 4.14 ± 3.05 years.
The most common skin type was Fitzpatrick type IV (n = 82, 78.8%). The most common distribution was malar (n = 54, 51.9%) followed by composite (36 cases, 34.6%) and centrofacial type (n = 14, 13.5%). The mean (±SD) MASI in our study population was 5.2 ± 3.49. Majority (n = 69, 66.3%) of our patients had MASI ≤6.
Family history of melasma was present in 39 (37.5%) patients. Sixty-three (60.6%) patients in our study were doing outdoor work and exposure to sunlight was the most common exacerbating factor as reported by 55 (52.9%) patients.
Among 94 women studied, 55 (58.5%) had normal menstrual cycle, whereas 24 (25.5%) gave a history of menstrual abnormality (oligomenorrhea-11 cases, menorrhagia-6 cases, hypomenorrhea-2 cases, amenorrhea-2 case, menorrhagia + polymenorrhea-2 cases, polymenorrhea-1 case). Apart from this, 11 (11.7%) had attained menopause, 3 (3.3%) had undergone hysterectomy (one for fibroid and two for dysfunctional uterine bleeding) and one had infertility. Pregnancy was reported as a cause of melasma in 7 (7.5%) women and both pregnancy and oral contraceptive pill intake by 1 (1.06%) woman.
Thirteen patients (12.5%) had been previously treated with HQ triple combination regimens (melalite-5, triglow-4, melacare-2, multiple agents-2) and 35 (33.7%) patients gave a history of other cosmetic application (fair and lovely-18, turmeric-11, talcum-1, fair ever-1, vicco turmeric-1, multiple creams-3). Nineteen patients had self-medicated with over-the-counter (OTC) ointments, the details of which were unavailable.
On Wood's lamp examination, 95 (91.3%) patients were classified as indeterminate type, six as mixed type (5.8%) and three as epidermal type (2.9%). In all 104 patients, dermoscopy revealed faint light brown background with accentuation of pseudoretes. Telangiectasia was noted in 39 patients (37.5%). Dermoscopic findings of melasma patients are listed in [Table 1].
Clinical, dermoscopic and histopathological characteristics of patients with exogenous ochronosis
Of 104 patients, only 5 (4.8%) patients had history and clinical features suggestive of EO. These patients had blue-black macules, caviar like papules and papulonodules clinically [Figure 1] and dark brown to blue globules dermoscopically [Figure 2]. However, occlusion of follicular opening, characteristically described in dermoscopy of EO, was not seen in any of the patients. Significantly, in all these five cases, history of topical medication was present. Four patients gave consent for biopsy, which showed increased basal pigmentation, pigment incontinence and pigment clumps in upper dermis (freely as well as in melanophages) in all four. In one case, brownish-yellow pigment clumps with "banana-shaped" fibers in the upper dermis along with swollen and homogenous collagen fibers were noted [Figure 3]. Hence, the diagnosis of EO could be confirmed histologically in only this case, giving prevalence of 0.9%. Masson Fontana staining could not be done due to error in sectioning and specimen was not available for further sectioning. The treatment history, clinical, dermoscopy and histology findings of patients with suspected EO are highlighted in [Table 2] and [Table 3].
|Table 3: Clinical, dermoscopic, and histopathological profile of patients with suspected EO |
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|Figure 1: Melasma patient with blue-grey pigmentation after prolonged application of hydroquinone|
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|Figure 2: Dermoscopic image of patient with suspected exogenous ochronosis|
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|Figure 3: Histopathological examination showing banana-shaped ochre colored fibers in the dermis (H and E, ×400)|
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In addition, all four specimens were found to have thinned out epidermis with flattened rete ridges, increased basal layer melanin and solar elastosis. One patient had comedo, and milia like lesions, but there was no evidence of ochronotic pigment in that patient. None of these patients had altered urine color or other signs of endogenous ochronosis.
| Discussion|| |
Melasma is difficult to treat, and both monotherapy and combination therapy have been used. HQ is the most commonly used depigmenting agent.  However, adverse effects such as skin irritation, phototoxic reactions with secondary postinflammatory hyperpigmentation, and irreversible EO have been reported with even mild concentration. 
Exogenous ochronosis is characterized by the deposition of microscopic, ochre-colored pigment in the dermis,  giving rise to asymptomatic blue-black macules on photo exposed areas, especially malar areas, temples, lower cheeks, and neck.  Three stages have been defined in EO: (i) Initial erythema and mild pigmentarychanges; (ii) hyperpigmentation, black colloid milia, and atrophy; (iii) papulonodule.  Histopathologically, it is characterized by yellow-brown or green curled banana-shaped ochronotic fibers. In advanced stages, there is degeneration of the ochronotic fibers, and formation of colloid milium. 
The diagnosis of EO relies on a combination of clinical acumen, high index of suspicion based on the history of prolonged use of skin lightening agents with no response or deteriorating features, and skin biopsy. Unfortunately, many patients are reluctant to undergo a biopsy for a facial cosmetic condition. Presence of characteristic findings in dermoscopy makes it easy for the dermatologist to diagnose EO by avoiding unnecessary biopsies.
There are few reports of dermoscopic examination of EO in literature. , Bluish-gray amorphous areas obliterating the follicular structures , and "speckling"  are described. It is to be noted that although the differences between "melasma" and Stage II and III EO are easily recognizable on dermoscopy, the greatest difficulty comes in differentiating melasma from stage I EO. 
Our study found that up to 67 (64.4%) patients of melasma had already received prior treatment (including Kligman's formulations, popular cosmetic creams and others) before they presented to us. Of these, 19 (18.3%) patients had a history of self-treatment with OTC medications.
These figures reflect an alarming trend in the quest of "fairness" in a country which is obsessed with white colored skin. However, what is worrisome is the trend of getting depigmentation creams OTC without doctor's prescription. Among those with a positive history of cosmetic use, fairness creams like fair and lovely ranked top followed by turmeric. This reflects the craze for fairness creams, which are portrayed as a panacea to the problems of a dark skin. Turmeric, incidentally, is widely used in South India as it is believed to possess beneficial effects on the skin, including lightening of skin tone.
Balkrishnan et al.  measured the quality of life in 102 white patients, and found that around 75% resorted some treatment for melasma. The slightly lower figures in our study may due to the low socio economic status, which precluded the frequent and long-term use of medications. Moreover, as melasma is more prominent in fair-skinned subjects as compared to those with a darker skin tone, it may be concluded that skin photo type influences treatment seeking behavior in melasma, with fair skinned patients resorting to treatment more frequently as compared to dark skinned ones.
A study in Chinese patients  revealed that EO occurred after use of HQ containing products from 1 to 20 years, with the majority having used it for more than 2 years. Though, it was previously believed that higher concentration of HQ for prolonged periods causes EO, a few cases caused by low concentration for shorter periods of use have been reported. In fact, EO has been reported after just 4 months of use too.  Apart from HQ, other offending agents include phenol, quinine injection, resorcinol and antimalarials. This may explain the high incidence of EO in Africa, where HQ adulterated with other chemicals is often used for an extended period of time without supervision.  It therefore appears that it is excessive, chronic and unsupervised use, rather than just high concentration of HQ, that is dangerous. This argument is supported by 72 clinical studies with a total of 20,814 subjects, using mainly 2-5% HQ from 8 weeks to 2 years. None of these studies reported EO when HQ was used under close physician follow-up. 
At present, there are no Indian studies correlating the use of skin lightening creams with incidence of EO. From the few case reports that are available, we can glean that EO developed after a prolonged use of HQ alone or in combination with retinoids, steroids and chemical peels, after 4-3 years. In a single case report by Zawar and Mhaskar,  where it developed after 3 months, the patient had other risk factors like prolonged hours of work in the sun with lack of adequate photo protection, initiation of treatment with 4% HQ rather than 2% HQ, self-medication, and vigorous rubbing of the affected area several times a day. The previous reports of EO from India ,,, are summarized in [Table 4]. The low frequency in this study (0.9%) rather closely mimics the incidence in the US,  reflecting a population wise difference in prevalence. Thus, the pathogenesis of EO may be more complex than just prolonged HQ application, with a role for genetic predisposition and skin type.
The very low incidence of EO in our study may be also explained by the following confounding factors: (i) Our study population had a skin type IV which made melasma less prominent and hence less disturbing cosmetically; this prevented prolonged, continual use of depigmenting agents. (ii) Most patients belonged to a low socio economic status and could not afford expensive skin lightening creams. (iii) Those patients who did use topical medication did so intermittently and not continuously.
Hence, contrary to popular belief, EO may actually be a very rare event considering the huge annual consumption of HQ. The exaggerated fears of HQ use causing EO may be unfounded, and at the same time, occurrences of EO can be minimized by careful medical supervision, limiting the duration of exposure and by stringent quality control measures in the skincare product market to prevent adulteration with other offending substances. The use of lower HQ concentrations, sun protection, early diagnosis, and suspension of treatment in case in whom there is no clinical improvement within 6 months are the measures that should be adopted for EO prevention. The level of awareness regarding EO should be raised amongst doctors who should be more vigilant about close monitoring of patients to prevent the development of this potentially disfiguring condition. Our study also highlights the futility of Wood's lamp in determining the type of melasma in Indian patients with Type IV-V skin, as the majority of the patients were seen to belong to indeterminate type.
| Conclusion|| |
Exogenous ochronosis is an uncommon disorder that can be clinically mistaken for other acquired facial melanoses like melasma or it can occur in patients with melasma owing to the prolonged use of topical skin lightening agents. The actual incidence of EO is quite low in Indian population, despite the common use of such agents, which might be due to under reporting or a general lack of awareness. Clinicians should be aware of the existence of this problem and appropriately educate the patients to stay away from OTC drugs.
Our study was limited by a small sample size, lack of a control group without melasma and recall bias regarding onset, risk factors and treatment. Moreover, since it is difficult to differentiate early stages of EO from melasma, it is possible that some cases of early EO may have been missed out as biopsy was performed only in four patients.
To the best of our knowledge, this is the first study in our sub-continent looking at the frequency of EO in melasma. Further large scale studies are required to shed more light on the magnitude of this problem in Indian population.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]