Hyperpigmented Macules and Patches on the Face: Exogenous Ochronosis or Lichen Planus Pigmentosus?

We present a case of a patient with a 10-year history of blue-black macules and patches on the face and an associated history of skin-lightening cream usage. The skin lightening cream contained hydroquinone, which is often associated with exogenous ochronosis (EO). Interestingly, the biopsy did not show characteristic findings of ochronosis, confusing the final diagnosis, however discontinuing the skin-lightening creams halted the progression of the patient's skin lesions supporting a diagnosis of EO. EO presents as asymptomatic hyperpigmentation after using products containing hydroquinone. This condition is most common in Black populations, likely due to the increased use of skin care products and bleaching cream containing hydroquinone in these populations. Topical hydroquinone is FDA-approved to treat melasma, chloasma, freckles, senile lentigines, and hyperpigmentation and is available by prescription only in the US and Canada. However, with the increased use of skin-lightening creams in certain populations, it is important for dermatologists to accurately recognize the clinical features of exogenous ochronosis to differentiate it from similar dermatoses. An earlier diagnosis can prevent the progression to severe presentations with papules and nodules. We summarize the clinical presentations diagnostic features, and treatment pearls, concluding with a discussion of the differential diagnoses.  J Drugs Dermatol. 2024;23(7):567-568.     doi:10.36849/JDD.8248.

Exogenous Ochronosis With Ocular Involvement From Chronic Use of Teavigo.

Exogenous ochronosis refers to accumulation of homogentisic acid metabolites in tissues, manifesting as pigmentation of affected tissues. Phenolic compounds are most commonly implicated, including hydroquinone, quinine, phenol, resorcinol, mercury, and picric acid. The affected connective tissues exhibit brownish discoloration when heavily pigmented and the histopathological appearance is characteristic with "banana-shaped" ochre-colored pigment deposits. Herein, the authors describe a rare case of exogenous ochronosis involving the conjunctiva, sclera and skin, as a result of chronic use of Teavigo (94% epigallocatechin gallate), a polyphenol compound with postulated antioxidant and antiapoptotic activity.

Hyperpigmentation: Looking beyond hydroquinone.

Hyperpigmentation is the most common complaint in the age group 40-45 years, seeking consultation for skin disorders. Hydroquinone is a commonly used depigmenting agent in clinical practice for treating hyperpigmentation. Prolonged use of hydroquinone has been associated with cancer risk and exogenous ochronosis. The CARES (The Coronavirus Aid, Relief, and Economic Security Act) Act of 2020 has instituted significant changes to hydroquinone containing OTC (over the counter) products, and consequently, many hydroquinone-based OTC products had to be withdrawn from the market. Henceforth, products containing hydroquinone would need US Food and Drug Administration approval via new drug application pathways for commercialization. Alternative treatment options to hydroquinone in clinical practice are reviewed in this paper with regard to their safety and efficacy vis a vis hydroquinone. Also, new potential treatment options such as thiamidol, Polypodium leucotomos, and glutathione are discussed. The review shows that these alternative depigmenting agents can be rationally combined to achieve desired treatment goals in the management of hyperpigmentation.

Dogliotti and Phillips classifications are unsuitable for grading the histopathological findings of exogenous ochronosis.

BACKGROUND: Cutaneous exogenous ochronosis (EO) is frequently graded and staged according to the Dogliotti or Phillips classification system, both in research studies and in clinical practice. There are no data to support the use of these systems in either of these settings. These systems additionally purport that the clinical and histopathological findings of EO are concordant; however, anecdotal evidence suggests otherwise. We aimed to determine the clinical-histopathological concordance rates in EO and to assess the suitability of the Dogliotti and Phillips classification systems for the grading and staging of EO lesions. METHODS: Five cutaneous EO cases diagnosed at our institution were studied. Clinical and histopathological data were obtained by medical record and histopathology slide review. Each case was assigned a clinical and histopathological grade according to both the Dogliotti and Phillips classifications. Clinical-histopathological concordance rates were determined for each classification. RESULTS: Clinical-histopathological concordance was seen in 80% and 60% of EO lesions when graded according to the Dogliotti and Phillips classifications, respectively. CONCLUSIONS: Cutaneous EO lesions do not consistently show clinical-histopathological concordance. Although the Dogliotti and Phillips classifications may have clinical utility, they are not suitable to grade EO histopathologically.

Corneal and Scleral Problems Caused by Skin-Lightening Creams.

PURPOSE: To present a case series of patients with corneal and scleral changes associated with the use of skin-lightening creams. This is the first report of corneal changes with these widely available creams. METHODS: Three patients of West African origin presented with strikingly similar skin, corneal, and scleral changes and were found to have all been using skin-lightening creams containing hydroquinone. Histopathology was obtained for 1 patient. RESULTS: Three patients were referred to the corneal clinics of 2 hospitals with corneal changes and a history of blurred vision for 1 to 3 years. There was a 60-year-old woman from Nigeria and a 68-year-old woman and a 73-year-old man both from Ghana. All 3 had been using skin-lightening lotions containing hydroquinone on their faces for between 3 and 15 years and had black-blue facial pigmentation of exogenous ochronosis, a recognized complication of these creams. Their corneas all had horizontal striae radiating across the posterior corneas with scleral thinning and plaques. Linear brown epithelial pigmentation was observed within the lower third of the corneas. Biopsy of the sclera in 1 patient showed ochronosis. CONCLUSIONS: We present previously unreported eye changes associated with the use of skin-lightening creams containing hydroquinone, with a triad of signs: posterior corneal striae radiating from 3 o'clock to 9 o'clock, thinning and plaques in the sclera, and a normal endothelial cell count. Similar pathological changes are seen in exogenous ochronosis, a recognized skin complication of hydroquinone, are seen in the sclera.

A role for interleukins in ochronosis in a chondrocyte in vitro model of alkaptonuria.

Alkaptonuria is a rare autosomal recessive condition resulting from inability to breakdown homogentisic acid (HGA), an intermediate in tyrosine degradation. The condition has a triad of clinical features, the most damaging of which is ochronotic osteoarthropathy. HGA is elevated from birth, but pigmentation takes many years. We hypothesise that interleukins play a role in initiation and progression of ochronotic osteoarthropathy. C20/A4 cells were cultured and maintained in 9-cm petri dishes containing either HGA at 0.33 mM, a single interleukin (IL-1ß, IL-6 or IL-10) at 1 ng/ml or a combination of HGA and a single interleukin. Statistical analysis of pigment deposits and cell viability was performed using analysis of variance with Newman-Keuls post-test. All cultures containing HGA showed a significant increase in pigment deposition compared to control and IL cultures alone. The cultures containing HGA and IL-6 showed a significant increase in pigment deposits compared to HGA alone. The cell viability counts across all cultures on day 10 demonstrated a significant decrease in cultures containing HGA compared to those which did not. There was no significant difference between cultures containing just HGA or those combined with an interleukin. This work demonstrates a role for cytokines present in the joint(s) in the pigmentation process, particularly IL-6, and that the presence of HGA in joint tissues appears more detrimental to chondrocytes than the presence of any of the interleukins found in response to joint injury, trauma and osteoarthritis (OA). This further supports the evidence that the arthropathy in alkaptonuria is much more severe and rapidly progressing.

Exogenous ochronosis: a comprehensive review of the diagnosis, epidemiology, causes, and treatments.

Exogenous ochronosis (EO) can be an unintended psychologically troubling condition for patients who are already being treated for longer-term hyperpigmentation disorders such as melasma. Early diagnosis is key in order that the offending agent can be stopped to prevent further disfiguring discoloration. EO can be diagnosed in the right clinical setting with the aid of dermatoscopy, which can assist in early diagnosis and may negate the need for a biopsy. Laser modalities using Q-switched lasers of longer wavelengths and combination laser dermabrasion treatments have shown the most significant results with minimal adverse events. However, further large-scale studies are needed to determine optimal treatment modalities. Although considered uncommon, the incidence of EO will likely continue to increase with the growth of immigrant populations and the use of skin-lightening agents above the FDA's recommended over-the-counter concentrations, without the guidance of a dermatologist.

Exogenous ochronosis - successful outcome after treatment with Q-switched Nd:YAG laser.

BACKGROUND: Exogenous ochronosis (EO), a disfiguring cutaneous complication of topical hydroquinone use, is difficult to treat. There are few reports of successful outcomes following treatment with different modalities. OBJECTIVE: We assessed the results of treatment of EO with the Q-switched Nd:YAG laser. MATERIAL AND METHODS: Patients with histologically-confirmed EO were treated with the Q-switched Nd:YAG laser. RESULTS AND CONCLUSION: Q-switched Nd:YAG laser treatment appears to be effective in reducing the dyschromia of EO.

Diagnostic utility of dermatoscopy in hydroquinone-induced exogenous ochronosis.

BACKGROUND: Hydroquinone is the preferred topical bleaching agent used in the treatment of melasma. The adverse effects of its chronic use are confetti-like depigmentation and exogenous ochronosis. Exogenous ochronosis manifests clinically with gray-brown or blue-black hyperpigmentation, as well as pinpoint hyperchromic caviar-like papules over the malar region. Dermatoscopic findings of ochronosis are unique and point towards a clue for its diagnosis. METHODS: Three cases of suspected hydroquinone-induced exogenous ochronosis while treating melasma were subjected to dermatoscopy and histopathology studies. RESULTS: Dermatoscopy in the areas of caviar-like hyperpigmentation revealed accentuation of the normal pseudo-rete of the facial skin with amorphous densely-pigmented structures obliterating some follicular opening and multiple thin, short arciform structures. On histopathological examination, curved ochre-colored structures, 'banana-shaped' fibers, were seen in the dermis of all patients. CONCLUSION: Exogenous ochronosis is difficult to treat. Dermatologists should be able to differentiate it from melasma and immediately discontinue hydroquinone. Exogenous ochronosis has characteristic features on dermatoscopy which may obviate the need for an invasive procedure of biopsy for its diagnosis.

Exogenous ochronosis: case report and literature review / Ocronose exógena: relato de caso e revisão de literatura

Exogenous ochronosis is a rare, cosmetically disfiguring condition, resulting from the longterm use of topical hydroquinone in treatment of melasma. It manifests as gray-brown or blue-black macules in hydroquinone-exposed regions. The exact incidence of ochronosis is unknown. High rates have been reported in the South African population, and it is rare in the United States. We report the case of a patient who developed exogenous ochronosis while using topical hydroquinone. It is necessary to recognize this disorder at the earliest stage and discontinue hydroquinone immediately, as its treatment is difficult. Sun exposure facilitates the formation of exogenous ochronosis and must be strictly avoided, although it is a practical problem in the tropical climate of Brazil, particularly for those who work outdoors.

Ocronose exógena é uma condição rara, cosmeticamente desfigurante, devido ao uso tópico indiscriminado de hidroquinona para tratamento do melasma. Manifesta-se como máculas marrom-acinzentadas ou preto-azuladas em áreas cutâneas do uso de hidroquinona. A exata incidência de ocronose Exógena é desconhecida. Altos índices têm sido relatados em populações sul-africanas, sendo rara nos Estados Unidos. Relatamos um caso de uma paciente que desenvolveu ocronose Exógena durante uso de hidroquinona para tratamento do melasma. É necessário o reconhecimento dessa patologia no seu estágio precoce e imediata descontinuação da droga, pois seu tratamento é difícil. A exposição solar é um fator precipitante e deve ser estritamente evitada, embora isso seja difícil no clima tropical do Brasil, especialmente para aqueles que trabalham ao ar livre.

Toxic effects of skin-lightening products in Canadian immigrants.

BACKGROUND: The cultural practice of skin bleaching is highly prevalent in Africa. Most reported cases of toxic effects of skin-lightening products occur in this region. OBJECTIVE: To describe cases of misuse of over-the-counter (OTC) cosmetic skin-lightening products occurring in Canadian immigrants. METHODS: Two cases of Canadian immigrants with severe complications from OTC skin-bleaching agents were identified in a community-based dermatology practice in Toronto. The case histories were reviewed and analyzed. RESULTS: A 28-year-old African-Canadian woman developed extensive striae from long-term use of a topical cream containing clobetasol that she had purchased in a Caribbean health food store. A 55-year-old African-Canadian woman developed exogenous ochronosis from the use of a topical bleaching agent she had purchased in Ghana. CONCLUSION: Cosmetic skin lightening with unregulated topical products occurs in Canada. Dermatologists working in Canada need to be aware of this practice to provide appropriate directive care.

Treatment of hyperpigmentation.

Hyperpigmentation is a common dermatologic condition that is seen in all skin types but is most prominent in skin of color. In skin of color, any inflammation or injury to skin can almost immediately be accompanied by alterations in pigmentation, either hyperpigmentation or hypopigmentation. Post-inflammatory hyperpigmentation can be observed in many skin conditions including acne, eczema, and contact dermatitis and treatment can be challenging. The goal is to reduce the hyperpigmentation without causing undesirable hypopigmentation or irritation in the surrounding area. This review will discuss current research on treatments for hyperpigmentation and approaches to treating this condition.

Aplicação da dermatoscopia no auxílio diagnóstico da ocronose exógena / Use of dermoscopy for diagnosis of exogenous ochronosis

A ocronose exógena consiste em hiperpigmentação crônica de áreas previamente tratadas com agentes tópicos como: a hidroquinona, a resorcina, os antimaláricos e o fenol. O diagnóstico precoce permite suspender prontamente o agente causador, uma vez que as opções terapêuticas disponíveis são escassas e com resultados insatisfatórios. Reportam-se três casos de ocronose exógena na face, diagnosticados pela dermatoscopia. O estudo dermatoscópico evidenciou estruturas amorfas de coloração cinza-enegrecido, algumas obliterando as aberturas foliculares. O exame histopatológico corroborou o diagnóstico.

Exogenous ochronosis consists of chronic hyperpigmentation of areas previously treated with topical agents such as hydroquinone, resorcinol, antimalarials and phenol. Early diagnosis allows to promptly suspend the causative agent and it is imperative since the available therapeutic options are scarce and have presented so far unsatisfactory results. Three cases of exogenous ochronosis on the face which were diagnosed with the use of dermoscopy are presented. Dermatoscopy showed blackish-gray amorphous structures, some obliterating the follicular openings. Histopathological examination confirmed the diagnosis.

Ocronose exógena induzida por hidroquinona: relato de quatro casos / Exogenous ochronosis hydroquinone induced: a report of four cases

A ocronose exógena é uma dermatose, aparentemente pouco frequente, caracterizada por hiperpigmentação negro-azulada fuliginosa, localizada na região onde foi aplicado o agente causador. Pode ser causada por uso de medicamentos sistêmicos, os antimaláricos e de uso tópico, como fenol, resorcinol, benzeno, ácido pícrico e a hidroquinona - que é um composto fenólico, com propriedade despigmentante, muito utilizado em formulações dermatológicas para o tratamento de melasma e outras hiperpigmentações. A fisiopatogenia deste processo ainda não está esclarecida e as abordagens terapêuticas são insatisfatórias. Relatam-se quatro casos de pacientes do sexo feminino que, após uso de preparados contendo hidroquinona, desenvolveram hiperpigmentação acentuada na face, caracterizadas no exame dermatológico e histopatológico como ocronose. Enfatiza-se a possibilidade de casos de ocronose exógena estarem sendo diagnosticados erroneamente, como falha de tratamento de melasma, e também para os riscos do uso indiscriminado de formulações, contendo hidroquinona, muitas vezes, sem acompanhamento médico.

Exogenous ochronosis is an infrequent dermatosis characterized as a dark blue hyperpigmentation localized where the causing agent was applied. It may be caused by the use of systemic medication such as antimalarials and by the use of topic substances such as phenol, resorcinol, benzene, or hydroquinone, which is a fenolic compound with depigmentation action, largely used in the treatment of melasma and other hyperpigmentation. The physiopathology of this process is not well clear up to this moment, and the therapeutic measures are not satisfactory either. Here we present four cases of female patients that developed hyperpigmentation on their faces after the use of hydroquinone containing compounds, characterized clinically and histological as ochronosi. We emphasize the possibility of exogenous ochronosis cases being misdiagnosed as a melasma treatment failure. We also emphasize the risks of the indiscriminated use of hydroquinone containing compounds, used, in many instances, without medical prescription.