Emmanuela Dapomaa Asante1; Hsuan Hsiang Chen2
Fonte de financiamento: Nenhuma
Conflito de interesse: Nenhum
Data de submissão: 30/11/2025
Decisão final: 21/12/2025
Como citar este artigo: Asante ED, Chen HH. Modalidades de tratamento para ocronose exógena: Uma revisão narrativa das abordagens terapêuticas atuais e emergentes. (Tratamento para ocronose exógena). Surg Cosmet Dermatol. 2026;18(2):e20260541.
Exogenous ochronosis is a chronic skin disorder characterized by dermal hyperpigmentation, often resulting from prolonged use of hydroquinone. This review analyzed 29 studies (2000-2025) assessing treatments for exogenous ochronosis. Laser and light-based therapies, particularly in combination regimens, showed the greatest efficacy, while microneedling and chemical peels provided moderate improvement. Topical agents alone offered limited benefit. Post-inflammatory hyperpigmentation was the most frequent adverse event. Emerging modalities, including intradermal vitamin C, exosome therapy, and platelet-rich fibrin lysate, demonstrated promising early results. Overall, multimodal and light-based therapies appear to be the most effective; however, further controlled studies are essential to confirm their safety and long-term outcomes.
Keywords: Ochronosis; Hyperpigmentation; Dermabrasion
The term “ochronosis” is derived from the Greek word ochre, meaning yellow discoloration, and was first described in the 18th century by Virchow, who noted the ochre-like pigmentation in tissues.1-3
Ochronosis refers to a bluish-gray discoloration of connective tissues caused by pigment deposition and is classified into endogenous and exogenous forms.4 Endogenous ochronosis, or alkaptonuria, is a rare autosomal recessive disorder resulting from homogentisic acid oxidase deficiency,5-10 which leads to systemic manifestations such as arthropathy, pigmentation, and organ calcification.11-19
Exogenous ochronosis (EO), by contrast, is an acquired disorder characterized by blue-black pigmentation of the skin, typically induced by chronic application of topical skin-lightening agents. Hydroquinone is the most commonly implicated compound, though resorcinol, phenol, quinine, picric acid, and mercury have also been linked to the condition.3 First described by Pick in 1906 and later associated with hydroquinone use by Findlay and De Beer in 1975, EO has since been recognized as an important adverse effect of long-term skin-lightening practices.3
EO is increasingly prevalent, particularly in populations with darker skin phototypes, where demand for skin-lightening is high and products are often unregulated. Notably, the risk of EO is not solely determined by hydroquinone concentration, as cases have been reported with low-strength formulations (2%), implicating cumulative dose and duration of exposure as central risk factors.14
Alcohol-based formulations may further heighten risk by enhancing percutaneous absorption.3 Additional predisposing factors include extensive or prolonged sun exposure, application over large body surface areas, and the presence of active melanocytes that interact with hydroquinone-induced metabolic pathways.15-17
The pathogenesis of EO remains incompletely understood. Several mechanisms have been proposed, including hydroquinone-induced stimulation of melanogenesis, its oxidation to quinones and melanin-like intermediates, and its inhibition of homogentisic acid oxidase leading to pigment polymerization in the dermis.20-23
Clinically, EO presents as bilaterally symmetric blue-black macules, predominantly over the malar regions, temples, and cheeks, progressing through 3 stages: mild erythema and pigmentation (stage I), hyperpigmentation with colloid milia (stage II), and papulonodular lesions (stage III).24-30
Diagnosis can be challenging, particularly in the early stages, when EO may mimic melasma. Dermoscopy may reveal gray-blue amorphous areas with obliteration of follicular openings, while reflectance confocal microscopy has found characteristic dermal structures.
Histopathology remains the gold standard for diagnosis, with hallmark ochre-colored, banana-shaped fibers in the dermis.3
Epidemiological data are limited due to underrecognition and misdiagnosis. Early reports suggested prevalence rates of up to 35% among Black populations in South Africa, but more recent evidence shows that EO also affects lighter skin phototypes, including Hispanic, European, and Asian populations.31-34
In the United States, a dermatology survey identified 512 suspected cases, of which 130 were biopsy-confirmed.30
Management of EO is difficult, as pigmentation is often persistent and sometimes irreversible. Discontinuation of hydroquinone and strict photoprotection are essential first steps, but improvement may take years. Pharmacological interventions such as retinoids, corticosteroids, antioxidants, and systemic agents yield variable results, while procedural approaches—including chemical peels, dermabrasion, microneedling, and energy-based devices such as Q-switched and Nd:YAG lasers—have shown promise but lack standardization.24,30
Given its growing prevalence, diagnostic challenges, and limited treatment success, EO represents an important dermatological concern. This review critically evaluates current pharmacological and non-pharmacological treatment modalities for EO, with emphasis on evidence from clinical case series, procedural outcomes, and emerging therapies, to guide future practice and research.
This study employed a narrative literature review to explore and evaluate treatment modalities for EO, with emphasis on effectiveness, safety, and emerging therapies. The review was guided by 3 objectives: (1) to identify the most effective treatment modalities, (2) to evaluate safety concerns and adverse effects, and (3) to highlight promising novel interventions.
The narrative review approach was chosen because it allows the integration of diverse sources of evidence, including case reports, case series, and retrospective studies, which constitute the majority of the EO literature. Unlike systematic reviews, which require homogeneous data, this method facilitates a broad overview of treatment trends, knowledge gaps, and potential innovations, making it particularly valuable for under-researched conditions.35-37
An extensive search was performed across PubMed, Scopus, Google Scholar, ScienceDirect, JAMA, the University of South Wales FINDit tool, and Surgical & Cosmetic Dermatology. The search covered publications from January 2000 to May 2025 using keywords and combinations such as “Exogenous Ochronosis,” “Hydroquinone-induced ochronosis,” “Treatment,” “Laser therapy,” “Microneedling,” “Dermabrasion,” and “Oral medication.” Boolean operators (“AND,” “OR”) were used to refine the search, and reference lists of key articles were screened to identify additional studies.
Included studies comprised peer-reviewed case reports, case series, retrospective studies, or systematic reviews reporting treatment outcomes in patients with clinically or histopathologically confirmed EO. Only English-language publications involving human subjects were considered. Studies exclusively on endogenous ochronosis, animal or in vitro research, studies not focusing primarily on treatment modalities, and non-English works without usable abstracts were excluded.
Twenty-nine articles met the inclusion criteria: 2 retrospective studies, 8 case series, and 19 case reports. Data were extracted into tables capturing author and year, study design, treatment modality, outcomes, and adverse effects. Findings were synthesized qualitatively, with particular attention to combination therapies and emerging approaches. A systematic review or meta-analysis was not feasible due to the heterogeneity in study designs and outcome measures.
The treatment of EO encompasses non-pharmacological measures, pharmacological approaches such as topical and oral medications, and procedural interventions like dermabrasion, microneedling, and energy-based device therapies.
A key step in the management of EO is the immediate discontinuation of the offending agent, although visible improvement may take years.19
Strict photoprotection, including broad-spectrum sunscreens, hats, UV-protective sunglasses and protective clothing, is also critical to prevent further pigmentation.3
Several case reports highlight the benefit of sunscreen as an adjunctive therapy. For example, Tekgöz et al.7 reported reduced hyperpigmentation after 7 months of sunscreen use and discontinuation of hydroxychloroquine. Similarly, Ceglio et al.,5 Bellew and Alster,2 and Gulwani et al.28 emphasized the use of broad-spectrum sunscreen during EO treatment. A narrative review by Simmons et al.30 also reported improved outcomes with sunscreen use in some cases. These findings underscore the importance of photoprotection in preventing disease progression and for protecting the skin during treatment.
Topical treatments alone have shown limited effectiveness in the management of EO. However, when combined with other therapies, they may provide clinical improvement. Commonly used topical agents include corticosteroids, retinoic acid, azelaic acid, kojic acid, topical calcineurin inhibitors, and tyrosinase inhibitors.
A 2007 case series by Charlín et al.6 described 4 women (skin phototypes IV–V) with long-standing melasma who developed progressive facial hyperpigmentation after 10–25 years of hydroquinone-based cream use (2%–6%). Clinical signs included blue-brown macules, caviar-like papules, and confetti-like depigmentation, consistent with Dogliotti Stage II EO. Histopathology confirmed pigment incontinence and yellow-brown banana-shaped fibers in the dermis.
Treatment with combinations of 0.05% retinoic acid, 20% azelaic acid, and kojic acid led to only partial or minimal improvement.6
Singh and Ramesh31 reported the case of a 44-year-old woman who developed bluish-black pigmentation after 1 year of skin-lightening cream use. Histopathology confirmed EO. Despite discontinuing the cream and using 0.05% topical retinoic acid with strict photoprotection, there was no notable improvement after 3 months.
Similarly, Qorbani et al.27 described 2 patients with EO secondary to hydroquinone and tretinoin use. In one case, desonide 0.5% lotion with photoprotection reduced inflammation but did not improve pigmentation. The second patient was treated with tazarotene 0.1% gel and pimecrolimus cream in conjunction with photoprotection, but pigmentation persisted for more than 1 year.
Patel and Shah24 reported the case of a 55-year-old woman with EO following 2 years of daily use of hydroquinone-containing cream. Clinical examination showed bluish-brown patches with erythema and telangiectasia. Despite discontinuing the cream, applying topical emollients and retinoid gel, and practicing strict photoprotection, only minimal improvement was observed after 2 months.
A recent retrospective study by Keshavamurthy Vinay et al.12 evaluated 29 patients with EO, predominantly women (93%) with skin phototypes III–VI. Most had a history of hydroquinone use for melasma, averaging 16 months. The malar region was the most commonly affected, with 41% of cases classified as Dogliotti stage I and 59% as stage II. Among 11 patients for whom treatment data were available, combination therapies demonstrated variable outcomes. Chemical peels with topical tacrolimus 0.1% led to moderate improvement over 6 months in 6 patients. A regimen of kojic acid, arbutin, and glycolic acid resulted in minimal improvement, while 1 patient receiving topical tacrolimus combined with oral medication achieved moderate improvement over 6 months.
Overall, topical pharmacological treatments for EO are largely adjunctive. Monotherapy rarely produces substantial improvements, and outcomes are generally enhanced when topical agents are combined with photoprotection, chemical peels, or systemic treatments. Despite limited efficacy, topical agents remain a cornerstone of EO management, particularly for patients with mild disease or as part of multimodal therapeutic strategies.
Oral medications are infrequently used in EO, generally alongside other therapies. Agents include tranexamic acid, corticosteroids, glutathione, and systemic retinoids.
Moche et al.22 reported 2 Black female patients with EO from prolonged hydroquinone use who developed cutaneous and systemic sarcoidosis. Treatment with oral prednisone (30 mg/day) and chloroquine (200 mg/day) led to improvement in both systemic and skin symptoms.
Pirrone et al.25 described a 51-year-old Filipino woman with histologically confirmed EO who received oral isotretinoin 20 mg 4 times daily, resulting in mild improvement.
Sunkara et al.32 reported the case of a 39-year-old woman with EO after 3 months of using a 4% hydroquinone cream. Oral glutathione was administered, leading to a 50% reduction in pigmentation after 4 months.
In a retrospective study by Keshavamurthy Vinay et al.,12 one patient received oral tranexamic acid as part of the treatment, achieving moderate improvement.
Procedural therapies for EO are typically considered when topical or oral medications provide limited benefit. These include dermabrasion, microneedling, and chemical peels, all of which aim to reduce dermal pigmentation through controlled skin injury or tissue remodeling. The available evidence is largely based on case reports, case series, and small retrospective studies, reflecting both the rarity and treatment-resistant nature of EO.
Dermabrasion induces superficial skin injury, triggering wound healing and dermal remodeling, which can improve skin appearance. It has demonstrated moderate to substantial success in selected EO cases, particularly when topical therapies fail. Sunkara et al.32 reported the case of a 39-year-old woman with EO from 3 months of 4% hydroquinone use who underwent microdermabrasion alongside photoprotection, achieving a 50% reduction in pigmentation after 4 months. Similarly, Lamas et al.15 described a 70-year-old woman with a 10-year history of EO who underwent facial dermabrasion with water sandpaper, combined with a nighttime topical regimen (0.05% desonide, 0.01% tretinoin, 2% alpha-bisabolol) and strict photoprotection. After 3 months, the patient exhibited a marked reduction in hyperpigmentation, highlighting the role of dermabrasion in achieving substantial pigment clearance when combined with adjunctive measures.
Microneedling involves the creation of micro-injuries within the dermis to stimulate collagen production and facilitate pigment reduction. Moerbono Mochtar et al.23 reported the cases of 3 women aged 45–50 years with long-standing EO who underwent biweekly microneedling using a 1-mm dermaroller over an 8-week period, associated with daily SPF 30 use. Improvements in pigmentation and vascular changes were noted by week 4, accompanied by increased patient satisfaction and physician-rated appearance scores. A larger 10-year retrospective study by Lazar et al.16 involving 25 patients with EO demonstrated that microneedling promoted dermal remodeling and achieved visible pigment reduction without substantial adverse effects, particularly in patients with darker skin types, indicating its safety and effectiveness as a procedural option.
Chemical peels employ caustic agents such as glycolic acid, salicylic acid, and trichloroacetic acid (TCA) to remove the epidermal and superficial dermal layers, promoting pigment reduction.
Franca et al.8 reported the case of a 40-year-old woman with EO who initially underwent a combination peel consisting of 5% hydroquinone, 5% retinoic acid, and 14% salicylic acid, which resulted in minimal improvement. A subsequent 20% TCA peel in combination with other treatment modalities led to complete resolution of the lesions.
Similarly, Keshavamurthy Vinay et al.12 reported moderate improvement in patients with EO treated with 30% glycolic acid peels. When glycolic acid peels were combined with topical medications, 6 patients experienced moderate pigment reduction over a 6-month period. These findings underscore that chemical peels may be more effective when used in combination with other treatment modalities rather than as monotherapy.
Overall, procedural treatments for EO provide valuable therapeutic options when conventional pharmacological approaches fail. Dermabrasion, microneedling, and chemical peels promote dermal remodeling and pigment reduction, with outcomes often enhanced when combined with topical agents and strict photoprotection. Although the available evidence is limited, these interventions have consistently demonstrated the potential to achieve partial to substantial improvement, particularly in long-standing or treatment-resistant cases. Further studies are needed to standardize protocols, optimize treatment combinations, and determine long-term efficacy and safety across diverse skin phototypes.
Kramer et al.14 described a case of a Hispanic woman with EO unresponsive to topical treatments who underwent treatment with a Q-switched ruby laser (694 nm, 7 J/cm² fluence, 5-mm spot size). The patient had noticeable clinical improvement, suggesting that Q-switched ruby lasers may represent a promising option for refractory EO.
Alster and Bellew2 reported the use of a Q-switched 755-nm alexandrite laser in 2 patients with hydroquinone-induced EO. The first patient underwent 6 sessions at 2-month intervals with a mean fluence of 7.8 J/cm², while the second patient underwent 4 sessions at 4-month intervals with a mean fluence of 6.9 J/cm². Both exhibited substantial lightening of pigmented areas without scarring or textural changes, and histopathological examination confirmed a reduction in dermal pigmentation.
Gil et al.9 assessed the use of intense pulsed light (IPL) therapy in a 63-year-old woman with Fitzpatrick skin phototype V diagnosed with EO. She underwent 6 IPL sessions (645 nm, pulse duration 6 ms, fluence 20–22 J/cm²), alongside topical therapy with 4% kojic acid and 0.2% salicylic acid and strict photoprotection. After 2 months, only mild clinical improvement had been achieved. Dermoscopic features of EO persisted, and reflectance confocal microscopy found unchanged subepidermal banana-shaped bodies, indicating IPL efficacy was limited.
França et al.8 reported the case of a 40-year-old woman with EO after prolonged hydroquinone use who underwent multiple treatment modalities. Four sessions of Q-switched Nd:YAG laser (1064 nm, 2.9–3.05 J/cm², 4-mm spot size) resulted in limited response. Subsequent treatment with ultrapulse CO₂ laser (5 W, 30-day intervals) resulted in partial improvement, particularly in the left malar region. IPL therapy (36 J, 10 ms) was then administered, followed by microdermabrasion and a chemical peel combining 5% hydroquinone, 5% retinoic acid, and 14% salicylic acid. Complete lesion clearance was achieved after 3 additional IPL sessions (36 J, 10 ms) in conjunction with 20% TCA peels.
Kanechorn-Na-Ayuthaya et al.11 described 3 patients with EO treated with Q-switched Nd:YAG (1064 nm) and fractional CO₂ lasers. In the first case, a 67-year-old Thai woman (skin phototype V) underwent 4 Q-switched Nd:YAG laser sessions (1.9–2.2 J/cm²) and 1 fractional CO₂ laser session, achieving progressive fading and smoother skin texture by the third session, despite transient post-inflammatory hyperpigmentation (PIH). The second case, that of a 58-year-old woman (skin phototype III) who underwent 4 Nd:YAG sessions and one CO₂ laser session, achieved noticeable improvement in pigmentation and skin tone after the third session, accompanied by temporary PIH. In the third case, a 66-year-old woman (skin phototype IV) underwent 2 Nd:YAG laser sessions followed by fractional CO₂ laser treatment, with minimal PIH and visible skin lightening and mild rejuvenation at 5 months. Overall, combination laser therapy resulted in gradual improvement of lesions and high patient satisfaction.
Tan33 evaluated 6 ethnic Chinese patients with histologically confirmed EO and concomitant melasma, classified according to Dogliotti staging: 4 with Stage I disease, 1 with Stage II, and 1 with Stage III. Treatment consisted of fortnightly Q-switched Nd:YAG (1064 nm) laser sessions using a low-fluence first pass (1.2 J/cm², 8- mm spot size) and targeted high-fluence passes (4–6 J/cm², 4-mm spot size) until petechiae or erythema appeared. Topical EMLA cream was applied before treatment, and post-treatment care included topical tetracycline and continuation of non-hydroquinone lightening agents. Patients with stage II and III disease showed marked improvement after 8 and 16 sessions, respectively, while patients with stage I disease demonstrated mild-to-moderate improvement. Pigment clearance was maintained, and no serious adverse events occurred, supporting the use of Q-switched Nd:YAG lasers, particularly with a multi-pass low-fluence and targeted high-fluence technique, for moderate-to-severe EO in darker skin phototypes.
Lee and Weiss17 reported the case of a 48-year-old woman with EO treated with IPL (570 nm, 12 J/cm², 15 ms) at 6-week intervals, with lightening of pigmentation after the initial session.
Liu et al.21 described a 50-year-old Chinese man (skin phototype IV) with Stage II EO who underwent 6 sessions of Q-switched Nd:YAG laser (1064 nm, 6–9 J/cm²) with no improvement, despite treatment adherence and discontinuation of hydroquinone.
Ko and Wang13 reported the case of a 50-year-old Chinese woman with EO treated with Q-switched Nd:YAG (1064 nm, 5.3 J/cm²) and Q-switched alexandrite (755 nm, 8.5 J/cm²) lasers. Pigmentation worsened after 2 sessions; the use of fractional CO₂ laser was recommended, but declined. Carvalho et al.4 described a 46-year-old woman (skin phototype V) treated with monthly fractional CO₂ laser sessions for 12 months, achieving substantial improvement. Pirrone et al.25 reported the case of a 51-year-old Filipino woman who experienced mild improvement with oral isotretinoin and topical corticosteroids, but subsequent fractional laser therapy over 3 sessions achieved marked lightening of the hyperpigmented lesions. Baca et al.1 described a 55-year-old woman (skin phototype IV) with long-standing EO refractory to multiple prior therapies, who underwent 9 sessions of fractional nonablative picosecond laser (1064/532 nm), achieving clear improvement in lesion color and texture.
Qian26 presented 2 cases of EO treated with microneedle pulsed radiofrequency adjunctive to laser therapy, with satisfactory outcomes.
Lee et al.18 reported the case of a 66-year-old woman treated with fractional CO₂ and Q-switched Nd:YAG lasers, with no clinical improvement after 3 sessions. Ceglio et al.5 described a 52-year-old man (skin phototype V) treated sequentially with Q-switched Nd:YAG laser (12 sessions), IPL (7 sessions), and fractional CO₂ laser (5 sessions), with the most notable improvement achieved after fractional CO₂ laser therapy. Lazar et al.16 conducted a 10-year review of 25 patients with EO (88% women, skin phototypes IV–VI) and found Q-switched alexandrite (755 nm) laser effective, with marked improvement in observed in 3 patients after a mean of 4.66 sessions.
Li and Zhang20 reported the case of a 28-year-old woman with concomitant EO and vitiligo who achieved improvement after 4 chemical peels and one IPL session.
Almutairi et al.38 reported the case of a 31-year-old man with refractory EO who responded to 3 sessions of picosecond alexandrite laser (755 nm) following prior unsuccessful treatment with Q-switched and 1064-nm picosecond laser therapy. The man achieved marked lesion improvement after 6 months with no complications.
Emerging treatment modalities for EO aim to improve therapeutic outcomes and patient satisfaction. One such novel approach involves intradermal vitamin C injections, which act as antioxidants and may reduce pigmentation. Another innovative modality is platelet-rich fibrin lysate (PRF-L), an autologous derivative of platelet-rich fibrin that is rich in growth factors and cytokines and may promote skin rejuvenation and pigment regulation.
A case series involving 3 healthy Javanese women aged 45–50 years explored the potential of PRF-L in the management of EO. Each patient had progressive facial hyperpigmentation previously diagnosed as melasma, with disease durations of 2, 5, and 6 years, a history of prolonged use of dermatologist-prescribed skin-lightening creams without follow-up or knowledge of their ingredients. Clinical examination revealed patchy hyperpigmentation, facial erythema, hypopigmented macules, and telangiectasia.
The diagnosis of EO was supported by skin stretching tests, Wood’s lamp, and dermoscopy. After informed consent was obtained, autologous PRF-L was prepared by collecting peripheral blood in 10-mL sterile tubes without anticoagulant, centrifugation at 2700 rpm (~400 g) for 12 minutes, and incubation of the isolated PRF gel at 4 °C for 24 hours to obtain the PRF-L supernatant. Facial skin was cleansed and anesthetized topically for 1 hour. PRF-L was administered using 2 methods: topical application followed by dermarolling (1-mm depth) on the right side of the face and intradermal injection with a 1-mL syringe on the left. Patients were instructed to apply SPF 30 sunscreen daily. The 2-month follow-up period included biweekly clinical photography, with 2 blinded physicians assessing improvement using a 10-point scale. Early improvements were noted on dermoscopic examination, and 1 patient demonstrated visible clinical improvement.23
Rajesh Gulwani et al.28 described a 45-year-old Indian man with bilateral cheek hyperpigmentation following intermittent use of multiple skin-lightening agents over a 9-year period, including a triple-combination cream (2% hydroquinone, 0.05% tretinoin, 0.1% mometasone) over 3 years. Clinical examination revealed blue-black macules on an erythematous background, and dermoscopy found dark globules in annular, arciform, and curvilinear patterns, follicular obliteration, and telangiectasia. Histopathological examination confirmed EO, revealing epidermal thinning, elastotic degeneration, and banana-shaped ochronotic bodies within the dermis. The patient underwent intradermal vitamin C (ascorbic acid) injections: 1 mL (100 mg) at 1-cm intervals across affected areas, repeated every 4 weeks for 3 sessions. Sunscreen to protect against ultraviolet, infrared, and visible light and a barrier-repair moisturizer containing hyaluronic acid, ceramide, squalene, and lecithin were prescribed. The treatment resulted in complete resolution of erythema within 1 month and approximately 80% improvement in hyperpigmentation after 3 months. The treatment regimen was well tolerated, with mild-to-moderate discomfort at injection sites.28
Plant-based exosome therapy represents another emerging therapeutic option. Widjaja et al.35 reported the case of a 39-year-old Indonesian woman with widespread facial hyperpigmentation following 8 months of using a 4% hydroquinone cream. She developed erythema and patchy pigmentation and had never used sunscreen. Clinical examination revealed dry, sallow skin with hyperpigmented macules, hypopigmented areas, and telangiectasia, supporting the diagnosis of EO. Treatment consisted of intradermal injections of 6 mL of a plant-derived exosome skin booster across facial zones, followed by topical application of 1.2 mL of exosome serum and dual-light photodynamic therapy (PDT) for 10 minutes per light source. A comprehensive skincare regimen was instituted, including a morning routine consisting of facial cleanser, toner, serum, and cream containing niacinamide, alpha-arbutin, 3-O-ethyl ascorbic acid, and tranexamic acid, as well as nighttime cream containing retinol. An SPF 50 hybrid sunscreen was introduced for photoprotection. At the 36-day follow-up, improvements in skin texture and tone were evident, with brighter, better-hydrated skin and a notable reduction in hyperpigmented patches, particularly on the cheeks.
These emerging therapies reflect a trend toward minimally invasive, regenerative, and targeted approaches for EO. PRF-L offers autologous growth factor-mediated modulation of pigmentation and dermal remodeling, demonstrating early dermoscopic and clinical improvements. Intradermal vitamin C provides antioxidant-mediated pigment reduction and skin repair, achieving substantial clinical improvement in severe EO. Plant-based exosome therapy, combined with topical agents and PDT, represents a multimodal approach that addresses pigmentation, inflammation, and skin barrier restoration.
Across these modalities, photoprotection remains a critical adjunctive measure, emphasizing the importance of using sunscreen to prevent further pigmentary changes and protect against ultraviolet, infrared, and visible light-induced skin damage. In addition, supportive skincare with barrier repair and antioxidant components may enhance overall treatment outcomes. Case reports and small case series suggest that these therapies are generally well tolerated, with minimal adverse effects such as mild injection-site pain and transient erythema, while resulting in measurable improvements in hyperpigmentation, erythema, telangiectasia, and skin texture.
Collectively, early evidence suggests that these innovative approaches can complement conventional EO management strategies, offering the potential for faster clinical improvement, greater patient satisfaction, and expanded therapeutic options for individuals with treatment-resistant cases. Long-term follow-up and larger studies are needed to establish standardized protocols, determine optimal dosing schedules, and compare efficacy with established procedural and pharmacological therapies. Nonetheless, PRF-L, intradermal vitamin C, and plant-based exosome therapy represent promising additions to the evolving therapeutic armamentarium for EO
Photoprotection is widely recommended, as EO is exacerbated by exposure to ultraviolet radiation. Bhattar et al.3 highlight its role in limiting disease progression, while Simmons et al.30 caution that sunscreen alone does not result in substantial cosmetic improvement. Across the literature, photoprotection is mostly used as an adjunctive therapy, suggesting that optimal outcomes are achieved when combining it with active therapies.
Topical agents, particularly in early-stage EO, demonstrate modest efficacy. Studies by Charlín et al.,6 Singh and Ramesh,31 and Qorbani et al.27 report limited response to retinoic acid, azelaic acid, corticosteroids, and calcineurin inhibitors. Although these agents theoretically target melanin production and inflammation, poor dermal penetration likely limits their effectiveness given the deep pigment deposits found in EO. Keshavamurthy Vinay et al.12 further demonstrated minimal improvement with topical monotherapy unless it was combined with peels or systemic agents. Thus, topicals should generally be considered adjunctive rather than definitive treatments.
A consistent observation across multiple studies4-6,9,12,13,15,24,27,31,33 is the near-universal history of hydroquinone use in patients who develop EO. This highlights a potentially underrecognized association between melasma management and the onset of EO, raising concerns about long-term safety, particularly in individuals with darker skin phototypes or prolonged hydroquinone use. Reevaluation of melasma guidelines and development of safer alternatives or stricter protocols may help reduce the incidence of EO.
Oral medications are used sporadically, primarily for atypical presentations or experimental purposes. Moche et al.22 reported corticosteroids and chloroquine for sarcoid-like EO, suggesting a possible role for systemic immunomodulation in inflammatory variants. More conventional agents, such as isotretinoin25 and glutathione,32 yield mild-to-moderate improvements in pigmentation, likely through cell turnover and reduction of oxidative stress. Oral tranexamic acid, traditionally prescribed for melasma, was modestly effective in one case,12 possibly due to anti-inflammatory effects. However, these findings are isolated, highlighting the need for controlled studies to assess safety and dosing.
Procedural interventions appear more promising, particularly for patients who do not respond to pharmacologic therapy. Dermabrasion has demonstrated notable reduction in pigmentation, especially when combined with topical agents and photoprotection.15 Microdermabrasion32 and microneedling16,23 have also shown favorable outcomes, particularly in individuals with darker skin phototypes, in whom dermal pigmentation is more pronounced. Microneedling offers the advantages of promoting dermal remodeling and enhancing topical drug absorption.
Chemical peels, particularly TCA, seem to outperform superficial peels such as glycolic acid. França et al.8 reported complete lesion resolution with 20% TCA after failure of treatment with superficial agents, whereas Vinay et al.12 observed only moderate improvement with 30% glycolic acid, underscoring the importance of peel depth. Sequential or combination approaches may further enhance efficacy, although variability in formulations, techniques, and patient factors complicate direct comparisons.
Laser and light-based therapies provide compelling but variable results. Q-switched lasers (ruby, Nd:YAG, alexandrite) have shown efficacy but may induce PIH or even worsen pigmentation, particularly in patients with darker skin phototypes.13 Fractional CO₂ lasers, alone or combined with Q-switched devices, have resulted in more consistent outcomes.4,5 IPL appears to be the most effective when added to multimodal regimens. Picosecond lasers have shown encouraging preliminary results with fewer adverse effects,38 but further validation is required.
Emerging regenerative therapies, including intradermal vitamin C injections, plant-based exosomes, and PRF-L, aim to restore dermal integrity while reducing pigmentation. Vitamin C injections achieved reductions in pigmentation of up to 80%,28 while plant exosomes and PRF-L were associated with improvements in skin quality and lightening.23,35 While promising, these early-stage studies have small sample sizes and limited long-term safety data.
Few studies report adverse effects. PIH is the most frequent, especially after laser-based therapies, posing particular risk for patients with darker phototypes, who represent a large share of EO cases. Reports of worsening pigmentation with Q-switched and alexandrite lasers13 underscore the need for caution. Microneedling, picosecond lasers, and select chemical peels, on the other hand, are generally well tolerated.
In conclusion, the management of EO requires a multimodal, individualized approach. Non-pharmacological measures remain foundational, topicals therapies provide adjunctive benefits, and procedural or energy-based interventions achieve the most consistent reduction in pigmentation. Emerging regenerative strategies may further expand treatment options, but high-quality studies are needed to optimize treatment protocols, minimize adverse events, and identify predictive factors for treatment response, particularly in individuals with darker skin phototypes
This review underscores the complexity of managing EO, a challenging pigmentary disorder. Among available therapeutic options, laser and light-based therapies—particularly when used in combination with other modalities—demonstrate the most consistent clinical efficacy, supporting a multimodal approach over monotherapy. Procedural treatments such as microneedling and chemical peels provide moderate improvement, whereas topical agents alone are generally ineffective, especially in long-standing disease or cases involving deep dermal pigmentation.
Regarding safety, PIH is the most frequently reported complication, particularly following laser-based therapies. Microneedling and picosecond lasers are generally well tolerated and may represent safer options for patients with darker skin phototypes, who are more susceptible to pigmentary rebound and adverse effects.
Emerging interventions, including intradermal vitamin C, plant-derived exosomes, and PRF-L, have shown promising preliminary results, potentially combining pigment reduction with dermal remodeling, barrier restoration, and local antioxidant and anti-inflammatory effects.
Overall, the management of EO remains multifaceted and requires individualized treatment plans based on pigmentation depth, histopathological severity, skin phototype, and treatment tolerance. Combination therapies appear to be the most effective, but further controlled studies are required to establish standardized protocols, confirm long-term safety, and validate emerging approaches for broader clinical application.
I would like to express my deepest gratitude to the Almighty God for the gift of life, strength, and wisdom that enabled me to undertake and complete this project.
My sincere thanks also go to my supervisor, Dr. Hsuan-Hsiang Chen, for his guidance, support, and encouragement throughout this work.
Finally, I would like to extend my heartfelt appreciation to the Merck Foundation for sponsoring my studies and making this academic journey possible.
This work was completed in partial fulfillment of the requirements for the Master of Science (MSc) in Dermatology in Clinical Practice at the University of South Wales.
Emmanuela Dapomaa Asante
ORCID: 0009-0006-8831-7943
Conception and design of the study, Preparation and writing of the manuscript, Critical review of the literature, Critical revision of the manuscript
Hsuan Hsiang Chen
ORCID: 0000-0003-2642-5114
Approval of the final version of the manuscript, Critical revision of the manuscript
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