A black woman, aged 35 years, presented with darkening skin on her cheeks bilaterally. She noticed the darkening after becoming pregnant with her first child. The lesions were asymptomatic and had slowly been expanding over the past eight months. No prior rash in the area of involvement was reported. The woman had not had prior treatment and was on no systemic medications. Poorly defined brown macules coalescing into patches were appreciated on the bilateral cheeks, nose, and upper lip on physical examination.
A Hispanic woman, aged 37 years, complained of darkening skin on her cheeks. She had previously been given the diagnosis of melasma and had been using hydroquinone 4% cream daily for three years. The woman felt that the dyspigmentation had been improving until it began to darken again over the past six months. She was compliant with adherence to a sun protection/avoidance regimen. On physical examination, blue-black macules that were coalescing into patches were appreciated on bilateral cheeks.
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Case #1: Melasma
Melasma is also referred to as chloasma or “the mask of pregnancy.” Chloasma is derived from chloazein, the Greek word for “to be green.” Since melasma is actually a brown to black pigmentation, the Greek word melas, which means “black,” was used as the root instead.
Approximately 90% of melasma cases occur in women, most commonly young to middle-aged women. The disorder is most prevalent in such darker skin phototypes as Hispanics, Africans, Middle-Easterners, and Asians.
The exact pathogenesis of melasma is unknown. However, important pathogenic factors include skin phototype, UV radiation, pregnancy, and certain hormones.1
Other medications, such as phenytoin-related anticonvulsants and phototoxic drugs, as well as autoimmune thyroid disease may also be aggravating factors. UV radiation plays a critical role. This is evident clinically, as the lesions are distributed in sun-exposed areas, and fading of the lesions occurs during the darker winter months.
It is believed that UV radiation from the sun causes melanocytes to produce increased amounts of melanin in the involved skin. Genetic predisposition plays a role in the development of melasma, because darker pigmented individuals are more prone to developing the disorder. Elevated levels of certain hormones produced during pregnancy and found in oral contraceptives, such as estrogen and possibly progesterone, are known to exacerbate the disease.
Melasma is characterized by symmetric, hyperpigmented patches that have an irregular outline. The three classical patterns of melasma include mandibular, malar, and centrofacial.
The centrofacial pattern — characterized by hyperpigmented patches localized to the chin, cheeks, upper lip, nose, and lateral forehead — is the most commonly seen form. The mandibular pattern is described by involvement of the ramus of the mandible, and the malar form is described by involvement of the cheeks and nose. Other affected areas may include the extensor forearms and upper chest.
In addition to the clinical classification scheme, lesions may also be categorized based on their appearance under Wood’s lamp illumination. The four subpatterns include epidermal, dermal, mixed, and indeterminate. Those lesions attributable to epidermal involvement should become accentuated under Wood’s lamp illumination, while those attributable to dermal involvement will blend in with uninvolved skin. This classification scheme is mainly used to predict whether the patient will respond to topical treatments.
Patients with the epidermal type typically respond well to treatment, whereas patients with the dermal type fail to respond. However, studies comparing the histopathologic findings with Wood’s lamp illumination have failed to prove a correlation.2
Melasma patches are most common during the summer months, as this is the time when many people venture outdoors and exposure to UV radiation is the highest. Patches are also very common among pregnant women. The “mask” often diminishes after birth, but melasma may persist in darker pigmented individuals.
Histologically, the involved skin contains an increased amount of melanin deposition throughout all layers of the epidermis. There is a normal to increased amount of epidermal melanocytes, and they are often enlarged with prominent dendrites.3
An increased number of melanin-containing macrophages may also be seen within the dermis. Ultrastructurally, the melanocytes contain an increased number of melanosomes, as well as mitochrondria, Golgi apparatus, and rough endoplasmic reticulum. This evidence supports the hypothesis that the melanocytes are hyperfunctional.
The differential diagnosis for melasma includes exogenous ochronosis, drug-induced hyperpigmentation, postinflammatory hyperpigmentation, poikiloderma of Civatte, nevus of Ota, erythema dyschromicum perstans, lichen planus pigmentosus, and actinic lichen planus. A thorough history that includes the color and distribution pattern, histologic features, and evaluation of primary lesions may help distinguish between these disorders.
Sun protection and avoidance are the best treatments for individuals with melasma. Instruct patients to wear wide-brimmed hats, UV-protective clothing, and a broad-spectrum sunscreen. Without strict sun protection and avoidance, all treatment regimens will fail.
Most commonly, a combination of topical hydroquinone (2%-4%), tretinoin (0.05%-0.1%) (Vesanoid), and a mild corticosteroid are used to treat melasma.4 Lightening usually begins to occur approximately two months after treatment is initiated. However, patients should be informed that it may take as long as six months to obtain desired results.
Other topical treatments include tretinoin or hydroquinone alone, glycolic acid, kojic acid, azelaic acid (Azelex, Finacea), and salicylic- and glycolic-acid peels. Deeper chemical peels, laser therapy, and dermabrasion may also be used but have a higher risk of scarring and further dyspigmentation. Cosmetic camouflage is an option for cases of recalcitrant melasma. Patients should be educated that all treatment options are aimed at lightening the areas, not erasing them completely.
The patient in this case was advised to adhere to a strict sun protection and/or avoidance regimen. She was also prescribed fluocinolone acetonide 0.01%, hydroquinone 4%, and tretinoin 0.05% cream to be used daily. Some improvement was noted at a follow-up appointment six months later.
Case #2: Exogenous ochronosis
There are endogenous and exogenous forms of ochronosis. The endogenous form, also referred to as alkaptonuria, is an autosomal recessive disease caused by the lack of homogentisic acid oxidase enzyme. This disorder results in the accumulation of homogentisic acid within connective tissues. The exogenous form is an acquired form that is caused by the application of such topical compounds as hydroquinone or phenol.
Ochronosis was first described in 1865 and named for the yellowish or ochre-like discoloration that is seen on microscopic examination. The first case of exogenous ochronosis was reported in 1912, after a patient used phenol to treat an ulceration on the lower extremity. It was not until 1975 that the first case of exogenous ochronosis attributable to topical hydroquinone was described.5
Endogenous ochronosis leads to the accumulation of homogentisic acid in such tissues as the ears, nose, sclerae, ligaments, tendons, and cartilage of the joints. Exogenous ochronosis is very rare and is caused by the use of certain skin-bleaching products.6
Hydroquinone cream is the primary skin-lightening product used worldwide. In 2000, the European Union banned the cream for cosmetic use. In 2006, the FDA almost banned the product because of carcinogenicity and reports of disfiguring ochronosis. Most recently, individual states have begun to ban the sale of hydroquinone.
It is believed that melanocytes metabolize hydroquinone into ringed structures that are the precursors of ochronotic fibers. It is also thought that certain bleaching products may inhibit homogentisic acid oxidase, thus increasing the concentration of homogentisic acid, which in turn leads to discoloration.
Other known causative agents include phenol, benzene, resorcinol, mercury, and picric acid. Even such systemic medications as quinine or antimalarials may inhibit the activity of homogentisic acid oxidase in the skin. The duration of use is directly proportional to the risk of developing exogenous ochronosis. Most patients have used the products for years before developing the condition.
If endogenous ochronosis affects the skin, it most commonly results in patchy brown pigmenatation caused by accumulation of homogentisic acid within the dermis. Systemically, endogenous ochronosis can cause osteoarthritis as well as blackening of cartilages, ligaments, and tendons. Pigmentation of the sclerae may also occur.
Exogenous ochronosis is characterized by a macular blue-black pigmentation on the portions of the face where the offending agent was applied. In severely involved areas, caviar-like papules (blue-black papules), milia, and nodules may occur.
Histologically, endogenous and exogenous ochronosis are essentially identical. However, the features are often more pronounced in the exogenous form. Ochronotic pigment is seen as fine granules that are appreciated in the tissue, endothelial cells of blood vessels, basement membrane, secretory cells of sweat glands, and within macrophages.7 The ochronotic pigment deposits within collagen bundles, causing homogenization and edema.
Some collagen bundles assume bizarre shapes and are often referred to as “bananas in the dermis.” Ochronotic pigment can also be found within elastic fibers. The histological picture is classic, so staining of the ochronotic pigment is not usually done. If needed, however, the pigment becomes black when stained with cresyl violet or methylene blue.
Melasma is the primary disease included in the differential diagnosis of exogenous ochronosis. Ironically, the main agent used to treat melasma, hydroquinone, is the chief causative agent of exogenous ochronosis. A careful history aimed at identifying a possible cause for the dyspigmentation may help determine whether there is reason to believe that the dyspigmentation may in fact be exogenous ochronosis.
Histologic examination is another way to differentiate between the two conditions. In the dermis, exogenous ochronosis will demonstrate a brown to yellow banana-shaped deposition, while melasma will display hyperactive and hyperfunctional melanocytes.
Argyria — gray to gray-black staining of the skin and mucous membranes produced by silver deposition — may also be considered in the differential diagnosis. In some patients, the entire skin may acquire the gray-black discoloration. The spleen, liver, and GI tract may also become affected.
There is no known treatment for exogenous ochronosis. Education on prevention is the best action. Once the diagnosis of exogenous ochronosis has been made, the use of bleaching creams must cease. Some fading of the discoloration can follow discontinuation.
Instruct the patient to follow strict sun protection and avoidance precautions. Do not prescribe creams containing such activating agents as phenols and tyrosine compounds. Advances in laser technology have given way to new treatments that may improve the discoloration, such as the Q-switched alexandrite 755nm laser.
A biopsy confirmed the diagnosis of exogenous ochronosis in the woman in this case. She was advised to discontinue the use of hydroquinone and adhere to a strict sun protection and/or avoidance regimen. Her disease was only mildly improved at follow-up.
Kerri Robbins, MD, is a resident in the Department of Dermatology at Baylor College of Medicine in Houston.
- Sanchez NP, Pathak MA, Sato S, et al. Melasma: a clinical, light microscopic, ultrastructural, and immunofluorescence study. J Am Acad Dermatol. 1981;4:698-710.
- Grimes PE, Yamada N, Bhawan J. Light microscopic, immunohistochemical, and ultrastructural alterations in patients with melasma. Am J Dermatopathol. 2005;27:96-101.
- Kang WH, Yoon KH, Lee ES, et al. Melasma: histopathological characteristics in 56 Korean patients. Br J Dermatol. 2002;146:228-37.
- Guevara IL, Pandya AG. Melasma treated with hydroquinone, tretinoin, and a fluorinated steroid. Int J Dermatol. 2001;40:212-215.
- Findlay GH, Morrison JG, Simson IW. Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams. Br J Dermatol. 1975;93:613-622.
- Gandhi V, Verma P, Naik G. Exogenous ochronosis after prolonged use of topical hydroquinone (2%) in a 50-year-old Indian female. Indian J Dermatol. 2012;57:394-5.
- Tidman MJ, Horton JJ, MacDonald DM. Hydroquinone-induced ochronosis—light and electronmicroscopic features. Clin Exp Dermatol. 986;11:224-228.