Are You Confident of the Diagnosis?

The diagnosis of melasma can be made with confidence in most cases based on the clinical history and physical examination findings. Clinicians should favor this diagnosis in a female patient complaining of new onset or increased prominence of irregularly shaped, often symmetric, hyperpigmented macules or patches on the face, particularly in the setting of recognized common precipitants such as recent ultraviolet (UV) exposure, irradiation, oral contraceptive pills, or gravidity. The condition may subjectively improve during periods of decreased UV exposure, eg, during the winter.

What you should be alert for in the history

Pertinent clinical history to be obtained by the examining physician includes: age of onset, recent or current pregnancy, and family history of the condition, use of oral contraceptives or other hormonal therapies, and full medication reconciliation. See Figure 1.

Figure 1.

Melasma. Symmetric, well demarcated, irregularly shaped, brown hyperpigmented patches on the face.

Continue Reading

In addition to the suggested exacerbating factors cited above, medications such as phenytoin-related anticonvulsants have also been implicated in the development of melasma. A number of other pharmacologic agents with either hyperpigmentation or phototoxicity in their side effect profiles may also play a role in the development of hyperpigmented lesions (see Table I). Furthermore, patients should be questioned about recent exposure to heavy metals such as mercury, as increased pigmentation may also be observed in this setting.

Table I.
Heavy Metals
Psychotrophic Drugs
Azidothymidine (AZT)
Oral contraceptives, and any other form of hormonal contraceptive such as certainIntrauterine devices (IUD) that can induce melasma
Topical hydroquinone
Characteristic findings on physical examination

On physical examination, the diagnosis of melasma should be favored if the patient displays well-demarcated light to dark brown hyperpigmented and often symmetrically distributed macules or patches with a predilection for the face. The macules traditionally appear in one of three observed patterns: centrofacial, malar, or mandibular.

Expected results of diagnostic studies

There is little value to obtaining serum or urine laboratory tests or utilizing other imaging modalities for further work up in this clinical entity, as the diagnosis is not dangerous and can typically be made from the history and physical examination alone

In addition to the characteristic physical examination findings upon visual inspection, one may choose to further confirm the diagnosis by Wood’s lamp examination and/ or skin biopsy. Although these two diagnostic modalities are not imperative to making the diagnosis, they may be helpful in determining the depth of pigment deposition and therefore predict the outcome to various treatment modalities.

For example, while patients with an epidermal pattern of pigment deposition (positive accentuation under Wood’s lamp) may respond well to topical treatments, patients with a mixed or dermal pattern (little to no accentuation under Wood’s lamp) are unlikely to benefit from exclusively topical treatments.

Upon histopathologic examination if a biopsy is performed, increased melanin is seen predominately in the basal layer of the epidermis, but can be seen in all layers of the epidermis. Variable amounts of melanin deposition can be seen in the dermis. See Figures 2 and 3.

Figure 2.

Histologic findings in Melasma. H&E shows a normal number of melanocytes for sun exposed skin, increased basal keratinocyte pigmentation and subtle perivascular melanophages.

Figure 3.

Fontana Masson staining highlights the increase in melanin in keratinocytes in all epidermal layers.

Diagnosis confirmation

The differential diagnosis of melasma includes other diseases of hyperpigmentation: (1) drug induced hyperpigmentation (see Table I for drugs); (2) post inflammatory hyperpigmentation secondary to any inflammatory skin process; (3) actinic lichen planus; (4) lichen planus pigmentosus; (5) solar lentigines; (6) exogenous ochronosis; (7) nevus of Ota; (8) erythema dyschromicum perstans; (9) poikiloderma of Civatte; (10) erythromelanosis follicularis faciei et colli; (11) heavy metal deposition; and (12) phytophotodermatitis.

Drug -induced hyperpigmentation can be blue, grey, or brown and may affect non-facial sites and be diffuse. Postinflammatory hyperpigmentation is seen after inflammation or injury in the skin and occurs most commonly in darker skin types. Lichen planus subtypes may occur anywhere on the body and are slightly raised patches or thin plaques with a purple-brown hue. Solar lentigines are well demarcated round macules and are often less than 2 cm in diameter.

Exogenous ochonosis results from prolonged use of topical hydroquinone and imparts a grey poorly demarcated macule. Nevus of Ota is a brown or grey unilateral macule that develops in adolescence and surrounds the orbit. Erythema dyschromicum perstans is an asymptomatic, symmetrically distributed, blue-grey macular eruption of unknown etiology that is most common in Hispanics.

Poikiloderma of Civatte is most commonly on the lateral neck and is an admixture of fine telangiectasias and hyperpigmentation due to chronic sun exposure. Erythromelanosis follicularis faciei et colli is characterized by reddish brown hyperpigmentaiton and follicular papules most often found on the bilateral cheeks, necks and triceps.

Topical application of metal containing products such as silver, lead, gold, arsenic, mercury, iron, and bismuth may result in heavy metal mucocutaneous deposition marked by brown to blue-grey macules. Phytophotodermatitis occurs after a after a substance (usually botanical) contact the skin with concomitant light exposure, resulting in a geometric brown macule at the areas of contact 1-3 days later.

Who is at Risk for Developing this Disease?

Melasma has a predilection for young to middle-aged females, especially individuals with higher Fitzpatrick skin phototypes, eg, those of Asian, Hispanic, African American and Middle Eastern ancestry.

Additionally, the association of melasma with an increased estrogen state has been well documented. Pregnancy itself, as well as exposure to estrogen and possibly progesterone (eg, the use of oral contraceptives or hormone replacement therapies) are well known risk factors.

It should be noted that especially in women of lighter skin phototypes, hyperpigmentation may resolve spontaneously in the postnatal period; however, melasma in the setting of exogenous estrogen may be less likely to resolve upon discontinuation of the offending agent. Thyroid disease has also been shown to be a risk factor for the development of melasma.

What is the Cause of the Disease?

The precise pathophysiologic mechanism for the development of melasma is still largely debated. A leading hypothesis suggests that ultraviolet B (UVB) irradiation induces an increase of two peptide derivatives of pro-opiomelanocortin (POMC), alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropin (ACTH). Alpha-MSH and ACTH then bind to the melanocortin-1 receptor and cause an induction of cyclic AMP (cAMP).

Activation of this cascade yields a proliferation of melanocytes and an increase in melanin synthesis in the affected skin. Histologically, there is a hyperpigmented basal layer, and increased number of melanocytes. There may also be melanin and melanophages in the papillary dermis.

As previously mentioned, other factors such as genetics, hormonal influences, and UV exposure have also been implicated in the development of this condition.

Systemic Implications and Complications


Treatment Options

Treatment options are summarized in Table II.

Table II.
Medical Treatment Surgical Procedures Physical Modalities
Combination therapy [hydroquinone (2-4%), tretinoin (0.05%-0.1%), and corticosteroid]   Gycolic acid peels
Hydroquinone monotherapy   Q-switched ruby laser
Mequinol   Q-switched alexandrite laser
Retinoids    Q-switched Nd:Yag laser
Azelaic acid   Nonablative fractionated laser
Kojic acid    Camouflage makeup
Licorice extract    
Ascorbic acid    
Soy proteins    
N-acetyl glucosamine    

Optimal Therapeutic Approach for this Disease

Monotherapy with hydroquinone (2-4%) remains the gold standard of treatment. Formulations containing 2% may be found over the counter, while 4% is by prescription only. It has been shown that hydroquinone works by inhibiting tyrosinase and thus decreasing the formation of melanin. This regimen is relatively safe for twice-daily use; however, side effects include allergic or irritant contact dermatitis, postinflammatory hyperpigmentation, as well as exogenous ochronosis. Patients should be advised of these risks although the latter entity is exceedingly rare and usually associated with long-term use of higher concentrations of hydroquinone (greater than 4%).

The authors do not recommend using higher hydroquinone products greater than 4%. Animal studies show an increased risk of some cancers with hydroquinone use. This has not been deemed relevant in humans due to the small amount of absorption.

Combination therapy with hydroquinone (2-4%), tretinoin (0.05-0.1%) and a corticosteroid (such as fluocinolone acetonide) is the most frequently prescribed agent for the treatment of melasma. This regimen has been shown to be more efficacious than treatment with monotherapy with any of the individual agents. Daily use is recommended in addition to sunscreen.

The most common adverse effects of this regimen include erythema, burning, itching, and peeling. Hydroquinone products should not be used for more than a few consecutive months as the risk of exogenous ochronosis increases with prolonged use. Patients should be counseled to use hydroquinone for 2 months and then take a 2-month hydroquinone holiday prior to restarting use.

A 2% concentration of Mequinol alone or in combination with tretinoin can be used as another skin-lightening modality, often as an alternative to hydroquinone. It is reported that it is generally not felt to be as efficacious as hydroquinone therapy and may cause unwanted depigmentation in some patients.

An alternative prescription modality is azelaic acid, which is available in 15-20% concentrations and is approved in the United States for treatment of papulopustular rosacea and mild to moderate acne. It should be applied twice daily, and has a relatively safe side effect profile. The most common complaint is mild burning or stinging upon application. The remaining treatment options listed above are cosmeceuticals that have been shown to have a skin-lightening effect. These are available over the counter.

A series of multiple, monthly glycolic acid peels can be helpful for melasma. If no improvement is seen after a few peels (3 – 4), this treatment modality is unlikely to be beneficial and should be abandoned. These results can be optimized if the patient is also using a hydroquinone cream on a regular basis.

Q-switched lasers and nonablative fractionated lasers are sometimes helpful for melasma, albeit often with temporary results. There is a significant risk that the melasma may also darken with these devices. Given this risk, it is prudent to do a test spot first, prior to treating the entire affected area.

Patient Management

In order to optimize outcome of any treatment modality, sun avoidance and protection strategies must be initiated, including the use of broad spectrum sunscreen with an SPF of at least 30, wide brimmed hats, and protective clothing (especially important if more diffuse involvement). All attempts should be made (via Wood’s lamp examination) to determine whether pigment deposition is epidermal versus dermal. In most cases, only the former will respond to topical therapy.

All of the described topical treatment options should be used as directed for a period of 2-3 months, after which the patient should be evaluated by the prescribing clinician to determine the response. Photodocumentation is encouraged to aid in follow up examination. If the response is suboptimal, changing or adding additional treatment modalities should be discussed with the patient.

Unusual Clinical Scenarios to Consider in Patient Management

Rare associations with thyroid disease have been recorded. This may or may not be a true association. If the patients review of systems is noncontributory, thyroid testing is not warranted with the finding of melasma alone. Pregnancy testing should be considered in the appropriate settings.

What is the Evidence?

Andersen, FA, Bergfeld, WF, Belsito, DV. “Final amended safety assessment of hydroquinone as used in cosmetics”. Int J Toxicol. vol. 29. 2010 Nov- Dec. pp. 274S-87. (A discussion of the safety profile of hydroquinone in cosmetic products.)

Draelos, ZN. “Skin lightening preparations and the hydroquinone controversy”. Dermatol Ther. vol. 20. 2007. pp. 308-13. (A discussion of the controversy surrounding the safety of hydroquinone, as well as a review of other topical treatment modalities.)

Grimes, PE. “Melasma etiologic and therapeutic considerations”. Arch Dermatol.. vol. 131. 1995. pp. 1453-7. (An excellent overview of the epidemiology of melasma, a review of the classification schemes for melasma, and a discussion of the histologic findings, as well as a summary of common treatment options.)

Grimes, PE, Yamada, N, Bhawan, J. “Light microscopic, immunohistochemical and ultrastructural alterations in patients with melasma”. Am J Dermatopathol. vol. 27. 2005. pp. 96-101. (A discussion regarding the ultrastructural changes, light microscopy features, and immunohistochemical findings in the skin of patients with melasma.)

Gueveara, IL, Pandya, AG. “Melasma treated with hydroquinone, tretinoin, and a fluorinated steroid”. Int J Dermatol. vol. 40. 2001. pp. 212-5. (A retrospective study evaluating the use of combination therapy with the agents described in the title.)

Gupta, AK, Gover, MD, Nouri, K, Taylor, S. “The treatment of melasma: A review of clinical trials”. J Am Acad Dermatol. vol. 55. 2006. pp. 1048-65. (A comprehensive overview of the mechanism of action, efficacy, safety, and tolerability of several of the leading physical and medical therapeutic options available for the treatment of melasma.)

Victor, FC, Gelber, J, Rao, B. “Melasma: a review”. J Cutan Med Surg. vol. 8. 2004 Mar-Apr. pp. 97-102. (An overview of the current hypotheses regarding the etiology and pathophysioogy of melasma as well as a discussion about the classification and treatment options.)