Melasma

01Pathophysiology

Melasma is a disorder of melanocyte hyperactivity, not melanocyte proliferation. This distinction matters on exams because it separates melasma from melanocytic neoplasms. The melanocytes in affected skin are functionally overactive and produce excess melanin, but their total number remains essentially normal.

The central drivers are ultraviolet radiation and hormonal influence. UV light stimulates melanogenesis through multiple pathways. It upregulates alpha-melanocyte-stimulating hormone ($\alpha \backslash alpha$-MSH), adrenocorticotropic hormone (ACTH), and stem cell factor (SCF) in keratinocytes, all of which signal neighboring melanocytes to increase melanin synthesis. This explains why melasma exclusively involves sun-exposed skin and why it worsens in summer or with increased UV exposure.

Estrogen and progesterone are potent stimulators of melanogenesis. Melanocytes express estrogen receptors, and activation of these receptors upregulates tyrosinase, the rate-limiting enzyme in melanin production. This hormonal link accounts for the strong clinical association with pregnancy (historically called chloasma or the "mask of pregnancy"), oral contraceptive pills, and hormone replacement therapy. During pregnancy, elevated estrogen and progesterone levels drive melanocyte activity, producing the classic facial hyperpigmentation that may partially or fully resolve postpartum.

A genetic predisposition is also well established. Melasma has higher prevalence in individuals with darker skin phototypes (Fitzpatrick III through V), and a family history is present in many patients. The genetic component likely involves polymorphisms in genes governing melanin synthesis, melanocyte signaling, and UV-induced DNA repair.

More recent research has identified a vascular component to melasma. Lesional skin shows increased expression of vascular endothelial growth factor (VEGF) and a higher density of dermal blood vessels compared to surrounding normal skin. This vascular element helps explain why melasma can be resistant to depigmenting therapies alone and why some treatment strategies now target vascularity.

The excess melanin can be deposited in the epidermis, the dermis (within melanophages), or both. This depth of pigment deposition directly determines the clinical appearance and the response to therapy. Epidermal melasma appears brown and responds better to topical depigmenting agents, while dermal melasma appears gray-brown or blue-gray and is more refractory to treatment.

02Classification and Clinical Manifestation

Distribution Pattern

Depth of Pigmentation (Wood's Lamp Classification)

Melasma Area and Severity Index (MASI)

The MASI score is used to quantify disease severity and track treatment response. It evaluates four facial regions (forehead, right malar, left malar, chin), scoring each for area of involvement (0 to 6), darkness of pigmentation (0 to 4), and homogeneity of pigmentation (0 to 4). The maximum score is 48, and a modified version (mMASI) omits the homogeneity component for simplicity.

03Diagnostic Workup

Melasma is fundamentally a clinical diagnosis. The combination of a characteristic patient profile (reproductive-age woman, darker skin phototype, hormonal trigger) with symmetric facial hyperpigmentation in a sun-exposed distribution is usually sufficient.

The Wood's lamp examination is the most important ancillary test and the one most commonly tested on exams. Its purpose is not to confirm the diagnosis but to classify the depth of pigment deposition, which directly informs treatment planning and prognosis counseling. To use the Wood's lamp correctly, the examination must be performed in a completely dark room. The 365 nm UV light causes epidermal melanin to fluoresce, making it appear more prominent. Dermal melanin does not fluoresce and will not change in appearance. Students should remember: if pigment is accentuated under Wood's lamp, it is epidermal and more likely to respond to topical depigmenting agents.

Dermoscopy is increasingly used and may appear in exam vignettes. On dermoscopy, epidermal melasma shows a brown diffuse or reticular pigment pattern, whereas dermal involvement shows gray or blue structureless areas and dermal melanophages.

Skin biopsy is reserved for cases where the clinical picture is atypical or another diagnosis (such as post-inflammatory hyperpigmentation, lichen planus pigmentosus, or cutaneous melanoma) cannot be excluded. Histopathology will show increased melanin within the basal layer, possibly extending to the suprabasal epidermis, along with solar elastosis and dermal melanophages in dermal-type disease. Importantly, there is no melanocyte atypia and no increase in melanocyte number, which distinguishes melasma from lentigo maligna and other melanocytic proliferations.

04Management and Treatment

Photoprotection is the single most important intervention and must be emphasized to every patient regardless of other treatments. Exam questions frequently test whether a student recognizes that depigmenting therapy without sun protection is futile. Broad-spectrum sunscreen with SPF 30 or higher should be applied daily and reapplied every two hours during sun exposure. Sunscreens containing iron oxide are preferred because they block visible light, which can independently stimulate melanogenesis in darker skin types through opsin-3 receptors. Physical sun avoidance and protective clothing are also essential.

The first-line pharmacologic therapy is the triple combination cream (also known as Kligman's formula or modified Kligman's formula): hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01%. This combination works synergistically. Hydroquinone inhibits tyrosinase and is the most potent topical depigmenting agent available. Tretinoin accelerates epidermal turnover and enhances hydroquinone penetration. Fluocinolone (a mild corticosteroid) reduces irritation from the other two agents and may independently inhibit melanogenesis. The cream is applied once nightly for 8 to 12 weeks, then tapered.

Hydroquinone monotherapy can be used where the triple combination is unavailable. The concentration ranges from 2% (available over the counter in some regions) to 4% (prescription strength). Continuous use should not exceed 4 to 6 months because prolonged application risks exogenous ochronosis, an irreversible blue-black discoloration of the skin. This is a commonly tested adverse effect.

Azelaic acid (15 to 20%) is a safe and effective alternative, particularly notable because it is pregnancy category B and can be used during pregnancy, when hydroquinone and tretinoin are contraindicated. It inhibits tyrosinase and has antiproliferative effects on hyperactive melanocytes.

Oral tranexamic acid at 250 mg twice daily has emerged as a treatment for refractory melasma. It works by inhibiting plasminogen activator, which reduces UV-induced prostaglandin and arachidonic acid release, thereby decreasing melanocyte-stimulating signals. It also reduces the vascular component of melasma. Before prescribing, screen for contraindications including active thromboembolic disease, history of deep vein thrombosis or pulmonary embolism, and concurrent use of combined oral contraceptives (additive thrombotic risk).

Chemical peels with glycolic acid (30 to 70%) serve as adjuncts to topical therapy. They enhance penetration of depigmenting agents and remove superficial melanin. Peels should be used cautiously in darker skin types due to the risk of post-inflammatory hyperpigmentation.

Laser therapy is a last resort for recalcitrant disease. Low-fluence Q-switched Nd:YAG laser (1064 nm) can target dermal melanin, but there is a well-documented risk of paradoxical rebound hyperpigmentation, especially in darker skin. This makes laser treatment a double-edged intervention that exam vignettes may test as a complication.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students lose points on melasma questions is by jumping to pharmacologic treatment without recognizing photoprotection as the foundation of management. A vignette may describe a woman already using hydroquinone cream with no improvement, and the correct next step is not to escalate therapy but to assess and reinforce strict sun protection. Without adequate UV avoidance, no depigmenting regimen will work.

A second frequent trap involves pregnancy. If the vignette presents a pregnant woman with facial hyperpigmentation, students must recognize that hydroquinone and tretinoin are contraindicated. The correct answer in this setting is azelaic acid (safe in pregnancy) combined with photoprotection, not the standard triple combination cream. Some students reflexively choose Kligman's formula as the first-line answer without screening for pregnancy status.

A third tested concept is the Wood's lamp interpretation. Students must know that accentuation of pigment under Wood's lamp indicates epidermal melanin and predicts a better treatment response, while absence of accentuation points to dermal melanin and a more refractory course. A question that provides Wood's lamp findings is almost certainly testing your ability to classify depth and counsel the patient appropriately regarding prognosis.

Finally, watch for the exogenous ochronosis trap. If a patient using hydroquinone develops worsening blue-black discoloration rather than lightening, the diagnosis is ochronosis from prolonged hydroquinone use, not treatment failure requiring a higher dose. The correct step is to discontinue hydroquinone immediately.

The core competency being tested across melasma questions is the ability to integrate patient demographics (reproductive-age woman, darker skin type, hormonal exposure) with a pattern-recognition diagnosis, select the appropriate workup (Wood's lamp classification), and sequence management correctly (photoprotection first, then tailored pharmacotherapy with awareness of contraindications).