What causes uneven skin tone

Pigmentation of skin depends on the amount and type of melanin, degree of skin vascularity, presence of carotene, and thickness of the stratum corneum ¹.

The skin consists of two layers:

1. a stratified squamous epithelium called the Epidermis and
2. a deeper connective tissue layer called the Dermis (Figure 1).

The brown tones of the skin result from the pigment-producing cells called melanocytes. Melanocytes are scattered among the basal cells of the stratum basale. They have numerous cytoplasmic processes that inject melanin—a black, yellow-brown, or brown pigment—into the basal cells in this layer and into the keratinocytes of more superficial layers. The ratio of melanocytes to stem cells ranges between 1:4 and 1:20 depending on the region examined. Melanocytes are most abundant in the cheeks, forehead, nipples, and genital region.

Differences in skin color result from varying levels of melanocyte activity, not varying numbers of melanocytes. Albinism is an inherited disorder characterized by deficient melanin production; individuals with this condition have a normal distribution of melanocytes, but the cells cannot produce melanin. It affects approximately one person in 10,000.

Figure 1. Skin structure

Figure 2. Structure and skin cells of the Epidermis

Skin hyperpigmentation usually results from an increased number, or activity, of melanocytes. Epidermal increases in melanin usually enhance with a Wood lamp, whereas dermal increases do not. Some disorders, such as melasma, may have dermal and epidermal changes and can be classified as mixed ².

• Hypopigmentation of skin may result from a reduction of melanocytes or from an inability of the melanocytes to produce melanin or properly transport melanosomes. Causes of hyper- and hypopigmentation are discussed in this article and are listed in Table 1.

• Certain skin pigmentation disorders are more common in certain skin types. The most commonly used system for identifying skin types is the Fitzpatrick system (Table 2) ³.

Table 1. Causes of uneven skin tone (hyper- and hypopigmentation)

Hyperpigmentation
Postinflammatory hyperpigmentation (acne, psoriasis, atopic and contact dermatitis, lichen planus, trauma, drugs, and fixed-drug eruptions)
Melasma
Solar lentigines
Ephelides (freckles)
Café-au-lait macules
Nevi
Melanoma and precursors
Hypopigmentation
Acquired (common)
Vitiligo
Pityriasis alba
Tinea versicolor
Postinflammatory hypopigmentation
Congenital (uncommon)
Albinism
Piebaldism
Tuberous sclerosis
Hypomelanosis of Ito

[Source ¹]

Table 2. Skin Type Classification

Skin type	Skin color	Characteristics
I	White; very fair; red or blond hair; blue eyes; freckles	Always burns, never tans
II	White; fair; red or blond hair; blue, hazel, or green eyes	Usually burns, tans with difficulty
III	Cream white; fair with any eye or hair color; very common	Sometimes mild burn, gradually tans
IV	Brown; typically Mediterranean skin	Rarely burns, tans with ease
V	Dark brown; Middle-Eastern skin types	Very rarely burns, tans very easily
VI	Black	Never burns, tans very easily

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[Source ³]

Table 3. Summary of common uneven skin tone disorders seen by doctors

Common uneven skin tone disorders and their treatments
Disorder	Description	Location	Cause
Postinflammatory hyperpigmentatin	Irregular, darkly-pigmented macules or patches	Previous sites of injury or inflammation	Trauma, inflammation
Treatment : Hydroquinone (Eldoquin Forte), azelaic acid (Azelex), retinoids, chemical peels, laser therapy; combination therapy is most effective
——————————————————–
Disorder	Description	Location	Cause
Melasma	Pigmented, well-defined macules; light brown, brown, or gray in color	Face (63 percent centrofacial, 21 percent malar, 16 percent mandibular), forearms	Pregnancy, oral contraceptives, phenytoin (Dilantin), idiopathic
Treatment : Sunscreen; combinations of: hydroquinone, retinoids, glycolic acid peels, topical steroids; laser therapy, intense pulsed light therapy for dermal lesions
——————————————————–
Disorder	Description	Location	Cause
Solar lentigines	1- to 3-cm macules, well-circumscribed, light yellow to dark brown, variegated color	Face, hands, forearms, chest, back, shins	Acute, chronic ultraviolet light exposure
Treatment : Hydroquinone, retinoids, chemical peels, laser therapy, cryotherapy
——————————————————–
Disorder	Description	Location	Cause
Ephelides	1- to 2-mm, shaply defined macules, red to tan to light brown in color	Childhood onset, face, neck, chest, arms, legs	Sun exposure in susceptible persons (i.e., skin types I to II)
Treatment : None needed; fades in winter months
——————————————————–
Disorder	Description	Location	Cause
Café-au-lait macules	Tan to brown patches, 1 to 20 cm, epidermal, present at birth or early childhood	Usually on trunk, but possible anywhere	Increased melanin in melanocytes, basal keratinocytes
Treatment : Laser therapy, surgical excision; cosmetic treatment
——————————————————–
Disorder	Description	Location	Cause
Vitiligo	Unpigmented macules and patches, sharply defined, 5 to 50 mm, coalescent	Face, hands, forearms, neck, genitalia, body folds, periorificial	Unknown, possibly immune-mediated
Treatment : Sunscreens, concealers, dyes, topical steroids, oral psoralens with psoralen ultraviolet A-range, narrow-band ultraviolet-B therapy, depigmentation, grafting

Hyperpigmentation Disorders

Postinflammatory Hyperpigmentation

Postinflammatory hyperpigmentation is a common consequence of an injury or inflammation to dark skin (Fitzpatrick types IV to VI see Table 2 above), resulting in lesions that can persist for months or years. This can be psychologically devastating to some people. Postinflammatory hyperpigmentation may also occur after laser therapy for other pigmented skin lesions, and may be transient or long lasting. A typical example can be seen in Figure 3.

Figure 3. Postinflammatory hyperpigmentation of distal right leg following resolution of dermatitis eruption

Postinflammatory hyperpigmentation presents as irregular, darkly pigmented macules and patches at sites of previous injury or inflammation. Treatment is often difficult, requiring prolonged courses of therapy and excellent patient compliance.

Available methods of treatment for postinflammatory hyperpigmentation include hydroquinone 3% or 4% (Eldoquin Forte) twice daily, azelaic acid 20% cream (Azelex) twice daily, salicylic or glycolic acid peels, retinoids, and laser therapy. However, monotherapy often produces unsatisfactory results. In one study, the addition of serial glycolic acid peels to a hydroquinone 2%/glycolic acid 10% combination twice daily and tretinoin 0.05% (Retin-A) at bedtime resulted in faster lightening without significant adverse effects ⁴. Additionally, retinoids such as tazarotene 0.1% cream (Tazorac) are well-tolerated and somewhat effective at reducing hyper-pigmentation and disease severity ⁵.

Pretreatment with topical therapies has been studied in patients with skin types I to III undergoing carbon dioxide laser resurfacing. No conclusive benefit was noted in one limited trial involving patients at the lowest risk for postin-flammatory hyperpigmentation ⁶. At present, no preventative measures have proven beneficial in any skin type.

Melasma

Melasma is a progressive, macular, nonscaling hypermelanosis of sun-exposed areas of the skin, primarily on the face and dorsal forearms. It is usually associated with pregnancy, oral contraceptives, or anticonvulsants (e.g., phenytoin [Dilantin]), or it may be idiopathic. Melasma affects women nine times more often than men, and it is more prominent in patients with skin types IV to VI (e.g., Asian, Middle Eastern, South American). It is usually asymptomatic, but it is often cosmetically distressing to the patient. Melasma typically presents in one of three patterns of distribution: centrofacial (63 percent), malar (21 percent), and mandibular (16 percent). It is usually, but not always, bilateral (Figure 4).

Figure 4. Melasma

Three types of melasma exist: epidermal, dermal, and mixed. Epidermal melasma tends to be light brown, enhancing under Wood lamp examination. Dermal melasma is usually grayish in color and nonenhancing. Mixed types are dark brown with variable enhancement.

Topical treatment with hydroquinone 3% or 4%, glycolic acid 10% peel, azelaic acid 20% cream, and retinoids (e.g., tretinoin 0.05% or 0.1% cream; adapalene 0.1% or 0.3% gel [Differin]) all have some effectiveness. Combination products with hydroquinone and retinoids, glycolic acid, or topical steroids seem to be somewhat more effective. Typically, treatment must be continued indefinitely to maintain effect ⁷. In one drug-company-sponsored study, a triple-combination treatment of fluocinonide 0.01%/hydroquinone 4%/tretinoin 0.05% cream (Tri-Luma) showed significantly greater effectiveness at improving dyspigmentation than treatment with any two of these ingredients combined, with mild side effects ⁸. Epidermal and mixed types are not often responsive to laser therapies and frequently result in significant postinflammatory hyperpigmentation; therefore, their use cannot be recommended. However, several small studies suggest that dermal or refractory/mixed-type melasmas may be effectively treated with laser therapy or by a combination of intense pulsed-light therapy and hydroquinone with sunscreen ⁹.

Prevention of melasma involves decreasing exposure of susceptible skin to ultraviolet (UV) rays. Opaque sunblocks with titanium dioxide or zinc oxide are most effective. There are transparent sunscreens containing these agents as well (e.g., Blue Lizard Sunscreen Sensitive SPF 30+, Neutrogena Sensitive Skin Sunblock 30+, Sol-bar Zinc Sunscreen SPF 38). Melasma that is induced by pregnancy or oral contraceptive use tends to fade within several months after delivery or medication cessation, so watchful waiting should be encouraged in these instances whenever possible.

Solar Lentigines

Solar lentigines (i.e., liver spots) are macular, 1- to 3-cm, hyperpigmented, well-circumscribed lesions on sun-exposed surfaces of the skin. They vary in color from light yellow to dark brown, and they often have a variegated appearance. The face, hands, forearms, chest, back and shins are the most common locations, erupting after acute or chronic UV exposure. White or Asian persons are most likely to develop solar lentigines, especially those with skin types I to III and a tendency to freckle (Figure 5).

Figure 5. Solar lentigines

Solar lentigines result from a local proliferation of basal melanocytes and a subsequent increase in melanization, differing from freckles, which result from increased melanin production. Systemic disorders presenting with multiple lentigines may include Peutz-Jeghers syndrome (gastrointestinal hamartomas; buccal, lip, perioral, or digital macules; onset at birth or early childhood), LEOPARD syndrome (multiple lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retarded growth, and sensorineural deafness), and LAMB syndrome (multiple lentigines, atrial and/or mucocutaneous myxomas, myxoid neurofibromas, ephelides, and blue nevi). Solar lentigines must be differentiated from premalignant lesions, such as pigmented actinic keratoses or lentigo maligna. Pigmented lesions with rapid growth or change, associated symptoms (e.g., pain, itching, easy or recurrent bleeding, poor healing), atypical lesions, or those with features suspicious for melanoma should be biopsied. Full thickness excisional biopsy or punch biopsy (for large lesions or those on the face or cosmetically sensitive area) is an acceptable method of biopsy in these instances. Solar lentigines can be distinguished clinically from flat seborrheic dermatoses or pigmented actinic keratoses by the absence of epidermal hyperkeratosis. Biopsy may facilitate diagnosis in uncertain cases.

Treatment of solar lentigines consists of ablative therapies (e.g., chemical peels, cryotherapy, laser therapy) or topical therapies (e.g., hydroquinone, retinoids), and is summarized in Table 4. Chemical peels with 30% to 35% trichloroacetic acid (Trichlor) solution or brief (i.e., less than 10 seconds) cryotherapy with liquid nitrogen have resulted in significant lightening of lentigines, but data are limited on long-term improvements, and recurrences are common. Additionally, cryotherapy can be painful, and prolonged treatment is associated with hypopigmentation ¹⁰. Laser therapy for solar lentigines has shown benefit in at least one small, randomized controlled trial, with effectiveness superior to liquid nitrogen cryotherapy. The frequency-doubled Q-switched neodymium-doped yttrium aluminum garnet (ND: YAG) laser produced the best cosmetic results and was tolerated best. Postinflammatory hyperpigmentation is a known complication of laser therapy, and must be considered when determining the best treatment option for each patient ¹¹.

Table 4. Treatment of Solar Lentigines

Treatment	Type/dose	Side effects
Chemical peels	30% to 35% trichloroacetic acid (Trichlor)	Transient stinging, burning, pain
Cryotherapy	Liquid nitrogen	Pain, hypopigmentation with prolonged exposure
Laser therapy	Neodymium-doped yttrium aluminum garnet (ND: YAG) laser	Pain, postinflammatory hyperpigmentation, redness, textural changes, hypopigmentation
Hydroquinone (Eldoquin Forte)	3% to 4% topical	Hypersensitivity, acne, ochronosis
Mequinol/tretinoin (Solage)	2% mequinol/0.01% tretinoin topical solution	Redness, dryness, itching, sensitivity
Retinoids	Tazarotene 0.1% cream (Tazorac); adapalene 0.1% or 0.3% gel (Differin)	Redness, dryness, itching, sensitivity

[Source ¹]

Topical therapies for solar lentigines are also available. Hydroquinone has been available for more than 30 years and is moderately effective. Adverse effects to hydroquinone include hypersensitivity, acneiform eruptions, and, rarely, ochronosis (i.e., blotchy hyperpigmentation) ¹². Additionally, the lightening effects of hydroquinone are slow (months), and relapse with medication discontinuation is the rule. More recently, a combination of mequinol/tretinoin (Solage) has been shown to be safe and effective in treating solar lentigines, and shows promise for prolonged maintenance ¹³. Retinoids such as tazarotene 0.1% cream and adapalene 0.1% or 0.3% gel may reduce the appearance of solar lentigines, but evidence is limited ¹⁴.

Prevention of solar lentigines depends on limiting sun exposure, using sunscreen regularly (especially in patients with fair skin [types I to III] and those prone to freckling), and preventing sunburns, especially after 20 years of age.

Ephelides

Ephelides (i.e., freckles) are small, 1- to 2-mm, sharply defined macular lesions of uniform color, most often found on the face, neck, chest, and arms. Color may vary from red to tan to light brown, and they may vary in number from a few to hundreds. Onset is usually in childhood after sun exposure. They are asymptomatic. Treatment of these lesions is not usually necessary, as they tend to fade during winter months. Cosmetically, undesired lesions can be treated similarly to lentigines (i.e., cryotherapy, hydroquinone, azelaic acid, glycolic acid peels, and laser therapy). These lesions should be differentiated from juvenile lentigines (2 to 10 mm) and solar lentigines (2 to 20 mm), which usually arrive later in life.

Café-au-lait macules

Café-au-lait macules are tan or brown macules ranging in size from 1 to 20 cm, which are present at birth or occur early in life. They are epidermal in origin, representing an increase in melanin in melanocytes and basal keratinocytes. They may be found on any body part, but often are located on the trunk (Figure 6). Ten to 30 percent of the population has an isolated café-au-lait macule ¹⁵.

Café-au-lait macules are asymptomatic and require treatment for cosmesis only. Laser therapies and surgical excision are effective. More than six café-au-lait lesions (5 mm or larger, prepubertal; and 15 mm or larger, postpubertal) should raise suspicion for an underlying systemic disorder such as tuberous sclerosis, neurofibromatosis, Albright syndrome, or Fanconi anemia ³.

Figure 6. Café-au-lait macules

Hypopigmented Lesions

Vitiligo

Vitiligo is a disfiguring skin disease resulting in loss of pigmentation. It results from an immune-mediated destruction of melanocytes. It presents with well-defined milky-white patches of skin (leukoderma). Vitiligo can be cosmetically very disabling, particularly in people with dark skin. Its exact cause is unknown. Vitiligo affects all skin types and is generally considered a cosmetic condition, but it can cause significant psychological distress, particularly to some black patients.

Lesions in vitiligo consist of unpigmented, sharply defined macules ranging in size from 5 to 50 mm. Some will have a rim of hyperpigmentation or erythema. Common sites of involvement include the face, neck, dorsal hands, genitalia, body folds, and axillae (Figure 7). Perioral, periorbital, periumbilical, and perianal lesions also occur.

Four types of vitiligo exist:

• Generalized vitiligo involves greater than 10 percent of the body surface area.
• Acral/acrofacial vitiligo typically involves the face and distal extremities (i.e., the so-called “tip/lip” pattern).
• Localized vitiligo tends to involve a smaller body surface area and is generally stable in nature.
• Segmental (i.e., single dermatome or extremity) vitiligo is more often present in children and has a poorer prognosis for treatment.

Who gets vitiligo ?

Vitiligo is found in 0.5 -1 percent of the general population and occurs in all races, affecting males and females equally. Family history of vitiligo is established in 25 to 30 percent of patients ¹⁵. Onset is often insidious, but is frequently related to a recent stress, illness, or trauma (e.g., sunburn). Peak onset is in the second and third decades of life, with 50 percent occurring before 20 years of age ¹⁵.

Even though most people with vitiligo are in good general health, they face a greater risk of having autoimmune diseases such as diabetes, thyroid disease (in 20% of patients over 20 years with vitiligo), pernicious anaemia (B12 deficiency), Addison disease (adrenal gland disease), systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and alopecia areata (round patches of hair loss).

A vitiligo-like leukoderma may occur in patients with metastatic melanoma. It can also be induced by certain drugs, such as immune checkpoint inhibitors (pembrolizumab, nivolumab) and BRAF inhibitors (vemurafenib, dabrafenib) used to treat metastatic melanoma. Vitiligo is also 3 times more common in haematology patients that have had allogeneic bone marrow and stem-cell transplants, than in the normal population.

Figure 7. Vitiligo

What causes vitiligo ?

Vitiligo is due to loss or destruction of melanocytes, which are the cells that produce melanin. Melanin determines the color of your skin, hair, and eyes. If melanocytes cannot form melanin or if their number decreases, skin color becomes progressively lighter.

The exact cause of vitiligo is unknown. It is thought to be a systemic autoimmune disorder, associated with deregulated innate immune response, although this has been disputed for segmental vitiligo. There is a genetic susceptibility and vitiligo is a component of some rare syndromes. The gene encoding the melanocyte enzyme tyrosinase, TYR, is likely involved.

There are three theories on the cause of vitiligo:

• The pigment cells are injured by abnormally functioning nerve cells.
• There may be an autoimmune reaction against the pigment cells.
• Autotoxic theory – the pigment cells self-destruct.

Current investigations are evaluating the pattern of cytokines (messenger proteins), particularly Interferon (IFN)-γ, and the role of the hair follicle in repigmentation.

How is vitiligo diagnosed ?

Vitiligo is normally a clinical diagnosis, and no tests are necessary to make the diagnosis. The white patches may be seen more easily under Wood lamp examination (black light).

Occasionally skin biopsy may be recommended, particularly in early or inflammatory vitiligo, when a lymphocytic infiltration may be observed. Melanocytes and epidermal pigment are absent in established vitiligo patches.

Blood tests to assess other potential autoimmune diseases or polyglandular syndromes may be arranged, such as thyroid function, B12 levels and autoantibody screen.

Clinical photographs are useful to document the extent of vitiligo for monitoring. Serial digital images may be arranged on follow-up. The extent of vitiligo may be scored according to the body surface area affected by depigmentation.

How is vitiligo treated ?

Treatment of vitiligo is currently unsatisfactory. Repigmentation treatment is most successful on face and trunk; hands, feet and areas with white hair respond poorly. Compared to longstanding patches, new ones are more likely to respond to medical therapy.

When successful repigmentation occurs, melanocyte stem cells in the bulb at the base of the hair follicle are activated and migrate to the skin surface. They appear as perifollicular brown macules.

General measures

Minimise skin injury: wear protective clothing

• A cut, a graze, a scratch may lead to a new patch of vitiligo

Cosmetic camouflage can disguise vitiligo. Options include:

• Make-up, dyes and stains
• Waterproof products
• Dihydroxyacetone-containing products “tan without sun”
• Micropigmentation or tattooing for stable vitiligo

Sun protection: stay indoors when sunlight is at its peak, cover up with sun protective clothing and apply SPF 50+ sunscreen to exposed skin.

• White skin can only burn on exposure to ultraviolet radiation (UVR); it cannot tan
• Sunburn may cause vitiligo to spread
• Tanning of normal skin makes vitiligo patches appear more obvious

Topical treatments

Topical treatments for vitiligo include:

• Corticosteroid creams. These can be used for vitiligo on trunk and limbs for up to 3 months. Potent steroids should be avoided on thin-skinned areas of face (especially eyelids), neck, armpits and groin.
• Calcineurin inhibitors (pimecrolimus cream and tacrolimus ointment. These can be used for vitiligo affecting eyelids, face, neck, armpits and groin.
• Experimental treatment with topical ruxolitinib, a janus kinase inhibitor, shows great promise for facial vitiligo.

Phototherapy

Phototherapy refers to treatment with ultraviolet (UV) radiation. Options include:

• Whole-body or localised broadband or narrowband (311 nm) UVB
• Excimer laser UVB (308 nm) or targeted UVB for small areas of vitiligo
• Oral, topical, or bathwater photochemotherapy (PUVA)

Phototherapy probably works in vitiligo by 2 mechanisms.

• Immune suppression—preventing destruction of the melanocytes
• Stimulation of cytokines (growth factors)

Treatment is usually given twice weekly for a trial period of 3–4 months. If repigmentation is observed, treatment is continued until repigmentation is complete or for a maximum of 1–2 years.

• Phototherapy is unsuitable for very fair skinned people.
• The treatment intensity aims for the vitiligo skin to be a light “carnation” pink
• If repigmentation is observed, treatment is continued until repigmentation is complete or for a maximum of 1–2 years.
• Treatment times are generally brief. The aim is to cause the treated skin to appear very slightly pink the following day.
• It is important to avoid burning (red, blistered, peeling, itchy or painful skin), as this could cause the vitiligo to get worse.

A meta-analysis included 35 unique studies reporting outcome after phototherapy for generalised vitiligo. Marked or clinically useful response was achieved in 36% after 12 months of NBUVB and in 62% after 12 months of PUVA. Face and neck responded better than trunk, which responded better than extremities. It was not very effective on hands and feet.

Systemic therapy

Systemic treatments for vitiligo include:

• Oral minocycline, a tetracycline antibiotic with anti-inflammatory properties
• Mini-pulses of oral steroids for 3 to 6 months, eg dexamethasone 2.5 mg, 2 days per week
• Subcutaneous afamelanotide

It is anticipated that monoclonal antibody biologic agents will be developed to treat vitiligo.

Surgical treatment of stable vitiligo

Surgical treatment for stable and segmental vitiligo requires removal of the top layer of vitiligo skin (by shaving, dermabrasion, sandpapering or laser) and replacement with pigmented skin removed from another site.

Techniques include:

• Non-cultured melanocyte-keratinocyte cell suspension transplantation.
• Punch grafting
• Blister grafts, formed by suction or cryotherapy
• Split skin grafting
• Cultured autografts of melanocytes grown in tissue culture

Depigmentation therapy

Depigmentation therapy, using monobenzyl ether of hydroquinone, may be considered in severely affected, dark skinned individuals.

Cyotherapy and laser treatment (eg 755 nm Q-switched alexandrite or 694 nm Q-switched ruby) have also been used successfully to depigment small areas of vitiligo.

Other Hypopigmentation Disorders

Other disorders commonly associated with hypopigmentation include pityriasis alba, tinea versicolor, postinflammatory hypomelanosis (i.e., loss of melanin), atopic dermatitis, psoriasis, and guttate parapsoriasis. Additionally, it may also result from dermabrasion, chemical peels, and intralesional steroid therapy.

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