Background

Postinflammatory hyperpigmentation (PIH) is a frequently encountered problem

and represents the sequelae of various cutaneous disorders as well as
therapeutic interventions. This acquired excess of pigment can be attributed to
various preceding disease processes that affect the skin such as infections,
allergic reactions, mechanical injuries, reactions to medications, phototoxic
eruptions, trauma (eg, burns), and inflammatory diseases (eg, lichen
planus, lupus erythematosus, atopic dermatitis).
PIH can also be seen following treatment with a number of electromagnetic
devices such as ultrasound, radiofrequency, lasers, light-emitting diodes, and
visible light, as well as secondary to microdermabrasion. Typically,
postinflammatory hyperpigmentation is most severe in patients whose basal cell
layer of the epidermis is disrupted such as lichenoid dermatoses or lupus
erythematosus.
Pathophysiology
Postinflammatory hyperpigmentation is caused by 1 of 2 mechanisms that result
in either epidermal or dermal melanosis. The epidermal inflammatory response
(ie, dermatitis) results in the release and subsequent oxidation of arachidonic
acid to prostaglandins, leukotrienes, and other products. These products of
inflammation alter the activity of both immune cells and melanocytes.
Specifically, these inflammatory products stimulate epidermal melanocytes,
causing them to increase the synthesis of melanin and subsequently to increase
the transfer of pigment to surrounding keratinocytes. Such increased stimulation
and transfer of melanin granules results in epidermal hypermelanosis.
On the contrary, dermal melanosis occurs when inflammation disrupts the basal
cell layer, causing melanin pigment to be released and subsequently trapped by
macrophages in the papillary dermis, also known as pigmentary incontinence.
Fibroblast-derived melanogenic growth factors may be salient in mesenchymalepithelial interactions modulating melanocyte function.[1]
Epidemiology
Frequency
United States
Postinflammatory hyperpigmentation is a universal response of the skin, but it is
more common in individuals with darker skin (Fitzpatrick skin types III to VI).
Postinflammatory hyperpigmentation can be caused by any inflammatory
process of the skin; however, it is more apparent in photo-induced dermatoses
and more severe in lichenoid dermatoses.

International
Internationally, postinflammatory hyperpigmentation is a common inflammatory
response of the skin, developing more commonly in darker skin. Despite their
lighter skin color, certain Asians (from Pacific rim countries such as Japan,
Taiwan, China) are more susceptible to developing PIH following one of the
inciting factors listed above.
Mortality/Morbidity
Morbidity associated with postinflammatory hyperpigmentation is related to the
underlying
inflammatory
process
that
causes
postinflammatory
hyperpigmentation. If the hyperpigmentation is located in cosmetically sensitive
regions, a significant amount of emotional distress may result.
Race
Although postinflammatory hyperpigmentation occurs in whites, it is more
common in darker pigmented individuals including African Americans or Asians.
Sex
Postinflammatory hyperpigmentation occurs with equal incidence in males and
females; it has no sexual predilection.
Age
Postinflammatory hyperpigmentation can occur in persons of any age.
History
A diagnosis of postinflammatory hyperpigmentation should be considered if a
history of a preceding pathologic process or injury to the affected area of
hyperpigmentation is present.
Physical
The distribution of the hypermelanotic lesions depends on the location of the
original inflammatory dermatosis. The color of the lesions ranges from light
brown to black, with a lighter brown appearance if the pigment is within the
epidermis (ie, epidermal melanosis) and a darker gray to bluish appearance if
lesions contain dermal melanin (ie, dermal melanosis). Note the image below.

Photo of a 42-year-old African American woman with macules of

postinflammatory hyperpigmentation on the left side of her face as a result of
acne excorie.
Causes
Postinflammatory hyperpigmentation can occur with various disease processes
that affect the skin. These processes include allergic reactions, infections,
trauma, and phototoxic eruptions. Fractional laser photothermolysis occasionally
induces postinflammatory hyperpigmentation.[2, 3]
Common
inflammatory
diseases
that
result
in
postinflammatory
hyperpigmentation include acne excorie, lichen planus, systemic lupus
erythematosus, chronic dermatitis, and cutaneous T-cell lymphoma, especially
erythrodermic variants.
Furthermore, lesions of
exposure to UV light
tetracycline, bleomycin,
gold, antimalarial drugs,

postinflammatory hyperpigmentation can darken with

and various chemicals and medications, such as
doxorubicin, 5-fluorouracil, busulfan, arsenicals, silver,
hormones, and clofazimine.

Diagnostic Considerations
Medication-induced pigmentation
Amiodarone (Cordarone)
Amitriptyline (Elavil)
Arsenic
Bismuth
Bleomycin (Blenoxane)
Busulfan (Myleran)
Clofazimine (Lamprene)
Cyclophosphamide (Cytoxan)
Daunorubicin (DaunoXome, Cerubidine)
Doxorubicin (Adriamycin)
Gold (may cause chrysiasis)
Mercury
Minocycline (Minocin)
Nitrogen mustard (topical)
Phenothiazines
Silver (may cause argyria)
Zidovudine (Retrovir)
Differential Diagnoses

Acanthosis Nigricans

Addison Disease

Amyloidosis, Lichen

Amyloidosis, Macular
Ephelides
Erythema Dyschromicum Perstans
Hemochromatosis
Lentingines
Lichen Planus
Melasma
Riehl Melanosis
Tinea Versicolor

Laboratory Studies
A Wood lamp examination enables distinction of epidermal postinflammatory
hyperpigmentation (PIH) from dermal postinflammatory hyperpigmentation.
Epidermal lesions tend to have accentuated borders under a Wood lamp
examination, whereas those of dermal lesions appear poorly circumscribed and
are not accentuated with a Wood lamp examination.
Procedures
If a history of preceding inflammatory dermatosis is unclear or absent, skin
biopsy is warranted to exclude other underlying causes of hyperpigmentation.
Staining of the biopsy specimen with Fontana-Masson silver stain for melanin
enables localization of the melanin in the epidermis and/or the dermis.
Histologic Findings
Epidermal postinflammatory hyperpigmentation involves increased melanin
pigment in the basal cell layer of the epidermis. Occasionally, giant melanosomes
are evident in the epidermis.
Dermal postinflammatory hyperpigmentation involves melanin pigment in the
upper dermis, with pigment incontinence due to increased numbers of
melanophages in the papillary dermis.
Medical Care
The treatment of postinflammatory hyperpigmentation (PIH) tends to be a
difficult and prolonged process that often takes 6-12 months to achieve the
desired results of depigmentation. Each of these treatment options potentially
improves epidermal hypermelanosis, but none is proven effective for dermal
hypermelanosis. Daily use of a broad-spectrum sunscreen (sun protection factor
[SPF] 15 or greater) is an essential part of any therapeutic regimen.
A variety of topical treatments have been used to treat epidermal
postinflammatory hyperpigmentation, with varying degrees of success. These

agents include hydroquinone, tretinoin cream, corticosteroids, glycolic acid (GA),

and azelaic acid.[4] Lightening of hyperpigmented areas may be achieved with
one of the previously named topical agents; however, a combination of topical
creams and gels, chemical peels, and sunscreens may be necessary for
significant
improvement.[5]They
are
only
effective
for
epidermal
hyperpigmentation.
Topical tretinoin 0.1% has been effective in treating postinflammatory
hyperpigmentation. GA peels, in combination with tretinoin and hydroquinone,
are an effective treatment of postinflammatory hyperpigmentation in darkcomplexioned individuals.[6] All-trans retinoic acid aqueous gel 0.1-0.4% may be
applied concomitantly with hydroquinonelactic acid ointment for bleaching. [7,
8]
After sufficient improvement of the hyperpigmentation is achieved, a
corticosteroid may be applied topically with hydroquinone to promote healing.
This combination of various topical therapeutic agents has been shown to be
beneficial, especially on the face.
Topical azelaic acid, which has been approved for the treatment of acne vulgaris,
is useful for postinflammatory hyperpigmentation as well. [9] In acne patients who
are prone to postinflammatory hyperpigmentation, azelaic acid may be a good
treatment option. The efficacy of tazarotene 0.1% cream for the treatment of
dyschromia associated with photoaging and for acne vulgaris may also be
beneficial, particularly in people with dark skin tone.[10]
Early and efficacious treatment of acne in patients with dark-toned skin helps
minimize pigmentary abnormalities.[11]
Other treatment modalities include use of trichloroacetic acid and gentle
cryotherapy with liquid nitrogen. Each method must be used with extreme
caution to avoid necrosis or blistering of the treated skin. These 2 methods of
treatment should be avoided in dark-skinned patients because of the risk of
permanent depigmentation and scarring.
Pigmented makeup creams have also been successfully used to camouflage
hyperpigmented skin to a hue similar to that of the surrounding unaffected skin.
More options will be available in the future. Retinaldehyde (RAL) has shown
depigmenting activity, while GA decreases the excess of pigment by a wounding
and reepithelization process. A combination of RAL 0.1% and GA 6% (Diacneal)
in the treatment of acne vulgaris and postinflammatory hyperpigmentation has
been reported.[12] The peroxidase inhibitor methimazole, a noncytotoxic inhibitor
of melanin production, is a possible agent for topical use in the years ahead. [13]
The efficacy and safety of a combined treatment regimen including serial GA
peels, topical azelaic acid cream, and adapalene gel in the treatment of
recalcitrant melasma was evaluated in 28 patients in a prospective, randomized,

controlled trial lasting 20 weeks. [14] Those receiving chemical peels underwent
serial GA peels in combination with topical azelaic acid 20% cream (twice daily)
and adapalene 0.1% gel (4 times daily, applied at night). Combined treatment
with serial GA peels, azelaic acid cream, and adapalene gel may be an effective
and safe therapy for recalcitrant melasma. Choi et al report that Lepidium
apetalum is a potential inhibitor of hyperpigmentation caused by UV radiation. [15]
Other studies suggest that decapeptide-12 was 17-fold more potent than
hydroquinone at inhibiting tyrosinase in vitro. . [16, 17] Decapeptide-12 was shown
not to be cytotoxic to melanocytes, making it a safer alternative to
hydroquinone. A pilot study by Hantash and Jimenez showed that twice a day
treatment for 4 months with decapeptide-12 formulated in a topical emulsion
also resulted in a 50% improvement in melasma in patients who had failed 6
months of Tri-Luma therapy.[17] The potential of decapeptide-12 as a therapeutic
option for melasma was recently reviewed.[18]
Depigmenting agents abound in a variety of formations. Aloe vera leaf extract
and its active ingredient aloin are considered potent skin depigmenting agents.
[19]
Delivery too can be important. Glabridin microsponge-loaded gel may be
beneficial in treating hyperpigmentation.[20]
Patients should never be treated with monobenzyl ether of hydroquinone
because of the risk of developing disfiguring depigmented patches of skin either
at the application site or at distal cutaneous sites.
Also see Skin Lightening and Depigmenting Agents
Surgical Care
Fractional photothermolysis may be used to treat postinflammatory
hyperpigmentation after or in conjunction with ablative carbon dioxide laser
resurfacing.[21, 22, 23] Paradoxically, successful treatment of postinflammatory
hyperpigmentation after two sessions of fractional carbon dioxide laser has been
described.[24] Laser treatment may be able to address dermal pigment deposition.
The 1064-nm Q-switched Nd:YAG laser with low-fluence treatment may be
considered in the treatment of postinflammatory hyperpigmentation caused by
procedures such as laser surgery and chemical peeling in Asian patients. [25]
The guideline from the British Association of Dermatologist, Guidelines for topical
photodynamic therapy: update,[23] may be of interest, as may Photodynamic
Therapy for the Dermatologist.
Medication Summary
Topical treatments include hydroquinone, azelaic acid, corticosteroids, tretinoin
cream, GA, and trichloroacetic acid.[26] Skin whitening products are used for

clinical treatment of postinflammatory hyperpigmentation. [27] They act at various

levels of melanin production in the skin, some being competitive inhibitors of
tyrosinase, while others inhibit the maturation of this enzyme or the transport of
melanosomes from melanocytes to surrounding keratinocytes. Soy products
containing serine protease inhibitors appear to have potential as a therapeutic
option
for
the
treatment
of
hyperpigmentation. [28] Postinflammatory
hyperpigmentation has also been treated using vitamin C with a full-face
iontophoresis mask and a mandelic/malic acid skin care regimen. [29] Extracts of
the tropical fern Polypodium leucotomos given orally may be beneficial as an
adjunctive approach.[30] Wide-spectrum sunscreens are an integral part of any
treatment regimen.
Winhoven et al reported successful therapy with oral isotretinoin in an Asian
patient.[31] Combined therapy using Q-switched ruby laser and cutaneous
bleaching with tretinoin and hydroquinone may be used for periorbital skin
hyperpigmentation in selected patients. [32] The efficacy and safety retinoids and
azelaic acid in individuals with a dark complexion has been demonstrated. [33]
Depigmenting Agents
Class Summary
These agents are used for gradual bleaching of hyperpigmented skin.
Hydroquinone (Alphaquin HP, Eldopaque Forte, Nuquin HP)
A 1,4-benzenediol that suppresses melanocyte metabolic processes, especially
enzymatic oxidation of tyrosine to 3,4-dihydroxyphenylamine. Exposure to sun
reverses effects and causes repigmentation.
Deterrence/Prevention
Patients with postinflammatory hyperpigmentation (PIH) should use sunscreen
on a daily basis to prevent any further darkening of lesions.
Prognosis
Postinflammatory hyperpigmentation tends to fade with time and therapy, as
previously discussed. Remnants of epidermal hyperpigmentation may persist for
indefinite periods, typically 6-12 months, after the initial inflammatory process
resolves. Dermal postinflammatory hyperpigmentation may even persist for
years.
Patient Education
Educate patients about the cause of postinflammatory hyperpigmentation,
prolonged therapy, and persistence of hyperpigmented lesions.

hydroquinone
Reduce Melanin Hyperpigmentation
Apply to affected areas and rub in thoroughly BID
Discontinue if no results after 2 mth
See also combo with fluocinolone and tretinoin
Adverse Effects
Frequency Not Defined
Mild skin irritation and sensitization (burning, stinging, and allergic dermatitis)
Dryness and fissuring of paranasal and infraorbital
Ochronosis
Colloid milium (after chronic use of up to 8 years)
Contraindications & Cautions
Contraindications
Hypersensitivity
Cautions
Contain sulfites that may cause allergic-type reactions
Avoid unecessary exposure to sunlight
Do not apply near eyes, to cut, abraded, or sunburned skin, after shaving or
using a depilatory agent; or over miliaria rubra (prickly heat)
Pharmacology
Mechanism of Action
Elicits reversible depigmentation of the skin by inhibiting enzymatic oxidation of
tyrosine to 3, 4-dihydroxyphenylalanine (DOPA); also suppresses other
melanocyte metabolic processes

Acanthosis nigricans ditandai dengan plak simetris, hiperpigmentasi, beludru

yang mungkin terjadi di hampir setiap lokasi tetapi paling sering muncul pada
daerah intertriginosa dari ketiak, pangkal paha, dan leher posterior. Posterior
leher adalah situs yang paling sering terkena pada anak-anak.
Acrochordons (tag kulit) sering ditemukan di sekitar daerah bencana. Kadangkadang, lesi acanthosis nigricans dapat hadir pada selaput lendir rongga mulut,
hidung dan laring mukosa, dan kerongkongan. Areola puting juga mungkin akan
terpengaruh. Keterlibatan mata, termasuk lesi papillomatous pada kelopak mata
dan konjungtiva, dapat terjadi. Perubahan kuku, seperti leukonikia dan
hiperkeratosis, telah dilaporkan.
Lesi nigricans acanthosis ganas secara klinis tidak dapat dibedakan dari
acanthosis nigricans jinak.

MELANOCYTOTIC EPIDERMAL HYPERMELANOSES

Lentigines are small, usually less than 5 mm in diameter, circumscribed, brown
to dark-brown to black, variegated to uniformly colored macules. They may be
found as isolated macules in sun-exposed areas or as multiple lesions on any
cutaneous surface, including the palms and soles. Lentigines are characterized
histologically by basilar hyperpigmentation with melanocyte proliferation in
elongated epidermal rete ridges. Syndromes with multiple lentigines in a
characteristic nonrandom pattern are know lentiginoses. Some lentiginoses have
a defined set of associated extracutaneous anomalies.
Lentigo simplex (See also Chap. 91)
Lentigo simplex is the term applied to isolated lentigines found on any cutaneous
site irrespective of UV exposure (Fig. 90-30). Apart from some lentiginoses,
there is no known genetic predisposition for lentigo simplex. Lentigo simplex also
can occur on the oral and genital mucosa. In the nail, lentigo simplex is a
possible cause of melanonychia striata longitudinalis.
Lentigo senilis et actinica, more commonly known as senile or actinic lentigo or
solar lentigo, is the term applied to lentigines induced by UV radiation (Fig. 9031). The prevalence of actinic lentigines is correlated with low-grade phototype
and increasing age. They are present in 90 percent of Caucasians older than 60
years. Sun-exposed areas, especially the face and hands, are involved. Their
diameters range from less than 1 mm to a few centimeters. They are usually
light brown, occasionally black. They may persist with minimal or no fading in
the absence of sun exposure. They differ from ephelides, which generally occur
in Caucasian children and fade or disappear when sun exposure is discontinued.
Specific variants include ink-spot lentigo, PUVA lentigo, sunbed lentigo. Ink-spot
lentigo is a variant characterized by its jet-black color and reticulated border.
PUVA lentigines are found in patients receiving extensive PUVA. Sunbed
lentigines have been described after the use of UVA sunbeds.

Vesikula dan bula dapat terjadi di lokasi yang berbeda pada lapisan kulit
1. Vesikel/bula intraepidermal atau suprabasal
a. spongiosis: vesikel atau bula yang terjadi karena proses spongiosis dimulai
dengan terjadinya edema interselular di antara sel-sel keratinosit yang terisi
cairan. Contoh: dermatitis kontak alergi (DKA)
b. degenerasi balon: vesikel atau bula terjadi karena proses degenerasi dimulai
dengan terjadinya edema intraselular biasanya karena adanya suatu proses
infeksi. Contoh: herpes zozter, herpes simplex
c. akantolisis: vesikel atau bula terjadi karena adanya proses akantolisis, yakni
hilangnya spina atau akanta atau jembatan antar sel, sehingga ikatan antara sel
menjadi hilang atau lepas, dan akhirnya akan terbentuk celah atau rongga yang
berisi cairan. Contoh: pemfigus
d. sub-corneal: vesikel atau bula terbentuk karena lepasnya stratum korneum
dari lapisan di bawahnya. Contoh: impetigo, miliaria kristalina
2.
Vesikel/bula
subepidermal
atau
infrabasal
atau
intradermal:
Vesikel atau bula infrabasal terjadi karena lepasnya lapisan basal dari membrana
basalis. Vesikel atau bula yang terbentuk biasanya akibat proses autoimun,
misalnya: bullous pemphigoid, dermatitis herpetiformis.