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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 2  |  Page : 82-92

Drug-induced pigmentation


Department of Dermatology (Skin and STD), Jawaharlal Institute of Postgraduate Medical Education and Research, Gorimedu, Puducherry, India

Date of Submission28-Jul-2021
Date of Decision16-Mar-2022
Date of Acceptance19-Apr-2022
Date of Web Publication12-Aug-2022

Correspondence Address:
Dr. Laxmisha Chandrashekhar
Department of Dermatology (Skin and STD), Jawaharlal Institute of Postgraduate Medical Education and Research, Gorimedu, Puducherry-605006
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/pigmentinternational.pigmentinternational_

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  Abstract 


Around 10% to 20% of all cases of acquired hyperpigmentation are drug-induced. The underlying pathogenesis for drug-induced pigmentation includes melanin accumulation, drug accumulation, toxic effects on melanocytes, and hypersecretion of adrenocorticotropic hormone and melanocyte-stimulating hormone among others. A step-by-step approach might help the dermatologist to diagnose a case of drug-induced pigmentation. Initial history should include a list of drugs taken, duration of intake of each drug, dose of the drug, and latency between drug intake and the onset of pigmentation. Examination findings might reveal specific patterns of pigmentation such as fixed drug eruption, serpentine supravenous pigmentation, flagellate pigmentation, melasma-like pigmentation, or reticulate pigmentation. The color of the pigment also helps in making a diagnosis. Besides, examination of the mucosa, hair, nails, and teeth is also essential. The histopathological examination might reveal whether the color is due to the drug itself, melanin, lipofuscin, or hemosiderin. Special staining, examination under polarized light, and electron microscopy are useful adjuncts in making a diagnosis. Often, drug-induced pigmentation is a diagnosis of exclusion and requires evaluation for other causes of pigmentation. Treatment options for drug-induced pigmentation include lowering the dose or replacing the drug with an effective alternative. Photoprotection and sunscreens also play an important role in treatment. Knowledge of the various patterns of drug-induced pigmentation is essential for all dermatologists to manage this condition.

Keywords: Drug-induced, depigmentation, hyperpigmentation, hypopigmentation, pigmentation


How to cite this article:
Narayanan A, Chandrashekhar L. Drug-induced pigmentation. Pigment Int 2022;9:82-92

How to cite this URL:
Narayanan A, Chandrashekhar L. Drug-induced pigmentation. Pigment Int [serial online] 2022 [cited 2022 Sep 26];9:82-92. Available from: https://www.pigmentinternational.com/text.asp?2022/9/2/82/353670



Drug-induced pigmentation is an abnormal skin pigmentation caused by different drugs. The mechanisms vary from the accumulation of melanin to the synthesis of specific substances. Histological evaluation often reveals the presence of melanin or other substances within dermal macrophages. The difficulty in ruling out other causes of pigmentation makes diagnosing this condition difficult.


  Epidemiology Top


The incidence of drug-induced pigmentation is hard to assess. Around 10% to 20% of all cases of acquired pigmentation are probably drug-induced.[1] The incidence of chemotherapy-induced pigmentary changes is around 17% in skin and 21% in hair.[2] Heavy metal-induced pigmentation has become scarce due to decreased usage.


  Etiopathogenesis Top


The etiopathogenesis of drug-induced pigmentation involves multiple mechanisms.

Melanin accumulation can occur due to epidermal melanocyte stimulation by the drug. It can also occur due to nonspecific inflammation caused by the drug. The melanin may be present free in the dermis or within dermal melanophages. These dermal macrophages are usually arranged in a perivascular pattern. Pigmentation caused by this mechanism often worsens with sun exposure.

The drug can get accumulated in the skin and result in pigmentation. It gets accumulated within dermal macrophages or gets scattered in the dermis. Few drugs undergo chemical changes to newer types of particles before pigmentation occurs. For example, sunlight transforms few, large, invisible gold granules into many smaller particles.

The pathophysiology of anticancer therapy-induced pigmentation is multifactorial. Pigmentation may occur at sites of acute or chronic trauma due to increased local blood flow. The underlying pathogenesis may involve: i) direct toxic effect on melanocytes resulting in melanin synthesis, ii) hypersecretion of adrenocorticotropic hormone and melanocyte-stimulating hormone due to adrenal toxicity, iii) deficiency in tyrosinase inhibitors, formation of stable drug-melanin complexes, and iv) keratinocyte toxicity with or without photosensitivity.

The pigmentation appears between 1 week to several months of treatment initiation. Usually, the pigmentation lightens with the discontinuation of the drug. But, in a few cases, the pigmentation persists.

Tyrosine kinase inhibitors decrease skin pigmentation via c-KIT pathway blockade and PDGF inhibition. Paradoxical cases of imatinib- induced-hyperpigmentation are also reported.[3] CD8 T-cell pathway causes the development of vitiligo-like lesions after selective PD-1 inhibitors treatment. This is mediated by CD49a+ CD103+ CD8 TRM cells. Interestingly, it is speculated that these cells may provide durable immunity against melanoma. Ipilimumab causes pigmentary changes due to CTLA-4 inhibition and immune activation against melanocytes.

Minocycline induces pigmentation due to iron accumulation.[4] This occurs due to vascular damage and lysis of RBCs. Around 15% of patients on long-term minocycline therapy develop hyperpigmentation.[5] The four patterns of minocycline-induced pigmentation are as follows:

Type I – dark blue-black macules over post-acne scars/sites of previous inflammation

Type II – localized or diffuse hyperpigmentation away from the site of inflammation/infection

Type III – muddy skin syndrome presents with diffuse brown-gray pigmentation. There is a tendency for photo-aggravation

Type IV – hyperpigmentation of vermillion area of lower lip.


  Approach to drug-induced pigmentation Top


Dermatologists consider drug-induced pigmentation when a temporal association with drug use is present. Drug-induced pigmentation occurs over months to a year. Few pointers to help with making a diagnosis are presented in [Table 1].
Table 1 Pointers for drug-induced pigmentation

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1. History

The physician should start with a list of medications (including natural remedies, alternative medications, and over-the-counter medications) currently taken by the patient. For example, one should enquire regarding gold treatments among patients with rheumatoid arthritis.[6] Similarly, patients presenting with malignancy and subsequent pigmentation should raise the possibility of chemotherapeutic drug-induced pigmentation. The physician should make a note of the change in intensity with time and dose of the drug. For example, amiodarone-induced pigmentation exhibits a dose-dependent relationship.[7] There is attenuation of pigmentation after stopping the triggering drug.

2. Examination

A careful examination of the skin and mucous membrane must be undertaken. The distribution, pattern, and color can help us identify the triggering drug. We must also look for the involvement or sparing of mucosae, nails, and hair.

a) Patterns
  1. Specific patterns are seen in drug-induced pigmentation. They include oval, serpentine supravenous, flagellate, melasma-like, photo-distributed, and reticulate pigmentation.
  2. Round/oval: Fixed drug eruptions (FDE) start as an erythematous to oedematous plaque. At the onset, these lesions may have a dusky violaceous hue or a central blister. With time, these lesions resolve with round or oval hyperpigmentation [Figure 1]. Any well-defined, round to oval, pigmentation macule should raise the possibility of FDE. The common areas involved are lips and genitalia. The common drugs that cause FDE are NSAIDs, paracetamol, cotrimoxazole, and tetracyclines.
    Figure 1 Fixed drug eruption to NSAIDs (Courtesy: Dr Akash P Mustari)

    Click here to view
  3. Serpentine supravenous pattern of pigmentation starts as an erythematous eruption over the venous network and resolves with supravenous pigmentation. It was first observed with 5-fluorouracil [Figure 2].[8] It can also be seen with docetaxel-based chemotherapy [Figure 3]. The pigmentation improves once the patient stops taking the triggering drug. Hydroxychloroquine-induced pigmentation persists for a long time despite the cessation of the drug.[9] Treatment of leprosy with minocycline also resulted in a similar phenomenon.[10]
    Figure 2 Pigmentation seen in a serpentine supravenous pattern after 5-fluorouracil injection (Courtesy: Dr Akash P Mustari)

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    Figure 3 Pigmentation seen in a serpentine supravenous pattern after 5-fluorouracil injection

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  4. Flagellate pigmentation is a linear or streaked pigmentation seen with bleomycin [Figure 4].[11] Trastuzumab[12] and docetaxel[13] have also been reported to cause flagellate erythema.
    Figure 4 Linear pigmentation seen over the trunk after treatment with bleomycin

    Click here to view
  5. Melasma-like pigmentation over the forehead and convexities of the cheeks is seen following imatinib therapy. This pigmentation occurs 3 months after starting therapy.[14] This pattern has also been reported with phenytoin,[15] barbiturate, and oral contraceptive pills. Hydroquinone-induced ochronosis also presents a similar pigmentation pattern [Figure 5].[16] Drugs causing phototoxic or photoallergic reactions also result in melasma-like pigmentation.
    Figure 5 Ochronosis secondary to hydroquinone presenting over the malar area (Courtesy: Dr Prashant Bharti)

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  6. Photo-distributed pattern of pigmentation is reported with long-term use of phenothiazines and tricyclic antidepressants. Minocycline-induced pigmentation has a tendency for photo-aggravation. Amiodarone causes blue-gray or purple pigmentation over the sun-exposed areas.
  7. Reticulate hyperpigmentation over the face and neck is reported following diltiazem therapy.[17]


b) Color

The color of skin pigmentation might also throw light on the triggering drug.
  1. Red: Clofazimine [Figure 6] and rifampicin cause reddish discoloration of skin and mucosae. Rifampicin causes reddish discoloration of urine.
    Figure 6 Reddish-brown discoloration over the face after clofazimine intake (Courtesy: Dr Prashant Bharti)

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  2. Yellow: Mepacrine[18] and ß-carotene[19] cause yellow discoloration of the skin. Drugs causing jaundice might also result in yellow-orange discoloration when they cause jaundice.
  3. Blue: Hydroxyurea,[20] silver salts,[21] and iron salts[18] cause blue pigmentation of the skin. Drugs causing methemoglobinemia may also cause blue discoloration. This includes dapsone, chloroquine, and indoxacarb.[22]
  4. Blue-black to blue-gray: Minocycline,[5] hydroxychloroquine,[23] amiodarone,[24] diltiazem,[17] and hydroxyurea[18] can cause blue-black to blue-gray pigmentation. It is also seen after treatment with gold salts.[25]


c) Mucosae

Retigabine causes blue/purple discoloration of the hard palate.[26] Imatinib causes hyperpigmentation of the hard palate.[27] Pemetrexed, sorafenib, sunitinib, and eltrombopag generally spare the mucous membranes.[18]

d) Teeth

Minocycline causes gray-green discoloration of teeth.[18] Imatinib and cyclophosphamide can cause pigmentation over the teeth.[18]

e) Nails

Minocycline causes a blue discoloration of the nail bed sparing the lunula.[28] In contrast, hydroxyurea also causes blue lunula.[20] Hydroxyurea can also cause pigmentation of nails [Figure 7]. Antimalarials cause blue-brown discoloration of nails due to the deposition of melanin and hemosiderin. Chemotherapeutics like cyclophosphamide [Figure 8] cause blue chromonychia due to matrix melanocyte activation.[28] Docetaxel is known to cause a blue lunula [Figure 9]. Silver salts might also cause blue nails. Carotenemia, antimalarials,[29] and tetracyclines cause yellow discoloration of nails
Figure 7 Pigmentation of nails due to hydroxyurea

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Figure 8 Blue chromonychia following cyclophosphamide infusion

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Figure 9 Blue lunula following docetaxel infusion

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f) Hair

Chloroquine causes bleaching of blond, light, brown, and red hair. Chloroquine at doses over 250 mg once daily can cause scalp hair lightening.[30] Para-aminobenzoic acid causes the darkening of brown and grey hair.[31] Both lightening and darkening of hair occur after 5 to 10 months of valproic acid intake.[30] Imatinib also causes both hair depigmentation[32] and hair darkening.[33] Chemotherapeutic agents also cause hair discoloration besides alopecia. Cisplatin causes post-alopecia regrowth of both lighter and darker hair.[34] Hair regrowth posttreatment with sorafenib can be more pigmented than the original. Sunitinib is also associated with similar changes.[30]

3. Histological patterns

There are various histopathological features that provide a clue toward the diagnosis. Minocycline, amiodarone, and antimalarials get deposited in the skin. Often the pigmentation is not due to the drug itself. Different combinations of melanin, hemosiderin, and lipofuscin might be the cause of pigmentation. Lipofuscin deposition in dermal macrophages is present in clofazimine- and amiodarone-induced pigmentation. In ochronosis, fragmented collagen fibers are present in the superficial dermis. They appear in the form of crescentic, golden-brown clumps. The pigment may be present in the dermis, within vessels, or within sweat glands.
  1. Histopathology: Skin biopsies from argyria might look normal at first look. Higher magnification reveals many small black dots on the walls of the vessels. These dots are present around the eccrine glands. They may be present free in the dermis and/or connective tissue sheaths around follicles.[35] Silver deposits in dark ground microscopy appear in a “stars in heaven” pattern.[36] In chrysiasis, deposits of black round granules are seen in macrophages in a perivascular pattern. They are larger than silver granules. They are not deposited in membranes. Bismuth deposition in the dermis appears as small granules. There may be involvement of the basement membranes.[37]
  2. Special staining: Clofazimine-induced lipofuscin pigment stains positive with Mallory`s hemofuscin stain.[38] Minocycline-induced pigmentation stains positive with Masson-Fontana and Perl stain.[39] Antimalarial-induced pigmentation stains with Perl stain, although in a weak manner. Amiodarone-induced yellow-brown pigment granules (seen in macrophages) stain positive with periodic acid-Schiff stain.[40] Methylene blue gives the collagen fibers a dark blue-black color in ochronosis.
  3. Polarized light: Orange-red birefringence of gold particles under cross-polarized light helps identify gold particles. Diffractive microscopy is superior to light microscopy in argyria and imipramine pigmentation.[41]
  4. Electron microscopy: In minocycline-induced pigmentation, electron-dense particles are present both inside and outside the macrophages.[39] In amiodarone-induced pigmentation, “myelin-like bodies” are present.[40] “Myelin-like bodies” are intracytoplasmic lysosomal membrane-bound bodies. In ochronosis, electron microscopy reveals electron-dense deposits in the elastic fibers and interstitium. Electron microscopy of argyria reveals electron-dense deposits measuring around 100 to 500 nm.[42]


Evaluation for other causes of pigmentation is essential always. A detailed summary of all drugs implicated in drug-induced pigmentation is given in [Table 2].
Table 2 Clinical features of drug-induced pigmentations

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  Differential diagnosis Top


Drug-induced pigmentation may mimic various pigmentary conditions including endocrine or metabolic disturbances. Melasma presents as a brown discoloration, which is often confused with imatinib-induced pigmentation. A similar pattern is also reported with phenytoin and oral contraceptive pills. Addison disease may present with the pigmentation of the mucosa. The blue lunula is reported in Wilson disease.[28] Wilson disease or hemochromatosis are differential diagnosis in patients with blue-gray pigmentation. Vitamin deficiencies (nicotinic acid, vitamin B12) results in a photo-aggravated pigmentation.[43]


  Treatment Top


Often the treatment requires lowering the daily dose of the drug. With cytotoxic drugs, pigmentation is an aesthetic concern of a life-saving drug. This makes treatment more difficult in cases where the pigmentation is dose-dependent.

Photoprotection is an important modality to decrease drug-induced pigmentation. Topical tacrolimus has been tried in the treatment of drug-induced pigmentation.[44] The role of topical depigmenting agents in such conditions is doubtful. QS alexandrite laser has shown promise in desipramine-induced pigmentation. There was a concomitant decrease in pigment granules on light microscopy.[45]


  Conclusion Top


Drug-induced pigmentation remains an interesting and challenging phenomenon to diagnose for dermatologists. A thorough medical history and examination help in making a diagnosis. Knowledge of the existing literature is essential to making a diagnosis. Treatment of this condition is challenging. Photoprotection is the most important step in management.[86]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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