REVIEW ARTICLE

Year : 2022  |  Volume : 9  |  Issue : 3  |  Page : 151-165

Perioral pigmentation

Siddharth Bhatt, Shekhar Neema, Biju Vasudevan
Department of Dermatology, AFMC, Pune, Maharashtra, India

Correspondence Address:
Dr. Shekhar Neema
Department of Dermatology, AFMC, Pune, Maharashtra
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/pigmentinternational.pigmentinternational_

ABSTRACT Perioral pigmentation is a commonly encountered condition in the skin Out Patient Department (OPD), occurring due to a variety of primary as well as secondary causes. The affection of the perioral skin being readily visible negatively impacts the patient’s quality of life. As the etiology of perioral pigmentation is multifactorial, treatment modalities vary according to the cause. The perioral skin, because of its location close to the mouth, is exposed to various allergens associated with food, saliva, toothpaste, cosmetics, etc., which can all lead to allergic manifestations resolving with pigmentation. Certain other dermatoses like melasma can first present with pigmentation over the perioral region. Infections like chikungunya and dengue and infestation with Demodex mite can also lead to pigmentation at this site. Perioral pigmentation can also be a marker of underlying systemic disease. Localized lentigines-like pigmentation can be associated with various cancer predisposition syndromes like Peutz-Jeghers syndrome. Diffuse pigmentation can occur due to Addison disease, vitamin deficiencies, or can be drug-induced. All these causes of pigmentation are seen more commonly in type IV and V skin. Currently, very little literature is available elucidating the cause of perioral pigmentation and the diagnostic approach. This article reviews the causes of perioral pigmentation and highlights their important features.

Keywords: Addison disease, erythrose peribuccale pigmentaire de Brocq, lip licker’s dermatitis, mustache melasma, perioral acanthosis nigricans, perioral dermatitis, perioral, Peutz-Jeghers syndrome, pigmentation, seborrheic melanosis

Introduction

Figure 1 Perioral area boundaries: 1. Skin boundary. Superior: inferior alar margin; inferior: superior border of the mental crease; 2. Lip boundary: lip anterior to stomion. Click here to view

Table 1 Causes of perioral pigmentation Click here to view

1. Disorders of focal hyperpigmentation
   1. Nonsyndromic
      1. Labial melanotic macule: It is a solitary well-demarcated dark brown macule located on the lower lip, generally seen in adult females. It has an irregular margin and the sizes can range from 1 to 8 mm. Color change over the lesion can cause confusion with melanoma, though luckily melanoma of the lips is a rare entity.^[1]
         
         Histopathological examination reveals increased basal pigmentation at the tip of rete ridges with mild perivascular infiltration and pigment incontinence at the level of the upper dermis. The number of melanocytes in the lesion are normal.^[2]
      2. Simple lentigines occurring in childhood can involve the lips [Figure 2]. It can be single, multiple, or agminated. Histopathology shows an increased number of melanocytes in the basal layer with elongated rete ridges but without any nest formation. Multiple labial lentigines can be seen as a part of lentiginosis syndrome which will be discussed in subsequent sections.

         Figure 2 Simple perioral lentigines. Click here to view

      3. Solar lentigines are commonly seen in fair-skinned elderly individuals and involve lips along with the skin. Histopathologically, it is characterized by an increased number of melanocytes with elongated, club-shaped, branched, or fused rete ridges. The epidermis in between the rete ridges is atrophic.
      4. Melanoacanthomas are rare benign lesions of the skin and mucosa occurring in adult dark-skinned individuals. It arises secondary to a traumatic stimulus and may resolve spontaneously. Histopathology shows acanthosis, basal hyperpigmentation, and dendritic melanocytes scattered throughout the thickness of the epithelium without any atypia.
      5. Malignancies: Melanoma of the lip is a rare entity that can range from a slow-growing inhomogeneous asymmetric patch to a rapidly enlarging mass with ulceration and bleeding over the lips. Mucosal melanomas are associated with a worse prognosis, having a 5-year survival rate of 5% as compared to their cutaneous counterparts.^[3] Other pigmented malignancies like pigmented Basal Cell Carcinoma (BCC), pigmented Bowen disease, and pigmented squamous cell carcinoma though rare can be seen over the lips and the surrounding skin.
      6. Flat warts occurring due to Human Papilloma Virus (HPV) 3 and 10 presenting as rapidly spreading flesh-colored to hyperpigmented papules can occur commonly over the perioral region due to the trauma induced by recurrent shaving in adult males. In children, warts over the perioral region can occur due to autoinoculation from warts on the fingers.^[4] Pigmented warts occur due to HPV 4, 60, and 65.^[5]
      7. Seborrheic keratosis and dermatosis papulosa nigra: Seborrheic keratosis is a common hyperpigmented hyperkeratotic nonmalignant epidermal tumor commonly occurring over the sun-exposed skin in adults. Dermatosis papulosa nigra is a common variant of seborrheic keratosis presenting as small, with 1 to 5 mm hyperpigmented papules of the sun-exposed site. Both of these conditions can occur over the perioral region.
   2. Lentiginosis syndromes
      
      Lentiginosis syndromes involving the skin around the perioral region can be divided based on the age of onset and the presence or absence of systemic symptoms.
      1. Onset in infancy without systemic symptoms: Inherited pattern of lentiginosis without any systemic involvement is an autosomal dominantly transmitted trait seen more commonly in African Americans. It is characterized by multiple lentigines in the centrofacial area including the lips and the oral mucosa. Other areas of involvement include buttock, elbow, hands, and feet.
      2. Onset in infancy with systemic symptoms: These include lentiginosis syndromes like: Peutz-Jeghers syndrome (PJS), Bandler syndrome, LEOPARD syndrome (lentigines, electrocardiogram conduction defects, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, sensorineural deafness), Carney complex, and centrofacial lentiginosis. All of the above conditions are inherited in an autosomal dominant fashion and start during infancy.
         1. PJS: It is characterized by the triad of mucocutaneous lentigines, hamartomatous intestinal polyps, and cancer predisposition. It occurs due to inherited or sporadically occurring mutation in the serine-threonine kinase 11 (STK11) tumor suppressor gene located in chromosome 19p13.3. Mucocutaneous hyperpigmentation starts in infancy with involvement of the perioral, periorbital, perinasal, and the perianal area. Similar hyperpigmented macules are also seen over the fingertips. These macules fade during puberty and adulthood.^[6] In a case series of 222 patients, perianal pigmentation was found in 94% of individuals, digital pigmentation in 73%, 65% had buccal mucosal pigmentation, while 21% had involvement at other sites.^[7] It is important to recognize these skin findings as the skin symptoms often predate the occurrence of the Gastro-Intestinal (GI) manifestations. The presence of skin lesions in an individual with a family history of PJS is diagnostic. The GI manifestations include hamartomatous polyps in the small intestine (jejunum, ileum, and duodenum: in decreasing order of incidence). Such polyps can also occur in the genitourinary system, lungs, intranasally, and gall bladder. These polyps can cause significant complications including intestinal obstruction, rectal prolapse, and GI bleeding. The malignancies associated with PJS include colorectal cancers arising from the adenomas, breast cancer, sex cord tumors with annular tubules, benign neoplasm of the ovaries, Sertoli cell tumor of the testes, adenoma malignum of the cervix, and pancreatic cancer. The overall chance of diagnosis of cancer by the age of 60 years is 55%.^[8] The individuals diagnosed with the condition should start surveillance with Upper Gastro-Intestinal (UGI) endoscopy and colonoscopy starting 8 years onwards. Regular surveillance for malignancy of other organs should also be done. Prophylactic mastectomy and hysterectomy with bilateral salpingo-oophorectomy may be considered to prevent gynecological malignancies.
         2. Carney complex: It is an autosomal dominant inherited condition occurring due to mutation in the PRKAR1A gene. Characteristic cutaneous manifestations include (i) lentigines over the centrofacial region, lips, oral mucosa, conjunctiva, inner and outer canthi, and genitalia. The lentigines occur during the peripubertal period and start to fade by the fourth decade; (ii) cutaneous or mucosal myxomas; (iii) blue nevi. Other manifestations like café au lait macule, skin tags, lipomas, and angiofibromas may occur but are not characteristic of the disorder. The various malignancies associated with the Carney complex include cardiac myxomas, breast myxomatosis, primary pigmented nodular adrenocortical disease, psammomatous melanotic schwannomas, growth hormone-producing pituitary adenomas, testicular Sertoli cell tumors, osteochondromyxoma, and thyroid cancer.
         3. Bandler syndrome: It is a lentiginosis syndrome involving the centrofacial skin, mucosa, and the fingers and is associated with intestinal vascular malformations.
         4. LEOPARD syndrome: It is an autosomal dominant inherited syndrome due to NSML gene mutation. Cutaneous manifestations are characterized by lentigines over the lips, face, neck, and upper trunk. Intraoral pigmentation is characteristically missing. Systemic manifestations include electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth retardation, and sensorineural deafness.
         5. Centrofacial lentiginosis: It is characterized by lentigines over the butterfly distribution (nose, cheeks) of the face along with upper lips, forehead, and eyelids. Systemic symptoms include bone abnormalities, dysraphism, endocrine disorders, and neuropsychiatric disorders.
      3. Onset in adolescence or adulthood without systemic symptoms
         1. Laugier–Hunziker syndrome: It is a rare acquired disorder characterized by the occurrence of lentigines over oral mucosa including the lips [Figure 3], fingers, along with longitudinal melanonychia. Though clear association is debated, some literatures mention an association with esophageal melanocytosis, actinic lichen planus, hypocellular marrow, and thrombocytopenia.^[9] It is an important differential of PJS in the childhood when GI manifestations of PJS have not yet occurred.

            Figure 3 Laugier–Hunziker syndrome. Click here to view

2. Disorders of diffuse hyperpigmentation
   1. Melasma of the upper lip (melasma mustache): Melasma is a common acquired pigmentary disorder of the face occurring more frequently in females with Fitzpatrick type IV/V skin. The centrofacial pattern of melasma which occurs in 64% of the patients can have involvement of the upper lip. This has also been termed mustache melasma [Figure 4].^[10] Significance of melasma at this location arises from the fact that it can often lead to confusion in diagnosis with other causes of PIH. A thorough history of any inflammation/injury at the site of hyperpigmentation can provide a clue to the diagnosis. Dermoscopy revealing sparing of the perifollicular region along with a pseudoreticular network can be a useful aid in diagnosis.^[11]

      Figure 4 Moustache Melasma. Click here to view

   2. Smoker’s melanosis: It is a brown to black colored pigmentation occurring on the lips, gums, and buccal mucosa of the smokers. It is postulated that mucosal melanin plays a role in the binding of toxic free radicals and polycyclic hydrocarbons and is hence upregulated in cases with chronic smoking.^[12] This increase in pigmentation by tobacco smoke is mediated through nuclear aryl carbon receptors which lead to increased microphthalmia-induced transcription factor (MITF) expression.^[13] This pigmentation generally subsides within 3 years of stopping smoking in most cases.^[14]
   3. Demodicosis: Demodicosis is defined as the presence of more than 5 mites/cm² in standardized skin surface biopsy. The presence of Demodex mites is mostly benign, in which case it involves the sebaceous hair follicles without any visible inflammation and appears as small projections from the pilosebaceous unit termed spinulate demodicosis. In a select few individuals, it can cause inflammatory dermatoses including papulopustular rosacea, perioral dermatitis, seborrheic dermatitis, blepharitis, etc. The facial involvement caused by demodicosis occurs mostly in the perioral and periocular regions. Therefore, any hyperpigmentation occurring in this region can lead to confusion with other differentials of hyperpigmentation. Pigmentation occurring due to demodicosis can be of various types. Firstly, it can be a smudgy brownish pigmentation occurring at the root of the cilia infested by the Demodex mites.^[15] Secondly, it can occur due to lichenification of the skin because of chronic itching of lesions of demodicosis. Thirdly, it can be due to PIH as a sequela of inflammatory disorders.^[16]
      
      Apart from depigmenting, therapy management of demodicosis requires prescription of acaricidal medications like ivermectin (0.2 mg/kg single dose), 5% permethrin, benzyl benzoate, and crotamiton lotion.^[17]
   4. Perioral acanthosis nigricans: Acanthosis nigricans is a dermatoses characterized by darkening and velvety papillomatous overgrowth of the epidermis. It is predominantly linked to insulin resistance, diabetes, obesity, and metabolic syndrome. Other etiologies include drugs, hereditary, syndromic, and malignancies. Though most common sites include neck, axilla, groin, and inframammary regions. A case of perioral acanthosis nigricans associated with metabolic syndrome resolving with metformin tablet has been reported in literature [Figure 5].^[18]

      Figure 5 Perioral acanthosis nigricans. Click here to view

   5. Post-inflammatory hyperpigmentation: It can occur either due to overproduction of melanin or due to dispersion of the pigment because of cutaneous inflammation in the dermis. Epidermal pigmentation occurs due to increased production or transfer of melanin to the surrounding keratinocytes. This is stimulated by prostanoids, cytokines, chemokines, reactive oxygen species, and other inflammatory mediators released during inflammation. Epidermal melanosis gives a tan, brown, or dark brown colour to the skin. Dermal inflammation on the other hand occurs when damaged keratinocytes release melanin which is phagocytosed by the macrophages giving a bluish-grey hue to the overlying skin^[19] [Figure 6]

      Figure 6 Post-inflammatory hyperpigmentation (post-Systemic Lupus Erythematosus). Click here to view

      1. Lip licker’s dermatitis: Lip licker’s dermatitis is an eczematous reaction occurring due to chronic contact with saliva. The constant drying and wetting cycle due to saliva disrupts the normal skin barrier and leads to inflammation. This ongoing inflammation drives further lip-licking perpetuating the cycle. It is commonly seen in school-going children and is found associated with impulse control disorder.^[20] When seen in adults, it is often associated with systemic disorders like Sjögren syndrome or neurological abnormalities.^[21] Some authors consider this to be a variant of atopic dermatitis.^[22] It is characterized by chronic red, dry, scaly lesions typically occurring in the distribution that corresponds to the reach of the patient’s tongue. Chronic inflammation in and around the region often leads to PIH.^[23],[24] Management includes behavioral modification along with emollients. Topical steroids and calcineurin inhibitors can be used to arrest ongoing inflammation.
      2. Seborrheic melanosis: It is used to describe the localized hyperpigmentation over the alar grooves and labiomental crease, occurring probably as a sequela of seborrheic dermatitis prevalent at these sites [Figure 7] and [Figure 8]. It is found more commonly in women. It is rare in children due to a relative lack of sebum. Often, the underlying signs of inflammation are missed by the patient in type 4 and 5 skin and the patient presents directly with skin pigmentation. A characteristic sign described in the literature is the lightening of pigmentation over the lower lip on stretching the skin or on asking the patient to purse the lower lip. This occurs due to the shadow effect over the labiomental fold caused by the overhanging lower lip. Dermoscopic examination reveals arborizing vessels, yellow scales over a light pink background, and helps to delineate the underlying pathology of seborrheic dermatitis. Pigmentary changes seen dermoscopically like the presence of thickened pseudonetwork, annular granular structure with brown dots substantiate the epidermal source of the pigmentation. This condition readily resolves with topical steroids and calcineurin inhibitors with the resolution of inflammation, burning, and lightening of the pigmentation. Topical bleaching agents like hydroquinone and kojic acid are less effective in treating the condition.^[25]

         Figure 7 Seborrheic melanosis (note the involvement of nasolabial folds and labiomental crease). Click here to view

         Figure 8 Seborrheic melanosis. Click here to view

      3. Perioral dermatitis: Perioral pigmentation is a subset of periorificial dermatitis occurring due to multiple etiologies, affecting areas surrounding the mouth with multiple inflammatory papules and vesicles with characteristic sparing of the vermillion border of the lip [Figure 9]. It affects adult females more commonly. It is commonly associated with topical steroid abuse, especially fluorinated steroids. Possible pathology behind this occurrence is the altered microbial flora with steroid usage. Other etiologies include fluorinated toothpaste, infections with Candida, Malassezia, and hormonal changes associated with pregnancy. These lesions often resolve with post-inflammatory pigmentation.^[24]

         Figure 9 Perioral dermatitis (note the sparing of the vermillion border of lip). Click here to view

      4. Perioral dermatitis in association with topical steroid abuse has been variously termed as topical steroid-induced perioral dermatitis (TOP STRIPED) or topical steroid-induced rosacea-like dermatitis (TOP SIDE RED) in literature.^[26] It classically occurs over the angles of lips and the ala of the nose and is associated with the overuse of topical steroids. It is characterized by flare-up of the inflammation on stopping the application of topical steroids after their long-term use. Later on, the lesions persist despite the usage of steroids.
         
         Management includes either stoppage or slow tapering of the topical steroid. Along with that topical calcineurin inhibitors, metronidazole, and clindamycin have been tried to control the flares.^[26] Oral tetracyclines like doxycycline (100 mg once a day) or minocycline (100 mg once a day) can be tried for 8 to 12 weeks. In recalcitrant cases, isotretinoin can be given starting at 0.2 mg/kg and then gradually tapering by 0.05 mg/kg to 0.1 mg/kg monthly.
      5. Erythrose peribuccale pigmentaire de Brocq: This disorder is characterized by hyperpigmentation surrounding the mouth likely due to certain photosensitive substances found in the cosmetics. It commonly occurs in the middle-aged women and is characterized by diffuse brown-red colored pigmentation present symmetrically around the mouth with characteristic sparing of the vermillion border. It may extend to the temples, forehead, and the angles of the jaw [Figure 10]. The erythema fluctuates but the pigmentation remains persistent unless the offending agent is removed.^[27]

         Figure 10 Erythrose peribuccale pigmentaire de Brocq. Click here to view

      6. Atopic dermatitis: Cheilitis forms a part of the minor criteria for diagnosis of atopic dermatitis formulated by Hanifin and Rajka. It is characterized by itching, hyperemia, dryness, tightness, cracking, and peeling of the surface of lips and corners of the mouth [Figure 11]. It can be associated with other symptoms of atopic dermatitis in 42.5% of patients or can be an isolated symptom of atopic dermatitis in 43.8% of the patients. It is more common in children of the age group of 7 to 11 years (51.7%). Respiratory allergies are also more common in children with atopic dermatitis with cheilitis as compared to those who do not have cheilitis (67.8% versus 50%).^[28] In moderate to severe forms, cheilitis is associated with lichenification of the skin. A significant increase in salivary Immunoglobulin E (IgE) levels is found in children with atopic dermatitis which is 10 folds higher than in healthy children. This might lead to an IgE-mediated sensitization of the cell membranes and inflammation of the lips and perioral region. Pro-inflammatory Interleukin(IL)-8 and Tumour Necrosis Factor(TNF)-alpha are also found to be increased in the saliva of atopic children. There is a significant decrease in lysozyme concentration in atopic children with cheilitis as compared to the atopic children who do not have cheilitis, emphasizing the role of disturbances in barrier immunity in the formation of cheilitis. The dominant organism detected is Staphylococcus aureus.^[28] Along with barrier creams and topical anti-inflammatory agents, oral drugs containing bacterial lysates and lysozyme have shown a good therapeutic effect.^[28]

         Figure 11 Atopic dermatitis. Click here to view

      7. Pigmented contact cheilitis: It is a reaction of the lips to an irritant or allergen leading to brown-black discoloration. Various causes postulated for the same include lipsticks containing isopalmityl diglyceryl sebacate, ricinoleic acid, dipentaerythritol fatty acid ester, ester gum, coal tar dyes, and other 1-phenylazo-2-naphthol derivatives. ^[29,[30] Hair dyes when applied to the moustache, due to paraphenylenediamine can also lead to pigmented contact dermatitis.^[31] Consumption of green tea has also been associated with allergic contact dermatitis of the lips due to the relatively high levels of nickel present in it.^[32] Initially, on the application of the product there is itching, burning, and swelling of the lips which may later resolve with purplish-black discoloration. The site of the hyperpigmentation may provide a clue toward the etiology. Pigmentation over the tips of the lips occurs in nickel allergy with green tea consumption, while pigmentation over the vermillion border is seen with allergens in the lipstick. Patch testing or open application tests can be done for suspected chemicals. Treatment involves avoidance of the offending agent along with topical immunosuppression for active inflammation. Pigmentation generally fades with avoidance but topical depigmenting agents can be given to hasten the process.
      8. Infections:
         1. Chikungunya: It is a self-limiting vector-borne viral infection caused by the arbovirus and transmitted by the Aedes mosquito. It is characterized by sudden onset of fever, joint pain, myalgia, headache, vomiting, and various types of cutaneous lesions. Cutaneous lesions generally appear 4 to 5 days after recovery of the fever. The different types of cutaneous lesions include maculopapular rash, vesicular rash, and hyperpigmentation. Centrofacial hyperpigmentation occurring over the nose and the cheeks is the most common cutaneous presentation of chikungunya. This pigmentation can be of various types including freckle-like, diffuse pigmentation of the face, pinna, and extremities, flagellate pigmentation, and pigmentation of existing acne lesions. Pigmentation over the tip of the nose has been termed as “chik sign.” The pathogenesis for this pigmentation is still unclear. Post-inflammatory pigmentation or increased intraepidermal melanin dispersions/retention triggered by the virus are currently postulated mechanisms.^[33]
         2. Dengue fever: Similar pigmentation over the centrofacial region has also been seen with dengue.^[34]
   6. Endocrine causes: Various endocrine disorders showing oral pigmentation include Addison disease, Cushing disease, Albright disease, acromegaly, and Nelson syndrome.
      
      Addison disease occurs due to adrenocortical suppression. Both primary and secondary causes of Addison disease can lead to diffuse bronze-colored pigmentation of the sun-exposed areas. This pigmentation is one of the earliest signs of the disease. It occurs due to increased secretion of melanotropic hormone along with adrenocorticotrophic hormone (ACTH). Apart from the oral pigmentation, pigmentation over the genital mucosa, flexural areas, and areas of friction and pressure is also seen with Addison disease though no single pattern of pigmentation is pathognomonic.
      
      Acromegaly results from excess growth hormone production by the pituitary gland due to a pituitary tumor. The pattern of pigmentation is similar to that found in Addison disease along the oral and genital mucosa, flexural creases, and previous scars.
      
      Cushing disease can also cause pigmentation in the same pattern as seen in Addison disease due to increased melanocyte-stimulating hormone (MSH) secretion along with ACTH. A similar secondary increase in the MSH along with ACTH can be seen in cases of adrenalectomy known as Nelson syndrome. Similar, Addisonian pattern pigmentation is also seen in cases of untreated chronic active hyperthyroidism.
   7. Vitamin deficiency: Vitamin B12 deficiency can cause mucocutaneous pigmentation involving the knuckle pads and oral mucosa. Recurrent angular stomatitis associated with the deficiency can resolve with hyperpigmentation of the angles of the mouth. Often vitamin B12 deficiency can masquerade Addisonian pigmentation.^[35] The pathogenesis behind pigmentation with vitamin B12 deficiency is associated with decreased concentration of reduced glutathione. Normally, glutathione has a tyrosinase-inhibiting effect, so the absence of reduced glutathione increases pigmentation. Pigmentation similar to that seen in vitamin B12 deficiency is also seen with folate deficiency.^[36] These causes of hyperpigmentation readily resolve on supplementation of the concerned vitamin.
   8. Drug-induced pigmentation: Drug-induced pigmentation is another important cause of perioral pigmentation. It causes pigmentation by a variety of mechanisms that are specific to the offending drug. Fixed drug eruptions can commonly involve the lip and the surrounding skin. In a study of 125 patients with fixed drug eruptions, involvement of lip was seen in 20.8% of individuals [Figure 12].^[37] It presents with slate brown-colored pigmentation or bluish-gray color due to pigment incontinence of the melanophages in the upper layer of the dermis.

      Figure 12 Fixed drug eruption. Click here to view

      
      
      Various other drugs like antimalarials, tetracycline, antipsychotics, zidovudine, and heavy metals like silver and gold lead to pigmentation over the photoexposed sites of the face. Oral contraceptive pills can exacerbate melasma and lead to increased pigmentation. Other drugs like clofazimine [Figure 13] can lead to a reversible diffuse mucocutaneous pigmentation all over the body due to drug deposition.

      Figure 13 Clofazimine-induced pigmentation. Click here to view

Treatment

Table 2 Treatment strategies according to causes of pigmentation Click here to view

Conclusion

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