Sebaceous Hyperplasia

Background

Sebaceous hyperplasia is a common, benign condition of sebaceous glands in adults of middle age or older. Lesions can be single or multiple and manifest as yellowish, soft, small papules on the face (particularly nose, cheeks, and forehead). Sebaceous hyperplasia occasionally also occurs on the chest,^[1] areola,^[2] mouth,^[3] scrotum,^[4] foreskin,^[5] shaft of penis,^[6] and vulva.^{[7, 8, 9]} Rarely reported variants have included a giant form,^[10] a linear^[11] or zosteriform arrangement, a diffuse form, a nevoid form,^[12] and a familial form. Lesions of sebaceous hyperplasia are benign, with no known potential for malignant transformation, but they may be associated with nonmelanoma skin cancer in transplantation patients.^{[13, 14, 15]}

Typical facial papules appear in middle age, are larger than lesions on the areola or mouth, and display a central dell that corresponds to a central follicular infundibular ostium.

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Pathophysiology

Sebaceous glands are found throughout the skin except on the palms and soles. They exist as a component of the pilosebaceous unit or, less frequently, open directly to the epithelial surface in areas of modified skin, including the lips and buccal mucosa (as Fordyce spots), glans penis or clitoris (as Tyson glands), areolae (as Montgomery glands), and eyelids (as meibomian glands). The largest and greatest numbers of sebaceous glands are found on the face, chest, back, and the upper outer arms.

These holocrine glands are composed of acini attached to a common excretory duct. The life cycle of a sebocyte, the cells that form the sebaceous gland, begins at the periphery of the gland in the highly mitotic basal cell layer. As sebocytes differentiate and mature, they accumulate increasing amounts of lipid and migrate toward the central excretory duct. The mature sebocytes complete their life cycle at the central duct and disintegrate, releasing their lipid contents as sebum. The turnover time from sebocyte production to disintegration is approximately 1 month.

Sebaceous glands are highly androgen sensitive, and, although the number of sebaceous glands remains approximately the same throughout life, their activity and size vary according to age and circulating hormone levels. Together, sebaceous and sweat glands account for the vast majority of androgen metabolism in the skin.

Sebocytes contain androgen-metabolizing enzymes, including 5-alpha-reductase type I, 3-beta-hydroxysteroid dehydrogenase, and 17-beta-hydroxysteroid dehydrogenase type II. These enzymes metabolize relatively weak circulating androgens, such as dehydroepiandrosterone-sulfate, into the more potent androgens, such as dihydrotestosterone. These, in turn, bind to receptors within the sebocytes, causing an increase in the size and metabolic rate of the sebaceous gland. Studies have shown that the activity of 5-alpha-reductase is higher in the scalp and facial skin than in other areas, so that testosterone and dihydrotestosterone stimulate more sebaceous gland proliferation in these areas. Estrogens, on the other hand, have been found to decrease sebaceous gland secretion.

In the perinatal period, the sebaceous glands are initially large and are likely responsible for the production of vernix caseosa often seen in newborns. The activity and size of the sebaceous glands regress shortly after birth, due to withdrawal of maternal hormones, and remain small throughout infancy and childhood. At puberty, sebaceous glands enlarge and become increasingly active due to increased production of androgens, reaching their maximum by the third decade of life. As androgen levels decrease with advancing age, the sebocyte turnover begins to slow down.

This decrease in cellular turnover results in crowding of primitive sebocytes within the gland, resulting in enlargement. In contrast to normal sebocytes that are engorged with lipid, the hyperplastic sebaceous glands contain small undifferentiated sebocytes with large nuclei and scant cytoplasmic lipid.^{[16, 17, 18]}

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Etiology

Facial papular sebaceous hyperplasia is thought to be caused by a decrease in the circulating levels of androgen associated with aging. Ultraviolet radiation is considered only a cofactor, because sebaceous hyperplasia occasionally occurs on areas of the body where sunlight is not a relevant issue, including the buccal mucosa, areolae, and vulva.

A decrease in circulating androgen results in smaller sebocytes with larger nuclei and lower lipid content, which migrate slowly through the sebaceous gland. As migration and disintegration of the sebocytes slows, the gland becomes enlarged, with a widened sebaceous duct and an increased number of basal cells.

Sebaceous hyperplasia has also been linked to long-term immunosuppression in post-transplantation patients taking cyclosporin A. Although the mechanism for this reaction is poorly understood, it is thought to be specific to the lipophilic cyclosporin A, considering that other immunosuppressants have not been strongly associated with an increased prevalence of sebaceous hyperplasia. Occasionally, presentation is delayed for months after completion of cyclosporin therapy.^[19] In 2017, a case of eruptive sebaceous hyperplasia was reported in a renal transplant patient treated with the immunosuppressant tacrolimus.^[20]

Although more commonly found in the older population, premature or familial cases have been reported in which younger individuals are affected with multiple lesions, suggesting a genetic predisposition. In these cases of premature familial sebaceous hyperplasia, extensive eruptions appear at puberty and tend to progress with age.^{[16, 17, 18]}

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Epidemiology

Frequency

Sebaceous hyperplasia is a common skin finding in aging adults, reported to occur in approximately 1% of the healthy US population. However, the prevalence of sebaceous hyperplasia has been reported to be as high as 10-16% in patients receiving long-term immunosuppression with cyclosporin A.^{[21, 22, 23]}

Sex

The difference in prevalence between men and women is unknown.

Age

Sebaceous hyperplasia is common in newborns.^[24] Of 1000 consecutive neonates examined in an Iranian prospective cohort study, 43.7% had sebaceous hyperplasia.^[25]

Typical facial papules begin to appear in middle age (usually fifth or sixth decade) and continue to appear into later life.

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Prognosis

Sebaceous hyperplasia has no direct association with malignant degeneration and is not a cause of morbidity beyond cosmetic concerns. Sebaceous hyperplasia has been reported in association with internal malignancy in the setting of Muir-Torre syndrome. Muir-Torre syndrome is a rare autosomal dominant disorder in which visceral malignancies, sebaceous neoplasms (eg, sebaceous adenoma, sebaceous carcinoma), and keratoacanthoma coincide. Colon cancer is the leading internal malignancy associated with Muir-Torre syndrome, followed by hematologic malignancies.^[26] Sebaceous hyperplasia alone does not signify a predisposition to cancer or represent a sign of Muir-Torre syndrome.

One study reported that 29.9% of patients with a renal transplant had sebaceous hyperplasia, and that 45.7% of these patients had a history of nonmelanoma skin cancer (NMSC), compared with 7.3% of patients without sebaceous hyperplasia. In this population, the association of NMSC with sebaceous hyperplasia remained significant after correction of factors such as age, sex, skin type, and duration since transplantation.^[14] Thus, the presence of sebaceous hyperplasias in the setting of renal transplantation may serve as a marker for an elevated risk of NMSC.

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Patient Education

Patients should be educated that sebaceous hyperplasias are benign and that treatment is primarily for cosmetic benefit. 

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History

Patients may be concerned for cosmetic reasons or may be worried about possible malignancy. Lesions are usually described as asymptomatic, soft, discrete, and yellow, with a surface that ranges from smooth to slightly verrucous. Patients may report one or multiple lesions at various locations on the face. Lesions may become red and irritated and bleed after scratching, shaving, or other trauma.

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Physical Examination

Sebaceous hyperplasia is often found incidentally upon examination. The classic appearance of facial sebaceous hyperplasia on physical examination reveals whitish-yellow or skin-colored papules that are soft and vary in size from 2-9 mm. These papules have a central umbilication from which a very small globule of sebum can sometimes be expressed. Some papules may be associated with characteristics similar to basal cell carcinoma, such as telangiectasia.

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Typical distribution of sebaceous hyperplasia on the forehead in a middle-aged male.

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Close-up of typical sebaceous hyperplasia on the face (red arrows).

Depending on the variant, sebaceous hyperplasia may be found singularly, grouped (as in the nevoid and linear form), diffuse, or extensive. Juxtaclavicular beaded lines are an additional variant characterized by closely placed papules arranged in parallel rows within the skin of the neck and overlying the clavicle.^[27]

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Juxtaclavicular beaded lines, a variant of sebaceous hyperplasia, in an elderly man.

Dermoscopy may be useful as a noninvasive tool to aid in the clinical diagnosis and in distinguishing between nodular basal cell carcinoma and sebaceous hyperplasia, reducing unnecessary surgery.^{[28, 29, 30, 31]}

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Complications

Irritation or bleeding may occur if lesions are in an area prone to trauma (eg, friction by a comb or brush).

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Laboratory Studies

No laboratory studies are necessary. Biopsy is occasionally indicated to exclude basal cell carcinoma.

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Histologic Findings

These lesions reveal discrete, enlarged glands. Within each gland, mature sebaceous lobules or acini surround and connect to a dilated central sebaceous duct. The lobules have one or more basal cell layers at their periphery, with undifferentiated sebocytes that contain large nuclei and scant cytoplasmic lipid, in contrast to normal sebocytes, which are engorged with lipid.

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Normal sebaceous gland histology. Courtesy of Cooper Heard, MD.

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Histology of sebaceous hyperplasia; enlarged sebaceous gland with multiple lobules grouped around a central dilated sebaceous duct. Courtesy of Cooper....

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Medical Care

Sebaceous hyperplasia is completely benign and does not require treatment; however, lesions can be cosmetically unfavorable and sometimes bothersome when irritated. Treatments are mostly mechanical. Lesions tend to recur unless the entire unit is destroyed or excised. Risk of permanent scarring must be considered when treating benign lesions.

A biopsy may be necessary if concern exists that the lesion is a basal cell carcinoma.

Therapeutic options include photodynamic therapy (with combined use of 5-aminolevulinic acid and visible light),^{[32, 33]} cryotherapy (liquid nitrogen), cauterization or electrodesiccation,^[34] topical chemical treatments (eg, with bichloracetic acid or trichloroacetic acid),^[35] laser treatment (eg, with argon, carbon dioxide, or pulsed-dye laser),^{[36, 37]} shave excision, and excision. Complications of these nonspecific destructive therapies include atrophic scarring or transient dyspigmentation.

Oral isotretinoin has proven effective in clearing some lesions after 2-6 weeks of treatment, but lesions often recur upon discontinuation of therapy. However, several cases of sustained improvement or clearance after cessation of therapy were reported in 2016, following cumulative doses ranging from 40-60 mg/kg.^[38] Daily treatment doses range from 0.5 mg/kg/day to 1 mg/kg/day.^[38] Maintenance doses of oral isotretinoin ranging from 10-40 mg every other day or 0.05% isotretinoin gel (not marketed in the United States) is rarely indicated as a suppressive treatment for widespread disfiguring sebaceous hyperplasia, which recurs despite therapy.^{[17, 39]} Oral isotretinoin should be prescribed by a physician who is experienced in oral retinoid therapy and only for patients without contraindications and fully compliant with all restrictions on this medication. Other topical retinoids are considered less effective in treating this condition.

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Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

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Isotretinoin (Amnesteem, Claravis, Myorisan, Sotret)

• Dosing, Interactions, etc.

Clinical Context:  Isotretinoin is a synthetic 13-cis isomer of naturally occurring tretinoin (trans -retinoic acid). Both agents are structurally related to vitamin A.

It decreases sebaceous gland size and sebum production and may inhibit sebaceous gland differentiation and abnormal keratinization. Isotretinoin is used initially for severe cystic/scarring acne. Because of its action in reducing sebaceous gland size, it is used in sebaceous hyperplasia in lower doses than in acne.

The optimal dose and duration used to treat sebaceous hyperplasia not established. Clearance has been achieved within 2 weeks in some patients. Others may take longer. Recurrence within 1 month after stopping is common.

A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

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Class Summary

Isotretinoin has been used for sebaceous hyperplasia because of its ability to temporarily shrink sebaceous glands. Lesions return after discontinuation of therapy. Consider only for the most severe disfiguring cases in men or women who cannot become pregnant. Should only be prescribed by dermatologic experts in oral retinoid therapy.

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