Hyperkeratosis of the Nipple and Areola

Etiology

Hyperkeratosis of the nipple and areola has no known etiology. However, some reported cases seem drug-induced, especially due to estrogens (for prostatic cancer), spironolactone, and certain anticancer medications, such as vemurafenib. No viral deoxyribonucleic acid is found within skin lesions of hyperkeratosis of the nipple and areola.[4][5][6]

Epidemiology

Hyperkeratosis of the nipple and areola may be observed in both sexes. However, about 80% of the reported cases occur in women, mainly in the second or third decade of life. About 150 cases of hyperkeratosis of the nipple and/or areola have been reported to date. Nevertheless, the prevalence of this condition is likely underestimated because the skin lesions are usually asymptomatic, and, subsequently, there may not be sufficient motivation for affected persons to seek medical care.[7][8]

Pathophysiology

Hyperkeratosis of the nipple and areola has an unclear pathophysiology. This condition occurrs mostly in women after puberty, its exacerbation during pregnancy, and its improvement after delivery, as well as its occurrence in some males during estrogen therapy, are suggestive of an important role played by hormones in the genesis of this condition.

Histopathology

On histopathological examination, hyperkeratosis of the nipple and areola exhibits orthokeratotic hyperkeratosis, filiform acanthosis, papillomatosis, and keratin plugging. There is also hyperpigmentation and elongated interconnected rete ridges. In the dermis, perivascular lymphocytic infiltration is frequently observed. These findings are nonspecific of hyperkeratosis of the nipple and areola as they may be observed in other dermatoses such as acanthosis nigricans, seborrheic keratosis, and epidermal nevus. Four reported cases of hyperkeratosis of the nipple and areola exhibited, in addition to the classic histological features, epidermal lymphocytic infiltrates mimicking Pautrier abscesses usually seen in mycosis fungoides. In these patients, no other cutaneous changes ordinarily found in mycosis fungoides could be seen.

History and Physical

Hyperkeratosis of the nipple and areola may be unilateral or bilateral. This condition may affect only the nipple, areola, or both. Rarely, hyperkeratotic patches may extend beyond the areolar region. The skin lesions are usually painless, with no discharge or associated lymphadenopathy. However, pruritus may be present in some patients. In men under estrogen therapy, gynecomastia may be observed in association with hyperkeratosis of the nipple and areola.

Hyperkeratosis of the nipple and areola occurs during puberty or pregnancy. There is usually diffuse pigmentation and a warty thickening of the nipples and/or areolae. Skin lesions may become darker and thicker during pregnancy and tend to improve after delivery. The skin thickening is variable from a simple hyperkeratosis to a tumoral aspect. In some women, breastfeeding may become impossible because of nipple lesions. No prepubertal onset of hyperkeratosis of the nipple and areola has been observed.

The classification initially proposed by Levy-Franckel divides hyperkeratosis of the nipple and areola into 3 types: (1) epidermal nevus, with unilateral involvement of a single breast, usually in a Blaschko linear pattern (observed equally in both genders); (2) hyperkeratosis of the nipple and areola associated with ichthyosis, with bilateral involvement of the breasts (observed equally in both genders); and (3) a bilateral type, generally affecting both nipples and areolae and observed mainly in females in the second or third decade of life.

A more recent classification divides hyperkeratosis of the nipple and areola into 2 types: (1) a primary or idiopathic type, and (2) a secondary type associated with another skin condition such as a naevi structure (mainly epidermal nevus but also organoid nevus leiomyomas) or a warty tumor (verruca, seborrheic keratosis), as well as ichthyosis, chronic eczema (including atopic dermatitis), Darier disease, acanthosis nigricans, terra firma dermatitis, reticulate and confluent papillomatosis, and cutaneous T-cell lymphoma. This second type of hyperkeratosis of the nipple and areola also includes breast lesions developed in pregnant women and males receiving estrogen therapy. In pregnant women, some physiological changes of the breast (such as pigmentation and nipple and areola enlargement) should be considered in the differential diagnosis of hyperkeratosis of the nipple and areola. There may be a challenging differentiating the idiopathic type of hyperkeratosis of the nipple and areola from the secondary type. The diagnosis is difficult as the histological aspects are similar, such as seborrheic keratosis, acanthosis nigricans, and epidermal nevus.

Seborrheic keratosis shares similar histological features with hyperkeratosis of the nipple and areola, and the diagnosis of seborrheic keratosis is likely if the papillomatous papules are well delimited. Furthermore, in seborrheic keratosis, discrete fibrosis of the upper dermis is usually observed on histological examination. Acanthosis nigricans may have a similar histological aspect as hyperkeratosis of the nipple and areola; however, it involves mainly flexural areas and is often associated with metabolic disorders. Epidermal nevus is usually unilateral and spreads beyond the areolar region, frequently following a Blashcko linear pattern.

Evaluation

Mammography and breast ultrasound examination are usually without anomalies in hyperkeratosis of the nipple and areola.

Treatment / Management

Hyperkeratosis of the nipple and areola does not resolve without treatment and tends to persist indefinitely. Various medical or surgical treatments may be indicated in this condition. Keratolytic topicals (salicylic acid, lactic acid) are first-line treatments. Nevertheless, they are rarely sufficient. Topical corticosteroids have almost no effect, even if they may relieve pruritus. Topical retinoids such as tretinoin 0.05% and isotretinoin have been used with little success. Calcipotriol, a topical vitamin D analog that regulates skin proliferation and differentiation, is poorly efficient. Topical hydroquinone combined with kojic acid may improve hyperpigmentation of the breast; however, no effect is obtained on hyperkeratosis. Systemic retinoids (etretinate, acitretin) were inefficient when used.

Physical destructive treatments, such as cryotherapy with liquid nitrogen and carbon dioxide laser, give more satisfactory results. Surgical excision is another possible therapy. Surgical options include shave excision, curettage, and areola removal, followed by skin graft reconstruction. Tangential excision using a radiofrequency surgical device was used in cutting mode in 2 female patients, with no recurrence after 7 to 9 months.

Differential Diagnosis

The differential diagnoses for hyperkeratosis of the nipple and areola include the following:

• Fox Fordyce disease
• Hyperkeratosis secondary to prolonged friction
• Mycosis fungoides involving the nipple and areola
• Pigmented basal cell carcinoma
• Seborrheic keratosis