Hyperkeratosis of the Nipple and Areola

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Background

Hyperkeratosis of the nipple and/or areola (HNA) is defined as excessive keratinization of the nipple and/or areola. Hyperkeratosis of the nipple and/or areola is characterized by hyperpigmented, verrucous or filiform, keratotic thickening of the nipple and/or areola, with a papillomatosis or velvety sensation to touch. Hyperkeratosis of the nipple and/or areola has classically been classified into the following three subsets[1, 2, 3] :

Perez-Izquierdo et al suggested an alternative classification, distinguishing two types: (1) those that are idiopathic or nevoid and (2) those that are secondary to other conditions.[4] Others have advocated that the term “nevoid” be replaced by “idiopathic”.[5, 6] Upon review of the literature, a recommended classification is into (1) primary hyperkeratosis of the nipple and/or areola, which is idiopathic,[7, 8, 9, 10, 11] and (2) secondary hyperkeratosis of the nipple and/or areola, which is associated with the following:

Pathophysiology

The pathophysiology of hyperkeratosis of the nipple and/or areola is unknown.

Epidemiology

Frequency

Hyperkeratosis of the nipple and/or areola is rare, and currently no domestic or international incidence rates have been documented in the literature.

Race

Hyperkeratosis of the nipple and/or areola has no reported racial predilection.

Sex

Hyperkeratosis of the nipple and/or areola is more common in females than in males. In a study of 45 primary hyperkeratosis of the nipple and/or areola patients 80% were females.[25]

Age

In females, hyperkeratosis of the nipple and/or areola most commonly occurs in those aged 10-40 years. Males with nevoid hyperkeratosis of the nipple and/or areola are often older than females, but no specific age distribution is reported.

Prognosis

Primary hyperkeratosis of the nipple and/or areola is not associated with mortality. The morbidity rate is low, and morbidity is primarily limited to the undesirable cosmetic results of the abnormal nipple and/or areola. The morbidity and mortality rates of secondary hyperkeratosis of the nipple and/or areola are those of the underlying diseases; thus, the rates with secondary hyperkeratosis of the nipple and/or areola may be greater than those with other types of hyperkeratosis of the nipple and/or areola.

Patient Education

Patient education of nevoid hyperkeratosis of the nipple and/or areola is important to help individuals understand their condition and to allow them to form realistic expectations regarding treatment. Patients should be warned that with topical preparations, a long period may pass before clinical improvement occurs. Treatment with an individual medication should be continued for at least 6 months before it is deemed a failure.

Lesions may recur after therapy is discontinued. In some patients, hyperkeratosis of the nipple and/or areola does not respond to any treatment.

History

The diagnosis of secondary hyperkeratosis of the nipple and/or areola is usually straightforward because the other cutaneous manifestations of the associated skin diseases that are the cause of the disease are apparent. Secondary hyperkeratosis of the nipple and/or areola associated with an epidermal nevus, organoid nevus, leiomyoma, or verruca usually involves only 1 nipple and/or areola. Secondary hyperkeratosis of the nipple and/or areola is bilateral when this clinical manifestation reflects the more widespread or systemic nature of the underlying disease. Women with unilateral primary hyperkeratosis of the nipple and/or areola lesions may have bilateral disease during pregnancy (secondary hyperkeratosis of the nipple and/or areola) Pregnancy may also produce thicker, darker lesions.

Primary hyperkeratosis of the nipple and/or areola is not associated with any underlying conditions and is an isolated finding. Skin biopsy findings may help confirm the diagnosis if it is unclear from the clinical presentation. Primary hyperkeratosis of the nipple and/or areola can occur unilaterally, but it most frequently affects both sides. In greater than 50% of the cases, primary hyperkeratosis of the nipple and/or areola affects both the nipple and areola. The cutaneous changes of nevoid hyperkeratosis of the nipple and/or areola are generally asymptomatic. Mild pruritus may result from poor hygiene. Most complaints reflect concern about the cosmetic appearance of the thickened hyperpigmented nipples and/or areolas.

Unilateral primary hyperkeratosis of the nipple and/or areola[14, 15, 26, 27] must be distinguished from an underlying breast carcinoma. Pain, bleeding, ulceration, a nipple discharge, or loss of normal anatomy with nipple retraction or loss of nipple should prompt immediate evaluation. Lesions recalcitrant to therapy also warrant investigation (ie, biopsy). The evaluation of these lesions should include complete bilateral breast examination with evaluation of the lymph nodes, mammography, and biopsy of the involved skin. Consultation with a surgical oncologist may be indicated if any of the above occurs.

The American Cancer Society has released 2012 guidelines for early detection of breast cancer.[28] These guidelines apply to women with the usual (average) risk for breast cancer and no symptoms of breast cancer. Older women or high-risk women (ie, family history of breast cancer) should discuss their risk factors with their doctor for more in-depth guidelines. For average-risk women, the guidelines are as follows:

Physical Examination

The affected nipple and/or areola are thickened and may be covered with hyperpigmented verrucous or filiform hyperkeratotic plaques (see the images below).



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An adult male with bilateral primary hyperkeratosis of the nipple and areola



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A close-up of the patient's right nipple/areola complex.



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A close up of the patient's nipple/areola complex.

No associated abnormalities of nipple and/or areola anatomy and underlying breast should be present.

Causes

The etiology of primary hyperkeratosis of the nipple and/or areola is unknown. The etiology of secondary hyperkeratosis of the nipple and/or areola is related to the underlying disorder.

Laboratory Studies

No blood or urine laboratory tests aid in the diagnosis of primary hyperkeratosis of the nipple and/or areola (HNA).

Imaging Studies

Imaging studies must be performed if any concern about underlying breast disease exists. Mammography should be performed, with or without ultrasonography. Ultrasonography of the nipple may demonstrate skin thickening.[29]

Other Tests

In cases of secondary hyperkeratosis of the nipple and/or areola, additional testing may be required. Malignant acanthosis nigricans associated hyperkeratosis of the nipple and/or areola requires possible endoscopy and/or colonoscopy and CT scanning. Cutaneous T-cell lymphoma–associated blood testing for clonality and CT scanning for staging may need to be performed.

Dermoscopy findings have mimicked a pigmented basal cell carcinoma in one case, with multiple blue-gray globules and leaflike areas.[30]

Procedures

The acquisition of a skin biopsy sample for histopathologic examination aids in differentiating nevoid hyperkeratosis of the nipple and/or areola from other conditions. The preferred method involves a 3- or 4-mm punch biopsy followed by closure with 6-0 Prolene sutures. An alternative suture material (eg, 5-0 or 6-0 plain gut [absorbable] suture) may be used if desired. This method provides the best cosmetic results, with minimal scarring and maintenance of the normal architecture of the nipple and/or areola.

Histologic Findings

Primary hyperkeratosis of the nipple and/or areola is characterized by variable orthokeratotic hyperkeratosis, slight acanthosis, and marked papillomatosis changes on routine hematoxylin and eosin–stained specimens. Additional findings reported include mild dermal lymphocytic perivascular inflammation[27, 31, 32] and epidermal spongiosis with microabscesses with normal lymphocytes.[33, 34] Histopathological features and an immunophenotype that paralleled those of mycosis fungoides have been reported.[34, 35] Immunostaining demonstrated epidermal infiltrate with CD3, a predominance of CD4 compared with CD8, and absence of CD7 expression. However, in both cases, no clonal T-cell population was identified.

In secondary hyperkeratosis of the nipple and/or areola, biopsy samples may reveal histologic findings related to the associated skin disease. An example includes cutaneous T-cell lymphoma–associated hyperkeratosis of the nipple and/or areola histology, which reveals epidermotropism with atypical lymphocytes.[17]

Approach Considerations

The clinical course of primary hyperkeratosis of the nipple and/or areola (HNA) is variable and often unpredictable. Many treatment modalities for primary hyperkeratosis of the nipple and/or areola have been used; however, the results of most are anecdotal and not verified in randomized, placebo-controlled clinical trials. In addition, reported results vary among individual patients and with various medications.

Surgery should be considered in cases in which the response to medical therapy is inadequate, for cosmetic reasons, and if there is an indication for concomitant surgery of the breast.[36]

Reported treatments of nevoid hyperkeratosis of the nipple and/or areola include the following:

Therapeutic options for secondary hyperkeratosis of the nipple and/or areola consist of the treatment options for the underlying dermatologic condition.[53]

Consultations

In some cases, consultation with a plastic surgeon may be appropriate.[46]

Long-Term Monitoring

The follow-up care for patients with primary hyperkeratosis of the nipple and/or areola (HNA) is based on the response to therapy and any change in the clinical presentation. A follow-up examination at 3-6 months after the initiation of therapy is reasonable. The patient should be instructed to return to the clinic immediately if any nipple discharge, nipple retraction, or palpable mass is present.

Monthly breast examinations are important for breast cancer surveillance, and they are mandatory for all patients with hyperkeratosis of the nipple and/or areola, especially if the disease is unilateral. Patients should be cautioned and educated not to attribute any changes in their breasts to the associated hyperkeratosis of the nipple and/or areola.

Author

Rabindranath Nambi, MD, Consulting Staff, Department of Dermatology, Dudley Group of Hospitals, UK

Disclosure: Nothing to disclose.

Specialty Editors

Michael J Wells, MD, FAAD, Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology

Disclosure: Nothing to disclose.

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Ivan D Camacho, MD, Dermatologist, Private Practice; Voluntary Assistant Professor of Dermatology, Department of Dermatology and Cutaneous Surgery, University of Miami, Leonard M Miller School of Medicine

Disclosure: Nothing to disclose.

Joshua R Freedman, MD, MS, Resident Physician, Department of Dermatology and Cutaneous Surgery, Jackson Memorial Hospital, University of Miami, Leonard M Miller School of Medicine

Disclosure: Nothing to disclose.

Kathryn Schwarzenberger, MD, Associate Professor of Medicine, Division of Dermatology, University of Vermont College of Medicine; Consulting Staff, Division of Dermatology, Fletcher Allen Health Care

Disclosure: Nothing to disclose.

Acknowledgements

Joseph C English III, MD Clinical Vice-Chairman for Quality and Innovation, Professor of Dermatology, Department of Dermatology, University of Pittsburgh School of Medicine

Joseph C English III, MD is a member of the following medical societies: American Academy of Dermatology and American Medical Association

Disclosure: Nothing to disclose.

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An adult male with bilateral primary hyperkeratosis of the nipple and areola

A close-up of the patient's right nipple/areola complex.

A close up of the patient's nipple/areola complex.

An adult male with bilateral primary hyperkeratosis of the nipple and areola

A close-up of the patient's right nipple/areola complex.

A close up of the patient's nipple/areola complex.