Table 1. Differential diagnosis of skin lesions of the nipple-areola complex.

PAS: periodic acid-Schiff; CK: cytokeratin; CEA: carcinoembryonic antigen; HER2/neu: human epidermal growth factor receptor 2; HMB: hydroxymethylbutyrate; HPE: histopathological examination; IHC: immunohistochemistry; MPD: mammary Paget’s disease; IgE: immunoglobulin E

[56-100]

Disease	Clinical features	Diagnostics
		HPE	IHC
MPD [44-54]	This disease may present with scaling, eczema, erythema, ulceration, erosion, hyperpigmentation of the nipple alveolar complex, and discharge preluding from the nipple.	In order to diagnose this disease an incisional biopsy that depicts ductal carcinoma must be performed. A biopsy will show PAS-positive mucin-containing vacuolated pagetoid cells.	Positive for CK 5/7, epithelial membrane protein, CEA, and HER2/neu overexpression.
Chronic eczema [55-61]	This disease may present with lichenification, erythema, and hyperpigmentation.	In order to diagnose this disease a patient's medical history must be analyzed as well as patients, symptom descriptions, familial history, triggers, and physical examinations.	Patch testing, skin biopsy, and blood tests indicate elevated levels of IgE antibodies.
Atopic dermatitis [56,57, 62-65]	This disease may present in the form of erythema, papules-vesicles, erosions, and pruritus.	In order to diagnose this disease a clinical examination must be performed as well as patient’s history should be taken into account. The following must be noted on the biopsy: irregular acanthosis, spongiosis, inflammatory cell infiltrate in the dermis, and elevated IgE levels.	-
Contact dermatitis [57,63-68]	This disease may present in the form of erythema, papules-vesicles, erosions, and pruritus.	In order to diagnose this disease clinicians must first identify the contacting agent and perform a patch test.	-
Psoriasis [69-73]	This disease may present with defined patches with erythema, scales, forms of infiltration, and pruritus.	In order to diagnose this disease a clinical examination must be performed, as well as a biopsy positive for regular acanthosis, hypogranulosis, Munro microabscesses, and Kojog´s pustules.	-
Bowen's disease [88-89]	This disease may present with patchy lesions, as well as slow growth, irregular borders, scaling, itching, and burning.	In order to diagnose this disease, a clinical examination must be performed as well as dermoscopy of irregular pigments, biopsies, and histopathological examination of biopsies.	-
Erosive adenomatosis of the nipple [87]	This disease often presents with ulcers on the surface of the nipple or areola, discharge pain, and itching.	In order to diagnose this disease a clinical examination as well as an analysis of the patient’s history, imaging studies, specifically mammography and breast ultrasounds. Lastly, a histopathological examination of a biopsy must be performed.	-
Nipple adenoma [53,54,77-84]	This disease often presents with firm nodules, crusting, or erosion of the nipple. Furthermore, the image seen in a mammography may depict sub-alveolar calcifications.	The diagnosis is determined via biopsy. The adenomatous proliferation of lactiferous ducts with surrounding myoepithelial cells without cellular atypia. There will be no PAS staining found on vacuolated cells.	Positive for CK 8/18 and p53.
Toker cell hyperplasia [74-76]	This disease often presents with enlargement or thickening of the nipple, papillomatous growth, color changes, itching, burning, nipple discharge, and hyperplastic changes in the ductal epithelium of the nipple.	The diagnosis is determined via biopsy. HPE: vacuolated pagetoid-like cells must stain positive for mucin with PAS without any cellular atypia. The stain may show normal or hyperplastic cells.	Positive for CK 7/8 and epithelial cell membrane antigen. Negative for p53 and HER2.
Malignant melanoma [51,53,54,97-100]	This disease often presents as a black ulcerative or crusting erosion of the nipple-areolar complex.	A biopsy is needed in order to differentiate pigmented varieties of MPD. HPE: melanin-containing cells in the epidermal layers with or without invasion. Stains that are negative for specific stains such as mucicarmine.	Positive for HMB, Melan B, S-100.
Invasive squamous cell carcinoma of the nipple [90,91]	This disease may present as scaly ulcerative lesions of the nipple alveolar complex.	A biopsy of the affected breast is needed for a definitive diagnosis. HPE - shows keratinizing and non-keratinizing epithelium in the absence of reactive epithelialization.	Positive for cytokeratin.
Basal cell carcinoma [92-95]	This disease may present as an ulcerative lesion of the nipple alveolar complex. This disease may also present with or without excoriation.	Pigmented basaloid cells in the epidermis extend to the dermis.	Positive for Ber-EP4.