Skin diseases of the nipple and areola complex (NAC) are numerous and difficult to diagnose, which is a great challenge for clinicians (1, 2). A variety of NAC skin tumors often share similar clinical manifestations with inflammatory skin diseases, so they are easily missed or misdiagnosed (3, 4). In addition, because of the unusual location of the diseases, patients are often reluctant to see the doctor. Delayed treatment often greatly

affects the prognosis. Although histopathological examination can confirm the diagnosis, a skin biopsy may influence the appearance and function of the NAC (5). Therefore, a better understanding of the clinical features of NAC skin diseases is of great value for the correct diagnosis. To improve dermatologists’ understanding of the clinical features of NAC lesions, we retrospectively analyzed the demographic data, disease constitution, rash characteristics, and inconsistency between the clinical and pathological diagnosis from 260 patients. These patients had NAC skin diseases that were confirmed by skin histopathology at Peking Union Medical College Hospital from October 2012 to October 2022.

In this retrospective study, we included 260 patients with NAC lesions that were confirmed by skin histopathology at Peking Union Medical College Hospital, China, from October 2012 to October 2022. The demographic data, disease constitution, rash characteristics, and inconsistency between the clinical and pathological diagnosis were analyzed retrospectively. This study was approved by the ethics committee of Peking Union Medical College Hospital.

To the best of our knowledge, our study is the largest single-center study of NAC skin diseases to date. We retrospectively analyzed the demographic data, disease constitution, rash characteristics, and inconsistency between the clinical and pathological diagnosis from 260 patients with NAC lesions that were confirmed by histopathology at Peking Union Medical College Hospital. Cinotti et al. retrospectively analyzed clinical data from 131 patients with NAC lesions from 13 hospitals in Italy (6). Their study included the following patient distribution: three with MM, 15 with PD, 66 with melanocytic nevus, seven with melanosis, 16 with SK, ten with eczema, and 14 with miscellaneous lesion (three with AN, one with angioma, one with bullous pemphigoid, one with epidermal cyst, one with Fordyce spots, one with hematoma, two with melanoacanthoma, one with mycosis fungoides, one with pigmented Bowen disease, one with radiodermatitis, and one with xerosis). The reasons of different disease spectrum between this two studies may be due to different research purposes and inclusion criteria. Our study was mainly to analyze the disease constitution and clinical characteristics of NAC lesions, and all diagnoses were confirmed by skin histopathology. However, Cinotti et al. focused on analyzing dermoscopic and confocal microscopic features of NAC lesions, and the enrolled patients were confirmed by skin histopathology or greater than a 1-year follow-up.

In our study, the most common biopsied NAC skin diseases were eczema and PD. PD is a relatively rare breast disease with an incidence of 1–3% among all breast cancers, which is often manifested as intraductal carcinoma in situ or invasive ductal carcinoma (7, 8). Clinical manifestations include itching, erythema, scales, erosion, ulcer, bloody secretion, or nipple retraction (9, 10). In the early stages, PD is often misdiagnosed as eczema, resulting in delayed treatment. In our study, late onset, unilateral involvement and predilection for the nipple are several characteristics of PD, which are different from eczema.

It has been reported that an age of 40–50 years is the peak time for benign breast diseases, and the incidence of malignant breast diseases increases after menopause (11). In the present study, the disease constitution in young patients aged 0–18 years were eczema, melanocytic nevus, lentigo, and syphilis, all of whom had benign diseases. This suggests that dermoscopy and other non-invasive examinations should be the first choice for young patients, and invasive examinations such as skin biopsy should be minimized to avoid affecting the development of nipple and areola in adolescents (12). For malignant diseases, there were 80 patients with PD in the present study. Among them, 29 were patients aged 30–49 years, and premenopausal patients accounted for about 36% of these patients. There were nine patients with cutaneous metastasis of breast cancer, among whom eight patients were over 50 years old. This indicated that cutaneous metastasis of breast cancer was more common after menopause. Other malignancies in the present study included Bowen disease, MM, primary cutaneous CD30-positive large cell anaplastic lymphoma, and SCC, which occurred in patients who were 56, 46, 37, and 35 years old, respectively. The onset age of NAC malignancies in our study was earlier than that reported in the literature, suggesting that clinicians should be alert to the possibility of malignant NAC lesions in patients over 30 years of age.

There are many kinds of skin tumors that occur in the nipple and areola, including benign tumors and malignant tumors (13). Spyropoulou et al. reviewed 337 previous publications on benign tumors of the nipple, including neurofibroma, leiomyoma, milium, AN, syringomatous adenoma, nevoid hyperkeratosis, fibroma, pseudolymphoma, and hemangioma (11). Benign tumors in the present study also included SK, soft fibroma, melanoacanthoma, eccrine hidrocystoma, dilated pore, keloid, sebaceous gland hyperplasia, lentigo, and melanocytic nevus. Reported malignant tumors included breast cancer, PD, mycosis fungoides, cancer cutaneous metastasis, lymphoma, sarcoma, SCC, basal cell carcinoma, and MM (14, 15). The malignancies in our study included PD, breast cancer cutaneous metastasis, Bowen disease, SCC, MM, and primary cutaneous CD30-positive large-cell anaplastic lymphoma. Both benign and malignant tumors can manifest as pruritus, exudation, lichenification, erosion, and nodular hyperplasia. It is difficult to accurately diagnose using imaging, and histopathology is the golden standard.

In addition to neoplastic skin diseases, there are relatively few reports on other kinds of NAC skin diseases. Inflammatory and infectious NAC skin diseases include atopic dermatitis, contact dermatitis, radiation dermatitis, psoriasis, syphilis, wart, atypical mycobacteria infection, hidradenitis suppurativa, intertrigo, confluent and reticulated papillomatosis, Fox–Fordyce disease, and pyoderma gangrenosum (16). Special diseases found in the present study included lichen planus, lichen sclerosis, primary cutaneous amyloidosis, and pemphigus vulgaris, which were rarely reported in the literature.

There were 18 male patients in the present study, and their disease spectrum was significantly different from that of female patients. The NAC skin diseases in males are mainly benign. Benign masses in the male breast include gynecomastia, epidermoid cyst, lipoma, intraductal papilloma, pseudohemangiomatous stromal hyperplasia, granulosa cell tumor, hemangioma, schwannoma, myofibroblastoma, and fibromatosis (17). Malignant skin diseases in the male breast are rare. Breast cancer cutaneous metastasis (17), PD (18), and basal cell carcinoma (19) have been reported. Unlike other malignancies, basal cell carcinoma of the breast is more common in men compared with women, which may be related to the exposure to sunlight for the male chest (19).

Nipple and areola complex skin diseases are easily misdiagnosed clinically. In our study, 87.5% of patients diagnosed histologically as AN were clinically considered as other diseases. AN is a rare benign epithelial neoplasm that occurs in the papillary ducts, and it mainly affects women aged 43 to 45 years, although it has also been reported in men and adolescents (20). Clinically, AN often manifests as unilateral nipple erythema, swelling, erosion, and exudation, which needs to be distinguished from cutaneous metastasis of breast cancer, PD, and eczema (21). If the patient is misdiagnosed with a malignant tumor, the extent of surgical resection is much larger, and the harm is great (22).

Dermoscopy and reflectance confocal microscopy (RCM) are widely used techniques for the diagnosis of skin diseases, and their diagnostic performance for NAC lesions has recently been made (1). The dermoscopic and reflectance confocal microscopic characteristics of the most common four diseases in our study are presented in Table 5 and Supplementary Figure 2. The dermoscopic features of eczema are linear vessels, scattered dotted vessels, and yellow scales (8). Histopathologically, linear vessels correspond to dilated vessels in the dermis parallel to the skin surface, mostly located below the dermal papillary layer. Dotted vessels correspond to apical dilated vessels of the dermal papilla. Yellow scales correspond to parakeratosis and hyperkeratosis. The most frequent dermoscopic criteria of non-pigmented MPD are pink structureless areas, white lines, dotted vessels, erosion/ulceration and white scales. The most frequent dermoscopic criteria of pigmented MPD are gray granules/dots, pink structureless areas and white lines (8). Vessels at dermoscopy correlate with dilated vessels at histopathology, but their shape can differ because the epidermis can have a squamous or a papillomatous hyperplasia with a consequent different orientation of the underlying vessels (1). Multiple blue-gray dots (peppering) correspond to melanophages in the papillary dermis, while the white scar areas to fibrosis (23). The shiny white streaks, originally termed chrysalis-like structures. The lines are generally oriented parallel or orthogonally to each other. These structures represent new or remodeled collagen bundles (23). The dermoscopic features of AN are whitish/yellowish hyperkeratosis, cherry-red dotted and linear vessels on a pinkish background or increased red serpiginous and annular structures. Histopathologically, these dermoscopic characteristics correspond to luminal openings and remaining epidermis (24). Most cases of SK exhibit the typical dermoscopic findings of fissures and ridges, hairpin vessels with white halo, comedo-like openings, and milia-like cysts. Histopathologically, these dermoscopic characteristics correspond to papillomatous surface of the epidermis, enlarged capillaries of the dermal papillae, pseudohorn cysts in the epidermis opened to the surface of the lesion and intraepidermal cysts, respectively (25).

In conclusion, we presented a large single-center study of biopsied NAC skin diseases. Eczema and PD are the most common biopsied skin diseases of the NAC. Late onset, unilateral involvement, and predilection for the nipple are several characteristics of PD, which are different from eczema. NAC skin diseases are easily misdiagnosed clinically, especially AN. A better understanding of the clinical features of NAC skin diseases is of great value for the correct diagnosis.

The data analyzed in this study is subject to the following licenses/restrictions: The dataset is in the data system of Peking Union Medical College Hospital and cannot be exported or disclosed. Requests to access these datasets should be directed to Y-PZ, zengyueping0917@126.com.

The studies involving human participants were reviewed and approved by Ethics Committee of Peking Union Medical College Hospital. The patients/participants provided their written informed consent to participate in this study.

CW wrote the manuscript. Q-NJ and KF collected patients’ data. Y-PZ revised the manuscript. All authors contributed to the article and approved the submitted version.