Nipple adenoma in a female patient presenting with persistent erythema of the right nipple skin: case report, review of the literature, clinical implications, and relevancy to health care providers who evaluate and treat patients with dermatologic conditions of the breast skin

NA is a benign proliferative process of lactiferous ducts of the nipple [2‐130]. Historically, NA has been known by a variety of other names in the literature, including nipple duct adenoma, papillary adenoma of the nipple, florid papillomatosis of the nipple, florid adenomatosis of the nipple, erosive adenomatosis of the nipple, papillomatosis of the nipple, subareolar sclerosing duct hyperplasia of the nipple, subareolar duct papillomatosis of the nipple, and superficial papillary adenomatosis of the nipple. NA was first described by Jones [3] in 1955 as “florid papillomatosis of the nipple ducts”. Ten years later in 1965, Taylor and Robertson [15] argued that the name “adenoma of the nipple” be used to describe such tumors with adenomatous proliferation into nipple stroma with little to no proliferation into the lumen of the nipple ducts. They differentiated an adenoma of the nipple as a separate process from that of ductal papillomatosis of the nipple [15]. Later on in 1972, in a report of 65 patients, Perzin and Lattes [26] argued for the name “papillary adenoma of the nipple” to describe what had previously been reported as florid papillomatosis of the nipple, adenoma of the nipple, florid adenomatosis of the nipple, subareolar duct papillomatosis of the nipple, and erosive adenomatosis of the nipple. After decades of reporting on this entity of the nipple in a fashion that has both separated and lumped the various suggested terminologies, the current accepted definition decided upon by the 2012 WHO classification of breast tumors was designated as “nipple adenoma” (NA) [2].

Histologically, NA can appear similar to other breast conditions (including syringomatous adenoma of the nipple, intraductal papilloma, adenomyoepithelioma, ductal carcinoma in situ, and invasive ductal carcinoma) as well as several dermatologic lesions (including syringoma of the skin, hidradenoma papilliferum, and syringocystadenoma papilliferum) [2, 15, 23, 26, 52, 118, 131]. The major histologic features of NAs are that they represent a ductal proliferation of glandlike structures within the stroma of the nipple, and generally have fairly well circumscribed borders but without encapsulation [8, 15, 23, 26, 52, 118]. Sclerosis/fibrosis may distort glands, mimicking an invasive growth pattern. Adenosis, cystic dilation, ductal hyperplasia, papillary hyperplasia, apocrine metaplasia, squamous metaplasia, and keratin cysts can be seen to varying degrees in NAs. Immunohistochemical stains can be useful to highlight the presence of two cell layers (i.e., epithelial and myoepithelial cells) [118, 132]. Specifically, p63, p40, calponin 1, h-caldesmon, CK5/6, CD10, or alpha smooth muscle actin and smooth muscle myosin can be used to highlight the presence of myoepithelial cells. Cytokeratin CK7 highlights the ductal epithelium and support the diagnosis. Recently, 5-hydroxymethylcytosine, an epigenetic modifier, has been suggested as a putative marker for NA [128].

The growth of NAs into the overlying dermis and epidermis, as well as erosion/ulceration through the epidermis is not infrequently seen [26, 52]. Interestingly, some cases which clinically appear to represent the erosion/ulceration of the NA through the epidermis are actually not due to erosion/ulceration of the NA through the epidermis, and instead represent the dilatation of major nipple ducts and the direct exposure of the papillomatous lesion lining those major nipple ducts to the surface of the nipple [26].

According to the WHO Classification of Tumours of the Breast [2], the 4 most common recognized histological subtypes of NA are: (1) adenosis type; (2) epithelial hyperplasia or papillomatosis type; (3) sclerosing papillomatosis or pseudo-infiltrating type; and (4) mixed type. The adenosis type shows proliferating glands extending from collecting ducts, is localized to the dermis, and typically lacks hyperkeratosis, inflammation, erosion, and/or ulceration. The papillomatosis type primarily has epithelial hyperplasia of the collecting duct epithelia and hyperplastic glandular ducts and is the type most commonly mistaken for mammary Paget’s disease of the nipple. In the sclerosing papillomatosis type, a pseudo-infiltrating pattern is distinguished by a prominence of proliferating epithelium into the stroma. Lastly, the mixed type may show features of any of the other three aforementioned subtypes. The patient presented in our current case report had both histologic evidence of adenosis and hyperplasia, most consistent with a mixed type of NA. It is our own personal opinion that most NAs will histologically display features in common across more than one of the aforementioned subtypes. Thus, the histological subtyping of NAs is somewhat arbitrary secondary to shared histologic features that can be seen within any given NA, and the resultant clinical relevance of the histological subtyping of NAs remains in question.

NA most typically presents in women in their 4th and 5th decades of life [26, 52]. However, it has also been reported in men [2, 12, 14, 20, 31, 44, 90, 96, 104, 107, 112, 123], as well as throughout childhood [86, 99, 106]. While most cases of NA are unilateral, there have been rare reports of bilateral disease [22, 28]. The initial clinical presentation is most often that of nipple skin erosion, crusting, inflammation, erythema, itching, and/or associated pain of the nipple region [3‐130]. The finding of serous and/or sanguineous discharge from the skin surface of the nipple profile is commonly reported as an initial presenting symptomatology and is generally secondary to the presence of a nipple skin erosive lesion. However, this serous and/or sanguineous discharge is often confused with genuine nipple discharge from the ducts within the nipple profile itself. In the more advanced presentations of NA, the nipple may become firm, nodular, and/or deformed. Clinically, NA may resemble mammary Paget’s disease of the nipple, squamous cell carcinoma of the nipple, eczema, psoriasis, or skin infection. Lastly, cases of NA have even rarely been reported to have arisen from a supernumerary mammary gland location [37, 109, 113].

The gold standard for making the most definitive final diagnosis of NA is histopathologic examination of a completely excised lesion [3‐130]. However, nipple tissue biopsy with histopathological evaluation and confirmation prior to complete lesion excision is highly recommended. Imaging studies, including mammography and breast ultrasound are generally unable to provide adequate information for confirming the presence of NA due to the similarity in tissue density of the nipple to the surrounding skin and the underlying breast tissue [129]. However, digital mammography should always be considered for ruling out any mammographic abnormalities in the underlying breast tissue when a patient presents with any significant nipple symptomatology. Breast ultrasound has been reported by some to be a potential useful tool for identifying NA, as based upon the findings of homogenous echogenicity and hypervascularity [79, 103, 105, 116], while others have found its use limited and inconclusive [129]. Breast magnetic resonance imaging has also been reported to allow for characterization of NA [81, 95, 111]. In addition to microscopic tissue section examination of excised tissues using hematoxylin and eosin and immunohistochemical techniques, cytologic examination using touch prep cytology [124], curettage/scrape cytology [117, 129] and fine needle aspiration [46, 47, 56, 70, 90, 124] has also been evaluated. Ozaki et al. [124] reported four cases of NA in which cytologic examination by brush cytology, aspiration cytology, and/or tumor imprint cytology were used to aide in the benign or malignant characterization of such lesions. All four of these NA cases showed a small to large papillary cluster of epithelial cells, round to oval nuclei, and with three of the four cases also having attached myoepithelial cells.

Dermatoscopic examination (i.e., diascopy) has also been proposed as a potentially useful diagnostic modality [127]. In 2015, Takashima et al. [127], reported a single case of NA in a 57-year old Japanese woman presenting with erosive erythema. Dermatoscopic evaluation of the nipple lesion showed linear, cherry-red structures thought to be representative of neoplastic tubular luminal openings of the NA. Interestingly, the dermatoscopic photography of the patient presented in our current case report demonstrated red serpiginous and annular structures rather than linear cherry-red structures as reported by Takashima et al. [127].

It is universally agreed upon that complete surgical excision of the entire NA is important for preventing local recurrence [3‐130]. As in our particular case, complete surgical excision has traditionally been accomplished by resection surgical excision of the right nipple profile, adjacent surrounding areolar skin, and superficial underlying breast and subcutaneous tissues [38, 118, 129]. However, more limited forms of complete surgical excision of the entire NA have been reported using a wedge resection technique [93, 94, 129], as well as a nipple splitting enucleation technique via a trans-nipple longitudinal incision made down through the long axis of the nipple profile to expose and extract the NA [80, 116, 119]. Likewise, Mohs micrographic surgery has been reported to be successfully used for NA excision and is thought to be curative [76, 84, 98]. Lastly, cryotherapy has been reported as a novel technique for eradication of a NA [74].

The potential for local recurrence of NA is always a concern with utilization of any of these more limited forms of complete lesion removal. When a NA grows from the nipple stroma and into the overlying dermis and epidermis or erodes through the epidermis, more limited forms of surgical excision, such as the nipple splitting enucleation technique, should not be considered. In such cases, complete excision of all involved nipple skin should be undertaken to assure complete lesion removal and to minimize the risk of local recurrence of the NA with the remaining nipple profile. In the case presented herein, in which the nipple adenoma clinically appeared to involve the nipple skin and histological was shown to involve the nipple dermis, our patient elected for complete surgical excision, primary skin closure, and no attempt at cosmetic reconstruction of a right “neo-nipple”. Since NA represents a benign proliferative process of the nipple, complete surgical excision is curative. It should be emphasized that any patient with a history of NA should be encouraged to maintain regular breast follow-up with continuation of annual clinical breast exams by their healthcare providers and annual digital screening mammography after successful NA removal.

It is well documented that incidental breast cancer has been detected at the time of the excision of a NA [2, 8, 12, 24, 26, 27, 48, 49, 52, 53, 57, 67, 75, 87, 121, 130]. While most of these incidental breast cancers are found at the time of the initial NA excision, there are rare cases in which breast cancer has been reported at the site where a NA was previously biopsied or excised [2, 24, 36, 53, 121]. Eusebi and Lester reported that 24 of 173 (13.9 %) cases of NA were associated with breast cancer [2]. Likewise, Rosen and Caicco reported that 9 of 51 (17.6 %) cases of NA were associated with breast cancer [52]. Nevertheless, it remains unclear as to whether the presence of a NA represents a risk factor the subsequent development of breast cancer. Additionally, it is unknown whether the incidence of NA is greater in patients with a positive family history of breast cancer [26, 52]. The coexistence of NA and ipsilateral or contralateral breast cancer has been reported in surgical specimens of breast tissue excised at the time of breast cancer surgery [8, 12, 24, 26, 27, 48, 49, 52, 57, 67, 75, 87, 121, 130]. When ipsilateral NA and carcinoma are synchronously observed within a breast, they most often represent two independent lesions, with the site of carcinoma being located at a distinct and separated geographic location from the site of the NA. Furthermore, the relative incidence of NA in patients with breast cancer versus patients without breast cancer is not known. Despite these previously suggested associations, NA is itself not a malignant lesion of the breast. Nevertheless, a definitive association of NA with the subsequent development of breast cancer, as well as a direct causal link for the transformation of a NA into a later developing breast cancer process, cannot be fully excluded.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal.