NA, also referred to as florid papillomatosis, erosive adenomatosis, superficial papillary adenomatosis, or papillomatosis of the nipple, was officially named "Nipple Adenoma" in the World Health Organization (WHO) 2012 classification of breast tumors. The WHO 2019 classification defines it as a benign epithelial lesion with lactiferous duct-like structures involving the nipple collecting ducts, surrounding stroma, and adjacent overlying epidermis. The first case of NA was reported in 1955 by David B. Jones, who termed it "Florid Papillomatosis of the Nipple Ducts" and suggested distinguishing it from Paget's disease [1]. The first case of nipple lesion in a boy was reported by Kou Fujisawa in 2018[2]. NA is more common in adult women and rare in men, with only a few cases reported in minors, almost all of which are girls. Clinical features of NA are variable; due to skin changes, it can be detected when small, with the most common clinical symptoms being nipple erosion, erythema, and nipple bleeding, followed by small nodules in the nipple-areolar area and nipple induration, which may also be accompanied by itching and pain [3]. NA is located beneath the nipple-areolar area, presenting as a small, round mass with clear boundaries from surrounding tissue, and a cut surface that is grayish-white or brownish-yellow, without a capsule. Epithelial hyperplasia with a partial or total obliteration of the lumen with intraductal papillary projections, presence of intraductal necrosis, and nipple may appear eroded and erythematous as glandular epithelium replaces squamous epithelium. Epithelial and myoepithelial cells are arranged in a double layer, and fibrosis or sclerosis of the stroma may cause glandular distortion, presenting a pseudo-infiltrative pattern, with squamous metaplasia and apocrine metaplasia, superficial keratin cysts, acanthosis, toker cell hyperplasia in the epidermis and multinucleated giant cells[4,5,6,7].According to the WHO classification of breast tumors, 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[8].
There is no consensus on the immunohistochemical profile of NA, especially regarding ER PR and HER2 status. Angel Fernandez-Flores suggested in his study that the immunophenotype of male NA is similar to that of females, with ER and PR being negative [9], but our study showed that the inner epithelial cells were ER and PR positive. In the outer myoepithelial cells, P63, smooth muscle myosin, calponin (SMA), and CK5/6 were positive, aiding in the differentiation from malignant tumors [5,6]. Jau-Yu Liau found activating PIK3CA mutations in 12/24 cases, KRAS in 1/24 cases, and BRAF mutations in 2/24 cases, dividing NA into (1) sclerosing adenomatous type and (2) epithelial hyperplasia pattern (UDH-like pattern). Sixty percent of adenomatous NA had mutations in PIK3CA, RAS, or BRAF (10/15). The mutation rate in adenomatous-like NA is higher than in usual-ductal-hyperplasia-like NA, but the difference is not statistically significant. Interestingly, concurrent PIK3CA and RAS mutations in breast cancer predict a higher histological grade, but in his study, tumors with combined PIK3CA and RAS mutations did not show atypical hyperplasia(ADH)features[10]. The study used Sanger technology instead of NGS (Next-generation sequencing technology) and had a small sample size, so further exploration of the molecular cytology aspect of NA is needed.
NA has a false-negative rate of about 33% in mammography due to the small size and superficial location of the mass [3]. Ultrasound lacks characteristics, presenting as a mass with or without cystic components and hypervascular on Doppler [11]. Nuclear magnetic resonance (MRI)shows mass enhancement but lacks features and is expensive, so it is not recommended12. Nipple biopsy confirmation and complete surgical excision remain the gold standard for the diagnosis and treatment of NA. However, with increased understanding of NA, new diagnostic tools such as dermatoscopy [13], fine-needle aspiration, and scrape cytology have been proposed. Traditional treatment is complete surgical excision. In our case, complete excision of the left nipple-areolar complex and subcutaneous tissue was performed, followed by purse-string suture to reshape the nipple and restore its appearance. As the pursuit of aesthetics and technological development continue, oncoplastic surgery, Mohs micrographic surgery, wedge resection technique, nipple split de-nucleation technique, and cryotherapy are gradually being applied in the treatment of NA [8].
Given the clinical non-specificity of NA, accurate differential diagnosis is essential to prevent unnecessary aggressive treatment. NA mainly needs to be distinguished from the following diseases: (1) Paget's disease, which, like NA, can manifest with eczematous changes in the nipple. However, Paget's disease is characterized by the presence of distinctive Paget cells throughout the epidermal layers, whereas Toker cells in NA are typically smaller. Paget's disease cells often exhibit nuclear pleomorphism and frequently test positive for HER2 and EMA [7]; (2) invasive ductal carcinoma, when NA presents a pseudo-infiltrative pattern, it may be confused with Invasive ductal carcinoma(IDC), but NA has a double layer of epithelial and myoepithelial cells, while breast cancer lacks myoepithelium and shows marked cellular atypia, common mitotic figures, and tumor nest formation, with immunohistochemical markers P63,CK5/6 helping to differentiate; (3) syringomatous tumor, which feature ducts of teardrop, comma, and branching shapes, and exhibit infiltrative growth with desmoplastic stroma. These tumors may show perineural invasion but do not involve the epidermis; (4) SCAP-TAA, as NA can be associated with apocrine metaplasia, Our initial biopsy mistakenly identified the condition as SCAP-TAA, which presents as cystic invaginations of the infundibular epithelium projecting into the dermis, covered by a double cell layer; the innermost layer is composed of columnar cells with decapitation secretion, and the outermost layer is composed of cuboidal cells with papillary projections, with immunohistochemical positivity for carcinoembryonic antigen(CEA) and epithelial membrane antigen(EMA)helping to differentiate[14].
Since NA is a benign proliferative process, complete excision is curative. However, as reported by Jones, M.W., and F.A. Tavassoli in 1995, five women with NA were found to have coexisting IDC or Ductal Carcinoma In Situ (DCIS) [15]. The relationship between NA and breast cancer remains undefined. Consequently, it is advisable for patients with NA to undergo long-term follow-up and observation post-treatment to detect any potential development of breast cancer or NA recurrence.