NAC reconstruction is a technique used in the final stage of breast reconstruction following total mastectomy for primary breast cancer. Composite nipple grafting has been described in the literature since the early 1970s, and the technique is now widely performed. Till date, only one report of breast cancer originating in a nipple reconstructed from tissue obtained from the contralateral/unaffected side has been identified via a PubMed search; however, that case involved Paget’s disease, not an invasive carcinoma [4]. A de novo carcinoma developed 6 years after the NAC reconstruction, and the donor nipple had no identifiable lesion, similar to the findings in this case. To our knowledge, that report documented the first case of Paget’s disease arising from a grafted nipple in the US literature.
Breast cancer is considered to develop from the epithelia of terminal duct lobular units (TDLUs), including cases of in situ and invasive carcinomas. TDLUs usually exist in distal mammary glands through a series of branches. On the other hand, major lactiferous ducts terminate in and exit from the mammary glands at the nipple, although there are cases where TDLUs exist in adjacent lactiferous ducts in the nipple. Kryvenko et al. investigated the frequency of TDLUs and occult neoplastic epithelial proliferation in grossly/clinically unremarkable nipples [5]. They observed TDLUs in 26% of nipples of tissue specimens from therapeutic or prophylactic mastectomies, while occult neoplastic epithelial proliferation was seen in 5% of grossly/clinically unremarkable, therapeutic mastectomy nipples. They also reported that the nipples were unremarkable in all cases of prophylactic mastectomies. Moreover, occult neoplastic proliferations in grossly unremarkable nipples were largely correlated with underlying carcinomas, but only two patients had a primary malignant neoplasm in their nipples. Based on these reports, it is difficult to confidently state whether grossly unremarkable donor nipples are afflicted by malignant neoplasms or not.
This case is also rare in terms of the origin of the invasive ductal carcinoma of the nipple. Very little has been published about breast cancers developing within the nipple, especially invasive ones. The first large series of carcinomas originating in the nipple was published in 1956 [6]. Of approximately 10,000 cases of malignant disease of the breast in patients undergoing surgery at the Mayo Clinic in 46 years, only 0.25% of cases originated in the nipple. Secondly, Sanders et al. have reported common features of invasive primary breast carcinomas originating in the nipple [7]. The frequency of those carcinomas was 0.3% in the report, and only 24 patients among more than 8000 breast carcinoma patients investigated in their study presented with symptoms related to the nipple. Of these patients, 42% had epithelial changes associated with in situ ductal carcinomas involving the skin of the nipple (Paget’s disease), with small foci of invasion into the dermis. The rest of the patients presented with a nipple mass with or without skin changes. Consistent with the case reported here, HER2 positivity was observed in tissue obtained from 60% of patients with Paget’s disease and 14% of patients with a nipple mass. The likelihood of lymph node metastases was not higher than that for carcinomas of similar sizes, and there was no disease recurrence following proper adjuvant therapy. Thus, invasive primary nipple carcinomas are rare, but conventional therapies for breast cancer treatment are also useful in such cases. In our case, we initially suspected Paget’s disease because of nipple erosion and the fact that no solid tumor was identified by palpation. The patient exhibited pagetoid spread of an invasive ductal carcinoma with comedo ductal components, without the presence of a palpable solid tumor. However, contrast scrape cytology suggested a ductal carcinoma because no melanin granules were observed in the malignant cells [8]. In contrast, considering that HER2 positivity is more frequent in Paget’s disease than in invasive ductal carcinoma, it cannot be denied that this carcinoma originated from Paget’s disease in terms of the immunoprofile. HER2 is overexpressed in 80–90%; ER and PgR are positive in approximately 40% and 30%, respectively, in Paget’s disease [9], in contrast with 15–30% positive for HER2 in invasive ductal carcinoma. However, there were only a few Paget cells within the squamous epithelium of the nipple, and most malignant cells had directly infiltrated the nipple surface, resulting in ulceration. In addition, the infiltrating malignant cells were not large cells with abundant eosinophilic cytoplasm like Paget cells. Therefore, they had likely originated from the invasive ductal carcinoma rather than Paget’s disease.
There has been a lot of discussion about the oncological safety of ABR after mastectomy for invasive breast cancer; however, a current literature review failed to show significant risks of either concurrent or delayed distant or local recurrence following ABR, relative to the risk in the absence of ABR. In this case, there were no remnant breast tissues in the right breast, except for the nipple and areola, and the malignant neoplasm arose from the flap of abdominal skin from a DIEP flap [10]. Thus, the malignancy was not defined as a local recurrence but as a new primary carcinoma, considering there were no right breast tissue components such as skin, blood, and lymphatic vessels around the malignant neoplasm. Although total mastectomy is usually recommended in cases of local recurrence of breast cancer, in this case, we performed a partial resection because the lesion was quite localized, and there was no mammary gland except for localized tissue beneath the nipple of the right breast, based on imaging, and the carcinoma seemed not to be related to lymphovascular invasion of the initial breast cancer.
It was unclear whether the de novo carcinoma arose before or after the NAC surgery. Surgical treatment might trigger the occurrence of malignant changes, although there are few case reports describing cancers developing in transferred tissues to support this scenario. Cancer development is a multi-faceted, dynamic series of events, and some new carcinogenic hypotheses have been described. Recently, the role of the microenvironment in driving tumor progression has been increasingly recognized [11]. Tumor formation begins when genetic abnormalities occur in cells that undergo rapid, unchecked proliferation. However, a tumor is not solely comprised of cancer cells; it is a heterogeneous collection of both cancer cells and surrounding noncancerous or stromal cells that work in concert with one another to promote unrestricted growth, infiltration, and propagation of malignancy throughout the body. In the microenvironment of carcinomas, tumor cells recruit various types of stromal cells such as fibroblasts, inflammatory cells, and endothelial cells, and their cellular interactions are important drivers of progressive tumor growth [12]. Expansion of the tumor stroma is often observed in invasive carcinomas; these changes result in desmoplasias, where tumors and stroma actively interact. Pathologically, our case presented scirrhous spread of a carcinoma in the absence of a palpable tumor; thus, we assumed that there was an expansion of a desmoplasia around those tissues.
A hypoxic environment is one of the key physiological and microenvironmental characteristics that differentiate tumors from normal tissues. The transcription factor hypoxia-inducible factor 1α and angiogenesis are important factors that regulate hypoxia-induced signaling cascades [13]. Hypoxia can drive and maintain genetic instability, resulting in a mutated phenotype. Moreover, hypoxia, along with acidosis, increases clonal selection, resulting in aggressive cancer phenotypes. As a result, stressors, including surgery, may induce oncogenic changes in tissue. In contrast, “nipple banking” was formally performed to rebuild a nipple, which is a technique in which a nipple is taken from a site on the ipsilateral breast, banked in the groin, and then later returned to the chest [14, 15]. Nevertheless, the nipple was taken in the case without apparent involvement of the nipple with carcinoma; some cases of the development of heterotopic carcinoma in the transplanted nipple were reported. This indicates that cancer cells in the transplanted nipple could survive in a hypoxic or ischemic environment. In our case, surgical stressors might also have affected the donor tissue of the left nipple, though the timing of generation of malignant cells was not definitive. Generally, careful preoperative screening for contralateral breast cancer should be performed before NAC reconstruction whether malignant lesions exist, though there were no signs of malignancy in the left breast in this case. Moreover, post-operative examinations are important because of the possibility of development of occult malignant tumors in the left breast; thus, we have continued to monitor the patient’s left breast carefully.
