Introduction

Basal cell carcinoma (BCC) is the most common cutaneous malignancy and accounts for approximately 80 percent of all nonmelanoma skin cancers [1]. Exposure to ultraviolet radiation is the main environmental risk factor associated with the development of BCCs, although they have also been found to occur less frequently in photo-protected sites. Albeit rare, BCCs of the nipple-areola complex (NAC) have been suggested as being more aggressive with higher rates of metastasis to regional lymph nodes [2]. To date, three cases of BCC of the NAC metastatic to the lymph nodes have been described. In comparison, metastatic BCCs from all anatomic sites have been described in a total of 364 cases from 1894 through 2011 [3]. As a result, there has been controversy over the management of BCCs of the NAC.

To address the surveillance and management of BCC of the NAC, an extensive world literature review was conducted to identify cases reported between 1893 and 2016. We review the characteristics of individuals who developed BCCs of the NAC and their management.

Methods

Using the PubMed database, a literature search was performed searching for articles related to BCC of the nipple or NAC published in the world literature. The following keywords were used: areola, basal cell carcinoma, and nipple. Relevant papers were reviewed, and the references cited in these papers were evaluated. Information pertaining to age, sex, site of BCC, morphology of BCC, histological subtype of BCC, presence of pigment on histology, previous history of BCC, risk factors, treatment, lymph node involvement, and clinical outcome was identified from each case report. Additional informed consent was obtained from one patient for whom identifying information is included in this article.

Results

Fifty-five patients with BCC of the nipple and areola have been reported in the world literature, including the patient described in Figs. 1 and 2 (Tables 1, 2) [2, 4–51]. BCC of this site occurred more frequently in males (35, 63.6%) than in females (20, 36.4%). The onset age ranged from 35 to 86 years old. The median onset age in males was 61 years, whereas the median onset age in females was 66 years. The onset age was not mentioned for one female [6].

Fig. 1
figure 1

a, b A previously unreported clinical presentation of basal cell carcinoma of the areola. Distant view (a) of a flesh-colored to hypopigmented dermal nodule on the upper medial quadrant of the right areola in a 67-year-old Caucasian male with Fitzpatrick skin type 2. He had a prior history of basal cell carcinoma on the left arm diagnosed 3 years earlier and presented with a 6-month history of a slowly enlarging, asymptomatic lesion on the right areola and adjacent breast. He had a prior history of moderate sun exposure as a young adult. He had no exposure to ionizing radiation and had no family history of basal cell carcinoma or basal cell nevus syndrome. Closer view (b) of the right breast shows the 7 × 7-mm flesh-colored to hypopigmented dermal nodule on the upper medial quadrant of his right areola and extending into the adjacent breast. A 3-mm punch biopsy was performed. The patient in these figures is also cited in Table 1 (case 35)

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Fig. 2
figure 2

a, b A previously unreported pathologic presentation of the basal cell carcinoma of the areola shown in Fig. 1. Low (a) and higher (b) magnification views of the pigmented basal cell carcinoma show nodular aggregates of basaloid tumor cells extending from the epidermis into the dermis (a). Deposits of melanin were present not only in the tumor cells but also in dermal melanophages (b). The residual tumor was excised using the Mohs micrographic technique, and clear margins were achieved after three stages. The final wound measured 20 × 14 mm and a layered side-to-side closure was used to close the surgical defect. The patient in these figures is also cited in Table 1 (case 35)

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Table 1 Clinical characteristics of males with basal cell carcinoma of the nipple-areola complex
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Table 2 Clinical characteristics of females with basal cell carcinoma of the nipple-areola complex
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BCCs of the nipple-areola complex were observed on the left (28/51, 54.9%) more frequently than the right (23/51, 45.1%). One patient had bilateral involvement of the areola [37]. Five cases did not report the side affected. The nipple was affected in 45 patients (81.8%); 22 of these individuals also had tumors that affected the areola.

The majority of patients reported were Caucasian (28/37, 75.7%). However, BCC of the NAC was also described in 7 Asians (18.9%), 1 African American (2.7%), and 1 Hispanic (2.7%) patient. Ethnicity or race was not described in 18 cases.

Clinical presentation was variable and presented as a plaque (17/34, 50%), nodule (8/34, 23.5%), papule (6/34, 17.6%), macule (2/34, 5.9%), or patch (1/34, 2.9%). Secondary changes were additionally noted: ulceration or erosion of the BCC was noted in 19 cases, scale in 10, and crust in 7. Clinically, eight BCCs were pigmented.

The most frequent BCC histologic type reported was nodular (18/42, 42.9%). Other histologic subtypes of BCC observed were superficial (13/42, 30.9%), mixed (7/42, 16.7%), fibroepithelioma of pinkus (4/42, 9.5%), and pigmented (11/42, 26.2%). Of mixed subtypes, four were noted to have aggressive features on histology, including infiltrative (3/7, 42.9%) and micronodular (1/7, 14.3%). Thirteen cases did not provide a histological subtype of BCC.

Removal of the tumor was the most common treatment (Tables 1, 2, and 3). This included either simple excision, being the most frequently performed (15/50, 30%), wide excision (14/50, 28%), or Mohs micrographic surgery (11/50, 22%) with examination of the margins during the excision to confirm complete tumor removal. Six patients had simple mastectomies as their initial modality of treatment (6/50, 12%).

Table 3 Initial treatment of basal cell carcinomas of the nipple-areola complex
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One patient received topical 5-flourouracil (5-FU) twice daily for 6 weeks [50]. One female was treated with etretinate followed by simple mastectomy [35]. In addition, two patients received no treatment [25, 36]. In five males, there was no mention of management.

One male had Mohs micrographic surgery, which showed the lactiferous ducts had been infiltrated; thus, a simple mastectomy was performed (2%) [32]. One male had a simple excision followed by radiotherapy, but 4 years later was noted to have recurrence in the axillary lymph node and thus had a simple mastectomy (2%) [2]. One female had a simple excision, but due to positive margins, she subsequently had a partial mastectomy (2%) [43].

Most of the patients (43/45, 95.6%) had no recurrence after successful treatment of their tumor. In ten patients, there was no mention of clinical outcome. There had been three reported cases of metastatic disease to the lymph nodes at the time of this review, and of these patients, one died from the disease.

Discussion

BCCs infrequently occur at unusual sites, such as the nipple and areola. Previous studies have noted a close histogenic relationship between BCCs and pilosebaceous units [52–54], and BCCs are therefore thought to arise in proportion to the number of pilosebaceous units present [25]. The nipple and areola are deficient in these units, which may explain the paucity of BCCs of the nipple and areola.

After an extensive world literature search, we identified 55 cases of BCC of the NAC from 1893 to 2016 (123 years). A 2009 review by Ferguson et al. revealed 33 cases of BCC of the nipple and areola [55]. Since 2009, 22 additional cases of BCC of the NAC have been reported in the world literature. This apparent increase in BCCs of this site may be due to a publication bias; however, this trend reflects an overall increased incidence of sporadic BCCs [56].

The increased incidence of BCC of the NAC observed in males (35, 63.6%) versus females (20, 36.4%) [2, 4–51] has been attributed to greater sun exposure of the chest in males [2, 13, 15, 20, 27, 41, 42]. Although ultraviolent light exposure is the major risk factor for the development of BCC, other etiologies include arsenic exposure, genetic predisposition, environmental exposures, immunosuppression, ionizing radiation exposure, injury (burns or trauma), light-colored skin, previous BCCs at another site, and sunburns. Although the majority of cases did not reveal possible risk factors of BCC of the NAC, our review revealed two males (Table 1, cases 11 and 26) [13, 27] and two females (Table 2, cases 8 and 13) [40, 44] had increased sun exposure to the chest from shirtless sunbathing. Nine patients (9/26, 34.6%) had a prior history of BCC [14, 17, 20, 21, 25, 28, 32]. Two males reported prior trauma to the chest (2/27, 7.4%) [14, 21]. One male had basal cell nevus syndrome (1/27, 3.7%) [28], and one male was immunosuppressed on chemotherapy for gastric cancer (1/27, 3.7%) [31].

To date, there have been eight patients with clinically pigmented BCCs of the NAC. Therefore, primary melanoma of the NAC, pigmented Paget disease, and pigmented epidermotropic metastases are important considerations in the clinical differential diagnosis of a pigmented lesion of the NAC. These can be differentiated by histologic examination and immunohistochemistry markers, such as CEA, cytokeratins, EMA, HMB-45, MART1, microphthalmia transcription factor (MiTF), and S-100 [29, 57].

Interestingly, two patients (including the patient described in Figs. 1 and 2) with histologic findings of pigmented BCC had flesh-colored non-pigmented clinical lesions [50]. The clinical presentation of one male with microscopic pigmented BCC was not described [6].

Confirmation of BCC of the NAC requires a biopsy, although other approaches are available to evaluate a suspected diagnosis of BCC, including confocal laser scanning microscopy and dermoscopy.

Confocal laser scanning microscopy, also known as reflective confocal microscopy, is a noninvasive diagnostic method that enables real-time imaging of the skin layers and cellular structures in the horizontal plane [58]. Classical findings of BCC on confocal laser scanning microscopy include five confocal imaging criteria: presence of elongated monomorphic basaloid nuclei, polarization of these nuclei along the same axis of orientation, heavy inflammatory infiltrate, increased vasculature, and pleomorphism of the overlying epidermis indicating actinic damage [59].

Dermoscopy is another noninvasive method that allows for the in vivo evaluation of structures and colors of the epidermis, dermoepidermal junction, and papillary dermis not visible to the unaided eye. Dermoscopic diagnosis of BCC involves the absence of a pigmented network and presence of at least one of the following classical criteria: multiple blue-gray globules, large blue-gray ovoid nests, maple leaf-like areas, spoke-wheel areas, arborizing telangiectasia, and ulceration [60]. Non-classical dermoscopic criteria are also helpful for the diagnosis of BCCs, especially early lesions, and include short fine superficial telangiectasia, concentric structures, multiple small erosions, multiple in-focus blue-gray dots, blue whitish veil, shiny pink-white areas, and milia-like cysts [61].

Due to the infrequent presentation of BCC of the NAC, there has been a lack of characteristic findings in the literature to aid in the diagnosis of BCC of the NAC. However, a recent review by Kitamura et al. revealed a dermoscopic feature of pigmented BCC of the NAC that was termed a ‘large black web.’ On dermoscopic evaluation, it was noted that the black network structure was thicker than the typical pigment network of the areola, and the surrounding area consisted of arborizing vessels and spoke-wheel areas. When this patient was compared with nine others diagnosed with superficial BCC of the trunk, the authors found that the ‘large black web’ was unique to BCC of the NAC and appeared to avoid the hair follicles [33].

Earlier investigations have reported an increased metastatic potential of BCC of the nipple and areola. These studies hypothesized that the increased lymphatics of the NAC may provide a direct route for tumor spread. There have been three cases of BCC of the NAC with lymph node involvement (Table 1, cases 2, 5, and 12) [2, 5, 8], which is a minimum metastatic rate of 5.5%. Since the outcome was not stated in ten patients and several patients had a short duration of follow-up after surgery, this rate could potentially be higher.

The histologic subtypes observed were most commonly nodular (42.9%) and superficial (30.9%); less often they showed pigment microscopically (11/42, 26.2%), mixed histology (16.7%), or fibroepithioloma of Pinkus variant (9.5%). Of the mixed subtypes, four cases were noted to have features associated with aggressive subtypes, such as infiltrative (3/7, 42.9%) and micronodular (1/7, 14.3%) BCCs.

Given the concern for higher metastatic potential or the presence of positive excision margins for tumors, nine patients underwent a simple mastectomy, although tissue-sparing surgery, such as simple excision, wide local excision, and Mohs micrographic surgery, was most commonly utilized. Recurrence of NAC BCC is low and was noted in one male who demonstrated lymph node involvement that occurred 4 years after simple excision [2].

Conclusion

BCC of the NAC has been reported in 55 individuals. More males were affected than females; the left side was affected more than the right. Most commonly, these tumors presented as plaques with ulceration. The most frequent histologic subtype of BCC of NAC was nodular BCC. Although previous reports raise the concern of metastatic potential, most patients have been successfully treated with excision of the tumor.