Breast-Conserving Surgery With Partial Nipple-Areola Resection Based on Mammary Gland Anatomy.

INTRODUCTION
The embryogenic mechanism of mammary gland development begins with the depression of the ectodermal mammary gland primordium, followed by branching to form the mammary gland [1]. The glandular lobes of the mammary gland are independent of each other; the collecting ducts in the nipple that drain milk from each lobe are not connected but are instead erect and open separately at the surface of the nipple tip [234]. A case of connection between neighboring glandular lobes at a site away from the nipple has been reported [5].
When the intraductal extension of breast cancer toward the nipple reaches the nipple–areola (NA) region, the risk of a positive margin on the dissected surface of the subareolar layer can be avoided by excising the entire layer from the areolar skin to the fascia. If the collecting duct with a noninvasive lesion in the nipple is resected up to the nipple surface opening, preserving the nipple with partial excision is theoretically possible. In addition, a full-layer resection under the partially resected nipple can ensure the creation of a safety zone under the nipple.
Considering the development and anatomy of the mammary gland, we devised a technique in which the NA region, including the lesion, was divided vertically. We aimed to evaluate the safety and efficacy of this surgical procedure on the basis of the current diagnostic accuracy of breast magnetic resonance imaging (MRI).

METHODS
Based on the developmental and anatomical independence of each mammary lobe, we devised breast-conserving surgery (BCS) with partial NA resection and examined the validity of this technique.

Patients
In this retrospective study, we evaluated 56 consecutive patients who underwent BCS with partial NA resection for breast cancer between May 2015 and March 2023.
The participants were patients with stage 0–IIA breast cancer. The indications for surgery were as follows: Space-occupying lesions were defined as primary lesions. The main lesion was located outside the NA region and was accompanied by intraductal extension within the NA region (Group 1). The main lesion partially extended to the subareolar area and was accompanied by intraductal extension within the NA region (Group 2). The main lesion partially extended to the subareolar area but was not accompanied by intraductal extension within the NA region (Group 3).
The clinical T stage (cT) and pathological T stage (pT) were compared.
All patients were female, aged 35–89 years with a mean age of 61.6 years. Thirty-nine patients were classified into Group 1, 13 into Group 2, and four into Group 3 (Supplementary Table 1).
This study was approved by the Institutional Review Board (IRB) of our hospital (IRB 24000041, registration No. 2023068). This study was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained preoperatively after explaining the surgical procedures.

Classification based on preoperative imaging
Breast MRI was performed using a 3.0 T MRI imager (Ingenia; Philips Medical System, Best, Netherlands) and a dedicated seven-channel coil, using eTHRIVE, three-dimensional T1–turbo field echo with fat suppression.
The intraductal extension patterns on preoperative breast MRI were also classified. Intraductal extension into the collecting duct within the nipple was classified as A1 (
Figure 1A
). Only one duct in the nipple clearly contrasted on the MRI scan. The intraductal extension under the nipple crossing the vertical line drawn from the outer edge of the nipple base to the chest wall was classified as A2 (Figure 1B). Intraductal extension under the areola was classified as A3 if it did not reach the perpendicular line drawn from the outer edge of the nipple base to the chest wall (Figure 1C). In Group 3, Ax (safety zone) was assigned because no intraductal extension toward the nipple within the NA region was observed on the preoperative breast MRI (Figure 1D). Ax was assembled out of the concern that contrast-enhanced MRI might fail to detect intraductal extension toward the nipple. The localized tumor was > 1 cm from the nipple base with no intraductal extension on imaging. A portion of the nipple was resected to ensure a safe resection.
MRI was performed with the patients in the prone position and was used as a standard imaging method to evaluate the extent of intraductal extension.

Surgical techniques
The nipple was partially resected from the center of the nipple tip surface at approximately 90° around the area containing the ductal opening of the glandular lobe with the lesion (quadrantectomy), and the entire tissue was directly excised under the nipple to the pectoralis muscle fascia. The areolar area with the lesion was similarly excised in all layers, from the skin to the pectoralis muscle fascia (Figure 2A). The skin excision was spindle-shaped, with an extended nipple–areola complex (NAC) area that resected the skin immediately above the main lesion (Figure 2B). Morphologically, partial mastectomy was performed with the mammary glands separated perpendicularly to the chest wall like a “cake slice” (Figure 2C).
In groups other than A1, the NA resection site was determined on the basis of the localized area of the glandular lobe with the lesion and the intraductal extension image toward the nipple. If the intraductal extension of the NA region was not within the resection area, a positive margin was created at the resection margin; a negative margin indicated that the lesion had been resected (Figure 2D).
The safety zone on the lateral side of the mammary glands was secured using preoperative imaging and intraoperative ultrasonography.
Similarly, skin excisions were made in a T-shape with concentric incisions and a spindle shape (Figure 2E).
The NAC wound was sutured with a simple closure.

Pathological classification based on resection specimens
Similar to the preoperative classification, the postoperative pathology for intraductal extension toward the nipple was classified into four categories: collecting duct within the nipple, duct under the nipple, duct under the areola, and duct outside the NA region, designated as P1, P2, P3, and P4, respectively.

Postoperative appearance
We compared standing frontal photographs of 22 patients > 3 years after surgery. The ratio of the short axis to the long axis of the postoperative NAC was also measured (Figure 3A). NAC displacement was defined as a clear displacement of the NAC when the vertical or horizontal deviation of the NAC on the left and right sides exceeded the diameter of the NAC on the normal side (Figure 3B and C).

Statistical analyses
The χ2 or Fisher’s exact test was used. p < 0.05 indicated a statistically significant difference. Statistical analyses were performed using Microsoft Excel (Microsoft, Redmond, USA).

RESULTS

Histopathological findings
Invasive carcinoma occurred in 34 patients (invasive carcinoma of no special type, 31 patients; invasive lobular carcinoma (ILC), two patients, and invasive micropapillary carcinoma, one patient). In situ carcinoma was observed in 22 patients (ductal carcinoma in situ [DCIS] in 22 patients).

T stage
Preoperative breast MRI-based diagnosis of cT and postoperative pathological diagnosis of pT were compared (Table 1). Of the 22 noninvasive cancer pTis, 14 cases were cTis and eight cases were cT1. Staging was matched for cTis in 14 patients, cT1 in 21 patients, and cT2 in three patients. Eight patients with cT1–pTis had no infiltrative zone, and seven patients with cT2–pT1 had an overestimation of the infiltrative zone, whereas one patient with cT1–pT2 had an underestimation of the infiltrative zone. The correlation coefficient between cT and pT classifications was 0.97.
There were only two cases of invasive cancer underestimation, with cT1–pT2 being invasive ductal carcinoma and cT2–pT3 being ILC.

Intraductal extension in the NA region
Preoperative breast MRI-based diagnoses A1–A3 for intraductal extension toward the nipple were compared with the postoperative pathological classifications P1–P4 (Table 2). P4 was found in eight patients. Among the 21 patients with A1, only six were correctly diagnosed. Furthermore, only one of the 25 patients with A2 was diagnosed with P1. In four patients with Ax, pathological results showed that the occupied site partially extended to the subareolar area, and the resection margins were negative. As shown in the preoperative images, no intraductal extension toward the nipple was observed in the NA region.
The positive predictive value of the MRI-based diagnosis for the pathological findings of intraductal extension into the NA region (P1 + P2 + P3/A1 + A2 + A3) was 84.6% (44/52 cases). The correlation coefficient between classifications A and P was 0.44, indicating a moderate association (Table 2).
In five of the 11 patients (A1–P2), the transverse and sagittal sections of the nipple were obliquely cut along the long axis of the nipple. Four patients had inverted nipples, and two patients had extremely low nipples.

Pathological cancer exposure at the margins of the resected specimen
In all 56 patients, the rapid intraoperative pathological sectioning of the resection margins was negative for cancer. Intraductal extension was pathologically evaluated at 5-mm intervals in all segments of the excised specimen. Postoperative pathological section retrieval revealed that six patients had positive margins (Table 2). Two patients (No. 1 and 2, A1–P1) had positive nipple-side margins (Supplementary Table 2). In the first case (No. 1), the papilla was slender and exposed to low-grade DCIS at the edge of the transect. Another case involved low-grade DCIS in a duct within the nipple that was discontinuous with the other lesion (No. 2). A second lesion was found in a partially excised inverted nipple (No. 5, A2–P2). The other positive cases were as follows: one positive deep margin under the areola (No. 4, A2–P2) and two positive lateral margins outside the NA region (No. 3, A1–P2, and No. 6, A2–P4). One positive surgical margin (No. 6, A2–P4) was due to improper intraoperative positioning. Only one patient had a positive lateral margin, which showed positive findings in the invasive area (No. 6, A2–P4). Positive margins were observed in four patients in the NA region and in two patients outside the NA region. No reoperation was performed, and boost irradiation was added to the residual breast irradiation in the postoperative period.

Axillary treatment
In 56 patients, preoperative imaging revealed no axillary lymph node metastases, and sentinel lymph node biopsy was performed. Four patients had sentinel node metastases and underwent an additional axillary lymph node dissection.

Skin excision from NA region to just above the tumor
The skin excision was spindle-shaped in 31 patients and T-shaped in 25 patients.

Postoperative irradiation
Postoperative whole-breast irradiation (50 Gy in 25 fractions) was administered to 49 patients. Subsequently, 10 Gy in five fractions of NA region boost irradiation was added to five patients. Furthermore, 53.2 Gy in 16 fractions of hypofractionated irradiation with boost irradiation was administered to seven patients.

Postoperative course
As of February 2025, there has been one case of recurrence and no cases of local recurrence. Postoperatively, the breasts were photographed periodically. None of the patients requested reoperation.

Subtypes and degree of intraductal extension toward the nipple
Of the 44 patients with intraductal extension in the NA region, 17 had carcinoma in situ, and 27 had invasive carcinoma (Table 3). The subtypes of invasive carcinoma were luminal A-like (LA) in 18 patients, luminal B-like human epidermal growth factor receptor 2 (HER2)-negative (LB) in four patients, luminal B-like HER2-positive (LB-HER) in one patient, hormone receptor (HR)-negative and HER2 type (HER) in three patients, and triple-negative type (TN) in one patient. In contrast, at P4, the luminal-type ratio was low in one patient with LA and two with TN. In the Ax group, there were two patients with LA, one with LB-HER, and one with TN. There was no significant difference in the proportion of subtypes between in situ and invasive carcinomas (p > 0.05). In invasive carcinoma, a significant difference (p = 0.020) was observed between subtype TN and the other subtypes when comparing P1 + P2 + P3 with P4.

Relationship between grades and subtypes of carcinoma in situ
Regarding the grade of carcinoma in situ, intermediate-grade was the most common both inside and outside the NA region (Supplementary Table 3). Based on subtype, LA was the most common, followed by LB-HER. LA was biased toward low and intermediate grades, whereas LB-HER was biased toward intermediate and high grades, showing differences in grade trends. P1 + P2 + P3 group and P4 were compared based on subtype and grade, but no significant differences were found (p > 0.05).

Eight cases in which intraductal extension did not reach the NA region
There were five cases of in situ carcinoma and three cases of invasive carcinoma (Supplementary Table 4). Among the five cases of carcinoma in situ, three were LA and two were LB-HER, whereas among the three cases of invasive carcinoma, two were TN and one was LA. Among the carcinomas in situ, two of the three LA cases were classified as intermediate-grade and one as low-grade. In contrast, in LB-HER, one case was classified as intermediate-grade and the other as high-grade.
Overall, there was one A1 case, five A2 cases, and two A3 cases at P4.

Postoperative appearance
The ratio of the short axis to the long axis of the postoperative NAC was ≥ 0.6 in all patients.
Eleven patients showed a definite reduction in breast volume on the operated side (Figure 3D-N). As shown in Figure 3K, the outer wing of the T-shaped skin excision was lengthened to resect the puncture path using a core needle biopsy (Figure 3O). The lower photographs show cases with marked decreases in breast volume (Figure 3L and N). Frontal views of the 11 patients showed two patients with clear vertical displacement between the right and left NACs (Figure 3M and N) and one patient with NAC deformation (Figure 3N).

Case 1 (A1–P1)
The left breast cancer occupied the upper-inner portion of the breast. Preoperative breast MRI scans revealed intraductal contrast in the nipple. Additionally, preoperative contrast-enhanced MRI scans of the coronal section of the nipple showed a localized contrast zone identical to that of the main lesion (upper-inner quadrant). This technique was performed using a spindle-shaped skin incision. The histopathological diagnosis was invasive ductal carcinoma (HER), pT1b (0.8 cm) N0 (sn). Intraductal extension was observed in the collecting duct of the nipple. No NAC deformities were observed 4 years after the surgery (Supplementary Figure 1).

Case 2 (A3–P3)
The left breast cancer occupied the upper outer-portion of the breast. Preoperative breast MRI revealed intraductal contrast under the areola. This technique was performed using a spindle-shaped skin incision. Histopathological diagnosis was DCIS as pTis (DCIS) N0 (sn). Deformation of the NAC was minimal 2 years after surgery (Supplementary Figure 2).

Case 3 (Ax)
The left breast cancer occupied the central portion. Preoperative breast MRI revealed a mass just below the areolar skin. This technique was performed using a T-shaped skin incision. The histopathological diagnosis was invasive ductal carcinoma (LA) as pT1b (0.7 cm) N0 (sn). Deformation of the NAC was minimal 5 years after surgery (Supplementary Figure 3).

DISCUSSION
For early-stage breast cancer with intraductal extension in the NA region, we showed that NAC preservation and even breast conservation can be performed with only partial resection of the NAC. Considering that this procedure has no precedent, we referred to findings of nipple involvement studied for NAC preservation in nipple-sparing mastectomy (NSM) research.
Studies have reported the necessity of ensuring satisfactory margins with NAC [678]. The indications and contraindications of NSM are detailed elsewhere [9]. Avoiding NAC necrosis because of insufficient blood flow as a complication of NSM surgery and ensuring negative margins under the NAC are the most important issues in preserving the NAC; however, these issues conflict with each other and with the local recurrence of NAC after surgery [10111213]. The indication for NSM is shifting from being determined based on clinical findings in cases of nipple involvement to being determined based on the diagnosis of intraductal extension toward the nipple on preoperative MRI [814151617]. Positive margins under NAC are a problem in NSM. The tumor–NAC distance is the most important factor [1517]. On MRI scans, if the tumor-NAC distance is > 1 cm, the margin under the NAC is considered negative, which is not a contraindication for NSM [1517]. Cancer remnants in the nipple have also been studied, with a report pointing to the presence of false-negative margins just below the nipple base and the risk of nipple preservation [14]. When non-mass enhancement extends just below the nipple on preoperative breast MRI scans, approximately half of the lesions are histologically found within the nipple [8].
The technique reported herein was developed on the basis of the idea that if the lesion is in situ under the NA region, the independence of the glandular lobe allows the partial excision of the nipple with lesions and the total layer excision “under the nipple” and the areola with lesions in the NA region with no residual cancer. Therefore, cases not indicated for NSM were included in this study.
Given that tumor diameter is also a risk factor for positive NAC margins [7], most patients in this study were in the early cT stage (cTis or cT1). Most patients (n = 45) had cTis and cT1, indicating that more patients with earlier-stage breast cancer underwent surgery (Table 1). In many cases, pTis was determined to be cT1. On the MRI scans, it was difficult to identify the true infiltrated area buried in the non-infiltrated area.
Intraductal extension into the nipple is not uncommon in breast cancer mastectomy specimens upon close examination of the nipple in mastectomy specimens of breast cancer [1418]. In addition, the rare presence of terminal duct lobular units at the base of the nipple may result in primary breast cancer [6]. Longitudinal nipple resection can prevent residual breast cancer. However, two cases of intraductal extension (P1) had positive margins on the nipple dissection surface. In A1–P1, the positivity rate is as high as 2/6 (Table 2). The following reasons may be considered for this. Although the collecting ducts within the papilla are independent, the main ducts of them are bundled and erect near the center of the nipple [234]. An incision was made on the affected side during the partial nipple resection. The ductal openings at the tip of the teat were not aligned at the edges. Various diameters of ductal openings and lumen sizes of the collecting ducts in the nipple have been reported [23419]. The internal structure of the nipple, as described above, was also a factor contributing to the positive results. Careful consideration should be given to the use of this procedure for the diagnosis of intraductal extension within the nipple (A1). Extending the quadrant resection of the nipple to include the center of the nipple tip as the resection area may be attempted in the future (Figure 2F and G).
Among the 21 patients (A1), only six were diagnosed with P1, indicating a tendency to excessively determine intraductal extension in the nipple preoperatively (Table 2).
Preoperative breast MRI scans with clear contrast of the collecting duct in the nipple have been previously reported to show cancerous growth on postoperative pathology without objective criteria for contrast intensity [2021]. In severely inverted nipples, the difference in height from the chest wall between the most sunken part of the nipple tip and the nipple base was not clear on MRI, nor was the duct running through the nipple. This nipple morphology may have caused overdiagnosis. The higher number of A1 than P1 was partly due to the fear of residual cancer in the inverted and low nipples. A1 and A2 were not clearly distinguishable morphologically on MRI scans; therefore, A1 was used. Because A1 and A2 cannot be clearly distinguished morphologically on MRI scans in inverted or low nipples, protocol changes may be required in the future. Cases that cannot be clearly differentiated may benefit from being classified as their own category. For A1 or A2, surgery can be performed as planned because it also corrects an inverted nipple; similarly, it may be performed for a low nipple because the slope of the nipple tip is not noticeable.
Among the A2 cases, only one (P1) showed a preoperative underestimation of the intraductal extension toward the nipple. Thus, the absence of clear intramammary contrast on preoperative contrast-enhanced MRI scans indicates virtually no intraductal extension into the nipple. A2 was considered a good indication for this procedure, given the absence of a positive margin under the nipple (Table 2).
Positive lateral margins outside the NA region were unrelated to our technique of resecting the NA region, including the intraductal extension toward the nipple (Supplementary Table 2).
Although ILC should be noted for the underestimation of spread on MRI, the margins were negative. In the diagnosis of DCIS spread, there were no lateral margin-positive cases, and the overestimation of Tis as T1 was prominent.
In four cases (Ax), breast cancer with no intraductal extension toward the nipple was observed in the NA region, and the margins were negative, demonstrating the effectiveness of this technique.
Postoperative pathology revealed that breast cancer was present outside the NA region in eight patients (P4), making partial NA excision unnecessary in these patients. At P4, the proportion of TN breast cancer was significantly higher in invasive carcinoma, and the proportion of LB-HER was high in carcinoma in situ, suggesting that these subtypes should be considered candidates for preoperative caution when implementing this technique to reduce P4 (Table 3). The proportion of A1–P4/A1 (1/21), A2–P4/A2 (5/25), and A3–P4/A3 (2/6) became P4 ratio increased as the degree of intraductal extension in the NA region decreased (Table 2). Furthermore, no cases of A3–P1 have been previously reported. For A3, a reduced surgery that completely preserves the nipple and limits the resection line to the area below the nipple, involving only partial resection of the areola, should also be considered (Figure 2H). For A2, the rate of A2–P2/A2 (10/25) was considered high-risk (Table 2).
The percentage of HR-positive and HER2-negative breast cancer without distant metastases has been reported to be 75.2% [22]. Among the subtypes of breast cancer with intraductal extension into the NA region, the proportion of LA (27/44) tends to be similar, and LA is not a specific subtype (Table 3).
Postoperative blood flow in the NAC was good, and no nipple necrosis occurred. None of the patients requested a reoperation. After BCS, displacement between the left and right NACs in the standing position occurred within eight years [23]. However, this study was retrospective, and an objective assessment tool was not initially envisioned. We compared the postoperative breasts using photographs to measure the NAC diameter, which is easy to compare, and used the displacement of the left and right NACs based on the NAC diameter as a standard. A few cases of noticeable deformation and displacement of the NAC were observed (Figure 3). In the future, an objective evaluation must be performed.
A limitation of this study is that it was a retrospective study conducted at a single institution, and the included cases were followed up for < 10 years. Furthermore, the MRI diagnosis of intraductal extension within the nipple depends on nipple morphology. When this procedure is performed for the first time, the target nipple must have normal morphology.
Postoperative irradiation may prevent recurrence in cases that are currently positive for truncation, which can be assessed in a long-term follow-up study.
In conclusion, we evaluated the safety and efficacy of this surgical procedure on the basis of the diagnostic accuracy of MRI. The technique reported in this study involves partial resection of the NAC to ensure a safe zone within the NA region. BCS with partial NA resection may allow for preservation of the NAC and conservation of the breast. This procedure was the first attempt at NAC preservation, and further validation studies are required.