
==== Front
J Breast Cancer
J Breast Cancer
JBC
Journal of Breast Cancer
1738-6756
2092-9900
Korean Breast Cancer Society

39069781
10.4048/jbc.2024.0077
Original Article
Safety of Atypical Ductal Hyperplasia at the Nipple Margin in Nipple-Sparing Mastectomy
https://orcid.org/0000-0002-1220-8146
Zhu Meizhen 1
https://orcid.org/0000-0002-5225-1747
Mao Jiefei 1
https://orcid.org/0000-0001-8381-1893
Fang Jun 2
https://orcid.org/0000-0002-5974-2135
Chen Daobao 1
1 Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
2 Department of Radiation Therapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
Correspondence to Meizhen Zhu. Department of Breast Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, No. 1 Eastern Banshan Road, Hangzhou 310022, China. zhumz@zjcc.org.cn
8 2024
16 7 2024
27 4 260269
27 3 2024
16 5 2024
11 7 2024
© 2024 Korean Breast Cancer Society
2024
Korean Breast Cancer Society
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Purpose

Controversies persist regarding contraindications for nipple-sparing mastectomy (NSM). This study aimed to assess the accuracy of subareolar frozen section analysis and identify risk factors for nipple-areola complex (NAC) recurrence post NSM.

Methods

Consecutive cases of primary invasive breast cancer undergoing NSM at our single center from January 2015 to December 2020 were retrospectively reviewed.

Results

The nipples were retained in 126 patients (127 breasts), and the areola was retained with nipple excision for five breasts. Frozen section analysis demonstrated a sensitivity of 81.8% and specificity of 95.3%. The NAC recurrence rate was 4.3% over a median follow-up period of 48 (30–105) months. An atypical ductal hyperplasia (ADH) at the margin emerged as an independent factor for NAC recurrence in multivariate Cox regression analysis (hazard ratio, 25.464; 95% confidence interval, 1.841–352.145; p = 0.016). Kaplan-Meier survival analysis revealed no statistically significant reduction in overall survival rates (log-rank test, p = 0.660).

Conclusion

Frozen sections of subareolar tissue are reliable and re-excision may be necessary when ADH is detected at the nipple margin in NSM. The NAC recurrence rate was low, and the outcome was favorable following wide local excision.

Breast Neoplasms
Mastectomy
Plastic Surgery Procedures
Recurrence
Medical Science and Technology Project of Zhejiang Province https://doi.org/10.13039/501100017594 2021RC045 Zhejiang Traditional Chinese Medicine Administration https://doi.org/10.13039/501100012175 2020ZB035
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pmcINTRODUCTION

Nipple-sparing mastectomy (NSM) represents a significant revolution in the history of breast surgery, preserving both the nipple-areola complex (NAC) and the breast skin [1]. Its acceptance within the medical community has steadily increased over the last two decades [23]. In comparison to total mastectomy, NSM has demonstrated advantages in terms of enhanced cosmesis, improved body image, and overall patient satisfaction [4]. Moreover, accumulating evidence suggests that NSM is a safe option for appropriately selected patients, with a relatively low risk of local recurrence [56].

However, controversies persist regarding relative contraindications for preserving the NAC, such as tumor-to-nipple distance, human epidermal growth factor receptor 2 (HER2)/neu overexpression, absence of estrogen receptors, high Ki-67 levels, and a younger age [78]. Multiple models have been established to predict NAC involvement [9]. Some institutions utilize intraoperative subareolar frozen sections to determine whether to retain or remove the nipple [810], while others rely solely on permanent paraffin histology [11]. Furthermore, achieving a consensus on the definition of a positive nipple margin, such as atypical ductal hyperplasia (ADH), remains elusive. ADH, a form of atypical hyperplasia often identified at the margin of breast-conserving surgery (BCS), signifies the proximity of the margin to the tumor, indicating a potential risk of recurrence [12]. However, there is still insufficient evidence to justify re-excision of ADH margins during BCS [13]. Notably, there is a dearth of literature addressing the management of nipple ADH margins for NSM.

This study aimed to assess the risk factors and treatment of NAC recurrence, along with the outcomes of patients with breast cancer who underwent NSM in our institution. Additionally, we evaluated the accuracy of subareolar frozen section analysis and share our operational experience in managing positive margins during the procedure.

METHODS

Study population

In this retrospective study, we reviewed all female breast cancer patients who underwent NSM and immediate breast reconstruction at our single center from January 2015 to December 2020. The study received approval from the Clinical Research Ethics Committee of Zhejiang Cancer Hospital (IRB-2020-327) and consent was obtained from all patients. The eligibility criteria included: 1) female patients with histologically confirmed primary invasive breast cancer without prior treatment and 2) patients who underwent NSM and immediate breast reconstruction. Patients were excluded from NSM if they met any of the following contraindications: 1) clinical NAC involvement, such as nipple depression or discharge; 2) radiologically suspected NAC involvement, such as nipple retraction or enhancement at breast magnetic resonance imaging (MRI); 3) inflammatory breast cancer; or 4) preoperative pathological confirmation of Paget’s disease of the nipple.

Surgical techniques

Subareolar frozen sections were prepared for all cases during surgery. Using a cold knife, a piece of tissue approximately 5 mm thick under the areola, including retro-areolar tissue and ductal tissue beneath the bottom of the nipple, was removed and sent for intraoperative frozen section analysis. A positive nipple margin was defined as cancer cells or ADH tissue detected in the frozen section. The intraoperative management of a positive margin included one of the following four strategies, which is determined through discussion among breast surgeons during the operation: subareolar re-shaving, nipple excision with areolar preservation, total NAC excision, or observation only. Specimens of subareolar tissue or removed NAC were routinely sent for permanent histology. In our breast pathology center, the removed NAC was longitudinally divided into two halves along the lactiferous duct, fixed in formalin, and paraffin-embedded for permanent histology. All patients underwent immediate autologous or prosthetic breast reconstruction. Systemic and radiotherapy treatments were determined by a multidisciplinary team.

Data collection

Clinicopathological and survival data, including age (stratified into two categories according to the definition of early-onset breast cancer [14]: ≤ 40 years, > 40 years), type of surgery, systemic and radiotherapy treatment, tumor-nipple distance (TND, measured using MRI and stratified into two categories according to the classification commonly used in previous studies [5]: < 1 cm, ≥ 1 cm), local or extensive calcification at mammography, histological type, single focality or multifocality, histological grade, lymphovascular invasion (LVI), subtype, tumor, node, metastasis (TNM) stage [15], were recorded. T1mi tumors were defined as those with an invasive size ≤ 1 mm in the greatest dimension. Most of the enrolled patients in this category had extensive multifocal ductal carcinoma in situ with microinvasion (DCIS-MI). Two cases of bilateral breast cancer were included. The results of subareolar intraoperative frozen section analysis and permanent final pathology were documented. Cancer recurrence at the NAC or breast flap was confirmed by incisional biopsy, while regional lymph node metastasis or distant metastasis was confirmed by pathology or imaging examination.

Statistical analysis

Categorical variables were analyzed using the χ2 test or Fisher’s exact test for univariate analysis to identify the association between clinicopathologic characteristics with cancer recurrence at the NAC. Univariate and multivariate Cox regression analyses were performed, and prognostic factors (p < 0.05) identified in the univariate analysis were further entered into multivariate analysis to identify independent risk factors associated with cancer recurrence at the NAC. Statistical analysis was conducted using R software (version 4.0.3; R Foundation for Statistical Computing, Vienna, Austria). All reported p-values were two-sided, and p < 0.05 was considered statistically significant.

RESULTS

A total of 137 patients (one with bilateral breast cancer) were initially considered for nipple retention (Supplementary Table 1), but ultimately, the nipples were retained in only 126 patients (one with bilateral breast cancer). The areola was retained with nipple excision for five breasts. Figure 1 shows that, out of 15 breasts with a positive nipple margin in the frozen section, three (20.0%) underwent a subareolar shave for biopsy; five (33.3%) underwent nipple excision with areolar preservation; six (40.0%) underwent total NAC excision; and one (6.7%) underwent observation only, without intervention. The final pathology results revealed tumor involvement or ADH in nine nipples out of these 15 breasts, with two nipples showing ADH of the remaining 123 breasts with a frozen section of a negative nipple margin (8.0% rate of positive nipple margin), in patients who opted for observation only. Notably, for all patients with a positive margin, for whom the NAC was retained, a diagnosed of ADH was determined based on the final pathology results. Among the 11 breasts that underwent nipple removal, only one of excised nipples (9.1%) showed residual tumor involvement. The intraoperative frozen section examination showed a sensitivity of 81.8% (9/11) and a specificity of 95.3% (121/127) (Table 1).

Figure 1 Management strategies and outcomes of frozen section analysis of positive nipple margins.

ADH = atypical ductal hyperplasia; DCIS = ductal carcinoma in situ; IDC = invasive ductal carcinoma.

Table 1 Subareolar frozen section analysis results compared to permanent section analysis results

Variables	Frozen section positive	Frozen section negative	Total	
Final pathology positive	9	2	11	
Final pathology negative	6	121	127	
Total	15	123	138	
Sensitivity (True Positive Rate) = True Positive/(True Positive + False Negative) × 100% = 9/(9 + 2) × 100% = 9/11 × 100% = 81.8%; Specificity (True Negative Rate) = True negative/(True Negative + False Positive) × 100% = 121/(121 + 6) × 100% = 121/127 × 100% = 95.3%.

Cancer recurrence at the NAC

A total of 126 patients (one with bilateral breast cancer, 127 breasts) with nipple or areolar preservation were followed up for a median duration of 48 (30–105) months postoperatively. Among them, 16/127 (12.6%) nipples experienced necrosis. Five patients (4.3%) had NAC cancer recurrence as the first event, four (3.4%) had breast skin or chest wall cancer recurrence as the first event, and two (1.7%) had distant metastases as the first event. Table 2 provides details of the characteristics and treatment of the five patients with NAC cancer recurrence. The time to recurrence ranged from 8 to 74 months. Histologically, the primary tumors were invasive breast cancer in two cases and DCIS-MI in three cases. Recurrent tumor histology identified invasive ductal carcinoma (IDC) in one case and DCIS in four cases. After wide local excision of the NAC, follow-up revealed that the patient with IDC experienced brain metastasis and underwent systemic treatment again. All five patients were still alive at the end of the follow-up period. The 5-year overall survival rates were 100% for patients with cancer recurrence at the NAC as the first event. Kaplan-Meier survival analysis showed no statistically significant differences in overall survival rates between patients with and without NAC recurrence as the first event (log-rank test, p = 0.660) (Figure 2).

Table 2 Characteristics and outcomes of patients with nipple-areola complex recurrence as the first event

No.	Age (yr)	Primary tumor	TTR months	Recurrent tumor	Follow-up after recurrence months	
TNM stage	Histology	Subtype	Margin	Treatment	Histology	Subtype	Treatment	
1	32	T3N0M0	IBC	HR+HER2+	N	CT, T, RT, HT	74	IDC	HR−HER2+	E, CT, T	24	
2	47	T2N0M0	IBC	HR−HER2+	N	CT, T, RT	8	DCIS	HR−	E	61	
3	51	T1miNmiM0	DCIS-MI	HR+HER2+	N	HT	32	DCIS	HR+	E, HT	35	
4	50	T1miN0M0	DCIS-MI	HR+HER2+	ADH	HT	8	DCIS	HR+	E, HT	52	
5	46	T1miN0M0	DCIS-MI	HR+HER2+	ADH	HT	17	DCIS	HR+	E, HT	44	
TNM = tumor, node, metastasis; TTR = time to recurrence; IBC = invasive breast cancer; HR+ = hormone receptor-positive; HER2+ = human epidermal growth factor receptor 2-positive; N = negative; CT = chemotherapy; T = target therapy; RT = radiotherapy; HT = hormonal therapy; IDC = invasive ductal carcinoma; HR− = hormone receptor-negative; E = excision; DCIS = ductal carcinoma in situ; DCIS-MI = ductal carcinoma in situ with microinvasion; ADH = atypical ductal hyperplasia.

Figure 2 Kaplan-Meier curves of overall survival according to the status of nipple-areola complex recurrence as the first event (Log‐rank p = 0.660).

NAC = nipple-areolar complex.

Risk factors for cancer recurrence at the NAC

The clinicopathological characteristics of the 110 breasts with cancer recurrence at the NAC (excluding breasts with locoregional recurrence outside the NAC or distant metastases as the first event) are detailed in Table 3. Univariate analysis (χ2 test or Fisher’s exact test) indicated that ADH at the nipple margin, DCIS-MI histology, T3 stage, and hormone receptor (HR)-positive HER2-positive subtype were associated with cancer recurrence at the NAC (Table 3). Univariate Cox regression analysis showed that the margin and histology results were prognostic factors (p < 0.05). Further multivariate analysis showed that ADH at the margin (hazard ratio, 25.464; 95% confidence interval, 1.841–352.145; p = 0.016) was as an independent factor associated with NAC cancer recurrence (Table 4).

Table 3 Clinicopathological characteristics of the patients and univariate analysis results of factors associated with nipple-areola complex recurrence as the first event

Variables	Patients (109 with one bilateral) (n = 110)*	NAC recurrence (n = 5)	p-value	
Age (yr)			0.398	
	≤ 40	46 (41.8)	1 (20.0)	
	> 40	64 (58.2)	4 (80.0)	
Margin			0.005	
	ADH	3 (2.7)	2 (40.0)	
	Negative	107 (97.3)	3 (60.0)	
Histology			0.035	
	DCIS-MI	19 (17.3)	3 (60.0)	
	IBC	91 (82.7)	2 (40.0)	
LVI			0.584	
	Yes	24 (21.8)	0 (0.0)	
	No	86 (78.2)	5 (100.0)	
Multifocality			0.318	
	Yes	25 (22.7)	2 (40.0)	
	No	85 (77.3)	3 (60.0)	
T stage			0.036	
	T1mi	20 (18.2)	2 (40.0)	
	T1	57 (51.8)	1 (20.0)	
	T2	31 (28.2)	1 (20.0)	
	T3	2 (1.8)	1 (20.0)	
N stage			0.730	
	N0	79 (71.8)	5 (100.0)	
	N1	22 (20.0)	0 (0.0)	
	N2	7 (6.4)	0 (0.0)	
	N3	2 (1.8)	0 (0.0)	
Subtype			0.006	
	HR+HER2−	54 (49.1)	0 (0.0)	
	HR+HER2+	20 (18.2)	4 (80.0)	
	HR−HER2−	14 (12.7)	0 (0.0)	
	HR−HER2+	22 (20.0)	1 (20.0)	
TND (cm)			0.187	
	≤ 1	52 (47.3)	4 (80.0)	
	> 1	58 (52.7)	1 (20.0)	
Extensive calcification			0.590	
	Yes	26 (23.6)	2 (40.0)	
	No	84 (76.4)	3 (60.0)	
Radiotherapy			0.321	
	Yes	34 (30.9)	0 (0.0)	
	No	76 (69.1)	5 (100.0)	
Values are presented as number (%). The p-value < 0.05 was performed as bold-styled p-values.

NAC = nipple-areola complex; ADH = atypical ductal hyperplasia; DCIS-MI = ductal carcinoma in situ with microinvasion; IBC = invasive breast cancer; LVI = lymphovascular invasion; HR+ = hormone receptor-positive; HER2− = human epidermal growth factor receptor 2-negative; HR− = hormone receptor-negative; HER2+ = human epidermal growth factor receptor 2-positive; TND = tumor-nipple distance.

*Four (3.4%) cases suffered breast skin or chest wall cancer recurrence and two (1.7%) cases suffered distant metastases as the first event were excluded in this table.

Table 4 Univariate and multivariate Cox regression analysis results of the factors associated with nipple-areolar complex recurrence as the first event

Variables	Univariable Cox regression analysis	Multivariable Cox regression analysis	
Hazard ratio (95% CI)	p-value	Hazard ratio (95% CI)	p-value	
Margin					
	Negative	1.000				
	ADH	52.000 (7.100–380.000)	< 0.001	27.000 (1.900–370.000)	0.014	
Histology					
	DCIS-MI	1.000				
	IBC	0.15 (0.024–0.880)	0.036	0.430 (0.038–4.800)	0.490	
The p-value < 0.05 was performed as bold-styled p-values.

CI = confidence interval; ADH = atypical ductal hyperplasia; DCIS-MI = ductal carcinoma in situ with microinvasion; IBC = invasive breast cancer.

DISCUSSION

NSM combined with immediate breast reconstruction is a vital surgical approach for selected breast cancer patients, offering improved aesthetic outcomes and psychological confidence, despite ongoing debates on oncologic safety and technical nuances. In our single-center analysis, frozen section assessment demonstrated a sensitivity of 81.8% and a specificity of 95.3%. The NAC cancer recurrence rate, over a median follow-up period of 48 (30–105) months, was 4.3%. Notably, ADH at the margin emerged as an independent factor associated with NAC cancer recurrence. Subsequent wide local excision and tailored systemic treatments led to favorable survival outcomes comparable to patients without NAC recurrence.

Given the global surge in NSM acceptance, broader eligibility criteria for nipple preservation have evolved [16]. According to National Comprehensive Cancer Network guidelines, meticulous patient selection is crucial, with clinical evidence of nipple involvement serving as a contraindication. Intraoperative assessment of the nipple margin is mandatory [17]. In our center, although there is no strict requirement on TNM stage, tumor size, or TND, patients considered for NSM are critically evaluated by physical examination and MRI preoperatively to exclude clinical involvement of the NAC. Routine intraoperative frozen sections of subareolar tissue aim to pathologically exclude NAC involvement, offering early detection and guiding reconstructive planning. As the trend towards single-stage NSM continues to grow globally, accurate intraoperative subareolar frozen section analysis will play an increasingly pivotal role.

The positive rates of the nipple margin have varied due to the definition of NAC positivity in previous studies [1819]. In our study, a positive nipple margin was defined as the presence of cancer cells or ADH tissue in retro-areolar and ductal tissue. The 8.0% positive nipple margin detected in our series aligns with other large-scale studies reporting rates of 5%–10% [2021]. Frozen section assessment demonstrated reliability, showing good concordance with permanent histology, with a sensitivity of 81.8% and a specificity of 95.3%. D'Alonzo et al. [18] reported similar rates of 88.4% for sensitivity and 94% for specificity. The management of positive nipple margins in our center encompassed the following four strategies: subareolar re-shaving, nipple excision with areolar preservation, total NAC excision, or observation only, with the latter being a patient-informed decision. Among the 11 cases of positive nipple removal, only one nipple exhibited residual cancer in permanent paraffin sections, which consistent with prior research findings [22]. This may be attributed to the small foci of cancer cells in the NAC that cannot be identified by current pathological examination techniques. Additionally, tumor cells located in the lactiferous duct may be lost during specimen incision, dehydration, embedding, sectioning, and staining processes [23]. Although there is a possibility of occult tumors in the NAC, the likelihood is relatively low at approximately 11.5%, based on the findings of a previous meta-analysis. Furthermore, the rate would be even lower in carefully selected patients [24].

Previously, several large-scale cohort studies have reported local recurrence rates of 3.5%–6.5% in patients who underwent NSM after 5 years of follow-up. Local recurrence was detected in the NAC at rates of 7.9%–27.3% in these studies [2526]. Wu et al. [82728] reported NAC recurrence rates of 1.9%–4.1%. Our study, after excluding patients with DCIS and with neoadjuvant chemotherapy, showed a relatively low NAC cancer recurrence rate of 4.3% over a median postoperative follow-up period 48 (30–105) months. Numerous studies have delved into risk factors for local recurrence, including the surgical margin, HR status, and TND [2930]. However, there has been a dearth of studies examining risk factors for NAC recurrence using multivariate analysis, often due to a limited number of events. Those studies have indicated that multifocality, negative HR status, HER2-positive subtype, high histological grade, and an extensive intraductal component are associated with cancer recurrence at the NAC [8]. In our study, factors such as ADH at the nipple margin, histology, T stage, and subtype were identified as being associated with cancer recurrence at the NAC. Importantly, ADH at the margin emerged as an independent factor associated with NAC cancer recurrence through multivariable analysis.

ADH represents an atypical proliferative lesion situated between normal hyperplasia and low-grade DCIS. However, a consensus on quantitative versus morphological criteria to distinguish ADH from DCIS has yet to be reached [31]. While studies on ADH at the margin in NSM are limited, several investigations have explored the safety of BCS with margins showing ADH. Current evidence from BCS, including from patients treated with neoadjuvant chemotherapy, suggests that the presence of ADH at surgical margins does not significantly increase the risk of ipsilateral breast cancer recurrence [1332]. This finding implies that routine re-excision of ADH at the margins in BCS may not be necessary. Nonetheless, the management of ADH in NSM remains a subject of controversy. Our study revealed that ADH at the nipple margin was a factor independently associated with NAC cancer recurrence, suggesting the potential necessity for re-excision management of ADH at the margin. Additionally, other factors such as age, histology, LVI, multifocality, TNM stage, subtype, TND, extensive calcification, and radiotherapy were not identified as risk factors for cancer recurrence at the NAC.

Here, we also shared our experience in the management and the outcomes of NAC recurrence. All patients with cancer recurrence at the NAC underwent wide local excision, and the majority received systemic treatment tailored to the recurrent tumor subtype. Only one patient developed distant metastasis and received chemotherapy plus targeted therapy, while the remaining four experienced local recurrence at the NAC. After a median follow-up period of 48 (30–105) months, all five patients were still alive. The survival outcome was similar for patients with and without NAC recurrence. It is noteworthy that NAC recurrence alone presented as a limited lesion with a favorable prognosis.

The main limitation of this study is its retrospective nature and the limited number of patients. However, with a relatively long follow-up time of 48 (30–105) months, our data are comparable to those of previous studies exploring the oncological safety of NSM surgery in a single-center analysis [833]. Furthermore, some studies have investigated the impact of intraoperative or postoperative radiotherapy on NAC recurrence [34]. In our study, none of the five patients with recurrent NAC received radiotherapy. Further research using multicenter prospective studies is warranted to confirm the effect of radiotherapy on NAC.

Our study underscores the reliability of intraoperative frozen section analysis of subareolar tissue for NAC retention. Despite the low incidence of cancer recurrence at the NAC, ADH at the margin emerged as the only independently associated risk factor. Following wide local excision and appropriate systemic treatment, patients with NAC recurrence exhibited a favorable prognosis. These findings suggest that frozen section assessment is dependable, and re-excision may be necessary when ADH is detected at the nipple margin in NSM.

SUPPLEMENTARY MATERIAL

Supplementary Table 1

Clinicopathological characteristics of 137 patients (138 breasts) who underwent nipple-retention surgery

Funding: This work was supported by grants from the Medical Science and Technology Project of Zhejiang Province (2021RC045) and Zhejiang Traditional Chinese Medicine Administration (2020ZB035).

Conflict of Interest: The authors declare that they have no competing interests.

Data Availability: The data that support the findings of this study are available from the corresponding author Meizhen Zhu upon reasonable request.

Author Contributions: Conceptualization: Zhu M.

Data curation: Mao J, Chen D.

Formal analysis: Zhu M.

Funding acquisition: Zhu M.

Investigation: Mao J, Fang J.

Methodology: Zhu M, Mao J, Fang J.

Software: Fang J.

Supervision: Chen D.

Validation: Chen D.

Visualization: Chen D.

Writing - original draft: Zhu M.

Writing - review & editing: Zhu M, Chen D.
==== Refs
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