Subareolar Tissue Biopsy Predicts Occult Nipple Involvement in Nipple-Sparing Mastectomies

Lucy X. Ma, MD; Aya Y. Michaels, MD; Paula S. Ginter, MD


Am J Clin Pathol. 2022;157(2):266-272. 

In This Article

Abstract and Introduction


Objectives: Subareolar tissue is examined during nipple-sparing mastectomy (NSM) to minimize the risk of occult malignancy within the preserved nipple. A positive subareolar tissue biopsy typically warrants subsequent nipple excision. We study the factors associated with a positive subareolar tissue biopsy, the rate of residual malignancy in subsequent nipple excisions, and the value of subareolar tissue biopsy intraoperative frozen section (IOF).

Methods: We identified 1,026 consecutive NSMs with separately submitted subareolar tissue biopsies over a 5.5-year period. Clinicopathologic data were reviewed. We examined concordance rates between subareolar tissue biopsy and subsequent nipple excisions as well as IOF diagnosis and permanent control diagnosis.

Results: Among cases of therapeutic NSM, the rate of a positive subareolar tissue biopsy was 7.2%. Multifocal/multicentric disease (P = .0005), presence of lymphovascular invasion (P = .033), and nodal involvement (P = .006) were significantly associated with a positive subareolar tissue biopsy. Thirty-nine of 41 cases with positive subareolar biopsies underwent subsequent nipple excision, with 20 (51%) showing residual carcinoma. Among all IOF samples, 9 (3.3%) showed a discrepancy between the IOF and permanent diagnoses, mostly because of false-negatives.

Conclusions: A positive subareolar tissue biopsy predicts residual carcinoma in the excised nipples in 51% of cases. IOF is accurate and reliable.


Nipple-sparing mastectomy (NSM) has become an increasingly popular oncologic surgical procedure for both prophylactic and therapeutic indications. Since the 1980s, NSM has been shown to improve cosmetic results and increase patient satisfaction, body image, and psychological adjustment.[1,2] Despite its superior aesthetics, NSM is associated with postoperative complications, such as skin flap and nipple necrosis, as well as oncologic risk. Advances in surgical techniques and tissue-perfusion technology have greatly improved ischemia-related complications.[3,4] The oncologic risk of NSM (ie, the risk of residual malignancy lingering within the preserved nipple-areola complex [NAC]), remains, however. Literature on predictive risk factors for NAC involvement by tumor is varied, and reported risk factors include tumor distance to the nipple, presence of nodal involvement, multicentricity, tumor size, and grade.[5–7] Although the oncologic safety of NSM has been debated, the most recent US National Comprehensive Cancer Network guidelines support the use of therapeutic NSM for early-stage, biologically favorable, and peripherally located tumors (>2 cm from the nipple), provided that there is with no clinical or radiographic evidence to suggest NAC involvement. Additionally, pathologic evaluation of the nipple margin is mandatory.[8,9]

A positive nipple margin biopsy prompts the excision of the nipple or NAC.[10] The overall rates of a positive subareolar tissue biopsy range widely, from 2.7% to 34.2%.[5,11–16] Adding to the confusion, rates of residual malignancy in the excised nipple or NAC following a positive biopsy also range widely, from 0% to 42.3%.[12–14,16–18] Reported low rates of residual malignancy challenge the utility of subareolar tissue biopsy as a predictor of occult nipple involvement and may result in overtreatment of patients with positive biopsy results.

Subareolar tissue biopsy evaluation is performed either as an intraoperative frozen section (IOF) consultation or as a specimen submitted for permanent pathology. The advantage of IOF includes the option for intraoperative removal of the nipple/NAC and conversion of NSM to skin-sparing mastectomy following a positive IOF result. Accordingly, a positive subareolar tissue biopsy on permanent pathology leads to a second, revisionary nipple/NAC excision procedure, which may be distressing for the patient. Additionally, it may negatively affect the final cosmetic appearance because of skin shortage that would otherwise have been corrected during the mastectomy.[15] The disadvantage of IOF concerns its accuracy, particularly with false-positives, because they lead to unnecessary removal of the nipple. Literature on the concordance between IOF and permanent control diagnoses is limited, although recent studies have reported good concordance, ranging from 84.6% to 95.4%.[13,19,20]

Here, we evaluate our institution's frequency of positive subareolar tissue biopsies, the rate of residual carcinoma in nipple/NAC excisions, and the accuracy of IOF. Additionally, we identify variables predictive of occult nipple involvement to improve patient selection for subareolar tissue biopsy IOF.