Nipple-Sparing Mastectomy: Large Review Supports Intraoperative Frozen Section Evaluation

Walter Alexander

March 01, 2022

A review of 1026 consecutive nipple-sparing mastectomies with separately submitted subareolar tissue biopsy specimens confirmed the value of subareolar intraoperative frozen section evaluations for predicting residual carcinoma. The analysis, published in the American Journal of Clinical Pathology, that found a positive subareolar tissue biopsy was predictive of carcinoma in the resected nipple in half of cases.

While the superior esthetics, patient satisfaction, body image, and psychological effects of nipple-sparing mastectomy are well documented, nipple-sparing mastectomy is associated with postoperative complications and oncologic risk, specifically of residual malignancy within the preserved nipple-areola complex.

Varying reports of risk factors for nipple-areola complex involvement by tumor in the literature include tumor distance to the nipple, presence of nodal involvement, multicentricity, tumor size, and grade.

The nipple or nipple-areola complex is generally excised after a positive nipple margin biopsy. Positivity ranges vary widely in studies, from 2.7% to 34.2% for subareolar tissue biopsies, and from 0% to 42.3% for residual malignancy in the excised nipple or nipple-areola complex following a positive biopsy. The authors attribute the wide ranges to the absence of standardized patient selection criteria, tissue sampling techniques, and positive margin definitions. The utility of subareolar tissue biopsy as a predictor of occult nipple involvement is challenged by these low reported rates of residual malignancy, because it may result in overtreatment of patients with positive biopsy results.

The use of therapeutic nipple-sparing mastectomy for early-stage, biologically favorable, peripherally located tumors (>2 cm from the nipple) without evidence of nipple-areola complex involvement, however, is supported in the most recent US National Comprehensive Cancer Network guidelines.

The advantage of intraoperative frozen sections over those based on specimens submitted for permanent pathology is that they allow the option of removing the nipple/nipple-areola complex and converting nipple-sparing mastectomy to skin-sparing mastectomy when there's a positive intraoperative frozen section result.

A positive subareolar tissue biopsy on permanent pathology, on the other hand, would lead to a subsequent revision procedure, potentially with less favorable cosmetic outcomes because of skin shortage.

But the disadvantage of the intraoperative frozen section is accuracy, with a potential for false positives leading to unnecessary nipple excision. Limited evidence, however, supports good concordance between diagnoses from intraoperative frozen sections and permanent pathology, with ranges from 84.6% to 95.4%.

The authors of the current study evaluated their own institution's (Cornell Weill, New York City) frequency of positive subareolar tissue biopsies, the rate of residual carcinoma in nipple/nipple-areola complex excisions, and intraoperative frozen section accuracy while also examining variables predictive of occult nipple involvement.

Among 1026 consecutive nipple-sparing mastectomies over a 5.5-year period, 570 nipple-sparing mastectomies were for therapeutic indications (most for invasive ductal carcinoma [348 cases], invasive lobular carcinoma [57 cases], and ductal carcinoma in situ [158 cases]), with 456 for prophylactic indications. Subareolar tissue biopsies were performed for 626 patients.

The positive biopsy rate of 7.2% (41/570) was consistent with historical rates of about 3% to 34%. A positive subareolar tissue biopsy was significantly associated with multifocal/multicentric disease (P = .0005), the presence of lymphovascular invasion (P = .033), and nodal involvement (P = .006).

These findings support other research showing that tumor distance from the nipple and maximum tumor size do not predict occult nipple involvement or other contradictions to nipple-sparing mastectomy.

Among the 39/41 patients with positive subareolar biopsies who underwent subsequent nipple excision, 20 (51%) showed residual carcinoma. This rate was generally higher than in previous reports, and the authors suggest that excision is warranted when subareolar tissue biopsies are positive. Alternative options, such as targeted radiation to the nipple/nipple-areola complex, need further exploration.

The authors state that the error rate of 3.3%, with sensitivity of 70% and specificity of 99%, attests to the reliability of intraoperative frozen section evaluation. Most discrepant cases were false negatives, attributable to sampling and interpretation errors. Low false positive rates and instances of subsequent benign findings on permanent section in this and other studies support the exercise of extreme caution and lean toward designating low-grade or borderline lesions at intraoperative frozen section as negative to prevent the loss of a benign nipple/nipple-areola complex.

Paula S. Ginter, MD, senior author of the study and clinical associate professor of medicine at NYU Langone Health, Mineola, New York, pointed to the low false positive rate among the 246 therapeutic nipple-sparing mastectomy patients in an interview with Medscape Medical News. Among the 20 with a positive intraoperative frozen section nipple biopsy, permanent section confirmed invasive carcinoma in eight and ductal carcinoma in situ in 11. "Based on our evidence, a positive intraoperative frozen section nipple biopsy will predict a positive permanent section diagnosis in 95% of cases," she said.

"Careful selection of patients for frozen section of the nipple margin in patients with high risk features for nipple involvement is a reasonable approach to potentially avoiding a second surgery," said Nina Tamirisa, MD, assistant professor of medicine at M.D. Anderson Cancer Center, in an interview with Medscape. Tamirisa, who was not involved in the study, added, "While false positive results are rare, the surgeon should counsel the patient prior to surgery and take into account patient preference and risk tolerance for a second surgery as part of the shared decision-making process. Additionally, the surgeon should confirm the pathologist's comfort level with intraoperative assessment of the nipple margin, which would impact surgical decision making as well as the patient's cosmetic outcome."

The study was independently supported. Ginter and Tamirisa report no relevant financial relationships.

Am J Clin Pathol. Feb 2022;157:266-272. Abstract

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