Nipple-sparing mastectomy is becoming an increasingly popular approach to the treatment and prophylaxis of breast cancer in appropriate surgical candidates, offering patients the psychological and aesthetic advantages of nipple-areola complex preservation and still providing a safe oncologic procedure.1–5 Traditional criteria for nipple-sparing mastectomy include an early-stage tumor that is smaller than 3 cm, a tumor-to-nipple distance of at least 2 cm, clinically negative axillary lymph nodes, absence of skin involvement on examination, and a negative retroareolar biopsy performed at the time of mastectomy.6
The primary oncologic concern with nipple-sparing mastectomy is the risk of occult nipple-areola complex involvement by disease, which has been reported in 0 to 58 percent of cases in the literature, varying widely between studies because of differences in selection criteria, definitions of nipple-areola complex involvement, and pathologic examination.7–9 More recent data suggest that this rate is closer to 5 to 25 percent.8,10,11 Risk factors for nipple-areola complex involvement include a retroareolar or central tumor location, tumor-to-nipple distance of 2.5 cm or shorter, tumor size greater than 2 cm, multifocal disease, stage III or IV disease, lymphovascular invasion or nodal involvement, estrogen receptor–negative status, progesterone receptor–negative status, and human epidermal growth factor receptor 2–positive status.7–9,12
Numerous studies have demonstrated that the risk of nipple-areola complex involvement increases with decreasing tumor-to-nipple distance.7–9,11–14 However, the cutoff distance for considering a patient an appropriate nipple-sparing mastectomy candidate remains controversial, with different groups recommending a minimum tumor-to-nipple distance of anywhere from 0.5 to 1 cm, to the more conventional 2 cm.7,9,14–16 Jensen argues that the decision to preserve the nipple-areola complex should be based on pathologic data alone, rather than any radiologic determinant of tumor-to-nipple distance.17,18 He advocates that nipple-areola complex preservation should be considered for any woman whose tumor can be excised with clear margins and does not extend to within 1 cm of the nipple-areola complex based on retroareolar biopsy.17,18
Further evidence of direct nipple-areola complex involvement, such as nipple discharge, nipple retraction, or Paget disease, may be elicited with a careful history and physical examination. Direct nipple-areola complex involvement may also be detected on preoperative imaging, which may reveal enhancement or thickening of the nipple-areola complex or direct continuity between the tumor and the nipple-areola complex.11 Magnetic resonance imaging is currently the most accurate imaging modality for assessing tumor size, tumor location, tumor-to-nipple distance, and the morphologic appearance of the nipple-areola complex.7,8,11,12,16,19 Reports of the sensitivity of magnetic resonance imaging in detecting occult nipple-areola complex involvement range from 32 to 61 percent, varying by study and with different definitions of nipple-areola complex involvement in the literature.7,8,11 Interestingly, a 2013 study by Steen et al., which reported a magnetic resonance imaging sensitivity of 56 percent, found that magnetic resonance imaging was actually inferior to a careful history and physical examination (sensitivity, 61 percent) at detecting nipple-areola complex involvement when a tumor-to-nipple distance cutoff of 1 cm was used.8
At the large, tertiary care, academic medical center at which the senior author (M.T.) practices, a tumor-to-nipple distance of less than 2 cm is not considered a contraindication to nipple-sparing mastectomy, provided that the patient has no evidence of direct nipple-areola complex involvement on history, physical examination, or preoperative imaging and otherwise meets the criteria for nipple-sparing mastectomy. For this reason, we have the opportunity to evaluate a large population of women who have undergone nipple-sparing mastectomy without being first selected by tumor-to-nipple distance and to determine whether a short tumor-to-nipple distance, in the absence of other evidence of direct nipple-areola complex involvement, increases the likelihood of nipple-areola complex involvement seen on pathologic examination.
PATIENTS AND METHODS
A retrospective review was conducted of all cases of nipple-sparing mastectomy followed by immediate implant-based reconstruction performed by the senior author (M.T.) between July of 2006 and December of 2014. Institutional review board approval for the study was obtained from Weill Cornell Medical College. Patients who had undergone nipple-sparing mastectomy for therapeutic purposes and who had a preoperative magnetic resonance imaging scan or sonogram available were included. The decision to perform preoperative magnetic resonance imaging and/or sonography was made by the physician working up the initial lesion, whether at our institution or at an outside facility. However, any patient who presented to our institution and was initially considering a lumpectomy would undergo preoperative magnetic resonance imaging (if not already performed) to determine whether they were appropriate candidates for breast conservation. Many of these patients ultimately decided to undergo nipple-sparing mastectomy. Nipple-sparing mastectomy cases performed for prophylactic purposes were excluded from the study, as were those who had neither a preoperative magnetic resonance imaging scan nor a sonogram available for review. Patients were not excluded because of demographic factors, comorbidities, oncologic burden, or postoperative results.
The mastectomies were performed by a number of different breast surgeons operating at the same tertiary care, academic medical center. Retroareolar biopsy specimens were obtained intraoperatively at the time of mastectomy and sent for both frozen and permanent pathologic examination. A single plastic surgeon, the senior author (M.T.), performed all of the breast reconstructions at the same medical center. The reconstructions were performed using either tissue expanders or permanent silicone or saline implants using a standard subpectoral approach. Acellular dermal matrix was placed for inferior and lateral coverage of the prosthesis at the discretion of the senior author. All patients received intravenous antibiotic prophylaxis within 30 minutes of the surgical incision and were prescribed prophylactic antibiotics for 1 week postoperatively. During postoperative visits, all patients were assessed by the senior author. Whenever possible, patients were followed at regular intervals for the first year postoperatively, and then annually.
Preoperative magnetic resonance imaging and sonography reports were reviewed. Patients were first stratified by nipple-sparing mastectomy candidacy using a tumor-to-nipple distance cutoff of greater than 2 cm as seen on sonography and/or magnetic resonance imaging. The same patients were then restratified by nipple-sparing mastectomy candidacy using a tumor-to-nipple distance cutoff of greater than 1 cm. Pathologic data were reviewed and all patients who required nipple-only or nipple-areola complex excision because of nipple-areola complex involvement were identified.
Rates of nipple excision for nipple-areola complex involvement were compared between the nipple-sparing mastectomy candidates and noncandidates using both imaging modalities (magnetic resonance imaging and/or sonography) and both tumor-to-nipple distance cutoffs (>2 cm and >1 cm). Binary variables were analyzed using a chi-square test and p values were reported. Statistical significance was set at a value of p < 0.05.
RESULTS
A total of 425 cases of nipple-sparing mastectomy followed by implant-based breast reconstruction were identified between July of 2006 and December of 2014. After excluding prophylactic cases and cases that had neither a preoperative magnetic resonance imaging scan nor a sonogram, 195 cases met our inclusion criteria. The 195 included patients had an average age of 49.1 years (range, 23 to 79 years), an average body mass index of 21.8 kg/m2 (range, 16.1 to 38.1 kg/m2), an average sternal notch–to-nipple distance of 21.8 cm (range, 16 to 29.5 cm), and an average breast base width of 13.9 cm (range, 10 to 18 cm) (Table 1). Two patients (1.0 percent) were current smokers, three patients (1.5 percent) were diabetics, 16 patients (8.2 percent) had undergone prior radiation therapy, and 76 patients (39.0 percent) had undergone prior lumpectomies (Table 1).
Nipple-only or nipple-areola complex excision was performed for therapeutic purposes in 22 of the 195 patients (11.3 percent). Complete nipple-areola complex excision was performed in eight patients, nipple-only excision in 13 patients, and areola-only excision in one patient. Nipple or nipple-areola complex excision was performed because of a positive retroareolar biopsy frozen section in 13 of the 22 patients. In all 13 of these patients, the retroareolar biopsy permanent pathologic evaluation confirmed the presence of disease with a final diagnosis of ductal carcinoma in situ (n = 6), invasive ductal carcinoma (n = 6), or invasive lobular carcinoma (n = 1). The final resection specimens showed residual disease in seven of the 13 patients and were negative for disease in six patients. Nipple or nipple-areola complex excision was performed because of a positive retroareolar biopsy permanent section in nine of the 22 patients, with a final diagnosis of ductal carcinoma in situ (n = 4), invasive ductal carcinoma (n = 2), invasive lobular carcinoma (n = 2), or intraductal papillary carcinoma (n = 1). The corresponding frozen sections for these nine patients were either negative (n = 4), atypical or suspicious (n = 3), or not sent (n = 2). The final resection specimens showed residual disease or atypia in two patients and were negative for disease in seven patients. Of note, lobular carcinoma in situ was not considered a positive finding on pathologic evaluation. Preoperative sonography had been performed in 169 of the 195 included patients (86.7 percent), magnetic resonance imaging in 152 patients (77.9 percent), and both sonography and magnetic resonance imaging in 126 patients (64.6 percent). Using sonography and a tumor-to-nipple distance cutoff of 2 cm, nipple-areola complex involvement was found in 11 of 103 nipple-sparing mastectomy candidates (10.7 percent) and seven of 66 noncandidates (10.6 percent) (p = 0.988) (Table 2 and Fig. 1). Using a tumor-to-nipple distance cutoff of 1 cm, nipple-areola complex involvement was found in 12 of 129 nipple-sparing mastectomy candidates (9.3 percent) and six of 40 noncandidates (15.0 percent) (p = 0.307) (Table 3 and Fig. 1).
Using magnetic resonance imaging and a tumor-to-nipple distance cutoff of 2 cm, nipple-areola complex involvement was found in 13 of 112 nipple-sparing mastectomy candidates (11.6 percent) and five of 40 noncandidates (12.5 percent) (p = 0.881) (Table 2 and Fig. 2). Using a tumor-to-nipple distance cutoff of 1 cm, nipple-areola complex involvement was found in 14 of 123 nipple-sparing mastectomy candidates (11.4 percent) and four of 29 noncandidates (13.8 percent) (p = 0.718) (Table 3 and Fig. 2).
When both sonography and magnetic resonance imaging were performed, the findings were concordant in 74 patients (57 candidates and 17 noncandidates) using a tumor-to-nipple distance cutoff of 2 cm. Nipple-areola complex involvement was then found in five of 57 concordant nipple-sparing mastectomy candidates (8.8 percent) and two of 17 concordant noncandidates (11.8 percent) (p = 0.711) (Table 2 and Fig. 3). Using a tumor-to-nipple distance cutoff of 1 cm, the sonography and magnetic resonance imaging findings were concordant in 86 patients (79 candidates and seven noncandidates). Nipple-areola complex involvement was then found in six of 79 concordant nipple-sparing mastectomy candidates (7.6 percent) and one of seven concordant noncandidates (14.3 percent) (p = 0.535) (Table 3 and Fig. 3).
Patients were followed postoperatively for an average of approximately 456 days (median, 321 days). Local recurrences developed in nine patients (4.6 percent), and an additional seven patients [nine breasts (4.6 percent)] developed metastatic disease.
DISCUSSION
Numerous studies have demonstrated that the risk of nipple-areola complex involvement increases as tumor-to-nipple distance decreases.7–9,11–14 However, no consensus has yet been reached as to the minimum tumor-to-nipple distance acceptable to allow for nipple-areola complex preservation at the time of mastectomy. Traditionally, a tumor-to-nipple distance cutoff of 2 cm has been considered a criterion for nipple-sparing mastectomy.9,12,16 More recent studies have suggested that tumor-to-nipple distance cutoffs of less than 2 cm may still be appropriate in nipple-sparing mastectomy. In 2016, for example, Ryu et al. performed a retrospective review of 266 nipple-sparing mastectomy cases with negative retroareolar biopsy results and showed that there was no difference in disease-free survival or local recurrence between the patients with tumor-to-nipple distances of less than and greater than 2 cm.15 Similarly, D’Alonzo et al. recommended that a tumor-to-nipple distance of 1 cm on magnetic resonance imaging could be considered a safe cutoff for nipple-sparing mastectomy candidacy based on their 2012 study of 100 mastectomy cases.14 Steen et al. found that even a careful history and physical examination was more sensitive (61 percent) than magnetic resonance imaging (56 percent) at detecting occult nipple-areola complex involvement when a tumor-to-nipple distance cutoff of 1 cm was used.8 A more recent prospective study by Ponzone et al. recommended a tumor-to-nipple distance cutoff of 5 mm in determining nipple-sparing mastectomy candidacy based on their prospective study of 112 nipple-sparing mastectomy cases in which the best predictors of nipple-areola complex involvement were found to be a tumor-to-nipple distance of within 5 mm on magnetic resonance imaging or a positive retroareolar biopsy result.7
Since 2002, Jensen has argued that nipple-areola complex preservation should be considered for any woman whose tumor can be excised with clear margins and does not extend to within 1 cm of the nipple-areola complex, focusing on the pathologic data provided by the retroareolar biopsy as the key determinant of nipple-sparing mastectomy candidacy rather than any preoperative radiologic measurement.17 Jensen has continued to defend his original criteria as others have argued for more conservative tumor-to-nipple distance cutoffs,18 citing the breast conservation therapy data presented in the National Surgical Adjuvant Breast and Bowel Project B-06 study as the most compelling data in support of his recommendations.17,18,20 The B-06 trial did not find any survival advantage after 20 years of follow-up when women with stages I and II breast cancer were randomized to total mastectomy (without nipple-areola complex preservation), lumpectomy alone, or lumpectomy with radiation therapy.20 Surgical margins were considered clear if there were no tumor cells present at the cut margin.20 If one considers a nipple-sparing mastectomy as a “giant lumpectomy,” as suggested by Jensen, it follows that nipple-areola complex excision should not confer any additional survival advantage if the surgical margins are already clear.17,18 Jensen further cites a 2014 consensus statement from the Society of Surgical Oncology and the American Society for Radiation Oncology in support of his guidelines, which argued that surgical margins should be considered clear in breast conservation therapy patients when no tumor cells are present at the inked margin (no ink on tumor).21 The consensus panel found no evidence that more widely clear margins reduced tumor recurrence rates in women with stages I and II invasive breast cancer undergoing lumpectomy with subsequent radiation therapy.21 Although our study supports the guidelines recommended by Jensen and although we agree with his conclusions, we are hesitant to extrapolate oncologic safety data from the breast conservation therapy literature. There are inherent differences in the management and follow-up of breast conservation therapy and nipple-sparing mastectomy patients that limit the generalizability of the breast conservation therapy data to nipple-sparing mastectomy patients. Most significantly, breast conservation therapy patients receive postoperative radiation therapy. Furthermore, breast conservation therapy patients generally receive more aggressive postoperative screening than their nipple-sparing mastectomy counterparts because they still have glandular tissue to be imaged. This may allow for earlier detection and treatment of local recurrences in the breast conservation therapy population. In contrast, local recurrences often have to present as a clinical finding before they are detected in nipple-sparing mastectomy patients.
In our retrospective review of 195 nipple-sparing mastectomy cases, we found no significant difference in the rates of pathology-confirmed nipple-areola complex involvement when cases were stratified by tumor-to-nipple distance using a cutoff of either 2 cm or 1 cm and using sonography, magnetic resonance imaging, or a combination of the two imaging modalities. Unfortunately, because we had access to only the imaging reports and not the images themselves, we were unable to obtain our own tumor-to-nipple distance measurements and were therefore unable to analyze tumor-to-nipple distance cutoffs of less than 1 cm. Nevertheless, we can conclude that a tumor-to-nipple distance as short as 1 cm should not be considered an absolute contraindication to nipple-sparing mastectomy.
As discussed previously, magnetic resonance imaging remains the most accurate imaging modality for determining tumor size and location and for assessing both the morphologic appearance and enhancement patterns of the nipple-areola complex.8,11,12,16,19 Its sensitivity in detecting occult nipple-areola complex involvement has been reported as 32 to 61 percent, depending on the study.7,8,11 In addition to determining the tumor-to-nipple distance, preoperative magnetic resonance imaging can provide evidence of direct nipple-areola complex involvement, such as nipple-areola complex enhancement, nipple-areola complex thickening, or direct continuity between the tumor and the nipple-areola complex.11 Cho et al. have shown that the presence of one of these findings on magnetic resonance imaging is associated with a sensitivity of 61 percent, a specificity of 88 percent, and an accuracy of 85 percent in detecting nipple-areola complex involvement.11 When two or more of these findings are present on magnetic resonance imaging, the sensitivity decreases to 56 percent, but the specificity increases to 99 percent and the accuracy increases to 94 percent.11
Based on these findings, we recommend considering nipple-sparing mastectomy in any patient, regardless of tumor-to-nipple distance, who would otherwise meet traditional nipple-sparing mastectomy criteria and who does not have evidence of direct nipple-areola complex involvement on history, physical examination, or preoperative imaging. The nipple-areola complex can subsequently be excised if the retroareolar biopsy results are positive on either frozen or permanent section, with only small additional morbidity for the patient. In so doing, we aim to minimize unnecessary nipple-areola complex sacrifice and still provide oncologically appropriate ablations.
Limitations of this study include its retrospective nature and the fact that we often had access to only the imaging reports, which prevented us from obtaining our own tumor-to-nipple distance measurements. Under other circumstances, we would have preferred to obtain our own measurements to better standardize these data, and to permit analysis of tumor-to-nipple distance cutoffs shorter than 1 cm. Nevertheless, this study is one of the largest to address the question of tumor-to-nipple distance cutoffs in nipple-sparing mastectomy and provides valuable data about a controversial subject in the literature. It is our hope that this information will help to guide practitioners as they counsel their patients and make their own determinations about nipple-sparing mastectomy candidacy.
CONCLUSIONS
Because no significant differences in the rates of pathology-confirmed nipple-areola complex involvement were seen when the cases were stratified by tumor-to-nipple distance using a cutoff of either 2 cm or 1 cm and using sonography, magnetic resonance imaging, or a combination of the two imaging modalities, we conclude that a tumor-to-nipple distance as short as 1 cm should not be considered a contraindication to nipple-sparing mastectomy. We would recommend instead that nipple-sparing mastectomy be considered in any patient who otherwise meets traditional nipple-sparing mastectomy criteria and who does not have evidence of direct nipple-areola complex involvement on history, physical examination, or preoperative imaging, such as nipple-areola complex thickening, nipple-areola complex enhancement, or direct continuity between the tumor and nipple-areola complex. A standard retroareolar biopsy should be performed at the time of mastectomy, and the nipple-areola complex can be excised if results of this biopsy are positive on either frozen or permanent section. With this recommendation, we aim to minimize unnecessary nipple-areola complex sacrifice and still provide oncologically appropriate ablations.
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