Recently, nipple-sparing mastectomy (NSM) with immediate reconstruction is preferred over skin-sparing mastectomy in patients whose tumors do not involve the nipple-areolar complex (NAC). Equal prognosis relative to that of skin-sparing mastectomy (recurrence or survival) with better cosmesis and quality of life after treatment has been confirmed for NSM.1–3 The delivery of intraoperative radiotherapy (IORT) to the NAC effectively reduces local cancer recurrence over the NAC after surgery, which further expanded the clinical application of NSM.4
Breast conservation therapy (BCT), which is composed of breast-conserving surgery and postoperative moderate-dose radiation therapy to eradicate microscopic residual tumor, is another favorable treatment modality for breast cancer, especially in patients with large breasts and small tumor located distant from the NAC. Breast conservation therapy provides acceptable cosmetic results with compatible prognosis in highly selected patients. With a local relapse rate of 2.8% to 14.8%, however, salvage mastectomy is often required once tumor recurrence develops after BCT.5,6
Radiotherapy is a major therapeutic component of BCT. Thus, surgery on previously radiated tissue is inevitable when local recurrence occurs after BCT. Although salvage mastectomy and immediate reconstruction remain a good choice for local recurrence after BCT,7,8 the role of NSM and immediate reconstruction for such patients remains controversial.9 We started applying NSM and immediate reconstruction in patients with breast cancer at our institute in 2008 whenever NSM was considered a safe procedure and intraoperative nipple core biopsy confirmed the nipple as free of breast cancer. With the gradual increase in NSM, some patients did experience local recurrence after prior BCT and required NSM and immediate reconstruction. The purpose of this study was to review our experiences and evaluate the oncological safety, cosmesis, and possible risk factors associated with complications as well as identify the role of NSM and optimal reconstructive procedures for patients who present with local recurrence after BCT.
MATERIALS AND METHODS
Patients and Selection Criteria
The study was reviewed and approved by the institutional review board committee at Chang Gung Memorial Hospital (IRB No. 201800651B0). A case-controlled, retrospective cohort study was performed with the collection of clinical data from 145 affected breasts in 142 patients who received NSM and immediate reconstruction at Chung Gang Memorial Hospital, Taiwan, between March 2008 and January 2017. Among the 145 affected breasts, 18 were identified as having recurrent breast cancer after BCT. The remaining 127 patients with primary breast cancer were selected as the control group. Patients who received NSM with immediate reconstruction for non-oncological reasons or a salvage procedure immediately after partial mastectomy with positive resection margin were excluded. The patients' demographic, anthropometric, and clinical data such as age, sex, personal history (ie, smoking), and underlying medical history (ie, hypertension, diabetes mellitus) were recorded. Preoperative chemotherapy, radiotherapy, and postoperative chemotherapy and radiotherapy were also collected for risk factor analysis. The cancer type (primary/secondary), tumor stage, affected side, and tumor recurrence were collected. Reconstruction methods were carefully reviewed. Postoperative acute complications were defined as complications that occurred within the first postoperative month. The rest were considered as chronic complications. Delay procedures were also recorded.
The incision placements for NSM were preoperatively discussed and determined by breast and reconstructive surgeons together. Nipple-sparing mastectomies were conducted by breast surgeons using a standard procedure. Nipple core biopsies were obtained, and the specimens were sent for frozen sectioning and intraoperative review by a pathologist to confirm safe preservation of the NAC without cancer involvement. The decision regarding IORT to the NAC was determined preoperatively by the radiation oncologist and breast surgeon and was performed after NSM but before reconstruction.
For autologous tissue reconstruction using free abdominal-based or profunda artery perforator flap, the flaps were elevated simultaneously during mastectomy. Implant-based reconstructions were performed after mastectomy. The decision regarding a direct-to-implant reconstruction or insertion of a tissue expander was made intraoperatively. Briefly, a mammary sizer was inserted subcutaneously and inflated to ideal size after mastectomy. The perfusion of both the preserved skin flap and the NAC were then carefully examined. Indocyanine green was systemically injected and traced using a customized infrared fluorescence video for evaluation of the perfusion to the NAC and skin flap if needed. If the skin flap and NAC were both considered well perfused, a direct-to-implant reconstruction was performed. If the perfusion to the skin flap or NAC was considered compromised, the tissue expander was inserted instead of the implant.
All statistical analyses were performed using SPSS software version 22.0 (IBM, Armonk, NY). For descriptive statistics, Mann-Whitney test was used to investigate continuous variables. The Pearson χ2 test and Fisher exact test were used to investigate associations between 2 categorical variables. P values less than 0.05 were considered statistically significant.
Patient Demographics, Tumor Characteristics, Related Treatments, and Oncological Results
Table 1 lists the patients' demographic data; tumor location, type, and size; cancer stage; preoperative and postoperative chemotherapy and radiotherapy; and oncological results from the 2 groups. No significant differences were observed between the 2 groups regarding age, smoking, hypertension, diabetic mellitus, tumor-affected side, cancer stage, excised tumor/breast volume, pre- and postoperative chemotherapy, or postoperative radiotherapy either for breast cancer recurrence or for distant metastasis (all P values >0.05). As expected, patents in the secondary NSM group have a much higher rate of previous radiation because of the previous breast conservation treatment (0% vs 77.8%, P < 0.001). The oncological results including local recurrence, contralateral breast cancer, and distant metastasis were equivalent between the primary and secondary NSM groups.
Patient Perioperative Characteristics
Table 2 shows the excised breast size and the reconstructive procedures that the patients received after mastectomy. Although the secondary NSM group tended to have more reconstruction done using autologous tissue whereas the primary group tended to have more implant reconstruction, the reconstructive method in both groups did not show any statistical difference (P = 0.090). The flap weight of the transferred flap and implant size were similar in both groups (P = 0.813 and P = 0.219, respectively). On average, the operation time in the secondary NSM group tended to be longer, but the difference did not reach statistical significance. The delivery of single-dose IORT to the NAC after NSM was performed to some of the patients in each group. Its related parameters including dose, irradiation time, and applicator diameter are recorded in Table 3 and are not significantly different between groups (all P > 0.05).
Postoperative Complications and Secondary Procedures
Table 4 illustrates the postoperative complications/revisions including immediate surgical complications and secondary touch-up procedures required during follow-up. The mean follow-up days were similar in both groups (45.3 ± 24.1 vs 45.5 ± 30.1 months, P = 0.367). Surgical complications were classified into vascular insufficiencies that required reexploration in free flaps, bleeding, hematoma, infection, seroma, nipple partial (including minor erosion), or total necrosis and skin flap/wound edge necrosis (divided into debridement and conservative treatment with wound care only). The secondary touch-up procedures were defined as procedures required for correcting the aesthetic result [ie, scar revision, release capsular contracture, nipple revision/reconstruction required nipple tattooing or local flap reconstruction, further deep inferior epigastric artery perforator (DIEP) flap reconstruction to replace implants, implant changes, and prosthesis removal]. Most of these parameters were not significantly different between the 2 groups. Difference was seen in total nipple necrosis, requirement of nipple reconstruction, and free DIEP flap to replace implants, where the secondary NSM group has higher incidence. Secondary breast reconstruction was required using a free DIEP flap in 3 (2.4%) and 3 (16.7%) patients in the primary and secondary NSM groups, respectively (P = 0.026). The reconstructions were performed to replace the implants and enhance reconstruction results.
The incidence of NAC necrosis, when partial and total necrosis rates were counted together, was not significantly different between groups. However, a higher rate of total nipple loss was observed in the secondary NSM group (0.8% vs 11.1%, P = 0.041). As a result, more nipple reconstructions as delay procedures were required in the secondary NSM group when compared with the primary NSM group (0.8% vs 11.1%, P = 0.041).
Looking specifically into the reconstruction method and complications regarding skin flap/wound edge necrosis and nipple partial or total necrosis, we further divided the secondary NSM group into 2 groups according to reconstruction method, that is, implant and autologous tissue reconstruction. The difference regarding the complications was nonsignificant (Table 5). Because IORT has been delivered to the NAC to enhance oncological results, the relationship between nipple and skin flap viability was also investigated. Table 6 illustrates the relationship between IORT and complications regarding nipple and skin flap perfusion in each group. The IORT did not have a significant effect on NAC viability with regard to the need for debridement or conservative wound care of nipple or skin necrosis in either the primary or secondary NSM group. In advance, when we compare patients who received IORT in the primary and secondary NSM groups, we again did not find significant difference with regard to nipple and skin flap complications. To understand whether previous radiation would impact the perfusion of nipple or skin flap, we compared the patients in the secondary NSM group who previously received radiotherapy with and without IORT in the current treatment. Previous radiotherapy did not increase the risk of nipple or skin flap necrosis (Table 7).
In current study, we found NSM with immediate reconstruction to be a safe and reliable procedure as a salvage surgery for breast cancer recurrence after BCT. Despite the fact that many of the patients with a history of BCT received prior surgery and radiotherapy, NSM presented with an equal overall complication rate, NAC viability, and local tumor recurrence compared with patients who received the same surgery as a primary procedure for breast cancer treatment.
Recently, NSM with immediate reconstruction has become a favorable option for breast cancer surgery when performed in highly selected patients. However, NSM carries an average tumor recurrence rate from 0% to 12%.10,11 Surgical complications, such as skin flap necrosis, were reported, ranging from 0% to 19.5%,12,13 with the possibility of NAC necrosis. In 1 recent systemic review study of the oncological safety of primary NSM, the average locoregional recurrence rate was found to be 2.38% and overall complication rate around 22.3%. The overall incidence of nipple necrosis, either partial or total, was around 5.9%.14 Nipple-areolar complex necrosis is a particular issue when patients have risk factors such as smoking, young age, higher body mass index, periareolar skin incision for mastectomy, or previous irradiation.15–20 Despite the concern that NSM may have a higher complication rate when performed in patients who had received previous radiation to the breasts and that irradiation is a major therapeutic component of BCT, it remains a considerable option when local recurrence occurs after BCT basing on our results. The incidence of preoperative radiotherapy was as high as 77.8% in our secondary NSM group; only 4 patients did not receive radiotherapy because of the type of tumor or patient personal factors. Although the incidence of preoperative radiotherapy was high for patients with previous BCT, similar overall results were found between the primary and secondary NSM groups in the current study. The only difference identified was total nipple necrosis rate, the requirement of nipple-areolar reconstruction, and the request of replacing implant with a free DIEP flap.
The overall acute complication rates in the primary and secondary NSM groups were 46.5% and 33.3%, respectively. The most frequent complications were skin necrosis (26.8% and 22.2% in the primary and secondary NSM groups, respectively) followed by nipple necrosis (18.9% and 11.1%, respectively). In-depth exploration of the results determined that nipple necrosis presented either locally in part of the nipple or total nipple necrosis. The total nipple necrosis rate was higher in the secondary NSM group (0.8% vs 11.1% in primary and secondary NSM, respectively; P = 0.041). Secondary nipple reconstruction was performed in 1 (0.8%) and 2 (11.1%) patients in the primary and secondary NSM groups, respectively. Higher requirement of nipple-areolar reconstruction is a reasonable result from higher total nipple necrosis rate in the secondary NSM group.
Factors that determined the viability of the skin flap and the NAC include surgical skills and previous radiation history. Preservation of adequate skin flap thickness and avoidance of thermal injuries are equally important to ensure well-perfused skin and NAC after mastectomy. In addition, previous radiotherapy may also play an important role. Of note, patients with secondary BCT often received radiotherapy after the first surgery. Our results did reveal a much higher incidence of previous radiotherapy history in the secondary NSM group, which is considered as contributing factors to the complications. In addition, our breast cancer treatment group started delivering IORT into the NAC in 2012 to help reduce local recurrence in the NAC after treatment. Supportive information regarding the use of IORT has been reported with good local control of the disease along with preservation of cosmesis with additional use of IORT.21 Intraoperative radiotherapy of NAC achieved comparable results with delay irradiation.4 In our series, IORT has been applied in a certain number of patients in both the primary and secondary NSM groups in this study with similar settings for irradiation and diameters of the applicators for IORT and dosing. The use of IORT in patients with secondary NSM raises the concern of damaging perfusion to the NAC given a previous history of radiation. According to our results, however, IORT on NAC did not contribute to higher incidence of partial or total nipple necrosis, either in the primary or secondary NSM groups (Tables 6, 7). Even if patients received previous radiotherapy, our results showed that the delivery of IORT or not to the NAC presented equal nipple or skin necrosis rate (Table 7). A possible reason for skin flap necrosis could be that radiotherapy blocked collateral perfusion across the NAC to the skin flap. After the learning curve and refinement of the IORT dosing and timing, we experienced less cases of skin flap necrosis that required debridement. Besides adjusting the dosing and delivery of IORT, we believe that the reconstructive method may play a role to reduce skin/nipple necrosis territory or depth because a well-vascularized tissue (autologous tissue) underneath the preserved nipple/skin flap can provide an environment for revascularization.
Along with our findings that more reconstructions in the secondary group were achieved using autologous tissue (not statistical significant), our experience suggested that delivery of well-vascularized tissue for reconstruction plays a positive role in preventing complications. In addition, many of these patients presented preoperatively with asymmetric breasts regarding volume, shape, and NAC level. Taken together, the aforementioned factors indicate that autologous tissue carries a unique advantage for reconstruction. Not only does this approach deliver a well-vascularized tissue under the breast skin and deliver perfusion to the NAC and skin flap, with skin paddle, but it also provides a valuable tissue replacement to correct the unbalanced NAC level (Figs. 1 and 2).
There were no different in secondary touch-up procedures between the primary and secondary NSM groups, suggesting an equal satisfaction of the aesthetic outcome between the primary and secondary NSM groups. Capsular contracture remains the main indication for revision surgeries for both groups. Interestingly, we also find that more patients requested a DIEP flap to replace the breast implant as a delay procedure in the secondary NSM group. Considering the unbalanced NAC and relative insufficiency of skin flap after previous BCT, symmetric aesthetic results are hardly achieved with the use of implant in unilateral breast reconstruction (either direct to the implant or tissue expander following with implant reconstruction). The requirement of a well-vascularized autologous tissue transfer (such as free DIEP flap in our series) to replace the breast implant is considered a reasonable choice.
With matched preoperative factors, including affected side, cancer type, mastectomy volume, cancer stage, pre- and postoperative chemotherapy, and radiotherapy, secondary NSM presented equal cancer recurrence rate with primary NSM. In a recent study from Murphy et al,22 in which the authors discussed the NSM for the management of recurrent breast cancer, they advocate the advantage of performing NSM with regard to ipsilateral recurrent breast cancer with low complication rate, and oncological safety in the short-term follow-up period also echoed our conclusion. A literature review identified a nipple recurrence rate from 0% to 12%.23 Our results seem to be very compatible with the reported results.
The application of NSM with immediate reconstruction for tumor recurrence after BCT aims to restore cosmesis; however, surgical and oncological safety should be emphasized. Our study confirmed similar surgical morbidity and tumor recurrence rates when the patients' general conditions were matched between primary and secondary NSM. The results supported the safety of performing NSM and immediate reconstruction in patients who develop local recurrence after BCT. However, specific considerations should be taken into account to avoid complications and manage properly poor tissue perfusion after previous BCT and radiotherapy. The use of autologous tissue can be a good option. Unlike autologous tissue, the use of direct-to-implant or tissue expander implantation for reconstruction after NSM requires well-perfused breast skin flap and NAC. As mentioned earlier, skin flap/nipple necrosis can be multifactorial. Besides previous radiation, surgical technique and thermal injury also present as important determining factors. Our group has been working gently to handle the skin flap and use plasma blade instead of traditional electrocauterization to reduce thermal injury during NSM. Poor skin flap perfusion increases the risk of poor wound healing and the resulting loss of the implant/tissue expander. We recommend immediate survey of tissue perfusion of both the skin flap and NAC by systemic indocyanine green injection. Downgrade reconstruction from implant into tissue expander, or even abandon reconstruction, should be considered once inadequate tissue perfusion is observed. In our study, we experienced 2 cases of nipple total loss in the secondary NSM group, who eventually required nipple reconstruction despite equal nipple complication between both groups. This also advocates the importance of checking the skin flap condition, especially the NAC circulation, and could give us a hint during the surgery, which could avoid further necrosis.
Despite the desirable results achieved in this report, our study presented with several limitations. The number of cases included in this study was relatively small with short follow-up times; further prospective study with more patient numbers and longer follow-up time will be performed years later to further conclude oncological safety.
Prior BCT did not contribute to higher surgical complications in patients who received NSM and immediate reconstruction as a salvage procedure after tumor local recurrence. Nipple-sparing mastectomy can be considered a good treatment option in highly selected patients after cancer recurrence with compatible overall surgical safety, oncological safety, and cosmesis. Care should be taken for possible higher nipple total necrosis rate in the secondary NSM patients, which could be avoided by meticulously checking the circulation of NAC intraoperatively in selected patients.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
nipple-sparing mastectomy; breast reconstruction; breast conservation therapy; flap reconstruction; implant