The Oncological Safety of Nipple-Sparing Mastectomy: A Systematic Review of the Literature with a Pooled Analysis of 12,358 Procedures

Article information

Arch Plast Surg. 2016;43(4):328-338
Publication date (electronic) : 2016 July 20
doi : https://doi.org/10.5999/aps.2016.43.4.328
1Department of Oncoplastic Breast Surgery, London Breast Institute, Princess Grace Hospital, London, UK.
2Department of Oncoplastic Breast Surgery, Medway NHS Trust, Medway, UK.
Correspondence: Kefah Mokbel. Department of Oncoplastic Breast Surgery, The London Breast Institute, Princess Grace Hospital, 42-52 Nottingham Place, London, UK. Tel: +44-207-908-2040, Fax: +44-207-908-2275, kefahmokbel@hotmail.com
Received 2015 May 26; Revised 2016 May 18; Accepted 2016 May 24.

Abstract

Nipple-sparing mastectomy (NSM) is increasingly popular as a procedure for the treatment of breast cancer and as a prophylactic procedure for those at high risk of developing the disease. However, it remains a controversial option due to questions regarding its oncological safety and concerns regarding locoregional recurrence. This systematic review with a pooled analysis examines the current literature regarding NSM, including locoregional recurrence and complication rates. Systematic electronic searches were conducted using the PubMed database and the Ovid database for studies reporting the indications for NSM and the subsequent outcomes. Studies between January 1970 and January 2015 (inclusive) were analysed if they met the inclusion criteria. Pooled descriptive statistics were performed. Seventy-three studies that met the inclusion criteria were included in the analysis, yielding 12,358 procedures. After a mean follow up of 38 months (range, 7.4–156 months), the overall pooled locoregional recurrence rate was 2.38%, the overall complication rate was 22.3%, and the overall incidence of nipple necrosis, either partial or total, was 5.9%. Significant heterogeneity was found among the published studies and patient selection was affected by tumour characteristics. We concluded that NSM appears to be an oncologically safe option for appropriately selected patients, with low rates of locoregional recurrence. For NSM to be performed, tumours should be peripherally located, smaller than 5 cm in diameter, located more than 2 cm away from the nipple margin, and human epidermal growth factor 2-negative. A separate histopathological examination of the subareolar tissue and exclusion of malignancy at this site is essential for safe oncological practice. Long-term follow-up studies and prospective cohort studies are required in order to determine the best reconstructive methods.

INTRODUCTION

In recent decades, advances in breast surgery and reconstruction have led to significant improvements in the quality of life for many patients who have undergone surgery for breast cancer. Although breast-conserving surgery has remained the treatment of choice for many, up to a third of patients still require, or request, a mastectomy in order to achieve local disease control. Currently, the indications for mastectomy include cases of invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) that are not amenable to breast-conserving surgery for a number of reasons, such as the size or distribution of disease, the possibility of a poor cosmetic outcome, local recurrence, contraindications to radiotherapy, or patient preference.

The primary aim of surgical intervention in breast cancer is to achieve optimal local disease control, although secondary aims have emerged, such as good cosmetic outcomes and high patient satisfaction. Mastectomy techniques have evolved from radical and modified mastectomy towards surgical methods that facilitate reconstruction and tend to lead to good cosmetic outcomes: the standard skin-sparing mastectomy (SSM) and, more recently, the nipple-sparing mastectomy (NSM).

Despite its advantages in terms of aesthetic outcomes, the use of NSM is controversial due to concerns regarding its oncological safety based on early reports of high rates of nipple malignancy, potentially leading to increased recurrence rates. However, more recent reports have suggested that the earlier studies may have exaggerated the risk [1]. Although patient satisfaction with the aesthetic outcome and oncological safety have historically been regarded as competing interests, more recently these two aims have evolved to become common goals and are no longer considered mutually exclusive outcomes, given appropriate patient selection. NSM is one such surgical option, designed to allow the local control of disease whilst optimising the cosmetic outcome. In NSM, the mammary tissue is removed, whilst the skin envelope and nipple-areola complex (NAC) are preserved. Preserving the NAC has been reported to be associated with multiple benefits, including better aesthetic outcomes, improved patient satisfaction, and psychosexual benefits, and its removal may, in selected cases, be an instance of overtreatment [2]. Additionally, leaving the NAC in situ can facilitate immediate breast reconstruction [3].

Currently, no universally agreed-upon criteria are used for patient selection for NSM. The suggested parameters include early-stage IBC (stage I to stage II) or DCIS where the tumour has a diameter smaller than 5 cm, is peripherally placed more than 2 cm from the areola, is oestrogen- and progesterone-positive and human epidermal growth factor-2 (HER2)-negative, with no evidence of multifocal or multicentric disease and no lymphovascular invasion [4]. The purpose of this study was to systematically review the literature in order to determine the rate of locoregional recurrence (LR) [5] following NSM as well as to determine the rates of overall complications and nipple necrosis in order to update standards of clinical practice when considering NSM.

METHODS

Search methodology

Electronic searches were performed using the PubMed and Ovid databases for studies evaluating NSM. The search terms that were used included 'nipple sparing mastectomy' and 'total skin sparing mastectomy' along with 'locoregional recurrence' and 'outcomes.' All studies published from January 1970 to January 2015 were reviewed and the references of appropriate articles were also evaluated for further relevant studies.

Selection criteria

The inclusion and exclusion criteria were defined before data collection was initiated. Studies that evaluated outcomes following NSM were included. All forms of reconstruction were included. All studies must have clearly defined whether patients underwent NSM or SSM; if this was unclear, the article was not included. In articles where both SSM and NSM were reviewed, the article was required to clearly state the outcomes of the NSM cohort separately. Retrospective and prospective studies were included. Fig. 1 outlines the selection process. Studies were excluded if they did not report appropriate outcomes as stated, if they did not specify the number of patients and the number of procedures involved, were not printed in English, or were reports, commentaries, reviews or letters.

Fig. 1

Flowchart outlining literature selection process

Data collection and analysis

The following data were collected: authors, study name, publication year, location of the study, journal of publication, type of study, number of patients, number of procedures, inclusion criteria for NSM, type of reconstruction, number of overall complications, nipple necrosis, LR, and aesthetic results. The pooled analysis of the rate of LR, the nipple necrosis rate, and the rate of overall complications was performed based on the number of patients included in each study. The primary outcome measures were the rate of overall LR recurrence, the overall complication rate, and the overall rate of nipple necrosis.

RESULTS

Seventy-three studies [5678910111213141516171819202122232425262728293031323334353637383940414243444546474849505152535455565758596061626364656667686970717273747576] reported LR rates, complication rates, and/or nipple necrosis rate following NSM. Table 1 presents the number of patients, the number of procedures, the LR rate, the complication rate, and the nipple necrosis rate. Almost all of the studies were retrospective (91%). The 73 studies yielded 12,358 procedures in 10,935 patients, and the indications included invasive breast cancer, risk-reduction surgery, and carcinoma in situ. The mean follow-up period was 38.3 months, with a range of 7.9–156 months. Pooled analysis demonstrated an overall LR rate of 2.38%, slightly higher than that found by Endara et al. [77] in 2013. The overall complication rate was 22% and the nipple necrosis rate was 5.9%, both lower than the rates found by Endara and colleagues. The majority of studies were published after 2011, reflecting the increasing popularity of NSM over time. A small subgroup analysis was carried out examining the average complication rates before and after 2013, and the results of this are shown in Fig. 2. A clear reduction was observed in the complication rate and the incidence of nipple necrosis after 2013.

Characteristics of the included studies, with the locoregional recurrence rate (LRR), overall complication rate, and nipple necrosis rate

Fig. 2

Average rates of complications and nipple necrosis

DISCUSSION

According to our pooled analysis, NSM may be an oncologically safe surgical treatment in carefully selected patients with breast cancer, as we found a low pooled LR rate of 2.38%, which is comparable to that found for conventional mastectomy, for which the LR rates for have been reported to be as high as 16% [4]. It can also lead to improved aesthetic outcomes with minimal scarring when combined with reconstruction. The main oncological concern with NSM is the possibility of leaving residual tumour cells within the skin envelope, which may manifest later as LR.

Histological studies following conventional mastectomy have reported residual glandular tissue in 5% of all biopsies, indicating that more radical surgery may not be guarantee of complete clearance [78]. In SSM performed in patients with invasive breast cancer, the prevalence of residual breast tissue has been reported to be as high as 59.5%, with residual disease in 9.5% [79], a finding echoed by Ho et al. [80], who reported that skin flaps exhibited residual malignancy in 23% of cases, most commonly in the skin overlying the tumour. However, a large systematic review from 2012 reported that the overall incidence rate of LR was only 0.9% after a mean follow-up of 38.4 months and that the skin flap recurrence rate was 4.2% following SSM [4], which was much lower than had been reported in single-centre studies.

The concern has been raised that leaving the NAC in situ could provide another site for possible recurrence. We have found a low LR rate, which corresponds to the findings of long-term single-centre studies. Stanec et al. [65] found an LR rate of 3.7% in the breast and 1.2% in the NAC after a mean follow-up of 63 months. Other studies have found no cases of NAC recurrence [4869]. Most recently, Sakurai et al. [55] followed up 788 patients who underwent NSM for an average of 78 months, and reported an NAC relapse rate of 3.7% and an LR rate of 8.2%, stating that no significant difference was found in overall survival and disease-free survival between NSM patients and conventional mastectomy patients at 21 years.

Tumour size is a parameter that has been used in the past to select suitable patients for NSM. In the studies analysed that included data on tumour size, the largest recorded was an average of 3.4±2.2 cm, which showed a 10.3% LR rate over an 18-month follow up [56]. More recently, Leclere et al. [67] reported a 5.3% LR rate in 41 cases, 18 of which involved a tumour size larger than 3 cm Moreover, it appears that as NSM becomes more popular, the number of patients with larger tumours undergoing NSM is steadily increasing, as described by Agarwal et al. [81]. They found that although 50% of patients had tumours less than 2 cm in diameter, the number of patients with tumours larger than 2 cm undergoing NSM increased over time, perhaps because as surgeons have become more familiar and confident with the technique, it has been possible to widen the clinical indications for which NSM can be considered as a management option The currently available data therefore appear to support the use of NSM even with larger tumours, although more long-term follow-up studies with larger populations are required in order to ensure that the risk of LR is minimised.

Another selection parameter that has been suggested is a tumour-to-nipple distance no smaller than 2 cm. Currently, when performing an NSM, a frozen section of the retroareolar tissue is required for intraoperative histological analysis in order to verify that the borders of the NAC are clear of disease. A recent study by Chattopadhyay et al. [66] found a 0% LR rate after 28.5 months in patients with a median tumour-to-nipple distance of 3.8 cm This low LR rate is echoed by Fortunato et al. [56], who found an LR rate of less than 1% after 26 months, despite a tumour-to-nipple distance of just 1 cm in 65% of cases suggesting that previous guidelines requiring a minimum distance of 2 cm may be outdated for carefully selected patients. In order to preoperatively evaluate the tumour-to-nipple distance, it has been suggested that patients undergo magnetic resonance imaging (MRI) before surgery as a way of predicting who would be suitable for NSM. Moon et al. [82] found a significant correlation between NAC enhancement on MRI and malignant invasion of the NAC, reporting a sensitivity of 93.8% and a specificity of 85.7%, indicating that presurgical MRI may be useful in selecting appropriate patients However, not all authors agree on the use of MRI, meaning that a combined approach, utilising both clinical evaluation and imaging techniques, may be best when determining patient suitability for NSM.

The tumour location within the breast is also considered an important parameter when assessing suitability for NSM, as centrally located tumours have been reported to be significantly associated with nipple margin involvement: one study found that centrally located tumours were associated with residual malignancy of the NAC in 40% of cases [68]. Most studies reporting on tumour location support this proposal [483]. Mallon et al. [4], in their large systematic review, stated that a retroareolar or central location was a factor influencing occult nipple malignancy, with an overall incidence of 35.2%, compared to only 9.7% for peripherally located tumours One study suggested that tumour location was the most important parameter in predicting NAC involvement, as only centrally located tumours showed a significant association with nipple involvement [83]. A retrospective study of 219 mastectomies demonstrated that peripheral tumours were found to involve the NAC in only 2.5% of cases, whereas for centrally located lesions the incidence was 68% [84]. In contrast, a recent small study of 28 patients concluded that NSM was an oncologically safe procedure regardless of tumour location [85]. More research is required in larger cohorts before central tumours can be deemed safe for NSM.

The histological subtype of the breast cancer may also have an impact on the LR rate after NSM. A systematic review suggested that the overall LR rate for invasive ductal carcinoma was 14.9%, whilst for DCIS it was 15.3%. The highest LR rate was for invasive lobular carcinoma, with an LR rate of 17.2% [4]. Recently, a study of 934 patients also investigated the LR rate of different histological types with a mean follow-up of 50 months, and found a 3.6% LR rate in the breast and a 0.8% recurrence rate in the NAC in patients who had had invasive carcinoma compared to a 4.9% LR rate in the breast and a 2.9% recurrence rate in the NAC in those who had had intraepithelial neoplasia, supporting the proposal that histological subtype may be an important factor when considering the suitability of NSM [86]. However, Kneubil et al. [45] found that having DCIS as a primary tumour was a significant predictor of NAC recurrence, although the LR rate was still acceptably low at 8.7%. Overall, the evidence regarding the impact of histological type on LR rate is scarce, and currently no adequate study has evaluated the differences in LR between all the different histological subtypes.

A further parameter that has been highlighted is the tumour receptor status, with tumours that are HER2-negative and oestrogen receptor-(ER) and progesterone receptor (PR)-positive having the best outcomes following NSM. Mallon et al. [4] found a significant increase in the LR rate in HER2-positive patients, with an overall incidence of 19.7%, compared to 10.1% in HER2-negative patients. Additionally, ER positivity was found to be protective, with an overall LR rate of 10.8%, compared to 14% in ER-negative patients, a trend also echoed by PR positivity. More recent studies have found similar results. A positive HER2 status has been consistently found to influence LR rates, and most authors agree that HER2 positivity should rule out NSM as an option for surgical management [86]. Petit et al. [86] found in their study that out of 11 patients that had LR, 9 exhibited HER2 overexpression, indicating a strong correlation between HER2 and LR in NSM. The evidence linking ER and PR status and NSM outcomes is currently scant, although a number of studies have examined the risk of LR in patients undergoing conventional mastectomy. One such study found that, with the addition of post-mastectomy radiation, the cumulative incidence of LR was 8.6% vs. 4.4% for ER-negative tumours and ER-positive tumours, respectively, and 8.5% vs. 3.4% for PR-negative and PR-positive tumours respectively [87]. Consequently, it can be concluded that a HER2-negative status coupled with a positive ER and PR status confers the best protection against LR and therefore would be suitable for NSM, providing the patient fits the other criteria discussed above.

Necrotic complications associated with NSM

The overall complication rate and the incidence of nipple necrosis were included as secondary outcomes of the pooled analysis. The overall complication rate was 22.3% and the nipple necrosis rate was 5.9%. Due to the extensive undermining of the NAC during NSM, it is thought that NSM may lead to an increased incidence of necrotic complications. A number of studies have reported data on nipple necrosis, with incidence rates ranging from 3.5% for total nipple necrosis to 12.1% for partial nipple necrosis [30606488]. Necrosis can occur as a quite early complication, with Radovanovic et al. [30] finding a major skin necrosis rate of 3% after just 6 weeks The concern with nipple necrosis is that it can lead to loss of the NAC at a later date [67].

Some studies have assessed whether any risk factors may be associated with an increased risk of nipple necrosis following NSM, because the identification of such risk factors could help clarify patient selection criteria. Some studies have linked a higher nipple necrosis rate with obesity [64], which may be due to the larger breast volume. Another factor that has been found to increase the risk is a positive retroareolar margin [53]; therefore, if possible, it is important to perform frozen section analysis intraoperatively in order to minimise this risk.

Consequently, it would appear that despite the risk of necrotic complications, the actual incidence of necrosis remains low, meaning that NSM may still be a viable option. Those at a higher risk, such as those with a higher body mass index or large breast volume, should be individually assessed for suitability with the options of an autologous tissue flap or two-stage reconstruction discussed in order to minimise the possibility of revisional surgery.

Radiotherapy and NSM

Radiotherapy is an important treatment option in the management of breast cancer, as it has been found to reduce the LR rate, with one study finding that patients who underwent radiotherapy had a LR rate of 8.5% compared to 28.4% in those that did not undergo radiotherapy over a 13-year follow-up period [15]. The use of radiotherapy in NSM has been a major topic of discussion, as it has been associated with an increase in long-term complications; if radiotherapy needs to be administered after a mastectomy, the reconstructed breast can also complicate the planning and delivery of the radiotherapy [89]. Radiotherapy is also associated with complications in the reconstructed breast, such as fat necrosis and volume loss in reconstructions using autologous tissue [90] and capsular contracture in those using implants [91]. In terms of nipple necrosis, however, it appears that including radiotherapy in the treatment of the patient does not increase the risk of NAC necrosis [92].

Preventing complications in NSM

One way in which the complication risk could be reduced is through the use of an acellular dermal matrix (ADM) in the reconstruction process. Small trials examining the use of ADMs with NSM have found that immediate breast reconstruction can be achieved with minimal complications [93]. One advantage is that use of an ADM allows the surgeon to use prepectoral placement, which has been reported to be associated with good patient satisfaction and excellent cosmetic results [94]. An example of NSM with immediate ADM-assisted implant based reconstruction can be seen in Fig. 3. No evidence is yet available on the effect of ADM use on necrotic complication rates.

Fig. 3

Example of bilateral NSM and immediate reconstruction

The use of an ADM should therefore be considered when planning an NSM and immediate reconstruction procedure with the goal of reducing complications.

CONCLUSIONS AND RECOMMENDATIONS FOR PRACTICE

A growing body of evidence suggests that NSM is oncologically adequate for early-stage IBC and DCIS in carefully selected patients. Patients with a peripherally located tumour less than 5 cm in diameter, located more than 2 cm from the NAC, not showing HER2 overexpression, and exhibiting a positive ER and PR status may be considered for NSM with or without adjuvant radiotherapy. NSM can facilitate immediate breast reconstruction, providing an aesthetically superior treatment option for women who are not suitable for breast-conserving surgery. The optimal integration of NSM and radiotherapy has yet to be established, but radiotherapy is not associated with an increased risk of post-mastectomy nipple necrosis. Dual procedures combining NSM and immediate breast reconstruction afford many advantages, including fewer hospital admissions and a reduced need for contralateral breast adjustment in order to achieve symmetry. In order to ensure the best outcomes, it is important to highlight appropriate patient selection in order to minimise the risk of LR, as well as requiring coordination between oncological and reconstructive surgeons and an effective multidisciplinary team. In the future, a meta-analysis investigating all of the factors that affect LR recurrence after NSM should be carried out in order to facilitate optimal long-term outcomes.

Notes

No potential conflict of interest relevant to this article was reported.

References

1. Simmons RM, Brennan M, Christos P, et al. Analysis of nipple/areolar involvement with mastectomy: can the areola be preserved? Ann Surg Oncol 2002;9:165–168. 11888874.
2. Laronga C, Kemp B, Johnston D, et al. The incidence of occult nipple-areola complex involvement in breast cancer patients receiving a skin-sparing mastectomy. Ann Surg Oncol 1999;6:609–613. 10493632.
3. Simmons RM, Adamovich TL. Skin-sparing mastectomy. Surg Clin North Am 2003;83:885–899. 12875600.
4. Mallon P, Feron JG, Couturaud B, et al. The role of nipple-sparing mastectomy in breast cancer: a comprehensive review of the literature. Plast Reconstr Surg 2013;131:969–984. 23629079.
5. Verheyden CN. Nipple-sparing total mastectomy of large breasts: the role of tissue expansion. Plast Reconstr Surg 1998;101:1494–1500. 9583478.
6. Mustonen P, Lepisto J, Papp A, et al. The surgical and oncological safety of immediate breast reconstruction. Eur J Surg Oncol 2004;30:817–823. 15336725.
7. Dao TN, Verheyden CN. TRAM flaps: a reconstructive option after bilateral nipple-sparing total mastectomy. Plast Reconstr Surg 2005;116:986–992. 16163083.
8. Margulies AG, Hochberg J, Kepple J, et al. Total skin-sparing mastectomy without preservation of the nipple-areola complex. Am J Surg 2005;190:907–912. 16307944.
9. Palmieri B, Baitchev G, Grappolini S, et al. Delayed nipple-sparing modified subcutaneous mastectomy: rationale and technique. Breast J 2005;11:173–178. 15871701.
10. Caruso F, Ferrara M, Castiglione G, et al. Nipple sparing subcutaneous mastectomy: sixty-six months follow-up. Eur J Surg Oncol 2006;32:937–940. 16829015.
11. Komorowski AL, Zanini V, Regolo L, et al. Necrotic complications after nipple- and areola-sparing mastectomy. World J Surg 2006;30:1410–1413. 16850148.
12. Mosahebi A, Ramakrishnan V, Gittos M, et al. Aesthetic outcome of different techniques of reconstruction following nipple-areola-preserving envelope mastectomy with immediate reconstruction. Plast Reconstr Surg 2007;119:796–803. 17312480.
13. Denewer A, Farouk O. Can nipple-sparing mastectomy and immediate breast reconstruction with modified extended latissimus dorsi muscular flap improve the cosmetic and functional outcome among patients with breast carcinoma? World J Surg 2007;31:1169–1177. 17464533.
14. Crowe JP, Patrick RJ, Yetman RJ, et al. Nipple-sparing mastectomy update: one hundred forty-nine procedures and clinical outcomes. Arch Surg 2008;143:1106–1110. 19015470.
15. Benediktsson KP, Perbeck L. Survival in breast cancer after nipple-sparing subcutaneous mastectomy and immediate reconstruction with implants: a prospective trial with 13 years median follow-up in 216 patients. Eur J Surg Oncol 2008;34:143–148. 17709228.
16. Sookhan N, Boughey JC, Walsh MF, et al. Nipple-sparing mastectomy: initial experience at a tertiary center. Am J Surg 2008;196:575–577. 18809066.
17. Regolo L, Ballardini B, Gallarotti E, et al. Nipple sparing mastectomy: an innovative skin incision for an alternative approach. Breast 2008;17:8–11. 17870535.
18. Voltura AM, Tsangaris TN, Rosson GD, et al. Nipple-sparing mastectomy: critical assessment of 51 procedures and implications for selection criteria. Ann Surg Oncol 2008;15:3396–3401. 18923874.
19. Wijayanayagam A, Kumar AS, Foster RD, et al. Optimizing the total skin-sparing mastectomy. Arch Surg 2008;143:38–45. 18209151.
20. Stolier A, Stone JC, Moroz K, et al. A comparison of clinical and pathologic assessments for the prediction of occult nipple involvement in nipple-sparing mastectomies. Ann Surg Oncol 2013;20:128–132. 23010730.
21. Paepke S, Schmid R, Fleckner S, et al. Subcutaneous mastectomy with conservation of the nipple-areola skin: broadening the indications. Ann Surg 2009;250:288–292. 19638905.
22. Garcia-Etienne CA, Cody Iii HS 3rd, Disa JJ, et al. Nipple-sparing mastectomy: initial experience at the Memorial Sloan-Kettering Cancer Center and a comprehensive review of literature. Breast J 2009;15:440–449. 19496781.
23. Gerber B, Krause A, Dieterich M, et al. The oncological safety of skin sparing mastectomy with conservation of the nipple-areola complex and autologous reconstruction: an extended follow-up study. Ann Surg 2009;249:461–468. 19247035.
24. Petit JY, Veronesi U, Orecchia R, et al. Nipple sparing mastectomy with nipple areola intraoperative radiotherapy: one thousand and one cases of a five years experience at the European institute of oncology of Milan (EIO). Breast Cancer Res Treat 2009;117:333–338. 19152026.
25. Chen CM, Disa JJ, Sacchini V, et al. Nipple-sparing mastectomy and immediate tissue expander/implant breast reconstruction. Plast Reconstr Surg 2009;124:1772–1780. 19952633.
26. Yueh JH, Houlihan MJ, Slavin SA, et al. Nipple-sparing mastectomy: evaluation of patient satisfaction, aesthetic results, and sensation. Ann Plast Surg 2009;62:586–590. 19387167.
27. Garwood ER, Moore D, Ewing C, et al. Total skin-sparing mastectomy: complications and local recurrence rates in 2 cohorts of patients. Ann Surg 2009;249:26–32. 19106672.
28. Sakamoto N, Fukuma E, Higa K, et al. Early results of an endoscopic nipple-sparing mastectomy for breast cancer. Ann Surg Oncol 2009;16:3406–3413. 19662457.
29. Colwell AS, Gadd M, Smith BL, et al. An inferolateral approach to nipple-sparing mastectomy: optimizing mastectomy and reconstruction. Ann Plast Surg 2010;65:140–143. 20606592.
30. Radovanovic Z, Radovanovic D, Golubovic A, et al. Early complications after nipple-sparing mastectomy and immediate breast reconstruction with silicone prosthesis: results of 214 procedures. Scand J Surg 2010;99:115–118. 21044925.
31. Kim HJ, Park EH, Lim WS, et al. Nipple areola skin-sparing mastectomy with immediate transverse rectus abdominis musculocutaneous flap reconstruction is an oncologically safe procedure: a single center study. Ann Surg 2010;251:493–498. 20134317.
32. Luo D, Ha J, Latham B, et al. The accuracy of intraoperative subareolar frozen section in nipple-sparing mastectomies. Ochsner J 2010;10:188–192. 21603376.
33. Salgarello M, Visconti G, Farallo E. Autologous fat graft in radiated tissue prior to alloplastic reconstruction of the breast: report of two cases. Aesthetic Plast Surg 2010;34:5–10. 19471898.
34. Mladenov M, Chervenyakov P, Daskalova I. Nipple-sparing mastectomy (subcutaneal mastectomy with preserving of the areolomammilar complex) like alternative of the modify radical mastectomy in selected cases. Khirurgiia (Sofiia) 2010;(6):23–27. 21972714.
35. Rawlani V, Fiuk J, Johnson SA, et al. The effect of incision choice on outcomes of nipple-sparing mastectomy reconstruction. Can J Plast Surg 2011;19:129–133. 23204883.
36. Spear SL, Willey SC, Feldman ED, et al. Nipple-sparing mastectomy for prophylactic and therapeutic indications. Plast Reconstr Surg 2011;128:1005–1014. 21738086.
37. Harness JK, Vetter TS, Salibian AH. Areola and nipple-areola-sparing mastectomy for breast cancer treatment and risk reduction: report of an initial experience in a community hospital setting. Ann Surg Oncol 2011;18:917–922. 21308484.
38. de Alcantara Filho P, Capko D, Barry JM, et al. Nipple-sparing mastectomy for breast cancer and risk-reducing surgery: the Memorial Sloan-Kettering Cancer Center experience. Ann Surg Oncol 2011;18:3117–3122. 21847697.
39. Jensen JA, Orringer JS, Giuliano AE. Nipple-sparing mastectomy in 99 patients with a mean follow-up of 5 years. Ann Surg Oncol 2011;18:1665–1670. 21174155.
40. Boneti C, Yuen J, Santiago C, et al. Oncologic safety of nipple skin-sparing or total skin-sparing mastectomies with immediate reconstruction. J Am Coll Surg 2011;212:686–693. 21463813.
41. Yang SJ, Eom JS, Lee TJ, et al. Recipient vessel selection in immediate breast reconstruction with free abdominal tissue transfer after nipple-sparing mastectomy. Arch Plast Surg 2012;39:216–221. 22783529.
42. Schneider LF, Chen CM, Stolier AJ, et al. Nipple-sparing mastectomy and immediate free-flap reconstruction in the large ptotic breast. Ann Plast Surg 2012;69:425–428. 22964678.
43. Spear SL, Rottman SJ, Seiboth LA, et al. Breast reconstruction using a staged nipple-sparing mastectomy following mastopexy or reduction. Plast Reconstr Surg 2012;129:572–581. 22373964.
44. Jensen JA, Lin JH, Kapoor N, et al. Surgical delay of the nipple-areolar complex: a powerful technique to maximize nipple viability following nipple-sparing mastectomy. Ann Surg Oncol 2012;19:3171–3176. 22829005.
45. Kneubil MC, Lohsiriwat V, Curigliano G, et al. Risk of locoregional recurrence in patients with false-negative frozen section or close margins of retroareolar specimen in nipple-sparing mastectomy. Ann Surg Oncol 2012;19:4117–4123. 22820937.
46. Peled AW, Foster RD, Garwood ER, et al. The effects of acellular dermal matrix in expander-implant breast reconstruction after total skin-sparing mastectomy: results of a prospective practice improvement study. Plast Reconstr Surg 2012;129:901e–908e.
47. Moyer HR, Ghazi B, Daniel JR, et al. Nipple-sparing mastectomy: technical aspects and aesthetic outcomes. Ann Plast Surg 2012;68:446–450. 22531398.
48. Warren Peled A, Foster RD, Stover AC, et al. Outcomes after total skin-sparing mastectomy and immediate reconstruction in 657 breasts. Ann Surg Oncol 2012;19:3402–3409. 22526909.
49. Algaithy ZK, Petit JY, Lohsiriwat V, et al. Nipple sparing mastectomy: can we predict the factors predisposing to necrosis? Eur J Surg Oncol 2012;38:125–129. 22056645.
50. Wagner JL, Fearmonti R, Hunt KK, et al. Prospective evaluation of the nipple-areola complex sparing mastectomy for risk reduction and for early-stage breast cancer. Ann Surg Oncol 2012;19:1137–1144. 21979111.
51. Blechman KM, Karp NS, Levovitz C, et al. The lateral inframammary fold incision for nipple-sparing mastectomy: outcomes from over 50 immediate implant-based breast reconstructions. Breast J 2013;19:31–40. 23252505.
52. Tanna N, Broer PN, Weichman KE, et al. Microsurgical breast reconstruction for nipple-sparing mastectomy. Plast Reconstr Surg 2013;131:139e–147e.
53. Lohsiriwat V, Rotmensz N, Botteri E, et al. Do clinicopathological features of the cancer patient relate with nipple areolar complex necrosis in nipple-sparing mastectomy? Ann Surg Oncol 2013;20:990–996. 23070785.
54. Sahin I, Isik S, Alhan D, et al. One-staged silicone implant breast reconstruction following bilateral nipple-sparing prophylactic mastectomy in patients at high-risk for breast cancer. Aesthetic Plast Surg 2013;37:303–311. 23322096.
55. Sakurai T, Zhang N, Suzuma T, et al. Long-term follow-up of nipple-sparing mastectomy without radiotherapy: a single center study at a Japanese institution. Med Oncol 2013;30:481. 23377926.
56. Fortunato L, Loreti A, Andrich R, et al. When mastectomy is needed: is the nipple-sparing procedure a new standard with very few contraindications? J Surg Oncol 2013;108:207–212. 23913775.
57. Burdge EC, Yuen J, Hardee M, et al. Nipple skin-sparing mastectomy is feasible for advanced disease. Ann Surg Oncol 2013;20:3294–3302. 23975304.
58. Rulli A, Caracappa D, Barberini F, et al. Oncologic reliability of nipple-sparing mastectomy for selected patients with breast cancer. In Vivo 2013;27:387–394. 23606696.
59. Romics L Jr, Stallard S, Weiler-Mithoff E. Oncologic safety of skin-sparing mastectomy followed by immediate breast reconstruction: rate and localization of recurrences, and impact of reconstruction techniques. Orv Hetil 2013;154:163–171. 23395741.
60. Munhoz AM, Aldrighi CM, Montag E, et al. Clinical outcomes following nipple-areola-sparing mastectomy with immediate implant-based breast reconstruction: a 12-year experience with an analysis of patient and breast-related factors for complications. Breast Cancer Res Treat 2013;140:545–555. 23897416.
61. Coopey SB, Tang R, Lei L, et al. Increasing eligibility for nipple-sparing mastectomy. Ann Surg Oncol 2013;20:3218–3222. 23975296.
62. Tancredi A, Ciuffreda L, Petito L, et al. Nipple-areola-complex sparing mastectomy: five years of experience in a single centre. Updates Surg 2013;65:289–294. 23888375.
63. Chen J, Lu Q, Wang X, et al. Breast reconstruction after skin-sparing mastectomy or nipple-sparing mastectomy for breast cance]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2013;27:872–875. 24063181.
64. Colwell AS, Tessler O, Lin AM, et al. Breast reconstruction following nipple-sparing mastectomy: predictors of complications, reconstruction outcomes, and 5-year trends. Plast Reconstr Surg 2014;133:496–506. 24572843.
65. Stanec Z, Zic R, Budi S, et al. Skin and nipple-areola complex sparing mastectomy in breast cancer patients: 15-year experience. Ann Plast Surg 2014;73:485–491. 24378808.
66. Chattopadhyay D, Gupta S, Jash PK, et al. Skin sparing mastectomy with preservation of nipple areola complex and immediate breast reconstruction in patients with breast cancer: a single centre prospective study. Plast Surg Int 2014;2014:589068. 25478220.
67. Leclere FM, Panet-Spallina J, Kolb F, et al. Nipple-sparing mastectomy and immediate reconstruction in ductal carcinoma in situ: a critical assessment with 41 patients. Aesthetic Plast Surg 2014;38:338–343. 24477519.
68. Eisenberg RE, Chan JS, Swistel AJ, et al. Pathological evaluation of nipple-sparing mastectomies with emphasis on occult nipple involvement: the Weill-Cornell experience with 325 cases. Breast J 2014;20:15–21. 24438063.
69. Wang F, Peled AW, Garwood E, et al. Total skin-sparing mastectomy and immediate breast reconstruction: an evolution of technique and assessment of outcomes. Ann Surg Oncol 2014;21:3223–3230. 25052246.
70. Kim SW, Lee HK, Kang SM, et al. Short-term outcomes of immediate breast reconstruction using an implant or tissue expander after mastectomy in breast cancer patients. Breast Cancer 2016;23:279–285. 25336184.
71. Adam H, Bygdeson M, de Boniface J. The oncological safety of nipple-sparing mastectomy - a Swedish matched cohort study. Eur J Surg Oncol 2014;40:1209–1215. 25186915.
72. Huston TL, Small K, Swistel AJ, et al. Nipple-sparing mastectomy via an inframammary fold incision for patients with scarring from prior lumpectomy. Ann Plast Surg 2015;74:652–657. 25003464.
73. Sood S, Elder E, French J. Nipple-sparing mastectomy with implant reconstruction: the Westmead experience. ANZ J Surg 2015;85:363–367. 24775119.
74. Peled AW, Irwin CS, Hwang ES, et al. Total skin-sparing mastectomy in BRCA mutation carriers. Ann Surg Oncol 2014;21:37–41. 23982256.
75. Poruk KE, Ying J, Chidester JR, et al. Breast cancer recurrence after nipple-sparing mastectomy: one institution's experience. Am J Surg 2015;209:212–217. 24946727.
76. Yao K, Liederbach E, Tang R, et al. Nipple-sparing mastectomy in BRCA1/2 mutation carriers: an interim analysis and review of the literature. Ann Surg Oncol 2015;22:370–376. 25023546.
77. Endara M, Chen D, Verma K, et al. Breast reconstruction following nipple-sparing mastectomy: a systematic review of the literature with pooled analysis. Plast Reconstr Surg 2013;132:1043–1054. 23924650.
78. Barton FE Jr, English JM, Kingsley WB, et al. Glandular excision in total glandular mastectomy and modified radical mastectomy: a comparison. Plast Reconstr Surg 1991;88:389–392. 1871214.
79. Torresan RZ, dos Santos CC, Okamura H, et al. Evaluation of residual glandular tissue after skin-sparing mastectomies. Ann Surg Oncol 2005;12:1037–1044. 16244800.
80. Ho CM, Mak CK, Lau Y, et al. Skin involvement in invasive breast carcinoma: safety of skin-sparing mastectomy. Ann Surg Oncol 2003;10:102–107. 12620902.
81. Agarwal S, Agarwal S, Neumayer L, et al. Therapeutic nipple-sparing mastectomy: trends based on a national cancer database. Am J Surg 2014;208:93–98. 24581994.
82. Moon JY, Chang YW, Lee EH, et al. Malignant invasion of the nipple-areolar complex of the breast: usefulness of breast MRI. AJR Am J Roentgenol 2013;201:448–455. 23883228.
83. Byon W, Kim E, Kwon J, et al. Magnetic resonance imaging and clinicopathological factors for the detection of occult nipple involvement in breast cancer patients. J Breast Cancer 2014;17:386–392. 25548588.
84. Banerjee A, Gupta S, Bhattacharya N. Preservation of nipple-areola complex in breast cancer: a clinicopathological assessment. J Plast Reconstr Aesthet Surg 2008;61:1195–1198. 17901007.
85. Atiyeh B, Dibo S, Zgheib E, et al. Skin sparing/skin reducing mastectomy (SSM/SRM) and the concept of oncoplastic breast surgery. Int J Surg 2014;12:1115–1122. 25178261.
86. Petit JY, Veronesi U, Orecchia R, et al. Risk factors associated with recurrence after nipple-sparing mastectomy for invasive and intraepithelial neoplasia. Ann Oncol 2012;23:2053–2058. 22231025.
87. Panoff JE, Hurley J, Takita C, et al. Risk of locoregional recurrence by receptor status in breast cancer patients receiving modern systemic therapy and post-mastectomy radiation. Breast Cancer Res Treat 2011;128:899–906. 21475999.
88. Chirappapha P, Petit JY, Rietjens M, et al. Nipple sparing mastectomy: does breast morphological factor related to necrotic complications? Plast Reconstr Surg Glob Open 2014;2:e99. 25289296.
89. Buchholz TA, Kronowitz SJ, Kuerer HM. Immediate breast reconstruction after skin-sparing mastectomy for the treatment of advanced breast cancer: radiation oncology considerations. Ann Surg Oncol 2002;9:820–821. 12374667.
90. Singletary SE, Robb GL. Oncologic safety of skin-sparing mastectomy. Ann Surg Oncol 2003;10:95–97. 12620899.
91. Evans GR, Schusterman MA, Kroll SS, et al. Reconstruction and the radiated breast: is there a role for implants? Plast Reconstr Surg 1995;96:1111–1115. 7568487.
92. Alperovich M, Choi M, Frey JD, et al. Nipple-sparing mastectomy in patients with prior breast irradiation: are patients at higher risk for reconstructive complications? Plast Reconstr Surg 2014;134:202e–206e.
93. Gunnarsson GL, Borsen-Koch M, Wamberg P, et al. How to perform a NAC sparing mastectomy using an ADM and an implant. Gland Surg 2014;3:252–257. 25493257.
94. Reitsamer R, Peintinger F. Prepectoral implant placement and complete coverage with porcine acellular dermal matrix: a new technique for direct-to-implant breast reconstruction after nipple-sparing mastectomy. J Plast Reconstr Aesthet Surg 2015;68:162–167. 25455288.

Article information Continued

Fig. 1

Flowchart outlining literature selection process

Fig. 2

Average rates of complications and nipple necrosis

Fig. 3

Example of bilateral NSM and immediate reconstruction

Table 1

Characteristics of the included studies, with the locoregional recurrence rate (LRR), overall complication rate, and nipple necrosis rate

References Study type No. of patients No. of procedures Type of reconstruction Follow-up time (mo, mean) LRR (%) Complications (%) Nipple necrosis (%)
Verheyden 1998 [5] Retrospective 20 30 Tissue expander/implant 75.5 (mean, range 3–126) 0 (0) 24 (80) 11 (36)
Mustonen et al. 2004 [6] Retrospective 34 34 Direct to implant, tissue expander/implant, autologous tissue 45.6 (mean, range 28.8–69.6) 4 (11.8) 23 (67.6) 6 (17.6)
Dao et al. 2005 [7] Retrospective 16 32 Autologous tissue - - 12 (37.5) 0 (0)
Margulies et al. 2005 [8] Retrospective 31 50 Tissue expander/implant 7.9 (mean, range 0.2–20.2) 0 (0) 9 (18) 7 (14)
Palmieri et al. 2005 [9] Retrospective 18 25 Direct to implant, tissue expander/implant 21 (mean, range 6–52) 0 (0) 1 (4) 1 (4)
Caruso et al. 2006 [10] Prospective 50 51 Implant, autologous tissue 66 (mean, range 9–140) 1 (1.9) 4 (8) 2 (4)
Komorowski et al. 2006 [11] Retrospective 38 38 Direct to implant, tissue expander/implant - - - 5 (13.1)
Mosahebi et al. 2007 [12] Retrospective 71 71 Direct to implant, autologous tissue 48 (mean, range 8–109) 0 (0) - -
Denewer and Farouk 2007 [13] Retrospective 41 41 Autologous tissue 7.9 (mean, range 4–11) 0 (0) 11 (26.8) 1 (2.4)
Crowe et al. 2008 [14] Prospective 110 149 Implant, autologous tissue - - - 2 (1.5)
Benediktsson and Perbeck 2008 [15] Prospective 272 272 - 156 (median, range 2.4–210) 52 (19.1) - -
Sookhan et al. 2008 [16] Retrospective 20 20 Implant 10.8 (mean) 0 (0) 3 (15) 2 (10)
Regolo et al. 2008 [17] Retrospective 70 102 Direct to implant, tissue expander and implant 16 (mean) 0 (0) - -
Voltura et al. 2008 [18] Retrospective 36 51 Autologous tissue 18 (mean, range 2–68) 2 (3.9) - -
Wijayanayagam et al. 2008 [19] Prospective 43 64 Direct to implant, tissue expander/implant, autologous tissue - - 23 (36) 2 (4.7)
Stolier et al. 2008 [20] Prospective 58 82 Direct to implant, autologous tissue - - 10 (7.2) 0 (0)
Paepke et al. 2009 [21] Prospective 96 109 Autologous tissue/ implant 34 (median) 1 (0.91) - 27 (25)
Garcia-Etienne et al. 2009 [22] Retrospective 25 42 Implant 10.5 (median, range 0.4–56.4) 0 (0) 6 (14) 3 (7.1)
Gerber et al. 2009 [23] Retrospective 60 60 Autologous tissue - 7 (11.6) - -
Petit et al. 2009 [24] Prospective 1,001 1,001 Direct to implant 20 (median, range 1–69) 14 (1.4) 358 (35.8) 90 (9)
Chen et al. 2009 [25] Retrospective 66 115 Direct to implant, tissue expander/implant - - - 25 (21.7)
Yueh et al. 2009 [26] Prospective 10 17 Direct to implant, tissue expander/implant, autologous tissue  - - 12 (70.6) 3 (17.6)
Garwood et al. 2009 [27] Prospective 72 106 Direct to implant, tissue expander/implant, autologous tissue 13 (median, range 1–65) 1 (0.9) - 17 (10.4)
Sakamoto et al. 2009 [28] Retrospective 87 89 - 52 (median) 0 (0) - 16 (18)
Colwell et al. 2010 [29] Retrospective 8 14 Direct to implant - - 1 (12.5) 0 (0)
Radovanovic et al. 2010 [30] Prospective 205 214 Direct to implant - - 35 (16) 9 (4.5)
Kim et al. 2010 [31] Prospective 152 152 Autologous tissue 60 (median) 3 (2) 40 (22.6) 40 (22.6)
Luo et al. 2010 [32] Retrospective 52 52 - - - - -
Salgarello et al. 2010 [33] Retrospective 33 42 Direct to implant - - 10 (23.8) 4 (9.5)
Mladenov et al. 2010 [34] Retrospective 52 57 Direct to implant 2-36 0 (0) - 13 (22.8)
Rawlani et al. 2011 [35] Retrospective 20 37 Direct to implant - - 16 (43.2) 9 (24.3)
Spear et al. 2011 [36] Retrospective 101 162 Direct to implant, autologous tissue 36.5 (mean, range 5–243) 0 (0) 46 (28.4) 7 (4.3)
Harness et al. 2011 [37] Retrospective 43 60 Direct to implant 18.5 (mean, range 6–62) 1 (1.7) 12 (20) 5 (8.3)
de Alcantara Filho et al. 2011 [38] Retrospective 200 353 Implant, autologous tissue 10.38 (median, range 0–109) 0 (0) 90 (25.5) 12 (3.3)
Jensen et al. 2011 [39] Prospective 99 149 Tissue expander/implant, autologous tissue 60.2 (median, range 12–144) 3 (2.01) 9 (6) 8 (6.3)
Boneti et al. 2011 [40] Retrospective - 281 Direct to implant, tissue expander/implant 25.3 (mean, range 3–102) 7 (2.5) 20 (7.1) -
Yang et al. 2012 [41] Prospective 92 92 Autologous tissue 18.1 (mean, range 5–34 months) 0 (0) - 12 (13)
Schneider et al. 2012 [42] Retrospective 19 34 Autologous tissue - - 2 (5.8) 1 (2.9)
Spear et al. 2012 [43] Retrospective 15 24 Direct to implant 13 (mean) 0 (0) 10 (41.6) 7 (29)
Jensen et al. 2012 [44] Prospective 20 313 Direct to implant, tissue expander/implant, autologous tissue - - - -
Kneubil et al. 2012 [45] Retrospective - 948 - 64 (median, range 18–113) 10 (1.05) - -
Peled et al. 2012 [46] Prospective 288 450 Tissue expander/implant 252 (56) 4 (0.9)
Moyer et al. 2012 [47] Retrospective 26 40 Direct to implant, tissue expander/implant, autologous tissue - - 16 (40) 15 (37.5)
Warren Peled et al. 2012 [48] Prospective 428 657 Direct to implant, tissue expander/implant, autologous tissue 28 (median, range 3–116) 4 (0.6) - 23 (3.5)
Algaithy et al. 2012 [49] Prospective 45 50 Direct to implant, tissue expander/implant - - - 13 (25)
Wagner et al. 2012 [50] Prospective 33 54 Direct to implant, tissue expander/implant, autologous tissue 15 (median, range 1–29) 0 (0) - 16 (29.6)
Blechman et al. 2013 [51] Retrospective 29 55 Direct to implant - - - 3 (6)
Tanna et al. 2013 [52] Retrospective 51 85 Autologous tissue - - - 11 (12.9)
Lohsiriwat et al. 2013 [53] Retrospective 934 934 Direct to implant, tissue expander/implant, autologous tissue 64 (median, range 18–113) 0 (0) - 40 (4.3)
Sahin et al. 2013 [54] Retrospective 21 41 Direct to implant - - 8 (19) 0 (0)
Sakurai et al. 2013 [55] Retrospective 788 788 - 78 (median) 65 (8.2) - 0 (0)
Fortunato et al. 2013 [56] Retrospective 121 138 Immediate, expaneders, prostheses, autologous flaps 28 (median) 1 (0.72) - 25 (18.1)
Burdge et al. 2013 [57] Retrospective 527 558 Immediate with prostheses or delayed two stage 18 (median) 4 of 39 (10.3) 93 (16.7) -
Rulli et al. 2013 [58] Retrospective 77 87 - 50.3 (mean) 3 (3.3) - 4 (4.6)
Romics et al. 2013 [59] Retrospective 253 253 Immediate reconstruction 112 (median) 21 (8.2) - -
Munhoz et al. 2013 [60] Retrospective 158 158 65.6 (mean) 6 (3.7)
Coopey et al. 2013 [61] Retrospective 370 645 - 22 (mean) 4 of 156 therapeutic cases (2.6) - 11 (1.7)
Tancredi et al. 2013 [62] Retrospective 55 55 Immediate reconstruction 21.7 (mean, range 3–55) 2 (3.6) 8 (14.5) 2 (3.6)
Chen et al. 2013 [63] Retrospective 56 56 Both immediate and delayed 40 (median, range 14–88) 0 (0) 5 (8.9) 0 (0)
Colwell et al. 2014 [64] Retrospective 285 500 Direct to implant, tissue expander/implant, autologous tissue 2.17 yr (mean) - 62 (12.4) 22 (4.4)
Stanec et al. 2014 [65] Retrospective 252 252 Varied 63 (median, range 1–180) 6 (5.5) - 29 (10.1)
Chattopadhyay et al. 2014 [66] Prospective 34 34 Immediate, autologous tissue, silicone implants 28.5 (median, range 18–38) 0 (0) 3 (8.8) 1 (2.9)
Leclere et al. 2014 [67] Retrospective 41 41 Immediate, prostheses, tissue expander or autologous tissue 7.1 ± 2.9 yr (mean, range 2–13 yr) 1 (5.3) - 9 (22)
Eisenberg et al. 2014 [68] Retrospective 215 325 - 33 (median) 1 (0.31) - -
Wang et al. 2014 [69] Retrospective 633 981 Immediate reconstruction 29 (median) 19 (3) 113 (11.6) 10 (1)
Kim et al. 2016 [70] Retrospective 19 19 - 22.4 (mean) 1 (5.3)
Adam et al. 2014 [71] Retrospective 67 69 Immediate implant based reconstruction 36 (median, range 4–162) 0 (0) - -
Huston et al. 2014 [72] Retrospective 318 318 Implant based reconstruction 505 day (mean, range 7–1,504 day) 3 (2.5) - 10 (8.2)
Sood et al. 2014 [73] Retrospective 87 118 - 30 (median) 4 (3.4) - -
Peled et al. 2014 [74] Retrospective 106 212 - 37 (mean) 1/ 27 therapeutic (3.7) - -
Poruk et al. 2015 [75] Retrospective 130 205 - 25.08+18 (mean) 2 (0.1) - -
Yao et al. 2015 [76] Retrospective 201 397 - 32.6 (mean) 4 (1) 10 (2.5) 7 (1.8)
Totals 10,935 12,358 - - 254/10676 (2.38) 1,357/6,091 (22.3) 602/10,143 (5.9)