The Place of Nipple-Sparing Mastectomy in the Treatment of Breast Cancer: Review of the Literature

Introduction: Mastectomy with conservation of the nipple-areola complex (NAC) in breast cancer care has been controversial with regards to the oncological safety of this procedure and the risk of complications including NAC necrosis. Aim: The objective of this study is to assess, through a literature review, the safety and reliability of a conservative NAC mastectomy in breast cancer treatment, paying attention to the rate of local recurrence and complications. Methods: A review of the literature was conducted from PubMed data, and articles published between January 2007 and December 2017, using the terms “nipple-sparing mastectomy”, “breast cancer”, “local recurrence”, “necrosis of the nipple”, “global complications”. The articles were analyzed with regards to the following parameters of evaluation: local recurrence, recurrence rate at NAC level, global complication rates and nipple necrosis rates. Results: In the 36 studies we selected, the average rate of local recurrence was 3.23%. The average rate of recurrence at the NAC was 0.81%. The average rate of complications was 20%. The average rate of necrosis of the NAC was 5.9%. The main factors of these recurrences were the tumor size > 5 cm and tumor stage > stage II. Conclusion: Conservative mastectomy of the nipple-areola complex offers an aesthetic advantage and oncological safety in carefully selected patients with breast cancer.


Introduction
The conservative treatment is the main procedure in the treatment of the major-

Methods
We conducted a literature review from PubMed data, and articles published between January 2007 and December 2017, using the terms "nipple-sparing mastectomy", "breast cancer", "local recurrence", "necrosis of the nipple", "global complications" (Figure 1).

Selection Criteria
-Studies had clearly defined patients who underwent mastectomies for breast cancer with preservation of the NAC, the results of this cohort should be indicated separately.
-Indications for breast cancer: Carcinoma in situ or invasive carcinoma.
-All types of reconstructions were included.
-All studies excluded clinical or histological invasion of the NAC.

Data Retrieved from the Articles
The author, year of publication, the number of nipple-sparing mastectomy procedures for breast cancer, the mean age of patients, the stage of the tumor, the tumor size, the histologic tumor type, the lymph node involvement, the average follow-up, the type of reconstruction, radiotherapy linked to treatment rates.
The evaluation parameters: local recurrence, recurrence rate at the NAC level, overall complications and nipple necrosis rates.
We then defined 3 subgroups of studies: -Study Group including stages of tumor.
-Study Group including the rate of patients who underwent radiotherapy.
-Study Group including the types of reconstruction.
Statistical analysis was performed with SPSS Version 20 software, the Pearson correlation test was used to assess correlations between the different impacts: recurrence rate, complication rate and necrosis over settings; follow-up period, the stage of the tumor, linked therapy, the type of reconstruction. Comparisons between groups were made with the Student support test for unpaired series. Differences were considered significant at P < 0.05.

Results
Publications on the place of a nipple-sparing mastectomy in breast cancer treatment are numerous. We selected 36 studies, including 29 retrospective studies and 7 prospective studies. The results and the main characteristics of these studies are listed in Table 1 and Table 2  19 studies showed the rate of complications and 29 showed the nipple necrosis rates.
The complication rate ranged from 0.6% to 42% with an average of 20%. NAC necrosis rate was from 0 to 20% with an average of 5.9%.
The majority of studies were carried out after 2011, a subgroup analysis was performed by examining the average rates of complications and necrosis of the NAC before and after 2011. Prior to 2011, the total complication rates were found in 5 studies with an average of 29.76% and NAC necrosis rate of 6.66%.
After 2011, the average rate of total complications was available for 13 studies, being at 16.24%. Data on nipple necrosis for this period were available in 18 studies with an average rate of 5.43%.
27 studies have provided information on histological types, with a predominance of invasive carcinomas, which represent 53% to 98%.
13 studies included patients with lymph node involvement, with rates ranging from 5% to 63%.
Under study group including tumor stages: Table 3. 11 studies reported information on the stages of the tumor with an average of 28% of tumors in stage 0. 39.4% in stage I, 17% in stage II and 4.91% in stage III.
The local recurrence was 1.4%: for Petit [25] and Maxwell [32] which included only stage I and II, for authors which included stages II and III, it was 2% for Kim and Jansen [27] [31] and 3.7% for Stanec [41].
Sub-group including radiotherapy rates: Table 4. 10 studies reported information on radiotherapy rates, notably the large series published by JY Petit [34] who studied a new protocol consisting of carrying out nipple-sparing mastectomies with associated intra-operative radiotherapy in 934 patients. For other studies, radiotherapy rates varied from 1% to 89.7%, with an average rate of 23.4%. The average rate of local recurrence was 4.75% and recurrence at the NAC is 0.73%. The average rate of necrosis was 5.6% for this group A. El Farouqi, A. Boumzough Open Journal of Obstetrics and Gynecology Sub-group study including the types of breast reconstruction: Table 5. 14 studies reported information for the type of breast reconstruction procedures totalling 2441 with 29.22% of immediate breast reconstruction, 45.84% received follow-up expander prosthesis and 25.37% autologous reconstruction.

Discussion
The current literature review was conducted to provide an overview of the current data available for the nipple-sparing mastectomy in breast cancer treatment and to evaluate the safety of this procedure.
The main constraint found is the oncological safety of this technique with the A. El Farouqi, A. Boumzough

Local Recurrence
Local recurrence after nipple-sparing mastectomy can occur in two ways.
Firstly, glandular tissue could be left behind in the NAC [52], or on the skin pouch in areas difficult to access on the periphery of the gland, especially with incisions in the crease under the breast [53]. Histological studies after conventional mastectomy reported residual glandular tissue in 5% of all biopsies, indicating that radical surgery does not guarantee complete removal [54]. In mastectomies with the preservation of the skin pouch, in patients with invasive breast cancer, the breast tissue was found, in 59.5%, to have cases of residual disease in 9.5% of patients [10]. [50] [51] with a mean follow-up ranging from 7.9 months 65.6 months.
The highest rates of local recurrence after nipple-sparing mastectomy are 11.7% (Geaber [23]) and 24% (Benediktsonn [17]). These figures can be explained by the longer follow-up periods. But there are many biases in these studies. In fact, there were no exclusion criteria, as 40% of tumors were N positive for Benediktsonn [17] and 53% N positive for Gerber [23].
The criteria for nipple sparing mastectomies are not always well defined and vary in studies between institutions.
The procedure has not been performed in patients with clinical involvement of the NAC in case of inflammatory cancer or in case of retro-areal central tumors.
The nipple-sparing mastectomy was performed for stage 0 to III and studies included 11 stages of the tumor, but we have not noticed significantly higher rates of local recurrence or relapse at the NAC in studies including stages II and III.
The tumor size is a parameter that has been used to select patients. In studies including data on tumor size, the largest recorded average tumor size was 3.4 ± 2.2 cm with a local recurrence rate of 10.3% over an 18-month follow-up [59].
More recently, Leclere [60] reported a local recurrence rate of 5.3%, including tumors of more than 3 cm.
Currently available data seem to support the success of the nipple-sparing mastectomy in the case of larger tumors, although longer-term follow-up studies with larger populations are needed to ensure the safety of the procedure.
Another selection parameter that has been suggested is a tumor-nipple distance of >2 cm. Currently, a retro-areal overlap is required for histological analysis to verify that NAC margins are healthy [61]. This overlap can help indicate an occult disease. This ranged from 5.6% to 31% [29]. Aleprovich described retro-areal biopsies as specific and of low sensitivity [62].
A recent study by Chattopadhyay [61] found a local recurrence rate of 0% after 28 months in patients with a mean tumor-nipple distance of 3.8 cm.
This low rate was confirmed by Fortunato [59] who found a local recurrence rate of less than 1% after 26 months follow-up, when tumor-nipple distance was only 1 cm in 65% of cases.

A. El Farouqi, A. Boumzough Open Journal of Obstetrics and Gynecology
Optimal tumor-nipple distance is not yet well defined, and the number of procedures in the studies is small and requires validation by larger studies.
To evaluate this distance preoperatively, clinical examination and imaging techniques are the best way to select patients; Moon [63] found that IBR had a sensitivity of 93.8% and a specificity of 85.7% for predicting the affected NAC.
Lymph node status was not found as a factor affecting the nipple, but there was no consensus to retain it as selection criteria for nipple-sparing mastectomies [25] [33].
Regarding the molecular parameters, the nipple-sparing mastectomy is not recommended in patients with vascular emboli, negative hormone receptors or HER2+, as with these patients local recurrences are more related to these molecular factors than to the preservation of the NAC [20].
Based on these selection criteria, the nipple-sparing mastectomy seems to be a safe procedure from an oncological perspective, in patients with breast cancer.
Although the risk of occult nipple disease is real, local recurrence rates are low.
The factors that expose significantly to the risk of local recurrence, are the tumor size and the stage > II (p < 0.05).

Complications
Several studies have evaluated complication rates and necrosis of the NAC after nipple-sparing mastectomy.
Total complications ranged from 0.6% to 42% with an average of 20%, and necrosis rates of the NAC from 0% to 20%, with an average of 5.29%.
These rates are low despite the necrotic risk of the procedure.
The complication rates and necrosis are lower after 2011, with a significant difference of p < 0.05, which reflects a good control of the surgical technique and the careful selection of patients.
It is likely that NAC necrosis is influenced by factors related to the patient and the surgical technique; authors have found obesity as a risk factor for necrosis [39]. Komorowski [64] showed that patient age of over 45 years is a risk factor.
Garwood [22] found that smoking is a factor associated with necrosis of the NAC. We have, however, not found age to be a factor associated with necrosis of the NAC.
Others have concluded that the type of incision has a negative impact, and this is the case of peri areolar incisions of over 30% of the areolar circumference [65].
Crowe suggests that the lateral incision is best to keep the blood supply to the NAC [66], but from the literature no incision seems to be ideal.
The preservation of subcutaneous fat also allows the preservation of the subdermal vascular network [67], where a thickness of 5 mm has been recommended to avoid necrosis of the NAC [17] [37] [65].
Radiation therapy has been considered by some as a contraindication of the nipple-sparing mastectomy, due to its overall complications [18] [68]. However, radiation therapy is not associated with a high risk of necrosis of the NAC [69].

A. El Farouqi, A. Boumzough Open Journal of Obstetrics and Gynecology
Petit et al. [25], whilst retaining 5 mm of glandular tissue under the NAC, administered an intraoperative dose of radiotherapy to reduce the risk of local recurrence. However, the results are comparable to those not using this technique.
In the 16 studies which included patients who underwent radiotherapy, we have not seen a significant increase in NAC necrosis rates compared to studies that did not include radiotherapy.
Studies including types of reconstruction (Table 4) showed a slight and nonsignificant increase in complication rates in cases of immediate breast reconstruction. This can be explained by a careful selection of patients and the use of acellular dermal matrices. Other studies have reached the same conclusions [70].
Garwood [22] found that immediate breast reconstruction by prosthesis could increase the rate of necrosis and therefore the use of expanders may reduce this risk.
We found that there is no ideal protocol, the decision is based on a preoperative and preoperative assessment of the subcutaneous thickness of the NAC [9] [53].

Conclusions
Despite the heterogeneity of the majority of retrospective studies, variable inclusion criteria and different methodologies, this review of the literature has shown that the nipple-sparing mastectomy is a reliable technique, and is oncologically safe, in patients with breast cancer.
These results have been achieved through a careful selection of patients which is based on clinical and imaging procedures. However, it is necessary to carry out further studies and especially to perform tests to determine further recommendations based on a high level of evidence.