Mastectomy is inevitable for some breast cancer patients,due to tumor size,tumor multicentric,type of tumor,or other reasons.The NSM and breast reconstruction technique provide a viable choice for these patients.NSM retains the natural envelope of the skin and nipple areola complex,achieving excellent aesthetic results. Neverthless,the preservation of NAC has also raised concern about occult nipple involvement,which has been discussed in many studies.In our study,the incidence of NAC involvement of patients underwent mastectomy and NSM were 14.0%，6.5% respectively.The former was similar to the incidence reported in several studies [15-19]. The difference between this two groups may resulted from that，our surgeons has the inclination to select patients with normal nipple,smaller tumor size,peripheral tumor,and negative lymph node.However,of merely 30 cases in our study,the NAC involvement incidence in NSM may be underestimated.
The local cancer recurrence rates(1.7-10.3%) after NSM have been reported in published studies[8, 20-22], but they had different patients inclusion criteria and duration of follow-up. Smith et al performed NSM for stages 0 to 3 breast cancer patients who had no clinical or imaging evidence of NAC involvement,the rate of local recurrence was 3.7%(median follow-up duration of 51 months).In a study by Kim et al,the incidence of local recurrence was only 2% during a median follow-up of 60 months.The indication of preserving NAC was any stage, any tumor size, and any tumor areola distance tumors with clinically normal nipple. Burdge et al found a local recurrence of 10.3% in patients with locally advanced disease (71.8 % lymph node status was positive,average tumor size was 3.8cm.),and the median follow-up duration was 18 months.During a median follow-up of 24 months in our research,we found the local recurrence was low(3.2%) after NSM,and all patients survived at the last follow-up.To some extent,we had validated the oncological safety of NSM in selected patients.
According to the recommendation of latest NCCN guidelines(2020.v3), the nipple-areolar complex (NAC) could be preserved in cancer patients selected by experienced multidisciplinary teams.Paget's disease, nipple discharge associated with cancer,and imaging evidence of the nipple or subareolar tissues involvement should be excluded,and nipple margin assessment is definitely needed.However,the standard assessment of NSM candidates and indications are still undefined and inconsistent.In our study,frozen section examination of nipple margin(retro-areolar tissue) were conducted in all NSM cases,whose results were all consistent to permanent paraffin sections.One patient sacrificed the NAC due to a positive nipple margin in NSM,but the removed NAC turned out no cancer involved.Smith et al used frozen sections rarely in the procedure of NSM,because they deemed that frozen section was less accurate than permanent pathologic examination,and has difficulty in distinguishing benign atypia from ductal carcinoma in situ (DCIS).In a study by D’Alonzo, a discoid specimen beneath the base of the nipple was obtained as nipple margin.They found that the sub-areolar/nipple tissue assessment had a sensitivity of 42.3% in predicting nipple involvement.Though the frozen sections showed a great concordance(92.1%) with final paraffin-embedded sections,it should be careful to remove the NAC when DCIS was diagnosed in the frozen section examination. Additionally, Ponzone suggested to perform double intra-operative assessment of subareolar ducts and proximal nipple ducts,to increase the sensitivity of intraoperative pathological assessment.
Meanwhile，we observed that patients with abnormal nipple signs(nipple discharge,bleeding,retraction, ulceration,palpable mass, skin thickened) were more likely to have NAC involvement(P＜0.001). Billar found abnormal nipple signs or symptoms had a 61% sensitivity,86% specificity, 45% positive predictive value (PPV), and 92% negative predictive value (NPV) for determining NAC involvement .Though as one of the most common symptoms in breast cancer, nipple discharge is not the contraindication of NAC preservation if there was no evidence of tumor invasion to nipple margin.Since nipple discharge is not necessarily the outcome of tumor invasion to NAC, and NAC only acts as a drain channel when breast cancer invades ducts far from the NAC.As reported，TND,tumor size,tumor location,lymph node status,and HER2 overexpression showed significantly correlation with NAC involment[26-28],which also had been demonstrated in our study.Weidong et al reported that patients with TND≤3cm,pathological tumor size＞2.5cm,central tumor, lymph node metastasis or HER2 overexpression were at higher risk of getting NAC involved .Additionally,they considered the lymphatic vascular invasion(LVI) as another crucial predictive factor,which had been mentioned in other studies as well .Gulben et al categorized patients into different risk groups by using tumor location, number of axillary lymph node status, and LVI.Patients with two or three risk factors were classified among the high-risk group，and patients with no or one risk factors were classified among the low risk group.The possibility of NAC involvement was 11.4 times higher in high-risk group compared to low risk group.
Though the effects of tumor size and TND had been confirmed,it has not been clearly determined the exactly cut-off figures on imaging or pathology.Study showed that the possibility of NAC involvement was lower when TND＞1cm measured by mammography or MRI.Especially for MRI,its NPV and PPV of predicting NAC involvement were 100%,39% respectively.Steen et al found TND＜2cm,tumor size＞2cm measured by MRI were significantly associated with nipple involvement .A study of patients with carcinoma in situ by Hwang et al reported that short TND and suspicion of nipple involvement on mammographic or MRI were predictive factors of NAC involvement,but ultrasound findings were not significantly correlated with NAC involvement.However,Lim found the tumors contacting or invading the nipple on US was significantly correlated with nipple involvement.In our research,all patients accepted ultrasound test preoperatively,which described and recorded the tumor location and tumor size.We found the incidence of NAC involvement in patients with tumor ultrasound size＞4cm，≤4cm were 36.7%，10.3% respectively(P＜0.001). Tumor size measured by ultrasound was significant predictive factors of NAC involvement,and Pearson correlation coefficient analysis demonstrated preoperative ultrasound can accurately represent histopathologic tumor size.Therefore,we confirmed the functional role of preoperative ultrasound test and recommend to apply it in the management of NSM.
As for the predictive model，A recent study produced a preoperative predictive model using seven factors,including MRI tumor size≥4cm, mammographic TND＜1cm,MRI TND＜1cm、MRI nipple enhancement,central tumor,multicentric/multifocal, clinical node involvement.Each factor scores 0 or 1 point,and the total scores were categorized into low (0–3), intermediate (4), or high (5–7) risk group.Patients in high risk group were recommended to sacrifice the NAC,and patients in the intermediate risk group who hoped to preserve NAC could undertake the frozen section examination.Besides,another study by Wang at al proposed a model consisting of tumor location, nuclear grade,and HER2 expression.Schecter at al reported a formula for predicting NAC involvement based on tumor size,TND and stage,which was found to have a sensitivity of 92%, specificity of 77%.The models developed in these studies are basing on more costly image testing or preoperative biopsy.The factors including pathological TND,tumor size,number of metastatic lymph node,HER2 overexpression，were generally known after surgery.Whereas,parameters of the predictive model in our study are much more easier to obtain.Basing on ultrasound tumor size,tumor location,and nipple signs,a predictive model were proposed to provide the possibility of NAC involvement.We found breast cancer patients with abnormal nipple signs,in central location, and tumor size ＞4cm,were most likely to develope NAC involvement (95.4%);patients with normal nipple signs,tumor in peripheral location,and tumor size ≤4cm had a lowest possibility(4.1%) of NAC involvement.