Breast neurotization along with breast reconstruction after nipple sparing mastectomy enhances quality of life and reduces denervation symptoms in patient-reported outcome: a prospective cohort study

Abstract

Objective:

Persistent postoperative sensory loss significantly limits breast reconstruction following mastectomy. In addition, the absence of sensation profoundly impacts patients’ physical well-being and overall quality of life. New surgical techniques involving nerve autograft intercostal nerve elongation have been introduced to neurotize reconstructed breasts. However, patient quality of life after neurotization has not been well evaluated. This study aimed to investigate improvements in patient quality of life in association with breast neurotization.

Methods:

A prospective cohort study of 132 patients treated at Chang Gung Memorial Hospital between January 2018 and December 2022 was conducted. Two groups of patients who underwent nipple-sparing mastectomy (NSM) and breast reconstruction were compared: those with (n = 67) and without (n = 65) breast neurotization. Patient-reported outcomes were assessed via the BREAST-Q reconstruction module questionnaire and an additional questionnaire measuring sensation, nipple satisfaction, and breast symptoms. Objective measurements were conducted via the Semmes–Weinstein monofilaments test.

Results:

With respect to patient-reported outcomes, the innervated group had significantly higher scores for nipple sensation and on the BREAST-Q domains of psychosocial well-being (71.6 ± 18.1 vs. 62.8 ± 18.6, P = 0.006), sexual well-being (56.9 ± 22.1 vs. 47.3 ± 20.7, P = 0.015), satisfaction with the medical team, as well as less frequent post-operative breast symptoms. In the subgroup analysis, the innervated group demonstrated higher scores in both autologous flap and implant-based reconstruction. Linear regression revealed a statistically significant relationship between objectively measured monofilament value and subjectively examined patient-reported outcomes: nipple sensation, breast sensation, and BREAST-Q score for the psychosocial well-being domain (coefficient: −4.922, P = 0.033).

Conclusion:

Breast reconstruction with autologous nerve graft neurotization yields improved sensory outcomes and has a statistically significant positive impact on the quality of life of breast reconstruction patients.

Introduction

Breast cancer is a prevalent concern among women worldwide, and mastectomy is often a necessary part of treatment. Although breast reconstruction techniques have evolved to restore physical form and aesthetic appearance, many mastectomy patients experience distressing consequences, such as diminished breast sensation.^[1-6^] Sensory loss can lead to long-term consequences, including numbness, pain, and a heightened risk of burn or thermal injury^[7,8^]. Furthermore, breast sensation is crucial in an individual’s sense of femininity and can influence aspects of mental well-being.^[9-11^] Overall, it is vital to physical and psychological well-being equally and has a significant effect on a patient’s quality of life (QoL).

Highlights.

• Neurotization significantly improves sensory outcomes post-breast reconstruction.

• Patients with neurotized breasts report better psychosocial and sexual well-being.

• Improved sensation correlates with higher quality of life and fewer breast symptoms.

In response to this critical issue, the concept of innervating reconstructed breasts has gained prominence. Various studies have explored the potential benefits of restoring breast sensation during reconstruction^[5,6,12,13^]. Previous neurotization methods involved mainly neurotizing autologous flaps. These approaches provide some level of sensory recovery to the transferred tissue, leading to the perception of reconstructed breast skin, especially in patients who underwent delayed breast reconstruction with abdominal flaps. However, skin-sparing or nipple-sparing mastectomy following immediate breast reconstruction has largely revolutionized the field of breast reconstruction, with better aesthetics and a lower psychological impact. The preserved mastectomy skin envelope requires a strategic approach for superficial neurotization, which can be difficult to achieve using traditional techniques. Further, traditional techniques to innervate the flap are not applicable in implant-based reconstruction.

To overcome these limitations, our group has introduced a novel technique to utilize the main branch of the intercostal nerve as a graft to elongate the lateral cutaneous branch of the intercostal nerve that was resected during mastectomy[14]. In Brief, the procedure begins by identifying the cut stumps of the lateral cutaneous branch of the intercostal nerve (usually from the 4th intercostal nerve, but can be from 3rd to 5th) through the mastectomy incision (immediate reconstruction) or the same incision in delayed reconstruction, and dissecting them proximally to access the bifurcation of the intercostal main branch beneath the rib. The main intercostal nerve is dissected and harvested to serve as an autologous nerve graft. Dissection of the intercostal nerve can be difficulty due to its close location to pleura. This is particularly difficult in patients who received radiotherapy before. The dissection is performed under a microscope using bipolar cautery to securely perform hemostasis and protect the pleura from injury. The nerve graft connects the severed end of the lateral cutaneous branch of intercostal nerve and the base of the nipple under the microscope with 9-0 nylon sutures (Fig. 1). Utilizing the intercostal nerve graft avoids extra donor site scars and reduces surgical time. Donor site morbidity is minimal, with negligible effects on respiratory function[15]. Detailed surgical technique is described in our team’s previous publication[14].

Figure 1.

(A) An intraoperative photo shows the elongation of the ruptured lateral cutaneous branch by using a nerve graft before DIEP flap inset. The nerve graft is prepared long enough to reach the nipple after flap inset. The small photo in the upper left corner is a pre-operative photo showing the incision site for mastectomy. (B) The neurotization technique of superficial neurotization: the main intercostal nerve serves as an autologous nerve graft that connects the lateral intercostal nerve and the base of the nipple after free DIEP flap inset, facilitating neurotization. The small photo in the upper left corner is a pre-operative photo showing the incision site for mastectomy.

Whereas surgical techniques for superficial breast neurotization yield significantly superior monofilament test results for sensation restoration, patient-reported outcomes remain underexplored. Given that objectively measured data may not directly correlate with subjective outcomes, this study primarily aims to evaluate the relationship between breast neurotization and patient-reported outcomes, including quality of life, sensation level, and denervation symptoms and the recovery. Secondary objectives include analyzing the effects of follow-up periods (postoperative 1- and 2-year) and reconstruction methods (autologous vs. implant-based) on these outcomes.

Patients and methods

A prospective cohort study of all patients who underwent nipple-sparing mastectomy and immediate breast reconstruction by the senior author JJH between 2018 and 2022 was conducted. The study was approved by the institutional review board (IRB number: 202101923B0 and was registered on ClinicalTrials.gov (unique identifying registration number: NCT06629012). The study was conducted in accordance with the ethical standards of the Declaration of Helsinki (1975). This work was reported in line with the STROCSS criteria[16]. Both autograft flaps and implant-based breast reconstruction cases were included. The exclusion criteria included patients who had follow-up durations of less than one year, underwent late nipple areola removal (n = 4) and experienced severe post-radiation skin necrosis (n = 1). A total of 132 patients were enrolled. Patients were divided into two groups: those with breast neurotization (innervated group, n = 67) and those without it (noninnervated group, n = 65) (Fig. 2). Subgroup analysis was further conducted on 132 patients to evaluate the impact of follow-up duration and reconstruction type on the relationship between neurotization and patient-reported outcomes. First of all, the latest response of the patient-reported outcome was compared in accordance with neurotization or not, and their reconstruction method. Patients with follow up of more than 12 months were included. However, the timing of assessments and their response to patient-reported outcome questionnaires varied as this can be affected and determined by patients’ availability, the completion of adjuvant radiotherapy, and the stabilization of the reconstructed site. We specifically identified the patient-reported outcome responded at 12-month follow up and 24-month follow up to further investigate the improvement of neurotization with time. Patients included in the subgroup of 1-year follow up included 47 in the innervated group and 53 in the non-innervated group. Patients recruited as 2-year follow up subgroup included 20 in the innervated group and 12 in the non-innervated group. Second, patients were analyzed based on reconstruction type and divided into autologous flap (innervated, n = 60; non-innervated, n = 30) and implant-based reconstruction groups (innervated, n = 7; non-innervated, n = 35). It is noteworthy that the limited sample size in the implant-based group.

Figure 2.

Patient enrollment flow chart.

Study design

Patient characteristic data were collected through chart review, and the variables included age (years), body mass index (BMI), smoking history, comorbidities, oncological treatment, reconstruction type, reconstruction timing, lymph node surgery, and surgical complications. The patient-reported outcomes were assessed via the BREAST-Q reconstruction module (version 2, Taiwan edition)[17], which was complemented by an additional questionnaire[18]. Objective sensory recovery was evaluated via the Semmes‒Weinstein monofilament 20-piece kit, indicated either as a value ranging from 1.65 to 6.65 or as a corresponding force ranging from 0.008 to 300 g. Both are interchangeable and have been used in previous studies^[3,12^].

The additional questionnaire (Table 1) comprises three sections related to the nipple and breast that were not covered by the standard BREAST-Q questionnaire. The first part focused on the general sensation of the nipple and breast skin. These questions directly assessed the level of sensation experienced by patients, utilizing a 5-point scale ranging from “No sensation” to “Normal sensation.” The second part consisted of eight questions relating to the nipple and areola complex. Responses ranging from “Dissatisfied” to “Very satisfied” were recorded. The scores from these eight questions were summed to form an overall score, with a maximum of 40. The first two sections were based on the questionnaire used in Peled et al’s 2019 study[18]. The third part comprised ten questions about breast symptoms encountered in the past 2 weeks. Patients were asked to assess the frequency of various symptoms, such as skin inflammation, eczema, dry skin, itching, sharp pain, and tingling. The scores from these questions were summed to calculate a total score, with a maximum of 50. In all three sections, higher scores indicated better outcomes.

Table 1.

Questionnaires measuring sensation, nipple satisfaction, and breast symptoms

Part 1. In the past two weeks, what level of sensation did you experience on the reconstructed side?
	No sensation	Minimal sensation	Slight sensation	Some sensation	Normal sensation
1. How much nipple sensation do you have on your reconstructed breast(s)?	1	2	3	4	5
2. How much skin sensation do you have on the rest of your reconstructed breast(s)	1	2	3	4	5
Part 2. In the past 2 weeks, on your reconstructed breast, how satisfied or dissatisfied are you with:
	Dissatisfied	Somewhat dissatisfied	Neutral	Somewhat satisfied	Very satisfied
1. The shape of your nipple(s)?	1	2	3	4	5
2. How your nipple(s) and areola(s) look?	1	2	3	4	5
3. How natural your nipple(s) look?	1	2	3	4	5
4. The color of your nipple(s) and areola(s)?	1	2	3	4	5
5. The height (projection) of your nipple(s)?	1	2	3	4	5
6. The position of your nipple(s) on your reconstructed breast(s)?	1	2	3	4	5
7. The sensation in your nipple(s) on your reconstructed breast(s)?	1	2	3	4	5
8. How similar your nipples look to each other?	1	2	3	4	5
Part 3. In the past 2 weeks, have you experienced the following condition at the reconstructed breast?
	All the time	Most of the time	Some of the time	A little of the time	None of the time
1. Have you experienced symptoms of skin inflammation?	1	2	3	4	5
2. Have you experienced eczema?	1	2	3	4	5
3. Has the color of your skin darkened?	1	2	3	4	5
4. Did you have issues with dry skin?	1	2	3	4	5
5. Have you experienced skin itching?	1	2	3	4	5
6. Have you been scratching your skin due to itching	1	2	3	4	5
7. Have you encountered sharp pain?	1	2	3	4	5
8. Have you encountered tingling sensations?	1	2	3	4	5
9. Have you encountered shooting pain?	1	2	3	4	5
10. Have you experienced the inability to ease the itchiness?	1	2	3	4	5

Statistical analysis

Descriptive statistics are presented as counts (n) and frequencies (%) for categorical data and means and standard deviations (SDs) for continuous data. P values for categorical variables were calculated using chi-square tests or Fisher’s exact tests. For numerical variables, parametric P values were calculated using independent t test, while nonparametric P values using the Mann–Whitney U test. Simple linear regression was used to estimate the association between monofilament value and patient-reported outcomes. A two-tailed P < 0.05 was considered statistically significant. The statistical analyses were conducted with IBM® SPSS® Statistics for Windows (Version 25.0).

Results

Patient characteristics

Figure 3 shows a case example of nipple-sparing mastectomy, reconstruction with a free deep inferior epigastric perforator (DIEP) flap, and neurotization. The patient was followed at the clinic for more than 2 years, with satisfactory results. Table 2 includes details about the characteristics of the patients in both groups. Significant differences in BMI, history of previous radiation, and reconstruction methods were noted. No statistically significant differences were noted in age, comorbidities, cancer staging, reconstruction timing, or surgical complications. Both groups fell within the normal BMI range, with the noninnervated group having a significantly lower BMI. In the innervated group, more than 80% of patients had autologous flap reconstruction, whereas in the noninnervated group, more than 50% had implant-based reconstruction. A significantly greater percentage of patients who previously received radiotherapy were in the innervated group. The mean monofilament value of the innervated group was 4.02 ± 1.15 with a median value of 4.31 and an interquartile range of 3.22 to 4.74.

Figure 3.

A 44-year-old female patient with left breast cancer, staged pT1mi, who received robot-assisted nipple-sparing mastectomy, free DIEP flap reconstruction, and neurotization. (A) Preoperative anterior view. (B, C, D) Anterior, right lateral, and left lateral views at 42 months postoperative follow-up. (E and F) The neurotization technique of superficial neurotization using nerve graft of the sketch and intraoperative picture. (G) Monofilament results of the breast skin of the healthy and the reconstructed breast at different follow-up time points as a result of sensory recovery.

Table 2.

Demographics of the patients in the innervated and noninnervated groups

	Innervated group (n = 67)	Noninnervated group (n = 65)	P
Age, years	44.3 ± 7.5	42.8 ± 6.9	0.24
BMI, kg/m2	23.5 ± 2.8	22.1 ± 3.3	0.008*
Smoking	2 (3%)	1 (2%)	0.59
Diabetes mellitus	2 (3%)	0 (0%)	0.16
Hypertension	5 (8%)	2 (3%)	0.27
Cancer staging			0.44
DCIS or PM	18 (27%)	12(19%)
I	27 (40%)	28 (44%)
II	13 (19%)	17 (27%)
III	9 (13%)	5 (8%)
IV	0 (0%)	1 (2%)
Lymph node surgery			0.859
None	19 (28%)	17 (26%)
SLNB	35 (52%)	37 (57%)
ALND	13 (19%)	11 (17%)
Previous radiotherapy	7 (11%)	1 (2%)	0.032*
Adjuvant radiotherapy	18 (27%)	11 (17%)	0.18
Reconstructive method			<0.001*
Implant	7 (10%)	35 (52%)
Free flaps
DIEP	54 (81%)	27 (42%)
PAP	6 (9%)	3 (5%)
Reconstructive timing			0.18
Immediate	63 (94%)	64 (98%)
Delayed	4 (6%)	1 (2%)
Monofilament value
Mean	4.02 ± 1.15
Medium	4.31
Interquartile range	3.22–4.74
Follow up, years	1.3 ± 0.5	1.3 ± 0.4	0.54

BMI, body mass index; DCIS, ductal carcinoma in situ; PM, prophylactic mastectomy; SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection; DIEP, deep inferior epigastric artery perforator; PAP, profunda artery perforator.

^*P < 0.05

Quality of life results

Compared with the noninnervated group, the innervated group presented higher scores across nearly all the domains of the BREAST-Q questionnaire (Table 3; Fig. 4). Six of the eleven domains, including psychosocial well-being (71.6 ± 18.1 vs. 62.8 ± 18.6, P = 0.006), sexual well-being (56.9 ± 22.1 vs. 47.3 ± 20.7, P = 0.015), satisfaction with the surgeon (87.0 ± 17.4 vs. 78.5 ± 19.5, P = 0.009), medical team (87.3 ± 17.3 vs. 80.3 ± 19.5, P = 0.03), staff (87.5 ± 16.7 vs. 79.8 ± 19.1, P = 0.02), and information provided by the surgeon (68.6 ± 17.6 vs. 62.3 ± 15.3, P = 0.03) reached statistical significance.

Table 3.

Comparison of patient-reported outcomes in the innervated and noninnervated groups

	Full marks	Innervated group (n = 67)	Noninnervated group (n = 65)	P
BREAST-Q domains
Psychosocial well-being	100	71.6 ± 18.1	62.8 ± 18.6	0.006*
Sexual well-being	100	56.9 ± 22.1	47.3 ± 20.7	0.015*
Satisfaction with breast	100	61.4 ± 13.2	57.7 ± 15.5	0.13
Physical well-being of chest	100	65.9 ± 16.6	63.0 ± 17.3	0.34
Physical well-being of abdomen	100	70.5 ± 15.2	67.3 ± 19.8	0.20
Satisfaction with information	100	68.6 ± 17.6	62.3 ± 15.3	0.03*
Satisfaction with the surgeon	100	87.0 ± 17.4	78.5 ± 19.5	0.009*
Satisfaction with medical team	100	87.3 ± 17.3	80.3 ± 19.5	0.03*
Satisfaction with other staff	100	87.5 ± 16.7	79.8 ± 19.1	0.02*
Satisfaction with implant	6	5.0 ± 1.1	5.7 ± 0.9	0.10
Satisfaction with abdomen	10	8.3 ± 1.6	8.1 ± 1.9	0.49
Additional questionnaire section 1: Sensation
Nipple sensation	5	2.6 ± 1.2	1.9 ± 1.0	0.002*
Breast sensation	5	3.1 ± 1.2	2.7 ± 1.1	0.07
Additional questionnaire section 2: Nipple satisfaction
Total score for nipple satisfaction	40	31.4 ± 6.8	29.8 ± 5.5	0.18
Additional questionnaire section 3: Breast symptoms
Total score of breast symptoms	50	42.8 ± 4.7	39.8 ± 7.2	0.018*
Skin inflammation	5	4.8 ± 0.5	4.6 ± 0.8	0.025*
Eczema	5	4.8 ± 0.6	4.5 ± 0.8	0.038*
Darkening of the skin color	5	4.3 ± 1.1	4.2 ± 1.1	0.74
Dry skin	5	4.1 ± 1.0	3.8 ± 1.1	0.11
Itching of the skin	5	4.1 ± 0.9	3.8 ± 1.0	0.10
Scratching of the skin due to itching	5	4.8 ± 0.5	4.5 ± 0.9	0.016*
Experience sharp pain	5	4.0 ± 1.0	3.8 ± 1.0	0.44
Numb sensation	5	3.7 ± 1.1	3.7 ± 1.3	0.82
Shooting pain	5	3.9 ± 0.9	3.7 ± 1.0	0.23
Inability to locate the itchy area	5	4.0 ± 1.0	3.6 ± 1.3	0.02*

The additional questionnaires for sensation, nipple satisfaction, and breast symptoms are listed in Table 1. The total scores for nipple satisfaction and breast symptoms are 40 and 50, respectively. Higher scores indicate a better outcome.

^*P < 0.05

Figure 4.

Scores on each of the BREAST-Q domains in the innervated and noninnervated groups. * Indicates P < 0.05.

For questions directly related to sensation, the innervated group reported higher scores in response to the following question: “How much skin sensation do you have on the rest of your reconstructed breast?” (3.1 ± 1.2 vs. 2.7 ± 1.1, P = 0.07). The innervated group also had significantly higher scores in response to the following question: “How much nipple sensation do you have on your reconstructed breast?” (2.6 ± 1.2 vs. 1.9 ± 1.0, P = 0.002). In terms of the total score for satisfaction with nipple aesthetics, there were no significant differences between the two groups (31.4 ± 6.8 vs. 29.8 ± 5.5, P = 0.18).

With respect to breast symptoms, the innervated group experienced less frequent discomfort and exhibited significant differences in the frequency of skin inflammation, eczema, and itching-related skin abrasions (Table 3; Fig. 5). The total score for all the breast symptom questions also differed significantly between the two groups (42.8 ± 4.7 vs. 39.8 ± 7.2, P = 0.018).

Figure 5.

Additional questionnaire scores of the innervated and noninnervated groups. * Indicates P < 0.05.

Quality of life results – subgroup analysis: one and two years after surgery

The demographic data of the patients who were grouped according to the presence or absence of neurotization at 1- and 2-year follow-up are provided in Supplementary Digital Content, Table 1, http://links.lww.com/IJSO/A22. At the 1-year mark, similar to the total population, the innervated group reported higher scores on 10 of the 11 BREAST-Q domains, with a significant difference observed in sexual well-being (57.6 ± 23.0 vs. 48.1 ± 22.0, P = 0.048) (Table 4; Fig. 6). These differences between the two groups became more pronounced at the two-year follow-up subgroup, with the innervated group showing significantly higher scores in psychosocial well-being (77.7 ± 16.5. vs. 56.5 ± 17.6, P = 0.002), satisfaction with the breast (61.9 ± 11.7 vs. 52.6 ± 5.9, P = 0.016), and satisfaction with the surgeon (91.5 ± 15.1 vs. 73.3 ± 17.4, P = 0.004), medical team (93.7 ± 14.2 vs. 74.8 ± 18.7, P = 0.007), and staff (94.4 ± 12.9 vs. 73.9 ± 16.7, P = 0.001).

Table 4.

Comparison of patient-reported outcomes in the innervated and noninnervated groups, subgroups: one- and two-year postoperative follow-up

		Postoperative 1 year			Postoperative 2 years
	Full marks	Innervated group (n = 47)	Noninnervated group (n = 53)	P	Innervated group (n = 20)			Noninnervated group (n = 12)		P
BREAST-Q domains
Psychosocial well-being	100	69.0 ± 18.3	64.2 ± 18.7	0.19	77.7 ± 16.5			56.5 ± 17.6	0.002*
Sexual well-being	100	57.6 ± 23.0	48.1 ± 22.0	0.048*	55.4 ± 20.2			44.3 ± 14.6	0.11
Satisfaction with breast	100	61.3 ± 13.9	58.8 ± 16.7	0.44	61.9 ± 11.7			52.6 ± 5.9	0.016*
Physical well-being of chest	100	64.6 ± 17.8	64.2 ± 16.2	0.89	68.9 ± 13.5			58.2 ± 21.4	0.89
Physical well-being of abdomen	100	70.1 ± 16.1	67.1 ± 17.6	0.50	71.4 ± 12.9			68.3 ± 34.1	0.76
Satisfaction with information from surgeon	100	67.9 ± 17.5	62.7 ± 15.6	0.12	70.1 ± 18.4			60.7 ± 14.8	0.14
Satisfaction with the surgeon	100	85.2 ± 18.1	79.7 ± 19.9	0.16	91.5 ± 15.1			73.3 ± 17.4	0.004*
Satisfaction with medical team	100	84.6 ± 17.9	81.5 ± 19.6	0.41	93.7 ± 14.2			74.8 ± 18.7	0.007*
Satisfaction with other staff	100	84.6 ± 17.4	81.1 ± 19.6	0.35	94.4 ± 12.9			73.9 ± 16.7	0.001*
Satisfaction with implant	6	4.8 ± 1.1	5.7 ± 1.0	0.07	6.0 ± 0			5.6 ± 0.5	-
Satisfaction with abdomen	10	8.3 ± 1.4	8.0 ± 2.0	0.44	8.4 ± 2.0			8.5 ± 1.3	0.91
Additional questionnaire section 1: Sensation
Nipple sensation	5	2.6 ± 1.1	2.0 ± 1.1	0.02*	2.6 ± 1.0			1.8 ± 0.8	0.02*
Breast sensation	5	3.0 ± 1.1	2.8 ± 1.1	0.45	3.4 ± 1.2			2.5 ± 0.8	0.03*
Additional questionnaire section 2: Nipple satisfaction
Total score for nipple satisfaction	40	30.4 ± 7.2	29.5 ± 5.5	0.47	33.5 ± 5.6		31.3 ± 5.1		0.27
Additional questionnaire section 3: Breast symptoms
Total score of breast symptoms	50	42.8 ± 4.5	39.8 ± 6.7	0.04*	42.8 ± 5.3	39.5 ± 9.3			0.24
Skin inflammation	5	4.8 ± 0.5	4.6 ± 0.7	0.13	4.9 ± 0.2	4.7 ± 0.5			0.08
Eczema	5	4.7 ± 0.6	4.5 ± 0.9	0.99	4.9 ± 0.3	4.8 ± 0.5			0.33
Darkening of the skin color	5	4.3 ± 1.2	4.3 ± 1.1	0.74	4.5 ± 1.1	3.9 ± 1.2			0.22
Dry skin	5	4.1 ± 1.1	3.8 ± 1.1	0.21	4.2 ± 0.9	3.8 ± 1.2			0.30
Itching of the skin	5	4.2 ± 0.9	3.7 ± 1.0	0.02*	3.9 ± 1.0	3.9 ± 1.2			0.97
Scratching of the skin due to itching	5	4.8 ± 0.4	4.5 ± 0.9	0.02*	4.8 ± 0.7	4.5 ± 1.2			0.51
Experience sharp pain	5	4.0 ± 1.0	3.9 ± 1.0	0.59	4.0 ± 1.0	3.8 ± 1.2			0.54
Numb sensation	5	3.5 ± 1.2	3.7 ± 1.3	0.48	4.1 ± 1.0	3.8 ± 1.5			0.62
Shooting pain	5	3.8 ± 1.0	3.7 ± 0.9	0.73	4.1 ± 0.9	3.4 ± 1.1			0.82
Inability to locate the itchy area	5	4.2 ± 0.9	3.5 ± 1.2	0.02*	3.7 ± 1.1	3.9 ± 1.4			0.63

The additional questionnaires for sensation, nipple satisfaction, and breast symptoms are listed in Table 1. The total scores for nipple satisfaction and breast symptoms are 40 and 50, respectively. Higher scores indicate a better outcome.

^*P < 0.05

Figure 6.

Scores on each BREAST-Q domain in the innervated and noninnervated groups at one- and two-year postoperative follow-up. * Indicates P < 0.05.

In terms of sensory outcomes, nipple sensation was significantly better in the innervated group than the noninnervated group at both the 1-year (2.6 ± 1.1 vs. 2.0 ± 1.1, P = 0.02) and 2-year (2.6 ± 1.0 vs. 1.8 ± 0.8, P = 0.02) time points, supporting the positive impact of neurotization on sensory recovery. The total score for breast symptoms did not significantly differ at the 2-year time point (42.8 ± 5.3 vs. 39.5 ± 9.3, P = 0.24), although at 1 year (42.8 ± 4.5 vs. 39.8 ± 6.7, P = 0.04), the innervated group reported significantly fewer symptoms. This may suggest that as postoperative time increased, the disparity in the frequency of experiencing uncomfortable breast symptoms diminished between the two groups (Table 4; Fig. 7).

Figure 7.

Additional questionnaire scores of the innervated and noninnervated groups at one- and two-year postoperative follow-up. * Indicates P < 0.05.

Quality of life results – subgroup analysis: reconstruction method and neurotization

As we performed autologous reconstruction more frequently in the neurotization group than in the noninnervated group, our next interest was to clarify whether the reconstruction method affected sensory recovery. Supplementary Digital Content, Table 2 (http://links.lww.com/IJSO/A22) includes the demographic data of the patients in each subgroup according to the reconstruction method. There were no differences in patients with or without neurotization in autologous or implant-based reconstruction, except that the neurotization patients in the implant reconstruction group had a more advanced cancer stage. Table 5 shows the patient-reported outcomes in terms of quality of life. In the autologous flap reconstruction subgroup, patients receiving neurotization reported better psychosocial well-being (72.1 ± 17.6 vs. 63.0 ± 19.5, P = 0.03), and nipple sensation (2.6 ± 1.2 vs. 2.0 ± 0.9, P = 0.02) and fewer breast symptoms (43.0 ± 4.5 vs. 39.2 ± 8.2, P = 0.03) than patients without neurotization did. In the implant-based reconstruction subgroup, although most of the items presented a trend toward better outcomes in patients with neurotization, the differences did not reach statistical significance, except that the patients with neurotization presented less itching on their breasts.

Table 5.

Comparison of patient-reported outcomes in the innervated and noninnervated groups, subgroups: autologous or implant reconstruction

		Autologous			Implant
	Full marks	Innervated group (n = 60)	Noninnervated group (n = 30)	P	Innervated group (n = 7)	Noninnervated group (n = 35)			P
Breast Q domains
Psychosocial well-being	100	72.1 ± 17.6	63.0 ± 19.5	0.03*	67.3 ± 23.0	62.6 ± 18.0	0.90
Sexual well-being	100	56.5 ± 21.4	48.0 ± 20.5	0.08	59.9 ± 28.6	46.7 ± 21.1	0.71
Satisfaction with breast	100	61.5 ± 13.6	60.1 ± 20.2	0.09	60.7 ± 10.3	55.6 ± 9.6	0.55
Physical well-being of chest	100	66.2 ± 16.9	61.2 ± 18.4	0.21	63.6 ± 15.2	64.6 ± 16.3	0.15
Physical well-being of abdomen	100	70.4 ± 15.3	66.1 ± 19.1	0.27	-	-	-
Satisfaction with information from surgeon	100	69.1 ± 18.1	64.6 ± 19.1	0.28	63.9 ± 12.8	60.4 ± 11.0	0.49
Satisfaction with the surgeon	100	87.3 ± 17.4	80.3 ± 20.7	0.10	84.6 ± 17.9	77.0 ± 18.6	0.32
Satisfaction with medical team	100	87.8 ± 17.0	82.3 ± 20.0	0.17	83.3 ± 20.8	78.6 ± 19.2	0.67
Satisfaction with other staff	100	87.9 ± 16.5	82.6 ± 18.0	0.17	84.1 ± 19.8	77.3 ± 20.0	0.49
Satisfaction with implant	6	–	–	–	5.0 ± 1.1	5.7 ± 0.9	0.23
Satisfaction with abdomen	10	8.4 ± 1.6	8.0 ± 1.9	0.38	–	–	–
Additional questionnaire section 1: Sensation
Nipple sensation	5	2.6 ± 1.2	2.0 ± 0.9	0.02*	2.3 ± 1.1	1.9 ± 1.1	0.42
Breast sensation	5	3.1 ± 1.1	2.8 ± 1.1	0.22	3.1 ± 1.5	2.7 ± 1.0	0.44
Additional questionnaire section 2: Nipple satisfaction
Total score for nipple satisfaction	40	31.4 ± 6.8	30.7 ± 5.7	0.65	30.8 ± 7.8	29.2 ± 5.3	0.56
Additional questionnaire section 3: Breast symptoms
Total score of breast symptoms	50	43 ± 4.5	39.2 ± 8.2	0.03*	42.4 ± 6.1	40.3 ± 6.4		0.53
Skin inflammation	5	4.8 ± 0.4	4.7 ± 0.5	0.18	4.9 ± 0.4	4.6 ± 0.7		0.42
Eczema	5	4.8 ± 0.6	4.5 ± 0.8	0.07	4.7 ± 0.5	4.5 ± 0.8		0.93
Darkening of the skin color	5	4.3 ± 1.2	4.3 ± 1.2	0.82	4.3 ± 1.1	4.2 ± 1.0		0.86
Dry skin	5	4.1 ± 1.0	3.9 ± 1.2	0.41	4.1 ± 0.9	3.8 ± 1.0		0.42
Itching of the skin	5	4.1 ± 1.0	4.0 ± 1.2	0.66	4.4 ± 0.8	3.6 ± 0.9		0.049*
Scratching of the skin due to itching	5	4.8 ± 0.5	4.5 ± 0.9	0.12	4.9 ± 0.4	4.4 ± 0.9		0.31
Experience sharp pain	5	4.0 ± 1.0	3.7 ± 1.1	0.25	4.3 ± 1.0	4.0 ± 1.0		0.47
Numb sensation	5	3.7 ± 1.1	3.3 ± 1.4	0.16	3.4 ± 1.3	4.1 ± 1.1		0.23
Shooting pain	5	3.9 ± 1.0	3.5 ± 1.1	0.08	3.9 ± 0.9	3.8 ± 0.9		1.0
Inability to locate the itchy area	5	4.0 ± 1.0	3.5 ± 1.1	0.11	4.3 ± 1.0	3.6 ± 1.1		0.14

The additional questionnaires for sensation, nipple satisfaction, and breast symptoms are listed in Table 1. The total scores for nipple satisfaction and breast symptoms are 40 and 50, respectively. Higher scores indicate a better outcome.

^*P < 0.05

Quality of life results – subgroup analysis: patient-reported outcome and follow up time

In order to understand if the improvement of sensory over time, we further analyze the patients with neurotization and without neurotization by comparing their repose at 1- and 2-year follow up (Supplementary Digital Content, Table 3, http://links.lww.com/IJSO/A22). Although the only significant finding presented in the innervated group with significant improvement in skin inflammation in the innervated group, we do find a trend of general improvement in the innervated group and a trend of general regress in the non-innervated group.

Sensory and Quality of Life Results

Linear regression analysis was conducted to examine the relationships between subjectively examined patient-reported outcomes and objectively measured monofilament values (Table 6; Fig. 8). Negative coefficients were noted and indicated that as the monofilament value increased, the corresponding BREAST-Q domain score decreased, reflecting lower patient satisfaction. Significant P values were obtained for the BREAST-Q domain for psychosocial well-being (coefficient: −4.922, P = 0.033) as well as for the additional questions relating to nipple sensation (coefficient: −0.373, P = 0.008) and breast sensation (coefficient: −0.338, P = 0.009).

Table 6.

Linear regression of the patient-reported outcome to monofilament value results in the innervated group

Dependent	Coefficient	Standard error	95% CI (lower, upper)	P
Psychosocial well-being	−4.922	2.247	−9.439, −0.406	0.033*
Sexual well-being	−3.170	2.882	−8.970, 2.630	0.277
Physical well-being of chest	−1.801	2.020	−0.891, 0.377	0.377
Satisfaction with breast	1.062	1.742	−2.439, 4.563	0.545
Satisfaction with information from surgeon	−1.150	2.238	−5.647, 3.347	0.610
Satisfaction with surgeon	−1.069	2.250	−5.591, 3.452	0.637
Satisfaction with medical team	−0.754	2.204	−5.182, 3.674	0.734
Satisfaction with other staff	−0.815	2.134	−5.103, 3.472	0.704
Additional questionnaire
Nipple sensation	−0.373	0.136	−0.646, −1.00	0.008*
Breast sensation	−0.338	0.125	−0.589, −0.086	0.009*
Total score of breast symptoms	−0.030	0.744	−1.548, 1.488	0.968

CI, confidence interval

^*P < 0.05

Figure 8.

Scatterplot showing the relationship between monofilament value and BREAST-Q domain: psychosocial well-being. The x-axis represents monofilament values, ranging from 1.65 to 6.65. Higher values indicate a lower level of sensation. The y-axis represents scores of the BREAST-Q domain: psychosocial well-being, ranging from 1 to 100. Higher scores indicate a better outcome.

Discussion

In the present study, patient-reported outcomes relating to nipple and breast neurotization were conducted via the BREAST-Q and our designed questionnaire measuring breast and nipple sensation, nipple aesthetics, and symptoms in breasts. Our results indicated that breast and nipple neurotization significantly improved patients’ psychosocial well-being, sexual well-being and nipple sensation, and reduced their symptoms after mastectomy, such as skin inflammation, chronic eczema, itching, and the inability to identify the itching area. Offering the procedure to patients also significantly enhanced their satisfaction with the medical team.

Patient-reported outcomes have gained increasing importance in clinical decision-making, as the acquisition of objective measurements does not inherently correspond to increased patient satisfaction. The enhancement in quality of life can reasonably support modifications in treatment approaches, including greater surgical complexity and financial investment. Research has been conducted on the patient-reported outcomes following mastectomy with reconstruction.^[19-25^] The influence of various factors, including patient demographics, mastectomy type, method of reconstruction, selection of flaps, timing of reconstruction, and effect of radiation, has been examined. However, studies focusing on patient-reported outcomes after breast reconstruction with neurotization are relatively rare.

Slezak et al were the first in the field to incorporate patient-reported outcomes in their research. Employing self-designed questions, they reported that patients with innervated transverse rectus abdominus myocutaneous (TRAM) flaps were more satisfied than those without neurotization[26]. Following Slezak et al, several researchers investigated patient QoL after breast neurotization, although the validity of the assessment measures remains uncertain.^[9,27-31^]

Temple et al used established QoL questionnaires, the Medical Outcomes Study 36-Item Short Form, the Body Image after Breast Cancer Questionnaire, and the Functional Assessment of Cancer Therapy-Breast and reported a significant enhancement in QoL following innervated TRAM flap procedures[9]. Cornelissen et al were the first to apply BREAST-Q scales in studies on breast neurotization, and revealed a statistically significant link between monofilament values and specific BREAST-Q domains in patients who underwent innervated DIEP flap reconstruction. These results are in alignment with those of our study[10].

Most of the aforementioned studies focused on breast neurotization with the techniques of neurotizing transferred flaps, which is different than our technique. Our current study, as a follow-up to our previous work[14], demonstrated that superficial breast neurotization through nerve autografts to elongate ruptured lateral intercostal nerve cutaneous branches yielded not only better monofilament data but also superior patient-reported outcomes. Our results also align with previous findings showing that regardless of the neurotization technique employed – either via innervated flap or nerve autograft neurotization – the innervated group consistently achieved better patient-reported outcomes.

In our study population, a statistically significant difference was observed in the type of reconstruction performed. In the innervated group, a greater proportion of patients underwent autologous flap reconstruction, whereas many patients in the noninnervated group underwent implant-based reconstruction. This disparity is attributed to the fact that we started providing the procedure to patients with free flap reconstruction. However, we started to offer the neurotization procedure to patients with nipple-sparing mastectomy and implant-based reconstruction after confirming the positive results from superficial nipple and breast skin neurotization.

In our analysis, the scores on the BREAST-Q “satisfaction with the breast” and “satisfaction with the implant” domains did not reach statistical significance. The former domain included questions assessing breast size, symmetry, naturalness, ability to fit in clothing, etc. The latter domain included questions about the visibility and palpability of the implant. Given that these two domains focused more on the aesthetic aspects of the breast rather than the sensation, their lack of statistical significance is understandable. Similarly, this can account for why the “total score of nipple satisfaction” domain did not reach statistical significance. Importantly, in addition to sensation, the appearance of the breast is a significant factor affecting patient satisfaction[22]. Similarly, scores on the BREAST-Q “physical well-being of chest” and “physical well-being of abdomen” domains were not significantly different between the two groups. These domains addressed issues, such as pain, tightness, difficulty moving the arms, etc. The absence of significant findings in association with these domains may be due to its focus on the physical condition of the reconstruction site, which is more related to the initial mastectomy technique, tension at the reconstruction site, impact of complications, wound healing, and consequences of adjuvant radiation therapy[32] rather than the recovery of sensation.

We further compared the time effect by separately grouped the patients into 1- and 2-year follow up in innervated and non-innervate group. There is a trend of improvement in the innervated group and a trend of regress in the non-innervated group despite without statistical difference. In addition, we hypothesize several factors may contribute to this result. Without nerve coaptation, some patients in the non-innervated group might perceive regained sensation as unpleasant or abnormal. For example, our results indicate that the non-innervated group experienced a higher frequency of sharp or shooting pain, possibly due to chronic irritation of severed nerve endings or the formation of neuromas. These factors could contribute to discomfort or hypersensitivity, negatively impacting patient-reported outcomes. However, the 2-year follow up group remains small in case number. Further study to recruit more patients with longer follow up time is required. Significantly higher scores on the BREAST-Q “psychosocial well-being” and “sexual well-being” domains were noted for the innervated group, which underscores the impact of breast sensation on psychological health, feminine body image, and intimate relationships[11].

Despite these convincing results, our study has certain limitations. First, we introduced an additional questionnaire that has not been validated in other studies. This decision was made because the current version of the BREAST-Q is insufficient for accurately investigating sensation recovery and quality of life and lacks questions focused on the nipple and areola complex. Recent studies highlighted the oncological safety of nipple-sparing mastectomy in selected patients and showed superior quality-of-life outcomes compared with those of skin-sparing mastectomy[33]. Additionally, studies have supported the role of breast neurotization in enhancing clinical outcomes[12]. Both findings indicate a need to expand the BREAST-Q to include relevant questions. Second, there was a notable difference of types of reconstruction among both the innervated and the noninnervated groups. The Mastectomy Reconstruction Outcomes Consortium Study (MROC) have shown that at 2 years post-operation, patients who underwent autologous reconstruction reported significantly higher BREAST-Q scores compared to implant reconstruction[25]. To verify the difference in scores between the innervated and noninnervated groups is attributed to the effect of neurotization rather than the reconstruction type, we conducted a subgroup analysis based on the reconstruction method. The results showed that the innervated group achieved better outcomes regardless of the reconstruction method. However, a disparity in the number of cases involving implant reconstruction exists. Further studies are needed to investigate the effects of autograft nerve neurotization on autologous flap and implant-based reconstructions. Third, monofilament test data were not consistently available for the patients in the noninnervated group, which limited the inclusion of data. Fourth, despite having a larger sample size than other studies in the field did, randomization or blinding was not used. Thus, a larger, randomized, double-blinded prospective study would yield more comprehensive data. We harvested the main intercostal nerve as nerve graft. Our patients did not report donor site morbidities, such as numbness or limitation on their breath and were satisfied with the recovery of breast sensation. However, further larger-scale study will be required to further confirm its effect on the donor site.

Conclusion

Breast reconstruction along with autologous nerve graft neurotization significantly improves patient-reported outcomes. This underscores its positive impact on the overall quality of life of breast reconstruction patients.

Ethical approval

The study was approved by the institutional review board of Chang Gung Memorial Hospital (IRB number: 202101923B0).

Consent

Written informed consent was obtained from the patients.

Sources of funding

The authors received no financial support for the research.

Author contributions

S.S.: data curation, formal analysis, investigation, visualization, writing – original draft, writing – review & editing. T.N.-J.C.: investigation, methodology, supervision, writing – review & editing. J.C.-Y.L.: conceptualization, investigation, methodology, writing – review & editing. C.-F.C., D.C.-F.C.: investigation, methodology, writing – original draft. S.-W.K.: data curation, project administration, visualization. W.-L.K.: conceptualization, investigation, methodology, writing – review & editing. J.-J.H.: conceptualization, data curation, investigation, methodology, supervision, visualization, writing – review & editing.

Conflicts of interest disclosure

None of the authors has conflicts of interest regarding any of the products, devices, or drugs mentioned in this manuscript.

Research registration unique identifying number (UIN)

ClinicalTrials.gov PRS (NCT06629012).

Guarantor

Jung-Ju Huang.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data sharing statement

The raw datasets generated within this study are available from the corresponding author on reasonable request.

Presentation

2023 Annual Meeting of Taiwan Society of Plastic Surgery.