Direct neurotization of free nipple grafts with cadaveric nerve grafts following mastectomy for gender affirming surgery

Free nipple grafting makes sensory recovery challenging. Permanent decreased sensation to touch and temperature in skin‐grafted skin is common. Direct neurotization of the nipple‐areolar complex (NAC) graft has been described. However, quantitative data regarding degree of nipple reinnervation possible is unknown. This study aims to quantify and qualify sensation recovery following nerve coaptation to reinnervate the NAC.

The free nipple grafting technique for nipple reconstruction following either breast reduction for macromastia in ciswomen, double incision mastectomy for gynecomastia in cismen or for gender affirming surgery in transmen and non-binary individuals makes sensory recovery by axonal regeneration impossible.With time, nerve regeneration from adjacent collateral sprouting is possible but objective sensory outcome data remains elusive (Terzis, 1976).Studies comparing skin from skin-grafted burn survivors to contralateral normal skin note decreased sensation to touch, cold, and warmth in skin-grafted skin (Williams et al., 1999).A study by Olson-Kennedy et al. assessing outcomes after gender-affirming mastectomy in transmen and nonbinary individuals noted that sensation loss was the most common complication after the procedure, with more than half experiencing temporary nipple-areolar complex (NAC) sensation loss and a third experiencing long-term sensation loss (Olson-Kennedy et al., 2018).Recent literature in breast reconstruction has described direct neurotization with cadaveric nerve grafting from the lateral intercostal nerve branches to the NAC dermal plexus in nipple sparing mastectomy, with significant improvement in postsurgical sensory outcomes.A technique by Rochlin et al. describing direct neurotization of the NAC with a lateral intercostal nerve following gender affirming mastectomy without allograft has been described (Rochlin et al., 2020).In this technique, a lateral intercostal nerve is sutured to de-epithelized skin on which the free nipple graft is subsequently placed.Sensory outcomes in the treatment group noted significant improvement in sensation of the nipple, areola, and peripheral breast tissue compared to the non-treatment group at follow-up.Gfrerer et al. subsequently described a technique using direct neurotization of the NAC skin graft with cadaveric nerve graft to bridge gaps from the lateral intercostals to the skin, expanding accessibility of direct neurotization of the free nipple grafts (Gfrerer et al., 2022).This study is the largest of its kind examining postoperative outcomes following an efficient nerve coaptation technique to reinnervate the NAC following free nipple grafting with cadaveric nerve graft.It is reproducible and provides superior sensory outcomes.

| PATIENTS AND METHODS
All patients undergoing mastectomy for gender dysphoria who desired nipple preservation from two surgeons at a single institution from 2020 to 2022 were offered cadaveric nerve allograft for possible nipple sensation regeneration upon consultation.Patients who consented to the procedure were enlisted in the study.IRB approval for the use of cadaveric nerve grafts for nerve grafting to the nipple areolar complex after free nipple grafting was granted by the home institution.

| SURGICAL TECHNIQUE
After completion of bilateral mastectomy for gender dysphoria a branch of the fourth lateral intercostal nerve was selected.The nerve was dissected from surrounding tissue.The nerve was transected and coapted to cadaveric nerve allograft using two 180 8-0 nylon sutures under loupe magnification (Figure 1).The nerve graft was placed inferior to the mastectomy plane (Figure 2).The distal end of the nerve graft was then elevated to the location of the free nipple graft and secured with 8-0 nylon.Total length of cadaveric nerve graft used ranged between 50 and 70 mm.The width was 1-2 mm.The surgeons then proceeded with subsequent mastectomy flap closure.
Demographic data collected included age, BMI, and medical comorbidities including but not limited to obesity, smoking history, diabetes or pre-diabetes, anxiety, depression, and asthma.Postoperative sensory outcome data was collected from November of 2020 through November of 2022.Semmes Weinstein testing was used in the clinic to assess for postoperative recovery of nipple sensation.Postoperative assessments of sensation were conducted by trained office staff.
Assessments were made at postoperative visits within 1 year of surgery (t <12 months) and greater than 1 year from surgery (t >12 months).
Patients were instructed to close their eyes.The filament was placed perpendicular to the skin until it bowed and patients were instructed to say "yes" if they noted sensation.The NAC was tested at the medial areola, nipple, and lateral areola.Filaments used included size 2.83 with a target force of 0.07 g (representing normal sensation), 3.61 with a target force of 0.4 g (representing minor diminished sensation to light touch), 4.31 with a target force of 2 g (representing diminished sensation to light touch), 4.56 with a target force of 4 g (representing loss of protective sensation), 6.65 with a target force of 300 g (representing sensation to deep pressure only and loss of sensation).The most common comorbidities included anxiety (7 patients, 15%) and depression (12 patients, 26%).The 46 patients represented 46 encounters and 92 nipples in the less than 1-year follow-up group and 24 encounters and 48 nipples in the greater than 1-year followup group.Demographics between these two cohorts were not statistically significant (Table 1).Of note, 13 people (26 nipples) were represented in both the less than 1-year follow-up group and the greater than 1-year follow-up group.In addition, eight people had multiple postoperative encounters and thus multiple values for Semmes Weinstein testing in the less than 1-year follow-up group and three people had multiple postoperative encounters and thus multiple Semmes Weinstein testing values in the greater than 1-year follow-up group.
Of the 92 nipples (representing 46 patients) tested within the less than 1-year follow-up group, 17 (18.5%)had sensation for the 2.83 monofilament size, 12 (13%) had sensation for the 3.61 monofilament size, and 25 (27.2%) had sensation for the 4.31 monofilament size (58.6%ranging from normal to diminished sensation to light touch, representing reinnervation).For the remaining 38 nipples, 21 (22.8%) had sensation for the 4.56 monofilament and 17 (18.5%)had sensation for the 6.65 monofilament (41.3% with loss of protective sensation or deep sensation only, representing lack of reinnervation) (Figure 3).A subset analysis of patients in the less than 1-year follow-up group with poor sensory outcomes (38 nipples) was performed.The 38-nipple testing datapoints originated from 12 patients.Four of these patients were obese as determined by a BMI >30 (33%) and one was noted to be a former smoker (8.3%).A subset analysis of the patients in the greater than 1-year follow-up group with poor sensory outcomes (14 nipples) was performed.The 14-nipple testing datapoints originated from 10 patients.Three of these patients were obese as determined by BMI >30 (30%) and one was noted to be an active smoker (10%).No other risk factors for poor surgical outcomes (including diabetes, HTN, CKD) were identified.
There were 13 people (26 nipples) that had Semmes Weinstein data in the less than 1-year follow-up group and the greater than 1-year follow-up group.Of the 26 nipples, 15 nipples (57.7%) had documented improvement in nipple sensation from less than 1-year from surgery to greater than 1-year follow-up group.Specifically, eight nipples (30.8%) tested with normal, minor diminished sensation to light touch or diminished sensation to light touch in the less than 1-year follow-up group.This number increased to 19 nipples (73%) in the greater than 1-year follow-up group.

| DISCUSSION
The use of skin graft for NAC reconstruction in double incision mastectomy patients inherently limits the degree of return of nipple sensation.Reinnervation of grafted skin takes a significant amount of time and is often incomplete.A paper by Terzis describes the reinnervation of grafted skin as the sprouting of several neuronal buds from the proximal nerve ending into young scar tissue (Terzis, 1976).These fibers can penetrate the dermis of grafts and may "enter empty Schwann cell sheaths and reinnervate preexisting terminals or ramify and disperse as naked nerve endings."Demonstration of this reinnervation is seen on electric microscopy and validated by electrophysiological responses in grafted skin.A study comparing long-term sensory outcomes in normal skin versus skin graft in burn patients noted that despite this reinnervation, significant decreases in sensitivity to touch, cold, and warmth thresholds remained in skin grafts and did not return to normal baselines (Nedelec et al., 2005).
The diminished return of sensation in NAC grafts used for NAC reconstruction can be mitigated by direct neurotization of NAC graft skin with cadaver nerve graft.Direct neurotization of the dermis has been shown in animal models to regenerate sensation in the corresponding anterior skin (Taminato et al., 2021).Habre et al., 2018).
In this study, more than half (58.7%) of nipples tested after free NAC graft direct neurotization with cadaveric nerve graft noted normal or diminished sensation to light touch within 1 year of surgery.
This value increased to 71% of nipples tested noting normal or diminished sensation to light touch after 1 year, indicating sensation recovery.Prior studies with direct skin neurotization in this patient population have failed to quantify the degree of sensation lost, just the presence or absence of sensation (Berry et al., 2012;Gfrerer et al., 2022;Nedelec et al., 2005;Olson-Kennedy et al., 2018;Rochlin et al., 2020)

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I G U R E 1 Nerve coaptation to cadaveric nerve graft.Cadaveric nerve graft coaptation to the lateral intercostal.A total of 159 mastectomies for gender dysphoria were performed during the study time frame.Of these mastectomies, 115 patients elected for direct neurotization of the NAC with cadaveric allograft.The remaining 44 patients either underwent non-neurotized double incision mastectomy with free nipple grafting, double incision mastectomy without free nipple grafting or the concentric circle technique.Data on follow-up with Semmes Weinstein testing during the collection period was limited to 46 patients.The average age was 23.6 years (range 16-41) and average BMI was 27.3 (range 19-45).
There were 48 nipples (representing 24 patients) included in the greater than 1-year follow-up group.Of the 48 nipples, 4 (8.3%) had sensation for the 2.83 monofilament, 11 (22.9%) had sensation for the 3.61 monofilament and 19 (39.6%) had sensation for the 4.31 monofilament size (70.8%ranging from normal to diminished sensation to light touch, representing reinnervation).For the remaining 14 nipples, 13 (27%) had sensation for the 4.56 monofilament and 1 (2%) had sensation for the 6.65 monofilament (29% with loss of protective sensation or deep sensation only, representing lack of reinnervation) (Figure4).

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I G U R E 2 Nerve coaptation to cadaveric nerve graft.Cadaveric nerve placement before NAC graft is secured.T A B L E 1 Demographics.
free NAC grafts used for reconstruction in patients undergoing double incision mastectomy for gender dysphoria remain poor.Nerve reinnervation is demonstrated by our findings of normal, mild diminished sensation to light touch and diminished sensation to light touch Semmes Weinstein monofilament testing in the majority of patients undergoing this procedure.These findings exceed what would be anticipated in return of sensation for a full thickness skin graft.
. Direct neurotization techniques of the NAC used in the breast cancer patient population have been shown to improve sensoryThis study is limited by loss to follow up, especially in the greater than 1 year group.Despite this limitation, this study is the first of its kind to include a large patient cohort and to quantify degree of sensory recovery using Semmes Weinstein monofilament testing in patients undergoing direct neurotization of NAC graft after double incision mastectomy for gender dysphoria.All patients recovered a degree of return of sensation, with 71% of patients demonstrating normal, minor diminished light touch or diminished light touch return of sensation after 1 year.This value is well beyond what would be expected in a full thickness skin graft.In addition, the authors are unable to provide a reliable control group for comparison in this study, as the vast majority of patients who elected for nerve grafting also elected for direct neurotization of the free nipple graft.