The first laryngeal allotransplantation in China: Perioperative condition and six-month follow-up

The loss of laryngeal function profoundly impacts the quality of life for specific patients with distorted laryngeal structure or total laryngectomy, particularly in social contexts. Consequently, allotransplantation has emerged as a potential solution for restoring laryngeal function. A significant milestone in this field was the successful total laryngeal transplant conducted by Strome et al[1] in 1998, demonstrating graft viability for an impressive 13-year postoperative period. Building upon this progress, Farwell et al[2] and Grajek et al[3] performed the second and third surgeries in 2012 and 2015, respectively. This study is an exploratory interventional study and was approved by the Institutional Review Board of the West China Hospital (No. 2017[362]). Written informed consent was obtained directly from the participant. The involved patient is a 65-year-old male presented with recurrent laryngeal squamous cell carcinoma (rT3N0M0) nine years after undergoing a right partial laryngectomy. Due to the severity of the laryngeal obstruction (grade 3) caused by the cancer recurrence, the patient required an emergency tracheostomy. Laryngoscopy revealed the presence of a lump on the laryngeal surface of the epiglottis, which was later confirmed through pathological examination as a recurrence of squamous cell carcinoma [Supplementary Figure 1, https://links.lww.com/CM9/C119]. Furthermore, a computed tomography (CT) scan demonstrated thickening and enhanced appearance of the left aryepiglottic fold, while no enlarged lymph node. Initially, the patient received a total laryngectomy. However, due to concerns about losing the ability to speak, the patient declined this procedure. Subsequently, the option of laryngeal transplantation was proposed. Following several comprehensive interviews with the patient and his family, they were fully informed about the potential risks involved and provided informed consent for the surgery. The transplantation surgery was carried out by Professor Chen’s team in April 2023. A 61-year-old donor was matched. The donor larynx was evaluated with no identifiable pathology. The entire larynx-thyroid-trachea-hypopharynx complex was procured with preservation with bilateral thyroid arteries and vein, along with superior laryngeal nerves and laryngeal recurrent nerves. Following procurement, the larynx was extracorporeally perfused with histidine-tryptophan-ketoglutarate (HTK) solution through superior thyroid artery and then stored in ice-solution mixture [Figure 1A].Figure 1: Detailed surgical procedure. (A) Perfusion of the larynx; (B) Narrow-field laryngectomy; (C) Fix the donor larynx to the recipient’s pharynx and tongue base; (D) Arterial anastomosis; (E) Venous anastomosis; (F) Nerve anastomosis; (G) Trachea anastomosis; (H) Skin closure.Total laryngectomy The recipient underwent a narrow-field laryngectomy [Figure 1B] with bilateral elective neck dissection, preserving and preparing the nerves and blood vessels involved. The fourth tracheal ring was preserved. Transplantation The larynx was primarily fixed by suturing the donor’s and recipient’s pharynx and tongue base [Figure 1C], and the donor’s thyroid cartilage was fixed to the recipient’s tongue root. End-to-end anastomoses were performed for proper blood flow, using 10-0 prolene sutures for arterial anastomoses [Figure 1D] and couplers for venous anastomoses [Figure 1E]. The bilateral recurrent laryngeal and superior laryngeal nerves were carefully anastomosed with 10-0 prolene sutures [Figure 1F]. The specific details and time taken for each procedure can be found in Supplementary Table 1, https://links.lww.com/CM9/C119. After completing the anastomoses, the donor’s trachea was sutured to the recipient’s fourth tracheal ring [Figure 1G], preserving the previous tracheostoma. Closure Thorough hemostasis was achieved, and the surgical procedure concluded by closing the subcutaneous and skin layers using 3-0 Vicryl (Ethicon Inc., NJ, USA) [Figure 1H]. After surgery, the patient received a standard immunosuppressive regimen comprising methylprednisolone, tacrolimus, and mycophenolate mofetil (MMF). The adjustment of the dosage was based on the serum tacrolimus [Supplementary Figure 2A, https://links.lww.com/CM9/C119] and mycophenolate concentration [Supplementary Figure 2B, https://links.lww.com/CM9/C119] as well as immune indexes including T, B, and Natural Killer (TBNK) subpopulation [Supplementary Figure 2C, D, https://links.lww.com/CM9/C119] and cytokine tests. However, the patient encountered multiple episodes of infections, including a wound infection caused by multidrug resistant Acinetobacter baumannii (MDRAB), Gram-negative bacteremia, multidrug resistant Klebsiella pneumoniae urinary tract infection and bacteremia, as well as cytomegalovirus (CMV) infection. To address these infections, a series of antimicrobial treatments including vancomycin, meropenem, tigecycline, caspofungin, sulfonamide, polymyxin E, and ganciclovir was administered, and the lab results were closely monitored for efficacy assessment [Supplementary Figure 3A, https://links.lww.com/CM9/C119] and potential kidney dysfunction [Supplementary Figure 3B, https://links.lww.com/CM9/C119]. The detailed treatment course and remarkable events are provided in Supplementary Table 2, https://links.lww.com/CM9/C119. Thyroid function remained mostly stable during the postoperative recovery; no supplements of thyroid hormone or calcium were required during the hospitalization or after discharge [Supplementary Figure 3C, https://links.lww.com/CM9/C119]. Regarding thyroid hormone and antibodies, there was a remarkable surge of thyroglobulin antibodies and thyroid peroxidase antibody on postoperative day 13 [Supplementary Figure 3D, https://links.lww.com/CM9/C119], which resulted from a thyroid biopsy, which turned out to be negative for any sign of graft rejection. The laryngoscopy on the 25th postoperative day demonstrated markedly swollen laryngeal mucosa [Supplementary Figure 1B, https://links.lww.com/CM9/C119], which resolved spontaneously before discharge [Supplementary Figure 1C, https://links.lww.com/CM9/C119]. No signs of bleeding or anastomosis dehiscence were observed. Following successful management of the infections and control of graft rejection, the patient was discharged on the 37th day post-surgery. Two days post discharge, the patient was readmitted for accidental removal of NGT. During this hospitalization, the patient experienced several infections, including urinary tract infection (UTI) and respiratory infection, which were effectively treated with a combination of antibiotics. The treatment course is detailed in Supplementary Table 3, https://links.lww.com/CM9/C119. After 28 days of collaborative treatment, the patient recovered and was discharged. Approximately five months post surgery, the patient was rehospitalized due to persistant high fever (40°C), with purulent sputum fatigue, chest discomfort, and mild dyspnea. Laboratory tests revealed a reduction in lymphocyte count, potentially attributed to mycophenolate mofetil [Supplementary Figure 2B, https://links.lww.com/CM9/C119]. Laryngoscopy discerned the presence of a hypertrophic plica mucosa situated in the postcricoid region [Supplementary Figure 1E, https://links.lww.com/CM9/C119], precisely at the site of the anastomosis, obstructing the esophageal orifice. Subsequently, a rigid-laryngoscopic procedure with laser resection of the hypertrophied hypopharyngeal mucosal plica was conducted. Regrettably after surgery, the patient experienced accidental aspiration of approximately 150 mL of rice puree during attempt to oral feeding, subsequently precipitating an episode of aspiration pneumonia. Following antibiotic therapy and supportive measures, as delineated in Supplementary Table 4, https://links.lww.com/CM9/C119, the patient’s pneumonia and associated maladies were ameliorated. On the 60th day following the surgery, the patient underwent the initial assessment of swallowing function. The epiglottis was unable to descend, resulting in a minor accumulation of pureed residue within both the vallecula and pyriform fossa [Supplementary Figure 1D, https://links.lww.com/CM9/C119]. This residue could be successfully cleared through the employment of repetitive swallowing maneuvers. Concurrently, the assessment revealed instances of pureed material entering the trachea, leading to episodes of coughing. Subsequently, the second evaluation, performed on the 150th day post-surgery, exhibited a persistent mild accumulation of pureed residue within both the vallecula and pyriform fossa. Nevertheless, the presence of an occlusive mucosal plica, obstructing the esophageal entrance, accentuated the incidence of leakage and aspiration, rendering them more pronounced [Supplementary Figure 1E, https://links.lww.com/CM9/C119]. The third assessment, conducted on the 180th day postoperatively, showed improved swallowing function with trace residue in both vallecula and pyriform fossa; the leakage and aspiration were minimized [Supplementary Figure 1F, https://links.lww.com/CM9/C119]. The obstruction imposed by the plica was successfully managed by the surgery, and the patient is now able to conduct oral semi-liquid feeding without aspiration. By the 9th day following the surgical intervention, the patient exhibited capacity to enunciate elementary vocabulary with a breathy phonatory quality, which was likely attributable to phonation facilitated by the aryepiglottic folds. Subsequently, during the first month post-surgery, laryngoscopic examination disclosed subtle oscillation of the vocal cords when the patient enunciated the phoneme “Yi”. Nevertheless, during a subsequent assessment of phonatory function utilizing laryngoscopy, it was discerned that the reinnervation of the recurrent laryngeal nerves remained suboptimal, as both vocal cords persisted in a lateral position. Upon conducting laryngoscopy on the 6th month post-surgery, a noticeable enhancement in vocal cord mobility was documented in comparison to the first postoperative month, indicating a progress of reinnervation. To conclude, the complexity of laryngeal transplantation necessitates further exploration of both surgical technique, perioperative and long-term care. Our study demonstrated the success and functional efficacy of the laryngeal allotransplantation. However, additional investigations on immunosuppressive strategies are warranted to develop a tailored regimen for laryngeal transplantation, ensuring optimal management of both rejection and infection. In addition, further functional follow-up should be undertaken to provide more detailed data for the surgery. Funding This research is funded by the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. 20HXJ5014) and Sichuan Science and Technology Program (No. 2022NSFSC1298). Conflicts of interest None.