The larynx is involved in major functions such as phonation, speech, swallowing, airway protection, and breathing (1). It is composed of various tissues, including muscles, cartilage, mucosa, nervous tissue, and connective tissue, making it a highly complex anatomical structure. Laryngeal transplantation is classified as a vascularized composite allograft (VCA), similar to hand (2), face (3, 4), or penile transplantation (5).

Total laryngectomy remains a high-volume surgical procedure, although laryngeal preservation strategies and nonsurgical treatments have grown increasingly important in the management of upper aerodigestive tract cancers (6). According to the World Health Organization, the global incidence of laryngeal cancer reached 189,191 new cases in 2022 (7). In the United States alone, around 5,000 total laryngectomies are performed annually (6). Besides oncological indications, this procedure may also be performed for severe trauma, stenosis, necrosis, post-radiotherapy complications, predisposition to chronic aspiration of food or recurrent laryngeal papillomatosis (8).

While total laryngectomy is generally considered safe (9), and significant advances have been made in rehabilitation strategies (10), losing one’s voice and living with a tracheostomy present substantial social and psychological challenges for patients and significantly impact their quality of life (11). Laryngeal transplantation has emerged as a potential life-enhancing treatment to restore function and form after total laryngectomy. Unlike life-saving organ transplants, such as those for the heart, lungs, or kidneys, this procedure is not essential for survival. Instead, its success is primarily assessed based on functional outcomes and associated morbidities. Thus, while it may not be sufficient on its own, precise microsurgical anastomosis of both vascular and neural structures is a necessary first step towards achieving satisfactory functional outcomes (12).

In 1928, American surgeon Franck Lahey laid the conceptual groundwork for laryngeal transplantation (13). However, the first human attempt—using a non-vascularized larynx—did not occur until 40 years later (14). It then took another 30 years to achieve the first successful human laryngeal transplantation (15). Throughout this timeline, animal studies have played a key role in refining surgical techniques, evaluating immunological tolerance, and assessing functional outcomes. These contributions have been instrumental in advancing the feasibility of laryngeal transplantation (16–20).

In this systematic review, the functional outcomes of laryngeal transplantation were examined, in both humans and preclinical models, highlighting key advancements and challenges. Furthermore, we discussed the post-operative rehabilitation strategies, immunosuppressive regimens, and future perspectives of this evolving field.

This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines (21). Due to the heterogeneity of data, a qualitative synthesis approach was chosen, and a meta-analysis was deemed unsuitable. The study protocol was registered with PROSPERO (registration number CRD420250653746) (22).

Laryngeal transplantation represents a type of VCA to restore laryngeal function. Currently, functional outcomes are encouraging in terms of swallowing, phonation, and speech, but vocal fold mobility and tracheostomy dependence persist as main barriers in the field. Furthermore, laryngeal transplantation is a procedure associated with significant morbidity and mortality.

Our synthesis of all published cases suggests that voluntary mobility of the vocal folds was never fully restored. Swallowing function, even if minor, was reported in most patients, while some no longer required a tracheostomy. Additionally, two-thirds of the patients regained phonatory and speech functions, fully or partially.

It is naturally challenging to compare functional outcomes across different types of VCA, as they restore inherently distinct functions. Nevertheless, it would appear that functional recovery in other VCA types has generally exceeded that seen in laryngeal VCA. In upper extremity VCA, studies report consistent return of protective sensation, voluntary movement, and, in many cases, fine motor skills within 12–24 months – (38–40). These outcomes are considered reproducible across centers and often surpass prosthetic alternatives (41, 42). Furthermore, early rehabilitation and interdisciplinary support were also shown to critically enhance functional outcomes and long-term success (43). Similarly, facial VCA has shown recovery of expression, speech, and psychosocial integration, with early sensory return and functional gains that exceed traditional reconstruction (44–46). Other VCA types, such as uterus, trachea, and abdominal wall have demonstrated key functional outcomes including live births, airway patency, and structural support (41, 47, 48).

Laryngeal VCA may benefit from validated functional outcome measures, adapted rehabilitation protocols, and multicenter collaboration to optimize results. Incorporating patient-reported outcomes and identifying biomarkers for graft function and rejection could further support long-term success.

Identifying causes of rejection and mortality is essential to improving the safety of any experimental procedure. In their 2017 review, Krishnan et al. outlined complications in the first two laryngeal transplant recipients: the first developed multiple infections (oropharyngeal candidiasis, tracheobronchitis, Pneumocystis carinii pneumonia), acute rejection at 15 months and 5 years, and signs of chronic rejection at 9 years, leading to graft explantation at 14 years. The second patient experienced mild infectious complications (pulmonary and catheter-related infections, mucosal candidiasis), and tacrolimus toxicity, with no rejection at 6 months (37). In a case series by Candelo et al., three of eleven patients died within 20 years—one from pulmonary embolism and two from sepsis—despite having functioning grafts. Complications were frequent but typical of major surgery, including early pneumothorax, perioperative hemorrhage, and late airway stenosis (33).

Reported causes of rejection and mortality in early laryngeal transplantation include opportunistic infections, immunosuppressive toxicity, and progressive chronic rejection, whereas deaths were primarily attributed to indirect postoperative complications such as pulmonary embolism and sepsis, rather than graft failure itself.

An essential factor in preventing graft rejection and patient mortality is the optimization of immunosuppressive therapies. Our study found corticosteroids (prednisone, methylprednisolone), antibodies (anti-thymocyte globulin, daclizumab), calcineurin inhibitors (cyclosporine, tacrolimus), antimetabolites (azathioprine, mycophenolate mofetil), and mTOR inhibitors (sirolimus), to be the most common immunosuppressants in laryngeal VCA. Mesenchymal stem cells were used in select cases. In the literature, Baudouin et al. analyzed the first three laryngeal VCA cases, noting a shift from high-dose cyclosporine to lower-dose rabbit anti-lymphocyte globulin and tacrolimus. Mycophenolate mofetil became standard, and prednisone remained effective across transplant types (49). In comparison in facial VCA, Huelsboemer et al. reported that facial VCA induction regimens typically consisted of corticosteroids, thymoglobulin, tacrolimus, and mycophenolate mofetil, with maintenance relying on tacrolimus, mycophenolate mofetil, corticosteroids, and extracorporeal photopheresis. In hand transplantation similar approaches were reported. Here, immunosuppressive regimens often included basiliximab and mTOR inhibitors such as sirolimus or everolimus (50). These parallels illustrate a shared immunosuppressive backbone across VCA types, emphasizing a core reliance on calcineurin inhibitors and antimetabolites, while also showcasing the progressive integration of adjunctive therapies like mTOR inhibitors and biologics. Notably, the inclusion of extracorporeal photopheresis in facial VCA highlights efforts to modulate the immune system while minimizing systemic toxicity. Moreover, hand VCA studies have explored steroid-sparing regimens and demonstrated successful tolerance protocols using costimulation blockade, pointing to future opportunities in laryngeal VCA. Looking forward, Baudouin et al. emphasized the importance of standardized immune surveillance, including pre-transplant crossmatching, anti-HLA antibody monitoring, and Luminex-based single-antigen assays (49). In experimental models, Lott et al. proposed pulsed everolimus in combination with anti–αβ T-cell receptor antibodies to reduce long-term toxicity, presenting a novel, less aggressive immunosuppressive strategy tailored to oncologic laryngeal transplants (51).

These findings suggest clinicians should re-evaluate immunosuppressive strategies in laryngeal VCA by drawing on advances from other VCA types. The successful application of maintenance strategies from facial and hand VCAs, including extracorporeal photopheresis or mTOR inhibitors, shows promise for adaptation. Furthermore, standardizing immune monitoring protocols—like HLA antibody tracking and single-antigen assays—could enhance early detection and management of rejection. Ultimately, translating these insights into clinical practice may help reduce morbidity, prolong graft survival, and enable broader adoption of laryngeal VCA.

Living without a larynx is not inherently life-threatening. Consequently, the risks associated with lifelong immunosuppression, such as increased susceptibility to malignancy (52), complex infection management (53), and the possibility of allograft rejection must be weighed carefully on a case-by-case basis. These concerns have been extensively addressed in the literature over the past two decades (26, 37, 54–56). Therefore, rigorous and validated assessment of functional outcomes in laryngeal transplantation is ethically imperative to ensure that patients can make fully informed decisions. Moreover, the issue of potential retransplantation, as has been encountered in facial transplantation, must be considered (44, 57). Laryngeal transplantation shares many systemic challenges with other forms of organ transplantation, including high treatment costs, variable insurance reimbursement, and limited graft availability. Importantly, demographic data, particularly regarding ethnicity and race, are not consistently reported. Institutions performing laryngeal transplantation should implement measures to ensure equitable access, such that recipients reflect the demographic diversity of the broader population. For example, in the series reported by Candelo et al., only 27% of recipients were women, with 9% identifying as Black, 45% as Hispanic, and 45% as White (33), an imbalance similarly noted in facial transplantation research (58).

Overall, clinical experience with laryngeal transplantation remains scarce. Therefore, multiple authors provided valuable insights on alternative approaches for larynx reconstruction. Here, Andrews et al. investigated hemilaryngeal transplantation (HLT) in a canine model as a solution for partial laryngeal defects, demonstrating that HLT was well-tolerated with successful revascularization and reinnervation of the thyroarytenoid muscle, leading to symmetric phonation and viable tissue (59). Supracricoid laryngectomy (SCL) may avoid the need for a permanent tracheostomy but often results in speech and swallowing deficits, comparable to those of a total laryngectomy. Zacharek et al. reported similar functional limitations in both laryngeal VCA and SCL (60). Looking into radial forearm flap reconstructions (RFFR) after total laryngectomy, functional outcomes were similar to laryngeal VCA. However, RFFR patients showed lower Voice-Related Quality of Life scores (i.e. a scale to assess the functional impact of voice disorders on daily activities) (61). Additional emerging modalities such as transoral robotic surgery (TORS) and tracheoesophageal voice prostheses have further expanded reconstructive possibilities. TORS offers a minimally invasive method for tumor resection with improved preservation of swallowing and voice (62), while voice prostheses remain a widely used solution for communication after laryngectomy (63, 64). Together, these findings supported the notion that laryngeal VCA might offer functional restoration that is at least comparable, if not superior, to conventional approaches, while maintaining a similar risk profile.

For clinicians, this suggests that laryngeal transplantation should be considered a viable reconstructive option in carefully selected patients, particularly those with traumatic or oncologic defects where conventional techniques would result in significant functional limitations. Despite challenges with vocal fold mobility, many patients regain swallowing, phonation, and speech, suggesting meaningful benefit. Outcomes may rival or exceed those of SCL or RFFR, especially in terms of quality of life. Given the high morbidity and resource intensity, strict patient selection and multidisciplinary planning remain critical. Patients should be counseled on the potential for improved voice and airway function, but also on the lifelong immunosuppression and current uncertainties in rejection monitoring, emphasizing the importance of long-term follow-up in specialized centers.

A key methodological limitation is the uncertain number of laryngeal transplants worldwide, for instance Krishnan et al.’s 2017 review found only two documented cases. They estimated at least 14 cases since 2002, based on Spanish-language abstracts, notably by Duque, Tinitinago, and Terris (37). It is highly probable that five of these cases correspond to those reported from Colombia in the 2024 case series by Candelo et al. (33). However, the reasons why the remaining nine cases were not included remain unclear. The scarcity of documented cases limits the ability to conduct large-scale comparative studies and calls for the establishment of an international registry to improve data collection.

Second, the articles included in this systematic review are not limited to original research papers, as is commonly the case in this type of research. The heterogeneity of sources (reviews, case series, commentaries, etc.) also poses a methodological limitation. This approach was necessitated by the limited availability of data and was also the strategy adopted in the systematic review conducted by Krishnan et al. (37).

Third, in the case reports and case series included in this review, data from standardized and reproducible evaluation tools for assessing vocal fold mobility, phonation, speech, swallowing, and airway patency were not consistently available, making direct comparisons between cases difficult. Combining validated questionnaires and objective tools would better capture both patient and clinician perspectives. This calls for the establishment of an international database to improve data collection, facilitate more consistent functional outcome assessments, and encourage long-term follow-ups. It would allow for large-scale comparative studies and meta-analyses.

Lastly, due to the experimental nature and high technical complexity of this procedure, early failures may have gone unreported in the literature. This inevitably introduces a potential reporting bias that is difficult to quantify when conducting descriptive statistical analyses based on case series. Establishing an international prospective registry is essential to address this limitation and improve data transparency.

Laryngeal transplantation is a type of VCA that can help restore the function and the form of the larynx. Larynx allotransplants show promising effects in improving the patient’s swallowing and phonation. However, significant limitations persist. To date, no recipient has regained full vocal fold mobility, and sustained decannulation remains rare, highlighting persistent deficits in neural reinnervation and airway autonomy. These functional constraints, combined with the burden of lifelong immunosuppression and associated morbidity, confine the procedure to an experimental domain. Regarding future research, three domains should be prioritized: first, the development of standardized, reproducible outcome measures that integrate objective functional data with patient-reported experiences, second, the optimization of surgical techniques and rehabilitation protocols through multicenter collaboration, and third, the exploration of novel immunomodulatory strategies aimed at reducing long-term systemic toxicity while preserving graft viability. A retrospective case-control study comparing functional outcomes between transplantation and non-transplantation controls after total laryngectomy could provide valuable insights, reinforcing the potential advantages of laryngeal transplantation and underscoring the necessity for further research in this field. Furthermore, recent advances in predictive modeling and early rejection diagnosis developed in the context of solid organ transplantation could be applied to laryngeal VCA, including those based on artificial intelligence. Such technologies could help improve the long-term management of patients.

At present, laryngeal transplantation is still considered an experimental procedure for select indications in specific patients. Its ethical justification depends on its capacity to deliver strong and sustainable improvements in quality of life. To better evaluate the functional outcomes and morbidity of laryngeal transplantation, patients should be followed over longer periods and assessed using standardized tools. Overall, this work calls for future cross-disciplinary research and international registers to determine the need for laryngeal transplants and better document outcomes over time.