38 Laryngeal Transplantation

The intricacy and complexity of the human voice is unique in the animal world. In social settings, our ability to interact verbally is critical to maintaining a sense of normalcy and optimizing quality of life. As our modern communicationcentered society becomes less dependent upon manual labor, our ability to effectively vocalize is increasingly essential in maintaining gainful employment. In patients who have undergone laryngectomy or have a severely dysfunctional larynx and have lost their ability to speak, many techniques have been developed to restore voice. These include vibratory speech via an electrolarynx, esophageal speech, or tracheoesophageal puncture. While these methods are successful in allowing most patients to communicate, the voice produced is often abnormal in clarity, volume, and duration. In multiple studies, these changes in voice have been shown to variably impact quality of life.1–3

Rather than replacing the complicated larynx with a mechanized vibratory source or a mucosal shunt for a vibrating air column, the transplantation of a larynx offers the potential for physiological return of function. Replacing a dysfunctional or lost larynx with a transplanted larynx has been the goal of surgeons for over 40 years. Starting with the work in dogs by Silver et al^4,5 and the reported transplantation of an avascular human laryngeal graft in 1969 by Kluyskens and Ringoir,⁶ the field of laryngeal transplantation was born. Questionnaire studies have shown that patients would be willing to trade the side effects of immunosuppressant medication to experience restoration of normal speech.⁷ Over the past four decades, tremendous work has been performed in animal models culminating in two successful North American larynx transplants and several reported transplants in South America.^8–13

History

In 1966, Silver et al first published their work on laryngeal transplantation in dogs, and in their 1970 article, they described 48 canine laryngeal transplants.^4,5 Several key observations came out of their work. First, all nonimmunosuppressed organs rejected at a microscopic level in 6 to 7 days. On a macroscopic level, rejection was visible in 7 to 8 days after transplant. This rejection was manifested by early edema, friability, and gray-yellow exudates followed by necrosis and cartilage exposure. Additional observations included the short time of ischemia tolerated by the nonperfused larynx. No perfusate was utilized and revascularization that took longer than 45 minutes was associated with ischemic necrosis.

In 1969, Kluyskens and Ringoir reported the first human larynx transplant after performing a laryngectomy in a 62-year-old man with larynx cancer. The organ was not revascularized but placed in a “wrap” of the recipient’s perichondrium to encourage revascularization. Postoperatively, there was ischemic necrosis noted on biopsy. Due to the severity of the cancer, they were unable to wait for a perfectly cross-matched donor. The donor organ transplanted was of the same blood type (O+) but only matched 3 of the other 10 antigens tested. Despite immunosuppression with prednisone, azathioprine, actinomycin-C, and antilymphocyte serum, the graft suffered rejection episodes as demonstrated by edema and partial necrosis. This early rejection was rescued by additional immunosuppression. The patient was able to have the nasogastric tube removed at 70 days, and leave the hospital at 3 months before succumbing to aggressive recurrent cancer at 8 months posttransplant.⁶ This poignant demonstration of the relationship of immunosuppression to cancer dramatically curbed the enthusiasm for this procedure.

While human transplantation was abandoned for nearly 30 years, experimental work on laryngeal transplant continued in animal models. Additionally, rapid evolution of the field of solid organ transplantation resulted in dramatic improvements in our understanding of immunology, immunosuppression, and graft tolerance. The successful transplantation of vascularized rat larynges was described in 1992 and 1994 by Strome’s group at the Cleveland Clinic.^10,11 Work on canine laryngeal preservation by Kevorkian et al⁹ demonstrated the ability to extend cold ischemia time and improve graft survival in a large mammalian model. More recently, a porcine model was developed to evaluate revascularization and the immunological response to transplantation.¹² These animal models advanced our understanding of the technical caveats of laryngeal transplantation and the immunosuppression necessary for graft survival.

Blood Supply

Successful larynx transplantation requires adequate blood supply and drainage. The blood supply to the larynx was beautifully described by Pearson in 1975.¹⁴ This blood supply is variable but follows a general pattern of a superior and inferior blood supply off the superior thyroid and inferior thyroid arteries, respectively. The superior laryngeal artery usually branches from the superior thyroid artery and enters the thyrohyoid membrane.¹⁵ An inferior laryngeal artery branches from the inferior thyroid artery to supply the posterior and cricoid region. Often a posterior inferior vessel is noted coming off the inferior thyroid. These branches also supply the membranous trachea and esophagus and provide another source of blood supply to the subglottis and posterior trachea. As any thyroid surgeon knows, there are also multiple vascular communications between the thyroid gland and the ligament of Berry and the underlying larynx and trachea. The inferior thyroid artery is an important contributor to the vascularity of the trachea.16 As many laryngeal transplant candidates are also deficient in tracheal length, this is a critical attribute of the inferior thyroid artery.

The venous system of the larynx is much less understood and studied. In Pearson’s study, a general pattern of veins following the arteries was demonstrated. The inferior laryngeal veins drained into the middle thyroid veins toward the jugular veins, whereas other inferior veins drained into the thyroid isthmus and inferior thyroid veins.¹⁴

Innervation

The innervation of the larynx has been widely studied and comprehensively described elsewhere in this book. The superior laryngeal nerve provides sensation to the majority of the glottic and supraglottic larynx after branching off of the vagus. Additionally, it supplies motor innervation to the cricothyroid muscle through its external laryngeal nerve branch. The recurrent laryngeal nerve provides subglottic sensation and motor innervations to the rest of the larynx. The recurrent laryngeal nerve typically bifurcates into an abductor and adductor branch before entering the larynx. This provides the opportunity to selectively reinnervate the larynx. However, it is increasingly clear that the innervation of the larynx is far more complex than the superficial description above. There is robust communication between these two main nerves through the nerve of Galen connecting the recurrent laryngeal nerve and superior laryngeal nerve in up to 81% of larynges.¹⁷ Denervation injuries demonstrate variable disability and healing. Similarly, reinnervation procedures have demonstrated less predictable results than surgeons would like. This unpredictable behavior has frustrated laryngologists and may be explained by variable neural anatomy including intralaryngeal branching and neural communications described above.¹⁸

Transplantation Results

Building on their significant animal research, Strome and colleagues performed the first vascularized laryngeal transplant in 1998.⁸ This patient had lost the function of his larynx from a motorcycle accident 20 years ago. He was aphonic, anosmic, and suffered from ageusia by report. After unsuccessful reconstructive attempts, he underwent laryngeal transplantation. Microvascular anastomoses were performed between both recipient and donor superior thyroid arteries. Venous anastomoses were performed between the donor jugular vein and the recipient facial vein on the right side and the middle thyroid veins on the left side. Microneurorrhaphies were performed between both superior laryngeal nerves and the right recurrent laryngeal nerve. Electromyography (EMG) was performed on the transplanted larynx 4 years after transplantation demonstrating innervations of bilateral cricoarytenoid and thyroarytenoid muscles.¹⁹ The intensity of EMG activity was only slightly reduced on the left side despite having only performing microneurorrhaphy on the right side.

His posttransplant course has been remarkable.²⁰

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