Laryngeal transplant: The future?

Varun Jitendra Dave

doi:10.4103/2347-8128.182851

REVIEW ARTICLE

Year : 2016 | Volume : 4 | Issue : 1 | Page : 12-15

Laryngeal transplant: The future?

Varun Jitendra Dave
Department of ENT, Government Medical College, Surat, Gujarat, India

Date of Web Publication

23-May-2016

Correspondence Address:
Varun Jitendra Dave
22, Karunalaya, Telli galli, Andheri (East), Mumbai - 400 069, Maharashtra
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/2347-8128.182851

Abstract

There is very less literature about laryngeal transplant, particularly in India. In the past, laryngeal transplant along with other “nonvital” organ transplant had been considered unethical as the risks associated with chronic immunosuppression outweighed the gains of the transplanted organ. However, with the advent of newer immunomodulatory drugs and drug delivery systems, the risks of immunosuppression are considerably low. This has prompted the growth and expansion of nonvital organ transplant which was evident by the first hand transplant performed in India. In the following discussion, the success of the two laryngeal transplants performed till date and the need for optimism in this field is outlaid. This article is directed toward all the ear-nose-throat and head-neck surgeons who treat laryngeal cancer on a regular basis.

Keywords: Everolimus, immunosuppression, laryngeal transplant

How to cite this article:
Dave VJ. Laryngeal transplant: The future?. J Head Neck Physicians Surg 2016;4:12-5

How to cite this URL:
Dave VJ. Laryngeal transplant: The future?. J Head Neck Physicians Surg [serial online] 2016 [cited 2023 Mar 30];4:12-5. Available from: https://www.jhnps.org/text.asp?2016/4/1/12/182851

Introduction

The larynx is an important organ of the upper airway, whose function is multi-fold: Voice production, airway-foodway separation, protection of lower airway, and respiration; further, the upper surface of epiglottis has sensory taste buds as well.

Unfortunately, laryngeal cancer is the third most common cancer overall and the second most common cancer in males in India.^[1] This is treated by either surgery (LASER or open partial or total laryngectomy) or radiotherapy. The larynx may also be damaged by trauma in accidents or due to homicidal or suicidal throat injuries.

The loss of larynx due to either tumor or trauma results in loss of voice and a permanent stoma in the neck with its attendant issues. Swallowing is compromised as well. The airway diversion results in loss of olfaction and the inability to occlude the glottis, which restricts the person's ability to lift heavy objects as well. Thus, the disease as well as the treatment inflicts severe damage to the patient's well-being and even if the patient is cured, he/she never completely regains his preinfliction quality of life.

Damage to the larynx is best prevented. Laryngeal carcinoma is largely a habit-related disease. Thus, cessation of tobacco smoking and alcohol is paramount to prevention of laryngeal cancer.

Genetic counseling for familial cancer may help as well. Use of seat belts while driving can prevent traumatic injury to the larynx in case of crashes.

The impact on quality of life has been significant in selecting the therapeutic approach. Even though open laryngectomy has shown better cure rates than functional preservation protocols (chemotherapy plus radiotherapy), its use is on the decline.^[2] This is because the functional outcomes regarding speech and swallowing postlaryngectomy are poor.^[3]

Current Methods of Rehabilitation

The current methods of rehabilitation postlaryngectomy are mainly directed toward restoration of voice while concerns regarding swallowing and neck stoma among others are not addressed satisfactorily. Moreover, Clements et al. reported that the current methods of voice restoration, i.e., electrolarynx, esophageal voice, and tracheoesophageal voice have proved to be unsatisfactory as fewer than 40% of laryngectomized patients were content with their new voice. Fewer than 50% of these patients were satisfied with their ability to interact with others and their quality of life.^[4] This results in loss of a person's identity.

Ideal Rehabilitation

This potentially large pool of patients requires a rehabilitative procedure which collectively addresses voice restoration, swallowing, and tracheostomal problems, thereby improving the patient's quality of life significantly. This would also motivate more patients to undergo laryngectomy rather than function preservation techniques, thus achieving better cure rates. A laryngeal transplant has the potential to be the ideal rehabilitation procedure as it fulfills all the aforementioned conditions.

Indications

In the past, laryngeal transplant was indicated only for patients who lost their larynges due to trauma or had large benign or low-grade malignant tumors. Risk of recurrence with chronic immunosuppression restricted its use in locally advanced laryngeal and hypopharyngeal tumors.^[5] However, newer techniques obligate the need to administer immunosuppression on a long-term basis, and the antitumor properties of drugs such as everolimus can be utilized in patients with locally advanced tumors. These patients form a large group of potential recipients.

Previous Laryngeal Transplants

The first ever laryngeal transplant was performed by Strome et al. in 1998 at Cleveland, USA.^[6] The patient had lost his larynx at a young age in a ski-doo accident, suffering clothesline injury and had been unemployed ever since. After finding a matched donor, the entire larynx, upper tracheal rings, thyroid, and parathyroid along with the blood and nerve supply were transplanted. Long-term immunosuppression with tacrolimus, mycophenolate mofetil, and methylprednisolone was used. The voice, swallowing, and taste gradually recovered fully over 12–14 months, and the patient was relieved of the neck stoma as well. An episode of rejection was noted at 15 months which was relieved by steroids. The patient reported an “immeasurable” improvement in his quality of life. Although previously unemployed, he became a motivational speaker after the procedure. However, 14 years postsurgery, the larynx had to be explanted as it developed chronic rejection not responding to treatment which turned cancerous thereafter. As human papillomavirus (HPV) was found in the specimen, it could not be said whether cancer developed as a result of the adverse effects of the prolonged immunosuppression or due to HPV. Nevertheless, the most illustrative insight provided by the case was that the patient had no regrets about the transplant even though it had to be explanted and requested a subsequent transplant if the opportunity arose.^[7]

The second laryngeal transplant was performed by Farwell et al. in 2010 at UC Davis Hospital, California, and had been successful too. The patient was a 39-year-old female who had damaged her larynx during multiple self-extubations while admitted to the ICU for pancreatic-renal transplant. Strome's retrieval technique of transplanting the larynx and trachea was augmented by Farwell et al. by retention of esophageal muscles attached to the posterior wall of trachea to increase the vascularized tissue on the membranous trachea, as well as by the addition of inferiorly based blood supply via the inferior thyroid artery to support the tracheal graft. Tacrolimus and leflunomide were used for long-term immunosuppression. The voice and swallowing have shown complete recovery and the patient has been able to lose the neck stoma too.^[8]

Despite it being an ideal rehabilitative procedure and its successful execution by Strome and Farwell, laryngeal transplant has not been popular till date. This is because the larynx has been considered a nonvital organ as survival without it is routine; lifelong immunosuppression and the risks associated with it have been considered unsuitable for transplantation of a nonvital organ. The learning curve for a laryngeal transplant is steep. Moreover, the complex and variable nature of the nervous supply of larynx have made laryngeal reinnervation procedure tricky with unpredictable results.^[9],[10] It took years of training and thousands of rat models for Strome to perform it on a human being. Postoperative recovery and care require great motivation from patients and caregivers and regular psychological assessment by a psychiatrist. The availability of a suitable donor, prolonged hospital stay, and the costs involved further make it difficult to be practiced everywhere by everyone.

Quality of Life Issues

Patients with laryngeal cancer report significantly low quality of life with suicidal ideations three times as common as normal people.^[11] Lehmann et al. conducted an interview of 700 laryngectomees which revealed that 50% of them lost their jobs, one-third of them suffered financial constraints, and every third person was unsatisfied with the voice rehabilitation.^[12] Thus, considering the effect of the loss of larynx on the patient's physical, mental, and social well-being and the resulting poor quality of life, the designation of the larynx as a nonvital organ should be revisited.

Donor

In 2007, Duque et al. supported 25 laryngeal donorsin vitro and reported a 90% graft survival rate of laryngeal donors at 2 years when the following selection criteria were used: (1) 18–50 years old; (2) no abuse of tobacco, cocaine, and marijuana; (3) gender and ABO blood type matched between donor and recipient (4) tracheal intubation time <3 days; (5) time in the intensive care unit <7 days; (6) duration of ischemia < 20 h. The larynx was infused with University of Wisconsin solution and preserved in simple hypothermia. The laryngeal donors were able to tolerate hemodynamic instability and did not require strict fluid management but required higher doses of vasoactive drugs as compared to multi-organ donors.^[13]

Immunosuppression

The risk of recurrence of carcinoma, repeated infections, and compliance to long-term immunosuppression therapy has been among the major concerns associated with laryngeal transplant. However, a newer drug, everolimus, a mammalian target of rapamycin inhibitor, has shown immunosuppressive as well as antitumor properties,^[14],[15] when given, as pulsed therapy has proven to be a viable option for immunomodulation.^[16] Khariwala et al.^[17] conducted a study which showed that everolimus, when given in rat laryngeal transplant models at high doses perioperatively followed by two “pulses” at 90 and 180 days led to minimal or no rejection of the transplants. Akst et al. too confirmed the efficacy of pulsed immunosuppression using tacrolimus.^[18] Shipchandler et al. injected 1 million squamous cell carcinoma cells into mice and then treated them with everolimus, tacrolimus, or their combination. Rats treated with everolimus alone showed significant reduction in squamous cell carcinoma cells as compared to other groups.^[19] Everolimus has shown good allograft preservation in human liver, cardiac, and renal transplants patients.^[20],[21] Its antitumor properties have been used in treatment of renal carcinoma too.^[22] However, it is to be used with caution along with cyclosporine and in patients with kidney diseases.^[23]

Studies have shown the willingness of patients to undergo a laryngeal transplant despite the high risks associated with chronic immunosuppression.^[24] With progress in the field of immunosuppression leading to decreased risks, the numbers of motivated patients are set to rise. For the same reason, other nonvital organ transplants such as hand and face transplants have gained popularity as well and are no longer considered “unethical.”

Strome et al. have devised a new rejection grading system which reproducibly grades rejection on the basis of gross and histologic findings with accuracy reaching 100% in rat models.^[25],[26]

Patient Willingness

Potter et al. conducted a study in which 404 laryngectomized patients were asked if they would undergo a laryngeal transplant under ideal conditions and 372 (75%) of them replied in the affirmative,^[24] where 59% of patients were ready even if the stoma persisted for breathing purpose and 68% were ready to stay in the hospital for 28 days for the procedure. Further, Reynolds et al. found that laryngectomized patients are willing to give up 1.2 years of their lives for a successful laryngeal transplant and a better future.^[27] Jo et al. conducted a similar study wherein they explained the risks and benefits of laryngeal transplant to different groups of people and found that most of them were willing to accept the transplant. They concluded that laryngeal transplant could be considered a viable rehabilitative procedure in the future.^[28]

Thus, there is a growing demand for a rehabilitative procedure that significantly improves the quality of life to make it similar to what it was before the laryngectomy. As the larynx is a multifunctional organ, no prostheses or implant or tissue transfer is likely to replace it satisfactorily.^[4] The best way to replace a larynx is with another larynx. The techniques in surgery appear to have been overcome and with the newer drugs and drug delivery systems; the risks of immunosuppression have been lowered considerably. This progress in immunosuppression is another milestone in the journey of laryngeal transplant. Laryngectomees appear to be willing to accept the risks associated with laryngeal transplant as well. However, the steep learning curve, costs involved, and follow-up will always require continuous endeavor from surgeons and high motivation on the part of the patients and caregivers.

Thus, there has been considerable progress in the field of laryngeal transplant since the turn of the century. The barriers which were earlier considered insurmountable have been tackled satisfactorily, further highlighting the need for optimism in this field.

Conclusion

Replacing a larynx with another larynx is the best way to rehabilitate a laryngectomized patient. Although still in its infancy, considerable progress has been made in the field of laryngeal transplant, which possesses great potential toward the rehabilitation of laryngectomized patients.

Acknowledgement

The author would like to thank Dr. Anil D'Cruz for his support and great vision which was instrumental in shaping and refining the article. The author would like to thank Professor Patrick J Bradley for his invaluable guidance and continuous support. The author would also like to thank Dr. Christopher De'Souza for his constant encouragement.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Consolidated Report of the Population Based Cancer Registries Incidence and Distribution of Cancer: 1990-96, National cancer registry programme. New Delhi: Indian council of Medical Research, 2001.
2.	Silver CE, Beitler JJ, Shaha AR, Rinaldo A, Ferlito A. Current trends in initial management of laryngeal cancer: The declining use of open surgery. Eur Arch Otorhinolaryngol 2009;266:1333-52.
3.	Hillman RE, Walsh MJ, Wolf GT, Fisher SG, Hong WK. Functional outcomes following treatment for advanced laryngeal cancer. Part I – Voice preservation in advanced laryngeal cancer. Part II – Laryngectomy rehabilitation: The state of the art in the VA System. Research Speech-Language Pathologists. Department of Veterans Affairs Laryngeal Cancer Study Group. Ann Otol Rhinol Laryngol Suppl 1998;172:1-27.
4.	Clements KS, Rassekh CH, Seikaly H, Hokanson JA, Calhoun KH. Communication after laryngectomy. An assessment of patient satisfaction. Arch Otolaryngol Head Neck Surg 1997;123:493-6.
5.	Narula T, Bradley P, Carding P, Hakim N, Rumsey N, Sokol D. Royal College of Surgeons of England. Laryngeal transplantation: Guidance for the delivery of services in the UK. 2011.
6.	Strome M, Stein J, Esclamado R, Hicks D, Lorenz RR, Braun W, et al. Laryngeal transplantation and 40-month follow-up. N Engl J Med 2001;344:1676-9.
7.	Lorenz RR, Strome M. Total laryngeal transplant explanted: 14 years of lessons learned. Otolaryngol Head Neck Surg 2014;150:509-11.
8.	Farwell DG, Birchall MA, Macchiarini P, Luu QC, de Mattos AM, Gallay BJ, et al. Laryngotracheal transplantation: Technical modifications and functional outcomes. Laryngoscope 2013;123:2502-8.
9.	Paniello RC. Laryngeal reinnervation. Otolaryngol Clin North Am 2004;37:161-81, vii-viii.
10.	Marina MB, Marie JP, Birchall MA. Laryngeal reinnervation for bilateral vocal fold paralysis. Curr Opin Otolaryngol Head Neck Surg 2011;19:434-8.
11.	Kam D, Salib A, Gorgy G, Patel TD, Carniol ET, Eloy JA, et al. Incidence of suicide in patients with head and neck cancer. JAMA Otolaryngol Head Neck Surg 2015;141:1075-81.
12.	Lehmann W, Krebs H. Interdisciplinary rehabilitation of the laryngectomee. Recent Results Cancer Res 1991;121:442-9.
13.	Duque E, Duque J, Nieves M, Mejía G, López B, Tintinago L. Management of larynx and trachea donors. Transplant Proc 2007;39:2076-8.
14.	Kovarik JM. Everolimus: A proliferation signal inhibitor targeting primary causes of allograft dysfunction. Drugs Today (Barc) 2004;40:101-9.
15.	Lott DG, Dan O, Lu L, Strome M. Long-term laryngeal allograft survival using low-dose everolimus. Otolaryngol Head Neck Surg 2010;142:72-8.
16.	Khariwala SS, Lorenz RR, Strome M. Composite tissue allograft transplantation: Laryngeal transplantation: Research, clinical experience, and future goals. Semin Plast Surg 2007;21:234-41.
17.	Khariwala SS, Dan O, Lorenz R. Pulsed immunosuppresion with everolimus and anti-αβ T-cell receptor: Laryngeal allograft preservation at six months. Ann Otol Rhinol Laryngol 2006;115:74-80.
18.	Akst LM, Siemionow M, Dan O, Izycki D, Strome M. Induction of tolerance in a rat model of laryngeal transplantation. Transplantation 2003;76:1763-70.
19.	Shipchandler TZ, Lorenz RR, Lee WT, Teker AM, Dan O, Strome M. Laryngeal transplantation in the setting of cancer: A rat model. Laryngoscope 2008;118:2166-71.
20.	Patel JK, Kobashigawa JA. Everolimus: An immunosuppressive agent in transplantation. Expert Opin Pharmacother 2006;7:1347-55.
21.	Koch M. Everolimus in liver and lung transplantation. Drugs Today (Barc) 2009;45:11-20.
22.	Ha SH, Park JH, Jang HR, Huh W, Lim HY, Kim YG, et al. Increased risk of everolimus-associated acute kidney injury in cancer patients with impaired kidney function. BMC Cancer 2014;14:906.
23.	Donders F, Kuypers D, Wolter P, Neven P. Everolimus in acute kidney injury in a patient with breast cancer: A case report. J Med Case Rep 2014;8:386.
24.	Lott DG, Shipchandler TZ, Dan O, Lorenz RR, Strome M. A new mouse laryngeal transplantation rejection grading system. Laryngoscope 2010;120:39-43.
25.	Potter CP, Birchall MA. Laryngectomees' views on laryngeal transplantation. Transpl Int 1998;11:433-8.
26.	Lorenz RR, Dan O, Fritz MA, Nelson M, Strome M. Rat laryngeal transplant model: Technical advancements and a redefined rejection grading system. Ann Otol Rhinol Laryngol 2002;111 (12 Pt 1):1120-7.
27.	Reynolds CC, Martinez SA, Furr A, Cunningham M, Bumpous JM, Lentsch EJ, et al. Risk acceptance in laryngeal transplantation. Laryngoscope 2006;116:1770-5.
28.	Jo HK, Park JW, Hwang JH, Kim KS, Lee SY, Shin JH. Risk acceptance and expectations of laryngeal allotransplantation. Arch Plast Surg 2014;41:505-12.