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Editorials and Perspectives: Overview

Airway Transplantation: A Debate Worth Having?

Birchall, Martin1,3; Macchiarini, Paolo2

Author Information
doi: 10.1097/TP.0b013e31816a10e4

Abstract

Laryngotracheal transplantation has been explored experimentally since almost the dawn of organ transplantation itself (1, 2). Laryngectomy for irreversible laryngeal disease, usually cancer, is a 19th century invention, and leaves recipients with impairment of many of the functions that allow us to interact as human beings. Combined with the recognition that a century of effort has failed to provide autologous or synthetic solutions that can replicate the complex functions of the larynx, the impetus to provide total replacement has been compelling. Despite this need and 40 years of research, however, there has only been one documented human total laryngeal transplant (3). Replacement of the trachea is theoretically less problematic as it does not perform complex neuromuscular actions, unlike the larynx. Nonetheless, the multiplicity of surgical and prosthetic options attempted for tracheal reconstruction over the last century suggests that none is ideal to adequately replace a structurally and biologically functioning trachea (4). This begs the question as to what, if any, is the future for airway transplantation. This overview seeks to answer this question. Sources of data are PubMed and published peer-reviewed abstracts from relevant meetings.

The Case Against Airway Transplantation

Let us start by putting the case for the prosecution. Laryngeal or tracheal transplantation are costly and difficult procedures, with unquantified morbidity and mortality (5). They are suitable for only a tiny number of patients presently. As long as we cannot reinnervate, their outcomes will be no better than those having conventional supportive treatments, such as tracheostomy, laser treatment, sleeve resection and reconstruction (6, 7). The major target population for transplantation has cancer, and immunosuppression of this group is at best hazardous and at worst unethical (8). In due course, scientific advances will cure such cancers anyway, and tissue engineering and stem cell technology will provide much better forms of reconstruction (9). Besides, most persons with a laryngectomy have a perfectly acceptable quality of life, so there is no real need for transplantation. These are all cogent arguments, which mean that the otolaryngological and thoracic surgical communities are, at best, divided on the future of laryngotracheal transplantation.

A Complex Operation With Unknown Morbidity

There is little doubt that retrieval and implantation of a larynx or trachea represents a major challenge. First the surgeon has to fight for his place with the established retrieval teams, whose work rightly take preference as they are for life-saving intent. Meanwhile, laryngectomy is performed in the recipient. Implantation requires anastomosis of a minimum of one superior thyroid artery and jugular vein (preferably both), and (for larynx) four separate nerves: two recurrent and two superior laryngeal nerves. Tracheostomy and, arguably, gastrostomy is required until recovery of swallowing and, hopefully, a respiratory movement occurs for laryngeal recipients. Similarly, tracheal replacement would require either endo- or extra-luminal multiple stenting to avoid airway collapse, and a temporary decompressing tracheostomy.

However, major head and neck cancer operations often take more than 8 hr, and involve a similar number of individual, if different, steps, so time alone is not a major consideration. Tracheostomy and gastrostomy are routine. In our large animal (pig) model, implantation takes a median of 5.5 hr (range 2.3–9.0) (10) (Figs. 1 and 2). In the National Health Service, an all-day head and neck cancer operation, preceded by all necessary preparation and followed by 3 weeks as an inpatient and associated drug costs comes to around £37,000 (US$74,000: Guy's Hospital London tariff). Our estimates suggest an identical figure for laryngeal and tracheal transplantation for the first 6 months. However, the continuing costs of immunosuppression give an additional monthly cost of between £350 and £500 (US$700–1,000) thereafter (extrapolated from human lung transplant modeling [11]). Our work on tracheal transplantation, also in pigs, suggests a shorter operating time, but similar long-term costs (12, 13). We argue that these excess costs, for laryngeal transplantation at least, are far from excessive given the potential returns in quality of life.

FIGURE 1.
FIGURE 1.:
Healthy laryngeal graft retrieved from a pig at 1 week. Normal vocal cords and laryngeal lumen (black arrow) and healthy vascular anastomoses (white arrow) are seen.
FIGURE 2.
FIGURE 2.:
Barium swallow examination showing competent swallowing without aspiration 1 week postlaryngeal transplantation in a pig recipient. Black arrows show barium contrast flowing normally through pharynx and esophagus. White arrow shows the radio-opaque line markings on the T-tube trachestomy. No contrast is seen in the graft or tracheal lumen.

A failed historical attempt to graft an unmatched, unvascularised mucosal patch into the skeleton of a larynx from which a cancer had been resected has given rise to much pessimism regarding the potential of airway transplantation (5). However, the qualified success of the first complete, revascularised laryngeal transplant has changed the picture considerably. The recipient, whose larynx had been damaged by trauma, has only had two possible acute rejection episodes in the first few months, and subsequently has regained normal swallowing and speech (3, 14). On the downside, he retains a tracheostomy and is still on low dose immunosuppression. Nonetheless, he is essentially well and working as a professional speaker some 10 years later (Strome, personal communication, 1997). The tolerability of the procedure receives further support from the quality of life rapidly attained by porcine recipients in our own series.

Most recently, there are reports of series of 20 laryngeal and tracheal transplants in Colombia and it is likely that most of the 14 cases reported to the International Registry on Hand and Composite Tissue Allotransplantation (15). It was reported to recent meetings in Washington and Rome that all the tracheal recipients are doing well, but that two of three laryngeal recipients, both with a laryngeal cancer operation primarily, subsequently died (16). Peer-reviewed published reports of this series are awaited with great interest. Hence, the limited information available suggests that laryngeal transplantation into patients without pre-existing cancer is likely to be well-tolerated with low morbidity, but that transplantation into cancer laryngectomy patients or those with tracheal cancer requires great caution.

Recent reports of tracheal replacement by fresh aortic allografts (17) or aortic autograft (18) in patients tracheal cancers should also be interpreted with cautiously until longer term results are seen in greater numbers. We believe that inappropriately fast uptake of such techniques may expose patients to greater risk than that from more conservative treatments which may produce at least as good results in length and quality of life (19).

There Are Few Potential Recipients

The ideal pool of patients for the first trials would also be those who have irreversible damage caused by trauma, as was the case for the 1998 laryngeal transplant. Such patients can generally be managed satisfactorily by conventional techniques (6, 7), so the pool of potential recipients for early trials at least is small: perhaps 1 to 200 in the UK. Nonetheless, for the reasons above, it is both sensible and ethical to transplant this group before embarking on the major challenge of cancer patients. The argument that was used for the first heart transplants, for example, that there is nothing to lose by trials does not apply to either group as death is far from inevitable, even from advanced laryngeal cancer. The operation is targeted at restoration of quality of life and not quantity.

There are approximately 1000 laryngectomies carried out per annum in the UK for cancer (20). Although many of these persons have poor performance status or are elderly, there is a subpopulation of younger, fitter patients with disease limited within the laryngeal skeleton that would be good potential recipients of a transplant. Immunosuppressed patients are, of course, more likely to develop cancers. However, correcting for premorbid smoking and drinking habits, there is little concrete evidence for an increase in head and neck cancer in transplant recipients (8). Furthermore, increasing numbers of liver transplants are being performed for persons with hepatic cancer, with good overall results. Although some patients might argue otherwise, it is counter-intuitive to immunosuppress someone to provide a short-term quality of life gain, only for them to die much sooner from recurrent disease. This is not only what happened to the 1969 patient (5), but also to the world's first tongue transplant recipient, who also had advanced squamous cancer, in 2004 (21). When we asked laryngectomees this very question, this was flagged as a major concern by them also (22).

Part of the problem here lies in our limited understanding of laryngeal and tracheal immunology, although, as with other areas of transplant research, detailed scientific study has led to as many questions as answers to date (23). For example, there is an unexplained, but possibly significant, difference in graft dendritic cell responses to transplantation between subsites of the same organ, which may lead to differential rates of rejection (Fig. 3). The present documented human laryngeal transplant is maintained on tacrolimus, which may raise the potential for recurrence if applied to patients who have had a cancer laryngectomy. A major breakthrough may have been reached, however, by the startling discovery that rapamycin, and its derivative everolimus, is not only an effective immunosuppressant, but also inhibits the growth of squamous cell cancer in vitro and in a rat model (24). Although the potential effects on wound healing may mitigate against using rapamycin as part of a starting regimen (25), its early introduction thereafter is almost certainly indicated. This may bring clinical trials in the main, and increasingly large, target population much closer than we previously thought.

FIGURE 3.
FIGURE 3.:
Multiple color immunohistochemistry of mucosal biopsies from a laryngo-tracheal graft in a minipig at 1 week posttransplantation between animals fully matched at major histocompatibility complex (MHC) loci. Images of supraglottis (a), subglottis (b), and trachea (c) all show a rich population of antigen presenting cells in the lamina propria at varying stages of activation (MHC class 2=blue; CD16=red; CD14=green; epithelial cells autofluoresce green also). Magenta and cyan cells represent dendritic cells in progressive stages of activation, coexpressing MHC class 2 with CD16 and CD14, respectively. Basement membrane is shown as a white line, and the airway lumen is marked “L.” The arrow shows a double staining activated dendritic cell. In this study, there was no significant change in numbers or activation of immunologically active cells at 1 week suggesting that ischemia-reperfusion injury is not a major feature of airway transplantation.

The most appropriate indications for tracheal transplantation (Fig. 4) would be unresectable benign disease, such as tracheopathia osteoplastica, relapsing polychrondritis, Wegener's granulomatosis, and trauma (26). Presently, these are either treated with palliative measures, with or without immunosuppression, or simply left untreated. However, such patients are very rare, and a commoner, though still rare, indication would be for extended-length low-grade cancers not involving mediastinum, specifically adenoid cystic. Currently, these patients are managed palliatively with irradiation, stents, repeated endobronchial debulking, and T-tube tracheostomies and a safe and reproducible method of tracheal replacement would indeed be welcome (22).

FIGURE 4.
FIGURE 4.:
Retrieval of a long segment of human trachea along with its vascular pedicle including the right inferior thyroid artery and cervical veins (a) that provide normal segmental revascularization as shown by angiography (b). This allotransplant requires immunosuppression similar to that used in clinical lung transplantation (see Ref. 13).

It is Not Possible to Restore Normal Laryngeal Neuromuscular Function

For many critics of laryngeal transplantation, this is the key point. It has long been known that direct repair of the recurrent laryngeal (main motor) nerve in man does not lead to functional recovery, but rather to a functionless synkinesis where adductor and abductor nerve fibers do not return to their appropriate target muscles (27). This conundrum has led to nerve and muscle transfer techniques, which “rob Peter to pay Paul” with mixed evidence of clinical effectiveness to date (28–31), although improvements are possible with careful selective intralaryngeal reinnervation (32, 33). We and others have hypothesized that part of the failure of these techniques lies in the slow rate of progression of reinnervation (1 mm per day), which allows aberrant intralaryngeal sprouting to occur (34). Thus, we have applied neurotrophins in vitro and in nerve transfer experiments in pigs with the aim of improving the speed and accuracy of reinnervation with encouraging results (35). These methods are now undergoing clinical trials in equine patients with recurrent nerve paralysis and favorable outcomes here should pave the way for similar trials in man. Meanwhile, progress is being made in the development of laryngeal pacemakers, triggered to stimulate abductor (opening) muscles on inspiration (Mueller, personal communication, 2007 [36]). Such devices offer the prospect of immediate return of appropriate respiratory function to a transplanted larynx and might be useful either on a long-term basis, or as a “baby-sitter,” preserving muscle fiber morphology and type-distribution until reinnervation occurs as a result of selective or transfer techniques, with or without neurotrophin support.

Scientific Advance Will Cure Throat Cancer Anyway

Laryngeal squamous cancer is not going away in a hurry. At the present rate of smoking cessation in the UK and US, its incidence is predicted to rise for the next 20 to 30 years and only then plateau, because of cohort effects (37). Meanwhile, the prevalence of smoking in developing nations is rocketing. Based on several substantial studies completing recruitment in the last 10 years, so-called “organ-preservation” treatment for laryngeal cancer has become de rigeur (38). Although the statistics tell us that these synchronous chemoradiation regimens have led to a fall in laryngectomy rates and a small increase in survival, long term experience has shown that the function of these “preserved” organs is, in many cases, nonexistent: stenosis, paralysis, pain, and edema lead to even worse quality of life than if the patient had a laryngectomy (39). Of course, there is an enormous body of work devoted to the development of less toxic and more effective treatments for all cancers, including those of larynx and trachea. However, international clinical trial databases (40) tell us that, for head and neck cancer at least, major breakthroughs with truly novel agents remain elusive. Furthermore, if the observations of preserved but functionless larynges tells us anything, it is that destroying a substantial cancer, even with less toxic methods, is not going to bring back cartilage, muscle and mucosa long since destroyed by disease. Indeed, we would argue that the very future of the oncologic surgeon lies not in ablation, but reconstruction and replacement, and that the armamentarium of the latter should include organ transplantation where this is the only real hope of full restoration of function.

It Will Soon be Possible to Assemble Functional Organ Replacements Without Transplantation

Tissue engineering, stem cell technology, and nanotechnology (in its myriad forms) all offer the possibility of creating “off the shelf” tissues and organs. We have already successfully used tissue engineered patches to reconstruct trachea and bronchus in the clinic (41), and have used fat- derived stem cells to generate nerve and Schwann cells for reinnervation (Kingham, unpublished data, 2008). Others have “grown” tissues such as muscle, and “organs” from stem cells (42). Combined with implantable, and increasingly small and biocompatible, pacemakers (32), it is theoretically possible to construct all the component parts of a larynx and make them function as such. However, experience to date with late 20th Century tissue transfer techniques and laryngeal prostheses suggests caution in such predictions (43). Success in generating phonation and airway protection usually demands a permanent tracheostomy (44), whereas success in achieving an adequate airway may lead to problems with phonation and aspiration of food (45). The human larynx is a unique, three-tiered sphincter supplied by more fine motor control fibers than any other part of the body. It successfully juggles the quite opposing requirements of phonation, deglutition and respiration with ease. Furthermore, it may have an important role in mediating tolerance to inhaled and ingested antigens (46). We believe that research into tissue engineering for laryngeal and tracheal replacement is absolutely justified. However, given the complexity and multiplicity of functions, it is hard to see how such an approach would replicate the potential total solution offered by successful transplantation.

As alternatives to transplantation for patients where conventional reconstruction techniques will not suffice, several experimental and clinical lines of research have been evaluated for tracheal replacement: synthetic substitutes, modified to avoid tissue reaction; implantation of nonviable tissues, including fixed trachea; adaptation and transfer of autogenous tissues, with or without scaffolding of foreign materials as patches or tubes; and tissue engineering. All but the latter have ultimately failed to reproduce a predictable or dependable tracheal substitute (7), the Achilles heels being the unique vascular supply of the cervical and intrathoracic trachea and biological issues.

We believe that tissue engineering techniques will offer a better way for long segment replacement of the tracheal airway than transplantation. Tissue engineering applies the principles of engineering, material science, and biology toward the development of biological substitutes that restore, maintain, or improve tissue function (9). This process of fabricating new, physiologic, functioning tissues may be obtained by (1) guided tissue regeneration with engineered matrices alone, (2) injection of allogenic or xenogenic cells alone, or (3) use of cells seeded on or within matrices (cell matrix construct), with the latter two approaches the most common. The use of isolated cell or cell substitutes avoids potential surgical complications and allows cell manipulation before injection but has the drawback of possible rejection or loss of function (47). The use of seeded matrices, the most common method in tissue engineering, is particularly relevant in the present context because these structures are biocompatible, bioabsorbable, nonimmunogenic, supportive of cell attachment and growth, and inductive of angiogenesis (Fig. 5). They may be created either by isolating the cells from host's body with a permeable membrane allowing exchange of nutrients (closed system) or by culturing in vitro the isolated cells and seeding them onto a scaffold, either synthetic or natural, that is implanted into the host after a given cultivation time (open system) (48). Available evidence suggests that single tissue constructs are unlikely to suffice, and that only a composite (mucosa, connective tissue, cartilage) tissue-engineered graft may substitute functionally for the native trachea. We are presently working towards this goal.

FIGURE 5.
FIGURE 5.:
Tissue engineered tracheae (detergent enzymatic method), by contrast with allografts, do not significantly express major histocompatibility complex class I (a) and II (b) antigens, resulting in a minimal risk of rejection (blue=nuclear stain, red=MHC; bar=100 μm). There is no membranous staining for MHC seen (faint red staining in (a) represents autofluorescence). Their outer and inner surfaces can be reseeded with recipient's chondrocytes (c) and stem cells, producing similar mechanical properties to normal trachea (tracheal rupture force and point of tracheal rupture). Scanning electron micrograph. Bar=20 μm.

The Loss of Useful Larynx and Trachea is Compatible With a Good Quality of Life

The 5-year survival of persons undergoing laryngectomy is approximately 40%. Thus, many persons live for years without a larynx. Although there is a very active minority who make the most of things and a few who actually return to work thereafter, the impact on quality of life is profound. A functioning larynx is necessary for normal speech, swallowing, lifting, coughing, straining, sniffing, smelling, tasting, and even kissing. These are the very functions that allow us to function in human society, and the impact of their loss should not be underestimated. Many patients become reclusive and depressed, despite putting a brave face on when presenting for follow-up in clinic (49). The loss of a long segment of trachea is, of course, incompatible with life. Our survey of the views of laryngectomees on the acceptability of laryngeal transplantation demonstrated widespread support for the idea, provided the questions of reinnervation and immunosuppression were satisfactorily addressed (18). Thus, while for some persons laryngectomy represents a challenge to be fought and overcome, for many it represents withdrawal from society and most would accept the risks of a transplant if it meant a return to normal functioning and to normal human society.

CONCLUSIONS

The jury remains out. The arguments against laryngeal transplantation are strong, but balanced, in our opinion, by the arguments in favor. The case for tracheal transplantation is more tenuous. We firmly believe that a twin-track of research into airway transplantation alongside research into tissue-engineering strategies is essential if we are to finally offer and alternative to the dehumanizing effects of a mutilating operation (laryngectomy) which has changed little in 150 years (50).

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Keywords:

Laryngeal transplantation; Tracheal transplantation; Tissue engineering; Reinnervation; Mucosal immunity

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