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Transplantation of the Hand, Face, and Composite Structures: Evolution and Current Status
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CLINICS IN PLASTIC SURGERY Clin Plastic Surg 34 (2007) 271–278
Transplantation of the Hand, Face, and Composite Structures: Evolution and Current Status Gordon R. Tobin, MDa,*, Warren C. Breidenbach, III, Diane J. Pidwell, PhDc, Suzanne T. Ildstad, MD, PhDd, Kadiyala V. Ravindra, MDe -
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Background and history Technical, biologic, and ethical considerations Technical considerations Biological considerations Ethical considerations Hand transplantation Transplantation of facial structures
Transplantation of hands, facial elements, and other body structures composed of multiple tissues (usually musculoskeletal structures with skin or other epithelial surface) is an emerging field in transplantation biology. As a group, these new transplants are called composite tissue allografts, which distinguishes them from conventional solid organ transplants (kidney, liver, heart, lung, and pancreas). Like solid organ transplants, composite tissue allografts contain living cellular tissues that require vascular connections to the recipient for survival, and require immunosuppression to prevent rejection. This distinguishes these transplants from acellular connective tissue allografts, many of which have been in clinical use for several years.
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b
MD
,
Laryngeal transplantation External ear transplantation Tongue transplantation Knee and femur transplantation Abdominal wall transplantation Penis transplantation Summary References
Composite tissue allografts have the potential to profoundly change the landscape of reconstructive plastic surgery, as millions of patients have major defects that are not reconstructable by conventional means. Examples of such defects include hand amputations, extreme facial disfigurements, and loss of functional structures, such as lips, eyelids, tongue, and larynx. Currently, all composite tissue allograft applications are in early stages of development and evaluation, with the longest follow-up studies now approaching 10 years. They are relatively few in number, with total cases reported now just over 60. The investigators who pioneered these initial cases assembled at the 6th International Symposium of Composite Tissue Allografts held in January
a
Division of Plastic Surgery, Department of Surgery, University of Louisville, Louisville, KY 40292, USA Kleinert, Kutz and Associates Hand Care Center, PLLC, Louisville, KY, USA c Transplant Immunology Laboratory, Jewish Hospital, Louisville, KY, USA d Institute of Cellular Therapeutics and Department of Surgery, University of Louisville, Louisville, KY 40292, USA e Transplant Section, Department of Surgery, University of Louisville, Louisville, KY 40292, USA * Corresponding author. E-mail address: [email protected] (G.R. Tobin). b
0094-1298/07/$ – see front matter ª 2007 Elsevier Inc. All rights reserved.
plasticsurgery.theclinics.com
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of 2006. Their reports and the initial publications now provide a sufficient volume of data for an early analysis. This article provides the first summary and analysis of results in this new field.
Background and history The idea to replace lost composite structures, such as limbs and facial elements, is as old as human trauma history. The inability to accomplish these goals was recognized long before the immune system and the biology of rejection were discovered. The field of transplantation immunology began with the clinical goal of skin resurfacing and composite tissue reconstruction for severe burn deformities suffered by British pilots and seamen burned in U-boat attacks during World War II. Working with plastic surgeons such as Tom Gibson, Peter Medawar and colleagues performed the first experimental studies in tissue immunology. Their work founded the science of transplantation and led to a 1960 Nobel Prize for Medawar. In the pioneering experiments of Medawar and other early investigators, lack of progress in transplantation of skin-bearing structures, plus progressive success with experimental renal allografts, turned the effort toward renal transplantation as the most promising prospect for the first clinical success. In 1954, Joseph Murray successfully transplanted a kidney between identical twins. Subsequently, renal allografts of progressively less histocompatibility were performed with introduction of immunosuppressive drugs, such as azathioprine. For these landmark procedures, Murray received the Nobel Prize in medicine, and he remains the only plastic surgeon so honored. These pioneering efforts inaugurated the era of organ transplantation, and success in renal allografts led progressively to liver, heart, lung, pancreas, and small bowel transplantation during the last decades of the 20th century. During that period, however, virtually no progress occurred in transplantation of skin or skin-bearing structures. This was attributed to a universally held concept that skin had antigenicity of such magnitude that skin-bearing transplants could not be maintained [1]. This notion was reinforced by a pioneering 1964 hand transplantation in Ecuador by Gilbert [2,3], which was technically successful but was rejected in spite of standard azathioprine and Prednisone immunosuppression of the time. Virtually no progress in composite tissue allograft transplantation occurred for over 30 years thereafter. Throughout this time, experimental limb transplantation in various species provided little long-termsurvival to support potential clinical application. During the last two decades of the 20th century, however, immunosuppressive drugs and regimens
substantially improved. The introduction of calcineuren inhibitors, cyclosporine A and then FK506 (tacrolimus), provided the basis for progressive success in liver, heart, pancreas, and lung transplantations [4,5]. Replacement of the purine-analog azathioprine with mycophenolate mofetil further improved effectiveness of immunosuppressive therapy [6]. These agents finally brought substantial improvement in experimental long-term limb survival in rodent models [7]. Impressed by these experimental results, the authors organized a composite tissue allograft research team at the University of Louisville in Kentucky, and were able to confirm these results and reproduce them in a large animal, preclinical model [8,9]. At the same time, Strome and colleagues [10] at the Cleveland Clinic were pursuing experimental studies of laryngeal transplantation, and Hofmann and colleagues [11–13] in Munich were pursuing experimental studies of knee transplantation. These efforts ultimately led to clinical application. Clinical hand composite allograft teams were formed in Louisville and Lyon, France, and hand allotransplantations were performed first in Lyon in September 1998, and in Louisville in January 1999 (Fig. 1) [14,15]. Those initial efforts have subsequently grown to create more than a dozen composite tissue allograft teams internationally, that have done over 50 clinical composite tissue allografts over the past 10 years. These include hand, larynx, knee/femur, abdominal wall, tongue, and, most recently, face and penis. Each of these specific allografts will be described and their outcomes to date analyzed in the following text.
Technical, biologic, and ethical considerations Before initiation of clinical hand transplantation, the Louisville Composite Tissue Allograft Team formally assessed the technical, biologic and ethical considerations for clinical introduction of composite tissue allografts [16]. The authors’ judgment was that among these issues, the ethical considerations would be the greatest challenge and would produce the most controversy and debate over time [17–19]. This judgment had been proven correct. In fact, as technical and immunological issues are solved, and as new allografts are introduced, the ethical issues have become even more debatable.
Technical considerations Although the technical aspects of hand transplantation were most impressive to the lay public, these techniques largely had been refined over many years of upper extremity replantation experience.
Hand, Face and Composite Structure Transplantation
Fig. 1. The world’s first successfulskin-bearingcomposite tissue allograft (intraoperative view). January 24, 1999. Louisville, Kentucky.
Procurement and retrieval techniques for donated organs were well-established in conventional solid organ transplantation, and composite tissue allografts were integrated readily into these protocols. The anatomic and technical aspects of muscle and myocutaneous flap transfer also provided background for knee/femur, abdominal wall, and other novel composite myocutaneous tissue allografts [20].
Biological considerations The biologic issues principally were related to an anticipated higher incidence of rejection than had been experienced in solid organ transplantation, because of the perceived greater antigenicity of the skin [1]. Experience to date with composite tissue allografts has not born that out, as rejection episodes and their control appear to be very similar to that of solid organs, and composite tissue allografts appear to have even better survival rates than solid organs when immunosuppression protocols are followed properly [21,22]. Immunosuppressive therapy for composite tissue allografts is virtually identical to that for solid organ transplantations. The incidence of metabolic complications and opportunistic infections appears to be very similar to solid organ transplantation [22,23]. Recently, there has been an exploration of steroid tapering, steroid sparing, and a various new antilymphocytic agents in solid organ transplantation. These initiatives have just been introduced in composite tissue allografts, and it is too early to assess results.
Ethical considerations Ethical considerations remain foremost in composite tissue transplantation clinical research. At the
heart of these issues is the fact that these grafts enhance quality of life, but are not essential for life, as are most solid organ transplants (Fig. 2). Moreover, the enhancement of quality of life is a subjective judgment that will vary between recipients. Extensive emphasis on ethics and related systems was central to initiating the Louisville composite tissue allograft program [17–19]. Essential components of the program are: Thorough psychological screening Involvement of family and analysis of support systems Provision of thorough rehabilitation therapy Ongoing monitoring Identification of systems for lifelong supply of immunosuppressive drugs Transparency of the process for independent oversight Full outcome sharing with other programs and review processes As one will see in this initial review of the world experience, these ethical principles have proved to be of enormous importance.
Hand transplantation Hand allografts comprise the largest group of composite tissue allografts, and they account for nearly half of such procedures performed. After the initial hand transplants in Lyon [14] and Louisville [15], hand transplantation teams were organized in Italy, Austria, Belgium, four sites in China, and most recently in Spain. From these centers, 27 hand transplantations have been done in 20 patients [22,23]. Thirteen of these were unilateral, and seven were bilateral (two in France, two in Austria, two in
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Fig. 2. Composite tissue allografts restore quality of life. The first Louisville recipient throws the Phillies’ opening game first pitch with his transplanted hand on April 12, 1999.
China and one in Spain). Virtually all were for distal forearm or wrist amputations, with the time since hand loss ranging from 2 months to 32 years. All transplants were technically successful with no vascular failures. Twelve of the patients experienced low-grade rejection episodes within the first year, and all were reversed completely in compliant patients. Immunosuppressive therapy included tacrolimus, mycophenolate mofetil, rapamycin, and steroids. All received induction therapy of monoclonal or polyclonal antibodies. Some were treated with topical immunosuppressive agents for rejection-associated skin rash. At this point, none of these patients have developed transplantationassociated malignancies or life-threatening complications. Some opportunistic infections occurred, and all were treated successfully. Immunosuppression-associated metabolic complications also were seen, including steroid-associated diabetes and aseptic necrosis of the femoral head. Good functional results occurred in patients compliant with medication and hand rehabilitation therapy. Most developed intrinsic muscle recovery, and all achieved protective sensation. Seventeen of the patients also achieved some degrees of discriminative sensation. As of January 2007, follow-up has been from 45 to 96 months, except for one new case done in November 2006. The initial Louisville patient of January 1999 has the longest surviving allograft. The first two hand transplants provided definitive paradigms for the subsequent experience [14,15]. The Louisville patient was selected carefully with thorough psychological screening and family involvement [24,25]. He was disciplined in taking medication, in monitoring compliance, in hand
rehabilitation therapy, and in all other aspects of care. As a result, his outcome is comparable with the best of hand replantation results, both in terms of restoration of daily activities and objective measurements (Figs. 3 and 4). He and his family express a high degree of satisfaction. This pattern has been repeated with the subsequent patients in the United States and Europe, where psychological screening has become a standard; immunosuppression has been provided, and progress has been monitored closely in all cases. Stable survival has been maintained on renal allograft dosages of immunosuppression, and functional results have approached those of replantations at the same level [22,23]. The single exception from the United States and European experience was the first patient transplanted by the team assembled in Lyon [14]. He was a unilateral hand amputee from New Zealand and had a hand transplantation in September 1988. From a technical point of view the result was excellent, but the patient was noncompliant with medical advice. He abandoned formal hand rehabilitation therapy, and he took immunosuppressive medications in an irregular and unmonitored fashion with insufficient dosages. As a result, the hand never acquired good function and it underwent progressive withering, with both psychological and progressive immunologic rejection. Two years after transplantation the patient requested reamputation, which was done by the original team [26–28]. This outcome reinforced controversies over this new field of surgery [22,29–31]. The pattern of progressive atrophy leading to graft loss from medication withdrawal and
Hand, Face and Composite Structure Transplantation
Fig. 3. Restored hand function for activities of daily living. (A) The first Louisville recipient handling cards. (B) The second Louisville recipient tying shoelaces.
gradual rejection seen in the first Lyon recipient also has been observed in six patients from the hand transplantation programs in China [23]. Although all of these transplants were initially successful, these late failures occurred, reportedly because the health care system of China changed during this period. This left these patients responsible for purchasing their immunosuppressive medications, which they could not afford and thus discontinued. This discontinuation of immunosuppression caused slow rejection and produced the pattern of progressive tissue atrophy and loss of function. Thus, all hand allograft loss to date has come from insufficient preoperative screening or inability to maintain immunosuppressive drug treatment rather than from technical failure.
In contrast, success has correlated strongly with thorough psychosocial screening, intense preoperative education, family involvement, a complete hand rehabilitation therapy program, assurances of ongoing medication supply, close monitoring, and follow-up.
Transplantation of facial structures At the time of the initial project organization in the mid 1990s, the authors’ team realized that craniomaxillofacial allografts transplantations would be technically possible. At that time, however, there were no clinical data on success rates and graft longevity from other composite tissue allografts, and facial allografts presented more complex problems including peer and public acceptance. Accordingly,
Fig. 4. Restored hand function of the first Louisville recipient graded by the Carroll test at 72 (of 99) in 2005.
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the authors determined that evaluation of hand transplantation results should precede the expansion into craniomaxillofacial regions. After 5 years of observation of clinical hand allografts and substantial discussions regarding ethical issues [32–34], the first transplantation of facial structures was done in November 2005, by Deavauchelle and colleagues [35]. This was for reconstruction of a traumatic dog bite defect of the central face that included all lip tissues, nose, and chin. Follow-up over the first year showed high quality functional and aesthetic results and progressive return of sensation and lip motor function. The immunosuppressive regimen followed that of hand transplants, consisting of induction therapy with anti-thymoglobulin, tacrolimus, mycophenolate mofetil, and progressively tapered prednisone. In addition, the recipient received two infusions of donor bone marrow cells. Transplant revascularization was accomplished by anastomosis of the right and left facial arteries and veins. Sensory nerves and the left facial motor nerves were anastomosed directly. A forearm skin flap from the same donor was transplanted simultaneously to an inframammary site for biopsies to monitor rejection. As with most of the hand transplants, two episodes of mild rejection occurred early, and these were reversed successfully. Subsequently, a second facial transplantation has been done in April 2006, by a team led by Guo Suzhong in Xian, China, for a recipient with traumatic loss of his right cheek, upper lip, and lower eye lid after a bear attack [36]. This procedure was technically successful with a good early aesthetic result and progressive functional restoration over the first 6 months. A minor revision was reported at 6 months after the surgery. Periodic updates on functional return and capabilities are anticipated. As of the beginning of 2007, at least two other teams in the United States and England have received regulatory clearance for facial composite tissue allografts, and others are in process.
Laryngeal transplantation One of the earliest clinical composite tissue allografts, and an important source of long-term follow-up, is the laryngeal transplant done in 1998 by a Cleveland Clinic team led by Strome [10,37]. This was done for a recipient with traumatic laryngeal loss 20 years earlier, and the transplantation involved the entire larynx, as well as adjacent tracheo–pharyngeal structures, including thyroid and parathyroid glands. Both superior laryngeal and one recurrent laryngeal nerves were anastomosed. This allograft had the advantage of a six out of six major HLA site match. Immunosuppression was
with anti-CD 3 antibody induction, cyclosporine, mycophenolate mofetil, and methylprednisolone, with conversion of cyclosporine to tacrolimus after a mild rejection episode at 15 months. Three episodes of tracheo-bronchitis, including one of Pneumocystis carnii, were experienced in the first 15 months. Patient satisfaction and the functional results have been excellent, with normal swallowing and a normal sounding voice having a range of one octave. Vocal intensity, maximum phonation time, and air flow all tested within normal limits [38]. These high-quality functional outcomes occurred in spite of some motor synkinesis that resulted from current techniques of recurrent nerve anastomoses. Strome and colleagues continue to work on techniques of surmounting this reinnervation issue in laryngeal transplants [37]. A second laryngeal transplant team headed by Luis Tintinago in Medellin, Columbia has done 14 clinical laryngo–tracheal allografts over the last 4 years, with six containing the larynx and eight being exclusively tracheal. The initial report of this experience is anticipated this year (Luis Tintinmago, MD, personal communication, 2006).
External ear transplantation In 2004, two external ears were transplanted along with the cephalocervical scalp in China for replacement of these structures after melanoma resection [39]. An initial technical success was reported, and a follow-up report is anticipated.
Tongue transplantation In 2003, a total tongue allograft was done in Vienna, Austria, by a team led by Ewers, Keimer, and Watzinger. Transplantation was done at the time of an oncologic resection of the recipient’s tongue. Surgery was a technical success, but the recipient later succumbed from the tumor recurrence [37]. This technique holds considerable promise for a structure that is otherwise nearly unreconstructable. However, like the ear/scalp transplant, immunosuppression of cancer patients warrants scrutiny.
Knee and femur transplantation Vascularized allografts of the femur, knee, joint, and surrounding muscles were among the earliest clinical composite tissue allografts, which were introduced in 1996 by a team in Munich, Germany, led by Hofmann [11,12]. These were done for segmental traumatic defects of the knee and femur that were beyond possibility of prosthetic reconstruction because of defect size or need for
Hand, Face and Composite Structure Transplantation
accompanying muscle tissue. Although none of these involve transplantation of skin, the tissues transplanted were otherwise the same as in the hand transplants. These allografts, too, are vascularized grafts of living cells, and they require immunosuppression postoperatively. This distinguishes them from acellular osteoarticular and connective tissue allografts widely used today. A 5-year follow-up of these procedures was reported in 2001, and a 10-year follow-up report is expected in the near future [13].
Abdominal wall transplantation Transplants of full-thickness ventral abdominal walls based on the rectus abdominus myocutaneous domain with an inferior epigastric vascular pedicle were introduced in 2003 at the University of Miami, Florida, by Levi and colleagues [40]. Initially, these were all done for children needing simultaneous intestinal and multivisceral transplants who had substantial loss of abdominal wall domain, and who would require immunosuppression for the intestinal and multivisceral grafts. Nine composite abdominal wall allografts were done in eight patients, with five surviving abdominal wall grafts and six surviving patients. The two deaths reported were unrelated to the abdominal wall grafts. Excellent visceral coverage and restoration of the abdominal wall were achieved. Subsequently, the same team has adapted this technique for abdominal wall transplantation in cases of intestinal autotransplantation for managing unresectable masses at the base of the mesentery that required ex vivo resection and replantation [41].
Penis transplantation In September 2006, a team at Guangzhou led by Hu [42] transplanted a penis to a recipient with a traumatic amputation defect. The immediate postoperative result was successful, and normal urination was restored immediately, but the recipient and his wife experienced psychological problems postoperatively and insisted on elective removal after 2 weeks. This incident reinforces, again, the need for careful psychological screening in recipients and families in composite tissue allografts.
Summary This analysis of the emerging field of composite tissue allotransplantation shows future promise for reconstruction of devastating defects that are currently unreconstructable by conventional means. In a 10-year period, just over 60 clinical composite tissue allografts have been transplanted,
including 25 hand transplants and lesser numbers of facial, laryngo–tracheal, ear, tongue, knee and femur, abdominal wall, and penis allografts. The technical results of these surgical transfers have been uniformly successful. Immunologic survival has been achieved using medications with dosages virtually identical to solid organ transplants, and survival has been as good as or better than solid organs, in spite of initial concerns about the antigenicity of the skin. Clinical failures have all resulted from breakdowns in management systems, which include inadequate preoperative psychological screening, tumor recurrence when used in oncologic settings, and inability to obtain the necessary immunosuppressive medications amidst a changing health care system. In the longer term, modification of immunologic strategies that lesson the risk and costs of current immunosuppressive regimens will enhance numbers and varieties of applications greatly. This emerging field is in a pioneering stage, with early results that show great future promise.
References [1] Murray JE. Organ transplantation (skin, kidney, heart) and the plastic surgeon. Plast Reconstr Surg 1971;47:425–31. [2] Gilbert R. Transplant is successful with a cadaver forearm. Med Trib Med News 1964;5:20–2. [3] Gilbert R. Hand transplanted from cadaver is reamputated. Med Trib Med News 1964;5:23–5. [4] Borel JF, Kis ZL. The discovery and development of cyclosporine (sandimmune). Transplant Proc 1991;23:1867–74. [5] Goto T, Kino T, Hatanaka H, et al. Discovery of FK-506, a novel immunosuppressant isolated from Streptomyces tsukubaensis. Transplant Proc 1987;19:4–8. [6] Allison AC, Eugui EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev 1993;136:5–28. [7] Benhaim P, Anthony JP, Ferreira L, et al. Use of combination of low-dose cyclosporine and RS61443 in a rat hindlimb model of composite tissue allotransplantation. Transplantation 1996; 61:527–32. [8] Ustuner ET, Zdichavsky M, Ren X, et al. Long-term composite tissue allograft survival in a porcine model with cyclosporine/mycophenolate mofetil therapy. Transplantation 1998;66:1581–7. [9] Jones JW Jr, Ustuner ET, Zdichavsky M, et al. Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy. Surgery 1999;126:384–8. [10] Strome M, Stein J, Esclamado R, et al. Laryngeal transplantation and 40-month follow-up. N Engl J Med 2001;344:1676–9.
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[11] Hofmann GO, Kirschner MH, Wagner FD, et al. Allogeneic vascularized transplantation of human femoral diaphyses and total knee joints— first clinical experiences. Transplant Proc 1998; 30:2754–61. [12] Hofmann GO, Kirschner MH. Clinical experience in allogeneic vascularized bone and joint allografting. Microsurgery 2000;20:375–83. [13] Hofmann GO, Kirschner MH. Allogeneic vascularized bone and joint transplantation. First five years experience. In: Dubernard J-M, editor. Composite tissue allografts. Paris: John Libbey Eurotest; 2001. p. 43–7. [14] Dubernard J-M, Owen E, Herzberg G, et al. Human hand allograft: report on first 6 months. Lancet 1999;353:1315–20. [15] Jones JW, Gruber SA, Barker JH, et al. Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team. N Engl J Med 2000;343:468–73. [16] Tobin GR, Breidenbach WC, Barker JH, et al. Hand transplantation: technical, biologic, and ethical considerations. Louisville Medicine 1998;183–5. [17] Siegler M. Ethical issues in innovative surgery: should we attempt a cadaveric hand transplantation in a human subject? Transplant Proc 1998; 30:2779–82. [18] Simmons PD. Ethical considerations in composite tissue allotransplantation. Microsurgery 2000;20:458–65. [19] Tobin GR, Breidenbach WC, Klapheke MM, et al. Ethical considerations in the early composite tissue allograft experience: a review of the Louisville Ethics Program. Transplant Proc 2005;37: 1392–5. [20] Tobin GR, Day TG Jr. Vaginal and pelvic reconstruction with distally based rectus abdominis myocutaneous flaps. Plast Reconstr Surg 1988; 81:62–70. [21] Thaunat O, Badet L, El-Jaafari A, et al. Composite tissue allograft extends a helping hand to transplant immunologists. Am J Transplant 2006;6: 2238–42. [22] Breidenbach WC, Tobin GR, Gorantla VS, et al. A position statement in support of hand transplantation. J Hand Surg [Am] 2002;27: 760–70. [23] Petruzzo P, Lanzetta M, Margreiter R, et al. International registry on hand and composite tissue transplantation [abstract #970]. In: Proceedings of the First Joint International Transplant Meeting of the American Society of Transplantation. 2006 World Transplant Congress. Boston, MA; July 22–27, 2006, p. 393. [24] Klapheke M. Transplantation of the human hand, psychological considerations. Bull Menninger Clin 1999;63:159–73. [25] Klapheke M, Marcell C, Creamer B, et al. Psychiatric assessment of candidates for hand transplantation. Microsurgery 2000;20:453–7.
[26] Dubernard JM, Owen E, Lefrancois N, et al. First human hand transplantation. Case report. Transpl Int 2000;13:S521–4. [27] Petruzzo P, Dubernard JM. Hand transplantation: Lyon experience. In: Dubernard JM, editor. Composite tissue allografts. Paris: John Libbey Eurotext; 2001. p. 63–7. [28] Kanitakis J, Jullien D, Petruzzo P, et al. Clinicopathologic features of graft rejection of the first human hand allograft. Transplantation 2003; 76(4):688–93. [29] Hettiaaratchy S, Butler PE, Lee WPA. Lessons from hand transplantations. Lancet 2001;357:494–5. [30] Tobin GR, Granger DK, Breidenbach WC. Hand transplantation follow-up. Lancet 2001;358: 1018. [31] Jones NF. Concerns about human hand transplantation in the 21st century. J Hand Surg [Am] 2002;27:771–87. [32] Morris PJ, Bradley JA, Doiyal L, et al. Facial transplantation: a working party report from the Royal College of Surgeons of England. Transplantation 2004;77:330–8. [33] Siemionow M, Agoglu G. Allotransplantation of the face: how close are we? Clin Plast Surg 2005; 32:401–9. [34] American Society for Reconstructive Microsurgery and American Society of Plastic Surgeons. Facial transplantation—ASPS/ASRM guiding principles. Arlington Heights (IL): American Society of Plastic Surgeons; 2006. Accessed December 4, 2006, Available at: http://www. microsurg.org/ftGuidelines.pdf. [35] Devauchelle B, Badet L, Lengele B, et al. First human face allograft: early report. Lancet 2006; 368:203–9. [36] Hospital performs first face transplant in China. People’s Daily Online (available at: http://english.peopledaily.com.cn/200604/15/ eng2006415_258530.html) Accessed on February 19, 2007. [37] Birchall MA, Lorez RR, Berke GS, et al. Laryngeal transplantation in 2005: a review. Am J Transplant 2006;6:20–6. [38] Lorez RR, Hicks DM, Shields RW Jr, et al. Laryngeal nerve function after total laryngeal transplantation. Otolaryngol Head Neck Surg 2004; 131:1016–8. [39] Jiang HQ, Wang Y, Hu XB, et al. Composite tissue allograft transplantation of cephalocervical skin flap and two ears. Plast Recontr Surg 2005; 115:31e–7e. [40] Levi DM, Tzakis AG, Kato T, et al. Transplantation of the abdominal wall. Lancet 2003;361:2173–6. [41] Selvaggi G, Levi DM, Kato T, et al. Expanded use of transplantation techniques: abdominal wall transplantation and intestinal autotransplantation. Transplant Proc 2004;36(5):1561–3. [42] Hu W, Zhang JL, Wu ZW, et al. A preliminary report of penile transplantation. Eur Urol 2006;50:851–3.
CLINICS IN PLASTIC SURGERY Clin Plastic Surg 34 (2007) 271–278
Transplantation of the Hand, Face, and Composite Structures: Evolution and Current Status Gordon R. Tobin, MDa,*, Warren C. Breidenbach, III, Diane J. Pidwell, PhDc, Suzanne T. Ildstad, MD, PhDd, Kadiyala V. Ravindra, MDe -
-
Background and history Technical, biologic, and ethical considerations Technical considerations Biological considerations Ethical considerations Hand transplantation Transplantation of facial structures
Transplantation of hands, facial elements, and other body structures composed of multiple tissues (usually musculoskeletal structures with skin or other epithelial surface) is an emerging field in transplantation biology. As a group, these new transplants are called composite tissue allografts, which distinguishes them from conventional solid organ transplants (kidney, liver, heart, lung, and pancreas). Like solid organ transplants, composite tissue allografts contain living cellular tissues that require vascular connections to the recipient for survival, and require immunosuppression to prevent rejection. This distinguishes these transplants from acellular connective tissue allografts, many of which have been in clinical use for several years.
-
b
MD
,
Laryngeal transplantation External ear transplantation Tongue transplantation Knee and femur transplantation Abdominal wall transplantation Penis transplantation Summary References
Composite tissue allografts have the potential to profoundly change the landscape of reconstructive plastic surgery, as millions of patients have major defects that are not reconstructable by conventional means. Examples of such defects include hand amputations, extreme facial disfigurements, and loss of functional structures, such as lips, eyelids, tongue, and larynx. Currently, all composite tissue allograft applications are in early stages of development and evaluation, with the longest follow-up studies now approaching 10 years. They are relatively few in number, with total cases reported now just over 60. The investigators who pioneered these initial cases assembled at the 6th International Symposium of Composite Tissue Allografts held in January
a
Division of Plastic Surgery, Department of Surgery, University of Louisville, Louisville, KY 40292, USA Kleinert, Kutz and Associates Hand Care Center, PLLC, Louisville, KY, USA c Transplant Immunology Laboratory, Jewish Hospital, Louisville, KY, USA d Institute of Cellular Therapeutics and Department of Surgery, University of Louisville, Louisville, KY 40292, USA e Transplant Section, Department of Surgery, University of Louisville, Louisville, KY 40292, USA * Corresponding author. E-mail address: [email protected] (G.R. Tobin). b
0094-1298/07/$ – see front matter ª 2007 Elsevier Inc. All rights reserved.
plasticsurgery.theclinics.com
doi:10.1016/j.cps.2007.01.001
272
Tobin et al
of 2006. Their reports and the initial publications now provide a sufficient volume of data for an early analysis. This article provides the first summary and analysis of results in this new field.
Background and history The idea to replace lost composite structures, such as limbs and facial elements, is as old as human trauma history. The inability to accomplish these goals was recognized long before the immune system and the biology of rejection were discovered. The field of transplantation immunology began with the clinical goal of skin resurfacing and composite tissue reconstruction for severe burn deformities suffered by British pilots and seamen burned in U-boat attacks during World War II. Working with plastic surgeons such as Tom Gibson, Peter Medawar and colleagues performed the first experimental studies in tissue immunology. Their work founded the science of transplantation and led to a 1960 Nobel Prize for Medawar. In the pioneering experiments of Medawar and other early investigators, lack of progress in transplantation of skin-bearing structures, plus progressive success with experimental renal allografts, turned the effort toward renal transplantation as the most promising prospect for the first clinical success. In 1954, Joseph Murray successfully transplanted a kidney between identical twins. Subsequently, renal allografts of progressively less histocompatibility were performed with introduction of immunosuppressive drugs, such as azathioprine. For these landmark procedures, Murray received the Nobel Prize in medicine, and he remains the only plastic surgeon so honored. These pioneering efforts inaugurated the era of organ transplantation, and success in renal allografts led progressively to liver, heart, lung, pancreas, and small bowel transplantation during the last decades of the 20th century. During that period, however, virtually no progress occurred in transplantation of skin or skin-bearing structures. This was attributed to a universally held concept that skin had antigenicity of such magnitude that skin-bearing transplants could not be maintained [1]. This notion was reinforced by a pioneering 1964 hand transplantation in Ecuador by Gilbert [2,3], which was technically successful but was rejected in spite of standard azathioprine and Prednisone immunosuppression of the time. Virtually no progress in composite tissue allograft transplantation occurred for over 30 years thereafter. Throughout this time, experimental limb transplantation in various species provided little long-termsurvival to support potential clinical application. During the last two decades of the 20th century, however, immunosuppressive drugs and regimens
substantially improved. The introduction of calcineuren inhibitors, cyclosporine A and then FK506 (tacrolimus), provided the basis for progressive success in liver, heart, pancreas, and lung transplantations [4,5]. Replacement of the purine-analog azathioprine with mycophenolate mofetil further improved effectiveness of immunosuppressive therapy [6]. These agents finally brought substantial improvement in experimental long-term limb survival in rodent models [7]. Impressed by these experimental results, the authors organized a composite tissue allograft research team at the University of Louisville in Kentucky, and were able to confirm these results and reproduce them in a large animal, preclinical model [8,9]. At the same time, Strome and colleagues [10] at the Cleveland Clinic were pursuing experimental studies of laryngeal transplantation, and Hofmann and colleagues [11–13] in Munich were pursuing experimental studies of knee transplantation. These efforts ultimately led to clinical application. Clinical hand composite allograft teams were formed in Louisville and Lyon, France, and hand allotransplantations were performed first in Lyon in September 1998, and in Louisville in January 1999 (Fig. 1) [14,15]. Those initial efforts have subsequently grown to create more than a dozen composite tissue allograft teams internationally, that have done over 50 clinical composite tissue allografts over the past 10 years. These include hand, larynx, knee/femur, abdominal wall, tongue, and, most recently, face and penis. Each of these specific allografts will be described and their outcomes to date analyzed in the following text.
Technical, biologic, and ethical considerations Before initiation of clinical hand transplantation, the Louisville Composite Tissue Allograft Team formally assessed the technical, biologic and ethical considerations for clinical introduction of composite tissue allografts [16]. The authors’ judgment was that among these issues, the ethical considerations would be the greatest challenge and would produce the most controversy and debate over time [17–19]. This judgment had been proven correct. In fact, as technical and immunological issues are solved, and as new allografts are introduced, the ethical issues have become even more debatable.
Technical considerations Although the technical aspects of hand transplantation were most impressive to the lay public, these techniques largely had been refined over many years of upper extremity replantation experience.
Hand, Face and Composite Structure Transplantation
Fig. 1. The world’s first successfulskin-bearingcomposite tissue allograft (intraoperative view). January 24, 1999. Louisville, Kentucky.
Procurement and retrieval techniques for donated organs were well-established in conventional solid organ transplantation, and composite tissue allografts were integrated readily into these protocols. The anatomic and technical aspects of muscle and myocutaneous flap transfer also provided background for knee/femur, abdominal wall, and other novel composite myocutaneous tissue allografts [20].
Biological considerations The biologic issues principally were related to an anticipated higher incidence of rejection than had been experienced in solid organ transplantation, because of the perceived greater antigenicity of the skin [1]. Experience to date with composite tissue allografts has not born that out, as rejection episodes and their control appear to be very similar to that of solid organs, and composite tissue allografts appear to have even better survival rates than solid organs when immunosuppression protocols are followed properly [21,22]. Immunosuppressive therapy for composite tissue allografts is virtually identical to that for solid organ transplantations. The incidence of metabolic complications and opportunistic infections appears to be very similar to solid organ transplantation [22,23]. Recently, there has been an exploration of steroid tapering, steroid sparing, and a various new antilymphocytic agents in solid organ transplantation. These initiatives have just been introduced in composite tissue allografts, and it is too early to assess results.
Ethical considerations Ethical considerations remain foremost in composite tissue transplantation clinical research. At the
heart of these issues is the fact that these grafts enhance quality of life, but are not essential for life, as are most solid organ transplants (Fig. 2). Moreover, the enhancement of quality of life is a subjective judgment that will vary between recipients. Extensive emphasis on ethics and related systems was central to initiating the Louisville composite tissue allograft program [17–19]. Essential components of the program are: Thorough psychological screening Involvement of family and analysis of support systems Provision of thorough rehabilitation therapy Ongoing monitoring Identification of systems for lifelong supply of immunosuppressive drugs Transparency of the process for independent oversight Full outcome sharing with other programs and review processes As one will see in this initial review of the world experience, these ethical principles have proved to be of enormous importance.
Hand transplantation Hand allografts comprise the largest group of composite tissue allografts, and they account for nearly half of such procedures performed. After the initial hand transplants in Lyon [14] and Louisville [15], hand transplantation teams were organized in Italy, Austria, Belgium, four sites in China, and most recently in Spain. From these centers, 27 hand transplantations have been done in 20 patients [22,23]. Thirteen of these were unilateral, and seven were bilateral (two in France, two in Austria, two in
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Fig. 2. Composite tissue allografts restore quality of life. The first Louisville recipient throws the Phillies’ opening game first pitch with his transplanted hand on April 12, 1999.
China and one in Spain). Virtually all were for distal forearm or wrist amputations, with the time since hand loss ranging from 2 months to 32 years. All transplants were technically successful with no vascular failures. Twelve of the patients experienced low-grade rejection episodes within the first year, and all were reversed completely in compliant patients. Immunosuppressive therapy included tacrolimus, mycophenolate mofetil, rapamycin, and steroids. All received induction therapy of monoclonal or polyclonal antibodies. Some were treated with topical immunosuppressive agents for rejection-associated skin rash. At this point, none of these patients have developed transplantationassociated malignancies or life-threatening complications. Some opportunistic infections occurred, and all were treated successfully. Immunosuppression-associated metabolic complications also were seen, including steroid-associated diabetes and aseptic necrosis of the femoral head. Good functional results occurred in patients compliant with medication and hand rehabilitation therapy. Most developed intrinsic muscle recovery, and all achieved protective sensation. Seventeen of the patients also achieved some degrees of discriminative sensation. As of January 2007, follow-up has been from 45 to 96 months, except for one new case done in November 2006. The initial Louisville patient of January 1999 has the longest surviving allograft. The first two hand transplants provided definitive paradigms for the subsequent experience [14,15]. The Louisville patient was selected carefully with thorough psychological screening and family involvement [24,25]. He was disciplined in taking medication, in monitoring compliance, in hand
rehabilitation therapy, and in all other aspects of care. As a result, his outcome is comparable with the best of hand replantation results, both in terms of restoration of daily activities and objective measurements (Figs. 3 and 4). He and his family express a high degree of satisfaction. This pattern has been repeated with the subsequent patients in the United States and Europe, where psychological screening has become a standard; immunosuppression has been provided, and progress has been monitored closely in all cases. Stable survival has been maintained on renal allograft dosages of immunosuppression, and functional results have approached those of replantations at the same level [22,23]. The single exception from the United States and European experience was the first patient transplanted by the team assembled in Lyon [14]. He was a unilateral hand amputee from New Zealand and had a hand transplantation in September 1988. From a technical point of view the result was excellent, but the patient was noncompliant with medical advice. He abandoned formal hand rehabilitation therapy, and he took immunosuppressive medications in an irregular and unmonitored fashion with insufficient dosages. As a result, the hand never acquired good function and it underwent progressive withering, with both psychological and progressive immunologic rejection. Two years after transplantation the patient requested reamputation, which was done by the original team [26–28]. This outcome reinforced controversies over this new field of surgery [22,29–31]. The pattern of progressive atrophy leading to graft loss from medication withdrawal and
Hand, Face and Composite Structure Transplantation
Fig. 3. Restored hand function for activities of daily living. (A) The first Louisville recipient handling cards. (B) The second Louisville recipient tying shoelaces.
gradual rejection seen in the first Lyon recipient also has been observed in six patients from the hand transplantation programs in China [23]. Although all of these transplants were initially successful, these late failures occurred, reportedly because the health care system of China changed during this period. This left these patients responsible for purchasing their immunosuppressive medications, which they could not afford and thus discontinued. This discontinuation of immunosuppression caused slow rejection and produced the pattern of progressive tissue atrophy and loss of function. Thus, all hand allograft loss to date has come from insufficient preoperative screening or inability to maintain immunosuppressive drug treatment rather than from technical failure.
In contrast, success has correlated strongly with thorough psychosocial screening, intense preoperative education, family involvement, a complete hand rehabilitation therapy program, assurances of ongoing medication supply, close monitoring, and follow-up.
Transplantation of facial structures At the time of the initial project organization in the mid 1990s, the authors’ team realized that craniomaxillofacial allografts transplantations would be technically possible. At that time, however, there were no clinical data on success rates and graft longevity from other composite tissue allografts, and facial allografts presented more complex problems including peer and public acceptance. Accordingly,
Fig. 4. Restored hand function of the first Louisville recipient graded by the Carroll test at 72 (of 99) in 2005.
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the authors determined that evaluation of hand transplantation results should precede the expansion into craniomaxillofacial regions. After 5 years of observation of clinical hand allografts and substantial discussions regarding ethical issues [32–34], the first transplantation of facial structures was done in November 2005, by Deavauchelle and colleagues [35]. This was for reconstruction of a traumatic dog bite defect of the central face that included all lip tissues, nose, and chin. Follow-up over the first year showed high quality functional and aesthetic results and progressive return of sensation and lip motor function. The immunosuppressive regimen followed that of hand transplants, consisting of induction therapy with anti-thymoglobulin, tacrolimus, mycophenolate mofetil, and progressively tapered prednisone. In addition, the recipient received two infusions of donor bone marrow cells. Transplant revascularization was accomplished by anastomosis of the right and left facial arteries and veins. Sensory nerves and the left facial motor nerves were anastomosed directly. A forearm skin flap from the same donor was transplanted simultaneously to an inframammary site for biopsies to monitor rejection. As with most of the hand transplants, two episodes of mild rejection occurred early, and these were reversed successfully. Subsequently, a second facial transplantation has been done in April 2006, by a team led by Guo Suzhong in Xian, China, for a recipient with traumatic loss of his right cheek, upper lip, and lower eye lid after a bear attack [36]. This procedure was technically successful with a good early aesthetic result and progressive functional restoration over the first 6 months. A minor revision was reported at 6 months after the surgery. Periodic updates on functional return and capabilities are anticipated. As of the beginning of 2007, at least two other teams in the United States and England have received regulatory clearance for facial composite tissue allografts, and others are in process.
Laryngeal transplantation One of the earliest clinical composite tissue allografts, and an important source of long-term follow-up, is the laryngeal transplant done in 1998 by a Cleveland Clinic team led by Strome [10,37]. This was done for a recipient with traumatic laryngeal loss 20 years earlier, and the transplantation involved the entire larynx, as well as adjacent tracheo–pharyngeal structures, including thyroid and parathyroid glands. Both superior laryngeal and one recurrent laryngeal nerves were anastomosed. This allograft had the advantage of a six out of six major HLA site match. Immunosuppression was
with anti-CD 3 antibody induction, cyclosporine, mycophenolate mofetil, and methylprednisolone, with conversion of cyclosporine to tacrolimus after a mild rejection episode at 15 months. Three episodes of tracheo-bronchitis, including one of Pneumocystis carnii, were experienced in the first 15 months. Patient satisfaction and the functional results have been excellent, with normal swallowing and a normal sounding voice having a range of one octave. Vocal intensity, maximum phonation time, and air flow all tested within normal limits [38]. These high-quality functional outcomes occurred in spite of some motor synkinesis that resulted from current techniques of recurrent nerve anastomoses. Strome and colleagues continue to work on techniques of surmounting this reinnervation issue in laryngeal transplants [37]. A second laryngeal transplant team headed by Luis Tintinago in Medellin, Columbia has done 14 clinical laryngo–tracheal allografts over the last 4 years, with six containing the larynx and eight being exclusively tracheal. The initial report of this experience is anticipated this year (Luis Tintinmago, MD, personal communication, 2006).
External ear transplantation In 2004, two external ears were transplanted along with the cephalocervical scalp in China for replacement of these structures after melanoma resection [39]. An initial technical success was reported, and a follow-up report is anticipated.
Tongue transplantation In 2003, a total tongue allograft was done in Vienna, Austria, by a team led by Ewers, Keimer, and Watzinger. Transplantation was done at the time of an oncologic resection of the recipient’s tongue. Surgery was a technical success, but the recipient later succumbed from the tumor recurrence [37]. This technique holds considerable promise for a structure that is otherwise nearly unreconstructable. However, like the ear/scalp transplant, immunosuppression of cancer patients warrants scrutiny.
Knee and femur transplantation Vascularized allografts of the femur, knee, joint, and surrounding muscles were among the earliest clinical composite tissue allografts, which were introduced in 1996 by a team in Munich, Germany, led by Hofmann [11,12]. These were done for segmental traumatic defects of the knee and femur that were beyond possibility of prosthetic reconstruction because of defect size or need for
Hand, Face and Composite Structure Transplantation
accompanying muscle tissue. Although none of these involve transplantation of skin, the tissues transplanted were otherwise the same as in the hand transplants. These allografts, too, are vascularized grafts of living cells, and they require immunosuppression postoperatively. This distinguishes them from acellular osteoarticular and connective tissue allografts widely used today. A 5-year follow-up of these procedures was reported in 2001, and a 10-year follow-up report is expected in the near future [13].
Abdominal wall transplantation Transplants of full-thickness ventral abdominal walls based on the rectus abdominus myocutaneous domain with an inferior epigastric vascular pedicle were introduced in 2003 at the University of Miami, Florida, by Levi and colleagues [40]. Initially, these were all done for children needing simultaneous intestinal and multivisceral transplants who had substantial loss of abdominal wall domain, and who would require immunosuppression for the intestinal and multivisceral grafts. Nine composite abdominal wall allografts were done in eight patients, with five surviving abdominal wall grafts and six surviving patients. The two deaths reported were unrelated to the abdominal wall grafts. Excellent visceral coverage and restoration of the abdominal wall were achieved. Subsequently, the same team has adapted this technique for abdominal wall transplantation in cases of intestinal autotransplantation for managing unresectable masses at the base of the mesentery that required ex vivo resection and replantation [41].
Penis transplantation In September 2006, a team at Guangzhou led by Hu [42] transplanted a penis to a recipient with a traumatic amputation defect. The immediate postoperative result was successful, and normal urination was restored immediately, but the recipient and his wife experienced psychological problems postoperatively and insisted on elective removal after 2 weeks. This incident reinforces, again, the need for careful psychological screening in recipients and families in composite tissue allografts.
Summary This analysis of the emerging field of composite tissue allotransplantation shows future promise for reconstruction of devastating defects that are currently unreconstructable by conventional means. In a 10-year period, just over 60 clinical composite tissue allografts have been transplanted,
including 25 hand transplants and lesser numbers of facial, laryngo–tracheal, ear, tongue, knee and femur, abdominal wall, and penis allografts. The technical results of these surgical transfers have been uniformly successful. Immunologic survival has been achieved using medications with dosages virtually identical to solid organ transplants, and survival has been as good as or better than solid organs, in spite of initial concerns about the antigenicity of the skin. Clinical failures have all resulted from breakdowns in management systems, which include inadequate preoperative psychological screening, tumor recurrence when used in oncologic settings, and inability to obtain the necessary immunosuppressive medications amidst a changing health care system. In the longer term, modification of immunologic strategies that lesson the risk and costs of current immunosuppressive regimens will enhance numbers and varieties of applications greatly. This emerging field is in a pioneering stage, with early results that show great future promise.
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