Coverage Policy Manual
Policy #: 2013011
Category: Surgery
Initiated: August 2017
Last Review: February 2019
  Transplant, Composite Tissue Allotransplantation, Hand and/or Face

Description:
Composite tissue allotransplantation (CTA) is defined as transplantation of histologically different tissues. CTA is being proposed for facial transplants in patients with severely disfigured faces, and for hand transplants in patients unsatisfied with prosthetic hands. The treatment has potential benefits in terms of functional status and psychosocial well-being. It also has potential risks, most notably those associated with a lifelong regimen of immunosuppressive drugs.
 
Background
Composite tissue allotransplantation (CTA) refers to the transplantation of histologically different tissue which may include skin, connective tissue, blood vessels, muscle, bone and nerve tissue. The procedure is also known as reconstructive transplantation. To date, primary applications of CTA have been hand and face (partial and full) transplantations, although there are also reported cases of several other CTAs, including transplantation of the larynx, knee and abdominal wall.
 
The first successful partial face transplant was performed in France in 2005. The first complete facial transplant was performed in Spain in 2010. In the United States, the first facial transplant was done in 2008 at the Cleveland Clinic; this was a near-total face transplant and included the midface, nose and bone. The first hand transplant with short-term success occurred in 1998 in France. However, the patient failed to follow the immunosuppressive regimen which led to graft failure and removal of the hand 29 months after transplantation. The first hand transplantation in the United States took place in Louisville, KY in 1999.
 
Hand and face transplants have been found to be technically feasible. According to the International Registry on Hand and Composite Tissue Allotransplantation (IRHCTT) website, as of January 2013, more than 50 patients worldwide have undergone technically successful hand transplants and 15 patients have had face transplants (IRHCTT). The most commonly performed face transplant procedure has been to restore the lower two-thirds of facial structure, especially the perioral area (i.e., lips, cheeks and chin) and in some cases the forehead, eyelids and scalp (Infante-Cossio, 2012).  
 
Facial transplantation has been performed on patients whose faces have been disfigured by trauma, burns, disease or birth defects and who are unable to benefit from traditional surgical reconstruction. Hand transplantations have been done in patients who lost a hand due to trauma or life-saving interventions causing permanent injury to the hand. To date, hand transplants have not been performed for congenital anomalies or loss of a limb due to cancer.
CTA procedures are complex and involve a series of operations using a rotating team of specialists. For face transplantation, the surgery may last 8 to 15 hours. Hand transplant surgery typically lasts between 8 and 12 hours. In all hand transplants, bone fixation occurred first and this was generally followed by artery and venous repair and then by suture of nerves and/or tendons. In all surgeries performed to date, the median and ulnar nerves were repaired. The radial nerve was reconstructed in about half of the procedures.
 
Unlike most solid organ transplantations e.g., kidney and heart transplants, CTA is not life-saving, and its primary aim is to increase a patient’s quality of life e.g., by having a more normal appearance and a sense of wholeness. In the case of facial transplantations in particular, there is a large potential psychosocial benefit of successful surgery. Moreover, it is hoped that function may be better following CTA than with alternative interventions e.g., grasping and lifting after hand transplants and basic functions such as blinking and mouth closure after facial transplants. In addition, in the case of face transplantation, the procedure may be less traumatic than “traditional” facial reconstructive surgery using the patient’s own tissue. For example, traditional procedures often involve dozens of operations whereas facial transplantation involves only a few operations.
 
CTA is associated with potential challenges and risks as well as potential benefits. Patients who undergo face or hand transplantation must adhere to a lifelong regimen of immunosuppressive drugs. Risks of immunosuppression include acute and chronic rejection, opportunistic infection that may be life-threatening and metabolic disorders such as diabetes, kidney damage and lymphoma. There are also potential adverse impacts on quality of life including the need to commit to a lifetime immunosuppression regimen. Other challenges include the need to actively participate in intensive physical therapy in order to obtain functionality and the potential for frustration and disappointment if functionality does not meet expectations. Moreover, there is the potential for allograft loss, which would lead to additional procedures in hand transplant patients, and there are limited reconstructive options for facial transplantation patients. Furthermore, in the case of hand transplants, there is a risk that functional ability e.g., grasping and lifting objects, may be lower than with a prosthetic hand, especially compared to newer electronic prosthetic devices. Due to the importance of selecting candidates who can withstand these physical and mental challenges, potential hand and face transplant recipients undergo extensive screening for both medical and psychosocial suitability.
 
Coding
There are no specific CPT codes for this procedure. It would be reported using combinations of existing codes or the unlisted code for the anatomic area (e.g., 26989 unlisted procedure, hands or fingers, 21499 unlisted musculoskeletal procedure, head or 21299 unlisted craniofacial or maxillofacial procedure).
  

Policy/
Coverage:
Composite tissue allotransplantation (CTA) of the hand and/or face does not meet member benefit certificate primary coverage criteria because there is a lack of scientific evidence of effectiveness. These procedures are currently being studied in clinical trials (NCT00722280; NCT01281267; NCT01140087; NCT01269164).   
 
For members with contracts without primary coverage criteria, composite tissue allotransplantation (CTA) of the hand and/or face is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
The policy was created in February 2013 with a search of the MEDLINE database through January 14, 2013. Following is a summary of the key literature to date.
 
Hand transplantation
According to the International Registry on Hand and Composite Tissue Allotransplantation (IRHCTT) website, as of January 2013 there are a total of 74 reported hand transplants worldwide in 53 patients (IRHCTT). Thirty patients underwent single hand transplants, 21 had double hand transplants and 2 had digital transplants.
 
The IRHCTT published an article describing registry data in 2011; at the time data were prepared for the article, hand transplants had been reported to the registry in a total of 39 patients (Petruzzo, 2011). The article stated that 85% of transplant recipients experienced at least one episode of acute rejection in the first year after transplant. Acute rejection episodes were reversible in all patients who were compliant with treatment. The most commonly reported complications were metabolic complications (35 of 39, 90%) and opportunistic infections (30 of 39, 77%). Transient hyperglycemia occurred in 17 patients (44%) and cytomegalovirus reactivation in 10 patients (26%). Ten patients required surgery for complications (n=2 arterial thrombosis, n=1 venous thrombosis, n=6 small area of skin necrosis and n=1 venous fistula). Five cases of graft loss were reported between day 5 and 275 after transplant. The early (day 5) graft loss occurred in a patient who underwent face and bilateral hand transplant, and this patient died at day 65 from cerebral anoxia. This was the only reported death in this series of patients. Hand function was reported in figures included in the article, but specific numbers e.g. mean function scores, were not included in the text of the article.
 
In 2012, Pei and colleagues in China reported on 15 hand allotransplantations in 12 patients (3 were bilateral transplantations) (Pei, 2012). The authors reported that all of the grafted hands had normal appearance and good blood circulation post-operatively. Acute rejection occurred in all patients; the majority of patients experienced acute rejection approximately once per year. At the 1 year follow-up, all grafts were viable and the graft appearance, skin color, vascularization, hair growth and nail growth were all normal. The authors reported that after 1 year, many patients could perform functional tasks that they had not been able to perform with a prosthesis. However, after a mean follow-up of 52 months (standard deviation [SD]: 36 months), only 8 hands were viable (including the 3 bilateral cases); 7 of 12 patients (58%) no longer had their transplanted hands. Six hands were removed because of severe rejection resulting in necrosis and the seventh patient experienced severe pain, stiffness and sensory loss. In all 6 cases, patients had not complied with the immunosuppressive regimen. Patient survival was 100%.
No studies comparing health outcomes in patients undergoing hand transplantation versus receiving hand/lower limb prostheses were identified.
 
Face transplantation
The IRHCTT 2011 publication reported that there had been 15 partial or full facial transplants worldwide, performed at 7 centers (Petruzzo, 2011). The authors reported a “high incidence” of acute rejection (the percentage of patients experiencing rejection was not included in the text of the article). The most common complications were opportunistic infections. There were 2 cytomegalovirus reactivations, 4 herpes virus infections, 1 Epstein Barr virus infection, 2 cutaneous mycoses and 8 bacterial infections. As noted in the section on hand transplant above, the only reported death was in a patient with both bilateral hand and facial transplants. The investigators reported findings of a survey about facial function that was conducted with patients 1 year after surgery. Ten or more (67%) reported no difficulty or only mild difficulty with nose function, chewing, swallowing, drinking, eating and smiling. Similar data on patient function prior to surgery were not reported.
 
Ongoing Clinical Trials
Human upper extremity (hand and forearm) allotransplantation (NCT00722280): This study aims to evaluate the risk of rejection after allograft transplantation and minimize the need for long-term high dose immunosuppression. It will test the “Pittsburgh Protocol”, an immunomodulatory strategy using donor bone marrow stem cells. Recipients will be selected from a population of adults 18-60 years-old with upper limb loss. The primary outcome is graft survival, and there will be up to 10 years of follow-up. The study is sponsored by the University of Pittsburgh. Estimated enrollment is 300 patients, and the estimated date of study completion is January 2018.
 
Several single-center case series studies are underway in the United States evaluating the outcomes of face transplant in small numbers of patients with severe facial deformities (between 2 and 5 patients per trial). Trial sponsors consist of the Brigham and Women’s Hospital (NCT01281267), the University of Maryland (NCT01140087), and Cleveland Clinic (NCT01269164).  
 
Summary
Composite tissue allotransplantation (CTA) involves allotransplantation of histologically different tissues. Preliminary experience with CTA of the hand and face suggest that the surgery is technically feasible. To date, however, only a limited number of patients worldwide have undergone CTA of the hand and/or face.
 
There are insufficient data on whether the procedure improves the net health outcome i.e., whether the potential benefits to patient’s quality of life outweigh the potential risks e.g., of surgical complications, immunosuppression and opportunistic infections. In addition, for hand transplantation, no published data are available comparing functional and quality-of-life outcomes compared to use of lower limb prostheses
 
Practice Guidelines and Position Statements
In March 2011, the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom published guidance on hand allotransplantation (NICE, 2013). The guidance stated that current evidence on the efficacy and safety of hand allotransplantation is inadequate in quantity. They recommended that the procedure only be available under special arrangements e.g., in a research setting.
 
In 2006, The American Society for Reconstructive Microsurgery (ASRM) and the American Society of Plastic Surgeons (ASPS) published guiding principles on facial transplantation for plastic surgeons (ASRM/ASPS, 2013). Selected principles are listed below:
 
“1. Facial transplantation should only be utilized for patients with severe facial deformities who cannot be helped through traditional reconstructive surgical measures.
2. Facial transplantation should only be undertaken in institutions with appropriate Institutional Review Boards familiar with the many intricacies for approval and application of new clinical procedures and protocols.
3. Facial transplantation should be conducted in the context of a transplant team having appropriate institutional resources and commitment to the project…
4. Appropriate patient selection criteria should be established and a complete risk/benefit ratio must be considered for each patient on a case-by-case basis.
5. To facilitate informed consent:
 
a. The physician must provide the patient with the latest and complete information on the risks associated with facial transplant.
 
b. The preoperative evaluation of potential donors may involve additional considerations as more experience is gained. At this time the results of facial transplantation are unknown. If early results are less than optimal, potential patients should be informed of any newly identified limitation of the procedure.
 
c. Patients must demonstrate a thorough understanding of all the known risks and benefits.
 
d. The physician should regard the facial transplantation procedure as experimental and it should be subjected to the evaluation of an independent research ethics committee.
 
e. The informed consent should include an alternative and acceptable solution for management of the recipients’ face in the event of transplant failure… “
 
2014 Update
A search of the MEDLINE database did not reveal any new randomized controlled trials evaluating hand or face transplants. No new information was identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
According to a review article published by Siemionow and colleagues, as of July 2013, a total of 89 upper-extremity transplants and 27 face transplants have been performed worldwide (Siemionow, 2013). Specific outcome data were not reported, but the authors stated that overall there had been positive experiences with reinnervation and recovery of thermal and mechanical sensation and a slower course of recovery for motor functioning. Three patients died following face transplants; 1 was non-compliant with immunosuppressive treatment, 1 had secondary squamous cell carcinoma of the hypopharynx and the third developed infection, graft failure and cardiac arrest after a combined face and double hand transplant.
 
Ongoing Clinical Trials
 
The Human upper extremity (hand and forearm) allotransplantation (NCT00722280): This study aims to evaluate the risk of rejection after allograft transplantation and minimize the need for long-term high dose immunosuppression. It will test the “Pittsburgh Protocol”, an immunomodulatory strategy using donor bone marrow stem cells. Recipients will be selected from a population of adults 18-60 years-old with upper limb loss. The primary outcome is graft survival, and there will be up to 10 years of follow-up. The study is sponsored by the University of Pittsburgh. Estimated enrollment is 300 patients, and the estimated date of study completion is January 2018.
 
Several case series studies are underway in the United States evaluating the outcomes of hand transplants in small number of patients. These include a study sponsored by the Christine M. Kleinert Institute for Hand and Microsurgery in Kentucky (NCT00711373) and a study sponsored by Brigham and Women's Hospital (NCT01293214). Each of the above studies is recruiting 10 patients. Small (recruiting 2-5 patients per trial) trials of facial transplants in patients with severe facial deformities are also underway. Trial sponsors consist of the Brigham and Women’s Hospital (NCT01281267), the University of Maryland (NCT01140087), (10) and Cleveland Clinic (NCT01269164).
  
2015 Update
 
A literature search conducted through January 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Hand Transplantation
Shores et al published the most comprehensive reporting of the worldwide experience with hand/upper limb transplant (Shores, 2015). The authors identified 72 patients: 37 received bilateral transplants and 35 unilateral, for a total of 107 transplanted hand/upper extremities. There are 4 known mortalities: 1 occurred after a bilateral hand transplant, and the other 3 followed multitype CTAs (ie, combined upper and lower-limb or combined upper-limb and face transplants). Twenty-four graft losses have been reported; 8 of these were also associated with multiple CTA procedures and another 7 occurred in China during their early experience with hand transplantation. In the United States, 21 known patients have undergone isolated upper limb transplantation; 13 were unilateral and 8 were bilateral (limb or digit) procedures. There was 1 immediate graft loss of the bilateral transplanted limb/digit. An additional 3 patients experienced hand loss at approximately 9 months, 2 years, and 4 years posttransplant, respectively. Few data on functional outcomes after hand transplantation have been reported. The authors noted that there is a lack of agreement on appropriate outcome measures and the level of transplantation varies greatly among patients, making it difficult to compare functional improvement.
 
Face Transplantation
Smeets et al systematically reviewed published reports of face transplants (Smeets, 2014). The authors included English language articles published through September 15, 2013, that provided data on at least 1 face transplant in humans. A total of 36 articles reported on 27 worldwide face transplantations. University Hospital Henri Mondor in Creteil, France, and Brigham and Women’s Hospital in Boston, Massachusetts, were the centers with the most experience. Ten of the 27 cases were full face transplants (the first successful full face transplant was in 2010) and the remainder were partial face transplants. The literature did not report any case of graft loss, hyperacute (within the first 48 hours) or chronic rejection, or graft- versus-host disease. However, all of the face transplant recipients with at least 1 year post-surgical follow-up were reported to experience at least 1 episode of acute rejection days or months after the procedure. Other common complications related to drug toxicity from immunosuppressive therapy, leading to opportunistic infections, metabolic disorders, and increased incidence of malignancy. There have been 3 reported cases of malignancy to date. Three deaths occurred in transplant recipients. One patient died 27 months after surgery due to lack of compliance with immunosuppressive therapy. A second death occurred in a French recipient who had multidrug-resistant infection and graft necrosis (this was an early transplant in France). The third patient died of recurrent cancer.
 
In terms of function, tactile sensitivity recovered a mean of 4.1 months after surgery when nerve repair was performed, and a mean of 7.3 months otherwise. Temperature sensitivity recovered a mean of 4.3 months with nerve repair and 12.5 months without nerve repair. Motor recovery began a mean of 7.8 months after surgery. Recovery of motor function has started with contractions of single muscles, and complex movements have appeared within the first year in a number of patients. Long-term results are still pending in most cases. After 5 years of follow-up, the first face transplant recipient was able to fully open her mouth, smile, speak, chew, and swallow.
 
Fischer et al identified a total of 29 face transplants performed through December 2013 and reported functional outcomes in 5 patients treated at their center (Fisher, 2014). The investigators compared each patient’s pre- and post-surgical functioning on various dimensions. Before surgery, all 5 patients had compromised respiration, breathing, sensation, and facial expression. After surgery, they had substantial recovery in all of these areas. In terms of breathing, the 5 patients were able to breathe through their noses post-surgery, and the 2 patients who previously had tracheostomy tubes had them removed. Speech became understandable to an unfamiliar listener 3 to 9 months after surgery. Three to 9 months post-surgery, the majority of allografts were responsive to light touch, and patients could distinguish between heat and cold. Facial expression, including the ability to smile, recovered after transplantation in all patients. Three of 5 patients were unable to chew solid food before surgery, and 2 patients had liquid leakage. All patients were capable of oral food intake 3 to 29 days after surgery, and 3 to 12 months after surgery, all had unrestricted or nearly unrestricted eating and drinking. The 2 patients with compromised ability to smell both reported a substantial improvement in smelling, comparable to their functioning before facial trauma. All 5 patients developed opportunistic infections (viral or bacterial) after facial transplantation.
 
In November 2013, the American Society for Surgery of the Hand published a position statement on hand Transplantation (ASSH, 2013). The organization recognized that hand transplantation is an alternative to prostheses and rehabilitation in appropriately selected patients yet continued to consider it an “innovative intervention”. The statement emphasized the need for further advances in the areas of patient selection, surgical technique and immunosuppression and recommended that, at this time, the procedure be carried out only in centers with extensive experience in both hand surgery and solid organ transplantation.
 
2016 Update
A literature search was conducted through December 2015 using the MEDLINE database. There was no new randomized controlled trials or other new information identified that would prompt a change in the coverage statement. Several clinical trials are ongoing [NCT01281267 (face transplantation for severe facial deformity); NCT0072228 (upper extremity allotransplantation); NCT01459107 (upper extremity allotransplantation)].  
 
2018 Update
A literature search conducted through January 2018 revealed no new information that would prompt a change in the coverage statement. One study identified had compared health outcomes in patients undergoing hand transplantation with those receiving hand/upper-limb prostheses.
 
The study, published in 2016 by Salminger et al, compared outcomes for 5 patients who had below-elbow hand transplantation with 7 patients who had prosthetic hands.7 There were 3 unilateral and 2 bilateral hand transplants, for a total of 7 transplanted hands. The prosthetic patients received myoelectric prostheses that were controlled by simple direct control. Functional assessments were undertaken a mean of 9.0 years (standard deviation [SD], 3.9 years) after transplantation. The following standardized instruments were used to evaluate function: the Action Research Arm Test, the Southampton Hand Assessment Procedure (SHAP), and the Disabilities of the Arm, Shoulder and Hand (DASH) measures. In addition, quality of life was assessed using the 36-Item Short-Form Health Survey (SF-36). There were no statistically significant differences between groups in functional scores on the standardized measures. For example, the mean SHAP score was 75.0 in the transplanted group and 75.4 in the prosthetic group. For the quality of life scores, transplant patients had significantly higher scores on the SF-36 role-emotional and mental health subscales and there were no significant differences on the SF-36 physical functioning, bodily pain, general health, or social functioning subscales. The authors did not report total SF-36 scores.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2019. No new literature was identified that would prompt a change in the coverage statement.
 

CPT/HCPCS:
21299Unlisted craniofacial and maxillofacial procedure
21499Unlisted musculoskeletal procedure, head
26989Unlisted procedure, hands or fingers

References: American Society for Reconstructive Microsurgery (ASRM) and the American Society of Plastic Surgeons (ASPS). Facial Transplantation-ASRM/ASPS Guiding Principles. Available online at: http://www.plasticsurgery.org/Documents/medical-professionals/health-policy/guiding-principles/Facial-Transplantation-ASRM-ASPS-Guiding-Principals.pdf. Last accessed January, 2013.

American Society for Surgery of the Hand.(2013) ASSH position statement on hand transplantation 2013. J Hand Surg Am. Nov 2013;38(11):2234-2235. PMID 24206988

Fischer S, Kueckelhaus M, Pauzenberger R, et al.(2015) Functional outcomes of face transplantation. Am J Transplant. Jan 2015;15(1):220-233. PMID 25359281

Infante-Cossio P, Barrera-Pulido F, Gomez-Cia T et al.(2012) Facial transplantation: a concise update. Med Oral Patol Oral Cir Bucal 2012 [Epub ahead of print].

International Registry on Hand and Composite Tissue Allotransplantation (IRHCTT). Available online at: http://www.handregistry.com. Last accessed January, 2013.

National Institute for Health and Clinical Excellence (NICE).(2013) Hand Allotransplantation. Available online at: http://www.nice.org.uk/nicemedia/live/12988/53627/53627.pdf. Last accessed January, 2013.

Pei G, Xiang D, Gu L et al.(2012) A report of 15 hand allotransplantations in 12 patients and their outcomes in China. Transplantation 2012; 94(10):1052-9.

Petruzzo P, Dubernard JM.(2011) The International Registry on Hand and Composite Tissue allotransplantation. Clin Transpl 2011:247-53.

Plast Reconstr Surg. Nov 14 2014. PMID 25401735(2014) Face transplantation: on the verge of becoming clinical routine? Biomed Res Int. 2014;2014:907272. PMID 25009821

Salminger S, Sturma A, Roche AD, et al.(2016) Functional and psychosocial outcomes of hand transplantation compared with prosthetic fitting in below-elbow amputees: a multicenter cohort study. PLoS One. 2016;11(9):e0162507. PMID 27589057

Shores JT, Brandacher G, Lee WA.(2015) Hand and Upper Extremity Transplantation: An Update of Outcomes in the Worldwide Experience. Plast Reconstr Surg. Feb 2015;135(2):351e-360e. PMID 25401735

Siemionow M, Gharb BB, Rampazzo A.(2013) Successes and lessons learned after more than a decade of upper extremity and face transplantation. Curr Opin Organ Transplant 2013; 18(6):633-9.

Sosin M, Rodriguez ED.(2016) The face transplantation update: 2016. Plast Reconstr Surg. Jun 2016;137(6):1841-1850. PMID 27219239

Sponsored by Brigham and Women's Hospital. Face Transplantation for Treatment of Severe Facial Deformity (NCT01281267). Available online at: www.clinicaltrials.gov. Last accessed January, 2013.

Sponsored by Brigham and Women's Hospital.(2014) Hand Transplantation for Treatment of Dominant Hand or Bilateral Hand Amputees (NCT01293214). Available online at: www.clinicaltrials.gov. Last accessed January, 2014.

Sponsored by Christine M. Kleinert Institute for Hand and Microsurgery.(2014) Allogeneic Hand Transplantation Composite Tissue Allotransplantation (HandCTA) (NCT00711373) . Last accessed July, 2014.

Sponsored by the Cleveland Clinic. Face Transplantation Clinical Trial (NCT01269164). Available online at: www.clinicaltrials.gov. Last accessed January, 2013.

Sponsored by the University of Maryland. Face Transplantation (NCT01140087). Available online at: www.clinicaltrials.gov. Last accessed January, 2013.

Sponsored by the University of Pittsburgh. Human upper extremity (hand and forearm) allotransplantation (NCT00722280). Available online at: www.clinicaltrials.gov. Last accessed January, 2013.

Wo L, Bueno E, Pomahac B.(2015) Facial transplantation: worth the risks? A look at evolution of indications over the last decade. Curr Opin Organ Transplant. Dec 2015;20(6):615-620. PMID 26536422


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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