Classification of Face Rejection: Banff classification for CTA
18
Jean Kanitakis and Linda C. Cendales
Contents 18.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 18.2 Rejection in Facial Allotransplantation . . . . . . . . 200 18.3 Pathologic Classification of Rejection in Face Transplantation: The Banff CTA-07 Score . . . . . . 201 18.4 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . 203 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
Abstract Facial allotransplantation (FA) has recently emerged as a new viable option for reconstruction of severe facial tissue defects that are not amenable to conventional reconstructive techniques. FA falls within the spectrum of Composite Tissue Allografts (CTA), and as such may undergo allograft rejection. The experience obtained so far from the limited number of FA shows that the recipients develop, in the first post-graft months, signs of (skin) rejection that can be reversed with adjustment of the immunosuppressive treatment. The severity of skin rejection can be assessed with a pathological score that was proposed during the 2007 Banff meeting in La Coruna, Spain (Banff CTA-07) and classifies rejection in five grades (0–IV) according to the severity of pathological changes in the skin. There are still several questions that remain so far unanswered regarding rejection in FA, including namely the role of skin-infiltrating cells and the possibility of development of chronic rejection. Abbreviations AMR CTA FA GVHD HES PAS
Antibody-mediated rejection Composite tissue allografts Facial allotransplantation Graft versus host disease Hematoxylin-eosin-saffron Periodic Acid Schiff stain
18.1 Introduction J. Kanitakis (*) Department of Dermatology/Laboratory of Dermatopathology, Edouard Herriot Hospital Group, Lyon, France e-mail:
[email protected]
Facial allotransplantation (FA) has recently emerged as a new viable option for reconstruction of severe facial tissue defects (secondary mostly to traumatic injuries and burns) that are not amenable to conventional
M.Z. Siemionow (ed.), The Know-How of Face Transplantation, DOI: 10.1007/978-0-85729-253-7_18, © Springer-Verlag London Limited 2011
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reconstructive techniques using autologous tissues. FA falls within the wider spectrum of Composite Tissue Allografts (CTA), i.e., allografts containing embryologically heterogeneous tissues such as skin, nerves, vessels, bones (including bone marrow), tendons, and muscles. Human FA provides various combinations of skin, muscle, and/or bone. After the first (partial) mid-face transplantation performed in France (Amiens/Lyon),1,2 ten additional facial allografts have been performed worldwide in humans in France (Paris and Amiens/Lyon), China (Xia), USA (Cleveland and Boston), and Spain (Valencia and Barcelona).3-9 Therefore, although the present results are promising, human FA remains a challenging, and for some, controversial procedure10 that is still in its experimental stage.11 In view of the small number of FA performed so far, and the fact that the latest ones have not yet been published in detail in the medical literature, only sparse data are available on mid- and long-term functional, esthetic and immunologic outcomes, so that the lessons that have so far been learned6 should be viewed as preliminary at best.
18.2 Rejection in Facial Allotransplantation Similarly to other types of allografts (including CTA), FA elicits a strong allo-immune response; therefore, their recipients need to receive life-long immunosuppression, following induction, in order to prevent allograft rejection. Despite this, the experience gained so far shows that CTA, including FA, regularly undergo episodes of graft rejection, namely, in the early post-graft period. These manifest clinically by cutaneous changes including pink or erythematous macules that may gradually progress (in the case of hand allografts) to red infiltrated, scaly lichenoid papules with or without edema and nail changes in more advanced cases.12-14 In the case of FA recipients, rejection has manifested clinically as early as from day 18 post-graft with diffuse redness of the allografted facial skin, and less frequently with edema and congestion.3-5,15 In the case of two FA recipients followed in Lyon, who received a sentinel vascularized skin flap of donor’s origin, erythematous macules and/or redness developed concomitantly with clinical lesions of the face.2,9,15 Rejection episodes can in most cases be reversed with adequate adjustment of the immunosuppressive treatment.
J. Kanitakis and L.C. Cendales
Early detection of rejection in FA is crucial in order to treat the recipient precociously so as to stop the development of persistent rejection. Experience obtained from previous CTA (mainly hands/forearms) showed that clinico-pathological evaluation of the skin is the most efficient way to detect allograft rejection. Skin biopsies obtained from CTA showed that pathological changes during allograft rejection vary in intensity depending on the severity of rejection. They affect initially the dermis and may spread to the epidermis and hypodermis at more advanced stages. Dermal changes consist mainly in an inflammatory cell infiltration with T-cells (including CD3+, CD4+, CD8+, TIA-1+ cytotoxic cells and FoxP3+ T-regulatory cells), CD68+ monocytic cells and more rarely eosinophils. This infiltrate initially forms perivascular cuffs and nodules, and later spreads to the interstitial dermis, the epidermis and hypodermis. Epidermal/adnexal changes include mainly keratinocyte necrosis/apoptosis, inflammatory cell exocytosis, more rarely spongiosis, acanthosis, papillomatosis, and ortho-hyperkeratosis. During very severe rejection episodes, the infiltrate may extend to the hypodermis, forming perivascular and periadnexal nodules. On the basis of the intensity of these changes, four scoring systems were initially proposed to assess the severity of CTA rejection.16-19 At the Ninth Banff Conference on Allograft Pathology in La Coruna, Spain, a symposium on CTA rejection was held (26 June 2007) and proposed a working classification (Banff CTA-07) for the categorization of CTA rejection.20 This classification was derived from a consensus discussion session attended by most senior authors of the afore-mentioned published classification systems. It was based on findings of skin rejection, since deeper tissues have not yet been, with few exceptions, sufficiently studied in human CTA. In one such case, where several tissues were studied during persistent rejection of a hand allograft due to non-adherence to the immunosuppressive treatment, the skin was found to be the most severely affected tissue,12 thus confirming previous findings obtained in animal models.21 It seemed therefore relevant to rely on skin findings for diagnosing rejection of skin-containing CTA. Additionally, the skin can be examined clinically and can be easily biopsied. The Banff CTA-07 symposium considered that the skin specimen necessary for evaluation of possible rejection should be obtained with a 4-mm (or larger) punch taken from the most erythematous and/or indurated (but apparently viable) area of involved skin. The structures required to constitute an adequate sample are the epidermis and its adnexa, dermis, subcutaneous tissue, and
18 Classification of Face Rejection:Banff classification for CTA
vessels. The recommendations for slide preparation are hematoxylin and eosin (H&E) and periodic acid Schiff (PAS) stains. Immunohistochemical labelings are recommended « as needed », based on HES findings and/or for research purposes; these include (but are not limited to) CD3, CD4, CD8, CD19, CD20, and CD68, as well as HLA-DR, CMV, and C4d.20
18.3 Pathologic Classification of Rejection in Face Transplantation: The Banff CTA-07 Score
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• Grade I (mild rejection): Mild (lymphocytic) perivascular infiltration – no involvement of the overlying epidermis (Fig. 18.2); • Grade II (moderate rejection): Moderate-to-dense perivascular inflammation (mainly lymphocytic), with or without mild epidermal and/or adnexal involvement (limited to spongiosis and exocytosis) – no epidermal necrosis or apoptosis (Fig. 18.3); • Grade III (severe rejection): Dense dermal inflammation and epidermal involvement with epithelial apoptosis and/or necrosis, interface dermatitis (Fig. 18.4); • Grade IV (necrotizing acute rejection): Frank necrosis of epidermis or other skin structures.
• Grade 0 (no rejection): No or rare inflammatory dermal infiltrates (some degree of perivascular inflammatory infiltrate can be found in biopsies of normal-looking skin, especially on the face) (Fig. 18.1);
The scoring systems established for grading rejection of skin-containing CTA, including the Banff CTA-07, have been used to assess rejection in the few cases of FA performed worldwide.3-5,9,15 Biopsies from FA have been taken from the allografted facial skin, the allografted oral mucosa, or the donor full-thickness skin placed as a sentinel skin graft on the recipient’s skin, serving as donor site for biopsies in order to spare the face.9,15 The established Banff CTA-07 as well as other
Fig. 18.1 Normal-looking skin from the chin of a face allograft recipient during the first days post-graft (grade 0 rejection) (HES stain)
Fig. 18.2 Grade I (mild) rejection (sentinel skin graft of a face allograft recipient): a mild perivascular lymphocytic infiltration is seen in the upper dermis (HES stain)
The Banff CTA-07 classification of CTA rejection, established in order to score rejection of skin-containing CTA, is a tiered system that comprises the following five grades (0–IV) of severity20:
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Fig. 18.3 Grade II (moderate) rejection (sentinel skin graft of a face allograft recipient): a moderate lymphocytic infiltration is seen in the upper edematous dermis, giving rise to exocytosis in the epidermis (HES stain)
Fig. 18.4 Grade III (severe) rejection (oral mucosa of a face allograft recipient): a dense lymphocytic infiltration is seen in the upper corium, associated to significant exocytosis, and basal cell vacuolization (HES stain)
J. Kanitakis and L.C. Cendales
systems proposed for CTA proved applicable for the assessment of FA rejection since they were based on changes observed in the skin, despite the fact that the latter may show some microscopic differences according to the anatomical location (e.g., face vs. hands) and is also slightly different from the oral mucosa. In the three patients where details on rejection were given, rejection grades varied from 0 to III. Cells infiltrating the skin included mainly CD3+, CD4+, CD8+, TiA-1+, and Fox-P3+ T-cells (Fig. 18.5).3,15 In the cases where skin and oral mucosa biopsies were taken concomitantly, the latter showed more severe changes compared with the former.4,5,15 The explanation of this finding is presently unknown; it could be related to a different distribution and density of antigenic structures/cells, such as endothelial and dendritic cells. Furthermore, when bilateral (right and left) mucosa biopsies were taken concomitantly, discrepancies were occasionally noted between the two sites as to rejection grade,15 suggesting a patchy infiltration pattern also observed and well described in solid organ transplants.
Fig. 18.5 FoxP3+ T-regulatory cells in the oral mucosa (corium and epithelium) of a mucosa of a face allograft recipient (immunoperoxidase revealed with diaminobenzidin)
18 Classification of Face Rejection:Banff classification for CTA
Complementary pathologic studies that have been investigated in order to get further insight into the mechanisms of rejection and ultimately diagnose it more specifically include: • Immunophenotyping of the cell infiltrate in the skin. As mentioned above, this is T-cell predominant, made of T-helper and cytotoxic T-cells (CD3+, CD4+, CD8+, TIA-1+) and FoxP3+ T-reg cells:15,22 Whether the composition of the infiltrate changes with time after transplantation, and overall whether the cellular markers studied correlate with the severity of rejection remains to be established; • Detection of C4d on skin biopsies. C4d is a complement degradation product deposited on endothelial cells of tissues during antibody-mediated rejection (AMR) in several allotransplants such as the kidney. The results obtained on CTA have so far been inconclusive: endothelial C4d deposition during CTA rejection in the skin has been reported in some studies,22,23 but not in others, including namely FA.24 The existence of AMR in CTA (supported by the presence of donor-specific antibodies) has not been convincingly shown so far. It should be reminded here that the pathological changes seen in the skin (and mucosa) of CTA during rejection are not specific, but can mimic a variety of inflammatory and tumoral dermatoses, including allergic contact dermatitis, (pseudo)lymphomas, insect bites, lichen planus, drug eruptions, dermatophytoses, viral rashes, and GVHD, to name but a few.25 Furthermore, as with other organ transplants, CTA rejection can coincide with other diseases (e.g., superficial fungal infection of the skin and/or oral mucosa). All these pitfalls should be known by the pathologists involved in interpretation of the slides so as not to overdiagnose rejection. Ancillary techniques, such as histochemical stains (PAS) or study of clonality of the lymphocytic infiltrate, may provide useful clues as to the correct diagnosis. In all cases, clinicopathologic correlation, entailing close collaboration between the pathologist and the transplant physicians, is mandatory for establishing the diagnosis of rejection.
18.4 Future Directions As pointed out above, pathological data regarding human FA and vascularized CTA in general are still
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very sparse; therefore, there are several issues in this domain that remain to be further studied and answered: • Which is the optimal tissue for assessing (globally) allograft rejection? This is not a purely theoretic question, since the decision to adjust/increase the immunosuppressive treatment usually relies on the result of pathological examination. Indeed, as stated previously, microscopic examination of tissues seems to be presently the most efficient indicator of CTA rejection. Both in experimental (animal) and human studies, the skin appeared as the most antigenic tissue among those contained in a CTA. After the advent of FA, it was noted that oral mucosa shows more severe pathological changes than the skin during rejection. The obvious advantage of oral mucosa versus skin is that post-biopsy scars on the former are not visible, contrasting with those of the facial skin that are most often visible and cosmetically undesired. Possible rejection of underlying deeper tissues (muscles, bone) in CTA (including FA) has not been studied so far pathologically, partly because biopsies of these tissues are (obviously) more difficult to obtain. The correlation between skin, mucosal, and underlying tissue rejection in CTA remains to be further studied, as this will allow to define which tissue reflects best, from a clinically relevant point of view, allograft rejection. • What is the functional role of cells infiltrating the skin regarding rejection/tolerance? The Banff CTA07 score does not take into account the immunophenotype of skin-infiltrating cells; however, it seems likely that phenotypically different cells (e.g., TIA1+ cytotoxic vs. FoxP3+ T-regulatory cells) play different, possibly opposing, roles in the local immunological process. Better knowledge of the function of these cells in the infiltrate of CTA will probably lead to amendments of the Banff CTA rejection score, in order to take into account the composition of the cell infiltrate. • Will chronic rejection develop in FA recipients? So far, chronic rejection (namely vasculopathy) has not been observed in FA nor in other CTA, with the exception of a hand-transplant patient who lost his graft because of arteriopathy.26 Of note, this patient was receiving reduced immunosuppressive treatment, a fact that may have contributed to devel opment of rejection, as happened with the first
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hand-transplant patient following treatment discontinuation.12 Thus, the possibility that chronic rejection will develop in FA in the long term cannot be excluded. The Banff CTA 07 does not presently include features of chronic rejection (such as myointimal vascular proliferation or fibrosis) but – as with other transplants – the scoring system will evolve, if necessary, as more clinical and experimental data becomes available. In solid organ (kidney) transplantation, higher incidences of acute rejection episodes are associated with higher rates of chronic rejection, and when considering the relatively high incidence of acute rejection observed in FA (as in hand-transplant) recipients, it may appear surprising that chronic rejection has not yet been seen more frequently. This could be due to several factors: (1) relatively short post-transplant follow-up (5 years in the case of FA), (2) low incidence of associated risk factors (such as hypertension and dyslipidemia) commonly seen in solid organ – but not CTA-transplant recipients, (3) a lower vascular susceptibility of CTA to the toxic effects of immunosuppressive drugs, and (4) early identification and reversal of acute rejection in FA transplants allowed by the possibility to rapidly diagnose skin rejection. Conversely, the relatively high frequency of diagnosis of rejection in CTA may be due, at least in part, to the fact that skin changes can be readily observed in CTA (as compared with other inner organ transplants). Whether chronic rejection will develop in the long term in the skin or other tissues in FA still remains to be observed. As noted above, the Banff CTA-07 will evolve as these data becomes available. Hopefully, the numerous questions that remain as yet unanswered in the field of human FA will be settled when larger clinicopathologic experience will be obtained in the future.
References 1. Devauchelle B, Badet L, Lengelé B, et al. First human face allograft: early report. Lancet. 2006;368:203-209. 2. Dubernard J, Lengelé B, Morelon E, et al. Outcomes 18 months after the first human partial face transplantation. N Engl J Med. 2007;357:2451-2460. 3. Guo S, Han Y, Zhang X, et al. Human facial allotransplantation: a 2-year follow-up study. Lancet. 2008;372:631-638.
J. Kanitakis and L.C. Cendales 4. Gordon CR, Siemionow M, Papay F, et al. The world’s experience with facial transplantation: what have we learned thus far? Ann Plast Surg. 2009;63:572-578. 5. Eaton L. Spanish doctors carry out first transplantation of a full face. BMJ. 2010;340:c2303. 6. Lantieri L, Meningaud JP, Grimbert P, et al. Repair of the lower and middle parts of the face by composite tissue allotransplantation in a patient with massive plexiform neurofibroma: a 1-year follow-up study. Lancet. 2008;372:639-645. 7. Pomahac B, Pribaz J, Eriksson E, et al. Restoration of facial form and function after severe disfigurement from burn injury by a composite facial allograft. Am J Transplant. 2011. doi: 10.1111/j.1600-6143.2010.03368.x. [Epub ahead of print] 8. Siemionow MZ, Papay F, Alam D, et al. Near-total human face transplantation for a severely disfigured patient in the USA. Lancet. 2009;374:203-209. 9. Morelon E, Testelin S, Petruzzo P, et al. New partial face allograft transplantation: report on first three months. Presented at: the XXIIIth International Congress of the Transplantation Society; August 15–19, 2010; Vancouver, British Columbia, Canada. 10. Strong C. An ongoing issue concerning facial transplantation. Am J Transplant. 2010;10:1115-1116. 11. Siemionow M, Gordon C. Overview of guidelines for establishing a face transplant program: a work in progress. Am J Transplant. 2010;10:1290-1296. 12. Kanitakis J, Jullien D, Petruzzo P, et al. Clinicopathologic features of graft rejection of the first human hand allograft. Transplantation. 2003;76:688-693. 13. Schneeberger S, Gorantla V, van Riet R, et al. Atypical acute rejection after hand transplantation. Am J Transplant. 2008; 8:688-696. 14. Cendales L, Breidenbach W. Hand transplantation. Hand Clin. 2001;17:449-510. 15. Kanitakis J, Badet L, Petruzzo P, et al. Clinicopathological monitoring of the skin and oral mucosa of the first human face allograft. Report on the first eight months. Transplantation. 2006;82:1610-1615. 16. Bejarano PA, Levi D, Nassiri M, et al. The pathology of fullthickness cadaver skin transplant for large abdominal defects. Am J Surg Pathol. 2004;28:670-675. 17. Schneeberger S, Kreczy A, Brandacher G, Steurer W, Margreiter R. Steroid- and ATG-resistant rejection after double forearm transplantation responds to Campath-1H. Am J Transplant. 2004;4:1372-1374. 18. Kanitakis J, Petruzzo P, Jullien D, et al. Pathological score for the evaluation of allograft rejection in human hand (composite tissue) allotransplantation. Eur J Dermatol. 2005;15:235-238. 19. Cendales L, Kirk A, Moresi M, et al. Composite tissue allotransplantation: classification of clinical acute skin rejection. Transplantation. 2006;81:418-422. 20. Cendales L, Kanitakis J, Schneeberger S, et al. The Banff 2007 working classification of skin-containing composite tissue allograft pathology. Am J Transplant. 2008;8:1396-1400. 21. Lee W, Yaremchuk M, Pan Y, Randolph MA, Tan CM, Weiland AJ. Relative antigenicity of components of a vascularized limb allograft. Plast Reconstr Surg. 1991;87:401-411. 22. Hautz T, Zelger B, Grahammer J, et al. Molecular markers and targeted therapy of skin rejection in composite tissue allotransplantation. Am J Transplant. 2010;10:1200-1209.
18 Classification of Face Rejection:Banff classification for CTA 23. Landin L, Cavadas P, Ibanez I, et al. CD3+ mediated rejection and C4d deposition in two composite tissue (bilateral hand) allograft recipients after induction with alemtuzumab. Transplantation. 2009;87:776-781. 24. Kanitakis J, McGregor B, Badet L, et al. Absence of C4d deposition in human composite tissue (hands and face) allograft biopsies: an immunoperoxidase study. Transplantation. 2007;84:265-267.
205 25. Kanitakis J. The challenge of dermatopathological diagnosis of rejection of composite tissue allografts: a review. J Cutan Pathol. 2008;35:738-744. 26. Breidenbach W, Ravindra K, Blair B, Burns C, et al. Transplant arteriopathy in clinical hand transplantation. Presented at: the 9th Meeting of the International Society of Hand and Composite Tissue Allotransplantation; September 11–12, 2009; Valencia, Spain.
