The Banff 2007 Working Classification of Skin-Containing Composite Tissue Allograft Pathology

Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of tissue defects. As with other allografts, CTA can undergo immune-mediated rejection; therefore standardized criteria are required for characterizing and reporting severity and types of rejection. This article documents the conclusions of a symposium on CTA rejection held at the Ninth Banff Conference on Allograft Pathology in La-Coruňa, Spain, on 26 June 2007, and proposes a working classification, the Banff CTA-07, for the categorization of CTA rejection. This classification was derived from a consensus discussion session attended by the first authors of three published classification systems, pathologists and researchers from international centers where clinical CTA has been performed. It was open to all attendees to the Banff conference. To the extent possible, the format followed the established National Institutes of Health (NIH) guidelines on Consensus Development Programs. By consensus, the defining features to diagnose acute skin rejection include inflammatory cell infiltration with involvement of epidermis and/or adnexal structures, epithelial apoptosis, dyskeratosis and necrosis. Five grades of severity of rejection are defined. This classification refines proposed schemas, represents international consensus on this topic, and establishes a working collective classification system for CTA reporting of rejection in skin-containing CTAs. Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of tissue defects. As with other allografts, CTA can undergo immune-mediated rejection; therefore standardized criteria are required for characterizing and reporting severity and types of rejection. This article documents the conclusions of a symposium on CTA rejection held at the Ninth Banff Conference on Allograft Pathology in La-Coruňa, Spain, on 26 June 2007, and proposes a working classification, the Banff CTA-07, for the categorization of CTA rejection. This classification was derived from a consensus discussion session attended by the first authors of three published classification systems, pathologists and researchers from international centers where clinical CTA has been performed. It was open to all attendees to the Banff conference. To the extent possible, the format followed the established National Institutes of Health (NIH) guidelines on Consensus Development Programs. By consensus, the defining features to diagnose acute skin rejection include inflammatory cell infiltration with involvement of epidermis and/or adnexal structures, epithelial apoptosis, dyskeratosis and necrosis. Five grades of severity of rejection are defined. This classification refines proposed schemas, represents international consensus on this topic, and establishes a working collective classification system for CTA reporting of rejection in skin-containing CTAs. Composite tissue allotransplantation (CTA) is an emerging discipline for the treatment of functionally significant tissue or limb defects. In contrast to solid organ transplants, CTAs often include skin as well as tissues of diverse embryological origin. Most CTA recipients have experienced reversible episodes of acute rejection (1Lanzetta M Petruzzo P Dubernard JM et al.Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation.Transpl Immunol. 2007; 18: 1-6Crossref PubMed Scopus (119) Google Scholar) but to date, no universally accepted criteria for CTA rejection reporting has been established. Histopathology plays a key role in diagnosis of rejection, in understanding the physiopathology of rejection and in facilitating management. Currently, four classification systems have been published and as such, a universally accepted grading scheme for ranking pathological severity of rejection is needed. Standardization is necessary for reporting clinical results and to establish objective end points for clinical trials. Recognizing that a dispersed and unstandardized development of CTA would present a major barrier for progress and reporting, a collaborative relationship was established with investigators with experience in clinical CTA worldwide to initiate the groundwork for a universally accepted histological classification. In addition, as immunomodulatory regimens are minimized, CTA will experience a growth period in the near future. This article describes a consensus schema for the stardardization of clinical reporting for the advancement of the study of the histopathology in CTA-containing skin for dissemination to the health care practice and medical community. As a working classification, the schema will continue to be refined in subsequent meetings as more clinical and experimental data become available for skin and other tissues used in CTAs. Investigators in the field of CTA including representatives from multiple sites reporting a clinical CTA in the past decade were invited to a consensus discussion on CTA histopathology at the Ninth Banff Conference on Allograft Pathology. In keeping with established National Institutes of Health (NIH) guidelines on Consensus Development Programs (2NIH Consensus Development Program. http://consensus.nih.gov/ABOUTCDP.htm (accessed on March 15, 2007).Google Scholar), this conference included: (1Lanzetta M Petruzzo P Dubernard JM et al.Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation.Transpl Immunol. 2007; 18: 1-6Crossref PubMed Scopus (119) Google Scholar) a broad-based nonadvocacy, independent panel gathered to give balanced, objective and knowledgeable focus to the topic, (2NIH Consensus Development Program. http://consensus.nih.gov/ABOUTCDP.htm (accessed on March 15, 2007).Google Scholar) freedom from scientific or financial conflict of interest from the speakers, (3Bejarano PA Levi D Nassiri M et al.The pathology of full-thickness cadaver skin transplant for large abdominal defects.Am J Surg Pathol. 2004; 28: 670-675Crossref PubMed Scopus (41) Google Scholar) predetermined questions defining the scope and the direction of the conference, and (4Kanitakis 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: 235-238PubMed Google Scholar) a systematic literature review of the topic. The presenters included the three first authors of the four classification systems published and investigators who have actively followed CTA patients from a clinicopathological view and/or published reports on CTA rejection. A pathologist from the center where the fourth classification system was published was also invited, provided a presentation and participated in the discussions. Six out of six western international centers with reported experience in hand transplantation at the time of the call were invited and five centers were represented. Furthermore, two out of two centers with experience in other CTA’s-containing skin were represented (i.e. face and abdominal wall). All published scoring systems for CTA were reviewed (3Bejarano PA Levi D Nassiri M et al.The pathology of full-thickness cadaver skin transplant for large abdominal defects.Am J Surg Pathol. 2004; 28: 670-675Crossref PubMed Scopus (41) Google Scholar, 4Kanitakis 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: 235-238PubMed Google Scholar, 5Schneeberger S Kreczy A Brandacher G et al.Steroid and ATG-resistant rejection after double forearm transplantation responds to Campath 1-H.Am J Transplant. 2004; 4: 1372-1374Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 6Cendales L Kleiner D Proposed classification of human composite tissue allograft acute rejection.Am J Transplant. 2003; 3: S154Google Scholar, 7Cendales L Kirk A Moresi M Ruiz P Kleiner D Composite tissue allotransplantation: Classification of clinical acute skin rejection.Transplantation. 2006; 81: 418-422Crossref PubMed Scopus (53) Google Scholar). In addition, a senior investigator in CTA was invited to provide a historic perspective. Each presenter provided data followed by a discussion. Of the presenters, five were clinical pathologists, three were surgeons and one was a basic investigator. The session was open to the public and all attendees of the Banff Conference. A total of 20 attendees provided oral and/or written comments to the questions posed. To date, 41 patients receiving skin-containing CTA’s have been reported; 28 have received hands, three faces, one knee with a skin island and nine abdominal walls. Essentially, all patients have experienced episodes of rejection (1Lanzetta M Petruzzo P Dubernard JM et al.Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation.Transpl Immunol. 2007; 18: 1-6Crossref PubMed Scopus (119) Google Scholar,8The challenge of dermatopathological diagnosis of rejection of composite tissue allografts: A review J Cutan Pathol (submitted).Google Scholar,10Diefenbeck M Wagner F Kirschner M Nerlich A Muckley T Hofmann G Outcome of allogeneic vascularized knee transplants.Transpl Int. 2007; 20: 410-418Crossref PubMed Scopus (32) Google Scholar). Clinical manifestations of rejection have been characterized by cutaneous changes including mild pink discoloration, gradual erythema, macules progressing to red infiltrated lichenoid papules with or without limb edema and onychomadesis in advanced rejection (1Lanzetta M Petruzzo P Dubernard JM et al.Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation.Transpl Immunol. 2007; 18: 1-6Crossref PubMed Scopus (119) Google Scholar,11Kanitakis J Jullien De Petruzzo P et al.Clinicopathologic features of graft rejection of the first human hand allograft.Transplantation. 2003; 76: 688-693Crossref PubMed Scopus (169) Google Scholar). Histological findings disclose predominantly lymphocytic inflammatory-cell infiltrate of variable density, epithelial intracellular edema (spongiosis), lymphocyte exocytosis and keratinocyte apoptosis (1Lanzetta M Petruzzo P Dubernard JM et al.Second report (1998–2006) of the International Registry of Hand and Composite Tissue Transplantation.Transpl Immunol. 2007; 18: 1-6Crossref PubMed Scopus (119) Google Scholar,12Dubernard J Lengele B Morelon E et al.Outcomes 18 months after the first human partial face transplantation.New Engl J Med. 2007; 357: 2451-2460Crossref PubMed Scopus (309) Google Scholar). Macroscopic skin changes in a case reported after steroid resistant rejection showed blisters in the superficial layers with epidermal desquamation. Histology revealed dermal and epidermal lymphocytic infiltration with apoptotic and necrotic keratinocytes (13Schneeberger S Kreczy A Brandacher G et al.Steroid- and ATG-resistant rejection after double forearm transplantation responds to Campath-1H.Am J Transplant. 2004; 4: 1372-1384Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The four published systems on grading CTA skin rejection ranked the degree of rejection based on evaluation of morphologic features (3Bejarano PA Levi D Nassiri M et al.The pathology of full-thickness cadaver skin transplant for large abdominal defects.Am J Surg Pathol. 2004; 28: 670-675Crossref PubMed Scopus (41) Google Scholar, 4Kanitakis 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: 235-238PubMed Google Scholar, 5Schneeberger S Kreczy A Brandacher G et al.Steroid and ATG-resistant rejection after double forearm transplantation responds to Campath 1-H.Am J Transplant. 2004; 4: 1372-1374Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 6Cendales L Kleiner D Proposed classification of human composite tissue allograft acute rejection.Am J Transplant. 2003; 3: S154Google Scholar, 7Cendales L Kirk A Moresi M Ruiz P Kleiner D Composite tissue allotransplantation: Classification of clinical acute skin rejection.Transplantation. 2006; 81: 418-422Crossref PubMed Scopus (53) Google Scholar). All systems illustrated substantial agreement on the basic grade stratification for acute rejection. All agreed that perivascular lymphocytic infiltrates become progressively denser and involve more vessels as the severity of rejection increases. The inflammation then extends to involve dermal stroma, epidermis (including the basal cell layer) and adnexa at moderate to marked grades of rejection. Epidermal apoptosis/necrosis is a marker of severe rejection in all of the published systems where it was observed. The classification based on full thickness, vascularized, myocutaneous-free flaps for closure of abdominal defects (3Bejarano PA Levi D Nassiri M et al.The pathology of full-thickness cadaver skin transplant for large abdominal defects.Am J Surg Pathol. 2004; 28: 670-675Crossref PubMed Scopus (41) Google Scholar) stratified rejection based on the extent of vessels infiltrated, from <10%, to 11–50% in mild, and to more than 50% in moderate and severe rejection. Severe rejection of abdominal wall grafts showed dyskeratosis and spongiosis. The discussion initiated with the following predetermined questions chosen by the CTA session committee chair in conjunction with investigators in the field: (1) Specimen and Slide Preparation: which structures are required to constitute an adequate sample? How will the biopsy be taken to appropriately reflect the clinical involvement? How many samples are required? What are the stains besides hematoxylin and eosin (H&E) that should be applied? (2) Scope of disease-acute: What are the basic features to diagnose rejection? What other features should be recorded and how? What should be excluded from acute rejection? (3) Lesion scoring-acute: How will severity be graded? (4) Scope of disease-chronic: What are the defining features of chronic injury? (5) Scope of disease-humoral: What information should be collected to define this effector mechanism in CTA? The questions were provided to the participants in both oral and written formats. Oral and written comments were collected throughout the consensus discussion session. This article represents the recompilation of the discussions including all oral and written comments. Allografts that include skin are distinctive in that rejection can be recognized by visual inspection. To include this unique feature of CTA, the clinical involvement as assessed visually at the time of biopsy or rejection should be reported as no visible changes, <10%, 10–50% and >50% of the CTA. Features include but are not limited to rash, edema, erythema, vesiculation, desquamation, necrosis and/or ulceration. To diagnose and classify skin rejection, specimen adequacy is defined as at least one 4-mm punch biopsy taken from the most reddened and/or indurated but apparently viable area of involved skin. Only one biopsy is required for diagnosis, to avoid unnecessary scarring, especially with multiple episodes of rejection. The structures required to constitute an adequate sample are the epidermis and its adnexa, dermis, subcutaneous tissue and vessels. The recommendations for slide preparation are hematoxylin and eosin (H&E) and periodic acid Schiff (PAS) stains. Immunohistochemical stains are also recognized as potentially important and are thus recommended “as needed” based on H&E findings and/or for research purposes. These included but are not limited to CD3, CD4, CD8, CD19, CD20 and CD68, as well as HLA-DR, CMV and C4d. The use of trichrome stain is not considered mandatory at this time but could be performed if desired. The basic features to diagnose and classify rejection requiring specific comment in diagnostic reports are immune cell infiltration, and epidermal and/or adnexal involvement namely spongiosis, apoptosis, dyskeratosis and necrosis. The cellular infiltrate can be mixed (e.g. including neutrophils) and not limited to lymphocytes. The pattern of the infiltrate should be characterized as perivascular or interstitial, focal or diffuse and dermal and/or hypodermal. Early signs of rejection may include the presence of scattered dermal infiltrates. Interface inflammation/dermatitis is an important feature to identify, as this may relate to the severity of the rejection or may signal a nonrejection etiology. Infiltration of eosinophils should be recorded descriptively but is not included in the current classification. This will allow the study of its significance in the future. As in other pathologies in which ulceration or necrosis develops, vasculitis may be either primary or secondary to the ulceration. Indications of rejection-related vasculitis include: absence of a history of trauma; involvement of vessels distant from the ulcer; multi-focality of the necrotizing process within the affected vessel; and involvement of several vessels within the biopsy, particularly vessels of various sizes and depths within the dermis. The pathologic and clinical features of immune and nonimmune processes are potentially overlapping and will require further study. Because there is insufficient data to absolutely exclude nonimmune conditions from a particular CTA biopsy, a descriptive observation is currently the appropriate format for reporting findings. As with solid organ transplants, other inflammatory, infectious or neoplastic processes may coincide with acute rejection. The acute/active skin rejection scoring system was divided in five grades, based on intensity and localization of infiltrates. The rejection classification is shown in Table 1.Table 1The Banff 2007 working classification of skin-containing composite tissue allograft pathologyGrade 0. No or rare inflammatory infiltrates.Grade I. Mild. Mild perivascular infiltration. No involvement of the overlying epidermis.Grade II. Moderate. Moderate-to-severe perivascular inflammation with or without mild epidermal and/or adnexal involvement (limited to spongiosis and exocytosis). No epidermal dyskeratosis or apoptosis.Grade III. Severe. Dense inflammation and epidermal involvement with epithelial apoptosis, dyskeratosis and/or keratinolysis.Grade IV. Necrotizing acute rejection. Frank necrosis of epidermis or other skin structures. Open table in a new tab Currently, insufficient data are available to define specific changes of chronic rejection in a CTA. 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CTAs that skin are unique in that rejection-related changes can be observed. it has been shown that significant perivascular infiltration with a skin (13Schneeberger S Kreczy A Brandacher G et al.Steroid- and ATG-resistant rejection after double forearm transplantation responds to Campath-1H.Am J Transplant. 2004; 4: 1372-1384Abstract Full Text Full Text PDF PubMed Scopus (0) Google L Hand Full Text PDF PubMed Google Scholar, JM E G et hand report on first Full Text Full Text PDF PubMed Scopus Google Scholar). of from chronic infiltration and injury have been at in the absence of significant infiltrates Spain, June the of and the that inflammation could as chronic it is important to the of CTA rejection in objective The of skin changes can be used as a clinical of rejection; the and of and/or other as of rejection to be as the of histological to To this the clinical of graft involvement has been as a for clinical presentation and severity of rejection. 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