Carmela D. Tan

Banff 2013 Meeting Report: Inclusion of C4d‐Negative Antibody‐Mediated Rejection and Antibody‐Associated Arterial Lesions

The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19–23, 2013, and was preceded by a 2‐day Latin American Symposium on Transplant Immunobiology and Immunopathology. The meeting was highlighted by the presentation of the findings of several working groups formed at the 2009 and 2011 Banff meetings to: (1) establish consensus criteria for diagnosing antibody‐mediated rejection (ABMR) in the presence and absence of detectable C4d deposition; (2) develop consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score), associated with improved inter‐observer agreement and correlation with clinical, molecular and serological data; (3) determine whether isolated lesions of intimal arteritis (“isolated v”) represent acute rejection similar to intimal arteritis in the presence of tubulointerstitial inflammation; (4) compare different methodologies for evaluating interstitial fibrosis and for performing/evaluating implantation biopsies of renal allografts with regard to reproducibility and prediction of subsequent graft function; and (5) define clinically and prognostically significant morphologic criteria for subclassifying polyoma virus nephropathy. The key outcome of the 2013 conference is defining criteria for diagnosis of C4d‐negative ABMR and respective modification of the Banff classification. In addition, three new Banff Working Groups were initiated.

Banff 2013 meeting report

The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19–23, 2013, and was preceded by a 2‐day Latin American Symposium on Transplant Immunobiology and Immunopathology. The meeting was highlighted by the presentation of the findings of several working groups formed at the 2009 and 2011 Banff meetings to: (1) establish consensus criteria for diagnosing antibody‐mediated rejection (ABMR) in the presence and absence of detectable C4d deposition; (2) develop consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score), associated with improved inter‐observer agreement and correlation with clinical, molecular and serological data; (3) determine whether isolated lesions of intimal arteritis (“isolated v”) represent acute rejection similar to intimal arteritis in the presence of tubulointerstitial inflammation; (4) compare different methodologies for evaluating interstitial fibrosis and for performing/evaluating implantation biopsies of renal allografts with regard to reproducibility and prediction of subsequent graft function; and (5) define clinically and prognostically significant morphologic criteria for subclassifying polyoma virus nephropathy. The key outcome of the 2013 conference is defining criteria for diagnosis of C4d‐negative ABMR and respective modification of the Banff classification. In addition, three new Banff Working Groups were initiated.

American Society of Echocardiography Clinical Recommendations for Multimodality Cardiovascular Imaging of Patients with Pericardial Disease: Endorsed by the Society for Cardiovascular Magnetic Resonance and Society of Cardiovascular Computed Tomography

Allan L. Klein, MD, FASE, Chair, Suhny Abbara, MD, Deborah A. Agler, RCT, RDCS, FASE, Christopher P. Appleton, MD, FASE, Craig R. Asher, MD, Brian Hoit, MD, FASE, Judy Hung, MD, FASE, Mario J. Garcia, MD, Itzhak Kronzon, MD, FASE, Jae K. Oh, MD, FASE, E. Rene Rodriguez, MD, Hartzell V. Schaff, MD, Paul Schoenhagen,MD, Carmela D. Tan,MD, and Richard D.White, MD,Cleveland and Columbus, Ohio; Boston, Massachusetts; Weston, Florida; Scottsdale, Arizona; Rochester, Minnesota; Bronx and New York, New York

Cardiac magnetic resonance detection of myocardial scarring in hypertrophic cardiomyopathy: correlation with histopathology and prevalence of ventricular tachycardia.

OBJECTIVES In hypertrophic cardiomyopathy (HCM) patients undergoing surgical myectomy, we sought to determine the association between pre-operative cardiac magnetic resonance (CMR) findings, small intramural coronary arteriole dysplasia (SICAD) on histopathology, and ventricular tachycardia (VT). BACKGROUND Myocardial scarring (fibrosis) and SICAD are frequently observed on histopathology in HCM patients. CMR measures wall thickness and detects scar. METHODS Sixty symptomatic HCM patients (62% men; mean age 51 +/- 14 years), with preserved ejection fraction (mean 64 +/- 5%) and no angiographic coronary disease underwent CMR (cine and delayed post-contrast) using a Siemens 1.5 T scanner, followed by septal myectomy. Maximal basal septal thickness was recorded on cine CMR. Scar was determined (percentage of total myocardium) on delayed post-contrast CMR images and quantified as none, mild (0% to 25%), moderate (26% to 50%), or severe (>50%). VT was assessed using Holter monitoring. Degree of SICAD was determined (normal, mild, moderate, and severe) on histopathology of surgical specimen. RESULTS SICAD and scar were seen in 45 (75%) and 38 (63%) patients, respectively. In 15 patients without SICAD, 12 (80%) had no scar; 23 (70%) patients with mild SICAD had mild scar on CMR. On multivariate analysis, degree of SICAD was independently associated with scar on CMR (Wald chi-square statistic: 6.8, p < 0.01). Patients with basal septal scar on CMR had higher VT frequency compared with those without (27% vs. 5%, p = 0.03). CONCLUSIONS A strong association exists between degree of SICAD and myocardial scarring seen on CMR.

The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation

During the last 25 years, antibody-mediated rejection of the cardiac allograft has evolved from a relatively obscure concept to a recognized clinical complication in the management of heart transplant patients. Herein we report the consensus findings from a series of meetings held between 2010-2012 to develop a Working Formulation for the pathologic diagnosis, grading, and reporting of cardiac antibody-mediated rejection. The diagnostic criteria for its morphologic and immunopathologic components are enumerated, illustrated, and described in detail. Numerous challenges and unresolved clinical, immunologic, and pathologic questions remain to which a Working Formulation may facilitate answers.

2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology.

The Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology have produced this position paper concerning the current role of endomyocardial biopsy (EMB) for the diagnosis of cardiac diseases and its contribution to patient management, focusing on pathological issues, with these aims: • Determining appropriate EMB use in the context of current diagnostic strategies for cardiac diseases and providing recommendations for its rational utilization • Providing standard criteria and guidance for appropriate tissue triage and pathological analysis • Promoting a team approach to EMB use, integrating the competences of pathologists, clinicians, and imagers.

The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: Evolution and current status (2005-2011)

From the Department of Pathology, Stanford University, Stanford, California; Universita of Padua Medical School, Padua, Italy; Royal Brompton and Harefield NHS Trust, London, United Kingdom; Hopital Europeen Georges Pompidou, Paris, France; David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, California; Intermountain Medical Center, Salt Lake City, Utah; Queen Elizabeth Hospital, Birmingham, United Kingdom; University of Utah, Salt Lake City, Utah; Cleveland Clinic, Cleveland, Ohio; Papworth Hospital, Papworth, United Kingdom; Brigham & Women’s Hospital, Boston, Massachusetts; Cedars Sinai Heart Institute, Los Angeles, California; University of Maryland School of Medicine, Baltimore, Maryland.

Antibody-Mediated Rejection in Human Cardiac Allografts: Evaluation of Immunoglobulins and Complement Activation Products C4d and C3d as Markers

Antibody‐mediated rejection (AMR) in human heart transplantation is an immunopathologic process in which injury to the graft is in part the result of activation of complement and it is poorly responsive to conventional therapy. We evaluated by immunofluorescence (IF), 665 consecutive endomyocardial biopsies from 165 patients for deposits of immunoglobulins and complement. Diffuse IF deposits in a linear capillary pattern greater than 2+ were considered significant. Clinical evidence of graft dysfunction was correlated with complement deposits. IF 2+ or higher was positive for IgG, 66%; IgM, 12%; IgA, 0.6%; C1q, 1.8%; C4d, 9% and C3d, 10%. In 3% of patients, concomitant C4d and C3d correlated with graft dysfunction or heart failure. In these 5 patients AMR occurred 56–163 months after transplantation, and they responded well to therapy for AMR but not to treatment with steroids. Systematic evaluation of endomyocardial biopsies is not improved by the use of antibodies for immunoglobulins or C1q. Concomitant use of C4d and C3d is very useful to diagnose AMR, when correlated with clinical parameters of graft function. AMR in heart transplant patients can occur many months or years after transplant.

Update on Cardiac Transplantation Pathology

CONTEXT The endomyocardial biopsy is the mainstay for monitoring acute allograft rejection in heart transplantation. Objective and accurate assessment of cellular and humoral types of rejection is important to optimize immunosuppressive therapy, avoid therapeutic complications, and improve patient outcome. The grading system for evaluation of heart transplant biopsies published in 1990 was revised in 2004 after more than a decade of implementation. OBJECTIVE In this review, we focus on a practical approach to the evaluation of human heart transplant biopsies as diagnostic surgical pathologic specimens. We discuss the revised International Society of Heart and Lung Transplantation working formulation. DATA SOURCES We reviewed pertinent literature, incorporating ideas and vast experience of participants in various work groups that led to the revision of the 1990 grading system. CONCLUSIONS The grading system for cellular rejection is presented with detailed light microscopic morphology and comparison of the 1990 and 2004 International Society of Heart and Lung Transplantation working formulations. We show how the pathologic recognition of cellular rejection and antibody-mediated rejection has evolved. We emphasize the interpretation of immunostains for complement components C4d and C3d in the diagnosis of antibody-mediated rejection. Evidence of regulation of complement activation in human heart transplant biopsies is presented in this context. We also discuss the pitfalls, caveats, and artifacts in the interpretation of allograft endomyocardial biopsies. Lastly, we discuss the pathology of human cardiac allograft vasculopathy in practical detail.

Correlation of Donor-Specific Antibodies, Complement and Its Regulators with Graft Dysfunction in Cardiac Antibody-Mediated Rejection

Antibody‐mediated rejection (AMR) is an immunopathologic process in which activation of complement often results in allograft injury. This study correlates C4d and C3d with HLA serology and graft function as diagnostic criteria for AMR. Immunofluorescence staining for C4d and C3d was performed on 1511 biopsies from 330 patients as part of routine diagnostic work‐up of rejection. Donor‐specific antibodies were detected in 95% of those with C4d+C3d+ biopsies versus 35% in the C4d+C3d– group (p = 0.002). Allograft dysfunction was present in 84% in the C4d+ C3d+ group versus 5% in the C4d+C3d− group (p < 0.0001). Combined C4d and C3d positivity had a sensitivity of 100% and specificity of 99% for the pathologic diagnosis of AMR and a mortality of 37%. Since activation of complement does not always result in allograft dysfunction, we correlated the expression pattern of the complement regulators CD55 and CD59 in patients with and without complement deposition. The proportion of patients with CD55 and/or CD59 staining was highest in C4d+C3d− patients without allograft dysfunction (p = 0.03). We conclude that a panel of C4d and C3d is diagnostically more useful than C4d alone in the evaluation of AMR. CD55 and CD59 may play a protective role in patients with evidence of complement activation.