CONSISTENCIES AND CONTROVERSIES IN THE APPLICATION OF THE INTERNATIONAL SOCIETY FOR HEART AND LUNG TRANSPLANTATION WORKING FORMULATION FOR HEART-TRANSPLANT BIOPSY SPECIMENS

Background: The International Society for Heart and Lung Transplantati on (ISHLT) working formulation was proposed in 1990 to promote standar dization in the interpretation of endomyocardial biopsy specimens obta ined after heart transplantation, especially in the setting of multice nter clinical trials and for publication purposes. Methods: To assess uniformity in interpretation, 16 pathologists experienced in posttrans plant endomyocardial biopsy specimen interpretation each read independ ently, in randomized order, an identical series of 23 biopsy specimens representing all ISHLT grades of rejection (n = 12) and other posttra nsplant biopsy findings (n = 11). The pathologists represented heart t ransplantation centers participating in the Rapamycin Treatment Trial for Grades 2 and 3A Rejection. The index diagnosis in each case was de termined by two pathology consultants who had concurred blindly on 22 of 23 (96%) biopsy specimen evaluations on their first independent rea ding. Discrepancies that would not affect clinical response (for examp le grades 0 versus 1A, 1A versus 1B, 3A versus 3B, 3B versus 4) were c onsidered minor; those that could alter therapy were considered major. Results: The 16 trial pathologists were in exact agreement with the i ndex diagnosis in 17 (mean) +/- 3 biopsy specimens (range 10 to 22) an d 20 (mean) +/- 2 biopsy specimens (range 16 to 22) if minor discrepan cies were excluded. Of 368 diagnoses rendered, 265 agreed exactly with the index diagnosis and 103 differed, of which 50 were minor discrepa ncies. The 53 major discrepancies included grades 1A/B versus 2, 22 di screpancies; 2 versus 3A, 11; Quilty B versus 2/3A, 10; biopsy site ve rsus 3A, 2; ischemic injury versus 3A/B, 2; Toxoplasma versus 3A, 2; p osttransplantation lymphoproliferative disorder versus 3B/4, 3; and Qu ilty B versus posttransplantation lymphoproliferative disorder, 1. Int erobserver agreement assessed by weighted kappa values was 0.67. Concl usions: First, there was agreement among the trial pathologists and th e index diagnosis (excluding minor discrepancies) in 85% of biopsy spe cimen interpretations. Second, of 53 major discrepancies, 43 (81%) inv olved grades 1A/B versus 2, 2 versus 3A, and Quilty B versus 2/3A. Thi rd, in 54% of instances in which biopsy findings other than rejection were misdiagnosed as rejection grades, the grade was sufficiently high to have adverse treatment implications. Fourth, the ISHLT working for mulation provides for a high degree of diagnostic consistency among ex perienced observers, and concordance could be further enhanced by clar ification of criteria for grade 2 rejection and Quilty B lesions.