Consistencies and controversies in the application of the International Society for Heart and Lung Transplantation working formulation for heart transplant biopsy specimens. Rapamycin Cardiac Rejection Treatment Trial Pathologists

J Heart Lung Transplant. 1996 Jul;15(7):728-35.


Background: The International Society for Heart and Lung Transplantation (ISHLT) working formulation was proposed in 1990 to promote standardization in the interpretation of endomyocardial biopsy specimens obtained after heart transplantation, especially in the setting of multicenter clinical trials and for publication purposes.

Methods: To assess uniformity in interpretation, 16 pathologists experienced in posttransplant endomyocardial biopsy specimen interpretation each read independently, in randomized order, an identical series of 23 biopsy specimens representing all ISHLT grades of rejection (n = 12) and other posttransplant biopsy findings (n = 11). The pathologists represented heart transplantation centers participating in the Rapamycin Treatment Trial for Grades 2 and 3A Rejection. The index diagnosis in each case was determined by two pathology consultants who had concurred blindly on 22 of 23 (96%) biopsy specimen evaluations on their first independent reading. Discrepancies that would not affect clinical response (for example grades 0 versus 1A, 1A versus 1B, 3A versus 3B, 3B versus 4) were considered minor; those that could alter therapy were considered major.

Results: The 16 trial pathologists were in exact agreement with the index diagnosis in 17 (mean) +/- 3 biopsy specimens (range 10 to 22) and 20 (mean) +/- 2 biopsy specimens (range 16 to 22) if minor discrepancies were excluded. Of 368 diagnoses rendered, 265 agreed exactly with the index diagnosis and 103 differed, of which 50 were minor discrepancies. The 53 major discrepancies included grades 1A/B versus 2, 22 discrepancies; 2 versus 3A, 11; Quilty B versus 2/3A, 10; biopsy site versus 3A, 2; ischemic injury versus 3A/B, 2; Toxoplasma versus 3A, 2; posttransplantation lymphoproliferative disorder versus 3B/4, 3; and Quilty B versus posttransplantation lymphoproliferative disorder, 1. Interobserver agreement assessed by weighted kappa values was 0.67.

Conclusions: First, there was agreement among the trial pathologists and the index diagnosis (excluding minor discrepancies) in 85% of biopsy specimen interpretations. Second, of 53 major discrepancies, 43 (81%) involved grades 1A/B versus 2, 2 versus 3A, and Quilty B versus 2/3A. Third, 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 formulation provides for a high degree of diagnostic consistency among experienced observers, and concordance could be further enhanced by clarification of criteria for grade 2 rejection and Quilty B lesions.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy / standards
  • Biopsy / statistics & numerical data
  • Graft Rejection / drug therapy
  • Graft Rejection / pathology
  • Heart Transplantation / pathology*
  • Heart Transplantation / standards
  • Heart Transplantation / statistics & numerical data
  • Heart-Lung Transplantation*
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Myocardium / pathology*
  • Observer Variation
  • Polyenes / therapeutic use
  • Sirolimus
  • Societies, Medical*


  • Immunosuppressive Agents
  • Polyenes
  • Sirolimus