Working Formulation
The 2013 ISHLT-WF addresses the pathologic diagnosis, grading criteria and reporting of cardiac AMR. It reflects a collaborative effort by pathologists from institutions in the US and Europe, acting as a subgroup of the ISHLT Pathology Council. Part of their effort included an interobserver reproducibility study focused on specific histologic findings using digitized slides from collected AMR cases. Results are mentioned in the 2013 ISHLT WF report; they showed "good", but far from perfect scoring agreement.
The 2013 ISHLT-WF differs from previous iterations by addressing AMR as a pathologic entity, separate from clinical parameters such as graft dysfunction and donor-specific antibody. Pathologic AMR, designated "pAMR", is graded on the basis of a combination of histopathological and immunopathological findings as follows:
pAMR0 - Negative histologic and immunopathologic evaluation (similar to ISHLT 0R for cellular rejection.
pAMR1 - Characterized by either histopathological changes [pAMR1 (H+)] or immunopathological findings [pAMR1 (I+)] but not both. Must designate either:
pAMR1(H+) - "Activated" endothelial and intravascular mononuclear cells by routine histology (H&E) with negative immunopathology studies.
pAMR1(I+) - Positive immunohistochemical or immunofluorescence staining according to criteria outlined further into the tutorial, with normal biopsy histology.
pAMR2 - Characterized by both histopathological changes and immunopathological findings (i.e. pAMR (H+) + pAMR (I+) = pAMR2).
pAMR3 - Severe antibody mediated rejection. This pattern is very rare, especially in the current era. It is similar to early descriptions of hyperacute rejection and shows significant overlap with severe cellular rejection - ISHLT 3R. This pattern is characterized by widespread myocyte injury, hemorrhage, prominent neutrophils, capillary fragmentation (pyknosis, karryorhexis), and marked edema. Complement staining is required for this diagnosis. Fibrin staining (by immunofluorescence) is reported to be a feature of severe AMR. These cases are usually associated with profound hemodynamic dysfunction and poor clinical outcomes.
The concept of coexisting cellular and antibody-mediated rejection is not new. In some of their earlier published work Hammond and colleagues as well as others have noted the mixed patterns. Currently, most transplant pathologists recognize that biopsies with the histopathologic and/or immunophenotypic findings of AMR also have a component of ACR. In most cases the ACR is low grade (Grade 1R in the 2005 revised grading scheme or focal mild/Grade 1A or diffuse mild/Grade 1B in the original 1990 scheme). Less commonly, however, higher grade of ACR such as 2R or 3R are encountered in association with AMR.
The ability to recognize mixed rejection obviously depends on the surveillance strategy for AMR. The 2013 ISHLT WF recommends that each component be separately evaluated and graded according to established criteria.
The concept of separation between the cellular and antibody mediated arms of the immune system may not be as rigid as theoretically proposed. There is increasing interest the commonality of the pathways.
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