This section of the tutorial will explain the International Society for Heart and Lung Transplantation (ISHLT) revised grading criteria.
Overview of Grading Scheme
In 1990, the International Society for Heart and Lung Transplantation (ISHLT) developed a standardized grading method to determine acute cellular rejection on endomyocardial biopsy. These grading criteria were revised in 2004 and are sometimes refered to as ISHLT-2004. These criteria have 4 levels of rejection (0R, 1R, 2R & 3R). The "R" stands for revised so as not to be confused with the ISHLT-1990 criteria (0, 1A, 1B, 2, 3A, 3B, & 4). At most institutions, a grade of 0R or 1R is not further treated and a grade of 2R or 3R is treated with increased immunosuppression. Thus it is vital for a pathologist to distinguish between low grade (0R & 1R) and high grade (2R & 3R) lesions.
The two key elements of acute cellular rejection are the presence of lymphocytes and myocyte injury. Other features of the endomyocardial biopsy may represent rejection mimickers, artifacts, helpful clues of rejection or the presence of other diseases. Thus it is important to recognize that successful interpretation of an endomyocardial biopsy for rejection is dependent on assessing only two features - infiltration and injury.
No evidence of rejection (OR)
The absence of any lymphocytic infiltration is termed - no evidence of cellular rejection - grade 0R. Essentially this is a clean biopsy containing only unremarkable endomyocardium. There may be non-rejection features on one of these biopsies such as a Quilty effect or biopsy site changes, but these can be reported separately and should not cause an increase in rejection grade.
Mild rejection (1R)
Mild rejection (1R) is defined as interstitial and/or perivascular infiltrate with up to 1 focus of myocyte injury. Because this definition includes any amount of lymphocytes in any pattern, a large and diverse range of biopsies will fit into this expansive category. The infiltrate can range from just a few perivascular lymphocytes to an extensive infiltrate of lymphocytes that are not injurious to more than a single focus of myocytes. The extent of infiltrate can overlap with the extent of infiltrate of a 2R lesion if the infiltrate has not caused more than a single focus of myocyte injury. Generally, eosinophils or neutrophils are not seen in biopsies graded 1R. Biopsies with a single focus of myocyte injury are particularly challenging. Was only a single focus found because the biopsy was barely adequate? Perhaps a Quilty effect is mimicking myocyte injury? It is often useful to convey to the clinician when a biopsy that meets grade 1R criteria is particulary busy or has a single focus of myocyte injury.
Moderate rejection (2R)
Moderate rejection (2R) is used when there are two or more foci of infiltrate with associated myocyte injury. These foci can be found on the same biopsy piece, separated by a small distance, or they can occur on different pieces or even at different levels through the material. Generally, two or more foci of myocyte injury are associated with at least a moderate cellular infiltrate across the entire biopsy. In the absence of a diffuse infiltrate, one should question whether or not they are overcalling myocyte injury and may think of other mimickers of rejection. It is always a good idea to convey to the clinicians the presence of 2R rejection on a biopsy as immediate treatment is warranted.
Severe rejection (3R)
Severe rejection (3R) is a diffuse process of myocyte injury where it is difficult to make out distinct foci of injury. Numerous eosinophils and some neutrophils are typical in this level of rejection. Generally there is a very heavy inflammatory infiltrate across the biopsy tissues. Edema, hemorrhage and vasculitis can all be features of this injury. With modern treatment protocols, a 3R rejection is quite rare and is most likely to occur if a patient has stopped taking their anti-rejection medications. Generally patients who have a 3R rejection have concurrent myocardial dysfunction. It is always a good idea to convey to the clinicians the presence of 3R rejection on a biopsy as immediate treatment is warranted.
Antibody Mediated Rejection
Antibody mediated rejection (AMR, AKA humoral rejection) is distinct from acute cellular rejection except in severe cases where the histologic findings may overlap. Histopathologic changes of AMR, seen on light microscopy, are endothelial cell swelling, macrophages filling small vessel lumens and edema. Staining for the complement split product C4d is generally used to identify the presence of AMR by immunohistochemistry or immunofluorescence.
Differences in ISHLT 1990 and 2004 criteria
As mentioned above, the ISHLT has had two separate grading criteria. The ISHLT-2004 criteria simplified the ISHLT-1990 criteria and eliminated categories that had no prognostic relevancy (ex ISHLT -1990 1A vs 1B and ISHLT 1990 grade 3B vs 4). The most controversial aspect of the change was the addition of the ISHLT-1990 grade 2 category (a single focus of myocyte injury) with the mild 1R category. Several institutions treat an ISHLT-1990 grade 2 differently than an ISHLT-2004 1R, by either instituting closer followup of the patient or treating the patient with increased immunosuppression. Thus it can be important to establish the significance of a single focus of injury on a biopsy at your institution to determine if this information needs to be conveyed to the clinicians when that finding is encountered.
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