Nodular Endocardial Infiltrates (Quilty Lesions) Cause Significant Variability in Diagnosis of ISHLT Grade 2 and 3A Rejection in Cardiac Allograft Recipients

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Background

Endomyocardial biopsy is used to guide therapy after heart transplantation. An accurate and reliable diagnosis of rejection is critical for proper patient management.

Methods

A sub-set of 827 biopsies from 273 patients were identified from 8 centers participating in the Cardiac Allograft Gene Expression Observational Study. These included all biopsies graded by local center pathologists as International Society for Heart and Lung Transplantation (ISHLT) Grade 1B or higher and also randomly chosen Grade 0 and 1A biopsies. Each of these cases was reviewed in a blinded manner by 3 study pathologists in the absence of clinical data. The study pathologists were assigned an ISHLT grade and noted nodular endocardial infiltrates (Quilty lesions).

Results

The study pathologists were significantly more likely than local pathologists to diagnose ISHLT Grade 0, 1A and 3B rejection and significantly less likely to diagnose ISHLT Grade 1B, 2 and 3A rejection. Concordance between local and study pathologists was lowest for Grade 2 (17% agreement). Quilty lesions were noted in 3.3% of local Grade 0 cases and in 31% and 37% of local Grade 2 and 3A cases, respectively. Quilty lesions were recognized by study pathologists in 35% of local Grade 2 cases “downgraded” to Grade 0 or 1, but in only 10% of local Grade 2 cases confirmed by study pathologists.

Conclusions

The greatest variability between pathologists in application of the ISHLT grading system is in Grade 2 biopsies, and Quilty lesions are a major contributing factor to the lack of concordance. Accurate application of the ISHLT grading system requires improved recognition and understanding of Quilty lesions.

Section snippets

Nodular endocardial infiltrates (Quilty lesions) and grade 2 rejection

In 1990, the Stanford group reported finding accumulations of lymphocytes with scattered plasma cells and prominent vascularity in the endocardium (Quilty A), which might extend into the subjacent myocardium (Quilty B).2 These were named after the first patient in whom they were recognized. These lesions are dense infiltrates, often without recognizable myocytes in their central portions, containing numerous capillary-sized vessels, and composed of plasma cells and central aggregates of B

The CARGO study

The Cardiac Allograft Rejection Gene Expression Observational Study (CARGO) was initiated in 2001 to explore the relationship between peripheral leukocyte gene expression and acute allograft rejection and other clinical outcomes. Through this work, gene expression patterns distinguishing acute cellular rejection from quiescence have been identified and are being validated for clinical use. Cardiac allograft recipients from 8 centers were enrolled and followed-up with blood sample and clinical

Clinical Study

Under institutional review board (IRB)-approved informed consent at each institution, patients enrolled in the CARGO study were enrolled at the time of transplantation and followed during their post-transplant course. At each biopsy encounter, clinical and pathologic data were recorded and a peripheral blood sample was obtained.

Cardiac Biopsy Pathology

For 562 patients from 8 centers, 3,968 biopsy encounters were recorded. A sub-set of 827 biopsies from 273 patients was identified; this sub-set included all biopsies

Distribution of ISHLT Grades According to Local Pathologists

Among the 3,968 biopsies from 562 patients read by local pathologists, the mean time from transplantation was 210.5 days (median 101 days, standard deviation 482.6 days). The clinical characteristics of the 273 patients who provided the 827 biopsies evaluated in the study are shown in Table 1. The distribution of ISHLT grades assigned by local pathologists at the 8 centers is shown in Table 2. Grade 3A and B rejection rates were very low (<3.8% of all biopsies). The vast majority of cases

Discussion

The variability between pathologists in assigning ISHLT biopsy grades to cardiac allograft biopsies has been noted previously.8, 9, 10 The contribution of the ISHLT Grade 2 histologic pattern to inter-observer variability in biopsy grading has also been recognized.3, 6, 11 There has also been, perhaps in response to this variability in diagnosis, a wide variety of clinical responses to asymptomatic Grade 2 biopsy.6, 12, 13, 14, 15 It is therefore important for those in clinical management to

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