Consensus diagnostic histopathological criteria for acute gastrointestinal graft versus host disease improve interobserver reproducibility

Abstract

Graft versus host disease (GvHD) is a clinically important complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its diagnosis relies on clinical and histopathological findings. In order to evaluate and improve inter-institutional diagnostic agreement on histological diagnosis and grading of acute gastrointestinal GvHD, we conducted a round robin test, which included 33 biopsies from 23 patients after HSCT. Five pathologists from different institutions independently evaluated the original sections from the biopsies submitted for diagnosis. Based on their results, consensus qualitative criteria for the assessment of typical histological features of GvHD (e.g., apoptosis, crypt destruction, mucosa denudation) were proposed, including detailed descriptions as well as histological images. In a second round robin test with involvement of the same pathologists, the reproducibility of both diagnosis and grading had improved. Remaining differences were mostly related to differential diagnostic considerations, including viral infection or toxic side effects of medication, which should be resolved by integrating histopathological findings with proper clinical information.

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation

“…The use of an independent GAC was planned to address the issue of empirical treatment for gastrointestinal GVHD in patients presenting with diarrhea, but the blinded adjudication of likely or presumptive acute GVHD events was unable to distinguish patients who received brincidofovir from those who received placebo [50]. Furthermore, a blinded review of all gastrointestinal biopsy specimens was also unable to distinguish histopathological features between brincidofovir-treated and placebo-treated patients [47]. These observations suggest either that brincidofovir can induce acute GVHD events due to enteral injury or that brincidofovir enterotoxicity can cause histopathological changes that cannot be differentiated from those seen in acute GVHD, analogous to what has been described for mycophenolate-associated gastrointestinal toxicity [51,52].…”

The association of histologic grade with acute graft‐versus‐host disease response and outcomes

“…Our institutional practice, however, is to grade GVHD prospectively and record it in our database. The histopathological diagnosis of GVHD has also been shown to be subject to substantial inter‐individual discrepancies; which can be improved upon with consensus among a group of pathologists . Although the pathology in this study was evaluated by several different pathologists, those reading biopsies were primarily a small group which are sub‐specialized within dermatopathology (for skin biopsies) and gastrointestinal pathology (for GI biopsies).…”

Graft-versus-Host Disease of the Gut: A Histologic Activity Grading System and Validation

“…The identification of an apoptotic cell was made per the NIH 2005 and NIH 2015 consensus documents, and illustrated by Ponec et al, Washington and Jagasia, and Kreft et al [1,2,5,12,28] A summary of our pathologic classification criteria, in tabular form, is presented in Supplemental Table 2. In summary, the classical appearance of an apoptotic cell was with condensed nuclear chromatin appearing as a clamshell, ring, or fragments, and eosinophilic red nucleoplasm, with cytoplasmic eosinophilia and shrinkage.…”

“…For purposes of enumeration if multiple nuclear fragments could be encompassed in a circle or elongated oval as depicted in Kreft et al, only one apoptotic cell is counted [28]. If two adjacent or nearby nuclear fragments with eosinophilic cytoplasm could conceivably have been derived from a single cell, only one apoptotic cell is counted.…”

“…The higher Sale-Lerner grades II, III, and IV may involve “exploding crypts”, apoptotic abscesses, degenerating crypts, or more severe changes. The characterization is largely reflective of Kreft et al, and may be different from some other systems in that mere loss of crypts is considered nonspecific and not evidence of activity or destruction [28] (Supplemental Table 2). There are no pathologic changes specific for chronic GVHD of the stomach, duodenum, or colorectum, as that is a clinical determination [1,2,5].…”