Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with high mortality. Liver involvement is common (based on elevated liver function tests) with most patients demonstrating acute hepatitis. Liver biopsies are frequently obtained in the setting of suspected HLH for the purpose of identification of erythrophagocytosis, and if present, this finding is thought to suggest or support the diagnosis of HLH. However, there are problems with this approach; in particular, we do not know whether this finding is reproducible or whether it is specific to HLH. Therefore, we conducted a multi-institutional study in which experienced liver pathologists reviewed images taken from liver biopsies from patients with normal liver, acute hepatitis, possible HLH, and clinical HLH to determine if there was agreement about the presence or absence of erythrophagocytosis, and to ascertain whether the finding corresponds to a clinical diagnosis of HLH. Twelve liver pathologists reviewed 141 images in isolation (i.e., no clinical information or diagnosis provided). These came from 32 patients (five normal, 17 acute hepatitis, six HLH, four possible HLH). The pathologists classified each image as negative, equivocal, or positive for erythrophagocytosis. Kappa was .08 (no agreement) for case-level and 0.1 for image-level (1.4% agreement, based on two images which were universally considered negative). There was no difference in the proportion of pathologists who diagnosed erythrophagocytosis among those with different diagnoses at case or image-level (p = 0.82 and p = 0.82, respectively). Thus, erythrophagocytosis is an entirely unreliable histologic parameter in liver, as it is irreproducible and not demonstrably associated with a clinical disease (namely, HLH). Unless and until more reliable guidelines can be established, pathologists should refrain from commenting on the presence or absence of erythrophagocytosis in liver biopsy.
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Data Availability
Raw data was collected at Columbia University. Derived data supporting the findings of this study are available from the corresponding author SL upon reasonable request.
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Funding
SK is being supported by the Young Investigator Grant of the National Kidney Foundation. This work was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.
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Niyati Desai: conceptualization, methodology, data curation, writing—original draft, writing—review and editing, visualization. Satoru Kudose: methodology, data curation, writing—original draft, writing—review and editing. Helen E. Remotti: case review, writing—review and editing. Armando Del Portillo: case review, writing—review and editing. Ladan Fazlollahi: case review, writing—review and editing. Michael J. Lee: case review, writing—review and editing. Yuqing Xiong: writing—review and editing. Roger K. Moreira: case review, writing—review and editing. Marcela Salomao: case review, writing—review and editing. Maria Isabel Fiel: case review, writing—review and editing. Raul S. Gonzalez: case review, writing—review and editing. Joseph Misdraji: case review, writing—review and editing. Ryan M. Gill: case review, writing—review and editing. John Hart: case review, writing—review and editing. David E. Kleiner: case review, writing—review and editing. Uta Drebber: case review, writing—review and editing. Andrew M. Bellizzi: case review, writing—review and editing. Stephen M. Lagana: conceptualization, methodology, case review, data curation, writing—original draft, writing—review and editing, visualization, supervision, project administration.
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The study complies with ethical standards and was approved by the Columbia University Irving Medical Center IRB.
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Desai, N., Kudose, S., Remotti, H.E. et al. Erythrophagocytosis is not a reproducible finding in liver biopsies, and is not associated with clinical diagnosis of hemophagocytic lymphohistiocytosis. Virchows Arch 484, 61–69 (2024). https://doi.org/10.1007/s00428-023-03683-7
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DOI: https://doi.org/10.1007/s00428-023-03683-7