Histologic Clues Favoring Cytomegalovirus Hepatitis in Liver Allograft Biopsies With Overlapping Rejection-Type Injury

Background Cytomegalovirus (CMV) hepatitis after liver transplantation may mimic or coexist with acute T-cell–mediated rejection (TCMR), complicating treatment decisions. We sought practical histologic features favoring CMV hepatitis in liver allograft biopsies with overlapping rejection-type changes. Methods We retrospectively studied 12 patients with CMV hepatitis and 12 CMV immunohistochemistry-negative acute TCMR controls. CMV hepatitis required viral cytopathic inclusions on hematoxylin and eosin sections at the index biopsy. Two liver pathologists, including one blinded reviewer, re-reviewed hematoxylin and eosin sections; discrepancies were resolved by consensus. C4d immunohistochemistry was performed on all index biopsies and reviewed descriptively. One CMV biopsy was excluded from comparative histologic analysis because the deeper study level was unreliable, leaving 11 CMV and 12 TCMR biopsies. Results Clinical and transplant characteristics were similar between groups. Plasma CMV DNA was detected in all tested CMV patients and absent in tested TCMR controls. Definite concurrent acute TCMR was diagnosed in 2 of 12 CMV biopsies, while 9 were indeterminate or not evaluable for TCMR. CMV hepatitis more often showed microgranulomas (7/11 vs 1/12; P = .009) and neutrophilic microabscesses (4/11 vs 0/12; P = .037). Bile duct injury was less frequent in CMV hepatitis (7/11 vs 12/12; P = .037) and was usually mild and patchy when present. Venous endotheliitis was common in both groups. Conclusions Microgranulomas, neutrophilic microabscesses, and less frequent, usually mild bile duct injury favor CMV hepatitis. These findings do not exclude concurrent TCMR but should prompt careful search for viral inclusions, a low threshold for CMV immunohistochemistry, and close clinicopathologic correlation.