Diagnosis and differential diagnosis of hepatic graft versus host disease (GVHD)

Abstract

Graft versus host disease (GVHD) is a common complication following allogeneic hematopoietic cell transplantation (HCT) that typically manifests as injury to the skin, gastrointestinal mucosa, and liver. In some cases, hepatic GVHD may be histologically indistinguishable from other disorders such as infection and drug-induced liver injury (DILI). Additionally, clinical signs and symptoms are frequently confounded by the superimposed effects of pretransplant chemoradiotherapy, immunotherapy (IT) (targeted to the underlying malignancy), GVHD prophylaxis, and infection. Thus, careful attention to and correlation with clinical findings, laboratory values, and histologic features is essential for diagnosis. This review, aimed at the practicing pathologist, will discuss current clinical and histologic criteria for GVHD, the approach to diagnosis of hepatic GVHD, and features helpful for distinguishing it from other entities in the differential diagnosis.

Keywords: Hematopoietic cell transplantation (HCT); drug-induced liver injury (DILI); graft versus host disease (GVHD); hepatic lymphoma; immunotherapy (IT); post-transplant lymphoproliferative disorder (PTLD); veno-occlusive hepatic disease.

Figure 1

Hepatic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (H&E stain: A, ×200; B, ×400; C, ×100; D, ×400). In acute GVHD (A and B), damage to bile duct epithelium characterized by enlarged and overlapping nuclei (reactive epithelial atypia), cytoplasmic eosinophilia and vacuolation. Portal inflammation is sparse. With longstanding GVHD (C and D), bile duct loss and portal fibrosis may be seen. GVHD, graft versus host disease.

Figure 2

Viral hepatitis (H&E stain). (A and B) Chronic hepatitis C typically shows well circumscribed portal lymphocytic infiltrates, with relatively little (if any) duct injury (A, ×400; B, ×600); (C and D) liver needle biopsy showing CMV hepatitis after HCT. CMV infection causes cytomegaly of infected hepatocytes. Large eosinophilic intranuclear inclusions surrounded by a clear halo and amphophilic small cytoplasmic inclusions are present in the hepatocytes (C, ×100; D, ×400); (E and F) liver needle biopsy showing adenoviral hepatitis after HCT (E, ×400; F, ×600). Numerous infected hepatocytes demonstrating “smudgy-appearing” nuclei. CMV, cytomegalovirus; HCT, hematopoietic cell transplantation.

Figure 3

Monomorphic PTLD after allogeneic hematopoietic stem cell transplantation. Needle core biopsy of liver mass showed diffuse large B-cell lymphoma type in a patient with history of AML, 1 year after allogenic HCT. By immunohistochemistry, the sheets of large atypical lymphoid infiltrates were diffusely positive for B-cell marker CD20 with high cell proliferation index Ki-67 (~90%). The lymphoma cells were negative for CD3. The lymphoma cells were positive for EBV by EBER in situ hybridization (A and B, H&E stain, A, ×100, B ×200; C and D, immunostains, ×100; E, immunostains, ×200; and F, in situ hybridization, ×400). PTLD, post-transplant lymphoproliferative disorder; HCT, hematopoietic cell transplantation; EBV, Epstein-Barr virus.

Figure 4

Hepatic GVHD in a male patient with history of T-cell lymphoma who received hematopoietic stem cell transplantation from a female donor (H&E stain). (A) Liver biopsy revealed lymphocytic infiltration of the portal tracts associated with ductulitis and endothelialitis (×400); (B) FISH study confirmed the lymphocytes were predominantly donor cells (XX) while the hepatocytes were recipient cells (XY) (×100). GVHD, graft versus host disease; FISH, fluorescence in situ hybridization.