Not only a small liver - The pathologist's perspective in the pediatric liver transplant setting

Abstract

Pediatric liver transplantation represents a safe and long-lasting treatment option for various disease types, requiring the pathologist's input. Indeed, an accurate and timely diagnosis is crucial in reporting and grading native liver diseases, evaluating donor liver eligibility and identifying signs of organ injury in the post-transplant follow-up. However, as the procedure is more frequently and widely performed, deceptive and unexplored histopathologic features have emerged with relevant consequences on patient management, particularly when dealing with long-term treatment and weaning of immunosuppression.

In this complex and challenging scenario, this review aims to depict the most relevant histopathologic conditions which could be encountered in pediatric liver transplantation. We will tackle the conditions representing the main indications for transplantation in childhood as well as the complications burdening the post-transplant phases, either immunologically (i.e., rejection) or non-immunologically mediated. Lastly, we hope to provide concise, yet significant, suggestions related to innovative pathology techniques in pediatric liver transplantation.

Keywords: acute complication; chronic complication; histopathology; next-generation pathology; pediatric liver transplantation.

Figure 1.

Overall representation of the main indications to PLTx (A) and the main pathologies affecting the transplanted liver (B). (A) Main indications to PLTx are usually grouped in cholestatic disease [e.g., biliary atresia (hematoxylin and eosin stain showing bile duct injury in a portal tract)], metabolic disorder [e.g., alpha-1 antitrypsin deficiency (PAS stain after diastase digestion highlighting intracytoplasmic globules accumulation in periportal hepatocytes)], neoplasia [e.g., hepatoblastoma (hematoxylin and eosin stain of an embryonal subtype)], acute liver failure [e.g., Wilson disease (rhodamine stain highlighting granular coarse deposits in hepatocytes)], and “Other” categories [e.g., polycystic liver (hematoxylin and eosin stain showing a cluster of intrahepatic cysts)], the latter containing heterogeneous conditions that could not be otherwise classified. (B) Post-transplant liver diseases could be sorted in acute complications [ischemic-reperfusion injury (hematoxylin and eosin stain showing parenchymal necrosis and neutrophils aggregates)], allograft rejection [T-cell mediated rejection (hematoxylin and eosin stain showing a portal tract with severe inflammatory infiltration and injury)], recurrent disorders [primary biliary sclerosis (hematoxylin and eosin stain showing periductal concentric fibrosis)], and de novo disease [cytomegalovirus hepatitis (immunohistochemical staining for cytomegalovirus highlighting positive nuclei of infected hepatocytes)].

Figure 2.

Non-immunological acute complications. (A) Terminal hepatic vein-centered pattern of injury in a case of ischemia-reperfusion injury (hematoxylin and eosin); (B) Several erythrocytes located underneath the rim of the liver capsule in a case of subcapsular hemorrhage.

Figure 3.

Pathologic features of antibody-mediated rejection (AMR) 14 days post-transplant. (A) Portal tract showing inflammation and endotheliitis in small portal vessels. (B) Strong staining in the portal vein with C4d staining (used to detect complement deposition).

Figure 4.

Pathologic features of rejection. (A) Mixed rejection infiltrate (lymphocytes, plasma cells, eosinophils) expanding a portal tract, presenting features of endotheliitis and bile duct injury. (B) Severe rejection infiltrate with conspicuous eosinophils, lymphoblasts, and plasma cells “obscuring” portal structures; notice how the infiltrate, although severe, is strictly confined to the portal tract, showing minimal parenchymal spillover only. (C) Severe centrilobular vein endotheliitis, showing endothelial cells swelling and detachment as well as immune cells aggressive behavior. (D) Bile duct loss in a portal tract of a liver affected by chronic rejection. (E) The absence of bile duct and ductular reaction are suggestive features of chronic rejection, whereas periportal hepatocyte ductular metaplasia is common and diffuse (cytokeratin 7 immunohistochemical staining). (F) Cytokeratin 19 further highlights the absence of bile duct and ductular reaction, similarly to cytokeratin 7, although it is not expressed by metaplastic hepatocytes (please, notice that tiles D, E, and F represent the same portal tract). (G) The plasma cell rich variant of rejection presents an inflammatory infiltrate with conspicuous plasma cells and interface hepatitis. (H) Centrilobular-based injury with hepatocyte apoptosis and necrosis and neutrophilic aggregates, is an additional characteristic feature of plasma cell rich rejection. (I) Immunohistochemical staining highlights plasma cells (here represented by MUM-1) and proves useful in evaluating the quantity of plasma cells and their location when dealing with plasma cell rich rejection,

Figure 5.

Pathological features of EBV-SMT. (A) Spindle cells with none/minimal cytological atypia organized in fascicles, no/minimal necrosis, and low mitotic index are characteristic features of EBV-SMT (A; hematoxylin and eosin). (B) Diffuse expression of smooth-muscle actin helps confirm the nature of EBV-SMT. (B) EBV-SMT usually presents a focal/heterogeneous positivity to desmin. (C) Proof of diffuse positivity to EBV [here represented by Epstein-Barr encoding region (EBER) in situ hybridization] is a required criterion to perform the diagnosis of EBV-SMT.