Pathology of Liver, Small Bowel, and Pancreas Transplantation

Gross Features

In hyperacute AMR, the liver becomes enlarged with congestion, hemorrhage, and variable degrees of necrosis. Vascular thrombi may be identified.

Microscopic Features

Severe, early (“hyperacute”) acute AMR is rarely biopsied because of the severe coagulopathy that develops in affected patients. Explanted, failed allografts show widespread parenchymal necrosis with congestion and hemorrhage ( Fig. 20.3A ). Neutrophilic infiltrates may be prominent, and vascular changes, including endothelial cell hypertrophy and inflammation, fibrinoid necrosis, and thrombus formation, can be seen. Bile ducts may also show ischemic injury caused by arterial thrombus.

Early histologic evidence of acute AMR includes centrilobular hepatocyte ballooning and cholestasis, sometimes accompanied by spotty or confluent hepatocyte necrosis ( Fig. 20.3B ). Portal edema, ductular reaction, and neutrophil-rich portal infiltrates are common yet nonspecific findings ( Fig. 20.3C ). Microvascular pathology is characteristic and includes endothelial cell hypertrophy or enlargement, capillary dilation, leukocyte sludging or margination, and edema. Sinusoidal infiltration by neutrophils and neutrophil-rich endothelial inflammation or “microvasculitis” affecting portal veins, portal capillaries, and central veins may be seen. More severe cases may show disruption of the microvasculature with portal and periportal hemorrhage, lobular inflammation, and hepatocyte necrosis. Necrotizing arteritis and lymphocytic intimal inflammation can be seen but are rare findings. Focal bile duct necrosis may also be seen because of thrombosis of the peribiliary plexus. Many patients exhibit mixed features of acute AMR and ACR. Tables 20.1 to 20.3 highlight scoring system for AMR.

The histologic features of chronic AMR are less well characterized. The vascular changes of acute AMR are less evident in chronic AMR. Portal, periportal, and perivenular lymphoplasmacytic inflammation with interface activity, perivenular necroinflammatory activity, and scarring are often present ( Table 20.4 ). Portal vein collagenization, biliary strictures, nodular regenerative hyperplasia, and obliterative arteriopathy may also be seen.

Microscopic Features

The classic histologic triad characteristic of ACR consists of (1) mixed but predominantly mononuclear portal inflammatory cell infiltrates, (2) bile duct inflammation or damage, and (3) subendothelial inflammation of portal veins or terminal hepatic venules (“endotheliitis”) ( Fig. 20.4A ). At least two of these features should be present to establish a diagnosis of ACR. This classic histologic picture most closely reflects the findings seen in patients with ACR occurring within the first 6 months after transplantation and is now often referred to as early ACR . The portal inflammatory infiltrates of early ACR include an admixture of enlarged (usually medium or large lymphocytes), “activated-appearing” lymphocytes, neutrophils and often eosinophils ( Fig. 20.4B ). The bile duct inflammation and damage seen in ACR include intraepithelial lymphocytes and cytologic changes that include cytoplasmic vacuolization, eosinophilia, and uneven spacing of nuclei. Subendothelial inflammation with associated endothelial cell injury and lifting of endothelial cells (“endotheliitis”) affects portal veins or terminal hepatic veins ( Fig. 20.4C ). Hepatic arterial involvement is rare. Recently, isolated “v” lesions (inflammatory, necrotizing, and/or obliterative arteriopathy) have been recognized and associated with impending ACR and/or chronic antibody-mediated rejection.

Late ACR most commonly shows similar features to early ACR, including predominantly mononuclear portal inflammation, inflammatory bile duct damage, and subendothelial inflammation. However, compared with early ACR, the inflammatory infiltrates are more homogenous and mononuclear, and there is less prominent endotheliitis and bile duct damage ( Fig. 20.4D ). Parenchymal injury in the form of low-grade interface activity, perivenular necroinflammatory activity, or patchy lobular activity is usually present.

Additional patterns of late ACR have been described under a variety of terms, including central perivenulitis, posttransplant chronic hepatitis, and plasma cell–rich rejection (also known as plasma cell hepatitis or de novo autoimmune hepatitis [AIH] ). Central perivenulitis is characterized by centrilobular perivenular inflammation with or without hepatocyte dropout, which may occur in combination with portal inflammatory infiltrates or in isolation (“isolated central perivenulitis”) ( Fig. 20.5 ). It may or may not be accompanied by portal vein or central vein endotheliitis, and this feature is not required for a diagnosis of ACR in this setting.

Posttransplant chronic hepatitis (also known as idiopathic posttransplant chronic hepatitis) shows histologic features that mimic chronic hepatitis, including mild chronic portal inflammatory infiltrates accompanied by minimal or focal interface activity. The portal infiltrates are more monotonous and the lymphocytes are less activated than those seen in typical ACR. Most cases do not show significant bile duct injury or endotheliitis. Lobular necroinflammatory activity is common and most prominent in the perivenular regions.

Plasma cell–rich rejection encompasses a histologic pattern of immune-mediated graft injury previously described as de novo AIH and posttransplant plasma cell hepatitis. It occurs in patients who lack a history of AIH. The histologic features include dense, plasma cell–rich portal and perivenular infiltrates, often with prominent interface activity and confluent necrosis, and C4d deposits can be demonstrated in the portal microvasculature. The diagnostic criteria for plasma cell–rich rejection are outlined in Table 20.5 .

Recently, a pattern of rejection with “hepatitis-like features” was described in patients who completely stop taking immunosuppressive agents. In this pattern, the lobular parenchyma shows activated lymphocytes within the sinusoids (“sinusoidal pattern”) or prominent necroinflammatory activity that is randomly distributed throughout the parenchyma ( Fig. 20.6 ). All of these findings may be seen in conjunction with portal-based ACR findings. In early stages, a lesser component of typical ACR involving the portal tracts is noted in close to 50% of cases but later in the posttransplant course that is less often seen.

Grading Acute T Cell–Mediated Rejection

After a diagnosis of ACR is established, the extent of injury is graded using the Banff global assessment as mild, moderate, or severe rejection. According to the 2016 Banff schema, the term indeterminate for rejection is used for cases that have portal or perivenular inflammatory infiltrates that could represent rejection but show insufficient tissue damage to meet criteria for a diagnosis of rejection. Mild ACR denotes cases in which rejection-type infiltrates are generally mild, seen in a minority of portal triads or perivenular areas. In portal-based rejection, the infiltrates remain confined within the portal spaces. In patients with isolated perivenular infiltrates, there is no confluent necrosis or hepatocyte dropout in mild ACR. In moderate rejection, the infiltrate expands most or all of the portal triads or perivenular areas with confluent necrosis or hepatocyte dropout limited to a minority of perivenular areas ( Fig. 20.7A ). Severe ACR shows the features described for moderate ACR and exhibits spillover of the inflammatory infiltrate into periportal areas or moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis involving a majority of perivenular areas ( Fig. 20.7B ). The findings may also be semiquantitatively scored to yield a “Rejection Activity Index” ( Table 20.6 ). The Rejection Activity Index is a numerical score intended to indicate severity of ACR based on the severity of the three features of ACR: portal inflammation, bile duct inflammation or damage, and venous endotheliitis. These grading schemas should only be applied after a diagnosis of ACR is established and should not be used to establish or refute a diagnosis of ACR.

Microscopic Features

Chronic rejection is characterized by obliterative arteriopathy and bile duct injury with progressive loss of small interlobular bile ducts. The histologic features can be divided into those of “early” and “late” stages, although there is no consistent time frame over which patients progress from early to late CR. A diagnosis of early CR suggests the changes are potentially reversible and can be applied when the majority of ducts exhibit degenerative, atrophic, or senescent changes characterized by cytoplasmic eosinophilia, irregular nuclear spacing, nuclear enlargement, nuclear hyperchromasia, and epithelial attenuation ( Fig. 20.8A ). Bile duct loss affects fewer than 50% of portal tracts in early CR. Mild portal inflammation and features of ACR, including central perivenulitis and perivenular hepatocyte dropout, are often seen in early CR. These diagnoses are not mutually exclusive, and evidence of both may be present simultaneously. Other changes, including spotty hepatocyte necrosis, centrilobular cholestasis, and perivenular fibrosis, may be seen. Hepatic arteriole loss (portal tracts lacking an arteriole) may be found in occasional (<25%) portal tracts.

In “late” CR, bile duct loss affects a least 50% of the portal tracts in a biopsy containing at least 10 portal tracts. Bile duct counting can be facilitated by cytokeratin (CK) 7 or CK19 staining. In late CR, there are also more extensive degenerative bile duct changes, marked centrilobular hepatocellular swelling and hepatocanalicular cholestasis, and prominent perivenular hepatocyte dropout with more severe perivenular (bridging) fibrosis. Central veins may show luminal obliteration. Late CR may eventually show cirrhosis as well as parenchymal extinction.

Although only rarely identified in needle biopsies, obliterative “foam cell” arteriopathy denotes the accumulation of foamy macrophages within arterial walls, resulting in luminal narrowing and impeding arterial blood flow ( Fig. 20.8B ). Although this is a very specific feature of CR, it primarily affects medium-sized and large-caliber perihilar arteries not sampled in needle biopsies. In the appropriate clinical context, a diagnosis of CR can be rendered on a needle biopsy if any one of the following features is present: (1) biliary epithelial atrophic changes affecting a majority of the bile ducts with or without bile duct loss, (2) foam cell obliterative arteriopathy, or (3) bile duct loss affecting 50% of the portal tracts.