Benign and malignant hepatocellular lesions in patients with vascular liver disease

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The liver is a unique organ because of its dual blood supply, 70%‐80% being derived from the portal vein and 20%‐30% being derived from the hepatic artery. These two vessels communicate at different levels, explaining that a decrease in the portal vein is compensated by an increase in arterial flow.1 When the hepatic venous system is chronically compromised, the portal vein tends to behave as a draining vein, leading to an increase in the hepatic arterial flow (Fig. 1). Finally, some arterial disorders are responsible by themselves for an increase in arterial flow. This increased hepatic arterial flow likely favors the development of hepatocellular liver tumors. In this article, we will describe the most common vascular liver diseases inducing hepatocellular tumors (Table 1).

Figure 1.

The illustrations above represent the liver vessels and liver nodules observed in the vascular disorders described in this article. (A) Normal vascular anatomy and normal liver enhancement during contrast enhanced imaging. (B) BCS. Abnormal hepatic veins showing complete occlusion, marked stenosis and hepatic venous collaterals. Decreased portal vein diameter and increased hepatic artery diameter resulting in increased liver enhancement on arterial‐phase imaging (liver appears brighter than normal liver in panel A). Multiple FNHs are hypervascular on arterial‐phase imaging. (C) Congenital portosystemic shunt. Complete portal flow deprivation and increased hepatic artery diameter resulting in increased liver enhancement on arterial‐phase imaging (liver appears brighter than normal liver in panel A). FNH (often large) are hypervascular on arterial‐phase imaging. (D) Hereditary hemorrhagic telangiectasia. Marked increased in size of hepatic arteries with arteriovenous and portovenous shunts (dotted circles). Increased patchy liver enhancement on arterial‐phase imaging (liver appears brighter than normal liver in panel A). Multiple FNHs are hypervascular on arterial‐phase imaging. (E) Cavernous transformation of the portal vein. Extrahepatic portal vein obstruction with portal cavernoma and increased hepatic artery diameter resulting in increased enhancement in peripheral liver segments on arterial‐phase imaging. Multiple small‐sized FNH are hypervascular on arterial‐phase imaging.

Table 1.

Prevalence of Liver Nodules in Vascular Liver Disorders

	Normal Liver	BCS	Congenital Portosystemic Shunts	HHT	Cavernous Transformation of the Portal Vein
FNH	Frequent	Very frequent	Very frequent	Very frequent	Very frequent
Hepatocellular adenoma	Rare	Possible	Possible	Rare	Rare
Hepatocellular carcinoma	Exceptional	Frequent	Rare	Rare	Rare

Figure 2.

Chronic BCS. (A) T2‐weighted MR image showing multiple hypointense liver nodules corresponding to FNHs. (B and C) On opposed‐phase (B) and fat‐suppressed (C) T1‐weighted MR images, FNHs are hyperintense relative to the liver. (D) On a contrast‐enhanced T1‐weighted MR sequence at the arterial phase, FNHs are enhanced in the arterial phase. A central scar is seen within the liver lesions. They become isointense to the liver on portal venous and delayed phases (data not shown).

Budd‐Chiari Syndrome

Budd‐Chiari syndrome (BCS) is characterized by an obstruction of the hepatic venous outflow tract in the absence of right heart failure or constrictive pericarditis. Benign regenerative nodules in association with BCS have been described in the literature since the 1990s, probably due to the major improvements in patient survival and advances in liver imaging. These benign regenerative nodules are seen only in patients with chronic BCS, and mostly correspond to focal nodular hyperplasia (FNH). Some imaging features are different from those of FNH seen on normal liver, such as hyperintensity on T1‐ and T2‐weighted magnetic resonance (MR) images, but they also are homogeneous, hypervascular, and the largest lesions often contain a central scar (Fig. 2).2, 3 In most cases, these lesions are multiple and their size does not exceed 3 cm in diameter. Progression either by size or number is often observed. In some cases, benign nodules display morphological features of hepatocellular adenomas characterized by well‐differentiated liver plates associated with increased number of unpaired arteries.

Patients with BCS are also at risk of hepatocellular carcinoma (HCC) (11 of 97 patients in a recent cohort followed up for a mean of 5 years), suggesting that BCS patients should be monitored for HCC development.4 Serum alpha‐fetoprotein seems quite specific for HCC in this setting. Patients with long‐standing inferior vena cava obstruction carry a much higher risk of developing HCC than those with pure hepatic vein involvement. At imaging, HCC usually appears hypervascular, heterogeneous, and solitary. Diagnosis of these two lesions might be challenging at imaging and hepatobiliary MR contrast agents are helpful. Liver biopsy is indicated in atypical cases or when significant changes occur over time. There is no evidence to date that benign regenerative nodules arising in patients with BCS degenerate into malignancy.5

Congenital Portosystemic Shunts

Portosystemic shunts in patients without a history of trauma, liver biopsy, portal thrombosis, cirrhosis, or portal hypertension are considered congenital. Appearance of the shunts is various, as they can be intrahepatic or extrahepatic, simple or multiple, and may induce partial or complete portal deprivation. It has been known for many years that patients with congenital portosystemic shunts may develop benign regenerative liver lesions that are thought to be related to deprivation of portal flow.6 Most of these patients present with multiple liver nodules, which are mostly FNHs but may represent other hepatocellular lesions such as hepatocellular adenoma or regenerative nodular hyperplasia.6 Interestingly, FNHs are more often atypical than in patients with normal livers and may enlarge over time.7 Complete and chronic portal deprivation could explain these atypias. In children, shunt closure can result in restoration of intrahepatic portal flow with complete or partial regression of benign liver lesions.8

Caution should, however, be taken for the diagnosis of benign regenerative lesions, as HCCs have been rarely reported in patients with congenital portosystemic shunts.9 Accordingly, liver biopsy should be considered, particularly in patients with atypical lesions at imaging.

Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu‐Osler‐Weber syndrome, is an autosomal dominant disorder that interferes with angiogenesis and its control mechanisms. Liver involvement is frequently associated with mutations in the ALK1 gene mutations (type 2) and ranges between 67% and 84% of HHT patients.10 The vascular abnormalities comprise microscopic telangiectasia and direct arteriovenous and portovenous shunts, leading to an increase in hepatic arterial flow. Consequently, HHT favors the development of nodular regenerative hyperplasia and FNH. The prevalence of FNH in HHT patients is estimated at 2.9%, which is much higher than in the general population.11 In this series, most patients with FNH had severe hepatic shunts and were women.11 During follow‐up, some FNHs may increase in size. On the other hand, in some patients, HHT may be revealed by multiple FNHs without visible intrahepatic shunts on imaging. Diagnosis of FNH associated with HHT relies on classical imaging criteria. Precontrast and contrast‐enhanced MR sequences using hepato‐specific contrast agents are helpful to differentiate FNH from large telangiectasia. Liver biopsy is theoretically contraindicated in HHT due to a higher risk of bleeding but can be discussed in multidisciplinary teams when imaging is atypical.

Some cases of HCC in association with HHT have been reported, but appear to be exceptional.12

Cavernous Transformation of the Portal Vein

Cavernous transformation of the portal vein (CTPV) is a compensatory response that aims to restore hepatic blood flow after portal vein thrombosis and can profoundly alter liver morphology. CTPV also changes vascular hemodynamics, including an increase in hepatic arterial flow, especially in the peripheral liver segments. Case reports have described benign nodules in patients with CTPV.13, 14

A recent series of 58 CTPV patients has found 12 (21%) patients with FNH and one with hepatocellular adenoma. As in the other vascular disorders, some patients with FNH showed a progressive clinical course.15

Other Vascular Disorders

Some noncirrhotic liver diseases leading to severe portal hypertension and/or liver congestion can also induce the development of benign regenerative nodules such as obliterative portal veinopathy, congenital hepatic fibrosis, and sinusoidal obstruction syndrome (16).

In conclusion, a variety of vascular disorders have been associated with hepatocellular tumors. The most common lesions by far are FNH but other benign tumors can be seen as well: nodular regenerative hyperplasia, hepatocellular adenoma. Imaging plays a major role but the diagnosis can be more difficult than in normal livers and may require histopathologic examination. Increase in size and number of these benign lesions is not exceptional. HCC is very rare except in patients with BCS.

Abbreviations

BCS

Budd‐Chiari syndrome

FNH

focal nodular hyperplasia

HCC

hepatocellular carcinoma

HHT

hereditary hemorrhagic telangiectasia

IVC

inferior vena cava.