Introduction:

Budd Chiari syndrome (BCS) is a rare hepatic disease caused by occlusion of hepatic venous outflow. BCS induces chronic liver congestion that leads to hepatomegaly, ascites, leg edema, collateral venous dilatation on the abdomen and portal hypertension. Several studies have suggested that hepatic congestion caused by obstruction of hepatic venous outflow can lead to cirrhosis and hepatocellular carcinoma (HCC) [1]. 

Here. we present a case of multicentric hepatocellular carcinoma against the background of chronic BCS in a 26-year-old man.

Clinical profile:

A 26-year-old man, first symptomatic in 2002, presented with complaints of jaundice and abdominal distension, which resolved on alternative medications. 

In 2004, he presented with haemoptysis. The upper GI scopy showed esophageal varices, for which endoscopic ligation was done. On further evaluation, MRI showed left hepatic vein (LHV) thrombosis. There was underlying protein C deficiency leading to a prothrombotic state. LHV stenting was done in 2007 and he was started on anticoagulation therapy. Two years later, he presented with abdominal pain. On evaluation, blockage of the stent had been  diagnosed which was conservatively managed. He was symptomatically better till September 2023, when he presented with three episodes of hematemesis and gradually increasing abdominal distension. 

On examination, the patient was pale and icteric with an enlarged spleen. Blood investigations revealed anemia, thrombocytopenia, hypoalbuminemia. There was mils elevation of bilirubin and liver enzymes. AFP and PIVKAA levels were raised. 

Radiological investigations:

A curvilinear ultrasound probe placed transversely over the right hypochondrium showed altered echotexture of the liver with surface irregularity. The right and middle hepatic veins were not seen and were replaced by collaterals. There was narrowing of the retrohepatic IVC. A stent was seen in the left hepatic vein which showed no colour flow on Doppler evaluation. A well-defined, encapsulated, hypoechoic lesion 7.6 x 5.3 x 6.4 cm with central vascularity was seen in segment VI, VII. Another lesion of similar morphology and sized 8.7        x 7.2 x 7.3 cm was seen in segments IVa, IVb. There was splenomegaly (16 cm) and moderate ascites. CEUS was performed with 2.5 ml of sulphur hexafluoride. The lesion in segment IVa, IVb showed intense homogenous centripetal arterial enhancement in 25-35 seconds with washout at around 2 minutes. (Fig 1 a,b,c )

Figure 1a: Ultrasonography shows well defined heterogeneously hypoechoic lesion in segment VI of liver

Figure 1b: Intensity vs time graph of contrast enhanced ultrasonography shows centripetal contrast enhancement of the lesion in segment IV with washout on delayed phase. (Green – liver parenchyma, Red – Periphery of the lesion, Yellow – Centre of the lesion)

Figure 3a: Axial T1 weighted MR image of the abdomen shows multifocal, multilobulated, well defined, variable sized, hypointense lesions with smooth margins

Figure 3b: Axial T2 weighted MR image of the abdomen shows the lesions to be hyperintense

Figure 3c: Diffusion weighted axial images of the abdomen shows the lesion in segment VI to have diffusion restriction with corresponding drop on ADC

Discussion:

BCS is caused by obstruction to hepatic venous outflow at any level from the small hepatic veins to the junction of the IVC with the right atrium. There are two forms of BCS based on the site of obstruction.: primary hepatic vein obstruction (classical BCS) and obstruction of the hepatic portion of the inferior vena cava (IVCO). The IVCO form is common in Asia and Africa but rarely reported in Western countries [2]. The major difference between classical BCS and IVCO is that the former is rarely associated with HCC, while the latter is frequently complicated by HCC [3].

HCC has been regarded as one of the major complications of BCS, and appears to develop chronically its progression [4]. The prevalence of HCC in patients with BCS varies in different regions. The incidence is high in Japan (41%), South Africa (48%), and the United States (25%) [5]. The incidence of HCC in patients with BCS is similar to that in patients with other chronic liver diseases (4–17%) [6].

Until now, the accurate pathogenesis of HCC in BCS has not been elucidated yet. Gwon et al [7] suggested that chronic liver injuries and congestion caused by obstruction of hepatic venous outflow might contribute to a fibrotic process and development of nodular type of HCC. Prolonged congestion can lead to hepatocyte necrosis, and its replacement with fibrous tissue results in fibrosis, which is assumed to be the mechanism of cirrhosis and HCC development [8]. This hypothesis is supported by frequent findings of liver parenchymal cirrhotic change adjacent to HCC in BCS context[9]. It has been reported that patients with long-standing inferior vena cava block have a 70-fold higher risk of developing HCC than those with pure hepatic vein block [10]. The frequency of occurrence of portal vein invasion was significantly lower in HCC patients with BCS than that in HCC patients with hepatitis, suggesting that extrahepatic metastases is less likely to occur in HCC patients with BCS.

Imaging studies in combination with clinical information are often essential for a definitive diagnosis of HCC, and can help to distinguish it from other hyper vascular masses [11]. HCC in patients associated with BCS was isodense or hypodense in nonenhanced CT images, and exhibited heterogeneous enhancement on arterial phase and washout on portal venous phase. Axial T1-weighted images, the nodules exhibited irregular and heterogeneous enhancement during the arterial phase, and washout during the portal venous phase. T2-weighted images showed that these nodules were hyperintense or isointense. In addition, the location, shape, size, number of nodules have a high value to distinguish HCC from benign nodules [12]. Most nodules of HCC were usually near the edge of liver, irregular, more than 3 cm in diameter, heterogeneous mass and solitary (≤3 nodules). Different and almost opposite features were found in benign nodules.

HCC in BCS typically manifests as a solitary large-sized nodule (mean diameter: 5–7 cm) [13], with a heterogenous appearance in CT and MRI imaging. As regards CT, the sensitivity for detecting HCC > 2 cm is considered high, reaching approximately 90%, but it falls significantly when the tumour size is smaller [14]. Although dedicated studies on CT performance in detecting HCC in BCS are lacking, it is also reasonable to believe that the accuracy is lower due to the parenchymal changes caused by the venous congestion and the frequent presence of regenerative nodules. On MRI, the appearance of HCC is highly variable, with around 60% of lesions exhibiting hypointensity on T1-weighted images and 60% showing hyperintensity on T2-weighted images. HCC nodules usually restrict diffusion on DWI, but some lesions, particularly well-differentiated ones, may not demonstrate significant restriction compared to the background liver parenchyma. Other characteristics traditionally reported, such as nodule-in-nodule appearance, enlargement hepatic arteries and tumour invasion of the portal system, can be observed in BCS patients as well [15].

After intravascular contrast administration, HCC nodules are typically hypervascular, with diffuse or, less frequently, central or peripheral, homogeneous or inhomogeneous hyperenhancement on arterial phase (APHE), followed by rapid washout in venous and delayed phase images on both CT and MRI. However, considering that approximately 25% of HCCs do not display washout in the portal and delayed phases, while up to one-third of FNH-like RNs can show it, the specificity of this feature for the diagnosis of HCC in BCS is relatively low. As reported by Van Wettere et al. [16], the association of homogeneous APHE and homogeneous washout was identified in one-third of benign lesions and in half of HCC cases. The resulting sensitivity and specificity for diagnosing HCC were 50% and 70%, respectively. When considering the combination of any type of APHE (homogeneous, peripheral or central) and any type of washout (homogeneous or peripheral), a sensitivity of 100% and a specificity of 61% were achieved. For this reason, given the risk of an unacceptable rate of false-positive results, the LI-RADS and AASLD/EASL criteria for the non-invasive diagnosis of HCC cannot be applied in BCS patients [17,18]. The differential diagnosis between FNH-like RNs and HCC becomes even more challenging due to the potential for the former to increase in size and/or in number. Therefore, it is important to consider additional features supportive of diagnosis of HCC, such as T1 hypointensity, hyperintensity in T2-weighted and high b-value DWI, and absence of a central scar on MRI [19].

Hepatobiliary contrast agents provide valuable help in the differential diagnosis, as HCC most often demonstrates a hypointense signal in HBP. Benign regenerative lesions typically appear isointense-to-hyperintense compared to the normal liver in HBP, regardless of the presence of washout on portal venous or delayed phase images.

In US imaging, HCC nodules are frequently heterogeneous in appearance, but they can display various variants, making it impossible to differentiate them from FNH-like RNs based solely on echogenicity. Hypervascularity on Doppler flow imaging and the presence of peripheral hypoechoic rim are also common findings, which do not provide significant assistance in the differential diagnosis. In CEUS imaging, the majority of HCC nodules demonstrate heterogeneous or homogeneous hyperenhancement during the arterial phase, which is consistent with the behaviour observed in other imaging modalities. Venous washout remains a typical feature, with around 80% of the malignant lesions exhibiting a hypoechoic appearance compared to the liver parenchyma in the portal phase, and nearly all of them demonstrating it in the delayed phase. In these terms, CEUS may help to differentiate benign regenerative nodules from HCC in BCS patients.[20]

The serum AFP level can be used for diagnosis and screening of HCC [20]. In addition, the serum AFP level significantly declined after TACE treatment, suggesting that the serum AFP level can be used to evaluate the efficacy of TACE treatment. The prognosis in patients with HCC remains poor because the high rate of tumour recurrence or the development of new tumour [21]. TACE has been shown to improve survival of patients with HCC in a randomized control trial. It has been reported that the 3- and 5-year survival rates of patients receiving TACE was 26-47% and 16-26%, respectively [22]. TACE is planned for the patient discussed above.

Conclusion:

The incidence of HCC in patients with BCS is similar to that in patients with other chronic liver diseases. Prolonged congestion is assumed to be the mechanism of cirrhosis and development of HCC. It is more commonly seen in the IVCO form of BCS. Our patient had features of narrowing of the retro hepatic IVC with non-visualisation of all three hepatic veins on imaging, secondary to underlying prothrombotic state. Screening patients with BCS using serum AFP levels is useful in early diagnosis of HCC. Any type of APHE (homogeneous, peripheral or central) and any type of washout (homogeneous or peripheral), on contrast enhanced imaging has high sensitivity and a relatively high specificity for the diagnosis of HCC. Additional features supportive of diagnosis of HCC, such as T1 hypointensity, hyperintensity in T2-weighted and high b-value DWI, and absence of a central scar on MRI are helpful in differentiating HCC and FNH-like RNs. There is risk of an unacceptable rate of false-positive results, the LI-RADS and AASLD/EASL criteria for the non-invasive diagnosis of HCC cannot be applied in BCS patients. In our patient thought there was a central scar in some of the lesions, the other imaging characteristics were pointing towards the diagnosis of multicentric HCC which was confirmed on histopathological examination. 

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Acknowledgment:

We are grateful to the Department of Pathology at our institution for providing us with the histopathology images and their description.