Hepatocelluar nodules in liver cirrhosis: hemodynamic evaluation (angiography-assisted CT) with special reference to multi-step hepatocarcinogenesis
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To understand the hemodynamics of hepatocellular carcinoma (HCC) is important for the precise imaging diagnosis and treatment, because there is an intense correlation between their hemodynamics and pathophysiology. Angiogenesis such as sinusoidal capillarization and unpaired arteries shows gradual increase during multi-step hepatocarcinogenesis from high-grade dysplastic nodule to classic hypervascular HCC. In accordance with this angiogenesis, the intranodular portal supply is decreased, whereas the intranodular arterial supply is first decreased during the early stage of hepatocarcinogenesis and then increased in parallel with increasing grade of malignancy of the nodules. On the other hand, the main drainage vessels of hepatocellular nodules change from hepatic veins to hepatic sinusoids and then to portal veins during multi-step hepatocarcinogenesis, mainly due to disappearance of the hepatic veins from the nodules. Therefore, in early HCC, no perinodular corona enhancement is seen on portal to equilibrium phase CT, but it is definite in hypervascular classical HCC. Corona enhancement is thicker in encapsulated HCC and thin in HCC without pseudocapsule. To understand these hemodynamic changes during multi-step hepatocarcinogenesis is important, especially for early diagnosis and treatment of HCCs.
KeywordsHepatocellular carcinoma Blood supply Multi-step hepatocarcinogenesis Early HCC Dysplastic nodule Liver
Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide. Approximately 80% of Japanese HCC cases are derived from HCV-associated liver cirrhosis and chronic hepatitis, and the remaining less than 20% of the patients are HBV positive. The patients with hepatitis B or C cirrhosis are especially classified as a very high-risk group. Ultrasonography is performed every 3–4 months for the very high-risk group. Because of the introduction of this surveillance system, the size of HCCs firstly detected during 2002–2003 (n = 33731) was less than 2 cm in 32.5% of all cases, 2.1–5.0 cm 47.0%, respectively . However, various types of hepatocellular nodules such as dysplastic nodule (DN) are also detected during screening procedures. Ultrasound and CT features of DNs and early HCCs are similar, and a precise differential diagnosis is impossible. Pathologically, human HCC develops in a multistep fashion from DN to classic hypervascular HCC. Therefore, for the early diagnosis of HCC, understanding of the concept of multi-step hepatocarcinogenesis and the sequential changes of imaging findings in accordance with multi-step hepatocarcinogenesis is important.
To understand the hemodynamics of HCC is important for the precise imaging diagnosis and treatment, because there is an intense correlation between its hemodynamic and pathophysiology. For this purpose, dynamic MDCT is most valuable because of its high spatial and contrast resolution. However, because of the dual blood supply of the liver and intravenous injection of the contrast medium, the precise analysis of hemodynamics by conventional MDCT is often difficult. By the introduction of dynamic CT during selective arteriography, including CT during arterial portography (CTAP) [2, 3] and CT during hepatic arteriography (CTHA) , it has become possible to visualize the distribution of the intra-hepatic portal and arterial blood flow separately with extremely high contrast resolution, and as a result, to analyze precisely the correlation between blood supply and pathophysiology. In this article, blood flow imaging features of HCC will be discussed based on the CTAP and CTHA imaging and pathophysiologic correlations with special reference to multi-step hepatocarcinogenesis.
Classification of hepatocellular nodules and multi-step hepatocarcinogenesis
The concept of multi-step hepatocarcinogenesis and related small hepatocellular nodules in the patients with chronic liver diseases, particularly those with cirrhosis or chronic hepatitis caused by hepatitis B or C viruses, was developed mainly in Japan. However, it had not been widely accepted throughout the world and the diagnostic criteria of these nodules different even among the world specialists. However, in 2009, the International Consensus Group for Hepatocellular Neoplasia organized by the world’s leading liver pathologists finally reached agreement .
According to this report, these nodules are divided into large regenerative nodule, low grade DN (L-DN), high-grade DN (H-DN), and HCC. In addition, small HCC (less than 2 cm) is divided into early HCC and progressed HCC. Early HCC has a vaguely nodular appearance and is well differentiated. Progressed HCC has a distinctly nodular pattern and is mostly moderately differentiated, often with evidence of microvascular invasion. L-DNs are vaguely or distinct nodular with mild increase in cell density and no cytologic atypia. H-DNs are more likely to show a vaguely nodular pattern with architectural and/or cytologic atypia, but the atypia is insufficient for a diagnosis of HCC. They show increased cell density, sometimes more than two times higher than the surrounding nontumoral liver, often with an irregular trabecular pattern. Unpaired arteries are found in most lesions, but usually not in great numbers. A nodule with largely H-DN features containing a subnodule of well-differentiated HCC can be seen. Early HCCs are vaguely nodular and are characterized by various combinations of the following major histologic features; (1) increased cell density more than two times that of the surrounding tissue, with an increased nuclear/cytoplasm ratio and irregular thin-trabecular pattern; (2) varying numbers of portal tracts within the nodule (intratumoral portal tracts); (3) pseudoglandular pattern; (4) diffuse fatty change; and (5) varying numbers of unpaired arteries. Any of the features listed above may be diffused throughout the lesion or may be restricted to an expansile subnodule (nodule-in-nodule). Most importantly, because all of these features may also be found in H-DNs, it is important to note that stromal invasion remains most helpful in differentiating early HCC from H-DNs. However, the application of these criteria is challenging because most histologic criteria are arrayed on a gradual spectrum and cannot be easily summarized as present or absent.
Because of these reasons as described above, it should be realized that there must be various degree of overlaps among imaging features of these nodules and they may show gradual changes during multi-step hepatocarcinogenesis.
Angiogenesis during multi-step hepatocarcinogenesis
Vascular endothelial growth factor (VEGF) is known to play a critical role in the neovascularization in the development and progression of malignant neoplasms [6, 7]. VEGF is produced by tumor cells, and its binding with VEGF receptors such as Flt-1 and Flk-1, which are expressed on vascular endothelial cells, leads to the proliferation and migration of endothelial cells. In addition, VEGF receptors expressed on tumor cells are involved in tumor proliferation in an autocrine loop via interaction with VEGF produced by the tumor cells themselves . Park et al.  reported that the expression of VEGF was correlated with angiogenesis and cell proliferation in hepatocarcinogenesis. On the other hand, tumors often encounter hypoxic conditions during their growth. Under such conditions, hypoxia inducible factor-1α (HIF-1α) promotes the transcriptional activity of angiogenesis-related molecules such as VEGF and erythropoietin by affecting the hypoxia response element and HIF-1α located in nuclei .
Multi-step changes of intranodular blood supply during hepatocarcinogenesis
To verify the histological background of the findings obtained by CTAP and CTHA, we analyzed morphometrically the vascular supply of DN and HCCs [10, 11], and suggested that the portal tracts including portal vein and hepatic artery were decreased in accordance with increasing grade of malignancy and virtually absent in HCCs. In contrast, abnormal arteries due to tumor angiogenesis developed in H-DN during the course of hepatocarcinogenesis, and were markedly increased in number in moderately differentiated HCCs.
Multi-step changes of drainage vessels (flow) during hepatocarcinogenesis
Hemodynamics of other hepatic cancers
Metastatic liver cancers show thin corona enhancement or early peritumoral enhancement on single-level dynamic CTHA . We named the former as “drainage pattern” and the latter as “arterio-portal (AP) shunt pattern”. In cases with drainage pattern, the tumor shows hypervascularity in early phase and thin peritumoral enhancement in late phase similar to hypervascular HCC without pseudocapsule, and the drainage route may be the connection between tumor sinusoids and hepatic sinusoids surrounding the tumor [14, 15]. In cases with AP shunt pattern, the tumor shows no definite enhancement except faint staining on the peripheral margin of the tumor, but early peritumoral enhancement with occasional wedge-shaped expansion is seen. The mechanism of this early enhancement is unknown, but peritumoral multicentric AP shunts due to the obstruction of the portal or hepatic venules can be one of the possible causes. Because abundant fibrous tissue is often contained in this kind of tumor, internal delayed enhancement is commonly associated. Mass-forming type of cholangiocarcinoma usually demonstrates AP shunt pattern. Among malignant primary liver cancer, cholangiolocellular carcinoma (bile ductular carcinoma) shows unique hemodynamics . It typically shows tumor hypervascularity with surrounding enhancement resembling AP shunt pattern in early phase and delayed internal enhancement on late phase, probably due to abundant cancer cells and fibrous tissues in the tumor with multiple entrapped portal tracts in the tumor (replacing infiltration type growth with the portal tracts incorporated into the tumor). Benign hypervascular hepatic masses such as cavernous hemanigoma, focal nodular hyperplasia (FNH) , angiomyolipoma and peliosis hepatis usually do not show corona enhancement, probably due to main drainage to hepatic vein. Two exceptions are hepatic adenoma and hypervascular hyperplastic nodule associated with alcoholic cirrhotic livers which commonly demonstrate corona enhancement . Understanding these hemodynamic differences among various kinds of hepatic mass lesions are important for differential diagnosis and treatment.
In conclusion, it is very important to know the hemodynamics of HCCs and related hepatocellular nodules for the understanding of pathophysiology and precise imaging diagnosis and treatment of HCCs. For this purpose, angiography-assisted CT is most valuable and accurate, but because of its invasiveness, blood flow imaging with contrast ultrasound, dynamic CT and MR imaging is necessary.
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