Advances in Understanding Hepatocellular Carcinoma Vasculature: Implications for Diagnosis, Prognostication, and Treatment

Abstract

Hepatocellular carcinoma (HCC) progresses through multiple stages of hepatocarcinogenesis, with each stage characterized by specific changes in vascular supply, drainage, and microvascular structure. These vascular changes significantly influence the imaging findings of HCC, enabling non-invasive diagnosis. Vascular changes in HCC are closely related to aggressive histological characteristics and treatment responses. Venous drainage from the tumor toward the portal vein in the surrounding liver facilitates vascular invasion, and the unique microvascular pattern of vessels that encapsulate the tumor cluster (known as a VETC pattern) promotes vascular invasion and metastasis. Systemic treatments for HCC, which are increasingly being used, primarily target angiogenesis and immune checkpoint pathways, which are closely intertwined. By understanding the complex relationship between histopathological vascular changes in hepatocarcinogenesis and their implications for imaging findings, radiologists can enhance the accuracy of imaging diagnosis and improve the prediction of prognosis and treatment response. This, in turn, will ultimately lead to better patient care.

INTRODUCTION

Liver cancer is the sixth most prevalent cancer worldwide and the third most common cause of cancer-related deaths in 2020. The incidence of and the number of deaths from liver cancer are anticipated to increase over the next 20 years [1,2]. Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and accounts for approximately 80% of all primary liver cancers [3].

Most contemporary guidelines recommend diagnosing HCC in high-risk patients using radiological hallmarks. These hallmarks are characterized by arterial phase hyperenhancement and washout and are based on histopathological changes in the vascular supply that occur during hepatocarcinogenesis [4,5,6]. During hepatocarcinogenesis, changes in vascular drainage contribute to microscopic and macroscopic vascular invasion, which is a significant determinant of treatment decisions and a well-established prognostic indicator [7]. Moreover, HCC treatment depends significantly on its vascular characteristics. Utilizing the dependence of HCC on the hepatic artery for blood supply, transarterial therapies such as transarterial chemoembolization and transarterial radioembolization have been employed [8,9,10]. In addition, HCC often exhibits high expression of angiogenic factors, such as vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2), leading to the frequent use of therapies targeting angiogenesis in systemic treatment [7,11]. Therefore, understanding the stepwise vascular changes that occur during the progression of hepatocarcinogenesis is crucial for diagnosing HCC, predicting prognosis, and determining treatment strategies [12].

In this review article, we explored the histopathological vascular evolution associated with hepatocarcinogenesis and its implications for imaging-based diagnosis, treatment, and prognosis of HCC.

Vascular Changes Associated With HCC Progression

HCC progresses in multiple steps, each characterized by distinctive histological and molecular changes. Histologically, progression follows a sequence from 1) regenerative nodules in a cirrhotic liver, 2) precancerous lesions, such as dysplastic nodules (DNs) or dysplastic foci, 3) early HCC, and 4) progressed HCC. It is important to note that progressive HCC is not a homogeneous group of tumors; instead, it exhibits various histological and molecular characteristics. In this review, we categorized progressed HCC into two stages based on tumor differentiation: moderately differentiated HCC (MD-HCC) and poorly differentiated HCC (PD-HCC). The vascular changes that occur at each stage of HCC are summarized in Figure 1.

Fig. 1. Summary of vascular changes and imaging implications in each stage of hepatocarcinogenesis. LC = liver cirrhosis, DN = dysplastic nodule, HCC = hepatocellular carcinoma, MD = moderately differentiated, PD = poorly differentiated, PV = portal vein, VETC = vessels that encapsulate tumor cluster.

Vascular System of Liver

The liver is nourished by a dual blood supply: the portal venous system, which delivers oxygen and nutrients, and the hepatic arteries. The portal vein supplies venous blood to the liver from the gastrointestinal tract and the spleen [13]. Meanwhile, the hepatic artery, portal vein, and bile duct run parallel to one another and are collectively referred to as the portal triad. Microscopically, the hepatic lobule is a basic structural unit of the liver. The hepatic vein lies at the center of the hepatic lobule and is surrounded by multiple portal triads that form a polygonal shape (Supplementary Fig. 1). Sinusoids, the liver microvasculature, connect the portal triad to the hepatic vein. Sinusoids are lined by liver sinusoidal endothelial cells, which are characterized by the absence of a basement membrane and the presence of fenestrations that facilitate the exchange of macromolecules between hepatocytes and blood [14].

Early Hepatocarcinogenesis Up to the Early HCC Stage

In early HCC, tumor cells acquire invasiveness and penetrate and destroy internal structures within the lesion, including hepatic veins, portal tracts, and fibrous septa [15]. This invasive growth of tumor cells is called stromal invasion and serves as histopathological evidence that early HCC is a malignant tumor [16]. Notably, as the intralesional hepatic vein lacks the surrounding fibrosis present around the portal triad, it is more vulnerable to destruction by stromal invasion. Consequently, as the number of intralesional hepatic veins within a lesion decreases, venous drainage from the lesion is redirected toward either the hepatic sinusoid or portal vein [17].

The progression of stromal invasion leads to the gradual destruction of the portal triad following the hepatic vein. Destruction of the portal triad causes a decrease in vascular supply, leading to intralesional hypoxia [18]. Hypoxia stimulates angiogenic signaling, including VEGF, which results in the growth of new arterial branches in HCC [19,20]. Unlike the original portal tracts, these newly developed arteries do not accompany the portal vein or bile duct and are thus referred to as unpaired arteries. The development of unpaired arteries begins in the early HCC stage and continues until MD-HCC. Therefore, it is common for the vascularity of a lesion to be lower than or similar to that of the surrounding non-tumor liver tissue during the early HCC stage [21]. Fatty changes occurring alongside a decrease in HCC vascularity are observed in approximately 40% of early HCC cases, particularly in lesions measuring 1 and 1.5 cm. At this stage, fatty changes often diffused throughout the lesion [18]. Although the lack of blood supply and increased cell density may cause intralesional hypoxia and fatty change, the molecular mechanism between the intralesional hypoxia and diffuse fatty changes remains elusive.

Sinusoidal capillarization refers to the acquisition of a capillary-like phenotype by liver sinusoidal endothelial cells, which includes the loss of fenestrae, accumulation of basement membranes, and alterations in cell-cell and cell-matrix interactions [22]. With sinusoidal capillarization, the expression of adhesion markers such as CD31 and CD34 increases, and these can be used to assess the distribution or density of capillarized sinusoids using immunohistochemistry [23]. Sinusoidal capillarization begins as a phenomenon of fibrogenesis and sinusoidal remodeling during liver cirrhosis, accelerates at the high-grade DN stage, and progresses rapidly to the early HCC and MD-HCC stages [20,24]. As sinusoidal capillarization is a gradual process, the degree of capillarization is not used to distinguish between early HCC and high-grade DNs [20,22,25].

Collectively, during the early HCC stage, tumor invasiveness triggers vascular changes. This stage is characterized by the destruction of preexisting vascular structures, accompanied by incomplete neoangiogenesis and sinusoidal capillarization. Owing to incomplete neoangiogenesis, arterial hyperenhancement is not commonly observed on CT or MRI in early HCC (Fig. 2). Additionally, only a small proportion (0%–31%) of early HCC exhibits arterial hyperenhancement [21,26,27]. Because early HCC does not show arterial hyperenhancement, it is challenging to diagnose using the diagnostic hallmarks of HCC [27]. Changes in vascular supply and drainage during this period are better visualized with CT during hepatic arteriography (CTHA) and CT during arterial portography (CTAP). In CTHA and CTAP, contrast media are injected into the hepatic artery and superior mesenteric artery through a catheter, respectively, allowing separate assessments of arterial and portal blood supplies [28]. Using these methods, it can be observed that both arterial and portal blood supplies are reduced in the early HCC stage [17].

Fig. 2. A 53-year-old male with alcoholic hepatitis and early HCC. A-F: Gadoxetic acid-enhanced MRI revealed an approximately 1.5-cm HCC in the right posterior liver (arrows). The lesion exhibits isointensity on the pre-contrast T1-weighted image (A), faint and partial hyperenhancement on the arterial phase (B), absence of washout on the portal phase (C), hypointensity on the hepatobiliary phase (D), mild hyperintensity on the diffusion-weighted image (b = 800) (E), and isointensity on the T2-weighted image (F). G: The lesion was identified as early HCC and displayed a vaguely nodular appearance in the gross specimen (arrows). H: A small number of unpaired arteries (arrowheads) were observed within the lesion (α-smooth muscle actin staining, ×100). I: Compared to the surrounding non-tumor liver (left side), partial sinusoidal capillarization occurred in the early HCC stage (right side) (CD34 staining, ×100). HCC = hepatocellular carcinoma.

Ancillary features such as high signal intensity on diffusion-weighted or T2-weighted images and hypointensity in the hepatobiliary phase can assist in differentiating early HCC from DNs [26,27]. A signal drop in the T1-opposed phase is also observed in 26%–53% of early HCC cases due to fatty changes [21,26]. However, fatty changes in HCC are not only limited to the early HCC stage but are also commonly observed in progressive HCC accompanied by fatty liver disease and metabolic syndrome [29].

Progressed HCC: MD-HCC

At this stage, the vascular changes that begin during early hepatocarcinogenesis are completed. The portal triad nearly disappears and, to compensate, the number of unpaired arteries significantly increases [20,22]. As a result, the HCC becomes almost entirely dependent on unpaired arteries for its vascular supply, resulting in hyperenhancement during the arterial phase compared to the non-tumor liver, which mainly relies on the portal vein for vascular supply [30,31]. Notably, the degree of arterial enhancement is significantly correlated with the density of unpaired arteries (Fig. 3) [32].

Fig. 3. A 61-year-old male with C-viral hepatitis and moderately differentiated HCC. A-C: CT revealed an approximately 2-cm HCC in the dome of the right liver. The lesion demonstrates isoattenuation on the pre-contrast image (A), hyperenhancement in the arterial phase (B), and an enhancing capsule and equivocal washout in the portal phase (C). D: The lesion was identified as moderately differentiated-HCC and exhibited high density of unpaired arteries (arrowheads) within the lesion (α-smooth muscle actin staining, ×200). E: Compared to the surrounding non-tumor liver (left side), completely capillarized capillary pattern microvessels were observed in the HCC (right side) (CD34 staining, ×100). HCC = hepatocellular carcinoma.

During the portal phase, the contrast media from the portal blood flow enhances the non-tumor liver, while HCC is not well enhanced because the contrast media that enters during the arterial phase exits, and there is limited incoming portal blood flow. This results in the relative hypoenhancement of HCC, known as washout. Other factors contributing to washout include high tumor cellularity with a small extracellular volume, expanded extracellular space of the fibrotic liver surrounding the tumor, and intrinsic hypoattenuation or hypointensity [33]. Many HCCs also exhibit a washout appearance in the delayed phase. However, the mechanism of washout observed in the delayed phase is not fully understood, although recent studies have indicated that variations in the extracellular volume percentage are significant [34].

Sinusoidal capillarization is observed in the predominant areas of most HCCs at this MD-HCC stage [20]. Notably, the density of capillarized sinusoids, often referred to as microvascular density (MVD), is associated with arterial phase hyperenhancement [35,36]. Additionally, as sinusoidal capillarization occurs in parallel with neoangiogenesis, it is uncertain whether their relationship is causal or merely correlative [20].

The hepatic vein nearly disappears in MD-HCC, and venous drainage occurs from the intratumoral sinusoids through the capsule to the peritumoral portal vein [17]. As a result, the area drained from the HCC is typically clearly visible on CTHA. As intrahepatic metastasis occurs primarily in this area, it can be utilized in planning surgical resections [37]. On dynamic CT and MRI, this phenomenon appears as a corona enhancement. However, unlike when employing CTHA, the observation of corona enhancement is limited due to the enhancement of the non-tumor liver in the portal phase.

Progressed HCC: PD-HCC Stage

The density of unpaired arteries in HCC, which is responsible for the intratumoral blood supply, is lower in PD-HCC than in MD-HCC [12,20,38]. Since unpaired artery density is closely associated with arterial hyperenhancement in HCC, a decrease in unpaired artery density leads to decreased arterial hyperenhancement [12,38]. However, the mechanism underlying the decrease in the density of unpaired arteries in PD-HCC is not well understood. A previous study suggested that the acquisition of hypervascularity at the MD-HCC stage led to a reduction in VEGF expression, resulting in decreased vascularity at the subsequent PD-HCC stage [38]. Notably, in the PD-HCC stage, the majority of cases display a heterogeneous enhancement pattern with a mix of hypervascular and hypovascular portions [38,39]. Furthermore, some tumors exhibit central hypovascularity with hyperenhancement in the outer rim, often referred to as rim-like enhancement (Fig. 4). In these cases, arterial phase rim enhancement is associated with various histological characteristics, including the macrotrabecular-massive (MTM) subtypes, fibrosis, and necrosis [40]. These features are believed to be additional factors contributing to the hypovascularity of PD-HCC.

Fig. 4. A 57-year-old male with B-viral hepatitis and poorly differentiated HCC. A-F: Gadoxetic acid–enhanced MRI revealed an approximately 4-cm HCC in liver segment 5. The lesion exhibits hypointensity in the pre-contrast T1-weighted image (A), rim enhancement in the arterial phase (B), hypointensity in the portal phase (C) and hepatobiliary phase (D), hyperintensity in the diffusion-weighted image (b = 800) (E), and hyperintensity on the T2-weighted image (F). G: The lesion was identified as poorly differentiated-HCC and displayed vessels that encapsulate the tumor cluster pattern and macrotrabecular patterns (CD34 staining, ±100). HCC = hepatocellular carcinoma.

As HCC progresses, the pattern and density of intratumoral sinusoidal vessels also change. Sinusoidal vessels can be classified into two patterns: a capillary pattern characterized by small, scattered microvessels with no or narrow lumens and a sinusoidal pattern featuring continuous branching and an obvious lumen structure [41]. The capillary pattern is more common in well-differentiated HCC (WD-HCC) and MD-HCC than in PD-HCC, whereas the incidence of a sinusoidal pattern progressively increases with HCC progression. Microvessels in the sinusoidal pattern are also associated with a lower MVD, and PD-HCC has been reported to have a lower MVD than MD-HCC [42,43]. Collectively, both unpaired arterial density and MVD decrease in PD-HCC, leading to reduced arterial hyperenhancement and more frequent tumor necrosis [12,43].

VETC Pattern: A Peculiar Microvascular Pattern Common in the Late Stage of Hepatocarcinogenesis

Recently, Fang et al. [44] described microvessels in a sinusoidal pattern that encapsulated and separated tumor clusters as “vessels that encapsulate the tumor cluster (VETC)” pattern. This is a specific type of sinusoidal pattern, and it is important to note that other sinusoidal patterns may not qualify as VETC patterns [45]. HCC with a VETC pattern (VETC-HCC) is commonly defined as HCC displaying any (≥1%–5%) VETC pattern within the tumor [44,46,47]. However, some studies recommend using a cutoff of 50%–55% of the tumor area for VETC, which is considered optimal for predicting prognosis [48,49]. The reported incidence of VETC-HCC varies widely, ranging from 22.0%–76.5% of HCC cases with a 1%–5% VETC area cutoff and 2.9%–36.5% with a 50%–55% cutoff [50].

Traditionally, the epithelial-mesenchymal transition (EMT) has been considered a crucial step in metastasis and is characterized by decreased cell-to-cell adhesion and increased migration and invasion, allowing cancer cells to enter the bloodstream [51]. However, the endothelium-encapsulated tumor clusters of VETC-HCC can directly enter the bloodstream without undergoing the complex invasion process associated with EMT (Fig. 5) [44,52]. Therefore, VETC-HCC can form tumor microemboli at intrahepatic and extrahepatic sites in an EMT-independent manner, frequently resulting in hematogenous spread, particularly to the lungs [48,53]. Additionally, VETC-HCC is associated with larger tumor sizes (>5 cm), more advanced stages, higher levels of serum alpha-fetoprotein and protein induced by vitamin K antagonist-II, and poorer differentiation [44,46,47,48].

Fig. 5. Schematic representation of two types of metastases of HCC. HCC = hepatocellular carcinoma, VETC = vessels that encapsulate tumor clusters, EMT = epithelial-mesenchymal transition.

VETC-HCC is frequently associated with MTM-HCC [48,54,55]. MTM-HCC is defined as HCC with a macrotrabecular pattern characterized by trabeculae thicker than six cells, predominating more than 50% of the tumor area [56]. MTM-HCC often features microvessels with a sinusoidal pattern, including VETC, and commonly shows the expression of hypoxia markers and necrosis [40,57]. Intralesional hypoxia and necrosis are believed to occur in central area of thick trabeculae that are located far from the vascular spaces, leading to insufficient oxygen supply. Due to its connection with several aggressive clinical and histological characteristics, VETC-HCC is linked to a poor prognosis following resection or transplantation [48,54].

The dynamic CT and MRI features of VETC-HCC are characterized by large tumor size (>5 cm), irregular rim-like enhancement in the arterial phase, and intratumoral necrosis (Fig. 4) [40,58,59]. Hypovascularity in VETC-HCC is speculated to arise from low MVD in HCCs exhibiting a sinusoidal pattern [40]. The pathological, clinical, and imaging characteristics of VETC-HCC are summarized in Table 1.

Table 1. Pathological, clinical, and imaging characteristics of VETC-HCC.

Pathological characteristics
	Micro and/or microvascular invasion
	Poor differentiation
	Macrotrabecular-massive subtype
Clinical characteristics
	Large tumor size
	Advanced stage
	High level of serum AFP and PIVKA-II
Imaging characteristics
	Large tumor size
	Irregular rim-like enhancement in the arterial phase
	Intratumoral necrosis

VETC-HCC = hepatocellular carcinoma with vessels that encapsulate tumor cluster pattern, AFP = alpha-fetoprotein, PIVKA-II = protein induced by vitamin K antagonist II

A previous report indicates that Ang2 is crucial for the formation of the VETC pattern. In a xenograft model of VETC-HCC, silencing Ang2 expression suppressed the VETC pattern and reduced metastasis [44]. Furthermore, HCC tissues with VETC patterns tend to exhibit high Ang2 expression [47,55]. Ang2, a proangiogenic factor in the angiopoietin/TIE2 pathway, plays a vital role in HCC angiogenesis and functions synergistically with the VEGF pathway [60]. Similar to the prevalence of HCCs with a VETC pattern in the advanced stages, the expression of Ang2 in HCC tissues typically occurs later than VEGF expression [61,62]. Notably, high Ang2 mRNA or protein expression in HCC tissues and high serum Ang2 levels are associated with poor prognoses [62,63,64].

Micro- and Macrovascular Invasion: HCC Dissemination via Altered Vascular Drainage

HCC commonly exhibits microvascular invasion (MiVI) and/or macrovascular invasion (MaVI), which indicate aggressive behavior, metastatic potential, and poor prognosis [7]. MiVI is defined as the presence of tumor emboli in the microscopic vessels of the tumor capsule or adjacent non-tumor liver [65]. However, the specific definition of MiVI differs significantly among studies, particularly in terms of the types of microvessels and their distance from the HCC where MiVI is observed [65].

MiVI can be observed in small, thin-walled vessels in the adjacent liver tissue or thicker-walled vessels such as the portal vein or hepatic vein. Some studies have also included the presence of tumor cells in the hepatic artery or lymphatic vessels as part of MiVI [65,66]. The reported prevalence of MiVI ranges widely from 15%–57% in surgically treated HCC, which is thought to reflect the variation in the stages of HCC included in the studies and the diversity in the definitions used [65]. Moreover, there have been attempts to further categorize MiVI pathologically, with reports indicating that the prognosis tends to be worse when MiVI is observed in multiple locations, involves a large number of invaded tumor cells, or includes invasion of microscopic portal veins [66,67].

MiVI is believed to result from tumor emboli originating from HCC that disseminate along the paths of blood drainage [68,69]. In progressed HCC, the drainage routes are primarily through the capsular microvessels and portal vein of the adjacent non-tumor liver, where MiVI commonly occurs [68]. Consequently, MiVI is believed to develop into a gross vascular invasion or intrahepatic metastasis. The fact that progressed HCC rarely drains directly into the hepatic vein might explain why HCC recurrence is much more common at intrahepatic sites than at extrahepatic sites.

MiVI is a widely recognized prognostic factor for HCC and is associated with poor disease-free and overall survival after hepatic resection and liver transplantation [65]. It is included as a poor prognostic factor in the 5th World Health Organization classification and 8th edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system [70,71]. One drawback of using MiVI as a prognostic factor is that it requires microscopic evaluation of the peritumoral area, meaning that it can only be identified after surgical treatment has been completed and cannot be assessed through biopsy before treatment. To overcome this limitation, numerous studies have aimed to predict MiVI non-invasively through imaging [72]. Imaging findings that indicate aggressive histopathological characteristics of HCC, such as large tumor size (>5 cm), multifocality, arterial phase rim enhancement, and non-smooth tumor margins, have been reported to be associated with MiVI (Fig. 6) [39,72]. Imaging features such as arterial phase peritumoral enhancement and peritumoral hypointensity in the hepatobiliary phase are also linked to MiVI and are thought to reflect peritumoral perfusion abnormalities caused by MiVI [39]. These imaging findings can be evaluated before treatment, potentially aiding in deciding between surgical resection and ablation or in assessing candidates for liver transplantation in the management of HCC [73,74,75].

Fig. 6. A 54-year-old man with moderately differentiated HCC with microvascular invasion and a satellite nodule. A-F: Gadoxetic acid-enhanced MRI revealed an approximately 3-cm HCC in liver segment 5/6. The lesion exhibits hypointensity on the pre-contrast T1-weighted image (A), hyperenhancement in the arterial phase (B), hypointensity in the portal phase (C) and hepatobiliary phase (D), hyperintensity in the diffusion-weighted image (b = 800) (E), and hyperintensity on the T2-weighted image (F). The lesion shows arterial phase peritumoral enhancement and peritumoral hypointensity in the hepatobiliary phase (arrows) and a non-smooth tumor margin in the portal and hepatobiliary phases, suggesting a high risk of microvascular invasion. A satellite nodule is observed in the area where the peritumoral change occurred (arrowheads). HCC = hepatocellular carcinoma.

MaVI is defined as the presence of a tumor in a major vessel that can be identified during macroscopic examination or imaging. MaVI is also a well-known poor prognostic factor and is part of established staging systems such as the Barcelona Clinic Liver Cancer (BCLC) classification, AJCC TNM stage, and selection criteria for liver transplantation [7,71,76]. The presence of MaVI not only affects tumor staging but is also crucial in making treatment decisions [77]. In HCC, MaVI predominantly presents as tumor thrombosis within the portal or hepatic veins. Although a hepatic mass accompanied by tumor in vein (TIV) often suggests HCC, a similar appearance can occur in intrahepatic cholangiocarcinoma (CCA) or combined HCC-CCA [78]. Among HCC patients, TIV is observed in 7%–60% of cases and is especially common in HCC displaying an infiltrative appearance, where it is seen in 68%–100% of such cases [77,79,80]. In instances where infiltrative HCC, it can mimic cirrhotic nodules, displaying a “cirrhotomimetic” appearance. Therefore, the presence of TIV can serve as a useful diagnostic clue for infiltrative HCC [79].

In patients with HCC, bland thrombosis may arise from portal hypertension or venous obstruction caused by the HCC [77]. Therefore, distinguishing between branch thrombosis and TIV is clinically important. Key CT and MRI features for differentiating TIV from bland thrombosis include unequivocal enhancement, an ill-defined venous wall, contiguity with the hepatic mass, restricted diffusion, shunting to the intravenous space, and signal intensity similar to that of the hepatic mass [77,81]. Notably, CT and MRI display a sensitivity of 62%–93% and specificity of 87%–100% for TIV. Overall, although their diagnostic accuracies are similar, MRI is known to have a marginally better sensitivity [82,83,84,85].

Systemic Treatment: Implication of Angiogenic Factors and Immunovascular Phenotype

Systemic therapy is recommended for advanced-stage (BCLC stage C) HCC. Sorafenib was the first systemic agent approved for HCC, and lenvatinib was later approved as a first-line drug after demonstrating non-inferiority to sorafenib [86,87]. Regorafenib serves as a second-line treatment, offering survival benefits to patients who show disease progression after sorafenib therapy [88]. HCC, characterized by its hypervascular nature, exhibits a high expression of angiogenic factors. The approved therapeutic agents target a variety of angiogenic factors: sorafenib targets VEGFR1-3 and PDGFR-β; lenvatinib targets VEGFR1-3, FGFR1-4, and PDGFR-α; regorafenib targets VEGFR1-3, PDGFR-β, FGFR1, and TIE2 [89]. Other second-line agents such as ramucirumab and cabozantinib also inhibit angiogenic factors such as VEGFR2 or TIE2 [89,90].

The scheme of systemic therapy for HCC has recently shifted toward immunotherapy, with atezolizumab-bevacizumab and durvalumab-tremelimumab combination therapies recommended as first-line drugs and sorafenib, lenvatinib, or durvalumab monotherapies suggested only when the former are not feasible [7]. Atezolizumab is an anti-PD-L1 antibody and immune checkpoint inhibitor, whereas bevacizumab is an anti-VEGFA antibody that targets the angiogenic factor VEGFA [90]. The combination of atezolizumab-bevacizumab not only provides anti-angiogenic effects but also enhances anticancer immunity in the immunosuppressed tumor microenvironment of HCC, creating synergy with atezolizumab [91]. In contrast, durvalumab and tremelimumab, which target anti-PD-L1 and anti-CTLA4 respectively, are immune checkpoint inhibitors [90,92]. Collectively, antiangiogenic therapy and immunotherapy are the two main types of systemic therapies for HCC (Fig. 7).

Fig. 7. Inhibition of angiogenic and immune checkpoint pathways by systemic therapeutic agents for HCC. HCC = hepatocellular carcinoma, CTLA4 = cytotoxic T-lymphocyte associated protein 4, PD1 = programmed cell death protein 1, PD-L1 = programmed cell death-ligand 1, VEGFA = vascular endothelial growth factor A, FGFR = fibroblast growth factor receptor, PDGFR = platelet-derived growth factor receptor, VEGFR = vascular endothelial growth factor receptor.

Interestingly, the vascular and immune phenotypes within the HCC microenvironment are closely intertwined, allowing classification into four groups: immune-high/angiostatic, immune-mid/angio-mid, immune-low/angiogenic, and immune-low/angio-low phenotypes [55]. The immune-high/angiostatic group is characterized by high lymphocyte infiltration and low expression of angiogenic factors, whereas the immune-low/angiogenic group exhibits low lymphocyte infiltration, high expression of angiogenic factors, histologic patterns of VETC and MTM, and frequent mutations in CTNNB1. Understanding the pathological and molecular diversity of HCC is crucial for determining the optimal sequence for systemic therapies. Indeed, VETC-HCC, recognized for its high expression of angiogenic factors, benefits from sorafenib treatment, whereas non-VETC-HCC does not [46]. Another report suggested that HCC with arterial phase rim enhancement, which is known to have aggressive clinicopathological characteristics, showed a more favorable response to atezolizumab-bevacizumab treatment [93]. However, research on therapeutic tailoring based on pathological, molecular, and imaging phenotypes of HCC is limited.

Summary and Future Perspectives

Vascular changes in HCC represent a complex, multistep process that occurs during hepatocarcinogenesis. The reliance of HCC on the hepatic artery for vascular supply is its primary cause of its diagnostic hallmark. In the early stages of HCC, typical imaging characteristics are often absent due to immature changes in the vascular supply. Hypovascularity and fatty acid changes are also observed more frequently. In the PD-HCC stage, dependence on the arterial vascular supply decreases while microvessels transform into a sinusoidal pattern. VETC-HCC, often emerging in the PD-HCC stage, displays atypical imaging features such as large tumor size, arterial phase rim enhancement, and necrosis. In HCC, along with changes in the vascular supply, there are also alterations in vascular drainage, with drainage transitioning from the hepatic vein to the portal vein of the surrounding non-tumor liver. Following these altered vascular drainage routes, tumor emboli frequently occur in the small vessels of the adjacent non-tumorous liver, a phenomenon known as MiVI. MiVI can progress to MaVI or intrahepatic metastasis.

The vascular changes that occur during multistep hepatocarcinogenesis lead to various imaging findings in HCC. The most widely used application of these imaging findings in clinical practice is the diagnosis of HCC [4,5,6]. Additionally, features such as fatty changes, commonly observed in early HCC, and corona enhancement, observed in progressed HCC, are also recommended as ancillary diagnostic features.

VETC-HCC and MiVI, which are commonly observed in the late stages of hepatocarcinogenesis, are well-known poor prognostic factors, and their associated imaging findings can be useful for predicting HCC prognosis [39,72]. Previous studies have suggested that these imaging findings are useful for the prognostic prediction of pathological findings [94]. However, most of these studies were retrospective, and multicenter prospective evidence is lacking. Another issue is that the evaluation of these imaging findings by radiologists is often subjective, leading to low inter-reader agreement [95].

Systemic therapy is increasingly used to treat HCC, with the most approved systemic agents targeting angiogenic or immune checkpoint pathways. Interestingly, the vascular phenotype and immune microenvironment of HCC are closely related, suggesting that imaging findings may predict the response to systemic therapy. Even when treated with atezolizumab-bevacizumab, the current first-line agent for HCC, 19%–37% of patients show no response and experience progressive disease after the first cycle [93,96,97]. As most systemic agents for HCC are costly, a reliable imaging biomarker for response prediction and optimization of the sequence of systemic agents is urgently needed for HCC treatment.

In conclusion, by understanding the intricate connections between histopathological vascular evolution and its implications for imaging findings in hepatocarcinogenesis, radiologists can enhance diagnostic accuracy and prognostic prediction, ultimately improving patient care.

Supplement

The Supplement is available with this article at https://doi.org/10.3348/kjr.2024.0307.