Imaging Features at the Periphery: Hemodynamics, Pathophysiology, and Effect on LI-RADS Categorization
Abstract
Liver lesions have different enhancement patterns at dynamic contrast-enhanced imaging. The Liver Imaging Reporting and Data System (LI-RADS) applies the enhancement kinetic of liver observations in its algorithms for imaging-based diagnosis of hepatocellular carcinoma (HCC) in at-risk populations. Therefore, careful analysis of the spatial and temporal features of these enhancement patterns is necessary to increase the accuracy of liver mass characterization. The authors focus on enhancement patterns that are found at or around the margins of liver observations—many of which are recognized and defined by LI-RADS, such as targetoid appearance, rim arterial phase hyperenhancement, peripheral washout, peripheral discontinuous nodular enhancement, enhancing capsule appearance, nonenhancing capsule appearance, corona enhancement, and periobservational arterioportal shunts—as well as peripheral and periobservational enhancement in the setting of posttreatment changes. Many of these are considered major or ancillary features of HCC, ancillary features of malignancy in general, features of non-HCC malignancy, features associated with benign entities, or features related to treatment response. Distinction between these different patterns of enhancement can help with achieving a more specific diagnosis of HCC and better assessment of response to local-regional therapy.
©RSNA, 2021
SA-CME LEARNING OBJECTIVES
After completing this journal-based SA-CME activity, participants will be able to:
■ Compare and contrast the techniques used for dynamic contrast-enhanced evaluation of the liver with various imaging modalities.
■ Describe the hemodynamics and pathophysiology of various peripheral imaging features that can be seen when evaluating hepatic observations at contrast-enhanced imaging.
■ Understand the mimics of hepatic observations with peripheral features and the associated pitfalls of LI-RADS in these scenarios.
Introduction
Hepatocellular carcinoma (HCC) is currently the fourth most common cause of cancer worldwide and the second leading cause of cancer-related mortality (1). The Liver Imaging Reporting and Data System (LI-RADS) allows noninvasive diagnosis of HCC in at-risk populations without the need for histopathologic confirmation (2). LI-RADS algorithms are based on radiologic features, derived primarily from multiphasic postcontrast imaging (3–7). Careful analysis of the enhancement kinetics of liver observations as well as the distribution and pattern of their enhancement is necessary to increase the accuracy of liver mass characterization. The histologic features, vascular supply, and vascular drainage of the observations affect their enhancement patterns and the resultant imaging features.
Historically, the presence of arterial phase hyperenhancement (APHE) and washout appearance were considered sufficient for diagnosis of HCC (8), but more recent evidence suggests that the morphology and pattern of enhancement as well as of washout are highly relevant to differentiate HCC from non-HCC malignancies (9), to distinguish recurrent HCC from posttreatment changes, and to potentially differentiate among certain subtypes of HCC (10). As such, LI-RADS version 2018 differentiates between different patterns of enhancement (eg, rim APHE vs nonrim APHE) to maintain high specificity for noninvasive diagnosis of HCC.
This article addresses our current understanding of enhancement patterns along the margins of liver observations and discusses their proposed underlying mechanism for each imaging modality (Table 1). We also review the approach to differentiating these entities. For the purposes of this article, we use the term peripheral to refer to imaging features intrinsic to a liver observation that are most pronounced at its periphery, the term peripheral capsule to refer to a rimlike structure distinguishable but not separable from the observation, and the term periobservational or perilesional to refer to imaging features surrounding and extrinsic to a liver observation.
Contrast-enhanced Liver Imaging Techniques
Multiphase contrast-enhanced imaging of the liver can be performed with CT, MRI, and US, provided that minimum acceptable technical parameters are met (29) (Table 2). The imaging modality and pharmacokinetics of the used contrast agent affect the appearance of liver observations (11,30). Regardless of the modality, imaging for HCC requires performance of multiple phases after injection of a contrast agent: late hepatic arterial phase (AP), portal venous phase (PVP), and subsequent phases including the equilibrium phase and delayed phase (DP) (when using extracellular contrast agents), transitional phase and hepatobiliary phase (HBP) (when using hepatobiliary contrast agents), or late phase (when using contrast-enhanced US [CEUS]).
The timing for these contrast-enhanced phases depends on the contrast agent used as well as patient and technical factors (29). Typically for CT and MRI, the late hepatic AP, PVP, and DP or transitional phase are performed with a 30–45-second, 60–75-second, and 3–5-minute delay after injection of contrast material, respectively (31). The HBP, which is specific to the MRI technique when using hepatobiliary agents, is typically performed with a 20-minute delay (32,33).
CEUS relies on agents composed of gas-filled particles encapsulated in a protein or lipid shell (microbubbles or microspheres). Microbubble contrast agents include octafluoropropane gas in a lipid shell, perfluorobutane gas with a phospholipid shell, perflutren in a shell made of human serum albumin, and sulfur hexafluoride gas with a phospholipid shell (34). These particles allow increased US echo generation within the blood pool, which enhances the vascular spaces and microcirculation within and between tissues (11,35). CEUS requires use of a contrast material–specific imaging mode, available as a software upgrade for most modern US systems (29).
Overview of Peripheral LI-RADS Features in Different Hemodynamic Phases
An algorithmic approach based on the temporal patterns of peripheral and periobservational enhancement and their morphology can be used to assess for the presence of LI-RADS features (Fig 1).
Visualization of a peripheral rim at noncontrast imaging, across all modalities, is due to central necrotic or cystic changes of the liver observation or to the presence of a capsule. A capsule is commonly hypoattenuating and hypointense at T1- or T2-weighted MRI when compared with the observation or its surrounding liver parenchyma (12,13).
Intravascular contrast material initially arrives at tissues supplied directly by large arterioles. Hyperenhancement during the AP at CT and MRI is due to densely concentrated arteries and arterioles. APHE during the late hepatic AP is due to rapid extravasation of contrast material through leaky capillaries into the interstitium, most commonly in the setting of inflammatory or neoplastic processes. By comparison, only the former mechanism is relevant to CEUS, as the microbubbles are too large to extravasate through even leaky capillaries and mainly contribute to enhancement if intravascular.
APHE at CT or MRI may qualify as an LI-RADS M (LR-M) (probably or definitely malignant, not necessarily HCC) feature, a major feature, ancillary features, or features of benign entities, depending on location and morphology (12,14). On the other hand, APHE at CEUS is due to increased vascular supply or vessel concentration relative to the center, such as in the case of peripheral vessels in a hemangioma or in peripheral vascular tissue with a necrotic, fibrous, or cystic core—for example, in malignancy or abscesses (13,15).
The PVP is defined by the arrival of contrast material into the portal venous system, which may coincide with the timing of arterially delivered contrast material accumulation in the interstitial tissues. Hypercellular malignant tissues that have a reduced volume of interstitial space will be hypoattenuating or hypointense to the background liver in the PVP and therefore show washout. The exact mechanism of washout at CT and MRI is not fully understood but is thought to be multifactorial, influenced by relative arterial blood flow, relative portal venous blood flow, and the relative volumes of the interstitial and vascular spaces.
Peripheral washout is due to the presence of tissues with high arterial flow, low portal venous flow, and small interstitial volumes at the periphery of a lesion. This pattern could be seen with cholangiocarcinoma, metastases, and some HCCs. Since this pattern is suggestive of cholangiocarcinoma and other non-HCC malignancies, it is considered an LR-M feature by LI-RADS version 2018 (12,14) (further discussed later). At CEUS, washout is purely a function of clearance of the contrast agent from the vascular space and is therefore variable and may be discordant with CT or MRI findings; differential accumulation of contrast material within the interstitial space does not play a role in CEUS (13,15).
In the DP at CT and MRI, contrast material has drained via venous outflow from most tissues but will continue to accumulate in certain areas, such as watery fibrotic tissues with large extracellular spaces. Therefore, enhancement in the DP may be due to the presence of fibrous tissue. When present along the periphery of a lesion, this feature is called an enhancing capsule (since the underlying histologic structure is thought to be either a true tumor capsule or a pseudocapsule), which is recognized by LI-RADS as a major feature of HCC (12,14).
Peripheral Observational Features
Targetoid Appearance
Targetoid appearance encompasses several imaging features that are suggestive of non-HCC malignancies. These features—which can be seen together or in isolation—include rim APHE, peripheral washout, delayed central enhancement, targetoid diffusion restriction, or targetoid appearance in the DP or HBP (Figs 2, 3) (16). Since these features are nontypical for HCC, they are recognized by LI-RADS version 2018 as LR-M features. Any of these features is sufficient to assign an LR-M category. The differential diagnosis for lesions with these features includes intrahepatic cholangiocarcinoma, combined HCC-cholangiocarcinoma, atypical HCC, and metastatic lesions (4,17). The underlying pathophysiology of these targetoid features is peripheral hypercellularity and central fibrosis or necrosis.
Rim APHE has been shown to be the most sensitive of all LR-M features for non-HCC malignancy, with sensitivity of 71% at MRI (17). Among non-HCC malignancies, it is the most sensitive LR-M feature for combined HCC-cholangiocarcinoma, with sensitivity of 58% and specificity of 85% at MRI (42,43). Benign entities such as infarct (Fig 6), abscess (Fig 7), and sclerosed hemangioma (Fig 8) may also exhibit rim APHE (44–46).
Differentiation of rim APHE from other peripheral enhancement patterns is important. Unlike rim APHE, enhancing capsule (which is a major feature of HCC) is a discrete structure from the lesion seen in the PVP or DP (further discussed later). In addition, the enhancing capsule will not be visible at CEUS (18). Rim APHE can also be confused with corona enhancement (which is an ancillary feature favoring malignancy). In contrast to rim APHE, corona enhancement has ill-defined borders (particularly along its outer edges) and involves the surrounding perilesional tissue. Rim APHE may be irregular and incomplete, mimicking a hemangioma. However, a hemangioma will have nodular and discontinuous peripheral enhancement during the AP.
Peripheral washout can be seen in mass-forming intrahepatic cholangiocarcinoma (Figs 9, 10). In contrast, abundant loose connective tissue in the central part of cholangiocarcinoma contains a high amount of extracellular volume, which results in delayed retention of extracellular contrast material at CT and MRI, further accentuating the peripheral washout. Atypical and scirrhous HCC has also been shown to have peripheral washout in some cases, although this is not classic (47).
Targetoid diffusion restriction is defined as concentric diffusion restriction at the periphery of an observation (Fig 3). Targetoid HBP appearance is another targetoid feature, referring to relative hyperintensity in the central portion of an observation during the HBP (16). This appearance is due to retention of contrast material in the central fibrotic portion of a lesion with mode-abundant extracellular space (20).
Peripheral Discontinuous Nodular Enhancement
Peripheral discontinuous nodular enhancement is the enhancement pattern characteristic of hemangioma. The nodular component of enhancement progressively increases in size centripetally and parallels the blood pool (Figs 11–12) (21). This type of enhancement pattern should not be confused with continuous peripheral irregular enhancement, which is a form of rim APHE and can be seen in non-HCC malignancies. Changes after local-regional treatment may also result in peripheral nodular enhancement (Fig 13). It should also be distinguished from satellite nodules surrounding an intrahepatic malignancy, which are a feature of intrahepatic metastasis associated with microvascular invasion (48–50).
Hemangiomas in cirrhotic liver may not exhibit the typical peripheral discontinuous nodular enhancement pattern. Hemangiomas in these patients may show rapid homogeneous enhancement or continuous peripheral nodular enhancement (21,51). Attention to other imaging findings (such as signal intensity characteristics on T2-weighted images) and comparison with prior imaging studies are helpful to differentiate atypical hemangiomas from malignant lesions. Over time, the hemangioma may undergo involution and sclerosis of vascular spaces and subsequently exhibit rim APHE (Fig 8) (51).
Peripheral Capsule
Enhancing Capsule Appearance
A fibrous capsule (FC) is specific to HCC and is rarely encountered with other tumors (52). FCs associated with HCC are composed almost entirely of collagen fibers and are thought to be perfused by portal venules (53); therefore, they tend not to enhance in earlier phases. After the PVP, FC enhancement gradually increases as contrast material slowly accumulates in the collagen matrix when extracellular contrast agents are used. As US contrast material does not accumulate in the extracellular space, FCs are not apparent at CEUS (11,22).
Occasionally, delayed peripheral or periobservational enhancement may occur owing to compressed tissue, in the absence of a true FC. This phenomenon is referred to as a pseudocapsule. Since true FCs cannot be reliably distinguished from pseudocapsules at imaging (54), LI-RADS uses the term enhancing capsule appearance or enhancing capsule to include both of these entities (6,23). The enhancing capsule is a major feature of HCC in the CT and MRI diagnostic algorithm.
It is important to accurately distinguish an enhancing capsule from background fibrosis in a cirrhotic liver. Therefore, to qualify as a major feature of HCC in the CT and MRI LI-RADS (2), an enhancing capsule must be thicker or more conspicuous than fibrosis around background nodules (2,5,16,23,24). Furthermore, the enhancing capsule appearance associated with HCC must be smooth in contour and uniform in thickness and must surround all or most of the observation at CT or MRI (Fig 14). These latter features are useful in helping distinguish enhancing FCs from periobservational perfusion-related phenomena.
Capsule formation is associated with progressed HCCs exhibiting expansile growth (Fig 15) (55), and the capsule is associated with a better prognosis when intact (4,56). Among all HCCs, an enhancing capsule may be seen in approximately 40%–75% of cases, with the high variability partially attributable to the fact that the capsule may not be discernible if hepatobiliary agents are used (23,24,57). Some studies have shown that small HCCs (≤2 cm) can have an enhancing capsule with an even higher frequency, with rates as high as 93%–96% (23,57). Therefore, a capsule can be an important imaging feature even in smaller observations.
Capsule appearance should be differentiated from other peripheral and periobservational enhancement patterns (Fig 15).
Nonenhancing Capsule Appearance
Nonenhancing capsule appearance is defined as a hypointense rim on T1- and T2-weighted images without appreciable enhancement in the postcontrast phases of CT and MRI (Fig 16) (4). It manifests as a hypointense rim in the HBP when hepatobiliary agents are used (4,24). The explanation of this finding is a fibrous capsule (FC) without appreciable enhancement at CT or MRI (3,24). The underlying pathophysiology remains unclear but may be due to decreased vascularity or smaller extracellular space in some FCs, such as in the setting of obstructed portal venous flow. This feature is considered an ancillary feature of HCC (2,16), although its effect on diagnostic accuracy in HCC is not well known (3).
A nonenhancing capsule should be thicker or more conspicuous than the fibrosis around the background regenerative nodules (3).
Periobservational Features
Corona Enhancement
Corona enhancement is an ancillary feature favoring malignancy in general but not HCC in particular (16). It refers to periobservational enhancement as a result of early venous drainage of tumor into nearby hepatic sinusoids or portal venules (3,55,59). The draining venules can sometimes be seen as bright branching structures along the route of drainage of the central hepatic nodule (59). This periobservational enhancement is ringlike with variable thickness and flame-shaped borders, can be contiguous with part or all of an observation (3,5,26), and peaks during the late AP and early PVP, when the tumor starts to wash out (Fig 18) (3,27).
Since corona enhancement is partially due to increased vascularity in the surrounding tissue, it may be recognized at CEUS (11,22). According to some reports, corona enhancement is found in 60%–81% of HCCs at MRI (3,60,61). Early HCCs drain via hepatic veins rather than via sinusoids or portal venules; therefore, corona enhancement will not be seen in early-stage HCCs (55,62).
Corona enhancement may be confused with other patterns. Flame-shaped or lobulated morphology with variable thickness (Fig 19) helps distinguish corona enhancement from an enhancing capsule, which is a smooth discrete structure with uniform thickness (3). Corona enhancement and capsule appearance may coexist. HCC with an FC that contains intracapsular portal venules may show corona enhancement via portal venules in addition to an enhancing capsule appearance in later phases. The altered venous drainage is most appreciable during the AP and PVP and may not be apparent in more delayed postcontrast phases when equilibrium is reached (63,64).
There may possibly be an increased incidence of micrometastatic disease within the enhancing corona, when present (6). As such, the presence of corona enhancement is an important prognostic factor, and the region with corona enhancement should be considered in treatment planning, whether by surgery or ablation (3,6,65).
Arterioportal Shunting
Arterioportal shunts are commonly due to aberrant vasculature in the setting of cirrhosis, owing to communication between a portal venule and hepatic arteriole with resultant alteration and redistribution of arterial flow. This communication can happen at different levels and in most instances is preexisting and physiologic. The existing connections between the arterioles and portal venules allow a compensatory increase in high-pressure arterial flow, via the hepatic arterial buffer response, whenever portal flow is decreased (66,67). Compromised portal flow can be the result of extrinsic compression, such as by a mass or thrombosis (18,28).
Arterioportal shunting classically manifests as wedge-shaped peripheral areas of transient hepatic intensity difference (THID) or transient hepatic attenuation difference (THAD) during the hepatic AP (Figs 20–22). This is best appreciated at multiphasic contrast-enhanced CT or MRI. Arterioportal shunts are not well seen at CEUS.
Focal shunts adjacent to a mass can occasionally mimic tumoral tissue (Fig 23). Attention to enhancement kinetics (such as lack of washout) and signal intensity with other sequences, when MRI is available, can help differentiate these entities (67). An arterioportal shunt associated with a mass may also mimic corona enhancement. These two phenomena can be distinguished, as a shunt will occur in the early AP, while corona enhancement will occur in the late AP and early PVP (16).
Local-Regional Therapy Response
Perilesional hyperemia is common after local-regional treatment of HCC and will typically resolve over time. Distinction between peripheral and perilesional imaging features after local-regional therapy has a profound effect on assignment of LI-RADS treatment response (LR-TR) viable, LR-TR equivocal, or LR-TR nonviable categories on the basis of the LI-RADS treatment response algorithm (Table 3) (16,72,73).
Nodular, masslike, or thick irregular tissue at or along the periphery of the treated lesion is concerning for viable tumor and is therefore categorized as LR-TR viable. Lack of any enhancement is compatible with LR-TR nonviable (Figs 24–25) (68,69). When findings are uncertain and not definitively compatible with perilesional hyperemia or residual viable tumor, it would be appropriate to assign a response category of LR-TR equivocal (Fig 24).
Posttreatment imaging studies should be carefully compared with pretreatment imaging studies to assess the overlap of posttreatment enhancement with the location and margins of the original tumor, to better distinguish between expected posttreatment changes and residual tumor. Viable HCC after local-regional treatment may demonstrate a posttreatment necrotic core with peripheral hyperenhancing tissue (68,72). Therefore, LR-TR viable observations may exhibit imaging features mimicking rim APHE (Figs 24–25), with peripheral irregular enhancement (Fig 13) similar to the pretreatment appearance, with nonperipheral washout (16).
Different local-regional treatments have different posttreatment imaging features that evolve over time. For example, after successful radiofrequency or microwave ablation, a tumor is expected to show no enhancement within the ablation zone (Figs 24–25). Any other pattern of enhancement is considered to be compatible with the LR-TR equivocal or LR-TR viable category (Fig 25) (70,71).
On the other hand, a thin rim of peripheral enhancement is often seen immediately after cryoablation, which is attributed to benign reactive hyperemia. This enhancement can persist for up to several months. Thickened or irregular rim enhancement is worrisome for viable tumor.
In the case of percutaneous ethanol ablation and transarterial bland or chemoembolization, a thin peripheral enhancing rim due to granulation tissue can persist for months, categorized as LR-TR nonviable. When ill-defined geographic perilesional enhancement surrounds a treated lesion, it may be due to perfusion alteration; if not readily distinguishable from nodular enhancing viable tumor at the periphery of a treated lesion, it should be considered LR-TR equivocal.
Transarterial radioembolization (TARE) has a decreased embolic effect compared with that of other transcatheter therapies. Combined with the gradual effects of radiation, TARE can result in persistent tumoral enhancement in the first 3–6 months of follow-up imaging (70). Perilesional parenchymal hyperemia, often in a segmental distribution, also occurs during this early follow-up period, further challenging interpretation for residual viable tumor after TARE.
Conclusion
Peripheral and periobservational enhancement patterns can be grouped into various categories with different implications for the final LI-RADS score of the observation. Familiarity with these patterns and their contributing pathophysiology can improve assessment and characterization of liver observations. The peripheral and periobservational emerging features that are not defined or recognized by LI-RADS at this time are beyond the scope of this review, but they may also prove valuable in differential diagnosis of liver observations.
Acknowledgment
We thank Kelly Kage for the illustrations.
1 Current address: Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Mass.
Presented as an education exhibit at the 2020 RSNA Annual Meeting.
For this journal-based SA-CME activity, the authors C.B.S., V.C., D.T.F., K.J.F., and K.M.E. have provided disclosures (see end of article); all other authors, the editor, and the reviewers have disclosed no relevant relationships.
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Article History
Received: Feb 17 2021Revision requested: May 18 2021
Revision received: June 04 2021
Accepted: June 10 2021
Published online: Sept 24 2021
Published in print: Oct 2021