JBR–BTR, 2007, 90: 475-481. HOW TO DIFFERENTIATE LIVER LESIONS IN CIRRHOSIS C. Bartolozzi, L. Crocetti, M.C. Della Pina1 The diagnosis of hepatocellular carcinoma is based on imaging examinations in combination with clinical and laboratory findings. Despite technological advances, imaging cirrhotic patients remains a challenging issue, since preneoplastic hepatocellular lesions, such as dysplastic nodules, mimic a small hepatocellular carcinoma. One of the key pathologic factors for differential diagnosis that is reflected in imaging appearances is the vascular supply to the lesion. It is accepted that imaging techniques may establish the diagnosis of hepatocellular carcinoma in nodules larger than 1 cm showing arterial hypervascularization and venous wash-out. In lesions that do not show a typical pattern, biopsy is still recommended. Contrast-enhanced ultrasound, spiral computed tomography or dynamic magnetic resonance imaging are required for characterization of lesions in cirrhotic liver. However, during the development of hepatocellular carcinoma, significant histological changes are present with or without an evident arterial supply of the nodule. Due to the ability of magnetic resonance to investigate differences in soft tissues and to exploit the properties of tissue-specific contrast agents, this imaging modality is particularly useful in the demonstration of the pathologic changes that take place at the histological level and at the level of the biliary and reticuloendothelial systems during carcinogenetic process in liver cirrhosis. Key-words: Liver, cirrhosis – Liver neoplasms. Hepatocellular carcinoma (HCC) is the fifth most frequent cancer in the world and the third most common cause of cancer mortality. HCCs mostly develop in patients with chronic liver disease caused by viral hepatitis, alcohol abuse and inborn metabolic errors. Eighty percent of all HCCs worldwide occur when the underlying chronic liver disease has reached the cirrhotic stage (1). The carcinogenesis in liver cirrhosis, i.e. the development and progression of a HCC in a chronically diseased liver, is a multistep and longterm process characterized by the progressive accumulation and interplay of genetic alterations and associated with the presence of distinct nodular lesions in the liver (2). These nodular lesions are associated with and can precede the growth and progression of well-differentiated HCCs (2). The availability of different imaging modalities help to investigate three parallel processes that take place during the carcinogenetic pathway towards dysplasia and full malignancy: the progressive capillarization of the sinusoids together with an increase in number of muscularized unpaired arterioles, the progressive loss of biliary polarization of the hepatocyte and the derangement of the microscopic secretory structure, and the progressive nodular depletion of Kupffer cells (3) . Purpose of this review is to provide information on the role that different imaging modalities have in the diagnosis of HCC in cirrhosis, investigating the vascular supply of the nodules and the pathologic changes that take place at the histological level and at the level of the biliary and reticuloendothelial systems. Assessment of blood supply to nodular lesions in cirrhosis The carcinogenesis in liver cirrhosis is morphologically associated with the presence of distinct nodular lesions in the liver (2). These hepatocellular nodules include hyperplastic lesions such as large regenerative nodules (LRNs) and neoplastic lesions such as low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs) (4,5). While LRNs are thought to carry a malignant potential not greater than that of the adjacent cirrhosis, neoplastic nodules (LGDNs and HGDNs) are considered precancerous (6). Clinical follow-up studies have revealed that a considerable proportion of HGDNs progress to a HCC within a few years (7). A recent detailed study on this subject showed that the risk of developing HCC is four-fold higher in patients having a HGDN; in contrast, the risk of malignant transformation of a LGDN is much lower (8). An LGDN is characterized by preserved hepatic architecture and lowgrade cytological atypias. Portal areas are present (3) and sometimes From: 1. Division of Diagnostic and Interventional Radiology, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy. Address for correspondence: Prof. C. Bartolozzi, M.D., Division of Diagnostic and Interventional Radiology, Pisa University Hospital, Via Roma 67, I-56125 Pisa, Italy. E-mail: [email protected] an increase in the number of unpaired arterioles can be detected (4,5). An HGDN is a neoplastic lesion with incipient malignancy. A number of architectural abnormalities can be documented and portal areas may be present or absent in the nodule. An increased number of unpaired arteries is usually detectable (9, 10). Therefore HGDNs have a vascular profile that partially overlaps with that of HCCs and distinction from well-differentiated HCC may be very difficult (9, 10). In well-differentiated HCC architectural abnormalities are associated with an abnormally high number of capillarized vessels, muscularized unpaired arterioles, and infiltration of portal tract / fibrous septa / veins by single hepatocytes (11). Sinusoidal capillarization and increase in number of non-triadal arteries give to the HCC nodules the typical arterial hypervascularization that is traditionally depicted by different imaging modalities (contrast enhanced computed tomography (CT), dynamic magnetic resonance imaging (MRI), contrast enhanced ultrasound (US)) and that is presently considered a fundamental noninvasive radiological criterion for the diagnosis of HCC in cirrhosis (12, 13). In the setting of a patient with cirrhosis a mass found incidentally or on screening US has a high likelihood of being HCC. The sequence of tests used to diagnose HCC depends on the size of the lesion (12) (Table I). Nodules found on US surveillance that are smaller than 1 cm should be followed with US at intervals from 3-6 months. Nodules between 1-2 cm should be investigated further with two dynamic studies, either CT scan, contrast- 476 JBR–BTR, 2007, 90 (6) isoechoic or hypoechoic appearance in the portal venous and delayed phases (Fig. 1) (18, 19). In contrast, LRN and DN usually does not show any early contrast uptake, and resemble the enhancement pattern of liver parenchyma in particular in the portal-venous and delayed phases. In two recent series, selective arterial enhancement at contrast US was observed in 91-96% of HCC lesions, confirming that contrast US may be a tool to show arterial neoangiogenesis of HCC (17, 18). Assuming findings at spiral CT as the gold standard, the sensitivity of contrast US in the detection of arterial hypervascularity was 97% in lesions larger than 3 cm, 92% in lesions ranging from 2 to 3 cm, 87% in lesions ranging from 1 to 2 cm, and 67% in lesions smaller than 1 cm (18). The vascular pattern of some nodules may be different from that at spiral CT with more nodules being positive only at contrastenhanced US. The proportion of these nodules may reach 19%, as reported in one study (19). This discrepancy may be because of the different vascular distribution of the US and CT contrast agents (being the first purely blood-pool contrast agents, and the latter intravascularinterstitial), the capacity of perfusional US, by working in continuous real-time, to detect hypervascularity lasting for only a short time or occurring very early, or both (19). Even at spiral CT typical HCC lesions shows clear-cut enhancement in the arterial phase and rapid wash-out in the portal venous and delayed phases (Fig. 2). In contrast, Table I. — Diagnostic criteria for HCC according to American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of Liver (EASL) (12). DIAGNOSTIC CRITERIA FOR HCC • Cyto-histological criteria • Non-invasive criteria (cirrhotic patients) 1. One imaging technique * Focal lesion > 2 cm with arterial hypervascularization and venous wash-out 2. Two coincident imaging techniques * Focal lesion 1-2 cm with arterial hypervascularization and venous wash-out * Three techniques considered: contrast US, CT, and dynamic MR imaging enhanced US or MRI with contrast. If the appearances are typical of HCC (i.e., hypervascular with washout in the portal/venous phase) in two techniques the lesion should be treated as an HCC. If the nodule is larger than 2 cm at initial diagnosis and has the typical features of HCC on a dynamic imaging technique, biopsy is not necessary for the diagnosis of HCC. Alternatively, if the AFP is > 200 ng/mL biopsy is also not required (12) (Table I). US is the imaging technique most commonly used worldwide for early detection of HCC in surveillance programs (12). The introduction of microbubble contrast agents and the development of contrast-specific scanning techniques have opened new prospects in liver US (14). Contrast-specific techniques produce images based on nonlinear acoustic effects of microbubbles A and display enhancement in grayscale, with high contrast and spatial resolution. The advent of secondgeneration agents and low mechanical index real-time scanning techniques has been instrumental in improving the easiness and the reproducibility of the examination (14-19) and has prompted the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of Liver (EASL) to introduce contrast-enhanced US in the diagnostic flow chart, as one of the imaging modalities useful to demonstrate the vascular pattern of nodules higher than 1 cm in diameter (12) (Table I). A typical HCC shows strong intratumoral enhancement in the arterial phase (i.e., within 25-35 seconds after the start of contrast injection) followed by rapid wash-out with B C Fig. 1. — HCC at contrast-enhanced US. The HCC nodule, with inhomogeneous hypo-hyperechoic appearance at baseline (A, arrow) shows strong intratumoral enhancement in the arterial phase (B, arrow) followed by rapid wash-out with slightly hypoechoic appearance in the delayed phase (C, arrow). LIVER LESIONS IN CIRRHOSIS — BARTOLOZZI et al A B 477 C D Fig. 2. — HCC at contrast-enhanced spiral CT. The HCC lesion in segment IV is barely visible at baseline scan (A), shows clear-cut enhancement in the arterial phase (B, arrow) and rapid wash-out in the portal venous (C, arrow) and delayed phases (D, arrow). A B C D Fig. 3. — HCC at dynamic MR imaging. The HCC lesion in segment II is hyperintense in T2-weighted image (A, arrow), hypointense in T1-weighted image (B, arrow), shows enhancement in Gadolinium-enhanced arterial phase (C, arrow) and results hypointense in the portal venous phase (D, arrow). LRN and DN usually fail to exhibit this feature and appear isoattenuating or hypoattenuating to surrounding liver parenchyma (20, 21). Identification of morphological features of HCC may support the diagnosis of HCC in questionable cases. Tumor capsule appears as a peripheral rim, which is hypoattenuating on unenhanced and arterial-phase images and hyperattenuating on delayed phase images. The CT detection rate of the capsule is strongly dependent on lesion size, and is low in small tumors because the capsule itself is thin and poorly developed (22). Internal mosaic architecture, with components showing various attenuation indexes on CT images, is another typical feature of HCC that, however, is usually detected in large nodular lesions. Invasion of portal vein branches, with partial or complete neoplastic thrombosis, is quite frequent in advanced tumors and is best shown on portal venous phase images. Neoplastic thrombi, however, may enhance in the arterial phase, like the main tumor (23). In a recent meta-analysis evaluating the accuracy of different imaging modalities in the diagnosis of HCC, spiral CT resulted to have a sensitivity of 67.5% (95% CI 55%- 80%) and a specificity of 92.5% (95%CI 89%-96%), abstracting and pooling the data coming form 10 studies using histopathology of the explanted liver as standard of reference (24). The variability of these results indicate the presence of a heterogeneity that is probably related to differences in technical details (e.g., variations in collimation and the contrast media infusion rate) and image interpretation, although no pertinent data were available. In five series that reported careful lesion-by-lesion imagingpathologic correlation in explanted livers, the sensitivity of spiral CT in detection of HCC lesions ranged 5279% (25-29). Interestingly, 92-100% of HCC lesions greater than 2 cm were diagnosed while only 10-43% of lesions smaller than 1 cm and 4465% of lesions of 1-2 cm were identified. In a recent series in which multidetector spiral CT was used, the sensitivity in diagnosing HCC of 1-2 cm was of 76% (29). False positive interpretations are usually caused by small lesions or pseudolesions (29-32). It is well known that hyperattenuating nodules may correspond to preneoplastic hepatocellular lesions, such as lLGDN and HGDNs (28, 30). Moreover small (less than 1.5 cm) flash-filling hemangiomas, which may enhance homogeneously in the arterial phase (30), can be misinterpreted as small HCC. However, these lesions usually do not exhibit contrast wash-out and show attenuation equivalent to that of the aorta during portal venous and delayed phase CT imaging (32). Nontumorous arterioportal shunts can also be a cause of pseudolesions, although in most cases they have the typical wedge-shaped and homogeneous appearance (with or without internal linear branching structures representing early opacification of portal veins during the arterial phase) and are isoattenuating or slightly hyperattenuating during the portal venous phase (33). Dynamic MRI well demonstrates the typical vascular features of overt HCC, that is, arterial phase enhancement with portal-venous and/or delayed phase wash-out (Fig. 3). This feature enables differentiation of frank HCC from LRN or DN, which usually are not hypervascular (Fig.4) (13). Nevertheless, as discussed for CT imaging, non-malignant hepatocellular lesions – especially HGDN – may show increased arterial blood supply and be indistinguishable from a small HCC. In addition, nontumorous arterioportal shunts may 478 JBR–BTR, 2007, 90 (6) A B C D E Fig. 4. — DN at dynamic MR imaging. The nodule in segment IV is hyperintense in T1-weighted image (A, arrow), does not show significant enhancement in the arterial phase (B, arrow), and results hypointense in the portal venous (C, arrow) and delayed phases (D, arrow). Dynamic subtraction image shows the lack of enhancement throughout the dynamic study (E, arrows). cause false-positive interpretations (34). In one study, the majority (93%) of hepatic arterial phase enhancing lesions less than 2 cm, that were occult at T2-weighted and portal and/or equilibrium phase MRI, had no correlative pathologic finding, even in patients with pathologically proved HCC (35). In series in which MRI findings were correlated with histopathologic results after thin-section slicing of the explanted liver, lesion-by-lesion analysis revealed a sensitivity of 3378%, with positive predictive values ranging 54-93% (25-27, 36, 37). In particular, 100% of HCC lesions greater that 2 cm were diagnosed while 4-71% of lesions smaller than 1 cm and 52-89% of lesions of 1-2 cm were identified. The clinical significance of these results is relevant. The ability to detect tumors larger than 2 cm with high sensitivity is significant because this size is the threshold for scoring additional priority points according to the Model of End-Stage Disease (38). State-of-the-art dynamic MRI outperforms single-detector spiral CT in the detection of small nodules: in one comparative study with explant correlation, the sensitivity for the identification of additional HCC lesions was significantly higher for MRI than for spiral CT in the range 12 cm (27). Assessment of histological changes in nodular lesions in cirrhosis During the development of HCC, significant histological changes are present with or without an evident arterial supply of the nodule. Due to the ability of MR to investigate differences in soft tissues and to exploit the properties of tissue-specific MR contrast agents, this imaging modality is particularly useful in the demonstration of the pathologic changes that take place at the histological level and the level of the A biliary and reticuloendothelial systems during carcinogenetic process in liver cirrhosis. In fact, HCC shows a variety of MRI features, that reflect the variable characteristics of this malignancy in tumor architecture, grading, stromal component, as well as intracellular content of certain substances, such as fat, glycogen, or metal ions, that greatly affect the appearance of the lesion on baseline T1-weighted and T2-weighted MR images (13) (Fig. 5, 6). The signal intensity may range from B Fig. 5. — Well-differentiated HCC at plain MR imaging. The nodule appears markedly hyperintense in T1-weighted image (A, arrow) due to the presence of glycoproteins, and isointense in T2-weighted image (B, arrow). LIVER LESIONS IN CIRRHOSIS — BARTOLOZZI et al A B Fig. 6. — HCC with fat deposits at plain MR imaging. The nodule appears hyperintense in T1-weighted in-phase image (A, arrow), and hypointense in T1-weighted out-of-phase image (B, arrow). hypointensity to isointensity to hyperintensity on T1-weighted images and from isointensity to hyperintensity on T2-weighted images. Hyperintensity on T1weighted images and isointensity on T2-weighted images are typical features of well-differentiated tumors, while hypointensity on T1weighted images and hyperintensity on T2-weighted images are usually associated with moderately or poorly-differentiated tumors (39). The signal intensity of HCC lesions may be inhomogeneous, reflecting the presence of areas with different degree of differentiation. Lesion signal intensity on baseline T1-weighted and T2-weighted images may help differentiate HCC from LRN or DN, although considerable overlap exists (39). During the carcinogenetic pathway towards dysplasia and full malignancy a progressive loss of biliary polarization of the hepatocyte with the derangement of the microscopic secretory structure takes place. While in LGDN the biliary domain of the cells is preserved and bile ducts are present in portal areas (3, 11), in HGDN biliary function can be partially impaired and bile ducts can be missing. In welldifferentiated HCC bile canaliculi are nearly always present between cells and bile pigment may be found in tumor cells or in dilated canaliculi. However, the organization of portal areas is completely lost and bile ducts are absent, causing the inefficient biliary drainage from the neoplastic tissue. Proliferation of welldifferentiated small HCCs is closely related to tumor dedifferentiation and moderately to poorly differentiated HCC tissues gradually replace the initial well-differentiated HCC (40). Biliary function is lost by tumoral cells and bile is rarely present in poorly differentiated HCC. Biliary function of hepatocellular nodule can be investigated by means of hepatobiliary or hepatocyte-selective contrast agents, which are paramagnetic compounds that are partially taken up by the hepatocytes and excreted in the biliary tract (41). In the hepatobiliary phase these agents produce sustained enhancement of liver parenchyma on T1-weighted images (41). HCC demonstrates variable uptake of hepatobiliary contrast 479 agents (42-44). This is a result of the fact that malignant cells of well-differentiated HCC may preserve hepatocellular function and may thus take up the contrast agent. Therefore, depending on the amount of residual hepatobiliary function of the cells and the degree of absence of portal areas in the tumor, the amount of uptake of the contrast agent can vary. HCC can be hyperintense, isointense or hypointense after administration of a hepatobiliary constrast-agent (4244). The HCC nodule is hypointense when the tumor cells fail to take up the contrast, while it is hyperintense when the biliary clearance of the contrast media is quicker in the surrounding parenchyma than in the nodule (42) (Fig. 7). Benign hepatocellular lesions, including LRNs and dysplastic nodules may have homogeneous, hyperintense enhancement simulating that of some HCC, and it can be difficult to differentiate these benign/premalignant lesions from HCC after the administration of hepatobiliary contrast agents (4345) (Fig. 8). Considering Kupffer cell population, it has been shown by histopathological studies that dysplastic lesions in cirrhosis possess an almost identical or sometimes slightly increased number of Kupffer cells when compared to cirrhotic parenchyma (46). In well differenti- A B C D E F Fig. 7. — HCC at Gd-EOB-DTPA enhanced MR imaging. The nodule in segment VII is slightly hyperintense in T2-weighted image (A, arrow), isointense in T1-weighted image (B, arrow), shows significant enhancement in the arterial phase (C, arrow) and results hypointense in the portal venous (D, arrow) and delayed (E, arrow) phases. In the hepatobiliary delayed phase (20 minutes) the nodule appears hypointense (F, arrow). 480 JBR–BTR, 2007, 90 (6) 10. 11. A B C 12. 13. D E F 14. Fig. 8. — DNs at Gd-EOB-DTPA enhanced MR imaging. Multiple nodules, (major located in segment VII , arrows), are slightly hypo- or isointense in T2-weighted image (A), hyperintense in T1-weighted image (B), do not show significant enhancement in the arterial phase (C) and result isointense in the portal venous (D) and delayed (E) phases. In the hepatobiliary delayed phase (20 minutes) the nodules appear iso- or hyperintense (F). ated HCC Kupffer cells may be present (46). In fact, in this small tumors endothelial cells morphologically resemble normal sinusoidal endothelial cells giving an environment similar to that of normal hepatic parenchyma (46). The amount of Kupffer cell in cancerous tissues decreases as tumor size increases and as grading of the tumor increases (46). MR reticuloendothelial-system (RES)-targeted contrast agents are superparamagnetic particles of iron oxide (SPIO) which produce distortions of local magnetic field resulting in signal loss on T2-weighted images. 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