Lesions In Cirrhosis Research Articles

Imaging Findings in Cirrhotic Liver: Pearls and Pitfalls for Diagnosis of Focal Benign and Malignant Lesions.

Cirrhosis is the end stage of chronic liver disease and causes architectural distortion and perfusional anomalies. It is a major risk factor for developing hepatocellular carcinoma (HCC). Common disease entities in noncirrhotic livers, such as hemangiomas, can be rare in cirrhotic livers, and benign entities such as confluent hepatic fibrosis and focal nodular hyperplasia-like lesions may mimic the appearance of malignancies,. HCC usually has typical imaging characteristics, such as the major features established by the Liver Imaging Reporting and Data System. However, HCC can also have a spectrum of atypical or uncommon appearances, such as cystic HCC, hypovascular HCC, or macroscopic fat-containing HCC. HCCs with certain genetic mutations such as CTNNB-1-mutated HCC can harbor unique imaging features not seen in other types of HCC. In addition, malignancies that are less common than HCC, such as cholangiocarcinoma and metastases, which can be difficult to differentiate, can still occur in cirrhotic livers. Atypical imaging features of benign and malignant lesions can be challenging to accurately diagnose. Therefore, familiarity with these features and an understanding of the prevalence of disease entities in cirrhotic livers are key in the daily practice of radiologists for evaluation of cirrhotic livers. The authors illustrate the typical and atypical features of benign and malignant lesions in cirrhosis and discuss the technical pitfalls and unique advantages associated with various imaging modalities in assessing cirrhotic livers, including noncontrast and contrast-enhanced US, CT, and MRI. Work of the U.S. Government published under an exclusive license with the RSNA. Quiz questions for this article are available in the supplemental material.

Research progress on cirrhosis reversal and recompensation

Previously, liver lesions in cirrhosis were considered irreversible, especially because the condition aggravated gradually after entering the decompensated phase, thus making it difficult to return to the compensated phase. At present, more and more evidence shows that some patients with decompensated liver cirrhosis can be recompensated after the cause is controlled and complications are managed. This article explores the research progress related to LC reversal and recompensation from three aspects: liver histopathology, liver function, and clinical complications.

Focal Liver Lesions other than Hepatocellular Carcinoma in Cirrhosis: Diagnostic Challenges.

Liver cirrhosis is associated with regenerative nodules and an increased risk of developing hepatocellular carcinoma (HCC). However, other benign and malignant liver lesions may also occur. Differentiating the other lesions from HCC is important for further therapeutic decisions. This review discusses the characteristics of non-HCC liver lesions in cirrhosis and their consequent appearance on contrast-enhanced ultrasonography (CEUS) with consideration of other imaging. Knowledge of this data would be helpful in avoiding misdiagnoses.

Focal liver lesions in cirrhosis: Role of contrast-enhanced ultrasonography.

Contrast-enhanced ultrasound (CEUS) represents a great innovation for the evaluation of focal liver lesions (FLLs). The main advantage of CEUS is the real-time imaging examination and the very low toxicity in patients with renal failure. Liver cirrhosis has been recognized as a major risk factor for the onset of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). HCC in liver cirrhosis develops as the last step of a complex that leads to the gradual transformation from regenerative nodule through dysplastic nodule to HCC. In patients with liver cirrhosis, a surveillance program is recommended consisting of ultrasound (US) for detecting small focal lesions. A wide spectrum of benign and malignant lesions other than HCC may be found in the cirrhotic liver and their differentiation is important to avoid errors in staging diseases that may preclude potentially curative therapies. Several published studies have explored the value of CEUS in liver cirrhosis and they have been shown to have excellent diagnostic and prognostic performances for the evaluation of non-invasive and efficient diagnosis of FLLs in patients at high risk for liver malignancies. The purpose of this article is to describe and discuss CEUS imaging findings of FLLs including HCC and ICC, all of which occur in cirrhotic livers with varying prevalence.

Hepatobiliary and Pancreatic: Liver lesions in cirrhosis: When to biopsy?

A 70-year-old man originally from Poland was referred to the hepatoma service for investigation of two liver lesions found during routine hepatocellular carcinoma (HCC) screening. Active medical history included both castrate sensitive metastatic prostate cancer and Child–Pugh A cirrhosis secondary to type 2 diabetes mellitus and previous heavy alcohol use. For his prostate cancer, he was treated with androgen deprivation therapy (ADT) with goserelin and received upfront docetaxel chemotherapy with prednisolone, before being enrolled on a clinical trial of enzalutamide. Prostate specific antigen (PSA) level remained suppressed at <0.01 μg/L on therapy. The patient was asymptomatic with no features of hepatic decompensation. His Child–Pugh status was A6. Biochemistry revealed preserved synthetic liver function; alpha fetoprotein (AFP) level was 5 μg/L. Computed tomography (CT) chest, abdomen, and pelvis demonstrated two 10-mm arterially enhancing hepatic nodules in segments 7/8 and 4a (Fig. 1a) with no portal venous washout (Fig. 1b). On magnetic resonance imaging (MRI) with Primovist, both lesions retained Primovist and hence both were indeterminate (Liver Imaging Reporting and Data System [LI-RADS]-3). Differentials at discussion at the Hepatoma Multidisciplinary meeting included regenerative or dysplastic nodules, given metastatic prostate cancer typically shows hypodensity on contrast-enhanced imaging. The nodules were followed up in tandem with the patient's prostate cancer at 6 monthly intervals and were stable on contrast-enhanced CT (LI-RADS 3) at 12 and 18 months (Fig. 1c) (LI-RADS 3) and therefore did not meet criteria for biopsy. In addition, there were numerous new pulmonary nodules. At 24 months however, CT revealed new lesions concerning for multifocal HCC (Fig. 1d), increase in the size of the segment 7 and 8 lesions with a new 1.5-cm lesion in segment 2 with washout (LI-RADS 5). The patient remained clinically stable and had a suppressed PSA level. He underwent an ultrasound guided biopsy of the segment 2 lesion. Histopathology was consistent with a diagnosis of metastatic small cell neuroendocrine carcinoma. The patient was commenced on single agent Carboplatin to treat his now de-differentiated small cell prostate cancer, to which he has responded well with interval response demonstrated on serial CT of pulmonary and liver lesions in addition to the bony disease on CT SPECT. The diagnosis of HCC is typically made on cross-sectional radiological findings without the need for confirmatory tissue in cirrhotics. LI-RADS scoring system has high sensitivity and specificity in diagnosing HCC in cirrhotic patients and is applicable to lesions ≥ 1 cm. Thus, biopsy is rarely required to diagnose HCC. Current guidelines support the use of the LI-RADS as a classification system for reporting liver lesions. The decision to biopsy is a contentious clinical question that is not definitively answered by current guidelines. Biopsy carries known risks of bleeding, tumor seeding, and failure to obtain adequate tissue for sampling. There are several mimics of HCC on imaging. Intrahepatic cholangiocarcinomas are known to mimic HCC. Tumors such as neuroendocrine tumors, squamous cell carcinoma metastases, and lung cancer metastases require pathological differentiation from HCC. Prostate cancer metastasis to the liver is heralded by hypoenhancement on contrast-enhanced imaging, whereas small cell prostate cancer itself is ill defined in imaging and there is currently a paucity of literature describing its imaging characteristics. It is aggressive in nature and 40–50% of cases are reported to occur in men with pre-existing prostate adenocarcinoma. The PSA is highly sensitive to progression of metastatic prostate adenocarcinoma but not to de-differentiated carcinoma, and it can therefore be difficult to differentiate de-differentiated prostate cancer from HCC in the cirrhotic patient. This case demonstrates that although current clinical practice guidelines deliver a safe approach to the diagnosis of HCC, alternative diagnoses can be missed if they carry similar characteristics on cross-sectional imaging, especially in cirrhotic patients and particularly in those with a cancer history. The role of biopsy in indeterminate liver lesions is often a discussion point and requires multidisciplinary team discussion, and the LI-RADS criteria should always be interpreted in the clinical context.

Uncommon imaging evolutions of focal liver lesions in cirrhosis.

The purpose of this article is to describe and illustrate uncommon imaging evolutions of benign (i.e., cyst, hemangioma, focal nodular hyperplasia-like nodules, and hepatic angiomyolipoma) and malignant (i.e., HCC and non HCC malignancies) lesions in a cirrhotic liver. The content highlights relevant pathogenesis and imaging clues for proper differential diagnosis. Revision of prior imaging and knowledge of these scenarios may help the abdominal radiologist to reach a noninvasive diagnosis and direct the patient to the most appropriate clinical management. Uncommon imaging evolutions of focal liver lesions in cirrhosis may represent a challenge for the abdominal radiologist, with atypical changes in size, and internal vascularization changes that may lead to misdiagnoses.

Spectrum of Pitfalls, Pseudolesions, and Potential Misdiagnoses in Cirrhosis.

The purposes of this article are to review a variety of pitfalls in liver imaging that can lead to the inaccurate diagnosis of focal hepatic lesions in cirrhosis, to describe the pathophysiologic processes of these pitfalls, and to provide specific clues for achieving the correct diagnoses. Cirrhosis complicates liver imaging. The distortion and replacement of normal liver parenchyma by fibrous and regenerative tissue can change the typical appearance of many benign lesions, causing them to be misinterpreted as malignancy. In addition, the high incidence and prevalence of hepatocellular carcinoma among patients with cirrhosis put radiologists on high alert for any suspicious findings, especially because not all hepatocellular carcinomas have a typical imaging appearance.

Current Role of Contrast-Enhanced Ultrasound in the Diagnosis of Hepatocellular Carcinoma

The routine use of microbubble ultrasound contrast agents for studies of the liver has overcome several limitations of conventional B-mode and Doppler ultrasound techniques. Contrast-enhanced patterns of liver lesions can be studied during all vascular phases (arterial, portal venous, late phases), as in contrast-enhanced computed tomography (CT) and contrast-enhanced magnetic resonance imaging (MRI). Furthermore, the use of contrastenhanced ultrasound (CEUS) to characterize focal lesions in cirrhosis has recently been recommended in the clinical practice guidelines issued by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). CEUS is a well-known, non-invasive technique that can be used to diagnose hepatocellular carcinoma (HCC) and can be performed in real time and under complete control of the ultrasound operator. In this review article, we summarize the basic concepts and techniques of CEUS, focusing on hepatic applications for the diagnosis of HCC. We also report the main guidelines regarding CEUS in the diagnosis of HCC, which have recently questioned its front-line role in clinical practice.

Optimized contrast-enhanced ultrasonography for characterization of focal liver lesions in cirrhosis: A single-center retrospective study.

Hepatocellular carcinoma (HCC) is the leading cause of death amongst cirrhotic patients. Its diagnosis and discrimination from non-HCC malignant lesions in cirrhosis includes contrast enhanced computed tomography (CECT), contrast enhanced magnetic resonance imaging (CEMRI), or, in selected cases, liver biopsy. The role of contrast-enhanced ultrasonography (CEUS) is still controversial. To evaluate whether, by selecting an appropriate 'time to wash-out' cut-off value, CEUS capability of discriminating between HCC and non-HCC malignancies in cirrhotic patients may be enhanced. We enrolled 282 cirrhotic patients who underwent CEUS at our institute, from January 2008 to January 2012, for focal liver lesions (FLLs) detected at ultrasound (US). We used liver biopsy and subsequent histological evaluation as the gold standard for correct classification of FLLs. We calculated the area under receiver operator characteristic curves for CEUS to distinguish patients with HCC from those with non-HCC malignancies. The best 'time to wash-out' cut-off values were selected. HISTOLOGICAL DIAGNOSIS OF FLLS WAS AS FOLLOWS: 34 benign lesions (i.e. 25 regenerative nodules and 9 dysplastic nodules) and 248 malignant lesions (223 well-to-moderately differentiated HCCs; 7 poorly-differentiated HCCs; 5 intrahepatic colangiocellular carcinomas (ICCs); 5 primary non-Hodgkin B-cell lymphomas (NHBLs); and 8 metastatic liver tumors). A time to wash-out > 55 s identified patients with HCC with the highest level of accuracy (92.7%). Similarly, a time to wash-out ≤ 55 s correctly identified the vast majority of the non-HCC malignancies (100% sensitivity, 98.2% specificity and diagnostic accuracy of 98.3%). CEUS is an accurate and safe procedure for discriminating FLLs in cirrhotic patients, especially when a cut-off time to wash-out of 55 s is chosen as a reference value.

Imaging of Liver Tumors in Patients with Chronic Liver Disease

Imaging techniques have become the accepted mainstay for the assessment of liver lesions in cirrhosis and, thanks to the improvement of their diagnostic capabilities in recent years, have further limited the need to resort to bioptic sampling. Hepatocellular carcinoma (HCC) is the most common cause of de-novo liver nodules in cirrhosis, and its diagnosis relies on noninvasive contrast-enhanced imaging studies. Diagnostic criteria have been extensively validated, and the vascular pattern deemed typical for HCC is an arterial hyperenhancement of the nodule followed by washout in the portal or late phase. This pattern provides a positive predictive value for the diagnosis of HCC of about 97 % in nodules in cirrhosis according to the literature. However, the need for a more precise differentiation from other malignancies arising in cirrhosis, making up the remaining about 3 %, and specifically intrahepatic cholangiocarcinoma, has over time led to changes in the recommendations for the noninvasive diagnosis of HCC in cirrhosis. The present review aims to report recently published interesting studies that have brought new insights into the problem of the characterization and differential diagnosis of liver tumors in chronic liver diseases.

Focal lesions in cirrhotic liver: what else beyond hepatocellular carcinoma?

Detection and characterization of focal lesions in the cirrhotic liver may pose a diagnostic dilemma. Several benign and malignant lesions may be found in a cirrhotic liver along with hepatocellular carcinoma (HCC), and may exhibit typical or atypical imaging features. In this pictorial essay, we illustrate computed tomography and magnetic resonance imaging findings of lesions such as simple bile duct cysts, hemangioma, focal nodular hyperplasia-like nodules, peribiliary cysts, intrahepatic cholangiocarcinoma, lymphoma, and metastases, all of which occur in cirrhotic livers with varying prevalences. Pseudolesions, such as perfusion anomalies, focal confluent fibrosis, and segmental hyperplasia, will also be discussed. Imaging characterization of non-HCC lesions in cirrhosis is important in formulating an accurate diagnosis and triaging the patient towards the most appropriate management.

Positron emission tomography scan for a hepatic mass

A 66-year-old male patient who is hepatitis C RNA positive, without cirrhosis, has been found to have a mass on ultrasound examination of the liver. Physical examination is unremarkable. The hemoglobin, white cell count and platelet counts are normal. The alkaline phosphatase is mildly elevated to 212 U/L(normal <115), the AST 112 U/L, and the ALT 128 U/L. The CA 19-9 is 82 U/mL (normal < 55 U/mL) and the alpha fetoprotein 12 ng /mL. A CT scan of the abdomen shows a vague mass in segment V of the liver without definite arterial enhancement. An MRI of the abdomen is carried out with contrast but the mass is still indeterminate on T1 and T2 imaging.

Focal liver lesions in cirrhosis: value of contrast-enhanced ultrasonography compared with Doppler ultrasound and α-fetoprotein levels

This study aimed to evaluate the diagnostic value of contrast-enhanced ultrasound (CEUS) in characterising focal liver lesions in cirrhosis and to validate its use in lesions discovered during surveillance for hepatocellular carcinoma (HCC). Between 2003 and 2006, 128 cirrhotic patients with focal liver lesions at baseline ultrasonography (US) were studied by power colour Doppler US (Doppler US) and CEUS. Serum alpha-fetoprotein (AFP) levels were assessed in all patients. Fine-needle biopsy or other reference modalities such as computed tomography (CT), magnetic resonance imaging (MRI) or digital subtraction angiography (DSA) were used as the gold standard. The accuracy of baseline US, Doppler US, AFP levels, combined US and AFP levels and combined US, Doppler US and CEUS in characterising focal liver lesions was assessed. Diagnostic performance was compared using the McNemar test. A total of 207 focal liver lesions (101 benign and 106 malignant) were identified in 128 patients. CEUS sensitivity and specificity for lesion characterisation were 96.2% and 97.0%, respectively, whereas its positive and negative predictive values were 97.1% and 96.1%. CEUS accuracy was 96.6%, higher than that of US (72.0%), Doppler US (70.0%), AFP levels (65.7%), combined US and Doppler US (70.0%) and combined US and AFP levels (90.3%). The differences between US and CEUS were statistically significant (p<0.05). CEUS can characterise focal liver lesions with 96.6% accuracy, a value higher than US, Doppler US, AFP levels, combined US and AFP levels and combined US and Doppler US. CEUS should therefore be used to characterise focal liver lesions detected during HCC surveillance of cirrhotic patients.

Guidelines for the use of contrast-enhanced ultrasound in hepatocellular carcinoma

Surveillance of patients at risk of developing hepatocellular carcinoma (HCC) relies on ultrasound (US) examinations performed at 6-month intervals. Early detection of HCC on a cirrhotic background is a challenging issue, since the US features of the different entities in the multi-step process of hepatocarcinogenesis – such as low-grade and high-grade dysplastic nodule – do overlap. Contrast-enhanced US allows reliable detection of arterial neo-angiogenesis associated with the malignant change. Several reports have shown that the ability of contrast-enhanced US to diagnose HCC currently approaches that of optimised multidetector computed tomography (CT) or dynamic magnetic resonance (MR) imaging protocols. The use of contrast-enhanced US to characterise nodular lesions in cirrhosis has recently been recommended by the clinical practice guidelines issued by the European Federation of Societies for Ultrasound in Medicine and Biology and the American Association for the Study of Liver Diseases. Contrast-enhanced US has also been successfully used to assess response of HCC to image-guided percutaneous ablation procedures. In this article, we discuss the advantages and limitations of contrast-enhanced US with respect to the other imaging modalities in the setting of HCC.

A morphometric model to minimize subjectivity in the histological assessment of hepatocellular carcinoma and its precursors in cirrhosis

To explore how morphometry can minimize subjectivity in the assessment of liver nodules in cirrhosis using a novel classification tool. Ten hepatocellular carcinoma (HCC), 6 large regenerative nodules (LRN), and 34 regenerative (cirrhotic) nodules (RN), obtained from cirrhotic explant livers, were analyzed using a Kontron-Zeiss KS400 image analyzer. We generated a morphometric model based on the analysis of volume fractions occupied by hepatocyte nuclei/cytoplasm, sinusoidal endothelium and lumen, neoplastic acini, fibrosis, centrilobular veins, portal arteries, veins and bile ducts, individual lesional arteries (smooth muscle actin), and capillarized sinusoids (CD34), and on surface fraction occupied by reticulin, and number in unit volume and size distribution of hepatocyte nuclei, and mean hepatocyte nucleus diameter and volume. Volume fraction of capillarized sinusoids and of individual lesional arteries were more prominent in HCC and LRNs, when compared with RN, whereas surface fraction of reticulin was markedly decreased in HCC. The morphometric values of these three features were integrated into our classification tool to construct a hybrid system, which reclassified the nodules in the same categories. Our novel hybrid classification tool may minimize subjectivity in the histological assessment of nodular lesions in cirrhosis.

Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma

I read with great interest the study by Forner et al.,1 which validates the American Association for the Study of Liver Disease guidelines. The methods and interpretation of the results, however, raise several concerns. It is well known that the biopsy of small nodular lesions in cirrhosis is not entirely reliable. In fact, needle placement may be difficult and a sampling error may occur. Moreover, it is very difficult to distinguish well-differentiated hepatocellular carcinoma (HCC) from dysplasia nodules on small biopsy specimens, because there is not a clear-cut dividing line between a dysplasia nodule and a well-differentiated tumor.2, 3 In the study by Forner et al.,1 however, a biopsy result was considered the gold standard, and the pathologic results of surgical samples in 60 HCC nodules were not well described. Were the abovementioned factors taken into account in the results of the study by Forner et al.?1 It is well known that cirrhosis is characterized by fibrous septa and many regenerative nodules. These features produce a coarse pattern on ultrasound, which may impair identification of small tumors.3 In the discussion of the study by Forner et al.,1 however, the authors stated that if they recruited patients with multiple nodules, the prevalence of HCC might have been higher. In fact, the patients with multiple nodules had commonly more regenerative nodules than HCC nodules. That is to say, if the authors recruited patients with multiple nodules, the prevalence of HCC might have been lower and the study would have validated the American Association for the Study of Liver Disease guidelines more effectively. Therefore, could the diagnosis of HCC nodules 20 mm or smaller be established without a positive biopsy if both contrast-enhanced ultrasound and magnetic resonance imaging are conclusive in patients with multiple nodules or a sole nodule? Ze-Zhou Song M.S.*, * Department of Ultrasound, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Glypican-3 Expression Distinguishes Small Hepatocellular Carcinomas From Cirrhosis, Dysplastic Nodules, and Focal Nodular Hyperplasia-like Nodules

Distinguishing small hepatocellular carcinoma (HCC) from other types of small focal lesions that occur in a cirrhotic liver can be difficult on the basis of morphologic features alone. We investigated whether the expression of glypican-3 (GPC3) could be an ancillary tool in the histopathologic diagnostic process. We performed immunohistochemistry for GPC3 on 16 low-grade dysplastic nodules, 33 high-grade dysplastic nodules, 13 focal nodular hyperplasia-like nodules, and 59 HCCs with a diameter less or equal to 3 cm present in the cirrhotic liver of 66 patients. Both resected lesions and lesions biopsied by needle were included and nonlesional cirrhotic parenchyma was also stained. In a subset of cases (23 samples of cirrhosis, 4 low-grade dysplastic nodules, 5 high-grade dysplastic nodules, 2 focal nodular hyperplasia-like nodules, and 18 HCCs), real time reverse transcriptase-polymerase chain reaction for GPC3 was performed. GPC3 expression was, both on immunohistochemistry and by real time reverse transcriptase-polymerase chain reaction, much higher in small HCCs than in cirrhosis and other types of small focal lesions, indicating that the transition from premalignant lesions to small HCC is associated with a sharp increase of GPC3 expression in a majority of cases. The sensitivity and specificity of a positive GPC3-staining for the diagnosis of HCC in small focal lesions was 0.77 and 0.96, respectively, in resected cases, and 0.83 and 1, respectively, for needle biopsies. Because the result of the staining was easily interpretable, immunohistochemistry for GPC3 is valuable ancillary tool in the histopathologic diagnosis of small focal lesions in cirrhosis.

Novel markers of cell kinetics to evaluate progression from cirrhosis to hepatocellular carcinoma

We investigated cell cycle kinetics of nodular lesions in cirrhosis to differentiate hepatocellular carcinoma (HCC) from its precursor lesions. Twelve small HCC, 10 regenerative (RN), six large regenerative (LRN), and five dysplastic nodules (DN), identified in explant cirrhotic livers of five consecutive patients transplanted at Royal Free Hospital in 2002. Immunoperoxidase for MCM2, geminin and Ki67 was performed and the percentage of positive cells counted. The proportion of cells expressing MCM2 was more than those expressing Ki67, which in turn was more than those expressing geminin (overall median=16%, 2% and 0.5%, respectively, P<0.001). There was a statistically significant trend of increasing Ki67 expression (P=0.006), from RN to HCC; this trend was not statistically significant for geminin (P=0.18) or MCM2 (P=0.51). The median percentage of cells expressing Ki67 was 1% in RN, 0.5% in LRN, 2.2% in DN and 5.4% in HCC. The combination of these markers identified four different cell kinetics patterns: 'resting' (G0 cells: MCM2 -ve, Ki67 -ve, geminin -ve); 'licensed' (MCM2 +ve, Ki67 -ve, geminin -ve); 'slowly growing' (G1 phase arrest, MCM2 +ve, Ki67 +ve, low (0.4%) geminin) and expanding (MCM2 +ve, Ki67 +ve, geminin +ve) nodules. The combination of MCM2, geminin and Ki67 could represent a valuable tool in the understanding of HCC progression in cirrhosis.

Contrast enhanced ultrasonography in characterization of focal liver lesions in cirrhosis: A prospective study of 96 patients

Contrast enhanced ultrasonography in characterization of focal liver lesions in cirrhosis: A prospective study of 96 patients

252 Nodular lesions in cirrhosis: Correlation between findings at contrast-enhanced ultrasound and pathologic examination of explanted livers

252 Nodular lesions in cirrhosis: Correlation between findings at contrast-enhanced ultrasound and pathologic examination of explanted livers