Contrast-enhanced Doppler ultrasonography in the diagnosis of hepatocellular carcinoma and premalignant lesions in patients with cirrhosis.

Hepatocellular carcinogenesis in cirrhosis is a multistage process that includes large regenerative nodules, dysplastic nodules, and hepatocarcinoma. The aim of this study was to establish whether contrast-enhanced Doppler ultrasonography (US) is able to distinguish between early hepatocellular carcinoma (HCC) and small nonmalignant nodules in cirrhosis. Between January 1998 and December 1999, 500 cirrhotic patients with no previous history of HCC or evidence of hepatic focal lesions were enrolled and prospectively followed-up with US every 6 months until December 2000. Sixty-one patients developed focal lesions, 12 multifocal, and 49 monofocal. Biopsy of focal lesions, contrast-enhanced Doppler US, and spiral computed tomography (CT) were performed in 41 consecutive patients with small (<3 cm) monofocal lesions. Twenty nodules were diagnosed as HCC and 21 as nonmalignant (14 large regenerative nodules, 3 low-grade, and 4 high-grade dysplastic nodules) by liver biopsy. Intratumoral arterial blood flow was detected in 19 of 20 (95%) HCC and 6 of 21 (28%) nonmalignant nodules by contrast-enhanced Doppler US (P<.0001). The mean peak resistance and pulsatility indices were 0.82 +/- 0.09 and 1.56 +/- 0.2 in HCC and 0.62 +/- 0.08 and 0.82 +/- 0.08 in dysplastic lesions (P =.002 and.0001), respectively. Spiral CT revealed arterial perfusion in 19 of 20 HCC and in 4 of 21 nonmalignant nodules (high-grade dysplastic nodules). Four of the apparently false-positive nodules at enhanced Doppler US were high-grade dysplastic nodules and 2 evolved to HCC during follow-up. In conclusion, contrast-enhanced Doppler US is a noninvasive, very sensitive technique in differentiating malignant and premalignant lesions from nonmalignant focal lesions in the liver.     

Radiologic diagnosis of hepatocellular carcinoma

Substantial recent technologic improvements in CT scanning, US scanning, and MR imaging, together with advances in the understanding of the optimal application of contrast administration techniques, have facilitated advances in radiologic imaging detection for HCC diagnosis. Despite a large number of earlier publications reporting a high sensitivity for imaging detection of HCC, more recent screening studies of large cirrhotic populations confirm that only 37% to 45% of HCC tumor nodules are detected by CT scanning, US scanning, or MR imaging. Future investigation will include efforts to improve the detection of small tumors and to characterize with greater specificity the spectrum of nodular changes that occur with cirrhosis. Although several small series have attempted to characterize cirrhotic nodules by evaluating the relative arterial or portal blood supply, these preliminary results require substantiation with larger series. Continued technologic advances such as multidetector helical CT scanning and new US and MR contrast agents under investigation may improve the imaging characterization of cirrhotic nodules.     

Early detection of hepatocellular carcinoma in patients with cirrhosis by alphafetoprotein, ultrasound and fine-needle biopsy

Hepatocellular carcinoma (HCC) may be detected at a relatively early stage in patients with liver cirrhosis regularly followed by screening programs using ultrasonography (US) and alpha-fetoprotein (AFP) measurement. Using both tests in 214 consecutive cirrhotic patients with no clinical signs of liver cancer, we detected HCC in 20 cases (9.4%). The sensitivity of US was greater (85%) than that of AFP (75%), and the combination of the two methods had a sensitivity of 100%. Only 50% of patients with focal liver lesions at US had a final diagnosis of HCC that was obtained in the majority of cases by US-guided fine needle biopsy.     

Magnetic resonance imaging of the cirrhotic liver: An update

Noninvasive imaging has become the standard for hepatocellular carcinoma(HCC) diagnosis in cirrhotic livers. In this review paper, we go over the basics of MR imaging in cirrhotic livers and describe the imaging appearance of a spectrum of hepatic nodules marking the progression from regenerative nodules to low- and high-grade dysplastic nodules, and ultimately to HCCs. We detail and illustrate the typical imaging appearancesof different types of HCC including focal, multifocal, massive, diffuse/infiltrative, and intra-hepatic metastases; with emphasis on the diagnostic value of MR in imaging these lesions. We also shed some light on liver imaging reporting and data system, and the role of different magnetic resonance imaging(MRI) contrast agents and future MRI techniques including the use of advanced MR pulse sequences and utilization of hepatocyte-specific MRI contrast agents, and how they might contribute to improving the diagnostic performance of MRI in early stage HCC diagnosis.     

Imaging diagnosis

The diagnosis of hepatocellular carcinoma (HCC) is based on imaging examinations in combination with clinical and laboratory findings. Despite technological advances, imaging cirrhotic patients remains a challenging issue because nonmalignant hepatocellular lesions, such as dysplastic nodules, mimic a small HCC. 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 HCC in nodules larger than 2 cm showing characteristic arterial hypervascularization. In lesions ranging from 1 to 2 cm, biopsy is still recommended, although a negative response can never be used to rule out malignancy completely. Although ultrasonography is widely accepted for HCC surveillance, spiral computed tomography (CT) or dynamic magnetic resonance imaging is required for diagnostic confirmation and intrahepatic tumor staging. These examinations have replaced invasive procedures, such as lipiodol CT, but remain relatively insensitive for the detection of tiny HCC lesions and tumor vascular invasion into peripheral portal vein branches.     

Adult cirrhotic liver explants: Precancerous lesions and undetected small hepatocellular carcinomas

BACKGROUND & AIMS: Despite recent advances in imaging techniques of the liver, it remains difficult to detect small precancerous lesions or hepatocellular carcinomas (HCCs) in cirrhotic livers. The goal of this study was to determine the prevalence of undetected small HCCs in liver explants of adult cirrhotic patients undergoing liver transplantation and to evaluate the association of HCCs with hepatic lesions considered premalignant. METHODS: Eighty consecutive liver explants were analyzed for the presence of macroscopically atypical nodules, which were then pathologically described as macroregenerative nodules, high-grade dysplastic nodules, areas of small liver cell dysplasia, and HCCs. RESULTS: The prevalence of HCC was 17.5% with a mean size of 11.6 mm. HCCs were more frequently found in men (22%) than in women (4.8%; P < 0.05) and in patients older than 50 years at the time of liver transplantation (35.7% vs. 7.7% in patients younger than 50 years; P < 0.05). The prevalence of HCCs was identical in alcoholic and viral cirrhosis. HCC nodules were significantly associated with the presence of high-grade dysplastic nodules. CONCLUSIONS: Small HCCs and precancerous lesions are frequently found in cirrhotic liver explants, especially in men older than 50 years. This finding should be included in the decision-making analysis for liver transplantation. (Gastroenterology 1996 Dec;111(6):1587-92)     

Imaging of hepatocellular carcinoma

Recent improvements in the treatment of hepatocellular carcinoma (HCC) have resulted in a need to identify the disease at an early stage. The wide range of imaging techniques available reflects the difficulty in demonstrating small HCC, particularly in the cirrhotic liver. This article reviews the current imaging techniques available for the diagnosis of HCC.     

Das hepatozellul?re Karzinom aus der Sicht des Internisten und des Chirurgen

Hepatocellular carcinoma (HCC) is the 5th most common cancer in the world and the 3rd cause of cancer-related death. Despite therapeutic advances, the overall survival of patients with HCC has not significantly improved in the last decades. Because in the majority of patients HCCs develop in a cirrhotic liver, the patient’s prognosis depends not only on the tumor stage but also on the liver function. Patients at an early stage with an asymptomatic single HCC with a maximum diameter of 5 cm or up to three nodules each less than 3 cm may benefit from curative therapies, including resection, liver transplantation, and percutaneous ablation. Patients exceeding these limits, but who are free of cancer-related symptoms and vascular invasion or extrahepatic spread, may benefit from palliation with chemoembolization. The advanced stage is characterized by mild cancer-related symptoms and/or vascular invasion or extrahepatic spread. Patients at this stage are eligible for treatment with sorafenib; however, a variety of other new drugs, including small molecules and antibodies, are being tested in randomized controlled trials. The development and evaluation of novel HCC treatment strategies as well as the implementation of existing measures and the development of new ones to prevent HCCs are of utmost importance. A better understanding of the clinical and molecular pathogenesis of HCCs should lead to improved diagnostic, therapeutic, and preventive strategies, with the aim to reduce the incidence of HCC, one of the most devastating malignancies worldwide.     

Pathology of hepatocellular carcinoma: recent update]

In recent years, growing number of literatures have supported the concept that large nodules usually found in cirrhotic livers represent premalignant lesions in the setting of chronic liver disease. With the use of advanced imaging techniques, nodules suspicious for malignancy have often been identified and resected. While some resected lesions were found to be small hepatocellular carcinomas (HCCs), others were not. Some of these non-malignant nodules were devoid of atypia, some had architectural or cytological atypia insufficient for a diagnosis of HCC though they are suggestive of a premalignant state, while others contained microscopic subnodules of HCC. In follow-up studies and series of explants from liver transplant centers, the occasional finding of microscopic foci of HCC in the nodules was confirmed and significant associations with HCC elsewhere in the same liver were established. Such findings suggested that these nodular lesions, which are referred as "dysplastic nodules" (or adenomatous hyperplasia), are probably a frequent pathway in human hepatocarcinogenesis. We discuss the pathological characteristics of dysplastic nodules and small HCCs.     

Spiral computed tomography versus ultrasound in the follow-up of cirrhotic patients previously treated for hepatocellular carcinoma: a prospective study

BACKGROUND/AIMS: To assess the value of hepatic-arterial-phase computed tomography (HAP-CT) versus ultrasound (US) plus alpha-fetoprotein (AFP) in the surveillance of cirrhotic patients with previously treated hepatocellular carcinoma (HCC). METHODS: Thirty-six cirrhotic patients, treated for single nodular HCC <4cm with complete response and no evidence of other focal lesions, were enrolled in a prospective study and underwent simultaneous AFP/US/spiral-CT follow-up every 6 months. Focal lesions were considered recurrences when they appeared as globular enhancement areas (EA) at HAP-CT and increased in size during the follow-up. RESULTS: Fifteen of 36 patients showed at least one focal lesion for a total of 43 EA: 38/43 increased in size, four did not change and one disappeared. EA were first observed after a follow-up of 9+/-4 (range 6-18) months. At the same time, no patient had either nodular lesion at US examination or diagnostic levels of AFP. In 22 matched lesions, diagnosis by CT was 8.2+/-3.5 months earlier than by US. In 13 patients, one evolved EA was submitted to US-guided biopsy and histological examination showed HCC in all cases. CONCLUSIONS: Periodical spiral-CT examination is more effective than US-AFP in early detection of HCC recurrence in cirrhotic patients successfully treated for HCC.     

Hepatic precancerous lesions and small hepatocellular carcinoma

Precancerous lesions that may be detected in chronically diseased, usually cirrhotic livers, include: clusters of hepatocytes with atypia and increased proliferative rate (dysplastic foci) that usually represent an incidental finding in biopsy or resection specimens; and grossly evident lesions (dysplastic nodules) that may be detected on radiologic examination. There are two types of small hepatocellular carcinoma (HCC) (defined as HCC that measures less than 2 cm): early HCC, which is well-differentiated and has indistinct margins; and distinctly nodular small HCC, which is well- or moderately differentiated, and is usually surrounded by a fibrous capsule. Precise diagnosis of precancerous and early cancerous lesions by imaging methods is often difficult or impossible. Detection of a dysplastic lesion in a biopsy specimen is a marker of increased risk for HCC development, and warrants increased surveillance. High-grade dysplastic nodules and small HCCs should be treated by local ablation, surgical resection, or liver transplantation.     

Detection of nodules in liver cirrhosis: spiral computed tomography or magnetic resonance imaging? A prospective study of 88 nodules in 34 patients

Detection and characterization of all focal lesions in the liver are critical for screening patients with chronic liver disease. The aim of this prospective study was to investigate the accuracy of magnetic resonance imaging (MRI) and spiral computed tomography for the diagnosis of hepatic nodules in cirrhotic patients when compared with pathological findings of the explanted liver. From February 1997 to July 1999, 34 cirrhotic patients waiting for orthotopic liver transplantation (OLT) (mean age, 53.5 +/- 9.3 years; 24 males) were included. All patients had MRI and spiral computed tomography examinations, and findings were matched with the histological findings. Data analyses were made using the McNemar chi-square test. Mean time between radiological examination (MRI or spiral computed tomography) and OLT was 43.8 +/- 39 days. A total of 88 nodules were found in the 34 patients: 54 hepatocellular carcinoma (HCC) (mean size, 18 +/- 10 mm) in 21 patients, 22 dysplastic nodules (mean size, 10.7 +/- 4.3 mm) in 11 patients, and 12 macroregenerative nodules in 13 patients. Lesion-by-lesion analyses showed that sensitivity of MRI and spiral computed tomography for nodule, HCC or dysplastic nodule diagnosis was 44.3 and 31.8% (P = 0.02), 61.1 and 51.9% (P = 0.2), and 27.3 and 0% (P = 0.04), respectively. Patient-by-patient analyses showed no statistical difference between spiral computed tomography and MRI for nodule diagnosis. In conclusion, in patients with liver cirrhosis, MRI is more accurate than spiral computed tomography for the detection of liver nodules and dysplastic nodules. However, tumour size is always a restricting factor for these two techniques, which are unable to detect small HCC in more than 60% of cases.     

The risk of hepatocellular carcinoma in cirrhotic patients with small liver nodules on MRI

BACKGROUND AND AIM: The presence of hepatocellular carcinoma (HCC) has important implications for patients with cirrhosis. Studies have not compared the risk of cancer in cirrhotic patients with small liver nodules to cirrhotic patients without nodules. Our aim was to determine the risk of HCC in cirrhotic patients with small liver nodules on MRI compared to those without nodules. METHODS: We conducted a prospective study to determine the rate of HCC in cirrhotic patients with and without liver nodules. Cases were patients with liver nodule(s) less than 2 cm on MRI and controls were cirrhotic patients without nodules. Kaplan-Meier estimates and multivariate analysis were performed to estimate the risk of HCC in the two groups. RESULTS: A total of 310 liver transplant candidates with a mean follow-up of 663 days were included in the study and 133 underwent liver transplant during follow-up. The 1-yr incidence of HCC in the liver nodule group and control group was 11% and 0.5%, respectively, p < 0.001. The adjusted risk for HCC in the liver nodule group was 25 times higher compared to the control group, HR = 25.1 [95% CI 8.0, 78.9]. In 133 candidates who underwent transplant with and without liver nodules the rate of HCC was 11 (50%) and 4 (3.6%), respectively, p < 0.001. CONCLUSION: The incidence of HCC in patients with small liver nodules is significantly higher compared to patients with cirrhosis without liver nodules. The presence of small liver nodules warrants increased imaging surveillance for HCC.     

Small hepatocellular carcinomas in patients with liver cirrhosis: potentials and limitations of contrast-enhanced power Doppler sonography

Detection and characterization of focal liver lesions are critical for patients with liver cirrhosis. The potential of contrast-enhanced sonography in the characterization of focal liver lesions is well established in the literature. However, prospective studies in the assessment of patients with suspected hepatocellular carcinoma (HCC) in liver cirrhosis are rare. B-mode imaging often cannot differentiate small focal lesions in cirrhotic livers. Also, power Doppler is not capable of characterizing small focal lesions in cirrhosis. Contrast-enhanced sonography with a first-generation enhancer seems to improve the accuracy of diagnosis of small HCC. The differentiation of HCC and dysplastic nodules is notoriously difficult. In addition, other arterial hypervascularized liver lesions should be considered, depending on the clinical background. The limitations and drawbacks of contrast-enhanced sonography should be considered. All imaging methods are of limited value in the detection of solid liver lesions smaller than 1 cm.     

Early hepatocellular carcinoma and dysplastic nodules

It has been established that small, equivocal nodular lesions such as dysplastic nodules (DNs) and small well-differentiated hepatocellular carcinomas (early HCCs) are frequently observed in noncancerous liver tissues resected along with HCCs and in explant cirrhotic livers. DNs are classified into low-grade DNs or high-grade DNs on the basis of cytological and architectural atypia; high-grade DNs show varying degrees of cytological or architectural atypia, or both. Early HCCs are indistinctly nodular and highly differentiated and are frequently difficult to differentiate from high-grade DNs. Although the pathological diagnosis of high-grade DNs and early HCCs is controversial, the presence of tumor cell invasion into the intratumoral portal tracts (stromal invasion) is a helpful clue for differentiating early HCC from high-grade DNs. It is highly suggested that many HCCs occurring in cirrhotic liver arise in DNs and develop to classical HCC in a multistep fashion.     

肝细胞癌癌前结节影像学特征的研究进展

肝细胞癌(HCC)发生是一个多步骤过程,在其发展中检测出HCC癌前病变和进展期HCC,对预测肿瘤行为、判断病变程度、采用最佳治疗策略、改善患者生存至关重要。肝脏成像技术的快速进展和广泛应用,尤其是肝细胞特异性对比剂钆塞酸二钠MRI(Gd-EOB-DTPA MRI)可提供肝结节血管变化、肝细胞功能信息,能够精确区分肝硬化再生结节、低度异型增生结节、高度异型增生结节、早期HCC(early HCC)和HCC,从而进行恶性进展的风险度分层。现综述Gd-EOB-DTPA MRI在HCC早期诊断中的价值,分析HCC多步发展过程中的关键概念,以及癌前病变最终可能转化成典型HCC的影像学表现。     

Liver Imaging Reporting and Data System criteria for the diagnosis of hepatocellular carcinoma in clinical practice: A pictorial minireview

Hepatocellular carcinoma (HCC) is the sixth most common cancer. The main risk factors associated with HCC development include hepatitis B virus, hepatitis C virus, alcohol consumption, aflatoxin B1, and nonalcoholic fatty liver disease. However, hepatocarcinogenesis is a complex multistep process. Various factors lead to hepatocyte malignant transformation and HCC development. Diagnosis and surveillance of HCC can be made with the use of liver ultrasound (US) every 6 mo. However, the sensitivity of this imaging method to detect HCC in a cirrhotic liver is limited, due to the abnormal liver parenchyma. Computed tomography (CT) and magnetic resonance imaging (MRI) are considered to be most useful tools for at-risk patients or patients with inadequate US. Liver biopsy is still used for diagnosis and prognosis of HCC in specific nodules that cannot be definitely characterized as HCC by imaging. Recently the American College of Radiology designed the Liver Imaging Reporting and Data System (LI-RADS), which is a comprehensive system for standardized interpretation of CT and MRI liver examinations that was first proposed in 2011. In 2018, it was integrated into the American Association for the Study of Liver Diseases guidance statement for HCC. LI-RADS is designed to ensure high sensitivity, precise categorization, and high positive predictive value for the diagnosis of HCC and is applied to “high-risk populations” according to specific criteria. Most importantly LI-RADS criteria achieved international collaboration and consensus among liver experts around the world on the best practices for caring for patients with or at risk for HCC.     

Early Stage Hepatocellular Carcinoma Detected during Intraoperative Ultrasonography

Objectives: Recently, it has been recognized that there are increasing incidences of hepatocellular carcinoma (HCC) multicentricity. Thus, intraoperatively detected hepatic lesions that were once thought to be metastatic lesions now need to be carefully reexamined to determine whether they are true metastatic lesions or the multicentric development of HCC. Methods: We investigated the histological characteristics of small nodular lesions detected during intraoperative ultrasonography in 33 consecutive patients with small HCC wbo underwent laparotomy at our institution. Results: Fourteen nodular lesions were found incidentally in 10 of 33 patients (30.3%), and were classified into tbe following three groups: 11 nodules in nine patients (27.3%) were HCC, two nodules in two patients (6.1%) were hemangioma, and one nodule in one patient (3.0%) was a large regenerative nodule. HCC therefore comprised 78.6% of tbe intraoperatively detected nodular lesions. Of the 11 HCCs, six were hyperechoic, four were hypoechoic, and one was isoechoic. Five (83.3%) of six small hyperechoic HCCs and two (50.0%) of four hypoechoic HCCs were well differentiated and retained their preexisting liver structure. Tbese findings closely coincide with the characteristics of early stage HCC. Thus, early stage HCC comprised 63.6% of tbe intraoperatively detected HCC cases. Conclusions: A certain proportion of small satellite HCCs detected during intraoperative ultrasonography in patients with small HCC, which were previously thought to be metastatic lesions from tbe main HCC, may instead he early stage HCCs. Such findings would also support the concept of the multicentric development of HCC. Approximately 60% of all small HCC cases detected intraoperatively may be early stage HCC. As a result, it is predicted that the emergence of HCC is either multicentric or unicentric, with early intrabepatic spread, altbough the former seems to be more common.     

International consensus on histologic diagnosis of early hepatocellular neoplasia

1. The precursor lesions for the development of hepatocellular carcinoma are believed to be high-grade dysplastic nodules. These lesions have atypical and proliferative features that distinguish them from normal or cirrhotic liver but are not sufficient for the diagnosis of carcinoma.
2. Individual HGDN are often heterogeneous and complete sampling may reveal regions of carcinoma within these otherwise benign lesions.
3. Invasion of stroma is considered a definitive feature of HCC. However, this feature is not always present in early HCC and is seldom found in needle biopsies.
4. Accurate diagnosis of dysplastic nodules and well-differentiated HCC requires skill and experience. However, accurate diagnosis with needle biopsies may be impossible if the highest grade of atypia is not sampled. Fine needle aspiration is not appropriate for small lesions that are expected to be early hepatic neoplasia. This technique should be reserved for suspected moderate- or poorly differentiated HCC.     

EUS for detection of the hepatocellular carcinoma: results of a prospective study

BACKGROUND: Early detection of hepatocellular carcinoma (HCC) and accurate determination of the number of lesions are critical in determining eligibility for liver transplantation or resection. Current diagnostic modalities (CT and magnetic resonance imaging [MRI]) often miss small lesions. OBJECTIVE: To compare the accuracy of the EUS with CT for the detection of primary tumors of the liver. DESIGN: Prospective single-center study. SETTING: Academic medical center. PATIENTS: Subjects at high risk of HCC (hepatitis B, hepatitis C, or alcoholic cirrhosis) were enrolled. INTERVENTIONS: US, CT, MRI, and EUS examinations of the liver were performed. Liver lesions identified during EUS underwent EUS-guided FNA (EUS-FNA). RESULTS: Seventeen patients were enrolled in the study. Nine of these patients had liver tumors (HCC, 8; cholangiocarcinoma, 1). EUS-FNA established a tissue diagnosis in 8 of the 9 cases. The diagnostic accuracy of US, CT, MRI, and EUS/EUS-FNA were 38%, 69%, 92%, and 94%, respectively. EUS detected a significantly higher number of nodular lesions than US (P = .03), CT (P = .002), and MRI (P = .04). For HCC lesions, a trend was observed in favor of EUS for the detection of more lesions than US (8 vs 2; P = .06) and CT (20 vs 8; P = .06). No complications were observed as a result of EUS-FNA. LIMITATIONS: Small sample size. CONCLUSIONS: EUS-FNA is a safe and accurate test for the diagnosis of HCC. EUS increases the accuracy of intrahepatic staging of the HCC by delineation of lesions, which are missed by CT and MRI. We recommend EUS for suspected HCC, particularly in cases that are being considered for liver transplantation.