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Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma
Abstract
To clarify the course of adenomatous hyperplasia (AH) of the liver, 17 patients with 20 biopsy-proven AH nodules were followed clinically for 1-5 years. At the initial biopsy the mean nodular diameter was 10 (SD 4) mm and the relative cellularity [( mean cellularity of AH divided by mean parenchymal cellularity] x 100) 141 (27). The criteria for diagnosis of malignant transformation of AH were both a doubling of nodular volume and changes on imaging. Between 6 and 50 months after biopsy, 9 of the 18 nodules which could still be accurately identified met the criteria for transformation; histological proof of hepatocellular carcinoma (HCC) was obtained later for 7 of these 9 nodules. The product of diameter and cellularity (transformation index) was the strongest predictor of the time to transformation. 9 AH nodules did not undergo transformation--7 did not meet one or both criteria and 2 became undetectable by imaging. Because of the high risk of malignant transformation, it can be concluded that AH is an absolute precursor of HCC. It should therefore be treated as a potential malignant disorder.
... Given that one of the major histologic differences between DNs and early HCCs is the degree of cellular density. 86 Kim et al. 26 hypothesized that DWI might be more sensitive in depicting histologic changes of borderline hepatocellular nodules than liver imaging using an extracellular space contrast agent. In particular, since in their study almost all hypervascular HCCs showed hyperintensity at DWI on the last follow-up, they questioned whether the HHNWAs showing diffusion restriction were already HCC. ...
... 92 Fatty change occasionally occurs during hepatocarcinogenesis and, except for the steatohepatic variant of HCC, its prevalence decreases incrementally with tumor size and histologic grade, thus generally being associated with a more favorable prognosis. 93 Conversely, in the early stage of hepatocarcinogenesis, fat deposition progressively increases from LGDNs to HGDNs, reaching a peak in early HCCs, 86 where it is observed in approximately 40% of cases. 94 In early HCC, in fact, the lack of blood supply that results from a gradual shift from the portal vessels to newly formed nontriad arteries, together with the increased cellular density, may cause transient hypoxia and, thus, lead to intratumoral fatty metamorphosis. ...
Recent technical advances in liver imaging and surveillance for patients at high risk for developing hepatocellular carcinoma (HCC) have led to an increase in the detection of borderline hepatic nodules in the gray area of multistep carcinogenesis, particularly in those that are hypointense at the hepatobiliary phase (HBP) and do not show arterial phase hyperenhancement. Given their potential to transform and advance into hypervascular HCC, these nodules have progressively attracted the interest of the scientific community. To date, however, no shared guidelines have been established for the decision management of these borderline hepatic nodules. It is therefore extremely important to identify features that indicate the malignant potential of these nodules and the likelihood of vascularization. In fact, a more complete knowledge of their history and evolution would allow outlining shared guidelines for their clinical-surgical management, to implement early treatment programs and decide between a preventive curative treatment or a watchful follow-up. This review aims to summarize the current knowledge on hepatic borderline nodules, particularly focusing on those imaging features which are hypothetically correlated with their malignant evolution, and to discuss current guidelines and ongoing management in clinical practice.
... Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, and commonly occurs in patients at high risk for this disease, especially cirrhosis. As is well known, HCCs usually develop via the multistep process of hepatocarcinogenesis. [1][2][3] In particular, high grade dysplastic nodules and pathologically early stage HCCs are known to be precursors of progressed HCCs, and can be regarded as borderline malignant nodules. 2,4 In contrast to progressed HCCs, vascular invasion or intrahepatic metastasis is not likely to occur in these borderline malignant hepatic nodules. ...
... The requirement for written informed consent was waived, and Institutional Review Board in VHS Medical Center approved this study. The inclusion criteria for this study were as follows: (1) cirrhotic patients who were diagnosed as HCC with Barcelona Clinic Liver Cancer (BCLC) stage A; 14 (2) those who underwent radiofrequency ablation (RFA) or surgical resection as an initial treatment for the HCC nodules; (3) patients with one or multiple non-hypervascular HBPI hypointense nodules up to five in number; (4) those who underwent repetitive gadoxetic acidenhanced liver MRI with regular intervals of six months or less; (5) patients were included in the analysis if initial MR work-up was done during the period from January 2010 to July 2015; and (6) the overall MR follow-up period was longer than 1 year. Those patients with six or more hypovascular HBPI hypointense nodules were excluded from the analysis to minimize the effect of clustering on statistical tests. ...
Background/aims:
The annual risk of transformation of non-hypervascular magnetic resonance (MR) hepatobiliary phase imaging (HBPI) hypointense nodules into hypervascular hepatocellular carcinomas (HCCs) was evaluated.
Methods:
Cirrhotic patients with non-hypervascular HBPI hypointense nodules were retrospectively analyzed if they were diagnosed as HCC and MR followed up longer than 1 year during the period from January 2010 to October 2016 with regular intervals of 3 to 6 months. Risk factors for transformation into hypervascular HCCs were analyzed using the Cox proportional hazard model.
Results:
Among the 103 non-hypervascular HBPI hypointense nodules meeting the inclusion criteria, transformation into hypervascular HCCs occurred in 44 tumors (42.7%). The median follow-up period was 24 months. Multivariate analysis revealed that hyperintensity on T2-weighted images (T2WI) and diffusion-weighted images (DWI) were the two independent predictors of transformation into hypervascular HCCs (p=0.036 and p=0.041, respectively). Most tumors with hyperintensity on T2WI or DWI on the initial or follow-up MR were transformed into hypervascular HCCs within the first year. Among the 22 nodules (21.3%) showing a new change in dynamic phases during follow-up, 14 nodules (13.6%) showed malignant transformations.
Conclusions:
The transformation rates of HBPI hypointense nodules into hypervascular HCCs could be predicted according to the initial or serial MRI findings.
... The concept of multistep carcinogenesis in chronic liver disease or a cirrhotic liver involves regenerating nodules, dysplastic nodules and finally HCC. [1][2][3] Surveillance via an ultrasound every six months is recommended for early detection. [4][5][6][7] Further cross-sectional imaging, including multiphasic computed tomography (CT) or dynamic contrast-enhanced magnetic resonance imaging (MRI) of the liver should be performed for lesion characterization. ...
Objective: To identify patient characteristics and MR imaging features of hypovascular hypointense nodules in the hepatobiliary phase (HBP) of gadoxetic acid-enhanced MR imaging in patients with chronic liver disease associated with progression to hypervascular hepatocellular carcinoma (HCC). Materials and Methods: The institutional review board approved this retrospective review of 40 patients with 60 hypovascular hypointense nodules in the HBP of gadoxetic acid-enhanced MR imaging. Univariate and multivariate Cox regression analyses for hypervascular HCC development were used to define variables, including initial nodule size, cause of cirrhosis, history of locoregional therapy of HCC, fat-containing, signal intensity on T1W, T2W, portal and equilibrium phases of dynamic phase, and DW images. The cumulative percentage incidence of hypervascularity and growth rate were calculated using the receiver operating characteristic (ROC) curve. Results: The prevalence of progression to hypervascular HCC was 45% (27 out of 60). The Multivariable Cox analysis of developing hypervascularization was an initial nodule diameter more than 1 cm. (P=0.027; HR 2.52; 95% CI: 1.11,5.74) The mean growth rate was significantly higher in subsequent hypervascular nodules than in those without hypervascularization (P < 0.001). The cumulative risk incidence of hypervascularization at 3, 6, 12, 24 months was 5%, 20%, 35%, 44 %, respectively. Conclusion: An initial nodule diameter of more than 1 cm and nodules with higher growth rates are significant predictive factors for hypervascular transformation of hypovascular hypointense nodules in the HBP of gadoxetic acid-enhanced MR imaging.
... Such borderline nodules consist of benign hepatocellular nodules or early-stage HCC pathologically. Because HCC progresses in stages from dysplastic nodules to early-stage HCC and finally to typical hypervascular HCC, non-hypervascular hypointense hepatic nodules in the HBP can be considered precursors to hypervascular HCC [49][50][51][52]. ...
Percutaneous ablation is a low-invasive, repeatable, and curative local treatment that is now recommended for early-stage hepatocellular carcinoma (HCC) that is not suitable for surgical resection. Poorly differentiated HCC has high-grade malignancy potential. Microvascular invasion is frequently seen, even in tumors smaller than 3 cm in diameter, and prognosis is poor after percutaneous ablation. Biopsy has a high risk of complications such as bleeding and dissemination; therefore, it has limitations in determining HCC tumor malignancy prior to treatment. Advances in diagnostic imaging have enabled non-invasive diagnosis of tumor malignancy. We describe the usefulness of ultrasonography, computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose positron emission tomography for predicting outcome after percutaneous ablation for HCC.
... Lesions which are smaller than 1cm in diameter and fail to be displayed on dynamic imaging are less likely to be malignant, especially if there is no cirrhosis [24]. However, even tiny nodules can be transformed into malignant ones over time [25,26] so patients must follow-up with ultrasound every 3 to 6 months in order to check for HCC development [23]. At the end when there is no increasing in the size over a period greater than one to two years patients can return to the routine surveillance program [23]. ...
Liver is the largest gland inside our body, and it is accounted for many functions in the body but like any other organ in the body it is prone to different disease but the most dangerous one of them is hepatocellular carcinoma. Hepatocellular carcinoma is fetal, and it is having low survival rate and it is resistant to the most of the know therapy that's why there is always a need for new treatment modalities. It has different causative agents, different staging methods, different mechanism for hepatocarcinogenesis and different treatment modalities like liver resection, liver transplantation and sorafenib. Tumor hypoxia is a common feature of hepatocellular carcinoma and other solid tumours, and it results from a lack of blood supply to the rapidly expanding cancer cells. Tumor hypoxia is an unfavourable prognosis factor since it enhances the tumor's aggressiveness and resistance to treatment, which is why reducing tumour hypoxia has a lot of therapeutic benefits for cancer patients. Drug resistance, metastasis, angiogenesis, metabolic shifting, radiotherapy resistance, and overall tumour aggressiveness and poor prognosis are all caused by hypoxia inducible factor 1, which causes drug resistance, metastasis, angiogenesis, metabolic shifting, radiotherapy resistance, and overall tumour aggressiveness and poor prognosis. There is keen research working on the tumor hypoxia and trying to discover new drugs and approaches to correct the tumor hypoxia like prodrugs activated by hypoxia, hyperbaric oxygen, nanoparticles, oral oxygen therapy and finally hypoxia inducible factors inhibitors like for example benzopyranyl 1,2,3-triazole, glyceollins and vorinostat.
... Intracellular fat accumulation, a common morphological characteristic of HCC, occurs in the context of ischemia and hypoxia dueto decreased portal vein and nontumoral artery flow, and insufficient unpaired arteries [75] . Thus, intracellular fat accumulation is gradually increased in low-grade dysplastic nodules, highgrade dysplastic nodules, and early-stage HCC [76,77] . However, with regard to intra-tumoral fatty infiltration in poorly differentiated HCC, controversy exists [75,78] . ...
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with a high mortality rate. Heterogeneity is the main biological characteristic of HCC, which manifests through the different biological behaviors of each phenotype and ultimately, affects patient prognosis and treatment efficacy. Various aggressive biological behaviors are considered to be associated with the poor prognosis of HCC patients including poor differentiation, microvascular invasion, intracellular fat accumulation, invasive growth, bile duct invasion or tumor thrombosis, and tumor spread and metastasis, and have been reported as prognostic biomarkers. In addition, HCC results from multifactor synergistic damage, and various factors related to genetics, molecular pathology and immunohistochemistry such as β-catenin, Ki67, cytokeratin-19, and epithelial cell adhesion molecule have an impact on HCC differentiation and prognosis. This article is an overview of the biological behaviors that lead to poor prognosis of HCC, and the roles of morphological and quantitative noninvasive imaging biomarkers in the evaluation and prediction of these behaviors. Some common biomarkers related to genetics, molecular pathology and immunohistochemistry are also briefly summarized. It is hoped that this review will provide clinicians and radiologists with an update on the development of liver imaging, and provide directions for the combination of radiology, genetics, molecular pathology and histopathology to better predict the prognosis of HCC patients.
... The second type is de novo intrahepatic recurrence (i.e., multicentric HCC). This type of recurrence accounts for 30-40% of recurrences after HCC treatments [19,20]. The second type of recurrence limit efforts aimed at addressing treatment efficacy between surgery and RFA. ...
Introduction: It remains unclear which of surgery or radiofrequency ablation (RFA) is the more effective treatment for small hepatocellular carcinoma (HCC). We aimed to compare survival between patients undergoing surgery (surgery group) and patients undergoing RFA (RFA group).
Methods: We conducted a randomized controlled trial involving 49 institutions in Japan. Patients with Child-Pugh scores ≤ 7, largest HCC diameter ≤ 3 cm, and ≤ 3 HCC nodules were considered eligible. The co-primary endpoints were recurrence-free survival (RFS) and overall survival (OS). The current study reports the final result of RFS, and the follow-up of OS is still ongoing.
Results: During 2009–2015, 308 patients were registered. After excluding ineligible patients, the surgery and RFA groups included 150 and 151 patients, respectively. Baseline factors did not differ significantly between the groups. In both groups, 90% of patients had solitary HCC. The median largest HCC diameter was 1.8 cm (interquartile range, 1.5–2.2 cm) in the surgery group and 1.8 cm (interquartile range, 1.5–2.3 cm) in the RFA group. The median procedure duration (274 versus 40 minutes, P
... The risk factors include male gender [124,125], old age, advanced histological stage, portal hypertension [126], and biochemical nonresponses to UDCA [127][128][129]. Other risk factors recognized are hepatitis B, C, alcoholic liver disease, NASH, blood transfusion [128], metabolic syndrome [124], and adenomatous hyperplasia as a precursor of HCC presented with malignancy disorder [130], lymphocytic piecemeal necrosis also associated with HCC. DNA methylation is important in development of tumor cells, it is necessary to ascertain when demethylation and hypomethylation occur during tumorigenesis. ...
TRIM, a multi-domain protein associated with N-terminal ring finger E3 ligase and C-terminal plant homeodomain/ bromodomain PHD chromatin interacting module, N-terminal ring finger known as ring B-boxes and coiled-coil RBCC domain with structure that underscores biochemical reaction which requires enzymes like E1, E2 and E3 of which E3 serves as receptor recognition for target proteins. Most TRIM proteins are E3 ligases in the ubiquitination cascade that translated in diverse physiological and biological processes such as differentiation, growth, transcription and oncogenesis. Implicated in pathological processes from Mendelian inherited disorders, cellular (plethora) processes like cell cycle regulation, innate immune response and apoptosis to cancer. Genetic factors are at high risk and contributed between 30%-50% disease prevalence like obesity, cirrhosis. TRIM28 (TIF1β), TRIM24 (TIF1α), TRIM33 (TIF1γ) are cofactors of tripartite motif TRIM subfamily protein, distinct transcriptional factors that correlate with each other and interact with other proteins both in functional and physical in cancer disease. Studies have shown that TRIM protein is a regulator in inflammatory, infectious and cancer diseases. This review focused on tripartite genes as a liver cancer target via regulating immune cells and the gut microbiome. More on research so far, disease development, progression and influence. Considering the incident rate and progression, genetic involvement remain challenging thus needs more insight on prognosis that will potentiate clinical effect with lesser adverse events and recurrences that will benefit the patients.
... As one of the major differences between dysplastic nodules and early HCCs is the degree of cellular density, DWI might provide a good insight into histological changes of hepatocellular nodules irrespective of vascularity. 78 Notably, since RN and low grade DN are usually histologically identical to the surrounding hepatic tissue, they are isointense on DWI. 79,80 On the other hand, HCC and high grade DN, show a progressive increase in cellular density, thickening of cellular plates, leading to progressive restriction of water mobility, which results in increased signal intensity on DWI. ...
Background:
In the setting of cirrhotic liver, the diagnosis of hepatocellular carcinoma (HCC) is straightforward when typical imaging findings consisting of arterial hypervascularity followed by portal-venous washout are present in nodules larger than 1 cm. However, due to the complexity of hepatocarcinogenesis, not all HCCs present with typical vascular behaviour. Atypical forms such as hypervascular HCC without washout, isovascular or even hypovascular HCC can pose diagnostic dilemmas. In such cases, it is important to consider also the appearance of the nodules on diffusion-weighted imaging and hepatobiliary phase. In this regard, diffusion restriction and hypointensity on hepatobiliary phase are suggestive of malignancy. If both findings are present in hypervascular lesion without washout, or even in iso- or hypovascular lesion in cirrhotic liver, HCC should be considered. Moreover, other ancillary imaging findings such as the presence of the capsule, fat content, signal intensity on T2-weighted image favour the diagnosis of HCC. Another form of atypical HCCs are lesions which show hyperintensity on hepatobiliary phase. Therefore, the aim of the present study was to provide an overview of HCCs with atypical enhancement pattern, and focus on their magnetic resonance imaging (MRI) features.
Conclusions:
In order to correctly characterize atypical HCC lesions in cirrhotic liver it is important to consider not only vascular behaviour of the nodule, but also ancillary MRI features, such as diffusion restriction, hepatobiliary phase hypointensity, and T2-weighted hyperintensity. Fat content, corona enhancement, mosaic architecture are other MRI feautures which favour the diagnosis of HCC even in the absence of typical vascular profile.
... Microscopic foci in the histological sections of the liver showed early hepatocellular carcinoma [21,22]. In the advanced stage, there were cell aggregates with eosinophilic cytoplasm and wellorganized enlarged nucleoli [23]. ...
Purpose:
Liver cancer stem cells are associated with tumor progression, metastasis, and resistance to chemotherapy. Therefore, it is important to understand the proteins that support the tumor microenvironment. The suppression of ZEB2 results from inactivation of the Wnt/β catenin pathway. Like RBM38, it suppresses tumor outgrowth and helps increase the survival of cancer patients. However, no studies have examined the direct roles of ZEB2 and RBM38 in the tumor microenvironment.
Methods:
We developed an early/advanced stage liver cancer mouse model using CD133+ cell injection that mimics liver cancer in all ways. Histology, Western blotting, and immunohistochemistry analyses were used to examine cancer progression.
Results:
Histologically, the early liver cancer showed microfoci structures; the advanced cancer showed distinct morphological changes with enlarged nucleoli and cell clumping. Immunohistochemical and Western blotting analyses of CD133 and ZEB2 proteins showed similar upregulated expression as the tumor progressed. However, RBM38 expression increased dramatically in early liver cancer but was downregulated in advanced liver cancer.
Conclusions:
ZEB2 favors a tumor microenvironment that supports liver cancer stem cell proliferation, while RBM38 expression negatively affects the tumor microenvironment and restricts liver cancer stem cell proliferation.
... Furthermore, HCC is known to dedifferentiate from hypovascular liver tumors (dysplastic nodules and well-differentiated HCC) to hypervascular tumors [13,14]. With this rationale, we therefore examined whether or not DAAs can suppress the growth and hypervascularization of hypovascular liver tumors. ...
Background and aims
Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) exert high anti-HCV activity and are expected to show anti-inflammatory effects associated with HCV elimination. Furthermore, hepatocellular carcinoma (HCC) is known to dedifferentiate from hypovascular tumors, such as dysplastic nodules or well-differentiated HCC, to hypervascular tumors. We therefore explored whether or not DAAs can suppress the growth and hypervascularization of hypovascular tumors.
Methods
We enrolled 481 patients with HCV genotype 1 infection who were treated with Daclatasvir and Asunaprevir therapy. Of these, 29 patients had 33 hypovascular tumors, which were confirmed by contrast-enhanced MRI or CT before therapy. We prospectively analyzed the cumulative incidence of HCC, i.e. the growth or hypervascularization of hypovascular tumors, and compared the HCC development rates between patients with hypovascular tumors and those without any tumors.
Results
The mean size of the hypovascular tumors was 11.3 mm. Twenty seven of 29 patients who achieved an SVR had 31 nodules, 19 of 31 nodules (61.3%) showed tumor growth or hypervascularization, and 12 (38.7%) nodules showed no change or improvement. The cumulative incidence rates of tumor growth or hypervascularization were 19.4% at 1 year, 36.0% at 2 years, 56.6% at 3 years, and 65.3% at 4 years. Among the patients who achieved a sustained virologic response, the cumulative HCC development rates of patients with hypovascular tumors was significantly higher than in those without any tumors. A Cox proportional hazard analysis showed that a history of HCC therapy, the presence of a hypovascular tumor, and AFP >4.6 ng/mL at the end of treatment were independent risk factors for HCC development.
Conclusion
Hypovascular tumors developed into HCC at a high rate despite the elimination of HCV by DAAs. As patients with hypovascular tumors were shown to have a high risk of HCC development, they should undergo strict HCC surveillance.
... This cytological change was originally described as "liver cell dysplasia" (Anthony et al., 1973;Stewart and Wild, 2014). These dysplastic lesions evolve into Hepatocellular carcinoma over time (Takayama et al., 1990;Sakamoto and Hirohashi, 1998). Therfore, focal HCC may occasionally be found on microscopic examination of dysplastic nodules (Arakawa et al., 1986). ...
Hepatocellular carcinoma (HCC) is the most common primary malignant neoplasm of the liver representing the fifth most common malignancy worldwide. This tumor is more common in men than women, with a ratio of 2.7:1. Unlike HCC, Dysplasia is the precancerous nature of liver nodules and is characterized by cellular and nuclear enlargement, nuclear pleomorphism, and multinucleation. Area based Adaptive Expectation Maximization (EM) uses texture, layout, and context features of cells, and grows clusters to obtain texton maps of nucleus. A discriminative model of nucleus and cytoplastic changes of tumor is built by incorporating texture, layout, and context information efficiently. A bootsrap regression model of nuclei and cytoplastic changes are built by incorporating the aforementioned features efficiently. Mean squared error, Peak Signal to Noise ratio and Dice similarity values are used to evaluate the method's classification performance. The proposed method provides high classification and segmentation accuracy of nucleus and extra nuclear content in HCC and dysplasia, which are exceedingly textured in histopathology images, when compared to Adaptive K means, EM method and the state-of-the-art method, Convolutional Neural Networks (CNN). As texton detection reduces the cluttered background of nuclei, the proposed method would be a convenient mechanism for the classification of nuclei and non-nuclear features. In conclusion, this system can detect more eligible cells of precancerous nature as well as malignant cells even in a cluttered background of nuclei.
... 8 DNs are currently considered as pre-cancerous lesions. [9][10][11] In general, DNs diameter range between 1 and 3cm, with smaller lesions being consistent with RNs. DNs are defined as RNs containing atypical cells with nuclear crowding and architectural derangement and a variable number of unpaired arterioles or capillaries without definite histologic signs of malignancy. ...
... Precise investigation and follow-up study of these tiny nodular lesions revealed that a number of HCCs progressed via multistage hepatocarcinogenesis, that is, from chronic liver disease to dysplastic nodules, early HCC, nodule-in-nodule HCC and finally to progressed HCC [37][38][39] ( Fig. 1). As the concept of early HCC spread, the multistage hepatocarcinogenesis process became accepted among clinicians. ...
Outcomes for patients with hepatocellular carcinoma (HCC) remain poor because the condition is often unresponsive to the available treatments. Consequently, the early and precise diagnosis of HCC is crucial to achieve improvements in prognosis. For patients with chronic liver disease, the assessment of liver fibrosis is also important to ascertain both the staging of fibrosis and the risk of HCC occurrence. Early HCC was first described in 1991 in Japan and was defined internationally in 2009. As the concept of early HCC spread, the multistage hepatocarcinogenesis process became accepted. Consequently, improvements in imaging technology made the early diagnosis of HCC possible. At present, the most appropriate therapeutic strategy for HCC is determined using an integrated staging system that assesses the tumor burden, the degree of liver dysfunction and the patient performance status; however, pathological and molecular features are not taken into account. The recent introduction of several new therapeutic agents will change the treatment strategy for HCC. Against this background, HCC subclassification based on tumor cellular and microenvironmental characteristics will become increasingly important. In this review, we give an overview of how pathological analysis contributes to understanding the development and progression of HCC and establishing a precision diagnosis of HCC.
... HBP hypointense nodules without arterial phase hyperenhancement (APHE) constitute an entity that is unique in gadoxetic acid-enhanced MRI [8]. Due to the fact that such borderline nodules are consisted of benign hepatocellular nodules or early HCCs on pathology and that HCCs follow a stepwise development from dysplastic nodules to early HCCs and finally to typical hypervascular HCCs, HBP hypointense nodules without APHE can be considered to be precursors for the development of hypervascular HCCs [9][10][11]. Furthermore, the presence of HBP hypointense nodules without APHE has been highlighted to be a significant risk factors for intrahepatic distant recurrences (IDR) after treatment of HCC through either hepatectomy or RFA [12][13][14][15][16][17][18][19]. ...
Objective:
To perform a systematic review and meta-analysis to determine intrahepatic distant recurrence (IDR) risk of hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) on pretreatment gadoxetic acid-enhanced MRI in patients with hepatocellular carcinoma (HCC) treated with either hepatectomy or radiofrequency ablation (RFA).
Methods:
PubMed and EMBASE databases were searched up to April 6, 2019. We included studies that evaluated HBP hypointense nodules without APHE as risk factors for IDR in HCC patients treated with either hepatectomy or RFA. Hazard ratios (HR) were meta-analytically pooled using random effects model. Subgroup analyses stratified to clinicopathologic variables were performed to explore heterogeneity. Methodological quality of included studies was assessed using Quality in Prognostic Studies (QUIPS) tool.
Results:
Eight studies with 842 patients were analyzed. The overall pooled HR for IDR was 2.44 (95% CI, 1.99-2.98) and were 2.14 (95% CI, 1.66-2.76) and 3.07 (95% CI, 2.19-4.31) for patients that underwent hepatectomy and RFA, respectively. No significant heterogeneity was present (I2 = 0%). The presence of these nodules was consistently shown to be significant factors for IDR in other subgroups (HR = 1.74-3.07). Study quality was generally moderate.
Conclusions:
HBP hypointense nodules without APHE are risk factors for IDR in HCC patients treated with either RFA or hepatectomy. Stratification of patient management with regard to performing additional tests or treatment for these nodules and modification of proper follow-up strategies may be required in patients with HCC who have these nodules on pretreatment gadoxetic acid-enhanced MRI.
Key points:
• HBP hypointense nodules without APHE constitute an entity that is unique in gadoxetic acid-enhanced MRI. • HBP hypointense nodules without APHE are risk factors for IDR in HCC patients treated with either RFA or hepatectomy. • Stratification of management and modification of proper follow-up strategies may be required in HCC patients who have these nodules on pretreatment gadoxetic acid-enhanced MRI.
... 15 Fat content varies throughout hepatocarcinogenesis. Hepatocytes tend to demonstrate higher fat content during early phases as dysplastic nodules or early HCCs. 50 The presence of diffuse fat in progressed HCCs is uncommon. 11,51 Iron deposition during this process also varies. ...
The incidence of hepatocellular carcinoma (HCC) is increasing, with this trend expected to continue to the year 2030. Hepatocarcinogenesis follows a predictable course, which makes adequate identification and surveillance of at-risk individuals central to a successful outcome. Moreover, imaging is central to this surveillance, and ultimately to diagnosis and management. Many liver study groups throughout Asia, North America and Europe advocate a surveillance program for at-risk individuals to allow early identification of HCC. Ultrasound is the most commonly utilized imaging modality. Many societies offer guidelines on how to diagnose HCC. The Liver Image Reporting and Data System (LIRADS) was introduced to standardize the acquisition, interpretation, reporting and data collection of HCC cases. The LIRADS advocates diagnosis using multiphase computed tomography or magnetic resonance imaging (MRI) imaging. The 2017 version also introduces contrast-enhanced ultrasound as a novel approach to diagnosis. Indeed, imaging techniques have evolved to improve diagnostic accuracy and characterization of HCC lesions. Newer techniques, such as T1 mapping, intravoxel incoherent motion analysis and textural analysis, assess specific characteristics that may help grade the tumor and guide management, allowing for a more personalized approach to patient care. This review aims to analyze the utility of imaging in the surveillance and diagnosis of HCC and to assess novel techniques which may increase the accuracy of imaging and determine optimal treatment strategies.
... The development of HCC from a cirrhotic liver is believed to be a multistep process [25,26]. Although pre-cancerous hepatic cells are currently not well defined, they are thought to originate from dysplastic nodules or individual hepatocytes exhibiting dysplasia [27][28][29][30]. It has been reported that GPC3 expression in dysplastic nodules of cirrhotic livers positively correlates with the degree of dysplasia [31,32], but the underlying mechanism is currently unknown. ...
Background:
Recently, Glypican-3 (GPC3) has been identified as a potential hepatocellular carcinoma (HCC) diagnostic and/or therapeutic target. GPC3 has been found to be up-regulated in HCC and to be absent in normal and cirrhotic liver. As yet, however, the molecular characteristics of GPC3 and its role in HCC cell physiology and development are still undefined.
Methods:
Human hepatocyte cultures were established from 10 HCC patients. Additional liver samples were obtained from 5 patients without cirrhosis and/or HCC. Soft agar colony formation, (co-)immunofluorescence and Western blot assays were used to characterize the hapatocyte cultures. The expression of GPC3 in the hepatocytes was silenced using siRNA, after which, apoptosis, scratch wound migration and transwell invasion assays were performed.
Results:
We found that in HCC precursor hepatocytes GPC3 is increasingly expressed in different forms and at different locations, i.e., a non-cleaved form (70 kDa) was found to be localized in the cytoplasm while a N-terminal cleaved form (N-GPC3: 40 kDa) was fond to be localized in the cytoplasm and at the extracellular side of hepatocyte membranes. In addition, we found that the non-cleaved form of GPC3 co-localizes with Furin-Convertase in the Golgi apparatus. We also found that, similar to GPC3, Furin-Convertase is expressed in HCC precursor cells, suggesting a role in GPC3 processing. Subsequent siRNA-mediated GPC3 silencing resulted in a temporary inhibition of cell proliferation, migration and ivasion, while inducing apoptosis in transformed hepatocytes.
Conclusion:
Our data reveal new aspects of the role of GPC3 in early hepatocyte transformation. In addition we conclude that GPC3 may serve as a new HCC immune-therapeutic target.
... (2) As with other cancers, HCC is characterized by an obvious multistep process of tumor progression. (3) In the initial stage, the damaged liver tissues evolve into small nodular hypercellular lesions called dysplastic nodules (DNs). These precancerous lesions develop into early HCC (eHCC), defined as small, welldifferentiated HCC of vaguely nodular type, and then into progressed HCC, characterized by a distinctly nodular appearance and frequent microvascular invasion. ...
Conclusion:
The findings suggest molecular markers of BANF1, PLOD3, and SF3B4 indicating early-stage HCC in precancerous lesion, and also suggest drivers for understanding the development of hepatocarcinogenesis. (Hepatology 2017).
... In the early stage of hepatocarcinogenesis, LGDNs, HGDNs, and early HCCs show increased fat accumulation in the hepatocytes when compared to that of the background liver [37] . The incidence increases from LGDN to HGDN and early HCC. ...
Background:
Rapid advances in liver imaging have improved the evaluation of hepatocarcinogenesis and early diagnosis and treatment of hepatocellular carcinoma (HCC). In this situation, detection of early-stage HCC in its development is important for the improvement of patient survival and optimal treatment strategies. Because early HCCs are considered precursors of progressed HCC, precise differentiation between a dysplastic nodule (DN), especially a high-grade DN, and early HCC is important. In clinical practice, these nodules are frequently called "borderline hepatic nodules."
Summary:
This article discusses radiological and pathological characteristics of these borderline hepatic nodules and offers an understanding of multistep hepatocarcinogenesis by focusing on the descriptions of the imaging changes in the progression of DN and early HCC. Detection and accurate diagnosis of borderline hepatic nodules are still a challenge with contrast enhanced ultrasonography, CT, and MRI with extracellular contrast agents. However, gadoxetic acid-enhanced MRI may be useful for improving the diagnosis of these borderline nodules.
Key messages:
Since there is a net effect of incomplete neoangiogenesis and decreased portal venous flow in the early stage of hepatocarcinogenesis, borderline hepatic nodules commonly show iso- or hypovascularity. Therefore, precise differentiation of these nodules remains a challenging issue. In MRI using hepatobiliary contrast agents, signal intensity of HCCs on hepatobiliary phase (HBP) is regarded as a potential imaging biomarker. Borderline hepatic nodules are seen as nonhypervascular and hypointense nodules on the HBP, which is important for predicting tumor behavior and determining appropriate therapeutic strategies.
... This cytological changes were originally described as Bliver cell dysplasia^ [1]. These dysplastic lesions have been shown to evolve into HCC over time [31,34]. Therefore, focal HCC may occasionally be found on microscopic examination of dysplastic nodules [2]. ...
The differentiation of a cluster of nuclei and multi-nucleation is a critical issue in automated diagnosis systems. Due to the similarities between said clusters and malignant nuclei, misclassification of these regions can affect the automated systems’ final decision. In this paper, a method for differentiating clusters from multi nucleated cells in histopathological images is proposed. Hepatocellular Carcinoma(HCC) and Dysplasia are characterized by cellular and nuclear enlargement, nuclear pleomorphism and multinucleation, which possess prominent threat Data was obtained from Global Hospital and Research Center from patients diagnosed with Hepatocellular Carcinoma and Dysplasia. This paper introduces a hybrid diagnosis method that uses texture, layout and context features of nuclei and cytoplastic cells in order to enhance the poor diagnosis of liver tumors in Infra Red (IR) images. We propose a Area based Adaptive Expectation Maximization(EM) that grows the clusters, which avoids the need for initial cluster selection in order to obtain texton maps of nuclei and cytoplasm. A linear regression model of nuclei and cytoplastic changes were built by incorporating the aforementioned features efficiently. The proposed method provides better classification and segmentation accuracy of nuclei and extra nuclear content in HCC and dysplasia, compared to the state-of-the-art methods like convolutional networks and classical methods like Adaptive K means and EM method in constant time. In conclusion, this system detects the malignant cells and the highly eligible precancerous cells which is cost effective and reproducible.
... More than 80% of HCCs occur in patients with chronic liver disease or cirrhosis [22]. Most HCCs develop from a low-grade dysplastic nodule to a high-grade dysplastic nodule and finally to hypervascular HCC [23,24]. Imaging of the liver is an important technique in the detection and diagnosis of HCC. ...
Background & Aims
Liver computed tomography and dynamic magnetic resonance imaging play an important role in the early detection of hepatocellular carcinoma. However, the American Association for the Study of Liver Diseases (AASLD) recommend the use of applied imaging studies for HCC diagnosis only in cirrhotic patients. This study aimed to comprehensively compare liver CT and dynamic MRI for HCC diagnosis before surgical resection over years in clinical practice, and also to compare the diagnostic differences between liver CT and dynamic MRI in HCCs with varying degrees of fibrosis.
Methods
841 patients with liver tumor who had liver CT or dynamic MRI examinations followed by surgical resection were included in the study. We defined typical HCC imaging characteristics as early enhancement in the artery phase and early washout in the venous phase. The tumor size was recorded based on pathological examination after surgery. The pathologic fibrosis score was verified by the METAVIR scoring classification.
Results
Among the 841 patients, 756 underwent liver CT and 204 underwent dynamic liver MRI before surgery. The etiologies of chronic liver disease included hepatitis B virus, hepatitis C virus, hepatitis B and C virus, and non-hepatitis B or C virus. The sensitivity and accuracy of liver CT or MRI for HCC diagnosis was approximately 80%~90%. Liver CT had a diagnostic accuracy for HCC similar to that of dynamic MRI, and liver fibrosis stage did not influence their diagnostic efficacies.
Conclusions
The application of 4-phase dynamic CT and MRI exhibit similar diagnostic accuracy for hepatocellular carcinoma, in tumors of sizes 1 to 2 cm and >2 cm. Liver fibrosis status did not affect the diagnostic accuracy of liver CT or MRI for HCC. The AASLD and EASL restrictions of dynamic imaging studies for HCC diagnosis to cirrhotic patients alone are unnecessary.
... Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide [1]. HCC develops through a multistep carcinogenic process from a dysplastic nodule (DN), to well-differentiated HCC, and finally to overt hypervascular HCC (moderate to poorly differentiated HCC) [2][3][4][5]. There is a well-known correlation between the hemodynamics of HCC and its physiology. ...
Background:
Hypovascular nodules often occur together with hypervascular hepatocellular carcinoma (HCC). However, it remains controversial whether hypovascular nodules associated with hypervascular HCC have any prognostic value. This study evaluated the prognostic impact of hypovascular nodules co-existing with hypervascular HCC as diagnosed by computed tomography during arterial portography (CTAP) and computed tomography during hepatic arteriography (CTHA), which can sensitively capture the dynamic changes in blood flow through the portal vein and hepatic artery in patients with early stage HCC.
Methods:
A total of 152 patients with hypervascular HCC (? 30 mm, ? 3 nodules), who underwent initial local ablation, were analyzed retrospectively. All patients received CTAP and CTHA prior to treatment. Overall survival (OS) was compared among group A (hypervascular HCC only, 107 patients) and group B (hypovascular nodules and hypervascular HCC, 45 patients).
Results:
Among all hypovascular nodules, 81% (46 of 57) developed hypervascularization within the follow-up period. The 1- and 2-year hypervascularization rates were 17% and 51%, respectively. OS was significantly longer for group A than for group B (P < 0.001). A Cox proportional-hazards model identified the presence of hypovascular nodules concurrent with hypervascular HCC as an independent poor prognostic factor.
Conclusion:
The prognosis of hypervascular HCC patients with hypovascular nodules detected during CTAP and CTHA is poor. Clinical HCC categories seem to be dissimilar between patients with and without hypovascular nodules.
The high morbidity rate of hepatocellular carcinoma (HCC) is mainly linked to late diagnosis. Early diagnosis of this leading cause of mortality is therefore extremely important. We designed a gene selection strategy to identify potential secretory proteins by predicting signal peptide cleavage sites in amino acid sequences derived from transcriptome data of human multistage HCC comprising chronic hepatitis, liver cirrhosis and early and overt HCCs. The gene selection process was validated by the detection of molecules in the serum of HCC patients. From the computational approaches, 10 gene elements were suggested as potent candidate secretory markers for detecting HCC patients. ELISA testing of serum showed that hyaluronan mediated motility receptor (HMMR), neurexophilin 4 (NXPH4), paired like homeodomain 1 (PITX1) and thrombospondin 4 (THBS4) are early-stage HCC diagnostic markers with superior predictive capability in a large cohort of HCC patients. In the assessment of differential diagnostic accuracy, receiver operating characteristic curve analyses showed that HMMR and THBS4 were superior to α-fetoprotein (AFP) in diagnosing HCC, as evidenced by the high area under the curve, sensitivity, specificity, accuracy and other values. In addition, comparative analysis of all four markers and AFP combinations demonstrated that HMMR-PITX1-AFP and HMMR-NXPH4-PITX1 trios were the optimal combinations for reaching 100% accuracy in HCC diagnosis. Serum proteins HMMR, NXPH4, PITX1 and THBS4 can complement measurement of AFP in diagnosing HCC and improve identification of patients with AFP-negative HCC as well as discriminate HCC from non-malignant chronic liver disease.
MR imaging is useful in the diagnosis and early detection of HCC. Characteristic findings for overt HCC, a pseudocapsule and an intratumoral mosaic pattern, are better demonstrated on MR imaging than by other imaging modalities such as ultrasound and CT scanning. Signal intensity on T2-weighted images is useful in evaluating the grade of malignancy of hepatocytic nodular lesions. Hyperintensity on T1-weighted MR imaging is almost always seen in precancerous hepatocellular lesions and in about one third of overt HCC tumors, whereas other hepatic tumors show hypointensity on T1-weighted MR imaging. In evaluating tumor vascularity, gadolinium-enhanced dynamic MR imaging is an essential and powerful tool.
Hepatocellular carcinoma (HCC) belongs to the most prevalent and deadliest cancers worldwide. It can be attributed to well-defined risk factors (mainly chronic viral hepatitis and alcoholic/nonalcoholic steatohepatitis) leading to liver cirrhosis, a premalignant condition for the development of preneoplastic hepatocellular lesions and finally liver cancer. By applying strict morphological criteria and a panel of immunohistological markers, early HCC can be differentiated from its precursor lesions and other highly differentiated hepatocellular lesions even in most biopsy specimens. Integrative characterization led to the association of histological features and molecular subgroups of human HCC. This potentially relevant clinical development was recognized by the recently updated WHO classification of liver cancer resulting in the introduction of several HCC subtypes. These are characterized by a distinct combination of histological and molecular features, biological behavior, and clinical characteristics, allowing for a distinction from other HCC without specified features. Whether this development sets the corner stone for precision oncology of human HCC patients must be monitored.
Objectives
To compare interreader agreement and diagnostic accuracy of LI-RADS v2018 categorization using quantitative versus qualitative MRI assessment of arterial phase hyperenhancement (APHE) and washout (WO) of focal liver lesions.Methods
Sixty patients (19 female; mean age, 56 years) at risk for HCC with 71 liver lesions (28 HCCs, 43 benign) who underwent contrast-enhanced MRI were included in this retrospective study. Four blinded radiologists independently assigned a qualitative LI-RADS score per lesion. Two other radiologists placed ROIs within the lesion, adjacent liver parenchyma, and paraspinal musculature on pre- and post-contrast MR images. The percentage of arterial enhancement and the liver-to-lesion contrast ratio were calculated for quantification of APHE and WO. Using these quantitative parameters, a quantitative LI-RADS score was assigned. Interreader agreement and AUCs were calculated.ResultsInterreader agreement was similar for qualitative and quantitative LI-RADS (κ = 0.38 vs. 0.40–0.47) with a tendency towards improved agreement for quantitatively assessed APHE (κ = 0.65 vs. 0.81) and WO (κ = 0.53 vs. 0.78). Qualitative LI-RADS showed an AUC of 0.86, 0.94, 0.94, and 0.91 for readers 1, 2, 3, and 4, respectively. The quantitative LI-RADS score where APHE/WO/or both were replaced showed an AUC of 0.89/0.84/0.89, 0.95/0.92/0.92, 0.93/0.91/0.89, and 0.91/0.86/0.88 for readers 1, 2, 3, and 4, respectively. Sensitivity of LR-4/5 slightly increased, while specificity slightly decreased using quantitative APHE.Conclusion
Qualitative and quantitative LI-RADS showed similar performance. Quantitatively assessed APHE showed the potential to increase interreader agreement and sensitivity of HCC diagnosis, whereas quantitatively assessed WO had the opposite effect and needs to be redefined.Key Points
• Quantitative assessment of arterial phase hyperenhancement shows the potential to increase interreader agreement and sensitivity to diagnose hepatocellular carcinoma.
• Adding quantitative measurements of major LI-RADS features does not improve accuracy over qualitative assessment alone according to the LI-RADS v2018 algorithm.
Background and aim:
Intermediate-stage hepatocellular carcinoma (HCC) targeted for transcatheter arterial chemoembolization (TACE) corresponds to a highly heterogeneous population for whom the factors predicting TACE efficacy have not been established. This study aimed to evaluate the impact of hypovascular hepatic nodules coexisting with intermediate-stage HCC as a significant predictive factor for TACE refractoriness.
Methods:
Sixty-six patients with intermediate-stage HCC who received initial TACE were retrospectively analyzed. Hypovascular hepatic nodules were detected by dynamic computed tomography or magnetic resonance imaging, as well as angiography, prior to all initial TACE. The time to TACE refractoriness (TTTR) was defined as the period from initial TACE until the diagnosis of TACE refractoriness.
Results:
Hypovascular hepatic nodules were detected in 36 patients (54.5%), 15 (41.7%) of whom had a single nodule, while 21 (58.3%) had multiple nodules, and the median size of the maximum nodule was 10 mm (range 5-80 mm). The median TTTR was 17.4 months in all patients and 7.3 and 33.1 months in patients with and without hypovascular hepatic nodules, respectively. The TTTR was significantly shorter for patients with hypovascular hepatic nodules than that for the other patients. In the multivariate analysis, the presence of hypovascular hepatic nodules (hazard ratio (HR), 7.016; 95% CI, 3.534-13.930; p < 0.001) and being out of the up-to-7 criteria (HR, 2.861; 95% CI, 1.493-5.486; p = 0.002) were independent risk factors for a short TTTR.
Conclusions:
The presence of hypovascular hepatic nodules with intermediate-stage HCC represents a significant predictive risk factor for TACE refractoriness.
OBJECTIVE. The objective of our study was to identify sonographic biomarkers predicting or indicating eventual malignant transformation of pathologically confirmed cirrhotic nodules. MATERIALS AND METHODS. Thirty-nine consecutive patients with 44 pathologically confirmed cirrhotic nodules (mean size, 17.5 ± 8.5 [SD] mm) who initially underwent contrast-enhanced ultrasound examination at detection and then underwent follow-up conventional ultrasound every 3-4 months thereafter were retrospectively included. Malignant transformation was identified on the basis of noninvasive diagnostic criteria for hepatocellular carcinoma or rebiopsy. Malignant transformation biomarkers were identified from clinical and sonographic variables and the performance thereof was evaluated using ROC curves. RESULTS. Fourteen nodules (31.8%) had eventual malignant transformation after a median follow-up time of 26.7 months. At initial detection, nodule size (hazard ratio [HR], 1.07; p = 0.019) and a contrast arrival time difference between the nodule and liver of more than 0.5 second (HR, 4.35; p = 0.011) were independent predictors for malignant transformation. The area under the ROC curve (A
z
) of initial nodule size (A
z
= 0.64, p = 0.131) and contrast arrival time difference between the nodule and liver (A
z
= 0.66, p = 0.029) improved after combining the two (A
z
= 0.75, p = 0.002). During follow-up, echogenicity change (p = 0.044), absolute growth rate (p < 0.001), and relative growth rate (p < 0.001) correlated with malignant transformation. Sensitivity analysis revealed that an absolute growth rate of 5 mm or greater in 6 months or a relative growth rate of 30% or greater in 6 months could be considered as threshold growth for identifying malignant transformation (specificity, 100.0%; positive predictive value, 100.0%). The absence of both echogenicity change and threshold growth was highly accurate in excluding malignant transformation (sensitivity, 100.0%; negative predictive value, 100.0%). CONCLUSION. The contrast arrival time difference between the nodule and liver at initial detection was useful in stratifying eventual malignant transformation risk for cirrhotic nodules. During follow-up, growth rate and echogenicity change correlated with malignant transformation; threshold growth on ultrasound may be considered a potential major feature in noninvasive diagnostic criteria of hepatocellular carcinoma.
Background and Aim
The natural course and clinical implications of hypovascular lesions on dynamic CT and/or Gd‐EOB‐DTPA‐enhanced MRI (EOB‐MRI) were investigated.
Methods
We followed the patients with hepatocellular carcinoma (HCC) who underwent hepatectomy between April 2009 and August 2012 to determine whether new classical HCCs developed from these unresected borderline lesions or emerged in different areas
Results
One hundred and eleven patients with hepatocellular carcinoma (HCC) were identified to have undergone examinations using both imaging modalities before hepatic resection. A total of 54 hypovascular lesions were detected. EOB‐MRI detected 51 lesions, while dynamic CT identified 21 lesions. Eleven lesions were resected at the time of the hepatectomy together with the main HCCs. Classical HCCs had developed from 52.5% of the 43 unresected lesions at 3 years after hepatic resection. Subsequently, we conducted a patient‐by‐patient analysis to compare the development of classical HCC from these hypovascular lesions and the emergence of de novo classical HCC in other areas. The 3‐year occurrence rate was 62.2% for the former group and 55.0% for the latter group (P = 0.83). Thus, although 52.2% of these hypovascular lesions had developed into classical HCCs at 3 years after the initial hepatectomy, de novo HCCs also occurred at other sites. Furthermore, new hypovascular lesions emerged after hepatectomy in 18‐29 % of patients irrespective of the presence or absence of hypovascular lesions at hepatectomy.
Conclusions
It remains uncertain whether these hypovascular lesions should be resected together with the main tumors at the time of hepatectomy.
Hepatocellular carcinoma (HCC) is one of the most common and most deadly cancers in the world. However, early detection through surveillance with ultrasonography will allow more effective treatment with a higher rate of cure. There are algorithms to identify those who are at sufficiently high risk to warrant surveillance. Surveillance methodology is established, and although the highest levels of evidence of efficacy are not available, the vast majority of studies do indicate that surveillance is effective in reducing mortality. Once a lesion has been identified by surveillance the recall procedures involve assessment of lesion size and radiological characteristics. If features diagnostic of HCC are found on imaging biopsy is not necessary. HCC is most often staged using the Barcelona Cancer of the Liver Clinic staging (BCLC). BCLC stage 0 is treated by local ablation, usually radiofrequency ablation. BCLC stage A is treated by resection, radiofrequency ablation, or liver transplantation depending on patient characteristics. BCLC stage B is usually treated by chemoembolization and BCLC stage C is treated with sorafenib. BCLC stage D is a terminal stage and requires best supportive care.
Cholangiocarcinoma is increasing in incidence. Unfortunately this cancer is seldom diagnosed early. If resection is not possible treatment is commonly with gemcitabine and cisplatin. A small number of patients can undergo liver transplantation after very aggressive surgery and chemotherapy.
In addition to classic HCC or cholangiocarcinoma there are variants which show features of both types, or features of a more stem cell phenotype. These are uncommon, and optimal treatment is unclear.
Purpose:
To evaluate outcomes and risk factors associated with hypervascularization in hypovascular, hepatobiliary phase (HBP) hypointense nodules (HHNs) without T2 hyperintensity on gadoxetic acid-enhanced magnetic resonance (MR) images in chronic liver disease patients.
Materials and methods:
222 HHNs were analyzed. Multivariate analysis with a Cox proportional hazard regression model was used.
Results:
41 nodules became hypervascular hepatocellular carcinoma (HCC). History of HCC, hyperintensity on T1WI or DWI, and higher growth rate were risk factors for hypervascularization (P < .05).
Conclusion:
History of HCC, hyperintensity on T1WI or DWI, and higher growth rate were associated with nodular progression to hypervascular HCC.
The Liver Imaging Reporting and Data System (LI-RADS) standardizes the interpretation, reporting, and data collection for imaging examinations in patients at risk for hepatocellular carcinoma (HCC). It assigns category codes reflecting relative probability of HCC to imaging-detected liver observations based on major and ancillary imaging features. LI-RADS also includes imaging features suggesting malignancy other than HCC. Supported and endorsed by the American College of Radiology (ACR), the system has been developed by a committee of radiologists, hepatologists, pathologists, surgeons, lexicon experts, and ACR staff, with input from the American Association for the Study of Liver Diseases and the Organ Procurement Transplantation Network/United Network for Organ Sharing. Development of LI-RADS has been based on literature review, expert opinion, rounds of testing and iteration, and feedback from users. This article summarizes and assesses the quality of evidence supporting each LI-RADS major feature for diagnosis of HCC, as well as of the LI-RADS imaging features suggesting malignancy other than HCC. Based on the evidence, recommendations are provided for or against their continued inclusion in LI-RADS. (©) RSNA, 2017 Online supplemental material is available for this article.
Introduction: HCC development in chronic Hepatitis C(CHC) cirrhotic patients may pass through two different path ways. One is (multistep) carcinogenesis process progressing from regeneration or cirrhotic nodule (RN) to low grade dysplastic nodule (LGDN), high grade dysplastic nodule (HGDN) then HCC. The other pathway is the de novo carcinogenesis.
Aim of the work: To assess the ability of DAA therapy to affect the progression of DNs to HCC .Also, we will assess the timing and pattern of HCC development.
Methods: Thirteen CHC patients (7 males and 6 females) with DNs discovered during their evaluation for DAA therapy.The presence of DN was first discovered by abdominal US and was confirmed by contrast enhanced (CE) abdominal CT or MRI. Response to antiviral therapy was evaluated by RT PCR at the end of treatment and 12 weeks post treatment.Change of the nature and diameter of DN was evaluated by CECT or MRI every 3 months.
Results:
At the end of treatment, RT PCR was below detection limit in 13 cases representing 100 % of cases. SVR(12 w) was achieved in 11 of 13 cases representing 84.6%.After 8 to 33 months of follow up (mean
15.23 months), the DN was changed to overt HCC in 5 cases (38.4 %), all of them occurred post treatment,3 of them had achieved SVR12, while 2 of them failed to achieve it. This figure is lower than that reported by Masahiro Kobayashi et al who reported that the HCC transformation rate of HGDN was 46.2% at one year in untreated chronic viral hepatitis patients.
Conclusion: DAA treatment of CHC patients with DNs does not accelerate their progression to HCC. The progression to HCC is
less than reported for untreated patients and is associated with treatment failure and more advanced liver disease at the end of treatment . Also, the progression of DN to HCC is not aggressive and all progressed cases are diagnosed at an early HCC stage.
Das hepatozelluläre Karzinom ist der weltweit vierthäufigste maligne Tumor mit einer Inzidenz von 20–150/100.000 Einwohner/Jahr in manchen Teilen von Asien und Afrika (Chen et al.1997). Es tritt wesentlich seltener in Westeuropa und in den Vereinigten Staaten (1–5/100.000 Einwohner/Jahr) auf, die niedrigste Inzidenz findet sich in Irland (0,1/100.000 Einwohner/Jahr). Es betrifft Männer im Schnitt 2- bis 4-mal häufiger als Frauen, wobei das Verhältnis ebenfalls geographischen Variationen unterliegt (Chen et al.1997).
The current classification system of liver segmental anatomy describes the liver as divided into eight independent functioning units or segments, each of which is served by its own vascular pedicle and biliary drainage. The current standard MRI examination of the liver includes a T2-weighted sequence, a T1-weighted sequence, and a dynamic contrast-enhanced sequence. The need for more accurate detection and characterization of the full spectrum of liver pathology has been the major impetus for continued development in intravenous contrast agents. Biliary hamartomas are benign biliary malformations, which are currently considered as part of the spectrum of fibropolycystic diseases of the liver due to ductal plate malformation. Characterization of focal liver lesions as benign or malignant is important because patients with known primary malignancies commonly have small hepatic lesions that are benign cysts or hemangiomas. Patients with congestive heart failure may present with hepatomegaly and hepatic enzyme elevations.
Computed tomography (CT) has always played a major role in liver imaging. Recent advances in magnetic resonance imaging (MRI) and ultrasound, such as three-dimensional high-resolution sequences, parallel imaging techniques, and new contrast agents, have also increased the popularity and utilization of these imaging methods (Bryant et al. 2004; Lee et al. 2000). Nevertheless, development of multidetector-row CT technology has helped CT continue to excel in its already established indications, i.e., detection and characterization of hepatic lesions, and to add new clinical indications, i.e., CT angiography for pre-procedural mapping and liver perfusion (Sahani et al., AJR 179(1):53–59, 2002; Sahani et al., Comput Assist Tomogr 28(4):478–484, 2004; Guiney et al., Radiology 229(2):401–407, 2003; Schroeder et al., Radiology 224(2):586–591, 2002). The rapid pace of development of this technology has challenged radiologists in terms of the cost of replacement of scanners, optimization of CT protocols for existing indications, and development of protocols for the new applications made possible by multidetector-row CT technology. This paper discusses the advantages of multidetector-row CT for liver imaging, suggests guidelines to improve image quality through optimization of scanning protocols and strategies for administration of contrast, and reviews the potential clinical applications.
We aimed to introduce the utility of diffusion-weighted images (DWI) in differentiating hepatocellular carcinoma (HCC) from dysplastic nodules (DN) in cirrhotic liver. DWI studies of the patients who had cirrhosis and HCC or cirrhosis and DN were evaluated retrospectively. Signal intensities of the lesions were classified as hyper-, iso- or hypointense on DWI. Apparent diffusion coefficient (ADC) and ADC ratios (the ratio between lesion ADC, and ADC of the surrounding liver parenchyma) was obtained, and mean values were compared. Statistical significance was set at p<0.05. Ninety-five lesions were diagnosed with HCC and forty-four lesions with DN from a total of 87 patients. The hyperintensity on DWI, mean ADC, and ADC ratio of HCCs were statistically significant (p<0.001 for all parameters). An ADC value of ≤ 1.316x10⁻³ mm²/s and an ADC ratio of ≤ 0.94 obtained by ROC curve analysis, were found to be the best cut-off values. DWI alone has a limited capability to detect HCC, but it can be used for imaging cirrhotic liver to supply ancillary findings in addition to dynamic contrast-enhanced MRI in diagnosing HCC.
In cirrhotic livers, several types of precursor lesions of hepatocellular carcinoma (HCC) have been identified. These lesions include both hepatocellular changes characterized by distinct atypias (small cell change and large cell change, previously termed small liver cell dysplasia and large liver cell dysplasia) and circumscribed dysplastic lesions that are either invisible on gross examination (dysplastic focus) or visible with the naked eye (dysplastic nodules). A dysplastic focus consists of a group of hepatocytes having dysplastic features, incidentally detected in histologic specimens and usually showing a diameter of less than 1 mm. Dysplastic hepatocytes in a dysplastic focus mostly show small cell change. Dysplastic nodules are single or multiple nodules ranging in diameter from few mm to 15 mm or even more. They are divided into two variants, low-grade dysplastic nodule and high-grade dysplastic nodules, depending on the degree of atypia. Dysplastic nodules have to be distinguished from large regenerative nodules (macroregenerative nodules).
In this chapter, we illustrate the imaging features of cirrhosis and the progression to hepatocellular carcinoma using an algorithmic approach. We will then discuss the various imaging features of hepatocellular carcinoma according to the LI-RADS (Liver Imaging-Reporting and Data Systems) criteria.
This chapter is intended to provide a state-of-the art overview of liver imaging with emphasis on the roles of sonography, CT, and MRI in the cirrhotic patient. Fundamentals of using imaging in a surveillance program to monitor the progression of cirrhosis and to detect hepatocellular carcinoma (HCC) are included. Imaging features are discussed that are useful in distinguishing among the various focal lesions that may be found in the cirrhotic liver, including regenerative, dysplastic, and malignant nodules.
Background:
Incidental detection of nonenhancing tumors during imaging studies for patients with classical hepatocellular carcinoma is not unusual. These tumors are considered to have a high potential of malignant transformation. The aim of this study was to clarify the natural history of such tumors.
Methods:
In 93 patients who underwent liver resection for hepatocellular carcinoma, 138 nonenhancing or enhancing nodules without washout were detected during dynamic computed tomography and observed without further treatments. We subsequently compared the cumulative occurrence of new hepatocellular carcinomas to that of the malignant transformation of these lesions. We additionally compared the appearance of new hepatocellular carcinomas between the patients with (n = 93) and without (n = 782) nonenhancing lesions or enhancing lesions without washout.
Results:
After a median follow-up period of 0.7 years (range, 0.2-6.8), the median intervals from resection to the appearance of new classical hepatocellular carcinoma and malignant transformation of nonenhancing lesions or enhancing lesions without washout were 1.6 years (95% confidence interval, 1.2-1.9) and 2.3 years (1.9-6.8 years; P = .002), respectively. On the other hand, the median intervals from resection to the appearance of new lesions in patients with and without nonenhancing lesions or enhancing lesions without washout were 1.6 years (95% confidence interval, 1.2-1.9) and 2.1 years (1.9-2.1 years; P = .031), respectively.
Conclusion:
During the natural history of nonenhancing lesions and enhancing lesions without washout that coexist with hepatocellular carcinoma, new lesions often develop prior to the malignant transformation of these lesions. This should be considered a risk factor for the appearance of new hepatocellular carcinoma.
Objectives
To evaluate the longitudinal risk to patients with cirrhosis of hypervascular hepatocellular carcinoma (HCC) developing from hypovascular hepatic nodules that show positive uptake of gadoxetic acid (hyperintensity) on hepatocyte phase images. Methods
In 69 patients, we evaluated findings from serial follow-up examinations of 633 hepatic nodules that appeared hypovascular and hyperintense on initial gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) until the nodules demonstrated hypervascularity and were diagnosed as hypervascular HCC. Cox analyses were performed to identify risk factors for the development of hypervascular HCCs from the nodules. ResultsThe median follow-up was 663 days (range, 110 to 1215 days). Hypervascular HCCs developed in six of the 633 nodules (0.9 %) in five of the 69 patients. The only independent risk factor, the nodule’s initial maximum diameter of 10 mm or larger, demonstrated a hazard ratio of 1.25. The one-year risk of hypervascular HCC developing from a nodule was 0.44 %. The risk was significantly higher for nodules of larger diameter (1.31 %) than those smaller than 10 mm (0.10 %, p < 0.01). Conclusions
Hypervascular HCC rarely develops from hypovascular, hyperintense hepatic nodules. We observed low risk even for nodules of 10 mm and larger diameter at initial examination. Key Points• Hypervascularization was rare on follow-up examination of hypovascular, hyperintense nodules• The risk of hypervascularization in a nodule increased with large size• Hypovascular, hyperintense nodules require neither treatment nor more intense follow-up
The epidemiology of hepatitis C-related hepatocellular carcinoma (HCC) is different in different parts of the world. In Italy, Japan, and other parts of Europe, the epidemic of hepatitis C started afar the World War II. In Japan, the epidemic seems to have peaked. Thus, hepatitis C-related HCC has been increasing in incidence, as patients with chronic hepatitis C age and develop advanced liver disease. However, in Japan the peak incidence of HCC might have passed. In Northern Europe and North America, the epidemic of hepatitis C infection started in the 1960s associated with injection drug use. Although the number of new cases of hepatitis C is not increasing any more, those who were infected in the 1960s–1980s have reached the age at which HCC is becoming common. Thus, there is a continued increase in hepatitis C-related HCC in these parts of the world. In addition, immigration from parts of the world where hepatitis C is common (Vietnam, Pakistan, Egypt) is contributing to the increase in HCC incidence. This trend is forecast to continue beyond 2020.
Cytochemical and electron microscopic investigations of neoplastic nodules induced in the rat liver by nitrosomorpholine or thioacetamide show that most neoplastic nodules are comprised of a rather heterogeneous cell population. At least four different types of altered hepatocytes can be distinguished: (a) "clear" glycogen storage cells with a dislocation and relative reduction of the granular endoplasmic reticulum; (b) "acidophilic" glycogen storage cells with a hypertrophy of the agranular endoplasmic reticulum; (c) fat-storing cells; and (d) basophilic cells poor in glycogen and rich in ribosomes. In addition, there are diverse intermediate cell types. The cytochemically demonstrable activity of glucose-6-phosphatase is reduced in most neoplastic nodules, but it may also be normal or even increased. The clear and the acidophilic cells precede the development of the neoplastic nodules by weeks and months. They usually form foci which are taken to be preneoplastic lesions. During the formation of neoplastic nodules and hepatocellular carcinomas originating for such foci the glycogen of the clear and the acidophilic cells is progressively reduced, whereas the number of ribosomes (basophilia) increases. This process, which may be accompanied by a transitory accumulation of fat, leads to the evolution of basophilic carcinoma cells. We conclude from these observations that the majority of the neoplastic nodules consist of a mixture of precancerous, definitely cancerous, and diverse intermediate cells. Neoplastic nodules in which basophilic cells prevail may already be carcinomas. Although the neoplastic nodules seem to be a frequent precursor of hepatocellular carcinomas, the latter may also develop without going through the nodule stage.
For the evaluation of adenomatous hyperplasia of the liver, which is a peculiar lesion easily mistaken for hepatocellular carcinoma (HCC), 83 cirrhotic livers with or without HCC were examined by means of gelatine injection methods. Nine cases with 11 lesions of adenomatous hyperplasia were found in this study (10.8%). Microangiographically, adenomatous hyperplasia was disclosed to be characterized by hypovascularity, a stretched but not enclosed vascular network enclosing the nodule and draining vessels with ordinary tapering. Corresponding to the microangiography, the presence of terminal portal triads was basically noted in the nodule. Results of the nuclear DNA estimation on adenomatous hyperplasia by microspectrophotometry also revealed different values from those of HCC. As to its possible precancerous state, adenomatous hyperplasia seems to be far distant from HCC.
The efficacy of various imaging procedures used for the diagnosis of small hepatocellular carcinomas (HCCs) (lesions no larger than 3 cm in diameter) was evaluated in a retrospective study of 100 patients. Seven patients with hepatic adenomatous hyperplastic nodules containing HCC foci were also assessed. In 89 patients, the lesion was initially detected during follow-up of chronic liver disease. In 21 patients, it was first diagnosed on the basis of elevated serum alpha-fetoprotein; in the remaining 79 it was diagnosed incidentally with imaging procedures. The overall sensitivities of sonography (84%), CT (84%), and angiography (81%) were compared with those of arterial angiographic CT (82%), portal angiographic CT (91%), lipiodol CT (93%), and intraoperative sonography (96%). The differences in sensitivity between angiography and lipiodol CT (p less than .05) and between intraoperative sonography and the other studies (p less than .01) were statistically significant. In 22 lesions smaller than 1 cm, the sensitivities of lipiodol CT and intraoperative sonography were high (83% and 86%, respectively). Adenomatous hyperplasias containing HCC foci were frequently detected by arterial angiographic CT and intraoperative sonography. These results show that sonography or CT and alpha-fetoprotein are useful in detecting small HCCs in screening programs of patients with chronic liver disease. Lipiodol CT and intraoperative sonography are necessary in patients who are candidates for surgery.
We describe the results of our study on the early detection of the development of hepatocellular carcinoma among patients with chronic liver disease. Over a period of 18 years, 33 patients were diagnosed as having hepatocellular carcinoma. From 1970 to 1978, we used serum alpha-fetoprotein determination, liver palpation, and radionuclide liver scans. In addition to alpha-fetoprotein determination, computed tomography and ultrasonography were introduced in 1979. However, we did not have any general guidelines for the use of these imaging modalities. From 1984 onwards, ultrasonography and serum alpha-fetoprotein determination have been performed every three months and computed tomography every year in patients whose right hepatic lobe had atrophied due to liver cirrhosis. On the basis of this screening program, 50% of the detected hepatocellular carcinoma (9/18) were found to be smaller than 1.9 cm in diameter, and tumor resection was performed in 11 out of 18 patients (61%).
From a series of 320 heptocellular carcinoma (HCC) cases treated surgically, we selected small nodular lesions that had not destroyed the preexisting liver structure grossly. After excluding metastases and large regenerative nodules, 58 lesions from 41 cases were chosen. All the lesions were hypercellular. Among them, 33 lesions showing histologic features of very well-differentiated HCC (Edmondson grade I), that is, small hepatocytes with little cellular atypia but with structural atypia, such as a thin trabecular structure of acinar formation in some areas, were classified as early HCC (eHCC). In seven eHCCs, areas of overt carcinoma, classified as Edmondson grade II, were found in the background of Edmondson grade I carcinoma. The remaining 25 lesions lacked structural atypia and were classified as adenomatous hyperplasia (AH). Among the AHs, 10 nodules with a very focal abnormal structure were subclassified as atypical adenomatous hyperplasia (AAH). There was a tendency for the size and cellularity of the atypical lesions to increase in order from AH to AAH to eHCC. All nodules larger than 1.5 cm were eHCC. A degree of cellularity more than twice that of a regenerative nodular was suggested to be an indicator of HCC. All small nodular lesions were associated with chronic liver disease. These histologic observations appear to explain the stepwise development of overt HCC from very well-differentiated eHCC, and of eHCC from AH probably through AAH, at least in cases of HCC associated with chronic liver disease.
A number of factors were analyzed for their predictive value in indicating the severity of haemolytic disease of the newborn (HDN) in 72 infants. The factors investigated were: maternal antibody titre in the indirect antiglobulin test, the number of antibody molecules on sensitized standard red cells evaluated by a radiometric antiglobulin test, the IgG subclass specificity and the reactivity in monocyte-monolayer assay (MMA) and in the rosette assays with lymphocytes and granulocytes from healthy individuals. The results of the MMA correlate much better with the severity of HDN than the antibody titre. In clinically unaffected infants the reactivity in the MMA never exceeded 20%, while in the severe/very severe group it was always greater than 20% (in 95% of very severe cases even above 50%). The number of IgG-bound molecules was also shown to closely correlate with the clinical severity and there was a much greater proportion of severe/very severe cases exhibiting combined IgG1 and IgG3 specificity. Of all the evaluations performed the rosette assays with lymphocytes and granulocytes were found to be less useful in predicting the severity of HDN.
Monoclonal antibodies specific for the Rh antigen D were used to sensitize red cells for use in a series of cellular assays. IgG3 anti-D was more efficient than IgG1 anti-D in promoting the attachment and lysis of red cells by human monocytes. In contrast, IgG1 anti-D was more efficient at mediating phagocytosis. The metabolic response of monocytes, measured by chemiluminescence (CL), was greater towards IgG3-sensitized red cells than IgG1-sensitized cells; however, the CL response was further increased when red cells were sensitized in antibody mixtures comprising both subclasses. Using monoclonal antibodies from five IgG1-secreting cell lines and from three IgG3-secreting cell lines, this synergistic increase was seen with 0/4 IgG1/IgG1 combinations, 0/2 IgG3/IgG3 combinations and 8/8 IgG1/IgG3 combinations. Synergism was observed only when both subclasses were present on the same red cells; mixing of IgG1-sensitized red cells with IgG3-sensitized red cells before addition to monocytes did not increase CL generation. The binding and phagocytosis of red cells by monocytes and the lysis of red cells by monocytes or lymphocytes were not greater when red cells were sensitized with IgG1 and IgG3 antibodies together compared to red cells coated with single subclasses.
Eight monoclonal antibodies (mabs) to the Rh antigen D produced by Epstein-Barr virus transformed B-lymphoblastoid cell lines from two individuals have been compared for their behaviour in in vitro cell-mediated assays. Three IgG1 Glm(1,17) and two IgG3 G3m(21) mabs from one donor and three IgG1 Glm(3) mabs from another were used. IgG3 anti-D mabs induced greater adherence and phagocytosis of sensitized red cells by U937 monocytes than IgG1 anti-D mabs or the polyclonal anti-D. Minimum sensitization levels for rosetting and phagocytosis by U937 monocytes were 2,000 molecules IgG/cell for IgG3 and 5,000 molecules/cell for IgG1 mabs; maximum rosetting mediated by both IgG1 and IgG3 mabs was obtained at 15,000-20,000 molecules/cell. The IgG3 anti-D mabs were comparable to polyclonal anti-D in mediating binding of sensitized red cells to gamma-interferon stimulated monocyte-derived cultured macrophages and were markedly more effective than the IgG1 anti-D mabs. However, in lymphocyte ADCC assays, only anti-D mabs which were IgG1 Glm(3) were effective in mediating high levels of lysis of sensitized red cells, unlike the IgG1 Glm (1,17) or IgG3 G3m(21) mabs. Minimum sensitization levels required for this lymphocyte-mediated red cell lysis were found to be approximately 5,000 molecules/cell with one IgG1 Glm(3) mab; maximum lysis with this mab was obtained at 10,000 molecules/cell. Polyclonal anti-D containing both IgG1 and IgG3 was effective in all three assays. These observations suggest that different isotypes and allotypes of anti-D antibodies mediate red cell removed or destruction by monocyte or lymphocyte effector cell through functionally dissimilar Fc receptor interactions.
Nodular hepatic lesions detected in 123 patients with chronic liver diseases were subjected to ultrasonically guided needle biopsy. Of these, 94 cases were diagnosed as hepatocellular carcinoma of a moderately or poorly differentiated type with classical histologic features of hepatocellular carcinoma. In 14 cases in whom hepatocytes had minimal atypical changes and were mostly of normotrabecular arrangement (one to two cells thick), a diagnosis of well-differentiated hepatocellular carcinoma was made on the basis of the following three histologic criteria: nuclear crowding, increased cytoplasmic basophilia and microacinar formation. The nodules which showed two or more of these findings were diagnosed as well-differentiated HCC. The diagnoses of these 14 cases were subsequently confirmed by clinical course, histology in the resected specimen and/or autopsy findings. The nodules that presented similar but equivocal changes were arbitrarily categorized as borderline lesions (five cases). The nodules showing the findings almost identical with those of pseudolobules were regarded as benign, large regenerative nodules (nine cases). The remaining one case had a hemangioma. Thus, these three histologic criteria proved to be useful in the biopsy diagnosis of nodular hepatic lesions, with certain limitations. Additionally, the majority of large regenerative nodules, borderline lesions and well-differentiated HCCs were found to be smaller than 2 cm.
Adenomatous hyperplastic nodules (AHNs) in the cirrhotic liver may be precurosors of hepatocellular carcinoma. These nodules have been demonstrated more frequently because of the increased use of ultrasonography (US) in the screening of high-risk patients. Treatment is a problem because surgical resection of a precancerous lesion is considered by some to be unadvisable in patients with high surgical risk. The authors used percutaneous ethanol injection with US guidance in five patients with AHNs that measured 1.4-2.6 cm. A total of 30 injections were performed, without complications. Lesions were undetectable or were reduced in size on follow-up US scans. All biopsies yielded necrotic material. No recurrences have been demonstrated with US after 9-21 months. Percutaneous ethanol injection is therefore proposed as a therapeutic alternative for small AHNs.
The livers of 345 autopsy cases of chronic liver disease were examined for macroregenerative nodule (MRN), a large nodular lesion more than 10 mm in diameter. A total of 86 lesions of MRN was found in 49 cases (14.2%): 32 were from 191 cases of hepatocellular carcinoma (HCC), 16 were from 148 cases of cirrhosis only, and one was from six cases of chronic hepatitis. The incidence (19.6%) and the size (12.1 mm) of MRN in macronodular type of cirrhosis were significantly higher and larger than those in other types of cirrhosis. Also, the average size of MRN lesions of cases with HCC (12 mm) was significantly larger than that of cases with cirrhosis only (10.5 mm). The incidence of liver cell dysplasia (LCD) in cases of MRN (67.3%) was significantly higher than that in cases without MRN (40.9%). The MRN lesions were divided into Type I and Type II, the latter having proliferative foci distinguishable from the surrounding tissue. Three of them contained atypical cells regarded as cancer. Type II lesions were larger in size, and cases with multiple MRN lesions were seen more frequently in cases of HCC. The average age of the patients with Type II lesion was 5 years older than those with Type I lesions. These findings suggest that MRN should not be ignored in the morphogenesis of HCC.
We present details of two separate nodular lesions of atypical adenomatous hyperplasia, within one of which a small area of overt hepatocellular carcinoma was detected. The patient was positive for serum hepatitis B surface antigen, and Southern blot analysis revealed that deoxyribonucleic acid from the lesions of hepatocellular carcinoma and surrounding atypical adenomatous hyperplasia showed the same restriction pattern of integrated hepatitis B virus deoxyribonucleic acid, indicating that the two lesions were derived from an identical clone. It was also indicated that the two separate lesions of atypical adenomatous hyperplasia were independently derived through clonal expansion of different cells.
One hundred five hepatocellular carcinomas less than 5 cm in diameter were resected in 75 patients. The tumors were studied with respect to their detection rate by angiography and their angiographic features. Angiography identified 86 (82%) of the 105 lesions, missing 19 (18%). The findings included tumor vessels (70%) and tumor staining (76%). Pathologic analysis of the 19 undetected lesions showed that 74% of them were smaller than 2 cm in diameter and that they were well-differentiated carcinomas. Forty percent of 100 lesions were in the anterosuperior subsegment of the right lobe.
Four IgG1 and three IgG3 human monoclonal antibodies specific for the blood group D(Rh) antigen were tested for their ability to mediate red cell-binding to macrophages in vitro. The IgG3 monoclonals were found to opsonize at a density of approximately 100 molecules per red cell, whereas the IgG1 antibodies were only active at a level of 10,000 molecules per cell. There was no substantial difference between the two IgG subclasses in their ability to bind to Fc receptors on macrophages and it is suggested that the more potent opsonic activity of IgG3 is the result of the relatively long hinge, leading to greater accessibility to the Fc receptor binding site on the Fc piece.
The Fc receptors on mononuclear cells were investigated by a rosette technique in which human erythrocytes were sensitized with a known number of molecules of anti-Rh antibodies (IgG1 or IgG3). The number of IgG molecules was quantitated by a radiometric antiglobulin test. The present quantitative evaluation reveals that (1) there is a logarithmic relationship between the proportion of rosettes and the amount of erythrocyte-bound immunoglobulin for both types of mononuclear cells, and for both subclasses; (2) similar percentage of rosettes can be obtained with fewer IgG3 than IgG1 molecules (about 1:4); (3) for a given number of erythrocyte-bound immunoglobulins a higher percentage of rosettes is observed with monocytes than with lymphocytes (ratios of about 3:1 for IgG1 and 5:1 for IgG3); (4) the minimum number of IgG3 molecules for adherence is 180-460 for monocytes, 520-1,300 for lymphocytes, whilst for IgG1 the numbers are 1,180-4,300 for monocytes and 3,400-14,200 for lymphocytes; (5) the minimum levels of sensitization by alloantibodies for adherence should be detectable by the antiglobulin test.
Five cases of an adenomatous hyperplastic nodule or a similar lesion resected from a cirrhotic liver in which early malignant foci were seen as small nodule-in-nodule lesions are described. These hyperplastic lesions were detected by imaging diagnosis in patients with nonalcoholic cirrhosis, mostly during routine clinical follow-up. In 2 patients, recurrence of hepatocellular carcinoma occurred 11 mo and 15 mo postresection. Thus, these nodule-in-nodule lesions in an adenomatous hyperplastic nodule seem to represent an early stage of hepatocarcinogenesis in humans. In nonalcoholic cirrhotic patients from Japan and Southeast Asia, in whom hepatocellular carcinoma is endemic, an adenomatous hyperplastic nodule or a similar hyperplastic lesion that occurs in cirrhotic livers may be preneoplastic and already committed to malignant transformation.
Fifty five small hepatocellular carcinoma less than 5 cm in diameter among 41 patients were examined by linear arrayed electronic scanning system with 3.5 MHz transducer. Characteristics of the sonogram were enhanced posterior echoes of the tumor, mosaic pattern of internal echoes, halo and lateral shadows. These findings are appeared in 69%, 64%, 35% and 22% of tumors respectively. Among 45 tumors from 2.1 cm to 5 cm in diameter, these findings are appeared in 81%, 73%, 40% and 24% respectively. Among 10 tumors less than 2 cm in diameter, these characteristics were rare and these minimal hepatocellular carcinomas were demonstrated as a simple low echo area. Fifty tumors in 39 patients were resected. Lobulation of the hepatocellular carcinoma on the cut surface of the resected specimen and mosaic pattern on the sonogram are closely connected with each other. Thin fibrous capsule of the hepatocellular carcinoma corresponded to halo and lateral shadows. Posterior echo enhancement was due to the softness of the hepatocellular carcinoma. By those four characteristics, hepatocellular carcinoma can be differentiated from hemangioma and metastatic liver tumor.
Forty-two patients with hepatic tumors were examined by serial computed tomography (CT), using bolus injection of contrast medium. Scanning was at 15, 60, and 120 sec postinjection at a slice level containing the tumor. The densities of the tumor, liver, and aorta were sampled on these and on precontrast CT images. The tumors were divided into four types according to the pattern derived by sequential plotting of the density difference between the tumor and the liver parenchyma. Type I manifested rapid and prolonged high tumor enhancement, in type II the tumor was enhanced rapidly but then quickly became less dense than the liver, in type III there was no significant change over time in the density difference between the tumor and the liver, and type IV showed no, or very little, tumor enhancement. All cavernous hemangiomas belonged to type I while two-thirds of the hepatomas wer type II. There was a good correlation between tumor vascularity on CT and angiography. We suggest that dynamic serial CT scanning technique may be an improvement over the conventional drip-infusion technique in assessing liver tumors.
MD); Division of Hematology and Oncology
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Viral Epidemiology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 (S. Z Wiktor, MD, W. A. Blattner, MD); Division of Hematology and Oncology, University of Alabama, Birmingham, Alabama 35294 (G. M. Shaw, MD); Department of Laboratory Medicine, University of California, San Francisco, California 94110 (E L. Murphy, MD). Correspondence to Dr M. Essex, Department of Cancer Biology, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
Hemolytic disease of the newborn American Association of Blood Banks Malignant transformation of adenomatous ADDRESSES: Departments of Surgery
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Benign epithelial tumors and tumorlike lesions of the liver
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Macroregenerative nodule of the liver: a clinicopathologic study of 345 autopsy cases of chronic liver disease
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