Overt Hepatocellular Carcinoma Research Articles

Serum Proteins, HMMR, NXPH4, PITX1 and THBS4; A Panel of Biomarkers for Early Diagnosis of Hepatocellular Carcinoma.

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.

Morphological, dynamic and functional characteristics of liver pseudolesions and benign lesions.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and one of the most common causes of death among patients with cirrhosis, developing in 1-8% of them every year, regardless of their cirrhotic stage. The radiological features of HCC are almost always sufficient for reaching the diagnosis; thus, histological confirmation is rarely needed. However, the study of cirrhotic livers remains a challenge for radiologists due to the developing of fibrous and regenerative tissue that cause the distortion of normal liver parenchyma, changing the typical appearances of benign lesions and pseudolesions, which therefore may be misinterpreted as malignancies. In addition, a correct distinction between pseudolesions and malignancy is crucial to allow appropriate targeted therapy and avoid treatment delays.The present review encompasses technical pitfalls and describes focal benign lesions and pseudolesions that may be misinterpreted as HCC in cirrhotic livers, providing the imaging features of regenerative nodules, large regenerative nodules, siderotic nodules, hepatic hemangiomas (including rapidly filling and sclerosed hemangiomas), segmental hyperplasia, arterioportal shunts, focal confluent fibrosis and focal fatty changes. Lastly, the present review explores the most promising new imaging techniques that are emerging and that could help radiologists differentiate benign lesions and pseudolesions from overt HCC.

Minimal Hepatic Encephalopathy and Biejia-Ruangan Are Associated with First Hospital Readmission in Nonalcoholic Cirrhosis Patients.

Introductionand Aim. Patients with cirrhosis are often hospitalized repeatedly for a variety of complications. This retrospective study aimed to assess the effects of minimal hepatic encephalopathy (MHE) and Biejia-Ruangan (BR) on first hospital readmission in nonalcoholic cirrhosis patients without previous overt hepatic encephalopathy (OHE) or hepatocellular carcinoma (HCC). Materials and Methods. A total of 176 hospitalized patients with nonalcoholic cirrhosis were included in this retrospective study. Patients who were first admitted to Beijing Ditan Hospital of Capital Medical University from January 2017 to September 2019 were enrolled. The primary endpoint was their first liver-related hospital readmission. The risk factors for readmission were analyzed by Cox proportional hazard regression analysis. Results. A total of 176 nonalcoholic cirrhosis patients without previous OHE or HCC were included; 57 patients (32.4%) were diagnosed with MHE, and 63 patients (35.8%) were administered BR (2 g, three times a day). Multivariate analysis revealed that nonalcoholic cirrhosis patients with MHE (HR, 5.805; 95% CI, 3.007–11.206; x, P < 0.001) and a higher Model for End-Stage Liver Disease (MELD) score (HR, 1.145; 95% CI, 1.068–1.227; P < 0.001) had an increased risk of first hospital readmission, and patients treated with BR (HR, 0.318; 95% CI, 0.151–0.670; P=0.003) had a decreased risk of first hospital readmission. Conclusion. MHE increased the risk of hospital readmission in nonalcoholic cirrhosis patients without previous OHE or HCC, and this risk was decreased by BR administration.

Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression.

Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLL protein family, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC, as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC regardless of CTNNB1 mutation status because β-catenin did not translocate into the nucleus due to the E-cadherin/β-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC, with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in target genes. Similarly, cell-cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC, with TP53 or RB1 gene mutations associated with chromosomal deletion of 4q or 16q. HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Collectively, these data show that as HCC progresses, additional molecular events exclusive of driver gene mutations cooperatively contribute to transcriptional activation of downstream targets according to methylation status. SIGNIFICANCE: In addition to driver gene mutations in the WNT and p53 pathways, further molecular events are required for aberrant transcriptional activation of these pathways as HCC progresses.

Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis

An unexpected early increase in incidence, recurrence and clinical aggressiveness of hepatocellular carcinoma (HCC) has been reported (and refuted) in patients with HCV-related cirrhosis following direct-acting antiviral (DAA) treatment. To address this controversy, we performed a prospective multicenter study on consecutively enrolled cirrhotic patients, with or without a history of HCC, undergoing DAA therapy. A total of 1,161 HCC-free cirrhotics (group 1) and 124 cirrhotics who had received a curative treatment for an HCC (group 2) were enrolled. Clinical features, including presence of undefined/non-malignant liver nodules (UNMNs), were analyzed with respect to HCC incidence and recurrence. During a median study time of 17 months in group 1 and 16 months in group 2, de novo HCC developed in 48 patients (yearly incidence 3.1/100 patient-years, 75% BCLC 0-A) and recurred in 40 (mean yearly incidence 29.9/100 patient-years, 83% BCLC 0-A). A peak of HCC instant incidence was observed at 4.2 months in group 1 patients with UNMNs, and at 7.7 months in group 2. By multivariable Cox regression models, UNMNs (hazard ratio [HR] 3.11; 95% CI 1.47-6.57: p= 0.003), ascites detected any time before enrolment (HR 3.04; 95% CI 1.23-7.51; p= 0.02), and alpha-fetoprotein log-value (HR 1.90; 95% CI 1.05-3.44; p= 0.03) were the variables independently associated with the incidence of de novo HCC, while history of alcohol abuse (HR 2.10; 95% CI 1.08-4.09; p= 0.03) and history of recurrence of HCC (HR 2.87; 95% CI 1.35-6.09; p= 0.006) were associated with HCC recurrence. An early high incidence of both de novo HCC, in patients with UNMNs, and recurrent HCC was observed in DAA-treated patients; this was not accompanied by increased tumor aggressiveness. This prospective study focuses on the risk of developing de novo or recurrent hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment in patients with hepatitis C-related cirrhosis. We found that DAA treatment was associated with an early high HCC incidence in patients with undefined or non-malignant nodules, as well as in those with a history of complete response to HCC treatment. Whether this is related to the presence of clinically undetectable nests of cancer cells or to precancerous lesions that may progress to overt HCC upon DAA treatment remains unanswered. No evidence of increased clinical aggressiveness was reported in de novo or recurrent HCC.

Cone-Beam CT–Guided Chemoembolization in Patients with Complete Response after Previous Chemoembolization but Subsequent Elevated α-Fetoprotein without Overt Hepatocellular Carcinoma

PurposeTo evaluate the performance of C-arm computed tomography (CT)–guided chemoembolization in patients with hepatocellular carcinoma (HCC) with serum α-fetoprotein (AFP) level > 20 ng/mL but with no overt tumor on CT and/or magnetic resonance imaging. Materials and MethodsFrom May 2010 to May 2017, 34 patients with HCC (25 men and 9 women; mean age, 59.7 y) who had elevated serum AFP levels (> 20 ng/mL) but no overt tumor on 6-mo imaging studies and had shown complete response (CR) after previous chemoembolization underwent C-arm CT–guided conventional chemoembolization. Three radiologists retrospectively reviewed the imaging studies (preprocedural images, C-arm CT scans, and follow-up images) in consensus, and clinical data including AFP levels were retrospectively obtained. Tumor detection by C-arm CT and treatment response after chemoembolization were assessed. ResultsHCC was imaged at the time of chemoembolization in 24 of 34 patients (70.6%). C-arm CT detected tumors in 25 patients (73.5%); 23 detections were true positives, 2 were false positives, and 1 was a false negative (diaphragm metastasis). Among the 23 patients with true-positive results, the first follow-up enhanced imaging studies showed CR (n = 17), partial response (n = 1), progressive disease (n = 4), and indeterminate status (n = 1; treated by percutaneous ethanol injection). ConclusionsC-arm CT–guided chemoembolization may help to detect and treat recurrent tumors in patients who have shown CR after previous chemoembolization but subsequently, during follow-up surveillance, had serum AFP levels > 20 ng/mL without an overt tumor evident on imaging studies.

FRI-486-Serum cytokines and chemokines correlated with tumor recurrrence and survival after surgical resection for overt and occult HBV-related hepatocellular carcinoma

FRI-486-Serum cytokines and chemokines correlated with tumor recurrrence and survival after surgical resection for overt and occult HBV-related hepatocellular carcinoma

Abstract No. 516 C-arm CT-guided chemoembolization in patients with elevated alpha-fetoprotein without overt hepatocellular carcinoma after remission by chemoembolization

Abstract No. 516 C-arm CT-guided chemoembolization in patients with elevated alpha-fetoprotein without overt hepatocellular carcinoma after remission by chemoembolization

Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis.

Hepatocellular carcinoma (HCC) recurrently develops in cirrhotic liver containing a number of regenerative nodules (RNs). However, the biological tumorigenic potential of RNs is still unclear. To uncover the molecular bases of tumorigenesis in liver cirrhosis, we investigated the genetic aberrations in RNs of cirrhotic tissues using next-generation sequencing. We isolated 205 RNs and 7 HCC tissues from the whole explanted livers of 10 randomly selected patients who had undergone living-donor liver transplantation. Whole-exome sequencing and additional targeted deep sequencing on 30 selected HCC-related genes were conducted to reveal the mutational landscape of RNs and HCCs. Whole-exome sequencing demonstrated that RNs frequently harbored relatively high-abundance genetic alterations, suggesting a clonal structure of each RN in cirrhotic liver. The mutation signature observed in RNs was similar to those determined in HCC, characterized by a predominance of C>T transitions, followed by T>C and C>A mutations. Targeted deep sequencing analyses of RNs identified nonsynonymous low-abundance mutations in various tumor-related genes, including TP53 and ARID1A. In contrast, TERT promoter mutations were not detected in any of the RNs examined. Consistently, TERT expression levels in RNs were comparable to those in normal livers, whereas every HCC tissue demonstrated an elevated level of TERT expression. Analyses of RNs constructing cirrhotic liver indicated that a variety of genetic aberrations accumulate in the cirrhotic liver before the development of clinically and histologically overt HCC. These aberrations in RNs could provide the basis of tumorigenesis in patients with liver cirrhosis.

MR with Gd-EOB-DTPA in assessment of liver nodules in cirrhotic patients.

To date the imaging diagnosis of liver lesions is based mainly on the identification of vascular features, which are typical of overt hepatocellular carcinoma (HCC), but the hepatocarcinogenesis is a complex and multistep event during which, a spectrum of nodules develop within the liver parenchyma, including benign small and large regenerative nodule (RN), low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC, and well differentiated HCC. These nodules may be characterised not only on the basis of their respective different blood supplies, but also on their different hepatocyte function. Recently, in liver imaging the introduction of hepatobiliary magnetic resonance imaging contrast agent offered the clinicians the possibility to obtain, at once, information not only related to the vascular changes of liver nodules but also information on hepatocyte function. For this reasons this new approach becomes the most relevant diagnostic clue for differentiating low-risk nodules (LGDN-RN) from high-risk nodules (HGDN/early HCC or overt HCC) and consequently new diagnostic algorithms for HCC have been proposed. The use of hepatobiliary contrast agents is constantly increasing and gradually changing the standard of diagnosis of HCC. The main purpose of this review is to underline the added value of Gd-EOB-DTPA in early-stage diagnoses of HCC. We also analyse the guidelines for the diagnosis and management of HCC, the key concepts of HCC development, growth and spread and the imaging appearance of precursor nodules that eventually may transform into overt HCC.

Management of subcentimetre arterially enhancing and hepatobiliary hypointense lesions on gadoxetic acid-enhanced MRI in patients at risk for HCC.

To investigate the significance of subcentimetre (≤1cm) arterially enhancing and hepatobiliary hypointense lesions (SAELs) observed on gadoxetic acid-enhanced magnetic resonance imaging (MRI) of patients at risk of hepatocellular carcinoma (HCC). A SAEL was defined as a subcentimetre hypervascular nodule exhibiting a hepatobiliary phase defect on gadoxetic acid-enhanced MRI. We included 52 SAELs from 46 patients in a HCC surveillance population. The HCC reference standard was pathologic confirmation or a nodule >1cm with typical imaging features of HCC at follow-up imaging. The malignancy rate and HCC-favourable imaging findings of SAELs were evaluated. The malignancy rate among SAELs was 57.7% (30/52). At diagnosis, all SAELs that progressed to overt HCC were treatable with curative intention. Venous or late dynamic phase washout was more frequently observed with malignant SAELs than with benign SAELs (57.7% vs. 30.6%; P = 0.01). If SAELs exhibiting washout were considered as HCC, sensitivity, specificity, and positive predictive value was 83.3%, 50%, and 69.4%, respectively. Among patients at risk of HCC, SAELs on gadoxetic acid-enhanced MRI exhibited high malignant potential. However, close observation may be an appropriate strategy for isolated SAELs. A washout appearance may be helpful for predicting malignancy. • Gadoxetic acid-enhanced MRI provides hepatobiliary phase (HBP) images. • Screening frequently detects subcentimetre arterially enhancing and hepatobiliary hypointense lesions (SAELs). • A majority of SAELs progressed to overt HCC within 2years. • A venous-phase washout appearance correlated significantly with malignancy in SAELs.

Association between non-hypervascular hypointense nodules on gadoxetic acid-enhanced MRI and liver stiffness or hepatocellular carcinoma

PurposeTo assess the association between non-hypervascular hypointense nodules (NHHNs) on gadoxetic acid-enhanced magnetic resonance imaging (MRI) and liver stiffness (LS) in patients with chronic liver disease, and analyzed their progression to overt hepatocellular carcinoma (HCC). MethodsBetween August 2012 and March 2016, a total of 714 consecutive patients who had undergone transient elastography for LS measurement and gadoxetic acid-enhanced MRI were investigated. The association between the presence of NHHNs on the hepatobiliary phase and LS, and the patient’s HCC status [none, presence of treatment-naïve HCC, or a history of previous HCC treatment] was assessed. In patients with these nodules, cumulative progression rates of nodules to overt HCC were compared with rates of new HCC development in other parts of the liver. ResultsThe prevalence of NHHNs was 16.8% (120/714). The presence of these nodules was significantly associated with the log LS (Odds ratio [OR], 1.48, p=0.002) and hepatitis B virus infection (OR, 3.14, p=0.017), regardless of the patient’s HCC status. The two year cumulative progression rate of overt HCC from corresponding nodules and rate of progression to HCC in other parts of the liver were 34.1% and 18.3%, respectively (p=0.071). ConclusionThe presence of NHHNs on gadoxetic acid-enhanced MRI was associated with higher LS and hepatitis B virus infection. Furthermore, these lesions frequently progressed to overt HCC.

Subcentimeter hypervascular nodules with typical imaging findings of hepatocellular carcinoma on gadoxetic acid-enhanced MRI: Outcomes of early treatment and watchful waiting.

To compare treatment outcomes of subcentimeter hypervascular nodules at high risk for developing into hepatocellular carcinomas (SHNHR) between early treatment and watchful waiting until progression to overt hepatocellular carcinoma (HCC) groups. SHNHRs were defined as subcentimeter hypervascular nodules with the usual imaging features of HCC on gadoxetic acid-enhanced magnetic resonance imaging (MRI). Among 63 patients with 74 SHNHRs, 27 (37 SHNHRs) received early treatment (treatment of < 1cm nodules), and 36 (37 SHNHRs) underwent watchful waiting until progression to overt HCC. Risk factor analysis was performed for recurrence-free and local recurrence-free survival. Among the 36 patients who adopted watchful waiting, 33 eventually underwent treatment because their SHNHRs progressed to overt HCC. For recurrence-free survival, significant risk factors included number of previous treatments (HR, 1.181; p < 0.001), tumour number (HR, 1.943; p = 0.009), and α-feto protein level (HR, 1.005; p = 0.037) in the multivariate analyses. Treatment strategy was not a significant risk factor for recurrence-free survival. For local recurrence-free survival from the date of treatment, only treatment modality (transarterial chemoembolization) (HR, 6.879; p = 0.002) was a significant risk factor. Recurrence-free survival was not significantly different between early treatment and watchful waiting for SHNHRs. • Recurrence-free survival did not vary between the two treatment strategies. • Treatment modality was a significant factor for local recurrence-free survival. • Number of treatments, tumour number, and α-FP were risk factors for recurrence.

Detection of Endogenous Iron Reduction during Hepatocarcinogenesis at Susceptibility-Weighted MR Imaging: Value for Characterization of Hepatocellular Carcinoma and Dysplastic Nodule in Cirrhotic Liver.

ObjectiveTo investigate the value of susceptibility-weighted imaging (SWI) for characterization of hepatocellular carcinoma (HCC) and dysplastic nodule (DN).Materials and MethodsSixty-eight cirrhotic patients with 89 hepatocellular nodules underwent SWI. The radiological features of hepatocellular nodules on SWI were classified into three types: type A (iso- or hypointensity, and background liver siderosis), type B (hyperintensity, and background liver siderosis), or type C (hyperintensity, and no background liver siderosis). Intranodular and background liver iron content was quantified and correlated with SWI pattern. Prussian blue staining was performed to quantify intranodular and background liver iron content.ResultsType A pattern (n = 12) contained 11 (91.7%) DNs and 1 (8.3%) HCC, Type B pattern (n = 66) comprised 1 (1.5%) DN and 65 (98.5%) HCCs (including 12 DN-HCCs and 53 overt HCCs), and type C pattern (n = 11) was exclusively seen in HCCs. The iron scores of DN-HCCs and overt HCCs were significantly lower than those of background livers [(0.091±0.30) VS (2.18±0.87), P = 0.000; (0.11±0.41) VS (2.16±0.97), P = 0.000; respectively]. There was no significant difference between iron scores of DNs and those of background livers [(1.92±0.29) VS (2.17±039), P = 0.191]. For lesion-based and patient-based analysis of HCCs (DN-HCCs and overt HCCs), type B pattern showed a sensitivity, specificity, accuracy, positive predicative value (PPV), and negative predicative value (NPV) of 84.4% and 84.4%, 91.7% and 75%, 85.4% and 83.8%, 98.5% and 98.2%, 47.8% and 23.1%, respectively.ConclusionSWI can provide valuable information for characterization of HCC and DN based on endogenous iron reduction during hepatocarcinogenesis.

Circulating microRNAs as biomarkers for diagnosis of early hepatocellular carcinoma associated with hepatitis B virus.

Hepatocarcinogenesis is a multistep process that evolves from cirrhosis or dysplastic nodule (DN), and eventually leads to overt hepatocellular carcinoma (HCC). Differentiation between early HCC and DN is an important issue in the clinical setting. This study aims to investigate the potential of circulating microRNA (miRNA) levels in the diagnosis of early HCC. RNA was extracted from sera of 30 chronic hepatitis B patients with pathologically proven DN and 120 age- and sex-matched patients with early HCC. Paired samples were collected from ten patients with DN who developed overt HCC in the follow-up. A panel of ten cancer-associated miRNAs was analyzed by quantitative real-time reverse-transcription polymerase chain reaction. Serum levels of miR-16, miR-122, miR-221, let-7b and miR-15b were significantly lower in patients with DN than in the HCC group. When DN progressed to overt HCC, serum miR-122, miR-let-7b and miR-15b levels increased significantly (p = 0.046, 0.043 and 0.044, respectively). As a single marker, α-fetoprotein (AFP) and miR-122 as well as let-7b had the similar performance for differentiate HCC from DN. As limited to subjects with normal AFP, let-7b resulted in a sensitivity of 84.8% and a specificity of 50% in separating HCC and DN with a cutoff value of 3.5 (p = 0.001). In conclusion, miR-122 and let-7b, which are upregulated in the serum of early-HCC patients, can be useful markers for differentiating early HCC from DN in chronic hepatitis B patients.

Subcentimeter hypervascular nodule with typical imaging findings of hepatocellular carcinoma in patients with history of hepatocellular carcinoma: natural course on serial gadoxetic acid-enhanced MRI and diffusion-weighted imaging.

To evaluate the natural course of subcentimeter hypervascular nodules at high risk for developing into hepatocellular carcinomas (SHNHR) using serial magnetic resonance imaging (MRI) in patients with a history of hepatocellular carcinoma (HCC). An SHNHR was defined as a subcentimeter hypervascular nodule having typical imaging findings of HCC on gadoxetic acid-enhanced MRI and diffusion-weighted imaging. We included 39 patients with 46 SHNHRs (mean size ± standard deviation, 6.1 ± 1.6 mm; range, 3.2 - 9.0 mm). Overt HCC was defined as pathology proven HCC or a nodule larger than 1 cm with typical imaging findings of HCC. The cumulative rate and the independent predictive factors for progression to overt HCC were evaluated. The median follow-up period was 139 days (range, 64 - 392 days). The cumulative progression rate to overt HCC at 3, 6, 9, and 12 months was 13.9%, 61.7%, 83.2%, and 89.9%. The initial size of SHNHR was a significant predictor of progression to overt HCC, with an optimal cut-off value of 5.5 mm. The progression rate of SHNHR to overt HCC within 12 months was high (89.9%) in patients with history of HCC. The initial size of SHNHR was an important predictor for progression to overt HCC. • Most SHNHRs (89.9%) progressed to overt HCCs within 12 months. • Initial size was an important predictor for progression to overt HCCs. • The optimal cut-off value for initial nodule size was 5.5 mm.

CT and MR imaging diagnosis and staging of hepatocellular carcinoma: part I. Development, growth, and spread: key pathologic and imaging aspects.

Computed tomography (CT) and magnetic resonance (MR) imaging play critical roles in the diagnosis and staging of hepatocellular carcinoma (HCC). The first article of this two-part review discusses key concepts of HCC development, growth, and spread, emphasizing those features with imaging correlates and hence most relevant to radiologists; state-of-the-art CT and MR imaging technique with extracellular and hepatobiliary contrast agents; and the imaging appearance of precursor nodules that eventually may transform into overt HCC.

TIE2-expressing monocytes: a possible cellular diagnostic and prognostic biomarker for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and the third leading cause of cancer-related deaths worldwide (1). Major risk factors for HCC include chronic infection by hepatitis B virus (HBV) or hepatitis C virus (HCV) and alcoholic liver cirrhosis. Advanced and symptomatic HCC disease is not amenable to curative surgery, therefore screening programs for high-risk populations are implemented to increase early detection and effective surgical treatment of HCC (2). However, a definitive diagnosis of HCC requires concordant findings from several invasive and non-invasive diagnostic parameters, including liver biopsy, serum alpha-fetoprotein (AFP) levels, computed tomography, or magnetic resonance imaging (2). Nevertheless, noninvasive imaging is not sufficiently sensible for detecting an early-stage HCC, similarly AFP has low sensitivity and specificity to be used as a screening biomarker (3). In this framework, effective biomarkers for the early detection as well the progression of HCC are greatly needed. Matsubara et al. in Hepatology (4) described the possible significance of circulating CD14+CD16+ monocytes expressing Tyrosine kinase with Ig and EGF homology domains 2 (TIE2) [TIE2-expressing monocytes (TEMs)] as biomarkers for the detection of both early- and late-stage HCC. Indeed, TIE2 is mainly expressed on endothelial cells and binds all the known angiopoietins (ANGs) and TEMs are peripheral as well as tumor-infiltrating myeloid cells presumed to be characterized by a profound pro-angiogenic activity (5-7). In particular, TEMs have been reported in tumors of the kidney, colon, pancreas and lung, as well as in soft tissue sarcomas (7) where angiogenesis is known to be important for tumor progression. In this framework, HCC is a highly vascularized tumor, the progression of early lesions to overt HCC is strongly associated with increase of vasculature (8,9) and the antiangiogenic drug, sorafenib prolongs to a certain extent survival of patients with advanced HCC. Matsubara et al. (4) report on the frequency of circulating TEMs in a cohort of 168 HCV-infected patients, of which 89 were with HCC. The investigators found that the frequency of TEMs was significantly higher in patients with HCC than HCV-infected patients without HCC or healthy subjects. No difference was found among HCC patients at different stages of the disease, thus establishing TEMs as a stage-independent, diagnostic biomarker for HCC. In addition, higher blood TEM levels correlate to a worse recurrence-free survival after HCC resection or radiofrequency ablation (RFA) therapy, suggesting a role for TEMs also as prognostic biomarker. Furthermore, they also identified TEMs in HCC tumor lesions preferentially localized in perivascular tumor areas correlating with increased microvessel density in the tumors. Therefore, it’s possibly suggesting that HCC-infiltrating TEMs are proangiogenic. Moreover, high circulating and intratumoral TEM levels correlate with a more advanced Child-Pugh stage, suggesting that TEM frequency correlates positively with the degree of liver inflammation/stage of cirrhosis and negatively with liver function. The biology underlying TEM’s involvement in human tumor angiogenesis and progression is essentially unknown and several questions need to be addressed in order to possibly improve HCC anti-angiogenetic therapy. Indeed, the proangiogenic activity exerted by TEMs in HCC may represent one of the reasons for the limited efficacy of sorafenib or other antiangiogenic treatments. Furthermore, elevated circulating levels of the TIE2 ligand, ANG2, correlate with a worse prognosis in untreated HCC patients and predict shorter survival in HCC patients treated with Sorafenib (10). The study by Matsubara et al. (4) is the first to present evidence suggesting that circulating TEMs may be a diagnostic biomarker for both early- and late-stage HCC, although they are not strictly peculiar of HCC but detectable also in other tumors (5,7). These very interesting findings need to be validated on a larger scale of HCC patients to confirm the relevance of TEMs as diagnostic/prognostic marker for HCC as well as therapeutic target for improving the efficacy of current treatments for HCC.

Oxidative damage in the progression of chronic liver disease to hepatocellular carcinoma: An intricate pathway

The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma (HCC) are still ill-defined; however, there is increasing evidence that the gradual accumulation of mutations, genetic and epigenetic changes which occur in preneoplastic hepatocytes results in the development of dysplastic foci, nodules, and finally, overt HCC. As well as many other neoplasias, liver cancer is considered an "inflammatory cancer", arising from a context of inflammation, and characterized by inflammation-related mechanisms that favor tumor cell survival, proliferation, and invasion. Molecular mechanisms that link inflammation and neoplasia have been widely investigated, and it has been well established that inflammatory cells recruited at these sites with ongoing inflammatory activity release chemokines that enhance the production of reactive oxygen species. The latter, in turn, probably have a major pathogenic role in the continuum starting from hepatitis followed by chronic inflammation, and ultimately leading to cancer. The relationship amongst chronic liver injury, free radical production, and development of HCC is explored in the present review, particularly in the light of the complex network that involves oxidative DNA damage, cytokine synthesis, telomere dysfunction, and microRNA regulation.

Hemodynamics and progression of a hypervascular focus in a borderline lesion of hepatocellular carcinoma: analysis by angiography-assisted CT and histopathology

To investigate the hemodynamics and progression of a hypervascular focus (HF) in a borderline lesion by dual-phase CT during hepatic arteriography (CTHA) and reveal the process of the transformation to hypervascular overt hepatocellular carcinoma (HCC). This study was performed with the approval of our institutional ethics committee, and informed consent for the retrospective usage of clinical materials was obtained from all the patients. The 121 nodules in 76 consecutive patients with liver cirrhosis and chronic hepatitis showing an HF in a borderline lesion on angiography-assisted CT were analyzed. Hemodynamic changes were observed in 24 patients who underwent repeated angiography-assisted CT. Histopathological analysis was conducted in eight nodules. HF was classifiable into type A (stain disappeared), B (stain prolonged), C (stain was washed out and corona-like drainage into the outer nodule was seen) and D (stain was washed out and corona-like drainage into the whole outer nodule was seen) on the late phase of CTHA and was seen to progress in this order on follow-up observation. Histopathologically, de-differentiated foci showed significantly higher expression of sinusoidal capillarization and unpaired arteries than background nodules and showed pseudocapsule, compressive and replacing growth at the border of the background nodule. HF showed multi-step progression and transformation to hypervascular overt HCC.