To identify magnetic resonance (MR) imaging features that enable prediction of early recurrence (<2 years) after curative resection of hepatocellular carcinoma (HCC) and to derive a preoperative ...prediction model.
This retrospective study was approved by the institutional review board. The requirement to obtain written informed consent was waived. A total of 268 patients who underwent hepatic resection for a single HCC from January 2008 to August 2011 were divided into two cohorts: a training cohort, which was used to derive a prediction model (n = 187), and a validation cohort (n = 81). All MR images from the training cohort were reviewed by two radiologists. A prediction model was constructed by using MR imaging features that were independently associated with early recurrence with use of multiple logistic regression analysis. The performance of the prediction model in the validation cohort was evaluated with respect to discrimination (ie, whether the relative ranking of individual predictions of subsequent early recurrence is in the correct order).
In the training cohort, four MR imaging features were independently associated with early recurrence: rim enhancement (odds ratio OR = 3.83; 95% confidence interval CI: 1.39, 10.52), peritumoral parenchymal enhancement in the arterial phase (OR = 2.64; 95% CI: 1.27, 5.46), satellite nodule (OR = 4.07; 95% CI: 1.09, 15.21), and tumor size (OR = 1.66; 95% CI: 1.31, 2.09). A prediction model derived from these variables showed an area under the receiver operating characteristic curve (AUC) of 0.788 in the prediction of the risk of early recurrence in the training cohort. When applied to the validation cohort, this model showed good discrimination (AUC, 0.783).
The prediction model derived from rim enhancement, peritumoral parenchymal enhancement, satellite nodule, and tumor size can be used preoperatively to estimate the risk of early recurrence after resection of a single HCC.
There is increasing evidence to support a multistep model of the process of human hepatocarcinogenesis. Precursor lesions are characterized by the appearance of dysplastic lesions in the form of ...microscopic dysplastic foci and macroscopic dysplastic nodules. There are 2 types of small hepatocellular carcinoma (HCC) (≤2 cm in diameter): (1) early HCC with an indistinct margin and (2) progressed HCC with a distinct margin. Pathologic diagnostic criteria for early HCC have recently been set up based on a consensus between Eastern and Western pathologists.
To review the nomenclature, pathology, and biomarkers of precursor and early lesions of HCC.
Literature review and illustrations from case materials were used.
Dysplastic foci are composed of large and small cell changes. Small cell change is considered to be a more advanced precursor lesion than large cell change, and large cell change is a rather heterogeneous lesion that may represent both reactive change and true dysplasia. Dysplastic nodules can be categorized as low or high grade according to the degree of atypia. High-grade dysplastic nodules have been reported to show molecular changes similar to HCC and have a high risk of malignant transformation. Early HCC, which may correspond to microinvasive carcinomas of other organs, is a well-differentiated HCC, and differential diagnosis between early HCC and high-grade dysplastic nodule is difficult. Identification of stromal invasion and application of a panel of markers (glypican-3, heat shock protein 70, and glutamine synthetase) is helpful for diagnosis of early HCC. Detection of precursor lesions of HCC is important in recognizing patients with higher risk of developing HCC, and diagnosis of early HCC can improve patient survival by allowing for early and adequate treatment.
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver carcinoma showing variable degrees of differentiation toward hepatocellular and cholangiocellular carcinoma. Its great ...heterogeneity in term of morphology, immunophenotype, molecular, radiological and clinical features represents a challenge still to overcome. The multidisciplinary 2018 International Consensus on the nomenclature of cHCC-CCA allowed to define key issues of this entity. Here we review the historical controversies of cHCC-CCA, resume the key elements of the 2018 consensus, now incorporated in the 2019 WHO classification, and propose a short survival guide to help surgical pathologists facing cHCC-CCA in their routine workup.
We investigated the clinical significance of a vascular growth pattern of hepatocellular carcinoma (HCC), the vessels that encapsulate tumor clusters (VETC), previously linked to HCC metastatic ...dissemination. VETC was assessed in a large multi‐institutional cohort of 541 resected HCCs from Italy, Korea and Japan, and matched against a full spectrum of clinical and pathological variables. The VETC phenotype (defined as ≥ 55% tumor area by CD34 immunostaining) was easily reproducible and reliably detectable in whole sections and small‐sized tissues of tissue microarray. VETC HCCs represented 18.9% of the whole series, the lowest proportion occurring in the cohort with smallest tumors (8.7%, Japanese series). VETC was significantly associated with several clinical and pathological features such as high alfa‐fetoprotein (AFP) level, tumor size greater than 5 cm, poor differentiation, macrotrabecular pattern, less compact pattern, less inflammatory infiltrates, and frequent microvascular invasion. VETC was associated with early recurrence (hazard ratio HR: 1.52 1.06‐2.19, P = 0.023), disease‐free survival (HR: 1.66 1.21‐2.27, P = 0.002), and overall survival (HR: 2.26 1.37‐3.72, P = 0.001) at multivariable analysis. VETC affected the survival in HCC patients stratified for etiology (hepatitis C virus/hepatitis B virus), vascular invasion, and specific molecular phenotypes (β‐catenin/GS+). This distinct vascular pattern was enriched in the recently reported macrotrabecular massive HCC subtype, which was seen in 7.8% (42 of 541) of patients and associated with high AFP levels and poor differentiation. Conclusion: The VETC pattern was found to be easily detectable in a consistent fraction of HCC and a powerful pathological finding affecting survival. This study suggests that the heterogeneous pattern of angiogenesis is involved in HCC behavior.
Sestrins (Sesns) protect cells from oxidative stress. The mechanism underlying the antioxidant effect of Sesns has remained unknown, however. The Nrf2-Keap1 pathway provides cellular defense against ...oxidative stress by controlling the expression of antioxidant enzymes. We now show that Sesn1 and Sesn2 interact with the Nrf2 suppressor Keap1, the autophagy substrate p62, and the ubiquitin ligase Rbx1 and that the antioxidant function of Sesns is mediated through activation of Nrf2 in a manner reliant on p62-dependent autophagic degradation of Keap1. Sesn2 was upregulated in the liver of mice subjected to fasting or subsequent refeeding with a high-carbohydrate, fat-free diet, whereas only refeeding promoted Keap1 degradation and Nrf2 activation, because only refeeding induced p62 expression. Ablation of Sesn2 blocked Keap1 degradation and Nrf2 activation induced by refeeding and thereby increased the susceptibility of the liver to oxidative damage resulting from the acute stimulation of lipogenesis associated with refeeding.
► Sestrins activate the Nrf2 pathway by promoting the autophagic degradation of Keap1 ► Keap1 degradation is fully dependent on the autophagy substrate p62 ► Keap1 degradation occurs in mice fed with high-carbohydrate, fat-free diets after fasting ► Sestrin2-deficient mice are susceptible to ROS damage resulting from the refeeding
Despite the clinical and genetic significance of macrotrabecular-massive hepatocellular carcinoma (MTM-HCC), its characteristics on imaging have not been described. This study aimed to characterise ...MTM-HCC on gadoxetic acid-enhanced MRI and to evaluate the diagnostic accuracy and prognostic value of these imaging characteristics.
We enrolled 3 independent cohorts from 2 tertiary care centres. The 3 cohorts consisted of a total of 476 patients who underwent gadoxetic acid-enhanced MRI and surgical resection for treatment-naïve single HCCs. Independent review of histopathology and MRI by 2 reviewers was performed for each cohort, and inter-reader agreement was evaluated. Based on the result of MRI review in the training cohort (cohort 1), we developed 2 diagnostic criteria for MTM-HCC and evaluated their prognostic significance. The diagnostic performance and prognostic significance were validated in 2 validation cohorts (cohorts 2 and 3).
We developed 2 diagnostic MRI criteria (MRIC) for MTM-HCC: MRIC-1, ≥20% arterial phase hypovascular component; MRIC-2, ≥50% hypovascular component and 2 or more ancillary findings (intratumoural artery, arterial phase peritumoural enhancement, and non-smooth tumour margin). MRIC-1 showed high sensitivity and negative predictive value (88% and 95% in the training cohort, and 88% and 97% in the pooled validation cohorts, respectively), whereas MRIC-2 demonstrated moderate sensitivity and high specificity (47% and 94% in the training cohort, and 46% and 96% in the pooled validation cohorts, respectively). MRIC-2 was an independent poor prognostic factor for overall survival in both training and pooled validation cohorts.
Using gadoxetic acid-enhanced MRI findings, including an arterial phase hypovascular component, we could stratify the probability of MTM-HCC and non-invasively obtain prognostic information.
Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a histopathologic subtype of HCC characterised by aggressive biological behaviour and poor prognosis. We developed imaging criteria based on liver MRI that could be used for the non-invasive diagnosis of MTM-HCC. HCCs showing imaging findings of MTM-HCC were associated with poor outcomes after hepatic resection.
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•Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is an aggressive subtype of HCC.•We revealed gadoxetic acid-enhanced MRI findings related to MTM-HCC.•Using MRI findings, we could non-invasively stratify the probability of MTM-HCC.•HCC without an arterial phase hypovascular component is highly unlikely to be MTM-HCC.•MRI findings of MTM-HCC could be a useful prognostic factor after surgical resection.
Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analyzed 489 CCAs from 10 countries, combining whole-genome (71 ...cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined 4 CCA clusters-fluke-positive CCAs (clusters 1/2) are enriched in
amplifications and
mutations; conversely, fluke-negative CCAs (clusters 3/4) exhibit high copy-number alterations and
/
expression, or epigenetic mutations (
) and
/
-related gene rearrangements. Whole-genome analysis highlighted
3' untranslated region deletion as a mechanism of
upregulation. Integration of noncoding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores-mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics, and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.
Integrated whole-genome and epigenomic analysis of CCA on an international scale identifies new CCA driver genes, noncoding promoter mutations, and structural variants. CCA molecular landscapes differ radically by etiology, underscoring how distinct cancer subtypes in the same organ may arise through different extrinsic and intrinsic carcinogenic processes.
.
Primary liver cancers (LCs), including HCC and intrahepatic cholangiocarcinoma (iCCA), are derived from a common developmental lineage, conferring a molecular spectrum between them. To elucidate the ...molecular spectrum, we performed an integrative analysis of transcriptome profiles associated with patients' radiopathologic features.
We identified four LC subtypes (LC1-LC4) from RNA-sequencing profiles, revealing intermediate subtypes between HCC and iCCA. LC1 is a typical HCC characterized by active bile acid metabolism, telomerase reverse transcriptase promoter mutations, and high uptake of gadoxetic acid in MRI. LC2 is an iCCA-like HCC characterized by expression of the progenitor cell-like trait, tumor protein p53 mutations, and rim arterial-phase hyperenhancement in MRI. LC3 is an HCC-like iCCA, mainly small duct (SD) type, associated with HCC-related etiologic factors. LC4 is further subclassified into LC4-SD and LC4-large duct iCCAs according to the pathological features, which exhibited distinct genetic variations (e.g., KRAS , isocitrate dehydrogenase 1/2 mutation, and FGF receptor 2 fusion), stromal type, and prognostic outcomes.
Our integrated view of the molecular spectrum of LCs can identify subtypes associated with transcriptomic, genomic, and radiopathologic features, providing mechanistic insights into heterogeneous LC progression.
Purpose
To define the optimal lexicon of major imaging findings on gadoxetic acid-enhanced MRIs to diagnose HCC to improve diagnostic performance of the LI-RADS.
Methods
Two hundred forty-one hepatic ...lesions (149 HCC, six other malignancies, 86 benign lesions) in 177 treatment-naïve patients at risk of HCC who underwent gadoxetic acid-MRIs from January 2013 to December 2015 were retrospectively reviewed using either histopathological or follow-up imaging findings as a standard reference. Two board-certified radiologists independently evaluated the imaging features and categorized the nodules based on the original and the following modified definitions in LI-RADS: (1) washout appearance in the portal venous phase (PVP) only versus that in the PVP or transitional phase, and (2) enhancing capsule only versus enhancing or non-enhancing capsule. Diagnostic performance and inter-observer agreement of LR-5 were assessed and compared between the algorithms using generalized estimation equation.
Results
The sensitivity 79.2% (95% confidence interval 71.9, 85.0) and accuracy 84.6% (79.5, 88.7) of LR-5 were significantly higher for modified lexicon compared with original LI-RADS 60.4% (52.3, 67.9) and 73.9% (67.9, 79.0);
P
< 0.001 in all cases. There was no significant difference in specificity 93.5% (86.2, 97.0) and 95.7% (89.0, 98.4);
P
= 0.153. Subgroups of lesions < or ≥ 2 cm showed similar tendencies. Inter-observer agreement for capsule appearance was fair to moderate, whereas that for other imaging findings was good to excellent.
Conclusions
Compared to original LI-RADS, LI-RADS with modified lexicon showed higher sensitivity for the diagnosis of HCC using gadoxetic acid-MRI, with similar specificity.
Liver stiffness measurement (LSM) using FibroScan accurately assesses the degree of liver fibrosis and the risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. ...This study investigated the usefulness of LSM as a predictor of HCC development in patients with chronic hepatitis B (CHB). A total of 1,130 patients with non‐biopsy–proven CHB who underwent LSM between May 2005 and December 2007 were enrolled in this prospective study. After LSM was performed, patients attended regular follow‐up as part of a surveillance program for the detection of HCC. The mean age of the patients (767 men, 363 women) was 50.2 years, and the median LSM was 7.7 kPa. Six hundred seventy‐two (59.5%) patients received antiviral treatment before or after enrollment. During the follow‐up period (median, 30.7 months; range, 24.0‐50.9 months), HCC developed in 57 patients (2.0% per 1 person‐year). The 1‐, 2‐, and 3‐year cumulative incidence rates of HCC were 0.80%, 3.26%, and 5.98%, respectively. On multivariate analysis, together with old age, male sex, heavy alcohol consumption (>80 g/day), serum albumin, and hepatitis B e antigen positivity, patients with a higher LSM (>8 kPa) were at a significantly greater risk of HCC development, with the following hazard ratios: 3.07 (95% confidence interval CI, 1.01‐9.31; P = 0.047) for LSM 8.1‐13 kPa; 4.68 (95% CI, 1.40‐15.64; P = 0.012) for LSM 13.1‐18 kPa; 5.55 (95% CI, 1.53–20.04; P = 0.009) for LSM 18.1‐23 kPa; and 6.60 (95% CI, 1.83‐23.84; P = 0.004) for LSM >23 kPa. Conclusion: Our data suggest that LSM could be a useful predictor of HCC development in patients with CHB. (HEPATOLOGY 2011)
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