Comprehensive characterization of viral integrations and genomic aberrations in HBV-infected intrahepatic cholangiocarcinomas.

BACKGROUND AND AIMS: Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought to identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV-infected iCCA (HBV-iCCA) tumors. APPROACH AND RESULTS: We profiled a cohort of 108 HBV-iCCAs using whole-genome sequencing, deep sequencing, and RNA sequencing, together with preconstructed data sets of HBV-infected HCC (HBV-HCC; n = 167) and combined hepatocellular cholangiocarcinoma (HBV-cHCC/CCA; n = 59), and conventional (n = 154) and fluke-related iCCAs (n = 16). Platforms based on primary iCCA cell lines to evaluate the functional effects of chimeric transcripts were also used. We found that HBV had inserted at multiple sites in the iCCA genomes in 45 (41.7%) of the tumors. Recurrent viral integration breakpoints were found at nine different sites. The most common insertional hotspot (7 tumors) was in the TERT (telomerase reverse transcriptase) promoter, where insertions and mutations (11 tumors) were mutually exclusive, and were accompanied by promoter hyperactivity. Recurrent HBV integration events (5 tumors) were also detected in FAT2 (FAT atypical cadherin 2), and were associated with enrichment of epithelial-mesenchymal transition-related genes. A distinctive intergenic insertion (chr9p21.3), between DMRTA1 (DMRT like family A1) and LINC01239 (long intergenic non-protein coding RNA 1239), had oncogenic effects through activation of the mammalian target of rapamycin (mTOR)/4EBP/S6K pathway. Regarding the mutational profiles of primary liver cancers, the overall landscape of HBV-iCCA was closer to that of nonviral conventional iCCA, than to HBV-HCC and HBV-cHCC/CCA. CONCLUSIONS: Our findings provide insight into the behavior of iCCAs driven by various pathogenic mechanisms involving HBV integration events and associated genomic aberrations. This knowledge should be of use in managing HBV carriers.

Standardizing the histological assessment of late posttransplantation biopsies from pediatric liver allograft recipients.

Excellent short-term survival after pediatric liver transplantation (LT) has shifted attention toward the optimization of long-term outcomes. Despite considerable progress in imaging and other noninvasive modalities, liver biopsies continue to be required to monitor allograft health and to titrate immunosuppression. However, a standardized approach to the detailed assessment of long-term graft histology is currently lacking. The aim of this study was to formulate a list of histopathological features relevant for the assessment of long-surviving liver allograft health and to develop an approach for assessing the presence and severity of these features in a standardized manner. Whole-slide digital images from 31 biopsies obtained ≥4 years after transplantation to determine eligibility for an immunosuppression withdrawal trial were selected to illustrate a range of typical histopathological findings seen in children with clinically stable grafts, including those associated with alloantibodies. Fifty histological features were independently assessed and, where appropriate, scored semiquantitatively by six pathologists to determine inter- and intraobserver reproducibility of the histopathological features using unweighted and weighted kappa statistics; the latter metric enabled distinction between minor and major disagreements in parameter severity scoring. Weighted interobserver kappa statistics showed a high level of agreement for various parameters of inflammation, interface activity, fibrosis, and microvascular injury. Intraobserver agreement for these features was even more substantial. The results of this study will help to standardize the assessment of biopsies from long-surviving liver allografts, aid the recognition of important histological features, and facilitate international comparisons and clinical trials aiming to improve outcomes for children undergoing LT.

Prognostic Molecular Indices of Resectable Hepatocellular Carcinoma: Implications of S100P for Early Recurrence.

BACKGROUND: Although hepatocellular carcinomas (HCCs) often recur in patients undergoing hepatectomy, there are no reliable biomarkers of this undesirable event. Recent RNA-based efforts have developed valuable genetic indices prognostic of cancer outcomes. We aimed to identify molecular predictors of early recurrence after resection of HCC, and reveal the genomolecular structure of the resected tumors. METHOD: Based on the transcriptomic and genomic datasets of 206 HCC samples surgically resected in the Asan Medical Center (AMC), we performed a differential gene expression analysis to identify quantitative markers associated with early recurrence and used the unsupervised clustering method to classify genomolecular subtypes. RESULTS: Differential gene expression profiling revealed that S100P was the highest-ranked overexpressed gene in HCCs that recurred within 2 years of surgery. This trend was reproduced in immunohistochemical studies of the original cohort and an independent AMC cohort. S100P expression also independently predicted HCC-specific mortality post-resection (adjusted hazard ratio 1.09, 95% confidence interval 1.01-1.19; p = 0.042). Validation in a Chinese cohort and in in vitro experiments confirmed the prognostic value of S100P in HCC. We further identified five discrete molecular subtypes of HCC; a subtype with stem cell features ('AMC-C4') was associated with the worst prognosis, both in our series and another two Asian datasets, and S100P was most strongly upregulated in that subtype. CONCLUSION: We identified a promising prognostic biomolecule, S100P, associated with early recurrence after HCC resection, and established the genomolecular architecture of tumors affecting clinical outcomes, particularly in Asian patients. These new insights into molecular mediators should contribute to effective care for affected patients.

Clinicopathological and molecular characterization of chromophobe hepatocellular carcinoma.

BACKGROUND AND AIMS: Chromophobe hepatocellular carcinoma (HCC) is a newly included subtype of HCC in the 5th edition of the WHO classification with distinctive histological features (chromophobic cytoplasm with anaplastic nuclei and pseudocyst formation) and is strongly associated with the alternative lengthening of telomeres (ALT) phenotype. However, the clinicopathologic characterization and molecular features of chromophobe HCC are unknown. METHODS: To comprehensively characterize chromophobe HCC, whole exome sequencing, copy number variation, and transcriptomic analyses were performed in 224 surgically resected HCC cases. Additionally, telomere-specific fluorescence in situ hybridization was used to assess ALT. These genomic profiles and ALT status were compared with clinicopathological features among subtypes of HCC, particularly chromophobe HCC and conventional HCC. RESULTS: Chromophobe HCC was observed in 10.3% (23/224) cases and, compared to conventional HCC, was more frequent in females (P = .023). The overall and recurrence-free survival outcomes were similar between patients with chromophobe HCC and conventional HCC. However, chromophobe HCC displayed significantly more upregulated genes involving cell cycle progression and DNA repair. Additionally, ALT was significantly enriched in chromophobe HCC (87%; 20/23) compared to conventional HCC (2.2%, 4/178; P < .001). Somatic mutations in ALT-associated genes, including ATRX, SMARCAL1, FANCG, FANCM, SP100, TSPYL5, and RAD52 were more frequent in chromophobe HCC (30.4%, 7/23 cases) compared to conventional HCC (11.8%, 21/178 cases; P = .024). CONCLUSIONS: Chromophobe HCC is a unique subtype of HCC with a prevalence of ~10%. Compared to conventional HCC, chromophobe HCC is associated with female predominance and ALT, although overall and recurrence-free outcomes are similar to conventional HCC.

Radiologic-Pathologic Correlation of Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement at Gadoxetic Acid-enhanced MRI: A Multicenter Study.

Background Hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) at gadoxetic acid-enhanced MRI may indicate hepatocellular carcinoma (HCC) or nonmalignant cirrhosis-associated nodules. Purpose To assess the distribution of pathologic diagnoses of HBP hypointense nodules without APHE at gadoxetic acid-enhanced MRI and to evaluate clinical and imaging features in differentiating their histologic grades. Materials and Methods This retrospective multicenter study included pathologic analysis-confirmed HBP hypointense nodules without APHE (≤30 mm) in patients with chronic liver disease or cirrhosis screened between January 2008 and June 2016. Central pathologic review by 10 pathologists determined final histologic grades as progressed HCC, early HCC, high-grade dysplastic nodule (DN), and low-grade DN or regenerative nodule. Gadoxetic acid-enhanced MRI features were analyzed by three radiologists. Multivariable logistic regression analyses with elastic net regularization were performed to identify clinical and imaging features for differentiating histologic grades. Results There were 298 patients (mean age, 59 years ± 10; 226 men) with 334 nodules evaluated, and progressed HCCs were diagnosed in 44.0% (147 of 334), early HCCs in 20.4% (68 of 334), high-grade DNs in 27.5% (92 of 334), and low-grade DNs or regenerative nodules in 8.1% (27 of 334). Serum α-fetoprotein level 100 ng/mL or greater (odds ratio, 2.7; P = .01) and MRI features including well-defined margin (odds ratio, 5.5; P = .003), hypointensity at precontrast T1-weighted imaging (odds ratio, 3.2; P < .001), intermediate hyperintensity at T2-weighted imaging (odds ratio, 3.4; P < .001), and restricted diffusion (odds ratio, 1.9; P = .04) were independent predictors for progressed HCC at multivariable analysis. Conclusion In patients at high risk for hepatocellular carcinoma (HCC), hepatobiliary phase hypointense nodules without arterial phase hyperenhancement at gadoxetic acid-enhanced MRI corresponded mainly to progressed HCCs, early HCCs, and high-grade dysplastic nodules. High α-fetoprotein level and some imaging features at MRI helped to differentiate progressed HCC from lower grade nodules. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Motosugi in this issue.

Assessment of liver fibrosis severity using computed tomography-based liver and spleen volumetric indices in patients with chronic liver disease.

OBJECTIVES: To evaluate whether the liver and spleen volumetric indices, measured on portal venous phase CT images, could be used to assess liver fibrosis severity in chronic liver disease. METHODS: From 2007 to 2017, 558 patients (mean age 48.7 ± 13.1 years; 284 men and 274 women) with chronic liver disease (n = 513) or healthy liver (n = 45) were retrospectively enrolled. The liver volume (sVolL) and spleen volume (sVolS), normalized to body surface area and liver-to-spleen volume ratio (VolL/VolS), were measured on CT images using a deep learning algorithm. The correlation between the volumetric indices and the pathologic liver fibrosis stages combined with the presence of decompensation (F0, F1, F2, F3, F4C [compensated cirrhosis], and F4D [decompensated cirrhosis]) were assessed using Spearman's correlation coefficient. The performance of the volumetric indices in the diagnosis of advanced fibrosis, cirrhosis, and decompensated cirrhosis were evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: The sVolS (ρ = 0.47-0.73; p < .001) and VolL/VolS (ρ = -0.77-- 0.48; p < .001) showed significant correlation with liver fibrosis stage in all etiological subgroups (i.e., viral hepatitis, alcoholic and non-alcoholic fatty liver, and autoimmune diseases), while the significant correlation of sVolL was noted only in the viral hepatitis subgroup (ρ = - 0.55; p < .001). To diagnose advanced fibrosis, cirrhosis, and decompensated cirrhosis, the VolL/VolS (AUC 0.82-0.88) and sVolS (AUC 0.82-0.87) significantly outperformed the sVolL (AUC 0.63-0.72; p < .001). CONCLUSION: The VolL/VolS and sVolS may be used for assessing liver fibrosis severity in chronic liver disease. KEY POINTS: • Volumetric indices of liver and spleen measured on computed tomography images may allow liver fibrosis severity to be assessed in patients with chronic liver disease.

Immunogenomic landscape of hepatocellular carcinoma with immune cell stroma and EBV-positive tumor-infiltrating lymphocytes.

BACKGROUND & AIMS: The immunogenomic characteristics of hepatocellular carcinomas (HCCs) with immune cell stroma (HCC-IS), defined histologically, have not been clarified. We investigated the clinical and molecular features of HCC-IS and the prognostic impact of Epstein-Barr virus (EBV) infection. METHODS: We evaluated 219 patients with conventional HCC (C-HCC) and 47 with HCC-IS using in situ hybridization for EBV, immunohistochemistry, multiplex immunofluorescence staining, and whole exome and transcriptome sequencing. Human leukocyte antigen types were also extracted from the sequencing data. Genomic and prognostic parameters were compared between HCC-IS and C-HCC. RESULTS: CD8 T cell infiltration was more frequent in HCC-IS than C-HCC (mean fraction/sample, 22.6% vs. 8.9%, false discovery rate q <0.001), as was EBV positivity in CD20-positive tumor-infiltrating lymphocytes (TILs) (74.5% vs. 4.6%, p <0.001). CTNNB1 mutations were not identified in any HCC-IS, while they were present in 24.1% of C-HCC (p = 0.016). Inhibitory and stimulatory immune modulators were expressed at similar levels in HCC-IS and EBV-positive C-HCC. Global hypermethylation, and expression of PD-1 and PD-L1 in TILs, and PD-L1 in tumors, were also associated with HCC-IS (p <0.001), whereas human leukocyte antigen type did not differ according to HCC type or EBV positivity. HCC-IS was an independent factor for favorable recurrence-free survival (adjusted hazard ratio [aHR] 0.23; p = 0.002). However, a subgroup of tumors with a high density of EBV-positive TILs had poorer recurrence-free (aHR 25.48; p <0.001) and overall (aHR 9.6; p = 0.003) survival, and significant enrichment of CD8 T cell exhaustion signatures (q = 0.0296). CONCLUSIONS: HCC-IS is a distinct HCC subtype associated with a good prognosis and frequent EBV-positive TILs. However, paradoxically, a high density of EBV-positive TILs in tumors is associated with inferior prognostic outcomes. Patients with HCC-IS could be candidates for immunotherapy. LAY SUMMARY: Hepatocellular carcinomas with histologic evidence of abundant immune cell infiltration are characterized by frequent activation of Epstein-Barr virus in tumor-infiltrating lymphocytes and less aggressive clinical behavior. However, a high density of Epstein-Barr virus-positive tumor-infiltrating lymphocytes is associated with inferior prognostic outcomes, possibly as a result of immune escape due to significant CD8 T cell exhaustion.

LI-RADS Classification and Prognosis of Primary Liver Cancers at Gadoxetic Acid-enhanced MRI.

Purpose To (a) evaluate the postsurgical prognostic implication of the Liver Imaging Reporting and Data System (LI-RADS) categories of primary liver cancers and (b) determine the performance of LI-RADS version 2017 in differentiating hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (IHCC) and combined hepatocellular-cholangiocarcinoma (cHCC-CC) at gadoxetic acid-enhanced MRI. Materials and Methods In this retrospective study, 194 patients with cirrhosis and surgically proven single primary liver cancer (53 with cHCC-CC, 44 with IHCC, and 97 with HCC) were evaluated with gadoxetic acid-enhanced MRI between 2009 and 2014. The mean patient age was 57 years (age range, 30-83 years). There were 155 men with a mean age of 56 years (range, 30-81 years) and 39 women with a mean age of 58 years (range, 38-83 years). Two independent readers assigned an LI-RADS category for each nodule. Overall survival (OS), recurrence-free survival (RFS), and their associated factors were evaluated by using the Kaplan-Meier method, log-rank test, and Cox proportional hazard model. Results In the multivariable analysis, the LI-RADS category was an independent factor for OS (hazard ratio, 4.2; P < .001) and RFS (hazard ratio, 2.6; P = .01). The LR-M category showed more correlation with poorer OS and RFS than did the LR-4 or LR-5 category for all primary liver cancers (P < .001 for both), HCCs (P = .01 and P < .001, respectively), and cHCC-CCs (P = .01 and P = .03, respectively). The LR-5 category had a sensitivity of 69% (67 of 97) and a specificity of 87% (84 of 97) in the diagnosis of HCC; most false-positive diagnoses (85%, 11 of 13) were the result of misclassification of cHCC-CCs. Conclusion The Liver Imaging Reporting and Data System (LI-RADS) category was associated with postsurgical prognosis of primary liver cancers, independent of pathologic diagnosis. The LI-RADS enabled the correct classification of most hepatocellular carcinomas (HCCs) and intrahepatic cholangiocarcinomas, whereas differentiation of combined hepatocellular-cholangiocarcinoma from HCC was unreliable. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Bashir and Chernyak in this issue.

Xanthogranulomatous cholecystitis shows overlapping histological features with IgG4-related cholecystitis.

AIMS: Xanthogranulomatous cholecystitis (XGC), an unusual histological variant of chronic cholecystitis, is characterised by mixed foamy histiocytic and lymphoplasmocytic infiltration and fibrosis. Radiologically, the poorly defined nodular growth pattern often leads to the misinterpretation of XGC as gallbladder cancer. In this study, we aimed to identify the relationship of XGC with IgG4-related cholecystitis. METHODS AND RESULTS: We re-evaluated 57 surgically resected XGCs and 104 conventional chronic cholecystitis cases, according to the histological features observed in IgG4-related disease, including lymphoplasmocytic infiltration, storiform fibrosis, obliterative phlebitis, and IgG4-positive plasma cells. XGCs contained a significantly increased mean number of IgG4-positive plasma cells [34.8/high-power field (HPF)] as compared with conventional chronic cholecystitis (4.8/HPF; P < 0.001), and 16 XGCs (28%) harboured >50 IgG4-positive cells per HPF. Nine XGCs (16%), including one case with IgG4-related autoimmune pancreatitis, showed 'the histological features suggestive of IgG4-related disease', as described in the consensus statement regarding this condition. Extracholecystic inflammatory extension (seven cases, P = 0.009) and mass-forming lesions (eight cases, P < 0.001) were more frequently seen in XGC cases with histological features suggestive of IgG4-related disease than in cases without those microscopic changes. CONCLUSIONS: XGCs with IgG4-positive cell infiltration are considered to be mimickers, as xanthogranulomatous inflammation generally contradicts a diagnosis of IgG4-related disease and is weakly associated with other typical organ manifestations of IgG4-related disease. However, XGC may be a concurrent condition, particularly in patients with IgG4-related disease in other organs.

The clinical implications of G1-G6 transcriptomic signature and 5-gene score in Korean patients with hepatocellular carcinoma.

BACKGROUND: Efforts have been made to classify Hepatocellular Carcinoma (HCC) at surgically curable stages because molecular classification, which is prognostically informative, can accurately identify patients in need of additional early therapeutic interventions. Recently, HCC classification based French studies on the expression of 16 genes and 5 genes were proposed. In 16-gene classification, transcriptomic signatures (G1-G6) were used to classify HCC patients into clinical, genomic and pathway-specific subgroups. In 5-gene score classification, the good or poor prognosis of HCC patients was predicted. The patient's cohort in these studies was mainly from Caucasian and African populations. Here, we aimed to validate G1-G6 and 5-gene score signatures in 205 Korean HCC patients since genomic profiles of Korean patients are distinct from other regions. METHODS: Integrated analyses using whole-exome sequencing, copy number variation and clinical data was performed against these two signatures to find statistical correlations. Kaplan-Meier, univariate and multivariate COX regression analysis were performed for Disease-Specific Survival (DSS) and Recurrence-Free Survival (RFS). RESULTS: The G2 and G3 subgroups of transcriptomic signature were significantly associated with TP53 mutations while G5 and G6 subgroups were significantly associated with CTNNB1 mutations which is in concordance with original French studies. Similarly, the poor prognosis group of 5-gene score showed shorter DSS (p = 0.045) and early RFS (p = 0.023) as well as a significant association with microvascular invasion, tumor size (> 5 cm), elevated AFP levels, and RB1 mutations. However, the 5-gene score was not an independent prognostic factor for survival. CONCLUSION: The G1-G6 and 5-gene signatures showed significant concordance between genetic profiles of Korean HCC patients and patients in original French studies. Thus, G1-G6 and 5-gene score signatures can be targeted as potential therapeutic biomarkers against HCC patients worldwide.

Histological expression of methionine adenosyl transferase (MAT) 2A as a post-surgical prognostic surrogate in patients with hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Deregulation of methionine adenosyltransferase (MAT) is involved in hepatocarcinogenesis. This study aimed to investigate the prognostic implications of the level of histological MAT1A and MAT2A in patients with resected hepatocellular carcinoma (HCC). METHODS: A total of 210 patients with HCC who underwent curative resection between 2004 and 2011 were included. The levels of MAT proteins were immunohistochemically measured. RESULTS: MAT1A and MAT2A were over-expressed in 134 (63.8%) and 124 (59.1%) of the 210 tumor tissues, respectively. Up-regulation of tumoral MAT1A was independently associated with male gender, and inversely related to tumors >5 cm (adjusted odds ratios [OR] 2.59, P = 0.008, and OR 0.44, P = 0.012, respectively). Enhanced MAT2A expression was significantly related to age ≥60 years and serum AFP >200 ng/mL (OR 0.51, P = 0.030; and OR 2.65, P = 0.003; respectively). Tumoral MAT2A over-expression independently predicted an increased rate of recurrence within 1 year after hepatectomy (adjusted hazard ratio [HR] 2.45, P = 0.012), but that was not the case for MAT1A expression (HR 0.90, P = 0.744). High MAT2A was also an independent predictor of early recurrence (HR 2.54, P = 0.034) in the subset of patients without microvascular invasion (n = 155). CONCLUSIONS: Over-expression of MAT2A in HCC may be a useful biomarker for predicting and monitoring tumor recurrence, especially early after hepatic resection.

Intrahepatic Cholangiocarcinoma in Patients with Cirrhosis: Differentiation from Hepatocellular Carcinoma by Using Gadoxetic Acid-enhanced MR Imaging and Dynamic CT.

Purpose To determine the imaging features at gadoxetic acid-enhanced magnetic resonance (MR) imaging of intrahepatic cholangiocarcinoma (IHCC) in a cirrhotic liver, with an emphasis on the distinction between IHCC and hepatocellular carcinoma (HCC) and on the comparison of nodule enhancement patterns between MR imaging and computed tomography (CT). Materials and Methods The institutional review board approved this study and waived the requirement for informed consent. Gadoxetic acid-enhanced MR and CT images in 72 consecutive patients (61 men; mean age, 56.6 years) with 78 IHCCs and one-to-one matched control patients (56 men; mean age, 56.6 years) with 77 HCCs were evaluated retrospectively by two independent readers. Findings that could differentiate IHCC from HCC were evaluated with univariate and multivariate analyses. Using the enhancement criteria and the Liver Imaging Reporting and Data System with modifications (mLI-RADS), the sensitivity and specificity for diagnosing HCC were calculated with conventional washout and portal venous phase (PVP) washout. Results At MR imaging with conventional washout, the specificities for diagnosing HCC were 94.9% (74 of 78) with the enhancement criteria and 96.2% (75 of 78) with mLI-RADS, while the use of PVP washout achieved 100% (78 of 78) specificity for diagnosing HCC with both diagnostic criteria at the expense of decreased sensitivity (from 76.6% [59 of 77] to 63.6% [49 of 77] with the enhancement criteria and from 64.9% [50 of 77] to 55.8% [43 of 77] with mLI-RADS, P ≤ .016). At CT, the sensitivities and specificities with conventional washout were 72.7% (56 of 77) and 97.4% (76 of 78), respectively, with the enhancement criteria and 67.5% (52 of 77) and 97.4% (76 of 78), respectively, with mLI-RADS. Conclusion The use of PVP washout instead of conventional washout at gadoxetic acid-enhanced MR imaging prevents the misclassification of IHCC as HCC in a cirrhotic liver but leads to a decreased sensitivity for HCC. © RSNA, 2016 Online supplemental material is available for this article.

Combined hepatocellular-cholangiocarcinoma: Gadoxetic acid-enhanced MRI findings correlated with pathologic features and prognosis.

PURPOSE: To evaluate gadoxetic acid-enhanced magnetic resonance imaging (MRI) findings of combined hepatocellular cholangiocarcinoma (cHCC-CC) with special emphasis on correlation of MRI findings with histopathologic tumor characteristics and survival outcomes after curative surgery. MATERIALS AND METHODS: Our Institutional Review Board approved this study, with a waiver of informed consent. For 82 patients (64 men, 18 women; mean age, 54.0 years; age range, 30-81) with surgically confirmed cHCC-CCs, we evaluated clinical features, histologic findings, and tumor morphologic and enhancement features on gadoxetic acid-enhanced liver MRI at 1.5T (n = 67) or 3.0T (n = 15). Imaging features of cHCC-CCs were correlated with pathologic findings according to the 2010 World Health Organization classification system. Tumors were categorized as hypervascular or nonhypervascular based on arterial phase enhancement and were compared with respect to overall and recurrence-free survival after curative-intent surgery. RESULTS: Of the 82 lesions, 48 showing global arterial phase enhancement were categorized as the hypervascular group, while 34 lesions demonstrating rim, peripheral, or isoenhancement were categorized as the nonhypervascular group. There was no significant difference in MRI findings between pathologic tumor types (classical type versus stem cell feature type, P = 0.324-1.0). Compared with the nonhypervascular group, the hypervascular group had a larger HCC component (P = 0.014), smaller CC component (P = 0.001), and lesser amount of fibrotic stroma (P = 0.006) on pathologic analysis and was an independent factor associated with better overall survival after surgical resection (P = 0.033). CONCLUSION: Gadoxetic acid-enhanced MRI findings of cHCC-CCs were diverse, reflecting heterogeneous histologic features. The hypervascular group on MRI is associated with a larger HCC component, smaller CC component, less fibrotic stroma, and better overall survival after curative surgery than the nonhypervascular group. LEVEL OF EVIDENCE: 4 J. MAGN. RESON. IMAGING 2017;46:267-280.

Diagnostic criteria for hepatocellular carcinoma ⩽3 cm with hepatocyte-specific contrast-enhanced magnetic resonance imaging.

BACKGROUND & AIMS: Current diagnostic imaging criteria for hepatocellular carcinoma (HCC) are dedicated to imaging with nonspecific extracellular contrast agents. This study aimed to evaluate diagnostic criteria for HCC ⩽3 cm on magnetic resonance imaging (MRI) with a hepatocyte-specific contrast agent through an inception cohort study. METHODS: Of 291 patients with chronic liver disease and new nodules of 1-3 cm in diameter at surveillance ultrasonography, 295 solid nodules (194 HCCs, 98 benign nodules, and three other malignancies) in 198 patients with a confirmed final diagnosis or ⩾24 months follow-up were evaluated on gadoxetic acid-enhanced MRI. Through univariate and multivariate logistic regression analyses, various diagnostic criteria were developed by combining significant MRI findings for diagnosing HCC. The diagnostic performance of each criterion was compared with that of the European Association for the Study of the Liver (EASL) criteria. RESULTS: Four MRI findings (arterial-phase hyperintensity, transitional-phase hypointensity, hepatobiliary-phase hypointensity, and rim enhancement) were independently significant for diagnosis of HCC ⩽3 cm. For whole nodules, EASL criteria showed the best performance for diagnosing HCC (sensitivity, 83.5%; specificity, 81.2%). For nodules ⩽2 cm in diameter, a new criterion (arterial-phase hyperintensity and hepatobiliary-phase hypointensity) showed a significantly higher sensitivity than that of the EASL criteria (83.0% vs. 74.5%, p=0.008), without a significantly different specificity (76.7% vs. 81.1%, p=0.125). CONCLUSIONS: EASL criteria exhibit the best diagnostic performance for HCC ⩽3 cm on hepatocyte-specific contrast-enhanced MRI. A newly identified criterion (arterial-phase hyperintensity and hepatobiliary-phase hypointensity) may increase the diagnostic sensitivity of small (⩽2 cm) HCC.

CT Features of Primary Graft Nonfunction after Liver Transplantation.

Purpose To determine computed tomographic (CT) features of primary graft nonfunction (PNF) after liver transplantation in comparison with those of early graft failure or death by identifiable causes. Materials and Methods Institutional review board approval was obtained and informed consent was waived. Among 3947 adult liver transplantations performed in one institution between May 2002 and May 2015, 72 patients died or had graft failure within 10 days, and 38 of them were evaluated with CT. PNF was diagnosed in 21 patients. The other 17 patients who died or had early graft failure were considered the non-PNF control group. On unenhanced CT images, graft attenuation was compared qualitatively. Graft attenuation was measured quantitatively and, if available, the difference between preoperative and postoperative CT (interval change) attenuation was evaluated. Unenhanced CT was evaluated for relative parenchymal enhancement. Statistical analyses included the Fisher exact and χ2 tests with Yates correction and the Student t test. Results On unenhanced CT images, grafts with PNF more commonly showed low (eight of 26 [31%]) or extremely low (18 of 26 [69%]) qualitative attenuation compared with grafts in the non-PNF group (three of 21 [14%], one of 21 [5%]; P < .001). The mean attenuation value (30.5 HU ± 10.8) was significantly lower and the mean interval change (24.7 HU ± 12.5) was significantly higher in the PNF group than in the non-PNF group (49.7 HU ± 8.0 and 9.7 HU ± 10.1, respectively; P < .001 and P = .001). There was no significant difference in the proportion of grafts that showed poor enhancement on postcontrast CT images between the PNF group and the non-PNF group (nine of 24 [38%] vs two of 20 [10%], respectively; P = .08). Conclusion Recipients with PNF after liver transplantation tended to show low or extremely low attenuation on unenhanced CT images, and this finding was seen more frequently in patients with PNF than in those who died of identifiable causes and in those with early graft failure. © RSNA, 2016 Online supplemental material is available for this article.

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma.

Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G>A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P=0.034) and more frequent pancreatic invasion (P=0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G>A transitions and G12D mutations) were significantly correlated with higher pT classification (P=0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P=0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P=0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal adenocarcinoma patients, namely those with wild-type KRAS and BRAF if they have metastatic disease, similar to colorectal cancer patients.

Optimal methods for measuring eligibility for liver transplant in hepatocellular carcinoma patients undergoing transarterial chemoembolization.

BACKGROUND & AIMS: We investigated the optimal radiologic method for measuring hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE) in order to assess suitability for liver transplantation (LT). METHODS: 271 HCC patients undergoing TACE prior to LT were classified according to both Milan and up-to-seven criteria after TACE by using the enhancement or size method on computed tomography images. The cumulative incidence function curves with competing risks regression was used in post-LT time-to-recurrence analysis. The predictive accuracy for recurrence was compared using area under the time-dependent receiver operating characteristic curves (AUC) estimation. RESULTS: Of the 271 patients, 246 (90.8%) and 164 (60.5%) fell within Milan and 252 (93.0%) and 210 (77.5%) fell within up-to-seven criteria, when assessed by enhancement and size methods, respectively. Competing risks regression analyses adjusting for covariates indicated that meeting the criteria by enhancement and by size methods was independently related to post-LT time-to-recurrence in the Milan or up-to-seven model. Higher AUC values were observed with the size method only in the up-to-seven model (p<0.05). Mean differences in the sum of tumor diameter and number of tumors between pathologic and radiologic findings were significantly less by the enhancement method (p<0.05). Cumulative incidence curves showed similar recurrence results between patients with and without prior TACE within the criteria based on either method, except for the within up-to-seven by the enhancement method (p=0.017). CONCLUSIONS: The enhancement method is a reliable tool for assessing the control or downstaging of HCC within Milan after TACE, although the size method may be preferable when applying the up-to-seven criterion.

Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification.

UNLABELLED: Hepatic resection is the most curative treatment option for early-stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (multivariate P = 0.038 and P = 0.012, respectively). FGF19 amplifications, known to activate Wnt signaling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (P = 0.017). CONCLUSION: RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients.

Loss of ARID1A expression is associated with poor prognosis in small intestinal carcinoma.

AIMS: To investigate AT-rich interactive domain-containing protein 1A (ARID1A) and p53 expression in small intestinal carcinoma (SIC) and to determine its prognostic significance. METHODS AND RESULTS: Immunohistochemical staining for ARID1A and p53 was performed in 178 SICs using a tissue microarray (TMA). Loss of or low ARID1A expression was observed in 36 (20.2%) and 60 (33.7%) of cases, respectively. Aberrant p53 expression was observed in 99 (55.6%) cases. Loss of or low ARID1A expression was found to be associated with signet ring cell carcinoma and undifferentiated carcinoma, a high-grade tumour, and a higher T stage. No relationship was found between aberrant p53 expression and clinicopathological factors or overall survival. Patients with loss of ARID1A expression, irrespective of p53 expressional status, showed significantly poorer overall survival than those expressing ARID1A. Multiple regression analysis revealed that grade and pT stage were associated significantly with ARID1A loss, and multivariate analysis showed that patients with high ARID1A expression had a lower risk of death than those with loss of ARID1A expression. CONCLUSIONS: Low or loss of ARID1A expression is correlated significantly with a high-grade tumour, higher T stage, and poorer overall survival. These findings suggest that ARID1A expression could be used as a prognostic marker in SIC.

MET is a predictive factor for late recurrence but not for overall survival of early stage hepatocellular carcinoma.

The MET and RON receptors are tyrosine kinases that form a non-covalent complex on the cell surface that functions in several steps of tumor progression. The purpose of this study was to determine the clinical significance of MET and RON expression on long-term survival and recurrence after curative resection in a large cohort of hepatocellular carcinoma (HCC) patients. We performed immunohistochemical analyses on microarrays of the tumors using antibodies against MET and RON. We evaluated the prognostic value of biomarker expression using Cox regression and the Kaplan-Meier method in 490 HCC patients. MET-positive patients had higher overall recurrence rates than MET-negative patients (P = 0.041); however, MET positivity was not associated with overall survival (OS) (P = .249). RON was not associated with overall recurrence rates and OS. MET was independently associated with late but not early phase recurrence. Particularly, the prognostic significance of MET is limited in early stage disease. MET+/RON+ patients had higher overall recurrence rates than those with the other expression patterns (P = 0.071), although the result did not reach statistical significance. Immunohistological activation of MET expression has no prognostic significance for OS in patients with HCC. However, MET positivity was correlated with late recurrence after HCC resection in early stage disease.