Classical Hepatocellular Carcinoma Research Articles

Novel nomograms based on microvascular invasion grade for early-stage hepatocellular carcinoma after curative hepatectomy

Microvascular invasion (MVI) is a critical risk factor for postoperative recurrence of hepatocellular carcinoma (HCC). This study aimed to firstly develop and validate nomograms based on MVI grade for predicting recurrence, especially early recurrence, and overall survival in patients with early-stage HCC after curative resection. We retrospectively reviewed the data of patients with early-stage HCC who underwent curative hepatectomy in the First Affiliated Hospital of Fujian Medical University (FHFU) and Mengchao Hepatobiliary Hospital of Fujian Medical University (MHH). Kaplan–Meier curves and Cox proportional hazards regression models were used to analyse disease-free survival (DFS) and overall survival (OS). Nomogram models were constructed on the datasets from the 70% samples of and FHFU, which were validated using bootstrap resampling with 30% samples as internal validation and data of patients from MHH as external validation. A total of 703 patients with early-stage HCC were included to create a nomogram for predicting recurrence or metastasis (DFS nomogram) and a nomogram for predicting survival (OS nomogram). The concordance indexes and calibration curves in the training and validation cohorts showed optimal agreement between the predicted and observed DFS and OS rates. The predictive accuracy was significantly better than that of the classic HCC staging systems.

Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma.

Acute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers a high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear. Herein, we explore HMBS alterations in a large series of 758 HCC cases, including 4 patients with AIP. We quantify the impact of HMBS mutations on heme biosynthesis pathway intermediates and we investigate the molecular and clinical features of HMBS-mutated tumors. We identify recurrent bi-allelic HMBS inactivation, both in patients with AIP acquiring a second somatic HMBS mutation and in sporadic HCC with 2 somatic hits. HMBS alterations are enriched in truncating mutations, in particular in splice regions, leading to abnormal transcript structures. Bi-allelic HMBS inactivation results in a massive accumulation of its toxic substrate porphobilinogen and synergizes with CTNNB1-activating mutations, leading to the development of well-differentiated tumors with a transcriptomic signature of Wnt/β-catenin pathway activation and a DNA methylation signature related to ageing. HMBS-inactivated HCC mostly affects females, in the absence of fibrosis and classical HCC risk factors. These data identify HMBS as a tumor suppressor gene whose bi-allelic inactivation defines a homogenous clinical and molecular HCC subtype. Heme (the precursor to hemoglobin, which plays a key role in oxygen transport around the body) synthesis occurs in the liver and involves several enzymes including hydroxymethylbilane synthase (HMBS). HMBS mutations cause acute intermittent porphyria, a disease caused by the accumulation of toxic porphyrin precursors. Herein, we show that HMBS inactivation is also involved in the development of liver cancers with distinct clinical and molecular characteristics.

A Practical Risk Classification of Early Recurrence in Hepatocellular Carcinoma Patients with Microvascular invasion after Hepatectomy: A Decision Tree Analysis.

This study was designed to establish risk classifications for early recurrence in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) after hepatectomy. The data of 563 HCC patients with MVI after hepatectomy from two hospitals were retrospectively reviewed. Kaplan-Meier curves and Cox proportional hazards regression models were used to analyse early recurrence. The risk classification for early recurrence was established by using classification and regression tree (CART) analysis and validated by using two independent validation cohorts from two hospitals. Multivariate analysis revealed that four indices, namely, infection of chronic viral hepatitis, MVI classification, tumour size, and serum alpha-fetoprotein (AFP), were independent prognostic factors for early recurrence in HCC patients with MVI. By CART analysis, MVI classification and serum AFP became the nodes of a decision tree and 3-stratification classifications that satisfactorily determined the risk of early recurrence were established. The area under the time-dependent receiver operating characteristic curve (AUC) values of the classification for early recurrence at 0.5, 1.0, and 2.0 years were 0.75, 0.73, and 0.71, respectively, which were all significantly higher than three common classic HCC stages (BCLC stage, Chinese stage, and TNM stage). The calibration curves showed good agreement between predictions by classification for early recurrence and actual survival outcomes. These prediction results also were confirmed in the independent internal and external validation cohorts. The 3 stratification classifications enabled satisfactory risk evaluation of early recurrence in HCC patients with MVI after hepatectomy.

A Case Report of Fibrolamellar Hepatocellular Carcinoma in a Young Adult

Among the four histopathological variants of hepatocellular carcinoma, Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma (HCC). It occurs in less than 1 % cases of hepatocellular carcinoma with distinct features as compared to classical HCC. It differs from typical HCC in terms of epidemiology, etiology, clinical presentation and prognosis. In this case report we are going to present a case of fibrolamellar variety of HCC in a 20-year young male with no history of previous liver disease and no characteristics features on Computed Tomography (CT) scan when compared with typical HCC. After discussing in multidisciplinary meeting, he underwent non anatomical liver resection which remained uneventful. Histopathology of the biopsy sample revealed FLHCC. No neoadjuvant therapy was given. Patient was kept on 1 year follow-up and no recurrence or metastasis occurred.

Combined Hepatocellular-Cholangiocarcinoma: An Update on Pathology and Diagnostic Approach.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver carcinoma displaying both hepatocytic and cholangiocytic differentiation within the same tumor. Relative to classic hepatocellular carcinoma (HCC), cHCC-CCA has more aggressive behavior and a poorer prognosis. Though recent advances have improved our understanding of the biology underlying cHCC-CCAs, they remain diagnostically challenging for pathologists because of their morphologic and phenotypic diversity. Accurate diagnosis of cHCC-CCA is important for patient management and prognostication. Herein, we review recent updates on cHCC-CCA, focusing on tumor classification, pathology, and diagnostic approach.

CtBP1 Mediates Hypoxia-Induced Sarcomatoid Transformation in Hepatocellular Carcinoma.

BackgroundSarcomatoid hepatocellular carcinoma (sHCC), a highly aggressive subtype of hepatocellular carcinoma (HCC), mostly transforms from classical hepatocellular carcinoma (cHCC). The study intended to explore the role of C-terminal binding protein 1 (CtBP1) in sarcomatoid transformation of hepatocellular carcinoma.MethodsWestern blotting and/or immunohistochemistry were used to confirm the expression of CtBP1 and other proteins in HCC cells, xenografts and clinical tissue samples. CtBP1 shRNA-expressing lentivirus was used to infect HepG2 cells to construct CtBP1 knockdown cells. Cell migration was determined by scratch wound assays and Transwell assays. Immunofluorescence was used to label the a-tubulin cytoskeleton to evaluate cell morphology. HepG2 cells were inoculated subcutaneously in nude mice to construct xenografts and beneath the liver capsule to evaluate in vivo metastasis.ResultsCompared to that in the cHCC area, CtBP1 expression was significantly upregulated in the sHCC area, as shown by immunohistochemistry. HE staining showed that cells in the sHCC area were spindle-shaped, while those in the cHCC area were polygonal. Immunohistochemically, the epithelial markers pancytokeratin (CK) and E-cadherin were partially or completely lost, while the expression of the mesenchymal marker vimentin was upregulated in the sHCC area. Moreover, HepG2, an HCC cell line with high expression of CtBP1, autonomously underwent sarcomatoid transformation, showing a sarcomatoid morphology and phenotype. HIF1a expression was upregulated in epithelial cells adjacent to the sHCC area. Hypoxia upregulated CtBP1 protein expression and induced an EMT phenotype with increased migration and a spindle-shaped morphology in HepG2 cells. Knockdown of CtBP1 partially reversed the EMT phenotype induced by hypoxia. Silencing CtBP1 completely blocked the sarcomatoid transformation of subcutaneous xenografts and decreased lung metastasis in subcapsular xenografts of the liver in nude mice.ConclusionCtBP1 plays a key role in hypoxia-induced EMT and sarcomatoid transformation in HCC and could be a candidate target for the management of sHCC.

Genomic characterization of rare molecular subclasses of hepatocellular carcinoma

Primary liver cancer, consisting of both cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC), is the second leading cause of cancer deaths worldwide. Our goal is to genomically characterize rare HCC subclasses to provide insight into disease biology. Leveraging The Cancer Genome Atlas (TCGA) to perform a combined analysis of CCA (n = 36) and HCC (n = 275), we integrated multiple genomic platforms, to assess transcriptional profiles, mutational signatures, and copy number patterns to uncover underlying etiology and linage specific patterns. We identified two molecular classes distinct from prototypical HCC tumors. The first, CCA-Like, although histologically indistinguishable from HCC, had enrichment of CCA mutations (IDH1, BAP1), mutational signatures, and transcriptional patterns (SOX9, KRT19). CCA-Like, however, retained a copy number landscape similar to HCC, suggesting a hepatocellular linage. The second, Blast-Like, is enriched in TP53 mutations, HBV infection, exposure related mutational signatures and transcriptionally similar to hepatoblasts. Although these subclasses are molecularly distinct, they both have a worse progression-free survival compared to classical HCC tumors, yet are clinically treated the same. The identification of and characterization of CCA-Like and Blast-Like subclasses advance our knowledge of HCC as well as represents an urgent need for the identification of class specific biomarkers and targeted therapy.

Fibrolamellar hepatocellular carcinoma treated with atezolizumab and bevacizumab: two case reports

BackgroundFibrolamellar hepatocellular carcinoma is a unique tumor of the liver that differs from the classical hepatocellular carcinoma in diagnosis, behavior, and possibly treatment. There is usually absent underlying liver disease, and it usually occurs in young patients. The survival outcomes in localized fibrolamellar hepatocellular carcinoma are perhaps better than in classical hepatocellular carcinoma if treated early and radically. On the other hand, the prognosis remains poor for locally advanced and metastatic fibrolamellar hepatocellular carcinoma. Many reports suggested a limited benefit from systemic chemotherapy. Sorafenib also did not show major effects on fibrolamellar hepatocellular carcinoma. Given the rarity of fibrolamellar hepatocellular carcinoma, lack of large studies, and absence of standard treatment, the treatment decisions rely on case reports, previously reported cases series, and expert opinions. Recent studies have shown promising effects of immunotherapy with checkpoint inhibitors in the first- and second-line therapy of hepatocellular carcinoma. Atezolizumab with bevacizumab regimen has been approved recently as a first-line treatment for classical hepatocellular carcinoma. Currently, there are no reports yet on the use of atezolizumab with bevacizumab for fibrolamellar hepatocellular carcinoma.Case reportIn this article, we present two Arabic patients with advanced fibrolamellar hepatocellular carcinoma who received atezolizumab and bevacizumab combinations but did not show any clinical benefits.ConclusionWhile atezolizumab and bevacizumab combinations had shown benefits in classical hepatocellular carcinoma, the current data showed a lack of benefit and tumor response in fibrolamellar hepatocellular carcinoma.

Hepatocellular Carcinoma With Atypical Imaging Features: Review of the Morphologic Hepatocellular Carcinoma Subtypes With Radiology-Pathology Correlation.

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer death in the United States with the incidence rate more than doubling in 20 years. HCC is unique since a noninvasive diagnosis can be achieved with imaging alone when specific clinical criteria and imaging characteristics are met, obviating the need for tissue sampling. However, HCC is a highly heterogeneous neoplasm. Atypical HCC subtypes vary significantly in their morphology, which can be attributed to specific histologic and molecular features, and can cause deviations from the classic imaging characteristics. The different morphologic subtypes of HCC frequently present a diagnostic challenge for radiologists and pathologists since their imaging and pathologic features can overlap with those of non-HCC malignancies. Identifying an atypical subtype can have important clinical implications. Liver transplant, albeit a scarce and limited resource, is the optimal treatment for conventional HCC, potentially curing both the tumor and the underlying pre-malignant condition. Some HCC subtypes as well as mimickers are associated with unacceptably high recurrence and poor outcome after transplant, and there remains limited data on the role and prognosis of liver transplantation for treatment of rare HCC subtypes. Other subtypes tend to recur later than classic HCC, potentially requiring a different follow-up scheme. This review will discuss the appearance of different HCC subtypes in relation to their histopathologic features. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3.

Diagnostic Performance of LI-RADS Version 2018 for Evaluation of Pediatric Hepatocellular Carcinoma.

Background The Liver Imaging Reporting and Data System (LI-RADS) has standardized the evaluation of adult but not pediatric hepatocellular carcinoma (HCC). Purpose To evaluate the performance of LI-RADS version 2018 for diagnosis of pediatric HCC. Materials and Methods This multi-institution retrospective study evaluated all available dynamic CT and/or MRI scans of pediatric (≤18 years) HCC from five institutions between July 2009 and April 2019. The control group included an equal number of other enhancing hepatic lesions. Blinded to final diagnosis, three radiologists independently applied LI-RADS version 2018 criteria. The reference standard was pathologic examination or more than 1 year follow-up. Sensitivity and specificity of LI-RADS were computed using a dichotomous classification of LR-1, LR-2, or LR-3 versus LR-4, LR-5, LR-TIV (tumor in vein), or LR-M (probably or definitely malignant but not HCC-specific) for predicting hepatic malignancy in the entire cohort and in patients at risk for HCC. Results The cohort consisted of 116 children: 58 with HCC (mean age, 12 years ± 5; 31 girls) and 58 with other enhancing hepatic masses (mean age, 12 years ± 5; 42 girls). Frequencies of major criteria in classic HCC for the three readers were as follows: nonrim arterial phase hyperenhancement, 49%-62% (19-24 of 39 patients); nonperipheral "washout," 36%-59% (14-23 of 39 patients); and enhancing "capsule," 28%-38% (11-15 of 39 patients). For the full cohort, the sensitivity of LR-4, LR-5, LR-TIV, or LR-M for malignancy among the three readers ranged from 85% (95% CI: 76, 94) to 88% (95% CI: 80, 96); specificity of LR-1, LR-2, or LR-3 for benignity ranged from 54% (95% CI: 40, 68) to 70% (95% CI: 57, 83). In the at-risk subgroup, sensitivity ranged from 58% (95% CI: 36, 80) to 68% (95% CI: 48, 89); specificity ranged from 56% (95% CI: 37, 74) to 63% (95% CI: 45, 81). All lesions categorized as LR-TIV (n = 10-13) were HCCs. Conclusion Liver Imaging Reporting and Data System version 2018 had moderate sensitivity but low specificity for the diagnosis of pediatric hepatocellular carcinoma (HCC), which had low frequencies of the major criteria used for adult HCC diagnosis. © RSNA, 2021 See also the editorial by Paltiel in this issue.

Prognostic nomograms and risk classifications of outcomes in very early-stage hepatocellular carcinoma patients after hepatectomy

BackgroundNumerous clinical models have been proposed to evaluate and predict recurrence and survival of hepatocellular carcinoma (HCC) patients in different stages after resection, but no model for very early-stage HCC. MethodsThe data of 661 very early-stage HCC patients after curative resection in our hospital were retrospectively reviewed. Kaplan-Meier curves and Cox proportional hazards regression models were used to analyze recurrence and survival. The risk classifications for recurrence and survival were established by using classification and regression tree analysis. The nomograms were constructed and validated using bootstrap resampling and an independent 186-patient validation cohort from the same institution. ResultsAccording to the results of multivariate analysis for prognosis after resection, decision trees and 3-stratification classifications that satisfactorily determined the risk of recurrence and survival were established. Based on these two risk classifications, a six-factor nomogram for predicting recurrence and a six-factor nomogram for predicting survival were created. The concordance indexes were 0.64 for recurrence nomogram, with a 95% confidence interval of 0.60–0.67, and 0.76 for survival nomogram, with a 95% confidence interval of 0.70–0.82. The calibration curves showed good agreement between the predictions made by the nomograms and the actual survival outcomes. These predicting results for recurrence and survival were better than three common classical HCC stages and were confirmed in the independent validation cohort. ConclusionsThe 3-stratification classifications enabled satisfactory risk evaluations of recurrence and survival, and the nomograms showed considerably accurate predictions of the risk of recurrence and survival in very early-stage HCC patients after curative resection.

The Safety and Efficacy of Camrelizumab and Its Combination With Apatinib in Various Solid Cancers

Background: Camrelizumab (SHR1210) is a high-affinity, humanized immunoglobulin programmed cell death 1 (PD-1) monoclonal antibody. It was developed by Jiangsu Hengrui Medicine Co. Ltd. and has been approved for relapsed or refractory classical Hodgkin lymphoma patients and hepatocellular carcinoma patients in China. Apatinib is an orally administered vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor and has been approved for advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma in China. Camrelizumab alone and its combination with apatinib have been used in the treatment of various solid cancers. Methods: We searched Embase, PubMed, and other databases with the keyword “camrelizumab” or “SHR1210,” and evaluated the safety and efficacy data of the involved studies. Adverse events (AEs) mentioned in at least two studies were summarized, including any grade and grade ≥3 treatment-related AEs. Meanwhile, efficacy data were collected, such as overall response rate (ORR), disease control rate (DCR), duration of response, 6-month progression-free survival (PFS) rate, median PFS time, 12-month overall survival rate, and median overall survival time. Results: The major AEs of camrelizumab alone were reactive cutaneous capillary endothelial proliferation, fatigue, aspartate aminotransferase increase, proteinuria, pruritus, and alanine transaminase increase. The ORR and DCR were 20.2% (95% CI: 15.1–26.6%, p = 0.000, I2 = 70.360) and 45.8% (95% CI: 39.0–52.7%, p = 0.256, I2 = 58.661), respectively. In the three studies of combination therapy, two studies were combined with apatinib and one combined with chemotherapy. For these studies, common AEs were hypertension, platelet count decrease, nausea, proteinuria, aspartate aminotransferase increase, and white blood cell count decrease. The pooled ORR, DCR, and 6-month PFS rate were 41.8% (95% CI: 29.7–54.9%, p = 0.220, I2 = 86.265), 82.4% (95% CI: 75.9–87.4%, p = 0.000, I2 = 55.207), and 56.2% (95% CI: 35.8–74.6%, p = 0.559, I2 = 79.739), respectively. Conclusion: Camrelizumab and its combination are tolerable and appear to be efficient in treating numerous solid cancers. The combination therapy appears to have better efficacy with durable toxicity. However, these remain to be shown in future studies. Besides, baseline lactate dehydrogenase, programmed cell death ligand 1 (PD-L1) expression, tumor mutation burden, and the incidence of reactive cutaneous capillary endothelial proliferation may be efficacy predictors and need to be clarified in further studies.

Surgical Indications for Hepatocellular Carcinoma with Non-hypervascular Hypointense Nodules Detected by Gd-EOB-DTPA-Enhanced MRI.

The surgical indication for non-hypervascular hypointense nodules (NHVN) detected incidentally on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) for classical hepatocellular carcinoma (HCC) is unknown. Our aim is to clarify the long-term outcomes in patients with this finding. We reviewed the cases of 290 HCC patients, including 66 patients with NHVN, who underwent Gd-EOB-MRI prior to hepatectomy, between October 2008 and December 2017 at our center. We divided the patients into three groups: a no-NHVN group, a treated NHVN group, and an untreated NHVN group. There was no significant difference in (RFS) or overall survival (OS) between the no-NHVN and untreated NHVN groups (p = 0.103 and 0.103, respectively). There was no significant difference between these two groups after propensity score matching. Multivariate analyses showed that microscopic intrahepatic metastases and the size of the main classical HCC, the target tumor, were independent prognostic factors of overall survival, but the presence of non-hypervascular hypointense nodules was not. There was no significant difference in RFS or OS between the treated NHVN and untreated NHVN groups (p = 0.158 and 0.109, respectively). Non-hypervascular hypointense nodules detected incidentally on Gd-EOB-MRI associated with targeted hypervascular HCC did not reflect prognosis of HCC after hepatectomy. Surgical procedures for classical enhancing HCC may be performed even if non-hypervascular hypointense nodules adjacent to the targeted HCC cannot be removed completely.

Sugar Alcohols Have a Key Role in Pathogenesis of Chronic Liver Disease and Hepatocellular Carcinoma in Whole Blood and Liver Tissues.

The major risk factors for hepatocellular carcinoma (HCC) are hepatitis C and B viral infections that proceed to Chronic Liver Disease (CLD). Yet, the early diagnosis and treatment of HCC are challenging because the pathogenesis of HCC is not fully defined. To better understand the onset and development of HCC, untargeted GC-TOF MS metabolomics data were acquired from resected human HCC tissues and their paired non-tumor hepatic tissues (n = 46). Blood samples of the same HCC subjects (n = 23) were compared to CLD (n = 15) and healthy control (n = 15) blood samples. The participants were recruited from the National Liver Institute in Egypt. The GC-TOF MS data yielded 194 structurally annotated compounds. The most strikingly significant alteration was found for the class of sugar alcohols that were up-regulated in blood of HCC patients compared to CLD subjects (p < 2.4 × 10−12) and CLD compared to healthy controls (p = 4.1 × 10−7). In HCC tissues, sugar alcohols were the most significant (p < 1 × 10−6) class differentiating resected HCC tissues from non-malignant hepatic tissues for all HCC patients. Alteration of sugar alcohol levels in liver tissues also defined early-stage HCC from their paired non-malignant hepatic tissues (p = 2.7 × 10−6). In blood, sugar alcohols differentiated HCC from CLD subjects with an ROC-curve of 0.875 compared to 0.685 for the classic HCC biomarker alpha-fetoprotein. Blood sugar alcohol levels steadily increased from healthy controls to CLD to early stages of HCC and finally, to late-stage HCC patients. The increase in sugar alcohol levels indicates a role of aldo-keto reductases in the pathogenesis of HCC, possibly opening novel diagnostic and therapeutic options after in-depth validation.

Diagnostic efficacy of dynamic liver imaging using qualitative diagnostic algorithm versus LI-RADS v2018 lexicon for atypical versus classical HCC lesions: A decade of experience from a tertiary liver institute

ObjectiveTo analyze and evaluate the diagnostic performance of conventional diagnostic (qualitative) imaging features versus LI-RADSv2018 lexicon for indeterminate and atypical Hepatocellular carcinoma (HCC) on dynamic liver imaging with reference to histopathology. Patients and methodsThis retrospective study (June 2009–June 2019) evaluated the performance characteristics of conventional imaging findings, versus the Liver Imaging Reporting and Data System (LIRADS) v2018, for interpretation of indeterminate and atypical HCC, in patients who underwent subsequent histopathological analysis (gold standard). A total of 100,457 dynamic hepatobiliary CT and MR examinations were performed over ten years at our institute. Using current international imaging guidelines, 3218 patients were found to have suspected liver cancer lesions on imaging. Classical enhancement pattern of typical HCC was seen in 2916 of these patients. These patients did not require further biopsy. We enrolled, the remaining (n = 302) patients, who underwent biopsy, into our study group. Two radiologists, blinded to pathology findings, reviewed and classified these lesions, in consensus, according to LI-RADS® lexicon and as per ‘conventional’ (Indeterminate, Atypical HCC, Classical HCC, other malignancies) imaging. The histopathology diagnosis was considered as the final diagnosis. Alpha feto protein (AFP) levels amongst various subgroups were compared. Statistical analysis was performed to calculate the efficacy of LIRADS versus qualitative imaging parameters in comparison with histopathology. ResultsA total of n = 302 patients, [89 % men (n = 269), mean age 57.08 ± 12.43 years] underwent biopsy for suspected liver lesions. Qualitative imaging had 92.3 % (CI 88.53–94.91) sensitivity, 41.4 % (CI 25.51–59.26) specificity, positive predictive value (PPV) of 93.7 % (CI 90.11–96.02), negative predictive value (NPV) of 36.4 % (CI 22.19–53.38), positive likelihood ratio (PLHR) of 1.575 (CI 1.40–1.77) and negative likelihood ratio of (NLHR) 0.19 (CI 0.13-0.26). It correctly classified 87.4 % of lesions diagnosed on pathology. In comparison, LI-RADS was found to have 92 % sensitivity, 55.5 % specificity, 97 % PPV, 30.3 %, NPV, PLHR 2.068 (CI 1.62–2.64), NLHR 0.15 (CI 0.11-0.18) and 89.7 % diagnostic accuracy. A total of 38 patients (17 false negative, 21 false positive lesions) had discordant diagnoses on imaging versus histopathology. The kappa agreement between LIRADs and qualitative Imaging was found to be 0.77 ± .07 (p < 0.001). LIRADS and qualitative imaging collectively had 97 % sensitivity, 30 % specificity, 91.9 % PPV, 55.6 % NPV, PLHR of 1.39 (CI 1.27–1.51) and NLHR of 0.09 (0.048-0.19) which was better than, either reporting system, independently. ConclusionIt was observed that the LI-RADS v2018 lexicon with qualitative imaging as a combination technique added extra value in interpretation of atypical HCC or indeterminate lesions on dynamic CT and MRI compared to either as ‘stand- alone’ reporting systems.

Bile duct involvement by hepatocellular carcinoma: A rare occurrence and poor prognostic indicator in bile duct brushing samples.

Hepatocellular carcinoma (HCC) rarely involves the biliary tree and may be inadvertently sampled on bile duct brushings (BDBs). The pathology archives of 5 institutions were searched for BDBs with HCC involvement. A total of 17 BDBs from 14 patients were obtained. There was a male:female ratio of 6:1; the median age of the patients was 59.5years (range, 22-80years). The median hepatic tumor size was 6.2cm (range, 2.2-13.0cm). HCC risk factors included viral hepatitis (5 patients), cirrhosis (5 patients), hemochromatosis (1 patient), and alcoholic steatohepatitis (1 patient). Jaundice with elevated bilirubin, liver enzymes, and α-fetoprotein was common. Endoscopic retrograde cholangiopancreatography demonstrated bile duct dilatation, polypoid intraductal masses (5 samples), clots/debris (2 samples), or strictures (4 samples). All BDBs had single and clustered large cells with naked atypical nuclei, granular cytoplasm, high nuclear/cytoplasmic ratios, and nuclei with prominent macronucleoli. Less common findings included clear/microvesicular cytoplasm (35%), papillae (29%), and anisonucleosis (35%). Classic HCC features (widened trabeculae [35%], endothelial wrapping [24%], multinucleation [24%], and cytoplasmic bile pigment [35%]) were uncommon. A total of 11 BDBs were diagnosed as malignant (10 with HCC and 1 with cholangiocarcinoma), 2 were diagnosed as atypical, and 1 BDB was diagnosed as negative; approximately two-thirds were found to have polysomy on fluorescence in situ hybridization. Approximately 71% of patients died of disease at a median of 3.5months. HCC may extend into the intrahepatic and/or extrahepatic biliary tree, causing masses and/or strictures that may be sampled on BDB. Although cytologically malignant, the classic features of HCC are uncommon, which can cause misdiagnosis. Cytopathologists should be mindful of this differential when evaluating BDBs, particularly when concomitant liver masses and/or HCC risk factors are present. Because of the associated high mortality and rapid rate of death, its presence should be conveyed clearly in pathology reports.

SMARCB1/INI1 Is Diagnostically Useful in Distinguishing α-Fetoprotein-producing Gastric Carcinoma from Hepatocellular Carcinoma.

Switch/sucrose non-fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), also named integrase interactor 1, is one of the core subunit proteins in the SWI/SNF ATP-dependent chromatin remodeling complex encoded at chromosomal position 22q11.2. Complete loss of SMARCB1 expression has been reported in various malignant tumors. Immunohistochemistry has demonstrated that SMARCB1 mutation/inactivation correlates well with loss of nuclear SMARCB1 expression. This study investigated SMARCB1 expression in hepatocellular carcinomas (HCCs) and α-fetoprotein (AFP)-producing gastric carcinomas by immunohistochemistry. For comparison, SMARCB1 immunostaining in intrahepatic cholangiocarcinoma (ICC) was also performed. Thirty classical HCCs, 30 ICCs and 10 AFP-producing gastric carcinomas were analyzed. Only one case of HCC had focal labeling of SMARCB1 in the nuclei. Twelve cases of ICC were immunopositive for SMARCB1, with either focal or diffuse reactivity. All AFP-producing gastric carcinomas were immunopositive for SMARCB1 in the nuclei, and the reactivity was consistently diffuse. SMARCB1 is a potential marker for distinguishing metastatic AFP-producing gastric carcinoma from HCC.

Significance of hypovascular lesions on dynamic computed tomography and/or gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging in patients with hepatocellular carcinoma.

The natural course and clinical implications of hypovascular lesions on dynamic computed tomography and/or gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging were investigated. We followed the patients with hepatocellular carcinoma (HCC) who underwent hepatectomy between April 2009 and August 2012 to determine whether new classical HCCs developed from these unresected borderline lesions or emerged in different areas. One hundred and eleven patients with HCC were identified to have undergone examinations using both imaging methods before hepatic resection. A total of 54 hypovascular lesions were detected. Gadolinium ethoxybenzyl-enhanced magnetic resonance imaging detected 51 lesions, while dynamic computed tomography identified 21 lesions. Eleven lesions were resected at the time of the hepatectomy together with the main HCCs. Classical HCCs had developed from 52.5% of the 43 unresected lesions at 3years after hepatic resection. Subsequently, we conducted a patient-by-patient analysis to compare the development of classical HCC from these hypovascular lesions and the emergence of de novo classical HCC in other areas. The 3-year occurrence rate was 62.2% for the former group and 55.0% for the latter group (P=0.83). Thus, although 52.2% of these hypovascular lesions had developed into classical HCCs at 3years after the initial hepatectomy, de novo HCCs also occurred at other sites. Furthermore, new hypovascular lesions emerged after hepatectomy in 18-29% of patients irrespective of the presence or absence of hypovascular lesions at hepatectomy. It remains uncertain whether these hypovascular lesions should be resected together with the main tumors at the time of hepatectomy.

Fibrolamellar Carcinoma: A Concise Review.

Fibrolamellar carcinoma is a rare primary hepatocellular malignancy arising in noncirrhotic livers of young individuals. Patients commonly present with a large solitary liver mass and nonspecific symptoms. Characteristic histologic features include large polygonal cells with oncocytic cytoplasm and prominent nucleoli separated into trabeculae and cords by dense parallel bands of collagen. Important differential diagnoses include classical hepatocellular carcinoma and intrahepatic cholangiocarcinoma, which may be distinguished by a judicious panel of immunohistochemical studies, including cytokeratin 7, CD68, and hepatocyte paraffin 1 (HepPar-1). In addition, fibrolamellar carcinomas are characterized by activation of protein kinase A. Prognosis of fibrolamellar carcinoma is similar to classical hepatocellular carcinoma occurring in the absence of liver cirrhosis and is strongly correlated with tumor resectability. Other treatment options include liver transplant, chemotherapy, and hepatic artery embolization. In this article, we review the clinical features, gross and microscopic pathology, molecular genetics, differential diagnosis, treatment, and prognosis of this rare and interesting tumor.

Synchronous Occurrence of Classic and Scirrhous Hepatocellular Carcinomas: A Case Report

: Scirrhous hepatocellular carcinoma (HCC) is a subtype of HCC that is characterized by abundant fibrous stroma admixed with tumor cells. Although imaging findings of scirrhous HCC differ from those of classic HCC, it is difficult to diagnose this rare neoplasm. Like classic HCC, scirrhous HCC frequently develops in patients with liver cirrhosis, but there has been no report of synchronous occurrence of classic and scirrhous HCCs. Here, we report synchronous classic and scirrhous HCCs in a 62-year-old man with early liver cirrhosis who underwent gadoxetic acid-enhanced and diffusion-weighted magnetic resonance imaging.