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ObjectiveWe previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy.DesignWe performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients.ResultsOur integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in TP53 mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in CTNNB1 mutations (93% vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-βcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes.ConclusionWe have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC.

Intrahepatic cholangiocarcinoma (ICCA) is a malignant epithelial neoplasm characterized by biliary differentiation within the liver. ICCA is molecularly heterogeneous and exhibits a broad spectrum of histopathological features. It is a highly aggressive carcinoma with high mortality and poor survival rates. ICCAs are classified into two main subtypes: the small-duct type and large-duct types. These two tumor types have different cell origins and clinicopathological features. ICCAs are characterized by numerous molecular alterations, including mutations in KRAS, TP53, IDH1/2, ARID1A, BAP1, BRAF, SAMD4, and EGFR, and FGFR2 fusion. Two main molecular subtypes—inflammation and proliferation—have been proposed. Recent advances in high-throughput assays using next-generation sequencing have improved our understanding of ICCA pathogenesis and molecular genetics. The diagnosis of ICCA poses a significant challenge for pathologists because of its varied morphologies and phenotypes. Accurate diagnosis of ICCA is essential for effective patient management and prognostic determination. This article provides an updated overview of ICCA pathology, focusing particularly on molecular features, histological subtypes, and diagnostic approaches.

ObjectiveTo assess the value of qualitative and quantitative MRI radiomics features for noninvasive prediction of immuno-oncologic characteristics and outcomes of hepatocellular carcinoma (HCC).MethodsThis retrospective, IRB-approved study included 48 patients with HCC (M/F 35/13, mean age 60y) who underwent hepatic resection or transplant within 4 months of abdominal MRI. Qualitative imaging traits, quantitative nontexture related and texture features were assessed in index lesions on contrast-enhanced T1-weighted and diffusion-weighted images. The association of imaging features with immunoprofiling and genomics features was assessed using binary logistic regression and correlation analyses. Binary logistic regression analysis was also employed to analyse the association of radiomics, histopathologic and genomics features with radiological early recurrence of HCC at 12 months.ResultsQualitative (r = − 0.41–0.40, p < 0.042) and quantitative (r = − 0.52–0.45, p < 0.049) radiomics features correlated with immunohistochemical cell type markers for T-cells (CD3), macrophages (CD68) and endothelial cells (CD31). Radiomics features also correlated with expression of immunotherapy targets PD-L1 at protein level (r = 0.41–0.47, p < 0.029) as well as PD1 and CTLA4 at mRNA expression level (r = − 0.48–0.47, p < 0.037). Finally, radiomics features, including tumour size, showed significant diagnostic performance for assessment of early HCC recurrence (AUC 0.76–0.80, p < 0.043), while immunoprofiling and genomic features did not (p = 0.098–0929).ConclusionsMRI radiomics features may serve as noninvasive predictors of HCC immuno-oncological characteristics and tumour recurrence and may aid in treatment stratification of HCC patients. These results need prospective validation.Key Points• MRI radiomics features showed significant associations with immunophenotyping and genomics characteristics of hepatocellular carcinoma.• Radiomics features, including tumour size, showed significant associations with early hepatocellular carcinoma recurrence after resection.

Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by hepatocellular differentiation. HCC is molecularly heterogeneous with a wide spectrum of histopathology. The prognosis of patients with HCC is generally poor, especially in those with advanced stages. HCC remains a diagnostic challenge for pathologists because of its morphological and phenotypic diversity. However, recent advances have enhanced our understanding of the molecular genetics and histological subtypes of HCC. Accurate diagnosis of HCC is important for patient management and prognosis. This review provides an update on HCC pathology, focusing on molecular genetics, histological subtypes, and diagnostic approaches.

ObjectiveSorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence.DesignTumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test.ResultsBIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4+ T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors.ConclusionIn BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation.Trial registration number NCT00692770.

ObjectiveThe diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed. We aimed to generate a novel molecular iCCA classifier that incorporates elements of the stroma, tumour and immune microenvironment (‘STIM’ classification).DesignWe applied virtual deconvolution to transcriptomic data from ~900 iCCAs, enabling us to devise a novel classification by selecting for the most relevant TME components. Murine models were generated through hydrodynamic tail vein injection and compared with the human disease.ResultsiCCA is composed of five robust STIM classes encompassing both inflamed (35%) and non-inflamed profiles (65%). The inflamed classes, named immune classical (~10%) and inflammatory stroma (~25%), differ in oncogenic pathways and extent of desmoplasia, with the inflammatory stroma showing T cell exhaustion, abundant stroma and KRAS mutations (p<0.001). Analysis of cell–cell interactions highlights cancer-associated fibroblast subtypes as potential mediators of immune evasion. Among the non-inflamed classes, the desert-like class (~20%) harbours the lowest immune infiltration with abundant regulatory T cells (p<0.001), whereas the hepatic stem-like class (~35%) is enriched in ‘M2-like’ macrophages, mutations in IDH1/2 and BAP1, and FGFR2 fusions. The remaining class (tumour classical: ~10%) is defined by cell cycle pathways and poor prognosis. Comparative analysis unveils high similarity between a KRAS/p19 murine model and the inflammatory stroma class (p=0.02). The KRAS-SOS inhibitor, BI3406, sensitises a KRAS-mutant iCCA murine model to anti-PD1 therapy.ConclusionsWe describe a comprehensive TME-based stratification of iCCA. Cross-species analysis establishes murine models that align closely to human iCCA for the preclinical testing of combination strategies.

Although gallbladder cancer is the most common biliary tract malignancy, squamous cell carcinoma of the gallbladder (GBSCC) is extremely uncommon, comprising approximately 1–4% of all malignant gallbladder tumors. Given its rare incidence, there are currently no established treatment guidelines for GBSCC. We reviewed the current data available through a comprehensive search of PubMed/MEDLINE and Embase. Although the clinical presentations of GBSCC and gallbladder adenocarcinoma (GBAC) are similar, GBSCCs are oftentimes larger and present with a higher histologic grade and more advanced pathological stage. Due to these aggressive features, the overall prognosis of GBSCC is significantly worse than GBAC, even after R0 resection. A combination of radical cholecystectomy with negative surgical margins along with systemic chemotherapy and/or radiotherapy appears to be the best treatment strategy based on the current limited literature. Mutational profiling using next-generation sequencing (NGS) can help clinicians identify and treat actionable mutations of this rare tumor. •Squamous cell carcinoma of the gallbladder is a rarer histologic variant than adenocarcinoma.•Squamous cell carcinoma has more aggressive clinical features than adenocarcinoma.•Squamous cell carcinoma demonstrates poorer survival than adenocarcinoma.•Effective treatment includes wide resection with negative margins along with adjuvant therapy.

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution. Immune-mediated selection pressures impact the clonal evolution of tumours. Here, in hepatocellular carcinoma the authors map spatio-temporal interactions between tumor and immune cells, highlighting the regulatory substrate of intra-tumoural heterogeneity that correlates with regional adaptive immune responses.

Cellular components of solid tumors including DNA are released into the bloodstream, but data on circulating-free DNA (cfDNA) in hepatocellular carcinoma (HCC) are still scarce. This study aimed at analyzing mutations in cfDNA and their correlation with tissue mutations in patients with HCC. We included 8 HCC patients treated with surgical resection for whom we collected paired tissue and plasma/serum samples. We analyzed 45 specimens, including multiregional tumor tissue sampling ( n  = 24), peripheral blood mononuclear cells (PMBC, n  = 8), plasma ( n  = 8) and serum ( n  = 5). Ultra-deep sequencing (5500× coverage) of all exons was performed in a targeted panel of 58 genes, including frequent HCC driver genes and druggable mutations. Mutations detected in plasma included known HCC oncogenes and tumor suppressors (e.g., TERT promoter, TP53 , and NTRK3 ) as well as a candidate druggable mutation ( JAK1 ). This approach increased the detection rates previously reported for mutations in plasma of HCC patients. A thorough characterization of cis mutations found in plasma confirmed their tumoral origin, which provides definitive evidence of the release of HCC-derived DNA fragments into the bloodstream. This study demonstrates that ultra-deep sequencing of cfDNA is feasible and can confidently detect somatic mutations found in tissue; these data reinforce the role of plasma DNA as a promising minimally invasive tool to interrogate HCC genetics.

Hepatic mesenchymal tumors (HMTs) are non-epithelial benign and malignant tumors with or without specific mesenchymal cell differentiation. They are relatively uncommon. Except for mesenchymal hamartoma, calcified nested stromal–epithelial tumor, and embryonal sarcoma, most mesenchymal lesions are not specific to the liver. Pathologists face challenges in diagnosing HMTs due to their diverse morphologies and phenotypic variations. Accurate diagnosis is critical for directing appropriate patient care and predicting outcomes. This review focuses on mesenchymal tumors with a relative predilection for the liver, including vascular and non-vascular mesenchymal neoplasms. It provides a thorough and up-to-date overview, concentrating on clinical and pathological features, differential diagnosis, and diagnostic approaches.