[Cholangiocarcinoma : Histopathological diagnosis, classification and molecular diagnostics-an update].

The term cholangiocarcinoma covers various malignant epithelial neoplasms with biliary differentiation. The aim of this article is to provide an update with new findings and developments on the etiology, pathogenesis, diagnosis, classification, and molecular diagnostics of intra- and extrahepatic cholangiocarcinomas based on the last review published in this journal in 2020. The basis is the currently available specialist literature, lectures, and discussions at congresses as well as our own findings.

Accurate MS-Based Diagnostic Amyloid Typing Using Endogenously Normalized Protein Intensities in Formalin-Fixed Paraffin-Embedded Tissue.

Amyloidoses are a group of diseases characterized by the pathological deposition of non-degradable misfolded protein fibrils. These include plasma cell neoplasms, chronic inflammatory conditions, and age-related disorders, among others. Precise identification of the fibril-forming, and thereby amyloidosis-type defining protein is crucial for prognosis and correct therapeutic intervention.

Distinct molecular profile and outcome of oligodendroglioma, IDH-mutant, 1p/19q-codeleted and TERTp-wildtype: a grade 1 oligodendroglioma of young patients?

Background: Oligodendrogliomas, characterized by isocitrate dehydrogenase (IDH) mutations and 1p/19q codeletion, often exhibit telomerase reverse transcriptase promoter (TERTp) mutations which have been linked to telomere maintenance (TM) and tumour proliferation. Although there are a few reports on a TERTp-wildtype subset of these tumours in adolescents and young adults, the frequency, molecular characteristics and prognostic implications of TERTp-wildtype status in oligodendrogliomas remains elusive.

Methods: We retrospectively analysed 166 IDH-mutant and 1p/19q-codeleted oligodendroglioma cases through comprehensive histopathological review and molecular analyses, including Sanger sequencing, DNA methylation profiling and whole exome sequencing (WES).

Advancing sarcoma diagnostics with expanded DNA methylation-based classification.

Purpose: Sarcomas pose a severe diagnostic challenge. A wide variety of these distinct entities need to be distinguished from each other and from less aggressive types of mesenchymal tumors, to ensure correct clinical management. A machine learning based classifier for sarcomas utilizing DNA methylation data from 1077 tumors recognizing 62 sarcoma types has already been developed and termed the sarcoma classifier, which we published in 2021.

An AI-assisted morphoproteomic approach is a supportive tool in esophagitis-related precision medicine.

Esophagitis is a frequent, but at the molecular level poorly characterized condition with diverse underlying etiologies and treatments. Correct diagnosis can be challenging due to partially overlapping histological features. By proteomic profiling of routine diagnostic FFPE biopsy specimens (n = 55) representing controls, Reflux- (GERD), Eosinophilic-(EoE), Crohn's-(CD), Herpes simplex (HSV) and Candida (CA)-esophagitis by LC-MS/MS (DIA), we identified distinct signatures and functional networks (e.

DNA methylation classifier to diagnose pancreatic ductal adenocarcinoma metastases from different anatomical sites.

Background: We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites.

Proteomic profiling reveals CEACAM6 function in driving gallbladder cancer aggressiveness through integrin receptor, PRKCD and AKT/ERK signaling.

Gallbladder cancer (GBC) presents as an aggressive malignancy with poor patient outcome. Like other epithelial cancers, the mechanisms of GBC cancer progression remain vague and efforts in finding targeted therapies fall below expectations. This study combined proteomic analysis of formalin-fixed paraffin-embedded (FFPE) GBC samples, functional and molecular characterization of potential oncogenes and identification of potential therapeutic strategies for GBC.

Morphomolecular Pathology and Genomic Insights into the Cells of Origin of Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma.

Cholangiocarcinomas are a highly heterogeneous group of malignancies that, despite recent progress in the understanding of their molecular pathogenesis and clinical management, continue to pose a major challenge to public health. The traditional view posits that cholangiocarcinomas derive from the neoplastic transformation of cholangiocytes lining the biliary tree. However, increasing genetic and experimental evidence has recently pointed to a more complex, and nuanced, scenario for the potential cell of origin of cholangiocarcinomas.

Lymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma.

Background And Aims: Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the intrahepatic (iCCA) or extrahepatic (eCCA) bile ducts with poor prognosis and limited treatment options. Prior evidence highlighted a significant contribution of the non-canonical NF-κB signalling pathway in initiation and aggressiveness of different tumour types. Lymphotoxin-β (LTβ) stimulates the NF-κB-inducing kinase (NIK), resulting in the activation of the transcription factor RelB.

Comparing Survival of Perihilar Cholangiocarcinoma After R1 Resection Versus Palliative Chemotherapy for Unresected Localized Disease.

Background: Resection of perihilar cholangiocarcinoma (pCCA) is a complex procedure with a high risk of postoperative mortality and early disease recurrence. The objective of this study was to compare patient characteristics and overall survival (OS) between pCCA patients who underwent an R1 resection and patients with localized pCCA who received palliative systemic chemotherapy.

Methods: Patients with a diagnosis of pCCA between 1997-2021 were identified from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) registry.

Integrative genomic analyses of European intrahepatic cholangiocarcinoma: Novel ROS1 fusion gene and PBX1 as prognostic marker.

Background: Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease.

Combined analysis of albumin in situ hybridisation and C reactive protein immunohistochemistry for the diagnosis of intrahepatic cholangiocarcinoma: towards a molecular classification paradigm.

Aims: Intrahepatic cholangiocarcinoma (iCCA) is a diagnosis of exclusion that can pose a challenge to the pathologist despite thorough clinical workup. Although several immunohistochemical markers have been proposed for iCCA, none of them reached clinical practice. We here assessed the combined usage of two promising diagnostic approaches, albumin in situ hybridisation (Alb-ISH) and C reactive protein (CRP) immunohistochemistry, for distinguishing iCCA from other adenocarcinoma primaries.

Differential Immunoexpression of Inhibitory Immune Checkpoint Molecules and Clinicopathological Correlates in Keratoacanthoma, Primary Cutaneous Squamous Cell Carcinoma and Metastases.

Beyond established anti-programmed cell death protein 1/programmed cell death ligand 1 immunotherapy, T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) and its ligand CD155 are promising novel inhibitory immune checkpoint targets in human malignancies. Yet, in cutaneous squamous cell carcinoma, evidence on the collective expression patterns of these inhibitory immune checkpoints is scarce. Complete tumour sections of 36 cutaneous squamous cell carcinoma, 5 cutaneous metastases and 9 keratoacanthomas, a highly-differentiated, squamoproliferative tumour, with disparately benign biologic behaviour, were evaluated by immunohistochemistry for expression of programmed cell death ligand 1 (Tumor Proportion Score, Immune Cell Score), TIGIT, CD155 and CD8+ immune infiltrates.

N-cadherin: A diagnostic marker to help discriminate primary liver carcinomas from extrahepatic carcinomas.

Distinguishing primary liver cancer (PLC), namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), from liver metastases is of crucial clinical importance. Histopathology remains the gold standard, but differential diagnosis may be challenging. While absent in most epithelial, the expression of the adherens junction glycoprotein N-cadherin is commonly restricted to neural and mesenchymal cells, or carcinoma cells that undergo the phenomenon of epithelial-to-mesenchymal transition (EMT).

Chromosome 8p engineering reveals increased metastatic potential targetable by patient-specific synthetic lethality in liver cancer.

Large-scale chromosomal aberrations are prevalent in human cancer, but their function remains poorly understood. We established chromosome-engineered hepatocellular carcinoma cell lines using CRISPR-Cas9 genome editing. A 33-mega-base pair region on chromosome 8p (chr8p) was heterozygously deleted, mimicking a frequently observed chromosomal deletion.

Promising Outcomes of Modified ALPPS for Staged Hepatectomy in Cholangiocarcinoma.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage procedure that can potentially cure patients with large cholangiocarcinoma. The current study evaluates the impact of modifications on the outcomes of ALPPS in patients with cholangiocarcinoma. In this single-center study, a series of 30 consecutive patients with cholangiocarcinoma (22 extrahepatic and 8 intrahepatic) who underwent ALPPS between 2011 and 2021 was evaluated.

Etiology-independent activation of the LTβ-LTβR-RELB axis drives aggressiveness and predicts poor prognosis in HCC.

Background And Aims: HCC is the most common primary liver tumor, with an increasing incidence worldwide. HCC is a heterogeneous malignancy and usually develops in a chronically injured liver. The NF-κB signaling network consists of a canonical and a noncanonical branch.

Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice.

Introduction: Scurfy mice have a complete deficiency of functional regulatory T cells (Treg) due to a frameshift mutation in the gene. The impaired immune homeostasis results in a lethal lymphoproliferative disorder affecting multiple organs, including the liver. The autoimmune pathology in scurfy mice is in part accompanied by autoantibodies such as antinuclear antibodies (ANA).

JNKs protect from cholestatic liver disease progression by modulating Apelin signalling.

Background & Aims: Cholestatic liver injury is associated with c-Jun N-terminal kinases (JNK) activation in distinct cell types. Its hepatocyte-specific function during cholestasis, however, has not yet been established. Therefore, in our present study, we investigated the role of JNK1/2 during cholestasis and dissected its hepatocyte-specific function.

The role of bariatric surgery on beta-cell function and insulin resistance in patients with nonalcoholic fatty liver disease and steatohepatitis.

Background: Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are strongly associated with obesity, metabolic syndrome, and insulin resistance (IR).

Objective: The aim of this study was to investigate the effects of metabolic surgery on pancreatic beta cell function and IR in patients with obesity and NAFLD.

Setting: University Hospital, Germany.