Biliary tract cancers (BTCs) are aggressive epithelial malignancies that can arise at any point of the biliary tree. Albeit rare, their incidence and mortality rates have been rising steadily over the past 40 years, highlighting the need to improve current diagnostic and therapeutic strategies. BTCs show high inter- and intra-tumour heterogeneity both at the morphological and molecular level. Such complex heterogeneity poses a substantial obstacle to effective interventions. It is widely accepted that the observed heterogeneity may be the result of a complex interplay of different elements, including risk factors, distinct molecular alterations and multiple potential cells of origin. The use of genetic lineage tracing systems in experimental models has identified cholangiocytes, hepatocytes and/or progenitor-like cells as the cells of origin of BTCs. Genomic evidence in support of the distinct cell of origin hypotheses is growing. In this review, we focus on recent advances in the histopathological subtyping of BTCs, discuss current genomic evidence and outline lineage tracing studies that have contributed to the current knowledge surrounding the cell of origin of these tumours.

Cell of origin in biliary tract cancers and clinical implications

Objective A detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options. Design We analysed a clinicopathologically well-characterised patient cohort (n=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) neoplastic precursor lesions of the biliary tract and correlated the results with an independent non-IPNB/ITPN associated CCA cohort (n=294). The triplet sample set of non-neoplastic biliary epithelium, precursor and invasive CCA was analysed by next generation sequencing, DNA copy number and genome-wide methylation profiling. Results Patients with invasive CCA arising from IPNB/ITPN had better prognosis than patients with CCA not associated with IPNB/ITPN. ITPN was localised mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small-duct and large-duct type intrahepatic CCA. IPNB exhibited mutational profiles of extrahepatic CCA, while ITPN had significantly fewer mutations. Most mutations were shared between precursor lesions and corresponding invasive CCA but ROBO2 mutations occurred exclusively in invasive CCA and CTNNB1 mutations were mainly present in precursor lesions. In addition, IPNB and ITPN differed in their DNA methylation profiles and analyses of latent methylation components suggested that IPNB and ITPN may have different cells-of-origin. Conclusion Integrative analysis revealed that IPNB and ITPN harbour distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles. In conclusion, IPNB/ITPN may represent a distinctive, intermediate form of intrahepatic and extrahepatic cholangiocarcinogenesis.

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Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis.

Introduction : Biliary tract cancer represents a heterogeneous group of malignancies characterized by dismal prognosis and scarce therapeutic options. Area covered In the last years a growing interest in BTCs pathology has emerged, thus highlighting a significant heterogeneity of the pathways underlying the carcinogenesis process, from both a molecular and genomic point of view. A better understanding of these differences is mandatory in order to deepen the behavior of this complex disease, as well as to identify new targetable target mutations, with the aim to improve the survival outcomes. The authors decided to provide a comprehensive overview of the recent highlights on BTCs, with a special focus on the genetic, epigenetic and molecular alterations which may have an interesting clinical application in the next future. Expert opinion In the last years, the efforts resulted from international collaborations have led to the identification of new promising targets for precision medicine approaches in the BTC setting. Further investigations and prospective trials are needed, but the hope is that these new knowledge in cooperation with the new technologies and procedures including bio-molecular and genomic analysis as well radiomic studies, will enrich the therapeutic armamentarium thus improving the survival outcomes in a such lethal and complex disease.

Cholangiocarcinoma: new perspectives for new horizons.

Details of human epidermal growth factor receptor 2 status in 454 cases of biliary tract cancer.

The overexpression of HER2 in breast cancer is a classic example for molecular targeted therapy, and it has been shown that classical anti-HER2 therapeutics were only effective in patients with HER2 overexpressing tumors. Therefore, in recent decades, pathologists have been focused on the reliable identification of HER2 overexpressing tumors. Based on the results of recent clinical trials in metastatic breast cancer with antibody-drug conjugates (ADCs), this diagnostic strategy for evaluation of HER2 is currently changing. It has been shown that the ADC trastuzumab-deruxtecan is effective not only against tumors with classical HER2 overexpression, but also against HER2-low tumors. These clinical trial results lead to a paradigm shift in the treatment of patients whose tumours were previously classified as HER2 negative. In addition to the identification of HER2 (score 3+) overexpressing tumors, it is necessary to identify HER2-low expressing tumors (defined as an immunohistochemistry (IHC) score of 1+ or IHC2+ with negative in situ hybridization).Due to the therapeutic consequences, it is important to quickly adapt the diagnostic workup and reporting to the new requirements. In addition, the new therapeutic options for anti-HER2 therapy lead to new challenges for standardization as well as to new scientific questions for the characterization of tumors with low HER2 expression.Die standardisierte HER2-Bestimmung beim Mammakarzinom und bei anderen Tumoren ist eine wichtige Aufgabe der Pathologie. Ziel der bisherigen Bestimmung war es, zuverlässig diejenigen Tumoren zu identifizieren, die eine Überexpression des HER2-Proteins aufweisen, die in der Regel mit einer Genamplifikation einhergeht. Nur in dieser Gruppe von Tumoren war eine zielgerichtete Anti-HER2-Therapie sinnvoll und erfolgversprechend. Durch neue Substanzen und die Ergebnisse klinischer Studien beim metastasierten Mammakarzinom hat sich dies nun geändert. Es konnte gezeigt werden, dass Trastuzumab-Deruxtecan, ein Konjugat aus einem Anti-HER2-Antikörper und einer zytotoxischen Substanz, auch dann einen Anti-Tumor-Effekt aufweist, wenn nur eine geringe Expression von HER2 im Tumorgewebe vorliegt.Die aktuellen Daten bedeuten einen Paradigmenwechsel für die Behandlung von Patientinnen, deren Tumoren bislang als HER2-negativ eingeordnet wurden. Ziel ist es jetzt, neben den Tumoren mit einer HER2-Überexpression (IHC 3+) auch die Tumoren mit einer geringen HER2-Expression (HER2-low, definiert als IHC 1+ oder 2+/ISH-negativ) zuverlässig zu identifizieren. Aufgrund der therapeutischen Konsequenzen ist es wichtig, die diagnostischen Algorithmen und Befundtexte in allen pathologischen Instituten sehr kurzfristig an die neuen Erfordernisse anzupassen. Unabhängig davon ergeben sich neue wissenschaftliche Fragen und Herausforderungen für die Standardisierung, die aktuell bearbeitet werden. 

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Neue Therapiemöglichkeiten beim metastasierten HER2-low-Mammakarzinom

Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past few decades, thereby limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored to the individual has shown substantial success in the recent past as a promising avenue for cancer therapy. In this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer. We identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%). None of the patients with equivocal (2+) immunohistochemical staining results exhibited gene amplification molecularly. In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%). HER2 gene amplification was not significantly associated with other clinical parameters, including survival. This study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients. Furthermore, we provide a robust testing algorithm that may be used prior to therapy administration in future clinical trials evaluating the role of HER2 as a predictive marker in cholangiocarcinoma.

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Melina Rausch

Papers

HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis.