ABSTRACT
Introduction
Advances in precision medicine have expanded access to targeted therapies and demand for molecular profiling of cholangiocarcinoma (CCA) patients in routine clinical practice. However, pathologists face challenges in establishing a definitive intrahepatic CCA (iCCA) diagnosis while preserving sufficient tissue for molecular profiling. Additionally, they frequently face challenges in optimal tissue handling to preserve nucleic acid integrity.
Areas covered
This article first identifies the challenges in establishing a definitive diagnosis of iCCA in a lesional liver biopsy while preserving sufficient tissue for molecular profiling. Then, the authors explore the clinical value of molecular profiling, the basic principles of single gene and next-generation sequencing (NGS) techniques, and the challenges in tissue sampling for genomic testing. They also propose an algorithm for best practice in tissue management for molecular profiling of CCA.
Expert opinion
Several practical challenges face pathologists during tissue sampling and processing for molecular profiling. Optimized tissue processing, careful tissue handling, and selection of appropriate approaches to molecular testing are essential to ensure that the highest possible quality of diagnostic information is provided in the greatest proportion of cases.
Article highlights
With the advent of targeted therapies, preserving high-quality tissue for molecular profiling for cholangiocarcinoma (CCA) has become crucial. Pathologists face several pre-analytical challenges during tissue sampling and processing for molecular profiling.
Pathologists must handle tissue samples meticulously to establish the diagnosis of CCA without tissue exhaustion to preserve sufficient tissue for molecular profiling. Where multiple pieces of tissue are received, it is strongly recommended that they be processed as two or more separate blocks so that a second block remains even if all the tissue in the first block is exhausted.
Best practices should be followed to ensure optimal tissue selection. Optimal blocks should contain adequate nucleic acid content and neoplastic cell percentages. Decalcified blocks, older blocks, and samples with prolonged ischemia, desmoplastic stroma, and/or large numbers of inflammatory cells are often suboptimal.
In the case of a single tissue block, it is crucial to use every available technique, including judicious use of immunohistochemistry and macrodissection, to obtain the most information possible from the available sample.
Next-generation sequence (NGS) technologies must evolve to accommodate lower-quality nucleic acids and deliver faster, comprehensive results. The interpretation of vast data generated by NGS will require expertise in integrating genomic data with traditional histopathology and non-genomic biomarkers.
The role of liquid biopsy for genomic alterations is expected to increase, given its comparable sensitivity to tissue testing in metastatic diseases. This approach could expedite treatment by identifying genomic targets before biopsy confirmation, assist in repeated testing for resistance alterations, and potentially enable early detection of clinical progression through monitoring circulating tumor DNA levels.
Acknowledgments
All medical writing activities followed the 2022 update of the Good Publication Practice (GPP 2022) guidelines. The views and opinions expressed are those of the authors. All authors meet the International Committee of Medical Journal Editors (ICMJE) authorship criteria and approve the final version of the manuscript. Medical writing and editorial support in preparing this paper were provided by Content Ed Net, UK.
Declaration of interest
The authors retained the editorial process, including the discussion, at all times. T Kendall received consulting fees from Resolution Therapeutics, Clinovate Health, Perspectum, and Kynos Therapeutics. T Kendall received payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Incyte, National Universities of Ireland, and Servier Laboratories. T Kendall is a committee member of the Cholangiocarcinoma UK, British Association for the Study of the Liver, Pathological Society of Great Britain and Ireland, and British Liver Transplant Group committee member (to Oct 2021). M Evans received consulting fees from Diaceutics for providing data on testing activity. M Evans received payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Incyte, Eli Lilly and Company, Amgen, AstraZeneca, Bristol-Myers Squibb and Merck Sharp and Dohme. M Evans received support for attending meetings and/or travel from Eli Lilly and AstraZeneca. M Evans received payments for attendance at advisory board meetings by Ei Lilly and Amgen. M Evans is a member of the Genomics Test Evaluation Working Group and appraiser of NICE guidelines on behalf of the Royal College of Pathologists. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.