In recent years, with the development of medical technology, the diagnosis and treatment of hepatocellular carcinoma (HCC) has been significantly improved, and innovative molecular tests for early detection and management of HCC are gradually being applied to clinical practice. This development raises a key question: With the rise of liquid biopsy techniques, will they replace traditional tissue biopsies? Or will both technologies continue to work? This article explores the challenges and potential of tissue biopsy and liquid biopsy for clinicians.
The role of tissue biopsy in HCC
Although tissue biopsy is not routinely used to diagnose HCC, it may be necessary in certain circumstances. For example, if a lesion between 1 and 2 cm is still inconclusive on dynamic contrast imaging, a biopsy can be performed to make a definitive diagnosis.
Biopsy is usually necessary in patients without concomitant cirrhosis, as the specificity of imaging for diagnosing HCC decreases in this setting. Liver tumor biopsy is indicated in patients with suspected intrahepatic cholangiocarcinoma, HCC-cholangiocarcinoma mix, or secondary malignancy, as histologic markers can distinguish HCC from other tumors. In addition, tissue biopsy evaluation of the liver of non-tumor patients can also help identify underlying liver disease and gain insight into the prognosis of HCC.
Another advantage of tissue biopsy is the ability to accurately classify HCC into various histological subtypes, such as the highly differentiated CTNNB1 mutant subtype and the poorly differentiated TP53 mutant subtype. While pathology-based biomarkers have not yet been shown to be clinically effective in guiding treatment selection, tissue biopsy may become a more routine diagnostic procedure in the era of precision medicine.
At the same time, there are some limitations to tissue biopsy (Figure 1). Due to sampling bias and tumor heterogeneity, the tissue obtained at the time of tissue biopsy may not be fully representative. In addition, liver biopsy increases the risk of pain, bleeding, and hypotension, tachycardia, pneumothorax, or biliary peritonitis.
Figure 1 Overview of the advantages and disadvantages of tissue biopsy versus liquid biopsy for hepatocellular carcinoma
Despite its limitations, tissue biopsy remains an important diagnostic tool, and with the advent of more targeted therapies, liver biopsy plays a greater role in guiding target identification and HCC management. In addition, as the biological complexity of HCC continues to be explored, the role of biomarkers and liver biopsy in guiding treatment selection and improving patient outcomes will become increasingly significant. Therefore, tissue biopsy remains an indispensable tool in cancer diagnosis.
The role of secondary liquid biopsy in HCC
In addition to providing serial samples, liquid biopsies can provide a wealth of genomic and transcriptomic information that would otherwise only be available through tissue biopsies. Continuous measurement of blood analytes within the treatment window with liquid biopsy can provide new insights into biological processes such as proteomic dynamics, matrix remodeling, metabolic reprogramming, and clonal diversity (Figure 1).
1. Circulating tumor cells
Analysis of circulating tumour cells (CTCs) is one of the earliest liquid biopsy methods used in oncology. CTCs migrate from the site of primary tumor or metastasis after tumor invasion to nearby blood vessels, thereby entering the systemic circulation, and their number is related to tumor burden. In addition, the analysis of CTCs provides a unique window into the observation of active cellular processes directly from tumors. Thus, CTC may be limited in its ability to detect early HCC, but it is useful for monitoring recurrence or response to treatment.
2. Cell-free DNA
Cell-free DNA (cfDNA) refers to a large number of circulating double-stranded DNA fragments associated with nucleosomes, while circulating tumour DNA (ctDNA) refers to smaller fragments (150 bp) released by apoptosis, necrosis, or active proliferation of tumor cells that temporarily exist in body fluids (< 2 hours). cfDNA is used to probe total, integrity, and copy number variation, as well as to detect methylation patterns, or to reflect the mutational signature of a patient's current tumor.
The main limitation of using cfDNA is that there is a strong correlation between the amount of ctDNA and lesion size, suggesting that early lesions are more difficult to detect than advanced disease. Therefore, cfDNA is a tool to detect relapse or treatment response and drug resistance.
3. Non-coding RNA species
Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) (25-30 bp) and long non-coding RNAs (>200 bp), are not translated into proteins, but serve as important regulatory elements involved in chromatin alterations, DNA transcription, and chromosomal circularization. ncRNAs are also involved in a variety of cellular processes in cancer pathogenesis, including cell proliferation, migration, invasion, and cell death. Their stability in the bloodstream makes them an indicator of liquid biopsy, as well as tissue-specific expression and the ability to distinguish cancer from precancerous lesions.
4. Extracellular vesicles
Extracellular vesicles (EVs) are lipid bilayer nanovesicles that are spontaneously produced and released into the extracellular environment by almost all mammalian cells and systematically spread to other organs. The main subclasses of EVs include exosomes, microvesicles, and apoptotic vesicles, each of which contains its own unique nucleic acid species. EVs are used as liquid biopsy analytes that reflect the genomic and transcriptomic status of the parental cells from which they originate, and EV-associated nucleic acid and proteomic signatures enable the detection of HCC and monitoring treatment response.
summary
In conclusion, both tissue biopsy and liquid biopsy are likely to play a greater role in the management of HCC patients in the near future. The advent of molecular diagnostics by tissue or liquid biopsy heralds a new era in the diagnosis and management of HCC, providing sensitive and versatile tools for all stages of the disease.
Bibliography:
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4. Lehrich BM, Zhang J, Monga SP, Dhanasekaran R. Battle of the biopsies: Role of tissue and liquid biopsy in hepatocellular carcinoma. J Hepatol. 2024 Mar; 80(3):515-530.
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