Preoperative prediction of microvascular invasion: Is invasive biopsy of HCC necessary?

Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsiesJournal of HepatologyVol. 76Issue 2PreviewMicrovascular invasion (MVI), a major risk factor for tumor recurrence after surgery in hepatocellular carcinoma (HCC), is only detectable by microscopic examination of the surgical specimen. We aimed to define a transcriptomic signature associated with MVI in HCC than can be applied to formalin-fixed paraffin-embedded (FFPE) biopsies for use in clinical practice. Full-Text PDF Reply to: Correspondence regarding “Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies”Journal of HepatologyVol. 77Issue 3PreviewWe strongly appreciate the interest motivated by our recently published article entitled “Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies”,1 and are pleased to consider the different concerns raised by Chao Li et al,2 Zi-Xiang Chen et al.3 and Ke-Chun Wang et al.4 Altogether, they demonstrate that microvascular invasion (MVI), a very major prognostic risk factor, is a challenging issue, and its prediction at the time of hepatocellular carcinoma (HCC) diagnosis remains a significant unmet need. Full-Text PDF We read with great interest the recent article published in Journal of Hepatology by Beaufrère and colleagues.[1]Beaufrère A. Caruso S. Calderaro J. Poté N. Bijot J.C. Couchy G. et al.Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies.J Hepatol. 2022; 76: 343-352Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Microvascular invasion (MVI) is widely recognized as a very important risk associated with recurrence and survival following hepatectomy for hepatocellular carcinoma (HCC). However, MVI can only be identified by histopathological examination on postoperative surgical specimens. Therefore, the development of a preoperative prediction model that can accurately identify MVI has become a research hotspot. Unlike many previous radiomics prediction models,2Lee S. Kim S.H. Lee J.E. Sinn D.H. Park C.K. Preoperative gadoxetic acid-enhanced MRI for predicting microvascular invasion in patients with single hepatocellular carcinoma.J Hepatol. 2017; 67: 526-534Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, 3Xu X. Zhang H.L. Liu Q.P. Sun S.W. Zhang J. Zhu F.P. et al.Radiomic analysis of contrast-enhanced CT predicts microvascular invasion and outcome in hepatocellular carcinoma.J Hepatol. 2019; 70: 1133-1144Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar, 4Renzulli M. Brocchi S. Cucchetti A. Mazzotti F. Mosconi C. Sportoletti C. et al.Can current preoperative imaging be used to detect microvascular invasion of hepatocellular carcinoma.Radiology. 2016; 279: 432-442Crossref PubMed Scopus (193) Google Scholar Beaufrère et al. developed a transcriptomic-based 6-gene signature for predicting MVI using liver biopsies of HCC before surgery. They declared that this signature has good performance for predicting MVI preoperatively. Although novel, we, herein, would like to raise the following concerns. First, according to some international clinical guidelines, tissue biopsy for the diagnosis of HCC is considered unnecessary for patients with characteristic imaging features of HCC.[5]Marrero J.A. Ahn J. Rajender Reddy K. ACG clinical guideline: the diagnosis and management of focal liver lesions.Am J Gastroenterol. 2014; 109 (quiz 1348): 1328-1347Crossref PubMed Scopus (228) Google Scholar,[6]Tapper E.B. Lok A.S. Use of liver imaging and biopsy in clinical practice.N Engl J Med. 2017; 377: 756-768Crossref PubMed Scopus (177) Google Scholar HCC is known to be diagnosed with ≥90% accuracy by imaging alone when a lesion is >2 cm, thus obviating the need for liver biopsy in nearly all cases, especially if the lesion is to be removed.[7]Di Martino M. De Filippis G. De Santis A. Geiger D. Del Monte M. Lombardo C.V. et al.Hepatocellular carcinoma in cirrhotic patients: prospective comparison of US, CT and MR imaging.Eur Radiol. 2013; 23: 887-896Crossref PubMed Scopus (74) Google Scholar Although knowing the MVI status before surgery may be helpful for surgical decision-making (such as whether to consider neoadjuvant therapy, wide-margin resection, or anatomic hepatectomy), there is still no high-level evidence that it confers a survival benefit. As an invasive procedure, percutaneous tissue biopsy of HCC is associated with some risks that should not be underestimated, including tumor seeding (in ∼3% of cases), potentially fatal bleeding (1∼2%), and, owing to sampling error, a low negative predictive value (14%).[6]Tapper E.B. Lok A.S. Use of liver imaging and biopsy in clinical practice.N Engl J Med. 2017; 377: 756-768Crossref PubMed Scopus (177) Google Scholar,[7]Di Martino M. De Filippis G. De Santis A. Geiger D. Del Monte M. Lombardo C.V. et al.Hepatocellular carcinoma in cirrhotic patients: prospective comparison of US, CT and MR imaging.Eur Radiol. 2013; 23: 887-896Crossref PubMed Scopus (74) Google Scholar Given the emerging development of liquid biopsy techniques such as circulating tumor cells, circulating tumor DNA, and exosomes,[8]von Felden J. Garcia-Lezana T. Schulze K. Losic B. Villanueva A. Liquid biopsy in the clinical management of hepatocellular carcinoma.Gut. 2020; 69: 2025-2034Crossref PubMed Scopus (38) Google Scholar,[9]Labgaa I. Villanueva A. Dormond O. Demartines N. Melloul E. The role of liquid biopsy in hepatocellular carcinoma prognostication.Cancers (Basel). 2021; 13Crossref PubMed Scopus (11) Google Scholar genomic or other omics-based biomarkers from blood or body fluid are recommended to replace HCC biopsy. Therefore, after weighing the pros and cons, we do not think that invasive biopsy of HCC is warranted for the preoperative prediction of MVI. Second, in real clinical settings, it can be difficult to convince patients who are about to undergo HCC resection to undergo additional tumor biopsy and genetic testing before surgery, not only because of cost but also waiting time. On the one hand, the cost of liver biopsy is considerable ($1,558 per biopsy in 2016 US dollars),[10]Tapper E.B. Sengupta N. Hunink M.G. Afdhal N.H. Lai M. Cost-effective evaluation of nonalcoholic fatty liver disease with NAFLD fibrosis score and vibration controlled transient elastography.Am J Gastroenterol. 2015; 110: 1298-1304Crossref PubMed Scopus (56) Google Scholar not to mention the cost of genetic testing. If health insurance does not cover this cost, the willingness and compliance of patients to agree to this additional test is very low. On the other hand, waiting for the analytic results of genetic testing takes a long time, at least 14∼20 days in most medical centers. The following issues must also be faced: i) whether both surgeons and patients are willing to wait so long before surgery, ii) whether patients need be discharged for a period of time after biopsy and then be re-admitted for surgery, iii) whether patients will experience anxiety and fear during the waiting period, and iv) whether their tumors will progress during the waiting period. Last but not least, it is also important to consider how to explain to patients if the predictive result is false-positive or false-negative. In conclusion, accurate prediction of MVI preoperatively is helpful for surgical decision-making and optimal allocation of medical resources, but the development of a suitable predictive tool should not only consider its predictive accuracy, but also its invasiveness, operational risk, time constraints, cost-effectiveness, and so on. Using preoperative HCC biopsy to predict MVI is the “icing on the cake” or “butter on bacon”, and warrants consideration by clinicians. As the authors point out, the results of this pilot study need to be confirmed by extensive study with further clinical data. Technological developments and cost reductions in genetic testing should enable the accurate, non-invasive and effective prediction of MVI before surgery for most patients with HCC. The authors received no financial support to produce this manuscript. Zi-Xiang Chen and Si-Yu Liu contribute equally to this paper. Conception: Zi-Xiang Chen, Si-Yu Liu, Xiang-Min Tong; Manuscript preparation: Zi-Xiang Chen, Si-Yu Liu; Critical revision: Xiang-Min Tong. All the authors reviewed the paper and approved the final version. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. The following are the supplementary data to this article: Download .pdf (.22 MB) Help with pdf files Multimedia component 1