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The association of microvascular invasion with satellite nodule, tumor multiplicity, tumor encapsulation and resection margin of hepatocellular carcinoma

  • Chao Li
    Affiliations
    Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China

    Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China

    Graduate School, Medical College of Soochow University, Suzhou, Jiangsu, China
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  • Wei Ouyang
    Affiliations
    Graduate School, Medical College of Soochow University, Suzhou, Jiangsu, China
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  • Tian Yang
    Correspondence
    Corresponding author. Address: Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; or Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China.
    Affiliations
    Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China

    Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China

    Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Medical University, Shanghai, China
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Published:April 10, 2022DOI:https://doi.org/10.1016/j.jhep.2022.03.036

      Linked Article

      To the Editor:
      We read with great interest the article by Beaufrère et al.
      • 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.
      Microvascular invasion (MVI) is known to be a major risk associated with worse prognosis after resection of hepatocellular carcinoma (HCC), but it can only be detected by microscopic examination of the surgical specimen. By using their routine formalin-fixed paraffin-embedded (FFPE) biopsies and RNA-sequencing analysis, Beaufrère et al. developed and validated a 6-gene signature panel which can accurately predict MVI preoperatively. Meanwhile, this biogenetical panel was also demonstrated to be independently associated with overall survival after HCC resection. Although inspiring, we would like to raise a discussion on the association between MVI and other clinicopathological features in this study.
      First, MVI and satellite nodules. Generally, satellite nodules are derived from MVI.
      • Okusaka T.
      • Okada S.
      • Ueno H.
      • Ikeda M.
      • Shimada K.
      • Yamamoto J.
      • et al.
      Satellite lesions in patients with small hepatocellular carcinoma with reference to clinicopathologic features.
      ,
      • Cong W.M.
      • Bu H.
      • Chen J.
      • Dong H.
      • Zhu Y.Y.
      • Feng L.H.
      • et al.
      Practice guidelines for the pathological diagnosis of primary liver cancer: 2015 update.
      Similar to MVI, satellite nodules are only detectable by microscopy in the peritumoral liver of the surgical specimen.
      • Okusaka T.
      • Okada S.
      • Ueno H.
      • Ikeda M.
      • Shimada K.
      • Yamamoto J.
      • et al.
      Satellite lesions in patients with small hepatocellular carcinoma with reference to clinicopathologic features.
      While difficult to distinguish MVI and satellite nodule histologically, a diagnosis of satellite nodules is appropriate.
      • Cong W.M.
      • Bu H.
      • Chen J.
      • Dong H.
      • Zhu Y.Y.
      • Feng L.H.
      • et al.
      Practice guidelines for the pathological diagnosis of primary liver cancer: 2015 update.
      Not surprisingly, Beaufrère et al. also revealed an independently high correlation between MVI and satellite nodules in their study, with adjusted odds ratios (ORs) of 158.41 by univariate and multivariate analysis. However, what puzzles us is why the authors used satellite nodules as a variable in the multivariate analysis to predict MVI, given that their purpose was actually to preoperatively predict MVI, while the presence of satellite nodules also needs to be identified postoperatively like MVI. This approach appears to be incorrect and will likely change the adjusted OR value of the 6-gene signature when predicting MVI.
      Second, MVI and tumor multiplicity. Among the 178 patients in the whole cohort of this study by Dr Beaufrère et al., 24 (13.5%) patients had multiple tumors (tumor number ≥2). Considering the high heterogeneity of HCC, whether these multiple tumor lesions are of monoclonal origin or polyclonal origin will be very different in their gene signature spectrum through tissue biopsy.
      • Dragani T.A.
      Risk of HCC: genetic heterogeneity and complex genetics.
      ,
      • Torrecilla S.
      • Sia D.
      • Harrington A.N.
      • Zhang Z.
      • Cabellos L.
      • Cornella H.
      • et al.
      Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma.
      In this study, however, the authors did not mention whether both FFPE biopsy and transcriptome sequencing were performed for each tumor lesion of patients with multiple tumors, whether the MVI status of each tumor lesion was respectively examined and marked, and whether the RNA-sequencing result had a one-to-one correspondence with the MVI status of each tumor lesion. In our opinion, ambiguity of important information or possible labeling errors will inevitably affect the interpretability and credibility of the results.
      Third, MVI and tumor encapsulation. Previous studies have shown that there is a negative correlation between tumor encapsulation and MVI, suggesting that once cancer cells of HCC break through the tumor capsule, the probability of forming MVI is greatly increased.
      • Cong W.M.
      • Bu H.
      • Chen J.
      • Dong H.
      • Zhu Y.Y.
      • Feng L.H.
      • et al.
      Practice guidelines for the pathological diagnosis of primary liver cancer: 2015 update.
      ,
      • Ariizumi S.
      • Yamamoto M.
      Prognostic impact of tumor encapsulation in patients with large hepatocellular carcinoma.
      In the literature, most prognostic studies on HCC resection did not overlook the potential effect of tumor capsulation.
      • Tung-Ping Poon R.
      • Fan S.T.
      • Wong J.
      Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma.
      ,
      • Imamura H.
      • Matsuyama Y.
      • Tanaka E.
      • Ohkubo T.
      • Hasegawa K.
      • Miyagawa S.
      • et al.
      Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy.
      Unfortunately, we did not find this important pathological feature which may be related to both MVI and overall survival after HCC resection in this study by Beaufrère et al.
      Fourth, MVI and resection margin. Another pity in this study is that the status of resection margin was not mentioned.
      • 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.
      Actually, given that the status of resection margin (narrow or wide) and MVI (positive or negative) both involve the chance of residual cancer cells being left in the liver remnant after HCC resection, they are likely to have a synergic effect on postoperative recurrence and survival.
      • Poon R.T.
      • Fan S.T.
      • Ng I.O.
      • Wong J.
      Significance of resection margin in hepatectomy for hepatocellular carcinoma: a critical reappraisal.
      Our team has reported that concomitant narrow resection margin (<1.0 cm) and positive MVI increases the risks of postoperative recurrence and death by about 2-fold in patients with solitary HCC.
      • Han J.
      • Li Z.L.
      • Xing H.
      • Wu H.
      • Zhu P.
      • Lau W.Y.
      • et al.
      The impact of resection margin and microvascular invasion on long-term prognosis after curative resection of hepatocellular carcinoma: a multi-institutional study.
      In conclusion, clarification of the aforementioned issues would greatly solidify the conclusions of this study.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      Conception: Chao Li, Tian Yang; Manuscript preparation: Chao Li, Wei Ouyang; Critical revision: Tian Yang. All the authors reviewed the paper and approved the final version. Chao Li and Wei Ouyang contributed equally to this work.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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