Morphophenotypic Classification of Hepatocellular Carcinoma: the Biliary/Stem Cell Subgroup and Worst Outcome—Implications on Patient Selection

Oliveira, Rui Caetano; Martins, Ricardo; Abrantes, Ana Margarida; Jesus, Ângela; Teixeira, Paulo; Canhoto, Carolina; Guerreiro, Pedro M.; Costa, Beatriz; Silva, Mário Rui; Tralhão, José Guilherme; Cipriano, Maria Augusta

doi:10.1007/s11605-020-04611-9

Cited by 2 publications

(3 citation statements)

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“…The immunophenotyping of HCC is therefore of added value in patient stratification. Some classifications have been suggested in the literature, conjugating morphological and IHC features, resorting to more or less simple scoring systems [60][61][62] and the more robust results are based on CK19 expression. Therefore, at least the assessment of CK19 should be performed, which may be of extra value in low-income countries.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Factors after Hepatectomy for Hepatocellular Carcinoma—The Importance of Pathological Immunophenotyping, the Steatohepatitic Subtype and the Impact of the Hepatic Pedicle Clamping

Viana,

Oliveira,

Martins

et al. 2024

Gastrointestinal Disorders

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Introduction: Hepatectomy (HP) is, along with liver transplantation, the only potentially curative treatment for Hepatocellular Carcinoma (HCC). The high prevalence of Metabolic Syndrome (MS) may be causing a shift in the HCC spectrum. Hepatic Pedicle Clamping (HPC), used to reduce perioperative bleeding during HP, has been theorized to increase the risk of recurrence. Cytokeratin 19 (CK19) and glypican-3 (GLP-3) have been identified as markers of worse prognosis in HCC. Materials and Methods: A clinical and pathological review of 59 patients undergoing HP for HCC between 2005 and 2013 was performed. Chronic liver disease was observed in 53 patients (89.8%), with cirrhosis in 54.2% [most frequent etiologies: ethylism (47.5%), HCV (25.4%) and HBV (11.9%)]. MS was in 36% of patients. In addition, 95% of patients had Child–Pugh class A and 5% class B, and there was a median MELD of 8 (6–18). A single nodule was observed in 46 patients (78%) with an average size of 5.4 cm. Microscopic vascular invasion (MiVI) was in 49% of patients and macroscopic (MaVI) in 17. HPC was in 43 patients (74.1%). Statistical analysis was performed with SPSS™ 21.0. Survival tests (Kaplan–Meier, log-rank and Cox regression). Statistical significance was with p < 0.05. Results: Major morbidity in 22% of patients. Mortality in 5.1%. Median overall survival (OS) of 71 months and median disease-free survival (DFS) of 37. In a multivariate analysis: MaVI (p = 0.001), MiVI (p = 0.005) and HCV infection (p = 0.002) were associated with worse OS; MS was associated with better OS (p = 0.001); MaVI (p = 0.000), MiVI (p = 0.035) and HPC (p = 0.012) were associated with worse DFS. CK19+/GLP-3− (p = 0.007) and CK19−/GLP-3+ (p = 0.029) patients were associated with worse DFS and CK19−/GLP-3− (p = 0.031) with better DFS. Discussion/Conclusions: HPC was an independent factor of worse DFS. The ischemia-reperfusion injury (IRI) produced by HPC could promote a more angiogenic and angioinvasive phenotype of tumor cells, resulting in higher recurrence. HCV etiology was associated with worse OS. MS was associated with better OS, highlighting the importance of a hepatectomy in these cases. The combined detection of CK19 and GLP-3 was an independent prognostic factor in HCC patients allowing for the identification of more aggressive tumors.

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Section: Discussionmentioning

confidence: 99%

Prognostic Factors after Hepatectomy for Hepatocellular Carcinoma—The Importance of Pathological Immunophenotyping, the Steatohepatitic Subtype and the Impact of the Hepatic Pedicle Clamping

Viana,

Oliveira,

Martins

et al. 2024

Gastrointestinal Disorders

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“…Among them, vascular invasion is a primary factor of tumor recurrence and metastasis. A study was using the markers that reflect aggressive tumor characteristics, such as vascularization, P53 overexpression, and biliary/stem cell markers, and found it seems adequate to the reality with effects in OS, feasible in biopsies, which may identify patients that could benefit from aggressive treatments [ 34 ]. So, we initially analyzed the relationship between clinical features and mRNAsi in HCC and found the HCC tissues exhibited a higher mRNAsi as the pathological tumor grade elevated and with the vascular invasion, and the higher mRNAsi predicted the shorter OS, which was in accordance with the research in ovarian cancer, colorectal cancer, and esophageal cancer [ 9 , 12 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…These results suggested the high BUB1 expression associated with high stemness may partly contribute to the poor outcome of HCC. Recent studies have tried to establish morphological and immunohistochemical patterns that could be important to individualized treatments to assess a better classification for the clinical reality [ 34 , 39 ]. In Tsujikawa and his colleagues research, they found the biliary/stem cell marker-positive group exhibited more aggressive features, such as poor tumor differentiation and increased frequency of portal vein invasion, and also the group has the shortest time to recurrence among the three groups [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of a Potential Stemness-Associated Biomarker in Hepatocellular Carcinoma

Zhang

Zeng

et al. 2022

Stem Cells International

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Background. Cancer stem cells (CSCs) are typically related to metastasis, recurrence, and drug resistance in malignant tumors. However, the biomarker and mechanism of CSCs need further exploration. This study is aimed at comprehensively depicting the stemness characteristics and identify a potential stemness-associated biomarker in hepatocellular carcinoma (HCC). Methods. The data of HCC patients from The Cancer Genome Atlas (TCGA) were collected and divided based on the mRNA expression-based stemness index (mRNAsi) in this study. Weighted gene coexpression network analysis (WGCNA) and the protein-protein interaction (PPI) network were performed, and the genes were screened through the Cytoscape software. Then, we constructed a prognostic expression signature using the multivariable Cox analysis and verified using the GEO and ICGC databases. Even more importantly, we used the three-dimensional (3D) fibrin gel to enrich the tumor-repopulating cells (TRCs) to validate the expression of the signature in CSCs by quantitative RT-PCR. Results. mRNAsi was significantly elevated in tumor and high-mRNAsi score was associated with poor overall survival in HCC. The positive stemness-associated (blue) module with 737 genes were screened based on WGCNA, and Budding uninhibited by benzimidazoles 1 (BUB1) was identified as the hub gene highly related to stemness in HCC. Then, the prognostic value and stemness characteristics were well validated in the ICGC and GSE14520 cohorts. Further analysis showed the expression of BUB1 was elevated in TRCs. Conclusion. BUB1, as a potential stemness-associated biomarker, could serve as a therapeutic CSCs-target and predicted the clinical outcomes of patients with HCC.

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Morphophenotypic Classification of Hepatocellular Carcinoma: the Biliary/Stem Cell Subgroup and Worst Outcome—Implications on Patient Selection

Cited by 2 publications

References 50 publications

Prognostic Factors after Hepatectomy for Hepatocellular Carcinoma—The Importance of Pathological Immunophenotyping, the Steatohepatitic Subtype and the Impact of the Hepatic Pedicle Clamping

Prognostic Factors after Hepatectomy for Hepatocellular Carcinoma—The Importance of Pathological Immunophenotyping, the Steatohepatitic Subtype and the Impact of the Hepatic Pedicle Clamping

Identification and Validation of a Potential Stemness-Associated Biomarker in Hepatocellular Carcinoma

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