Tumour epithelial and stromal characteristics of hepatocellular carcinomas with abundant fibrous stroma: fibrolamellar versus scirrhous hepatocellular carcinoma

Kim, Young Joo; Rhee, Hyungjin; Yoo, Jeong Eun; Alves, Venâncio Avancini Ferreira; Kim, Gi Jeong; Kim, Hye Min; Herman, Paulo; Chagas, Aline Lopes; Kim, Haeryoung; Park, Young Nyun

doi:10.1111/his.13219

Cited by 31 publications

(36 citation statements)

References 22 publications

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“…Negative control included in all assays: slides incubated with secondary antibody only (Figure S1 ). Positive control used in this study is the mesenchymal fibroblasts stained positive for FAP (Figure 1 E), we also refer to the positive results in various cancer cells including HCC from previous studies 5 , 15 , 16 . Photographs of representative fields were captured under ZEISS N-ACHROPLAN microscope (ZEISS, Germany).…”

Section: Methodsmentioning

confidence: 57%

The Expression of FAP in Hepatocellular Carcinoma Cells is Induced by Hypoxia and Correlates with Poor Clinical Outcomes

Zou¹,

Liu²,

Zhang³

et al. 2018

J. Cancer

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Fibroblast activation protein (FAP) is a serine protease that has been reported in fibroblasts and some carcinoma cells, which correlates with poor patient outcomes. FAP can be induced under hypoxia which is also vital in the malignant behaviors of cancer cells. However, the role of FAP and its correlation with hypoxia has not been investigated in HCC cancer cells. In tissues from post-surgical HCC patients in our center, we adopted immunohistochemistry staining (IHC), western blot and quantitative RT-PCR to detect the expression levels of FAP and the hypoxia related marker, hypoxia inducible factor 1α (HIF-1α). X-tile software was used for the determination of high and low expression of FAP and HIF-1α after the IHC analysis. Clinicopathological analysis, Kaplan-Meier analysis and Cox regression model were performed. In-vitro experiments were performed to confirm the relationship between FAP and hypoxia in HCC cancer cell lines (HepG2, Huh7 and MHCC97H). Results revealed that expression levels of FAP and HIF-1α were significantly correlated (Pearson r2 = 0.2753, p < 0.0001) in IHC analysis of the 138-patient cohort. Western blot and quantity RT-PCR indicated parallel changes in 11 post-surgical fresh frozen tissues. The HIF-1α and FAP expression were associated with serum AFP, TNM, tumor size and vascular invasion. Cox regression analysis showed that HIF-1α/ FAP combination were the independent predictor for overall survival (OS) and time-to-recurrence (TTR) in post-surgical HCC patients. Kaplan-Meier analyses revealed that the patient with high levels of HIF-1α, FAP and combined HIF-1α/FAP had the shortest OS and TTR. In-vitro experiments showed that FAP was increased in hypoxic HCC cancer cell lines in parallel with that of HIF-1α and three EMT markers (E-cadherin, Snail and TWIST). In conclusion, the up-regulation of FAP in HCC cancer cells under hypoxia can be indicative of poor prognosis in patients.

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Section: Methodsmentioning

confidence: 57%

The Expression of FAP in Hepatocellular Carcinoma Cells is Induced by Hypoxia and Correlates with Poor Clinical Outcomes

Zou¹,

Liu²,

Zhang³

et al. 2018

J. Cancer

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“…A detailed morphological observation is strongly recommended during the pathological diagnosis of CHC. Both scirrhous type HCC and K7‐ or K19‐positive HCC can be differential diagnoses of INT; however, these tumors mainly have typical HCC cell forms and can be differentiated with careful morphological observation . Additionally, due to wide structural diversities, such as strands and gland‐like structures and marked desmoplastic stroma, INT could be misdiagnosed as iCCA .…”

Section: Discussionmentioning

confidence: 99%

“…Both scirrhous type HCC and K7-or K19positive HCC can be differential diagnoses of INT; however, these tumors mainly have typical HCC cell forms and can be differentiated with careful morphological observation. 3,[17][18][19] Additionally, due to wide structural diversities, such as strands and gland-like structures and marked desmoplastic stroma, INT could be misdiagnosed as iCCA. 8 In the pathological diagnosis in CHC, IHC staining is helpful, but not essential.…”

Section: Discussionmentioning

confidence: 99%

Malic enzyme 1 is a potential marker of combined hepatocellular cholangiocarcinoma, subtype with stem‐cell features, intermediate‐cell type

Mihara

Akiba

Ogasawara

et al. 2019

Hepatology Research

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Aim Combined hepatocellular cholangiocarcinoma, subtype with stem‐cell features, intermediate‐cell subtype (INT) shows various histological appearances and could be misdiagnosed as intrahepatic cholangiocarcinoma (iCCA). In the present study, we aimed to identify specific histological diagnostic markers of INT. Methods We extracted RNA from FFPE sections of six INT, five iCCA, and five hepatocellular carcinoma (HCC) cases and compared gene expression between INT, iCCA, and HCC by microarray analysis. We then undertook immunohistochemical (IHC) staining of potential key molecules identified by microarray analysis, the conventional hepatocytic marker, hepatocyte paraffin (HepPar)‐1, and the cholangiocytic markers, keratin (K) 7 and K19, on 35 INT, 25 iCCA, and 60 HCC cases. Results Microarray analysis suggested that malic enzyme 1 (ME1) was significantly upregulated in INT. Immunohistochemical analysis revealed that the positive rates of ME1 in INT, iCCA, and HCC were 77.1% (27/35), 28.0% (7/25), and 61.7% (37/60), respectively. Analysis of classification and regression trees based on IHC scores indicated that HepPar‐1 could be a good candidate for discriminating HCC from the others with high sensitivity (93.3%) and high specificity (96.7%). A multiple logistic regression model and receiver operating characteristic curve analysis based on the IHC scores of ME1, K7, and K19 generated a composite score that can discriminate between INT and iCCA. Using this composite score, INT could be discriminated from iCCA with high sensitivity (88.6%) and high specificity (88.0%). Conclusions We propose that ME1 is a useful diagnostic marker of INT when used in combination with other hepatocytic and cholangiocytic markers.

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“…1 HCCs. 24 Recently, DNAJB1-PRKACA gene fusion has been demonstrated in fibrolamellar HCC, and hence FISH for PRKACA gene rearrangement has been proposed to be a good diagnostic tool for this tumor. 25,26 The prognosis of fibrolamellar HCC has been shown to be better than for con-ventional HCCs that arise in cirrhotic livers, but similar to HCCs in non-cirrhotic livers.…”

Section: Fibrolamellar Hcc (Fibrolamellar Carcinoma)mentioning

confidence: 99%

Histopathological Variants of Hepatocellular Carcinomas: an Update According to the 5th Edition of the WHO Classification of Digestive System Tumors

Kim

Jang

Park³

2020

J Liver Cancer

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Hepatocellular carcinoma (HCC) is heterogeneous in pathogenesis, phenotype and biological behavior. Various histopathological features of HCC had been sporadically described, and with the identification of common molecular alterations of HCC and its genomic landscape over the last decade, morpho-molecular correlation of HCC has become possible. As a result, up to 35% of HCCs can now be classified into histopathological variants, many of which have unique molecular characteristics. This review will provide an introduction to the variously described histopathological variants of HCC in the updated WHO Classification of Digestive System Tumors.

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Tumour epithelial and stromal characteristics of hepatocellular carcinomas with abundant fibrous stroma: fibrolamellar versus scirrhous hepatocellular carcinoma

Cited by 31 publications

References 22 publications

The Expression of FAP in Hepatocellular Carcinoma Cells is Induced by Hypoxia and Correlates with Poor Clinical Outcomes

The Expression of FAP in Hepatocellular Carcinoma Cells is Induced by Hypoxia and Correlates with Poor Clinical Outcomes

Malic enzyme 1 is a potential marker of combined hepatocellular cholangiocarcinoma, subtype with stem‐cell features, intermediate‐cell type

Histopathological Variants of Hepatocellular Carcinomas: an Update According to the 5th Edition of the WHO Classification of Digestive System Tumors

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