Tumour epithelial and stromal characteristics of hepatocellular carcinomas with abundant fibrous stroma: fibrolamellar versus scirrhous hepatocellular carcinoma.
OBJECTIVE
The scirrhous variant of hepatocellular carcinoma (S-HCC) and fibrolamellar HCC (FL-HCC) are less common subtypes of HCC that are characterized by abundant fibrous stroma. Here, we aimed to investigate differences in the tumour microenvironment and the tumour epithelial cell characteristics of S-HCC and FL-HCC.


RESULTS
Whole tissue sections of 17 S-HCCs and 9 FL-HCCs were subjected to immunohistochemical stains for keratin 7 (K7), K19, EpCAM, CD56/NCAM, CD163, CD68, pSTAT3, FAP, CCN2 and Ki-67. FL-HCC patients were younger than S-HCC patients (P < 0.001), and chronic liver disease was seen in the background of 88.2% of S-HCC and in none of the FL-HCC. CD68 and CD163-positive tumour-infiltrating macrophages, and FAP-positive cancer-associated fibroblasts (CAFs) were more abundant in the stroma of S-HCCs compared to FL-HCCs (all P < 0.05). Tumour epithelial K19 expression was more frequent in S-HCCs compared to FL-HCCs (P = 0.023). Significant positive correlations were seen between pSTAT3 expression status in tumour epithelial cells and CAFs, the extent of stromal CAF and macrophage infiltration and K19 expression status. No significant differences were seen for K7, EpCAM, CD56/NCAM, CCN2 expression and Ki-67 labelling index between S-HCCs and FL-HCCs.


CONCLUSIONS
S-HCC and FL-HCC are subtypes of HCC with extensive fibrosis, and the nature of the fibrous stroma differs between them. While the stroma of FL-HCC is composed of dense lamellated collagenous bands with sparse cellular components, S-HCC demonstrates more abundant CAF and tumour-infiltrating macrophages and stemness-related marker expression, suggesting the presence of a complex tumour microenvironment that may influence the aggressive behaviour of S-HCCs.
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
Young-Joo
YJ
Kim
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
Hyungjin
H
Rhee
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
Jeong Eun
JE
Yoo
Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil.
Venancio A F
VAF
Alves
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
Gi Jeong
GJ
Kim
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
Hye Min
HM
Kim
Department of Surgery, University of São Paulo School of Medicine, São Paulo, Brazil.
Paulo
P
Herman
Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil.
Aline
A
Chagas
Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Haeryoung
http://orcid.org/0000-0002-4205-9081
H
Kim
Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
Young Nyun
YN
Park
D000293:Adolescent; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002648:Child; D005260:Female; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D059016:Tumor Microenvironment; D055815:Young Adult
cancer-associated fibroblast; fibrolamellar hepatocellular carcinoma; scirrhous hepatocellular carcinoma; tumour microenvironment