Tumour stemness and poor clinical outcomes in haemochromatosis patients with hepatocellular carcinoma

Daniel M Di Capua; William Shanahan; Michele Bourke; Navneet Ramlaul; Josh Appel; Aoife Canney; Neil G Docherty; Erinn McGrath; Eabha Ring; Fiona Jones; Marie Boyle; Janet McCormack; Tom Gallagher; Emir Hoti; Niamh Nolan; John D Ryan; Diarmaid D Houlihan; Aurelie Fabre

doi:10.1136/jcp-2022-208679

Tumour stemness and poor clinical outcomes in haemochromatosis patients with hepatocellular carcinoma

J Clin Pathol. 2023 May 30:jcp-2022-208679. doi: 10.1136/jcp-2022-208679. Online ahead of print.

Authors

Daniel M Di Capua^#¹, William Shanahan^#², Michele Bourke^#², Navneet Ramlaul², Josh Appel², Aoife Canney³, Neil G Docherty^{4

5}, Erinn McGrath¹, Eabha Ring², Fiona Jones², Marie Boyle², Janet McCormack⁶, Tom Gallagher^{4

7}, Emir Hoti^{4

7}, Niamh Nolan¹, John D Ryan^{8

9}, Diarmaid D Houlihan^#¹, Aurelie Fabre^#^{10

4

6}

Affiliations

¹ HIstopathology, St Vincent's University Hospital, Dublin, Ireland.
² Liver Unit, St Vincent's University Hospital, Dublin, Ireland.
³ Histopathology, University Hospital Galway, Galway, Ireland.
⁴ University College Dublin School of Medicine, Dublin, Ireland.
⁵ Diabetes Complications Research Centre, Conway Institute, University College Dublin, Dublin, Ireland.
⁶ Reseach Pathology Core, Conway Institute, University College Dublin, Dublin, Ireland.
⁷ Hepatobiliary and Transplant Surgery, St Vincent's University Hospital, Dublin, Ireland.
⁸ Hepatology Unit, Beaumont Hospital, Dublin, ireland.
⁹ RCSI University of Medicine and Health Sciences, Dublin, Ireland.
¹⁰ HIstopathology, St Vincent's University Hospital, Dublin, Ireland a.fabre@svuh.ie.

^# Contributed equally.

PMID: 37253536
DOI: 10.1136/jcp-2022-208679

Abstract

Aims: Patients with haemochromatosis (HFE) are known to have an increased risk of developing hepatocellular carcinoma (HCC). Available data are conflicting on whether such patients have poorer prognosis, and there is lack of data regarding the biology of HFE-HCC. We compared the course of HFE-HCC with a matched non-HFE-HCC control group and examined tumour characteristics using immunohistochemistry.

Methods: In this tertiary care-based retrospective analysis, 12 patients with HFE and 34 patients with alcohol/non-alcoholic steatohepatitis who underwent initially successful curative HCC therapy with ablation or resection were identified from our registry. Time to tumour progression was compared. Resected liver tissue from a separate cohort of 11 matched patients with HFE-HCC and without HFE-HCC was assessed for the expression of progenitor and epithelial-mesenchymal transition markers using immunohistochemistry.

Results: The median follow-up was 24.39 and 24.28 months for patients with HFE-HCC and those without HFE-HCC, respectively (p>0.05). The mean time to progression was shorter in the HFE group compared with the non-HFE group (12.87 months vs 17.78 months; HR 3.322, p<0.05). Patients with HFE-HCC also progressed to more advanced disease by the end of follow-up (p<0.05). Immunohistochemical analysis of matched HFE-HCC and non-HFE-HCC explants demonstrated increased expression of the cancer stem cell markers EpCAM (epithelial cell adhesion molecule) and EpCAM/SALL4 (spalt-like transcription factor 4) coexpression in HFE-HCC specimens (p<0.05). There was a high frequency of combined tumour subtypes within the HFE cohort.

Conclusions: This study demonstrates that the clinical course of patients with HFE-HCC is more aggressive and provides the first data indicating that their tumours have increased expression of progenitor markers. These findings suggest patients with HFE-HCC may need to be considered for transplant at an earlier stage.

Keywords: cancer stem cells; iron; liver.