Estudio del PIVKA-II y de otros marcadores angiogénicos y metastásicos en el trasplante hepático por hepatocarcinoma

Laburpena

Hepatocellular carcinoma (HCC) accounts for 75-85% of all liver neoplasms. Orthotopic liver transplantation (OLT) is the best treatment option, as it could simultaneously cure the tumor and the underlying cirrhosis. Despite strict selection criteria, recurrences occur in 6%-18% of patients transplanted for HCC, and the prognosis of these patients is unfavourable. Serum alpha-fetoprotein (AFP) has been routinely used as a tumor marker for HCC. However, the high morbidity and mortality of this disease has encouraged the search for new biomarkers to monitor recurrence after transplantation in patients with HCC. Protein induced by vitamin K absence or antagonist-II (PIVKA-II) is a known tumor marker of HCC. Recent studies on the relationship between serum PIVKA-II level and various clinicopathological factors of HCC have shown that elevated PIVKA-II may be associated with worse tumor behavior and prognosis in HCC patients. Furthermore, several molecules are also involved in the process of angiogenesis and metastasis in HCC and some of them could play an important role in the follow-up of the transplanted patient. The aim of this study is to evaluate the role of PIVKA-II and other tumor markers (IL-6, IL-8, OPN, GPC3 and MMP-1) to monitor HCC patients after OLT, complementing AFP, as well as to study the relationship between these biomarkers and disease progression and survival after transplantation. For this purpose, an observational analytical prospective dynamic cohort study was carried out between September 2014 and May 2021, in which serum levels of the aforementioned biomarkers were measured in 46 HCC patients, in compliance with the Milan criteria, from the Clinical University Virgen de la Arrixaca Hospital (HCUVA, Murcia) and the Asturias Central Hospital (HUCA). Blood samples were collected before transplantation, at 1 month, 6 months, 1 year, 2 years and 3 years after transplantation. After analysis of the results, PIVKA-II correlated statistically significantly with some clinicopathological features, such as tumour size and number of pre-transplant transarterial chemoembolizations (TACEs), as well as with laboratory parameters indicative of poor prognosis, such as C-reactive protein (CRP), lactate dehydrogenase (LDH) and alkaline phosphatase. IL-6, IL-8 and MMP-1 were also associated with clinicopathological features of HCC before transplantation. Levels of PIVKA-II, AFP, IL-8 and MMP-1 were significantly decreased after transplantation and increased in patients with tumour recurrence. Although not reaching statistical significance, pre-transplant levels of PIVKA-II were more predictive of post-transplant tumour recurrence than AFP, improving this predictive capacity when both biomarkers were used together. In addition, elevated serum PIVKA-II levels before liver transplantation were associated with poorer overall survival (OS) and recurrence-free survival (RFS) after transplantation. In conclusion, a higher serum concentration of PIVKA-II may indicate a higher tumour volume and a worse clinical stage before transplantation in HCC patients. Monitoring PIVKA-II levels in HCC transplant recipients reflects the occurrence of tumour recurrence after transplantation and could be used, complementing AFP and imaging tests, as a novel biomarker reflecting early recurrence of HCC. Likewise, IL-6, IL-8, and MMP-1 could also be useful biomarkers in liver transplantation for HCC.