Letter to the Editor: Toward biology-driven transplant oncology: The role of PIVKA-II in alpha-fetoprotein-normal hepatocellular carcinoma

Abstract

Liver transplantation is the most effective therapy for selected patients with hepatocellular carcinoma (HCC). However, post-transplant recurrence limits long-term survival. Current transplant selection guidelines predominantly rely on morphological criteria, such as the Milan criteria. These criteria incompletely capture the biological heterogeneity of HCC. This limitation is particularly evident in HCC in which alpha-fetoprotein (AFP) levels are normal, leading to clinically occult aggressive tumor biology. This invited letter to the editor examines the clinical implications of the recent study published in the World Journal of Gastrointestinal Oncology by Abbas et al in which they identified PIVKA-II as a marker of aggressive tumor behavior in AFP-normal HCC. The elevated PIVKA-II levels were strongly associated with adverse biological features, including disease beyond the Milan criteria and portal vein tumor thrombosis despite normal AFP levels. PIVKA-II successfully stratified patients with a high likelihood of aggressive disease even when conventional imaging criteria were met. The framework for transplant oncology is constantly evolving, and we highlight that PIVKA-II may complement existing morphologic and biomarker-based selection models. We particularly emphasize the potential role of PIVKA-II in refining transplant eligibility, guiding downstaging strategies, and improving surveillance and waitlist management in patients with normal AFP levels. While prospective validation is required, incorporation of PIVKA-II for transplant evaluation represents a meaningful step toward biology-driven, precision-based allocation in HCC management.

Key Words: Des-gamma-carboxy prothrombin; Hepatocellular cancer; Alpha-fetoprotein; Hepatic transplantation; Organ transplantation; Milan criteria

Core Tip: Hepatocellular carcinoma with normal alpha-fetoprotein (AFP) levels is a frequently missed when transplantation selection relies heavily on morphological criteria and AFP levels. Emerging evidence identified PIVKA-II as a robust marker of aggressive tumor biology in this subgroup. PIVKA-II successfully categorized high-risk disease despite favorable imaging and normal AFP levels. Integration of PIVKA-II with existing selection frameworks will enable a shift toward biology-driven transplant oncology and reduce post-transplant recurrence.

TO THE EDITOR

Liver transplantation (LT) is the most effective therapy for carefully selected patients with hepatocellular carcinoma (HCC). Nevertheless, post-transplant recurrence significantly decreases long-term survival. Transplant eligibility is primarily guided by morphological criteria, most notably the Milan criteria that was derived from a landmark study by Mazzaferro et al[1] in 48 patients from Milan, Italy. These criteria rely on tumor size (a single lesion ≤ 5 cm), number (up to 3 lesions each ≤ 3 cm), and the absence of vascular invasion rather than intrinsic tumor biology.

Subsequent guidelines, including the University of California San Francisco (UCSF) criteria (single tumor of size ≤ 6.5 cm, up to 3 tumors with a total diameter ≤ 8 cm, and no vascular invasion or extrahepatic spread), modestly broadened patient eligibility. However, these models still primarily rely on imaging to determine the disease burden. Although these criteria have improved clinical outcomes, they fail to account for the marked biological heterogeneity of HCC. Transplant decision-making increasingly includes factors such as tumor biology, response to downstaging, liver function, and donor type. A recent study by Abbas et al[2], published in the World Journal of Gastrointestinal Oncology, has provided important insights into the prognostic value of PIVKA-II in patients with HCC and normal alpha-fetoprotein (AFP) levels, a subgroup of patients in whom biological risk is often underestimated.

AFP-normal HCC: A blind spot in transplant oncology

AFP traditionally served as a surrogate marker of tumor aggressiveness and recurrence risk. Elevated AFP is also considered by many physicians in transplant selection models. However, 30%-40% of HCC cases present with normal AFP levels, and some of these cases include tumors with vascular invasion and rapid progression. The reliance on AFP and imaging alone may result in patients with unknown biologically aggressive tumors being listed for transplantation, thereby increasing the risk of post-transplant recurrence.

Abbas et al[2] directly addressed this limitation. In a cohort of 113 patients with AFP-normal HCC, elevated PIVKA-II levels were strongly associated with aggressive tumor biology defined by disease beyond the Milan criteria and/or portal vein tumor thrombosis. Notably, PIVKA-II levels ≥ 400 mAU/mL were independently associated with an aggressive phenotype on multivariable analysis, and all patients with PIVKA-II ≥ 4000 mAU/mL belonged to the aggressive group[2]. These findings suggest that PIVKA-II can discover biologically aggressive HCC when AFP is normal.

Biological rationale and supporting evidence

PIVKA-II, also known as des-γ-carboxy prothrombin, is produced by malignant hepatocytes due to impaired vitamin K-dependent carboxylation. PIVKA-II has also been implicated in tumor angiogenesis, cellular proliferation, and vascular invasion, providing a strong biological rationale for its association with aggressive tumor behavior[3,4].

Several studies demonstrated the prognostic value of PIVKA-II in predicting microvascular invasion, poor differentiation, and early recurrence after curative therapy[5-8]. Poté et al[7] observed that PIVKA-II outperformed AFP in predicting microvascular invasion while Lai et al[9] confirmed the value of PIVKA-II in predicting post-transplant recurrence. Importantly, recent studies investigating populations with negative or low levels of AFP demonstrated that PIVKA-II retains prognostic significance even when AFP fails[9-11]. Abbas et al[2] strengthened this evidence by focusing exclusively on patients with AFP-normal HCC.

Implications for transplant selection

The findings by Abbas et al[2] support a shift in transplant selection toward an integration of biological information. Patients within the Milan criteria but with markedly elevated PIVKA-II levels likely have aggressive disease and a high risk of recurrence after transplantation despite favorable imaging. Conversely, patients beyond the Milan criteria but with low PIVKA-II levels may represent a biologically indolent subgroup suitable for downstaging and eventual transplantation.

Several expanded selection guidelines, including the UCSF, Up-to-Seven, total tumor volume < 115 cm³, Toronto criteria, and Kyoto criteria, reflect this evolving paradigm. Notably, the Kyoto criteria incorporate a PIVKA-II cutoff of ≤ 400 mAU/mL and allow transplantation in patients with up to 10 tumors ≤ 5 cm in size. While clinical outcomes have been acceptable, the liberal tumor number limit has deterred widespread adoption. In patients with normal AFP levels, incorporation of PIVKA-II within established frameworks such as the UCSF criteria (5-year survival of 85%) may offer a pragmatic approach to refine risk stratification and maintain excellent long-term outcomes[12].

PIVKA-II should be viewed as a complement to existing morphological criteria and AFP-based models rather than a replacement for them. The greatest value of integrating PIVKA-II into existing guidelines will be better capturing the biology of the tumor to make more accurate clinical decisions.

Implications for surveillance and waitlist management

Surveillance strategies in patients with cirrhosis and normal AFP levels are suboptimal because as imaging alone fails to detect biologically aggressive tumors at an early stage. Incorporation of PIVKA-II into surveillance protocols will facilitate early identification of disease and a timely referral for transplant evaluation or locoregional therapy. Serial PIVKA-II assessment may also provide insight into tumor dynamics and treatment response in patients who are on a transplant waitlist. Declining PIVKA-II levels after locoregional therapy may reflect a favorable biological response, whereas persistently elevated or increasing levels of PIVKA-II may prompt reassessment of transplant candidacy.

LIMITATIONS AND FUTURE DIRECTIONS

The study by Abbas et al[2] was limited by its retrospective design, single-center cohort, and the absence of post-transplant survival or recurrence endpoints. Additionally, their definition of aggressive tumor biology incorporated features correlating with PIVKA-II, thereby potentially amplifying the observed associations. Nonetheless, the consistent biological trend observed in this population with AFP-normal HCC underscored the clinical relevance of this biomarker. Future prospective, multicenter studies are required to validate PIVKA-II thresholds, assess dynamic changes over time, and determine the effect of PIVKA-II-guided selection on post-transplant outcomes. Integration of PIVKA-II with AFP, radiological response, and emerging liquid biopsy tools may further refine precision-based transplant oncology[13].

CONCLUSION

Abbas et al[2] reinforced a central tenet of modern transplant oncology: Tumor biology is as important as tumor morphology. In AFP-normal HCC PIVKA-II emerged as a powerful marker of aggressive disease and a promising addition to refine transplant selection and surveillance. While prospective validation is needed, integration of PIVKA-II into existing evaluation guidelines represents a meaningful step toward biology-driven transplant allocation and improved long-term outcomes after LT.