Multifaceted role of histopathology in liver transplantation for hepatocellular carcinoma: A narrative review towards precision prognosis

Abstract

Hepatocellular carcinoma is a leading cause of cancer mortality globally. Liver transplantation is considered the best curative treatment for selected patients, as it removes the tumor and restores hepatic function. However, organ scarcity requires precise prognostic stratification. Histopathology is the essential bridge between morphology and biology, offering unique insights into tumor aggressiveness that imaging cannot capture. Öztürk et al recently published a study in the World Journal of Transplantation, analyzing a large United States transplant cohort analysis, which reveals clear differences in the risk profiles of macrovascular invasion and microvascular invasion. A central prognostic factor is macrovascular invasion. Macrovascular invasion indicates a poor prognosis, whereas microvascular invasion, detectable only histologically, defines an intermediate risk, highlighting the need for meticulous and standardized pathological examination. Prognostic accuracy is further refined by factors such as histological grading and specific subtypes (e.g., macrotrabecular-massive). Histopathological data guide clinical decision-making throughout the transplant process, from candidate selection to individualized surveillance. The incorporation of microvascular invasion or poor differentiation into predictive models improves patient management. In the future, digital pathology and artificial intelligence will automate the detection of prognostic markers, while molecular profiling will deepen our understanding of tumors at the morpho-molecular level. Within this integrated framework, histopathology has evolved into a dynamic science that is essential for the implementation of precision medicine for liver transplantation in cases of hepatocellular carcinoma. The liver explant has become a valuable repository of biological information that informs risk, guides therapy, and expands the field of transplant oncology.

Key Words: Hepatocellular carcinoma; Liver transplantation; Histopathology; Vascular invasion; Tumor differentiation; Prognostic stratification; Precision medicine

Core Tip: Histopathological assessment remains indispensable for liver transplantation in hepatocellular carcinoma, providing crucial information about tumor biology that imaging alone cannot capture. This editorial emphasizes how vascular invasion, tumor differentiation, and histologic subtyping critically refine prognostic stratification and guide individualized post-transplant management. By integrating standardized sampling with digital pathology and molecular profiling, pathology evolves from a diagnostic discipline into a predictive and decision-shaping science, optimizing organ allocation for hepatocellular carcinoma transplantation and improving long-term outcomes for patients.

This editorial refers to “Association of vascular invasion and tumor differentiation on post-liver transplant outcomes in patients with hepatocellular carcinoma” by Öztürk et al, 2025; https://dx.doi.org/10.5500/wjt.v15.i4.109609.

---

INTRODUCTION

Hepatocellular carcinoma (HCC) continues to represent one of the most formidable challenges in oncology and hepatology. Globally, it ranks as the sixth most common cancer and is a leading cause of cancer-related mortality, with its incidence propelled by the converging epidemics of chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, and its more severe form, non-alcoholic steatohepatitis[1-3]. For selected patients, liver transplantation (LT) is the definitive curative treatment, offering the unique dual benefit of eradicating the tumor and replacing the failing cirrhotic liver, addressing both the oncological and hepatic insufficiency aspects of the disease[3-5]. This life-saving intervention, however, must be judiciously balanced against the critical scarcity of donor organs. In this resource-limited environment, the precise identification of patients who will derive the greatest long-term survival benefit is paramount for optimizing organ allocation and maximizing the public health impact of transplantation[6,7].

LITERATURE REVIEW

A literature search was conducted using multiple literature databases, including PubMed, MEDLINE, ScienceDirect and Cochrane Library, with the keywords “hepatocellular carcinoma”, “liver transplant”, “vascular invasion”, “microvascular invasion”, “macrovascular invasion”, “Milan criteria”, “needle biopsy”, “liver explant”, “risk prediction”, “tumor grade”, “histological subtypes” and “transplant eligibility”, applied alone and in combination. Additional studies were selected from the reference list of the identified articles and current guidelines. There was no date restriction implemented in order to capture the seminal publications that laid the foundations for current concepts in HCC and LT.

HISTOPATHOLOGY AS THE INDISPENSABLE ARBITER OF TUMOR BIOLOGY

For decades, candidate selection for LT has been guided by visible tumor characteristics, primarily following the Milan criteria. These criteria require a single tumor ≤ 5 cm or up to three nodules ≤ 3 cm, with no evidence of vascular invasion or extrahepatic spread[4]. These radiological benchmarks have proven remarkably effective at identifying a cohort of patients with 5-year survival rates exceeding 70%[8]. However, a puzzling paradox exists: Some patients who meet these strict imaging criteria still experience HCC recurrence post-transplant, whereas other patients who modestly exceed these limits have favorable long-term outcomes[9]. The fundamental limitation is that inherent biological variability prevents imaging and size/number metrics alone from serving as reliable indicators of future risk or underlying biological aggressiveness. It is in this critical gap that histopathology emerges not as a mere ancillary diagnostic tool but as a cornerstone of modern transplant oncology, providing an unparalleled window into the microscopic determinants of tumor behavior.

VASCULAR INVASION: DECODING THE HIERARCHICAL SPECTRUM OF AGGRESSION

The prognostic power of histopathology is powerfully illustrated by its ability to characterize vascular invasion. The recent and robust study published in World Journal of Transplantation by Öztürk et al[10], analyzing a large United States transplant cohort, provides compelling evidence that differentiates the risk profiles of macrovascular invasion (MaVI) and microvascular invasion (MVI). MaVI, defined as gross tumor involvement of the main portal vein or hepatic veins, is typically identifiable on pre-transplant imaging. It has long been synonymous with a poor prognosis, correlating with post-transplant recurrence rates exceeding 70% within 2 years and significantly reduced survival, rendering it a relative or absolute contraindication to transplantation in most allocation systems[11,12].

Consistent with this, Öztürk et al[10] showed markedly reduced 1-, 3-, and 5-year post-transplant survival rates (83.6%, 66.6%, and 55.7%, respectively) for patients with MaVI in the explant. However, the relatively low incidence of MaVI (1.8% in their cohort) means that it likely represents only the most obvious sign of aggressive disease. MVI, a more common and clinically significant finding, was detected in 12.6% of the explants in Öztürk et al’s study[10]. MVI is defined by the presence of microscopic clusters of tumor cells in portal venules, hepatic venules, or capsular vessels. Because even advanced imaging modalities like contrast-enhanced magnetic resonance imaging cannot detect MVI, a definitive diagnosis is only possible through histopathology[13]. The work of Öztürk et al[10] identified MVI as an intermediate-risk factor and confirmed that the extent of vascular involvement - whether absent, microscopic, or macroscopic - accurately predicts the tumor’s biological aggressiveness. This finding aligns with a broad body of literature establishing MVI as one of the most potent independent predictors of recurrence and mortality, often irrespective of morphological criteria like tumor size and number[14].

The assessment of MVI requires a sophisticated and active process, rather than mere passive observation. Its distribution can be focal and heterogeneous, increasing the risk of undersampling. Therefore, optimal pathological results require a comprehensive, protocol-driven examination of the lesion, with multiple blocks taken from the tumor periphery and the transition zone to healthy liver tissue, as this is where invasion is most likely[15]. Studies have demonstrated that such standardized sampling protocols significantly improve the detection rate and prognostic value of MVI, underscoring that the quality of the pathological analysis is directly linked to the accuracy of risk stratification[14,16].

TUMOR DIFFERENTIATION AND THE EMERGENCE OF PROGNOSTIC SUBTYPES

Beyond vascular invasion, histopathological assessment provides a second pillar of prognostic information: Tumor differentiation grade. The study by Öztürk et al[10] revealed that poorly differentiated tumors were overrepresented in the MaVI cohort and were independently associated with higher mortality. This reinforces the established consensus that histological grade, commonly evaluated using systems like Edmonson-Steiner, is a robust predictor of post-LT recurrence and survival[17]. Poorly differentiated tumors show aggressive cell growth, abnormal architecture, and an enhanced intrinsic capacity for invasion and metastatic spread. It is important to acknowledge the inherent challenges of grading, including interobserver variability and the limited concordance between pre-transplant biopsy results and final explant pathology, which stem from intratumoral heterogeneity[18]. The evaluation of the explant is the gold standard for determining the tumor’s biological potential at the time of surgical removal. The histopathological landscape of HCC is far richer than the assessment of vascular invasion and grade alone. Significant advancements in the recognition and characterization of special histological subtypes, which comprise approximately 30% of all cases, have led to more precise prognostic predictions[19,20]. These subtypes must be routinely included in histopathological assessments to create a comprehensive risk profile.

Macrotrabecular-massive variant

The macrotrabecular-massive (MTM) variant is a highly aggressive subtype of HCC, characterized by thick tumor trabeculae (often > 6 cells thick). It is strongly associated with a high frequency of MVI and MaVI, elevated serum alpha-fetoprotein (AFP), and early post-LT recurrence. Its identification serves as a significant indicator of elevated risk, even in cases where the tumor falls within the Milan criteria[21,22].

Steatohepatitic HCC

The steatohepatitic subtype of HCC is often linked to non-alcoholic steatohepatitis and exhibits morphological features mimicking non-tumoral steatohepatitis. While its prognosis post-LT is not yet fully understood, this subtype is associated with specific molecular alterations (e.g., interleukin 6/signal transducer and activator of transcription 3 signaling), suggesting a unique biological pathway that may influence clinical behavior and response to therapy[23].

Fibrolamellar carcinoma

Fibrolamellar carcinoma is a distinct type of liver cancer that generally affects young people with no pre-existing cirrhosis and features a distinct morphology and molecular profile. While historically considered to have a better prognosis, its recurrence risk post-transplant remains substantial and necessitates careful long-term surveillance[24]. By including these subtypes in the pathological report, explant evaluation can better predict tumor behavior than standard methods, transforming pathology from a purely descriptive discipline to an integrative specialty that provides valuable insights into tumor biology.

CLINICAL TRANSLATION: FROM CANDIDATE SELECTION TO PRECISION MANAGEMENT

The implications of these histopathological findings critically extend across the entire transplant journey, from the first steps to long-term follow-up.

Refining pre-transplant candidate selection

While imaging criteria remain the gold standard for initial waitlisting, histopathology obtained via pre-operative biopsy can offer valuable preliminary insights into the tumor’s biology[15]. The presence of a poorly differentiated component or an aggressive subtype like MTM on biopsy could, in some centers, influence the decision to prioritize or decline a transplant, or at least justify a more prolonged observation period to evaluate tumor biology before proceeding with a definitive allocation[25]. This is particularly relevant in the context of expanding inclusion criteria (e.g., University of California, San Francisco criteria, Extended Toronto criteria, “up-to-7” rule), where histopathological correlates of MVI risk could help identify which patients beyond Milan are still likely to achieve excellent outcomes[26-28].

Regarding the indication for preoperative biopsy, we do not recommend its routine use in cirrhotic patients presenting with lesions that show the typical radiological criteria for HCC in accordance with the American Association for the Study of Liver Diseases/European Association for the Study of the Liver guidelines. In these cases, imaging-based diagnosis has sufficient specificity and avoids the risk associated with needle sampling. Biopsy is reserved for situations in which radiological diagnosis is inconclusive, in non-cirrhotic patients (for whom imaging specificity is lower), or when histological confirmation would modify therapeutic strategy (e.g., differential diagnosis with cholangiocarcinoma or mixed tumors)[19,29].

While pre-transplant tumor biopsy may provide valuable preliminary insights into tumor biology, its routine use remains controversial. Concerns regarding sampling error, intratumoral heterogeneity, bleeding risk, and potential tumor seeding have historically limited its widespread adoption[30-32]. In current clinical practice, the decision to perform a biopsy is often weighed against imaging characteristics, serum biomarkers, and the patient’s overall clinical status rather than applied systematically. The ability of preoperative biopsy to faithfully reflect the histological grade of the tumor in the explant is limited. The literature demonstrates modest concordance, particularly in the detection of poorly differentiated tumors[30-32]. Furthermore, the multifocal and heterogeneous nature of HCC promotes sampling error, leading to a significant risk of underestimating the tumor grade. Multicenter studies such as that by Court et al[33] have shown that biopsy-obtained grade does not improve pretransplant prognostic stratification, whereas definitive explant grade does add predictive power. This finding indirectly quantifies the magnitude of the error; the prognostic value of biopsy grade is insufficient, with low sensitivities and concordance rarely exceeding 50%-60%. Therefore, although biopsy has diagnostic value, its prognostic utility remains limited and should be interpreted cautiously[5,15,33].

Personalizing post-transplant management and adjuvant therapy

Explant histopathology reaches its full potential for guiding clinical management in the post-transplant period. A detailed pathological report documenting MVI, poor differentiation, or an aggressive subtype acts as a fundamental risk stratification tool. Patients identified as “high-risk” should be subjected to a stricter, tailored surveillance protocol, with more frequent cross-sectional imaging and AFP monitoring, especially in the first 2 years, the period of highest recurrence risk[11].

Post-transplant surveillance should be adapted to the histopathological risk factors present in the explant. Evidence supports a stratified approach, with low risk patients (no MVI, well-differentiated grade, small single nodules, absence of aggressive subtypes) recommended imaging every 6-12 months, intermediate risk patients (focal MVI, moderate differentiation, multifocal nodularity) recommended imaging every 4-6 months during the first 2 years, and high risk patients (extensive MVI, poor differentiation, MTM subtype, elevated AFP) recommended intensive-surveillance imaging every 3 months in the first year and every 4-6 months thereafter. Risk-prediction models such as RETREAT or the more recent SIMAP500 allow for quantitative and reproducible stratification, integrating morphological variables with serum markers and explant findings. Adopting one of these models may standardize follow-up intervals and identify subgroups that would benefit from more intensive surveillance[34-38].

Beyond surveillance, this histopathological risk stratification justifies the consideration of adjuvant therapies. Although no universal standard exists, the use of mammalian target of rapamycin inhibitors (e.g., sirolimus, everolimus), which combine immunosuppressive with antiproliferative and anti-angiogenic properties, has been specifically proposed for patients with adverse histological findings, with some studies showing a benefit in recurrence-free survival[39,40]. Beyond immunosuppression tailoring, post-transplant management strategies under investigation include adjuvant systemic therapies such as sorafenib and immune checkpoint inhibitors targeting the programmed death-1/programmed death-ligand 1 axis[41-43]. While results remain heterogeneous and evidence is evolving, these approaches highlight the need for refined pathological risk stratification to guide patient selection.

Similarly, the integration of histopathological data into quantitative predictive models, such as the “Metroticket 2.0 Model” or a potential “composite histopathological risk score,” could refine prognostic stratification enormously, enabling true personalization of follow-up and adjuvant strategies[44]. A composite histopathological risk score will represent a forward-looking framework for post-transplant prognostication. Such a score could integrate variables including the extent of MVI (focal vs extensive), tumor differentiation grade, presence of aggressive growth patterns (e.g., MTM subtype), and proliferative activity (e.g., mitotic count or Ki-67 index). Although not yet standardized, these parameters are increasingly being recognized as biologically and clinically relevant[45].

THE HORIZON: DIGITAL PATHOLOGY, ARTIFICIAL INTELLIGENCE, AND MOLECULAR INTEGRATION

The convergence of new technology is dramatically reshaping the future of histopathology in LT for HCC, elevating its role from foundational to transformative.

Digital pathology and artificial intelligence

The digitization of histology slides enables the application of sophisticated algorithms commonly referred to as artificial intelligence (AI) and machine learning algorithms. These systems are already demonstrating remarkable capability in detecting subtle patterns of MVI, quantifying microvascular density, and classifying differentiation grade and histological subtypes with an accuracy and reproducibility that can surpass conventional human assessment[46-48]. AI can analyze vast areas of tissue impartially, potentially identifying sub-visual histological features of aggressiveness, thereby standardizing pathology reports and mitigating subjective variability. Deep learning models are being developed to predict recurrence risk directly from whole-slide images, heralding a new era of data-driven prognostication[49].

We recommend adopting a uniform minimum dataset based on the principles of the College of American Pathologists protocols and the International Collaboration on Cancer Reporting. The minimum items we consider as necessary for inclusion in any liver biopsy report of suspicious HCC are specimen type and number of cores; percentage of tumor represented; histological grade according to Edmonson-Steiner or an equivalent system; morphological subtype, highlighting whether MTM or other high risk subtypes are present; presence of vascular invasion, if identifiable (recognizing that true MVI can only be confirmed in the explant); proliferative index or mitotic count; the immunohistochemical panel used and interpretation; and diagnostic limitations due to small sample size or artifacts. Standardization of these elements will facilitate intercenter comparison, improve the quality of prognostic models, and increase reproducibility in multicenter studies[45,50-52].

Molecular profiling and the morpho-molecular paradigm

The seamless integration of explant histopathology with molecular profiling opens a new dimension of prognostic stratification. Genomic studies have uncovered recurrent driver events in HCC, such as telomerase reverse transcriptase promoter mutations, β-catenin activation, and tumor protein 53 alterations[53]. Importantly, these mutations are often correlated with histological phenotypes; for example, tumors with β-catenin activation are typically well differentiated and cholestatic, whereas tumor protein 53 mutations are frequently found in poorly differentiated and MTM variants[20,45,53,54]. This synergy between morphology and molecular biology paves the way for “morpho-molecular” classifiers that could provide a more precise composite prognosis than either modality alone. Furthermore, characterizing the tumor immune microenvironment - including tumor-infiltrating lymphocytes and immune checkpoint expression - could refine stratification and guide the future application of immunotherapy in the post-LT setting[54]. HCC recurrence after LT reflects underlying mechanisms of tumor initiation, progression, and metastasis, involving genetic alterations, molecular signaling pathways, and tumor-immune interactions. Although these aspects were not the primary focus of the study by Öztürk et al[10], they represent a critical future direction for integrating histopathology with molecular and immunological profiling within a morpho-molecular paradigm[55,56].

CONCLUSION

The study by Öztürk et al[10] confirms the prognostic significance of MaVI and MVI and tumor differentiation for patients undergoing HCC transplantation. The collective evidence demands that we view histopathology not as a static repository of these conventional parameters but as a dynamic and evolving discipline. Expanding routine evaluation to include tumor subtype classification, supplemented with digital AI and molecular integration, provides a multidimensional and robust framework for predicting post-LT survival. This establishes the critical role of pathology not merely as a diagnostic tool but as a central pillar of evidence-based, precision medicine in transplantation. The hepatic explant is more than a surgical specimen; it is a source of biological information. Advanced histopathology is the key to unlocking these data, which informs immediate clinical decisions, optimizes organ allocation, and paves the way for future research aimed at improving outcomes for patients with HCC.