Pulmonary metastasectomy for recurrent hepatocellular carcinoma after liver transplantation: A therapeutic challenge

Abstract

Recurrence of hepatocellular carcinoma remains the leading cause of mortality after liver transplantation (LT), with the lungs representing the most frequent extrahepatic site. This review evaluates the role of pulmonary metastasectomy in carefully selected LT recipients, with a focus on patient selection criteria, surgical indications, and multimodal treatment strategies. A scoping review was conducted using the PubMed database. The search incorporated the following terms: “hepatocellular carcinoma”, “pulmonary metastasectomy”, “liver transplantation”, “recurrence”, and “tumor biology”. Studies published in English from 2005 onward were included if they specifically addressed pulmonary metastases in post-LT patients. Non-transplant populations and non-English articles were excluded. Studies were selected based on their relevance to the topic. Evidence, primarily from small retrospective series, supports pulmonary metastasectomy in highly selected patients with lung-limited disease. Favorable prognostic factors include a disease-free interval exceeding 12 months, low or normal alpha-fetoprotein levels, and limited metastatic burden. Reported 5-year overall survival rates range from 33% to 43%, indicating a potential survival benefit in appropriately selected cases. Pulmonary metastasectomy offers a valuable therapeutic option for LT recipients with resectable, lung-confined recurrence and favorable tumor biology. For unresectable or disseminated disease, alternative strategies including locoregional and systemic therapy should be pursued within a multidisciplinary framework.

Key Words: Hepatocellular carcinoma; Pulmonary metastasectomy; Liver transplantation; Recurrence; Tumor biology

Core Tip: Liver transplantation is a definitive treatment for hepatocellular carcinoma, yet recurrence occurs 8%-20% of patients, with the lung being the most common extra-hepatic site. Pulmonary metastasectomy offers meaningful survival benefit in carefully selected patients with resectable, lung-limited disease and favorable tumor biology. Patient selection should prioritize disease-free survival, alpha-fetoprotein levels, and oligometastatic pattern, rather than immunosuppression management alone. We emphasize the need for rigorous, biology-driven selection criteria and prospective studies to define the role of surgery within a multimodal approach to extra-hepatic hepatocellular carcinoma recurrence.

INTRODUCTION

Liver transplantation (LT) represents a cornerstone in the curative treatment of hepatocellular carcinoma (HCC) in selected patients, with outcomes that have progressively improved due to advances in surgical techniques, perioperative care, and patient selection[1,2]. The adoption of the Milan criteria established HCC as a globally accepted indication for LT, providing reproducible oncologic results and long-term survival comparable to non-oncologic indications[3,4]. In the United States, HCC accounted for over 10% of liver transplant recipients in 2023[5]; in Italy and throughout Southern Europe and Asia, where HCC represents approximately 40%-50% of LT indications, this percentage is substantially higher[6]. These geographic differences underscore the global relevance of HCC recurrence after LT as a clinical challenge. The progressive refinement of selection criteria, including biological markers such as alpha-fetoprotein (AFP), has allowed us to move beyond purely morphological parameters. Several expanded criteria models report 1- and 5-year survival rates of up to 90% and 75%, respectively. Despite these advances, post-transplant recurrence remains the main determinant of long-term mortality. Recurrence rates vary from 8% to 20% depending on HCC characteristics at the time of transplantation, and are influenced by tumor burden, microvascular invasion, and pre-transplant AFP levels[5-8]. Most recurrences occur within the first two years and are predominantly extra-hepatic, with pulmonary involvement in approximately 30%-50% of cases - resulting in an estimated 200-400 new cases per year in Italy alone[9]. The management of pulmonary recurrence after LT therefore constitutes a clinically relevant and unsolved issue.

PULMONARY RECURRENCE AFTER LT: A FRAMEWORK FOR MANAGEMENT

A crucial first step in approaching pulmonary recurrence is to distinguish between resectable and unresectable disease and whether the metastases are limited to the lung or part of a wider multi-site dissemination. Surgically resectable lung-limited disease is best characterized by an oligometastatic presentation (typically ≤ 3-4 nodules), a favorable disease-free interval (> 12 months), normal or near-normal AFP at recurrence, and the absence of extrapulmonary involvement.

These features collectively define “favorable tumor biology” - a concept that incorporates the biological behavior of the tumor as a primary determinant of surgical candidacy[10]. A proposed treatment algorithm integrating these variables is illustrated in Figure 1. Unresectable patients, including those with bilateral extensive disease, multi-site spread, or unfavorable biological features, should be considered for locoregional ablation, systemic targeted therapy, or optimized immunosuppressive regimens.

Figure 1 Clinical decision-making algorithm for the management of pulmonary metastases from hepatocellular carcinoma after liver transplantation. The flowchart illustrates the diagnostic and therapeutic pathway based on disease extension, resectability, and tumor biology. High-risk patients or those with unfavorable biology are directed toward systemic or locoregional therapies, while those with favorable biological features (e.g., disease-free interval > 12 months, low alpha-fetoprotein) are candidates for surgical resection. Conversion to mammalian target of rapamycin inhibitors and multidisciplinary team involvement are highlighted as core components of the multimodal approach. LT: Liver transplantation; HCC: Hepatocellular carcinoma; CT: Computed tomography; AFP: Alpha-fetoprotein; DCP: Des-gamma-carboxy prothrombin; ICIs: Immune checkpoint inhibitors; mTORi: Mammalian target of rapamycin inhibitors; MDT: Multidisciplinary team; DFI: Disease-free interval; RFA: Radiofrequency ablation; SBRT: Stereotactic body radiation therapy; TKIs: Tyrosine kinase inhibitors.

Pulmonary metastasectomy is the preferred treatment for selected patients with isolated lung recurrence, preserved liver function, and adequate functional reserve. The primary surgical objective is complete resection (R0) with maximal preservation of lung parenchyma, favoring wedge resection or nodulectomy when technically feasible.

Evidence supporting pulmonary metastasectomy in LT recipients is limited but encouraging. Jeong et al[10] reported outcomes in 52 patients undergoing lung resection for HCC recurrence after LT, with 5-year survival rates of 33.9%. A retrospective Italian multicenter experience reported a 5-year overall survival of 43%, with a median survival of 51 months[11]. Importantly, early recurrence and elevated AFP at the time of metastasectomy were associated with worse survival, whereas the number and size of pulmonary nodules did not significantly impact outcomes in these series.

BIOMARKERS AND TUMOR BIOLOGY

Traditional morphologic criteria have progressively been complemented by biological markers that better capture metastatic potential, microvascular invasion, and proliferative activity.

AFP remains central; however, additional biomarkers provide more refined prognostic information. Des-gamma-carboxy prothrombin (DCP) is strongly associated with microvascular invasion, poor differentiation, and early recurrence. Elevated pre-LT DCP levels correlate with increased post-LT recurrence and reduced survival, even in AFP-negative patients, and it is incorporated into expanded selection criteria such as the Kyoto criteria[12].

AFP-L3% reflects a more aggressive HCC phenotype. Higher AFP-L3 fractions are linked to vascular invasion, early recurrence, and inferior survival. Importantly, AFP-L3% may be elevated despite normal total AFP, identifying biologically aggressive tumors that would otherwise be underestimated[13]. The MoRAL score, combining AFP and DCP, has been validated as a predictor of post-LT recurrence and survival. High MoRAL values identify patients at elevated risk despite meeting conventional morphologic criteria, supporting its use for refining transplant eligibility and tailoring surveillance intensity[14].

SYSTEMIC THERAPIES AND IMMUNE CHECKPOINT INHIBITORS

The role of conventional systemic chemotherapy in pulmonary recurrence after LT is limited, with median overall survival often reported below 20 weeks[15,16]. However, the landscape of systemic therapy has been transformed by tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs).

Sorafenib has shown survival benefits in advanced HCC and post-transplant data suggest acceptable safety in selected recipients. More recently, a multicenter real-world study by Lo Prinzi et al[17] compared lenvatinib vs sorafenib as first-line therapy for post-LT recurrent HCC, finding lenvatinib associated with superior overall survival and manageable toxicity profiles, including higher rates of hypertension compared to the hand-foot syndrome typical of sorafenib.

The introduction of ICIs has transformed the systemic treatment landscape of advanced HCC. Since 2020, the associations of atezolizumab-bevacizumab and durvalumab-tremelimumab have demonstrated superior overall survival when compared with tyrosine kinase inhibitors, establishing ICIs as the preferred first-line therapy in non-transplant HCC patients. In the LT setting, however, the use of ICIs remains unclear due to the high risk of acute allograft rejection. Several case series reported rejection rates as high as 25% to 40%, often occurring early and sometimes refractory to intensified immunosuppression. Fatal rejection has been reported, particularly with programmed death 1 inhibitors. These safety concerns have limited the routine use of ICIs in liver transplant recipients, despite their proven efficacy in the general HCC population. Nevertheless, emerging evidence suggests that ICIs may be considered in highly selected patients with post-LT recurrence, particularly when disease is refractory to locoregional therapy and tyrosine kinase inhibitors. Favorable outcomes have been reported in individuals with long graft-to-ICI intervals, stable baseline immunosuppression, and an absence of donorspecific antibodies[18,19].

LOCOREGIONAL AND IMMUNOSUPPRESSIVE STRATEGIES

Mammalian target of rapamycin inhibitors

Growing interest has focused on the antineoplastic properties of mammalian target of rapamycin inhibitors (mTORi). Several studies have demonstrated lower recurrence rates and survival benefits with mTORi-based immunosuppression compared to calcineurin inhibitor-based regimens after LT for HCC[20-23]. Switching to mTORi (such as everolimus or sirolimus) should be considered upon diagnosis of recurrence, balancing oncologic benefits against risks of impaired wound healing or infections[24-26].

Radiofrequency ablation

Radiofrequency ablation has emerged as a valuable alternative for patients with limited pulmonary disease (typically < 3 cm) who are unsuitable for surgery. Recent studies suggest complete response rates approaching 92% with a favorable safety profile, positioning radiofrequency ablation as an effective option for non-surgical candidates or those with high operative risk.

CONCLUSION

Pulmonary recurrence of HCC after LT represents a complex therapeutic challenge in which patient selection must be guided primarily by tumor biology rather than anatomical features alone. Surgical resection offers a clinically meaningful survival benefit in patients with resectable lung-limited disease and favorable biology, while locoregional and systemic therapies provide important alternatives for non-surgical candidates and for those with multi-site dissemination.

A fundamental, yet unresolved, question for resectable, lung-limited disease concerns whether upfront surgery is preferable to a neoadjuvant approach. Neoadjuvant systemic therapy before lung metastasectomy could serve a dual purpose: Inducing tumor response and, critically, providing a therapeutic window to assess the biological behavior of the disease. Patients with stable or responsive disease to neoadjuvant treatment would logically be better surgical candidates than those with rapid biological progression. To our knowledge, there are currently no prospective data addressing this question in the post-LT setting, and it represents a priority for future research.

A multidisciplinary approach integrating surgery, locoregional therapies, systemic treatments, and optimized immunosuppression is mandatory. The rarity and heterogeneity of this condition limit the development of standardized treatment pathways. Larger collaborative datasets and prospective multicenter registries are essential to enabling meaningful patient stratification and evidence-based therapeutic strategies.