Transplant vs. Resection for Non-HCC Malignancies of the Liver

Abstract

Background: Surgical resection (SR) and liver transplantation (LT) are the main curative options for non-hepatocellular carcinoma (non-HCC) liver malignancies, including colorectal liver metastases (CRLMs), intrahepatic cholangiocarcinoma (iCCA), hilar cholangiocarcinoma (hCCA), and neuroendocrine tumor liver metastases (NETLMs). Resection aims for negative margins and adequate hepatic reserve, while LT offers treatment for unresectable disease but is limited by donor scarcity, immunosuppression, and ethical constraints. Methods: A targeted literature search (2005–2025) was conducted using PubMed and Google Scholar with predefined MeSH terms combining “liver resection,” “hepatectomy,” and “liver transplantation” across non-HCC malignancies. Relevant studies, reviews, and guidelines were included. Results: For CRLMs, SR remains standard with 5-year overall survival (OS) up to 58%, while LT offers 60–83% in highly selected unresectable cases. In iCCA, resection achieves median survival around 40 months, and LT yields OS up to 69% in very early or neoadjuvant-controlled disease. For hCCA, the Mayo protocol combining neoadjuvant therapy with LT provides 5-year OS of 65–80%. In NETLMs, LT achieves 63–97% OS under strict criteria. Conclusions: SR remains first-line for resectable non-HCC malignancies, while LT provides superior outcomes in unresectable yet biologically favorable disease, emphasizing careful selection and organ allocation.

1. Introduction

Liver transplantation (LT) vs. surgical resection (SR) for primary or secondary neoplasm of the liver is a critical debate owing to the imbalance of benefits and risks associated with each of them. The risk of incomplete resection predisposing to recurrence with SR is balanced against the waitlist for the allocation of donors and the post-transplant requirement for immunosuppressive drugs and the associated risks that comes along with LT. Resectability requires complete removal of the tumor with negative margins, preservation of adequate liver function and absence of extrahepatic or systematic disease [1,2,3]. Tumor biology or type also plays a large role in this, especially with non-hepatocellular carcinoma (HCC) malignancies [4]. Historically, SR has been the mainstay treatment for many primary and secondary liver tumors, but in recent decades, there has been a favorable increase in LT that has been superior in long-term survival for patients with unresectable disease [5].

In this narrative review, we aim to briefly discuss the benefits, risks and intervention of choice in performing SR vs. LT for patients with non-HCC malignancies, such as colorectal liver metastases (CRLMs), intrahepatic cholangiocarcinoma (iCCA), hilar cholangiocarcinoma (hCCA) and neuroendocrine tumor liver metastases (NETLMs).

2. Materials and Methods

A targeted literature search was conducted using PubMed and Google Scholar to identify studies addressing SR and LT in non-HCC liver malignancies. The search strategy incorporated keywords such as “Liver transplantation”, “hepatectomy”, “colorectal liver metastases”, “intrahepatic cholangiocarcinoma”, “hilar cholangiocarcinoma” and “neuroendocrine tumor liver metastases.” Boolean operators (AND, OR) were used to refine and expand the search scope where appropriate. The detailed search strategy used to identify relevant literature on resection and transplantation for non-HCC liver malignancies is outlined in

Table 1. Literature search strategy for identifying studies on surgical resection and liver transplantation in non-hepatocellular carcinoma (non-HCC) liver malignancies.

Mesh Terms	Database	Time Frame
((“Colorectal Neoplasms” AND “Liver Neoplasms” AND “Neoplasm Metastasis”) OR (“colorectal liver metastases” OR “liver metastasis colorectal” OR “metastatic colorectal cancer to liver”)) AND ((“Liver Transplantation” OR “liver transplant” OR “orthotopic liver transplantation” OR “OLT”) OR (“Hepatectomy” OR “liver resection” OR “hepatic resection”))	Pubmed, Google Scholar	2005–2025
((“Cholangiocarcinoma” AND (“Intrahepatic” OR “Liver Neoplasms”)) OR (“intrahepatic cholangiocarcinoma” OR “iCCA”)) AND ((“Liver Transplantation” OR “liver transplant” OR “orthotopic liver transplantation” OR “OLT”) OR (“Hepatectomy” OR “liver resection” OR “hepatic resection”))	Pubmed, Google Scholar	2005–2025
((“Cholangiocarcinoma” AND “Hilum Hepatis”) OR (“hilar cholangiocarcinoma” OR “perihilar cholangiocarcinoma” OR “Klatskin tumor”)) AND ((“Liver Transplantation” OR “liver transplant” OR “orthotopic liver transplantation” OR “OLT”) OR (“Hepatectomy” OR “liver resection” OR “hepatic resection”))	Pubmed, Google Scholar	2005–2025
((“Neuroendocrine Tumors” AND “Liver Neoplasms”) OR (“neuroendocrine tumor liver metastases” OR “NET liver metastasis” OR “metastatic neuroendocrine carcinoma to liver”)) AND ((“Liver Transplantation” OR “liver transplant” OR “orthotopic liver transplantation” OR “OLT”) OR (“Hepatectomy” OR “liver resection” OR “hepatic resection”))	Pubmed, Google Scholar	2005–2025

. Eligible sources included peer-reviewed original research articles, systematic reviews, meta-analyses, clinical guidelines, and narrative reviews published in English between 2005 and 2025. Studies were selected based on their relevance to surgical management of non-HCC liver tumors, including cholangiocarcinoma, metastatic colorectal cancer and neuroendocrine tumors with a focus on clinical outcomes, indications, and evolving transplant criteria. We also explored the references of the included studies to include associated data revolving around the same topic. This review prioritizes SR and LT strategies for non-HCC malignancies due to their increasing clinical relevance and the expanding evidence base. A narrative review format was employed to synthesize findings and highlight key developments in surgical and transplant oncology from the onset.

3. General Background

The principle behind performing SR or LT varies according to the type of tumor and its characteristics, especially resectability and preoperative assessment of the patient. For CRLMs, estimating a possible negative margin with a functional liver remnant, venous and bile drainage and adequate perfusion are key factors before considering liver resection [6]. For NETLMs, hormonal symptom control, functional hepatic parenchyma remnant and survival advantage is prioritized for SR, and even cytoreduction with a 70% threshold can be considered in case of extrahepatic metastases [7]. For iCCA and hCCA, achieving an R0 resection and absence of extra regional lymph node involvement, decompensated cirrhosis and portal hypertension are prioritized before proceeding for SR [1,8,9].

LT came to light during the early 1980s, starting with the pioneer operation by Thomas Starzl in 1967 for an adult with hepatoblastoma. This procedure started with 20 transplant centers in 1984 and later expanded to be performed in more than 100 transplant centers in 80 countries by 2013 [10]. Patients who need LT are allocated modified end-stage liver disease (MELD) scores that are used to prioritize the sickest and stratify them accordingly in the waitlist. However, owing to waitlist dropout due to tumor progression and undermining the risk of mortality, MELD exception points are awarded to certain neoplasms like NETLMs and hCCA by Organ Procurement and Transplantation Network (OPTN) Liver and Intestinal Organ Transplantation Committee [11].

Candidates with unresectable or nonresectable iCCA, NETLMs or CRLMs may be considered for MELD exception under specific circumstances, reflecting favorable tumor biology and disease control. For iCCA, eligibility requires biopsy confirmation, unresectability, tumor size of less than or equal to 3 cm, and at least six months of radiologic stability following locoregional or systemic therapy without new or extrahepatic lesions. For NETLMs, criteria include unresectable disease of gastro-entero-pancreatic origin, well- or moderately differentiated histology, and no extrahepatic disease after curative resection of the primary tumor for a minimum of six months. For CRLMs, candidates should have resected primary colorectal cancer, microsatellite-stable and BRAF wild-type tumors, absence of extrahepatic disease, and stable hepatic involvement after systemic therapy for at least six months [12]. Although CRLMs were initially excluded from MELD exception consideration, recent updates to the national guidance now include them under highly selective criteria, acknowledging emerging evidence supporting liver transplantation in this subset of patients. Meanwhile, iCCA is not yet eligible for a standard scoring, hence, it lacks clear guidelines for LT eligibility and tends to follow nonstandard guidelines based on clinical practice or prospective clinical trials [13,14]. Patient selection criteria have been summarized in

Table 2. Patient selection criteria for liver transplants in non-HCC malignancies.

Tumor Type	Guidelines	Name of Guidelines/Criteria
CRLM	On a general consensus, unresectable CRLMs without progressive disease on a well-defined treatment protocol Not eligible for MELD exception points—recent OPTN guidance has included them No standard guidelines Oslo criteria are used as an exclusion criterion that negatively affects survival: Tumor size > 5.5 cm Carcinoembryonic antigen level > 80 µg/L Resection of the primary cancer less than 2 years before transplant Progression of metastases at the time of transplant	Oslo score
iCCA	Not eligible for MELD exception points No standard guidelines Informal guidelines based on a prospective clinical trial Unresectable iCCA No extrahepatic metastases Non-progressive disease for at least 6 months while receiving neoadjuvant chemotherapy	-
hCCA	Inclusion criteria: Biopsy-/cytology-proven malignancy CA 19-9 > 100 U/mL in the absence of cholangitis Hilar mass < 3 cm on imaging Received protocol-based neoadjuvant therapy with lymph node metastases exclusion through operative staging Exclusion criteria: Tumor below the cystic duct Intra- or extrahepatic metastases.	UNOS, OPTN
NETLM	Age < 60 At least 6 months of no extrahepatic disease and recurrence before MELD request Bilobar disease confined to the liver Tumor involvement < 50% of liver Unresectable liver metastases Gastropancreatic origin NETLM or WHO-classified NET are eligible for MELD exception points	UNOS, OPTN/Milan

CRLM—colorectal liver metastases, iCCA—intrahepatic cholangiocarcinoma, hCCA—hilar cholangiocarcinoma, NETLM—neuroendocrine tumor liver metastases, MELD—Model for End-Stage Liver Disease, UNOS—United Network for Organ Sharing, OPTN—Organ Procurement and Transplantation Network.

.

4. Colorectal Liver Metastases (mCRC)

4.1. Epidemiology and Biology

In the United States, the third most common malignancy is colorectal cancer, which also ranks second for cancer-related mortality, with more than 50% of affected patients developing metastases to the liver (CRLMs) [15,16]. The liver’s portal venous system where majority of the body’s venous outflow converges and its anatomical accessibility makes it a site of choice for tumors to metastasize [17,18]. The biologic nature of CRLMs are heterogeneous and molecular features such as RAS and BRAF mutations lead to poor prognosis [19,20]. Prognostic factors that alter the prognosis include tumor burden, which depends on the number and size of metastases, bilobar vs. unilobar involvement, synchronous vs. metachronous metastasis, primary tumor location and carcinogenic embryo antigen (CEA) levels [19,21]. Of these, patients with a right-sided primary tumor with liver involvement have worse outcomes than left-sided tumors with the same [21].

4.2. Resection Outcomes

Hepatic resection is the only effective curative treatment option for patients with CRLM and has the ability to significantly prolong survival [22,23]. According to the National Cancer Comprehensive Network guidelines (NCCN), proposed treatment protocol for patients with colorectal metastases include (1) neoadjuvant chemotherapy for 2–3 months, followed by staged or synchronous hepatectomy and colectomy for metastatic liver disease; or (2) staged or synchronous hepatectomy and colectomy and/or local therapy [24]. A general consensus is that a synchronous resection is performed for a single or superficial metastases, whereas a staged resection is performed for extended liver lesions under suspicion of increased morbidity and mortality risk [25,26]. SR has proven to have excellent long-term survival results of up to 58% [27,28]. In a study by Hsu et al. on 230 patients who underwent SR for solitary CRLMs, the 3- and 5-year overall survival rates were 72.3 and 59.8%, respectively. They also highlighted that key independent predictors that negatively impacted overall survival in their study were age ≥ 70 years, pre-surgical hypoalbuminemia, resection margin width < 10 mm initial node stage, and neutrophil-to-lymphocyte ratio (NLR) ≥ 3 post surgery [29]. Despite the survival benefits, these patients are at a higher risk of recurrence post-index operation, with more than half of them having a recurrence within the 2-year period [30]. In a study by Hajibandeh et al. on CRLMs SR of 472 patients, they reported a 56% recurrence rate with a median time to recurrence of 1.6 years [31]. Another multi-institutional study by Hallet et al. of 2320 patients undergoing liver resection for CRLMs experienced a recurrence rate of 47.4% at a median time of 10 months and 89% by 3 years [32].

4.3. Transplantation Outcomes

LT was proposed as a potential curative option for patients with unresectable CRLMs in the early 1980s. However, results were discouraging due to high recurrence rates and poor overall survival < 20%. Many factors were contributive, including unbalanced immunosuppression risk, inefficient chemotherapeutic regimen, and higher mortality risk with LT [33]. This setback was offset by the SECA I trial in 2013, which was performed at the Oslo University Hospital on 21 patients with unresectable CRLMs, showing excellent post-LT 5-year survival rates of 60% [34]. The same group later performed a SECA II trial with even better results. The trial reported an 83% overall 5-year survival rate for 15 patients with unresectable CRLMs. When grouped by the Oslo criteria [14] reported in Table 2 previously, six patients in this study with a favorable prognosis showed a 60% 10-year overall survival rate [35]. While these studies were typically Norwegian, a North American study by Hernandez et al. reported 10 patients having unresectable CRLMs and an overall survival rate of 100% with a median follow-up of 1.5 years [36].

4.4. Comparative Insights

Both LT and SR come with advantages of their own, but superiority over the other depends on many factors like resectability status, cost, feasibility of the procedure (organ allocation in case of transplant), survival, recurrence, etc. Chief among the indications for not performing a surgical resection is unresectability, but this can be reversed with chemotherapy or liver-directed treatment in order to achieve resectability [24,37,38]. However, this does not apply to all patients, as each has varied presentation, making LT the only solution for some. Lately, transplantation has been gaining recognition due to its excellent overall survival outcomes over performing a surgical resection for select patients [34,35,36]. Recent evidence, including trials such as the TRANSMET, have provided solid evidence that chemotherapy in combination with LT showed a significant impact on overall survival for unresectable CRLMs [39]. Unlike SR, LT for CRLMs is not standardized in terms of eligibility and is still rarely performed due to very strict protocols. Even so, estimates show that adding CRLMs to an already established recipient pool would only increase the LT needs by 1–2%, i.e., 0.2–0.5 patients per million people per year [40]. The risk of donor organ scarcity also raises ethical concerns. Acute liver failure, HCC, and a host of other indications have competing interests against which CRLMs should be balanced, which would help benefit patients seeking LT.

5. Intrahepatic Cholangiocarcinoma (iCCA)

5.1. Epidemiology and Biology

Cholangiocarcinoma is an aggressive liver cancer, accounting for 10–20% of primary hepatic malignancies and second only to HCC [41,42]. Its incidence is rising globally, with the highest rates in Southeast Asia, mostly due to Fascioliasis infection, though its rate is also increasing in Western countries (0.3–3.4 per 100,000) [1,43]. Risk factors for iCCA include chronic biliary inflammation, viral hepatitis (HBV, HCV), cirrhosis, and metabolic disease; yet many patients present without a clear etiology [1,44,45,46]. Diagnosis is often delayed, leaving fewer than 40% eligible for curative resection [42,47]. Biological heterogeneity, vascular invasion, and a desmoplastic microenvironment drive a high recurrence rate and poor survival despite treatment [41,48].

The poor prognosis of iCCA is mainly attributed to its aggressive biology. Molecular and genetic heterogeneity, including frequent TP53, KRAS, and CDKN2A mutations, drives rapid progression and therapy resistance [49,50,51]. A desmoplastic and immunosuppressive tumor microenvironment impedes immune responses and reduces treatment efficacy [52]. Early vascular and lymphatic invasion results in multifocal disease, nodal metastases, and high recurrence rates [41]. Lastly, epigenetic dysregulation further promotes malignant transformation, while stromal barriers and molecular diversity underlie resistance to chemotherapy and immunotherapy [52,53]. Collectively, these biological hallmarks explain the late diagnosis, limited therapeutic options, and poor outcomes that define iCCA.

5.2. Resection Outcomes

SR remains the standard of care for patients harboring iCCA. The American Association for the Study of Liver Diseases (AASLD) recommends referral to a specialized center with the goal of R0 resection and lymphadenectomy. Candidates will typically have solitary, resectable tumors without extrahepatic disease and with adequate liver reserve; cirrhosis and portal hypertension are relative contraindications to surgery [1]. Notably, even after performing surgery, recurrence occurs in 50–70% of cases—mostly within two years—resulting in a median survival rate of ~40 months and a 5-year survival rate ranging from 25 to 70%, depending on surgical margins, nodal status, and tumor features [54,55,56]. Six months of adjuvant capecitabine is now the standard of care based on the BILCAP trial, while neoadjuvant strategies remain under investigation [57].

5.3. Transplantation Outcomes

LT for iCCA remains controversial and is not routinely recommended by the United Network for Organ Sharing (UNOS) or European guidelines due to historically poor outcomes and high disease recurrence. Recent studies, however, identified two contexts where it may be considered: (1) “very early” iCCA (≤2 cm) in cirrhotic patients unfit for resection due to inadequate liver reserve, and (2) locally advanced, unresectable disease confined to the liver with durable stability or response to ≥6 months of neoadjuvant therapy [58,59,60,61]. In such highly selected patients, a 5-year overall survival of 42–69% and recurrence-free survival up to 75% have been reported [62,63].

5.4. Comparative Insights

Recent data, including patient-level meta-analyses and registry studies, demonstrate that LT can achieve 5-year overall survival rates of approximately 53% in highly selected patients [8,60,64,65]. However, these outcomes are only comparable to SR in stage-matched cohorts and remain inferior to outcomes for other accepted LT indications. The majority of iCCA cases are not eligible for LT due to tumor size, tumor multifocality, vascular invasion, or progression while awaiting transplant [60,66].

6. Hilar Cholangiocarcinoma (hCCA/Klatskin Tumor)

6.1. Background

Hilar cholangiocarcinoma, also known as perihilar or Klatskin tumor, is the most common form of bile duct cancer, arising at the confluence of the right and left hepatic ducts. Diagnosis is often delayed, as initial symptoms such as jaundice, weight loss, and fatigue are nonspecific. Established risk factors include primary sclerosing cholangitis (PSC), hepatolithiasis, and liver fluke infection, although most cases occur sporadically. Prognosis remains poor, and optimal management requires evaluation at high-volume hepatobiliary centers with multidisciplinary expertise [3]. The Bismuth–Corlette classification is frequently used to describe the anatomical extent of ductal involvement and plays a central role in assessing resectability [67].

6.2. Resection Outcomes

SR remains the cornerstone of treatment for resectable disease [68]. Operations often require extended hepatectomy with caudate lobectomy and, in many cases, complex biliary or vascular reconstruction due to the tumor’s tendency for longitudinal spread and vascular encasement [69]. Achieving an R0 margin is the most important prognostic factor, but this is technically demanding, and perioperative morbidity and mortality remain substantial [69]. Even after successful R0 resection, five-year survival typically ranges from 25 to 50%, and recurrence is common. Careful preoperative assessment of hepatic reserve and the future liver remnant is essential, and techniques such as portal vein embolization are often employed to reduce operative risk [70,71].

6.3. Transplantation Outcomes

For patients with localized but unresectable disease, LT using the Mayo Clinic protocol combining neoadjuvant chemoradiation followed by transplantation has transformed outcomes [72]. In highly selected patients (tumor ≤ 3 cm, no nodal or distant metastases, and no prior transperitoneal biopsy), five-year survival rates approach 65–80%, exceeding those achieved with resection even in expert centers [73]. A meta-analysis of 20 studies including 428 patients reported a pooled five-year overall survival of 65.1% (95% CI 55.1–74.5%), with intention-to-treat survival of 53–65% [74]. These results have been confirmed by multicenter validation studies [75]. Nonetheless, LT faces significant challenges, including organ scarcity, dropout during neoadjuvant therapy, and the long-term burden of immunosuppression.

6.4. Comparative Insights

Direct comparisons between SR and LT suggest that LT offers superior long-term survival in strictly selected, unresectable cases, whereas both strategies can yield excellent outcomes when patients are carefully chosen. A recent single-center study from Mayo Clinic (1993–2023) compared patients treated with the Mayo protocol to those undergoing resection, with or without vascular reconstruction. In the as-treated analysis, LT achieved longer median overall survival than resection without vascular resection (78.0 vs. 58.2 months, p = 0.03) and markedly outperformed resection with vascular resection (25.8 months, p < 0.001). However, once dropout was incorporated into intention-to-treat analysis (41% for LT vs. 28% for SR), overall survival did not differ significantly between groups (31.7 vs. 38.5 months, p = 0.19). Perioperative mortality was comparable (4% for LT, 7–8% for resection) [73].

A multicenter North American analysis further compared LT and SR in patients meeting strict Mayo criteria (<3 cm, node-negative, no metastases). In matched cohorts, LT was associated with significantly improved five-year survival (64% vs. 18%, p < 0.001). Notably, even among patients with technically resectable early-stage disease, LT conferred a survival advantage, including on intention-to-treat analysis (p = 0.049) [76].

7. Neuroendocrine Tumors with Liver Metastases (NETLMs)

7.1. Epidemiology and Biology

NETs are rare, slowly progressing neoplasms with a variable biologic nature that stem from the widespread neuroendocrine system [77]. They can be commonly grouped into two categories owing to their heterogeneous nature: indolent and aggressive [78]. The first group involves well-differentiated neoplasms with a less aggressive nature, arising primarily in the gastrointestinal tract (85%), whereas the latter includes high-grade neoplasms that are poorly differentiated [78,79,80]. These gastrointestinal NETs have a common predilection to metastasize to the liver, and majority of them have this presentation at the onset of diagnosis [81,82,83]. In 2012, according to a Surveillance, Epidemiology, and End Results (SEER) database study on a large population in the United States, the incidence of gastrointestinal NETs was noted to be 3.56 per 100,000 persons [84]. Based on the SEER database, the incidence of NETLM is 27%, but Frilling and Clift report that this remains vague as data registries tend to classify them as distant metastases over NETLMs [85].

7.2. Resection Outcomes

If resectable, SR has been reported to offer excellent results of curative treatment for NETLM, making it the primary modality of choice aimed at overall survival outcomes [78]. In a study on SR of isolated, disseminated NETLMs of 119 patients by Frilling et al., the 3-, 5- and 10-year survival rates were reported at 76.4%, 63.9% and 46.5% for the entire cohort [86]. Chakedis et al., also reported in their study on 581 patients undergoing SR for NETLMs, out of which curative resection patients (n = 396) had a 1-, 5- and 10-year overall survival rate of 97%, 68%, and 45%, respectively [87]. Muttillo et al. reported in their systematic review on treatment strategies for NETLMs that SR is highly effective in long-term survival and symptom control with acceptable mortality and comorbidity. They also highlight that despite failure to achieve R0 resection in some cases, cytoreductive surgery would still be an option to resect as much tumor possible to achieve symptomatic control [88]. Palliative measures such as tumor debulking with partial hepatectomy has been supported by studies to improve survival without compromising liver function [89,90]. However, despite SR patients devoid of extrahepatic disease but with unilobar or singular metastatic spread, patients had a five-year recurrence rate of nearly 80% as reported by Mazzaferro et al. [91]; Mayo et al. reported a 94% 5-year recurrence rate in 339 patients who underwent SR for NETLMs [92].

7.3. Transplantation Outcomes

Approximately 0.2–0.3% of NETLMs undergo LT in the United States and Europe, which is quite rare. However, there has not been a clear guideline on patient selection, which makes accurate assessment challenging [93]. Both Milan and UNOS guidelines, which allocate exception MELD points [94,95] for LT, have been used for patient selection. They emphasize low-grade tumors (G1/G2), portal drainage, and a history of stable disease or pre-LT curative resection of all extrahepatic lesions. While both criteria are stringent, UNOS includes additional requirements such as a negative PET scan for metastases and a lack of recurrence for at least three to six months [78]. Survival and recurrence post-LT are highly dependent on strict patient selection and adherence to the Milan criteria. Five-year overall survival rates were noted to be between 63 and 97%, with higher rates observed in patient cohorts adhering to Milan criteria [15,96,97]. The largest LT series of NETLMs in Europe with 213 patients by Le Treut et al. reported that survival can reach between 60 and 80% [15,98]. Similarly, studies have reported an average of 5-year recurrence rates at an average of 31–56% [96,97,99].

7.4. Comparative Insights

The decision to perform SR or LT will often hinge on the resectability status of the tumor, although this alone does not decide which among the two would be a feasible procedure for NETLMs. Moris et al. report that despite curative intent with R0/R1 resection leading to a long-term survival, NETLMs with bilobar and distant disease make these patients ineligible for SR [96]. Similarly, Elzein et al. report that inevitable recurrence and poor survival plague the long-term success of LT for NETLMs [93]. However, in a comparative review between SR and LT of 455 NETLM patients, Eshmuminov et al. have reported that tumor biology plays a key role in influencing favorable outcomes for LT, especially in the case of a low-grade tumor within the Milan criteria [4].

8. Cross-Cutting Themes Between Surgical Resection and Transplantation and Future Directions

A summary of key outcomes comparing surgical resection and liver transplantation across non-HCC malignancies is presented in

Table 3. Comparative outcomes of SR versus LT for non-HCC liver malignancies.

Tumor Type	Surgical Resection— Key Outcomes	Liver Transplantation— Key Outcomes	Clinical Implications
CRLMs	5-year OS: up to 58%; recurrence > 50% within 2 years; median time to recurrence 10–20 months.	5-year OS: 60–83% (SECA I/II); 10-year OS: up to 60% in low Oslo score patients.	SR is standard for resectable disease; LT for unresectable, biologically favorable tumors.
iCCA	Median survival: ~40 months; 5-year OS: 25–70%; recurrence 50–70%.	5-year OS: 42–69% in “very early” or neoadjuvant-controlled disease.	LT restricted to highly selected patients; SR remains first-line for resectable tumors.
hCCA	5-year OS: 25–50% after R0 resection; recurrence common.	5-year OS: 65–80% (Mayo protocol with neoadjuvant therapy); comparable perioperative mortality (4–8%).	LT superior for unresectable, localized disease meeting Mayo criteria.
NETLMs	5-year OS: 63–68% (up to 97% in 1 year); recurrence 80–94% within 5 years.	5-year OS: 63–97% (adhering to Milan/UNOS criteria); recurrence 31–56%.	LT for low-grade, liver-confined disease; SR preferred for resectable or debulking cases.

CRLM—colorectal liver metastases, iCCA—intrahepatic cholangiocarcinoma, hCCA—hilar cholangiocarcinoma, NETLM—neuroendocrine tumor liver metastases, UNOS—United Network for Organ Sharing.

. Non-HCC malignancies are a significant contribution to the overall hepatic disease burden, and a multidisciplinary need for treating them should be prioritized. Patient selection criteria are key for either of the procedures. In CRLMs, SR can provide reasonable survival outcomes for patients with resectable disease [22], whereas for unresectable disease in select patients, LT showed a significant survival advantage [34,35]. For iCCA, SR is often the mainstay treatment with excellent survival outcomes if resection can achieve R0 [54,55,56], whereas LT is usually discouraged by UNOS but performed in select conditions, which provided excellent survival and disease-free results [58,59]. In hCCA, SR is the cornerstone, but there is a higher incidence of recurrence [70,71], whereas LT offers superior survival for unresectable disease in highly selected patients [73]. For NETLMs, SR is highly effective in tumor clearance, debulking and symptomatic control [86,87,88], whereas LT offers survival advantage for patients with strict Milan criteria inclusion and low-grade tumors [4]. Resectability, strict patient selection, margin status and tumor biology are factors used to stratify the patients by eligibility for SR or LT. SR techniques continue to improve and are not hampered by ethical concerns but will remain limited. For LT, there are adequate guidelines for NETLMs and hCCA [95], whereas CRLMs [14] and iCCA [58,59,60,61] depend on non-standardized scoring systems and guidelines. Additionally, lessons learned from these malignancies can be applied to other rare hepatic malignancies (hepatic epithelioid hemangioendothelioma, hemangiopericytoma, hepatic angiosarcoma, hepatic adenomatosis with malignant risk, hepatoblastoma, embryonal sarcoma, and biliary rhabdomyosarcoma).

9. Future Directions for LT

Borderline resectable or unresectable cases should undergo attempts to downstage for resection but also be considered for LT [100,101,102,103]. While LT is currently limited due to organ availability, methods such as donation after circulatory death (DCD) and extended-criteria donors are increasingly backed by advances in organ perfusion technologies, such as normothermic machine perfusion and hypothermic oxygenated perfusion. These strategies have improved graft viability, reduced complications, and enabled the use of marginal livers, thereby expanding the donor pool, potentially expanding the use of LT for primary or metastatic diseases confined to the liver [104]. Other potential future directions for LT involve the role of next-generation sequencing (NGS) to identify mutations in KRAS/MAPK, TP53, PI3K-Akt/mTOR, and Notch pathways for iCCA tumors [105]. Multi-gene mRNA panels and circulating biomarkers (e.g., cell-free DNA) are being investigated to improve accuracy in predicting metastatic behavior [16]. The Banff Human Organ Transplant Panel supports transcriptome analysis of allograft tissue to identify molecular signatures of injury and rejection. Artificial intelligence-driven systems are used for diagnosis to combine multidimensional biomarker data for improved risk stratification and personalized care [106].

10. Conclusions

SR and LT represent complementary, rather than competing, strategies in the management of non-HCC liver malignancies. Resection remains the standard of care for technically feasible tumors with preserved hepatic reserve, whereas LT offers a survival advantage for unresectable but biologically favorable disease when performed under strict selection criteria and structured protocols. The future of surgical oncology in this field hinges on expanding the donor pool through living donations, optimizing neoadjuvant and systemic therapies, and integrating artificial intelligence-driven predictive models to refine patient selection. A multidisciplinary approach balancing oncologic benefit, ethical allocation, and long-term survivorship will ultimately define the optimal role of SR vs. LT in this complex landscape.