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PLASTIC RECONSTRUCTIVE AND REGENERATIVE SURGERY

Transplant oncology

No. 3: Special Issue 1 - June 2025 - Transplant oncology

Liver transplantation for vascular tumors

Authors

Quirino Lai , Jan Lerut , Paolo De Simone

Key words: vascular tumors, epithelioid hemangioendothelioma, hemangiosarcoma, hemangiopericytoma
DOI: 10.57603/EJT-1543
Publication Date: 2025-09-10

Abstract

Non-hepatocellular, non-cholangiocellular cancers are an overlooked area in medical and surgical hepatology. These rare tumors cover a broad spectrum, and their diagnostic and treatment protocols are not standardized due to their infrequent occurrence, diverse clinical presentations, and variable progression. This article summarizes current knowledge about hepatic vascular tumors such as epithelioid hemangioendothelioma, hemangiosarcoma, hemangiopericytoma, and hepatic small vessel neoplasm, based on recent literature and findings from the detailed European Liver Transplant Registry. Particular attention is given to the role of liver transplantation (LT) in the
treatment of these rare tumors. To improve outcomes for all these rare liver tumors, multimodal therapies − including radical surgery, multi-drug and/or targeted chemotherapies, and eventually external beam radiotherapy − are urgently needed. LT will play an increasingly important role in this less-understood field of modern hepatobiliary oncology.

Abbreviations

CCC: cholangiocellular cancer

DFS: disease-free survival

ELITA: European Liver and Intestine Transplant Association

ELTR: European Liver Transplant Registry

FDG-PET: fluorodeoxyglucose positron emission tomography

H&E: hematoxylin and eosin

HCC: hepatocellular carcinoma

HEHE: hepatic epithelioid hemangioendothelioma

HIHE: hepatic infantile haemangioendothelioma

HPC: haemangiopericytoma

HHS: hepatic haemangiosarcoma

HSVN: hepatic small vessel neoplasm

IHC: immunohistochemical/immunohistochemistry

LT: liver transplantation

PDGFR: platelet-derived growth factor receptor

PS: patient survival

TA(C)E: trans-arterial (chemo-)embolization

UNOS: United Network for Organ Sharing

VEGF: vascular endothelial growth factor

INTRODUCTION

Liver tumors develop, in decreasing order of frequency, from epithelial (hepatocytes, cholangiocytes) and mesenchymal (endothelial) cells. Unlike hepatocellular (HCC) and cholangiocellular cancers (CCC), diagnostic and therapeutic strategies for other rare primary neoplasms are still not standardized 1-3. This situation is due not only to their diverse clinical, morphological, and histopathological presentations but also to the limited awareness within the medical community about these “orphan” diseases, defined as diseases occurring in fewer than 6 per million people 4-9. Unsurprisingly, many debates about their optimal management continue. This article aims to provide an up-to-date overview of vascular liver tumors, based on recent literature and data from the European Liver Registry (ELTR), with particular attention to the potential role of liver transplantation (LT) in their treatment options 10-13.

Vascular tumors were once thought to exist on a spectrum, from benign hemangioma to the less aggressive epithelioid hemangioendothelioma (HEHE) and the most aggressive hemangiosarcoma (HSS). However, recent molecular biology studies have shown that this idea was incorrect; these tumors arise from very different mutations. HSS has mutations in HRAS, KRAS, NRAS, and PTPRB. The translocation t(1;3)(p36;q25) creates the EHE-specific fusion oncogene WWTR1-CAMTA1. Additionally, a small subset (6%) of HEHE patients carries the YAP1-TFE3 fusion oncogene 14,15.

HEPATIC EPITHELIOID HAEMANGIOENDOTHELIOMA (HEHE)

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor characterized by an epithelioid and histiocytoid appearance, originating from vascular endothelial or pre-endothelial cells. EHE accounts for less than 1% of all vascular tumors. HEHE is a rare (< 1 per million people), low-grade malignancy 4,16,17. Dail and Liebow first identified this tumor as a lung tumor; later, EHE was found in soft tissues, the head and neck region, pleura, bones, and many other organs. The first case series of 32 cases, published in 1984, was expanded by Makhlouf to include 137 patients 16,18. The Haemangioendothelioma, Epithelioid Hemangioendothelioma, And Related vascular Disorders Support Group internet database shows that EHE is most common in the liver, either alone (21%) or combined with lung lesions (18%), followed by isolated bone (14%) and lung (12%) lesions 19. Pulmonary and hepatic lesions tend to behave similarly 17.

HEHE is more common in middle-aged women (female/male ratio: 4/1) but is rare in children 20. Although a causal relationship between chronic Bartonella infection and the development of HEHE has been suggested through the induction of vaso-proliferation, no definitive etiological factor has been identified 21. The clinical presentation is highly variable and non-specific, ranging from an asymptomatic state (25% of patients) to (the rare) hepatic failure. Upper abdominal discomfort or pain (60%), weight loss (20%), impaired general condition due to weakness and fatigue (20%), and dyspnea (5%) are the most frequent symptoms. Hepatosplenomegaly (30%) is common; jaundice, portal hypertension, and Budd-Chiari syndrome, caused by tumor compression or venous infiltration, are rare (5%). One-third of cases present with cholestasis and cytolysis. Kasabach-Merritt syndrome is rare, and serum tumor markers are always normal in the absence of underlying liver disease.

Two typical imaging features associated with tumor progression are observed: initially, peripheral, nodular, usually bi-lobar, and subcapsular lesions (“peripheral pattern”) are present. Later, these lesions (“diffuse pattern”) become confluent; eventually, macrovascular invasion and remodeling of the non-tumorous parenchyma occur. Most often, larger HEHE lesions on contrast MRI images show late, peripheral, ring arterial enhancement with progressive enhancement toward the center (targetoid appearance) 22. Capsular retraction and focal calcifications (due to central tumor necrosis) may develop. Angiography (if performed) reveals only moderate vascularization, with displacement of the intrahepatic vascular tree by the tumor masses; thus, liver biopsy is not inherently contraindicated. Thoracic CT scan, scintigraphy, and FDG-PET scanning are necessary for staging the disease (23). Chest lesions may be pulmonary, pleural, or mediastinal. There are three main thoracic patterns. Most commonly (60%), the lungs contain bilateral multiple or solitary pulmonary nodules (up to 5 cm in 10-20% of cases) or multiple pulmonary reticulonodular opacities; less favorably, pleural invasion appears as diffuse infiltrative thickening. Bone metastases manifest as osteolytic lesions 24,25. HEHE diagnosis relies on a high index of suspicion, integrating clinical and radiological findings: the presence of numerous intrahepatic tumors in young, predominantly female adults presenting good health despite a typically long-lasting clinical history 9,10,12. Histopathology, including H&E and immunohistochemical (IHC) staining combined with molecular biology, confirms the diagnosis (Figs. 1A-D). Cytology may assist, but histology on larger (laparoscopically obtained) samples is necessary to differentiate HEHE from HHS, secondary malignancies, and other rare tumors 9,26,27. Macroscopic examination reveals multiple fibrous masses with characteristic, necrosis-related, central zones; microscopic examination shows pleomorphic, medium to large-sized epithelioid cells spreading within sinusoids and small veins, while preserving portal tract landmarks. Lymph nodes can be negative on H&E but positive on IHC. Cellular atypia, nuclear fission, spindle cell presence, tumor necrosis, and a Ki-67 index > 10-15% indicate an aggressive tumor 17,26,28,29. A European cohort suggested that HEHE was more aggressive in pediatric patients, but this was not confirmed by the UNOS survey 30. IHC markers of vascular endothelium − factor VIII-related antigen, Fli-1 (a protein expressed by the endothelium), and CD31, CD34, ERG (an ETS family transcription factor expressed on endothelial cells) − confirm the diagnosis 14,31. Concordant clinical, radiologic, histopathologic, cytologic, IHC, and molecular findings will confirm the diagnosis.

Four important findings help differentiate HHS from HEHE: a higher incidence in men, eventual involvement of environmental and toxic factors (see further), greater aggressiveness (often linked to compromised liver function), and destruction of lobular and portal landmarks on histology 11,13,26,32.

The treatment algorithm for HEHE is complicated due to its rarity and unpredictable behavior. The role of surgery has been questioned for a long time because of well-documented cases of spontaneous, long-term surviving patients (up to 28 years), the frequent absence of symptoms (25%), the presence of extra-hepatic lesions at the time of diagnosis (45%), the lack of prognostic clinical or histological criteria, the high recurrence rate after surgery (33%), and the lack of detailed long-term outcome reports 10,12,17,18,30. The Pittsburgh (16 patients), Canadian multicenter (11 patients), and UNOS (110 patients) studies reported 5-year patient survival (PS) and disease-free survival (DFS) rates after liver transplantation ranging from 64% to 82% and 60% to 69% 30,32,33. The 2006 Mehrabi review (286 patients) favored partial and total liver resection as the preferred treatment options 34-36. Five-year PS rates after partial resection, liver transplantation, chemo-/radiotherapy, and therapeutic abstention were 75%, 55%, 30%, and 4.5%, respectively. Unfortunately, partial resection is only feasible in less than 10% of patients with a single or a few (≤ 4) lesions. The Mayo experience reported a 62% five-year PS after partial resection in 11 selected patients 36.

The value of non-surgical approaches, such as radiotherapy, tumor ablation, trans-arterial (chemo-)embolization (TA(C)E), hormone treatment, systemic or locoregional radio-chemotherapy, and anti-angiogenic or anti-tumor pharmacotherapy, remains difficult to assess due to the lack of standardization and especially the absence of long-term follow-up data. Radiotherapy can be useful for controlling local pain.

The 2007 and 2017 ‘ELTR-ELITA HEHE reports,’ including 149 HEHE patients with long-term follow-up, changed the outlook for these patients worldwide 10,12,13. Both publications shifted ‘medical awareness’ toward these patients, evident from the sharp increase in registry-reported cases and the high number of personal online consultations. The ELTR-ELITA studies confirmed that liver transplantation (LT) can be a curative treatment, with 5- and 10-year post-transplant survival rates of 81% and 77%, and notably, disease-free survival (DFS) rates of 79% and 73%. Pre-transplant treatment (28%), lymph node invasion (27%), and limited extrahepatic disease (26.8%) did not significantly affect outcomes, whereas micro- and macrovascular invasion (13% and 48%) did. The Leuven group even reported successful sequential (lung after liver) and simultaneous liver-lung transplants − despite pleural and diaphragmatic invasion at transplantation − with ten- and eight-year post-transplant survival and seven- and one-year survival, respectively, without signs of disease progression, even with bone metastases present at the time of transplantation, in cases of multifocal chest and liver disease 37.

Recurrent disease, occurring within and outside the graft in 25% of patients, remains a concern. When it occurs, an aggressive approach is warranted, as prolonged disease-free survival can be achieved. The value of re-liver transplantation (re-LT) still needs to be determined (26). The ELITA-ELTR study demonstrated that long-term DFS is also achievable with multifocal disease; these results may even encourage considering pre-emptive LT in asymptomatic patients.

The development of prognostic scores and effective neoadjuvant and adjuvant oncologic therapies is essential for progress. Lau et al. identified pulmonary lesions, multi-organ involvement, disease progression, ascites presence, age 55 or older, and male gender as poor prognostic factors 19. The ELITA-ELTR-HEHE study developed a predictive score based on macrovascular and hilar lymph node invasion, as well as waiting time. Using five-year DFS rates of 94%, 77%, and 38.5% for low (0-2 points), intermediate (3-5 points), and high (6-10 points) scores, respectively, a therapeutic HEHE algorithm has been proposed 13. A waiting period of several months on the LT list can be a helpful tool to differentiate HEHE from HHS, as the latter typically progresses rapidly within months of diagnosis (Fig. 2).

Several drugs have been tested in small numbers of EHE, HHS, and liver sarcoma patients, targeting angiogenic pathways with agents such as bevacizumab, oral tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, and paclitaxel), or non-VEGF angiogenic pathways (angiopoietin peptibody, PDGFR, and Endoglin inhibitors). Other vascular-targeted agents − thalidomide, lenalidomide, interferon, and beta-blockers − as well as chemotherapies (cyclophosphamide, doxorubicin, carboplatin-etoposide) and beta-blockers have also been tested. Because these tumors contain VEGF receptors, treatments based on anti-VEGF antibodies seem logical. A higher density of these receptors and beta-adrenergic receptors might improve outcomes 38-45. Phase II trials by the French sarcoma group (sorafenib; 15 HEHE patients) and the Eastern Cooperative Oncology Group (bevacizumab; 7 HEHE patients) involving advanced, non-resectable, metastatic cases showed disease stabilization for up to 10 months in 20-40% of patients, with 10% achieving partial response at six months 46,47.

A better understanding of the biochemical, histological (including mitotic index and pleomorphism), and molecular behavior of this little-understood disease is necessary to evaluate the effectiveness of emerging neo- and adjuvant treatments and to identify aggressive tumor subtypes 34,48,49. Confirming the monoclonal origin of all different lesions in a multifocal hepatic EHE within the same patient is important, as it suggests that multifocality and extrahepatic spread are likely metastatic implants from the same neoplastic clone rather than the previously believed occurrence of multiple different clones occurring simultaneously. The Leuven group is expanding this clonal research to include both hepatic and extra-hepatic lesions to verify this hypothesis. If confirmed, (neo-)adjuvant medical treatments could be equally effective for both hepatic and extra-hepatic lesions 50.

HEPATIC INFANTILE HAEMANGIOENDOTHELIOMA

Hepatic infantile HE (HIHE), the most common hepatic tumor in infants (< 3 years old), is usually diagnosed within the first six months of life. HIHE is more common in females and presents with (a)symptomatic hepatosplenomegaly, failure to thrive, congestive cardiac failure (15%) due to intra-tumor arteriovenous shunting, and cutaneous hemangiomas (20-40%). It appears as a histologically benign tumor. Histology identifies two types of HIHE: the ‘benign’ type I and the more pleomorphic type II. Tumors with type II features remain difficult to diagnose and differentiate from angiosarcoma. Because of their more aggressive morphology and behavior, many now consider them under childhood HHS 51. The differentiation between HEHE and (type I) HIHE is because the latter does not metastasize. Several lesions occurring simultaneously in different organs such as the spleen, lungs, and bones are likely separate lesions. HEHE can be distinguished from HIHE based on different age-related clinical and pathological features. The natural history of HIHE varies; up to two-thirds of symptomatic patients die from complications such as heart failure 19,34. In some cases, including the ELTR-ELITA vascular tumor study, HHS foci have been reported. These patients tend to have an extremely poor outcome. Treatment options include anti-angiogenic drugs (using or combining high-dose steroids, interferon, chemotherapy, or radiotherapy), as well as interventional radiological and surgical interventions 19,52,53. The Boston group developed an algorithm for treating these children 19. Partial hepatectomy is recommended for a solitary lesion or lesions confined to one liver lobe; liver transplantation (LT) is needed for diffuse lesions and responses to steroid therapy. In cases of rapid tumor growth, HHS should be suspected, and futile LTs should be avoided 54.

HEPATIC HAEMANGIOSARCOMA

HHS is the most common primary liver sarcoma, accounting for up to 2% of all primary liver tumors. It occurs mainly during the sixth and seventh decades of life and is more common in males (M/F ratio: 3/1). It is rarely seen in children 34,55-57. HHS has been linked to many environmental carcinogens such as thorium dioxide, vinyl chloride monomer, radium, pesticides, external radiation, cyclophosphamide, arsenical compounds, use of androgenic/anabolic steroids, and iron, but most cases are sporadic 9,16,58,59. The delay between toxic exposure and tumor development can be extremely long-up to 65 years! 58,59. The diagnosis can be difficult, even with modern imaging and pathology 32,60-63. Macroscopically, HHS appears as an ill-defined, spongy, hemorrhagic nodule or nodules involving the entire liver. Four growth patterns have been described: multiple nodules, a large dominant mass, and more rarely, diffusely infiltrating macro-nodular tumors 4,16. At diagnosis, 40% of patients show extra-hepatic disease, mostly in the lungs, spleen, bones, and adrenal glands. HHS patients tend to be more severely ill than those with HEHE; they often present signs of portal hypertension and liver failure. Hepatosplenomegaly, thrombocytopenia, pain, jaundice, ascites, peripheral edema, and signs of acute abdomen related to frequent tumor rupture can also be present 11,55.

The “ELTR-ELITA HHS study,” which included 20 liver recipients, provided better insight into the differential diagnosis with HEHE and the limited value of LT in its treatment. All but one patient were symptomatic. The most common symptoms and signs included weakness and fatigue (75%), upper abdominal pain and discomfort (60%), anorexia and nausea (50%), hepatomegaly (80%), weight loss (60%), jaundice, and ascites (45%). Portal hypertension (25%) and acute liver failure (10%) may also be part of the disease presentation. MRI imaging typically shows progressive, heterogeneous, nodular enhancement toward the center, with hemorrhage seen in 64%. Pathology reveals diffuse bi-lobar involvement in nearly all cases.

Outcomes after partial or total hepatectomy (LT) are very poor; all patients die within a median of six months due to recurrent disease 11,55,56,64-83. Therefore, LT is considered an absolute contraindication for HHS 11,75. The combination of surgery and adjuvant chemotherapy extends survival, reaching 84 months in the exceedingly rare case of a resectable solitary or multinodular confined form. Encouraging results of chemotherapy have been reported in some cases of multinodular, metastasized HHS 84. TAE is useful in the case of bleeding after tumour rupture 85. Radiotherapy is not helpful due to the radio-resistant character of the tumour 86. Similar to HEHE, the search for adequate medical therapy, based on the expression of angiogenic growth factor receptors and vascular-targeted agents, are needed to improve the outcome. Some drug combinations and immunotherapy (anti-PD1), occasionally combined with standard chemotherapy, led to sporadic (partial) response 55,87,88.

HAEMANGIOPERICYTOMA (HPC)

HPC, an uncommon vascular tumor comprising less than 2% of soft tissue sarcomas, arises from the pericytes of Zimmermann, small oval cells that surround the capillaries. HPC is usually seen in adults of both genders as a painless mass. The lower limbs, abdomen, retroperitoneal space, head, neck, and central nervous system are most commonly affected, while liver involvement is rare. They can present as solitary or multiple lesions. HPC appears as hypervascular, well-circumscribed lesion(s) containing spindle-shaped cells. Half of them are malignant. Large tumor size (> 20 cm), more than four mitoses per 10 high-power fields, presence of pleomorphic cells with specific chromatin patterns, and central necrosis or intra-tumor hemorrhage suggest malignant transformation. Histology, molecular biology, and IHC help differentiate it from other sarcomas 89-91.

The clinical presentation varies widely, ranging from no symptoms to paraneoplastic syndromes at diagnosis or during metastasis development. Hypoglycemia, caused by the release of insulin-like growth factors, appears in the later stages of the disease. Although aggressive surgery is the preferred treatment for both primary and metastatic lesions, two-thirds of patients experience recurrence even after R0 resection. The roles of chemo- and radiotherapy remain uncertain. Detecting recurrence is challenging due to tumor size variability and the lack of specific markers. PET scans are highly useful for diagnosis and follow-up if the initial tumor showed tracer uptake. After R0 resection, five-year disease-free survival (DFS) reaches 50%. Long-term follow-up is necessary since 10% of tumors recur after five years. Reoperative surgery may be helpful in cases of paraneoplastic syndromes, especially hypoglycemia 91. In the ELTR-ELITA vascular tumor study, four patients were identified, two with primary HPC and two with metastatic HPC. One (metastatic) patient had a DFS of 12 years after liver transplant and multiple abdominal, thoracic, and orthopedic reinterventions 92. Radio- and chemotherapy have proven to be unsuccessful, although some partial responses have been achieved using combination therapies such as temozolomide and bevacizumab. As with other soft tissue sarcomas, identifying specific molecular tumor markers will be essential to improve prognosis 93.

HEPATIC SMALL VESSELS NEOPLASM (HSVN)

Recently, HSVN has been described as an infiltrative hepatic neoplasm. Despite this infiltrative nature (which mimics HHS) and shared GNAQ and GNA14 mutations (also seen in some types of HHS and Kaposiform HE), HSVN is considered a benign or low-grade tumor because it lacks cellular atypia and increased proliferation 94,95. Diagnosis requires detailed histological and molecular biology examination. Resection is the treatment. Given its rarity, infiltrative nature, and limited information, the benign versus potentially low-grade, malignant nature of this tumor type is under question 96.

CONCLUSIONS

Vascular tumors represent a diagnostic and therapeutic challenge for clinicians, mainly because of their rarity and their protean clinical, morphological, and histopathological manifestation. The complex and many times difficult differential diagnosis between these tumour types has been refined using immunohistochemistry and molecular biology. Surgery is the mainstay in the therapeutic algorithm. As partial hepatectomy is possible only in a minority of patients due to tumour multifocality, total hepatectomy (or LT) frequently remains the only therapeutic option. In case of HEHE, pre-emptive or therapeutic LT report excellent five-year disease-free survival even if the limited extrahepatic disease is present. Conversely, HHS patients have an unfortunate outcome; partial resection is rarely possible and LT is absolutely contraindicated due to the universal, rapid recurrence and short-term survival. LT is also futile in case of rapidly evolving (type II) HIHE. Despite the high recurrence rate, surgery, including LT, can offer a good palliation in HPC especially when a paraneoplastic syndrome is present. For all vascular tumors, eff medical (neo-) adjuvant treatment targeting the “diseased” vessels is needed to improve outcome 97.

Conflict of interest statement

The authors declare no conflict of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

QL: was responsible for the conception, design, analysis, and writing of the study; QL, JL, PDS: were involved with the collection and interpretation of data; QL, JL, PDS: participated in data management, review and editing of the manuscript.

Ethical consideration

Not applicable

History

Received: June 23, 2025

Accepted: July 29, 2025

Figures and tables

Figure 1. A) Contrast-enhanced CT scan showing multiple hypodense nodules in the liver consistent with HEHE; B)Intraoperative view during liver transplantation showing the explanted liver; C) Gross pathological specimen of the explanted liver with multiple whitish nodules scattered throughout the parenchyma; D) Immunohistochemical staining for factor VIII highlighting cytoplasmic positivity in neoplastic endothelial cells.

Figure 2. ELTR therapeutic algorithm for HEHE. HEHE: hepatic epithelioid hemangioendothelioma; LT: liver transplantation; HHS: hepatic hemangiosarcoma; FU: follow-up; IS: immunosuppression; mTORi: mammalian target of rapamycin inhibitors; CHTH: chemotherapy.

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Quirino Lai - Hepatobiliary and Organ Transplantation Unit, Sapienza University of Rome, Umberto I Polyclinic of Rome, Rome, Italy. Corresponding author - lai.quirino@libero.it

Jan Lerut - Institute for Experimental and Clinical Research, Université catholique Louvain, Brussels, Belgium

Paolo De Simone - Liver transplant program, University of Pisa; Pisa, Italy

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Lai, Q., Lerut, J. and De Simone, P. 2025. Liver transplantation for vascular tumors. European Journal of Transplantation. 1, 3 (Sep. 2025), 29–38. DOI:https://doi.org/10.57603/EJT-1543.
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