2024 EASL意见书：罕见原发性肝癌

Summary

In recent years, owing to advances in our understanding of hepatocarcinogenesis, rare primary liver cancers (PLCs), including combined hepatocellular-cholangiocarcinoma, fi brolamellar carcinoma, and hepatic epithelioid hemangioendothelioma have garnered increased attention. In this position paper, an international panel of experts representing oncology, hepatology, pathology, radiology, surgery, and molecular biology has summarised the available information and evidence on the pathogenesis, diagnosis, and treatment of rare PLCs. While clinical trials of systemic treatments are underway for some rare PLCs, it is evident that more research, involving national and international collaboration, is required.

© 2024 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Introduction

In recent years, rare primary liver cancers (PLCs), including combined hepatocellular-cholangiocarcinoma (cHCC-CCA), fi brolamellar carcinoma (FLC), and hepatic epithelioid hemangioendothelioma (HEHE) have garnered increasing attention owing to an evolving understanding of molecular carcinogenesis in the liver and advances in therapeutic options for PLCs. Individually, most entities comprise less than $1\mathcal{2}\%$ of all PLCs but taken together, rare PLCs constitute a clinically relevant percentage of all PLCs. Thus, to what extent treatment algorithms and new systemic options may be extrapolated to these rare PLCs is a question that increasingly arises at many multidisciplinary tumour boards. In this position paper, an international panel of experts representing oncology, hepatology, pathology, radiology, and surgery, has summarised the available information and evidence on the pathogenesis, diagnosis, and treatment of rare PLCs using a systematic approach. Based on our summary, we have derived concluding statements and algorithms to help guide the management of these patients. However, because of the lack of robust data in most areas, our position paper is not an evidence-based clinical practice guideline and consequently, no level of evidence and level of recommendation will be provided. Without doubt, more research, for example through international registries and cooperation within ERN Rare-Liver (European Reference Network on Rare Liver Diseases), is required to improve the management of rare PLCs. For some entities, clinical trials testing systemic treatments are underway; however, in other areas additional activities are necessary. This is especially true for the treatment of cHCC-CCA and FLC, since these patients

have been excluded from international phase III trials in hepatocellular carcinoma (HCC).

## Combined hepatocellular-cholangiocarcinoma

Histology and de fi nition

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a PLC that, by de fi nition, corresponds to a solitary tumour mass containing a hepatocellular component and a cholangiocellular component, both unequivocally identi fi ed under the microscope on H&E-stained slides ( Fig. 1 A). 1 Thus, cHCCCCA is not the presence of HCC and cholangiocarcinoma (CCA) in a single patient in separate nodules. Macroscopically, cHCC-CCA lacks distinctive features and can solely be recognised through microscopic examination, requiring proper sampling adjusted to the tumour ’ s size. All kinds of architectural patterns and cytological features that exist in HCC and CCA can be found. 1 – 4 No minimal proportion of each component is required to make the diagnosis. 1 While immunohistochemistry can corroborate biphenotypic differentiation, it cannot independently establish the diagnosis without prior detection of both components on H&E slides. 1 , 2 Immunohistochemical markers indicative of hepatocytic differentiation (mainly HepPar1 and Arginase-1) exhibit greater speci fi city than sensitivity, whereas markers of cholangiocytic differentiation (keratin 7 and keratin 19) are more sensitive than speci fi c. 3 The two components can either be intermingled or close to each other and cancer stem cells can be seen in the transition area. 1 Nestin is a promising biomarker for the identi fi cation of cHCCCCA and its expression correlates with worse clinical

 Fig. 1. Combined hepatocellular-cholangiocarcinoma: Main histopathological and imaging characteristics and treatment management. (A) Histological features. a) Microscopic features (H&E stain). At lower magni fi cation (scale bar $500~\upmu\mathrm{m})$ ), the tumour contains two different areas, one, on the left, with pseudoglandular and trabecular architectural features characteristic of hepatocellular carcinoma, and one, on the right, with small tubules scattered in a dense fi brous background, suggestive of cholangiocarcinoma. b) At higher magni fi cation (scale bar $200~\upmu\mathrm{m}$ , the hepatocellular component is made of polygonal cells with an abundant eosinophilic cytoplasm and little stroma c) and the cholangiocellular component shows small tortuous ductular structures within a fi brotic stroma. (B) Imaging features. d) peripheral but no clear central enhancement (arterial phase), e) peripheral persistent hyperenhancement along with faint central wash out in portovenous phase. (C) Proposed algorithm for the management of patients with combined hepatocellular-cholangiocarcinoma. TACE, transarterial chemoembolisation; TARE, transarterial radioembolisation.

outcome. 5 , 6 In a subset of cases, the double phenotype is seen at the cellular level and the carcinoma looks homogeneous, made of uniform small cells, intermediate between hepatocytes and cholangiocytes. 7 In these very rare cases, immunohistochemistry is essential for recognising the double phenotype. 1 These PLCs are speci fi cally called intermediate cell carcinomas. Undifferentiated carcinomas of the liver are epithelial tumours lacking speci fi c morphological and immunohistochemical differentiation features.

Statement

' The diagnosis of cHCC-CCA is based on histology and requires the detection of both HCC and CCA components in one nodule. Nestin expression is associated with a worse prognosis. In very rare cases, the double phenotype is seen at the cellular level by immunohistochemical co-expression of hepatocyte and cholangiocyte markers. These very rare PLCs are termed intermediate cell carcinomas.

## Epidemiology and risk factors

The prevalence of cHCC-CCA varies among different studies due to dif fi culties in terms of diagnosis and the evolution of its de fi nition over time. According to the World Health Organization, cHCC-CCA accounts for $2–5\%$ of all PLCs while population-based studies suggest a prevalence of only $1\%$ . 1 , 8 – 10 cHCC-CCA primarily affects adults between the age of 60 and 65 years. 8 , 11 – 13 The sex distribution is similar to that of HCC, with male patients accounting for $70\%$ to $80\%$ of cases. 8 , 11 – 17 Along with male sex, cHCC-CCA shares other risk factors with HCC and CCA. In Eastern countries, hepatitis B virus infection represents the major risk factor, with frequencies exceeding $50\% $ in most studies. 14 , 18 – 21 Conversely, risk factors like hepatitis C virus infection, metabolic dysfunctionassociated steatohepatitis and alcohol-related steatohepatitis are more commonly reported in Western countries. 16 , 17 , 22 , 23 Compared to HCC, which occurs on a background of cirrhosis in $90\%$ of cases, only $50\%$ of cHCC-CCA cases in Western and Eastern countries develop in the presence of cirrhosis, probably due to relevant differences in in fl ammationdriven carcinogenesis and cellular origin. 16 , 17 , 19 , 24

Statement

' cHCC-CCA account for $1\%$ to $5\%$ of all PLCs and develop in a cirrhotic liver in only $50\%$ of cases.

Molecular biology

Several molecular studies have con fi rmed that cHCC-CCA are monoclonal tumours harbouring a median number of 60 to 70 non-synonymous coding mutations per tumour. 25 – 27 In terms of genetic alterations, both mutations in genes classically involved in HCC (telomerase reverse transcriptase [ TERT ] promoter, catenin beta 1 [ CTNNB1 ]), in intrahepatic CCA ( KRAS , isocitrate dehydrogenase 1 [ IDH1 ] and fi broblast growth factor receptor 2 [ FGFR2 ]) or in both tumours ( TP53 and BRCA1 associated protein-1 [ BAP1 ]) have been identi fi ed in cHCCCCA. 19 , 24 – 27 The percentage of TERT promoter mutations is

around $\mathcal{2}5\%$ , which is intermediate between intrahepatic CCA $(6\%)$ and HCC (50-60%). 25 , 28 However, it must be emphasised that the type and the frequency of mutations in driver genes in cHCC-CCA demonstrate signi fi cant variations according to available studies. 26

Statement

' cHCC-CCA is a monoclonal tumour harbouring genetic alterations commonly identi fi ed either in HCC ( TERT promoter, CTNNB1 ), in intrahepatic CCA ( KRAS , IDH1 , FGFR2 ), or in both tumour entities ( TP53 , BAP1 ).

## Imaging features for diagnosis and staging

Unlike HCC in a patient with cirrhosis, speci fi c radiological features enabling the diagnosis of cHCC-CCA have not been identi fi ed on computed tomography (CT) or magnetic resonance imaging (MRI) ( Fig. 1 B). A retrospective study evaluating the performance of LI-RADS (Liver Imaging Reporting And Data System) criteria in 61 patients with cHCC-CCA revealed that major criteria (arterial phase hyperenhancement and washout, enhancing capsule) could lead to misdiagnosis as HCC in over half of cases $(54\%)$ , and that only taking LR-M targetoid or nontargetoid ancillary features into account (rim or peripheral arterial phase hyperenhancement, portal venous or delayed phase progressive central enhancement, liver surface retraction, marked diffusion restriction, or peripheral washout appearance) allows for classi fi cation of cHCC-CCA $(88.5\%$ of cases with cHCC-CCA displayed at least one ancillary feature). 29 Nevertheless, a distinct pattern enabling the differentiation of cHCC-CCA from other non-HCC malignancies has not been identi fi ed. 29 Elevated serum carbohydrate antigen 19- 9 (CA19-9) and/or alpha-fetoprotein (AFP) are not reliable for cHCC-CCA diagnosis, although they could raise the suspicion of cHCC-CCA.

Statement

' Speci fi c radiological features enabling the diagnosis of cHCC-CCA have not been identi fi ed.

## Surgery and liver transplantation

Surgery represents the only curative treatment for cHCCCCA 30 , 31 ( Fig. 1 C). Many factors may in fl uence the feasibility of surgical intervention, such as the presence and severity of underlying liver disease, tumour size, and the presence of vascular invasion. cHCC-CCA is similar to HCC in terms of vascular involvement, and intrahepatic mass-forming CCA in terms of lymph node metastasis. 12 Surgical resection appears to lead to longer survival compared to non-surgical treatment, and major hepatectomy with wide resection margins seems the most appropriate approach. 30 , 32 The need for lymphadenectomy has not yet been determined 33 , 34 : the relative rarity of the disease and the diffuse lymphatic drainage of the liver do not allow for any strong recommendation. However, survival rates of patients resected for cHCC-CCA appear to be lower than for patients with HCC, with a mean disease free- and overall

survival (OS) of 13 and 31 months, respectively, suggesting that the clinical behaviour of cHCC-CCA is more similar to that of intrahepatic mass-forming CCA. 21

Few studies have focused on patients with cHCC-CCA who underwent liver transplantation (LT) and the results are controversial, with conclusions in favour 35 , 36 and against 37 , 38 this indication. Well or moderately differentiated cHCC-CCA is associated with better post-transplant survival than poorly differentiated cHCC-CCA which accounts for the majority of cases. 35 The rarity of the disease, the lack of experience, and the controversial results do not allow for any strong recommendation.

Statement

' Surgical resection represents the only curative treatment for cHCC-CCA. The role of lymphadenectomy and LT is still unclear.

Locoregional treatment

Based on the complete remission rates after treatment of either HCC or CCA, local thermal ablation may be considered as an alternative curative-intent therapy for cHCC-CCA in tumours up to $3\,\mathrm{\cm^{39,40}}$ ( Fig. 1 C). Locoregional treatments have been studied in several retrospective small cohorts of patients with cHCC-CCA. Kim et al. reported responses (partial response or stable disease with ${>}50\%$ tumour necrosis) in 35 of 50 patients $(70\%)$ treated by transarterial chemoembolisation (TACE) and noted a strong association between response and arterial hyperenhancement. 41 Furthermore, the authors reported that survival after TACE was negatively associated with low tumour vascularity, high Child-Pugh class, and portal vein invasion when a multivariate analysis was performed. 41 A retrospective single-centre cohort of 22 patients with cHCC-CCA undergoing transarterial radioembolisation (TARE) reported an objective response rate (ORR) of $55\%$ and disease control in $65\%$ . 42 Lack of response to treatment, bilobar disease, presence of multiple tumours, and elevated CA19-9 were associated with poor survival. 42

Statement

' Both TACE and TARE are viable options for tumour control in unresectable non-metastatic cHCC-CCA. Local thermal ablation is effective in tumours up to 3 cm.

Systemic treatment

There is no clear consensus on the optimal systemic treatment approach or the best candidate regimen in cHCC-CCA. In the clinical setting, patients with unresectable cHCC-CCA are often treated according to the guidelines for either HCC or CCA ( Fig. 1 C). We do not have randomised-controlled prospective studies, therefore clinical decision-making has to be based on retrospective data, which is subject to possible selection bias. 43 – 46 Table 1 outlines studies involving more than 10 patients. 11 , 47 – 52 Kim et al. 50 highlighted the selection bias present in many published studies. The authors compared patients

treated with sorafenib and individuals receiving cytotoxic chemotherapy, exploring both fi rst- and second-line treatments as well as other treatment types. As a result, the heterogeneous patient population, diverse cytotoxic chemotherapy regimens, and different treatment lines collectively contribute to selection bias, precluding its use as a basis for endorsing one approach over another. Notably, the number of patients with cirrhosis in the sorafenib group signi fi cantly differed from that in the cytotoxic chemotherapy group $(p\,=\,0.002)$ , a key prognostic factor in fl uencing patient outcomes. 50 Furthermore, cytotoxic chemotherapy encompasses various regimens, including platinum-based (such as gemcitabine plus cisplatin, fl uoropyrimidines plus cisplatin, or adriamycin plus cisplatin) and non-platinum-containing cytotoxic chemotherapy (single-agent fl uoropyrimidines or gemcitabine monotherapy). Given these considerations, it is essential to await the results of ongoing clinical trials before formulating recommendations. In this regard, there are two phase II studies focusing on patients with cHCC-CCA. The fi rst is dedicated to second-line treatment and recently completed recruitment (NCT03230318). This phase II trial involves patients with unresectable advanced intrahepatic CCA and cHCC-CCA harbouring FGFR2 gene fusions (determined by central laboratory fl uorescence in situ hybridization [FISH]) or FGFR2 gene mutations/ampli fi cations (based on next-generation sequencing commissioned by the study centre). These patients will receive oral derazantinib capsules at 300 mg once daily, with the primary endpoint being ORR. The second phase II study (NCT05211323) is comparing the impact of adding bevacizumab and atezolizumab to gemcitabine and cisplatin (chemotherapy) vs. chemotherapy and atezolizumab in unresectable or advanced cHCC-CCA.

Statement

' Data on systemic treatments for unresectable cHCC-CCA are limited to retrospective series testing treatments recommended either for advanced HCC or CCA. Data from phase II trials speci fi cally enrolling patients with cHCC-CCA are awaited. If enrolment in a clinical trial is not available, fi rst-line systemic treatment validated for HCC and CCA are available options following discussion by a multidisciplinary tumour board.

Fibrolamellar carcinoma

Histology and de fi nition

Fibrolamellar carcinoma (FLC), also known as fi brolamellar hepatocellular carcinoma, 53 is an exceptionally rare form of PLC that usually occurs in young patients without liver disease. 1 Macroscopically, FLC lesions are often large, welldelineated, and may mimic focal nodular hyperplasia (FNH) due to the abundance of fi brotic tissue that divides the tumour mass and converges in the centre creating a central scar-like appearance 1 ( Fig. 2 A). Histologically, FLC can be recognised by the abundant fi brotic stroma but mostly by the characteristic features of the tumour cells, which exhibit an abundant granular and strongly eosinophilic cytoplasm. 1 , 53 , 54 The stroma is organised in dense and thick fi brotic bundles around the cords of neoplastic cells, and focal calci fi cation may be recognised. 1

Comments

708

Descriptive Descriptive

47

et al.

(2017)

Author (year)

Drug

Selection bias

2025

|||||Publications|Publications||| |---|---|---|---|---|---|---|---| |Author (year)|Drug| Area/ country | Inclusion period | ¥N0. patients |Design|Outcome|Comments| |Salimon et al. (2017)47|Gemcitabine plus platinum-based CHT|France|2008 to2017||||| |Kobayashi et al. (2018)48| Gemcitabine/cisplatin or|||30|Retrospective|OS,PFS|Descriptive| ||fluorouracil/cisplatin or|Japan|2002 to 2015|38|Retrospective|DCR,OS| Descriptive| |Trikalinos et al. (2018)49| sorafenib or others ||||||| || Gemcitabine plus 5-FU or gemcitabine plus platinum |USA|1999 to 2006|¥68|| CDR, disease progression, OS, PFS | Selection bias| |Kim et al. (2021)50| Sorafenib or cytotoxic CHT||1999 to 2015|99|||| |Gigante et al. (2022)11| Platinum-based therapy,| Korea France |2009 to 2020|¥8:3|| ORR, OS, PFS OS,PFS | Selection bias Descriptive | || TKIs or other CHT regimens ||||||| |Pomej et al. (2023)51| Cytotoxic CHT or non-cytotoxic CHT |Europe|2003 to 2022|A4||OS,ORR| Selection bias| |Jang et al. (2023)225| or atezolizumab plus bevacizumab|Korea|2015 to 2021|25||OS,PFS| Descriptive| |Gigante et al. (2023)52| or pilimumab plus nivolumab Atezolizumab-Bevacizumab |France|2020 to 2022|16||ORR, OS, PFS|Descriptive| |||||Clinical trials|||| |ID/Sponsor|Arms - Drug||Status| Estimated enrolment |Phase|Aim| Estimated study completion date | |NCT03230318;|||||| ORR in advanced patients who received once per day at 300 mg of derazantinib capsules || | Basilea Pharmaceutica| Derazantinib single arm (iCCA and cHCC-CCA) ||Completed| 148 with FGFR2 genetic alterations |||2022| | NCT05211323; National Cancer Institute |||Recruiting|¥88|||2025| || CHT plus atezolizumab vs. CHT plus bevacizumab and atezolizumab |||||||

et al.

Gemcitabine plus platinum-based CHT

Gemcitabine/cisplatin or uorouracil/cisplatin or fl

(2018)

sorafenib or others

48

Descriptive

Selection bias

Selection bias

Trikalinos

et al.

(2018)

49

Gemcitabine plus 5-FU

Sorafenib or cytotoxic CHT

(2021)

Kim

50

et al.

(2022)

Gigante

et al.

Platinum-based therapy,

Descriptive

11

51 (2023)

TKIs or other CHT regimens

et al.

(2023)

Jang

Pomej

225

Cytotoxic CHT or non-cytotoxic CHT

et al.

Nivolumab or pembrolizumab

or atezolizumab plus bevacizumab

Estimated study completion date

or pilimumab plus nivolumab Atezolizumab-Bevacizumab

2022

Descriptive

et al.

(2023)

52

Gigante

ID/Sponsor

Journal of Hepatology, October 2024 . vol. 81

j

Arms - Drug

NCT03230318;

Derazantinib single

or gemcitabine plus platinum

704 – 725

Basilea Pharmaceutica

arm (iCCA and cHCC-CCA)

Salimon Kobayashi

NCT05211323; National

vs.

Cancer Institute

CHT plus atezolizumab

CHT plus bevacizumab and

atezolizumab

Area/ country

France Japan

USA

Korea France

Europe Korea

France

 Fig. 2. Fibrolamellar carcinoma: Main histopathological and imaging characteristics and treatment management. (A) Histological features a) Microscopic features (H&E stain). Thick trabeculae of collagen partition the tumoral lesion that is made of large neoplastic cells showing a granular eosinophilic cytoplasm (scale bar $200\;\upmu\mathrm{m})$ . b) A pale body is recognized, as well as other hyaline inclusions (scale bar $50~\upmu\mathrm{m})$ . c) Tumoral cells are diffusely positive for K7 (scale bar $50~\upmu\mathrm{m})$ ). (B) Imaging features d) Heterogeneously enhanced lesion with lobulated margins and central stellate scar (arterial phase CT, e) Relatively high signal intensity in diffusion-weighted MRI. (C) Proposed algorithm for the management of patients with fi brolamellar carcinoma. TACE, transarterial chemoembolisation; TARE, transarterial radioembolisation.

The tumour cells, arranged in nests and clustered between the fi brotic lamellar bands, are large, polygonal, and have a centrally located vesicular nucleus and a prominent nucleolus. 1 Mitoses are rare, nuclear pleomorphism is low. Cytoplasmic inclusions are common and include so-called pale bodies which correspond to fi brinogen. 1 Fat accumulation and bile pigment are also observable. 1 FLCs are positive for hepatocytic markers, but, in contrast to HCC, the neoplastic cells frequently express keratin 7. 55 , 56

Statement

' The diagnosis of FLC is based on histology from biopsies or surgical specimens requiring a well-de fi ned tumour nodule composed of abundant dense fi brotic tissue and large tumoral hepatocytes with a granular eosinophilic cytoplasm. Diffuse keratin 7 expression can help to distinguish FLC from HCC.

Epidemiology and risk factors

FLC accounts for approximately $1\%$ of $\mathsf{P L C s}^{57,58}$ with a low incidence rate of 0.2 new diagnoses per million person-years. 59 FLC predominantly affects young adults, typically diagnosed between the ages of 20 and 30 years, 43 although some paediatric cases have been reported. 60 FLCs are equally distributed in both sexes, with a male-to-female ratio of 1:1, and without predilection for any particular ethnicity. 43 , 58 In contrast to HCC, the aetiology of FLC remains unclear. It usually develops on the background of a normal liver parenchyma without a history of viral hepatitis or metabolic dysfunction, and in the absence of underlying liver in fl ammation. 61 , 62 FLC is not associated with cirrhosis or chronic liver diseases and well-de fi ned major risk factors for FLC have not been reported. 58 , 62 , 63

Statement

' FLCs account for approximately $1\%$ of all PLCs and usually occur in young non-cirrhotic adults.

Molecular biology

Almost all FLCs harbour a DNAJB1 - PRKACA fusion – due to a focal deletion in chromosome 19. 64 This fusion gene is responsible for an oncogenic addiction through constitutive activation of the protein kinase A pathway. 65 , 66 Exceptional cases of FLC, without a DNAJB1 - PRKACA fusion, have been described in patients with Carney complex due to germline inactivating mutations in PRKAR1A . 67 DNAJB1 - PRKACA fusion can be detected either by FISH or PCR in clinical practice. 54 Even if the DNAJB1 - PRKACA fusion is not fully pathognomonic of FLC, as the fusion can also be identi fi ed in oncocytic pancreatic and biliary neoplasms, the clinical presentation between these two entities is completely different and, consequently, the identi fi cation of a DNAJB1 - PRKACA fusion in a solid mass-forming liver tumour is considered as pathognomonic of FLC. 68 One of the differential diagnoses is a subtype of HCC harbouring somatic mutations of BAP1 and

PKA activation because these tumours have a fi brolamellar-like pattern at histology, and they occur in patients in their forties, in both sexes and in the absence of classic HCC risk factors. 69

Statement

' The presence of a DNAJB1-PRKACA fusion is pathognomonic of FLC if found in a mass-forming liver tumour. BAP1 mutations de fi ne a speci fi c subgroup of HCC with fi brolamellar-like histological features occurring in older patients.

Imaging features for diagnosis and staging

FLC usually presents as a large, heterogeneously enhanced lesion with lobulated margins and a central stellate scar, with or without calci fi cations 70 ( Fig. 2 B). In addition to these features in dynamic contrast-enhanced sequences, FLC shows a tendency towards high signal intensity on diffusion MRI. 71 , 72 In most patients with FLC, serum AFP is not elevated, thus it should not be used for the diagnosis of FLC. Although some other markers have been described such as B12-binding proteins, none of them has been validated. 73 , 74 Discriminating FLC from benign FNH is sometimes challenging because they can both display central scars. At imaging, FNH usually displays uptake of hepato-biliary contrast agent in late phase MRI, in contrast to FLC. Moreover, the apparent diffusion coef fi cient value in diffusion-weighted MRI is lower in FLC than in FNH. 75 , 76 However, despite some features to differentiate FLC and FNH, ultimately histology is necessary to con fi rm the diagnosis.

Statement

' No speci fi c radiological pattern exists for FLC. FLC usually presents as a large, heterogeneously enhanced lesion with a central scar. Histology, either via biopsy or primary resection in cases with high suspicion and resectable tumours, is necessary for de fi nitive diagnosis.

Surgery and liver transplantation

Patients with FLC often present with advanced disease which includes involvement of regional lymph nodes $(30–50\%)$ and distant metastasis $(30–40\%)$ . 77 When feasible ( i.e. in patients without cirrhosis), surgical resection represents the only curative treatment option ( Fig. 2 C). In a systematic review of 575 patients, Mavros et al. reported that the 5-year survival rate of patients who underwent resection of FLC was $70\%$ compared to $0\%$ among patients who did not undergo surgical resection. 78 Complete surgical resection with negative margins (R0) has been associated with improved long-term OS. 77 In addition to R0 resection, regional lymph node dissection is warranted because of the high incidence of lymph node metastasis $(30\%)$ and regional recurrence in patients with nodal disease. 79 , 80 Factors associated with a poor prognosis after surgical resection include lymph node metastasis, multiple tumours, metastatic disease at presentation, and vascular invasion. 81 Among patients presenting with these factors, recurrence is relatively common after resection with rates ranging from 40-

$100\%$ . 82 Therefore, close follow-up is required after resection. If recurrence is detected, repeat surgical resection may be warranted and has been associated with good results. 83

While there are no established criteria, LT is reserved for patients with large/multiple FLCs that are not resectable in the setting of no extrahepatic disease. A UNOS (United Network for Organ Sharing) analysis of 63 patients who underwent LT demonstrated 1-year, 3-year, and 5-year OS rates of $96\%$ , $80\%$ , and $48\%$ , respectively. 84 In a separate systematic review, the 1-year, 3-year, and 5-year OS rates after LT for FLC were reported to be $63–100\%$ , $43–75\%$ , and $29–55\%$ , respectively. 85

mOS (months)

23.1 NR NR NR

38.6 NR 56 19 NR 12.5 14

10.6 NR

mPFS (months)

NR NR NR NR

NR

9

NR 3.9 NR 2.6 2.7

2.4 NR

2b, recombinant interferon a

Statement

ORR %

62.5 32

0 0

37.5 50 25

3 0 0 0

0

43

' Complete surgical resection and lymphadenectomy achieve 5-year OS rates of $70\%$ and, if resection is not feasible, LT is an option in patients with unresectable FLC in the absence of metastases.

9 (8) 25

8 9

8

22 (14)

8 (8) 35 15

9 8

9

14

No. patients (evaluable)

Locoregional treatment

Based on the complete remission rates achieved in HCC, local thermal ablation may be considered as an alternative curative therapy for FLC only in case of early diagnosis of a tumour < 3 cm in size, 39 although locoregional treatment strategies have not been formally assessed in $\mathsf{F L C}^{\mathrm{86}}$ ( Fig. 2 C). In addition, since most tumours exhibit arterial hyperenhancement similar to typical HCC, TACE or TARE also represent an option in patients with unresectable tumours. 87 – 89

Statement

' Locoregional therapy ( i.e. TACE or TARE) may represent an option for unresectable FLC.

2b

a

5-FU and rIFN

Regimen

5-FU + IFN

PIAF

Capecitabine + IFN

2b plus NIV 3 mg/kg

5-FU + IFN

a Cisplatin containing regimens 5-FU and rIFN

ENMD-2076 (anti-Aurora Kinase A inhibitor)

Neratinib Everolimus

Letrazole/leurolide

Letrazole/leurolide plus Everolimus

Nivolumab and lenvatinib

Systemic treatment

FLC has been excluded from all major therapeutic trials in HCC and consequently there are limited prospective data ( Fig. 2 C). The main studies and trials on systemic therapy in FLC are listed in Table 2 . Cytotoxic chemotherapy has been regarded as the standard approach and the combination of 5- fl uorouracil (5-FU) and alfa interferon has been evaluated in several studies. 81 , 90 – 92 Nine patients were included in a prospective phase II trial of 5-FU $(200\ \mathsf{m g/m^{2}/d}$ for 21 days of a 28 day cycle) combined with subcutaneous recombinant interferon alfa-2b (rIFN a 2b 4 MU/m 2 every 3 weeks). 90 Among the eight evaluable patients, fi ve responded $(62.5\%)$ and a median OS of 23.1 months was reported. Two single-centre retrospective studies using this regimen have reported response rates of $32\%$ and $37\%$ among 25 and 8 patients, respectively. 81 , 91 The regimen has also been evaluated in combination with nivolumab in a single-centre retrospective study. 92 Only patients who received at least six cycles and had one follow-up scan were evaluated and there was considerable variation in the administration on 5-FU and interferon. 92 Despite these sources of potential bias, the response rate among 14 evaluable patients was $50\%$ , suggesting a possible additional bene fi t of nivolumab in these patients. Based on the observation that mTOR

brolamellar carcinoma.

fi

Design

Phase II prospective

Non-randomised retrospective single centre

Phase II prospective multicentre Phase II prospective multicentre

Retrospective single centre Retrospective single centre Retrospective single centre

Randomised phase II

Retrospective single centre

94

Table 2. Systemic therapy regimens for

90

91

95

92 (2013)

(2003)

81 (2020)

2021 226

(2020) (2021)

93

96

et al.

Author (year)

et al.

Patt YZ

Kaseb AO

et al. et al.

et al. et al.

(2020)

uorouracil; IFN, interferon; NIV, nivolumab; NR, not reported; ORR, objective response rate; OS, overall survival; PIAF, cisplatin, IFN, doxorubicin, and 5-FU; PFS, progression free survival; rIFN

(2022)

Maniaci V (2009)

Lamarca A Gottlieb S

Abou-Alfa G Abou-Alfa G

et al.

et al.

Dika IE

fl

Kent P

5-FU, 5- alfa-2b.

and S6 kinase are overexpressed in $\mathcal{2}5\%$ of cases and that FLC is sometimes associated with pregnancy or oral contraceptive use, everolimus, letrozole, and leuprolide were evaluated as single agents and in combination in a small randomised phase II trial. 93 A FLC cohort was included in the basket study of the pan-HER irreversible tyrosine kinase inhibitor neratinib. 94 Among the 15 patients recruited, no responses were observed. 94 The identi fi cation of the DNAJB1 - PRKACA fusion gene as an oncogenic driver of FLC raised the possibility that inhibition of aurora kinase A might be an effective strategy, but a prospective multicentre trial of ENMD-2076 achieved only one response (3%) among 35 heavily pre-treated patients. 95 The low tumour mutational burden suggests that FLC is unlikely to bene fi t from immune checkpoint inhibitors alone and there have been no prospective studies reported to date. Nivolumab and lenvatinib have been evaluated in the neoadjuvant setting and a response rate of $43\%$ was reported for the 14 patients treated. 96 A number of case reports have shown variable outcomes with a complete response reported for one patient treated with the combination of ipilimumab and nivolumab 97 but no response for two patients treated with atezolizumab and bevacizumab 98 or single agent pembrolizumab. 99

Alternative approaches are being explored. Preclinical and initial clinical experience using DNAJB1 - PRKACA -derived peptides has demonstrated the induction of persisting vaccineinduced DNAJB1 - PRKACA -speci fi c T-cell responses 100 and clinical trials are ongoing (NCT04248569). The anti-apoptotic protein BCL-XL has been found to be overexpressed in FLC compared to adjacent normal tissue and has been targeted using a proteolysis targeting chimera which selectively degrades BCL-XL via the VHL ubiquitin E3 ligase. 101 Pre-clinical studies have shown promising results in combination with irinotecan. 101

Hepatocellular carcinoma on adenoma

Epidemiology, risk factors and molecular biology

Hepatocellular adenomas (HCAs) are rare primary benign liver tumours derived from hepatocytes. HCAs occur mostly in young women taking oral contraception (incidence of 3/ 100,000 women on oral contraception). Bleeding and malignant transformation are major complications observed in 10- $\scriptstyle{20\%}$ and ${\mathfrak{<}}5\%$ of the cases, respectively. 102 HCAs can be divided into major molecular subgroups associated with speci fi c risk factors and clinical behaviours: hepatocyte nuclear factor 1 alpha-inactivated mutated HCA, in fl ammatory HCA, $\upbeta$ -catenin activated HCA with exon 3 or exon 7, 8 mutations of CTNNB1 $(\mathsf{b}^{\ominus\times3}\mathsf{H C A}$ or b ex7, 8 HCA), and sonic hedgehog $\mathsf{H C A}^{103,104}$ ( Table 3 ). In fl ammatory HCA may also acquire CTNNB1 mutations, resulting in mixed in fl ammatory $\upbeta$ -catenin HCA. Male sex and exon 3 mutations of CTNNB1 in the tumour are the main risk factors for malignant transformation. 103 A two-step model explains the mechanism of malignant transformation of HCA to HCC in most cases with 1 the occurrence of mutations of CTNNB1 in exon 3, and 2 telomerase reactivation mainly caused by TERT promoter mutation. 104 Of note, malignant transformation occurs also in other HCA molecular subgroups but with a lower incidence $(40\%$ of malignant transformation in $\mathsf{b}^{\mathsf{e x3}}\mathsf{H C A}$ vs. $4–5\%$ in other molecular subgroups). 103 Mutations in exon 3 of CTNNB1 can be detected either by molecular biology or by immunohistochemistry (glutamine synthase overexpression [sensitive and speci fi c] and nuclear translocation of $\upbeta$ -catenin [less sensitive but highly speci fi c]). 103 , 105 A diagnosis of HCC on HCA requires either the presence of both components ( “ nodule in nodule ” ), or clinical information about a history of incompletely resected HCA at the same location.

Statement

' To date, the most used regimen for the systemic treatment of FLC is the combination of 5-FU and interferon, with response rates of $25–62.5\%$ . New strategies are based on the evolving understanding of the biology of FLC.

Statement

' In patients with HCA, male sex and/or CTNNB1 exon 3 mutations are associated with an increased risk of malignant transformation into HCC. Identi fi cation of TERT promoter mutations in HCA is frequently associated with malignant transformation.

Table 3. Description of the main molecular subgroups of HCA.

||Genetic alterations|Risk factors|Histology/IHC|Complications| |---|---|---|---|---| |HNF1A inactivated| Bi-allelic inactivating mutations of HNF1A ||Tumour steatosis, complete| Familial adenomatosis if germline HNF1A mutation | |Inflammatory| mutations of HNF1A IL6ST, JAK1, STAT3, FRK, ROS1, GNAS ||loss of LFABP in the tumour|| ||| Obesity, alcohol, OC | dilatation, dystrophic arteries, SAA and CRP difuse expression in the tumour | Inflammatory syndrome Rare SAA amyloidosis | |CTNNB1 mut. exon 3*|CTNNB1 exon 3|Androgen, male| Cytological atypia, glutamine synthase homogeneous or heterogeneous dliffuse overexpression and nuclear | Malignant transformation| |CTNNB1 mut. exon 7.8*|CTNNB1 exon 7 or 8|| Glutamine synthase patchy overexpression and no nuclear B-catenin in tumour || | Sonic hedgehog activated|INHBE/GL/1fusion|Obesity| Small monotonous hepatocytes, Haemorrhage |Bleeding|

CRP, C reactive protein; CTNNB1, catenin beta 1; FABP, fatty acid-binding protein; GNAS, guanine nucleotide binding protein (G Protein), alpha stimulating activity polypeptide 1; HCA, hepatocellular adenoma; HNF1A, hepatocyte nuclear factor 1 A; INHBE, inhibin subunit beta E; IHC, immunohistochemistry; IL6T, interleukin 6 cytokine family signal transducer; JAK1, Janus kinase 1; OC, oral contraception; SAA, serum amyloid A; STAT3, signal transducer and activator of transcription 3. \* CTNNB1 mutated HCA are also in fl ammatory in half of the cases.

Imaging features for diagnosis and staging

Both HCA and HCC most commonly present as hyperenhancing tumours on arterial phase. However, a wash out pattern in the porto-venous phase of contrast-enhanced CT or MRI facilitates HCC diagnosis. 106 Therefore, in patients with HCA under surveillance, changes in wash out patterns along with symmetric or asymmetric lesion growth are suggestive of malignant transformation. 106 Although there are no speci fi c radiological features to detect the CTNNB1 -mutated HCA subtype on imaging, preliminary data indicate that the uptake of gadoxetic acid during the hepatobiliary phase is associated with marked activation of the $\upbeta$ -catenin pathway and could be used to identify ${\mathsf{b}}^{\mathtt{e x3}}{\mathsf{H C A}}.$ . 102 , 107 Currently, liver biopsy is recommended.

Statement

' Speci fi c radiological features for HCC on HCA are lacking. Changes in wash-out patterns along with symmetric or asymmetric lesion growth suggests malignant transformation of HCA.

Surgery and liver transplantation

Resection should be considered in patients with high-risk features, i.e. male patients, increasing size by ${\tt>}20\%$ compared to baseline imaging, no reduction in size after 6 months of discontinuation of hormonal therapy in HCAs, $\upbeta\cdot$ -catenin-activated subtype, imaging features suggestive of malignant transformation. 108 , 109 Complete surgical resection should be the goal. Hepatectomy for benign liver lesions such as HCA is generally safe with a perioperative mortality of less than $1\%$ and severe morbidity of less than $10\%$ . 110 , 111 Both open and minimally invasive approaches have been shown to be safe. 112 The number of HCA lesions ( i.e. hepatic adenomatosis) and risk features are not correlated with HCA-related complications, so surgical decision-making in this patient population should be the same. 113 When patients have disseminated disease with one or two dominant high-risk HCAs, selective resection of these lesions can be performed, keeping the other lesions under surveillance. LT should generally be performed only in exceptional cases. 114 In particular, LT should be considered in patients who have multiple lesions that are highly suspicious for malignant transformation $(\mathsf{b}^{\mathsf{e x3}}\mathsf{H C A})$ that cannot be removed by resection alone. Other rare indications for LT include the presence of recurrent HCA that cannot be re-treated by resection, the presence of HCA-related portosystemic venous shunts, or recurrent life-threatening HCA-related bleeding due to tumours that cannot be removed by resection alone. 115 , 116

Statement

' Surgical indications for HCA-related HCC are the same as for HCC linked to other aetiologies, i.e. BCLC stage A and a single nodule ${\tt>}2$ cm in size. LT is performed only in exceptional cases with multiple suspicious HCAs or if recurrent life-threatening complications are not amenable to resection alone.

Locoregional treatment

Both local ablation and locoregional intraarterial therapies are part of the therapeutic armamentarium proposed by guidelines for the management of HCC. 117 , 118 Treatment recommendations for HCC arising from HCA should be based on those recommendations. 118

Statement

' Locoregional treatment of HCC developing on HCA is based on recommendations for HCC.

Systemic treatment

Although not speci fi cally addressed in the international guidelines, HCC arising on HCA is susceptible to the same treatments as HCC arising on cirrhosis and/or other aetiologies, such as the new standard of care fi rst-line treatment consisting of an anti-PD-L1 (programmed death ligand 1) and VEGFA (vascular endothelial growth factor A)-targeted antibodies or anti-PD-L1 and anti-CTLA-4 (cytotoxic T lymphocyte antigen 4) antibodies. Since CTNNB1 mutations occur early in the transition from HCA to $\mathsf{H C C}^{104}$ and approximately two-thirds of patients with HCC on HCA are $\upbeta$ -catenin-activated, 119 , 120 b - catenin-targeted therapy may be a future option for these rare patients.

Statement

' Systemic treatment for HCC arising on HCA is based on recommendations for patients with HCC.

Hepatic epithelioid haemangioendothelioma

Histology and de fi nition

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare malignant vascular tumour of the liver fi rst described by Ishak in a series of 32 patients. 121 Of note, epithelioid hemangioendothelioma can also arise in other organs such the lung or bone. Single or multiple, HEHEs range from small nodules to large masses that have a fi rm, white to grey appearance, macroscopically resembling CCA ( Fig. 3 A). Histologically, HEHEs demonstrate variable cellularity with a sclerotic, hypocellular centre and a much more cellular and blurred periphery with in fi ltrative margins. Within the lesion, there are remnants of partially obliterated portal tracts and central veins, while at the invasive front, tumour cells in fi ltrate the sinusoids between the liver cell plates. 1 , 122 The tumour cells – either isolated, or forming cords and small nests embedded in the fi bro-hyaline, sometimes myxoid stroma – show variable aspects, mostly epithelioid with a pale cytoplasm, or signet-ring like with a lumen that may contain red blood cells, but also spindle or stellate cells. Nuclear pleomorphism and mitoses can be seen. By immunohistochemistry, their endothelial nature is recognised by positivity for CD31, CD34, ERG and factor VIII-related antigen, which help in the differential diagnosis with CCA. Most HEHEs are low-grade malignancies, so Ki67 expression is low. Nuclear CAMTA1 expression, a surrogate marker of the

A

 Major features are multiple coalescent tumors, halo/target enhancement, and capsular retraction.

C

 Fig. 3. Hepatic epithelioid hemangioendothelioma: Main histopathological and imaging characteristics and treatment management. (A) Histological features. a) Microscopic features (Scale bar $100\;\upmu\mathrm{m})$ . On H&E stain, the tumour is made of epithelioid cells with a pale cytoplasm scattered in a hyaline stroma, or of signed-ring like cells with a vacuole that sometimes contains red blood cells. b) By immunohistochemistry the vascular nature of the tumoral cells is recognized on the CD34 stain, c) the proliferation is very low (Ki67 immunohistochemistry) d) and a nuclear CAMTA1 expression is observed. (B) Imaging features. e) subcapsular, coalescent lesion with retraction of hepatic surface. Target sign with concentric layers on T2-weighted image, f) hypointense lesions with peripheral enhancement in arterial phase, g) lollipop sign at portal phase image with tumour and obstructed hepatic vein ( “ candy and stick ” ). (C) We proposed an algorithm for the management of patients with hepatic epithelioid hemangioendothelioma. TACE, transarterial chemoembolisation; TARE, transarterial radioembolisation.

CAMTA1 - WWTR1 fusion, is a highly sensitive and speci fi c marker for HEHE, being positive in up to $86\% $ of all cases. 123 , 124 Rare cases of centrolobular vein involvement with obstruction of hepatic venous out fl ow leading to Budd-Chiari syndrome have been described. 125

Statement

' HEHE is a vascular tumour made of epithelioid cells showing variable cellularity with a sclerotic centre and in fi ltrative margins. Nuclear CAMTA1 expression is diagnostic in up to $86\%$ of cases.

Epidemiology and risk factors

HEHEs account for less than $1\%$ of PLCs, with an estimated incidence ranging from 0.1 to 1 case per 100,000. 121 , 126 Median age of presentation is between 35 and 45 years, spanning from 12 to 86 years in a large series of 137 cases. 122 HEHE is more commonly observed in women (ranging between $60–80\%$ in different studies). 127 , 128 In terms of ethnicity, an analysis of the National Cancer Institute ’ s SEER (Surveillance, Epidemiology, and End Results) database, which included 120 cases of HEHE, found a higher incidence in the white population. 129 The aetiology of HEHE remains unclear as no de fi nitive risk factor has been con fi rmed. Several elements have been proposed as potential risk factors, including oral contraception, alcohol consumption, granulomatous diseases (sarcoidosis and Crohn ’ s disease), vinyl chloride, asbestos, or thorotrast exposure, and viral hepatitis (hepatitis B and C) but none has been consistently demonstrated. 122 , 126 , 128 , 130

Statement

' HEHE is more common in young adult women with normal liver and its aetiology remains unclear.

Molecular biology

Regardless of their localisation, all HEHEs harbour pathognomonic somatic genetic alterations. Approximately $90\%$ of cases are de fi ned by the presence of the CAMTA1 - WWTR1 gene fusion, that results from a translocation t(1;3) (p36.3;q25) and involves the calmodulin-binding transcription activator CAMTA1 , and WWTR1 , a TAZ-transcriptional coactivator. More rarely, a YAP1 - TFE3 fusion is detected. 131 , 132 These genetic alterations have never been detected in other types of tumours, including hepatic angiosarcoma (HAS), suggesting that they may serve as bona fi de diagnostic criteria for HEHE. Of note, these fusions are also identi fi ed in HEHEs that develop outside the liver. In vitro , the CAMTA1 - WWTR1 gene fusion has been shown to activate the Hippo pathway through TAZ. 133 The CAMTA1 - WWTR1 gene fusion can be detected using PCR or FISH or, as reported above, indirectly via the nuclear overexpression of CAMTA1 on immunohistochemistry. 124 , 134

Statement

' Presence of somatic CAMTA1-WWTR1 or YAP1-TFE3 fusions are pathognomonic of HEHE; the fusions are also detected in primary extrahepatic epithelioid hemangioendothelioma.

Imaging features for diagnosis and staging

There are no speci fi c radiological features that characterise HEHE ( Fig. 3 B). 135 However, a recent study that included 740 lesions in 93 patients, reported that, in contrast to arterial hyperenhancement, a target sign with hyperdense inner rim in plain CT, as well as retraction of the liver capsule in lesions close to the liver margin are frequently found. 136 In addition, because of the vascular nature of the tumour, portal or venous branches ending at the tumour lesions, occur in $10–20\%$ of tumours ( “ lollipop sign ” ). 136 Most patients present with diffuse liver disease and a high proportion of coalescent tumours. 137 Metastases of other malignancies should be considered and excluded as a differential diagnosis to HEHE. 136 , 138

Statement

' Speci fi c radiological features for HEHE are lacking and therefore tumour biopsy is necessary. However, target sign and liver capsule retraction, as well as the “ lollipop sign ” from vascular structures ending at tumour lesions guide HEHE diagnosis.

Surgery and liver transplantation

Curative therapy for proven HEHE can be divided into three categories: surgical resection, LT, and minimally invasive ablative therapy like radiofrequency ablation via an open, laparoscopic or complete percutaneous approach ( Fig. 3 C). The goal of curative surgical treatment is to treat each tumour site in a manner that allows for adequate margins to prevent residual growth, recurrence, and/or metastatic occurrence. The choice of the appropriate therapy is highly dependent on the age and condition of the patient, the number of lesions, the location within the liver, and the quality and size of the future remnant liver. Adequate future remnant liver is needed to sustain postoperative regeneration of the liver after any therapy. A multidisciplinary team discussion preferably at a combined hepato-pancreato-biliary and transplant centre is advisable for these complex cases.

LT represents an established option in many countries. Resection is often challenging because HEHE often presents late with large lesions and multifocality. Considering the average age of patients with HEHE, complete resection may be indicated even when extreme resections are necessary. 139 , 140 ALPPS (associating liver partition with portal vein ligation for staged hepatectomy) has been described in the context of a case report. 141 Survival after resection seems to be similar to

that after LT, but cases are hardly comparable, because decisions are made on an individual basis. 140 In a study using data from the European Liver Transplant Registry, selected LT patients with resected extrahepatic spread $\mathsf{(n=41)}$ ) displayed similar 5-year survival rates to patients without extrahepatic lesions receiving LT alone $(\mathsf{n}=108)$ ) $(82\%$ vs. $72\%$ ). 142 To the best of our knowledge no randomised trials on HEHE and surgery exist. Hilar lymph node involvement and macrovascular ingrowth in fi nal pathology specimens are considered independent factors for recurrence and poorer prognosis. 142

Statement

' Both LT and surgical resection (with or without additional preoperative ablation) serve as options for HEHE with curative intent, with transplantation considered if complete resection is not feasible. Extrahepatic metastases do not represent an absolute contraindication to LT and resection.

resection and LT being the most frequent treatment options, approximately $\mathcal{2}5\%$ of patients receive systemic treatment during their lifetime. 126 However, consensus on the best systemic treatment options is lacking, especially since the current data is retrospective, as summarised in Table 4 (adapted from the ESMO consensus document published in 2021). 147 Therefore, we await the results of ongoing clinical trials. Current trials are evaluating various regimens: eribulin (microtubule targeting agent, NCT03331250), trametinib (MEK inhibitor, NCT03148275), gemcitabine plus pazopanib $(\mathsf{C T}\!+\!\mathsf{T K I}$ , NCT01532687), and IK-930 (TEAD Inhibitor, NCT05228015).

Statement

' There is no consensus on the best systemic treatment options and treatment decisions are based on recommendations from a multidisciplinary tumour board.

Locoregional treatment

The vascular nature of HEHE renders most patients amenable to intraarterial tumour-targeted therapies ( Fig. 3 C). However, studies on locoregional treatments in HEHE are retrospective and limited to small cohorts. A recent paper evaluating the role of image-guided percutaneous ablation in patients with HEHE showed that up to $94.3\%$ of ablated tumours did not progress and in cases where progression occurred, it manifested with lesions amenable to further ablation. The paper highlights the role of percutaneous ablation in the treatment of HEHE. 143

In a series of 25 patients, four were treated exclusively by TACE whereas TACE was used for downstaging to LT in two patients. 144 No differences in OS were observed between patients treated with LT and those treated with TACE alone. Moreover, patients in whom TACE was used as a downstaging treatment achieved survival of 1-9 years. 144 The heterogeneity and limited size of patient cohorts prohibits clear recommendations. However, TACE could represent an additional treatment to curative surgical strategies or a palliative alternative. 145 At present, only one case report has been published on successful TARE in HEHE. 146

Hepatic angiosarcoma

Histology and de fi nition

Hepatic angiosarcoma (HAS) is a high-grade malignant vascular neoplasm and represents the most common sarcoma of the liver. 1 , 148 Grossly, HASs have variable appearance, from numerous poorly de fi ned solid nodules to large spongy, necrotic, and haemorrhagic masses. 149 Histological differentiation is also variable, ranging from irregular and tortuous cavernous vascular spaces lined by protruding endothelial cells with hyperchromatic nuclei and fi lled with blood, to papillary protrusions within the sinusoids. When poorly differentiated, HAS consists of malignant spindle cells with pleomorphic and bizarre nuclei diffusely obliterating the sinusoids and forming hypercellular solid areas. 1 , 149 Mitoses are numerous and extramedullary haematopoiesis may be observed. The endothelial markers CD31, CD34, ERG and factor VIII-related antigen are positive, con fi rming the vascular lineage, but these markers may be less expressed in poorly differentiated HAS. 1 , 149 The high proliferation rate is con fi rmed by immunodetection of Ki67. P53 is overexpressed in most cases. These two features help to differentiate HAS from hepatic small vessel neoplasm, a recently described in fi ltrative vascular tumour thought to be a low-grade neoplasm. 150 , 151

Statement

' The vascular nature of HEHE renders most patients amenable to transarterial therapies, especially TACE. Intraarterial treatment options are discussed in case of limited extrahepatic (oligometastatic) disease that is refractory to or not suitable for surgery, ablation or stereotactic body radiation therapy.

Statement

' HAS is the most frequent sarcoma of the liver and shows variable degrees of differentiation with frequent p53 overexpression and a high proliferation rate con fi rmed by immunodetection of Ki67.

Systemic treatment

According to the consensus document from ESMO (the European Society for Medical Oncology), in patients with localised, resectable HEHE, there is no evidence supporting the use of systemic therapies 147 ( Fig. 3 C). Moreover, active surveillance is the initial recommended option for cases presenting with asymptomatic locoregional or systemic metastases. Despite

Epidemiology and risk factors

HAS represents approximately $0.1{\mathrm{-}}2\%$ of all PLCs, with an estimated incidence of 0.5-2.5 cases per 10,000,000 individuals. 152 However, a recent analysis of the SEER database reported an increase in the number of cases over time. 153 HAS mainly affects adults, with a peak incidence in the sixth and seventh decades of life, 154 with a male to female ratio of 3-

Position Paper

147

Table 4. Major available series (

>

5 patients) on systemic treatments in advanced epithelioid haemangioendothelioma (adapted from Stacchiotti

Study type

).

et al.

Median PFS

Disease response

Evidence of

et al.

Ciof

Journal of Clinical

A

Multicentre, retrospective

fi

et al.

Oncology suppl. 2011

Prospective, phase II

Chevreau C Cancer. 2013

Prospective, phase II

institution

et al. Annals of Oncology. 2013 et al. Anticancer Research. 2015 Agulnik M Yousaf N

Retrospective, single

No

Retrospective analysis of prospective studies

et al.

Acta oncologica. 2017

Kollar A

et al. BMC Cancer. 2018 Shiba S

Multicentre, retrospective

Multicentre, retrospective

Journal of Hepatology, October 2024 . vol. 81

et al.

||Study type| Number of patients | CAMTA1/TFE3 assessment* | Regimens (n. patients)| Evidence of prior progression | Disease response| Median PFS (months) | |---|---|---|---|---|---|---|---| | Cioffi A et al. Journal of Clinical Oncology suppl. 2011 |Multicentre, retrospective|③4|¥70||¥20|ORR=0|| | Cioffi A et al. Journal of Clinical Oncology suppl. 2011 |Multicentre, retrospective|③4|¥70| Anthracycline (±ifosfamide)(16) Other cytotoxic (6) Sorafenib (6) |¥20|ORR=0|48| | Cioffi A et al. Journal of Clinical Oncology suppl. 2011 |Multicentre, retrospective|③4|¥70||¥20|ORR=0|| |||③4|¥70| Metronomic cyclophosphamide (2) Thalidomide (2) |¥20| BR = SD BR=SD || ||||||¥20||| || Prospective, phase I |¥1９|¥70|Imatinib (2)|20|BR=SD|| | Chevreau C et al. Cancer.2013 ||||Sorafenib|Yes|ORR = 13% (2/15)|| | Agulnik M et al. Annals of Oncology. 2013 Yousaf N et al. | Prospective, phase Il ||20|Bevacizumab|20|ORR = 29% (2/7)|| |Anticancer Research. 2015|Retrospective, single|19|20|||BR = PR (celecoxib, 1 patient);|| |Anticancer Research. 2015||19|20| caelyx, celecoxib, celecoxib + lenalidomide, doxorubicin, imatinib, carboplatin and paclitaxel, cyclophosphamide and vinblastine, ||SD (other regimens)|| ||||| cyclophosphamide and vinblastine, axitinib, cyclophosphamide and etoposide, ifosfamide and doxorubicin, thalidomide, axitinib, pazopanib, |||| || Retrospective analysis|10|20|Pazopanib|Yes|ORR = 20% (2/10)|| | Kollar A et al. Acta oncologica. 2017Acta oncologica. 2017 Shiba S et al.Shiba S et al. BMC Cancer. 2018 | of prospective studies ||||||26| ||Multicentre, retrospective|10|20| Carboplatin + paclitaxel + bevacizumab (CPB); paclitaxel; pazopanib; bevacizumab; streptozocine; cisplatin + epirubicin + |¥20|BR = PR (CPB);|| | Engel ER et al. J Pediatr Hematol Oncol. 2019 |Multicentre, retrospective||Yes (1/6)|bevacizumab (CEB)||SD (other regimens)|| ||||| Sirolimus|Yes|ORR = 50% (3/6)|| || Retrospective analysis of prospective studies ||Yes| VAIA/VAC/CEVAIE, paclitaxel lenalidomide, INF, pazopanib |¥20|ORR=0|| | Pediatr Blood Cancer. 2020. Stacchiotti S et al. |Multicentre, retrospective|38|Yes|Sirolimus (plasma level of 15-20 ng/d)|Yes|ORR = 11% (4/37)|| |Cancer. 2021||||Anthracycline-based (33)||ORR = 3% (1/33)|| | Frezza AM et al. Cancer Med. 2021 |Multicentre, retrospective||Yes|| Yes (19/33) Yes (6/11) ||| ||||Yes| Weekly paclitaxel (11) Pazopanib (12) IFN-α 2b (15) |Yes (10/12)| ORR = 9% (1/11) ORR=0 |2.9| ||||| Pazopanib (12) IFN-α 2b (15) Others (27) ||ORR = 7% (1/15)| 2.9 8.9 | |||||| Yes (12/15) Yes (24/27) ||ZA|

IFN

Engel ER

J Pediatr Hematol

Oncol. 2019

Sparber-Sauer M

et al.

Retrospective analysis of prospective studies

Pediatr Blood Cancer. 2020.

et al.

Multicentre, retrospective

Stacchiotti S Cancer. 2021

Multicentre, retrospective

j

et al.

Frezza AM

Cancer Med. 2021

704 – 725

Regimens (n. patients)

\*Immunohistochemistry or molecular testing.

717

\*

CAMTA1/TFE3 assessment

Number of patients

No

No

No

No

No

Yes (1/6)

Yes

Yes

Yes

34

15

7

19

10

10

6

6

38

73

4:1. 155 The aetiology of HAS remains unknown in approximately $75\%$ of cases, while an association with speci fi c risk factors can be found in the remaining $\mathcal{2}5\%$ . 152 , 156 One of the most well-known risk factors is vinyl chloride monomer exposure. 157 – 159 The latency period between vinyl chloride exposure and the development of HAS is approximately 20 years, potentially explaining the slow gradual decline in diagnoses among highly exposed workers. 130 , 160 It is worth noting that HAS associated with vinyl chloride exposure can occur in the presence of cirrhosis, unlike in other cases. 161 Other identi fi ed risk factors include exposure to thorotrast, 162 androgenic steroids, 163 arsenic ingestion, 164 and exposure to radium. 165 Although rarely, additional risk factors such as urethane, 166 cyclophosphamide, 167 and oral contraceptive use, 168 have been described. Conversely, any involvement of viral hepatitis in HAS development has never been demonstrated. 153 , 169

Statement

' Vinyl chloride exposure is a well-known risk factor for HAS and may lead to HAS after a latency period of up to 20 years.

Molecular biology

Very few data are available on the molecular pathogenesis of HAS. Old studies have reported KRAS mutations in vinyl chloride-related HAS, whereas more recent studies reported TP53 mutations or mutations in mTOR pathway genes in sporadic HAS ( MTOR , PIK3CA , PTEN ). 170 – 172

Statement

' Some studies reported TP53 mutations or mutations in mTOR pathway genes in sporadic HAS.

Imaging features for diagnosis and staging

No speci fi c feature enables the radiological diagnosis of HAS. On cross sectional imaging, this tumour may appear as a solitary mass or as multiple nodules or masses with heterogeneous and progressive enhancement. 173

Statement

' No speci fi c feature enables the radiological diagnosis of HAS.

Surgery and liver transplantation

Literature on surgery for HAS is extremely limited and for this reason recommendations are based exclusively on small retrospective series. Indeed, most patients are diagnosed with metastasis and/or extensive growth and are therefore not amenable to surgery. Surgery, usually combined with chemotherapy, is the only treatment that offers a very small chance of cure for patients with HAS. Resected patients tend to live

longer (3.6, and 15 months) 174 , 175 than patients receiving best supportive care (1.3 months) 176 and long-term survival is probably limited to those patients who tolerate both surgery and chemotherapy. 177 , 178 Time between diagnosis and surgery should be limited as much as possible in the few patients who are eligible for resection. It is recommended that only resection with a free margin should be attempted. 176 Due to the very aggressive nature of HAS and its poor outcome, LT is not considered a viable therapeutic option. 179

Statement

' Owing to the marked aggressiveness of HAS, surgery is rarely appropriate and is reserved for patients in whom a radical resection can be achieved. LT is not considered a viable option in patients with HAS.

Locoregional treatment

Reports on locoregional treatments either describe their role only in the management of HAS-related complications, such as embolisation in case of bleeding, 153 or are limited by their retrospective nature and low number of cases included. 173 TACE may be used to prevent fatal tumour rupture and massive haemorrhage, especially in patients with a large tumour burden. 175 The role of Yttrium-90-based TARE has been explored in a cohort of liver-dominant metastatic soft tissue sarcomas or primary hepatic sarcomas, including HAS. 180 Patients had a median liver progression-free survival of 9 months, and an ORR and disease control de fi ned by mRECIST at 3 months of $56.7\%$ and $80.0\%$ , respectively. 180

Statement

' Currently, locoregional treatments are mostly used in the management of HAS-related complications and there is no strong evidence to recommend TACE as an active treatment.

Systemic treatment

HAS has been included within trials of angiosarcoma (AS) more broadly, and AS in turn has often been included in trials for soft tissue sarcomas. Furthermore, HAS represent only $4\%$ of ASs and are associated with a dismal prognosis. 181 Hence, the evidence base for systemic therapy in HAS is very poor and clinical practice is largely informed by therapeutic approaches applied in AS in general. The mainstay of therapy for AS is anthracycline- or taxane-based chemotherapy. 182 , 183 Pooled analysis of 11 prospective trials of anthracycline-containing therapy for soft tissue sarcomas identi fi ed 108 patients of whom $\mathcal{2}5\%$ had a complete or partial response. 184 Median OS was 9.9 months and the combination of ifosfamide with doxorubicin was associated with better outcomes compared to single agent anthracycline. 184 Weekly paclitaxel was evaluated in a phase II trial in AS, with a reported response rate of $17\%$ . 185 These data were con fi rmed in a subsequent study which combined 8 prospectively and 10 retrospectively included patients and reported a $35\%$ ORR. 186 The Asian

Sarcoma Consortium reviewed therapy for AS and found that of 276 patients, $53\%$ received fi rst-line chemotherapy (paclitaxel in 68 patients and liposomal doxorubicin in 28) resulting in a median OS of 11.9 and 10.6 months, respectively, a statistically non-signi fi cant difference. 187

Given the vascular nature of this tumour, anti-angiogenics have been explored. A small, randomised trial comparing weekly paclitaxel with and without bevacizumab failed to demonstrate any additional bene fi t for bevacizumab. 188 Patients with AS have also been included in trials evaluating kinase inhibitors and anti-VEGF therapy for soft tissue sarcomas with response rates of 11-14% for sorafenib, $0\%$ for sunitinib and $12\%$ for bevacizumab. 182 A retrospective study reported a $\scriptstyle{20\%}$ ORR among 40 patients with AS treated with pazopanib. 189

There is limited data on immunotherapy, however, no responses were reported among the fi ve patients with AS included in a prospective trial of durvalumab and tremelimumab for soft tissue sarcomas. 190 By contrast, in a small retrospective study including 25 patients, of whom 11 had visceral disease, an ORR of $18\%$ was observed for single agent pembrolizumab. 191

Statement

' Patients with advanced HAS have a poor prognosis but may derive some bene fi t from systemic therapy with anthracycline- or taxane-based chemotherapy. Anti-angiogenics have shown variable bene fi t and immunotherapy has yet to provide convincing evidence of ef fi cacy in HAS.

Very rare primary liver cancers

Herein, we highlight the histological features, as well as limited clinical and outcome information, on some very rare PLCs. Primary hematolymphoid tumours of the liver are beyond the scope of this position paper.

Hepatoblastoma in adults

In $90\%$ of cases, hepatoblastoma (HB) occurs in children under 5 years of age, representing the most common primary malignant liver tumour in the paediatric population, with an annual incidence of 0.5-1.5 per million. 192 Until the end of 2018, only 69 cases of adult HB had been reported, mostly with rather dismal prognosis due to late presentation with large liver mass and right upper quadrant pain, and high recurrence after surgery. 193 HB in adults is associated with cirrhosis in only $\mathcal{2}5\%$ of cases. 194 Based on a review of 45 cases published until 2011, Rougemont and colleagues have identi fi ed marked differences between paediatric and adult cases, and thus, the existence of HB in adults remains controversial. 194 The main differential diagnosis in adults is HCC with signi fi cant histological overlap. As in children, the primary treatment for HB in adults is complete surgical removal. TACE has been used for the treatment of HB in both the neoadjuvant and palliative setting. In a small study involving 16 patients with HB, TACE was administered in one to three sessions, with tumour size reduction ranging from $19.0\%$ to $82.0\%$ and an average decrease in AFP values of $60.0\%$ . 195 TACE facilitated subsequent complete surgical removal in 13 cases, and there were no signi fi cant adverse

effects. Surgical specimens showed an average of $87\%$ necrotic tissue, indicating that TACE, either alone or in combination with surgery, is an effective treatment option for HB. While this study primarily focused on infants and children, other reports suggest similar treatment effectiveness in adults. Since HB is sensitive to cytotoxic agents, such as cisplatin and doxorubicin, 196 neoadjuvant risk-adapted systemic therapy is recommended by the International Childhood Liver Tumor Strategy Group (SIOPEL, www.siopel.org ). Further investigation is needed to con fi rm whether application of the paediatric HB protocol is bene fi cial in adult HB.

Mucinous cystic neoplasms

Mucinous cystic neoplasms (MCN) of the liver and biliary tract consist of multilocular cystic lesions without communication with the bile duct, lined by a cuboidal or columnar epithelium with variable quantities of mucin secretion, supported by an ovarianlike stroma expressing oestrogen and progesterone receptors on immunohistochemistry. 1 MCN are categorised as showing low grade or high grade dysplasia (previously named cystadenoma), or as associated with invasive carcinoma (previously named cystadenocarcinoma). 197 – 199 MCNs occur almost exclusively in women of various ages. 200 The presence of at least one major feature (tick septation, nodularity) and one minor feature (upstream biliary dilatation, thin septations, internal haemorrhage, perfusion change and ${\vartriangleleft}3$ coexistent hepatic cysts) on MRI is suggestive of MCN. 201 Diagnosis of MCN with invasive carcinoma at imaging is challenging, although the presence of large mural nodules may indicate malignant transformation. 202 Both serum and cystic levels of CA19-9 or carcinoembryonic antigen could be elevated in simple biliary cysts, and in MCN with or without an invasive component, and are thus not useful for the differential diagnosis. 197 , 203 , 204 Surgical resection is the treatment of choice in MCN with dysplasia due to the risk of malignant transformation and for all MCNs with invasive carcinoma, resulting in a 5-year OS rate of $65–70\%$ . 203 , 205 , 206

Neuroendocrine neoplasms

Primary hepatic neuroendocrine neoplasms (PHNENs) include well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). 1 They primarily affect adults aged 40-50 years and their diagnosis is challenging as symptoms are unspeci fi c and radiological fi ndings also lack speci fi city. Molecular data is limited; however, a study including 22 cases of PHNEN revealed that $14\%$ harbour TP53 and SETD1B mutations, 207 although alterations in NOTCH3 and BRD4 genes have also been described. 208 The histological fi ndings for PHNENs are similar to those of NETs and NECs that develop in other organs with no liver-speci fi c fi ndings, and mixed neuroendocrine-non-neuroendocrine neoplasms with either a HCC or a CCA component have also been identi fi ed. 1 PHNENs are exceedingly rare and de fi ning the primary nature requires careful exclusion of another primary location, as metastases are more frequent. Consequently, the diagnosis of PHNEN is based on the presence of a NET or NEC in the liver and the absence of any clinical, endoscopic, or imaging evidence for another site of origin. 209 Prognosis is better compared with HCC, with 5-year OS rates of $80\%$ . 210 Surgery represents the cornerstone of PHNEN treatment. 211 , 212

Carcinosarcoma

Hepatic carcinosarcoma (HCS) is a very rare $(\ll1\,\%)$ PLC composed of carcinomatous (either hepatocellular or cholangiocellular) and sarcomatous components. The sarcomatous part shows morphological and immunohistochemical evidence of a speci fi c mesenchymal lineage. If the “ sarcomatous ” component is only showing a spindle cell morphology without speci fi c proven mesenchymal differentiation, the tumour should be referred to as sarcomatoid HCC or CCA. 213 HCS affects primarily adult males at a median age of 61 years. 1 , 214 Pre-operative diagnosis of HCS is dif fi cult, as imaging features are not speci fi c, and biopsies frequently result in misdiagnosis. 215 , 216 Moreover, sarcomatous differentiation has been described for HCC and CCA even after treatment, complicating this diagnosis. Surgery represents the only treatment available with a median OS of 6 months. 215

Liver squamous cell carcinoma

Primary squamous cell carcinoma of the liver is de fi ned by the presence of morphological evidence of squamous differentiation and immunohistochemical reactivity for K5/6, p63, p40, K14 and K56 that indicate keratinized squamous epithelial origin. 217 – 219 However, immunohistochemistry alone is not suf fi cient to make the diagnosis, and a metastatic origin has to be excluded carefully. When primary, squamous cell carcinomas arise from the biliary epithelium and affect males at a ratio of 19:16 and a median age of 67 years. 218 , 219 Although surgery is sometimes feasible, the median OS is typically less than 12 months. 218

Leiomyosarcoma

Primary leiomyosarcoma of the liver (LMS) originates from smooth muscle cells of intrahepatic vessels, bile ducts or the round ligament. 220 , 221 LMS arising from the inferior vena cava can be misleadingly considered as a primary of the liver. LMS can be observed in childhood and adulthood with a male-tofemale ratio of 1:1. 222 Diagnosis is performed at histology when atypical spindle cells with eosinophilic cytoplasm and blunt ended nuclei growing in a fascicular pattern are found and other hepatic/extrahepatic tumours with spindle cell morphology have been excluded. 1 , 223 By immunohistochemistry, smooth muscle differentiation is con fi rmed by smooth muscle actin and, less frequently, desmin expression. Surgery represents the only curative treatment with a median OS of 19 months. 224

Embryonal sarcoma

Embryonal sarcoma of the liver (ESL) is a primary malignant neoplasm unique to the liver observed mostly in children and rarely in adults. ESL presents as a large tumour composed of undifferentiated spindle or stellate cells and pleomorphic giant cells showing PAS-positive diastase-resistant inclusions. The immunophenotype is not speci fi c with varying expression of keratin. Cells are haphazardly distributed in a fi bromyxoid stroma. 1

Conclusion and unmet needs

This position paper emphasises that our understanding of the pathophysiology and management of rare PLCs is still limited, with a lack of robust evidence for clinical application. The poor prognosis associated with most of these rare PLCs underscores the importance of coordinating clinical care and research efforts to address the primary unmet needs in this fi eld. In terms of clinical management, a network of specialised clinicians, supported by multidisciplinary tumour boards dedicated to rare PLC, should be established at national or even international level ( e.g. ERN Rare-Liver). Expert pathologists should also be integrated into this network to ensure a standardised pathological and immunohistochemical approach for con fi rming the diagnosis of these rare tumours. Furthermore, it is essential to facilitate access to sequencing platforms capable of conducting genomic analyses to identify the key genetic mutations characteristic of these cancers (such as DNAJB1-PRKACA fusion, CAMTA1-WWTR1 fusion, etc.). This could prove invaluable in diagnosing challenging cases and searching for potentially targetable genetic alterations. Given the extremely low incidence of these cancers, international collaboration is imperative to facilitate the development of preclinical models, identify new therapeutic targets, establish retro- and prospective databases to better understand clinical behaviour, and create biobanks of serum, plasma, and tissue to identify new diagnostic, prognostic, and predictive biomarkers. Since most clinical trials testing new drugs in HCC or CCA typically exclude patients with rare PLCs, it is crucial to initiate dedicated phase II clinical trials on an international scale. This will ensure our ability to enrol enough patients for meaningful research outcomes. Lastly, fostering closer collaboration with patients and their families is essential to provide them with comprehensive information about their diseases and treatment options, as well as to involve them in the development of national networks and international research programmes.

Af fi liations

1 Cancer Center Esslingen, Klinikum Esslingen, D-73730 Esslingen, Germany; 2 Department of Gastroenterology and Hepatology, University Medical Center HamburgEppendorf, European Reference Network Hepatological Diseases (ERN RARE-LIVER), D-20246 Hamburg, Germany; 3 Department of Experimental and Clinical Medicine, Internal Medicine and Hepatology Unit, University of Firenze, Florence, Italy; 4 Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, F-75006, Paris, France; 5 Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, ERN RARE-LIVER, University of Groningen, Groningen, The Netherlands; 6 Department of Oncology, Royal Free Hospital and UCL Cancer Institute, University College London, London UK; 7 Liver Unit, Avicenne Hospital, AP-HP, ERN RARE-LIVER, Paris-Seine-Saint-Denis University, Bobigny, France; 8 Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States; 9 Barcelona Clinic Liver Cancer (BCLC) group. Institut d ’ Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; 10 Liver Oncology Unit, Liver Unit, Hospital Clinic de Barcelona, ERN RARE-LIVER, Barcelona, Spain; 11 Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain. Barcelona University, Barcelona, Spain; 12 Department of Radiology, University Hospital, LMU Munich, Munich, Germany; 13 Institute of Pathology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland; 14 Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072, Milan, Italy; Division of Hepatobiliary & General Surgery, Department of Surgery - IRCCS, Humanitas Research Hospital, ERN RARE-LIVER, via Manzoni 56, Rozzano, 20089, Milan, Italy; 15 Institut du Cancer Paris CARPEM, AP-HP, Department of Oncology, Hopital Européen Georges Pompidou, F-75015, Paris, France

Abbreviations

5-FU, 5- fl uorouracil; AS, angiosarcoma; BAP1, BRCA1 associated protein-1; CA19-9, carbohydrate antigen 19-9; cHCC-CCA, combined hepatocellularcholangiocarcinoma; CCA, cholangiocarcinoma; CT, computed tomography; CTNNB1, catenin beta 1; FGFR2, fi broblast growth factor receptor 2; FISH, fl uorescence in situ hybridization; HCA, hepatocellular adenoma; HCC, hepatocellular carcinoma; IDH1, isocitrate dehydrogenase 1; IFN, interferon; LT, liver transplantation; MRI, magnetic resonance imaging; ORR, objective response rate; OS, overall survival; PLC, primary liver cancer; PFS, progression-free survival; rIFN a 2b, recombinant interferon alfa-2b; TACE, trans arterial chemoembolization; TARE, transarterial radioembolization; TERT, telomerase reverse transcriptase.

Financial support

The authors did not receive any fi nancial support to produce this manuscript.

Con fl ict of interest

HW received consulting and lecture fees from Roche, AstraZeneca, Eisai, Bayer, Ipsen, Incyte, Lilly, MSD, and BMS. JCN received research grants from Bayer and Ipsen. MR served as a consultant or on advisory boards and/or received travel support from Bayer, BMS, Roche, Ipsen, AstraZeneca, Eisai, Geneos Therapeutics, UniveralDx, MSD and Lilly, received lecture fees from Bayer, BMS, Gilead, AstraZeneca, ROCHE and Lilly and Institutional research grants from Bayer and Ipsen. JR received consulting and lecture fees from Boston Scienti fi c, SIRTEX, Terumo. JR received research grants Boston Scieniti fi c, SIRTEX. CC, RDK, TM, TMP, CS, GT, JZR have no con fl ict of interest.

Please refer to the accompanying ICMJE disclosure forms for further details.

Authors ’ contributions

HW and JCN suggested experts for the panel, which was then approved by the EASL governing board. All panel members discussed the outline of the position paper and prepared speci fi c sections based on their medical and research speciality. CC compiled and arranged the manuscript. All authors conducted proofreading. Open questions and all statements were discussed in virtual conferences, and all authors approved the fi nal version of the manuscript.

Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/ j.jhep.2024.06.004 .

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