INTRODUCTION

Accurate non-invasive differentiation between hepatocellular carcinoma (HCC) and other primary liver malignancies is critical, as treatment strategies and prognoses diverge significantly.^1,2 While the majority of liver nodules in high-risk patients are HCC, the identification of intrahepatic cholangiocarcinoma (iCCA) and combined hepatocellular-cholangiocarcinoma (cHCC-CCA) remains a formidable diagnostic dilemma.³ Despite the wide adoption of standardized imaging criteria, such as the Liver Imaging Reporting and Data System (LI-RADS),⁴ the fact that these tumors often exist on a biologic and pathological continuum frequently blurs their radiologic distinction from HCC, challenging the high specificity required for non-invasive diagnosis.

This diagnostic ambiguity stems from the diverse histopathologic nature of primary liver cancers. Although most primary liver cancers manifest as either HCC, characterized by hepatocellular differentiation, or iCCA, characterized by biliary differentiation, these are not strictly dichotomous entities but rather exist along a biological spectrum. cHCC-CCA further complicates this landscape; as a primary liver cancer where HCC and iCCA histologic components intermingle within a single tumor, its imaging features have been reported to resemble either HCC or iCCA.^5,6 Moreover, iCCA itself is not a monolithic entity but comprises small-duct and large-duct types.^7,8 The small-duct type, in particular, often shares common etiologies with HCC, such as chronic liver disease and cirrhosis, and can exhibit hypervascularity on imaging, further challenging radiologic differentiation.

These diagnostic challenges carry significant clinical implications, as misidentifying iCCA or cHCC-CCA as HCC can lead to inappropriate management, such as locoregional ablation or liver transplantation.⁹ While some cases of cHCC-CCA or iCCA exhibit imaging features characteristic of the LI-RADS category M (LR-M) category or present with serological abnormalities that necessitate a biopsy, the procedure itself remains problematic. Biopsy does not always provide a definitive diagnosis due to profound intratumoral heterogeneity, which a limited tissue sample may fail to fully capture. Furthermore, a subset of cHCC-CCA and iCCA can manifest with imaging features virtually indistinguishable from HCC, leading to potential misclassification.¹⁰

Therefore, this review aims to navigate the diagnostic gray zone of primary liver cancers, exploring the radiologic-pathologic correlations of iCCA and cHCC-CCA, and discussing practical, multidisciplinary strategies to address these diagnostic dilemmas.

THE CONCEPT OF LI-RADS AND THE LR-M CATEGORY IN DIFFERENTIATION OF PRIMARY LIVER CANCERS

The LI-RADS framework is applied exclusively to patients at high risk for HCC, which includes those with cirrhosis of any etiology (except for congenital hepatic fibrosis) or chronic Hepatitis B virus infection even in the absence of cirrhosis.¹¹ In patients who do not meet these high-risk criteria, a definitive diagnosis of HCC cannot be established based on imaging features alone, even if the findings are otherwise characteristic of HCC; in such instances, pathologic confirmation is mandatory.

Within the LI-RADS system, the LR-M category denotes a high probability of malignancy that is not specific to HCC.^11,12 While it is primarily intended to capture iCCA and cHCC-CCA, it is important to note that certain aggressive HCC subtypes, such as keratin-19 positive, macrotrabecular-massive, or those with vessels encapsulating tumor clusters, as well as poorly differentiated HCCs, can also manifest with LR-M features.^13,14

LR-M imaging features are broadly categorized into targetoid and non-targetoid features. Targetoid features, such as rim arterial phase hyperenhancement (APHE), peripheral washout, delayed central enhancement, targetoid appearance in transitional phase or hepatobiliary phase (HBP), and targetoid restriction in diffusion-weighted images (DWI) are often seen in non-HCC malignancies. These findings reflect a specific pathologic architecture characterized by peripheral hypercellularity and arterialization in conjunction with central fibrosis or ischemia.¹¹ Any lesion exhibiting these targetoid features is automatically assigned to the LR-M category. Conversely, non-targetoid features (e.g., infiltrative appearance, marked restricted diffusion, and necrosis or severe ischemia) can also suggest an LR-M designation; however, if a lesion satisfies the strict criteria for LI-RADS category 5 (LR-5), which indicates definite HCC, the LR-5 classification takes precedence over non-targetoid LR-M features.¹¹ This hierarchical approach is designed to maintain the exceptionally high specificity required for the non-invasive diagnosis of HCC.

IMAGING FEATURES ACCORDING TO HISTOPATHOLOGIC SUBTYPES: IMPLICATIONS FOR HCC DIAGNOSIS

The 2019 World Health Organization (WHO) classification stratifies iCCA into two histopathologic subtypes: the large duct type and the small duct type.¹⁵ Understanding the distinction between large and small duct types is critical in the diagnostic process, as their differing pathological features lead to distinct imaging patterns that can significantly impact the differentiation from HCC.

Large duct type iCCA: targetoid features and LR-M categorization

The large duct type iCCA typically arises from the perihilar large bile ducts or their peribiliary glands and is often associated with chronic biliary diseases.^7,15 Pathologically, this subtype is characterized by a central desmoplastic stroma with relatively sparse tumor cells, surrounded by a peripheral rim of viable, densely packed cancer cells.⁸

Reflecting this histologic architecture, large duct type iCCA manifests the classic targetoid appearance on dynamic imaging.^7,8 On computed tomography (CT) or magnetic resonance imaging (MRI), it typically shows peripheral rim APHE corresponding to the cellular periphery, followed by progressive centripetal enhancement due to the slow wash-in of contrast media into the central fibrous stroma.^7,16,17 On DWI, a targetoid restriction pattern is frequently observed, characterized by severe diffusion restriction in the cellular periphery and relatively less restriction in the central fibrotic area.^7,18 Furthermore, on the HBP of gadoxetic acid (Gd-EOB-DTPA) enhanced MRI, the tumor exhibits an EOB-cloud appearance (central hyperintensity surrounded by a hypointense rim), reflecting contrast retention in the central fibrous stroma (Fig. 1).^19-21 Another characteristic imaging feature of large duct type iCCA is bile ductal involvement. Since large duct type iCCA typically originates within the grossly visible large bile ducts, the tumor often encases the duct of origin. This ductal involvement typically results in upstream bile duct dilatation at the tumor's periphery and leads to a mixed morphology, combining mass-forming and periductal-infiltrating growth patterns.^8,22 Given the common LR-M features and bile ductal involvement, large duct type iCCA is generally distinguishable from HCC, facilitating appropriate triage for biopsy.

Small duct type iCCA: a confounder reducing the specificity of HCC diagnosis

In contrast, small duct type iCCA arises from relatively small bile ducts located peripheral to the second confluence or from bile ductules (canals of Hering), and shares key risk factors with HCC, such as chronic viral hepatitis and liver cirrhosis.^8,22 Grossly, the small duct type exhibits a purely mass-forming growth pattern; pathologically, it is characterized by high cellularity and preserved vascularity, notably lacking the prominent central fibrous stroma seen in the large duct type.^8,23

These histologic characteristics can result in an imaging phenotype that closely mimics HCC (Fig. 2).^8,24,25 Due to high cellularity and the absence of central fibrosis, small duct type iCCA frequently displays non-rim APHE rather than rim APHE.^8,22 Moreover, several studies have indicated that a subset of these tumors can exhibit a washout appearance in the portal venous or delayed phases.^16,24 On gadoxetic acid-enhanced MRI, HBP images typically show homogeneous hypointensity due to the absence of organic anion transporting polypeptide (OATP) 1B1/3 transporter expression, a feature also shared by the majority of HCCs.^16,26

This mimicry poses a significant challenge to the non-invasive diagnosis of HCC. As highlighted in a recent review, while the non-peripheral washout feature is critical for distinguishing malignancy from benign lesions, its specificity is reduced when distinguishing HCC from hypervascular non-HCC malignancies, such as small duct iCCA.²⁷ In addition, because small duct type iCCA is frequently associated with chronic liver disease and cirrhosis, it is often subject to LI-RADS application. Consequently, a nodule showing non-rim APHE and washout may technically meet the LR-5 criteria (definitely HCC), yet the possibility of small duct iCCA remains, potentially reducing diagnostic specificity.^8,15,28

Potential clues to differentiation between iCCA and HCC

Despite the overlap in vascular patterns, careful evaluation of ancillary features may provide clues to the biliary origin. Capsular retraction, caused by intratumoral fibrosis pulling on the liver capsule, is a highly specific sign favoring iCCA over HCC, although it is more frequent in the large duct type.^7,25 Signs of ductal involvement, such as peritumoral bile duct dilatation disproportionate to the tumor size, also suggest large duct type iCCA. However, ductal involvement is less common in small duct type iCCA; therefore, the sensitivity of this sign is lower in the small duct subtype.^7,8 Additionally, the presence of satellite nodules or multifocality is common in iCCA, though it can also be seen in aggressive HCCs.¹⁸ While not definitive, some studies suggest that iCCA may show more uniform and stronger diffusion restriction compared to HCC, or retain a targetoid appearance even when enhancement patterns mimic HCC.¹⁸ However, it is crucial to acknowledge that a small proportion of iCCAs, especially small lesions in a cirrhotic liver, can manifest the diagnostic hallmarks of HCC (non-rim APHE and non-peripheral washout) without these ancillary features. Thus, reliable differentiation based solely on imaging is limited in such cases.^8,22,29 This limitation underscores the importance of integrating clinical contexts and maintaining a low threshold for biopsy in equivocal cases (Table 1).

THE DIAGNOSTIC DILEMMA: cHCC-CCA

According to the 2019 WHO classification, cHCC-CCA represents the unequivocal presence of both HCC and iCCA components within a single tumor.^15,30 The relative proportions of HCC and CCA components can vary significantly, and the imaging manifestations of cHCC-CCA are also remarkably diverse. Consequently, this tumor poses a formidable challenge for imaging differentiation from its pure counterparts.

Imaging spectrum reflecting histologic dominance

The imaging appearance of cHCC-CCA typically reflects its histological composition and the spatial distribution of its components within the tumor.^5,6 Specifically, cHCC-CCAs with a predominant HCC component commonly manifest with imaging findings that mimic HCC, such as non-rim APHE and non-peripheral washout.^6,31 Conversely, those with a predominant iCCA component typically exhibit features characteristic of iCCA, often fulfilling the LR-M criteria. In some instances, the imaging manifestations of cHCC-CCA present as a mixture of both entities, reflecting the intermingled histologic components.

The most clinically problematic cases are HCC-dominant cHCC-CCAs, which frequently present with imaging features similar to HCC. If the possibility of a combined tumor is not suspected based on other clinical features, such as the absence of liver cirrhosis or discordant tumor markers, these patients may be misdiagnosed with HCC and undergo treatments like locoregional ablation or liver transplantation. However, such management may be oncologically inadequate for the more aggressive CCA component.⁹ Conversely, when the CCA component predominates or features of both components are distinct, the tumor may show rim APHE, progressive central enhancement, or mixed vascular patterns, often leading to categorization as LR-M.^5,32

Limitation of biopsy due to intratumoral heterogeneity

The histopathologic confirmation remains the gold standard for the diagnosis of cHCC-CCA. However, surgical resection, which provides the entire specimen for evaluation, is often not feasible in patients with advanced disease or poor underlying liver function. In such cases, histopathologic diagnosis must rely on core needle biopsy. However, the inherent intratumoral heterogeneity and sampling limitations of core needle biopsy impose significant structural constraints on its diagnostic accuracy.^10,33 Due to limited sampling, a core needle biopsy sample often fails to capture the minor histologic components of cHCC-CCA. If the needle samples only the HCC-like area, the diagnosis will be limited to HCC; conversely, if it targets the CCA component, the lesion may be diagnosed as iCCA. This sampling error is not merely a technical failure but an inherent risk of diagnosing a heterogeneous tumor with limited tissue, often leading to misclassification as a single entity (HCC or iCCA) rather than the true combined tumor (Fig. 3).⁵

Targetoid features as a prognostic biomarker

Recent evidence suggests that the imaging phenotype, specifically the presence of targetoid or LR-M features, serves as a crucial prognostic biomarker across primary liver malignancies, transcending the dichotomous histologic diagnosis. In the context of cHCC-CCA, tumors exhibiting an HCC-like imaging pattern (non-rim APHE) tend to have better survival outcomes compared to those with an iCCA-like or targetoid pattern (rim APHE, progressive enhancement).^32,34 This prognostic trend aligns with observations in iCCA, where the small duct type (often displaying HCC-like vascularity) generally shows a more favorable prognosis than the large duct type (typical targetoid appearance).^22,35 Furthermore, this concept extends to HCC as well; HCCs that exhibit LR-M features, such as rim APHE or targetoid restriction on diffusion-weighted imaging, are associated with more aggressive histologic subtypes, higher recurrence rates, and poorer overall survival compared to typical HCCs.^13,35-38 Thus, the presence of targetoid imaging features serves as a universal marker of biological aggressiveness, necessitating a more cautious therapeutic approach regardless of the specific tumor type.

PRACTICAL CHALLENGES AND MULTIDISCIPLINARY STRATEGIES IN THE REAL WORLD

Given the complex imaging spectrum of primary liver cancers discussed above, discordance between imaging appearance, tumor markers, and pathologic results is not uncommon. This section outlines practical considerations for navigating these diagnostic dilemmas.

Navigating diagnostic discordance: imaging vs. tumor markers

When the imaging diagnosis does not align with the serological profile, it serves as a critical checkpoint in the diagnostic workflow.

First, if a nodule exhibits a typical HCC pattern (LI-RADS LR-5) but is accompanied by a clinically suspicious tumor marker profile (e.g., significant elevation of carbohydrate antigen 19-9 [CA19-9] with normal alpha-fetoprotein [AFP]), the diagnosis of definite HCC warrants reconsideration. While mild elevation of CA19-9 can be non-specific, a discordant profile may suggest the presence of a biliary component, such as in small duct type iCCA or cHCC-CCA with an HCC-predominant pattern.³⁹ In such cases, despite the imaging fulfillment of LR-5 criteria, proceeding directly to local treatment without histologic confirmation carries a risk of inadequate management; thus, a multidisciplinary discussion is essential.

Conversely, if a tumor presents with LR-M features (e.g., targetoid appearance) favoring iCCA but is associated with significantly elevated AFP levels, the possibility of cHCC-CCA or atypical HCC (e.g., poorly differentiated or scirrhous type) should be considered over pure iCCA.⁴⁰

However, it is noteworthy that a simultaneous evaluation of tumor markers for both HCC and iCCA is not always feasible in clinical practice. Typically, for patients suspected of having HCC, AFP and protein induced by vitamin K absence or antagonist-II (PIVKA-II) are prioritized, whereas CA19-9 and carcinoembryonic antigen (CEA) are commonly evaluated in those suspected of having iCCA. In certain regions, such as South Korea, the number of tumor markers covered by national health insurance is strictly regulated. Consequently, the selection of biomarkers is often determined based on the initial imaging impression, which can lead to incomplete serological profiling if the imaging phenotype is misleading.

Regional lymphadenopathy: a helpful but limited clue

The status of regional lymph nodes can serve as an ancillary clue when the primary tumor's features are equivocal. Since lymph node metastasis is not common in HCC at the time of diagnosis, the presence of regional lymphadenopathy in the setting of a liver mass may shift the differential diagnosis toward iCCA or cHCC-CCA.^40,41 Furthermore, the identification of lymphadenopathy on preoperative imaging has practical implications beyond diagnosis. It influences surgical planning regarding the necessity of lymph node dissection, which is often considered for iCCA or cHCC-CCA but is not standard for HCC.

However, this finding must be interpreted with caution. In patients with chronic viral hepatitis or liver cirrhosis, reactive lymphoid hyperplasia is frequently observed and can mimic metastatic adenopathy on CT or MRI.⁴² Therefore, while lymphadenopathy can support a diagnosis of non-HCC malignancy, it is not definitive evidence. Conversely, the absence of lymphadenopathy does not rule out iCCA or cHCC-CCA, particularly in early-stage disease or small duct type tumors.

The reality of biopsy: modality differences and sampling limitations

While core needle biopsy is often the next step for lesions categorized as LR-M, the procedure has significant practical limitations. Although B-mode ultrasound is the most common imaging guidance for core needle biopsy, this modality has a substantial limitation in visualizing intratumoral heterogeneity. Intratumoral heterogeneity, which commonly manifests as a targetoid appearance or specific hypervascular areas on CT or MRI, and diffusion restriction or T2 signal intensity differences on MRI, is often indistinguishable on B-mode ultrasound.

This lack of visibility can hinder the targeted sampling of specific tumor components, potentially leading to sampling errors, for instance, missing the HCC component in a mixed tumor.^5,9 In cases with heterogeneous enhancement patterns, the use of contrast-enhanced ultrasound (CEUS) might be helpful. A recent study demonstrated that the use of CEUS in treated HCC increased the conspicuity of viable portions and showed higher biopsy success rates.⁴³

Increasing the number of tumor cores obtained from different areas of the tumor may theoretically increase diagnostic yield. However, this approach must be balanced against the increased risk of complications, such as bleeding.⁴⁴ Therefore, the decision to perform a biopsy should be made based on careful risk-benefit assessment.

If the biopsy result is discordant with the imaging phenotype and clinical markers, the possibility that the sample does not represent the entire tumor should be acknowledged, and clinical decision- making should rely on an integrated interpretation of radiologic, serologic, and pathologic findings.

FUTURE DIRECTIONS: RADIOMICS AND ARTIFICIAL INTELLIGENCE

While visual assessment by radiologists combined with a multidisciplinary team approach remains the standard clinical practice for non-invasive evaluation, it is inherently subjective and may not fully capture the complex intratumoral heterogeneity of combined tumors. To bridge this gap, recent research has explored the potential of radiomics and artificial intelligence as objective diagnostic aids. Several retrospective studies have demonstrated that machine learning algorithms and radiomics signatures extracted from contrast-enhanced CT, MRI, or ultrasound can differentiate cHCC-CCA from HCC or iCCA with promising accuracy.^45-47 Furthermore, integrated models, such as radiomics nomograms, that combine quantitative imaging features with clinical data (e.g., tumor markers) have shown improved diagnostic performance, aligning with the clinical necessity of a multimodal approach.⁴⁸ However, the clinical applicability of these technologies remains limited. Current evidence is predominantly derived from single-center, retrospective cohorts in specific geographic regions, raising concerns regarding the generalizability of these models to diverse populations with different liver disease etiologies. Therefore, rigorous external validation, algorithm interpretability, and data standardization are essential prerequisites before these advanced analytical tools can be adopted into routine clinical workflows.

CONCLUSION

The differentiation of iCCA, HCC, and cHCC-CCA remains a formidable challenge due to the overlapping imaging features and shared risk factors. However, recognizing the nuances of histopathologic subtypes and the continuous imaging spectrum of combined tumors allows for a more refined diagnostic approach. Importantly, the imaging phenotype, particularly the presence of targetoid features, serves as a valuable biomarker for biological aggressiveness and prognosis across these entities. Ultimately, optimal patient management requires an integrated, multidisciplinary approach that synthesizes imaging findings, tumor markers, and clinical context, rather than relying on a single modality.

Article information

Conflicts of Interest

Hyungjin Rhee and Jaeseung Shin are editorial board members of Journal of Liver Cancer, and were not involved in the review process of this article. Otherwise, the authors have no conflicts of interest to disclose.

Ethics Statement

This review article is fully based on articles which have already been published and did not involve additional patient participants. Therefore, IRB approval is not necessary.

Funding Statement

This work was supported by a grant from National Research Foundation of Korea (NRF), funded by the Korea government (MSIT) (No. RS-2023-00208307, RS-2025-00516874).

Data Availability

Not applicable.

Author Contributions

Conceptualization: JS, HR

Data curation: TC, SYH, HR

Funding acquisition: JS

Methodology: JS, TC

Writing - original draft: JS, HR

Writing - review & editing: JS, TC, SYH, HR

Figure 1.

Large duct type intrahepatic cholangiocarcinoma in a 72-year-old male. (A-D) Multiphase CT images (pre-contrast, arterial, portal venous, and delayed phases) and (E-H) gadoteric acid-enhanced MRI images (pre-contrast, arterial, portal venous, and delayed phases) demonstrate a mass with typical imaging features of large duct type iCCA. On (B, F) the arterial phase, the tumor shows peripheral rim hyperenhancement, followed by (C, G) progressive centripetal enhancement on the subsequent venous and (G, H) delayed/transitional phases. (I) Diffusion-weighted imaging (b=800 s/mm²) displays targetoid restriction. (J) Axial and (K) coronal T2-weighted images show peritumoral bile duct dilatation, which can serve as an ancillary clue for large duct type iCCA. After surgical resection, the tumor histology reveals (L) large glands consisting of tall columnar cells on hematoxylin-eosin staining (original magnification, ×200), (M) positivity for intracellular mucin on mucicarmine stain (original magnification, ×200), and (N) positive expression of S100P, and negative expression of N-cadherin and CD56 (not shown), suggesting large duct (original magnification, ×200). CT, computed tomography; MRI, magnetic resonance imaging; iCCA, intrahepatic cholangiocarcinoma.

Figure 2.

Small duct type intrahepatic cholangiocarcinoma in a 68-year-old male. (A-D) Multiphase CT images (pre-contrast, arterial, portal venous, and delayed phases) and (E-I) gadoxetic acid-enhanced MRI images (pre-contrast, arterial, portal venous, transitional, and hepatobiliary phases) reveal a mass-forming tumor. While small duct type iCCA often mimics hepatocellular carcinoma (HCC) with global non-rim hyperenhancement, this case demonstrates a subtle targetoid appearance on the arterial phase (B, F) and heterogeneous, prolonged enhancement with partial washout on (D, H) the delayed/transitional phases, as well as (I) subtle hypointensity in the hepatobiliary phase. (J) Diffusion- weighted imaging (b=800 s/mm²) and (K) T2-weighted images show targetoid appearance. Mild capsular retraction is also observed. Following surgical resection, the tumor histology reveals (L) small glands consisting of cuboidal cells on hematoxylin-eosin staining (original magnification, ×200) and (M) positivity for C-reactive protein; these findings, along with negativity for S100P and intracellular mucin on mucicarmine stain (not shown), are consistent with the small duct type. CT, computed tomography; MRI, magnetic resonance imaging.

Figure 3.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) in a 55-year-old male with chronic hepatitis B. (A-D) Multiphase CT images (pre-contrast, arterial, portal venous, and delayed phases) demonstrate a predominantly hypovascular mass with suspected nodular arterial phase hyperenhancement at periphery (B). The tumor is accompanied by left portal vein thrombosis, categorized as LR-TIV, and partial involvement of the left intrahepatic bile duct (C, D). (E-I) Gadoxetic acid-enhanced MRI images (pre-contrast, arterial, portal venous, transitional, and hepatobiliary phases) show a mostly hypovascular tumor with thin peripheral rim arterial phase hyperenhancement (F). (J) Diffusion- weighted imaging (b=800 s/mm²) displays diffusion restriction without a distinct targetoid appearance, and (K) T2-weighted imaging illustrates the heterogeneous tumor architecture. Given the atypical imaging features, an initial core needle biopsy was performed. (L) Hematoxylin- eosin staining of the biopsy specimen reveals distinct hepatocellular carcinoma (HCC) features (*Edmondson grade II) alongside focal bile duct differentiation (†), raising the possibility of a combined tumor. (M) Following surgical resection, hematoxylin-eosin staining of the surgical specimen definitively confirms a cholangiocarcinoma-predominant cHCC-CCA. Both the HCC component (*) and the cholangiocarcinoma component (†poorly differentiated adenocarcinoma) are clearly visible side-by-side. A marked sarcomatoid carcinoma component was also present (not shown). CT, computed tomography; LR-TIV, Liver Imaging Reporting and Data System tumor in vein; MRI, magnetic resonance imaging.

References

• 1. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of hepatocellular carcinoma. J Hepatol 2025;82:315−374.ArticlePubMed
• 2. Korean Liver Cancer Association (KLCA), National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. J Liver Cancer 2023;23:1−120.ArticlePubMedPMCPDF
• 3. Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020;17:557−588.ArticlePubMedPMCPDF
• 4. Chernyak V, Fowler KJ, Kamaya A, Kielar AZ, Elsayes KM, Bashir MR, et al. Liver imaging reporting and data system (LI-RADS) version 2018: imaging of hepatocellular carcinoma in at-risk patients. Radiology 2018;289:816−830.ArticlePubMedPMC
• 5. Majeed NF, Macey M, Amirfarzan MB, Sharifi S, Wortman JR. MRI features of combined hepatocellular-cholangiocarcinoma. Abdom Radiol (NY) 2025;50:169−184.ArticlePubMedPDF
• 6. Shen YT, Yue WW, Xu HX. Non-invasive imaging in the diagnosis of combined hepatocellular carcinoma and cholangiocarcinoma. Abdom Radiol (NY) 2023;48:2019−2037.ArticlePubMedPDF
• 7. Joo I, Lee JM, Yoon JH. Imaging diagnosis of intrahepatic and perihilar cholangiocarcinoma: recent advances and challenges. Radiology 2018;288:7−13.ArticlePubMed
• 8. Rhee H, Kim MJ, Park YN, An C. A proposal of imaging classification of intrahepatic mass-forming cholangiocarcinoma into ductal and parenchymal types: clinicopathologic significance. Eur Radiol 2019;29:3111−3121.ArticlePubMedPDF
• 9. Fowler KJ, Sheybani A, Parker RA 3rd, Doherty S, Brunt EM, Chapman WC, et al. Combined hepatocellular and cholangiocarcinoma (biphenotypic) tumors: imaging features and diagnostic accuracy of contrast-enhanced CT and MRI. AJR Am J Roentgenol 2013;201:332−339.ArticlePubMed
• 10. Gigante E, Ronot M, Bertin C, Ciolina M, Bouattour M, Dondero F, et al. Combining imaging and tumour biopsy improves the diagnosis of combined hepatocellular-cholangiocarcinoma. Liver Int 2019;39:2386−2396.ArticlePubMedPDF
• 11. American College of Radiology. LI-RADS® CT/MRI v2018 core [Internet]. Reston (US): American College of Radiology; [cited 2026 Jan 31]. Available from: https://edge.sitecorecloud.io/americancoldf5f-acrorgf92a-productioncb02-3650/media/ACR/Files/RADS/LI-RADS/LI-RADSCT-MRI-2018-Core.pdf
• 12. Lee S, Kim YY, Shin J, Son WJ, Roh YH, Choi JY, et al. Percentages of hepatocellular carcinoma in LI-RADS categories with CT and MRI: a systematic review and meta-analysis. Radiology 2023;307:e220646.ArticlePubMed
• 13. Hwang SH, Rhee H. Radiologic features of hepatocellular carcinoma related to prognosis. J Liver Cancer 2023;23:143−156.ArticlePubMedPMCPDF
• 14. Loy LM, Low HM, Choi JY, Rhee H, Wong CF, Tan CH. Variant hepatocellular carcinoma subtypes according to the 2019 WHO classification: an imaging-focused review. AJR Am J Roentgenol 2022;219:212−223.ArticlePubMed
• 15. World Health Organization (WHO) Classification of Tumours Editorial Board. Digestive tumours. Edited by WHO Classification of Tumours Editorial Board: WHO classification of tumours. 5th ed. Lyon, IARC Publications. 2019.
• 16. Kim R, Lee JM, Shin CI, Lee ES, Yoon JH, Joo I, et al. Differentiation of intrahepatic mass-forming cholangiocarcinoma from hepatocellular carcinoma on gadoxetic acid-enhanced liver MR imaging. Eur Radiol 2016;26:1808−1817.ArticlePubMedPDF
• 17. Rimola J, Forner A, Reig M, Vilana R, de Lope CR, Ayuso C, et al. Cholangiocarcinoma in cirrhosis: absence of contrast washout in delayed phases by magnetic resonance imaging avoids misdiagnosis of hepatocellular carcinoma. Hepatology 2009;50:791−798.ArticlePubMed
• 18. Park HJ, Kim YK, Park MJ, Lee WJ. Small intrahepatic mass-forming cholangiocarcinoma: target sign on diffusion-weighted imaging for differentiation from hepatocellular carcinoma. Abdom Imaging 2013;38:793−801.ArticlePubMedPDF
• 19. Joo I, Lee JM, Lee DH, Jeon JH, Han JK, Choi BI. Noninvasive diagnosis of hepatocellular carcinoma on gadoxetic acid-enhanced MRI: can hypointensity on the hepatobiliary phase be used as an alternative to washout? Eur Radiol 2015;25:2859−2868.ArticlePubMedPDF
• 20. Jeong HT, Kim MJ, Chung YE, Choi JY, Park YN, Kim KW. Gadoxetate disodium-enhanced MRI of mass-forming intrahepatic cholangiocarcinomas: imaging-histologic correlation. AJR Am J Roentgenol 2013;201:W603−W611.ArticlePubMed
• 21. Teo T, Chawla A. The cloud sign of mass-forming intrahepatic cholangiocarcinoma. Abdom Radiol (NY) 2020;45:237−238.ArticlePubMedPDF
• 22. Park S, Lee Y, Kim H, Yu MH, Lee ES, Yoon JH, et al. Subtype classification of intrahepatic cholangiocarcinoma using liver MR imaging features and its prognostic value. Liver Cancer 2022;11:233−246.ArticlePubMedPMCPDF
• 23. Ariizumi S, Kotera Y, Takahashi Y, Katagiri S, Chen IP, Ota T, et al. Mass-forming intrahepatic cholangiocarcinoma with marked enhancement on arterial-phase computed tomography reflects favorable surgical outcomes. J Surg Oncol 2011;104:130−139.ArticlePubMed
• 24. Iavarone M, Piscaglia F, Vavassori S, Galassi M, Sangiovanni A, Venerandi L, et al. Contrast enhanced CT-scan to diagnose intrahepatic cholangiocarcinoma in patients with cirrhosis. J Hepatol 2013;58:1188−1193.ArticlePubMed
• 25. Kim SA, Lee JM, Lee KB, Kim SH, Yoon SH, Han JK, et al. Intrahepatic mass-forming cholangiocarcinomas: enhancement patterns at multiphasic CT, with special emphasis on arterial enhancement pattern - correlation with clinicopathologic findings. Radiology 2011;260:148−157.ArticlePubMed
• 26. Min JH, Kim YK, Choi SY, Kang TW, Lee SJ, Kim JM, et al. Intrahepatic mass-forming cholangiocarcinoma: arterial enhancement patterns at MRI and prognosis. Radiology 2019;290:691−699.ArticlePubMed
• 27. Joo I. Preventing false positive imaging diagnosis of HCC: differentiating HCC from mimickers and practical strategies. J Liver Cancer 2025;25:217−232.ArticlePubMedPMCPDF
• 28. Shin J, Lee S, Yoon JK, Chung YE, Choi JY, Park MS. LI-RADS major features on MRI for diagnosing hepatocellular carcinoma: a systematic review and meta-analysis. J Magn Reson Imaging 2021;54:518−525.PubMed
• 29. Huang B, Wu L, Lu XY, Xu F, Liu CF, Shen WF, et al. Small intrahepatic cholangiocarcinoma and hepatocellular carcinoma in cirrhotic livers may share similar enhancement patterns at multiphase dynamic MR imaging. Radiology 2016;281:150−157.ArticlePubMed
• 30. Brunt E, Aishima S, Clavien PA, Fowler K, Goodman Z, Gores G, et al. cHCC-CCA: consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation. Hepatology 2018;68:113−126.PubMedPMC
• 31. Potretzke TA, Tan BR, Doyle MB, Brunt EM, Heiken JP, Fowler KJ. Imaging features of biphenotypic primary liver carcinoma (hepatocholangiocarcinoma) and the potential to mimic hepatocellular carcinoma: LI-RADS analysis of CT and MRI features in 61 cases. AJR Am J Roentgenol 2016;207:25−31.ArticlePubMed
• 32. Jeon SK, Joo I, Lee DH, Lee SM, Kang HJ, Lee KB, et al. Combined hepatocellular cholangiocarcinoma: LI-RADS v2017 categorisation for differential diagnosis and prognostication on gadoxetic acid-enhanced MR imaging. Eur Radiol 2019;29:373−382.ArticlePubMedPDF
• 33. Kim TH, Kim H, Joo I, Lee JM. Combined hepatocellular-cholangiocarcinoma: changes in the 2019 World Health Organization histological classification system and potential impact on imaging-based diagnosis. Korean J Radiol 2020;21:1115−1125.ArticlePubMedPMCPDF
• 34. Zhou C, Wang Y, Ma L, Qian X, Yang C, Zeng M. Combined hepatocellular carcinoma-cholangiocarcinoma: MRI features correlated with tumor biomarkers and prognosis. Eur Radiol 2022;32:78−88.ArticlePubMedPDF
• 35. Kim YY, Yeom SK, Shin H, Choi SH, Rhee H, Park JH, et al. Clinical staging of mass-forming intrahepatic cholangiocarcinoma: computed tomography versus magnetic resonance imaging. Hepatol Commun 2021;5:2009−2018.ArticlePubMedPMCPDF
• 36. Choi SH, Lee SS, Park SH, Kim KM, Yu E, Park Y, et al. LI-RADS classification and prognosis of primary liver cancers at gadoxetic acid-enhanced MRI. Radiology 2019;290:388−397.ArticlePubMed
• 37. Rhee H, An C, Kim HY, Yoo JE, Park YN, Kim MJ. Hepatocellular carcinoma with irregular rim-like arterial phase hyperenhancement: more aggressive pathologic features. Liver Cancer 2019;8:24−40.ArticlePubMedPMCPDF
• 38. Shin J, Lee S, Kim SS, Chung YE, Choi JY, Park MS, et al. Characteristics and early recurrence of hepatocellular carcinomas categorized as LR-M: comparison with those categorized as LR-4 or 5. J Magn Reson Imaging 2021;54:1446−1454.PubMed
• 39. Kassahun WT, Hauss J. Management of combined hepatocellular and cholangiocarcinoma. Int J Clin Pract 2008;62:1271−1278.ArticlePubMed
• 40. Rhee H, Park JH, Park YN. Update on pathologic and radiologic diagnosis of combined hepatocellular-cholangiocarcinoma. J Liver Cancer 2021;21:12−24.ArticlePubMedPMCPDF
• 41. Ye L, Schneider JS, Ben Khaled N, Schirmacher P, Seifert C, Frey L, et al. Combined hepatocellular-cholangiocarcinoma: biology, diagnosis, and management. Liver Cancer 2023;13:6−28.ArticlePubMedPMCPDF
• 42. Kang JG, Chung T, Kim DK, Rhee H. Imaging findings of intrahepatic cholangiocarcinoma for prognosis prediction and treatment decision-making: a narrative review. Ewha Med J 2024;47:e66.ArticlePubMedPMCPDF
• 43. Yoo J, Lee DH. Usefulness of contrast-enhanced ultrasound-guided biopsy for suspected viable hepatocellular carcinoma after treatment: a single-arm prospective study. Ultrasonography 2024;43:88−97.ArticlePubMedPMCPDF
• 44. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD; American Association for the Study of Liver Diseases. Liver biopsy. Hepatology 2009;49:1017−1044.ArticlePubMed
• 45. Deng X, Liao Z. A machine-learning model based on dynamic contrast-enhanced MRI for preoperative differentiation between hepatocellular carcinoma and combined hepatocellular-cholangiocarcinoma. Clin Radiol 2024;79:e817−e825.ArticlePubMed
• 46. Liu X, Khalvati F, Namdar K, Fischer S, Lewis S, Taouli B, et al. Can machine learning radiomics provide pre-operative differentiation of combined hepatocellular cholangiocarcinoma from hepatocellular carcinoma and cholangiocarcinoma to inform optimal treatment planning? Eur Radiol 2021;31:244−255.ArticlePubMedPDF
• 47. Xiao Y, Huang P, Zhang Y, Lu X, Zhou C, Wu F, et al. Component prediction in combined hepatocellular carcinoma-cholangiocarcinoma: habitat imaging and its biologic underpinnings. Abdom Radiol (NY) 2024;49:1063−1073.ArticlePubMedPDF
• 48. Zhou Y, Zhou G, Zhang J, Xu C, Zhu F, Xu P. DCE-MRI based radiomics nomogram for preoperatively differentiating combined hepatocellular-cholangiocarcinoma from mass-forming intrahepatic cholangiocarcinoma. Eur Radiol 2022;32:5004−5015.ArticlePubMedPDF

Figure & Data

References

Citations

Citations to this article as recorded by