Hepatocellular carcinoma with extensive fatty change: a case description

Introduction

Hepatocellular carcinoma (HCC) with fatty change, has traditionally been associated with small, well-differentiated tumors (1). It is hypothesized to arise from ischemic stress during the transition from portal-to-arterial vascular supply in early carcinogenesis (2,3). However, emerging evidence challenges this notion, with sporadic reports of large HCCs retaining diffuse fatty features (4,5). This case report aims to describe a large HCC located in the perihepatic space with extensive fatty change, of which its imaging features closely mimic liposarcoma. This case highlights two critical gaps in the current diagnostic frameworks for HCC. First, there is an overreliance on cirrhotic backgrounds, which can lead to underdiagnosis, as up to 13% of HCCs occur in non-cirrhotic livers, which are frequently associated with metabolic dysfunction-associated steatotic liver disease (MASLD) (6-8). Second, the integration of molecular pathology, which is essential for distinguishing HCC from other mimicking lesions, is frequently delayed due to reliance on ambiguous imaging findings. Such delays not only prolong the diagnostic process but also hinder the timely development of appropriate therapeutic strategies. By presenting the diagnostic process and treatment response, we hope to broaden the understanding of the HCC phenotype with significant steatosis and highlight the importance of integrating imaging findings with serum biomarkers and histopathological evaluation, particularly in patients without cirrhosis or with atypical imaging features.

Case presentation

A 65-year-old Chinese male with no prior history of cirrhosis, hepatitis, tuberculosis, or metabolic disorders presented to West China Hospital for evaluation of facial paralysis. During preoperative screening two months earlier, an abdominal computed tomography (CT) scan incidentally identified a heterogeneous low-attenuation lesion (Hounsfield units: −50 to −120) in the right perihepatic space, predominantly composed of adipose tissue. The patient denied smoking, alcohol consumption, or a family history of malignancies. Serologic testing confirmed prior hepatitis B vaccination [anti-hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antibody (HBcAb) positive], with normal liver function tests.

Laboratory analysis demonstrated elevated serum biomarkers, including protein induced by vitamin K absence-II (PIVKA-II) at 350 mAU/mL (normal: 6–32.5 mAU/mL) and alpha-fetoprotein (AFP) at 13.20 ng/mL (normal: <7 ng/mL). Carcinoembryonic antigen, carbohydrate antigen 19-9 (CA19-9), and Carbohydrate antigen 125 (CA125) levels were within normal limits.

Imaging studies revealed multifocal fat-containing lesions. Ultrasonography identified circumferential perihepatic adipose thickening, with a maximum thickness of 2.2 cm. Non-contrast CT demonstrated a 12.2 cm × 1.5 cm irregular, well-demarcated, patchy low-density mass in the right perihepatic space, accompanied by smaller nodular lesions in the perisplenic region, parietal peritoneum, and mesentery. Dynamic contrast-enhanced CT demonstrated mild arterial-phase enhancement (20–30 HU increase) and portal-phase contrast retention without wash-out (Figure 1). Magnetic resonance imaging (MRI) confirmed mixed high signal intensity on T1-weighted in-phase and T2-weighted sequences, with signal dropout on T1-weighted out-of-phase imaging, consistent with macroscopic fat (Figure 2).

Figure 1 Dynamic contrast-enhanced abdominal CT findings. (A) Non-contrast axial image demonstrates an irregular heterogeneous low-attenuation mass in the right perihepatic space (red arrow). (B) Arterial-phase axial image reveals mild enhancement of intralesional solid components. (C) Portal venous-phase axial image shows persistent contrast retention without wash-out. (D) Coronal reconstruction delineates the craniocaudal extent of the primary tumor (red arrow). Additional metastatic deposits (yellow arrows) are observed in the perisplenic region (A), parietal peritoneum (E) and mesentery (F), displaying similar fat-containing morphology. CT, computed tomography.

Figure 2 MRI characteristics of the tumor (red arrows). (A) Axial T1-weighted in-phase image demonstrates a heterogeneously hyperintense mass in the right perihepatic space. (B) Axial T1-weighted out-of-phase image reveals marked signal dropout, consistent with intralesional macroscopic fat content. (C) Coronal T2-weighted image shows mixed hyperintensity with hypointense septations. MRI, magnetic resonance imaging.

Initial differential diagnoses included liposarcoma, primarily due to the adipose predominance of the lesion. Laparoscopic exploration and biopsy were performed to obtain a definitive diagnosis. During the procedure, yellow, “cloud-shaped” lesions were observed, protruding from the surface in the diaphragmatic roof, round ligament, anterior abdominal wall, lateral abdominal wall, and pelvic cavity. The lesions were densely clustered on the right diaphragmatic roof, with scattered smaller lesions elsewhere, ranging in size from 0.2 to 3.0 cm. Some lesions exhibited a granular appearance, were irregular in shape, showed infiltrative characteristics, and were susceptible to hemorrhage upon palpation. Histopathological analysis revealed lipid-rich monocytes, proliferative lipoblasts, and numerous histocytes. Immunohistochemistry (IHC) confirmed hepatocellular differentiation (CK8/18⁺, HepPar-1⁺, Arg⁺, GS⁺, HSP70⁺) and excluded liposarcoma [MDM2/CDK4 fluorescence in situ hybridization (FISH)-negative]. The Ki-67 proliferation index was 30%, suggesting aggressive biology (Figure 3).

Figure 3 Histopathological and partial immunohistochemical characteristics of the tumor. (A) Hematoxylin and eosin staining revealed numerous atypical cells, cancerous trabeculae, and extensive fatty change. IHC staining demonstrated diffuse positivity in tumor cells for CK8/18 (B), HepPar-1 (C), Arg (D), GS (E), and HSP70 (F), with negativity for MDM2 (G) and CDK4 (H). The Ki-67 proliferation index was estimated at approximately 30% (I). Magnification: A: ×100; B-I: ×200. IHC, immunohistochemistry.

A definitive diagnosis of HCC with extensive fatty change and abdominopelvic implantation metastasis was established. The patient received combined targeted therapy (lenvatinib 12 mg/day) and immunotherapy (camrelizumab 200 mg every 3 weeks). Serial imaging over 12 months documented significant tumor regression and a reduction in the fatty component, with no evidence of recurrence or treatment-related adverse events (Figure 4).

Figure 4 Longitudinal CT assessment of therapeutic response. (A) Baseline image (pre-treatment) depicts a heterogenous low-attenuation mass with prominent intralesional fat content. (B) Six-month follow-up image demonstrates partial tumor regression and reduced fatty components. (C) Twelve-month follow-up image confirms sustained therapeutic efficacy, with further tumor shrinkage and near-complete resolution of adipose tissue. CT, computed tomography.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This case presents a novel clinicopathological entity: HCC with extensive fatty change arising in the right perihepatic space (12.2 cm × 1.5 cm) accompanied by abdominopelvic implantation metastasis. This occurrence has not been previously reported in the literature. Traditionally, fatty steatosis has been associated with small, early-stage HCCs due to ischemic stress during the portal-to-arterial vascular transition (1,9-11). However, this case challenges that paradigm by demonstrating that large, well-differentiated HCCs can retain diffuse fatty features, even in extrahepatic locations.

This case further extends the clinicopathological spectrum of HCC and offers a valuable reference for the diagnosis and treatment of similar cases. The persistence of extensive fatty change in large extrahepatic lesions presents a dual challenge to the conventional paradigms of HCC diagnosis and management. The tumor’s atypical location in the perihepatic space and the absence of cirrhosis underscore the limitations of imaging-centric diagnostic frameworks, particularly when adipose predominance obscures classic vascular enhancement patterns (e.g., arterial hyperenhancement with wash-out). This diagnostic ambiguity highlights the need for a revised approach that integrates biomarker stratification (e.g., AFP ≥10 ng/mL or PIVKA-II >40 mAU/mL) to prioritize HCC suspicion, multiphase MRI with hepatobiliary contrast to detect pseudocapsular enhancement, and early histopathological validation via laparoscopic biopsy, paired with IHC staining and FISH assays to exclude mimics such as liposarcoma. Furthermore, the patient’s non-cirrhotic HCC aligns with emerging evidence implicating MASLD in hepatocarcinogenesis, even in non-fibrotic livers (6,12). Moreover, in MASLD-related HCC, the proportion of patients with significantly elevated serum AFP levels may be lower than that in virus-related HCC, suggesting reduced diagnostic sensitivity of AFP in non-viral etiologies (6). This underscores the importance of incorporating metabolic risk stratification into HCC surveillance protocols, utilizing tools such as vibration-controlled transient elastography or the fibrosis-4 index for patients with obesity or diabetes (13). Collectively, these insights advocate for a paradigm shift toward multidisciplinary diagnostics, where advanced imaging, molecular pathology, and metabolic profiling converge to mitigate diagnostic delays and optimize therapeutic precision in the face of increasingly heterogeneous HCC presentations.

Limitations

Despite its novel insights, the findings of this study cannot be generalized to all populations due to its nature as a single case report. The absence of histopathological assessment of non-tumoral liver tissue prevents definitive confirmation of MASLD as the underlying etiological factor. In addition, although liposarcoma was excluded by IHC staining and FISH assays, further analyses such as liver-type fatty acid-binding protein staining or HNF1A gene mutation testing were not conducted to definitively rule out HNF1A-inactivated hepatocellular adenoma, which can also present with marked steatosis. Nevertheless, the high Ki-67 proliferation index and metastatic behavior in this case strongly support the diagnosis of HCC.

Conclusions

In conclusion, this case broadens the clinicopathological spectrum of HCC by demonstrating that extensive fatty change can occur in large, extrahepatic tumors. This underscores the necessity for clinicians to move beyond cirrhosis-centric diagnostic frameworks and adopt a multidisciplinary approach that integrates advanced imaging, molecular pathology, and metabolic profiling when imaging features are atypical or cirrhosis is absent. Such a paradigm shift is essential for reducing diagnostic delays and optimizing therapeutic outcomes in the evolving landscape of hepatocarcinogenesis.

Acknowledgments

None.

Footnote

Funding: This work was supported by the Sichuan Foundation for Distinguished Young Scholars (No. 2022JDJQ0049) and 1.3.5 Project of Center for High Altitude Medicine, West China Hospital, Sichuan University (No. GYYX24004).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2855/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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