Giant Atypical Hepatocellular Adenoma of Unknown Etiology in a Young Male: A Case Report

Abstract

We report a case of giant hepatocellular adenoma (HCA) in a 24-year-old man. The patient had no definite known risk factors, and both the clinical manifestations and imaging findings were nonspecific, making preoperative diagnosis difficult. Also, the inconsistency between intraoperative frozen-section findings and postoperative routine histopathology further complicated the diagnostic process. In fact, hepatocellular carcinoma (HCC) was initially suspected preoperatively, while postoperative pathology temporarily suggested focal nodular hyperplasia (FNH). The diagnosis was ultimately confirmed as HCA after expert pathological consultation at a tertiary center. The patient underwent right hepatectomy and cholecystectomy, with no significant adverse complications observed during the 1-year follow-up. This case highlights that HCA should be included in the differential diagnosis of hepatic space-occupying lesions in young male patients without clearly identifiable risk exposures. Moreover, when the nature of the lesion cannot be definitively established by preoperative or intraoperative pathology, surgical resection remains an important approach with both diagnostic and therapeutic value.

Introduction

HCAs are rare benign neoplasms arising from hepatocytes, occurring at a rate of 3–4 per 100,000.¹ Among men, the incidence is even lower.¹ Risk factors for the development of HCAs include oral contraceptives, androgen hormone imbalance, obesity, alcohol intake, antiepileptic drugs, liver vascular disease, chronic viral hepatitis, cirrhosis, previous malignancy, and germline genetic susceptibility.^1–3 Although HCA is a benign lesion, it is associated with potential risks of spontaneous rupture, hemorrhage, and malignant transformation.⁴ Herein, we report a case of giant HCA of unknown etiology in a young man. The case was atypical in its clinical presentation, imaging characteristics, and pathological findings, resulting in a complex diagnostic process and offering important clinical insights. This report aims to explore the possible etiologies of HCAs in young male patients and make an additional analysis of the new molecular subtypes of hepatic adenoma, described recently in the literature. A comprehensive review of the literature indicates that such cases have rarely been reported.

Case Report

General Information

A 24-year-old unmarried man was admitted with a 1-year history of a hepatic nodule. He was asymptomatic and had no history of substance abuse. Vital signs were as follows: BP 117/80 mmHg, RR 31 breaths/min, PR 91 beats/min, and temperature 36.0°C. Physical examination revealed a painless bile mass in the right upper abdomen, with no other remarkable findings. Laboratory investigations showed: PLT 387 × 10⁹/L (reference range, 125–350 × 10⁹/L), ALT 19.70 U/L (9–50 U/L), AST 25.2 U/L (15–40 U/L), and TBIL 20.6 μmol/L (0–26 μmol/L). Serum AFP and CEA were within normal limits. Hepatitis viral markers were negative. Genetic testing for metabolic disorders was not performed.

Contrast-enhanced abdominal computed tomography (CT) revealed a giant intrahepatic mass with multiple low- to heterogeneous-density areas, with attenuation values of approximately 17.1–30.4 HU (Figure 1A). Hepatobiliary contrast-enhanced magnetic resonance imaging (MRI) demonstrated hepatomegaly with a predominantly right-lobe mass measuring approximately 12.3×16.6 cm. The lesion showed iso-intensity on both T1- and T2-weighted imaging, an ill-defined margin, and multiple punctate and patchy areas of short T1 and long T2 signal intensity. Diffusion-weighted imaging showed heterogeneous restricted diffusion. Dynamic contrast-enhanced imaging demonstrated heterogeneous arterial enhancement with decreased delayed-phase enhancement.

Figure 1.

Contrast-enhanced CT images on admission. (A) Contrast-enhanced CT demonstrated a right hepatic tumor measuring approximately 168.41 mm in maximum diameter; (B) The middle hepatic vein was clearly visualized along its entire course (arrow).

Given the presence of a giant hepatic mass of uncertain etiology and the inability to exclude malignancy, a multidisciplinary team discussion was conducted to assess surgical feasibility. Imaging showed an adequate future liver remnant, particularly with compensatory enlargement of the left lateral lobe. The tumor was closely related to the middle hepatic vein, but the vein remained clearly visualized and intact throughout its course (Figure 1B). No definite invasion of the right hepatic artery or right portal vein branch was identified, suggesting a low likelihood of major vascular involvement. Preservation of the middle hepatic vein was planned whenever possible to maintain venous drainage of the remnant liver and reduce the risk of postoperative hepatic congestion and liver failure.

Assessment of hepatic functional reserve revealed an indocyanine green retention rate at 15 minutes (ICG-R15) of 2.6%. Based on commonly used preoperative criteria for evaluating hepatic functional reserve before hepatectomy,^5,6 an ICG-R15 value below 10% is generally considered to indicate preserved hepatic reserve and acceptable tolerance for major hepatic resection, whereas elevated values suggest impaired hepatic reserve and an increased risk of postoperative liver dysfunction. In this case, the patient’s ICG-R15 was markedly below the 10% threshold, supporting the feasibility and safety of right hepatectomy. Therefore, after a comprehensive evaluation of the imaging findings, laboratory results, and the treatment preferences of the patient and his guardian, an open right hepatectomy with cholecystectomy was performed, and further management was planned according to the intraoperative frozen-section findings.

Surgical Procedures and Process

The operation was performed under general anesthesia with endotracheal intubation. A right subcostal J-shaped incision was made, and the abdomen was entered layer by layer. Intraoperative exploration revealed a giant tumor in the right hepatic lobe, measuring approximately 18×16 × 13 cm (Figure 2A). The round and falciform ligaments were divided first, followed by dissection of the hepatocolic, hepatorenal, right triangular, and right coronary ligaments, allowing complete mobilization of the right liver and exposure of the bare area up to the inferior vena cava. Cholecystectomy was then performed. At the first hepatic hilum, the right hepatic artery and right portal vein branch were carefully dissected (Figure 2B), clipped with He-mo-lock, and divided, after which a clear ischemic demarcation line appeared in the right liver (Figure 2A).

Figure 2.

Key intraoperative findings during right hepatectomy. (A) Intraoperative view of a giant tumor in the right hepatic lobe. A distinct ischemic demarcation line (arrow) appeared after occlusion of the right hepatic inflow; (B) Intraoperative hilar dissection showing gradual exposure of the right hepatic artery (upper arrow) and the right portal vein branch (lower arrow).

Under intermittent Pringle maneuver, hepatic parenchymal transection was carried out along the ischemic line, with stepwise division of the intrahepatic vessels and bile ducts. Parenchymal transection was then continued from the gallbladder fossa toward the right notch of the hepatic hilum, exposing and dividing the right hepatic duct. The right hepatic vein, the short hepatic veins, and the segment VIII tributaries of the middle hepatic vein were subsequently divided, and the right hepatic lobe was removed integrally. The resected specimen is shown in Figure 3A and 3B. After meticulous hemostasis was achieved, one negative-pressure drain and one rubber drain were placed. Estimated blood loss was approximately 500 mL. Intermittent inflow occlusion was performed four times, each lasting approximately 15 minutes. Intraoperative frozen-section analysis suggested a hepatocellular dysplastic nodule with hepatocellular cholestasis; however, well-differentiated hepatocellular carcinoma could not be excluded, pending formal paraffin histopathology and immunohistochemical evaluation.

Figure 3.

Gross pathological findings of the resected hepatic tumor. (A) Gross specimen of the resected liver tumor, measuring approximately 18×16 × 13 cm; (B) The cut surface of the tumor was heterogeneous brown-tan, with focal yellowish fat-like areas (arrow).

Results

The initial postoperative pathological assessment at our institution favored FNH, and further expert consultation was recommended. Immunohistochemical staining showed CK8/18 (+), CK19 (−), CD34 (vascular +), AFP (−), P53 (wild type), Ki-67 (1%), HepPar-1 (+), CD10 (partial +), GPC-3 (−), HSP70 (−), GS (+), CK7 (−), and D2-40 (lymphatic vessel +). In contrast, pathological consultation at Peking Union Medical College Hospital favored a diagnosis of hepatocellular adenoma (HCA). The immunohistochemical findings were HSP70 (scattered +), Hepatocyte (+), CK8/18 (+), CD34 (partial +), CK7 (−), CK19 (−), GPC-3 (scattered weak +), AFP (scattered +), Ki-67 (3%), P53 (wild type), CD10 (partial +), GS (+), and D2-40 (scattered +).

On postoperative day 9, the patient developed abdominal pain after removal of the abdominal drain. Contrast-enhanced CT revealed a small hyperdense focus in the operative field, consistent with a small amount of intraperitoneal hemorrhage. Initial laboratory tests revealed: CRP 13.84 mg/L (reference range, 1–10 mg/L), RBC 3.56 × 10¹²/L (4.3–5.8 × 10¹²/L), Hb 103.0 g/L (130–175 g/L), and PLT 456 × 10⁹/L (125–350 × 10⁹/L). After symptomatic treatment, including topical thrombin, the bloody drainage gradually decreased, and liver function progressively recovered. The patient was discharged on postoperative day 11.

Contrast-enhanced CT before discharge demonstrated an intact portal vein, left hepatic artery, and middle hepatic vein (Figure 4A). Follow-up contrast-enhanced CT at 1, 3, and 12 months after surgery showed gradual resolution and eventual complete disappearance of the perihepatic fluid collection (Figure 4B–D). No significant postoperative complications were observed during follow-up.

Figure 4.

Postoperative CT follow-up findings. (A) Pre-discharge contrast-enhanced CT images demonstrating patency of the middle hepatic vein (arrow); (B–D) CT images obtained at 1, 3, and 12 months after surgery, respectively, demonstrating progressive involution of the perihepatic fluid collection, with almost complete resolution by 12 months.

Discussion

HCA, otherwise known as hepatic adenoma, is a rare benign epithelial liver tumor with a marked sex- and age-related difference in incidence. In adults, the incidence is estimated at 3–4 cases per 100,000 population. HCA is commonly associated with exogenous estrogen intake, usually in the form of oral contraceptive pills, and therefore occurs predominantly in women of reproductive age, whereas male patients are relatively uncommon.^7–9 In contrast, HCA is exceedingly rare in children, with an estimated incidence of only 1 case per 1,000,000 population, and is most frequently associated with inherited metabolic disorders or abnormal underlying liver conditions.^10,11 Moreover, the lesion is also associated with steroid abuse, Fanconi anemia, aplastic anemia, metabolic syndrome, and glycogen storage disease (GSD).¹² Although HCA is a benign lesion, it carries a risk of hemorrhage and malignant transformation.¹³ The main factors associated with malignant transformation of HCA are male sex,¹⁴ a large tumor size,¹⁵ and CTNNB1 mutations in exon 3, leading to the aberrant activation of the Wnt/β-catenin signaling pathway.¹⁶ Accordingly, the European Association for the Study of the Liver (EASL) recommends elective resection in all male patients irrespective of adenoma size and in female patients with lesions >5 cm.^13,14 Furthermore, all cases with confirmed CTNNB1 exon 3 mutations should undergo surgical resection.¹⁷ Therefore, in the present case of a giant hepatic mass, particularly in the setting of atypical imaging findings and the inability to reliably exclude malignancy preoperatively, we adopted a more proactive clinical management strategy. Surgical resection served not only a therapeutic but also an important diagnostic one.^18,19

The present case was atypical in both its epidemiological background and diagnostic course. The patient was a previously healthy young man without established high-risk factors for HCC, such as viral hepatitis or cirrhosis.^20–22 However, HCA is also uncommon in young men, particularly in the absence of a reported history of medication use. This atypical clinical background reduced the diagnostic predictability before surgery. Based on the imaging findings, well-differentiated HCC was initially considered preoperatively. Intraoperative frozen section suggested a hepatocellular dysplastic nodule, while postoperative routine pathology favored FNH. The diagnosis was ultimately revised to HCA after expert pathological consultation at a superior hospital. This diagnostic course underscores the substantial overlap that may exist among hepatocellular lesions in both imaging and pathological evaluation. In particular, when a lesion is large and accompanied by fatty change, hemorrhage, or signal heterogeneity, HCA may exhibit enhancement patterns and imaging characteristics similar to those of FNH or even well-differentiated HCC, thereby complicating preoperative characterization.^7,11 However, the natural history and management of these two entities differ markedly. Once FNH has been confidently established by high-quality imaging, neither further surveillance nor surgical intervention is usually required. By contrast, HCA carries risks of hemorrhage and malignant transformation and therefore warrants a more active therapeutic approach.⁷ Current consensus suggests that contrast-enhanced MRI, particularly with hepatobiliary-specific contrast agents, represents the optimal imaging modality for differentiating HCA from FNH. Nevertheless, MRI is not infallible for accurate HCA subtyping, identifying approximately 80% of adenomas. When imaging findings are inconclusive, pathology remains the cornerstone of definitive diagnosis.⁷ Notably, steatotic FNH represents an atypical variant of FNH and may mimic HCA, especially in patients with underlying hepatic steatosis.¹⁸ However, when typical imaging features of FNH are preserved, steatotic FNH can still be diagnosed with high imaging specificity.¹⁸ In retrospect, intralesional fat may have confounded the differential diagnosis and contributed to the initial impression of FNH, whereas the marked signal heterogeneity and lack of typical FNH features were more suggestive of HCA.

Moreover, this case underscores the real-world challenges and ongoing controversies in the pathological diagnosis of HCA. HCA is a heterogeneous entity that currently encompasses 6 molecular subtypes: hepatocyte nuclear factor 1A (HNF1A)-mutated HCA, inflammatory HCA (IHCA), CTNNB1 (gene coding for β-catenin)-mutated HCA in exon 3 (b^ex3HCA), CTNNB1-mutated HCA in exon 7 or 8 (b^ex7,8HCA), sonic hedgehog HCA (shHCA), and unclassified HCA.¹⁶ Interestingly, each subtype is associated with specific clinical and pathological features and various risks of complications.^8,16 Indeed, although the 2019 World Health Organization (WHO) Classification of Digestive System Tumours has incorporated recent advances in the molecular classification of HCA, the diagnosis of some hepatocellular neoplasms lying between adenoma and well-differentiated HCC remains particularly challenging, as their morphology, immunophenotype, and biological behavior may not be entirely concordant. In the literature, borderline HCAs are described as HCAs with focal architectural/cytologic atypia or reticulin loss that are not sufficient for an unequivocal diagnosis of HCC.^23,24 In addition, clinically atypical settings, such as HCA occurring in men or in patients at the extremes of age, may further complicate diagnostic interpretation and clinical decision-making.^24,25 Therefore, immunohistochemistry, special stains, and molecular testing remain key tools for the diagnosis and subtyping of HCA. Available evidence suggests that HCA subtyping should be determined through a combined evaluation of markers, including LFABP, SAA/CRP, GS, and β-catenin.²⁶ In the distinction between HCA and HCC, GPC3, HSP70, GS, and reticulin staining provide important diagnostic clues; notably, in highly well-differentiated lesions, the combination of GS and HSP70 is often more valuable than GPC3 alone.²⁷ In the present case, the low Ki-67 proliferation index, wild-type P53 status, and the lack of a diffuse immunophenotype supporting HCC ultimately favored a diagnosis of HCA. However, the discordance among the intraoperative frozen-section diagnosis, postoperative paraffin histopathology, and expert consultation findings reflects the persistent challenges in the pathological diagnosis of such borderline hepatocellular lesions and further underscores the need for continued investigation.

In case of borderline histologic features within HCAs, we recommend searching for β-catenin activation using immunohistochemistry (GS and/or β-catenin immunostainings). In the case of β-catenin activation, suggestive of b^ex3HCA, surgical resection should be recommended because of the high risk of malignant transformation of these tumors, according to current guidelines.¹⁸ Further testing for TERT promoter mutations may also be useful in determining whether malignant transformation has occurred. Detection of a TERT promoter mutation should raise strong suspicion for progression from HCA to HCC and warrants management as a malignant lesion. In the absence of TERT promoter mutation, other molecular alterations suggestive of HCC should be investigated.¹⁷ Hematoxylin and eosin (H&E) staining of the archival paraffin-embedded sections showed fibrovascular septa and abnormal vessels at low magnification, without well-formed portal tracts or definite ductular reaction (Figure 5A). At higher magnification, the lesional hepatocytes were arranged in trabecular patterns and separated by delicate vascular septa, with abundant cytoplasm, round to oval nuclei, and mild cytological atypia (Figure 5B). Another higher-power field showed relatively regular hepatocyte morphology, focal fibrous septum-like structures with stromal inflammatory cell infiltration, mild dilatation of adjacent hepatic sinusoids, and fine yellow-brown granular cytoplasmic pigment deposition suggestive of lipofuscin deposition (Figure 5C). Overall, these findings supported the diagnosis of a hepatocellular neoplasm with atypical histological features. GS immunohistochemistry showed diffuse homogeneous staining, without a typical “map-like” staining pattern (Figure 5D). On this basis, β-catenin immunohistochemistry was retrospectively performed on the archived paraffin-embedded tissue to assess β-catenin pathway activation and potential malignant risk. The lesional hepatocytes showed predominantly membranous staining, without definite nuclear β-catenin expression (Figure 5E). CD34 immunohistochemistry highlighted vascular structures and focal sinusoidal endothelial staining within the lesion (Figure 5F). Thus, although GS positivity was observed, the absence of nuclear β-catenin staining did not support typical β-catenin nuclear translocation or a definitive diagnosis of β-catenin-activated HCA (β-HCA). However, because CTNNB1 mutation testing and additional subtype-related immunohistochemical markers, including LFABP and SAA/CRP, were not performed, more precise molecular subtyping could not be achieved, which represents a limitation of the present study.

Figure 5.

Histopathological and immunohistochemical findings. (A) Low-magnification H&E staining (×40) showing fibrous vascular septa and abnormal vessels, without well-formed portal tracts or definite ductular reaction; (B) Higher-magnification H&E staining (×100) showing lesional hepatocytes were arranged in trabecular patterns and separated by delicate vascular septa, with abundant cytoplasm and round to oval nuclei showing mild cytological atypia; (C) Another higher-magnification H&E-stained image (×100) showing relatively regular hepatocyte morphology, focal fibrous septum-like structures with stromal inflammatory cell infiltration, and mild dilatation of the adjacent hepatic sinusoids. Fine yellow-brown granular cytoplasmic pigment deposition, suggestive of lipofuscin deposition, was observed in some hepatocytes; (D) GS immunohistochemistry (×100) showing diffuse homogeneous staining, without a typical “map-like” staining pattern; (E) β-catenin immunohistochemistry (×200) showing predominantly membranous staining without definite nuclear expression; (F) CD34 immunohistochemistry (×100) highlighting vascular structures and focal sinusoidal endothelial staining within the lesion.

On the other hand, previous studies have shown that the risk of malignant transformation in HCA is markedly higher in men than in women. Farges et al¹⁴ reported that, in their cohort, the risk of malignant transformation was approximately 4% in women but as high as 47% in men. Among cases with malignant transformation, about two-thirds exhibited β-catenin activation and approximately one-third showed cytological atypia, both of which are high-risk features more frequently observed in male patients. Moreover, most lesions undergoing malignant transformation were relatively large, with a median diameter of up to 10 cm.¹⁴ Additionally, the recommended first-line therapy is resection of larger (>5cm) or growing lesions, aiming to remove the whole tumor and all risk of malignant transformation.²⁸ In the present case, the patient was male, the lesion was giant, and preoperative imaging could not exclude well-differentiated HCC. Preoperative percutaneous liver biopsy was not performed because the lesion was considered surgically resectable and showed diagnostic uncertainty with potential malignant risk on imaging. Considering the risks of biopsy, including bleeding, sampling error, and potential tumor seeding, surgical resection was considered more appropriate. Intraoperative frozen section also failed to provide a definitive benign diagnosis. Therefore, even though the final postoperative diagnosis ultimately favored HCA, surgical resection was still well justified. For such atypical, large hepatic lesions that are difficult to characterize preoperatively, an active surgical approach based on careful evaluation offers both diagnostic and therapeutic value. In summary, the most important clinical implication of this case lies not merely in its rarity but in the fact that distinguishing HCA from HCC and FNH directly determines the therapeutic strategy, whereas in atypical cases, this distinction cannot always be established before surgery.

We remained cautious in analyzing the potential risk factors in the present case. Current guidelines identify the principal risk factors for HCA as estrogen exposure, anabolic steroid use, obesity or metabolic syndrome, metabolic dysfunction-associated fatty liver disease, glycogen storage disease, and certain alcohol-related backgrounds.³ Based on the available clinical history and medical records, the patient had no definite documented exposure to several established high-risk factors. However, we acknowledge that other potential confounding factors, such as detailed dietary habits, longitudinal body weight changes, and physical activity, were not comprehensively investigated. Notably, the patient reported long-term sleep deprivation due to work-related reasons. Based on this observation, we speculate that, in the absence of classical risk factors, long-term staying up late or chronic sleep deprivation may represent a non-classical background factor worthy of attention; however, there is currently no direct evidence supporting it as an independent cause of HCA. Nevertheless, existing studies suggest that circadian rhythm disruption may contribute indirectly to liver tumorigenesis. Moreover, the International Agency for Research on Cancer (IARC) has classified night shift work as a probably carcinogenic exposure to humans, although this classification was not based on direct epidemiological evidence for HCA or liver cancer.²⁹ Experimental studies by Jennifer Padilla et al further suggest that chronic circadian disruption may promote the development of NAFLD-related liver cancer.³⁰ Therefore, in the present case, chronic sleep deprivation is more appropriately interpreted as a biologically plausible but unproven exploratory hypothesis. Given the current level of evidence and the incomplete assessment of potential confounding factors, it should not be regarded as a definitive etiological factor for HCA.

Conclusion

This case reports a rare, giant hepatocellular tumor in a young male patient, highlighting the importance of differentiating HCA from FNH and well-differentiated HCC in diagnostically challenging hepatocellular lesions. For large, atypical lesions that are difficult to characterize preoperatively, surgical resection has both diagnostic and therapeutic value. However, as a single case report without systematic molecular pathological testing, this study cannot establish a causal relationship, and the assessment of molecular subtype and malignant potential remains limited. Another limitation of this study is the relatively short follow-up duration. Although no evidence of recurrence was observed during the 12-month follow-up period, this duration remains insufficient to fully evaluate the long-term recurrence risk. Continued long-term surveillance is therefore necessary.

Funding Statement

This work was funded by S&T Program of Chengde, China (Grant no.202204A037).

Abbreviations

HCA, hepatocellular adenoma; HCC, hepatocellular carcinoma; FNH, focal nodular hyperplasia; BP, Blood pressure; RR, Respiratory Rate; PR, Pulse Rate; PLT, Platelet Count; ALT, Alanine Aminotransferase; AST, Aspartate Aminotransferase; TBIL, Total Bilirubin; AFP, Alpha-Fetoprotein; CEA, Carcinoembryonic Antigen; CT, computed tomography; MRI, magnetic resonance imaging; ICG-R15, indocyanine green retention rate at 15 minutes; CRP, C-reactive protein; RBC, red blood cell; Hb, hemoglobin; GSD, glycogen storage disease; EASL, the European Association for the Study of the Liver; HNF1A, hepatocyte nuclear factor 1A; I-HCA, inflammatory HCA; b^ex3HCA, β-catenin mutated hepatocellular adenoma in exon 3; b^ex7,8HCA, β-catenin mutated hepatocellular adenoma in exon 7 or 8 shHCA sonic hedgehog HCA; WHO, the World Health Organization; β-HCA, β-catenin-activated HCA; H&E, Hematoxylin and eosin; IARC, the International Agency for Research on Cancer.

Data Sharing Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Declarations

The Ethics Committee of Affiliated Hospital of Chengde Medical University approved the case report involving a human participant. According to the policy of Affiliated Hospital of Chengde Medical University, no additional institutional approval was required for the publication of the case details. The case report was conducted in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the patient for the publication of this case report and any potentially identifiable images or data included in this article.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.