INTRODUCTION

Primary liver cancer is the sixth most common cancer worldwide. In South Korea, it ranks fifth among males and sixth among females.^1,2 In 2020, 15,152 patients (11,150 males and 4,002 females) were newly diagnosed with hepatocellular carcinoma (HCC) in South Korea. The crude incidence rate of HCC was 29.5 per 100,000 people, and the age-standardized rate was 14.5 per 100,000 people.² HCC accounts for most primary liver cancer cases.³

Orbital metastasis is a rare phenomenon, accounting for 1-13% of all orbital tumors. Orbital metastasis occurs in approximately 2-5% of patients with systemic malignancies,^4-6 with the most common primary tumors being breast cancer, melanoma, and prostate cancer.^6-8 Orbital metastasis often presents with symptoms related to the orbit, leading to its detection before the primary tumor is diagnosed.^7,9 Orbital metastasis from HCC is extremely rare (3.4% of all orbital metastases),^10-12 and histologically confirmed cases are even more limited.^11,12 As of January 2024, 45 cases of orbital metastasis associated with HCC had been reported worldwide.¹³

This report describes two cases: one in which orbital metastasis of HCC was found in a patient with no prior cancer diagnosis presenting with ocular symptoms, and the other in a patient being followed up for HCC who developed orbital metastasis. We report these cases, along with a review of the literature.

CASE REPORT

Case 1

A 62-year-old male presented to the emergency department with a sudden loss of vision in the right eye. He reported conjunctival injection in the right eye starting 1 week prior to presentation. Three days before the visit, he developed right eye proptosis, eyelid swelling, and progressive visual deterioration, which ultimately led to complete vision loss 2 days prior to presentation. The patient denied a history of chronic medical conditions but reported treatment for hepatitis B virus (HBV) infection many years ago without regular follow-up. His alcohol consumption was limited to social drinking and he noted a family history of HCC in his father.

Ophthalmological examination revealed significant proptosis, severe chemosis, and inferior scar changes. Laboratory tests and orbital computed tomography (CT) scans were performed. An initial orbital CT scan revealed a lobulated, heterogeneously enhancing solid tumoral lesion measuring approximately 6.5×3.6×3.5 cm (length × width × height) in the right greater wing of the sphenoid with multifocal bony destruction, raising suspicion for metastasis or an unusual primary tumor such as sarcoma (Fig. 1). Laboratory tests showed the following results: total bilirubin, 1.33 mg/dL; alkaline phosphatase, 270 U/L; aspartate aminotransferase, 240 U/L; alanine aminotransferase, 112 U/L; C-reactive protein, 1.27 mg/dL; alpha-fetoprotein (AFP), >60,500 ng/mL. Additionally, hepatitis B surface antigen positivity was confirmed, suggesting an ongoing HBV infection, potentially in the inactive carrier phase, although prior virological data were unavailable. Albumin and prothrombin times were within normal limits, with no evidence of ascites or encephalopathy, and his liver function was classified as Child-Pugh class A.

He was subsequently admitted for further evaluation, with plans to undergo whole-body positron emission tomography/CT (WBP) to determine the origin of the cancer and proceed with surgery for an orbital mass biopsy. WBP revealed a hypermetabolic mass in the right orbital space with invasion into adjacent structures, bones, and the intracranial cavity. Multiple hypermetabolic lesions were also observed in both hemilivers (the largest was located in the right lobe), both lungs, and multiple bones, including the skull, skull base, right maxilla, right scapula, left 1st, 3rd, and 9th ribs, T6 vertebra, both pelvic bones, and the left femur (Fig. 2). On the basis of these findings, extensive malignant lesions involving the right orbital space, liver, lungs, and bones were suspected. To determine the primary cancer site, the patient underwent a superior orbitotomy and orbital mass biopsy under general anesthesia.

Before the biopsy results were available, considering the patient’s history of chronic HBV infection, liver cancer was suspected as the primary origin. Liver CT revealed a huge heterogeneously enhancing mass, nearly replacing the right liver, measuring approximately 13.7 cm, with arterial phase hyperenhancement, obliteration of the right posterior portal vein, and a probable tumor thrombus in the P8 branches, strongly suggestive of a primary malignant hepatic tumor such as HCC or a combined tumor with intrahepatic metastases (Fig. 3).

Histopathological examination of the orbital mass confirmed metastasis from the HCC. Immunohistochemical staining was positive for AFP, arginase-1, hepatocyte-specific antigen, and glypican-3. Based on the American Joint Committee on Cancer (AJCC) 8th edition TNM staging system, the patient was classified as having T4N0M1 HCC.

A multidisciplinary discussion with medical and radiation oncology specialists regarding the treatment options was conducted. Palliative chemotherapy and radiotherapy were considered. The patient initially opted for palliative chemotherapy with lenvatinib and received localized palliative radiotherapy. Surgical intervention was planned if orbital decompression and pain relief could not be achieved using systemic therapy. Given the advanced cancer stage and poor prognosis, counseling regarding advance directives and end-of-life care was provided.

Case 2

A 59-year-old male patient presented to the emergency department with periorbital swelling and orbital sensory impairment on the right side. He reported that symptoms had gradually developed in the early part of the month and progressively worsened thereafter. The patient had been diagnosed with HCC during regular liver clinic follow-ups for HBV-related liver cirrhosis (LC) while receiving entecavir. He had undergone three sessions of transarterial chemoembolization and was on sorafenib therapy.

At the time of the initial emergency department visit, ophthalmological examination revealed no significant findings, and the patient was discharged on request. However, brain magnetic resonance imaging (MRI) performed during the visit later revealed soft tissue swelling with diffuse enhancement in the right periorbital soft tissue without bone involvement. The initial presumptive diagnosis was cellulitis (Fig. 4).

One week later, during outpatient follow-up, the MRI results were reviewed. By this time, the patient’s symptoms had worsened, with increasing pain and visual impairment in the right eye. The patient was admitted for further evaluation and treatment. Laboratory findings led to the patient being classified as Child-Pugh class A.

An orbital CT scan performed 9 days after the MRI scan revealed bone destruction of the right orbital post-lateral wall with an enhancing mass extending intracranially and intraorbitally, potentially compressing the right optic nerve at the orbital apex (Fig. 5). These findings were suggestive of malignancy, which was more likely than an invasive fungal infection. A complete blood count showed no leukocytosis, and the C-reactive protein level was normal. However, empirical treatment with cefazolin and amphotericin B was initiated because cellulitis could not be completely ruled out, and an aspergillus galactomannan antigen assay was positive (index, 0.55). Despite antimicrobial and antifungal therapies, the swelling persisted, although eyeball pain and erythema improved with acetaminophen use.

To confirm the diagnosis, the patient underwent a superolateral orbitotomy and intraorbital mass biopsy under general anesthesia. Intraoperatively, the periosteum appeared thickened and irregular with a concurrent supraorbital bone defect. Histopathological examination revealed a poorly differentiated carcinoma with a trabecular growth pattern (Fig. 6), and bone destruction was attributed to bone metastasis. Considering the patient’s established diagnosis of HCC, the liver was strongly suspected to be the primary site of origin. Based on the AJCC 8th edition TNM staging system, the patient was classified as having T4N0M1 HCC.

Although further evaluation using WBP and consideration of radiotherapy were discussed, the patient refused all additional diagnostic tests and treatments and opted for discharge against medical advice, being subsequently lost to follow-up.

DISCUSSION

HCC and LC can lead to ocular manifestations owing to hepatic dysfunction, impaired homeostasis, opportunistic infections, and neoplastic metastasis.^14,15 In rare cases, orbital symptoms may serve as the initial presentation of liver disease, necessitating a differential diagnosis based on clinical symptoms. The differential diagnosis of exophthalmos with or without decreased visual acuity in patients with chronic liver disease includes retinopathy with soft exudates, central retinal artery/vein occlusion, bacterial endogenous endophthalmitis, endogenous fungal endophthalmitis, and ocular metastasis.

First, retinopathy characterized by soft exudates can occur in patients with LC, potentially due to impaired hepatic synthetic function and hemodynamic changes associated with portal hypertension.¹⁶ Second, hypercoagulability in patients with HCC and LC may lead to central retinal artery occlusion or central retinal vein occlusion, resulting in acute vision loss.^17,18 Third, if a hepatic abscess or sepsis occurs during the course of HCC treatment, bacterial endogenous endophthalmitis may develop, presenting with symptoms such as visual impairment, ocular pain, and conjunctival injection.¹⁹ Fourth, acute and chronic liver failure are significant risk factors for fungal infections, which can cause endogenous fungal endophthalmitis, a sight-threatening condition. This condition is commonly associated with immunosuppression and intravenous drug use, which allows opportunistic pathogens to reach the eye via hematogenous dissemination.²⁰ Fifth, in cases of ocular metastasis, common clinical presentations include proptosis (52%), diplopia (34%), ophthalmoplegia (29%), palpable mass (22%), orbital pain (19%), visual impairment (19%), and ptosis (16%).¹⁹ Even in patients with an underlying liver disease, these symptoms must not be overlooked as solely systemic complications, and the possibility of orbital metastasis should be considered.

Although HCC is a relatively prevalent malignancy, orbital metastases are exceptionally rare.¹³ Because orbital metastases are typically associated with advanced-stage malignancies, even when orbital involvement is suspected, histopathological confirmation and definitive treatment strategies are infrequently undertaken.⁹

The median interval from the initial cancer diagnosis to orbital metastasis has been reported to be approximately 13 months, indicating that orbital metastases tend to develop after a prolonged disease course. Notably, 60% of patients present with isolated orbital metastasis without evidence of extrahepatic spread.^10,13 Owing to these factors, orbital metastases from HCC may be underrecognized. However, given the poor prognosis of HCC with orbital metastasis⁷ and the lack of optimal therapeutic strategies, early and accurate diagnosis is essential.

Orbital metastasis can be the first manifestation of HCC in patients with no history of cancer. Zanetto et al.¹⁸ reported that 66.7% of patients with orbital metastasis had no prior diagnosis of HCC. Therefore, HCC should not be excluded based solely on the absence of a previous diagnosis. Consequently, when orbital lesions are detected, it is critical to evaluate the underlying risk factors, such as LC and viral hepatitis.

The two cases presented in this report illustrate the different diagnostic pathways that lead to orbital metastasis of HCC. The first patient had no prior cancer diagnosis and orbital metastasis was the initial presentation of HCC. Initially, there was no documented history of liver disease; however, serological testing revealed anti-HBV antibody positivity, confirming past HBV infection and treatment history. In contrast, the second patient had a known history of HBV-related HCC and had undergone multiple treatments, including sorafenib therapy. The patient developed orbital symptoms that were initially diagnosed as cellulitis and treated with antibiotics. However, further evaluation confirmed orbital metastasis. In both cases, a thorough assessment of ocular symptoms, medical history, and appropriate imaging and histopathological examinations facilitated the accurate diagnosis of orbital metastasis from HCC.

Orbital bone involvement in HCC metastasis may involve either primary bone metastasis or soft tissue metastasis with secondary bone invasion. In case 1, WBP identified multiple bone metastases, including the skull, ribs, vertebrae, and pelvis, along with an orbital mass with bony destruction in the sphenoid wing. This suggests that the orbital lesion likely originated as a metastasis in the orbital bone and extended into the orbital cavity, although soft tissue metastasis with secondary bone invasion cannot be excluded. In contrast, in case 2, brain MRI performed 9 days prior to the orbital CT revealed a soft tissue mass without bone involvement, while the subsequent CT showed bone destruction of the orbital post-lateral wall. This temporal sequence indicated that the orbital metastasis initially involved the soft tissue, with rapid secondary bone invasion. These distinct patterns align with previous reports of orbital metastasis of HCC, in which bone involvement may occur through either hematogenous spread to the bone or direct extension from soft tissue lesions.¹⁰

In case 2, empirical antimicrobial and antifungal therapy combined with acetaminophen for analgesia led to improvement in eyeball pain and erythema, initially suggesting cellulitis. However, persistent facial swelling and histopathological findings of a poorly differentiated carcinoma without inflammation or fungal infection excluded infectious etiologies. Improvement in pain and erythema likely resulted from the analgesic and mild anti-inflammatory effects of acetaminophen, while persistent swelling was attributable to tumor-related tissue destruction obstructing venous return. This case highlights the risk of misdiagnosing orbital metastasis of HCC as an infectious condition such as cellulitis, emphasizing the need for thorough histopathological evaluation to guide accurate diagnosis.

Therapeutic approaches for orbital metastases from HCC are primarily palliative because of the advanced stage at diagnosis and poor prognosis, with a median survival of often less than 12 months.¹³ Systemic therapies, such as tyrosine kinase inhibitors (e.g., lenvatinib or sorafenib), aim to control tumor progression, whereas localized treatments, including radiotherapy or surgical debulking, target symptom relief, such as pain or proptosis.⁷ The decision between systemic and local therapies depends on the extent of the disease, patient performance status, and symptom burden. In cases of isolated or minimally disseminated orbital metastasis, local therapies may provide temporary palliation. However, systemic progression often limits long-term outcomes.¹⁰ Therefore, early multidisciplinary consultation is critical to guide individualized treatment planning and optimize both the quality of life and disease control.

When orbital involvement suggests metastasis, additional imaging studies, such as CT, MRI, and PET/CT, should be performed to identify the primary tumor and confirm orbital metastasis, particularly in patients with an unclear oncological history. If necessary, biopsy should be considered to establish a definitive diagnosis and guide appropriate management.⁹

Article information

Conflicts of Interest

The authors have no conflicts of interest to declare.

Ethics Statement

This study was approved by the Institutional Review Board of Seoul National University Bundang Hospital (B-2503-959-702).

Funding Statement

Not applicable.

Data Availability

Not applicable.

Authors Contributions

Conceptualization: EL, JWK

Data curation: EL

Visualization: EL

Supervision: ESJ, JHP, SHJ, JWK

Writing - original draft preparation: EL, JWK

Writing - review and editing: JWK

Figure 1.

Initial orbital CT scan of case 1. A lobulated, heterogeneously enhancing solid tumoral lesion was observed in the right greater wing of the sphenoid, with multifocal bony destruction. CT, computed tomography.

Figure 2.

Whole body PET/CT scan of case 1. Multiple hypermetabolic lesions were observed in the right orbital space, both hemilivers, both lungs, and multiple bones, including the skull, skull base, right maxilla, right scapula, left 1st, 3rd, and 9th ribs, T6 vertebra, both pelvic bones, and the left femur. PET/CT, positron emission tomography/computed tomography.

Figure 3.

Liver CT scan of case 1. A heterogeneously enhancing mass (13.7 cm) nearly replacing the right liver with arterial phase hyperenhancement was observed. CT, computed tomography.

Figure 4.

Brain MRI of case 2. Soft tissue swelling with diffuse enhancement in the right periorbital soft tissue was observed. MRI, magnetic resonance imaging.

Figure 5.

Orbital CT scan of case 2. Bone destruction of the right orbital post-lateral wall with an enhancing mass extending intracranially and intraorbitally (green arrows) was observed. CT, computed tomography.

Figure 6.

Pathology of case 2. Poorly differentiated carcinoma with a trabecular pattern (hematoxylin & eosin, ×100).

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