Introduction

Liver cancer, predominantly hepatocellular carcinoma (HCC), represents a major global health concern. According to the most global estimates from GLOBOCAN 2022, liver cancer accounted for approximately 866,000 new cases and 758,000 deaths worldwide, ranking among the leading causes of cancer-related mortality globally [1, 2]. In the United States, liver cancer is associated with approximately 43,429 new cases and 30,931 deaths annually, underscoring the aggressive nature of the disease and its high mortality burden [3].

HCC is a highly aggressive cancer, with metastases occurring in approximately 50% to 75% of patients over the course of the disease [4].

Common risk factors for liver cancer include chronic infections with hepatitis B virus (HBV) or hepatitis C virus (HCV), excessive alcohol consumption, and metabolic dysfunction-associated steatotic liver disease, often related to obesity and metabolic syndrome, as well as environmental exposure to aflatoxins. Liver cancer is frequently asymptomatic in its early stages, but as the disease progresses, patients may experience symptoms such as abdominal pain, unintended weight loss, and general malaise [5].

The diagnosis of HCC is typically confirmed by identifying its characteristic imaging features, heterogeneous arterial phase enhancement followed by washout in the portal venous phase on multiphase magnetic resonance imaging (MRI) or computed tomography (CT) scans, particularly in the setting of underlying chronic liver disease [6].

Surgery, orthotopic liver transplant (OLT) or ablation is the standard curative approach to early-stage HCC, depending on liver function and tumor burden [7]. For advanced HCC, systemic therapies are applied, with first-line options including atezolizumab plus bevacizumab (Atezo/Bev), durvalumab plus tremelimumab (Durva/Treme), lenvatinib, and sorafenib. Second-line treatments encompass regorafenib, cabozantinib, and ramucirumab, particularly for patients with elevated alpha-fetoprotein (AFP) levels. Palliative care is essential for patients with end-stage liver disease or poor performance status [8–10].

The incidence of extrahepatic metastases in HCC is estimated to range from 15% to 50%, with the lungs (47–55%). Lymph nodes (45–53%), bones (28–37%), and adrenal glands (11–12%) are the most commonly affected sites [11]. Less frequently, HCC may metastasize to the peripheral peritoneal cavity, brain, spleen, pancreas, gallbladder, diaphragm, skin, and gastrointestinal tract [11]. The presence of extrahepatic spread typically advances the disease of Barcelona Clinic Liver Cancer (BCLC) stage C or D and is associated with reduced survival [11]. Nevertheless, prognosis is more strongly influenced by intrahepatic tumor burden and patient performance status than by the presence of extrahepatic metastases [11].

In this case, we present a rare case of HCC with an unusual pattern of metastatic spread, including sequential involvement of the choroid and oral cavity. To our knowledge, this is one of the few reported cases of HCC with choroidal and oral metastases, highlighting the importance of recognizing atypical metastatic presentations and integrating multidisciplinary evaluation into ongoing management.

Timeline

A detailed timeline summarizing the patient’s clinical progression, treatment interventions, and metastatic evolution is presented in Figure 1.

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Figure 1. Chronological time of disease progression and management. The diagram illustrates the sequence of key clinical events, including initial diagnosis of hepatocellular carcinoma, locoregional therapies with Y-90 radioembolization and TACE, and development of pulmonary metastases, initiation of systemic immunotherapy with Durva/Treme, radiotherapy, and subsequent disease progression with orbital and oral metastases. Planned systemic therapy with lenvatinib is also indicated. Durva/Treme: durvalumab plus tremelimumab; HCC: hepatocellular carcinoma; LLL: left lower lobe; PET/CT: positron emission tomography/computed tomography; pt: patient; RLL: right lower lobe; SBIRT: stereotactic body image-guided radiotherapy; TACE: transarterial chemoembolization; Y-90: yttrium-90.

Case presentation

Diagnostics

Initial MRI of the liver in May 2020 revealed a 4.8 cm arterially enhancing lesion with washout in the liver dome involving segments 4A and 8, consistent with HCC by Liver Imaging Reporting and Data System (LI-RADS) criteria. Surveillance chest imaging beginning in December 2021 identified two small pulmonary nodules, with subsequent follow-up in March 2022 demonstrating interval growth of one nodule in the left lower lobe, which was resected and pathologically confirmed as metastatic moderately differentiated HCC. Multiple CT and MRI scans performed during immunotherapy from 2023 to 2024 showed stable or mixed responses in the treated hepatic lesions and variable responses among the pulmonary nodules, eventually giving way to progressive mediastinal lymphadenopathy. PET/CT in December 2024 confirmed FDG-avid mediastinal and hilar lymphadenopathy with no osseous involvement on bone scan. Later follow-up PET/CT revealed ongoing progression with hypermetabolic mediastinal lymphadenopathy and a new FDG-avid oral cavity lesion (Figure 2). Ophthalmologic evaluation disclosed bilateral posterior vitreous detachment (PVD) on dilated funduscopic examination. Multimodal imaging of the left eye identified a solitary choroidal mass in the superotemporal macula, with spectral-domain optical coherence tomography showing dome-shaped choroidal elevation, overlying retinal distortion, and associated subretinal fluid. Fundus autofluorescence demonstrated hyperautofluorescence with central heterogeneity, and indocyanine green (ICG) angiography revealed no additional choroidal lesions in either eye. These ocular findings were highly suggestive of choroidal metastasis (Figure 3). MRI of the face noted a small elliptical nodule in the left posterolateral lobe along the retina, potentially representing a retinal metastatic lesion, along with asymmetric enhancement in the right maxilla centered around the first molar and extending into the oral cavity, although visualization of the oral cavity was limited by metal artifacts from dental hardware. Recurrent oral bleeding prompted esophagogastroduodenoscopy (EGD), which initially identified a Mallory-Weiss tear, although a repeat examination during the same admission showed no active bleeding or stigmata of recent hemorrhage. Physical examination revealed a polypoid mass on the maxillary gingiva, and biopsy of this lesion confirmed metastatic HCC, with microscopic findings of ulcerated squamous mucosa, florid inflamed granulation tissue, and infiltrating nests, cords, and trabeculae of epithelial cells exhibiting abundant eosinophilic granular cytoplasm, round nuclei with prominent nucleoli, and increased mitotic activity. Immunohistochemistry demonstrated positivity for pancytokeratin, HepPar-1, and glypican-3 (focally), while staining was negative for CK7 (Figure 4).

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Figure 2. Axial contrast-enhanced computed tomography (CT) image of the neck (soft-tissue window). It shows a hyperdense lesion involving the right maxillary alveolar ridge, consistent with metastatic involvement of the oral cavity.

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Figure 3. Multimodal imaging of the left eye demonstrating choroidal metastasis. (L) Fundus near-infrared reflectance imaging shows a well-defined, dome-shaped lesion involving the macula; (R) spectral-domain optical coherence tomography (SD-OCT) reveals a dome-shaped choroidal mass with overlying retinal elevation and associated subretinal fluid, consistent with a solitary choroidal metastasis.

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Figure 4. Intraoral clinical photograph. It shows a polypoid mass involving the right maxillary gingiva, identified as the source of recurrent oral bleeding. Histopathologic examination of the biopsy specimen confirmed metastatic hepatocellular carcinoma (HCC).

Discussion

In HCC, early detection and awareness of common metastatic sites are essential for optimizing treatment strategies and improving prognosis. Accurate risk stratification plays a key role in minimizing unnecessary expenses, treatment delays, and disease-related complications [12]. A national study conducted in 2014 analyzed data from over 50,000 HCC patients using the University Health Consortium (UHC) and Nationwide Inpatient Sample database [13]. It found that extrahepatic metastases occur in approximately 13–36% of cases, the most frequent sites being the lungs (6%), bones (3%), peritoneum (3%), regional lymph nodes (2%), spleen (1%), and adrenal glands (1%) [12, 13]. Similarly, a 2011 study assessing outcomes in HCC patients with distant metastases reported that the lungs (39.5%), lymph nodes (34.2%), bones (25.4%), and adrenal glands (8.8%) were the most commonly affected sites, with less frequent involvement of the brain (1.2%), spleen (0.6%), and breast (0.3%), totaling 376 metastatic events in 342 patients [13]. In contrast, metastases to the orbital and oral cavity remain exceedingly rare and often underrecognized in clinical practice.

Orbital metastases account for only 3–7% of all orbital masses, usually presenting unilaterally 92%, while only 8% of patients have bilateral involvement, while oral cavity involvement is estimated in just 1–3% of cases [14]. These metastases typically occur in advanced stages of cancer and may, in rare cases, precede the diagnosis of the primary tumor [15]. Among primary tumors, lung, prostate, and breast cancer are the most frequently associated with orbital metastasis [15]. Oral cavity metastases are more commonly linked to cancer of the thyroid, kidney, and lung. Within the orofacial area, the mandible is the most frequently involved site (81%), and similar to primary HCC, metastatic disease shows a predominance in males [16].

In this report, we present a unique case of HCC with metastases to both the oral cavity and the orbit. HCC-related metastases to either site are extraordinarily uncommon, and simultaneous involvement of both anatomical regions has not been previously described. This case highlights the rare and aggressive nature of disease dissemination and represents an exceptional presentation in the literature.

Metastatic spread in HCC primarily occurs via the hematogenous route, most commonly to the lungs, and is often associated with pulmonary involvement. Another possible route was described by Vitale et al. [17]. They reported a case of metastatic HCC involving the parotid gland in the absence of pulmonary metastases [17]. The author explained that via Batson’s plexus (BPP), a network of valveless veins is located in the epidural space between the spinal column and dura mater. Malignant cells entering this plexus can bypass the pulmonary, caval, and portal venous systems by lodging directly in the venous and sinusoidal networks of bone connected to the BPP [16–19]. Another possible route of orbital involvement is through initial infiltration of the orbital bone, which subsequently extends into adjacent orbital soft tissue [19]. In the present case, the patient had biopsy-confirmed pulmonary metastases prior to the development of choroidal and oral lesions, supporting hematogenous dissemination as the primary route of spread. BPP may have contributed as a secondary pathway, facilitating tumor seeding to uncommon sites, such as the orbit and maxillofacial region, particularly in the setting of advanced disease and mediastinal lymphadenopathy. This combined mechanism underscores the aggressive biology and extensive dissemination potential of advanced HCC observed in our patient.

In addition to anatomical pathways such as BPP, the seed and soil hypothesis may provide a complementary explanation for the metastatic pattern observed in this case. This concept suggests that tumor cells (seeds) preferentially colonize distant sites (soil) with a microenvironment, including stromal components, cytokine signaling, and vascular characteristics, which play a critical role in supporting tumor progression and metastatic spread. Although orbital and oral metastases from HCC are rare, local microenvironmental factors may create conditions that support tumor cell implantation and proliferation at these sites. While this remains speculative, it may help explain the occurrence of metastases in these uncommon locations [20].

The proposed pathways relevant to this case are summarized schematically in Figure 5.

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Figure 5. Schematic illustration of metastatic dissemination in advanced hepatocellular carcinoma (HCC). Tumor spread occurs primarily via hematogenous dissemination to the lungs, followed by secondary systemic dissemination to the choroid and oral cavity. A potential contributory role of Batson’s venous plexus is shown schematically.

Orbital metastases are typically classified into four distinct types based on their clinical presentation: infiltrative (restricted eye movement and occasionally enophthalmos), mass effect (proptosis or displacement of the globe), inflammatory (reduced vision, eye pain, redness), and functional (cranial nerve dysfunction, visual symptoms without prominent external signs) [4, 19]. Our patient’s symptoms—progressive floaters, blurred vision, and lack of pain or redness—were consistent with the functional category. Ophthalmologic imaging identified a solitary choroidal mass, and although biopsy was not performed, clinical and radiographic findings strongly supported the diagnosis of choroidal metastasis.

In clinical practice, the decision to pursue a biopsy for suspected orbital metastasis depends on the level of diagnostic certainty and its potential impact on management. Biopsy is generally recommended in cases where the primary is unknown, imaging findings are atypical, or when histopathological confirmation would influence treatment decisions. The potential benefit of biopsy lies in providing a definitive histopathological diagnosis, particularly in cases of diagnostic uncertainty or when it may alter therapeutic management. However, in patients with a known primary malignancy and characteristic imaging features, a presumptive diagnosis may be sufficient. Previous case reports have emphasized that the decision to perform orbital biopsy should be guided by a careful assessment of whether the results would alter clinical management, given the associated procedural risk, including visual loss, hemorrhage, and diplopia. In addition, other reports highlighted that the orbital metastases may be misdiagnosed due to atypical presentation, leading to delays in appropriate oncologic management, and have recommended comprehensive staging and multidisciplinary evaluation prior to biopsy [21]. In the present case, the diagnosis of choroidal metastasis was supported by clinical context and multimodal imaging, and the patient declined biopsy, making non-invasive evaluation the preferred approach.

Similarly, oral metastases can present with a variety of symptoms, including localized pain, inflammation, or paresthesia, which often complicates and delays diagnosis [14]. In this case, the patient experienced recurrent oral bleeding initially attributed to a Mallory-Weiss tear. However, subsequent examination revealed a polypoid mass on the maxillary gingiva, which was confirmed by biopsy to be metastatic HCC. MRI showed asymmetric enhancement of the right maxilla with extension into the oral cavity, consistent with local invasion.

Histologically, oral metastatic HCC lesions may exhibit strands or duct-like structures composed of hepatocyte-like cells within a richly vascular stroma. These features can mimic adenocarcinoma due to a pseudo-glandular pattern or appear poorly differentiated, making it challenging to determine the tumor’s original type. Therefore, immunohistochemical (IHC) staining is essential for diagnosis [16]. In our case, IHC demonstrated strong positivity for pancytokeratin, HepPar-1, and glypican-3, confirming the diagnosis of metastatic HCC.

For orbital metastases, therapeutic strategies are primarily palliative due to typically advanced stages at presentation and limited survival, often less than 12 months [22]. Patients with HCC that has metastasized to the orofacial region generally face a poor prognosis, with an average overall survival (OS) of just 21 weeks and only 15% surviving beyond one year after diagnosis [23]. The apparent difference in survival between oral and orbital metastases may reflect underlying differences in overall disease burden and pattern of dissemination. Oral metastases are often associated with more widespread systemic disease, which may contribute to a more advanced clinical stage at presentation. In contrast, orbital metastases may be detected earlier due to prominent visual symptoms, potentially allowing for earlier clinical evaluation. Additionally, variability in reported outcomes may reflect differences in treatment approaches, as well as limitations related to the small number of cases available in the literature. Therefore, these survival estimates should be interpreted with caution [20, 21].

This outlook remains unfavorable even with treatment directed at the primary tumor, such as surgery, radiotherapy, TACE, or systemic therapy [23]. The decision to pursue systemic versus local therapy depends on disease extent, patient performance status, and symptom burden. In cases with isolated or limited involvement, local treatments may provide temporary symptom control; however, systemic progression often limits long-term outcomes. Therefore, early multidisciplinary evaluation is crucial to tailor treatment plans and optimize both quality of life and disease management [22].

Clinically diagnosed cases of HCC metastasizing to the orbit are exceedingly rare. Over the past 39 years, only 33 cases have been reported in the literature, with the earliest reported in 1980 [15, 24].

The first documented case of HCC metastasizing to the mandible was reported by Dick et al. in 1957 [25]. Since that initial report, approximately 80 cases of oral metastasis from HCC have been documented, with the most comprehensive literature review to date summarizing 77 of them [23]. A comprehensive review by Pesis et al. [26] published in 2014 analyzed 41 cases of HCC metastasis to the jaws reported prior to 2012, highlighting the rarity of oral cavity involvement and its frequent presentation as an initial manifestation of disease. These historical cases are summarized as a single entry in Table 1, while the present review emphasizes more recently reported individual cases to provide updated clinical context.

We conducted a systematic search of PubMed for reports of orbital and oral metastases from HCC published over the past decade. This review identified a total of 76 cases, comprising 17 orbital and 59 oral cavity metastases. The clinical details of these patients are summarized in Table 1. Notably, our case is the only documented instance of HCC presenting simultaneous metastases to both the orbital and the oral cavity. Although prior reports have described the involvement of each site separately, no previous publication has reported concurrent metastases to both regions. This underscores the rarity of our case and highlights the aggressive and widespread nature of disease dissemination. To the best of our knowledge, this represents one of the very few reported cases of HCC with synchronous metastases to both the choroid and oral cavity.

In advanced HCC, rare metastatic sites such as the orbit and oral cavity can emerge, often presenting with subtle or misleading symptoms that may be easily overlooked. Because these atypical presentations, such as persistent visual disturbances or unexplained oral bleeding, can signal disease progression, they warrant prompt and targeted clinical evaluation. Managing such complex cases effectively requires a dedicated multidisciplinary approach to ensure that these unusual symptoms are addressed within a comprehensive care plan.