Stereotactic body radiotherapy using the CyberKnife system for cutaneous metastasis of hepatocellular carcinoma: a case description

Introduction

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide (1). Although substantial progress has been made in diagnostic techniques and therapeutic strategies, tumor recurrence and distant metastasis continue to pose significant threats to long-term survival (2). The lungs, bones, and adrenal glands are recognized as the most frequent sites of HCC metastasis, whereas cutaneous involvement is relatively rare (3). Previous studies have shown that the incidence of skin metastasis is only 0.8% (4). However, the clinical burden associated with cutaneous metastasis warrants careful consideration.

Cutaneous metastatic lesions can significantly impair quality of life. Proliferation of malignant cells within the skin often results in nodular lesions that are accompanied by persistent pain and may progress to ulceration or bleeding (5). In addition, skin metastases are frequently misdiagnosed as benign tumors, such as lipomas or sebaceous cysts. Such diagnostic delays may impede appropriate intervention and are associated with reduced survival (6).

At present, the management of metastatic HCC is centered primarily on systemic therapy. In the setting of oligometastatic disease, the integration of local ablative approaches with systemic treatment has been shown to improve clinical outcomes and alleviate symptoms, thereby enhancing quality of life (7). Stereotactic body radiotherapy (SBRT) is a non-invasive form of high-precision external beam radiotherapy that delivers ablative radiation to target lesions over a limited number of fractions, typically ranging from 3 to 10 in HCC (8). This technique achieves a steep dose gradient, allowing effective tumor control while minimizing exposure to surrounding normal tissues (9). The CyberKnife represents an advanced platform for SBRT. Its principal strengths include the combination of real-time image guidance, such as X-ray imaging or cone-beam computed tomography (CBCT), with a flexible robotic delivery system. This configuration permits continuous target tracking and automated beam adjustment throughout treatment (10). To date, published reports describing the use of CyberKnife for the treatment of cutaneous metastases from HCC are extremely limited. The present case report provides a detailed description of a patient with an isolated cutaneous metastatic lesion from HCC who was successfully treated with CyberKnife-based SBRT, with the aim of informing clinical decision-making in similar cases.

Case presentation

The patient was a 68-year-old woman with a history of hepatitis B virus infection diagnosed in 2002 and liver cirrhosis identified in October 2020. Antiviral therapy with oral entecavir dispersible tablets had been administered on a long-term basis. In December 2020, a progressive elevation in serum alpha-fetoprotein (AFP) levels was noted, reaching 422 ng/mL. Subsequently, contrast-enhanced abdominal magnetic resonance imaging (MRI) was performed (Figure 1), which demonstrated a space-occupying lesion in hepatic segment VIII measuring approximately 1.0 cm × 0.8 cm and was considered highly suggestive of malignancy. Additional diagnostic evaluations revealed no evidence of distant tumor dissemination.

Figure 1 Abdominal MRI performed in December 2020. A hepatic lesion located in segment VIII was identified and clinically diagnosed as hepatocellular carcinoma based on the patient’s medical history. (A) Early arterial phase MRI scan, (B) late arterial phase MRI scan, (C) early portal venous phase MRI scan, (D) delayed phase MRI scan. The red arrow indicates the hepatic lesion. MRI, magnetic resonance imaging.

In the context of a prolonged history of chronic hepatitis B, established cirrhosis, and increased AFP levels, a clinical diagnosis of primary HCC was made. The patient elected to undergo local radiotherapy using the CyberKnife system. The treatment plan for primary liver cancer with CyberKnife was generated using the G4 CyberKnife system with MultiPlan software (version 4.0.2). The prescribed dose was 50 Gy delivered in 5 fractions, with the 72% isodose line covering the planning target volume (PTV). The PTV was required to receive at least 95% of the prescribed dose (PTV D95% ≥47.5 Gy). Respiratory motion management was performed using the Synchrony respiratory tracking system, with fiducial markers implanted around the lesion for tracking. For the skin metastasis, four fiducial markers were implanted within 4 cm of the lesion. The treatment plan was generated using the VSI CyberKnife system with MultiPlan software (version 4.1.6). The gross tumor volume (GTV) was contoured on CT images, and the PTV was defined as the GTV plus a 3-mm margin. The prescribed dose was 50 Gy delivered in 10 fractions, with the 80% isodose line covering the PTV, and PTV D95% ≥47.5 Gy. Due to the fixed location of this superficial lesion, the 6D skull tracking algorithm was used for target tracking, without the need for respiratory motion management. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. No acute radiation dermatitis (grade 0) or treatment-related worsening of pain was observed during or after treatment. At the most recent follow-up (October 2025), no late toxicities, including skin ulceration, subcutaneous fibrosis, or rib pain, were reported. Liver function was assessed before and after treatment. Serum albumin, total bilirubin, and prothrombin time remained within normal ranges, with no evidence of radiation-induced liver injury. Radiation exposure to surrounding normal tissues remained within the tolerance thresholds recommended by the TG-101 guidelines for SBRT (Figure 2).

Figure 2 Stereotactic body radiotherapy treatment plan generated using the G4 CyberKnife MultiPlan software (version 4.0.2). A total prescribed dose of 50 Gy was delivered in five fractions.

No additional anti-tumor therapy was administered following the initial treatment. The patient was monitored at three-month intervals through December 2022, during which time no evidence of tumor recurrence or metastatic disease was detected. In February 2023, a newly developed cutaneous mass was noted in the right upper abdominal region and was associated with localized tenderness. Subsequent contrast-enhanced abdominal MRI revealed a nodule in the subcutaneous tissue measuring 0.89 cm × 0.66 cm. There was no indication of recurrence at the original hepatic lesion site (Figure 3). Further evaluation with chest computed tomography and cranial MRI demonstrated no signs of disease relapse or distant metastasis.

Figure 3 Abdominal MRI performed in February 2023 demonstrating an oval-shaped, well-circumscribed mass with homogeneous high signal intensity within the subcutaneous tissue (arrow). (A) Early arterial phase, (B) late arterial phase, (C) early portal venous phase, (D) delayed phase. The enhancement pattern of the cutaneous metastasis from hepatocellular carcinoma across different phases is shown. MRI, magnetic resonance imaging.

It should be noted that prior to the development of the cutaneous metastatic lesion, the patient had not undergone any invasive procedures such as percutaneous liver biopsy, radiofrequency ablation, transarterial chemoembolization, or hepatic resection. The only prior local treatment was CyberKnife radiotherapy for the primary hepatic tumor. Therefore, the subcutaneous metastasis was considered spontaneous.

An aspiration biopsy of the cutaneous nodule was performed. Histopathological examination and immunohistochemical analysis confirmed the lesion as a metastasis originating from the hepatic malignancy. Tumor cells exhibited strong and diffuse immunoreactivity for HepPar-1 and Ki-67 (Figures 4,5). The patient subsequently elected to receive repeat CyberKnife treatment. Four fiducial gold markers were implanted in the skin surrounding the metastatic lesion, all positioned within a 4-cm radius. Following CT-based localization, the GTV and organs at risk, including the normal liver, lungs, and spinal cord, were delineated. The PTV was defined by expanding the GTV by a uniform margin of 3 mm. A total radiation dose of 50 Gy was delivered over 10 fractions. Dose constraints for surrounding normal tissues complied with the tolerance limits recommended in the TG-101 guidelines for SBRT (Figure 6). By October 2023, the cutaneous metastatic lesion had completely resolved (Figure 7). At the most recent follow-up in October 2025, no recurrence of the primary hepatic tumor or development of new metastatic lesions was observed. The detailed clinical timeline and serial serum AFP levels are shown in Figure 8.

Figure 4 Immunohistochemical staining for HepPar-1. (A) Strong and diffuse positivity for HepPar-1 was present in the cells of the nodular tissue (immunohistochemical staining for HepPar-1, 100×). (B) HepPar-1 immunohistochemical staining at higher magnification (400×).

Figure 5 Immunohistochemical staining for Ki-67. (A) Strong and diffuse nuclear positivity for Ki-67 was observed in the cells of the nodular tissue (original magnification 100×). (B) Ki-67 immunohistochemical staining at higher magnification (400×).

Figure 6 SBRT treatment plan designed using the VSI CyberKnife MultiPlan software (version 4.1.6). The prescribed radiation dose was 50 Gy, administered in 10 fractions. SBRT, stereotactic body radiation therapy.

Figure 7 Abdominal MRI performed in October 2023 following SBRT, demonstrating complete resolution of the subcutaneous metastatic lesion. (A) Early arterial phase, (B) late arterial phase, (C) early portal venous phase, (D) delayed phase. No residual enhancing lesion is seen in any phase. The red arrow indicates the site of the previously treated lesion, which has completely resolved. MRI, magnetic resonance imaging; SBRT, stereotactic body radiation therapy.

Figure 8 Timeline and the timeline graph of serum AFP levels. The horizontal axis represents time, and the vertical axis represents serum AFP levels (ng/mL). Key clinical events are indicated by arrows above the corresponding time points. AFP, alpha-fetoprotein.

All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of 980 Hospital of the People’s Liberation Army Joint Logistics Support Forces (No. 2025-KY-242). Written informed consent was obtained from the patient for the 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 report describes an uncommon presentation of cutaneous metastasis originating from HCC that was successfully treated with SBRT delivered via the CyberKnife system. In routine clinical practice, skin or subcutaneous metastasis from HCC is infrequently encountered (3). The majority of published cases are linked to iatrogenic tumor dissemination, including seeding along needle tracts following percutaneous interventions or surgical procedures. In contrast, spontaneous cutaneous metastasis occurring in the absence of prior invasive manipulation, as observed in the present case, is particularly rare (11). The patient's clinical history confirmed no previous percutaneous interventions or surgical procedures that could have resulted in needle tract seeding.

Accordingly, it is plausible that changes within the cutaneous microenvironment may contribute to the development of skin metastases from HCC through related biological pathways. The presence of cutaneous metastasis in patients with HCC generally reflects a more aggressive tumor phenotype and is often interpreted as an indicator of systemic disease dissemination. From a diagnostic perspective, the histopathological identification of skin metastasis from HCC can be challenging. Such lesions must be distinguished from other primary or metastatic skin tumors (5), and immunohistochemical analysis is typically required to establish a definitive diagnosis. Hepatocyte paraffin-1 (HepPar-1) is regarded as one of the most sensitive markers for hepatocellular differentiation (12). In the present case, strong positivity for HepPar-1 and Ki-67, together with the documented clinical history, supported a diagnosis of cutaneous metastasis originating from HCC.

Surgical resection was initially considered as a therapeutic option; however, the patient was of advanced age with a history of liver cirrhosis and poor general condition. The patient expressed a clear preference for non-invasive treatment, and the presence of thrombocytopenia increased the risk of surgical bleeding. Consequently, surgical intervention was not pursued.

Following the occurrence of this rare cutaneous metastasis, multiple treatment modalities were available, including electron beam therapy and other radiotherapeutic approaches. This patient had previously received CyberKnife treatment for the primary hepatic tumor, achieving long-term local control (disease-free for more than two years). The patient explicitly preferred to undergo the same non-invasive technique again. Furthermore, the cutaneous metastatic lesion was located in close proximity to the previous radiation field. The steep dose gradient characteristic of CyberKnife allows for precise irradiation of the metastatic lesion while minimizing cumulative dose to the adjacent liver and surrounding skin. Based on these individualized factors, CyberKnife treatment was selected for this case. It should be noted that due to the extreme rarity of cutaneous metastasis from HCC, no large-scale clinical trials or treatment guidelines currently provide definitive recommendations regarding the choice of radiotherapy technique for such lesions. This case report aims to provide clinicians with a feasible reference for individualized treatment.

Literature review reveals limited reports on the outcomes of local treatment for cutaneous metastasis from HCC. Most reported cases have been managed with surgical excision or conventional radiotherapy. In the series reported by Jia et al. (12), surgical resection achieved local control in 10 of 12 patients, with 2 recurrences during follow-up. Ahn et al. (11) reported 3 cases of needle tract seeding, all treated with surgical excision, with no recurrence observed during follow-up periods of 6-24 months. Morishita et al. reported a case of giant facial cutaneous metastasis from primary HCC, which showed significant tumor shrinkage after transarterial embolization (TAE) following immunotherapy with atezolizumab plus bevacizumab (13). The present case adds to this limited body of evidence, demonstrating sustained local control with more than two years of follow-up. Compared with surgical excision, SBRT offers a non-invasive alternative, particularly suitable for patients with limited functional status or lesions located in anatomically challenging positions.

The CyberKnife system utilized in this case represents an advanced form of SBRT characterized by the generation of a markedly steep dose gradient. This feature allows maximal sparing of the surrounding normal skin and underlying tissues. At the same time, the technology enables delivery of a highly concentrated radiation dose to the target lesion, with rapid dose fall-off to adjacent normal structures, thereby enhancing treatment precision and safety (14).

Previous studies have demonstrated that the risk of skin toxicity associated with SBRT is closely influenced by the distance between the target lesion and the skin surface, as well as by radiation beam configuration. These investigations have also highlighted the advantages of the CyberKnife system in achieving precise dose modulation when treating cutaneous metastatic lesions (15). Owing to its non-invasive nature and high level of dosimetric accuracy, CyberKnife-based SBRT may be particularly appropriate for older patients with limited functional status or for those who are not suitable candidates for surgical intervention. In the present case, CyberKnife was applied to treat a localized cutaneous metastasis, and durable local control was achieved, with no evidence of tumor recurrence during more than two years of follow-up.

Despite these favorable findings, several limitations should be considered. As a single case report, the level of evidence is limited. The therapeutic benefit observed requires validation through larger retrospective series or prospective cohort studies. In addition, the optimal dose and fractionation schedule for SBRT in the management of cutaneous metastases from HCC have yet to be clearly defined. Overall, this case provides preliminary support for the use of SBRT-based local ablation, exemplified by the CyberKnife system, as a potentially feasible treatment approach that may offer sustained local control in appropriately selected patients with oligometastatic subcutaneous lesions arising from HCC.

Acknowledgments

None.

Footnote

Funding: This work was supported by the 2022 Medical Science Research Project Plan of Hebei Province (No. 20220231).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0343/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 Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Bethune International Peace Hospital (No. 2025-KY-242). Written informed consent was obtained from the patient for the 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/.

References

1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
2. Brown ZJ, Tsilimigras DI, Ruff SM, Mohseni A, Kamel IR, Cloyd JM, Pawlik TM. Management of Hepatocellular Carcinoma: A Review. JAMA Surg 2023;158:410-20. [Crossref] [PubMed]
3. Arora S, Harmath C, Catania R, Mandler A, Fowler KJ, Borhani AA. Hepatocellular carcinoma: metastatic pathways and extra-hepatic findings. Abdom Radiol (NY) 2021;46:3698-707. [Crossref] [PubMed]
4. Natsuizaka M, Omura T, Akaike T, Kuwata Y, Yamazaki K, Sato T, Karino Y, Toyota J, Suga T, Asaka M. Clinical features of hepatocellular carcinoma with extrahepatic metastases. J Gastroenterol Hepatol 2005;20:1781-7. [Crossref] [PubMed]
5. Fang L, Simman R, Workman L, Ayoub S, Bratton C. Malignant wound aetiology, diagnosis and management: a case series and literature review. J Wound Care 2024;33:102-17. [Crossref] [PubMed]
6. Jaros J, Hunt S, Mose E, Lai O, Tsoukas M. Cutaneous metastases: A great imitator. Clin Dermatol 2020;38:216-22. [Crossref] [PubMed]
7. Farsad K, Nabavizadeh N, Kardosh A, Jou JH, Naugler WE, Kolbeck KJ. Combined locoregional and systemic therapy for advanced hepatocellular carcinoma: finally, the future is obscure. Ann Transl Med 2020;8:1700. [Crossref] [PubMed]
8. Lewis S, Barry A, Hawkins MA. Hypofractionation in Hepatocellular Carcinoma - The Effect of Fractionation Size. Clin Oncol (R Coll Radiol) 2022;34:e195-e209. [Crossref] [PubMed]
9. Abe T, Iwanaga M, Igari M, Hirai R, Kumazaki Y, Noda SE, Kato S. Stereotactic body radiotherapy with CyberKnife for liver-confined hepatocellular carcinoma: systematic review and meta-analysis. J Radiat Res 2025;66:451-8. [Crossref] [PubMed]
10. Cheng Y, Lin Y, Long Y, Du L, Chen R, Hu T, Guo Q, Liao G, Huang J. Is the CyberKnife© radiosurgery system effective and safe for patients? An umbrella review of the evidence. Future Oncol 2022;18:1777-91. [Crossref] [PubMed]
11. Ahn DW, Shim JH, Yoon JH, Kim CY, Lee HS, Kim YT, Kim YJ. Treatment and clinical outcome of needle-track seeding from hepatocellular carcinoma. Korean J Hepatol 2011;17:106-12. [Crossref] [PubMed]
12. Jia J, Luo J, Zou B, Feng M, Liu L, Yu S, Zheng S, Yu J. Non-iatrogenic implantation of cutaneous metastasis from hepatocellular carcinoma. J Cancer Res Clin Oncol 2023;149:1513-9. [Crossref] [PubMed]
13. Morishita A, Tani J, Oura K, Tadokoro T, Fujita K, Masaki T. Giant cutaneous metastasis from hepatocellular carcinoma. JGH Open 2022;6:361-2. [Crossref] [PubMed]
14. Shyllon S, Penfold S, Dalfsen R, Kirkness E, Hug B, Rowshanfarzad P, Devlin P, Tang C, Le H, Gorayski P, Grogan G, Kearvell R, Ebert MA. Dosimetric comparison of proton therapy and CyberKnife in stereotactic body radiation therapy for liver cancers. Phys Eng Sci Med 2024;47:1203-12. [Crossref] [PubMed]
15. Srivastava SP, Jani S, Pinnaduwage D, Xiangsheng Y, Castaneda D, Patel S, Thawani N, Das IJ, Sorensen SP. Understanding Parameters Affecting Surface Dose to Reduce Skin Toxicity in Patients Treated with SBRT. International Journal of Radiation Oncology, Biology, Physics 2019;105:E773-4. [Crossref]