Omr A Mownh ,, John D Lehy , Jeffrey Summers , Stephen M Gregory ,Nigel D Heton

a Institute of Liver Studies, King’s Healthcare Partners, King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK

b Department of Oncology, Maidstone and Tunbridge Wells NHS Trust, Maidstone ME16 9QQ, UK

Granulosa cell tumor (GCT) is the most common sex cordstromal tumor, comprising 5% of all ovarian malignancies [1].The disease course is indolent, and the majority of cases present at stage 1.However, metastases may develop with potential sites being peritoneum, lung, brain, liver and bone [2].Due to the rarity of the disease, published evidence for management of granulosa cell tumor liver metastases (GCTLM) is limited.Surgical resection is the optimal treatment in instances where there is a high chance of achieving complete resection [3].With regards to unresectable GCTLM there is a paucity of evidence to guide treatment strategy.

There is evidence demonstrating GCT sensitivity to radiation therapy and therefore in cases of GCTLM, radiation therapy is a potential, but unproven, treatment modality [4].Selective internal radiation therapy (SIRT) for liver malignancy has demonstrated efficacy for disease control of hepatocellular carcinoma (HCC) and colorectal (CRLM) and breast cancer liver metastases [5-7].SIRT is recommended for advanced stages of HCC and CRLM by the UK National Institute for Health and Care Excellence (NICE) [ 8 , 9 ].However, NICE does not currently recognize GCTLM as suitable for SIRT.We report a case of GCTLM where SIRT was considered to offer disease control.Exceptional approval from the regional oncology panel was successful and treatment given.

A 63-year-old female with a history of subtotal hysterectomy,left salpingo-oophorectomy and right ovarian cystectomy for GCT was referred having developed right-sided ureteric obstruction secondary to local retroperitoneal recurrence four years later.This was treated with debulking surgery which included partial right ureterectomy (reconstructed with primary anastomosis) and inferior vena cava repair with saphenous vein graft.Surveillance computed tomography (CT) scan 8 years later demonstrated multiple small, low-density liver lesions which were suspicious for GCTLM.

Magnetic resonance imaging (MRI) and lesional biopsy confirmed the diagnosis of GCTLM.The lesions did not display avidity on fluorodeoxyglucose (FDG) positron emission tomography (PET)scan.Laparoscopic resection of two liver metastases was performed and histological analysis confirmed the GCT origin.The tumors measured 12 and 14 mm with margins microscopically free of disease.However, the background liver was noted to have histological features of cirrhotic transformation consisting of regenerative nodules of 2-5 mm in diameter.Portal and lobular inflammation was noted to be mild.Steatosis was seen in 10% of hepatocytes with balloon degeneration of hepatocytes focally observed,although serum markers of liver function (bilirubin, alkaline phosphatase, aspartate aminotransferase and gamma-glutamyl transferase) were normal.The cause of cirrhosis was not clear but may have been caused by autoimmune hepatitis.

Surveillance CT and MRI at 6 months post-surgery showed multiple liver lesions in the right hemi-liver.The left hemi-liver was clear of disease but due to the established liver disease (with evidence of oesophageal varices), portal pressure measurements and transjugular liver biopsies were performed to assess for safety of right hepatectomy.Portal pressures were normal, but the liver biopsy showed septal bridging fibrosis with focal nodular demarcation.Focal subsinusoidal fibrosis was present with mild portal inflammation.Minimal steatosis was seen with focal minimal steatohepatitis.Overall, the appearances were in keeping with macronodular cirrhosis and concordant with the histological findings from the prior hepatectomy.Liver transplantation was considered but was precluded by the development of a spinal metastasis.

The patient received radiotherapy for the lumbar spinal metastasis with good response.A 22 mm nodule in the left lung base and 12 mm nodule in the right upper lobe were identified with appearances suspicious for lung metastases.Given that burden of extrahepatic disease was low and potentially treatable, an application was made to the regional oncology panel for consideration of SIRT based on reports of a high degree of sensitivity of GCT to radiotherapy.The application was successful and the patient proceeded to planning arteriography (stage 1 SIRT).This identified satisfactory distribution of99mTc-macro-aggregated albumin with an acceptable lung shunt of 2%.Four weeks later, stage 2 SIRT took place using Yttrium-90 resin microspheres to a right lobe volume of 585 mL (mean dose 47 Gray) with the dose split to two delivery sites.

Response to SIRT was assessed with CT at 6 weeks post procedure.The images showed a good response with the tumors decreasing in size and appearing necrotic ( Figs.1 and 2 ).The previously noted pulmonary lesion appeared stable.

Fig.1.CT images prior to treatment with selective internal radiation therapy ( A ) with post-treatment images demonstrating evidence of response ( B ).CT: computed tomography.

Fig.2.Further CT images prior to treatment with selective internal radiation therapy ( A ) with post-treatment images demonstrating evidence of response ( B ).CT: computed tomography.

The lung metastases were treated with stereotactic ablative radiotherapy (SABR) 6 months following the SIRT treatment to the liver.The dose of 55 Gray was delivered in 5 fractions and the treatment was well tolerated.The post-treatment CT scan showed good response with the right upper lobe metastasis reduced in size from 12 to 10 mm and a left lower lobe metastasis reduced from 22 to 10 mm.At 9 months following SIRT follow-up, CT confirmed that the patient remained without evidence of progressive liver disease.

GCTs are associated with late recurrence up to 25 years following initial diagnosis [10].In this case the diagnosis of liver metastases occurred 12 years following resection of the primary tumor.To our knowledge, this is the first reported instance of SIRT being used for the treatment of GCTLM.Treatment resulted in regression of liver metastases with FDG-PET scan demonstrating non-avidity at 6 months follow-up.

SIRT is a locoregional radiation therapy utilizing radioisotopecontaining microspheres which are injected via hepatic arterial branches feeding tumor [11].The procedure consists of two stages.In the first stage non-invasive imaging is examined and a planning angiogram is obtained.The risk of lung shunt is assessed and the optimal dose of radiation therapy is calculated based on the tumor size, vasculature and degree of shunt.In the second stage, the radiation-containing microspheres are injected.The procedure has a favorable safety profile compared with externally delivered radiotherapy due to the short penetration distance of beta-irradiation,limiting the radiation effects to the liver [12].Radiation-induced liver disease may affect up to 4% of cases.Other complications include radiation pneumonitis (depending on the degree of lung shunt), gastrointestinal ulcers and non-specific symptoms (similar to post-transarterial chemoembolization syndrome).

The main indication for SIRT is for treatment of HCC.The SARAH randomized-controlled trial included HCC patients with locally advanced disease, failed transarterial chemoembolisation and unresectable disease [5].SIRT was demonstrated to be safe in this group of patients with comparable mean overall survival when compared with sorafenib.This finding was supported by the SIRveNIB study where SIRT was also found to be associated with fewer complications than sorafenib [13].In early unresectable HCC, SIRT has been shown to downstage disease in up to 27% of cases to allow liver transplantation or resection [14].

For CRLM, the SIRFLOX trial compared the addition of SIRT to chemotherapy with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) and bevacizumab.The SIRT group was associated with superior response in liver disease burden, but with no difference in mean overall survival [15].Forty percent of patients in this study had extrahepatic disease.A meta-analysis by Wasan et al.which included this trial and the FOXFIRE and FOXFIRE-Global trials concluded that the addition of SIRT to systemic chemotherapy did not improve overall survival [6].

Therapeutic guidance for many conditions in the UK is overseen by NICE.In March 2020, NICE recommended SIRT as an option for treating CRLM patients who were intolerant of chemotherapy or had disease refractory to first and second line agents [8].In March 2021, HCC was added by NICE as an indication for SIRT for Child-Pugh A cirrhosis where transarterial chemoembolization(TACE) was not possible [9].In reporting this case we have demonstrated that SIRT results in tumor regression in GCTLM and should be considered for cases where surgery is not feasible.

Acknowledgment

None.

CRediT authorship contribution statement

Omar A Mownah:Formal analysis, Writing - original draft.John D Leahy:Writing - original draft.Jeffrey Summers:Methodology, Writing - review & editing.Stephen M Gregory:Methodology, Writing - review & editing.Nigel D Heaton:Conceptualization, Supervision, Writing - review & editing.

Funding

None.

Ethical approval

This study was approved by the Local Ethics Committee.Consent for publication was obtained from the patient.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.