A Case Report of Choroidal Metastasis from Renal Cell Carcinoma during Sunitinib Treatment: A Tumor “Pharmacologic Sanctuary”?

A Case Report of Choroidal Metastasis from Renal Cell Carcinoma during Sunitinib Treatment: A Tumor “Pharmacologic Sanctuary”? Raffaele Longo1*, Julie Egea1, Natacha Naoun1, Marco Campitiello1, Christian Platini1, Nada Eid1, Laurent Hennequin2, Jean-Marc Perone3 and Philippe Quétin4 1Division of Medical Oncology, “CHR Metz-Thionville”, 1 Allée du Château, 57085 Ars-Laquenexy, France 2Division of Radiology, “CHR Metz-Thionville”, 1 Allée du Château, 57085 Ars-Laquenexy, France 3Division of Ophthalmology, “CHR Metz-Thionville”, 1 Allée du Château, 57085 Ars-Laquenexy, France 4Division of Radiotherapy, “CHR Metz-Thionville”, 1 Allée du Château, 57085 Ars-Laquenexy, France


Introduction
The incidence of intraocular metastasis is between 2% and 9%, according to the international literature, the leading causes being lung and breast cancer in men and women, respectively [1,2]. Renal cell carcinoma (RCC) is the thirteenth most common cancer in the world; its main secondary locations are lung, liver, bone and subcutaneous tissues. We present a case report describing a patient with a metachronous choroidal metastasis (CM) from a RCC during Sunitinib therapy.

Case Report
In July 2006, a 52-year-old, Caucasian man was surgically treated for clear-cells RCC (stage I). The follow-up was uneventful until February 2015 when he was hospitalized for acute dyspnea. Laboratory tests were in the normal range. Chest CT-scan showed a distal, bilateral, pulmonary embolism associated with multiple lung and lymph node metastases ( Figure 1A, red arrows). PET-scan confirmed the metastatic lesions. A CTguided, percutaneous biopsy of a mediastinal lymph node was performed. Histology showed the presence of malignant epithelial cells with clear cytoplasm and small nuclei, arranged in a compact-alveolar (nested) or acinar growth pattern interspersed with intricate, arborizing vasculature. Immunoistochemical staining was positive for AE1/AE3, CD10 and vimentin and negative for TTF-1 and cytokeratin 7. This pattern was consistent with a metastasis from clear-cells RCC ( Figure 1B). According to Motzer/Heng classification, the patient was classified as intermediate risk FAF may be used to aid in the evaluation of the tumor margin. In 17% of CM patients, a primary neoplastic source may never be found. In this population it would be beneficial to obtain a definitive diagnosis through FNAB, with a preservation of visual function [1][2][3][4][5].
Whole-body PET/CT can be useful for clinical evaluation of CM patients. It allowed the screening of the entire body and directed extraocular biopsy. Commonly used for tumor staging, PET/CT can play a pivotal role in the detection of the primary cancer [1][2][3][4][5]. CM from RCC on therapy, as in our case, remains very exceptional. Chin et al. [9] described a rapid involution of RCC-associated CM with oral Sunitinib, which is in contradiction with our case where we showed a tumor response of lymph node and lung metastases but an isolated choroidal tumor progression, the choroid representing probably a "pharmacologic tumor sanctuary" during Sunitinib treatment. We have no hypothesis that could explain this difference in efficacy of Sunitinib compared to the case described by Chin et al. [9].
There is no international recommendation for CM treatment. The standard treatment remains external beam radiotherapy, applying 30 Gy in 10 fractions or 40 Gy in 20 fractions. The reported complete response and improved visual acuity rates are 80% and 57% to 89%, respectively [10,11]. Radiation therapy consistently shows rapid symptom alleviation, yield excellent local control and functional outcomes. However, there are only few reports on late toxicity after 6months given the unfavorable prognostic of CM patients. Selected patients may live more than two years, underlying the need to better assess mean and long term outcomes. Some authors have favored exclusive systemic strategies with omission of irradiation. The current literature suffers from the scarcity of prospective trials. Duration of tumor response following systemic therapy is rarely reported but appears less favorable as compared to radiotherapy. Systemic treatments may be proposed for pauci-symptomatic CM in a polymetastatic context while radiation therapy remains necessary in symptomatic CM either upfront or as an alternating treatment. Focalized radiation like brachytherapy and proton therapy may be proposed for isolated CM with long diseasefree interval between primary and CM, as these techniques have the potential to yield better tumor and functional outcomes in patients with long life expectancy [10,11].
The prognosis of CM patients is poor but is strictly correlated to the histology and the presence of concurrent extraocular metastases [1][2][3][4][5][6]. Our case also raises the question of how to treat patients presenting an isolated disease progression in the sites which are very difficult to be reached by systemic treatment. Based on tumor response of the other extraocular metastases, we decided to carry on Sunitinib therapy without changing systemic treatment, as we considered choroid as a "pharmacologic tumor sanctuary".

Conclusion
To our knowledge, this is the only case of RCC-associated CM during Sunitinib therapy in a patient responding to the treatment in the other extraocular sites. This isolated choroidal tumor progression is probably related to a poor intraocular diffusion of Sunitinib and/or its active metabolites which do not reach a sufficient drug concentration leading to a tumor control at this site. Choroid could represent a "pharmacologic tumor sanctuary" to Sunitinib therapy. and, from March to July 2015, he received a total of 3 cycles of Sunitinib therapy at the standard dose of 50 mg daily, following a "4 weeks on/2 weeks off " schedule. Whole-body CT-scan, realized after 3 cycles of treatment, showed a tumor response with an impressive reduction of lung and lymph node metastases ( Figure 1C, red arrows).
However, a few days after this radiology restaging, the patient presented a brutally, unexplained, blurred vision in his right eye. The fundoscopy revealed a hypopigmented, circumscribed, tumor, choroidal lesion associated with a secondary retinal detachment. A concurrent cataract did not allow us to take any picture of this lesion. At a new revision of the brain CT-scan images, an intra-ocular metastasis was identified ( Figure 1D, red arrow), associated with a secondary retinal detachment ( Figure 1D, green arrow). An external radiotherapy (30 Gy in 10 fractions) was administered without any relevant, clinical benefit. Considering tumor response in the other metastatic sites, Sunitinib treatment was continued and it is now ongoing.
The underlying CM mechanism is still unclear. The eye is a particular site. Blood ocular barrier systeme includes blood-aqueous and blood-retinal barrier. Until now, there are no conclusive studies about physiological properties of this barrier and intraocular drug molecular biodisponibility, particularly for cancer treatment [7]. Sunitinib is a small molecule that simultaneously inhibits multiple receptor tyrosine kinases (RTKs) that are implicated in tumour growth, pathologic angiogenesis and metastatic progression. Sunitinib has been showed to inhibit a wide range of kinases and was identified as a potent inhibitor of platelet-derived growth factor receptor β (PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-Like Tyrosine Kinase-3 (FLT3), colony stimulating factor receptor type 1 (CSF-1R) and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib and its primary active metabolite (SU012662) are metabolized primarily by the cytochrome P450 enzyme, CYP3A4. SU012662 comprises 23 to 37% of the total exposure [8].
To our knowledge, there are no data concerning intraocular diffusion of Sunitinib and its metabolites.