A 24-year-old male patient complained of abdominal pain in August 2018. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) scan detected a mass in his left kidney, with Mayo level IV inferior vena cava tumor thrombus ( Figure 1 ). He had no family history and a radical nephrectomy and inferior vena cava thrombectomy were performed in September 2018. Intraoperative examination found the tumor extended to the right atrium and invaded the wall of the vena cava. A grayish-yellow mass with 11 cm x 7 cm in size with papillary arrangement, irregular nucleus, and large nucleoli and renal venous tumor thrombus formation was identified ( Figure 1 ). Resection margins were negative, and 8 lymph nodes around the renal pedicle were negative. Histology showed was high-grade RCC, papillary type with vena cava tumor thrombus ( Supplementary Figure 1 ). Immunohistology chemistry (IHC) staining indicated CK(pan)(+), p63(-), Napsin A(-), PAX-8(+), Vimentin (+), CK7(-), CD10(+), E-cadherin(+), CD117(-), P504S(+), TFE3(-). Pathological staging was pT3cN0M0, stage III.
Genomic profiling of DNA extracted from tumor specimen and peripheral white cell was performed through next-generation sequencing (NGS). NGS results revealed that TMB (tumor mutation burden) value was 4.03 mutants/Mb and the microsatellite state was stable. IHC indicated that PD-L1 Tumor Proportion Score (TPS) was 25% ( Supplementary Figure 1 ).
Germline mutations of his peripheral blood revealed one FH (Fumarate hydratase) gene germline mutation p.G346Vfs*11 was identified, which has been confirmed as a pathogenic mutation. His tumor sections were stained with anti-FH and anti-2-succinocysteine (2SC) antibodies to confirm the diagnosis ( Supplementary Figure 1 ). His final diagnosis was hereditary leiomyomatosis and renal cell cancer (HLRCC), an unusual and highly aggressive form of renal carcinoma. Furthermore, a CYP2C19 p.P227P mutation was detected, which is reported to contribute to a minor (10%) pathway of axitinib metabolism.
Sunitinib (50-mg QD orally) was used as an adjuvant treatment after surgery. Abdominal enhanced CT in May 2019 suggested metastatic lesions in the liver and right adrenal gland ( Figure 3 ). Axitinib (5-mg BID orally) was used as first-line treatment. Response evaluation by B-ultrasound after 1 month confirmed progression of disease ( Supplementary Figure 2 ). Based on the results of KEYNOTE-426 which demonstrated axitinib in combination with pembrolizumab conferred a survival benefit for patients with advanced RCC in the first line setting, subsequent treatment with this was given from June 2019 but dosing of pembrolizumab was 100 mg every 3 weeks due to economic considerations. Response evaluation after one dose of pembrolizumab showed a partial response, with shrinkage of hepatic and right adrenal lesions, and response persisted for 5 months ( Supplementary Figure 1 ). However, the patient developed vision deterioration within 3 weeks of the first dose of pembrolizumab, but he did not inform the doctor. In January 2020, his vision deteriorated quickly, and he was referred to an ophthalmologist.
A slit-lamp examination revealed no kerato-precipitates. Tyndall effect was observed and anterior chamber (AC) cells were not obvious in both eyes. His best corrected visual acuity (BCVA) was 0.4 in the both eyes. The intraocular pressure was 13 mmHg in the right eye and 11 mmHg in the left eye. Dilated fundus examination indicated vitreous floaters were not obvious. Large areas of depigmentation were observed in retina, and local pigmentation were noticed ( Figure 2 ). Posterior and inferior retinal detachment was observed. Ultrasound examination detected minimal echogenicity in the vitreous and posterior and inferior retinal detachment. Fluorescein (FFA) angiography showed dotted hyperfluorescence in early phase and a little leakage in the maculae. Optical coherence tomography (OCT) revealed neuroepithelial detachment with spotty to patchy high signal, and the choroid is thickened significantly.
The diagnosis was posterior uveitis with bilateral retinal detachment. Immune-related tests and infection-related tests were also performed to rule out uveitis caused by infection or tumor metastasis. The complete blood count (CBC) results were normal and his erythrocyte sedimentation rate (ESR) was increased. Serologic investigations revealed negative for bacterial infection, rheumatoid factor, and tuberculosis. Serum cytokine release was tested, including IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma, and IL-17A. Among these, IL-6 and IL-17A were increased ( Table 1 ). From the time of occurrence, the ocular adverse events may due to immune checkpoint inhibitor. Based on the CTCAE (Common Terminology Criteria for Adverse Events; version 5.0), his ocular irAE was categorized as grade 3. He was treated with intravenous methylprednisolone 60 mg (1 mg/kg) systematically, followed by oral methylprednisolone. Treatment with topical prednisolone acetate (1%) every 2 h was initiated in the both eyes. Follow-ups of OCT is shown in  Figure 3 . Eye MRI at January 2020 also confirmed a thickening of posterior walls ( Figure 3 ). His endocrine results indicated hypothyroidism, which was considered as an irAE, and levothyroxine tablets were commenced.
Our multidisciplinary team decided to permanently discontinue his use of pembrolizumab. At follow-up in February 2020, progressive disease in his adrenal, hepatic and bones were observed ( Supplementary Figure 3 ). There was no indication of metastatic lesions in his eyes. Third-line systemic therapy of bevacizumab and erlotinib was initiated, and the patient responded well to the combination therapy. The timeline of his diagnosis, treatment and onset of irAE were shown in  Supplementary Figure 4 .