Eyelid Metastasis as the Initial Presentation of a Renal Cell Carcinoma: a Case Report and Review of the Literature.

Introduction: Renal clear cell carcinoma(ccRCC) accounts for about 85% of patients with renal carcinoma and is the most common pathological type of renal cancer. Renal clear cell carcinomas usually metastasize to the lungs, lymph nodes, liver, bones, and brain, with rare skin metastases, especially to the eyelids. In this study, we report the third current case of renal clear cell carcinoma with eyelid mass as its initial presentation. Case presentation: In this study, we describe in detail the case of a 62-year-old male patient with clear cell carcinoma of the kidney whose rst symptom was a mass of the right eyelid. The patient had no clinical manifestations other than eyelid mass before the diagnosis of renal clear cell carcinoma. After resection of eyelid mass, postoperative pathological and immunohistochemical studies showed clear cell carcinoma of the kidney. Subsequently, a computed tomography scan disclosed bilateral renal tumors, bilateral adrenal nodules, and nodules in the upper lobe of the left lung. At the time of writing, the patient was receiving sunitinib treatment and receiving regular outpatient follow-up. Discussion and conclusion: Metastasis of renal carcinoma to the eye is rare, especially with an eyelid mass as the initial presentation. If they occur before the diagnosis of cancer or years after nephrectomy, the diagnosis of the tumor may be missed. In this study, we report the rare case and review reports of renal cell carcinoma metastasizing to the eye to raise our awareness of this rare phenomenon.


Introduction
Renal clear cell carcinoma (RCC) is the most common form of renal tumor, accounting for up to 85% of cases. Men are more common than women (1.7 to 1), and most are older, with an average age of 64 [1,2]. Renal cell carcinoma has a poor prognosis, with an overall 5-year survival rate of 74%, a decrease to 53% in patients with local metastasis (stage III), and a 5year survival rate of less than 10% (16-20 months) in patients with distant metastasis (stage IV) [3,4]. A puzzling feature of distant metastasis of renal cell carcinoma is the long incubation period between initial diagnosis and the onset of metastatic disease, and the maximum incubation period reported in existing cases exceeding 25 years. This feature makes it di cult to follow up RCC patients [5]. We reviewed reports of RCC metastases to the eye. These reported cases were initially suspected to be eye diseases such as uveal melanoma, sebaceous cysts, lachrymal mixed tumor and orbital hemangioma, but were subsequently histologically con rmed to be metastatic renal cell carcinoma. These rare eye metastases can have a variety of eye symptoms and can be ignored and delayed if they occur before the cancer is diagnosed or years after nephrectomy. In this study, we reported a clear cell carcinoma of the kidney with an eyelid mass as the rst manifestation, and reviewed reports of RCC metastasis to the eye to improve our understanding of this rare phenomenon.

Case Report
A 62-year-old man was found to have a slow growth of upper eyelid nodules in his right eye one year ago. His vision, intraocular pressure, and fundus examination were all within the normal range, without skin ulcers, pigmentation, or tenderness (Fig. 1a). Plastic surgeons removed the eyelid tumor three months ago. Postoperative histopathological examination showed that the eyelid mass consisted of round and oval cell nests rich in hyaline cytoplasm, surrounded by abundant vascular network ( Fig. 1c and d). The immunohistochemical characteristics of the tumor (Vim+, CD10+, CK+, pax-8 +, RCC+, P504S+) were consistent with the characteristics of RCC ( Fig. 1e and f). Subsequently, a computed tomography (CT) scan revealed a circular soft tissue shadow of 83mm and 13mm in diameter at the lower pole of the left kidney and the lower pole of the right kidney, with uneven density. (Fig. 1b).In addition, positron emission and computer tomography (PET/CT) also revealed bilateral adrenal nodules and metastatic pulmonary nodules of 8 mm in the upper lobe of the left lung. According to the pathological stage (T4NxM1) and the patient's wishes, the patient nally chose the conservative treatment with the oral targeted drug sunitinib and monthly outpatient follow-up. This research was approved by the ethics committee of The First A liated Hospital of Medical College of Xi'an Jiaotong University, and written informed consent was obtained from the relative of the patient.

Discussion
At present, there is no standardized treatment for renal carcinoma with eyelid metastasis. We consider that patients with renal carcinoma with eyelid metastasis should be actively treated, and patients with single eyelid metastasis without metastasis of other organs should be surgically removed. Due to the special biological characteristics of renal carcinoma cells, most renal carcinomas are not sensitive to chemotherapy and radiotherapy. Previous studys showed that the prognosis of patients with simple surgical resection and metastasis combined with postoperative radiotherapy, cytokines, and immunotherapy was not satisfactory. In the era of targeted therapy, several large retrospective studies have shown that, for patients with metastatic renal cancer who can withstand surgery, targeted therapy after tumor reduction nephrectomy has a better prognosis than simple targeted therapy [6,7]. Besides, targeted drug combination therapy can be used as the second-line treatment for metastatic renal cancer. Following the FDA approval of sunitinib combined with everolimus for the second-line treatment based on this study in 2016, the current NCCN guidelines also recommend sunitinib combined with everolimus for the second-line treatment for patients with metastatic renal cancer [8]. The combination of targeted drugs and immune checkpoint inhibitors is also a trend in the treatment of metastatic renal cancer. Preclinical studies have shown that anti-angiogenic drugs can enhance the anti-tumor immune effect of the tumor microenvironment, and immune checkpoint inhibitors may induce a lasting response, so anti-angiogenic drugs combined with immune checkpoint inhibitors have a broad prospect for treatment strategies [9]. Therefore, for patients with single eyelid metastasis but no other metastasis, resection of primary renal carcinoma, metastasis, and combined targeted drug therapy may prolong the survival time and improve the quality of life of patients.
Distant metastases to renal clear cell carcinoma most frequently occur in the lung (45-50%), bone (10-49%), liver (14-20%), and brain (2-16%) [10]. It is unusual for RCC to metastasize to the eyelid with an eyelid mass as the rst symptom. Although hematogenous spread and lymphatic metastasis are the most common routes of tumor metastasis to the eyelid, no tumor invasion of the tissues around the eye and no metastasis to the skin was observed in this patient, so it was di cult for our patient to distinguish which type of metastasis was present. It is not clear why patients with renal cancer develop metastases many years after the removal of the primary lesion. The metastasis is not necessarily related to tumor size, that is, sometimes the primary tumor is large but does not metastasize. Sometimes the tumor is small and asymptomatic but has distant metastases. The prognosis of renal cell carcinoma with multiple metastases has always been poor, and early detection of renal cell carcinoma may improve 5-year survival. Debraj Shome et al. reviewed 71 reported cases of RCC metastases to the eye from 1934 to 2004 [11]. Here, we reviewed 35 cases of RCC metastases to the eyes reported in the English literature between 2004 and 2020 (Table 1) [5,. These two studies include 107 cases with metastasis to the eyebrow (1 case, 0.93%), extraocular muscles (1 case, 0.93%), tear ducts (3 cases, 2.80%), retinal (3 cases, 2.80%), conjunctival (4 cases, 3.74%), eyelid (5 cases, 4.70%), ciliary body (6 cases, 5.61%),iris (10 cases, 9.34%), choroid (29 cases, 27.10%), orbital (39 cases, 36.44%) and the other 6 cases intraocular metastatic RCC (5.61%). Metastasis of renal cell carcinoma may occur many years after nephrectomy or maybe the rst manifestation of the primary malignancy. It is associated with the latency between the initial diagnosis and metastatic presentation, which further increases the di culty of diagnosis, so histopathological examination after the removal of the surface mass is necessary. The distant metastasis of renal cancer is often the rst symptom, carefully looking for the primary foci only found in the kidney, thus it can be seen that the abnormal things in any part of the body, especially unknown sources, should think of the possibility of renal cancer metastasis.RCC metastases to the eye are rare, so urologists need to be aware of any recently discovered super cial masses during RCC follow-up.

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There are only two other reports in the literature of eyelid metastatic renal cell carcinoma that are similar to the initial presentation of our case. A total of 13 cases (36.11%) with eye symptoms as the rst manifestation were listed in our review, and 23 cases (63.89%) with eye metastases after diagnosis of renal cancer. Among the cases with ocular metastasis studied by Debraj Shome, MD et al., 39 cases (54.93%) had no previous history of renal cell carcinoma and 32 cases (45.07%) had a previous history of renal cell carcinoma. The reason for this difference may be the development and popularization of medical imaging, histopathology and immunohistochemistry. At present, there is no standard treatment for eye metastasis of renal clear cell carcinoma. Postoperative oral targeted drugs, targeted drugs combined with immune checkpoint inhibitors are used in the treatment of these diseases. Renal clear cell carcinoma metastases to the eye are rare and may occur many years after nephrectomy, or may be the rst manifestation of primary malignancy. Once diagnosed, these diseases are usually advanced, so urologists should pay attention to them during RCC follow-up.