Uncommon site of metastasis from renal cell carcinoma: Case report

Highlights • Renal carcinoma represents 1–3% of visceral malignancies.• Metastases of renal tumors may manifest up to a decade after initial injury.• Gallbladder represents a rare site of metastatic site, with few reports in the literature.


Background
Renal cell carcinomas (CCR) account for 1%-3% of all malignant visceral neoplasms and 90% of renal tumors. Its prevalence has increased in the recent years and the presence of latent distant metastasis is characteristic of RCC and may manifest more than a decade after nephrectomy. Clear Cell (CC) RCC is the most common type of renal cancer, accounting for 75% of all primary kidney tumours [1].
Gallbladder (GB) is a rare site of metastasis, with few robust reports in the literature containing clear descriptions of imaging, surgical and anatomopathological parts that add information for its recognition [2,3]. The clinical diagnosis of this entity may be laborious, due to the similar characteristics to benign lesions. We report a case of metastasis from RCC to GB and pancreas nine years after initial diagnosis. The work has been reported in line with the SCARE criteria [4].

Case presentation
Male patient, 74 years old, nine years post right videolaparoscopic radical nephrectomy for grade 2 clear-cell adenocarcinoma, T3BN0M0 (not subjected to systemic chemotherapy), during annual onset on private practice setting, it was found a gallbladder polyp with 0.7 × 0.7 cm on computed tomography (CT). He was completely asymptomatic. After one year, in 2017, CT was repeated with evidence of polyp growth to 1.7 × 1.3 cm. Investigation was complemented with Magnetic Resonance Imaging (MRI), which evidenced T2-weighted hypointense and T1-weighted hyperintense lesion, with early and persistent contrast enhancement and     [3] exophytic bulging of the underlying outer vesicular margin, showing irregular contours ( Fig. 1A and B). T1-weighted hypointense and T2-weighted slightly hyperintense nodular formation was also evidenced in the body portion of the pancreas, with 1.5 × 1.2 cm (Fig. 2). Chest CT and bone scintigraphy were also conducted, which showed no secondary lesions in bones and lungs. He had no alteration in laboratory exams (Table 1) [5]. One month later, the patient was subjected to videolaparoscopic cholecystectomy associated to endoscopic ultrasound (EUS) intraoperatively for investigation of the pancreatic nodule.
The anatomopathological examination of the surgical specimen -gallbladder (Fig. 3)   projection of splenomesenteric confluence, next to the splenic vein. Puncture of the lesion was conducted, which cytology was suggestive of clear-cell carcinoma. Because this is an indolent disease with oligometastasis, local ablative treatment with fractionated stereotactic radiation therapy with a dose of 40 Gy was selected. The patient has stable disease one year after radiation therapy.
IMAGE 1A: Expansive formation on the right lateral body wall of the gallbladder, with 1.7 × 1.3 cm, showing pronounced early and persistent contrast enhancement and promoting exophytic bulging of the underlying outer vesicular margin, which shows irregular contours (Red circle). 1B: T2-weighted hypointense expansive formation in the right lateral body wall of the gallbladder (Yellow circle) and T2-weighted slightly hyperintense nodular formation in the body portion of the pancreas (White circle).

Discussion
RCC is one the most lethal tumors of the urological system. Its five-year survival rate in all stages is approximately 69% [2]. This is a tumor of high metastatic potential, whether synchronous or metachronous, and the main distant lesion sites by frequency are: lungs, bones, liver, lymph nodes, adrenal glands, and brain [2,6]. One third of the cases already present with synchronous metastasis upon diagnosis. Other 30% will develop metachronous disease, with 10% with late diagnosis, sometimes ten years post-nephrectomy [7,8].
GB tumors are often diagnosed as polypoid masses and have a wide range of differential diagnoses. The most common are primary vesicular adenomas and adenocarcinomas. Metastases in this organ are rare events in the clinical practice, with primary stomach tumors, melanomas and RCC being the main origins [8].
CT is the most common imaging method in oncology for planning the therapeutic strategy; however, even with this tool, differentiation between primary vesicular tumors and metastatic lesions is still difficult [2,9], with biopsy combined with immuno-histochemistry being required for confirmation of diagnosis. In primary tumors, increased CEA and CK7 levels and moderately increased CK10 levels are found. In cases of RCC metastasis, high levels of vimentin are found, with negative CL7 results [2].
There are about 50 RCC metastasis to the gallbladder reported in the literature, from 1963 to the present day, but a significant part of them was diagnosed at autopsy [3,7,10,11] therefore without description of the diagnostic, therapeutic and follow-up process.
Unlike primary gallbladder carcinoma, RCC metastases are predominantly found in male patients, with low incidence of gallstones association [7]. Most cases present as polypoid or pedunculated lesion, as the case reported herein. The diagnosis is usually made accidentally in follow-up examinations, and patients are asymptomatic. Clear Cells was the responsible for almost all cases of metastasis to this organ [7,12].
RCC metastasis to the gallbladder occurs by the systemic dissemination of the disease, not by contiguity, since its appearance is late (average of four years post-nephrectomy [7]), the metastatic lesion is present on the intraluminal surface of the gallbladder, rather than externally (on serosal surface), and there is no predilection of laterality of the RCC -55% of the GB metastases occur from the right kidney and 45% from the left kidney [9].
A review of RCC metastasis conducted in 2012 evidenced the presence of RCC metastasis to the gallbladder and pancreas in 21% of the patients analyzed, even surpassing lung metastasis [9]. Lung is usually the site of highest rate of metastasis from RCC, with about 60% [13]. Nevertheless, this association was not observed in a review of pancreatic metastasis from RCC, where only one out of 72 patients had such association [14]. In our report, pancreatic metastasis associated with vesicular metastasis has also been diagnosed.
A systematic review in 2015 defined a follow-up algorithm for gallbladder polyps. Based on the risk of malignancy found, polyps greater than 10 mm should be submitted to a surgical procedure, polyps smaller than 4 mm can be observed, with follow up every 2 or 3 years, and polyps between 4 and 10 mm should have their probability of malignancy calculated based on the following criteria: single polyp, sessile polyp and patient age. Polyps with a probability of malignancy greater than 18% should also be resected [15]. In the context of patients with history of RCC, RCC metastasis to the GB should be considered.

Conclusion
Gallbladder is an unusual site of RCC metastasis; therefore, its diagnosis deserves no active investigation in patients with history of the disease. However, all vesicular lesions in this population should be given attention and surgical treatment should be considered, regardless of the size of the lesion, even when the primary tumor has been treated many years before.