Metastatic renal clear cell carcinoma mimicking a gallbladder polyp: Case report and literature review

Highlights • Metastases to gallbladder from renal cell carcinoma are very rare.• Most of the cases are diagnosed incidentally, and both clinical presentation and physical examination are unspecific.• Imaging although its specificity can’t make the difference between primary gallbladder carcinoma and metastasis from RCC.• Only pathological examination of the specimen after cholecytectomy with immunochemistery can assess the diagnosis.


Introduction
Renal cell carcinoma (RCC) is a rare tumor accounting for 3% of all malignancies in adults [1]. This tumor has a great propensity to metastasize synchronously or metachronously to various anatomic sites [2]. The metastatic locations of an RCC are mainly lungs, bones, lymph nodes, liver, and adrenal glands. Gallbladder remains an extremely rare metastatic site. To our knowledge, only 58 cases of gallbladder metastasis from RCC have been reported so far. Herein we report a case of intraluminal polypoid metastasis of clear RCC in gallbladder mimicking gallbladder polyp. Clinic- Fig. 1. Abdominal thin slices CT scan in axial plan : non enhanced (a), arterial (b) and portal acquisition (c). Coronal oblique thin slice CT scan (d): Lobulated density mass, in the gallbladder, with intense arterial enhancement after contrast injection, and retracting gallbladder wall (black arrows). It was associated with gallstones (white arrow).
ing 30 × 31 mm, with lobulated contours retracting the gallbladder wall. An intense arterial enhancement after contrast injection was noted. Intraluminal gallstones were found (Fig. 1). Clinically, the patient was asymptomatic. On physical exam, neither abdominal tenderness nor icterus was noted. Laboratory exams didn't show biological cholestasis (total bilirubin 0.5 mg/dL, direct bilirubin 0.1 mg/dL, aspartate transaminase 16 IU/L and alanine transaminase 11 IU/L). Despite the lack of biliary symptoms and based on the radiologic appearance of the tumor on CT scan, we suggested a possible diagnosis of gallbladder primary carcinoma. A laparoscopic cholecystectomy was performed. The postoperative course was uneventful and the patient was discharged two days after the operation.
The cholecystectomy specimen had a 3 × 2.5 cm polypoid mass protruding in the lumen located 4 cm from the fundus of the gallbladder. Cut surface of the mass was homogenous, yellowish and soft, with foci of hemorrhage. Microscopically, the polyp consisted of clear cell sheets, nests, and cords separated with a delicate capillary vascular network (Fig. 2). Some areas of solid and alveolar pattern were seen. Tumor cells had an abundant, clear cytoplasm surrounded by a distinct cell membrane. The nucleus was round and uniform (Fig. 3). The diagnosis of metastatic RCC was confirmed by immunohistochemical stains, which showed strong positivity for    After 18 months period of regular follow up, CT scan showed no recurrence and the patient is free from disease.

Discussion
RCC represents around 5% and 3% of all malignancies, respec-tively in men and women [4]. At the time of presentation, almost one-third of the patients are metastatic. Thereabouts 25 to 50% of the patients will develop metastases after radical nephrectomy [5].  The most common metastatic sites are lungs, bones, lymph nodes, liver and brain [6]. Metastases to the gallbladder from RCC are extremely rare with a 0.58% frequencies reported in large autopsy reviews [7]. Malignant melanomas are the first cause of metastasis in the gallbladder, followed by other digestive system carcinomas [8]. The pathogenesis of metastasis development in the gallbladder is explained by authors as a process whether resulting from direct invasion or from the blood spread of tumor cells secondary to vascular invasion [9] and it is more likely to raise metachronously. Based on a systematic Pubmed search using the keywords "gallbladder metastasis renal cell carcinoma", we found 58 published cases in the literature. All the cases are summarized in (Table 1). The data has been analyzed using SPSS version 19.0 software. The main limitation of our analysis is the lack of information in some cases. Analysis of the data collected showed that 69.5% of the patients were male while 30.5% were female. The RCC occurred at a mean age of 58 years. The free median interval disease was 4.81 years. These results are similar to those found in the literature [10]. At the time of diagnosis, the gallbladder was the unique site of metastasis in 75.4%. When other metachronous metastases are diagnosed, the main sites are lungs 8.8% or multiple (more than 3) in 5.3%. Other sites are pancreas, contralateral kidney, adrenal gland, scalp, and stomach. Most of the time, the diagnosis is made incidentally on CT scan, with an incidence of 63.5% according to our review. The most frequent symptoms in the clinical presentation are abdominal pain (28.8%), haematuria (3.4%), nausea and vomiting (1.7%). The physical examination is generally poor. When the metastasis is synchronous with the RCC, symptoms may be related to the primary tumor. Clinically, the challenge is to make the differential diagnosis between primary gallbladder carcinoma and metastasis from RCC. Though its rarity, the primary gallbladder carcinoma incidence is higher. That's why in about half the cases according to the literature like the present case, there is a misdiagnosis and the final diagnosis is carried out after the final pathological examination.
Radiological findings can raise information and orient the diagnosis although the difference between both diagnoses remains difficult. In its literature review, Neves et al. [10], find that lesion on CT scan is more likely to be played/pedunculated and not associated with gallstones. These findings are in accordance with our data as we found that the lesion is described as popped in 90.6% while the association with gallstones is in only 18.2% of the cases. Kitamura et al. [11], described a hyper-vascular and strongly enhanced lesion on CT scan that suggests metastasis from RCC whereas primary gallbladder cancer does not present such radiological patterns. Strong enhancement of the lesion was found in our review in 86.2% of the cases. But these radiological features that describe the metastasis are not always present. In our case, the tumor was described as a density mass in the gallbladder, with lobulated contours retracting the gallbladder wall. An intense arterial enhancement after contrast injection was noticed. Gallstones were also found.
The final diagnosis is made on specimen pathological examination. Macroscopically, it is generally a well-circumscribed polypoid mass with a narrow stalk located in the fundus. Neves [10] described it as a pedunculated mass with hemorrhage in the protruded portion. Low and high power fields reveal a prominent vascular proliferation as well as tumor cells with a clear cytoplasm along with vascular interstitial tissue that reminds the features of a renal primary tumor. This proliferation develops under the mucosal epithelial layer of the gallbladder. The surface is covered by gallbladder epithelium. Other lesions like adenomyomatosis or chronic cholecystitis may be associated [12]. Immunohistochemical staining is performed to assess the diagnosis and shows positivity to AE1/AE3, Vimentin, CD10 and RCC with no expression of S100, cytokeratin or CEA.
Either way, surgical treatment is required, and an R0 resection laparoscopic cholecystectomy is performed as the tumor is generally developed with the mucosa. When there is a doubt of locally advanced tumors, a frozen section can be performed to check the serosal involvement. When metastasectomy is achievable, surgery must be done to prolong overall and cancer-specific survival [11], especially with favorable disease factors as a solitary metastasis, and a long free disease interval.
Recent literature reviews [9,10,13], found more than half of those patients alive with no evidence of disease, despite the short follow up. According to our review, we identified 34 cases with follow up included. The mean follows up time was 26.94 months, with recurrence occurring in 35.3% of the cases. Most of the recurrences were multiple in 66.7%. Other recurrences involved pancreas 16.7%, bones 8.3% or lungs 8.3%. The death occurred in 6 cases (17.1%). Some authors tried to identify prognosis factors in their multivariate analysis: Shyr et al. [14] demonstrated that time from initial diagnosis of the RCC was the only favorable predictor of survival with 5 years survival estimated to 59% whereas Kavoluis [15] found that both disease-free interval and single site metastasis are prognosis factors.
The use of chemotherapy (n = 2), radiation therapy (n = 1) or antiangiogenic (n = 1) was described in some cases as an adjuvant treatment, without concrete evidence for their role after metastasectomy. Several phases 3 studies are on their ways to investigate their place in adjuvant treatment [10].

Conclusion
Metastasis to the gallbladder from an RCC is an uncommon entity. We must keep in mind the diagnosis when a tumor is detected in the gallbladder by the US or CT scan, mostly incidentally. The difference between primary gallbladder carcinoma and metastasis from RCC is difficult, and the final diagnosis is often made on pathological examination. R0 cholecystectomy is required, especially when it is a single metastasis, to provide remission and increase survival.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethical approval
Given the nature of the article, a case report, no ethical approval was required.

Consent
Written informed consent was obtained from the patient for publication of this case and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Registration of research studies
This does not apply as it is a case report of a patient who has given written consent and has been de-identified. It is therefore not prospective research involving human participant.

Provenance and peer review
Not commissioned, externally peer-reviewed.

Declaration of Competing Interest
The authors have no conflict of interest to declare.