Two cases of gallbladder metastasis from renal cell carcinoma and review of literature
© Costa Neves et al. 2016
Received: 26 June 2015
Accepted: 10 March 2016
Published: 22 March 2016
Renal cell carcinoma accounts for 90 % of renal neoplasms and metastatic disease is common. One third of newly diagnosed cases will have synchronous metastases at diagnosis and further 25–50 % will develop metachronous disease.
This study presents two new cases of gallbladder metastasis from renal cell carcinoma (RCC) from our institution and reviews the published literature. The final cohort included 52 evaluable patients. M/F ratio was 2:1 and median age was 62.5 years. Most patients were diagnosed incidentally after follow-up or staging imaging for RCC. Of the patients with available histology, all except one were clear cell type (n = 39) and 92 % were polypoid. Thirty-six patients demonstrated metachronous gallbladder metastasis with median disease-free interval (DFI) from nephrectomy of 4 years. The most frequent site of metastasis was the contralateral kidney (46.7 %) followed by the pancreas and lung. The median disease-free interval (DFS) after cholecystectomy was 37 months. Three- and five-year OS rates were 74 and 62 %, respectively. Age younger than 45 years (p = 0.008) and DFI <24 months (p = 0.049) were associated with decreased OS.
RCC metastasis to the gallbladder is associated with an unusual pattern of concomitant metastasis. Symptoms are not common. Simple cholecystectomy is associated with increased OS and nil local or port site recurrence. Young age and short DFI are associated with decreased OS.
KeywordsCancer Gallbladder Kidney neoplasms Clear cell metastatic renal cell carcinoma
Renal cell carcinoma accounts for approximately 3 % of malignancies in adults and 90 % of renal neoplasms . Metastatic disease is common, and one third of newly diagnosed cases will have synchronous metastatic disease at presentation. A further 25–50 % will develop metachronous disease . Latent distant metastasis is characteristic of renal cell carcinoma (RCC) and can manifest more than a decade after nephrectomy in about 10 % of patients .
Clear Cell (CC) RCC is the most common type of renal cancer, accounting for 75 % of all primary kidney tumours. Similar to other malignancies, RCC may undergo differentiation to more aggressive histological types. Sarcomatoid transformation is present in 5 % of RCC, although these do not in themselves represent a distinct histological entity . Spindle cell morphology, similar to sarcomas, can occur in all types of RCC but is most often seen in clear cell and chromophobe RCC . These patients have an adverse stage stratified prognosis with a median survival of 4–19 months .
The most common sites of metastasis of RCC are the lung, bone, liver, adrenal gland, brain and contralateral kidney but have been documented in nearly every organ. Gallbladder involvement is reported in <1 % of cases. The outcome for metastatic RCC is poor, bearing a 5-year survival rate of approximately 5–10 %, but curative resection of metastasis in selected patients is known to improve long-term survival [4, 7].
Materials and methods
Review of literature
No. of cases
Saudi J Kidney Dis Transpl 2013 Jan;24(1):100–4
Pol PrzeglChir 2012 Jun;84(6):313–6
OncolLett 2012 May;3(5):1136–1138
Cir Esp 2014 Apr;92(4):295–6
Case Rep Med 2011;2011:671645
UrolOncol 2012 Jul–Aug;30(4):476–81
Case Rep Oncol 2010 Jan 29;3(1):30–34
Arch Pathol Lab Med 2010 Jul;134(7):1003–9
OncolLett 2010 May;1(3):507–509
Cases J. 2009 Oct 29;2:172
UgeskrLaeger 2009 Aug 24;171(35):2486–7
Eur J Med Res 2009;14:90–2
GastroenterolClinBiol 2008 Aug–Sep;32(8–9):788–9
J HepatobiliaryPancreatSurg 2008;15(2):209–12
Indian J Gastroenterol 2006 May–Jun;25(3):161–2
Asian J Surg2006 Jul;29(3):145–8
ActaChirBelg 2003 Apr;103(2):233–4
Yonsei Med J 2003 Apr 30;44(2):355–8
Jpn J UrolSurg2002;15:67
Surg Today 2002;32(1):89–92
Saudi J Kidney Dis Transpl 2000 Oct–Dec;11(4):587–92
J Radiol 1999 Jul;80(7):739–40
Int J Urol 1998 May;5(3):288–90
Jpn J Gastroenterol 1997;94:68
J Ultrasound Med 1996 Oct;15(10):725–8
Urology 1995 Nov;46(5):722–5
Urology 1995 May;45(5):867–9
Dig Dis Sci 1994 Nov;39(11):2476–9
Urology 1991 Aug;38(2):184–6
Clin Imaging 1991 Oct–Dec;15(4):293–5
Dig Dis Sci 1991 Apr;36(4):520–3
Jpn J GastroenterolSurg 1990;23:1952
UgeskrLaeger 1983 Oct 17;145(42):3261
Mayo ClinProc 1963;38:225
The two case reports presented resulted from a 5-year retrospective search through The Royal Marsden Hospital’s histopathological archives from gallbladder specimens. Data was collected through review of patient history, operative notes, pathology reports, and medical records after consent.
Statistical analysis was performed with the Statistical Package of the Social Sciences (SPSS), version 17.0. The primary endpoints of the study were DFI between resection of primary renal tumour and presentation of metachronous gallbladder metastasis. Overall survival (OS) was calculated from the date of operation for the gallbladder metastasis to the date of disease-related death and was censored at the time of last follow-up for patients that were alive or at the time of death when unrelated to the disease. The impact of clinicopathological characteristics on OS was analysed using both the Kaplan-Meier and univariate Cox regression methods. Survival outcomes between groups were compared with the log-rank test.
A chi-square test, Mann-Whitney non-parametric test and Fischer’s exact test were used when appropriate for calculating the association between clinicopathological characteristics and interval between resection of primary renal tumour and presentation of metachronous gallbladder metastasis, recurrence or disease-related death. A p value of less than 0.05 was considered statistically significant.
In February 2012, a 60-year-old female presented with a urinary tract infection (UTI), right loin pain and haematuria. In spite of effective treatment of the UTI, the loin pain persisted. Evaluation by biphasic enhanced CT confirmed the presence of a 4-cm hypo-attenuating mass occupying the lower pole of the right kidney without invasion of the major renal vein or cava and without lymph node enlargement. A number of nodules highly suggestive of metastasis were present in both lungs, the largest measuring 6.5 mm. CA 19.9, CA 15.5 and CEA were negative. The patient underwent an uneventful laparoscopic right radical nephrectomy. Histology of the specimen showed CC RCC Leibovich score 1, pT1aN0 and Fuhrman grade 3.
The patient did not receive adjuvant therapy and remained disease-free after 2 months of follow-up.
A 57-year-old male with a previous history of resected melanoma from the right arm (T1a) presented with sudden onset of acute abdominal pain and macroscopic haematuria in May 2011. A CT scan showed a 12 × 10 × 8 cm mass in the left kidney extending into the hilum consistent with RCC and a gallbladder polyp. A number of bilateral small peripheral and sub-pleural pulmonary nodules measuring less than 5 mm and of indeterminate nature were present. In June 2011, the patient underwent an open radical nephrectomy and adrenalectomy, with an uneventful recovery. Pathology revealed a CC RCC Fuhrman 4 with extensive sarcomatoid changes and areas of necrosis, invading muscular veins of renal sinus including the main renal vein but without invasion of perinephric fat. All nodes were negative for malignancy, staging the tumour as pT3bN0.
The next month, the patient experienced two episodes of severe upper abdominal pain, nausea and vomiting which completely subsided after administration of intravenous morphine, accompanied by unremarkable CT emergency scans. He had a Barium swallow test and an upper gastrointestinal endoscopy, both of which were normal. On the third episode of acute abdominal pain in July, he finally underwent a laparoscopic cholecystectomy with relief of symptoms. Histopathology revealed a 22 × 15 × 8 mm polyp with normal mucosa composed of nested/alveolar pattern of moderate-sized polygonal cells with clear cytoplasm and well-defined cytoplasm borders, round central nuclei with a moderate degree of nucleolar prominence, occasionally multinucleated, with fine fibro-vascular septae present within thin wall vessels and an admixture of inflammation and foamy macrophages at the periphery of the polyp. Immunohistochemistry showed these cells to express AE1/AE3, Vimentin, CD10 and RCCAg with no expression of S100 or CEA, consistent with the diagnosis of metastatic CC RCC.
The patient was followed up in an outpatient clinic accompanied by CTs at 3, 6 and 12 months post-op and annually thereafter. The bilateral lung lesions remained stable without adjuvant treatment, and the patient remained disease-free until date (total follow-up of 38 months).
Results of literature review
Patient, primary tumour and gallbladder metastasis characteristics
No. of patients (%) or median (range)
No. of patients available for analysis
Median age (years)
Stage of RCC at presentation
Gallbladder with other metastasis
Gallbladder with other metastasis
Median size of gallbladder tumour, cm
Extent of invasion of gallbladder
Presence of gallstones
Clear cell RCC
RCC type not specified
In most of the cases, the diagnosis was made incidentally during a radiographic exam for staging or on follow-up (74.4 %, n = 39). When symptomatic, the majority of cases presented with acute or chronic biliary symptoms. Of the cases with available pathology of the gallbladder RCC metastasis, all except one were confirmed to be CC RCC, the remaining being classified as RCC “type not specified”. The gallbladder lesion was persistently polypoid/pedunculated and intraluminal in 92 % of cases. The mean size was 25 mm (range 8–75). Mucosal invasion was evident in 65 %, and gallstones were present in only 15.6 % (7/45).
The majority of patients (36/52–69.2 %) demonstrated metachronous gallbladder metastasis with a median DFI of 4 years (range 0.25–27). DFI was not predicted by sex, staging, incidental diagnosis vs. symptomatic disease, single vs. multiple metastases, macroscopic appearance of gallbladder tumour, its extent of invasion in the gallbladder wall or presence of gallstones.
Presentation of all sites of metastasis
No. of patients (%) or median (range)
No. of patients available for analysis
Metastatic disease presentation
Metastasis to only gallbladder
Metastasis to other sites
Sites of other metastases
Contralateral kidney (%)
All patients had cholecystectomy and seven received adjuvant therapy.
Intervention, follow-up and outcome
No. of patients (%)
No. of patients available for analysis
Median follow-up time, years, median (range)
5-year OS, %
Median DFS, months (95 % CI)
No evidence of disease
Alive with metastasis
Death from metastasis
Baseline clinicopathologic characteristics and their association with OS in univariate analysis
No. of patients (%)
HR (95 % CI)
No. of patients available for analysis
Single vs. multiple
Interval from resection of primary to diagnosis of metastasis
Despite the great tendency of RCC to metastasize synchronously or metachronously to numerous anatomical sites, metastasis to the gallbladder is rare. Our review of literature found 54 cases published by 43 papers dated since 1963. Fifty cases were considered evaluable for this report and with the addition of our two cases provided a total cohort of 52 evaluable cases, thus representing the most extensive and complete database on this subject to date.
Unlike primary gallbladder cancer, RCC metastases to the gallbladder show a clear male predominance and a low incidence of concomitant gallstone disease [8, 9]. Moreover, the majority has a polypoid or pedunculated morphology (46/50) whereas primary gallbladder cancer has a diffuse wall thickening morphology .
The median DFI was 4 years, which is consistent with the results found by Chung et al. in their review in 2012 . We found a statistically significant decrease in OS for patients younger than 45 years old and when the DFI was less than 24 months.
The clear cell type was responsible for practically all cases of metastasis of RCC to the gallbladder. It is still not clear if this is due to the fact that CC RCC is the most frequent type of RCC or whether this type of metastasis is exclusive to clear cell type. A sarcomatoid component generally implies a more aggressive behaviour and bears a median survival of 4–19 months after diagnosis , but our second case patient had no recurrence throughout a follow-up period of 38 months despite sarcomatoid histology.
The diagnosis of gallbladder lesion was predominantly radiographic at initial staging or at follow-up after nephrectomy. The management of gallbladder polyps remains controversial, but a review of literature published in 2012 stated that gallbladder polyps >10 mm, symptomatic, fast growing, sessile or wide-based; polyps with long pedicles; any size of polyp in patients >50 years of age; concurrent gallstones; polyps in the setting of primary sclerosing cholangitis; or abnormal gallbladder ultrasound are considered indications for surgery . In the context of patients with a history of RCC, the suspicion of a metastasis should be considered.
A simple cholecystectomy is recommended for pedunculated tumours because gallbladder cancers of pedunculated type often remain within the mucosa, regardless of the tumour size . In our review, no patients with RCC who underwent a simple cholecystectomy for a metastatic polypoid lesion developed local recurrence suggesting that a simple cholecystectomy is adequate when a metastasis of RCC is suspected. Laparoscopic cholecystectomy followed by a frozen section is appropriate when there is no evidence of serosal involvement at laparoscopy , as port site metastases from gallbladder cancer have been reported .
It is interesting to notice that the presence of concomitant metastasis is different when there is gallbladder involvement. In our cohort, involvement of the contralateral kidney was the most frequent site of concomitant disease, exhibiting a frequency of 46.7 %, contrasting with the reported 5 % when gallbladder involvement is absent . Pancreatic and lung involvement showed a frequency of 26.7 % each. This is intriguing, as the lung is usually the most frequent site of RCC metastasis, occurring in up to 60 % of patients , and pancreatic involvement is reported in only 2 % of cases .
In our first case report, small bilateral lung lesions were identified and the CT suggested these to be metastatic disease. However, these lesions regressed completely 5 months after nephrectomy without adjuvant treatment. The nature of these lesions remains uncertain, because there was no tissue pathology confirmation of metastatic disease. The initial stability of the lesions and posterior total regression point towards a more probable inflammatory nature, in spite of the absence of respiratory symptoms, but spontaneous regression of lung metastasis from RCC after nephrectomy is reported [17, 18]. In our second case report, the patient also demonstrated bilateral small lung lesions, some of them described as inflammatory on CT. These lesions never regressed but also did not progress throughout a 38-month follow-up, suggesting the diagnosis of lung metastasis as unlikely.
Several phase 3 randomized controlled studies are currently in place for adjuvant treatment with sunitinib, sorafenib, pazopanib, axitinib and everolimus. As the results from these trials have not been published yet, there is still no current evidence to support adjuvant treatment after nephrectomy for RCC [1, 4].
Gallbladder metastasis from RCC is an uncommon event. Most cases are asymptomatic, hence the importance of radiological follow-up after nephrectomy. All gallbladder polypoid lesions in patients with a history of RCC mandate treatment, and simple cholecystectomy is associated with increased OS and nil local or port site recurrence published to date. The presence of gallbladder metastasis indicates an alteration in the pattern of subsequent disease with relapse in the contralateral kidney being the most common site of recurrence. Young age and short DFI are associated with decreased OS.
Written informed consent was obtained from the patients for publication of these case reports and any accompanying images. Copies of the written consent are available for review by the Editor-in-Chief of this journal.
None. No funding to declare.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Ljungberg B, Bensalah K, Canfield S, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015;67(5):913–24. doi:https://doi.org/10.1016/j.eururo.2015.01.005.View ArticlePubMedGoogle Scholar
- Sand M, Bechara FG, Kopp J, et al. Gallbladder metastasis from renal cell carcinoma mimicking acute cholecystitis. Eur J Med Res. 2009;14:90–2.View ArticlePubMedPubMed CentralGoogle Scholar
- McNichols DW, Segura JW, De Weerd JH. Renal cell carcinoma: long term survival and late recurrence. J Urol. 1981;126(1):17–23.PubMedGoogle Scholar
- Bellmunt J, Puente J, Garcia De Muro J, et al. SEOM clinical guidelines for the treatment of renal cell carcinoma. ClinTranslOncol. 2014;16((12)):1043–50.Google Scholar
- Cheville JC, Lohse CM, Zincke H, et al. Sarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome. Am J SurgPathol. 2004;28(4):435–41.View ArticleGoogle Scholar
- Yan Y, Liu L, Zhou J, et al. Clinicopathologic characteristics and prognostic factors of sarcomatoid renal cell carcinoma. J Cancer Res ClinOncol. 2014;2.Google Scholar
- Kavolius JP, Mastorakos DP, Pavlovich C, et al. Resection of metastatic renal cell carcinoma. J ClinOncol. 1998;16(6):2261–6.Google Scholar
- Fang X, Gupta N, Shen SS, et al. Intraluminal polypoid metastasis of renal cell carcinoma in gallbladder mimicking gallbladder polyp. Arch Pathol Lab Med. 2010;134(7):1003–9. doi:https://doi.org/10.1043/2009-0453-OA.1.PubMedGoogle Scholar
- Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Arch Surg. 1997;112(1):26–30.View ArticleGoogle Scholar
- Chung PH, Srinivasan R, Lineham WN, et al. Renal cell carcinoma with metastases to the gallbladder: four cases from the National Cancer Institute (NCI) and review of the literature. UrolOncol. 2012;30(4):476–81. doi:https://doi.org/10.1016/j.urolonc.2010.04.010.Google Scholar
- Andrén-Sandberg A. Diagnosis and management of gallbladder polyps. North American Journal of Medical Sciences 2012. N Am J Med Sci. 2012;4(5):203–11. doi:https://doi.org/10.4103/1947-2714.95897.View ArticlePubMedPubMed CentralGoogle Scholar
- Furukawa H, Kosuge T, Shimada K, et al. Small polypoid lesions of the gallbladder: differential diagnosis and surgical indications by helical computed tomography. Arch Surg. 1998;133(7):735–9.View ArticlePubMedGoogle Scholar
- Sultania M, Pandey D, Sharma J, et al. Delayed isolated port-site metastasis of gallbladder cancer following laparoscopic cholecystectomy: report of two cases. J Gastrointest Cancer. 2014;45 Suppl 1:188–91. doi:https://doi.org/10.1007/s12029-014-9622-y.View ArticlePubMedGoogle Scholar
- Blute ML, Thibault GP, Leibovich BC, et al. Multiple ipsilateral renal tumors discovered at planned nephron sparing surgery: importance of tumor histology and risk of metachronous recurrence. J Urol. 2003;170(3):760–3.View ArticlePubMedGoogle Scholar
- Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996;335(12):865–75.View ArticlePubMedGoogle Scholar
- Machado NO, Chopra P. Pancreatic metastasis from renal carcinoma managed by Whipple resection. A case report and literature review of metastatic pattern, surgical management and outcome. JOP. 2009;10(4):413–8.PubMedGoogle Scholar
- GarcíaTabar PJ, Montoya Lirola MD, EtxepareArrosagaray P, et al. Spontaneous disappearance of pulmonary metastasis secondary to renal cell carcinoma after nephrectomy. Presentation of a case and review of the literature. ActasUrol Esp. 1997;16(5):430–4.Google Scholar
- Chang KC, Chan KL, Lam CW. Spontaneous regression of renal cell carcinoma metastases. Hong Kong Med J. 1999;5(1):72–5.PubMedGoogle Scholar