Surg Today (2002) 32:89–92

Gallbladder Metastasis of Renal Cell Carcinoma: Report ofTwo Cases

Tatsuya Aoki1, Keiichiro Inoue

1, Akihiko Tsuchida

1, Toshiaki Aoki

1, Kazuhiko Kasuya

1, Keiichi Kitamura

1,

Yasuhisa Koyanagi1, and Tohru Shimizu

2

Departments of 1Surgery and 2Surgical Pathology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan

staining. We examined specimens using various stain-ing methods other than H&E together with electronmicroscopy. We herein report our findings and alsomake a review of the pertinent literature.

Case Reports

Case 1

A 63-year-old man was found to have a gallbladdertumor during a routine health checkup by ultrasonogra-phy in June 1994. He had a history of nephrectomy forright renal cell carcinoma (RCC) in 1967. Abdominalultrasonography showed a hyperechoic mass with amosaic pattern, measuring 7.5 � 3.0 cm in diameter,filling the gallbladder. Abdominal computed tomogra-phy (CT) clearly demonstrated a pedunculated tumor inthe gallbladder without infiltration outside the gallblad-der wall and swelling lymph nodes (Fig. 1). Abdominalangiography disclosed a hypervascular tumor. Thepatient underwent a cholecystectomy in July 1994. Theresected specimen showed a polypoid tumor accompa-nied by hemorrhagic change (Fig. 2). Histologically,the mucosal surface was covered with yellowish-whitefibrous necrotic tissue but contained no tumor cells. Thetumor was located under the lamina propria mucosaewith subserosal invasion. Tumor cells proliferatedthrough abundant vascular structures and revealedalveolar, tubular and, in part, papillary growth (Fig. 3).All tumor cells were polygonal with clear cytoplasmand eccentric hyperchromatic nuclei. The cells werepositive for PAS, vimentin, and CD10, but negative forcarcinoembryonic antigen (CEA), carbohydrate anti-gen (CA19-9), Leu-M1, epithelial membrane antigen(EMA), and cytokeratin 7 (CK7). An electron-micro-scopic examination showed the cytoplasm to containabundant glycogen granules and lipid droplets (Fig. 4).Based on these findings, this patient was diagnosed to

Abstract We report two extremely rare cases of me-tastasis to the gallbladder from renal cell carcinoma. Inboth men, aged 63 and 80 years, a pedunculated poly-poid gallbladder tumor was incidentally found 27 and8 years after surgery for renal cell carcinoma, respec-tively. The tumors showed hypervascularity on diagnos-tic imaging. A histopathological examination showedno tumor cells in the gallbladder mucosa, but clear cellcarcinoma was predominantly observed below the mu-cosal layer. Furthermore, based on various specific andimmunohistochemical studies as well as the electron-microscopic findings, the patients were pathologicallydiagnosed to have gallbladder metastasis of renal cellcarcinoma.

Key words Gallbladder metastasis · Renal cell carci-noma · Clear cell carcinoma

Introduction

Although renal cell carcinoma (RCC) frequently metas-tasizes to distant organs with a rich blood flow suchas the lung, liver, and bone, metastasis to the gallblad-der is extremely rare; it is most often detected inciden-tally at autopsy.1–3 We experienced two patients withmetachronous metastasis to the gallbladder from RCC.To the best of our knowledge, only 20 patients, includ-ing our two cases, with this metastatic disease have beenpreviously reported.4–21 A histopathological differentialdiagnosis is necessary to distinguish primary clear cellcarcinoma of the gallbladder and metastatic involve-ment; however, the previously reported cases wereroutinely examined only by hematoxylin–eosin (H&E)

Reprint requests to: A. TsuchidaReceived: February 16, 2001 / Accepted: September 11, 2001

90 T. Aoki et al.: Gallbladder Metastasis of RCC

have clear cell carcinoma metastasized from RCC. Atpresent, 6 years after the second operation, he hasshown no evidence of recurrence without any additionaltherapies.

Case 2

In December 1999, an 80-year-old man was found tohave a gallbladder tumor during follow-up examina-tions after surgery for left RCC, which was performed in1992. He had undergone a left upper lobectomy for leftlung metastasis from RCC in 1993. Abdominal ultra-sonography showed a pedunculated mass in the gall-bladder (4.5 � 2.5 cm), which revealed a predominantlyhypoechoic tumor partially associated with hyperechoiclesions. Abdominal CT also disclosed a pedunculatedpolypoid mass at the fundus of the gallbladder withcontrast enhancement. In January 2000, he underwent a

cholecystectomy. Although the cut surface of tumor wassolid and yellowish-white, the mucosal surface had anormal morphology. The tumor cells were locatedmainly in the lamina propria mucosae and partiallyinfiltrated into the muscular layer. Histologically, clearcell type cancerous cells with small nuclei formed nestedstructures with abundant microvessels in the stroma,which were positive for PAS, vimentin (Fig. 5), Leu-M1,and CD10, but negative for CEA, Sudan IV, EMA, andCK7. Electron microscopy showed abundant glycogenicgranules in the cytoplasm with only a few scattered lipiddroplets. Based on these findings, gallbladder metasta-sis from RCC was diagnosed. He has shown no sign ofrecurrence for 2 years after the last surgery without anyadditional therapies.

Fig. 1. Postcontrast computed tomography scan showing apedunculated mass in the gallbladder

Fig. 2. The cut surface of a resected specimen showing apolypoid tumor accompanied by hemorrhaging inside themass

Fig. 3. Microscopic findings of the gallbladder tumor. A histo-logical examination revealed clear cell carcinoma (H&E stain,�40)

Fig. 4. Electron microscopic findings of the cytoplasm showedabundant glycogen granules (white arrow) and lipid droplets(black arrow)

91T. Aoki et al.: Gallbladder Metastasis of RCC

Discussion

One of the most notable features of RCC is its unusualand even bizarre pattern of metastatic disease. It is wellknown to metastasize mainly to the lung, bone, brain,liver, or adrenal gland; however, the gallbladder is arare site of the distant metastases. The incidence ofgallbladder metastasis was reported to be 0.57% (3 outof 523 autopsies) in a study by Bennington et al.,2 and0.58% (4 out of 687 autopsies) by Weiss et al.3 To thebest of our knowledge, only 20 surgically resected pa-tients, including our two cases, have been reported inthe literature.4–21 They ranged in age from 43 to 84 years(mean 65.5 years), and 18 were men and 2, women. Theprimary site of renal carcinoma was located in the rightkidney in 9 patients, left kidney in 10, and ectopic kid-ney in 1. No difference was observed between the rightand left kidneys. The time of diagnosis for gallbladdermetastasis was synchronous in 10 patients and meta-chronous in 10. The metachronous tumors were de-tected from 3 months to 27 years after a nephrectomy(mean 9.3 years); 8 patients developed metastatic gall-bladder tumors more than 3 years after the initialsurgery. Eleven patients developed multiple organmetastases in addition to the gallbladder metastasis, insuch areas as the lung, bone, adrenal gland, contralat-eral kidney, duodenum, thyroid gland, muscle, pan-creas, chest wall, and skin. Using autopsy findings,Willis reported that secondary carcinoma hemato-genously metastasizing from primary organs to the gall-bladder initially generates small flat nodules below themucosal layer and then grows as a pedunculated tumor,but is rarely greater than several millimeters in size.22

However, all the resected specimens in the literature,including our two cases, had a pedunculated mass mea-suring over 19mm in maximum diameter.

Macroscopically, a metastatic gallbladder tumor fromRCC is a polypoid or infiltrating nodular mass, with ayellowish-white cut surface and contains either necrosisor hemorrhaging in part. Case 1 of the present study wasaccompanied by hemorrhaging, showing a hypoechoiclesion on ultrasonography. As pointed out by Willis,22

metastatic tumors are rarely associated with ulceration,which was seen in only 1 of the 20 cases.12 Microscopi-cally, clear cell tumors form solid sheets, trabeculae, orglandular and papillary structures with abundant clearcytoplasm and central or eccentric hyperchromaticnuclei. For the differential diagnosis, primary gall-bladder clear cell carcinoma, initially reported by Tysonand Piney,23 is important, but is also extremely rare.Albores-Saavedra and Henson pointed out that: (1) thepresence of other patterns, especially one of a well-differentiated adenocarcinoma with mucin production,supports a diagnosis of a primary carcinoma; (2) severedysplasia or carcinoma in situ in the adjacent mucosasuggest a primary carcinoma; (3) the metastatic car-cinoma may be limited to the muscle layer and peri-muscular connective tissue, and not involve the mucosa,whereas primary tumors involve the mucosa.24 The tu-mors in our two patients were consistent with thesemetastatic findings with a history of nephrectomy forRCC. Therefore, both a clinical and histological diagno-sis of gallbladder metastasis of RCC was made.

In the present study, we performed specific andimmunohistochemical staining as well as electron-microscopic examinations. As far as we know, no simi-lar examinations have been reported on specimens frompatients with surgically resected gallbladder metastasisof RCC. The two patients we studied had positive PASand CD10 staining,25 thus strongly indicating thesetumors to be clear cell carcinoma. Although Sudan IVstaining should be positive in RCC, the specimen in case2 was negative, because the tumor was shown to befilled by glycogen granules with a few lipid droplets byelectron microscopy. Leu-M1, a surface marker presentin the proximal tubule epithelium of normal kidney, wasnegative in case 1, but positive in case 2. This discrep-ancy possibly resulted from the low specificity of theLeu-M1 antibody. Bittinger et al. reported that a differ-ential diagnosis was possible, since primary clear cellcarcinoma of the gallbladder was strongly positive forCEA, EMA, and CK7 but negative for vimentin, whileRCC was negative for CEA, EMA, and CK7 but posi-tive for vimentin.26 Since our results were closely consis-tent with the findings of Bittinger et al., we made adifferential diagnosis of gallbladder metastasis of RCCbased on the histological examinations.

Regarding adjuvant therapy after surgery, 9 out of20 patients underwent adjuvant immunotherapy witheither interferon or interleukin, in addition to chemo-therapy or hormonal therapy. As a result, 6 patients

Fig. 5. The cytoplasm is diffusely stained by the anti-vimentinantibody (�40)

92 T. Aoki et al.: Gallbladder Metastasis of RCC

were alive and 3 died; however, no consensus has beenreached on the indications for these therapies, becausethe number of cases is too small and the other 3 cases,including our cases, were able to survive without anyadditional therapies. Regarding the prognosis, the pa-tients with multiple organ metastasis generally result ina poor prognosis; however, this point remains obscurebecause there were no descriptions of the prognosis in 7of these cases.

In conclusion, gallbladder metastasis from RCC is arare disease and is relatively easy to diagnose, basedon a history of RCC and the findings of a pathologicalexamination including specific and immunohistochemi-cal staining.

Acknowledgment. The authors are indebted to Professor J.Patrick Barron, of the International Medical CommunicationsCenter of Tokyo Medical University, for his review of themanuscript.

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