Renal cell carcinomas (RCCs) represents on average over 90% of all malignancies of the kidney. Approximately 20%-30% of patients with RCC have metastatic disease at presentation and nearly 50% of patients with advanced disease die within 5 years of diagnosis. Global incidence of RCC continues to grow steadily with the increase in incidentally discovered lesions during imaging studies. Up to 50%-60% of RCCs may be incidentally found in asymptomatic patients at abdominal imaging studies performed for other indications . Recent advances in the understanding of the genetic basis of RCC have provided unique insights into the underlying histologic and biological diversity of renal cancer. Renal cell carcinoma is considered a byproduct of genetic events that may involve gain-of-function of proto-oncogenes, loss-of-function of cancer suppressor genes, or both . Different histologic subtypes of renal cell carcinoma have characteristic clinical, genetic, and biological profiles. Indeed, the 2004 World Health Organization recognizes that RCC is a clinicopathologically heterogeneous malignant neoplasm that can be classified into clear cell, papillary, chromophobe, collecting duct, medullary carcinoma, and unclassified categories. Clear cell RCC is the most common histologic subtype representing 70%-75% of all RCCs. Papillary RCC and chromophobe RCC account for 15%-20% of the remainder of the RCCs . Distinct differences in biological behavior and long-term prognosis among different subtypes of RCC makes the correct histologic diagnosis critically important. Clear cell RCC is characterized by glycogen and lipid-rich clear cells within a regular network of small, thin-walled blood vessels. Papillary RCC typically consists of papillae containing a delicate fibrovascular core and covered by epithelial cells. Chromophobe RCCs are histologically characterized by large polygonal pale cells with prominent cell membranes and perinuclear clearing .
Clear cell RCC is characterized by its great propensity to metastasize synchronously or metachronously to various anatomic sites. Clear cell RCCs most commonly metastasize hematogenously via the vena cava primarily to the lung, although lymphatic metastases also occur. Retrograde metastasis along the paravertebral veins, the vena testicularis/vena ovarii, intra-renal veins, or along the ureter may also occur . The most common sites of metastasis are the lung, bone, brain, liver, adrenal gland, the other kidney, and rarely, organs such as the vertebrae, stomach, spleen, pancreas, and diaphragm . Clear cell RCC is well known for its propensity to metastasize to unusual sites. Metastatic renal cell carcinoma in gallbladder is extremely rare. Indeed, the gallbladder was recognized as a site of metastasis in only 4 out 687 cases (0.58%) in large autopsy reviews . Furthermore, metastatic gallbladder lesions are infrequent; melanoma, stomach, pancreas, ovary, canal bowel, biliary duct and breast carcinomas are those that have the highest probability of metastasis. Half of the cases are synchronic . To our knowledge, only 40 cases of metastatic renal cell carcinoma in gallbladder were reported in the literature.
Clinical findings are not specific enough to arrive at a final diagnosis. Metastatic tumors in gallbladder usually appear in 39 to 84-year-old-males, who have a personal history of cancer without previous biliary pathology, while primary tumors prevail in women over 65 years of age with biliary lithiasis . In case of synchronous gallbladder metastasis, the primary renal cell cancer is found by TDM-scan who shows both lesions. However, imaging diagnosis may not be conclusive in making a differential diagnosis between primary and secondary tumors. Ultrasonography is the initial approach in the diagnosis of gallbladder tumors. Metastases can appear under different hyperechoic masses bigger than 1 cm, close to the gallbladder wall without posterior echogenic shadowing . Primary tumors appear as solid mass occupying the entire wall thickness, or as a polypoid lesion with increased vascularization . Invasion of the mucosal layer is another radiological finding that can help to differentiate between a primary gallbladder tumor and metastasis in the computed tomography scan. If the mucosa is not infiltrated, indicating an invasion from the serosa layer, the primary gallbladder tumor can be excluded .
The pathologic study is the key of diagnosis. Macroscopically, reported metastatic renal cell carcinoma of the gallbladder showed a single, intraluminal, polypoid or pedunculated mass. In one reported case, like in our case, the metastatic renal cell carcinoma was a free-floating polyp within the lumen of the gallbladder with no apparent involvement of the gallbladder wall . The clear cell RCC is typically golden yellow on cut surface, due to the rich lipid content of its cells. Necrosis and hemorrhage are commonly present. Microscopically, almost all cases showed clear cell renal carcinoma . Clear cell RCC is architecturally diverse, with solid, alveolar and acinar pattern, the most common. The carcinomas typically contain a regular network of small thin-walled blood vessels, a diagnostically helpful characteristic of this tumor. The alveolar and acinar structures may dilate, producing microcystic and macrocystic patterns. Tumor cells have an abundant clear cytoplasm surrounded by a distinct cell membrane. High grade tumors may contain minority populations of cells with eosinophilic cytoplasm. The nuclei tend to be round or uniform with finely granular, evenly distributed chromatin. Depending upon the grade, nucleoli may be inconspicuous, small, or large and prominent. Most clear cell RCCs have little associated inflammatory response . Metastatic clear cell RCC in gallbladder is confirmed by immunohistochemistry, using vimentin and CD10 in particular. In our case, the tumor cells were positive for vimentin, CD10, and pancytokeratin, but negative for CK7, CEA, chromogranin, synaptophysin and CD68.
The specific diagnosis of polypoid gallbladder masses is problematic. Because of the morphologic characteristics of metastatic clear cell RCC in gallbladder, this tumor should be distinguished from other polypoid lesions in the gallbladder with clear cell morphology, including clear cell carcinoma of gallbladder, clear cell carcinoid tumors, paragangliomas and cholesterol polyps. Clear cell morphology is identical in both metastatic clear cell RCC and clear cell carcinoma of gallbladder. Indeed, clear cell carcinomas of the gallbladder are composed of clear cells arranged in glands, sheets, nests, trabeculae and papillary structures. The predominance in women and the presence of gallstones, mucin and other components, including conventional adenocarcinomas, or squamous differentiation in clear cell carcinoma helps depart a primitive clear cell carcinoma of gallbladder . However, in some cases, only immunohistochemical study can establish with certainty the primitive or metastatic character of carcinoma. Indeed, while some markers like broad spectrum cytokeratin and epithelial membrane antigen (EMA) are expressed by both tumor types, others are specific to one or the other. Thus, vimentin and CD10 are expressed only in clear cell renal cell carcinoma; CEA is expressed only in gallbladder carcinomas . In our case, tumor cells expressed vimentin and CD10. Immunostaining with CEA was negative. Metastatic clear cell RCC should also be differentiated from a clear cell carcinoid tumor of the gallbladder. In the latter, tumor cells arrange in nests and tubules within a delicate capillary vascular network. However, they typically invade through the muscular layer into perimuscular soft tissue. Immunohistochemical stains are helpful in differentiating metastatic clear cell RCC from clear cell carcinoid tumor of the gallbladder. The latter is positive for neuroendocrine markers. Metastatic clear cell renal cell carcinoma and clear cell carcinoma of the gallbladder are negative for neuroendocrine markers . Paraganglioma is extremely rare in gallbladder. It appears as a small, well-circumscribed nodule protruding to the external surface of the gallbladder. The tumor is composed of chief and sustentacular cells arranged in a zellballen pattern. Furthermore, tumor cells in paraganglioma are positive for neuroendocrine markers with positive staining for S100 in the sustentacular cells . Cholesterol polyps are small, yellow, multilobulated polyps attached to the gallbladder mucosa by a thin pedicle. Histologically, the tumor is composed of foamy histiocytes covered by gallbladder mucosa and lack the delicate arborizing capillary network seen in clear cell renal carcinoma. These histiocytes are positive for oil-red O and CD68 but negative for epithelial markers by immunohistochemistry .
In all gallbladder findings with suspected malignancy, or benign lesions larger than 1 cm, a cholecystectomy should be performed to obtain a definitive diagnosis . Cholecystectomy with R0 resection has been demonstrated to be the only factor that increases survival mainly in isolated cases of metastasis . Synchronous metastasis of RCC in the gallbladder at the time of nephrectomy does not correlate with poor prognosis. Acute cholecystis as a clinical presentation is associated with poor prognosis . The five-year survival rate following cholecystectomy for RCC is 35-50%. According to Chung et al. , 63% of patients with one gallbladder metastasis have a two-year survival, while in the case of multiple metastases this rate decreases to 23% following cholecystectomy.
Last case reports showed that solitary metastasis of renal cell carcinoma in the gallbladder without evidence of involvement of other anatomic sites correlated with better survival . Simple cholecystectomy for metastatic renal cell carcinoma may provide favorable long-term survival of patients with renal cell carcinoma .