Case 6 -

Metastatic Renal Cell Carcinoma to Liver Jennifer A. Brainard

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Clinical History: A 36 year old woman presented with a 4x5x2.3 cm liver mass adjacent to the vena cava and multiple lung nodules. Case 6 - Figure 1 Case 6 - Figure 2 The liver aspirate is highly cellular. Large, cohesive cell fragments in a bloody background are seen at low magnification. Case 6 - Figure 3 In addition to large aggregates, small groups and single cells are seen. Capillaries are seen within the larger cell groups. The individual cells do not resemble normal hepatocytes. The cell population is relatively uniform and no bile duct epithelium is seen, consistent with a neoplasm involving liver. Case 6 - Figure 4 Numerous thick-walled capillaries with adherent tumor cells, termed "transgressing capillaries" are prominent in this image. Case 6 - Figure 5 A large cohesive cluster with transgressing capillaries is also seen in this Pap stained slide. Case 6 - Figure 6 A higher magnification view of thick walled capillaries associated with a large tumor cell aggregate. Capillaries traverse the cell groups but endothelial wrapping is not seen. Hemosiderin pigment is present. Case 6 - Figure 7 The individual tumor cells have moderate to abundant amounts of cytoplasm. The cytoplasm of the tumor cells is vacuolated. In some cells, the vacuoles are single and appear "punched out". In others, multiple variably sized vacuoles are seen. There is a hint of some eosinophilic fibrillar material within this cell group. Case 6 - Figure 8 The Pap stain highlights eccentric nuclei with vesicular chromatin, slight nuclear membrane irregularities and prominent nucleoli. Case 6 - Figure 9 A similar Diff Quik image shows a small cluster of multivacuolated tumor cells with relatively uniform nuclei, low N/C ratios and indistinct cell borders. Cytologic Diagnosis: Metastatic adenocarcinoma with clear cell features, consistent with metastatic renal cell carcinoma. Histology Diagnosis: Prior renal cell carcinoma, clear cell type, Furman nuclear grade 2 of kidney, status post radical nephrectomy. The tumor in the liver is morphologically similar to the primary kidney tumor and is consistent with a metastasis. Cytologic Findings: The liver mass yielded a cellular sample consisting of large cohesive tumor cell aggregates. The cellular aggregates show a rich network of intersecting capillaries--so called "transgressing endothelium". Peripheral endothelial wrapping is not seen. In the Diff Quik stained slides, a hint of eosinophilic basement-membrane material is seen among tumor cells. At high magnification, the tumor cells are large with low nuclear/cytoplasmic ratios and ill-defined cell borders. Many of the cells showed variably sized single and multiple cytoplasmic vacuoles. The cells have eccentric nuclei and prominent nucleoli. Discussion: The diagnosis of metastatic conventional (clear cell) renal cell carcinoma in fine needle aspirate (FNA) specimens may be quite challenging. To complicate matters, this tumor has a predilection for metastasis and often presents in metastatic sites prior to the identification of the primary tumor. Approximately one third of patients will have metastases at the time of diagnosis. In the liver, a common diagnostic problem is distinguishing metastatic renal cell carcinoma from primary hepatocellular carcinoma, particularly the clear cell variant. Renal cell carcinoma (RCC) accounts for 2% of visceral malignancies. The majority, 70-80% are conventional clear cell carcinomas. The peak incidence of RCC is in the 5th and 6th decades with a male predominance, though these tumors can occur over a wide age range. Conventional renal cell carcinoma is associated with loss of genetic material from the short arm of chromosome 3, the site of the von Hippel-Lindau gene, either due to deletion, translocation or the loss of the entire chromosome. In the liver, metastatic renal cell carcinoma most commonly presents as multiple nodules. A single metastatic focus, as in this case, may be seen. Aspirate samples from renal cell carcinoma are usually highly cellular, with cells arranged in large cohesive aggregates as well as singly. Due to the highly vascular nature of these tumors, deceptively low cellularity samples may be obtained due to bleeding. A cell block preparation is often quite helpful in achieving a diagnostic sample in cases with excess blood. Microscopically, an arborizing network of capillaries is often seen traversing the large tumor cell groups. These "transgressing capillaries" tend to be thick -walled and tortuous. Another distinctive feature in renal cell carcinoma aspirates is the presence of eosinophilic basement membrane material. This material is predominantly extracellular and fibrillary and is best seen in Romanowsky stains. In general, the presence of basement membrane material in a metastatic tumor of unknown primary should suggest a renal primary tumor. However caution is warranted when dealing with a metastasis in the liver, as similar eosinophilic hyaline globules have been described in hepatocellular carcinoma. The individual tumor cells comprising conventional renal cell carcinoma are large and polygonal with abundant granular to vacuolated cytoplasm and low nuclear/cytoplasmic ratios. Cytoplasmic vacuoles may be single or multiple. In tumor cells with multiple cytoplasmic vacuoles, the vacuoles tend to vary in size. Nuclei are characteristically large and eccentrically placed with prominent nucleoli. There is overlap in cytologic features between metastatic conventional renal cell carcinoma to liver and primary hepatocellular carcinoma. Clinical information and ancillary immunohistochemical staining are often required to supplement cytomorphology. Hepatocellular carcinoma most commonly occurs in patients over 50 years old in the setting of cirrhosis, though these tumors can also be seen in young adults and children. Hepatocellular carcinoma may present as either single or multiple liver nodules or with diffuse involvement. An elevated serum alpha-fetoprotein (AFP) >4000 ng/ml is characteristic. There is currently no serum biomarker elevated in patients with renal cell carcinoma and not all patients with hepatocellular carcinoma will present with an elevated AFP. Metastatic renal cell carcinoma enters the differential diagnosis of moderately or poorly differentiated hepatocellular carcinoma. Aspirates from these hepatocellular carcinomas are highly cellular with cells arranged in cohesive clusters and singly. The cohesive groups typically consist of round, smoothly contoured nests and thickened trabecula. Numerous stripped atypical nuclei with prominent nucleoli may be seen in the background of cytologic smears. Trabecular architecture with cells arranged in cords separated by sinusoidal capillaries is highly suggestive of hepatocellular carcinoma and may be best appreciated in a cell block. The vascular pattern of hepatocellular carcinoma may provide a clue to the correct diagnosis. While both HCC and RCC may show a pattern of transgressing endothelium, peripheral wrapping of the tumor cell nests and trabecula by endothelium is not seen in RCC and is pathognomonic of HCC. Importantly, endothelial cells are infrequently encountered in aspirate samples from benign liver. A variety of hyaline globules may be seen in hepatocellular carcinoma. These are generally intracytoplasmic round to ovoid and eosinophilic. These globules may represent Mallory hyaline, alpha-1-antitrypsin or amorphous material within endoplasmic reticulum. Similar hyaline globules have been described in renal cell carcinoma, though extracellular fibrillar eosinophilic material is more common. As a result, the presence of hyaline globules is not diagnostically helpful in this setting. Individual tumor cells derived from hepatocellular carcinoma are large, polygonal and resemble hepatocytes. They have well defined cell borders, moderate amounts of granular cytoplasm, increased N/C ratios, and central round nuclei with prominent nucleoli. Microscopic evidence of bile production by tumor cells is diagnostic of HCC, though not all tumors produce bile. Clear cell hepatocellular carcinoma is a well recognized cytological variant that accounts for fewer than 10% of HCC cases. These tumors have been associated with female gender, hypoglycemia and a more aggressive clinical course, particularly in Asian patients. However, these associations are controversial and remain the subject of debate. By definition, clear cell hepatocellular carcinoma shows a predominance of vacuolated tumor cells secondary to accumulation of abundant cytoplasmic glycogen. The architectural patterns and cytologic features are otherwise the same as those of conventional hepatocellular carcinoma. Several cases of intrahepatic clear cell cholangiocarcinoma have also been described and must be distinguished from both clear cell hepatocellular carcinoma and metastatic clear cell adenocarcinoma. These rare tumors show a spectrum of patterns. Exclusion of an extrahepatic primary tumor and immunohistochemistry are required for diagnosis. Immunohistochemistry often plays a critical role in aiding the distinction of primary hepatocellular carcinoma from metastatic adenocarcinoma in general. A variety of markers is well described and helpful in this setting, as summarized in Table 1. The specific markers used in the differential diagnosis of hepatocellular carcinoma and metastatic renal cell carcinoma deserve special mention. Importantly, conventional hepatocellular carcinoma and the clear cell variant show identical staining patterns. These markers are summarized in Table 2. Hep Par 1 is currently the most sensitive and specific marker for hepatocellular carcinoma. This antibody shows diffuse granular cytoplasmic staining of both normal and neoplastic hepatocytes. Polyclonal CEA stains the majority of hepatocellular carcinomas with a characteristic canalicular staining pattern. Conventional renal cell carcinoma is uniformly negative for both markers. The majority of conventional renal cell carcinomas express the RCC antigen in a membranous pattern. Unfortunately, RCC has been shown to have a much lower sensitivity (20% in one series) in metastatic sites. Hepatocellular carcinoma is negative for RCC. Due to its low sensitivity in metastases, a positive RCC result is diagnostically useful, while a negative result is not. Most renal cell carcinomas also show membranous staining for CD10. This may be confused with the canalicular staining by CD10 typical of hepatocellular carcinoma. PAX-2 is a nuclear transcription factor expressed in the majority of conventional renal cell carcinomas, including those in metastatic sites. This marker is negative in hepatocellular carcinoma. MOC-31, is a cell surface glycoprotein expressed in most metastatic adenocarcinomas to liver and cholangiocarcinoma. The majority of renal cell carcinomas are positive for MOC-31 in a membranous pattern, while HCC is negative. Vimentin is positive in most renal cell carcinomas and negative in hepatocellular carcinoma. Both tumors are generally negative for cytokeratin 7 and 20. 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