Case 6 -
Metastatic Renal Cell Carcinoma to Liver
Jennifer A. Brainard
Click on each slide thumbnail image for an enlarged view
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.
Metastatic adenocarcinoma with clear cell features,
consistent with metastatic renal cell carcinoma.
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.
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
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
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.
The rare clear cell variant of cholangiocarcinoma stains positively for cytokeratin 7, and CAM 5.2.
Some tumors are positive for cytokeratin 19 and EMA. Membranous staining for CD56 has also been
described. These tumors are negative for Hep-par 1, CD10, and polyclonal CEA.
|Marker ||HCC ||Adenocarcinoma|
|Hep-par 1 ||++ ||--|
|CEA, polycl ||++|
|MOC31 ||-- ||++|
|CK-7 ||-- ||++|
|CK-20 ||-- ||++|
|CEA, monocl ||-- ||+/-|
|AFP ||+/- ||--|
|Marker ||HCC ||Metastatic RCC|
|Hep-par 1 ||++ ||--|
|CEA, polycl ||++|
|RCC ||-- ||+/-|
|MOC31 ||-- ||++|
|CK-7 ||-- ||--|
|CK-20 ||-- ||--|
|vimentin ||-- ||++|
|PAX-2 ||-- ||++|
|AFP ||+/- ||--|
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