Tumors In The Liver - Diagnostic Problems
Case 5 -
Metastatic Renal Cell Carcinoma
Linda D. Ferrell, M.D.
Wendy L. Frankel, M.D.
53 year old man who was found to have a 3 cm mass in his
liver on an abdominal CT scan.
The mass appeared yellow and hemorrhagic. The
surrounding liver was normal. Sections show tumor composed of cells with clear cytoplasm.
Diagnosis: Metastatic Renal Cell Carcinoma
In most cases, the clinical history will be the most helpful feature in distinguishing tumors.
H&E useful features seen more commonly with HCC include cirrhotic liver or chronic hepatitis.
Features seen more frequently with metastatic lesions include multiple masses in a non-cirrhotic liver.
- Mucin: Most HCC are negative but combined HCC-cholangiocarcinomas can be positive.
- Reticulin: Helpful in distinguishing benign from malignant hepatocellular tumors.
- Alpha-fetoprotein (AFP): AFP is a reasonably specific marker for hepatocellular carcinoma;
however, the staining tends to be patchy and completely absent in more than half of the HCCs, and
particularly has been noted to be absent in small, well-differentiated HCCs. AFP is useful when positive
- Polyclonal CEA: pCEA highlights the bile canaliculi, and is relatively specific for
hepatocellular differentiation, but only tends to stain the well to moderately-differentiated HCC's.
This stain will also delineate outer cellular membranes in adenocarcinomas, which can potentially mimic a
canalicular pattern on tangential sectioning.. The interpretation of pCEA is hindered by confusion in
determining staining pattern in some cases – luminal with pseudoglandular HCC, membranous vs canalicular
in some adenocarcinomas.
- Other adenocarcinoma markers (MOC-31, Ber-Epi-4, Leu-M1, etc): Negative in most HCC and
positive in most adenocarcinomas
- Cytokeratins: Hepatocytes express the low molecular weight cytokeratins including 8 and
18, CAM5.2; while most adenocarcinomas express both low and high molecular weight cytokeratins.
Cytokeratin AE1/3 is positive in adenocarcinomas and negative in many HCC. CAM5.2 cannot be used in
isolation since cytokeratin CAM5.2 and AE1/3 will stain most adenocarcinomas. Cytokeratin 7 is negative
in most HCC, but will focally stain smaller ductular-like hepatocytes or some acinar structures within
HCC in our experience. Cytokeratin 7 is positive in many adenocarcinomas. Cytokeratin 20 is negative in
HCC and positive some adenocarcinomas primarily colorectal. Cholangiocarcinoma are Cytokerain 7+ and
Cytokeratin 20+ or – and so are similar to many metastatic adenocarcinomas. Cytokeratin stains are
useful for site of origin in some cases of metastatic adenocarcinoma
- HepPar1, Hepatocyte: A newer hepatocyte antibody (Hep Par 1)
is relatively specific for hepatocellular differentiation and only rarely stains adenocarcinomas. This
antibody stains in a granular pattern within the cytoplasm to a varying degree within tumors with
hepatocytic differentiation, but as with the polyclonal CEA, tends to be less sensitive for the poorly
differentiated HCCs. Hepatoid adenocarcinomas reported positive
- CD10: Pattern of staining is similar to pCEA in HCC and negative in most adenocarcinomas.
Advantage over pCEA – less confusion with determining pattern; disadvantage over pCEA – less sensitive .
- CD34: CD34 typically stains the endothelial-lined trabeculae in HCC and highlights the increased
- ER/PR: Most HCC are negative. Be careful with determining site of origin of tumor. Up to
20% of adenocarcinomas can be positive and some metastatic breast carcinomas are negative.
- Her2-Neu: HCC are negative, while some adenocarcinomas are positive.
Differential between other tumors and HCC:
Distinction from adenocarcinoma. Monoclonal CEA is often diffusely
positive in some types of adenocarcinomas, and usually does not stain hepatocellular tumors. Polyclonal
CEA stains adenocarcinomas (membranous and cytoplasmic) in a different pattern from HCC (canalicular).
Leu-M1, MOC31, B-72.3, and Lex tend to be positive in adenocarcinomas and negative HCC and
when used in combination with CEA and perhaps the hepatocyte antibody (see above) can be helpful to
distinguish poorly differentiated adenocarcinomas from HCC. Routine histochemical stains for the
epithelial mucins such as mucicarmine or periodic acid-Schiff with digestion (PASD) are often helpful as
mucins should not be present in HCC except in combined HCC-cholangiocarcinoma and in some cases of
fibrolamellar variant of HCC (FLHCC). One must take some care in the interpretation of the PASD stain,
however, since this method also reacts with many cytoplasmic glycoproteins produced by hepatocytes,
resulting in a possible false positive interpretation. A combination of CK7, 19, and 20 profiles can be
helpful as these tend to be positive in cholangiocarcinoma (CK19 is essentially always positive in
cholangiocarcinoma) or metastatic carcinoma and negative in hepatocellular carcinoma.
Suggested panel for HCC vs adenocarcinoma (metastatic or cholangiocarcinoma):
Hepatocyte, pCEA, MOC-31. In our experience, this panel correctly
classified 99% of tumors.
Add to help determine site of origin if necessary:
Cytokeratin 7 and 20.
Distinction from neuroendocrine tumors. HCC can also be difficult to
distinguish from a neuroendrocrine neoplasm as both can form acinar or trabecular-like structures, and
can be composed of relatively large tumor cells with abundant eosinophilic cytoplasm and round nuclei.
Features that favor a neuroendocrine tumor in such cases are a prominent vascular or capillary network,
and/or stromal hyalinization. These neuroendocrine tumors can rarely arise as a primary lesion in the
liver, but otherwise, are almost always metastatic. Focal neuroendocrine differentiation has been noted
in HCC, including the fibrolamellar variant, as well as in hepatoblastoma, using various markers such as
neuron specific enolase (NSE), protein gene product 9.5 (PGP 9.5), vasoactive intestinal peptide (VIP),
calcitonin, and S-100 but diffuse staining with a marker such as chromogranin or synaptophysin would
strongly support a neuroendocrine tumor.
Distinction from other tumor types. Clear cell carcinomas in the liver
can pose a diagnostic challenge to distinguish the clear cell variant of HCC from clear cell renal cell
carcinoma metastatic to the liver. In a cirrhotic liver, the diagnosis of clear cell variant of HCC can
be made with enough certainty that stains would not be necessary. However, for lesions in a noncirrhotic
liver without significant AFP elevation, the likelihood of a metastatic lesion makes differentiation more
critical. Keratin profiles are not helpful as both of these tumors typically show similar staining
(positive for CAM5.2, negative for CK7 and 20). However, HCC of these clear cell types will often
demonstrate polyclonal CEA canalicular staining, while renal cell carcinomas show no canalicular
pattern. Other useful markers are EMA, which tends to be positive in RCC and negative in HCC, and the
hepatocyte antibody (see above) that does not stain RCC.
Melanomas can also mimic HCCs, but S-100 and HMB-45 are usually, but not always, negative
in hepatocellular tumors. Rarely, an adrenal cortical tumor may need to be distinguished from a primary
hepatocellular tumor. In these instances, positive staining for inhibin A, which has a high percentage
of positivity in adrenal tumors but not in hepatacytic lesions may be helpful in addition to the
hepatocyte markers previously discussed such as polyclonal CEA and hepatocyte antibody. The use of
immunohistochemistry in the differentiation of HCC from primary mesenchymal tumors will be discussed
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* Positive in hepatoid variant, ** Rarely positive in the cytoplasm
| ||HCC ||Adenocarcinoma ||RCC ||NET|
|AFP ||+/- ||-* ||- ||-|
|Hepatocye ||+ ||-* ||- ||-|
|pCEA ||+ (canalicular) ||+|
|LMWCk (8,18) ||+ ||+ ||+ |
|Ck7 ||- ||+- ||- ||-|
|Ck20 ||- ||-+ ||- ||-|
|CD10 ||+/- (canalicular) ||-** ||+ |
|MOC31 ||- ||+ ||- ||-|
|Chromogranin ||- ||- ||- ||+|
|EMA || || ||+ |
|Vimentin ||- ||- ||+ |