College of American Pathologists

2012 — July Case of the Month

Posted July 10, 2012


CAP Foundation Online Case of the Month

Click Slide Image to View Case with DigitalScope

After reading the summary, try answering the three related multiple-choice questions below.

A 50-year-old woman presented with abdominal pain for 6 months. CT scan showed a hypervascular liver mass, with no evidence of cirrhosis. Liver lobectomy was performed and showed a 6.0 cm tumor on sectioning. Immunohistochemistry revealed that the tumor cells were Hep-Par +, MOC31 –, PAX-2 –, S100 –, HMB-45 –, chromogranin – and synaptophysin –.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 21, and is hepatocellular carcinoma.

Criteria for Diagnosis and Comments:
Slides show a neoplastic proliferation of large polygonal cells, separated by a rich vascular stroma with prominent sinusoid-like vessels. The majority of tumor cells show clear cytoplasm, and are arranged in nests and 3 – 4 cells thick trabeculae. Fat vacuoles and cytoplasmic eosinophilic globules (Mallory hyaline) are seen in many tumor cells. The morphological and immunophenotypic features establish the diagnosis of hepatocellular carcinoma (HCC).

Clear cell HCC has to be distinguished from other clear cell tumors. The presence of bile and Mallory hyaline can establish the diagnosis of HCC based on H&E sections, but immunohistochemistry is required in most cases. Expression of Hep-Par 1 with negative MOC31 in the appropriate clinical and morphological setting confirms the diagnosis of HCC. Hep-Par 1 has high sensitivity for HCC and is expressed in nearly all cases of clear cell HCC. Hep-Par 1 is negative in most adenocarcinomas originating in the pancreas, biliary tree, breast and colorectum. Strong expression has been noted in lung and gastroesophageal adenocarcinomas, but is generally accompanied by strong MOC31 expression. Hepatoid adenocarcinomas of the gastrointestinal tract are also positive for Hep-Par 1. If the staining with Hep-Par 1 is weak or absent, but suspicion of HCC persists based on clinical and imaging findings, other markers of hepatocellular differentiation can be sought such as polyclonal CEA (p-CEA) or glypican-3 (GPC-3). p-CEA shows a canalicular pattern of staining, which is considered pathognomonic of HCC. In contrast, most adenocarcinomas show luminal or cytoplasmic pattern of staining with p-CEA. Both Hep-Par 1 and p-CEA have low sensitivity for poorly-differentiated HCC (around 50%). GPC-3 can be helpful in this situation as it has higher sensitivity for poorly-differentiated HCC. MOC31, a cell surface glycoprotein is negative in >90% of HCC, while majority of adenocarcinomas are positive. This antibody along with one or more hepatocellular markers is extremely useful for the diagnosis of HCC.

Renal cell carcinoma is also a highly vascular neoplasm composed of polygonal cells, and can be indistinguishable from clear cell HCC on morphologic grounds. Expression of hepatocellular markers Hep-Par 1 and p-CEA (canalicular pattern) is not observed in renal cell carcinoma. PAX-2, a renal-restricted nuclear transcription factor, is expressed in 70 – 80% of metastatic clear cell renal cell carcinomas, and less commonly in other subtypes of renal cell carcinoma. Higher grades of clear cell carcinoma can have decreased expression. PAX-2 is negative in HCC. Unlike HCC, MOC31 is positive in 60 – 70% of renal cell carcinomas. Other markers like RCC antibody and vimentin have a lower sensitivity and are less useful. CD10 does not distinguish between RCC and HCC as it can be expressed in both tumors.

Melanomas can undergo clear cell change (balloon cell melanoma) due to degeneration of premelanosomes or accumulation of lipid or glycogen. Liver metastasis from these tumors can mimic clear cell HCC morphologically. Melanocytic markers like S100, HMB-45 and Melan A are negative in hepatocellular tumors, while melanomas do not express Hep-Par 1 or polyclonal CEA. GPC-3 is not helpful in this differential diagnosis as it can be expressed in melanomas.

Adrenocortical carcinoma can have overlapping histological features with clear cell HCC. The expression of inhibin, Melan A and calretinin in adrenocortical carcinoma distinguishes it from HCC. Inhibin is expressed in around 70% of adrenocortical carcinomas and Melan A in 50 – 60%. The sensitivity can be improved to >80% by combination of both antibodies. Adrenocortical carcinomas express synaptophysin, but are negative for chromogranin. Most adrenocortical carcinomas are negative for pancytokeratin, as well as hepatocyte markers like Hep-Par 1 and p-CEA.

The epithelioid variant of angiomyolipoma (AML) can have clear cells and is difficult to distinguish from HCC on morphologic grounds alone. Most AMLs in the liver are not associated with tuberous sclerosis and often lack fat. Once the diagnosis is suspected, immunohistochemical confirmation is easy because of their characteristic staining profile. AML strongly co-expresses smooth muscle markers like smooth muscle actin and melanoma markers (i.e., HMB-45, Melan A). S100 is typically negative. Cytokeratin, Hep-Par 1 and polyclonal CEA are not expressed in AML.

Neuroendocrine carcinomas (carcinoids) are almost always metastatic, but can rarely arise as a primary lesion in the liver. Neuroendocrine carcinomas can have clear cells and may be comprised of polygonal tumor cells in acinar or trabecular patterns similar to HCC. Stromal hyalinization, if present, favors a neuroendocrine tumor. The majority of neuroendocrine carcinomas express one or more neuroendocrine markers (chromogranin, synaptophysin) as well as MOC31. CD56, a less specific neuroendocrine marker, is not helpful as if can be positive in HCC as well. Hep-Par 1 is consistently negative in neuroendocrine neoplasms.

Carcinomas from a wide variety of sites can exhibit clear cell features, including those originating in the bile duct, prostate, endometrium, vagina, cervix, ovary, salivary gland and thyroid. The clinical presentation, and pattern of immunoreactivity with cytokeratins (like CK7/CK20) and lineage specific markers such as TTF-1, PSA, etc. can help to confirm the diagnosis. Other tumors with clear cells include squamous cell carcinoma, germ cell tumors like seminoma, and sarcomas like epithelioid leiomyosarcoma.

Supplementary Questions: For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Which of the following is true about the use of Hep-Par 1 in the diagnosis of hepatocellular carcinoma (HCC)? A. Not useful in distinction from renal cell carcinoma
B. Sensitivity is high (>80%) in poorly differentiated HCC
C. Sensitivity is low (<50%) in clear cell HCC
D. Strong expression can occur in metastatic adenocarcinomas from lung and stomach
2. Which of the following immunohistochemical results favors renal cell carcinoma metastatic to liver over hepatocellular carcinoma? A. Cytokeratin 7 and 20 negative
B. Hep-Par 1 positive
C. MOC31 negative
D. PAX-2 positive
3. Which of the following is TRUE about making an immunohistochemical diagnosis of HCC? A. AFP has high sensitivity, but low specificity
B. Cytoplasmic reactivity with polyclonal CEA is specific for hepatocellular differentiation
C. Glypican-3 has lower sensitivity for poorly differentiated HCC than Hep-Par 1
D. MOC31 expression is seen in a small minority of HCC


  1. Fan Z, van de Rijn M, Montgomery K, et al. Hep Par 1 antibody stain for the differential diagnosis of hepatocellular carcinoma: 676 tumors tested using tissue microarrays and conventional tissue sections. Mod Pathol. 2003:16:137-144.
  2. Gokden N, Gokden M, Phan DC, McKenney JK. The utility of PAX-2 in distinguishing metastatic clear cell renal cell carcinoma from its morphologic mimics: an immunohistochemical study with comparison to renal cell carcinoma marker. Am J Surg Pathol. 2008:32:1462-1467.
  3. Kakar S, Gown AM, Goodman ZD, Ferrell LD. Best practices in diagnostic immunohistochemistry: hepatocellular carcinoma versus metastatic neoplasms. Arch Pathol Lab Med. 2007:131:1648-1654.
  4. Morrison C, Marsh W Jr, Frankel WL. A comparison of CD10 to pCEA, MOC-31 and hepatocyte for the distinction of malignant tumors in the liver. Mod Pathol. 2002:15:1279-1287.
  5. Pan CC, Chen PC, Tsay SH, Ho DM. Differential immunoprofiles of hepatocellular carcinoma, renal cell carcinoma, and adrenocortical carcinoma: a systemic immunohistochemical survey using tissue array technique. Appl Immunohistochem Mol Morphol. 2005:13:347-352.
  6. Shafizadeh N, Ferrell LD, Kakar S. Utility and limitations of glypican-3 expression for the diagnosis of hepatocellular carcinoma at both ends of the differentiation spectrum. Mod Pathol. 2008;21:1011-1018.

Sanjay Kakar, MD FCAP
Surgical Pathology Committee
UCSF and VA Medical Center-San Francisco
San Francisco, CA