Interesting Case July 2020

Case contributed by:
Alison Chan, D.O. and Karen Matsukuma, M.D., Ph.D.
University of California Davis, Department of Pathology and Laboratory Medicine, Sacramento, CA

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Clinical History

A 55-year-old female with a history of endometrial cancer, status post total abdominal hysterectomy 6 years prior, presented with intermittent right-sided abdominal pain for one week. A CT abdomen/pelvis with contrast demonstrated a 7.3 cm liver mass with adjacent perihepatic hematoma. No radiologic evidence or history of chronic liver disease was noted. Laboratory investigation showed an unremarkable CBC, AST of 21 IU/L, ALT of 24 IU/L, and alkaline phosphatase of 75 IU/L. Serologies for Hepatitis B and C were negative. Tumor marker values were as follows: alpha-fetoprotein 816.5 ng/mL, CA-125 43.7 U/mL, CA 19-9 40.7 U/mL, and carcinoembryonic antigen 1.9 ng/mL. A liver biopsy was performed.

Pathologic Findings

Figure 1: Low power view of the liver biopsy.

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Figure 2: Medium power view of the liver biopsy shows a vaguely nodular sheet of monomorphic neoplastic cells, interrupted by slit-like vascular spaces.

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Figure 3: High power view of the liver biopsy shows relatively uniform tumor cells with round to oval nuclei and moderate to abundant clear cytoplasm.

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Figure 4: Immunohistochemical stains demonstrating focal expression of glypican-3 and CK7, and diffuse expression of AE1/AE3.

Biopsy Immunohistochemical Stains

AE1/AE3               Positive (diffuse, strong)

Glypican-3           Positive (focal)

Hep Par1              Negative

Arginase 1           Negative

CK7                        Positive (focal)

PAX 8                    Negative

ER                           Negative

PR                           Negative


Hepatocellular carcinoma, clear cell variant


Given the extremely high serum alpha-fetoprotein level and patchy positivity for glypican-3, the findings were deemed most consistent with hepatocellular carcinoma with clear cell features. Re-review of the arginase 1 stain also revealed very focal positivity. Hepatectomy was subsequently performed (Figure 5).

Figure 5: Low power view of the partial hepatectomy specimen shows juxtaposition of the clear cell component (right side) with areas demonstrating more conventional hepatocellular differentiation (left side).   

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Figure 6: High power view of the optically clear cells of clear cell HCC.

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The clear cell variant of hepatocellular carcinoma (HCC) is one of the many subtypes of HCC, representing 3-7% of HCCs overall. The current World Health Organization criteria require at least 80% clear cell morphology for classification as clear cell HCC, whereas other observers require only 50% clear cell component. Interestingly, some studies show an association with Hepatitis C and better overall prognosis compared to classical HCC. Additionally, while many patients with clear cell HCC have cirrhosis, several studies highlight the existence of clear cell HCC in non-cirrhotic livers.

The defining histologic feature of clear cell HCC is the presence of tumor cells with large, optically clear cytoplasm due to accumulation of glycogen or, less commonly, lipid. The neoplastic cells can be arranged in trabecular, solid, and/or acinar patterns, and are not typically associated with significant intra-tumoral fibrosis.

Given the prominent intracytoplasmic accumulation of glycogen or lipid, clear cell HCC can demonstrate atypical imaging findings, and biopsy may be necessary to confirm the diagnosis. On abdominal ultrasound, increased echogenicity may be observed; on unenhanced CT there may be decreased attenuation; and on MRI, the tumor may be interpreted as having a fatty component. Consequently, the radiologic differential diagnosis may include hepatic adenoma (e.g., HNF1-inactivated subtype), angiomyolipoma, and other lipid-rich tumors.

When predominantly clear cell morphology is observed in a mass-directed liver biopsy (as in the current case), a wide differential diagnosis that includes primary and metastatic clear cell carcinomas should be considered. In addition to clear cell HCC, primary liver tumors such as clear cell variant of fibrolamellar HCC, classical HCC with foamy histiocytes, epithelioid angiomyolipoma, and clear cell cholangiocarcinoma are diagnostic possibilities. Metastatic carcinomas with clear cell morphology, including clear cell renal cell carcinoma, adrenal cortical carcinoma, clear cell adenocarcinomas of the salivary gland and female genitourinary tract, clear cell neuroendocrine tumors, yolk sac tumor, and metastases from other sites such as lung and thyroid are also important to consider. The co-existence of cytologic findings of classical HCC (e.g., abundant granular, eosinophilic cytoplasm, round, centrally placed nuclei with prominent nucleolus), intracytoplasmic or canalicular bile, Mallory-Denk bodies, and/or background chronic liver disease are clues to hepatic origin.

Also within the differential diagnosis are steatohepatitic variant of HCC and HCC with steatosis. The steatohepatitic variant of HCC is characterized by steatosis, ballooning degeneration, intra-tumoral inflammation, Mallory-Denk bodies, and pericellular fibrosis (Figure 7), whereas HCC with steatosis contains foci of intra-tumoral steatosis but lacks the hepatocyte ballooning, Mallory-Denk bodies, and inflammation (Figure 8). Although in some instances clear cell HCC may be composed of neoplastic hepatocytes containing tiny droplets of lipid resembling microvesicular steatosis (rather than glycogen) or may contain distinct areas of fatty change, it will lack the constellation of features that define steatohepatitis. Additionally, the vast majority of steatohepatitic HCCs arise in a background of non-alcoholic fatty liver disease or alcoholic liver disease. Thus, the presence or absence of a hepatocyte injury pattern (e.g., ballooning degeneration, intra-tumoral inflammation, pericellular fibrosis) and steatosis in the tumor and fatty liver disease in the background liver will facilitate distinction of steatohepatitic HCC from clear cell HCC. When necessary, PAS stain can aid in the distinction of HCC with steatosis from clear cell HCC (when due to glycogen accumulation).

Figure 7: Steatohepatitic variant of HCC. Note the prominent ballooned hepatocytes (center), inflammation, Mallory-Denk bodies, and steatosis. Image courtesy of Sadhna Dhingra M.D.

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Figure 8: HCC with steatosis. Image courtesy of Sadhna Dhingra M.D.

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In a subset of cases, immunohistochemistry is necessary to distinguish between the diagnostic possibilities. It is important to note that Hep Par1 expression can be patchy and variable in clear cell HCC (presumably due to displacement of normal cytoplasm by the abundant glycogen or lipid). Additionally, a subset of ovarian clear cell carcinomas expresses Hep Par1. Glypican-3, while occasionally mistaken as a specific marker of hepatocellular carcinoma, can be expressed in many tumors (e.g., yolk sac tumor, chromophobe renal cell carcinoma, lung carcinoma, cholangiocarcinoma, melanoma), and thus by itself is insufficient to confirm hepatocellular origin. CD10 and polyclonal CEA, other well-known markers of hepatocellular differentiation, can be positive in clear cell HCC but are similarly insufficient for confirming liver origin without other supportive features. In our case, because of the patient’s history of uterine cancer, markers of gynecologic carcinoma were performed (PAX8, ER, PR), all of which were negative. Interestingly, PAX8 may be positive in up to 20% of clear cell HCCs – adding to the list of immunohistochemical caveats for this tumor. Finally, although HCCs (including clear cell HCC) usually do not express cytokeratin AE1/AE3, it is important to remember that 15% of HCCs express AE1/AE3. Likewise, although CK7 expression is not typical of clear cell HCCs, focal positivity does not exclude it.

Take Home Points:

  1. When a liver biopsy demonstrates a predominantly clear cell neoplasm, a wide differential diagnosis including primary and metastatic clear cell tumors should be considered.
  2. The presence of cytologic features of classical HCC, bile, or Mallory-Denk bodies within the lesion and/or background chronic liver disease are helpful clues to hepatocellular origin.
  3. Clear cell HCC may demonstrate patchy and/or weak staining for Hep Par1 and arginase 1. Thus, a panel approach to immunohistochemical work-up (to both rule in and rule out entities) is recommended.


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