Liver & intrahepatic bile ducts
Hepatocellular carcinoma
HCC - clear cell variant
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Last author update: 25 September 2024
Last staff update: 25 September 2024
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PubMed Search: Clear cell hepatocellular carcinoma
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Practice question #1 | Practice answer #1 | Practice question #2 | Practice answer #2Cite this page: Ashfaq M, Gonzalez RS. HCC - clear cell variant. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/livertumorclearcellHCC.html. Accessed August 1st, 2025.
Definition / general
- Rare form of hepatocellular carcinoma (HCC) distinguished histologically by cells that appear empty due to abundant clear cytoplasm (Curr Med Imaging 2023 May 22 [Epub ahead of print])
- Considered a cytological variant of HCC by WHO in 2012 but a subtype of HCC by WHO in 2019
Essential features
- Accounts for 7.3 - 12.5% of HCC and has a better prognosis than other subtypes (Radiol Case Rep 2019;14:1377)
- Affects predominantly female patients and frequently presents as a solitary encapsulated tumor
- Microscopically consists of clear cells with abundant glycogen
ICD coding
Epidemiology
- Highest incidence in Asia (50% cases in China), followed by Europe (10%), Africa (7.8%), North America (5.1%) (J Hepatol 2020;72:250)
- Hepatitis B and hepatitis C infections remain the most important risk factors for HCC, though an increasing number of new cases are due to nonalcoholic steatohepatitis (J Hepatol 2020;72:250)
- Median age of diagnosis 60 - 64 years among men and 65 - 69 years among women (Hepatology 2021;73:4)
- Compared with other forms of HCC, clear cell variant has a higher prevalence in women (Asia Pac J Clin Oncol 2017;13:e312)
Sites
- Can arise anywhere in the liver
- Most common sites of metastasis include lungs (31.5%), lymph nodes (19.0%) and bones (16.7%) (Intern Med 2022;61:189)
Pathophysiology
- Pathophysiology for clear cell HCC is similar to HCC in general: progression from dysplastic foci to dysplastic nodule to HCC (F1000Res 2016;5:879)
Etiology
- Risk factors for clear cell HCC are similar to HCC in general: chronic hepatitis B and hepatitis C virus infection, alcohol consumption, nonalcoholic fatty liver disease, metabolic syndrome / obesity, type 2 diabetes mellitus, aflatoxin B1 exposure, tobacco exposure (Hepatology 2021;73:4)
Clinical features
- Constitutional symptoms include weight loss (91.2%) and easy fatigability (91.2%)
- Common gastrointestinal symptoms include early satiety (88.1%), abdominal pain (87.7%), abdominal distention (80.3%), anorexia (78.5%)
- Common clinical signs include hepatomegaly (78.8%) and abdominal tenderness (41.2%) (BMC Gastroenterol 2023;23:321)
Diagnosis
- HCC in general can be diagnosed without tissue sampling
- Ultrasonography: 51 - 87% sensitive and 80 - 100% specific
- Contrast enhanced ultrasound: 90% sensitive and 97% specific
- Triphasic CT scan: 65% sensitive and 96% specific
- MRI: 77 - 90% sensitive and 84 - 97% specific (StatPearls: Hepatocellular Carcinoma [Accessed 14 August 2024])
- Confirmation of clear cell subtype generally requires tissue sampling and histologic review
Laboratory
- Raised serum alpha fetoprotein levels
- Raised levels of CA 19-9
- Hepatitis B and hepatitis C virus markers (Hepatol Res 2008;38:291)
Radiology description
- On MRI, clear cell HCC shows signal loss on opposed phase images, which is attributed to cytoplasmic fat within tumor cells
- This feature can complicate differentiation from steatohepatic HCC
- May exhibit early enhancement and rapid washout, similar to other HCCs; however, pseudocapsule helps in distinguishing clear cell HCC from other HCC
- HCC with only focal clear cells may not exhibit the focal enhancement pattern (AJR Am J Roentgenol 2022;219:212)
Radiology images
Images hosted on other servers:
Mass with discontinuous capsule
Rim enhancing hypointense mass
Prognostic factors
- Clear cell HCC has a better prognosis compared to other common variants of HCC
- Prognosis and survival outcomes improve with increasing proportion of clear cells in the tumor (World J Gastroenterol 2010;16:764)
- Rate of recurrence is lower than other variants of HCC
- Overall survival and recurrence rates depend on several factors, including serum alpha fetoprotein levels, vascular invasion and background cirrhosis (Ann Surg Oncol 2011;18:1955)
- After resection, the most important predictor of postoperative survival is Edmondson grade (Asia Pac J Clin Oncol 2017;13:e312)
Case reports
- 57 year old man with huge primary clear cell HCC (Curr Med Imaging 2023 May 22 [Epub ahead of print])
- 62 year old man with cirrhosis and clear cell HCC (Rare Tumors 2012;4:e29)
- 65 year old woman with primary clear cell HCC (Radiol Case Rep 2019;14:1377)
Treatment
- Same as for other forms of HCC: surgical resection / liver transplantation, tumor ablation, transarterial therapy, systemic chemotherapy, sorafenib (kinase inhibitor) (StatPearls: Hepatocellular Carcinoma [Accessed 14 August 2024])
Gross description
- External surface of the tumor may appear nodular or congested with a tan appearance, depending on the fat and glycogen content of the cells
- Cut surface may be solid with variegated areas consisting of cystic spaces
- Adjacent liver may or may not be cirrhotic (J Cancer Res Ther 2015;11:656)
Gross images
Images hosted on other servers:
Unencapsulated mass, variegated surface
Microscopic (histologic) description
- Majority of tumor cells have abundant clear cytoplasm due to intracytoplasmic glycogen deposition, giving the cells a bland appearance
- WHO requires > 80% of tumor to show clear cell morphology
- Reported criteria in China include > 50% clear cells and diagnosis by > 2 pathologists (World J Gastroenterol 2010;16:764)
- Can be hard to differentiate clear cytoplasm from lipid droplets, though some degree of steatosis is permissible in clear cell HCC (J Liver Cancer 2020;20:17)
- Growth patterns can range from sheets of cells to trabeculae with or without pseudoglands or a combination of patterns
- Tumor is partially or completely encapsulated, with occasional hemorrhage or necrosis
- Tumor does not show fibrosis except in the capsule and in areas of hemorrhage and necrosis (Mod Pathol 2000;13:874)
Microscopic (histologic) images
Contributed by Raul S. Gonzalez, M.D.
Clear cells on biopsy
Bland cells, clear cytoplasm
Clear cells on biopsy
Bland cells, clear cytoplasm
Resection
Glycogen accumulation, pleomorphic cells
Positive stains
- HepPar1, glypican 3, polyclonal CEA (as for other HCC)
- Periodic acid-Schiff stain highlights intracytoplasmic glycogen (Mod Pathol 2000;13:874)
Negative stains
Molecular / cytogenetics description
- Clear cell HCCs have been shown to be enriched in IDH1 R132C mutations (World J Surg Oncol 2017;15:82)
Sample pathology report
- Liver, mass, targeted core biopsy:
- Hepatocellular carcinoma, moderately differentiated, with clear cell features (see comment)
- Background hepatic parenchyma with cirrhosis
- Comment: The lesion is clearly malignant, consisting of moderately differentiated cells resembling hepatocytes with prominent cleared out cytoplasm. If the majority of the tumor resembles the portion sampled on biopsy, then the lesion likely represents clear cell hepatocellular carcinoma, which reportedly has an improved prognosis compared to hepatocellular carcinoma, not otherwise specified.
Differential diagnosis
- Metastatic clear cell renal cell carcinoma:
- Can be morphologically indistinguishable from clear cell HCC
- Positive for PAX8; negative for HepPar1 (Mod Pathol 2000;13:874)
- Primary clear cell cholangiocarcinoma:
- Epithelioid angiomyolipoma:
- Metastatic adrenal cortical carcinoma:
- Can show cytoplasmic clearing
- Positive for SF1; negative for HepPar1 (Rare Tumors 2012;4:e29)
Practice question #1
A 55 year old man with a history of chronic hepatitis B infection presents with weight loss. Imaging reveals a solitary liver mass. A biopsy of the lesion is shown. Immunohistochemical staining shows positivity for HepPar1 and the lesion lacks significant steatosis. Which of the following is the most likely diagnosis?
- Clear cell cholangiocarcinoma
- Clear cell hepatocellular carcinoma
- Hepatocellular adenoma
- Metastatic clear cell renal cell carcinoma
Practice answer #1
B. Clear cell hepatocellular carcinoma. The patient's history of chronic hepatitis B infection, along with the histologic findings and positive immunostaining with HepPar1, make the diagnosis of clear cell hepatocellular carcinoma most likely. Answer A is incorrect because cholangiocarcinoma is negative for HepPar1; clear cell cholangiocarcinoma is rare but can occur. Answer C is incorrect because hepatocellular adenoma is a benign tumor usually seen in young women with a history of oral contraceptive use and it lacks histologic atypia and cleared out cytoplasm. Answer D is incorrect because while metastatic clear cell renal cell carcinoma has similar histology to clear cell hepatocellular carcinoma, it is negative for HepPar1 and instead shows positivity for markers such as PAX8.
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Reference: HCC - clear cell variant
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Reference: HCC - clear cell variant
Practice question #2
Which of the following is true about clear cell hepatocellular carcinoma?
- It has a worse prognosis than conventional hepatocellular carcinoma
- It is typically solitary and encapsulated
- Only 10% of tumor cells need to have clear cytoplasm to make the diagnosis
- Tumor cells are negative on periodic acid-Schiff staining
Practice answer #2
B. It is typically solitary and encapsulated. In addition to its characteristic morphology, clear cell hepatocellular carcinoma has typical gross features as well, including being solitary (rather than multifocal) and demonstrating a capsule. Answer A is incorrect because clear cell HCC has a better prognosis than conventional HCC. Answer C is incorrect because WHO criteria require 80% clear cells for the diagnosis, though other systems may recommend 50%. Answer D is incorrect because the cleared out tumor cells are full of glycogen, meaning they will stain positive on periodic acid-Schiff.
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Reference: HCC - clear cell variant
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Reference: HCC - clear cell variant
