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Year : 2015  |  Volume : 11  |  Issue : 3  |  Page : 656

Clear cell hepatocellular carcinoma: Back to the basics for diagnosis

1 Department of Pathology, GB Pant Hospital, New Delhi, India
2 Department of Gastrointestinal Surgery, GB Pant Hospital, New Delhi, India
3 Department of Radiology, GB Pant Hospital, New Delhi, India

Date of Web Publication9-Oct-2015

Correspondence Address:
Dr. Meeta Singh
Department of Pathology, RM 325, Academic Block, GB Pant Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.136041

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 > Abstract 

Hepatocellular carcinoma (HCC) is a common cancer world-wide with a higher incidence in Asia. Clear cell variant of HCC (CCHCC) has a frequency ranging from 0.4% to 37%. The presence of 90-100% clear cells is rare. In the present case, a 35-year-old female patient presented with fever and a large abdominal mass in the right hypochondrium. Histology of the tumor revealed >95% clear cells and after taking multiple sections from different areas of tumor only few scattered cells with eosinophilic cytoplasm were found. Immunohistochemistry with Hep Par 1, Glypican 3 and polyclonal carcinoembryonic antigen were negative as were all other markers for metastatic clear cell tumors. Histological diagnosis was based on routine H and E sections showing a histological pattern of architecture with thickened trabeculae. We describe a rare case of CCHCC with >95% clear cells and no immunoreactivity in tumor cells in a non-cirrhotic liver.

Keywords: Clear cell, hepatocellular carcinoma, Hep Par 1

How to cite this article:
Sakhuja P, Mishra PK, Rajesh R, Sharma AK, Gondal R, Singh M. Clear cell hepatocellular carcinoma: Back to the basics for diagnosis. J Can Res Ther 2015;11:656

How to cite this URL:
Sakhuja P, Mishra PK, Rajesh R, Sharma AK, Gondal R, Singh M. Clear cell hepatocellular carcinoma: Back to the basics for diagnosis. J Can Res Ther [serial online] 2015 [cited 2022 Jul 5];11:656. Available from: https://www.cancerjournal.net/text.asp?2015/11/3/656/136041

 > Introduction Top

Clear cell variant of hepatocellular carcinoma (CCHCC) has been described with a frequency ranging from 0.4 to 37% of HCC in different studies, the variation probably due to the non-uniformity of diagnostic criteria. [1] While some have considered clear cells <30% as sufficient for diagnosis, others diagnose CCHCC only when the tumor contains >30% clear cells. [2]

The presence of 90-100% clear cells is rare. [3] Hep Par1 immunostain distinguishes HCC-CC from other clear cell malignancies with sensitivity of 90% and specificity of 100%. [4]

We describe a rare case of CCHCC with >95% clear cells and no or only focal immunoreactivity in tumor cells, in a non-cirrhotic patient.

 > Case Report Top

A 32-year-old female patient was admitted with low grade fever for 1 month, along with pain and lump in the abdomen. She had been using oral contraceptive pills for last 4 years.

Examination revealed hepatomegaly with irregular surface. Liver function test was normal. Alpha-fetoprotein (AFP) was <5 ng/mL. Viral serology hepatitis B virus and hepatitis C virus (HCV) were negative.

Ultrasonography and color Doppler revealed a highly vascular well-circumscribed hypoechoic mass in the left lobe liver with calcification. Contrast enhanced computed tomography (CECT) in the arterial phase showed a well-circumscribed mass with a non-enhancing scar/necrotic area. Uniform enhancement of the lesion was seen in the venous phase [Figure 1]a and b. CECT and magnetic resonance image (MRI) suggested an atypical giant hemangioma in the left lobe of the liver. Thus, based on clinical and radiological features, the differential diagnosis included: Giant hemangioma, fibrolamellar HCC and focal nodular hyperplasia.
Figure 1: (a) Contrast enhanced computed tomography in the arterial phase showing a well-circumscribed mass with a non-enhancing scar/necrotic area, evidence of small scattered serpiginous vessels and focal calcification, (b) Uniform enhancement of the lesion was seen in the venous phase

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The tumor was resected with a small cuff of liver tissue. Non-tumor liver appeared non-cirrhotic on pre-operative examination.

Grossly, the tumor measured 18 cm × 14 cm × 11 cm and weighed 1.25 kg. The external surface of the tumor was nodular and congested. Cut surface was solid with variegated areas with small cystic spaces measuring 0.2-1 cm. Adjacent liver tissue included in the specimen appeared non-cirrhotic.

Histologically, the tumor was well-demarcated by a capsule in most areas. The tumor cells were arranged in trabeculae and nests composed of polygonal cells with clear cytoplasm [Figure 2]a and b. Macronucleoli and nuclear inclusions were seen focally. Intracellular bile, Mallory hyaline or eosinophilic inclusions were not seen. Less than 5% cells showed granular eosinophilic cytoplasm. Adjacent non-tumor liver was non-cirrhotic and showed occasional tumor nodule [Figure 2]c.
Figure 2: (a) Trabeculae and sheets of clear cells separated by thin sinusoids, (hematoxylin and eosin ×40), (b) Predominantly clear cells and focal necrosis (hematoxylin and eosin ×100), (c) Tumor cells (T) are negative for Hep Par 1 while adjacent non-cirrhotic liver is positive (Hep Par 1 immunostain, ×40), (d) Peritrabecular sinusoidal cells showing immunoreactivity with CD34 (CD34 immunostain, ×200)

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Tumor cells showed focal presence of glycogen as revealed by periodic acid Schiff positive diastase sensitive staining. Oil red - O stain for fat showed focal presence of lipid droplets.

A panel of antibodies was used to differentiate from other clear cell tumors; however, the tumor cells show only focal rare immunoreactivity with Hep Par, considered inconclusive and negative for Glypican 3. There was no immunoreactivity with panCK, MOC31, polyclonal carcinoembryonic antigen (pCEA), synaptophysin, chromogranin, epithelial membrane antigen (EMA), vimentin, S-100, Human melanoma black-45 (HMB-45), CD10, cytokeratin 7 (CK7), CK20, ubiquitin and AFP. CD34 was positive in peritrabecular sinusoidal cells giving the classical pattern usually observed in HCC [Figure 2]d.

Despite inconclusive Hep Par1 immunostain a diagnosis of CCHCC was given as all other clear cell tumors were also ruled out by immunohistochemistry (IHC) and the classical trabecular pattern strongly supported the diagnosis.

Retrospectively, the patient was investigated for a possibility of clear cell tumor elsewhere metastasizing to the liver. Even after an exhaustive clinic-radiological work-up including MRI, no primary was found in the kidneys, adrenals, thyroid, ovary, salivary gland or gut.

Post-operative course was uneventful; however, the patient returned with a biopsy proven local recurrence after 6 months, proven on biopsy [Figure 3]. She declined further treatment.
Figure 3: Post-operative magnetic resonance image after 6 months showing multiple lesions on T2 image

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 > Discussion Top

Clear cell HCC usually shows similar clinical characteristics as conventional HCC. [5]

Clear cell change in HCC is not infrequent and CCHCC has a reported frequency of 0.4-37%. [1] More than 50% HCCs may have foci of clear cells. However, the presence of >90% clear cell in an HCC is rare. [6],[7]

Clear cell change may be due to the presence of glycogen or lipid in the cytoplasm of tumor cells. Other clear cell tumors that can metastasize to liver include renal cell carcinoma (RCC), adrenal cortical carcinoma, clear cell sarcoma, angiomyolipoma and clear cell variants of pulmonary, squamous cell and neuroendocrine carcinoma.

A panel of antibodies including Hep Par1, polyclonal CEA, CD34, HMB45, melan A, RCC, chromogranin, synaptophysin, vimentin, thyroid transcription factor-1, EMA and S-100 should be able to establish a diagnosis of HCC and rule out other clear cell tumors.

In the hepatobiliary region, clear cell carcinoma gall-bladder, cholangiocarcinoma and clear cell bile duct adenoma have all been described. These show immunoreactivity with CK7 and are Hep Par negative.

In the present case, all immunohistochemical stains were negative; thus, a provisional diagnosis of CCHCC on morphology was given. Sensitivity and specificity for Hep Par 1 for CCHCC may be 90% and 100% respectively. [5] However, like in the present case, others have also reported inconclusive IHC patterns in CCHCC. [8]

Hep Par 1 usually shows a coarse granular cytoplasmic staining. In clear cells however, pattern can be patchy and variable as seen in a study of 10 CCHCC by Murakata et al. [4] This may be due to the scanty cytoplasmic organelles.

In situ hybridization for albumin mRNA can help differentiate CCHCC from other clear cell carcinomas metastatic to the liver and clear cell neoplasms in the retroperitoneum. [9]

Ultrastructurally, clear cells of CCHCC have abundant glycogen storage and a variable degree of fat vacuoles. The organelles may be reduced in size and number [3] clear cells may indicate well-differentiated HCC, their percentage may decrease as tumor enlarges. Background liver is usually cirrhotic, a normal liver is rare. [4],[6],[10]

CCHCC can pose a diagnostic challenge as their radiological appearance can differ from conventional HCC. Tumors with fatty change or clear cell change have greater echogenicity on ultrasound and sometimes appear like a hemangioma.

Prognosis of CCHCC is variable and has been reported as better than similar to and worse than classic HCC. [4] In a study on 43 cases, CCHCC Liu et al. found a better prognosis was related to the higher proportion of clear cells. [1] Other factors that have been implicated as having prognostic significance are capsule formation, association with HCV infection, bland versus aggressive morphologic features and aneuploid deoxyribonucleic acid content. [1] Favorable outcome has been reported with surgical resection. [5]

To conclude, we report a case of CCHCC that defied usual clinical, radiological and immunohistochemical diagnostic features. Diagnosis was based on conventional H and E histological sections thus reinforcing the importance of the latter.

 > Acknowledgment Top

The authors would like to thank members of the Laennec Liver Pathology Society for their prompt help in confirming the diagnosis.

 > References Top

Liu Z, Ma W, Li H, Li Q. Clinicopathological and prognostic features of primary clear cell carcinoma of the liver. Hepatol Res 2008;38:291-9.  Back to cited text no. 1
Buchanan TF Jr, Huvos AG. Clear-cell carcinoma of the liver. A clinicopathologic study of 13 patients. Am J Clin Pathol 1974;61:529-39.  Back to cited text no. 2
Yang SH, Watanabe J, Nakashima O, Kojiro M. Clinicopathologic study on clear cell hepatocellular carcinoma. Pathol Int 1996;46:503-9.  Back to cited text no. 3
Murakata LA, Ishak KG, Nzeako UC. Clear cell carcinoma of the liver: A comparative immunohistochemical study with renal clear cell carcinoma. Mod Pathol 2000;13:874-81.  Back to cited text no. 4
Lao XM, Zhang YQ, Jin X, Lin XJ, Guo RP, Li GH, et al. Primary clear cell carcinoma of liver - Clinicopathologic features and surgical results of 18 cases. Hepatogastroenterology 2006;53:128-32.  Back to cited text no. 5
Emile JF, Lemoine A, Azoulay D, Debuire B, Bismuth H, Reynès M. Histological, genomic and clinical heterogeneity of clear cell hepatocellular carcinoma. Histopathology 2001;38:225-31.  Back to cited text no. 6
Adamek HE, Spiethoff A, Kaufmann V, Jakobs R, Riemann JF. Primary clear cell carcinoma of noncirrhotic liver: Immunohistochemical discrimination of hepatocellular and cholangiocellular origin. Dig Dis Sci 1998;43:33-8.  Back to cited text no. 7
Geramizadeh B, Boub R, Rahsaz M. Histologic differentiation of hepatocellular carcinoma from adenocarcinoma by a simple panel: Evaluation of the pitfalls. Indian J Pathol Microbiol 2007;50:507-10.  Back to cited text no. 8
Oliveira AM, Erickson LA, Burgart LJ, Lloyd RV. Differentiation of primary and metastatic clear cell tumors in the liver by in situ hybridization for albumin messenger RNA. Am J Surg Pathol 2000;24:177-82.  Back to cited text no. 9
Takahashi A, Saito H, Kanno Y, Abe K, Yokokawa J, Irisawa A, et al. Case of clear-cell hepatocellular carcinoma that developed in the normal liver of a middle-aged woman. World J Gastroenterol 2008;14:129-31.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3]

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