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 ╗  Abstract
 ╗ Introduction
 ╗  Materials and Me...
 ╗ Results
 ╗ Discussion
 ╗ Conclusion
 ╗  References
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  Table of Contents  
Year : 2017  |  Volume : 54  |  Issue : 4  |  Page : 634-639

Clinicopathologic characteristics of Wnt/β-catenin-deregulated hepatocellular carcinoma

1 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication30-Jul-2018

Correspondence Address:
Dr. Munita Bal
Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_655_17

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 ╗ Abstract 

BACKGROUND: Activation of Wnt/β-catenin pathway has been implicated as a mechanism of oncogenesis of hepatocellular carcinoma (HCC). CTNNB1 mutation, which encodes for β-catenin, has been found to be the most common underlying genetic alteration. In this study, we evaluated the frequency of aberrant β-catenin expression in our cohort of HCC cases and explored its correlation with clinicopathologic features. METHODS: Fifty-three cases of histologically proven HCC were included in this study. Nuclear expression (with or without cytoplasmic staining) in >5% tumor cells was regarded as positive for β-catenin. Comparison with clinicopathologic features of β-catenin-negative HCC cases (controls) was also done. RESULTS: Nuclear β-catenin positivity was seen in 20 (37.7%) HCC cases. Median age was 60.5 years, and male-to-female ratio was 5.7:1. Alpha-fetoprotein (AFP) levels were normal in half of the patients (P = 0.03). Approximately 36.8% of hepatitis B virus-related, 50% of hepatitis C virus-related, and 35% of viral marker-negative HCC were positive for β-catenin. Median tumor size was 8.7 cm. Majority (53%) of β-catenin-positive HCCs were unicentric, and a significant proportion (65%) displayed a well-differentiated histology (P = 0.11). No specific histological type was associated with β-catenin positivity. Although not statistically significant, more patients (57%) with β-catenin-positive HCCs developed recurrence or progressive disease than β-catenin-negative patients (35%). CONCLUSIONS: Aberrant β-catenin expression was seen in a substantial proportion of our HCC cases. β-catenin-positive HCC was associated with normal AFP levels, unicentric tumors, well-differentiated histology, and an unfavorable outcome.

Keywords: Clinicopathologic, immunohistochemistry, Wnt signaling, β-catenin

How to cite this article:
Verma A, Bal M, Ramadwar M, Deodhar K, Patil P, Goel M. Clinicopathologic characteristics of Wnt/β-catenin-deregulated hepatocellular carcinoma. Indian J Cancer 2017;54:634-9

How to cite this URL:
Verma A, Bal M, Ramadwar M, Deodhar K, Patil P, Goel M. Clinicopathologic characteristics of Wnt/β-catenin-deregulated hepatocellular carcinoma. Indian J Cancer [serial online] 2017 [cited 2022 Aug 19];54:634-9. Available from:

 ╗ Introduction Top

Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity. It is the fifth most common cause of malignancy in males and the ninth most common in females. Overall, it is the fifth most common cause of cancer and the second most common cause of cancer-related mortality. More than 780,000 cases are reported every year.[1],[2] Incidence of HCC is more in China and the Indian subcontinent compared to the western world.[2] Prognosis is poor with 5-year survival being approximately 5%–16%.[1] Surgery remains the mainstay of treatment due to lack of success with chemotherapy or targeted therapy. Therefore, gaining insights into the underlying signaling pathways operative in HCC tumorigenesis is imperative.

Several pathways such as Wnt/β-catenin, HGF, EGF, TGFβ, and p53 have been evaluated and implicated in its oncogenesis.[3],[4] Among these, aberrant Wnt/β-catenin signaling pathway has been found to play a critical role in HCC tumorigenesis. Activation of Wnt/β-catenin signaling is triggered by somatic mutations in numerous genes such as CSF1R, CTNNB1, KRAS, BRAF, NRAS, ERBB2, MET, PIK3CA, JAK1, and SMO.[5] Among these, mutation of CTNNB1 gene appears to be the most common cause for activation of Wnt signaling pathway. CTNNB1 gene encodes for β-catenin, a key protein that integrates the intercellular E-cadherin–catenin adhesion system with intracellular Wnt signaling pathway.[5]

β-catenin expression in HCC ranges between 12% and 80% in the literature.[5] This hints at its potential role as a biomarker. A few studies have evaluated the correlation of β-catenin expression with clinicopathologic features and prognosis in HCC; however, results of these studies have yielded conflicting observations.[5],[6],[7],[8],[9],[10]

The aim of the present study was to evaluate β-catenin overexpression in HCC and its correlation with clinicopathologic features in our cohort of patients.

 ╗ Materials and Methods Top

Fifty-three cases of histopathologically proven HCC in which β-catenin immunohistochemistry was already performed between 2012 and 2015 were evaluated. Hematoxylin and eosin slides were retrieved from the archives of the department of pathology, and diagnosis was confirmed in accordance with the WHO classification.[11] Clinical and treatment details were recorded from patient charts and electronic medical records (EMR). Viral marker status, alpha-fetoprotein (AFP) levels, tumor size, histologic grade, multi/unicentric details, and presence of background cirrhosis were recorded.

Immunohistochemistry was performed on 5-μ sections derived from formalin-fixed paraffin-embedded tissues on automated Ventana Benchmark XT. Polyclonal β-catenin from Acris, Germany, at a dilution of 1:1000 was used. Tumors showing unequivocal nuclear staining with or without cytoplasmic staining in more than 5% of tumor cells were considered positive. Cases with membranous or cytoplasmic reactivity alone were considered negative. Comparison between β-catenin-positive cases (Group 1) and β-catenin-negative cases (Group 2) was also done.

Demographic, clinical, and disease-related variables were presented as frequency (percentage) and mean (standard deviation) and median as appropriate. Median age was compared using Mann–Whitney U-test. Categorical variables were analyzed using Chi-square test or Fisher's exact test (SPSS, IBM V20.0). P < 0.05 was considered statistically significant.

 ╗ Results Top

Demographic and clinicopathological details

A total of 53 cases were evaluated. Briefly, these included 45 in-house hospital cases and 8 consultation cases from the files of Munita Bal, Mukta Ramadwar and Kedar Deodhar. Age ranged from 19 to 87 years (mean 60.9 years; median 62 years), with a male-to-female ratio of 3.8:1. Hepatitis B virus (HBV) surface antigen reactivity was seen in 42.2% of the cases, 13.3% were positive for hepatitis C virus (HCV), while viral markers were negative in 44.4% of the cases. Of all the cases, 94.3% cases were Child–Pugh Class A and 2.9% each were of Class B and Class C (94.3+2.9+2.9= 100.1%). Barcelona Clinic Liver Cancer (BCLC) Stage A was present in 22.9% of the cases, BCLC Stage B in 42.9%, BCLC Stage C in 22.9% cases, and BCLC Stage D in 11.4% of the cases (22.9+42.9+ 22.9+11.4= 100.1%). AFP levels were raised in 72.1% cases and were normal in 27.9% cases. Albumin was below the reference range in 27.9% cases, and globulin was above the reference range in 76.7% cases.

Treatment and follow-up (F/U) details were available for 31 cases. F/U ranged from 2 to 36 months (median f/u – 6 months and mean f/u – 10 months). Ten patients underwent surgical excision alone, four patients were managed by single-agent sorafenib, transarterial chemoembolization (TACE) alone was performed in four cases, while one patient underwent transarterial radioembolization (TARE). TACE with sorafenib was given to four patients and TARE with sorafenib to one patient. One patient underwent excision following TACE while one patient underwent excision with sorafenib and radiotherapy. Palliative care was advised to five patients. Fourteen patients developed progression or recurrence. Four patients died of the disease while 10 patients were alive with disease and 17 were alive without disease at the last f/u.

Median tumor size was 8.7 cm (range 2.6–18 cm). Multicentric tumor was seen in 52.8% of the cases while 47.2% cases were unicentric. Well-differentiated HCC was seen in 47.2% of all the cases, 41.5% cases were moderately differentiated, while the remaining 11.3% cases were poorly differentiated HCC. Many cases had changes associated with cirrhosis (66.7%), chronic hepatitis (14.3%), and portal triaditis (9.5%) in the adjacent liver. HepPar1 was positive in all cases. Glypican-3 was positive in 82.6% of the cases. CK7, CK20, and CK19 were negative in all cases. CD34 highlighted the sinusoids.

β-catenin expression

Nuclear β-catenin positivity was seen in 20 cases (37.7%) [Figure 1]. In benign liver adjacent to the tumor in excision specimens, moderate membranous staining of hepatocytes and strong membranous staining of bile ducts was seen. No nuclear staining was seen in the benign liver [Figure 2].
Figure 1: (a) Well-differentiated hepatocellular carcinoma (Biopsy; H and E, ×100). (b) Diffuse nuclear β-catenin (IHC, ×200). (c) Well-differentiated hepatocellular carcinoma (excision; H and E, ×200). (d) Focal nuclear β-catenin (IHC, ×400)

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Figure 2: β-catenin showing membranous staining of biliary epithelium (strong) and hepatocytes (moderate) (IHC, ×100)

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Correlation of clinicopathological variables with β-catenin positivity

Clinicopathological details and their correlation with β-catenin positivity of all cases are summarized in [Table 1]. β-catenin positivity in male patients was seen in 40.5% whereas 27.3% of female patients were β-catenin positive (P = 0.50). Nuclear β-catenin positivity was seen in 36.8% of HBV-positive cases, 50% of HCV-positive cases, and 35% of patients with negative viral markers (P = 0.79). Among cases with raised AFP levels, only 29.0% were positive for β-catenin, while among the cases with normal AFP levels, 66.7% were positive for nuclear β-catenin, and the association was statistically significant (P = 0.03). Approximately 52.9% of unicentric cases while 26.3% of multicentric cases were positive (P = 0.10). β-catenin positivity was seen in 52% of well-differentiated carcinoma, 22.7% of moderately-differentiated carcinoma, and 33.3% of poorly-differentiated carcinoma (P = 0.11). No specific histological pattern was associated with β-catenin positivity.
Table 1: Clinicopathological details and their correlation with β-catenin positivity

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Comparison of β-catenin-positive (Group 1) and β-catenin-negative (Group 2) groups

Details of β-catenin-positive cases and comparative analysis between the two groups have been summarized in [Table 2] and [Table 3], respectively. The mean and median ages of the two groups were similar. Even though Group 1 had a higher male preponderance compared to Group 2 (M: F of 5.7:1 versus 3.1:1), it was not statistically significant (P = 0.53). The average size of the tumor in both groups was 8.7 cm (P = 0.97). Interestingly, β-catenin positivity was more common in unicentric HCC with a multicentric-to-unicentric ratio of 1:1.8 in Group 1 compared to 1.75:1 of Group 2 (P = 0.10), however, the difference was not statistically significant. There was no statistically significant difference in viral marker positivity (58.8% of Group 1 and 53.6% of Group 2). A statistically significant difference (P = 0.04) for well-differentiated tumor grade between the two groups was identified (65% in Group 1 vs. 36.4% in Group 2). Moderately-differentiated carcinomas formed approximately 25% and 51.5% of Group 1 and Group 2 tumors, respectively. Although not statistically significant, Group 1 patients had a tendency toward adverse outcome; 57.1% cases in Group 1 (f/u in 14 cases) and 35.3% in Group 2 (f/u in 17 cases) developed recurrence or progressive disease (P = 0.22). In Group 1, three patients died of disease, five patients were alive with disease, and six patients were alive without disease. In Group 2, only 1 patient died, 5 were alive with disease, and 11 were alive without disease.
Table 2: Details of β-catenin-positive cases

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Table 3: Comparing β-catenin-positive and β-catenin-negative groups

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 ╗ Discussion Top

β-catenin is an intracellular protein playing an important role in cellular junctions and adhesions as a part of Wnt signaling pathway as well as in tyrosine kinase signaling. The Wnt proteins bind to the cell surface frizzled receptors. Binding of these proteins activates the signaling pathway culminating into the activation of β-catenin. Among cells in resting state without stimulation, the pathway is inactive and β-catenin is stored in degraded state. β-catenin in the cytoplasm binds to a destruction complex. This complex comprises adenomatous polyposis coli (APC), casein kinase 1 (CK1), axin, and glycogen synthase kinase-3β (GSK-3β). GSK-3β, axin/conduction, and APC protein phosphorylate β-catenin and then degrade it by ubiquitin-dependent pathway. When the Wnt proteins bind to the frizzled receptors, it leads to inactivation of APC, CK1, axin, and GSK-3β, and thus, inactivates the destruction complex. This leads to the release of β-catenin from the complex and accumulation in the cytoplasm. Subsequently, β-catenin translocates and accumulates in the nucleus where it binds to lymphoid enhancer factor or T-cell factor. This leads to the transcription of target genes [Figure 3].[12] In adults, liver β-catenin probably plays a role in hepatic zone formation.[13] Mutations activating CTNNB1 gene and inactivating axin and GSK-3β genes are seen in HCC.[3] Stabilization of β-catenin is achieved by mutation of the gene, usually at the N-terminal domain, rendering it refractory to phosphorylation by GSK-3β and increasing its activity.[14],[15] Decreased cellular adhesion may help in tumor metastasis.[16]
Figure 3: (a) In the absence of Wnt, β-catenin is degraded by a complex of axin, adenomatous polyposis coli protein, casein kinase 1, and glycogen synthase kinase-3β. Casein kinase 1 and glycogen synthase kinase-3β phosphorylate β-catenin and it is degraded. (b) Binding of Wnt ligand to frizzled and low-density lipoprotein receptor-related protein-5/6 (LRP5/6) activates Wnt pathway, which through protein disheveled inactivates the degradation complex. β-catenin is, therefore, not degraded and translocates into the nucleus. In the nucleus, it binds to the T-cell factor/lymphoid enhancer factor to activate the target gene

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A wide range (12%–80%) of cases with β-catenin overexpression has been reported in various studies. One of the reasons for this is that various groups have used different criteria for overexpression.[5] A few studies used nuclear positivity and a few used cytoplasmic and/or nuclear positivity, while others used complex criteria comprising percentage and intensity to describe overexpression.[17] Studies considering only nuclear expression have reported β-catenin between 9% and 50% with most quoting approximately 20%–40%, a result similar to our study which showed overexpression in 37.7% of the cases.[18],[19],[20],[21],[22],[23] β-catenin overexpression probably shows ethnic variation with higher expression in Asians and lower in Black Africans.[5],[15]

Interestingly, studies suggest a potential causal link between Wnt/β-catenin activation and HCC arising in the background of viral hepatitis.[24],[25],[26] In HCC-derived cell-lines, HCV core protein correlates with increased WT1 expression and genes inhibitory to Wnt/β-catenin signaling are methylated in HCV-related HCC.[24] Interestingly, mutations in axin1 correlate with HBV-associated HCC whereas β-catenin mutations correlate with non-HBV-associated tumors.[26] β-catenin overexpression is probably seen more commonly in patients with associated HCV infection, which is similar to our result where 50% of HCV-positive cases were positive for nuclear β-catenin (though in our study, the number of HCV-positive cases is small); however, there was no significant correlation in the meta-analysis by Chen et al.[5],[19] A few studies reported an association with HBV while others did not.[5],[27] Ban et al. concluded that β-catenin overexpression is not associated with exposure to aflatoxin B1.[17] Mao et al. found that nuclear β-catenin was more common with older patients and males but less common with increased AFP and HBV. Most of these findings are concordant with our findings where nuclear β-catenin positivity was significantly associated with normal AFP levels.[6]

Results of β-catenin overexpression with histological parameters are conflicting. While some studies associate β-catenin overexpression with well-differentiated tumors or lower tumor grade,[4],[6],[9],[20] others associate it with poor differentiation and higher grade.[7],[8] In the present study, nuclear β-catenin overexpression showed statistically significant correlation with well-differentiated carcinoma. Kondo et al. suggested that probably β-catenin is not an early event and is associated with disease progression.[10] In the meta-analysis by Chen et al., there was significant correlation between nuclear/cytoplasmic β-catenin and vascular invasion and metastasis; however, there was no correlation with tumor grade and stage.[5] Fujito et al. reported that cases with β-catenin overexpression had better survival and was an independent variable; however, Chen et al. concluded that cytoplasmic and/or nuclear β-catenin was an independent variable associated with poor prognosis.[5],[28] Interestingly, a study by Inagawa et al. found that β-catenin overexpression was more common in tumors with better differentiation but was more commonly associated with recurrence and death.[20] Hsu et al. found that nuclear β-catenin associated with CTNNB1 gene mutation had a better 5-year survival rate compared to cases with nuclear β-catenin expression and wild-type CTNNB1 gene.[29] Our findings are similar to the study of Inagawa et al. and the meta-analysis of Chen et al. in showing that β-catenin overexpression is associated with well-differentiated carcinoma on histology and poor outcome.

In some studies, the number of cases with CTNNB1 gene mutation was more than β-catenin overexpression, whereas in others the overexpression cases were more than the mutation cases.[3],[18],[19],[30] The latter may be due to other mutations involving GSK-3β,axin, and Wnt genes which can cause overexpression of β-catenin without CTNNB1 gene mutation.[19]

β-catenin alterations are also seen in other hepatic tumors, albeit with varying frequency. Nuclear β-catenin expression and CTNNB1 gene mutation are seen in 63%–100% and 13%–50% cases of hepatoblastoma, respectively. Nuclear β-catenin expression in intrahepatic cholangiocarcinoma is seen in approximately 15%–40% of cases, whereas mutation of CTNNB1 gene has not been reported. CTNNB1 gene mutation and β-catenin overexpression have not yet been reported in fibrolamellar HCC.[31],[32],[33],[34],[35],[36] Nuclear β-catenin staining is seen in approximately 15%–20% of hepatocellular adenoma (HA).[37],[38]CTNNB1 gene mutation in HA is seen in 3%–15% of the cases.[37],[39],[40] This subtype of HA shows atypia with pseudoglandular formation histologically and has the highest propensity to progress to HCC.[37],[39]

 ╗ Conclusion Top

Thus, activation of Wnt signaling is a common feature in hepatic neoplasms. In our cohort of Indian patients, β-catenin positive HCC were associated with distinctive clinicopathologic features and a relatively less favorable outcome. We concede that the retrospective nature, limited sample size, clinical information, and follow-up are the limitations of our study. Biopsy evaluation in inoperable cases also precluded the evaluation of background pathology.

Briefly, this study demonstrated the prevalence of aberrant Wnt/β-catenin signaling in a significant proportion of HCC cases. Moreover, β-catenin HCC tended to be associated with normal AFP levels, unicentric masses, well-differentiated histology, and unfavorable outcome. Preclinical studies with inhibitors targeting Wnt/β-catenin signaling have shown promising results in eliminating sorafenib-resistant stem-like cells in HCC.[41] Prospective studies on larger cohorts are needed to validate the findings of this study that will aid in identifying a subset that may benefit from targeted therapy with Wnt pathway inhibitors.

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Conflicts of interest

There are no conflicts of interest.

 ╗ References Top

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  [Table 1], [Table 2], [Table 3]

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