|Year : 2019 | Volume
| Issue : 3 | Page : 384-390
|Clinicopathological correlation of cancer stem cell markers Oct-4 and CD133 expression as prognostic factor in malignant lesions of gallbladder: An immunohistochemical study
Naseem Fatima1, Anand Narain Srivastava1, Jaya Nigam2, Nishi Tandon1, Rumana Ahmad3, Vijay Kumar4
1 Department of Pathology, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
2 Department of Surgical Gastroenterology, King George's Medical University, Lucknow, Uttar Pradesh, India
3 Department of Biochemistry, Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh, India
4 Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India
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|Date of Web Publication||26-Jul-2019|
| Abstract|| |
Background: Gallbladder cancer (GBC) is the most frequent biliary tract cancer, with high morbidity and poor prognosis, and shows early metastasis and invasiveness. No reliable biomarkers are available for detection of GBC progression. Aim: To investigate the immunohistochemical expression of Oct-4 and CD133 in malignant and nonneoplastic lesions of gallbladder and to analyze the clinical significance of the expressions related to clinicopathological parameters. Settings and Design: This is a prospective case control study, conducted in medical college background. Materials and Methods: A total of 103 cases of gallbladder were grouped into malignant lesions (n = 48) and nonneoplastic lesions (simple epithelial hyperplasia; n = 35 and chronic cholecystitis; n = 20). All tissue samples were evaluated for expression of Oct-4 and CD133 using immunohistochemistry in an effort to elucidate the correlation between their expressions with clinicopathological parameters. Statistical Analysis: The final score was calculated by multiplying the intensity to the percentage of positive cells. The scores ≥2 were considered as positive. Results: Significant positive correlation of higher expression levels of Oct-4 and CD133 were observed in malignant as compared to nonneoplastic lesions of gallbladder (P < 0.0001). High expression of Oct-4 and CD133 were significantly associated with tumor grading (Oct-4, P = 0.04; CD133, P = 0.02), staging (Oct-4, P = 0.03; CD133, P = 0.02), and liver metastasis (Oct-4, P = 0.01; CD133, P = 0.007). Significantly reduced survival was observed with high expression of Oct-4 (P = 0.002). No significant correction was observed between CD 133 and survival. Conclusion: This study revealed that high expression level of Oct-4 may provide a new insight for the prognosis of the disease in terms of clinical staging and grade.
Keywords: Cancer stem cell marker, gallbladder cancer, immunohistochemistry, prognosis, survival
|How to cite this article:|
Fatima N, Srivastava AN, Nigam J, Tandon N, Ahmad R, Kumar V. Clinicopathological correlation of cancer stem cell markers Oct-4 and CD133 expression as prognostic factor in malignant lesions of gallbladder: An immunohistochemical study. Indian J Pathol Microbiol 2019;62:384-90
|How to cite this URL:|
Fatima N, Srivastava AN, Nigam J, Tandon N, Ahmad R, Kumar V. Clinicopathological correlation of cancer stem cell markers Oct-4 and CD133 expression as prognostic factor in malignant lesions of gallbladder: An immunohistochemical study. Indian J Pathol Microbiol [serial online] 2019 [cited 2021 Jan 28];62:384-90. Available from: https://www.ijpmonline.org/text.asp?2019/62/3/384/263465
| Introduction|| |
In India, gallbladder cancer (GBC) is the third most common malignancy of biliary tract as per the Indian Council of Medical Research registry of 2006--2008; it is ten times more common in North India than in South Indian population., GBC is a leading cause of cancer death in women. Most of the GBC cases are typically diagnosed at the advanced stages because of lack of clinical appearance, which are nonspecific and majority of cases are found incidentally at the time of histopathological examination for cholecystectomy. GBC is reported with high rate of recurrence and metastasis due to poor response to chemotherapy and radiotherapy. Convincing evidences report that gallbladder stones are found to be strongly associated factor that causes inflammation, which is considered as main carcinogenic mechanism for GBC development, but their exact role as a cause for GBC is still not clear.
Detection of the cancer at an earlier stage can have a greater chance for surgical cure, which could improve the 5-year survival to around 80%. The high mortality rate of GBC is because approximately 70% of patients with GBC having advanced stage of disease at the time of presentation. According to a recent new concept, cancer stem cells (CSCs) are a long lived, rare subpopulation of undifferentiated tumor cells within the total tumor cells in tumor mass. They are aggressive and chemotherapy and radiotherapy resistant, and show potential role in tumor recurrence. The Oct-4 (octamer-binding transcription factor 4) also known as POU5F1; transcription factor gene is known as a master pluripotency gene. Recent research has reported that high expression of Oct-4 stem cell marker is associated with disease progression, increased metastasis, and shorter cancer-related survival as compared to tumors with moderate and low Oct-4 expression. CSCs express stem cell marker genes, particularly Oct-4, thus, suggesting the vital role of Oct-4in tumor development and progression. Prominin-1 (CD133) is one of the most commonly used markers for CSCs, and has been identified as a CSC surface marker in cancer. High expression of CD133 has been associated with more aggressive tumor in certain cancers, such as breast, pancreas, lung, and colon.,,, However, studies related to human cancer, the correlation of CSC markers Oct-4, and CD133 with clinical prognosis have been very limited in GBC.
This study was designed to investigate the immunohistochemical expression levels of Oct-4 and CD133 in malignant and nonneoplastic lesions of gallbladder and to correlate it with clinicopathological outcome.
| Materials and Methods|| |
This was a prospective case control study including a total of 103 gallbladder specimens, 48 malignant (GBC) tissues, and 55 nonneoplastic (35 simple epithelial hyperplasia and 20 chronic cholecystitis). All tissue samples were collected between 2014 and 2017 from the Department of Surgery. Nonneoplastic gallbladder tissues (simple epithelial hyperplasia, chronic cholecystitis) were collected from the patients diagnosed as cases of inflammatory gallbladder disease based on clinical evaluation and were confirmed by ultrasound examination and underwent laparoscopy or open cholecystectomy. Malignant gallbladder tissues (GBC cases) were collected from the patients suspected of having GBC based on clinical evaluation (ultrasonography and computed tomography), who underwent for exploration of primary GBC followed by either radial surgery or biopsy of metastatic lesion found during exploration. Patients with any other type of cancer or who received prior chemoradiotherapy or operated earlier, and also with any known immunodeficiency disorder were excluded from this study. Sample size was calculated using the formula n = Zα2pq/L2T; final size of the sample was 40 in each group (malignant and nonneoplastic).
This study was ethically approved by Institutional Ethics Committee (R_Cell/EC/2014/01, August 11, 2014) and was conducted according to Helsinki guidelines.
The resected specimens were immediately fixed in 10% buffered formalin; tissue-embedded paraffin blocks were prepared using routine procedures. Hematoxylin–eosin staining was done on 5-μm-thick sections cut from the tissue blocks. The cut tissue sections were placed on glass slide followed by deparaffinization with xylene and graded ethanol. After hematoxylin–eosin staining, the slides were examined for the confirmation of malignant and nonneoplastic cases, and were assessed for clinical staging. The pathological staging was done according to American Joint Committee on cancer tumor node metastasis staging seventh edition. The data of overall survival of GBC patients were obtained from the clinical record available in the departments and also through phone calls.
Immunohistochemical staining was performed on formalin fixed paraffin-embedded tissues. Single 5-μm-thick section was prepared and dried at 60°C for 1 h. The section was deparaffinized by three changes of xylene and absolute alcohol (90%, 70%, and 50%) each for 3 min followed by 30 s rinse under running water. Microwave antigen retrieval procedure was performed using antigen retrieval buffer (pH 9, EnVision™ FLEX, Dako). Tissues were washed with Tris buffer (pH 7.4) and hydrogen peroxide was used to block nonspecific peroxidase reactions. Sections were incubated with polyclonal primary anti CD133 with dilution of 1:70 (Proteintech USA) and polyclonal primary anti Oct-4 with dilution of 1:100 (Proteintech, USA) at 4 °C for overnight in a humidified chamber. After three washes with Tris buffer, each slide was incubated with secondary antibody (EnVision™, FLEX/HRP, DAKO, USA) for 30 min. After washing the slides thrice with Tris buffer, each slide was incubated for 5 min in chromagen (3,3'-diaminobenzidine) to develop a brown-colored stain followed by Tris washing and slides were counterstained with hematoxylin. In all immunohistochemical procedures, seminoma and normal kidney tissues were used as positive controls for Oct-4 and CD133 antibodies, respectively. The positive expression of CD 133 was located in membrane and cytoplasm, whereas positive expression of Oct-4 was located in cytoplasm and as well as in the nucleus.
The staining intensity of Oct-4 and CD133 expression was graded from negative to strong (0+ to 3+) as follows: 0 no staining; 1+ weekly positive; 2+ moderately positive; 3+ strongly positive. The percentage of positivity was done on the basis of positive tumor cells: as 0 for no staining; 1 for ≤25% of cells; 2 for 25% to 50% of cells; 3 for 51%–75%; and 4 for >-75% of cells. The final score was calculated by multiplying the intensity to the extent of positivity, ranged from 0 to 12. The scores ≥2 were considered as positive. The mean of the final score was used to define low and high expression. Slides were examined by two independent observers, who were unaware of the clinical findings of the samples.
Statistical analysis was performed using Graph Pad Prism version 5.0 by GraphPad Software, Inc., California, USA. Continuous variables were expressed as means (±) SD range. The association between Oct-4 and CD133 expressions and clinopathological characteristics of gallbladder patients were investigated using one-way analysis of variance (ANOVA) test, Fisher's exact test, and Chi-squared test. Survival analysis was performed using the Kaplan–Meier method to calculate overall and disease-free survival rates among different groups. These groups were then compared using log-rank method. Two sided P < 0.05 was considered as significant.
| Results|| |
All 35 patients with simple epithelial hyperplasia had a mean age of 43.91 ± 1.77, range (23–65), and included females 65.7%. Gallstones were present in 68.5%. About 20 patients with chronic cholecystitis were reported with mean age 36.25 ± 2.52, range (22–60), included females 60%, and gallstones were found in 65%. In total, 48 malignant gallbladder cases were found with a mean age 51.10 ± 1.41; range (28–70), included females 68.7%, and gallstones were found in 62.5%.
The clinicopathological characteristics of all patients enrolled in the study is summarized in [Table 1].
|Table 1: Characteristics of malignant (GBC) and nonneoplastic (chronic cholecystitis, simple epithelial hyperplasia gallbladder) lesions of patients (n=103)|
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Expression levels of Oct-4 and CD133 in malignant and nonneoplastic lesions of gallbladder
Oct-4 was stained in the cytoplasm as well as in the nucleus of the cells with strong-to-mild intensity. Mucosal lining cells showed diffused cytoplasmic staining in simple epithelial hyperplasia of gallbladder. Oct-4 staining was found positive in GBC 31/48 (64.5%), simple epithelial hyperplasia 5/35 (14.2%), and chronic cholecystitis 3/20 (15%). Among 31 cases of GBC, Oct-4 staining showed mild-to-strong intensity with 15%–80% extent. Strong staining was observed in 12/31 (38.7%), moderate staining 14/31 (45.1%), and mild staining 5/31 (16.1%). Five cases of simple epithelial hyperplasia showed strong staining 1/5 (20%), moderate 2/5 (40%), and mild staining 2/5 (40%). Among three positive cases of chronic cholecystitis, all three cases showed mild-to-moderate staining [Figure 1].
|Figure 1: Representative immunohistochemical expression of Oct-4 in nonneoplastic lesion (a) and malignant lesions (b, c, and d) of gallbladder (Magnification 40×)|
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CD133 expression was located in the membrane and occasionally in the cytoplasm of the cell. Positive expression of CD133 was observed in malignant lesions 40/48 (83.3%), simple epithelial hyperplasia 13/35 (37.1%), and chronic cholecystitis 8/20 (40%). Strong immunostaining of CD133 was present in the invasive areas of human GBC tissue with mild-to-moderate intensity, ranging from 10% to 90% of tumor areas in all 40 positive cases of GBC.
In 40 positive cases of GBC, strong staining was found in 24/40 (60%), moderate staining 11/40 (27.5), and mild staining 5/40 (12.5%). In total, 13 positive cases of simple epithelial hyperplasia showed strong staining in 4/13 (30.7%), and mild-to-moderate staining was observed in 9/13 (69.2%). Among eight positive cases of chronic cholecystitis, moderate staining was observed in 3/8 (37.5) and mild staining was observed in 5/8 (62.5%) [Figure 2].
|Figure 2: Representative immunohistochemical expressions of CD 133 in nonneoplastic lesion (a) and malignant lesions (b, c, and d) of gallbladder (Magnification 40×)|
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Positive significant correlation was found between high expression of Oct-4 and CD133 in malignant lesions when compared to nonneoplastic lesions of gallbladder (Oct-4: P < 0.0001; CD133: P < 0.0001) [Table 2].
|Table 2: Expression level of Oct-4 and CD133 in malignant and nonneoplastic lesions of gallbladder|
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Association between expression levels of Oct-4 and CD133 with clinicopathological features of patients with GBC
In GBC patients, statistically significant difference was observed in expression of Oct-4 and CD133 with tumor differentiation (Oct-4: P = 0.04; CD133: P = 0.02). Positive high expression of Oct-4 and CD133 was observed in poorly differentiated tumors when compared with well and moderately differentiated tumors. Positive Oct-4 expression level was significantly associated with size of tumor (P = 0.03), whereas no association was observed with CD 133 expression with tumor size (P = 0.12). Higher expression levels of Oct-4 and CD133 were significantly associated with clinical staging (Oct-4: P = 0.03; CD133: P = 0.02), and strong positive expression levels of Oct-4 and CD133 were found significantly associated with liver metastasis (Oct-4: P = 0.01; CD133: P = 0.007). No significant difference was observed between expression levels of Oct-4 and CD133 with clinicopathological parameters, such as sex, age, presence or absence of gallstones, and presence or absence of abdominal pain [Table 3].
|Table 3: Relationship between Oct-4 and CD133 expression with clinicopathological parameters of GBC|
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Follow-up of the patients was possible through phone calls and routine hospital visit, among 48 patients, patients survived less than one year was found (58.3%; 28/48). Oct-4 expression was found positive in 31 follow-up patients and CD133 expression was found positive in 40 follow-up patients. The positive significant correlation was observed between Oct-4 expression and overall survival (positive expression versus negative expression: P = 0.002, hazard ratio 0.30, 95% confidence interval of ratio -0.14 to 0.764). CD133 expression did not correlate with overall survival and disease free survival (positive expression versus negative expression: P = 0.48, hazard ratio 0.84, 95% confidence interval of ratio 0.33 to 2.14 [Figure 3].
|Figure 3: Kaplan–Meier analysis of overall survival of patients with GBC (n = 48). (a) Overall survival GBC patients in relation to CD133 positive and negative expressions (log-rank = 0.848, P= 0.48). (b) Overall survival GBC patients in relation to Oct-4 positive and negative expressions ((log-rank = 0.30, P= 0.002)|
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| Discussion|| |
To be best of our knowledge, this is the first study which covers positive higher expression of Oct-4 and CD 133 together in malignant and nonneoplastic lesions of gallbladder in PubMed indexed English literature. Few studies have been reported previously correlating high expression of Oct-4 and CD133 in various cancers to their increased progression and metastasis., Oct-4 is known to be a critical pluripotency marker, which shows a nuclear localization. However, two studies done in recent past have shown that Oct-4 protein not only localize in the nucleus but also in the cytoplasm., In this study, the results showed that Oct-4 expression was found in the cytoplasm as well as in nucleus of the cell. Furthermore, there are only two studies done in relation to Oct-4 expression in gallbladder lesion, which have reported that Oct-4 staining was found in the cytoplasm and occasionally in the nucleus., A number of studies have been performed in various cancers, concluding that Oct-4 has showed cytoplasmic as well as nuclear staining.,,,, The frequency of Oct-4 expression in malignant lesions of gallbladder was 64.5%, and in nonneoplastic lesions, it was 14.2% in simple epithelial hyperplasia and 15% chronic cholecystitis. The expression level of Oct-4 appeared to have mild-to-moderate staining in most of the cases of simple epithelial hyperplasia and also mild-to-moderate staining was observed in cases of chronic cholecystitis. Zou et al. have conducted a similar study, and concluded that expression of Oct-4 was significantly higher in adenocarcinoma than that in pericancerous tissues of gallbladder. Li et al. have demonstrated the similar results in nonsmall cell lung cancer.
The frequency of positive CD133 expression in malignant lesions of gallbladder was 83.3% and in nonneoplastic lesion were 37.1% in simple epithelial hyperplasia and 30% in chronic cholecystitis. Strong CD133 expression was observed in membrane and cytoplasm of cancer cells. Similar to our findings, Chen et al. have reported that CD133 positive cells display a higher expression of Oct-4, which plays an important role in self-renewal and may represent as a proliferative potential for generating lung cancer cells. Zhang et al. also reported that CD133 was highly positive in colon carcinoma and weak staining was observed in clear cell renal cell carcinoma. Shi et al. performedin vivo tumorigenicity experiment have suggested that CD133 positive cells show CSC-like characteristics with ability of self-renewal property and high tumorigenicity in human GBC. However, we observed the strong staining of CD133 in cancer cells of invasive depth, especially in cases of poorly differentiated adenocarcinoma gallbladder.
A numbers of studies have demonstrated that Oct-4 and CD133 expression has been significantly associated with histological parameters, early lymph node metastasis, and advanced T stage. Hong et al. and Arne et al. have shown significant correlation between expression of CD133 and clinicopathological parameters such as tumor differentiation, tumor mass, lymph node metastasis, invasion, and overall survival., In line with their findings, our study also found that higher expression of Oct-4 and CD133 was significantly associated with tumor differentiation and clinical staging. It was found that Oct-4 was significantly associated with tumor size, but CD133 expression showed no association with tumor size. However, no significant correlation was found between the presence of gallstone and pain in abdomen for both the markers. Similar results have been reported by Zhang et al. Asignificant correlation between Oct-4 expression and tumor grade, stage, and tumor mass has been found by them.Hatifi et al. have revealed the significant correlation between expression level of Oct-4 with grading and staging. However, no significant relation of Oct-4 level has been observed with sex and age in tissue samples of bladder cancer. Zou et al. have reported that higher expression level of Oct-4 was significantly correlated with differentiation, tumor mass, and lymph node metastasis in benign and malignant lesions of gallbladder.
In contrast to our study, Hadi et al. conducted a similar study and concluded the positive expression of Oct-4 associated with staging and sex and no statistically significant relation was found between Oct-4 expression and age of the patients, and tumor grade and lymph node in rectosigmoid adenocarcinoma.
Furthermore, higher expression of Oct-4 was found to be significantly associated with overall survival of patients with GBC; in our study, shorter survival period was found in patients with higher expression level of Oct-4 as compared to lower expression. No significant correlation was found between CD133 expression and overall survival of GBC patients. In contrast to our findings, Mizukami et al. have reported cytoplasmic expression of CD133 expression to be closely associated with poor prognosis. Jiang et al. have reported poor overall survival in GBC. However, controversial results were reported in other biliary tract cancers., Zhou et al. have not found any significant correlation between CD133 expression and survival of colorectal cancer patients, whereas Bonetti et al. have found inverse correlation between the CD133 expression and disease-free survival in colorectal cancer.
Limitations of the study
Further studies are required to better understand the dynamics and correlation between Oct-4 and CD133 expressions in GBC. This would lead to development and establishment of Oct-4 and CD133 as a useful marker for prognosis and therapeutic in GBC.
| Conclusion|| |
In this study, it was concluded that positive significant correlation of Oct-4 and CD133 expression was found in malignant lesions as compared to nonneoplastic lesions of gallbladder. Positive significant correlation was also observed in tumor differentiation clinical staging and liver metastasis. These findings focus on the prognostic role of Oct-4 and CD133 in GBC. Thus, these markers might in future become important biomarkers for detection of progression of GBC.
The authors are grateful to Era's Lucknow Medical College and Hospital, Era University, which helped in completing this research work successfully and provided all infrastructural and research facilities. Authors are also thankful to Abdul Kalam Technical University, Lucknow (AKTU) for Ph.D. registration (Miss Naseem Fatima 13BIOTECH1237).
Financial support and sponsorship
This paper is a part of work supported by a grant from Council of Science and Technology, U.P. (CST-UP), India (CST/SERPD/D-300).
Conflicts of interest
There are no conflicts of interest.
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Anand Narain Srivastava
Department of Pathology, Era's Lucknow Medical College and Hospital, Lucknow - 226 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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