|Year : 2016 | Volume
| Issue : 2 | Page : 102-107
Immunohistochemical study of p53, Ki-67, epidermal growth factor receptor, and sex-determining region Y-box 2 in squamous cell carcinoma of tongue
Pallavi D Bhayekar, Vandana L Gaopande, Avinash R Joshi, Amruta B Jadhav
Department of Pathology, Smt Kashibai Navale Medical College and General Hospital, Pune, Maharashtra, India
|Date of Submission||01-Sep-2016|
|Date of Acceptance||08-Dec-2016|
|Date of Web Publication||19-Dec-2016|
Dr. Vandana L Gaopande
Department of Pathology, Smt Kashibai Navale Medical College and General Hospital, Off Katraj Bypass Highway Flyover, Narhe, Ambegaon, Pune - 411 041, Maharashtra
Source of Support: None, Conflict of Interest: None
Objective: Tongue cancer (TC) is one of the most common oral cancers. Prognostic evaluation of this tumor includes histologic grade and TNM stage. In this study, we evaluated the expression of p53, Ki-67, epidermal growth factor receptor (EGFR), and sex-determining region Y-box 2 (SOX2) and correlated it with the clinicopathologic variables to assess their potential for use as prognostic markers. We compared the p53 positive and negative group.
Design: A retrospective and prospective study with 45 cases of biopsy proven TC which were studied for the expression of p53, Ki-67, EGFR, and SOX2. The results were correlated with known clinicopathologic variables using Chi-square test. The p53 positive and negative groups were compared.
Materials and Methods: Archieved blocks of biopsy proven TC were retrieved. Using 4 micron sections of the blockes immunostaining for p53, Ki67, EGFR and SOX2 was done.
Results: P53 expression was 68.9%, Ki-67 was 88.9%, EGFR was 48.9%, and SOX2 was 35.6%. Expression of p53 and Ki-67 did not show any correlation with any of the clinicopathologic variables. There was a statistically significant association between EGFR expression and lymph node (LN) positivity (P = 0.001). Stage of tumor and SOX2 positivity showed a significant correlation (P = 0.03). The comparison of p53 positive and negative groups did not reveal a significant difference.
Conclusion: p53-negative TC is not significantly different from the p53-positive TC at presentation. The absence of mutant p53 in more than 30% TC points toward the possible etiological role of human papillomavirus in TC. Larger studies are needed to evaluate the possible use of EGFR for prediction of LN metastasis and SOX2 as a prognostic marker.
Keywords: Epidermal growth factor receptor, immunohistochemistry, Ki-67, p53, sex-determining region Y-box 2, tongue cancer
|How to cite this article:|
Bhayekar PD, Gaopande VL, Joshi AR, Jadhav AB. Immunohistochemical study of p53, Ki-67, epidermal growth factor receptor, and sex-determining region Y-box 2 in squamous cell carcinoma of tongue. BLDE Univ J Health Sci 2016;1:102-7
|How to cite this URL:|
Bhayekar PD, Gaopande VL, Joshi AR, Jadhav AB. Immunohistochemical study of p53, Ki-67, epidermal growth factor receptor, and sex-determining region Y-box 2 in squamous cell carcinoma of tongue. BLDE Univ J Health Sci [serial online] 2016 [cited 2021 Jul 26];1:102-7. Available from: https://www.bldeujournalhs.in/text.asp?2016/1/2/102/196089
Tongue is a muscular organ associated with the functions of taste, speech, mastication, deglutition, touch, and temperature. Worldwide, oral cancer (OC) is the sixth most prevalent cancer, ranking eighth in developed countries and third in the developing countries. OC accounts for 30% of all cancers in India. It is the most common cancer in India, accounting for 50%-70% of total cancer mortality and accounts for highest incidence among Asian countries. In the oral cavity, most common sites are the buccal mucosa, floor of mouth, lateral and ventral tongue, and the retromolar trigone. Squamous cell carcinomas (SCCs) represent 90%-95% of the oral cavity malignant neoplasms. Males are two to six times more likely to be affected than females due mainly to their higher intake of alcohol and tobacco. The etiological factors of OC include tobacco use in its various forms (pan chewing, betel quid chewing, use of khaini, gutkha, pan masala, zarda, kharra and nus, smoking of cigarettes, cigars, pipe, bidi, hookah, chillum), alcoholism, viral infections such as human papillomavirus (HPV) and herpes simplex virus-1, human immunodeficiency virus, poor oral hygiene, and sharp tooth. Nitrosamines constitute the most abundant carcinogen in tobacco smoke. It can damage the DNA of cells leading to point mutations. These point mutations lead to deregulation of tumor suppressor genes, the best characterized being P53. In recent years, HPV-positive OCs have been extensively studied. They are reported to have several unique features such as young age at presentation (<40 years), never married males, usually well-differentiated and fast-growing tumors which may be basaloid, good response to chemo-radiotherapy (RT), innovative targeted therapy and/or immunostimulating strategies, and better overall survival rates.,, The common sites for tongue cancer (TC) are anterior two-third at or near the edges (50%), posterior one-third (20%), dorsum (10%), tip (10%), and undersurface (10%). The most common type of TC is SCC. This disease most commonly begins as a patch of leukoplakia, erythroplakia, or speckled leukoplakia (premalignant conditions). Histologically, these lesions may show hyperplasia, dysplasia, carcinoma in situ, or SCC. Symptoms of TC include painless swelling or ulcer on the surface, excessive salivation, fetor oris, ankyloglossia, pain, hoarseness of voice, and dysphagia. Diagnosis is confirmed by biopsy. SCC of the tongue is graded into well, moderately, and poorly differentiated SCC depending on the extent of keratinization and cellular anaplasia. The staging of this neoplasm is done according to the TNM system of the American joint committee on cancer (AJCC).
P53 known as the "guardian of genome" is a tumor suppressor gene. P53 assists in DNA repair by arresting cell cycle in G1 phase and inducing the DNA repair genes. A cell with damaged DNA that cannot be repaired is directed by P53 to undergo apoptosis. With homozygous loss of P53, DNA damage goes unrepaired; mutations become fixed in dividing cells, and this leads to malignant transformation of the cell.
Ki-67 is a nuclear antigen expressed in dividing cells (S, G1, G2, and M phase of cell cycle) but nonexistent in resting cells (G0 phase). Therefore, it is commonly used to assess the proliferative activity in a neoplasm.
Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein and is a member of family of tyrosine kinase growth factor receptors. A number of ligands such as epidermal growth factor and transforming growth factor-α bind to EGFR and lead to downstream activation of Ras, which ultimately leads to cell cycle progression, decreased apoptosis, as well as increased angiogenesis and metastatic properties.
Sex-determining region Y-box 2 (SOX2) is a transcription factor coding gene located at 3q26.33 that is essential for maintaining self-renewal or pluripotency of undifferentiated embryonic stem cells. SOX2 has a critical role in the maintenance of embryonic and neural stem cells and holds great promise in research involving induced pluripotency, an emerging field of regenerative medicine. Cancer stem cell hypothesis states that tumors may be initiated and maintained by a subset of cells that maintain or acquire stem cell properties and that each tumor contains a subpopulation of cells that are capable of self-renewal and differentiation into multiple cell lineages. Cancer stem cells have been identified in several solid tumors such as breast cancer and colon cancer. Neural stem cells expressing SOX2 are capable of both self-renewal and producing differentiated neural cells, both of which are necessary hallmarks of stem cells.
| Materials and Methods|| |
We selected 45 biopsy-proven cases of SCC of the tongue. The records and the histopathology (HP) slides of all cases were retrieved. The clinical information was tabulated in an Excel sheet. The HP slides were reviewed, and the cases graded and staged. Cases were divided into groups depending on lymph node (LN) metastasis, histological grade (low and high grade), and tumor volume (<8 cm3 and >8 cm3 ). For immunohistochemistry (IHC), we used routinely processed paraffin-embedded tissue blocks. From each block, four sections (3 μ) were cut. Sections were picked up on poly-L-lysine-coated glass slides. Antigen retrieval was done in tris buffer using a pressure cooker. The primary antibodies used were p53 (Novocastra, clone DO7), Ki-67 (Novocastra, clone MM1), EGFR (Novocastra, clone EGFR.25), and SOX2 (BioGenex, clone EPR3131). The chromogen used was 3,3'-diaminobenzidine hydrochloride. Positive as well as negative control tissue sections were included with every batch. The IHC slides were evaluated by two pathologists independently. The average of their independent findings was taken as a final result. For p53 and Ki-67, tumors were evaluated as positive if more than 10% of tumor cells displayed moderate to strong nuclear staining and negative if otherwise [Figure 1]a and b., The membrane and cytoplasmic staining of EGFR was evaluated using a scoring system, in which percentage of cells stained (0 - no cells stained, 1-1%-30%, 2-31%-50%, and 3 - more than 50%) and intensity of stain (0-3) were given scores [Figure 1]c. The final score was calculated by adding the two scores. Tumors were EGFR positive if the final score was five or more. The nuclear staining of SOX2 was evaluated using scoring system, in which percentage of nuclei stained (0 - no nuclei stained, 1-1%-10%, 2-11%-50%, 3 - more than 50%) and intensity of stain (0 - no staining, 1 - weakly stained, 2 - moderately stained, 3 - strongly stained) were given scores [Figure 1]d. Final score was calculated by multiplying the two scores. Tumors were evaluated as SOX2 positive when the final score was more than 3. Data analysis was done using SPSS software version 15 (manufacuted by SPSS Inc., Chicago). Association between study groups was assessed using Chi-square test. P < 0.05 was considered statistically significant.
|Figure 1: Immunohistochemistry (a) nuclear immunostaining for P53 (×400), (b) nuclear immunostaining for Ki-67 (×400), (c) membrane and cytoplasmic immunostaining for epidermal growth factor receptor (×400), (d) nuclear immunostaining for sex-determining region Y-box 2 (×400)|
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| Results|| |
The clinicopathological features of all 45 cases are summarized in [Table 1]. There was no statistically significant association between tumor grade and LN metastasis. Six of the 23 high-grade tumors (26.1%) and six of the 22 low-grade tumors (27.3%) showed a tumor volume of more than 8 cm3 . There was no statistically significant association between tumor grade and tumor volume. The results of IHC and their correlation with LN status, tumor grade, and tumor stage are tabulated in [Table 2]. There was a statistically significant association between EGFR expression and LN positivity (P = 0.001) [Figure 2]a. There was a statistically significant association between stage of tumor and SOX2 positivity (P = 0.03) [Figure 2]b. Comparison of p53-positive TC and p53-negative TC is tabulated in [Table 3]. There was no significant difference between the two groups although the p53 negative group patients have a lower mean age and a higher incidence of LN metastasis at presentation.
|Figure 2: Significant statistical findings (a) bar diagram showing relationship between epidermal growth factor receptor expression and lymph node positivity, (b) bar diagram showing relationship between sex-determining region Y-box 2 expression and stage of tongue cancer|
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|Table 2: The results of immunohistochemistry and their correlation with lymph node status, grade, and stage |
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| Discussion|| |
Multiple genetic events which cause loss of cycle cell control, evasion from apoptosis, and telomerase reactivation are responsible for oral carcinogenesis. The genetic abnormalities associated with head and neck cancer (HNC) include the loss of heterozygosity of certain chromosomes (3p14, 9p21, 17p13, 8p, 11q, 13q, 14q, 6p, 4q27, and 10q23) and amplification, deletion, upregulation or downregulation of certain oncogenes or tumor-suppressor genes, including EGFR, P53, Rb, p65, cyclooxygenase 2, p16, cyclin D1, and phosphatase and tensin homolog.
The mutations or epigenetic inactivations of P53, p16, and Rb genes are the key events in oral carcinogenesis. In a study of head and neck (HN) carcinomas, 69% tumors showed p53 gene mutations. They found good correlation between P53 mutations and p53 protein overexpression. They postulated that mutant p53 overexpression is an early event in the multistep process of HN epithelial cell carcinogenesis but is not associated with disease progression.
In HPV-induced OC, the P53 and Rb genes are intact, but their protein products are inactivated by E6 and E7 HPV proteins with subsequent upregulation of p16 expression through loss of feedback inhibition.,, Therefore, these cancers are negative for mutant p53 by IHC. HPV virus may also be detected in tumors with mutated or inactivated P53 and Rb genes, where it is proposed that these tumors are multifactorial and cells transformed due to tobacco-alcohol are infected by HPV. Inactivating p53 mutations have emerged as a dominant genetic event of oral carcinogenesis in The Cancer Genome Atlas More Details series with the mutational rate of 69.8%.,,, Functional inactivation of TP53 may also occur through mechanisms such as overexpression or amplification of MDM2, which mediates p53 proteasomal degradation and p53 protein degradation by the HPV E6 oncoprotein.,
P53 expression reported by various studies in literature is in range of 46%-82%.,,, We have found an overall positivity of 68.9%, and on statistical analysis, there was no correlation with tumor stage, grade, and LN metastasis. In literature, isolated studies reporting correlation between p53 expression and LN metastasis, histological grade, and prognosis are found.,,, P53 positivity was significantly associated with higher risk of disease-specific survival and recurrence-free mortality of HNCs in a recent study. P53 is one of the surrogate markers for identifying HPV-positive OC. The chemoradiosensitivity of HPV-positive tumors is thought to be because of the preserved wild-type p53 gene with functional apoptotic pathways. The most frequent molecular alteration carried by HPV-negative HNSCCs is the p53 mutation which correlates with poor response to chemotherapy and RT.,, They also have a poor prognosis. In a recent study, multivariate analysis showed that p53 positivity was significantly associated with higher risk of disease-specific survival and recurrence-free mortality of HNC. The presence of nonfunctional p53 in pretreatment biopsy was predictive of incomplete histopathological response to neoadjuvant cisplatin/fluorouracil chemotherapy as assessed in surgical specimens of locally advanced oral SCC (OSCC). P53 immunoexpression predicted major response (80% reduction of tumor size) to platinum- and fluorouracil-based induction chemotherapy in HNSCC.[37 ] In the present study, p53-positive TCs were seen in older patients and had a lower frequency of LN metastasis as compared to p53-negative TCs [Table 3].
Our finding of Ki-67 immunoexpression in 88.9% cases is lower than other reports (92%-100%).,, Statistical analysis did not show any correlation between Ki-67 expression with other prognostic factors. It has been reported that Ki-67 expression has a significant effect on the cumulative survival rate of TC patients. A recent study found no correlation between Ki-67 staining and LN metastasis. There are reports where significant correlation between tumor grade and Ki-67 expression was found.,
EGFR expression was noted in 48.9% of our cases. Several studies have reported EGFR expression in the range of 39%-50%.,,,, We found that EGFR expression was significantly associated with LN metastasis (P < 0.05). A similar finding was reported by other study. There are conflicting reports of preferential expression of EGFR in either well-differentiated tumors or poorly differentiated tumors.,,, We did not find statistically significant correlation between tumor grade and EGFR expression although a higher percentage of low-grade tumors were EGFR positive (59%) as compared to high-grade tumors (39%). In the present study, EGFR expression when correlated with tumor stage showed no significance. A similar result was obtained by others. IHC overexpression of EGFR protein is associated with a poor prognosis and is a strong and independent unfavorable prognostic factor in HNSCC patients., Cetuximab which has been approved for the treatment of HNSCC by the regulatory agencies of the United States and Europe is a monoclonal antibody which binds with high affinity to the extracellular domain of EGFR and blocks the binding of endogenous ligands resulting in inhibition of the receptor function. It also induces downregulation of EGFR and targets cytotoxic immune effector cells toward EGFR expressing tumor cells (antibody dependent cell-mediated cytotoxicity). The role of cetuximab in the treatment of HNSCC is now well established. In locally advanced HNSCC addition of cetuximab to RT improves locoregional control and overall survival when compared to RT alone. It is recommended that in recurrent (R) or metastatic (M) HNSCC combination of a platinum-based regimen and cetuximab should be considered as the standard first-line regimen for patients who can tolerate this treatment. Single agent cetuximab is recommended for patients those R or M patients who progressed on platinum-based chemotherapy. Studies published to date suggest no association between level of EGFR expression in HNSCC and clinical responses to EGFR inhibitors.
In the present study, SOX2 was expressed in 16 (35.6%) out of 45 cases. There was statistically significant correlation between stage of tumor and SOX2 expression (P = 0.03). Multivariate analysis was not possible due to limited number of cases. In the present study, SOX2 positivity did not show a significant correlation with LN metastasis. According to Du et al., SOX2 positivity was frequent in node-negative oral tongue SCC and SOX2 was involved in tumor progression. A study by Michifuri et al. in 2012 found a significant correlation between SOX2 staining and LN metastasis (P < 0.001). In the present study, no significant correlation was found between tumor grade and SOX2 positivity. In a recent study, 88% of the node negative, nonmetastatic, T1/T2 OSCCs expressed SOX2 and high nuclear SOX2 expression in the invasive front was associated with longer disease-free period than low SOX2-expressing carcinomas after postoperative RT.
| Conclusion|| |
P53-negative TC is not significantly different from the p53-positive TC at presentation. The absence of mutant p53 in more than 30% TC points toward the possible etiological role of HPV in TC. EGFR expression in TC cannot predict the tumor stage and larger studies are needed to evaluate the possible use of EGFR for prediction of LN metastasis. Larger studies are also needed to investigate the possible use of SOX2 expression for prognostication of TC.
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Conflicts of interest
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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