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Year : 2022  |  Volume : 15  |  Issue : 4  |  Page : 501-506  

E-cadherin as a Prognostic Biomarker in Oral Squamous Cell Carcinoma: A Pilot Study at Tertiary Care Hospital

Department of Pathology, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha, Maharashtra, India

Date of Submission31-Mar-2021
Date of Decision20-Jan-2022
Date of Acceptance20-Jan-2022
Date of Web Publication16-Mar-2022

Correspondence Address:
Nitin M Gangane
Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_240_21

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Introduction: In a recent survey of cancer mortality in India, oral cavity cancer was listed as the leading cause of mortality in men, causing 29% of cancer-related deaths. Objective: The aim is to investigate the expression of E-cadherin to elucidate its role in determining the biological activity of the disease as a reliable and potential marker. Materials and Methods: E-cadherin immune-reactivity was evaluated in ten randomly selected fields in consecutive 50 cases diagnosed with oral squamous cell carcinoma (OSCC) and in each case, its mean was taken for the evaluation of E-cadherin expressing cells. The distribution and intensity of immunostaining E cadherin were also semi-quantitatively evaluated. Results: The most prevalent age group involved was the fifth decade and alveolus was the main site. The most common histological subtype was found to be well-differentiated squamous cell carcinoma and stage IV was the most common subtype in our study. The P value was significant for association between differentiation of tumor, staining location, and expression of E-cadherin (P value-0.002). E cadherin expression was compared with mortality; we found five out of seven death cases showing strong E cadherin expression, however, this was not statistically significant. Conclusions: Clinical and histopathological characteristics of malignancy, such as metastasis, recurrence, low survival, and poor tumor differentiation, have been associated with low expression of E-cadherin in OSCC.

Keywords: E-cadherin, immunohistochemistry, lymph node, squamous cell carcinoma

How to cite this article:
Khan H R, Patil BU, Gangane NM. E-cadherin as a Prognostic Biomarker in Oral Squamous Cell Carcinoma: A Pilot Study at Tertiary Care Hospital. Med J DY Patil Vidyapeeth 2022;15:501-6

How to cite this URL:
Khan H R, Patil BU, Gangane NM. E-cadherin as a Prognostic Biomarker in Oral Squamous Cell Carcinoma: A Pilot Study at Tertiary Care Hospital. Med J DY Patil Vidyapeeth [serial online] 2022 [cited 2022 Jul 5];15:501-6. Available from: https://www.mjdrdypv.org/text.asp?2022/15/4/501/339733

  Introduction Top

Oral squamous cell carcinoma (OSCC) develops as a molecular and histological multistep process. It progresses in a sequential manner of histopathological alterations which ranges from hyperplasia through dysplasia to carcinoma in situ and ultimately invasive carcinoma.[1]

According to World Health Organization (WHO) estimation, the incidence of oral cancer varies from one to ten cases per 100,000 people in most of the countries. Hence, oral cancer has become a significant cause of global public health concern.[2]

Oral cavity cancer has been identified as the leading cause of mortality in men in a recent survey of cancer mortality in India causing 22.9% of cancer-related deaths.[3]

Many etiological factors have been identified in recent WHO publications and many other studies in the corners of the world.[2],[4],[5],[6]

Carcinogenesis is triggered by number of genetic events, including the activation of oncogenes and inactivation of transforming growth factors. As a result, there is an urgent need to implement molecular and genetic research initiatives into the modification that causes cancer on global scale.[7] Therefore, efforts to identify novel molecular predictors of behavior and their therapeutic targets remain a high priority.

E-cadherin is being a 120 kDa transmembrane glycoprotein which is encoded by the CDH1/E-cadherin gene located on chromosome 16q22.1. It negatively regulates cell proliferation and is considered a tumor suppressor gene.[8] During embryogenesis E-cadherin downregulation normally occurs in the context of an epithelial-mesenchymal transition (EMT).[9],[10] This allows cells migration to other embryonic layers. Likewise, after undergoing an EMT involving reduced E-cadherin expression, neoplastic cells migrate and invade distant organs in malignant tumors of epithelial origin.[9]

It has been found that tumor progression and metastasis are associated with loss of its expression in tumor cells.[11],[12],[13] It leads to loss of cell–cell adhesion and cell junctions mediated by E-cadherin homophilic binding. This allows cells to metastasize by dissociating from the primary tumor, invading surrounding tissues, and migrating to distant sites.

The purpose of this study is to investigate the expression of E-cadherin in different grades and stages of OSCC and to elucidate its role as a reliable and potential marker in determining the biological behavior of the disease.

  Materials and Methods Top

The study was approved by Institutional ethics committee before commencement of study. Tissues were obtained from all the specimens like biopsy from oral cavity and resection specimens. Consecutive 50 cases diagnosed to have OSCC were selected in retrospective manner from records of department of Pathology. Cases received neoadjuvant cancer therapy and cases where adequate representative tissue is unavailable for immunohistochemistry were excluded from study. Relevant clinical and pathological data, such as age, gender, dimensions of the tumors, and the presence of lymph node metastases, were obtained from the clinical documents, gross records, and pathological reports of these patients. Follow-up data of these patients were obtained from hospital information system, radiotherapy department, and the records of the cancer registry. Hematoxylin and eosin-stained slides were retrieved and screened to obtain the best section for immunohistochemistry. Sections from normal oral mucosa obtained at cut margins during resection of the tumor were taken as controls. It was used to assess normal expression of E-cadherin.

In each case, E-cadherin immunoreactivity was evaluated in ten randomly selected fields and its mean was taken for evaluation of E-cadherin expressing cells. Furthermore, distribution and intensity of E-cadherin immunostaining were assessed semi quantitatively by two independent observers to eliminate inter observer bias.

The presence of brown color immunostaining of the cell membrane and cytoplasm was defined as E-cadherin immunopositivity. Based on their localization as either membrane, cytoplasmic, or both cytoplasmic and membranous expression, E-cadherin expression pattern was reported in all groups.

  Results Top

The outcome of cancer depends on many proven prognostic factors which include age, sex, grade of tumor and stage of clinical disease. In the present era, biomarkers are also considered important factors in predicting the patient outcome.

Age of the patients in this study ranged from 38 to 73 years. Fifth decade was most common (19; 38%) whereas lowest number of cases were seen in the eighth decade and majority of the patients in our study were male (45; 90%).

Most common site of occurrence was alveolus (21; 42%) followed by buccal mucosa (19; 38%), gingivobuccal sulcus (7; 14%), and least common site found was lips (3; 6%).

Well-differentiated squamous cell carcinoma (SCC) (25, 50%) was found to be the most common histological subtype and stage IV (33; 66%) was the most common subtype in our study.

While observing the staining location of E cadherin among different grades of OSCC, both cytoplasmic and membranous staining was equally common in well and moderately differentiated subtype. In poorly differentiated OSCC, staining was commonly localized in cytoplasm as seen in [Table 1]. The P value was significant for association between differentiation of tumor and staining location (P value– 0.015).
Table 1: Comparison of the staining location between different grades and stages of oral squamous cell carcinoma

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On comparing staining location among different stages of OSCC, it was found that stage IV which was the most common subtype, showed both membranous and cytoplasmic staining (14 cases; 42.42%) followed by cytoplasmic staining. Stage III which was the second most common subtype had membranous staining in majority of the cases (6 cases; 42.85) as shown in [Table 1] (P value– 0.336).

Strong E cadherin expression was seen in well-differentiated SCC in 16 (64%) cases with the absence of expression in poorly differentiated subtype in 3 (75%) cases. The P value was significant for association between differentiation of tumor and expression of E-cadherin (P value-0.002). There was no case showing heterogeneous pattern of E cadherin expression.

All cases showing the absence of E cadherin expression were in stage I of the disease. Strong E cadherin expression was seen in 66.6%, 57.14%, 51.51% cases of stages II, III, and IV, respectively (P value– 0.786) [Table 2].
Table 2: Comparison of the staining intensity between different grades, stages, and metastatic oral squamous cell carcinoma

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Both well and moderately differentiated subtypes had 48% cases, each with the presence of metastasis, while majority of nonmetastatic cases belonged to well-differentiated subtype (52%).

When E cadherin expression was compared in metastatic and nonmetastatic groups, strong expression was observed in 16 (64%) cases and 11 (44%) cases of metastatic and nonmetastatic groups, respectively. Weak expression was observed in 7 (28%) cases and 12 (48%) cases in metastatic and nonmetastatic groups, respectively. Equal number of cases showing absent expression in both groups [Table 2].

Comparing different grades of tumor with or without metastasis and E cadherin expression showed well-differentiated subtype with metastasis had strong E cadherin expression in 10 cases (83.33%) as compared to well differentiated subtype without metastasis which had 7 (53.84%) cases with weak expression and 6 (46.15%) cases with strong expression. Moderately differentiated subtype with metastasis had more number of cases (6 cases 50%) with strong expression than those without metastases (4 cases, 44.44%) [Table 3].
Table 3: Correlation of histological grades of oral squamous cell carcinoma with metastasis and E cadherin expression

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All 50 cases were followed till the end of this study. The average period of follow-up was 15 months. Seven of them are dead due to disease, three of these seven cases were well-differentiated subtype without metastasis.

Our study also showed that mortality increased with advancement in the stage of the disease. Stage IV had largest mortality, six out of seven deaths (85.71%), while stages II had no death.

With reference to stages of OSCC, out of total seven deaths, six deaths were from stage IV subtype. In our study, when E cadherin expression was compared with mortality, we found five out of seven death cases showing strong E cadherin expression, however, this was not statistically significant.

  Discussion Top

In India, cancer is common and oral cancer is of great importance to public health. The overall number of people with the disease is estimated to be around 2.5 million. Every year over 0.8 million new cases were detected and around 0.55 million succumbed to death.[14]

According to GLOBOCAN report in 2012, oral cancer shares approximately 2.1% of newly registered cancer cases. This study also suggests that approximately 145,000 deaths have occurred because of oral cancer and 77% of which in less developed regions.[15]

Tobacco and alcohol have synergetic effects in oral cancer development and people who use both are at especially high risk of developing it.[16] Tobacco-associated carcinogens permeate the mouth tissues because of dehydrating effect of alcohol on cell membranes. Heavy drinking leads to nutritional deficiencies and can lower the body's natural ability to use antioxidants to prevent cancer formation.[17]

In our study, the most common risk factor observed was different forms of tobacco. Carcinogens present in tobacco that makes oral cavity more vulnerable to cancer. Early occurrence of carcinoma and amount of tobacco consumption is directly proportional to each other. The most affected site both in males (49%) and females (40%) were buccal mucosa and gingivobuccal sulcus followed by alveolus which was 25% and 31%, respectively. The male predominance over female may be because of the fact that their indulgence in outdoor activities is greater in comparison to females. These findings are consistent with other studies.[18],[19] Development of carcinoma has been attributed to the tobacco quid placement in the gingivobuccal sulcus region. Western countries have high consumption of alcohol and smoking. Therefore, tongue and floor of mouth carcinoma are more common in western population.

Fifth decade was most common (19, 38%) whereas lowest number of cases were seen in eighth decade. The findings of present study are in agreement with other authors that most patients of oral cancer are adults above the age of 30 years.[20],[21]

In India, majority of the patients report late in advance stages. This could be due to either patient delay in seeking professional care, professional delay in making a diagnosis and start of treatment, or both. Most of the patients do not have knowledge of cancer-related symptoms and seek medical care in later stage of the disease.

In the advanced stages, loss of intercellular adherence in neoplastic cells follows a dedifferentiation process. Cadherin adhesion molecules, specifically E-cadherin in the epithelial tissue, primarily maintain intercellular adhesion.[22]

The study by Akhtar et al.[23] showed that E-cadherin membranous positivity decreased and cytoplasmic positivity increased as the tumor grade increased from well to poorly differentiated SCC, leading to poor prognosis. Findings of all studies including present indicate that there was decrease in membranous positivity with increase in tumor grade from well to poorly differentiated carcinoma.

Our findings are in agreement with a studies[23],[24] who were observed that degree of E-cadherin expression decreased as the grade of the tumor was increased.

Our study contradicts Tanaka et al.[25] observations, their study dealt with 159 OSCC cases, documenting the association between the expression of molecules associated with the E-cadherin and the presence of metastasis of the neck, and showing a substantial relationship between decreased expression of E-cadherin and OSCC invasiveness.

Increased E-cadherin immunoreactivity was observed by Hung et al.[26] in metastatic OSCC lesions. The results of the current study and available literature show that there are no clear-cut results on the degree of expression and the presence and absence of metastases.

In the present study, we found that E-cadherin exhibited a moderate or strong membranous expression in well-differentiated cases. There were few cases that showed a negative or weak expression of E-cadherin among the poorly differentiated cases.

Williams et al.[27] in their study found that 15 out of 19 cases of carcinoma showed loss of membranous staining for E-cadherin. All the four poorly differentiated cases in their study showed a loss of E-cadherin expression. This could be due to the limited number of cases that were analyzed.

No other study has made this comparison in the available literature. However, the findings of our study suggest that there is no association between intensity of expression with differentiation of tumor with and without metastasis. This is possibly due to the fact that no correlation with metastasis is demonstrated by differentiation itself.

The findings of present study also indicate that degree of tumor and presence or absence of metastasis is not related to survival. In oral cancer staging, even a T4 tumor without metastasis can be stage IV.[28] Only stage of disease may be only factor which may predict survival. The fact also emphasizes the importance of finding new biomarkers to predict patient's outcome in cancer patients.

Accordingly, low expression of E-cadherin in OSCC has been associated with clinical and histopathological features of malignancy, such as metastasis, recurrence, low survival, and poor tumor differentiation,[29] and it has been referred to by some authors as a “high-risk marker of malignancy.”[30] E-cadherin gene expression may show variations in the proportion of epithelial or mesenchymal tissue, as well as variations in the precise tumor area from which the sample is obtained (front of tumoral advance or central tumor area), which constitutes possible limitation of these studies.

Some of these findings in our study which do not agree with available literature may be due to number of cases included in individual studies, follow-up cases, availability of treatment facilities, and treatment compliance of the patient. Therefore, it is important that multicentric studies taking into consideration, all variables are necessary before finalizing importance of new biomarker in predicting patient outcome and even for future patient specific treatment protocols.

  Conclusions Top

E-cadherin expression depended on histological grading of OSCC. It was also found that as the tumor grade increase, there was decrease in membranous positivity. However, there was no correlation with the stage of disease. The degree of expression of E cadherin also did not have any correlation with the absence or presence of metastasis. However, this may be due to the fact that differentiation itself did not show any association with metastasis. It is important that before finalizing importance of new biomarker in predicting patient outcome and future patient-specific protocols, the studies must take into account number of cases included in the study; follow-up of patients with and without disease, availability of treatment facilities, and patient compliance of treatment protocols.

Financial support and sponsorship

The authors would like to thank financially aided by Research Grant committee of institute.

Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3], [Table 1], [Table 2], [Table 3]


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