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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 17  |  Issue : 3  |  Page : 662-665

Study of expression of epithelial cadherin in benign and malignant epithelial lesions of uterine cervix


1 Department of Pathology, S. N. Medical College, Agra, Uttar Pradesh, India
2 Department of Obstetrics and Gynaecology, S. N. Medical College, Agra, Uttar Pradesh, India

Date of Submission05-Jun-2020
Date of Decision25-Dec-2020
Date of Acceptance24-Oct-2021
Date of Web Publication2-Nov-2022

Correspondence Address:
Dr. Pooja Agarwal
79, Gandhi Nagar, By Pass Road, Agra - 282 003, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdmimsu.jdmimsu_215_20

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  Abstract 


Context: Epithelial cadherin (E-cadherin) is inversely proportional to the histologic grade of squamous cell carcinoma (SCC) of the cervix and is reduced with the increasing grade of cervical intraepithelial neoplasia, with downregulation upon transition to cervical intraepithelial neoplasia and further to invasive cancer. Aims: The aim of the study was to study the expression of E-cadherin in benign and malignant epithelial cervical lesions and to compare the results statistically. Settings and Design: The cross-sectional study was hospital based conducted in the department of pathology from January 2018 to March 2019. Methods: The study was carried out on sixty biopsy specimen of cervix (33 malignant, 4 premalignant, and 23 benign lesions). Two sections were taken; one for hematoxylin and eosin and other for E-cadherin immunohistochemical staining. Statistical Analysis Used: Statistical analysis was done using Chi-square test and Fisher's exact test. Results: In well-differentiated SCC, the majority cases (40%) revealed membranous staining while in moderately differentiated SCC and poorly differentiated SCC, the most common staining pattern was membranous and cytoplasmic (70% and 45.4%, respectively). In adenocarcinoma, 66.6% of cases had membranous pattern of staining, whereas two cases (33.3%) were negative. In High-grade Squamous Intraepithelial Lesion (HSIL), 75% of cases had membranous staining. Pure membranous pattern of staining of E-cadherin showed a progressive decline with a loss of differentiation while pure cytoplasmic revealed a reverse pattern. Conclusions: We concluded that, in malignant lesions, there is a loss of membranous E-cadherin pattern as compared to benign lesions. Furthermore, there is a progressive decline in pure membranous staining of E-cadherin with increase in shift to cytoplasmic staining as differentiation decreases.

Keywords: Epithelial cadherin, squamous cell carcinoma cervix, High-grade Squamous Intraepithelial Lesion (HSIL)


How to cite this article:
Gupta P, Agarwal P, Kumar L, Prakash S, Yadav P. Study of expression of epithelial cadherin in benign and malignant epithelial lesions of uterine cervix. J Datta Meghe Inst Med Sci Univ 2022;17:662-5

How to cite this URL:
Gupta P, Agarwal P, Kumar L, Prakash S, Yadav P. Study of expression of epithelial cadherin in benign and malignant epithelial lesions of uterine cervix. J Datta Meghe Inst Med Sci Univ [serial online] 2022 [cited 2023 Feb 1];17:662-5. Available from: http://www.journaldmims.com/text.asp?2022/17/3/662/360191




  Introduction Top


Cervical cancer is the most frequent type of cancer in women in some developing countries. The majority of women are diagnosed in their mid-40s or 50s.[1] Epithelial cadherin (E-cadherin) is a 120 kDa transmembrane glycoprotein involved in homotypic and heterotypic calcium-dependent cellular adhesions. The cervix, in which dysplasia-to-carcinoma sequence is well established, offers a useful medium to comparatively study the expression of proteins involved in cell-to-cell adhesion in dysplastic and invasive epithelium. Previous studies have shown that the immunohistochemical expression of E-cadherin is inversely proportional to the histologic grade of squamous cell carcinoma (SCC) of the cervix and was reduced in parallel with the increasing grade of cervical intraepithelial neoplasia, with major downregulation upon transition to cervical intraepithelial neoplasia and further to invasive cancer.[2] This study was carried out to study the expression of E-cadherin in benign and malignant epithelial cervical lesions and to compare the results statistically.


  Methods Top


The study was carried out on sixty biopsy specimen of cervix received in the department of pathology from January 2018 to March 2019. We selected 33 malignant, four premalignant, and 23 benign lesions for our study. Samples were fixed in 10% neutral-buffered formalin for duration of 12–24 h. Fixation for a long duration >72 h was avoided. Paraffin blocks were made and 3–4 μm sections were taken on poly-L-lysine-coated slides. Two sections were taken; one was processed for hematoxylin and eosin staining while other for E-cadherin immunohistochemical staining ([EP700Y] Rabbit Monoclonal Primary Antibody of Cell Marque).

Statistics

In the SCC, statistical correlation of membrane staining for E-cadherin was calculated using Chi-square (Pearson) test and compared with 23 benign lesions which were taken as control because they revealed a homogenous membranous pattern of staining for E-cadherin in all the cases. The P value came out to be <0.0001, which is statistically significant. It indicated that loss of membranous E-cadherin positivity is associated with SCC. Risk ratio was calculated to see association between a loss of membranous pattern of staining of E-cadherin and malignancy which came out to be 4.8, i.e., there is 4.8 times the chance that malignancy is there if there is loss of E-cadherin. In adenocarcinomas, the Fisher's exact probability test was done to detect statistical significance of membranous pattern of E-cadherin staining with adenocarcinoma. The P value came out to be <0.000631, which holds statistical significance. The risk ratio came out to be 1.5. This significant correlation also suggests the same thing, that the loss of membranous staining pattern of E-cadherin is associated with adenocarcinoma.


  Ethical clearance Top


The Institutional Ethics Committee of S. N. Medical College, Agra, Uttar Pradesh, has approved the Research work proposed to be carried out at S. N. Medical College, Agra, Uttar Pradesh, Date : 27th August 2019 with Reference no SNMC/EC/2019-20/278.


  Results Top


We studied 23 benign lesions, four premalignant lesions, and 33 malignant lesions by immunohistochemistry for staining patterns of E-cadherin. The most common age group involved in benign lesion was 31–40 years. The most common age group involved in well-differentiated SCC (WDSCC), poorly differentiated SCC (PDSCC), adenocarcinoma, and in HSIL was 41–50 years. In moderately differentiated SCC (MDSCC), both 41–50 years and 51–60 years were equally involved. The mean age for WDSCC, MDSCC, and PDSCC was 62.6 years, 52.3 years, and 51.6 years, respectively. There was progressive decline in the mean age with loss of differentiation. The staining pattern of E-cadherin in benign lesions was seen as strong membranous staining [Figure 1]. In WDSCC, the majority cases (40%) revealed membranous staining [Figure 2]. 40% of cases were negative for E-cadherin staining and 20% of cases revealed both membranous and cytoplasmic positivity. In MDSCC, most common staining pattern observed was membranous and cytoplasmic (70%), with membranous staining being weaker than normal cervical epithelium staining [Figure 3]. This was followed by cytoplasmic staining seen in 30% of cases. In PDSCC, membranous along with cytoplasmic pattern of staining was most predominant, seen in 45.4% of cases, while cytoplasmic in 36.4% of cases [Figure 4]. Two cases were negative for E-cadherin, and both had evidence of lymph node metastasis. In adenocarcinoma, 66.6% of cases had membranous pattern of staining, while two cases (33.3%) were negative for E-cadherin. One case of neuroendocrine tumor encountered was negative for E-cadherin. In HSIL, 75% of cases had membranous staining, which was weak and heterogeneous as compared to benign lesions. Pure membranous pattern of staining of E-cadherin showed a progressive decline with the loss of differentiation. 40% WDSCC had membranous pattern while no case of MDSCC and PDSCC revealed pure membranous pattern of staining. Pure cytoplasmic pattern of E-cadherin immunoreactivity revealed a reverse pattern, i.e., it increased with decreasing differentiation. Hence, we observed that a shift in staining pattern from membranous to cytoplasmic could be regarded as a sign of loss of differentiation [Table 1]. In most of the malignant lesions, membranous staining pattern was lost (37.8%). Nearly 32.4% of cases revealed a fragmented pattern of membranous staining, i.e., membranous staining was usually seen involving small clusters of epithelial cells at periphery of larger tumor islands. Only 29.7% of malignant lesions had membranous staining for E-cadherin that was retained throughout the tumor (with or without cytoplasmic staining). In our study, when membranous staining was present in malignant lesions, it was usually seen in small clusters and not throughout the tumor [Table 2].
Figure 1: Membranous pattern of epithelial cadherin staining in chronic cervicitis (IHC, ×40)

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Figure 2: Well-differentiated squamous cell carcinoma showing pure membranous pattern of epithelial cadherin staining (IHC, ×40)

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Figure 3: Moderately differentiated squamous cell carcinoma showing membranous and cytoplasmic epithelial cadherin staining (IHC, ×40)

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Figure 4: Poorly differentiated squamous cell carcinoma showing membranous and cytoplasmic epithelial cadherin staining (IHC, ×40)

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Table 1: Staining pattern of epithelial cadherin in malignant and premalignant lesions

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Table 2: Membranous staining pattern of epithelial cadherin in malignant and premalignant lesions

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  Discussion Top


The present study was conducted to study the expression of E-cadherin in benign and malignant epithelial lesions of uterine cervix and to compare the results statistically. In our study, the most common age group observed in benign lesions was 31–40 years (52.2%) and in malignant lesions was 41–50 years (45.4%). The mean age of benign and malignant along with premalignant lesions was 40.75 ± 7.25 and 51.2 ± 3.15, respectively. There was a progressive increase in the mean age with loss of differentiation. Almost similar results were seen in the study done by Li et al., with mean age being 39.40 years in normal cervices, 39.98 years in cervical intraepithelial neoplasia, and 50.18 years in SCC.[3] The most common benign lesion in our study was cervicitis (82.6%), followed by granulomatous lesion (8.7%). Actinomycosis and reparative changes each constituted 4.3% of all cases. The most common malignant lesion in our study was PDSCC which was 33.33%, closely followed by MDSCC which came out to be 30.3%. There were six cases of adenocarcinoma, five cases of WDSCC, and one case of neuroendocrine tumor. In all 23 benign lesions of uterine cervix, staining pattern was seen as membranous which was strong and homogenous (seen in basal and parabasal layers sparing the superficial layers). In SCC, we observed that 50% of cases had both membranous and cytoplasmic E-cadherin staining, 26.9% had only cytoplasmic staining, 15.4% came out to be negative for E-cadherin, and 7.7% of cases showed membranous positivity for E-cadherin. Agnihotri et al.[4] observed membranous positivity in 9% cases of SCC, which was in concordance with our study. We observed that 19.2% of SCC had retained the pattern of membranous staining, 38.5% of cases of SCC had fragmented membranous expression of E-cadherin, and 42.3% had lost expression. The P value for membranous pattern of staining in SCC when compared with benign lesions was <0.0001, which is statistically significant. Similar results were seen by Carico et al.,[5] Myong,[6] Crasta et al.,[7] and Cavalcante et al.[8] Koay et al. observed 12/21 cases of SCC had focal decrease in E-cadherin staining, with weak and fragmented staining where tumor cells were infiltrating, which is in agreement with our study.[9] In MDSCC, we observed that the maximum cases of MDSCC (70%) showed membranous and cytoplasmic staining followed by only cytoplasmic staining (30%). This was in concordance with the study of Agnihotri et al.[4] They also observed both membranous and cytoplasmic E-cadherin staining in maximum cases (40%), only cytoplasmic staining in 30% cases, and only membranous staining in 30% of cases. In PDSCC, we detected membranous and cytoplasmic E-cadherin staining in 45.5% of cases followed by only cytoplasmic staining in 36.4% of cases. Nearly 18.2% of cases had negative staining. No case had only membranous pattern of staining. Agnihotri et al.[4] also observed a loss of membranous staining in all cases of PDSCC. We observed loss of membranous pattern of staining with decreasing grades of differentiation. Similar results were observed by Agnihotri et al.[4] We observed that 66.6% of adenocarcinoma cases had membranous staining and 33.3% of them had a negative expression of E-cadherin. Nearly 33.3% of cases each had retained, fragmented, and lost membranous pattern of E-cadherin expression and P value came out to be <0.000631, which holds statistical significance. Almost similar results were seen in the study done by Rodríguez-Sastre et al.[10] In our study, 75% of HSIL cases had membranous staining (weak and heterogeneous) and 25% had both membranous and cytoplasmic staining. Our findings were concordant with that of Rodríguez-Sastre et al.[10] They detected membranous expression of E-cadherin in 60% of cases and cytoplasmic expression in 58% of cases. Munhoz NG[11] also observed that 56% CIN III had membranous expression of E-cadherin. Simionescu et al.[12] observed two cases of HSIL showing membranous expression only in 5%–50% of cells and the rest of HSIL <5% staining pattern. Similar results were seen by Cavalcante et al.,[8] Crasta et al.,[7] and Li et al.[3] We observed one case of neuroendocrine tumor, which showed negative immunoexpression for E-cadherin. In WDSCC, out of the two cases negative for E-cadherin one case had evidence of lymph node metastasis. In PDSCC, two cases which were negative for E-cadherin both had evidence of lymph node metastasis. Inoue et al.[13] had also observed decreased staining pattern in metastatic lymph node. Agnihotri et al.[4] also observed that 25% of cases which showed weak and homogenous staining in primary tumor had evidence of lymph node metastasis.

[TAG:2]Conclusion [/TAG:2]

We concluded that, in malignant lesions, there is a loss of membranous E-cadherin pattern as compared to benign lesions, in which the E-cadherin staining is membranous and strong with sparing of superficial layers. Furthermore, there is progressive decline in pure membranous staining of E-cadherin with an increase in shift to cytoplasmic staining as differentiation decrease. This is supported by P < 0.0001 for SCC and <0.000631 for adenocarcinoma. Thus, we conclude that E-cadherin can prove to be a useful marker for cervical epithelial malignancies. However, studies with a larger sample size are required to further validate this.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kurman RJ, Ellenson LH, Ronnett BM. Carcinoma and other tumors of the cervix. In: Witkiewicz AK, Wright TC, Ferenczy A, Ronnett BM, Kurman RJ, editors. Blaustein's Pathology of the Female Genital Tract. 6th ed. New York: Springer; 2011. p. 261-3.  Back to cited text no. 1
    
2.
Fadare O, Reddy H, Wang J, Hileeto D, Schwartz PE, Zheng W. E-cadherin and beta-catenin expression in early stage cervical carcinoma: A tissue microarray study of 147 cases. World J Surg Oncol 2005;3:38-49.  Back to cited text no. 2
    
3.
Li B, Shi H, Wang F, Hong D, Lv W, Xie X, et al. Expression of E-, P- and N-Cadherin and its clinical significance in cervical squamous cell carcinoma and precancerous lesions. PLoS One 2016;11:e0155910.  Back to cited text no. 3
    
4.
Agnihotri P, Akhtar K, Siddiqui SA, Sherwani RK. Cervical cancer metastasis: Significance of E-cadherin and vimentin. Clin Res 2015;1:1-5.  Back to cited text no. 4
    
5.
Carico E, Atlante M, Bucci B, Nofroni I, Vecchione A. E-cadherin and alpha-catenin expression during tumor progression of cervical carcinoma. Gynecol Oncol 2001;80:156-61.  Back to cited text no. 5
    
6.
Myong NH. Loss of E-cadherin and acquisition of vimentin in epithelial-mesenchymal transition are noble indicators of uterine cervix cancer progression. Korean J Pathol 2012;46:341-8.  Back to cited text no. 6
    
7.
Crasta J, Ravikumar G, Koorse S, Siddharta P, Vallikad E. Expression of adhesion molecule epithelial cadherin and matrix metalloproteinase-9 in squamous neoplasia of the uterine cervix. Southern African J Gynaecol Oncol 2016;8:4-8.  Back to cited text no. 7
    
8.
Cavalcante JR, Sampaio JP, Maia Filho JT, Vieira RB, Eleutério J Jr., Lima RC Jr., et al. Progressive loss of E-cadherin immunoexpression during cervical carcinogenesis. Acta Cir Bras 2014;29:667-74.  Back to cited text no. 8
    
9.
Koay MH, Crook M, Stewart CJ. Cyclin D1, E-cadherin and beta-catenin expression in FIGO Stage IA cervical squamous carcinoma: Diagnostic value and evidence for epithelial-mesenchymal transition. Histopathology 2012;61:1125-33.  Back to cited text no. 9
    
10.
Rodríguez-Sastre MA, González-Maya L, Delgado R, Lizano M, Tsubaki G, Mohar A, et al. Abnormal distribution of E-cadherin and beta-catenin in different histologic types of cancer of the uterine cervix. Gynecol Oncol 2005;97:330-6.  Back to cited text no. 10
    
11.
Munhoz NG, Rodrigues DA, Takase Y, Pedregosa JF, Rodrigues JO, Miyazaki K, et al. The use of molecular markers (p16, Ki-67 and E-cadherin) in uterine cervical biopsies. Open Pathol J 2009;3:10-7.  Back to cited text no. 11
    
12.
Simionescu C, Mărgăritescu C, Stepan A, Georgescu CV, Niculescu M, Muntean M. The utility of p16, E-cadherin and Ki67 in cervical squamous intraepithelial lesions diagnosis. Rom J Morphol Embryol 2010;51:621-6.  Back to cited text no. 12
    
13.
Inoue M, Ogawa H, Miyata M, Shiozaki H, Tanizawa O. Expression of E-cadherin in normal, benign, and malignant tissues of female genital organs. Am J Clin Pathol 1992;98:76-80.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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