Expression of Molecular Markers and Risk Categorization in Pre-neoplastic and Non-neoplastic Cervical Lesions

A. K. Roy^1, , D. Ghosh¹, G. K. Mandal², K. Datta³, N. Murmu⁴, P. Tudu⁵, P. Nath⁶ and S. Mandal³

¹Department of Pathology and Cancer Screening, Chittaranjan National Cancer Institute, Kolkata, India

²Department of Pathology, Hospital Wing, Chittaranjan National Cancer Institute, Kolkata, India

³Department of Epidemiology and Biostatistics, Chittaranjan National Cancer Institute, Kolkata, India

⁴Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, India

⁵Department of Radio Diagnosis, Chittaranjan National Cancer Institute, Kolkata, India

⁶Department of Medical Oncology, Chittaranjan National Cancer Institute, Kolkata, India

Cite this paper:
A. K. Roy, D. Ghosh, G. K. Mandal, K. Datta, N. Murmu, P. Tudu, P. Nath and S. Mandal. Expression of Molecular Markers and Risk Categorization in Pre-neoplastic and Non-neoplastic Cervical Lesions. Journal of Cancer Research and Treatment. 2015; 3(1):11-18. doi: 10.12691/jcrt-3-1-3

Abstract

Worldwide, cervical cancer is the fourth most common cancer in women [1]. It is preceded by many stages of pre-neoplastic lesions classified as Atypical squamous cells of undetermined significance (ASC-US) / Atypical squamous cells cannot exclude HSIL (ASC-H), Low-grade squamous intraepithelial lesion (LSIL), and High-grade squamous intraepithelial lesion (HSIL) (Bethesda, 2001). However, a large proportion of cases of epithelial malignancy arise from apparently normal cell and also from the LSIL where as many HSILs remain static for many years [2]. In this study, many important markers and epidemiological parameters Pap smears were examined to look for high risk cases of cervical non-malignant lesions. Methods: A total of 60 cases and controls were selected by colposcopic examination and smears were collected. Slides were used for immunohistochemical staining for four markers: p53, Ki-67, PCNA and CEA and PAP stain. All experimentally generated data were analyzed by Epi Info (TM) 3.5.3. Results: Expression of PCNA, p53, Ki-67 and CEA were significantly associated with both in Epithelial Cell Abnormalities (ECA) and Negative for Intraepithelial Lesion or Malignancy (NILM). Among HSIL, LSIL and ASCUS, HSIL was more common in Muslim women in comparison to Hindus. Whereas inflammatory lesions like RCC and RCCI were more common in Hindu population. Muslim women have a more normal Cytopathology smear than Hindus. Conclusions: Both the NILM and ECA cases carry risk for cancer conversion. Women with High grade Squamous Intraepithelial lesion or HSIL with PCNA, p53, Ki-67 and CEA strong positivity may have a higher risk of developing cervical cancer.

Keywords:
ASCUS HSIL LSIL cervical cancer biomarkers premalignant lesions

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Figures

References:

[1]	Cancer Fact Sheets. Globocan 2012. IARC.
[2]	Kim, J., M Adel-el-Naggar, D., Lee, J.S., Corrales, C., Lippman, S.S., Hong, W.K., Hittleman, W.N., “Chromosome polysomy and Histological Characteristics in oral premalignant Lesions”, Cancer epidemiology, Biomarkers and Prevention, 10. 319-325. 2001.
[3]	Sherman, M.E., Shiffman, M.H., Lörincz, A.T., Manos, M.M., Scott, D.R., Kurman, R.J., Kiviat, N.B., Stoler, M., Glass, A.G., Rush, B.B. “Toward objective quality assurance in cervical cytopathology: correlation of cytopathologic diagnoses with detection of high-risk human papillomavirus types”, Am J ClinPathol, 102. 182-187. 1994.
[4]	Arbyn, M., Bergeron, C., Klinkhamer, P., Martin-Hirsch, P., Siebers, A.G., Bulten, J., “Liquid compared with conventional cytology”, ObstetGynecol, 111. 167-77. 2008.
[5]	American Cancer Society, “American Cancer Society Guidelines for the Early Detection of Cancer”, 2014. Available: http://www.cancer.org/healthy/findcancerearly/cancerscreeningguidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer.[29/10/14].
[6]	Alberto, M., “Inflammation by remote control”, NATURE, 435. 752-753. 2005.
[7]	Zur Hausen, H., “Papillomaviruses and cancer: from basic studies to clinical application”, Nat Rev Cancer, (5). 342-50. 2002.
[8]	Kurt, J., Arieh, A. “Inflammatory pathways in cervical cancer – the University of Cape Town’s contribution”, South African Medical Journal, 102. 6. 2012.
[9]	NHS choice information, gov. UK, “Causes of Cervical Cancer”, 2013. Available:http://www.nhs.uk/Conditions/Cancer-of-the-cervix/Pages/Causes.aspx. 17.6.2013.
[10]	Zvi, K., “PCNA: structure, functions and interactions”, Oncogene , 14 (6). 629-640. 1997.
[11]	J O Goel, M., Somani, K., Mehrotra, A., Singh, U., Mehrotra, R., “Immunohistochemical Expression of Cell Proliferating Nuclear Antigen (PCNA) and p53 Protein in Cervical Cancer”, J Obstet Gynaecol India, 62(5). 557-561. 2012.
[12]	Stephen, T.O., Michelle, S.L., Laimonis, A.L., “Roles of the E6 and E7 Proteins in the Life Cycle of Low-Risk Human Papillomavirus Type 11”, J Virol, 78(5). 2620-2626. 2004.
[13]	Klaes, R., Friedrich, T., Spitkovsky, D., et al, “Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri”, Int J Cancer, 92(2). 276-284. 2001.
[14]	Missaoui, N., Hmissa, S., Dante, R., Frappart, L., “Global DNA methylation in precancerous and cancerous lesions of the uterine cervix”, Asian Pac J Cancer Prev, 11(6). 1741-4. 2010.
[15]	Schmidt, D., Bergeron, C., Denton, K.J., Ridder, R., “European CINtec cytology Study group. P16/Ki-67 dual-stain cytology in the triage of ASCUS and LSIL Papanicolaou cytology: results from the European equivocal or mildly abnormal Papanicolaou cytology study”, Cancer Cytopathol, 119. 158-166. 2011.
[16]	Tendler, A.1., Kaufman, H.L., Kadish, A.S. “Increased carcinoembryonic antigen expression in cervical intraepithelial neoplasia grade 3 and in cervical squamous cell carcinoma”, Hum Pathol, 31(11). 1357-62. 2000.
[17]	Stoler, M.H., Schiffman, M., “Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study”, JAMA, 285(11). 1500-5. 2001.
[18]	Lucy Balian, R., “Cancer”. Vol 665–667, (Article first published online: 27 SEP 2000).
[19]	Renuka N., Arshiya, S., “Cytopathological study of Cervical Smear: A Hospital Bas ed Retrospective Study”, Medical Journal of Islamic World Academy of Sciences, 22(1). 42-49. 2014.
[20]	Priore, G., “Glob. libr. women's med” (2008 Under review - Update due 2014). ISSN: 1756- doi 10.3843/GLOWM.10225.
[21]	Jussawalla, D.J., Jain, D.K., Yeole, B.B., Natekar, M.V., Rajgopalan, T.R., “Cancer Incidence in Greater Bombay (1973-75)”. Bombay Cancer Registry, The Indian Cancer Society, Parel, p 9-21. 1980.
[22]	Indian Council of Medical Research, “Cervical Cancer, NoncommunicableDiseases”, Annual Report of the Director General, p 82-84. 1988-89.
[23]	Brinton, L.A., Reeves, W.C., Brenes, M.M., Herrero, R., de Britton, R.C., Gaitan, E., Tenorio, F., Garcia, M., Rawls, “Parity as a risk factor for cervical cancer”, Am J Epidemiol, 130. 486-496. 1989.
[24]	Bayo, S., Bosch, F.X., de Sanjose, S., Munoz, N., Combita A.L., Coursaget, P., Diaz, M., Dolo, A., van den Brule, A.J., Meijer, C.J. “ Risk factors of invasive cervical cancer in Mali”, Int J Epidemiology, 31. 202-209. 2002.
[25]	International Institute for Population Sciences (IIPS) & ORC Macro, “National Family Health Survey (NFHS-2), 1998-99”, Mumbai: IIPS, India, 2000.
[26]	Gulati, S.C., Suresh S., et al, “Fertility and rich status in Uttaranchal and Uttar Prades a district level analysis, fertility and rch status in Uttar Pradesh”, Population research centre institute of economic growthuniversity enclave, delhi-7, 1996.
[27]	International Institute for Population Sciences (IIPS), “National Family Health Survey (MCH and Family Planning), India 1992–93”, IIPS, Bombay, 1995.
[28]	Fujita, M.1., Tase, T., Kakugawa, Y., Hoshi, S., Nishino, Y., Nagase, S., Ito, K., Niikura, H., Yaegashi, N., Minami, Y., “Smoking, earlier menarche and low parity as independent risk factors for gynecologic cancers in Japanese: a case-control study”, Tohoku J Exp Med, 216(4). 297- 307. 2008.
[29]	Jennifer, S.S., “A shorter interval between menarche and first sexual intercourse is associated with increased risk of high-grade cervical disease. Women’s health.Cohort study”, F.Evid Based Nurs, 17. 6-7. 2014.
[30]	Mulazim, H.B., Kanwal, S., Samina, Q., Muhammad, M.M., Shahida, N., Samina, N., “Clinicopathological importance of Papanicolaou smears for the diagnosis of premalignant and malignant lesions of the cervix”, J Cytol, 29(1). 20-25. 2012.
[31]	Van HR (2007) Human papillomavirus and circumcision: a meta-analysis. J Infect 54:490-6.
[32]	Walboomers, J.M., Jacobs, M.V., Manos, M.M., Bosch, F.X., Kummer, J.A., Shah, K.V., Snijders, P.J., Peto, J., Meijer, C.J., Muñoz, N., “Human papillomavirus is a necessary cause of invasive cervical cancer worldwide”, J Pathol, 189(1). 12-9. 1999.
[33]	Bosch, F.X., Manos, M.M., Muñoz, N., Sherman, M., Jansen, A.M., Peto, J., Schiffman, M.H., Moreno, V., Kurman, R., Shah, K.V., “Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group”, J Natl Cancer Inst, 87(11). 796-802. 1995.
[34]	Ho, G.Y., Burk, R.D., Klein, S., Kadish, A.S., Chang, C.J., Palan, P., et al., “Persistent genital human papillomavirus infection as a risk factor for persistent cervical dysplasia”, J Natl Cancer Inst 87:1365-71. 1995.
[35]	Riethmuller, D., Gay, C., Bertrand, X., Bettinger, D., Schaal, J.P., Carbillet, J.P., Lassabe, C., Arveux, P., Seilles, E., Mougin, C., “Genital human papillomavirus infection among women recruited for routine cervical cancer screening or for colposcopy determined by Hybrid Capture II and polymerase chain reaction”, Diagn Mol Pathol, 8. 157-64. 1999.
[36]	Ho, G.Y., Bierman, R., Beardsley, L., Chang, C.J., Burk, R.D., “Natural history of cervicovaginal papillomavirus infection in young women”, N Engl J Med, 338.423-8. 1998.
[37]	Woodman, C.B., Collins, S., Winter, H., Bailey, A., Ellis, J., Prior, P., Yates, M., Rollason, T.P., Young, L.S., “Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study”, Lancet, 357. 1831-6. 2001
[38]	Dillner, J., Lehtinen, M., Bjorge, T., Luostarinen, T., Youngman, L., Jellum, E., Koskela, P., Gislefoss, R.E., Hallmans, G., Paavonen, J., Sapp, M., Schiller, J.T., et al., “Prospective seroepidemiologic study of human papillomavirus infection as a risk factor for Invasive cervical cancer”, J Natl Cancer Inst, 89.1293-9. 1997.
[39]	Zielinski, G.D., Snijders, P.J., Rozendaal, L., Voorhorst, F.J., van der Linden, H.C., Runsink, A.P., de Schipper, F.A., Meijer, C.J., “HPV presence precedes abnormal cytology in women developing cervical cancer and signals false negative smears”, Br J Cancer, 85. 398-404. 200.
[40]	Ruediger, K., Stefan, M.W., Ruediger, R., Nicolas, W., Matthias, D., Achim, S., Beatrix, L., Peter, M., Magnus, K.D., “Detection of High-Risk Cervical Intraepithelial Neoplasia and Cervical Cancer by Amplification of Transcripts Derived from Integrated Papillomavirus Oncogenes 1”, Cancer Res, 59. 6132. 1999.
[41]	Cheng, Y.W., Wu, M.F., Wang, J., Yeh, K.T., Goan, Y.G., Chiou, H.L., Chen, C.Y., Lee, H., “Human papillomavirus 16/18 E6 oncoprotein is expressed in lung cancer and related with p53 inactivation”, Cancer Res, 67. 10686-10693. 2007.
[42]	Diana, K.J.T., et al., “Expression of E6, p53 and p21 proteins and physical state of HPV16 in cervical cytologies with and without low grade lesions”, Int J ClinExp Med, 7(1). 186-193. 2014.
[43]	Shailaja, S., Jasmita, D., Mukta, P., “p53 and bcl2 expression in malignant and premalignant lesions of uterine cervix and their correlation with human papilloma virus 16 and 18”, South Asian J Cancer, 3(1). 48-53. 2014.
[44]	Maeda, M.Y., Simoes, M., Wakamatsu, M., “Relevance of the rates of PCNA,Ki-67,and p53 according to the epithelial compartment in cervical erv lesions”, Pathologica, 93(3). 189-95. 2001.
[45]	Vasilescu, F., Ceausu, M., Cristina, T., et al., “p53,p63and ki-67 assesment in HPV induced cervical neoplasia”, Romanian Journal of Morphology and Embroylog, 50 (3). 357-361. 2009.
[46]	Zeng, Z., Del, P.G., Cohen, J.M. et al., “MIB 1 expression in cervical papanicolau tests correlates with dysplasia in subsequent cervical biopsies”, applimmunohistochemMolMorphol, 10.15-9. 2002.