P16INK4A Immunohistochemistry as a Gold Standard for Cervical Cancer and Precursor Lesions Screening
-
Mahdieh FARZANEHPOUR
,
Ahad MUHAMMADNEJAD
,
Setareh AKHAVAN
,
Amir Nader EMAMI RAZAVI
,
Somayeh JALILVAND
,
Vahid SALIMI
,
Ebrahim FAGHIHLOO
,
Ehsan KAKAVANDI
,
Mohammad FARAHMAND
,
Mohammad SHAYESTEHPOUR
,
Farzad BABAKHANI
,
Talat MOKHTARI AZAD
Abstract
Background: High-risk (HR) Human papillomaviruses (HPVs) are known as the main factors implicated in the pathogenesis of cervical preinvasive and invasive lesions. Therefore, the presence or absence of HR-HPV can be followed for the prognosis of low-grade and high-grade squamous intraepithelial lesions. Since the overexpression of p16INK4a protein depends on the presence of transcriptionally-active HPV, and due to its availability and simple interpretation, it may be considered as a proper marker to diagnose cervical cancer.
Methods: An immunohistochemical analysis of p16INK4a was performed in 72 cervical tissue specimens at Imam Khomeini Complex Hospital (Tehran, Iran) from 2016 to 2018. The performance parameters were calculated and compared using receiving operating characteristics curve (ROC) details.
Results: p16INK4a is significantly up-regulated in the cervical cancer samples in comparison with that in normal samples. Moreover, the ROC data showed the potential ability of p16INK4a under determined conditions as a diagnostic marker for CIN 2-3 staging and invasive cervical cancer. The molecular typing disclosed the attendance of HPV DNA in 44.4% of cases (32/72) with a predominance of HPV type 16.
Conclusion: The molecular biomarker p16INK4a can be a good candidate for the early diagnosis and prognosis of cervical cancer in HPV-infected patients. Considering the increase in the expression level of p16INK4a in cancer and precancer tissues, p16INK4a may be used for early detection of cervical cancer.
1. Bosch FX, Lorincz A, Munoz N, et al (2002). The causal relation between human papillomavirus and cervical cancer. J Clin Pathol, 55(4):244-65.
2. Swick AD, Chatterjee A, De Costa A-MA, et al (2015). Modulation of therapeutic sensitivity by human papillomavirus. Radiother Oncol, 116(3):342-5.
3. Suzich JA, Ghim SJ, Palmer-Hill FJ, et al (1995). Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas. Proc Natl Acad Sci U S A, 92(25):11553-7.
4. Lyon (2007). Human papillomaviruses. IARC monographs on the evaluation of carcinogenic risks to humans. 90:1-636.
5. Walboomers JM, Jacobs MV, Manos MM, et al (1999). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol, 189(1):12-9.
6. van Bogaert LJ (2012). P16INK4a immunocytochemistry/immunohistochemistry: need for scoring uniformization to be clinically useful in gynecological pathology. Ann Diagn Pathol, 16(5):422-6.
7. McLaughlin-Drubin ME, Crum CP, Munger K (2011). Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming. Proc Natl Acad Sci U S A, 108(5):2130-5.
8. Bibbo M, DeCecco J, Kovatich AJ (2003). P16INK4A as an adjunct test in liquid-based cytology. Anal Quant Cytol Histol, 25(1):8-11.
9. Cuschieri K, Wentzensen N (2008). Human papillomavirus mRNA and p16 detection as biomarkers for the improved diagnosis of cervical neoplasia. Cancer Epidemiol Biomarkers Prev, 17(10):2536-45.
10. Tsoumpou I, Arbyn M, Kyrgiou M, et al (2009). p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer Treat Rev, 35(3):210-20.
11. Romagosa C, Simonetti S, Lopez-Vicente L, et al (2011). p16(INK4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene, 30(18):2087-97.
12. Crum CP (1998). Detecting every genital papilloma virus infection: what does it mean? Am J Pathol, 153(6):1667-71.
13. Doutre S, Omar T, Goumbri-Lompo O, et al (2018). Cervical intraepithelial neoplasia (CIN) in African women living with HIV: role and effect of rigorous histopathological review by a panel of pathologists in the HARP study endpoint determination. J Clin Pathol, 71(1):40-45.
14. Nicol AF, Nuovo GJ, Salomao-Estevez A, et al (2008). Immune factors involved in the cervical immune response in the HIV/HPV co-infection. J Clin Pathol, 61(1):84-8.
15. Shi SR, Key ME, Kalra KL (1991). Antigen retrieval in formalin-fixed, paraffin-embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. J Histochem Cytochem, 39(6):741-8.
16. Svec A, Mikyskova I, Hes O, et al (2003). Human papillomavirus infection of the epididymis and ductus deferens: an evaluation by nested polymerase chain reaction. Arch Pathol Lab Med, 127(11):1471-4.
17. Eng J (2005). Receiver operating characteristic analysis: a primer. Acad Radiol, 12(7):909-16.
18. Branca M, Ciotti M, Santini D, et al (2004). p16(INK4A) expression is related to grade of cin and high-risk human papillomavirus but does not predict virus clearance after conization or disease outcome. Int J Gynecol Pathol, 23(4):354-65.
19. Tringler B, Gup CJ, Singh M, et al (2004). Evaluation of p16INK4a and pRb expression in cervical squamous and glandular neoplasia. Hum Pathol, 35(6):689-96.
20. Wang SS, Trunk M, Schiffman M, et al (2004). Validation of p16INK4a as a marker of oncogenic human papillomavirus infection in cervical biopsies from a population-based cohort in Costa Rica. Cancer Epidemiol Biomarkers Prev, 13(8):1355-60.
21. Queiroz C, Silva TC, Alves VA, et al (2006). P16(INK4a) expression as a potential prognostic marker in cervical pre-neoplastic and neoplastic lesions. Pathol Res Pract, 202(2):77-83.
22. Dai CY, Furth EE, Mick R, et al (2000). p16(INK4a) expression begins early in human colon neoplasia and correlates inversely with markers of cell proliferation. Gastroenterology, 119(4):929-42.
23. Milde-Langosch K, Bamberger AM, Rieck G, et al (2001). Overexpression of the p16 cell cycle inhibitor in breast cancer is associated with a more malignant phenotype. Breast Cancer Res Treat, 67(1):61-70.
24. Di Vinci A, Perdelli L, Banelli B, et al (2005). p16(INK4a) promoter methylation and protein expression in breast fibroadenoma and carcinoma. Int J Cancer, 114(3):414-21.
25. Zhao P, Mao X, Talbot IC (2006). Aberrant cytological localization of p16 and CDK4 in colorectal epithelia in the normal adenoma carcinoma sequence. World J Gastroenterol, 12(39):6391-6.
26. Hilliard NJ, Krahl D, Sellheyer K (2009). p16 expression differentiates between desmoplastic Spitz nevus and desmoplastic melanoma. J Cutan Pathol, 36(7):753-9.
27. Jung A, Schrauder M, Oswald U, et al (2001). The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, and p16INK4A and is a region of low proliferation. Am J Pathol, 159(5):1613-7.
28. Natarajan E, Saeb M, Crum CP, et al (2003). Co-expression of p16(INK4A) and laminin 5 gamma2 by microinvasive and superficial squamous cell carcinomas in vivo and by migrating wound and senescent keratinocytes in culture. Am J Pathol, 163(2):477-91.
29. Svensson S, Nilsson K, Ringberg A, et al (2003). Invade or proliferate? Two contrasting events in malignant behavior governed by p16(INK4a) and an intact Rb pathway illustrated by a model system of basal cell carcinoma. Cancer Res, 63(8):1737-42.
30. Horree N, van Diest PJ, Sie-Go DM, et al (2007). The invasive front in endometrial carcinoma: higher proliferation and associated derailment of cell cycle regulators. Hum Pathol, 38(8):1232-8.
31. Palmqvist R, Rutegard JN, Bozoky B, et al (2000). Human colorectal cancers with an intact p16/cyclin D1/pRb pathway have up-regulated p16 expression and decreased proliferation in small invasive tumor clusters. Am J Pathol, 157(6):1947-53.
32. Fahraeus R, Lane DP (1999). The p16(INK4a) tumour suppressor protein inhibits alphavbeta3 integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of alphavbeta3 to focal contacts. EMBO J, 18(8):2106-18.
33. Chintala SK, Fueyo J, Gomez-Manzano C, et al (1997). Adenovirus-mediated p16/CDKN2 gene transfer suppresses glioma invasion in vitro. Oncogene, 15(17):2049-57.
34. Ansari-Lari MA, Staebler A, Zaino RJ, et al (2004). Distinction of endocervical and endometrial adenocarcinomas: imm-unohistochemical p16 expression correlated with human papillomavirus (HPV) DNA detection. Am J Surg Pathol, 28(2):160-7.
35. Horn LC, Richter CE, Einenkel J, et al (2006). p16, p14, p53, cyclin D1, and steroid hormone receptor expression and human papillomaviruses analysis in primary squamous cell carcinoma of the endometrium. Ann Diagn Pathol, 10(4):193-6.
36. McCluggage WG, Jenkins D (2003). p16 immunoreactivity may assist in the distinction between endometrial and endocervical adenocarcinoma. Int J Gynecol Pathol, 22(3):231-5.
37. Melgoza F, Brewster WR, Wilczynski S, et al (2006). p16-Positive small cell neuroendocrine carcinoma of the endometrium. Int J Gynecol Pathol, 25(3):252-6.
38. Cioffi-Lavina M, Chapman-Fredricks J, Gomez-Fernandez C, et al (2010). P16 expression in squamous cell carcinomas of cervix and bladder. Appl Immunohistochem Mol Morphol, 18(4):344-7.
39. Galgano MT, Castle PE, Atkins KA, et al (2010). Using biomarkers as objective standards in the diagnosis of cervical biopsies. Am J Surg Pathol, 34(8):1077-87.
40. Guedes AC, Brenna SM, Coelho SA, et al (2007). p16(INK4a) Expression does not predict the outcome of cervical intraepithelial neoplasia grade 2. Int J Gynecol Cancer, 17(5):1099-103.
41. Khleif SN, DeGregori J, Yee CL, et al (1996). Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity. Proc Natl Acad Sci U S A, 93(9):4350-4.
42. Carozzi F, Confortini M, Dalla Palma P, et al (2008). Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol, 9(10):937-45.
43. Carozzi F, Gillio-Tos A, Confortini M, et al (2013). Risk of high-grade cervical intraepithelial neoplasia during follow-up in HPV-positive women according to baseline p16-INK4A results: a prospective analysis of a nested substudy of the NTCC randomised controlled trial. Lancet Oncol, 14(2):168-76.
44. Denton KJ, Bergeron C, Klement P, et al (2010). The sensitivity and specificity of p16(INK4a) cytology vs HPV testing for detecting high-grade cervical disease in the triage of ASC-US and LSIL pap cytology results. Am J Clin Pathol, 134(1):12-21.
45. Guo M, Hu L, Baliga M, He Z, et al (2004). The predictive value of p16(INK4a) and hybrid capture 2 human papillomavirus testing for high-grade cervical intraepithelial neoplasia. Am J Clin Pathol, 122(6):894-901.
46. Nieh S, Chen SF, Chu TY, et al (2005). Is p16(INK4A) expression more useful than human papillomavirus test to determine the outcome of atypical squamous cells of undetermined significance-categorized Pap smear? A comparative analysis using abnormal cervical smears with follow-up biopsies. Gynecol Oncol, 97(1):35-40.
47. Yoshida T, Fukuda T, Sano T, et al (2004). Usefulness of liquid-based cytology specimens for the immunocytochemical study of p16 expression and human papillomavirus testing: a comparative study using simultaneously sampled histology materials. Cancer, 102(2):100-8.
48. Bosch FX, de Sanjose S (2003). Human papillomavirus and cervical cancer--burden and assessment of causality. J Natl Cancer Inst Monogr, (31):3-13.
49. Klaes R, Benner A, Friedrich T, et al (2002). p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia. Am J Surg Pathol, 26(11):1389-99.
50. Klaes R, Friedrich T, Spitkovsky D, et al (2001). Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer, 92(2):276-84.
51. Negri G, Egarter-Vigl E, Kasal A, et al (2003). p16INK4a is a useful marker for the diagnosis of adenocarcinoma of the cervix uteri and its precursors: an immunohistoche-mical study with immunocytochemical correlations. Am J Surg Pathol, 27(2):187-93.
52. Sano T, Oyama T, Kashiwabara K, et al (1998). Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol, 153(6):1741-8.
2. Swick AD, Chatterjee A, De Costa A-MA, et al (2015). Modulation of therapeutic sensitivity by human papillomavirus. Radiother Oncol, 116(3):342-5.
3. Suzich JA, Ghim SJ, Palmer-Hill FJ, et al (1995). Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas. Proc Natl Acad Sci U S A, 92(25):11553-7.
4. Lyon (2007). Human papillomaviruses. IARC monographs on the evaluation of carcinogenic risks to humans. 90:1-636.
5. Walboomers JM, Jacobs MV, Manos MM, et al (1999). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol, 189(1):12-9.
6. van Bogaert LJ (2012). P16INK4a immunocytochemistry/immunohistochemistry: need for scoring uniformization to be clinically useful in gynecological pathology. Ann Diagn Pathol, 16(5):422-6.
7. McLaughlin-Drubin ME, Crum CP, Munger K (2011). Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming. Proc Natl Acad Sci U S A, 108(5):2130-5.
8. Bibbo M, DeCecco J, Kovatich AJ (2003). P16INK4A as an adjunct test in liquid-based cytology. Anal Quant Cytol Histol, 25(1):8-11.
9. Cuschieri K, Wentzensen N (2008). Human papillomavirus mRNA and p16 detection as biomarkers for the improved diagnosis of cervical neoplasia. Cancer Epidemiol Biomarkers Prev, 17(10):2536-45.
10. Tsoumpou I, Arbyn M, Kyrgiou M, et al (2009). p16(INK4a) immunostaining in cytological and histological specimens from the uterine cervix: a systematic review and meta-analysis. Cancer Treat Rev, 35(3):210-20.
11. Romagosa C, Simonetti S, Lopez-Vicente L, et al (2011). p16(INK4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene, 30(18):2087-97.
12. Crum CP (1998). Detecting every genital papilloma virus infection: what does it mean? Am J Pathol, 153(6):1667-71.
13. Doutre S, Omar T, Goumbri-Lompo O, et al (2018). Cervical intraepithelial neoplasia (CIN) in African women living with HIV: role and effect of rigorous histopathological review by a panel of pathologists in the HARP study endpoint determination. J Clin Pathol, 71(1):40-45.
14. Nicol AF, Nuovo GJ, Salomao-Estevez A, et al (2008). Immune factors involved in the cervical immune response in the HIV/HPV co-infection. J Clin Pathol, 61(1):84-8.
15. Shi SR, Key ME, Kalra KL (1991). Antigen retrieval in formalin-fixed, paraffin-embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. J Histochem Cytochem, 39(6):741-8.
16. Svec A, Mikyskova I, Hes O, et al (2003). Human papillomavirus infection of the epididymis and ductus deferens: an evaluation by nested polymerase chain reaction. Arch Pathol Lab Med, 127(11):1471-4.
17. Eng J (2005). Receiver operating characteristic analysis: a primer. Acad Radiol, 12(7):909-16.
18. Branca M, Ciotti M, Santini D, et al (2004). p16(INK4A) expression is related to grade of cin and high-risk human papillomavirus but does not predict virus clearance after conization or disease outcome. Int J Gynecol Pathol, 23(4):354-65.
19. Tringler B, Gup CJ, Singh M, et al (2004). Evaluation of p16INK4a and pRb expression in cervical squamous and glandular neoplasia. Hum Pathol, 35(6):689-96.
20. Wang SS, Trunk M, Schiffman M, et al (2004). Validation of p16INK4a as a marker of oncogenic human papillomavirus infection in cervical biopsies from a population-based cohort in Costa Rica. Cancer Epidemiol Biomarkers Prev, 13(8):1355-60.
21. Queiroz C, Silva TC, Alves VA, et al (2006). P16(INK4a) expression as a potential prognostic marker in cervical pre-neoplastic and neoplastic lesions. Pathol Res Pract, 202(2):77-83.
22. Dai CY, Furth EE, Mick R, et al (2000). p16(INK4a) expression begins early in human colon neoplasia and correlates inversely with markers of cell proliferation. Gastroenterology, 119(4):929-42.
23. Milde-Langosch K, Bamberger AM, Rieck G, et al (2001). Overexpression of the p16 cell cycle inhibitor in breast cancer is associated with a more malignant phenotype. Breast Cancer Res Treat, 67(1):61-70.
24. Di Vinci A, Perdelli L, Banelli B, et al (2005). p16(INK4a) promoter methylation and protein expression in breast fibroadenoma and carcinoma. Int J Cancer, 114(3):414-21.
25. Zhao P, Mao X, Talbot IC (2006). Aberrant cytological localization of p16 and CDK4 in colorectal epithelia in the normal adenoma carcinoma sequence. World J Gastroenterol, 12(39):6391-6.
26. Hilliard NJ, Krahl D, Sellheyer K (2009). p16 expression differentiates between desmoplastic Spitz nevus and desmoplastic melanoma. J Cutan Pathol, 36(7):753-9.
27. Jung A, Schrauder M, Oswald U, et al (2001). The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, and p16INK4A and is a region of low proliferation. Am J Pathol, 159(5):1613-7.
28. Natarajan E, Saeb M, Crum CP, et al (2003). Co-expression of p16(INK4A) and laminin 5 gamma2 by microinvasive and superficial squamous cell carcinomas in vivo and by migrating wound and senescent keratinocytes in culture. Am J Pathol, 163(2):477-91.
29. Svensson S, Nilsson K, Ringberg A, et al (2003). Invade or proliferate? Two contrasting events in malignant behavior governed by p16(INK4a) and an intact Rb pathway illustrated by a model system of basal cell carcinoma. Cancer Res, 63(8):1737-42.
30. Horree N, van Diest PJ, Sie-Go DM, et al (2007). The invasive front in endometrial carcinoma: higher proliferation and associated derailment of cell cycle regulators. Hum Pathol, 38(8):1232-8.
31. Palmqvist R, Rutegard JN, Bozoky B, et al (2000). Human colorectal cancers with an intact p16/cyclin D1/pRb pathway have up-regulated p16 expression and decreased proliferation in small invasive tumor clusters. Am J Pathol, 157(6):1947-53.
32. Fahraeus R, Lane DP (1999). The p16(INK4a) tumour suppressor protein inhibits alphavbeta3 integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of alphavbeta3 to focal contacts. EMBO J, 18(8):2106-18.
33. Chintala SK, Fueyo J, Gomez-Manzano C, et al (1997). Adenovirus-mediated p16/CDKN2 gene transfer suppresses glioma invasion in vitro. Oncogene, 15(17):2049-57.
34. Ansari-Lari MA, Staebler A, Zaino RJ, et al (2004). Distinction of endocervical and endometrial adenocarcinomas: imm-unohistochemical p16 expression correlated with human papillomavirus (HPV) DNA detection. Am J Surg Pathol, 28(2):160-7.
35. Horn LC, Richter CE, Einenkel J, et al (2006). p16, p14, p53, cyclin D1, and steroid hormone receptor expression and human papillomaviruses analysis in primary squamous cell carcinoma of the endometrium. Ann Diagn Pathol, 10(4):193-6.
36. McCluggage WG, Jenkins D (2003). p16 immunoreactivity may assist in the distinction between endometrial and endocervical adenocarcinoma. Int J Gynecol Pathol, 22(3):231-5.
37. Melgoza F, Brewster WR, Wilczynski S, et al (2006). p16-Positive small cell neuroendocrine carcinoma of the endometrium. Int J Gynecol Pathol, 25(3):252-6.
38. Cioffi-Lavina M, Chapman-Fredricks J, Gomez-Fernandez C, et al (2010). P16 expression in squamous cell carcinomas of cervix and bladder. Appl Immunohistochem Mol Morphol, 18(4):344-7.
39. Galgano MT, Castle PE, Atkins KA, et al (2010). Using biomarkers as objective standards in the diagnosis of cervical biopsies. Am J Surg Pathol, 34(8):1077-87.
40. Guedes AC, Brenna SM, Coelho SA, et al (2007). p16(INK4a) Expression does not predict the outcome of cervical intraepithelial neoplasia grade 2. Int J Gynecol Cancer, 17(5):1099-103.
41. Khleif SN, DeGregori J, Yee CL, et al (1996). Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity. Proc Natl Acad Sci U S A, 93(9):4350-4.
42. Carozzi F, Confortini M, Dalla Palma P, et al (2008). Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol, 9(10):937-45.
43. Carozzi F, Gillio-Tos A, Confortini M, et al (2013). Risk of high-grade cervical intraepithelial neoplasia during follow-up in HPV-positive women according to baseline p16-INK4A results: a prospective analysis of a nested substudy of the NTCC randomised controlled trial. Lancet Oncol, 14(2):168-76.
44. Denton KJ, Bergeron C, Klement P, et al (2010). The sensitivity and specificity of p16(INK4a) cytology vs HPV testing for detecting high-grade cervical disease in the triage of ASC-US and LSIL pap cytology results. Am J Clin Pathol, 134(1):12-21.
45. Guo M, Hu L, Baliga M, He Z, et al (2004). The predictive value of p16(INK4a) and hybrid capture 2 human papillomavirus testing for high-grade cervical intraepithelial neoplasia. Am J Clin Pathol, 122(6):894-901.
46. Nieh S, Chen SF, Chu TY, et al (2005). Is p16(INK4A) expression more useful than human papillomavirus test to determine the outcome of atypical squamous cells of undetermined significance-categorized Pap smear? A comparative analysis using abnormal cervical smears with follow-up biopsies. Gynecol Oncol, 97(1):35-40.
47. Yoshida T, Fukuda T, Sano T, et al (2004). Usefulness of liquid-based cytology specimens for the immunocytochemical study of p16 expression and human papillomavirus testing: a comparative study using simultaneously sampled histology materials. Cancer, 102(2):100-8.
48. Bosch FX, de Sanjose S (2003). Human papillomavirus and cervical cancer--burden and assessment of causality. J Natl Cancer Inst Monogr, (31):3-13.
49. Klaes R, Benner A, Friedrich T, et al (2002). p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia. Am J Surg Pathol, 26(11):1389-99.
50. Klaes R, Friedrich T, Spitkovsky D, et al (2001). Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer, 92(2):276-84.
51. Negri G, Egarter-Vigl E, Kasal A, et al (2003). p16INK4a is a useful marker for the diagnosis of adenocarcinoma of the cervix uteri and its precursors: an immunohistoche-mical study with immunocytochemical correlations. Am J Surg Pathol, 27(2):187-93.
52. Sano T, Oyama T, Kashiwabara K, et al (1998). Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol, 153(6):1741-8.
| Files | ||
| Issue | Vol 49 No 2 (2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v49i2.3095 | |
| Keywords | ||
| Human papillomavirus; p16INK4A; Immunohistochemistry | ||
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How to Cite
1.
FARZANEHPOUR M, MUHAMMADNEJAD A, AKHAVAN S, EMAMI RAZAVI AN, JALILVAND S, SALIMI V, FAGHIHLOO E, KAKAVANDI E, FARAHMAND M, SHAYESTEHPOUR M, BABAKHANI F, MOKHTARI AZAD T. P16INK4A Immunohistochemistry as a Gold Standard for Cervical Cancer and Precursor Lesions Screening. Iran J Public Health. 2020;49(2):312-322.
