p16INK4A Expression in Squamous Cell Carcinomas of the Vagina and the Vulva in Tunisian Women

  • Missaoui, Nabiha (Research Unit UR14ES17, Cancer Epidemiology and Cytopathology in Tunisian Center, Faculty of Medicine) ;
  • Abdelkarim, Soumaya Ben (Pathology Department, Farhet Hached Hospital) ;
  • Mokni, Moncef (Pathology Department, Farhet Hached Hospital) ;
  • Hmissa, Sihem (Research Unit UR14ES17, Cancer Epidemiology and Cytopathology in Tunisian Center, Faculty of Medicine)
  • Published : 2015.01.22


Background: The role of $p16^{INK4A}$ expression in uterine cervix cancer is well established. In the remaining female lower genital tract cancers, the importance of $p16^{INK4A}$ up-regulation is less clear. In our study, we analyzed the role of $p16^{INK4A}$ expression and HPV infection in carcinomas of the vulva and the vagina in Tunisian women. Materials and Methods: We conducted a retrospective study of 30 carcinomas including 15 vulvar squamous cell carcinomas (SCCs) and 15 vaginal SCCs. Immunohistochemistry was used to determine $p16^{INK4A}$ expression. HPV detection and typing was by in situ hybridization. Results: $p16^{INK4A}$ expression was detected in 86.7% of vaginal SCCs with a strong and diffuse immunostaining in 60% of cases, and also in 73.3% of vulvar SCCs with focal immunoreactivity in 53.3% The association between $p16^{INK4A}$ expression and HPV infection was significant in vaginal SCCs (p=0.001) but not vulvar SCCs (p>0.05). Conclusions: $p16^{INK4A}$ expression could be used as a useful marker for HPV positivity in vaginal SCCs similar to that described in uterine cervix cancers. However, our data support the presence of 2 different mechanisms for $p16^{INK4A}$ expression in HPV-related and HPV-unrelated vulvar carcinomas.


  1. Benevolo M, Mottolese M, Marandino F, et al (2006). Immunohistochemical expression of p16(INK4a) is predictive of HR-HPV infection in cervical low-grade lesions. Mod Pathol, 19, 384-91.
  2. Bose S, Evans H, Lantzy L, et al (2005). p16(INK4A) is a surrogate biomarker for a subset of human papilloma virus-associated dysplasias of the uterine cervix as determined on the Pap smear. Diagn Cytopathol, 32, 21-4.
  3. Carter JJ, Madeleine MM, Shera K, et al (2001). Human papillomavirus 16 and 18 L1 serology compared across anogenital cancer sites. Cancer Res, 61, 1934-40.
  4. Chan MK, Cheung TH, Chung TK, et al (1998). Expression of p16INK4 and retinoblastoma protein Rb in vulvar lesions of Chinese women. Gynecol Oncol, 68, 156-61.
  5. Cheah PL, Looi LM, Teoh KH, et al (2012). p16(INK4a) is a useful marker of human papillomavirus integration allowing risk stratification for cervical malignancies. Asian Pac J Cancer Prev, 13, 469-72.
  6. Daling J, Madeleine M, Schwartz S, et al (2002). A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol, 84, 263-70.
  7. de Sanjose S, Alemany L, Ordi J, et al (2013). Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva. Eur J Cancer, 49, 3450-61.
  8. Ferreira M, Crespo M, Martins L, et al (2008). HPV DNA detection and genotyping in 21 cases of primary invasive squamous cell carcinoma of the vagina. Mod Pathol, 21, 968-72.
  9. Franco EL (1996). Epidemiology of anogenital warts and cancer. Obstet Gynecol Clin North Am, 23, 597-623.
  10. Genoves J, Alameda F, Mancebo G, et al (2014). Human papillomavirus detection and p16INK4a expression in cervical lesions: a comparative study. Hum Pathol, 45, 826-33.
  11. Hachana M, Ziadi S, Amara K, et al (2010). No evidence of human papillomavirus DNA in breast carcinoma in Tunisian patients. Breast, 19, 541-4.
  12. Hampl M, Sarajuuri H, Wentzensen N, et al (2006). Effect of human papillomavirus vaccines on vulvar, vaginal, and anal intraepithelial lesions and vulvar cancer. Obstet Gynecol, 108, 1361-8.
  13. Hellman K, Silfversward C, Nilsson B, et al (2004). Primary carcinoma of the vagina: factors influencing the age at diagnosis. The Radiumhemmet series 1956-96. Int J Gynecol Cancer, 14, 491-501.
  14. Hellman K, Lindquist D, Ranhem C, et al (2014). Human papillomavirus, p16(INK4A), and Ki-67 in relation to clinicopathological variables and survival in primary carcinoma of the vagina. Br J Cancer, 110, 1561-70.
  15. Hoevenaars BM, Avoort IA, Wilde PC, et al (2008). A panel of p16(INK4A), MIB1 and p53 proteins can distinguish between the 2 pathways leading to vulvar squamous cell carcinoma. Int J Cancer, 123, 2767-73.
  16. Kalof AN, Cooper K (2006). p16INK4a immunoexpression: surrogate marker of high-risk HPV and high-grade cervical intraepithelial neoplasia. Adv Anat Pathol, 13, 190-4.
  17. Keating T, Cviko A, Riethdorf S, et al (2001). Ki-67, cyclin E, and p16INK4 are com- plimentary surrogate biomarkers for human papilloma virus-related cervical neoplasia. Am J Surg Pathol, 25, 884-91.
  18. Knopp S, Bjorge T, Nesland JM, et al (2004). p16INK4a and p21Waf1/Cip1 expression correlates with clinical outcome in vulvar carcinomas. Gynecol Oncol, 95, 37-45.
  19. Kurshumliu F, Thorns C, Gashi-Luci L (2009). p16INK4A in routine practice as a marker of cervical epithelial neoplasia. Gynecol Oncol, 115, 127-31.
  20. Lambert AP, Anschau F, Schmitt VM (2006). p16INK4A expression in cervical prema- lignant and malignant lesions. Exp Mol Pathol, 80, 192-6.
  21. McCluggage WG, Jenkins D (2003). p16 immunoreactivity may assist in the distinction between endometrial and endocervical adenocarcinoma. Int J Gynecol Pathol, 22, 231-5.
  22. Merino MJ (1991). Vaginal cancer: the role of infectious and environmental factors. Am J Obstet Gynecol, 165, 1255-62.
  23. Missaoui N, Hmissa S, Frappart L, et al (2006). p16INK4A overexpression and HPV infection in uterine cervix adenocarcinoma. Virchows Archiv, 448, 597-603.
  24. Missaoui N, Hmissa S, Rengaswamy, et al (2010b). p16INK4A overexpression is a useful marker for uterine cervix lesions. Ann Biol Clin, 68, 409-14.
  25. Missaoui N, Trabelsi A, Hmissa S, et al (2010c). p16INK4A overexpression in precancerous and concerous lesions of the uterine cervix in Tunisian women. Pathol Res Pract, 206, 550-5.
  26. Missaoui N, Trabelsi A, Parkin DM, el al (2010a) Trends in the incidence of cancer in the Sousse region, Tunisia, 1993-2006. Int J Cancer, 127, 2669-77.
  27. Nabi S, Trimeche M, Ziadi S, et al (2006). Prevalence of high risk oncogene HPV by in situ hybridization and by PCR in condyloma acuminata in the region of the Tunisian Center. Tunis Med, 84, 170-6.
  28. O'Neill CJ, McCluggage WG (2006). p16 expression in the female genital tract and its value in diagnosis. Adv Anat Pathol, 13, 8-15.
  29. Parkin D, Bray F (2006). The burden of HPV-related cancers. Vaccine, 24, 11-25.
  30. Riethdorf L, Riethdorf S, Lee KR, et al (2002). Human papillomaviruses, expression of p16, and early endocervical glandular neoplasia. Hum Pathol, 33, 899-904.
  31. Riethdorf S, Neffen EF, Cviko A, et al (2004). p16INK4A expression as biomarker for HPV 16-related vulvar neoplasias. Hum Pathol, 35, 1477-83.
  32. Rocco JW, Sidransky D (2001). p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp Cell Res, 264, 42-55.
  33. Rufforny I, Wilkinson EJ, Liu C, et al (2005). Human papillomavirus infection and p16(INK4a) protein expression in vulvar intraepithelial neoplasia and invasive squamous cell carcinoma. J Low Genit Tract Dis, 9, 108-13.
  34. Santos M, Landolfi S, Olivella A, et al (2006). p16 overexpression identifies HPV-positive vulvar squamous cell carcinomas. Am J Surg Pathol, 30, 1347-56.
  35. Siriaunkgul S, Settakorn J, Sukpan K, et al. (2014). HPV detection and genotyping in vulvar squamous cell carcinoma in northern Thailand. Asian Pac J Cancer Prev, 15, 3773-8.
  36. Srivastava V, Patel B, Kumar M, et al (2013). Cyclin D1, retinoblastoma and p16 protein expression in carcinoma of the gallbladder. Asian Pac J Cancer Prev, 14, 2711-5.
  37. Srodon M, Stoler MH, Baber GB, et al (2006). The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VaIN). Am J Surg Pathol, 30, 1513-8.
  38. Tringler B, Grimm C, Dudek G, et al (2007). p16INK4a expression in invasive vulvar squamous cell carcinoma. Appl Immunohistochem Mol Morphol, 15, 279-83.
  39. van der Avoort IA, Shirango H, Hoevenaars BM, et al (2006). Vulvar squamous cell carcinoma is a multifactorial disease following two separate and independent pathways. Int J Gynecol Pathol, 25, 22-9.
  40. Vinyuvat S, Karalak A, Suthipintawong C, et al (2008). Interobserver reproducibility in determining p16 overexpression in cervical lesions: use of a combined scoring method. Asian Pac J Cancer Prev, 9, 653-7.
  41. von Knebel Doeberitz M (2002). New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections. Eur J Cancer, 38, 2229-42.
  42. Wells M, Ostor AG, Crum CP, et al (2003). Tumors of the breast and female genital organs. IARC Press, Lyon, France.
  43. Wu X, Matanoski G, Chen VW, et al (2008). Descriptive epidemiology of vaginal cancer incidence and survival by race, ethnicity, and age in the United States. Cancer, 113, 2873-82.
  44. zur Hausen H (2002). Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer, 2, 342-50.

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