Virchows Archiv

, Volume 445, Issue 6, pp 616–620

P16INK4a expression and progression risk of low-grade intraepithelial neoplasia of the cervix uteri

  • Giovanni Negri
  • Fabio Vittadello
  • Fabio Romano
  • Armin Kasal
  • Francesco Rivasi
  • Salvatore Girlando
  • Christine Mian
  • Eduard Egarter-Vigl
Original Article

Abstract

The aim of the study was to evaluate the immunohistochemical expression of p16INK4a as a marker of progression risk in low-grade dysplastic lesions of the cervix uteri. p16INK4a immunohistochemistry was performed on 32 CIN1 with proven spontaneous regression of the lesion in the follow-up (group A), 31 (group B) with progression to CIN3 and 33 (group C) that were randomly chosen irrespective of the natural history of the lesion. p16INK4a staining pattern was scored as negative (less than 5% cells in the lower third of dysplastic epithelium stained), as focally positive (≤25%) and as diffuse positive (>25%). A diffuse staining pattern was detected in 43.8% of CIN1 of group A, 74.2% of group B and 56.3% of group C. No p16INK4a staining was detected in 31.3% and 12.9% CIN1 lesions of groups A and B, respectively. Overall, 71.4% and 37.8% of p16INK4a-negative and diffusely positive CIN1 had regressed at follow-up, whereas 28.6% and 62.2% negative and diffusely positive CIN1 were progressed to CIN3, respectively (P<0.05). All CIN3 lesions analyzed during follow-up of group B were diffusely stained for p16INK4a. Although p16INK4a may be expressed in low-grade squamous lesions that undergo spontaneous regression, in this study, CIN1 cases with diffuse p16INK4a staining had a significantly higher tendency to progress to a high-grade lesion than p16INK4a-negative cases. p16INK4a may have the potential to support the interpretation of low-grade dysplastic lesions of the cervix uteri.

Keywords

p16 Immunohistochemistry Human papilloma virus Cervical intraepithelial neoplasia Progression Regression 

References

  1. 1.
    Agoff NS, Lin P, Morihara J, Mao C, Kiviat NB, Koutsky LA (2003) p16INK4a expression correlates with degree of cervical neoplasia: a comparison with Ki-67 expression and detection of high-risk HPV types. Mod Pathol 16:665–673CrossRefPubMedGoogle Scholar
  2. 2.
    Chan JK, Monk BJ, Brewer C Keefe KA, Osann K, McMeekin S, Rose GS, Youssef M, Wilczynski SP, Meyskens FL, Berman ML (2003) HPV infection and number of lifetime sexual partners are strong predictors for “natural” regression of CIN2 and 3. Br J Cancer 15:1062–1066CrossRefGoogle Scholar
  3. 3.
    Dalstein V, Riethmuller D, Pretet JL Le Bail Carval K, Sautiere JL, Carbillet JP, Kantelip B, Schaal JP, Mougin C (2003) Persistence and load of high-risk HPV are predictors for development of cervical lesions: a longitudinal French cohort study. Int J Cancer 106:396–403CrossRefPubMedGoogle Scholar
  4. 4.
    El Hamidi A, Kocjan G, Du M-Q (2003) Clonality analysis of archival cervical smears. Correlation of monoclonality with grade and clinical behaviour of cervical intraepithelial neoplasia. Acta Cytol 47:117–123PubMedGoogle Scholar
  5. 5.
    Gallo G, Bibbo M, Bagella L Zamparelli A, Sanseverino F, Giovagnoli MR, Vecchione A, Giordano A (2003) Study of viral integration of HPV-16 in young patients with LSIL. J Clin Pathol 56:532–536CrossRefPubMedGoogle Scholar
  6. 6.
    Giarre M, Caldeira S, Malanchi I Ciccolini F, Leao MJ, Tommasino M (2001) Induction of pRb degradation by the human papillomavirus type 16 E7 protein is essential to efficiently overcome p16INK4a-imposed G1 cell cycle arrest. J Virol 75:4705–4712CrossRefPubMedGoogle Scholar
  7. 7.
    Ho GYF, Bierman R, Beardsley L, Chang CJ, Burk RD (1998) Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 338:423–428CrossRefPubMedGoogle Scholar
  8. 8.
    Huang LW, Chao SL, Chen TJ (2003) Reduced Fhit expression in cervical carcinoma: correlation with tumor progression and poor prognosis. Gynecol Oncol 90:331–337CrossRefPubMedGoogle Scholar
  9. 9.
    Kjaer SK, van den Brule AJ, Paull G Svare EI, Sherman ME, Thomsen BL, Suntum M, Bock JE, Poll PA, Meijer CJ (2002) Type specific persistence of high risk human papillomavirus (HPV) as indicator of high grade cervical squamous intraepithelial lesions in young women: population based prospective follow up study. BMJ 325:572CrossRefPubMedGoogle Scholar
  10. 10.
    Klaes R, Woerner SM, Ridder R Wentzensen N, Duerst M, Schneider A, Lotz B, Melsheimer P, von Knebel Doeberitz M (1999) Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res 59:6132–6136PubMedGoogle Scholar
  11. 11.
    Klaes R, Friedrich T, Spitkowsky D, Ridder R, Rudy W, Petry U, Dallenbach-Hellweg G, Schmidt D, von Knebel Doeberitz M (2001) Overexpression of p16INK4a as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 92:276–284CrossRefPubMedGoogle Scholar
  12. 12.
    Klaes R, Benner A, Friedrich T, Ridder R, Herrington S, Jenkins D, Kurman RJ, Schmidt D, Stoler M, von Knebel Doeberitz M (2002) p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia. Am J Surg Pathol 26:1389–1399CrossRefPubMedGoogle Scholar
  13. 13.
    Kruse AJ, Baak JP, Janssen EA Bol MG, Kjellevold KH, Fianne B, Lovslett K, Bergh J (2003) Low- and high-risk CIN 1 and 2 lesions: prospective predictive value of grade, HPV, and Ki-67 immuno-quantitative variables. J Pathol 199:462–470CrossRefPubMedGoogle Scholar
  14. 14.
    Negri G, Egarter-Vigl E, Kasal A, Romano F, Haitel A, Mian C (2003) p16INK4a is a useful marker for the diagnosis of adenocarcinoma of the cervix uteri and its precursors. An immunohistochemical study with immunocytochemical correlations. Am J Surg Pathol 27:187–193Google Scholar
  15. 15.
    Ostor AG (1993) Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol 12:186–192PubMedGoogle Scholar
  16. 16.
    Ozalp SS, Yalcin OT, Tanir HM Dundar E, Yildirim S (2002) Bcl-2 expression in preinvasive and invasive cervical lesions. Eur J Gynaecol Oncol 23:419–422PubMedGoogle Scholar
  17. 17.
    Sano T, Oyama T, Kashiwabara K, Fukuda T, Nakajima T (1998) Expression status of p16 protein is associated with human papilloma virus oncogenic potential in cervical and genital lesions. Am J Pathol 153:1741–1748PubMedGoogle Scholar
  18. 18.
    Sano T, Oyama T, Kashiwabara K, Fukuda T, Nakajima T (1998) Immunohistochemical overexpression of p16 protein associated with intact retinoblastoma protein expression in cervical cancer and cervical intraepithelial neoplasia. Pathol Int 48:580–585PubMedGoogle Scholar
  19. 19.
    Schlecht NF, Platt RW, Duarte-Franco E Costa MC, Sobrinho JP, Prado JC, Ferenczy A, Rohan TE, Villa LL, Franco EL (2003) Human papillomavirus infection and time to progression and regression of cervical intraepithelial neoplasia. J Natl Cancer Inst 95:1336–1343CrossRefPubMedGoogle Scholar
  20. 20.
    Schneider V (2003) CIN prognostication: will molecular techniques do the trick? Acta Cytol 47:115–116PubMedGoogle Scholar
  21. 21.
    The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group (2000) Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. J Natl Cancer Inst 92:397–402CrossRefPubMedGoogle Scholar
  22. 22.
    Tringler B, Gup CJ, Singh M, Groshong S, Shroyer AL, Heinz DE, Shroyer KR (2004) Evaluation of p16INK4a and pRb expression in cervical squamous and glandular neoplasia. Hum Pathol 35:689–696CrossRefPubMedGoogle Scholar
  23. 23.
    Ueda J, Enomoto T, Miyatake T Ozaki K, Yoshizaki T, Kanao H, Ueno Y, Nakashima R, Shroyer KR, Murata Y (2003) Monoclonal expansion with integration of high-risk human papillomavirus is an initial step for cervical carcinogenesis: association of clonal status and human papillomavirus infection with clinical outcome in cervical intraepithelial neoplasia. Lab Invest 83:1517–1527CrossRefPubMedGoogle Scholar
  24. 24.
    von Knebel Doeberitz M (2002) New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections. Eur J Cancer 38:2229–2242CrossRefPubMedGoogle Scholar
  25. 25.
    Wollscheid V, Kuhne-Heid R, Stein I Jansen L, Kollner S, Schneider A, Durst M (2002) Identification of a new proliferation-associated protein NET-1C4.8 characteristic for a subset of high-grade cervical intraepithelial neoplasia and cervical carcinomas. Int J Cancer 99:771–775CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Giovanni Negri
    • 1
  • Fabio Vittadello
    • 1
  • Fabio Romano
    • 1
  • Armin Kasal
    • 1
  • Francesco Rivasi
    • 2
  • Salvatore Girlando
    • 3
  • Christine Mian
    • 1
  • Eduard Egarter-Vigl
    • 1
  1. 1.Department of PathologyGeneral Hospital BolzanoBolzanoItaly
  2. 2.Department of Pathologic Anatomy and Forensic Medicine, Section of PathologyUniversity of Modena and Reggio EmiliaModenaItaly
  3. 3.Department of Surgical PathologyS. Chiara HospitalTrentoItaly

Personalised recommendations