Virchows Archiv

, Volume 445, Issue 6, pp 610–615 | Cite as

P16INK4A positivity in benign, premalignant and malignant cervical glandular lesions: a potential diagnostic problem

  • N. Murphy
  • C. C. B. B. Heffron
  • B. King
  • U. G. Ganuguapati
  • M. Ring
  • E. McGuinness
  • O. Sheils
  • J. J. O’Leary
Original Article

Abstract

A wide array of immunohistochemical markers have been evaluated with respect to their specificity in staining dysplastic cervical cells in cervical biopsies and cervical cytological smears. However, there is still a significant demand for better biomarkers to identify neoplastic cervical glandular and squamous epithelial cells precisely. The CDKN2A gene, located on chromosome 9p21, encodes the tumour suppressor protein, p16INK4A, which decelerates the cell cycle by inactivating CDK4 and CDK6. The aim of this study was to compare and contrast the expression pattern of p16INK4A in benign and neoplastic glandular lesions and tubo-endometrioid metaplasia. All cases in each category displayed some p16INK4A expression. Adenocarcinoma and in situ cases showed a combination of intense nuclear and cytoplasmic staining. It was observed that all cases of tubo-endometrioid metaplasia showed occasional nuclear positivity and definite cytoplasmic staining. These findings may have important implications for the potential utility of p16INK4A as a biomarker for glandular dysplastic lesions. While p16INK4A has been demonstrated to be an excellent marker of cervical dysplasia in squamous neoplastic lesions of the cervix, it has potential pitfalls in cervical glandular lesions that may limit the utility of this biomarker in resolving the nature of suspicious glandular lesions, particularly in cytopathology.

Keywords

Adenocarcinoma in situ Cervical glandular intraepithelial neoplasia p16INK4A 

References

  1. 1.
    Anderson G, Gordon KC (1996) Tissue processing, microtomy and paraffin sections. In: Bancroft JD, Stevens A (eds) Theory and practice of histological techniques, 4th edn. Churchill & Livingstone, New YorkGoogle Scholar
  2. 2.
    Brown LJ, Wells M (1986) Cervical glandular atypia associated with squamous intraepithelial neoplasia: a premalignant lesion? J Clin Pathol 39:22–28PubMedGoogle Scholar
  3. 3.
    Cameron, RI, Maxwell, P, Jenkins D, McCluggage WG (2002) Immunohistochemical staining with MIB1, bcl2 and p16INK4A assists in the distinction of cervical glandular intraepithelial neoplasia from tubo-endometrial metaplasia, endometriosis and microglandular hyperplasia. Histopathology 41:313–321CrossRefPubMedGoogle Scholar
  4. 4.
    Cina SJ, Richardson MS (1997) Immunohistochemical staining for Ki-67 antigen, carcinoembryonic antigen, and p53 in the differential diagnosis of glandular lesions of the cervix. Mod Pathol 10:176–180PubMedGoogle Scholar
  5. 5.
    Ducatman BS, Wang HH (1993) Tubal metaplasia: a cytologic study with comparison to other neoplastic and non-neoplastic conditions of the endocervix. Diagn Cytopathol 9:98–103PubMedGoogle Scholar
  6. 6.
    Fountain JW, Karayiorgou M, Ernstoff MS, Kirkwood JM, Volck DR, Titus-Ernstoff L, Bouchard B, Vijayasaradhi S, Houghton AN, Lahti J et al (1992) Homozygous deletions within human chromosome band 9p21 in melanoma. Proc Natl Acad Sci U S A 89:10557PubMedGoogle Scholar
  7. 7.
    Friedell G, McKay D (1953) Adenocarcinoma in situ of the endocervix. Cancer 6:887–897PubMedGoogle Scholar
  8. 8.
    Goldstein NS, Ahmad E (1998) Endocervical glandular atypia: does a preneoplastic lesion of adenocarcinoma in situ exist? Am J Clin Pathol 110:200–209PubMedGoogle Scholar
  9. 9.
    Havrilesky LJ, Alvarez AA, Whitaker RS, Marks JR, Berchuck A (2001) Loss of expression of the p16 tumour suppressor gene is more frequent in advanced ovarian cancers lacking p53 mutations. Gynecol Oncol 83:491–500CrossRefPubMedGoogle Scholar
  10. 10.
    Healy E, Rehman I, Angus B, Rees JL (1995) Loss of heterozygosity in sporadic primary cutaneous melanoma. Genes Chromosomes Cancer 12:152PubMedGoogle Scholar
  11. 11.
    Hopkins MP, Morley GW (1991) A comparison of adenocarcinoma and squamous cell carcinoma of the cervix. Obstet Gynecol 77:912–917PubMedGoogle Scholar
  12. 12.
    Johnson JE, Rahemtulla A (1999) Endocervical glandular neoplasia and its mimics in ThinPrep Pap tests. A descriptive study. Acta Cytol 43:369–375PubMedGoogle Scholar
  13. 13.
    Jonasson JG, Wang HH (1992) Tubal metaplasia of the uterine cervix: a prevalence study in patients with gynaecological pathologic findings. Int J Gynecol Pathol 11: 89–95PubMedGoogle Scholar
  14. 14.
    Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, Hussey C, Tran T, Miki Y, Weaver-Feldhaus J, McClure M, Aitken JF, Anderson DE, Bergman W, Frants R, Goldgar DE, Green A, MacLennan R, Martin NG, Meyer LJ, Youl P, Zone JJ, Skolnick MH, Cannon-Albright LA. (1994) Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 8:22CrossRefGoogle Scholar
  15. 15.
    Keating JT, Cviko A, Riethdorf S, Riethdorf L, Quade BJ, Sun D, Duensing S, Sheets EE, Munger K, Crum CP (2001) Ki-67, Cyclin E, and p16 are complimentary surrogate biomarkers for human papilloma virus-related cervical neoplasia. Am J Surg Pathol 25:884–891PubMedGoogle Scholar
  16. 16.
    Klaes R, Friedrich T (2001) Overexpression of p16 as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 92:276–284CrossRefPubMedGoogle Scholar
  17. 17.
    Krane JF, Granter SR (2001) Papanicolaou smear sensitivity for the detection of adenocarcinoma of the cervix: a study of 49 cases. Cancer 93:8–15CrossRefPubMedGoogle Scholar
  18. 18.
    Kudoh K, Ichikawa Y, Yoshida S, Hirai M, Kikuchi Y, Nagata I, Miwa M, Uchida K (2002) Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer. Int J Cancer 99:579–582CrossRefPubMedGoogle Scholar
  19. 19.
    Liao SY, Brewer C (1994) Identification of MN antigen as a marker of cervical intraepithelial squamous and glandular neoplasia and cervical carcinoma. Am J Pathol 145:598–609PubMedGoogle Scholar
  20. 20.
    Marques T, Andrade LA (1997) Endocervical tubal metaplasia: morphological concepts and practical importance. Rev Assoc Med Bras 43:21–24PubMedGoogle Scholar
  21. 21.
    McCluggage WG (2002) Recent advances in immunohistochemistry in gynaecological pathology. Histopathology 40:309–326CrossRefPubMedGoogle Scholar
  22. 22.
    McCluggage WG (2003) Endocervical glandular lesions: controversial aspects and ancillary techniques. J Clin Pathol 56:164–173CrossRefPubMedGoogle Scholar
  23. 23.
    McCluggage WG, Maxwell P, McBride HA, Hamilton PW, Bharucha H (1995) Monoclonal antibodies Ki67 and MIB1 in the distinction of tuboendometrial metaplasia from endocervical adenocarcinoma and adenocarcinoma in situ in formalin-fixed material. Int J Gynecol Pathol 14:209–216PubMedGoogle Scholar
  24. 24.
    Murphy N, Ring M, Killalea AG, Uhlmann V, O’Donovan M, Mulcahy F, McGuinness E, Griffin, Martin C, Sheils O, O’Leary JJ (2003) P16INK4A as a marker for cervical dyskaryosis: CIN and cGIN in cervical biopsies and ThinPrep smears. J Clin Pathol 56:56–63CrossRefPubMedGoogle Scholar
  25. 25.
    Negri G, Egarter-Vigl E, Kasal A, Roman F, Haitel A, Mian C (2003) p16INK4A is a useful marker for the diagnosis of adenocarcinoma of the cervix uteri and its precursors. Am J Surg Pathol 27:187–193CrossRefPubMedGoogle Scholar
  26. 26.
    Nielsen GP, Stemmer-Rachaminov AO (1999) Immunohistochemical survey of p16 expression in normal human adult and infant tissues. Lab Invest 79:1137–1141PubMedGoogle Scholar
  27. 27.
    Novotny DB, Maygarden S (1992) Tubal metaplasia—a frequent potential pitfall in the cytologic diagnosis of endocervical glandular dysplasia on cervical smears. Acta Cytol 36:1–10PubMedGoogle Scholar
  28. 28.
    Olivia E, Clement PB (1995) Tubal and tubo-endometrioid metaplasia of the uterine cervix. Unemphasized features that may cause problems in differential diagnosis: a report of 25 cases. Am J Clin Pathol 103:618–623PubMedGoogle Scholar
  29. 29.
    Pacey F, Ayer B, Greenberg M (1988) The cytologic diagnosis of adenocarcinoma in situ of the cervix uteri and related lesions. III. Pitfalls in diagnosis. Acta Cytol 32:325–330PubMedGoogle Scholar
  30. 30.
    Riethdorf L, O’Connell JT (2000) Differential expression of MUC2 and MUC5AC in benign and malignant glandular lesions of the cervix uteri. Virchows Arch 437:365–371CrossRefPubMedGoogle Scholar
  31. 31.
    Riethdorf L, Riethdorf S (2002) Human papillomaviruses, expression of p16 and early endocervical glandular neoplasia. Hum Pathol 33:899–904CrossRefPubMedGoogle Scholar
  32. 32.
    Saegusa M, Machida BD, Okayasu I (2001) Possible associations among expression of p14 (ARF), p16 (INK4A), p21 (WAF1/CIP1), p27 (KIP1) and p53 accumulation and the balance of apoptosis and cell proliferation in ovarian carcinomas. Cancer 92:1177–1189CrossRefPubMedGoogle Scholar
  33. 33.
    Saigo PE, Wolinska WH (1985) The role of cytology in the diagnosis and follow up of patients with cervical adenocarcinoma. Acta Cytol 29:785–794PubMedGoogle Scholar
  34. 34.
    Sano T, Oyama 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
  35. 35.
    Schwartz S, Weiss N (1986) Increased incidence of adenocarcinoma of the cervix in young women in the United States. Am J Epidemiol 124:1045–1047PubMedGoogle Scholar
  36. 36.
    Segal GH, Hart WR (1990) Cystic endocervical tunnel clusters: a clinicopathologic study of 29 cases of so-called adenomatous hyperplasia. Am J Surg Pathol 14:895–903PubMedGoogle Scholar
  37. 37.
    Selvaggi SM, Haefner HK (1997) Microglandular endocervical hyperplasia and tubal metaplasia: pitfalls in the diagnosis of adenocarcinoma on cervical smears. Diagn Cytopathol 16:168–173CrossRefPubMedGoogle Scholar
  38. 38.
    Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA (1996) Role of the INK4a locus in tumour suppression and cell mortality Cell 85:27CrossRefGoogle Scholar
  39. 39.
    Suh KS, Silverberg SG (1990) Tubal metaplasia of the uterine cervix. Int J Gynecol Pathol 9:122–128PubMedGoogle Scholar
  40. 40.
    Umezaki K, Sanezumi M (1998) Immunohistochemical demonstration of aberrant glycosylation and epidermal growth factor receptor in tubal metaplasia of the uterine cervix. Gynecol Oncol 70:40–44CrossRefPubMedGoogle Scholar
  41. 41.
    Von Knebel Doeberitz M (2001) New molecular tools for efficient screening of cervical cancer. Dis Markers 17:123–128PubMedGoogle Scholar
  42. 42.
    Williams GH, Romanowski P, Morris L, Madine M, Mills AD, Stoeber K, Marr J, Laskey RA, Coleman N (1998) Improved cervical smear assessment using antibodies against proteins that regulate DNA replication. Proc Natl Acad Sci U S A 95:14932–14937CrossRefPubMedGoogle Scholar
  43. 43.
    Wong YF, Chung TK (1999) Methylation of p16 in primary gynaecologic malignancy. Cancer Lett 136:231–235CrossRefPubMedGoogle Scholar
  44. 44.
    Yoshinouchi M, Hongo A (2000) Alteration of the CDKN2/P16 gene is not required for HPV-positive uterine cervical cell lines. Int J Oncol 16:537–541PubMedGoogle Scholar
  45. 45.
    Young RH, Scully RE (1989) Atypical forms of microglandular hyperplasia of the cervix simulating carcinoma: a report of 5 cases and a review of the literature. Am J Surg Pathol 13:50–56Google Scholar
  46. 46.
    Zaino RJ (2000) Glandular lesions of the uterine cervix. Mod Pathol 13:261–274CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • N. Murphy
    • 1
    • 2
  • C. C. B. B. Heffron
    • 1
  • B. King
    • 1
  • U. G. Ganuguapati
    • 1
  • M. Ring
    • 1
    • 2
  • E. McGuinness
    • 2
  • O. Sheils
    • 2
  • J. J. O’Leary
    • 1
    • 2
  1. 1.Department of PathologyCoombe Women’s HospitalDublin 8Ireland
  2. 2.Trinity CollegeDublinIreland

Personalised recommendations