Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Apr;80(1-2):38–43. doi: 10.1038/sj.bjc.6690318

In squamous cell carcinoma of the vulva, overexpression of p53 is a late event and neither p53 nor mdm2 expression is a useful marker to predict lymph node metastases

A G Emanuels 1, J Koudstaal 2, M P M Burger 2, H Hollema 2
PMCID: PMC2363016  PMID: 10389975

Abstract

To offer more tailored treatment to individual patients with squamous cell carcinoma of the vulva, more accurate prediction of lymph node metastases is required. As p53 and mdm2 are genes known to be involved in the development of other tumours, we studied expression of p53 and mdm2 in carcinogenesis of squamous cell carcinoma of the vulva and their clinical relevance. Archival material of 141 T1 and T2 vulvar tumours were used. Of the 141 primary tumours, the corresponding 39 lymph node metastases (LNM) were studied, and in 90 cases the pre-existent epithelia adjacent to the tumour (EAT) and in 14 cases vulvar intraepithelial neoplasia adjacent to the tumour (VIN) was also investigated. Detection of p53 and mdm2 protein was immunohistochemically performed. Scoring categories were: negative (1); weakly positive (2); moderately to markedly positive (3); and markedly positive (4). Overexpression of p53 was seen in 56% of the LNM, 39% of the primary tumours, 21% of the VIN lesions and 0% in the group of EAT. No relation was found between overexpression of p53 in the primary tumour and LNM. Expression of mdm2 was seen in 14% of the primary tumours, of which four cases were marked positive. In the group of LNM no mdm2-positive staining was observed. In the group of EAT, 25% was mdm2-positive, of which six cases were marked positive. In the group of VIN, 36% showed moderate (score 3) mdm2 expression. No relation was found between expression of mdm2 and LNM. In squamous cell carcinoma, overexpression of p53 is a late event in carcinogenesis. Marked expression of mdm2 is rarely seen in vulvar carcinomas, indicating that aberrant p53 cannot induce mdm2 expression. LNM cannot be predicted by detection of these proteins. © 1999 Cancer Research Campaign

Keywords: vulvar carcinoma, p53, mdm2, metastasis

Full Text

The Full Text of this article is available as a PDF (295.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barak Y., Juven T., Haffner R., Oren M. mdm2 expression is induced by wild type p53 activity. EMBO J. 1993 Feb;12(2):461–468. doi: 10.1002/j.1460-2075.1993.tb05678.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bosari S., Viale G., Roncalli M., Graziani D., Borsani G., Lee A. K., Coggi G. p53 gene mutations, p53 protein accumulation and compartmentalization in colorectal adenocarcinoma. Am J Pathol. 1995 Sep;147(3):790–798. [PMC free article] [PubMed] [Google Scholar]
  3. Bosari S., Viale G. The clinical significance of p53 aberrations in human tumours. Virchows Arch. 1995;427(3):229–241. doi: 10.1007/BF00203389. [DOI] [PubMed] [Google Scholar]
  4. Charpin C., DeVictor B., Andrac L., Amabile J., Bergeret D., LaVaut M. N., Allasia C., Piana L. p53 quantitative immunocytochemical analysis in breast carcinomas. Hum Pathol. 1995 Feb;26(2):159–166. doi: 10.1016/0046-8177(95)90032-2. [DOI] [PubMed] [Google Scholar]
  5. Chu J., Tamimi H. K., Ek M., Figge D. C. Stage I vulvar cancer: criteria for microinvasion. Obstet Gynecol. 1982 Jun;59(6):716–719. [PubMed] [Google Scholar]
  6. Coulter L. K., Wolber R., Tron V. A. Site-specific comparison of p53 immunostaining in squamous cell carcinomas. Hum Pathol. 1995 May;26(5):531–533. doi: 10.1016/0046-8177(95)90249-x. [DOI] [PubMed] [Google Scholar]
  7. Dazard J. E., Augias D., Neel H., Mils V., Marechal V., Basset-Séguin N., Piette J. MDM-2 protein is expressed in different layers of normal human skin. Oncogene. 1997 Mar 6;14(9):1123–1128. doi: 10.1038/sj.onc.1200922. [DOI] [PubMed] [Google Scholar]
  8. Emanuels A., Hollema H., Suurmeyer A., Koudstaal J. A modified method for antigen retrieval MIB-1 staining of vulvar carcinoma. Eur J Morphol. 1994 Aug;32(2-4):335–337. [PubMed] [Google Scholar]
  9. Esrig D., Elmajian D., Groshen S., Freeman J. A., Stein J. P., Chen S. C., Nichols P. W., Skinner D. G., Jones P. A., Cote R. J. Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med. 1994 Nov 10;331(19):1259–1264. doi: 10.1056/NEJM199411103311903. [DOI] [PubMed] [Google Scholar]
  10. Esrig D., Spruck C. H., 3rd, Nichols P. W., Chaiwun B., Steven K., Groshen S., Chen S. C., Skinner D. G., Jones P. A., Cote R. J. p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Am J Pathol. 1993 Nov;143(5):1389–1397. [PMC free article] [PubMed] [Google Scholar]
  11. Flørenes V. A., Oyjord T., Holm R., Skrede M., Børresen A. L., Nesland J. M., Fodstad O. TP53 allele loss, mutations and expression in malignant melanoma. Br J Cancer. 1994 Feb;69(2):253–259. doi: 10.1038/bjc.1994.48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hartwell L. H., Kastan M. B. Cell cycle control and cancer. Science. 1994 Dec 16;266(5192):1821–1828. doi: 10.1126/science.7997877. [DOI] [PubMed] [Google Scholar]
  13. Kagie M. J., Kenter G. G., Tollenaar R. A., Hermans J., Trimbos J. B., Fleuren G. J. p53 protein overexpression is common and independent of human papillomavirus infection in squamous cell carcinoma of the vulva. Cancer. 1997 Oct 1;80(7):1228–1233. doi: 10.1002/(sici)1097-0142(19971001)80:7<1228::aid-cncr5>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  14. Kennedy S. M., Macgeogh C., Jaffe R., Spurr N. K. Overexpression of the oncoprotein p53 in primary hepatic tumors of childhood does not correlate with gene mutations. Hum Pathol. 1994 May;25(5):438–442. doi: 10.1016/0046-8177(94)90114-7. [DOI] [PubMed] [Google Scholar]
  15. Kessis T. D., Slebos R. J., Han S. M., Shah K., Bosch X. F., Muñoz N., Hedrick L., Cho K. R. p53 gene mutations and MDM2 amplification are uncommon in primary carcinomas of the uterine cervix. Am J Pathol. 1993 Nov;143(5):1398–1405. [PMC free article] [PubMed] [Google Scholar]
  16. King L. A., Okagaki T., Gallup D. G., Twiggs L. B., Messing M. J., Carson L. F. Mitotic count, nuclear atypia, and immunohistochemical determination of Ki-67, c-myc, p21-ras, c-erbB2, and p53 expression in granulosa cell tumors of the ovary: mitotic count and Ki-67 are indicators of poor prognosis. Gynecol Oncol. 1996 May;61(2):227–232. doi: 10.1006/gyno.1996.0130. [DOI] [PubMed] [Google Scholar]
  17. Kohlberger P., Kainz C., Breitenecker G., Gitsch G., Sliutz G., Kölbl H., Tschachler E., Reinthaller A. Prognostic value of immunohistochemically detected p53 expression in vulvar carcinoma. Cancer. 1995 Nov 15;76(10):1786–1789. doi: 10.1002/1097-0142(19951115)76:10<1786::aid-cncr2820761016>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  18. Lane D. P. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. doi: 10.1038/358015a0. [DOI] [PubMed] [Google Scholar]
  19. Lassam N. J., From L., Kahn H. J. Overexpression of p53 is a late event in the development of malignant melanoma. Cancer Res. 1993 May 15;53(10 Suppl):2235–2238. [PubMed] [Google Scholar]
  20. Marchetti A., Buttitta F., Pellegrini S., Merlo G., Chella A., Angeletti C. A., Bevilacqua G. mdm2 gene amplification and overexpression in non-small cell lung carcinomas with accumulation of the p53 protein in the absence of p53 gene mutations. Diagn Mol Pathol. 1995 Jun;4(2):93–97. doi: 10.1097/00019606-199506000-00004. [DOI] [PubMed] [Google Scholar]
  21. McCann A. H., Kirley A., Carney D. N., Corbally N., Magee H. M., Keating G., Dervan P. A. Amplification of the MDM2 gene in human breast cancer and its association with MDM2 and p53 protein status. Br J Cancer. 1995 May;71(5):981–985. doi: 10.1038/bjc.1995.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Milde-Langosch K., Albrecht K., Joram S., Schlechte H., Giessing M., Löning T. Presence and persistence of HPV infection and p53 mutation in cancer of the cervix uteri and the vulva. Int J Cancer. 1995 Nov 27;63(5):639–645. doi: 10.1002/ijc.2910630507. [DOI] [PubMed] [Google Scholar]
  23. Momand J., Zambetti G. P., Olson D. C., George D., Levine A. J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992 Jun 26;69(7):1237–1245. doi: 10.1016/0092-8674(92)90644-r. [DOI] [PubMed] [Google Scholar]
  24. Oliner J. D., Kinzler K. W., Meltzer P. S., George D. L., Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 1992 Jul 2;358(6381):80–83. doi: 10.1038/358080a0. [DOI] [PubMed] [Google Scholar]
  25. Prokocimer M., Rotter V. Structure and function of p53 in normal cells and their aberrations in cancer cells: projection on the hematologic cell lineages. Blood. 1994 Oct 15;84(8):2391–2411. [PubMed] [Google Scholar]
  26. Przygodzki R. M., Finkelstein S. D., Langer J. C., Swalsky P. A., Fishback N., Bakker A., Guinee D. G., Koss M., Travis W. D. Analysis of p53, K-ras-2, and C-raf-1 in pulmonary neuroendocrine tumors. Correlation with histological subtype and clinical outcome. Am J Pathol. 1996 May;148(5):1531–1541. [PMC free article] [PubMed] [Google Scholar]
  27. Quesnel B., Preudhomme C., Fournier J., Fenaux P., Peyrat J. P. MDM2 gene amplification in human breast cancer. Eur J Cancer. 1994;30A(7):982–984. doi: 10.1016/0959-8049(94)90128-7. [DOI] [PubMed] [Google Scholar]
  28. Shurbaji M. S., Kalbfleisch J. H., Thurmond T. S. Immunohistochemical detection of p53 protein as a prognostic indicator in prostate cancer. Hum Pathol. 1995 Jan;26(1):106–109. doi: 10.1016/0046-8177(95)90122-1. [DOI] [PubMed] [Google Scholar]
  29. Sun X. F., Carstensen J. M., Zhang H., Stål O., Wingren S., Hatschek T., Nordenskjöld B. Prognostic significance of cytoplasmic p53 oncoprotein in colorectal adenocarcinoma. Lancet. 1992 Dec 5;340(8832):1369–1373. doi: 10.1016/0140-6736(92)92558-w. [DOI] [PubMed] [Google Scholar]
  30. Vogt T., Zipperer K. H., Vogt A., Hölzel D., Landthaler M., Stolz W. p53-protein and Ki-67-antigen expression are both reliable biomarkers of prognosis in thick stage I nodular melanomas of the skin. Histopathology. 1997 Jan;30(1):57–63. doi: 10.1046/j.1365-2559.1996.d01-558.x. [DOI] [PubMed] [Google Scholar]
  31. Wu X., Bayle J. H., Olson D., Levine A. J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993 Jul;7(7A):1126–1132. doi: 10.1101/gad.7.7a.1126. [DOI] [PubMed] [Google Scholar]
  32. Xerri L., Bouabdallah R., Camerlo J., Hassoun J. Expression of the p53 gene in Hodgkin's disease: dissociation between immunohistochemistry and clinicopathological data. Hum Pathol. 1994 May;25(5):449–454. doi: 10.1016/0046-8177(94)90116-3. [DOI] [PubMed] [Google Scholar]
  33. Younes M., Lebovitz R. M., Bommer K. E., Cagle P. T., Morton D., Khan S., Laucirica R. p53 accumulation in benign breast biopsy specimens. Hum Pathol. 1995 Feb;26(2):155–158. doi: 10.1016/0046-8177(95)90031-4. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES