Abstract
Oral lichen planus (OLP) is a chronic muco-cutaneous inflammatory disease defined as a precancerous condition. We determined the expression patterns of proliferation markers topoisomerase IIα (topo IIα) and Ki-67 and an intermediated filament protein cytokeratin-19 (CK-19) in atrophic OLP. These markers were selected because our recent microarray analysis indicated they might aid in identification of potentially malignant lesions. The expression patterns were correlated with the DNA content of these lesions shown to be useful in detection lesions at risk for malignant transformation of OLP. A series of 81 formalin-fixed, paraffin-embedded biopsies from 70 patients suffering from atrophic OLP were immunostained with monoclonal antibodies against topo IIα, Ki-67 and CK-19 using standard methods. Of the 70 patients, there were eight patients who had dysplastic changes in OLP lesions. During the follow-up, altogether five patients got cancer in the OLP area even though no dysplastic changes were present in the preceding lesion. On light microscopy, 500 cells were examined in the basal and parabasal epithelial layers of biopsy samples at 400× magnification. All biopsy samples were topo IIα positive and approximately 70% of the counted cells were positive. Strong staining of topo IIα was significantly correlated with dysplasia (P = 0.019), basal cell hyperplasia (P = 0.005) and ulceration (P = 0.008) in the samples. Ki-67 was expressed in all samples but only 36% of the cells were positive. CK-19 positivity was found in 29% of the specimens. Histological parameters were not related to either Ki-67 or CK-19. The comparison of the staining patterns with the DNA content of lesions showed that strongly stained cells with topo IIα were significantly more frequent in the samples with 2.5cER higher than 15% than in those below 15% (P = 0.013; Mann–Whitney). The percentage of the measured cells is 2.5cER exceeding the 2.5c value on the DNA scale. We earlier showed that this cut-off value of 2.5cER discriminated DNA aneuploidy. To conclude, topo IIα is a proliferation and also an apoptotic marker in atrophic OLP lesions and it might have a predictive value in oral lichen planus lesions prone to develop malignancy.
Similar content being viewed by others
Abbreviations
- OLP:
-
Oral lichen planus
- topo IIα:
-
Topoisomerase IIα
- CK-19:
-
Cytokeratin-19
- ER:
-
Exceeding rate
- PI:
-
Proliferating index
References
Akimitsu N, Kamura K, Tone S, Sakaguchi A, Kikuchi A, Hamamoto H, Sekimizu K (2003) Induction of apoptosis by depletion of DNA topoisomerase IIalpha in mammalian cells. Biochem Biophys Res Commun 307:301–307
Berger JM, Gamblin SJ, Harrison SC, Wang JC (1996) Structure and mechanism of DNA topoisomerase II. Nature 379:225–232
Bloor BK, Malik FK, Odell EW, Morgan PR (1999) Quantitative assessment of apoptosis in oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88:187–195
Brown DC, Gatter KC (1990) Monoclonal antibody Ki-67: its use in histopathology. Histopathology 17:489–503
Bruno S, Darzynkiewicz Z (1992) Cell cycle dependent expression and stability of the nuclear protein detected by Ki-67 antibody in HL-60 cells. Cell Prolif 25:31–40
Brustmann H, Naude S (2002) Expression of topoisomerase IIalpha, Ki-67, proliferating cell nuclear antigen, p53, and argyrophilic nucleolar organizer regions in vulvar squamous lesions. Gynecol Oncol 86:192–199
Davies L, Hardin NJ, Beatty BG (2006) Can Ki-67 predict recurrence of NO squamous cell carcinoma of the tongue? Ann Otol Rhinol Laryngol 115:12–17
Dissanayake U, Johnson NW, Warnakulasuriya KA (2003) Comparison of cell proliferation in the centre and advancing fronts of oral squamous cell carcinomas using Ki-67 index. Cell Prolif 36:255–264
Gibbons D, Fogt F, Kasznica J, Holden J, Nikulasson S (1997) Comparison of topoisomerase II alpha and MIB-1 expression in uterine cervical squamous lesions. Mod Pathol 10:409–413
Girod SC, Pfeiffer P, Ries J, Pape HD (1998) Proliferative activity and loss of function of tumour suppressor genes as ‘biomarkers’ in diagnosis and prognosis of benign and preneoplastic oral lesions and oral squamous cell carcinoma. Br J Oral Maxillofac Surg 36:252–260
Gonzalez-Moles MA, Caballero R, Rodriguez-Archilla A, Ruiz-Avila I, Bravo I (1996) Prognosis value of the expression of Ki-67 for squamous cell carcinoma of the oral cavity. Acta Stomatol Belg 93:159–165
Hafian H, Venteo L, Sukhanova A, Nabiev I, Lefevre B, Pluot M (2004) Immunohistochemical study of DNA topoisomerase I, DNA topoisomerase II alpha, p53, and Ki-67 in oral preneoplastic lesions and oral squamous cell carcinomas. Hum Pathol 35:745–751
Heck MM, Earnshaw WC (1986) Topoisomerase II: a specific marker for cell proliferation. J Cell Biol 103:2569–2581
Heck MM, Hittelman WN, Earnshaw WC (1988) Differential expression of DNA topoisomerases I and II during the eukaryotic cell cycle. Proc Natl Acad Sci USA 85:1086–1090
Jalava P, Kuopio T, Juntti-Patinen L, Kotkansalo T, Kronqvist P, Collan Y (2006) Ki67 immunohistochemistry: a valuable marker in prognostication but with a risk of misclassification: proliferation subgroups formed based on Ki67 immunoreactivity and standardized mitotic index. Histopathology 48:674–682
Lindberg K, Rheinwald JG (1989) Suprabasal 40 kd keratin (K19) expression as an immunohistologic marker of premalignancy in oral epithelium. Am J Pathol 134:89–98
Lynch BJ, Guinee DG, Jr. Holden JA (1997) Human DNA topoisomerase II-alpha: a new marker of cell proliferation in invasive breast cancer. Hum Pathol 28:1180–1188
Mattila R, Alanen K, Syrjanen S (2004) DNA content as a prognostic marker of oral lichen planus with a risk of cancer development. Anal Quant Cytol Histol 26:278–284
McPherson JP, Goldenberg GJ (1998) Induction of apoptosis by deregulated expression of DNA topoisomerase IIalpha. Cancer Res 58:4519–4524
Mirtti T, Kallajoki M, Aaltonen M, Alanen K (2001) Cyclin A and Ki-67 with DNA content in benign and malignant prostatic epithelial lesions. Anal Quant Cytol Histol 23:229–237
Moll R (1998) Cytokeratins as markers of differentiation in the diagnosis of epithelial tumors. Subcell Biochem 31:205–262
Nie M, Zhong L, Zeng G, Li B (2002) The changes of cytokeratin 19 during oral carcinogenesis. Zhonghua Kou Qiang Yi Xue Za Zhi 37:187–190
Raybaud H, Fortin A, Bairati I, Morency R, Monteil RA, Tetu B (2000) Nuclear DNA content, an adjunct to p53 and Ki-67 as a marker of resistance to radiation therapy in oral cavity and pharyngeal squamous cell carcinoma. Int J Oral Maxillofac Surg 29:36–41
Roland NJ, Caslin AW, Bowie GL, Jones AS (1994) Has the cellular proliferation marker Ki67 any clinical relevance in squamous cell carcinoma of the head and neck? Clin Otolaryngol 19:13–18
Ruutu M, Johansson B, Grenman R, Syrjanen S (2005) Two different global gene expression profiles in cancer cell lines established from etiologically different oral carcinomas. Oncol Rep 14:1511–1517
Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182:311–322
Scully C, Beyli M, Ferreiro MC, Ficarra G, Gill Y, Griffiths M, Holmstrup P, Mutlu S, Porter S, Wray D (1998) Update on oral lichen planus: etiopathogenesis and management. Crit Rev Oral Biol Med 9:86–122
Stathopoulos GP, Kapranos N, Manolopoulos L, Papadimitriou C, Adamopoulos G (2000) Topoisomerase II alpha expression in squamous cell carcinomas of the head and neck. Anticancer Res 20:177–182
Taniguchi Y, Nagao T, Maeda H, Kameyama Y, Warnakulasuriya KA (2002) Epithelial cell proliferation in oral lichen planus. Cell Prolif 35 Suppl 1:103–109
van der Velden LA, Manni JJ, Ramaekers FC, Kuijpers W (1999) Expression of intermediate filament proteins in benign lesions of the oral mucosa. Eur Arch Otorhinolaryngol 256:514–519
Warnakulasuriya KA, Johnson NW (1996) Importance of proliferation markers in oral pathology. Curr Top Pathol 90:147–177
WHO World Health Organization Collaborating Centre for Oral Precancerous Lesions (1978) Definition of leukoplakia and related lesions; an aid to study precancer. Oral Surg Oral Med Oral Pathol 46:518–539
Willman JH, Holden JA (2000) Immunohistochemical staining for DNA topoisomerase II-alpha in benign, premalignant, and malignant lesions of the prostate. Prostate 42:280–286
Yoshida K, Yamaguchi T, Shinagawa H, Taira N, Nakayama KI, Miki Y (2006) Protein kinase C delta activates topoisomerase IIalpha to induce apoptotic cell death in response to DNA damage. Mol Cell Biol 26:3414–3431
Acknowledgments
The authors thank Mrs. Marja Uola for her assistance in histological sections. We acknowledge Dr. Kari Syrjänen for the statistical analysis. This study was supported by a grant from the Hilkka Brusiin Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mattila, R., Alanen, K. & Syrjänen, S. Immunohistochemical study on topoisomerase IIα, Ki-67 and cytokeratin-19 in oral lichen planus lesions. Arch Dermatol Res 298, 381–388 (2007). https://doi.org/10.1007/s00403-006-0711-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00403-006-0711-z