Advertisement
Research Article| Volume 50, ISSUE 3, P177-184, June 2008

Download started.

Ok

High expression of Ki-67 and cyclin D1 in invasive extramammary Paget's disease

      Summary

      Background

      Invasive extramammary Paget's disease (EMPD) is commonly associated with a poor prognosis. Although early detection of micro invasion can improve the prognosis, diagnosis is not always straightforward in some EMPD cases. Several clinical studies have proposed mechanisms underlying the increased invasiveness of EMPD; however, molecular markers indicative of the invasiveness have yet to be well characterized.

      Objective

      The purpose of this study was to identify a reliable immunohistochemical marker for predicting the risk of invasion and metastasis in EMPD cases.

      Methods

      A total of 32 specimens from 23 primary EMPD cases were analyzed by immunohistochemical staining. In formalin-fixed, paraffin-embedded tissue sections, immunolabeling of tumor cells were scored by stain intensity on a four-tiered scale. Using antibodies against several tumor proliferation markers, such as Her2, p53, Ki-67, cyclin D1 and Bcl-2, we determined the correlation between the expression of these molecular markers and the types of EMPD lesions (in situ, invasive or metastatic).

      Results

      In contrast to Her2, p53 and Bcl-2, which are similarly expressed among different types of lesions, Ki-67 and cyclin D1 are expressed at significantly higher levels in invasive lesions than in situ lesions (P < 0.01 and P < 0.05, respectively). Furthermore, the mean of the sum of Ki-67 and cyclin D1 expression scores was significantly higher in invasive lesions, compared to the scores obtained for in situ lesions. In addition, the difference was more significant (P ≤ 0.001) than each of these independent marker.

      Conclusion

      Combined high expression of Ki-67 and cyclin D1 was highly associated with invasive lesions of EMPD.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Dermatological Science
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Kanitakis J.
        Mammary and extramammary Paget's disease.
        J Eur Acad Dermatol Venereol. 2007; 21: 581-590
        • Zollo J.D.
        • Zeitouni N.C.
        The Roswell Park Cancer Institute experience with extramammary Paget's disease.
        Br J Dermatol. 2000; 142: 59-65
        • Evans A.T.
        • Neven P.
        Invasive adenocarcinoma arising in extramammary Paget's disease of the vulva.
        Histopathology. 1991; 18: 355-360
        • Murata Y.
        • Kumano K.
        • Tani M.
        Underpants-pattern erythema: a previously unrecognized cutaneous manifestation of extramammary Paget's disease of the genitalia with advanced metastatic spread.
        J Am Acad Dermatol. 1999; 40: 949-956
        • Batinac T.
        • Zamolo G.
        • Coklo M.
        • Hadzisejdic I.
        • Stemberger C.
        • Zauhar G.
        Expression of cell cycle and apoptosis regulatory proteins in keratoacanthoma and squamous cell carcinoma.
        Pathol Res Pract. 2006; 202: 599-607
        • Lebeau S.
        • Masouve I.
        • Berti M.
        • Auqsburger E.
        • Saurat J.H.
        • Borradori L.
        • et al.
        Comparative analysis of the expression of ERBIN and Erb-B2 in normal human skin and cutaneous carcinomas.
        Br J Dermatol. 2005; 152: 1248-1255
        • Liang S.B.
        • Furihata M.
        • Takeuchi T.
        • Iwata J.
        • Chen B.K.
        • Sonobe H.
        • et al.
        Overexpression of cyclin D1 in nonmelanocytic skin cancer.
        Virchows Arch. 2000; 436: 370-376
        • Hollstein M.
        • Sidransky D.
        • Vogelstein B.
        • Harris C.C.
        p53 mutations in human cancers.
        Science. 1991; 253: 49-53
        • Baker S.J.
        • Markowitz S.
        • Fearon E.R.
        • Willson J.K.
        • Vogelstein B.
        Suppression of human colorectal carcinoma cell growth by wild-type p53.
        Science. 1990; 249: 912-915
        • Sliutz G.
        • Schmidt W.
        • Tempfer C.
        • Speiser P.
        • Gitsch G.
        • Eder S.
        • et al.
        Detection of p53 point mutations in primary human vulvar cancer by PCR and temperature gradient gel electrophoresis.
        Gynecol Oncol. 1997; 64: 93-98
        • Hietanen S.H.
        • Kurvinen K.
        • Syrjänen K.
        • Grénman S.
        • Carey T.
        • McClatchey K.
        • et al.
        Mutation of tumor suppressor gene p53 is frequently found in vulvar carcinoma cells.
        Am J Obstet Gynecol. 1995; 173: 1477-1482
        • Hynes N.E.
        • stern D.F.
        The biology of erbB-2/neu/her-2 and its role in cancer.
        Biochim Biophys Acta. 1994; 1198: 165-184
        • Wells A.
        Tumor invasion: role of growth factor-induced cell motility.
        Adv Cancer Res. 2000; 78: 31-101
        • Olayioye M.A.
        • Neve R.M.
        • Lane H.A.
        • Hynes N.E.
        The ErbB signaling network: receptor heterodimerization in development and cancer.
        EMBO J. 2000; 19: 3159-3167
        • Slamon D.J.
        • Clark G.M.
        • Wong S.G.
        • Levin W.J.
        Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.
        Science. 1987; 235: 177-182
        • Dowsett M.
        • Bartlett J.
        • Ellis I.O.
        • Salter J.
        • Hills M.
        • Mallon E.
        • et al.
        Correlation between immunohistochemistry (Hercep Test) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centers.
        J Pathol. 2003; 199: 418-423
        • Hunter T.
        • pines J.
        Cyclins and cancer. II. Cyclin D and CDK inhibitors come of age.
        Cell. 1994; 79: 573-582
        • Gerdes J.
        Ki-67 and other proliferation markers useful for immunohistological diagnostic and prognostic evaluations in human malignancies.
        Semin Cancer Biol. 1990; 1: 199-206
        • Isola J.J.
        • Helin H.J.
        • Helle M.J.
        • Kallioniemi O.P.
        Evaluation of cell proliferation in breast carcinoma. Comparison of Ki-67 immunohistochemical study, DNA flow cytometric analysis, and mitotic count.
        Cancer. 1990; 65: 1180-1184
        • Bouzubar N.
        • Walker K.J.
        • Griffiths K.
        • Ellis I.O.
        • Elston C.W.
        • Robertson J.F.
        • et al.
        Ki67 immunostaining in primary breast cancer: pathological and clinical associations.
        Br J Cancer. 1989; 59: 943-947
        • Hockenbery D.
        • Nunez G.
        • Milliman C.
        • Schreiber R.D.
        • Korsmeyer S.J.
        Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death.
        Nature. 1990; 348: 334-336
        • Lin N.
        • Uchi H.
        • Moroi Y.
        • Fukiwake N.
        • Dainichi T.
        • Takeuchi S.
        • et al.
        Expression of the p38 MAPK, NF-kappaB and cyclin D1 in extramammary Paget's disease.
        J Dermatol Sci. 2007; 45: 187-192
        • Ellis P.E.
        • Fong L.F.
        • Rolfe K.J.
        • Crow J.C.
        • Reid W.M.
        • Davidson T.
        • et al.
        The role of p53 and Ki67 in Paget's disease of the vulva and the breast.
        Gynecol Oncol. 2002; 86: 150-156
        • Takata M.
        • Fujimoto A.
        • Aoki H.
        • Hatta N.
        • Ooi A.
        • Takehara K.
        erbB-2 overexpression but no activation of beta-Catenin gene in extramammary Paget's disease.
        J Invest Dermatol. 1999; 113: 258-262
        • Meissner K.
        • Rivière A.
        • Haupt G.
        • Löning T.
        Study of neu-protein expression in mammary Paget's disease with and without underlying breast carcinoma and in extramammary Paget's disease.
        Am J Pathol. 1990; 137: 1305-1309
        • Brummer O.
        • Stegner H.E.
        • Böhmer G.
        • Kühnle H.
        • Petry K.U.
        HER-2/neu expression in Paget disease of the vulva and the female breast.
        Gynecol Oncol. 2004; 95: 336-340
        • Kanitakis J.
        • Thivolet J.
        • Claudy A.
        p53 protein expression in mammary and extramammary Paget's disease.
        Anticancer Res. 1993; 13: 2429-2433
        • Zhang C.
        • Zhang P.
        • Sung C.J.
        • Lawrence W.D.
        Overexpression of p53 is correlated with stromal invasion in extramammary Paget's disease of the vulva.
        Hum Pathol. 2003; 34: 880-885
        • Fu W.
        • Lobocki C.A.
        • Silberberg B.K.
        • Chelladurai M.
        • Young S.C.
        Molecular markers in Paget disease of the breast.
        J Surg Oncol. 2001; 77: 171-178
        • Joensuu H.
        • Pylkkanen L.
        • Toikkanen S.
        Bcl-2 protein expression and long-term survival in breast cancer.
        Am J Pathol. 1994; 145: 1191-1198
        • Bozzetti C.
        • Nizzoli R.
        • Naldi N.
        • Guazzi A.
        • Camisa R.
        • Bella M.A.
        • et al.
        Bcl-2 expression on fine-needle aspirates from primary breast carcinoma: correlation with other biologic factors.
        Cancer. 1999; 87: 224-230