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Concordance of the HER2 protein and gene status between primary and corresponding lymph node metastatic sites of extramammary Paget disease

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Abstract

Recent studies have reported the overexpression of human epidermal growth factor receptor 2 (HER2) in primary extramammary Paget disease (EMPD). These results indicate that therapies that target HER2 may be useful in treating metastatic EMPD, for which the prognosis is poor. However, there is limited information on the expression and gene amplification of HER2 in metastatic EMPD. Twenty-six corresponding lymph node metastatic sites of primary EMPD underwent immunohistochemical evaluation of HER2 protein overexpression. In cases of HER2 protein overexpression, further analysis into the amplification of the HER2 gene was undertaken using dual colored in situ hybridization. In the corresponding lymph node metastasis of EMPD, HER2 protein overexpression and gene amplification were detected in 38 % and 19 % of cases, respectively. In 22 out of 26 cases (85 %), there were no differences in HER2 protein overexpression between the primary tumors and the corresponding lymph node metastasis (kappa coefficient 0.65). Likewise, HER2 gene amplification status was concordant in 92 % of cases (kappa coefficient 0.75). HER2 status is in good overall concordance between primary tumors and the corresponding metastatic sites. As there was a discrepancy in a minority of cases, HER2 status should be evaluated at both the primary and the metastatic sites, whenever possible.

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References

  1. Londero AP et al (2013) A review of extramammary paget’s disease: clinical presentation, diagnosis, management and prognosis. J Med Med Sci 4(4):134–148

    Google Scholar 

  2. Lloyd J, Evans DJ, Flanagan AM (1999) Extension of extramammary Paget disease of the vulva to the cervix. J Clin Pathol 52(7):538–540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shepherd V, Davidson EJ, Davies-Humphreys J (2005) Extramammary Paget’s disease. BJOG 112(3):273–279

    Article  PubMed  Google Scholar 

  4. Mazoujian G, Pinkus GS, Haagensen DE Jr (1984) Extramammary Paget’s disease–evidence for an apocrine origin. An immunoperoxidase study of gross cystic disease fluid protein-15, carcinoembryonic antigen, and keratin proteins. Am J Surg Pathol 8(1):43–50

    Article  CAS  PubMed  Google Scholar 

  5. Hart WR, Millman JB (1977) Progression of intraepithelial Paget’s disease of the vulva to invasive carcinoma. Cancer 40(5):2333–2337

    Article  CAS  PubMed  Google Scholar 

  6. Hatta N et al (2008) Extramammary Paget’s disease: treatment, prognostic factors and outcome in 76 patients. Br J Dermatol 158(2):313–318

    CAS  PubMed  Google Scholar 

  7. Hata M et al (2014) Radiation therapy for lymph node metastasis from extramammary Paget’s disease. J Eur Acad Dermatol Venereol JEADV 28(7):873–877

    Article  CAS  PubMed  Google Scholar 

  8. Tanaka R et al (2013) Human epidermal growth factor receptor 2 protein overexpression and gene amplification in extramammary Paget disease. Br J Dermatol 168(6):1259–1266

    Article  CAS  PubMed  Google Scholar 

  9. Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7(7):505–516

    Article  CAS  PubMed  Google Scholar 

  10. Tai W, Mahato R, Cheng K (2010) The role of HER2 in cancer therapy and targeted drug delivery. J Control Release 146(3):264–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schelfhout VR et al (2000) Pathogenesis of Paget’s disease: epidermal heregulin-alpha, motility factor, and the HER receptor family. J Natl Cancer Inst 92(8):622–628

    Article  CAS  PubMed  Google Scholar 

  12. Choi YD et al (2005) Lymphovascular and marginal invasion as useful prognostic indicators and the role of c-erbB-2 in patients with male extramammary Paget’s disease: a study of 31 patients. J Urol 174(2):561–565

    Article  PubMed  Google Scholar 

  13. Mukai H (2010) Treatment strategy for HER2-positive breast cancer. Int J Clin Oncol 15(4):335–340

    Article  CAS  PubMed  Google Scholar 

  14. Wolff AC et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 131(1):18–43

    CAS  PubMed  Google Scholar 

  15. Brugmann A et al (2011) Testing HER2 in breast cancer: a comparative study on BRISH, FISH, and IHC. Appl Immunohistochem Mol Morphol AIMM 19(3):203–211

    Article  PubMed  Google Scholar 

  16. Horii R et al (2014) Comparison of dual-color in situ hybridization and fluorescence in situ hybridization in HER2 gene amplification in breast cancer. Breast Cancer 21(5):598–604

    Article  PubMed  Google Scholar 

  17. Nitta H et al (2008) Development of automated brightfield double in situ hybridization (BDISH) application for HER2 gene and chromosome 17 centromere (CEN 17) for breast carcinomas and an assay performance comparison to manual dual color HER2 fluorescence in situ hybridization (FISH). Diagn Pathol 3:41

    Article  PubMed  PubMed Central  Google Scholar 

  18. Viera AJ, Garrett JM (2005) Understanding interobserver agreement: the kappa statistic. Fam Med 37(5):360–363

    PubMed  Google Scholar 

  19. Tsuda H et al (2001) Detection of HER-2/neu (c-erb B-2) DNA amplification in primary breast carcinoma—Interobserver reproducibility and correlation with immunohistochemical HER-2 overexpression. Cancer 92(12):2965–2974

    Article  CAS  PubMed  Google Scholar 

  20. Dybdal N et al (2005) Determination of HER2 gene amplification by fluorescence in situ hybridization and concordance with the clinical trials immunohistochemical assay in women with metastatic breast cancer evaluated for treatment with trastuzumab. Breast Cancer Res Treat 93(1):3–11

    Article  CAS  PubMed  Google Scholar 

  21. Dowsett M et al (2003) Correlation between immunohistochemistry (HercepTest) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centres. J Pathol 199(4):418–423

    Article  CAS  PubMed  Google Scholar 

  22. Wolff AC et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31(31):3997–4013

    Article  PubMed  Google Scholar 

  23. Kennecke H et al (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28(20):3271–3277

    Article  PubMed  Google Scholar 

  24. Wakabayashi S et al (2012) Dramatic clinical response of relapsed metastatic extramammary Paget’s disease to trastuzumab monotherapy. Case Rep Dermatolog Med 2012:401362

    CAS  Google Scholar 

  25. Takahagi S et al (2009) Metastatic extramammary Paget’s disease treated with paclitaxel and trastuzumab combination chemotherapy. J Dermatol 36(8):457–461

    Article  CAS  PubMed  Google Scholar 

  26. Karam A et al (2008) HER-2/neu targeting for recurrent vulvar Paget’s disease A case report and literature review. Gynecol Oncol 111(3):568–571

    Article  CAS  PubMed  Google Scholar 

  27. Hanawa F et al (2011) A case of metastatic extramammary Paget’s disease responding to trastuzumab plus paclitaxel combination therapy. Case Rep Dermatol 3(3):223–227

    Article  PubMed  PubMed Central  Google Scholar 

  28. Vincent-Salomon A et al (2002) HER2 status in patients with breast carcinoma is not modified selectively by preoperative chemotherapy and is stable during the metastatic process. Cancer 94(8):2169–2173

    Article  CAS  PubMed  Google Scholar 

  29. Simon R et al (2001) Patterns of her-2/neu amplification and overexpression in primary and metastatic breast cancer. J Natl Cancer Inst 93(15):1141–1146

    Article  CAS  PubMed  Google Scholar 

  30. Shimizu C et al (2000) c-erbB-2 protein overexpression and p53 immunoreaction in primary and recurrent breast cancer tissues. J Surg Oncol 73(1):17–20

    Article  CAS  PubMed  Google Scholar 

  31. Tanner M, Jarvinen P, Isola J (2001) Amplification of HER-2/neu and topoisomerase IIalpha in primary and metastatic breast cancer. Cancer Res 61(14):5345–5348

    CAS  PubMed  Google Scholar 

  32. Xu R et al (2002) Amplification of Her-2/neu gene in Her-2/neu-overexpressing and -nonexpressing breast carcinomas and their synchronous benign, premalignant, and metastatic lesions detected by FISH in archival material. Mod Pathol 15(2):116–124

    Article  PubMed  Google Scholar 

  33. Carlsson J et al (2004) HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review. Br J Cancer 90(12):2344–2348

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Aoyama K et al (2010) A comparison of HER2/neu gene amplification and its protein overexpression between primary breast cancer and metastatic lymph nodes. Jpn J Clin Oncol 40(7):613–619

    Article  PubMed  Google Scholar 

  35. Niikura N et al (2012) Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J Clin Oncol 30(6):593–599

    Article  PubMed  Google Scholar 

  36. Houssami N et al (2011) HER2 discordance between primary breast cancer and its paired metastasis: tumor biology or test artefact? Insights through meta-analysis. Breast Cancer Res Treat 129(3):659–674

    Article  CAS  PubMed  Google Scholar 

  37. Edgerton SM et al (2003) erbB-2 (HER-2) and breast cancer progression. Appl Immunohistochem Mol Morphol AIMM 11(3):214–221

    Article  CAS  PubMed  Google Scholar 

  38. Symmans WF et al (1995) Breast cancer heterogeneity: evaluation of clonality in primary and metastatic lesions. Hum Pathol 26(2):210–216

    Article  CAS  PubMed  Google Scholar 

  39. Heppner GH (1989) Tumor cell societies. J Natl Cancer Inst 81(9):648–649

    Article  CAS  PubMed  Google Scholar 

  40. Kerbel RS (1990) Growth dominance of the metastatic cancer cell: cellular and molecular aspects. Adv Cancer Res 55:87–132

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are thankful to Sachiko Miura, M.T., Chizu Kina, M.T. and Ms. Kozue Suzuki for technical assistance. This work was supported in part by National Cancer Center Cancer Reserch Developing Fund (23-A-11, 23-A-17, 23-A-22) and Grant-in Aid for young scientists (B) Grant Number 25860979.

Authors’ Contributions

RT organized patient clinical data, carried out experimental works, and drafted the manuscript. YS made the main concept of the study, carried out experimental works, and drafted the manuscript. HT analyzed the results, made an interpretation of data and revised the manuscript. KN, AT and AT participated in organizing patient clinical data and helped to draft the manuscript. YF and MF revised the manuscript. NY participated in its design and coordination, revised the manuscript and gave final approval of the version to be published. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan

    Ryota Tanaka, Kenjiro Namikawa, Akira Takahashi, Arata Tsutsumida, Manabu Fujimoto & Naoya Yamazaki

  2. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan

    Yuko Sasajima & Hitoshi Tsuda

  3. Department of Dermatology, Tsukuba University, Ibaraki, Japan

    Ryota Tanaka, Yasuhiro Fujisawa & Manabu Fujimoto

  4. Department of Pathology, School of Medicine, Teikyo University, Tokyo, Japan

    Yuko Sasajima

  5. Second Department of Pathology, National Defense Medical College, Saitama, Japan

    Hitoshi Tsuda

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  1. Ryota Tanaka
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Correspondence to Ryota Tanaka.

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Tanaka, R., Sasajima, Y., Tsuda, H. et al. Concordance of the HER2 protein and gene status between primary and corresponding lymph node metastatic sites of extramammary Paget disease. Clin Exp Metastasis 33, 687–697 (2016). https://doi.org/10.1007/s10585-016-9804-z

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  • DOI: https://doi.org/10.1007/s10585-016-9804-z

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