Annals of Surgical Oncology

, Volume 14, Issue 12, pp 3403–3411 | Cite as

Cell Cycle Regulators Show Diagnostic and Prognostic Utility for Differentiated Thyroid Cancer

  • Adrienne Melck
  • Hamid Masoudi
  • Obi L. Griffith
  • Ashish Rajput
  • Graeme Wilkins
  • Sam Bugis
  • Steven J. M. Jones
  • Sam M. Wiseman
Endocrine Tumors Original Papers

Abstract

Background

Differentiated thyroid cancer (DTC) generally has a favorable outcome, but some patients develop local recurrence and/or distant metastases and ultimately die of their disease. Molecular markers that accurately predict tumor behavior are lacking. This study’s aim was to ascertain the role of cell cycle regulators in predicting malignant histology and tumor behavior in DTC.

Methods

Tissue microarrays consisting of 100 benign and 105 malignant thyroid lesions, plus 24 lymph node samples, were stained for p16, p21, p27, p53, p57, p63, cyclin D1, cyclin E, and mdm2. Statistical analysis was used to compare the expression of the markers in benign versus DTC lesions and correlate their expression with clinicopathologic characteristics.

Results

p16, p21, cyclin D1, and cyclin E showed significantly (P < .001) increased expression in DTCs compared with benign thyroid lesions (54.7% vs. 5%, 71.7% vs. 38%, 87.1% vs. 45.7%, and 72.3% vs. 37.4%, respectively). There was no significant difference in expression between benign lesions and DTC for the remaining markers. p16 expression correlated significantly with extrathyroidal tumor extension (P = .02) and the presence of cancer in lymph nodes (P = .03). A total of 73% vs. 45% of the cancers of patients with and without lymph node involvement, respectively, stained positive for p16 (P = .01).

Conclusions

There is a statistically significant difference in the expression of p16, p21, cyclin D1, and cyclin E between DTCs and benign thyroid lesions, and p16 expression correlates with clinicopathologic variables predicting poor outcomes for DTC. These results suggest that evaluation of cell cycle derangement in thyroid tumors may serve as a useful tool for both DTC diagnosis and prognosis.

Keywords

Thyroid cancer Cell cycle regulators Tissue microarray 

References

  1. 1.
    Melck A, Bugis S, Baliski C, et al. Hemithyroidectomy: the preferred initial surgical approach for management of Hürthle cell neoplasm. Am J Surg 2006;191:593–7PubMedCrossRefGoogle Scholar
  2. 2.
    Wiseman SM, Baliski C, Irvine R, et al. Hemithyroidectomy: the optimal initial surgical approach for individuals undergoing surgery for a cytological diagnosis of follicular neoplasm. Ann Surg Oncol 2006;13:425–32PubMedCrossRefGoogle Scholar
  3. 3.
    Lundberg AS, Weinberg RA. Control of the cell cycle and apoptosis. Eur J Cancer 1999;35:531–9PubMedCrossRefGoogle Scholar
  4. 4.
    Yang A, McKeon F. P63 and P73: P53 mimics, menaces and more. Nat Rev Mol Cell Biol 2000;1:199–207PubMedCrossRefGoogle Scholar
  5. 5.
    Massague J. G1 cell-cycle control and cancer. Nature 2004;432(7015):298–306PubMedCrossRefGoogle Scholar
  6. 6.
    Michael D, Oren M. The p53–mdm2 module and the ubiquitin system. Semin Cancer Biol 2003;13:49–58PubMedCrossRefGoogle Scholar
  7. 7.
    van de Rijn M, Gilks CB. Applications of microarrays to histopathology. Histopathology 2004;44:97–108PubMedCrossRefGoogle Scholar
  8. 8.
    Nocito A, Kononen J, Kallioniemi OP, Sauter G. Tissue microarrays (TMAs) for high-throughput molecular pathology research. Int J Cancer 2001;94:1–5PubMedCrossRefGoogle Scholar
  9. 9.
    Parker RL, Huntsman DG, Lesack DW, et al. Assessment of interlaboratory variation in the immunohistochemical determination of estrogen receptor status using a breast cancer tissue microarray. Am J Clin Pathol 2002;117:723–8PubMedCrossRefGoogle Scholar
  10. 10.
    Ferenc T, Lewinski A, Lange D, et al. Analysis of p16INK4A protein expression in follicular thyroid tumors. Pol J Pathol 2004;55:143–8PubMedGoogle Scholar
  11. 11.
    Siironen P, Nordling S, Louhimo J, Haapiainen R, Haglund C. Immunohistochemical expression of Bcl-2, Ki-67, and p21 in patients with papillary thyroid cancer. Tumour Biol 2005;26:50–6PubMedCrossRefGoogle Scholar
  12. 12.
    Wang S, Wuu J, Savas L, Patwardhan N, Khan A. The role of cell cycle regulatory proteins, cyclin D1, cyclin E, and p27 in thyroid carcinogenesis. Hum Pathol 1998;29:1304–9PubMedCrossRefGoogle Scholar
  13. 13.
    Ferenc T, Lewinski A, Lange D, et al. Analysis of P53 and P21WAF1 proteins expression in follicular thyroid tumors. Pol J Pathol 2004;55:133–41PubMedGoogle Scholar
  14. 14.
    Ito Y, Yoshida H, Nakano K, et al. Expression of p57/Kip2 protein in normal and neoplastic thyroid tissues. Int J Mol Med 2002;9:373–6PubMedGoogle Scholar
  15. 15.
    Preto A, Reis-Filho JS, Ricardo S, Soares P. P63 expression in papillary and anaplastic carcinomas of the thyroid gland: lack of an oncogenetic role in tumorigenesis and progression. Pathol Res Pract 2002;198:449–54PubMedCrossRefGoogle Scholar
  16. 16.
    Horie S, Maeta H, Endo K, Ueta T, Takashima K, Terada T. Overexpression of p53 protein and MDM2 in papillary carcinomas of the thyroid: correlations with clinicopathologic features. Pathol Int 2001;51:11–5PubMedCrossRefGoogle Scholar
  17. 17.
    Simon R, Mirlacher M, Sauter G. Tissue microarrays in cancer diagnosis. Expert Rev Mol Diagn 2003;3:421–30PubMedCrossRefGoogle Scholar
  18. 18.
    Torhorst J, Bucher C, Kononen J, et al. Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol 2001;159:2249–56PubMedGoogle Scholar
  19. 19.
    Wiseman SM, Makretsov N, Nielsen TO, et al. Coexpression of the type 1 growth factor receptor family members HER-1, HER-2, and HER-3 has a synergistic negative prognostic effect on breast carcinoma survival. Cancer 2005;103:1770–7PubMedCrossRefGoogle Scholar
  20. 20.
    Cheang MC, Treaba DO, Speers CH, et al. Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1D5 in predicting survival. J Clin Oncol 2006;24:5637–44PubMedCrossRefGoogle Scholar
  21. 21.
    Wiseman SM, Masoudi H, Niblock P, et al. Anaplastic thyroid carcinoma: expression profile of targets for therapy offers new insights for disease treatment. Ann Surg Oncol 2007;14:719–29PubMedCrossRefGoogle Scholar
  22. 22.
    Liu CL, Prapong W, Natkunam Y, et al. Software tools for high-throughput analysis and archiving of immunohistochemistry staining data obtained with tissue microarrays. Am J Pathol 2002;161:1557–65PubMedGoogle Scholar
  23. 23.
    Cady B, Rossi R, Silverman M, Wool M. Further evidence of the validity of risk group definition in differentiated thyroid carcinoma. Surgery 1985;98:1171–8PubMedGoogle Scholar
  24. 24.
    Boltze C, Zack S, Quednow C, et al. Hypermethylation of the CDKN2/p16INK4A promoter in thyroid carcinogenesis. Pathol Res Pract 2003;199:399–404PubMedCrossRefGoogle Scholar
  25. 25.
    Lam AK, Lo CY, Leung P, Lang BH, Chan WF, Luk JM. Clinicopathological roles of alterations of tumor suppressor gene p16 in papillary thyroid carcinoma. Ann Surg Oncol 2007;14:1772–9PubMedCrossRefGoogle Scholar
  26. 26.
    Barroeta JE, Baloch ZW, Lal P, Pasha TL, Zhang PJ, LiVolsi VA. Diagnostic value of differential expression of CK19, Galectin-3, HBME-1, ERK, RET, and p16 in benign and malignant follicular-derived lesions of the thyroid: an immunohistochemical tissue microarray analysis. Endocr Pathol 2006;17:225–34PubMedCrossRefGoogle Scholar
  27. 27.
    Jain M, Khan A, Patwardhan N, et al. Follicular variant of papillary thyroid carcinoma: a comparative study of histopathologic features and cytology results in 141 patients. Endocr Pract 2001;7:79–84PubMedGoogle Scholar
  28. 28.
    Dong Y, Walsh MD, McGuckin MA, et al. Increased expression of cyclin-dependent kinase inhibitor 2 (CDKN2A) gene product P16INK4A in ovarian cancer is associated with progression and unfavorable prognosis. Int J Cancer 1997;74:57–63PubMedCrossRefGoogle Scholar
  29. 29.
    Evangelou K, Bramis J, Peros I, et al. Electron microscopy evidence that cytoplasmic localization of the p16(INK4A) “nuclear” cyclin-dependent kinase inhibitor (CKI) in tumor cells is specific and not an artifact. A study in non–small cell lung carcinomas. Biotech Histochem 2004;79:5–10Google Scholar
  30. 30.
    Arifin MT, Hama S, Kajiwara Y, et al. Cytoplasmic, but not nuclear, p16 expression may signal poor prognosis in high-grade astrocytomas. J Neurooncol 2006;77:273–7PubMedCrossRefGoogle Scholar
  31. 31.
    Shoji T, Tanaka F, Takata T, et al. Clinical significance of p21 expression in non–small-cell lung cancer. J Clin Oncol 2002;20:3865–71PubMedCrossRefGoogle Scholar
  32. 32.
    Gomyo Y, Ikeda M, Osaki M, et al. Expression of p21 (waf1/cip1/sdi1), but not p53 protein, is a factor in the survival of patients with advanced gastric carcinoma. Cancer 1997;79:2067–72PubMedCrossRefGoogle Scholar
  33. 33.
    Lu X, Toki T, Konishi I, Nikaido T, Fujii S. Expression of p21WAF1/CIP1 in adenocarcinoma of the uterine cervix: a possible immunohistochemical marker of a favorable prognosis. Cancer 1998;82:2409–17PubMedCrossRefGoogle Scholar
  34. 34.
    Pickett CA, Agoff SN, Widman TJ, Bronner MP. Altered expression of cyclins and cell cycle inhibitors in papillary thyroid cancer: prognostic implications. Thyroid 2005;15:461–73PubMedCrossRefGoogle Scholar
  35. 35.
    Basolo F, Pinchera A, Fugazzola L, et al. Expression of p21 ras protein as a prognostic factor in papillary thyroid cancer. Eur J Cancer 1994;30A:171–4PubMedCrossRefGoogle Scholar
  36. 36.
    Ito Y, Kobayashi T, Takeda T, et al. Expression of p21 (WAF1/CIP1) protein in clinical thyroid tissues. Br J Cancer 1996;74:1269–74PubMedGoogle Scholar
  37. 37.
    Khoo ML, Beasley NJ, Ezzat S, Freeman JL, Asa SL. Overexpression of cyclin D1 and underexpression of p27 predict lymph node metastases in papillary thyroid carcinoma. J Clin Endocrinol Metab 2002;87:1814–8PubMedCrossRefGoogle Scholar
  38. 38.
    Slingerland J, Pagano M. Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol 2000;183:10–7PubMedCrossRefGoogle Scholar
  39. 39.
    Basolo F, Caligo MA, Pinchera A, et al. Cyclin D1 overexpression in thyroid carcinomas: relation with clinico-pathological parameters, retinoblastoma gene product, and Ki67 labeling index. Thyroid 2000;10:741–6PubMedCrossRefGoogle Scholar
  40. 40.
    Lazzereschi D, Sambuco L, Carnovale Scalzo C, et al. Cyclin D1 and cyclin E expression in malignant thyroid cells and in human thyroid carcinomas. Int J Cancer 1998;76:806–11PubMedCrossRefGoogle Scholar
  41. 41.
    Muro-Cacho CA, Holt T, Klotch D, Mora L, Livingston S, Futran N. Cyclin D1 expression as a prognostic parameter in papillary carcinoma of the thyroid. Otolaryngol Head Neck Surg 1999;120:200–7PubMedCrossRefGoogle Scholar
  42. 42.
    Brzezinski J, Migodzinksi A, Gosek A, Tazbir J, Dedecjus M. Cyclin E expression in papillary thyroid carcinoma: relation to staging. Int J Cancer 2004;109:102–5PubMedCrossRefGoogle Scholar
  43. 43.
    Schwartz GK, Shah MA. Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol 2005;23:9408–21PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2007

Authors and Affiliations

  • Adrienne Melck
    • 1
  • Hamid Masoudi
    • 2
    • 3
  • Obi L. Griffith
    • 4
  • Ashish Rajput
    • 3
  • Graeme Wilkins
    • 5
  • Sam Bugis
    • 1
  • Steven J. M. Jones
    • 4
  • Sam M. Wiseman
    • 1
    • 3
  1. 1.Department of SurgerySt. Paul’s Hospital, University of British ColumbiaVancouverCanada
  2. 2.Department of PathologySt. Paul’s Hospital, University of British ColumbiaVancouverCanada
  3. 3.Genetic Pathology Evaluation Center at theProstate Research Center of Vancouver General Hospital, British Columbia Cancer Agency, and University of British ColumbiaVancouverCanada
  4. 4.Department of Medical GeneticsUniversity of British Columbia, British Columbia Cancer Agency, and Michael Smith Genome Sciences CenterVancouverCanada
  5. 5.Department of MedicineSt. Paul’s Hospital, University of British ColumbiaVancouverCanada

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