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

  • Endocrine Tumors
  • Original Papers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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.

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References

  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;191:593–7

    Article  PubMed  CAS  Google Scholar 

  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;13:425–32

    Article  PubMed  Google Scholar 

  3. Lundberg AS, Weinberg RA. Control of the cell cycle and apoptosis. Eur J Cancer 1999;35:531–9

    Article  PubMed  CAS  Google Scholar 

  4. Yang A, McKeon F. P63 and P73: P53 mimics, menaces and more. Nat Rev Mol Cell Biol 2000;1:199–207

    Article  PubMed  CAS  Google Scholar 

  5. Massague J. G1 cell-cycle control and cancer. Nature 2004;432(7015):298–306

    Article  PubMed  CAS  Google Scholar 

  6. Michael D, Oren M. The p53–mdm2 module and the ubiquitin system. Semin Cancer Biol 2003;13:49–58

    Article  PubMed  CAS  Google Scholar 

  7. van de Rijn M, Gilks CB. Applications of microarrays to histopathology. Histopathology 2004;44:97–108

    Article  PubMed  Google Scholar 

  8. Nocito A, Kononen J, Kallioniemi OP, Sauter G. Tissue microarrays (TMAs) for high-throughput molecular pathology research. Int J Cancer 2001;94:1–5

    Article  PubMed  CAS  Google Scholar 

  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;117:723–8

    Article  PubMed  Google Scholar 

  10. Ferenc T, Lewinski A, Lange D, et al. Analysis of p16INK4A protein expression in follicular thyroid tumors. Pol J Pathol 2004;55:143–8

    PubMed  CAS  Google Scholar 

  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;26:50–6

    Article  PubMed  CAS  Google Scholar 

  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;29:1304–9

    Article  PubMed  CAS  Google Scholar 

  13. Ferenc T, Lewinski A, Lange D, et al. Analysis of P53 and P21WAF1 proteins expression in follicular thyroid tumors. Pol J Pathol 2004;55:133–41

    PubMed  CAS  Google Scholar 

  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;9:373–6

    PubMed  CAS  Google Scholar 

  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;198:449–54

    Article  PubMed  CAS  Google Scholar 

  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;51:11–5

    Article  PubMed  CAS  Google Scholar 

  17. Simon R, Mirlacher M, Sauter G. Tissue microarrays in cancer diagnosis. Expert Rev Mol Diagn 2003;3:421–30

    Article  PubMed  CAS  Google Scholar 

  18. Torhorst J, Bucher C, Kononen J, et al. Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol 2001;159:2249–56

    PubMed  CAS  Google Scholar 

  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;103:1770–7

    Article  PubMed  CAS  Google Scholar 

  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;24:5637–44

    Article  PubMed  CAS  Google Scholar 

  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;14:719–29

    Article  PubMed  Google Scholar 

  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;161:1557–65

    PubMed  CAS  Google Scholar 

  23. Cady B, Rossi R, Silverman M, Wool M. Further evidence of the validity of risk group definition in differentiated thyroid carcinoma. Surgery 1985;98:1171–8

    PubMed  CAS  Google Scholar 

  24. Boltze C, Zack S, Quednow C, et al. Hypermethylation of the CDKN2/p16INK4A promoter in thyroid carcinogenesis. Pathol Res Pract 2003;199:399–404

    Article  PubMed  CAS  Google Scholar 

  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;14:1772–9

    Article  PubMed  Google Scholar 

  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;17:225–34

    Article  PubMed  CAS  Google Scholar 

  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;7:79–84

    PubMed  CAS  Google Scholar 

  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;74:57–63

    Article  PubMed  CAS  Google Scholar 

  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;79:5–10

    CAS  Google Scholar 

  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;77:273–7

    Article  PubMed  CAS  Google Scholar 

  31. Shoji T, Tanaka F, Takata T, et al. Clinical significance of p21 expression in non–small-cell lung cancer. J Clin Oncol 2002;20:3865–71

    Article  PubMed  CAS  Google Scholar 

  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;79:2067–72

    Article  PubMed  CAS  Google Scholar 

  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;82:2409–17

    Article  PubMed  CAS  Google Scholar 

  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;15:461–73

    Article  PubMed  CAS  Google Scholar 

  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:171–4

    Article  PubMed  CAS  Google Scholar 

  36. Ito Y, Kobayashi T, Takeda T, et al. Expression of p21 (WAF1/CIP1) protein in clinical thyroid tissues. Br J Cancer 1996;74:1269–74

    PubMed  CAS  Google Scholar 

  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;87:1814–8

    Article  PubMed  CAS  Google Scholar 

  38. Slingerland J, Pagano M. Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol 2000;183:10–7

    Article  PubMed  CAS  Google Scholar 

  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;10:741–6

    Article  PubMed  CAS  Google Scholar 

  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;76:806–11

    Article  PubMed  CAS  Google Scholar 

  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;120:200–7

    Article  PubMed  CAS  Google Scholar 

  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;109:102–5

    Article  PubMed  CAS  Google Scholar 

  43. Schwartz GK, Shah MA. Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol 2005;23:9408–21

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, St. Paul’s Hospital, University of British Columbia, C303-1081 Burrard Street, V6Z 1Y6, Vancouver, BC, Canada

    Adrienne Melck MD, MPH, Sam Bugis MD, FRCSC & Sam M. Wiseman MD, FRCSC

  2. Department of Pathology, St. Paul’s Hospital, University of British Columbia, C303-1081 Burrard Street, V6Z 1Y6, Vancouver, BC, Canada

    Hamid Masoudi MD

  3. Genetic Pathology Evaluation Center at the, Prostate Research Center of Vancouver General Hospital, British Columbia Cancer Agency, and University of British Columbia, Vancouver, BC, Canada

    Hamid Masoudi MD, Ashish Rajput MD & Sam M. Wiseman MD, FRCSC

  4. Department of Medical Genetics, University of British Columbia, British Columbia Cancer Agency, and Michael Smith Genome Sciences Center, Vancouver, BC, Canada

    Obi L. Griffith BSc & Steven J. M. Jones PhD

  5. Department of Medicine, St. Paul’s Hospital, University of British Columbia, C303-1081 Burrard Street, V6Z 1Y6, Vancouver, BC, Canada

    Graeme Wilkins MD, FRCP

Authors
  1. Adrienne Melck MD, MPH
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  2. Hamid Masoudi MD
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  3. Obi L. Griffith BSc
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  5. Graeme Wilkins MD, FRCP
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  6. Sam Bugis MD, FRCSC
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  8. Sam M. Wiseman MD, FRCSC
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Correspondence to Sam M. Wiseman MD, FRCSC.

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Melck, A., Masoudi, H., Griffith, O.L. et al. Cell Cycle Regulators Show Diagnostic and Prognostic Utility for Differentiated Thyroid Cancer. Ann Surg Oncol 14, 3403–3411 (2007). https://doi.org/10.1245/s10434-007-9572-8

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  • DOI: https://doi.org/10.1245/s10434-007-9572-8

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