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Biological Differential Diagnosis of Follicular Thyroid Tumor and Hürthle Cell Tumor on the Basis of Telomere Length and hTERT Expression

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

Abstract

Background

The most difficult thyroid tumors to diagnose by histology are follicular carcinomas (FTCs) and Hürthle cell carcinomas (HCCs). Telomere alteration and human telomerase reverse transcriptase (hTERT) expression have been observed in most human cancers and are known to be a feature of malignancy. The purpose of this study was to clarify whether hTERT protein expression and telomere alteration could be applicable biological markers for distinguishing FTC from HCC.

Methods

We investigated a total of 78 thyroid tumor cases, including 14 FTCs, 47 follicular adenomas (FTAs), 5 HCCs, and 12 Hürthle cell adenomas (HCAs). hTERT protein expression was examined by immunohistochemistry, and telomere length was determined by tissue quantitative fluorescence in situ hybridization.

Results

Positivity for hTERT protein expression was observed in 86 % of FTCs and 49 % of FTAs. Telomeres in FTCs were significantly shorter than those in FTAs. All HCCs and HCAs (100 %) expressed hTERT protein. Telomeres in HCCs were significantly shorter than those in HCAs.

Conclusions

Our results suggest that hTERT protein expression and telomere shortening would be applicable as biological markers to distinguish FTC from FTA. Previous studies have suggested that follicular tumor and Hürthle cell tumor should be classified biologically as distinct tumors. All Hürthle cell tumors expressed hTERT protein and HCCs had markedly shortened telomeres, suggesting that follicular tumor and Hürthle cell tumor might be biologically distinct entities.

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References

  1. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985–1995. Cancer. 1998;83:2638–48.

    Article  CAS  PubMed  Google Scholar 

  2. Passler C, Scheuba C, Prager G, Kaczirek K, Kaserer K, Zettinig G, Niederle B. Prognostic factors of papillary and follicular thyroid cancer: differences in an iodine-replete endemic goiter region. Endocr Relat Cancer. 2004;11:131–9.

    Article  CAS  PubMed  Google Scholar 

  3. Mazzaferri EL, Young RL, Oertel JE, Kemmerer WT, Page CP. Papillary thyroid carcinoma: the impact of therapy in 576 patients. Medicine. 1977;56:171–96.

    Article  CAS  PubMed  Google Scholar 

  4. Machens A, Holzhausen HJ, Dralle H. The prognostic value of primary tumor size in papillary and follicular thyroid carcinoma. Cancer. 2005;103:2269–73.

    Article  PubMed  Google Scholar 

  5. Yokozawa T, Miyauchi A, Kuma K, Sugawara M. Accurate and simple method of diagnosing thyroid nodules the modified technique of ultrasound-guided fine needle aspiration biopsy. Thyroid. 1995;5:141–5.

    Article  CAS  PubMed  Google Scholar 

  6. DeLellis RA, Lloyd RV, Heitz PV, Eng C, editors. World Health Organization classification of tumors. Pathology and genetics of tumors of endocrine organs. vol 49. Lyon: IRAC; 2004. p.134.

  7. Nikiforova MN, Biddinger PW, Caudill CM, Kroll TG, Nikiforov YE. PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am J Surg Pathol. 2002;26:1016–23.

    Article  PubMed  Google Scholar 

  8. Dettmer M, Vogetseder A, Durso MB, et al. MicroRNA expression array identifies novel diagnostic markers for conventional and oncocytic follicular thyroid carcinomas. J Clin Endocrinol Metab. 2013;98:E1–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Ganly I, Ricarte Filho J, Eng S, et al. Genomic dissection of Hurthle cell carcinoma reveals a unique class of thyroid malignancy. J Clin Endocrinol Metab. 2013;98:E962–72.

    Google Scholar 

  10. Kushchayeva Y, Duh QY, Kebebew E, D’Avanzo A, Clark OH. Comparison of clinical characteristics at diagnosis and during follow-up in 118 patients with Hurthle cell or follicular thyroid cancer. Am J Surg. 2008;195:457–62.

    Article  PubMed  Google Scholar 

  11. Shaha AR, Loree TR, Shah JP. Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery. 1995;118:1131–8.

    Article  CAS  PubMed  Google Scholar 

  12. Kushchayeva Y, Duh QY, Kebebew E, Clark OH. Prognostic indications for Hürthle cell cancer. World J Surg. 2004;28:1266–70.

    Article  PubMed  Google Scholar 

  13. Yutan E, Clark OH. Hürthle cell carcinoma. Curr Treat Options Oncol. 2001;2:331–5.

    Article  CAS  PubMed  Google Scholar 

  14. Lang W, Choritz H, Hundeshagen H. Risk factors in follicular thyroid carcinomas. A retrospective follow-up study covering a 14-year period with emphasis on morphological findings. Am J Surg Pathol. 1986;10:246–55.

    Article  CAS  PubMed  Google Scholar 

  15. Grant CS, Hay ID, Ryan JJ, Bergstralh EJ, Rainwater LM, Goellner JR. Diagnostic and prognostic utility of flow cytometric DNA measurements in follicular thyroid tumors. World J Surg. 1990;14:283–9.

    Article  CAS  PubMed  Google Scholar 

  16. Sugino K, Ito K, Mimura T, Kameyama K, Iwasaki H, Ito K. Hürthle cell tumor of the thyroid: analysis of 188 cases. World J Surg. 2001;25:1160–3.

    Article  CAS  PubMed  Google Scholar 

  17. Haigh PI, Urbach DR. The treatment and prognosis of Hürthle cell follicular thyroid carcinoma compared with its non-Hürthle cell counterpart. Surgery. 2005;138:1152–8.

    Article  PubMed  Google Scholar 

  18. Ito Y, Hirokawa M, Higashiyama T, et al. Prognosis and prognostic factors of follicular carcinoma in Japan: importance of postoperative pathological examination. World J Surg. 2007;31:1417–24.

    Article  PubMed  Google Scholar 

  19. Sugino K, Kameyama K, Ito K, et al. Does Hürthle cell carcinoma of the thyroid have a poorer prognosis than ordinary follicular thyroid carcinoma? Ann Surg Oncol. 2013;20:2944–50.

    Article  PubMed  Google Scholar 

  20. Blackburn EH. Structure and function of telomeres. Nature. 1991;350:569–73.

    Article  CAS  PubMed  Google Scholar 

  21. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–60.

    Article  CAS  PubMed  Google Scholar 

  22. von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002;27:339–44.

    Article  Google Scholar 

  23. Harley CB, Villeponteau B. Telomeres and telomerase in aging and cancer. Curr Opin Genet Dev. 1995;5:249–55.

    Article  CAS  PubMed  Google Scholar 

  24. de Lange T. Telomeres and senescence: ending the debate. Science. 1998;279:334–55.

    Article  PubMed  Google Scholar 

  25. DePinho RA. The age of cancer. Nature. 2000;408:248–54.

    Article  CAS  PubMed  Google Scholar 

  26. Svenson U, Roos G. Telomere length as a biological marker in malignancy. Biochim Biophys Acta. 2009;1792:317–23.

    Article  CAS  PubMed  Google Scholar 

  27. Wyatt HD, West SC, Beattie TL. InTERTpreting telomerase structure and function. Nucleic Acids Res. 2010;38:5609–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Kammori M, Nakamura K, Hashimoto M, Ogawa T, Kaminishi M, Takubo K. Clinical application of human telomerase reverse transcriptase gene expression in thyroid follicular tumors by fine-needle aspirations using in situ hybridization. Int J Oncol. 2003;22:985–91.

    CAS  PubMed  Google Scholar 

  29. Furugori E, Hirayama R, Nakamura K, Kammori M, Esaki Y, Takubo K. Telomere shortening in gastric carcinoma with aging despite telomerase activation. J Cancer Res Clin Oncol. 2000;126:481–5.

    Article  CAS  PubMed  Google Scholar 

  30. Nakamura K, Furugori E, Esaki Y, et al. Correlation of telomere lengths in normal and cancers tissue in the large bowel. Cancer Lett. 2000;158:179–84.

    Article  CAS  PubMed  Google Scholar 

  31. Kammori M, Takubo K, Nakamura K, et al. Telomerase activity and telomere length in benign and malignant human thyroid tissues. Cancer Lett. 2000;159:175–81.

    Article  CAS  PubMed  Google Scholar 

  32. O’Sullivan JN, Bronner MP, Brentnall TA, et al. Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet. 2002;32:280–4.

    Article  PubMed  Google Scholar 

  33. Meeker AK, Gage WR, Hicks JL, et al. Telomere length assessment in human archival tissues: combined telomere fluorescence in situ hybridization and immunostaining. Am J Pathol. 2002;160:1259–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Sugishita Y, Kammori M, Yamada O, et al. Amplification of the human epidermal growth factor receptor 2 gene in differentiated thyroid cancer correlates with telomere shortening. Int J Oncol. 2013;42:1589–96.

    CAS  PubMed  Google Scholar 

  35. Kammori M, Kanauchi H, Nakamura K, et al. Demonstration of human telomerase reverse transcriptase in human colorectal carcinomas by in situ hybridization. Int J Oncol. 2002;20:15–21.

    CAS  PubMed  Google Scholar 

  36. Aida J, Izumiyama-Shimomura N, Nakamura K, et al. Telomere length variations in 6 mucosal cell types of gastric tissue observed using a novel quantitative fluorescence in situ hybridization method. Hum Pathol. 2007;38:1192–200.

    Article  CAS  PubMed  Google Scholar 

  37. Kammori M, Izumiyama N, Nakamura K, et al. Telomere metabolism and diagnostic demonstration of telomere measurement in the human esophagus for distinguishing benign from malignant tissue by tissue quantitative fluorescence in situ hybridization. Oncology 2006;71:430–6.

    Article  PubMed  Google Scholar 

  38. Kawauchi K, Ihjima K, Yamada O. IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3′-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells. J Immunol. 2005;174:5261–69.

    Article  CAS  PubMed  Google Scholar 

  39. Kurabayashi R, Takubo K, Aida J, et al. Luminal and cancer cells in the breast show more rapid telomere shortening than myoepithelial cells and fibroblasts. Hum Pathol. 2008;39:1647–55.

    Article  CAS  PubMed  Google Scholar 

  40. Lo CY, Chan WF, Lam KY, Wan KY. Follicular thyroid carcinoma: the role of histology and staging systems in predicting survival. Ann Surg. 2005;242:708–15.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Lang BH, Lo CY, Chan WF, Lam KY, Wan KY. Prognostic factors in papillary and follicular thyroid carcinoma: their implications for cancer staging. Ann Surg Oncol. 2007;14:730–8.

    Article  PubMed  Google Scholar 

  42. Asari R, Koperek O, Scheuba C, Riss P, Kaserer K, Hoffmann M, Niederle B. Follicular thyroid carcinoma in an iodine-replete endemic goiter region: a prospectively collected, retrospectively analyzed clinical trial. Ann Surg. 2009;249:1023–31.

    Article  PubMed  Google Scholar 

  43. Heaphy CM, Baumgartner KB, Bisoffi M, Baumgartner RN, Griffith JK. Telomere DNA content predicts breast cancer-free survival interval. Clin Cancer Res. 2007;13:7037–43.

    Article  CAS  PubMed  Google Scholar 

  44. Donaldson L, Fordyce C, Gilliland F, et al. Association between outcome and telomere DNA content in prostate cancer. J Urol. 1999;162:1788–92.

    Article  CAS  PubMed  Google Scholar 

  45. Frías C, García-Aranda C, De Juan C, et al. Telomere shortening is associated with poor prognosis and telomerase activity correlates with DNA repair impairment in non-small cell lung cancer. Lung Cancer. 2008;60:416–25.

    Article  PubMed  Google Scholar 

  46. Wang Y, Meeker AK, Kowalski J, et al. Telomere length is related to alternative splice patterns of telomerase in thyroid tumors. Am J Pathol. 2011;179:1415–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Umbricht CB, Conrad GT, Clark DP, et al. Human telomerase reverse transcriptase gene expression and the surgical management of suspicious thyroid tumors. Clin Cancer Res. 2004;10:5762–8.

    Article  CAS  PubMed  Google Scholar 

  48. Wang Y, Kowalski J, Tsai HL, et al. Differentiating alternative splice variant patterns of human telomerase reverse transcriptase in thyroid neoplasms. Thyroid. 2008;18:1055–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Thomas GA, Williams D, Williams ED. The clonal origin of thyroid nodules and adenomas. Am J Pathol. 1989;134:141–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C. Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab. 2003;88:2745–52.

    Article  CAS  PubMed  Google Scholar 

  51. Sarquis MS, Weber F, Shen L, et al. High frequency of loss of heterozygosity in imprinted, compared with non imprinted, genomic regions in follicular thyroid carcinomas and atypical adenomas. J Clin Endocrinol Metab. 2006;91:262–9.

    Article  CAS  PubMed  Google Scholar 

  52. Thompson NW, Dunn EL, Batsakis JG, Nishiyama RH. Hürthle cell lesions of the thyroid gland. Surg Gynecol Obstet. 1974;139:555–60.

    CAS  PubMed  Google Scholar 

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Acknowledgment

The authors thank Dr. Mitsuyoshi Hirokawa (Kuma Hospital) for pathological diagnosis, Dr. Steven S. S. Poon (Terry Fox Laboratory, British Columbia Cancer Research Center) for preparation of software for measurement of telomere length, and also Miyoko Matsumoto (Kanaji Thyroid Hospital) for assistance with manuscript preparation.

Disclosures

None of the authors have any competing financial interests to declare.

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Authors and Affiliations

  1. Department of Laboratory, Kanaji Thyroid Hospital, Tokyo, Japan

    Yoshiyuki Sugishita PhD, Makoto Kammori MD, PhD, Kazuko Yamazaki BS & Tetsu Yamada MD, PhD

  2. Department of Surgery, Kanaji Thyroid Hospital, Tokyo, Japan

    Makoto Kammori MD, PhD, Tatsuya Fukumori MD, PhD, Kei-ichi Yoshikawa MD, PhD & Tetsu Yamada MD, PhD

  3. Department of Human Care, Teikyo Heisei University, Tokyo, Japan

    Osamu Yamada MD, PhD

  4. Division of Breast and Endocrine Surgery, Shinshu University School of Medicine, Nagano, Japan

    Ken-ichi Ito MD, PhD

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  1. Yoshiyuki Sugishita PhD
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  2. Makoto Kammori MD, PhD
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  3. Osamu Yamada MD, PhD
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  4. Kazuko Yamazaki BS
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Correspondence to Makoto Kammori MD, PhD.

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Sugishita, Y., Kammori, M., Yamada, O. et al. Biological Differential Diagnosis of Follicular Thyroid Tumor and Hürthle Cell Tumor on the Basis of Telomere Length and hTERT Expression. Ann Surg Oncol 21, 2318–2325 (2014). https://doi.org/10.1245/s10434-014-3552-6

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  • DOI: https://doi.org/10.1245/s10434-014-3552-6

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