Endocrine Pathology

, Volume 17, Issue 4, pp 387–398 | Cite as

Differential expression of human telomerase catalytic subunit mRNA by In situ hybridization in pheochromocytomas

  • Zuojie Luo
  • Jianling Li
  • Yinfen Qin
  • Yan Ma
  • Xinghuan Liang
  • Jing Xian
  • Decheng Lu
  • Minyi Wei
  • Jack Y. Yang
  • Mary Qu Yang
  • Zhiheng He
Clinical Research

Abstract

In pheochromocytomas, it is very difficult to predict malignant potential by conventional histology or immunohistochemical and molecular markers. We investigated the expression of human telomerase catalytic component (hTERT) mRNA, hTERT protein, Ki-67 antigen, and p27kip1 in pheochromocytomas (27 benign, 7 suspected malignant, and 7 malignant), and evaluated the possibility of expressions of these proteins, and hTERT mRNA serve as diagnostic markers for predicting the biological behavior of these tumors. All tumors showed the classical histology and typical immunohistochemical pattern. By in situ hybridization, hTERT mRNA was expressed in 5/7 malignant tumors (defined as the presence of metastasis and/or extensive local invasion) as compared with 3/27 benign tumors. We examined the hTERT by immunohistochemistry to confirm the mRNA. hTERT mRNA expression was correlated with hTERT protein expression. All benign tumors exhibited no immunopositivity or <1% of cells stained for Ki-67 antigen. Six out of seven malignant tumors have shown either hTERT mRNA expression or Ki-67 immunoreactivity While no statistical difference in p27kip1 expressions was observed among benign, malignant, and suspected malignant tumors, there was a statistical difference between the normal adrenal medulla samples and tumors (p<0.001). Thus, hTERT mRNA detection by in situ hybridization, hTERT expression, and Ki-67 antigen expression are all useful tools for differentiating malignant from benign pheochromocytomas.

Key Words

Pheochromocytoma hTERT mRNA hTERT Ki-67 p27kip1 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Nakamura TM, Cech TR. Reversing time: origin of telomerase. Cell 92: 587–590, 1998.PubMedCrossRefGoogle Scholar
  2. 2.
    Meyerson M. Role of relomerase in normal and cancer cells. J Clin Oncol 18: 2626–2634, 2000.PubMedGoogle Scholar
  3. 3.
    Kim NW, Piatyszek MA, Prowse KR, et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015, 1994.PubMedCrossRefGoogle Scholar
  4. 4.
    Tang SJ, Dumot JA, Wang L, et al. Telomerase activity in pancreatic endocrine tumors. Am J Gastroenterol 97(4):1022–1030, 2002.PubMedCrossRefGoogle Scholar
  5. 5.
    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 10:5762–5768, 2004.PubMedCrossRefGoogle Scholar
  6. 6.
    Orlando C, Gelmini S. Telomerase in endocrine and endocrine-dependent tumors. J Steroid Biochem Mol Biol 78(3):201–214, 2001.PubMedCrossRefGoogle Scholar
  7. 7.
    Michalides RJ. Cell cycle regulators: mechanisms and their role in aetiology, prognosis, and treatment of cancer. J Clin Pathol 52:555–568, 1999.PubMedGoogle Scholar
  8. 8.
    Hommura F, Dosaka-Akita H, Mishina T, et al. Prognostic significance of p27KIP1 protein and Ki-67 growth fraction in non-small cell lung cancers. Clin Cancer Res 6:4073–4081, 2000.PubMedGoogle Scholar
  9. 9.
    Manne U, Jhala NC, Jones J, et al. Prognostic significance of p27kip-1 expression in colorectal adenocarcinomas is associated with tumor stage. Clin Cancer Res 10:1743–1752, 2004.PubMedCrossRefGoogle Scholar
  10. 10.
    Schrantz N, Beney GE, Auffredou MT, et al. The expression of p18INK4 and p27kip1 cyclin-dependent kinase inhibitors is regulated differently during human B cell differentiation. J Immunol 165:4346–4352, 2000.PubMedGoogle Scholar
  11. 11.
    Motti ML, Califano D, Troncone G, et al. Complex regulation of the cyclin-dependent kinase inhbitor p27kipl in thyroid cancer cells by the PI3K/AKT pathway: regulation of p27kipl expression and localization. Am J Pathol 166:737–749, 2005.PubMedGoogle Scholar
  12. 12.
    Lloyd RV, Jin L, Qian X, et al. Aberrant p27kipl expression in endocrine and other tumors. Am J Pathol 150:401–407, 1997.PubMedGoogle Scholar
  13. 13.
    Pace V, Pharmates E, Germann PG. Pheochromocytomas and ganglioneuromas in the aging rats: morphological and immunohistochemical characterization. Toxicol Pathol 30(4):492–500, 2002.PubMedGoogle Scholar
  14. 14.
    Isobe K, Yashiro T, Omura S, et al. Expression of the human telomerase reverse transcriptase in pheochromocytoma and neuroblastoma tissues. Endocr J 51(1):47–52, 2004.PubMedCrossRefGoogle Scholar
  15. 15.
    Elder EE, Xu D, Hoog A, et al. KI-67 and hTERT expression can aid in the distinction between malignant and benign pheochromocytoma and paraganglioma. Mod Pathol 16(3):246–255, 2003.PubMedCrossRefGoogle Scholar
  16. 16.
    Thompson LD. Pheochromocytoma of the adrenal gland scaled score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 26(5):551–566, 2002.PubMedCrossRefGoogle Scholar
  17. 17.
    Linnoila RI, Keiser HR, Steinberg SM, et al. Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathologic study of 120 cases including unusual histologic features. Hum Pathol 21:1168–1180, 1990.PubMedCrossRefGoogle Scholar
  18. 18.
    van der Harst E, Bruining HA, Jaap Bonjer H, et al. Proliferative index in phaeochromocytomas: does it predict the occurrence of metastases? J Pathol 191:175–180, 2000.PubMedCrossRefGoogle Scholar
  19. 19.
    Kimura N, Watanabe T, Noshiro T, et al. Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extradrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol 16(1):23–32, 2005.PubMedCrossRefGoogle Scholar
  20. 20.
    Nakamura TM, Morin GB, Chapman KB, et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 277:955–959, 1997.PubMedCrossRefGoogle Scholar
  21. 21.
    Hadar T, Shvero J, Yaniv E, et al. Expression of p53, Ki-67 and Bcl-2 in parathyroid adenoma and residual normal tissue. Pathol. Oncol Res. 11(1):45–49, 2005.PubMedCrossRefGoogle Scholar
  22. 22.
    Bravaccini S, Sanchin MA, Amadori A, et al. Potential of telomerase expression and activity in cervical specimens as a diagnostic tool. J Clin Pathol 58(9):911–914, 2005.PubMedCrossRefGoogle Scholar
  23. 23.
    Culhaci N, Sagol O, Karademir S, et al. Expression of transforming growth factor beta-1 and p27Kipl in pancreatic adenocarcinomas: relation with cell-cycle-associated proteins and clinicopathologic characteristics. BMC Cancer 5:98, 2005.PubMedCrossRefGoogle Scholar
  24. 24.
    Catzavelos C, Bhattacharya N, Ung YC, et al. Decreased levels of the cell-cycle inhibitor p27Kipl protein: prognostic implications in primary breast cancer. Nat Med 3:227–230, 1997.PubMedCrossRefGoogle Scholar
  25. 25.
    Porter PL, Malone KE, Heagerty PJ, et al. Expression of cell-cycle regulators p27Kipl and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med 3:222–225, 1997.PubMedCrossRefGoogle Scholar
  26. 26.
    Horikawa I, Barrett JC. Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms. Carcinogenesis 24(7):1167–1176, 2003.PubMedCrossRefGoogle Scholar
  27. 27.
    Hiyama E, Hiyama K, Yokoyama T, et al. Correlating relomerase activity levels with human neuroblastoma outcomes. Nat Med 1:249–255, 1995.PubMedCrossRefGoogle Scholar
  28. 28.
    Boltze C, Mundschenk J, Unger N, et al. Expression profile of the telomeric complex discriminates between benign and malignant pheochromocytoma. J Clin Endocrinol Metabol 88(9):4280–4286, 2003.CrossRefGoogle Scholar
  29. 29.
    Kubota Y, Nakada T, Sasagawa I, et al. Elevated levels of telomerase activity in malignant pheochromocytoma, Cancer 82:176–179, 1998.PubMedCrossRefGoogle Scholar
  30. 30.
    Bamberger CM, Else T, Bamberger AM, et al. Telomerase activity in benign and malignant adrenal tumors. Exp Clin Endocrinol Diabetes 107:272–275, 1999.PubMedCrossRefGoogle Scholar
  31. 31.
    Isola JJ, Helin HJ, Helle MJ, et al. Evaluation of cell proliferation in breast carcinoma. Comparison of Ki-67 immunohistochemical study, DNA flow cytometric analysis and mitotic count. Cancer 65:1180–1184, 1990.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2006

Authors and Affiliations

  • Zuojie Luo
    • 1
  • Jianling Li
    • 1
  • Yinfen Qin
    • 1
  • Yan Ma
    • 1
  • Xinghuan Liang
    • 1
  • Jing Xian
    • 1
  • Decheng Lu
    • 1
  • Minyi Wei
    • 1
  • Jack Y. Yang
    • 2
  • Mary Qu Yang
    • 3
  • Zhiheng He
    • 4
  1. 1.Department of EndocrinologyGuangxi Medical University and First Affiliated HospitalNanning, GuangxiChina
  2. 2.Massachusetts General HospitalHarvard Medical School and Harvard UniversityBostonUSA
  3. 3.U.S. Department of Health and Human ServicesNational Human Genome Research InstituteRockvilleUSA
  4. 4.The Research DivisionIoslin Diabetes Center, Harvard Medical SchoolBostonUSA

Personalised recommendations