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The changing faces of corticotroph cell adenomas: the role of prohormone convertase 1/3

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Abstract

The spectrum of corticotroph cell adenomas is very wide. Though rarely, silent corticotroph cell adenomas (SCA) may transform into corticotroph cell adenomas associated with Cushing’s disease (CD). The aim of the study was to investigate the role of prohormone convertase 1/3 (PC1/3) in the transformation of SCA into CD. We reviewed the records of 1259 consecutive endoscopic endonasal procedures for pituitary adenomas from 1998 to 2013. Of these, 132 were CD and 44 were SCA. During the follow-up, three patients with SCA showed a clear transformation from SCA into CD and underwent surgery once again to remove the recurrent tumour. The PC1/3 expression was analysed by both immunohistochemistry and quantitative real time-polymerase chain reaction (qRT-PCR) in primary and recurrent tumours. The immunohistochemical PC1/3 expression was negative or weak in the three patients in the initial phase of SCA, while a strong expression was observed in the majority of neoplastic cells in tissue specimens obtained from the same three patients at the time of recurrence as CD. The immunohistochemical PC1/3 expression showed a strict correlation with the PC1/3 levels obtained by qRT-PCR. In 14 cases of SCA with no change of phenotype during the follow-up, the immunohistochemical PC1/3 expression was low and strictly associated with the level of PC1/3 obtained by qRT-PCR both in primary (14/14 cases) and in recurrent tumours (4/4 cases). Our study provides insight into the crucial role of the PC1/3 protein in the transformation of phenotype from SCA to CD.

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References

  1. K. Kovacs, E. Horvath, T.A. Bayley, S.T. Hassaram, C. Ezrin, Silent corticotroph cell adenoma with lysosomal accumulation and crinophagy. A distinct clinicopathologic entity. Am. J. Med. 64(3), 492–499 (1978). doi:10.0002/93437890236-X

    Article  CAS  PubMed  Google Scholar 

  2. E. Horvath, K. Kovacs, D.W. Killinger, H.S. Smyth, M.E. Platts, W. Singer, Silent corticotropic adenomas of the human pituitary gland: a histologic, immunocytologic, and ultrastructural study. Am. J. Pathol. 98(3), 617–638 (1980)

    CAS  PubMed  PubMed Central  Google Scholar 

  3. B.W. Scheithauer, A.J. Jaap, E. Horvath, K. Kovacs, R.V. Lloyd, F.B. Meyer, E.R. Laws Jr., W.F. Young Jr., Clinically silent corticotroph tumors of the pituitary gland. Neurosurgery 47(3), 723–729 (2000). discussion 729–730

    CAS  PubMed  Google Scholar 

  4. G. Raverot, A. Wierinckx, E. Jouanneau, C. Auger, F. Borson-Chazot, J. Lachuer, M. Pugeat, J. Trouillas, Clinical, hormonal and molecular characterization of pituitary ACTH adenomas without (silent corticotroph adenomas) and with Cushing’s disease. Eur. J. Endocrinol. 163(1), 35–43 (2010). doi:10.1530/EJE-10-0076

    Article  CAS  PubMed  Google Scholar 

  5. E. Melcescu, A.W. Gannon, A.D. Parent, J.F. Fratkin, W.C. Nicholas, C.A. Koch, A. Galhom, Silent or subclinical corticotroph pituitary macroadenoma transforming into cushing disease: 11-year follow-up. Neurosurgery 72(1), E144–E146 (2013). doi:10.1227/NEU.0b013e3182750850

    Article  PubMed  Google Scholar 

  6. E. Jouanneau, A. Wierinckx, F. Ducray, V. Favrel, F. Borson-Chazot, J. Honnorat, J. Trouillas, G. Raverot, New targeted therapies in pituitary carcinoma resistant to temozolomide. Pituitary 15(1), 37–43 (2012). doi:10.1007/s11102-011-0341-0

    Article  CAS  PubMed  Google Scholar 

  7. T. Psaras, J. Honegger, R. Buslei, W. Saeger, D. Klein, D. Capper, R. Meyermann, M. Mittelbronn, Atypical type II silent corticotrophic adenoma developing into Cushing’s disease upon second recurrence. Exp. Clin. Endocrinol. Diabetes 115(9), 610–615 (2007). doi:10.1055/s-2007-984437

    Article  CAS  PubMed  Google Scholar 

  8. L.R. Salgado, M.C. Machado, A. Cukiert, B. Liberman, C.T. Kanamura, V.A. Alves, Cushing’s disease arising from a clinically nonfunctioning pituitary adenoma. Endocr. Pathol. 17(2), 191–199 (2006). doi:10.1385/EP:17:2:191

    Article  PubMed  Google Scholar 

  9. S.E. Baldeweg, J.R. Pollock, M. Powell, J. Ahlquist, A spectrum of behaviour in silent corticotroph pituitary adenomas. Br. J. Neurosurg. 19(1), 38–42 (2005). doi:10.1080/02688690500081230

    Article  CAS  PubMed  Google Scholar 

  10. T. Sano, K. Kovacs, S.L. Asa, S. Yamada, N. Sanno, S. Yokoyama, H. Takami, Pituitary adenoma with ‘honeycomb Golgi’ appearance showing a phenotypic change at recurrence from clinically nonfunctioning to typical Cushing disease. Endocr. Pathol. 13(2), 125–130 (2002). doi:10.1385/EP:13:2:125

    Article  PubMed  Google Scholar 

  11. R.G. Gheri, W. Boddi, F. Ammannati, J. Olivotto, C. Nozzoli, A. Franchi, L. Bordi, M.L. Luisi, P. Mennonna, Two-step development of a pituitary adenoma: from hyperprolactinemic syndrome to Cushing’s disease. J. Endocrinol. Invest. 20(4), 240–244 (1997)

    Article  CAS  Google Scholar 

  12. T. Mindermann, K. Kovacs, C.B. Wilson, Changes in the immunophenotype of recurrent pituitary adenomas. Neurosurgery 35(1), 39–44 (1994)

    Article  CAS  Google Scholar 

  13. R.A. Bonner, K. Mukai, J.H. Oppenheimer, Two unusual variants of Nelson’s syndrome. J. Clin. Endocrinol. Metab. 49(1), 23–29 (1979). doi:10.1210/jcem-49-1-23

    Article  CAS  PubMed  Google Scholar 

  14. S. Ohta, S. Nishizawa, Y. Oki, T. Yokoyama, H. Namba, Significance of absent prohormone convertase 1/3 in inducing clinically silent corticotroph pituitary adenoma of subtype I—immunohistochemical study. Pituitary 5(4), 221–223 (2002)

    Article  CAS  Google Scholar 

  15. V. Hook, L. Funkelstein, T. Toneff, C. Mosier, S.R. Hwang, Human pituitary contains dual cathepsin L and prohormone convertase processing pathway components involved in converting POMC into the peptide hormones ACTH, alpha-MSH, and beta-endorphin. Endocrine 35(3), 429–437 (2009). doi:10.1007/s12020-009-9163-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. A.W. Artenstein, S.M. Opal, Proprotein convertases in health and disease. N. Engl. J. Med. 365(26), 2507–2518 (2011). doi:10.1056/NEJMra1106700

    Article  CAS  PubMed  Google Scholar 

  17. T. Tateno, H. Izumiyama, M. Doi, T. Yoshimoto, M. Shichiri, N. Inoshita, K. Oyama, S. Yamada, Y. Hirata, Differential gene expression in ACTH-secreting and non-functioning pituitary tumors. Eur. J. Endocrinol. 157(6), 717–724 (2007). doi:10.1530/EJE-07-0428

    Article  CAS  PubMed  Google Scholar 

  18. I. Takumi, D.F. Steiner, N. Sanno, A. Teramoto, R.Y. Osamura, Localization of prohormone convertases 1/3 and 2 in the human pituitary gland and pituitary adenomas: analysis by immunohistochemistry, immunoelectron microscopy, and laser scanning microscopy. Mod. Pathol. 11(3), 232–238 (1998)

    CAS  PubMed  Google Scholar 

  19. R.V. Lloyd, L. Jin, X. Qian, B.W. Scheithauer, W.F. Young Jr., D.H. Davis, Analysis of the chromogranin A post-translational cleavage product pancreastatin and the prohormone convertases PC2 and PC3 in normal and neoplastic human pituitaries. Am. J. Pathol. 146(5), 1188–1198 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  20. L. Scopsi, M. Gullo, F. Rilke, S. Martin, D.F. Steiner, Proprotein convertases (PC1/PC3 and PC2) in normal and neoplastic human tissues: their use as markers of neuroendocrine differentiation. J. Clin. Endocrinol. Metab 80(1), 294–301 (1995). doi:10.1210/jcem.80.1.7829629

    Article  CAS  PubMed  Google Scholar 

  21. A. Righi, L. Morandi, E. Leonardi, A. Farnedi, G. Marucci, A. Sisto, G. Frank, M. Faustini-Fustini, M. Zoli, D. Mazzatenta, R. Agati, M.P. Foschini, Galectin-3 expression in pituitary adenomas as a marker of aggressive behavior. Hum. Pathol. 44(11), 2400–2409 (2013). doi:10.1016/j.humpath.2013.05.020

    Article  CAS  PubMed  Google Scholar 

  22. A. Righi, L. Jin, S. Zhang, G. Stilling, B.W. Scheithauer, K. Kovacs, R.V. Lloyd, Identification and consequences of galectin-3 expression in pituitary tumors. Mol. Cell. Endocrinol. 326(1-2), 8–14 (2010). doi:10.1016/j.mce.2010.04.026

    Article  CAS  PubMed  Google Scholar 

  23. O. Mete, S.L. Asa, Clinicopathological correlations in pituitary adenomas. Brain Pathol. 22(4), 443–453 (2012). doi:10.1111/j.1750-3639.2012.00599.x

    Article  PubMed  Google Scholar 

  24. O. Mete, S.L. Asa, Therapeutic implications of accurate classification of pituitary adenomas. Semin. Diagn. Pathol. 30(3), 158–164 (2013). doi:10.1053/j.semdp.2013.06.002

    Article  PubMed  Google Scholar 

  25. H. Nishioka, N. Inoshita, O. Mete, S.L. Asa, K. Hayashi, A. Takeshita, N. Fukuhara, M. Yamaguchi-Okada, Y. Takeuchi, S. Yamada, The complementary role of transcription factors in the accurate diagnosis of clinically nonfunctioning pituitary adenomas. Endocr. Pathol. 26(4), 349–355 (2015). doi:10.1007/s12022-015-9398-z

    Article  CAS  PubMed  Google Scholar 

  26. H. Alahmadi, D. Lee, J.R. Wilson, C. Hayhurst, O. Mete, F. Gentili, S.L. Asa, G. Zadeh, Clinical features of silent corticotroph adenomas. Acta. Neurochir. (Wien.) 154(8), 1493–1498 (2012). doi:10.1007/s00701-012-1378-1

    Article  Google Scholar 

  27. M. Zoli, M. Faustini-Fustini, D. Mazzatenta, G. Marucci, E. De Carlo, A. Bacci, E. Pasquini, G. Lanzino, G. Frank, ACTH adenomas transforming their clinical expression: report of 5 cases. Neurosurg. Focus 38(2), E15 (2015). doi:10.3171/2014.11.FOCUS14679

    Article  PubMed  Google Scholar 

  28. G. Mustacchi, M.P. Sormani, P. Bruzzi, A. Gennari, F. Zanconati, D. Bonifacio, A. Monzoni, L. Morandi, Identification and validation of a new set of five genes for prediction of risk in early breast cancer. Int. J. Mol. Sci. 14(5), 9686–9702 (2013). doi:10.3390/ijms14059686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. K.J. Livak, T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4), 402–408 (2001). doi:10.1006/meth.2001.1262

    Article  CAS  Google Scholar 

  30. S. Gibson, D.W. Ray, S.R. Crosby, T.L. Dornan, A.M. Jennings, J.S. Bevan, J.R. Davis, A. White, Impaired processing of proopiomelanocortin in corticotroph macroadenomas. J. Clin. Endocrinol. Metab. 81(2), 497–502 (1996). doi:10.1210/jcem.81.2.8636257

    Article  CAS  PubMed  Google Scholar 

  31. M. Reincke, B. Allolio, W. Saeger, D. Kaulen, W. Winkelmann, A pituitary adenoma secreting high molecular weight adrenocorticotropin without evidence of Cushing’s disease. J. Clin. Endocrinol. Metab. 65(6), 1296–1300 (1987). doi:10.1210/jcem-65-6-1296

    Article  CAS  PubMed  Google Scholar 

  32. Lila, A.R., Sarathi, V., Bandgar, T.R., Shah, N.S.: Paradoxical response to dexamethasone and spontaneous hypocortisolism in Cushing’s disease. BMJ Case Rep. 2013 (2013). doi:10.1136/bcr-2012-008035

  33. R.D. Brown, G.R. Van Loon, D.N. Orth, G.W. Liddle, Cushing’s disease with periodic hormonogenesis: one explanation for paradoxical response to dexamethasone. J. Clin. Endocrinol. Metab. 36(3), 445–451 (1973). doi:10.1210/jcem-36-3-445

    Article  CAS  PubMed  Google Scholar 

  34. V. Popovic, D. Micic, M. Nesovic, T. Howlett, I. Doniach, A. Kendereski, P. Djordjevic, D. Manojlovic, J. Micic, M. Besser, Cushing’s disease cycling over ten years. Exp. Clin. Endocrinol. 96(2), 143–148 (1990). doi:10.1055/s-0029-1211003

    Article  CAS  PubMed  Google Scholar 

  35. T. Miyoshi, F. Otsuka, J. Suzuki, K. Inagaki, M. Takeda, Y. Kano, T. Yamashita, T. Ogura, I. Date, Y. Tanaka, K. Hashimoto, H. Makino, Periodic secretion of adrenocorticotropin in a patient with Cushing’s disease manifested during pregnancy. Endocr. J. 52(3), 287–292 (2005). doi:10.1507/endocrj.52.287

    Article  PubMed  Google Scholar 

  36. S. Asano, H. Ooka, R. Okazaki, T. Ishikawa, H. Ochiai, M. Nakashima, F. Ide, I. Hasegawa, S. Miyawaki, H. Nakaguchi, M. Murakami, Y. Ogino, K. Takano, A. Matsuno, Long-term remission of cyclic Cushing’s disease that was diagnosed and treated surgically in non-active phase. Endocr. J. 54(3), 407–412 (2007). doi:JST.JSTAGE/endocrj/K06-218

    Article  PubMed  Google Scholar 

  37. V. Bonert, N. Bose, J.D. Carmichael, Cyclic Cushing’s disease with misleading inferior petrosal sinus sampling results during a trough phase. Neurosurg. Focus 38(2), E7 (2015). doi:10.3171/2014.12.FOCUS14780

    Article  PubMed  Google Scholar 

  38. K.I. Alexandraki, G.A. Kaltsas, A.M. Isidori, S.A. Akker, W.M. Drake, S.L. Chew, J.P. Monson, G.M. Besser, A.B. Grossman, The prevalence and characteristic features of cyclicity and variability in Cushing’s disease. Eur. J. Endocrinol. 160(6), 1011–1018 (2009). doi:10.1530/EJE-09-0046

    Article  CAS  PubMed  Google Scholar 

  39. N.J. Vaughan, C.M. Laroche, I. Goodman, M.J. Davies, J.S. Jenkins, Pituitary Cushing’s disease arising from a previously non-functional corticotrophic chromophobe adenoma. Clin. Endocrinol. (Oxf.) 22(2), 147–153 (1985)

    Article  CAS  Google Scholar 

  40. Y. Kojima, S. Suzuki, K. Yamamura, G. Ohhashi, I. Yamamoto, Comparison of ACTH secretion in Cushing’s adenoma and clinically silent corticotroph adenoma by cell immunoblot assay. Endocr. J. 49(3), 285–292 (2002)

    Article  CAS  Google Scholar 

  41. A. Matsuno, R. Okazaki, Y. Oki, T. Nagashima, Secretion of high-molecular-weight adrenocorticotropic hormone from a pituitary adenoma in a patient without Cushing stigmata. J. Neurosurg. 101(5), 874–877 (2004). doi:10.3171/jns.2004.101.5.0874 Case report

    Article  PubMed  Google Scholar 

  42. M.E. Cooper, R.M. Murray, R. Kalnins, J. Woodward, G. Jerums, The development of Cushing’s syndrome from a previously silent pituitary tumour. Aust. N.Z. J. Med. 17(2), 249–251 (1987)

    Article  CAS  Google Scholar 

  43. A.G. Lania, S. Ferrero, R. Pivonello, G. Mantovani, E. Peverelli, A. Di Sarno, P. Beck-Peccoz, A. Spada, A. Colao, Evolution of an aggressive prolactinoma into a growth hormone secreting pituitary tumor coincident with GNAS gene mutation. J. Clin. Endocrinol. Metab. 95(1), 13–17 (2010). doi:10.1210/jc.2009-1360

    Article  CAS  PubMed  Google Scholar 

  44. J. Hardy, M. Somma (eds.) Acromegaly. Surgical Treatment by Transsphenoidal Microsurgical Removal of the Pituitary Adenoma. (Raven Press, New York), 1979) 209–217

    Google Scholar 

  45. C.B. Wilson, A decade of pituitary microsurgery. The Herbert Olivecrona lecture. J. Neurosurg. 61(5), 814–833 (1984). doi:10.3171/jns.1984.61.5.0814

    Article  CAS  PubMed  Google Scholar 

  46. DeLellis R.A., Lloyd R.V., Heitz P.U., Eng C. (eds.) World Health Organization Classification of Tumors: Pathology and Genetics: Tumors of Endocrine Organs. (2004)Please provide name of publisher and place of publication in DeLellis et al. (2004).

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Acknowledgments

The authors thank the following members of the team for their contributions to patient care and data collection: Dr. Giorgio Frank for his skilful contribution as project manager of the Centre of Pituitary and Endoscopic Skullbase Surgery, IRCCS Institute of Neurological Sciences of Bologna (ISNB); Dr. Carmelo Sturiale, chief of the Neurosurgery Unit, IRCCS Institute of Neurological Sciences of Bologna (ISNB).

Funding

This research was supported with grants from Department of Biomedical and Neuromotor Sciences (DIBINEM) of the University of Bologna (Fund for Fundamentally Oriented Research).

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    Authors and Affiliations

    1. Department of Pathology, Rizzoli Institute, Bologna, Italy

      Alberto Righi

    2. IRCCS Institute of Neurological Sciences of Bologna (ISNB), Bellaria Hospital, Via Altura, 3, Bologna, 40139, Italy

      Marco Faustini-Fustini

    3. Department of Biomedical and Neuro-Muscular Sciences, Section of Anatomic Pathology ‘M.Malpighi’ at Bellaria Hospital, University of Bologna, Bologna, Italy

      Luca Morandi, Valentina Monti, Sofia Asioli & Maria Pia Foschini

    4. Department of Neurosurgery, Center of Pituitary Tumors and Endoscopic Skull Base Surgery, IRCCS Institute of Neurological Sciences of Bologna (ISNB), Bellaria Hospital, Bologna, Italy

      Diego Mazzatenta

    5. Department of Neuroradiology, IRCCS Institute of Neurological Sciences of Bologna (ISNB), Bologna, Italy

      Antonella Bacci

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    Alberto Righi and Marco Faustini-Fustini contributed equally to the study.

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    Righi, A., Faustini-Fustini, M., Morandi, L. et al. The changing faces of corticotroph cell adenomas: the role of prohormone convertase 1/3. Endocrine 56, 286–297 (2017). https://doi.org/10.1007/s12020-016-1028-0

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