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Cyclin A in nonfunctioning pituitary adenomas

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Abstract

Purpose

Assess cyclin A in nonfunctioning pituitary adenomas (NFPA) and compare its expression in non-invasive and non-proliferative tumors with invasive and proliferative tumors (12× higher risk of recurrence).

Methods

Quantitative real time polymerase chain reaction to analyze cyclin A using normal pituitary gland as reference. Fold change (FC) > 1 was considered as increased. Tumor invasion was based on Knosp criteria (grades 3–4 considered invasive) and proliferation on the presence of at least two of three criteria: Ki-67 ≥ 3%; mitoses > 2/10; positive p53. Both groups were compared with Mann–Whitney test considering p value < 0.05 as statistically significant.

Results

Thirty-one patients with NFPA were included. Tumors were mainly of gonadotrophic origin (74.2%), followed by corticotrophic (19.4%) and lactotrophic (3.2%) origins and null-cell adenomas (3.2%). Median tumor diameter was 3.5 cm (1.8–8.0) and Ki-67 was 3.0% (0.3–11%). Sixteen patients had tumors classified as non-invasive and non-proliferative and 15 as invasive and proliferative. Median FC was 0.31 in all tumors (0.13–1.94). Cyclin A was not related to invasion or proliferation (FC 0.41 in non-invasive and non-proliferative tumors and FC 0.30 in invasive and proliferative tumors; p = 0.968). Four (12.9%) patients had tumors that exhibited increased cyclin A [median FC of 1.04 (1.02–1.94)]—three of gonadotrophic origin and one null-cell adenoma, with two tumors classified as non-invasive and non-proliferative and two tumors classified as invasive and proliferative. Median tumor diameter in these samples was 3.4 cm (2.4–3.6) and Ki-67 was 5.1% (2–11%).

Conclusions

Cyclin A was increased in a minority of NFPA and does not seem to be related to invasion or proliferation.

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References

  1. M.B.S. Lopes, The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathol. 134(4), 521–535 (2017). https://doi.org/10.1007/s00401-017-1769-8

    Article  CAS  PubMed  Google Scholar 

  2. S. Melmed, Pituitary tumors. Endocrinol. Metab. Clin. N. Am. 44(1), 1–9 (2015). https://doi.org/10.1016/j.ecl.2014.11.004

    Article  Google Scholar 

  3. Y. Greenman, N. Stern, Non-functioning pituitary adenomas. Best Pract. Res. Clin. Endocrinol. Metab. 23(5), 625–638 (2009). https://doi.org/10.1016/j.beem.2009.05.005

    Article  CAS  PubMed  Google Scholar 

  4. H. Buurman, W. Saeger, Subclinical adenomas in postmortem pituitaries: classification and correlations to clinical data. Eur. J. Endocrinol. 154(5), 753–758 (2006). https://doi.org/10.1530/eje.1.02107

    Article  CAS  PubMed  Google Scholar 

  5. W. Saeger, D.K. Ludecke, M. Buchfelder, R. Fahlbusch, H.J. Quabbe, S. Petersenn, Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur. J. Endocrinol. 156(2), 203–216 (2007). https://doi.org/10.1530/eje.1.02326

    Article  CAS  PubMed  Google Scholar 

  6. R.V. Lloyd, O.R., G. Klöppel, J. Rosai. WHO Classification of Tumours of Endocrine Organs, 4th edn. (IARC Press, Lyon, 2017).

  7. J.W. Tomlinson, N. Holden, R.K. Hills, K. Wheatley, R.N. Clayton, A.S. Bates, M.C. Sheppard, P.M. Stewart, Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 357(9254), 425–431 (2001)

    Article  CAS  PubMed  Google Scholar 

  8. D.S. Olsson, B.A. Bengtsson, Hypopituitarism-needs modern individualized treatment. Endocrine 56(1), 1–3 (2017). https://doi.org/10.1007/s12020-016-1211-3

    Article  CAS  PubMed  Google Scholar 

  9. J.R. Anderson, N. Antoun, N. Burnet, K. Chatterjee, O. Edwards, J.D. Pickard, N. Sarkies, Neurology of the pituitary gland. J. Neurol. Neurosurg. Psychiatry 66(6), 703–721 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. L.E. Wildemberg, A. Glezer, M.D. Bronstein, M.R. Gadelha, Apoplexy in nonfunctioning pituitary adenomas. Pituitary 21(2), 138–144 (2018). https://doi.org/10.1007/s11102-018-0870-x

    Article  PubMed  Google Scholar 

  11. L.N. Vieira, C.L. Boguszewski, L.A. Araujo, M.D. Bronstein, P.A. Miranda, N.R. Musolino, L.A. Naves, L. Vilar, A.J. Ribeiro-Oliveira, M.R. Gadelha, A review on the diagnosis and treatment of patients with clinically nonfunctioning pituitary adenoma by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism. Arch. Endocrinol. Metab. 60(4), 374–390 (2016). https://doi.org/10.1590/2359-3997000000179

    Article  Google Scholar 

  12. K. Boelaert, N.J. Gittoes, Radiotherapy for non-functioning pituitary adenomas. Eur. J. Endocrinol. 144(6), 569–575 (2001)

    Article  CAS  PubMed  Google Scholar 

  13. Y. Chen, C.D. Wang, Z.P. Su, Y.X. Chen, L. Cai, Q.C. Zhuge, Z.B. Wu, Natural history of postoperative nonfunctioning pituitary adenomas: a systematic review and meta-analysis. Neuroendocrinology 96(4), 333–342 (2012). https://doi.org/10.1159/000339823

    Article  CAS  PubMed  Google Scholar 

  14. B.W. Scheithauer, K.T. Kovacs, E.R. Laws Jr, R.V. Randall, Pathology of invasive pituitary tumors with special reference to functional classification. J. Neurosurg. 65(6), 733–744 (1986). https://doi.org/10.3171/jns.1986.65.6.0733

    Article  CAS  PubMed  Google Scholar 

  15. L. Kasuki, G. Raverot. Definition and diagnosis of aggressive pituitary tumors. Rev. Endocr. Metab. Disord. (2019). https://doi.org/10.1007/s11154-019-09531-x

  16. M.R. Gadelha, G. Trivellin, L.C. Hernandez Ramirez, M. Korbonits, Genetics of pituitary adenomas. Front. Horm. Res. 41, 111–140 (2013). https://doi.org/10.1159/000345673

    Article  CAS  PubMed  Google Scholar 

  17. R. Yu, S. Melmed, Pathogenesis of pituitary tumors. Prog. Brain Res. 182, 207–227 (2010). https://doi.org/10.1016/S0079-6123(10)82009-6

    Article  CAS  PubMed  Google Scholar 

  18. S. Melmed, Pathogenesis of pituitary tumors. Nat. Rev. Endocrinol. 7(5), 257–266 (2011). https://doi.org/10.1038/nrendo.2011.40

    Article  CAS  PubMed  Google Scholar 

  19. V. Quereda, M. Malumbres, Cell cycle control of pituitary development and disease. J. Mol. Endocrinol. 42(2), 75–86 (2009). https://doi.org/10.1677/JME-08-0146

    Article  CAS  PubMed  Google Scholar 

  20. C. Desdouets, G. Matesic, C.A. Molina, N.S. Foulkes, P. Sassone-Corsi, C. Brechot, J. Sobczak-Thepot, Cell cycle regulation of cyclin A gene expression by the cyclic AMP-responsive transcription factors CREB and CREM. Mol. Cell. Biol. 15(6), 3301–3309 (1995). https://doi.org/10.1128/mcb.15.6.3301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. A. Loukil, C.T. Cheung, N. Bendris, B. Lemmers, M. Peter, J.M. Blanchard, Cyclin A2: at the crossroads of cell cycle and cell invasion. World J. Biol. Chem. 6(4), 346–350 (2015). https://doi.org/10.4331/wjbc.v6.i4.346

    Article  PubMed  PubMed Central  Google Scholar 

  22. C. Miao, Z. Wang, J. Yang, J. Li, X. Gao, Expression and mutation analysis of Cyclin A and Ki-67 in glioma and their correlation with tumor progression. Oncol. Lett. 10(3), 1716–1720 (2015). https://doi.org/10.3892/ol.2015.3474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. C.H. Yam, T.K. Fung, R.Y. Poon, Cyclin A in cell cycle control and cancer. Cell. Mol. Life Sci. 59(8), 1317–1326 (2002). https://doi.org/10.1007/s00018-002-8510-y

    Article  CAS  PubMed  Google Scholar 

  24. S. Diederichs, N. Baumer, P. Ji, S.K. Metzelder, G.E. Idos, T. Cauvet, W. Wang, M. Moller, S. Pierschalski, J. Gromoll, M.G. Schrader, H.P. Koeffler, W.E. Berdel, H. Serve, C. Muller-Tidow, Identification of interaction partners and substrates of the cyclin A1-CDK2 complex. J. Biol. Chem. 279(32), 33727–33741 (2004). https://doi.org/10.1074/jbc.M401708200

    Article  CAS  PubMed  Google Scholar 

  25. H.E. Turner, Z. Nagy, N. Sullivan, M.M. Esiri, J.A. Wass, Expression analysis of cyclins in pituitary adenomas and the normal pituitary gland. Clin. Endocrinol. 53(3), 337–344 (2000)

    Article  CAS  Google Scholar 

  26. B. Henglein, X. Chenivesse, J. Wang, D. Eick, C. Brechot, Structure and cell cycle-regulated transcription of the human cyclin A gene. Proc. Natl Acad. Sci. USA 91(12), 5490–5494 (1994)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. A.R. Rosenberg, F. Zindy, F. Le Deist, H. Mouly, P. Metezeau, C. Brechot, E. Lamas, Overexpression of human cyclin A advances entry into S phase. Oncogene 10(8), 1501–1509 (1995)

    CAS  PubMed  Google Scholar 

  28. K. Allan, R.C. Jordan, L.C. Ang, M. Taylor, B. Young, Overexpression of cyclin A and cyclin B1 proteins in astrocytomas. Arch. Pathol. Lab. Med. 124(2), 216–220 (2000). https://doi.org/10.1043/0003-9985(2000)1242.0.CO;2

    Article  CAS  PubMed  Google Scholar 

  29. M. Furihata, T. Ishikawa, A. Inoue, C. Yoshikawa, H. Sonobe, Y. Ohtsuki, K. Araki, S. Ogoshi, Determination of the prognostic significance of unscheduled cyclin A overexpression in patients with esophageal squamous cell carcinoma. Clin. Cancer Res. 2(10), 1781–1785 (1996)

    CAS  PubMed  Google Scholar 

  30. R.D. Mashal, S. Lester, C. Corless, J.P. Richie, R. Chandra, K.J. Propert, A. Dutta, Expression of cell cycle-regulated proteins in prostate cancer. Cancer Res. 56(18), 4159–4163 (1996)

    CAS  PubMed  Google Scholar 

  31. J. Kushner, G. Bradley, B. Young, R.C. Jordan, Aberrant expression of cyclin A and cyclin B1 proteins in oral carcinoma. J. Oral Pathol. Med. 28(2), 77–81 (1999). https://doi.org/10.1111/j.1600-0714.1999.tb02000.x

    Article  CAS  PubMed  Google Scholar 

  32. J. Trouillas, P. Roy, N. Sturm, E. Dantony, C. Cortet-Rudelli, G. Viennet, J.F. Bonneville, R. Assaker, C. Auger, T. Brue, A. Cornelius, H. Dufour, E. Jouanneau, P. Francois, F. Galland, F. Mougel, F. Chapuis, L. Villeneuve, C.A. Maurage, D. Figarella-Branger, G. Raverot, A. Barlier, M. Bernier, F. Bonnet, F. Borson-Chazot, G. Brassier, S. Caulet-Maugendre, O. Chabre, P. Chanson, J.F. Cottier, B. Delemer, E. Delgrange, L. Di Tommaso, S. Eimer, S. Gaillard, M. Jan, J.J. Girard, V. Lapras, H. Loiseau, J.G. Passagia, M. Patey, A. Penfornis, J.Y. Poirier, G. Perrin, A. Tabarin,Members of HYPOPRONOS, A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathol. 126(1), 123–135 (2013). https://doi.org/10.1007/s00401-013-1084-y

    Article  PubMed  Google Scholar 

  33. R. Zahr, M. Fleseriu, Updates in diagnosis and treatment of acromegaly. Eur. Endocrinol. 14(2), 57–61 (2018). https://doi.org/10.17925/EE.2018.14.2.57

    Article  PubMed  PubMed Central  Google Scholar 

  34. L.K. Nieman, B.M. Biller, J.W. Findling, J. Newell-Price, M.O. Savage, P.M. Stewart, V.M. Montori, The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 93(5), 1526–1540 (2008). https://doi.org/10.1210/jc.2008-0125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. S. Melmed, F.F. Casanueva, A.R. Hoffman, D.L. Kleinberg, V.M. Montori, J.A. Schlechte, J.A. Wass, S. Endocrine, Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 96(2), 273–288 (2011). https://doi.org/10.1210/jc.2010-1692

    Article  CAS  PubMed  Google Scholar 

  36. E. Knosp, E. Steiner, K. Kitz, C. Matula, Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33(4), 610–617 (1993). https://doi.org/10.1227/00006123-199310000-00008. discussion 617-618

    Article  CAS  PubMed  Google Scholar 

  37. P. Lundin, F. Pedersen, Volume of pituitary macroadenomas: assessment by MRI. J. Comput. Assist. Tomogr. 16(4), 519–528 (1992). https://doi.org/10.1097/00004728-199207000-00004

    Article  CAS  PubMed  Google Scholar 

  38. 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). https://doi.org/10.1007/s12022-015-9398-z

    Article  CAS  PubMed  Google Scholar 

  39. M.E. Torregrosa-Quesada, A. Garcia-Martinez, S. Silva-Ortega, S. Martinez-Lopez, R. Camara, C. Fajardo, C. Lamas, I. Aranda, A. Pico. How valuable is the RT-qPCR of pituitary-specific transcription factors for identifying pituitary neuroendocrine tumor subtypes according to the new WHO 2017 criteria? Cancers 11(12), (2019). https://doi.org/10.3390/cancers11121990

  40. A. de Almeida Verdolin, E.B. Lamback, N. Ventura, A. Guasti, P.J. da Mata Pereira, M.R. Gadelha, L. Chimelli. Collision sellar lesions: coexistence of pituitary adenoma and Rathke cleft cyst-a single-center experience. Endocrine (2019). https://doi.org/10.1007/s12020-019-02149-8

  41. K.R. Normann, K.A.B. Oystese, J.P. Berg, T. Lekva, J. Berg-Johnsen, J. Bollerslev, N.C. Olarescu, Selection and validation of reliable reference genes for RT-qPCR analysis in a large cohort of pituitary adenomas. Mol. Cell. Endocrinol. 437, 183–189 (2016). https://doi.org/10.1016/j.mce.2016.08.030

    Article  CAS  PubMed  Google Scholar 

  42. 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). https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  43. M. Musat, V.V. Vax, N. Borboli, M. Gueorguiev, S. Bonner, M. Korbonits, A.B. Grossman, Cell cycle dysregulation in pituitary oncogenesis. Front. Horm. Res. 32, 34–62 (2004). https://doi.org/10.1159/000079037

    Article  CAS  PubMed  Google Scholar 

  44. H. Nakabayashi, I. Sunada, M. Hara, Immunohistochemical analyses of cell cycle-related proteins, apoptosis, and proliferation in pituitary adenomas. J. Histochem. Cytochem. 49(9), 1193–1194 (2001). https://doi.org/10.1177/002215540104900916

    Article  CAS  PubMed  Google Scholar 

  45. G. O’Hurley, E. Sjostedt, A. Rahman, B. Li, C. Kampf, F. Ponten, W.M. Gallagher, C. Lindskog, Garbage in, garbage out: a critical evaluation of strategies used for validation of immunohistochemical biomarkers. Mol. Oncol. 8(4), 783–798 (2014). https://doi.org/10.1016/j.molonc.2014.03.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. H.P. Sinn, A. Schneeweiss, M. Keller, K. Schlombs, M. Laible, J. Seitz, S. Lakis, E. Veltrup, P. Altevogt, S. Eidt, R.M. Wirtz, F. Marme, Comparison of immunohistochemistry with PCR for assessment of ER, PR, and Ki-67 and prediction of pathological complete response in breast cancer. BMC Cancer 17(1), 124 (2017). https://doi.org/10.1186/s12885-017-3111-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. C. Ramirez, S. Cheng, G. Vargas, S.L. Asa, S. Ezzat, B. Gonzalez, L. Cabrera, G. Guinto, M. Mercado, Expression of Ki-67, PTTG1, FGFR4, and SSTR 2, 3, and 5 in nonfunctioning pituitary adenomas: a high throughput TMA, immunohistochemical study. J. Clin. Endocrinol. Metab. 97(5), 1745–1751 (2012). https://doi.org/10.1210/jc.2011-3163

    Article  CAS  PubMed  Google Scholar 

  48. I. Kalaszczynska, Y. Geng, T. Iino, S. Mizuno, Y. Choi, I. Kondratiuk, D.P. Silver, D.J. Wolgemuth, K. Akashi, P. Sicinski, Cyclin A is redundant in fibroblasts but essential in hematopoietic and embryonic stem cells. Cell 138(2), 352–365 (2009). https://doi.org/10.1016/j.cell.2009.04.062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. F. Traganos, Cycling without cyclins. Cell Cycle 3(1), 32–34 (2004)

    Article  CAS  PubMed  Google Scholar 

  50. S. Jordan, K. Lidhar, M. Korbonits, D.G. Lowe, A.B. Grossman, D. Cyclin, and cyclin E expression in normal and adenomatous pituitary. Eur. J. Endocrinol. 143(1), R1–R6 (2000). https://doi.org/10.1530/eje.0.143r001

    Article  CAS  PubMed  Google Scholar 

  51. N.A. Hibberts, D.J. Simpson, J.E. Bicknell, J.C. Broome, P.R. Hoban, R.N. Clayton, W.E. Farrell, Analysis of cyclin D1 (CCND1) allelic imbalance and overexpression in sporadic human pituitary tumors. Clin. Cancer Res. 5(8), 2133–2139 (1999)

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Diego de Araújo Santos and Heliomar Pereira Marcos for preparing the histopathological sections.

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Authors and Affiliations

  1. Neuroendocrinology Research Center/ Endocrinology Division, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Elisa B. Lamback, Leandro Kasuki & Mônica R. Gadelha

  2. Neuropathology and Molecular Genetics Laboratory, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil

    Alexandro Guterres, Carlos Henrique de Azeredo Lima, Debora Aparecida Silva, Aline Helen da Silva Camacho, Leila Chimelli & Mônica R. Gadelha

  3. Radiology Division, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil

    Monique Alvares Barbosa

  4. Pathology Division, Instituto Nacional do Câncer, Rio de Janeiro, Brazil

    Aline Helen da Silva Camacho

  5. Neuroendocrinology Division, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil

    Leandro Kasuki & Mônica R. Gadelha

  6. Endocrinology Division, Hospital Federal de Bonsucesso, Rio de Janeiro, Brazil

    Leandro Kasuki

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Lamback, E.B., Guterres, A., Barbosa, M.A. et al. Cyclin A in nonfunctioning pituitary adenomas. Endocrine 70, 380–387 (2020). https://doi.org/10.1007/s12020-020-02402-5

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