The silent variants of pituitary tumors: demographic, radiological and molecular characteristics



Tumors of the anterior pituitary gland (PTs) are mostly benign tumors with a low prevalence, which has nevertheless increased with advances in brain radiology techniques. Nearly half of PTs are not associated with a clinical endocrine syndrome. These tumors have been indistinctly named non-functioning pituitary adenomas (NFPAs) or silent pituitary tumors (SPTs) and the mechanisms of silencing are not fully known.


To study the frequency and characterize the silent variant of PTs in a large local series, and to assess their pituitary adenohypophyseal gene expression.


This observational, cross-sectional study was performed in a Pituitary Tumor Center of Excellence and involved 268 PTs. After identifying the different subtypes according to the immunohistochemical (IHC) expression of adenohypophyseal hormones, we studied their gene expression by RT-qPCR.


We found that silent tumors were larger and more invasive, but not more proliferative than their functional counterparts. The RT-qPCR complements the IHC typification of PTs, reducing the proportion of null-cell subtype. Finally, some silent PT subtype variants showed lower specific adenohypophyseal hormone gene expression than their functional counterparts, which may contribute to the absence of endocrine manifestations.


This paper highlights the importance of identifying the silent variant of the PTs subtypes. As expected, silent tumors were larger and more invasive than their functioning counterparts. However, there was no difference in the proliferation activity between them. Finally, the lower specific gene expression in the silent than in the functioning counterparts of some PTs subtypes gives insights into the silencing mechanisms of PTs.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.


  1. 1.

    Agustsson TT, Baldvinsdottir T, Jonasson JG et al (2015) The epidemiology of pituitary adenomas in Iceland, 1955–2012: a nationwide population-based study. Eur J Endocrinol 173(5):655–664.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Drummond J, Roncaroli F, Grossman AB, Korbonits M (2019) Clinical and pathological aspects of silent pituitary adenomas. J Clin Endocrinol Metab 104(7):2473–2489.

    Article  PubMed  Google Scholar 

  3. 3.

    Tjörnstrand A, Gunnarsson K, Evert M et al (2014) The incidence rate of pituitary adenomas in western Sweden for the period 2001–2011. Eur J Endocrinol 171(4):519–526.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Aflorei ED, Korbonits M (2014) Epidemiology and etiopathogenesis of pituitary adenomas. J Neurooncol 117(3):379–394.

    Article  PubMed  Google Scholar 

  5. 5.

    Fernandez A, Karavitaki N, Wass JAH (2010) Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf) 72(3):377–382.

    Article  Google Scholar 

  6. 6.

    Kontogeorgos G, Kovacs K, Horvath E, Scheithauer BW (1993) Null cell adenomas, oncocytomas, and gonadotroph adenomas of the human pituitary: an immunocytochemical and ultrastructural analysis of 300 cases. Endocr Pathol 4(1):20–27.

    Article  PubMed  Google Scholar 

  7. 7.

    Scheithauer BW, Jaap AJ, Horvath E et al (2000) Clinically silent corticotroph tumors of the pituitary gland. Neurosurgery 47(3):723–730.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Xu Z, Ellis S, Lee CC et al (2014) Silent corticotroph adenomas after stereotactic radiosurgery: a case–control study. Int J Radiat Oncol Biol Phys 90(4):903–910.

    Article  PubMed  Google Scholar 

  9. 9.

    Cho HY, Cho SW, Kim SW, Shin CS, Park KS, Kim SY (2010) Silent corticotroph adenomas have unique recurrence characteristics compared with other nonfunctioning pituitary adenomas. Clin Endocrinol (Oxf) 72(5):648–653.

    Article  Google Scholar 

  10. 10.

    Osamura RY, Lopes MBS, Grossman A, Kontogeorgos G (2017) WHO classification of tumours of the pituitary. In: Lloyd RV, Osamura RY, Klöppel RJ (eds) WHO classification of tumours of endocrine glands, 4th edn. Lyon, IARC, pp 11–63

    Google Scholar 

  11. 11.

    García-Martínez A, Sottile J, Fajardo C et al (2018) Is it time to consider the expression of specific-pituitary hormone genes when typifying pituitary tumours? PLoS ONE.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Sanchez-Tejada L, Sanchez-Ortiga R, Lamas C et al (2017) Contribution of molecular analysis to the typification of the non-functioning pituitary adenomas. PLoS ONE.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Cooper O, Ben-Shlomo A, Bonert V, Bannykh S, Mirocha J, Melmed S (2010) Silent corticogonadotroph adenomas: clinical and cellular characteristics and long-term outcomes. Horm Cancer 1(2):80–92.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Kovacs K, Horvath E, Bayley TA, Hassaram ST, Ezrin C (1978) Silent corticotroph cell adenoma with lysosomal accumulation and crinophagy. A distinct clinicopathologic entity. Am J Med 64(3):492–499.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Raverot G, Wierinckx A, Jouanneau E et al (2010) 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.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Tateno T, Izumiyama H, Doi M et al (2007) Differential gene expression in ACTH-secreting and non-functioning pituitary tumors. Eur J Endocrinol 157(6):717–724.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Tani Y, Sugiyama T, Izumiyama H, Yoshimoto T, Yamada S, Hirata Y (2011) Differential gene expression profiles of POMC-related enzymes, transcription factors and receptors between non-pituitary and pituitary ACTH-secreting tumors. Endocr J 58(4):297–303. Accessed 01 Feb 2018

  18. 18.

    Seltzer J, Ashton CE, Scotton TC, Pangal D, Carmichael JD, Zada G (2015) Gene and protein expression in pituitary corticotroph adenomas: a systematic review of the literature. Neurosurg Focus.

    Article  PubMed  Google Scholar 

  19. 19.

    García-Martínez A, Cano DA, Flores-Martínez A et al (2019) Why don’t corticotroph tumors always produce Cushing’s disease? Eur J Endocrinol 181(3):351–361.

    Article  PubMed  Google Scholar 

  20. 20.

    Mete O, Lopes MB (2017) Overview of the 2017 WHO classification of pituitary tumors. Endocr Pathol 28(3):228–243.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Imber BS, Lin AL, Zhang Z et al (2019) Comparison of radiographic approaches to assess treatment response in pituitary adenomas: is RECIST or RANO good enough? J Endocr Soc 3(9):1693–1706.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Knosp E, Steiner E, Kitz K, Matula C (1993) Pituitary adenomas with invasion of the cavernous sinus space. Neurosurgery 33(4):610–618.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Raverot G, Burman P, McCormack A et al (2018) European society of endocrinology clinical practice guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol 178(1):G1–G24.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Mete O, Cintosun A, Pressman I, Asa SL (2018) Epidemiology and biomarker profile of pituitary adenohypophysical tumors. Mod Pathol 31(6):900–909.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Cooper O, Melmed S (2012) Subclinical hyperfunctioning pituitary adenomas: the silent tumors. Best Pract Res Clin Endocrinol Metab 26(4):447–460.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Kontogeorgos G, Thodou E (2016) The gonadotroph origin of null cell adenomas. Hormones 15:243

    Article  Google Scholar 

  27. 27.

    Lopes MBS (2017) The 2017 World Health Organization classification of tumors of the pituitary gland: a summary. Acta Neuropathol 134(4):521–535.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Nishioka H, Inoshita N, Mete O et al (2015) The complementary role of transcription factors in the accurate diagnosis of clinically nonfunctioning pituitary adenomas. Endocr Pathol 26(4):349–355.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Manojlovic-Gacic E, Engström BE, Casar-Borota O (2018) Histopathological classification of non-functioning pituitary neuroendocrine tumors. Pituitary 21(2):119–129.

    Article  PubMed  Google Scholar 

  30. 30.

    Torregrosa-Quesada ME, García-Martínez A, Silva-Ortega S et al (2019) 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 (Basel) 11(12):1990.

    CAS  Article  Google Scholar 

  31. 31.

    Balogun JA, Monsalves E, Juraschka K et al (2015) Null cell adenomas of the pituitary gland: an institutional review of their clinical imaging and behavioral characteristics. Endocr Pathol 26(1):63–70.

    Article  PubMed  Google Scholar 

  32. 32.

    Asa SL, Ezzat S (2016) Aggressive pituitary tumors or localized pituitary carcinomas: defining pituitary tumors. Expert Rev Endocrinol Metab 11(2):149–162.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Trouillas J, Jaffrain-Rea ML, Vasiljevic A, Raverot G, Roncaroli F, Villa CC (2020) How to classify the pituitary neuroendocrine tumors (PitNET)s in 2020. Cancers (Basel).

    Article  Google Scholar 

  34. 34.

    Casanueva FF, Barkan AL, Buchfelder M et al (2017) Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): a pituitary Society Statement. Pituitary.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Alahmadi H, Lee D, Wilson JR et al (2012) Clinical features of silent corticotroph adenomas. Acta Neurochir (Wien) 154(8):1493–1498.

    Article  Google Scholar 

  36. 36.

    Cooper O (2015) Silent corticotroph adenomas. Pituitary 18(2):225–231.

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Langlois F, Lim DST, Yedinak CG et al (2018) Predictors of silent corticotroph adenoma recurrence; a large retrospective single center study and systematic literature review. Pituitary 21(1):32–40.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Yamada S, Ohyama K, Taguchi M et al (2007) A study of the correlation between morphological findings and biological activities in clinically nonfunctioning pituitary adenomas. Neurosurgery 61(3):580–584

    Article  Google Scholar 

  39. 39.

    Langlois F, Lim DST, Varlamov E et al (2017) Clinical profile of silent growth hormone pituitary adenomas; higher recurrence rate compared to silent gonadotroph pituitary tumors, a large single center experience. Endocrine 58(3):528–534.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Jahangiri A, Wagner JR, Pekmezci M et al (2013) A comprehensive long-term retrospective analysis of silent corticotrophic adenomas vs hormone-negative adenomas. Neurosurgery 73(1):8–17.

    Article  PubMed  Google Scholar 

  41. 41.

    Cohen-Inbar O, Xu Z, Lee CC et al (2017) Prognostic significance of corticotroph staining in radiosurgery for non-functioning pituitary adenomas: a multicenter study. J Neurooncol 135(1):67–74.

    Article  PubMed  Google Scholar 

  42. 42.

    Ioachimescu AG, Eiland L, Chhabra VS et al (2012) Silent corticotroph adenomas: Emory University cohort and comparison with ACTH-negative nonfunctioning pituitary adenomas. Neurosurgery 71(2):296–303

    Article  Google Scholar 

  43. 43.

    Chinezu L, Jouanneau E, Vasiljevic A, Trouillas J, Raverot G (2013) Silent GH pituitary tumor: diagnostic and therapeutic challenges. Ann Endocrinol (Paris) 74(5–6):491–495.

    Article  Google Scholar 

  44. 44.

    Chinezu L, Vasiljevic A, Trouillas J, Lapoirie M, Jouanneau E, Raverot G (2017) Silent somatotroph tumour revisited from a study of 80 patients with and without acromegaly and a review of the literature. Eur J Endocrinol 176(2):195–201.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Kovacs K, Lloyd R, Horvath E et al (1989) Silent somatotroph adenomas of the human pituitary. A morphologic study of three cases including immunocytochemistry, electron microscopy, in vitro examination, and in situ hybridization. Am J Pathol 134(2):345–353

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Trouillas J, Sassolas G, Loras B et al (1991) Somatotrpic adenomas without acromegaly. Pathol Res Pract 187(8):943–949.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Yamada S, Aiba T, Sano T et al (1993) Growth hormone-producing pituitary adenomas: correlations between clinical characteristics and morphology. Neurosurgery 33(1):20–27.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Tampourlou M, Ntali G, Ahmed S et al (2017) Outcome of nonfunctioning pituitary adenomas that regrow after primary treatment: a study from two large UK centers. J Clin Endocrinol Metab 102(6):1889–1897.

    Article  PubMed  Google Scholar 

  49. 49.

    Saeger W, Ludecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S (2007) Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol 156:203–216

    CAS  Article  Google Scholar 

  50. 50.

    Kirkman MA, Jaunmuktane Z, Brandner S, Khan AA, Powell M, Baldeweg SE (2014) Active and silent thyroid-stimulating hormone-expressing pituitary adenomas: presenting symptoms, treatment, outcomes, and recurrence. World Neurosurg 82(6):1224–1231.

    Article  PubMed  Google Scholar 

  51. 51.

    Wang EL, Qian ZR, Yamada S et al (2009) Clinicopathological characterization of TSH-producing adenomas: special reference to TSH-immunoreactive but clinically non-functioning adenomas. Endocr Pathol 20(4):209–220.

    CAS  Article  PubMed  Google Scholar 

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We thank J. Abarca (Neurosurgery Department, Hospital General Universitario de Alicante, Alicante, Spain), I. Monjas (Otolaryngology Department, Alicante General University Hospital, Alicante, Spain), P. Riesgo (Neurosurgery Department, University Hospital La Ribera, Valencia, Spain), J.A. Simal (Neurosurgery Department, Polytechnic University Hospital La Fe, Valencia, Spain), and H. Sandoval (Neurosurgery Department, University of Albacete Hospital Complex, Albacete, Spain) for their surgical contributions. We also thank the biobanks of the University of Albacete Hospital Complex, Alicante General University Hospital, and Polytechnic University Hospital La Fe.


This work is funded by Novartis Oncology through the Spanish Society of Endocrinology and Nutrition (SEEN). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information




Conceptualization, MET, AGM and AP; methodology, MET, AGM, SSO, IA and AP; validation, MET, AGM, SSO, IA and AP; formal analysis, MET, AGM, ASB and AP; investigation, MET, AGM and AP; resources, MET, AGM, SSO, IA, RC, CF, CL and AP; writing—original draft preparation, MET, AGM and AP; writing—review and editing, MET, AGM, ASB, SSO, IA, RC, CF, CL and AP; supervision, AGM and AP; project administration, AGM and AP; funding acquisition, AP All authors have read and agreed to the published version of the manuscript.

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Correspondence to A. Pico.

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The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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Torregrosa-Quesada, M.E., García-Martínez, A., Sánchez-Barbie, A. et al. The silent variants of pituitary tumors: demographic, radiological and molecular characteristics. J Endocrinol Invest (2021).

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  • Pituitary tumors
  • Non-functioning pituitary adenomas (NFPA)
  • Silent pituitary tumors (SPTs)
  • Adenohypophyseal hormone gene expression