, Volume 57, Issue 1, pp 35–45 | Cite as

Early postoperative growth in non-functioning pituitary adenomas; A tool to tailor safe follow-up

  • Kristin Astrid ØysteseEmail author
  • Manuela Zucknick
  • Olivera Casar-Borota
  • Geir Ringstad
  • Jens Bollerslev
Endocrine Methods and Techniques



Non-functioning pituitary adenomas are common, and the treatment and follow-up of these patients represent a multidisciplinary challenge. First line treatment is transphenoidal surgery, with debulking or total removal of tumour. A substantial portion of the tumours relapse after surgery, and there is no consensus of how to follow these patients postoperatively. Our aim was to characterize the postoperative growth of non-functioning pituitary adenomas and correlate it to clinical and paraclinical data.


We retrospectively registered 52 patients operated for non-functioning pituitary adenomas, with four or more consecutive MR-investigations not interrupted by secondary treatment. Adenoma volumes were estimated by the Cavalieri principle with summation of manually drawn areas multiplied by slice interval. Growth curves were modelled and tumour volume doubling time was calculated for 39 tumours with regrowth after surgery.


A total of 13 tumours showed exponential growth, 10 linear growth and 16 logistic growth after surgery. The remaining 13 did not show regrowth of tumour. Seven of the exponential growing tumours underwent secondary surgery, compared to one and two of linear and logistic growing tumours (p = 0.03), respectively. Initial tumour volume doubling time was significantly lower in logistic growing tumours than in exponential growing tumours (p < 0.01). Men had tumours with lower tumour volume doubling time than women (p = 0.03). None of the tumours demonstrated signs of accelerated growth.


Residual tumours following surgery frequently grow. The logistic growing tumours had the fastest initial growth in our cohort. We found no indication of accelerated growth, whereby the tumour volume doubling time might be used to predict a “worst-case” scenario when planning follow-up of these patients.


Anterior pituitary Tumour volume doubling time Non-functioning pituitary adenoma Growth dynamics prognosis 


Author contributions

K.A.Ø. and J.B. designed the research studies. K.A.Ø. and G.A.R. performed the volume registrations. O.C.B. performed the immunohistochemical investigations. M.Z. performed the growth model fitting. K.A.Ø. and M.Z. analyzed the data. K.A.Ø., M.Z., O.C.B., G.A.R. and J.B. wrote the manuscript.

Compliance with ethical standards

Conflict of interest

Jens Bollerslev is a member of the advisory board of JCEM and Endocrine. The remaining authors declare that they have no competing interests.

Ethical approval

The study was approved by the regional ethics committee and hospital authority

Informed consent

The informed consentwas obtained from all living patients.


  1. 1.
    A. Tjornstrand, K. Gunnarsson, M. Evert, E. Holmberg, O. Ragnarsson, T. Rosen, H. Filipsson Nystrom, The incidence rate of pituitary adenomas in western Sweden for the period 2001-2011. Eur. J. Endocrinol. 171(4), 519–526 (2014). doi: 10.1530/eje-14-0144 CrossRefPubMedGoogle Scholar
  2. 2.
    T.T. Agustsson, T. Baldvinsdottir, J.G. Jonasson, E. Olafsdottir, V. Steinthorsdottir, G. Sigurdsson, A.V. Thorsson, P.V. Carroll, M. Korbonits, R. Benediktsson, The epidemiology of pituitary adenomas in Iceland, 1955-2012: a nationwide population-based study. Eur. J. Endocrinol. 173(5), 655–664 (2015). doi: 10.1530/eje-15-0189 CrossRefPubMedGoogle Scholar
  3. 3.
    P.U. Freda, A.M. Beckers, L. Katznelson, M.E. Molitch, V.M. Montori, K.D. Post, M.L. Vance, Pituitary incidentaloma: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 96(4), 894–904 (2011). doi: 10.1210/jc.2010-1048 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    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). doi: 10.1159/000339823 CrossRefPubMedGoogle Scholar
  5. 5.
    R. Reddy, S. Cudlip, J.V. Byrne, N. Karavitaki, J.A. Wass, Can we ever stop imaging in surgically treated and radiotherapy-naive patients with non-functioning pituitary adenoma? Eur. J. Endocrinol. 165(5), 739–744 (2011). doi: 10.1530/eje-11-0566 CrossRefPubMedGoogle Scholar
  6. 6.
    S. Brochier, F. Galland, M. Kujas, F. Parker, S. Gaillard, C. Raftopoulos, J. Young, O. Alexopoulou, D. Maiter, P. Chanson, Factors predicting relapse of nonfunctioning pituitary macroadenomas after neurosurgery: a study of 142 patients. Eur. J. Endocrinol. 163(2), 193–200 (2010). doi: 10.1530/eje-10-0255 CrossRefPubMedGoogle Scholar
  7. 7.
    E.P. O’Sullivan, C. Woods, N. Glynn, L.A. Behan, R. Crowley, P. O’Kelly, D. Smith, C.J. Thompson, A. Agha, The natural history of surgically treated but radiotherapy-naive nonfunctioning pituitary adenomas. Clin. Endocrinol. 71(5), 709–714 (2009). doi: 10.1111/j.1365-2265.2009.03583.x CrossRefGoogle Scholar
  8. 8.
    M. Losa, P. Mortini, R. Barzaghi, P. Ribotto, M.R. Terreni, S.B. Marzoli, S. Pieralli, M. Giovanelli, Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence. J. Neurosurg. 108(3), 525–532 (2008). doi: 10.3171/jns/2008/108/3/0525 CrossRefPubMedGoogle Scholar
  9. 9.
    G. Soto-Ares, C. Cortet-Rudelli, R. Assaker, A. Boulinguez, C. Dubest, D. Dewailly, J.P. Pruvo, MRI protocol technique in the optimal therapeutic strategy of non-functioning pituitary adenomas. Eur. J. Endocrinol. 146(2), 179–186 (2002)CrossRefGoogle Scholar
  10. 10.
    F. Roelfsema, N.R. Biermasz, A.M. Pereira, Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis. Pituitary. 15(1), 71–83 (2012). doi: 10.1007/s11102-011-0347-7 CrossRefPubMedGoogle Scholar
  11. 11.
    A. Sav, F. Rotondo, L.V. Syro, A. Di Ieva, M.D. Cusimano, K. Kovacs, Invasive, atypical and aggressive pituitary adenomas and carcinomas. Endocrinol. Metab. Clin. North. Am. 44(1), 99–104 (2015). doi: 10.1016/j.ecl.2014.10.008 CrossRefPubMedGoogle Scholar
  12. 12.
    Y. Greenman, N. Stern, Optimal management of non-functioning pituitary adenomas. Endocrine. 50(1), 51–55 (2015). doi: 10.1007/s12020-015-0685-8 CrossRefPubMedGoogle Scholar
  13. 13.
    E. Chatzellis, K.I. Alexandraki, Androulakis, II, Kaltsas, G.: Aggressive pituitary tumors. Neuroendocrinology. 101(2), 87–104 (2015). doi: 10.1159/000371806 CrossRefPubMedGoogle Scholar
  14. 14.
    A.K. Laird, Dynamics of tumor growth. Br. J. Cancer. 13, 490–502 (1964)CrossRefGoogle Scholar
  15. 15.
    M. Schwartz, A biomathematical approach to clinical tumor growth. Cancer 14, 1272–1294 (1961)CrossRefGoogle Scholar
  16. 16.
    V.P. Collins, R.K. Loeffler, H. Tivey, Observations on growth rates of human tumors. Am. J. Roentgenol. Radium. Ther. Nucl. Med. 76(5), 988–1000 (1956)PubMedGoogle Scholar
  17. 17.
    M.W. Retsky, D.E. Swartzendruber, R.H. Wardwell, P.D. Bame, Is Gompertzian or exponential kinetics a valid description of individual human cancer growth? Med. Hypotheses. 33(2), 95–106 (1990)CrossRefGoogle Scholar
  18. 18.
    I.A. Rodriguez-Brenes, N.L. Komarova, D. Wodarz, Tumor growth dynamics: insights into evolutionary processes. Trends. Ecol. Evol. 28(10), 597–604 (2013). doi: 10.1016/j.tree.2013.05.020 CrossRefPubMedGoogle Scholar
  19. 19.
    S. Nakasu, Y. Nakasu, T. Fukami, J. Jito, K. Nozaki, Growth curve analysis of asymptomatic and symptomatic meningiomas. J. Neurooncol. 102(2), 303–310 (2011). doi: 10.1007/s11060-010-0319-1 CrossRefPubMedGoogle Scholar
  20. 20.
    A.L. Stensjoen, O. Solheim, K.A. Kvistad, A.K. Haberg, O. Salvesen, E.M. Berntsen, Growth dynamics of untreated glioblastomas in vivo. Neuro. Oncol. 17(10), 1402–1411 (2015). doi: 10.1093/neuonc/nov029 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    J. Honegger, S. Zimmermann, T. Psaras, M. Petrick, M. Mittelbronn, U. Ernemann, M. Reincke, K. Dietz, Growth modelling of non-functioning pituitary adenomas in patients referred for surgery. Eur. J. Endocrinol. 158(3), 287–294 (2008). doi: 10.1530/eje-07-0502 CrossRefPubMedGoogle Scholar
  22. 22.
    Y. Tanaka, K. Hongo, T. Tada, K. Sakai, Y. Kakizawa, S. Kobayashi, Growth pattern and rate in residual nonfunctioning pituitary adenomas: correlations among tumor volume doubling time, patient age, and MIB-1 index. J. Neurosurg. 98(2), 359–365 (2003). doi: 10.3171/jns.2003.98.2.0359 CrossRefPubMedGoogle Scholar
  23. 23.
    J.A. Balogun, E. Monsalves, K. Juraschka, K. Parvez, W. Kucharczyk, O. Mete, F. Gentili, G. Zadeh, Null cell adenomas of the pituitary gland: an institutional review of their clinical imaging and behavioral characteristics. Endocr. Pathol. 26(1), 63–70 (2015). doi: 10.1007/s12022-014-9347-2 CrossRefPubMedGoogle Scholar
  24. 24.
    C.Y. Hsu, W.Y. Guo, C.P. Chien, D.M. Ho, MIB-1 labeling index correlated with magnetic resonance imaging detected tumor volume doubling time in pituitary adenoma. Eur. J. Endocrinol. 162(6), 1027–1033 (2010). doi: 10.1530/eje-09-1100 CrossRefPubMedGoogle Scholar
  25. 25.
    E. Monsalves, S. Larjani, B. Loyola Godoy, K. Juraschka, F. Carvalho, W. Kucharczyk, A. Kulkarni, O. Mete, F. Gentili, S. Ezzat, G. Zadeh, Growth patterns of pituitary adenomas and histopathological correlates. J. Clin. Endocrinol. Metab. 99(4), 1330–1338 (2014). doi: 10.1210/jc.2013-3054 CrossRefPubMedGoogle Scholar
  26. 26.
    H.J. Gundersen, T.F. Bendtsen, L. Korbo, N. Marcussen, A. Moller, K. Nielsen, J.R. Nyengaard, B. Pakkenberg, F.B. Sorensen, A. Vesterby et al.. Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 96(5), 379–394 (1988)CrossRefGoogle Scholar
  27. 27.
    J.K. Varughese, C.N. Breivik, T. Wentzel-Larsen, M. Lund-Johansen, Growth of untreated vestibular schwannoma: a prospective study. J. Neurosurg. 116(4), 706–712 (2012). doi: 10.3171/2011.12.jns111662 CrossRefPubMedGoogle Scholar
  28. 28.
    J.K. Varughese, T. Wentzel-Larsen, F. Vassbotn, G. Moen, M. Lund-Johansen, Analysis of vestibular schwannoma size in multiple dimensions: a comparative cohort study of different measurement techniques. Clin. Otolaryngol. 35(2), 97–103 (2010). doi: 10.1111/j.1749-4486.2010.02099.x CrossRefPubMedGoogle Scholar
  29. 29.
    N. Lenders, S. Ikeuchi, A.W. Russell, K.K. Ho, J.B. Prins, W.J. Inder Longitudinal evaluation of the natural history of conservatively managed non-functioning pituitary adenomas. Clin. Endocrinol.. (2015).  10.1111/cen.12879
  30. 30.
    A. Colao, M.D. Bronstein, P. Freda, F. Gu, C.C. Shen, M. Gadelha, M. Fleseriu, A.J. van der Lely, A.J. Farrall, K. Hermosillo Resendiz, M. Ruffin, Y. Chen, M. Sheppard, Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J. Clin. Endocrinol. Metab. 99(3), 791–799 (2014). doi: 10.1210/jc.2013-2480 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    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). discussion 617-618PubMedGoogle Scholar
  32. 32.
    A.S. Micko, A. Wohrer, S. Wolfsberger, E. Knosp, Invasion of the cavernous sinus space in pituitary adenomas: endoscopic verification and its correlation with an MRI-based classification. J. Neurosurg. 122(4), 803–811 (2015). doi: 10.3171/2014.12.jns141083 CrossRefPubMedGoogle Scholar
  33. 33.
    M.A. Mooney, D.A. Hardesty, J.P. Sheehy, R. Bird, K. Chapple, W.L. White, A.S. Little Interrater and intrarater reliability of the Knosp scale for pituitary adenoma grading. J. Neurosurg. 1–6 (2016).  10.3171/2016.3.jns153044
  34. 34.
    O. Casar-Borota, S.L. Fougner, J. Bollerslev, J.M. Nesland, KIT protein expression and mutational status of KIT gene in pituitary adenomas. Virchows Arch. 460(2), 171–181 (2012). doi: 10.1007/s00428-011-1185-8 CrossRefPubMedGoogle Scholar
  35. 35.
    O. Casar-Borota, K.A. Oystese, M. Sundstrom, L. Melchior, V. Popovic A high-throughput analysis of the IDH1(R132H) protein expression in pituitary adenomas. Pituitary. (2016).  10.1007/s11102-016-0720-7
  36. 36.
    M. Stone, An asymptotic equivalence of choice of model by cross-validation and Akaike’s criterion. J. R. Stat. Soc. Series B Methodol. 39(1), 44–47 (1977)Google Scholar
  37. 37.
    G.A. Ringstad, K.E. Emblem, D. Holland, A.M. Dale, A. Bjornerud, J.K. Hald, Assessment of pituitary adenoma volumetric change using longitudinal MR image registration. Neuroradiology. 54(5), 435–443 (2012). doi: 10.1007/s00234-011-0894-7 CrossRefPubMedGoogle Scholar
  38. 38.
    E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij, New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer. 45(2), 228–247 (2009). doi: 10.1016/j.ejca.2008.10.026 CrossRefGoogle Scholar
  39. 39.
    O. Cooper, S. Melmed, Subclinical hyperfunctioning pituitary adenomas: the silent tumors. Best Pract Res. Clin. Endocrinol. Metab. 26(4), 447–460 (2012). doi: 10.1016/j.beem.2012.01.002 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    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. (2015). doi: 10.1007/s12022-015-9398-z CrossRefGoogle Scholar
  41. 41.
    A. Fernandez, N. Karavitaki, J.A. Wass, Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin. Endocrinol. (Oxf). 72(3), 377–382 (2010). doi: 10.1111/j.1365-2265.2009.03667.x CrossRefPubMedGoogle Scholar
  42. 42.
    D.S. Olsson, A.G. Nilsson, I.L. Bryngelsson, P. Trimpou, G. Johannsson, E. Andersson, Excess Mortality in Women and Young Adults With Nonfunctioning Pituitary Adenoma: A Swedish Nationwide Study. J. Clin. Endocrinol. Metab. 100(7), 2651–2658 (2015). doi: 10.1210/jc.2015-1475 CrossRefPubMedGoogle Scholar
  43. 43.
    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 CrossRefPubMedGoogle Scholar
  44. 44.
    T. Daems, J. Verhelst, A. Michotte, P. Abrams, D. De Ridder, R. Abs, Modification of hormonal secretion in clinically silent pituitary adenomas. Pituitary. 12(1), 80–86 (2009). doi: 10.1007/s11102-008-0085-7 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Section of Specialized Endocrinology, Department of EndocrinologyOslo University Hospital RikshospitaletOsloNorway
  2. 2.Faculty of MedicineUniversity of OsloOsloNorway
  3. 3.Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical SciencesUniversity of OsloOsloNorway
  4. 4.Department of Immunology, Genetics and PathologyUppsala University, Rudbeck LaboratoryUppsalaSweden
  5. 5.Department of Clinical Pathology and CytologyUppsala University Hospital, Rudbeck LaboratoryUppsalaSweden
  6. 6.Department of PathologyOslo University HospitalOsloNorway
  7. 7.Department of Radiology and Nuclear MedicineOslo University Hospital- RikshospitaletOsloNorway
  8. 8.Section of Specialized Endocrinology, Department of EndocrinologyOslo University Hospital RikshospitaletOsloNorway

Personalised recommendations