Acta Neurochirurgica

, Volume 156, Issue 3, pp 451–461 | Cite as

Nonfunctioning pituitary adenomas: association of Ki-67 and HMGA-1 labeling indices with residual tumor growth

  • Andrej ŠteňoEmail author
  • Jozef Bocko
  • Boris Rychlý
  • Martin Chorváth
  • Peter Celec
  • Martin Fabian
  • Víťazoslav Belan
  • Juraj Šteňo
Clinical Article - Brain Tumors



The postoperative biological behavior of nonfunctioning pituitary adenomas (NFPAs) is variable. Some residual NFPAs are stable long-term, others grow, and some recur despite complete removal. The usual histological markers of tumor aggressiveness are often similar between recurring, regrowing, and stable tumors, and therefore are not reliable as prognostic parameters. In this study, the clinical utility of proliferation indices (labeling index, Li) based on immunohistochemistry targeted at antigens Ki-67 and High-mobility group A1 (HMGA-1) for prediction of NFPA prognosis was investigated.


Fifty patients with NFPAs were investigated. In each patient, Ki-67 and HMGA-1 Li were evaluated. Based on postoperative magnetic resonance images, patients were classified as tumor-free (18 patients), or harboring a residual tumor (32 patients). The latter group was further subdivided into groups with stable tumor remnants (11 patients) or progressive tumor remnants (21 patients).


The median follow-up period was 8 years. No significant relationship between HMGA-1 Li and residual tumor growth was found. Growing residual tumors showed a trend towards higher Ki-67 Li compared with stable ones (p = 0.104). All tumor remnants with Ki-67 Li above 2.2 % were growing. The relationship between residual tumor growth and Ki-67 Li exceeding the cutoff value of 2.2 % was significant (p = 0.01 in univariate, p = 0.044 in multivariate analysis).


The prognostic significance of the HMGA-1 antigen was not confirmed. In contrast, the Ki-67 Li provides useful and valuable information for the postoperative management of NFPAs. In residual adenomas with a Ki-67 Li above 2.2 %, regrowth should be expected, and these tumors may require shorter intervals of follow-up magnetic resonance imaging (MRI) and/or early adjuvant therapy. Future larger studies are needed to confirm the results of this study.


Pituitary adenoma HMGA-1 Ki-67 Residual tumor Recurrence Regrowth 



This study was supported by a grant from the Scientific Grant Agency of the Ministry of Education of the Slovak Republic and the Slovak Academy of Sciences (VEGA) number 1/1166/10.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Abe T, Sanno N, Osamura YR, Matsumoto K (1997) Proliferative potential in pituitary adenomas: measurement by monoclonal antibody MIB-1. Acta Neurochir 139:613–618PubMedCrossRefGoogle Scholar
  2. 2.
    Brown DC, Gatter KC (1990) Monoclonal antibody Ki-67: its use in histopathology. Histopathology 17:489–503PubMedCrossRefGoogle Scholar
  3. 3.
    Comtois R, Beauregard H, Somma M, Serri O, Aris-Jilwan N, Hardy J (1991) The clinical and endocrine outcome to trans-sphenoidal microsurgery of nonsecreting pituitary adenomas. Cancer 68:860–866PubMedCrossRefGoogle Scholar
  4. 4.
    Cottier JP, Destrieux C, Brunereau L, Bertrand P, Moreau L, Jan M, Herbreteau D (2000) Cavernous sinus invasion by pituitary adenoma: MR imaging. Radiology 215:463–469PubMedCrossRefGoogle Scholar
  5. 5.
    de Aguiar PH, Aires R, Laws ER, Isolan GR, Logullo A, Patil C, Katznelson L (2010) Labeling index in pituitary adenomas evaluated by means of MIB-1: is there a prognostic role? A critical review. Neurol Res 32:1060–1071PubMedCrossRefGoogle Scholar
  6. 6.
    Dekkers OM, Pereira AM, Roelfsema F, Voormolen JH, Neelis KJ, Schroijen MA, Smit JW, Romijn JA (2006) Observation alone after transsphenoidal surgery for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 91:1796–1801PubMedCrossRefGoogle Scholar
  7. 7.
    Dubois S, Guyétant S, Menei P, Rodien P, Illouz F, Vielle B, Rohmer V (2007) Relevance of Ki-67 and prognostic factors for recurrence/progression of gonadotropic adenomas after first surgery. Eur J Endocrinol 157:141–147PubMedCrossRefGoogle Scholar
  8. 8.
    Ekramullah SM, Saitoh Y, Arita N, Ohnishi T, Hayakawa T (1996) The correlation of Ki-67 staining indices with tumour doubling times in regrowing non-functioning pituitary adenomas. Acta Neurochir 138:1449–1455PubMedCrossRefGoogle Scholar
  9. 9.
    Fedele M, Pentimalli F, Baldassarre G, Battista S, Klein-Szanto AJ, Kenyon L, Visone R, De Martino I, Ciarmiello A, Arra C, Viglietto G, Croce CM, Fusco A (2005) Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas. Oncogene 24:3427–3435PubMedCrossRefGoogle Scholar
  10. 10.
    Fedele M, Fusco A (2010) Role of the high mobility group A proteins in the regulation of pituitary cell cycle. J Mol Endocrinol 44:309–318PubMedCrossRefGoogle Scholar
  11. 11.
    Ferrante E, Ferraroni M, Castrignanò T, Menicatti L, Anagni M, Reimondo G, Del Monte P, Bernasconi D, Loli P, Faustini-Fustini M, Borretta G, Terzolo M, Losa M, Morabito A, Spada A, Beck-Peccoz P, Lania AG (2006) Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors. Eur J Endocrinol 155:823–829PubMedCrossRefGoogle Scholar
  12. 12.
    Filippella M, Galland F, Kujas M, Young J, Faggiano A, Lombardi G, Colao A, Meduri G, Chanson P (2006) Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study. Clin Endocrinol 65:536–543CrossRefGoogle Scholar
  13. 13.
    Fusco A, Fedele M (2007) Roles of HMGA proteins in cancer. Nat Rev Cancer 7:899–910PubMedCrossRefGoogle Scholar
  14. 14.
    Gejman R, Swearingen B, Hedley-Whyte ET (2008) Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Hum Pathol 39:758–766PubMedCrossRefGoogle Scholar
  15. 15.
    Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133:1710–1715PubMedGoogle Scholar
  16. 16.
    Gözü H, Bilgiç B, Hazneci J, Sargın H, Erkal F, Sargın M, Sönmez B, Orbay E, Şeker M, Bozbuğa M, Bayındır Ç (2005) Is Ki-67 Index a useful labeling marker for invasion of pituitary adenomas? Turk Jem 4:107–113Google Scholar
  17. 17.
    Greenman Y, Ouaknine G, Veshchev I, Reider-Groswasser II, Segev Y, Stern N (2003) Postoperative surveillance of clinically nonfunctioning pituitary macroadenomas: markers of tumour quiescence and regrowth. Clin Endocrinol 58:763–769CrossRefGoogle Scholar
  18. 18.
    Hentschel SJ, McCutcheon IE, Moore W, Durity FA (2003) P53 and MIB-1 immunohistochemistry as predictors of the clinical behavior of nonfunctioning pituitary adenomas. Can J Neurol Sci 30:215–219PubMedGoogle Scholar
  19. 19.
    Honegger J, Prettin C, Feuerhake F, Petrick M, Schulte-Mönting J, Reincke M (2003) Expression of Ki-67 antigen in nonfunctioning pituitary adenomas: correlation with growth velocity and invasiveness. J Neurosurg 99:674–679PubMedCrossRefGoogle Scholar
  20. 20.
    Hsu CY, Guo WY, Chien CP, Ho DM (2010) MIB-1 labeling index correlated with magnetic resonance imaging detected tumor volume doubling time in pituitary adenoma. Eur J Endocrinol 162:1027–1033PubMedCrossRefGoogle Scholar
  21. 21.
    Jaffrain-Rea ML, Di Stefano D, Minniti G, Esposito V, Bultrini A, Ferretti E, Santoro A, Faticanti Scucchi L, Gulino A, Cantore G (2002) A critical reappraisal of MIB-1 labelling index significance in a large series of pituitary tumours: secreting versus non-secreting adenomas. Endocr Relat Cancer 9:103–113PubMedCrossRefGoogle Scholar
  22. 22.
    Jane JA, Thapar K, Laws ER (2011) Pituitary Tumors: Functioning and Nonfunctioning. In: Winn RH (ed) Youmans Neurological Surgery. Elsevier Saunders, pp 1476–1510Google Scholar
  23. 23.
    Kawamoto H, Uozumi T, Kawamoto K, Arita K, Yano T, Hirohata T (1995) Analysis of the growth rate and cavernous sinus invasion of pituitary adenomas. Acta Neurochir 136:37–43PubMedCrossRefGoogle Scholar
  24. 24.
    Knosp E, Kitz K, Perneczky A (1989) Proliferation activity in pituitary adenomas: measurement by monoclonal antibody Ki-67. Neurosurgery 25:927–930PubMedCrossRefGoogle Scholar
  25. 25.
    Knosp E, Steiner E, Kitz K, Matula C (1993) Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33:610–617PubMedCrossRefGoogle Scholar
  26. 26.
    Landolt AM, Shibata T, Kleihues P (1987) Growth rate of human pituitary adenomas. J Neurosurg 67:803–806PubMedCrossRefGoogle Scholar
  27. 27.
    Lath R, Chacko G, Chandy MJ (2001) Determination of Ki-67 labeling index in pituitary adenomas using MIB-1 monoclonal antibody. Neurol India 49:144–147PubMedGoogle Scholar
  28. 28.
    Lillehei KO, Kirschman DL, Kleinschmidt-DeMasters BK, Ridgway EC (1998) Reassessment of the role of radiation therapy in the treatment of endocrine-inactive pituitary macroadenomas. Neurosurgery 43:432–438PubMedCrossRefGoogle Scholar
  29. 29.
    Lloyd RV, Kovcs K, Young WF Jr, Farrell WE, Asa SL, Trouillas J, Kontogeorgos G, Sano T, Scheithauer BW, Horvath E (2004) Tumours of the Pituitary Gland. In: DeLellis RA, Lloyd RV, Heitz PU (eds) Pathology and Genetics: Tumours of Endocrine Organs (World Health Organization Classification of Tumours). IARC Press, Lyon, France, pp 10–47Google Scholar
  30. 30.
    Losa M, Franzin A, Mangili F, Terreni MR, Barzaghi R, Veglia F, Mortini P, Giovanelli M (2000) Proliferation index of nonfunctioning pituitary adenomas: correlations with clinical characteristics and long-term follow-up results. Neurosurgery 47:1313–1318PubMedCrossRefGoogle Scholar
  31. 31.
    Losa M, Mortini P, Barzaghi R, Ribotto P, Terreni MR, Marzoli SB, Pieralli S, Giovanelli M (2008) Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence. J Neurosurg 108:525–532PubMedCrossRefGoogle Scholar
  32. 32.
    Mahta A, Haghpanah V, Lashkari A, Heshmat R, Larijani B, Tavangar SM (2007) Non-functioning pituitary adenoma: immunohistochemical analysis of 85 cases. Folia Neuropathol 45:72–77PubMedGoogle Scholar
  33. 33.
    Mastronardi L, Guiducci A, Spera C, Puzzilli F, Liberati F, Maira G (1999) Ki-67 labelling index and invasiveness among anterior pituitary adenomas: analysis of 103 cases using the MIB-1 monoclonal antibody. J Clin Pathol 52:107–111PubMedCrossRefGoogle Scholar
  34. 34.
    Mastronardi L, Guiducci A, Puzzilli F (2001) Lack of correlation between Ki-67 labelling index and tumor size of anterior pituitary adenomas. BMC Cancer 1:12PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Matsuyama J (2012) Ki-67 expression for predicting progression of postoperative residual pituitary adenomas: correlations with clinical variables. Neurol Med Chir (Tokyo) 52:563–569CrossRefGoogle Scholar
  36. 36.
    Messerer M, De Battista JC, Raverot G, Kassis S, Dubourg J, Lapras V, Trouillas J, Perrin G, Jouanneau E (2011) Evidence of improved surgical outcome following endoscopy for nonfunctioning pituitary adenoma removal. Neurosurg Focus 30:E11PubMedCrossRefGoogle Scholar
  37. 37.
    Mizoue T, Kawamoto H, Arita K, Kurisu K, Tominaga A, Uozumi T (1997) MIB1 immunopositivity is associated with rapid regrowth of pituitary adenomas. Acta Neurochir 139:426–431PubMedCrossRefGoogle Scholar
  38. 38.
    Nakabayashi H, Sunada I, Hara M (2001) Immunohistochemical analyses of cell cycle-related proteins, apoptosis, and proliferation in pituitary adenomas. J Histochem Cytochem 49:1193–1194PubMedCrossRefGoogle Scholar
  39. 39.
    Paek KI, Kim SH, Song SH, Choi SW, Koh HS, Youm JY, Kim Y (2005) Clinical significance of Ki-67 labeling index in pituitary macroadenoma. J Korean Med Sci 20:489–494PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Pan LX, Chen ZP, Liu YS, Zhao JH (2005) Magnetic resonance imaging and biological markers in pituitary adenomas with invasion of the cavernous sinus space. J Neurooncol 74:71–76PubMedCrossRefGoogle Scholar
  41. 41.
    Picozzi P, Losa M, Mortini P, Valle MA, Franzin A, Attuati L, Ferrari da Passano C, Giovanelli M (2005) Radiosurgery and the prevention of regrowth of incompletely removed nonfunctioning pituitary adenomas. J Neurosurg 102(Suppl):71–74PubMedCrossRefGoogle Scholar
  42. 42.
    Pizarro CB, Oliveira MC, Coutinho LB, Ferreira NP (2004) Measurement of Ki-67 antigen in 159 pituitary adenomas using the MIB-1 monoclonal antibody. Braz J Med Biol Res 37:235–243PubMedCrossRefGoogle Scholar
  43. 43.
    Righi A, Agati P, Sisto A, Frank G, Faustini-Fustini M, Agati R, Mazzatenta D, Farnedi A, Menetti F, Marucci G, Foschini MP (2012) A classification tree approach for pituitary adenomas. Hum Pathol 43:1627–1637PubMedCrossRefGoogle Scholar
  44. 44.
    Rishi A, Sharma MC, Sarkar C, Jain D, Singh M, Mahapatra AK, Mehta VS, Das TK (2010) A clinicopathological and immunohistochemical study of clinically non-functioning pituitary adenomas: a single institutional experience. Neurol India 58:418–423PubMedCrossRefGoogle Scholar
  45. 45.
    Roelfsema F, Biermasz NR, Pereira AM (2012) Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis. Pituitary 15:71–83PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Saeger W, Lüdecke 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 156:203–216PubMedCrossRefGoogle Scholar
  47. 47.
    Saeger W, Lüdecke B, Lüdecke DK (2008) Clinical tumor growth and comparison with proliferation markers in non-functioning (inactive) pituitary adenomas. Exp Clin Endocrinol Diabetes 116:80–85PubMedCrossRefGoogle Scholar
  48. 48.
    Salehi F, Agur A, Scheithauer BW, Kovacs K, Lloyd RV, Cusimano M (2009) Ki-67 in pituitary neoplasms: a review–part I. Neurosurgery 65:429–437PubMedCrossRefGoogle Scholar
  49. 49.
    Salehi F, Agur A, Scheithauer BW, Kovacs K, Lloyd RV, Cusimano M (2010) Biomarkers of pituitary neoplasms: a review (Part II). Neurosurgery 67:1790–1798PubMedCrossRefGoogle Scholar
  50. 50.
    Sav A, Rotondo F, Syro LV, Scheithauer BW, Kovacs K (2012) Biomarkers of pituitary neoplasms. Anticancer Res 32:4639–4654PubMedGoogle Scholar
  51. 51.
    Scheithauer BW, Gaffey TA, Lloyd RV, Sebo TJ, Kovacs KT, Horvath E, Yapicier O, Young WF Jr, Meyer FB, Kuroki T, Riehle DL, Laws ER Jr (2006) Pathobiology of pituitary adenomas and carcinomas. Neurosurgery 59:341–353PubMedCrossRefGoogle Scholar
  52. 52.
    Schreiber S, Saeger W, Lüdecke DK (1999) Proliferation markers in different types of clinically non-secreting pituitary adenomas. Pituitary 1:213–220PubMedCrossRefGoogle Scholar
  53. 53.
    Soto-Ares G, Cortet-Rudelli C, Assaker R, Boulinguez A, Dubest C, Dewailly D, Pruvo JP (2002) MRI protocol technique in the optimal therapeutic strategy of non-functioning pituitary adenomas. Eur J Endocrinol 146:179–186PubMedCrossRefGoogle Scholar
  54. 54.
    Tanaka Y, Hongo K, Tada T, Sakai K, Kakizawa Y, Kobayashi S (2003) Growth pattern and rate in residual nonfunctioning pituitary adenomas: correlations among tumor volume doubling time, patient age, and MIB-1 index. J Neurosurg 98:359–365PubMedCrossRefGoogle Scholar
  55. 55.
    Thapar K, Kovacs K, Scheithauer BW, Stefaneanu L, Horvath E, Pernicone PJ, Murray D, Laws ER Jr (1996) Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38:99–106PubMedCrossRefGoogle Scholar
  56. 56.
    Turner HE, Stratton IM, Byrne JV, Adams CB, Wass JA (1999) Audit of selected patients with nonfunctioning pituitary adenomas treated without irradiation—a follow-up study. Clin Endocrinol 51:281–284CrossRefGoogle Scholar
  57. 57.
    Turner HE, Nagy Z, Gatter KC, Esiri MM, Wass JA, Harris AL (2000) Proliferation, bcl-2 expression and angiogenesis in pituitary adenomas: relationship to tumour behaviour. Br J Cancer 82:1441–1445PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    van den Bergh AC, van den Berg G, Schoorl MA, Sluiter WJ, van der Vliet AM, Hoving EW, Szabó BG, Langendijk JA, Wolffenbuttel BH, Dullaart RP (2007) Immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma: beneficial effect on local control without additional negative impact on pituitary function and life expectancy. Int J Radiat Oncol Biol Phys 67:863–869PubMedCrossRefGoogle Scholar
  59. 59.
    Wang EL, Qian ZR, Rahman MM, Yoshimoto K, Yamada S, Kudo E, Sano T (2010) Increased expression of HMGA1 correlates with tumour invasiveness and proliferation in human pituitary adenomas. Histopathology 56:501–509PubMedCrossRefGoogle Scholar
  60. 60.
    Widhalm G, Wolfsberger S, Preusser M, Fischer I, Woehrer A, Wunderer J, Hainfellner JA, Knosp E (2009) Residual nonfunctioning pituitary adenomas: prognostic value of MIB-1 labeling index for tumor progression. J Neurosurg 111:563–571PubMedCrossRefGoogle Scholar
  61. 61.
    Wolfsberger S, Kitz K, Wunderer J, Czech T, Boecher-Schwarz HG, Hainfellner JA, Knosp E (2004) Multiregional sampling reveals a homogenous distribution of Ki-67 proliferation rate in pituitary adenomas. Acta Neurochir 146:1323–1327PubMedCrossRefGoogle Scholar
  62. 62.
    Wolfsberger S, Wunderer J, Zachenhofer I, Czech T, Böcher-Schwarz HG, Hainfellner J, Knosp E (2004) Expression of cell proliferation markers in pituitary adenomas–correlation and clinical relevance of MIB-1 and anti-topoisomerase-IIalpha. Acta Neurochir 146:831–839PubMedGoogle Scholar
  63. 63.
    Woollons AC, Hunn MK, Rajapakse YR, Toomath R, Hamilton DA, Conaglen JV, Balakrishnan V (2000) Non-functioning pituitary adenomas: indications for postoperative radiotherapy. Clin Endocrinol 53:713–717CrossRefGoogle Scholar
  64. 64.
    Yamada S, Ohyama K, Taguchi M, Takeshita A, Morita K, Takano K, Sano T (2007) A study of the correlation between morphological findings and biological activities in clinically nonfunctioning pituitary adenomas. Neurosurgery 61:580–584PubMedCrossRefGoogle Scholar
  65. 65.
    Yildirim AE, Divanlioglu D, Nacar OA, Dursun E, Sahinoglu M, Unal T, Belen AD (2013) Incidence, hormonal distribution and postoperative follow up of atypical pituitary adenomas. Turk Neurosurg 23:226–231PubMedGoogle Scholar
  66. 66.
    Yokoyama S, Hirano H, Moroki K, Goto M, Imamura S, Kuratsu JI (2001) Are nonfunctioning pituitary adenomas extending into the cavernous sinus aggressive and/or invasive? Neurosurgery 49:857–862PubMedGoogle Scholar
  67. 67.
    Zada G, Woodmansee WW, Ramkissoon S, Amadio J, Nose V, Laws ER Jr (2011) Atypical pituitary adenomas: incidence, clinical characteristics, and implications. J Neurosurg 114:336–344PubMedCrossRefGoogle Scholar
  68. 68.
    Zhao D, Tomono Y, Nose T (1999) Expression of P27kip1 and Ki-67 in pituitary adenomas: an investigation of marker of adenoma invasiveness. Acta Neurochir 141:187–192PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Andrej Šteňo
    • 1
    Email author
  • Jozef Bocko
    • 2
  • Boris Rychlý
    • 2
  • Martin Chorváth
    • 3
  • Peter Celec
    • 4
  • Martin Fabian
    • 5
  • Víťazoslav Belan
    • 5
  • Juraj Šteňo
    • 1
  1. 1.Department of NeurosurgeryComenius University, Faculty of Medicine, University Hospital BratislavaBratislavaSlovakia
  2. 2.Cytopathos s.r.o.BratislavaSlovakia
  3. 3.Department of Stereotactic RadiosurgerySt. Elisabeth Cancer InstituteBratislavaSlovakia
  4. 4.Institute of Molecular BiomedicineComenius University Faculty of MedicineBratislavaSlovakia
  5. 5.Dr. Magnet s.r.o.BratislavaSlovakia

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