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01-03-2014 | Clinical Article - Brain Tumors

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

Authors: Andrej Šteňo, Jozef Bocko, Boris Rychlý, Martin Chorváth, Peter Celec, Martin Fabian, Víťazoslav Belan, Juraj Šteňo

Published in: Acta Neurochirurgica | Issue 3/2014

Abstract

Background

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.

Methods

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).

Results

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).

Conclusions

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.

Abe T, Sanno N, Osamura YR, Matsumoto K (1997) Proliferative potential in pituitary adenomas: measurement by monoclonal antibody MIB-1. Acta Neurochir 139:613–618PubMedCrossRef

Brown DC, Gatter KC (1990) Monoclonal antibody Ki-67: its use in histopathology. Histopathology 17:489–503PubMedCrossRef

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 68:860–866PubMedCrossRef

Cottier JP, Destrieux C, Brunereau L, Bertrand P, Moreau L, Jan M, Herbreteau D (2000) Cavernous sinus invasion by pituitary adenoma: MR imaging. Radiology 215:463–469PubMedCrossRef

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 32:1060–1071PubMedCrossRef

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 91:1796–1801PubMedCrossRef

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 157:141–147PubMedCrossRef

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 138:1449–1455PubMedCrossRef

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 24:3427–3435PubMedCrossRef

10.

Fedele M, Fusco A (2010) Role of the high mobility group A proteins in the regulation of pituitary cell cycle. J Mol Endocrinol 44:309–318PubMedCrossRef

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 155:823–829PubMedCrossRef

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 65:536–543CrossRef

13.

Fusco A, Fedele M (2007) Roles of HMGA proteins in cancer. Nat Rev Cancer 7:899–910PubMedCrossRef

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 39:758–766PubMedCrossRef

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 133:1710–1715PubMed

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 4:107–113

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 58:763–769CrossRef

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 30:215–219PubMed

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 99:674–679PubMedCrossRef

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 162:1027–1033PubMedCrossRef

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 9:103–113PubMedCrossRef

22.

Jane JA, Thapar K, Laws ER (2011) Pituitary Tumors: Functioning and Nonfunctioning. In: Winn RH (ed) Youmans Neurological Surgery. Elsevier Saunders, pp 1476–1510

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 136:37–43PubMedCrossRef

24.

Knosp E, Kitz K, Perneczky A (1989) Proliferation activity in pituitary adenomas: measurement by monoclonal antibody Ki-67. Neurosurgery 25:927–930PubMedCrossRef

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 33:610–617PubMedCrossRef

26.

Landolt AM, Shibata T, Kleihues P (1987) Growth rate of human pituitary adenomas. J Neurosurg 67:803–806PubMedCrossRef

27.

Lath R, Chacko G, Chandy MJ (2001) Determination of Ki-67 labeling index in pituitary adenomas using MIB-1 monoclonal antibody. Neurol India 49:144–147PubMed

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 43:432–438PubMedCrossRef

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 10–47

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 47:1313–1318PubMedCrossRef

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 108:525–532PubMedCrossRef

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 45:72–77PubMed

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 52:107–111PubMedCrossRef

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 1:12PubMedCentralPubMedCrossRef

35.

Matsuyama J (2012) Ki-67 expression for predicting progression of postoperative residual pituitary adenomas: correlations with clinical variables. Neurol Med Chir (Tokyo) 52:563–569CrossRef

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:E11PubMedCrossRef

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 139:426–431PubMedCrossRef

38.

Nakabayashi H, Sunada I, Hara M (2001) Immunohistochemical analyses of cell cycle-related proteins, apoptosis, and proliferation in pituitary adenomas. J Histochem Cytochem 49:1193–1194PubMedCrossRef

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 20:489–494PubMedCentralPubMedCrossRef

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 74:71–76PubMedCrossRef

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):71–74PubMedCrossRef

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 37:235–243PubMedCrossRef

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 43:1627–1637PubMedCrossRef

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 58:418–423PubMedCrossRef

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 15:71–83PubMedCentralPubMedCrossRef

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 156:203–216PubMedCrossRef

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 116:80–85PubMedCrossRef

48.

Salehi F, Agur A, Scheithauer BW, Kovacs K, Lloyd RV, Cusimano M (2009) Ki-67 in pituitary neoplasms: a review–part I. Neurosurgery 65:429–437PubMedCrossRef

49.

Salehi F, Agur A, Scheithauer BW, Kovacs K, Lloyd RV, Cusimano M (2010) Biomarkers of pituitary neoplasms: a review (Part II). Neurosurgery 67:1790–1798PubMedCrossRef

50.

Sav A, Rotondo F, Syro LV, Scheithauer BW, Kovacs K (2012) Biomarkers of pituitary neoplasms. Anticancer Res 32:4639–4654PubMed

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 59:341–353PubMedCrossRef

52.

Schreiber S, Saeger W, Lüdecke DK (1999) Proliferation markers in different types of clinically non-secreting pituitary adenomas. Pituitary 1:213–220PubMedCrossRef

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 146:179–186PubMedCrossRef

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 98:359–365PubMedCrossRef

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 38:99–106PubMedCrossRef

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 51:281–284CrossRef

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 82:1441–1445PubMedCentralPubMedCrossRef

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 67:863–869PubMedCrossRef

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 56:501–509PubMedCrossRef

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 111:563–571PubMedCrossRef

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 146:1323–1327PubMedCrossRef

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 146:831–839PubMed

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 53:713–717CrossRef

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 61:580–584PubMedCrossRef

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 23:226–231PubMed

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 49:857–862PubMed

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 114:336–344PubMedCrossRef

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 141:187–192PubMedCrossRef

Title: Nonfunctioning pituitary adenomas: association of Ki-67 and HMGA-1 labeling indices with residual tumor growth
Authors: Andrej Šteňo
Jozef Bocko
Boris Rychlý
Martin Chorváth
Peter Celec
Martin Fabian
Víťazoslav Belan
Juraj Šteňo
Publication date: 01-03-2014
Publisher: Springer Vienna
Published in: Acta Neurochirurgica / Issue 3/2014
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
DOI: https://doi.org/10.1007/s00701-014-1993-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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