Clinical Tumor Growth and Comparison with Proliferation Markers in Non-functioning (Inactive) Pituitary Adenomas

Abstract

Background: As the development of clinically silent pituitary adenomas is not yet fully understood, the radiologically measured growth of inactive pituitary adenomas should be compared with adenoma classification and immunostainings for proliferation markers.

Material and methods: In 32 patients with non-functioning adenomas (NFA) from 45 operations with retrospectively available preoperative series of magnetic resonance imaging (MRI) we measured the largest growing diameter (LGD) in mm/ year. The adenomas were immunostained for Ki-67 (MiB-1), PCNA, p53 protein, IGF- and PTH-related protein. The positive nuclei for MiB-1, PCNA, and p53 protein were counted and their labelling indices (LI) were calculated. The clinical measurements were compared with these data and were statistically analysed (Spearman test, Whitney-U-test).The growth rate per year was available in 28 cases. We chosed three grades of LGD: less than 1.5 mm in diameter in 9 patients (32%), between 1.5 and 3.0 mm in 11 patients (39%) and more than 3.0 mm in 8 patients (29%).

Results: MiB-1 positive nuclei were found in 42% of adenomas, PCNA positive nuclei in 58% and p53 positive nuclei in 16%. IGF 1 was immuno-stained in 84% of adenomas. The mean LI for MiB-1 was 0.12 in adenomas growing less than 1.5 mm and 0.34 in adenomas growing more than 1.5 mm per year. For non-invasive adenomas, the MiB-1 LI was 0.03, for invasive adenomas it was 0.126 and for strongly invasive adenomas 0.212. The MiB-1 LI was lower in null cell adenomas than in FSH/LH adenomas. All these data for MiB-1 showed no statistically significant differences (p<0.05). PCNA LI in adenomas growing less than 1.5 mm per year was 0.51 in contrast to LI of 1.12 for those growing more than 1.5 mm. In non-invasive adenomas the PCNA LI was 0.796, in invasive adenomas 0.655 and in diffuse strongly invasive ones 1.011. Null cell adenomas had a lower PCNA LI than FSH/LH cell adenomas.

Conclusions: Statistically significant differences were measured for the growth rate und the PCNA expression. P53 was immunostained in invasive adenomas only. There were no correlations to the clinical growth rate, but p53 expression correlated significantly to numbers of MiB-1 positive nuclei and PCNA positive nuclei. IGF-I expression was found to correlate inversely with age of patients. We recommend the use of PCNA if correlations to progression of tumor growth are wanted.

non-functioning (inactive) pituitary adenoma - pituitary - tumor growth - digital follow-up - Ki-67 - PCNA - p53 - IGF-I

References

• 1 Atkin SL, Green VL, Hipkin LJ, Landolt AM, Foy PM, Jeffreys RV, White MC. A comparison of proliferation indices in human anterior pituitary adenomas using formalin-fixed tissue and in vitro cell culture.  J Neurosurg. 1997;  87 85-88
• 2 Blevins LS, Verity DK, Allen G. Aggressive pituitary tumors.  Oncology. 1998;  12 1307-1316
• 3 Buchfelder M, Fahlbusch R, Adams EF, Kiesewetter F, Thierauf P. Proliferation parameters for pituitary adenomas.  acta neurochir (Wien). 1996;  65 (Suppl) 18-21
• 4 Buckley N, Bates AS, Broome JC, Strange RC, Perrett CW, Burke CW, Clayton RN. P53 protein accumulates in Cushings adenomas and invasive non- functional adenomas.  J Clin Endocrinol Metab. 1994;  79 1513-1516
• 5 Ekramullah SM, Saitoh Y, Arita N, Ohnishi T, Hayakawa T. The correlation of Ki-67 staining indices with tumor doubling times in regrowing non-functioning pituitary adenomas.  acta neurochir (Wien). 1996;  138 1449-1455
• 6 Espay AJ, Azzarelli B, Williams LS, Bodensteiner JB. Recurrence in pituitary adenomas in childhood and adolescence.  J Child Neurol. 2001;  16 364-367
• 7 Ezzat S, Snyder PJ, Young WF, Boyajy LD, Newman C, Klibanski A, Molitch ME, Boyd AE, Sheeler L, Cook DM. Octreotide treatment of acromegaly. A randomized, multicenter study.  Ann Intern Med. 1992;  117 711-718
• 8 Fellbaum C, Radaszkiewicz T, Ruhri C, Putz B, Lehmacher W, Hofler H. c-myc mRNA expression in non-Hodgkin's lymphomas.  Virchows Arch B Cell Pathol. 1992;  62 61-68
• 9 Gandour-Edwards R, Kapadia SB, Janecka IP, Martinez AJ, Barnes L. Biologic markers of invasive pituitary adenomas involving the sphenoid sinus.  Modern Pathol. 1995;  8 160-164
• 10 Hentschel SJ, MacCutcheon IE, Moore W, Durity FA. P53 and MIB-1 immunohistochemistry as predictors of the clinical behavior of nonfunctioning pituitary adenomas.  Canad J Neurol Sci. 2003;  30 215-219
• 11 Honegger J, Prettin C, Feuerhake F, Petrick M, Schulte-Monting J, Reincke M. Expression of Ki-67 antigen in nonfunctioning pituitary adenomas: correlation with growth velocity and invasiveness.  J Neurosurg. 2003;  99 674-679
• 12 Hough AJ, Hollifield JW, Page DL, Hartmann WH. Prognostic factors in adrenal cortical tumours.  Amer J Clin Pathol. 1979;  72 390-399
• 13 Hsu DW, Hakim F, Biller BM, Monte S, Zervas NT, Klibanski A, Hedley WE. Significance of proliferating cell nuclear antigen index in predicting pituitary adenoma recurrence.  J Neurosurg. 1993;  78 753-761
• 14 Ito M, Enomoto H, Usa T, Villadolid MC, Ohtsuru A, Namba H. et al . Expression of parathyroid hormone related peptide in human pituitary tumours.  J clin Pathol. 1993;  46 682-683
• 15 Kawamoto H, Uozumi T, Arita K, Yano T, Hirohata T. Analysis of the growth rate and cavernous sinus invasion of pituitary adenomas.  acta neurochir (Wien). 1995;  136 37-43
• 16 Klencki M, Kurnatowska I, Slowinska-Klencka D, Lewinski A, Pawlikowski M. Correlation between PCNA expression and AgNOR dots in pituitary adenomas.  Endocr Pathol. 2001;  12 163-169
• 17 Lloyd RV, Kovacs K, Young Jr WF, Farrell WE, Asa SL, Trouillas J, Kontogeorgos G, Sano T, Scheithauer BW, Horvath E, Watson Jr RE, Lindell EP, Barkan AL, Saeger W, Nosé V, Osamura RY, Ezzat S, Yamada S, Roncaroli F, Lopes MBS, Vidal Ruibal S. Tumours of the pituitary gland. In: DeLellis RA, Lloyd RV, Heitz PU, eds. Pathology and Genetics. Tumours of Endocrine Tumours. 1 ed. Lyon: International Agency for Research and Cancer (IARC) 2004: 9-48
• 18 Lüdecke DK, Lüdecke B, Abe T, Saeger W. Management of large non-secreting pituitary adenomas: Prognostication of growth and regrowth.  Endocr Pathol. 1998;  9 409
• 19 Rudolph P, MacGrogan G, Bonichon F, Frahm SO, Mascarel I, Trojani M, Durand M, Avril A, Coindre JM, Parwaresch R. Prognostic significance of Ki-67 and topoisomerase II alpha expression in infiltrating ductal carcinoma of the breast. A multivariate analysis of 863 cases.  Breast Cancer Res Treat. 1999;  55 61-71
• 20 Spada A. Growth factors and human pituitary adenomas.  Eur J Endocrin. 1998;  138 255-257
• 21 Thapar K, Kovacs K, Scheithauer BW, Stefaneanu L, Horvath E, Pernicone PJ, Murray D, Laws Jr ER. Proliferative activity and invasiveness among pituitary adenomas and carcinomas: An analysis using the MIB-1 antibody.  Neurosurgery. 1996;  38 99-106
• 22 Thapar K, Scheithauer BW, Kovacs K, Pernicone PJ, Laws Jr ER. p53 expression in pituitary adenomas and carcinomas: Correlation with invasiveness and tumor growth fractions.  Neurosurgery. 1996;  38 765-770
• 23 Slooten H van, Schaberg A, Smeenk D, Moolenaar AJ. Morphologic characteristics of benign and malignant adrenocortical tumors.  Cancer. 1985;  55 766-773
• 24 Weiss LM, Medeiros LJ, Vickery AL. Pathologic features of prognostic significance in adrenal cortical carcinoma.  Amer J Surg Pathol. 1989;  13 202-206

Correspondence