The role of hormonal status, morphological subtypes and proliferative marker Ki-67 labeling index on long-term outcomes in patients with acromegaly: a single tertiary center’s experience

Year 2023, Volume: 5 Issue: 4, 383 - 388, 27.10.2023

Çağlar Keskin , Mustafa Şahin , Saba Kiremitçi , Esra Erden Asena Gökçay Canpolat , Şule Canlar , Murat Cinel , Özge Baş Aksu , Özgür Demir , Rıfat Emral , Sevim Güllü , Demet Çorapçıoğlu

https://doi.org/10.38053/acmj.1343934

Abstract

Aims: Acromegaly is a rare disorder resulting from benign growth hormone secreting pituitary adenomas. Many factors affect long-term outcomes in acromegaly. In this study we aimed to investigate effects of hormonal status, morphological subtypes, immunohistochemical expression of pituitary hormones and Ki-67 labeling index on long-term outcomes in patients with acromegaly.
Methods:. We collected the medical and pathological records of sixty-four patients who underwent surgery for growth hormone (GH) secreting somatotroph tumors between 2005-2017.
Results: The remission rate after surgery was 48% (31/64) in all patients (33% for macroadenomas, 94% for microadenomas; p <0.001) with a median follow up of 48 months (12-198). There was no significant relationship between Ki-67 labeling index and remission status (p=0.140). The remission group were significantly older than the nonremission group [47 (21-67) vs 36 (18-56); p=0.012]. We found a statistically significant positive correlation between insulin-like growth factor 1 (IGF-1) levels and Ki-67 labeling index (r=+0.382, p=0.004). Also, there was a significant positive correlation between tumor size and GH (r=+0.368, p=0.027). There was no difference between densely and sparsely granulated adenomas in terms of surgical remission (p=0.866). In multivariate regression analysis, tumor size ≥ 10 mm (macroadenoma) was significant independent variable in predicting remission [95% CI [16.95 (1.92-142)]; p=0.011]. The baseline cortisol levels was correlated negatively with the Ki-67 labeling index (r=+0.293, p=0.02).
Conclusion: The Ki-67 labeling index was not associated with surgical remission in patients with acromegaly. However, the Ki-67 labeling index was higher in younger patients and those with larger adenomas.

Keywords

Acromegaly, Ki-67 labeling index, Growth Hormone, Remission

References

• Hazer DB, Işık S, Berker D, et al. Treatment of acromegaly by endoscopic transsphenoidal surgery: surgical experience in 214 cases and cure rates according to current consensus criteria. J Neurosurg. 2013;119(6):1467-1477.
• Nomikos P, Buchfelder M, Fahlbusch R. The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical ‘cure’. Eur J Endocrinol. 2005;152(3):379-387.
• Katznelson L, Laws ER, Melmed S, et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933-3951.
• Rieger A, Rainov NG, Ebel H, et al. Factors predicting pituitary adenoma invasiveness in acromegalic patients. Neurosurg Rev. 1997;20(3):182-187.
• Fusco A, Zatelli MC, Bianchi A, et al. Prognostic significance of the Ki-67 labeling index in growth hormone-secreting pituitary adenomas. J Clin Endocrinol Metab. 2008;93(7):2746-2750.
• Alimohamadi M, Ownagh V, Mahouzi L, Ostovar A, Abbassioun K, Amirjmshidi A. The impact of immunohistochemical markers of Ki-67 and p53 on the long-term outcome of growth hormone-secreting pituitary adenomas: a cohort study. Asian J Neurosurg. 2014;9(3):130-136.
• Thapar K, Kovacs K, Scheithauer BW, et al. Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery. 1996;38(1):99-106; discussion -7.
• Filippella M, Galland F, Kujas M, et al. Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study. Clin Endocrinol (Oxf). 2006;65(4):536-543.
• Salehi F, Agur A, Scheithauer BW, Kovacs K, Lloyd RV, Cusimano M. Ki-67 in pituitary neoplasms: a review--part I. Neurosurgery. 2009;65(3):429-437; discussion 37.
• Knosp E, Kitz K, Perneczky A. Proliferation activity in pituitary adenomas: measurement by monoclonal antibody Ki-67. Neurosurgery. 1989;25(6):927-930.
• Giustina A, Chanson P, Bronstein MD, et al. A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab. 2010;95(7):3141-148.
• Melmed S, Braunstein GD, Horvath E, Ezrin C, Kovacs K. Pathophysiology of acromegaly. Endocr Rev. 1983;4(3):271-290.
• Wang YY, Waqar M, Abou-Zeid A, et al. Value of early post-operative growth hormone testing in predicting long-term remission and residual disease after transsphenoidal surgery for acromegaly. Neuroendocrinology. 2022;112(4):345-357.
• Antunes X, Ventura N, Camilo GB, et al. Predictors of surgical outcome and early criteria of remission in acromegaly. Endocrine. 2018;60(3):415-422.
• Babu H, Ortega A, Nuno M, et al. Long-term endocrine outcomes following endoscopic endonasal transsphenoidal surgery for acromegaly and associated prognostic factors. Neurosurgery. 2017;81(2):357-366.
• Jaffrain-Rea ML, Di Stefano D, Minniti G, et al. A critical reappraisal of MIB-1 labelling index significance in a large series of pituitary tumours: secreting versus non-secreting adenomas. Endocr Relat Cancer. 2002;9(2):103-113.
• Mohseni S, Aboeerad M, Sharifi F, Tavangar SM, Mohajeri-Tehrani M. Associations of Ki-67 labeling index with clinical and paraclinical features of growth hormone-secreting pituitary adenomas: a single center report from Iran. Int J Endocrinol Metab. 2019;17(2):e81983.
• Pinto EM, Bronstein MD. [Molecular aspects of pituitary tumorigenesis]. Arq Bras Endocrinol Metabol. 2008;52(4):599-610.
• Mastronardi L, Guiducci A, Puzzilli F. Lack of correlation between Ki-67 labelling index and tumor size of anterior pituitary adenomas. BMC Cancer. 2001;1:12.
• Mazal PR, Czech T, Sedivy R, et al. Prognostic relevance of intracytoplasmic cytokeratin pattern, hormone expression profile, and cell proliferation in pituitary adenomas of akromegalic patients. Clin Neuropathol. 2001;20(4):163-171.
• Yamada S, Aiba T, Sano T, et al. Growth hormone-producing pituitary adenomas: correlations between clinical characteristics and morphology. Neurosurgery. 1993;33(1):20-27.
• Obari A, Sano T, Ohyama K, et al. Clinicopathological features of growth hormone-producing pituitary adenomas: difference among various types defined by cytokeratin distribution pattern including a transitional form. Endocr Pathol. 2008;19(2):82-91.
• Brzana J, Yedinak CG, Gultekin SH, Delashaw JB, Fleseriu M. Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience. Pituitary. 2013;16(4):490-498.
• Swanson AA, Erickson D, Donegan DM, et al. Clinical, biological, radiological, and pathological comparison of sparsely and densely granulated somatotroph adenomas: a single center experience from a cohort of 131 patients with acromegaly. Pituitary. 2021;24(2):192-206.
• Shahrestani S, Cardinal T, Micko A, et al. Neural network modeling for prediction of recurrence, progression, and hormonal non-remission in patients following resection of functional pituitary adenomas. Pituitary. 2021;24(4):523-529.
• Sakayama K, Mashima N, Kidani T, Miyazaki T, Yamamoto H, Masuno H. Effect of cortisol on cell proliferation and the expression of lipoprotein lipase and vascular endothelial growth factor in a human osteosarcoma cell line. Cancer Chemother Pharmacol. 2008;61(3):471-479.
• Dong J, Li J, Cui L, et al. The proliferative effect of cortisol on bovine endometrial epithelial cells. Reprod Biol Endocrinol. 2019;17(1):97.
• Fernandez-Rodriguez E, Casanueva FF, Bernabeu I. Update on prognostic factors in acromegaly: is a risk score possible? Pituitary. 2015;18(3):431-440.
• Yildirim AE, Sahinoglu M, Divanlioglu D, et al. Endoscopic endonasal transsphenoidal treatment for acromegaly: 2010 consensus criteria for remission and predictors of outcomes. Turk Neurosurg. 2014;24(6):906-912.
• Shirvani M, Motiei-Langroudi R. Transsphenoidal surgery for growth hormone-secreting pituitary adenomas in 130 patients. World Neurosurg. 2014;81(1):125-130.