Fibroblast Growth Factor Receptor-4 Expression in Pituitary Adenomas is Associated with Aggressive Tumor Features

Abstract

Purpose To investigate the relationship of Fibroblast Growth Factor Receptor-4 (FGFR-4) expression with radiologic, pathologic, and clinical parameters in pituitary adenomas.

Methods Among 307 patients who underwent pituitary surgery for a pituitary adenoma between 2000 and 2015, we included 161 patients (53 gonadotroph, 26 corticotroph, 25 null cell, 22 lactotroph, 13 somatotroph, 8 adenomas with unusual combination, 7 Pit-1 positive adenomas, and 7 lactosomatotroph) based on availability of pathology specimens. Patients’ radiologic, pathologic, and clinical parameters were determined. FGFR-4 immunostaining was evaluated using a semi-quantitative histologic score (H-score).

Results The mean follow-up period was 61 (IQR=32–84) months. The median H-scores for FGFR-4 were higher in patients without remission, those with residual lesion, and T2-hyperintense adenoma (p<0.05). Ki-67 level was higher in patients without remission compared to those in remission (p<0.05). The mean Ki-67 levels did not differ between patients with and without residual lesion or T2-hyperintense tumor (p>0.05). There was no significant difference (p>0.05) when the H-score and Ki-67 levels were assessed in terms of sex, sellar-dural invasion, Knosp and a grading system for superior, inferior, parasellar, anterior and posterior tumor extension Classification, tumor function or presence of poor subtype. Adenomas with Ki-67 expression ≥3% had higher FGFR4 expression levels than those with <3% expression (p=0.002). There was a weak positive correlation between H-score and Ki-67 (p=0.011; r=0.201).

Conclusions Higher levels of FGFR-4 in pituitary adenomas could be use a marker for more aggressive tumor behavior.

Key words

FGFR-4 - Ki-67 - pituitary adenomas - tumor aggressiveness

Publication History

Received: 27 October 2020
Received: 06 May 2021

Accepted: 27 May 2021

Article published online:
12 July 2021

• References

• 1 Mete O, Ezzat S, Asa SL. Biomarkers of aggressive pituitary adenomas. J Mol Endocrinol 2012; 49: R69-R78
• 2 Asa SL, Ezzat S. Genetics and proteomics of pituitary tumors. Endocrine 2005; 28: 043-048
• 3 Trouillas J, Roy P, Sturm N. et al. A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case–control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathol 2013; 126: 123-135
• 4 Serioli S, Doglietto F, Fiorindi A. et al. Pituitary adenomas and invasiveness from anatomo-surgical, Radiological, and Histological Perspectives: a systematic literature review. Cancers (Basel) 2019; 11: 1936
• 5 Nishioka H, Inoshita N. New WHO classification of pituitary adenomas (4th edition): assessment of pituitary transcription factors and the prognostic histological factors. Brain Tumor Pathol 2018; 35: 57-61
• 6 Trouillas J, Jaffrain-Rea M-L, Vasiljevic A. et al. How to classify pituitary neuroendocrine tumors (PitNET)s in 2020. Cancers (Basel) 2020; 12: 514
• 7 McCormack A, Dekkers OM, Petersenn S. et al. Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. Eur J Endocrinol 2018; 178: 265-276
• 8 Ezzat S, Smyth HS, Ramyar L, Asa SL. Heterogenous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas. J Clin Endocrinol Metab 1995; 80: 878-884
• 9 Ezzat S. The role of hormones, growth Ffctors and their receptors in pituitary tumorigenesis. Brain Pathol 2006; 11: 356-370
• 10 Ramírez C, Cheng S, Vargas G. et al. Expression of Ki-67, PTTG1, FGFR4, and SSTR 2, 3, and 5 in nonfunctioning pituitary adenomas: A high throughput TMA, immunohistochemical study. J Clin Endocrinol Metab 2012; 97: 1745-1751
• 11 Tateno T, Asa SL, Zheng L. et al. The FGFR4-G388R polymorphism promotes mitochondrial STAT3 serine phosphorylation to facilitate pituitary growth hormone cell tumorigenesis. PLoS Genet 2011; 7: e1002400
• 12 Nakano-Tateno T, Tateno T, Hlaing MM. et al. FGFR4 polymorphic variants modulate phenotypic features of cushing disease. Mol Endocrinol 2014; 28: 525-533
• 13 Qian ZR, Sano T, Asa SL. et al. Cytoplasmic expression of fibroblast growth factor receptor-4 in human pituitary adenomas: relation to tumor type, size, proliferation, and invasiveness. J Clin Endocrinol Metab 2004; 89 -1904 1911
• 14 Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 2000; 7: 165-197
• 15 Ezzat S, Zheng L, Asa SL. Pituitary tumor-derived fibroblast growth factor receptor 4 isoform disrupts neural cell-adhesion molecule/N-cadherin signaling to diminish cell adhesiveness: a mechanism underlying pituitary neoplasia. Mol Endocrinol 2004; 18: 2543-2552
• 16 Cavallaro U, Niedermeyer J, Fuxa M, Christofori G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol 2001; 3: 650-657
• 17 Ezzat S, Zheng L, Zhu X-F. et al. Targeted expression of a human pituitary tumor–derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis. J Clin Invest 2002; 109: 69-78
• 18 Gejman R, Swearingen B, Hedley-Whyte ET. Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Hum Pathol 2008; 39: 758-766
• 19 Lee EH, Kim KH, Kwon JH, Kim HD, Kim YZ. Results of immunohistochemical staining of cell-cycle regulators: The prediction of recurrence of functioning pituitary adenoma. World Neurosurg 2014; 81: 563-575
• 20 Miermeister CP, Petersenn S, Buchfelder M. et al. Histological criteria for atypical pituitary adenomas – data from the German pituitary adenoma registry suggests modifications. Acta Neuropathol Commun 2015; 3: 50
• 21 Noh T-W, Jeong HJ, Lee M-K. et al. Predicting recurrence of nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 2009; 94: 4406-4413
• 22 Hasanov R, Aydoğan Bİ, Kiremitçi S. et al. The Prognostic roles of the Ki-67 proliferation index, P53 expression, mitotic index, and radiological tumor invasion in pituitary adenomas. Endocr Pathol 2019; 30: 49-55
• 23 Hentschel SJ, McCutcheon IE, Moore W. et al. p53 and MIB-1 immunohistochemistry as predictors of the clinical behavior of nonfunctioning pituitary adenomas. Can J Neurol Sci 2003; 30: 215-219
• 24 Yamada S, Ohyama K, Taguchi M. et al. A study of the correlation between morphological findings and biological activities in clinically nonfunctioning pituitary adenomas. Neurosurgery 2007; 61: 580-585
• 25 Knosp E, Steiner E, Kitz K. et al. Pituitary adenomas with invasion of the cavernous sinus space. Neurosurgery 1993; 33: 610-618
• 26 Edal AL, Skjodt K, Nepper-Rasmussen HJ. SIPAP: A new MR classification for pituitary adenomas. Acta Radiol 1997; 38: 30-36
• 27 Heck A, Ringstad G, Fougner SL. et al. Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly. Clin Endocrinol (Oxf) 2012; 77: 72-78
• 28 Katznelson L, Laws ER, Melmed S. et al. Acromegaly: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014; 99: 3933-3951
• 29 Ozkaya HM, Keskin FE, Tuten A. et al. Late-night salivery cortisol is unadulterated in patients with polycystic ovarian syndrome (PCOS), irrespective of disease phenotype, and in obese women, irrespective of the presence of PCOS. Endocr Pract 2017; 23: 1045-1052
• 30 Nieman LK, Biller BMK, Findling JW. et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93: 1526-1540
• 31 Amlashi FG, Swearingen B, Faje AT. et al. Accuracy of late-night salivary cortisol in evaluating postoperative remission and recurrence in Cushing’s disease. J Clin Endocrinol Metab 2015; 100: 3770-3777
• 32 Rutkowski MJ, Aghi MK. Medical versus surgical treatment of prolactinomas: an analysis of treatment outcomes. Expert Rev Endocrinol Metab 2018; 13: 25-33
• 33 Gerges MM, Rumalla K, Godil SS. et al. Long-term outcomes after endoscopic endonasal surgery for nonfunctioning pituitary macroadenomas. J Neurosurg 2021; 535-546
• 34 Osamura RY, Lopes MBS, Grossman A. et al. Introduction. World Heal Organ Classif Tumours Endocr Organs. 4th ed.. Lyon: 2017: 1
• 35 Osamura RY, Lopes MBS, Grossman A. et al. Pituitary adenoma. World Heal. Organ. Classif. tumours Endocr. organs. 4th ed.. Lyon: 2017: 14-18
• 36 Yao X, Gao H, Li C. et al. Analysis of Ki67, HMGA1, MDM2, and RB expression in nonfunctioning pituitary adenomas. J Neurooncol 2017; 132: 199-206
• 37 Monsalves E, Larjani S, Loyola Godoy B. et al. Growth patterns of pituitary adenomas and histopathological correlates. J Clin Endocrinol Metab 2014; 99: 1330-1338
• 38 Brito LP, Lerário AM, Bronstein MD. et al. Influence of the fibroblast growth factor receptor 4 expression and the G388R functional polymorphism on Cushing’s disease outcome. J Clin Endocrinol Metab 2010; 95: E271-E279
• 39 Itoh N, Ornitz DM. Functional evolutionary history of the mouseFgf gene family. Dev Dyn 2008; 237: 18-27
• 40 Kosaka N, Sakamoto H, Terada M. et al. Pleiotropic function of FGF-4: its role in development and stem cells. Dev Dyn 2009; 238: 265-276
• 41 Kook S-H, Jeon Y-M, Lim S-S. et al. Fibroblast growth factor-4 enhances proliferation of mouse embryonic stem cells via activation of c-Jun signaling. PLoS One 2013; 8: e71641
• 42 Morita K, Takano K, Yasufuku-Takano J. et al. Expression of pituitary tumour-derived, N-terminally truncated isoform of fibroblast growth factor receptor 4 (ptd-FGFR4) correlates with tumour invasiveness but not with G-protein alpha subunit ( gsp ) mutation in human GH-secreting pituitary adenomas. Clin Endocrinol (Oxf) 2008; 68: 435-441
• 43 Key G, Becker MHG, Baron B. et al. New Ki-67-equivalent murine monoclonal antibodies (MIB 1-3) generated against bacterially expressed parts of the Ki-67 cDNA containing three 62 base pair repetitive elements encoding for the Ki-67 epitope. Lab Investig 1993; 68: 629-636