Elsevier

Human Pathology

Volume 44, Issue 11, November 2013, Pages 2400-2409
Human Pathology

Original contribution
Galectin-3 expression in pituitary adenomas as a marker of aggressive behavior

https://doi.org/10.1016/j.humpath.2013.05.020Get rights and content

Summary

The purpose of this retrospective study was to investigate the role of galectin-3 (LGALS3) expression in predicting the recurrence and the progression potential of prolactin (PRL) and adrenocorticotropic hormone (ACTH)–producing pituitary adenomas and its correlation with the RUNX1 and RUNX2 transcription factors involved in the regulation mechanism of LGALS3 expression. Clinical, neuroradiologic, and follow-up data from 92 pituitary adenomas, including 59 PRL cell adenomas and 33 ACTH-functioning pituitary adenomas, were collected. The LGALS3 expression was analyzed by both immunohistochemistry and quantitative real time-polymerase chain reaction, whereas RUNX1 and RUNX2 were analyzed by quantitative real time-polymerase chain reaction only. The data obtained indicated that invasive growth with suprasellar extension, Ki-67 labeling index, and LGALS3 immunohistochemical and/or LGALS3 messenger RNA levels are the most important histologic features for assessing a high risk of progression or recurrence of PRL- and ACTH-functioning pituitary adenomas. Multivariate Cox regression analysis assessed LGALS3 immunohistochemical positivity in at least 30% of neoplastic cells and/or LGALS3 messenger RNA positivity (P < .001) as strong predictive factors of recurrence/tumor progression followed by a Ki-67 labeling index greater than 3% (P = .019) in the 81 cases in which follow-up data were available. In addition, a significant correlation between LGALS3 and RUNX1 expression levels (P = .0435) was found. This retrospective immunohistochemical and molecular study demonstrated that LGALS3 expression appeared to be a predictive factor of the aggressive behavior of PRL- and ACTH-functioning pituitary adenomas, and its expression was correlated with RUNX1 expression levels.

Introduction

Galectin-3 (LGALS3) is a β-ganglioside binding lectin that is up-regulated during neoplastic progression and metastasis in several human malignancies such as in thyroid, colon, liver, and brain tumors [1]. Therefore, LGALS3 expression has been proposed as a potential diagnostic and/or prognostic marker in tumors located in different organs [1], [2], [3], [4].

In the pituitary gland, a unique phenomenon is observed: LGALS3 is expressed in normal prolactin (PRL)- and adrenocorticotropin (ACTH)-producing cells as well as in folliculostellate cells. A different distribution of LGALS3 gene products and LGALS3 protein in pituitary tumors (both adenomas and carcinomas) has been reported, with the highest level of LGALS3 expression in PRL and functioning ACTH pituitary adenomas (PAs) with respect to normal PRL- and ACTH-producing cells [5].

Previous studies on pituitary tumorigenesis have speculated that pituitary carcinoma develops from an adenoma through a stepwise series of genetic alterations [6] including overexpression of the LGALS3 gene and the LGALS3 protein [5]. Furthermore, Jin et al [7] pointed out that, in ACTH-subtype adenomas, LGALS3 is a useful immunohistochemical marker for differentiating silent from functioning ACTH PAs.

Zhang et al [8] suggested that RUNX1 and RUNX2, RUNX family transcription factors that allow tumor proliferation and progression, are involved in the regulation mechanism of LGALS3 expression in both normal and neoplastic pituitary glands. Accordingly, RUNX1 and RUNX 2 up-regulate the LGALS3 gene by direct binding to its promoter region, therefore partially contributing to pituitary tumor growth regulation.

Recently, Stilling et al [9], examining the expression of specific microRNAs in normal pituitary tissue and in ACTH tumors, found that microRNA-493, which binds the LGALS3 and RUNX2 genes, is up-regulated in ACTH carcinomas as compared with adenomas and normal pituitary tissue.

The purpose of this study was to investigate the role of LGALS3 overexpression in predicting the recurrence and the progression potential of PRL- and ACTH-functioning PAs using immunohistochemistry and quantitative real time-polymerase chain reaction (qRT-PCR) and its correlation with RUNX1 and RUNX2 transcription factors.

Section snippets

Cases

All PRL- and ACTH-functioning PAs present in the files of the Section of Anatomic Pathology of the Department of Biomedical and Neuromotor Sciences of the University of Bologna at Bellaria Hospital from January 1992 to December 2009 were retrieved. Moreover, 61 PAs of other main types (25 silent type I or II ACTH, 14 null cell, 6 gonadotropic cell, 11 growth hormone [GH; 6 densely and 5 sparsely granulated], 4 mammosomatotroph, and 1 thyrotropin [TSH]) were randomly selected as negative

Clinical and pathologic features

Ninety-two PAs met the inclusion criteria, 59 PRL cell adenomas and 33 ACTH-functioning PAs. Patient age ranged from 12 to 78 years (mean, 38 years) at the time of the first surgical treatment. Fifty-nine patients (64.1%) were female, and 33 (35.9%) were male.

On operative and neuroradiologic inspection, most tumors (56/92; 60.9%) were macroadenomas with suprasellar extension in 34 patients (36.9%) and tumor invasion in 21 patients (22.8%). A high mitotic index (>1 per 10 high-power field [HPF])

Discussion

Although mechanisms regulating pituitary tumor development and progression are still unclear, some light has been shed on the biology of these tumors by recent studies [13], [14], demonstrating that gene expression disruption driven by epigenetic changes has an important role in pituitary tumorigenesis [15], [16]. In particular, recent studies have suggested that methylation is important for the regulation of LGALS3 expression in normal and neoplastic pituitary glands [4]. These analyses showed

Acknowledgments

We thank Dr Greta Maini for helping with the molecular analysis.

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Funding: This work was financed by grants from University of Bologna and from Associazione Sostegno e Assistenza Neoplasie (ASAN), Bologna. Elisa Leonardi was supported by a Sandro Cavagnino and Vanda Vanini Grant from the Centro Interdipartimentale Ricerca sul Cancro (CIRC) “Giorgio Prodi,” University of Bologna.

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