Research Article: Contribution of molecular analysis to the typification of the non-functioning pituitary adenomas

Date Published: July 10, 2017

Publisher: Public Library of Science

Author(s): Laura Sanchez-Tejada, Ruth Sanchez-Ortiga, Cristina Lamas, Rosa Camara, Pedro Riesgo, Carmen Fajardo, Francisco Ignacio Aranda, Antonio Pico, Raul M. Luque.


The WHO Classification of Tumours of Endocrine Organs considers the inmunohistochemical characterization of pituitary adenomas (PA) as mandatory for patient diagnosis. Recent advances in the knowledge of the molecular patterns of these tumours could complement this classification with gene expression profiling.

Within the context of the Spanish Molecular Registry of Pituitary Adenomas (REMAH), a multicentre clinical-basic research project, we analysed the molecular phenotype of 142 PAs with complete IHC and clinical information. Gene expression levels of all pituitary hormones, type 1 corticotrophin-releasing hormone receptor, dopamine receptors and arginine vasopressin receptor 1b were measured by quantitative real-time polymerase chain reaction. In addition, we used three housekeeping genes for normalization and a pool of nine healthy pituitary glands from autopsies as calibration reference standard.

Based on the clinically functioning PA (FPA: somatotroph, corticotroph, thyrotroph and lactotroph adenomas), we established the interquartile range of relative expression for all genes studied in each PA subtype. That allowed molecularly the different PA subtypes, including the clinically non-functioning PA (NFPA). Afterwards, we estimated the concordance of the molecular and immunohistochemical classification with clinical diagnosis in FPA and between them in NFPA. The kappa values were higher in molecular than in immunohistochemical classification in FPA and showed a bad concordance in all NFPA subtypes.

According to these results, the molecular characterization of the PA complements the IHC analysis, allowing a better typification of the NFPA.

Partial Text

Pituitary adenomas (PA) constitute 10%–15% of intracranial neoplasms. They are currently classified according to their clinical, biochemical, radiological and inmunohistochemical (IHC) characteristics as well as their tumour behaviour [1, 2, 3].

The study was performed within the context of the Spanish Molecular Registry of Pituitary Adenomas (REMAH), a Spanish Multicentre Clinical-Basic Project [12]. The study complies with the Declaration of Helsinki and other applicable laws and received approval from the Local Ethics Committee (CEIC Hospital General Universitario de Alicante). None of the donors was from a vulnerable population and all donors or next of kin provided written informed consent that was freely given. One of the patients was 14 years old boy and his parents signed his informed consent.

In this study, we show the molecular typification of a large series of PA. The main strength of the article is the complete clinical, biochemical and immunohistochemical studies of all patients. Moreover, all molecular studies were performed in the same molecular laboratory. Conversely, the main limitation of the study is that the immunohistochemical studies were performed locally in the four University hospitals participants. As immunohistochemistry is a semi-quantitative technique and depends largely of the antibodies chosen, this fact biases significantly the inmunohistochemical results. Indeed, we observed an important variability in the IHC results between the four participating centresmeanwhile in the Lyon’s pathological series, using sensitive IHC techniques, the percentage of NC adenomas were reduced from 10% in 1992 to 1% in 2012 [16]. The variability in the IHC results between the four participating centres is detailed in “S3 Table”.

In this large series, molecular profiling showed higher accuracy than the immunohistochemical study in the identification of pituitary adenomas subtypes. This finding entails changes in the known prevalence of these tumours with possible clinical repercussions. Indeed, the prevalence of silent CT, a tumour PA subtype that often behaves aggressively, increases significantly with the molecular compared to IHC techniques. Moreover, gene expression allows reclassification of a large part of the IHC null cell adenomas. Therefore, the molecular profiling complements the pathological information of the IHC in the study of PA, although previous medical treatments may act as confounders by modifying the gene expression. Even though the not centralized performance of IHC analysis in this study could bias the IHC results, this fact increases the value of the molecular typification of PA as complement of the IHQ information in NFPA. However, it is worth highlighting the importance that an expert pathologist carefully identifies the used tissue for molecular analysis.




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