Endocrine Abstracts (2009) 20 S12.3

Molecular and histological prognostic markers in pituitary tumors

J Trouillas1,2, A Wierinckx1,4, C Auger1,2, E Jouanneau3, M Jan5, L Villeneuve3, E Dantony6, G Raverot1,2 & J Lachuer1,2

1INSERM, U842, Lyon, France; 2Université de Lyon1, Faculté de Médecine Laennec, Lyon, France; 3Hospices Civils de Lyon, Lyon, France; 4ProfileXpert, Bron, Lyon, France; 5Faculté de Médecine, département de Neurochirurgie, Tours, France; 6UMR 5558, Laboratoire Biostatistique santé, Pierre-Bénite, France.

Although most pituitary tumors are benign, some are invasive or aggressive. In the absence of specific markers of malignancy, only tumors with metastases are considered malignant. Recently we identified a marker set of invasion, proliferation and aggressiveness in prolactin (PRL) tumors1. We will present the prognostic value of histological and molecular markers in PRL tumors and their usefulness in other types of pituitary tumors.

Forty-five patients, 23 men and 22 women, with a PRL tumor were operated by transsphenoidal surgery, with a long post- surgical outcome (mean follow-up: 124 months; 36–300 months). The tumor size and the invasion were studied by radiology (MRI). Histological (mitoses and labeling for Ki-67, P53, PTTG) and transcriptomic (microarrays and q-RTPCR) methods were performed. Thirty-nine tumors were classified into 3 groups: non-invasive (n=17), invasive (n=15), and aggressive-invasive with histological signs of proliferation (n=7) tumors. Two tumors are considered as malignant, on the presence of metastasis, 5 and 16 years after primary surgery. Two statistical analyses, taking into account the histological groups and the post-surgical out come were performed in 39 patients (15 patients with remission and 24 patients with persistence and progression in 9 of them). The expression of each gene was compared to the histological classification using a non-parametric test and to the follow-up using a survival model.

By radiology, these 45 PRL tumors consisted of 8 microadenomas and 37 macroadenomas (volume>0.5 cm3). By histology, the detection of 4 markers of proliferation (mitosis, Ki-67, PTTG and P53) confirmed that no marker per se could distinguish between invasive and non-invasive tumors. However, mitoses and Ki-67, PTTG and p53 labelings were significantly different in 7 invasive tumors, which were classified as aggressive-invasive tumors. These results are consistent with the existence of 3 groups of PRL tumors. By q-RTPCR analysis, we found that one gene implicated in invasion (ADAMTS6) and 6 genes of proliferation (CRMP1, PTTG, ASK, CCNB1, AURKB, CENPE) were differentially expressed between the 3 groups of tumors (P=0.038 to P<0.0001). The survival analysis revealed that 6 genes (ADAMTS6, PTTG, ASK, CCNB1, AURKB, CENPE) were differentially up- or down regulated with high degree of significance (P=0.0028 to P<0.0004) in those patients either in remission or with persistent or progressive tumors. By the same methodology applied to other types of tumors other genes were found.

In conclusion, molecular and histological markers are useful in classifying the PRL tumors into three groups. Differential expression of some genes may predict the aggressiveness and recurrence potential specifically in PRL tumors, but other genes are found in other types of pituitary tumors.

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