Progress in the Diagnosis and Classification of Pituitary Adenomas

Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

Pituitary adenomas may hypersecrete hormones (including prolactin, growth hormone and adrenocorticotropic hormone, and rarely follicle-stimulating hormone, luteinizing hormone or TSH) or may be nonfunctional. Despite their high prevalence in the general population, these tumors are invariably benign and exhibit features of differentiated pituitary cell function as well as premature proliferative arrest. Pathogenesis of dysregulated pituitary cell proliferation and unrestrained hormone hypersecretion may be mediated by hypothalamic, intrapituitary and/or peripheral factors. Altered expression of pituitary cell cycle genes, activation of pituitary selective oncoproteins or loss of pituitary suppressor factors may be associated with aberrant growth factor signaling. Considerable information on the etiology of these tumors has been derived from transgenic animal models, which may not accurately and universally reflect human tumor pathophysiology. Understanding subcellular mechanisms that underlie pituitary tumorigenesis will enable development of tumor aggression markers as well as novel targeted therapies.