Atypical pituitary adenomas: clinical characteristics and role of ki-67 and p53 in prognostic and therapeutic evaluation. A series of 50 patients

Abstract

The aim of the study was to assess incidence rate, hormonal activity, and local invasiveness and evaluate outcomes of so-diagnosed atypical pituitary adenomas that underwent endoscopic endonasal surgery at the Division of Neurosurgery of Università degli Studi di Napoli Federico II. According to the 2004 WHO classification, atypical pituitary adenomas are defined by an invasive growth, Ki-67/MIB-1 proliferative index greater than 3 %, high p53 immunoreactivity, and increased mitotic activity. A retrospective analysis of a series of 434 pituitary adenomas that underwent endoscopic endonasal surgery at our department between March 2007 and February 2013 was performed. Fifty adenomas (11.5 %) met the criteria of diagnosis of atypical lesions; 10 (21.6 %) of the 50 patients were recurrent tumors with a previous transsphenoidal surgery. Forty-one (82 %) were macroadenomas, and 21/50 (42 %) showed a clear invasion of the cavernous sinus. Histotype of atypical adenomas figured out to be nonfunctioning in 23 cases (46 %), PRL secreting in 10 cases (20 %), ACTH secreting and GH secreting each apart in 8 patients (16 %), and in a single case a GH/PRL secreting adenoma (2 %). The Ki-67 labeling index ranged from 3.5 to 22.5 % (mean 5.6 %). Tumor recurrence was observed in six cases (12 %) after a mean time of 18 months (range 9-24 months). Mean follow-up was 36.5 months (range 2-80 months). Atypical pituitary adenomas account for ca. 10 % of all pituitary adenomas; these lesions have peculiar features. It should be considered that a strong immunopositivity of p53 and higher Ki-67 LI could predict an increased risk of tumor recurrence, but more studies and larger series are expected to confirm and enlarge the diagnostic and therapeutic management process of these lesions.

Validation of a clinicopathological score for the prediction of post-surgical evolution of pituitary adenoma: retrospective analysis on 566 patients from a tertiary care centre

“…Moreover, in the 2004 WHO classification, high mitotic index and a Ki-67 LI ≥3% were considered effective prognostic markers of PAs (4,5,8,9,14,15,16,17,18,19,20,21). Expression of p53 was also included among potential outcome predictors (8), but is remained unclear whether its expression was an independent factor of aggressive behaviour because of the different cutoffs used in literature to differentiate tumours with low and high risk of recurrence/progression together with the high inter-observer variability (1,4,5,9,18).…”

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

“…R 3.4. 8 In patients with rapid tumour progression on temozolomide treatment, we suggest a trial with other systemic cytotoxic therapy. Given the variety of chemotherapeutic agents that have been reported, we cannot suggest a particular regimen (+000).…”

“…Such tumours often, but not always, exhibit one of the 3 markers (Ki-67 ≥3%, and/or increased mitoses, and/or p53 expression). Tumours exhibiting 2 or 3 markers were found to account from 2.5% to 10% in surgical series (5,6,7,8). Pituitary carcinomas, defined by the presence of craniospinal and/or systemic metastasis, are rare, and reported to account for 0.2% of pituitary tumours (9,10).…”

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

“…The 2004 WHO classification considered all benign tumours as either typical adenomas or atypical adenomas tumours showing 'borderline or uncertain behaviour' (Keblad et al 2007). The latter tumours exhibited invasive growth, high mitotic index, an elevated mitotic index, a Ki-67 labelling index (LI) >3% as well as extensive nuclear staining for p53 (Del Basso De Caro et al 2016. In recent studies, pituitary tumour recurrence could be predicted by using mitoses, invasion, Ki-67 labelling index (>3%), or extensive p53 immunoreactivity (≥20%) (Del Basso De Caro et al 2016).…”

“…The latter tumours exhibited invasive growth, high mitotic index, an elevated mitotic index, a Ki-67 labelling index (LI) >3% as well as extensive nuclear staining for p53 (Del Basso De Caro et al 2016. In recent studies, pituitary tumour recurrence could be predicted by using mitoses, invasion, Ki-67 labelling index (>3%), or extensive p53 immunoreactivity (≥20%) (Del Basso De Caro et al 2016). However, it should be noted that the revised WHO classification, due for publication in 2017, has rejected the 'typical/ atypical' classification, and instead emphasises staining with Ki-67, and the degree of invasiveness as revealed by surgical and radiological findings; p53 staining should be reserved for special cases, whereas electron microscopy is rarely of value.…”