Effects of Octreotide Treatment on the Proliferation and Apoptotic Index of GH-Secreting Pituitary Adenomas

Abstract

To investigate the effects of octreotide administration on the growth rate of GH-secreting pituitary adenomas, we measured both the Ki-67 labeling index (LI) and the apoptotic index in tumor specimens from octreotide-treated or matched untreated acromegalic patients. Thirty-nine patients who received octreotide until the day of or the day before surgery and 39 untreated patients matched for sex, age, tumor size, extension, and invasiveness were studied. Immunocytochemical analysis was performed on paraffin-embedded material using a monoclonal antibody (MIB-1) directed against a proliferation-associated nuclear antigen, Ki-67, to measure the growth fraction. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick endlabeling method, using a monoclonal antibody recognizing areas of DNA fragmentation. The Ki-67 LI and apoptosis were counted on separate slides in at least 1000 evaluable cells. Octreotide-treated patients showed a lower Ki-67 LI (1.8 +/- 0.3%) than untreated controls (3.8 +/- 0.7%; P < 0.02). Overall, the mean Ki-67 LI of treated patients was 53% lower than that in untreated patients. The antiproliferative effect of octreotide occurred independently of tumor extension and invasiveness. Octreotide-treated and untreated patients showed similar apoptotic indexes (0.6 +/- 0.2% and 0.8 +/- 0.3%, respectively). There was a positive correlation between the Ki-67 LI and the apoptotic index (r = 0.29; P < 0.03). Our study demonstrates that acromegalic patients receiving chronic octreotide treatment have a lower value of the proliferation marker Ki-67, but no significant difference in the apoptotic index compared with matched untreated patients. The antiproliferative effect of octreotide on GH-secreting adenomas should imply a lower risk of tumor growth during long-term chronic treatment with the drug.

Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations

“…This indicates that preoperative pharmacological treatment introduces an important limitation in the use of AIP immunostaining as a marker of invasiveness in somatotropinomas. This is similar to the effect of SSA pretreatment on the Ki67 index, which can be significantly reduced by the antiproliferative effects of SSA in GH-PA (Losa et al 2001, Jaffrain-Rea et al 2002. Overall, low AIP expression was also associated with higher preoperative GH/IGF1 levels.…”

Discontinuation of octreotide LAR after long term, successful treatment of patients with acromegaly: is it worth trying?

“…Both, the anti-secretory and the anti-proliferative effects of SA are dependent on the expression of somatostatin receptors (sst) by the tumor (particularly sst2 and to a lesser extent sst5) (22,23). Activation of sst1, sst2, sst4, and sst5 results in cell cycle arrest as reflected by a low Ki-67 index and by an increased proportion of cells in G1 and M (24). In keeping with these findings, morphological changes in tumors pretreated with octreotide have not been particularly striking; there is acidophilia and interstitial fibrosis and a moderate reduction in cytoplasmic volume; however, no necrosis is found (25).…”

Correlation between clinical characteristics and proliferative activity in patients with craniopharyngioma

“…12 To put these values into perspective, pituitary adenomas, the most frequent benign tumour of the pituitary gland, seem to have a lower proliferation activity. [13][14][15] Among several characteristics, only presence of a strong inflammatory reaction and diabetes insipidus at presentation were independently associated with high Ki-67 LI. It is possible that craniopharyngiomas with a high proliferative index may induce a strong inflammatory reaction.…”