- Department of Neurosurgery, Hospital Universitário Antônio Pedro, Rio de Janeiro, Brazil
- Department of Pathology, Hospital Universitário Antônio Pedro, Rio de Janeiro, Brazil
- Department of Endrocrinology, Hospital Universitário Antônio Pedro, Rio de Janeiro, Brazil
- Department of Neurosurgery, Galeão Air Force Hospital, Rio de Janeiro, Brazil
José Alberto Landeiro
Department of Pathology, Hospital Universitário Antônio Pedro, Rio de Janeiro, Brazil
DOI:10.4103/2152-7806.170536Copyright: © 2015 Surgical Neurology International This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: José Alberto Landeiro, Fonseca EO, Cruz Monnerat AL, Taboada GF, Sereno Cabral GA P, Antunes F. Nonfunctioning giant pituitary adenomas: Invasiveness and recurrence. Surg Neurol Int 26-Nov-2015;6:179
How to cite this URL: José Alberto Landeiro, Fonseca EO, Cruz Monnerat AL, Taboada GF, Sereno Cabral GA P, Antunes F. Nonfunctioning giant pituitary adenomas: Invasiveness and recurrence. Surg Neurol Int 26-Nov-2015;6:179. Available from: http://surgicalneurologyint.com/surgicalint_articles/nonfunctioning-giant-pituitary-adenomas-invasiveness-and/
Background:We report our surgical series of 35 patients with giant nonfunctioning pituitary adenomas (GNFPA). We analyzed the rule of Ki-67 antigen expression in predicting recurrence.
Methods:Thirty-five patients were operated between 2000 and 2010. Suprassellar extension of the tumors were classified according to Hardy and Mohr based on magnetic resonance (MR) studies. Pituitary endocrine function and MR scans were assessed preoperatively and at 1, 6, and 12 months postoperatively. Immunohistochemical studies were based in regard to the expression of the proliferative Ki-67 index and the hormonal receptor for luteinizing hormone, follicle stimulating hormone, growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, and prolactin. Tumors specimens were obtained from 35 patients with GNFPA. Endoscopic transsphenoidal surgery was the approach of choice.
Results:Thirty-five patients were submitted to 49 surgeries, 44 (89.8%) were transsphenoidal and 5 (10.2%) were transcranial. The most frequent preoperative complaints were visual acuity impairment and visual field defect in 25 (71.2%) and 23 (65.7%) cases, respectively. Improvement of visual acuitiy and visual field deficit after surgery was seen in 20 (80%) and 17 (73.9%) patients, respectively. Endocrinological deficits were encountered in 20 patients (57.1%). After surgery, 18 patients (51.4%) required hormonal replacement. Three patients had visual symptoms related to pituitary apoplexy and recovered after surgery. The Ki-67 labeling index (LI) ranged from 3% was present in 5 patients and the recurrence committed 3 patients.
Conclusion:In our series, regardless the improvement of visual function and compressing symptoms, 5 patients with expression of Ki-67 LI more than 3% experienced a recurrence.
Keywords: Invasiveness, Ki-67, pituitary adenoma, recurrence
Pituitary adenomas represent 10–15% of all primary brain tumors.[
MATERIALS AND METHODS
We retrospectively reviewed 35 consecutive patients diagnosed with GNFPA whom underwent endonasal endoscopic transsphenoidal resection assisted by neuronavigation from January 2000 to December 2010 at Galeão Air Force Hospital (HFAG) and Antônio Pedro University Hospital (HUAP).
Each patient was investigated preoperatively with laboratory studies (total blood count, glucose, creatinine, serum sodium level, serum potassium level, coagulogram) and ophthalmological assessment. Endocrinological study included serum level of thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), growth hormone (GH), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol, testosterone, tetra-iodothyronine, cortisol, and insulin such as growth factor-1.
Imaging studies included head computed tomography (CT) and magnetic resonance (MR). All tumors were classified as giant (≥30 mm suprasellar extension above the planum sphenoidale). Cavernous sinus invasion was classified according to Knosp et al.[
Endonasal endoscopic transsphenoidal surgery (ETSS) was the approach of choice. The details of this technique have been previously described.[
Decompression of pituitary gland, optic pathway, and surrounding brain structures were the main goals of the surgery. Asymptomatic cavernous sinus invasion was managed conservatively, leaving residual tumor during surgery. Postoperatively, further assessments were performed at 1, 6, and 12 months after surgery and annually after the 1st year.
We obtained paraffin blocks for each case at the archives of HUAP and HFAG and subject them to immunocytochemistry for specific antibodies: ACTH, FSH, GH, LH, PRLs, and TSH. Ki-67, a nuclear antigen expressed in G1, G2, and synthesis phases of the cell cycle but not in the quiescent G0 phase, was measured to assess proliferation using the MIB-1 technique in paraffin – embedded tissue.[
Stored paraffin blocks related to the selected cases were obtained for optical microscopy, cut and subjected to immunohistochemical technique (mouse monoclonal anti-ACTH, DAKO, clone O2A3, IgG1 isotype, kappa, code M3501, dilution 1:400; mouse monoclonal anti-FSH, DAKO, clone 10, isotype IgG1, Kappa code M3504, 1:50 dilution; mouse monoclonal anti-LH, DAKO, clone C93 1:300 dilution; rabbit polyclonal anti-GH/somatotrophin-GH, DAKO, GH immunogenic purified isolated from human pituitary gland, code A0570, 1:400 dilution; rabbit monoclonal anti-human-PRL, DAKO, code 0569, dilution 1:200–1:300; rabbit monoclonal anti-TSH, DAKO, clone 0042, code M3503, 1:50 dilution; mouse monoclonal anti-human-Ki-67 DAKO, clone MIB-1, code M7240, 1:200 dilution). Filed and or cut slides stained with hematoxylin eosin were analyzed together with an immunocytochemical study for correct identification of adenomas. Strong and diffuse markings were considered positive; otherwise, the cases were negative or focally positive. We counted 1000 cells tumors/case and the results were expressed in percentage of tumor cells with positive nuclei.
Thirty-five consecutive patients were assessed, 19 males (54.2%) and 16 females (45.8%); mean age was 48.2 ± 2.3 years, ranging between 34 and 76 years. The review period ranged from 1 to 10 years.
The transsphenoidal approach was the first choice, and all the surgeries were done under image-guide navigation. A single ETSS was performed in 21 patients [
(a) Coronal T1-weighted magnetic resonance imaging scan demonstrating giant sellar lesion with suprasellar and parasellar extensions (Knosp Grade 1), optic chiasm compression. (b) Postoperative (endoscopic transsphenoidal surgery) coronal T1-weighted magnetic resonance imaging, showing an excellent decompression of optic chiasm
(a and b) Postgadolinium coronal (a) and sagittal (b) preoperative T1-weighted magnetic resonance imaging, showing intense enhancement of sellar tumor, with suprasellar and parasellar extensions. (c and d) Postoperative (after two surgeries) coronal (c) and sagittal (d) postoperative T1-weighted magnetic resonance imaging after radical removal
After surgery, 17 patients (73.9%) improved visual field deficit and 20 (80%) improved visual acuity. Two patients experienced visual worsening after the surgery. A headache improved in 15 (75%) patients and hormonal replacement was required in 18 (51.4%) patients [
Transitory diabetes insipidus occurred in 9 (25.7%) patients. Mean duration was 2.1 ± 0.4 weeks. No patient developed permanent diabetes insipidus.
The most dangerous complication was an injury to a cavernous segment of carotid artery during an ETSS. The patient developed pseudoaneurysm that was treated with a stent, but developed severe motor deficit.
Reoperation due to recurrence was necessary in 5 patients, and 3 of them (60%) had Ki-67 Li more than 3%. There was no mortality.
On the basis of immunohistochemical studies, the following data were obtained: There were 9 null-cell adenomas, 16 gonadotrophic adenomas, five silent ACTH-cell adenomas, two silent TSH (STSH) adenomas, two plurihormonal adenomas (GH, PRL, and glycoprotein) one silent somatotroph adenoma [
MIB-1 was applied in all patients. The samples were positive in all cases. The Ki-67 Li ranged from 1% to 4.8%. In 30 cases, the Ki-67 Li was <3%. In 5 (14.2%) patients Ki-67 Li was above 3% [
Median follow-up period was 49 ± 3.8 months. Postoperative MR after 1 and 6 months showed no residual tumor in 11 patients (31.4%), and 21 patients (60%), respectively. After 1-year, 14 (40%) patients had a residual mass but without signs or symptoms of compression of surrounding brain structures. Some possible explanations for these findings are fat graft and small clot reabsorption, necrosis of residual tumor, and late diaphragma sellae descent.
Nonfunctioning pituitary tumors are relatively common. However, due to the lack of clinical syndromes, these tumors are diagnosed late when patients present compression syndromes as a headache, hypopituitarism, and visual field defects. Although there are many reports of tumors shrinkage during therapies with dopamine agonists,[
In our series, 35 patients with GNFPAs were operated. All patients presented with suprasellar extension 30 mm or more above the planum sphenoidale; 5 patients had a subfrontal extension, and seven had cavernous sinus invasion confirmed by MR. The endoscopic transsphenoidal approach under image-guide navigation system was the first procedure even in patients with subfrontal extension. Our policy in relation to cavernous sinus invasion in asymptomatic patients with GNFPAs is expectant. The optimal management of GNFPAs sometimes requires two or more approaches to obtain a maximal removal.[
Ki-67 and p53 are referred as indicators of aggressive behavior in the World Health Organization classification of endocrine tumors.[
Our study investigated the proliferative index of GNFPA. In our series, 35 patients with GNFPA were operated, and tumors were classified according to immunohistochemical studies. Pathological studies were performed on paraffin blocks. After immunohistochemical studies, blocks were submitted for Ki-67 evaluation. Most of the tumors were gonadotropic and null-cells adenomas. Of these, seven showed cavernous sinus invasion, four were immunoreactive for silent ACTH adenomas, two for gonadotropic adenomas, and one for STSH adenoma.
MIB-1 antibody was positive in all samples, and Ki-67 index ranged from <1% to 4.8%. Thirty patients had their samples with Ki-67 index <3% and in those patients, recurrence was noticed in 2 (6.67%) patients. Three of 5 reoperated patients had Ki-67 index >3%. Complete removal of GNPAs is very infrequent and in our series, after 1-year, 40% of the patients had residual tumors, but without symptoms. Our policy in relation to residual tumors is close observation of the patients, with surgery being indicated only if the tumor causes symptoms or shows progressive growth. Although modern methods of radiotherapy[
Cavernous sinus invasion is very challenging for a pituitary neurosurgeon. Some authors[
Several markers can be used as a predictive value with regard to the clinical course of the pituitary adenomas and Ki-67 LI was the most widely used,[
Although medical management play role in the treatment of some functioning pituitary adenomas, this is not true for NFPAs. The development of new agents for medical therapies including dopamine agonists as dopastin[
Despite the advances in pituitary surgery with new refinements such as endoscopy and neuronavigation, radical removal of GNFPA remains challenging. Maximal removal and decompression of optic pathway and surrounding brain structures offer the best chance to control the disease. Close follow-up with surveillance scans should be performed, and extreme caution on radiation therapy indications are the best measures to those patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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