Raffaella Barzaghi

Results of Transsphenoidal Surgery in a Large Series of Patients with Pituitary Adenoma

OBJECTIVE: To report the efficacy and safety of microsurgical transsphenoidal surgery in a series of previously untreated patients with pituitary adenoma. METHODS: One thousand one hundred forty consecutive patients undergoing transsphenoidal resection of a pituitary adenoma at our department from January 1990 through December 2002 were included in our study. Postoperative results were classified uniformly during the period of the study. Patients were considered in remission of disease when strict hormonal and radiological criteria of cure were met. RESULTS: The most frequent tumor type was clinically nonfunctioning adenoma (NFPA) (33.2%), followed by growth hormone-secreting adenoma (28.1%), adrenocorticotropin-secreting adenoma (23.0%), prolactin-secreting adenoma (13.2%), and last, thyrotropin-secreting adenoma (2.5%). The patient population was 59.7% female and 40.3% male. Mean age was 43.0 ± 0.4 years. There were 788 macroadenomas (69.1%), and in 233 patients (20.4%), the tumor invaded one or both cavernous sinuses. The overall rate of early surgical success was achieved in 504 (66.1%) of the 762 patients with a hormone-active adenoma. Surgical outcome was better in patients with microadenomas than in patients with macroadenomas (78.9% and 55.5%, respectively), whereas tumors invading the cavernous sinus had a poorer outcome (7.4%). In patients with NFPA, no residual adenoma was present in 234 patients (64.8%). Normalization of visual defects occurred in 117 (40.5%) of the 289 patients with visual disturbances and improved in another 148 patients (51.2%). Three patients (0.3%) died as a consequence of surgery. CONCLUSION: Transsphenoidal surgery is an effective and safe treatment for most patients with pituitary adenoma and could be considered the first-choice therapy in all cases except for prolactinomas responsive to dopamine agonists. Other treatment methods, such as radiotherapy, stereotactic radiosurgery, and medical therapy, play an important role in patients not cured by surgery.

Proliferation index of nonfunctioning pituitary adenomas: Correlations with clinical characteristics and long-term follow-up results

OBJECTIVEThe recurrence of nonfunctioning pituitary adenomas (NFPAs) after surgical removal is common. The aim of our study was to investigate and correlate the growth fraction of NFPAs with clinical characteristics and long-term follow-up results. METHODSTumor specimens were obtained from 101 consecutive patients with NFPAs (48 female patients and 53 male patients; mean age, 52.0 ± 1.5 yr). Specimens were immediately fixed in 10% buffered formalin and then embedded in paraffin. The Ki-67 antigen was assessed by immunocytochemical analysis using the monoclonal antibody MIB-1. The Ki-67 antigen labeling index (LI) was determined by counting a total of at least 1000 neoplastic nuclei. RESULTSThe mean Ki-67 LI for the 101 patients was 2.4 ± 0.3% (range, 0–23.0%). Only age at surgery was inversely correlated with the Ki-67 LI; sex, maximal tumor diameter, and invasiveness into the cavernous sinuses did not significantly affect the Ki-67 LI. The mean follow-up period was 39.7 ± 2.1 months. During follow-up monitoring, 23 patients experienced tumor recurrence, after a mean period of 28.6 ± 4.8 months. Invasiveness of the tumor on preoperative magnetic resonance imaging scans was the strongest predictor of late tumor recurrence, followed by previous pituitary surgery, younger age, and lack of postoperative radiotherapy. The Ki-67 LI had no independent prognostic value. CONCLUSIONOur study suggests that the clinical characteristics of patients with NFPAs, except for age at surgery, are not correlated with the Ki-67 LI. Moreover, the Ki-67 LI does not seem to provide independent information to identify patients at high risk for tumor recurrence.

Surgical treatment of giant pituitary adenomas: strategies and results in a series of 95 consecutive patients.

OBJECTIVEGiant pituitary adenomas, defined as those measuring at least 4 cm in maximum diameter, are a therapeutic challenge. We report our experience in a large, consecutive series of patients with giant adenomas. METHODSBetween 1990 and 2004, 95 patients with a giant pituitary adenomas underwent surgery at our department. Nonfunctioning pituitary adenoma was the most frequent type (n = 70; 73.7%), whereas hormone-secreting adenomas numbered only 25 (26.3%). The mean age at the time of surgery (±standard error of the mean) was 48.4 ± 1.5 years; there were 66 men (69.5%) and 29 women (20.5%). RESULTSIn total, 111 surgical procedures were performed. Of these, 85 approaches (76.6%) were transsphenoidal and 26 (23.4%) were transcranial. Visual improvement occurred in 59 of the 79 patients with preoperative defect who could be evaluated after surgery (74.7%). Radical tumor excision was obtained in 14 patients (14.7%). Adjuvant medical and radiation therapies led to 74.5% (95% confidence interval, 62.7–86.4%) control of tumor growth at 5 years. This was not different in patients with nonfunctioning pituitary adenomas compared with patients with hormone-secreting tumors. In the subgroup of patients with nonfunctioning pituitary adenomas, radiation therapy had a protective role against tumor growth (P < 0.01). CONCLUSIONMaximal surgical removal of giant adenomas through the transsphenoidal or transcranial approach, or both, aimed to relieve compression of the optic pathway and reduce tumor volume as much as possible, offers the best chances to control the tumor when followed with adjuvant medical and radiation therapies.

Determination of the proliferation and apoptotic index in adrenocorticotropin-secreting pituitary tumors: Comparison between micro- and macroadenomas

We investigated the growth fraction and cell loss fraction in a large group of patients with Cushings disease subdivided according to tumor size. Fifty-one patients, 8 males and 43 females, aged 12 through 61 years (mean age 34.6 +/- 1.5 years), were studied. Thirty-six patients had a microadenoma and the remaining 15 a macroadenoma. Immunohistochemical 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 dUTP nick end labeling method, using a monoclonal antibody recognizing areas of DNA fragmentation. Ki-67 labeling index and apoptosis were counted on separate slides in at least 1000 evaluable cells. Patients with a macroadenoma had a significantly higher value of Ki-67 index (9.3 +/- 2.7%) than patients with microadenoma (2.8 +/- 0.5%; P < 0.002), whereas the apoptotic index was not significantly different in the two groups (1.7 +/- 0.8% in macroadenomas versus 0.8 +/- 0.3% in microadenomas). Our study shows that ACTH-secreting macroadenomas are characterized by a higher cell growth fraction than microadenomas, whereas the cell loss fraction is not different. A high proliferation rate seems to play a major role in determining the progression from small to large pituitary tumors in Cushings disease.

Desmopressin stimulation test before and after pituitary surgery in patients with Cushing's disease

OBJECTIVE The desmopressin test has been proposed as a useful tool for the differential diagnosis of Cushings disease. The aim of our study was to investigate, in a large series of patients with Cushings disease, the incidence of a positive ACTH and cortisol response to desmopressin. Moreover, we repeated the test soon after surgery to verify its usefulness in the assessment of early and late surgical results.

Persistent Adrenocorticotropin Response to Desmopressin in the Early Postoperative Period Predicts Recurrence of Cushing's Disease

CONTEXT Patients with Cushings disease (CD) often show an ACTH and cortisol response to desmopressin (DDAVP). OBJECTIVE We tested whether persistence of a positive response to DDAVP after successful surgery identifies patients at risk of CD recurrence. DESIGN We prospectively included all CD patients who had a positive response to DDAVP before successful surgery from 1995 through 2007. SETTING The study was performed at a university hospital. PATIENTS One hundred seventy-four patients with CD, 148 women and 26 men, mean age 36.1 +/- 0.8 yr, were studied. The median follow-up after surgery was 58 months (interquartile range 22-93 months). INTERVENTION DDAVP test was performed immediately before and after surgery. MAIN OUTCOME MEASURE An ACTH and cortisol increment of at least 30 and 20% above baseline, respectively, were considered as a positive response to DDAVP. The risk of CD recurrence was analyzed according to the postoperative hormonal response to DDAVP. RESULTS Recurrence of CD occurred in 19 patients (10.9%). The recurrence-free survival at 5 yr was 89.8% [95% confidence interval (CI) 84.2-95.4]. Patients with a positive ACTH response had a 5-yr recurrence-free survival of 82.6% (95% CI 70.6-94.6%) as compared with 94.0% (95% CI 88.2-99.8%; P < 0.01) in patients without it. Multivariate analysis showed that persistence of a positive ACTH response to DDAVP was significantly associated with CD recurrence. CONCLUSION Positive ACTH response to DDAVP after surgery is associated with an increased risk of CD recurrence. However, the specificity and predictive value of this finding are low.

Endocrine inactive and gonadotroph adenomas: Diagnosis and management

Endocrine inactive pituitary adenomas represent about one quarter of all pituitary tumors. By immunocytochemistry, most of these tumors are positive for intact gonadotropins and/or their subunits. Clinical presentation is usually secondary to mass effect symptoms, such as visual disturbances, headache, and hypopituitarism. Differential diagnosis is usually accomplished by neuroradiologic studies, even though in selected cases positron emission tomography and/or single photon emission tomography may aid to distinguish pituitary adenomas from other endocrine inactive lesions, such as meningiomas and craniopharyngiomas. Surgical management is usually considered the first choice treatment for patients with endocrine inactive pituitary adenomas because it is very effective in ameliorating symptoms of chiasmal compression and headache. Radical removal of the tumor, however, is difficult to obtain because of the frequent invasiveness into the cavernous sinus. Radiation therapy diminishes the likelihood of tumor recurrence, especially in patients with demonstrable tumor remnants after surgery. Medical therapy with dopaminergic drugs, somatostatin analogs, or gonadotropin-releasing hormone agonists or antagonists causes mild reduction of tumor size in few patients and, therefore, seems to be of limited value in the therapeutic management of patients with endocrine inactive pituitary adenomas.

Presentation and surgical results of incidentally discovered nonfunctioning pituitary adenomas: evidence for a better outcome independently of other patients' characteristics

OBJECTIVE Few data are available on the surgical results in patients with incidentally discovered nonfunctioning pituitary adenoma (NFPA). We investigated the efficacy and safety of surgery in patients with incidentally discovered NFPA. DESIGN Retrospective analysis of prospectively recorded outcomes. METHODS From 1990 to 2011, of 804 consecutive patients undergoing surgery for NFPA, 212 cases had an incidentally discovered tumor (26.4%). Among them, 117 patients were asymptomatic, while 95 had some visual and/or hormonal deficit. The main outcome of the study was to evaluate the frequency of radical resection as judged on the first postoperative neuroimaging study and detection of recurring disease during long-term follow-up. RESULTS Postoperative residual tumor was detected in 8.9% of patients with asymptomatic incidentalomas as compared with 31.2% of patients with symptomatic incidentalomas (P<0.001) and 41.2% of patients in the control group (P<0.001). Multivariate analysis confirmed that having an asymptomatic incidentaloma was independently associated with a better outcome. The 5-year recurrence-free survival in patients with incidentaloma was 86.8% (95% CI 80.2-92.4%) as compared with 77.9% (95% CI 73.6-82.2%; P<0.01) in the control group. This difference was almost completely due to a lower frequency of relapse in asymptomatic patients. Multivariate analysis confirmed the independent lower risk of tumor recurrence in asymptomatic NFPA. CONCLUSION Our study shows for the first time that surgically treated patients with asymptomatic NFPA have a better early and long-term outcome that is independent from all the other demographic, clinical, and morphologic characteristics of the patients.

Surgical management of thyrotropin-secreting pituitary adenomas.

The reported cases of hyperthyroidism due to a TSH-secreting pituitary adenoma have steadily increased in previous years; however, information about the results and long term outcome after pituitary surgery is scanty.Twenty-four patients with a TSH-secreting adenoma underwent pituitary surgery at our department in the last 15 years. Hypersecretion of other pituitary hormones was diagnosed in 7 patients. Three patients were euthyroid at the time of surgery because of previous ablative thyroid therapies.The success rate of surgery strictly depends on the criteria used. Normalization of elevated FT3 and FT4 levels occurred in 17 of the 21 patients with preoperative hyperthyroidism: however, only those with early postoperative undetectable TSH level (12 cases) had no recurrence of disease during follow-up and no residual tumor tissue on postoperative MRI, whereas recurrence of hyperthyroidism occurred in 3 of the 5 patients without postoperative TSH inhibition. All 3 euthyroid patients had a subtotal removal of the tumor, as judged by postoperative MRI.Surgical removal is the therapy of choice of TSH-secreting adenomas, whereas radiotherapy and medical treatment with somatostatin analogues are usually reserved to patients with incomplete tumor removal. A thorough postoperative evaluation is necessary to discriminate between complete and partial remission of disease.