Postoperative surveillance of clinically nonfunctioning pituitary macroadenomas: markers of tumour quiescence and regrowth

BACKGROUND: Postoperative management of clinically nonfunctioning pituitary adenomas (NFPA) presents difficult challenges. There are no good serum markers for presence or growth of the tumour, medical treatment is not effective and radiotherapy carries the risk of significant side-effects. OBJECTIVE: The purpose of this study was to investigate the natural history and biological behaviour of surgically treated NFPA, with a special effort to identify characteristics indicative of a more aggressive course that could assist in the clinical decision-making process. STUDY DESIGN: Patients operated on at our institution for NFPA undergo uniform routine clinical follow-up at the endocrine clinic. Magnetic resonance imaging (MRI) studies are performed 3, 6 and 12 months after transsphenoidal surgery and yearly thereafter for the first 5 years. Subsequently, imaging is performed once every 2 years or as clinically indicated. From 1992 onwards, no patient received immediate postoperative radiation therapy. PATIENTS: One hundred and twenty-two patients (78M/45F) operated on at our institution since 1989 and with a minimal follow-up of 1 year comprised the study group. MEASUREMENTS: Tumour size and characteristics were determined by MRI using a modification of Hardy's and Wilson's classifications. Maximal tumour height was also recorded and the information was routinely stored in a computerized database. RESULTS: Mean (+/- SD) follow-up was 51 +/- 31 months. Fourteen patients received postoperative radiation therapy. Subsequent tumour growth was observed in five of them, reduction in tumour size in four and no size changes in five. One hundred and eight patients did not receive postoperative radiation. Tumour enlargement occurred in 41 of 78 and in six of 30 patients with and without residual tumour after operation (P = 0.0024). The presence of cavernous sinus invasion before surgery [P = 0.02, odds ratio (OR) 2.72; confidence interval (CI) 1.1-6.43] and the extent of suprasellar extension in the postoperative tumour remnant (P = 0.0054 for presence of stage A, OR 4.4; 95% CI 1.5-12.5; and P = 0.012 for presence of stages B or C, OR 16.2; CI 1.8-144) were strong independent predictors of tumour enlargement. CONCLUSION: Our data may ease the selection of patients in whom radiation therapy is likely to be necessary for tumour control, and confirms that close postoperative follow-up is an adequate primary approach in low-risk patients.     

Prevalence of alpha-subunit hypersecretion in patients with pituitary tumors: clinically nonfunctioning and somatotroph adenomas.

Hypersecretion of the pituitary glycoprotein hormone alpha-subunit has been reported in pituitary adenomas, particularly in clinically nonfunctioning tumors and somatotroph adenomas. However, the prevalence of such hypersecretion has not been precisely defined. Using both a new highly sensitive and specific monoclonal antibody assay and a polyclonal antibody assay, serum levels of free alpha-subunit were compared in 63 unselected patients with these tumors, 19 patients with acromegaly, and 95 normal controls. In all patients the monoclonal assay detected a significantly greater number of subjects with elevated alpha-subunit levels than did the polyclonal assay (21 vs. 14; P less than 0.01). Fourteen of the 63 patients with clinically nonfunctioning tumors (22%) had elevated serum alpha-subunit levels in the monoclonal assay vs. 11 (17%) in the polyclonal assay. Among the 19 patients with acromegaly, the prevalence was 7 (37%) and 3 (16%) using the monoclonal and polyclonal assays, respectively. Twenty-eight (44%) of the patients with clinically nonfunctioning pituitary adenomas were female. Eleven (39%) of the women were under 45 yr old, as were 10 (29%) of the men. We conclude that the prevalence of free alpha-subunit hypersecretion in patients with clinically nonfunctioning and somatotroph adenomas may be higher than previously recognized, and that a sensitive and specific monoclonal antibody free alpha-subunit assay may provide a useful tumor marker in these patients. The prevalence of clinically nonfunctioning pituitary tumors among younger men and women may also have been previously under-estimated.     

The postoperative monitoring of nonfunctioning pituitary adenomas

Clinically nonfunctioning pituitary tumors are common in tertiary endocrine practice. Although it is widely accepted that patients with these adenomas require long-term surveillance after surgery-particularly those with macroadenomas, which grow much more frequently than microadenomas-a consensus on postoperative monitoring and treatment strategies is lacking. The indications for radiotherapy, which has seen a decline in use over the past decade, are not clear, although most experts would agree that residual tumor mass after surgery, as well as tumor expansion into the cavernous sinus, indicate the need to consider postoperative radiotherapy. In patients not treated with radiotherapy after surgical treatment of a nonfunctioning adenoma, MRI of the tumor should be performed annually for the first 6 years and every 2 years thereafter. In addition, silent adrenocorticotropic hormone-secreting tumors can behave more aggressively if they recur, and tumor regrowth can also occasionally be found in patients after classical pituitary apoplexy, which suggests that individuals with these conditions should also be monitored carefully after surgery. However, at which point this scanning routine can be ceased remains the subject of debate, as few data on late recurrence of nonfunctioning pituitary adenomas exist.     

Reversible hypopituitarism in patients with large nonfunctioning pituitary adenomas

Detailed pituitary function studies were conducted on 26 patients with large nonfunctioning pituitary adenomas before and 2-3 months after transsphenoidal adenomectomy. Basal serum PRL, GH, TSH, LH, FSH, and ACTH levels were measured, and dynamic studies of their secretion were made. Preoperatively, GH deficiency was found in all 26 patients (100%), hypogonadism in 25 patients (96%), hypothyroidism in 21 patients (81%), and adrenal insufficiency in 16 patients (62%). Serum PRL levels were low (1.5-4 ng/ml) in 5 patients, normal (5-20 ng/ml) in 9 patients, and mildly elevated (21-53 ng/ml) in the remaining 12 patients. After selective adenomectomy, variable improvement in pituitary function occurred in 17 patients, worsening in 1 patient, and persistence of hypopituitarism in 8 patients. After surgery, normal thyroid function was documented in 12 of the 21 patients (57%) who were hypothyroid preoperatively. Similarly, 6 of the 16 patients (38%) with adrenal insufficiency recovered normal adrenal function, and 8 of the 25 patients (32%) with hypogonadism recovered normal gonadal function. GH deficiency persisted in all but 4 patients (15%). Serum PRL levels decreased in all patients, and only 5 had midly elevated levels after surgery. The presence of a normal or mildly elevated serum PRL level before surgery in these patients was of value in predicting possible recovery of pituitary function after surgery; none of the 5 patients with low preoperative serum PRL levels had any improvement in pituitary function after surgery. A rise in serum TSH levels after TRH administration before surgery also was helpful in predicting possible recovery from hypopituitarism. Most patients who had a rise in serum TSH level in response to TRH stimulation preoperatively recovered some pituitary function after adenomectomy. In contrast, no improvement in pituitary function occurred in patients who had blunted responses to TRH preoperatively. Improvement in pituitary function occurred more often in patients with tumors measuring 25 mm or less than in those with larger tumors. In conclusion, significant improvement in pituitary function may occur after surgical adenomectomy for nonsecreting pituitary tumors. A rise in serum TSH levels in response to TRH stimulation preoperatively suggested the presence of viable pituitary tissue in these patients with hypopituitarism. The presence of a normal or mildly elevated serum PRL level before surgery also suggested the presence of functioning pituitary lactotrophs. These observations suggest that compression of the portal circulation is a possible mechanism for hypopituitarism in this setting.(ABSTRACT TRUNCATED AT 400 WORDS)     

Silent corticotroph adenomas have unique recurrence characteristics compared with other nonfunctioning pituitary adenomas

Objective The prevalence of silent corticotroph adenomas (SCAs) is not rare among nonfunctioning pituitary adenomas (NFPAs); however, it is unknown whether the clinical significance of SCAs differs from that of NFPAs without ACTH immunoreactivity (non‐SCAs). Our goal was to compare the clinical characteristics and natural history between patients with SCAs and non‐SCAs. Design/patients We reviewed the medical records of all patients who underwent transsphenoidal surgery for NFPAs from January 1990 to October 2007 at the Seoul National University Hospital. Measurements We analysed whether clinical manifestations at diagnosis, postoperative recurrence rate and recurrence characteristics differed between SCA and non‐SCA patients. Results In total, 28 patients with SCAs and 134 patients with non‐SCAs were analysed. The mean age at the time of diagnosis was 44 years (range, 13–67 years) in the SCA group and 50 years (18–79 years) in the non‐SCA group (P = 0·026), with respective follow‐up periods of 5·2 (range, 1·0–16·0 years) and 4·2 years (0·5–16·1 years) (P = 0·255). Overall recurrence rates of SCAs and non‐SCAs were 25·0% and 26·9% respectively (P = 0·839). More than two recurrences (P = 0·001) and recurrence after more than 5 years (P = 0·040) were associated with SCAs. Multiple recurrences of SCAs were confined to younger patients. Conclusion The overall recurrence rate was similar between SCAs and non‐SCAs. However, young patients with SCAs had a higher frequency of multiple and late recurrences, which showed more aggressive tumour behaviour. Therefore, we suggest that patients with SCAs, especially patients diagnosed at a young age, require careful long‐term monitoring.     

Analysis of hormone secretion by clinically nonfunctioning human pituitary adenomas using the reverse hemolytic plaque assay

The reverse hemolytic plaque assay was used to study hormone release in vitro by seven clinically nonfunctioning human pituitary adenomas associated with no clinical or biochemical evidence of hormone excess. Four of seven tumors were oncocytomas, one a null cell adenoma, and two gonadotroph adenomas based on immunocytochemical and ultrastructural features. In all seven tumors, plaques were formed with antiserum against beta FSH; four produced plaques for beta LH, and five for glycoprotein hormone alpha-subunit. The percentage of plaque-forming cells and the mean size of plaques were smaller than those of clinically functioning adenomas studied for comparison (five GH- and/or PRL-producing adenomas). These results correlated with those of hormone release in tissue culture, immunocytochemistry on paraffin secretions of the tumors, and immunocytochemistry after reverse hemolytic plaque assay. We conclude that clinically nonfunctioning pituitary adenomas release small quantities of hormones, primarily gonadotropins, and that hormone release is attributable to only a small percentage of tumor cells.     

Treatment and follow-up of clinically nonfunctioning pituitary macroadenomas

CONTEXT: Although the majority of pituitary macroadenomas are clinically nonfunctioning, treatments as well as follow-up strategy for this condition lack evidence from randomized studies. Evidence Acquisition: We evaluated the evidence of treatment and follow-up strategies for clinically nonfunctioning adenomas. PubMed was searched for articles on nonfunctioning adenomas in November 2007, and references of selected articles were assessed for potentially relevant articles. Evidence Synthesis: All evidence for treatment and follow-up for nonfunctioning adenomas is based on observational studies. The most effective treatment is transsphenoidal surgery, indicated in patients with visual field defects. A wait-and-see approach may be considered in nonfunctioning macroadenomas not reaching to the optic chiasm. Some of these tumors ( approximately 10%) will show spontaneous regression, whereas in approximately 50% there will be progression within 5 yr observation. Postoperative radiotherapy should not be applied to all patients after surgery but can be considered in patients with large postoperative remnants of the tumor. During follow-up careful assessment and replacement of pituitary insufficiencies should be performed. Magnetic resonance imaging is advised with intervals of 1-3 yr and evaluation of visual fields when appropriate. Recurrence rates are reported to be 6-46% after transsphenoidal surgery, whereas after postoperative radiotherapy, recurrence rates of 0-36% are reported. Long-term sequelae of nonfunctioning macroadenomas are hypopituitarism, persistent visual field defects, and decreased quality of life. Whether nonfunctioning macroadenomas are associated with an increased mortality is still a matter of debate. CONCLUSION: Clinically nonfunctioning pituitary macroadenomas, although benign in nature, need individualized treatment and lifelong radiological and endocrinological follow-up.     

Short-term treatment with cabergoline can lead to tumor shrinkage in patients with nonfunctioning pituitary adenomas

This study was carried out to evaluate the effectiveness of cabergoline in the treatment of nonfunctioning pituitary adenomas (NFPA), in a short-term follow-up period. Nineteen patients (10 men and 9 women) followed at the University Hospital of Brasilia and harboring nonfunctioning pituitary macroadenomas were enrolled in the study. Eleven patients were previously submitted to transsphenoidal surgery, and in 8 patients no previous treatment had been instituted. Their response to the use of cabergoline (2 mg/week) by 6 months was evaluated. Significant tumor shrinkage (above 25 % from baseline tumor volume) was observed in 6 (31.6 %) of the 19 patients, and no adverse effects were observed during treatment. In 9 patients (47.4 %), a reduction in tumor volume of at least 10 % was noted, whereas tumor growth was observed in four patients (increase above 25 % was only observed in one patient). Cabergoline (2 mg/week) can lead to significant tumor shrinkage in NFPA in a considerable number of patients, and this effect can be observed early (6 months after starting medication). Thus, this therapeutic strategy may be a low cost and safe alternative for treatment of NFPA in patients with remnant or recurrent tumor after transsphenoidal surgery or in those not operated by contraindications or refusal to surgical procedure.     

Patterns of gastrin secretion in patients with nonfunctioning pituitary adenomas.

The presence of gastrin in pituitary tissue as well as gastrin hypersecretion by some pituitary adenomas have been documented using different methodological approaches. In the present study, serum gastrin levels were measured in 93 patients with nonfunctioning pituitary adenoma, i.e. a condition lacking a reliable marker of the disease. Elevated gastrin levels (85-2, 180 ng/l; normal range: 15-80 ng/l) were found in 14/93 patients (15%), the highest values being observed in one patient with MEN I syndrome. In all but MEN I hypergastrinemic patient, a severe gastric hypochlorhydria (Basal Acid Output: 0.04 +/- 0.1 mmol H+/h) unresponsive to pentagastrin (Maximum Acid Output: 0.1 +/- 0.2 mmol H+/h) was seen. Secretin injection caused gastrin to increase in the patient with MEN I and in another hypergastrinemic patient. Antiparietal cells autoantibodies were positive in 3/11 patients. No changes in gastrin concentrations were found after administration of several agents usually employed in the evaluation of pituitary function, except a significant gastrin reduction after octreotide injection. In two hypergastrinemic patients who underwent pituitary adenomectomy, the high gastrin levels did not change after surgery. Finally, gastrin was undetectable in the culture media of 15 pituitary adenomas surgically removed from both normo- and hypergastrinemic patients and immunocytological studies of tumor cells did not show any gastrin staining. In conclusion, although in patients with pituitary adenomas serum gastrin evaluation is indicated in order to document the presence of a MEN I syndrome, the present data show that high gastrin levels cannot be taken as a specific marker of nonfunctioning pituitary adenomas unless the peripheral origin of hypergastrinemia is excluded.     

Management of nonfunctioning pituitary adenomas (NFAs): observation

Clinically nonfunctioning pituitary adenomas (NFAs) range from those causing significant hypothalamic/pituitary dysfunction and visual field compromise due to their large size to those being completely asymptomatic. In the absence of hypersecretion, hypopituitarism or visual field defects, patients with NFAs may be followed by periodic surveillance using MRI to detect tumor enlargement. In some cases, endocrine tests are also needed during observation to discover new pituitary dysfunction. Enlargement of NFAs without treatment occurs in about 10% of microadenomas and 23% of macroadenomas. Growth of a pituitary incidentaloma, the development of visual field defects or the development of hypopituitarism are potential indications for surgery during follow up.     

(99m)Technetium pentavalent dimercaptosuccinic acid scintigraphy in the follow-up of clinically nonfunctioning pituitary adenomas after radiotherapy

BACKGROUND: It is still difficult to differentiate pituitary adenoma remnants from postradiotherapy fibrosis by computed tomography (CT) or magnetic resonance imaging (MRI), especially in patients with clinically nonfunctioning pituitary adenomas (NFA), lacking circulating markers to follow disease progression or cure. OBJECTIVE: We investigated the usefulness of scintigraphy with technetium-99m pentavalent dimercaptosuccinic acid [(99m)Tc(V)DMSA], shown previously to detect most pituitary GH- and PRL-secreting adenomas and NFA, with tumour-to-background ratios (T/B) as high as 25-fold. PATIENTS: Eighteen patients with NFA (study group), 10 patients with GH- and three patients with PRL-secreting adenomas (control group), all of whom had undergone previous surgery. DESIGN: The study was an open longitudinal design. Pituitary CT/MRI and (99m)Tc(V)DMSA scintigraphy was performed before and 1, 3 and 5 years after conventional radiotherapy. Tumour size was measured as maximal diameter of the residual lesion, while uptake of (99m)Tc(V)DMSA was measured as a T/B ratio. RESULTS: At study entry, pituitary (99m)Tc(V)DMSA uptake was found in 13 NFA (72.2%), seven GH-secreting (70%) and all PRL-secreting adenomas; remnant tumour was documented by CT/MRI in all 31 patients. Maximal remnant diameter was significantly higher in patients with positive (13.3 +/- 0.9 mm) than in those with negative scintigraphy (7.0 +/- 0.3 mm, P < 0.001). During the 5-year follow-up postradiotherapy, a significant decrease in (99m)Tc(V)DMSA uptake (9.7 +/- 0.8 vs. 3.2 +/- 0.5, P < 0.0001) occurred in all but three patients. Two NFA patients died of tumour invasion 19 and 36 months after radiotherapy and one acromegalic patient had no change in his hormone levels. In the eight negative patients (five NFA and three GH), scintigraphy remained negative throughout follow-up. A remarkable shrinkage of the remnant tumour was observed in both the patients with negative (from 7.0 +/- 0.3 to 1.9 +/- 0.6 mm, P < 0.001) and in those with positive scintigraphy (from 13.3 +/- 0.9 to 7.3 +/- 0.6 mm, P < 0.001). At the end of the study, CT/MRI showed evident remnant tumour in 13 of 16 NFA (81.2%), nine GH-secreting (90%) and all three prolactinomas (100%), while the scintigraphy was negative (T/B < 1) or faintly positive (T/B 1-2) in eight of 16 NFA (50%), five GH-secreting (50%) and one prolactinoma (33.3%). CONCLUSIONS: Functional imaging of pituitary remnant adenomas (> 10 mm in size) by (99m)Tc(V)DMSA depicts viable pituitary adenoma remnants. This approach may be of clinical value in patients with clinically nonfunctioning adenomas to monitor the effects of radiotherapy.     

Long-term treatment with the dopamine agonist quinagolide of patients with clinically non-functioning pituitary adenoma

OBJECTIVE: This study was performed to evaluate the effect of prolonged treatment with the dopamine agonist quinagolide on serum gonadotropin and alpha-subunit concentrations and tumor volume in patients with clinically non-functioning pituitary adenomas (CNPA). DESIGN: Ten patients with CNPA were treated with quinagolide (0.3 mg daily). The median duration of treatment was 57 months (range 36-93 months). Blood samples for measurement of serum gonadotropin and alpha-subunit concentrations were drawn before treatment, after 5 days, and at each outpatient visit. Computerized tomography or magnetic resonance imaging of the pituitary region and Goldmann perimetry were done before and at regular intervals during treatment. RESULTS: A significant decrease of serum FSH, LH or alpha-subunit concentrations was found in nine patients. The levels remained low during the entire treatment period. In two out of three patients with pre-existing visual field defects a slight improvement was shown during the first months of treatment, but eventually deterioration occurred in all three patients. A fourth patient developed unilateral ophthalmoplegia during treatment. During the first year tumor volume decreased in three patients, but in two of them regrowth occurred after a few months. In six patients progressive tumor growth occurred despite sustained suppression of gonadotropin or alpha-subunit levels. CONCLUSIONS: Long-term treatment of patients with CNPA with high doses of the dopamine agonist quinagolide could not prevent progressive increase in tumor size in most patients. It remains unproven whether quinagolide retards CNPA growth. Additional studies are needed to investigate whether subgroups of patients, e.g. those with positive dopamine receptor scintigraphy or those with marked hypersecretion of intact gonadotropins or subunits, will respond more favorably to treatment with dopamine agonists.     

Dopamine receptor expression and function in clinically nonfunctioning pituitary tumors: comparison with the effectiveness of cabergoline treatment

The aim of this study was to correlate dopamine receptors and D(2) isoform expression with the cabergoline effect on alpha-subunit secretion in vitro and tumor mass in vivo in clinically nonfunctioning pituitary tumors. Eighteen patients were subjected to neurosurgery, and a tumor sample was used for dopamine receptor and D(2) isoform expression evaluation by RT-PCR and the in vitro functional studies. After neurosurgery, nine of 18 patients with persistent tumor were treated with cabergoline and tumor mass was evaluated before and after 1 yr treatment. D(2) receptor was expressed in 67% of cases. D(2long) was found in 50%, D(2short) in 17%, and both D(2) isoforms in 33% of cases. D(4) receptor was also expressed in 17% of cases. The in vitro inhibition of alpha-subunit concentration was found in 56% of cases and was associated with D(2) expression (chi(2) = 5.6; P < 0.05). After 1 yr of cabergoline treatment, tumor shrinkage was evident in 56% of patients and was associated with D(2) expression (chi(2) = 5.6; P < 0.05). The expression of D(2short) rather than D(2long) isoform is associated with the most favorable response of the tumor to cabergoline treatment. In conclusion, this study demonstrates D(2) receptor expression and function in nearly 70% of cases, suggesting a role of this drug in the treatment schedule of clinically nonfunctioning pituitary tumors.     

In vitro secretion of FSH by cultured clinically nonfunctioning and gonadotroph pituitary adenomas is directly correlated with locally produced levels of activin A

OBJECTIVE: Expression of mRNAs encoding activin and its antagonists inhibin and follistatin has been described in human pituitary adenomas, including clinically nonfunctioning adenomas (NFAs) and gonadotroph adenomas (Gn-omas). Since many of the NFAs and Gn-omas secrete FSH in vitro, we hypothesized that locally produced activin may stimulate secretion of FSH in these pituitary adenomas. PATIENTS AND METHODS: Pituitary adenoma tissue was obtained from 38 patients diagnosed preoperatively as having NFAs (n = 17), Gn-omas (n = 5), prolactinomas (n = 6) or growth hormone (GH)-producing adenomas (n = 10). Actual protein levels of activin, inhibin, follistatin, FSH and LH were measured in media of these 38 cultured pituitary adenomas. In addition, we investigated correlations between concentrations of these growth factors and hormones in NFAs and Gn-omas. RESULTS: Gn-omas were found to secrete significantly more activin A in their culture medium than PRL- and GH-producing adenomas (P < 0.05). Inhibin A and inhibin B protein levels in culture media were very low. A positive correlation between levels of activin A and FSH (r = 0.56, P < 0.005) was found, while no correlation between activin A and LH could be detected. Furthermore, levels of follistatin were positively correlated with activin A levels (r = 0.73, P < 0.0005). Comparison of the activin A:follistatin ratio with the measured FSH protein levels showed an even stronger relationship (r = 0.79, P < 0.0005). CONCLUSIONS: It is concluded that levels of activin A, follistatin and FSH in media of cultured nonfunctioning adenomas and gonadotroph adenomas are positively correlated. This suggests that these adenomas secrete FSH in response to the relatively high locally produced levels of activin A.