CONTEXT: Few studies have recently re-examined the efficacy of neurosurgery in prolactinoma patients operated for various indications.
OBJECTIVE: To analyze outcomes of patients with a prolactinoma treated by transsphenoidal surgery, to identify factors associated with remission and relapse, and to evaluate if surgical debulking allows for better hormonal control in patients with preoperative resistance to dopamine agonists (DAs).
PATIENTS AND METHODS: This was a retrospective review of patients with a benign prolactinoma followed preoperatively and postoperatively in our department and treated by transsphenoidal surgery (n=63; 45 women; mean age: 31 ± 14 years).
RESULTS: Postoperative remission was obtained in 63% of microprolactinomas, 60% of noninvasive macroprolactinomas, and none of the invasive macroprolactinomas. Better remission rate was independently predicted by lower diagnostic prolactin (PRL) levels and by the lack of abnormal postoperative residual tissue (P<0.05). A recurrence of hyperprolactinemia was observed in 34% of patients after a median follow-up period of 36 (7-164) months. In patients with preoperative DA resistance treated again after surgery, there was a significant reduction in PRL levels postoperatively (26 (6-687) ng/ml) vs preoperatively (70 (22-1514) ng/ml; P<0.01) under a lower DA dose, and about half of the patients had PRL normalization.
CONCLUSIONS: Recurrence of hyperprolactinemia is observed in one-third of prolactinoma patients after surgical remission and may occur as late as 13 years after surgery. Resistance to DA can be considered as a good surgical indication, as partial tumor resection allows for better hormonal control with a lower dose of DAs.
BACKGROUND: Long-term dopamine agonist (DA) therapy is recommended as a first-line approach for the management of microprolactinomas. However, DA therapy may be poorly tolerated by some patients, and therefore some patients continue to prefer surgery over DA therapy.
AIM: The aim of our study was to evaluate factors associated with favorable outcomes after surgical treatment of microprolactinomas in women.
METHODS: Thirty-two women (mean age 31.0 ± 8.2 years) with confirmed microprolactinomas who were operated using transsphenoidal approach were included to the study. Twenty-two (61 %) women had previous DA therapy and ten (39 %) women preferred surgery as a first treatment. Mean follow-up was 4.2 ± 2.7 years. Surgery was considered to be effective and remission achieved if serum prolactin was normal without DA therapy and there were no signs of tumor re-growth on neuroimaging.
RESULTS: Nine (47.4 %) patients in whom remission was achieved did not receive preoperative DA therapy when compared to one (7.7 %) patient in whom remission was not achieved (p = 0.02). Remission after operation was achieved in nine out of ten (90 %) patients who did not receive DA therapy compared to ten out of 22 patients (45.5 %) who were treated with DAs (p = 0.01). The independent factor associated with good outcome following surgical treatment was no preoperative DA therapy (RR = 14.57 (1.43-148.1), p = 0.02). Surgical complications were permanent diabetes insipidus in two patients (6.3 %) and transient DI in five (15.6 %) patients.
CONCLUSIONS: The main factor associated with favorable microprolactinoma surgery outcome in women was the absence of preoperative DA therapy.
It has been reported that prolactinomas treated with Bromocriptine (BROM) show fibrosis that may interfere with complete surgical resection. The same has not been reported for Cabergoline (CAB). We retrospectively studied 24 consecutive patients (13 females, mean age 40 years, range 16-60) with histopathologically confirmed prolactinomas undergoing surgical resection at Johns Hopkins Hospital between 1992 and 2009. We compared these prolactinomas to 34 patients (22 females, mean age 42.9 years, range 15-75) with GH-secreting adenoma. The operative notes from 7 different neurosurgeons were reviewed to catalog the tumors as fibrous or not fibrous. Of the 24 prolactinomas, 21 (87.5%) were previously treated with DA. Indication for surgery was: DA resistance (n.5), DA intolerance (n.6), persistent mass effect (n.7) and CSF leak (n.3). Five (14.7%) of GH-secreting adenomas, were exposed to DA and/or somatostatin analogs. We found that 54% of prolactinomas and only 6% of GH-secreting adenomas were described as fibrous. 10/12 (77%) of prolactinomas exposed to BROM for at least 1 month, 2/9 (22%) exposed to CAB only, and 1/3 (33%) not previously treated were fibrous (P < 0.05). The mean BROM cumulative dose was 406 mg (range 75-1,375), while CAB dose was 28 mg (range 6-70). Only 18% of non-fibrous prolactinomas had been exposed to BROM. Only 3 patients had persistent biochemical remission (2 treated with CAB and 1 not treated). Patients exposed to BROM for at least 1 month are more likely to have tumor fibrosis than patients that are untreated or treated with CAB.
OBJECTIVE: Normalization of serum prolactin concentrations in patients with prolactinomas is an accepted endpoint of therapy. Clinical signs and symptoms of hyperprolactinemia are usually resolved when prolactin levels are lowered to within the normal range. While most patients are treated with dopamine agonist drugs, some patients require surgical resection of their tumors. We sought to determine whether preoperative treatment with dopamine agonists alters the outcome of surgical intervention.
METHODS AND RESULTS: We present an analysis of 253 patients with prolactinomas treated surgically during the period of time when dopamine agonist therapy was first introduced and prior to its widespread use as first-line therapy. We compared both short- and long-term outcomes of patients treated with dopamine agonists prior to surgery with those undergoing surgery as their initial treatment modality. Our data showed that that patients treated with dopamine agonists prior to surgery experienced greater reductions in prolactin levels, had lower prolactin levels, were more likely to have normal prolactin levels at long term follow-up, and were less likely to require additional therapy to control their prolactin levels.
CONCLUSION: Our study provides strong evidence suggesting that, regardless of initial prolactin level, preoperative dopamine agonist therapy is not detrimental. In fact, pretreatment with dopamine agonist drugs, possibly by inducing tumor regression, seemed to improve the surgeon's ability to resect a greater percentage of the tumor and led to better control of the prolactin level.
OBJECTIVE: To examine relationships between pituitary tumors and lesion size, invasiveness, resectability, deoxyribonucleic acid ploidy, cell cycle profile, mitotic activity, and immunoreactivity for MIB-1, proliferating cell nuclear antigen (PCNA), p27Kip1, and p53.
PATIENTS AND METHODS: One hundred fifty-three adenomas of most pathological subtypes, including 20 medically treated and prolactin and growth hormone-containing tumors, as well as 10 premetastatic tumors and 13 pituitary carcinomas, were studied.
RESULTS: Significant (P < 0.05) differences were noted between functional versus nonfunctional adenomas (percent aneuploidy, percent S phase, p27Kip1 labeling indices [LI], male sex, tumor size, and frequency of visual disturbance); Cushing's versus silent adrenocorticotropin adenomas (percent hypertetraploidy, p53 LI, tumor size, visual disturbance, and resectability); untreated versus medically treated prolactin cell adenomas (MIB-1 LI, p53 LI, and resectability); untreated versus medically treated growth hormone-containing adenomas (percent diploidy, percent S phase, MIB-1 LI, p53 LI, and p27 LI); untreated prolactin cell adenomas versus premetastatic tumors (percent hypertetraploidy, PCNA LI, p53 LI, invasiveness, and resectability); untreated growth hormone-containing adenomas versus premetastatic tumors (percent diploidy, percent S phase, PCNA LI, p53 LI, invasiveness, and resectability); Cushing's adenomas versus premetastatic tumors (percent diploidy, percent hypertetraploidy, percent S phase, MIB-1 LI, p53 LI, tumor size, invasiveness, visual disturbance, and resectability); Nelson's adenomas versus premetastatic tumors (p53 LI, tumor size, invasiveness, and resectability); silent adenomas as a whole versus nonfunctional adenomas (percent nondiploid, percent S phase, invasiveness, and respectability); silent adrenocorticotropin adenomas I and II versus silent adenoma Subtype III (invasiveness); silent adrenocorticotropin adenoma Subtypes I and II versus premetastatic tumors (MIB-1 LI and invasiveness); silent adenoma Subtype III versus premetastatic tumors (PCNA and p53 LI); and premetastatic tumors versus metastatic pituitary carcinomas (MIB-1 LI).
CONCLUSION: Only trends toward differences were noted between Cushing's versus Nelson's adenomas and between prolactinomas of reproductive female patients versus those of menopausal female patients and male patients. Too few "atypical adenomas" were encountered to permit their comparison with premetastatic tumors, but our results suggest that most pituitary carcinomas arise by malignant transformation from adenomas.
The management of invasive giant prolactinomas (IGP) has been an area of some controversy. The relative roles of transsphenoidal surgery, craniotomy, radiation therapy and dopamine agonist based medical therapy are gradually becoming clarified. We report the results of management of 30 patients with IGP. Surgery was the initial therapy in 18 patients and was nearly always followed by adjunctive treatment with radiotherapy and/or bromocriptine. A second group of 12 patients had initial therapy with bromocriptine; 6 had subsequent radiotherapy and only 1 had transsphenoidal surgery. Outcomes with regard to relief of mass effect, visual improvement, pituitary function and complications of therapy were superior in the bromocriptine treated patients.
Medical therapy with dopaminergic drugs is the preferred initial treatment for symptomatic prolactin (PRL)-secreting adenomas; but in recent years, there has been a renewed interest in surgery. The aim of this study is to report a large series of patients operated for prolactinoma in the last 10 yr. A total of 120 consecutive patients (93 female, 27 male) underwent surgery from January 1990 to December 1999. Their mean age at surgery was 29.7 +/- 0.9 yr. Fifty-nine patients (49.2%) had a microadenoma, and the remaining 61 (50.8%) had a macroadenoma, of which 24 (20%) were intrasellar and 37 (30.8%) were extrasellar adenoma. Magnetic resonance imaging signs of invasion of the cavernous sinus were detected in 18 patients (15.0%). Thirty-one patients (25.8%) had never been treated before, whereas the remaining 89 (74.2%) had received dopaminergic drugs. After surgery, normalization of PRL levels occurred in 77 patients (64.2%). Logistic regression analysis showed that the only predictive factor of unsuccessful surgery was a high preoperative PRL level. Recurrence of hyperprolactinemia occurred in 13 of the 77 cured patients (16.9%) during a mean follow-up of 50.2 +/- 3.0 months; the 5-yr disease-free survival was 75.9%. Extrasellar extension of the tumor and presence of a postoperative PRL response to TRH were associated with a lower risk of relapse. In summary, surgery normalized PRL levels and relieved symptoms of hyperprolactinemia in most patients. Recurrence of hyperprolactinemia occurred within 4 yr after surgery. Transsphenoidal surgery can be offered as a definitive therapy, especially to patients with intrasellar tumors.
OBJECTIVE: Prolactinomas are frequently treated primarily with dopamine agonists; however, these agents have disadvantages and require life-long therapy. We therefore reassessed transsphenoidal microsurgery as an alternative therapy.
METHODS: We reviewed the data for 121 female patients treated surgically for prolactinomas between 1976 and 1979 (Group 1) and 98 patients treated between 1988 and 1992 (Group 2).
RESULTS: Of 219 women, 92% with preoperative prolactin (PRL) values of < or = 100 ng/ml and 91% with intrasellar microadenomas experienced initial remission; 80 to 88% of patients with intrasellar macroadenomas or macroadenomas showing moderate suprasellar extension or focal sphenoid sinus invasion experienced remission. Women with PRL values of > 200 ng/ml and those with larger and more invasive adenomas experienced poorer outcomes (37-41% remission). Lower preoperative PRL values and adenoma stage were the best predictors of initial surgical outcomes. At the most recent evaluations, 89% of women who experienced initial remission continued to experience clinical remission; 85% exhibited normal PRL values, and 5% demonstrated mild, asymptomatic, recurrent hyperprolactinemia (PRL values of < 34 ng/ml). In Group 1, 84% of patients continued to experience remission (82% with normal PRL values) after a median follow-up period of 15.6 years. In Group 2, 97% of patients continued to experience remission (88% with normal PRL values) after a median follow-up period of 3.2 years. Lower postoperative PRL values were the best predictors of long-term remission.
CONCLUSION: Transsphenoidal microsurgery is an effective alternative to long-term medical therapy for selected patients with prolactinomas. Successful outcomes and long-term remission were achieved in patients with microadenomas and noninvasive macroadenomas.
OBJECTIVE: Dopamine agonists are the primary therapeutic modality for the majority of patients with prolactinomas, with pituitary surgery reserved for those patients intolerant of or resistant to these agents. Most published surgical series, however, contain patients treated by surgery as the primary therapeutic modality. Previous exposure to dopamine agonists or the selection of patients with prolactinomas resistant to conventional therapy may potentially compromise the surgical success rate. The purpose of this study was to evaluate the efficacy and safety of pituitary surgery for prolactinomas in a tertiary referral centre where the majority of patients were operated on after treatment with dopamine agonists.
DESIGN: A retrospective review of the outcome of pituitary surgery for prolactinomas performed at a tertiary neurosurgical centre by a single neurosurgeon.
PATIENTS: Twenty-three patients underwent excision of a macro and 11 excision of a micro-prolactinoma.
MEASUREMENTS: Pituitary tumour diameter was determined by CT or MRI imaging. Pre and post-operative measurements were made of serum PRL concentration (off dopamine agonist therapy), free T4, free T3, LH and testosterone (males). Post-operative restoration of a menstrual cycle was taken to indicate resolution of hypogonadism in female patients.
RESULTS: The majority (73.9%) of the patients with macro and all with micro-prolactinomas had received dopamine agonists preoperatively. Of the 23 patients with macroprolactinomas, in whom the median preoperative PRL concentration was 13255 mU/l, 17 (73.9%) had radiological evidence of suprasellar extension and 5 (21.7%) cavernous sinus invasion. Only 4 (17.4%) of the patients with macroprolactinomas had a normal serum PRL post-operatively, although there was an improvement in visual fields in 66% of those with preoperative defects. The median preoperative PRL concentration was 4309 mU/l in the patients with microprolactinomas, significantly lower than in the macroprolactinoma group (P = 0.02). Despite a significant fall in serum PRL postoperatively (median PRL 860 mU/l, P = 0.0001), only 45.5% of patients had a normal serum PRL concentration after surgery.
CONCLUSIONS: The cure rate following pituitary surgery for prolactinomas in a tertiary referral centre was low when compared with previous series in which surgery was used as the primary therapeutic modality. We suggest this may result both from dopamine agonist pretreatment and the referral of prolactinomas resistant to conventional therapy. The outcome is probably a more realistic reflection of the results of pituitary surgery for prolactinomas as currently practised in the majority of neuroendocrine centres.
Few studies have recently re-examined the efficacy of neurosurgery in prolactinoma patients operated for various indications.
OBJECTIVE:
To analyze outcomes of patients with a prolactinoma treated by transsphenoidal surgery, to identify factors associated with remission and relapse, and to evaluate if surgical debulking allows for better hormonal control in patients with preoperative resistance to dopamine agonists (DAs).
PATIENTS AND METHODS:
This was a retrospective review of patients with a benign prolactinoma followed preoperatively and postoperatively in our department and treated by transsphenoidal surgery (n=63; 45 women; mean age: 31 ± 14 years).
RESULTS:
Postoperative remission was obtained in 63% of microprolactinomas, 60% of noninvasive macroprolactinomas, and none of the invasive macroprolactinomas. Better remission rate was independently predicted by lower diagnostic prolactin (PRL) levels and by the lack of abnormal postoperative residual tissue (P<0.05). A recurrence of hyperprolactinemia was observed in 34% of patients after a median follow-up period of 36 (7-164) months. In patients with preoperative DA resistance treated again after surgery, there was a significant reduction in PRL levels postoperatively (26 (6-687) ng/ml) vs preoperatively (70 (22-1514) ng/ml; P<0.01) under a lower DA dose, and about half of the patients had PRL normalization.
CONCLUSIONS:
Recurrence of hyperprolactinemia is observed in one-third of prolactinoma patients after surgical remission and may occur as late as 13 years after surgery. Resistance to DA can be considered as a good surgical indication, as partial tumor resection allows for better hormonal control with a lower dose of DAs.
