Endoscopic endonasal transsphenoidal surgery for functional pituitary adenomas

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Object

The purpose of this study was to analyze preoperative predictors of endocrinological remission following endonasal endoscopic resection of therapy-resistant prolactin-, growth hormone (GH)–, and adrenocorticotropic hormone (ACTH)–secreting pituitary adenomas and to establish benchmarks for cure by using the most recent consensus criteria.

Methods

The authors reviewed a prospective database of 86 consecutive functional pituitary adenomas that were resected by a purely endoscopic endonasal transsphenoidal technique. Extent of resection was evaluated on postoperative contrast-enhanced MR imaging. Endocrinological remission was defined according to the most recent consensus criteria.

Results

The majority of functional adenomas (62.8%) were classified as macroadenomas (> 1 cm in maximum diameter), and 20.9% of lesions had invaded the cavernous sinus (CS) at the time of surgery. A gross-total resection was achieved in 75.6% of all patients. The rate of endocrinological remission differed between various types of functional adenomas. Cure rates were 92.3% (microadenomas) and 57.1% (macroadenomas) for prolactinomas, 75% (microadenomas) and 40% (macroadenomas) for GH-secreting tumors, and 54.5% (microadenomas) and 71.4% (macroadenomas) for ACTH-secreting tumors. Lower rates of cure occurred in GH-secreting macroadenomas due to a high rate of CS invasion, and in ACTH-secreting adenomas due to a high rate of lesions that were not visible on preoperative MR imaging. Whereas univariate analysis showed that macroadenoma, suprasellar, cavernous extension, or extent of resection correlated with cure, on multivariate analysis, only extent of resection and suprasellar extension predicted cure. One patient developed postoperative meningitis that was complicated by hydrocephalus requiring a ventriculoperitoneal shunt. Two patients developed postoperative panhypopituitarism, and 2 patients suffered from CSF leaks, which were treated with lumbar CSF diversion.

Conclusions

This paper reports benchmarks for endocrinological cure as well as complications in a large series of purely endoscopic pituitary surgeries by using the most recent consensus criteria. The advantages of extended endonasal approaches are most profound in tumors with suprasellar extension and CS invasion.

Abbreviations used in this paper: ACTH = adrenocorticotropic hormone; CS = cavernous sinus; GH = growth hormone; GKS = Gamma Knife surgery; GTR = gross-total resection; IGF-I = insulinlike growth factor–I; PRL = prolactin.

Abstract

Object

The purpose of this study was to analyze preoperative predictors of endocrinological remission following endonasal endoscopic resection of therapy-resistant prolactin-, growth hormone (GH)–, and adrenocorticotropic hormone (ACTH)–secreting pituitary adenomas and to establish benchmarks for cure by using the most recent consensus criteria.

Methods

The authors reviewed a prospective database of 86 consecutive functional pituitary adenomas that were resected by a purely endoscopic endonasal transsphenoidal technique. Extent of resection was evaluated on postoperative contrast-enhanced MR imaging. Endocrinological remission was defined according to the most recent consensus criteria.

Results

The majority of functional adenomas (62.8%) were classified as macroadenomas (> 1 cm in maximum diameter), and 20.9% of lesions had invaded the cavernous sinus (CS) at the time of surgery. A gross-total resection was achieved in 75.6% of all patients. The rate of endocrinological remission differed between various types of functional adenomas. Cure rates were 92.3% (microadenomas) and 57.1% (macroadenomas) for prolactinomas, 75% (microadenomas) and 40% (macroadenomas) for GH-secreting tumors, and 54.5% (microadenomas) and 71.4% (macroadenomas) for ACTH-secreting tumors. Lower rates of cure occurred in GH-secreting macroadenomas due to a high rate of CS invasion, and in ACTH-secreting adenomas due to a high rate of lesions that were not visible on preoperative MR imaging. Whereas univariate analysis showed that macroadenoma, suprasellar, cavernous extension, or extent of resection correlated with cure, on multivariate analysis, only extent of resection and suprasellar extension predicted cure. One patient developed postoperative meningitis that was complicated by hydrocephalus requiring a ventriculoperitoneal shunt. Two patients developed postoperative panhypopituitarism, and 2 patients suffered from CSF leaks, which were treated with lumbar CSF diversion.

Conclusions

This paper reports benchmarks for endocrinological cure as well as complications in a large series of purely endoscopic pituitary surgeries by using the most recent consensus criteria. The advantages of extended endonasal approaches are most profound in tumors with suprasellar extension and CS invasion.

The transsphenoidal approach for resection of a pituitary adenoma was first performed by Herman Schloffer more than 100 years ago.37 Subsequently, the transsphenoidal approach created great interest, and a variety of modifications of this approach were described shortly thereafter. As discussed in a report by Henderson,18 Harvey Cushing was the first to present a large clinical series of 231 transsphenoidal pituitary adenoma resections in 1939. However, because lack of adequate preoperative imaging made it impossible to foretell the size and configuration of the adenomas, he abandoned the procedure in favor of transcranial approaches. The majority of neurosurgeons followed Cushing's lead, and it was not until the advent of 2 technological milestones that the transsphenoidal technique resurfaced. First, the development of imaging techniques such as CT and MR imaging provided accurate information about the size and location of a lesion and allowed for appropriate patient selection and determination of the appropriate surgical access. Second, the introduction of the operating microscope and later endoscopy greatly improved intraoperative illumination and visualization. Although there are numerous studies reporting the endocrinological outcome following microsurgical transsphenoidal resection of functional pituitary adenomas,1,4–7,11,15,17,20,21,23,25,26,28,29,31,33,34,39,41,43–46 there is a paucity of literature reporting the endocrinological outcome following use of a purely endoscopic transsphenoidal technique.8,12,19,36 Moreover, continuous re-evaluation of endocrinological outcomes following surgical treatment of functional pituitary lesions is necessary to keep up with the latest definitions of postoperative endocrinological remission. Based on improvements in follow-up data, criteria for endocrinological remission following resection have constantly evolved over time. Here we present our singlecenter experience in which we used the latest criteria for an endocrinological cure for PRL-, GH-, and ACTH-secreting adenomas3,9,16 in a cohort treated with a purely endoscopic endonasal transsphenoidal technique.

Methods

Patient Demographic Data

We analyzed a prospectively collected database of all patients who underwent endoscopic endonasal surgery for a functional pituitary adenoma at Weill Cornell Medical College, New York–Presbyterian Hospital between February 2004 and June 2010, as a collaboration between the departments of Neurosurgery and Otolaryngology. Functional tumors were resected by the senior authors (T.H.S. and J.A.B.) using a purely endoscopic endonasal transsphenoidal approach. This study was approved by the institutional review board. For each operation, the duration of surgery, estimated blood loss, relevant laboratory values, adjuvant treatments, and complications were recorded.

Radiographic Evaluation

Prior to resection, all patients underwent contrastenhanced MR imaging. Tumor invasion of the CS was defined according to the following criteria: three-quarters or more encasement of the internal carotid artery, obliteration of the carotid sulcus venous compartment, or crossing of the lateral intercarotid line by the tumor.10 Routinely, the surgical site was analyzed by contrast-enhanced MR imaging on postoperative Day 1, 3 months after surgery, and then at yearly intervals.

Surgical Technique

Prior to surgery, all patients received antibiotics and glucocorticoids, and intrathecal fluorescein was used in 73% of cases to label CSF.32 We use Brainlab neuronavigation for all of our cases. A detailed description of the procedure has been published previously.19,24,35,38 Briefly, after application of topical cocaine to the nasal mucosa, the mucosa of the middle turbinates is infiltrated with a mixture of 1% lidocaine and epinephrine (1:100,000). The sphenoid ostia are identified bilaterally and enlarged by removal of bone. We then use a tissue shaver to resect the posterior third of the nasal septum. Using a high-speed drill and curettes, the anterior wall of the sella is opened. We attempt to resect microadenomas en bloc, whereas macroadenomas are first internally decompressed by removing the inferior portion of the tumor, followed by resection of the lateral portions. This maneuver prevents the suprasellar arachnoid from herniating down into the sella. Resection of extensive suprasellar components may require an extended approach to the lesions, including removal of the tuberculum sellae and planum sphenoidale.24 Tumor is dissected off the medial CS wall. In case of CS invasion, the dura mater is opened medial to the internal carotid artery, and tumor can be easily removed from this area. Although it is also possible to open the CS lateral to the carotid, one must carefully weigh the safety of this maneuver with the increased extent of resection that it will facilitate, and how this will affect the long-term outcome of the patient, compared with treatment with stereotactic radiosurgery. The skull base defect is closed in a multilayered fashion.27

Endocrinological Evaluation

All patients underwent pre- and postoperative endocrinological evaluation for free cortisol, ACTH, free thyroxine, thyroid-stimulating hormone, PRL, GH, IGF-I, testosterone, estradiol, luteinizing hormone, and folliclestimulating hormone to assess for endocrinological derangements (except for 1 patient, who was lost to endocrinological follow-up). The diagnosis of a prolactinoma was made based on serum PRL levels of > 150 ng/ml in combination with typical clinical symptoms.9 In patients with prolactinoma, endocrinological remission was defined as postoperative PRL levels of < 20 ng/ml in females or < 15 ng/ml in males. The diagnosis of Cushing disease was based on either abnormal 24-hour urinary free cortisol or abnormal results on low-dose dexamethasone suppression tests, defined as failure of 1 mg of dexamethasone to reduce plasma cortisol levels to < 1.8 μg/ml the next morning.3,30 In Cushing disease, endocrinological remission was defined as an early morning cortisol level measurement of ≤ 1.8 μg/ml obtained within 48 hours after surgery or a normalization of the 24-hour urinary free cortisol.3 The diagnosis of acromegaly was based on abnormal basal fasting levels of GH and IGF-I.16 Biochemical remission was defined as a normal IGF-I level combined with a glucose-suppressed GH level of ≤ 0.4 ng/ml, or alternatively, combined with a basal GH level of ≤ 1 ng/ml. The IGF-I level was always evaluated according to age-adjusted diagrams.16

Statistical Evaluation

Continuous variables are shown as the mean values ± the SEM and the range. Categorical values are shown as percentages. Continuous variables between patients with prolactinomas, acromegaly, or Cushing disease were analyzed by ANOVA, followed by a Tukey post hoc test. Tumor diameter between cured and noncured patients was assessed using a Mann-Whitney U-test. Binary logistic regression was used to determine the effect of extent of resection, tumor size, suprasellar extension, and invasion of the CS on endocrinological remission. A conditional backward stepwise method was used to calculate a multivariate logistic regression model. Preoperative and postoperative hormone levels in serum were assessed using a paired Student t-test. A p value < 0.05 was considered significant. Statistical analyses were performed using SPSS software (version 18.0 for Macintosh).

Results

Overall Patient Characteristics

At total of 86 patients underwent resection of functional pituitary adenomas in which a purely endoscopic transsphenoidal technique was used. The cohort was composed of 37 male and 49 female patients with a mean age of 45.2 years (range 12–82 years; Table 1). Our series contains 35 patients with prolactinomas, 18 with Cushing disease, and 33 with GH-secreting adenomas. The majority of patients (85%) who underwent resection sought medical attention for symptoms related to excess hormone production. The remaining patients complained of severe headaches (4.7%), diplopia (3.5%), or vision loss (10.5%). Patients with diplopia and vision loss had significantly larger adenomas compared with the rest of the cohort (3.3 cm and 2.6 cm, respectively, vs 1.2 cm maximum tumor diameter; p < 0.001). In patients with loss of vision, visual field testing revealed bitemporal defects in 3 patients, binasal defects in 1 patient, or hemianopia in 2 patients. One-third of patients with acute vision loss where found to have pituitary apoplexy on MR imaging. The remaining 2 patients with apoplexy presented with acute onset of severe headaches. In our cohort, 20.9% of patients had undergone a previous resection. Preoperative MR imaging revealed macroadenomas (maximum diameter > 1 cm) in two-thirds of our patients. Invasion of the CS was present in 20.9%, and suprasellar tumor extension was detected in 29.1%. Whereas the pituitary–hypothalamic axis was intact in the majority of patients (89.5%), 6 patients were found to have hypogonadism, 2 had hypothyroidism, and 1 suffered from both panhypopituitarism and diabetes insipidus prior to surgery.

TABLE 1:

Characteristics in 86 patients with functional pituitary adenomas

CharacteristicTotalType of Pathology
PRL-SecretingACTH-SecretingGH-Secreting
no. of patients86351833
sex
 M37 (43.0%)13 (37.1%)5 (27.8%)19 (57.6%)
 F49 (57.0%)22 (62.9%)13 (72.2%)14 (42.4%)
mean age in yrs (± SEM)45.2 ± 1.836.3 ± 2.5*53.8 ± 3.849.9 ± 2.6
previous op
 yes18 (20.9%)8 (22.9%)6 (33.3%)4 (12.1%)
 no68 (79.1%)27 (77.1%)12 (66.6%)29 (87.9%)
max tumor diameter
 <1 cm32 (37.2%)13 (37.1%)11 (61.1%)8 (24.2%)
 >1 cm54 (62.8%)22 (62.9%)7 (38.9%)25 (75.8%)
invasion of CS
 yes18 (20.9%)5 (14.3%)3 (16.7%)10 (30.3%)
 no68 (79.1%)30 (85.7%)15 (83.3%)23 (69.7%)
suprasellar extension
 yes25 (29.1%)14 (40.0%)3 (16.7%)8 (24.2%)
 no61 (70.9%)21 (60.0%)15 (83.3%)25 (75.8%)
apoplexy
 yes5 (5.8%)5 (14.3%)0 (0.0%)0 (0.0%)
 no81 (94.2%)30 (85.7%)18 (100.0%)33 (100.0%)

* Significant according to ANOVA (p < 0.001) and the Tukey post hoc test (p < 0.01) compared to GH-secreting lesions; p < 0.001 compared to ACTH-secreting adenomas.

Surgical Results

Endoscopic endonasal transsphenoidal procedures lasted an average of 167.3 minutes (range 79–380 minutes). The mean estimated blood loss was 133.1 ml (range 20–900 ml) for all procedures in this cohort. Significant suprasellar tumor extension required an extended transsphenoidal approach in 5 patients (5.8%). Labeling of CSF by intrathecal fluorescein revealed intraoperative CSF leaks in 47% of procedures. As expected, adenomas with intraoperative CSF leaks had a significantly larger diameter compared with the remaining adenomas (1.9 cm vs 1.2 cm, p < 0.01). The skull base defect was closed in a multilayered fashion with vomer (28%), Porex (4%), fat (57%), fascia lata (4%), and DuraSeal (83%). A nasoseptal flap was used in 7 patients, the majority of whom had intraoperative CSF leaks. Moreover, tumors that required nasoseptal flaps had a significantly larger diameter than tumors in which no flap was used (2.5 cm vs 1.4 cm, p < 0.05). Postoperative imaging revealed a GTR in 75.6% of all patients in our cohort (Table 2). The rate of GTR was 90.6% for microadenomas and 66.7% for macroadenomas. Once functional adenomas had invaded the CS, the rate of GTR decreased to 33.3%. Thus, invasion of the CS was a significant negative predictor for GTR (OR 0.076, p < 0.001; 95% CI 0.023–0.255), whereas tumor diameter and suprasellar extension were not predictors of extent of resection. The average hospital stay was 4.3 days (range 2–32 days). The average length of the follow-up period from resection to laboratory testing was 22.8 months (range 1–76 months; Table 2).

TABLE 2:

Outcome in 86 patients with functional pituitary adenomas*

CharacteristicTotalType of Pathology
PRL-SecretingACTH-SecretingGH-Secreting
no. of patients86351833
GTR
 yes65 (75.6%)26 (74.3%)13 (72.2%)26 (78.8%)
 no21 (24.4%)9 (25.7%)5 (27.8%)7 (21.2%)
EC85
 yes51 (60.0%)24 (70.6%)11 (61.1%)16 (48.5%)
 no34 (40.0%)10 (29.4%)7 (38.9%)17 (51.5%)
EC in microadenomas32
 yes24 (75.0%)12 (92.3%)6 (54.5%)6 (75.0%)
 no8 (25.0%)1 (7.7%)5 (45.5%)2 (25.0%)
EC in macroadenomas53
 yes27 (50.9%)12 (57.1%)5 (71.4%)10 (40%)
 no26 (49.1%)9 (42.9%)2 (28.6%)15 (60.0%)
EC in adenomas w/ CS invasion18
 yes7 (38.9%)3 (60.0%)1 (33.3%)3 (30.0%)
 no11 (61.1%)2 (40.0%)2 (66.7%)7 (70.0%)
GKS
 yes12 (14.0%)3 (8.6%)4 (22.2%)5 (15.2%)
 no74 (86.0%)32 (91.4%)14 (77.8%)28 (84.8%)
mean time of last FU in mos (± SEM)22.8 ± 2.222.3 ± 3.424.8 ± 5.122.2 ± 3.9

* EC = endocrinological cure; FU = follow-up.

† One patient was lost to endocrinological follow-up.

Prolactinomas

In the current series, 35 patients with PRL-secreting adenomas underwent an endoscopic transsphenoidal tumor resection (Table 1). The mean age of this group was 36.3 years (range 12–73 years), and it was composed of 22 female and 13 male patients. Those with prolactinomas were significantly younger compared with patients with GH- or ACTH-secreting adenomas (p < 0.001). The majority (80%) of these patients had attempted medical therapy to control excess PRL secretion. Medical therapy failed for 3 main reasons: 1) insufficient control of excess hormone secretion (12 patients); 2) enlargement of the pituitary adenoma despite maximum medical therapy (5 patients); and 3) intolerable adverse medication effects (11 patients). Seven patients with PRL-secreting adenomas underwent resection without a trial of medical therapy. Five of these patients presented with acute vision loss, and 2 presented with severe headaches, of which apoplexy was the cause in 5 patients. All adenomas complicated by apoplexy were prolactinomas. Analysis of preoperative imaging revealed an average maximum diameter of 1.5 cm (range 0.4–4 cm). Thus, 62.9% of prolactinomas were classified as macroadenomas. Endoscopic endonasal transsphenoidal surgery resulted in a GTR in 74.3% of patients with PRL-secreting adenomas (Table 2). Similarly, 70.6% of patients with prolactinomas achieved endocrinological remission. Of the 24 cured patients, 1 required additional GKS. Resection led to a significant reduction of immediate postoperative (p < 0.05) and last follow-up (p < 0.001; Table 3) serum PRL levels compared with preoperative levels. Of 29 patients with prolactinomas who had an intact pituitary–hypothalamic axis preoperatively, 24 remained intact. Two patients developed new hypothyroidism, 2 had hypogonadism, and 1 had diabetes insipidus.

TABLE 3:

Endocrinological outcome in 86 patients with functional pituitary adenomas

OutcomeHormone Level
PRL (ng/ml)ACTH (pg/ml)Cortisol (mg/ml)GH (ng/ml)IGF-I (ng/ml)
excess serum hormone levels
 preop684.9 ± 308.485.4 ± 19.116.5 ± 4.230.3 ± 8.2833.5 ± 56.5
 postop107.9 ± 50.142.0 ± 18.213.6 ± 4.33.9 ± 1.2469.7 ± 42.5
 at last FU34.1 ± 11.845.0 ± 14.49.8 ± 2.02.3 ± 0.9295.6 ± 40.1

Cushing Disease

Our cohort included 18 patients in whom Cushing disease was diagnosed based on endocrinological and clinical evaluation (Table 1). Patients with Cushing disease were on average 53.8 years old (range 25–82 years). There were 13 female and 5 male patients. The gross majority of patients (72.2%) with ACTH-producing adenomas presented with classic cushingoid symptoms. Two patients received the diagnosis of Cushing disease during the workup for intractable hypertension, and 1 patient during the workup for diplopia. Analysis of preoperative imaging revealed an average maximum tumor diameter of 0.8 cm (range 0–2.3 cm). The ACTH-secreting adenomas were significantly smaller compared with both PRL- (p < 0.05) and GH-secreting (p < 0.01) adenomas. Thus, only 38.9% of ACTH-secreting adenomas were classified as macroadenomas. No distinguishable pituitary pathological features could be identified on preoperative MR imaging in 4 patients. These patients underwent exploration of the pituitary gland without further prior workup, and endocrinological remission was achieved in 2 of these 4 patients. Two patients did not achieve biochemical remission according to our criteria. One of them has ACTH and serum cortisol levels that remain consistently within normal limits 33 months after the procedure, whereas the other patient had good relief of his symptoms for 6 years, but eventually suffered from a recurrence requiring repeat resection, resulting again in alleviation of his excess cortisol production. Endoscopic endonasal transsphenoidal surgery resulted in GTR in 72.2% of patients with Cushing disease (Table 2). However, only 61.1% of patients achieved endocrinological cure. Biochemical remission rates were 50% in patients with lesions that were not visible on preoperative imaging, 54.5% in all microadenomas, and 71.4% in macroadenomas. Of 11 patients with ACTH-secreting adenomas that were cured, 2 underwent GKS. Endoscopic endonasal transsphenoidal resection led to a significant reduction of postoperative ACTH levels in serum compared with preoperative serum levels (p < 0.05; Table 3). Of 16 patients with Cushing disease who had an intact pituitary–hypothalamic axis preoperatively, 4 developed defects in one axis.

Growth Hormone–Producing Adenomas

A total of 33 patients suffered from excess GH secretion (Table 1). This cohort consisted of 14 female and 19 male patients, and the average age was 49.9 years (range 20–77 years). Two-thirds of patients with GH-producing adenomas presented with classic acromegalic symptoms. Four GH-secreting adenomas were diagnosed incidentally, 2 patients sought medical attention for headaches, and 1 patient each sought help for complaints of bone pain, joint pain, diplopia, amenorrhea, or sleep apnea. Evaluation of GH-secreting adenomas on preoperative MR imaging revealed an average maximum diameter of 1.7 cm (range 0.6–4 cm). Thus, 75.8% of patients with acromegaly had macroadenomas, and 30.3% of GH-secreting adenomas had invaded the CS. A GTR was achieved in 78.8% of patients, and 48.5% fulfilled criteria for endocrinological cure (Table 2). Biochemical cure was achieved in 75% of GH-secreting microadenomas, whereas the rate was lower in macroadenomas (40%) due to a high proportion of tumors with invasion of the CS. Of 17 patients who achieved endocrinological remission, 2 underwent GKS. Endoscopic endonasal transsphenoidal resection led to a significant reduction of GH levels in serum immediately postoperatively (p < 0.01) as well as at last follow-up (p < 0.05) compared with preoperative levels (Table 3). A significant reduction of serum levels of IGF-I was also observed postoperatively (p < 0.001) as well as at the last follow-up (p < 0.001) compared with preoperative serum levels. Of 32 patients with GH-secreting adenomas who had an intact pituitary–hypothalamic axis preoperatively, 2 suffered from panhypopituitarism and 2 from hypogonadism following endoscopic endonasal transsphenoidal resection.

Predictors for Endocrinological Remission

Adenomas allowing for endocrinological remission had a significantly smaller diameter compared with lesions that were not cured (1.2 cm vs 1.8 cm, respectively; p < 0.05; Fig. 1). Accordingly, univariate logistic regression identified GTR, a maximum adenoma diameter of < 1 cm, lack of suprasellar extension, and lack of CS invasion as positive predictors for endocrinological cure (Table 4). When combining these significant predictors in a multivariate analysis, only GTR and suprasellar tumor extension remained significant independent predictors for biochemical remission.

Fig. 1.
Fig. 1.

Graph showing association of tumor size with endocrinological remission. Adenomas that allow for biochemical cure by endoscopic transsphenoidal resection have a significantly smaller maximum diameter on univariate analysis compared with the remaining adenomas (p < 0.05). Horizontal bars indicate the mean values.

TABLE 4:

Predictors for endocrinological cure in 86 patients with functional pituitary adenomas*

Adenoma CharacteristicsUnivariate AnalysisMultivariate Analysis
ORp Value95% CIORp Value95% CI
GTR4.400.0061.54–12.573.950.0131.344–11.63
no suprasellar extension3.230.0171.23–8.522.860.0421.040–7.856
microadenoma2.890.0311.10–7.58NS
no CS invasion3.010.0441.03–8.80NS

* NS = not significant.

Postoperative Complications

There was no operative or perioperative death in this cohort. There was 1 case of meningitis leading to hydrocephalus requiring a shunt (Table 5). Two patients developed postoperative CSF leaks, which were treated with 4 days of CSF diversion via lumbar drainage. Two patients developed sinusitis after the surgery. One patient complained of a unilateral dry eye requiring treatment with artificial tears.

TABLE 5:

Complications in 86 patients with functional pituitary adenomas

Type of ComplicationNo. of Patients (%)Treatment
meningitis & communicating hydrocephalus1 (1.2)antibiotics & ventriculoperitoneal shunt
CSF leak2 (2.3)lumbar CSF diversion
panhypopituitarism*2 (2.3)hormone replacement
sinusitis2 (2.3)antibiotics
dry eye1 (1.2)artificial tears

* In patients with intact pituitary–hypothalamic axis preoperatively.

Discussion

In this series of patients, we present endocrinological outcome according to the most recent updated criteria for endocrinological cure following a purely endoscopic endonasal transsphenoidal surgery for functional pituitary adenomas. The criteria for endocrinological cure have evolved over the last decades, and until now there has been little universal consensus. The use of different criteria makes comparisons of endocrinological outcomes between different surgical series difficult. For the current series we used the latest consensus criteria for diagnosis of postoperative endocrinological remission for acromegaly, Cushing disease, and prolactinomas.3,9,16 Because the endoscopic technique constitutes the latest refinement of transsphenoidal surgery,40 a comparison of our results with a standard microscopic transsphenoidal technique was performed.

In our series endocrinological cure was achieved for 70.6% of PRL-secreting adenomas. This is similar to the weighted average cure rate (62%) derived from several microscopic series.29,33,39,43 It is obvious that the value of this comparison is limited due to heterogeneities of adenoma size and invasiveness, follow-up times, and definition of endocrinological cure. However, it further corroborates previous claims of equal efficiency of endoscopic technique for achieving biochemical cure in PRL-secreting adenomas.12,14 In a study of endoscopic transsphenoidal surgery by Dehdashti and colleagues,12 the same criteria for endocrinological cure for PRL-secreting adenomas were used as in the current series (Table 6). However, adenoma characteristics are quite different. In the current series, 8.6% of PRL-secreting adenomas required an extended approach for appropriate access to suprasellar portions, whereas adenomas that required extended approaches were excluded by Dehdashti et al. Moreover, the rate of CS invasion was higher in the current series (14.3%) compared with the aforementioned study (8%). This may explain the slightly higher biochemical cure rate (88%) reported by Dehdashti and colleagues for their 25 prolactinomas. The second published series reporting endocrinological outcome following endoscopic transsphenoidal adenoma resection has a patient cohort that appears to be more similar to ours.14 Despite endocrinological criteria that were not as stringent as in our series (maximum serum PRL level for female patients was 30 ng/ml, compared with 20 ng/ml in the current series), the cure rate for Frank and colleagues14 (75.7%) is similar to the rate achieved in our series. Endoscopic transsphenoidal resection yielded endocrinological cure rates above 85% for PRL-secreting microadenomas in both studies12,14 as well as in the current series. Endocrinological remission rates for PRL-secreting adenomas with invasion of CS differ among the series. Whereas Frank and colleagues report a cure rate (36.5%) that is comparable to the current series (60.0%), Dehdashti and colleagues do not report cures in patients with this type of lesion.

TABLE 6:

Literature review of endocrinological remission following transsphenoidal surgery*

Authors & YearPRL-SecretingACTH-SecretingGH-SecretingFU (mos)
No. of PtsGTRECNo. of PtsGTRECNo. of PtsGTREC
Frank et al., 200666NA75.7%56NA67.8%83NA69.0%54.0
Dehdashti et al., 20082592.0%88.0%2785.0%81.0%3485.0%71.0%19.0
present study3574.3%70.6%1872.2%61.1%3378.8%48.5%22.8

* NA = not available; Pts = patients.

For ACTH-secreting adenomas an average cure rate of 78% is reported in the major microscopic series.4,7,17,21,41,46 In our series endocrinological remission was achieved in 61.1% of patients. A low rate of cure (50%) was detected in adenomas that were obscure on preoperative imaging. Moreover, endocrinological cure was achieved in only 40% of patients with visible adenomas of < 5-mm diameter on preoperative MR imaging, whereas endocrinological cure was obtained in 100% of microadenomas > 5 mm. Poor preoperative visualization of ACTH-secreting adenomas is a well-documented poor prognostic factor for endocrinological remission.6 Accordingly, we detected lower cure rates in ACTH-secreting microadenomas compared with those reported in studies by Frank et al.14 and Dehdashti et al.12 (54.5%, 67.7%, and 100%, respectively), whereas the cure rates for macroadenomas were comparable (71.4%, 62.5%, and 68%, respectively).

The current literature on microscopic transsphenoidal resection of GH-secreting adenomas suggests an average cure rate of approximately 67%.1,15,23,31,44,45 In the current study endocrinological remission was achieved in only 51.5% of GH-secreting adenomas. The rate of biochemical cure for GH-secreting microadenomas was 75% in the current series, and thus was similar to the rates reported by Frank and colleagues14 (83%) as well as by Dehdashti and colleagues12 (83%). Given the large proportion of GH-secreting macroadenomas that had invaded the CS, it is not surprising that we detected lower cure rates in GH-secreting macroadenomas compared with studies by Frank et al. and Dehdashti et al. (40%, 64.5%, and 70.1%, respectively).

The current patient cohort includes a great proportion of adenomas with invasion of the CS (20.9%). Using a microsurgical transsphenoidal approach, Kitano and colleagues22 report a 67% rate of endocrinological remission in 12 patients with GH-secreting pituitary adenomas invading the CS. Kitano and colleagues used a microscopic endoscope-assisted transsphenoidal technique to reach tumors that had invaded the CS. The mean blood loss was approximately 1000 ml, compared with approximately 132 ml for tumors with CS invasion in our current cohort. Kitano and colleagues report a 26% rate of transient extraocular palsy, whereas this complication did not occur in the current series. The aggressiveness used to achieve resection of intracavernous tumor varies in the endoscopic literature. Whereas in one recent endoscopic series the investigators did not attempt resection of tumor from the CS,12 Frank and Pasquini13 report endocrinological remission in 43% of functional tumors with invasion of the CS resected using the endoscopic technique. A similar rate of cure was achieved in the current series (38.9%). It is our opinion that one must balance risk with benefit when operating in the CS, and it may be preferable to control residual tumor with stereotactic radiosurgery rather than to achieve GTR associated with a risk morbidity.

A potential limitation of the current study is the relatively short follow-up time of 22.8 months. The occurrence of late recurrences following resection of functioning adenomas in patients with assumed endocrinological cure is well established.2,17,42,46 These recurrences have been the main motivation to introduce more and more stringent criteria for endocrinological cure. Early results from recent endoscopic series12,14 as well as the current study, in which no recurrences were observed in patients who achieved endocrinological remission, are encouraging. However, continued monitoring of these patient cohorts is required to eventually provide long-term endocrinological remission rates following endoscopic resection of functional pituitary adenomas.

Conclusions

An endoscopic transsphenoidal resection of functional pituitary adenomas leads to endocrinological remission in 60% of patients. Importantly, our treatment regimen of endoscopic resection in combination with GKS for possible residual disease allows for endocrinological remission in a significant proportion of functional adenomas with CS invasion as well as in recurrent adenomas, while minimizing procedure-related morbidity.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Schwartz, Hofstetter. Acquisition of data: Hofstetter, Shin, Mubita. Analysis and interpretation of data: Schwartz, Hofstetter. Drafting the article: Hofstetter, Shin. Critically revising the article: Schwartz, Huang, Boockvar, Anand. Reviewed final version of the manuscript and approved it for submission: Schwartz. Statistical analysis: Hofstetter.

References

  • 1

    Abosch ATyrrell JBLamborn KRHannegan LTApplebury CBWilson CB: Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab 83:341134181998

  • 2

    Amar APCouldwell WTChen JCWeiss MH: Predictive value of serum prolactin levels measured immediately after transsphenoidal surgery. J Neurosurg 97:3073142002

  • 3

    Arnaldi GAngeli AAtkinson ABBertagna XCavagnini FChrousos GP: Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab 88:559356022003

  • 4

    Barbetta LDall'Asta CTomei GLocatelli MGiovanelli MAmbrosi B: Assessment of cure and recurrence after pituitary surgery for Cushing's disease. Acta Neurochir (Wien) 143:4774822001

  • 5

    Beauregard CTruong UHardy JSerri O: Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clin Endocrinol (Oxf) 58:86912003

  • 6

    Bochicchio DLosa MBuchfelder M: Factors influencing the immediate and late outcome of Cushing's disease treated by transsphenoidal surgery: a retrospective study by the European Cushing's Disease Survey Group. J Clin Endocrinol Metab 80:311431201995

  • 7

    Boggan JETyrrell JBWilson CB: Transsphenoidal microsurgical management of Cushing's disease. Report of 100 cases. J Neurosurg 59:1952001983

  • 8

    Cappabianca PCavallo LMColao ADel Basso De Caro MEsposito FCirillo S: Endoscopic endonasal transsphenoidal approach: outcome analysis of 100 consecutive procedures. Minim Invasive Neurosurg 45:1932002002

  • 9

    Casanueva FFMolitch MESchlechte JAAbs RBonert VBronstein MD: Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol (Oxf) 65:2652732006

  • 10

    Cottier JPDestrieux CBrunereau LBertrand PMoreau LJan M: Cavernous sinus invasion by pituitary adenoma: MR imaging. Radiology 215:4634692000

  • 11

    De PRees DADavies NJohn RNeal JMills RG: Transsphenoidal surgery for acromegaly in wales: results based on stringent criteria of remission. J Clin Endocrinol Metab 88:356735722003

  • 12

    Dehdashti ARGanna AKarabatsou KGentili F: Pure endoscopic endonasal approach for pituitary adenomas: early surgical results in 200 patients and comparison with previous microsurgical series. Neurosurgery 62:100610172008

  • 13

    Frank GPasquini E: Endoscopic endonasal cavernous sinus surgery, with special reference to pituitary adenomas. Front Horm Res 34:64822006

  • 14

    Frank GPasquini EFarneti GMazzatenta DSciarretta VGrasso V: The endoscopic versus the traditional approach in pituitary surgery. Neuroendocrinology 83:2402482006

  • 15

    Freda PUWardlaw SLPost KD: Long-term endocrinological follow-up evaluation in 115 patients who underwent transsphenoidal surgery for acromegaly. J Neurosurg 89:3533581998

  • 16

    Giustina AChanson PBronstein MDKlibanski ALamberts SCasanueva FF: A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab 95:314131482010

  • 17

    Hammer GDTyrrell JBLamborn KRApplebury CBHannegan ETBell S: Transsphenoidal microsurgery for Cushing's disease: initial outcome and long-term results. J Clin Endocrinol Metab 89:634863572004

  • 18

    Henderson WR: The pituitary adenomata. A follow-up study of the surgical results in 338 cases (Dr. Harvey Cushing's series). Br J Surg 26:8119211939

  • 19

    Hofstetter CPMannaa RHMubita LAnand VKKennedy JWDehdashti AR: Endoscopic endonasal transsphenoidal surgery for growth hormone-secreting pituitary adenomas. Neurosurg Focus 29:4E62010

  • 20

    Invitti CPecori Giraldi Fde Martin MCavagnini F: Diagnosis and management of Cushing's syndrome: results of an Italian multicentre study. J Clin Endocrinol Metab 84:4404481999

  • 21

    Jarrahy RSuh RBerci GShahinian HK: Endoscopic pituitary surgery: an in vivo model for transnasal transsphenoidal hypophysectomy. J Laparoendosc Adv Surg Tech A 9:2112191999

  • 22

    Kitano MTaneda MShimono TNakao Y: Extended transsphenoidal approach for surgical management of pituitary adenomas invading the cavernous sinus. J Neurosurg 108:26362008

  • 23

    Krieger MDCouldwell WTWeiss MH: Assessment of longterm remission of acromegaly following surgery. J Neurosurg 98:7197242003

  • 24

    Laufer IAnand VKSchwartz TH: Endoscopic, endonasal extended transsphenoidal, transplanum transtuberculum approach for resection of suprasellar lesions. J Neurosurg 106:4004062007

  • 25

    Laws ERVance MLThapar K: Pituitary surgery for the management of acromegaly. Horm Res 53:Suppl 371752000

  • 26

    Laws ER JrKern EB: Complications of trans-sphenoidal surgery. Clin Neurosurg 23:4014161976

  • 27

    Leng LZBrown SAnand VKSchwartz TH: “Gasket-seal” watertight closure in minimal-access endoscopic cranial base surgery. Neurosurgery 62:5 Suppl 2ONSE342ONSE3432008

  • 28

    Ludecke DKAbe T: Transsphenoidal microsurgery for newly diagnosed acromegaly: a personal view after more than 1,000 operations. Neuroendocrinology 83:2302392006

  • 29

    Maira GAnile CDe Marinis LBarbarino A: Prolactinsecreting adenomas—surgical results. Can J Neurol Sci 17:67701990

  • 30

    Nieman LKBiller BMFindling JWNewell-Price JSavage MOStewart PM: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 93:152615402008

  • 31

    Nomikos PBuchfelder MFahlbusch R: The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical ‘cure.’. Eur J Endocrinol 152:3793872005

  • 32

    Placantonakis DGTabaee AAnand VKHiltzik DSchwartz TH: Safety of low-dose intrathecal fluorescein in endoscopic cranial base surgery. Neurosurgery 61:3 SupplONS161ONS1662007

  • 33

    Randall RVLaws ER JrAbboud CFEbersold MJKao PCScheithauer BW: Transsphenoidal microsurgical treatment of prolactin-producing pituitary adenomas. Results in 100 patients. Mayo Clin Proc 58:1081211983

  • 34

    Rees DAHanna FWDavies JSMills RGVafidis JScanlon MF: Long-term follow-up results of transsphenoidal surgery for Cushing's disease in a single centre using strict criteria for remission. Clin Endocrinol (Oxf) 56:5415512002

  • 35

    Schaberg MRAnand VKSchwartz TH: 10 pearls for safe endoscopic skull base surgery. Otolaryngol Clin North Am 43:9459542010

  • 36

    Schaberg MRAnand VKSchwartz THCobb W: Microscopic versus endoscopic transnasal pituitary surgery. Curr Opin Otolaryngol Head Neck Surg 18:8142010

  • 37

    Schloffer H: Erfolgreiche Operationen eines Hypophysentumors auf Nasalem Wege. Wien Klin Wochenschr 20:6216241907

  • 38

    Schwartz THAnand VK: The endoscopic endonasal transsphenoidal approach to the suprasellar cistern. Clin Neurosurg 54:2262352007

  • 39

    Smallridge RCMartins AN: Transsphenoidal surgery for prolactin-secreting pituitary tumors: a study of 28 cases and review of the literature. South Med J 75:9639681982

  • 40

    Tabaee AAnand VKBarrón YHiltzik DHBrown SMKacker A: Endoscopic pituitary surgery: a systematic review and meta-analysis. Clinical article. J Neurosurg 111:5455542009

  • 41

    Tagliaferri MBerselli MELoli P: Transsphenoidal microsurgery for Cushing's disease. Acta Endocrinol (Copenh) 113:5111986

  • 42

    Toms GCMcCarthy MINiven MJOrteu CHKing TTMonson JP: Predicting relapse after transsphenoidal surgery for Cushing's disease. J Clin Endocrinol Metab 76:2912941993

  • 43

    Tyrrell JBLamborn KRHannegan LTApplebury CBWilson CB: Transsphenoidal microsurgical therapy of prolactinomas: initial outcomes and long-term results. Neurosurgery 44:2542631999

  • 44

    van't Verlaat JWNortier JWHendriks MJBosma NJGraamans KLubsen H: Transsphenoidal microsurgery as primary treatment in 25 acromegalic patients: results and follow-up. Acta Endocrinol (Copenh) 117:1541581988

  • 45

    Wilson CB: A decade of pituitary microsurgery. The Herbert Olivecrona lecture. J Neurosurg 61:8148331984

  • 46

    Yap LBTurner HEAdams CBWass JA: Undetectable postoperative cortisol does not always predict long-term remission in Cushing's disease: a single centre audit. Clin Endocrinol (Oxf) 56:25312002

Article Information

Address correspondence to: Theodore H. Schwartz, M.D., Department of Neurological Surgery, Weill Cornell Medical College, New York–Presbyterian Hospital, 525 East 68th Street, Box 99, New York, New York 10021. email: schwarh@med.cornell.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Graph showing association of tumor size with endocrinological remission. Adenomas that allow for biochemical cure by endoscopic transsphenoidal resection have a significantly smaller maximum diameter on univariate analysis compared with the remaining adenomas (p < 0.05). Horizontal bars indicate the mean values.

References

1

Abosch ATyrrell JBLamborn KRHannegan LTApplebury CBWilson CB: Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab 83:341134181998

2

Amar APCouldwell WTChen JCWeiss MH: Predictive value of serum prolactin levels measured immediately after transsphenoidal surgery. J Neurosurg 97:3073142002

3

Arnaldi GAngeli AAtkinson ABBertagna XCavagnini FChrousos GP: Diagnosis and complications of Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab 88:559356022003

4

Barbetta LDall'Asta CTomei GLocatelli MGiovanelli MAmbrosi B: Assessment of cure and recurrence after pituitary surgery for Cushing's disease. Acta Neurochir (Wien) 143:4774822001

5

Beauregard CTruong UHardy JSerri O: Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clin Endocrinol (Oxf) 58:86912003

6

Bochicchio DLosa MBuchfelder M: Factors influencing the immediate and late outcome of Cushing's disease treated by transsphenoidal surgery: a retrospective study by the European Cushing's Disease Survey Group. J Clin Endocrinol Metab 80:311431201995

7

Boggan JETyrrell JBWilson CB: Transsphenoidal microsurgical management of Cushing's disease. Report of 100 cases. J Neurosurg 59:1952001983

8

Cappabianca PCavallo LMColao ADel Basso De Caro MEsposito FCirillo S: Endoscopic endonasal transsphenoidal approach: outcome analysis of 100 consecutive procedures. Minim Invasive Neurosurg 45:1932002002

9

Casanueva FFMolitch MESchlechte JAAbs RBonert VBronstein MD: Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol (Oxf) 65:2652732006

10

Cottier JPDestrieux CBrunereau LBertrand PMoreau LJan M: Cavernous sinus invasion by pituitary adenoma: MR imaging. Radiology 215:4634692000

11

De PRees DADavies NJohn RNeal JMills RG: Transsphenoidal surgery for acromegaly in wales: results based on stringent criteria of remission. J Clin Endocrinol Metab 88:356735722003

12

Dehdashti ARGanna AKarabatsou KGentili F: Pure endoscopic endonasal approach for pituitary adenomas: early surgical results in 200 patients and comparison with previous microsurgical series. Neurosurgery 62:100610172008

13

Frank GPasquini E: Endoscopic endonasal cavernous sinus surgery, with special reference to pituitary adenomas. Front Horm Res 34:64822006

14

Frank GPasquini EFarneti GMazzatenta DSciarretta VGrasso V: The endoscopic versus the traditional approach in pituitary surgery. Neuroendocrinology 83:2402482006

15

Freda PUWardlaw SLPost KD: Long-term endocrinological follow-up evaluation in 115 patients who underwent transsphenoidal surgery for acromegaly. J Neurosurg 89:3533581998

16

Giustina AChanson PBronstein MDKlibanski ALamberts SCasanueva FF: A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab 95:314131482010

17

Hammer GDTyrrell JBLamborn KRApplebury CBHannegan ETBell S: Transsphenoidal microsurgery for Cushing's disease: initial outcome and long-term results. J Clin Endocrinol Metab 89:634863572004

18

Henderson WR: The pituitary adenomata. A follow-up study of the surgical results in 338 cases (Dr. Harvey Cushing's series). Br J Surg 26:8119211939

19

Hofstetter CPMannaa RHMubita LAnand VKKennedy JWDehdashti AR: Endoscopic endonasal transsphenoidal surgery for growth hormone-secreting pituitary adenomas. Neurosurg Focus 29:4E62010

20

Invitti CPecori Giraldi Fde Martin MCavagnini F: Diagnosis and management of Cushing's syndrome: results of an Italian multicentre study. J Clin Endocrinol Metab 84:4404481999

21

Jarrahy RSuh RBerci GShahinian HK: Endoscopic pituitary surgery: an in vivo model for transnasal transsphenoidal hypophysectomy. J Laparoendosc Adv Surg Tech A 9:2112191999

22

Kitano MTaneda MShimono TNakao Y: Extended transsphenoidal approach for surgical management of pituitary adenomas invading the cavernous sinus. J Neurosurg 108:26362008

23

Krieger MDCouldwell WTWeiss MH: Assessment of longterm remission of acromegaly following surgery. J Neurosurg 98:7197242003

24

Laufer IAnand VKSchwartz TH: Endoscopic, endonasal extended transsphenoidal, transplanum transtuberculum approach for resection of suprasellar lesions. J Neurosurg 106:4004062007

25

Laws ERVance MLThapar K: Pituitary surgery for the management of acromegaly. Horm Res 53:Suppl 371752000

26

Laws ER JrKern EB: Complications of trans-sphenoidal surgery. Clin Neurosurg 23:4014161976

27

Leng LZBrown SAnand VKSchwartz TH: “Gasket-seal” watertight closure in minimal-access endoscopic cranial base surgery. Neurosurgery 62:5 Suppl 2ONSE342ONSE3432008

28

Ludecke DKAbe T: Transsphenoidal microsurgery for newly diagnosed acromegaly: a personal view after more than 1,000 operations. Neuroendocrinology 83:2302392006

29

Maira GAnile CDe Marinis LBarbarino A: Prolactinsecreting adenomas—surgical results. Can J Neurol Sci 17:67701990

30

Nieman LKBiller BMFindling JWNewell-Price JSavage MOStewart PM: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 93:152615402008

31

Nomikos PBuchfelder MFahlbusch R: The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical ‘cure.’. Eur J Endocrinol 152:3793872005

32

Placantonakis DGTabaee AAnand VKHiltzik DSchwartz TH: Safety of low-dose intrathecal fluorescein in endoscopic cranial base surgery. Neurosurgery 61:3 SupplONS161ONS1662007

33

Randall RVLaws ER JrAbboud CFEbersold MJKao PCScheithauer BW: Transsphenoidal microsurgical treatment of prolactin-producing pituitary adenomas. Results in 100 patients. Mayo Clin Proc 58:1081211983

34

Rees DAHanna FWDavies JSMills RGVafidis JScanlon MF: Long-term follow-up results of transsphenoidal surgery for Cushing's disease in a single centre using strict criteria for remission. Clin Endocrinol (Oxf) 56:5415512002

35

Schaberg MRAnand VKSchwartz TH: 10 pearls for safe endoscopic skull base surgery. Otolaryngol Clin North Am 43:9459542010

36

Schaberg MRAnand VKSchwartz THCobb W: Microscopic versus endoscopic transnasal pituitary surgery. Curr Opin Otolaryngol Head Neck Surg 18:8142010

37

Schloffer H: Erfolgreiche Operationen eines Hypophysentumors auf Nasalem Wege. Wien Klin Wochenschr 20:6216241907

38

Schwartz THAnand VK: The endoscopic endonasal transsphenoidal approach to the suprasellar cistern. Clin Neurosurg 54:2262352007

39

Smallridge RCMartins AN: Transsphenoidal surgery for prolactin-secreting pituitary tumors: a study of 28 cases and review of the literature. South Med J 75:9639681982

40

Tabaee AAnand VKBarrón YHiltzik DHBrown SMKacker A: Endoscopic pituitary surgery: a systematic review and meta-analysis. Clinical article. J Neurosurg 111:5455542009

41

Tagliaferri MBerselli MELoli P: Transsphenoidal microsurgery for Cushing's disease. Acta Endocrinol (Copenh) 113:5111986

42

Toms GCMcCarthy MINiven MJOrteu CHKing TTMonson JP: Predicting relapse after transsphenoidal surgery for Cushing's disease. J Clin Endocrinol Metab 76:2912941993

43

Tyrrell JBLamborn KRHannegan LTApplebury CBWilson CB: Transsphenoidal microsurgical therapy of prolactinomas: initial outcomes and long-term results. Neurosurgery 44:2542631999

44

van't Verlaat JWNortier JWHendriks MJBosma NJGraamans KLubsen H: Transsphenoidal microsurgery as primary treatment in 25 acromegalic patients: results and follow-up. Acta Endocrinol (Copenh) 117:1541581988

45

Wilson CB: A decade of pituitary microsurgery. The Herbert Olivecrona lecture. J Neurosurg 61:8148331984

46

Yap LBTurner HEAdams CBWass JA: Undetectable postoperative cortisol does not always predict long-term remission in Cushing's disease: a single centre audit. Clin Endocrinol (Oxf) 56:25312002

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