We conducted a retrospective review of medical records of 30 adult patients with acromegaly who underwent pituitary surgery and were seen for follow-up in two university hospitals (VU University Medical Center (VUmc) n = 21, and Academic Medical Center (AMC) n = 9) in Amsterdam, the Netherlands. For data on long-term outcome two patients were lost to follow-up because treatment was continued outside our university hospitals. Patients underwent surgery between March 2001 and December 2009 by a total of three different neurosurgeons over time.

Medical records, including laboratory investigations and surgical reports, were monitored for patient characteristics. Different symptoms of GH hypersecretion or tumor expansion were registered. Date of diagnosis of acromegaly was the date of demonstration of elevated levels of insulin-like growth factor-I (IGF-I) adjusted for age and sex, or GH levels above reference range, both accompanied by clinical symptoms of acromegaly. The diagnosis was confirmed in all cases by an oral glucose tolerance test (OGTT), and a nadir GH during an OGTT of <3 mU/L (1 μg/L) excluded acromegaly. Follow-up started on the date of the first surgery. In all cases efforts were made to remove as much tumor tissue as possible and to preserve the function of the surrounding normal pituitary gland. Surgical complications were recorded. Endoscopic surgery was routinely performed as first-line treatment, sometimes preceded by medical therapy. Preoperative treatment with GH-lowering drugs, dopamine agonists or somatostatin analogues, was registered. Hypopituitarism—both before and after surgery—was evaluated using laboratory investigations, stimulatory tests or basal plasma hormone levels together with matching substitution therapy prescribed by the attending endocrinologist, obtained from the medical records.

Remission after surgery was retrospectively based on the opinion of the attending endocrinologists. They had based their judgement on the consensus at that time, aiming at normal IGF-I levels adjusted for age and sex and the absence of active clinical symptoms. An OGTT was occasionally done. Postoperative remission was verified if the patients were still having normal IGF-I or random GH levels at later follow-up, no clinical symptoms of acromegaly and no new therapy was initiated. Patients receiving GH-lowering drugs after surgery were not classified as being in remission at long-term evaluation of outcome, despite reaching normal IGF-I levels. A recurrence was defined as an initial remission followed by a considerable rise in GH or IGF-I levels, recurrent symptoms or newly introduced therapy.

GH and IGF-I levels were determined in two different endocrine laboratories. Preoperative GH and IGF-I levels were monitored as a basal measurement without the influence of GH-lowering drugs. The assays used for hormone measurements changed over the long time period of the study. At the VUmc GH was assayed by an immunometric assay (Sorin Biomedica, Italy) until 2002, an immunoluminometric assay (ILMA) (Advantage, Nichols Institute Diagnostics, USA) until 2006, followed by an ILMA (Immulite 2500, DPC/Siemens Diagnostics, LA, USA) onwards. At the AMC GH was assayed by ILMA (Nichols Institute Diagnostics) until 2007, and by immunofluorescence assay (IFMA) (DELFIA, PerkinElmer Inc., UK) onwards. The GH assays were calibrated against the WHO second International Standard 98/574. At the VUmc, serum IGF-I was determined by IRMA (DSL, Webster, TX, USA) until 2001, and by ILMA (Liaison and Advantage, Nichols Institute Diagnostics,) until 2006, followed by chemiluminescence (Immulite 2500, DPC/Siemens Diagnostics) onwards. At the AMC, for IGF-I determination IRMA (DSL) was used until 2004 and ILMA (Nichols Institute Diagnostics) until 2006. From 2006 chemiluminescence (Immulite 2000, DPC/Siemens Diagnostics) was used to determine IGF-I. The IGF-1 assays were standardized to the WHO International Reference Reagent 87/518. When necessary, conversion factors based on method comparisons performed by both laboratories were applied to all IGF and GH values to make these comparable. The results of IGF-I concentration are expressed as the percentage of the upper limit of current normal range (%ULN) for age and sex [¹⁹].

Of the 30 patients included in the study all had retrievable preoperative imaging of the pituitary, being an MRI scan with thin section T1-weighted spin echo sequences in sagittal and coronal planes, usually with intravenous contrast (gadolinium). Two experienced neuroradiologists, being unaware of surgical outcome, evaluated each MRI scan independently. All MRI scans were revised twice and the results are presented as means. A systematic, standardised pituitary MRI analysis form was constructed using criteria formulated by Bourdelot et al. [¹⁸] with a few modifications. The percentage of intracavernous ICA encasement and the length of this encasement along the artery in the cavernous sinus—measured in millimetres—were added as criteria.

Medline was searched using the terms “acromegaly” and “surgery”. Studies from 2000 onwards were selected on title and abstract for those investigating predictors of surgical outcome in GH-secreting adenomas, and based on the content which in particular described the classification method for tumor characteristics.

Categorical data are expressed as number (percentage) and continuous data as median (range) due to skewed distributions. Analyses included Student’s t tests, Chi-square tests or non-parametric tests when appropriate. Logistic regression was used to analyse predictors of initial surgical outcome. The continuous variables were tested for linearity and when indicated dummy variables were used. In the univariate analyses odds ratio’s (OR) and 95 % confidence intervals (CI) were determined for all patient and tumor characteristics. For the univariate analysis a significance level of 0.05 was used. Multivariable analysis was performed using backward logistic regression. For this analysis a more liberal p value of <0.20 was used with respect to variable selection because a p value of 0.05 can lead to selection bias and optimism as a result of overfitting, meaning that the model is too closely adapted to the data [²⁰]. Subsequently, due to the relatively small number of patients a more liberal p value is desirable. The quality of the model was tested by the Hosmer–Lemeshow test for goodness-of-fit, by calculating the c-statistic (area under the curve) for discriminative ability and R square for the explained variance. The statistical analyses were performed by the statistical software package SPSS version 15.0 for Windows (SPSS Inc., Chicago, IL, USA).

In 30 patients (median age 43.6 (23.9–65.3), 40 % women) data on follow-up was available. Median follow-up was 1.1 years (0.3–7.6). Table 1 shows the patient characteristics at baseline. The cohort included 27 macroadenomas (tumor size >10 mm) and 3 microadenomas. There was a considerable range in time between diagnosis and surgery and preoperative GH and IGF-I concentrations. Of the patients 37 % received GH-lowering drugs prior to surgery, either somatostatin analogues (91 %) or dopamine agonists (9 %). Hypopituitarism was described in 30 % of patients preoperatively, with gonadal deficiency being most prevalent. Of symptoms related to tumor expansion, headache was present in 41 % of patients. Visual field defects were reported in 7 patients (23 %), all having a macroadenoma at initial evaluation.

Two pair of neuroradiologists revised 30 pituitary MRI scans on the standardised analysis form, assessing tumor size and extension (suprasellar, infrasellar and parasellar). Additionally, encasement of the ICA was determined, and if this exceeded 25 %, the length along the artery was measured. The combined results are presented in Table 2. Forty-seven percent of revised adenomas were larger than 20 mm. Suprasellar extension was present in 77 % of the adenomas, extension in the sphenoidal sinus (infrasellar) in 50 % and suspected extension into the cavernous sinus (parasellar) in 90 % of cases, including 17 % massive extension. Encasement of the ICA was measured in percentages and divided into four groups, <25 %, 25–50 %, 50–75 %, >75 %. Twenty patients (67 %) demonstrated encasement over 25 %. The encasement was more than 75 % in 10 % of the patients, with a median length over the artery of 15 mm.

The initial remission rate of the total cohort was 30 %. Of the 21 patients with persistent disease after the first surgery, 16 received GH-lowering medical treatment. Four patients underwent a second TSS and one received radiotherapy, after which one patient achieved biochemical remission. Long-term remission after multiple therapies was reached in 32 %, excluding patients who achieved biochemical remission with GH-lowering drugs. Of the 9 patients with initial remission, one (11 %) suffered recurrence of the GH-secreting adenoma. During follow-up, no patient died. In 80 % of cases surgical complications were not reported. Leakage of cerebral spinal fluid was the most frequent complication (13 %) and could be managed by lumbar drainage in two cases, and resolved without intervention in the remaining two patients. Hypopituitarism was present in 50 % of patients after surgery, compared to 30 % before surgery. Gonadal and adrenal insufficiently were the most prevalent pituitary insufficiencies. Persistent diabetes insipidus occurred in two cases. Of the seven patients complaining of visual field defects, four patients reported significant improvement postoperatively. In one of these cases this information was lacking.

When only investigating patient characteristics, being a male patient significantly increased the odds for persistent disease after initial pituitary surgery. Preoperative hypopituitarism and short and long time between diagnosis and surgery (compared to intermediate) showed a p value of 0.17. Receiving GH-lowering medication prior to surgery tended to lower the odds for persistent disease (OR 0.32, 95 % CI 0.06–1.62; p = 0.17). Because medical pre-treatment was not randomised in this study, prognostic factors were compared between treated and untreated patients (data not shown). There were no significant differences. Tumor characteristics based on the standardised revision of pituitary MRI were stratified by most distinctive cut-off value (indicated in Table 2), resulting in: tumor size >20 versus <20 mm, suprasellar extension without optic chiasm involvement or more versus simple sellar diaphragm bulge or less, and probable parasellar extension with sign of invasion below ICA or more versus probable parasellar extension with no sign of invasion below ICA or less. The encasement of the ICA was studied as >25 % and more than 6 mm in length versus <25 % or less than 6 mm in length. Univariate analysis of tumor characteristics showed tumor size, infrasellar extension and parasellar extension to tend to be independent predictors of persistent disease, reaching borderline significance levels. When a multivariable predictive model was made for both patient and tumor characteristics, sex and parasellar extension were included to make the best fitted model (Hosmer–Lemeshow test p = 0.84), with an area under the curve of 0.83 (95 % CI 0.68–0.98) and an explained variance of 42 % (Table 3).

The authors declare no conflict of interest.

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ULN upper limit of normal range

ICA internal carotid artery

Bold horizontal lines indicates most distinctive cut-off values per characteristic for regression analysis

ULN upper limit of normal range, ICA internal carotid artery

NR not reported

^a Pure endoscopic transsphenoidal surgery