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Departments of Endocrinology, Metabolism, and Diabetes (P.D., D.A.R., N.D., J.S.D., M.F.S.); Biochemistry (R.J.); Histopathology (J.N.); Ear, Nose, and Throat Surgery (R.G.M.); and Neurosurgery (J.V.), University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom
Address all correspondence and requests for reprints to: Prof. M. F. Scanlon, Department of Endocrinology, Metabolism and Diabetes, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom. E-mail: scanlonmf{at}cf.ac.uk.
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Abstract |
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Fifty-seven of 90 (63%) patients remained in remission after surgery. Seventy-nine percent of patients with microadenomas but only 56% of patients with macroadenomas achieved remission (P < 0.001). Eighty-six percent of patients with preoperative GH levels below 10 µg/liter (day profile or after oral glucose tolerance test) went into remission, compared with 51% of patients with GH levels above 25 µg/liter at diagnosis (P < 0.002). The remission rate was also related to the period of surgery that was significantly higher in 1998–2001 (76%; P < 0.05) compared with 1990–1997 (54%) and 1980–1989 (63%).
There were no recurrences or perioperative deaths. Meningitis occurred in 3% of patients, cerebrospinal fluid rhinorrhea in 7%, and permanent diabetes insipidus in 15%. The proportion of patients who developed new anterior pituitary hormone deficiencies and panhypopituitarism was significantly less in the period 1998–2001 (P < 0.001) when compared with the periods from 1990–1997 and 1980–1989.
Transsphenoidal surgery is a safe and effective treatment for acromegaly, and our results compare favorably with those from published series. The presence of an intrasellar lesion and low preoperative GH levels is a good predictor of remission in the long term, but historically in our center this can only be achieved in a significant proportion of patients at the expense of some degree of hypopituitarism. However, surgical outcome in our center, including a reduced frequency of hypopituitarism, has improved significantly over time, coincident with the arrival of a dedicated pituitary neurosurgeon and the use of selective adenomectomy as the preferred surgical approach wherever possible.
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Introduction |
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Various biochemical criteria for remission have been suggested in the past, including a random GH measurement less than 2.5 µg/liter (8, 9, 10, 11), mean GH value from a day curve less than 2.5 µg/liter (12, 13), nadir GH value after an oral glucose tolerance test (OGTT) less than 1.0 µg/liter (10, 14, 15, 16), and a normal age-related IGF-I level (16). Published series have reported different remission rates based on application of the above varying criteria (10) and the skill and expertise of the surgeon involved. The importance of adequate treatment is highlighted by recent data indicating that lowering GH levels to less than 2.5 µg/liter reverses the premature mortality of acromegaly (9, 11), and an international consensus conference in 1999 suggested rigorous criteria for remission (cure) of acromegaly including normal age-related IGF-I and nadir GH levels during an OGTT of less than 1.0 µg/liter (16). This was further ratified in May 2000 by the Acromegaly Treatment Workshop in their consensus statement (17).
We have used these criteria to analyze the data from our center in 90 acromegalic patients undergoing transsphenoidal surgery over a 20-yr period and compared results with those reported from other centers.
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Subjects and Methods |
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Data from a total of 100 consecutive patients undergoing surgery were reviewed. Eight patients underwent surgery at a different center to ours whereas data in two patients were incomplete and were excluded from the series, which ultimately comprised 90 patients who underwent pituitary surgery. Four patients died during the course of the follow-up but were included in the series because we had sufficient follow-up data from clinic visits. The mean age of patients was 61 (range, 29–86) yr, and there were 44 males and 46 females. The mean follow-up after surgery was 10.9 yr (range, 6 months to 20 yr).
The diagnosis of acromegaly was made clinically and biochemically after lack of suppression of GH to below 1.0 µg/liter during OGTT. Serum IGF-I levels were used in diagnosis and follow-up only since 1990 when the assay became available. All patients underwent preoperative assessment according to a standard protocol that included measurement of free T4, TSH, prolactin (PRL), LH, FSH, and testosterone or estradiol. The pituitary-adrenal axis was assessed by either a short ACTH stimulation test (short synacthen test; SST) or insulin tolerance testing (ITT) as appropriate.
All patients underwent pituitary computerized tomography or magnetic resonance imaging. Tumors were classified as microadenomas (diameter < 10 mm) and macroadenomas (diameter > 10 mm). Macroadenomas were further divided into intrasellar (IS) and extrasellar (ES), with ES macroadenomas showing evidence of extension into the suprasellar cistern or third ventricle or lateral invasion into the cavernous sinus. Where no tumor was visible on imaging, it was classed as a microadenoma. Immunohistochemical characteristics of tumors were available in 88 patients.
Surgical remission or cure involved fulfilling all of the following criteria (depending on the availability at the time): mean GH from a day curve (five-point day curve; samples collected at 0900, 1000, 1100, 1300, and 1500 h) less than 2.5 µg/liter, a nadir GH value after OGTT of less than 1.0 µg/liter, and a normal age-related IGF-I level.
Operations were performed by two ear, nose, and throat surgeons (A and B) and one neurosurgeon (C) over this period. Surgeon A operated between 1980 and 1989, surgeon B between 1990 and 1997, and surgeon C between 1998 and 2001. A total of 33 patients (36%) underwent total hypophysectomy, and 57 underwent selective adenomectomy.
Patients received peri- and postoperative iv antibiotics (surgeons A and B) and hydrocortisone. Basal and dynamic pituitary function testing including assessment of GH secretory status was performed in almost all patients at 4–6 wk postoperatively (in three patients, GH day curve measurements were performed within 1 wk of surgery). Pituitary function tests included measurements of PRL, thyroid, and gonadal function and ACTH reserve using the ITT (or SST where hypoglycemia was contraindicated). Pituitary hypothyroidism was diagnosed if serum T4 was low with an inappropriately low TSH. Low serum gonadotropins in the presence of low sex steroid levels was the basis for diagnosing hypogonadism. ACTH insufficiency was based on a subnormal cortisol response of less than 500 nmol/liter using ITT and 550 nmol/liter using SST. Diabetes insipidus (DI) was assessed, where necessary, using the standard water deprivation test. All patients who were deemed to be in remission underwent subsequent annual GH day profile and IGF-I measurements. In those with mean day curve GH levels greater than 2.5 µg/liter, further surgery and/or radiotherapy and/or medical therapy was considered. Appropriate written informed consent was obtained from all patients undergoing therapeutic procedures.
GH and IGF-I assays
Between 1980 and 1989, serum GH was measured using an in-house RIA, whereas between 1989 and 1999 it was measured using an immunoradiometric assay (IDS Ltd., Tyne and Wear, UK). From 1999, an automated two-site Nichols Advantage chemiluminescent immunoassay (Nichols Institute Diagnostics, San Juan Capistrano, CA) was used. The Nichols Advantage assay for GH has intra- and interassay coefficients of variation of 4.8 and 5.8%, respectively, in assay midrange.
Serum IGF-I concentrations were measured between 1990 and 2001 using a RIA (Biosource, Nivelles, Belgium) and since 2001 using Nichols Advantage chemiluminescent immunoassay with intra- and interassay coefficients of variation of 5.2 and 5.7%, respectively, in assay midrange. For IGF-I measurements, normal ranges according to age were provided by the manufacturer.
Statistical analysis
The 
2 test was used to calculate outcome in relation to tumor size and to compare cure and complication rates between surgeons in different periods; the parametric t test was used on transformed data where appropriate. P < 0.05 was considered significant. Data analysis was performed using the SPSS 11.0 for Windows (SPSS Inc., Chicago, IL) statistical package.
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Results |
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-subunit of glycoprotein) in 86 (96%) patients showed that 44 (51%) were immunoreactive for GH alone, 37 (43%) for both GH and PRL, and a varying degree of mixed reactivity was observed in the remainder. There were no significant differences in the preoperative GH levels and remission rates based on the different immunohistochemical characteristics of the tumors. Twenty-eight of 44 (64%) of those that stained positive for GH were in remission, whereas 21 of 37 (57%) that were positive for both GH and PRL were in remission. Outcome of transsphenoidal surgery
According to the criteria adopted in our series, 57 of 90 (63%) patients went into remission after surgery. The remaining 33 patients received medical therapy (dopamine agonists and/or somatostatin analog), and 31 underwent external beam radiotherapy in addition. Of those in remission after surgery, there has been no recurrence so far.
A mean postoperative GH day profile below 2.5 µg/liter was achieved in 63 of 90 (70%) patients, whereas a nadir GH value of less than 1.0 µg/liter after OGTT was achieved in 57 of 90 (63%) patients (Table 1
). IGF-I measurements were available in only 37 patients preoperatively, and in 25 (68%) patients they were normalized after surgery (Table 1). In the 12 patients in which IGF-I levels did not normalize, there was a mean postoperative fall in IGF-I levels of 35% (range, 7–65%).
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. Twenty-three of 29 (79%) patients with microadenomas and 27 of 36 (75%) with IS macroadenomas were in remission, compared with 7 of 25 (28%) with ES macroadenomas. Overall, 50 of 65 (77%) patients with intrasellar adenomas (micro and macro) were in remission, indicating the relevance of both tumor size (P < 0.001) and intrasellar confinement (P < 0.002).
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. There was no change in the proportion of tumors in different size categories or in the preoperative GH levels over these years.
Table 3 shows the remission rates after surgery in relation to tumor size and preoperative GH level. Success rate was inversely related to preoperative GH levels, with 18 of 21 (86%) patients presenting with GH levels less than 10 µg/liter achieving remission compared with 23 of 45 (51%) whose GH levels were greater than 25 µg/liter at diagnosis (P < 0.002).
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During follow-up four patients died, but none of the deaths were related to or occurred in the immediate postoperative period (within 1 month of surgery). Table 4 shows the postoperative complications in our patients relating to the period of surgery. There were three documented cases of meningitis (3%) diagnosed by cerebrospinal fluid (CSF) examination and treated successfully by antibiotics. Six patients had CSF rhinorrhoea (7%), and two required continuous lumbar drainage. One patient developed intracerebral and subdural hemorrhage after surgery requiring surgical drainage. DI occurred in 30 patients in the immediate postoperative period and was permanent in 14 (15%) patients requiring long-term desmopressin treatment. In 16 (17%) patients, DI was transient and lasted for a maximum period of 1 wk. One patient developed inappropriate antidiuretic hormone secretion and one had a cerebrovascular accident, whereas two patients developed deep venous thrombosis requiring anticoagulation.
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Thirty-three of 90 (37%) patients remained eupituitary after transsphenoidal surgery. Thirty-nine of 90 (43%) patients were rendered panhypopituitary; 22% (20 of 90) had evidence of new anterior pituitary hormone deficiencies, three had TSH (3%), seven had LH/FSH (8%), 15 had ACTH (17%), and 20 had GH (22%). The results are summarized in Table 5. The size of the tumor had no significant effect on the development of either anterior pituitary hormone deficiency or panhypopituitarism.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Meaningful comparison of data between centers has been difficult in the past because of variation in the selected criteria of cure or remission. These have been based on either single measures or various combinations of random/mean GH day profile levels (often with different cut-off values), nadir GH values after OGTT and IGF-I measurements (Table 6).
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We chose to define remission as achievement of a mean postoperative GH day curve less than 2.5 µg/liter, a nadir GH value after OGTT of less than 1.0 µg/liter, and a normal age-related IGF-I level, performed at 4–6 wk postoperatively. Using all of these stringent criteria, our overall remission rate was 63% which compares favorably with other similar series of 33% (8), 34% (21), 42% (12), 49% (10), 55% (22), 56% (23), 67% (24), 68% (13), and 70% (25). Indeed, compared with the most recent similar series of Kreutzer et al. (25), our long-term remission rates of 70, 63, and 68% are very similar to theirs of 68, 61, and 70%, respectively, when cure was defined by postoperative GH less than 2.5 µg/liter, nadir GH less than 1.0 µg/liter, and normal IGF-I, respectively.
The influence of tumor size and extrasellar extension on outcome is quite clearly borne out in our series with 79% of microadenomas (and 75% intrasellar macroadenomas) achieving remission, compared with 56% of macroadenomas (and only 28% extrasellar macroadenomas). This compares well with the published series so far, and only Ahmed et al. (13) have achieved a marginally better remission rate (60%) for macroadenomas compared with ours of 56% (Table 6). Therefore, our results, in keeping with many others, indicate that remission after surgery is dependent not only on tumor size but also on intrasellar confinement.
We have not had any relapses so far after a mean follow-up of nearly 11 yr. This is in contrast to most series in which reported relapse rates have varied between 1 and 10% as follows: 3%, Sheaves et al. (12); 4.3%, Ross and Wilson (26); 10%, Grisoli et al. (27); 6%, Osman et al. (10); 6%, Swearingen et al. (28); 7%, Abosch et al. (29); 7%, Ahmed et al. (13); and 1% each Laws et al. and Kreutzer et al. (24, 25), depending on the rigor of the follow-up analysis.
Kreutzer et al. (25) have shown lower remission rates for tumors with mixed GH/PRL immunostaining (50%) compared with those positive only for GH (62.5%). Our findings are similar with 58% remission rates for those with mixed GH/PRL immunostaining and 64% for tumors that stained exclusively for GH (statistically nonsignificant).
The importance of preoperative GH levels on optimal outcome was evident with an 86% remission rate in our patients with preoperative GH levels below 10 µg/liter compared with 51% when GH levels were greater than 25 µg/liter at diagnosis. This is consistent with previous reports (12, 13, 21, 23).
Our results suggest that transsphenoidal surgery for acromegaly is a safe procedure with minimal complications. As in our series, there were no deaths related to surgery reported by others (12, 25, 26, 29). Complications directly related to surgery in our series showed somewhat higher CSF leak of 7% compared with the following: 2%, Sheaves et al. (12) and Ross and Wilson (26); 2%, Abosch et al. (29); and 1.7%, Kreutzer et al. (25). The incidence of meningitis has been reported at less than 2% in most series (23, 26, 29, 30). Our figure of 3% was slightly higher but less than the 8% incidence reported by Sheaves et al. (12). Fifteen percent of our patients developed permanent DI, which is higher than the 8% reported by Sheaves et al. (12), 2.6% by Ross and Wilson (26), 7.2% by Ahmed et al. (13), and 2% by Abosch et al. (29). The incidence of new anterior pituitary hormone deficiency of any axis developing postoperatively was 22% in our group of patients, which is comparable to Sheaves et al. (12) but higher than the 8% reported by Hardy and Somma (30) and 14% by Ahmed et al. (13). Only 37% of our patients remained eupituitary after surgery, which is much less than those of Hardy and Somma, 76% (30); and Sheaves et al., 73% (12). The reason for higher rates of CSF leak, permanent DI, and hypopituitarism in our series is probably due in part to the higher proportion of macroadenomas in our cohort (68%). Additionally, surgery involved total hypophysectomy in over one third of the patients and was a particular practice of surgeon A between 1980 and 1989.
Quite reasonably, it has been suggested that pituitary surgery should be undertaken by specialists to achieve better surgical outcomes (31, 32, 33). When analysis of outcomes is compared between surgeons in our center, it is clear that results have improved over time with enhanced remission and a reduction in the rates of hypopituitarism and complications. These advances cannot be accounted for by changes in tumor size or in preoperative GH levels because there were no significant differences in these parameters over these years. The improvements may, however, be attributable to better preoperative imaging and a change in surgical approach, with increased emphasis on selective procedures wherever possible. In addition, we speculate that some of the improvements may be related to the move in 1998 to a single surgeon operating on all patients with pituitary disease in our center. Others have reported similar findings (13, 31, 34, 35) and reinforce the need for centers to employ dedicated, experienced pituitary surgeons in treating all patients with acromegaly.
In conclusion, using stringent criteria of remission, our results compare well with similar series, although it is hoped that recent standardization of remission criteria will enable improved future comparison of surgical outcomes between different centers. Outcomes for macroadenomas, however, continue to be less than satisfactory, although with the advent and development of modern microsurgical techniques including endoscopy-assisted microsurgery, neuronavigation, and intraoperative hormone assays, operative success for acromegaly may continue to improve with further reductions in morbidity and mortality.
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Footnotes |
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Received November 21, 2002.
Accepted April 16, 2003.
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