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Endocrine Care |
Departments of Neurological Surgery (J.K., E.R.L.), Internal Medicine (Endocrinology and Metabolism) (M.L.V.), and Pathology (Neuropathology) (M.B.S.L.), University of Virginia Health System, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Edward R. Laws, Jr., M.D., Department of Neurological Surgery, University of Virginia Health System, P.O. Box 800212, Charlottesville, Virginia 22908-0212. E-mail: EL5G{at}virginia.edu
Abstract
The results of transsphenoidal surgery as initial therapy for GH-secreting pituitary adenomas in 57 acromegalic patients were analyzed retrospectively. Patients with prior surgery or radiation therapy were excluded from the study. Three different criteria were used to define remission: glucose-suppressed (nadir) GH less than 1.0 µg/liter, a normal sex- and age-adjusted IGF-I level, and postoperative random GH levels of 2.5 µg/liter or less. Additionally, we analyzed the neuropathological data, including immunohistochemistry and ultrastructural categorization, and the surgical complications.
The short-term remission rate (6-wk postoperative follow-up visit), as determined by a random GH measurement of 2.5 µg/liter or less, was 48.8%; the remission rate, as determined by nadir GH, was 51.4%. For 57 patients followed for 12 months or more after surgery (mean, 37.7 months), surgical remission was achieved in 70.2%, 66.7%, and 61.1%, respectively, for patients assessed by normal IGF-I, random GH, and nadir GH. One patient (1.1%) developed recurrence of active acromegaly 81 months after initially successful surgical therapy. Extrasellar growth of the tumor (P = 0.04) and dural invasion by the adenoma (P = 0.008) were significant univariate predictors of a poor outcome. Tumor size was significantly greater in patients with persistent or recurrent acromegaly (P = 0.02). Patients with tumors of the ultrastructural categories of mixed GH/PRL cell and mammosomatotroph adenomas had the lowest remission rates (50% and 42.9%, respectively). There were no perioperative deaths, and there was no serious morbidity. The permanent complication rate was 3.3% (1 permanent DI and 2 nasal septal perforations).
Surgical management of acromegaly currently provides prompt, effective, and satisfactory initial treatment for the majority of patients. Using stringent criteria for remission, primary transsphenoidal surgery for GH-secreting pituitary adenomas is effective and often definitive therapy for acromegaly. These results provide a benchmark for the contemporary results of surgical management as assessed by modern outcome criteria.
HARVEY CUSHING’S FIRST operation for acromegaly took place in 1909. Dr. Cushing recognized that acromegaly was produced by a growth factor and thought that hypertrophy of the pituitary gland was part of the syndrome and perhaps the etiology (1). Since then our understanding of the pathophysiology, diagnosis, and treatment of GH-secreting pituitary adenomas has improved dramatically.
The importance of prompt normalization of excess GH production is underlined by studies that demonstrate a significant increase in mortality in patients with active acromegaly, ranging from two to three times that of an age- and sex-matched normal population (2, 3, 4, 5). The increased risk of premature mortality is reversed by lowering mean serum GH levels to less than 2.5 µg/liter (2, 4).
Definitions of satisfactory remission of acromegaly after treatment
have changed as hormone assays have become more sensitive and more
reliable (6, 7, 8, 9). In addition to lowering the GH below a
critical level to reduce the risk of premature mortality, the goals of
treatment should include restoration of a normal pulsatile GH secretion
pattern, a normal GH response to oral glucose administration, and a
normal level of circulating IGF-I (8, 9, 10). An
international consensus conference held in 1999 resulted in the
publication of new, rigorous criteria for remission ("cure") of
acromegaly (11), viz. IGF-I normal for age, and
nadir GH during oral glucose tolerance test (OGTT) less than 1.0
µg/liter. It was recognized that the actual normal level of nadir GH
was usually lower (
0.04 µg/liter), but was difficult to resolve
accurately at such low levels considering the vagaries of analytical
techniques used from one institution to another. Eventually, reliable
methods universally used will allow a more precise level for nadir GH
(12).
We present the data from 57 patients with acromegaly treated with selective transsphenoidal microsurgery as primary management. This analysis was conducted using modern criteria, and it provides a benchmark assessing the efficacy of this form of surgical therapy and allows for comparison of 3 biochemical tests in the same cohort of patients, and the assessment of remissions as defined by the 1999 consensus conference (11).
Subjects and Methods
This is a retrospective analysis of patients referred to a combined neuroendocrine pituitary service at the University of Virginia Health Sciences Center. All patients with a GH-secreting pituitary tumor evaluated and treated with surgery as initial therapy between July 1, 1992, and February 1, 1998, were analyzed. Follow-up information was obtained from periodic visits to our pituitary clinic or through contacts by letter or telephone with the patient’s referring physician or with the patient and family.
The database included clinical symptoms and signs, the preoperative laboratory and imaging results, operative findings, results of surgery, complications, clinical outcome, and postoperative management. The pathological studies included immunohistochemistry and ultrastructural analysis of the surgical specimens, as previously described (13).
All patients had active acromegaly, underwent transsphenoidal microsurgery as initial therapy, and were followed for at least 12 months after surgery. Patients with prior surgery, radiation therapy, or medical therapy were excluded from the analysis. All surgical procedures were performed by one neurosurgeon.
There were three stages of postoperative analysis: 1) immediate postoperative results (1–3 d after surgery), 2) short-term (between 1–12 months after surgery), and 3) long term (>12 months after surgery; mean, 37.7 after surgery).
Surgical remission was defined as postoperative GH of less than 1 µg/liter (nadir GH) during an OGTT and a normal serum IGF-I (somatomedin C) level adjusted for age and sex. Random GH levels were correlated with the other remission criteria. Patients who did not meet the criteria of normal IGF-I and nadir GH less than 1 µg/liter were considered to have persistent acromegaly. With rare exceptions, all patients in remission had at least one random GH measurement less than 2.5 µg/liter. The one patient who had an initial remission but subsequently developed abnormal GH and IGF-I concentrations was categorized as having recurrent acromegaly. Data for remission as defined by GH levels of 5 µg/liter or less are provided so that comparison can be made with prior reports of surgical outcome (14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24).
Tumors were classified by size and invasiveness. Microadenomas are 10 mm or less in diameter, and macroadenomas are larger than 10 mm in diameter. Invasive tumors were those noted to have either gross or microscopic evidence of dural invasion at the time of surgery.
Assays
GH was measured using a chemiluminescence immunoassay (Nichols Institute Diagnostics, San Juan Capistrano, CA) with a sensitivity of 0.1 µg/liter. The interassay variation was 4.1% at a mean GH level of 0.92 µg/liter and was 5.8% at a mean GH level of 2.40 µg/liter. Serum IGF-I was measured using a chemiluminescence immunoassay (Nichols Institute Diagnostics) that employs a large excess of IGF-II that blocks IGF-binding proteins from recombining with IGF-I after acid dissociation. The interassay variation was 5.4% at a mean IGF-I value of 215 µg/liter and 7.4% at a mean IGF-I of 811 µg/liter. Normal ranges according to age were provided by the manufacturer.
Statistical analysis
Analyses included t test, 
2
tests, and ANOVA, using the STATISTICA software package [STATISTICA
student’s (classroom) version for Windows 95/NT developed by StatSoft,
Tulsa, OK]. Univariate and multiple regression analysis and assessment
of the association of different database variables by means of
correlation tables and calculation of the Spearman correlation
coefficient were also performed.
Patient population
The medical records of 89 patients with GH-secreting pituitary tumors were reviewed. Seventeen patients had insufficient reliable data for the 12-month analysis. Fifteen patients had undergone prior therapy for GH-secreting pituitary tumors and were excluded from the series, which ultimately consisted of 57 patients.
The results of immunocytochemical and electron microscopic studies of the tumors in the series of 57 patients were considered along with the complications of surgery.
Demographic data
The series consisted of the 57 patients who had transsphenoidal
surgery as initial therapy and for whom there was more than 1 yr of
follow-up clinical and laboratory information. This group included 37
women and 20 men, aged 16–71 yr, with a mean age of 43.9 yr (Table 2
).
The men were significantly younger than the women. The mean follow-up
after surgery was 37.7 months. The preoperative laboratory
investigations are presented in Table 1
along with the size and invasiveness of the pituitary tumors. All
patients were treated with transseptal transsphenoidal pituitary
surgery (25), except for 1 patient who had both
transsphenoidal surgery and a subsequent craniotomy to remove a large
extension of the tumor involving the frontal lobe.
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Appropriate written informed consent was obtained from all patients for all therapeutic procedures.
Results
At long-term follow-up, 40 of 57 patients (70.2%) were in
remission after surgery alone. One patient, initially meeting remission
criteria, developed a late recurrence of acromegaly. Patients who did
not achieve remission were given either medical treatment,
radiosurgery, or combination therapies (Table 2
). No patient was treated with
conventional fractionated radiotherapy.
Hormone measurements obtained during the immediate postoperative period
(postoperative d 1–3) revealed that 58.3% of the patients had a
random GH level of 2.5 µg/liter or less, and 79.2% had values of 5.0
µg/liter or less (Table 3). Despite the
relatively short time after surgery, serum IGF-I measurements in 19
patients during the immediate postoperative period were normal in 10
(52.6%). There were only 6 OGTTs conducted during the immediate
postoperative period. Three of these patients had a nadir GH level
below 1.0 µg/liter and remained in remission during the entire
follow-up period. The other patients had nadir GH concentrations of
3.2, 1.5, and 1.9 µg/liter, respectively. They all had persistent
acromegaly based on subsequent studies.
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). Twenty-one of 43 (48.8%) patients tested had a random GH level of
2.5 µg/liter or less, and 65.1% had values of 5.0 µg/liter or
less. In 35 patients all 3 acromegaly-related hormone measurements,
IGF-I, OGTT (nadir GH), and random GH, were obtained, and in 19 of the
35 patients (54%) all 3 values met the defined remission criteria. The
IGF-I and nadir GH measurements were closely correlated (r = 0.53;
P = 0.0008). The correlation between IGF-I and random
GH was r = 0.48 and P = 0.003.
Long-term follow-up hormone measurements are presented in Table 3.
Forty of 57 patients (70.2%) had a normal serum IGF-I level after
surgical management only; 11 of 18 (61.1%) patients had
glucose-suppressed GH levels of less than 1.0 µg/liter, and 24 of 36
patients (66.7%) had a random GH value of 2.5 µg/liter or less
(86.1% had values of 5.0 µg/liter or less).
Spearman correlation coefficients showed that an elevated (>10 µg/liter) preoperative random GH (r = 0.52; P = 0.00005), abnormal (>1.0 µg/liter) preoperative OGTT nadir GH values (r = 0.52; P = 0.001), and dural invasion by the tumor (r = 0.32; P = 0.02) were significantly correlated with a poor outcome. Tumor size (microadenoma vs. macroadenoma; P = 0.057) was a borderline predictor. Preoperative IGF-I levels (P = 0.57) were not correlated with outcome.
Using logistic regression analysis, preoperative random GH levels above 10 µg/liter (P = 0.0006), dural invasion (P = 0.008), and extrasellar extension of the tumor (P = 0.043) were all significant univariate predictors. Multivariate analysis, however, revealed that a preoperative random GH level greater than 10 µg/liter (P = 0.008) and dural invasion (P = 0.013) were the only remaining significant predictors of persistent disease.
Random GH levels below 5 µg/liter obtained immediately postoperatively correlated significantly with outcome (r = 0.56; P = 0.00004), whereas IGF-I values measured during the first 3 postoperative d, as expected (7), did not (r = 0.35; P = 0.13).
Ophthalmological results
Eight patients, all with suprasellar macroadenomas, had preoperative visual field deficits; one developed pituitary apoplexy causing acute, almost complete, blindness in both eyes. In six of the eight patients visual function improved postoperatively; in two patients, including the one with apoplexy, visual deficits remained unchanged. There was no new postoperative impairment of visual function.
Complications of surgery
There were no deaths. Transient endocrine disturbances were the most frequent postoperative problem. Three patients developed transient syndrome of inappropriate antidiuretic hormone secretion with symptomatic hyponatremia (26), and transient diabetes insipidus occurred in two patients. One patient developed permanent diabetes insipidus. Two patients had postoperative nasal septal perforations without significant symptoms, and one patient developed sinusitis.
Postoperative cerebrospinal fluid rhinorrhea occurred in one patient and resolved after 3 d of continuous lumbar drainage.
Pathology analysis
Immunohistochemistry for seven major pituitary hormones (GH, PRL,
ACTH, LH, FSH, TSH, and 
-subunit of glycoproteins) was performed in
all 57 patients (Table 4). The minority
of tumors were immunoreactive for GH only (8 of 57). Over half of the
tumors were positive for GH and PRL (29 of 57), with varying degrees of
reactivity. In 62% of these specimens (18 of 29), the adenomas were
also immunoreactive for 1 or more of the glycoprotein hormones; the
combination of GH and glycoproteins immunopositivity was observed in 16
specimens.
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50%) and a lower preoperative GH level among sparsely
granulated variants. Six specimens were mixed adenomas consisting of densely granulated GH cells and sparsely granulated PRL cells. Five of these mixed tumors were macroadenomas with suprasellar extension. All were invasive tumors, and the preoperative basal GH (mean, 99.1 µg/liter) and PRL levels (mean, 67.5 µg/liter) were higher than in other tumor types; remission occurred in only 50% of these patients. Almost all of the patients with mixed tumors had clinical evidence of hyperprolactinemia, i.e. hypogonadism, amenorrhea, or galactorrhea.
Four adenomas were mammosomatotroph adenomas with immunopositivity for GH and PRL. Despite a moderate incidence of dural invasion (43%), patients with this type of tumor had the lowest remission rate (42.9%). As expected, mixed cell and mammosomatotroph adenomas had significantly higher mean preoperative PRL levels than densely and sparsely granulated tumors. Additionally, the mean preoperative GH levels in mixed cell tumors were higher than those in any other ultrastructural tumor type.
One patient had an acidophilic stem cell tumor that was large and partially necrotic. This patient initially presented with secondary amenorrhea and galactorrhea and minimal features of acromegaly. Her preoperative PRL level was the highest measured in the entire series at 170 µg/liter; the preoperative GH (19.0 µg/liter) and IGF-I (271.0 µg/liter; normal range for age, 114–492 µg/liter) levels were also elevated. There was also one case of a mixed, sparsely granulated, GH cell adenoma associated with an intrasellar gangliocytoma (27).
Discussion
Definition of remission
It is evident that defining the remission of acromegaly requires more than the determination of a single hormone concentration. In addition to a favorable clinical response and mean random GH levels below 2.5 µg/liter (2), remission criteria include a glucose-suppressed (nadir) GH level less than 1.0 µg/liter and a normal sex- and age-adjusted IGF-I level (11). Buchfelder et al. (28) published a detailed analysis of recurrent acromegaly after transsphenoidal surgery and emphasized that the OGTT with GH measurements provided better prognostic information than random GH determinations. Another careful study by Stoffel-Wagner et al. (9) supported this finding and demonstrated that only by means of a nadir GH level, with a normal response defined as suppression of GH to less than 1.0 µg/liter, could patients with active acromegaly be completely distinguished from healthy control subjects and cured patients. Although IGF-I levels correlate well with clinical activity of acromegaly (18), it has been reported that they might be insufficient in predicting the long-term benefit of surgery (29). These results provide evidence that the use of a single test, such as IGF-I, may be of limited value in the follow-up and outcome assessment of surgically treated acromegaly (6, 29).
Surgical management
Sheaves et al. (22) reported on 100 acromegalic patients treated with transsphenoidal surgery; the remission rate was 42% (61% for microadenomas and 23% for macroadenomas) using the criterion of a random GH level less than 2.5 µg/liter. The influence of tumor size on outcome was emphasized, because only 23% of patients with a macroadenoma met the postoperative remission criterion. Freda et al. (18) reviewed 115 surgically treated patients with remission criteria of normal IGF-I or nadir GH of 2 µg/liter or less. The overall remission rate was 61%, and the recurrence rate was 5.4% with up to 2.5 yr follow-up (18). Swearingen et al. (4) reported 149 acromegalic patients with long-term follow-up. The remission rate overall, defined by normal IGF-I or nadir GH less than 2 µg/liter, was 83%. Clearly, most individual criteria for remission are not absolute, and reported recurrence rates will vary slightly with the rigor of the follow-up analysis.
Immunocytochemical and ultrastructural aspects
Our results confirm the theory of a close histogenetic relationship between somatotrophs and lactotrophs. Neoplastic transformation within a stem cell-like progenitor seems to lead to multiple lines of differentiation in the GH-secreting adenomas (27, 30). We have documented a heterogeneous population of adenomas distributed in four major groups according to their immunohistochemical profile (16% GH only, 25% GH and glycoproteins, 21% GH and PRL, 33% GH, PRL, and glycoproteins) (31).
About half of the patients in this series showed signs and symptoms of both acromegaly and hyperprolactinemia (32). Three morphological tumor types of GH-secreting adenomas commonly express GH and PRL: the mixed GH cell/PRL cell adenoma, the mammosomatotroph cell adenoma, and the acidophilic stem cell adenoma. Eleven of the patients had ultrastructural findings of these tumors. There was a good correlation between the preoperative levels of PRL and these three categories of tumors, in that patients with these mixed tumors had the highest PRL values of the series. This may indicate that in the population of patients with acromegaly and hyperprolactinemia, the incidence of a nonpure GH cell tumor, i.e. a mixed adenoma, is high.
Moreover, this category of mixed adenomas had the lowest remission rate in the entire series. Although the remission rate after surgical treatment was 70.2% in the series, remission rates of the mixed GH cell/PRL cell adenomas and the mammosomatotroph adenomas were 50% and 42.9%, respectively. Our results should alert the clinicians that in the population of patients with acromegaly and hyperprolactinemia, the probability of a mixed adenoma is high, and therefore, these patients may require more aggressive adjunctive therapy after surgery.
Conclusion
Surgical treatment of GH-secreting pituitary adenomas should ideally be performed by an experienced pituitary surgeon (33) supported by an equally experienced team of endocrinologists, radiologists, and anesthesiologists to achieve the best initial results and the highest probability of remission for acromegaly. Further advances and experience with modern microsurgical techniques, including the use of neuronavigation systems and endoscopy-assisted microsurgery, will improve the likelihood of total tumor removal, particularly in macroadenomas extending into the cavernous sinus, and will therefore result in improvement in remission rates for surgically treated acromegaly. Taking into account our outcome and complication results and those described in the recent literature, we believe that transsphenoidal surgery for GH-secreting pituitary adenomas is the appropriate initial treatment for most acromegalic patients, and that medical therapy and stereotactic radiosurgery should be used as adjuvant treatments to lower the mortality associated with uncontrolled hypersomatotropism when surgery has failed.
Acknowledgments
We thank Virginia ("Cookie") Wagner, R.N.; Pam Leake; C. J. Woodburn; and Barbara Behnke for their constant support in gathering the follow-up data and for the preparation of the manuscript.
Footnotes
Abbreviations: OGTT, Oral glucose tolerance test.
Received August 4, 2000.
Accepted May 3, 2001.
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