Results of transsphenoidal microsurgery for growth hormone-secreting pituitary adenoma in a series of 214 patients

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✓ Of 214 patients with acromegaly who underwent transsphenoidal microsurgical resection of a pituitary adenoma, 54% had growth hormone (GH) levels below 5 ng/ml and 74% had levels less than 10 ng/ml immediately after surgery. Among the 174 patients who could be contacted for long-term follow-up review (average duration 76 months), most recent GH determinations were available for 165. Of these 165 patients, 131 (79.4%) have a GH level less than 5 ng/ml and 153 (92.7%) have a level below 10 ng/ml; these represent 75.3% and 87.9%, respectively, of the total 174 patients reviewed. Fifty-two patients received postoperative radiation therapy. Nine patients underwent reoperation. There were five cases of tumor recurrence following an apparent surgical cure (4.3%), nine new instances of anterior pituitary hypofunction (5%), and five failures of multimodality therapy (2.3%). There were no perioperative deaths, five cases of cerebrospinal fluid leak requiring surgical repair (2.2%), and four cases of postoperative meningitis (1.8%). Permanent diabetes insipidus did not occur. Two of 52 patients who were irradiated postoperatively had severe complications; 23 (54.8%) of 42 patients who were available for follow-up evaluation had developed panhypopituitarism; and eight (19%) of 42 had normal pituitary function an average of 44 months postirradiation.

Acromegaly requires swift, effective treatment, not only to prevent crippling cosmetic and orthopedic deformities but also to forestall the life-threatening metabolic effects of growth hormone (GH) hypersecretion. Although acromegaly progresses slowly, it severely affects life span: 50% of untreated patients die by the age of 50 years,38 a death rate twice that of the general population.129 Many forms of therapy have been introduced since 1886, when Pierre Marie first described this disease,88 but there has been persistent controversy about which of them is the safest and most effective.26,55

A variety of surgical approaches, including cryohypophysectomy, brachytherapy, craniotomy, and transsphenoidal resection, have been used either alone or with various pharmacological regimens,16,29,105,119 or with conventional high-energy photon or particle irradiation.37,84 Among the surgical techniques, the transsphenoidal microsurgical procedure has been used almost exclusively since the early 1970's,79 when the procedure was greatly refined with such technological improvements as televised fluoroscopy and the surgical microscope, systematic documentation of the pathological anatomy, and sophisticated neuroradiological and endocrinological techniques permitting early diagnosis.

Although the advantage of the transsphenoidal approach in the surgical treatment of acromegaly is unquestioned, its relative safety and long-term efficacy as primary therapy have not been established unequivocally. The cumulative results of long-term follow-up review in a large series of patients treated with the transsphenoidal technique are reported, providing data for comparison with findings in similar surgical series and the documented results of radiation37,68,84 and medical therapies.29,86

Summary of Cases

From July, 1970, to September, 1984, 221 patients with acromegaly were treated on the Neurosurgical Service at the University of California, San Francisco (UCSF). All patients exhibited the classic signs and symptoms of acromegaly. A detailed history and physical examination including neurosurgical, endocrinological, and neuro-ophthalmological evaluations were obtained preoperatively. Neuroendocrinological evaluations of the anterior pituitary axes were performed before and after the operation, either at UCSF or by the referring endocrinologist; the decision to begin replacement therapy was made by the patient's endocrinologist or internist.

A retrospective review and follow-up evaluations of the patients in this series, either directly or through their physicians, were conducted between October, 1985, and February, 1986. These reviews constitute the basis of this report. Some of these patients have been included in previous reports.15,115

Growth hormone dynamic testing, including tests of glucose suppression, thyrotropin releasing hormone (TRH) stimulation, and/or insulin tolerance, was performed before or after operation in approximately one-third of the patients. Neuroradiological studies included plain x-ray films of the skull, sellar polytomography, polytomographic pneumoencephalography, selective carotid arteriography, and computerized tomography (CT). Between 1978 and 1985, magnified CT reconstructions of the sellar region in two planes replaced all other radiographic studies. Since 1985, magnetic resonance imaging has been used almost exclusively for diagnostic scanning assessments.

After all neuroradiological, operative, and pathological findings were correlated, the adenomas were classified according to the amount of sellar destruction (grade) and suprasellar extension (stage)53,54 according to a system detailed elsewhere.15 Tumor size was recorded during the operation, and the extent of resection was ascertained by the surgeon (C.B.W.).

The strategy for each procedure was tailored to the size, shape, location, and consistency of the individual tumor;55 preoperative preparations and the approach to the sella have been described.51–54,124,126 Because the transsphenoidal procedure is short and postoperative stress is minimal, the patient's age or medical status rarely contraindicates the operation.124 Alternative operative approaches and their indications have been described elsewhere.73

Results

The demographic data for our series of 221 patients are presented in Table 1. Nearly two-thirds of the tumors were grade II adenomas, and there were relatively few true microadenomas (less than 1.0 cm; Table 2). The mean tumor size was 1.8 cm (standard error of the mean 0.74 mm), and 78.5% of the adenomas were confined to the sella or suprasellar cisterns. Preoperative GH values were retrieved for 204 patients (Table 1): 17 patients (8.3%) had a fasting GH level less than 10 ng/ml, whereas 69 (33.8%) had a level over 50 ng/ml.

TABLE 1

Characteristics of the series of 221 patients with acromegaly

CharacteristicCasesMean Age* (yrs)
No.Percent  
sex 
 male 1326039.0
 female 894045.5
 total cases 22110041.6
preop GH level† (ng/ml) 
 < 5 42
 < 10 178
 < 50 13566
 > 50 6934
 total cases 204100

Age range: 13 to 75 years; six patients were younger than 21 years of age.

Growth hormone (GH) data for only 204 patients were available for review. Cumulative numbers of patients are given for value categories < 50 ng/ml.

TABLE 2

Distribution of grade, stage, and size of adenomas in 218 transsphenoidal operations*

Tumor Grade Tumor StageTumor Size
GradeCasesStageCasesSize (cm)Cases
No.%No.%No.%   
I199011051< 1.0 1614
II13160A61281.0–1.9 5447
III3717B942.0–2.9 3026
IV3114C105> 2.9 1614
D21 
E2612 

No tumor was found in three additional cases; in three others these data are not known. Grade and stage according to the classification of Wilson.125

Data on adenoma size was not retrievable in 102 cases. Percentages are based on the 116 cases in which the size of the adenoma was known.

One hundred and fifty-three patients (71.5%) had received no treatment for their acromegaly before referral to UCSF, whereas 61 patients (28.5%) had previously undergone irradiation, surgery, medical therapy, or a combination of these therapies. In eight cases, no preoperative history was available for review.

Results of the complete preoperative endocrinological evaluation, including tests of thyroid function, adrenal responsiveness, and gonadotropin and prolactin levels, were available for 77 patients. In 45 patients (58.4%) at least one axis was abnormal (low gonadotropin levels in 37, abnormal adrenal responsiveness in 20, and thyroid dysfunction in 15). Seventeen (22.1%) of these 77 patients had hyperprolactinemia. One patient had suffered pituitary apoplexy.116

Seven patients were excluded from the final evaluation for the following reasons. Two patients who were evaluated before 1974 had a biopsy only, another underwent only ventriculoperitoneal shunting before receiving radiation therapy, and one had cryoprobe application during the resection. The operative records for three patients were not available.

The 214 patients included in the study underwent a total of 224 transsphenoidal operations. An adenoma was found in 221 procedures. In 202 of these, the operation was considered a gross total resection, but the surgeon was confident of a cure in only 158 cases (78.2% of the gross total resections, or 70.5% overall). In three cases, no tumor was found. In one of these, laboratory error in a determination of GH performed at another institution was the basis for a mistaken diagnosis. In another, an intracavernous tumor detected by selective venous sampling was the source of disease. In the third case, the cause of disease was not identified, but may have been an ectopic source of GH-releasing factor hypersecretion.80,112

Fasting morning GH levels obtained immediately postoperatively were available for 204 patients: 117 patients (57.4%) had levels less than 5 ng/ml and 160 (78.4%) had levels less than 10 ng/ml; 56% of patients for whom surgery was their initial therapy had postoperative GH levels less than 5 ng/ml, whereas only 44% of the patients who had prior therapy had similarly low postoperative levels. Fifty-two patients were referred for postoperative radiation therapy: 39 because of persistently elevated GH levels, 10 prophylactically for invasive tumor, two for recurrence of disease, and one for persistent clinical disease. All patients whose postoperative GH level was less than 5 ng/ml showed clinical improvement. Only one patient with a postoperative level under 10 ng/ml did not enter remission but continued to have clinical progression of disease; this was one of the 52 patients referred for postoperative irradiation.

All complications occurring perioperatively and throughout the period of follow-up review (average duration 76 months) were compiled. Of the 224 operations evaluated, 44 (19.6%) resulted in one or more complications postoperatively (Table 3). No patients died of causes related to their operation, and none had a stroke. There were no cases of permanent diabetes insipidus. The 11 cases of cerebrospinal fluid (CSF) leak were controlled, although two patients (of whom one had previously received surgery elsewhere and the other had undergone irradiation preoperatively) required multiple procedures, including a craniotomy, to correct the problem. The nine cases of infection were controlled with routine antibiotic therapy. Two patients sustained injury to the carotid artery, which was repaired and then evaluated angiographically; in neither case were there sequelae. The three cases of cranial nerve dysfunction were transient. Hyponatremia affected seven patients and resolved with simple measures. Three procedures were terminated because of severe intraoperative bleeding. In one case, the operation was concluded successfully after a coagulopathy was corrected. In the second, the patient underwent a successful craniotomy. The third patient was referred for radiation therapy.

TABLE 3

Postoperative complications of transsphenoidal surgery in this series*

ComplicationNo. of Cases
carotid artery injury2
cerebrospinal fluid leak
 requiring surgical repair5 (2.2)
 responding to simple measures6
cranial nerve palsy3
death0
diabetes insipidus requiring readmission1
epistaxis1
gastrointestinal hemorrhage1
graft site hematoma1
graft site infection1
hyponatremia7
meningitis4 (1.8)
myocardial infarct excluded1
operative hemorrhage3
oronasal fistula1
pneumonia3
retained pack1
septal perforation5
sinusitis5
stroke0
tooth discoloration1
tooth numbness3

Percentages are given (in parentheses) to facilitate comparison with other published data.

Long-Term Follow-Up Review

Follow-up reviews of 1 year or more were obtained for 174 patients (Table 4). The follow-up period ranged from 12 to 157 months (mean duration 76 months). None of these 174 patients, as assessed by both their own evaluation and physical examination for stigmata of the disease, presently has clinically active acromegaly, although some patients continue to be hypertensive or suffer from progressive osteoarthritis.

TABLE 4

Results of transsphenoidal resections for growth hormone (GH)-secreting pituitary adenomas in this series*

Preop TreatmentPostop GH Level (ng/ml)Cases Referred For RTLong-Term ResultsMost Recent GH Level (ng/ml)
< 5< 10> 10UnknownCasesRT Given< 5< 10> 10Unknown  
none (153 cases)86 (56)119 (78)19 (12)15 (10) 30 (20)117 (77)23 (20)87 (74)102 (87)8 (7)7 (6)
yes (71 cases)31 (44)41 (58)25 (35)4‡ (6) 22 (31)57 (80)21 (37)44 (77)51 (89)4 (7)2 (4)
total (224 cases)117 (52)160 (71)44 (20)19 (9) 52 (23)174 (81)44 (25)131 (75)153 (88)12 (7)9§ (5)

Percentage of patients in each category (in parentheses) is relative to the number of patients in the preoperative treatment category for Columns 2 to 7, or to the number of patients in the long-term follow-up category for Columns 8 to 12. RT = radiation therapy.

Mean follow-up period 76 months.

One patient underwent reoperation for elevated GH level erroneously reported by a referring institution.

All nine patients are in clinical remission, for a mean follow-up period of 69 months.

Recent Growth Hormone Determinations

Of the 165 patients for whom most recent GH determinations were available, 131 (79.4%) had a GH level less than 5 ng/ml and 153 (92.7%) had a level less than 10 ng/ml. Nine other patients have been in clinical remission for a mean of 69 months but have not undergone recent GH determinations.

Postoperative Irradiation

Follow-up records were available for 44 of the 52 patients who underwent radiation therapy postoperatively. Among these 44 were 30 patients who had postoperative GH levels over 5 ng/ml of whom 21 (70%) now have GH levels less than 5 ng/ml and 24 (80%) have levels less than 10 ng/ml. The 10 patients irradiated prophylactically continue to be in remission. The two patients who were irradiated for recurrent tumor had GH levels below 5 ng/ml at their most recent examination. Two (4.5%) of the 44 patients suffered serious complications from irradiation; one developed radiation necrosis of the temporal lobes requiring a craniotomy to resect the necrotic tissue, and the other suffered progressive visual loss from radiation damage to the optic pathways. Panhypopituitarism had developed in 23 (54.8%) of 42 irradiated patients. Eight patients (19%) continued to have normal pituitary function an average of 44 months after completion of radiation therapy.

Therapeutic Failure
Multimodality Therapy

Five patients (2.3%) were considered therapeutic failures because their GH levels have remained over 10 ng/ml despite surgery, irradiation, and bromocriptine therapy (Table 5). All had preoperative GH levels greater than 100 ng/ml and tumors at least 15 mm in diameter that produced sellar destruction.54,55 One of these patients had previously undergone surgery and bromocriptine therapy (Case 1), and one had had radiation therapy (Case 5).

TABLE 5

Summary of five acromegalic patients considered therapeutic failures*

Case No.Tumor CharacteristicsPreop GH Level (ng/ml)Latest GH Level (ng/ml)Current Status
GradeStageSize (mm)    
1IVE2026520.0steady decline in GH after RT, bromocriptine
2III03015511.9steady decline in GH 6 yrs after RT
3IV01825027.0steady decline in GH 1 yr after RT
4III01510510.0steady decline in GH 3 yrs after RT
5IV046319.0steady decline in GH 3 yrs after RT

GH = growth hormone; RT = radiation therapy.

Grade and stage according to the classification of Wilson;125 — = unknown.

Persistent hypersecretion

Nine patients underwent a second transsphenoidal exploration because of persistently elevated GH levels, and one required a third exploration. Residual tumor was resected in seven cases. In the other three cases, no tumor was found: one of these was the patient with falsely elevated GH levels reported from another institution; in one case, a third operation was performed for what eventually proved to be an intracavernous tumor; and in one case, no tumor was found but the patient has responded to sellar irradiation. Postoperatively, GH levels were restored to less than 5 ng/ml in three of the seven patients, two of whom have required no additional therapy; five subsequently underwent irradiation. Overall, of the eight patients with verified elevated GH levels, six have most recent levels less than 5 ng/ml and two (only one of whom has undergone irradiation) have levels of 5 and 12 ng/ml.

New Postoperative Endocrinological Deficit

Of the 172 patients who did not receive postoperative radiation therapy, nine (5.2%) had postoperative onset of a new hypofunction in one or more anterior pituitary axis (Table 6 ).89 Four patients required thyroid replacement and one received testosterone injections. Only four patients (2.3%) were devoid of all anterior pituitary function postoperatively; one (Case 7) had previously undergone a cryohypophysectomy and two (Cases 8 and 14) had been irradiated preoperatively. Three of these four patients who were rendered panhypopituitary had had preoperative dysfunction in at least one axis, a factor prognostically linked to an increased likelihood of further dysfunction postoperatively.89 Thus, only one (0.9%) of the 107 patients who received no therapy other than surgery was rendered panhypopituitary by the operation; this same patient was the only one with normal anterior pituitary function preoperatively and diminished function in more than a single axis after the operation.

TABLE 6

Summary of nine patients with new hypopituitarism after transsphenoidal microsurgery*

Case No.Tumor Characteristics Preop GH Level (ng/ml)Preop HypofunctionPreop TreatmentEndocrine Replacement
GradeStageSize (mm)     
6III0209.8none none testosterone 
7II045.6thyroid prior surgery panhypopituitarism 
8IID20.0gonadotropins irradiation panhypopituitarism 
9III042.4none none thyroid 
10IIAnone none thyroid 
11IIA1279.0gonadotropins none thyroid 
12IIA15> 40.0none irradiation thyroid 
13III045.0none none panhypopituitarism 
14III0154.2thyroid irradiation panhypopituitarism 

GH = growth hormone; — = not known.

Grade and stage according to the classification of Wilson.125

Eighty-nine patients who have had no therapy other than transsphenoidal operation were available for follow-up evaluation. Only five (5.6%) of these had new hypofunction postoperatively, one of whom had suffered pituitary apoplexy preoperatively. Only 14 (15.7%) of the 89 patients have any degree of anterior pituitary hypofunction an average of 69 months postoperatively.

Recurrence of Acromegaly

In five (4.3%) of the 117 patients who had GH levels less than 5 ng/ml immediately after their initial operation, biochemical and/or clinical signs of active acromegaly resumed after a period of time during which they had normal GH levels (Table 7). One patient (Case 15) had an invasive tumor, but there was no pattern of characteristics among these patients that was predictive of a high likelihood of recurrence. In one patient (Case 16), a single determination showed an elevated GH level; after a short course of bromocriptine therapy, the GH level has remained normal — a response that would not be expected in a true case of tumor recurrence.29,86,94,120 One patient (Case 20) underwent a second operation and apparently was cured; two patients (Cases 15 and 18) are in remission after undergoing irradiation. One patient died and the recurrence cannot be confirmed. Three of these five patients underwent testing of GH dynamics postoperatively. Two had glucose suppression tests with serum GH levels decreasing from 3.4 to 1.2 ng/ml and increasing from 1.4 to 2 ng/ml with oral glucose loading; the third underwent TRH stimulation with a baseline value of 5.3 rising to 6.9 ng/ml.

TABLE 7

Summary of five patients with postoperative biochemical and/or clinical recurrence of acromegaly*

Case No.Time to Recurrence (mos)Tumor GradeTumor StagePreop GH Level (ng/ml) Postop GH Level (ng/ml)Current Status
153IIIE25.7 1.5GH 1.7 ng/ml 63 mos after RT
1636IIIA49.5 3.4resolved after brief course of bromocriptine
1848IIA> 30.0 1.3recurred in cavernous sinus; GH 1.7 ng/ml 9 mos after RT
1968II026.0 3.6died after myocardial infarct; GH reported as 83 ng/ml
2054IIA24.6 3.7in remission 7 yrs after 2nd op

GH = growth hormone; RT = radiation therapy.

Grade and stage according to the classification of Wilson.125

Growth Hormone Dynamics

Postoperative testing of GH dynamics has been advocated in order to predict those patients who will have recurrence or will require radiation therapy.1,7,9,41,44,57,62,83,96,97 Seventy-one of our patients who had long-term follow-up evaluation underwent such tests. Of these, 36 either failed to suppress GH with glucose loading17,93,97,101 or showed GH stimulation with injection of TRH.7,9,40,41,59,60,96–98 Immediately postoperatively, 14 of these 36 patients had GH levels less than 5 ng/ml. Fifteen of the 36 patients for whom GH dynamics predicted therapeutic failure have had no clinical or biochemical recurrence of their disease over a mean follow-up period of 101 months and with no postoperative therapy of any kind. Of the other 21 patients for whom GH dynamics predicted failure, 16 had radiation therapy. In 15 patients the most recent GH levels were less than 10 ng/ml, and in one the level was 11.9 ng/ml. Four patients have had no further treatment, and their GH levels are in the range of 5 to 10 ng/ml. One patient underwent sellar exenteration by craniotomy and 13 years later has a GH level less than 1 ng/ml. Of the 35 patients for whom dynamic testing was equivocal or predicted a good outcome, three had a recurrence. Three of the five patients whose adenomas recurred had postoperative GH levels under 2 ng/ml, a level that in some studies has been associated with complete normalization of GH dynamics.9,131

Postmortem Findings

Six patients died of other illnesses during the period of long-term follow-up review. One patient died of pneumonia at the age of 67 years, one of breast carcinoma at 62 years, one of carcinoma of the lung at 65 years, one of stroke at 70 years, one of myocardial infarction at 63 years, and one of brain abscess at 27 years. The brain abscess occurred 6 years after surgery and irradiation. The two patients who underwent autopsy showed residual tumor.

Discussion
Transsphenoidal Microsurgery

Published reports on the transsphenoidal microsurgical approach to GH-secreting adenomas include 30 surgical series (Table 8).3,7,9,12,14,21,24,42–44,50,55,57,58,65,69,70,82,83,87,90,91,93,97,101,109,113,114,122,132 The demographic make-up of our series correlates with that of these other series.14,82,120 The compiled GH levels obtained immediately after surgery in these series correspond closely with those in our own. In a similar large series, Laws, et al.,82 studied 140 patients, of whom 61.7% had postoperative GH levels under 5 ng/ml and 80.5% had levels under 10 ng/ml. Wass and colleagues118 have also reported the results of long-term follow-up evaluations of 100 patients with acromegaly who underwent transsphenoidal microsurgery as their first therapeutic intervention. Control of disease, defined as a serum GH level under 10 ng/ml, was achieved in 80% of cases postoperatively and in 83% after postoperative radiation therapy. There were six cases of recurrence and four of persistent acromegaly during an average follow-up period of 112.5 months. Our results differ from those reported previously, however, in that there were no deaths in our series and no instance of permanent diabetes insipidus.

TABLE 8

Cumulative results in 30 surgical series of patients*

No. of CasesPostop GH Levels (ng/ml)DeathsNew HypopituitarismPermanent Diabetes InsipidusComplications 
< 5< 10     
1360 466/771 807/1094 12/1156 178/1014 22/847 66/982 
 (60.4%) (73.8%) (1.04%) (17.6%) (2.6%) (6.7%) 

Expressed as number of cases in each category/total cases reported, with percentages in parentheses. GH = growth hormone. Data derived from: Allen, et al.,3 Arafah, et al.,7 Arosio, et al.,9 Atkinson, et al.,12 Balagura, et al.,14 Bøhmer, et al.,21 Bynke, et al.,24 Fletcher and Dalton,42 García-Uría, et al.,43 Giovanelli, et al.,44 Guibout, et al.,50 Hardy, et al.,55 Hoyte and Martin,57 Hulting, et al.,58 Kinnman,65 Knappe, et al.,69 Kondo, et al.,70 Laws, et al.,82 Leavens, et al.,83 Lüdecke, et al.,87 Nabarro,90 Nowakowski, et al.,91 Quabbe,93 Schaison, et al.,97 Schuster, et al.,101 Teasdale, et al.,109 Tindall and Tindall,113 Tucker, et al.,114 Weiss,122 and Zampieri, et al.132

The rate of new hypopituitarism in our patients was slightly lower than that generally reported for surgical series,55,89,108,113,114,121 and much lower than that reported for series managed with primary radiation therapy.4,37,67,68,72,76,84,103 McLanahan, et al.,89 investigating the incidence of anterior pituitary hypofunction after transsphenoidal surgery for adenomas, noted that small tumors, intact preoperative function, and a somatotrophic or prolactin-secreting adenoma were favorable factors for preservation or restoration of function. In patients with intact function preoperatively, they noted a 9% incidence of new impaired function postoperatively, as compared with an 18% incidence in patients with preoperative impairment.

The overall complication rates are difficult to compare because most reports cite only the most serious complications (such as CSF leak or meningitis). Laws,79 in a thorough review, detailed the complications of 810 transsphenoidal procedures for all indications. The mortality rate for their series was 0.5%; CSF rhinorrhea occurred in 1.5% of cases, stroke in 0.5%, meningitis in 0.3%, and permanent diabetes insipidus in 1.2%. Serious complications occurred in 3.6% of patients overall, and less serious complications in 3.3%. Large tumors and prior surgery appeared to predispose patients to complications. The somewhat higher complication rate reported for our series reflects all known complications that accrued over the duration of follow-up review.

Radiation Therapy

A number of patients in our series benefited from postoperative irradiation. After an average of 86 months, 21 of 30 patients irradiated because of persistent elevation of GH levels currently have levels less than 5 ng/ml; and two patients irradiated because of postoperative recurrence have had long-term remission.

Radiation therapy is effective in the treatment of acromegaly and is often suggested as an alternative to primary surgical management.5,6,95 Several reports detail the results obtained in patients treated with conventional radiation therapy37,48,71,72,95,103 or with heavy-particle or proton-beam irradiation,35,66–68,75–78 or compare the results of several forms of therapy.37 Primary irradiation, however, has been associated with a significant failure rate;5,46,55,68,72,95 32 patients in our series were referred for surgical treatment after undergoing unsuccessful radiation therapy. There are, in addition, several disadvantages to radiation therapy. Two to 10 years may elapse after irradiation before GH levels reach acceptable levels, during which time the patient continues to have active acromegaly.5,37,48,66,68,74,76,95 In two recently reported series, 19% of patients still had GH levels over 10 ng/ml 10 years after undergoing conventional irradiation,37 and 15% of patients had similarly elevated levels 10 years after undergoing heavy-particle irradiation.84 As the survival curve for patients with acromegaly treated successfully with primary radiation therapy continues to compare unfavorably with that for such high-risk groups as a diabetic population,77 it would appear that this delay may be of consequence. In contrast, surgery produces a dramatic decline in serum GH levels within hours after the resection of the adenoma.3,24,87

Irradiation may produce any of several serious complications, including visual failure,8,11,13,18–20,22,23,28,30,37,56,68,103,106 malignant second neoplasms,47,49,103,110,117,123,129 and cerebral damage.8,11,35,63,64,92,103,106 The intellectual and psychological effects of sellar irradiation have never been documented.104 Considering the long latency of some of these complications, reported figures probably underestimate their true incidence.

In our series, two patients (4.5%) have suffered devastating permanent complications of irradiation. In contrast, while the rate of serious complications of surgery was also approximately 4%, there were no permanent sequelae — a result corroborating findings in other reports.79 It must be considered, though, that the patients referred for postoperative irradiation are usually those presenting the more difficult problems, who risk a higher likelihood of complications in obtaining control of their disease. As radiation therapy techniques have been improved, fewer complications have been reported in more recent series.8

Radiation therapy is also associated with a significant rate of hypopituitarism.4,7,29,68,72,84,103 While 81% of the patients in this series who were irradiated postoperatively required replacement therapy, surgery alone produced new deficits in only 4%. The preservation of pituitary function is especially desirable in younger patients who wish to maintain fertility and to avoid a lifelong requirement for medication.127

The efficacy of radiation therapy as a primary mode of therapy is compromised by the delay in its therapeutic effect and its significant failure rate when used primarily.5,46,55,68,72,95 Although irradiation is a highly effective postoperative adjuvant to surgery for patients with residual adenoma, the high rate of hypopituitarism and the rare but unequivocal possibility of catastrophic complications makes its indiscriminate use postoperatively a dangerous practice.

Results of Primary Surgery vs. Surgery After Prior Therapy

The results in this series, as in series reported previously,12,15,55,108 indicate that patients who are treated initially with transsphenoidal microsurgery fare better than those who have undergone prior attempts to control their disease (Table 4). Fifty-six percent of those without previous therapy had postoperative GH levels less than 5 ng/ml, as compared to only 44% with prior treatment (p < 0.05 by chi-square analysis). This difference remained unchanged when controls for confounding factors such as preoperative GH level and tumor size, grade, and stage were applied. In addition, the incidence of postoperative complications was slightly higher among the previously treated patients, at a level of 24.6% in comparison with 20.3% in the group with no prior treatment (value not significant). Previously treated patients comprised four of the five cases of CSF leak requiring surgical repair, four of the six cases with CSF leaks controlled with simple techniques, and one of the four cases of meningitis, among the more serious complications (Table 3).

The difficulty of operating within a sella scarred from previous therapy has been described elsewhere.55 Laws, et al.,80 discussed extensively the results of transsphenoidal surgery for various indications in patients who had undergone irradiation, surgery, or chemotherapy preoperatively. As in our series, complications were more frequent in previously treated patients, and were especially likely after a prior craniotomy. There was poorer control of endocrine hyperfunction syndromes in previously treated patients, particularly in patients treated previously for acromegaly; in these, the success rate at an average follow-up period of 37 months was 56% compared with 65% to 70% in previously untreated patients.

Among patients with prior therapy, those who had only had surgery previously showed the poorest rate of postoperative remission (17.6%), the highest rate of need for further therapy (88.2%), and the second highest rate of panhypopituitarism (87.5%). Patients who had previously been either treated medically or irradiated suffered no loss of benefit in the immediate postoperative period (Table 9). This discrepancy between groups with prior treatment did not persist over the course of long-term follow-up evaluation (Table 4). Only about 7% of the patients who had prior surgery, irradiation, or medical therapy have most recent GH levels that remain clearly abnormal. Several factors may account for this convergence of outcome; among them is that many of the previously treated patients underwent irradiation before (31 of 61 patients) or after (21 of 61 patients) their operation at UCSF, which may have had a late effect in reducing GH levels.48,74 The deleterious effects of as much as 6 more years of active acromegaly for some of these patients have not been documented, but the claim that such effects are negligible26 must be viewed with caution.77

TABLE 9

Role of previous therapy in outcome (61 patients)*

Mode of Previous TherapyNo. of CasesPostop GH Levels (ng/ml)Postop TherapyCurrently PanhypopituitaryCurrent GH Level < 5 ng/mlMean Follow-Up Period (mos)
< 5< 10> 10      
surgery18341315141587
irradiation14911126881
medical988121747
surgery + irradiation1024523491
medical + irradiation434000463
medical + surgery302111068
medical + surgery + irradiation322103356
total cases61273522222841
no previous therapy151861181925118270

This table does not include the eight patients undergoing reoperation at UCSF, shown in Table 4.

Eight patients in our series underwent reoperation for persistently or recurrently elevated GH levels; three of these did not require radiation therapy. The potential benefit of reoperation has been debated, and several authors counsel against repeat operations.113,114 The higher complication rate for patients with previous operations implies that only experienced pituitary surgeons should perform repeat transsphenoidal surgery. We presently adhere to the following indications for consideration of reoperation: 1) recurrence after what was considered a curative total resection; 2) radiological evidence of a recurrent intrasellar mass; and 3) cases in which irradiation is undesirable or contraindicated.

Factors Influencing Outcome

Several factors appeared to have prognostic significance in our series. Patients who had grade IV tumors fared considerably worse than those with lower-grade lesions;54,121 there was no significant difference in the immediate outcome for patients with tumors of grades I through III (Table 10). Patients with extrasellar extension (Stages C, D, and E) were less likely to be in remission postoperatively than those with less severe tumors (Table 11). When outcome was compared with the preoperative GH values (Table 12), only 56.5% of patients with preoperative growth hormone levels greater than 50 ng/ml, as compared to 83% of patients with lower preoperative values, were in remission postoperatively (p < 0.005 by chi-square analysis). Similar results have been obtained previously in several series,14,15,41,44,58,82,120 but not universally.7 An analysis of the results plotted on a continuum showed no sharp cutoff points at which outcome corresponded to a specific GH level, but rather showed the remission rate decreasing linearly in relation to increasing preoperative GH levels. All six therapeutic failures in our series were in patients with preoperative GH levels greater than 100 ng/ml. Tumor size correlated only weakly with outcome (Table 13), which was a rather surprising result.108

TABLE 10

Comparison of tumor grade and immediate postoperative outcome in 218 patients*

Tumor GradeTotal CasesNo. (%) of Cases With Postop GH Levels (ng/ml):
< 5< 10> 10Unknown  
I1913 (68)16 (84)2 (11)1
II13175 (57)100 (76)20 (15)11
III3721 (57)28 (76)5 (14)4
IV317 (23)13 (42)17 (55)1

This table includes only cases for which these data were available. Tumor grade is according to the classification of Wilson.125 GH = growth hormone.

TABLE 11

Comparison of tumor stage and immediate postoperative outcome of transsphenoidal microsurgery*

Tumor StageTotal CasesNo. (%) of Cases With Postop GH Levels (ng/ml):
< 5< 10> 10Unknown  
011061 (56)83 (76)19 (17)8
A6137 (61)50 (82)6 (10)5
B95 (56)6 (67)3 (33)0
C112 (18)5 (46)4 (36)2
D20 (0)0 (0)1 (50)1
E2611 (42)14 (54)10 (38)2

Tumor stage is according to the classification of Wilson.125 GH = growth hormone.

TABLE 12

Comparison of preoperative growth hormone (GH) level and immediate postoperative outcome in 204 patients*

Preop GH Level (ng/ml)Total CasesNo. (%) of Cases With Postop GH Level (ng/ml):
< 5< 10> 10Unknown  
< 10 1712 (71)14 (82)0 (0)3 (18)
10–50 11871 (60)98 (83)6 (5)14 (12)
> 50 6928 (41)39 (57)26 (38)4 (6)

This table includes only cases for which these data were available.

TABLE 13

Comparison of tumor size and immediate postoperative outcome in 117 patients*

Tumor Size (mm)Total CasesNo. (%) of Cases With Postop GH Level (ng/ml):
< 5< 10> 10Unknown  
< 10 1610 (63)13 (81)1 (6)2
10–20 5537 (67)47 (85)3 (6)5
> 20 4627 (59)38 (83)7 (15)1

This table includes only cases for which these data were available. GH = growth hormone.

The role of the histological signs of invasiveness in clinical decision-making has not been established,102,130 and we do not use histological criteria (other than that of malignancy) in planning treatment. The presence of persistent tumor at autopsy, despite clinical and biochemical evidence of cure during life, has been reported.131 Rates of microscopic dural invasion as high as 85% for pituitary adenomas in general have also been reported.102 On the basis of such findings, the presence of a true plane of dissection has been questioned,130 and the routine use of topical agents like absolute alcohol or Zenker's solution,130 of postoperative irradiation,102,130,131 or of total hypophysectomy44 has been recommended. However, if the potential for recurrence was as high as 85%, we would anticipate at least a somewhat higher recurrence rate than 4.3% in our patients who did not undergo irradiation or total hypophysectomy. We believe that the data on dural invasion require confirmation, or their significance requires interpretation.

Precise biochemical criteria for postoperative cure or remission are difficult to define.9,27,33,41,44,57,62,83,96,101,120 It is now the consensus that patients with postoperative GH levels over 10 ng/ml still have active disease9 and, in recent series,14,108,113,114 a fasting serum GH level less than 5 ng/ml has replaced the 10-ng/ml level as the benchmark value.81,115 However, it has been reported that 25% of normal volunteers may have single fasting GH levels above the 5 ng/ml limit,101 and patients with active acromegaly and levels below 5 ng/ml have also been reported.9,39 As random GH levels in patients with acromegaly are known to vary widely throughout the day,31 it has been said that a fall in GH levels to any arbitrary value (although often utilized as the criterion for successful treatment in clinical studies15,24,44,81,87,114), does not by itself imply a cure.33,44,96,97,101 For this reason, various dynamic9,36,40,45,57,96,97,120 or time-integrated2,25,33,34,61,62,101,111 tests are now widely used, and it has become clear that the more of these tests that are applied postoperatively, the lower the apparent “cure” rate falls,41,58 until some authors have concluded that current therapeutic techniques will be rendered obsolete by more sophisticated biochemical documentation of residual adenoma.58 In fact, complete postoperative normalization of all dynamic parameters is probably very rare,41,58,97,120,121 and some authors have questioned whether the patient's health is served at all by the aggressive pursuit of biochemical goals.33,108

The use of somatomedin and insulin-like growth factor levels for the documentation of disease activity has been debated.27,32–34,97,107,131 Some authors have expressed a preference for measuring the primary tumor secretory product, GH, rather than a variably coupled related substance.33 In a recent review of this subject, Schaison, et al.,97 advocated the use of multiple biochemical parameters in sequential fashion in order to avoid the pitfalls of the individual tests. Arosio, et al.,9 also advocated testing multiple dynamic parameters preoperatively to maximize the number of abnormal responses that can be followed postoperatively. Watanabe, et al.,120 reported the progressive improvement of abnormal responses over several months postoperatively and suggested repeating the provocative tests before final judgment is rendered.7

As more than 40% of the patients in our series who had persistently abnormal dynamic test results postoperatively have shown no sign of recurrence an average of almost 9 years later, we cannot advocate these tests as the sole determinant of the need for adjuvant therapy.44 Among the 174 patients who had long-term follow-up monitoring are 89 patients for whom the transsphenoidal operation was the only form of therapy administered; 69 (84.1%) of these have most recent GH levels of less than 5 ng/ml and all have levels below 11 ng/ml after an average follow-up period of 70 months. The recommendation that radiation therapy be given postoperatively to all patients130,131 must be reconsidered in light of these findings.

The most reliable prognostic indicator in our series appears to be the immediate postoperative GH level. Among 117 patients with postoperative GH levels below 5 ng/ml, only five (4.3%) have had a recurrence of elevated GH levels. The cause of these recurrences may have been incomplete resection,87 but the possibility that they resulted from abnormal hypothalamic-pituitary interaction10,34,41,85,100 or multifocal adenomas80,99,128 cannot be excluded. Three of these five patients had equivocal dynamic test results. Only 10.6% of patients who had postoperative GH levels less than 5 ng/ml have required any additional therapy for acromegaly, whereas 21.2% of patients with postoperative GH levels between 5 and 10 ng/ml and 82.4% of those with levels over 10 ng/ml have required subsequent therapy (Table 14).

TABLE 14

Comparison of immediate postoperative GH level with need for further therapy*

Postop GH Level (ng/ml)Total CasesTreatment After Transsphenoidal Operation
RTOtherBoth  Total
No.%
< 5948111011
5–1033430721
> 1034152112882
unknown1351646
total174327125129

GH = growth hormone; RT = radiation therapy.

It is evident that there is a group of patients who will have long-lasting remission postoperatively with no further therapy. What is needed is a method for determining which patients among those who show clinical improvement and have postoperative GH levels less than 10 ng/ml will require prophylactic irradiation in order to ensure permanent arrest of their disease. This determination must be made immediately postoperatively, when the patients' tumor burden is at its minimum and they are most likely to benefit from radiation therapy.127

A review of the results of treatment in 214 patients with acromegaly over 14 years for predictive factors shows that a postoperative GH level below 5 ng/ml is a powerful predictor of long-term outcome. Similar conclusions were recently reported by Watanabe, et al.120 When the individual patient's preoperative GH level, the grade and stage of the lesion, and the previous treatment history are considered together with the postoperative GH levels and the completeness of surgical resection, an excellent prognostic estimation can be made.37,113 The role of dynamic GH testing in predicting ongoing acromegalic cardiovascular disease, and thus longevity, and the role of histological characteristics in determining the risk of recurrence require further clarification. Presently, patients with postoperative GH levels over 10 ng/ml, an invasive lesion (Stage D or E, grade IV), or known residual adenoma are considered for adjuvant radiation therapy.

The goals of the pituitary surgeon have been stated: 1) to eliminate the mass effects of the tumor; 2) to eliminate the undesirable endocrine hyperactivity; 3) to retain existing anterior pituitary function; and 4) to achieve these goals immediately and with minimal morbidity (immediate treatment is a particularly important goal in patients compromised by acromegalic cardiomyopathy or refractory diabetes mellitus).5,7,68,108,125,127 A last goal is to predict accurately the need for adjuvant therapy. While there is always room for improvement, these goals have been met reasonably well in this series of patients. Improved early detection and, consequently, earlier operation would reduce the number of patients having poor prognostic factors and would contribute to a desired improvement in operative results.

Transsphenoidal microsurgery, together with adjuvant radiation therapy when specifically indicated,7,82,103 offers the patient who has acromegaly an excellent chance for a durable remission and possible cure of this disease. The classification of acromegaly as a “more or less intractable” disorder26 would no longer seem justified.

Acknowledgments

The authors gratefully acknowledge the contributions to this effort made by the patients and referring physicians who responded to our requests for information. We thank Mary Ellen Kuhlmann for assistance in the preparation of the paper and Susan Eastwood for editorial advice.

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