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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2552
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 5 1796-1801
Copyright © 2006 by The Endocrine Society

Observation Alone after Transsphenoidal Surgery for Nonfunctioning Pituitary Macroadenoma

O. M. Dekkers, A. M. Pereira, F. Roelfsema, J. H. C. Voormolen, K. J. Neelis, M. A. Schroijen, J. W. A. Smit and J. A. Romijn

Departments of Endocrinology and Metabolic Diseases (O.M.D., A.M.P., F.R., M.A.S., J.W.A.S., J.A.R.), Neurosurgery (J.H.C.V.), and Radiotherapy (K.J.N.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Address all correspondence and requests for reprints to: O. M. Dekkers, M.D., M.A., Department of Endocrinology and Metabolic Diseases C4-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: o.m.dekkers{at}lumc.nl.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objective: Transsphenoidal surgery is the treatment of choice for nonfunctioning pituitary macroadenomas (NFMA). In this study we evaluated the long-term effects of a treatment strategy in which postoperative radiotherapy was not routinely applied to patients with NFMA.

Design: This was a retrospective follow-up study.

Patients: We included 109 consecutive patients (age 56 ± 13 yr) operated for NFMA between 1992 and 2004.

Results: Radiological imaging revealed a macroadenoma in all patients, with suprasellar extension in 96% and parasellar/infrasellar extension in 36% of cases. Visual field defects were present in 87% of the patients and improved in 84% of these patients after surgery. Only six patients received postoperative radiotherapy. Ten patients died during the follow-up period. Ninety-seven patients could be assessed for tumor regrowth or tumor recurrence after a mean follow-up period of 6.0 ± 3.7 yr. In nine patients there was evidence for tumor regrowth, and in one patient tumor recurrence was observed. The mean time to tumor growth/recurrence after initial therapy was 6.9 (range 3–12) yr. Follow-up duration was found to be an independent predictor for tumor regrowth.

Conclusion: Transsphenoidal surgery without postoperative radiotherapy is an effective and safe treatment strategy for NFMA, without evidence for tumor regrowth in 90% of all patients, at least for the duration of follow-up presented in this study. Additional studies are required to exclude higher regrowth and recurrence rates during prolongation of the duration of follow-up.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
NONFUNCTIONING PITUITARY macroadenomas (NFMAs) are the most prevalent macroadenomas (1, 2). The main presenting symptoms of NFMAs are visual field defects and hypopituitarism due to mass effects. Transsphenoidal surgery is the treatment of choice because medical treatment in general is not effective in reducing the size of NFMAs. However, during long-term follow-up after transsphenoidal surgery, there is tumor growth in 12–46% of the patients (3, 4, 5, 6). Therefore, some centers provide postoperative radiotherapy in a selection of the patients to prevent tumor regrowth (6, 7, 8, 9). Nonetheless, even after postoperative radiotherapy, tumor regrowth was reported in 2–36% of the radiated patients (4, 5, 6, 9). In addition, radiotherapy induces a higher incidence of hypopituitarism during long-term follow-up (10, 11, 12) and is associated with rare complications such as secondary brain tumors (13). Therefore, a restrictive indication for postoperative radiotherapy seems appropriate.

Prospective trials evaluating the effect of postoperative radiotherapy on regrowth rates of NFMAs have not been published. Retrospective studies, involving homogeneous cohorts of transsphenoidal operated NFMAs with a long follow-up period, are scarce (3, 4, 5, 6, 9, 14, 15). Only two studies (3, 15) have been published in consecutive NFMA patients with a wait-and-see policy after transsphenoidal surgery. These studies, comprising 71 and 51 patients, respectively, report tumor growth in 21 and 26% during long-term follow-up. However, these reports do not propose a wait-and-see policy for all NFMA patients. The aim of the present study was to evaluate the long-term effects of a wait-and-see policy after transsphenoidal surgery for NFMAs on tumor recurrence rates in an unselected, homogeneous, single-center cohort of 109 consecutive patients operated for NFMAs. Postoperative radiotherapy was applied in only six of the 109 patients.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patient selection

Between 1992 and 2004, 109 consecutive patients were treated by transsphenoidal surgery for NFMA (diameter > 1 cm) at the Leiden University Medical Center. All operations were performed by one of two neurosurgeons. For complete assessment of the patients, we reviewed the patient records of all departments involved in the treatment of NFMAs. Patients were assessed at presentation before surgery, within the first 2 months after surgery, and subsequently every 6 months during prolonged follow-up. Clinical characteristics, visual field defects, pituitary function, and magnetic resonance imaging (MRI) images were assessed. Pre- and postsurgical data were available for all 109 patients. In 97 patients at least two postoperative MRI scans were available, enabling the evaluation of radiological tumor regrowth or recurrence. Ten patients died during the follow-up period, one postoperatively. The duration of follow-up in each patient was determined by the interval between the date of transsphenoidal surgery and the date of the last MRI scan. In six patients, postoperative radiotherapy was applied. Patients receiving prophylactic radiotherapy were treated with conventional external radiotherapy. All these patients received 46 Gy. Three patients were treated with 220-degree arc therapy and three patients with three-field arrangement that included left lateral, right lateral, and anterior portals.

NFMA was diagnosed if there was neither clinical nor biochemical evidence of hormonal overproduction and histopathological evaluation revealed an adenoma. Histological examination confirmed the diagnosis of pituitary adenoma in all, except five, patients, in whom appropriate histological assessment was precluded due to necrosis of the tumor. Adenomas were classified according to immunohistochemistry as either negative or positive for one or more hormone and/or their subunits.

Definitions

GH deficiency was defined as an IGF-I level below the reference range for age and sex (16) and/or an insufficient rise in GH levels (absolute value < 3 µg/liter) after stimulation during an insulin tolerance test. Prior studies (16, 17, 18) demonstrated that patients with multiple pituitary hormone deficiencies, including two or more pituitary hormone deficiencies other than GH deficiency, had a likelihood of approximately 95% of harboring severe growth hormone deficiency. Based on these data, we classified patients in whom GH stimulation test data were lacking but who were deficient in three other pituitary axes as being GH deficient. When secondary amenorrhea was present for more than 1 yr, premenopausal women were defined as LH/FSH deficient. Postmenopausal women were defined as LH/FSH deficient when gonadotropin levels were below the normal postmenopausal range (LH < 10 U/liter, FSH < 30 U/liter). In men, LH/FSH deficiency was defined as a testosterone level below the reference range (8.0 nmol/liter). TSH deficiency was defined as a total or free T4 level below the reference range. ACTH deficiency was defined as a basal cortisol level at 0800 h of less than 0.12 µmol/liter and/or an insufficient increase in cortisol levels (absolute value < 0.55 µmol/ liter) after a CRH stimulation test or insulin tolerance test. Hypopituitarism was defined by the presence of one or more pituitary hormone deficiencies. Diabetes insipidus was defined as polyuria not reacting to fluid restriction but reacting to administration of vasopressin.

The pituitary tumors were assessed by MRI scanning. Tumor extension was classified as suprasellar, parasellar/infrasellar, or combined suprasellar and parasellar/infrasellar extension. MRI imaging was performed in all patients within 6 months after transsphenoidal surgery, for the second time 1 yr later, and subsequently with increasing intervals. Patients were classified according to the postoperative MRI as having residual tumor or not having residual tumor. Patients with uncertain MRI diagnosis with respect to tumor residue were classified as having residual tumor (15). Tumor regrowth was defined as an increase in size of residual tumor. Recurrence was defined as appearance of tumor mass in a patient without residual tumor mass on postoperative MRI.

Ophthalmological evaluation included assessment of visual acuity and visual fields, performed by a Humphrey or Goldmann perimeter before and a few weeks after surgery. Patients who had persistent visual field deficits after surgery or noticed visual disturbances any time during prolonged follow-up were reassessed by the ophthalmologist.

Statistical analysis

The unpaired t test was used for continuous variables. The {chi}2 test and the McNemar test were used for categorical data. Binary logistic regression was performed to explore possible determinants of tumor growth. Tumor regrowth-free survival was analyzed with the method of Kaplan and Meier. SPSS software (version 12.0; SPSS Inc., Chicago, IL) was used. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Preoperative patient characteristics (Table 1Go)

The most prevalent presenting symptoms were visual field defects (87%) and headache (39%). NFMA presented as apoplexy in eight cases. Radiological imaging by MRI revealed a macroadenoma in all patients, with suprasellar extension in 96% and parasellar/infrasellar extension in 36% of cases. Hypopituitarism was present in 80% of all patients and panhypopituitarism in 29%.


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  		TABLE 1. Patient characteristics before surgery

 
Surgical treatment

All patients were treated by transsphenoidal surgery. One patient died of subarachnoidal bleeding 2 d after surgery, resulting in a perioperative mortality rate of 0.9%. Repeat surgery within 6 months after initial treatment was performed in 6% of cases (n = 7), for a large residual tumor mass (n = 4), persisting liquor leakage (n = 2), and profuse bleeding (n = 1). Repeat surgery was performed by transcranial approach, except in the two patients with leakage of cerebrospinal fluid.

Transsphenoidal surgery was followed by radiotherapy in six patients. The decision to apply prophylactic radiotherapy was based on the presence of a large residual tumor (n = 3) or a residual tumor with strongly positive immunostaining for ACTH (n = 3).

Immunohistochemistry could be assessed in 95% of cases and was positive in 65%. Of all cases, 39% harbored a silent gonadotropic adenoma and 11% a silent corticotropic adenoma, and 9% were immunoreactive for multiple hormones.

Postoperative MRI revealed residual tumor in 73% of all cases.

Postoperative evaluation: visual field defects and pituitary deficiencies (Table 2Go)

Visual field deficits improved in 84% of cases after surgery (complete recovery 21%; partial recovery 63%). Visual field defects stabilized in 13% and deteriorated in only three patients after surgery.


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  		TABLE 2. Effect of transsphenoidal surgery on pituitary function

 
After surgical treatment, 90% of the patients were LH/FSH deficient, 83% GH deficient, 60% ACTH deficient, and 57% TSH deficient. Hypopituitarism was present in 95% of cases and panhypopituitarism in 44%. When compared with the presurgical data, surgery significantly increased LH/FSH (P < 0.01) and TSH deficiency (P < 0.05) as well as panhypopituitarism (P < 0.001). Preoperative prolactin levels less than 2 µg/liter (n = 19) were not associated with significantly higher rates of preoperative or postoperative pituitary deficiencies. Transient diabetes insipidus occurred in 28% of cases. After surgery there was a significant decrease in prolactin levels in both women and men (P < 0.01). In women, mean prolactin decreased from 29.1 ± 25.3 to 9.4 ± 9.1 µg/liter, in men from 14.1 ± 13.7 to 4.3 ± 3.3 µg/liter.

Long-term postsurgical follow-up (Fig. 1Go)

Ninety-seven patients could be assessed for recurrence with a mean follow-up period of 6.0 ± 3.7 yr and a median follow-up period of 5.0 yr (range 1–14 yr). Residual tumor was present in 70 patients. Six of the 97 patients had received postoperative radiotherapy.


Figure 1
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  		FIG. 1. Kaplan-Meier curve for growth-free survival rates in patients with and without residual tumor.

 
Long-term tumor control of NFMAs in our series was achieved in the absence of regrowth/recurrence in 90% of all patients. Tumor regrowth was observed in nine patients, after a mean follow-up of 6.3 yr (range 3–11 yr). In one patient, initially classified as 2B macroadenoma, recurrence occurred after 12 yr follow-up. In the six patients treated with prophylactic radiotherapy, no tumor regrowth was observed. For the total cohort, the tumor growth-free survival rates 5 and 10 yr after initial surgery, were 94 and 81%. In patients with residual tumor on MRI, regrowth-free survival rates 5 and 10 yr after initial surgical treatment were 92 and 74% (see also Fig. 1Go). In patients without residual tumor, recurrence-free survival rates 5 and 10 yr after initial surgical treatment were 100 and 100%.

Tumor regrowth was associated with an increase in visual field defects in four patients. Tumor regrowth and recurrence were treated by radiotherapy (n = 9) and repeat surgery followed by radiotherapy (n = 1).

Binary logistic regression analysis was performed to determine possible independent predictors for tumor growth. The following parameters were evaluated: gender, prophylactic radiotherapy, follow-up duration, any positive immunohistochemistry, positive immunohistochemistry for ACTH, parasellar/infrasellar tumor extension, and residual tumor on MRI. Follow-up duration was the only independent predictor (P < 0.05) for tumor growth. Although analysis pointed toward residual tumor as an independent predictor for regrowth, this did not reach statistical significance (P = 0.1).

Ten patients died during the follow-up period. The main causes of death were malignancy (n = 3), cardiovascular disease (n = 2), and cerebrovascular disease (n = 2). There were no deaths due to cerebral malignancies.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
This study demonstrates that transsphenoidal surgery without postoperative radiotherapy is an effective and safe treatment strategy for NFMAs, at least for the duration of follow-up presented in this study. Long-term tumor control of NFMAs in our series was achieved in the absence of regrowth/recurrence in 90% of all patients. Even in the case of residual tumor, in 87% no tumor regrowth was observed. These data, observed after 6 yr of follow-up, do not justify prophylactic postoperative radiotherapy. Moreover, even in the case of regrowth during long-term follow-up, radiotherapy is still effective to stabilize or regress tumor growth (5). With this restrictive treatment strategy, the majority of patients will not be exposed to potential long-term sequelae of radiotherapy, whereas in patients with recurrences, the starting point of radiotherapy is delayed for several years.

Six patients received postsurgical radiotherapy because of large residual tumor (n = 3) or residual tumor with strongly positive immunostaining for ACTH (n = 3). The reason for radiotherapy in ACTH-positive tumors was mainly historical. Previous studies proposed that there was a higher regrowth rate in ACTH-positive tumors (14, 19). However, in a recent study from Bradley et al. (20), positive immunostaining for ACTH did not seem to increase recurrence rates. In the worst-case scenario, in case the six patients would have developed tumor regrowth without radiotherapy, the rate of patients without tumor regrowth or recurrence in our series would still be 85%. Moreover, even if tumor growth occurred in 15% of all patients, it does not justify prophylactic postoperative radiotherapy.

Perioperative mortality was minimal in our series (0.9%) and comparable with those reported in other studies (3, 4, 7). Visual field defects improved in more than 80% of the patients, which is comparable with other studies in which improvement of visual field defects has been reported in 75–100% (3, 4, 14, 21). Surgical treatment in our study did not reverse pituitary deficiencies. We summarized previous studies on the effect of transsphenoidal surgery on pituitary function in NFMAs in Table 3Go because the data of these studies are conflicting. Some studies (21, 22, 23, 24, 25) report, to a variable degree, an improvement in pituitary function, whereas others (3, 9, 26) could not demonstrate significant improvement in pituitary function or even reported a decrease in pituitary function (8, 27). Therefore, the aim of transsphenoidal surgery should be improvement of visual field defects, rather than improvement of pituitary function.


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  		TABLE 3. Effect of transsphenoidal surgery in NFMA on pituitary function

 
We found 11 previous studies that evaluated the effects of long-term follow-up after transsphenoidal surgery, with and/or without postoperative radiotherapy, on tumor control of NFMAs. These studies are all retrospective studies like our study. These studies differed with respect to the selection of patients with NFMAs. In five studies results of long-term follow-up in selected, nonconsecutive groups of patients after surgery for NFMAs are presented (Table 4Go) (14, 20, 28, 29, 30). In those studies, patients were selected from postoperative patients with NFMAs only if they had not received radiotherapy and did not have locally invasive tumors (28, 30), only if gross removal of the tumor was achieved (29), or only if immunostaining was positive for ACTH (14, 20). During long-term follow-up without postoperative radiotherapy, tumor growth rates in those studies ranged between 6 and 35% (20, 28, 29, 30). Postoperative radiotherapy for NFMAs with positive immunostaining for ACTH resulted in a regrowth rate of 20 vs. 35% without radiotherapy (20).


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  		TABLE 4. Effect of transsphenoidal surgery with/without postoperative radiotherapy (RT) on tumor growth in selected NFMA series

 
In Table 5Go, we summarized seven other studies (including our study) (3, 4, 5, 6, 9, 15, 29) that evaluated the effects of long-term follow-up in unselected, consecutive patients after surgery for NFMAs. In some of these studies (5, 9), postoperative radiotherapy was applied in a small number of patients. The main problem in the interpretation of the therapeutic value of postoperative radiotherapy is that the indications for postoperative radiotherapy were not clearly defined in some of the studies (6, 9). The study of Park et al. (5) provided postoperative radiotherapy when tumor removal was incomplete. Regrowth rates in patients without postoperative radiotherapy ranged between 11 and 46%, whereas regrowth rates after postoperative radiotherapy ranged between 2 and 36% during long-term follow-up. There is a suggestion of a benefit of postoperative radiotherapy on long-term tumor recurrence in some (5, 6) but not all studies (4). Therefore, the true benefit of postoperative radiotherapy is not straightforward in individual patient care. Finally, from Tables 4Go and 5Go, it becomes evident that the average duration of follow-up in all series is limited to only 4.3–7.4 yr after surgery. Prolongation of the follow-up duration may result in a higher rate of recurrence or regrowth than appreciated by the currently available data.


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  		TABLE 5. Effect of transsphenoidal surgery with/without postoperative radiotherapy (RT) on tumor growth in unselected NFMA series

 
The possible benefit of postoperative radiotherapy, i.e. a decrease in long-term regrowth rate of NFMAs, has to be balanced against potential side effects of radiotherapy. The contribution of postoperative radiotherapy to the development of pituitary deficiencies is independent of tumor regrowth (10, 11, 12). Increased mortality is reported in patients with hypopituitarism, compared with age-matched controls (31, 32, 33, 34). In addition to very rare complications such as optic nerve atrophy and visual deterioration (12, 35, 36), there is about 2.5% cumulative risk of second brain tumors 20 yr after radiotherapy (13, 37). Finally, there are indications that radiotherapy for pituitary adenomas may adversely affect quality of life (38). Nonetheless, postoperative radiotherapy might be considered in selected patients with incomplete tumor removal, large residual tumor, and panhypopituitarism.

Tumor regrowth occurred in nine patients and tumor recurrence in only one patient. In only four of these patients, increase in tumor volume was accompanied by visual field defects. This indicates, that in a wait-and-see policy, MRI scanning is the principal method for detection of tumor regrowth/recurrence because ophthalmological assessment can still be normal at the time tumor growth can already be detected by MRI.

In conclusion, transsphenoidal surgery for NFMAs is a safe and effective procedure without evidence for tumor growth in 90% of all patients after 6-yr follow-up. Based on the data presented in this study, we advocate a postsurgical wait-and-see procedure, which will prevent unnecessary exposure to potential sequelae of radiotherapy in the majority of patients. Additional studies are required to assess tumor control during prolongation of the duration of follow-up.


   Footnotes
 
Disclosure statement: All the authors (O.M.D., A.M.P., F.R., J.H.C.V., K.J.N., M.A.S., J.W.A.S., and J.A.R.) have nothing to declare.

First Published Online February 28, 2006

Abbreviations: MRI, Magnetic resonance imaging; NFMA, nonfunctioning pituitary macroadenoma.

Received November 23, 2005.

Accepted February 16, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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O M Dekkers, S Hammer, R J W de Keizer, F Roelfsema, P J Schutte, J W A Smit, J A Romijn, and A M Pereira
The natural course of non-functioning pituitary macroadenomas
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N. P. Singh and V. K. Panwar
Case Report of a Pituitary Macroadenoma Treated With Artemether
Integr Cancer Ther, December 1, 2006; 5(4): 391 - 394.
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O. M. Dekkers, A. A. van der Klaauw, A. M. Pereira, N. R. Biermasz, P. J. Honkoop, F. Roelfsema, J. W. A. Smit, and J. A. Romijn
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