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Pituitary Magnetic Resonance Imaging Is Not Required in the Postoperative Follow-Up of Acromegalic Patients with Long-Term Biochemical Cure after Transsphenoidal Surgery

Departments of Endocrinology and Metabolism (E.J.M.Z., E.P.M.C., N.R.B., F.R., A.M.P., J.W.A.S., J.A.R.) and Radiology (P.A.B., F.T.W.-D.B., L.J.M.K., M.A.V.B.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands

Address all correspondence and requests for reprints to: Dr. E. P. M. Corssmit, Department of Endocrinology and Metabolism, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail: e.p.m.corssmit{at}lumc.nl.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
After successful transsphenoidal surgery for acromegaly, life-long follow-up is required, because 10–15% of patients develop recurrence of disease. We assessed whether it is safe to perform postoperative follow-up with only biochemical evaluation in acromegalic patients initially cured by transsphenoidal surgery. We studied 32 patients cured after transsphenoidal surgery for acromegaly during a follow-up of 8.7 ± 6.4 yr (mean ± SD). Serial measurements of serum GH during glucose tolerance test and magnetic resonance imaging (MRI) scans were performed. Serial MRI scans were reevaluated by three independent neuroradiologists, who were blinded for the clinical and biochemical data, for growth of suspected tumor tissue. Twenty-three patients remained biochemically cured in the long term, whereas nine of the 32 patients developed recurrence of disease, indicated by elevated serum GH concentrations during glucose tolerance test and clinical symptoms/signs. None of the 23 patients with long-term biochemical cure showed growth of tumor tissue according to two neuroradiologists, whereas the third neuroradiologist assessed three of 23 patients as having tumor growth despite continuing biochemical cure. In the nine patients with biochemical recurrence, no tumor growth was found in the series of postoperative MRI scans, according to two of the three independent radiologists, whereas the third radiologist found tumor growth in four patients with recurrent disease. In conclusion, in patients with acromegaly, initially cured by transsphenoidal surgery, it appears safe to check for recurrent disease during long-term follow-up of these patients by biochemical markers only.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
TRANSSPHENOIDAL SURGERY WITH selective removal of the GH-producing adenoma provides direct postoperative cure in 60–80% of patients with acromegaly (1, 2, 3, 4). However, during long-term follow-up, 10–15% of patients initially cured by surgery develop recurrence of disease (1, 3, 5). Recurrent disease can be detected by serial biochemical assessments and radiological imaging. Biochemical tests include oral glucose tolerance tests (GTT) and measurement of serum GH and IGF-I concentrations. In addition, a paradoxical increase in GH upon TRH stimulation predicts recurrence, especially if it is also present preoperatively (3, 5).

Magnetic resonance imaging (MRI) is the best imaging technique for evaluation of pituitary adenomas at present (6, 7, 8). MRI is also recommended for follow-up of surgically treated patients, and even yearly evaluation is sometimes advised (9, 10). Residual or recurrent tissue of pituitary tumors is visible on postoperative MRIs (8, 11). However, MRI lacks specificity with respect to the interpretation of abnormal sellar contents, especially in patients who had previous pituitary surgery. Postoperative changes may not be a reflection of residual or recurrent adenomas (9, 12). MRI follow-up studies indicate that the interpretation of early postoperative MRI scans is difficult due to these postoperative changes and should therefore be delayed (13, 14) or compared with consecutive MRI scans (15, 16). In general, however, the diagnosis of recurrent active acromegaly after initial successful surgical treatment is based on abnormal biochemical tests and clinical symptoms and signs that develop thereafter.

At present, it is unclear whether serial MRI studies are required in the follow-up of patients treated by surgery without biochemical evidence of recurrent disease, although it is recommended in guidelines from a recent consensus meeting (10, 17). Therefore, the aim of the present study was to determine whether it is safe to perform postoperative follow-up with only biochemical evaluation in patients with long-term remission after surgery by comparing biochemical and radiological results.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Between 1977 and 2002, 108 of 164 consecutive operated patients with acromegaly achieved initial cure by transsphenoidal surgery in our center. For the present study we selected all cured patients who had at least two postoperative MRI scans and had not received radiotherapy. One cured patient was excluded because of preoperatively applied radiotherapy, and 13 patients were excluded because of postoperative prophylactic irradiation for suspected incomplete tumor removal or persistent paradoxical reactions of serum GH levels to TRH. In 62 initially cured patients (57 in long-term remission and five with recurrence in follow-up), only one or no MRI assessment was performed, and they were also excluded from the present study. Thirty-two patients who underwent successful transsphenoidal surgery had two or more postoperative pituitary MRI assessments and were eligible for the present study.

The preoperative diagnosis of acromegaly was made on the basis of the characteristic symptoms and signs and was confirmed by insufficient suppression of GH concentrations during GTT and the radiological presence of a pituitary tumor. Postoperative cure was defined as sufficient GH suppression during GTT (see below) and a (mean) serum GH concentration less than 2.5 µg/liter determined by RIA and 1.9 µg/liter determined by immunofluorometric assay (IFMA; 5 mU/liter) (5). The size of the GH-producing pituitary adenomas was classified preoperatively according to the criteria of Hardy et al. (18). For the present study, the classification was simplified to microadenoma (I), noninvasive macroadenoma (II), and invasive macroadenoma (III). During follow-up, the patients were evaluated by yearly assessments of (mean) GH and GTT. Recurrent disease was defined by an insufficient fall in serum GH concentration in the GTT and/or a mean serum GH concentration above 2.5 µg/liter determined by RIA and 1.9 µg/liter determined by IFMA (5 mU/liter) in combination with return of signs/symptoms.

MRI

All included patients had at least two postoperative pituitary MRI scans. For the purpose of this study, all postoperative MRI scans were reevaluated for the growth of an abnormal sellar mass suspect for tumor tissue by three independent, experienced neuroradiologists (A, B, and C) who were blinded for the clinical and biochemical data of the patients. The three neuroradiologists carefully scored the MRI studies, in relation to the previous MRI studies obtained in each patient, with respect to any increase in tumor size or in contrast enhancement. Coronal MRI series consisted of T1SE and T2TSE sequences with 3-mm slices (0.3-mm gap) and a 512 matrix. Sagittal imaging was performed with a T1SE sequence with 3-mm slices (0.3 mm gap) and a 256 matrix. The studies were performed on Somatom 1.5 T machines (Philips Electronic Instruments, Mahway, NJ). Images were evaluated on configuration and aspect of the tissue in the sella turcica before and after the administration of gadolinium chelate. In general, the first postoperative MRI showed undefined masses, potentially consisting of postoperative changes, such as packing material (fat), granulation tissue, blood or tumor tissue. Therefore, a series of MRI scans was considered positive only in the case of growth of a mass on serial MRI scans.

The indication for postoperative MRI assessments had been suspicion of recurrent adenomas in all patients with biochemical evidence of recurrent GH excess. In the other patients, with persistent biochemical cure, the indication was based on the individual preferences of the presiding physician regarding the strategy of follow-up of patients with persistent biochemical cure of active acromegaly. Radiological data obtained from computed tomography scans, used in the years before MRI was the standard radiological investigation, were not used in the present analysis.

Biochemical parameters

During GTT, 75 g glucose were administered orally, and plasma GH levels were measured every 30 min for 2 h. GH was measured by RIA until 1993 and, subsequently by IFMA. The RIA (Biolab/Serono, Coinsins, Switzerland) was calibrated against WHO International Reference Preparation 66/21, with an interassay coefficient of variation (CV) less than 5%, an intraassay CV of 4%, and a detection limit of 0.25 µg/liter (for conversion from micrograms per liter to milliunits per liter, multiply by 2). The IFMA (Wallac, Turku, Finland), specific for the 22-kDa GH protein, was calibrated against WHO International Reference Preparation 80-505, with an intraassay CV of 1.6–8.4% between 0.096 and 15.38 µg/liter and a detection limit of 0.012 µg/liter; it used human biosynthetic GH (Pharmacia Biotech, Uppsala, Sweden) as a standard (for conversion from micrograms per liter to milliunits per liter, multiply by 2.6). A normal suppression of GH during GTT was defined by values less than 1.25 µg/liter (2.5 mU/liter) for the RIA and less than 0.38 µg/liter (1 mU/liter) for the IFMA (19, 20, 21, 22).

The IGF-I concentration was measured from 1986 onward by RIA (Incstar Corp., Stillwater, MN), with intra- and inter-assay CVs less than 11% and a detection limit of 11.4 µg/liter. The SD scores were calculated from normal values obtained from 137 healthy controls measured in the same laboratory. Normal values for serum IGF-I concentrations (mean ± 2 SD) were 89–257 µg/liter (20–40 yr of age), 59–19 µg/liter (40–60 yr of age), and 37–189 µg/liter (60–80 yr of age).

Sustained biochemical cure was defined by a normal suppression of GH levels to glucose loading and/or a (mean) serum GH concentration below 1.9 µg/liter (determined by IFMA) at the last evaluation.

Statistics

For statistics, SPSS 10.0 for Windows (SPSS, Inc., Chicago, IL) was used. Descriptive data were described using the mean ± SD unless stated otherwise. Sensitivity, specificity, and predictive values of serial MRI assessments in patients with and without cure were calculated using the persisting normal or abnormal biochemistry in continuing follow-up as a reference for outcome.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patient characteristics

Thirty-two patients with acromegaly were studied (Tables 1 and 2). The mean age at operation was 46 ± 12 yr (range, 18–73 yr), and there was an equal sex distribution. Seven patients had microadenoma, 23 patients had noninvasive macroadenoma, and only two patients had invasive macroadenoma. Transsphenoidal surgery established cure in all patients. The mean postoperative glucose-suppressed GH was 0.3 ± 0.2 µg/liter. The mean duration of postoperative follow-up was 8.7 ± 6.4 yr (range, 1.1–23.7 yr). The mean time between surgery and the first postoperative MRI was 3.1 ± 5.0 yr (range, 0–17 yr), and the mean number of MRI scans available for evaluation was 3 ± 1/patient (range, 2–6).

MRI in patients with long-term biochemical cure

The first postoperative MRI scans of the 23 patients without biochemical evidence of recurrent disease showed indefinite postoperative changes in all patients, as did the MRI scans of the nine patients who did have recurrent disease. According to the evaluation by two of three radiologists (A and B), none of the consecutive MRI series showed growth or change in the configuration of the sella turcica in these 23 patients. The third neuroradiologist (C) scored three of the 23 postoperative MRI series as positive for a mass increase, generating false positive results, because the continuing biochemical follow-up was used as the gold standard (Table 3).

In two of nine patients, the series of postoperative MRI scans started before biochemical evidence of recurrent disease was found. In the other seven patients, the series of postoperative MRI scans started after biochemical evidence of recurrent disease was obtained. Two radiologists (A and B) considered all postoperative MRI series in these nine patients to be negative for growth of tumor tissue and/or change in configuration of the sella. However, the third radiologist (C) assessed the serial postoperative MRI scans in four of these nine patients with biochemical evidence of recurrent disease to be positive for tumor growth (Table 2).

Seven of the nine patients with recurrent GH excess, including three patients without any clue for recurrence on MRI, received somatostatin analog therapy for recurrence of disease. One of these seven patients received this treatment after an unsuccessful second operation. Remarkably, this patient underwent secondary surgery on the basis of a mass suspected for microadenoma on serial MRI scanning. However, this adenoma was recognized in the blinded reevaluation by one of the three neuroradiologists only. Two of the nine patients preferred to be followed without additional treatment, because they did not have any clinical signs/symptoms of active acromegaly.

The positive predictive values of MRI for the presence of recurrent pituitary disease were very low (for the three blinded radiologists, 0, 0, and 0.57, respectively; Table 3).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The incidence of recurrent disease in acromegalic patients after initial successful transsphenoidal surgery is 10–15% in the long term, necessitating life-long follow-up (1, 5). This study indicates that in recurrent acromegaly, pituitary tumor growth is unlikely in the absence of biochemical evidence of GH excess in patients initially cured by surgery. Moreover, MRI has a low sensitivity in detecting the growth of adenomatous tissue in patients with biochemical evidence of recurrent GH excess. In other words, repetitive biochemical testing suffices for long-term postoperative screening of acromegalic patients initially cured by transsphenoidal surgery.

In the present study we evaluated the predictive value of MRI by assessing the increase in the amount of tissue and/or the change in configuration on serial postoperative MRI scans. In these patients after transsphenoidal surgery, the presence of residual adenoma cannot be detected only by a single, early postoperative MRI, due to nonspecific postoperative changes, in agreement with prior MRI follow-up studies in pituitary adenomas (13, 14, 15, 16). In our biochemical, well characterized cohort of patients with this rare disease, long-term biochemical and clinical follow-up data were used. The biochemical follow-up in combination with clinical data could be used as a gold standard, because this extended beyond (before and after) the radiological follow-up.

There may be discrepancies between the different biochemical criteria to define cure or recurrence of acromegaly. In a follow-up study of our group, IGF-I and suppressed GH levels were both normal in most patients in remission, although they were discordant in 16% of patients (3). This discrepancy has also been reported by other groups (23, 24). Conversely, other publications used IGF-I levels to define cure and recurrence and showed discordant results in some patients with respect to GH levels. For instance, Freda et al. (25) defined cure by normal IGF-I levels and showed that some of these patients have subtle abnormalities in GH suppression after GTT. This abnormal pattern of GH suppression may be associated with increased risk of recurrence in some, but not all, patients. Unfortunately, we could not evaluate the effect of their strategy in our patients, as IGF-I measurements were missing in some of the patients, because they were operated before the availability of the IGF-I assay. Nonetheless, it appears that there are some discrepancies in the outcome of different biochemical criteria to define cure and recurrence regardless of the hierarchy chosen between the different criteria. Finally, we have used the same criteria to define cure in a study of long-term survival in acromegaly and found that survival was almost normal in patients during long-term follow-up who fulfilled the above-mentioned criteria (26).

For the purpose of this study, the three independent neuroradiologists were blinded for clinical and biochemical data. This approach resulted in negative results in the reevaluation in all patients with recurrent disease according to two radiologists and in four of nine according to the third neuroradiologist. Therefore, serial MRI scans have a poor positive predictive value for detecting recurrence of pituitary adenoma after transsphenoidal surgery; this proves that MRI has only a limited additive value in diagnosing recurrent pituitary disease. However, we cannot exclude that in clinical practice the knowledge of clinical and biochemical data by the radiologists at the time of MRI evaluation may lead to a greater sensitivity in detecting pituitary changes. Nonetheless, our data indicate that MRI is not helpful in the long-term postoperative follow-up of GH-producing pituitary adenomas, because MRI scans could not adequately confirm the diagnosis of recurrent tumor tissue despite clear biochemical evidence of recurrent disease.

The postoperative series of MRI scans of patients with long-term biochemical cure did not show recurrent disease according to two independent neuroradiologists. The third radiologist, however, assessed three of the 23 postoperative MRI series of patients with long-term biochemical cure as positive for tumor growth, even though these patients remained in ongoing long-term biochemical and clinical cure. This suggests that the difficulty in interpretation due to postoperative changes in the sella produces a variation in interpretations, at least in some patients.

GH-producing tumors grow slowly, and recurrences require many years to develop (5, 6). The growth of the tumor and changes in the configuration of the sella determine whether a recurrent pituitary adenoma is visible on MRI. The combination of the slow growth rate of GH-producing tumors with postoperative radiological changes in the configuration of the pituitary on MRI make serial MRI apparently less suitable for general follow-up compared with biochemical parameters.

Fortunately, GH suppression during GTT appears to be an appropriate tumor marker for recurrent active disease. This test appears to be positive before suspicion is raised on MRI in these patients. In our series, MRI scans made without any biochemical indication of recurrent GH excess have never led to suspicion for recurrence or any therapeutic consequences. This is in agreement with a study correlating changes seen on postoperative MRI and hormonal evaluation, stating that MRI is not useful in the follow-up of pituitary microadenoma in general (27). In accordance, biochemical parameters are considered to be the most important parameters during long-term follow-up. Moreover, biochemical parameters are determinants of morbidity and mortality, whereas MRI is only an adjuvant diagnostic procedure according to a recent consensus statement (17).

MRI was reported to be highly sensitive to evaluate the efficacy of surgery in nonfunctioning pituitary macroadenomas, although the residual tumor volumes did not appear to change during the first 2 yr after surgery, and in 18% of the MRI scans residual tumors could not be differentiated from scar tissue formation (11). The efficacy of MRI in differentiating residual tumor from postoperative surgical changes was rated highly in a mixed group of hormonally active and inactive tumors (8). This observation seems to be in contrast with our findings. However, the underlying pathophysiology of the adenomas is different in the two studies, because we studied only patients with GH-producing tumors. In contrast to our patients, most endocrine-inactive pituitary adenomas lack sensitive biochemical markers. Alterations in these markers of endocrine-active pituitary tumors precede the development of radiological evidence of recurrent pituitary disease, at least in acromegaly. Moreover, the follow-up of our initially cured patients was aimed at detection of recurrent, not residual, disease.

In our opinion, the use of MRI in the follow-up of successfully operated acromegalic patients can be restricted to those patients, who have biochemical evidence of recurrent disease. The reason for advising that yearly MRIs be performed in patients surgically treated for (hormone-secreting) pituitary adenomas remains unclear (10). Even in patients with recurrent active acromegalic disease, MRI is able to visualize mass increase in only a small number of patients. Therefore, we advise obtaining a single postoperative MRI about 4–6 months after surgery to serve as a baseline observation. This baseline MRI will allow differentiation between postoperative changes and recurrent adenoma growth on follow-up MRI, which would be required only in the case of clinical or biochemical suspicion for recurrence. The findings from the present study suggest that radiological follow-up by MRI is not necessary in patients with long-term cure.

	Footnotes

 
Abbreviations: CV, Coefficient of variation; GTT, glucose tolerance test; IFMA, immunofluorometric assay; MRI, magnetic resonance imaging.

Received December 15, 2003.

Accepted June 11, 2004.

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