British Journal of Radiology (2005) 78, 110-115
© 2005 British Institute of Radiology
doi: 10.1259/bjr/51245688
The role of somatostatin receptor scintigraphy in patients with pituitary adenoma or post-surgical recurrent tumours
M J Acosta-Gómez, MD1,
M A Muros, MD, PhD1,
J M Llamas-Elvira, MD, PhD1,
A Ramírez, MD, PhD1,
S Ortega, MD1,
G Sabatel, MD1,
C Ramos, MD1 and
A de la Riva-Aguilar, MD, PhD2
1 Department of Nuclear Medicine, Virgen de las Nieves Hospital, Avda. de las Fuerzas Armadas 2, 18014 Granada and 2 Department of Neurosurgery, University Hospital "Reina Sofía", Córdoba, Spain
Correspondence: Dr Maria Angustias Muros, Servicio de Medicina Nuclear, Hospital Virgen de las Nieves, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain
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Abstract
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To assess the role of scintigraphy with 111In-DTPA-D-Phe-octreotide (111In-octreotide) in the diagnosis of pituitary adenomas and in the evaluation of post-surgical recurrent or residual tumours, we performed scintigraphy with 111In-DTPA-D-Phe-octreotide (SRS) in 35 patients: 14 patients with confirmed pituitary tumours and 15 with confirmed recurrent tumours. Clinical, biochemical and histological analyses, conventional images (CT/MRI), and follow-up assessments during a period of 1 year to 4 years were recorded in all patients. In the present study, scintigraphy with 111In-octreotide showed positive uptake in 10 out of 14 patients with confirmed pituitary tumour and in 13 out of 15 patients with confirmed recurrent tumour, with an overall sensitivity of 79%. SRS showed better results in growth hormone (GH)- and prolactin (PRL)-secreting tumours (7/8 patients correctly identified) than in other adenomas (3/9). SRS detected recurrence of adenocorticotrophic hormone (ACTH)-secreting tumours (4/5 patients correctly identified) and non-secreting tumours (5/7 patients correctly identified). 111In-octreotide scintigraphy, in combination with other imaging modalities, is useful in the diagnosis and follow-up of pituitary tumours. It allows scar tissue to be differentiated from tumour recurrence after surgical treatment and ensures better selection of patients who will benefit from medical treatment with somatostatin analogues.
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Introduction
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The in vivo visualization of somatostatin receptors is becoming more widely used to diagnose neuroendocrine tumours and to assess the therapeutic effects of somatostatin analogues in these patients [1]. Somatostatin receptors have been demonstrated in vitro in most cases of growth hormone (GH)-secreting adenomas and in some cases of thyroid stimulating hormone (TSH)-secreting adenomas and prolactinomas. Controversial results have been reported in other types of pituitary adenomas, such as non-secreting adenomas [2–5]. GH-secreting tumours express somatostatin receptor subtypes 2, 3 and 5, whereas non-secreting adenomas mainly express subtype 3 [6].
In the diagnostic work-up of patients with pituitary adenomas, CT and MRI play a principal role in defining the localization and tumour size, as in all brain tumours, but histological diagnosis can only be performed post-operatively. MRI is now the investigation of choice in diagnosis of pituitary adenomas. Micro-adenomas are defined as being smaller than 10 mm in size and usually present because of endocrine dysfunction (the most common is prolactinoma). 80–85% of micro-adenomas are visible on unenhanced T1 weighted MR images and 33–50% are seen as areas of hyperintensity on T2 weighted images, and enhancement with dynamic scanning is only necessary in a minority of cases. Macro-adenomas are more likely to be non-functioning and present because of mass effect on adjacent structures such as the optic chiasm. MRI signal characteristics do not necessarily assess the consistency of the tumour accurately but the superior and inferior extent of tumour is well demonstrated by MRI.
It is not easy to distinguish between recurrent/residual tumour and scar/necrotic tissue after surgery [7]. The scintigraphic visualization of hypophyseal tumours may be of value for predicting the response to somatostatin analogue treatment and for the post-surgical detection of small or residual tumours that are undetectable on MRI. Although some authors have reported that somatostatin receptor scintigraphy (SRS) did not permit visualization of post-surgical tumours that were not visible on MRI [8], other authors have described its utility to detect minimal post-surgical residual tumours [9].
The present study aimed to assess the utility of SRS in the diagnosis of pituitary adenomas and in the evaluation of post-surgical recurrent or residual tumours.
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Patients and methods
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Patients
We performed a prospective study of 35 patients referred to our Department of Nuclear Medicine for suspicion of pituitary tumour or suspicion of pituitary tumour recurrence over 5 years (1997–2001). 35 patients (23 females, 12 males) aged between 9 years and 77 years (mean age 43 years) were referred by the Departments of Neurosurgery, Endocrinology and Radiotherapy. All patients gave their informed consent to undergo the scintigraphy. The Ministry of Health approved the compassionate use of the radiopharmaceutical in all cases. 18 of the patients were referred for suspected tumour recurrence due to the persistence or post-surgical onset of clinical symptoms (n=9) or elevated levels of hormone markers (n=9). Tumour types in these patients included: adenocorticotrophic hormone (ACTH)-secreting (n=5), GH-secreting (n=3), prolactin (PRL)-secreting (n=2), follicle stimulating hormone (FSH)-secreting adenomas (n=1) and non-secreting adenomas (n=7). The remaining 17 patients were referred for suspicion of pituitary adenomas, presenting with PRL-secreting (n=4), GH-secreting (n=4), ACTH-secreting (n=3) adenomas, non-secreting adenomas (n=3), and thyroid stimulating hormone (TSH)- (n=1), FSH- (n=1), and leutinizing hormone (LH)- (n=1) secreting adenomas. None of 18 patients referred for suspected tumour recurrence were included in the primary tumours group.
Clinical data and biochemical determinations were recorded for all patients prior to the scintigraphic examination. The analytical findings included levels of GH, somatomedin C, insulin-like growth factor-1 (IGF1) growth factor, prolactin, TSH, ACTH, FSH, and LH, and the results of stimulation and inhibition tests of these hormones. CT or MRI and ophthalmological (visual field) studies were carried out in all cases. The mean follow-up period was 2.5 years (range 1–4 years).
A tailored therapeutic approach was developed for each patient, using somatostatin analogues, radiosurgery, medical treatment or surgery as appropriate. Five patients (three with pituitary adenomas and two with tumour recurrence) underwent surgery and the pathological report confirmed the presence of pituitary adenoma or tumour recurrence. The diagnosis was confirmed in the remainder by imaging tests (CT or MRI) in conjunction with analytical results and clinical findings.
[111In-DTPA-D-Phe]-octreotide scintigraphy
The scintigraphy was performed with 185–220 MBq (5–6 mCi) of 111In-chloride-DTPA-D-Phe-octreotide (Octreoscan) obtained from a simple Mallinckrodt kit (Mallinckrodt Ibérica S.A. Spain), which was intravenously administered to all patients. No post-administration adverse reactions or side effects were detected in any patient. Image acquisition was with single-head (Siemens Orbiter; Gammasonics, IL) and double-head (AXIS2; Picker International, Nuclear Medicine Division, Cleveland, OH) gamma cameras with medium energy collimator. Planar images were obtained 4 h, 24 h and 48 h post-injection in all patients, with at least 500 000 counts/acquired per image or 10 min image–1. Tomographic images (SPECT) were obtained 4 h and 24 h post-injection, if using the double-head camera, through a 360° orbit, acquiring 60 steps at 40 s step–1, using a 64 x 64 matrix. The image analysis was performed by two nuclear medicine specialists according to a qualitative evaluation system visually comparing the tracer uptake in the suspected tumour with that in the skull [10–12]. The grades were defined as follows:
- Grade 0: absence of tracer uptake, no visualization of tumour activity, considered negative;
- Grade I: slight tracer uptake, similar to that in skull;
- Grade II: moderate tracer uptake with good visualization of tumour; uptake slightly greater than that in skull;
- Grade III: intense tracer uptake; uptake clearly greater than that in skull.
MRI
MRI was performed using a 0.5-T scanner (GE Max Medical System, Milwaukee, WI). T1 weighted gradient echo imaging (without contrast) was performed with a repetition time (TR) of 380 ms and echo time (TE) of 12 ms. T2 weighted and proton density variable echo (VE) imaging was performed with a TR of 2600 ms, TE of 40–120 ms, and T1 weighted spin-echo (SE) with a TR of 600 ms, and TE of 25 ms. Studies were also performed with paramagnetic contrast: T1 weighted SE imaging, using sections of 3 mm thickness with 4 mm section interval. Images were obtained in the coronal and axial planes.
CT
CT scan was carried out before and after intravenous infusion of contrast medium using a third generation Siemens Somatom CR scanner. Section thickness was 4 mm.
Analytical studies: hormone determinations
The following hypophyseal hormones were determined in all patients: GH, ACTH, PRL, TSH, FSH, and LH. IGF1 growth factor was also measured. The determinations were made by radioimmunoanalytical techniques for FSH, LH and PRL (Diagnostic System Laboratories, Inc., TX), GH (IRMA, Immunotech, France), TSH (IRMA, Immunodiagnostic Systems Ltd., UK), and ACTH (Nichols Institute, CA, USA). Hormone inhibition and stimulation tests were carried out: inhibition test with dexamethasone for ACTH-secreting tumours and oral glucose overload test for GH-secreting tumours.
Follow-up
All patients were followed up every 6 months, provided no clinical situations occurred requiring more urgent assessment or admission. The follow-up consisted of: MRI examinations, which were always compared with previous images, hormonal analytical determinations, and clinical examinations.
Complete remission was defined as normalization of all clinical sings with normal tumour markers (including basal and dynamic responses of hypophyseal hormones) at 1 year after therapy with no evidence of residual tumour on CT or MRI. The patient was considered to have tumour recurrence if clinical, biochemical and/or neuroradiological signs of tumour activity were detected after therapy.
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Results
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Among the 17 patients referred for suspicion of pituitary tumour, SRS was positive in 10 patients (Table 1
, Figure 1). The MRI was positive in all 10 patients. Two of these 10 patients underwent surgery and the pathological report confirmed the presence of pituitary adenoma; six patients were treated with somatostatin analogues, and the remaining two patients (with smaller tumour size) received radiosurgery or medical treatment. In follow-up studies, all 10 patients showed clinical, biochemical and/or radiographic improvements after therapy. According to their tracer uptake, eight patients were scored with Grades II or III and two patients with Grade I. Each patient with Grade I had GH-secreting adenoma less than 1 cm in size.
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Figure 1. (a) Anterior and (b) lateral images of 111In-chloride-DTPA-D-Phe-octreotide accumulation in the tumour site in a patient (N° 17) with thyroid stimulating hormone (TSH)-secreting adenoma. The images were taken in a Siemens single-head gamma camera 24 h after tracer administration.
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SRS was negative in seven patients. In three of these, the absence of the disease was confirmed by conventional imaging studies, biochemical findings, and clinical follow-up. The initial MRI examination was positive in one case (N° 15), but subsequent biochemical and clinical follow-up ruled out the presence of adenoma in this patient.
Scintigraphy failed to detect the presence of tumour in four patients: two with non-secreting adenomas, one with an ACTH-secreting adenoma of less than 1 cm, and one with a prolactinoma.
SRS showed better results in GH- and PRL-secreting tumours (7/8 patients correctly identified) than in other adenomas (3/9).
Among the 18 patients examined for recurrent/residual pituitary tumour, SRS was positive in 13 patients (Table 2). Of these, one (with largest tumour size) underwent repeat surgery, five (with highest uptake grades, II and III) were treated with somatostatin analogues, two with radiosurgery, three underwent medical treatment and one patient was treated with radiotherapy and somatostatin analogues. The remaining patient (N° 27) refused treatment. In all 13 patients, the recurrence was confirmed by clinical and biochemical data and MRI results. In two of the patients (N° 19 and 25) with positive SRS, the MRI gave a negative result (Figure 2), and the recurrence was demonstrated by clinical and biochemical results in follow-up. SRS was negative in five patients: the absence of recurrence was demonstrated by imaging tests and follow-up in three cases, whereas in the remaining two patients, recurrence was confirmed by imaging (MRI and CT) and the evaluation of post-treatment improvements. MRI was negative for recurrence in four patients. The absence of recurrence was confirmed in two of them (N° 26 and 31).
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Figure 2. (a) MRI in the patient N° 21. Represent a study in a coronal view showing a small recurrent tumour in contact with right optic nerve. (b) Lateral images of 111In-chloride-DTPA-D-Phe-octreotide accumulation in the recurrent tumour site in a patient (N° 21) with recurrent adenocorticotrophic hormone (ACTH)-secreting adenoma. The images were taken in a Siemens single-head gamma camera 24 h after tracer administration.
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SRS correctly diagnosed 16 of the 18 patients with suspected recurrence, whereas MRI correctly diagnosed 14 of the 17 patients who had MRI (one patient refused MRI).
According to our results, SRS showed the best results in cases of recurrence of ACTH-secreting tumours (4/5 patients correctly identified) and non-secreting tumours (5/7 patients correctly identified).
In the present study, scintigraphy with 111In-octreotide showed uptake in 10 out of 14 patients with confirmed pituitary tumour and in 13 out of 15 patients with confirmed recurrence, with an overall sensitivity of 79%.
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Discussion
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The presence of high-affinity somatostatin receptors in most neuroendocrine tumour cells allows the in vivo scintigraphic visualization of neuroendocrine tumours after the intravenous administration of a radiolabelled somatostatin analogue. The diagnosis of suspected cases of pituitary tumour or pituitary tumour recurrence can be based on CT and MRI but the definitive diagnosis depends on histopathological study following surgery. When tumour recurrence is suspected, it can be difficult to distinguish between residual tumour and scarring associated with post-surgical changes using CT or MRI [7]. Scintigraphy with 111In-octreotide allows the visualization of pituitary tumours on the basis of fundamental characteristics of membrane receptors. Initially, these studies used 123I-Tyr3-octreotide to radiolabel somatostatin analogues [1, 13–15]. Subsequently, the use of 111In-DTPA-D-Phe-Octreotide became widespread and iodine labelling was abandoned. In the present study, scintigraphy with 111In-octreotide showed positive uptake in 10 out of 14 patients with confirmed pituitary tumour and 13 out of 15 patients with confirmed recurrence, with an overall sensitivity of 79%. Reports on the sensitivity of this technique have been variable, ranging from 37% found by Schmidt et al [12], who studied 24 patients and obtained positive uptake in only nine (9/24), to 88.5% described by Colao et al [16] in a study of 38 patients with pituitary adenomas. In our study, the best results were for GH- and PRL-secreting tumours (7/8), similar to the findings of Legovini et al [17] and Oppizzi et al [18]. Among our five patients with pituitary tumour that did not secrete GH or PRL, three showed tracer uptake (1 TSH-secreting adenoma, 1 LH-secreting adenoma and 1 non-secreting adenoma). Van Royen et al [19] showed uptake in five out of six patients with non-GH-secreting pituitary adenoma (2 non-functioning, 2 TSH-secreting, 1 prolactinoma and 1 Nelson's syndrome). In our study, two patients with suspicion of FSH- and LH-secreting tumours were correctly diagnosed using SRS. The utility of SRS was less for non-secreting adenomas in our study, with uptake in one out of the three patients who showed grade II uptake and underwent surgical treatment. Oppizzi et al [18] found uptake in 14 out of 22 patients and Schmidt et al [12] detected uptake in six out of 14 such patients. On the other hand, Duet et al [5] found uptake in five out of five patients with non-secreting adenoma. We studied one patient diagnosed with ACTH-secreting adenoma and detected no uptake, in keeping with several other studies. De Herder and coworkers detected no uptake in eight patients with ACTH-secreting adenoma and Stalla et al suggested that the elevated cortisol levels in patients with ACTH-secreting adenoma may inhibit the expression of somatostatin receptors [20–22].
Among the patients with confirmed tumour recurrence, SRS correctly detected 13 out of 15 patients. Plökinger et al [8] studied 10 patients after surgery for GH-secreting pituitary adenoma. Seven of them with tumours associated with persistent elevation of GH levels were not detected by scintigraphy. They concluded that SRS is not useful in detecting tumour recurrence in cases with a negative MRI result. In our study, tumour recurrence was diagnosed by SRS in 13 patients and two of them had a negative MRI. The diagnosis of recurrence was subsequently confirmed in all cases. Lauriero et al [9] showed uptake in eight of 10 patients (4 GH-secreting and 6 PRL-secreting adenomas) diagnosed with tumour recurrence. Both patients in our study with suspected recurrence of PRL-secreting tumour showed positive uptake. Out of seven patients in our study with recurrence of non-secreting adenoma, five had positive uptake of octretide, with no false positive cases.
In the present study, scintigraphy showed good results in patients with suspected recurrence of ACTH-secreting pituitary adenoma, with detection in four out of the five patients. Various authors have studied the presence of somatostatin receptors in pituitary adenomas and the inhibitory effects of somatostatin, including on ACTH-secreting adenomas, with very variable results [23]. Spada et al [24] studied the inhibitory effects of somatostatin in vivo in six patients with ACTH-secreting pituitary adenoma who underwent transesphenoidal surgery, and all showed positive results, implying that these tumours must have somatostatin receptors. In contrast, no uptake was shown by receptor scintigraphy in any of the 19 patients with Cushing's disease or eight patients with ACTH-secreting pituitary adenoma in a prospective in vivo study by De Herder et al, although uptake was present in eight out of 10 patients with ectopic secretion of ACTH [20]. This discrepancy may be due to the long-term exposure of patients with ACTH-secreting adenoma to excessive levels of circulating cortisol. This exposure could negatively influence the expression of somatostatin receptors [20], whose presence in these tumours has been confirmed by in vitro studies [6, 22, 24]. The present study demonstrates there may be a use for SRS in patients with suspected recurrence of ACTH-secreting pituitary adenoma, although the sample size was small.
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Conclusions
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SRS, in combination with other imaging modalities, is a useful tool in the diagnosis and follow-up of pituitary tumours. This method allows scar tissue to be differentiated from tumour recurrence after the surgical treatment of pituitary adenomas and showed good results in the detection of recurrence of ACTH-secreting adenoma, although a larger sample size is required to verify this finding. SRS identifies patients with presence of positive receptors for somatostatin, who can then be selected for medical treatment with analogues of somatostatin.
Received for publication April 6, 2004.
Revision received August 23, 2004.
Accepted for publication September 27, 2004.
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References
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Abstract
Introduction
