University Hospital Rotterdam 3015 GD Rotterdam, The Netherlands
Address correspondence and requests for reprints to: Wouter W. de Herder, Department of Internal Medicine III, University Hospital Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: deherder{at}inw3.azr.nl
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Introduction |
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The five different membrane-associated somatostatin receptor subtypes (sst15) that have been cloned to date show a distinct pharmacological binding profile of structurally related octapeptide somatostatin analogs in comparison with that of native somatostatin. Somatostatin-14 and 28 both bind with high affinities to sst15. The presently available octapeptide somatostatin analogsOctreotide (Sandostatin and Sandostatin LAR, Novartis, Basle, Switzerland) and Somatuline (Lanreotide, Ipsen, Paris, France)bind with a high affinity to sst2 and sst5, show a low affinity to sst3, and no affinity to sst1 and sst4 (2). The efficacy of these octapeptide analogs in patients with neuroendocrine tumors is determined by the expression of somatostatin analog-binding receptor subtypes on these tumors. Tumors and metastases, which bear sst2 (and sst3 and sst5), can be visualized in vivo using gamma camera pictures obtained after injection of 111In-pentetreotide (OctreoScan, Mallinckrodt, Inc., Petten, The Netherlands) (2). In a large European multicenter trial, 350 patients with carcinoids and islet cell tumors were investigated with this scintigraphic technique. 111In-pentetreotide scintigraphy was positive in 87% of carcinoids (n = 184), 73% of gastrinomas and nonsecreting islet cell tumors (n = 49 and n = 49, respectively), 46% of insulinomas (n = 24), 88% of VIP-omas (n = 8), all 5 glucagonomas, and none of 2 somatostatinomas (3).
The most common localization of an ectopic source of ACTH secretion is in the chest. Bronchial carcinoids may prove particularly difficult to localize. In 14 papers, mainly case reports, 111In-pentreotide scintigraphy could identify true occult ACTH-secreting lesions not visualized by conventional radiological techniques in 13 out of 16 patients. Eleven of these tumors were bronchial carcinoids (4). Of course, the outcome in these papers has been greatly biased by the general medical attitude of reporting positive results only.
Torpy et al.(5) now report (see page 1186) their experience using chest and abdominal computed tomography (CT) or MRI protocols, and 111In-pentetreotide scintigraphy and single photon emission tomography (SPECT) in localizing the source of ectopic ACTH production in 18 consecutive patients who were analyzed in a single clinical center (5). These, authorities, recognized worldwide in endocrine imaging, could identify these sources at first radiological examination in 7 out of 18 patients. At repeated radiological imaging, another 3 were identified. Consequently, conventional radiology was successful in 10 out of 18 patients. In 9 patients, the source of ectopic ACTH production was localized in the chest; 4 of these were bronchial carcinoids. Chest CT and MRI visualized one lesion in the neck. In this study, 111In-pentetreotide localized the source at the first examination in 6 out of 18 patients. Two scintigrams at initial examination and another one at follow-up were considered false positive. In one patient, follow-up scintigraphy pointed to abnormal uptake at a different site compared with the initial pathological scintigram. However, these studies were performed after surgical removal of the source of ectopic ACTH production and cure of the Cushing syndrome.
Tabarin et al.(6) report their multicenter experience of 12 patients with occult ectopic ACTH-secreting tumors (see page 0000). In this series, whole body CT or MRI identified the source of ectopic ACTH production at initial examination in only 2 patients with confirmed diagnoses, and possibly in another patient in whom the diagnosis was not confirmed. At follow-up, CT or MRI identified the source in another 2 patients with confirmed diagnoses and in another one without a confirmed diagnosis. Consequently, conventional radiology was positive in only 4 out of 12 patients with a proven diagnosis. In this study, 111In-pentetreotide scintigraphy localized the source at the first examination in only 1 patient with a confirmed diagnosis and possibly in 2 other patients without confirmation of the diagnosis. One scintigram was considered false positive. Importantly, single photon emission tomography studies were only performed in a subgroup of 7 patients, and 4 patients were injected with 111In-pentetreotide at a lower dose (4 mCi instead of 6 mCi) than generally recommended. In this study, the source of ectopic ACTH production was localized in the chest in 3 patients and potentially, though not proven, in one other. All these 3 sources were carcinoids.
Both studies clearly demonstrate the frustration of identifying the source of ectopic ACTH secretion when using conventional radiological imaging techniques or 111In-pentetreotide scintigraphy. They differ with regard to patient selection and primary diagnosis, single center against multicenter approach, and diversity of imaging protocols. Although not systematically tested, both studies show that, in the case of a negative baseline 111In-pentetreotide scan, future repeated scintigraphy would prove useless.
Should 111In-pentetreotide scintigraphy be
discouraged as a diagnostic tool in the work-up of patients with the
syndrome of (occult) ectopic ACTH secretion? Without doubt, the
substantial number of patients who have been cured as a result of
positive tumor localization by this technique and who have been
reported in the literature can not be refuted. This technique provides
whole body information, which is a major advantage over conventional
radiology. Particularly, the detection of brain or skeletal metastases,
as described in one of the patients in the study by Torpy et
al., can significantly alter the therapeutic approach in these
patients (5). This technique also provides additional functional
information; a positive scintigram points to the presence of functional
receptors for octapeptide somatostatin analogs (7, 8). Treatment of
these scan-positive patients with octapeptide somatostatin analogs may
then result in correction of hypercortisolism and thus improve
metabolic control and tissue healing before performing curative
surgery. These drugs have also been used successfully as palliative
therapy in inoperable patients (8). Also, experimental targeted
radiotherapy with -, or ß-emitting isotopes coupled to
somatostatin (analogs) can presently be considered in patients with
strong uptake of 111In-pentetreotide in the
pathologic lesions and who are resistant to conventional therapies (9, 10). As already pointed out by Torpy et al. and Tabarin
et al. (5, 6), the specificity of
111In-pentetreotide scintigraphy is low.
Sst2 and sst5 have also been recognized
in vitro and in vivo on a variety of other
neoplastic tissues like lymphomas and in non-neoplastic processes like
granulomas and lesions in systemic autoimmune diseases (3). However,
with the use of advanced CT and MRI protocols small bronchial
carcinoids can also be easily confused with pulmonary vascular shadows
(see ref (1). In rare cases, tumor deposits expressing
sst2, sst3, and sst5, and those not
expressing these receptor subtypes may coexist in the same patient. In
these patients, 111In-pentetreotide
scintigraphy partially gives false-negative results (3).
111In-pentetreotide can also be used in
combination with a hand-held radionuclide probe for intraoperative
scanning in search of tumor deposits in scan-positive patients (11). In
the near future, the development of new classes of radiolabeled
somatostatin subtype-selective analogs can be expected that may
hopefully further improve the scintigraphic localization of ectopic
ACTH-secreting tumors.
In our opinion, because no single imaging technique has optimal accuracy in the localization of ectopic ACTH-secreting tumors, combinations of conventional radiology and 111In-pentreotide scintigraphy should presently be employed to optimally locate this proverbial needle in the haystack.
Received February 2, 1999.
Accepted February 8, 1999.
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References |
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