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A Reappraisal of the Utility of Somatostatin Receptor Scintigraphy in Patients with Ectopic Adrenocorticotropin Cushing’s Syndrome

Departments of Endocrinology, Diabetes, and Metabolism (S.T., M.C., N.T.), Nuclear Medicine (H.G., F.R., I.H.), Radiology (C.M.), Pathology (D.R.), and Thoracic and Vascular Surgery (I.B.), Evangelismos Hospital, 10676 Athens, Greece

Address all correspondence and requests for reprints to: Dr. S. Tsagarakis, Department of Endocrinology, Diabetes, and Metabolism, Evangelismos Hospital, 10676 Athens, Greece. E-mail: stsagara{at}otenet.gr.

	Abstract

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Ectopic ACTH hypersecretion is a rare cause of Cushing’s syndrome. Bronchial carcinoids are the most common neoplasms causing the occult ectopic ACTH syndrome (EAS). Localization of these tumors is often difficult. The diagnostic utility of somatostatin receptor scintigraphy (SRS) in EAS has been studied in a limited number of patients with conflicting results. Herein we report our experience with 12 consecutive cases. Histological confirmation was obtained in nine patients, the majority being bronchial carcinoids. Among the seven patients with histologically confirmed bronchial carcinoids, SRS was performed in six patients. In three patients SRS correctly localized a bronchial carcinoid tumor at presentation. In the remaining three it became positive after 8, 22, and 27 months during follow-up. In two patients SRS was positive without any finding in the corresponding conventional imaging study. In two patients positive computed tomography/magnetic resonance imaging preceded SRS localization. There was no false positive SRS. Among three patients with highly suspected EAS, SRS was positive in one. Both patients with EAS due to medullary thyroid carcinoma had focal positive uptake. In summary, in this study a substantial number of patients had positive tumor localization by SRS. Therefore, SRS is a useful tool in the evaluation of patients with EAS.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
ECTOPIC ACTH HYPERSECRETION is a rare cause of ACTH-dependent Cushing’s syndrome (1, 2). It frequently presents a major diagnostic challenge because it is often indistinguishable from pituitary-dependent Cushing’s syndrome. Moreover, even when ectopic ACTH secretion is highly suspected, localization of ACTH-secreting tumors is often difficult (3). Bronchial carcinoids are the most commonly reported neoplasms causing the occult ectopic ACTH syndrome (EAS) (4). They are often small and may escape detection with conventional imaging [computed tomography (CT)/magnetic resonance imaging (MRI)] (5). To date, the diagnostic utility of somatostatin receptor scintigraphy (SRS) in the localization of such tumors with EAS has been studied in a limited number of patients with conflicting results. Several studies in the form of case reports supported the usefulness of SRS in localizing tumors with ectopic ACTH secretion (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17). However, the outcome of these studies was biased by the attitude to report only positive results. In contrast, two recent studies investigating the outcome of SRS in relatively large cohorts of patients with EAS provided discouraging results regarding the localizing ability of SRS in these patients (18, 19). These cohorts included several patients in whom, although highly suspected of harboring ectopic ACTH-secreting tumors, no diagnosis in a substantial proportion of the reported cases was reached at the completion of these studies. In the present study we report our experience of SRS on consecutive cases presenting in our unit with clinical and biochemical evidence of EAS. In this series, histological confirmation was obtained in most patients, the majority of whom harbored bronchial carcinoid tumors.

	Subjects and Methods

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Between 1991 and 2002, a total of 12 patients with EAS were investigated in our unit. Diagnosis of ACTH-dependent Cushing’s syndrome was based on standard biochemical criteria, and the possibility of EAS was raised by the absence of a central/peripheral ACTH gradient during bilateral inferior petrosal sinus sampling (20).

SRS

Whole body planar SRS using [¹¹¹In]pentetreotide was performed in 11 patients during initial workup and/or follow-up. For data acquisition and processing a two-head -camera was used. Imaging was carried out at 2–4 and 24 h after the injection of 6 mCi [¹¹¹In]DTPA-octreotide (Octreoscan R, Mallinckrodt Medical BV, Petten, The Netherlands), iv. A whole body image was always obtained as well as digital images of the area of interest of 256 x 256 matrix size by imaging to a minimum of 5 x 10⁵ counts. A SPECT image was also obtained if necessary. Corresponding CT imaging was interpreted by a single radiologist (C.M.), who was aware of the SRS findings. SRS evaluators were also aware of existing CT findings. SRS and CT findings underwent a final reassessment before submission of this report; diagnostic clues during this final reevaluation were identical to those obtained during the initial evaluation of the images.

Hormone measurements

Serum cortisol was assayed using a direct RIA featuring an iodine-125 radioligand and cortisol antibody-coated tubes (Coat-A-Count, Cortisol RIA, Diagnostic Products, Los Angeles, CA). The reported sensitivity of the assay used is 6 nmol/liter, with the lower detection limit for routine use set at 28 nmol/liter. Intra- and interassay coefficients of variation for cortisol concentrations of 28, 140, and 750 nmol/liter were 6, 2.5, and 4% and 6, 6, and 4.5%, respectively. Plasma ACTH was measured by a highly specific immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). Inter- and intraassay coefficients of variation were 8 and 4%, respectively.

	Results

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At the time of the analysis a final diagnosis was histologically confirmed in nine patients and included seven bronchial carcinoids and two medullary thyroid carcinomas (MTC). In the remaining three cases, although a provisional diagnosis of a bronchial carcinoid tumor was obtained in two of them, no surgery or histological confirmation was available. SRS findings among these groups of patients were as follows.

Bronchial carcinoids

Among the seven patients with histologically confirmed bronchial carcinoids, SRS was performed in six patients at presentation and/or during follow-up. The remaining patient, investigated partly in our center, did not undergo SRS imaging, but, as reported elsewhere, had a lasting remission of hypercortisolemia before surgery by long-acting somatostatin analog therapy (21). The results of SRS in combination with CT imaging and outcome of the six cases are shown in Table 1. In three patients SRS correctly localized a bronchial carcinoid tumor at presentation. In the remaining three it became positive after 8, 22, and 27 months of follow-up. In two patients SRS and conventional imaging studies were both positive at presentation (Fig. 1). In two patients (one at presentation and one during follow-up) SRS was positive without any finding in the corresponding conventional imaging study (Fig. 2). In the remaining two patients positive CT/MRI preceded SRS localization. In total, eight of the 13 scans performed in these patients were positive. There were no false positive scintigraphic findings. False positive conventional imaging was obtained in one patient. Interestingly, in the three patients with positive SRS at presentation mean cortisol levels were lower than in the three patients with negative scans (19 ± 10 vs. 40 ± 8 µg/dl or 528 ± 278 vs. 1112 ± 222 nmol/liter; P = 0.02).

View larger version (79K): [in this window] [in a new window]   FIG. 1. SRS (A) and corresponding CT scan (B) demonstrating positive uptake and a small nodular lesion (arrow) at the left lower lobe of the lung at presentation of case 6.

View larger version (121K): [in this window] [in a new window]   FIG. 2. SRS (posterior view) in case 2 performed 27 months from presentation, showing uptake in the left lower lung. The corresponding pulmonary CT scan was negative, but both CT and MRI showed a lesion (arrow) in the tail of the pancreas, which led to unnecessary laparotomy.

The results of SRS in this subgroup are presented in Table 2. In one patient (case 7) a positive scan was obtained 10 yr from presentation along with a positive CT finding compatible with a bronchial carcinoid tumor. However, this patient has been eucortisolemic after prior adrenalectomy and refused thoracic surgery. In the second patient (case 8) despite extensive investigation no tumor was found with both SRS and CT/MRI imaging. This patient did not attend further follow-up. In another case (case 9) CT of the chest was positive, whereas SRS was negative. This patient went into spontaneous long-lasting remission and refused further investigation.

Two patients in this series had histologically confirmed MTC with positive ACTH immunostaining. Both of these cases had positive focal uptake during SRS performed at presentation. Both patients had palpable thyroid nodules, and a provisional diagnosis of MTC was based on calcitonin measurements in both patients and positive cytology in one of them.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This is one of the largest single center cohort studies investigating the outcome of SRS in localizing tumors with ectopic ACTH secretion and one demonstrating a high diagnostic yield of this modality in such patients. Thus, a total of nine of 11 cases studied with SRS had at least one positive scan, which was true positive based on subsequent histology in eight of these cases. In good agreement, De Herder and co-workers (22) reported that eight of 10 patients with EAS were positive on SRS; however, in their study only one of the scintigraphically positive cases was truly occult. Bronchial carcinoids were the most common tumor encountered in this cohort. This is not surprising because this is the most common type of tumor with the occult ectopic Cushing’s syndrome presented in an endocrine unit. SRS successfully localized all six histologically confirmed cases of bronchial carcinoids and possibly one of the two highly suspected cases. These findings are in good agreement with several case reports demonstrating the utility of SRS in localizing bronchial carcinoid tumors with EAS.

Two recent cohort studies, however, have questioned the utility of SRS in patients with EAS. The study by Torpy et al. (18) comprising 18 patients investigated in a single center showed positive SRS in only six patients, whereas in the multicenter study by Tabarin and co-workers (19) SRS was positive in only three of the 12 cases studied. There are several explanations for the lower diagnostic yield of SRS observed in these studies. The study by Torpy et al. (18) originating from a center with well recognized expertise in the investigation of patients with Cushing’s syndrome included several patients in whom the diagnosis had escaped for years before their recruitment for SRS. Tumor dedifferentiation may have had a negative impact on SRS outcome (23). In fact, three of the six SRS-negative tumors were either poorly differentiated or metastatic. In contrast and in good agreement with our results, four of the six bronchial carcinoids were SRS positive. In both studies the overall diagnostic yield was low, with no final diagnosis obtained in six of the 18 patients studied by Torpy et al. (18) or in five of the 12 patients studied by Tabarin et al. (19). It is of note that the majority of undiagnosed patients in both studies have only been investigated once. It is generally believed that most of these patients harbor small bronchial carcinoids, and as shown by our study, they may escape detection with SRS for years after their initial presentation. More worrisome was the finding by Tabarin et al. (19) that all three histologically confirmed bronchial carcinoids were SRS negative; however, this latter study has been criticized for using lower doses of radio labeled [¹¹¹In]pentetreotide and no SPECT imaging (24).

It has been suggested that as all patients with positive SRS also had a positive corresponding conventional imaging, SRS is not superior to conventional imaging (18, 19). In our cohort, however, in two of our cases SRS was the earliest finding pointing to an intrathoracic lesion. Similar findings were also reported in case report forms. It has also been suggested that SRS should not be repeated during the follow-up in patients with a previously negative scintigram (19). However, as shown by the present study, patients with initial negative scans eventually demonstrated a positive uptake even years after initial presentation. This was particularly useful for one patient (case 5). In this case a positive CT scan preceded SRS uptake. The patient underwent thoracic surgery, but no tumor was found. Subsequent SRS uptake corresponding to the same persistent lesion on CT enforced us to reoperate at the same site, with eventual cure of the patient. The mechanism underlying the subsequent positive SRS after a negative initial evaluation is unclear. It may not be related to technical reasons, as all patients, except case 1, were investigated in a single center by the same technique and the same group of jointly working nuclear doctors. The possibility that subsequent SRS localization was due to an increase in the size of the tumor lesion cannot be refuted. However, SRS, as shown by this and other reports, is able to detect small lesions (as small as 0.6 cm in the present study) in the chest. Inhibition of somatostatin receptor expression by elevated cortisol levels may be an alternative explanation (25). In fact, the mean cortisol levels of patients who had a positive SRS at presentation were significantly lower than those observed in SRS-negative patients. However, in view of the small number of patients studied and the lack of knowledge of the particular somatostatin receptor subtype expressed by the tumors, we cannot reach a definite conclusion regarding this hypothesis.

It is also remarkable that no false positive SRS was observed in our series. In contrast, Torpy et al. (18) reported false positive scans on six occasions due to radiation fibrosis, inflammation, and an accessory spleen, which were readily apparent by conventional imaging. These researchers did not emphasize, however, the frequency of false positive conventional imaging leading to further invasive testing in some of their cases. In our study false positive conventional imaging was obtained in three cases leading to unnecessary surgical interventions (cases 2, 7, and 8). In fact, in one of these cases (case 2) with SRS pointing to a bronchial carcinoid and conventional imaging pointing to a pancreatic tail tumor, laparotomy was performed with no success. After this a subsequent CT scan demonstrated a thoracic lesion corresponding to the SRS finding, which when removed cured the patient. This finding reinforces previous suggestions that a combination of positive SRS and conventional imaging enhances the chances of correctly localizing these tumors (24).

In summary, along with other similar studies our study demonstrates the frustration of identifying the source of ectopic ACTH secretion by both conventional imaging and SRS. In this study, however, a substantial number of patients have been cured as a result of positive tumor localization by SRS. Therefore, it is postulated that combination of conventional radiology with SRS should be repeatedly employed in the evaluation of these patients to optimize location of these tumors and resolve a problem that represents the endocrinologist’s (and patient’s) nightmare.

	Footnotes

 
Current address for C.M.: Second Department of Radiology, University of Athens, 10676 Athens, Greece.

Abbreviations: CT, Computed tomography; EAS, ectopic ACTH syndrome; MRI, magnetic resonance imaging; MTC, medullary thyroid carcinoma; SRS, somatostatin receptor scintigraphy.

Received March 26, 2003.

Accepted June 14, 2003.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tsagarakis, S. Articles by Thalassinos, N. Search for Related Content PubMed PubMed Citation Articles by Tsagarakis, S. Articles by Thalassinos, N. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Carcinoid Tumors Cushing's Syndrome