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EXTENSIVE CLINICAL EXPERIENCE |
Departments of Endocrinology (A.M.I., G.A.K., C.P., V.F., P.J.J., J.P.M., A.B.G., G.M.B.) and Academic Radiology (R.H.R.), St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom; and Department of Endocrinology (J.N.-P.), Division of Clinical Sciences, University of Sheffield, Sheffield S5 7AU, United Kingdom
Address all correspondence and requests for reprints to: Professor A. B. Grossman, Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom. E-mail: a.b.grossman{at}qmul.ac.uk.
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Abstract |
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Objective: The objective of this study was to analyze the clinical, biochemical, and radiological features, management, and treatment outcome of patients with EAS.
Design: This was a retrospective case-record study.
Setting: The setting for this study was a tertiary referral hospital center.
Patients: Forty patients with EAS were studied.
Main Outcome Measures: Clinical, biochemical, and radiological features and response to therapy and survival were measured.
Results: The median follow-up was 5 yr (range, 2–30 yr). None of the dynamic tests achieved 100% accuracy, but bilateral inferior petrosal sinus sampling showed an absent central gradient in all but one case (one of 12). Imaging correctly identified the lesion at first investigation in 65% of cases. Bronchial carcinoid tumors were the most common cause of EAS (n = 12; 30%), followed by other neuroendocrine tumors (n = 13, 32.5%). In 12.5% of patients, the source of EAS was never found. Octreotide scintigraphy and whole-body venous sampling were of limited value. Surgical attempt at curative resection was successful in 83% (10 of 12) of patients with bronchial carcinoid tumors; others responded generally well to adrenolytic therapy or bilateral adrenalectomy. Tumor histology and the presence of distant metastases were the main predictors of overall survival (P < 0.05).
Conclusions: A variety of tests and imaging studies are necessary for the correct diagnosis of the EAS, but even then, up to 20% of cases present a covert or occult EAS syndrome. These cases require a prolonged follow-up, review, and repetition of diagnostic tests and scans.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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With the development of improved biochemical and imaging techniques, EAS is being recognized more frequently, and several reports have described the features of EAS as opposed to CD (6, 7, 8, 9, 10). However, most of these studies included a relatively small number of patients with EAS, originating from different institutions with considerable variability in investigational protocols and assays (9, 10); only two large series have to date been published in detail (11, 12), both from the National Institutes of Health (NIH).
We have therefore analyzed the clinical, biochemical, and radiological features in all patients with EAS who presented with symptoms and signs of CS; the distinct feature of the present analysis is that all patients were investigated on the basis of an established investigational protocol, updated as novel diagnostic techniques became available, and were treated and followed up in the same unit, thus minimizing the effects that differences in data accrual, investigational and analytical methods, and therapeutic options might produce.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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All cases were drawn from those entered in the St. Bartholomew’s Hospital Cushing’s database in the years 1969–2001: 318 patients were classified as having ACTH-dependent CS; 274 had CD, and 44 had EAS. However, full records and a minimum follow-up of 2 yr were available for only 40 of the 44 patients with EAS. Patients with small-cell carcinomas (SCCs) were included in the analysis only when the major presenting complaints were related to symptoms and signs of CS. The study was approved as an institutional case-note review. Data on some of the included patients have been presented partially in previous publications (4, 13, 14, 15).
Diagnosis of CS
The diagnosis of CS was based on clinical features associated with hypercortisolemia, an elevated midnight sleeping cortisol level, and lack of suppression of serum cortisol after an oral 2-mg/d 48-h low-dose dexamethasone suppression test (2, 16). After the diagnosis of ACTH-dependent CS was made, the following tests were used to distinguish patients with EAS from patients with CD: 1) the high-dose dexamethasone suppression test (HDDST) (2 mg of dexamethasone every 6 h for 48 h) (15); 2) the human CRH test (two patients had ovine sequence CRH) and/or desmopressin test (13, 14); 3) bilateral inferior petrosal sinus sampling (BIPSS) with estimation of the ACTH ratio between the IPS and the periphery (IPS/P) before and after CRH stimulation, from 1984 onward (4); and 4) measurement of urinary 5-hydroxyindolacetic acid, urinary catecholamines, plasma calcitonin, fasting plasma gut peptides (gastrin, vasoactive intestinal peptide, pancreatic polypeptide, glucagon, somatostatin, and neurotensin), serum 
-fetoprotein, carcinoembryonic antigen, serum PTH, and serum ß-human chorionic gonadotropin (ß-HCG) (15).
Radiological investigation
All patients had a chest radiograph (CXR) performed. Imaging varied according to availability and advances in techniques; a computerized tomography (CT) scan of the chest and upper abdomen was used. Following the availability of magnetic resonance, imaging of the pituitary, abdomen, and/or the pelvis was also obtained. When the source of ACTH secretion was not evident after radiological investigation, whole-body venous catheterization and sampling (WBCS) was performed in attempt to localize the ectopic source (from 1970 onward) (16). From 1990 onward, whole-body radionuclide imaging, initially with 123I-meta-iodobenzylguanidine (123I-MIBG) (n = 6) and later with 111In-octreotide (n = 8), was also available. In patients in whom no source of the EAS was found on routine imaging, repeated diagnostic scans were performed every 6–12 months.
Preoperative management
Correction of the hypercortisolemia was attempted using adrenolytic medication. Patients with a diagnosis other than SCC were considered for surgical resection (n = 20), either curative or cytoreductive (17). To minimize surgical complications, control of the hypercortisolemia was always attempted preoperatively.
Definitive diagnosis of EAS and definition of overt, covert, and occult EAS
A confirmed diagnosis of EAS was made on the basis of histological confirmation on tissue obtained either from primary lesions or metastases during surgical removal or diagnostic biopsies or autopsy specimens (n = 35). In all patients, the diagnosis was further confirmed by positive ACTH immunoreactivity (n = 15) and/or complete/partial resolution of the hypercortisolemia after tumor removal/debulking (n = 19). One patient had repeated investigations over a period of 6 yr, which failed to locate an ectopic source, and she also failed to respond to total hypophysectomy. She died suddenly of pulmonary collapse, and a mesothelioma was found at autopsy, but ACTH immunohistochemistry was unavailable. In five patients, no tumor was ever found; however, long-term follow-up with repeated pituitary imaging and dynamic testing of the hypothalamic-pituitary-adrenal axis, including BIPSS, were highly suggestive of EAS, and these patients underwent bilateral adrenalectomy. None of these patients developed Nelson’s syndrome or a pituitary magnetic resonance imaging (MRI) abnormality (18). This patient group will now be defined as having occult ACTH secretion. All patients with confirmed tumor histology were divided into two groups: 1) patients presenting with hypercortisolemia with the tumoral source being detected after initial endocrine and radiological investigations were defined as having overt EAS (n = 26), and 2) patients presenting with hypercortisolemia in whom no tumor was detected at initial investigation but which became evident on subsequent evaluation were defined as having covert EAS (n = 9). These two groups were systematically compared.
Assays and investigations
All assay measurements and radiological investigations were performed at St. Bartholomew’s Hospital. The assays, techniques, and interpretations of the investigational procedures have been described previously (4, 13, 14, 15, 16, 19, 20).
Statistical analysis
In the differential diagnosis, the presence of EAS was considered to be a positive response (disease). This included the BIPSS, where a lack of a central gradient was taken as a positive response in terms of the diagnosis of EAS. Descriptive statistics are presented as median values accompanied by the 25th–75th percentile ranges, if not otherwise stated. Nonparametric tests were used for comparisons between groups. Correlation was estimated using Spearman’s rank correlation coefficients. Survival was analyzed using the Kaplan-Meier method. Significance was taken as P < 0.05. All analyses were carried out using Stata Statistical Software (Stata Corp., College Station, TX).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The majority of patients presented with classical signs and symptoms of CS (Table 2). Among the 40 patients, signs considered to be highly suggestive of CS such as proximal myopathy, thinning of the skin, and bruising were noticed in 62.5, 60, and 50% of patients, respectively (2). When the clinical features of patients with SCC were compared with those with other sources, major differences were found for the degree of hypokalemia (2.4 vs. 2.9 mmol/liter), skin pigmentation [six of nine (67%) vs. five of 26 (19%)], ankle edema [six of nine (67%) vs. 11 of 26 (27%)], and psychiatric disorders [two of nine (22%) vs. 17 of 26 (65%)]. Important differences were found in the rapidity of onset of symptoms and in time to diagnosis between SCC and the other sources (Table 2). When patients with overt and covert EAS were compared, no significant differences in clinical symptoms or signs, nor in hormonal or biochemical characteristics, were found (Table 2).
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In four patients, cortisol levels fluctuated markedly during follow-up, suggesting the presence of a cyclical CS (2).
Diagnosis of CS
All patients had 0900 h plasma ACTH levels (mean, 358.03 ng/liter; median, 164 ng/liter; 96.2–374.5 ng/liter) and serum cortisol [mean, 63.0 µg/dl; median, 47.5 µg/dl; 36.2–72.4 µg/dl (1739 and 1310 nmol/liter; 1000–2000 nmol/liter)] levels above the normal reference range; none showed a midnight cortisol less than 1.7 µg/dl (<50 nmol/liter) or suppression to the low-dose dexamethasone suppression test.
Differential diagnosis of CS
Overall, 32 patients underwent a HDDST; 29 of 32 (91%) showed no serum cortisol suppression after the HDDST, defined as a more than 50% suppression of the baseline value. Three patients with histologically proven EAS showed more than 50% cortisol suppression after the HDDST (sensitivity, 91%), but only one, according to our redefined criterion (20), of a more than 60% suppression (sensitivity, 97%). Data on the CRH stimulation test were available for 18 patients: 17 (94%) exhibited no cortisol or ACTH response (13, 21) after CRH administration; however, one patient with a bronchial carcinoid tumor demonstrated a cortisol rise from 20.6 µg/dl (568 nmol/liter) at baseline to a peak of 26.2 µg/dl (722 nmol/liter) at 45 min. The results on the combination of the diagnostic criteria on suppression and stimulation tests in the differential diagnosis of CS have been reported recently (20).
Tumor markers other than ACTH
The levels of one or more tumor markers were elevated in 22 patients with EAS. Plasma calcitonin was the most commonly elevated tumor marker observed in 11 patients (median, 1.14 µg/liter; 25th–75th, 0.31–24.5; reference range, <0.08 µg/liter), including two of three of patients with MTCs. Plasma gastrin was elevated in 11 patients, including seven with islet cell tumors. Urinary 5-hydroxyindoleacetic acid was elevated only in two of 20 patients with NETs not associated with a carcinoid syndrome. Plasma glucagon was elevated in three patients with islet cell tumors. Plasma somatostatin was elevated in two patients with MTC and SCLC. Other markers were only sporadically elevated.
BIPSS
Twelve patients underwent BIPSS, eight with associated CRH stimulation; 11 of 12 patients demonstrated a less than 2:1 (basal) or less than 3:1 (stimulated) central to peripheral ACTH gradient (actual < 1.8), whereas a single patient (with a mesothelioma) had a more than 3 gradient (basal, 2.8; and post-CRH, 13.1). The single patient who exhibited a positive response to peripheral CRH administration and who also suppressed by more than 60% during the HDDST (false-positive result) showed no significant basal or stimulated central to peripheral gradient. None of the patients with an undiagnosed source of ACTH secretion, occult EAS, showed a positive gradient on the BIPSS.
WBCS
Twenty-two patients in whom the diagnosis was still not evident after basic imaging underwent WBCS (16). This identified the source of EAS in four cases (two thymic carcinoids, one mediastinal lymph node, and one MTC). This test was performed in 11 patients in which the standard radiological investigations had failed to localize the source of ACTH and in a further 11 patients as confirmation of suspected lesions seen on imaging. Three of these four patients were investigated before the introduction of CT scanning, and one in 1983 when CT imaging was generally of very low resolution.
Radiological investigation
A variety of imaging procedures were performed in an attempt to localize the ACTH-producing tumor, and these varied over time as different imaging modalities became available (Fig. 1). A plain chest radiograph revealed the presence of a tumor in five of 12 patients with bronchial carcinoids and in five of seven patients with SCLC. CT scanning of the chest correctly identified the lesion in two of four patients with lung tumors, in two of two patients with MTC, and in 10 of 12 patients with bronchial carcinoid tumors; four of these patients had an 111In-octreotide scan that did not reveal any pathological uptake. Two of 12 patients with bronchial carcinoid tumors had an 123I-MIBG scan that did not reveal the primary in either but did reveal the presence of metastases (liver and eyes) in one patient.
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). The size of the other tumors is reported in Table 1
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Overall, 15 of 40 patients underwent MRI of the pituitary gland, but in no case did it show any clear evidence of an adenoma at presentation or follow-up.
Management and follow-up
To obtain rapid control of the hypercortisolemia in patients with SCCs, treatment was initiated with metyrapone and followed by ketoconazole and/or mitotane; control of hypercortisolemia was usually obtained within 2 wk. In total, 28 patients received steroidogenesis inhibitors for periods of 4 wk to 96 months (median, 9 months). One patient required iv treatment with etomidate to control the hypercortisolemia (22). In general, eucortisolism was obtained in all patients without any major adverse effects necessitating discontinuation of the treatment.
Curative surgery and tumor debulking were performed whenever possible. Overall, 12 patients had a single primary lesion and underwent an attempt at curative resection; 83% (10 of 12) of patients with NETs had a complete and 17% a partial remission of the hypercortisolemia and 50% recovered their pituitary-adrenal axis within 1 month, whereas the rest continued on replacement therapy for a median of 5 yr (range, 2–7 yr). Bilateral adrenalectomy was performed in 12 patients (nine of 12 disseminated, three of five occult) at an average of 39 ± 39 (mean ± SD) months from presentation. As additional therapy, 14 of 40 received external radiotherapy to the mediastinum and 11 of 40 patients received appropriate chemotherapy, whereas two patients with NETs received 131I-MIBG therapy.
At the last follow-up visit, 15 of 40 patients, all with NETs, were alive. Patients with aggressive tumors died of complications due to the tumor itself or as a consequence of previous excessive cortisol secretion (pancreatitis, peritonitis with perforation, opportunistic infection, cardiac failure). The median duration of follow-up was 60 months: 12 of 40 patients obtained complete remission, whereas two showed partial remission; both these patients are still alive. Figure 2 shows the survival curves for all patients. Survival analysis revealed that tumor histology and, in the subgroup of NETs, the presence of nonlymph node metastases, were the most important prognostic factors predicting overall survival (P < 0.05). In five of 40 patients, the tumor remained occult (two of these patients died at 13 and 45 months; no autopsy available), whereas the other three are still alive (72, 192, and 204 months of follow-up, respectively).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In our series, the lung still remains the major organ harboring an ectopic ACTH-secreting tumor (47.5%), with the majority of cases being bronchial carcinoid tumors (30%) followed by SCLCs (17.5%). Bronchial carcinoid tumors exhibit malignant potential and may share common histological features with SCLC, thus representing part of a tumor spectrum (23). We believe that control of the excess cortisol burden represents an important part of their management (11, 24, 25). We found that there is still a significant minority of patients (12.5% in our group) in whom the source of EAS cannot be found even after repeated evaluation and prolonged follow-up. However, this number is less than that reported in other series, probably reflecting the improvement in imaging modalities and prolonged follow-up (9, 10, 12). In such patients, a false-negative BIPSS remains a possibility; however, in two of five, pituitary exploration was performed, and no abnormality was found; the elevated tumor markers and the consistency of the other dynamic tests all pointed toward an ectopic source of ACTH (26).
The recorded clinical features of patients with EAS in this series were broad, resembling those found in patients with CD even in some patients with SCLC (9, 10). No major differences were found between patients with overt or covert EAS, suggesting that tumor mass does not necessarily predict the secretory characteristics of the tumor or the clinical features of the syndrome.
Although patients with the EAS tend to have higher ACTH levels than patients with CD, there is no clear distinction between these two entities (Table 2). We have also recently reported very high ACTH levels in a cohort of patients with pituitary macroadenomas, whose clinical and biochemical features to some extent mimicked those of the EAS (21). No statistically significant difference was found between patients with covert or overt EAS. These data are in contrast with previous publications showing some discriminatory value of baseline ACTH (9, 27) but are consistent with the recent large NIH series (12).
Several tests have been proposed to establish the differential diagnosis of CS. In this study, only 3.1 and 5.5% of patients with EAS obtained a response to the HDDST (using serum cortisol percentage change from baseline) and the CRH test, respectively. Thus, although each test on its own may be of relatively limited diagnostic accuracy, a lack of response to both tests has a very high, albeit not perfect, sensitivity for the diagnosis of EAS. A single patient showed responsivity to both tests but no BIPSS gradient, whereas a second single patient showed an apparent central gradient on BIPSS (false-negative) but absent responsivity to dynamic testing, although it still remains possible that despite all investigations, this patient with a mesothelioma had CD (however, total hypophysectomy had not been curative). Thus, although a false-negative BIPSS for EAS is rare, it does occur (26, 28). Our previously published analysis that included 209 patients with CD showed a 93–97% specificity for the various combinations of the two tests (20), confirming the high diagnostic accuracy of this approach. Indeed, we (20) and others before us (29, 30) found that most patients with CD who failed to respond to the CRH showed an adequate suppression to dexamethasone. Overall, these percentages are slightly higher than figures reported by others (7, 9, 12, 15, 31, 32, 33, 34, 35, 36, 37), we believe that at least in part reflect the higher reliability of the formal 2-d dexamethasone suppression tests for serum cortisol (rather than urinary steroids or the overnight test) (2) and the use of revised response criteria (20). Unfortunately, criteria defined in the referral centers often do not perform with the same accuracy when applied in nonspecialized centers and therefore should be interpreted with caution.
Modern cross-sectional imaging techniques revealed the primary lesion in most patients, and even when tumors were covert, repeated imaging was usually ultimately successful (Table 3). State-of-the-art multidetector CT allows the acquisition of eight, 16, or 24 slices in 1 sec. Our current protocol in this situation is to scan from the lung apices to the iliac crests in 2.5-mm intervals after iv injection of contrast medium. MRI was helpful in resolving equivocal CT findings or where the CT was negative and a high index of suspicion persisted for an ectopic source, particularly within the abdomen. MRI is of little value to identify small bronchial carcinoids, but it may be of value in imaging the mediastinum and thymic lesions. In the abdomen, we have found it to be as sensitive, and on occasion even more sensitive, than CT in identifying small pancreatic islet cell tumors. When scanning the pancreas, our own experience shows that a fat-suppressed gradient echo T1w sequence is the most helpful; in looking at the mediastinum, spin echo or gradient axial and coronal T1w and T2w sequences are usually required. In agreement with the recent large NIH series (12), both WBCS studies and 111In-octreotide scintigraphy were generally unhelpful.
After the localization of the lesion responsible for EAS, the optimal management is surgical excision; all these patients were treated with adrenolytic medication and, if necessary, bilateral adrenalectomy. Survival analysis revealed that the prognosis of patients with EAS is correlated with the tumor histology. Patients with SCC had the worst prognosis, whereas patients with other tumors, especially bronchial carcinoid tumors, often showed prolonged survival. Patients with an occult source of ACTH but adequate control of hypercortisolemia also had a good prognosis. The follow-up of the present study is probably the longest available on patients with EAS. Interestingly, tumor types and sizes, responses to biochemical tests, relapses, and survival rates are nearly identical with those reviewed by Ilias et al. (12) at the NIH, the largest published series, indicating a substantial continuity between the American and European series.
In summary, the findings of this study reveal that bronchial carcinoid tumors constitute the most common cause of the EAS mostly presenting with classical symptoms/signs of CS. Basal investigations exhibit a considerable overlap with those of CD, but BIPSS was only falsely suggestive of CD in a single patient with the EAS. Although in the past imaging modalities often failed to localize small carcinoid tumors, modern diagnostics in expert hands are highly accurate. Where the source defies optimal imaging, interval adrenolytic therapy with later reinvestigation is recommended.
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Footnotes |
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First Published Online November 22, 2005
Abbreviations: BIPSS, Bilateral inferior petrosal sinus sampling; CS, Cushing’s syndrome; CT, computerized tomography; CXR, chest radiograph; EAS, ectopic ACTH secretion; HDDST, high-dose dexamethasone suppression test; 123I-MIBG, 123I-meta-iodobenzylguanidine; MRI, magnetic resonance imaging; MTC, medullary carcinoma of the thyroid; NET, neuroendocrine tumor; SCC, small-cell carcinoma; SCLC, small-cell lung carcinoma; WBCS, whole-body venous catheterization and sampling.
Received July 12, 2005.
Accepted November 9, 2005.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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