Q J Med 1999; 92: 335-340
© 1999 Association of Physicians
Is whole-lung CT scanning still necessary in all cases of ACTH-dependent Cushing's syndrome in the era of petrosal sinus sampling?
From the Sir George E. Clark Metabolic Unit, 1 Department of Radiology, and 2 Regional Endocrine Laboratory, Royal Victoria Hospital, Belfast, UK
Received 1 July 1998 and in revised form 8 April 1999
Professor A.B. Atkinson, Sir George E. Clark Metabolic Unit, Royal Victoria Hospital, Belfast BT12 6BA
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Summary |
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We reviewed 31 patients in whom both bilateral inferior petrosal sinus sampling without CRH stimulation, and a CT scan of the lungs were done. Twenty-five had normal lung CT scans, of whom 23 had a higher inferior petrosal sinus : peripheral ACTH ratio
1.5. After careful follow-up, none was subsequently shown to have ectopic ACTH syndrome. Six had abnormal lung CT scans, of whom two had ratios 1.5. In these two patients, other investigations suggested pituitary disease, and pituitary surgery led to apparent cure. Of the remaining four patients, who had ratios <1.5, two had incidental lung findings, and pituitary abnormalities were demonstrated at pituitary surgery. The third underwent bilateral adrenalectomy, and no evidence of ectopic ACTH syndrome has emerged as yet after 4 years follow-up. The fourth had a small-cell carcinoma of the lung, confirmed histologically. Our series suggests that whole-lung CT scanning is only necessary in cases of ACTH-dependent Cushing's syndrome where bilateral inferior petrosal sinus sampling has not demonstrated a significant increase in petrosal sinus ACTH levels as compared with the peripheral level. Thus, in our experience the test is now only necessary in those patients (approximately 25%) where the ratio is 
1.5. |
Introduction |
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The differential diagnosis of ACTH-dependent Cushing's syndrome is difficult. Clinically, pituitary-dependent and ectopic ACTH syndromes may be indistinguishable, and discrimination using traditional tests such as dexamethasone suppression and metyrapone testing is often inconclusive. Some patients with ectopic ACTH syndrome respond to dexamethasone and metyrapone, while others with pituitary-dependent Cushing's syndrome do not.1–6 High-resolution CT scanning of the pituitary demonstrates abnormalities in <60% of patients with definite Cushing's disease,3,7,8 and although MRI scanning is a little more sensitive,3,9 the presence of an adenoma does not confirm the source of abnormal ACTH secretion, as incidental pituitary adenomas have been identified in 2.7–27% of the general population.10,11
Because of these diagnostic difficulties, and because more than half of tumours responsible for the ectopic ACTH syndrome are located in the thorax,12,13 with CT scanning of the thorax being helpful in their localization,13–15 it has been our practice to perform whole-lung CT scanning on all patients with ACTH-dependent Cushing's syndrome.
More recently, the usefulness of bilateral inferior petrosal sinus sampling and measurement of plasma ACTH in the differential diagnosis of ACTH-dependent Cushing's syndrome has been highlighted,16–21 and we have previously reported our own early experience.22 With the availability of this latter test, we have reviewed our experience of both tests in an attempt to determine whether it is still necessary to perform whole-lung CT scanning in every case of ACTH-dependent Cushing's syndrome. We present the results of 31 patients with ACTH-dependent Cushing's syndrome who underwent both bilateral inferior petrosal sinus sampling and CT scanning of the thorax.
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Methods |
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Thirty-one patients with ACTH-dependent Cushing's syndrome were studied between April 1984 and June 1992. There were 25 female and six male patients, with a mean age of 42.2 years at the time of presentation. All patients had symptoms and signs suggestive of hypercortisolism. The diagnosis of Cushing's syndrome was made after demonstrating increased 24-h urinary free cortisol production and lack of suppression of serum cortisol response following low-dose dexamethasone.23 All patients underwent bilateral inferior petrosal sinus sampling and CT scanning of the thorax. The technique used for petrosal sinus sampling has been reported previously.22 In this series, CRH stimulation was not used routinely (see Discussion). Plasma ACTH (pg/ml) was estimated by radioimmunoassay.24 All 31 patients gave informed verbal consent prior to the sampling procedure.
CT scanning of the thorax was performed using a standard 10 mm incremental scan. More recently, spiral CT has been used (5 mm slice, 8 mm/s—table speed 137 kV). These are reformatted initially at standard algorithm and 10 mm contiguous slice, but can be reformatted at final sections and on high-resolution algorithm in any area of potential abnormality.
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Results |
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Bilateral simultaneous catheterization with sampling of blood from the inferior petrosal sinus was successful in 25 patients. In six others, unilateral samples were obtained, and the petrosal sinus to peripheral ACTH ratio was
1.5 in four of the six. The ACTH levels for the left and right inferior petrosal sinuses, the inferior petrosal sinus to peripheral ACTH ratio (calculated using the higher of the two inferior petrosal sinus ACTH measurements and the peripheral ACTH value), the results of CT scan of the thorax and the duration of follow-up are outlined in Table 1
. There was no morbidity following petrosal sinus sampling.
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Patients with a higher inferior petrosal sinus to peripheral ACTH level ratio
1.5 (n=25)In 23 patients (patients 1–23, Table 1
) the higher of the two inferior petrosal sinus values : peripheral ACTH level (IPS : PER) ratio was 1.5 and the CT scan of thorax was normal. In 18 of these patients, cortisol fell markedly post-operatively. Five (patients 5, 14, 15, 16, 19) were not cured after pituitary surgery. Four of the five underwent further procedures, a fifth (patient 19) having died from an unrelated cause prior to further treatment. No evidence of ectopic ACTH production has emerged in any of the remaining 22 patients after a mean follow-up of 4.3 years.
Two others (patients 24 and 25, Table 1) had both an IPS : PER ratio greater than 1.5 and an abnormal CT scan of thorax. In one (patient 24) the higher IPS : PER ratio was 8.6 and CT scan showed a small opacity anterior to the left hilum which radiologically was felt to be vascular in origin. In other respects, this patient behaved as a classical case of pituitary-dependent Cushing's syndrome, with suppression of plasma cortisol following high-dose dexamethasone administration and an increment in plasma cortisol of 219% after intravenous corticotrophin-releasing hormone. Based on all of these findings, a decision to proceed to pituitary surgery was made, and after this there was remission of hypercortisolism. No evidence of ectopic ACTH production has emerged in this patient after 2 years follow-up. In the second case (patient 25) CT scan of thorax showed a 3 cm anterior mediastinal mass consistent with a thymoma. A unilateral petrosal sinus sample demonstrated an increase in the ACTH level there with an IPS : PER ratio of 2.9. ACTH levels measured in the proximal, mid and distal brachiocephalic vein, which receives the venous drainage from the anterior mediastinum, were similar to peripheral values. CT scanning of the pituitary suggested a mass lesion, and 0800 h serum cortisol suppressed from 435 to 76 nmol/l after eight doses of 2 mg dexamthasone over 48 h. A decision to proceed to pituitary surgery was made. At surgery, a pituitary adenoma was identified and removed, and hypercortisolism has not recurred. The histology finding of an adenoma was strong evidence against the diagnostic possibility of ectopic CRF production by a thymoma, which was actively considered prior to pituitary surgery.
Patients with a higher inferior petrosal sinus to peripheral ACTH ratio <1.5 (n=6)
Six patients (patients 26–31, Table 1) had IPS : PER ratios <1.5. Two (patients 26 and 27) had a normal CT scan of the lungs. The first (patient 26) had an IPS : PER ratio of 1.3 and the second an IPS : PER ratio of 1.1. Both patients had bilateral adrenalectomy, in patient 26 after unsuccessful pituitary surgery (advised, early in our experience of petrosal sinus sampling, on the basis of suppression after high-dose dexamethasone and demonstration of a lucent defect on CT scan of pituitary) and in patient 27 as a primary treatment. No evidence of ectopic ACTH has emerged in either patient after 8 and 7 years, respectively, of careful clinical follow-up.
Four (patients 28, 29, 30, 31) had IPS : PER ratios <1.5 and abnormal CT scans of thorax. In patient 28, the IPS : PER ratio was 0.92, and CT scan of the lungs showed mediastinal lipomatosis with no evidence of tumour. There was a brisk response to CRH (increment 154%) and full suppression with high-dose dexamethasone (0800 h serum cortisol falling from 317 to 85 nmol/l). Based on this evidence, pituitary surgery was advised. In patient 29, the IPS : PER ratio was 1.0, and CT scan showed a pleural shadow. However, previous pituitary surgery prior to her referral to our unit had demonstrated a pituitary adenoma but had failed to cure hypercortisolism. Repeat pituitary surgery was advised. Both patients had basophil adenomas confirmed histologically. No evidence of ectopic ACTH production has emerged in either after 3 and 9 years follow-up, respectively. In patient 30, CT scan of the thorax showed a healed granuloma, and the IPS : PER ratio was 1.1. Both adrenal glands were abnormal on CT scan, and ACTH was measurable at 29 ng/l. Following dexamethasone (2 mg six-hourly for 48 h), serum cortisol suppressed from 510 mmol/l to 205 nmol/l. The diagnosis was considered in keeping with bilateral adrenal nodular hyperplasia. Bilateral adrenalectomy was performed, and histology confirmed this diagnosis. No evidence of ectopic ACTH production has emerged after 4 years of follow-up.
Finally, in patient 31, ACTH levels in the one inferior petrosal sinus sampled were markedly elevated, but peripheral ACTH values were higher, with a ratio of 0.6. Chest X-ray showed a raised hemidiaphragm. CT scan of the lungs showed mediastinal lymphadenopathy and a raised left hemidiaphragm. Subsequent bronchoscopy and biopsy confirmed a small-cell carcinoma of the lung. Treatment with both ketoconazole and metyrapone caused suppression of serum cortisol, but despite treatment with cyclophosphamide and radiotherapy, the patient died 14 months after presentation.
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Discussion |
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Transsphenoidal microsurgery has made it possible to cure hypercortisolism due to a pituitary adenoma with preservation of pituitary adrenal function in the majority of patients.25–31 Therefore precise identification of the source of ACTH production is necessary in order to ensure a correct treatment choice in patients with ACTH-dependent Cushing's syndrome. Indeed, a number of cases where pituitary surgery had failed to cure the patient have subsequently been shown to be due to occult ectopic ACTH secretion.12,27,32
In this series of 31 patients, 25 had IPS : PER ratios 1.5. Two of these had abnormal CT scans of thorax showing a vascular opacity in one and a thymoma in the other. After further investigation (see Results), pituitary surgery was undertaken in both and hypercortisolism was cured. None of the 25 subjects has subsequently developed evidence of ectopic ACTH production after a mean follow-up of 4.5 years.
The remaining six patients had ratios <1.5. Of these, four had abnormalities on CT scan of their lungs. Careful investigation of the four patients led to correct identification of the source of ACTH. One had a small-cell carcinoma of lung, and was the one patient in the series with proven ectopic ACTH syndrome. The lymphadenopathy seen on CT scan was not apparent on routine chest X-ray.
The yield of ectopic ACTH syndrome in this series was one of 31 patients, and one of six where the petrosal sinus ratio was 1.5 or less. We stress again that although we quote ratios, we have previously emphasized the absolute need to study most carefully the actual levels of ACTH (Table 1), in order to ensure that any calculated ratio is meaningful in terms of the assay used. We have not routinely used CRH during petrosal sinus sampling as some have advocated.19,20,33 However, some of our non-significant ratios might have become significant if this technique had been used routinely, and as our experience of the usefulness of sampling has grown, we have become less likely to advocate pituitary sampling when a meaningful step up has not been established. We also point out that other groups use 2.0 rather than 1.5 as the basal ratio required to establish a step up. This would reduce to 20 from 25 the number in our series with a positive ratio.
In other centres, referral patterns may differ and the incident of ectopic ACTH syndrome may be greater. The previous literature has convincingly shown the value of whole-lung CT scanning in ACTH-dependent Cushing's syndrome.13,14 Our series where 25 patients with a distinct inferior petrosal sinus gradient have been followed-up for a prolonged period without evidence of any occult ectopic source emerging, strongly suggests that it is now reasonable to perform whole-lung CT scanning only in patients where there is not a significantly increased inferior petrosal ACTH level. Our experience suggests that it will still be needed in approximately 25% of patients if an unstimulated ratio of 1.5 is used as the cut-off, or 35% if a value of 2.0 is applied. The percentage may be smaller if routine CRH stimulation is used at the time of petrosal sinus sampling. Because of the high incidence of negative CT and MR pituitary scans and the significant numbers of positive scans in the normal population (for review see Elster34) we do not advise pituitary surgery on the basis of abnormal scanning unless the lesion is large, a relatively uncommon finding in Cushing's syndrome. Orth35 has recently reviewed the literature on the various high-dose dexamethasone tests. If these tests are used, then more stringent criteria than previously used should be applied, and we agree that none of them will correctly characterize every patient with ACTH-dependent Cushing's syndrome. Another indirect non-invasive test is the CRH test with measurement of peripheral serum cortisol levels. Our own experience of this test is that approximately one third of cases do not meet a stringent response criterion of >50% serum cortisol rise (Atkinson AB unpublished observations). Hence, for the present, we prefer to establish directly whether there is a step up in ACTH at the petrosal sinus level.
It might be argued that one should continue to perform CT scans of the chest and only perform inferior petrosal sinus sampling, an invasive procedure, if other anomalous test results are obtained. Against this argument are: (a) the radiation doses used in scanning; (b) the tolerability, safety and low incidence of side-effects of petrosal sinus sampling when the operator is skilled and experienced;16,18–22,35 (c) the fact that whole-lung CT scanning will fail to localize a considerable percentage of cases of ectopic ACTH syndrome;13,14 and (d) the fact that in most series pituitary-dependent hypercortisolism is the most common cause, and petrosal sinus sampling often yields conclusive evidence that the pituitary is the cause of the syndrome.
We conclude that CT scanning of the lung is now only necessary in cases of ACTH-dependent Cushing's syndrome where bilateral inferior petrosal sinus sampling does not demonstrate a significant gradient in ACTH in either sinus as compared with the peripheral value.
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Acknowledgments |
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We wish to thank the nursing staff of the Metabolic and Endocrine Surgery Units, Royal Victoria Hospital. We are particularly grateful for the assistance of our neurosurgical colleagues, Mr T. Fannin, Mr D.S. Gordon and Mr J. Gray. We thank Mrs Marie Loughran for preparing the manuscript. Dr A. Heaney was in receipt of a Research Fellowship for the Royal Victoria Hospital, Belfast.
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References |
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