Clinical Radiology (1993)48, 11-17
The Radiological Investigation of Occult Ectopic ACTH-Dependent Cushing's Syndrome J. M. VINCENT, P. J. T R A I N E R * , R. H. R E Z N E K t, A. J. M A R C U S t , J. E. D A C I E t , P. A R M S T R O N G and G. M. BESSER*
Departments of Academic Radiology, ~Radiology and *Endocrinology, St Bartholomew's Hospital, West Smithfield, London The radiological features of 14 patients with Cushing's syndrome due to 'occult' ectopic A C T H syndrome have been reviewed. In 11 of the 14 patients (79%), the ACTH-producing tumour was located in the thorax. Bronchial carcinoid tumours (eight patients) were the single most common source of 'occult' ectopic A C T H production with thymic carcinoid tumours (two patients) and mediastinal metastases from a medullary carcinoma of the thyroid gland (one patient) accounting for the other intrathoracic tumours. The tumours were usually small with five of the eight bronchial carcinoid tumours measuring between 4 and 10 mm in diameter. Since it remains difficult to distinguish between pituitary-dependent Cushing's disease and 'occult' ectopic ACTH-dependent Cushing's syndrome both clinically and biochemicaHy, the role of radiology remains vital. Vincent, J.M., Trainer, P.J., Reznek, R.H., Marcus, A.J., Dacie, J.E., Armstrong, P. & Besser, G.M. (1993). Clinical Radiology 48, 11-17. The Radiological Investigation of Occult Ectopic ACTH-Dependent Cushing's Syndrome
Accepted for Publication 15 March 1993
Spontaneous Cushing's syndrome is rare. It results from excess cortisol production secondary to A C T H hypersecretion in 80% of patients, or to an autonomous adrenocortical tumour in the remaining 20%. Pituitary adenomas account for 84% of cases of ACTH-dependent Cushing's syndrome (Cushing's disease), the remainder are due to ectopic A C T H secretion from a non-pituitary source [1]. Ectopic ACTH-dependent Cushing's syndrome is encountered in two forms. The classical overt ectopic A C T H syndrome may be clinically distinguished from Cushing's disease by a short history, lack o f clinical features of Cushing's syndrome, weight loss, severe myopathy, pigmentation and hypokalaemia [1,2]. A C T H levels are typically very high and in most cases the causative neoplasm is readily identified, almost always a small cell lung carcinoma. In contrast, it is now recognized that small 'occult' ectopic A C T H secreting tumours may present with a more chronic clinical picture identical to Cushing's syndrome resulting from a pituitary or adrenal adenoma. It may be very difficult to decide whether Cushing's disease is due to excess A C T H production from a pituitary turnout or whether it is due to occult ectopic A C T H production on biochemical or radiological grounds [1]. Even when the biochemical evidence strongly suggests the ectopic A C T H syndrome, the localization of the tumour may be very difficult. The radiological investigation of such patients with 'occult' ectopic A C T H production presents a major challenge. Occult ectopic A C T H secreting tumours are often small and their detection requires meticulous examination. Despite recent technological advances, including simultaneous bilateral inferior petrosal sinus sampling and the corticotrophin releasing hormone (CRH) stimulation test, the precise diagnosis remains Correspondence to: Dr Janette Vincent, Academic Department of Radiology, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE.
Table 1 - The aetiology of spontaneousCushing'ssyndromeseen at St Bartholomew'sHospital in 235 patients seen between 1969 and 1991
ACTH-dependent Pituitary Cushing's disease Ectopic ACTH 'overt' ectopic ACTH 'occult' ectopic ACTH Macronodular adrenal hyperplasia ACTH source uncertain ACTH-independent Adrenal adenoma Adrenal carcinoma
197 155 28 14 14 2 12 38 22 16
difficult [3-5]. The accurate localization of an ectopic source of A C T H production requires close collaboration between radiologist and endocrinologist. We present a review of patients with occult ectopic ACTH-dependent Cushing's syndrome with emphasis on the results of their radiological investigation.
P A T I E N T S AND M E T H O D S Two hundred and thirty-five patients presenting with Cushing's syndrome to the Department of Endocrinology at St Bartholomew's Hospital between 1969 and 1991 were reviewed (Table 1). The radiological examinations performed on the 14 patients with occult ectopic A C T H production were assessed. These studies included plain radiography, conventional tomography, CT scans, ultrasonograms, venous sampling and angiography. The age and sex of the patients, the duration of symptoms of Cushing's syndrome, the biochemical features and the delay in localization of the source of ectopic A C T H production were analysed (Table 2). Body CT was performed on 12 patients; three patients were examined prior to 1983 using an EMI 5005 scanner,
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CLINICAL RADIOLOGY
Table 2 - Patient details No.
1 2 3 4 5 6 7 8 9 I0 11 12 13 14
Age/ sex
42/M 26/F 49/F 17/F 56/F 37/F 72/F 54/F 36/M 42/F 43/M 75/F 34/M 55/M
History (months)
9 48 3 8 years 12 18 24 45 48 12 9 6 18 12
Delay in diagnosis (months)
Turnout site~histology
Size
Biochemical details
54 2 0.5 6 30 4 3* 55 3 18 1 6 5 10
Bronchial carcinoid 1.5 cm Bronchial carcinoid 0.4 cm (1 cm)t Bronchial carcinoid 1 cm Bronchial carcinoid 0.5 cm Bronchial carcinoid 2 cm Bronchial carcinoid 0.8 cm (1.5 cm)l" Bronchial carcinoid 1 cm Bronchial carcinoid Thymic carcinoid 4 • 3 cm Thymic carcinoid 3.5 cm Medullary ca thyroid Islet cell tumour, pancreas 1.5 cm Islet cell tumour, pancreas 3 cm Phaeochromocytoma 3 cm
Dexamethasone suppression test (high dose)
K+ (mmol/l)
Cortisol (nmol/l)
ACTH (pg/ml)
2.8 2.9 3.2~/ 2.0 2.4 2.5 2.3~/ 3.2 2.9 3.2
980 942 823 5400 300 1080 978 725 835 870
2.0 2.4 2.0
1500~ 2400 1540
165 69 244 37 515 141 92 121 230 82 185 25 134 123
Test terminated at 24 h + ----
Age stated in the table indicates the age at the time of diagnosis of Cushing's syndrome. * There was a 3 month delay in the localization of the adrenal metastasis. The primary bronchial carcinoid tumour was detected at the post-mortem examination. t The measurement in brackets refers to the size of the nodule demonstrated by CT. At pathologicalexamination the bronchial carcinoid tumour was enclosed within an abscess. $ Patient on K + losing diuretics at presentation. wCyclic Cushing's syndrome with variable levels of cortisol, at times within normal limits. Normal ranges: K + 3.5-5 mmol/kg, cortisol at 0900 h < 700 nmol/l, ACT~ 10-80 pg/ml. The results of the high dose dexamethasone suppression test are shown by' - ' indicating a failure to lower the levels of urinary and/or serum cortisol by more than 50% and ' + ' indicating suppression of the cortisol levels. In one patient the test was terminated at 24 h. eight p a t i e n t s were e x a m i n e d a f t e r 1983 using a G E 9800 scanner, a n d one p a t i e n t ( p a t i e n t 7) was e x a m i n e d o n b o t h C T scanners. C o n t i g u o u s i m a g e s using a section thickness o f 10 m m were p e r f o r m e d t h r o u g h the chest a n d a b d o m e n . A d d i t i o n a l thin-section images were perf o r m e d t h r o u g h suspicious a r e a s as required. I m a g e s d u r i n g c o n t r a s t e n h a n c e m e n t (100 ml i o d i n a t e d c o n t r a s t ) were o b t a i n e d t h r o u g h the p a n c r e a s a n d a d r e n a l glands a n d a n y o t h e r identified region o f a b n o r m a l i t y , such as the m e d i a s t i n u m o r hilum. T h e c o n t r a s t - e n h a n c e d images were o b t a i n e d by r a p i d sequential scanning with 5 m m table i n c r e m e n t a t i o n , starting after the injection o f 50 ml i n t r a v e n o u s c o n t r a s t m e d i u m a n d scanning was continued d u r i n g the injection o f a f u r t h e r 50 ml o f c o n t r a s t medium. U l t r a s o n o g r a p ' h y was p e r f o r m e d in six patients, with e x a m i n a t i o n o f the t h y r o i d g l a n d in three a n d a b d o m i n a l u l t r a s o n o g r a p h y in f o u r patients. A s the p e r i o d o f review spans m a n y years the e q u i p m e n t used varied; however, the recent e x a m i n a t i o n s were p e r f o r m e d o n a n . A l o k a S S D 680 u l t r a s o u n d machine. Systemic whole b o d y v e n o u s s a m p l i n g was p e r f o r m e d in 13 p a t i e n t s via the f e m o r a l vein u n d e r local anaesthetic. Measurement of ACTH and other appropriate tumour m a r k e r s was m a d e . In each p a t i e n t between 10 to 20 sites were s a m p l e d d e p e n d i n g on the clinical indication. A small a m o u n t o f c o n t r a s t m e d i u m was injected at each site to confirm the p o s i t i o n o f the c a t h e t e r tip before sampling. A C T H secretion f r o m b o t h p i t u i t a r y a n d ectopic sources is i n t e r m i t t e n t a n d pulsatile; therefore, simultaneous p e r i p h e r a l samples were o b t a i n e d with each central s a m p l e [6]. I n a d d i t i o n to systemic v e n o u s sampling, p r i o r to 1985, high internal j u g u l a r s a m p l e s were o b t a i n e d from eight patients with ectopic A C T H secreting t u m o u r s . Subsequently, three p a t i e n t s have u n d e r g o n e simultaneous bilateral inferior p e t r o s a l sinus. In one o f the three patients inferior p e t r o s a l sinus s a m p l e s were t a k e n before a n d after c o r t i c o t r o p h i n releasing h o r m o n e stimulation.
RESULTS (A) Patient Group
T h e ages o f the 14 p a t i e n t s (9 female a n d 5 male) at the time o f d i a g n o s i s o f C u s h i n g ' s s y n d r o m e r a n g e d f r o m 17 to 75 years. A l l p a t i e n t s presented with the signs a n d s y m p t o m s o f 'classical' C u s h i n g ' s s y n d r o m e . T h e d u r a t i o n o f these s y m p t o m s h a d varied f r o m 3 m o n t h s to 8 years. T h e interval between establishing the d i a g n o s i s o f C u s h i n g ' s s y n d r o m e a n d the localization o f the source o f e c t o p i c A C T H p r o d u c t i o n r a n g e d f r o m 0.5 to 54 m o n t h s (Table 2). H y p o k a l a e m i a ( p l a s m a p o t a s s i u m < 3.5 m m o l / 1) was p r e s e n t in all patients. T h e 9 a m cortisol level at p r e s e n t a t i o n r a n g e d f r o m 300 to 5400 nmol/1 (average 1471 nmol/1; n o r m a l < 700 nmol/1) a n d the A C T H level r a n g e d f r o m 25 to 515 ng/l (average 170 ng/1; n o r m a l 1080 ng/l). T h e high dose d e x a m e t h a s o n e s u p p r e s s i o n test (8 m g / d a y for 48 h) failed to lower the levels o f u r i n a r y a n d / o r s e r u m cortisol b y m o r e t h a n 50% in 13 o f the 14 p a t i e n t s tested. T h e high dose d e x a m e t h a s o n e suppression test resulted in s u p p r e s s i o n o f the levels o f u r i n a r y a n d s e r u m cortisol in one p a t i e n t ( p a t i e n t 8) l e a d i n g to a p r e s u m p t i v e b u t incorrect d i a g n o s i s o f C u s h i n g ' s disease ( T a b l e 2). I n all p a t i e n t s the ectopic source o f A C T H secretion was histologically p r o v e n , following surgical resection o f the t u m o u r (11 patients), b y u l t r a s o u n d - g u i d e d b i o p s y o f a liver m a s s with c o n f i r m a t i o n o f the p r i m a r y p a n c r e a t i c t u m o u r at s u b s e q u e n t a d r e n a l e c t o m y (one p a t i e n t ) , a n d at p o s t - m o r t e m e x a m i n a t i o n in two patients. (B) Source o f Eetopic A C T H Production and Method of Localization (a) Bronchial Carcinoid Tumours
A small b r o n c h i a l c a r c i n o i d t u m o u r was r e s p o n s i b l e for the i n a p p r o p r i a t e A C T H p r o d u c t i o n in seven female a n d one m a l e p a t i e n t (Figs 1, 2, 3). T h e t u m o u r was
OCCULT ECTOPIC ACTH-DEPENDENT CUSHING'S SYNDROME
Fig. 1 - C T scan demonstrating a 1 cm pulmonary nodule (arrow) in the right lower lobe in a 26-year-old female patient with Cushing's syndrome (patient 2). Pathological examination revealed a 4 m m bronchial carcinoid tumour enclosed by an abscess, accounting for the larger radiological abnormality.
Fig. 2 - C T scan using 5 m m sections showing a 5 n u n diameter pulmonary nodule (arrow) adjacent to a vessel in the right middle lobe in a 17-year-old female patient with Cushing's syndrome (patient 4). At surgery a small bronchial carcinoid t u m o u r was removed.
diagnosed 'following surgical resection o f the lung nodule in six and at post-mortem examination in two patients. In one o f the two patients diagnosed at post-mortem examination, a right hilar lymph node was infiltrated by metastatic carcinoid tumour which showed immunostaining for ACTH. Despite a careful examination of the lungs the primary lung tumour in this case could not be identified, presumably due to its extremely small size. At surgery the diameters of the tumours measured from 0.4 to 2.0 cm, five of the tumours measuring 1 cm or less. In two patients (patients 2 and 6) the tumour was enclosed within an abscess and therefore the radiological abnormality was larger than the tumour (Fig. 1). CT o f the chest was performed in seven of the eight patients. One patient presented prior to the introduction of CT (patient 1). The initial chest radiographs on this patient were normal, the nodule becoming visible on subsequent examination, 54 months after Cushing's syndrome was diagnosed. In four of the seven patients examined by CT, the chest radiograph was normal, even oh review, and the pulmonary nodules were identified only by CT (Figs I and 2). In one of these patients (patient 4) the initial CT scan performed with contiguous 10 mm sections failed to demonstrate the tumour. A subsequent
13
examination with contiguous 5 mm sections detected a tumour nodule less than 5 mm in diameter (Fig. 2). In a further patient (patient 6), the chest radiograph demonstrated a 1.5 cm nodule. CT o f the chest and abdomen was performed confirming the presence of a non-calcified pulmonary nodule and demonstrating diffusely enlarged adrenal glands with no evidence of an intra-abdominal tumour. Two patients (patients 7 and 8) were examined only using the EMI 5005 scanner which failed to identify the lung nodules. In both patients, the bronchial carcinoid tumour was not diagnosed until the post-mortem examination. In one of these patients repeated radiological examinations of the chest, including CT, demonstrated non-specific linear shadowing and poorly-defined opacities bilaterally, but failed to diagnose the primary bronchial carcinoid tumour. CT of the abdomen demonstrated diffuse bilateral adrenal enlargement with focal mass lesions, larger on the left than the right side. Systemic venous sampling showed marked elevation of the levels of A C T H in the adrenal veins and to a lesser extent in the azygos and thymic veins. Pathological examination of the adrenal glands following bilateral adrenalectomy revealed nodular hyperplasia with histological evidence of carcinoid metastases. Later in the course of her illness, a CT scan revealed multiple liver metastases. The presumed primary bronchial tumour measuring 1 cm was diagnosed at post-mortem examination. Further metastatic deposits involved the liver, pancreas, the first lumbar vertebra and pituitary gland. In the second patient, the EMI 5005 CT scan was normal. Systemic venous sampling on two occasions revealed elevated levels of A C T H in the thymic veins and conventional lateral tomography of the mediastinum demonstrated thymic enlargement. At thymectomy, the thymus was diffusely enlarged with no palpable nodule and histological examination failed to demonstrate a tumour. At post-mortem, 1 year later, malignant infiltration, which showed immunostaining for ACTH, was demonstrated in a hilar lymph node; however, the presumed primary bronchial carcinoid tumour was not found. Venous sampling was performed in seven of the eight patients with bronchial carcinoid tumours. In three patients no elevated levels of A C T H were demonstrated either from intrathoracic or intra-abdominal veins. In three patients, slightly elevated levels of A C T H were detected from disparate sites; however, these were not felt to be clinically significant. Although the venous sampling in these patients did not directly localize the source of A C T H production, the results made an extrathoracic source less likely. In the remaining patient (patient 8) elevated levels of A C T H in the thymic veins led to an incorrect presumptive diagnosis of thymic carcinoid tumour.
( b ) Thymic Carcinoid Tumours Thymic carcinoid tumours were diagnosed in two patients (patients 9 and 10) following surgical resection of the radiographically-demonstrated anterior mediastinal mass. Both patients were examined by chest radiographs, conventional tomography and venous sampling. Both patients presented prior to the introduction of CT; however, CT was performed on one of the two patients later in their series of investigations (Fig. 4). The initial chest radiographs and conventional tomography were
14
CLINICAL RADIOLOGY
(e)
(a)
(a)
(b)
(e) Fig. 3 - A 56-year-old female patient with Cushing's syndrome (patient 5). At surgery a 2 em bronchial carcinoid t u m o u r was removed. (a) Coned magnified view of the right lower zone from the C X R dated 12/12/88 which was reported to be normal. In retrospect a small nodule is visible adjacent to the right heart border (arrow). (b) Coned magnified view of the right lower zone from the C X R dated 3/12/90 which demonstrated a nodule adjacent to the right heart border (arrow). (c) Unenhanced C T soan dated 1988 through the nodule contiguous with the right heart border (arrow). (d) Contrastenhanced CT scan dated 1988 demonstrating enhancement of the pulmonary nodule (arrow). (e) Contrast-enhanced CT scan dated 1990 demonstrating increase in the size of the pulmonary nodule and increase in the extent of distal atelectasis seen anterior to the nodule (open arrow).
normal in both patients. Systemic venous sampling showed elevated levels of ACTH in the mediastinal veins of both patients, promptingrepeated radiographic examinations directed specifically at the anterior mediastinum.
(c) Medullary Carcinoma of the Thyroid Gland One patient (11) presented with Cushing's syndrome due to mediastinal lymph node metastases from a medullary carcinoma of the thyroid gland. The chest radiograph
OCCULT ECTOPIC ACTH-DEPENDENT CUSHING'S SYNDROME
15
revealed elevated levels of A C T H in the right adrenal vein. The mass proved to be an A C T H and calcitonin (but non-catecholamine) secreting phaeochromocytoma.
DISCUSSION
Fig. 4 - EMI 5005 CT scan demonstrated an anterior mediastinal mass (arrow), anterior to the main pulmonary artery, shown to be a thymic carcinoid tumour at surgery (patient 10).
was normal. The anterior mediastinal mass and several enlarged mediastinal lymph nodes were identified by chest CT. Selective venous sampling revealed evidence of secretion o f a bombesin-like peptide by the tumour which, acting as a corticotrophin releasing factor, led to pituitary A C T H excess [7].
(d) Intra-abdominal Turnouts Intra-abdominal tumours were identified in four patients (patients 12, 13, 14 and 7). Two patients (patients 12, 13) were shown to have islet cell tumours of the pancreas, one patient (patient 14) had a phaeochromocytoma of the right adrenal gland, and one (patient 7) had adrenal hyperplasia and histological evidence of carcinoid metastases from a primary bronchial carcinoid tumour diagnosed at post-mortem examination (see above). Abdominal CT and ultrasonography in one of the two patients with an islet cell tumour of the pancreas (patient 12), initially revealed a solitary 1.5 cm hyperechoic lesion in the left lobe of the liver (Fig. 5a) and a normal pancreas. Contrast-enhanced CT images through the liver lesion showed that the lesion enhanced (Fig. 5b, c) and the mass was initially thought to be a haemangioma. Subsequently a liver biopsy revealed malignant cells, consistent with a metastatic deposit from an islet cell tumour of the pancreas. Ultrasonography at the time of the biopsy demonstrated multiple hypoechoic and target lesions throughout the liver measuring up to 1.5 cm in diameter. In addition a 1.5 cm mass was shown in the pancreas (Fig. 5d) with a probable 1 cm lymph node in the coeliac region. The liver lesions were more difficult to visualize on the CT images and the pancreatic lesion could not be seen. At surgery the pancreatic mass and multiple liver metastases were confirmed. In the second patient (patient 13) abdominal ultrasonography, EMI scanning and selective coeliac axis angiography demonstrated a large pancreatic mass. Selective venous sampling from multiple sites was non-contributory. At surgery a large islet cell tumour of the pancreas wag resected. EMI CT performed on one patient (patient 14) demonstrated a large mass involving the right adrenal gland. Selective venous sampling performed after the scan
There are two major problems facing the endocrinologist with a patient who has Cushing's syndrome due to occult ectopic A C T H production. First, it can be difficult clinically and on biochemical testing to distinguish Cushing's syndrome due to occult ectopic A C T H production from pituitary-dependent Cushing's disease, in which the excess of A C T H production derives from a pituitary tumour [1,8]. The second problem is to determine the source of ectopic A C T H production. The precise demonstration of the cause of Cushing's syndrome remains difficult but vital, since when this is correctly established, 80% of patients with Cushing's disease can be cured by trans-sphenoidal hypophysectomy and the same number by complete excision of the occult tumour in the ectopic A C T H syndrome [9-12]. ACTH-secreting pituitary microadenomas are usually small, having an average diameter of 5 mm [13]. Computed tomography (CT) has been reported to have a 47% sensitivity in identifying ACTH-secreting pituitary adenomas compared to 77% for magnetic resonance [14]. However, as non-functioning adenomas have been identified at autopsy in 27% of unselected patients dying of non-endocrine diseases [15], potential exists for false positive interpretation of pituitary imaging and consequent inappropriate attempts at trans-sphenoidal hypophysectomy. The non-pituitary tumours causing occult ectopic Cushing's syndrome are also small and difficult to identify radiologically in many patients. Where an ectopic source is suspected or the results of all the biochemical investigation remain inconclusive, meticulous radiological examination of possible ectopic sites of A C T H production is required. The chest is the most common site of ectopic ACTH-producing tumours. In our series an intrathoracic source was present in 11 of the 14 patients (79%). We found bronchial neuroendocrine tumours o f the carcinoid type to be the single most common source of ectopic ACTH, responsible for Cushing's syndrome in eight of the 14 patients (57%), a higher percentage than demonstrated in previous series (42%) [8,16-20]. The tumours varied in size from 0.4 to 2 cm. Thus, bronchial carcinoid tumours responsible for Cushing's syndrome are usually small and their detection requires careful analysis of subtle abnormalities to allow the differentiation of a tumour from incidental pulmonary opacities and normal vascular structures. Because the lesions may be so small, the chest radiograph is often normal and computed tomography is required to demonstrate the offending tumour. In most patients contiguous 10 mm CT sections will demonstrate a bronchial carcinoid tumour responsible for the syndrome. Calcification was not identified in any of the bronchial carcinoid tumours in our series. Extensive calcification of bronchial carcinoid tumours has been reported but it is rare in tumours less than 2 cm in diameter [21]. Thin-section, high-resolution CT images performed before and after intravenous contrast administration, as in patient 5, may demonstrate marked enhancement of the nodule, which could prove valuable in differentiating bronchial carcinoid tumours, which are
16
CLINICAL RADIOLOGY
(a) (e)
(3)
(d)
Fig. 5 - A 75-year-old female patient with Cushing's syndrome resulting from the production of ACTH by an islet cell tumour of the pancreas with multiple liver metastases (patient 12). (a) Longitudinal scan through the left lobe of the liver dated 1988 demonstrating a solitary 1.5 cm hyperechoic lesion (arrow). The pancreas appeared normal. (b, c) Corresponding CT scans through the liver lesion performed before (b) and after (r intravenous contrast demonstratingenhancement of the livernodule (arrow). The pancreas appeared normal. (d) Axial ultrasound imagedated 1989demonstrating a 1.5 cm hypoechoic nodule in the body of the pancreas (arrow). usually vascular, from benign lesions, such as hamartoma, granulomas and tuberculosis, which demonstrate little contrast enhancement [22]. D o p p m a n et al. [23] compared magnetic resonance (MR) imaging with CT in the detection of A C T H - p r o d u c i n g bronchial carcinoid tumours. In six patients the lesions were identified by both CT and MR. In four patients the lesions were shown by M R and were visible on the C T images only in retrosPect in two of these patients. M R was not performed on any patients with bronchial carcinoid tumours in our series. A coexistent calcified lesion, subsequently shown to be active tuberculosis, was identified in one patient (patient 3) and incidental non-specific pulmonary opacities were present on chest radiographs and/or CT in five patients which could have been mistakenly diagnosed as a source for the ectopic A C T H production. Thymic carcinoid tumours were the next most frequent intrathoracic source of ectopic A C T H in our series. Although the chest radiograph may demonstrate an abnormal mediastinal contour in patients with thymic tumours, in both patients chest radiography and conventional tomography were initially normal. CT is able to identify small lesions which do not distort the mediastinal contour and allows delineation o f normal vascular structures [24]. One patient (patient 11) with an intrathoracic source of A C T H secretion was shown to have a mediastinal mass caused by mediastinal metastases from a
medullary carcinoma of the thyroid gland. This tumour has previously been identified as a cause ofectopic A C T H production in approximately 3% of patients with occult ectopic A C T H production [8,16-20]. Abdominal ultrasonography and CT should be performed with particular attention to the pancreas and adrenal glands as possible sites of the primary t u m o u r and the liver for evidence of metastatic disease. The CT examination should include images following rapid injection of intravenous contrast with 5 m m or 10 m m contiguous images, depending on the region to be included in the examination. Pancreatic islet cell tumours are often small and highly vascular. The t u m o u r m a y not distort the margins of the pancreas a n d m a y only be identified as an area of increased contrast enhancement compared with the adjacent gland. Nodules within the adrenal glands may be confusing. Phaeochromocytoma (one of the 14 patients in our series) is an unusual cause of ectopic A C T H production but if suspected, adrenergic blocking agents should be used prior to intravenous contrast administration [25]. Nodular hyperplasia of the adrenal glands typically causes more marked enlargement of the gland in patients with ectopic ACTH-dependent Cushing's syndrome than in patients with Cushing's disease [16,26,27]. The nodules can reach up to 4-5 cm in size and simulate an adenoma but usually the rest of the adrenal gland appears hyper-
OCCULT ECTOPIC ACTH-DEPENDENTCUSHING'S SYNDROME plastic. Also, focal n o d u l e s do n o t usually display the p o s t - c o n t r a s t e n h a n c e m e n t p a t t e r n seen in p h a e o c h r o m o c y t o m a . Metastases from a m a l i g n a n t carcinoid t u m o u r c a n lead to diagnostic c o n f u s i o n (as in p a t i e n t 7), especially if a small lung lesion c a n n o t be identified. Systemic v e n o u s sampling for levels of A C T H did n o t localize the source of A C T H p r o d u c t i o n in a n y o f the patients with p r i m a r y b r o n c h i a l carcinoid t u m o u r s , F i n dling e t aL [28] reported the presence o f a n a r t e r i o - v e n o u s A C T H g r a d i e n t in a p a t i e n t with ectopic A C T H p r o d u c tion due to a bronchial carcinoid t u m o u r ; however, arterial s a m p l i n g for A C T H is n o t routinely p e r f o r m e d a n d was n o t performed in a n y of o u r cases. A l t h o u g h systemic v e n o u s s a m p l i n g was p e r f o r m e d in 13 patients, it d e m o n s t r a t e d the source in only four patients; patients 9 a n d 10 with thymic carcinoid t u m o u r s , p a t i e n t 11 with mediastinal metastases from a m e d u l l a r y c a r c i n o m a o f the thyroid gland, a n d p a t i e n t 14 with a n a d r e n a l p h a e o c h r o m o c y t o m a . Even t h o u g h it failed to show the source in the other patients it was still helpful. I n the patients s h o w n to have small i n t r a p u l m o n ary lesions o n C T or c o n v e n t i o n a l r a d i o g r a p h y , a negative systemic sampling, which did n o t sample the p u l m o n ary circulation, focused further a t t e n t i o n o n the small p u l m o n a r y lesions as a potential cause. S i m u l t a n e o u s bilateral inferior petrosal sinus sampling for A C T H , with c o r t i c o t r o p h i n releasing h o r m o n e ( C R H ) s t i m u l a t i o n , is usually reserved for patients t h o u g h t to have pituitaryd e p e n d e n t C u s h i n g ' s Disease. However, it was performed in three o f o u r occult ectopic A C T H s y n d r o m e patients. I n all patients, the levels of A C T H were n o t raised in the inferior petrosal sinus, i n c l u d i n g samples following C R H s t i m u l a t i o n in two patients.
CONCLUSION I n our series, 79% of t u m o u r s responsible for the occult ectopic A C T H s y n d r o m e were located in the chest. O f these, the m a j o r i t y were due to small b r o n c h i a l carcinoid t u m o u r s which are either n o t visible or are easily overlooked~ o n chest radiographs a n d m a y even be difficult to detect with CT. Other potential sources of A C T H in the a b d o m e n such as small islet cell t u m o u r s o f the pancreas a n d p h a e o c h r o m o c y t o m a m a y also be responsible, a n d the radiological investigation needs to include these regions. Meticulous radiographic technique, frequently c o m b i n i n g a n u m b e r o f imaging m o d a lities is vital to avoid overlooking significant b u t subtle a b n o r m a l i t i e s or conversely overinterpreting i n n o c e n t incidental findings. It is often necessary to repeat the radiological e x a m i n a t i o n s at regular intervals if the findings are n o r m a l or non-specific. The results m u s t be assessed in the context o f the clinical a n d biochemical features with careful c o n s u l t a t i o n between the radiologist a n d endocrinologist.
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