European Journal of Endocrinology (2005) 152 521–525 ISSN 0804-4643

CASE REPORT 18 18 [ F]fluoro-2-deoxy-D-glucose ([ F]FDG) positron emission tomography imaging of thymic carcinoid tumor presenting with recurrent Cushing’s syndrome Athina Markou, Patrick Manning, Banu Kaya, Sam N Datta, Jamshed B Bomanji1 and Gerard S Conway Departments of Endocrinology and 1Nuclear Medicine, Middlesex Hospital, Mortimer Street, London W1T 3AA, UK (Correspondence should be addressed to G Conway; Email: [email protected])

Abstract We report a case of a young woman with Cushing’s syndrome (CS), in whom although endocrine investigations and negative pituitary imaging were suggestive of ectopic ACTH secretion, the results of inferior petrosal sinus (IPS) sampling after coricotropin-releasing hormone (CRH) stimulation were suggestive of pituitary ACTH hypersecretion. 111In-labelled octreotide and high-resolution computer tomography (CT) revealed a lesion possibly responsible for the ACTH source in the . Thymect- omy confirmed concomitant ectopic CRH and probable ACTH production by a thymic neuroendocrine carcinoma. After an 8-year remission period the patient developed a clinical and biochemical relapse. A high-resolution computed tomography (CT) scan of the thorax showed a 2-cm nodule in the thymic 18 18 bed, which was positive on a [ F]fluoro-2-deoxy-D-glucose ([ F]FDG) positron emission tomography (PET) scan. However, a repeated thymectomy did not result in remission. A repeat [18F]FDG PET study showed persistent disease in the thymic bed and also uptake in the adrenals. The patient underwent bilateral , which resulted in clinical remission. A further [18F]FDG PET scan 8 months later showed no progression of the thymic tumor and confirmed complete excision of the adrenals. This is a rare case of concomitant CRH and ACTH secretion from a thymic carcinoid tumor; the case illustrates the usefulness of functional imaging with [18F]FDG PET in the diagnosis, management and follow-up of neuroendocrine tumors.

European Journal of Endocrinology 152 521–525

Case report sampling after corticotropin-releasing hormone (CRH) stimulation, however, was more in keeping with Cush- A 25-year-old woman initially presented with recent- ing’s disease than with ectopic ACTH production as it onset depression, hirsuitism, acne and bruising sugges- showed a brisk ACTH increment following CRH admin- tive of Cushing’s syndrome (CS); clinical examination istration (Table 1); a pituitary magnetic resonance ima- revealed arterial hypertension (170/120 mmHg) and ging (MRI) scan was normal. An initial computed mild proximal myopathy. Subsequent investigations tomography (CT) scan of the thorax was normal but þ 111 1 showed hypokalemic alkalosis (serum K , 2.3 mmol/l scintigraphy with octreotide In-[D-Phe ]-DTPA- 111 (normal range 3.5–5.0 mmol/l); HCO3, 32 mmol/l octreotide ( In-pentetreotide, Mallinckrodt Medical, (normal levels 24^2 mmol/l)), marked hyperandrog- St. Louis, MO, USA) showed tracer activity in the enemia (testosterone, 12.5 nmol/l (normal range thymus (Fig. 1A). A further high-resolution CT 0.5–2.5 nmol/l)), normal fasting glucose concen- showed a 2-cm thymic nodule in the upper mediasti- trations and autonomous hypercortisolemia (elevated num. Whole-body catheterization and sampling did 24-h urinary free cortisol (UFC) of 4064 nmol per not reveal an ectopic ACTH source. However, a greater 24 h (normal range 20–300 nmol per 24 h), serum than 3:1 CRH gradient suggestive of ectopic CRH pro- midnight cortisol of 1161 nmol/l and inadequate corti- duction between the left brachiocephalic vein (BCV) sol suppression to a formal low-dose dexamethasone and superior vena cava (SVC) and their simultaneous suppression test). peripheral samples (BCV, 90 pg/ml and SVC, An ectopic source of adrenocorticotropic hormone 100 pg/ml vs 30 pg/ml respectively) was shown. (ACTH) secretion was suggested by a marked elevated Based on the above findings a working diagnosis of a plasma ACTH concentration (1350 ng/l (normal neuroendpcrine tumor of the thymus (thymic carcinoid values ,25 ng/l)), and a failure to suppress serum tumor) secreting CRH was made. cortisol following a high-dose dexamethasone The patient underwent a mediastinotomy and thy- suppression test (HDDST). Inferior petrosal sinus (IPS) mectomy. A central firm nodule within the thymus

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Table 1 Inferior petrosal sinus (IPS) sampling with CRH neuroendocrine tumor manifested as CS; it identifies stimulation. the usefulness of radionuclear methods in identifying the ectopic source. Although the presenting clinical pic- ACTH (ng/l) ture, biochemical findings and negative pituitary ima- Time (min) Left IPS Right IPS Peripheral ging were suggestive of ectopic ACTH hypersecretion, this was not substantiated by the results of IPS after 0 479 1110 364 3 1500 1960 434 CRH stimulation, which were indicative of pituitary 8 990 1900 490 ACTH hypersecretion. Subsequent investigation using 15 526 1760 498 111In-labelled octreotide initially revealed the original ectopic source of ACTH secretion while imaging with PET revealed the presence of recurrent disease thus was totally excised. Histopathology revealed a well-dif- directing to the appropriate treatment. Therefore, the ferentiated neuroendocrine carcinoma with tumor possibility of aberrant hormonal secretion from neuro- invasion into the lymphatic lumina, which stained posi- endocrine tumors should always be considered, par- tively for neuron-specific enolase (NSE), chromogranin ticularly when there are confounding biochemical A and synaptophysin, ACTH and CRH. The patient 111 results; in such cases the application of thin-section made an uneventful recovery and a repeat In-pente- and spiral CT of the chest should be used as a first treotide scan 2 weeks later showed no tracer uptake in line of investigation. If this proves negative, or in the mediastinum. cases with small ambiguous lesions where there is a Following a prolonged remission the patient presented need for confirming their neuroendocrine origin, func- 8 years later with depression and typical features of CS, tional imaging (i.e.111In-labelled octreotide and/or suggestive of disease relapse. Further investigations PET) can be extremely helpful in establishing the cor- revealed a plasma potassium concentration of rect diagnosis (1). 3.6 mmol/l, serum testosterone of 6.8 nmol/l and a 24-h 111 IPS sampling has been claimed to exert an almost UFC of 32 078 nmol per 24 h. Imaging with In-pente- 100% sensitivity and specificity in establishing the treotide was negative whereas a high-resolution CT scan source of ACTH hypersecretion in cases of ACTH- of the mediastinum showed a possible 2-cm nodule in the dependent CS (2–5). In our case, although the results thymic bed. Positron emission tomography (PET) using 18 18 obtained from the other investigations were consistent [ F]fluoro-2-deoxy-D-glucose ([ F]FDG) showed with ectopic ACTH CS, IPS revealed a central-to-periph- increased tracer uptake in the pre-aortic region, imply- eral ACTH gradient of .3 after CRH stimulation, con- ing a metabolically active lesion and prominent uptake sistent with Cushing’s disease (2). As these results were of tracer by the adrenals (Fig. 1B and C). originally conflicting we investigated the possibility of Following a repeated thoracotomy, the histology of the presence of a factor that could de-suppress the pitu- the remaining tumor showed relatively monomorphous itary corticotrophs such as CRH, by exerting a stimulat- cells with round nuclei, eosinophilic cytoplasm and ing effect. Ectopic CRH secretion, although very rare, prominent nucleoli, mitotic figs. and areas of necrosis. has been very well described before and it is a well- Both vascular and lymphatic invasion was seen. Immu- established pitfall of IPS when used for the differential nohistochemistry was positive for chromogranin A, diagnosis of ACTH-dependent CS (6–9). This suspicion synaptophysin, ACTH and cytokeratin but not CRH. was reinforced further when imaging with 111In- Post-operatively, there was little clinical improvement labelled octreotide revealed a possible neuroendocrine and serum cortisol levels remained elevated. A repeat 18 tumor in the anterior mediastinum, which was con- [ F]FDG PET study showed two small glucose avid firmed on subsequent CT imaging. Following whole- areas of uptake adjacent to the thymic bed and persist- body catheterization and sampling, a CRH gradient ent avid uptake by the adrenals (standardized uptake between the left BCV and SVC and their simultaneous values of 5.9 for left and 6.1 for right adrenal). Further peripheral samples (BCV, 90 pg/ml and SVC, thoracic surgery was not thought possible and the 100 pg/ml vs 30 pg/ml respectively) was revealed as patient underwent a successful bilateral adrenalectomy, indicated from the localization studies. Although which lead to clinical and biochemical remission. sampling from the vena cava did not reveal a gradient Plasma ACTH levels remained high. A further 18 for ACTH, we speculate that there was ACTH co- [ F]FDG PET study 8 months later showed ongoing secretion because of the positive immunostaining of activity in the thymic bed but no progression (Fig. the excised tumor. 1D); she remains well 2 years after her adrenalectomy. The difference in peripheral plasma ACTH levels observed at the initial evaluation and during the IPS/peripheral sampling can be explained by the spon- Discussion taneous fluctuations of CRH secretion by the tumor. To date, approximately 58 cases of neuroendocrine The present case describes an extremely rare case of an carcinomas of the thymus associated with CS (mostly ectopic CRH and most probably ACTH co-secreting attributed to ACTH production) have been reported in

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Figure 1 Patient with thymic carcinoid tumor. (A) 111In-pentetreotide scan shows tracer uptake in the thymus (curved arrow). (B and C) [18F]FDG PET images: coronal sections show [18F]FDG avid thymic lesion (large arrow) and a further coronal section more posteriorly shows high uptake in the adrenal glands (small arrows). (D) [18F]FDG PET study acquired post-thymectomy and post-adrenalectomy shows activity in residual tissue (large arrow). the literature (10, 11). Ectopic CRH production, from tumor, a hypothalamic gangliocytoma and small cell various tumors, has been documented and these carcinoma of the lung and prostate (6–9, 12–15). included: a medullary carcinoma, bronchial There have been two reports of thymic CRH production carcinoids, a pheochromocytoma, a retropancreatic (16, 17). In such cases functional imaging coupled

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Downloaded from Bioscientifica.com at 09/30/2021 04:50:07AM via free access 524 A Markou and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2005) 152 with conventional imaging has recently been used to 2 Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, localize endocrine tumors. In this particular case, Katz DA, Cutler GB Jr & Loriaux DL. Petrosal sinus sampling 18 with and without corticotrophin-releasing hormone for the prior to repeated thymectomy, [ F]FDG PET scintigra- differential diagnosis of Cushing’s syndrome. New England Journal phy and high-resolution CT were the only modalities of Medicine 1991 325 897–905. that detected recurrent tumor. 111In-pentetreotide ima- 3 Landolt AM, Schubiger O, Maurer R & Girard J. The value of ging identified the primary site but failed to localize the inferior petrosal sinus sampling in diagnosis and treatment of Cushing’s disease. Clinical Endocrinology 1994 40 485–492. site of recurrence, which probably reflects either 4 Kaltsas GA, Giannulis MG, Newell-Price JD, Dacie JE, Thakkar C, reduced number or lack of somatostatin receptors in Afshar F, Monson JP, Grossman AB, Besser GM & Trainer PJ. A the metastatic lesions. Following the repeated thymect- critical analysis of the value of simultaneous inferior petrosal omy, [18F]FDG PET was the only modality that contin- sinus sampling in Cushing’s disease and the occult ectopic ued to show residual tumor, which was in keeping with adrenocorticotropin syndrome. Journal of Clinical Endocrinology and Metabolism 1999 84 487–492. the patient’s clinical picture; the high metabolic turn- 5 Newell-Price J & Grossman AB. The differential diagnosis of Cush- over of the adrenals was also clearly demonstrated. It ing’s syndrome. Annals of Endocrinology 2001 62 173–179. has been shown that only 5% of normal adrenals are 6 Case records of the Massachusetts General Hospital. A 20-year- seen on the [18F]FDG PET scan. When co-registered old woman with Cushing’s disease and a pulmonary module. 18 New England Journal of Medicine 1987 317 1648–1658. [ F]FDG PET/CT studies are quantified the adrenal 7 O’Brien T, Young WF Jr, Davila DG, Scheithauer BW, Kovacs K, uptake is fairly low with standardized uptake values Horvath E, Vale W & Van Heerden JA. Cushing’s syndrome associ- ranging between 0.95 and 2.46 (18). ated with ectopic production of corticotrophin-releasing hor- PET using [18F]FDG reflects the glucose turnover in a mone, corticotrophin and vasopressin by a pheochromocytoma. lesion. Increased tracer uptake implies increased meta- Clinical Endocrinology 1992 37 460–467. 8 Young J, Deneux C, Grino M, Oliver C, Chanson P & Schaison G. bolic activity of a lesion. 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