Endocrine Journal 2010, 57 (8), 679-686

Among ACTH-dependent Cushing’s syndrome (CS), ectopic ACTH syndrome (EAS) caused by non-pituitary ACTH-secreting tumors accounts for 9-18% [1]. Most of the ectopic source of ACTH secretion are slow-growing and occult tumors in the thorax [2]. Since the treatment of choice for EAS is complete resection of the tumor, the correct localization and confirmation of the ectopic ACTH source is crucial. However, it is often difficult to localize an occult and indolent tumor, essentially bronchial carcinoid tumor, by conventional imaging tests; up to 50% of EAS are undetectable by computed tomography (CT) and mag-netic resonance imaging (MRI) [3].

Somatostatin receptor scintigraphy (SRS) has been shown to be a useful tool for the visualization of a wide variety of neuroendocrine tumors (NETs) to lo-

Ectopic ACTH syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing’s disease

Yuji Tani1), Toru Sugiyama1), Shinichi Hirooka2), Hajime Izumiyama1) and Yukio Hirata1)

1)Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan2)Department of Pathology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan

Abstract. A 75-year-old woman was admitted to our hospital because of a poor glycemic control. She was found to have Cushingoid feature and dynamic endocrine tests showed elevated plasma ACTH and cortisol levels, lack of their circadian rhythm, non-suppressibility to high-dose dexamethasone, responsiveness to CRH, but not to DDAVP, and suppression to octreotide. Pituitary MRI showed an equivocal small lesion. CT scan of the chest showed two nodular lesions in the right lung (S5, S7), while a mild uptake was noted only in S5 lesion by FDG-PET, but positive uptake was only in S7 lesion by somatostatin receptor scintigraphy (SRS). Inferior petrosal sinus sampling revealed a gradient of plasma ACTH after CRH stimulation, consistent with the diagnosis of Cushing’s disease. She underwent middle and inferior lobectomy of the right lung. The resected tumor in S7 was consistent with the diagnosis of a bronchial carcinoid tumor with positive ACTH immunoreactivity, while that of S5 was cryptococcal granuloma. RT-PCR revealed abundant expressions of POMC and SSTR (-1, -2, -5), but not of CRHR and V1bR. Postoperatively, abnormal endocrine data were normalized along with improvement of hypertension and diabetes. This was a diagnostic challenging case with ectopic ACTH syndrome indistinguishable from Cushing’s disease by various endocrine and imaging tests, among which SRS successfully localized the tumor responsible for ectopic ACTH secretion.

Key words: Ectopic ACTH syndrome, Somatostatin receptor scintigraphy, Bronchial carcinoid tumor, Octreotide, Neuroendocrine tumor

calize the primary tumor as well as the recurrent and/or the metastatic tumors. The ability of SRS to local-ize tumors depends on the subtype and the amount of somatostatin receptor (SSTR) expressed and the tumor size [4].

We described herein a challenging case of ACTH-dependent CS with discordant results of various endo-crine and imaging tests. CT scan of the chest revealed two nodular lesions in the lung, one with uptake by [18F]fluorodeoxy-glucose (FDG) positron emission tomography (PET) scan and another with uptake by SRS, while an equivocal small lesion was detected on pituitary MRI. Dynamic endocrine test revealed hy-perresponse to corticotropin-releasing hormone (CRH) stimulation, but no suppression to high-dose dexam-ethasone, whereas positive ACTH gradient during in-ferior petrosal sinus sampling (IPSS) after CRH stim-ulation was consistent with the clinical diagnosis of Cushing’s disease (CD). However, the resected lung tumor corresponding to the nodular lesion with a sig-nificant uptake by SRS was consistent with the diag-nosis of bronchial carcinoid tumor causing EAS.

Received Apr. 26, 2010; Accepted Jun. 4, 2010 as K10E-129Released online in J-STAGE as advance publication Jun. 15, 2010Correspondence to: Yukio Hirata, MD, PhD, Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail: yhirata.cme@tmd.ac.jp

original

680 Tani et al.

[5-7] were synthesized by Greiner bio-one (Tokyo, Japan) (Table 1). The PCR products were examined by 2% agarose gel electrophoresis. DNA contamina-tion in the samples was examined by the parallel ex-periments without reverse transcriptase (RT).

Case Report

A 75-year-old woman with three-year history of di-abetes and dyslipidemia was admitted to our hospi-tal because of poor glycemic control. She had hyper-tension at the age of 71 and was treated with calcium-channel blocker (amlodipine), angiotensin receptor blocker (olmesartan) and β-blocker (bisoprolol), and had percutaneous coronary intervention for coro-nary heart disease a year earlier. On admission, she presented with Cushingoid features (moon facies, purpura and skin atrophy) and high blood pressure (145/79 mmHg), and was found to have osteoporo-sis. Laboratory examination revealed elevated fasting plasma glucose (184 mg/dL) and glycated hemoglobin (HbA1c: 8.1 %). She had markedly increased urinary free cortisol excretion (1706 μg/day), elevated lev-els of plasma ACTH (158 pg/mL), and serum cortisol (31.6 μg/dL). Plasma pro-GRP level (263 pg/mL), a neuroendocrine tumor marker, was elevated. Dynamic endocrine tests revealed lack of ACTH/cortisol circa-

methods

Immunohistochemical studyImmunohistochemical staining was performed on

formalin-fixed, paraffin-embedded specimens of the resected tumor samples by the avidin-biotin-peroxi-dase complex (ABC) method using an auto-staining machine (Ventana Benchmark HX System, Ventana Medical System, Tucson, AZ, USA), according to the manufacturer’s protocols. Primary antibodies used were mouse monoclonal anti-ACTH, anti-Ki-67, rab-bit polyclonal anti-chromogranin A and anti-synapto-physin (Dako, Glostrup, Denmark).

Reverse transcription-polymerase chain reaction de-tection (RT-PCR)

Written informed consent for the analysis of the surgical tumor specimen was obtained from the pa-tient. Total RNA was extracted from the resected tu-mor tissue using RNA zol (GIBCO/BRL, Carlsbad, CA), and cDNA synthesized using a First-Strand cDNA Syntheses Kit (Amersham Pharmacia Biotech Inc., NJ) according to the manufacturer’s instructions. PCR primers of human proopimelanocortin (POMC), two splicing variants (gE, PX) in exon 3 [6], CRH type 1 receptor (CRHR), arginine vasopressin receptor 1B (V1bR) and SSTR1-5 designed in earlier reports

Table 1 PCR primers used for RT-PCR

Primers Sequences PCR product size

POMC gEForward 5’-GAGGGCAAGCGCTCCTACTCC-3’

261 bpReverse 5’-GGGGCCCTCGTCCTTCTTCTC-3’

POMC PXForward 5’-CTACGGCGGTTTCATGACCT-3’

100 bpReverse 5’-CCCTCACTCGCCCTTCTTG-3’

CRHRForward 5’-TCCGTCTCGTCAAGGCCCTTC-3’

600 bpReverse 5’-GGCTCATGGTTAGCTGGACCAC-3’

V1bRForward 5’-CAGCAGCATCAACACCATCT-3’

221 bpReverse 5’-CCATGTAGATCCAGGGGTTG-3’

SSTR-1Forward 5’-AGACGGCCACCAACATCTAC-3’

450 bpReverse 5’-GCACGTAGCACAGGCAGATA-3’

SSTR-2Forward 5’-GACAAGCAATGCAGTCCTCA-3’

500 bpReverse 5’-CTGTGTACCAAGCCCCAGAT-3’

SSTR-3Forward 5’-TCTGCTACCTGCTCATCGTG-3’

290 bpReverse 5’-TTGAAGCGGTAGGAGAGGAA-3’

SSTR-4Forward 5’-AAGCTCATCAACCTGGGCGTG-3’

635 bpReverse 5’-GGGTTCTGGTTGCAGGGCTTC-3’

SSTR-5Forward 5’-CTCTCTCTGGACCTTGTGCC-3’

310 bpReverse 5’-ACGAGCAAACAGGTACGCTT-3’

681Ectopic ACTH syndrome confirmed by SRS

Table 2 Dynamic endocrine tests before and after surgeryBefore surgery Circadian rhythm and DST* (clock) 8:00 16:00 23:00 8:00

ACTH (pg/mL) 158 148 122 90Cortisol (μg/dL) 31.6 31.4 26 22.8

CRH (100 μg, i.v.) (min) 0 30 60 90 120ACTH (pg/mL) 143 358 245 202 156Cortisol (μg/dL) 41.5 50.2 57.8 49.0 45.2

DDAVP (4 μg, i.v.) (min) 0 30 60 90 120 ACTH (pg/mL) 146 168 163 163 160Cortisol (μg/dL) 63.3 62.3 64.0 63.4 66.9

Octreotide (100 μg, s.c.) (hour) 0 2 4 6 24 ACTH (pg/mL) 86 40 62 62 76Cortisol (μg/dL) 26.7 17.6 18.2 20.7 18.5

IPS sampling after CRH stimulation right left peripheralACTH (pg/mL) 458 213 131C/P ratio 3.5 1.6

*Dexamethasone (8 mg) was given orally at 23:00 the day before.

After surgeryCircadian rhythm and DST* (clock) 8:00 16:00 23:00 8:00

ACTH (pg/mL) 23 19 14Cortisol (μg/dL) 10.6 8.1 4.5 2.4

CRH (100 μg, i.v.) (min) 0 30 60 90 120ACTH (pg/mL) 20 78 62 48 41Cortisol (μg/dL) 5.4 16.1 18.5 20.6 19.4

*Dexamethasone (1 mg) was given orally at 23:00 the day before. Circadian rhythm/DST and CRH were perfomed after cessation and 24 h withdrawal of hydrocortisone replacement (20mg/day), respectively.

dian rhythm, no suppression to overnight high-dose (8 mg) dexamethasone suppression test (DST), hyper-response to CRH stimulation, but not to desmopres-sin (DDAVP) stimulation (Table 2). Subcutaneous administration of octreotide decreased plasma ACTH and cortisol levels (Table 2). These physical and en-docrine data were consistent with a clinical diagnosis of ACTH-dependent CS.

To differentiate Cushing’s disease (CD) from EAS, various imaging modalities were performed. CT scan of the chest (Fig. 1A) revealed two nodular lesions in the right lung; one in the middle lobe (S5) with a size of 5×6 mm and the other in the inferior lobe (S7) with a size of 17×8 mm. 18F-FDG PET scan showed a slight uptake in the S5 lesion (Fig. 1B), but not in the S7 lesion. SRS showed abnormal uptake of 111In-pen-tetreotide only in the S7 lesion, but not in the S5 le-sion (Fig. 1C). Brain MRI (Fig. 2) showed an equiv-ocal small non-enhanced area in the pituitary gland,

suggestive of a microadenoma or cyst. IPSS showed a distinct ACTH gradient after CRH stimulation; central to peripheral (C/P) ratios of the right and the left IPS were 3.5 and 1.6, respectively (Table 2). These discor-dant results from the endocrine and imaging tests sug-gested either EAS by the pulmonary tumor in S7 and/or pituitary microadenoma causing CD. Treatment with metyrapone (750 mg/day) and octreotide (200 μg/day) led to normalization of her plasma ACTH and cortisol levels (Fig. 3).

Based on the positive result by SRS in combina-tion with octreotide responsiveness and elevation of pro-GRP, the presumptive diagnosis of EAS seemed more likely than that of CD. After obtaining an in-formed consent from the patient, she underwent thora-coscopic partial resection of middle and inferior lobe of the right lung. Histopathologically, the resected tu-mor in S7 was consistent with the diagnosis of bron-chial carcinoid tumor with positive immunostainings

682 Tani et al.

Fig. 2 Dynamic-enhanced magnetic resonance imaging (mRI) of the pituitary by a 1.5 tesla scanner An equivocal small low-intensity area (3mm) of the pituitary gland as indicated by an arrow.

for ACTH and other neuroendocrine tumor markers (chromogranin A, synaptophysin) (Fig. 4) with Ki-67 index (0.8 %), while the tumor in S5 was diagnosed with the pulmonary cryptococcosis. RT-PCR of the S7 tumor clearly showed increased expression of POMC (gE, PX) and SSTR (-1, -2, -4, -5) without DNA con-tamination (Fig. 5), but extremely low expression of V1bR and CRHR (data not shown).

Postoperative course was uneventful, but replace-

Fig. 1 Diagnostic imaging tests (A) Chest CT scan; nodular lesion (17×8 mm) in S7 and (5×6 mm) in S5 of the right lung as indicated by arrows, (B) [18F] fluorodepxy-glucose (FDG) positron emission tomography (PET) scan; a slight uptake in the S5 as indicated by an arrow, and (C) horizontal and (D) sagittal view of somatostatin receptor scintigraphy using 111In-labeled pentetreotide; abnormal uptake in the S7 as indicated by arrows.

ment with hydrocortisone (300 mg/day) was initi-ated, tapered and discontinued. Her postoperative plasma ACTH and cortisol levels became normalized (Fig. 3) with complete suppression to overnight low-dose (1 mg) DST after cessation of replacement thera-py, and normal response to CRH stimulation 24h after withdrawal of hydrocortisone (20 mg/day) (Table 2). Postoperative blood pressure was normalized with-out any medication, and her glycemic state was well

683Ectopic ACTH syndrome confirmed by SRS

Fig. 4 Histopathology of the resected S7 tumor of the right lung (A) Microscopic appearance consistent with bronchial carcinoid tumor (HE). Immunostainings for (B) ACTH,

(C) chromogranin A, and (D) synaptophysin (magnification ×100).

Fig. 5 gene expressions of PomC and SSTR subtype in the tumor RT-PCR on 2% agarose gel electrophoresis revealed several distinct bands for (A) POMC variants gE (261 bp), PX (100 bp),

and (B) SSTR subtype-1 (450 bp), -2 (500 bp), -4 (635 bp), and -5 (310 bp), respectively. (+) with and (-) without reverse transcriptase (RT). M: molecular size marker in base pairs (bp).

Fig. 3 Perioperative changes of plasma ACTH and crtisol levels Changes of plasma ACTH(●) and serum cortisol(□) levels are shown. Treatment is shown in the upper panel.

684 Tani et al.

controlled even after discontinuation of insulin. Two years after the surgery, she was free from tumor recur-rence and hypercortisolism.

Discussion

EAS, a rare cause of ACTH-dependent CS [8], fre-quently presents a major diagnostic challenge because it is often indistinguishable from CD. Imaging studies are the cornerstone of EAS management because early localization, confirmation and surgical removal of the tumor constitute the curative treatment [9]. However, the tumors causing EAS are often too small and occult to be detected by conventional imaging modalities, such as CT and MRI scan [10]. Since a single positive finding may represent a false-positive result, combina-tion of anatomical and functional imaging tests should be taken into account in such cases with a question-able, but equivocal tumor [11].

It has been reported that FDG-PET for detection of the ectopic ACTH source has a sensitivity of 64% and positive predictive values of 53 % [2]. In this case, FDG-PET showed no significant uptake by the S7 tu-mor which was later identified as bronchial carcino-id tumor, but mild uptake by the S5 tumor which was found to be a cryptococcal granuloma. Since FDG-PET is known to identify tumors with high proliferative activities [12], it is reasonable to assume that the granu-lomatous lung lesion seems metabolically-more active than bronchial carcinoid tumor with low Ki-67 index.

It has been reported that SRS for detection of the ectopic ACTH source have sensitivity of 57 % and positive predictive values of 79 % [2]. SRS using 111In-pentetreotide is a useful tool to detect neuroendo-crine tumors with abundant expression of SSTRs [13], among which octreotide binds with higher affinity to SSTR-2 and SSTR-5. However, the expression pat-tern of SSTR subtype in bronchial carcinoid tumors have not yet been extensively investigated. In the pres-ent case, CT scan of the chest revealed two nodular lesions in the right lung (S5 and S7). Since adminis-tration of octreotide reduced plasma ACTH level, the presence of SSTR-2 and/or -5 in the ectopic ACTH-producing tumor is strongly suggested. In fact, SRS showed a significant uptake of radioactivity in the S7, but not in the S5 lesion, of the right lung, and the re-sected tumor in the S7 lesion expressed SSTR (-1, -2, -4, -5) mRNAs, but not SSTR-3 mRNA, as evaluated by RT-PCR.

In the present case, RT-PCR analyses also showed that the resected carcinoid tumor exhibited very low expressions of V1bR and CRHR mRNAs. The low V1bR expression is consistent with the lack of ACTH response to DDAVP stimulation, while the low CRHR expression excludes the possibility of ACTH secre-tion from the tumor by CRH. Although CRH test is currently considered as a reliable and noninvasive di-agnostic test for the differential diagnosis of ACTH-dependent CS, 30 % of patients with EAS exhibit false-positive results [14].

IPSS with CRH stimulation has been regarded as the most accurate and reliable method to differentiate CD from EAS with high sensitivity (88-100 %) and speci-ficity (90-100 %) [10, 15, 16]. A distinct gradient of the ACTH levels between the IPS and the peripheral veins with C/P ratios of ≥2.0 before and ≥3.0 after CRH stim-ulation, makes the definite diagnosis of CD. Although there are several possible causes of false-negative find-ings, including anatomical abnormalities, precluding satisfactory catheterization, false-positive cases have been rarely reported [17]. However, the present case showed a clear step-up (C/P ratio: 3.5) after CRH stim-ulation. Possible ectopic production of CRH by the same tumor was excluded by RT-PCR and immunohis-tochemical study (unpublished observation). The pos-sible coexistence of subclinical CD could not be com-pletely excluded in the present case because of the postoperative detectable plasma ACTH levels and the relatively short term (2 months) of glucocorticoid re-placement. However, the results of the postoperative endocrine tests with normal circadian rhythm, complete suppression by overnight low-dose (1 mg) DST, and normal response to CRH stimulation all argue against this possibility. Thus, the positive result of IPSS and normal response to CRH stimulation in the present case may be partly explained by the unusual sensitivity of pituitary corticotroph to CRH, such as during the trough period of cyclic hormonogenesis by the tumor. In fact, such false-positive IPSS results have been reported in cases with EAS similar to ours [18, 19].

In summary, we presented a diagnostic challenging case of EAS with pituitary and lung tumors indistin-guishable from CD based on the results from various endocrine and imaging tests, among which SRS suc-cessfully localized the tumor responsible for the ecto-pic source of ACTH. SRS, although not approved in Japan yet, proves to be a useful tool to localize the ec-topic ACTH source in such cases with multiple and/or

685Ectopic ACTH syndrome confirmed by SRS

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Acknowledgments

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