ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(3): 192–196 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2013.871518


Cushing’s syndrome secondary to ectopic ACTH secretion from carcinoid tumor within an ovarian mature teratoma: a case report and review of the literature Baoyou Huang, Xueqing Wu, Qing Zhou, Yan Hu, Hongqin Zhao, Hua Zhu, Qian Zhang, and Feiyun Zheng



A 46-year-old woman with Cushing’s syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) secretion caused by primary ovarian mature teratoma with carcinoid components was presented in our case. The patient manifested sustained hypercortisolemia without circadian rhythm and a lack of suppression of either low-dose dexamethasone suppression test (LDDST) or high-dose dexamethasone suppression test (HDDST). There was no evidence of a pituitary mass or secretion of other hormones. After careful clinical evaluation, no other tumor masses were found. Resection of the ovarian tumors led to sharp reduction of serum ACTH and cortisol concentrations. Immunohistochemistry showed positivity in CgA, Syn, CK, NSE. To the best of our knowledge, there are rare reports of an ACTH-secreting carcinoid components located in an ovarian mature teratoma, and bilateral ovarian mature teratoma makes it rarer.

Carcinoid tumor, Cushing’s syndrome, ectopic ACTH secretion, immunohistochemistry, ovarian teratoma

Introduction Cushing’s syndrome (CS) with non-pituitary tumors was described more than eight decades ago; however, our knowledge and experience is limited partly owing to the rarity of this syndrome, variability in clinical presentation, and heterogeneity of underlying tumors. Based on the previous literature, it is estimated that CS due to ectopic adrenocorticotropic hormone (ACTH) secretion (CS-EAS) constitutes 8–18% of all causes of CS [1]. We will report a case on CS-EAS with our clinical experience and review previous literatures.

Case report A 46-year-old woman, para 2, complained about severe hypertension, repeated dizziness, abnormal menstruation, edema, weight gain and weakness, was hospitalized to the Department of Endocrinology in February 2008 for evaluation and treatment. She had bilateral tubal ligation 20 years ago after the delivery of her second child. Her father died of colon cancer when she was 40 years old. She had a four-year history of hypertension, taking 12.5 mg Captopril three times every day, but the blood pressure fluctuated between 150/100 mmHg and 200/120 mmHg. On physical examination, she had a BMI of 28.13 kg/m2 (Weight: 65 kg, Height: 152 cm) and characteristic appearance, that is, a moon face, central obesity, obvious supraclavicular fat pad, mild Buffalo hump, skin striae and edema. Laboratory findings: The basal serum cortisol concentrations were 725.79 nmol/l at 8 am, 526.92 nmol/l at 4 pm and Address for correspondence: Feiyun Zheng, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Province, Wenzhou 325000, China. Tel: +8613858798841. E-mail: [email protected]

History Received 12 June 2013 Accepted 29 November 2013 Published online 7 January 2014

696.53 nmol/l at 0 am (reference range 240–618 nmol/l at 8 am; 0–276 nmol/l at 4 pm;5310 nmol/l at 0 am), meanwhile the basal serum adrenocorticotropic hormone (ACTH) concentrations were 128 ng/l at 8 am and 123 ng/l at 4 pm (reference range 0–46 ng/l). Both were elevated with no circadian rhythm. In both the lowdose dexamethasone suppression test (LDDST) and high-dose dexamethasone suppression test (HDDST), there was no an overnight suppression of cortisol (Table 1). The serum levels of estrogen (E2) 723 pmol/l, luteinizing hormone (LH) 5.27 IU/l and follicle-stimulating hormone (FSH) 5.59 IU/l were in the premenopausal range. The serum and urinary catecholamine (Norepinephrine, Epinephrine, Dopamine) levels were in the normal range. Plasmatic production of the renin–angiotensin system (RAS) (rennin, angiotensin-II, aldosterone in lying and standing positions) levels, serum electrolytes, blood gas analysis, tumor markers were all normal. Imaging examinations: The transvaginal ultrasound examination (10 March) found a 49  30  51 mm cyst on the right side of the uterus and the left ovary with partial hyperechoic nodules, and the initial diagnosis was a right ovarian teratoma and a dubious left ovarian teratoma (Figure 1). The scanning of thoraco-abdominal computerized tomography (CT) (7 March) showed multiple small stones in left renal collecting system and no suspicious adrenal tumor. The cranial magnetic resonance imaging (MRI) (26 March) showed no abnormal signal in the pituitary. Electrocardiogram and ultrasonic cardiogram showed changes in hypertensive heart disease. The X-ray chest film, the renal, bilateral renal arteries and carotid arteries had no abnormal findings. The patient underwent a laparotomy on 24 March 2008. A 5  3  5 cm tumor was located in the left ovary and soybeansize nodules at the fundus of the right ovary. Macroscopically, both had a yellow viscous lipid organization, including hair,

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Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Province, Wenzhou, China

Cushing’s syndrome secondary to ectopic ACTH secretion *low-dose dexamethasone suppression test: 1.5 mg dexamethasone orally at 11 pm, with measurement of an 8 am serum cortisol the next day (28 February). yhigh-dose dexamethasone suppression test: 8 mg dexamethasone orally at 11 pm, with measurement of an 8 am serum cortisol the next day (29 February). zThe first operation was performed on 24 March 2008. ô NR: normal range. xThe patient injected hydrocortisone 200 mg at the first day after the second operation.

415 241.48 98.98 32 14 90.1 7200 3800 2900 100 4.10 – – 108/78 53 103 55.66# 42.21 16 510 102.6 7200 4600 2000 100 3.68 – – 110/87 55 57 59.27# 893.93"x 510 510 69.12 9900 6900 2000 100 3.52 7.367 21.5 127/90 57 27 40.16# 17.52 18" 11 80.1 5200 3000 1300 100 3.73 – – 100/72 60 – 504.94 (30.42%) – 97" – – – – – – – – – 185/128" 65 – 682.94 (5.90%) – 118" – – – – – – – – – 164/108" 65 Days post-1st operationz Serum Cortisol (8 am), nmol/l (NRô240–618) Serum Cortisol (4 pm), nmol/l (NR0-276) Serum ACTH (8 am), ng/l (NR0-46) Serum ACTH (4 pm), ng/l (NR0-46) Fasting Blood Glucose, mg/dl (70.2–109.8) Leucocyte, /mm3 (NR 4000–10 000) Neutrophil, /mm3 (NR 2000–7000) Lymphocyte, /mm3(NR 800–4000) Eosinophil, /mm3 (NR 100–500) Serum Potassium, nmol/l (NR3.5–5.5) Arterial PH (NR7.35–7.45) Serum Bicarbonate, mmol/l (NR 21.4–27.3) Blood Pressure, mmHg (NR90–140/60–90) Weight kg

– 725.79" 526.92" 128" 123" 106.2 6400 5100 800 0# 4.2 7.417 22.6 180/110" 65

21/04/08 Nifedipine 29/02/08 HDDSTy Nifedipine Antisterone 28/02/08 LDDST* Nifedipine Antisterone 26/02/08 Baseline Captopril Laboratory parameters Drags

Table 1. Overview of the laboratory findings.

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21/05/08 Nifedipine Prednisone

07/08/08 Prednisone

13/05/09 –

DOI: 10.3109/09513590.2013.871518


smooth wall. Without sending intra-operative frozen pathology, the patient underwent bilateral ovarian tumor resection. The two-week post-operative pathology confirmed bilateral mature teratomas and carcinoid components located in right side. Immunohistochemistry (IHC) showed positivity in CgA (chromogranin A), Syn (synaptophysin), CK (cytokeratin), NSE (neuronspecific enolase) (Figure 2) and negativity in vimentin (VIM) and epithelial membrane antigen (EMA). In addition, the positivity of Ki-67 varied from a low of 3% to 5% and the S-100 was focus. In a four-week post-operative study, the patient’s serum cortisol were sharply declined to 40.16 nmol/l at 8 am, 17.52 nmol/l at 4 pm, and the ACTH were 18 ng/l at 8 am and 11 ng/l at 4 pm. She was diagnosed as adrenal insufficiency. Then 10 mg prednisone in the morning and 5 mg in the night was the hormone supplement treatment. Furthermore, weight lost (from 65 to 60 kg) and blood pressure declined (100/72 mmHg) with the dose of reduced nifedipine occurred (Table 1). The second operation, namely, bilateral salpingo-opherectomy, radical hysterectomy, pelvic lymph node dissection and omentum resection, was performed on 20 May 2008. The final pathology was no abnormal findings with negative pelvic lymph nodes and omentum. She had four courses of chemotherapy of BEP regimen (bleomycin, etoposide, cisplatin) every three weeks per cycle. She did take prednisone for over one year without any other drags. One year post-operatively, clinical features of the CS were nonexistent. Her serum cortisol and ACTH level, and blood pressure were in normal ranges. There is no evidence of metastasis or relapse after a five-year follow-up (Table 1).

Discussion We report a patient presenting with CS secondary to ectopic ACTH secretion (CS-EAS). Before the operation, the patient performed the clinical features of CS, including the characteristic appearance and elevated serum ACTH and cortisol levels, and negative LDDST and HDDST. However, the resection of ovarian tumors led to sharp reduction of serum ACTH and cortisol concentrations immediately, even lower than the normal ranges. After the first one-year follow-up, the clinical features of CS disappeared and the serum ACTH and cortisol levels were normalized. Thus, our assumption was that the excess ACTH originated from the ovarian tumor. As we know, CS secondary to ectopic ACTH-secreting caused by primary ovarian carcinoid is quite rare. What makes this case intriguing is the association of CS with the ectopic ACTH-secreting carcinoid tumor in one case with complete data comparing pre-operation with post-operation. Diagnosis As our case, the diagnosis of ectopic ACTH-dependent CS can be divided into three steps. Firstly, we need to certain the secretory function, called the diagnosis of CS. Shamim Ejaz et al. summarized important clinical and laboratory parameters associated with CS [2], including hypertension (systolic blood pressure4140 mmHg), hyperglycemia (fasting blood glucose of 126 mg/dl), hematological (leukocytosis if WBC is 411 000/ mm3, neutrophilia if neutrophil count is 47300/mm3, lymphopenia if lymphocyte count is 51000/mm3 and eosinopenia if eosinophil count is 540/mm3), electrolyte abnormalities (hypokalemia was defined as a serum potassium 53.5 mmol/l) and Alkalosis (bicarbonate 430 mmol/l). The patient had the typical clinical features of hypercortisolemia, that is, weight gain, skin changes, menstrual irregularities, weakness and worsening hypertension uncontrolled with anti-hypertensive drags. In addition, markedly elevated serum cortisol level with no circadian rhythm and negative LDDST can eliminate some pseudo-Cushing states such as obesity and eosinopenia were presented (Table 1).

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B. Huang et al.

Gynecol Endocrinol, 2014; 30(3): 192–196

Figure 1. Trans-vaginal Pelvic Ultrasound: (A) a 49  30  51 mm cyst on the right side of the uterus; (B) a 9  5  8 mm hyperechoic nodule in the left ovary.

The next step requires the etiology of CS by identifying an ACTH-dependent hypercortisolism. Typically patients with ectopic ACTH production have high ACTH levels (420 ng/l), negative HDDST and demonstrate absent pituitary adrenal responses to corticotropin-releasing hormone (CRH). However, this is not always unequivocal as 20–40% of patients with ectopic ACTH demonstrates cortisol suppression on HDDST and 10–15% responds to CRH stimulation [3]. According to the research from the University of Texas MD Anderson Cancer Center in 2011 [2], CS-EAS was defined as plasma ACTH more than 15 pg/ ml in patients with tumors known to be associated with ectopic ACTH secretion, or positive ACTH immunostaining of nonpituitary tumors, or inferior petrosal sinus sampling (IPSS, ACTH at 10 min after CRH injection compared with baseline value) that suggested an ectopic source, determined by a central peripheral ACTH ratio of less than 2 at baseline or less than 3 after CRH stimulation. For primary cortisol-producing adrenal adenoma or carcinoma, serum ACTH is suppressed and can hardly be detected with ACTH-independent CS. Additionally, the negative HDDST is suggestive of ectopic ACTH or primary adrenal disease rather than a pituitary source of ACTH. The outstanding detectable ACTH and negative HDDST are consistent with ectopic ACTHdependent CS in our case (Table 1). The last step is the localization of the source of ectopic ACTH, which can be problematic. IPSS study or octreotide scintigraphy can be efficacious and accurate for the specific localization. Until the post-operation pathology and the sharp decline of serum cortisol and ACTH levels, we did not really realize the localization of the source of ectopic ACTH. Reviewing the previous literature, ectopic ACTH-producing tumors originate mainly from four different histological categories including small cell carcinomas of the lung (50%), pheochromocytomas (3%), pancreatic islet cell tumors (10%) and carcinoid tumors (15%) [4]. The ectopic ACTH-producing syndrome has been documented in medical literature mainly in case reports in a wide range of ovarian tumors including steroid cell tumor, androblastoma, endometrioid adenocarcinoma, carcinoid tumors and teratomas. We have a summary of CS-EAS caused by primary ovarian tumors from previous literatures (Table 2). Carcinoid tumors are distinct neuroendocrine neoplasms with characteristic histological, clinical and biological properties. Primary ovarian carcinoid tumors, classified insular, trabecular, strumal and mucinous carcinoid [17], account for less than 1% of all carcinoid tumors and less than 0.1% of all ovarian

neoplasms [18]. Nearly all primary ovarian carcinoids are unilateral, and the contralateral ovary may contain cystic teratoma, mucinous tumors or Brenner tumors. Most of the ovarian carcinoid tumors are asymptomatic, therefore, physical or ultrasound examinations inadvertently found a pelvic mass. Carcinoid syndrome, which is characterized with flushing, abdominal pain, diarrhea, and pulmonary and cardiovascular changes, occurs only in 1/3 of the women with primary ovarian carcinoid tumor [19]. The carcinoid tumor is the most common neuroendocrine neoplasmin in the ovary and most are of teratomatous origin. Usually a dermoid cyst is present in up to 90% of tumors, and the carcinoid tumor is seen grossly as a solid nodule of tan or yellowish tissue adjacent to or protruding into a cyst. Approximately 66% of ovarian carcinoid tumors manifest as localized lesions, while 22–31% present with distant spread [18]. The diagnosis of carcinoid tumors is supported by immunoreactivity with antibodies to CgA. Treatment and prognosis Management of patients with ectopic ACTH requires control of the hypercortisolemia as soon as the diagnosis is established [20]. Actually, we should pay attention to the rapid declined ACTH or cortisol levels, which lead to hypocortisolemia even adrenal crisis, so receiving stress doses of steroids is important. Our patient came to hypocortisolemia after ectopic ACTHsecreting tumor resected, which led to decrease in the secretion of adrenal cortex, so exogenous steroids were required. However, exogenous steroids suppress the HPA axis, and the full recovery requires gradually reducing the dose of glucocorticoid before cessation. As widely known, ovarian carcinoid tumors have low malignant potential and the basical treatment is surgical excision. Although surgical staging is not required for the carcinoid tumors, the entire peritoneal cavity should be systematically inspected and the ovaries should be assessed for size, tumor involvement, capsular rupture, external excrescences and adherence to surrounding structures. If the patient is young with the desire of children, the fertility-sparing surgery such as ovarian tumor resection or unilateral salpingo-oophorectomy (USO) was appropriate. If the patient is perimenopausal or postmenopausal, total abdominal hysterectomy and bilateral salpingo-oophorectomy (BSO) should be performed [21]. Whether need pelvic lymph node dissection or chemotherapy is controversial. Now the patient is healthy and disease-free survival with a five-year follow-up.

Cushing’s syndrome secondary to ectopic ACTH secretion

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DOI: 10.3109/09513590.2013.871518


Figure 2. (A, B) Paraffin sections of the excised ovarian tumor stained with hematoxylin and eosin showed mature teratoma (A), carcinoid tumor (B). (C–F) Immunohistochemical staining represented positivity in chromogranin A (C), synaptophysin (D), cytokeratin (E) and neuron-specific enolase (F).

Table 2. Summary of previous literatures of CS-EAS*caused by primary ovarian tumors. Number 1 2 3 4 5 6 7 8 9 10 11 12


Year Patient Age

Axiotis CA 1987 Young RH 1987 Schlaghecke R 1989 Kasperlik-Zaluska AA 1993 Crawford S 1994 Ball SG 1996 Watson J 2001 Sworczak K 2002 Suzuki T 2003 Candrina R 2005 Orbetzova M 2009 Sawathiparnich P 2009

1 3 1 1 1 1 1 1 1 1 1 1

24 35–52 65 33 59 63 37 19 66 26 60 6

Pathology Pituitary adenoma within a benign cystic ovarian teratoma [5] Steroid cell type and had metastasized within the abdomen [6] Carcinoid tumor in right ovary [7] Bilateral ovarian androblastoma with double, gynandroblastic differentiation in one ovary [8] Bilateral moderately differentiated endometrioid adenocarcinoma, recurrent ovarian tumor [9] Primary ovarian carcinoma [10] Functional pituitary tissue within an ovarian dermoid cyst [11] Ovarian steroid cell tumor [12] Ovarian adenocarcinoma [13] Pituitary microadenoma within a mature ovarian teratoma [14] Ovarian carcinoma [15] Ovarian steroid cell tumor [16]

*CS-EAS: Cushing’s syndrome (CS) due to ectopic adrenocorticotropic hormone (ACTH) secretion.


B. Huang et al.

Gynecol Endocrinol, 2014; 30(3): 192–196

Acknowledgements Baoyou Huang, Xueqing Wu, Qing Zhou, Yan Hu, Hongqin Zhao, Hua Zhu, Qian Zhang and Feiyun Zheng have contributed significantly in drafting the manuscript, literature review and revising it critically.



Declaration of interest We declare no conflict of interest and are solely responsible for the content of this paper. All the authors have given final approval for publication.



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Cushing's syndrome secondary to ectopic ACTH secretion from carcinoid tumor within an ovarian mature teratoma: a case report and review of the literature.

A 46-year-old woman with Cushing's syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) secretion caused by primary ovarian mature teratom...
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