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Introduction

Paraneoplastic Cushing's syndrome (CushingPS) has been attributed to ectopic adrenocorticotropin (ACTH) secretion (EAS), which may result in several types of tumors, including carcinoid and pancreatic neuroendocrine tumors, small cell lung cancer and thyroid medullary carcinoma (1). The bronchopulmonary carcinoid tumor (BCT) accounts for 1–2% of all adult malignancies of the lung and 20–30% of all carcinoid tumors (2–5).

Based on the World Health Organization classification, BCTs are divided into typical carcinoids, which are low-grade tumors with a low mitotic rate, and atypical carcinoids, which are intermediate-grade tumors with a higher mitotic rate and/or necrosis. Typical carcinoids are approximately four times more common than atypical carcinoids. The worldwide incidence of BCT is 0.2–2 per 100,000 individuals annually, with the majority of studies reporting a higher incidence in women compared with men, and in Caucasian compared with African-American individuals (2–4,6–8). Several reports have suggested that the incidence of BCT is increasing (3,4,8); however, this may be partly due to the increased use of advanced medical imaging techniques that are more sensitive in detecting asymptomatic tumors.

In general, BCTs are considered to be low- to moderate-grade malignant tumors; however, when associated with CushingPS, they are clinically aggressive (9). The present study reports a rare case of CushingPS in a teenager who was diagnosed with BCT and lymphadenopathy.

Case report

In September 2014, an 18-year-old man visited the Department of Endocrinology, The First Affiliated Hospital of China Medical University, Liaoning, presenting with a 3-month history of rapid weight gain (15 kg) characterized by central obesity involving the trunk and face with sparing of the limbs. The patient additionally complained of polyuria, polydipsia and progressive muscle weakness. The patient's height was 167 cm and his weight was 83 kg. The patient's blood pressure was 160/100 mmHg at presentation. Physical examination revealed typical Cushingoid features, including fat pads along the collarbone, back of the neck (buffalo hump) and face (moon face), along with generalized purple striae and hair growth on the back and both arms.

Routine laboratory test results revealed the following: Leukocytosis (11.4×109/l) with neutrophilia (81.2%); hyperglycemia (11.2 mmol/l); hypokalemia (2.54 mmol/l); metabolic alkalosis (pH 7.56); base excess, 6.8 mmol/l; and standard HCO3−, 31.7 mmol/l. A marked elevation in serum cortisol (00:00 h, 1,397.0 nmol/l; 08:00 h, 1,750.0 nmol/l; 15:00 h, 1,566.0 nmol/l) and ACTH (00:00 h, 149.8 pg/ml; 08:00 h, 211.0 pg/ml; 15:00 h, 198.6 pg/ml) levels was also observed, without diurnal rhythm. Additional examinations revealed no response to either low- or high-dose dexamethasone suppression. Based on the aforementioned findings, CushingPS due to EAS was initially suspected. Abdominal computed tomography (CT) and brain magnetic resonance imaging (MRI) scans revealed no abnormalities in the adrenal and pituitary glands. A chest CT scan revealed a mass in the right middle lung measuring 1.2 cm in diameter, which was evidenced by bilateral and diffusely scattered micronodular shadows. Whole-body 18fluorine-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) confirmed a high 18F-FDG uptake in the right middle lung [maximum standard uptake value, (SUVmax), 5.68] and lobar lymph node (SUVmax, 4.89; Fig. 1), which supported the clinical diagnosis of CushingPS associated with right middle lung cancer.

Figure 1. 18F-FDG positron-emission tomography scan showing high 18F-FDG uptake in (A) a right middle lobe nodule and (B) a lobar lymph node. 18F-FDG, 18fluorine-fluorodeoxyglucose.

The patient was subsequently treated with ketoconazole (1,000 mg/day) and intravenous potassium supplementation for 1 week. Following the decrease of the plasma cortisol levels, the middle lobe was resected with hilar and mediastinal lymph node dissection.

Tissue specimens were fixed with 10% neutral formalin and embedded in paraffin, and 4-µm-thick sections were prepared. Immunostaining was performed using the avidin–biotin–peroxidase complex method (Ultrasensitive™, MaiXin, Fuzhou, China). Paraffin sections were dewaxed in xylene and rehydrated in graded alcohols. Antigen retrieval was performed by heating the sections for 1.5 min in 0.01 mol/L citrate buffer, pH 6.0. Non-specific staining was reduced by incubation in blocking buffer containing goat serum (SP KIT-B1; Maixin-Bio, Fuzhou, China) for 30 min. Then, the sections were incubated with ACTH antibody (rabbit polyclonal to ACTH, dilution, 1/200, cat no. ab74976, Abcam) overnight at 4°C. The following day, the sections were incubated with appropriate secondary antibodies for 30 min. The reaction was visualized using DAB (DAB-0031; Maixin-Bio) plus chromogen. Specimens were examined using a BX50 microscope (Olympus Corp. Tokyo, Japan). For serum controls, 1% BSA in PBS was used in place of the primary antibody as a negative control. Pathology indicated a typical carcinoid tumor with lobar lymph node metastasis, staged as IIA (T1aN1M0). Immunohistochemistry additionally revealed that the tumor was positive for ACTH (Fig. 2). Symptoms were alleviated following surgery. Blood pressure, plasma glucose, potassium, cortisol, ACTH and 24-h urinary cortisol were normalized within a week. The postoperative recovery was uneventful, and the patient was discharged 14 days after the surgery. No CushingPS or tumor recurrence was noted at the 3-month postoperative follow-up. In addition, the patient had lost 13 kg (Fig. 3). Postoperative chemotherapy was administrated for four courses (Docetaxel 75mg/m2 and Cisplatin 75mg/m2), and the patient reached 15-months follow-up with no CushingPS or tumor recurrence.

Figure 2. (A) Gross pathology of the carcinoid tumor revealed a grey-white mass with clear boundaries measuring 1.2 cm in diameter. (B) Microscopic examination of the specimen showed a typical carcinoid tumor (hematoxylin and eosin staining; magnification, ×200). (C) Immunohistochemical staining showed positivity of the tumor cells for adrenocorticotropin (magnification, ×200).

Figure 3. Patient with paraneoplastic Cushing's syndrome (A) upon presentation and (B) at the 3-month postoperative follow-up.

Discussion

CushingPS due to BCT is a rare clinical occurrence, which has been reported in only a few case reports and case series. In fact, to the best of our knowledge, only four published surgical studies have reported data from >5 patients (10–13). According to a report of 19 BCT-induced CushingPS cases, the mean age of the patients was observed to be 43 years (11). Terzolo et al (12) reported 14 cases of EAS associated with a variety of tumor types of patients aged 26–76 years (mean age 53 years), with CushingPS being the predominant diagnosis in patients of advanced age, suggesting an increased occurrence of CushingPS in elderly compared with young individuals. However, sporadic cases of CushingPS in young patients have additionally been reported. Arioglu et al (13) reported a case of CushingPS in a 9-year-old girl, which was attributed to ectopic hormone secretion. The present study reported a case of CushingPS secondary to BCT in a teenager, which suggested an early onset of the syndrome.

EAS is difficult to diagnose and accurately localize. Symptoms typically manifest 6–84 months ahead of the diagnosis, with the average time to diagnosis ranging up to 24 months (14). In 12–19% of patients, the source of the tumor is unknown (15,16). Imaging modalities, including CT and MRI, lack the sensitivity and specificity required to identify an ectopic ACTH lesion (16). 111Indium-labeled octreotide scintigraphy (111In-OCT) has been reported as an effective diagnostic modality, as 80% of BCTs express receptors for somatostatin (17). 111In-OCT is considered helpful in the localization of EAS tumors. In addition, it may enable rapid, non-invasive differential diagnosis between ACTH-secreting pituitary adenomas and malignancies caused by EAS, followed by radioguided surgery in the treatment of bronchial carcinoid (18). 18FDG-PET and 18F-Fluorine-18-l-dihydroxyphenylalanine (18F-DOPA)-PET scans should also be considered as a secondary diagnostic tool for early diagnosis of EAS when conventional imagery fails to detect the presence of tumors (19). FDG-PET has a sensitivity of 64% and a positive predictive value of 53% in the identification of EAS (20). In the present case, 18F-FDG PET indicated an EAS tumor and a metastatic lymph node; the patient underwent radical resection, which led to the amelioration of the clinical symptoms.

Surgery is considered to be one of the preferred treatment options for localized ectopic lesions, and leads to a reduction in cortisol levels (17). In the present case, a right middle lobectomy with mediastinal lymph node resection was selected based on the pathological diagnosis of a typical carcinoid and lobar lymph node metastasis (stage N1). As reported, 87% of typical carcinoids do not present with lymph node involvement. Combined with CushingPS, a higher rate of lymph node metastasis and postoperative local recurrence rate was found (10,21). These findings indicated that BCT with CushingPS is an aggressive clinical entity. Lobectomy combined with complete lymphadenectomy is recommended for carcinoid tumors associated with CushingPS (10,14,22); otherwise, an occult residual metastatic lymph node may present, leading to persistent or recurrent CushingPS (11).

Patients with CushingPS are at increased risk of life-threatening infection and venous thromboembolism (23); however, due to their resistance to cytotoxic agents and radiation (10), such patients generally have a poor prognosis. In a clinical study conducted by the MD Anderson Cancer Center, 82% of patients with CushingPS caused by small-cell lung cancer succumbed to their condition within 2 weeks of the initiation of chemotherapy. Rectifying the patients' biochemical profile over a period of a few weeks prior to chemotherapy markedly improved the prognosis (24). Regulating the production of cortisol drastically alleviated the complications. Ketoconazole (200–1,200 mg/day) has been shown to inhibit the enzymes 11-hydroxylase and 17-hydroxylase in the cortisol biosynthesis pathway, and has been widely used due to its rapid mechanism of action and low frequency of side-effects (25). The present study demonstrated that ketoconazole combined with potassium supplementation was able to effectively control the preoperative hormone and ion levels of the patient. Ketoconazole treatment resulted in the biochemical and hormonal improvement of the patient with EAS; however, this drug may impair the cortisol response to stress; therefore, replacement corticosteroids should be considered for patients that exhibit a hormonal response, and use of moderate- to high-dose corticosteroids is recommended for any potential stress situations. Successful treatment of the underlying tumor is key to controlling the syndrome (26). A diminished objective response and sensitivity to first-line therapy and lack of a response to second-line therapy are indicators of the necessity to initiate palliative care early at first line and exclusively at relapse (27).

In conclusion, the present study reported a rare case of CushingPS in a teenager with BCT and N1 lymph node metastasis. The present findings suggested that BCT associated with CushingPS may be associated with a young age of onset, high rate of lymphadenopathy and poor prognosis. Radical resection of the lung and systemic lymph nodes may provide complete relief from symptoms.

Acknowledgements

The current study was supported by the Natural Science Foundation of Liaoning Province (grant no. 2015020561) and the Fund for Scientific Research of The First Hospital of China Medical University (grant no. fsfh1514).

References