ORIGINAL
* SINCE 1925*
Cyclic Cushing’s syndrome caused by neuroendocrine tumor: a case report
Kewei Wang1) *, Fuqiang Liu2),3),4) *, Chuanlong Wu3),4), Yan Liu3),4), Lin Qi3),4), Xiaohan Yang3),4), Huizhen Zheng2), Aixia Ma2), Jiahui Wu2), Fei Yan2),3),4), Xinguo Hou2), 3),4), Li Chen2),3),4), Ming Dong2),3),4) and Weikai Hou2),3),4)
1) School of Medicine, Shandong University, Jinan 250012, China
2) Department of Endocrinology, Qilu Hospital of Shandong University, Jinan 250012, China
3) Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, China
4) Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province medicine & health, Jinan 250012, China
Abstract. Cushing’s syndrome (CS) is a clinical syndrome characterized by hypercortisolemia. Cyclic Cushing’s syndrome (CCS), which exhibits a periodic or irregular increasing pattern in cortisol, is a rare type of Cushing’s syndrome. A 37-year- old man came to our hospital because of repeated dizzy spells, weakness and hypercortisolemia lasting two weeks. Endocrinological examinations indicated CCS with periodic and intermittent increases in cortisol. Enhanced computed tomography (CT) revealed space occupying lesions on the upper lobe of left lung, and biopsy eventually proved that these were pulmonary carcinoid tumors with ectopic ACTH secretion, which was subsequently manifested a Cushing’s syndrome. PET-CT, ultrasound and biopsy of the thyroid gland indicated bilateral thyroid papillary carcinoma. CT scan showed bilateral nodular hyperplasia of the adrenal gland. Enhanced magnetic resonance imaging (MRI) confirmed that the high signal disappeared on the posterior lobe of the pituitary gland and that the pituitary stalk shifted left, which was suspected to be non- functional pituitary microadenoma. The patient underwent surgery involving resection of the left upper pulmonary lobe and the mediastinal lymph node around the hilus pulmonis, which resulted in complete remission of CCS. The patient then chose elective surgery for the thyroid papillary carcinoma. An analysis of the patient’s genomic DNA identified a novel mutation in PDE11A: c.2032 (exon 12) G > A, which is associated with primary pigmented nodular adrenocortical disease (PPNAD). This is a novel mutation which has been no previous public clinical report on this mutation as it relates to this disease.
Key words: Cyclic Cushing’s syndrome, Neuroendocrine tumor, Primary pigmented nodular adrenocortical disease (PPNAD), PDE11A
CUSHING SYNDROME (CS) results from hypercorti- solemia caused by pituitary adenoma, ectopic ACTH tumors, adrenocortical carcinoma or hyperplasia. How- ever, cyclic Cushing’s syndrome (CCS) refers to cyclic and periodic production of cortisol [1]. Until now, rele- vant clinical reports of CCS have remained limited.
Patients with CCS exhibit substantial fluctuations in cortisol levels over time, so that clinical features may be quite varied and complex, rendering diagnosis of this
Submitted Jun. 16, 2018; Accepted Nov. 13, 2018 as EJ18-0168
Released online in J-STAGE as advance publication Dec. 19, 2018 Correspondence to: Dong Ming, Department of Endocrinology, Qilu Hospital of Shandong University, 107# Wenhua Xi Road, Lixia District, Jinan 250012, P.R. China.
E-mail: dr_dongming@163.com
Correspondence to: Hou Weikai, Department of Endocrinology, Qilu Hospital of Shandong University, 107# Wenhua Xi Road, Lixia District, Jinan 250012, P.R. China.
E-mail: pro.hwk@163.com
*These authors contributed equally to this work.
disease is quite difficult.
The possibility of CCS should be considered in patients who appear to go through periods of spontane- ous recurrence and remission of hypercortisolism. Low- dose (0.50 mg) and high-dose (2 mg) dexamethasone suppression tests (DST) can be used to identify the type of Cushing’s syndrome.
Treatment consists, whenever possible, of surgical excision of the tumor after controlling the hypercortiso- lemia. Medical intervention is the treatment of choice to produce a rapid decrease in high glucocorticoid levels.
Case Report
A 37-year-old man was admitted to our hospital on June 15, 2016 because of repeated attacks of dizziness, weakness and hypercortisolemia lasting two weeks. A year prior, he felt dizzy and weak and experienced facial edema without any obvious cause. He was admitted to a local hospital with a diagnosis of “interstitial lung dis-
| Time | Serum cortisol (ug/dL) | Serum ACTH (pg/dL) | 24 hUFC (nmol/24 h) | |
|---|---|---|---|---|
| 2016.03.06 | 39.10 | Not measured | 575.8 | |
| 2016.05.19 | 6.23 | Not measured | 88.7 | |
| 2016.06.05 | >63.31 | Not measured | 10,827.2 | |
| 2016.06.16 | 8:00 | 4.39 | 89.04 | |
| 16:00 | 5.84 | 58.18 | 105.0 | |
| 0:00 | 5.34 | 52.5 | ||
| 2016.07.02 | 8:00 | 128.80 | >1,500.00 | |
| 16:00 | 55.74 | 177.90 | >14,193.8 | |
| 0:00 | 60.00 | 207.70 | ||
| 2016.07.20 | 10.61 | 15.73 | 103.6 | |
| 2016.08.19 | 3.71 | 17.68 | 65.8 | |
ACTH, Adrenocorticotropic hormone; 24-h UFC, 24-hours urinary free cortisol; Normal reference range: serum cortisol 8:00 8.7-22.4 µg/dL, 16:00 <10 µg/dL; serum ACTH, 4.7-48.8 pg/dL; 24-h UFC, 9.6-124.0 nmol/24 h.
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ease” 6 months ago. His blood pressure was 154/94 mmHg; the lowest serum potassium was 2.43 mmol/L. After shock therapy with methylprednisolone, anti- inflammation and potassium supplement treatment lasted 8 days. The pneumonia syndrome was well controlled. Three months ago, the patient experienced limb edema and took spironolactone without a doctor’s recommenda- tion. The curative effect was not good but the symptoms later underwent remission. One month earlier, he was admitted to a local hospital for central obesity. One
round of endocrinologic examinations of serum cortisol and 24-hUFC demonstrated first increasing levels and a second round normal level (Table 1). He was then hospi- talized again after his highest blood pressure reaching 180/110 mmHg. Since the onset of disease, he had gained 5 kg in body weight.
The patient was referred to our hospital for further evaluation and treatment. Upon admission, he presented with Cushingoid features (moon face, central obesity, purpura and body mass index of 27.5 kg/m2) (Fig. 1),
| After Hospitalization | Normal Range | |
|---|---|---|
| SBP/DBP (mmHg) | 131/90 | 90-120/60-80 |
| BMI | 27.5 | 18.5-23.9 |
| Potassium (mmol/L) | 2.96 | 3.5-5.5 |
| TG (mmol/L) | 13.79 | 0.30-1.70 |
| Glutamate dehydrogenase (GLDH) (U/L) | 35.4 | <7.4 |
| Alkaline phosphatase (AKP) (U/L) | 134 | 45-125 |
| Progastrin-releasing peptide Pro-GRP (ng/L) | 91.26 | <50 |
| LH (mIU/mL) | 0.98 | 1.5-9.3 |
| FSH (mIU/mL) | 0.43 | 1.5-12.4 |
| Prolactin (PRL) (ng/ml) | 26.13 | 2.1-17.7 |
| TSH (uIU/mL) | 2.61 | 0.35-5.5 |
| PTH (pg/mL) | 76.98 | 15-65 |
| Renin (uIU/mL) | Aldosterone (ng/dL) | Aldosterone/rennin activity ratio (ARR) | |
|---|---|---|---|
| Clinostatism | 5.70 | 5.62 | 0.98 |
| Orthostatism | 14.00 | 7.84 | 0.56 |
| Day | Cortisol (ug/dL) at 8:00 |
|---|---|
| 1 | 128.8 |
| 2 | 90.25 |
hypertension, and hypokalemia (Table 2) although he had consistently taken potassium supplementation. Insis- tent examinations of the level of cortisol demonstrated losing regular ultradian rhythm, which was not consistent with the clinical symptoms of hypercortisolemia (Table 1). PTH level was higher than normal limits and bone density film showed osteoporosis and a high risk of fracture. A 75-g oral glucose tolerance test (OGTT) confirmed impaired glucose tolerance (IGT) (0-min: 4.72 mmol/L and 120-min: 8.26 mmol/L), and the func- tion of islet cells was normal. The wide use of plasma aldosterone/plasma rennin activity ratio (ARR) as a marked increase in the detection rate of primary aldoste- ronism (Table 3) [2]. The ratio less than 3.7, which can rule out primary aldosteronism [3]. Endocrinological examination of 17a-OHP, androstenedione and dehy- droepiandrosterone sulfate (DHEAS) levels were normal, which ruled out congenital adrenal cortical hyperplasia (CAH) and indicated the possibility of endogenous Cushing’s syndrome [4]. Functional endocrine tests
| Day | Cortisol (ug/dL) at 8:00 |
|---|---|
| 1 | 128.8 |
| 2 | 119 |
revealed a lack of ACTH/cortisol circadian rhythms and no suppression in response to an overnight low-dose (0.50 mg) and high-dose (2 mg) dexamethasone suppres- sion test (DST) (Tables 4, 5), which suggested ectopic ACTH. Combinations of repeated examinations of serum cortisol and 24-hUFC, the level of serum cortisol showed a cyclic pattern as it peaked three times and bottomed out twice (Table 1). These examinations confirmed the diag- nosis of CCS and that its fluctuation cycle was 30 days.
Enhanced CT of the lung revealed space occupying lesions on the upper lobe of the left lung (Fig. 2). Com- bined with a pulmonary pathological biopsy, the diagno- sis was pulmonary carcinoid tumor, a kind of pulmonary neuroendocrine tumor. CT scan of the adrenal gland indi- cated bilateral adrenal nodular hyperplasia and hyper- trophy (Fig. 3). PET-CT, ultrasound and biopsy of the thyroid gland indicated bilateral thyroid papillary carci- noma. Enhanced magnetic resonance imaging (MRI) showed that the high signal disappeared on the posterior lobe of the pituitary gland, and the pituitary stalk shifted
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left (Fig. 4). Endocrinological hormonal data showed PRL level was higher than normal range but less than 200 ng/ml, while LH and FSH level was less than nor- mal limits (Table 2). MRI and hormonal data both sug- gested non-functional pituitary microadenoma [5].
Therapy: The patient underwent a left lung upper lobe resection and pulmonary portal mediastinal lymph node dissection by single port laparoscopic surgery. The dis- section area of the tumor was 1.8 cm x 1.6 cm. The pathology demonstrated neuroendocrine tumors (Fig. 5). Immunohistochemical examinations showed ACTH(+) (Fig. 6), CK(+), CK7 cell(+), Syn(+), CgA(+), CD56(+),
TTF-1(+), CK5/6(-) and P63(-). After the operation, reexamination of serum and urinary cortisol showed nor- mal values (Table 1). Then the patient chose an elective surgery for his thyroid papillary carcinoma.
Discussion
Cyclic Cushing’s syndrome (CCS) refers to the excess production of cortisol with a cyclic or periodic pattern. Patients with CCS do not have unique, fixed clinical features. Spontaneous periodic and irregularly occurring fluctuations in common manifestations of Cushing’s
syndrome, including excess weight, central adiposity, edema, hypertension, hypokalemia or hyperglycemia, during the course of the illness have been noted.
At present, reported cases of CCS are quite rare. It is difficult to identify the fluctuating symptoms of the disease so that the diagnosis is not easy. Thus, regular detection of serum cortisol and the results of dexametha- sone suppression testing should be viewed with extreme caution in patients who was suspected with CCS. The diagnosis of cyclicity has been defined as the occurrence of at least three peaks and two troughs of plasma cortisol level [6].
In this patient, levels of Pro-GRP was high before the operation but it decreased to normal after the operation, which proved that increased Pro-GRP is a marker for neuroendocrine lesions. Although Pro-GRP is used as a serum tumor marker for small cell lung cancer (SCLC), elevated serum Pro-GRP concentrations have been ob- served in some non-small-cell lung cancers (NSCLCs). Serum Pro-GRP-positive patients may have manifested neuroendocrine differentiation, which can be used to pre- dict the locations of lesions and prognosis of the disease [7]. After the pulmonary carcinoid operation, the CCS was released.
The precise mechanism of periodic hypercortisolism is largely unknown. Cyclic Cushing’s syndrome can be caused by adrenal hyperplasia or tumor, hypophysoma and ectopic ACTH tumor. Influences of ghrelin as well as changes in dopaminergic tone have been described as possible underlying mechanisms [8]. Tumor infarction and periodic spontaneous bleeding would be an alterna- tive explanation for periodic ACTH and cortisol release [9]. Cyclic Cushing’s syndrome should be suspected in a
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patient with typical clinical findings of Cushing’s syn- drome but normal biochemistry. Repeated measurement of serum ACTH and urinary cortisol excretion is re- quired to establish the diagnosis.
To explore the genetic reason of cyclic Cushing’s syn- drome, we conducted a whole-genome association study of this patient and found a single base-pair mutation: c.2032 (exon 12) G > A in PDE11A (rs201629965) on chromosome 2 (Fig. 7). The genetic defect was a mis- sense mutation in the PDE11A gene, which was linked to primary pigmented nodular adrenocortical disease (PPNAD) type 2, a rare form of ACTH-independent Cushing’s syndrome.
The patient was presented with cushingoid features (moon face, central obesity, purpura and body mass index of 27.5 kg/m2) accompanied with hypertension (131/90 mmHg) and hypokalemia. These symptoms accord with clinical manifestation of PPNAD [10]. Based on the novel mutation and symptoms of the patient, PPNAD may exist in the patient. However, adre-
nal biopsy and pathological examination which may con- firm the existence of PPNAD in this patient were not performed, since the reexamination of endocrinological data showed normal values and symptoms of the patient turned to be better after the operation. In addition, the patient’s parents have been dead for many years, and he doesn’t have any siblings, so we couldn’t learn whether his diseases were hereditary and perform genetic analysis in his immediate family. Therefore, whether PPNAD exists in this patient contributing to the occurrence of CCS needs further exploration.
In this case, the patient was diagnosed with pulmonary neuroendocrine tumors, bilateral thyroid papillary carci- noma, and suspected to have non-functional pituitary microadenoma and PPNAD. The genetic mutation c.2032 (exon 12) G > A in PDE11A (rs201629965) pro-
vided opportunities for further exploration in pathogene- sis of PPNAD. To explore pathogenicity of the genetic mutation, we will still plan for a follow-up visit to this patient.
Acknowledgements
This work was financially supported by Shandong Provincial Natural Science Foundation, China (grant number ZR2016HB34).
Disclosure
None of the authors have any conflicts of interest associated with this research.
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