Thoracic Cancer ISSN 1759-7706

CASE REPORT

Ectopic Cushing syndrome in small cell lung cancer: A case

report and literature review
Hang-yu Zhang1 & Jun Zhao2
1 Department of Interventional Therapy, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University
Cancer Hospital and Institute, Beijing, China
2 Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University
Cancer Hospital and Institute, Beijing, China

Keywords Abstract
Ectopic Cushing’s syndrome; paraneoplastic
Small cell lung cancer (SCLC) is a neuroendocrine tumor with the potential to
syndromes; small-cell lung cancer.
secrete various peptides or hormones that can lead to paraneoplastic syndromes,
Correspondence such as Ectopic Cushing syndrome (ECS). Because of the aggressive nature of the
Jun Zhao, Department of Thoracic Medical syndrome and its atypical features, ECS in small-cell lung cancer is difficult to
Oncology, Peking University Cancer Hospital, diagnose and has a poor prognosis. We report a case of a 74-year-old male
No. 52 Fucheng Road, Haidian District, Beijing patient who presented with severe hypokalemia, proximal muscle weakness,
100142, China. peripheral edema, metabolic alkalosis, and worsening hyperglycemia. The patient
Tel: +86 135 2146 9355
was eventually diagnosed with stage IV primary small-cell lung cancer and sur-
Fax: +86 10 8819 6562
Email: [email protected]
vived three months after diagnosis. We reviewed published articles to determine
any new diagnostic techniques or advantages in the treatment regimen.
Received: 8 September 2016;
Accepted: 4 October 2016.

doi: 10.1111/1759-7714.12403

Thoracic Cancer 8 (2017) 114–117

Introduction hyperglycemia. Clinical features, diagnosis, treatment, and

Ectopic Cushing’s syndrome (ECS) is the second most com- new developments in ECS are discussed.
mon paraneoplastic syndrome that occurs with small cell lung
cancer (SCLC) (1–5% of cases).1 Up to 50% of ECS cases are
Case report
lung tumors, including carcinoid tumors (30–46% ECS cases)
and SCLC (8–20% ECS cases).2–4 SCLC patients with ECS A 74-year-old man with a history of 20 pack-years smoking
have a poorer prognosis because of their advanced stage, poor and 18 years of type 2 diabetes mellitus (T2DM) suffered
response to chemotherapy, increased susceptibility to severe general weakness and worsening hyperglycemia for a month.
infections, and greater incidence of thromboembolic phenom- His initial blood pressure was 135/70 mmHg, his respiratory
rate 20 breaths per minute, heart rate 81 beats per minute,
ena.5,6 Most patients present electrolyte disturbances and mus-
and he had a normal temperature. He was categorized as
cle weakness rather than the typical clinical features of
Eastern Cooperative Oncology Group (ECOG) grade 2.
Cushing’s syndrome (CS). Studies have suggested that SCLC
A laboratory examination revealed the following: white
patients with adrenal metastases may also tend to develop blood cell count, 10.42 × 109/L; neutrophil, 90.74%; hemoglo-
ECS as a result of their location, as corticosteroids are synthe- bin, 14.3 g/dL; platelet count, 203 × 109/L; potassium,
sized more abundantly in the areas adjacent to the adrenal 2.95 mmol/L; calcium, 1.91 mmol/L; serum alanine amino-
metastasis.7 We report a case of SCLC with Cushing’s syn- transferase, 93 IU/L; aspartate aminotransferase, 43 IU/L;
drome and bilateral adrenal metastases in a 74-year-old man D-dimer, 8.18 μg/mL; and C-reactive peptide, 3.7 mg/L. Arte-
presenting with severe hypokalemia, proximal muscle weak- rial blood gas analysis resulted in pH 7.511, pCO2 37.3 mmHg,
ness, peripheral edema, metabolic alkalosis, and worsening pO2 67.3 mmHg, Glu 13.1 mmol/L, Lac 3.6 mmol/L, BE

114 Thoracic Cancer 8 (2017) 114–117 © 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited and is not used for commercial purposes.
H. Zhang & J. Zhao A case of Ectopic Cushing syndrome

Figure 1 Right lower lobe mass conforms to malignant features with

mediastinal and right hilar lymph node metastasis.

Figure 2 Multiple occupied lesions in the liver, considered metastases.

5.95 mmol/L and oxygen saturation of 95.8%, which indi-

cated metabolic alkalosis. The patient’s adrenocorticotropic
hormone level was 299.10 PG/Ml (7.2–63.3 PG/mL) and
serum cortisol level was >63.44 μg/dL (4.4–19.9 μg/dL),
which indicated CS.
Chest enhanced computed tomography (CT) scans
showed a right lower lobe mass, conformed to malignant
features with mediastinal and right hilar lymph node
metastasis and double lung metastases (Fig 1). Abdominal
enhanced CT scans showed multiple occupied lesions in
the liver, considered as metastases. Bilateral adrenal
nodules were also considered as metastases (Figs 2–3).
Pituitary imaging was normal. A biopsy was performed
with CT-guided lung puncture and the pathology con-
firmed small cell carcinoma.
After confirmation of the diagnosis, the patient received
spironolactone and intravenous potassium supplementa-
tion to treat the refractory hypokalemia. Considering the
poor performance status of this patient, we suggested oral
Figure 3 Bilateral adrenals nodules, considered metastases.
etoposide in the first cycle at 50 mg per day, days 1–10,
every three weeks. Treatment was ceased on the eighth day
because of diarrhea (Common Terminology Criteria for the exclusion of other causes of CS, histopathologic findings,
Adverse Events grade 2). In the second cycle, the patient and clinical improvement after chemotherapy.
received etoposide via intravenous infusion. During treat-
ment his electrolyte imbalances were corrected, the target
Discussion
lesions in the lung were slightly reduced, and his general
state was much better. However, systemic chemotherapy Ectopic Cushing’s syndrome secondary to lung cancer is
was ceased because of the onset of herpes zoster. The rare and limited papers have reported this syndrome since
patient died of liver failure three months after diagnosis. it was first described by Brown in 1928.4 ECS in SCLC does
The limitations faced in this case included the lack of avail- not usually exhibit the classic signs of CS and CS could
ability of 24-hour urine cortisol and inferior petrosal sinus also appear during effective chemotherapy.8,9 The wide
sampling (IPSS). However, the diagnosis was based on strong variety of clinical manifestations make it more difficult to
clinical grounds, firm laboratory findings of hypercortisolism, diagnose ECS in SCLC, especially at early clinical stages.

Thoracic Cancer 8 (2017) 114–117 © 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd 115
A case of Ectopic Cushing syndrome H. Zhang & J. Zhao

Table 1 Reports of ECS in SCLC

Author Year Patient no. Clinical presentation Treatment Survival Follow-up

Shepherd13 1992 23 Edema (83%) Chemotherapy 3.5 months

Muscle weakness (61%)
Ilias3 2005 3 Muscle weakness (82%) Chemotherapy with/without 1–48 months
Hypertension (78%) endocrine therapy
Hadem14 2007 1 Muscle weakness Ketoconazole 2 months
Hyperglycemia Chemotherapy
Hypokalemia
Suyama9 2011 1 Hypokalemia Mitotane 5 months
Diabetes Chemotherapy
Hypertension
Jeong12 2015 1 Hypokalemia metabolic alkalosis Ketoconazole 15 months
Hypertension Spironolactone
Chemotherapy
Ghazi4 2015 4 Muscle weakness Not mentioned 2 weeks to 3 months
Hyperglycemia
Hypokalemia
Aoki15 2016 1 Hypertension Chemotherapy 6 months
Hypokalemia
Muscle weakness

ECS, Ectopic Cushing’s syndrome; SCLC, small-cell lung cancer.

Small-cell lung cancer patients with ECS have a very poor patient cannot tolerate chemotherapy, metyrapone should
prognosis, living only three to six months. This makes early be administered.
diagnosis much more important. IPSS is the most reliable In conclusion, SCLC with ECS is a rare disease with a
examination for ECS, but it may not be feasible in many poor prognosis. Early diagnosis is challenging but impor-
institutes.3,10 Complete imaging examination, related blood tant. SCLC patients with muscle weakness, new onset or
and urine tests, low dose and high dose dexamethasone worsening hyperglycemia, severe hypokalemia, and bilat-
tests, immunohistochemical characteristics, and cell prolif- eral adrenal metastasis should receive adequate attention
eration potential (Ki-67) should be considered when suspi- and extensive examination should be conducted to confirm
cious of ECS. If a lesion cannot be located on CECT, then a diagnosis. Systemic chemotherapy with steroidogenesis
ostroscan will also not be effective for detection.3,11 inhibitors or glucocorticoid receptor antagonist represents
Jeong et al. suggested that controlling the high cortisol a new treatment regimen. Control of severe hypercortiso-
level and then administering systemic chemotherapy may lism before administering systemic chemotherapy may
achieve longer survival.12 With the exception of systemic achieve longer survival.
chemotherapy, ketoconazole, metyrapone, etomidate,
mitotane, and mifepristone can be used to reduce circu-
lating glucocorticoids.5 Previous reports have shown that Acknowledgments
there is a tendency to prolong survival when the high
Author contributions are as follows: Dr. Zhang contributed
level of cortisol is controlled before initiating treatment
to data collection, manuscript drafting and literature
(Table 1). Ketoconazole has been widely accepted for the
research. Dr. Zhao contributed to clinical treatment and
treatment of ECS since first reported in 1985 because of
manuscript revision for important intellectual content. The
patient tolerance in spite of moderate toxicity, such as
authors thank the patient who participated in this study.
nausea and liver injury.16 However, ketoconazole may
increase the risk of chemotherapy toxicity because it is a
strong inhibitor of cytochrome P450 3A4. Thus, metyra-
pone has been reported to be a better choice. For severe
Disclosure
adrenocorticotropic hormone-dependent CS, metyrapone No authors report any conflict of interest.
and ketoconazole combination or mitotane, metyrapone,
and ketoconazole combination therapy could be an alter-
native to control the cortisol level earlier. Chemotherapy References
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116 Thoracic Cancer 8 (2017) 114–117 © 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd
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Thoracic Cancer 8 (2017) 114–117 © 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd 117