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Difficulties in Diagnosis and Management of Ectopic Cushing Syndrome

      Abstract

      A 18-year-old man presented to a local hospital with muscle weakness, facial edema, and a 6 kg weight gain over 2 months. After a complete work-up, he was diagnosed with pituitary Cushing syndrome and treated with a bilateral adrenalectomy for Cushing syndrome and pituitary radiotherapy for Nelson syndrome. Twenty-five years later, his ectopic source of adrenocorticotropic hormone was revealed as a pulmonary neuroendocrine tumor, and a pulmonary resection was performed. Subsequently, a biochemical and clinical remission including hyperpigmentation was achieved.

      Key Words

      Adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome, Cushing disease is likely to be diagnosed in approximately 85% of cases, the remaining patients have nonpituitary tumors that secrete ACTH and 2% of pulmonary neuroendocrine tumors are reported to be ectopic ACTH-producing tumors.
      • Grossman AB
      • Kelly P
      • Rockall A
      • Bhattacharya S
      • McNicol A
      • Barwick T
      Cushing's syndrome caused by an occult source: difficulties in diagnosis and management.
      • Sakuraba M
      • Murasugi M
      • Oyama K
      • et al.
      Diagnosis and surgical treatment of ectopic adrenocorticotropic hormone-producing pulmonary tumors accompanied by Cushing syndrome.
      Once the ectopic origins of ACTH other than the pituitary gland are suspected, careful examination by diagnostic imaging is necessary. Although inferior petrosal sinus sampling (IPSS) helps in excluding a pituitary origin, no information about the source of ectopic ACTH is easily obtained.
      • Dall'Asta C
      • Santambrogio Luigi
      • Castellani M
      • Ambrosi B
      Difficulties in diagnosis and treatment of ectopic ACTH-producing tumors of the chest.
      Therefore, some patients undergo a resection of the pituitary gland or resection of the hypertrophied adrenal gland during a prolonged course without a definitive diagnosis.
      We report a patient with an ectopic ACTH-producing pulmonary neuroendocrine tumor, which was not diagnosed for more than 20 years.

      CASE REPORT

      A 43-year-old man was referred for a lung mass. Twenty-five years before this, he presented to a local hospital with muscle weakness, facial edema, and a 6 kg weight gain over 2 months. The basal endocrinology and low-dose dexamethasone suppression test confirmed Cushing syndrome, and after a high-dose dexamethasone suppression test, he failed to suppress cortisol by more than 50%, and initial ACTH was detectable at levels of 104 pg/ml. After a thorough investigation of pituitary CT, chest and abdomen CT scan, but not IPSS, there was no evidence of pituitary or ectopic lesion. Although an abdominal CT scan revealed normal shape and an upper normal size adrenal gland, considering his young age and being a single son, a bilateral adrenalectomy was performed for the treatment of Cushing syndrome. After 2 years, the hyperpigmentation on his face and oral cavity was aggravated, and although there was no abnormality on his pituitary gland in the sella MRI, he was diagnosed with Nelson syndrome and received radiotherapy on his pituitary gland. After that, the patient was under steroid therapy with antihypertensive drugs, but he still had an elevated ACTH level and the hyperpigmentation continued. Six months before the current evaluation, he suffered from a leg fracture and a preoperative chest radiograph revealed a 3-cm rounded opacity in the right lung. A chest CT confirmed three nodules with regular margins in the right middle lobe and an enlarged hilar node. A positron emission tomography scan showed mild hypermetabolism in the mass and node (Figure 1). A percutaneous needle biopsy revealed a neuroendocrine tumor. The preoperative level of ACTH was 9280 pg/ml and it might have resulted from these lesions. The patient underwent a right middle lobectomy and a complete mediastinal, hilar lymph node dissection. On permanent pathologic examination, there were three separate nodules at the same lobe and four metastatic nodes at subcarinal, hilar, and peribronchial area; therefore, pathologic stage is IIIB (T4N2M0). Histology showed neuroendocrine carcinoma with positive immunostaining for ACTH (Figure 2). Subsequently, a biochemical findings (ACTH level is 95 pg/ml 2 years after operation) normalized, clinical remission including hyperpigmentation disappeared, and 24 months after operation, the patient is cured (Figure 3).
      Figure thumbnail gr1
      FIGURE 1A, chest radiograph showing a 3-cm sized round opacity in the right lung; B, positron emission tomography with 18fluorodeoxyglucose demonstrating hypermetabolism (mSUV = 2.6) on right middle lobe; C, chest CT imaging of the chest showing nodules with regular margins in the right middle lobe (left: the biggest nodule, right: second nodule, third nodule was not shown).
      Figure thumbnail gr2
      FIGURE 2The specimen was immunohistochemical stained by ACTH (×400).
      Figure thumbnail gr3
      FIGURE 3Preoperative (A) and postoperative (B) skin pigmentation: face and hands. A, preoperative images; B, postoperative images (2 years after operation).

      COMMENT

      When faced with ACTH-dependent Cushing syndrome, it is very difficult to differentiate Cushing disease from ectopic origin. In a brain MRI, a lack of demonstrable tumor is often seen in cases of Cushing disease and even in an IPSS, a clear central gradient is almost a pathognomonic finding in Cushing disease but a negative central gradient might be seen in a minority of patients with Cushing disease.
      • Grossman AB
      • Kelly P
      • Rockall A
      • Bhattacharya S
      • McNicol A
      • Barwick T
      Cushing's syndrome caused by an occult source: difficulties in diagnosis and management.
      Therefore, a standard technique in localizing ACTH-producing tumors is not available so far. In the case described, both a pituitary CT scan and sella MRI failed to demonstrate a pituitary tumor and there was no evidence of an ectopic source of ACTH, it was felt that this was probably a case of pituitary-dependent Cushing syndrome at that time.
      The mean interval between the onset of Cushing syndrome and the definite diagnosis of an ectopic ACTH- producing tumor was reported to be 24 months, and that between the onset and surgery was 52 months, but an interval of more than 20 years is very rare.
      • Pass HI
      • Doppman JL
      • Nieman L
      • Stovroff M
      • et al.
      Management of the ectopic ACTH syndrome due to thoracic carcinoids.
      • Shrager JB
      • Wright CD
      • Wain JC
      • et al.
      Bronchopulmonary carcinoid tumors associated with Cushing's syndrome: a more aggressive variant of typical carcinoid.
      This long interval is partly because the tumor diameter is less than 1.0 cm in many patients, so that a chest radiograph shows no abnormalities and the tumor grows very slowly.
      • Sakuraba M
      • Murasugi M
      • Oyama K
      • et al.
      Diagnosis and surgical treatment of ectopic adrenocorticotropic hormone-producing pulmonary tumors accompanied by Cushing syndrome.
      During a prolonged course of disease, some patients undergo a resection of the pituitary gland or resection of the hypertrophied adrenal glands. To detect an ectopic source, some investigator suggested that dedicated imaging with chest, abdominal, and pelvic CT scans, plus possibly a MRI of the mediastinum and pelvis are prudent.
      • Grossman AB
      • Kelly P
      • Rockall A
      • Bhattacharya S
      • McNicol A
      • Barwick T
      Cushing's syndrome caused by an occult source: difficulties in diagnosis and management.
      Scintigraphy with either 123I-meta-iodobenzylguanidine or 111In-octreotide has varying reported use in diagnosing ectopic source. A positron emission tomography with 18fluorodeoxyglucose is an interesting technique that might prove useful, at least for detecting fast-growing tumors, although 11C-5-hydroxytryptophan, if available, might be more promising.
      • Grossman AB
      • Kelly P
      • Rockall A
      • Bhattacharya S
      • McNicol A
      • Barwick T
      Cushing's syndrome caused by an occult source: difficulties in diagnosis and management.
      • Dall'Asta C
      • Santambrogio Luigi
      • Castellani M
      • Ambrosi B
      Difficulties in diagnosis and treatment of ectopic ACTH-producing tumors of the chest.
      • Goldsmith SJ
      • Kostakoglu LA
      • Somrov S
      • Palestro CJ
      Radionuclide imaging of thoracic malignancies.
      In this case, when the hyperpigmentation was aggravated, it was unclear if Nelson syndrome had developed because there was no microadenoma in a sella MRI, and after radiotherapy on the pituitary gland, the hyperpigmentation continued. Therefore, the hyperpigmentation might be aggravated with an increase of ACTH from the ectopic source.
      Survival of patients with ectopic ACTH syndrome depends on the source of the primary tumor; those with a small-cell lung carcinoma fare poorly, but the more indolent tumors, especially the pulmonary neuroendocrine, show prolonged survival.
      • Jackman DM
      • Johnson BE
      Small-cell lung cancer.
      In the case of a pulmonary neuroendocrine tumor, despite long delays in surgical therapy, an anatomic resection with a complete mediastinal lymphadenectomy decreases a local recurrence and results in a favorable prognosis.
      • Deb SJ
      • Nichols FC
      • Allen MS
      • et al.
      Pulmonary carcinoid tumors with Cushing's syndrome: an aggressive variant or not?.

      ACKNOWLEDGMENTS

      The authors received no financial support in the preparation of this article.

      REFERENCES

        • Grossman AB
        • Kelly P
        • Rockall A
        • Bhattacharya S
        • McNicol A
        • Barwick T
        Cushing's syndrome caused by an occult source: difficulties in diagnosis and management.
        Nat Clin Pract Endocrinol Metab. 2006; 11: 642-647
        • Sakuraba M
        • Murasugi M
        • Oyama K
        • et al.
        Diagnosis and surgical treatment of ectopic adrenocorticotropic hormone-producing pulmonary tumors accompanied by Cushing syndrome.
        Jpn J Thorac Cardiovasc Surg. 2003; 51: 656-659
        • Dall'Asta C
        • Santambrogio Luigi
        • Castellani M
        • Ambrosi B
        Difficulties in diagnosis and treatment of ectopic ACTH-producing tumors of the chest.
        Eur J Cardiothorac Surg. 2002; 21: 149-151
        • Pass HI
        • Doppman JL
        • Nieman L
        • Stovroff M
        • et al.
        Management of the ectopic ACTH syndrome due to thoracic carcinoids.
        Ann Thorac Surg. 1990; 50: 52-57
        • Shrager JB
        • Wright CD
        • Wain JC
        • et al.
        Bronchopulmonary carcinoid tumors associated with Cushing's syndrome: a more aggressive variant of typical carcinoid.
        J Thorac Cardiovasc Surg. 1997; 114: 367-375
        • Goldsmith SJ
        • Kostakoglu LA
        • Somrov S
        • Palestro CJ
        Radionuclide imaging of thoracic malignancies.
        Thorac Surg Clin. 2004; 14: 95-112
        • Jackman DM
        • Johnson BE
        Small-cell lung cancer.
        Lancet. 2005; 366: 1385-1396
        • Deb SJ
        • Nichols FC
        • Allen MS
        • et al.
        Pulmonary carcinoid tumors with Cushing's syndrome: an aggressive variant or not?.
        Ann Thorac Surg. 2005; 79: 1132-1136