[Case Study]: Cushing's Syndrome Caused by an Occult Source: Difficulties in Diagnosis and Management

Ashley B Grossman; Philip Kelly; Andrea Rockall; Satya Bhattacharya; Ann McNicol; Tara Balwick

Disclosures

Nat Clin Pract Endocrinol Metab. 2006;2(11):642-647. 

In This Article

Summary and The Case

Summary

Background: A 24-year-old woman presented with a 12.5 kg weight gain over 6 months (mostly abdominal), hirsutism, acne, ankle edema, polydipsia, nocturia, back pain, pigmentation, poor libido and lightened menses to our hospital in May 1986. She had been treated for the previous 2 years with furosemide and spironolactone for peripheral edema, and had stopped the combined oral contraceptive 2 months previously. She did not take tobacco, recreational drugs or alcohol. Upon physical examination she was grossly Cushingoid with florid clinical manifestations.
Investigations: Serum potassium and bicarbonate, circadian rhythm of cortisol, low-dose and high-dose dexamethasone suppression tests, plasma adrenocorticotropic hormone (ACTH), corticotropin releasing-hormone stimulation test, CT scan of the pituitary, plain chest radiology, CT scan of the chest and abdomen, trans-sphenoidal pituitary biopsy and histology, CT scan and MRI of the thorax, MRI of the pituitary, octreotide scintigraphy, gastroscopy, colonoscopy, gut peptides, tumor markers, urine 5-hydroxyl-indole-acetic acid, resection, histology, immunocytochemistry and in situ hybridization.
Diagnosis: Occult ectopic ACTH syndrome from a presumed appendiceal neuroendocrine tumor. The tumor was only identified some 20 years from initial presentation.
Management: Adrenolytic therapy before bilateral adrenalectomy to cure Cushing's syndrome, glucocorticoid and mineralocorticoid replacement therapy, and then repeated surveillance over 20 years to locate the ectopic source of ACTH. This was finally identified by CT scan and excised at laparotomy.

The Case

A 24-year-old woman presented with a 12.5 kg weight gain over 6 months (mostly abdominal), hirsutism, acne, ankle edema, polydipsia, nocturia, back pain, pigmentation, poor libido, and lightened menses to our hospital in May 1986. Peripheral edema had been treated with furosemide and spironolactone for the previous 2 years, and she had stopped the combined oral contraceptive 2 months previously when the referring endocrinologist had suspected Cushing's syndrome. She did not take tobacco, recreational drugs or alcohol.

Upon physical examination she was grossly Cushingoid with thin skin, round, plethoric facies with acne and severe hirsutism, supraclavicular and interscapular fat pads, pigmented knuckles and axillae and purple, livid striae on the abdomen and around the shoulder girdle, and she had proximal myopathy. The patient was taken off diuretics and initial investigations revealed hypokalemia with alkalosis. The basal endocrinology and low-dose dexamethasone suppression test (LDDST; 2 mg dexamethasone per day for 48 h) confirmed Cushing's syndrome and suggested periodicity ( Table 1 ). After a high-dose dexamethasone suppression test (HDDST; 8 mg dexamethasone per day for 48 h), she failed to suppress 09:00 h cortisol by more than 50%. ACTH was detectable at levels of 204 ng/l and 48 ng/l on two consecutive mornings, which also suggested cycling ( Table 1 ). Pituitary CT scan showed no lesion. Circulating cortisol and ACTH levels did not rise after 100 μg ovine corticotropin-releasing hormone (CRH) was given. Bilateral inferior petrosal sinus sampling (BIPSS) for ACTH was abandoned twice as, on each occasion, the patient had 'cycled out' and become eucortisolemic. Chest CT scan was normal, while abdominal CT scan revealed hyperplastic adrenals. Whole-body catheter and sampling for ACTH during active disease revealed no gradient. Basal gonadotropin levels were normal, she was growth-hormone deficient with no diabetes insipidus, and testosterone levels were 4.3 nmol/l (normal range <3 nmol/l) and suppressed on the LDDST with otherwise normal androgen levels. The diagnosis of Cushing's syndrome was made. Although the results of the HDDST and CRH tests suggested the possibility of an ectopic source, because of her youth, and the presence of ACTH-dependent Cushing's syndrome with no ectopic source being found after a detailed search, it was felt that this was probably a case of pituitary-dependent Cushing's syndrome, Cushing's disease. Adrenolytic therapy (750 mg metyrapone every 8 h) was commenced for 6 weeks before trans-sphenoidal pituitary surgery. As mean daily cortisol levels were below 100 nmol/l, 2.5 mg prednisolone twice daily was prescribed, together with metyrapone.

At trans-sphenoidal surgery no tumor was found, despite a thorough exploration and biopsy. Postoperatively, hypercortisolemia persisted (at 09:00 h, basal serum cortisol level was 900 nmol/l); the histology did not show any evidence of a pituitary tumor. ACTH was now, therefore, considered to probably originate from an ectopic source. Every 6 h, 750 mg metyrapone (with 2.5 mg prednisolone twice daily) were recommenced, together with 2 g mitotane (also known as o',p'-DDD) every 8 h. Despite this treatment, biochemical control was suboptimal, and necessitated bilateral adrenalectomy in October 1986, and subsequent routine replacement therapy with hydrocortisone (10 mg on waking, and 5 mg at lunch and early evening time) and fludrocortisone (100 μg once daily) for life.

After convalescence, the ectopic ACTH source was again sought, by CT scanning and MRI of the thorax and octreotide scintigraphy, as well as surveillance procedures—but to no avail. On extended follow-up, every 6-12 months, the patient remained well and searches for the source were periodically made with thoracic and abdominal CT scanning, octreotide scintigraphy and, on a single occasion, gastroscopy and colonoscopy. Tests for the presence of gut peptides, tumor markers, and urine 5-hydroxyl-indole-acetic acid were negative; Nelson's syndrome did not occur, and levels of ACTH remained approximately constant in the region of 20-60 ng/l, 2 h after morning hydrocortisone. Pituitary MRI did not reveal a lesion. The patient married, had two children, and then divorced and remained well with regular menstruation.

In late 2005, CT scan showed a small lesion with the characteristics of a neuroendocrine tumor, in front of the aortic bifurcation which seemed to be arising from the appendix or cecal mesentery (Figure 1). Prior imaging was reviewed; this mass was present, although smaller, in May 2004 (Figure 2), but was absent before that. This suggested an ectopic source. In January 2006, a 3 cm by 2 cm tumor arising from the tip of the appendix and adherent to the retroperitoneum and ileal mesentery was found at laparotomy and removed at appendicectomy with en bloc resection of the adherent mesentery. The histology was typical of a carcinoid tumor with metastases to mesenteric and local nodes. Immunostaining for ACTH was negative; the block was sent for in situ hybridization for the ACTH precursor, pro-opiomelanocortin, but this was also negative. Postoperatively, the patient recovered well and was discharged.

Figure 1.

 

Venous phase intravenous and oral contrast enhanced CT scan (LightSpeed Ultra®, GE Healthcare, Waukesha, WI), 5 mm slice, pitch 1.35, showing a tumor (arrow) with a fleck of calcification, typical of a neuroendocrine tumor. The tumor seemed to be arising from the tip of the appendix. Taken late in 2005.

Figure 2.

Venous phase intravenous and oral contrast enhanced CT scan (LightSpeed Ultra®), 5 mm slice, pitch 1.35, showing the tumor (arrow) depicted in Figure 1 to have been present and smaller, yet overlooked 18 months earlier; however, as the tumor, being attached to the mesoappendix, was potentially mobile the apparent change in size might have been caused by a change in orientation. Taken in May 2004.

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