The patient underwent surgery in November 2001 and a tumor measuring 3.4 cm in diameter was removed from the lower lobe of the left lung. Pathologic examination showed that the tumor was a carcinoid that immunocytochemically was positive to ACTH, chromogranin, and specific neuronal enolase. Metastasis of the tumor was found in two excised lymph nodes.
Postsurgically the patient had a significant improvement. She became normokalaemic and normotensive, with resolution of her clinical symptoms. One, 2, and 3 months after the operation her cortisol and ACTH levels were within normal range.
MATERIALS AND METHODS
All endocrine tests were carried out between 0800 and 1100. The high-dose dexamethasone-suppression test was performed by administering an oral dose of 2 mg every 6 hours during a 2-day period. Blood was withdrawn for cortisol measurements at 0900. For CRH stimulation 100 μg human CRH (Ferring Arzneimittel GmbH, Kiel, Germany) was injected IV. Blood was withdrawn through an indwelling cannula before (−15) and 0, 15, 30, 45, 60, 90, and 120 minutes after the initiation of test. Inferior petrosal sinus sampling was carried out in the neuro-angiography suite. Under local anesthesia, the femoral vein was cannulated. Two “multipurpose” catheters (Cordis Corporation, Miami, FL) with guide wire were advanced into the right and left inferior petrosal sinuses, guided by digital subtraction imaging with the injection of small quantities of non-ionic water soluble contrast (Lopamidol). Human CRH (100 μg) and 10 μg DDAVP/Desmopressin Acetate (Ferring AB, Malmo, Sweden) were injected intravenously after both inferior petrosal sinus sampling catheters were in place. Samples were taken simultaneously from both inferior petrosal sinuses and a peripheral vein before (0) and at 5, 10, 15, 60, 90, and 120 minutes after the bolus injection. In patients with a pituitary source of excess ACTH production, the petrosal/peripheral gradient of ACTH (without or with CRH stimulation) is greater than 2 or 3, respectively, whereas localization to either side of pituitary can be predicted with 55% to 80% accuracy if the gradient across the two sides is greater than 1.4 [11–13].
Samples for ACTH were collected in EDTA tubes on ice, and plasma separated by centrifugation within 30 min and stored at −20°C until assayed. Plasma ACTH was determined by a commercially available two-site highly sensitive immunoradiometric assay (Nichols, Bad Nauheim, Germany). Urinary-free cortisol excretion was determined by RIA (NEN, Dreilich, Germany) and serum cortisol was measured by commercially available immunoradiometric assay (Diachel, Webster, TX).
The diagnosis and differential diagnosis of Cushing syndrome is one of the most perplexing problems in endocrinology and still remains a challenge for endocrinologists. Cushing syndrome caused by ectopic ACTH production was first described in 1928 by Brown  and is recognized to occur in association with small cell carcinoma of the bronchus and carcinoid tumors of the bronchus, pancreas, and thymus, but is most commonly caused by bronchial carcinoid . Some carcinoid tumors with associated Cushing syndrome produce corticotrophin-releasing factor instead of, or as well as, ACTH.
In our case, which had clear clinical features of Cushing syndrome, the urine-free cortisol value of 1122.6 (μmol/molCr/24h) was considered diagnostic . Our suspicion that we were dealing with an ectopic ACTHdependent Cushing syndrome, despite the presence of a pituitary tumor on MRI, was based on the low potassium, high ACTH levels and failure of serum cortisol and urine-free cortisol to suppress after the high-dose dexamethasone suppression test. We considered the abnormality on pituitary imaging as a coincidence, as it is known that approximately 10% of the normal adult population has pituitary abnormalities on MRI that are compatible with pituitary microadenoma known as “pituitary incidentaloma” [16,17]. The finding of two nodules in the upper part of the lower lobe of the left lung on chest CT further supported the diagnosis of ectopic Cushing syndrome.
To differentiate pituitary adenomas from the ectopic ACTH syndrome it is necessary to use stimulation tests. The most powerful test for determining the origin (pituitary vs. ectopic) and lateralization (left vs. right hemipituitary) of an ACTH-secreting lesion is inferior petrosal sinus sampling with simultaneous administration of ovine CRH [11,18]. The results of all these tests, which were performed in our patient, confirmed the diagnosis of an ectopic ACTH-dependent Cushing syndrome.
Although the typical clinical course of Cushing syndrome is one of continuous progression, cases in which cortisol production fluctuates have been reported. In particular, so-called cyclical Cushing syndrome has been described, which is characterized by peaks of cortisol production interspersed with normal levels [5,19–22]. Cyclical Cushing syndrome is an unusual phenomenon first observed in a patient with ectopic ACTH production from a bronchial adenoma and later being described in patients with pituitary or adrenal tumors . Affected subjects have temporary biochemical and clinical remission of hypercortisolism caused by periodic hormonogenesis by the tumor, as illustrated also by our case. In an extensive study, Atkinson et al.  found that cycles of excess cortisol secretion varying in duration between 12 hours and 85 days. The criteria that they suggested for diagnosis of cyclicity consisted of three peaks and two troughs of cortisol production with similar intervals between the peaks. These criteria existed in our patient, who had approximately 45-day intervals between the peaks.
The etiology of periodic hormonogenesis in ectopic Cushing syndrome is not fully understood. Three hypotheses have been proposed. The first is that the increase in hormone production follows the tumoral growth and development of new ACTH-secreting cells, whereas the decreased hormonal production is caused by areas of patchy necrosis in the ACTH-secreting tumor [5,23], which could account for intermittent ACTH secretion and thus variable degrees of adrenal stimulation. A second possibility as yet uncharacterized inhibitors or stimulators of ACTH release, elaborated within the tumor or other tissue, and finally, that the tumor is responsive but insensitive to feedback control . So a sluggish delayed response would result in cyclicity.
Surgical removal of the tumor is the treatment of choice. Recently it has been shown that SM-a are effective in reducing cortisol levels in such patients and could be used preoperatively or in cases where surgical intervention is impossible because of lack of localization of the tumor [8–10]. Our case confirms previous data concerning the usefulness of this therapeutic regime in reducing cortisol and ACTH levels in patients with ectopic ACTH hormonogenesis. Moreover, to our knowledge, this is the first report, which shows such a beneficial effect using the new long acting somatostatin analogue Sandostatin LARR, which is most probably superior to other forms of SM-a treatment because of the convenience of administration (once every month) and favorable tolerability by patients. Unfortunately, OctreoScan was not performed for technical reasons. One can argue that the reduced levels of ACTH and cortisol were caused by another trough of cyclicity and not to the medication. However, the fact that the cortisol levels became normal immediately after the first injection and remained so for the whole period of treatment is in favor of the latter. In our patient, SM-a induced only a partial ACTH drop; this decrease however, was sufficient to normalize cortisol secretion. The partial effect of octreotide suggests either a defective transduction system on the tumor cells or a heterogeneous population of responsive and non-responsive tumor cells. However, a different type of Sm receptor being expressed by the tumor cannot be excluded.
There are several key points illustrated by this case report. Periodic hormonogenesis can render the diagnosis of Cushing syndrome (particularly because of ectopic ACTH production) difficult, because the results of the stimulatory and suppressive tests depend on the time at which they are performed. Hypokalemia and high ACTH levels, which do not suppress after high-dose dexamethasone suppression, should alert the clinician to the diagnosis of ectopic ACTH syndrome even in the presence of a pituitary adenoma like lesion. Finally, although the surgical removal of the ectopic source of ACTH is the treatment of choice, long acting somatostatin analogue treatment before surgery, in order to make the patient eucortisolemic, in cases were localization of the tumor is not possible, or when the patient is too frail to undergo surgery, should be considered.
1. Trainer PJ, Grossman A: The diagnosis and differential diagnosis of Cushing syndrome. Clin Endocrinol (Oxf) 1991; 34: 317–30.
2. Orth DN: Cushing syndrome. N Engl J Med 1995; 332: 791–803.
3. Wajchenberg BL, Mendonca BB, Liberman B, et al.: Ectopic adrenocorticotropic hormone syndrome. Endocr Rev 1994; 15: 752–87.
4. Meier CA, Biller BMK: Clinical and biochemical evaluation of Cushing syndrome. Endocrinol Metab Clin North Am 1997; 26: 741–62.
5. Bailey RE. Periodic hormonogenesis – A new phenomenon. Periodicity in function of a hormone-producing tumor in man. J Clin Endocrinol 1971; 32: 317–27.
6. Sakiyama R, Ashcraft WW, Van Herle AJ: Cyclic Cushing syndrome. Am J Med 1984; 77: 944–6.
7. Aron DC, Howlett TA: Pituitary incidentalomas. Endocrinol Metab Clin North Am 2000; 29: 205–21.
8. Phlipponneau M, Nocaudie M, Epelbaum J, et al.: Somatostatin analogs for the localization and preoperative treatment of an adrenocorticotropin-secreting bronchial carcinoid tumor. J Clin Endocrinol Metab 1994; 78: 20–4.
9. Van den Bruel A, Bex M, Van Dorpe J, et al.: Occult ectopic ACTH secretion due to recurrent lung carcinoid: long-term control of hypercortisolism by continuous subcutaneous infusion of octreotide. Clin Endocrinol (Oxf) 1998; 49: 541–6.
10. Peri A, Bemporad D, Parenti G, et al.: Cushing syndrome due to intermittent ectopic ACTH production showing a temporary remission during a pulmonary infection. Eur J Endocrinol 2001; 145: 605–11.
11. Oldfield EH, Doppman JL, Nieman LK, et al.: Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing syndrome. N Engl J Med 1991; 325: 897–905.
12. de Herder WW, Uitterlinden P, Pieterman H, et al.: Pituitary tumour localization in patients with Cushing disease by magnetic resonance imaging: Is there a place for petrosal sinus sampling? Clin Endocrinol (Oxf) 1994; 40: 87–92.
13. Findling JW, Doppman JL: Biochemical and radiologic diagnosis of Cushing syndrome. Endocrinol Metab Clin North Am 1994; 23: 511–37.
14. Brown WH: A case of pluriglandular syndrome (diabetes of bearded woman). Lancet 1928; ii: 1022–3.
15. Tsigos C, Chroussos GP: Differential diagnosis and management of Cushing syndrome. Ann Rev Med 1996; 47: 443–61.
16. Molitch ME, Russell EJ: The pituitary “incidentaloma”. Ann Intern Med 1990; 112: 925–31.
17. Hall WA, Luciano MG, Doppman JL, et al.: Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med 1994; 120: 817–20.
18. Findling JW, Kehoe ME, Shaker JL, et al.: Routine inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing syndrome: Early recognition of the occult ectopic ACTH syndrome. J Clin Endocrinol Metab 1991; 73: 408–13.
19. Brown RD, Van Loon GR, Orth DN, et al.: Cushing disease with periodic hormonogenesis: one explanation for paradoxical response to dexamethasone. J Clin Endocrinol Metab 1973; 36: 445–51.
20. Sakiyama R, Ashcraft MW, Van Herle AJ: Cyclic Cushing syndrome. Am J Med 1984; 77: 944–6.
21. Atkinson AB, Kennedy AL, Carson DJ, et al.: Five cases of cyclical Cushing syndrome. Br Med J 1985; 291: 1453–7.
22. Vagnucci AH, Evans E: Cushing disease with intermittent hypercortisolism. Am J Med 1986; 80: 83–8.
© 2003 Lippincott Williams & Wilkins, Inc.
23. Thorner MO, Martin WH, Ragan GE, et al.: A case of ectopic ACTH syndrome: diagnostic difficulties caused by intermittent hormone secretion. Acta Endocrinol 1982; 99: 364–70.