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Cyclical Cushing Syndrome Caused by Intermittent Ectopic ACTH Homogenesis Responsive to Somatostatin Analogues

Kaltsas, Th. MD*; Krassas, G. E. MD*; Pontikides, N. MD*; Tsotsia, E. MD*; Tsagarakis, S. MD, PHD†

Case Report
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Cushing disease accounts for 80% to 85% of ACTH-dependent disease, whereas 15% to 20% is caused by ectopic sources. Cyclical Cushing syndrome is an unusual phenomenon and is frequently associated with a pituitary adenoma. Diagnostic and therapeutic problems arise when diagnostic tests are performed in the “quiescent phase” of the disease at a time when cortisol levels are normal, when the tests confirm a cyclic ectopic hypercortisolemic pattern but no tumor can be identified, or when radiologic evaluation reveals a coincidental pituitary abnormality.

We present the case of a 29-year-old female with clinical Cushing syndrome caused by periodic hormonogenesis from an ectopic ACTH-secreting tumor, which was proved to be a bronchial carcinoid that responded to long acting somatostatin analogue (SM-a) treatment (Sandostatin LAR). The patient also had a coexisting pituitary microadenoma.

Recently, the SM-a octreotide has been shown to be effective in reducing cortisol levels in several communications. 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 that shows such a beneficial effect using the new long acting SM-a (Sandostatin LAR).

*From the Department of Endocrinology and Metabolism, Panagia Hospital, Thessaloniki, Greece.

†From the Department of Endocrinology and Metabolism, Evagelismos Hospital, Athens, Greece.

Address correspondence and reprint requests to: G. Krassas, M.D., Associate Professor of Medicine, Department of Endocrinology and Metabolism, Panagia Hospital, N. Plastira 22, N. Krini 55132, Thessaloniki, Greece. Telephone: +30 2310 447444; Fax: +30 2310 447444; E-mail: krassas@the.forthnet.gr

The diagnosis of Cushing syndrome remains one of the most difficult challenges in clinical endocrinology. The source of steroid excess is classified as either corticotropin (ACTH)-dependent (80%) or ACTH-independent (adrenal autonomy) 20% [1]. Cushing disease accounts for 80% to 85% of ACTH-dependent disease, whereas 15% to 20% of cases are caused by ectopic sources [2,3]. The tumors that produce the ectopic corticotropin syndrome are primarily of neuroendocrine cell origin. Small cell lung cancer is the most common cause of ectopic ACTH production, but usually in these patients the advanced and widespread malignancy dominates the clinical picture and the length of survival is short. Such patients rarely develop the classical, clinically recognizable Cushing syndrome, and usually seek treatment for a rapid wasting disease, hyperpigmentation, hypokalemia, myopathy, and diabetes mellitus. On the contrary, bronchial carcinoid is the most common cause of ectopic ACTH syndrome, presenting with clinical features of classical Cushing syndrome [4].

Cyclical Cushing syndrome is an unusual manifestation first observed in a patient with ectopic ACTH production from a bronchial adenoma and the term “periodic or intermittent hormonogenesis” has also been used to describe this phenomenon [5]. It is most frequently associated with a pituitary adenoma [6]. Periodic hormonogenesis adds difficulty in the diagnostic workup of Cushing syndrome because the different tests used may be intermittently normal depending on the time at which they are performed. Moreover, further diagnostic and therapeutic problems arise, when biochemical tests confirm cyclical ectopic hypercortisolemic pattern, but no tumor can be found or pituitary radiologic evaluation reveals a coincidental adenoma-like lesion, a finding that is present in up to 10% of normal adults [7].

Recently, the somatostatin analogue (SM-a) octreotide has been shown to be effective in reducing cortisol levels in several publications [8–10]. We report a patient with cyclical Cushing syndrome caused by periodic hormonogenesis from an ectopic ACTH-secreting tumor, which was proved to be a bronchial carcinoid responsive to the new long acting SM-a (Sandostatin LAR) treatment. The patient also had a coincidental pituitary microadenoma.

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CASE REPORT

A 29-year-old female patient presented in May 2001 at the department of Endocrinology, Panagia Hospital with weakness, muscle wasting, easy bruising, central obesity, increased weight by 6 kg in the last couple of months, moon face, striae, acne, deterioration of preexisting slight hirsutism, menstrual abnormalities, alopecia, polyuria, and hyperpigmentation although she has not been exposed to the sun. On clinical examination she had the typical features of Cushing syndrome and was found to be hypertensive (180– 100 mmHg). The initial laboratory findings (Table 1) showed that the patient had ACTH-dependent Cushing syndrome. Abdominal computed tomography (CT) showed bilateral hyperplasia of the adrenals, whereas sellar magnetic resonance imaging (MRI) revealed a 2-mm diameter tumor of in the right side of the pituitary gland.

Because of the low serum potassium levels and failure of cortisol response to high-dose dexamethasone suppression, an ectopic source of ACTH secretion was suspected and a readmission for further investigation was arranged. During her readmission (June, 2001) her cushingoid features were noted to have improved. She was amenorrheic but there was improvement in acne, moon face and weakness. She had lost 4 kg of weight and she was normo- to hypotensive, so her antihypertensive therapy was discontinued. The endocrine-biochemical investigations during her second admission (Table 2) revealed that the patient was normokalaemic without hypercortisolemia or hyperandrogenemia. Chest CT revealed two nodules, approximately 1.8 cm each, in the upper part of the lower lobe of the left lung. Bronchoscopy did not reveal abnormalities. The patient was discharged at her request for family reasons.

She returned 35 days later and reported that she had been in good health up to the previous week when her symptoms recurred. On examination she was hypertensive, with new striae, loss of hair, weakness, and increase in body weight (6 kg). Repeat laboratory investigations (Table 3) showed that the patient was again hypokalaemic and hypercortisolemic. A CRH test was performed with 100 μg CRH IV (Table 4), followed by inferior petrosal venous sinus sampling before and after combined CRH (100 μg CRH IV) and vasopressin (10 μg DDAVP IV) stimulation. The results of these tests (Table 5) confirmed the diagnosis of an ectopic ACTH-dependent Cushing syndrome with periodic hormonogenesis. Immediately after the final investigation and while she was waiting for thoracic surgery, the patient began treatment with the long acting somatostatin analogue (Sandostatin LAR, Novartis Pharma AG, Basle, Switzerland) 30 mg IM once every month. Serum ACTH, cortisol, and free urinary cortisol levels were measured every week for 4 consecutive weeks. A decrease in both serum and urine cortisol levels was found compared with baseline, which normalized at the end of the fourth week (Table 6). The patient had also a significant improvement in her clinical symptomatology. Because of these favorable results, her LAR treatment was continued and blood was taken every 2 weeks for ACTH and cortisol measurements. These results are presented in Table 6. Plasma ACTH levels also decreased to approximately 60% of baseline by the end of the fourth week, and remained so for the rest of the examination period (Table 6).

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.

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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).

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DISCUSSION

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 [14] 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 [4]. 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 [15]. 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 [6]. 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. [21] 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 [5]. 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.

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CONCLUSION

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.

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