Bronchopulmonary carcinoid presenting as dexamethasone suppressible Cushing's syndrome.
In this report, we present a patient with dexamethasone suppressible Cushing's Syndrome (CS) from an ectopic tumor producing ACTH. The tumor could not be visualized by standard radiological imaging. Due to the patient's poor condition, intolerance to steroidogenesis inhibitors, and in order to avoid empiric adrenalectomy, a bronchoscopy was preformed and identified a small submucosal bronchopulmonary carcinoid tumor (BPC). This mass was partially resected at the time of the procedure. This case report demonstrates the complexity of the diagnostic pathways of CS including the possibility that ectopic tumors causing CS may be suppressed by dexamethasone and the utility of bronchoscopy in localizing and possibly resecting BPC if imaging is negative. BPC account for less than 1% of causes of CS. Yet, BPC are the most common cause of ectopic ACTH production causing CS. (1) It has also been hypothesized that this subtype of carcinoids have a more unfavorable outcome. (2) Whether this is because of the associated CS or because of a more locally aggressive tumor is unclear. (2,3)
A 52-year-old female presented with a right adrenal hemorrhage. At that time, she was found to be hypokalemic and hypertensive with signs of CS including truncal obesity, striae, glucose intolerance, hirsutism, and depression. Because of the adrenal hemorrhage, right adrenalectomy was performed, and an adrenal mass was removed which was negative for neoplasm. Post-surgical twenty-four hour urine cortisol was 2700 [micro]g/24hr (normal 10-100 [micro]g/24hr). Serum ACTH level was 911 pg/ml (normal <46pg/ml) indicating ACTH dependent secretion of cortisol. Pituitary MRI was unremarkable.
Postoperatively, the patient continued to have hypokalemia and hyperglycemia. She required large amounts of potassium and potassium sparing diuretics to maintain normal serum levels. Insulin was needed to control her hyperglycemia. Multiple classes of anti-hypertensives were necessary to control her blood pressure. High dose dexamethasone test was performed to distinguish between a pituitary and ectopic source. This test did suppress cortisol production. The patient was referred for inferior petrosal sinus vein sampling, which surprisingly did not show a central to peripheral ACTH gradient. Since petrosal vein sampling was negative, another source of ACTH was sought.
CT scan of the chest, abdomen, and pelvis was negative aside from left adrenal hyperplasia. Octreotide scanning was also negative. Adrenalectomy was considered since no tumor could be localized for resection. With laboratory data supporting ectopic ACTH production, yet imaging being persistently negative, it was decided to perform bronchoscopy to explore for possible BPC. An endobronchial lesion was discovered at the basilar segmental bronchi of the left lower lobe (Figure 1). Partial removal of the mass was performed with the assistance of laser. Pathology of the 5mm specimen revealed well differentiated neuroendocrine cells with positive staining for synaptophysin, chromogranin, and ACTH. Therefore, the diagnosis of BPC secreting ACTH was made (Figure 2). The patient initially did have some improvement in ACTH and cortisol levels immediately following the procedure. Hypokalemia also improved. However, over the course of the next 2-3 weeks ACTH and cortisol returned to pre-procedure levels and the patient once again suffered from the effects of hypercortisolism. Since the mass could only be partially resected with bronchoscopy, the residual tumor continued to produce ACTH. The patient developed pneumonia and significant atelectasis which made a lobectomy for total excision impossible. The patient died approximately 6 weeks after diagnosis from sepsis.
CS was initially described by Harvey Cushing in 1932. In the initial description, Cushing described a patient with the classic signs and symptoms of glucocorticoid excess. Cushing's initially described case was shown to be secondary to overproduction of ACTH from a pituitary adenoma. (4) Other causes of CS have been identified which are secondary to a primary adrenal process (adenoma or carcinoma) or secondary to ectopic ACTH production, most commonly associated with BPC of the lung.
The high dose dexamethasone test was developed to differentiate pituitary versus ectopic causes of CS. It consists of administering 8mg of dexamethasone between 2300 and 2400 hours with measurement of 0800 hour serum cortisol. If the morning cortisol is less than 5 mcg/ dL, or if there is more than a 50% decrease in the baseline morning cortisol then cortisol production is considered suppressible.(5) Pituitary Cushing's Disease is only somewhat resistant to feedback inhibition whereas ectopic tumors producing ACTH are usually completely resistant to feedback inhibition. (6)
The first diagnostic dilemma in this case was that the initial laboratory data suggested Cushing's Disease since the patient had an elevated ACTH and dexamethasone suppressibility. However, pituitary MRI was negative and inferior petrosal sampling did not show a central to peripheral ACTH gradient. These findings left us with an ectopic source of ACTH as the most likely diagnosis. Dexamethasone suppressibility of BPC causing CS has been demonstrated previously in the literature. (7,8) Ilias et al. reported that 6-14% of ectopic sources of CS demonstrated dexamethasone suppression in their case series. Most of these cases were BPC. (8) This case serves to alert physicians that high dose dexamethasone may in fact suppress ACTH produced by BPC. In fact, with suppressibility, BPC should be added to the differential diagnosis of CS.
The second diagnostic dilemma with this case lies with the localization of this ectopic source of CS. The patient did not have any pulmonary symptoms at the time of presentation. Most BPC tumors arise in the proximal airways and cause symptoms such as cough, wheezing, or hemoptysis. However, a quarter of patients with tumors located more peripherally are completely asymptomatic. (9) Such was the case with our patient. CT scan was performed of the chest, abdomen, and pelvis which was negative for tumor. Octreotide scan was also performed looking for a carcinoid tumor. This was again negative. Adrenalectomy was seriously considered to control the extreme glucocorticoid excess in this patient. Since BPC is the most common cause of ectopic ACTH secretion, (1,8,10) and since these tumors may show suppressibility in response to dexamethasone, a bronchoscopy was empirically done. This procedure found a small BPC which was partially resected. CT scanning should always be the next step when diagnostic testing points to an ectopic source of CS. Previous case series have shown that CT imaging localized the tumor in approximately 75-88% of cases of ectopic Cushing's. (9,10) BPC that result in ectopic ACTH secretion are usually very small and average between 4-10mm. (11) In addition to their small size, CT may also be less sensitive when detecting centrally located BPC because they may be mistaken for vessels. (12) Ilias et al. showed that octreotide scanning demonstrated only a 49% sensitivity and did not detect any tumors not already seen on conventional imaging. (8) CT and octreotide scanning are most useful when used in a complementary process. However, up to 19% of ectopic ACTH secreting tumors may never be identified with imaging. (7) In this case, the only treatment option is bilateral adrenalectomy or steroidogenesis inhibitors. Therefore, localization is extremely important both to avoid this drastic procedure and also to achieve cure of the BPC through resection. Previous literature has also suggested that if the CS does not disappear after treatment, the presence of residual disease is likely present. If long term recurrence of CS occurs, there is likely relapse of the carcinoid tumor. (13)
This case report demonstrates that BPC may be suppressed by dexamethasone. We encourage physicians to consider BPC in the differential when corticosteroid production is suppressed with high dose dexamethasone. We also suggest adding empiric bronchoscopy to the diagnostic algorithm when no pituitary source is identified and radiographic imaging is negative.
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Sarah Sofka, MD
West Virginia University
Timothy Jackson, MD
West Virginia University
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|Title Annotation:||Scientific Article|
|Author:||Sofka, Sarah; Jackson, Timothy|
|Publication:||West Virginia Medical Journal|
|Article Type:||Case study|
|Date:||Jan 1, 2013|
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