Hap

Chapter 10

Functional Cortical Neoplasms Ali Zarrinpar and Michael W. Yeh

Introduction Adrenocortical neoplasms affect men and women equally. While they do not spare children [1], the prevalence of these tumors does increase with age, up to 7% in adults older than 50 [2, 3]. Many are found incidentally at autopsy [4] or by imaging done for other purposes. They may be detected because of symptoms or signs related to hormone production [5, 6] or size [5]. Some even appear outside of the actual adrenal gland [7]. Tumors of the adrenal cortex are classified according to function and malignancy. Functional adrenocortical tumors hypersecrete hormones that reflect their cells of origin. Tumors that produce aldosterone, cortisol, and sex steroids correspond to the zona glomerulosa, zona fasciculata, and zona reticularis, respectively. The fraction of detected adrenocortical tumors that are functional has increased from 50 to 79% in recent series [3, 8, 9]. Interestingly, acquired hyperplasia and adenomas may start out as nonfunctional processes and only later result in clinical manifestations of hormonal excess [10]. Adrenocortical carcinomas also frequently elaborate multiple hormones; however, these aggressive neoplasms will be specifically addressed in depth in Chap. 11. This chapter will cover the usually benign variants of functional tumors of the adrenal cortex. These tumors may cause hyperaldosteronism (Conn’s syndrome), hypercortisolism (Cushing’s syndrome), and, less commonly, virilizing or feminizing syndromes due to sex steroid excess. It is important to note that the distinction between benign and malignant adrenocortical tumors may be difficult to establish preoperatively, intraoperatively, and even on histopathology. Surgical specimens should be analyzed by pathologists experienced in using the microscopic criteria for malignancy, such as the Weiss revisited index (WRI) or the van Slooten index (VSI) [11–13]. Although routine use is currently not recommended, there are molecular markers such as IGF-II overexpression and allelic losses at 17p13 with immunohistochemistry M.W. Yeh () David Geffen School of Medicine, University of California, Los Angeles, CA, USA e-mail: [email protected] C. Sturgeon (ed.), Endocrine Neoplasia, Cancer Treatment and Research, vol 153, DOI 10.1007/978-1-4419-0857-5_10, © Springer Science+Business Media, LLC 2010

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of Cyclin E or Ki-67 that are being used experimentally to assess malignancy [3]. Ultimately, the diagnosis of adrenal malignancy is based on clinical behavior, i.e., local invasion, recurrence, or development of distant metastases over time. Thus, the histopathologic diagnosis of atypical adenoma mandates serial surveillance crosssectional imaging to screen for the possibility of metastatic disease. Genetic alterations found in familial cases of adrenocortical tumors include TP53 (17q13) in Li-Fraumeni syndrome, menin (11q13) in multiple endocrine neoplasia type 1, PRKARIA (17q22-24) in Carney complex, and p57kip2 (CDKN1C), KCNQ10T, H19, and IGF-II overexpression in Beckwith–Wiedemann syndrome. Mutations in menin, TP53, and CYP21 are also found in sporadic adrenocortical tumors. Treatment, in general, consists of adrenalectomy for all functional adenomas. Laparoscopic adrenalectomy is the preferred approach in almost all cases. Laparoscopic resection is relatively contraindicated in tumors larger than 10 or 12 cm, in those that are locally invasive, and in known carcinomas [14]. Some surgeons will approach considerably smaller tumors with a conventional open technique based on concerns over safety and malignant potential.

Primary Hyperaldosteronism and Aldosteronoma Hyperaldosteronism results in loss of potassium in the urine, retention of sodium, and hypertension [15, 16]. The hypertension can be moderate to severe and resistant to medication. The hypersecretion of aldosterone due to renal artery stenosis, or low-flow states such as congestive heart failure and cirrhosis, is considered secondary hyperaldosteronism. In these cases, high levels of aldosterone are the result of high renin levels, and the underlying causes need to be addressed. Primary hyperaldosteronism, on the other hand, is due to autonomous aldosterone oversecretion, which leads to suppression of renin levels via negative feedback on the juxtaglomerular apparatus. Primary hyperaldosteronism predominantly occurs in people between the ages of 30 and 50 years and has a slight male predilection. According to most reports, it accounts for approximately 1% of cases of hypertension [17]. Studies examining widespread screening of hypertensive populations reported a 10–40% prevalence of primary hyperaldosteronism [18], though these elevated figures are generally thought to reflect strong referral bias. The current consensus is that the actual prevalence of primary hyperaldosteronism in unselected hypertensive patients is approximately 5–13% [19]. The use of the plasma aldosterone concentration to plasma renin activity ratio (PAC/PRA) to screen hypertensive patients for primary hyperaldosteronism has been shown to increase the absolute number of unilateral adrenal-producing adenomas identified; however, the PAC/PRA ratio is nonspecific for this tumor because it is also positive in cases of primary hyperaldosteronism due to bilateral adrenal hyperplasia [20]. Studies comparing subjects biochemically confirmed to have primary hyperaldosteronism with controls matched for age and systolic blood pressure have

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demonstrated that primary hyperaldosteronism is independently associated with a significantly increased risk of stroke, myocardial infarction, atrial fibrillation, arterial wall stiffness, urinary albumin excretion, and left ventricular hypertrophy [21]. Much of this comorbid disease appears to improve 1 year after resection of an aldosterone-producing adenoma. Primary hyperaldosteronism may be due to a solitary aldosterone-producing adenoma as in the classic Conn’s syndrome (constituting about 60% of cases), bilateral idiopathic hyperplasia (35%), unilateral adrenal hyperplasia (~2%), adrenocortical carcinoma ( 3X normal

24 hr urine free cortisol x 2 1-3X normal Late evening cortisol x 2

145 ng/dL

Unlikely Cushing's Syndrome

Undetectable ACTH-independent disease

Probable Cushing's Syndrome

ACTH

Detectable/Elevated ACTH-dependent disease Mass > 6 mm

CT of adrenals

Localization

> 3 µg/dL

Low-dose dexamethasone suppression test

1.8 - 3 or high suspicion Normal

Biochemical Diagnosis

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Primary Adrenal (15%)

Suppression

High dose dexamethasone suppression test

(+) Gradient

Bilateral inferior petrosal sinus sampling (-) Gradient

Management

Pituitary ACTH Cushing's Disease (75%)

Adrenalectomy 90% effective

Pituitary MRI

Chest/Abd CT, Somatostatin receptor scintigraphy

Transsphenoidal pituitary microsurgery 75% effective Failure

Ectopic ACTH (1,000 pg/mL). Conversely, ACTH levels are characteristically suppressed or undetectable (7 ng/mL) to be a sensitive and specific test for androgen secreting adrenocortical tumors [90]. Feminizing tumors can be worked up by looking for elevated urine or serum 17-ketosteroids and estrogen levels.

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Treatment Sex steroid-producing tumors should be surgically removed whenever possible. Malignancy is difficult to diagnose histologically. It may be suggested by the presence of local invasion, recurrence, or distant metastases. Patients who are not acceptable surgical candidates can have chemical adrenolysis, using drugs such as mitotane, aminoglutethimide, ketoconazole, and flutamide. These agents may also be useful achieving palliation in patients with metastatic disease [96].

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