Tumor Localization

Imaging Evaluation

Imaging techniques can help to clarify the etiology of hypercortisolism. These usually include MRI of the pituitary and computed tomography (CT) scanning of the adrenal glands. CT and MRI scans of the chest and abdomen and isotope scans are also employed when searching for ectopic ACTH-secreting tumors.

Bilateral enlargement of the adrenal glands with preservation of a relatively normal overall glandular configuration is observed in both CD and ectopic ACTH production (71,72). Approximately 10% to 15% of patients with ACTH-dependent CS demonstrate bilateral adrenocortical nodules (macronodular hyperplasia).

Pituitary adenomas are arbitrarily subdivided into microadenomas and macroadenomas, defined respectively as having a diameter smaller or larger than 10 mm. A more important criterion than size is the topographic location of pituitary adenomas. For instance, adenomas (even when they are small) near the cavernous sinus or posterior pituitary (containing, for instance, vasopressin) can have a greater effect on endocrine function, remission rates, and vision (if near the optic chiasm), than more centrally located adenomas. The majority of pituitary ACTH-secreting tumors are microadenomas with a diameter <10 mm. Currently, MRI scanning is the imaging procedure of choice to visualize pituitary adenomas. Pituitary adenomas are usually best demonstrated on coronal postcontrast T1-weighted images with diminished gadolinium enhancement (hypoenhancing) where they appear as foci of reduced signal intensity (hypointense) within the pituitary gland (73,74). On unenhanced scans, however, ACTH-producing adenomas are detected in only 40% of patients with CD (75). Current MRI techniques have a sensitivity of approx 70% and specificity of approx 85% in detecting ACTH-secreting microadenomas as small as 3 mm (73).

The incidence of pituitary incidentalomas detected by MRI is approx 10% in the general population compared with <27% in autopsy series (74). Most incidentalomas are <5 mm in size and can be mistaken for ACTH-secreting adenomas, which can also occur at this size. Differential diagnosis can be achieved with inferior petrosal or cavernous sinus sampling, which should be employed before any transsphenoidal surgery in patients with Cushing's syndrome whose tumor is not visible or equivocal.

CT scanning with contrast infusion demonstrates microadenomas in less than 20% of patients with bona fide lesions on subsequent surgery. Thus, pituitary CT should be performed only if necessary to demonstrate bone anatomy before transsphenoidal surgery.

Catheterization Studies

Distinguishing CD from ectopic ACTH syndrome frequently presents a major diagnostic challenge. Both pituitary microadenomas and ectopic ACTH-secreting tumors may be radiologically occult and may have similar clinical and laboratory features. Bilateral inferior petrosal venous sinus and peripheral vein catheterization with simultaneous collection of samples for ACTH measurement is one of the most specific tests available to localize the source of ACTH production (76,77).

Venous blood from the anterior pituitary drains into the cavernous sinuses and subsequently into the superior and inferior petrosal sinuses. From there, blood exits the jugular foramen and joins the internal jugular vein (Fig. 1, upper panel). Catheters are led into each inferior petrosal sinus via the ipsilateral femoral vein. Samples for measurement of plasma ACTH are collected from each inferior petrosal sinus and a peripheral vein both before and after injection of 1 ^g/kg body weight of oCRH in the United States and 100 ^g hCRH in Europe. Patients with ectopic ACTH syndrome have no ACTH concentration gradient between either inferior petrosal sinus and the peripheral sample (Fig. 1, lower panel) (76). A ratio >2.0 in basal ACTH samples between either or both of the inferior petrosal sinuses and a peripheral vein is highly suggestive of CD (95% sensitivity, 100% specificity). Patients with ectopic ACTH secretion have a gradient of less than 1.6/1. Stimulation with CRH during the procedure with the resulting ACTH outpouring increases the bilateral inferior petrosal sinus sampling (BIPSS) sensitivity for detecting corticotroph adenomas to 100% when peak ACTH central to peripheral ratio is >3.0 (Fig. 1, lower panel). Petrosal sinus sampling must be performed bilaterally and simultaneously, because the sensitivity of the test drops to less than 70% with unilateral catheterization. A false-negative test result with bilateral inferior petrosal sinus sampling (BIPSS) may ensue from a hypo-plastic inferior petrosal sinus (<2% of patients with surgically proven CD) (78).

BIPSS is technically difficult and, as with all invasive procedures, can never be risk free even in the most experienced hands (79,80). It should be reserved only for patients with classic CS and negative or equivocal MRI of the pituitary and patients with positive pituitary MRI but equivocal suppression and stimulation tests. In the former group, BIPSS unequivocally distinguishes ACTH-secreting pituitary adenomas from lung and thymic carcinoid tumors and provides lateralization data of potential value to the surgeon. In the latter group, BIPSS will exclude the possibility of a pituitary incidentaloma, which can be visualized on MRI in as many as 10% of young women. The most common complication is a groin hematoma at the site of the venipuncture. Major neurologic complications occur in less than 1% of patients (79,80). In more than 100 patients, the overall complication rate was 13%, including permanent diabetes insipidus, deep venous thrombosis, and pneumonia (80). The diagnostic accuracy of BIPSS

in identifying pituitary ACTH hypersecretion is >95%, whereas it is only 60% in lateralizing the adenoma, owing to variable patterns of venous drainage. Routine presampling venography may allow more accurate interpretation of lateralizing ACTH gradients during BIPSS (81). Catheterization of the cavernous sinuses and jugular veins has also been performed in the diagnosis of CD, with high sensitivity and specificity. Although cavernous sinus sampling may be more accurate than BIPPS in predicting the side of the pituitary in which the tumor resides, it can also be more risky than BIPSS (82) (John Doppman, personal experience).

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