Primary Adrenal Causes of Cushing's Syndrome

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1 Primary Adrenal Causes of Cushing's Syndrome Diagnosis and Surgical Management ROGER R. PERRY, M.D.,* LYNNETTE K. NIEMAN, M.D.,t GORDON B. CUTLER, JR., M.D.,t GEORGE P. CHROUSOS, M.D.,t D. LYNN LORIAUX, M.D.,t JOHN L. DOPPMAN, M.D., WILLIAM D. TRAVIS, M.D.," and JEFFREY A. NORTON, M.D.* Cushing's syndrome is rare with only 2% of patients having a primary adrenal cause of hypercortisolism. We have developed a strategy to evaluate patients with suspected Cushing's syndrome and to localize the pathologic condition responsible for the hypercortisolism. This report reviews the last 11 consecutive patients who had a primary adrenal cause of hypercortisolism. Each patient had elevated 24hour urine free cortisol and 17hydroxycorticosteroid excretion consistent with hypercortisolism. All but one patient had undetectable plasma ACTH levels. No patient suppressed urinary steroid levels with highdose dexamethasone and only one patient increased plasma ACTH or cortisol levels with ocrh, findings that were consistent with a pituitaryindependent form of hypercortisolism. No patient had a pituitary tumor detected by computed tomography or magnetic resonance imaging, and eight patients had adrenal tumors accurately imaged. MRI of the adrenal glands correctly diagnosed adenoma in 5 of 6 patients with adenomas, carcinoma in 1 patient, and ACTHproducing pheochromocytoma in 1 patient. One tumor classified as carcinoma by MRI appeared on pathologic examination to be an adenoma. Three patients underwent petrosal sinus sampling for measurement of ACFH before and after ocrh administration, and each had petrosal sinus ACTH levels equal to peripheral levels, consistent with a primary adrenal cause of hypercortisolism. Two of these patients had typical bilateral pigmented micronodular adrenocortical disease and the third patient had macronodular adrenocortical hyperplasia. Each of the 11 patients was cured of hypercortisolism by unilateral or bilateral adrenalectomy and no patient has developed recurrent disease during the 7 to 29 month followup period. New modalities including the ovine CRH test, MRI, and petrosal sinus sampling have improved the evaluation of certain patients with Cushing's syndrome. P5 ATIENTS WITH CUSHING'S SYNDROME have symptoms and signs affecting virtually every organ system. Physician recognition and diagnosis ofthe syndrome is often delayed because endogenous hyper Correspondence and reprint requests: Jeffrey A. Norton, M.D., Surgery Branch, National Cancer Institute/NIH, Building 1, Room 2B5, Bethesda, MD 2892 Accepted for publication: September 2, From the Surgical Metabolism Section, Surgery Branch, * and the Laboratory of Pathology,"I National Cancer Institute, the Developmental Endocrinology Branch, National Institute of Child Health and Human Development,t and the Department of Radiology of the Clinical Center,f National Institutes of Health, Bethesda, Maryland cortisolism is rare (1 patients per 1 million),' the signs of hypercortisolism occur in other disease processes, the changes may be subtle, and no particular symptom or sign occurs in every patient. Without recognition and proper treatment, Cushing's syndrome results in high rates of morbidity and mortality. Untreated patients have a 5 year survival rate of 5% with most deaths resulting from infection or cerebrovascular disease.2 In the 195s, the treatment of choice for Cushing's syndrome was bilateral adrenalectomy, which markedly increased survival compared to untreated patients.2 However, it later became clear that most patients with Cushing's syndrome do not have primary adrenal disease.3 Adrenalectomy is now used principally for patients with primary adrenal disease, occult ectopic ACTH syndrome, or pituitary disease that is refractory to other treatments. The diagnosis of Cushing's syndrome requires recognition of the clinical syndrome confirmed by appropriate laboratory tests. Both biochemical and radiological studies are necessary to achieve a diagnostic accuracy approaching 1%. Recent advances, including the ovine corticotropin releasing hormone (ocrh) stimulation test,47 adrenal magnetic resonance imaging (MRI),8 9 and petrosal sinus sampling,' have facilitated the preoperative diagnosis of these patients. The strategy for the diagnosis and localization of the causes of Cushing's syndrome that we have employed at the National Institutes of Health (NIH) is outlined in Figure 1. This report will review our last 11 consecutive patients with Cushing's syndrome due to pri 59

2 6 r Howc_dNs _iii D"K. Tom (Se d g 24h Wm Fm Co"o 24h Urhe 17OHS / Cm. P kre*andrwi ocrh Too (hd*w ACTH) Low loahigih Dow Dox. Ttg, _~~~~~~~~~~~~~1 oh ATuH I I ocrh:actht rocrh:a _ IcR Cortdo I Coier Dex.: Low Doae D x: Low Do r High Dos High Dow Petrosl ACTH Gradient BI. Adrenal Hyperrophy Uni. or Bitel Macronodues Pituitery Adenma Pituitery Adenoma vs. Ectopic CRH (rare) Pblm CRH Macronodule vs. Autonomous Adrenal Adenoma lodochoesterol Uptake Radilogi Localization of Surce CTA/RIAel CT/MRI Sob Petr Sinu Sampin I Ectopic I No Posal ACTH Gradient BN. Adrenal Hypertrophy Chao CT/MRI Abdomen CT/MRI Bronchoscopy N"dle Aspiration Other Hormore (Catechoamines, Calcitonin, Gastrin, VIP, PP, Neurotensn, etc.) PERRY AND OTHERS ocrh: ACTH Urdetecal Dox: Low Doe High Dome ACTH Undetectable Adenoma Carcnoma Micronodular Des (nl. CT/MRI) * Adenoma vs. Carcinoma ld lrs Uptake FIG. 1. Diagnostic approach for the patient with suspected Cushing's syndrome. The first step is to establish hypercortisolism with the overnight dexamethasone suppression test and 24hour urine free cortisol and 17 OHS excretion. If these tests demonstrate hypercortisolism, the results of the ocrh test and dexamethasone suppression test will discriminate between pituitarydependent and pituitaryindependent causes. Further localization requires radiologic studies including CT and/or MRI of the adrenal glands and sella turcica and/or petrosal sinus sampling. Additional studies may be indicated based on the tentative diagnosis as indicated in the figure (t, value increased; 1, value decreased;, value unchanged). mary adrenal disease, with emphasis on the diagnostic evaluation and the current indications and technical approach to adrenalectomy. Biochemical Evaluation Methods The records of 11 consecutive patients with an adrenal cause of Cushing's syndrome who were treated between 1985 and 1988 were reviewed. All patients were studied prospectively according to the diagnostic protocol outlined in Figure 1. Hypercortisolism was evaluated by measuring morning and evening plasma cortisol, 24hour urine free cortisol (UFC), and 24hour urine 1 7hydroxycorticosteroid (17OHS) excretion. Pituitary dependence or independence was assessed with the 6day lowdose and highdose dexamethasone suppression test and the ocrh stimulation test.4'5 A positive response of the dexamethasone test consistent with Cushing's disease (pituitary etiology) was defined as a decrease ofurinary 17hydroxy Ann. Surg. July 1989 corticosteroids of 2 5% or urinary free cortisol of 8% of the mean baseline levels on the second day of highdose dexamethasone administration. Ovine CRH was given at a dose of 1 mcg/kg iv and a positive response (consistent with Cushing's disease) was defined as an increase in the mean level of adrenocorticotropic hormone (ACTH) or cortisol of more than four times the intraassay coefficient of variation of the mean baseline concentration. The typical intraassay coefficient of variation was 6% for baseline ACTH levels between 9 and 3 pg/ml and cortisol levels between 4 and 35,g/dl. The interassay coefficient of variation was 14% to 26% for ACTH and 9% to 12% for cortisol.s Additional hormonal tests including 24hour urine catecholamines, vanillylmandelic acid (VMA), and metanephrines, plasma calcitonin, and other peptide hormone tumor markers were performed, if indicated, to attempt to localize the source of ectopic ACTH secretion (Fig. 1). Radiological Evaluation Computed tomography (CT) and/or magnetic resonance imaging (MRI) of the adrenal glands and the pituitary gland were performed in all patients. Petrosal sinus sampling was performed in patients in whom initial biochemical evaluation indicated a primary adrenal cause of Cushing's syndrome and in whom CT or MRI either failed to show an adrenal abnormality or indicated bilateral diffuse or nodular hyperplasia consistent with Cushing's disease. Bilateral simultaneous sampling of both petrosal sinuses and a peripheral vein for plasma ACTH levels was performed before and after ocrh administration.' Patients with Cushing's disease generally have a gradient greater than 1.6:1 in ACTH levels on one side compared to the contralateral side and to the periphery. Patients with a primary adrenal etiology have low ACTH levels that are similar in the petrosal sinuses and peripheral veins. In addition, iodocholesterol scans were performed in some patients with an uncertain diagnosis in whom a primary adrenal etiology was suspected but no adrenal abnormality could be imaged by CT or MRI scanning. As previously reported,8'9 the MRI T2weighted image intensity ofthe adrenal tumor was compared to the image intensity of the liver. If the intensity of the adrenal mass was more than three times that of the liver, the tumor was presumptively considered a pheochromocytoma based on MRI criteria. If the adrenal gland image was slightly (approximately 1.5 to 2.5 times) brighter than the liver, the tumor was considered a probable carcinoma, and if the adrenal image was equal to or less bright than the adjacent liver, the tumor was predicted to be a benign adenoma. The prospective diagnoses of adrenal masses based on MRI criteria were subsequently compared to the pathologic diagnoses of the specimens.

3 Vol. 21 * No. I Surgery and Pathology All patients underwent either unilateral or bilateral adrenalectomy. The posterior approach with resection of the 12th rib was performed for small lesions even if bilateral adrenalectomy was necessary. Bilateral adrenalectomy was performed through two separate posterior incisions. The anterior approach was chosen for all adrenal lesions greater than 6 cm in diameter, or if the MRI indicated carcinoma or pheochromocytoma, or if additional abdominal disease requiring surgical treatment was present. In general, adrenal arteries and veins were controlled by hemoclips and not suture. Adrenalectomy specimens were examined carefully for cortical and medullary abnormalities. The glands were weighed and examined grossly by a single pathologist for diffuse or localized abnormalities such as nodularity, hyperplasia or atrophy. These gross abnormalities were correlated with microscopic and clinical findings resulting in subclassification according to previously described criteria for adrenal adenoma,"113 carcinoma,113 pheochromocytoma, " diffuse cortical hyperplasia, " bilateral primary pigmented micronodular adrenocortical disease,""4'16 and macronodular hyperplasia. " Results The results are grouped according to the final pathologic diagnosis. The four diagnoses were adrenal cortical neoplasm (adenoma and carcinoma, n = 7), adrenal medullary neoplasm (pheochromocytoma, n = 1), bilateral primary pigmented micronodular adrenocortical disease (n = 2), and bilateral adrenocortical macronodular hyperplasia (n = 1). Signs and Symptoms CUSHING'S SYNDROME FC, C C., C C: 2co la C) 2 4 5D.8 I ' N U' t 'T U W) I o o en _ ap _ t _4. o11 oo e o e urt. as < Z,orX z moi I o o e 8.l e s e c) al 2 61 All except one ofthe 11 patients were female. The mean age of all patients was 39.6 years (range, 14 to 65 years). The two female patients with pigmented micronodular disease were the youngest with a mean age of 17 years (Table 1). Weakness and weight gain (truncal obesity) were the most common presenting symptom and sign, respectively, with 8 of 11 patients presenting with each. The remainder of the symptoms and signs are listed in Table 1 in order of decreasing frequency. No single symptom or sign occurred in every patient. C C.,. :. * ' "ci VI) _ I) In ei. U ' ou a. Endocrine Studies c N en _ O. Plasma ACTH levels were low in all patients except one who had an ACTHproducing pheochromocytoma (Table 2). Twentyfourhour urine free cortisol and 17 hydroxycorticosteroid levels were elevated in all 11 patients. The ochr test did not increase plasma ACTH or cortisol levels significantly in any patient except one, = o 2 ' <: < <: < CE

4 62 TABLE 2. Establishment ofhypercortisolism and Pituitary Independence in Patients with a Primary Adrenal Cause ofcushing's Syndrome Per cent Urine Per cent Morning Delta Per cent Delta 17OHS Per cent Delta Plasma Delta Plasma Cortisol Urinefree UFC with High mg/gr 17OHS with Pathologic ACTH ACTH Cortisol with cortisol Dose creatine/ HighDose Group n pg/ml with ocrh mcg/dl ocrh mcg/24 h Dexamethasone 24 h Dexamethasone Reference range <425* > +25%t 42* > +25%t 295* 8 to 1%t 26* 5 to 1%t Adrenal cortical 7 <4 +7.5% % % % neoplasm (2.6, 5.1) (, +197) (1.4, 24.) (16, +87) (94, 873) (74, +78) (9.2, 2.7) (46, +36) Adrenal % ,7 34% 15 35% medullary neoplasm Adrenal cortical 2 <4 % % % % micronodular (18.4, 18.6) (2, +4) (195, 349) (+46, +1) (9.5, 13.5) (+33, +51) disease Adrenal cortical 1 <4 % % 22 Not done % macronodular hyperplasia All numbers for groups with n > 1 are listed as medians with the range given in parentheses. * Normal range. t Response seen in patients with Cushing's disease. Pituitaryindependent forms of Cushing's Syndrome should have less stimulation. PERRY AND OTHERS Ann. Surg. * July 1989 t Range for patients with Cushing's Disease. Pituitaryindependent forms ofcushing's Syndrome should have less suppression. Normal subjects have essentially complete suppression (to the assay detection limit) with highdose dexamethasone. which is consistent with the diagnosis of a primary adrenal cause of Cushing's syndrome in 9 of 1 patients and ectopic ACTH syndrome in the final patient. Highdose dexamethasone did not suppress urine free cortisol and 17hydroxycorticosteroid levels in any patient, which is consistent with a nonpituitary cause of Cushing's syndrome in all 11 patients (Table 2). The patient with an ACTHproducing pheochromocytoma had elevated 24 hour urine VMA, metanephrines, and catecholamines. Radiologic Studies Preoperative CT of the sella turcica was normal in all patients (Table 3). CT ofthe adrenal glands was abnormal in nine patients and normal in the two patients with micronodular hyperplasia. The seven patients with adrenal cortical neoplasms each had a unilateral adrenal mass with a normal or atrophic contralateral adrenal gland. The one patient with an ACTHproducing pheochromocytoma had bilateral adrenal hyperplasia visible on CT (Fig. 2) and T2weighted MRI demonstrated a central area of increased signal in the right gland consistent with a pheochromocytoma. This lesion was not suspected clinically or on CT exam. The patient with macronodular adrenal hyperplasia had bilateral massive nodular enlargement of both adrenal glands on CT. CT documented the size and location of the adrenal pathologic condition in 82% of the patients with no falsepositive results. Magnetic resonance imaging T1weighted images gave results similar to CT. It identified the size and location of the adrenal pathologic condition in 82% of patients with no falsepositive results. In addition, the T2weighted image accurately predicted the final pathologic diagnosis in 7 of 8 (88%) tumors, including a pheochromocytoma (Fig. 2), a carcinoma (Fig. 3), and 5 of 6 adenomas. However, T2weighted MR image predicted a carcinoma in one patient who appears to have an adrenal adenoma (Table 3). The patients with primary bilateral adrenocortical disease (2 micronodular and 1 macronodular) each underwent petrosal sinus sampling for ACTH levels with and without ocrh to document that no pituitary source of increased ACTH was present. In each patient petrosal sinus ACTH levels were bilaterally less than the detection limit of 4 to 6 pg/ml and no change in levels was elicited following ocrh. In addition, iodocholesterol scans were performed in these patients with scanning attempted 48 hours after administration of the iodocholesterol. Two patients (one with pigmented micronodular disease and one with macronodular hyperplasi had uptake in both adrenal glands, but the other patient with pigmented micronodular disease had no accumulation of iodocholesterol in either adrenal gland. Surgery and Pathologic Condition A unilateral adrenalectomy was performed in eight patients and bilateral adrenalectomy in three patients. All patients were cured of endogenous hypercortisolism. Patients undergoing unilateral adrenalectomy were maintained after operation on maintenance doses of hydrocortisone ( 12 to 15 mg/m2/day) until the cortisol response

5 Vol. 21 No.lI CUSHING'S SYNDROME TABLE 3. Localization Studies in Patients with a Primary Adrenal Cause of Cushing's Syndrome Number with Number with Number with Number in whom MR Abnormal Abnormal Abnormal T2 Ratio Predicted Pathologic Group n Adrenal CT (%) Pituitary CT (%) Adrenal MR (%) Pathologic Diagnosis (%) Adrenal cortical neoplasm 7 7 (1) () 7 (1) 6 (86) Adrenal medullary neoplasm Adrenal cortical micronodular disease 2 ()* () ()* () Adrenal cortical macronodular hyperplasia * CT and MRI were normal in these 2 patients but iodocholesterol scan indicated hyperfunction of both adrenals in one patient. 63 to ACTH was normal (6 to 12 months). Patients undergoing bilateral adrenalectomy were maintained after operation on maintenance doses of hydrocortisone and mineralocorticoid (fluorinef R 5 to 1 mcg/day). All patients had immediate postoperative hydrocortisone doses rapidly tapered so that maintenance doses were reached by postoperative days 5 to 7. The posterior approach was chosen in five patients for either small adrenal cortical adenomas or micronodular adrenal disease. The mean weight of the adrenal adenomas resected through the back was 12 grams and the four resected micronodular disease glands had a mean weight of 5 g (Table 4). The anterior or flank approach was chosen in six patients and each patient had either large hyperplastic adrenal glands or large adrenal neoplasms. Glands removed anteriorly included a carcinoma and a pheochromocytoma, which were larger than glands removed via the posterior approach (Table 4). There were no complications except for one patient who suffered a temporary axillary nerve injury with dominant extremity paresis. The final pathologic diagnosis was adrenal cortical adenoma in 6 patients, pheochromocytoma with associated diffuse adrenocortical hyperplasia in 1 patient, adrenal cortical carcinoma in 1 patient, bilateral primary pigmented micronodular adrenocortical disease in 2 patients, and bilateral adrenocortical macronodular hyperplasia in 1 patient (Table 4). The three patients with bilateral nodular adrenal cortical abnormalities deserve special mention. The patient with macronodular hyperplasia had markedly thickened adrenal cortices with multiple nodules ranging in size from several millimeters to 4 cm. The total weight of both glands combined was 95 g. Histologically the cortical macronodules were composed of large cells with clear to granular cytoplasm alternating with compact eosinophilic cells. Both patients with pigmented micronodular disease had small to normalsized adrenal glands with a combined weight of 9.5 g in one and 9.4 g in the other. The crosssectioned surface of each gland revealed multiple brown to gray 1 mm to 2 mm pigmented nodules. Histologically these nodules were circumscribed but not encapsulated and consisted of large cells with darkly eosinophilic cytoplasm containing varying amounts of brown cytoplasmic pigment. Occasional foci of lipomatous change were seen in the nodules. The intervening adrenal cortex among these nodules was atrophic. Discussion The diagnostic evaluation of patients with Cushing's syndrome has advanced during the past 5 years. New tests such as the ovine CRH test,47 petrosal sinus sampling for ACTH levels,' and magnetic resonance imaging of the adrenal glands8'9 have contributed to the ability to achieve an accurate diagnosis. These tests have been incorporated into our diagnostic protocol for patients with Cushing's syndrome (Fig. 1, Table 5) and are currently undergoing prospective evaluation in a large series of patients. Most patients (75%) who present with Cushing's syndrome have Cushing's disease due to an ACTHproducing pituitary adenoma.' Often these pituitary adenomas are microadenomas and are not seen on high resolution CT.'7 Bilateral petrosal sinus sampling for ACTH in the patient with Cushing's disease will usually demonstrate a gradient and thereby localize the tumor to one half of the pituitary gland, enabling the neurosurgeon to successfully resect it.' In addition, petrosal sinus sampling can provide diagnostic information in the patient with ectopic ACTH syndrome or primary nodular adrenocortical disease whose condition is confusing, because patients with Cushing's disease have a clear ACTH gradient between the petrosal sinus and the peripheral veins, whereas patients with ectopic ACTH syndrome or primary nodular adrenocortical disease do not.'8 The present study excluded patients with Cushing's disease (pituitary adenom and patients with ectopic ACTH syndrome from nonadrenal sources and focused only on patients with a primary adrenal cause of Cushing's syndrome. Each patient in this study had clear biochemical evidence for hypercortisolism (elevated 24hour urine free cortisol and 1 7hydroxycorticosteroid excretion; Table 2). In addition, no patient in this study had normal suppression of urinary steroid levels following the oral administration of lowdose dexamethasone, again consistent with Cushing's syndrome. Highdose dexamethasone

6 64 PERRY AND OTHERS Ann. Surg. July 1989 FIGS. 2AC. (A) Computed tomography reveals bilateral hyperplastic adrenal glands (arrows) with a fullness on the right. (B) T,weighted (SE 64) image reveals a hyperplastic left adrenal of low signal intensity (single left arrow) and a right adrenal mass (double right arrows) of a signal intensity comparable to liver (adrenal/liver ratio = 1). (C) T2weighted image (SE 2/8) reveals a very bright right adrenal mass (adrenal mass/liver ratio >3). On other cuts, the left adrenal appeared of low signal intensity. failed to suppress urinary free cortisol levels or urinary 1 7OHCS levels by 8% or 5%, respectively, in all 11 patients, and ocrh administration did not increase plasma ACTH or cortisol levels by 25% in 1 of the 11 patients (Table 2). Thus, these indirect tests were useful in excluding pituitarydependent Cushing's disease, but the ocrh test lacked 1% diagnostic accuracy for this purpose. ACTH levels were low in all but one patient and thus were also consistent with a primary adrenal cause of hypercortisolism in 9 1% of the patients. Finally, pituitary imaging studies failed to demonstrate an abnormality in any patient (Table 3). However, this information is of limited diagnostic usefulness because approximately 6% of patients with Cushing's disease will have microadenomas that are not seen with CT.'7 Patients with endocrinologic evidence for a primary adrenal source of Cushing's syndrome (hypercortisolism, low ACTH levels, failure of suppression with highdose

7 VOl. 21. NO. I CUSHING'S SYNDROME 65 FIG. 2. (Continued) dexamethasone, and failure of stimulation with ocrh) have, in most cases, a solitary adrenal mass (as in 7 of the 11 patients in this study). With the above endocnnological evidence and a clear unilateral abnormality on CT or MRI, the evaluation is complete. The only remaining question for the surgeon is what type of incision to make. The MRI scan can help answer that question. It can provide evidence for a carcinoma (Fig. 3) that requires the anterior or thoracoabdominal approach to allow complete abdominal exploration and enbloc tumor resection. The posterior approach is preferred for small adrenal cortical masses (< 6 cm) or micronodular adrenals (Table 4), especially because patients with Cushing's syndrome usually have truncal obesity, which can hinder the abdominal approach. The adrenal glands are more readily accessible in these patients via the posterior approach and there are less incidences of perioperative morbidity. However, general access is limited with the posterior approach and with larger tumors (2 6 cm) we would ordinarily select the anterior or flank approach. One patient had ectopic ACTH syndrome due to an ACTHsecreting adrenal pheochromocytoma.19,2 We recommend measurement of urinary catecholamines in patients with suspected ectopic ACTH syndrome (Fig. 1). Patients with ectopic ACTH syndrome often have the most severe degree of Cushing's syndrome. This 38yearold woman had plasma and urinary cortisol levels much greater than the other patients (Table 2) and such severe weakness that she was almost bedridden. CT and MRI documented bilateral adrenal enlargement with an adrenal mass on one side and contralateral diffuse enlargement (Figs. 2A and B). The MRI T2weighted image demonstrated marked brightness of the adrenal mass consistent with a pheochromocytoma (Fig. 2C). After preoperative preparation with phenoxybenzamine and propranolol, the pheochromocytoma was resected through an abdominal approach. The final three patients with bilateral nodular adrenocortical disease were the most challenging diagnostically. As stated before, endocrinological evaluation of these patients was consistent with a primary adrenal cause of hypercortisolism (Table 2). However, CT and MRI examinations depicted normal adrenal glands in two patients and diffuse macronodular enlargement of both glands in the final patient. Petrosal sinus sampling was performed in each patient and levels of ACTH were low, consistent with a pituitaryindependent cause of hypercortisolism. In young female patients who may have bilateral pigmented micronodular adrenal disease, we recommend iodocholesterol scans to attempt to demonstrate that the cortisol excess is coming from the adrenal glands as opposed to ectopic adrenal rest tissue or a factitious source (Fig. 1). lodocholesterol scans were performed in both micronodular patients, but one patient failed to have increased uptake in the adrenal glands. Nevertheless, adrenal glands resected from both patients had bilateral pigmented micronodular adrenal disease (Table 4) identical to the previous descriptions ofthat pathologic entity as a primary adrenal cause of hypercortisolism.'j146 Recent observations support the hypothesis that hypercortisolism in pigmented micronodular disease may be due to circulating immunoglobulins that stimulate adrenal steroidogenesis.2' The patient with macronodular adrenocortical hyperplasia is the most problematic from an etiologic standpoint. This adrenal abnormality is usually associated with a longstanding ACTHsecreting pituitary microade

8 66 PERRY AND OTHERS Ann. Surg. * July 1989 FIGS. 3AC.(A) CT shows a 6cm mass (arrows) replacing the left adrenal gland in a patient with Cushing's syndrome. (B) T, weighted magnetic resonance scan shows a mass of low signal intensity comparable with liver (adrenal mass/liver ratio =.9). (C) T2 weighted MR scan shows a bright left adrenal mass with a mass/liver ratio of 2, compatible with diagnosis of malignant cortical tumor. Pathologic examination confirmed the diagnosis of adrenocortical carcinoma. noma."'22 It may be that this patient had a transition from Cushing's disease to autonomous cortisolsecreting adrenal macronodules that suppressed peripheral ACTH levels to low or undetectable levels. This explanation has been proposed recently for a similar patient.23 Our patient is now being closely followed for evidence of an emerging pituitary adenoma. In summary, a diagnostic strategy for the evaluation of patients with Cushing's syndrome has been presented (Fig. 1) with the focus on patients with primary adrenal causes

9 Vol. 21.No. I CUSHING'S SYNDROME 67 4 E'j FIG. 3. (Continued) ofendogenous hypercortisolism. The experience includes patients with adrenal cortical tumors (both adenoma and carcinom, adrenal medullary tumors producing ACTH, and bilateral nodular adrenocortical disease. Each patient was cured of cortisol excess by unilateral or bilateral adrenalectomy and no patient has developed recurrent hypercortisolism, although followup is short (mean, 14.6 months; range 7 to 29 months). The results of this study demonstrate that significant changes have occurred in the diagnostic workup of patients with Cushing's syndrome. New modalities including the ovine CRH test, petrosal sinus sampling, and magnetic resonance imaging each may add more certainty to the evaluation of these difficult patients. Because these studies do increase cost, all studies may not be indicated in all patients. Patients with primary adrenal tumors need only the establishment of hypercortisolism and an imaging study such as CT or MRI. However, patients with primary bilateral adrenocortical disease TABLE 4. Surgical Approach and Pathologic Findings ofpatients with a Primary Adrenal Causefor Cushing's Syndrome Mean Mean Weight of Weight of Number with Pathology of Gland, Gland, Posterior Specimens, Posterior Pathology of Specimens, Anterior Pathologic Group n Approach (%) Posterior Approach Approach (g) Anterior Approach Approach (g) Adrenal cortical 7 3 (43) Adenoma 12 1 cancer 167 neoplasm 3 adenomas 33 Adrenal medullary 1 None Pheochromocytoma with 3 neoplasm diffuse hyperplasia of adjacent cortex Adrenal cortical 2 2 (1) Bilateral pigmented 5 None micronodular 12 mm nodules disease Adrenal cortical 1 None Bilateral macronodular 47 macronodular cortical hyperplasia hyperplasia (34 cm diameter nodules)

10 68 PERRY AND OTHERS Ann. Surg. July 1989 TABLE 5. Results ofdiagnostic Evaluation HighDose ocrh Dexamethasone CT/MRI Petrosal Sinus lodocholesterol Serum ACTH Test Test Sella CT/MRI Adrenals Sampling Scan Pituitary Normal to mildly + >5% suppression +/ Mild bilateral + + Cushing's elevated enlargement or normal Ectopic Normal to No suppression Enlarged bilaterally + ACTH markedly or normal elevated Adrenal Undetectable No suppression Unilateral adrenal NA Adenomas + neoplasms mass Carcinomas Micronodular Undetectable No suppression Minimal diffuse disease enlargement ("knobby") or normal * At 48 hours. May become positive if studied for longer intervals. +, positive test;, negative test; +/, test may be positive or negative. NA, not applicable. can benefit from the ocrh test and petrosal sinus sampling to verify the diagnosis and allow appropriate surgical therapy. References 1. Loriaux DL, Cutler GB. Diseases of the adrenal glands. In Kohler PO, ed. Clinical Endocrinology. New York: John Wiley and Sons, 1986: Plotz CM, Knowlton AI, Ragan C. The natural history of Cushing's syndrome. Amer J Med 1952; 13: Orth DN, Liddle GW. Results of treatment in 18 patients with Cushing's syndrome. N Engl J Med 197 1;285: Chrousos GP, Schulte HM, Oldfield EH, et al. The corticotropinreleasing factor stimulation test. N Engl J Med 1984;31: Nieman LK, Chrousos GP, Oldfield EH, et al. The ovine corticotropinreleasing hormone stimulation test and the dexamethasone suppression test in the differential diagnosis of Cushing's syndrome. Ann Intern Med 1986;15: Chrousos GP, Schuermeyer TH, Doppman J, et al. Clinical applications of corticotropinreleasing factor. Ann Intern Med 1985;12: Gold PW, Loriaux DL, Roy A, et al. Responses to corticotropinreleasing hormone in the hypercortisolism of depression and Cushing's disease. Pathophysiologic and diagnostic implications. N Engl J Med 1986;314: Reinig JW, Doppman JL, Dwyer AJH, et al. Adrenal masses differentiated by MR. Radiology 1986;158: Doppman JL, Reinig JW, Dwyer AJ, et al. Differentiation of adrenal masses by magnetic resonance imaging. Surgery 1987; 12: Oldfield EH, Chrousos GP, Schulte HM, et al. Preoperative lateralization of ACTHsecreting pituitary microadenomas by bilateral and simultaneous inferior petrosal venous sinus sampling. N Engl J Med 1985;312: Page DL, DeLellis RA, Hough AJ. Tumors of the Adrenal, Atlas of Tumor Pathology, Second Series, Fascicle 23, Armed Forces Institute of Pathology, Hough AJ, Hollifield JW, Page DL, Hartmann WH. Prognostic factors in adrenal cortical tumors. A mathematical analysis ofclinical and morphologic data. Am J Clin Pathol 72:39399, Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8: , Shenoy BV, Carpenter PC, Carney JA. Bilateral primary pigmented nodular adrenalcortical disease. Rare cause of the Cushing syndrome. Am J Surg Pathol 8:335344, McArthur RB, Bahn RC, Hayles AB. Primary adrenocortical nodular dysplasia as a cause of Cushing's syndrome in infants and children. Mayo Clin Proc 1982;57: Larsen JL, Cathey WJ, Odell WD. Primary adrenocortical nodular dysplasia, a distinct sybtype of Cushing's syndrome. Case report and review of the literature. Am J Med 1986;8: Saris SC, Patronas NJ, Doppman JL, et al. Cushing syndrome: pituitary CT scanning. Radiology 1987;162: Zovickian J, Oldfield EH, Doppman JL, et al. Usefulness of inferior petrosal sinus venous endocrine markers in Cushing's disease. J Neurosurg 1988;68: Spark RF, Connolly PB, Gluckin DS, et al. ACTH secretion from a functioning pheochromocytoma. N Engl J Med 1979;31: Jessop DS, Cunnah D, Millar JG, et al. A pheochromocytoma presenting with Cushing's syndrome associated with increased concentrations of circulating corticotrophinreleasing factor. J Endocrinol 1987;l 13: Wulffratt MM, Drexhage HA, Wiersinga WM, et al. Immunoglobulins of patients with Cushing's syndrome due to pigmented adrenocortical micronodular dysplasia stimulate in vitro steroidogenesis. J Clin Endocrinol Metab 1988;66: Doppman JL, Miller DL, Dwyer AJ, et al. Macronodular adrenal hyperplasia in Cushing disease. Radiology 1988;166: Hermus AR, Pieters GF, Smals AG, et al. Transition from pituitarydependent to adrenaldependent Cushing's syndrome. N Engl J Med 1988;318:96697.