Review Article
ADRENOCORTICAL CARCINOMA: DIAGNOSIS, EVALUATION AND TREATMENT
LINDA NG AND JOHN M. LIBERTINO
From the Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts
ABSTRACT
Purpose: We describe the presenting features, imaging methods, prognosis of and treatment approach to adrenocortical carcinoma.
Materials and Methods: A comprehensive literature review of adrenal carcinoma was per- formed using PubMed and a review of current urology, oncology, radiology and pathology journals.
Results: The incidence of adrenocortical tumors has been reported to be approximately 2/1 x 106 population, although this value may be an underestimate due to an increase in the incidence of unexpected adrenal masses or incidentalomas in the last decade. There has been a bimodal age incidence of adrenal carcinoma with most patients 40 to 50 years old in the studies reviewed. Overall the prevalence of adrenal tumors was slightly higher in females with most presenting with Cushing’s syndrome. Of the 602 adrenal tumors reviewed 62% were functional and 38% were nonfunctional. Modern day imaging, including ultrasound, computerized tomography (CT) and magnetic resonance imaging, have greatly improved the diagnosis and staging of adrenal carcinoma. Surgical removal of a localized tumor and absent metastatic disease were associated with improved survival. Medical therapy with mitotane and its successors in patients with metastatic disease appear to be of little benefit for improving survival.
Conclusions: Based on a review of the literature we recommend that hormone levels should be determined in symptomatic and asymptomatic patients with adrenal masses. CT should be the first study done to define an adrenal mass. All solid incidentalomas greater than 5 cm. on CT or magnetic resonance imaging should be removed surgically. The best chance of survival was achieved by surgical extirpation with the value of adjuvant therapy yet to be determined.
KEY WORDS: adrenal glands; carcinoma, adrenal cortical; adrenal cortex neoplasms
Adrenocortical carcinoma is rare with an estimated inci- dence of between 0.5 and 2/1 × 106 patients yearly.1 Due to its rarity there is a paucity of data on its natural history and response to therapy despite improvements in clinical detec- tion and molecular understanding. We outline a strategy for diagnosis, detection and treatment through a review of our clinical data as well as that at other institutions.
MATERIALS AND METHODS
Between 1936 and 1999, 602 patients with adrenal carci- noma presented to 4 American and 3 foreign institutions, including Cleveland Clinic, Memorial Sloan-Kettering, Roswell Park Cancer Institute and Lahey Clinic in the United States, Biela’nski Hospital in Poland, General Hospi- tal in Beijing, China and Hospital das Clinicas in San Paulo, Brazil.2-8 This particular series of patients were chosen based on the large size of the individual center experience, the current nature of the data and the similarity in patient selection criteria.
Cases were identified at each institution through chart review, searching the tumor registry, searching pathology records or a combination of these methods. These patients underwent clinical, radiological and hormonal evaluations with the diagnosis confirmed by pathological study. Followup studies, including additional radiological and hormonal in-
vestigations, were performed at each institution. Tumors were classified as functioning when they were associated with endocrine manifestations or elevated hormone levels. Nonfunctioning tumors were defined as tumors that did not secrete hormones above normal levels.
Staging at diagnosis was based on the TNM system,9 and on the results of radiological and pathological studies. Stage I disease was defined as a primary adrenal tumor less than 5 cm. in diameter. Stage II was defined as a primary tumor greater than 5 cm. in diameter. Tumors of each stage showed no local or distant extension. In contrast, stage III disease was defined as a primary tumor of any size with limited extension into peri-adrenal fat or to regional lymph nodes. Stage IV disease was defined as a primary tumor of any size invading adjacent organs or with spread to distant sites. Survival distributions in the review series were determined by the Kaplan-Meier method.1º
RESULTS
Patient age, sex, tumor location and stage at diagnosis. Adrenal carcinoma develops at all ages from early infancy to the seventh and eighth decades of life.2,6,11 However, there appears to be a bimodal age distribution with the first peak occurring before age 5 years and the second peak in the fourth to fifth decade of life.11, 12 In our review of 602 patients
approximately 95% were 40 to 50 years old. The mean age of the 20 patients in the study of Wajchenberg et al was signif- icantly lower because they included a higher percent of those younger than 10 years.8 At most institutions children were not treated or they comprised a small percent of the overall number of patients described. Generally pediatric patients with adrenal carcinoma have a better prognosis because they present with a hormonal syndrome that may make cancer detection easier, leading to earlier surgical intervention. Except in 1 study,5 in the series reviewed no statistically significant differences were noted in the survival rate based on adult age at diagnosis. In the series of Tritos et al age less than 54 years at diagnosis was associated with poorer prog- nosis.5
The sex distribution in patients with adrenal carcinoma appears to vary in reviewed series (see table). In 1 series there was an equal distribution of the 2 sexes,2 whereas in most others there was a predominance of women3,5,6,8 and in 2 there was a slight male predominance.4,7 This discrepancy among series may be related to the type of department that provided the epidemiological data. Data from endocrine clin- ics, where patients are treated who have functional tumors with hypercortisolism and/or hyperandrogenism, showed a female predominance, while oncology clinics showed a male predominance or equal distribution of the 2 sexes. Most se- ries showed no correlation of survival with patient sex, whereas 1 suggested a better survival rate in women.6
Most studies reviewed show a left prevalence of adrenal carcinoma, while 1 indicated a right preponderance (see table).7 Patients with large adrenal tumors, especially those arising from the right adrenal gland, should undergo evaluation of the vena cava for thrombus.13 In the series reviewed 9% to 19% of patients presented with vena caval extension. Adrenal carcinoma was bilateral in approxi- mately 2% to 6% of cases.2-8
CLINICAL PRESENTATION
By the criteria defined 62% of the 602 adrenal tumors reviewed were functional and 38% were nonfunctional (Appendix 1). The number of functional tumors may actually be higher than reported because some nonfunctional tumors later become functional. Moreover, tumors may produce me- tabolites that are in such low quantities that physiological changes may not be observed.
In patients with hormone secreting adrenocortical tumors associated endocrine symptoms result from the secretion of cortisol or aldosterone and their precursors, namely adrenal androgens and/or estrogens. The most common syndrome associated with adrenocortical tumors in adults is Cushing’s syndrome. This condition has previously been reported in 30% to 40% of patients with adrenocortical tumors.14 In our review 39.5% of functional tumors presented with Cushing’s syndrome. The combination of Cushing’s syndrome and vir- ilization was evident in 24% of the population with adreno- cortical carcinoma. The most common clinical manifestations in patients with adrenal carcinoma were weight gain/centripe- tal obesity, muscle wasting, hypertension and acne. Hirsutism and oligomenorrhea were often present in those with a com-
ponent of virilization. Bertagna and Orth reported that vir- ilization is a characteristic differentiating Cushing’s syn- drome due to adrenal carcinoma from Cushing’s syndrome due to adenoma.15 The theory is that androgenic steroid excess develops in patients with adrenal carcinoma because androgenic steroid precursors are not converted to glucocor- ticoids as efficiently as in those with adenoma. However, Daitch et al observed that, while most patients with adreno- cortical tumors presented with mixed endocrine abnormali- ties (including virilization), most patients with adenoma also presented with mixed endocrine syndromes.16 Virilization alone has been reported in 20% to 30% of patients with functional adrenocortical carcinoma.17 Our review of studies in children and adults revealed virilization in 20%. However, in studies predominantly of adults pure virilization was noted in only 3% to 5%.4,5 This discrepancy may be due to the presentation of virilization as the most common hormonal syndrome in the pediatric population (72%).18 In women vir- ilization may manifest as oligomenorrhea, hirsutism, cystic acne, excessive muscle mass, voice deepening, temporal bald- ing, increased libido and clitoromegaly. In young girls viril- ization presents as heterosexual precocious puberty. Pure testosterone neoplasms have been reported to have a higher incidence in females, be smaller (less than 6 cm.) and behave in a more benign manner
As pure hormonal syndromes, feminization and hyperaldo- steronism are much less common manifestations of adreno- cortical carcinoma. Feminization occurred in 6% of cases in the reviewed series and hyperaldosteronism developed in 2.5%. Presenting often as gynecomastia, most feminizing tu- mors have been reported to be larger, more malignant and be more common in males. These tumors secrete androstenedi- one, which is converted peripherally to estrogen.
Most patients with nonfunctioning tumors or no recogniz- able endocrine symptoms presented with clinical manifesta- tion related to tumor growth or with the incidental finding of an adrenal mass on imaging performed for unrelated rea- sons. The most common complaint was abdominal pain and/or a palpable tumor. Other clinical features included weight loss, weakness, fever, anorexia, nausea and myal- gia.4,6,8 Some patients presented with symptoms of meta- static disease before a primary diagnosis was established. Dyspnea and thoracic pain may present due to exaggerated tumor growth.19 Other unusual clinical manifestations re- ported in patients with adrenocortical carcinoma included hematuria, lower extremity edema, the Budd-Chiari syn- drome and urinary obstruction.8, 19
HORMONAL STUDIES
Several hormonal studies are useful for establishing or confirming excessive steroid secretion (Appendix 2). Hormonal investigation can also be used to monitor patients with adrenocortical carcinoma. Hypercortisolism is best es- tablished by measuring the 24-hour urinary excretion of cor- tisol. Orth recommended that urinary cortisol should be meas- ured in 2 and preferably 3 consecutive 24-hour urine specimens.2º More than 90% of patients with Cushing’s syn- drome have urinary free cortisol values greater than 200
| References | No. Pts. | % Sex | Mean Age | % Primary Side | % Clinical Feature | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| M | F | M | F | Lt. | Bilat. | Rt. | Functional | Nonfunctional | ||
| Bodie et al2 | 82 | 50 | 50 | 51 | 42 | 51 | 6 | 43 | 49 | 51 |
| Pommier and Brennan3 | 73 | 38 | 62 | 37 | 43 | - | - | 60 | 40 | |
| Zografos et al4 | 53 | 57 | 43 | 51 | 51 | 60 | 4 | 36 | 36 | 64 |
| Tritos et al5 | 31 | 48 | 52 | 59 | 53 | 58 | – | 42 | 48 | 52 |
| Kasperlik-Zaluska et al6 | 105 | 29 | 81 | 53 | 38 | 50 | 2 | 48 | 75 | 25 |
| Xiao et al7 | 211 | 55 | 45 | 41 | 37 | 42 | 3 | 55 | 72 | 28 |
| Wajchenberg et al8 | 47 | 21 | 79 | 20 | 20 | - | - | - | 94 | 6 |
µg./24 hours, whereas 97% of normal individuals have values less that 100 µg./24 hours.14 Ideally the way to determine whether a patient has adrenocorticotropic hormone (ACTH) dependent or independent hypercortisolism is the concurrent measurement of plasma ACTH and cortisol by 2-site immuno- radiometric tests.2º If plasma cortisol is greater than 50 µg./dl. and ACTH is less than 5 pg./ml., cortical secretion is ACTH independent and the patient has a primary adrenal problem. In contrast, if plasma ACTH is greater than 50 pg./ml., cortisol secretion is ACTH dependent and the patient has Cushing’s disease, ectopic ACTH or the corticotropin releasing hormone syndrome. If the 2-site immunoradiometric assay is not available, the classic high dose dexamethasone suppres- sion test (2 mg. every 6 hours for 2 days) can be done to differentiate pituitary from adrenal Cushing’s syndrome. In patients with adrenal adenoma carcinoma plasma and urinary free cortisol fail to be suppressed. Several plasma and urinary steroids are elevated in Cushing’s syndrome as a result of functioning adrenocortical tumors, including plasma dehydroepiandrosterone (DHEA) and its sulfate deriv- ative DHEA-S, 45- androstenediol, 44-androstenedione, preg- nenolone, 17-hydroxypregnenolone and 11-deoxycortisol as well as urinary 17-ketosteroid (17-KS), 17-hydroxycorticosteroid (17-OHCS) and the tetrahydrometabolite of 11-deoxycortisol.17 These steroids may be elevated because in adrenocortical car- cinoma many steroid enzymes are defective, leading to ineffi- cient steroid production and a buildup of various steroid pre- cursors. In the series reviewed the most common steroids assayed were 24-hour urinary excretion of 17-KS and 17-OHCS, and plasma DHEA and DHEA-S.
The clinical diagnosis of adrenal induced virilization was confirmed by measuring serum testosterone, serum adrenal androgens (DHEA and DHEA-S) and 24-hour 17-KS.17 Plasma estradiol and/or estrone can be used to confirm fem- inization. while plasma aldosterone and plasma renin activ- ity can be used to confirm hyperaldosteronism. All patients with incidentalomas should also undergo hormonal assess- ment. Limited evaluation is recommended unless there are clinical stigmata, such as Cushing’s syndrome or virilization. In those cases hormonal evaluation is indicated based on the symptoms. As proposed by Ross and Aron,21 total urinary catecholamine and metanephrine should be evaluated to rule out pheochromocytoma and potassium should be assessed in patients with hypertension.
IMAGING
Imaging is the key to diagnosing adrenal carcinoma. Ultrasonography of the adrenal gland has proved to be effec- tive for identifying adrenal masses but it is limited by depen- dence on operator skills and patient body habitus.22,23 Xiao et al reported an 87% detection rate with a false-negative rate of 12%.7 Most adrenal tumors appear as smoothly rounded, solid masses replacing the usual triangular or cres- cent configurations of the adrenal gland. Moreover, ultra- sound can identify the displacement of adjacent structures caused by the tumor.
Computerized tomography (CT) is considered the diagnos- tic study of choice for evaluating adrenal masses. Because of surrounding adipose tissue in the retroperitoneum, adrenal glands are easily visible on CT. On thin section CT nodules as small as 3 to 5 mm. can be identified.24, 25 Xiao et al reported a 98% detection rate with less than a 10% false-positive and negative rate.7 CT provides information on size, homogene- ity, calcification, the area of necrosis and the extent of local invasion. Many groups have attempted to differentiate benign versus malignant adrenal masses based on size. Belldegrun et al noted that 92% of adrenal carcinomas were greater than 6 cm.26 Most groups indicate that malignant adrenal lesions tend to be 5 cm. or greater, present with blurred margins and an irregular shape, and show heterog-
enous contrast enhancement (fig. 1).25,26 In reviewed series CT was also most widely used for he detecting distant me- tastasis.
Magnetic resonance imaging (MRI) is superior to CT in some aspects. MRI allows assessment of tumor thrombosis in blood vessels, particular in the inferior vena cava, and adre- nal and renal veins. Studies also show that MRI can accu- rately distinguish primary malignant adrenocortical carcino- mas, nonfunctioning adenomas and pheochromocytomas by comparing the ratio of the signal intensity of T1 and T2- weighted images.27,28 Primary malignant adrenocortical le- sions have an intermediate to high signal intensity on T2- weighted images (fig. 2). Low signal intensity is usually more indicative of nonfunctional adenoma. Pheochromocytoma has a characteristic light bulb image on T2-weighted studies.
Other more invasive imaging, such as adrenal cortical scin- tigraphy with (125I)iodocholesterol scanning, venography and arteriography are reserved for cases in which information in addition to that provided by CT and/or MRI is needed. Radio cholesterol scintigraphy can complement biochemical and radiological imaging data to identify abnormal adrenal func- tion in adenoma cases and suggest adrenal carcinoma or delineate the functional status of adrenal masses.29 Selective arteriography may help to distinguish adrenal masses from upper pole renal tumors.
PATHOLOGICAL FINDINGS AND STAGING
Several previous studies have suggested that tumor size alone cannot be used to determine the biological behavior of adrenal tumors.30,31 Others have suggested that tumor size is a useful criterion for distinguishing benign masses from malignant adrenal tumors.16, 32, 33 In the study of Daitch et al patients with adenoma presented with tumors a mean plus or minus SE of 3.3 + 1.0 cm. in diameter.16 In our series review the adrenal carcinoma diameter in adults was 4 to 25 cm. (mean 9.8 ± 4.1). The cut surface generally showed a variegated pattern with soft, friable individual nodules and frequent areas of necrosis and hemorrhage. Histologically adrenocortical tumors consisted of lipid depleted cells with granular cytoplasm, and large multiple nuclei and nucleoli (fig. 3).34
Because the differentiation of benign from malignant ad- renocortical tumors is difficult, several macroscopic and mi- croscopic criteria have been collectively used to define malig- nancy in adrenal tumors. Macroscopically a wet weight of more than 500 gm., a grossly lobulated cut surface, necrotic areas, and/or calcifications and intratumoral hemorrhages has been used to predict malignancy.17,30 Microscopically a list of 9 histological criteria proposed by Weiss has been used
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to predict adrenocortical tumors that metastasize or recur locally, including high nuclear grade, mitotic rate greater than 5/50 per high power field, atypical mitotic figures, eo- sinophilic tumor cell cytoplasm, diffuse architecture present in 33% or greater of the tumor, necrosis, invasion of venous structures, invasion of sinusoidal structures and capsular invasion.3º Using this system Weiss reported that 24 nonme- tastasizing or nonrecurrent adrenal cortical tumors had 2 or fewer histological criteria, whereas 18 of 19 malignant tu- mors had 4 or more of the 9 features. Weiss et al proposed in a later study that the criteria for malignancy should include 3 or more of these criteria.35
The staging system for adrenocortical carcinoma depends on tumor size, adjacent organ invasion, lymph node involvement and distant metastases. In most reports of adrenal carcinoma the tumor generally presented at an advanced stage (stage IV).2-5,7 Of the patients reviewed 21%, 20%, 20% and 39% were classified with stages I to IV disease at diagnosis, respectively (fig. 4). In the series reviewed the most common sites of metas- tasis were the liver in 48% of cases, lung in 45%, lymph nodes in 29% and bone in 13%. Local invasion most commonly in- volved the kidneys (26% of cases) and inferior vena cava (9% to 19%). Metastases were also reported in the pancreas, brain, diaphragm, small intestine and thyroid. Staging is helpful for defining treatment and prognosis.
TREATMENT
The treatment of all primary adrenal tumors is surgical. In the reviewed series 55% of patients underwent complete surgi- cal excision of the tumor.2-4 Most patients underwent complete ipsilateral adrenalectomy, while others underwent adrenalec- tomy plus nephrectomy or adrenalectomy, nephrectomy and splenectomy. In patients with intracaval thrombus complete
surgical extirpation facilitated by cardiac bypass techniques provided the best chance of survival.13 Thoracoabdominal, an- terior and subcostal incisions were most commonly made. The approach was based on adrenal gland and lesion size, patient body habitus, and operating surgeon experience and prefer- ence.36 Although laparoscopic surgery can be performed for small adrenal tumors with no invasion of adjacent structures and/or venous thrombus,37 no laparoscopic surgery was per- formed in the reviewed series. The most commonly recorded complications were bleeding/hematoma and adrenal insufficiency. The recurrence rate after complete resection was 35% to 85%.
In regard to the surgical removal of tumor recurrences 2 studies compared survival in patients who underwent a sec- ond surgical procedure versus those who received chemother- apy after recurrence. There was longer survival in the sur- gical group and surgical intervention was recommended when possible for tumor recurrence.38-41 Pommier and Brennan also reported greater median survival in patients treated aggressively with surgical excision for tumor recur- rence versus those treated medically (56 versus 19 months).3 Wajchenberg et al reported no change in prognosis with further resection.8 In regard to tumors that cannot be com- pletely excised surgically some groups suggest a benefit from maximal tumor debulking,38,39 whereas others suggest that surgical palliation does not influence patient survival.8,40
Medical therapy was administered in patients in whom disease was unresectable and in those in whom recurrent or metastatic disease could not be treated with reoperation. Mitotane (o,p’-DDD) has been used as the mainstay of ther- apy for adrenocortical carcinoma. By causing alterations in mitochondrial function, blocking adrenal steroid 11-B- hydroxylation and altering the extra-adrenal metabolism of cortisol and androgens mitotane acts as an adrenolytic
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agent.14,17,42 The side effects of mitotane, which are dose related, include weakness, somnolence, confusion, lethargy and headache. Many reviewed series did not show improved survival when mitotane was given primarily for unresectable disease or in adjunctive fashion with mitotane given xx.3-8 However, other studies showed more encouraging results.2,42 Several alternative chemotherapeutic agents, including cis- platin, etoposide, 5-fluorouracil, doxorubicin, vincristine, suramin and gossypol, have been used with variable re- sults.6,14 Radiotherapy has also been performed but mainly for palliation in patients with bone metastases.
PROGNOSIS
The prognosis of adrenocortical carcinoma in adults is gener- ally poor. Children with adrenocortical tumors have a better prognosis than adults.18 In our reviewed series mean survival was approximately 18 months. The overall 5-year survival rate after diagnosis was 15% to 47%.2-8 Most series showed no statistically significant differences in survival based on patient age, gender or tumor functional status. However, stage was a significant prognostic factor.2-8 For stages I to IV tumors ap- proximate 5-year survival was 30% to 45%, 12.5% to 57%, 5% to 18% and 0%, respectively. Highly aggressive and unresectable tumors progressed rapidly within a few months. Surgical resec- tion was the only therapy for adrenocortical carcinoma that significantly prolonged survival, particularly when disease was detected at stages I and II. Median survival in patients with unresectable tumors was 3 to 9 months, whereas after complete resection median survival was 13 to 28 months.
DISCUSSION
Due to the low incidence of adrenocortical carcinoma at med- ical centers it has been difficult to gain experience in diagnosing and treating these tumors. We reviewed studies of adrenocor- tical tumors at several institutions to provide an overview of presenting features, hormonal evaluation and imaging tech- niques used to identify these lesions. There has been a bimodal age incidence of adrenal carcinoma with most adults presenting at ages 40 to 50 years. Except for the study of Tritos et al5 series did not show a statistically significant difference in the survival rate based on adult age. In most series there was a predomi- nance of women3,5,6,8 with no significant correlation of survival
with patient sex. Presentation on the left side was more com- mon with few tumors presenting bilaterally.
Classifying tumors as functional or nonfunctional based on endocrine manifestations and hormonal activity was a sig- nificant guideline to appropriate evaluation and manage- ment. Of the 602 tumors evaluated in this review 62% were functional and 38% were nonfunctional. Most studies did not show a statistically significant difference in survival based on functionality in adults. However, in the pediatric popula- tion the presentation of adrenocortical carcinoma with a hor- monal syndrome makes cancer detection easier, leading to earlier detection and a better prognosis.18 In this review the most common hormonal presentation in adrenal carcinoma cases was Cushing’s syndrome, followed by Cushing’s syn- drome plus virilization and virilization alone. Feminization and hyperaldosteronism alone were rare presentations of adrenocortical carcinoma. Most patients with nonfunctioning tumors presented with incidentalomas, pain and/or a palpa- ble tumor. Hormonal studies facilitated classification and subsequent tumor treatment (Appendix 2).
Improved imaging techniques have made the evaluation of tumors easier. CT remains the technique of choice for an initial study, although the size of adrenal tumors may be underestimated slightly. In addition, most groups advocate CT for evaluating distant metastases. MRI is more sensitive for evaluating adrenal tumors for vena caval extension and distinguishing benign from malignant tumors.
Histologically the criteria proposed by Weiss et al has greatly improved the uniformity of evaluating adrenal tu- mors.30,35 As in previous studies, in our series review adre- nal carcinomas were larger than benign adrenal masses (mean 9.8 cm.). Staging by the TNM system showed that most adrenal tumors present at late stages.
CONCLUSIONS
Adrenocortical carcinoma is a rare aggressive tumor that often presents at advanced stages. Stage at diagnosis is the most significant prognostic factor, while age, sex and tumor functionality are not. Complete resection is the only effective treatment with the value of mitotane and other medical therapy yet to be determined.
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ADRENOCORTICAL CARCINOMA
APPENDIX 1: CLINICAL PRESENTATION OF ADRENOCORTICAL CARCINOMA
Functioning tumors (62%)
Cushing’s syndrome Cushing’s syndrome plus virilization Virilization Feminization Hyperaldosteronism
Incidentally found
Nonfunctioning tumors (38%)
Incidentally found Abdominal pain
Abdominal mass
Weight loss, malaise Metastasis
| Tumor presentation | Hormonal studies |
|---|---|
| Cushing's syndrome | Consecutive 24-hour urinary cortisol Immunoradiometric 2-site assay (concurrent plasma ACTH and cortisol) or high dose dexamethasone suppression Serum adrenal androgens DHEA and DHEA-S Urinary 24-hour 17-OH CS and 17-KS |
| Virilization | Serum testosterone Serum adrenal androgens DHEA and DHEA-S Urinary 24-hour 17-KS |
| Mixed (Cushing's syndrome plus virilization) | Combine studies for each condition |
| Feminization | Plasma estradiol and/or estrone |
| Hyperaldosteronism | Plasma aldosterone Plasma renin activity |
| Incidentaloma | R/O pheochromocytoma with total urinary catecholamines and meta- nephrines K+ when hypertension is present If any endocrine clinical stigmata are present, perform followup studies for each |
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