Diagnosis and Treatment of Functioning and Nonfunctioning Adrenocortical Neoplasms Including Incidentalomas
Norman W. Thompson, M.D.,* and Polly S. Y. Cheung, M.D.t
Approximately one half of clinically detected adrenocortical neoplasms are benign and functioning. Most are solid and present with signs and symptoms of glucocorticoid (Cushing’s syndrome) or mineralocorticoid (Conn’s syndrome) excess. The other half of solid neoplasms are primary adrenocortical carcinomas, about half of which are functioning.
Nonfunctioning adrenocortical lesions are currently being diagnosed more often because of their incidental discovery during abdominal CT scanning. They may be cysts, adenomas, or other rare benign lesions such as myelolipomas. Occasionally they are carcinomas.
CLINICAL MANIFESTATIONS
Cushing’s syndrome is the most common clinical presentation of adrenocortical tumors. It is produced by the continuing presence of excess glucocorticoids in the body. Typical features include obesity of the trunk, head, and neck, plethora, hirsutism, hypertension, proximal muscle weak- ness and wasting, thin skin, purple striae, weight gain, easy bruising, and acne of the face and trunk. Amenorrhea, osteoporosis, and glucose intol- erance are also seen frequently. The onset of the syndrome is usually insidious and often precedes diagnosis by one or more years. Hypertension in Cushing’s syndrome is usually moderate and sustained, but its late complications, including congestive heart failure and cerebral thrombosis,
*Professor of Surgery and Chief, Division of Endocrine Surgery, University of Michigan Medical Center, Ann Arbor, Michigan
tLecturer in Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong
are the most common causes of death in those with untreated and advanced disease. 36
About 65 per cent of patients with Cushing’s syndrome have Cushing’s disease, an ACTH-producing pituitary adenoma (pituitary-dependent Cush- ing’s syndrome). These patients have bilateral adrenal hyperplasia. Primary nodular adrenal hyperplasia associated with Cushing’s syndrome has re- cently been recognized as an entity distinct from adrenal hyperplasia secondary to ACTH-secreting pituitary adenoma or multiple cortical ade- nomas.
Twenty per cent of patients with Cushing’s syndrome have an adre- nocortical tumor and 15 per cent have an ectopic source of ACTH such as a nonpituitary neoplasm. Certain clinical features may help to differentiate these various causes of Cushing’s syndrome. In malignant tumors of the adrenal cortex, cortisol is synthesized inefficiently and results in an excessive production of androgen precursors from aberrant synthetic pathways. Thus, hirsutism and virilization are much more common in patients with adren- ocortical carcinoma than in those with cortical adenomas.4 Rapidly growing malignant tumors of nonpituitary origin often have obvious findings caused by the primary tumor, and they tend to produce very high concentrations of ACTH and hence cortisol. Hypokalemia and edema resulting from the salt-retaining property of cortisol often predominate. Benign tumors often are associated with a more indolent course and a gradual evolution of the syndrome over months or years. Differentiation of the specific causes of Cushing’s syndrome requires biochemical tests, which will be discussed later.
In females, virilizing tumors are characterized by amenorrhea, hirsu- tism, deepening of the voice, increased libido, increased muscle mass, and enlargement of the clitoris. In children, precocious puberty may occur, with early phallic enlargement, development of a beard, and pubic and axillary hair growth. These patients must be differentiated from patients with congenital adrenal hyperplasia, idiopathic hirsutism, and other causes of precocious puberty. In adult males, a virilizing tumor may sometimes be recognized only as a space-occupying lesion or after metastases have occurred.
Feminizing tumors are even less common than those causing masculin- ization and are almost always malignant. They are usually far-advanced when first detected in women. A male with an estrogen-producing adrenal tumor may develop gynecomastia and impotence before the tumor has attained large size or has spread to other sites. If the clinical symptoms have led to early detection, curative resection may be possible in some cases.
It is not uncommon for a malignant adrenocortical tumor to manifest initially as a palpable abdominal mass. About half of the clinically nonfunc- tioning tumors manifest this way. Abdominal or back pain due to an unsuspected metastatic lesion can be the initial presenting feature of an adrenocortical carcinoma. Fever of unknown origin may develop if tumor necrosis has occurred. Central necrosis is common in very large lesions.
| TEST | METHOD | NORMAL VALUES | VALUES IN CUSHING'S SYNDROME | COMMENTS |
|---|---|---|---|---|
| Plasma cortisol (AM/PM) | Blood sample | AM 3-34 µg/100 ml PM 0-22 µg/100 ml | Loss of AM and PM variation. Elevated | Many false-positive and false-negative values. Loss of variation in acutely ill and alcoholic patients |
| Urinary free cortisol | 24-hour urine collection | 108 µ/day | Elevation > 108 µg/day | Useful screen when a reliable 24-hour urine can be obtained. Few false- positive or false- negative results |
| Urinary 17-OHCS and 17-KS | 24-hour urine collection | 3-7 mg/day/gm urine creatinine | > 10 mg/day/gm urine creatinine | Much overlap between normal and Cushingoid patients and those with Cushing's disease |
| Single-dose overnight dexamethasone suppression | Administer 1 mg dexamethasone orally at midnight. Measure AM plasma cortisol | 3.5-10 µg/100 ml (depending on assay method) | No suppression. Levels 3.5-10 ug/100 ml | Low incidence of false- negative results. False-positive results in patients on phenytoin or estrogens |
| 2-mg (low-dose) dexamethasone suppression | Administer 0.5 mg dexamethasone orally every 6 hours for 2 days. Measure 24-hour urinary 17- hydroxy steroids | 2.5 mg/day/gm urine creatinine | 4 mg/day/gm urine creatinine | Definitive diagnostic test for Cushing's syndrome |
BIOCHEMICAL EVALUATION
Although the clinical presentation alone may be sufficient to suggest the diagnosis of a specific syndrome, many adrenal lesions do not manifest all the clinical features or may not produce enough hormones to give rise to any specific clinical syndrome. Studies of adrenocortical function and the pituitary-adrenal axis are therefore important to confirm the diagnosis and differentiate the various etiologies.
Biochemical Diagnosis of Cushing’s Syndrome
The various biochemical tests used to diagnose Cushing’s syndrome are summarized in Tables 1 and 2.
Screening Tests. Plasma cortisol levels in normal subjects show char- acteristic diurnal variation, reflecting the diurnal variation in secretion of ACTH from the anterior pituitary. Early morning cortisol (6:00 A.M.) levels are higher than those measured in the evening (6:00 PM). The evening values of cortisol in normal subjects are usually less than 5 mg/dl. Patients with Cushing’s syndrome typically show elevated plasma cortisol levels with loss of diurnal rhythm. In some cases, the early morning plasma cortisol level may be within the normal range, and in even milder cases, loss of
| TEST | METHOD | ADRENAL ADENOMA | PITUITARY ADENOMA | ECTOPIC ACTH | NODULAR HYPERPLASIA | COMMENTS |
|---|---|---|---|---|---|---|
| High-dose dexamethasone suppression | Obtain baseline 24-hour urine 17-OHCS level. Administer 2 mg dexamethasone orally every 6 hours for 2 days. Measure 24-hour urine 17-OHCS on second day of test | Nearly all patients fail to suppress to 40% of baseline | Nearly all patients suppress to 40% of baseline | No suppression in 75% of patients. Tumors may exhibit cyclic hormonogenesis | No suppression in most patients | Most useful in distinguishing pituitary disease from nonpituitary causes of Cushing's syndrome |
| Plasma ACTH levels by RIA | Blood sample | Low or undetectable | Normal or elevated | Normal or elevated | Normal, elevated, or low | Important to determine whether adrenal adenoma or ectopic ACTH |
| Metyrapone test | Administer 750 mg metyrapone orally every 4 hours for 6 doses. Obtain urinary 24-hour 17-OHCS day before, day of, and day after metyrapone administration | Fall in urinary 17- OHCS excretion | Increase in 17- OHCS excretion | About half of patients will show an increase (small sample tested) | About half of patients will show an increase (small sample tested) | Phenytoin and estrogens increase hepatic metabolism |
diurnal rhythm may be the only abnormality. False-positive values may occur in obese subjects, alcoholics, and acutely ill patients, and false- negative results have been common in previous studies.
Daily urinary excretions of 17-hydroxycorticosteroids (17-OHCS) and 17-ketosteroids (17-KS) reflect the basal cortisol production rate. In Crapo’s10 study, however, normal excretion of 17-OHCS occurred in 11 per cent of 315 patients and false-positive results were found in 27 per cent of 173 normal obese subjects; normal excretion of 17-KS was found in 24 per cent of 235 patients with Cushing’s syndrome. The main source of overlap between normal subjects and those with Cushing’s syndrome occurs when excretion values are near the upper limit of normal range. Measurement expressed as mg per day per gm of urine creatinine improves the diagnostic yield slightly.27
The determination of urinary free cortisol excretion provides a sensitive screening test for the diagnosis of Cushing’s syndrome in the basal state. Only 3.3 per cent of 479 control subjects in Crapo’s10 study had elevated values, and 5.6 per cent of 248 patients with Cushing’s syndrome had normal excretion. The low incidence of false-positive and false-negative results makes 24-hour urinary free cortisol measurement a useful screening test for ambulatory patients when a reliable 24-hour urine collection can be obtained.
The single-dose overnight dexamethasone suppression test was pop- ularized by Pavlatos and colleagues.34 The test is performed by giving 1 mg of dexamethasone by mouth at 11 PM and then obtaining an 8 AM plasma cortisol level the following morning. In normal subjects, the 8 AM cortisol level will be suppressed to below 5 µg/dl, whereas patients with Cushing’s syndrome maintain plasma cortisol concentrations above this level. False- negative results are rare, occurring in 1.9% of 154 patients in Crapo’s10 study. However, false-positive results can occur in obese subjects, chroni- cally ill patients, and subjects taking phenytoin or estrogens. Furthermore, the upper limit of normal suppression of the 8 AM cortisol level varies in different laboratories from 3.5 to 10 µg/dl, depending on the assay method. Confusion may arise when the result is borderline.
The low-dose dexamethasone suppression test devised by Liddle28 is the most valuable test for establishing the diagnosis of Cushing’s syndrome. Dexamethasone, being 30 times more potent than cortisol, will suppress pituitary production of ACTH and thus lower cortisol production. It is administered at the dose of 0.5 mg orally every six hours for two consecutive days. On the second day of administration, 24-hour urinary 17-OHCS excretion is measured. In normal subjects, this parameter is suppressed to below 2.5 mg per day per gm of urine creatinine. Patients with Cushing’s syndrome show resistance to such low-dose suppression and usually excrete 4 mg or more 17-OHCS per day per gram of urine creatinine.
Tests for Determining Etiology. When the diagnosis of Cushing’s syndrome is established, it is then necessary to determine the etiology of the adrenocortical hyperfunction. The tests commonly used include the high-dose dexamethasone suppression test, basal plasma ACTH level, metyrapone test, and ACTH stimulation test.
The high-dose dexamethasone suppression test is performed by giving
2 mg of dexamethasone orally every six hours for two days and determining the daily urine 17-OHCS excretion on the second day. According to criteria established by Liddle and colleagues,29 reproducible reduction of 17-OHCS excretion by 40 per cent or more of the baseline is positive for suppression. Nearly all patients with Cushing’s disease show suppression and nearly all patients with adrenal tumor fail to show suppression. About 75 per cent of patients with primary nodular adrenal hyperplasia and all patients with the ectopic ACTH syndrome fail to show suppression with high-dose dexa- methasone. This test is therefore useful for distinguishing pituitary disease from nonpituitary causes of Cushing’s syndrome.
Measurement of plasma ACTH by radioimmunoassay is helpful in distinguishing adrenal tumors from Cushing’s disease or the ectopic ACTH syndrome. Patients with adrenal tumors usually have low or undetectable plasma ACTH levels (less than 10 pg/ml). Patients with ectopic ACTH syndrome often have plasma ACTH levels well above the assay sensitivity. Patients with Cushing’s disease usually also have elevated ACTH levels, although the ACTH level may be within the normal range. A plasma ACTH level above 200 pg/ml is diagnostic of the ectopic ACTH syndrome. Patients with nodular adrenal hyperplasia can have undetectable, normal, or even elevated plasma ACTH levels, although the ACTH level is usually sup- pressed.
Metyrapone is a drug that blocks the 11-beta-hydroxylation of 11- deoxycortisol to cortisol. When administered in sufficient doses to achieve adequate inhibition of 11-beta-hydroxylation, metyrapone causes a rise in 17-OHCS excretion in normal subjects and patients with Cushing’s disease, whereas in patients with adrenal tumors it causes a drop in urinary 17- OHCS excretion and may cause clinical changes suggesting relative adrenal insufficiency. For the test, 750 mg of metyrapone is administered orally every four hours for six doses, and urinary 24-hour 17-OHCS is measured the day before, the day of, and the day after. About half of the patients with ectopic ACTH syndrome and nodular adrenal hyperplasia will show an increase in 17-OHCS excretion when tested with metyrapone.
ACTH, when administered exogenously by an eight-hour infusion of 50 units, causes an increase in 17-OHCS excretion in normal patients and patients with ACTH hypersecretion and in 50 per cent of patients with adrenocortical adenomas. Patients with adrenocortical carcinoma show no response to ACTH stimulation. The ACTH stimulation test adds little information to that obtained from differential tests already described and is not done routinely.
The measurement of urinary 17-KS helps in the recognition of adren- ocortical carcinoma. The normal 24-hour excretion is about 10 mg for females and 15 mg for males. It is usually slightly increased in patients with Cushing’s syndrome due to benign adenoma, but is markedly elevated in patients with carcinoma to levels above 40 mg/day.2 This marked elevation of 17-KS in adrenal carcinoma is related to the inefficient utilization of intermediates at various stages of steroid synthesis, which leads to abnormal metabolism of the steroids. 30
Biochemical Findings in Virilizing Adrenal Tumors
Increased levels of plasma androgens, including testosterone and androstenedione, are found in both adrenal and gonadal causes of viriliza- tion. However, dehydroepiandrosterone (DHEA) is secreted almost exclu- sively from the adrenal gland. Measurements of DHEA and DHEA-sulphate (DHEAS) show elevation in patients with adrenal tumors but are normal in ovarian causes of virilization. Some patients with idiopathic hirsutism may have elevated DHEA. This disorder can be differentiated from virilizing adrenal tumor by the dexamethasone suppression test. Excretion of 17-ketosteroids is suppressed in idiopathic hirsutism but fails to be suppressed in adrenal virilizing tumor. More often, adrenal tumors produc- ing virilization are diagnosed by a combination of biochemical findings and an enlarged adrenal mass on computed tomography. Findings of extremely high levels of DHEA and urinary 17-ketosteroids suggest a malignant adrenal tumor.
Biochemical Findings in Nonfunctioning Adrenocortical Tumors
Adrenocortical tumors are regarded as nonfunctioning if there are no clinical signs and symptoms of hormonal excess. The absence of clinical effects may be a consequence of the following: (1) the tumors form precursor steroids without hormonal activity, (2) the tumors produce inactive com- pounds, although they are corticosteroids, (3) the tumors produce active hormones, but in insufficient amounts to produce clinical effects, or (4) the tumors are truely nonfunctioning and are unable to form steroids.
With the wide application of increasingly sensitive CT scans, more adrenal masses are discovered incidentally. In some reports, increased excretion of steroids is actually demonstrated in clinically nonfunctioning tumors. 4, 26 Some may have apparently normal steroid excretion but respond abnormally to pharmacologic tests using dexamethasone or metyrapone. 26 Studies of nonfunctioning adrenal tumor cells in vitro show release of corticosteroids that may be increased after stimulation by ACTH or metyr- apone. 17, 32
Because of the wide spectrum of biochemical findings in adrenocortical tumors, measurement of basal secretion and excretion of corticosteroids, pharmacologic testing using dexamethasone, metyrapone, and ACTH, and measurement of precursor steroid excretion, including 17-hydroxyproges- terone and its metabolites should be performed in patients with apparently clinically nonfunctioning tumors.
DIAGNOSTIC IMAGING
When the clinical diagnosis of cortisol-, androgen-, or estrogen-pro- ducing tumor is confirmed by biochemical tests, localization of the adrenal tumor prior to operation is required. CT scanning of the adrenal gland is currently the most commonly used method of localization. It can identify adrenal tumors as small as 1 cm in diameter. 15 Because of its high sensitivity, CT scanning has replaced the more traditional tests, such as intravenous
pyelography, retroperitoneal pneumography, nephrotomography, selective arteriography, and venography, which are less desirable because of their invasive nature. In general, tumors more than 6 cm in diameter are suspected to be malignant. A CT scan can delineate the relationship of an adrenal tumor to the surrounding structures, such as the kidney, liver, pancreas, spleen, or other contiguous organs. Enlargement of periaortic or vena caval lymph nodes and liver metastases can be shown as well. In cases of malignancy, selective arteriography and vena cavography may be required when extent of tumor invasion into the vena cava and local structures needs to be defined. Magnetic resonance imaging is also proving useful for demonstrating the site and size of the tumor as well as whether there is vascular involvement.
Scintigraphy using 131I-6-beta-iodomethyl-19 norcholesterol (NP-59) is currently used as an adjunct to a CT scan in adrenal imaging because it reflects the pathophysiologie process in the adrenal-pituitary axis.39 In patients with Cushing’s syndrome, four imaging patterns are recognized: (1) bilateral increased uptake, (2) asymmetric and bilateral increased uptake, (3) lateralized uptake, and (4) bilateral nonvisualization.47 Increased uptake on one side with nonvisualization on the other side is pathognomonic for an adrenocortical adenoma. Despite the fact that functioning adrenocortical carcinomas may produce cortisol, the uptake of NP-59 per gram of tumor is too low to allow for imaging. Enough cortisol is produced, however, to suppress pituitary ACTH release, and therefore the uptake of NP-59 by the contralateral adrenal gland is suppressed, resulting in bilateral non- visualization. Asymmetric bilateral uptake may distinguish primary adrenal nodular hyperplasia from pituitary-dependent and ectopic ACTH causes of Cushing’s syndrome.
In contrast to cortisol-producing adrenocortical tumors, androgen- and estrogen-producing tumors do not usually suppress pituitary ACTH secre- tion unless cortisol is being secreted concomitantly. Although the tumor itself is not imaged, concentration of the radionuclide in the remaining ipsilateral gland and the contralateral adrenal gland produces bilateral uptake with marked asymmetry, thus lateralizing the lesion. 14, 41 Recently, we have observed a patient with a large androgen-producing adrenocortical carcinoma that caused nonvisualization of the ipsilateral adrenal but visu- alization of the contralateral gland.7 Such nonvisualization may be expected with complete destruction of the normal adrenal cortex.
TREATMENT
Adrenocortical Adenoma
When the tumor is lateralized, unilateral excision of the adrenal gland bearing the tumor is the treatment of choice. A posterior retroperitoneal approach employing a hockey-stick incision allows good exposure of the adrenal bed after resection of the twelfth rib.46 Tumors less than 4 cm in diameter can usually be resected without difficulty through this approach. In patients with Cushing’s syndrome, the posterior approach carries the
advantage of lower incidences of wound infection, dehiscence, and post- operative ileus. In the rare patient with bilateral adrenal adenomas, bilateral posterior incisions and the use of two surgical teams are effective. 43
Preoperatively, patients with evidence of hypercortisolism should be prepared with steroids for operation, which should also be continued postoperatively. Hydrocortisone, 100 mg, is given intravenously immedi- ately prior to operation and repeated in 100-mg doses every four to six hours for the next 24 hours. A maintenance dose of oral cortisol, 25 to 37.5 mg per day taken in divided doses, is achieved in five to seven days and continued after discharge. The contralateral suppressed adrenal gland usually recovers in three to six months, and steroid replacement may then be tapered off gradually. Some patients have relative adrenocortical insuf- ficiency for up to one year and must be warned that steroid replacement may be necessary in times of stress.
Patients with Cushing’s syndrome have increased susceptibility to infection and risk of thromboembolism. Therefore, perioperative antibiotics and low-dose heparin should be given. The patient should wear antiembolic stockings during operation.
The operative mortality associated with unilateral adrenalectomy for benign adenomas is almost zero, and the morbidity is minimal.43 Cure is achieved in 100 per cent of cases, and the physical signs of Cushing’s syndrome usually disappear within a year. Survival following successful surgery is not significantly different from that in the normal population. 18
Adrenocortical Carcinoma
Adrenocortical carcinomas are highly aggressive tumors. About half are functioning and half are nonfunctioning.20 The average size of the tumor when diagnosed is 10 to 12 cm in diameter.8, 11, 45 About 70 to 75 per cent of patients have metastases to the liver, lungs, lymph nodes, or bone when diagnosed.22, 23, 27 Results of treatment with conventional surgery, radio- therapy, and chemotherapy have been poor.19, 35, 48 The majority of the patients die of recurrence or metastases. Approximately 40 per cent of patients are candidates for curative resection. Overall, the five-year survival rates range from 16 to 30 per cent despite surgery, adjuvant chemotherapy, and/or radiotherapy. 11, 20, 33
Surgical resection of the tumor with any adjacent involved organ is critically important in achieving a possible cure. A transabdominal or thoracoabdominal approach, with the incision extending across the costal margin to the eighth or ninth rib, is preferred to allow adequate exposure of a large tumor and contiguous organs for resection. Even when complete resection is not possible because of invasion into vital structures, maximal debulking of the tumor mass should be undertaken.
Intravascular extension of the tumor into the inferior vena cava should not be a contraindication to complete resection in some cases. With the help of cardiopulmonary bypass, we were able to resect a right-sided tumor with tumor thrombus extending from the inferior vena cava to the right atrium in a patient without any known systemic metastases.7 En bloc resection of the tumor with kidney and perirenal fat should be performed if indicated by extension of the primary tumor into the kidney. For a left-
sided tumor, the resection may require distal pancreatectomy and splenec- tomy. Lymph node metastases along the aorta and vena cava should be excised. Liver metastases, which are readily accessible by wedge resection, should also be removed. Aggressive efforts to excise all gross tumor should be attempted, especially when the tumor is producing a clinical syndrome.
Since the observation that the insecticide DDT caused selective necrosis of the zona fasciculata and zona reticularis of the adrenal cortex in dogs, the ortho, para prime derivative (o,p’-DDD, mitotane) has been used in clinical trials. In the early 1960s, encouraging results were first reported. Objective tumor regression was observed in 34 to 61 per cent of patients.3, 21, 31 In these series, however, large doses of mitotane using 10 gm daily were used in patients with advanced disease or inoperable cancers. Adverse effects, including nausea, vomiting, diarrhea, muscle weakness, rash, leu- kopenia, and thrombocytopenia, were observed in most of the patients. It was also observed that interrupted treatment caused exacerbation of the disease and made subsequent therapy less effective. Nevertheless, mitotane has been administered for as long as 12 years in some patients and has maintained remission without harmful effects. 22
Mitotane’s adrenocorticolytic effects during prolonged therapy neces- sitate corticosteroid replacement in all patients and mineralocorticoid re- placement in some. A recent study of our patients showed that aggressive surgical therapy combined with early adjuvant mitotane therapy, continued indefinitely in low doses, prolonged survival from 10.3 months to 46.6 months. The longest survivals were observed in patients who had additional operations for recurrent disease and who were then treated with mitotane immediately afterward, even when all gross tumor could not be excised. 40 It appears that the effectiveness of mitotane depends on the bulk of tumor present. Adverse effects of mitotane are also found to be dose dependent. Our policy now is to perform a curative procedure when feasible or aggressive surgical debulking followed by early postoperative mitotane therapy. An initial daily dose of 6 gm is used for two to three weeks after operation, followed by a maintenance dose of 2 to 4 gm daily, given indefinitely. Cortisone replacement therapy is invariably needed with long- term therapy, at an average dose of 30 mg per day. Patients with evidence of mineralocorticoid insufficiency are treated with up to 0.1 mg of fludro- cortisone acetate each day. Most patients have tolerated the low-dose mitotane therapy well. For patients with carcinoma that was confined to the adrenal gland and has been grossly resected for cure, the value of prophylactic mitotane therapy remains to be proven. Nevertheless, in historical series, more than 50 per cent of patients in this group have developed recurrence. We have been using mitotane prophylactically for such patients treated during the past five years, with encouraging results.
Nodular Adrenal Hyperplasia
In 1964, Kirschner and associates25 described a syndrome of hypercor- tisolism that was associated with multiple small hyperfunctioning adrenal nodules that secondarily suppressed endogenous ACTH secretion. 25 Sub- sequently this rare cause of Cushing’s syndrome was referred to as primary nodular adrenal hyperplasia (NAH). The typical pathologic picture includes
the presence of multiple small nodules in both adrenal glands with diffuse hyperplastic or atrophic cortices. The nodules range in size from microscopic to several centimeters in diameter, with multiple small nodules being the most common (usually < 3 mm). The nodules may be black, brown, red, green, or yellow. Ten to 20 per cent of patients with bilateral adrenal hyperplasia are estimated to have this type.23 Onset varies from infancy to the seventh decade but usually occurs in young patients. The mean age is 18 years.
The biochemical findings are heterogeneous. Most patients have hy- percortisolism with variable response to dexamethasone suppression. The plasma ACTH levels range from undetectable to elevated. A typical patient will have elevated plasma cortisol levels that are not suppressed by high- dose dexamethasone, and low plasma ACTH levels. Both CT scan and NP- 59 scintiscans may show bilateral adrenal enlargement. ACTH-producing pituitary tumors are invariably absent. The pathogenesis has been uncertain, although familial cases have been reported.12 Association with cardiac myxomas and Peutz-Jegher syndrome-like hyperpigmentation has been reported. 38 A complete description of the complex syndrome was presented by Carney and associates5 in 1985, and it is now known as the Carney’s complex. The syndrome consists of the occurrence of two or more of the following conditions: (1) myxomatous masses: cardiac myxomas, cutaneous myxoma and/or mammary myxoid fibroadenoma; (2) spotty pigmented lesions of the skin: lentigines and blue nevi, with a predilection for the buccal mucosa, palate, and perianal area; (3) endocrine disorders: primary pigmented nodular adrenocorticoid disease (PPNAD) (the most common), large-cell calcifying Sertoli cell tumor of the testes, and growth hor- mone-producing pituitary adenomas. The disease complex runs in families, but the mode of genetic transmission is not yet known.
Nodular adrenal hyperplasia is usually treated with bilateral adrenalec- tomy via the posterior approach. No pituitary irradiation is required after operation, as to date no cases of Nelson’s syndrome have been encountered. With clinical recognition of the complex, echocardiography should be performed to detect the presence of cardiac myxomas. These may be multiple or recurrent and should be excised when detected. Cardiac myxoma is the major cause of death in this group of patients.
INCIDENTALOMAS
With the wide application of ultrasonography and CT scanning, the incidental finding of a radiologic abnormality, apparently adrenal in origin, has presented a problem for clinical management. These asymptomatic adrenal masses are termed “incidentalomas.”
These clinically silent tumors occur in 0.6 to 1.3 per cent of all upper abdominal CT scans performed for other reasons. 40, 41 They vary in size from 0.5 cm to more than 6 cm in diameter. They may be cortical adenomas, cortical carcinomas, pheochromocytomas, ganglioneuromas, cysts, myeloli- pomas, or adrenal metastases from other tumors. 15 Although most of them prove to be benign cortical adenomas, careful evaluation of any adrenal
mass should be carried out to guide appropriate treatment. Functioning cortical carcinomas and pheochromocytomas have been confirmed by op- eration despite lack of clinical suspicion. 37, 44
Biochemical evaluations of adrenal cortical and medullary hormone secretions should be carried out. They should include the dexamethasone suppression test as well as measurements of early morning and evening plasma cortisol levels; urinary 17-OHCS and 17-KS; plasma androgens, including testosterone, androstenedione, renin, and aldosterone; urinary vanillylmandelic acid; epinephrine and norepinephrine; metanephrine and normetanephrine; and plasma catecholamines (see Table 1). Any biochem- ical proof of hormone hypersecretion is an indication for operation.
Further functional studies using NP-59 and 131I meta-iodobenzyl guan- idine (131I-MIBG) scintiscans may be performed to detect tumors functioning at subclinical levels. Asymmetric increase in uptake or nonvisualization of the adrenal mass can help to differentiate benign from malignant tumors.
Magnetic resonance imaging (MRI) has been reported to be able to distinguish adrenal metastases, carcinomas, and pheochromocytomas from adrenal adenomas, lipomas, myelolipomas, and cysts by differences in the signal intensities of the images of various organs.38 This capability may be of great help in determining whether or not an individual’s incidentaloma should be resected, observed, or needle biopsied.
Masses over 6 cm have a high chance of being malignant and should be operated on despite lack of demonstrated function. Most cystic masses are endothelial cysts, either lymphangiomatous or angiomatous, or pseu- docysts, formed by hemorrhage into normal glands. Cystic degeneration does, however, occur in pheochromocytoma and benign cortical tumors. 24 Aspiration under ultrasound or CT guidance may decompress the cyst, and its benignity may be determined by cytologic examination of the aspirate. Biochemical functions should be assessed before a cyst is punctured, in case a cystic pheochromocytoma has been overlooked. Confirmation of metastases from other primary tumors can eliminate unneccessary opera- tions for adrenal masses. Suspicion of malignant adrenal cells prompted by results of needle aspiration cytology is an indication for operation.
For adrenal masses that are less than 3 cm in diameter without biochemical function and that have benign imaging characteristics, most surgeons agree that a follow-up CT scan should be done at three to six months. Operation is chosen when there is evidence of enlargement or growth of the mass. Treatment of truly nonfunctioning masses between 3 and 6 cm in diameter is more controversial. Many surgeons are uncomfort- able about these masses and will advocate operation;16, 37 others, however, tend to observe them by CT scans9, 15 because the chance of malignancy is low when the tumor is smaller than 6 cm and because benign adenomas are not known to become malignant. Our present policy is to operate on all patients with incidentalomas 3 cm or more in diameter except those in patients over the age of 60 with normal biochemistry and imaging charac- teristics.
SUMMARY
The most important functional tumors of the adrenal cortex are those that secrete cortisol or aldosterone in excess. Biochemical testing when
appropriately utilized can diagnose and differentiate the cause of Cushing’s syndrome, and when an adrenal adenoma is found, surgical excision is curative. The diagnosis and surgical treatment of primary aldosteronism are straightforward today, and localization of the usual small cortical tumor producing the syndrome can be achieved by CT and NP-59 scanning or selective venous assays. Adrenocortical carcinomas are relatively rare, are usually incurable when diagnosed, and are an important consideration in the incidentally discovered adrenal mass found by CT scanning.
REFERENCES
1. Abecassis M, McLoughlin MJ, Langer B, et al: Serendipitous adrenal masses: Prevalence, significance, and management. Am J Surg 149:783-788, 1985
2. Bauman A, Bauman CG: Virilizing adrenocortical carcinoma. Development in a patient with salt-losing congenital adrenal hyperplasia. JAMA 248:3140, 1982
3. Bergenstal DM, Hertz R, Lipsett MB, et al: Chemotherapy of adrenocortical cancer with o,p’-DDD. Ann Intern Med 53:672-682, 1960
4. Bertagna C, Orth DN: Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med 71:855-875, 1981
5. Carney JA, Gordon H, Carpenter PC, et al: The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 64:270-283, 1985
6. Charbonnel B, Chatal JF, Ozanne P: Does the corticoadrenal adenoma with “pre-Cushing’s syndrome” exist? J Nucl Med 22:1059-1061, 1981
7. Cheung PSY, Thompson NW: Adrenocortical carcinoma with right atrial extension: Surgical management using cardiopulmonary bypass. Surgery (in press)
8. Cohn K, Brennan M: Adrenocortical carcinoma. Surgery 100:1170-1177, 1986
9. Copeland PM: The incidentally discovered adrenal mass. Ann Intern Med 98:940-945, 1983
10. Crapo L: Cushing’s syndrome: A review of diagnostic tests. Metabolism 28:955-977, 1979
11. Didolkar MS, Bescher RA, Elias EG, et al: Natural history of adrenal cortical carcinoma: A clinicopathologic study of 42 patients. Cancer 47:2153-2161, 1981
12. Donaldson MDC, Grant DB, O’Hare GM, et al: Familial congenital Cushing’s syndrome due to bilateral nodular adrenal hyperplasia. Clin Endocrinol 14:519-526, 1981
13. Eddy RL, Jones AL, Gilliland PF, et al: Cushing’s syndrome: A prospective study of diagnostic methods. Am J Med 55:621-630, 1973
14. Freitas JE, Beierwaltes WH, Nishiyama RH: Adrenal hyperandrogenism: Detection by adrenal scintigraphy. J Endocrinol Invest 1:59-64, 1978
15. Geelhoed GW, Druy EM: Management of the adrenal incidentaloma. Surgery 92:866-884, 1982
16. Glazer HS, Weyman PJ, Sagel SS, et al: Nonfunctioning adrenal masses: Incidental discovery on computed tomography. AJR 139:81-85, 1982
17. Hamberger B, Curstedt T, Werner S: Release of corticosteroids from human adrenals in vitro. World J Surg 10:776-780, 1986
18. Hamberger B, Russell CF, van Heerden JA, et al: Adrenal surgery: Trends during the seventies. Am J Surg 144:523-526, 1982
19. Haq MM, Legha SS, Samaan NA, et al: Cytotoxic chemotherapy in adrenal cortical carcinoma. Cancer Treat Rep 64:909-913, 1980
20. Henley DJ, van Heerden JA, Grant CS, et al: Adrenal cortical carcinoma-a continuing challenge. Surgery 94:926-931, 1983
21. Hutter AM, Kayhoe DE: Adrenal cortical carcinoma: Results of treatment with o, p’-DDD in 138 patients. Am J Med 41:581-592, 1966
22. Jarabak J, Rice K: Metastatic adrenal cortical carcinoma: Prolonged regression with mitotane therapy. JAMA 246:1706-1707, 1981
23. Joffe SN, Brown C: Nodular adrenal hyperplasia and Cushing’s syndrome. Surgery 94:919-925, 1983
24. Kearney GP, Mahoney EM, Maher E, et al: Functioning and nonfunctioning cysts of the adrenal cortex and medulla. Am J Surg 134:363-368, 1977
25. Kirschner MA, Powell RD Jr, Lipsett MB: Cushing’s syndrome: Nodular cortical hyper- plasia of adrenal glands with clinical and pathological features suggesting adrenocortical tumor. J Clin Endocrinol Metab 24:947-955, 1964
26. Lewinsky BS, Grigor KM, Syminton T, et al: The clinical and pathologic features of “non- hormonal” adrenocortical tumors: Report of twenty new cases and review of the literature. Cancer 33:778-790, 1974
27. Liddle GW: Cushing’s syndrome. In Eisentein AB (ed): The Adrenal Cortex. Boston, Little, Brown, 1967, pp 523-551
28. Liddle GW: Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 20:1539-1560, 1960
29. Liddle GW, Nicholson WE, Island DP, et al: Clinical and laboratory studies of ectopic humoral syndromes. Recent Prog Horm Res 26:283-305, 1969
30. Lipsett MB, Wilson H: Adrenocortical cancer: Steroid biosynthesis and metabolism evaluated by urinary metabolites. J Clin Endocrinol Metab 22:906-915, 1962
31. Lubitz JA, Freeman L, Okun R: Mitotane use in inoperable adrenal cortical carcinoma. JAMA 223:1109-1112, 1973
32. Matsuo K, Kawai K, Tsuchiyama H: Non-functioning adrenocortical adenoma in culture: Quantitative and morphological observations. Acta Pathol Jpn 35:871-884, 1985
33. Nader S, Hickey RC, Sellin RV, et al: Adrenal cortical carcinoma: A study of 77 cases. Cancer 52:707-711, 1983
34. Pavlatos FC, Smilo RP, Fordham PH: A rapid screening test for Cushing’s syndrome. JAMA 193:720, 1965
35. Percarpio B, Knowlton AH: Radiation therapy of adrenal cortical carcinoma. Acta Radiol 15:288-292, 1976
36. Poltz CM, Knowlton AH, Ragan C: The natural history of Cushing’s syndrome. Am J Med 13:597-614, 1952
37. Prinz RA, Brooks MH, Churchill R, et al: Incidental asymptomatic adrenal masses detected by computed tomographic scanning. Is operation required? JAMA 248:701-704, 1982
38. Reinig JW, Doppman JL, Dwyer AJ, et al: Adrenal masses differentiated by MRI. Radiology 158:81-84, 1986
39. Sarkar SD, Beierwaltes WH, Ice RD, et al: A new and superior adrenal scanning agent, NP-59. J Nucl Med 16:1038-1042, 1975
40. Schteingart DE, Motazedi A, Noonan RA, et al: Treatment of adrenal carcinomas. Arch Surg 117:1142-1146, 1982
41. Schteingart DE, Seabold JE, Gross MD, et al: Iodocholesterol adrenal tissue uptake and imaging in adrenal neoplasms. J Clin Endocrinol Metab 52:1156-1161, 1981
42. Schweizer-Cagianut M, Salomon F, Hedinger CE: Primary adrenocortical nodular dys- plasia with Cushing’s syndrome and cardiac myxomas, a peculiar familial disease. Virchows Arch A 397:183-192, 1982
43. Scott HW Jr, Abumrad NN, Orth DN: Tumors of the adrenal cortex and Cushing’s syndrome. Ann Surg 201:586-594, 1985
44. Seddon JM, Baranetsky N, van Boxel PJ: Adrenal incidentalomas: Need for surgery. Urology 25:1-7, 1985
45. Thompson NW: Adrenocortical carcinoma. In Thompson NW, Vinik AI (eds): Endocrine Surgery Update. New York, Grune & Stratton, 1983, pp 119-128
46. Thompson NW, Allo M: Tumors of the suprarenal glands. In Comprehensive Textbook of Oncology. Moossa AR, Robson MC, Schimpff SC (eds): Baltimore, Williams & Wilkins, 1986, pp 1065-1076
47. Thrall JH, Freitas JE, Beierwaltes WH: Adrenal scintigraphy. Sem Nucl Med 8:23-41, 1978
48. van Slooten H, van Oosterom AT: CAP (cyclophosphamide, doxorubicin, and cisplatin) regimen in adrenal cortical carcinoma. Cancer Treat Rep 67:377-379, 1983
2920-D Taubman Health Center 1500 East Medical Center Ann Arbor, Michigan 48109