Tumors of the Adrenal Cortex and Cushing’s Syndrome
H. WILLIAM SCOTT, JR., M.D., NAJI N. ABUMRAD, M.D., DAVID N. ORTH, M.D.
Fifty-nine patients with Cushing’s syndrome, due to adreno- cortical tumor, were studied and treated during the period 1953 through 1983 at Vanderbilt University Medical Center. Cushing’s syndrome is caused by hypercortisolism that can be due to (1) medicinal use of steroids, (2) excess pituitary secretion of adrenocorticotropin (ACTH) (Cushing’s disease), (3) adrenocortical tumor, benign or malignant, and (4) the ectopic ACTH syndrome. Clinical and endocrinologic features of Cushing’s syndrome are described, and differential diagnosis of adrenocortical tumor by precise endocrinologie studies is detailed. Computerized axial tomographic (CAT) scan is cur- rently the most accurate imaging modality for preoperative localization of tumors. Preoperative differential diagnosis be- tween adrenocortical adenoma and carcinoma has become fairly accurate. Operative approaches in each category are described. Follow-up from 1 to 30 years has been completed for all patients, except for one who was lost after 7 years. Results of surgical treatment of adrenocortical adenomas are excellent, but the salvage from adrenocortical carcinomas is poor.
T HE SYNDROME DESCRIBED by Harvey Cushing1 in 1932 was based on a series of patients that he had studied during a 20-year period with manifestations of moon facies, truncal obesity, hypertension, polyphagia, polydipsia, polycythemia, and susceptibility to pulmo- nary infections. In four of the eight patients in his series, basophil adenomas of the pituitary were found at au- topsy, and Cushing ascribed the syndrome to pituitary basophilism.
Anderson and her co-workers in 1938 were among the first to present evidence that the probable common denominator in all cases of Cushing’s syndrome was hyperactivity of the adrenal cortex. Subsequently, largely due to the work of Anderson,2 Albright,3 Thorn,4 and other endocrinologists, it has become well-established that the fundamental hormonal basis of the syndrome described by Cushing is hypercortisolism.
In addition to the exogenous use of steroid hormones in medical therapy, hypercortisolism occurs sponta- neously from three endogenous causes: (1) bilateral
From the Department of Surgery, Section of Surgical Sciences, and Division of Endocrinology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
adrenal cortical hyperplasia under the stimulatory effect of excess secretion of adrenocorticotropin (ACTH) by the pituitary (which usually contains a secreting tumor); (2) bilateral adrenal cortical hyperplasia under the stim- ulus of ectopic ACTH secreted by a paraendocrine or nonendocrine tumor, such as certain carcinomas of the lung; and (3) primary tumors of the adrenal cortex that secrete cortisol autonomously.5
Clinical Manifestations and Pathophysiology of Cushing’s Syndrome
During the period 1953 through 1983 at Vanderbilt University Medical Center, over 300 patients with Cush- ing’s syndrome unrelated to the medicinal use of steroids were studied and treated. The age range was 9 months to 71 years, and two-thirds of the patients were female. Sixty-five per cent of this group proved to have pituitary dependent hypercortisolism (Cushing’s Disease); 20% had hypercortisolism caused by adrenocortical tumors; and 15% had hypercortisolism due to nonpituitary tu- mors that produced ACTH (ectopic ACTH syndrome).
The manifestations of Cushing’s syndrome caused by adrenocortical tumors in a previously reported series of 28 patients are summarized in Table 1.6 As is readily apparent in the table, several patients had only a few of the classical manifestations of the syndrome originally described by Cushing; even obesity and hypertension were occasionally absent.
Although the various clinical manifestations of en- dogenous Cushing’s syndrome tend to be similar in frequency and pattern of distribution, whether it is caused by adrenocortical tumor, pituitary dependent adrenocortical hyperplasia, or the ectopic ACTH syn- drome,5,7 there may be certain distinctive features. Ma- lignant tumors of the adrenal cortex often synthesize cortisol relatively inefficiently and only at the expense of excessive secretion of androgenic precursors. There-
Reprint requests: H. William Scott, Jr., M.D., Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
fore, hirsutism is much more common in patients with these tumors. Furthermore, these tumors often grow rapidly, so Cushing’s syndrome may become florid in a relatively short period of time. Rapidly growing malig- nant tumors of nonpituitary origin often rapidly produce very high plasma concentrations of ACTH and, thus, of cortisol. In these patients, the salt-retaining properties of cortisol may at first predominate, resulting in hypo- kalemia and edema. A much more gradual evolution of the syndrome occurs and develops over a period of many months or several years in patients with benign adrenocortical tumors, pituitary dependent adrenocor- tical hyperplasia, or occasionally, relatively indolent nonpituitary tumors causing the ectopic ACTH syn- drome.
Excessive secretion of cortisol in Cushing’s syndrome results in a catabolic depletion of protein with diminution of the mass of connective tissue and muscle of the affected patient. Skin becomes atrophic and thin with protein resorption of the corium. Increased capillary fragility is manifested by ecchymoses and petechial hemorrhages. Axillary and abdominal striae result from splitting of protein-depleted corium by accumulations of adipose tissue with purplish erythema reflecting the well-vascularized, subcutaneous fatty layer. The altered skin is sometimes so friable that it may readily be denuded by simple removal of adhesive tape. Children characteristically show growth retardation, muscular weakness, and osteoporosis; pathologic fractures are common.
The accelerated protein breakdown results in increased gluconeogenesis and diminished carbohydrate tolerance. Overt diabetes may result from these processes. Another common result of altered protein and carbohydrate metabolism is impaired wound healing.
Accompanying the excessive protein breakdown is an abnormal accumulation of fat with deposition especially in the face, neck, back, and trunk. The cervicodorsal fat pad has been characterized as a “buffalo hump.” The increase in the supraclavicular fat pads with resultant loss of the concavity of the supraclavicular fossae is one of the more reliable clinical signs.
Accumulation of fat in the face often produces the characteristic “moon facies.” Fat accumulation in the trunk is often strikingly severe in contrast to the muscular wasting and thinning of the arms and legs, which usually occur simultaneously.
Weakness and easy fatigability are directly related to protein catabolismand the severe depletion of muscle mass. Hypertension-often with associated headache- develops because of salt and water retention with expan- sion of the extracellular volume. There is a distinct tendency in many of these patients to develop metabolic
| Number | Per cent | |
|---|---|---|
| Central Obesity | 26/28 | 93 |
| Hypertension | 26/28 | 93 |
| Weakness | 23/28 | 82 |
| Hirsutism | 22/28 | 79 |
| Impaired glucose tolerance | 22/28 | 79 |
| Mental aberrations | 16/28 | 57 |
| Ecchymoses | 16/28 | 57 |
| Osteoporosis | 15/28 | 54 |
| Edema | 13/28 | 46 |
| Striae | 10/28 | 36 |
| Menstrual abnormalities | 9/12 | 75 |
* Scott HW, Jr. Tumors of the adrenal cortex and Cushing’s syndrome. Seventh National Cancer Conference Proceedings. Philadelphia: Lip- pincott, 1973:513-521.
alkalosis with attendant hypokalemia. When severe, hypokalemia accentuates the muscle weakness.
Amenorrhea is a common symptom in adolescent girls and premenopausal women. Hirsutism, acne, and other aspects of virilization occur in women and pre- cocious sexual development can occur in girls and boys.
Emotional instability is frequently observed in patients with Cushing’s syndrome, and more severe mental dis- orders that extend to the psychoses, in which depression and paranoia predominate, are not uncommon.5,7
Endocrinologic Diagnosis of Cushing’s Syndrome
Although the clinical manifestations alone may be sufficiently clear to suggest the diagnosis of Cushing’s syndrome, it is often necessary and always desirable to confirm the clinical impression by precise studies of adrenocortical function and pituitary-adrenal relation- ships. These studies are of fundamental importance in differentiating Cushing’s syndrome caused by pituitary dependent adrenocortical hyperplasia, nonpituitary tu- mors (ectopic ACTH syndrome), and adrenocortical tumors. Furthermore, some degree of help may be offered in preoperative differentiation of Cushing’s syn- drome caused by adrenal adenoma and that caused by adrenocortical carcinoma.
Plasma cortisol levels in normal subjects show char- acteristic diurnal variation, reflecting diurnal variation in the anterior pituitary’s secretion of ACTH. Plasma ACTH and cortisol levels measured in the early morning (6:00 A.M.) are higher than those measured in the evening (6:00 P.M.). Characteristically, normal subjects have evening values of plasma cortisol concentrations less than 5 µg/dl. In striking contrast, patients with Cushing’s syndrome do not have the normal diurnal variation in plasma cortisol levels. Although the early
morning plasma cortisol levels in patients with Cushing’s syndrome may fall within the normal range, late evening values are distinctly elevated (usually well above 12 µg/dl).5,7,8
Another laboratory estimation of the activity of the adrenal cortex in secreting cortisol is measurement of the daily urinary excretion of 17-hydroxycorticosteroids (17-OHCS). Normal unstressed adults excrete 3 to 11 mg of 17-OHCS in 24 hours, and patients with Cushing’s syndrome usually excrete more than 12 mg/day. The accuracy of the urine collection, and at the same time, an adjustment for body size can be obtained by relating the quantity of 17-OHCS to the quantity of creatinine in the urine. Patients with Cushing’s syndrome almost always excrete more than 10 mg of 17-OHCS per gram of creatinine, while normal subjects excrete 3 to 7 mg of 17-OHCS per gram of creatinine.5,7,8
Pavlatos, Smilo, and Fordham9 have popularized a screening test for Cushing’s syndrome that consists of giving the subject 1 mg of dexamethasone at 11 P.M. and then drawing blood for plasma cortisol concentration at 8 A.M. Most normal subjects will have suppression of plasma cortisol concentrations of 5 ug/dl or less, while patients with Cushing’s syndrome maintain plasma cortisol concentrations in excess of this amount.
At Vanderbilt, we believe the most valuable tests for establishment of the diagnosis of Cushing’s syndrome are the dexamethasone suppression tests devised by Grant Liddle.10 These are based on the urinary 17- OHCS response to low and high doses of the synthetic steroid, dexamethasone, which has 30 times the potency of cortisol and which, like cortisol, suppresses ACTH secretion by the pituitary. In normal subjects, dexa- methasone 0.5 mg orally every 6 hours causes a fall in urinary excretion of 17-OHCS to less than 2.5 mg/day in 48 hours. Patients with Cushing’s syndrome show resistance to suppression at this low dosage of dexa- methasone. In the experience at Vanderbilt, this abnor- mal resistance to the suppressive effect of dexamethasone in low dosage is characteristic of patients with Cushing’s syndrome.5,10
When the diagnosis of Cushing’s syndrome has been established, it is then necessary to determine the etiology of the adrenocortical hyperfunction. In the patient with Cushing’s syndrome due to excess pituitary ACTH secretion, a high dosage of dexamethasone (oral doses of 2 mg every 6 hours for 2 days) inhibits pituitary ACTH secretion, and urinary 17-OHCS excretion is completely or almost completely suppressed. On the contrary, the patient who has adrenocortical tumor, which produces cortisol autonomously, characteristically shows no evidence of plasma or urinary 17-OHCS suppression with high dose dexamethasone administra- tion.
Since patients with the ectopic ACTH syndrome produced by nonpituitary tumors also show resistance to high dose dexamethasone suppression, they must be differentiated from patients with Cushing’s syndrome caused by adrenocortical tumors. This can best be done by measuring plasma immunoreactive ACTH activity. If the patient has a high plasma ACTH level, the diagnosis is Cushing’s syndrome caused by autonomous secretion of ACTH by a nonpituitary tumor. If the plasma ACTH concentration is low (less than 10 pg/ ml), the test indicates the presence of an adrenocortical tumor. In such a situation the cortisol produced auton- omously by the tumor causes chronic suppression of pituitary ACTH secretion. This leads to atrophy of the adrenal cortex, both contralateral to and contiguous to the tumor.5,10
Among other endocrine studies that can be helpful in the diagnosis of Cushing’s syndrome and the endocri- nologic differentiation between ACTH-dependent adre- nocortical hyperplasia and adrenocortical tumor are the metyrapone test, the ACTH stimulation test, and mea- surement of urinary 17-ketosteroid levels. The drug, metyrapone (METOPIRONE®) blocks 11-beta-hydrox- ylation in the adrenal cortex and, thus, the conversion of compound S (11-deoxycortisol) to cortisol. When patients with Cushing’s syndrome are tested with this drug, those with pituitary-dependent adrenocortical hy- perplasia show an increased output of 17-OHCS in urine, while those with the ectopic ACTH syndrome have a variable response (remain the same or rise), and those with Cushing’s syndrome due to adrenocortical tumor characteristically have a fall in urinary 17-OHCS.8
The ACTH stimulation test offers further diagnostic information. In response to an 8-hour infusion of 50 units of ACTH, normal subjects increase their urinary 17-OHCS excretion three- to five-fold over basal level. Patients with Cushing’s syndrome due to adrenocortical hyperplasia caused by ACTH hypersecretion by either pituitary or nonpituitary tumors respond normally or even hyperrespond. In contrast, patients with adrenal carcinoma and Cushing’s syndrome are characteristically unresponsive to ACTH stimulation, although very rare exceptions have been reported. About half of the patients who prove to have benign adrenal adenoma have shown a normal increase in urinary 17-OHCS secretion after intravenous infusion of 50 units of ACTH.8
Additional help in the recognition of adrenocortical carcinoma as a cause of Cushing’s syndrome can be obtained from measurements or urinary 17-ketosteroids. Normal 24-hour urinary 17-ketosteroid excretion aver- ages about 10 ± 5 mg for females and 15 ± 5 for males. While slight increases in these levels of 17-ketosteroid excretion occur in many patients with Cushing’s syn- drome due to benign adenoma, extremely high levels of
urinary 17-ketosteroid excretion (in the range of 40 to >100 mg per 24 hours) are commonly associated with adrenocortical carcinoma.5-8,10
Clinical Experience with Adrenocortical Tumors and Cushing’s Syndrome
In the period 1953 through 1983 at Vanderbilt Uni- versity Medical Center, 59 patients with Cushing’s syn- drome due to adrenocortical tumors were studied and treated predominantly by surgical procedures. There were 50 females and nine males in this group. Ages ranged from 9 months to 71 years with an average of 35 years; eight of these patients were children of 15 years and under. There were 37 patients with benign tumors and 22 patients whose tumors proved to be malignant.
Results of Endocrinologic Evaluation
In this series of patients, the endocrinologic diagnosis of an adrenal tumor as the cause of Cushing’s syndrome was accurately made before operation in every case. Except for several of the early patients in whom data are incomplete, the laboratory findings that were consis- tently observed in our patients with Cushing’s syndrome due to adrenocortical tumors included basal elevations of urinary 17-OHCS levels, loss of diurnal rhythm in plasma cortisol secretion, resistance to high dose dexa- methasone suppression, and subnormal levels of plasma ACTH activity.
Efforts to differentiate benign from malignant tumors before operation were not based on endocrinologic grounds alone. Some help was provided in this regard by the characteristic unresponsiveness of adrenocortical carcinomas to ACTH stimulation, combined with ex- tremely high (>40 mg/24 hrs) basal urinary 17-ketoste- roid levels in most of the patients with adrenal carci- nomas. In contrast, only one patient with histologically benign adrenal adenoma, proven also by prolonged follow-up, had urinary 17-ketosteroids in the range of 40 mg/24 hours.
Results of Evaluation by Clinical Examination and Diagnostic Imaging
Localization of adrenal tumors prior to operation was accurately accomplished in all but four patients who were seen in the early part of this series. In 10 patients with large tumors (8 carcinomas and 2 adenomas), physical examination alone served to localize the tumor before operation, but confirmation by diagnostic imaging was obtained in each case.
In our early experience,11 intravenous pyelography, retroperitoneal pneumography, and nephrotomography
R
were of considerable value in localization of adrenal tumors, but these imaging techniques were largely re- placed by flush and selective arteriography in the decades of the 1960s and 1970s. We have rarely used adrenal phlebography.
More recently, angiography has been supplanted in preoperative localization by computerized axial tomo- graphic (CAT) scanning of the adrenals. Accuracy for tumors over 1 to 2 cm in diameter has been astonishingly good (Fig. 1) “False positives,” however, have increased in incidence in many clinics with inaccurate identification of smaller masses in the adrenal areas by CAT scanning. 12
Carcinomas are generally 6 cm in diameter or greater by the time the clinical diagnosis of Cushing’s syndrome is made. These larger tumors can be quite accurately delineated by preoperative CAT scans and much helpful information is provided concerning the tumor’s invasive and metastatic characteristics.
Choice of Surgical Approaches
In the first seven patients of this series, a transabdom- inal approach was used to excise the adrenal tumor. In most of the early patients, a long transverse or “bucket handle” abdominal incision was used, which was ex- tended across the costal margin into a lower intercostal space in three patients with very large tumors.11
In the last 20 years, we have preferred to use the posterior retroperitoneal approach to adrenal adenomas in patients with Cushing’s syndrome.7 This is a result of the increased accuracy of diagnostic imaging in localizing adrenal tumors prior to operation, as well as increased clinical and laboratory accuracy in preoperative differ- entiation between the smaller benign adenomas and the much larger adrenal carcinomas. It has been our expe-
TABLE 2. Cushing’s Syndrome Due to Adrenocortical Adenoma
37 Patients-6 males, 31 females
Age: 9 Months to 63 years
RX: Surgical excision
Operative mortality: None
Cured: 100%
Follow-up: 37 Patients
Living and Well 33 (1 to 30 years)
Died 4
(3 Months, 17 Months, 10 Years, and 12 Years)
rience that the posterior retroperitoneal approach to the adrenal area through the bed of the resected eleventh rib provides excellent exposure, and is associated with less postoperative morbidity than is a transabdominal or thoracoabdominal procedure. In the last two decades, we have reserved the anterior abdominal approach with thoracic extension for the resection of adrenal carcino- mas.7 In the last 52 patients of this series, our surgical approach to the adrenal area in patients with Cushing’s syndrome due to adrenal tumor has been guided by these considerations.
In the middle years of this study, it was our practice to use bilateral posterior incisions with a two-team approach and expose both adrenal glands simultaneously when preoperative considerations indicated benign ade- noma.6,7 With the greater diagnostic accuracy of the CAT scan in localizing small tumors and in delineating normal adrenal glands, we have discontinued the routine use of bilateral incisions for adrenal adenoma, except in the rare occurrence of bilateral adenomas (1.7% in this series).
When a carcinoma of the adrenal causing Cushing’s syndrome appears likely on preoperative study, we have usually employed the thoracoabdominal approach to the tumor. As a rule, the abdominal component of the incision is made first. After confirmation of the location of the tumor, search for intraabdominal metastases, and appraisal of resectability of the tumor, the incision is extended across the costal margin into the eighth or ninth intercostal space. With division of the diaphragm, the incision provides wide exposure of the adrenal and kidney on the side of the tumor. Simple excision usually suffices in the case of benign adrenocortical adenoma. Radical nonmanipulative en bloc resection of the adrenal tumor with the kidney and the surrounding perirenal fat is indicated in removal of adrenal carcinomas, which are usually highly aggressive neoplasms.
Results of Surgical and Endocrinologic Management Adrenocortical Adenomas
Among the 37 patients who proved to have benign adrenal adenomas confirmed by endocrinologic study, surgical pathologic examination, and clinical follow-up,
there were six males and 31 females. Ages ranged from 9 months to 63 years.
One patient who had large (70 gm) bilateral adreno- cortical adenomas required bilateral total adrenalectomy. Another patient who had a single adenoma combined with bilateral adrenocortical hyperplasia was also treated by bilateral adrenalectomy. The other 35 patients had solitary adenoma as the cause of Cushing’s syndrome, and each was treated by unilateral adrenalectomy with excision of the tumor. There were no hospital fatalities (Table 2).
In preparation for the stress of anesthesia and opera- tion, each patient was given steroidal support prior to, during, and after operation. Hydrocortisone 100 mg (or its steroidal equivalent) was usually given intravenously immediately prior to operation and thereafter repeated in 100 mg doses every 4 to 6 hours for the next 24 hours. Rapid reduction of this dosage to a maintenance dose of oral cortisol 25 mg per diem was usually accomplished within 5 to 7 days. Fludrocortisone (FLORINEF®) was added to the daily steroidal mainte- nance program prior to discharge. Excepting the two patients with total bilateral adrenalectomy in whom permanent cortisol support was required, the patients were weaned off cortisol within 3 to 6 months.
Postoperative complications included four patients with wound infections, one with transient pleural effu- sion, and one with transient atelectasis and fever. Ureteral injury occurred at operation in another patient, but was repaired successfully with no residual uropathy during follow-up.
Follow-up studies of these patients with adrenal ade- noma range from more than 1 year to 30 years. All patients were cured of hypercortisolism and Cushing’s syndrome by excision of the adenoma(s).
Figure 2 illustrates the current (September 1984) follow-up status of the 37 patients. Thirty-two patients are alive and well with no evidence of recurrent tumor or hypercortisolism. One patient was free of disease for 7 years and then lost to follow-up. Four patients have died of intercurrent disease during the period of follow- up: two died at 3 months and 10 years, respectively, of myocardial infarction; one died 17 months after unilat- eral adrenalectomy from pulmonary embolism after an operation for intestinal obstruction; and a fourth patient died 12 years after adrenalectomy of metastatic breast cancer.
Adrenocortical Carcinoma
Among the 22 patients with Cushing’s syndrome caused by adrenocortical carcinoma, there were 19 fe- males and three males, ranging in age from 5 to 71 years. Four patients were children 5 to 15 years of age.
7
6
LIVING AND WELL
5
NUMBER
DEAD
OF
4-
PATIENTS
L LOST TO FOLLOW UP
3.
2.
1
L
<1
1
2
3
S
4
5
6
7
8
9
10
I
12
13
15 16
7 18 19
20 2
22
24 25
5 26 27 28 29
YEARS
The development of the clinical manifestations of Cushing’s syndrome was rapid (3 to 6 months) in 19 of the patients. In one patient the full-blown manifestations of Cushing’s syndrome developed much more gradually (2 years), and this patient was considered to have a benign adenoma with endocrinologic cure until tumor and hypercortisolism recurred 12 years after excision. The other two patients had only a few clinical manifes- tations of Cushing’s syndrome over periods of 1 and 6 years, respectively, before each was found to have a massive, incurable malignant tumor. Each of the latter proved to have adrenocortical carcinomas that produced predominantly a cortisol precursor.
Resection of tumor was essayed in all patients but was not accomplished successfully in four. One of these, an 11-year-old child, died with renal failure and shock 7 days after attempted removal of a massive adrenal carcinoma that involved the aorta, inferior vena cava, and the hilar structures of both kidneys. In three other patients with massive adrenal carcinomas that had me- tastasized to, or infiltrated the liver, and/or invaded the inferior vena cava, the tumor could not be safely resected and only biopsy was done. Operative mortality rate was 4.5% (Table 3).
Complications after operation included a wound in- fection in one patient; an acute urinary tract infection in another; persistent hypokalemia with nausea, vomit- ing, and diarrhea in another patient; and a fourth patient sustained femoral artery thrombosis after a preoperative arteriogram and congestive heart failure in the postop- erative period.
One or more reoperations for recurrence of localized masses of tumor were done during the period of follow- up in six patients and in another patient reoperation was done for Budd-Chiari syndrome. There was a single postoperative death from caval laceration with exsan- guinating hemorrhage after one of the secondary oper- ations.
TABLE 3. Cushing’s Syndrome Due to Adrenocortical Carcinoma
22 Patients-3 males and 19 females
Age: 5 to 71 years
Operative mortality: 1 (4.5%)
Cured: 2 males (9%)
Follow-up: 21 patients
2 living and well (9 and 23 years)
19 patients died: (10: 2 to 24 months) (9: 3 to 16 years)
Follow-up status of these 22 patients with adrenocor- tical carcinoma is illustrated in Figure 3. Two male patients have been cured of Cushing’s syndrome and their malignant tumor. These two patients are alive and well with no stigmata of tumor or hypercortisolism 9 and 23 years, respectively, after resection of the primary adrenal carcinoma.
Eighteen of the other 19 patients have died of recurrent and metastatic adrenal carcinoma. One patient, who had advanced breast cancer when Cushing’s syndrome developed and an adrenal carcinoma was removed, died with metastases of carcinoma of the breast.
As seen in Figure 3, ten of the 18 patients who died during the follow-up period lived only 2 to 24 months. In these patients, neither secondary operations for re- current tumor nor the chemotherapeutic drug mitotane (Lysodren®) proved to be of much palliative benefit.
Nine other patients with adrenal carcinoma lived from 3 to 16 years after resection of the primary tumor. In several of these patients, reoperation for excision of recurrent masses of tumor provided transitory palliative benefit. Mitotane was used at some point, and often in multiple courses in most of these patients with transitory benefit in several. It seemed to help more in inhibiting the biosynthesis of cortisol and the control of Cushing’s syndrome than in retarding the growth of the malignant tumor.
One patient in this group had successful removal of a left adrenal tumor diagnosed as a benign adenoma
7
6
LIVING
5
NUMBER OF PATIENTS
DEAD
4
3
2
1
<1
I
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23 24 2
27 2 29
YEARS
with relief of hypercortisolism for 12 years before recur- rence of Cushing’s syndrome and the development of a large left adrenal carcinoma. Despite radical resection of the adrenal carcinoma, there was recurrence of tumor and hypercortosolism within 18 months. Moderate tran- sitory palliation was provided by mitotane until the patient’s death’ 16 years after the initial “benign ade- noma” was excised.
Discussion
Cushing’s syndrome (hypercortisolism) is a potentially lethal endocrinopathic disorder that can be caused by medicinal use of steroid hormones and by three endog- enous sources: (1) ACTH-producing pituitary, tumors with bilateral adrenocortical hyperplasia and excessive cortisol secretion; (2) cortisol-producing tumors of the adrenal cortex, either benign or malignant,. and (3) nonpituitary tumors, usually malignant (such as small cell carcinomas of the lung), that produce ectopic ACTH and bilateral adrenocortical hyperplasia with excessive secretion of cortisol. Precise endocrinologic study can differentiate these three endogenous causes with accuracy in most cases. Tumors of the adrenal cortex are second in frequency to pituitary tumors as a cause of recognized Cushing’s syndrome, since many cases of ectopic ACTH syndrome go unrecognized .:
In the period 1953 through 1983 at Vanderbilt Uni- versity Medical Center, 59 patients with adrenocortical tumors and Cushing’s syndrome were studied and treated. Of the several modalities of diagnostic imaging that have been helpful in preoperative localization of the adrenal tumor, the CAT scan currently seems to be the most accurate. In 37 patients with benign adreno- cortical adenomas confirmed by endocrinologic study, surgical pathologic examination, and clinical follow-up, surgical excision of the adenoma(s) resulted in endocri- nologic cure in 100% without operative mortality. Fol- low-up from over 1 to 30 years has shown no recurrence of tumor or hypercortisolism in any patient.
. In contrast, however, in 22 patients with adrenocortical carcinoma in this series, only two patients have proved
to be endocrinologic cures with freedom from recurrent tumor for 9 and 23 years, respectively. The rest of the patients have died of malignant disease.
Clearly the more frequent benign adrenocortical ad- enomas can be excised with curative results in almost all cases. Adrenocortical carcinomas, however, are highly aggressive tumors that are infrequently cured by radical surgical extirpation and are highly resistant to radiation therapy and present day chemotherapy.
Acknowledgement
The authors are grateful to Mrs. Mary Moore Sanders for her assistance in collecting and collating data and in preparation of this manuscript.
References
1. Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Bull Johnş Hopkins Hosp 1932; 50:137.
2. Anderson E, Haymaker W, Joseph M. Hormonal and electrolyte studies of patients with hyperadrenocortical syndrome (Cushing’s syndrome). Endocrinology 1938; 23:398.
3. Albright F, Parson W, Bloomberg E. Therapy in Cushing’s syn- drome. J Clin Endocrinol 1941; 1:375.
4. Thorn GW, Renold AE, Winegrad AI. Some effects of adrenal cortical steroids on intermediary metabolism. Br Med J 1957; 2:1009.
5. Liddle, GW. Cushing’s syndrome. In Eisenstein AB, ed. The adrenal cortex, 1967. Boston: Little, Brown & Co., 1967:523- 552.
6. Scott HW, Jr, Foster JH, Rhamy RK, et al. Surgical management of adrenocortical tumors with Cushing’s syndrome. Ann Surg 1971; 173:892-905.
7. Scott HW Jr, Liddle GW, Mulherin JL, et al. Surgical experience with Cushing’s disease. Ann Surg 1977; 185:524-534.
8. Bertagna C, Orth DN. Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951-1978). Am J Med 1981; 71: 855-875.
9. Pavlatos FC, Smilo RP, Fordham PH. A rapid screening test for Cushing’s syndrome. JAMA 1965; 193:720.
10. Liddle GW. Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 1960; 20: 1539-1560.
11. Scott HW, Foster JH, Liddle GW, Davidson ET. Cushing’s syndrome due to adrenocortical tumor. Ann Surg 1965; 162: 505-516.
12. Geelhoed GW, Druy EM. Management of the adrenal “inciden- taloma”. Surg 1982; 92:866-874.
DISCUSSION
DR. COLIN G. THOMAS, JR. (Chapel Hill, North Carolina): I wish to compliment Dr. Scott on the excellence of his presentation. I am fortunate enough to have had an opportunity to review this well- written manuscript.
Dr. Scott has had extensive experience, and I would certainly endorse most of what he says. The essential issue is to differentiate a benign from a malignant adrenal tumor. This obviously influences the surgical approach and what is done at the operation.
Our experience, which has been primarily in children, has indicated that at times it may be very difficult to make this differentiation. The pathologists have a number of criteria, but they too sometimes find the diagnosis confusing. It looks like one of the better criteria may just be the size of the tumor, and Dr. Scott has also alluded to that.
Dr. Scott has also emphasized that some of the endocrinologic findings may be helpful, and indicates that the ACTH stimulation test, if positive, is indicative of a benign tumor in 50% of the patients. I would submit that this has a specificity rate equal to flipping a coin.
In general, our approach has been to treat each tumor that is greater