Clinical and Laboratory Findings and Results of Therapy in 58 Patients with Adrenocortical Tumors Admitted to a Single Medical Center (1951 to 1978)
CHRISTINE BERTAGNA, M.D .* DAVID N. ORTH, M.D. Nashville, Tennessee
From the Department of Medicine and Cancer Research Center, Vanderbilt University Medical Center, Nashville, Tennessee. This study was supported in part by National Cancer Institute Research grants 2-R25-CA19429 and 2-RO1- CA11685 and by grant 5-MO1-RR00095 from the National Institutes of Health, U.S. Public Health Service, Bethesda, Maryland. Requests for re- prints should be addressed to Dr. David N. Orth, Division of Endocrinology, Vanderbilt University Medical Center North, Room A-4215, Nash- ville, TN 37232. Manuscript accepted June 8, 1981.
* Present address: Division of Clinical Re- search, Roussel-Uclaf Pharmaceuticals, 35 Boulevard des Invalides, Paris, France 75005.
We reviewed 150 findings in 58 patients (14 males and 44 females) with adrenocortical tumors (26 with adenoma and 32 with carci- noma) admitted to Vanderbilt Hospital during 28 years. In general, our findings agree with those reported by others in multi-institutional series or literature reviews. Adenomas took longer to diagnose than carcinomas. Adenomas usually caused Cushing’s syndrome, but two caused virilization and three caused no endocrine syndrome. There was no difference in time required for diagnosis of carcinoma in men or women or in those with Cushing’s syndrome, virilization or no endocrine syndrome. Urinary 17-hydroxycorticoid (17-OHCS) levels were similar in those with adenoma and those with carcinoma, but 17-ketosteroid (17-KS) levels were usually less than 20 mg per day in patients with adenoma and greater than 20 mg per day in patients with carcinoma. Adenomas were uniformly independent of endogenous ACTH stimulation, but frequently responded to ex- ogenous ACTH. As with adenomas, no carcinoma demonstrated normal suppression with dexamethasone or normal response to metyrapone, but only one responded to exogenous ACTH. Some patients had no clinical Cushing’s syndrome despite high levels of plasma cortisol and urine 17-OHCS. “Nonfunctional” tumors prob- ably merely secreted insufficient steroids to cause signs and symptoms. Patients with adenoma were uniformly cured by surgical tumor resection. Occasional patients with carcinoma enjoyed long survival despite incomplete resection of their tumors, but most pa- tients died of recurrent or metastatic carcinoma within seven years, often within a year or two. Small tumor size and benign histologic features were insufficient to predict benign clinical behavior. The adrenocorticolytic drug, o,p’DDD, offered objective remission for only an occasional patient.
Adrenal tumors are usually categorized as benign versus malignant or as functional versus “nonfunctional,” the last term generally implying that insufficient steroid is produced to elevate basal plasma or urinary adrenocorticosteroid levels or cause clinical signs or symptoms.
Adrenocortical nodules of more than 1 cm in diameter are found in 1.5 percent to 8.7 percent of unselected postmortem examinations [1,2] and are more frequent in older people [1] and those with hy- pertension [3]. Benign “nonfunctional” adrenocortical tumors are only rarely diagnosed during life, and malignant “nonfunctional” tumors
6
ADENOMA
5
4
3
2
NUMBER OF PATIENTS
I
O
7
CARCINOMA
6
5
4
3
(DOC)
2
1
0
0
10 20
30 40
50
60
70
80
AGE AT DIAGNOSIS (YEARS)
are also very infrequent, comprising perhaps only 0.2 percent of all reported carcinomas [4].
Functional tumors may cause hypercortisolism (Cushing’s syndrome), hyperaldosteronism (hyperten- sion) and hyperandrogenism (virilization); more rarely, they may cause hyperestrogenism (feminization) or hypoglycemia. They may secrete steroids without causing any clinical endocrinologic syndrome. These tumors are infrequent; most large series consist of cases collected from the literature [5,6] or gathered from several centers [7-9]. A few series of adrenal carcinomas have been reported [4,10,11], but very few in which both adenomas and carcinomas have been studied [12,13].
Fifty-eight patients with adrenocortical tumors (ex- cluding those patients with hyperaldosteronism) have been admitted to Vanderbilt University Hospital since 1951 and evaluated in a reasonably consistent manner. They include the 15 patients reported in 1965 by Scott et al. [14] and are the subject of this paper.
PATIENTS AND METHODS
The patients’ charts were reviewed retrospectively, and items in 150 categories were extracted from each chart, comprising data concerning demography, clinical history, findings on
physical examination, blood cell counts, serum chemistry results, plasma and urinary steroid levels, modes of treatment and evolution of clinical and chemical indices after treatment. Although the problems inherent in the subjective nature of some of these data and the fact that they were recorded by many different physicians over a 28-year period were rec- ognized, the non-numerical items were ranked in a semi- quantitative manner. They were entered, stored and retrieved with the CLINFO computer system [15] of the Vanderbilt University General Clinical Research Center.
A patient was said to have Cushing’s syndrome if he or she had clinical features of the syndrome and high 24-hour urinary 17-OHCS levels that failed to be suppressed during admin- istration of dexamethasone, 0.5 mg every 6 hours for two days [16]. A female was said to be virilized if she had male pattern baldness, deep voice, male musculature, or clitoro- megaly; one boy with precocious puberty was said to be virilized. Patients who had no recognized clinical endocrine syndrome were said to have “nonfunctional” tumors.
The differentiation between adenomas and carcinomas was based upon the original pathologic diagnosis, except one (in Patient 26) diagnosed as an adenoma that later metasta- sized. In all, 26 patients with adenoma and 32 patients with carcinoma were evaluated.
Patients 1 to 22 had Cushing’s syndrome and adenoma, Patients 23 to 26 had Cushing’s syndrome and carcinoma, Patient 37 had adenoma with virilization only, Patients 38 to 44 had carcinoma and virilization only, Patients 45 to 47 had adenoma and no clinical endocrine syndrome or hypertension only, and Patients 48 to 58 had carcinoma and no endocrine syndrome or hypertension only.
Urinary 24-hour 17-OHCS [17] and 17-KS [18] levels, plasma corticosteroid levels [19,20], urine creatinine levels [21] and other clinical chemistry values were determined in the Vanderbilt University Hospital or Clinical Research Center laboratories by methods in routine use at the time.
RESULTS AND COMMENTS
All Patients with Adrenal Tumors
Patient Age. The incidence of functional tumors had one peak in the first decade and another later, occurring at about 35 years for adenoma and at about 50 years for carcinoma (Figure 1), similar to findings in a previous report [6]. No “nonfunctional” tumor occurred in a child; most occurred in the 30 to 70 age group. In a re- view of 133 cases of “nonfunctional” adrenal carci- noma, most occurred in adults aged 40 to 60 years, but a few were found in children [5].
Patient Sex. Only four of the 26 adenomas and two of the 22 functional carcinomas occurred in men (Table 1), but seven of 10 patients with “nonfunctional” car- cinomas were men, in agreement with other reports [4,6-8]. Hutter and Kayhoe [8] observed that the fre- quency and incidence rates of adrenal carcinoma are consistently higher for men than for women in most tumor registries and suggested that this apparent dis- crepancy is due to the facts that (1) functional tumors
tend more often to be the subjects of clinical case re- ports and (2) the endocrine syndromes are more easily detected in women.
Endocrine Syndrome. Most of our patients with functional tumors, as in other series [4,6,8], presented with Cushing’s syndrome, often associated with virili- zation. However, several patients, particularly women with carcinoma, presented with virilization alone. Two patients apparently had hypertension as their only possible endocrine manifestation. One of these (Patient 58) had a tumor producing deoxycorticosterone (DOC). The other patient (47) had had hypertension for at least 15 years; a previous endarterectomy for unilateral renal artery stenosis had resulted in only limited, temporary improvement. Subsequently, she was found to have a suprarenal mass and, although peripheral serum aldo- sterone levels were normal and the saline suppression test was equivocal, bilateral adrenal venous sampling demonstrated lateralization of aldosterone, proges- terone, and 17-hydroxyprogesterone secretion. Her plasma DOC levels ranged from 28 to 46 (normal, 2 to 13 ng/dl), and her DOC/cortisol ratio was about 4 (normal, ≤0.0007). Although her hypertension was probably based on excess mineralocorticoids, she is included in this series because of nonsuppressible urinary 17-OHCS levels and the absence of a normal diurnal rhythm in plasma cortisol.
Six patients in the “nonfunctional” group had hy- pertension, but this was not thought to be of endocrine etiology. Patient 45 had moderate hypertension, edema, metrorrhagia and depression, none of which improved after removal of her adrenal adenoma. Patient 46 had had hypertension for 15 years and insulin-dependent diabetes for five years, neither of which improved after removal of her adenoma, which was discovered inci- dentally during investigation of pyelonephritis. Patient 51 had had chronic glomerulonephritis and hypertension for 6 years prior to discovery of his adrenal carcinoma. He died two months after surgery from renal failure due to chronic renal disease and ligation of a segmental renal artery required to resect the carcinoma. His hy- pertension, which was even more severe postopera- tively, was thought to be secondary to renal disease. Patients 48, 50, 52 and 53 had adrenal carcinoma and only mild hypertension. Patient 48 had had mild hyper- tension and amenorrhea since age 37. Her blood pressure decreased to 130/70 mm Hg, but amenorrhea persisted after surgery at age 43. Patient 50 had had hypertension for seven years prior to surgery. His blood pressure fluctuated from normal to mildly hypertensive, without apparent relationship to subsequent develop- ment of metastatic disease, during the six years he survived after surgery. Patient 52 had the same degree of hypertension 15 years after successful resection of
| Adenoma | Carcinoma | Total | |||
|---|---|---|---|---|---|
| Women | Men | Women | Men | ||
| Cushing's syndrome only | 17 | 4 | 0 | 2 | 23 |
| Cushing's and virilization | 1 | 0 | 12 | 0 | 13 |
| Virilization only | 1 | 0 | 7 | 0 | 8 |
| HBP* | 1 | 0 | 1 | 0 | 2 |
| No endocrine | 2 | 0 | 3 | 7 | 12 |
| syndrome | |||||
| Totals | 22 | 4 | 23 | 9 | 58 |
* Excluding patients with primary hyperaldosteronism.
her tumor. Patient 53 was 65 years old at the time of diagnosis; his tumor was not resected.
Patients with Cushing’s Syndrome
Of the 36 patients who presented with Cushing’s syn- drome, 22 had an adenoma and 14 had a carcinoma (Table I). During the same period of time, 136 patients with pituitary Cushing’s disease and, since 1961, 23 with ectopic ACTH syndrome were evaluated at Van- derbilt University Hospital.
Initial Symptoms. Weight gain (Patients 1, 5, 7, 8, 10, 11, 16,19, 20 and 22) or a change in fat distribution (Patients 2, 14 and 18) and weakness (Patients 3, 4, 12, 13 and 21) were the most frequent of the initial one or two symptoms in patients with adenoma; easy bruising (Patients 2, 8, 14 and 15), hypertension (Patients 9, 19 and 22), kidney stones (Patients 9, 12 and 13), edema (Patients 15 and 16), hirsutism (Patients 11 and 18), acne (Patients 6 and 17), psychological problems (Pa- tients 5 and 7), plethora, finger cramps, growth arrest, oligomenorrhea and diabetes (Patients 4, 6, 10, 17 and 21, respectively) were also listed. Weight gain (Patients 23, 25, 28, 29, 30, 31, 33, 34, 35 and 36) and hirsutism (Patients 24, 26, 27, 34 and 35) were the most frequent symptoms in patients with carcinoma; oligomenorrhea (Patients 23, 25, 28 and 36), weakness (Patients 24 and 29), edema (Patients 27 and 32), bruising, diabetes, headache and moon face (Patients 26, 30, 31 and 33, respectively) were also cited.
The duration of symptoms before diagnosis was twice as long (29.4 ± 4.87 months, mean ± SEM) for patients with adenoma as for those with carcinoma (14.6 ± 4.37 months). This discrepancy is somewhat similar to that of 36 months reported for five patients with adenoma versus six months for nine patients with carcinoma [22]. The mean duration of symptoms be- fore diagnosis in our patients was not significantly dif- ferent in men and women.
| Adenoma (n = 22) | Carcinoma (n = 14) | Adenoma vs. Carcinoma | |||
|---|---|---|---|---|---|
| Number* | Percent+ | Number* | Percent+ | ||
| Moon facies | 22/22 | 100 | 12/12 | 100 | n.s.# |
| Supraclavicular fatpads | 16/16 | 100 | 8/8 | 100 | n.s. |
| Dorsocervical fatpad | 19/20 | 95 | 12/12 | 100 | n.s. |
| Truncal obesity | 22/22 | 100 | 12/12 | 100 | n.s. |
| Plethora | 16/17 | 94 | 11/11 | 100 | n.s. |
| Skin thinning | 9/9 | 100 | 1/9 | 11 | p <0.01 |
| Easy bruising | 18/20 | 90 | 6/10 | 60 | n.s. |
| Striae | 14/21 | 67 | 1/9 | 11 | p <0.05 |
| Weakness | 16/17 | 94 | 7/9 | 78 | n.s. |
| Fatigue | 8/9 | 89 | 5/7 | 71 | n.s. |
| Weight gain | 17/21 | 81 | 10/12 | 83 | n.s. |
| Weight loss | 2/21 | 10 | 0/12 | 0 | n.s. |
| Osteoporosis | 8/16 | 50 | 4/7 | 57 | n.s. |
| Backache | 6/13 | 46 | 1/2 | ||
| Oligomenorrhea§ | 6/11 | 55 | 5/5 | ||
| Hirsutism§ | 14/18 | 78 | 11/11 | 100 | p <0.01 |
| Acne | 9/10 | 90 | 8/8 | 100 | n.s. |
| Temporal hair loss$ | 6/9 | 67 | 4/4 | ||
| Clitoromegaly§ | 1/13 | 8 | 6/7 | 86 | p <0.01 |
| Deepened voices | 0/3 | 4/5 | |||
| Male musculature§ | 0/2 | 1/1 | |||
| Headache | 12/14 | 86 | 5/9 | 56 | n.s. |
| Visual disturbance | 8/15 | 53 | 3/6 | 50 | n.s. |
| Infection | 3/3 | 1/1 | |||
| Edema | 12/20 | 60 | 8/10 | 80 | n.s. |
| Peptic ulcer | 3/4 | 1/1 | |||
| Abnormal wound healing | 1/1 | 0/1 | |||
| Rash | 4/4 | 2/2 | |||
| Insomnia | 4/4 | 2/2 | |||
| Hypertension | 14/16 | 88 | 5/7 | 71 | n.s. |
| Left ventricular hypertrophy | 12/21 | 57 | 0/8 | 0 | p <0.01 |
| Diabetes | 8/11 | 73 | 4/7 | 57 | n.s. |
| Renal stones | 3/4 | 0/2 | |||
* X/Y; where X = number of patients in whom symptom or sign was positive, and Y = number of patients in whom symptom or sign was specifically mentioned.
1 X/Y X 100; calculated only when Y >0.4n.
x2 test. In the case of hirsutism, the degree of hirsutism was taken into account (10 patients with adenoma ☒ and one with carcinoma had only slight hirsutism).
§ Females only.
Chief Complaints, Symptoms and Signs at Time of Diagnosis (Tables II, III, and IV). At the time of diag- nosis, in the 13 patients with adenoma for whom a chief complaint was recorded, high blood pressure (Patients 9, 15, 19 and 22) and weakness (Patients 2, 3 and 21) were cited most frequently; central redistribution of fat (Patients 10 and 18), syncope (Patient 5) and moon face (Patient 13) were also cited. In the eight patients with carcinoma for whom a chief complaint was recorded, weight gain (Patients 28, 29 and 34) and edema (Patients 30 and 33) were most frequent; hirsutism (Patient 25) and abdominal mass (Patient 35) were also listed. Nine patients with adenoma and six with carcinoma were referred to Vanderbilt for further evaluation, so the chief complaint at the time of diagnosis was not recorded.
Most of the symptoms and signs that were recorded
at the time of diagnosis (Table II) occurred with similar frequencies in patients with adenoma and those with carcinoma, including central obesity, presence and amount of weight gain, osteoporosis, and weakness. However, less skin thinning and striae occurred among patients with carcinoma. If patients with striae were compared with those without, weight gain was greater in those with (21.6 ± 5.2 versus 10.0 ± 2.3 kg, re- spectively) and 24-hour 17-KS levels were significantly greater in those without striae (p <0.01; Wilcoxon test). There was a higher frequency of hirsutism and virili- zation among patients with carcinoma. Of the 18 female patients with adenoma, Patients 7, 8 and 18 had oligo- menorrhea, Patients 10, 14 and 17 had amenorrhea, two were prepubertal (Patients 1 and 11), two were post- menopausal (Patients 3 and 21), one had had a hyster-
| Patient No. | Age (yr) at Diagnosis/ Race/Sex | Interval (mo), First Symptom to Diagnosis | Plethora/ Moon Face/ Truncal Obesity | Percent Ideal Body Wt. | Weight Change (lb)/ Interval (mo) | Striae/ Easy Bruisa- bility | Hirsutism/ Acne/Temporal Hair Loss/ Clitoromegaly | Weakness/ Fatigue | Backache/ Osteo- porosis | Headache/ Visual Distur- bances | Edema | Blood Pressure (mm Hg) | LVH by X-Ray |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cushing's syndrome | |||||||||||||
| 1 | 0.8/W/F | 6 | 3+/4+/4++* | 171 | (4+)/6 | 1+/- | 0/-/-10 | -/- | -/- | -/- | 0 | 255/110 | 0 |
| 2 | 48/W/M | 18 | 3+/3+/2+ | 115 | 18/12 | 3+/3+ | Male | 2+/- | -/2+ | -/- | 2+ | 180/110 | - |
| 3 | 56/W/F | 12 | 2+/2+/2+ | 107 (diet) | -18/12 | -/2+ | 0/-/-/- | 3+/- | 0/2+ | 0/1+ | 1+ | 235/120 | キ |
| 4 | 39/W/F | 54 | 3+/2+/3+ | 111 | 16/48 | 1+/2+ | 1+/1+/0/0 | -/2+ | 2+/0 | 2+/0 | 2+ | 155/90 | 0 |
| 5 | 34/B/F | 72 | -/1+/1+ | 117 | 14/12 | 1+/1+ | 1+/2+/1+/0 | -/0 | 0/0 | -/0 | 1+ | 160/95 | + |
| 6 | 51/W/M | 36 | 2+/2+/2+ | 104 | 15/- | 3+/3+ | Male | 2+/2+ | -/- | 2+/- | 2+ | 180/110 | + |
| 7 | 37/W/F | 12 | 2++/3+/2+ | 94 (diet) | 18/9 | 0/2++ | 1+/2++/14/0 | 2+/- | -/1+ | -/- | 0 | 165/95 | + |
| 8 | 44/W/F | 24 | 2+/2+/2+ | 138 | 27/24 | 2+/1+ | 1+/-/0/0 | 2++/- | 0/2+ | 2+/1+ | 2++ | 185/105 | + |
| 9 | 38/B/F | 18 | 0/1+/1+ | 147 | 9/12 | 0/0 | 1+/-/0/- | 0/- | 2+/- | 2+/1+ | 0 | 155/110 | + |
| 10 | 14/W/F | 48 | 2+/3+/2+ | 131 | (3+)/48 | 0/2+ | 2+/1+/-/0 | -/- | 0/2+ | 2+/- | 0 | 192/160 | ± |
| 11 | 4/W/F | 9 | 2+/3+/2+ | 161 | 5/9 | 0/0 | 2+/2+/-/Yes | -/- | 2+/2+ | 2+/- | 0 | 200/160 | 0 |
| 12 | 30/W/M | 10 | 2+/3+/3+ | 101 | -9/6 | 1+/1+ | Male | 2+/2+ | -/0 | 3+/0 | - | 150/102 | + |
| 13 | 45/W/M | 24 | 2+/3+/1+ | - | 9/24 | 0/2+ | Male | 2+/2+ | -/1+ | 1+/0 | 1+ | 153/100 | 0 |
| 14 | 23/W/F | 9 | -/2+/2+ | 100 | 0/- | 2+/3+ | 2+/-/-/- | 2+/1+ | -/0 | 2+/0 | 1+ | 150/110 | 0 |
| 15 | 45/W/F | 48 | 2+/2+/2+ | 90 | 7/36 | 2+/2+ | 1+/-/-/- | 1+/- | -/0 | 1+/1+ | 2+ | 180/100 | ± |
| 16 | 25/W/F | 84 | 3+/3+/3+ | 135 | 36/84 | 3+/2+ | 1+/2+/1+/0 | 3+/- | 2+/0 | -/1+ | 2+ | 160/110 | + |
| 17 | 23/W/F | 12 | 2+/3+/2+ | 104 | (1+)/- | 2+/2+ | 2+/2+/2+/0 | 2+/- | 2+/- | 2+/1+ | 0 | 160/110 | + |
| 18 | 27/W/F | 5 | -/2+/2++ | 108 | -/- | 3+/- | 1+/2+/1+/0 | 1+/1+ | -/- | 0/0 | 0 | 130/85 | 0 |
| 19 | 35/B/F | 30 | -/2+/3+ | 122 | 31/30 | 1+/1+ | 0/-1-10 | 1+/- | -/0 | -/1+ | 2+ | 180/100 | + |
| 20 | 24/W/F | 36 | 2+/2+/2+ | 127 | 25/36 | 3+/1+ | 1+/2+/1+/0 | 2+/2+ | 2+/0 | 3+/- | 0 | 132/88 | 0 |
| 21 | 56/W/F | 12 | 2+/2+/2+ | 161 | 0/- | 0/2+ | 01-1-1- | 2+/- | -/- | -/2+ | 1+ | 160/95 | 0 |
| 22 | 43/W/F | 60 | -/2+/2+ | 111 | (3+)/60 | 0/1+ | 2+/-/-10 | 2+/2+ | -/0 | -/0 | - | 130/95 | 0 |
| Virilization only | |||||||||||||
| 37 | 4/W/F | 7 | 0/0/0 | 88 | 0/- | 0/- | 1+/2+/-/Yes | -/- | 0/- | 0/- | - | 95/56 | - |
| No endocrine syndrome or hypertension only | |||||||||||||
| 45 | 46/W/F | 12 | -/0/0 | 93 | 0/- | 0/0 | 0/-/-/- | -/2++ | 1+/0 | 2++/- | 3+ | 165/92 | 0 |
| 46 | 69/B/F | 0 | 0/0/0 | 127 | 0/- | 0/1+ | 0/-/0/0 | 0/- | -/- | -/- | 0 | 150/86 | - |
| (treated) | |||||||||||||
| 47 | 60/W/F | 180 | 0/0/1+ | 106. | 0/- | 0/- | -1-1-1- | -/1+ | -1- | -/1+ | 1+ | 196/94 | + |
| (treated) | |||||||||||||
NOTE: - = not recorded; 0 = absent; 1+ = slight; 2+ = mild; 3+ = moderate; 4+ = severe; + = present; ± = possible.
| Patient No. | Age (yr) at Diagnosis/ Race & Sex | Interval (mo), First Symptom to Diagnosis | Plethora/ Moon Face/ Truncal Obesity | Percent Ideal Body Wt. | Weight Change (lb)/ Interval (mo) | Striae/ Easy Bruisa- bility | Hirsutism/ Acne/Temporal Hair Loss/ Clitoromegaly | Weakness/ Fatigue | Backache/ Osteo- porosis | Headache/ Visual Distur- bances | Edema | Blood Pressure (mm Hg) | LVH by X-Ray |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cushing's syndrome | |||||||||||||
| 23 | 49/W/F | 40 | 2+/2+/2+* | 110 | 16/36 | 0/2+ | 2+/2+/2+/1+ | 2+/- | 1+/2+ | 0/0 | 1+ | 190/100 | 0 |
| 24 | 5/W/M | 12 | 1+/1+/1+ | 131 | 0/- | -/- | 3+/2+/2+/- | -/2+ | -/0 | 0/- | - | 150/110 | - |
| 25 | 28/W/F | 16 | 2+/2+/1+ | 96 | 15/18 | 0/0 | 3+/2+/-/1+ | 0/0 | -/0 | -/- | 2+ | 150/95 | 0 |
| 26 | 52/W/F | 4 | 2+/2+/2+ | 104 | 4/6 | 0/2+ | 2+/1+/2+/0 | 1+/- | -/2++ | 0/0 | - | 136/100 | 0 |
| 27 | 71/W/F | 16 | 3+/3+/2+ | - | -/- | -/3+ | 2+/-/2+/- | 3+/- | -/3+ | 1+/- | 2+ | 170/90 | - |
| 28 | 15/W/F | 6 | 2+/2+/1+ | 114 | 9/6 | 0/0 | 2+/3+/-/1+ | 2+/2+ | -/0 | 2+/- | 2++ | 140/90 | 0 |
| 29 | 61/W/F | 10 | 2+/2+/2+ | 112 | 3/- | 0/2+ | 2++/-/2+/0 | 3+/3+ | -/- | 3++/1+ | 2++ | 150/90 | 0 |
| 30 | 40/W/F | 16 | 2+/2+/2+ | 126 | 14/16 | 0/0 | 1+/-/2+/- | 2+/- | -/- | -/- | - | 150/100 | 0 |
| 31 | 32/W/M | 3 | -/2+/2+ | - | (3+)/3 | -/- | Male | -/- | -/- | 2+/- | 2+ | 240/160 | - |
| 32 | 59/W/F | 7 | -/-/2+ | - | 0/- | -/2+ | -1-1-1- | 1+/- | -/- | -/1+ | 0 | - | - |
| 33 | 11/B/F | 1 | 3+/-/1+ | 149 | (3+)/1 | 0/- | -1-1-1- | -/1+ | -/1+ | 2+/- | 0 | 210/155 | 0 |
| 34 | 8/W/F | 3 | 1+/2+/2+ | 107 | 5/3 | 0/0 | 1+/3+/-/1+ | 0/0 | -/- | 0/0 | 2+ | 165/130 | 0 |
| 35 | 47/W/F | 6 | -/-/- | - | -/- | -/- | 3+/2+/-/- | -/- | -/- | -/- | - | - | - |
| 36 | 30/W/F | 60 | 2+/2+/2+ | 167 | 45/60 | 3+/1+ | 2+/2+/1+/- | -/2+ | 0/- | -/1+ | 2+ | 180/114 | 0 |
| Virilization only | |||||||||||||
| 38 | 2/W/F | 20 | -/-/- | 107 | 0/- | -/- | 2+/-/2+/1+ | -1- | -/- | -1- | - | 130/70 | |
| 39 | 3/W/F | 2 | 1+/-/- | 105 | 0/- | -/- | 2+/2+/3+/1+ | -/- | -/- | -/- | - | 115/85 | |
| 40 | 44/W/F | 12 | -1-1- | 100 | -1/1 | -/- | 2+/0/-/- | -/2+ | -/- | 2+/- | - | 115/74 | |
| 41 | 68/W/F | 37 | 2+/-/- | 80 | -3/5 | -/- | 2+/-/2+/- | -/- | -/2+ | 0/0 | 1+ | 170/80 | |
| 42 | 1/W/F | 4 | 0/0/0 | 89 | 0/- | 0/- | 1+/1+/-/1+ | -/- | -/- | -/- | - | - | |
| 43 | 51/W/F | 7 | 0/0/0 | 97 | -4/3 | -/- | 3+/-/2++/1+ | 2+/- | -/- | 1+/0 | - | 150/95 | |
| 44 | 57/W/F | 12 | 0/0/- | 116 | -/- | -/2+ | 3+/-/2+/- | -/- | -/2+ | -/- | - | 150/82 | |
| No endocrine syndrome or hypertension only | |||||||||||||
| 48 | 42/W/F | 69 | 0/0/0 | 133 | 18/40 | 0/0 | 1+/-/-/- | -/- | -/- | 1+/- | 0 | 150/95 | |
| 49 | 35/W/M | 7 | -1-1- | - | 9/8 | -/- | Male | 2+/2+ | -/- | 2++/- | 1+ | 100/65 | |
| 50 | 52/W/M | 43 | -/-/- | 125 | 0/- | -/0 | Male | 2+/- | -/- | 2+/- | - | 155/90 | 0 |
| 51 | 46/W/M | 26 | 0/0/0 | 80 | -/- | 0/- | Male | 0/0 | 0/0 | 0/0 | 0 | 185/125 | + |
| 52 | 50/B/F | 1 | 0/0/0 | 118 | -/- | 0/0 | 0/-/-/- | 0/0 | -/- | -/- | - | 150/90 | - |
| 53 | 65/W/M | 6 | -/-/- | 127 | -/- | -/- | Male | -/- | -/- | 0/- | - | 150/95 | - |
| 54 | 63/W/M | 10 | -/-/- | - | -22/8 | -/2+ | Male | 4++/- | -/- | -/- | - | 100/70 | - |
| 55 | 29/W/F | 22 | 0/0/0 | 84 | -14/12 | -/- | -/-1-10 | 2+/- | -/0 | 1+/0 | - | 125/70 | 0 |
| 56 | 33/W/M | 0 | 0/0/0 | 98 | 0/- | 0/0 | Male | -/- | -/- | 0/0 | 0 | 120/70 | |
| 57 | 44/W/M | 15 | -/-/- | .70 | -4/5 | -/- | Male | -/- | -/- | -/- | - | 110/70 | - |
| 58 | 34/W/F | 56 | 0/-/- | 86 | 0/- | -/- | -/-/0/- | -/- | -/0 | 0/2+ | 2+ | 165/110 | + |
NOTE: - = not recorded; 0 = absent; 1+ = slight; 2+ = mild; 3+ = moderate; 4+ = severe; + = present.
| Normal Values | Adenoma (n = 22) | Carcinoma (n = 14) | |||
|---|---|---|---|---|---|
| Number | Mean (range) | Number | Mean (range) | ||
| PCV | M: 42-50% F: 37-44% | 17 | 43.8 (32.5-49) | 10 | 48.2 (39.1-54.5) |
| WBC | 5,000-10,000/mm3 | 17 | 11,138 (6,700-20,700) | 10 | 10,840 (6,900-17,600) |
| Lymphocytes | 20-40% | 15 | 18.6 (6-37) | 9 | 20.6 (7-28.5) |
| Eosinophils | 1-3% | 15 | 1.2 (0-4) | 9 | 0.3 (0-1) |
| Monocytes | 2-6% | 15 | 6.1 (1-15) | 9 | 6.7 (2-19) |
| Glucose | 60-110 mg/dl | 13 | 112 (72-270) | 6 | 151 (55-430) |
| Uric acid | M: 3-7 mg/dl F: 1.5-6 mg/dl | 9 | 5.9 (3.5-9.0) | 5 | 5.5 (5.0-6.0) |
| Cholesterol | 150-300 mg/dl | 15 | 267 (220-345) | 7 | 282 (185-350) |
| Na+ | 135-145 meq/liter | 17 | 143 (135-152) | 10 | 139 (130-145) |
| K+ | 3.5-5.5 meq/liter | 18 | 4.0 (2.5-5.2) | 10 | 3.9 (3.0-4.9) |
| CI- | 95-110 meq/liter | 15 | 102 (88-112) | 10 | 98 (89-108) |
| HCO3 | 22-32 meq/liter | 17 | 29.7 (20.2-37.5) | 10 | 27.2 (22.0-31.5) |
| Ca | 8.5-11 mg/dl | 11 | 10.0 (9.0-11.0) | 6 | 10.3 (9.4-10.8) |
| Patient No. | Blood Cell Counts | Serum Electrolyte and Blood Chemistry Results | |||||||
|---|---|---|---|---|---|---|---|---|---|
| PCV (%) | Total WBC (cells/mm3) | Eosino- phils/ Lymphocytes (% total WBC) | K+/Na+/ CI-/HCO3 (meq/liter) | Choles- terol (mg/dl) | Ca (mg/dl) | Uric Acid (mg/dl) | Fastng Blood Glucose (mg/dl) | 2-Hr GTT (mg/dl) | |
| Cushing's syndrome | |||||||||
| 1 | 40 | 20,000 | 0/28 | 7.9/137/100/20 | - | - | - | 74 | 108 |
| 2 | - | 20,400 | 0/14 | -/-1-1- | - | 9.2 | - | - | - |
| 3 | 43 | 8,450 | 0/16 | 2.5/138/92/38 | - | - | - | 72 | 192 |
| 4 | 45 | 11,875 | 0/6 | 4.1/135/99/- | 230 | - | - | 78 | 86 |
| 5 | 40 | 8,500 | 0/27 | 5.2/147/99/31 | 280 | - | 4.0 | 73 | 159 |
| 6 | 45 | 13,600 | 0/13 | 3.5/-/-/34 | - | - | - | 100 | 290 |
| 7 | 47 | 9,870 | 1/37 | 4.4/139/-/- | 345 | 9.5 | - | 112 | 406 |
| 8 | 49 | 11,300 | 2/25 | 4.5/138/103/23 | 220 | 9.0 | - | 94* | 161 |
| 9 | 46 | 9,700 | 0/17 | 4.5/138/106/24 | 232 | - | - | 120 | 276 |
| 10 | 40 | 8,500 | 4/17 | 2.5/140/106/25 | 250 | 9.6 | 9.0 | 104 | 138 |
| 11 | 41 | 16,000 | 0/31 | 3.6/143/97/32 | - | 11.8 | - | 86 | - |
| 12 | 40 | 15,800 | 0/10 | 3.8/141/99/27 | 265 | 9.9 | 5.6 | 122 | 399+ |
| 13 | 49 | 10,400 | 0/14 | 3.0/146/103/30 | 235 | 9.8 | 4.4 | 79 | 219 |
| 14 | 44 | 8,500 | 1/12 | 4.2/147/112/25 | 205 | 10.0 | 3.5 | 89 | 99+ |
| 15 | 45 | 7,700 | 1/16 | 4.3/146/110/30 | 235 | 10.4 | 4.2 | 95* | - |
| 16 | 48 | 10,300 | 1/15 | 4.2/149/106/36 | 325 | 10.3 | 3.7 | 88 | 160 |
| 17 | 46 | 12,700 | 1/14 | 2.8/152/107/28 | 240 | 11.0 | 4.7 | 88 | - |
| 18 | 49 | 9,900 | 1/13 | 4.0/142/-/- | - | 9.7 | 5.1 | 166* | 126+ |
| 19 | 40 | 13,700 | 1/10 | 3.7/143/88/33 | 345 | 10.4 | 9.0 | 130 | - |
| 20 | 47 | 20,700 | 2/8 | 4.9/149/109/26 | 261 | 10.9 | 5.2 | 95* | - |
| 21 | 40 | 6,700 | 0/16 | 3.8/142/100/35 | 245 | 9.8 | 6.2 | 270* | - |
| 22 | 32 | 11,500 | 1/16 | 4.6/145/100/27 | 311 | 9.9 | 6.0 | 88* | - |
| Virilization only | |||||||||
| 37 | 38 | 7,400 | 12/50 | 4.7/143/103/26 | 125 | 10.2 | 3.4 | 85* | - |
| No endocrine syndrome or hypertension only | |||||||||
| 45 | 42 | 14,200 | 2/18 | 4.6/146/100/26 | 300 | 9.0 | - | 95* | - |
| 46 | 40 | 7,100 | 1/40 | 4.3/140/97/29 | 225 | 9.7 | 5.4 | 248* | - |
| 47 | 44 | 10,700 | 2/21 | 3.1/140/97/31 | 175 | 9.9 | 6.5 | 419* | - |
* Random blood sugar; 1 2 hours postprandial.
| Patient No. | Blood Cell Counts | Serum Electrolyte and Blood Chemistry Results | |||||||
|---|---|---|---|---|---|---|---|---|---|
| PCV (%) | Total WBC (cells/mm3) | Eosino- phils/ Lymphocytes (% total WBC) | K+/Na+/ CI-/HCO3 (meq/liter) | Choles- terol (mg/dl) | Ca (mg/dl) | Uric Acid (mg/dl) | Fasting Blood Glucose (mg/dl) | 2-Hr GTT (mg/dl) | |
| Cushing's syndrome | |||||||||
| 23 | 50 | 6,900 | 1/11 | 4.1/140/98/25 | 325 | 8.8 | - | 91 | - |
| 24 | 42 | 9,900 | 0/40 | 4.2/140/95/29 | - | 10.2 | - | - | - |
| 25 | 52 | 11,900 | 0/16 | 3.6/144/108/22 | 185 | 9.2 | - | 94 | 300 |
| 26 | 54 | 11,100 | 1/28 | 4.0/141/99/32 | 255 | 9.4 | 5.4 | 80* | 144 |
| 27 | 44 | 9,200 | 0/14 | 4.9/134/95/28 | 295 | 10.8 | 5.0 | 430* | - |
| 28 | 53 | 8,600 | 0/38 | 4.0/137/98/30 | 325 | 10.3 | 5.7 | 72 | 159 |
| 29 | 49 | 14,400 | 0/7 | 3.3/145/102/27 | 240 | 10.8 | 6.0 | 98 | - |
| 30 | 39 | 8,300 | -/- | 3/143/97/30 | 350 | 10.5 | 5.2 | 150* | - |
| 31 | - | - | -/- | -/-1-1- | - | - | - | - | - |
| 32 | - | - | -/- | -/-/-/- | - | - | - | - | |
| 33 | 54 | 10,500 | 0/16 | 3.9/130/89/24 | - | - | - | 68* | |
| 34 | 44 | 17,600 | 1/15 | 4.3/138/100/24 | - | - | - | 77 | |
| 35 | - | - | -/- | -/-1-1- | - | - | - | - | |
| 36 | 40 | 7,300 | 1/19 | 2.5/143/95/40 | 180 | 9.2 | 3.5 | 76 | - |
| Virilization only | |||||||||
| 38 | 41 | 18,700 | 0/20 | 5.5/139/107/19 | - | 11.7 | - | - | - |
| 39 | 48 | 4,600 | 0/58 | 4.5/130/92/20 | - | 10.0 | - | 65* | - |
| 40 | 41 | - | -/- | 3.7/135/91/- | - | - | - | - | |
| 41 | 50 | 8,800 | 2/7 | 3.2/156/101/34 | 220 | 11.1 | 6.4 | 87* | |
| 42 | 40 | 13,800 | 2/69 | 4.2/142/106/18 | 170 | 11.2 | 4.0 | 100* | |
| 43 | 43 | 12,100 | 0/13 | 4.0/144/104/30 | 170 | 9.7 | 3.5 | 135* | - |
| 44 | - | - | -1- | -/-/-1- | - | - | - | - | - |
| No endocrine syndrome or hypertension only | |||||||||
| 48 | 52 | 14,700 | 1/14 | 4.3/136/100/28 | - | 9.7 | - | 70 | 160 |
| 49 | - | 12,500 | 1/11 | 5.5/142/107/18 | 162 | 10.2 | - | 88 | - |
| 50 | 39 | 10,100 | 1/27 | 3.6/140/101/23 | - | - | 5.2 | - | - |
| 51 | 36 | 13,200 | 1/24 | -/-1-1- | - | 9.7 | 6.3 | 87 | 2011 |
| 52 | 36 | 7,600 | 3/39 | -/-1-1- | - | - | - | 126* | 278 |
| 53 | 24 | 11,800 | 1/21 | -/-/-/- | - | - | - | - | - |
| 54 | 34 | 15,100 | 0/13 | -/-1-1- | 110 | 8.9 | - | 116* | - |
| 55 | 39 | 5,900 | 9/44 | 4.0/134/101/- | 120 | 10.3 | 3.4 | 87* | - |
| 56 | 36 | 9,100 | 6/25 | 4.0/142/103/35 | 180 | 8.9 | 5.6 | 117* | - |
| 57 | - | - | -/- | 3.9/144/106/33 | 198 | 9.5 | - | 80* | - |
| 58 | 32 | 8,400 | 0/20 | 2.5/143/95/40 | 180 | 9.2 | 3.5 | 76 | - |
* Random blood glucose; + postprandial.
ectomy (Patient 22), and the other seven had normal menstrual histories. Of the nine female patients with carcinoma for whom data were recorded, Patients 25, 30 and 36 had oligomenorrhea, Patients 23 and 28 had amenorrhea, three were postmenopausal (Patients 27, 29 and 32) and one was prepubertal (Patient 34). Two patients with adenoma had recently lost weight, but no patient with carcinoma had done so. Symptomatic di- abetes was present in six (Patients 6, 7, 10, 12, 17 and 18) of nine patients with adenoma for whom data were recorded, one (Patient 21) had had glucosuria, and an- other (Patient 22) had had an abnormal fasting blood glucose results, four (Patients 5, 8, 9 and 20) had no diabetic history. Of seven patients with carcinoma questioned, two (Patients 26 and 28) had symptomatic diabetes, two (Patients 29 and 30) had had an abnormal fasting blood glucose level, and three (Patients 33, 34
and 36) had no diabetic history. Blood pressure was similar in both groups: mean systolic/diastolic blood pressure was 169/112 mm Hg in patients with adenoma and 176/112 in those with carcinoma. There was, however, a much higher frequency of electrocardio- graphic evidence of left ventricular hypertrophy in pa- tients with adenoma (12 of 21) than in those with car- cinoma (none of eight), perhaps reflecting longer du- ration of hypertension in patients with adenoma. Of the 17 patients with adenoma in whom possible psycho- logical illness was recorded, 12 (Patients 1, 4, 5, 6, 8, 9, 12, 13, 15, 16, 19 and 21) reported being unusually irritable, three others reported lethargy, manic-de- pressive symptoms or depression (Patients 11, 17, and 20, respectively), and one (Patient 22) was under treatment for depression. Three of those with carcinoma (Patients 26, 28 and 33) were irritable, one (Patient 36)
was slightly confused, and another (Patient 34) denied any psychological symptoms.
Initial Blood Cell Counts (Tables V, VI, and VII). The values were similar in both groups of patients (Table V). The mean hematocrit and total white blood cell count were higher in both groups than in the general popula- tion, whereas the percents of lymphocytes and eosin- ophils were lower than normal.
Initial Blood Chemistry (Tables V, VI, and VII). There were no significant differences between the two groups (Table V) in terms of blood sugar or serum uric acid, cholesterol, calcium or electrolyte levels. Four of 21 patients with adenoma and two of 11 with carcinoma had a serum potassium level of less than 3.5 meq/liter. Four of four patients with adenoma had a fasting blood glucose level above 110 mg/dl, six other patients had a blood glucose level above 150 mg/dl 2 hours after a standard oral glucose load, and another had insulin- dependent diabetes. Thus, 11 of the 14 patients with adenoma tested had evidence of glucose intolerance. Among the 10 patients with carcinoma tested, none had an abnormal fasting blood glucose, but two had an ab- normal 2-hour value during the oral glucose tolerance test, and another had clinical diabetes. Thus, only four of the 10 patients with carcinoma tested had docu- mented evidence of glucose intolerance.
Most patients had serum electrolyte values within the normal range; when abnormal, they were in the direc- tions previously described for hypercortisolism: low potassium and chloride levels, high sodium and bicar- bonate levels. There appeared to be fewer instances of high fasting blood glucose values but more of high cholesterol levels than have previously been reported for Cushing’s syndrome of any etiology.
Endocrine Studies. Initial steroid levels (Tables VIII and IX): Baseline 24-hour urinary 17-OHCS levels varied from 7 to 30 mg/g creatinine for most patients. One patient with adenoma had several normal values in addition to several elevated values, it is possible she represented a case of cyclical cortisol hypersecretion [23], but she was not studied long enough to document this. Three patients with adenoma and three with car- cinoma had 17-OHCS values above 35 mg/g creatinine. There was no significant difference between the values of the two groups (21.5 ± 2.4 mg/g creatinine for those with adenoma and 23.2 ± 2.1 mg/g creatinine for those with carcinoma), which were similar to those previously reported by Martin and Hamman [24] and Schteingart et al. [12]; none had the very high levels reported by others [13,22].
Basal 24-hour urinary 17-KS excretion was consis- tently below 20 mg/g creatinine in patients with ade- noma with two exceptions, a young girl who was the only patient with adenoma with definite virilization in addition to Cushing’s syndrome and a man who had
noted increased hair growth on his upper back over a period of several months, but in whom it was difficult to define any clear physical signs of “hypervirilization.” In the patients with adenoma, 24-hour 17-KS excretion was 15.1 ± 2.3 mg/g creatinine, as compared with 56.2 ± 13.9 mg/g creatinine for patients with carcinoma; excretion ranged from 18 to 165 mg/g creatinine in the patients with carcinoma and usually exceeded that of 17-OHCS. In contrast, 17-KS excretion was within the normal range for sex in 15 patients with adenoma, whereas 17-OHCS excretion was clearly elevated in all of them. In 1951, Forbes and Albright [25] observed that patients with adenomas often had lower 17-KS levels than did those with pituitary Cushing’s disease, whereas 17-KS levels were highest in patients with carcinoma, and others [4,12,24] have since confirmed high 17-KS excretion by patients with adrenal carcin- mas. The dissociation of 17-KS from 17-OHCS secre- tion by adrenal carcinomas appears to be due to the relative inefficiency with which they are able to convert steroid precursors to cortisol.
Response to dexamethasone (Figure 2, Tables VIII and IX): The 19 patients with adenoma and 11 patients with carcinoma who underwent the high-dose dexa- methasone suppression test (2 mg every 6 hours for two days) [16] before treatment did not demonstrate sup- pression (Figure 2); in many, urinary 17-OHCS excretion actually increased, although slight variations were dif- ficult to interpret because of varying baseline excretion, a rather common feature in patients with adrenal tu- mors. This failure to demonstrate suppression is con- sistent with the concept that hypercortisolemia caused by the adrenocortical tumor suppresses endogenous ACTH secretion by the intrinsically normal pituitary gland; thus, ACTH secretion cannot be further sup- pressed by dexamethasone administration, and basal secretion of cortisol by the tumor, independent of en- dogenous ACTH stimulation, is unaffected.
Response to metyrapone (Figure 3, Tables VIII and IX): None of the 17 patients with adenoma and seven patients with carcinoma tested had an increase in uri- nary 17-OHCS levels on the day of or the day after metyrapone administration [26]; all but one of the pa- tients with adenoma and all of those with carcinoma had lower 17-OHCS levels on the day of or day after me- tyrapone than on any other day they were measured (Figure 3). This lack of response is consistent with the concept that chronic hypercortisolemia suppresses pituitary ACTH secretory capacity and, as a conse- quence, also causes atrophy of the normal adrenal cortices. Although ACTH may be secreted in response to the metyrapone-induced hypocortisolemia (Table VIII), it apparently is insufficient to stimulate a detectable increase in cortisol secretion by the tumors or the atrophic adrenal cortices.
| Patient No. | 24-Hr Urinary 17-OHCS/17-KS (mg/g creatinine/24 hr) | Tumor Wt. (g)/ Size (cm)/side (L or R) | Post-Treatment Evolution | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Plasma ACTH (pg/ml) | Plasma Cortisol (ug/dl) | Cushing's Syndrome Improved/ Cured (mo after treatment) | Normal Steroids Basal/ After Metyr- | Length of Follow-Up (mo after treatment) | ||||||||
| Basal | After 2 Days High-Dose Dexameth- asone | Day after Metyr- apone | Day of ACTH | A.M./ P.M. | After 2 Days High-Dose Dexameth- asone | After ACTH | apone/ After ACTH (mo after treatment) | |||||
| Cushing's syndrome | ||||||||||||
| 1 | 6.15/0.65* | -/- | -/- | -/- | -/- | 126/6.5 × 7 × 5/L | -/5 | 72/-/- | 18 | |||
| 2 | 15-32/10-21* | -/- | -/- | 40,26/14,20* | -/- | -/3 X 3 X 3/L | -18 | -1-1- | 1.5 | |||
| 3 | 14-32/5-17* | 27/16* | 22/12* | 49/24* | -/- | 16/3 (diam)/L | 4/- | 12/12/24 | 8 | |||
| 4 | 5-19/2-9* | 20/8* | 11/8* | 18,18/10,11* | -/- | 15/2 × 2.2 × 1.3/L | 3/17 | 3/3/18 | 12 | |||
| 5 | 12-23/14-23 | 14/23 | 13/12 | 23/28 | <0.11+ | -/- | 17/2.5 X 2 X 1.5/R | -/4 | 5/5/- | 11 | ||
| 6 | 21-25/8-9 | 29/14 | 20/3 | 61/ -* | 29/29 | -/7 (diam)/R | -/6 | 8/8/- | 0.6 | |||
| 7 | 20-31/12-14 | 24/16 | 25/9 | -/- | <0.10+ | -/- | 108/7.5 × 6 × 6/L | -/3 | 2/2/7 | 7 | ||
| 8 | 15-23/5-6 | 19/7 | 14/6 | 45/12 | <0.181 | 18/19 | 17.5/3.5 X 3 X 2.5/L | 1/8 | 3/3/84 | 9 | ||
| 9 | 2-10/3-20 | 14/18 | 4/4 | 11/24 | -/17 | 26 | 32/4 (diam)/R | 5/24 | 18/-/- | 3.5 | ||
| 10 | 13-21/15-19 | 19/19 | 9/9 | 18/18 | <0.10+ | -/- | 47/5.5 X 5.2×3/L | 2/4 | -/-/- | 5 | ||
| 11 | 36-55/20-63 | -/- | -/- | 45/30 | <1.2+ | 26/24 | 64/5 (diam)/L | 5/9 | 8/8/15 | 8 | ||
| 12 | 13-40/24-50 | 44/49 | 25/32 | 101/43 | <7 | 26/26 | 44 | 87 | -/2.5 × 2.5 × 2.5/L | 5/12 | 12+/ | 8 |
| <0.18+ | 12+/- | |||||||||||
| 13 | 14-17/13-14 | 18/13 | 12/12 | 36/10 | <20 | 22/22 | 68 | 12.5/2.5 X 2 X 2.5/L | 5/11 | 10+/ | 1.8 | |
| .5 X 1.5 × 1/L | 10+/- | 4 | ||||||||||
| 14 | 17-19/8-10 | 21/6 | 11/7 | 75/19* | 47 | 24/24 | 118 | 20/4 X 3 X 3/L | -/- | -/-/- | 0.1 | |
| 15 | 10-13/10-24 | 10/11 | 7/12 | 13/13 | 212* | 16/16 | 28 | 20/4 × 2 × 3/L | -/6 | 15/-/15 | 1.2 | |
| 16 | 12-14/6-10 | 13,15/6,10 | 11,14/6,7 | 41/17 | 200# | 24/- | 26 | 66 | 16/4 × 3.5 X 1.5/L | -/7 | 18/-/18 | 1.6 |
| 17 | 29-44/6-17 | 52/9 | 24/8 | 98/22 | 26/27 | 24 | 81 | 13.5/3 X 3 × 2.5/L | -/6 | 12/12/12 | 1 | |
| 18 | 14,15/3,4 | 22/4 | 8/2 | -/- | <30 | 17/18 | 21 | 25/6 × 4 × 2.5/L | -/- | -/-/- | 0.1 | |
| 210± | ||||||||||||
| 19 | 12-18/6-9 | 17/19 | 11/5 | 23/18 | <15 | 22/23 | 30 | 30/3 X 3 X 3/L | 5/12 | 15+/-/- | 1.2 | |
| 20 | 8-24/10-12 | 10/12 | 7/12 | 13/11 | 50 | 21/20 | 18 | 35 | 14/2.5 X 2 × 1.6/R | 4/13 | -/-/- | 1.1 |
| 21 | 15-43/9-24 | 15/10 | -/- | 79/17 | 32/- | 25 | 170 | -/5 × 4 × 4/R | 8/11 | 9+/9+/- | 1.0 | |
| 22 | 14-52/12-43 | 13/15 | 13/11 | 103/53 | 35/32 | 26 | 50 | 30/3 × 2.8 X 0.5/R | -/- | -/-/- | - | |
| 0.8 (diam) | ||||||||||||
| Virilization only | ||||||||||||
| 37 | 6-10/61-71 | 6/86 | -/- | -/- | 14/6 | 9.6/3 × 2.5 X 1.5/L | -/- | 24/1/- | 2 | |||
| No endocrine syndrome or hypertension only | ||||||||||||
| 45 | 18-23/10-14 | 35/18 | 20,11/15,13 | 94/25 | -/- | -/7 X 3 X 3/R | -/- | 2/2/27 | 9 | |||
| 46 | 5,5/12,16 | 4/11 | 10/29 | 51/55 | <10 | 13/12 | 6 | 130/6 (diam)/L | -/- | 8/8/- | 0.7 | |
| 38+ | ||||||||||||
| 47 | 10-13/8-12 | 6/7 | -/- | 24/17 | 44 | 13/12 | 10 | 49 | 16/3.5 X 2.8 × 2.5/R | -/- | -/-/- | - |
| 0.6 (diam) | ||||||||||||
* mg/24 hr. f mU/dl; * Morning after metyrapone.
| Patient No. | 24-Hr Urinary 17-OHCS/17-KS (mg/g creatinine/24 hr) | Plasma Cortisol (µg/dl) | Tumor Wt. (g)/ Size (cm)/Side (L or R) | Length of Follow-Up (mo after treatment) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Basal | After 2 Days High-Dose Dexameth- asone | Day after Metyr- apone | Day of ACTH | Plasma ACTH (pg/ml) | A.M./ P.M. | After 2 Days High-Dose Dexameth- asone | After ACTH | |||
| Cushing's syndrome | ||||||||||
| 23 | 17/60 | -/- | -/- | 23/43 | -/- | 384/-/R | 16 | |||
| 24 | 19-21/22-24 | 19/18 | 15/18 | 17/23 | - | -/- | -/3.4 (diam)/L | 16.7 (alive) | ||
| 25 | 21-22/38-47 | 17/49 | 11/44 | 26/67 | <0.1* | 22/45 | 40 | 410/-/R | 6.4 | |
| 26 | 8-12/23-42 | 15/50 | 6/25 | 16/43 | - | 19/20 | 39/-/R | 3.3 | ||
| 27 | 25-28/39-72 | 21/51 | 14/36 | 42/47 | <3 | -/- | -/11 (diam)/L | 0.6 | ||
| 28 | 18-20/44-51 | 20/37 | -/- | 19,25/49,41 | - | 23/21 | 21 | 24 | 233/-/L | 4 |
| 29 | 25,34/24,28 | 29/27 | 20/8 | 44/30 | <20 | 30/28 | 30 | 60 | 45/-/R | 2.4 |
| 30 | 27,28/18,20 | 25/23 | 12/12 | 38/25 | 31/29 | 32 | 32 | 240/-/L | 6.8 | |
| 31 | -/- | -/- | -/- | -/- | -/- | -/"grapefruit"/R | 7.1 | |||
| 32 | -/- | -/- | -/- | -/- | -/- | -/-/L | 2.5 | |||
| 33 | 13/461 | 24/95+ | -/- | 19/39+ | -/- | 1,800/-/R | 0 | |||
| 34 | 31/165 | -/- | -/- | 32/114 | -/- | 1,400/-/L | 0.5 | |||
| 35 | -/- | -/- | -/- | -/- | -/- | -/-/L | 5.8 | |||
| 36 | 29-32/76-110 | 31/115 | 27/102 | -/- | 36/40 | 38 | No surg/-/R | 0.6 | ||
| Virilization only | ||||||||||
| 38 | -/271 | -/- | -/- | -/- | -/- | 340/-/L | 18 (alive) | |||
| 39 | 1,6/227,3541 | 10/297+ | -/- | -/- | -/- | -/11 (diam)/L | 1.4 | |||
| 40 | -/- | -/- | -/- | -/- | -/- | -/"volleyball"/L | 7 | |||
| 41 | 22-45/101-176 | 27/83 | 40/128 | 32/183 | 33 | 19/- | 19 | 25 | No surg/-/- | 1.3 |
| 42 | 8-10/7-8 | -/- | -/- | -/- | 26/6 | 5/-/L | 7 (alive) | |||
| 43 | 33,36/229-247 | 57/291 | -/- | 54/239 | 36/32 | 29 | No surg/9 (diam)/L | 0.2 | ||
| (+R?) | ||||||||||
| 44 | 28,29/40,45 | 23/42 | 28/66 | 85/85 | - | 27/23 | 357/-/L | 1 | ||
| No endocrine syndrome or hypertension only | ||||||||||
| 48 | 18/14 | 19/17 | -/- | 27/19 | 19/- | 700/14 × 9 × 8/L | 8.5 | |||
| 49 | 11,19/48,64 | 11/35 | -/- | -/- | -/- | 3,300/-/R | 0.1 | |||
| 50 | -/- | -/- | -/- | -/- | -/- | 6,850/30 (diam)/L | 6.4 | |||
| 51 | 8/54 | -/- | -/- | -/- | -/- | 1,510/25 (diam)/L | 0.2 | |||
| 52 | -/- | -/- | -/- | -/- | -/- | 1,802/22 (diam)/L | 28 (alive) | |||
| 53 | -/- | -/- | -/- | -/- | -/- | -/-/L | 1 | |||
| 54 | -/- | -/- | -/- | -/- | -/- | -/-/- | 0.6 | |||
| 55 | 6,6/8,10 | -/- | -/- | -/- | -/- | 425/13.5 X 10 × 3.5/L | 0.5 | |||
| 56 | 4,4/16,20 | 1/12 | -/- | -/- | 14/4 | 5 | 150/8 (diam)/L | 3 (alive) | ||
| 57 | -/- | -/- | -/- | -/- | -/- | -/"big"/L | 1 | |||
| 58 | 11-13/9-10 | 11/- | 4/- | 9/- | 22/18 | 13 | 21 | -/"football"/R | 8.3 | |
* mU/dl; t mg/24 hr.
ADRENOCORTICAL TUMORS-BERTAGNA, ORTH
BASAL
DEX
BASAL
DEX
43
24-HR URINE 17-OHCS ( mg/g creatinine )
50
17
12
40
p
30
36
6
44
7
28
29
3
14
41
20
45
8
27
5
13 19
48
24
10
25
18
21
33
26
16
22
10
4
15
58
49
37
20
9
47
39
46
o
56
0
0
0
*
ADENOMAS
CARCINOMAS
BASAL
ACTH
BASAL
ACTH
(202); 12*
24-HR URINE 17-OHCS (mg/g creatinine)
100
22*
44*
80
17*
21*
14*
60
6
*
13
*
como
16 *
43
40
27
11
30
34
41
2
5
19
29
48
20
25
20
28
33
4
10
23
24
15
9
26
58
0
ADENOMAS
CARCINOMAS
24-HR URINE 17-OHCS ( mg/g creatinine)
50
BASAL METYR BASAL METYR
40
41
17
22
30
36
27
44
7
12
6
3
20
45
8
29
oma
19
24
16
5
10
15
4
58 q
30
4
25
18
9
20
26
46
0
0
ADENOMAS
CARCINOMAS
Response to ACTH infusion (Figure 4, Tables VIII and IX): In response to an 8-hour infusion of 50 U of ACTH, 10 patients with adenoma, but none with carci- noma, responded normally (doubling or more of basal 24-hour 17-OHCS values on the day of infusion); in the nine other patients with adenoma and 10 with carci- noma tested, 17-OHCS increased by less than 50 per- cent or decreased (Figure 4). Three patients with ade- noma had very prolonged responses to ACTH, with 17-OHCS levels remaining more than twice basal values for at least three days. Together with the results of the dexamethasone suppression test, these data indicate that about half of the adenomas could respond to maximal stimulation by exogenous ACTH with a further increase in cortisol secretion, even though basal tumor cortisol secretion was not dependent upon endogenous ACTH; thus, these adenomas were ACTH-independent, but ACTH-responsive. The other adenomas and all of the carcinomas were both independent of and nonresponsive to ACTH, even in supraphysiological doses.
The increase in 17-KS levels on the day of ACTH infusion did not correlate with the increase in 17-OHCS levels. Of those patients with increased 17-KS levels, most barely doubled their baseline values, and only one had a marked increase. A similar dissociation between the increases in 17-OHCS and 17-KS levels in response to ACTH stimulation was noted by Ross et al. [27]. The
50
a. m.
p.m.
a.m.
p. m.
PLASMA CORTISOL ( ug /dl )
40
22
36
30
30
43
6
27
44
29
11
12
42
19
14
16
28
20
20
13
25
41
26
8
18
48
058
37
46
15
56 q
10
9
47
*
*
*
0
ADENOMAS
CARCINOMAS
total amounts of 17-OHCS and 17-KS excreted during the day of stimulation correlated well with the total amounts of each excreted during basal days, whereas there was no correlation between the percent increase in 17-OHCS and basal 17-OHCS, and a negative cor- relation existed between the percent increase in 17-KS and basal 17-KS.
Plasma cortisol (Figures 5 and 6, Tables VIII and IX): Basal plasma cortisol was the same in the two groups, ranging from 18 to 40 µg/100 ml in both morning and evening (Figure 5), demonstrating lack of a consistent normal diurnal rhythm. Plasma cortisol was not suppressed by low- or high-dose dexamethasone administration in any patient (Figure 6). Only one of four patients with carcinoma had a plasma cortisol level greater than 40 µg/dl after ACTH, and none greater than 60 µg/dl, but seven of nine patients with adenoma had post-ACTH plasma cortisol levels greater than 40 µg/dl, and five were greater than 60 µg/dl. Thus, the results of plasma cortisol measurements were consistent with and confirmed the urinary 17-OHCS results.
Pathology. Adenomas (Table VIII): At operation, each patient with adenoma had a well encapsulated tumor, which varied in size from 2.2 X 2 X 1.5 cm to 7 X 6.5 X 5 cm and in weight from 12.5 g for the whole adrenal, including the tumor, to 126 g for the tumor alone (mean, 36 g; median, 20 g); only two (in Patients 1 and 7) weighed more than 70 g, and another (in Patient 6) was 7 cm in diameter (estimated weight, about 90 g).
BASAL
DEX
ACTH
BASAL
DEX
ACTH
(170) , 21
120
14
PLASMA CORTISOL (µg/dl)
100
80
17
13
60
29
8
40
22
20
36
25
43
30
12
9
20
16
28
19
41
0 58
18
468
56
47
O
0
0
ADENOMAS
CARCINOMAS
The adenoma was on the left side in 15 cases and on the right in seven. In six patients, the contralateral adrenal was said to be normal, atrophic in five others. In one (Patient 12), the tumor was embedded in the tail of the pancreas; no normal left adrenal gland was identified. In one (Patient 13), there were two adenomas; in another (Patient 22), an adenoma and a small nodule. In none was there capsular or blood vessel invasion by either gross or microscopic examination. In a few cases, the presence of giant cells (Patients 4 and 11) and areas of hemorrhage or necrosis (Patients 7, 11, 18, 19 and 21) were noted, but the final diagnosis was that of a benign tumor. The follow-up of these patients ranges from eight months to 18 years; in no case has there been evidence of recurrence or metastasis.
Carcinomas (Table IX): One of the patients with carcinoma who had Cushing’s syndrome (Patient 36) did not undergo operation; the diagnosis was made on the basis of the patient’s markedly abnormal steroid excretion and arteriography, which revealed a large, abnormally vascularized suprarenal mass and liver metastases. In 11 patients, tumor weight ranged from 39 g to 1,800 g (mean, 508 g; median, 240 g). Two others (Patients 32 and 35) underwent operation else- where; we have no record of the sizes of their tumors.
1(45)
40
24-HR URINE 17-OHCS (mg/g creatinine )
30
20
10
VVXI
0
PREOP
1
3
5
7
9
11
13
15
18
24
48
MONTHS AFTER SURGERY
The primary tumor was on the left side in seven in- stances and on the right side in seven instances.
Tumor weight did not correlate with plasma cortisol concentration or with urinary steroid excretion, in pa- tients with either adenoma or carcinoma.
The three smallest tumors-39 g, 45 g and 3 to 4 cm diameter (estimated weight, 8 to 18 g)-were encap- sulated and were “removed completely.” The first was diagnosed as an adenoma, but recurred after three years and two months. The second was diagnosed as a possible carcinoma and metastasized after 14 months. The third was diagnosed as carcinoma, but the patient was well and free of disease 17.5 years after surgery. Two patients had metastases at the time of diagnosis, and five had invasion of the surrounding structures. Previous authors have emphasized the dif- ficulty in making the pathologic diagnosis of malignancy in adrenal tumors [12]. Some authors have found large tumor weight to be a reliable indicator of malignancy [13], others have relied upon disproportionately high excretion of 17-KS as compared with 17-OHCS, and still others find the histologic characteristics of the tumor to be a good predictor of subsequent biologic behavior in most cases. Small size and benign histologic features of a tumor are certainly not always sufficient, as dem- onstrated by Patient 26, whose 39-g tumor was diag- nosed as an adenoma, but who later had metastases. Hough et al. [28] at Vanderbilt have recently reported the value of an index combining several histologic and clinical features, derived from many of the same pa-
tients we describe here, in predicting the behavior of adrenal tumors.
Evolution. Patients with adenoma (Figure 7, Tables VIII and X): Clinical course: One with adenoma (Patient 2) died of unrelated disease 17 months after the removal of his tumor; all other patients are alive and well.
Patients were given cortisol, cortisone acetate, prednisone, or ACTH for 18 days to 23 months after surgery as replacement therapy. Most of their symp- toms had disappeared and they had lost the clinical features of Cushing’s syndrome three to 11 months after operation.
Clinical signs and laboratory values: A comparison of some preoperative and postoperative values is shown in Table X. Body weight decreased significantly, but remained 10 percent or more above the ideal for sex and age in 28 percent of patients. Blood pressure also decreased significantly, although systolic blood pres- sure remained greater than 145 mm Hg in 25 percent and diastolic pressure greater than 95 mm Hg in 15 percent of patients. The hematocrit and total white blood cell count decreased significantly, and the percent of eosinophils and lymphocytes increased significantly. The increase in serum potassium was not significant, although no patient’s potassium level was less than 3.5 meq/liter after surgery. Serum bicarbonate and cho- lesterol levels decreased significantly and, to a lesser degree, so did serum chloride values; serum sodium levels did not change significantly. Three patients with abnormal fasting blood glucose levels preoperatively had normal values after surgery.
Steroid production: All patients had very low daily urinary 17-OHCS excretion immediately after surgery (Figure 7). This gradually increased to a normal range of 4 to 6 mg/g creatinine over the next three to 24 months. These observations are in general agreement with those of Graber et al. [29], who studied plasma ACTH and corticosteroid concentrations in patients recovering from prolonged pituitary suppression by glucocorticoids and found that both plasma ACTH and plasma 17-OHCS levels remained low for about one month after steroid withdrawal, that plasma ACTH in- creased to normal levels or above over the next two to five months, causing plasma 17-OHCS to increase gradually, and that both plasma cortisol and ACTH levels finally returned to normal after about nine months.
Response to ACTH: Thirteen patients received ei- ther a standard intravenous ACTH infusion test or in- tramuscular ACTH injection test within two weeks of surgery. Four patients showed no response, eight pa- tients responded much less than normal for a subject with both adrenal glands, and one patient responded normally. When tested serially, the patients’ responses to ACTH increased progressively and were normal
| Before Surgical Cure | After Surgical Cure | Paired t Test n (p) | |||||
|---|---|---|---|---|---|---|---|
| n | Mean ± SD | >ULN/<LLN No. (%) | n | Mean ± SD | >ULN/<LLN No. (%) | ||
| Syst BP (mm Hg) Diast BP (mm Hg) | 22 | 170.1 ± 30.5 | 19 (86% )/- | 20 | 135.6 ± 32.2 | 5 (25% )/- | 20 (<0.001) |
| 22 | 110.1 ± 23.6 | ||||||
| 16 (73% )/- | 20 | 82.8 ± 16.3 | 3 (15%)/- | 20 (<0.001) | |||
| % Ideal body wt. | 21 | 124 ± ー | 13 (62% )/0 (0 % ) | 18 | 101 ± ー | 5 (28%)/0 (0 %) | 18 (<0.001) |
| PCV (%) | 21 | 43.9 ± 3.8 | 9 (43 % )/2 (10%) | 18 | 39.7 ± 3.9 | 0 (0%)/4 (22%) | 17 (<0.001) |
| WBC (cells/mm3) | 22 | 12,293 ± 4,203 | 14 (64%)/0 (0%) | 18 | 7,782 ± 1,863 | 3 (17%)/1 (6%) | 18 (<0.001) |
| Lymphocytes (%) | 22 | 16.9 ± 8.1 | 0 (0%)/17 (77%) | 15 | 29.6 ± 6.8 | 1 (7%)/1 (7% ) | 15 (<0.001) |
| Monocytes (%) | 22 | 6.5 ± 4.0 | 11 (50% )/3 (14 %) | 15 | 6.2 ± 3.0 | 8 (55%)/0 (0 %) | 15 (>0.30) |
| Eosinophils (%) | 22 | 0.9 ± 1.3 | 1 (5% )/11 (50%) | 15 | 3.4 ± 2.1 | 9 (60% )/2 (13%) | 15 (0.005) |
| Na (meq/liter) | 20 | 142.7 ± 4.5 | 7 (35 % )/0 (0% ) | 18 | 140.3 ± 2.8 | 0 (0 % )/0 (0%) | 17 (0.030) |
| K+ | 20 | 3.85 ± 0.6 | 0 (0%)/4 (20%) | 18 | 4.2 ± 0.24 | 0 (0% )/0 (0%) | 18 (0.135) |
| (meq/liter) | |||||||
| CI (meq/liter) | 19 | 101.9 ± 5.8 | 1 (5%)/2 (11%) | 17 | 105.0 ± 2.1 | 0 (0%)/0 (0%) | 15 (0.040) |
| HCO3 (meq/liter) | 20 | 29.2 ± 4.5 | 6 (30%)/1 (5%) | 17 | 25.5 ± 3.2 | 0 (0%)/1 (6%) | 17 (<0.001) |
| Ca | 15 | 9.9 ± 0.56 | 0 (0 % )/0 (0 % ) | 14 | 9.6 ± 0.56 | 0 (0%)/0 (0%) | 12 (0.068) |
| (mg/dl) | |||||||
| Uric acid (mg/dl) | 13 | 5.5 ± 1.8 | 3 (23%)/0 (0% ) | 12 | 5.4 ± 1.5 | 2 (17% )/0 (0%) | 10 (>0.30) |
| Cholesterol (mg/dl) | 17 | 258.6 ± 45.6 | 3 (23% )/0 (0%) | 17 | 217.3 ± 41.9 | 0 (0%)/0 (0%) | 15 (<0.001) |
| SMA glucose (mg/dl) | 18 | 110.6 ± 47.0 | 4 (22%)/0 (0%) | 16 | 99.8 ± 20.4 | 2 (12%)/0 (0 % ) | 13 (0.255) |
| Fasting blood glucose (mg/dl) | 10 | 95.9 ± 19.3 | 3 (30%)/0 (0 % ) | 8 | 85.0 ± 9.0 | 0 (0%)/0 (0 % ) | 8 (>0.30) |
NOTE: ULN = upper limit of normal; LLN = lower limit of normal; - none or not calculated.
within two to 12 months after surgery in nine of 11 pa- tients; two patients still had very low responses to ACTH 10 and 12 months after surgery, and each received cortisol replacement therapy for 22 months after sur- gery. These observations are consistent with the model proposed by Graber et al. [29] and further indicate that in those patients with preoperative response to ACTH, the adenoma, not the nontumorous adrenal cortices, was the source of the increased cortisol secretion.
Response to metyrapone: Of six patients tested within seven months of surgery, only one had a normal response, and that was at seven months. Eight patients were tested later, and the response returned to normal within 12 to 24 months in seven; in one, the response to metyrapone was still not normal after five years, but was normal at seven years. In all patients, the response to ACTH returned to normal before the response to
metyrapone did. Since the response to metyrapone requires both a pituitary with ACTH secretory reserve that is normally responsive to hypocortisolemia and an adrenal cortex that is normally responsive to the physiologic levels of endogenous ACTH released, either one or both of these capacities appeared to be deficient in our patients for several months to years after surgical cure of their hypercorticism. Graber et al. [29] found that plasma ACTH concentrations were normal to ele- vated in their patients even before steroid secretion returned to normal, but that the adrenal gland was re- sponsive to modest doses of exogenous ACTH (0.1 U per hour for 24 hours). It would appear probable, therefore, that in our patients the pituitary was also secreting normal or even supernormal amounts of ACTH basally two to five months after surgery, but that insufficient ACTH was secreted in response to metyr-
33
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28
YEARS AFTER INITIAL TREATMENT
apone administration to stimulate a normal increase in cortisol secretion by the remaining adrenal glands for seven months to five years after surgery.
Patients with carcinoma (Figure 8, Table IX): Clinical course: One (Patient 24) was alive and well 16.7 years after operation, but all other patients died at intervals varying from immediately postoperatively to 16 years postoperatively (Figure 8). Recurrences or metastases occurred four months to four years post- operatively, except for one patient (23) in whom the disease-free interval was 11.7 years. Metastases were most often found in the lungs (seven patients), liver (three patients) or elsewhere in the abdomen. Eleven patients received o,p’DDD for two months or more [30]. In two of these (Patients 25 and 30), the detectable tumor disappeared for one year and two and a half years; lung metastases recurred in the latter patient despite continued administration of o,p’DDD, and she died 6.8 years after surgery. In two other patients (32 and 36), there was some clinical improvement; seven patients had neither clinical nor objective improve- ment.
Patients with Virilization Only
One girl with adenoma (Patient 37) and three other girls and four women with carcinoma presented with virili- zation only, having no other signs or symptoms of Cushing’s syndrome. The four children were 18 months to four years old; the four women were 44 to 67 years old.
Symptoms, Signs and Chief Complaints. The mean interval between the first symptoms and diagnosis was 14.3 months for patients with carcinoma, similar to that
for patients with Cushing’s syndrome due to carcinoma (14.6 months). The first symptom of the presence of the tumor was hirsutism (Patients 38, 39, 40 and 43) and/or virilization (Patients 37, 38 and 42) in six of eight cases, acne, weakness, hot flashes, diabetes (Patients 39, 40, 43 and 44) and hypertension and an abdominal mass (Patient 41) were also cited. The chief complaint was virilization (Patients 37, 42 and 43), abdominal mass (Patients 39 and 40), weakness or “adrenal cancer” (Patients 41 and 44, respectively).
Steroid Levels and Responses (Figures 2 to 5, Tables VIII and IX). All except one patient (Patient 41) had high to very high urinary 17-KS values, ranging from 40 to 354 mg per day. The three adult patients with carci- noma who were studied also had elevated baseline 17-OHCS excretion (22 to 45 mg per day), which was in the range of that found in patients presenting with Cushing’s syndrome. Like those of patients with Cushing’s syndrome, the urinary steroid levels failed to be suppressed with high-dose dexamethasone or to be increased after metyrapone administration (Figures 2 and 3). In contrast to the lack of response to ACTH ad- ministration observed in patients with carcinoma causing Cushing’s syndrome, however, ACTH caused a normal 2.5-fold increase in urinary 17-OHCS in one patient (Patient 44), a moderate (1.6-fold) increase in another (Patient 43), but no response in the third patient (41) tested (Figure 4). These three patients also had high plasma cortisol levels (18 to 36 µg/dl) with no diurnal rhythm (Figure 5). It is not clear why these patients, who had marked hypercortisolemia, did not have clinical evidence of Cushing’s syndrome. Lipsett and Wilson [31] have suggested that some patients with carcinoma
have high tetrahydrodeoxycortisol (THS) levels in their urine, accounting for the high urinary 17-OHCS levels. Since THS is a metabolite of the biologically-inactive precursor of cortisol, 11-deoxycortisol (Compound S), it follows that inactive deoxycortisol might be a product of the carcinoma, and total urinary 17-OHCS values might not accurately reflect the secretion of biologi- cally-active glucocorticoids. Indeed, urinary THS was elevated in one of our patients in whom it was mea- sured. However, her plasma cortisol level was also markedly increased. It is possible that the anabolic ef- fects of androgens may counteract the catabolic actions of glucocorticoids in these patients.
The child with an adenoma (Patient 37) had normal or only slightly increased urinary 17-OHCS levels that were not, however, normally suppressible with dexa- methasone, a normal plasma cortisol level and a normal cortisol diurnal rhythm. Presumably her tumor was producing mostly androgens and only little cortisol, and her normal ACTH-cortisol secretory control mecha- nisms were still relatively intact. A child with carcinoma (Patient 39) also had only slight elevation of urinary 17-OHCS levels despite marked increase in 17-KS excretion. The last child (Patient 42) in whom steroid measurements were made had near-normal 17-OHCS levels, normal 17-KS levels and normal plasma cortisol levels with a normal diurnal rhythm. However, her plasma testosterone level was increased, as has been reported previously [32].
Pathology and Evolution (Tables VIII and IX). The patient with an adenoma had a well-encapsulated, 9.6-g, histologically benign tumor. She is well two years after surgery. One child (Patient 38) had a 340-g tumor; al- though it appeared benign histologically, it had invaded the adrenal vein and was, therefore, called malignant. The patient was well 18 years after removal (Figure 8). A third patient (Patient 42) had a 5-g tumor that ap- peared malignant histologically. She is well seven years after surgical removal of the tumor. The other five pa- tients had large tumors. Two (Patients 41 and 43) did not undergo operation; one had bilateral vascular suprarenal masses visualized by arteriography with massive in- volvement of the liver, and the other had pulmonary nodular densities and a palpable abdominal mass; di- agnosis was confirmed at autopsy. These two patients and two others in whom metastases developed after a disease-free interval following surgery were treated with the adrenocorticolytic drug, o,p’DDD. There was some objective tumor regression in one patient, but no im- provement in the other three. Three of the five patients with virilization only who died of carcinoma had me- tastases at the time of diagnosis; they died seven weeks to seven years after beginning treatment.
In all instances, the tumor was on the left side, with the possibility of bilateral tumor in one case.
Patients with Clinically Nonfunctional Tumors or with Hypertension Only
Patients with Adenoma (Tables III, VI and VIII). One of the three patients with a clinically nonfunctional ad- enoma (Patient 45) came to medical attention because of edema and metrorrhagia; she had been moderately irritable. She had no signs or symptoms of glucocorti- coid excess (except, possibly, for high blood pressure and a history of glucosuria), but her elevated basal 17-OHCS and 17-KS levels, lack of response to dexa- methasone or metyrapone and marked response to ACTH were typical of patients with Cushing’s syndrome due to adrenal adenoma. Since neither plasma cortisol nor urinary THS levels were measured, we cannot ex- plain the absence of Cushingoid features in this patient. She had an adenoma of the right adrenal cortex mea- suring 7 X 3 cm. The tumor in the second patient (Pa- tient 46) was a chance finding on an intravenous py- elogram performed to evaluate pyelonephritis. She had fever and confusion as her initial symptoms and fever as her chief complaint. She had been slightly irritable and had a history of elevated fasting blood glucose levels. Her normal urinary 17-OHCS level was not suppressed with dexamethasone, but increased nor- mally after metyrapone administration, and responded dramatically to ACTH infusion. Her plasma cortisol level was repeatedly in the range of 11 to 12 ug/dl in the late evening. Her tumor was a 130-g well-encapsulated adenoma. The steroid studies are consistent with the concept that her tumor was independent of endogenous ACTH stimulation for basal cortisol secretion, but had only recently secreted enough cortisol to replace nor- mal adrenocortical secretion-thus, the normal re- sponse to metyrapone. It was the adenoma that was responsive to exogenous ACTH and to endogenous ACTH secreted in response to metyrapone, since there was no response to either ACTH infusion or steroid withdrawal soon after surgery. Patient 47 was being evaluated for hypertension, which was her only com- plaint. Her daily urine 17-OHCS excretion was 11 to 12 mg/g creatinine, was partially suppressible with dexamethasone and responded normally to ACTH; she had no metyrapone test. Her morning plasma cortisol level was normal, but there was no diurnal rhythm. Her right adrenal gland weighed 16 g and contained two benign-appearing nodules measuring 3.5 X 2.8 X 2.5 cm and 0.6 cm in diameter, respectively. The sur- rounding cortical tissue was hyperplastic. Bilateral adrenal vein sampling revealed higher concentrations of aldosterone, progesterone, and 17-OH-progesterone on the right side than on the left. These last two patients have been treated only recently, so that the evolution of their disease remains to be seen.
Patients with Carcinoma (Tables IV, VII and IX). Ten patients (48 to 57) had clinically nonfunctional adre-
nocortical carcinoma, and another (Patient 58) had a DOC-producing tumor and will be discussed sepa- rately.
Symptoms, signs and chief complaints: Six patients (48, 49, 52, 53, 55 and 57) had pain and three (Patients 49, 50 and 54) had weakness as one of the initial two symptoms, one patient (51) noted a mass, one (Patient 55) had fever, another patient (56) had a mass discov- ered on an intravenous pyelogram performed to eval- uate pyelonephritis, and another (Patient 48), who had oligomenorrhea, had a calcified mass found during x-ray examination to evaluate sciatic pain; vertigo (Patient 53) and headache (Patient 57) were also listed. Mean du- ration of symptoms before diagnosis was 20 months, similar to that for patients with functional carcinoma. The chief complaint or reason for referral was a mass for four patients (48, 50, 51 and 52), weakness for Pa- tients 49 and 54, arm pain for Patient 53 and abdominal pain for Patient 57. Only two patients were questioned about diabetes: Patient 48 had symptomatic diabetes and Patient 50 had no diabetic history. No psychological evaluation was recorded for any patient. Patient 52 had normal menses.
Steroid levels and responses (Table IX): In only six patients were steroid levels measured before treatment. One (Patient 55) had normal basal 17-OHCS and 17-KS levels. Another (Patient 56) had normal basal 17-OHCS and normal plasma cortisol levels with a normal diurnal rhythm, but his basal 17-KS levels were elevated. His urinary 17-OHCS was suppressed normally with dexa- methasone. A third (Patient 48) had high basal urinary 17-OHCS levels that did not demonstrate suppression with dexamethasone, but responsed slightly to ACTH infusion. Urinary THS (8.6 mg per 24 hours) accounted for some of her increased 17-OHCS [31]. Her plasma cortisol levels were high-normal. One female patient (51), in whom only one baseline measurement was obtained before surgery, had normal urinary 17-OHCS and high 17-KS levels. Another female patient (49) had moderately increased 17-OHCS and high 17-KS levels, neither of which was normally suppressed by dexa- methasone administration. Two male patients were first studied at Vanderbilt with recurrences after surgery; initial studies were performed elsehwere. In one (Patient 50), basal urine 17-OHCS levels were reported to be normal, to be unsuppressed with dexamethasone, but to be increased after metyrapone (+60 percent) and ACTH administration; basal urine 17-KS levels were reported to be elevated, to be unsuppressed with dexamethasone, but to be increased slightly with ACTH. In the other (Patient 57), urinary 17-OHCS and 17-KS and plasma cortisol levels were all reported to be nor- mal and to demonstrate normal suppression with dexamethasone. Others [33,34] have found that non- functioning tumors can produce pregnenolone, the
metabolites of which can be measured in urine. One of our patients had abnormally high plasma pregnenolone and 17-OH-pregnenolone levels while taking dexa- methasone, as has previously been reported [35].
Thus, there are several explanations for the lack of clinical evidence of steroid excess in these patients. In males, isolated elevation of 17-KS may be insufficient to cause clinically recognizable hypervirilization. The degree and/or duration of hypercorticism may have been insufficient to cause clinical manifestations in some patients. In others, the tumor may have secreted only enough cortisol to replace normal adrenal secre- tion. Some tumors seemed to secrete only 17-KS. There was no evidence of steroid secretion by one patient’s carcinoma.
It should be noted again that basal steroid secretion by these tumors is frequently erratic and may render interpretation of responses to agents such as ACTH and dexamethasone difficult. These tests must often be repreated in order to document a consistent response or lack thereof.
Pathology and evolution (Table IX, Figure 8): In two patients, the diagnosis was based on examination of biopsy specimens of metastases to the humerus (Patient 53) or lymph nodes (Patient 54); they died one year and six months later with supportive therapy only. The eight others had adrenal exploration. The smallest tumor weighed 150 g and was completely removed; the patient (56) is well three years later. The other tumors weighed between 425 g and 6,850 g. One patient (55) died six months after incomplete tumor resection, and another (51) died of renal failure two months after complete resection (Figure 8). Two patients had me- tastases at the time of operation; one (Patient 49) died three weeks later despite treatment with o,p’DDD, and the other (57) died one year later. In two patients, me- tastases became clinically apparent five and a half years and seven years after resection of the tumor; one (Patient 50) received irradiation with objective benefit, and one (Patient 48) received o,p’DDD with partial re- mission; they died six and a half and eight and a half years after surgery, respectively. One patient (52) is alive and free of carcinoma 28 years after surgery, al- though the tumor, which had invaded the aorta, was not completely resected; she received postoperative ra- diotherapy.
Similar observations concerning the age at presen- tation, male predominance, frequency of left-sided tu- mors, initial symptoms of pain, mass and fatigue, large size of the tumors and occurrence of very long survival times despite histologic criteria of malignancy have been made by Lewinsky et al. [5] in their review of reported cases of “nonfunctional” adrenocortical carcinomas.
Patient with DOC-producing carcinoma: One 34
year old woman (Patient 58) had a predominantly DOC-producing adrenocortical carcinoma [36]. Hy- pertension had developed five years previously, and she presented with a large abdominal mass, weakness, edema, vomiting and hypokalemic alkalosis. She had neither Cushing’s syndrome nor virilization, yet her urinary 17-OHCS levels were increased, were not suppressed with dexamethasone, and did not respond to either metyrapone or ACTH (Figures 2 to 4, Table IX); plasma cortisol was increased and showed no diurnal rhythm. Her excretion of 17-KS, however, was normal. A large, nonresectable tumor invading the liver, left kidney and inferior vena cava was found at laparotomy, and biopsy revealed adrenal carcinoma. The patient received o,p’DDD for 18 months, after which it was discontinued because of lack of response and persistent nausea and vomiting. The patient died 8.3 years after surgery.
SUMMARY
Patients with adrenocortical tumors are relatively rare, so that no single physician or medical institution de- velops extensive experience in the diagnosis and treatment of this disease. We have summarized data recorded in the charts of the 58 patients with adreno- cortical tumors, excluding those with aldosterone- producing tumors, who were evaluated at Vanderbilt University Hospital from 1951 through 1978. Although this group of patients is not as large as some previously reported, our review has the advantage of including all of a relatively large number of patients with both benign and malignant tumors admitted to and evaluated, treated and followed up in a single medical center. Furthermore, because of our interest in pituitary-adrenocortical function, many of these patients were more extensively studied in the Vanderbilt Clinical Research Center than they would have been elsewhere.
In general, our patients appear to be similar to those described by others. Almost all patients with adenomas, but less than half of those with carcinomas, had Cush- ing’s syndrome, with weight gain and central obesity as the most common initial symptoms. Although the mean duration of symptoms before diagnosis was a year longer for patients with Cushing’s syndrome who had adenoma than for those who had carcinoma, there was no difference between men and women and none be- tween carcinomas that caused Cushing’s syndrome, virilization alone or no clinical endocrine syndrome. Baseline 24-hour urinary 17-OHCS levels were of no value in distinguishing adenomas from carcinomas, but daily 17-KS excretion of less than 20 mg/g creatinine was strongly suggestive of adenoma, and greater than 20 mg/g creatinine was strongly suggestive of carci- noma. None of the patients with Cushing’s syndrome responded normally to metyrapone administration. Only
half of the patients with adenoma, but none of those with carcinoma, responded normally to ACTH. In those pa- tients with adenoma who did have response to ACTH, the adenoma itself, not the nontumorous adrenal cortex, was the source of the additional cortisol. There was no correlation between tumor weight and amount of steroid excreted. Neither small tumor size nor benign histologic features were sufficient to predict benign biologic be- havior by the tumor.
Clinical Cushing’s syndrome disappeared three to 11 months after successful resection of tumors, but pa- tients remained dependent upon steroid replacement for as long as 22 months. Baseline steroid production and response to exogenous ACTH stimulation regularly returned to normal well before the response to metyr- apone. Only one patient with adrenal carcinoma causing Cushing’s syndrome is still living, almost 17 years after surgery; metastasis or recurrence was found in the others four months to 11.7 years after surgery. In two patients treated with o,p’DDD, clinically-detectable tumor disappeared for one to two and a half years, but in nine others treated, there was only slight improve- ment, if any. The patients died at intervals from imme- diately to 16 years after surgery.
All except one of the patients who presented with virilization only, including a female child with an ade- noma, had high to very high urinary 17-KS excretion. Three adult patients also had urine 17-OHCS and plasma cortisol levels in the range seen in patients with Cushing’s syndrome, but had no signs of glucocorticoid excess. The explanation for this phenomenon is not clear, but may involve the anabolic effects of high cir- culating levels of adrenal androgens. As in patients with Cushing’s syndrome, tumor size and histologic features were not reliable indices of subsequent benign or ma- lignant behavior. One of four patients treated with o,p’DDD had a brief period of objective tumor regres- sion; the others obtained no apparent benefit.
Three patients with adenoma and 10 with carcinoma had no apparent clinical endocrine syndrome except, possibly, hypertension. One patient with adenoma had baseline steroid levels and responses to tests that were typical of patients with Cushing’s syndrome, but no clinical features of glucocorticoid excess. Two others had normal or only slightly increased glucocorticoid production, but absence of a normal plasma cortisol diurnal rhythm. In patients with carcinoma, pain and weakness were the most common initial symptoms. Their urine 17-OHCS levels were usually normal or only slightly elevated, but resistant to suppression with dexamethasone. Urinary 17-KS levels, on the other hand, were usually high. With one notable exception, a woman who is alive and well 28 years after receiving postoperative irradiation following incomplete resection of a carcinoma invading the aorta, the patients with
clinically “nonfunctional” carcinoma fared about the same as those with Cushing’s syndrome or viriliza- tion.
One patient had carcinoma that produced predomi- nantly DOC and had typical signs of mineralocorticoid excess. She remained in reasonable health for more than seven years after incomplete resection of the tumor, but died at home 8.3 years after surgery.
The ideal objectives in the treatment of adrenocor- tical tumors include eradicating any tumor threatening the patient’s health, lowering steroid secretion to nor- mal, avoiding permanent endocrine deficiency and avoiding permanent dependency on medications [37]. In patients with adrenal adenoma, all of these objectives were achieved by complete surgical resection of the tumor. Maintenance steroid therapy was usually re- quired for several months postoperatively due to chronic suppression of pituitary ACTH secretion and resultant atrophy of the remaining adrenal cortex. A few patients with adrenal carcinoma were also cured by surgery followed, in one case, by postoperative irradiation. In a minority of those patients with inoperable or recurrent carcinoma, administration of o,p’DDD offered tempo- rary objective improvement. Hypercortisolism can be ameliorated by administration of metyrapone or ami- noglutethimide, alone or in combination. However,
earlier diagnosis, perhaps assisted by techniques such as abdominal computerized axial tomographic scans in patients in whom the diagnosis is suspected, appears to offer the best hope for improving the prognosis for patients with carcinoma of the adrenal cortex.
ACKNOWLEDGMENT
We are very grateful to Mr. Howard B. Johnston for his generous assistance in devising suitable programs for the CLINFO Computer; to Dr. Grant W. Liddle, many patients of whom are included in this report, for his valuable advice concerning the study and helpful criti- cism of the manuscript; to Dr. John W. Hollifield for his generous cooperation concerning his patients with adrenal carcinoma treated with o,p’DDD; to Dr. H. William Scott, Jr., for his kind assistance in providing current information on his surgical patients; to Mr. Donald P. Island, under whose direction most of the hormone determinations on the plasma and urine of these patients were performed; to the many physicians who referred these patients to us or participated in their care, especially Dr. Scott and Dr. Robert K. Rhamy, who performed the surgery on almost all of these patients; and to Ms. Sue Warrington and Ms. Linda D. D’Errico for transcribing the manuscript.
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