Adrenocortical Carcinoma with Hyperadrenocorticism
A Clinical, Metabolic, and Hormonal Study
HERTA SPENCER, M.D .; ISAAC LEWIN, M.D .; DANIEL LASZLO, M.D., New York; ROY HERTZ, M.D., Bethesda, Md .; ATTALLAH KAPPAS, M.D., and THOMAS F. GALLAGHER, Ph.D., New York
The cooperative effort of three groups of investigators made it possible to study the clinical course and the metabolic and hor- monal derangement of a patient with adre- nal carcinoma and the responsiveness of the tumor to hormone stimulation and Am- phenone (1,2-bis [/-aminophenyl]-2-methyl- propanone-1-dihydrochloride ) therapy.1-5 This study covers a period of four years during which three stages of the course of Cushing’s syndrome were investigated. The first stage illustrates the presence of signifi- cant hormonal and metabolic aberrations, al- though there was a paucity of clinical signs and symptoms. The second stage, which followed the removal of an adrenal tumor, illustrates the reversibility of Cushing’s syndrome in both clinical and biochemical parameters. This remission, considered to be a “cure,” lasted, however, only approxi- mately three and one-half years. It was interrupted by the sudden emergence of pronounced virilization associated with sig- nificant hormonal and metabolic aberrations. This third stage was due to widespread metastases of a hormone-producing adrenal cortical carcinoma. It was possible to dem- onstrate at this time that this highly malig- nant tumor was responsive to hormonal and chemotherapeutic influence. Hormone pro- duction of this tumor was unequivocally
Submitted for publication March 21, 1957.
Montefiore Hospital (Drs. Spencer, Lewin, and Laszlo), National Cancer Institute (Dr. Hertz), and Sloan-Kettering Institute for Cancer Re- search (Drs. Kappas and Gallagher).
This study was supported by grants from the National Cancer Institute ([C-1540] and [C-322]), National Institute of Arthritis and Metabolic Diseases (A-855), United States Public Health Service, and the American Cancer Society.
increased by adrenocorticotropin, probably depressed by exogenous cortisone, and sig- nificantly inhibited by Amphenone.6-8
I. Clinical Course
STAGE 1 .- Early Cushing’s Syndrome Due to an Adrenal “Adenoma”
A 42-year-old woman was admitted to Monte- fiore Hospital in November, 1951, with a tentative diagnosis of Cushing’s syndrome because of hyper- tension and slight hirsutism present for many years, sudden development of amenorrhea, and “fullness of the face.” There was a history of familial hypertrichosis. She had shaved her face and legs since puberty, and the hair growth on the abdomen had increased recently. Menses were normal until the onset of amenorrhea, four months prior to hospitalization. Symptoms of pregnancy or menopause were denied. Aches in the legs and tiredness present for many years were pronounced for eight months and were related to emotional difficulties. She had “migraine” headaches in the past, and recently, occasional frontal headaches. The weight remained constant (115 1b. [52.2 kg.]) for the past five years. There was no history of easy bruisability, back pain, change in libido, edema, polydipsia or polyuria, heat intolerance, or in- fection. She had not received any hormone therapy.
The patient was of normal female contour ; weight was 52.3 kg .; height, 160 cm. There was no acne, striae, ecchymosis, moon facies, or ab- normal fat distribution. Fine hair growth was present on the face and coarse hair on the fore- arms and thighs. Some hair extended from the mons pubis toward the umbilicus, but there was no distinct male escutcheon. There was no bone tenderness or kyphosis. The thyroid gland was not enlarged. The blood pressure was 170/105 mm. Hg. There was minimal hypertensive ret- inopathy, and the cardiac status was within normal limits. No abdominal organs or masses were palpable. On pelvic examination a uterine mass, assumed to be a fibromyoma, was felt, and the clitoris seemed to be slightly enlarged.
The frog test for pregnancy was negative, and there was no evidence of pheochromocytoma. The
RC
visual fields were normal. The roentgenograms of the skull were normal; those of the spine showed minimal osteoporosis. The intravenous pyelogram showed the left kidney to be lower than the right. Therefore, a presacral air insufflation was per- formed which showed a left suprarenal mass (Fig. 1).
The results of the various laboratory tests are listed in Table 1. The oral glucose tolerance test was diabetic in type (Fig. 2, Curve A). The serum calcium was determined five times and ranged from 11.1 to 11.9 mg. per 100 cc., except on one occasion, when it was 13.2 mg. per 100 cc.
After completion of the clinical, metabolic, and hormone studies, the patient received 40 mg. of corticotropin (ACTH) on two days prior to opera- tion, and cortisone was added on the day of operation.
A left translumbar exploration* revealed re- placement of almost the entire left adrenal by a well-encapsulated yellowish friable tumor measur- ing 10X9X9 cm. and weighing 140 gm. (Fig. 3). Histologically it was an adrenocortical tumor (Fig.
* Operation was performed by Dr. L. A. Orkin, Attending Surgeon in Urology, Montefiore Hos- pital, on Dec. 19, 1951.
Spencer et al.
200
4
180
.A
160
A- PREOPERATIVE
BLOOD SUGAR mg%
140
B- POST - OPERATIVE, 5,mos.
C- RECURRENCE
120
100
80
-8
60
Y
40
C
20
0
0
1
2
3
4
HOURS
5
4), showing focal areas of bizarre cells and in- creased mitotic activity.
STAGE 2 .- Recovery from Cushing’s Syndrome and Development of Hypoadrenalism
The patient had hypotension, elevation of tem- perature, anorexia, and lassitude on the first post- operative day. Three such episodes recurred later, concomitant with the discontinuation of hormone therapy. These symptoms disappeared promptly after corticotropin therapy was reinstituted. This indicated the responsiveness of the remaining right adrenal gland to corticotropin.
The hypertrichosis of the face started to clear within six weeks following the operation and disappeared four months later. Menses reappeared two and one-half months after removal of the adrenal “adenoma.” The patient continued to com- plain of fatigue for several months after the op- eration, but she resumed work eventually. She received occasional small doses of corticotropin or cortisone, with variable relief of symptoms. Hypo- adrenalism was suspected. The serum electrolytes,
the blood pressure, and the Robinson-Power-Kepler test were normal. The fasting blood sugar, how- ever, was slightly lower than normal, and the oral glucose tolerance test was flat (Fig. 2, Curve B). When this test was repeated two hours after the oral administration of 50 mg. cortisone, the fol- lowing values were obtained: fasting, 71 mg. per 100 cc .; 30 minutes after the ingestion of 100 gm. of glucose, 133 mg. per 100 cc .; 60 minutes, 143 mg. per 100 cc. ; 21/2 hours, 134 mg. per 100 cc. The rise of the blood sugar following the intravenous glucose tolerance test was somewhat less than in normals. The urinary steroid assays performed during this phase (see Hormone Studies) con- firmed the clinical impression of hypoadrenalism. The hypoadrenal state subsided gradually, and no substitution therapy was necessary. Physical ex- amination as well as laboratory studies performed repeatedly up to three years following the opera- tion revealed no abnormalities.
STAGE 3 .- Emergence of Virilizing Signs Due to Local Recurrence and Widespread Metastases
The patient returned three and one-half years after the removal of the adrenal tumor because of recurrent facial hair growth and increasing irrita- bility for which she sought psychiatric help. The menstrual periods were regular up to two months prior to the second admission. She had marked facial hirsutism; masculine hair distribution of arms, chest, and abdomen; a “moon” facies, and enlargement of the clitoris. No striae or acne were present. The blood pressure was 170/110 mm. Hg; the liver was enlarged, extended 4-5 fingerbreadths below the right costal margin, and was irregular and nodular, consistent with liver metastases. A presacral air insufflation disclosed multiple masses in the suprarenal area, indicative of recurrent adrenal malignancy. The roentgenograms of the
chest and skull were normal; those of the dorso- lumbar spine showed mild osteoporosis, but no bone metastases were demonstrated.
The laboratory tests of this phase are listed in Table 1. The oral glucose tolerance curve was again of the diabetic type (Fig. 2, Curve C). The serum calcium ranged from 10.6-11.4 mg. per 100 cc. The alkaline phosphatase was moderately elevated.
It was decided to reexplore this patient. A 150 mg. dose of cortisone was given orally on the day
| Test | Preoperative | Mo. After | Operation | Metastatic Phase | ||
|---|---|---|---|---|---|---|
| 5 | 17 | |||||
| Blood sugar | ||||||
| mg./100 cc. | 92 | 69 | 65 | 63 | ||
| Ca, mg./100 cc. | 11.6 | 10.8 | 10.7 | 11.0 | ||
| Alkaline phos- | ||||||
| phatase. | ||||||
| Bodansky | ||||||
| units | 4.4 | 4.7 | 4.1 | 7.0 | ||
| P, mg./100 cc. | 3.2 | 4.1 | 3.3 | 3.1 | ||
| Na, mEq./L. | 141 | 134 | 140 | 142 | ||
| Cl, mEq./L. | 102 | 101 | 102 | 99 | ||
| K, mEq./L. | 4.2 | 4.0 | 4.7 | 4.7 | ||
| CO,, mEq./L. | 29.3 | 23.2 | 24.6 | 26.5 | ||
| BUN, mg./100 | cc. 13.6 | 12.7 | 15.8 | 18.2 | ||
| Hb., gm./100 cc. | 14.4 | 11.9 | 10.8 | 15.0 | ||
| RBC, million/ | ||||||
| cu. mm. | 4.8 | 4.0 | 3.6 | 3.6 | ||
| WBC | 11.700 | 7700 | 7900 | 11.200 | ||
| Differential | 1-3 | Normal | Normal | 90% | ||
| WBC count | Myelocytes | polymor- | ||||
| and | phonuclear | |||||
| metamyelocy- | cells, 2% | |||||
| tes | young | |||||
| forms | ||||||
| Eosinophils | 42 | 164 | 0 | |||
| BMR, % | +42 | +1 | -4 | -- 5 | ||
| BP. mm. Hg | 170/100 | 140/90 | 125/80 | 170/110 | ||
| ECG | Inverted T : | Normal | Left | |||
| ventricular | ||||||
| hypertrophy | ||||||
| Body weight, | ||||||
| kg. | 51.8 | 50.9 | 50.0 | 51.4 | ||
prior to operation. An exploratory operation through a left lumbar incision was performed in July, 1955, and multiple huge nodular tumor masses were identified in the retroperitoneal space, especial- ly in the area of the left adrenal. Also numerous periaortic lymph nodes were found to be involved by tumor. Approximately 200 gm. of this re- current tumor were removed together with the left kidney. The microscopic examination showed this tumor to be carcinoma of adrenal cortical origin (Fig. 5). Cortisone was continued post- operatively, and the dose was gradually decreased. Fifteen days postoperatively, when the patient received 25 mg. of cortisone per day, the tempera- ture rose to 103 F and the blood pressure dropped to 95/70. This was thought to be due to hypo- adrenocorticism. The dose of cortisone was in- creased, resulting in prompt improvement. Six weeks after the operation cortisone was gradually withdrawn.
Eighteen days after the withdrawal of cortisone Amphenone was administered for ten days. The single dose of Amphenone varied from 0.75 to 0.5 gm. and was given every three hours. The daily dose of Amphenone and the changes of blood pressure and temperature are listed in Table 2. Because of drowsiness, a rise in temperature, and a slight decrease of the blood pressure the dose
of Amphenone was decreased on the second day. Since the blood pressure further decreased and the temperature rose to 103 F, Amphenone was omitted for one day on the third day of treatment. The patient was drowsy most of the time during the course of Amphenone, and her dietary intake had considerably decreased. The hepatic metastases be- came tender and appeared to decrease in size. The temperature remained elevated and rose to 104 F on the 10th day of treatment. Amphenone was discon- tinued; the patient was given sulfisoxazole (Gantri- sin) because a urine culture was positive for Escherichia coli. However, the temperature be- came normal within 12 hours after discontinuation of Amphenone, and the blood pressure rose to 150/100 mm. Hg.
Ten days after Amphenone therapy the patient had severe abdominal pain, and peritonitis secon- dary to a perforated peptic ulcer was suspected. Because of the widespread metastatic disease and the patient’s poor condition she was treated con- servatively. She improved on the medical regimen. Two weeks later she became icteric; her course was rapidly downhill. Two days prior to her death she vomited large amounts of blood. Death occurred four years after the initial diagnosis of Cushing’s syndrome was made.
| Pre-Amphenone | Days of Amphenone Administration | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | ||
| Amphenone, gm./day | 0 | 6 | 3.75 | 0 | 3.5 | 4 | 4 | 4 | 4 | 4 | 3.5 |
| Temperature * | Normal for 30 days | 100.6 | 103.6 | 103.0 | 101.2 | 100.4 | 99.2 | 101.2 | 101.8 | 102.2 | 104.0 |
| Blood pressure t | 160/100 - 180/100 | 150/110 | 150/105 | 110/90 | 120/90 | 130/85 | 115/90 | 135/90 | 120/90 | 120/90 | 125/90 |
* Highest reading of the day.
t Lowest reading of the day.
| Stage of Disease | Dura- tion of | Body Wt. Kg. | Nitrogen, Mg./24 Hr. | Phosphorus, Mg./24 Hr. | Calcium, Mg./24 Hr. | Sodium, mEq./24 Hr. | Potassium, mEq./24 Hr. | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study, Days | Intake | Urine | Stool | Bal. Intake | Stool Bal. Urine | S Bal. Intake | Urine | Stool | Bal. | Intake | Urine | Stool | Bal. | ||||||
| Preoperative | 18 | 51.2 | 8,439 | 9,420 | 988 | -1, ,979 660 | 541 | 248 129 162 | 201 | 215 254 | 88.0 | 74.8 | 1.2 | +12.0 | 56.2 | 52.9 | 7.0 | -3.7 | |
| 5 Mo. | |||||||||||||||||||
| postoperative | 8 | 49.8 | 10,850 | 8,386 | 761 | +1,703 758 | 439 168 +151 180 81 176 77 | 107.6 | 99.3 | 1.6 | 6.7 | 63.4 | 52.5 | 4.5 | +7.4 | ||||
| Metastatic phase | 10 | 50.6 | 10,672 | 10,834 | 1,260 | 1,422 702 | 682 | 208 188 147 | 260 | 205 318 | 137.5 | 119.8 | 4.0 | +13.7 | 49.6 | 43.5 | 12.7 | 6.6 | |
| Amphenone therapy | 10 | 4.8 | |||||||||||||||||
| 3,096 | 6,642 | 695 | 4,241 258 | 371 | 127 240 78 | 128 | 178 228 | 66.5 | 24.6 | 8.7 | +33.2 | 19.7 | 25.7 | -10.8 | |||||
Necropsy revealed widespread metastases from an adrenal cortical carcinoma. The liver weighed 2800 gm. and was studded with multiple yellow nodules with elevated brown edges, simulating adrenal tissue. Similar masses were present in the retroperitoneal space. There was one small tumor nodule in the lung parenchyma. In the first part of the duodenum there was a perforated ulcer, 2.5 cm. in diameter, leading into a walled-off cavity containing 200 ml. of blood. The right adrenal weighed 8 gm. and showed no gross or microscopic abnormalities. The right kidney weighed 175 gm. and showed no abnormalities. The thyroid gland weighed 25 gm .; histologically it showed no abnormal findings. The pelvic mass was a large fibromyoma of the uterus. The sec- tions of the vertebrae, sternum, and ribs showed thinning and considerable atrophy of the trabeculae, but there was no tumor involvement of bone. Three parathyroid glands were identified; they did not show any gross or microscopic abnormality. Permission for the examination of the brain could not be obtained.
II. Metabolic Study
The patient was studied on the metabolic research ward during each of the three stages of the disease. She received an analyzed low-calcium diet containing ap- proximately 150 mg. of calcium and 600 mg. of phosphorus per day.9 Balances of nitrogen, calcium, phosphorus, sodium, and potassium were determined (Table 3). Cal- cium tolerance tests were performed in each stage of the disease (Table 4).
The diet and the excreta were analyzed for nitrogen, calcium, phosphorus, sodium, and potassium on aliquots of each six-day metabolic period. Nitrogen was determined by the Kjeldahl method ; phosphorus, by the method of Fiske and Subbarow 10; urinary calcium, by the method of Shohl and Ped- ley.11 Calcium of the diet and stool was determined on acid ashed aliquots of six-day metabolic pools. Sodium and po- tassium of the diet and excreta were deter- mined on aliquots of six-day pools by the flame photometer.
STAGE 1 .- This study lasted 18 days. On an average daily intake of 1.3 gm. of pro- tein per kilogram the nitrogen balance was negative. Also, the phosphorus, calcium, and potassium balances were negative. The
ADRENOCORTICAL CARCINOMA-HYPERADRENOCORTICISM
| Stage of Disease | Serum | Urinary Calcium, Mg./Day | Ca Retention, % of Ca Injected# | Urinary Phosphorus, Mg./Day | |||||
|---|---|---|---|---|---|---|---|---|---|
| Ca, Mg. /100 cc. | P. Mg. /100 cc. | Spontaneous* | Inducedt | Spontaneous* | Induced + | ||||
| Preoperative | 11.9 | 3.0 | 204 | 548 | 23 | 826 | 514 | ||
| 11.1 | 3.9 | 218 | 456 | 47 | 601 | 528 | |||
| Mo. after | 5 | 11.3 | 4.1 | 44 | 122 | 83 | 444 | 265 | |
| operation | ₹ | 17 | 9.5 | 3.6 | 27 | 89 | 86 | 526 | 231 |
| 17 16 | 10.7 | 3.4 | 25 | 119 | 79 | 469 | 321 | ||
| Metastatic | 11.7 | 3.4 | 107 | 338 | 51 | 830 | 668 | ||
| phase | 10.0 § | 3.3 | 330 | 543 | 55 | 739 | 746 | ||
* Day before test.
t Day of test.
# 50 ml. of 10% calcium gluconate (469 mg. Ca++) was infused.
$ Performed 4 72 mo. after the first test in the metastatic phase.
intravenous calcium tolerance test was per- formed twice.3,12,13 This test revealed poor retention of the infused calcium; the uri- nary phosphorus excretion decreased on the day of the calcium infusion in both tests.
STAGE 2 .- Five months after the removal of the adrenal tumor the balances of nitro- gen, phosphorus, and potassium became positive. The calcium balance became nor- mal owing to a marked decrease of urinary calcium excretion. The calcium tolerance test showed a striking change; the spon- taneous (preinfusion) and the induced (day of infusion) calciuria decreased con- siderably, and the retention of the infused calcium increased to levels which were even higher than observed in normals. The test repeated 17 and 171/2 months postopera- tively showed principally the same results. The urinary phosphorus decreased consid- erably on the days of the tests.
STAGE 3 .- The calcium tolerance test gave results similar to those obtained in the two tests prior to operation, although the urinary calcium was not as high as in Stage 1. How- ever, the calcium retention decreased again to low levels similar to the preoperative phase. A repeat calcium tolerance test per- formed two months later gave similar re- sults, although the urinary calcium had further increased to 330 mg. per 24 hours. It is of interest to note that the phosphaturia did not decrease during this latter test, but increased by a few milligrams. Metabolic studies revealed that the balances of nitro- gen, phosphorus, calcium, and potassium became again negative and were similar to Spencer et al.
those of Stage 1. The negative calcium balance was mainly due to increase of the urinary calcium excretion.
An attempt was made to study the metab- olism of this patient during the 10-day period of Amphenone therapy. The data obtained are listed in Table 3, although their significance is very questionable, since the dietary intake decreased progressively, and the patient’s clinical state became too critical to measure balances reliably.
III. Hormone Studies
(a) Methods
Twenty-one separate urine collection periods of this patient were studied in the time interval from 1951 to 1955. Of this total, detailed examinations of individual urinary steroids were made in eight periods. In Stage 1, Period 1, a four-day collection before removal of the adrenocortical tumor. In Stage 2, Period 2, a 13-day collection five months after removal of the tumor. In Stage 3, Period 5, a four-day control obtained after recurrence of metastatic disease; Period 8, a one-day period representing the third day of corticotropin admin- istration (20 mg. per day, intravenously) ; ap- proximately 6 weeks later, Period 11, a two-day collection was obtained while the patient receivexl a maintainance dose of 62 mg. of cortisone orally per day; Period 13 represents a five-day collection made 3 weeks after cortisone was discontinued; Period 16, a three-day collection of Days 7 through 9 during the 10 days of treatment with Amphenone (4 gm. per day); Period 18 repre- sents a one-day collection 8 days after Amphenone was discontinued.
All collections were complete and were processed immediately following enzymatic and acid hydro- lysis of urinary steroid conjugates. Isolation and quantitation of individual steroid metabolites was
| Compounds | Pre- operative | Post- operative 5 Mo. | Metastatic Phase | |||||
|---|---|---|---|---|---|---|---|---|
| Control | Corti- cotropin | Cortisone | Post cortisone | Amphenone | Post- Am- phenone | |||
| 11-Ketoetiocholanolone | 1.9 | 0.5 | 5.8 | 12.2 | 3.8 | 5.3 | 1.0 | 6.4 |
| 11-Hydroxyetiocholanolone | 5.7 | 0.1 | 6.3 | 12.1 | 4.6 | 5.6 | 1.8 | 6.1 |
| 11-Hydroxyandrosterone | 5.6 | 0.1 | 9.2 | 15.8 | 6.1 | 6.6 | 2.1 | 8.9 |
| Etiocholanolone | 8.4 | 0.3 | 61.9 | 85.1 | 40.5 | 62.1 | 25.2 | 90.0 |
| Androsterone | 1.3 | 0.5 | 17.2 | 29.3 | 17.1 | 24.1 | 9.1 | 31.0 |
| Dehydroisoandrosterone | 1.0 | 0.1 | 87.3 | 128.2 | 45.2 | 178.0 | 1.3 | 118.0 |
| Date | 12/51 | 4/52 | 7/55 | 7/55 | 9/55 | 10/55 | 10/55 | 10/55 |
| Period | 1 | 2 | 5 | 8 | 11 | 13 | 16 | 18 |
*Values expressed in milligrams per 24 br.
done, employing the extensive methodology de- scribed previously.14,15
(b) Results
The values for each of the isolated com- pounds are reported in milligrams per 24 hours in Table 5. The three 11-oxygenated steroids isolated were as follows: 11-hydrox- yandrosterone (3a, 118-dihydroxyandro- stane-17-one), 11-hydroxyetiocholanolone (3a, 118-dihydroxyetiocholane-17-one), and 11-ketoetiocholanolone (3a-hydroxyetiocho- lane-11,17-dione). The three 11-desoxy- steroids isolated were androsterone (3a- hydroxyandrostane-17-one), etiocholanolone (3a-hydroxyetiocholane-17-one) and dehy- droisoandrosterone (30-hydroxy-45-andro- stene-17-one).
The preoperative control (Period 1) reveals normal levels of androsterone and dehydroisoandrosterone but increased amounts of the 11-oxygenated steroids and etiocholanolone compared with normal women.16 After surgical removal of the tumor (Period 2), the excessive amounts of these steroids disappeared; indeed, the 11-oxygenated compounds dropped to levels below normal. With recurrence of symp- toms of hyperadrenalism secondary to func- tional metastases a striking alteration in the steroid excretion pattern occurred ( Pe- riod 5). The 11-oxygenated steroids re- turned to excessive levels and were higher than those seen in the preoperative period (Period 1); there was a marked increase in androsterone and etiocholanolone produc- tion, and most striking of all was the pronounced elevation in dehydroisoandro-
sterone, a steroid which now exceeded in amount any of the other compounds.
Under corticotropin stimulation (Period 8), a significant increase in tumor steroido- genesis occurred. Attention is called in par- ticular to the very marked increase in dehydroisoandrosterone. This increase alone, quite apart from that exhibited by the other steroids, is unequivocal evidence of the capacity of this neoplasm to respond to adrenocorticotropin.
The steroid response to exogenous corti- sone (Period 11) must be considered in relation to the control periods several weeks preceding (Period 5) and following (Pe- riod 13) the administration of this hormone, since a more immediate control could not be obtained. With this qualification, exogenous cortisone seems to have induced a signifi- cant depression of tumor steroidogenesis. This depression of steroid production was manifest particularly in the amounts of the 11-desoxysteroids, since the 11-oxygenated compounds include the degradation products of administered cortisone.
During the administration of Amphenone (Period 16), a striking reduction in steroid production by the tumor occurred. The 11-oxygenated steroids dropped significant- ly, and, for reasons discussed previously,5 the levels reported here are undoubtedly higher than the true values. There was a marked decrease in dehydroisoandrosterone as well, and androsterone and etiocholano- lone diminished appreciably. After the end of Amphenone administration (Period 18) the tumor reverted to the previous high level of steroid production.
ADRENOCORTICAL CARCINOMA-HYPERADRENOCORTICISM
Comment
Many case reports and reviews have ap- peared on Cushing’s syndrome and Cush- ing’s disease since pituitary basophilism 17 was first described in 1932. Plotz et al.,18 Soffer et al.,20 and Cope et al.21 have reported on large series of such patients, and the nor- mal and the pathologic physiology of the human adrenal cortex have recently been re- viewed.19,22 Bilateral adrenal hyperplasia is the most frequent cause of Cushing’s syn- drome, while benign or malignant tumors of the adrenal cortex occur in less than one-third of such patients.23
Early diagnosis and definitive therapy are of prime importance in all cases, since an approximately 50% mortality was re- ported to occur within five years of the known onset of the disease; cardiovascular complications are the principal cause of death in young adults with Cushing’s syn- drome.18 The fully developed clinical entity of Cushing’s syndrome can easily be recog- nized. Patients with less overt manifesta- tions, however, present difficult diagnostic problems. For instance, Browne et al.24 described a patient in whom nephrolithiasis was the initial clinical manifestation of Cushing’s syndrome, the typical features of which developed several months later. Cope reported a patient with an adrenocortical carcinoma and increased 17-ketosteroid excretions in whom there were no clinical symptoms other than those referable to thyrotoxicosis.25 Soffer reported a 40-year- old man with a functioning adrenocortical carcinoma whose only presenting symptom was edema.20 Psychologic changes may also precede the somatic manifestations. 18,23
Clinical manifestations in the patient re- ported here were initially not very pro- nounced. There had been a slight increase in long-standing mild hypertrichosis, as well as cessation of menses preceding admission for study. In addition mild hypertension and osteoporosis were noted. There was no significant alteration in the character or distribution of body tissue, and there were no striae, plethora, easy bruisability, or Spencer et al.
other characteristic skin changes. In con- trast to these minimal clinical expressions of adrenocortical disease, major hormonal and metabolic derangements existed which gave evidence of significant hyperfunction of this gland. Roentgenographic demon- stration of an adrenal tumor confirmed these observations.
Several metabolic studies have previously been reported on patients with Cushing’s syndrome. Cushing cites a study of Aub on a 15-year-old girl with pituitary baso- philism who had an abnormally high urinary calcium excretion although the serum cal- cium was normal.26 Albright et al.27,28 Kep- ler et al.,29,30 and Soffer et al.31 have studied metabolic balances and the effects of therapy in patients with Cushing’s syndrome. Car- ter et al.32 noted negative nitrogen, calcium, and phosphorus balances in only 3 of 13 and elevated 17-ketosteroid excretions in only 8 of 16 such patients with advanced disease. Metabolic studies performed in the patient reported here revealed negative bal- ances of nitrogen, phosphorus, potassium, and calcium similar to the results of balance studies of other investigators.29-34
The abnormalities of the skeletal system and of bone metabolism which may occur in Cushing’s syndrome warrant comment. Al- though osteoporosis and even collapse of vertebrae occur frequently and are readily diagnosed in the advanced stages of the disease,18,20 the recognition of early osteo- porosis presents a difficult problem. The roentgenograhic changes may be minimal, and the serum calcium 18,20 and alkaline phosphatase 18 are usually within normal limits. The increased urinary calcium ex- cretion and the impaired calcium retention demonstrated by the calcium tolerance test 3.12,13 may help establish the early diag- nosis of osteoporosis. Indeed, this was true in the patient reported here and in 15 of the 17 patients studied at the New York Hos- pital, by Carter, Horwith, and Shorr. 35
The difficulties of prognosis in a patient following removal of an encapsulated ad- renal tumor are well illustrated by this case.
This patient was free of hyperadrenocor- ticism for three and one-half years, as evidenced by return of normal menses, re- version of the blood pressure to normal, and studies of urinary steroid excretion. Indeed, there was clinical and biochemical evidence of hypoadrenalism for several months after the operation. Metabolic bal- ances showed a change from the catabolic to the anabolic phase, and the calcium tol- erance test showed a reversal to a pattern indicative of the repair of osteoporosis. During the subsequent three and one-half years her clinical course was normal. The ultimate emergence of marked virilization in the terminal, metastatic phase was pre- ceded by several months of psychological disturbances. At this time the menstrual cycle was still normal, and the patient was able to continue full-time employment. With the resurgence of the somatic mani- festations of hyperadrenocorticism, the balances of nitrogen, phosphorus, potas- sium, and calcium again became negative, and the calcium tolerance test reverted to the preoperative pattern.
The suppression of adrenal and thyroid function by Amphenone in animals and in man and the toxicity associated with the administration of this compound have been described.6-8 The drowsiness, decrease of blood pressure, and the elevation of the temperature observed in this patient are in agreement with observations made in other patients. The histologic changes of the ad- renal and thyroid gland noted in experimen- tal animals were not seen in this patient. This is probably due to the fact that the patient died one month after discontinuation of therapy.
The steroid isolation studies in this pa- tient revealed several interesting and sig- nificant functional characteristics of this patient’s tumor. During the local phase of this neoplasm (Stage 1, Period 1), this patient’s steroid excretion pattern was char- acterized by an increase in the 11-oxygen- ated metabolites as well as in the 11-desoxy compound etiocholanolone. This combina-
tion of derivatives suggests that the princi- pal synthetic activity of this tumor was directed toward the production of hydro- cortisone and its 11-desoxy intermediates. The clinical expression of this hyperadre- nalism, Cushing’s syndrome in a mild form, was consistent with this interpretation of the nature of the excess adrenal hormone. Following surgical removal of the tumor (Stage 2, Period 2), the steroid pattern reverted to that indicative of a low level of endogenous adrenal activity consistent with the period of hypoadrenalism manifested clinically by this patient.
The later development of functionally active metastases in this patient (Stage 3) was associated with a major shift in the character of the excess hormone produced, as well as in its clinical manifestations. There was a marked elevation in the 11- oxygenated steroids during this period. In addition, there was an even more striking increase in steroids lacking the oxygen function at carbon-11. This increase was especially notable with dehydroisoandro- sterone, a substance whose production has frequently been noted to be excessive in adrenocortical malignancy.
The change in the character of steroido- genesis during this phase suggests that the production of androgens, or substances in- termediate to androgens, predominated. The superposition of masculinizing signs at this time upon the previous clinical status is confirmation of this change in hormone production. Thus, during all three stages of this patient’s tumor there were character- istic alterations in its steroid hormone syn- thetic activity consistent with the clinical manifestations.
The capacity of this tumor to respond to exogenous hormone was another signifi- cant functional characteristic demonstrated in this study. The response to corticotropin was unequivocal and particularly striking insofar as the production of dehydroisoan- drosterone was concerned. As noted above, suppression of the functional capacity of the tumor produced by cortisone must be pre-
Vol. 100, Oct., 1957
sumed on the basis of a comparison of steroid production during this period with steroid production during Periods 5 and 13. This comparison strongly suggests that such suppression did, in fact, take place.
The response to Amphenone makes it evident that a nonhormonal influence could be brought to bear upon this tumor, as well. This suppression of steroidogenesis pro- duced by this chemotherapeutic agent was profound (Period 16), although steroid production returned to the previous level when the compound was discontinued ( Pe- riod 18). This rapid return to a high level of steroid production implies that Amphe- none has a functional influence rather than a lethal effect on the tumor, which is in keeping with the results of previous studies of the effect of this agent on adrenal func- tion.8.36
These results thus establish clearly that unresponsiveness to exogenous or endoge- nous hormonal control cannot be considered a distinguishing characteristic of adreno- cortical malignancy. The necessity for in- dividual and detailed consideration of the functional status of these tumors is there- fore apparent. The observations on the suppressive influence of Amphenone empha- size further the possibility of a chemothera- peutic approach to the control of tumors of this type and serve to stimulate a search for related substances with less general toxicity and more prolonged effectiveness.
Summary
The clinical, metabolic, and hormonal changes in a patient with hyperadreno- corticism due to adrenocortical carcinoma were studied over a period of four years. During its initial localized phase this tumor produced excessive amounts of steroid of a type consistent with the associated clinical and metabolic expressions of mild Cushing’s syndrome. During its metastatic phase, sig- nificant alterations in hormone production occurred in keeping with the superposition of marked signs of virilization upon the previous clinical status.
At a time when the tumor was widely disseminated it was still possible to demon- strate some degree of control over its func- tional status by corticotropin and cortisone and by the chemotherapeutic agent Amphe- none.
Dr. H. M. Zimmerman, Chief, Division of Laboratories, and his staff cooperated in this study and gave permission for use of the pathological material.
Montefiore Hospital, 210th St. & Bainbridge Ave. (67).
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