Adrenal Cortical Hyperfunction Associated with Bronchogenic Carcinoma*
H. G. McDANIEL, + J. A. PITTMAN, M.D., S. R. HILL, M.D. and W. R. STARNES Birmingham, Alabama
I N 1928 Brown described Cushing’s syndrome associated with a nonendocrine tumor [1], and since then there have been a number of such cases reported in association with many different types of tumors. The most common concurrent malignancy is bronchogenic car- cinoma, which in almost every case is of the oat cell type. The next most common tumor is thymoma, and the third is carcinoma of the pancreas [2]. Cushing’s syndrome has also been reported in association with carcinoma of the gallbladder [3], prostate [4], thyroid [5], kidney [6], colon [7], trachea [8], pheochromocytoma [6,9,10], sympathicoblastoma [17] and bronchial adenoma [12]. These reports have stimulated interest in the relationship between hyper- activity of the adrenal cortex and neoplasms. The following case, concerning a man with oat cell carcinoma of the lung and increased adrenal steroid production, resembles a number of others reported in that the patient lacked the classic physical findings of Cushing’s syndrome despite an increased urinary excretion of 17-hydroxycorticosteroids (17-OH). The indi- vidual C19 and C21 steroids have been chroma- tographically separated and quantitated (see Chart I for nomenclature), and the results com- pared with those obtained in normal subjects before and after the administration of ACTH (adrenocorticotropic hormone).
CASE REPORT
The patient (E. V.) was a sixty-nine year old ambulatory white man who was admitted to the Birmingham Veterans Administration Hospital on May 5, 1959, because of an episode of “heaviness” in his arms and chest pain which had persisted for two or three hours the night prior to admission. The
administration of nitroglycerin did not relieve the pain and, during this episode, he had dyspnea, palpita- tions and hypotension. Past history revealed that he had had hypertension for seventeen years, and dyspnea on exertion and angina pectoris for four years. His blood pressure was in the range of 180/100 mm. Hg despite therapy with Serpasil,® 0.5 mg. per day, for the past four years. Onc weck before admis- sion, his doctor had noticed bilateral pedal edema and had prescribed 1 gm. of chlorothiazide daily.
The physical examination revealed a well de- veloped, obese, white man. He was well oriented although somewhat dyspneic during questioning. The blood pressure was 220/104 mm. Hg, pulse 108 and regular, respirations 24 per minute, and the temperature was normal. Numerous senile keratoses were present over the trunk, face and arms. The fundi showed nicking of the veins at arterial junctions but no hemorrhages or exudates. Moist inspiratory rales were heard over the bases of both lungs. The cardiac point of maximal impulse was at the mid- clavicular line in the sixth intercostal space. A grade 1 systolic murmur was heard along the left sternal border. The femoral pulses were strong. The liver edge was palpable 3 cm. below the right costal margin. No striae, pedal edema, buffalo hump, cen- tral obesity, rounding of the face or neurologic abnormalities were present.
The hematocrit was 52 vol. per cent, white blood count 17,000 per cu. mm., blood urea nitrogen 32 mg. per cent and the venous pressure was 115 to 130 mm. of normal saline solution. The arm to tongue circulation time (Decholin®) was eighteen to twenty- two seconds. The serum electrolyte values were sodium 144 mEq. per L., chloride 113 mEq. per L., potassium 5.2 mEq. per L. and carbon dioxide combining power 24 mEq. per L. The serum trans- aminase level was 16 and 41 units on two occasions. An electrocardiogram obtained on admission showed no abnormality. Cardiomegaly and loculated fluid in the right minor fissure were noted on the chest film. A two-hour postprandial blood sugar was 93
* From the Radioisotope and Medical Services, Veterans Administration Hospital, Birmingham, and the Depart- ment of Medicine, University of Alabama Medical Center, Birmingham, Alabama. This work was supported by funds from U. S. Public Health Service Grant CY-5301, the Veterans Administration Endocrine Cooperative Study, and a grant from the G. D. Searle Co. Manuscript received August 13, 1962.
t U. S. P. H. S. Post-Junior Research Fellow.
| Date | Volume (ml./24 hr.) | Creatinine (gm./24 hr.) | 17-OH (mg./24 hr.) | 17-KS (mg./24 hr.) | Aldosterone (blue tctrazolium) |
|---|---|---|---|---|---|
| 6/29/59* | 900 | 1.42 | 26.2 | 18.0 | - 4.7 |
| 7/1/59 | 839 | 1.13 | 25.86 | 16.7 | 14.8 |
| 7/4/59 | 3,320 | 1.71 | 23.46 | 18.33 | 10.0 |
| Normal values ± 1 S. D. t | 6 ± 5 | 15 ± 5 | 6.6 ± 1.9 |
* Average of a forty-eight hour pool. This urine specimen was collected before spironolactone was started. The only medications the patient was receiving were a diuretic (acetazolamide) and digitalis. The second and third speci- mens were collected during spironolactone administration. The patient appeared comfortable during these periods despite his edema.
t For this laboratory.
mg. per cent. An x-ray series of the gastrointestinal tract revealed a small sliding hiatal hernia and probable antral gastritis. Subsequent chest films revealed a peripheral homogenous density and hilar enlargement on the right, suggestive of carcinoma.
While in the hospital the patient had numerous episodes of rapid heart rate, usually appearing thirty minutes after eating. Pedal edema developed (2 plus) refractory to therapy with digitalis, meralluride (Mercuhydrin®) and acetazolamide (Diamox®). Orthopnea occurred at the same time and he was
| Steroid* | Patient (E. V.) | Steroid | Normal Subjects | ||
|---|---|---|---|---|---|
| 6/29/59+ | 7/4/59 | Con- trol | ACTH (day 2) | ||
| A | 0 | 0 | A | 1.4 | 1.5 |
| THA (a and ₿) | 4.4 | 3.2 | THA | 3.5 | 3.0 1.7 |
| «-THA | 1.2 | ||||
| B | 0 | 0 | B | 0.9 | 0.6 |
| THB (a and B) | 3.7 | 9.5 | THB | 5.7 | 6.1 |
| E | 0 | 0 | a-THB | 4.6 | 6.2 |
| THE and a-THE | 30.9 | 10.6 | E | 4.3 | 2.0 |
| F | 5.4 | 0.1 | THE | 30.5 | 20.5 |
| THE | 40.3 | 51.6 | F | 3.6 | 6.5 |
| THS | 7.7 | 7.3 | THE | 23.7 | 30.5 |
| S | 0 | 7.2 | a-THF | 11.5 | 10.0 |
| THQ | 0 | 4.6 | THS | 2.8 | 5.6 |
| THF : THE ratio | 1.30 | 4.87 | THF: THE ratio | 1.15 | 1.97 |
NOTE: The dates and conditions of collection of specimens are as given under Table r. The values during ACTH stimulation, with their controls, were obtained on urine specimens obtained from fifteen healthy young and middle-aged men. After collecting the control urine, ACTH was given at eight hourly intervals, 80 U.S.P. units of the gel intramuscularly per injection, for two days, and the “ACTH urine” was collected the second day.
* See Chart I for abbreviations.
t Average of a forty-eight hour pool.
considered to be in congestive heart failure. An attempt was made to induce diuresis with the oral administration of spironolactone (Aldactone®), 100 mg. every six hours. Control urine samples were collected for determination of baseline steroid excre- tion levels before spironolactone was administered. He was then given spironolactone for five days (June 30 to July 4), then it was discontinued because of the development of a pruritic rash. He was given 1 ml. of meralluride sodium intramuscularly with the last dose of spironolactone, and over the following eighteen hours diuresis occurred and he lost 7 pounds. On the following night he complained of severe chest pain and shortness of breath. A few minutes later he was found pulseless; he died despite all efforts to resus- citate him. No anticoagulants were administered.
The autopsy revealed an anaplastic bronchogenic carcinoma, oat cell type, arising from the bronchus of the lower lobe of the right lung. The tumor had spread to the hilar area, periaortic nodes and adrenal glands. Distal to the carcinoma were multiple abscesses of the lung. There was a small organizing infarct in the lower lobe of the right lung, near the minor fissure.
The heart weighed 620 gm., and both ventricles were hypertrophied. There was moderate athero- sclerosis of the coronary arteries. White fibrous patches were present in the myocardium of the left ventricle. No recent infarct was detectable.
The right adrenal weighed 23 gm., the left 50 gm. after trimming. Both adrenal glands had extensive matastases, with only a rim of normal adrenal tissue remaining. Microscopically the architecture of the cortex was distorted and it was difficult to be sure whether or not it was hyperplastic. The calyces and pelves were not dilated. There was no obstruction of the inferior vena cava by tumor growth. The head was not included in the autopsy.
Urinary steroid levels are given in Tables I, II and III.
CHART I STEROID NOMENCLATURE
C19 Steroids
| E | Etiocholan-3a-ol,17-one | (Etiocholanolone) |
|---|---|---|
| A | Androsten, 3a-ol, 17-one | (Androsterone) |
| DHEA | 5-Androsten-38-ol, 17-one | (Dehydroepiandrosterone) |
| OE | Etiocholan-3a-ol, 11,17-dione | (11-ketoetiocholanolone) |
| OA | Androstan-3a-ol, 11,17-dione | (11-ketoandrosterone) |
| OHA | Androstan-3x, 11-diol, 17-one | (118-hydroxyandrosterone) |
| OHE | Etiocholan-3x, 113-diol, 17-one | (118-hydroxyetiocholanolone) |
| C21 Steroids | ||
| A | 4-Pregnene-21-ol, 3,11,20-trione | (11-dehydrocorticosterone) |
| THA | 5₿ pregnane-3x, 21-diol-116, 20-dione | (Tetrahydro-11-dehydrocorticosterone) |
| allo-THA | 5a pregnane-3, 21-diol-118, 20-dione | (allo-Tetrahydro-11-hydrocorticosterone) |
| B | 4-Pregnene-118, 21-diol-3, 20-dione | (Corticosterone) |
| THB | 56 pregnane-3x, 118, 21-triol-20-one | (Tetrahydrocorticosterone) |
| allo-THB | 5a pregnane-3a, 118, 21-triol-20-one | (allo-Tetrahydrocorticosterone) |
| E | 4-Pregnene-17a, 21-diol-3,11,20-trione | (Cortisone) |
| THE | 58 pregnane-3a, 17a, 21-triol-11,20-dione | (Tetrahydrocortisone) |
| allo-THE | 5a pregnane-3a, 17a, 21-triol-11,20-dione | (allo-Tetrahydrocortisone) |
| F | 4-Pregnene-118, 17a, 21-triol-3,20-dione | (Cortisol) |
| THF | 58 pregnane-3a, 118, 17a, 21-tetrol-20-one | (Tetrahydrocortisol) |
| allo-THF | 5a pregnane-3a, 118, 17a, 21-tetrol-20-one | (allo-Tetrahydrocortisol) |
| S | 4-Pregnene-17a, 21-diol-3, 20-dione | (11-Deoxycortisone) |
| TSH | 56 pregnane-3a, 17a, 21-triol-20-one | (Tetrahydro-11-deoxycortisone) |
| Q | 4-Pregnene-21-ol-3, 20-dione | (11-Deoxycorticosterone) |
| THQ | 56 pregnane-3a, 21-diol, 20-dione | (Tetrahydro-11-deoxycorticosterone) |
| allo-THQ | 5a pregnane-3a, 21-diol, 20-dione | (allo-Tetrahydro-11-deoxycorticosterone) |
COMMENTS
The clinical picture seen in patients with hy- peradrenalcorticism and a nonendocrine tumor is variable. Edema, polyuria and polydipsia are usually present. Diabetes mellitus is almost always found, as is hypertension. The classic physical findings of Cushing’s syndrome have been present in only about half the cases reported. This is said to be due to the fact that hyperadrenocorticism was not present long enough for the classic signs of Cushing’s syn- drome to have developed, since most of these patients have a rapidly fatal course. In fact there is some evidence indicating that the administration of cortisone accelerates the course of bronchogenic carcinoma [13]. These pa- tients are usually older than those with ordinary Cushing’s syndrome, and there is no female predominance.
The tumors found in association with Cush- ing’s syndrome have already been mentioned. It is of interest that oat cell carcinoma of the lung, which makes up only 9 per cent of bron- chogenic carcinomas [14], has been found in almost every case of Cushing’s syndrome
reported in association with cancer of the lung. Cohen et al. reported that the thymomas seen with Cushing’s syndrome are composed entirely of epithelial cells [12]. They found that two
| Steroid | Patient (E. V.) | Normal Subjects | ||
|---|---|---|---|---|
| 6/29/59 | 7/4/59 | Control | ACTH (day 2) | |
| OHE | 15.8 | 16.6 | 7.6 | 11.' |
| OHA | 10.4 | 59.0 | 7.0 | 9.4 |
| OE | 18.3 | 0 | 8.1 | 15.4 |
| OA | 11.8 | 0 | 7.3 | 6.1 |
| C1903 total | 56.3 | 75.6 | 30.0 | 42.8 |
| DHEA | 0 | 0 | 15.2 | 13.0 |
| E | 11.2 | 10.2 | 27.0 | 22.7 |
| A | 6.4 | 4.7 | 17.9 | 13.6 |
| C1902 total | 17.6 | 14.9 | 60.1 | 49.3 |
| E: A ratio | 1.75 | 2.16 | 1.50 | 1.67 |
NOTE: See legends of previous tables and Chart I for abbreviations.
430 Bronchogenic Carcinoma and Adrenocortical Hyperactivity-McDaniel et al.
bronchial adenomas in patients with Cushing’s syndrome closely resembled the thymomas associated with Cushing’s syndrome, and also had some histologic similarities with oat cell carcinoma of the lung. They suggested that these three types of neoplastic cells originate in a common cell type. The pancreatic malignancies have been both islet cell tumors (functioning and nonfunctioning) [15-17], and adenocar- cinoma [18].
The autopsy findings in the cases reported have revealed bilateral hyperplasia of the adrenal glands. These are usually very hyper- plastic, weighing 10 to 20 gm. per gland. One of the patients of Billinghurst et al. [19] had an adrenal cortical adenoma. Metastases to the adrenal glands have been present in about half of the patients with lung cancers and associated Cushing’s syndrome. Histologic examinations of the adrenal glands have shown hyperplasia of the zona fasciculata with encroachment on the zona glomerulosa. Large, peculiar, eosino- philic, vacuolated cells are seen in the zona fasiculata [8,17,20]. Metastatic lesions may or may not be present in the liver and anterior pituitary. Hyaline changes in the basophils of the anterior pituitary have been reported [3,20].
Hypokalemic alkalosis has been present in a large number of these cases [21] and may be accompanied by marked weakness. It has been seen in several patients with none of the physical stigmata of Cushing’s syndrome. The hypo- kalemia has been shown to be due to the loss of potassium through the kidneys. Because of the severe potassium wasting, which is fairly un- common in uncomplicated Cushing’s disease, the aldosterone excretion has been measured and found to be normal in many cases and increased in only a few [4,20,22]. The edema in the patient described herein did not respond to therapy with a potent aldosterone antagonist alone, and his urinary aldosterone values were normal even though he had congestive heart failure and increased 17-hydroxycorticosteroid values.
Bagshawe [21] noted a close correlation between the occurrence of hypokalemic alka- losis and the presence of neoplasms associated with Cushing’s syndrome. In a series of 111 patients with Cushing’s syndrome he found twenty-three patients with hypokalemic alka- losis, and twenty-one of these had either an endocrine or nonendocrine malignancy. Christy
et al. [23] believe that the presence or absence of hypokalemic alkalosis depends upon the amount of cortisol (hydrocortisone) produced by the adrenals. This may be correlated with Bagshawe’s report in that most of his patients with malignancies had very high levels of steroid production, unlike the patient in the present report.
Some patients with bronchogenic carcinoma have had increased 36 metabolites in the urine, suggesting an adrenal carcinoma. A few patients have had a steroid suppression test. The output of steroids decreased in some, showing that the adrenals were under control of a stimulus still responsive to blood levels of glucocorticoid [24,25]. In most patients treated by pituitary radiation or adrenalectomy there has been some regression of the signs and symptoms of adrenal hyperfunction but no patient has lived long enough following removal of his tumor to see whether the symptoms would disappear.
In studying the relationship between non- endocrine cancer and adrenal function, a number of interesting observations have been made. In 1952, Dobriner found 118-hydroxy- etiocholanolone (OHE) in the urine of patients with cancer, but in only two of twenty normal persons. He believed that gonadal and adrenal dysfunction was present in patients with various types of cancer [26]. Subsequent technical improvements have shown that this metabolite is present in the urine of most normal persons. (Table III.) It was, however, present in this patient in abnormally large quantities. Slaun- white et al. [27] found increased conversion of exogenous cortisone to 11-ketoetiocholanolone (OE) and 118-hydroxyetiocholanolone (OHE) in three patients with prostatic cancer and one of three patients with bronchogenic carcinoma. Sholiton et al. [28] have reported loss of the normal diurnal variation in 17-hydroxycorti- costeroids in patients with bronchogenic carci- noma, similar to that seen in patients with uncomplicated Cushing’s syndrome. Sommers [29-31] has made extensive autopsy studies in patients with cancer and found histologic changes in the pituitary, adrenals and gonads. Parker and Sommers [32] and Sholiton et al. [33] found an increased incidence of adrenal hyperplasia in patients dying of cancer, using a cortical width of 2 mm. or more as the criterion of adrenocortical hyperplasia.
Many others have reported finding high AMERICAN JOURNAL OF MEDICINE
steroid levels in patients with various types of cancers [31,34-36]. Cortisone has been shown numerous times to increase the number of takes of transplanted tumors in mice and the incidence of widespread metastases [37-40]. This is thought to be related to the decreased antibody response to tumor tissue and to changes in the ground substance and connective tissue allowing a more rapid spread to tumor cells in tissues.
These findings raise a number of interesting questions. (1) Is the association fortuitous? (2) Is there some common factor which produces both disorders in the same patient? (3) Does the adrenal abnormality come first, then the in- creased steroid production which induces forma- tion or growth of cancer in a susceptible person? (4) Or does the tumor come first and evoke increased adrenal activity? In the case of bronchogenic carcinoma it seems unlikely that the association is simply fortuitous, because of the high incidence of oat cell carcinoma in these patients compared with other patients with bronchogenic carcinoma. At autopsy the over-all incidence of carcinoma in patients with Cushing’s syndrome is about the same as it is for those with myocardial infarction [41].
The best evidence to date indicates that the increased steroid output in patients with non- endocrine tumors and associated Cushing’s syndrome is the result of adrenal cortical stimulation by an ACTH-like substance formed by the tumor. Some neoplasms appear to make substances similar to parathyroid hormone, insulin, antidiuretic hormone or erythropoietin. Increased blood levels of ACTH-like activity have been reported in patients with malig- nancies and Cushing’s syndrome [42-44], and corticotropin-like activity was found in one oat cell carcinoma of the lung associated with Cushing’s syndrome [44]. The pituitary of this same patient (uninvolved with tumor) showed an unusually low concentration of ACTH, con- sistent with the postulate that the tumor was producing a similar substance. Furthermore, the urinary steroid level was not suppressed by the administration of 8 mg. of dexamethasone per day.
The urinary steroid patterns presented in Tables I and II are consistent with this postulate, since they most closely resemble those seen in normal subjects after ACTH stimulation. They do not resemble those seen in the presence of
specific adrenal defects, such as adrenogenital syndrome or hyperaldosteronism, although the finding of compounds S and THQ in one urine specimen is of interest. These metabolites are not normally present even after ACTH stimula- tion and might reflect a relative deficiency of 118 hydroxylase activity. However, the presence of large quantities of E, F, THE and THE is against this simple explanation. It is of interest that in patients with Cushing’s syndrome due to bilateral adrenal hyperplasia the urinary steroid patterns resemble those of this patient in several respects [45]; namely, a low percentage of C:21 metabolites of compounds A and B (including intact A and B) and elevated metabolites of compound F (not including F itself, the per- centage of which remains approximately nor- mal). The very high level of OHA in the second specimen is certainly abnormal. A possible effect of spironolactone on the biosynthesis or metabolism of the steroids in this second speci- men cannot be excluded, even though chromato- graphic studies indicate that this is not a metabolite of spironolactone. The complete absence of DHEA is also noteworthy, especially in connection with the values for S, THS and THQ in the C21 steroid pattern. Although the over-all pattern of the 17-ketosteroids (17-KS) is consistent with ACTH-like stimulation, the total value was not increased. This might be explained by the fact that none of the urinary steroid levels were extremely elevated in this patient so that these values (about 18 mg. per day), which may have been above his basal level, did not exceed the normal range. In some of the other patients described the urinary 17-ketosteroid levels also were elevated.
SUMMARY
A patient is described with oat cell carcinoma of the lung who had increased total 17-hydroxy- corticosteroids and normal total 17-ketosteroids in the urine. The urinary steroid patterns were found to resemble those seen in Cushing’s syn- drome from bilateral adrenal cortical hyper- plasia and in normal subjects after ACTH stimulation. The relationships between non- endocrine tumors and Cushing’s syndrome, and between cancer and adrenocortical hyperfunc- tion, are discussed. It is concluded that the most reasonable explanation for the adrenocortical hyperactivity, in the light of existing knowledge,
VOL. 35. SEPTEMBER 1963
432 Bronchogenic Carcinoma and Adrenocortical Hyperactivity-McDaniel et al.
is that the “nonendocrine” tumor produces a substance with ACTH-like activity.
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