Adrenocortical Hyperplasia Associated with Bronchogenic Carcinoma
BRYAN HUDSON, M.D. AND JAMES EVANS, M.B., B.S. Diabetic and Metabolic Unit, Alfred Hospital, Prahran, Victoria, Australia
AT N ENIGMATIC group of extrapul- monary syndromes is now known to be associated with bronchogenic car- cinoma (1). The combination of this disease with adrenocortical hyperplasia has been recorded on several occasions since it was first described by Hurst Brown in 1928 (2-17). In most reports, attention has been drawn to distinctive changes in plasma electrolyte concen- trations, hypokalemia and alkalosis be- ing conspicuous abnormalities. Although basal levels of urinary steroids have been recorded in a number of patients, only occasional reference has been made to the changes in these levels following corticotrophin (ACTH) or other treat- ments (17).
The purpose of this report is to de- scribe the clinical features and labora- tory findings of a patient in whom the association between bronchogenic car- cinoma and adrenocortical hyperplasia existed, and in whom changes in the levels of plasma and urinary steroids fol- lowing treatment with ACTH, SU-4885 [2-methyl-1,2-bis- (3 pyridil)-1-propa- none; Metopiron-Ciba’] and dexa- methasone were investigated.
Case Report
J. G., a 64-year-old male, was admitted to the hospital on March 10, 1960, with
1 We are indebted to Dr. V. G. Balmer, Ciba Co. Pty. Ltd., Australia, for the supply of Metopiron used in this study.
ABSTRACT. A patient is described in whom adrenocortical hyperplasia and bronchogenic carcinoma were shown to coexist. The re- sponses of this patient to treatment with the 118-hydroxylase inhibitor SU-4885, suppres- sion with dexamethasone and stimulation with ACTH are presented. Because of a paradoxic response to these various stimuli, it was believed that this patient was suffer- ing from an adrenocortical tumor. The pos- sible reasons for this error are analyzed.
a provisonal diagnosis of diabetic ketosis. He stated that he had been well until seven days before admission, when he noted dryness of the mouth, and 48 hours later he became thirsty and weak and passed excessive quantities of urine. He complained of nausea and vomiting for three days prior to admission.
He denied other symptoms-in par- ticular, cough, weight change or ab- normal bruising. Three years previously a subtotal thyroidectomy had been per- formed for toxic nodular goiter, follow- ing which his health had been excellent. Prior to this operation he had smoked 40 cigarettes per day, but had since ceased.
One sister had been treated for dia- betes mellitus; there was no family history of cancer.
Physical examination revealed a well- built middle-aged man who, apart from occasional bouts of nausea and vomiting, was in no serious distress. Other than hypertension (B.P. 190/110) and gly- cosuria (2%), he showed none of the classic stigmata of Cushing’s syndrome. Striae, obesity and bruising were absent. Apart from minimal sacral and ankle
edema, the remainder of the physical examination showed no abnormality. No clubbing of the fingers was noted.
Glucose and ketone bodies were pres- ent in the urine but albumin was not detected.
Course in Hospital
The provisional diagnosis of diabetic ketosis was revised once the results of chemical examination of the patient’s plasma became known. Fluid loss was corrected and 50 units of regular insulin were given, but no other specific ther- apy was administered.
The presence of increased adreno- cortical function, suggested by the ob- servation of hypokalemia and alkalosis in plasma, was confirmed by the finding of abnormally high levels of 17-hydroxy- steroids (17-OH-CS) in the plasma and of 17-ketogenic (17-KGS) and keto- steroids (17-KS) in the urine.
The results of laboratory investiga- tions performed during the first few hospital days are summarized in Table
1. Radiologic examination showed the skull to be within normal limits and the lung fields to be moderately congested, with some widening of the superior mediastinal shadow. No significant ab- normalities were observed in the cer- vical, dorsal or lumbar vertebrae.
Six days after admission, the patient was placed on a diet containing approxi- mately 40 mEq of sodium and 110 mEq of potassium per day and, although there was an increase in the concentra- tion of plasma potassium (4.0-4.2 mEq /liter), alkalosis still persisted (31-36 mmole/liter) and the patient occasion- ally complained of muscle weakness. During this period the patient showed no remarkable physical changes; in par- ticular, none of the features normally associated with Cushing’s syndrome be- came manifest. Over a three-week period, however, he developed unequivocal club- bing of the fingers.
Although steroid levels in urine and plasma confirmed the presence of in- creased adrenocortical function, doubt
| Examination | Results | |
|---|---|---|
| Hemoglobin | 12.6 g/100 ml | |
| Leukocytes | 10,000/cu mm Mature neutrophils 8,200; band forms 1,100; lymphocytes 500; monocytes 200/cu mm | |
| Glucose Tolerance | Fasting | 205 mg/100 ml |
| (50 g glucose orally) | ¿ hour | 250 mg/100 ml |
| 1 hour | 300 mg/100 ml | |
| 1 } hours | 290 mg/100 ml | |
| 2 hours | 255 mg/100 ml | |
| Plasma Electrolytes | Na 150 | Cl. 85 |
| (mEq/liter) | K 2.0 | HCO3 43 |
| Ca 4.9 | Prot. 17 | |
| pH 7.51 | Urea 25 mg/100 ml | |
| Plasma 17-OH-CS | 62.1 | |
| (ug/100 ml) | ||
| Urinary KGS KS mg/24 hr | 225.2 | |
| 57.1 | ||
| ECG | Flattened T waves. Accentuated U waves. Suggestive of hypokalemia. | |
remained as to the nature of this lesion. Because of the widening of the superior mediastinum, with tracheal compres- sion and esophageal displacement, and the presence of finger clubbing, bron- choscopy was performed. This confirmed the presence of tracheal narrowing but showed no evidence of an intrinsic bronchial lesion.
Because the pattern of response of urinary and plasma steroids to the ad- ministration of dexamethasone and of SU-4885 suggested the presence of an autonomous lesion, presacral air insuf- flation was performed. Twelve hundred ml of air was introduced presacrally and, in combination with intravenous pyelog- raphy, the adrenal areas were examined by tomography. The left kidney was thought to be displaced downward, and on its upper pole was an apparently lobulated tumor with dimensions of ap- proximately 9 ×6 cm. The right adrenal shadow was clearly outlined and was thought to be a little larger than normal.
At operation, performed 32 days after admission, the left adrenal gland was ex- posed through a lumbar incision, was found to be enlarged and nodular, and was removed. The right adrenal, al- though not seen, was palpated, was estimated to be normal in size and was not removed. Manual exploration of the left lung and pleural cavity failed to detect any abnormalities.
The adrenal, which weighed 30 grams, showed marked lobulation to naked eye examination; and histologically there was diffuse adrenocortical hyperplasia involving principally the zona fascicu- lata. No metastases were found in the gland.
For the first week after surgery the patient’s convalescence was uneventful. Supportive therapy with cortisone ace- tate, initially in doses of 300 mg per day, was reduced to 75 mg per day at the
end of this time. However, physical and radiologic signs thought to be consistent with collapse of the left lower lobe were noted one week postoperatively. By the tenth postoperative day x-ray films of the chest, despite physiotherapy and antibiotics, showed a dense opacity in the left midzone, extending from the hilum. At about the same time, marked peripheral edema appeared, which be- came less after diuretics. The patient died suddenly on the twelfth postoper- ative day.
Autopsy Findings
Autopsy was performed 12 hours after death. The body, that of a well- nourished middle-aged man, showed edema of the lower limbs and clubbing of the fingers.
Examination of the lungs showed that the bronchus of the left lower lobe was surrounded, near its origin, by a small area of dense white tissue, clearly neo- plastic in nature. This extended into an area of pneumonic consolidation that reached into the apex of the left lower lobe. Lymph nodes in the hilum, the su- perior and posterior mediastinum were en- larged and soft and appeared inflamed. Microscopically, the area of hard tissue surrounding the left lobe bronchus was seen to arise from and to infiltrate the bronchial wall. It consisted of sheets of poorly differentiated tumor cells and was regarded as being an “oat cell” carcinoma. The tumor tissue also had invaded the parenchyma of the left lower lobe diffusely and was responsible for the pneumonic consolidation seen on naked-eye examination. All enlarged lymph nodes were found to be infiltrated with partially necrotic cancer tissue.
Nodules of tumor tissue were found throughout the substance of the liver; the largest, which had the appearance of an abscess cavity about 5 cm in diam-
eter, was filled with opalescent fluid. Microscopically, all nodules were found to be composed of poorly differentiated cancer tissue similar to that found in the lung. Stroma was virtually absent and necrosis was conspicuous.
The pancreas showed both old and recent inflammation and was surrounded by several areas of fat necrosis.
The right adrenal gland, which weighed 15 g, showed diffuse hyperplasia that appeared to involve principally the zona fasciculata. There were no metas- tases found in the gland.
The trachea showed narrowing in the region of the superior mediastinum, but the cause for this was not apparent.
The pituitary was normal in size but, microscopically, showed hyalinization in the basophils, the changes being con- sistent with those originally described by Crooke (18).
Methods
Urine samples were collected over chloro- form and aliquots stored at 4 C. In the event of delay between collection and proc- essing, a large bulk of the sample was ex- tracted at pH 2 by the method of Edwards et al. (19), and the ether/ethanol extract, after reduction in volume, was stored in a concentrated form at -15 C. For the collec- tion of plasma samples, heparin was used as anticoagulant, the cells and plasma being separated immediately after collection and the plasma being stored frozen.
Urinary 17-ketosteroids were determined by the method of Sheath (20) and 17-keto- genic steroids by the method of Norym- verski et al. (21). Fractionation of urinary 17-ketosteroids was performed by the method of Kellie and Wade (22), except that solvolysis (23) was used for the hydrolysis of ketosteroid sulfates instead of continuous extraction at pH 1. Cortisol metabolites (free cortisol, tetrahydrocortisone and tetra- hydrocortisol) were estimated after enzymat- ic hydrolysis and extraction of the sample with ethyl acetate, followed by preliminary paper chromatography in the system tolu- ene/ethylene glycol (24). The zone more polar than cortisone was rechromatographed
in the E2B system (25). After location of free cortisol and tetrahydro metabolites with blue tetrazolium, the areas were eluted and the steroids were estimated as Porter-Silber (26) chromogens.
Plasma 17-OH-CS was estimated by the method of Peterson et al. (27), but for the estimation of plasma 17-OH-CS after SU- 4885 the modification described by Gold et al. (28) was adopted. Plasma dehydro- epiandrosterone (DHEA) and total 17- ketosteroids were estimated by the method of Hudson and Oertel (29).
Results of Steroid Studies
Basal Values. Urinary excretion of 17- ketosteroids ranged between 57.2 and 79.1 and of 17-ketogenic steroids be- tween 225 and 264 mg per day. The plasma 17-OH-CS was 93.3 and 108.4 ug per 100 ml on the third day after admis- sion, and on the sixteenth hospital day these had risen to 156.4 and 159.3 ug per 100 ml, the samples being collected at 8.00 AM and 5.30 PM on each day. Plasma DHEA and total 17-ketosteroids were 251.5 and 329.4 ug per 100 ml, re- spectively (normal mean values: 131 and 181 µg per 100 ml) (29).
Fractionation of urinary 17-ketoste- roids gave the following values (mg per 24 hours as DHEA equivalents):
| DHEA | 6.1 |
| Androsterone | 7.4 |
| Etiocholanolone | 9.4 |
| 11-Oxy-17-ketosteroids | 17.2 |
Cortisol metabolites were estimated to be present in the following amounts (mg per 24 hours):
| Free cortisol | 5.6 |
| Tetrahydrocortisol | 37.9 |
| Tetrahydrocortisone | 18.6 |
Suppression with Dexamethasone .? Two dose levels were used (30): 0.5 mg and 2.0 mg every six hours for two consecu- tive two-day periods. The levels of
2 Generously donated by Mr. John Fogarty, of Merck Sharp & Dohme (Aust.) Pty. Ltd.
ACTH 40 W. I.V.
SU4885 750 mqm Q.Q.H.
300
(6 HOURS)
PLASMA
17-OHCS 160.2
89.1
200
100
DEX AMETHASONE
1
0.5 MG Q.I.D. 1
2.0MG Q.I.D
PLASMA IZOHCS 81-8
4
URINARY
100-7
17.KETOGENIC STEROIDS
200
100
DAYS
MGM/24 HR.
urinary 17-ketogenic steroids during this treatment are shown in Fig. 1. No signifi- cant changes were observed in the levels of 17-ketosteroids.
Response to ACTH. The response of plasma 17-OH-CS to a six-hour intra- venous infusion of ACTH (40 IU) showed the following results:
| Time (hr) | 0 | 2 | 4 | . 6 |
| Plasma level (µg/100 ml) | 119.7 | 138.3 | 140.0 | 164.1 |
On the same day, the level of urinary 17- ketogenic steroids rose from 240 to 301 mg per day (Fig. 1), but there was very little alteration in the level of urinary 17- ketosteroids.
Response to SU-4885. There was an appreciable fall in the level of urinary 17-ketogenic steroids following the oral administration of SU-4885 in doses of 750 mg every four hours for 48 hours (31). These changes are depicted in Fig.
1, in which are noted also the levels of plasma 17-OH-CS just prior to and at the termination of treatment with SU- 4885. These levels also fell significantly. No significant changes were observed in the levels of urinary 17-ketosteroids dur- ing this period.
Discussion
If the association of bronchogenic carcinoma and adrenal hyperplasia are accepted as being more than fortuitous, and as a disease entity per se, then this patient might reasonably be described as a “typical” example. The combina- tion of hypertension, impaired carbo- hydrate tolerance, hypokalemia, alka- losis and a rapid downhill course have been observed commonly in other pa- tients. It is of interest that none of the overt clinical manifestations of Cush- ing’s syndrome were present in this pa- tient nor in more than half the other pa- tients previously recorded. Since these features were absent, despite markedly elevated levels of plasma cortisol, it seems reasonable to surmise that the de- velopment of increased adrenocortical function had been sudden and, by the time the patient sought medical atten- tion, of short duration. The presence of hypokalemia and alkalosis, apparently so typical of this disease, cannot always be explained on the basis of increased secretion of aldosterone since, in the few patients in whom this was determined, it was found to be normal.
The high levels of free cortisol in both plasma and urine indicate that this steroid was the principal secretory prod- uct of the hyperplastic adrenals. This is further reflected by the high levels of urinary tetrahydrocortisol and tetra- hydrocortisone, and by the abnormally high levels of 11-oxygenated-17-keto- steroids. The high values for urinary DHEA, androsterone and etiocholano-
lone suggest that all pathways of steroid biosynthesis were stimulated in this pa- tient, the change in the steroid produc- tion being quantitative rather than qualitative.
The main problem in this particular patient was to decide whether or not the adrenal secretion was autonomous. In attempting to answer this question, paradoxic responses were observed fol- lowing suppression with dexamethasone, stimulation with ACTH and treatment with SU-4885. The failure of urinary 17- ketogenic steroid excretion and of the levels of plasma 17-OH-CS to be de- pressed significantly by increasing doses of dexamethasone permitted one of two conclusions: either the adrenal tissue was functioning autonomously or the source of ACTH was resistant to the usual restraint exerted by such doses of synthetic steroid. In this patient it was concluded erroneously that the adrenal cortex was functioning autonomously and was therefore the site of tumor. From the findings of Meador et al. (32) that bronchial tumor tissue from a similar patient showed corticotrophic activity, it seems reasonable to postu- late that a similar mechanism was oper- ating in this patient. If the cancer tissue was producing a corticotrophin-like sub- stance- and for this we have no direct evidence-it presumably was un- affected by the normal mechanisms that regulate the release of pituitary ACTH.
Assuming that this postulate is cor- rect, the responses to SU-4885 and to exogenous ACTH are now interpreted more readily. The extent of the response (44ug/100 ml) of plasma 17-OH-CS to ACTH in this patient indicated that the adrenal cortex was able to be stimulated and that an autonomous adrenocortical lesion was unlikely to be present. This observation, apparently paradoxic in view of the failure to suppress plasma or
urinary steroid levels with dexametha- sone, may be interpreted now on the basis that the bronchial tumor was secreting a corticotrophic substance that resulted in an increased adrenocortical mass, and hence in an increased re- sponsiveness to ACTH. Additional evi- dence of chronic corticotrophic activity is suggested by the weight of the adrenals (45 g), which is unusual even for conventional adrenal hyperplasia.
Changes in the levels of urinary 17- KGS following SU-4885 were considered to indicate the presence of an autono- mous lesion since, in other patients with Cushing’s syndrome resulting from ad- renocortical hyperplasia, exaggerated re- sponses have been observed (31). Fur- ther, in patients with Cushing’s syn- drome due to adrenal tumor, either no change or a fall in the rate of steroid ex- cretion has been noted. Such should not have been the only interpretation, how- ever, since it is reasonable to assume that this would be the response if the source of ACTH was unaffected by the normal mechanisms that regulate its se- cretion from the anterior pituitary.
It is of some interest to note that there was a significant fall in the levels of urinary 17-KGS during treatment with SU-4885. This observation suggests that this drug may have an action other than that commonly assigned to it (118- hydroxylase inhibition) and that steroid biosynthesis may be arrested at some stage prior to 17-hydroxylation, result- ing in the production of steroid hor- mones whose metabolites are not esti- mated as 17-KGS. In this patient in- sufficient urine was available to examine this possibility further.
Some details of two patients with bronchogenic carcinoma and adreno- cortical hyperplasia have been recorded by Christy. Although no figures are quoted, “a response to SU-4885” was
observed, in contrast with the observa- tions made in our patient.
In the majority of patients with Cush- ing’s syndrome, the cause of the disorder can be defined on chemical grounds. Thus, following stimulation with ACTH or suppression with dexamethasone, changes in the levels of urinary or plasma steroids usually enable the differentia- tion to be made between adrenocortical hyperplasia and tumor. Although re- ports on changes in steroid excretion in patients with Cushing’s syndrome in re- sponse to treatment with SU-4885 are not numerous, it seems clear that urinary 17-KGS or 17-OH-CS in patients with “ordinary” Cushing’s syndrome due to adrenocortical hyperplasia show an ex- aggerated rise following the administra- tion of this drug. By contrast, in Cush- ing’s syndrome due to tumor, there usually is little or no change in the rate of steroid excretion of such metabolites after such treatment. In view of the limited evidence in patients with this syndrome, we can do no more than speculate whether or not this absence of response to treatment with SU-4885 and dexamethasone may be a unique feature of Cushing’s syndrome due to adreno- cortical hyperplasia and bronchogenic carcinoma.
Acknowledgments
We wish to thank Miss Ida Ekkel for her valuable technical assistance with steroid deter- minations, Dr. K. N. Morris for his surgical as- sistance and Dr. A. V. Jackson, Director, De- partment of Pathology, for the autopsy findings.
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