ADRENOCORTICAL HYPERPLASIA OCCURRING WITH METASTATIC CARCINOMA OF THE PROSTATE: REPORT OF A CASE EXHIB- ITING INCREASED URINARY ALDOSTERONE AND GLUCOCORTICOID EXCRETION*
GEORGE D. WEBSTER, JR. M.D.t, JOSEPH C. TOUCH- STONE, PH.D. AND MINORU SUZUKI, M.D .;
The Chemical Section, Department of Medicine; the Department of Obstetrics and Gynecology; and the Laboratories of Pathological Anatomy, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
ABSTRACT
The case is presented of a 68-year-old male with extensively metastasizing carcinoma of the prostate, in whom severe hypokaliemic alkalosis developed. The urinary excretion of aldosterone and of glucocorticoids was greatly in- creased and at autopsy bilateral adrenal hyperplasia was found. Despite the elevated glucocorticoid excretion, the only clinical findings suggesting Cushing’s syndrome were hyperglycemia and glycosuria. Limited metabolic studies re- vealed renal wasting of potassium, the constant excretion of an acid urine, and the continued ability to concentrate the urine. Review of the literature sug- gests that there is a causal relationship in the coexistence of adrenal hyper- plasia and cancer of other organs, but it cannot be stated which disease process is primary. In the present case, the prostatic carcinoma seems definitely to have developed first. The possible role of estrogen therapy and castration in the de- velopment of adrenal hyperplasia in this case should be considered.
T HE coexistence of adrenocortical hyperplasia and malignant neo- plasms of other organs is common enough to suggest strongly that this association is not merely coincidental. Kovach and Kyle (1) recently re- viewed 7 cases (including their own) of Cushing’s syndrome associated with undifferentiated carcinoma of the lung. Several other cases have been reported (2-5). The high incidence of thymic tumors in patients with
Received January 10, 1959.
* This investigation was supported in part by research grants H-340 and A-1509 from the National Institutes of Health, U. S. Public Health Service and the C. Mahlon Kline Fund of the Department of Medicine.
t Present address: Department of Medicine, Jackson Memorial Hospital, Miami 36, Florida.
# Present address: Department of Pathology, Barnes Hospital, St. Louis 10, Missouri.
Cushing’s syndrome has been noted in several reviews (6-8). Four cases of pancreatic carcinoma were found among 114 cases of adrenal hyperfunction by Plotz et al. (7). Parker and Sommers (9, 10) recently reported an in- creased incidence of histologic evidence of adrenal hyperplasia in patients dying of cancer as compared with noncancerous controls.
It has been noted that in cases of adrenocortical hyperplasia associated with carcinoma of the lung, profound electrolyte abnormalities develop more frequently than in cases of Cushing’s syndrome, causing speculation about the possible role of aldosterone (1). Urinary excretion of this hor- mone has been determined in 2 cases of bronchial carcinoma associated with marked hypokaliemic alkalosis and elevated glucocorticoid excretion (3, 11); in both, it was found to be low. This report describes a patient with an extensively metastasizing prostatic carcinoma in whom hypokaliemic alkalosis developed. The urinary excretion of aldosterone was elevated, as was that of other cortical hormones, and at autopsy bilateral adrenocortical hyperplasia was found.
CASE HISTORY
W.K. (No. 071074) was a 68-year-old white male, first admitted to the Hospital of the University of Pennsylvania in September 1955, with a three-year history of increas- ing lower urinary-tract obstruction. The past history included an episode described as “hypertensive encephalopathy” in 1953, and episodes of tachycardia for which inter- mittent quinidine therapy had been prescribed. Positive findings included obstruction from a symmetrically enlarged prostate, a blood urea nitrogen level of 15 mg. per 100 ml., a fasting blood sugar level of 78 mg. per 100 ml., and blood pressure 140/90 mm. Hg. A transurethral prostatectomy was performed; histologic examination of the tissue re- vealed adenocarcinoma. The patient then underwent bilateral orchiectomy, and treat- ment with diethylstilbestrol (10 mg. daily) was begun. He was later treated for two months with chlorotrianisene (a synthetic estrogenic compound) in a dosage of 12 mg. daily. In June 1956 he was admitted to another hospital because of a constricting pain in the chest. Blood pressure was 130/70, the blood urea nitrogen level was 27 mg. per 100 ml., and the fasting blood sugar level was 90 mg. per 100 ml. An electrocardiogram showed “evidence of myocardial impairment.” Chlorotrianesine was started again and given for the next fourteen months. In August 1957, he was readmitted to another hospital for evaluation of rectal bleeding. Proctoscopy revealed an extrinsic rectal mass. The concentration of blood urea nitrogen was 25 mg. per 100 ml., and of serum acid phosphatase, 0.5 Bodansky unit per 100 ml. Polyestradiol phosphate was prescribed in a dosage of 40 mg. intramuscularly every two weeks.
In October 1957, the patient entered the Hospital of the University of Pennsylvania for his second and final admission. One week prior to admission he had become confused, lethargic and anorectic. He complained of muscular weakness, especially when climbing stairs. The family had noted a transient “swollen” appearance of his face and abdomen, which had disappeared by the time of admission. Urinary and fecal incontinence had also developed. A review of the past history revealed that for twenty years the patient had had symptoms of chronic constipation which had become worse in the year preceding admission, and for which the patient had treated himself frequently with laxatives. Occasionally treatment would result in diarrhea with 6 to 10 stools daily, but usually
1 to 2 semiformed stools were passed daily. There had been no increase in diarrhea or in the use of laxatives in the weeks prior to admission. There was neither a personal nor a familial history of diabetes mellitus.
On admission, October 24, 1957, the patient was confused, argumentative and un- cooperative. Blood pressure was 150/80 mm. Hg, and temperature, pulse and respira- tions were normal. He appeared well developed and well nourished, but was moderately dehydrated. His skin, facies and fat distribution were normal. Axillary hair was absent and pubic hair was scant. Slight glandular enlargement was palpable in the right breast. The heart was normal except for moderate enlargement. The testes were absent. Rectal examination revealed a stony-hard, irregular, prostatic mass. Patellar and biceps re- flexes were absent.
X-ray examinations of the chest showed no evidence of metastatic disease, but there was segmental atelectasis of the left lower lobe. An intravenous urogram demonstrated normal function of the left kidney and moderate hydronephrosis of the right renal pelvis and ureter.
The initial urine specimen showed a neutral reaction, specific gravity of 1.025, albu- min 4 plus, sugar 3 plus, and a large amount of acetone; the sediment contained many red blood cells. The concentration of fasting blood sugar was 305 mg. per 100 ml., and of blood urea nitrogen 32 mg. per 100 ml. The serum sodium level was 141 mEq., potassium 1.8 mEq., chloride 85 mEq., and carbon dioxide 50.2 mEq. per liter. Alkaline and acid phosphatase levels were 6.1 and 0.5 Shinowara units per 100 ml. respectively. Serum albumin concentration was 2.7 Gm., and globulin 1.8 Gm. per cent. An electrocardiogram showed depression of the ST segments in the precordial leads and in leads I, II, a VL and a VF. The QT interval was .44 second at a rate of 90 per minute.
Hyperglycemia and glycosuria were controlled with 50 units of regular insulin daily. Intravenous potassium chloride was administered, and later oral potassium supplements were well tolerated. The patient seemed somewhat stronger but continued to be con- fused and uncooperative despite improvement in the biochemical abnormalities.
The urine (24-hour specimens) was analyzed in order to determine whether potassium depletion was secondary to renal or to gastro-intestinal loss. During the period of intra- venous potassium repletion the urinary concentration of potassium was 37-55 mEq. per liter, and of sodium 0.5-2.6 mEq. per liter. Although the serum potassium level was still subnormal, it was thought that these findings were not definitely diagnostic of renal wastage of potassium. Controlled metabolic balance studies were then performed.
Metabolic studies. The patient was transferred to the Metabolic Ward and given a synthetic diet containing less than 5 mEq. of potassium per day and 125 mEq. of sodium. The latter value was chosen to avoid stimulation of aldosterone production, since the urine was to be analyzed for aldosterone content during this period. Feces could not be collected.
Serum values and urinary electrolyte values are listed in Table 1 and Figure 1. The low intake of potassium was continued for fifty-seven hours. The urinary potassium excretion was 70 mEq. the day before potassium deprivation when the intake was 180 mEq. On the second day of deprivation, excretion was 46 mEq. despite a progressive fall in serum potassium concentration. During the remaining nine hours of low intake, the patient excreted an additional 32 mEq. of potassium.
In serial electrocardiograms, ST segment depression and QT prolongation which had been present on admission had reverted towards normal by the time potassium restric- tion was begun, and did not recur with the redevelopment of hypokaliemia. However, tachycardia developed with a changing cardiac mechanism. Auricular fibrillation, auricular flutter and paroxysmal auricular tachycardia with block all appeared at various
| Period | Potas- sium intake (mEq.) | Urine* | Blood and serumt | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Vol. (ml.) | Specific gravity | Solute conc. (mOsm./ L.) | pH | Na m Eq. | K m Eq. | CI mEq. | NH3 m Eq. | Titr. ac.# m Eq. | Creat- inine (mg./ 100 ml.) | Na (mEq./ L.) | K (mEq./ L.) | CI (mEq./ L.) | CO2 (mEq./ L.) | pH§ | ||
| 1 (24 hrs.) | 4 | 1200 | 1.028 | 727 | 5.30 | 17 | 54 | 31 | 32 | 26 | 1.5 | 142 | 3.1 | 97 | 31.0 | 7.38 |
| 2 (24 hrs.) | 4 3 | 840 575 | 1.025 1.022 | 665 659 | 5.30 5.25 | 6 17 | 46 32 | 10 31 | 26 15 | 16 11 | 1.8 | 146 | 2.9 | 101 | ||
| (9 hrs.) | 31.3 | 7.40 | ||||||||||||||
| 3(15 hrs.) | 107 | 770 | 1.025 | 681 | 5.38 | 7 | 31 | 15 | 23 | 14 | 1.8 | 149 | 2.6 | 102 | 31.0 | |
* Urine volume and urinary electrolyte values are expressed as total quantity excreted during the period indicated in column 1.
t Blood samples were drawn at the beginning of the period.
# Titratable acidity to pH 7.4.
§ “Arterialized” capillary blood.
times and were unaffected by digitalis and quinidine therapy. Because of this complica- tion potassium repletion was begun, but the tachycardia continued.
Fifteen hours after beginning potassium repletion the metabolic studies were discon- tinued. During the succeeding twenty-four hours fever of 103º F. developed, in associa-
50
*
SERUM VALUES
Balance Period
45
X
DEAL
NA
155
40
CO2
X
00
o
35
*-*
145
o
O
o
30
4.5
25
K
3.5
135
.
·
2.5
·
1.5
+ 200
+ 150
K BALANCE
+ 100
50
Intake
Y
Urine
0
Output
- 50
DAY
0 1 2 3 4 5 6 7 8 9 10 11 12
tion with signs of pneumonia, cardiac decompensation and shock. The patient died the following day.
Steroid studies. Methods and Results. Soon after admission, urine specimens were analyzed for steroid content. The 24-hour excretion of 17-ketosteroids was 17 mg. and 34 mg., and of 17-hydroxycorticoids 34 mg. and 41 mg. (Porter-Silber method).
Urinary aldosterone and glucocorticoid excretion were then measured during the first two days of the metabolic study. The urine was collected over chloroform and the two 24-hour specimens were pooled. The day following collection, the urine was adjusted to pH 4.5 and incubated with @-glucuronidase (Ketodase) for forty-eight hours at 37º C. After extraction with chloroform and ethylacetate the urine was then adjusted to pH 1, allowed to stand for twenty-four hours and re-extracted with chloroform and ethylacc- tate. The combined organic phases were washed with saturated bicarbonate and water and evaporated to dryness in a vacuum at a temperature not over 45° C. Preliminary determinations of alpha-ketolic content by the blue-tetrazolium reduction method of Touchstone and Hsu (12) showed an excretion of 41 mg. per twenty-four hours as com- pared to the normal values of 3-6 mg. The extracts were then subjected to paper chro-
| Compound | Patient | Normal* |
|---|---|---|
| Aldosterone | .06 | .005 |
| Cortisol | 2.1 | .05 |
| Cortisone | 1.2 | .10 |
| Tetrahydrocortisol and tetrahydrocortisonet | 9.2 | 6.0 |
| Tetrahydrocorticosteronet | .5 | .3 |
| Tetrahydro-17-OH-desoxycorticosterone (tetrahydro-S)t | . 6 | .02 |
* Maximum values found in normal subjects.
t Semiquantitative estimates.
matography as previously described in detail (13). The cortisone zone which also con- tained aldosterone and several other alpha-ketolic substances was eluted and rechro- matographed in the butyl-acetate: formamide system described by Mattox and Lewbart (14). This afforded the separation of aldosterone from relatively large quantities of un- known alpha-ketols. Aldosterone, cortisol and cortisone were then determined quantita- tively by the blue-tetrazolium reduction method (12).
In Table 2 are listed the quantitative measurements of aldosterone, cortisol and cortisone, and semi-quantitative estimates of several of the other alpha-ketols in the urine of this patient. Included also are maximum “normal” values determined by these methods. Aldosterone excretion was 60 µg. per twenty-four hours, which represents more than a tenfold increase over the maximum normal excretion. Excretions of cortisol, cortisone and tetrahydro-S were 2.1, 1.2 and 0.6 mg. per twenty-four hours, respectively: these values represent twelve- to fortyfold increases above normal. A more detailed dis- cussion of the steroid pattern in this case is in preparation (15).
Postmortem findings. Autopsy was performed five hours after death. The remnant of prostatic tissue was completely replaced by a large, firm, yellowish-gray mass invading and compressing the urinary bladder, rectum and right uretero-vesical orifice. The tumor was a poorly differentiated adenocarcinoma with blood vessel invasion. Metas-
tases were found in the lungs, spleen, liver, left kidney, adrenals, pituitary and lumbar vertebrae.
The right adrenal weighed 19 Gm., and the left 20 Gm. The cortex of each adrenal measured from 0.2 to 0.3 cm. in thickness. Microscopically, the adrenal cortices showed a striking hyperplasia of the zona fasciculata, with peculiar large eosinophilic cells which were reminiscent of those in the “androgenic” or X zone of the fetal adrenal and which contained abundant lipoid substance. The glomerular zone was inconspicuous and rec- ognizable only in a few microscopic areas (Fig. 2). There were small foci of metastatic tumor cells in the cortex of each adrenal, similar to those seen elsewhere, but the amount of the tumor tissue was not sufficient to influence the total weight of either adrenal sig- nificantly. The pituitary was normal in size, weighing 0.5 Gm. Histologically, acidophilic and chromophobe cells were present in normal proportions in the anterior lobe. Baso- philic cells were dimensionally increased and contained vacuoles of variable size and hyaline granules within their cytoplasm (Crooke’s change; Fig. 3). One area in the an- terior lobe showed a small number of grouped metastatic tumor cells. Sections of the
lumbar vertebral bone marrow demonstrated massive replacement of marrow tissue by similar tumor cells.
Other endocrine organs, including the parathyroid, thyroid and islets of the pancreas, were not remarkable either grossly or microscopically. The kidneys grossly had the coarsely granular surface of nephrosclerosis, and microscopically contained occasional focal areas of cortical stromal fibrosis with sclerosed glomeruli. Although the distal con- voluted tubules showed some dilation, the hydropic changes ascribed to potassium de- pletion were not present. The heart was the seat of small and large foci of myocardial fibrosis, and dissection of the coronary arteries revealed marked atheromatous narrowing of the lumen by thickening of the intima.
A sample of skeletal muscle obtained at autopsy was analyzed for sodium, potassium and chloride content. The results, expressed as mEq. per 100 Gm. of fat-free dry tissue are listed in Table 3, together with normal values (16).
| Electrolytes (mEq./100 Gm. of fat-free solids) | |||
|---|---|---|---|
| K | Na | Cl | |
| Patient W.K. | 35 | 18 | 15.1 |
| Normal subjects* | 42.2±2.6 | 15.1±2.9 | 8.6±1.8 |
* Talso et al. (16).
DISCUSSION
Urinary steroid excretion
This patient’s pattern of elevated glucocorticoid excretion was similar to that in other cases of adrenal hyperplasia (17). The excretion of the re- duced form of Substance S, though elevated, was not of the order of magni- tude seen in cases of adrenocortical carcinoma (18). The more significant finding is the elevated output of aldosterone; normal excretion of this hormone is the usual finding in patients with adrenal hyperplasia (3, 15, 19) although moderate increases have been reported (19, 20). The reports of normal aldosterone excretion in 2 cases of adrenal hyperplasia associated with lung tumors is perhaps unexpected, since these patients exhibited marked electrolyte abnormalities (3, 11).
It is of interest that in our patient the hyperplasia histologically ap- peared to be of the zona fasciculata; hyperplasia of the zona glomerulosa was identifiable only in a few microscopic foci. It has been stated that aldo- sterone production normally takes place in the zona glomerulosa, at least in the rat and the cow (21).
In view of the large quantities of glucocorticoids excreted daily, the absence of clinical features of Cushing’s syndrome was striking. The only manifestations detected were hyperglycemia and glycosuria. The most
obvious explanation is that elevated glucocorticoid production had not been present long enough for the development of the expected classic changes. However, Brooks (22) compiled the available data on urinary glucocorticoids in the reported cases of primary aldosteronism and pointed out that although the rates of excretion of these steroids were moderately to markedly elevated in several patients, in none did the usual appear- ance of Cushing’s syndrome develop.
Urinary potassium excretion
Because of the patient’s history of constant use of laxatives, it was nec- essary to establish whether potassium depletion was caused by gastro- intestinal or by renal loss. It is stated that a urinary potassium excretion of less than 20 mEq. per day by a hypokaliemic patient exonerates the kidneys as the pathway for depletion (22), but exceptions to this are to be found in the literature (23, 24). Conversely, the daily excretion of more than 20 mEq. of potassium by a hypokaliemic patient does not necessarily indicate deficient renal conservation, if potassium repletion is under way. Therefore, a trial of potassium deprivation may be necessary to establish renal wasting. The subject of this report showed no tendency to conserve potassium over a 57-hour period of deprivation, indicating that renal loss was more important than gastro-intestinal loss in the development of his potassium depletion.
Acidification of urine
Whereas it is stated that patients with primary aldosteronism character- istically excrete a neutral or alkaline urine (25), this patient excreted an acid urine. During the first two days of potassium deprivation, the urine pH was 5.3 and the average 24-hour excretions of ammonia and titratable acidity were 29 mEq. and 21 mEq., respectively (Table 1). The diet at this time contained a slight excess of fixed cation.
Studies by several investigators (26-29) of mechanisms for the acidifica- tion of urine in patients with primary aldosteronism have shown a normal to moderately decreased capacity for the excretion of hydrogen ion; how- ever, a greater-than-normal proportion of this is excreted as ammonia and the urinary pH is increased. This pattern is the same as that seen in experi- mental potassium depletion (30, 31). Patients with primary aldosteronism recover the capacity to excrete urine with an acid pH when potassium re- pletion is accomplished either before or after removal of the adrenocortical tumor. It therefore seems probable that this defect results from potassium depletion (27, 29).
A possible explanation for the ability of Patient W.K. to excrete an acid urine may be that potassium repletion was complete before measurements
of urine pH were made. However, hypokaliemia was still present and the potassium content of skeletal muscle obtained post mortem (Table 3) was reduced to a degree comparable to that of the patient reported by Chalmers et al. (26).
Concentration of urine
Most patients with potassium depletion are unable to produce a con- centrated urine (32). Patient W.K. consistently excreted urine with a specific gravity greater than 1.020. Estimation of the effect of glycosuria on these measurements was not possible during the first days of observa- tion when depletion was most severe, but during the period of potassium deprivation the specific gravity remained high and the urine solute concen- tration fell only slightly (Table 1). This finding correlates well with the lack of potassium depletion nephropathy noted as autopsy and, as in the case of urinary acidity, might be taken as further evidence that potassium depletion was not profound.
Relationship of adrenal hyperplasia to prostatic carcinoma
The relationship between the adrenal hyperplasia and the carcinoma of the prostate can only be speculated upon, in the light of present knowledge. The other reported cases of clinically apparent adrenocortical hyperplasia co-existing with cancer elsewhere in the body were mainly in patients with pulmonary tumors. Parker and Sommers (9), however, approaching the question primarily from the cancer standpoint, reported a statistically sig- nificant increase in the incidence of histologic adrenocortical hyperplasia in patients with any type of carcinoma (5.9 per cent) as compared to patients without carcinoma (3.1 per cent). Adrenal hyperplasia was more common when more than one type of carcinoma was present, and when the primary growth was located in the respiratory tract, prostate or gastro-intestinal tract. In a later study limited to cases of prostatic carcinoma, the results were similar (10). None of these patients was known to have had clinical or biochemical evidence of adrenal hyperactivity. The authors stated that there appeared to be no relationship between the incidence of adrenal hyperplasia and the degree of wasting or stress, at least as evaluated by loss of weight. It should be emphasized that the diagnosis of adrenocortical hyperplasia in these studies was based upon the width of the cortex in mi- croscopic sections. It is well known that estimation of the functional status of the adrenal by morphologic techniques is uncertain.
Even if one accepts the foregoing data as evidence that the association of adrenal hyperplasia and carcinoma is more than coincidental, it does not answer the question of whether the adrenal plays a part in the pathogenesis of carcinoma or whether the hyperplasia results from some stimulation,
direct or indirect, of the adrenal by the carcinoma. That the adrenal is stimulated by the carcinoma is suggested by other histologic studies show- ing an even greater incidence of changes in the anterior pituitary in pa- tients with carcinoma as compared to patients without carcinoma (10, 33, 34). These alterations in the pituitary, which consist of “Crooke’s change” and hypertrophy of the “amphophilic” cells, are thought to be definite evidence of adrenal hyperactivity.
In the subject of the present report, the adrenal hyperplasia would seem definitely to have developed sometime following the appearance of the prostatic carcinoma. It is not known whether the metastatic cells in the adrenals and pituitary are an important finding: they were not found in some of the previous cases. It would seem unlikely that metastatic tissue per se exerts a stimulatory effect upon the adrenals. If such stimulation existed, adrenal hyperplasia might be expected to be even more common because of the frequency of metastasis to the adrenals, especially from prostatic carcinoma.
Castration and estrogen therapy are still other factors which should be considered as possibly playing a role in the etiology of the adrenal hyper- plasia in this case. Under certain conditions castration and estrogenic stimulation lead to adrenal hyperplasia and pituitary adenomata in experi- mental animals (35). The higher incidence of Cushing’s syndrome in fe- males as compared to males (7) suggests that estrogenic activity may play a part in this condition in the human subject.
Acknowledgments
The authors are grateful to Dr. Boland Hughes, who kindly allowed us to carry out these studies on his patient. Our thanks go also to Dr. Peter Kohler for his help in the management of the patient, and to Dr. H. T. Enterline for reviewing the pathologic ma- terial. The aid of Mrs. Clasina Ingwerson and the nursing staff of the Metabolic Unit was invaluable.
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