Adrenal Cortical Carcinoma Producing Solely Mineralocorticoid Effect*
LAURANCE V. FOYE, JR., M.D. and THOMAS V. FEICHTMEIR, M.D. San Francisco, California
T HE familiar clinical syndromes produced by adrenal cortical hyperfunction are frequently associated with varying de- grees of electrolyte and water imbalance. These abnormalities, consisting of sodium retention, increased potassium excretion, expansion of the blood volume and, frequently, hypertension, have been reproduced in experimental animals and man by the administration of large doses of 11-desoxycorticosterone1 or with aldosterone.2,3 The metabolic and virilizing abnormalities typical of the spontaneously occurring syn- dromes are not produced by the experimental use of the mineralocorticoids.
The production of electrolyte and water defects by adrenal cortical hyperfunction or tumors in the absence of the metabolic or virilizing effects has not been reported. The authors had the opportunity of studying a patient with an adrenal cortical carcinoma pro- ducing solely mineralocorticoid effect, presuma- bly due to excessive aldosterone secretion.
METHODS
The patient was maintained on a diet provid- ing 5 gm. sodium chloride daily throughout his hospitalization. Daily collections of twenty-four- hour urine specimens were made and serum sodium, potassium, chlorides and CO2 analyses were performed daily during each period of changing clinical state or therapy. Analyses made on the urines included sodium, potassium, chloride, creatinine, 17-ketosteroids and total or free corticoids. During periods of relative stability in the clinical status these measure- ments were performed two to three times each week.
Blood volumes were determined by the radio- chromium-tagged red cell method.4 Excretion of
17-ketosteroid in the urine was measured by the method reported by Drekter et al.5 The Porter- Silber method6 was used to measure urinary free corticoids and the method of Norymberski7 was used to determine total corticoids (17- ketogenic steroids).
CASE REPORT
Patient H. W., a sixty year old Negro man, entered the hospital on November 20, 1953, com- plaining of inability to walk for the previous eight or nine days. He stated that he had been in good health until approximately eight months prior to entry when he noted the gradual onset of severe thirst, polyuria and polydipsia. His appetite remained good and there was no weight loss. Approximately nine days prior to entry he noted the onset of rapid progression of aching and weakness in all extremities. He became unable to lift his arms above the horizontal position or to lift his feet from the floor when standing. There had never been any previous similar episodes.
On his three previous admissions (for hemor- rhoidectomy and anoplasty) dating from May to October 1953, the urine was consistently nega- tive for sugar and acetone, and fasting blood sugars were normal on two occasions. An electro- cardiogram taken in July 1953, showed “LVH with persistent high U waves.” The patient had been hypertensive on all previous admissions. The blood pressure ranged from 200/135 to 176/110. The specific gravity of his urine never exceeded 1.009. Serum urea nitrogen and creatinine determinations were normal on two occasions. In July 1953, a twenty-four-hour urine specimen measured 3,520 cc. and the creatinine clearance was 81 cc. per minute.
Physical examination revealed a well devel- oped, moderately obese, ruddy-faced, elderly
* From the Medical and Pathology Services, Veterans Administration Hospital, San Francisco, Calif., and the Univer- sity of California and Stanford University Medical Schools.
man (Fig. 1), complaining of severe thirst. Blood pressure was 175/112.
The skin was warm and dry and the mucous membranes were very dry. There was no lymph- adenopathy and no venous distention. The eyegrounds showed moderate A-V nicking and generalized arteriolar narrowing. The lungs were clear. The heart was enlarged 3 cm. to the left of the mid-clavicular line in the sixth inter- costal space; rhythm was normal and no mur- murs were heard. The abdomen was soft, without striae or masses. The liver was 1.5 cm. below the right costal margin on inspiration and was non-tender. The spleen was not felt. The genitalia were normal. Deep muscle reflexes were markedly hypoactive, especially the biceps and quadriceps. Muscle power was markedly decreased without evident wasting. The patient was unable to rise from a sitting position. The sensory system was normal.
Laboratory studies on entry were as follows: white cells, 7,800; differential: neutrophils, seg- mented 78 per cent; non-segmented 3 per cent; lymphocytes, 17 per cent; monocytes, 2 per cent; DECEMBER, 1955
hemoglobin, 15.1 gm. per cent; packed cell volume, 42 cc. per cent; and corrected sedi- mentation rate, 11 mm. per hour. Urinalysis revealed a pH of 6.5; specific gravity, 1.005; albumin, trace; sugar, negative; acetone, nega- tive; and centrifuged sediment, negative. Kahn and Kolmer tests were negative. Blood chemis- tries were as follows: urea nitrogen, 10.0 mg. per cent; creatinine, 1.3 mg. per cent; fasting blood sugar (Somogyi), 71 mg. per cent; blood sugar two hours postprandial, 89 mg. per cent; al- bumin, 2.4 gm. per cent; globulin, 1.8 gm. per cent; total cholesterol, 222 mg. per cent; cholesterol esters, 134 mg. per cent; sodium, 150 mEq./L .; potassium, 1.8 mEq./L .; chlo- rides, 90 mEq./L .; CO2 53 mEq./L .; serum cal- cium, 4.55 mEq./L .; phosphorus, 0.74 mM./L .; alkaline phosphatase, 3.8 units (King-Arm- strong). Arterial oxygen saturation 87.0 per cent; venous oxygen saturation 79.5 per cent. Fasting eosinophil count, 36 and 12 per cu. mm. on separate occasions. X-ray of the chest re- vealed only moderate left ventricular enlarge- ment. Skull x-rays were normal. Intravenous
250
200
EOSINOPHILS
150
100
50
60
CORTICOIDS 17-KETOSTEROIDS
mg. /24 hr. URINE
50
40
CORTICOIDS
30
20
15
10
5
17-KETOSTEROIDS
175
WEIGHT
170
Ibs.
165
160
FLUID INTAKE - URINE OUTPUT
7.0
OPERATION
6.0
INTAKE
5.0
LITERS
OUTPUT
4.0
3.0
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SERUM Na”, CI, CO2
140
130
120
110
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100
90
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80
70
K*
60
5.0
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CO2
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40
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Na”, cl
400
K
150
300
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150
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CORTISONE
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ACTH
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8
15
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JAN
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-
1953
26
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1954
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pyelograms showcd a normally functioning up- per urinary tract with no evidence of renal displacement. X-rays did not reveal any evidence of osteoporosis. An electrocardiogram revealed low T waves in V4 through V 6 with depression of the ST segment and U waves in V2 through V5 and was thought to be compatible with left ventricular hypertrophy. Urinary 17-ketosteroid studies were repeatedly normal, ranging from 6 to 15 mg. per twenty-four hours. Urinary corticoid excretions were constantly elevated, the values being 25 to 60 mg. per twenty-four hours (Norymberski method: normal range, 9.6 to
19.2 mg. per twenty-four hours). (Fig. 2.) An electroencephalogram was reported as being mildly, non-focally abnormal. The blood vol- ume was 83 cc. per kg. (normal, 66 cc. per kg.). Biopsy of the biceps muscle revealed swollen fibers showing fatty infiltration and chronic inflammation. (Fig. 3A.)
The fluid intake and urine output ranged be- tween 5 and 7 L. daily and were not influenced by pitressin intravenously or subcutaneously. The urine output responded immediately to restriction of the fluid intake with a resulting severe thirst.
DECEMBER, 1955
On December 3, 1953, the patient was started on a regimen of oral potassium chloride, 100 mEq. daily, with immediate and marked im- provement in his thirst, weakness and abnormal reflexes. This therapy had no effect on the fluid intake and output, the patient’s weight, the steroid excretion, or the fasting blood sugar. The serum sodium decreased to 145 mEq./L .; the serum potassium increased to 4 mEq./L .; the chlorides increased to 105 mEq./L .; and the CO2 decreased to 30 mEq./L. The urinary excretion of potassium rose from 30 mEq. per twenty-four hours to approximately 100 mEq. per twenty-four hours. The electrocardiogram showed return of the T wave and ST segment changes to normal and considerable decrease in the size of the U waves. The arterial oxygen saturation increased to 91 per cent and the venous oxygen saturation decreased to 57 per cent.
On January 4, 1954, a retroperitoneal air study showed a right suprarenal, triangular mass which was thought to represent an adrenal tumor. (Fig. 4.)
On January 18, 1954, bilateral adrenal exploration by the lumbar route was performed.
The left adrenal was found to be normal in size and appearance. However, there was a 4 cm. mass replacing the right adrenal gland which was completely removed. (Fig. 5.) On section this tumor was canary yellow and there was a normal medulla and a small amount of residual cortex tissue. This tumor consisted of three distinct cellular patterns. (Fig. 6.) The patient did very well following surgery and his thirst, strength, fluid intake and output, serum electro- lytes, fasting eosinophil count, blood volume, muscle biopsy (Fig. 3B) and electroencephalo- gram returned to normal. The urine 17-keto- steroids remained normal and the urinary corticoids dropped to a level of 20 mg. per twenty-four hours. The U waves disappeared from the electrocardiogram. The patient was discharged without medications on February 27, 1954.
The patient was readmitted on April 17, 1954, because of return of his thirst, polyuria and polydipsia over the previous ten days. Physical examination revealed a blood pressure of 172/ 128, pulse 82 per minute, temperature 98.4ºF. The liver was 3 cm. below the right costal margin and slightly tender. The neurologic examination was normal. Physical findings were otherwise unchanged since his previous entry. Repeat hemogram, urinalysis, fasting blood sugar and x-rays of the chest and skull were normal. Serum potassium was 2.0 mEq./L .; sodium, 165 mEq./L .; chlorides, 96 mEq./L .; and CO2, 45 mEq./L. The electrocardiogram at this time showed high U waves and the electroencephalogram again was diffusely ab- normal. Excretion of 17-ketosteroid, which was
AMERICAN JOURNAL OF MEDICINE
DECEMBER, 1955
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normal initially, rose terminally to the markedly abnormal value of 278 mg. per twenty-four hours and the urinary corticoid excretion rose to 31 mg. per twenty-four hours (Porter-Silber method: normal, less than 1 mg. per twenty-four hours). The fluid intake and output ranged from 2 to 5 L. per twenty-four hours. Fasting eosino- phil counts showed a decrease from initially normal values to levels of five to twelve cells per cu. mm. A twenty-four-hour urine specimen was analyzed* for aldosterone content.& The resulting value was 12 ug. per 100 minutes (normal 4.8 per 100 minutes), DCA equivalent.
The patient was again started on treatment with potassium chloride supplements, with moderate improvement in his symptomatology and a return to normal of the T and U wave changes present on the electrocardiogram. However, his condition rapidly deteriorated and, on August 15, 1954, masses were felt in the liver for the first time and a x-ray of the chest demon- strated a markedly elevated right diaphragm. Five days later the patient died. Autopsy exam- ination revealed a huge right retroperitoneal tumor mass with numerous metastases to the liver (Fig. 7), lungs and bone marrow. The left adrenal gland was approximately half the normal size. The metastases histologically resembled the cell types present in the original right adrenal tumor.
COMMENTS
This case of adrenal cortical carcinoma is unusual in several respects.
1. The patient on entry had symptoms of severe hypokalemia and clinical findings at- tributable to an excess of mineralocorticoid activity. At no time did the patient demonstrate the “cushingoid” facies or fat distribution, striae, increased venous pressure, generalized edema or impaired carbohydrate metabolism. To our knowledge a case of adrenal tumor producing an isolated mineralocorticoid excess has not been previously reported.
2. The severity of the hypokalemia was such that the patient was incapacitated by muscular weakness; reflexes were nearly absent; muscle biopsy showed degenerative changes; electro- cardiogram showed U waves and ST-T wave changes; electroencephalogram was diffusely abnormal and the arterial oxygen saturation was markedly decreased as was the arteriovenous oxygen difference. All of these findings reverted
* Performed by Dr. John Luetscher.
to normal upon the institution of oral potassium chloride replacement therapy.
The disappearance of the electrocardiogra ST-T abnormalities upon repair of the potassium deficit was quite unexpected since these ab- normalities had been attributed to the left ventricular hypertrophy which clinically per- sisted. However, these electrocardiograma findings reappeared during the patient’s relapse and again disappeared promptly when potas- sium supplements were again administered. (Fig. 8.)
The diffuse electroencephalographic abnor- mality consisted of the presence of regular, slow 7 to 712 CPS waves. The electroencephalogram became normal with potassium replacement but upon relapse it again became diffusely although mildly abnormal. (Fig. 9.) This record was characterized by irregular, slow activity which is probably characteristic of a more severe metabolic defect than the original electro- encephalogram. These changes have been re- ported in untreated cases of Addison’s disease or in Addison’s disease treated only with DOCA.1
The increase in the arterial oxygen saturation (from 87 to 91 per cent) and the arteriovenous oxygen difference (from 7.5 to 34.0 per cent) with potassium replacement suggests that the degree of potassium deficit interfered with the ability of hemoglobin to take up oxygen at the lungs and to release it to the tissues. One of us (T. F.) has since produced severe hypo- kalemia in normal dogs and found a similar decrease in arterial oxygen saturation and A-V oxygen difference which was corrected by potassium replacement.
It is also of interest that during the severe hypokalemia a biceps muscle biopsy revealed muscle cell degeneration and lymphocytic in- filtration, whereas after potassium replacement a biopsy from the same muscle was normal.
We postulate that the abnormalities described are due to hypokalemia, which in turn causes intracellular acidosis and thereby interference with oxygen utilization. The resultant tissue hypoxia readily explains all the abnormalities that were corrected by potassium replacement in this patient.
3. Diabetes insipidus was among the diag- noses initially considered in this case. However, the severe electrolyte abnormalities and the failure of the constant polyuria to respond to pitressin, either intravenously or subcutaneously, rapidly eliminated this diagnosis as a possibil-
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ity. The 5 to 7 L. urine output dropped imme- diately to below 2,000 cc. when water was withheld, although this resulted in severe thirst. We believed that the polyuria was secondary to the severe thirst and resultant polydipsia caused by the marked hypernatremia. The hypernatremia, thirst and polydipsia improved somewhat on potassium replacement and re- turned completely to normal upon removal of the adrenal tumor. A “diabetes insipidus-like” syndrome characterized by thirst, polydipsia,
polyuria, sodium retention and potassium loss has been produced in normal dogs by the administration of DOCA. 9
4. Throughout the initial phase of the pa- tient’s illness and for three months after his adrenalectomy the urinary 17-ketosteroid ex- cretion remained normal. Then coincident with the onset of his gradual decline the excre- tion values began to rise, terminally reaching the value of 278 mg. per twenty-four hours. Throughout his course the urinary corticoids
AMERICAN JOURNAL OF MEDICINE
were elevated and returned to normal levels only during the three months following adre- nalectomy. Thereafter they rose to markedly abnormal levels. During this latter period urinary aldosterone assays were also elevated. Since aldosterone is not measured in the 17-ketosteroid or corticoid tests, and since there was no evidence in this patient of any effects not attributable to mineralocorticoid activity, we are unable to explain the source of these urinary steroids.
SUMMARY
A case of carcinoma of the adrenal cortex producing solely mineralocorticoid effect is presented and some of the manifestations briefly discussed. The abnormalities produced by the resulting severe hypokalemia seem of special interest and suggest impairment of oxygen transport and utilization, with inter- ference with cerebral, myocardial and muscle metabolism.
Acknowledgments: Many people contributed to the study of this case. Our special thanks to Dr. Forrest M. Willett, Dr. Robert Fischer and Dr. Peter Lewis for their assistance and advice, to Miss Barbara Chapman for the steroid analyses, and to Miss Kay Hyde for the prepara- tion of the charts.
REFERENCES
1. THORN, G. W., JENKINS, D., LAIDLAW, J. C., GOETZ, F. C., DINGMAN, J. F., ARONS, W. L., STREETEN, D. H. P. and McCRACKEN, B. H. Pharmacologic aspects of adrenocortical steroids and ACTH in man. New England J. Med., 248: 232, 1953.
2. SIMPSON, S. A., TAIT, J. F. and BUSH, I. E. Secretion of a salt-retaining hormone by the mammalian adrenal cortex. Lancet, 2: 226, 1952.
3. KERWICK, A. and PAWAN, G. L. S. Oral aldosterone, effect in a case of Addison’s disease. Lancet, 2: 162, 1954.
4. REILLY, W. A., FRENCH, R. M., LAU, F. Y. K., SCOTT, K. G. and WHITE, W. E. Whole blood volume determinations by radio-chromium-tagged red cells. Circulation, 9: 571, 1954.
5. DREKTER, I. J., PEARSON, S., BARTCZAK, E. and Mc- GAVACK, T. H. A rapid method for the determina- tion of total urinary 17-ketosteroids. J. Clin. Endocrinol., 7: 795, 1947.
6. PORTER, C. C. and SILBER, R. H. A quantitative color reaction for cortisone and related 17, 21-dihydroxy- 20-ketosteroids. J. Biol. Chem., 185: 201, 1950.
7. NORYMBERSKI, J. K., STUBBS, R. D. and WEST, H. F. Assessment of adrenocortical activity by assay of 17-ketogenic steroids in urine. Lancet, 1: 1276, 1953.
8. LUETSCHER, J. A. and JOHNSON, B. B. Chromato- graphic separation of the sodium-retaining corticoid from the urine of children with nephrosis, com- pared with observations on normal children. J. Clin. Investigation, 33: 276, 1954.
9. RAGAN, C., FERREBEE, J. W., PHYFE, P., ATCHLEY, D. W. and LOEB, R. F. Syndrome of polydipsia and polyuria induced in normal animals by desoxy- corticosterone acetate. Am. J. Physiol., 131: 73, 1940.