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Hyperaldosteronism Due to Unsuspected Adrenal carcinoma: Discovery During Investigation of hypertension in a Young Woman
0022-534 7/81/1266-0783$02.00/0 THE JOURNAL OF UROLOGY
Vol. 126, December Printed in U.S. A..
Copyi:ight © 1981 by The Williams & Wilkins Co.
HYPERALDOSTERONISM DUE TO UNSUSPECTED ADRENAL CARCINOMA: DISCOVERY DURING INVESTIGATION OF HYPERTENSION IN A YOUNG WOMAN CLARENCE K GRIM, ARUNABHA GANGULY, MOO-NAM YUM, JOHN P. DONOHUE AND MYRON H. WEINBERGER From the Departments of Internal Medicine, Pathology and Urology, Indiana University School of Medicine, Indianapolis, Indiana
ABSTRACT
During investigation for hypertension a 19-year-old black woman was found to have an unsuspected adrenal carcinoma. Hyperaldosteronism was established as the cause of the hypertension by observing suppressed plasma renin activity and nonsuppressible plasma aldoste:rone concentration. The causal relationship was confirmed by a cure of the hypertension and a return in the responsiveness of the renin-angiotensin-aldosterone axis to normal after :removal of the carcinoma. This :report emphasizes the value of a comprehensive investigation of hypertension, especially in young patients. Adrenal carcinoma causing hyperaldosteronism, first reand Feichtmeir, 1 is rare. Patients usually present with hypertension and severe hypokalemia, and usually have been >30 years old but only a small number have been reported. 2- 5 We report the incidental discovery of an adrenal carcinoma causing hyperaldosteronism in a young woman during the systematic investigation of hypertension using a standardized and comprehensive protocol. 6 CASE REPORT
A 19-year-old black woman was referred for evaluation of hypertension detected during a pre-employment physical examination. A 3-year history of well controlled hypertension was elicited. The menstrual and medical history was normal. Family history was negative for hypertension or adrenal disease. The woman had not received any medication for 4 to 5 months. Blood pressure ranged between 140 to 150/100 to 115 mm. Hg and pulse was 92 per minute. Fine facial hair and small breasts were noted. The remainder of the examination, including external genitalia, was normal. The patient had mild anemia. Serum sodium was 138 mEq./1. and potassium ranged between 3.4 and 3.6 mEq./1. Urinary 17-ketosteroids were 53.2 mg./dl. and 17hydroxycorticosteroids were 5.6 mg./dl. Vanillyl mandelic acid and metanephrine values were normal. Selective abdominal angiography revealed a large, vascular, left suprarenal mass, with areas of calcification (fig. 1, A). The presumptive radiologic interpretation of a probable pheochromocytoma was not supported by urinary catecholamine measurements. Adrenal venography also suggested a vascular adrenal mass lesion (fig. 1, B) and an adrenal scan using 131 iodine iodocholesterol showed no uptake by the left adrenal gland (fig. 2). To evaluate the renin-angiotensin-aldosterone axis a standardized protocol, including a saline infusion, was performed, followed by furosemide administration as described. 7 Blood was collected before and at the end of the infusion for electrolytes, plasma renin activity and aldosterone concentration. The next day the patient received 3 doses of 40 mg. furosemide at 10 a.m., and 2 and 6 p.m. The sodium intake was restricted to 10 mEq. during that day. Blood was drawn before medication and after 2 hours of ambulation on the next day for the same measurements. These studies were repeated 10 months postoperatively. Plasma renin activity, cortisol and aldosterone concentration were measured by radioimmunoassays. 6 ComparAccepted for publication November 7, 1980. Supported in part by United States Public Health Service Grant HL-14159, Specialized Center of Research in Hypertension and R000750, General Clinical Research Center. 783
ative values from 114 normal subjects and from 236 patients with well characterized forms of primary and secondary hypertension have been reported previously. 6 The results are shown in the table and demonstrate renin suppression with nonsuppressible aldosterone values that returned to normal postoperatively. On surgical exploration a large left adrenal tumor was found and removed. The tumor weighed 150 gm. and measured 10 7.5 X 5 cm. There was no gross evidence of invasion of surrounding tissues or lymphatics by the encapsulated tumor. The cut surface of the tumor was pinkish to gray-tan in color, with a large central area of fibrosis and focal calcification. Small speckles were seen scattered on the cut surface. Only a thin rim of adrenal cortical tissue was recognized in the subcapsular area. Microscopically, the tumor was found to be highly vas·· cular and consisted of large polygonal cells with abundant, eosinophilic cytoplasm (fig. 3). Chromaffin granules were absent. The tumor cells had oval nuclei with prominent nucleol.i and exhibited moderate pleomorphism. Mitoses were uncommon. In the yellow-speckled areas the tumor cells had finely vacuolated cytoplasm. In a section through a medium-sized vein the tumor cells were seen encroaching upon and invading the vascular wall. Under the electron microscope the tumo:r cells showed numerous round or oval mitochondria with platelike cristae (fig. 4). Giant mitochondria were encountered frequently. Profiles of granular and agranular endoplasmic reticulum were fairly abundant. No neurosecretory granules were found. Postoperatively, the blood pressure decreased to normal. The patient was studied 10 months later, at which time the blood pressure was 100/70. A 24-hour urinary measurement of 17hydroxycorticoids was 3 mg. and of 17-ketosteroids it was 2.9 mg. DISCUSSION
The detection of an adrenal carcinoma in this young woman during investigation of hypertension was unexpected since she did not present with any clinical clues of an underlying adrenal disorder. On investigation she had unequivocal evidence of hyperaldosteronism with mild hypokalemia. Suppressed plasma renin activity in the face of abnormally high plasma aldosterone concentration under standardized stimulatory and suppressive conditions supported the impression that the peraldosteronism was of a primary nature. The reversal of of these abnormalities after the removal of the adrenal carcinoma confirmed the causal relationship. It is well known that no single morphologic change can be
784
GRIM AND ASSOCIATES
FIG. 1. A, selective arteriography shows left suprarenal mass. B, adrenal venography emphasizes (arrows) hypervascular nature of tumor
FIG. 2. Adrenal scan demonstrates uptake of radiocholesterol (arrow) by right adrenal only
Results of renin-aldosterone measurements Preop. Plasma Renin Activity (ng./rnl./3 hrs.)
Postop. 10 Mos. Plasma Aldosterone (ng./100 ml.)
Plasma Renin Activity (ng./rnl./3 hrs.)
Plasma Aldosterone (ng./100 ml.)
7.0
10.3
2.2
2.4
----------------------------------------------
Before saline Normal black women
1.0
31
5.5 ± 0.7
35.8 ± 6.5
After saline Normal black women
1.0 1.2 ± 0.2
19 4.2 ± 0.5
Before furosemide Normal black women
3.4 ± 0.6
After furosemide Normal black women
2.7 23.3 ± 3.1
1.0
4.4
71.2
HYPERALDOSTERONISM DUE TO ADRENAL CARCINOMA
taken as a criterion in differentiating between an ad_icenal cortical adenoma and a carcinoma. The tumor of this patient was considered to be a cortical carcinoma because of its size (> 100 and because of vascular invasion and the fine structural c.1.11n<:1on accompanying adrenal carsecretion of steroids other than
785
aldosterone. Excessive desoxycorticosterone has been reported in adrenal carcinoma. 9 Patients with adrenal carcinoma have been reported to have steroid abnormalities suggestive of an 11-,8 hydroxylase deficiency. 10• u However, in conditions of adrenal hyperfunction in which desoxycorticosterone secretion is high, aldosterone secretion often is low. 12 The plasma aldosterone level after saline infusion in our was similar to that seen in patients with primary aldosteronis1TL 7 The carcinoma in our patient also produced an excess of androgens, as evidenced by the elevated 17-ketosteroids, facial hair and small breasts. Adrenal carcinomas often secrete > 1 of hormones. 11 They can produce increased amounts of corticoids as well, resulting in Cushing's syndrome. Our had no clinical or biochemical evidence of Cushing's Mineralocorticoid excess as the sole biochemical of hormone secretion in adrenal carcinoma is unusual. 2 Hence, the term primary aldosteronism had been avoided most investigators to describe these patients, although they mirnic the syndrome closely. The measurements of metabolites of glucocorticoids or androgens may provide the only clue to the possibility of adrenal carcinoma in an otherwise unsuspected patient. We believe that this case illustrates the potential benefit of careful investigation of hypertension, especially in young subjects. Furthermore, it reveals the ease with which the u1s,1s1,,v"1" of primary aldosteronism can be made, using saline suppress plasma aldosterone levels and furosemide to stimulate plasma renin levels. 6 • 7 The value of such a rigidly defined protocol to reduce the cost and time of evaluation has been well documented. 6 Finally, the localization of the site of the lesion greatly assists in the surgical management of the disorder. 7 REFERENCES 1. Foye, L. V., Jr. and Feichtmerr, T. V.: Adrenal cortical carcinoma producing solely mineralocorticoid effect. Amer. J. Med., 19: 966,
Fm. 3. Light micrograph shows tumor cells grouped in nests or thin layer of fibrovascular tissue. Some tumor vacuoles. H & E, reduced from X320.
1955. 2. Salassa, T. M., Weeks, R. E., Northcutt, R. C. and Carney, J. A.: Primary aldosteronism and malignant adrenocortical neopl.asia. Trans. Amer. Clin. Climatol. Ass., 86: 163, 1974. 3. Six, R., Leclercq, R. and Noeninckx, F.: Hypermineralocorticoidisrn: the sole clinical manifestation of an adrenal cortical carcinoma.
Fw. 4. In this electron micrograph several tumor cells are seen surrounded in part by basal lamina. Note abundant round mitochondria and few lipoid droplets. Intercellular junction complexes and endoplasmic reticulum system are not well developed. Reduced from X6,480.
786
GRIM AND ASSOCIATES
Acta Clin. Belg., 27: 426, 1972. 4. Shah, S., McReynolds, C. R., Decker, D. D. and Hoofer, W. D.: Aldosteronism-hypokalemia. Adenocarcinoma of adrenal gland. J. Kansas Med. Soc., 76: 277, 1975. 5. Revach, M., Shilo, S., Cabili, S., Rubenstein, Z. and Selzer, G.: Hyperaldosteronism caused by adrenal cortical carcinoma. Isr. J. Med. Sci., 13: 1123, 1977. 6. Grim, C. E., Weinberger, M. H., Higgins, J. T. and Kramer, N. J.: Diagnosis of secondary forms of hypertension. A comprehesive protocol. J.A.M.A., 237: 1331, 1977. 7. Weinberger, M. H., Grim, C. E., Hollifield, J. W., Kem, D. C., Ganguly, A., Kramer, N. J., Yune, H. Y., Wellman, H. and Donohue, J. P.: Primary aldosteronism: diagnosis, localization, and treatment. Ann. Intern. Med., 90: 386, 1979.
8. Tannenbaum, M.: Ultrastructural pathology of the adrenal cortex. Path. Ann., 8: 109, 1973. 9. Crane, M. G. and Harris, J. J.: Desoxycorticosterone secretion rates in hyperadrenocorticism. J. Clin. Endocr., 26: 1135, 1966. 10. Touchstone, J.C., Bulaschenko, J., Richardson, E. M. and Dohan, F. C.: The excretion of pregnane-3a,l 7a,21-triol 20-one (tetrahydro S) in normal and pathologic urine. J. Clin. Endocr. Metab., 17: 250, 1957. 11. Lipsett, M. D., Hertz, R. and Ross, G. T.: Clinical and pathophysiologic aspects of adrenocortical carcinoma. Amer. J. Med., 35: 374, 1963. 12. Biglieri, E. G., Schambelan, M. and Slaton, P. E., Jr.: Effect of adrenocorticotropin on desoxycorticosterone, corticosterone and aldosterone excretion. J. Clin. Endocr., 29: 1090, 1969.
Vol. 126, December Printed in U.S. A..
Copyi:ight © 1981 by The Williams & Wilkins Co.
HYPERALDOSTERONISM DUE TO UNSUSPECTED ADRENAL CARCINOMA: DISCOVERY DURING INVESTIGATION OF HYPERTENSION IN A YOUNG WOMAN CLARENCE K GRIM, ARUNABHA GANGULY, MOO-NAM YUM, JOHN P. DONOHUE AND MYRON H. WEINBERGER From the Departments of Internal Medicine, Pathology and Urology, Indiana University School of Medicine, Indianapolis, Indiana
ABSTRACT
During investigation for hypertension a 19-year-old black woman was found to have an unsuspected adrenal carcinoma. Hyperaldosteronism was established as the cause of the hypertension by observing suppressed plasma renin activity and nonsuppressible plasma aldoste:rone concentration. The causal relationship was confirmed by a cure of the hypertension and a return in the responsiveness of the renin-angiotensin-aldosterone axis to normal after :removal of the carcinoma. This :report emphasizes the value of a comprehensive investigation of hypertension, especially in young patients. Adrenal carcinoma causing hyperaldosteronism, first reand Feichtmeir, 1 is rare. Patients usually present with hypertension and severe hypokalemia, and usually have been >30 years old but only a small number have been reported. 2- 5 We report the incidental discovery of an adrenal carcinoma causing hyperaldosteronism in a young woman during the systematic investigation of hypertension using a standardized and comprehensive protocol. 6 CASE REPORT
A 19-year-old black woman was referred for evaluation of hypertension detected during a pre-employment physical examination. A 3-year history of well controlled hypertension was elicited. The menstrual and medical history was normal. Family history was negative for hypertension or adrenal disease. The woman had not received any medication for 4 to 5 months. Blood pressure ranged between 140 to 150/100 to 115 mm. Hg and pulse was 92 per minute. Fine facial hair and small breasts were noted. The remainder of the examination, including external genitalia, was normal. The patient had mild anemia. Serum sodium was 138 mEq./1. and potassium ranged between 3.4 and 3.6 mEq./1. Urinary 17-ketosteroids were 53.2 mg./dl. and 17hydroxycorticosteroids were 5.6 mg./dl. Vanillyl mandelic acid and metanephrine values were normal. Selective abdominal angiography revealed a large, vascular, left suprarenal mass, with areas of calcification (fig. 1, A). The presumptive radiologic interpretation of a probable pheochromocytoma was not supported by urinary catecholamine measurements. Adrenal venography also suggested a vascular adrenal mass lesion (fig. 1, B) and an adrenal scan using 131 iodine iodocholesterol showed no uptake by the left adrenal gland (fig. 2). To evaluate the renin-angiotensin-aldosterone axis a standardized protocol, including a saline infusion, was performed, followed by furosemide administration as described. 7 Blood was collected before and at the end of the infusion for electrolytes, plasma renin activity and aldosterone concentration. The next day the patient received 3 doses of 40 mg. furosemide at 10 a.m., and 2 and 6 p.m. The sodium intake was restricted to 10 mEq. during that day. Blood was drawn before medication and after 2 hours of ambulation on the next day for the same measurements. These studies were repeated 10 months postoperatively. Plasma renin activity, cortisol and aldosterone concentration were measured by radioimmunoassays. 6 ComparAccepted for publication November 7, 1980. Supported in part by United States Public Health Service Grant HL-14159, Specialized Center of Research in Hypertension and R000750, General Clinical Research Center. 783
ative values from 114 normal subjects and from 236 patients with well characterized forms of primary and secondary hypertension have been reported previously. 6 The results are shown in the table and demonstrate renin suppression with nonsuppressible aldosterone values that returned to normal postoperatively. On surgical exploration a large left adrenal tumor was found and removed. The tumor weighed 150 gm. and measured 10 7.5 X 5 cm. There was no gross evidence of invasion of surrounding tissues or lymphatics by the encapsulated tumor. The cut surface of the tumor was pinkish to gray-tan in color, with a large central area of fibrosis and focal calcification. Small speckles were seen scattered on the cut surface. Only a thin rim of adrenal cortical tissue was recognized in the subcapsular area. Microscopically, the tumor was found to be highly vas·· cular and consisted of large polygonal cells with abundant, eosinophilic cytoplasm (fig. 3). Chromaffin granules were absent. The tumor cells had oval nuclei with prominent nucleol.i and exhibited moderate pleomorphism. Mitoses were uncommon. In the yellow-speckled areas the tumor cells had finely vacuolated cytoplasm. In a section through a medium-sized vein the tumor cells were seen encroaching upon and invading the vascular wall. Under the electron microscope the tumo:r cells showed numerous round or oval mitochondria with platelike cristae (fig. 4). Giant mitochondria were encountered frequently. Profiles of granular and agranular endoplasmic reticulum were fairly abundant. No neurosecretory granules were found. Postoperatively, the blood pressure decreased to normal. The patient was studied 10 months later, at which time the blood pressure was 100/70. A 24-hour urinary measurement of 17hydroxycorticoids was 3 mg. and of 17-ketosteroids it was 2.9 mg. DISCUSSION
The detection of an adrenal carcinoma in this young woman during investigation of hypertension was unexpected since she did not present with any clinical clues of an underlying adrenal disorder. On investigation she had unequivocal evidence of hyperaldosteronism with mild hypokalemia. Suppressed plasma renin activity in the face of abnormally high plasma aldosterone concentration under standardized stimulatory and suppressive conditions supported the impression that the peraldosteronism was of a primary nature. The reversal of of these abnormalities after the removal of the adrenal carcinoma confirmed the causal relationship. It is well known that no single morphologic change can be
784
GRIM AND ASSOCIATES
FIG. 1. A, selective arteriography shows left suprarenal mass. B, adrenal venography emphasizes (arrows) hypervascular nature of tumor
FIG. 2. Adrenal scan demonstrates uptake of radiocholesterol (arrow) by right adrenal only
Results of renin-aldosterone measurements Preop. Plasma Renin Activity (ng./rnl./3 hrs.)
Postop. 10 Mos. Plasma Aldosterone (ng./100 ml.)
Plasma Renin Activity (ng./rnl./3 hrs.)
Plasma Aldosterone (ng./100 ml.)
7.0
10.3
2.2
2.4
----------------------------------------------
Before saline Normal black women
1.0
31
5.5 ± 0.7
35.8 ± 6.5
After saline Normal black women
1.0 1.2 ± 0.2
19 4.2 ± 0.5
Before furosemide Normal black women
3.4 ± 0.6
After furosemide Normal black women
2.7 23.3 ± 3.1
1.0
4.4
71.2
HYPERALDOSTERONISM DUE TO ADRENAL CARCINOMA
taken as a criterion in differentiating between an ad_icenal cortical adenoma and a carcinoma. The tumor of this patient was considered to be a cortical carcinoma because of its size (> 100 and because of vascular invasion and the fine structural c.1.1
785
aldosterone. Excessive desoxycorticosterone has been reported in adrenal carcinoma. 9 Patients with adrenal carcinoma have been reported to have steroid abnormalities suggestive of an 11-,8 hydroxylase deficiency. 10• u However, in conditions of adrenal hyperfunction in which desoxycorticosterone secretion is high, aldosterone secretion often is low. 12 The plasma aldosterone level after saline infusion in our was similar to that seen in patients with primary aldosteronis1TL 7 The carcinoma in our patient also produced an excess of androgens, as evidenced by the elevated 17-ketosteroids, facial hair and small breasts. Adrenal carcinomas often secrete > 1 of hormones. 11 They can produce increased amounts of corticoids as well, resulting in Cushing's syndrome. Our had no clinical or biochemical evidence of Cushing's Mineralocorticoid excess as the sole biochemical of hormone secretion in adrenal carcinoma is unusual. 2 Hence, the term primary aldosteronism had been avoided most investigators to describe these patients, although they mirnic the syndrome closely. The measurements of metabolites of glucocorticoids or androgens may provide the only clue to the possibility of adrenal carcinoma in an otherwise unsuspected patient. We believe that this case illustrates the potential benefit of careful investigation of hypertension, especially in young subjects. Furthermore, it reveals the ease with which the u1s,1s1,,v"1" of primary aldosteronism can be made, using saline suppress plasma aldosterone levels and furosemide to stimulate plasma renin levels. 6 • 7 The value of such a rigidly defined protocol to reduce the cost and time of evaluation has been well documented. 6 Finally, the localization of the site of the lesion greatly assists in the surgical management of the disorder. 7 REFERENCES 1. Foye, L. V., Jr. and Feichtmerr, T. V.: Adrenal cortical carcinoma producing solely mineralocorticoid effect. Amer. J. Med., 19: 966,
Fm. 3. Light micrograph shows tumor cells grouped in nests or thin layer of fibrovascular tissue. Some tumor vacuoles. H & E, reduced from X320.
1955. 2. Salassa, T. M., Weeks, R. E., Northcutt, R. C. and Carney, J. A.: Primary aldosteronism and malignant adrenocortical neopl.asia. Trans. Amer. Clin. Climatol. Ass., 86: 163, 1974. 3. Six, R., Leclercq, R. and Noeninckx, F.: Hypermineralocorticoidisrn: the sole clinical manifestation of an adrenal cortical carcinoma.
Fw. 4. In this electron micrograph several tumor cells are seen surrounded in part by basal lamina. Note abundant round mitochondria and few lipoid droplets. Intercellular junction complexes and endoplasmic reticulum system are not well developed. Reduced from X6,480.
786
GRIM AND ASSOCIATES
Acta Clin. Belg., 27: 426, 1972. 4. Shah, S., McReynolds, C. R., Decker, D. D. and Hoofer, W. D.: Aldosteronism-hypokalemia. Adenocarcinoma of adrenal gland. J. Kansas Med. Soc., 76: 277, 1975. 5. Revach, M., Shilo, S., Cabili, S., Rubenstein, Z. and Selzer, G.: Hyperaldosteronism caused by adrenal cortical carcinoma. Isr. J. Med. Sci., 13: 1123, 1977. 6. Grim, C. E., Weinberger, M. H., Higgins, J. T. and Kramer, N. J.: Diagnosis of secondary forms of hypertension. A comprehesive protocol. J.A.M.A., 237: 1331, 1977. 7. Weinberger, M. H., Grim, C. E., Hollifield, J. W., Kem, D. C., Ganguly, A., Kramer, N. J., Yune, H. Y., Wellman, H. and Donohue, J. P.: Primary aldosteronism: diagnosis, localization, and treatment. Ann. Intern. Med., 90: 386, 1979.
8. Tannenbaum, M.: Ultrastructural pathology of the adrenal cortex. Path. Ann., 8: 109, 1973. 9. Crane, M. G. and Harris, J. J.: Desoxycorticosterone secretion rates in hyperadrenocorticism. J. Clin. Endocr., 26: 1135, 1966. 10. Touchstone, J.C., Bulaschenko, J., Richardson, E. M. and Dohan, F. C.: The excretion of pregnane-3a,l 7a,21-triol 20-one (tetrahydro S) in normal and pathologic urine. J. Clin. Endocr. Metab., 17: 250, 1957. 11. Lipsett, M. D., Hertz, R. and Ross, G. T.: Clinical and pathophysiologic aspects of adrenocortical carcinoma. Amer. J. Med., 35: 374, 1963. 12. Biglieri, E. G., Schambelan, M. and Slaton, P. E., Jr.: Effect of adrenocorticotropin on desoxycorticosterone, corticosterone and aldosterone excretion. J. Clin. Endocr., 29: 1090, 1969.