Case Reports
ISOLATED PRIMARY ALDOSTERONISM IN A PATIENT WITH ADRENAL CARCINOMA AND XY/XXY MOSAIC KLINEFELTER’S SYNDROME
JULIO PASCUAL, FERNANDO LIAÑO,* AUGUSTO GARCÍA-VILLANUEVA, J. L. SALVADOR, JOSÉ A. HERRERO AND JOAQUÍN ORTUÑO
From the Departments of Nephrology and General Surgery, Hospital Ramón y Cajal, Madrid, Spain
ABSTRACT
Although breast cancer, germ cell tumors and other neoplasms are known to occur in patients with Klinefelter’s syndrome, adrenal carcinoma has not yet been reported in such patients. We describe a rare case of severe primary aldosteronism as the unique manifestation of a large adrenocortical carcinoma in a patient with Klinefelter’s syndrome. Complete biological and hor- monal evaluation was performed. Surgical treatment was successful and the patient remained asymptomatic with normal biological and hormonal values after 1 year of followup. (J. Urol., 144: 1454-1456, 1990)
Patients with Klinefelter’s syndrome are known to have a higher incidence of neoplasms, with breast cancer and germ cell tumors being the most frequent associations.1-3 Other iso- lated reports of neoplasms in patients with Klinefelter’s syn- drome include prostatic carcinoma,4 bronchogenic carcinoma,5 bladder cancer,6 leukemia,7 lymphoma8 and interstitial cell tumor of the testis.9
Primary aldosteronism rarely is caused by adrenocortical carcinoma; in most cases it results from benign adenoma or bilateral hyperplasia.10, 11 Patients usually have Cushing’s syn- drome, virilization or feminization because carcinomas almost invariably produce large amounts of steroids.12, 13 Adrenocorti- cal carcinomas that only produce excessive amounts of miner- alocorticoids are rare.14 To our knowledge such neoplasms have not been associated with Klinefelter’s syndrome. We present a case in which severe primary aldosteronism was the unique clinical feature expressed by a large adrenocortical carcinoma successfully diagnosed and treated in a patient with Klinefelter’s syndrome.
CASE REPORT
A 65-year-old man had a 4-month history of polyuria, poly- dipsia, muscle weakness, anorexia and a 10 kg. weight loss. He was married and sexually active but with no descendants. Physical examination revealed a eunuchoid body habitus with small testicles. Blood pressure was 140/80 mm. Hg and no evidence of Cushing’s syndrome or feminization was noted. Examination of a buccal smear revealed an XXY/XY mosai- cism.
Peripheral blood was normal, as was renal function. Serum potassium was 1.7 mEq./1. and serum bicarbonate 46 mEq./1. Levels of serum glucose, uric acid, triglycerides, cholesterol, bilirubin and transaminases were normal. Lactic dehydroge- nase was 744 IU/1. Hormonal studies demonstrated suppressed plasma renin activity and serum aldosterone levels of greater than 200 ng./dl. (out of our laboratory range). Urinary 17- ketosteroid level was 26 mg. per day, plasma cortisol 14.8 ng./ dl. with normal circadian rhythm, basal testosterone 406 ng./
Accepted for publication May 25, 1990.
*Requests for reprints: Servicio de Nefrología, Hospital Ramón y Cajal, Carr. Colmenar Viejo km 9,100, 28034 Madrid, Spain.
dl. and 17-hydroxyprogesterone 3.7 ng./ml. Urinary metane- phrines were 574 ug./24 hours, urinary adrenalin 6 µg./24 hours and noradrenaline 42 ug./24 hours. Thyroid hormones and tirotrophin were normal.
Abdominal ultrasonography and computerized tomographic (CT) scanning revealed a 17 cm. left adrenal mass with calci- fications, without liver or kidney involvement and no retroper- itoneal lymphadenopathic condition (fig. 1). At left subcostal laparotomy a large vascularized 20 × 13 cm. suprarenal mass was found. Nearby structures were displaced but not infiltrated. There were no abdominal metastases. The tumor was removed with the regional lymph nodes (fig. 2). Adrenocortical carci- noma was suspected in light of the tumor and was confirmed by histological examination (fig. 3). There were extensive areas of brown tissue with tumor cell necrosis and hemorrhage. There was moderate tumor pleomorphism with no vascular or peri- capsular invasion by cancer. Broad fibrous bands in the tumor with a diffuse growth pattern were seen. Lymph node exami- nation only showed reactive lymphadenitis. Blood samples drawn from the left renal vein before and after tumor extirpa- tion demonstrated aldosterone values of 166 and 28 ng./dl., respectively.
Aldosterone plasma levels were undetectable and plasma renin activity was 0.6 ng./ml. per hour 1 week postoperatively. At 2 months the aldosterone plasma levels were 6.9 (basal) and 14.7 (stimulated) ng./dl., and renin plasma activity was 4.2 (basal) and 7.4 (stimulated) ng./ml. per hour (see table for normal values).
At 1 year the patient was alive without any recurrent symp- toms, and with normal hormonal and biochemical serum values, and normal ultrasonography findings.
Laboratory methods. The patient was admitted to the ne- phrology service at our hospital. Equilibration was achieved on a constant diet containing 120 mEq. sodium and 70 mEq. potassium. After overnight recumbency venous samples were obtained at 8 a.m. to measure plasma steroid, renin activity, aldosterone, 17-hydroxyprogesterone and testosterone levels. Also, 24-hour urine specimens were collected to measure excre- tion of 17-ketosteroids, 17-hydroxycorticosteroids, cortisol, me- tanephrines, adrenaline and noradrenaline. After the 8 a.m. sample was obtained the patient assumed the upright posture
for 4 hours and then another sample was taken. Cortisol diurnal rhythm was determined for 24 hours by successive samples obtained at 8 a.m. and 8 p.m.
Plasma urinary sodium and potassium levels were measured by standard internal flame photometry. Urinary excretion of Porter Silver chromogens, used to assess 17-ketosteroid and 17-hydroxycorticosteroid levels, was measured for 24 hours by standard techniques. Plasma renin activity was measured by angiotensin I radioimmunoassay and plasma aldosterone by direct radioimmunoassay. Cortisol also was measured by radio- immunoassay.
| Parameters | Pt. | Normal |
|---|---|---|
| Serum potassium (mEq./l.) | 1.7 | 3.5-5.3 |
| Serum bicarbonate (mEq./l.) | 46 | 22-27 |
| Lactic dehydrogenase (IU/l.) | 744 | 230-460 |
| Plasma renin activity (ng./ml./hr.) | Undetectable | 0.3-7 |
| Serum aldosterone (ng./dl.) | >200 | 10-70 |
| Urinary 17-ketosteroids (mg./24 hrs.) | 26 | 8-26 |
| Plasma cortisol (ng./dl.) | 14.8 | 6-23 |
| Basal testosterone (ng./dl.) | 406 | 300-900 |
| 17-hydroxyprogesterone (ng./ml.) | 3.7 | 0.31-2.17 |
| Urinary metanephrines (pg./24 hrs.) | 574 | 7-547 |
| Urinary adrenaline (µg./24 hrs.) | 6 | <20 |
| Urinary noradrenaline (µg./24 hrs.) | 42 | <100 |
DISCUSSION
Klinefelter’s syndrome affects phenotypically male patients characterized by hypergonadotropic hypogonadism, azoosper- mia, gynecomastia, small firm testes and an extra X chromo- some. Several investigators have suggested that the occurrence of neoplasms, particularly germ cell tumors, in patients with Klinefelter’s syndrome may not be coincidental. One could speculate that malignant transformation of germ or endocrine cells in Klinefelter’s syndrome involves complex interactions within the abdominal hormonal milieu. Mukerjee and associ- ates noted that in a patient with XY/XXY mosaic Klinefelter’s syndrome and bronchogenic carcinoma the XXY fibroblasts transformed 3 times more frequently when exposed to SV-40 virus than did the XY population, and 3 to 10 times more than a normal control population.5 Whatever the process, certain cells in patients with Klinefelter’s syndrome are prone to give rise to a malignant cell line and probably are susceptible to oncogenic stimuli. Breast cell carcinoma, germ cell neoplasms and other malignancies have been described in the presence of Klinefelter’s syndrome.1-9 To our knowledge there are no re- ports of aldosterone-producing adrenocortical carcinoma asso- ciated with Klinefelter’s syndrome.
Adrenocortical carcinoma is a rare and highly aggressive tumor. Approximately three-fourths of these lesions are met- astatic when diagnosed and approximately 40% are candidates for curative resection. Half of them are functioning and half are nonfunctioning. When functioning, they usually cause Cushing’s syndrome, the adrenogenital syndrome, precocious puberty, primary hyperaldosteronism or a mixed syndrome.12, 13, 15
Although pure primary aldosteronism most often results from benign adenoma10 or hyperplasia,11 it may also indicate the presence of an adrenocortical carcinoma that produces an ex- cessive amount of mineralocorticoids alone.14, 16-23
When compared with other patients with primary aldoster- onism, patients with carcinoma have lower serum potassium levels.16 Basal plasma aldosterone and renin levels, as well as response to the upright position or to serum saline infusion, were of limited value in distinguishing adenomas from carci- nomas.18, 21 Farge and associates suggested that tumor calcifi- cations appear to be determinant in the diagnosis of malig- nancy.16 Although ultrasonography did not reveal this finding in our patient, CT scanning demonstrated a small amount of calcification. Moreover, the presence of an enlarged tumor suggested a malignant adrenal neoplasm.23 Histologically, it is difficult to distinguish between adenomas and carcinomas in certain cases.24 In our patient the diagnosis of adrenal carci- noma was based on tumor size, cell necrosis and broad fibrous bands transversing the tumor. There was no capsular or vas- cular involvement, and mitotic figures were moderate. To im- prove survival an aggressive surgical approach is recommended, resecting the tumor with any adjacent involved organs and lymph nodes. Whether ortho-para-dichlorodiphenyldichloro- ethane (O,p’DDD) in a satisfactorily removed tumor confined to the adrenal can be considered as a prophylactic drug still is unknown, although hopeful results have been achieved by
some.25 While there is no clear evidence to consider serum aldosterone level as a specific marker of aldosterone-producing adrenocortical carcinoma, we have put our trust in it as a good indicator of disease activity followup. Despite the poor prog- nosis of adrenal carcinomas12 our patient remained asympto- matic with normal aldosterone values and no evidence of re- currence after 1 year of followup.
In summary, we report a rare case of primary aldosteronism due to adrenocortical carcinoma with isolated excess of aldo- sterone production in a patient with Klinefelter’s syndrome. Careful biochemical and hormonal studies should be obtained in patients with symptoms or signs of primary aldosteronism, especially in those with low serum potassium levels. Surgical treatment is mandatory to achieve a successful outcome. The serum aldosterone level may be a good marker for disease activity.
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