Isolated Clinical Syndrome of Primary Aldosteronism in Four Patients with Adrenocortical Carcinoma
DOMINIQUE FARGE, M.D. GILLES CHATELLIER, M.D. JEAN-YVES PAGNY, M.D. XAVIER JEUNEMAITRE, M.D. PIERRE-FRANÇOIS PLOUIN, M.D. PIERRE CORVOL, M.D. Paris, France
From the Service d’Hypertension Artérielle Hô- pital Broussais, 96 rue Didot, Paris, France. Re- quests for reprints should be addressed to Dr. Dominique Farge, Service d’Hypertension Artér- ielle, Hôpital Broussais, 96 rue Didot, 75674 Paris Cedex 14, France. Manuscript submitted October 31, 1986, and accepted April 23, 1987.
Adrenocortical carcinoma is a rare disorder that can be revealed by an isolated syndrome of mineralocorticoid excess. In a retrospective study of 137 patients referred to our hypertension clinic in the past 10 years for primary aldosteronism, four cases of adrenocortical carcinoma were identified. The clinical presentation of these patients was similar to that of patients with Conn’s adenoma, but preoperatively, malignant tumoral primary aldosteronism was suspected because of profound hypokalemia, marked elevation in plasma aldosterone levels, and enlarged size and weight of an heterogenous adrenal tumor with internal calcifications. Malignancy was confirmed by the histologic features. No prognostic criteria could be established and two patients died despite specific surgery, which was performed in all cases. More recent developments in the use of mitotane led to the addition of adrenocorticolytic therapy in the remaining two patients, who are still alive at the time of this report.
Adrenocortical carcinoma is a rare disorder with an estimated incidence of only 0.023 percent of all malignancies [1]. These tumors have been divided into functional and non-functional. In most cases, patients show Cushing’s syndrome and virilization or feminization due to abnormal steroid production by the tumor, and clinical symptoms rapidly lead to a diagnosis [2]. Occasionally, the tumor produces an excessive amount of mineralocorticoids only. Therefore, although pure primary aldosteronism most often results from benign adrenocortical adenoma [3] or from bilateral hyperplasia [4], it may also indicate the presence of an adreno- cortical carcinoma [5]. In a recent review of the literature, among 35 cases of adrenocortical carcinomas, Slee et al [6] found only seven patients with the isolated syndrome of primary aldosteronism, in which hypertension and hypokalemic alkalosis resumed the clinical features.
In the past 10 years, 137 patients were admitted to our hypertension clinic for high blood pressure and hypokalemic alkalosis related to primary aldosteronism; 85 patients demonstrated tumoral primary aldo- steronism. Among them, four had an adrenocortical carcinoma. In order to identify unusual features that increase the suspicion of malignant tumoral primary aldosteronism, we analyzed the four patients’ respective clinical courses and specificity (Table I), as compared with other patients who had benign tumoral primary aldosteronism.
PATIENTS AND METHODS
The four patients were admitted to the hypertension clinic at Hôpital Broussais, Paris, France, because primary aldosteronism was suspected. A complete hospital work-up was performed 10 days after discontinuation of drugs once equilibration had been achieved on a constant metabolic diet,
| Patients (n = 81) with Adenoma (mean ± SD) | Patients with Carcinoma | ||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | ||
| Age (years) | 43 ± 10 | 40 | 51 | 56 | 17 |
| Duration of hypertension | 91 ± 82* | 13 | 50 | 50 | 26 |
| before surgery (months) | |||||
| Serum potassium (meq/liter) | 2.9 ± 0.5 | 1.9 | 1.4 | 3.2 | 2.3 |
| Presence of calcification on ultrasound/CT scan | 0/0 | +/+ | +/+ | +/+ | +/+ |
| Tumor size (cm) | 3×3 | 13 × 4 | 35 × 25 | 6× 5 | 15 × 12 |
| Outcome | Alive | Dead | Dead | Alive | Alive |
CT = computed tomographic.
* Data were obtained from 60 patients with a surgically proved benign adrenal tumor.
containing 120 meq of sodium and 70 meq of potassium. After overnight recumbency, the following procedures were done: Venous blood samples were obtained at 8 A.M. to measure plasma steroids, renin, and aldosterone levels. Twenty-four-hour urine specimens were collected to mea- sure excretion of 17-ketosteroids, 17-hydroxycorticoster- oids, cortisol, and aldosterone. After the 8 A.M. sample was obtained, patients assumed the upright posture for one hour, after which time a second sample was taken. A serum saline infusion test was performed as previously described [7]. Cortisol diurnal rhythm was evaluated over 24 hours by two successive venous samples obtained at 8 A.M. and at 4 P.M. For the cortisol stimulation test, venous plasma sam- ples were obtained at 8 A.M., and one hour later after intramuscular injection of 0.25 mg of beta 1-24-tetrasoac- tide (Synacthène, CIBA-GEIGY, France) equivalent to 25 international units of ACTH. Administration of 1 mg of dexamethasone at midnight was performed to assess corti- sol suppression at 8 A.M. Plasma and urinary sodium and potassium were measured by standard internal flame pho- tometry. Urinary excretion of Porter Silber chromogens, used to assess 17-ketosteroids and 17-hydroxycorticoster- oids levels was measured for 24 hours by standard tech- niques. Urinary aldosterone excretion was determined by radioimmunoassay of the chromatographically isolated al- dosterone 18 glucuronide, after 24 hours of hydrolysis at pH 1 [8]. Plasma renin activity was measured by angiotensin I radioimmunoassay [9], and plasma aldosterone was mea- sured by direct radioimmunoassay [10]. Deoxycorticoste- rone, and 11-desoxycortisol were measured by radioimmu- noassay after chromatographic isolation on LH 20 Sepha- dex [11]. Cortisol was measured by competitive protein binding analysis after chromatographic isolation [12]. Nor- mal values of these determinations are shown in the tables. All patients had normal levels of vanillymandelic acid, metanephrines, and catecholamines on two separate 24- hour urine collections.
CASE REPORTS
Patient 1. A 40-year-old white woman was hospitalized because tumoral primary aldosteronism was suspected. Hypertension had been diagnosed for one year and treated with oxprenolol (80 mg per day). She complained of head-
aches and muscle weakness, and primary aldosteronism was diagnosed with profound hypokalemia (1.9 meq/liter) and metabolic alkalosis (bicarbonate = 36 meq/liter). Ami- loride (20 mg per day) was given, and the patient was referred to our clinic. Subsequent blood pressure was 200/ 100 mm Hg. Physical findings were otherwise normal, in- cluding skin and hair distribution, with no evidence of Cush- ing’s syndrome. Hormonal studies (Table II) demonstrated suppressed plasma renin activity, hyperaldosteronism, and high urinary cortisol excretion, whereas plasma cortisol and 11-desoxycortisol, progesterone, 17-ketosteroid proges- terone, and estradiol levels were normal. The concentra- tions of other plasma steroids derived from 17-ketosteroids were low: dehydroepiandrosterone sulfate at 0.11 ng/ml (normal: 1.5 to 10 ng/ml), androstenedione at 0.22 ng/ml (normal: 0.5 to 2 ng/ml), and testosterone at 0.11 ng/ml (normal: 3.5 to 11 ng/ml). Intravenous pyelography showed that the right kidney was compressed by an upper mass. Ultrasound examination and computed tomographic scan- ning of the abdomen revealed a 5 X 5-cm right adrenal mass with central calcifications (Figure 1), and no evidence of liver or kidney involvement. Arteriography showed hy- pervascularization of the tumor. Blood samples were ob- tained to determine aldosterone and cortisol levels and their respective ratios (A/C) in the right adrenal (A/C = 23), the left adrenal (A/C = 6.3), and the inferior vena cava below the renal veins (A/C = 8). This sensitive sampling tech- nique [13] demonstrated a right/left gradient in aldosterone secretion. A right adrenal tumor 13 X 4-cm was removed and adrenocortical carcinoma was diagnosed in light of capsular invasion and infiltration of blood vessels by malig- nant cells. Daily hydrocortisone (40 mg) and 9-alpha-fludro- cortisone (25 µg) were given postoperatively. Blood pres- sure and hormonal levels returned to normal. After a six- month symptom-free period, the patient was readmitted for recurrent hypermineralocorticism and high blood pressure, Cushing’s features, and an increase in urinary excretion of 17-ketosteroids and 17-hydroxycorticosteroids. Ultrasound and computed tomographic scanning of the abdomen yield- ed normal findings. Administration of mitotane was started, but the patient died within eight days, with pulmonary and pericardial metastasis.
Patient 2. A 51-year-old black man, from the French West
| (Normal Values) | Patients (n = 81) with Adenoma (mean ± SD) | Patients with Carcinoma | ||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | |||
| Plasma renin activity (ng/ml/hour) | ||||||
| Supine | (0.5-1.8) | 0.20 ± 0.22 | 0.35 | 0.12 | 0.30 | 0.03 |
| 1-Hour upright | (1.1-3.9) | 0.34 ± 0.33 | 0.60 | 0.12 | 0.50 | 0.05 |
| Plasma aldosterone (ng/dl) | ||||||
| Supine | (5-12) | 45.9 ± 29.0 | 115 | 13 | 38 | 35 |
| 1-Hour upright | (15-30) | 69.4 ± 41.4 | 180 | 13 | 54 | 60 |
| Serum saline infusion | (<5) | 29.3 ± 18.1* | 105 | 10 | - | 25 |
| Urinary aldosterone at pH 1 | (2-10) | 36.6 ± 21.7 | 100 | 53 | - | 48 |
| (per 24 hours) | ||||||
| Plasma cortisol (ug/dl) | ||||||
| 8 A.M. | (15 ± 3) | 17.6 ± 6.7+ | 15.9 | 18 | 11.5 | 12 |
| 4 P.M. | 9.5 ± 3.7+ | 15.7 | - | 9 | 8 | |
| Before/after ACTH | 19/21 | 18/19 | 6/15 | 45/90 | ||
| 24-Hour urinary cortisol (ug) | (50-100) | 80.4 ± 44.4 | 390.0 | 341.0 | 34.6 | 228.0 |
| 17-Ketosteroids (mg) | (men, 3-9) | 21.8 | - | 13.9 | ||
| (women, 3-6) | 17.3 | - | ||||
| 17-Hydroxycorticosteroids (mg) | (men, 10-15) | 19.6 | 33.1 | |||
| (women, 5-10) | 3.5 | - | ||||
* Data were obtained in 54 of 81 patients with adenoma.
+ Data were obtained in 22 of 81 patients with adenoma.
Indies, was referred to our clinic in 1977 for muscle weak- ness and headaches. He had been hypertensive for three years and was being treated with acebutolol, hydrochloro- thiazide, and alpha-methyldopa. In 1977, initial studies showed marked hypokalemia (potassium: 1.4 meq/liter), suppressed plasma renin activity, and increased urinary aldosterone excretion; therefore, primary aldosteronism was diagnosed. The results of intravenous pyelography and renal arteriography were normal. The patient was dis- charged with a prescription for spironolactone, since he refused to participate in further investigations. In February 1981, he returned to France since his blood pressure was 220/130 mm Hg, fundi were at a grade-3 hypertensive stage, and the liver was enlarged. He had no virilization or Cushing’s syndrome. Hormonal studies (Table II) demon- strated sustained primary aldosteronism and increased uri- nary cortisol excretion; plasma cortisol, 11-deoxycortisol, progesterone, 17-hydroxyprogesterone, dehydroepiandros- terone sulfate, and androstenedione levels were all normal. Abdominal ultrasound and computed tomographic scanning revealed a large heterogeneous adrenal tumor with central calcifications. In April 1981, a 35 X 25-cm metastatic adrenocortical carcinoma, weighing 1,230 g, was removed with the right kidney. Abdominal exploration revealed me- tastasis in the epiploic lymph nodes. The liver appeared normal. Both glucocorticoids and mineralocorticoids were given postoperatively, and for the next three months, blood pressure and hormonal levels remained normal. Symptoms eventually recurred and the patient died five months later from liver failure with ascites and abdominal metastasis. Patient 3. A 56-year-old woman, who had been hyperten- sive for seven years and treated for four, had become
resistant to multiple therapy and was thus referred to our clinic. Her blood pressure was 226/114 mm Hg, and the results of physical examination were normal. Biologic and hormonal studies showed hypokalemia (3.2 meq/liter), sup- pressed plasma renin activity, and high plasma aldosterone levels (Table II), associated with an increased level of deoxycorticosterone of 1.19 ng/ml (normal: 0.03 to 0.09
A
B
C
D
ng/ml). Plasma and 24-hour urinary cortisol levels were normal, but plasma 11-desoxycortisol was elevated at 3.82 ng/ml (normal: 0.2 to 1 ng/ml). Plasma cortisol was normal- ly suppressed from 11.5 to 3 µg/ 100 ml by administration of dexamethasone. Administration of ACTH during spironolac- tone treatment induced a normal response in plasma corti- sol (Table II). After administration of ACTH, 11-deoxycorti- sol remained high at 7.34 ng/ml (normal: 0.8 to 4 ng/ml), as did deoxycorticosterone at 2.18 ng/ml (normal: 0.09 to 0.30 ng/ml). Therefore, this patient had a mineralocorticoid ex- cess with high plasma deoxycorticosterone and aldoste- rone levels. In addition, a partial deficiency in 11-beta- hydroxylase activity was inferred since plasma 11-deoxy- cortisol was elevated whereas cortisol and its regulation were normal. Intravenous pyelography demonstrated down- ward displacement of the right kidney. The computed tomo- graphic scan showed a 5-cm right adrenal heterogeneous solid mass with intratumoral calcifications and necrosis (Figure 1). A well-encapsulated adrenal tumor of 6 X 5 cm, weighing 84 g, was surgically removed. On histologic ex- amination, adrenocarcinoma was diagnosed using the crite- ria of Hough et al [14] for malignant adrenocortical tumors. Tumor cells with a high mitotic index and pleomorphic nuclei were present. Focal tumor cell necrosis was ob- served in isolated areas. The tumor exhibited a primarily trabecular pattern, but there was no diffuse growth pattern or capsular or vascular invasion. Lymph nodes were nor- mal. A month later, without any treatment, postoperative blood pressure and hormonal values were normal, including basal plasma deoxycorticosterone (0.064 ng/ml) and 11- desoxycortisol (0.28 ng/ml). Treatment by mitotane was then started and, at the time of this writing, the patient is alive with normal clinical features and hormonal levels. There is no evidence of metastatic disease after a 10- month follow-up period.
Patient 4. A 17-year-old white man, who had been found hypertensive two years earlier, showed resistance to both beta blockers and captopril and was therefore referred to us in June 1986. Two weeks after the medication was stopped, blood pressure was 188/132 mm Hg. Clinical examination revealed slight bilateral gynecomastia but no other abnormalites. Biologic findings showed profound hy- pokalemia (2.3 meq/liter) and mild metabolic alkalosis (bi- carbonate: 29 meq/liter). Hormonal studies (Table II) re- vealed suppressed plasma renin activity and hyperaldoste- ronism. Cortisol circadian rhythm and response to ACTH were normal as was cortisol suppression with dexametha- sone (from 12 to 4.5 µg/100 ml), but 24-hour urinary corti- sol excretion was elevated. Testosterone was decreased to 1.64 ng/ml (normal: 3.5 to 11 ng/ml). Estradiol and estrone secretion were normal as were levels of follicle-stimulating hormone, luteinizing hormone, and serum prolactin. Ab- dominal ultrasound and computed tomographic scanning (Figure 1) showed an 8 X 10-cm heterogenous calcified right adrenal tumor, with central hemorrhage and necrosis and consequent displacement of the liver, the right kidney, and the inferior vena cava. In July 1986, a right adrenal tumor of 15 X 12 cm, weighing 285 g, was removed. Exploration of the abdomen revealed compression of the
inferior vena cava but no tumor infiltration or metastatic lymph nodes. Adrenocortical carcinoma was suspected in light of the tumor mass and was confirmed on histologic examination. Two thirds of the tumor consisted of brown tissue with tumor cell necrosis and hemorrhage. Epithelial clear cells with numerous mitoses displayed hyperchroma- tic nuclei with a high nuclear cytoplasmic ratio. In addition to the tumor pleomorphism and high mitotic index, we observed vascular invasion by cancer cells and the pres- ence of broad fibrous bands in the tumor, which had a diffuse growth pattern. No tumor cells were present in the capsule. Postoperative blood pressure and hormonal levels were normal and, one month later, treatment with mitotane was started. The patient is alive at the time of this writing, with no recurrence of the symptoms and no evidence of metastatic disease.
COMMENTS
From 1976 to 1986, more than 18,000 hypertensive patients were referred to our clinic and 137 presented with a clinical syndrome of primary aldosteronism. Com- plete adrenal imaging work-up showed the presence of unilateral tumoral primary aldosteronism in 85 of them, and 73 underwent laparotomy. Among the latter, 69 patients had a surgically proved benign Conn’s adenoma and four had adrenocortical carcinoma. This 3 percent incidence of adrenocortical carcinoma among patients with primary aldosteronism appeared higher than previ- ously reported. Review of the literature showed that the calculated incidence of adrenocortical carcinoma is two persons for one million population per year [1]. Although this discrepancy could be attributed to the patients stud- ied, who were already selected for high blood pressure, to our knowledge, a similar experience has not been report- ed by other hypertension clinics. This relatively high inci- dence of adrenal carcinomas emphasizes the need for careful evaluation of every patient with primary aldostero- nism. In these four cases, several features were determi- nant in the diagnosis of malignant adrenal tumor.
When compared with other patients with primary aldo- steronism in whom Conn’s syndrome was suspected, patients with carcinoma had low serum potassium levels (Table I). In 81 patients with benign tumoral primary aldosteronism, the mean serum potassium electrolyte value was 2.9 ± 0.5 meq/liter, whereas Patients 1, 2, and 4 had serum potassium values of 1.9 meq/liter, 1.4 meq/liter, and 2.3 meq/liter, respectively. However, when we compared their mean supine plasma aldoste- rone levels to the mean values observed in patients with Conn’s adenoma (45.9 ± 29.0 ng/dl), only Patient 1 showed a marked elevation at 115 ng/dl. Plasma renin and aldosterone responses to the upright posture or to serum saline infusion were not different from those ob- served in patients with either adenomas or bilateral adre- nal hyperplasia [7,13]. Other studies in patients with
adrenocortical tumors, presenting as pure primary aldo- steronism, had also shown that basal plasma aldosterone levels, as well as response to the upright position or to serum saline infusion, were of limited value in distinguish- ing adenomas from carcinomas because of the overlap between the two groups [15, 16]. Additional biochemical findings may be helpful for a differential diagnosis. In a study of 58 patients with adrenocortical tumors (26 ade- nomas and 32 carcinomas), Bertagna and Orth [ 17] found that urinary 17-ketosteroid excretion was the same in the two groups, but daily 17-hydroxycorticosteroid excretion greater than 20 mg strongly suggested carcinoma. In the current report, the urinary 17-hydroxycorticosteroid ex- cretion was above 20 mg per day in only three of the four patients, so this criterion was not sufficient to establish a definitive diagnosis.
However, careful hormonal evaluation demonstrated the potential capacity of cancer cells to produce a varied spectrum of adrenal steroid hormones [18]. Patient 3 initially fulfilled the established diagnostic criteria for pure primary aldosteronism, but her plasma deoxycorticoste- rone and 11-desoxycortisol levels were also high. The patient had no stigmata of Cushing’s syndrome, and was hypertensive because of a primary mineralocorticoid ex- cess [2]. Since the tumor did not synthetize cortisol or other potent glucocorticoids, a partial deficiency in 11- beta-hydroxylase enzymatic activity was inferred. To our knowledge, only three cases of adrenocortical carcinoma with such a clinical presentation have been previously reported [15]. Patients 1 and 2 presented isolated clinical features of primary aldosteronism, similar to Conn’s [3] original description. However, despite the absence of Cushing’s syndrome and the normal glucose tolerance, laboratory data subsequently showed an associated ex- cess of glucocorticoids. Several explanations were ad- vanced for the lack of clinical symptoms despite an excess of androgens or glucocorticoids [17]. In male patients, isolated elevation in 17-hydroxycorticosteroid levels may have been insufficient to cause clinically rec- ognizable hypervirilization. In both sexes, the degree and/ or duration of hypercorticism may have not been sufficient to induce clinical manifestations, or the tumor may have secreted just enough cortisol to replace normal adrenal secretion. Thus, despite complete hormonal evaluation in patients with primary aldosteronism, the results hardly appeared to predict benign and/or malignant tumors.
Difficulty in early diagnosis of adrenocortical carcino- ma was also the result of the deep retroperitoneal location of these tumors. Recent improvements in ultrasound and computed tomographic scanning techniques have made the detection of a mass in the adrenal region easier [19]. In this report, although angiography remained a valuable adjunct for evaluating tumor blood supply in Patient 1, only ultrasound and computed tomographic scanning allowed
an accurate and rapid diagnosis in all the other patients without the use of invasive procedures [20]. Abdominal computed tomographic scanning has been efficient in defining tumoral primary aldosteronism [21], but no valid criteria could be found to differentiate adenomas from carcinomas [22]. In our study, both ultrasound and com- puted tomographic scanning revealed internal tumor cal- cifications in each case of adrenocortical carcinoma. Using the same screening procedures, none of the other patients with primary aldosteronism caused by Conn’s syndrome or bilateral hyperplasia showed any calcifica- tions. Presence of tumor calcifications has rarely been reported in adrenal carcinomas [15], but in our experi- ence, it appeared determinant in the diagnosis of malig- nant adrenal tumors. Another important radiologic and pathologic characteristic of the carcinomas was their size at the time of presentation. Most aldosterone-producing adenomas were less than 3 cm in diameter [23]. No tumor of less than 30 g in weight, regardless of the histologic appearance, has proven to be malignant [24]. Carcinomas, at the time of their diagnosis, tend to be larger [1]. Enlarged tumor size and weight at the time of surgery might have been due to delayed diagnosis. How- ever, both Patients 3 and 4 had been hypertensive for 50 months prior to surgery, and no correlation could be established with their tumor size or weight, which were, respectively, 1,230 g and 84 g. In addition, among the other patients with Conn’s adenoma, high blood pressure had been observed from 12 to 372 months prior to the diagnosis. The mean duration of hypertension in 60 of them had been 91.2 ± 82 months before surgery. There- fore, in our experience, enlarged size or weight of an adrenal tumor above 3 cm in diameter with the presence of internal calcifications appeared highly suggestive of malignancy. Further studies will be needed to establish the specificity of such findings in definitively diagnosing adrenocortical carcinoma. Although the histologic diagno- sis of a malignant adrenocortical tumor is difficult to establish, several specific criteria were extensively re- viewed by Hough et al [14]. In the current report, adreno- cortical carcinoma was definitively assessed on histologic findings. Multiple mitotic figures, pleomorphic nuclei or cytoplasms, hemorrhages, and/or necrosis were always evidence of malignancy [25]. In Patients 3 and 4, no capsular invasion was observed, but the growth pattern, vascular invasion or tumor cell necrosis, and enlarged tumor mass were the most significant criteria for malig- nancy [14].
Despite attempts to cure adrenal carcinomas surgical- ly, the prognosis has remained poor. To date, no correla- tion has been found between either the tumor’s functional status, or the presence of local extension or distant me- tastasis at the time of diagnosis, and the patient’s ultimate course [24,26]. Mitotane has been used since 1959 in the
treatment of metastatic adrenal carcinoma [27] and may induce tumor regression. Bertagna and Orth [ 17] reported temporary objective improvement in 32 patients treated with mitotane. However, in all studies, survival prognosis has varied from days to years [28]. Because of the rapid fatal outcome observed in Patients 1 and 2, treatment with mitotane was started one month after surgery in Patients 3 and 4. Although both are still alive at the time of this report, with normal blood pressure and absence of clinical or biologic abnormalities, we lack sufficient fol- low-up to evaluate the potential benefits of mitotane.
In conclusion, isolated symptoms of primary aldostero- nism may reflect adrenocortical carcinoma. Complete
biologic and hormonal work-up should be obtained, especially in patients presenting with very low serum potassium levels, and systematic abdominal ultrasound and computed tomographic scanning should be per- formed. Enlarged tumor size, necrosis, or hemorrhages with internal calcifications of the tumor favor a diagnosis of malignancy, and prompt surgical treatment should be undertaken.
ACKNOWLEDGMENT
We would like to thank Miss G. Caspari for reviewing the manuscript and Miss C. Loury for her excellent assistance in typing the manuscript.
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