Steroid Profile in an Adrenocortical Carcinoma Producing Aldosterone
K. Müssig1 M. Wehrmann2
M. Horger3
R. Teichmann4 C. Maser-Gluth5 H .- U. Häring1 D. Overkamp1
Abstract
We report a rare case of primary aldosteronism due to an adreno- cortical carcinoma. A 61-year-old woman with a history of hy- pertension and hypokalemia was referred for evaluation of a 4.2 cm measuring adrenal mass without secondary signs of ma- lignancy. Endocrinological testing was consistent with primary aldosteronism. The patient underwent surgical resection of the adrenal mass; histology revealed an adrenocortical carcinoma. Postoperatively blood pressure, serum potassium, and aldoster- one returned to normal. Four months after adrenalectomy, the patient presented again with hypokalemic hypertension and
was found to have metastatic disease. Endocrinological investi- gation revealed primary aldosteronism and subclinical autono- mous glucocorticoid hypersecretion. Careful hormonal investi- gation should be obtained in patients with adrenal masses caus- ing excessive aldosterone secretion. In uncertain cases of pri- mary aldosteronism, we would suggest to measure 18-hydroxy- cortisol levels, as excessive amounts may indicate adrenocortical carcinoma.
Key words
Adrenocortical carcinoma · primary aldosteronism · mineralocor- ticoid hypertension . 18-hydroxycortisol
Introduction
With an incidence of 2 to 10 cases per one million population and an estimated percentage of 0.05-0.2% of all malignancies adre- nocortical carcinoma is a rare form of cancer (Kopf et al., 2001). Adrenal malignancies are subdivided into endocrine active and endocrine inactive tumours. When diagnosed almost all patients with adrenocortical carcinoma are symptomatic either because of endocrine abnormalities or because of tumour mass effects.
About half of the patients present with endocrine disturbances, among them Cushing’s syndrome (more than 50% of endocrine symptoms) and to a lesser extent virilization and feminization (Schulick and Brennan, 1999). Hypokalemic hypertension caused by primary aldosteronism is a very rare manifestation (Allolio et al., 2002). However, cases of adrenocortical carcinoma producing aldosterone require clinical attention. Therefore we want to con- tribute another case.
Affiliation
1 Department of Internal Medicine, Division of Endocrinology, Metabolism, and Pathobiochemistry, University Hospital of Tübingen, Germany
2 Department of General Pathology, University Hospital of Tübingen, Germany
3 Department of Diagnostic Radiology, University Hospital of Tübingen, Germany
4 Department of General Surgery, University Hospital of Tübingen, Germany
5 Steroid Laboratory, Department of Pharmacology, University of Heidelberg, Germany
Correspondence
Dr. Karsten Müssig, M.D · Medizinische Klinik IV · Universitätsklinikum Tübingen ·
Otfried-Müller-Straße 10 . 72076 Tübingen · Germany · T + 49 (0) 7 07 12 98 36 70 . F + 49 (0) 7071 29 27 84 . E-mail: karsten.muessig@med.uni-tuebingen.de
Received: May 24, 2004 . First decision: September 20, 2004 . Accepted: December 10, 2004
Bibliography
Exp Clin Endocrinol Diabetes 2005; 113: 236-240 @ J. A. Barth Verlag in Georg Thieme Verlag KG . Stuttgart . New York .
DOI 10.1055/s-2005-837663 . ISSN 0947-7349
| Preoperative supine | upright | 1 week after OP supine | 4 months after OP upright | 5 months after OP upright | Normal range | |
|---|---|---|---|---|---|---|
| Serum aldosterone concentration | 299 | 385 | 64 | 640 | 1008 | supine 10-160 pg/ml, upright 40-310 pg/ml |
| Plasma renin activity | 0.31 | 0.45 | 0.93 | 0.16 | 0.16 | supine 0.12 - 1.59 ng Angl · ml-1 . h-1, upright 0.15-2.12 ng Angl · ml-1 . h-1 |
| Urine aldosterone concentration | 32 | 6-25 µg/24 h | ||||
| Serum aldosterone concentration/plasma renin activity ratio | 96 | 86 | 7 | 400 | 630 | ng/dl per ng · ml-1 . h-1 |
A serum aldosterone concentration (in ng/dl) to plasma renin activity (in ng· ml-1 . h-1) ratio ≥20 and a serum aldosterone concentration ≥ 15 ng/dl indicate probable pri- mary aldosteronism (Young, 2003)
Material and Methods
Serum and urinary aldosterone levels, shown in Table 1, were de- termined using a commercial radioimmunoassay (RIA) kit (Diag- nostic Systems Laboratories, Inc., Webster, Texas, USA). Intraas- say coefficients of variation (C.V.s) were <8% and interassay C.V.s were < 10%. Plasma renin activity was measured with a commercial RIA kit (Biochem Immunosystems, Freiburg, Ger- many). Intraassay C.V.s and interassay C.V.s were ≤6%.
The steroids shown in Table 3 were determined in the steroid laboratory of the Dept. of Pharmacology, University of Heidel- berg. All steroids analyzed were measured by specific RIAs using tritiated steroids (Amersham Biosciences, Freiburg, Germany) and specific antibodies, raised and characterized in the steroid laboratory, as described elsewhere (Vecsei et al., 1983). Prior to quantification by RIAs steroids were extracted from plasma with organic solvents and chromatogaphically purified using Celite columns (Celite 545 AW; Sigma Aldrich, Taufkirchen, Germany). Intraassay C.V.s were < 10% and interassay C.V.s were < 15%.
Case Report
A 61-year-old woman was referred to our department for evalu- ation of a right adrenal tumour. On admission the patient report- ed arterial hypertension since 6 months, 3 months intermittent fronto-temporal headache, and muscle weakness. The patient’s medical history revealed type 2 diabetes mellitus of 12 years du- ration and Hashimoto’s thyroiditis. No other endocrine disorders were reported. Clinical examination showed a mildly overweight woman (160 cm, 68.9 kg, BMI 27 kg/m2) in good general health. Blood pressure was increased (160/94 mm Hg) with a pulse rate of 64/min. Routine haematological and biochemical findings were normal except for marked hypokalemia (2.2 mmol/l, nor- mal range 3.6-5.0). As shown in Table 1, plasma renin activity was low normal and serum and urine aldosterone concentrations as well as the serum aldosteron concentration to plasma renin
activity ratio were elevated suggesting primary hyperaldoste- ronism.
There were no clinical signs of hypercortisolism; cortisol and ACTH plasma levels were normal. Plasma concentrations of DHEAS, androstendione, and testosterone were within the nor- mal range. A computed tomography scan was performed on a Volume Zoom scanner (Siemens, Forchheim, Germany) with a slice collimation of 4× 1 mm and 6 mm feed/rotation resulting in a pitch of 1.5. Unenhanced CT revealed a 4.2 x 3.0 cm mass in the right suprarenal lodge with compression of the inferior caval vein. The tumour’s density was between 15 and 42 Hounsfield units (HU). After IV contrast material administration, the mass showed inhomogeneous enhancement with a peak density of 115 HU. No calcifications were found. The tumour’s borders were slightly irregular (Fig. 1).
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Table 2 Histological evaluation according to Weiss criteria (Weiss et al., 1984) revealed adrenocortical carcinoma
Feature
| Nuclear grade Ill or IV | III |
| Mitotic rate > 5 per 50 HPF | >20 |
| Atypical mitoses | present |
| Clear cells | ca. 20% |
| ≤ 25% of the tumour | present |
| Diffuse architecture | present |
| Necrosis | present |
| Invasion of venous structures | present |
| Invasion of sinusoidal structures | present |
| Invasion of tumour capsule | present |
| Mitotic rate per 50 HPF | 47/50 HPF |
| Mib1 (Ki67)-expressing cells | ca. 30% |
HPF, high power field
The CT attenuation level higher than 10 HU on unenhanced CT, the heterogeneity after application of contrast material, and the slightly irregular margins of the adrenal mass were suspicious of adrenocortical carcinoma. However, malignancy can only be di- agnosed in the presence of metastases, lymphadenopathy, or in- vasion into surrounding tissue. Since there were no secondary signs of malignancy, a laparoscopic adrenalectomy was per- formed. The patient refused preoperative treatment with the al- dosterone antagonist spironolactone, therefore, she underwent the adrenalectomy without pretreatment. Intraoperatively there were no signs of infiltration of surrounding tissues or lymphatics by the encapsulated tumour; conversion to open adrenalectomy was not necessary. Histology of the 150 g weighing tumour re- vealed an adrenal carcinoma according to the Weiss criteria (Weiss et al., 1984) with capsular and venous invasion (Table 2). Immunohistochemistry showed about 30% Mib 1 (Ki67)-ex- pressing cells corresponding to the high mitotic rate in the light microscopic examination (Table 2).
The intervention was functionally successful as blood pressure, serum potassium, and serum aldosterone concentrations re- turned to normal (Table 1). Postoperatively the patient did not develop signs of hypoaldosteronism, although a pretreatment with the aldosterone antagonist spironolactone was not per- formed. The patient was informed of optional adjuvant therapies (oral administration of the adrenocorticolytic drug mitotane [Lysodren; 1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloro- ethane, o,p’-DDD] or fractionated radiation of the adrenal region) but decided against any therapy. A short-term control visit to our outpatient clinic was arranged. Four months after adrenalec- tomy, the patient again presented with hypokalemic hyperten- sion (blood pressure 155/100 mmHg and serum potassium 3.2 mmol/l, normal range 3.6-5.0). Hormone studies showed low normal plasma renin activity and increased serum aldoster- one concentration as well as a markedly elevated serum aldo- sterone concentration to plasma renin activity ratio indicating a relapse of primary hyperaldosteronism (Table 1). Computed to- mography of the chest and abdomen revealed lung secondaries
| Adrenal steroids | Plasma levels | Normal range |
|---|---|---|
| 11-deoxycorticosterone | 150.8 | 2.0 - 15.0 ng/dl |
| Corticosterone | 1.5 | 0.1-2.0 µg/dl |
| 18-hydroxycorticosterone | 197.4 | 12.0 -55.0 ng/dl |
| 17-hydroxypregnenolone | 1019 | 30-350 ng/dl |
| 17-hydroxyprogesterone | 228 | 40-220 ng/dl |
| 21-deoxycortisol | 18.1 | 2.0- 15.0 ng/dl |
| 11-deoxycortisol | 1.17 | 0.1-0.3 µg/dl |
| Cortisol | 16.4 | 5.6-20.0 µg/dl |
| Cortisone | 1.1 | 1.5-3.0 µg/dl |
| 18-hydroxycortisol | 3126 | 30-130 ng/dl |
| Dehydroepiandrosterone | 434 | 200 - 750 ng/dl |
| Dehydroepiandrosterone sulfate | 62 | 10-100 µg/dl |
| Androstenedione | 71 | 30-80 ng/dl |
| Androstanediol glucuronide | 141 | 90-200 ng/dl |
| Testosterone | 32 | 20- 80 ng/dl |
| Dihydrotestosterone | 8 | 3 -23 ng/dl |
and retroperitoneal and mediastinal lymph node disease with- out evidence of local recurrence. Evaluation of the adrenal ste- roids revealed markedly increased plasma levels of 18-hydroxy- cortisol (24-fold), the mineralocorticoid precursors 11-deoxycor- ticosterone (10-fold) and 18-hydroxycorticosterone (3.5-fold), as well as the glucocorticoid precursors 17-hydroxypregnenolone (3-fold) and 11-deoxycortisol (4-fold) (Table 3). Plasma levels of corticosterone, cortisol (Table 3), and ACTH (3.9 pmol/l, normal range 2.0-11.0) were normal. Urinary cortisol levels were in- creased (253 µg/24 h, normal range 12-90) suggesting subclini- cal autonomous glucocorticoid hypersecretion, as the patient was free of signs of hypercortisolism. Plasma levels of DHEAS, androstendione, and testosterone were within the normal range.
The patient again refused therapy with the adrenocorticolytic drug mitotane (Lysodren, o,p’-DDD) as well as polychemother- apy based on cisplatin and etoposide. For control of blood pres- sure and hypokalemia the patient is treated with spironolactone and potassium substitution. She is regularly seen by her family doctor, who reported that she was in good general health 1 year after primary aldosteronism has been diagnosed.
Discussion
The present case of an adrenocortical carcinoma causing primary aldosteronism reflects the importance of a thorough endocrino- logical investigation in patients presenting with an adrenal mass. On diagnosis of primary aldosteronism, our patient did not show signs of hypercortisolism and plasma levels of cortisol and ACTH were within the normal range. We failed to rule out hypercorti- solism definitely by a dexamethasone suppression test or an as- sessment of urinary cortisol concentration. However, since co-
| Criterion | Aldosterone-secreting adenoma | Aldosterone-secreting carcinoma |
|---|---|---|
| Sex (female/male) | 2.2:1 | 1.8:1 |
| Age (years) | 15-75 | 24-68 |
| (Mean) | (42) | (41) |
| Side (left/right) | 2.4:1 2% bilateral | 1.75:1 |
| Size (cm) | 0.5-5 | 2-15 |
| Weight (g) | 1-200 | 30->2000 |
| (Mean) | (8.8) | (690) |
secretion of aldosterone and cortisol has previously been report- ed in adrenal tumours (Kurtulmus et al., 2004), a low-dose dexa- methasone suppression test should be part of any endocrinolog- ical evaluation of an adrenal mass, also in those causing primary aldosteronism. The failure to diagnose subclinical autonomous glucocorticoid hypersecretion can endanger the patient who undergoes adrenalectomy because of possible postoperative de- velopment of secondary adrenal insufficiency. On recurrence of primary aldosteronism 4 months after the intervention, our pa- tient showed subclinical autonomous glucocorticoid hypersecre- tion. After all, we do not know whether the adrenal mass already co-secreted cortisol on diagnosis of aldosteronism. A co-secre- tion of aldosterone and cortisol only on recurrence of adrenal carcinoma, initially producing selectively aldosterone, has been reported previously (Arteaga et al., 1984) and is therefore also possible in our patient. However, all these speculations would have been unnecessary, if we had ruled out definitely hypercor- tisolism preoperatively by the appropriate test.
The preoperative CT showed an adrenal mass with findings sus- picious of an adrenocortical carcinoma (CT attenuation level higher than 10 HU on unenhanced CT, heterogeneity, and slightly irregular margins) (Grumbach et al., 2003). The clinical charac- teristics of aldosterone-secreting adrenal adenomas and carcino- mas are summarized in Table 4. The profound hypokalemia, found in our patient on admission, is also not typical of adrenal adenomas causing primary aldosteronism. Whereas patients with an adrenocortical carcinoma secreting aldosterone present more often with a marked hypokalemia (Farge et al., 1987).
However, there were no secondary signs of malignancy (distant metastases, lymphadenopathy, or invasion into surrounding tis- sue). Therefore, we decided to perform a laparoscopic adrenalec- tomy (LA). LA has become the standard for the surgical treatment of apparently benign adrenal lesions smaller than 60 mm (Smith et al., 1999), whereas, LA for primary malignancies and meta- static disease of the adrenal is controversial. Invasive adrenal carcinoma is unquestionably an absolute contraindication for LA. However, an increasing number of studies report that LA can be used in experienced hands for large, potentially malignant tu- mours and demonstrates that results of LA for malignant lesions are similar to those of open adrenalectomy, without its morbid-
ity (Sturgeon and Kebebew, 2004; MacGillivray et al., 2002; Henry et al., 2002). In general, LA should be performed meticu- lously, with the goal of achieving complete tumour resection without disruption of the adrenal capsule. If local invasion is ob- served during surgery, a conversion to open adrenalectomy should be performed. In our patient, conversion to open adrena- lectomy was not indicated, as there were no signs of infiltration into surrounding tissue. When primary aldosteronism recurred in our patient, there was no local recurrence suggesting that LA was performed with due caution.
On relapse, the hormonal measurements revealed, beside the markedly elevated plasma concentrations of aldosterone and the mineralocorticoid precursors 11-deoxycorticosterone and 18-hydroxycorticosterone, increased plasma levels of the gluco- corticoid precursors 17-hydroxypregnenolone and 11-deoxycor- tisol. The normal cortisol plasma levels despite increased con- centrations of 11-deoxycortisol, could be a sign of a decreased ac- tivity of 11ß-hydroxylase (CYP11B1), as described previously in adrenocortical carcinoma (Saha et al., 1990) as well as in primary aldosteronism (Jamieson et al., 1996). Alternatively, cortisol and 11-deoxycortisol may serve as substrates of aldosterone syn- thase (CYP11B2) (Ulick et al., 1983) resulting in excessive amounts of 18-hydroxycortisol. 18-Hydroxycortisol and 18-oxo- cortisol are markedly increased in patients with primary aldos- teronism due to adrenal adenomas or glucocorticoid-suppressi- ble aldosteronism (Gomez-Sanchez et al., 1988). Mosso et al. re- ported that in primary aldosteronism 18-hydroxycortisol levels are about 2.5 times higher compared to essential hypertensives or normotensives (Mosso et al., 2001). In patients with glucocor- ticoid-suppressible aldosteronism 18-hydroxycortisol levels were even 10 times higher than the normal upper limit. Since in our patient 18-hydroxycortisol concentration was 24 times in- creased, excessive amounts of 18-hydroxycortisol may be indica- tive for primary aldosteronism due to adrenocortical carcinoma. Unfortunately, 18-hydroxycortisol levels had not been measured in our patient preoperatively. Therefore, we cannot exclude that 18-hydroxycortisol levels only increased with recurrence of pri- mary aldosteronism, as adrenocortical carcinomas can change their steroid profile during dedifferentation and during meta- static disease (Hisamatsu et al., 2002). We screened the litera- ture for 18-hydroxycortisol levels in adrenocortical carcinoma causing primary aldosteronism, but we did not find case studies that reported on this steroid metabolite.
In our patient, the clinical outcome is probably predicted by the high mitotic rate and venous invasion in the adrenocortical carci- noma, as mitotic activity and venous invasion correlated best with metastasizing or recurring adrenocortical tumours (Weiss et al., 1989). The number of mitotic figures has also been reported to correlate as an independent prognostic factor with survival rates for patients undergoing curative resection for adrenocorti- cal carcinomas (Harrison et al., 1999).
In summary, we describe a very rare manifestation of an adreno- cortical carcinoma with biochemically proven primary aldoste- ronism. The present case reflects the importance of a thorough endocrinological investigation in patients presenting with an adrenal mass. Furthermore, we report on imaging and clinical characteristics that may help distinguish adrenocortical carcino-
ma causing primary aldosteronism from adrenal adenoma. In uncertain cases of primary aldosteronism, we would suggest to measure 18-hydroxycortisol levels, as excessive amounts may indicate adrenocortical carcinoma.
Acknowledgements
The authors thank Davina Burt, Ph.D., for proof reading the manuscript.
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