CASE REPORT
Adrenocortical carcinoma producing 11-deoxycorticosterone: A rare cause of mineralocorticoid hypertension
K. Müssig1, M. Wehrmann2, M. Horger3, C. Maser-Gluth4, H-U. Häring1, and D. Overkamp1
1Division of Endocrinology, Metabolism and Pathobiochemistry, Department of Internal Medicine;
2Department of General Pathology; 3Department of Diagnostic Radiology, University of Tübingen;
4Steroid Laboratory, Department of Pharmacology, University of Heidelberg, Heidelberg, Germany
Abstract. A 37-yr-old man presented with the classic signs of mineralocorticoid excess hy- pertension and hypokalemia. The cause was not aldosterone excess, but elevation of plasma 11-deoxycorticosterone (DOC). Computed tom- ography (CT) scans showed a large right adrenal mass without signs of metastatic disease. The tumor was removed by open laparotomy, and histology revealed an adrenocortical carcinoma.
Two yr after diagnosis, the patient is in good gen- eral condition and there is no sign of recurrence or metastatic disease, despite the large tumor size. DOC producing adrenocortical carcinomas causing mineralocorticoid hypertension are very rare, so far only 10 cases have been described in the literature.
(J. Endocrinol. Invest. 28: 61-65, 2005) @2005, Editrice Kurtis
INTRODUCTION
The combination of hypertension, hypokalemia, metabolic alkalosis, and low plasma renin activity characterises mineralocorticoid hypertension (1). Hypokalemic hypertension, caused by mineraloco- rticoids other than aldosterone, is rare (2). We here present a patient with an adrenocortical carcinoma producing 11-deoxycorticosterone (DOC) leading to hypokalemic hypertension. DOC is an aldosterone precursor and is itself a potent mineralocorticoid (3).
MATERIALS AND METHODS
Serum and urinary aldosterone levels were determined using a commercial radioimmunoassay (RIA) kit (Diagnostic Systems Laboratories, Inc., Webster, Texas, USA). Intra-assay coefficients of variation (CVs) and inter-assay CVs were <8 and <10%, respec- tively. Plasma renin activity was measured with a commercial RIA kit (Biochem Immunosystems, Freiburg, Germany). Intra-assay CVs and inter-assay CVs were ≤ 6%.
Steroids mentioned in Table 2 were determined in the steroid laboratory of the Department of Pharmacology, University of Heidelberg. All steroids analyzed were measured by specific RIA, using tritiated steroids (Amersham Biosciences, Freiburg, Germany) and specific antibodies, raised and characterised in the steroid laboratory, as described elsewhere (4). Prior to RIAs, steroids were extracted from plasma or urine (pre-treated with B-glucuronidase) with organic solvents and chromatographical- ly purified using Celite columns (Celite 545 AW; Sigma Aldrich, Taufkirchen, Germany). Intra-assay CVs and inter-assay CVs were 10 and <15%, respectively.
CASE REPORT
A 37-yr-old male was referred to our Department for work-up of suspected pheochromocytoma in December 2001.
Arterial hypertension had been discovered some weeks previously by chance, when the patient had performed a blood pressure self measurement. Ultrasonography of the abdomen had revealed a large tumor in the right epigastrium. Computed to- mography (CT) had been performed on a Somatom AR. Star scanner (Siemens, Forchheim, Germany). Scan parameters had been: 5 mm slice thickness and 5 mm feed/rotation resulting in a pitch of 1. On unenhanced images, a right suprarenal mass with a size of 8.8x10.5 cm had been found. It had revealed a non-homogenous density, with values
Key-words: Mineralocorticoid excess, hypokalemic hypertension, adrenocortical carcinoma, 11-deoxycorticosterone.
Correspondence: D. Overkamp, MD, Medizinische Klinik IV, Universität- sklinikum Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany. E-mail: Dietrich.Overkamp@med.uni-tuebingen.de Accepted July 7, 2004.
A
19112-2001
A
SOMATOM AR.STAR
21-OCT-1964
VB41A
H-SP-CR
14:35: 12.12
TP -188.0
IMA 20
SPI 3
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10
KV 130
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nA 83
TI 1.50
GT 0.0
SL 5.0/5.0
345 -7/-12
AB40 SO
1211930
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202 39
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B
SOMATOM AR.STAR
19112-2001
A
VB41A
08-NOV-2001
H-SP-CR
14:44:59.49
TP -190.0
IMA 56
SPI 12
R
10
C
n
kV 130 mA 83
TI 1.50
GT 0.0
SL 5.0/5.0
345 -9/-12
AB40 SO
W
202
1211330
100 ML ULTRAVIST 300 I.V.
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59
between 20 and 110 Hounsfield U which was due presumably to recent hemorrhage (Fig. 1A). Forty sec after IV contrast material administration, the tu- mor had showed intense peripheral enhancement with large central hypointensity due to necrosis (Fig. 1B). A slow wash-out phenomenon had been verified in the portal-venous phase.
Since urine epinephrine concentration had been found to be slightly elevated, the attending physi- cian postulated pheochromocytoma.
On admission to our Department, the patient re- ported an unremarkable past medical history. In particular, hints at endocrine disorders were missing. The patient was unmedicated and free of symptoms or signs. Specifically, on questioning, palpitations, unmotivated sweating or intermittent facial pallor were denied. Clinical examination showed an adult male of normal body composition (179 cm, 70 kg) and good general condition. Blood pressure and 24- h ambulatory systolic and diastolic blood pressure were slightly raised (Table 1), the pulse rate was nor- mal. The liver and spleen were not enlarged. Routine hematological and biochemical findings were normal except for slight hypokalemia (Table 1). TSH, free T4 and free T3 levels were within the normal range. An ECG was normal without signs of hypertrophy and arrhythmias.
Since urinary catecholamine excretion was within the normal range and iodine131-meta-iodoben- zylguanidine (MIBG) scintigraphy was negative, a catecholamine producing tumor was unlikely. There were no clinical signs of hypercortisolism. Basal hormone levels of cortisol (19.3 µg/dl, normal range 5-23) and ACTH (6.8 pmol/l, normal range 2-11) and diurnal rhythms were within the normal range. Plasma levels of the androgens androstendi- one (210 ng/dl, normal range 30-310), testosterone (385 ng/dl, normal range 240-830), and dehydroe- piandrostendione sulfate (363 µg/dl, normal range 109-666) were within the normal range.
As the combination of an adrenal mass, hypoka- lemia and hypertension raise the suspicion of a mineralocorticoid-producing tumor, and since primary aldosteronism is the most common cause of mineralocorticoid induced hyperten- sion, renin activity and aldosterone concen- tration were measured. Serum aldosterone concentration was found to be normal, urinary
| Investigation | Normal range | |
|---|---|---|
| BP | 160/100 | <135/85 mmHg |
| 24-h ambulatory BP | Mean value 147/104 | <130/80 mmHg |
| Serum potassium | 3.4 | 3.6-5.0 mmol/l |
| Serum aldosterone | 43 | 10-160 pg/ml |
| Urinary aldosterone | 1.62 | 6-25 µg/24h |
| Plasma renin activity | 0.2 | 0.12-1.59 ng Angl/ml/h |
BP: blood pressure.
| Pre-operative | Post-operative | Normal range | |
|---|---|---|---|
| Plasma | |||
| 11-deoxycortisol | 0.68 | 0.07 | 0.1-0.3 µg/dl |
| 18-hydroxycorticosterone | 35.9 | - | 12.0-55.0 ng/dl |
| 18-hydroxycortisol | 70 | - | 30-130 ng/dl |
| 11-deoxycorticosterone | 347.2 | 4.0 | 2.0-15.0 ng/dl |
| 17-hydroxypregnenolone | 1150 | 165 | 30-350 ng/dl |
| 17-hydroxyprogesterone | 174 | - | 40-220 ng/dl |
| 21-deoxycortisol | 1.0 | - | 2.0-15.0 ng/dl |
| Urinary | |||
| Aldosterone-18-glucuronide | 6.9 | - | 3.5-17.5 µg/24 h |
| Tetrahydroaldosterone | 79 | 28 | 10-70 µg/24 h |
| Free aldosterone | 0.35 | - | 0.1-0.4 µg/24 h |
| Free 18-hydroxycorticosterone | 7.9 | 3.1 | 1.6-6.5 µg/24 h |
| Free deoxycorticosterone | >9.0 | 0.07 | 0.1-0.4 µg/24 h |
| Free 18-hydroxydeoxycorticosterone | 6.22 | 0.54 | 0.2-1.8 µg/24 h |
| Free 18-hydroxycortisol | 126 | - | 40-145 µg/24 h |
The pre-operative increased parameters were remeasured after surgery.
aldosterone concentration to be decreased, and plasma renin activity within the low normal range (Table 1). Thus, primary aldosteronism was ex- cluded and mineralocorticoid precursor steroids were evaluated as a possible cause of mineralo- corticoid hypertension. The plasma and urinary concentration of DOC was found to be markedly increased (Table 2). There was also a marked in- crease of 17-hydroxypregnenolone and a slight increase of deoxycortisol. However, aldosterone
| Feature | |
| Nuclear Grade Ill or IV | Ill focal IV |
| Mitotic rate >5 per 50 HPF* | 0-5 |
| Atypical mitoses | Present |
| Clear cells | Ca. 30% |
| ≤25% of the tumor | Absent |
| Diffuse Architecture | Present |
| Necrosis | Present |
| Invasion of venous structures | Absent |
| Invasion of sinusoidal structures | Present |
| Invasion of tumor capsule | Present |
| Mitotic rate per 50 HPF | 2/50 HPF |
| Mib1 (Ki67)-expressing cells | <5% (ca. 2-3%) |
*HPF: high power field.
and cortisol were not augmented suggesting a functional defect of 11-hydroxylase.
Ultrasonography was repeated and confirmed a 9x12x10 cm large, non homogenous, sharply de- marcated mass in the right adrenal region. Magnetic resonance tomography established a large, central- ly necrotic adrenal tumor without signs of infiltrating adjacent organs. Abdominal angiography revealed an adrenal mass supplied by the right inferior supra- renal artery. Despite the tumor’s considerable size, there was no evidence for metastatic disease on CT scans of the abdomen and chest.
Since the tumor’s size was indicative of a high risk of malignancy, the tumor was removed by open laparotomy. The tumor measured 14x9x7 cm in diameter and weighed 440 g. Histology revealed an adrenal carcinoma according to the Weiss criteria (5) (Table 3). There was evidence of capsular invasion, whereas transgression of the tumor capsule was not shown (Fig. 2). Immunohistochemistry revealed about 2-3% Mib 1 (Ki67)-expressing cells corre- sponding to the low mitotic rate in the light micro- scopic examination. Post-operatively, blood pres- sure, serum potassium concentration and plasma DOC returned to normal (Table 2). Since resection of the tumor led to a normalisation of DOC plasma concentration, this compound served as a tumor marker in the clinical follow-up of the patient.
The patient was informed of optional adjuvant therapies {oral administration of the adrenocortico-
Periadrenal fat
Capsule
Tumor cells
lytic drug mitotane [Lysodren; 1-(2-chlorophenyl)- 1-(4-chlorophenyl)-2,2-dichloroethane, o,p’-DDD] or fractionated radiation of the adrenal region}, but decided against any adjuvant therapy.
The patient has since then regularly been seen in our outpatient Department. When he last presented in January 2004, there was no evidence of recurrent disease, neither from the results of hormonal testing nor from a CT scan of the abdomen and chest.
DISCUSSION
Mineralocorticoid hypertension caused by isolated deoxycorticosterone producing adrenocortical carcinoma without excess of aldosterone or cortisol is very rare and has been documented in just a few case reports (6-11).
The clinical presentation of our patient was unre- markable, except for mild hypertension discovered by chance performing a blood pressure self meas- urement and slight hypokalemia. At the time of diagnosis, almost all patients with adrenocortical carcinoma are symptomatic either because of en- docrine abnormalities or because of tumor growth. 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 (12). However, hypokalemic hypertension caused by aldosteronism or excessive deoxycorticosterone secretion is a very infrequent manifestation.
In the few cases of adrenocortical carcinoma produ- cing DOC described in the literature, clinical findings, besides hypertension and hypokalemia, were: fa-
tigue (3 cases), muscle weakness (3 cases), nycturia (2 cases), abdominal pain (2 cases), edema, weight loss, weight gain, increased thirst, and gross hematuria. In our patient, hypokalemia as well as hypertension were mild despite severely elevated DOC plasma concentration (23 times normal). In the reported cases of adrenocortical carcinomas producing similar levels of DOC as in our patient, marked hypokalemia was more prevalent (6, 7, 9, 11), consistent with previ- ous studies showing that in patients with adrenal ma- lignancies producing aldosterone, hypokalemia was more profound compared to patients with benign adrenal lesions (13). In the reported case studies of DOC-producing adrenocortical carcinomas, pro- found hypokalemia was found to be associated with severe hypertension.
Another aspect of the present case, which ap- pears to be of interest, is its benign clinical course. Following more than two yr after diagnosis of an adrenocortical carcinoma, there are no signs of local recurrence or metastatic disease despite a very large tumor size (14 cm). Tumor size has been shown to be an independent prognostic factor. Pa- tients with adrenocortical carcinoma larger than 12 cm have a worse outcome than those with smaller malignant adrenal lesions (5-yr survival rate: 22 vs 53%) (14). However, 5-yr survival is not equivalent to cure, since 85% of patients who were operated with curative intent have local recurrence or metastatic disease within 5 yr (15). In our patient, the good clinical outcome may be due to the low mitotic rate of the adrenocortical carcinoma, as mitotic activity has been shown to be the most important patho- logic determinant of survival in patients with adrenal carcinoma (16). Malignant primary adrenal tumors have a poor prognosis with a total 5-yr survival rate of approximately 38 % (17). Approximately 30 % of patients with adrenal carcinoma already have metastatic disease at the time of diagnosis (18). In patients with DOC-producing adrenal carcinoma operated upon with curative intent, the longest survival free of metastatic disease that has been described in literature is 48 months (6). By contrast, patients who had already metastases when adreno- cortical carcinoma secreting DOC was diagnosed had a very poor outcome (7, 8).
The benign clinical course of our patient without us- ing mitotane as adjuvant therapy is in accordance with previous studies showing that patients who received potentially curative resection adjuvant treatment with mitotane did not improve 5-yr survival rate (17).
In summary, this case demonstrates that it is worth- while to perform a thorough endocrinological investigation, in particular in cases presenting with atypical clinical findings or biochemical analyses
(hypokalemic hypertension with plasma renin activ- ity and plasma aldosterone concentration within the normal range). This not only serves to unravel the individual physiopathology, but as in our case, the substance identified as causative of endocrine hy- pertension can also serve as a tumor marker and thus be useful in the clinical follow-up of the patient.
ACKNOWLEDGMENTS
The authors thank Davina Burt, Ph.D., for proofreading the manuscript.
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