CASE REPORT Two cases of adrenocortical carcinoma presenting as Conn’s syndrome
AN Dixon and RF Bing The Glenfield Hospital NHS Trust, Groby Road, Leicester LE3 9QP, UK
Keywords: adrenocorticol carcinoma; aldosterone
Introduction
Primary hyperaldosteronism most often results from benign adenoma or bilateral hyperplasia of the adre- nal glands and only rarely is it caused by adreno- cortical carcinoma.1 We present two cases in which adrenocortical carcinomas presented as Conn’s syn- drome.
Case 1 Initial presentation
A 25-year-old white male schoolteacher presented with a several month history of progressive pain and weakness of the proximal muscles, and at initial presentation was found to have hypertension. His background medical history was unremarkable, and he was taking no regular medication. On clinical examination his pulse rate was 80 bpm and supine blood pressure was 200/140 mm Hg. He had reduced power of the proximal muscles but sensation and tendon reflexes were symmetrically normal. Urinal- ysis demonstrated haematuria but no proteinuria. ECG demonstrated voltage-criteria for left ventricu- lar hypertrophy. Plasma electrolytes were as fol- lows: sodium 150 mmol/l, potassium 1.7 mmol/l and bicarbonate 49 mmol/l. Urea was 5.1 and full blood count and plasma viscosity was normal. Chest X-ray was unremarkable and heart size was normal.
Special investigation
Further investigation included the following. Paired lying and 4 h post-standing plasma renin and aldos- terone: plasma renin lying was 0.6 pmol/L (normal range 1.1-4.5 pmol/L) and standing 1.5 pmol/L; aldosterone lying was 5838 pmol/L (normal range
<445 pmol/L) and standing 6811 pmol/L (normal range 110-850 pmol/L). Diurnal variation of plasma cortisol was determined by measuring levels at 8 am and midnight on three consecutive days. This dem- onstrated loss of diurnal variation: day 1-239 and 170 nmol/l, day 2-165 and 95 nmol/l, and day 3- 242 and 159 nmol/l. A CT scan of the adrenal glands showed a large right adrenal tumour measuring 3 cm (Figure 1). A 75-selenocholesterol-labelled scan to demonstrate relative uptake of isotope by the adre- nal glands showed approximately equal uptake: right adrenal gland 0.09% uptake and left 0.11% uptake (normal range 0.1-0.3%). High-resolution gas chromatographic urine steroid profile demon- strated high excretion levels of both cortisol metab- olites and aldosterone precursors.
R
Correspondence: Dr AN Dixon, The Glenfield Hospital NHS Trust, Groby Road, Leicester LE3 9QP, UK. Fax: 0116 2563422 Received 18 April 2000; accepted 23 April 2000
Clinical course
A diagnosis of primary hyperaldosteronism was made on the basis of hypertension, hypokalaemia, metabolic alkalosis and an elevated and non-sup- pressible plasma aldosterone. The patient was initially treated with the aldosterone-antagonist spironolactone. On the basis of the findings of the CT scan, the size of the adrenal gland being far in excess of the normal size of an adrenal adenoma, a right adrenalectomy was performed. After surgery, although plasma electrolytes returned to normal (sodium 145 mmol/L, potassium 5.1 mmol/L and bicarbonate 27 mmol/L) the patient required anti- hypertensive treatment (nifedipine 40 mg b.d. and atenolol 50 mg o.d.) to adequately control his blood pressure.
Six months after the original surgery, plasma elec- trolytes were once again found to be abnormal: sodium 146 mmol/L, potassium 3.1 mmol/L and bicarbonate 35 mmol/L. Random aldosterone level was >800 pmol/l. A CT scan of the abdomen dem- onstrated a large mass above the right kidney with probable invasion of the right lobe of the liver and extension behind the right kidney. At exploratory laparotomy a right nephrectomy with excision of most of the tumour and enucleataion of the liver metastasis was performed. Histology showed that the tumour was composed of sheets, strands, trabec- ulae and nests of large polygonal cells with a high mitotic index, and consistent with adenocarcinoma (Figure 2a and 2b).
After surgery the patient was treated with dexamethasone and mitotane, and later received three courses of chemotherapy (5-fluorouracil and cisplatin).
Eighteen months after the original surgery, the patient was readmitted with general deterioration and breathlessness. He was found to have pulmon- ary oedema and despite aggressive treatment died several days later. At post-mortem examination, left ventricular failure secondary to severe left ventri- cular hypertrophy was found. The tumour was confined to the abdomen with most of it within the pelvis, involving the pelvic wall and omentum, and further deposits on the posterior aspect of the liver.
Figure 3 shows a graph of serum potassium and serum sodium plotted against time with various interventions indicated.
Case 2 Initial presentation
A 34-year-old white male manual worker was referred for further investigation of hypertension and hypokalaemia. He had originally been admitted to a district hospital with a severe frontal headache and a blood pressure of 170/120 mm Hg. The patient gave an 18-month history of intermittent frontal headache and was receiving clonidine for a presumed diagnosis of migraine. In his previous
a
b
medical history he had treatment of Hirschsprung’s Disease by surgical excision of aganglionic bowel at the age of 6 months. Although he had a history of chronic constipation he denied laxative abuse.
During his original admission the patient was investigated as follows. Urinalysis showed pro- teinuria but no haematuria. ECG was normal with no voltage-criteria for left ventricular hypertrophy. Chest X-ray was normal. Plasma electrolytes showed sodium 143 mmol/L, potassium 2.0 mmol/L and bicarbonate 26 mmol/L. Urea was 4.0 and full blood count, ESR, 24-h urine collection for catecholamines and CT scan of the head were normal.
On the basis of hypertension, hypokalaemia and alkalosis a possible diagnosis of hyperaldosteronism was made and the patient was started on treatment with spironolactone and referred to a tertiary centre for further investigation.
Adrenocorticol carcinoma AN Dixon and RF Bing
Adrenalectomy
Nephrectomy and enucleation of liver metastases
Patient died
Na+
Spironlactone
Spironlactone
Mitotane
K+
150
5FU Cisplatin
6
5
4
140
3
2
1
130
0
Sept
Oct
Nov
Dec
Jan
Feb
Mar
April
May
June
July
Aug
Sept
Oct
Nov
Dec
Jan
Feb
Mar
April
May
June
1985
1986
1987
Special investigation
Paired lying and standing plasma renin and aldos- terone levels were performed after stopping antihy- pertensive treatment for 2 weeks. Plasma renin was <0.2 pmol/l both lying and standing (normal range 1.1-4.5 pmol/l); plasma aldosterone lying was 1900 pmol/l (normal range <445 pmol/l) and 4-h post-standing standing was 2550 pmol/l (normal range 110-850 pmol/l). Plasma aldosterone after infusion of 2 litres of normal saline over 3 h was 2595 pmol/l. At 9 am plasma cortisol was 701 nmol/l. Plasma aldosterone remained markedly elevated (1235 pmol/l) and was non-suppressible after 4 days of treatment with dexamethasone 0.5 mg q.d.s.
A CT scan of the abdomen demonstrated a well- defined 5 x 7-cm lesion in the region of the left adre- nal gland. The appearances were consistent with an adrenal carcinoma and the liver was normal. A radioisotope adrenal scan showed uptake of both adrenal glands to be within normal limits.
Clinical course
On the basis on these findings the patient underwent left adrenalectomy. Histopathological examination of the tumour demonstrated frequent mitotic figures as well as pleomorphic and multinucleated cells with large hyperchromatic nuclei indicating adreno- cortical carcinoma (Figure 4a and 4b). After surgery, the patient’s blood pressure was adequately con- trolled without any antihypertensive treatment and plasma electrolytes returned to normal (sodium 139 mmol/L and potassium 4.7 mmol/L, urea 6.2). The patient received post-operative radiotherapy to the adrenal bed.
Six months after surgery, the patient remained
well and blood pressure, plasma electrolytes and ultrasound scan and CT scan of the liver were all normal. However, 18 months after the original sur- gery an ultrasound scan of the liver showed hepatic metastases: one within the left lobe measuring 9 cm, and two with in the left lobe measuring 7 and 5 cm. This was confirmed on CT scanning but there was no evidence of recurrence within the adrenal bed. At this time blood pressure was normal, serum pot- assium was 3.9 mmol/l and random plasma aldos- terone was within normal range at 190 pmol/l (100- 500 pmol/l). The patient received chemotherapy (5- fluorouracil, cisplatin and doxorubicin) followed by right hemi-hepatectomy and cryotherapy to the met- astasis within the left lobe of the liver. Histology confirmed metastatic adrenal adenocarcinoma. Despite further intervention with repeated courses of chemotherapy and a left hemi-hepatectomy the patient died 4 years after the original surgery.
Discussion
The majority of causes of primary hyperaldosteron- ism are from benign lesions, namely adrenocortical adenomas or hyperplasia. Primary hyperaldosteron- ism due to adrenocortical carcinoma has only rarely been described. Only 26 cases have been reported in the literature since the first case was described in 1955.2 Nineteen cases were reported up until 1984 (reviewed by Stone and colleagues3 and only seven cases have been reported since.4-7
Adrenocortical carcinomas are usually defined, on the basis of biochemical and clinical findings, as either ‘functioning’, or ‘non-functioning’. The majority of cases are functioning and patients often present with evidence of Cushing’s syndrome, due to excess glucocorticoid steroids, adrenogenital syn-
a
b
drome (virilisation and feminization) from excess sex steroids, or mixed syndromes. Although adreno- cortical carcinomas are rare, accounting for less than 0.05% of all carcinomas, they tend to be highly aggressive, with approximately 75% being meta- static at the time of diagnosis, and the 5-year mor- tality rate approximately 75-90%.8
It is useful to be able to differentiate between benign and malignant causes of primary hyperaldos- teronism since this may determine the mode of treat- ment. Previous investigators found that in benign causes of primary hyperaldosteronism blood press- ure tended to fluctuate with time, and serum potass- ium was usually above 2.9 mmol/L, whereas with malignant causes, diastolic blood pressure tended to be persistently above 110 mm Hg, and serum potass- ium was usually below 2.5 mmol/L.9 Both of the patients presented here concur with these findings of malignant primary hyperaldosteronism.
Radioisotope scanning was performed in both
patients to assess the relative uptake by the adrenal glands. It is interesting to note that in both cases there was no difference in radioisotope uptake despite the significant size of each tumour on the CT scan. Only one previous case study of hyperaldo- steronism due to adrenal carcinoma described the use of radioisotope imaging.1º In this case there was no uptake by the affected adrenal gland. Previous case reports have either not performed or have not reported upon radioisotope imaging.
It is interesting to note that in Case 2, the behav- iour of the tumour changed with time. As the tumour became more aggressive and metastasised it became non-functioning. Presumably, as the tumour became progressively more poorly differentiated over time and gained the ability to metastasise, it lost the ability to synthesis or secrete steroid hor- mone. Brookes and colleagues described a similar phenomenon in 1972.11 In their case of a patient with an aldosterone-secreting adrenal carcinoma with pulmonary metastases when the primary tumour was removed the weakness of the patient improved and the serum potassium remained within the normal range without the need for potassium supplements or spironolactone. Although they did not measure serum aldosterone post-operatively it was presumed that the pulmonary metastatic deposits were not secreting mineralocorticoid-active steroid. In contrast, in Case 1 aldosterone continued to be produced despite removal of the primary tumour.
Other investigators have suggested that aldos- terone is a good marker of disease activity at follow- up after removal of the adrenocortical carcinoma.5 However the findings presented here in the patient with Case 2 and the previous patient described by Brookes and colleagues11 suggests that secretion of aldosterone is sometimes lost with metastatic spread and therefore is a poor marker of disease activity.
We present two cases of hypertension, hypokalae- mia and alkalosis due to hyperaldosteronism from adrenocortical carcinoma. This is a rare condition but must be considered in the causes of primary hyperaldosteronism if early diagnosis and surgical treatment is going to improve survival. Radioisotope imaging does not appear to be a useful investigation in the management of these patients since both cases presented here showed no difference in uptake despite large tumour size on CT scanning. Further- more, in the follow-up management of patients with surgically treated aldosterone-secreting adrenocort- ical carcinomas the ability of the tumour to syn- thesise or secrete aldosterone may be lost when metastatic potential is gained and it is therefore not a useful marker of disease activity.
References
1 Richie PR, Gittes RF. Carcinoma of the adrenal cortex. Cancer 1980; 45: 1957-1964.
2 Foye LV, Feichtmeier TV. Adrenal cortical carcinoma
producing solely mineralocorticoid effect. Am J Med 1995; 19: 966-975.
3 Stone NN, Janoski A, Muakkassa W, Shpritz L. Min- eralocorticoid excess secondary to adrenal cortical car- cinoma. J Urology 1984; 132: 962-965.
4 Farge D et al. Isolated clinical syndrome of primary aldosteronism in four patients with adrenocortical car- cinoma. Am J Med 1987; 83: 635-640.
5 Pascual J et al. Isolated primary aldosteronism in a patient with adrenal carcinoma and XY/XXY mosaic Klinefelter’s syndrome. J Urology 1990; 144: 1454- 1456.
6 Weingartner K et al. Isolated clinical syndrome of pri- mary aldosteronism in a patient with adrenocortical carcinoma. Urol Int 1995; 55: 232-235.
7 Taylor W, Carroll D, Bethwaite P. Adrenal carcinoma
presenting as Conn’s syndrome (letter). Aust NZ J Med 1997; 27: 201-202.
8 King DR, Lack EE. Adrenocorical carcinoma - A clini- cal and pathological study of 49 cases. Cancer 1979; 44: 239-244.
9 Ganguly A, Donohue JP. Primary aldosteronism: pathophysiology, diagnosis and treatment. J Urol 1983; 129: 241.
10 Grim CE et al. Hyperaldosteronism due to unsuspected adrenal carcinoma: discovery during investigation of hypertension in a young woman. J Urol 1981; 126: 783-786.
11 Brooks RV, Felix-Davies D, Lee MR, Robertson PW. Hyperaldosteronism from adrenal carcinoma. Br Med J 1972; 1: 220-221.