[Case Report]
A Rare Case of Primary Aldosteronism Caused by Bilateral Functioning Adrenocortical Adenomas with Renal Cell Carcinoma
Akiko HIROSE, Yosuke OKADA, Ayumi FUKUSHIMA and Yoshiya TANAKA The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan. Yahatanishi-ku, Kitakyushu 807-8555, Japan
Abstract: We report a rare case of bilateral primary aldosteronism with renal cell carci- noma. A 55-year-old woman developed symptoms of hypertension and hypokalemia. The cause of these symptoms was suspected to be primary aldosteronism, based on the high levels of plasma aldosterone concentrations (PAC) and low levels of plasma rennin activity (PRA), resulting in a high PAC/ PRA ratio. Abdominal CT and MRI revealed tumor masses in both adrenal glands, and a large left renal mass. The preoperative diagnosis was primary aldosteronism due to bilateral functioning adrenocortical adenomas and left renal cell carcinoma. The patient underwent left radical nephrectomy and right partial adrenalectomy. The Pathological diagnosis was left renal cell carcinoma and bilateral functioning adrenocortical adenomas. Primary aldosteronism due to bilateral functioning adrenocortical adenomas is relatively rare and its com- plication with renal cell carcinoma is an extremely rare case.
Key words: primary aldosteronism, bilateral adrenocortical adenomas, renal cell carcinoma. (Received 19 August 2005, accepted 1 November 2005)
Introduction
Primary aldosteronism is found in 20% of hypertension cases at autopsy, and in 0.05 to 2% of patients with hypertension [1-3]. In 80 to 90% of cases, primary aldosteronism is caused by unilateral adrenal adenoma [4]. The other 10 to 20% of patients with primary aldosteronism have bilateral adrenal hyperplasia, i.e., idiopathic aldosteronism [5]. How- ever, in about 1% of patients with primary aldosteronism, the condition is caused by bilat- eral functioning adrenocortical adenomas, forming a relatively rare subset of primary aldosteronism [3]. Here we report a rare case of primary aldosteronism due to bilateral functioning adrenocortical adenomas with renal cell carcinoma.
| Urine | PH 5.0, prot(2+), | Biochemistry | TP | 8.1 g/dl | |
| glu(-), ket(-), | Alb | 5.0 g/dl | |||
| O.B. (TR) | AST | 20 IU/l | |||
| cytology : class I | ALT | 168 IU/l | |||
| T-bil | 0.6 mg/dl | ||||
| LDH | 215 IU/l | ||||
| U-Na | 72 mEq/day | Ca | 9.7 mg/dl | ||
| U-K 33 mEq/day | Cre | 0.5 mg/dl | |||
| U-Cl | 94 mEq/day | BUN | 17 mg/dl | ||
| Na | 149 mEq/l | ||||
| ABG | PH | 7.478 | K | 3.2 mEq/l | |
| (room air) | PaO2 68 mmHg | CI | 103 mEq/l | ||
| PCO2 44.9 mmHg | PPG | 126 mg/dl | |||
| HCO3 | 33.7 mmol/l | CRP | 0.1 mg/dl | ||
| BE | +9.5 mmol/l | Complete | WBC | 4,500 /p 1 | |
| blood cell | RBC | 443x104 /p 1 | |||
| count | Hb | 13.3 g/dl | |||
| others | ESR | 27 mm/hr | Ht | 39.0% | |
| Plt | 22.9×104/px1 | ||||
Case Report
A 33-years-old woman was diagnosed with hypertension, and her arterial blood pressure increased gradually. At 52 years, she was prescribed nifedipine. Although candesartan was added to the treatment of hypertension two years later, her blood pressure remained high (systolic blood pressure; 170-190 mmHg, diastolic blood pressure; 80-110 mmHg). She was admitted to the Department of Orthopedics with traumatic bone fracture. During the admission, she was found to have hypokalemia (serum K 2.1 mEq/ l ), an elevated level of urinary potassium (27.1 mEq/ l ), and abdominal computed tomography (CT) showed bi- lateral adrenal tumors and left renal tumor. In December 2001, she was admitted to our hospital to determine the relationship between persistent hypertension and bilateral adrenal tumors.
Physical examination on admission showed body height of 157.2 cm and weight 48.7 kg. Her arterial blood pressure was 187/90 mmHg with antihypertensive agents, pulse rate of 78 beats/minute and body temperature of 37.2℃. Her consciousness level was clear. There were no clinical signs of anemia or jaundice, and struma and superficial lymph node were not palpable. The abdomen was flat and soft without any tenderness, but the left kidney was palpable on the flank leision. Physical examination of the chest and extremities was unremarkable, and neurological examination was within normal range.
The laboratory findings are listed in Table 1. Urinary protein 2+, urine occult blood ±, urine cytology class II, complete blood cell was normal. Serum electrolytes were Na 149 mEq/ l and K 3.2 mEq/ l. Although serum potassium was low, the level of urinary potas-
| ACTH | 23.1 pg/ml | (4.4~48.0) | Adrenaline | 7.6 pg/ml (<100) |
| Cortisol | 27.4 mg/dl | (2.7~15.5) | Noradrenaline | 53.0 pg/ml (100~450) |
| Rennin | 0.28 ng/ml/hr | (0.5~2.0) | Dopamine | 362.7 pg/ml (<20) |
| Aldosterone | 550.0 pg/ml | (35.7~240.0) | U-aldosterone | 12.0 µg/day |
( : Normal Value
a
b
(ng/ml/h)
(pg/ml)
(mg/dl) (pg/ml)
5
1000
30
70
(27.4)
25
60
4
800
(780)
Rennin
Aldosterone
20
50
3
600
(550)
Cortisol
ACTH
40
15
2
400
30
10
20
O
(23.1)
1
200
(0.28)
(0.55)
5
10
(4.30)
(2.50)
0
0
0
0
Baseline
After loading
Baseline
After loading
0-0 : Aldosterone, * ---. : Rennin, .-.: Cortisol, @ --- @: ACTH.
sium was elevated (33 mEq/day). Arterial blood gas analysis showed metabolic alkalosis (PO2 68 mmHg, HCO3 33.7 mmol/ l , BE +9.5 mmol/ l ).
Endocrinological survey
The following endocrinological tests were undertaken while the patient was on 7 g/day of NaCl diet with nifedipine. The basal levels of various hormones are displayed in Table 2. The ratio of plasma rennin activity (PRA) to plasma aldosterone concentrations (PAC) was elevated. PRA remained low after stimulation with furosemide and standing test (Fig. la). Administration of dexamethasone at 2 mg suppressed the plasma cortisol and ACTH levels (Fig. 1b).
Ultrasonography and CT revealed two adrenal masses, each measuring 2.0 cm in dia- meter, in both the right and left adrenal glands (Fig. 2Aa). Moreover, a left renal tumor was detected on CT (Fig. 2Ab). It appeared heterogeneous with no invasion, and no celiac lymph node enlargement was detected on abdominal CT. Magnetic resonance imaging (MRI) showed bilateral adrenal tumors each measuring 2.5 cm in diameter, and slightly higher in intensity than in the liver on T2-weighted images (Fig. 2B). The 13’I-adsterol scin- tigram, with dexamethasone suppression, revealed abnormal uptake in both adrenal glands and slightly diminished uptake in the left adrenal gland (Fig. 2C).
A-a
A-b
q 1
-
0
R
R
10
10
₾
KV 120
1
MA 240
KV 120
TI 0.75
HA 240
GT 0.0
TI 0.75
SL 5.0/5.0
GT 0.0
320 12/-35
SL 5.0/5.0
ABSOUL0
W
320
320 12/-35
1215630
CE
C
60
ABSOULO
1
320
1215630
CE
€
60
B
C
TR-4664 TE=80
FA-90/160
55 F 0109454-9
01.18.2002
Posterior
/EXP
01:18PM
/F sat
75
PE: $
R
L
C : BI-adsterol scintigram during dexamethasone suppression showed an abnormal uptake in both adre- nal glands.
Clinical course and Pathological findings (Fig. 3).
Based on the severe hypertension. hypokalemia. low PRA. high PAC. PAC/PRA ratio> 2.0. no response of PRA to stimulation with intravascular injection of furosemide (20 mg) in combination with 2 g/day of NaCl diet and standing position, and uptake in both adrenal glands of “I-adsterol scintigram. the diagnosis was primary aldosteronism due to bilateral functioning adrenocortical adenomas. Therapy commenced before the operation with 100 mg/day of spironolactone. which resulted in immediate improvement of hypokalemia and hypertension. The adrenal tumors and the left kidney tumor were resected surgically at the 27th day of admission in the Department of Urology of our hospital. The patient underwent left radical nephrectomy and right partial adrenalectomy. The resected adrenal tumors ap- peared yellowish brown on the cut surface. measured 2.0× 1.5× 1.5 cm in size and weighed
(mmHg)
200
150
100
60
40
30
20 (mg)
200
150
BP
100
50
0
(mEq/l)
Rennin 0.28 ng/ml/hr
Rennin <0.1 ng/ml/hr Aldosterone 25 pg/ml
5
Aldosterone 550 pg/ml
4
K
3
2
1
0
10
20
30
40
(day)
****: Nifedipine 40 mg, : Slow K 16 mg, IIIII: Dexamethasone 2 mg, XXXXX : Spiromolactone 100 mg, (ZZZZ : hydrocortisone, : operation.
-: systolic blood pressure, — A: diastolic blood pressure.
10.0 g (left adrenal tumor), and measured 2.0×1.5×1.5 cm in size and weighed 5.0 g (right adrenal tumor). Histopathologically, both tumors were composed of a proliferation of the clear type cells with a foamy appearance arranged in sheets or trabeculae, associated with adenoma (Fig. 4). On the other hand, the left renal tumor measured 10.0×5.0×3.5 cm in size, and histopathological examination revealed renal cell carcinoma (G1, INFa, v(-), pT2). No metastases were detected in the lymph nodes. Following the operation, the pa- tient received hydrocortisone. The replacement therapy was tapered off gradually and she was treated with 10 mg/day of hydrocortisone. Postoperatively, the PRA and PAC levels were within normal limits, and arterial blood pressure control showed improvement without the use of antihypertensive agents, together with a gradual increase in serum potassium level. Furthermore, no metastasis has been detected until the writing of this report.
Discussion
We report here a rare case of primary aldosteronism with bilateral adrenal adenomas and renal cell carcinoma. Primary aldosteronism due to adrenocortical adenoma is usually caused by unilateral functioning adrenocortical adenoma; bilateral functioning adrenocorti- cal adenomas represent only 1% of primary aldosteronism, therefore bilateral adrenocortical adenomas are rare [3]. When bilateral adrenal tumors are detected, it is important to differ-
a
b
entiate between bilateral adrenocortical adenomas and idiopathic hyperaldosteronism with bilateral hyperplasia, because the treatments are completely different. Surgery is generally selected for bilateral adrenocortical adenomas, while pharmacotherapy is selected for idi- opathic hyperaldosteronism. If bilateral total adrenalectomy is performed. the patient needs to be treated with lifelong hydrocortisone replacement therapy. Therefore, a correct pre- operative diagnosis is critical. However. it is often difficult to differentiate adrenocortical adenoma from idiopathic hyperaldosteronism by endocrinological surveys and imaging studies. Moreover. it is reported that even if bilateral adrenal adenomas are diagnosed by imaging studies, hemilateral adrenal adenoma is a non-functioning adenoma [8]. Our pa- tient was diagnosed with primary aldosteronism after the admission to hospital. based on the characteristic symptoms of hyperadrenalcorticalism. such as hypertension and hypokalemia. and hormonal findings. Moreover, she was found to have left renal cell carcinoma. based on the large heterogeneous tumor detected in the left kidney on abdominal CT. and the urine cytology was class III. Because this patient had bilateral adrenal tumors with renal cell car- cinoma. we had to rule out other causes of bilateral adrenal masses. The differential diag- nosis includes: 1) bilateral adrenal tumors, 2) right adrenal adenoma with left adrenal metas- tatic tumor, and 3) idiopathic hyperaldosteronism. In general. if the diagnosis is adrenocor- tical tumor, the standing test or furosemide loading test is associated with a decrease in the level of PAC. but the level of PAC is increased in idiopathic hyperaldosteronism [9, 10]. In our case, the standing test did not affect the PRA level. which remained suppressed. The PAC level was slightly elevated. but not significantly. making it difficult to differentiate adrenocortical adenoma from idiopathic hyperaldosteronism. Although we could not make a definite diagnosis by abdominal CT and abdominal MRI. the patient was finally diagnosed with bilateral adrenocortical adenomas because ""I-adsterol scintigram with dexamethasone suppression treatment revealed abnormal uptake in both adrenal glands. In general. when it is difficult to diagnose by endocrinological and/or imaging studies or loading test. venous
sampling from the suprarenal vein is useful for diagnosis. However, the present case was complicated with the left renal cell carcinoma and 131I-adsterol scintigram revealed abnormal uptake strongly in the right adrenal gland more than the other side, and therefore no such procedure was undertaken.
Renal cell carcinoma with adrenal metastases is clinically common. Saitoh et al. [11] reported that the incidences of ipsilateral and contralateral adrenal metastases in renal cell carcinoma were 17% and 11%, respectively, in their 1,451 autopsy cases. However, the presence of only bilateral adrenal metastases with no metastases in any other organ is comparatively rare [12, 13]. Although our patient had a relatively large renal cell carcinoma, the tumor showed no invasion on abdominal CT and MRI. However, we could not com- pletely exclude metastases preoperatively, because hematogenous metastasis from the kidney to the adrenal gland is described as being common. Because no metastases were detected in the other organs known to be commonly affected by renal cell carcinoma, such as the lungs, liver and bone, we did not find any positive evidence to suspect adrenal metastases. Accordingly, left radical nephrectomy and right partial adrenalectomy were performed.
Histopathologically, both tumors were composed of a proliferation of clear-type cells with a foamy appearance arranged in sheets or trabeculae, features compatible with adreno- cortical adenoma. Previous studies indicated that blood pressure control improved post- operatively without the need of antihypertensive agents in 75% of adrenocortical adenoma cases. Likewise, our patient showed improved blood pressure control after the operation. Therefore, we considered this finding as further negative evidence of idiopathic hyper- aldosteronism. In addition, it is noteworthy that our patient was able to avoid permanent hormone replacement therapy and improved her blood pressure by performing left adrenec- tomy and right partial adrenectomy against bilateral primary aldosteronism. Only a few cases of primary aldosteronism with renal cell carcinoma have been reported so far [14, 15]. Hence, we can consider bilateral primary aldosteronism with renal cell carcinoma cases as a rare condition. A causal relationship between primary aldosteronism and renal cell carci- noma is unknown, although it would be interesting to define the relationship between both diseases.
In conclusion, we reported a very rare case of primary aldosteronism due to bilateral functioning adrenocortical adenomas with renal cell carcinoma.
Acknowledgments
The authors wish to thank Dr. M. Hisaoka (Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Japan) for the histopathological support and diagnosis for this case.
References
1. Lund JO, Nielsen MD & Giese J (1981): Prevalence of primary aldosteronism. Acta Med Scand 646 (Suppl): 54-57
2. Streeten DHP, Tomycz N & Anderson GH Jr (1979): Reliability of screening methods for the diagno- sis of primary aldosteronism. Am J Med 67: 403-413
3. Hiramatsu K, Yamada T, Yukimura Y, Komiyama I, Ichikawa K, Ishihara M, Nagata H & Izumiya T (1981): A screening test to identify aldosterone-producing adenoma by measuring plasma rennin ac- tivity. Arch Intern Med 141: 1589-1593
4. Ferris JB, Beeveres DG & Brown JJ (1978): Low rennin (“primary”) hyperaldosteronism - differenti- cal diagnosis and distribution of sub-groups within the syndrome. Am Heart J 95: 641-658
5. Weinberger MH, Grim CE, Hollifield JW, Kem DC, Ganguly A, Kramer NJ, Yune HY, Wellman H & Donohue JP (1979): Primary aldosteronism. Diagnosis, localization and treatment. Ann Int Med 90: 386-395
6. Morioka Y, Umeda T, Ooishi S, Iwaoka D & Satho T (1988): A case of primary aldosteronism associ- ated with multiple adenoma. Clin Endocrinol 36: 477-482
7. Conn JW, Knopf RF & Neebit RM (1984): Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Am J Surg 107: 159-172
8. Favre L, Jacot-des-Combes E, Morel P, Hanser H, Rindel A-M, Megevand R & Vallotton MB (1980): Primary aldosteronism with bilateral adrenal adenomas. Virchows Arch A 388: 229-236
9. North RH & Biglieri EG (1988): Primary hyperaldosteronism. Med Clin N Am 72: 1117-1131
10. Salton PE, Sambelam M & Biglieri EG (1969): Stimulation and suppression of aldosterone secretion in patients with an aldosterone producing adenoma. J Clin Endocrinol Metab 29: 239-250
11. Saitoh H, Nakayama M, Nakamura K & Satoh T (1982): Distant metastasis of renal adenocarcinoma in nephrectomized cases. J Urol 127: 1092-1095
12. Hukuhara H, Yamaguchi K, Nishimura Y & Tominaga T (1999): Renal cell carcinoma with bilateral adrenal metastases: A case report. Nishinihon J Urol 61: 44-47 (in Japanese)
13. Masuda F, Suzuki H & Suzuki M (1992): Bilateral adrenal metastasis from renal cell carcinoma. Acta Urol Jpn 38: 933-935 (in Japanese)
14. Hirata Y, Fujita Y, Nomura T, Imagawa M, Nakagawa M & Nomura Y (2000): Primary aldosteronism in a long-term hemodialysis patient: A case report. Nishinihon J Urol 62: 305-308 (in Japanese)
15. Kudo S, Kawaguchi T & Suzuki T (2000): Two case report of unilateral adrenal hyperplasia with contralateral renal cell carcinoma. Nippon Hinyokika Gakkai Zasshi 91: 565-569 (in Japanese)
両側副腎腺腫による原発性アルドステロン症に腎細胞癌を合併した稀な一例
廣瀬 暁子,岡田 洋右,福島 あゆみ,田中 良哉 産業医科大学 医学部 第一内科学教室
要 旨: 我々は、両側副腎腺腫による原発性アルドステロン症に腎細胞癌を合併した稀な症例 を経験したので報告する.症例は55歳女性.高血圧,低 K血症,血中アルドステロン濃 度,レニン活性高値より原発性アルドステロン症が疑われた. 腹部 CT および MRI に て、両側副腎腫大,左腎腫瘍を伴っていたことより,両側機能性副腎腺腫と腎細胞癌の 合併と考え,左腎摘出術,右副腎部分摘出術を施行. 病理組織にて,両副腎は両側機能性 副腎腺腫,左腎は腎細胞癌と診断. 原発性アルドステロン症で両側機能性腺腫を呈する ことは稀であり,さらに腎細胞癌を合併することは極めて稀である.
キーワード: 原発性アルドステロン症,両側副腎腺腫,腎細胞癌.
J UOEH (産業医大誌)27 (4):315-323 (2005)