A Case of Renin-Producing Adrenocortical Cancer
KAYO YAMANAKA, MAKOTO IITAKA, MUNEMICHI INABA, TOSHISUKE MORITA, HIRONOBU SASANO* AND SHIGEHIRO KATAYAMA
The Fourth Department of Medicine, Saitama Medical School, Saitama 350-0495, Japan
* The Department of Pathology, Tohoku University School of Medicine, Sendai 980-8575, Japan
Abstract. Here we report a case of a renin-producing adrenocortical carcinoma. A 57-year-old woman was referred to our hospital complaining of thirst and generalized muscle weakness. She was diagnosed as being hypertensive and diabetic with associated hypokalemia and she had a hard elastic mass with a diameter of 10 cm on the left side of her neck. An abdominal computed tomography scan revealed a suprarenal mass on the left side (8.5x 8×6.5 cm). Endocrinological examination demonstrated a marked elevation in the patient’s serum glucocorticoid and sex steroid hormones as well as plasma renin activity. Histological examination of a sample taken from the neck mass revealed a metastasis from an adrenal carcinoma, which was stained positively with antibodies against cytochrome P450 and renin, establishing the diagnosis of a renin-producing adrenocortical carcinoma. Trilostane was effective in reducing serum cortisol levels, but mitotane was ineffective.
Key words: Adrenal carcinoma, Renin-producing tumor, Hypertension, Hypokalemia, Trilostane, Mitotane (Endocrine Journal 47: 119-125, 2000)
THE first case of secondary hypertension induced by a renin-secreting renal tumor was described in 1967 by Robertson et al. [1]. Three months later, the se- cond case was reported by Kihara et al., who used the term “juxtaglomerular cell tumor” [2]. Conn et al. proposed the term “primary reninism” for the clinical syndrome of hypertension associated with hypokale- mia resulting from the high plasma levels of active renin secreted by a tumor [3]. Since then many cases have been described (see the review by Lindop et al. [4]). More than half of all renin-producing tumors are renal in origin, and juxtaglomerular cell tumors are the most common. A few cases of non-renal renin-producing tumor have also been reported in patients with carcinomas such as carcinoma of the lung, pancreas, and ovary [4]. Adrenal cortical car-
cinoma is also a very rare tumor. To date, there is only one report of a renin-producing carcinoma of the adrenal cortex [5]. However, with the advent of abdominal sonography and/or a computed tomography (CT), the early detection of adrenal tumors has become easier. It has been reported that the incidence of such tumors is approximately 1 case per 1,700,000 population, accounting for 0.02% of cancers, according to the Third National Cancer Survey [6]. Here, we report a case of a renin- producing adrenocortical carcinoma.
Case report
A 57-year-old woman was referred to our hospital complaining of thirst and generalized muscle weak- ness. Two years prior to this, she had been diag- nosed as hypertensive and given hypotensive agents. Six months before admission, she complained of feeling thirsty, exhibited polydipsia and polyuria, and was suffering from a generalized fatigue and edema in her legs. The patient was diagnosed as
having diabetes mellitus and was admitted to a hospital. She was then referred to another hospital, where she was given an injection of intermediate in- sulin, subcutaneously at 8 U/day. An elastic hard mass with a diameter of 10 cm was found on the left side of her neck. Furthermore, an abdominal tumor was observed on a CT scan and her serum potassium level was less than 2 mEq/1. Based on these findings, this patient was referred to our hospital for further evaluation and treatment.
On admission, her blood pressure was 178/110 (right side) and 180/100 (left side) mmHg, and her pulse rate was 96 beats/min. She presented with a moon face associated with hirsutism and a loss of hair on the frontal head. A mass that was slightly hard and barely moveable was found on the left clavicle. There were no respiratory sounds from her left lung, no palpable mass on her abdomen and no bruit. Her legs were edematous. The patient’s muscular power was decreased but she was able to walk using a cane.
Urinalysis revealed that patient had glycosuria. Blood cell counts were as follows: white blood cells 4,180/pl (neutrophils 81.6%, eosinophils 0.2%, monocytes 7%, lymphocytes 7.8%), red blood cells 356×104/pl, hemoglobin 11.6 g/dl, hematocrit 33.8%, mean cell volume 94.9 fl, mean cell hemo- globin 32.4 pg, mean cell hemoglobin concentration 34.2 g/dl, platelets 23.9 × 104/pl. A biochemical ex-
amination of the patient’s blood revealed no ab- normalities in liver function except for a rise in lactate dehydrogenase levels of 1320 IU/1 (normal range: 107-220) and a reduction in cholinesterase of 1906 IU/1 (normal range: 3600-7600), total protein of 5.4 g/dl (normal range: 6.5-8.0) and albumin of 2.8 g/dl (normal range: 4.3-5.5). Her serum potas- sium level was 2.3 mEq/1 despite oral potassium supplementation, while serum sodium and chloride levels were 145 and 96 mEq/1, respectively. Her fasting plasma glucose level was 164 mg/dl and glycosylated hemoglobin A1c was 11.6% (normal range: 4.3-5.6). Arterial blood gas analysis revealed metabolic alkalosis.
On a chest X-ray film, the left costophrenic angle was dull. A CT scan of the patient’s neck (Fig. 1, left) revealed a large heterogeneous solid mass (5 × 8 cm) in the area of the left neurovascular bun- dle, which was compressing the trachea and the carotid artery to the right side. The left jugular vein was not detected. On her abdominal CT scan (Fig. 1, right), a large solid mass (8.5× 8×6.5 cm) was found in the left suprarenal region, but was clearly separated from the left kidney. Other multiple solid mass lesions were observed around the abdominal aorta and inferior vena cava. Stenosis of renal ar- teries was not observed. The adrenal mass was not visible in a 131I adosterol scintigram.
The patient’s daily urinary excretion of 17-
hydroxycorticosteroids (17-OHCS), free cortisol and 17-ketosteroids (17-KS) was elevated (28.3 mg, 717 µg and 44.4 mg, respectively). The result of the endocrinological examination is shown in Fig. 2. Plasma adrenocorticotropic hormone (ACTH) levels were less than 5 pg/ml throughout the day and cor- tisol concentrations were 47.6 µg/dl at 6.00 a.m., 55.4 µg/dl at noon, and 46.4 µg/dl at 6.00 p.m., im- plicating no diurnal rhythm. Administation of 500 mg of metyrapone did not augment ACTH secretion (<5-10.2 pg/ml), although the serum con- centration of cortisol was decreased from 98.9 to 13.0 µg/dl, and the 11-deoxycortisol level was in- creased from 17.2 to 113 ng/ml (normal range: 0.11- 0.6). Dehydroepiandrosterone (DHEA) sulfate (13,300 ng/ml) and testosterone levels (347 ng/dl) were higher than the normal range. Plasma renin activities (PRA) were from 9.2 to >20 ng/ml/h and aldosterone concentrations from 82 to 110 pg/ml. Plasma concentrations of angiotensin I and II were 18,000 pg/ml (normal range: < 110) and 55 pg/ml (normal range: < 22), respectively. Angiotensin converting enzyme activity was 8.6 IU/1/37℃, which was within the normal limits (8.3-21.4). Plasma levels of epinephrine and norepinephrine were <5 pg/ml (normal range: < 100) and 233 pg/ml (normal range: 100-450), respectively.
We performed a needle aspiration biopsy of the mass found in the neck, the pathological examination of which revealed malignant cells. The level of cor-
tisol in the aspirated fluid was 236 µg/dl, much higher than that in found in the patient’s serum at that time (42.1 µg/dl), implicating metastasis from the adrenal carcinoma. An open biopsy was carried out in order to obtain more histological information about the neck mass. Light microscopic examina- tion (Fig. 3) revealed a trabecular structure consisting of small round and polyhedral cells with round nuclei and fine cytoplasmic granules. There were a few tubular elements, and a few mitotic cells were ob- served. Immunohistochemistry using an antiserum against mouse submandibular gland renin, at a dilu- tion of 1 : 100 (a gift from Prof. Kazuo Murakami, Tsukuba University, Ibaragi, Japan), and a Vecstain ABC kit (Vector Labs, Burlingame, CA, U.S.A.), the method for which is described elsewhere [7], demon- strated a finely granular dark brown reaction product throughout the cytoplasm of the cells (Fig. 4). The specimen was also stained with specific antibodies against 38-HSD (38-hydroxysteroid dehydrogenase /44,5-isomerase), and cytochrome P450scc (side- chain cleavage enzyme), P450c17 (17a-hydroxylase), P450c11 (11-hydroxylase) and P450c21 (21-hydroxy- lase), as reported previously [8]. As shown in Fig. 5, the specimen stained positively for antibodies against P450scc, 33-HSD and P450c17. Although not shown in Fig. 5, the staining obtained with antibodies against both P450c11 and P450c21 was only weakly positive.
cholesterol
DHEA - S
13300ng/ml (400-3500)
pregnenolone
17OH-pregnenolone
DHEA
progesterone
4.4ng/ml → (0.2-31.6)
17OH-progesterone
5.27 ng/ml (0.2- 4.5)
androstenedione
DOC
0.32ng/ml
11- deoxycortisol
testosterone
(0.03- 0.33)
17.2ng/ml (0.11-0.6)
347 ng/dl (10-60)
corticosterone
18- OHB
cortisol
estradiol
47.6 u g/ dl
(4.0- 18.3)
1 47 pg/ ml (<25)
aldosterone 82 pg/ml → (22.9- 159)
cortisone
dihydrotestosterone
Clinical Course
We administered slow-release nifedipine (40 mg/day), slow-release potassium (24 mEq/day) and spironolactone (50-100 mg/day) to improve hypokalemia and hypertension (Fig. 6). After a diagnosis of adrenal carcinoma with metastasis to the neck, trilostane, 33-HSD inhibitor, was given at 120-240 mg/day to diminish cortisol secretion and improve hypokalemia. As shown in Fig. 6, trilostane administration at 180 mg/day reduced the
urinary excretion of 17-OHCS, 17-KS, and serum cortisol levels to 39.1 mg/day, 100.4 mg/day, and 31.5 µg/dl, respectively. When we increased the daily dose of trilostane to 240 mg/day and added mitotane at 1.5 to 3.0 g/day, serum cortisol levels decreased to 22.6 µg/dl, and urinary excretion of 17-OHCS and 17-KS was reduced to 21.3 mg/day and 63.7 mg/day, respectively. Trilostane had to be discontinued because of the development of liver dysfunction, as evidenced by elevated aspartate aminotransferase (GOT) and alanine aminotrans- ferase (GPT) levels, and mitotane was given alone at
nifedipine L 40mg
slow-K
1800mg
spironolactone 100mg
trilostane 120mg
180
240
1.5g
3.0
mitotane
160
4.5
140
Serum Cortisol (1 g/dl)
120
100
80
60
40
20
0
200
mg/day
150
urinary 17-KS
100
urinary 17-OHCS
50
0
0
20
40
60
80
day
30
aldosterone
200
Plasma Renin Activity (PRA : ng/ml/h)
20
150
Serum Aldosterone
PRA
100
(pg/ml)
10
50
0
0
0
20
40
60
80
day
4.5 g/day. Serum cortisol levels subsequently in- creased to more than 100 µg/dl. The patient had a generalized edema associated with a massive pleural effusion, resulting in dyspnea. She died 92 days after admission. Unfortunately, an autopsy was not per- mitted.
Discussion
Renin-producing tumors are very rare. Most of them are of renal origin and juxtaglomerular cell tumors are the most common. Non-renal renin- producing tumors include carcinoma of the lung, pancreas, urinary bladder and ovary [4]. Iimura et
al. reported the first case of adrenal tumor that produced renin, aldosterone and sex steroid [5]. Our case may be the second reported of an adrenal tumor that produced and secreted renin into the circulation. However, our case is different from that of Iimura et al. in the steroid synthetic pattern (i.e., in the case described here the tumor produced corticosteroids and sex steroids). In fact, the patient exhibited the characteristics of Cushing’s syndrome. Elevated levels of progesterone, 17-OH-progesterone, DHEA- sulfate, 11-deoxycortisol and cortisol indicate the activation of an enzyme for steroid 17a-hydroxyla- tion, P450c17, an essential regulatory enzyme in both glucocorticoid and sex steroid hormone biosynthesis. We have reported previously that a number of
adrenal carcinoma cells did not express all of the en- zymes required for the synthesis of biologically active corticosteroids, and there is some discrepancy be- tween mRNA and protein expression [9]. In our case, trilostane, an inhibitor of 33-HSD, seemed to be effective, at least in part, as evidenced by a decrease in serum cortisol levels as well as in the uri- nary excretion of 17-OHCS. The development of trilostane-induced liver damage, dictated us to add mitotane, i.e., op’DDD [1,1 dichloro-2(O-chloro- phenyl)ethane]. Mitotane inhibits all of the adrenal enzymes except P45017a. In a study of 77 cases of adrenal cortical carcinoma, 47 of 49 patients who received op’DDD were followed up; the treatment was considered to be moderate-to-very effective in 9 patients (19.1%). However, in the present case, mitotane did not appear to be so effective on glucocorticoid synthesis inhibition. This may be related to the fact that immunologically, P450c17 was very strongly labeled.
Renin has been shown, immunohistochemically, to exist in human adrenal tissue, and biochemical characterization of this adrenal enzyme has demon- strated similarities between this renin and purified kidney renin [11]. The renin activity was predomi- nantly in the cortex rather than in the medulla of the adrenal tissue. Carcinoma of the adrenal cortex may have the potential to synthesize and secrete renin. Based on the rarity of renin-produc- ing adrenocortical carcinomas, however, some other factors would be required to activate renin synthesis and secretion. In our case, plasma angio- tensin I levels were extremely high, 160 times the normal value, although plasma angiotensin II levels were only two times the normal value. It is hard to explain such a discrepancy between angiotensin I and II, but since angiotensin converting enzyme levels were within the normal range, thus would in-
dicate that a huge amount of substrate (angiotensin I) could not be converted to angiotensin II because of the limited amount of angiotensin converting enzyme available. Renin release from the juxta- glomerular cell tumor has been reported to respond to changes in posture and/or in sodium intake [4, 12]. Renin release in some cases has also been reported to increase after angiotensin converting enzyme inhibition, and decrease after ß-blockade [4, 13]. However, we recently reported one case of jux- taglomerular cell tumor that did not respond to these manuevers, including administration of the an- giotensin II receptor antagonist, TCV-116 [7]. In renin-producing adrenal carcinomas [5], the ad- ministration of captopril (75 mg/day) increased PRA that was associated with a normalization of plasma angiotensin II levels. In the present case, because of a poor generalized condition, we could not inves- tigate whether or not renin secretion from the adrenal tissue would respond to various stimuli such as changes in posture and/or in sodium intake and ad- ministration of angiotensin converting enzyme inhi- bitor, angiotensin II receptor antagonist, or B-block- er.
Finally, there was a marked hypokalemia in this case despite normal plasma aldosterone concentra- tions. A high normal deoxycorticosterone (DOC) might result in a severe hypokalemia. Alternatively, excessive glucocorticoid production might be a cause of a low plasma potassium level, although we could not determine the activity of 118-hydroxy-steroid dehydrogenase, the mutation of which has been proved to be a cause of the syndrome of apparent mineral corticoid excess [14]. However, this pos- sibility is unlikely because such a syndrome will ap- pear in the infant with low levels of plasma renin activity and aldosterone.
References
1. Robertson PW, Klidjian A, Harding LK, Walters G, Lee MR, Robb-Smith AHT (1967) Hypertension due to a renin-secreting renal tumor. Am J Med 43: 963- 967.
2. Kihara I, Kitamura S, Hoshino T, Seida H, Watanabe T. (1968) A hitherto unreported vascular tumor of the kidney: A proposal of juxtaglomerular cell tumor.
Acta Pathol Jpn 18: 197-206.
3. Conn JW, Cohen EL, Lucas CP, McDonald WJ, Mayor GH, Blough WM, Eveland WC, Bookstein JJ, Lapides J (1972) Primary reninism. Hypertension, hyperreninemia, and secondary aldosteronism due to renin-producing juxtaglomerular-cell tumors. Arch Intern Med 130: 682-696.
4. Lindop GBM, Leckie BJ, Mimran A (1990) Renin- secreting tumors. In The Renin-Angiotensin System (eds., Robertson JIS, Nicholls MG), Gower Medical Publishing, pp 54.1-54.12.
. Iimura O, Shimamoto K, Hotta D, Nakata T, Mito T, Kuwamoto Y, Dempo K, Ogihara T, Naruse K (1986) A case of adrenal tumor producing renin, aldosterone and sex steroid hormones. Hypertension 8: 951-956.
6. Third National Cancer Survey: Incidence data (1975) National Cancer Institute monograph 41. DHEW Publication No. (NIH) 75-787; US Department of Health Education and Welfare; Public Health Serv- ice, National Institute of Health, National Cancer Institute, Bethesda, Maryland.
7. Kashiwabara H, Inaba M, Itabashi A, Ishii J, Katayama S (1997) A case of renin-producing juxta- glomerular tumors: Effect of ACE inhibitor or an- giotensin II receptor antagonist. Blood Pressure 6: 147-153.
8. Sasano H, Mason JI, Sasano N (1989) Immuno- histochemical study of cytochrome P-45017g in hu- man adrenocortical disorders. Hum Pathol 20: 113- 117.
9. Sasano H, Suzuki T, Nagura N, Nishikawa T (1993)
Steroidgenesis in human adrenocortical carcinoma: Biochemical activities, immunohistochemistry and in situ hybridization of steroidogenic enzymes and histopathologic study in nine cases. Human Pathol 24: 397-404.
10. Nadar S, Hickey RC, Sellen RV, Samaan NA (1983) Adrenal cortical carcinoma: A study of 77 cases. Cancer 52: 707-711.
11. Naruse M, Sussman CR, Naruse K, Jackson R, Inagami T (1983) Renin exists in human adrenal tissue. Endocrinology 57: 482-487.
12. Brown JJ, Lever AF, Robertson JIS, Fraser R, Morton JJ, Tree M, Bell PRF, Davidson JK, Ruthven IS (1973) Hypertension and secondary hyperaldo- steronism associated with a renin-secreting renal juxtaglomerular-cell tumor. Lancet ii: 1228-1232.
13. Mimran A, Leckie BJ, Fourcade JC, Baldet, Navratli H,Barjon P (1978) Blood pressure, renin-angiotensin system and urinary kallikrein in a case of juxtaglo- merular cell tumor. Am J Med 65: 527-536.
14. Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC (1995) Human hypertension caused by mutations in the kidney isozyme of 118-hydroxy- steroid dehydrogenase. Nature Genet 10: 394-399.