Arterial hypertension and ovarian tumour in a girl: what is the link?
Laurent Balu1,
Jean-Marie Gasc5,
Liliane Boccon-Gibod2,
Philine De Vries3,
Philipe Blanc4,
Vincent Guigonis1,
Georges Deschênes1,
Albert Bensman1 and
Tim Ulinski1
1 Department of Pediatric Nephrology, 2 Department of Pathology and 3 Department of Surgery, Hôpital Trousseau, 26, Av du Docteur Netter, 75012 Paris, France, 4 Department of Pediatrics, Hôpital de Poissy, 78300 Poissy, France and 5 Inserm U36, Collège de France, 11, place Marcelin Berthelot, 75231 Paris Cedex 05, France
Correspondence and offprint requests to: T. Ulinski, Department of Pediatric Nephrology, Hôpital Trousseau, 26, Av. du Docteur Netter, 75012 Paris, France. Email: tim.ulinski{at}trs.ap-hop-paris.fr
Keywords: arterial hypertension; children; ovary; prorenin; renin; tumour
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Introduction
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Patients with renin-producing tumours are characterized by high circulating active renin and aldosterone levels, hypokalaemia and high blood pressure. Most renin-secreting tumours are of renal origin and are thought to arise from the juxtaglomerular apparatus. Extrarenal renin-secreting tumours are very rare. Pulmonary [1], pancreatic [2], orbital [3] and other origins have been described. Ovarian renin-secreting tumours responsible for secondary hypertension are exceptional. Only one paediatric case has been described in the literature [4].
The role of the ovarian renin angiotensin system has been identified [5]. It plays a crucial role in reproductive functions such as folliculogenesis, oocyte maturation, ovulation, steroid synthesis, and the formation of the corpus luteum. The amount of secreted renin in the ovary is comparatively low so that secondary hypertension due to ovary derived renin is observed only in situations of tumour formation.
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Case report
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A 14-year-old pubertal girl (61 kg; 153 cm) presented first with a 5 day history of increasingly severe headache and sudden vomiting on the fifth day motivating her emergency consultation. Her arterial blood pressure was 190/140. Physical examination revealed a left pelvic mass, moderate obesity and facial flush. Neurological examination was normal. Neither androgenic nor glucocorticoid excess nor any other anomaly was detected. Six months prior to the described episode she presented with abundant metrorrhagia necessitating oestrogen/progesterone treatment.
Laboratory investigations revealed normal renal function (serum creatinin = 36 µmol/l), low serum potassium (2.5 mEq/l), and urinary sodium was <10 mEq/l. Plasma renin levels (46 pg/ml; normal: 22±11 pg/ml) were moderately increased, plasma prorenin levels (2162 pg/ml; normal: 307±133) and aldosterone (>1150 pg/ml; normal: 70±20 pg/ml) were strongly increased before administration of ACE inhibitors. The remaining serum and urine electrolyte analyses, including proteinuria, hormone analysis, as well as red and white blood cell count, were normal. Tumour markers (AFP, beta HCG, CEA) were negative. Ultrasound investigation revealed a solid left ovarian tumour of 5.5 x 4.9 x 5.0 cm and neither kidney showed any parenchymal or vascular anomaly. Cardiac ultrasound showed a left ventricular hypertrophy (mass: 128 g/m2; normal: 61±17 g/m2). Ophthalmological examination revealed hypertensive retinopathy grade III. MIBG scintigraphy did not show any pathological signal. Pelvic scan confirmed the solid ovarian tumour. Arterial hypertension was first treated with continuous IV Nicardipin (3 mg/h) perfusion and once controlled, treatment was switched to oral Captopril (50 mg twice daily). Ovarectomy was performed and ACE inhibitor treatment was tapered off over several days. Post-surgery blood pressure was normal (120/80). The tumour showed a homogeneous structure and was encapsulated without necrotic parts. Histological examination revealed a homogeneous proliferation of cells with abundant eosinophil cytoplasm, large nuclei and a low mitotic activity. No Leydig cells were detected. The tumour was identified as a Sertoli cell tumour. A routine technique was used to immunostain sections of the tumour with antibodies to renin and prorenin and revealed positive signals for both peptides (Figure 1). The girl is doing well 12 months after ovarectomy, her blood pressure is normal with complete regression of left ventricular hypertrophy (mass: 69 g/m2).

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Fig. 1. Immunostaining of renin (A) and prorenin (B) with antibodies specific for each form. Cells immunostained for renin or prorenin appear organized in clusters or trabeculae forming epithelial types of structures: both the cell renin and prorenin contents are weak because neither form is stored in cells and is rapidly secreted, probably in a non-regulated, constitutive fashion.
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Discussion
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A moderately elevated plasma renin (PR) level was detected in our patient. Such elevated PR may be due to a stimulation of the juxtaglomerular apparatus secondary to renal vascular damage. In situations of high PR and normal renal vascularization, renin-secreting tumours have to be suspected. Many cases of renin-secreting tumours have been described and most of them have a renal origin. Juxtaglomerular cell is the most common origin, although rare cases of clear cell carcinoma [6], Wilms tumour [6] and mesoblastic nephroma [7] have been reported. Several localizations of non-renal renin-secreting tumours have been described. Table 1 summarizes these rare tumours, their characteristics, their clinical manifestation, and outcome. Only one paediatric ovarian renin-secreting tumour has been reported [4]. Plasma prorenin was extremely increased in our patient. Prorenin is an inactive precursor of renin. Under physiological conditions prorenin constitutes 5090% of total renin plasma concentration, while the rest is active renin. If active renin is chronically stimulated to high levels (sodium depletion, disturbances in renal perfusion) circulating prorenin levels are increased only
24-fold [8]. However, in the case of renin-secreting tumours plasma and tissue prorenin levels are in general strongly increased up to 100-fold [9]. The plasma prorenin level in our patient was increased by 8-fold. The association of very high prorenin levels with only moderately increased PR can be due to inefficient precursor processing in tumour cells. Therefore, the analysis of the plasma prorenin concentration might be a useful tool to differentiate between a renin-secreting tumour and other situations with elevated PR [10].
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Table 1. Characteristics, clinical data and outcome of the 22 patients with extrarenal renin-secreting tumours reported in the literature
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Compared to tumours derived from the juxtaglomerlar apparatus the in situ hybridization of the tumour described here revealed a relatively weak signal for renin but a comparatively stronger signal for prorenin, suggesting either continuous renin secretion without significant storage or relatively weak renin production compared to prorenin synthesis. The tumour showed low mitotic activity suggesting slow tumour development over several months or years as suspected by increased left ventricular mass and hypertensive retinopathy. It can be hypothesized that in the case of very high renin secretion, clinical symptoms would probably have appeared earlier. In a retrospective study it has been reported that four out of eight ovarian tumours showed positive immunohistochemical staining for renin without elevated renin plasma levels and normal blood pressure in the respective patients. In one of these patients, elevated plasma prorenin levels have been detected. The degree of renin secretion seems to be higher in tumours of juxtaglomerular origin and are extremely variable among the different extrarenal renin-secreting tumours. Excessive prorenin secretion is frequently found in such tumours.
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Teaching points
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- Renin-secreting tumours should be suspected in patients with arterial hypertension especially if hypokalaemia is present.
- Non-renal renin-secreting tumours are rare in adults and exceptional in children.
- In patients with such tumours, plasma prorenin levels might be extremely increased compared to PR levels because of inefficient precursor processing in tumour cells.
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Acknowledgments
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We are grateful to Dr Azizi's laboratory team in the Georges Pompidou European Hospital for the measurement of renin and prorenin plasma levels.
Conflict of interest statement. None declared.
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