Recurrent Hypertensive Cerebral Hemorrhages in a Boy Caused by a Reninoma: Rare Manifestations and Distinctive Electron Microscopy Findings

Abstract

J Clin Hypertens (Greenwich). 2012;14:802–805. ©2012 Wiley Periodicals, Inc.

Recurrent cerebral hemorrhages caused by hypertension secondary to reninoma are extremely rare in children. Because of its detrimental effects on children’s health, the importance of early diagnosis of and treatment for reninoma should be emphasized. Here, the authors present a 10‐year‐old boy with intermittent headaches and neurologic deficiency symptoms caused by hypertension. A reninoma in the right kidney was detected and successfully treated with laparoscopic partial nephrectomy. Two cell types were revealed in the tumor tissue under electron microscopy: renin secreting tumor cells and mast cells. This rare case expands our knowledge of hypertension in children and provides direct evidence that mast cells may infiltrate reninoma.

Reninoma, also termed juxtaglomerular cell tumor, is rare and may cause secondary hypertension by secreting excessive renin. The tumor is typically found in young adults in their 20s or 30s. Approximately 90 cases have been reported to date, 4 of which were younger than 10 years. ¹ , ² , ³ The tumor may lead to severe complications if diagnosis is delayed. Herein, we report a 10‐year‐old boy with recurrent cerebral hemorrhages caused by a reninoma, which was successfully treated by laparoscopic nephron‐sparing surgery. Electron microscopy revealed that there were two main cell types present in the tumor. One contained renin, and the other was confirmed as mast cells. The mechanism and consequences of mast cell infiltration are still unknown. To the best of our knowledge, this is the first report of recurrent cerebral hemorrhages caused by reninoma in children.

Case Report

A 10‐year‐old boy was referred to our hospital due to intermittent headaches, dizziness, and lethargy for 2 years. Eight months ago, he had a severe headache, accompanied by nausea, vomiting, and lethargy. These symptoms lasted for about 15 hours and resolved spontaneously. One month ago, after an episode of severe headache and transient loss of consciousness, he exhibited motor disturbance on his right side. Physical examination at a local children’s hospital revealed a blood pressure of 210/180 mm Hg. A computed tomographic (CT) scan revealed acute hemorrhage and encephalomalacia lesions of bilateral basal ganglia (Figure 1), suggesting chronic and recurrent cerebral hemorrhages caused by prolonged uncontrolled hypertension. The patient was then referred to our hospital for further treatment. His medical history was unremarkable and there was no family history of hypertension. On physical examination, he was 144 cm in height and weighed 44 kg. His muscle strength in the right upper and lower extremities was IV. His metabolic profile was unremarkable except for a low potassium level of 2.8 mmol/L (normal values, 3.5–5.5 mmol/L). The 24‐hour urinary catecholamine excretion levels and free cortisol level were in the normal range. His peripheral plasma renin activity (PRA) was >12 ng/mL/h (normal values, 0.93–6.56 ng/mL/h), above the upper limit of measurement. His serum angiotensin II level was 320 pg/mL (normal values, 29–71.6 pg/mL) and aldosterone 19.7 ng/dL (normal range, 8.6–13.8 ng/dL). Doppler ultrasound and magnetic resonance angiography (MRA) of renal arteries did not reveal any abnormalities. An abdominal CT scan demonstrated a less enhanced mass in the right kidney (Figure 2).

Figure 1.

 Computed tomographic images of the head showing left basal ganglia hemorrhage and right basal ganglia encephalomalacia (indicated by arrows).

Figure 2.

 Computed tomographic images of the reninoma. (A) In plain scan, the tumor appeared isodense to the renal parenchyma (black arrow). (B) In contrast enhancement, the tumor was less enhanced than the renal parenchyma (white arrow).

A combination of antihypertensive drugs, including controlled‐release nifedipine (30 mg daily), metoprolol (12.5 mg twice per day), and losartan (25 mg daily), were administrated to the patient and blood pressure gradually decreased to 140/110 mm Hg. The patient underwent a right partial nephrectomy via laparoscopy. The tumor was found in the ventromedial mid‐zone of the right kidney and was removed uneventfully. Four days after surgery, peripheral PRA level decreased to 0.49 ng/mL/h and serum potassium level increased to 4.0 mmol/L. After the operation, 30‐mg/d nifedipine was administrated to the patient to maintain his BP to about 115/78 mm Hg. Six months later, nifedipine was discontinued and his BP was stable at about 110/65 mm Hg since then. No headache or dizziness reoccurred. Follow‐up examinations have been regularly conducted up to the present.

The gross pathology demonstrated a well‐encapsulated, grey‐pink solitary lesion measuring 2 cm in diameter. Histologically, the tumor was composed of cells with indistinct cell borders and moderate amounts of eosinophilic cytoplasm (Figure 3). The nuclei were slightly pleomorphic, with round, oval, or spindle shapes. Although there were prominent nuclear atypia, no mitoses were seen. Immunohistochemistry staining showed that the cells were positive for vimentin, CD34, and CD31 (vascular marker) but negative for smooth muscle actin (SMA), chromogranin A (CgA), S‐100, HMB45, and AE1/AE3. Ki‐67 index was approximately 20%. Periodic acid‐Schiff staining was positive.

Figure 3.

 Light microscopy showed that the tumor was composed of cells with indistinct cell borders and moderate amount of eosinophilic cytoplasm. The nuclei were pleomorphic with round, oval, or spindle shapes.

Two cell types were observed in the tumor under electron microscopy. One cell type was recognized as juxtaglomerular tumor cell because there were typical rhomboidal renin granules in the cytoplasm (Figure 4). These cells had irregular nuclei and contained many granular endoplasmic reticulum and Golgi apparatus. In addition, there were a variable number of rhomboidal, polygonal, and round cytoplasmic granules. The other cell type was considered to be mast cells, as they had regular round nuclei and contained many round granules of different sizes in the cytoplasm (Figure 5). There were some finger‐like protrusions on the surface of these mast cells. No rhomboidal crystal granules or irregular nucleus were seen. The mast cells scattered in the tumor tissue, and the ratio of mast cell to tumor cell was approximately 1:10.

Figure 4.

 Electron microscopy of reninoma showed typical rhomboid‐shaped renin protogranules (white arrow).

Figure 5.

 Electron microscopy of reninoma showed a mast cell with round nuclear, fine finger‐like protrusions on the surface and numerous round electron dense cytoplasmic granules of varying sizes. Granules varied between 0.4 μm and 1.6 μm with a mean diameter of approximately 0.5 μm. No rhomboid‐shaped renin protogranules were seen.

Discussion

Reninoma is characterized by high renin level, hypokalemia, and secondary hyperaldosteronism in the absence of renal artery stenosis. Headache and dizziness related to hypertension are common in affected patients, although recurrent cerebral hemorrhages and chronic encephalomalacia in children is rarely reported, ³ , ⁴ which made this case an extremely rare clinical entity. This severe complication may be caused by long‐term uncontrolled hypertension, thus early diagnosis of and treatment for reninoma is crucial to the patient’s health. Reportedly, the average duration of symptoms was 2.6 years in children before the diagnosis was made. ⁴ , ⁵ Although nearly 90 cases have been reported, only 4 of them were younger than 10. ⁵ The present patient had hypertension for about 2 years, suggesting that reninoma might have occurred when he was 8 years old. Even though ultrasound, CT, and magnetic resonance imaging are helpful, it is still difficult to make a diagnosis because of the small size and low incidence of tumors in children. Segmental renal vein sampling may provide more diagnostic information. ⁴

Rhomboid‐shaped rennin protogranules in cytoplasma under electron microscopy is a characteristic feature of reninoma. ⁶ However, renin protogranules may also be seen in other renal and extrarenal tumors, such as Wilm’s tumor, rhabdoid tumor, lung cancer, paraovarian tumor, and fallopian tube adenocarcinoma. ⁷ , ⁸ Immunohistochemical staining would be helpful for differential diagnosis.

Reninoma is usually benign and solitary; however, 3 malignant cases have been reported at the ages of 51, 52, and 8 years, respectively, one of which was multicentric in origin. ¹ , ⁹ , ¹⁰ Little evidence suggests that there is a relationship between cell morphology and malignancy; however, vascular invasion is a clue of potential malignancy. Changes of the number of some chromosomes, such as loss of chromosome 9, 11 (or 11q), or X or gain of additional chromosome 10 and other aneuploid karyotype or complex genomic imbalance might also be associated with local recurrence or distant metastasis. ² , ¹¹ , ¹² In our case, the relatively higher Ki‐67 index (approximately 20%) may indicate a high risk for malignancy. The patient has been regularly followed up postoperatively by checking blood pressure and serum potassium. Plasma renin activity will be measured when necessary.

Surprisingly, numerous mast cells were seen in tumor tissue under electron microscopy, which was consistent with the previous report by Philli and Mukherjee. ¹³ Mast cells are barely distinguishable from tumor cells under light microscopy. ⁶ , ¹³ Mast cells are derived from bone‐marrow hematopoietic progenitor cells and will infiltrate peripheral tissues close to mucosal surfaces, such as skin, respiratory tract, and gastrointestinal tract. They will be recruited to the injured tissue that has been attacked by xenobiotics. ¹⁴ As we know, mast cells play an important role in allergies and pathogen immune responses during infections. In recent years, mast cells are recognized as modulators of tumor microenvironments. They may facilitate tumor growth and metastasis by releasing mediators such as histamine, interleukin (IL) 8, and tryptase to disrupt normal blood vessel barriers. ¹⁴ , ¹⁵ , ¹⁶ Mast cells may also suppress antitumor immune response by regulating cytotoxic T and NK cells activities through secretion of various cytokines, such as IL‐1β, tumor necrosis factor α, and IL‐18. ¹⁷ In this patient, whether infiltration of mast cells happens after tumor formation or is a risk factor for tumorigenesis is not clear and deserves further study.

Surgery is currently the only possible treatment. Choice of either radical or partial nephrectomy is based on tumor location and size. Most patients will exhibit normal blood pressure after surgery. In our case, persistent hypertension, although less severe postoperatively, might be due to the thickening or sclerosis of arterial walls as a result of a long‐term hypertension. ⁶ Indeed, the patient was found to have hypertensive retinopathy of grade IV by examination of ocular fundus.

Conclusions

The possibility of reninoma should be considered when a child presents with hypertension. This rare case expands our knowledge of hypertension in children and provides direct evidence of mast cell infiltration in reninoma, even though the roles they play in tumorigenesis and development is still unknown.

Acknowledgment and disclosures:  We give our appreciation to Lianming Liao for his kind work to refine the article. This study was supported by the Natural Science Foundation of China (No: 81100416). The first two authors contributed equally to this work. The authors have no financial disclosures or conflicts of interest to declare. The article was written independently.