Path. Res. Pract. 187, 354-359 (1991)

Juxtaglomerular Cell Tumor of the Kidney Morphological, Immunohistochemical and Ultrastructural Studies of a New Case J. A. L6pez G-Asenjo, J. Blanco Gonzalez, L. Ortega Medina and J. Sanz Esponera Department of Pathology, Hospital Universitario San Carlos, Madrid, Spain

SUMMARY

The authors describe a juxtaglomerular Cell Tumor (feCT) in a hypertensive young man whose symptomatology disappeared when the jeCT was removed. The clinical diagnosis was made before surgery by selective determination of plasma renin activity level in both renal veins and in the draining vein of the tumor. This neoplasm is benign and usually occurs in young patients. The morphological, immunocytochemical and ultrastructural features are described. Other renin-secreting tumors and the theories about histogenesis of jeCT are discussed.

Introduction In 1967 Robertson32 described a small renal tumor in a 16-year-old male with severe hypertension. Although the histopathologic features of the tumor were very much akin to an hemangiopericytoma, there were some clinical differences, like the severe hypertension and the hypokalemia. Histochemistry revealed a similarity in staining between the neoplasm and the juxtaglomerular apparatus, with PAS positive, and fuchsinophilic granules. At least 115 of the neoplastic cells were positive with Bowie's technique and showed fluorescence with Thioflavine T. In homogenates from the tumor, great amounts of renin were detected. Ultrastructurally electron-dense intracytoplasmic rhomboid or trapezoid granules, 0.7 [t in diameter were seen. Some months later, Kihara 19 , who had described an almost identical case proposed the term "juxtaglomerular cell tumor". The clinical syndrome of hypertension, hyperreninemia and secondary hyperaldosteronism associated with these tumors is due to the release of excessive amounts of renin from the tumor cells 6. Since those initial reports, to our knowledge, 23 cases of JGCT have been published to date1-5, 7-9, 11-15, 19,20,22,26,27,29-36,38,39. 0344-0338/9110187-0354$3.5010

Case Report A 24-year-old man, diagnosed as having arterial hypertension two years before, was admitted to hospital. His clinical symptoms were pulsating headache, tiredness, nocturia and polyuria. On physical examination the only pathological finding was a high arterial pressure (200/ 130 mm Hg). Systematic analytical studies (blood, urine, SMA-12, proteinogram and ionogram) were within normal ranges. Bacteriological, serological and immunological tests (antinuclear antibodies and LE phenomenon) were negative. The plasma renin activity in peripheral blood, renal veins and in the draining vein of the tumor are shown in Table 1. Urine: Aldosterone 51.5 [tg/24 h. 4 mg/24 h. 17 CO 13 mg/24 h; 17 OH 16.2 mg/24 h. Vanillylmandelic acid: 4 mg/24 h. IV urography showed in the left kidney a rounded mass with cystic appearance that compressed both middle and superior pyelocalyceal systems; ureter and bladder were normal. On ultrasonography the echogenic features of the mass were also cystic. Abdominal CT revealed that the lesion was placed on the anterior and medial aspect of the left kidney, it proved to be solid with a prominent vascular pattern. ©

1991 by Gustav Fischer Verlag, Stuttgart

Juxtaglomerular Cell Tumor · 355 Table 1. Plasma renin activity (normal ranges: 5-12 nglmllh) IVC (above renal veins) RRV LRV

18.37 17.56 35.20 40.50 14.80

DVT

IVC (below renal veins)

IVC = Inferior Vein Cave; RRV = Right Renal Vein; LRV Renal Vein; DVT = Draining Vein of Tumor

= Left

A left nephrectomy was performed. After surgery both plasma renin activity and urine aldosterone returned to normal values, and the patient at present remains with a mean arterial pressure of 120/80 mmHg.

Material and Methods Material selected from the tumor for light microscopy was prepared following the conventional technique (by paraffin wax embedding) after fixation in 10% formalin. Sections were stained with hematoxylin and eosin, Masson's trichrome, PAS, PASdiastase, reticulin and thioflavine T. Small pieces selected for electron microscopy were fixed in 3 % glutaraldehyde, post-fixed in osmium tetra oxide and embedded in Araldite. Some fragments were frozen in Freon cooled with liquid nitrogen. Sections, 6 fA, thick, were cut on cryostat and indirect immunoperoxidase and PAP techniques were performed ; the antibodies used are shown in Table 2. Table 2. Immunohistochemistry Antibody

Source

Staining

Renin Vimentin NSE S-IOO AEI-3 F-VIII

Sera lab Labsystem Dako Dako Hybritech Dako

+++ ++ +/+/-

Pathology

Gross Findings The tumor, situated at the hilar level, was round in shape measuring 6 X 4 X 3 cm. It was well-defined from the adjacent renal parenchyma. The outer surface was smooth and glistening with prominent vascularization. On section the surface was homogeneous and white-yellowish.

Light Microscopy Findings The tumour showed a homogeneous neoplastic pattern and was well-delimited by a connective capsule. The proliferating cells were of epithelioid appearance. They formed trabeculae with sparse intervening stroma and were situated in a perithelial fashion around dilated blood

Fig. 1. Homogenous appearance with remarkable perithelial arrangement of the neoplastic cells (HE, x 264).

vessels with very thin walls formed only by endothelium (Fig. 1). These vessels frequently formed "deer's antler" figures. The cells were monomorphous, showing a minimal nuclear pleomorphism with a very low mitotic index. Masson's trichrome showed fuchsinophilic granules in the cytoplasm which were also PAS positive (Fig. 2). There were no tubules included in the neoplasm and a great number of mast cells were widespread throughout the tumor.

Electron Microscopic Findings In the ultrastructural study, the perithelial pattern (Fig. 3) and the epithelioid appearance of the cells were noted. They were surrounded by a discontinuous basal lamina. The cytoplasm was rich in rough endoplasmic reticulum and mitochondria, without microfilaments, and frequent electron-dense granules of different shapes (Fig. 4). Some of them, rhomboid in shape, were present in the cisterns of the Golgi complex. The other ones were large and round, being in close relation with the endoplasmic reticulum (Fig. 5). There were also other mediumsized granules.

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J. A. Lopez G-Asenjo et al.

Immunohistochemistry The cytoplasm of the neoplastic cells was heavily stained with antibodies against renin and vimentin, but was only faintly stained with S-100 and NSE. Keratins, F-VIII and desmin were negative (Table 2). Discussion ]GCTwas first recognized in 1967 by Robertson et al.3 2, who described a renin-producing renal cortical tumor causing severe hypertension in a young man. Since this initial report 23 cases have been published (Table 3) 1-5, 7-9, 11-15, 19,20,22,26,27,29-36,38,39. The mean age is 24 years and the range is from 7 to 58 years. The female-male ratio is 1.7 : 1. The most important symptoms are arterial hypertension which is usually accompanied by headache, tiredness, nocturia and "nervousness". Most cases showed also hypokalemia. Macroscopically they are small tumors that are clearly defined from the renal parenchyma by a connective capsule. Light microscopy is characterized by a homoge-

Fig. 3. Blood vessels surrounded by neoplastic cells which are in close relation to vascular wall (EM, x 3300).

Fig. 2. Epithelioid cells with prominent granular cytoplasm (MASSON, x 528). Inset: Intense cytoplasmic positivity for renin (PAP, x 528).

neous morphology with a solid growth, formed by epithelioid-like cells about 10!l in diameter with a granular cytoplasm that is best seen with Masson, PAS, Bowie, Gomori and Thioflavine T stains. The tumours have a very prominent vascular proliferation with thin vessels, whose walls are formed only by endothelium; the neoplastic cells showing a prominent perithelial arrangement. Other common features, although not so frequent, are mast cells and tubules within the neoplastic mass. The latter has been interpreted as suggesting the hamartomatous nature of the lesion. Sometimes a dense sympathetic innervation has been described!. Electron microscopy is very characteristic. We can recognize the ultrastructural hallmark of the juxtaglomerular apparatus cells, the electrondense cytoplasmic bodies. Rhomboid crystalline structures in close relation to Golgi apparatus in the paranuclear situation (protogranules) are seen 2,31. These are the most immature form of granules, but intermediate forms and fully developed granules surrounded by a unit membrane can also be seen. There is a

Juxtaglomerular Cell Tumor . 357

maturative sequence in the development of secretory granules. Mature forms are derived from either growth or by fusion of protogranules 1,2,7,9,41. On the other hand electron microscopy reveals the epithelioid nature of the neoplastic cells. They are partially surrounded by basal lamina and endowed with a lot of rough endoplasmic reticulum, mitochondria and prominent Golgi apparatus. Some cases have been reported with smooth muscle microfilaments 1, 2, 9, 35, although these were not present in our cases. Immunohistochemistry has proved the presence of renin in the tumor cells both with immunofluorescence and with immunozymatic techniques 22- 24 , 34, 37. The histogenesis is controversial. Initially, and based on histologic criteria, these neoplasms were considered haemangiopericytomas3. However, nowadays its origin from the juxtaglomerular cells has been sufficiently proved by histochemical, ultrastructural and immunohistochemical data. Some authors have suggested an hamartomatous origin 17 but they have never been seen as congenital tumors,

Fig. 5. Electron-dense renin granules. The rhomboidal bodies are found mainly around the Golgi apparatus and more rounded forms in the peripheral cytoplasm (EM, x 19000).

Fig. 4. Polygonal cells with numerous mitochondria, rough endoplasmic reticulum, electron dense granules of different shapes and discontinuous basal lamina (EM, x 4100).

so the idea that they are actually neoplasms has prevailed. Other neoplasms, renal or extrarenal, can secrete renin (Table 4). With an antibody against purified renin, and with immunoperoxidase techniques, Lindop has proved positivity in 50% of nephroblastomas picked at random 24,25,28. In the same study renin has been found in renal cell carcinomas 18, 21 ,23 although there was no clinical evidence of hyperreninism. This fact suggests that an inactive renin, in prohormone form, is produced while in juxtaglomerular cell tumors active renin is detected together with high levels of plasma renin activity6. Among the renin secreting extrarenal tumors it is necessary to quote the undifferentiated small cell carcinomas of the lung 16 . Renin secretion has been reported in other neoplasms such as ductal carcinoma of pancreas, orbital hemangiopericytoma 4o , liver hamartoma lO and in two pelvic tumors of uncertain histogenesis described by Aurell et al. in 1981. Some alveolar soft tissue sarcomas

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Lopez G-Asenjo et al.

Table 3. JGCT: Reported cases Case

Age

Sex

Loc.

Size (cm)

B.P.

Reference

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

16 23 37 13 18 7 24 38 25 17 15 26 16 47 30 18 20 58 27 21 69 11 22 24

M F F M M F M F M F F F F M F F F M F M F F F M

L L R R R L R

3 2 4 3.5 1.5 0.8 2 2 1 4 0.8 1.5 1.2

2501150 1861110 2601150 2201170 200/130 180/130 190/136 2201150 2201170 1901118 1801120 2201162 2001120 2601140 2101140 2101150 220/130 220/120 190/140 193/130 220/130 200/170 230/135 200/130

Robertson et al. Kihara et al. Eddy et al. Bonnin et al. Conn et al. More et al. Schambelan et al. Gherardi et al. 0rjavik et al. T akahasi et al. Connor et al. Minran et al. Warshaw et al. Hanna et al. EI Matri et al. Valdes et al. Lam et al. Squires et al. Baruch et al. Baruch et al. Baruch et al. Dennis et al. Martinez-Amenos Present Case

L L R R L R L R L R L R L L L L

that have been positive with immunohistochemistry using partially purified antibodies against renin have yielded negative results when purified antibodies have been used. In the case we present its gross size is remarkable, compared with the cases previously reported. Moreover it is the largest one published to date. In spite of its size and the immunocytochemical and ultrastructural evidence of renin production, the hypertension was easily controlled with low salt diet. We found no tubular structures, but the ultrastructural and immunocytochemical features were similar to other JGC tumours described in the literature. The demonstration of medium-sized filaments, of vim en tin type with monoclonal antibodies, and the absence of expression of a wide spectrum keratins confirm the mesenchymal differentiation of the tumor.

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1.5 1.5 3.5 4.5 5 3 3 5.0 0.45 6.0

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Received February 14, 1990 . Accepted June 27, 1990

Key words: Juxtaglomerular cell tumor - Hypertension - Renin - Renal tumor - Hyperaldosteronism Jose A. Lopez G-Asenjo, Servicio de Anatomia Pathologic a, Hospital Universitario San Carlos, Plaza de Cristo Rey s.n., Madrid 28040, Spain