A c t a Path. Jrp. 27(4): 567-586,

1977

EXTRARENAL RENIN-SECRETING TUMOR ASSOCIATED WITH HYPERTENSION

Hiroyuki OHMORI*, Makoto MOTOI*,Hiromichi SATO*,Akira TSUTSUMI*, Katsuo OGAWA*, Hisako FUJIWARA**, Toshiaki KAGEYAMA***, Takeo YOSHINOUCHI****, and Hisamitsu YOKOYAMA**** Department of Pathology, Department of Ophthalmology, Department of Neurosurgery, Department of Third Internal Medicine, Okayamu University Medical School, Okayama (Received on Nov. 11, 1976)

Described herein is a n autopsy case of a 16-year-old female with severe hypertension, hyperreninemia and secondary aldosteronism. She had had a progressively growing tumor of her right orbita from the age of 4. The tumor was partially excised 13 months before death. A high content of a renin-like material was detected in the excised tumor, which was histologically a hemangiopericytoma. Bowie stain revealed some granules in small number of tumor cells and electron microscopic study showed some cytoplasmic granules. Following the operation, hypertension was somewhat improved, but the levels of plasma renin activity and plasma aldosterone concentration remained elevated, because the tumor was partially resected. At autopsy, the tumor invaded into the cranial base and right frontal lobe, and metastasized to the lungs. In the present case, renal renin-secreting tumor, malignant hypertension and renovascular hypertension were ruled out by the clinical and pathological studies. ACTA PATH. JAP. 27: 567-586, 1977.

Introduction I n 1967, ROBERTSON et described the first case of a renal renin-secreting tumor. who proposed the term Three months later a similar case was described by KIHARAet “juxtaglomerular cell tumor’’ to this tumor which showed histological features of hemangiopericytoma. Since then additional cases have been rep0rted.~1~7~~~~~~~,27,P2,lr1,90 All these cases showed hypertension and hyperreninemia which were cured by surgical removal. Other reported renal tumors associated with hypertension and hyperreninemia were Wilms’ tumors,W1 a renal hamartomatous alterationla and a clear cell oarcinoma.ls An oat-cell carcinoma1s and an epithelial liver harnartoma5 have been described as extrarenal tumors with elevated plasma renin activity. In the former case, there was no episode of hypertension, although plasma renin activity level and aldosterone secretion rate were elevated and the tumor tissue contained a. renin-like material, The A% EL, X R (3, .ma %t % @* / J 4 l BE3 AP, %lLJ !a%%[email protected] &&, tiwl A% Present address : Department of Pathology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700 567 %*3

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latter case had hypertension and elevated plasma renin activity level which disappeared after removal of the tumor. However, there was no description as to secondary aldosteronism and renin content of the tumor. The kidneys of both cases were not examined. The present report concerns an autopsy case of a girl with orbital tumor which was considered to secrete a renin-like material causing hypertension, hyperreninemia and secondary aldosteronism. Case Repmt

The patient was a 16-year-old girl at autopsy, She was born as an immature baby with 2230 g of body weight a t full term. I n February, 1963, at the age of 4, her father struck the lateral region of her right eye by fiat hand. After that her right conjunctiva became hyperemic. Three months later right exophthalmus appeared and gradually progressed. In March, 1965, she was admitted to the Department of Ophthalmology, Okayama University Hospital with marked exophthalmus of the right eye. A subcutaneous nodule, a small fmger-tip in size, was palpated at the medial region of the right eye. Her blood pressure was 120/70mmHg. The examinations of blood and urine were normal. Carotid angiography revealed an abnormal shadow a t the posterior region of the right eye, which suggested a hemangiomatous lesion. Only a small specimen was taken for the histological examination, because the bleeding was massive during operation (the 1st operation) and her family rejected the ophthalectomy. Afterwards, the tumor was exposed to Goao irradiation therapy (200 rads ~ 6 0 for , 4 months) without much effect. During the next eight years after discharge, she had been treated conservatively without the examination of blood pressure. The tumor had increased in size gradually and she had sometimes an episode of nasal bleeding. I n January, 1974, she began to complain of nasal obstruction. In March, 1974, a t the age of 15, she was admitted to the Department of Neurosurgery, Okayama 3 in size, was palpable a t the University Hospital. A pulsating tumor, 6 ~ 6 x cm region of right eye and filled the right nasal cavity compressing the nasal septum to the left side (Fig. 1). Her blood pressure was 200/130 mmHg. hintiscanning showed abnormal uptake of the right orbital region, suggesting the hemangiomatous tumor. Carotid angiography suggested that the tumor might extend into intracranial region. Electroencephalogram showed the slow wave in the right frontal region. For the examination and control of hypertension, she was transferred to the Department of

Fig. 1. The patient before the second operation.

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Third Internal Medicine. Fundoscopic examination of the left eye showed only slght narrowing of arterioles. Electrocardiogram suggested left ventricular hypertrophy. The urine examination was negative for protein and sugar, and the sediment was normal. The red blood cell count was 501 x 104/mm3;white blood cell count 7900 /mm3; hemoglobin 10.8 g/dl and hematocrit 35%. The erythrocyte sedimentation rate was 39 mm/hr and 73 mm/2hr. The serum potassium value during regular diet (NaC1 intake: 15 g/day) was 3.0 mEq/l and serum sodium 133.2 mEq/l. The serum chloride was 98 mEq/l; calcium 10.1 mg/dl; iron 24 pg/dl and copper 169 pgldl. The total protein was 8.6 g/dl (albumin 53.3; alpha-1 3.0; alpha-2 9.5; beta 13.1 and gammaglobulin 20.9 percent). SGOT was 26 unit; SGPT 15 unit; CCF minus; TTT 2 unit; ZTT 7 unit; LDH 315 W. unit and Al-P-ase 3.6 B.L. unit. The cholesterol was 216 mg/dl; triglyceride 139 mg/dl; NEFA 760 pEp/l; phospholipid 134 mg/dl and beta-lipoprotein 453 mg/dl. The serum uric acid was 3.8 mg/dl; blood urea nitrogen 7 mg/dl; serum creatinine 0.4 mg/dl; urinary creatinine 0.4 g/day ; creatinine clearance 71.4 ml/min and GFR 116.3 ml/min. The PSP test was 26.7% in 15 min. and 70.2% in 120 min. The fasting blood sugar was 120 mg/dl. The 50 g GTT showed levels of 184, 176, 160, 130 and 88 mg/dl a t 30, 60, 90, 120 and 180 minutes, respectively. The triosorb test was 27.7%; tetrasorb 10.7 pg/dl and BMR-7%. The rate of excretion of 17-OHCS was 7.66 mg/24 hr and 17-KS 2.29 mg/24 hr. The test for urinary vanillylmandelic acid and Regitine test were negative. The urinary catecholamine determination demonstrated 47.5 pg/day. Plasma renin activity (PRA) values were 10.76 and 17.26 ng/ml/hr during regular diet (NaCl intake 15 mg/day and overnight Table 1. Laboratory Data before the ZZnd Operation

NaCl intake

Date

Medication

PRA" (ng/ml/hr) Upright bent

Normal Value April 9, '74

(4 hr)

0.5-4

1

PACa' Recum(ng/dl) bent

5.81f3.60

Serum

N~

K (mEq/L) (mEq/L) 136-152 135.4

3.5-5.5 3.9

10.10

135.1

3.7

aa. 89

12

I

24

I

-NaCI intake -TCMTsJ 3-6 g/dey -4I mg/day

14.36

-NaCl intake

10.76

29

I

14 15 16 17

18

-

I

15.50

28.13

133.2

3.0

12.94

14.80

17.64

133.0

3.6

-NaCI intake -SPLA4) I 6g/day -200mglday

PRA: Plasma Renin Activity * ) TCM": "richlormethiazide

11

17.26

PAC: Plaema Aldosterone Concentration 4 ) SPLA: Spironolactone

570

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recumbency), the normal value being 0.5-4.0ng/ml/hr, and PRA values were 22.89 and 14.36 ng/ml/hr during low sodium diet (NaC1 intake 3-5 g/day and overnight recumbency). Elevation in PRA did not respond well to postural change as shown in Table I . Plasma aldosterone concentration (PAC) was 28.13 ng/dl (NaC1 intake 15 g and overnight recumbency), the normal value being 5.812~3.60ng/dl. From the laboratory data mentioned above it became clear that reninism with hypertension was possible. From the finding of the eyeground and renal function, the possibility of malignant hypertension was considered to be unlikely, and two possibilities, i.e., renal renin-secreting tumor or renovascular hypertension, were considered. No thrills or bruits were noted over the fIank region. Renoscintigram, intravenous pyelography and pneumoretroperitoneum failed to reveal abnormal findings. Abdominal aortography demonstrated no constriction of renal arteries and their branches. But multiple small arteriovenous connections in the central portion of the left kidney were detected (Fig. 2). Therefore, in order to ascertain whether this abnormal finding might be associated with renin secretion, PRA in venous blood from the left kidney, from inferior vena cava below renal veins and from inferior vena cava above renal veins were evaluated. Results showed no elevated level of PRA of left renal vein compared with that of inferior vena cava as shown in Table a. Table 2. PRA” of Left Renal Vein and Inferior Vena Cava

Vein Left renal vein

IVCa) below renal veins IVCa) above renal veins 1)

PRA: Plasma Renin Activity

PRA (ng/ml/hr)

1s. 80 17.16 15.44

IVC: Inferior Vena Cava

During the examination for the cause of hypertension, headache, vomiting and convulsion with transient unconsciousness sometimes occurred, and left exophthalmus also appeared. Her blood pressure was somewhat regulated to 164 mmHg (means), systolic and 112 mmHg (means), diastolic by the mediation with spironolactone (100200 mg/day), clonidine hydrochloride (0.45 mg/day) and trichlormethiazide (6 mg/ day).

Fig. 2. Aortography demonstrating multiple small arteriovenous connections in central portion of the left kidney. Fig. 3. Gross appearance of the tumor excised at the second operation,

: : :

alseroxygen (4-3 mg/day) a-methg dopa (750mg&y) 1-(2-chloroethyl)-3-cyclohexyl nitrosourea (total, 360 mg) CHPR : chlorpropamide (250 mg/day) 0: clonidine hydrochloride (0.15-0.3+ 0.45 mg/day) CLOF : clofibrate (750 mg/day)

&O a-MD CC" Coeo

:

CoeUirradiation to naaal tumor (total 7000R) ISOSOR: isosorbitol (90 ml/day) IVC : inferior vena cava PAC : plasma aldosterone concentration PITR : pitressin tannate (5p-25 &day) POT : potassium asparate (1.8-.2.7g/day) PRA : plasma renin activity

: : : : :

TCMT

SPLA

RES

PSL

PROPR

Table 3. C l i n i d Course before and after the IInd Operation

drowsy ~ernicoma

~ronranolol130me/dav) &e&aolone' (2&-30;& mg/day) reserpine. (0.4 mg/day) spironolactone (200+ 100-+50mg/ day 1 trichlormethiazide ( 4 4 6 mg/day)

~~~~

vomiting

01

r

4

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Although the cause of hypertension remained unknown, the excision of orbital tumor (IInd operation) was performed on 6, June, 1974. The tumor filled the right orbita and invaded into the nasal cavities, paranasal cavities (maxillar and frontal sinus) and also frontal lobe of the brain. Only the tumor in the right orbital region was excised. The excised tumor was approximately 7 cm in diameter, hemorrhagic and elastic firm with partial encapsulation of fibrous tissue (Fig. 3). The excised tumor tissue was divided into three pieces. They were frozen for evaluation of renin content, and fixed in 10% formalin and 2.5% glutaraldehyde in phosphate buffer for light and electron microscopic studies, respectively. During about eight months after operation, her blood pressure was regulated to 152 niinHg (means), systolic and 96 mmHg (means), diastolic with only the administration of spironolactone (100-50 mg/ day) as shown in Table 3. However the levels of PRA and PAC remained elevated. Although CosOirradiation (total 7000 rads) t o the tumor of nasal cavities and CCNU therapy was performed, these effect was only slight. I n November, 1974, the skin covering the right orbital space was broken and necrotic discharge appeared. I n February, 1975, hypertension became severe again with exaggerated PRA and PAC' levels. Medication with spironolactone (50 mglday), reserpin (0.4 mg/day) and alphamethyldopa (750 mglday) did not drop the blood pressure as shown in Table 3. Polyuria (2800-9800 ml/day) also appeared. The specific gravity was from 1010 t o 1015. Urinary volume was not satisfactorily regulated with the medication of pitressin tannate (2.5-5 ulday). The left exophthalmus progressed and the examination of the left optic fundus revealed optic atrophy. In May, 1975, her consciousness sotnetimes became drowsy, lethalgic and semicomatous. Convulsion, vomiting and high fever often occurred. I n spite of tracheotomy and artificial respiration with respirator, she died of respiratory distress on 31, July, 1975.

Renin Content of the Turnm The renin content of the tumor taken a t the second operation was estimated by the courtesy of Drs. 8. FUKUCHI and T. MIURA a t the Department of Internal Medicine, Pukushima Medical College. The content of a renin-like material in the tumor tissue was 1.403-2.225 x lo3 ng Angiotensin I generated/g. wet tissuelhr by radioimmunoassay using the method of CONN e l aL4

Light Microscopic Studies of Surgical Specimens The following represents a retrospective report on the specimens from the first and second operations. ______

~~~

~

~

.

_

~_ _ __ ___ ~

Fig. 4. Tumor taken at the first operation showing sheets of polygonal cells with epithelioid appearance between endothelial-lined vascular spaces. H-E. x 200. Fig. 5. Reticulin fibers surrounding tumor cells and separating them from the endothelial lining. Silver impregnation, Watmabe's method. x 200. Figs. 6 and 7. Tumor taken at the second operation showing same patterns as the specimen of the first operation. Fig. 6. H-E.x 100. Fig. 7. Silver impregnation, Watanabe's method. x 200.

_

~

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1) Specimen taken at theJirst operation: This specimen was very small. The tumor cells were composed of mainly polygonal cells with epithelioid appearance. The cytoplasms were pale and had vaguely defined cell borders (Fig. 4). Cellular atypism and mitosis were not observed. The tumor cells were associated with thin-walled blood vessels which were lined by endothelial cells. Silver impregnation showed welldeveloped reticulin fibers surrounding the tumor cells and separating them from the endothelial lining (Fig. 5). Bowie stain showed no granules in the tumor cells of this minute specimen. A few mast cells were scattered.

2) Specimen taken at the second operation: The histological pictures of this specimen essentially resembled those of the specimen taken a t the first operation (Figs. 6, 7 ) except the following findings. Some tumor cells showed anaplastic changes with giant cells (Fig. 8), although mitotic figures were very scanty. There were small necrotic and hemorrhagic foci in the tumor tissue. Bowie stain showed some granules in a small number of tumor cell cytoplasms (Figs. 9, 10). They were found mainly in anaplastic cells. They were also stained red with azan stain and were fairly positive with PAS reaction after amylase digestion. Numerous mast cells were scattered throughout the tumor (Fig. lla). The cytoplasms of mast cells were filled with granules stained with Bowie stain (Fig. llb). ElectrMz Microscopic Studies of the Tumor Taken at Operation There were the tumor cells with dark and clear cytoplasms, and also intermediate ones. The organelles developed well in the darker tumor cells rather than in clear ones (Fig. 12). Some cisternae of the rough endoplasmic reticulum showed roughly parallel stacks (Fig. 12) and others showed cystic dilatation (Fig. 13). They contained flocculent material. Other organelles seen included developed Golgi apparatus, free ribosomes, abundant mitochondria and centrioles. Some tumor cells had intracytoplasmic fibrillar structures. I n some cells the nuclei were oval or round in shape, while in others they were irregular. The tumor cells were separated from each other by basement membranes. There were intracytoplasmic granules of high electron density measuring from 0.16 p to 1 p, with or without clear surrounding membrane, and also intracisternal granules of relatively low density. Some of them were adjacent to the Golgi apparatus (Fig. 14). The shapes of many granules were round, oval or polygonal, and those of small number of granules were rhomboidal (Fig. 15). Some granules were uniformly dense but others were not homogenous in density and granular without crystalline structures. Some tumor cells had only one or two granules but others had several t o ten or more. The mast cells were filled with intracytoplasmic granules .

-~

Fig. 8. Some tumor cells of the specimen taken at the second operation showing anaplasia with giant cells. H-E. x 200. Figs. 9 and 10. Tumor cells with some intracytoplasmic granules. Fig. 9. Bowie stain. x 1OOO. Fig. 10. Bowie stain. x 1800. Figs. l l a and llb. Many mast cells seen between tumor cells (a) and higher magnification showing abundant granules in the oytupleem (b). Fig. l l a . Bowie stain. x 200. Fig. l l b . Bowie stain. x 1,800.

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Fig. 12. Dark and clear tumor cells are seen. Roughly parallel stacks of rough endoplasmic reticulum are seen in dark tumor cells. Stained with uranyl acetate and lead &rate. x 9,300.

of different size, shape and electron density (Fig. 16) Autopsy Findings The autopsy was performed five hours after death. She was 153 cm tall, and weighed 46 kg. The skin covering the right orbital space showed ulceration with necrotic discharge. The tumor recurred in the right orbital region, and invaded into the nasal cavities and left orbital region. The tumor also invaded into the cribral, sphenoidal and frontal bones involving paranasal cavities and furthermore into the right frontal lobe (Figs. 17, 18). The tumor invading the brain was 7.0x4.5x3.5 cm in size involving orbital, rectal and superior frontal gyri (Fig. 19). The tumor was elastic firm and its cut-surface was mottled greyish and whitish in color with scattered foci of hemorrhage. The tumor also metastasized to both lungs forming several bean-sized nodules (Fig. 20). The histological pictures of the tumor were essentially the same as -~

~~

-

~~

- ~-

Fig. 13. Tumor cells showing cystic dilatation of rough endoplasmic reticulum, abundant mitochondria, cytoplasmic fibrillar structures (arrows) and some granules of varing size. x 8,600. Fig, 14. Tumor cell showing some granules adjacent to the Golgi complex (G). X 15,000.

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Fig. 15. Several granules varying in shape and size, and an intracisternal granule are seen (arrow). x 30,000. Fig. 16. Mast cell adjacent to a clear tumor cell showing numerous cytoplasmic granules. x 6,000.

those of the tumor excised a t the second operation except for pyknotic changes of the nuclei (Pigs. 21, 22). However, Bowie stain did not reveal so distinctly purplish-blue granules not only in the tumor cells but also in mast cells like those of the surgical material. The right cerebral hemisphere around the tumor was very edematous and compressed the left cerebral hemisphere. The left cerebral hemisphere was not invaded by the tumor, but a slit-like hemorrhagic focus was found in the left superior frontal gyms (Fig. 19). Both optic tracts and lateral geniculate bodies were atrophic, and the right one was more marked than the left one. Brain stem, cerebellum and spinal cord showed no abnormal macroscopic findings. Microscopic studies showed gliovis of olivary nuclei, destruction of the Purkinje cells and degeneration of posterior and lateral tracts of the spinal cord. The basal meninges were colored brownish by the heniosiderin Fig. 17. Gross appearance of the tumor protruding from the anterior cranial fossa. Fig. 18. Gross appearance of the cerebral base. The tumor invading into the right frontal lobe. Fig. 19. Frontal section of the cerebral hemisphere passing through the genu of the corpus callosum. The tumor involves the right orbital, rectal and superior frontal gyri and there is a slit-like hemorrhagic focus in the left superior frontal gyrus. Fig. 20. Gross appearance of the lung. Note subpleural metastatic nodules. Fig. 21. Tumor invading into the bone. H-E. x 100. Fig. 22. Tumor metastasizing to the lung. H-E. x 200.

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deposition. Pituitary gland was not invaded by the tumor although the tissues around it were invaded. Microscopically there was hemosiderin deposition in the posterior lobe. Hypophyseal stalk and hypothalamus were normal. The left kidney weighed 166 g and measured 1 0 . 5 ~ 6 . 5 x 5cni, and the right 150 g and 10 x 6 ~ 4 . 8cm. The renal capsules were stripped easily and the surfaces were smooth, The left kidney had three small foci of yellowish cortical nodules and the right kidney had two of them (Fig. 23), which were histologically due to fresh infarction. Capillary spaces of the glomeruli were filled with fresh fibrinous thrombi (Fig. 24), but no other significant changes were found in the glomeruli. Tubules showed cloudy swelling and vacuolar degeneration. Some concentric medial hypertrophy of small arteries and arteriolar hyalinization were found. There were no infarcted scars or tubular atrophy in both kidneys. Juxtaglonierular (JG) cells of both kidneys showed hyperplastic appearance (Figs. 26, 26). There were only a few glomeruli having Bowie positive granules in the juxtaglonierular cells, but the vast majority did not contain any granules. Macroscopic and microscopic studies showed no evidence of stenosis in the renal arteries and their branches. However, microscopic examination of the left kidney revealed a slight proliferation of small dilated veins in the peripelvic fatty tissue (Fig. 27). The heart was slightly hypertrophic (350 g) with patent foramen ovale. There was no abnormality in the large blood vessels. Many thrombi were found in the small blood vessels of many organs. Both lungs were voluminous with increased consistency (left: 464 g, right: 526 g) and their cut-surfaces were rough and reddish-brown in color. Microscopically, bronchopneumonia with hyaline membrane formation and intraalveolar fibrosis was remarkable. The left adrenal gland weighed 8.7 g and right 8.0 g. In the left adrenal cortex, there were two rice grain-sized foci of fresh infarction. The zona glomerulosa was somewhat hyperplastic with much lipid and was clearly demarcated from the zona fasciculata (Fig. 28). Spironolactone body was not seen in spite of the medication of spironolactone. The liver showed degeneration and necrosis of liver cells in midzonal zone with inflammatory cell infiltration and without cholestasis. The pancreas showed small fibrotic foci with scanty lymphocyte infiltration and disappearance of zymogen granules of acinar cells. Thyroid and mammary glands showed slight atrophy.

Fig. 23. A fresh cortical infarction of the left kidney (arrow). H-E. x 3.5 Fig. 24. Glomerular capillaries filled with fresh fibrinous thrombi. PTAH. x 200. Fig. 25. Vascular pole of the glomerulus in the left kidney showing hyperplasia of J G Bowie stain. x 400. Fig. 26. Vascular pole of the glomerulus in the right kidney showing hyperplasia of JG Bowie stain. x 400. Fig. 27. Small vascular malformation showing slight proliferation of small dilated containing fresh thrombi. H-E. x 7. Fig. 28. The zona glomerulosa showing somewhat hyperplastic appearance with much H-E. x 200.

cells. cells. veins lipid.

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Discussion

From the result of tissue assay for renin content, it was suggested that hypertension, hyperreninemia and secondary aldosteronism were due t o the secretion of a renin-like material by orbital tumor. The content of a renin-like material in the tumor tissue taken at the second operation was 1.403-2.225 x lo3 ng Angiotensin I generatedlg wet tissuelhr. This content is 4.3-6.7 times higher than the renin content of adjacent renal cortex of the juxtaglomerular cell tumor reported by TERASHIMA et aE.42 This comparison is considered to be reliable, since the tissue assay of both cases were performed by the same investigators in the same institute using the same method. The presence of renin or renin-like material in tissues other than kidneys has been reported in several organs of various species.3B,10~17~13~12 GANTEKel n1.12 described that the brain renin of the dogs differed from renal renin in its pH optimum, immunological behavior and action on the synthetic tetradecaptide. illthough there remains a problem whether or not the renin-like material of the present case is the same material as renal renin, it is known that the other tissues have only small amount of renin or renin-like material as compared with the kidneys.W7J3 Histologically, the intracytoplasniic granules were detected in the turnor cells with Bowie stain. The relationship between the specific granules of J G cells and renal renin has been confirmed. Intracytoplasmic granules stained with Bowie stain were detected in the renal renin-secreting tumors except for the cases of Wilms’ tumor.2sj11 It is known that nonspecific granules of j uxtaglomerular apparatus or tubular epithelium were also stained with Bowie stain.’ However, the fact that the present tumor contained a renin-like material may support that these granules are associated with a renin-like material. Although the granules of autopsy materials were not so distinctly stained purplish-blue as surgical material, it seems likely to be due t o postmortem change or anoxic change a t the end stage of her illness. It has been known in electron microscopic studied on J G cells that SG1 granules containing rhomboidal crystallines are formed in Golgi apparatus, SG2 granules are formed by the fusion of SG1 granules and furthermore SG2 granules niature to SG3 granules which are round in shape and amorphous or fine-granular. These types of granules were detected in juxtaglomerular cell t u m 0 r s . 3 ~ 1 ~ ~I n~ the ~ ~ ~present ~ 1 2 ~case we found cytoplasmic granules of round, oval, polygonal or rhomboid shape and also intracisternal granules. But it was difficult to distinguish these granules from et aZ.42 described that SG1 or SG2 granules without lysosomal lysosomes. TERASHIMA enzyme fused to lysosomes and were resolved by lysosomal enzyme t o result in mature SG3 granules. On the other hand, FISCHER et aLBand LEE et ~ 1 described . ~ ~ that the specific granules were lysosomes themselves in their property and origin. It seems very difficult to distinguish mature granules associated with renin from lysosomes. I n the present case we could not find the rhomboidal crystallines corresponding to SG1 or SG2 granules in JG cells, and it could not be clarified whether or not the renin-like material in the present case was the same as the human renal renin. The other features of the tumor cells were similar to those of juxtaglomerular cell tumor.

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It is of interest that numerous mast cells were scattered throughout the tumor. This phenomenon has also been described in the juxtaglomerular cell t ~ m ~ r . ~ r ~ ~ SEALEY el ~ 1 and . SCHLATMANN ~ ~ et ~ 1 . 3 4 demonstrated the in-vitro and in-vivo inhibition of renin by heparin which has been known to be contained in mast cells. Therefore, in the present case, the occurrence of mast cells may support that the tumor secreted a renin-like material. The tumor was histologically exanlined three times including autopsy material. Retrospectively all the specimens had essentially the same histological features of hemangiopericytoma. Heniangiopericytonia was described first in 1942 by STOUTand MIJRRAY~' and then many cases have been reported arising from various tissues. There has been no description of hemangiopericytoma secreting renin other than juxtaglomerular cell tumor which showed the same histological pattern in all reported cases. CONN et nl. classified reninisni with hypertension in primary reninisni associated with renin-secreting tumor and secondary reninisni which was caused by malignant hypertension and stenosis of renal artery. In the present case, renal tumorous lesion was not detected. Malignant hypertension was ruled out by clinical and pathological studies. Aortography and pathological studies revealed no constriction or stenosis of the renal arteries and their branches. However, a small area of slight proliferation of small veins was microscopically found in the left peripelvic fatty tissue where arteriovenous connection was revealed by aortography. This finding might be associated with congenital arteriovenous fistula of cirsoid type. Even if it would be SO, hyperrenineniia would be considered not due to this change by the following reasons. 1) The microscopic findings of the J G cells and renal parenchymal tissues of the left kidney were not different from those of the right kidney. 2) The PRA value of the reviewed left renal vein was not higher than that of inferior vena cava. 3) TAKAHA et congenital arteriovenous fistulas and classified them in cirsoid and aneurysmal types by the roentogenological and pathological findings. Nine cases of cirsoid type were not reviewed had hypertension. However, the hypertension of the 3 cases8,43~36 cured by nephrectoniy. The other 5 cases had coexsisting lesions, such as a fusiforni stenosis of the branch of renal arterys, renal infar~tion,'~renal insufficiency and ,~~ which aneurysm,21aldosterone-producing adrenal tumorg6or t h r o m b o s i ~ respectively, could be the cause of hypertension. Another case of MALLOY et nl.25 showed good response to the medication, and they explained that the arteriovenous fistula of their case might not be the cause of hypertension. Therefore, it seems unlikely that the renal arteriovenous fistula of cirsoid type causes hypertension of renin-dependent Goldblatt type. Glomerular capillaries and some blood vessels of the kidneys had thrombi in their lumens as well as in the blood vessels of other organs, and several foci of cortical infarction were found. They were considered to be fresh changes by the disseminated intravascular coagulopathy a t the end stage of her illness. The JG cells of both kidneys in the present cases were hyperplastic. However,

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the hyperplasia of J G cells was considered not to exist before or during earlier period of administration of spironolactone, and seemed to be due to the long-term administration of spironolactone by the following reasons. 1) Before or during earlier period of spironolactone administration, the elevation in PRA did not respond well t o postural change. If the J G cells were hyperplastic and would secrete much renin at that time, “upright” PRA should markedly rise compared with “recumbent” PRA.3~38The “upright” PRA rises even in normal subjects, while the PRA of the patients with primary aldosteronism, whose J G cells should be atrophic, does not respond well to postural change.38 Therefore it seems likely that the J G cells in the present case were rather atrophic at that time. 2 ) The J G cells of the renal cortex in the renal reninsecreting tuniors were not hyperplastic except for the t w o cases in which adrenal glands were removed before the renin-secreting tumors were found. In these cases, the salt and water loss due to adrenal insufficiency might stimulate the J G apparatus. In the present case, adrenalectoniy was not done, but this patient was medicated with spironolactone for a long term. It is known that spironolactone acts primarily on receptors located in the renal tubules and accerelates salt and water excretion, which stimulates J G apparatus. LOWUER and L1DDLEz3 reported that PRA level rose during the course of the administration with spironolactone to the patient with low-renin essential hypertension, and even if spironolactone was discontinued, PRA level remained higher than the level before administration. These results would suggest to us that JG cells were stiniulated and became hyperplastic by long-term salt and water loss due to the administration of spironolactone. Furthermore. P A R K E reported R ~ ~ that the patients with primary aldosteronisni showed the J G cells to be normal in some and hyperplastic in others. All the patients were medicated with spironolactone and the PRA increased in every instance to levels often above normal although the PRA of these patients should be low. Therefore, in the present case it is considered that the J G cellsmight be stiniulated to l)econie hyperplastic by the long-term administration of spironolactone. It was not uncertain as to the time when orhital tiinior had the ability to secrete a renin-like material during the course of tumor growth. She had neither hypertension nor hypokaleniia a t least a t the tinie of the first operation and the onset of hypertension was obscure. The tumor might secrete too little renin-like material to cause syniptonies while the tumor remained small in size. Because the content of a reninlike material in this tumor ( 1 . 4 0 3 - 2 . 2 2 5 ~ 1 0ng~ Ang l/g/hr) was much lower than the renin content of the juxtaglomerular cell tumor (1.6 x 106 ng Ang l/g/hr) reported by TERASHIMA et n1.,42while the size of the tumor in the present case was much larger. On the other hand, the finding that the intracytoplasmic granules stained with Bowie stain were found mainly in the anaplastic tumor cells might suggest that the functional differentiation to secrete a renin-like material was switched on when anaplastic changes occurred in the tumor cells. It is well known that ectopic hormone-producing tuniors show morphological a n a p l a ~ i a . ~ ~ I n conclusion, the present case showed the clinical syndrome that CONN et aL4 proposed as primary reninisni, and pharniacologic and pathological examination

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suggested that the orbital tumor might secrete a renin-like material. Acknowledgement: We are grateful to Dr. I. KIHARA,Niigata University, for his helpful criticism on histological study and also to Dr. J. ITOH,Kawasaki Medical College, for his helpful advice on electron microscopic study.

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