DIAGNOSTIC
The Radiology
N. Reed Dunnick, M.D. David S. Hartman, CDR, MC, USN Kerry K. Ford, M.D. Charles J. Davis, Jr., COL, MC, USA Edward S. Amis, Jr., CAPT, MC, USN
Index
terms:
Hypertension,
benign
hemartoma,
8[1].314)
neoplasms,
R
#{149} Kidney
neoplasms,
Radiology
From
the
321-326,
Department
sity Medical Department
Genitourinary tute of Pathology, of Radiology Services
thesda,
MD;
Regional ceived Sept. The private strued partment
of Radiology,
Pathology (C.J.D.), Washington, (D.S.H.)
formed
Medical July
and
15,
8; revision opinions views as official of the
the
Center, 1982;
San
accepted
received
Armed the Health
authors
or as reflecting Army, Navy,
Forces Departments
Diego,
CA
the Insti-
UniSciences,
of Radiology, and
Oct.
Univer-
(C.J.D.),
of the
or assertions of the
DC;
Department
Duke
(N.R.D., K.K.F.); (D.S.H.) and
Pathology
University and
#{149} Kidney
1983
Center, Durham, NC of Radiologic Pathology
BeNaval
(E.S.A.).
revision
Re-
requested
29.
jc
contained and or
are
herein not
the views Defense.
to be
are
the
con-
of the
De-
METHODS
RESULTS
diagnosis
May
AND
The nine patients ranged in age from 14 to 57 years; 7/9 were women (TABLE I). The diagnosis was established histologically in all nine cases. Radiographic material consisted of excretory urograms (eight cases), sonograms (seven cases), computed tomograms (three cases), and angiograms (nine cases). All ultrasound and computed tomographic (CT) examinations were performed with commercially available equipment. The adjacent renal cortex provided the reference for determining the relative echogenicity of the tumors, which were rated as hypoechoic, isoechoic, or hyperechoic.
diagnosis.
ultrasound
147:
SUBJECTS
#{149} (Kidney,
neoplasms
tumors of the juxtaglomerular cells (reninomas) rare but curable cause of significant hypertension. Since description by Robertson in 1967 (1), fewer than 20 cases reported. While the clinical and pathologic features of this have been well documented, previous reports of the rafindings have been limited to isolated case reports (2-18). the radiographic features of nine cases of juxtaglomerular and review the clinical, pathologic, and radiographic of these tumors.
ENIN-PRODUCING
are a the original have been neoplasm diographic We present cell tumor manifestations
8(1)720.
8[1].310)
computed-tomographic
Kidney
1
systemic,
neoplasm,
of Juxtaglomerular
Tumors1
Nine cases of proven juxtaglomerular tumor of the kidney are reviewed. Each patient presented with hypertension; elevated peripheral renin levels were found in four patients. As in past studies, this tumor occurred more frequently in women (7/9 cases). Although the patients tended to be younger (mean age, 31 years) than those with essential hypertension, all but two patients were more than 20 years of age. In all cases, the tumor was solitary, well-defined, and curable by surgery. The tumor was identified by excretory urography in 5/8 patients who underwent this procedure. A solid renal mass was detected in each of the seven patients examined by ultrasound. Since the tumor tends to be isodense with normal renal parenchyma, it is sometimes not seen on computed tomography without intravenous contrast material. Arteriography revealed a hypovascular mass in each of the nine patients. The combination of a hypovascular solid renal mass in a patient with elevated renin but no renal artery lesions should suggest the diagnosis of a juxtaglomerular cell tumor.
(Kidney,
RADIOLOGY
Nine patients presented with hypertension or a clinical manifestation of hypertension (TABLE I). The hypertension was sustained in seven patients and episodic in two patients. In two patients (cases 2 and 6) the juxtaglomerular tumor was discovered during the initial demonstration of hypertension. The other patients had hypertension from 13 months to 23 years prior to discovery of the juxtaglomerular cell tumor. In six of the patients, hypertension had been inadequately controlled with antihypertensive medication. One patient, presenting with acute flank pain, hypotension, and anemia, was found to have a large retroperitoneal hemorrhage associated with a small juxtaglomerular cell tumor. Peripheral serum renin levels were recorded in five patients and clearly elevated levels were found in three patients. In one patient the peripheral renin level was normal and in another the level of peripheral renin was slightly elevated but selective renal vein renin levels were normal. One patient had nonlateralizing selective renins although no peripheral renin was recorded. The radiologic findings are summarized in TABLE II. Excretory urograms were available for review in seven patients. In five, a solitary noncalcified renal mass ranging in size from 3.5 to 6 cm was identified (Figs. 1 and 2). The two cases with a normal urogram were subsequently discovered to have a juxtaglomerular cell tumor measuring 2 and 4 cm, respectively. One patient with a 3.5-cm tumor was described as having a normal urogram but the radiographs were not available for review. A solid tumor was identified by ultrasound in each of the seven 321
Figure
1.
Case
8.
a.
b.
a. b.
I:
TABLE
Clinical
Case No.
Age/Sex
1 2 3 4 5 6 7 8 9
14/F 15/F 21/F 28/F 29/M 29/F 41/F 47/F 57/M
*
H:
Case No.
Right Right Left Right Right Right Right Left Right Initially
Not I NP
Duration of HPT
160/110 146/100 120/84*
l3mo 2mo 2yrs 8yrs “years” 3mos 23yrs 9yrs
-
220/120 160/110 165/115 170/110 -
from the lower and demonstrates
Elevatedt -
Normal -
renal
vein
to
Cured Cured Cured -
Elevated Elevated Elevated
Cured Cured Cured Cured
-
-
-
-
Response Surgery
renins.
Findings
Excretory Urography
as normal.
available for review. = not performed.
#{149} Radiology
mass arising the tumor
Peripheral Renin
Blood Pressure
Mass Mass* Normalt Mass Normal Normal NP Mass Mass interpreted
a 3.5-cm confirms
Findings
Radiographic
Side of Tumor
1 2 3 4 5 6 7 8 9
322
urogram reveals renal arteriogram
With antihypertensive medication. Mildly elevated peripheral renin; normal
TABLE
*
An excretory Selective left
Computed Tomography Enhances NPt NP NP NP NP Solid NP Solid
Ultrasound
Arteriography
Tumor Size (cm)
Solid Solid Solidt Solid NP NP Solid Solid Solid
Hypovascular Hypovascular Hypovascular Hypovascular Hypovascular Hypovascular Hypovascular Hypovascular Hypovascular
3.0 4.0 3.5 4.5 4.0 2.0 4.0 3.5 6.5
pole of the left its hypovascular
kidney
(arrow). nature.
cases in which it was performed (Fig. 3), including one patient whose urogram was normal. Four of the tumors were hyperechoic, one was isoechoic, and one hypoechoic (case 9). In case 2, the tumor was demarcated from norma! parenchyma by a hyperechoic rim corresponding to a tumor pseudocapsu!e. In case 9, a central hyperechoic focus was surrounded by a less echogenic area corresponding to hemorrhage. Gross examination of the hypoechoic mass demonstrated a solid tumor with occasional scattered small cysts. CT revealed a renal mass in each of the three patients in which it was performed. In all cases the mass was sharply marginated and ranged in size from 3 to 6.5 cm. In case 1 the tumor was isodense with normal renal parenchyma on the unenhanced scan, and was seen only on the enhanced scan (Fig. 4). In case 7 (unenhanced scan only) the periphery of the mass was isodense with normal renal parenchyma (Fig. 3). The central portion of the mass was denser than the norma! kidney and corresponded to hemorMay
1983
Case 9.
Figure 2.
b.
a.
b. c.
rhage within the tumor. In case 9 (enhanced scan only) a 6.5-cm mass was less dense than normal rena! parenchyma (Fig. 2). Arteriography was performed on all nine patients, either to further define the renal mass or to establish renal artery stenosis as the cause of elevated renin levels. All underwent selective renal arteriography, and four patients also underwent aortography. In each case the tumor was identified as a well-defined, hypovascular mass with displacement of adjacent vessels, mmI
A”7
An excretory urogram demonstrates a large mass in the upper pole of the right kidney. Since the mass lies in the medial aspect it has produced a more vertical alignment of the kidney. On CT examination the tumor is seen as a discrete mass that does not enhance as much as the normal kidney. The typical hypovascular appearance is seen on a selective renal arteriogram.
imal neovascularity, and no tumor blush (Figs. 1, 2, and 5). In one patient (case 1) a previous arteriogram used to evaluate the renal arteries, which was obtained without complete selective injections, was normal, while the repeat arteriogram with selective views of an accessory artery revealed the tumor. In case 5, angiography demonstrated a large hypovascular extrarenal mass with renal displacement and separation of the kidney and adrenal gland. The kidney appeared intrinsically normal on the angiogram.
Pathologic examination revealed a small extrarenal juxtaglomerular cell tumor with a large perinephric hematoma.
DISCUSSION About 50% of previously reported cases of juxtaglomerular cell tumor have involved patients 20 years of age or younger. Our series confirms the young age of presentation (mean age, 31 years), but indicates that the tumor often occurs in adults. All but two of R1in1nav
#{149}
Figure
3.
Case
7.
b.
a.
a. b.
Figure
4.
Case
A 4.0-cm solid mass A CT scan obtained (arrow) representing
(m) is identified in the upper without intravenous contrast hemorrhage.
area
of increased
attenuation
b. The CT examination Following intravenous
prior to contrast contrast agent
enhancement injection
our patients were more than 20 years of age. The previously reported preponderance of women with this tumor was also confirmed. The most frequent presenting symptoms include moderate to severe headache (hypertension), polydipsia, polyuria, including enuresis (kaliopenic nephropathy), and intermittent neuromusclar complaints (hypokalemia) (6). In rare cases, patients may present with acute flank pain, hypotension, and anemia secondary to massive hemorrhage from the tumor. Hypertension, frequently moderate to severe, is invariably present and may be accompanied by retinopathy. Hy. pertension is often present for many years, uncontrolled by antihypertensive medication (1-3, 5, 10, 11, 13-15, 18, 19). Although usually sustained, rarely is the hypertension paroxysmal (17). An abdominal or flank bruit is typically absent. 324
kidney by ultrasound. a crescent-shaped
1.
a. a. b.
pole of the right material revealed
#{149} Radiology
was a 3.0-cm
normal. mass is seen
in the
posteromedial
The peripheral renin level is usually elevated, with evidence of secondary aldosteronism that persists even if the hypertension is controlled medically. The plasma renin activity may or may not increase with renin-releasing stimuli (sodium restriction, upright position), indicating some autonomy of renin release by the tumor (4, 6, 7, 14). Although renal function is normal unless complicated by hypertensive nephropathy, mild proteinuria is not uncommon (1, 2, 5, 8, 11, 13, 14, 19) and may result from glomerulosclerosis or from the action of angiotension on the kidney (20, 21). A knowledge of the pathology of the juxtaglomerular cell tumor is helpful in understanding the radiologic findings. The tumor is usually small, solitary, and confined to the kidney. Although the average tumor size in previously reported cases is 2 to 3 cm, occasionally a large mass (6.5 cm) is encountered
aspect
of the
right
kidney.
(case 9). The tumor may be as small as several millimeters in diameter and not detectable on initial gross inspection (11). While most are located just beneath the renal capsule (1,7, 13, 19), the tumor may arise near the renal pelvis (2) or in rare cases within the pennephric space, perhaps from an embryonic rest. On gross inspection, the juxtaglomerular cell tumor is usually tan or gray, sharply marginated, and often demarcated from the surrounding parenchyma by a pseudocapsule. Small foci of hemorrhage within the tumor are common (1-3, 8, 14), but the massive extrapenitoneal hemorrhage seen in case 5 is very unusual. Microscopically, these tumors consist of sheets and/or cords of cells associated with numerous blood vessels (Fig. 6). Most cells are round with granular cytoplasm and vesicular nuclei with inconspicuous nucleoli. May
1983
Figure
5.
Case
6.
Figure
6
Photomicrograph. The tumor consists of sheets and cords of cells associated with numerous blood vessels. Note that the walls of the blood vessels are composed of tumor cells (arrow). (H-E x 160)
Selective right renal arteriogram splaying of vessels (arrows) mass in the lower pole.
demonstrates around a 2.0-cm
Focally, the cells are elongated and reminiscent of smooth muscle. This latter cell type often forms eddies about minute vascular channels. The media of small arteries and arterioles may be composed of numerous cells identical to those of the tumor, thus recapitulating the morphology of hyperplastic juxtaglomerular cells of the juxtaglomerular apparatus (Fig. 6). This is the most characteristic histologic feature. Cytoplasmic granules can be demonstrated with the PAS or Bowie stains. Numerous lymphocytes and variable numbers of mast cells and eosinophils are also present. Some juxtaglomerular tumors are admixed with a tubular or tubulopapillary lesion identical to the common cortical adenoma, producing a biphasic picture for which some observers have postulated a hamartomatous origin (11). Electron microscopy demonstrates that most tumor cells contain polygonal, polyhedra!, or elongated protogranules, which are the ultrastructural markers of juxtaglomerular cells in man (16). Also present are irregularly rounded, membrane-bound mature granules. Although the light microscopic picture is usually characteristic, the ultrastructural identification of typical protogranules establishes the diagnosis with certainty. The tumor may contain 20,000 to 30,000 times as much renin as the adjacent renal cortex (5-8, 13), and tissue cultures of the tumor may have increased renin levels (6). Vnliimp
1d7
Niimh.r
Due to the rarity of these tumors, no definitive statement regarding the biological behavior of a given case can be made. Thus far, the tumors have not demonstrated aggressive or metastatic potential. Although the excretory urogram demonstrated a mass in over half of our cases, 75% of previously reported tumors did not show up on the urogram (3, 5, 10, 12, 14, 16, 18, 19). This high false-negative rate appears directly related to small tumor size and lack of calcification. In our experience, the juxtaglomerular cell tumor is usually echogenic, possibly because of the numerous interfaces between the juxtaglomerular cells and the abundant small vascular channels within the tumor. Although these findings are undoubtedly nonspecific, sonographic examination is useful for confirming that the mass is solid, as well as for further localizing and characterizing the tumor. Hemorrhage and necrosis may be identified as hypoechoic areas within the mass (17). Occasionally, a hypoechoic solid tumor without evidence of necrosis is encountered. The CT findings of juxtaglomerular cell tumors are nonspecific. Unlike most other primary renal neoplasms, however, the juxtaglomerular cell tumor may be small and isodense with normal renal parenchyma and, therefore, may not be detected on unenhanced scans (case 1). Thus, enhanced scans should be obtained in all cases. CT may also be helpful in identifying the extent of the tumor as well as detecting intratumor hemorrhage (case 7) or necrosis. Despite the presence of abundant microscopic vascular spaces within the tumor, arteniography even with selective injections demonstrates a hypo-
vascular mass (4-9, 12, 15-18). As the aortogram is often normal, selective injections should be made if no cause for the high renin hypertension is discovered on the aortic injection. Selective renal angiograms are rarely normal (19). In these and other equivocal cases, measuring renal vein renin levels (including segmental sampling) may be helpful in localizing the tumor (13, 19). Arteriography is also useful to (a) eliminate renal artery stenosis as the cause of the excess renin production, (b) determine the degree of vasculanity of the tumor, and (c) outline the vascular anatomy, which is especially important if heminephrectomy or local excision is to be performed. Excision of the tumor is curative. Relief of the hypertension may be dramatic, with a return to normal pressure very soon after surgery (1, 4, 5, 8, 13, 17). Less commonly, this reversal requires several days (6, 7, 9, 11, 1 6). Postoperatively, plasma renin, potassium, and aldosterone levels also gradually return to normal. Although most previously reported patients have undergone nephrectomy (1-9, 11, 13, 14, 17, 19), local excision appears equally effective (12, 15, 16, 18). We are unaware of any juxtaglomerular cell tumor that has been locally invasive, recurred, or metastasized. Differential diagnostic considerations for a patient with hypertension, hypenreninism, and secondary hyperaldosteronism also include renal artery stenosis, incipient malignant hypertension, renin-secreting tumors, and other masses that compress the renal artery or renal parenchyma. Renal artery stenosis can be excluded by a normal renal angiogram. Malignant hypertension can be ruled out if hyperaldosteronism persists after adequate hypotensive medical treatment. Rarely Radiology
325
#{149}
is renin secreted in renal cell carcinoma or Wilms tumor (23-26). As most renal cell carcinomas are quite vascular, differentiation should be possible in most cases. The average Wilms tumor is relatively large (12 cm), with a peak mcidence in the second year of life. Similarly, most other renal masses that compress the renal artery or renal parenchyma with subsequent release of renin from the kidney can probably be distinguished from the juxtaglomerulan cell tumor by their large size and/or characteristic radiographic features. Very rarely do tumors of the lung, liver, or orbit (22, 27, 28) produce renin. Patients with appropriate clinical and radiographic findings with a normal radiographic evaluation of the kidneys should have a thorough evaluation of these sites as well. In conclusion, the juxtaglomerular cell tumor represents a rare, curable cause of hypertension. Because of the typical clinical and radiographic findings, correct preoperative diagnosis is possible in most cases.
References
2.
3.
,
6.
7.
8.
9.
10.
Acknowledgments: radiologists
and
We thank pathologists
who
the many sent
us
material that became the basis for this study. We also thank the secretarial staff of the Department of Radiologic Pathology, Mrs. Rose Boyd of the Department of Radiology, Duke University Medical Center, and the Medical Illustration Division of the Armed Forces Institute of Pathology.
i i
12.
13.
14. David S. Hartman, M.D. Department of Radiologic Pathology Armed Forces Institute of Pathology Washington, D.C. 20012
326.
Radiology
15.
.
Robertson PW Klidjian A Harding LK et al. Hypertension due to a renin-secreting tumour. Amer J Med 1967; 43:963-976. Kihara L Kitamura S. Hoshino T, et al. A hitherto unreported vascular tumor of the kidney: a proposal of “ju.xtaglomerular cell tumor.” Acta Path Jap 1968; 18:197-206. Eddy RL, Sanchez SA. Renin-secreting renal neoplasm and hypertension with hypokalemia. Ann Intern Med 1971; 75:725729. Lee MR. Renin-secreting kidney tumors. A rare but remediable cause of serious hypertension. Lancet 1971; 2:254-255. Bonnin JM, Hodge RL, Lumbers ER. A renin-secreting tumour associated with hypertension. Aust NZ J Med 1972; 2: 178-181. Conn JW, Cohen EL, Lucas CP, et al. Primary reninism. Hypertension, hyperreninemia, and secondary aldosteronism due to renin-producing juxtaglomerular cell tumors. Arch Intern Med 1972; 130:682-696. Brown JJ, Lever AF, Robertson JIS, et al. Hypertension and secondary hyperaldosteronism associated with a renin-secreting renal ju.xtaglomerular-cell tumor. Lancet 1973; 2:1228-1232. Schambelan M, Howes EL, StockigtJR, et al. Role of renin and aldosterone in hypertendue to a renin-secreting tumor. Am J Med 1973; 55:86-92. Davidson JK, Clark DC. Renin-secreting juxtaglomerular-cell tumour. Br J Radiol 1974; 47:594-597. Gherardi GJ, Arya 5, Hickler RB. Juxtaglomerular body tumor: a rare occult but curable cause of lethal hypertension. Hum Pathol 1974; 5:236-240. Hirose M, Arakawa K, Kikuchi M, et al. Primary reninism with renal hamartomatous alteration. JAMA 1974; 230:12881292. Connor C, Bennett CM, Lindstrom R, et al. hypertension and JG cell tumor. Kidney mt 1975; 8:437. Oqavik OS, Fauchald MP, Hovig T, et al. Renin-secreting renal tumour with severe hypertension. Acta Med Scand 1975; 197: 329-335. Takahashi T, Miura T, Sue A, et al. A case of juxtaglomerular cell tumor diagnosed preoperatively. Nephron 1976; 17:483495. Baldet P. Mimran A. Renin-secreting benign “juxtaglomerular cell” tumor of the
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kidney, microscopic and electron microscopic study. (translation) Ann Anat Pathol (Paris) 1977; 22:21-40. Barajas L, Bennett CM, Connor C, Lindstrom RR. Structure of a juxtaglomerular cell tumor: the presence of a neural component: a light and electron microscopic study. Lab Invest 1977; 37:357-368. Hanna W, Tepperman B, Logan AG, et al. Juxtaglomerular cell tumour (reninoma) with paroxysmal hypertension. Can Med Assoc J 1979; 120:957-959. El Matni A, Ben AH, Slim R, et al. Another case of hypertension due to a tumour of the juxtaglomerular apparatus. (translation) Urol Nephrol (Paris) 1980; 86:33-36. Warshaw BL, Anand SK, Olson DL, et al. Hypertension secondary to a renin-producing juxtaglomerular cell tumor. J Pediatr 1979; 94:247-250. Bohrer Ml’, Deen WM, Robertson CR, Brenner BM. Mechanism of angiotension Il-induced proteinuria in the rat. Am Physiol 1977; 233:13-21. Bauman JW, Jr. On the mechanism of angiotensin-induced proteinuria. I. Studies in aminonucleoside nephrotic rats and in saralasin blockade. Nephron 1981; 27:47-50. Ohmori H, Motoi M, Sato H, et a!. Extrarenal renin-secreting tumor associated with hypertension. Acta Pathol Jap 1977; 27:567-586. Marosvari I, Kontor E, Kallay K. Reninsecreting Wilms’ tumour. Lancet 1972; 1: 1180. Ganguly A, GnibbleJ, Tune B, Kempson RL, Luetscher JA. Renin-secreting Wilms’ tumor with severe hypertension. Report of a case and brief review of renin-secreting tumors. Ann Intern Med 1973; 79:835-837. Hollifield JW, Page DL, Smith C, et al. Renin-secreting clear cell carcinoma of the kidney. Arch Intern Med 1975; 135:859864. Jacobi GH, BeyerJ, Philipp T, Marbeger M. The etiology of hypertension in patients with renal cell carcinoma. (Meeting abstract) Presented at the 75th Annual Meeting of the American Urological Association, San Francisco, May 18-22, 1980. Hauger-Klevene JH. High plasma renin activity in an oat cell carcinoma: a reninsecreting carcinoma? Cancer 1970; 26: 1112-1114. Cox JN, Paunier L, Vallotton MB. Epithelial liver hamartoma, systemic arterial hypertension and renin hypersecretion. Vitchows Arch [Path Anat] 1975; 366:15-26.
May
1983
