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Accelerated Hypertension in a 54-year-old Woman
0022-534 7/81/1256-0859$02.00/0 Vol. 125, June Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1981 by The Williams & Wilkins Co.
Clinicopathologi cal Conference ACCELERATED HYPERTENSION IN A 54-YEAR-OLD WOMAN JAMES KOZLOWSKI,* ANTHONY SCHAEFFER,t FRANCESCO DELGRECO,t EARL WENDEL,§ HARVEY NEIMAN,11 CHARLES NADLER,1 RYOICHI OYASU,** DENISE HIDVEGitt ANP TADASHI INAGAMitt From the Departments of Urology, Medicine, Radiology and Pathology, Northwestern University Medical School, Chicago, Illinois
PRESENTATION OF CASE§§
Dr. James Kozlowski. A 54-year-old black woman, gravida 0, para 0, was hospitalized on December 26, 1979. She had been under treatment since 1974 for congestive heart failure and hypertension. Blood pressure before the patient was treated was 210/110 mm. Hg. Two weeks before this hospitalization the woman suffered an acute onset of dyspnea, orthopnea and a "feverish feeling". Medical history included a hysterectomy for fibroid disease of the uterus in 1960 and a hemorrhoidectomy in 1970. Before hospitalization the patient's condition was well controlled on 50 mg. hydrochlorothiazide daily and 250 mg. methyldopa 4 times a day, with an associated blood pressure of 150/90 mm. Hg. In addition, the woman received 0.125 mg. digoxin daily. The patient had a 40-pack per year smoking history and admitted to a 14-pound weight loss in the antecedent 2 months. Physical examination revealed a thin, chronically ill black woman. Her temperature was lOOF and the blood pressure was 200/122 mm. Hg in both arms without orthostatic change. Other pertinent findings included 1) blurring of the optic disk margins, 2) prominent neck vein distension, 3) bibasilar rales, 4) a left precordial heave and thrill associated with an S4 and S3 gallop rhythm and a grade 4/6 holosystolic murmur along the left sternal border and axilla, 5) hepatomegaly with a liver edge palpable 8 cm. below the costal margin, 6) a left flank bruit and 7) pedal edema. Pertinent laboratory findings included 1) a hematocrit of 33 per cent and white blood count of 11,300 per mm. with 71 per cent neutrophils, 1 per cent band forms, 12 per cent lymphocytes, 14 per cent monocytes and 2 per cent eosinophils; 2) urinalysis revealed 100 white blood cells per high power field and urine culture showed no growth; 3) serum potassium was 2.9 mEq./1. and carbon dioxide was 32 mEq./1., along with a Supported in part by Grant RR48 from the Division of Research Resources, National Institutes of Health. * Chief Resident, Veteriyis Administration Lakeside Hospital and Instructor in Urology, Northwestern University Medical School. t Assistant Professor of Urology, Northwestern University Medical School. t Chief of Service, Nephrology/Hypertension and Professor of Medicine, Northwestern University Medical School. § Assistant Professor of Urology, Northwestern University Medical School. II Associate Professor of Radiology, Northwestern University Medical School. 1 Associate Professor of Medicine, Northwestern University Medical School. * * Professor of Pathology, Northwestern University Medical School. tt Assistant Professor of Pathology, Northwestern University Medical School. tt Professor of Biochemistry, Vanderbilt University Medical School. §§Presented at Surgical Grand Rounds, Northwestern University Medical School, May 19, 1980. 859
blood urea nitrogen of 16 mg./dl. and a serum creatinine of 1.0 mg./dl.; 4) blood gases demonstrated pH 7.55, carbon dioxide pressure 38 and oxygen pressure 44 on room air. A chest x-ray was consistent with congestive heart failure. An electrocardiogram revealed left ventricular hypertrophy with strain. Urinary vanillyl mandelic acid, catecholamine and metanephrine were within normal limits. Dr. Charles Nadler. Our initial medical assessment was that of severe hypertension, with associated biventricular failure and mitral insufficiency in a patient with formerly easily controlled blood pressure. Antihypertensive therapy was increased in what finally proved to be a futile effort to control the blood pressure. On December 27 the blood pressure was 200/110 mm. Hg. Methyldopa was increased to 500 mg. 4 times a day, furosemide ~as added and the digoxin was increased along with the potassium supplement. The blood pressure remained elevated and hydralazine and prazosin were added. The left flank bruit strongly suggested that secondary hypertension, perhaps of renovascular origin, might be responsible for the clinical deterioration. Consequently, an excretory urogram (IVP) and renogram were requested. Dr. Harvey Neiman. The IVP demonstrated an absent or non-functioning left kidney. The right kidney was enlarged, presumably on the basis of compensatory hypertrophy. In addition, there was a bifid collecting system that also demonstrated some subtle distortion and compression (fig. 1). However, the IVP was otherwise interpreted as normal. A renogram on January 14 revealed virtually absent function on the left side and slightly decreased function on the right. Dr. Anthony Schaeffer. Our impression at that time was that the hypertension possibly was caused by excessive renin production by the small left kidney. On January 22 the blood pressure was 208/120. A modest lowering of the blood pressure was noted after the administration of propranolol. However an increase in the symptoms of congestive heart failure and dontinued severe hypertension required addition of clonidine to the existing regimen. Our initial plan was to perform a left nephrectomy because of the refractory, severe hypertension, which persisted despite aggressive medical therapy. Renal vein renin determinations were done and, much to our surprise, the renin ratio between t~e right side and the left was 12:1, indicating that the right kidney was the source of the exaggerated renin production. On February 1 the blood pressure was 200/104 and spironolactone was added to the pre-existing regimen, which now included clonidine, propranolol, prazosin, hydralazine, methyldopa and furosemide. On February 2 aortography and selective renal angiography were performed. On February 4 the patient had a lOlF fever associated with right upper quadrant pain and right subcapular discomfort. The Murphy's sign was positive but the bilirubin test was normal.
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cells with granular or finely vacuolated eosinophilic cytoplasm. The nuclei were round and the membrane had regular outlines. The chromatin was fine and uniformly distributed. Nuclear pleomorphism was observed occasionally. The nuclei contained small nucleoli. Cytological features observed in the sample were consistent with a benign process arising in the tubular epithelium. CLINICAL DIAGNOSIS AND MANAGEMENT
Dr. Francesco DelGreco. The striking features in this patient when hospitalized included accelerated hypertension and severe congestive heart failure. This syndrome had intervened within a short period, since the woman had been known to be mildly hypertensive and in compensated heart failure until recently.
FIG. 1. IVP demonstrates absence or non-function of left kidney. Right kidney is somewhat enlarged but appears otherwise normal.
With a presumed diagnosis of acute cholecystitis ultrasonography of the gallbladder and kidneys was obtained. DISCUSSION OF RADIOLOGY
Doctor Neiman. Because of advanced atherosclerotic disease of the abdominal aorta and iliac vessels an axillary approach was required. The aortogram demonstrated a single right main renal artery without evidence of stenosis and absence of a left main renal artery. Selective injection of contrast material into the right main renal artery demonstrated minimal, fine vascularity in the area of the renal pelvis but a discrete mass lesion was not identified. The fine vascularity probably was owing to the normal pelvic and capsular branches (fig. 2). The ultrasound examination, using a 5.0 MHz. medium focused transducer, demonstrated with transverse and longitudinal sections an ovoid, sharply marginated echogenic mass that appeared to be related to the right kidney. The mass markedly distorted the renal parenchyma and compressed the adjacent liver. A scan of the gallbladder revealed the presence of multiple stones (fig. 3). To establish more firmly the nature of this mass and to define better its site of origin a computerized tomography (CT) scan was performed on February 6. The scan corroborated the relationship of this low attenuation mass to the right kidney (fig. 4). Doctor Schaeffer. The patient's condition remained guarded. Although the episode of biliary colic responded to conservative management the blood pressure remained refractory to multidrug therapy and minoxidil was added. Since the mass in question involved a solitary, functional kidney an ultrasoundguided needle biopsy of the lesion was performed on February
FIG. 2. Selective injection of right main renal artery reveals some fine vascularity in area of renal pelvis. Discrete mass lesion is not seen.
7.
Dr. Denise Hidvegi. Material obtained from the tumor by percutaneous fine needle aspiration revealed small clusters of
FIG. 3. Renal ultrasound demonstrates large echogenic mass related to right kidney.
ACCELERATED HYPERTENSION IN 54-YEAR-OLD WOMAN
861
hypovascular or avascular on angiography. Papillary adenocarcinomas account for the majority of these tumors. However, metastatic carcinoma of the kidney, infiltrating carcinoma of the renal pelvis and necrotic hypemephromas are other neoplastic processes that may present with an avascular or hypovascular angiographic pattern. 2- 5 The cytology obtained from the percutaneous aspiration was non-diagnostic but was more consistent with a renal cell carcinoma than a metastatic or transitional cell carcinoma, which might be amenable to non-surgical management. DISCUSSION OF SURGERY
FIG. 4. CT scan demonstrates relationship of mass to right kidney
Institution of vigorous drug therapy was of no obvious benefit. In this setting it is mandatory to search for mechanisms that might be responsible for the worsening of hypertensive cardiovascular disease. In our patient there was no evidence of renal insufficiency and the urinary excretion of vanillyl mandelic acid, catecholamine and metanephrine was normal. Other endocrine mechanisms also could be excluded. Since the clinical examination revealed a flank bruit on the left side acute renovascular disease appeared a distinct possibility. In our experience as well as in that of others renovascular disease and renal disease previously unrecognized are not unusual in accelerated hypertension. Timed IVP revealed a large right kidney and a shrunken left kidney. Since renin secretion by this kidney might explain the severe hypertension the renal vein renin activity was measured. The results of this study were markedly abnormal, although unexpected, in that renin activity was suppressed in the left renal blood but greatly increased in the opposite main renal vein. These results verified in duplicate samples from each side pointed to the right kidney as the source of renin secretion. However, renal arteriography performed subsequently did not reveal obvious disease of the right renal artery, while it failed to visualize the left renal artery. Elevated renal renin levels in the absence of demonstrable renal arterial lesions may be interpreted as falsely positive for a variety of factors. In our patient no technical errors had been made in collecting the blood samples. The radioimmunoassay was done carefully and the results were highly reproducible, with an intra-assay variation of <1.0 per cent. Other factors for potential error also were eliminated, although some question remained concerning the effect of antihypertensive drugs on renin release. It should be noted that although atherosclerotic and fibromuscular lesions of the renal arteries are associated most commonly with renin hypersecretion other lesions may be responsible. These lesions can be intrinsic or extrinsic. In our patient there was no obvious evidence of an intrinsic lesion of the right renal artery and its branches. However, the high renin activity levels in the right renal vein did suggest to us the possibility of primary reninism caused by a renin-secreting tumor, which could not be visualized, or of an extrinsic lesion involving the hilar vasculature. 1 CLINICAL DIAGNOSIS AND MANAGEMENT
Doctor Schaeffer. Even in retrospect we were impressed by the lack of caliceal and arteriolar displacement, as well as the hypovascularity of the large renal mass demonstrated so dramatically by ultrasonography and CT scan. The echogenicity of the mass clearly suggested tumor rather than cyst. About 10 to 25 per cent of the renal cell carcinomas are
Dr. Earl Wendel. On February 22, 1980 abdominal exploration was done through a midline incision. After the right colon was mobilized and a Kocher maneuver was used to mobilize the duodenum a firm apparently encapsulated mass was noted in the right renal hilus. The mass was impacted with the anterior renal hilus, compressing the vessels. It also was attached to the renal capsule anteriorly at the hilus. The mass was mobilized with sharp and blunt dissection, detached from the capsular attachment, and then enucleated from the renal hilus. Bleeding from hilar vessels was controlled by suture ligatures after the renal artery was surrounded with a sling and compressed, and the kidney was covered with iced saline slush. Avitene and tamponade controlled the oozing from the raw renal parenchymal surface. Nephrectomy of the atrophic left kidney was then accomplished. The gallbladder had numerous adhesions and multiple stones, and a cholecystectomy was performed. At this point the urine was noted to be slightly blood tinged but it was elected not to explore the right renal hilus. The patient tolerated these procedures well and sustained no intraoperative complications. It should be emphasized that our general plan of surgical treatment in this medically unstable patient was to remove the right renal tumor as the first priority. This was to be accomplished in as simple a fashion as possible with the preservation of as much renal tissue as feasible. 6 After the patient tolerated this procedure the non-functioning left kidney would be removed. Finally, because of the high risk of postoperative acute cholecystitis, a cholecystectomy was performed. POSTOPERATIVE COURSE
Doctor Kozlowski. The patient required assisted ventilation and a Swan-Ganz catheter for several days. The blood pressure was 100/90 mm. Hg in the immediate postoperative period. No 1 antihypertensive medication was required during this interval. Convalescence was uneventful except for a transient urine leak from the right collecting system. The patient was discharged from the hospital on March 20, with a blood pressure of 140/90 mm. Hg on 50 mg. hydrochlorothiazide daily and 250 mg. methyldopa 3 times a day. Doctor Nadler. During the year postoperatively the blood pressure averaged 150/90 mm. Hg on the same medications and 0.125 mg. digoxin daily. There has been no evidence ofrecurrent carcinoma. DISCUSSION OF PATHOLOGY
Dr. Ryoichi Oyasu. The specimen received consisted of a tumor, a gallbladder containing calculi and the left kidney. The mass removed from the hilus of the right kidney weighed 215 gm. and measured 11 X 9 X 7 cm. The outer space was smooth and gray-white with an area of recent hemorrhage (fig. 5, A). Cut surfaces were yellow but a prominent, cystic necrotic area also was noted (fig. 5, B). Punctate foci of recent hemorrhage were noted subcapsularly. Multiple sections taken from various regions of the tumor demonstrated a uniform histological pattern, consisting of micropapillae projecting into the small lumina of the tubules (fig. 6). The lining cells were cuboidal and uniform in size, and contained clear cytoplasm and round to
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CLINICOPATHOLOGICAL CONFERENCE
FIG. 5. A, large mass removed from hilus of right kidney shows smooth surface with area of fresh hemorrhage. B, cut surface of mass shows prominent area of cystic, necrotic degeneration.
oval nuclei. The cells constituting the papillae were larger than the cells lining the tubules and had an eosinophilic granular cytoplasm. No periodic-acid, Schiff-positive granules digestible with diastase could be demonstrated in the tumor cells. Psammoma bodies were found occasionally within the well developed papillae (fig. 6). Mitotic figures were rare and vascular channels were not particularly prominent. Ultrastructurally, the tumor cells were replete with lipid vacuoles and exhibited well developed microvilli. The mitochondria varied in number and size. Those in the clear cells were fewer in number than those cells constituting the papillae, which exhibited numerous mitochondria and fewer fat vacuoles. The left kidney was small, weighing 82 gm. The capsule was adherent to the cortex. The cortical surface generally was smooth and revealed a focus of recent hemorrhagic necrosis. The lumen of the major renal artery was narrowed markedly at one point by a large calcific atheromatous plaque. Microscopic examination of the left kidney revealed generalized atrophy of the tubules, marked arteriosclerosis of the major vessels and interstitial fibrosis. Many glomeruli revealed total or subtotal sclerosis. Mild arteriolar sclerosis was present throughout the kidney. Multiple cholesterol emboli occluded many of the interlobular and arcuate arteries. An attempt was made to visualize renin within the tumor by the immunoperoxidase technique. None could be demonstrated using the peroxidase-antiperoxidase immune complex method and the rabbit antirenin antibody kindly provided by Dr. Tadashi Inagami of Vanderbilt University. On the other hand, a positive reaction clearly was demonstrated in the juxtaglomerular apparatus of the left kidney. A portion of frozen tumor tissue was sent to Doctor Inagami's laboratory for the assay of renin activity but no measurable activity could be detected. ANATOMICAL DIAGNOSIS
We concluded that the tumor was a juxtarenal cell carcinoma. It arose in the subcapsular region and grew as an extrarenal mass, being connected to the kidney by a fibrous band. Furthermore, the tumor was a pure papillary carcinoma, consisting of clear and granular cells. Finally, compression of the right hilar vessels by this juxtarenal tumor was responsible for the fulminant, refractory hypertension noted clinically. COMMENT
Doctor Kozlowski. This case certainly represented a diagnostic dilemma and was associated with 2 features that deserve special emphasis. First, the papillary variant of renal cell carcinoma is an intriguing entity. It has been reported to comprise up to 14 per cent of renal malignancies. The lesion may attain substantial size and may have the following associated features: 1) a thick capsule, 2) 32 per cent show calcification that is characteristically peripheral, 3) significant tumor necrosis is
FIG. 6. Numerous micropapillary projections and few scattered psammoma bodies. H & E stain.
seen in more than two-thirds of the reported cases, 4) cystic degeneration and 5) a predictable hypovascularity that seems to correlate with the amount of tissue necrosis present. The histopathology already has been discussed but a few points deserve re-emphasis. Psammoma bodies are demonstrated in about 20 per cent of the cases of papillary renal cell carcinoma. According to Robbins, on occasion, single necrotic cells may constitute seed crystals that become incrusted by the deposition of calcium salts. The progressive aquisition of outer layers may create a lamellar configuration called a psammoma body because of its resemblance to a grain of sand. Other papillary cancers, most notably thyroid, share this predilection. 10 More importantly, histiocytic infiltration of the papillary cores (foam cells) has been cited as a particularly favorable prognostic sign. Indeed, the substantial amounts of necrosis and cystic degeneration often seen are thought to represent the result of a mobilized immune defense system. Furthermore, there is some inferential evidence to suggest that some of these lesions may have a distal tubular origin. In fact, hyperplastic changes have been noted occasionally in the collecting tubules of adjacent normal papillae and may represent a pre-neoplastic phenomenon. Clinically, this tumor variant is associated with more favorable survival statistics than its non-papillary counterpart. An 89 per cent 5-year survival rate has been quoted for stage 1 tumors. 7- 11 The second feature of this case that warrants special comment is the severe hypertension. Between 20 and 40 per cent of patients with adenocarcinoma of the kidney will manifest some degree of systolic/ diastolic hypertension. Several different etiologies have been proposed or reported. 1) Hypertension may be associated with a Goldblatt effect as a consequence of hilar
863 ,.,.ascula:r the etiology of the seve:re mc,.,,·c,an,,, noted in this case. The total occlusion of the left renal artery at its takeoff from the aorta and the low left renal vein renin would seem to negate the left kidney as a significant contributor to the severe, sustained hypertension. In retrospect, the markedly elevated right renal vein renin reflected the effect of hilar compression the large spherical mass. 2) Elevated renin production may be a consequence of compressive ischemia of normal renal tissue adjacent to the mass. This mechanism also may have been operative in the case under discussion. 3) Massive arteriovenous shunting could result in a marked increase of the intravascular compartment, high output cardiac failure and systolic hypertension. 4) Erythropoietin production by renal tumors is said to occur in about 4 per cent of the cases. A significant secondary polycythemia may be associated with an increase in preload and consequent systolic hypertension. 5) Decreased degradation of angiotensin II and aldosterone might be implicated in the presence of massive hepatic metastases. 6) Renin-secreting renal tumors have been reported. There are 2 well documented cases ofrenin-secreting adenocarcinoma in the literature. Interestingly, both of these lesions were highly differentiated clear cell tumors. Similarly, 2 cases of renin-producing Wilms tumor have been reported to date. Of course, the juxtaglomerular cell tumor and its more malignant counterpart, the hemangiopericytoma, have been similarly implicated. 12 - 19
5. 6. 7. 8.
9.
10. 11. 12.
13. 14. 15.
REFERENCES
16.
1. Kaplan, N. M.: Clinical Hypertension, 2nd ed. Baltimore: The
Williams & Wilkins Co., p. 225, 1978. 2. Blath, R. A., Mancilla-Jimenez, R. and Stanley, R. J.: Clinical comparison between vascular and avascular renal cell carcinoma. J. Urol., 115: 514, 1976. 3. Lang, E. K.: Diagnosis of renal parenchymal tumors. In: Genitourinary Cancer. Edited by D. G. Skinner and J. B. deKemion. Philadelphia: W. B. Saunders Co., chapt. 3, pp. 40-83, 1978. 4. McLaughlin, A. P., III, Talner, L. B., Leopold, G. R. and McCullough, D. L.: Avascular primary renal cell carcinoma:
17. 18.
19.
vafrcd pathologic and angiogrn.phic features. J. UroL, Hl: 587, 1974. Watson, R. C., Fleming, R. J. and Evans, J. A.: Arteriography in the diagnosis of renal carcinoma. Review of 100 cases. Radiology, 9.1.: 888, 1968. Graham, S. D., Jr. and Glenn, J. F.: Enucleative surgery for renal malignancy. J. Urol., 122: 546, 1979. Boczko, S., Fromowitz, F. B. and Bard, R. H.: Papillary adenocarcinoma of kidney. A new perspective. Urology, 14: 491, 1979. Glenn, J. F.: Renal tumors. In: Campbell's Urology, 4th ed. Edited by J. H. Hanison, R. F. Gittes, A. D. Perlmutter, T. A. Stamey and P. C. Walsh. Philadelphia: W. B. Saunders Co., vol. 2, chapt. 27,pp. 967-983, 1979. Mancilla-Jimenez, R., Stanley, R. J. and Blath, R. A.: Papillary renal cell carcinoma. A clinical, radiologic and pathologic study of 34 cases. Cancer, 38: 2469, 1976. Robbins, S. L. and Cotran, R. S.: Pathologic Basis of Disease, 2nd ed. Philadelphia: W. B. Saunders Co., pp. 49-50, 1979. Willis, J. S., Santos, R. M. and Ashley, P. F.: Renal papillary adenocarcinoma. Clin. Rad., 30: 53, 1979. Ganguly, A., Gribble, J., Tune, B., Kempson, R. L. and Luetscher, J. A.: Renin-secreting Wilms' tumor with severe hypertension. Report of a case and brief review of renin-secreting tumors. Ann. Intern. Med., 79: 835, 1973. Gordon, D.: The extrarenal manifestations of hypemephroma. Canad. Med. Ass. J., 88: 61, 1963. Hollifield, J. W., Page, D. L., Smith, C., Michelakis, A. M., Staab, E. and Rhamy, R.: Renin-secreting clear cell carcinoma of the kidney. Arch. Intern. Med., 135: 859, 1975. Lee, M. R.: Renin-secreting kidney tumours. A rare but remediable cause of serious hypertension. Lancet, 2: 254, 1971. lVlerrin, C.: Renal neoplasms. In: Principles and Management of Urologic Cancer. Edited by N. Javadpour. Baltimore: The Williams & Wilkins Co., chapt. 13, pp. 377-403, 1979. Nielsen, H. 0.: Arterial hypertension due to a renin-producing renal carcinoma. Scand. J. Urol. Nephrol., 9: 293, 1975. Skinner, D. G. and deKernion, J. B.: Clinical manifestations and treatment of renal parenchymal tumors. In: Genitourinary Cancer. Edited by D. G. Skinner and J.B. deKernion. Philadelphia: W. B. Saunders Co., chapt. 5, pp. 107-133, 1978. Tveter, K. J.: Unusual manifestations of renal carcinoma. A review of the literature. Acta Chir. Scand., 139: 401, 1973.
THE JOURNAL OF UROLOGY
Copyright© 1981 by The Williams & Wilkins Co.
Clinicopathologi cal Conference ACCELERATED HYPERTENSION IN A 54-YEAR-OLD WOMAN JAMES KOZLOWSKI,* ANTHONY SCHAEFFER,t FRANCESCO DELGRECO,t EARL WENDEL,§ HARVEY NEIMAN,11 CHARLES NADLER,1 RYOICHI OYASU,** DENISE HIDVEGitt ANP TADASHI INAGAMitt From the Departments of Urology, Medicine, Radiology and Pathology, Northwestern University Medical School, Chicago, Illinois
PRESENTATION OF CASE§§
Dr. James Kozlowski. A 54-year-old black woman, gravida 0, para 0, was hospitalized on December 26, 1979. She had been under treatment since 1974 for congestive heart failure and hypertension. Blood pressure before the patient was treated was 210/110 mm. Hg. Two weeks before this hospitalization the woman suffered an acute onset of dyspnea, orthopnea and a "feverish feeling". Medical history included a hysterectomy for fibroid disease of the uterus in 1960 and a hemorrhoidectomy in 1970. Before hospitalization the patient's condition was well controlled on 50 mg. hydrochlorothiazide daily and 250 mg. methyldopa 4 times a day, with an associated blood pressure of 150/90 mm. Hg. In addition, the woman received 0.125 mg. digoxin daily. The patient had a 40-pack per year smoking history and admitted to a 14-pound weight loss in the antecedent 2 months. Physical examination revealed a thin, chronically ill black woman. Her temperature was lOOF and the blood pressure was 200/122 mm. Hg in both arms without orthostatic change. Other pertinent findings included 1) blurring of the optic disk margins, 2) prominent neck vein distension, 3) bibasilar rales, 4) a left precordial heave and thrill associated with an S4 and S3 gallop rhythm and a grade 4/6 holosystolic murmur along the left sternal border and axilla, 5) hepatomegaly with a liver edge palpable 8 cm. below the costal margin, 6) a left flank bruit and 7) pedal edema. Pertinent laboratory findings included 1) a hematocrit of 33 per cent and white blood count of 11,300 per mm. with 71 per cent neutrophils, 1 per cent band forms, 12 per cent lymphocytes, 14 per cent monocytes and 2 per cent eosinophils; 2) urinalysis revealed 100 white blood cells per high power field and urine culture showed no growth; 3) serum potassium was 2.9 mEq./1. and carbon dioxide was 32 mEq./1., along with a Supported in part by Grant RR48 from the Division of Research Resources, National Institutes of Health. * Chief Resident, Veteriyis Administration Lakeside Hospital and Instructor in Urology, Northwestern University Medical School. t Assistant Professor of Urology, Northwestern University Medical School. t Chief of Service, Nephrology/Hypertension and Professor of Medicine, Northwestern University Medical School. § Assistant Professor of Urology, Northwestern University Medical School. II Associate Professor of Radiology, Northwestern University Medical School. 1 Associate Professor of Medicine, Northwestern University Medical School. * * Professor of Pathology, Northwestern University Medical School. tt Assistant Professor of Pathology, Northwestern University Medical School. tt Professor of Biochemistry, Vanderbilt University Medical School. §§Presented at Surgical Grand Rounds, Northwestern University Medical School, May 19, 1980. 859
blood urea nitrogen of 16 mg./dl. and a serum creatinine of 1.0 mg./dl.; 4) blood gases demonstrated pH 7.55, carbon dioxide pressure 38 and oxygen pressure 44 on room air. A chest x-ray was consistent with congestive heart failure. An electrocardiogram revealed left ventricular hypertrophy with strain. Urinary vanillyl mandelic acid, catecholamine and metanephrine were within normal limits. Dr. Charles Nadler. Our initial medical assessment was that of severe hypertension, with associated biventricular failure and mitral insufficiency in a patient with formerly easily controlled blood pressure. Antihypertensive therapy was increased in what finally proved to be a futile effort to control the blood pressure. On December 27 the blood pressure was 200/110 mm. Hg. Methyldopa was increased to 500 mg. 4 times a day, furosemide ~as added and the digoxin was increased along with the potassium supplement. The blood pressure remained elevated and hydralazine and prazosin were added. The left flank bruit strongly suggested that secondary hypertension, perhaps of renovascular origin, might be responsible for the clinical deterioration. Consequently, an excretory urogram (IVP) and renogram were requested. Dr. Harvey Neiman. The IVP demonstrated an absent or non-functioning left kidney. The right kidney was enlarged, presumably on the basis of compensatory hypertrophy. In addition, there was a bifid collecting system that also demonstrated some subtle distortion and compression (fig. 1). However, the IVP was otherwise interpreted as normal. A renogram on January 14 revealed virtually absent function on the left side and slightly decreased function on the right. Dr. Anthony Schaeffer. Our impression at that time was that the hypertension possibly was caused by excessive renin production by the small left kidney. On January 22 the blood pressure was 208/120. A modest lowering of the blood pressure was noted after the administration of propranolol. However an increase in the symptoms of congestive heart failure and dontinued severe hypertension required addition of clonidine to the existing regimen. Our initial plan was to perform a left nephrectomy because of the refractory, severe hypertension, which persisted despite aggressive medical therapy. Renal vein renin determinations were done and, much to our surprise, the renin ratio between t~e right side and the left was 12:1, indicating that the right kidney was the source of the exaggerated renin production. On February 1 the blood pressure was 200/104 and spironolactone was added to the pre-existing regimen, which now included clonidine, propranolol, prazosin, hydralazine, methyldopa and furosemide. On February 2 aortography and selective renal angiography were performed. On February 4 the patient had a lOlF fever associated with right upper quadrant pain and right subcapular discomfort. The Murphy's sign was positive but the bilirubin test was normal.
860
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cells with granular or finely vacuolated eosinophilic cytoplasm. The nuclei were round and the membrane had regular outlines. The chromatin was fine and uniformly distributed. Nuclear pleomorphism was observed occasionally. The nuclei contained small nucleoli. Cytological features observed in the sample were consistent with a benign process arising in the tubular epithelium. CLINICAL DIAGNOSIS AND MANAGEMENT
Dr. Francesco DelGreco. The striking features in this patient when hospitalized included accelerated hypertension and severe congestive heart failure. This syndrome had intervened within a short period, since the woman had been known to be mildly hypertensive and in compensated heart failure until recently.
FIG. 1. IVP demonstrates absence or non-function of left kidney. Right kidney is somewhat enlarged but appears otherwise normal.
With a presumed diagnosis of acute cholecystitis ultrasonography of the gallbladder and kidneys was obtained. DISCUSSION OF RADIOLOGY
Doctor Neiman. Because of advanced atherosclerotic disease of the abdominal aorta and iliac vessels an axillary approach was required. The aortogram demonstrated a single right main renal artery without evidence of stenosis and absence of a left main renal artery. Selective injection of contrast material into the right main renal artery demonstrated minimal, fine vascularity in the area of the renal pelvis but a discrete mass lesion was not identified. The fine vascularity probably was owing to the normal pelvic and capsular branches (fig. 2). The ultrasound examination, using a 5.0 MHz. medium focused transducer, demonstrated with transverse and longitudinal sections an ovoid, sharply marginated echogenic mass that appeared to be related to the right kidney. The mass markedly distorted the renal parenchyma and compressed the adjacent liver. A scan of the gallbladder revealed the presence of multiple stones (fig. 3). To establish more firmly the nature of this mass and to define better its site of origin a computerized tomography (CT) scan was performed on February 6. The scan corroborated the relationship of this low attenuation mass to the right kidney (fig. 4). Doctor Schaeffer. The patient's condition remained guarded. Although the episode of biliary colic responded to conservative management the blood pressure remained refractory to multidrug therapy and minoxidil was added. Since the mass in question involved a solitary, functional kidney an ultrasoundguided needle biopsy of the lesion was performed on February
FIG. 2. Selective injection of right main renal artery reveals some fine vascularity in area of renal pelvis. Discrete mass lesion is not seen.
7.
Dr. Denise Hidvegi. Material obtained from the tumor by percutaneous fine needle aspiration revealed small clusters of
FIG. 3. Renal ultrasound demonstrates large echogenic mass related to right kidney.
ACCELERATED HYPERTENSION IN 54-YEAR-OLD WOMAN
861
hypovascular or avascular on angiography. Papillary adenocarcinomas account for the majority of these tumors. However, metastatic carcinoma of the kidney, infiltrating carcinoma of the renal pelvis and necrotic hypemephromas are other neoplastic processes that may present with an avascular or hypovascular angiographic pattern. 2- 5 The cytology obtained from the percutaneous aspiration was non-diagnostic but was more consistent with a renal cell carcinoma than a metastatic or transitional cell carcinoma, which might be amenable to non-surgical management. DISCUSSION OF SURGERY
FIG. 4. CT scan demonstrates relationship of mass to right kidney
Institution of vigorous drug therapy was of no obvious benefit. In this setting it is mandatory to search for mechanisms that might be responsible for the worsening of hypertensive cardiovascular disease. In our patient there was no evidence of renal insufficiency and the urinary excretion of vanillyl mandelic acid, catecholamine and metanephrine was normal. Other endocrine mechanisms also could be excluded. Since the clinical examination revealed a flank bruit on the left side acute renovascular disease appeared a distinct possibility. In our experience as well as in that of others renovascular disease and renal disease previously unrecognized are not unusual in accelerated hypertension. Timed IVP revealed a large right kidney and a shrunken left kidney. Since renin secretion by this kidney might explain the severe hypertension the renal vein renin activity was measured. The results of this study were markedly abnormal, although unexpected, in that renin activity was suppressed in the left renal blood but greatly increased in the opposite main renal vein. These results verified in duplicate samples from each side pointed to the right kidney as the source of renin secretion. However, renal arteriography performed subsequently did not reveal obvious disease of the right renal artery, while it failed to visualize the left renal artery. Elevated renal renin levels in the absence of demonstrable renal arterial lesions may be interpreted as falsely positive for a variety of factors. In our patient no technical errors had been made in collecting the blood samples. The radioimmunoassay was done carefully and the results were highly reproducible, with an intra-assay variation of <1.0 per cent. Other factors for potential error also were eliminated, although some question remained concerning the effect of antihypertensive drugs on renin release. It should be noted that although atherosclerotic and fibromuscular lesions of the renal arteries are associated most commonly with renin hypersecretion other lesions may be responsible. These lesions can be intrinsic or extrinsic. In our patient there was no obvious evidence of an intrinsic lesion of the right renal artery and its branches. However, the high renin activity levels in the right renal vein did suggest to us the possibility of primary reninism caused by a renin-secreting tumor, which could not be visualized, or of an extrinsic lesion involving the hilar vasculature. 1 CLINICAL DIAGNOSIS AND MANAGEMENT
Doctor Schaeffer. Even in retrospect we were impressed by the lack of caliceal and arteriolar displacement, as well as the hypovascularity of the large renal mass demonstrated so dramatically by ultrasonography and CT scan. The echogenicity of the mass clearly suggested tumor rather than cyst. About 10 to 25 per cent of the renal cell carcinomas are
Dr. Earl Wendel. On February 22, 1980 abdominal exploration was done through a midline incision. After the right colon was mobilized and a Kocher maneuver was used to mobilize the duodenum a firm apparently encapsulated mass was noted in the right renal hilus. The mass was impacted with the anterior renal hilus, compressing the vessels. It also was attached to the renal capsule anteriorly at the hilus. The mass was mobilized with sharp and blunt dissection, detached from the capsular attachment, and then enucleated from the renal hilus. Bleeding from hilar vessels was controlled by suture ligatures after the renal artery was surrounded with a sling and compressed, and the kidney was covered with iced saline slush. Avitene and tamponade controlled the oozing from the raw renal parenchymal surface. Nephrectomy of the atrophic left kidney was then accomplished. The gallbladder had numerous adhesions and multiple stones, and a cholecystectomy was performed. At this point the urine was noted to be slightly blood tinged but it was elected not to explore the right renal hilus. The patient tolerated these procedures well and sustained no intraoperative complications. It should be emphasized that our general plan of surgical treatment in this medically unstable patient was to remove the right renal tumor as the first priority. This was to be accomplished in as simple a fashion as possible with the preservation of as much renal tissue as feasible. 6 After the patient tolerated this procedure the non-functioning left kidney would be removed. Finally, because of the high risk of postoperative acute cholecystitis, a cholecystectomy was performed. POSTOPERATIVE COURSE
Doctor Kozlowski. The patient required assisted ventilation and a Swan-Ganz catheter for several days. The blood pressure was 100/90 mm. Hg in the immediate postoperative period. No 1 antihypertensive medication was required during this interval. Convalescence was uneventful except for a transient urine leak from the right collecting system. The patient was discharged from the hospital on March 20, with a blood pressure of 140/90 mm. Hg on 50 mg. hydrochlorothiazide daily and 250 mg. methyldopa 3 times a day. Doctor Nadler. During the year postoperatively the blood pressure averaged 150/90 mm. Hg on the same medications and 0.125 mg. digoxin daily. There has been no evidence ofrecurrent carcinoma. DISCUSSION OF PATHOLOGY
Dr. Ryoichi Oyasu. The specimen received consisted of a tumor, a gallbladder containing calculi and the left kidney. The mass removed from the hilus of the right kidney weighed 215 gm. and measured 11 X 9 X 7 cm. The outer space was smooth and gray-white with an area of recent hemorrhage (fig. 5, A). Cut surfaces were yellow but a prominent, cystic necrotic area also was noted (fig. 5, B). Punctate foci of recent hemorrhage were noted subcapsularly. Multiple sections taken from various regions of the tumor demonstrated a uniform histological pattern, consisting of micropapillae projecting into the small lumina of the tubules (fig. 6). The lining cells were cuboidal and uniform in size, and contained clear cytoplasm and round to
862
CLINICOPATHOLOGICAL CONFERENCE
FIG. 5. A, large mass removed from hilus of right kidney shows smooth surface with area of fresh hemorrhage. B, cut surface of mass shows prominent area of cystic, necrotic degeneration.
oval nuclei. The cells constituting the papillae were larger than the cells lining the tubules and had an eosinophilic granular cytoplasm. No periodic-acid, Schiff-positive granules digestible with diastase could be demonstrated in the tumor cells. Psammoma bodies were found occasionally within the well developed papillae (fig. 6). Mitotic figures were rare and vascular channels were not particularly prominent. Ultrastructurally, the tumor cells were replete with lipid vacuoles and exhibited well developed microvilli. The mitochondria varied in number and size. Those in the clear cells were fewer in number than those cells constituting the papillae, which exhibited numerous mitochondria and fewer fat vacuoles. The left kidney was small, weighing 82 gm. The capsule was adherent to the cortex. The cortical surface generally was smooth and revealed a focus of recent hemorrhagic necrosis. The lumen of the major renal artery was narrowed markedly at one point by a large calcific atheromatous plaque. Microscopic examination of the left kidney revealed generalized atrophy of the tubules, marked arteriosclerosis of the major vessels and interstitial fibrosis. Many glomeruli revealed total or subtotal sclerosis. Mild arteriolar sclerosis was present throughout the kidney. Multiple cholesterol emboli occluded many of the interlobular and arcuate arteries. An attempt was made to visualize renin within the tumor by the immunoperoxidase technique. None could be demonstrated using the peroxidase-antiperoxidase immune complex method and the rabbit antirenin antibody kindly provided by Dr. Tadashi Inagami of Vanderbilt University. On the other hand, a positive reaction clearly was demonstrated in the juxtaglomerular apparatus of the left kidney. A portion of frozen tumor tissue was sent to Doctor Inagami's laboratory for the assay of renin activity but no measurable activity could be detected. ANATOMICAL DIAGNOSIS
We concluded that the tumor was a juxtarenal cell carcinoma. It arose in the subcapsular region and grew as an extrarenal mass, being connected to the kidney by a fibrous band. Furthermore, the tumor was a pure papillary carcinoma, consisting of clear and granular cells. Finally, compression of the right hilar vessels by this juxtarenal tumor was responsible for the fulminant, refractory hypertension noted clinically. COMMENT
Doctor Kozlowski. This case certainly represented a diagnostic dilemma and was associated with 2 features that deserve special emphasis. First, the papillary variant of renal cell carcinoma is an intriguing entity. It has been reported to comprise up to 14 per cent of renal malignancies. The lesion may attain substantial size and may have the following associated features: 1) a thick capsule, 2) 32 per cent show calcification that is characteristically peripheral, 3) significant tumor necrosis is
FIG. 6. Numerous micropapillary projections and few scattered psammoma bodies. H & E stain.
seen in more than two-thirds of the reported cases, 4) cystic degeneration and 5) a predictable hypovascularity that seems to correlate with the amount of tissue necrosis present. The histopathology already has been discussed but a few points deserve re-emphasis. Psammoma bodies are demonstrated in about 20 per cent of the cases of papillary renal cell carcinoma. According to Robbins, on occasion, single necrotic cells may constitute seed crystals that become incrusted by the deposition of calcium salts. The progressive aquisition of outer layers may create a lamellar configuration called a psammoma body because of its resemblance to a grain of sand. Other papillary cancers, most notably thyroid, share this predilection. 10 More importantly, histiocytic infiltration of the papillary cores (foam cells) has been cited as a particularly favorable prognostic sign. Indeed, the substantial amounts of necrosis and cystic degeneration often seen are thought to represent the result of a mobilized immune defense system. Furthermore, there is some inferential evidence to suggest that some of these lesions may have a distal tubular origin. In fact, hyperplastic changes have been noted occasionally in the collecting tubules of adjacent normal papillae and may represent a pre-neoplastic phenomenon. Clinically, this tumor variant is associated with more favorable survival statistics than its non-papillary counterpart. An 89 per cent 5-year survival rate has been quoted for stage 1 tumors. 7- 11 The second feature of this case that warrants special comment is the severe hypertension. Between 20 and 40 per cent of patients with adenocarcinoma of the kidney will manifest some degree of systolic/ diastolic hypertension. Several different etiologies have been proposed or reported. 1) Hypertension may be associated with a Goldblatt effect as a consequence of hilar
863 ,.,.ascula:r the etiology of the seve:re mc,.,,·c,an,,, noted in this case. The total occlusion of the left renal artery at its takeoff from the aorta and the low left renal vein renin would seem to negate the left kidney as a significant contributor to the severe, sustained hypertension. In retrospect, the markedly elevated right renal vein renin reflected the effect of hilar compression the large spherical mass. 2) Elevated renin production may be a consequence of compressive ischemia of normal renal tissue adjacent to the mass. This mechanism also may have been operative in the case under discussion. 3) Massive arteriovenous shunting could result in a marked increase of the intravascular compartment, high output cardiac failure and systolic hypertension. 4) Erythropoietin production by renal tumors is said to occur in about 4 per cent of the cases. A significant secondary polycythemia may be associated with an increase in preload and consequent systolic hypertension. 5) Decreased degradation of angiotensin II and aldosterone might be implicated in the presence of massive hepatic metastases. 6) Renin-secreting renal tumors have been reported. There are 2 well documented cases ofrenin-secreting adenocarcinoma in the literature. Interestingly, both of these lesions were highly differentiated clear cell tumors. Similarly, 2 cases of renin-producing Wilms tumor have been reported to date. Of course, the juxtaglomerular cell tumor and its more malignant counterpart, the hemangiopericytoma, have been similarly implicated. 12 - 19
5. 6. 7. 8.
9.
10. 11. 12.
13. 14. 15.
REFERENCES
16.
1. Kaplan, N. M.: Clinical Hypertension, 2nd ed. Baltimore: The
Williams & Wilkins Co., p. 225, 1978. 2. Blath, R. A., Mancilla-Jimenez, R. and Stanley, R. J.: Clinical comparison between vascular and avascular renal cell carcinoma. J. Urol., 115: 514, 1976. 3. Lang, E. K.: Diagnosis of renal parenchymal tumors. In: Genitourinary Cancer. Edited by D. G. Skinner and J. B. deKemion. Philadelphia: W. B. Saunders Co., chapt. 3, pp. 40-83, 1978. 4. McLaughlin, A. P., III, Talner, L. B., Leopold, G. R. and McCullough, D. L.: Avascular primary renal cell carcinoma:
17. 18.
19.
vafrcd pathologic and angiogrn.phic features. J. UroL, Hl: 587, 1974. Watson, R. C., Fleming, R. J. and Evans, J. A.: Arteriography in the diagnosis of renal carcinoma. Review of 100 cases. Radiology, 9.1.: 888, 1968. Graham, S. D., Jr. and Glenn, J. F.: Enucleative surgery for renal malignancy. J. Urol., 122: 546, 1979. Boczko, S., Fromowitz, F. B. and Bard, R. H.: Papillary adenocarcinoma of kidney. A new perspective. Urology, 14: 491, 1979. Glenn, J. F.: Renal tumors. In: Campbell's Urology, 4th ed. Edited by J. H. Hanison, R. F. Gittes, A. D. Perlmutter, T. A. Stamey and P. C. Walsh. Philadelphia: W. B. Saunders Co., vol. 2, chapt. 27,pp. 967-983, 1979. Mancilla-Jimenez, R., Stanley, R. J. and Blath, R. A.: Papillary renal cell carcinoma. A clinical, radiologic and pathologic study of 34 cases. Cancer, 38: 2469, 1976. Robbins, S. L. and Cotran, R. S.: Pathologic Basis of Disease, 2nd ed. Philadelphia: W. B. Saunders Co., pp. 49-50, 1979. Willis, J. S., Santos, R. M. and Ashley, P. F.: Renal papillary adenocarcinoma. Clin. Rad., 30: 53, 1979. Ganguly, A., Gribble, J., Tune, B., Kempson, R. L. and Luetscher, J. A.: Renin-secreting Wilms' tumor with severe hypertension. Report of a case and brief review of renin-secreting tumors. Ann. Intern. Med., 79: 835, 1973. Gordon, D.: The extrarenal manifestations of hypemephroma. Canad. Med. Ass. J., 88: 61, 1963. Hollifield, J. W., Page, D. L., Smith, C., Michelakis, A. M., Staab, E. and Rhamy, R.: Renin-secreting clear cell carcinoma of the kidney. Arch. Intern. Med., 135: 859, 1975. Lee, M. R.: Renin-secreting kidney tumours. A rare but remediable cause of serious hypertension. Lancet, 2: 254, 1971. lVlerrin, C.: Renal neoplasms. In: Principles and Management of Urologic Cancer. Edited by N. Javadpour. Baltimore: The Williams & Wilkins Co., chapt. 13, pp. 377-403, 1979. Nielsen, H. 0.: Arterial hypertension due to a renin-producing renal carcinoma. Scand. J. Urol. Nephrol., 9: 293, 1975. Skinner, D. G. and deKernion, J. B.: Clinical manifestations and treatment of renal parenchymal tumors. In: Genitourinary Cancer. Edited by D. G. Skinner and J.B. deKernion. Philadelphia: W. B. Saunders Co., chapt. 5, pp. 107-133, 1978. Tveter, K. J.: Unusual manifestations of renal carcinoma. A review of the literature. Acta Chir. Scand., 139: 401, 1973.