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Persistent Hematuria During Pregnancy
0022-5347 /80/1231-0084$02.00/0 Vol. 123, January
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1980 by The Williams & Wilkins Co.
Clinicopathologi cal Conference PERSISTENT HEMATURIA DURING PREGNANCY JOHN H. TEXTER, JR.,* MARK BELLINGER,t ERNEST KAWAMOTO+ WARREN W. KOONTZ, JR.§
AND
From the Departments of Surgery and Pathology, Division of Urology, Medical College of Virginia, Richmond, Virginia
ray demonstrated the fetal skeleton structures and a ground glass appearance to the left renal fossa. A single film approximately 10 minutes after the contrast medium was injected s~owed a. normally functioning but slightly hypertrophied right kidney with a moderately full collecting system and ureter (fig. 1). There was no visualization of the left kidney or its collecting system. A presumptive diagnosis of left hydronephrosis was made, most likely secondary to a congenital ureteropelvic junction obstruction. The patient was placed at bedrest and the bleeding stopped the next day. The hematocrit remained stable. The patient was kept at bedrest for 4 additional days and, subsequently, was discharged from the hospital. No further difficulties were encountered until December 24 when gross hematuria again was experienced on 2 separat~ voidings. The hematocrit and hemoglobin remained unchanged and no other symptoms were experienced. On physical examination the uterus had enlarged consistent with the duration of the pregnancy. Strong fetal movements and fetal heart tones again were recorded. On January 31, 1977 the patient was hospitalized for the second time because of recurrent gross hematuria. The patient was otherwise asymptomatic and the pregnancy appeared to be progressing according to schedule. When the woman was hospitalized the hemoglobin was 11.4 gm., alt?ough during the next 24 hours it decreased to 8.5 gm. Two umts of whole blood were transfused and the urine cleared shortly thereafter. No further bleeding was encountered at that time and the patient was again discharged from the hospital after several days of bedrest and observation. The third hospitalization took place on February 17 because of the reappearance of gross hematuria. However, this time the hematuria was associated with the sudden onset of sharp left flank pain and pain in the left shoulder. The patient had been feeling well until 3 hours before hospitalization, when the hematuria suddenly reappeared and the pain was noticed on the left side. At that time she had been climbing some stairs at her home when she felt a sudden popping sensation in the left back and flank area. Immediately thereafter the urine turned bright red and the pain was experienced in the left flank and shoulder within a half hour. The woman was acutely ill, with a marked degree of tenderness and discomfort over the left flank area. Physical findings suggested an expanding mass in the left flank. Movement and elevation of the left leg produced pain in the left costovertebral area and along the left psoas muscle. The blood pressure was 118/80 and pulse rate was 90. The hemoglobin was 10.9, with a white cell count of 11,000. The blood platelet count was 295,000, with a fibrinogen of 480. The uterus was consistent with a pregnancy of 37 weeks. There were good fetal heart tones and active fetal movements. A repeat sonogram demonstrated an increase in the size of the left renal fossa mass. Amniocentesis revealed a lecithin compatible with adequate maturation of the fetus. A left bulb retrograde ureterogram showed a dilated clot-filled distal ureter (fig. 2). Because of the findings of an acute catastrophic event in the left renal fossa the patient was prepared for an operation. With a left flank
PRESENTATION OF CASEII
Dr. John H. Texter, Jr. A 38-year-old white woman was admitted to our hospital for the first time on October 12, 1976 because of the sudden onset of total gross hematuria. She was gravida IV, Para 1, abortus 2, and she was 17 weeks pregnant. The last menstrual period had been on June 12, 1976 and the expected date of delivery was March 20, 1977. The pregnancy ha~ b~en progressing normally until 5 days before this hospitalization, when the woman experienced frequency of urination and mild dysuria. The symptoms improved after oral ampicillin was administered. However, 24 hours before hospitalization gross hematuria occurred. Multiple, long stringy clots were passed per urethram. Two years earlier the patient had had an episode of left back pain associated with fever and chills and diagnosis had been left pyelonephritis. The condition had been treated on an outpatient basis and cleared promptly with the use of oral antibiotics. In 1966 the patient had suffered lower right abdominal pain and a benign cyst of the ovary was removed. No difficulty was encountered postoperatively and the urine was described as normal. The patient's first pregnancy was uncomplicated and a normal vaginal delivery produced a healthy boy. On p~ysical examination the patient appeared acutely ill and pale, with a temperature of 99.6F, pulse 130 per minute, and blood pressure 120/70 supine and 110/40 sitting. Except for tachycardia heart and chest examinations were normal. On abdominal examination the uterus was non-tender and palpable, consistent with a 17-week gestation. There were active fetal movements and a fetal heart rate of 140 per minute. There was no flank mass or costovertebral angle tenderness. The introitus was unremarkable and the vagina was free of blood. Rectal and extremity examinations were within normal limits. A catheterized urine specimen was grossly bloody and numerous stringy clots were voided spontaneously per urethram. A subsequent urine culture yielded no growth. The admission hematocrit was 16.4 per cent and the hemoglobin was 5.2 gm. per cent. The white blood count was 11,800 and the platelet count was 202,000. The coagulation profile was within normal limits. Shortly after hospitalization the patient received 5 units of whole blood. Blood pressure stabilized at 130/80 and the pulse rate decreased to 80 per minute. Ultrasound examination of the abdomen demonstrated a gravid uterus in the midline and a large cystic mass in the area of the left kidney. Cystoscopy was performed shortly after the woman was hospitalized. Bloody urine again was noted in the bladder but the urethra and bladder mucosa was normal. Clear urine efflux was visualized from the right ureteral orifice. Bloody efflux was seen from the left ureteral orifice. A 2-exposure excretory urogram was done. The plain x* Associate Professor of Surgery, Division of Urology.
t Chief Resident of Urology, Department of Surgery.
:j: Surgical Pathology Fellow, Department of Pathology. § Professor & Chairman, Division of Urology, Department of Surgery. II Case presented at Urology Grand Rounds, March 3, 1978.
84
PERSISTENT HEMATURIA DURING PREGNANCY
85
cm. On the x-rays a thin line of ureteral stump was noted (fig. 3). The patient was hospitalized. A sonogram showed multiple cystic lesions of the left ovary. Subsequent reports from ureteral washings did not demonstrate any malignant cells. Because of these findings the patient was scheduled for exploration and removal of the left distal ureteral stump. DIFFERENTIAL DIAGNOSIS
Dr. Mark Bellinger. This patient presents several diagnostic dilemmas: 1) the physiologic alterations that normally occur in the urinary tract during pregnancy, 2) the effect of these changes on a congenital or acquired obstruction of the upper urinary tract, 3) pyelonephritis of pregnancy, 4) the incidence of gross hematuria as related to the pyelonephritis, 5) spontaneous rupture of the kidney, 6) the etiology of bleeding from the ureteral stump after nephrectomy and 7) the hazards of diagnostic radiation to the developing fetus. 1 The form and function of the urinary tract are altered greatly
FIG. 1. X-ray 10 minutes after injection of contrast agent shows moderately hypertrophied right kidney. Gravid uterus and skeletal parts of fetus are identified easily at this stage of pregnancy. There is no visualization of left kidney or its collecting system.
approach left nephrectomy and partial ureterectomy were done. A large hydronephrotic kidney that had ruptured spontaneously was identified. Approximately 800 cc clotted blood were noted in the renal fossa. The ureteropelvic junction was consistent with a left ureteral junction obstruction of congenital origin. The patient and fetus tolerated the operation well. However, on February 25 spontaneous uterine contractions developed and the patient entered active labor. Approximately 4 hours later a viable female infant weighing 6 pounds 1 ounce was delivered. The Apgar ratings were 9, 10 and 9. After delivery the patient experienced no further difficulty. However, on the evening of February 27 she again passed bloody urine and several small clots. Cystoscopy was done immediately and several clots were noted in the bladder, with a small clot extruding from the left ureteral orifice. Clear efflux was coming from the right ureteral orifice. A retrograde bulb ureterogram showed several filling defects in the stump of the ureter, consistent with retained blood clots. After cystoscopy the urine cleared and no further problems were encountered. The postnephrectomy and delivery recovery period was uncomplicated and the patient was discharged from the hospital. She was followed as an outpatient and continued to have clear urine until January 13, 1978. At that time she noticed the sudden onset of gross painless hematuria for the first time since her previous hospitalization in February 1977. She experienced no abdominal discomfort, fever or chills and there was no history of trauma. Physical findings were unremarkable, with a well healed left flank incision from the previous nephrectomy. The voided urine was grossly bloody and contained several small clots. Cystoscopy was done immediately and showed normal bladder mucosa and clear efflux from the right ureteral orifice. A small stringy clot was seen protruding from the left ureteral orifice. Bladder washings were taken for cytological examination and a left bulb retrograde ureterogram was attempted. On engaging the tip of the catheter it could be advanced only 0.5
FIG. 2. Bulb retrograde ureterogram on left side just before left nephrectomy. Patient was bleeding actively at this time and blood clots were noted at orifice. Infant's skull is visible in true pelvis.
FIG. 3. Retrograde ureterogram approximately 1 year after left nephrectomy. Only small volume of contrast medium entered ureteral stump and catheter would not advance beyond 0.5 cm.
86
CLINICOPATHOLOGICAL CONFERENCE
during pregnancy. The most impressive changes are seen in the upper collecting system when dilatation of the ureters above the pelvic brim is associated with atonia and dilatation of the renal pelvis. Generally, these changes are more evident on the right side. There generally are considered to be 2 factors involved: 1) mechanical and 2) hormonal. The mechanical factors are obvious. Ureteral compression at the bony pelvic brim is caused by the gravid uterus. The obstruction typically is more pronounced on the right side because of dextrorotation of the uterus, the slight prominence of the right iliac artery at the pelvic brim and the compression by the sigmoid colon as it passes over the left ureter. The hormonal influences on the urinary collecting system are believed by many investigators to be more important than mechanical factors. Estrogen and progesterone induce atonia and relaxation and, thus, produce dilatation of the entire urinary collecting system. Similar effects are seen in the musculature of the gastrointestinal tract and the abdominal vasculature. These muscle-relaxing effects are similar to those noted upon the gravid uterus and are essential to allow uterine enlargement and to prevent early uterine contractions. 2 The end result of these influences is upper tract dilatation, which becomes most evident in 7 and 8 months of pregnancy and then gradually declines thereafter. These changes resolve usually by 3 months postpartum. Since the urinary tract becomes dilated and hypotonic during pregnancy it is more susceptible to infection. In years past pyelonephritis during pregnancy was a serious problem. In 1930 Crabtree and Prather reported on 46 patients hospitalized with pyelonephritis of pregnancy. 3 Six of these patients died, while 25 suffered induced or spontaneous abortions. Only 17 became afebrile and completed the pregnancy. The seriousness of this problem decreased markedly after the era of antibiotic therapy as reflected by Folger. 4 Although antibiotic therapy now makes control of the urinary tract infections routine the underlying stasis and obstruction remain unchanged and make the urinary system with congenital or acquired obstruction markedly susceptible to infection, which is difficult to eradicate. The patient with congenital ureteropelvic obstruction is susceptible to pyelitis and pyelonephritis that may smolder along in the face of adequate antibiotic therapy. The relevance of this to our patient will become evident. The clinical manifestations of ureteropelvic junction obstruction usually are related to symptoms of obstruction to the renal pelvis and may present as flank pain classically episodic in nature and associated with increased fluid intake or diuresis. Alternatively, the patient may complain of chronic flank or back pain. There may be intermittent fever, nausea and vomiting, and lower tract irritative symptoms associated with infection of the lower urinary tract. Gross or microscopic hematuria may be associated with ureteropelvic junction obstruction but it must be remembered that infection superimposed on obstruction will predispose to hematuria in any situation. Spontaneous rupture of the kidney is a rare event. In 1933 Abeshouse reported on 61 cases reviewed in the literature and 3 cases of his own. 5 He noted 2 classifications of kidney rupture: 1) spontaneous and 2) traumatic. Both occurred primarily in kidneys with underlying anatomic abnormalities, such as hydronephrosis secondary to stone or stricture, postoperative changes or congenital lesions. It is known commonly that such anatomic defects make a kidney susceptible to minimal trauma, even a slight bump on the side that may go unrecognized to the patient and physician. Sudden contraction of the abdominal musculature has been associated with renal rupture. Spontaneous non-traumatic renal rupture is a rare event. Spontaneous perirenal hematoma was first described by Wunderlich in 1856 and has been termed Wunderlich's disease. The symptom complex is typified by abdominal pain, flank mass and signs of internal blood loss. In 1933 Polkey and Vynalek ligated renal veins in dogs and were able to produce spontaneous perirenal
hemorrhage. 6 They thought that increased venous pressure and subsequent congestion resulted in spontaneous bleeding. They reviewed 200 cases and found, as with renal rupture, a high incidence of anatomic lesions. A search of the literature reveals that aside from anatomic lesions the most common cause for spontaneous rupture is renal infection. Thus, this patient represents a congenital ureteropelvic junction obstruction, a documented episode of clinical pyelonephritis, and may have had traumatic renal rupture secondary to abdominal contraction or psoas contraction while climbing the stairs. It also could have been a spontaneous rupture of a chronically infected kidney. The documented gross hematuria may have originated in this kidney. The remaining consideration is one of bleeding from a ureteral stump after nephrectomy and partial ureterectomy. The passage of blood and clots from a ureteral stump within the first postoperative week was thought to result from retained blood in the ureteral stump at the time of the original operation. The fact that the patient remained free of hematuria for 11 months would be further reassuring. However, the occurrence of new bleeding 11 months later is an entirely different matter. We are left with a differential diagnosis of bleeding from a ureteral stump. Could it be neoplastic, infectious, calculus-related, vascular, an adjacent process with ureteral involvement or a primary ureteral lesion? Primary ureteral tumors are rare neoplasms, making up approximately 1 per cent of urinary tract malignancies. 7 There is marked male predominance and the peak age of presentation is the fifth to the eighth decades. 8 The primary presenting symptom is gross hematuria, which :nay be associated with colic if there is formation and passage of large blood clots. The most common site of origin is the distal ureter. The most common cell type is that of transitional cell carcinoma but benign papillomas also are noted. Sarcomas are extremely rare lesions. Since transitional cell carcinoma is a "field change" disease one must investigate the entire urothelium closely to eliminate the possibility of other synchronous lesions. Squamous cell carcinoma is even more uncommon and would be suspected if there is a history of chronic infection or calculi in the retained ureteral remnant. 9 Metastatic neoplasms to the ureter are quite rare but one must consider the possibility that hematuria could be caused by direct invasion by an adjacent tumor. Although hemangiomas of the ureter are rare they are reported to be lesions that present with hematuria. Infectious processes may involve the ureteral stump. V esicoureteral reflux may result in an infected pocket that is difficult to eradicate and present as a chronic bacterial infection that may result in chronic ureteritis, ureteritis cystica and stone formation. Each of these may present as chronic urinary infection rarely with gross hematuria. Tuberculous ureteritis would be unlikely unless primary renal tuberculosis was present. Endometriosis may involve the ureter and produce hematuria, as may inflammatory bowel lesions. There are no other findings or history that would suggest either of these entities. Other extremely rare ureteral lesions are leukoplakia, granulomas and amyloidosis. Next, we should consider the radiographic findings. However, before these are described it is appropriate to consider the topic of radiation risk for diagnostic studies during pregnancy. Sternberg has discussed the topic of radiation biology and its effect on the pregnant woman and fetus. 10 The risk of radiation damage to the fetus of women exposed to large amounts of radiation during nuclear bombing and accidents continues to be a controversy. The leukemogenic and teratogenic effects are well documented. In regard to diagnostic radiography the ill effects are far less clear. There have been questionable reports of leukemias in offspring and minor morphologic changes in several cases but more work is needed in this field. However, Sternberg and others have pointed out that diagnostic radiology
PERSISTENT HEMATURIA DURING PREGNANCY
during pregnancy does carry a risk. This risk must be taken into consideration by the patient and physician because of the hazard to the mother and fetus. This risk must be compared to the danger facing the mother and fetus that the radiologic procedures are trying to delineate and the therapeutic modalities that are being considered. The post-injection x-rays from October 1976 clearly show the fetal skeletal parts. There is no visualization of the left kidney or its collecting system. Only a ground glass appearance of the left loin is seen, which is consistent with a soft tissue mass. The right kidney is hypertrophied, suggesting that it has been the sole functioning renal organ for considerable time. There is minimal dilatation of the collecting system consistent with this stage of the pregnancy. The retrograde ureterogram on February 17, 1977, just before the left nephrectomy and partial ureterectomy, shows the fetal head descended well into the bony pelvis. The distal left ureter is dilated greatly with filling defects in the upper portion consistent with blood clots similar to that seen during cystoscopy. The repeat and final left retrograde x-ray from January 13, 1978 is of poor quality but shows a dramatic change in the ureteral stump. Only a thin wisp of contrast medium fills the stump lumen and much of the medium escapes back into the bladder. A definite filling defect is evident at the tip of the column of contrast medium. The absence of calcification in the area of the ureteral stump would appear to eliminate a stone as etiology for the hematuria. Unfortunately, only bladder washings could be obtained for cytology and no good specimens were obtained from the ureter. We are left with a 38-year-old woman with recurrent ureteral stump bleeding 11 months after nephrectomy for renal rupture. The kidney was hydronephrotic secondary to a congenital ureteropelvic junction obstruction. Review of the kidney and renal pelvis does not provide us with evidence of a renal parenchyma or collecting system neoplasm. The patient had no history of bowel complaints or symptoms of endometriosis and there apparently was no endometriosis present at the time of the right ovarian cystectomy. We do have a history of pyelonephritis and this is confirmed in the microscopic examination of the renal parenchyma but there is no evidence of chronic lower urinary tract infection since the delivery of the last child. The likelihood of a ureteritis or calculus formation diminishes. Evidence points to a primary ureteral lesion and the filling defect that was presumed to be a blood clot initially may, indeed, have been clots but it also is possible that a primary ureteral tumor may have been present at that time as well. The second retrograde ureterogram strongly suggests a ureteral stump filled with a neoplasm. The statistics would favor either a transitional cell carcinoma of the ureteral stump or benign papilloma. In view of the negative cytologies a low grade tumor or benign papilloma would seem most likely. Despite the fact that the patient is young the other possibilities, such as sarcoma, hemangioma and squamous cell carcinoma, are far less likely. For this reason my primary diagnosis would be a papillary lesion of the ureteral stump. However, because of the possibility of a transitional cell carcinoma exploration and excision of the ureteral stump along with the cuff of the bladder would appear to be indicated.
87
Otherwise, the bladder was normal. The ureteral and bladder cuff specimen was then removed from the operative field and an immediate frozen section was obtained by the pathologist for diagnostic purposes. DISCUSSION OF PATHOLOGY
Dr. Ernest Kawamoto. The left kidney removed at the initial operation on February 17, 1977 showed changes of long-standing hydronephrosis and pyelonephritis. It measured 18 X 6 X 6 cm., being enlarged by severe dilatation of its pelvis and caliceal system. The renal capsule was adherent to the cortical surface, which contained some flat irregular scars. The renal parenchyma was thinned and microscopically showed diffuse replacement by fibrous tissue having a dense mononuclear inflammatory infiltrate. In addition to the signs of hydronephrosis and pyelonephritis there was rupture of 1 pole of the kidney and the capsule was covered by a recent blood clot. The renal parenchyma was diffusely hemorrhagic, while the pelvic and caliceal systems were filled with chocolate-colored fluid consistent with an older blood clot. The resected portion of the left ureter was dilated uniformly to 1 cm. in diameter. Its wall was slightly edematous and contained some neutrophils, lymphocytes and plasma cells. No tumor was noted in either the kidney or ureteral segment. The specimen removed during the second operation in January 1978 was the left ureteral stump and cuff of bladder. It measured 14 cm. in length, of which the distal 2.5 cm. was totally unremarkable. The remainder of the stump was fusiform in shape and was distended up to 2 cm. in diameter. The middle of the stump was most severely distended and contained a 5.5 cm. mucosal tumor that occluded the lumen of the involved section. The tumor was soft, extremely papillary and white to pale yellow (fig. 4). Microscopically, the tumor was composed of closely set, delicate papillary fronds of connective tissue lined by many layers of neoplastic transitional cells. The cells contained some variation in size,, while their nuclei showed variation in nuclear size and hyperchromatism. The base of the tumor generally extended to the junction of the lamina propria and muscularis. Focally, the tumor invaded the muscularis superficially (fig. 5). A review of the cytologic smears of the preoperative bladder washings and attempts at ureteral washings showed no malignant cells. However, since the catheter could only be advanced 0.5 cm. into the ureter the washings probably did not reach the tumor and can, retrospectively, be considered inadequate. When it has been pOjilsible to perfoffil brushing cytology has been shown to be a promising technique for diagnosing ureteral tumors.II
DISCUSSION OF SURGERY
Doctor Texter. As suggested by Doctor Bellinger I was concerned about a neoplasm of the residual ureteral stump, despite the negative cytological examination. At the time of the operation the left ureter was identified easily and freed from the surrounding tissue. There were no palpable lymph nodes evident and no adjacent fibrosis that would suggest extension of the disease process into the periureteral tissue. A soft tissue mass measuring approximately 1 X 2 cm. was palpable within the ureteral lumen and could be moved slightly with manipulation of the ureter. The bladder was opened and a 1 cm. cuff of bladder wall was excised around the left ureteral orifice.
FIG. 4. Gross specimen of ureteral stump opened longitudinally demonstrates tumor projecting in lumen. Proximal 2½ cm. of ureter are unremarkable.
88
CLINICOPATHOLOGICAL CONFERENCE
only approximately 1 per cent of all carcinomas of the upper urinary tract. It is a disease that favors the male population 2 to 1 but also is seen more often in patients in the sixth, seventh and eighth decades. 13 This patient is extremely young for such a tumor but has a good prognosis since grade 1 ureteral tumors are reported to have an 80 per cent 5-year survival rate. This case again proves the adage that gross hematuria is cancer until proved otherwise and raises the question of whether patients with ureteral stumps secondary to previous non-neoplastic nephrectomy should have a retrograde ureterogram and washing cytologies performed at the time of each cystoscopic examination.14 REFERENCES 1. Kittredge, W. E. and Crawley, J. R.: Surgical renal lesions associated with pregnancy. J.A.M.A., 162: 1353, 1956.
2. Bergman, H.: The Ureter. New York: Harper & Row, Publishers, 1967. 3. Crabtree, E.G. and Prather, G. C.: Clinical aspects ofpyelonephritis in pregnancy. New Engl. J. Med., 202: 357, 1930. 4. Folger, G. K.: Pain and pregnancy; treatment of painful states
FIG. 5. Microscopic section of tumor and ureteral wall. Neoplastic transitional cells extend to junction of lamina propria and muscularis. At several foci cells have invaded superficially muscularis. There was no extension through entire ureteral wall. The pathological diagnosis then is hydronephrosis of the left kidney (1977), chronic pyelonephritis of the left kidney (1977), rupture of the left kidney (1977) and grade 1 to 2 transitional cell carcinoma with superficially focal invasion of the left ureteral stump (1978). DISCUSSION
Dr. Warren W. Koontz, Jr. This patient presents several important points. First, it is not unusual that a patient with a well differentiated grade 1 to 2 transitional cell carcinoma would have a negative cytological examination, even if the specimen was adequate from the left ureteral stump. The National Bladder Cancer Collaborative Group-A report revealed that only 43 to 47 per cent of the patients studied with grade 1 to 2 transitional cell carcinoma of the bladder had positive urine cytologies. 12 However, if one looked at the grade 3 to 4 lesions the percentage of positive cytological examinations increased to 93 per cent. For low grade ureteral tumors brush cytological examination is better than ordinary bladder washing cytologies. Primary tumors of the ureter are infrequent and account for
complicating pregnancy, with particular emphasis on urinary calculi. Obst. Gynec., 5: 513, 1955. 5. Abeshouse, B. S.: Rupture of the kidney pelvis: review of the literature. Surg., Gynec. & Obst., 60: 710, 1935. 6. Polkey, H.J. and Vynalek, W. J.: Spontaneous nontraumatic perirenal and renal hematomas. Arch. Surg., 26: 196, 1933. 7. Brettler, A.: Primary carcinoma of the ureter. Canad. Med. Ass. J., 88: 1169, 1963.
8. McIntyre, D., Pyrah, L. N. and Raper, F. P.: Primary ureteric neoplasms. With a report of forty cases. Brit. J. Urol., 37: 160, 1965.
9. Amar, A. D.: Squamous cell carcinoma of the ureteral stump 40 years after nephrectomy. J. Urol., 91: 337, 1964. 10. Sternberg, J.: Radiation risk in pregnancy. Clin. Obst. Gynec., 16: 235, 1973. 11. Bibbo, M., Gill, W. B., Harris, M. J., Lu, C. T., Thomsen, S. and
Wied, G. L.: Retrograde brushing as a diagnostic procedure of ureteral, renal pelvic and renal calyceal lesions. A preliminary report. Acta Cytol., 18: 139, 1974. 12. National Bladder Cancer Collaborative Group-A: Cytology and histopathology of bladder cancer cases in a prospective longitudinal study. Cancer Res., 37: 2911, 1977. 13. Persky, L., Kursh, E. D. and Soloway, M.: Uroepithelial tumors. In: Urology in Practice. Edited by C. J. Devine, Jr: and J. F. Stecker, Jr. Boston: Little Brown & Co., pp. 653-690, 1978. 14. Summers, J., Wilkerson, J. and Foster, S.: Transitional cell carcinoma and residual ureters after nephrectomy for infection. J. Urol., 108: 246, 1972.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1980 by The Williams & Wilkins Co.
Clinicopathologi cal Conference PERSISTENT HEMATURIA DURING PREGNANCY JOHN H. TEXTER, JR.,* MARK BELLINGER,t ERNEST KAWAMOTO+ WARREN W. KOONTZ, JR.§
AND
From the Departments of Surgery and Pathology, Division of Urology, Medical College of Virginia, Richmond, Virginia
ray demonstrated the fetal skeleton structures and a ground glass appearance to the left renal fossa. A single film approximately 10 minutes after the contrast medium was injected s~owed a. normally functioning but slightly hypertrophied right kidney with a moderately full collecting system and ureter (fig. 1). There was no visualization of the left kidney or its collecting system. A presumptive diagnosis of left hydronephrosis was made, most likely secondary to a congenital ureteropelvic junction obstruction. The patient was placed at bedrest and the bleeding stopped the next day. The hematocrit remained stable. The patient was kept at bedrest for 4 additional days and, subsequently, was discharged from the hospital. No further difficulties were encountered until December 24 when gross hematuria again was experienced on 2 separat~ voidings. The hematocrit and hemoglobin remained unchanged and no other symptoms were experienced. On physical examination the uterus had enlarged consistent with the duration of the pregnancy. Strong fetal movements and fetal heart tones again were recorded. On January 31, 1977 the patient was hospitalized for the second time because of recurrent gross hematuria. The patient was otherwise asymptomatic and the pregnancy appeared to be progressing according to schedule. When the woman was hospitalized the hemoglobin was 11.4 gm., alt?ough during the next 24 hours it decreased to 8.5 gm. Two umts of whole blood were transfused and the urine cleared shortly thereafter. No further bleeding was encountered at that time and the patient was again discharged from the hospital after several days of bedrest and observation. The third hospitalization took place on February 17 because of the reappearance of gross hematuria. However, this time the hematuria was associated with the sudden onset of sharp left flank pain and pain in the left shoulder. The patient had been feeling well until 3 hours before hospitalization, when the hematuria suddenly reappeared and the pain was noticed on the left side. At that time she had been climbing some stairs at her home when she felt a sudden popping sensation in the left back and flank area. Immediately thereafter the urine turned bright red and the pain was experienced in the left flank and shoulder within a half hour. The woman was acutely ill, with a marked degree of tenderness and discomfort over the left flank area. Physical findings suggested an expanding mass in the left flank. Movement and elevation of the left leg produced pain in the left costovertebral area and along the left psoas muscle. The blood pressure was 118/80 and pulse rate was 90. The hemoglobin was 10.9, with a white cell count of 11,000. The blood platelet count was 295,000, with a fibrinogen of 480. The uterus was consistent with a pregnancy of 37 weeks. There were good fetal heart tones and active fetal movements. A repeat sonogram demonstrated an increase in the size of the left renal fossa mass. Amniocentesis revealed a lecithin compatible with adequate maturation of the fetus. A left bulb retrograde ureterogram showed a dilated clot-filled distal ureter (fig. 2). Because of the findings of an acute catastrophic event in the left renal fossa the patient was prepared for an operation. With a left flank
PRESENTATION OF CASEII
Dr. John H. Texter, Jr. A 38-year-old white woman was admitted to our hospital for the first time on October 12, 1976 because of the sudden onset of total gross hematuria. She was gravida IV, Para 1, abortus 2, and she was 17 weeks pregnant. The last menstrual period had been on June 12, 1976 and the expected date of delivery was March 20, 1977. The pregnancy ha~ b~en progressing normally until 5 days before this hospitalization, when the woman experienced frequency of urination and mild dysuria. The symptoms improved after oral ampicillin was administered. However, 24 hours before hospitalization gross hematuria occurred. Multiple, long stringy clots were passed per urethram. Two years earlier the patient had had an episode of left back pain associated with fever and chills and diagnosis had been left pyelonephritis. The condition had been treated on an outpatient basis and cleared promptly with the use of oral antibiotics. In 1966 the patient had suffered lower right abdominal pain and a benign cyst of the ovary was removed. No difficulty was encountered postoperatively and the urine was described as normal. The patient's first pregnancy was uncomplicated and a normal vaginal delivery produced a healthy boy. On p~ysical examination the patient appeared acutely ill and pale, with a temperature of 99.6F, pulse 130 per minute, and blood pressure 120/70 supine and 110/40 sitting. Except for tachycardia heart and chest examinations were normal. On abdominal examination the uterus was non-tender and palpable, consistent with a 17-week gestation. There were active fetal movements and a fetal heart rate of 140 per minute. There was no flank mass or costovertebral angle tenderness. The introitus was unremarkable and the vagina was free of blood. Rectal and extremity examinations were within normal limits. A catheterized urine specimen was grossly bloody and numerous stringy clots were voided spontaneously per urethram. A subsequent urine culture yielded no growth. The admission hematocrit was 16.4 per cent and the hemoglobin was 5.2 gm. per cent. The white blood count was 11,800 and the platelet count was 202,000. The coagulation profile was within normal limits. Shortly after hospitalization the patient received 5 units of whole blood. Blood pressure stabilized at 130/80 and the pulse rate decreased to 80 per minute. Ultrasound examination of the abdomen demonstrated a gravid uterus in the midline and a large cystic mass in the area of the left kidney. Cystoscopy was performed shortly after the woman was hospitalized. Bloody urine again was noted in the bladder but the urethra and bladder mucosa was normal. Clear urine efflux was visualized from the right ureteral orifice. Bloody efflux was seen from the left ureteral orifice. A 2-exposure excretory urogram was done. The plain x* Associate Professor of Surgery, Division of Urology.
t Chief Resident of Urology, Department of Surgery.
:j: Surgical Pathology Fellow, Department of Pathology. § Professor & Chairman, Division of Urology, Department of Surgery. II Case presented at Urology Grand Rounds, March 3, 1978.
84
PERSISTENT HEMATURIA DURING PREGNANCY
85
cm. On the x-rays a thin line of ureteral stump was noted (fig. 3). The patient was hospitalized. A sonogram showed multiple cystic lesions of the left ovary. Subsequent reports from ureteral washings did not demonstrate any malignant cells. Because of these findings the patient was scheduled for exploration and removal of the left distal ureteral stump. DIFFERENTIAL DIAGNOSIS
Dr. Mark Bellinger. This patient presents several diagnostic dilemmas: 1) the physiologic alterations that normally occur in the urinary tract during pregnancy, 2) the effect of these changes on a congenital or acquired obstruction of the upper urinary tract, 3) pyelonephritis of pregnancy, 4) the incidence of gross hematuria as related to the pyelonephritis, 5) spontaneous rupture of the kidney, 6) the etiology of bleeding from the ureteral stump after nephrectomy and 7) the hazards of diagnostic radiation to the developing fetus. 1 The form and function of the urinary tract are altered greatly
FIG. 1. X-ray 10 minutes after injection of contrast agent shows moderately hypertrophied right kidney. Gravid uterus and skeletal parts of fetus are identified easily at this stage of pregnancy. There is no visualization of left kidney or its collecting system.
approach left nephrectomy and partial ureterectomy were done. A large hydronephrotic kidney that had ruptured spontaneously was identified. Approximately 800 cc clotted blood were noted in the renal fossa. The ureteropelvic junction was consistent with a left ureteral junction obstruction of congenital origin. The patient and fetus tolerated the operation well. However, on February 25 spontaneous uterine contractions developed and the patient entered active labor. Approximately 4 hours later a viable female infant weighing 6 pounds 1 ounce was delivered. The Apgar ratings were 9, 10 and 9. After delivery the patient experienced no further difficulty. However, on the evening of February 27 she again passed bloody urine and several small clots. Cystoscopy was done immediately and several clots were noted in the bladder, with a small clot extruding from the left ureteral orifice. Clear efflux was coming from the right ureteral orifice. A retrograde bulb ureterogram showed several filling defects in the stump of the ureter, consistent with retained blood clots. After cystoscopy the urine cleared and no further problems were encountered. The postnephrectomy and delivery recovery period was uncomplicated and the patient was discharged from the hospital. She was followed as an outpatient and continued to have clear urine until January 13, 1978. At that time she noticed the sudden onset of gross painless hematuria for the first time since her previous hospitalization in February 1977. She experienced no abdominal discomfort, fever or chills and there was no history of trauma. Physical findings were unremarkable, with a well healed left flank incision from the previous nephrectomy. The voided urine was grossly bloody and contained several small clots. Cystoscopy was done immediately and showed normal bladder mucosa and clear efflux from the right ureteral orifice. A small stringy clot was seen protruding from the left ureteral orifice. Bladder washings were taken for cytological examination and a left bulb retrograde ureterogram was attempted. On engaging the tip of the catheter it could be advanced only 0.5
FIG. 2. Bulb retrograde ureterogram on left side just before left nephrectomy. Patient was bleeding actively at this time and blood clots were noted at orifice. Infant's skull is visible in true pelvis.
FIG. 3. Retrograde ureterogram approximately 1 year after left nephrectomy. Only small volume of contrast medium entered ureteral stump and catheter would not advance beyond 0.5 cm.
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during pregnancy. The most impressive changes are seen in the upper collecting system when dilatation of the ureters above the pelvic brim is associated with atonia and dilatation of the renal pelvis. Generally, these changes are more evident on the right side. There generally are considered to be 2 factors involved: 1) mechanical and 2) hormonal. The mechanical factors are obvious. Ureteral compression at the bony pelvic brim is caused by the gravid uterus. The obstruction typically is more pronounced on the right side because of dextrorotation of the uterus, the slight prominence of the right iliac artery at the pelvic brim and the compression by the sigmoid colon as it passes over the left ureter. The hormonal influences on the urinary collecting system are believed by many investigators to be more important than mechanical factors. Estrogen and progesterone induce atonia and relaxation and, thus, produce dilatation of the entire urinary collecting system. Similar effects are seen in the musculature of the gastrointestinal tract and the abdominal vasculature. These muscle-relaxing effects are similar to those noted upon the gravid uterus and are essential to allow uterine enlargement and to prevent early uterine contractions. 2 The end result of these influences is upper tract dilatation, which becomes most evident in 7 and 8 months of pregnancy and then gradually declines thereafter. These changes resolve usually by 3 months postpartum. Since the urinary tract becomes dilated and hypotonic during pregnancy it is more susceptible to infection. In years past pyelonephritis during pregnancy was a serious problem. In 1930 Crabtree and Prather reported on 46 patients hospitalized with pyelonephritis of pregnancy. 3 Six of these patients died, while 25 suffered induced or spontaneous abortions. Only 17 became afebrile and completed the pregnancy. The seriousness of this problem decreased markedly after the era of antibiotic therapy as reflected by Folger. 4 Although antibiotic therapy now makes control of the urinary tract infections routine the underlying stasis and obstruction remain unchanged and make the urinary system with congenital or acquired obstruction markedly susceptible to infection, which is difficult to eradicate. The patient with congenital ureteropelvic obstruction is susceptible to pyelitis and pyelonephritis that may smolder along in the face of adequate antibiotic therapy. The relevance of this to our patient will become evident. The clinical manifestations of ureteropelvic junction obstruction usually are related to symptoms of obstruction to the renal pelvis and may present as flank pain classically episodic in nature and associated with increased fluid intake or diuresis. Alternatively, the patient may complain of chronic flank or back pain. There may be intermittent fever, nausea and vomiting, and lower tract irritative symptoms associated with infection of the lower urinary tract. Gross or microscopic hematuria may be associated with ureteropelvic junction obstruction but it must be remembered that infection superimposed on obstruction will predispose to hematuria in any situation. Spontaneous rupture of the kidney is a rare event. In 1933 Abeshouse reported on 61 cases reviewed in the literature and 3 cases of his own. 5 He noted 2 classifications of kidney rupture: 1) spontaneous and 2) traumatic. Both occurred primarily in kidneys with underlying anatomic abnormalities, such as hydronephrosis secondary to stone or stricture, postoperative changes or congenital lesions. It is known commonly that such anatomic defects make a kidney susceptible to minimal trauma, even a slight bump on the side that may go unrecognized to the patient and physician. Sudden contraction of the abdominal musculature has been associated with renal rupture. Spontaneous non-traumatic renal rupture is a rare event. Spontaneous perirenal hematoma was first described by Wunderlich in 1856 and has been termed Wunderlich's disease. The symptom complex is typified by abdominal pain, flank mass and signs of internal blood loss. In 1933 Polkey and Vynalek ligated renal veins in dogs and were able to produce spontaneous perirenal
hemorrhage. 6 They thought that increased venous pressure and subsequent congestion resulted in spontaneous bleeding. They reviewed 200 cases and found, as with renal rupture, a high incidence of anatomic lesions. A search of the literature reveals that aside from anatomic lesions the most common cause for spontaneous rupture is renal infection. Thus, this patient represents a congenital ureteropelvic junction obstruction, a documented episode of clinical pyelonephritis, and may have had traumatic renal rupture secondary to abdominal contraction or psoas contraction while climbing the stairs. It also could have been a spontaneous rupture of a chronically infected kidney. The documented gross hematuria may have originated in this kidney. The remaining consideration is one of bleeding from a ureteral stump after nephrectomy and partial ureterectomy. The passage of blood and clots from a ureteral stump within the first postoperative week was thought to result from retained blood in the ureteral stump at the time of the original operation. The fact that the patient remained free of hematuria for 11 months would be further reassuring. However, the occurrence of new bleeding 11 months later is an entirely different matter. We are left with a differential diagnosis of bleeding from a ureteral stump. Could it be neoplastic, infectious, calculus-related, vascular, an adjacent process with ureteral involvement or a primary ureteral lesion? Primary ureteral tumors are rare neoplasms, making up approximately 1 per cent of urinary tract malignancies. 7 There is marked male predominance and the peak age of presentation is the fifth to the eighth decades. 8 The primary presenting symptom is gross hematuria, which :nay be associated with colic if there is formation and passage of large blood clots. The most common site of origin is the distal ureter. The most common cell type is that of transitional cell carcinoma but benign papillomas also are noted. Sarcomas are extremely rare lesions. Since transitional cell carcinoma is a "field change" disease one must investigate the entire urothelium closely to eliminate the possibility of other synchronous lesions. Squamous cell carcinoma is even more uncommon and would be suspected if there is a history of chronic infection or calculi in the retained ureteral remnant. 9 Metastatic neoplasms to the ureter are quite rare but one must consider the possibility that hematuria could be caused by direct invasion by an adjacent tumor. Although hemangiomas of the ureter are rare they are reported to be lesions that present with hematuria. Infectious processes may involve the ureteral stump. V esicoureteral reflux may result in an infected pocket that is difficult to eradicate and present as a chronic bacterial infection that may result in chronic ureteritis, ureteritis cystica and stone formation. Each of these may present as chronic urinary infection rarely with gross hematuria. Tuberculous ureteritis would be unlikely unless primary renal tuberculosis was present. Endometriosis may involve the ureter and produce hematuria, as may inflammatory bowel lesions. There are no other findings or history that would suggest either of these entities. Other extremely rare ureteral lesions are leukoplakia, granulomas and amyloidosis. Next, we should consider the radiographic findings. However, before these are described it is appropriate to consider the topic of radiation risk for diagnostic studies during pregnancy. Sternberg has discussed the topic of radiation biology and its effect on the pregnant woman and fetus. 10 The risk of radiation damage to the fetus of women exposed to large amounts of radiation during nuclear bombing and accidents continues to be a controversy. The leukemogenic and teratogenic effects are well documented. In regard to diagnostic radiography the ill effects are far less clear. There have been questionable reports of leukemias in offspring and minor morphologic changes in several cases but more work is needed in this field. However, Sternberg and others have pointed out that diagnostic radiology
PERSISTENT HEMATURIA DURING PREGNANCY
during pregnancy does carry a risk. This risk must be taken into consideration by the patient and physician because of the hazard to the mother and fetus. This risk must be compared to the danger facing the mother and fetus that the radiologic procedures are trying to delineate and the therapeutic modalities that are being considered. The post-injection x-rays from October 1976 clearly show the fetal skeletal parts. There is no visualization of the left kidney or its collecting system. Only a ground glass appearance of the left loin is seen, which is consistent with a soft tissue mass. The right kidney is hypertrophied, suggesting that it has been the sole functioning renal organ for considerable time. There is minimal dilatation of the collecting system consistent with this stage of the pregnancy. The retrograde ureterogram on February 17, 1977, just before the left nephrectomy and partial ureterectomy, shows the fetal head descended well into the bony pelvis. The distal left ureter is dilated greatly with filling defects in the upper portion consistent with blood clots similar to that seen during cystoscopy. The repeat and final left retrograde x-ray from January 13, 1978 is of poor quality but shows a dramatic change in the ureteral stump. Only a thin wisp of contrast medium fills the stump lumen and much of the medium escapes back into the bladder. A definite filling defect is evident at the tip of the column of contrast medium. The absence of calcification in the area of the ureteral stump would appear to eliminate a stone as etiology for the hematuria. Unfortunately, only bladder washings could be obtained for cytology and no good specimens were obtained from the ureter. We are left with a 38-year-old woman with recurrent ureteral stump bleeding 11 months after nephrectomy for renal rupture. The kidney was hydronephrotic secondary to a congenital ureteropelvic junction obstruction. Review of the kidney and renal pelvis does not provide us with evidence of a renal parenchyma or collecting system neoplasm. The patient had no history of bowel complaints or symptoms of endometriosis and there apparently was no endometriosis present at the time of the right ovarian cystectomy. We do have a history of pyelonephritis and this is confirmed in the microscopic examination of the renal parenchyma but there is no evidence of chronic lower urinary tract infection since the delivery of the last child. The likelihood of a ureteritis or calculus formation diminishes. Evidence points to a primary ureteral lesion and the filling defect that was presumed to be a blood clot initially may, indeed, have been clots but it also is possible that a primary ureteral tumor may have been present at that time as well. The second retrograde ureterogram strongly suggests a ureteral stump filled with a neoplasm. The statistics would favor either a transitional cell carcinoma of the ureteral stump or benign papilloma. In view of the negative cytologies a low grade tumor or benign papilloma would seem most likely. Despite the fact that the patient is young the other possibilities, such as sarcoma, hemangioma and squamous cell carcinoma, are far less likely. For this reason my primary diagnosis would be a papillary lesion of the ureteral stump. However, because of the possibility of a transitional cell carcinoma exploration and excision of the ureteral stump along with the cuff of the bladder would appear to be indicated.
87
Otherwise, the bladder was normal. The ureteral and bladder cuff specimen was then removed from the operative field and an immediate frozen section was obtained by the pathologist for diagnostic purposes. DISCUSSION OF PATHOLOGY
Dr. Ernest Kawamoto. The left kidney removed at the initial operation on February 17, 1977 showed changes of long-standing hydronephrosis and pyelonephritis. It measured 18 X 6 X 6 cm., being enlarged by severe dilatation of its pelvis and caliceal system. The renal capsule was adherent to the cortical surface, which contained some flat irregular scars. The renal parenchyma was thinned and microscopically showed diffuse replacement by fibrous tissue having a dense mononuclear inflammatory infiltrate. In addition to the signs of hydronephrosis and pyelonephritis there was rupture of 1 pole of the kidney and the capsule was covered by a recent blood clot. The renal parenchyma was diffusely hemorrhagic, while the pelvic and caliceal systems were filled with chocolate-colored fluid consistent with an older blood clot. The resected portion of the left ureter was dilated uniformly to 1 cm. in diameter. Its wall was slightly edematous and contained some neutrophils, lymphocytes and plasma cells. No tumor was noted in either the kidney or ureteral segment. The specimen removed during the second operation in January 1978 was the left ureteral stump and cuff of bladder. It measured 14 cm. in length, of which the distal 2.5 cm. was totally unremarkable. The remainder of the stump was fusiform in shape and was distended up to 2 cm. in diameter. The middle of the stump was most severely distended and contained a 5.5 cm. mucosal tumor that occluded the lumen of the involved section. The tumor was soft, extremely papillary and white to pale yellow (fig. 4). Microscopically, the tumor was composed of closely set, delicate papillary fronds of connective tissue lined by many layers of neoplastic transitional cells. The cells contained some variation in size,, while their nuclei showed variation in nuclear size and hyperchromatism. The base of the tumor generally extended to the junction of the lamina propria and muscularis. Focally, the tumor invaded the muscularis superficially (fig. 5). A review of the cytologic smears of the preoperative bladder washings and attempts at ureteral washings showed no malignant cells. However, since the catheter could only be advanced 0.5 cm. into the ureter the washings probably did not reach the tumor and can, retrospectively, be considered inadequate. When it has been pOjilsible to perfoffil brushing cytology has been shown to be a promising technique for diagnosing ureteral tumors.II
DISCUSSION OF SURGERY
Doctor Texter. As suggested by Doctor Bellinger I was concerned about a neoplasm of the residual ureteral stump, despite the negative cytological examination. At the time of the operation the left ureter was identified easily and freed from the surrounding tissue. There were no palpable lymph nodes evident and no adjacent fibrosis that would suggest extension of the disease process into the periureteral tissue. A soft tissue mass measuring approximately 1 X 2 cm. was palpable within the ureteral lumen and could be moved slightly with manipulation of the ureter. The bladder was opened and a 1 cm. cuff of bladder wall was excised around the left ureteral orifice.
FIG. 4. Gross specimen of ureteral stump opened longitudinally demonstrates tumor projecting in lumen. Proximal 2½ cm. of ureter are unremarkable.
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only approximately 1 per cent of all carcinomas of the upper urinary tract. It is a disease that favors the male population 2 to 1 but also is seen more often in patients in the sixth, seventh and eighth decades. 13 This patient is extremely young for such a tumor but has a good prognosis since grade 1 ureteral tumors are reported to have an 80 per cent 5-year survival rate. This case again proves the adage that gross hematuria is cancer until proved otherwise and raises the question of whether patients with ureteral stumps secondary to previous non-neoplastic nephrectomy should have a retrograde ureterogram and washing cytologies performed at the time of each cystoscopic examination.14 REFERENCES 1. Kittredge, W. E. and Crawley, J. R.: Surgical renal lesions associated with pregnancy. J.A.M.A., 162: 1353, 1956.
2. Bergman, H.: The Ureter. New York: Harper & Row, Publishers, 1967. 3. Crabtree, E.G. and Prather, G. C.: Clinical aspects ofpyelonephritis in pregnancy. New Engl. J. Med., 202: 357, 1930. 4. Folger, G. K.: Pain and pregnancy; treatment of painful states
FIG. 5. Microscopic section of tumor and ureteral wall. Neoplastic transitional cells extend to junction of lamina propria and muscularis. At several foci cells have invaded superficially muscularis. There was no extension through entire ureteral wall. The pathological diagnosis then is hydronephrosis of the left kidney (1977), chronic pyelonephritis of the left kidney (1977), rupture of the left kidney (1977) and grade 1 to 2 transitional cell carcinoma with superficially focal invasion of the left ureteral stump (1978). DISCUSSION
Dr. Warren W. Koontz, Jr. This patient presents several important points. First, it is not unusual that a patient with a well differentiated grade 1 to 2 transitional cell carcinoma would have a negative cytological examination, even if the specimen was adequate from the left ureteral stump. The National Bladder Cancer Collaborative Group-A report revealed that only 43 to 47 per cent of the patients studied with grade 1 to 2 transitional cell carcinoma of the bladder had positive urine cytologies. 12 However, if one looked at the grade 3 to 4 lesions the percentage of positive cytological examinations increased to 93 per cent. For low grade ureteral tumors brush cytological examination is better than ordinary bladder washing cytologies. Primary tumors of the ureter are infrequent and account for
complicating pregnancy, with particular emphasis on urinary calculi. Obst. Gynec., 5: 513, 1955. 5. Abeshouse, B. S.: Rupture of the kidney pelvis: review of the literature. Surg., Gynec. & Obst., 60: 710, 1935. 6. Polkey, H.J. and Vynalek, W. J.: Spontaneous nontraumatic perirenal and renal hematomas. Arch. Surg., 26: 196, 1933. 7. Brettler, A.: Primary carcinoma of the ureter. Canad. Med. Ass. J., 88: 1169, 1963.
8. McIntyre, D., Pyrah, L. N. and Raper, F. P.: Primary ureteric neoplasms. With a report of forty cases. Brit. J. Urol., 37: 160, 1965.
9. Amar, A. D.: Squamous cell carcinoma of the ureteral stump 40 years after nephrectomy. J. Urol., 91: 337, 1964. 10. Sternberg, J.: Radiation risk in pregnancy. Clin. Obst. Gynec., 16: 235, 1973. 11. Bibbo, M., Gill, W. B., Harris, M. J., Lu, C. T., Thomsen, S. and
Wied, G. L.: Retrograde brushing as a diagnostic procedure of ureteral, renal pelvic and renal calyceal lesions. A preliminary report. Acta Cytol., 18: 139, 1974. 12. National Bladder Cancer Collaborative Group-A: Cytology and histopathology of bladder cancer cases in a prospective longitudinal study. Cancer Res., 37: 2911, 1977. 13. Persky, L., Kursh, E. D. and Soloway, M.: Uroepithelial tumors. In: Urology in Practice. Edited by C. J. Devine, Jr: and J. F. Stecker, Jr. Boston: Little Brown & Co., pp. 653-690, 1978. 14. Summers, J., Wilkerson, J. and Foster, S.: Transitional cell carcinoma and residual ureters after nephrectomy for infection. J. Urol., 108: 246, 1972.