Back pain, hematuria, and positive urinary cytology

Back pain, hematuria, and positive urinary cytology


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M.D. M.D. M.D.



From the Departments Columbia-Presbyterian

of Urology, Medicine, Radiology, Medical Center, New York

Case Presentation ABBIE I. KNOWLTON, M.D.+: This sixty-eightyear-old Hispanic woman was admitted to the Columbia-Presbyterian Medical Center for investigation of left flank pain of one months duration. At age sixty-two, the patient was seen for the first time because of back pain. In her urine she was found to have a trace of albumin (5+) 5 to 10 white and many red blood cells per high-power field. The urine culture was negative for bacteriuria. She received a course of sulfisoxazole, and repeat urinalysis revealed no red blood cells. Findings on intravenous pyelogram (IVP) were normal, and cystoscopy revealed trigonitis and a tight urethral meatus. One year later, she returned with a one-week history of dysuria and hematuria. Urine cultures again were negative for bacteriuria, and after another course of sulfisoxazole, microscopic hematuria persisted. A complete blood cell count and blood chemistry determinations (SMA-12, SMA-6) were normal, but the erythrocyte sedimentation rate (ESR) was 31 mm./hr. Many red blood cells continued to show in the urinary sediment. A tuberculin skin test (PPD) was negative. At age sixty-four, she returned and because of an elevated blood pressure 170/110 mm. Hg, methyldopa therapy was started. Later in the same year, she again complained of back pain, and her urine sediment was loaded with red blood cells with enterococci isolated on urine culture. After ampicillin treatment, follow-up culture was negative but microscopic hematuria persisted. Repeat IVP and chest x-ray film were unremarkable. A suspicious area was seen in the urinary bladder, but findings on repeat examination were normal. Three separate


*This case record was edited by Nicholas A. Romas, M.D. (Urology), and Myron Tannenbaum, M.D. (Pathology). t AssociateClinical Professorof Medicine.


and Pathology,

urine cytologic determinations were positive for malignant cells. She was instructed to have careful follow-up because of the positive findings. She was lost to follow-up until age sixty-eight when she returned complaining of low back pain radiating to her right leg. In the interim, at age sixtyfive, she had been in another hospital because of hematuria, and a right nephrectomy had been performed. The pathologic report from this hospital was: hydronephrosis and hydroureter with acute and chronic pyelonephritis, arterial and arteriolar changes consistent with nephrosclerosis. After discharge, hematuria recurred, and eight months after her initial kidney operation she underwent a second operation. According to the patient “a drain was placed” and removed subsequently. No further hematuria was noted. At age sixty-eight, six months before her last admission to Columbia-Presbyterian Medical Center, she had increased chronic back pain. Two months prior to admission, the pain became severe and radiated to the right thigh. One month later this diminished, but left flank pain radiating to the left hip and thigh then developed. She also noted anorexia and a JO-pound weight loss. Her history was otherwise unremarkable except she was a heavy cigarette smoker for approximately eighteen years, and she had a family history of hypertension. Physical examination showed she was obese with a right flank scar, a 22-cm. scar in the right lower abdominal quadrant, and a I5-cm. midline subumbilical scar. There was a questionable mass in the right lower quadrant, but no distention or tenderness was present. There was tenderness over the lumbar spine and pain on the left side on straightleg raising, but her reflexes were normal. Complete blood cell count and chemistries (SMA12, SMA-6) were within normal limits except for an elevated calcium of 11.2 mg./lOO ml. The urine revealed proteinuria (trace) with many white blood

cells and 2 to 3 red blood cells per high-power field.


/ JUNE1980


The urine culture and 3 urinary cytologic determinations were negative. Treatment with saline infusions returned the calcium to a normal range. At cystoscapic examination, chronic cystitis was noted, and no right ureteral orifice was visualized. She was intermittently febrile with negative blood cultures. Treatment with cephalexin was started with no change in her febrile course. She died of a sudden cardiac arrest. Differential


NICHOLAS A. ROMAS, M.D. *: Her history begins at age sixty-two when she was seen for low back pain, and she was found to have microscopic hematuria and sterile pyuria. In spite of the negative culture, she was treated with sulfonamide, and repeat urinalyses were negative. The IVP was reported as normal, and cystoscopy revealed urethral stenosis with trigonitis (3+) which could explain the microscopic hematuria. In light of the sterile pyuria, the urologic staff considered tuberculosis; but the skin test was negative, and no cultures were obtained for tuberculosis. In the urinary tract, the incidence of this disease with a negative skin test result is rare. In fact, the laboratory will not accept urine for tuberculosis culture unless there is a positive skin test result or a strong clinical suspicion. What else could explain these findings? In chronic pyelonephritis often there are pathogens in the urinary sediment, and only after multiple cultures do they become apparent. At this time, the most likely diagnosis is chronic cystitis with associated urethral stenosis which is common in the female patient. One year later she returned with a history of dysuria and gross hematuria, but no comments were made as to whether there were any other associative symptoms. Her urine culture again was negative, but after treatment with sulfonamide, she still had persistent hematuria. This often is evidence of an occult urinary tract malignancy, but repeat IVP and cystoscopy were unremarkable. The only abnormality was an elevated ESR. She was not seen again until one year later when she had an elevated blood pressure and treatment with methyldopa was instituted. This finding was not unexpected since there was a strong family history of hypertension. Again she was seen for low back pain, microscopic hematuria, and, for the first time, her urine culture was positive for microorganisms. I am not certain how this specimen was procured for we all know the difficulty in obtaining proper specimens in the female patient. She was treated with ampicillin, and while her culture became negative microscopic hematuria persisted. As an outpatient, she was found to have a suspicious lesion on the trigone of the urinary bladder, at which time she was admitted to the urology

service. Repeat IVP was thought to be normal, and a repeat cystoscopy was unremarkable. However, urinary cytologic examination of three separate urinary specimens were reported to be positive for malignant cells. Carcinoma in situ was suspected, and the patient was advised to return in three months for biopsy of the bladder. Carcinoma in situ may be suspected usually when erythematous patches are noted on the urothelium, and it also has been reported on urothelium which may appear to be grossly normal. I would like to emphasize the importance of positive urinary cytologic findings when reported by a well-trained and reliable pathologist such as Dr. Tannenbaum. With positive urinary cytology, it is possible to detect transitional cell carcinoma as early as three months or as late as five to seven years before it appears clinically. Unfortunately we did not have the opportunity to follow up this patient, and she was seen three years later complaining of low back pain which radiated down her leg. This brings us to the present admission. She reports that she underwent removal of her kidney at another hospital. Because of recurrent hematuria, eight months later she underwent a second operation but was unable to state what was done at this procedure. Interestingly the patient had not experienced any further bleeding after the second operation. The pathologic report indicated hydroureteronephrosis with pyelonephritis. The past findings of a positive urinary cytology could be indicative of a renal parenchymal tumor, metastatic disease, or urothelial tumor. May we review the radiologic studies at this time? JOHN H. M. AUSTIN, M.D. f : An intravenous urogram done at Columbia-Presbyterian Medical Center prior to her right nephrectomy, shows a normal outline of the two kidneys and normal calyces bilaterally. The right ureter appears to be normal until about a third of the way down, where a slight convexity narrows the ureter and apparently blocks further passage of the contrast material (Fig. 1A). On a right posterior oblique projection (i.e., the right posterolateral aspect of the patient is against the cassette and the x-ray beam enters the patient anterolaterally on the left), a thin arcuate line of contrast medium is just barely seen. Distally, the right ureter is not evident. The left ureter and urinary bladder appears to be normal. It would be most unusual for focal narrowing, this eccentric and gradual, to represent a calculus or blood clot. Neoplasm, intrinsic or extrinsic, must be the first consideration, Unfortunately, we have no data on the inferior extent of the lesion. On her last admission, her left kidney was slightly enlarged, presumably representing compensatory hypertrophy after right nephrectomy. An important finding is that the right lateral margin of the vertebral body at L4 is absent on frontal view. On lateral view, most of the anterior margin

-“Associate Professor of Clinical Urology.











of Clinical





dj lymph node, massiwly replaced by metastati r section shows 2 nests ofmctastatic moderat ,ir, magnajication x 2001. (C) Lumbar spine with destru 1’ ,s

iA) Cross w&on of para-aortic arising in uwter . (B) Microscopic

carcinoma transitional cell carcinoma metastatk tumor.


tumor; chronic urinary trac : infection; cardiac arrest secondary to :n~lmonary Pathologic

hypertension; embolus.


MARIA SHEVCHUK, M.D.*: Pathologically, we have two basic disease processes, i.e., her underlying disease process is apparently present for at least six years, and the second is al acute terminal illness. We will discuss them in that order. The pathologic report from the other hcspital, which we must depend on since we were not privy to review the slides, indicates that the patient did have two operations. The first operation wa,; a nephrectomy with removal of the proximal ureter. As Dr. Romas mentioned, the pathologic repot was significant hydronephrosis and infection as well as nephrosclerosis which most patients have a: age sixty-eight. Therefore, at that point there was a markedly dilated renal pelvis and upper ureter, and no cause for this dilatation was found. eight months later, was The second operation, performed for the removal cf the rest of that ureter, at which time transitional ~:ell carcinoma that had invaded through all the layers of the ureter and had spread into the periureteric fat was found. At autopsy, the patient wis examined for the consequences of the ureteric c:.rcinoma with particular attention to the lumbar spirle. In the area of aortic bifurcation there was a large mass which was apparently a para-aortic 1 {mph node (Fig. 2A). Histologically, there was a tllin crescent of lymphoid --*Instructor, Department of Pathology.


/ JUNE 1980 / VOLUME


nd cPII ~‘ntiatrd


tissue and extensive replacement i’> rldtastatic tumor. On higher magnification, we ret flize the classic appearance of a moderately drf L ntiated transitional cell carcinoma (Fig. 2A). I’~I inlarged lymph node with metastatic tumor was x lj iaccent to the L4 vertebral body, and it was the p t ologist’s impression that the tumor seemed to spi but from the lymph node and invaded the vertc 1 al body (Fig. 2C). The metastatic tumor virtually cll~troyed the whole vertebral body. Histologically tlhe bone was entirely replaced by metastatic tumo N#viththe same appearance of the lymph node r~ t tastasis. There was metastasis also in the right ad -Ilal. The remainder of her urinary tract was unrem: ~rl~able. This bring us to the other basic patholt TIC entity in this woman which is the terminal illSip ss. She suffered a massive pulmonary embolus, thl’ ,8a-called saddle embolus which involved both Illlmonary veins (Fig. 3). Thrombosis was found in tile deep pelvic veins, and this may have been the source of the pulmonary embolism. As you know, I.~ulmonary embolization is a common complication i I patients who are (I) obese, as she was, and (2) immobilized because of pain, surgery, or other conditio~is. Histologically, the lungs showed marked congest io.1 which was associated with the acute emboliz:ltron. No pneumonitis was found. There was ev dence of terminal aspiration because vegetable fit ers were present in the major bronchi, but they h:d not yet incited an inflammatory response. In summary, the two basic pathologic pr :ilcesses in this case were a ureteral carcinoma with netastasis and a terminal pulmonary embolizaticln which is common in these cases. Every clinicopathological exercise, I think, should have a message or a lesson


FIGURE 3. Close-up of saddle main branches of pulmonary embolus.

embolus; note both vein occluded by

to be learned for future patient care. This case brings out several points. The first is to respect positive urinary cytologic findings, particularly if there are three consecutive positive specimens that are diagnosed in a competent laboratory. As Dr. Romas mentioned in those cases, one can expect a lesion to appear somewhere in the transitional epithelial system, i.e., the renal pelvis, ureter, or bladder. In this case the lesion apparently was present but was minimal and was not detected early. The second is, if a patient has hematuria, particularly in the absence of bacteriuria and in an older age group, cystitis should not be assumed without an adequate workup, and the patient should not be lost to follow-up. The third is, if hydronephrosis and hydroureter are found, it is the responsibility of the clinician to find the cause. Apparently the x-ray films showed the patient had a mild degree of hydroureter and hydronephrosis early on in her clinical course. She certainly had a significant degree while she was in the other hospital, but an extensive search for the cause of the unilateral hydronephrosis apparently was not done. The point to remember is that transitional cell carcinoma of the renal pelvis and of the ureter can be noninvasive and superficial for several years and can shed malignant cells and cause hematuria. Once these tumors become invasive, they are fatal frequently. Therefore, it behooves the


clinician to try to identify these lesions early when the cure rate is virtually 100 per cent and prevent the course of events that occurred in this case. DOCTOR ROMAS: I would like to ask you about the source of the massive embolus which appears so large in your slide. DOCTOR SHEVCHUK: We usually do not dissect the legs to any degree because this causes problems for the mortician. If we have to find thromboses, we try to approach from above and obtain as much vasculature as possible without making an incision on the leg. The veins are small and do not appear to be the source of the embolus, but she could have had more emboli in her vena cava which then embolized into the lung. DOCTOR ROMAS: What about the rest of the urinary bladder and the left ureter? Is there any evidence of carcinoma in situ? DOCTOR SHEVCHUK: That is virtually impossible to determine on autopsy material unless the autopsy is done very soon after death. Transitional epithelium undergoes such degeneration that we rarely see transitional cells, and with carcinoma in situ, it is impossible to see. If small papillary tumors were present, the architecture would reveal the lesions not the cytologic examination. DOCTOR KNOWLTON: Are there any further comments? DOCTOR AUSTIN: Even though we did not show it, one radiologic sign is worth mentioning: a ureteral calculus usually causes ureteral spasm, so distal to the calculus the ureter immediately narrows. On the other hand, a neoplasm arising from the ureteral mucosa may occupy the lumen but will not cause spasm, so distal to the tumor the ureter is not narrowed. If the mass is large enough to dilate the lumen, then immediately inferior to the tumor the lumen is dilated. This is known as the Bergman sign. This observation is a useful differential point in determining if a focal obstruction is calculous or neoplastic. Anatomic


Transitional cell carcinoma of right ureter with metastasis to vertebrae, para-aortic node, and right adrenal; pulmonary embolus (massive). References 1. Koss LG: Cytology in the diagnosis of bladder cancer, in Cooper EH, and William RE (Eds.): The Biology and Clinical Management of Bladder Cancer, London. Blackwell Scientific Publications, 1975, p. 111. 2. Richie JP: Management of ureteral tumors, in Skinner DG, and deKernion JB (Eds.): Genitourinary Cancer, Philadelphia, W. B. Saunders Co., 1978, p. 150.

Preparation of this Case Record has been made possible by a generous grant to the Columbia-Presbyterian Medical Center from Norwich-Eaton Pharmaceuticals



JUNE 1980