PRIMER ON
`KIDNEY DISEASES
`
`Second Edition
`
`EDITOR
`ARTHUR GREENBERG
`Division of Nephrology
`· Department of Medicine
`Duke University
`Durham, Nonh Carolina
`
`ASSOCIATE EDITORS
`
`Alfred K. Cheung
`Division of Nephrology and Hypertension
`University of Utah School of Medicine
`and Veterans Affairs Medical Center
`Salt Lake City, Utah
`
`Ronald J. Falk
`Department of Medicine
`Division of Nephrology
`University of North Carolina
`Chapel Hill, North Carolina
`
`Thomas M. Coffmann
`Division of Nephrology
`Department of Medicine
`Duke University and Durham
`Veterans Administration Medical Center
`Durham, North Carolina
`J. Charles Jennette
`Department of Pathology
`and Labf}ratory Medicine
`University of North Carolina
`Chapel Hill, North Carolina
`
`Nl=National Kidney Foundation™
`
`San Diego
`
`London
`
`ACADEMIC PRESS
`Boston
`New York
`
`Sydney
`
`Tokyo
`
`Toronto
`
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`Bahnson 1998
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`

`

`The opinions expressed and approaches recommended are those of
`the authors and not those of the National Kidney Foundation or Academic
`Press. Great care has been taken by the authors and editors to maintain
`the accuracy of the information contained herein. However, neither
`Academic Press nor the National Kidney Foundation nor the editors and
`authors can be held responsible for errors or for any consequences arising
`from the use of this information.
`
`This book is printed on acid-free paper. @
`
`Copyright © 1998, 1994 by National Kidney Foundation
`
`All Rights Reserved.
`y form or by any
`No part of this publication may be reproduced or transmitted in
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`Library of Congress Cataloging-in-Publication Data
`
`Primer on kidney diseases I edited by Arthur Greenberg ... {et al.}.
`p.
`cm.
`Includes index.
`ISBN 0-12-299090-0
`1. Kidneys--Diseases. 2. Nephrology.
`II. National Kidney Foundation
`date.
`[DNLM: 1. Kidney Diseases. 2. Kidney--Pathology. WJ 300 N2773
`1994)
`1994
`RC902.N28
`616.6' l--dc20
`DNLM/OLC
`for Library of Congress
`
`I. Greenberg, Arthur,
`
`94-26276
`CIP
`
`PRlN'IED IN CANADA
`97
`98
`99 00 01
`
`02 FR 9 8
`
`7 6 5 4
`
`3 2 1
`
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`

`58. Renal and Urinary Tract Neoplasia
`
`371
`
`rected. Infection usually cannot be eradicated in patients
`with nephrolithiasis without removal of the calculi, either
`by surgical means (in the case of larger or staghorn calculi)
`or by lithotripsy (in the case of smaller stones). Patients
`with indwelling catheters will continue to develop episodes
`of infection despite treatment of individual episodes as they
`arise. Infections caused by pseudomonas and enterococci
`are especially prone to recurrence. Chronic and recurrent
`infections of the urinary tract may lead to suppurative
`sequelae or to loss of functioning renal tissue with subse(cid:173)
`quent impaired renal function.
`
`Prevention
`
`Urinary catheters should not be used unless they are
`medically indicated. Sterile insertion and maintenance of a
`closed catheter system can reduce the incidence of catheter(cid:173)
`associated urinary tract infections. Condom catheters may
`be an alternative. As the prevalence of infection increases
`with the duratiqn of catheterization, catheters should al(cid:173)
`ways be removed as soon as possible. In particular, the
`junction between the distal catheter and the collecting sys(cid:173)
`tem should remain closed, downhill gravity drainage should
`be maintained at all times, and sterile technique should be
`used whenever urine is drained from the collecting bag.
`Detailed guidelines for prevention of catheter-associated
`infections have been published elsewhere. Antimicrobial
`prophylaxis has no ·value in chronically catheterized pa(cid:173)
`tients or in most patients with intermittent asymptomatic
`
`bacteriuria. Antimicrobial prophylaxis should be provided
`to patients undergoing prostatic surgery or other urological
`procedures since such prophylaxis prevents postoperative
`urinary tract infection and urosepsis. All pregnant women
`should be screened for bacteriuria in the first trimester and
`treated if positive.
`
`Bibliography
`Hooton TM, Scholes D, Hughes JP, et al.: A prospective study of
`risk factors for symptomatic urinary tract infections in young
`women. N Engl J Med 355:468-474, 1996.
`Johnson JR, Stamm WE: Urinary tract infections in women: Diag(cid:173)
`nosis and treatment. Ann Intern Med 11:906-912, 1989.
`Lipsky BA: Urinary tract infections in men: Epidemiology, patho(cid:173)
`physiology, diagnosis, and treatment. Ann Intern Med 110:138-
`150, 1989.
`Schaeffer AJ, Jones JM, Dunn JK: Association of in vitro Esche(cid:173)
`richia coli adherence to vaginal and buccal epithelial cells with
`susceptibility of women to recurrent urinary tract infections.
`N Engl J Med 304:1062-1066, 1981.
`Stamm WE: Catheter-associated urinary tract infections: Epidemi(cid:173)
`ology, pathogenesis, and prevention. Am J Med 91(Suppl
`3B):65S-71S, 1991.
`Stamm WE, Hooton TM, Johnson JR, et al.: Urinary tract infec(cid:173)
`tions: From pathogeneis to treatment. J Infect Dis 159:400-
`406, 1989.
`Stamm WE, Hooton TM: Management of urinary tract infections
`in adults. N Engl J Med 329:1328-1334, 1993.
`Strom BL, Collins M, West SL, Sreisberg J, Weller S: Sexual
`activity, contraceptive use, and other risk factors for symptom(cid:173)
`atic and asymptomatic bact~riuria. Ann Intern Med 107:816-
`823, 1987.
`
`RENAL AND URINARY TRACT NEOPLASIA
`ROBERT R. BAHNSON
`
`It is estimated that in 1996, approximately 83,000 individu(cid:173)
`als will be diagnosed with cancer of urinary organs (bladder,
`kidney, and other urinary) and roughly 24,000 deaths from
`urinary neoplasia will occur. In addition, more than 317,000
`men will be diagnosed with cancer of the prostate and more
`than 41,000 will die from this common malignancy (Table
`1). Neoplasms of the kidney, renal pelvis, ureter, bladder,
`and prostate will be discussed separately highlighting their
`etiology, pathology, diagnosis, staging, and treatment.
`
`RENAL NEOPLASMS
`·Etiology
`The most common cancer of the kidney is renal cell
`carcinoma. The tumor is more common in men, with a
`male : female ratio of roughly 2: 1. It is generally a tumor
`of adults, with peak incidence between the fifth and seventh
`decades of Jife. A recessive oncogene located on chromo(cid:173)
`some 3p (short arm) is associated with the formation of
`
`Primer on Kidney Diseases, Second Edition
`
`j
`
`Copyright 1998 © by the National Kidney Founciation
`All rights or reproduction in any form reserved.
`
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`

`372
`
`Robert R. Bahnsen
`
`TABLE I
`
`Estimated new cases of urinary
`organ cancer
`
`Estimated deaths from urinary
`organ cancer
`
`Men
`Women
`Total
`
`Bladder
`38,300
`14,600
`52,900
`
`Kidney and
`other urinary
`18,500
`12,100
`30,600
`
`Prostate
`317,000
`
`Bladder
`7800
`3900
`11,700
`
`Kidney and
`other urinary
`7300
`4700
`12,000
`
`Prostate
`41,400
`
`both sporadic and familial renal cell carcinoma. This obser(cid:173)
`vation is supported by findings of loss of chromosome 3p
`alleles in renal cell carcinomas from patients with von
`Rippel-Lindau (VHL) disease. VHL syndrome is a heredi(cid:173)
`tary disease characterized by spinal and cerebellar heman(cid:173)
`gioblastomas, retinal angiomas, pheochromocytomas, renal
`and pancreatic cysts, cystadenomas of the epididymis, and
`renal cell carcinomas. From 28 to 45% of VHL patients
`will develop renal cell carcinomas of the clear cell type.
`The tumors in these patients occur early in life (mean age
`at diagnosis is 39 years) and are frequently multiple and
`bilateral. No definite causal relC1;tionship between environ(cid:173)
`mental carcinogens and the development of renal cell carci(cid:173)
`noma has been documented.
`Patients with chronic end stage renal disease (ESRD)
`often develop acquired cystic disease of the kidney
`(ACDK). Approximately 1 to 4% of these patients develop
`renal carcinoma. This rate i's roughly three to six times
`greater than that of the general population.
`
`Pathology
`The proximal tubular cell has been identified by electron
`microscopy and monoclonal antibodies as the origin of
`renal cell carcinoma. The tumor is generally composed of
`four common histologic types: clear cell, granular cell, tu(cid:173)
`bulo papillary, and sarcomatoid. These cells grow in solid
`sheets, trabecular patterns, or less commonly in papillary
`configurations. The sarcomatoid renal cell carcinoma is also
`known as the bone-metastasizing variant because of its
`predilection for bony metastases. This histologic subtype
`is characterized by aggressive clinical behavior and a
`poor prognosis.
`
`Diagnosis
`Renal cell carcinoma has often been called the internist's
`tumor due to the variety of its presentation and the uncom(cid:173)
`mon number of systemic syndromes that have been re(cid:173)
`ported to occur in patients with the disease (Table 2). The
`classic triad of flank pain, palpable mass, and hematuria is
`present in only 10% of patients and is often an indication
`of advanced disease. The majority of clinically confined
`renal tumors are now discovered serendipitously by ultra(cid:173)
`sound, computed tomography (CT), and magnetic reso(cid:173)
`nance imaging (MRI). As an initial radiologic test, ultra(cid:173)
`sound can distinguish cystic, solid, and complex renal
`masses. Any mass that does not meet the criteria for simple
`
`cyst should be further evaluated by CT. As a single diagnos(cid:173)
`tic imaging study_, CT scanning is probably the best method
`to evaluate a suspected renal mass lesion as it gives fairly
`reliable information about the local extension of tumor,
`lymph node involvement, and presence of tumor thrombus
`in the renal vein or inferior vena cava. Renal arteriography
`is seldom necessary unless required for· the planning of
`parenchyma sparing surgery.
`The issue of screening for renal cell carcinoma in VHL
`and ACKD is controversial (see Chapter 45). Since renal
`involvement in VHL occurs in 28 to 66% of patients and
`bilateral renal cell cancers develop in 63 to 75% of those
`with renal lesions it has been recommended by some that
`such lesions be followed by annual CT examinations.
`ACKD increases significantly in frequency after 3 years
`of dialysis. As in VHL, CT is probably the best imaging
`technique. Clearly any patient with VHL or ACKD with
`symptoms or hematuria should undergo a complete im-
`aging evaluation.
`·
`
`Staging
`Staging of kidney carcinoma is best performed using the
`tumor, node, metastases {TNM) classification agreed on by
`the International Union Against Cancer and the American
`Joint Committee on Cancer {Table 3). Cost effective clini(cid:173)
`cal staging of patients can be accomplished with a history
`and physical exam, chest X ray, liver function tests, and
`serum calcium determination. The most frequent sites of
`metastases in decreasing order of frequency are lymph
`nodes, lung, liver, and bone. Patients with a palpable liver
`or abnormalities of liver functions should have further ra(cid:173)
`diographic or radionuclide imaging of the liver. Symptoms
`of skeletal involvement or an increase in serum calcium or
`alkaline phosphatase should prompt a radionuclide bone
`scan.
`
`Treatment
`The only successful treatment for patients with localized
`renal cell carcinoma is surgical extirpation. Radial nephrec(cid:173)
`tomy, removal of the kidney with its surrounding fascia!
`envelope (Gerota's) and the ipsilateral adrenal gland, is
`the preferred surgical approach. The 5-year survival of
`patients with node negative tumors without metastases
`ranges from 47 to 82%. The presence of positive lymph
`nodes or distant metastasis augurs poorly for survival be(cid:173)
`yond 2 years. Regrettably,. radiation therapy and chemo-
`
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`58. Renal and Urinary Tract Neoplasia
`
`373
`
`TABLE 2
`Incidence of Systemic Syndromes in Patients
`with Renal Cell Carcinoma
`
`Syndrome
`
`Raised erythrocyte sedimentation rate
`Hypertension
`Anemia
`Cachexia, Weight loss
`Pyrexia
`Abnormal liver function
`Raised alkaline phosphatase
`Hypercalcemia
`Polycythemia
`Neuromyopathy
`Amyloidosis
`
`%
`
`55.6
`37.5
`36.3
`34.5
`17 .2
`14.4
`10.1
`4.9
`3.5
`3.2
`2.0
`
`therapy have been of limited value in this disease. Several
`studies have failed to confirm an advantage to treated pa(cid:173)
`tients who received either pre- or postoperative radiother(cid:173)
`apy. Multiple, single agent, and combination chemotherapy
`trials have proven that renal cell carcinoma is highly resis(cid:173)
`tant to commonly employed cytoxic agents. The single most
`active drug appears to be vinblas~ine, but objective re(cid:173)
`sponse rates are too low to justify its routine use.
`The most promising therapy of metastatic renal cell carci(cid:173)
`noma in the past decade has been immunotherapy. Non(cid:173)
`specific active, systemic immunotherapy with bacillus
`Calmette-Guerin (BCG) or Cornybacterium parvum has
`shown only modest success. Cytokine therapy utilizing in(cid:173)
`terferons has shown response rates reported in the 15 to
`20% range. Most patients who respond have undergone
`nephrectomy, have an excellent pretreatment performance
`status, and have limited pulmonary metastases. Rosenberg
`and colleagues at NCI have used adoptive immunotherapy
`with lymphokine-activated killer (LAK) cells and interleu(cid:173)
`kin-2 (IL-2). They reported a 35% objective response rate
`in 72 patients with renal cell carcinoma. Since then, efforts
`of this group have focused on using genetically altered
`tumor infiltrating lymphocytes (TIL) which are grown from
`single-cell tumor suspensions cultured in IL-2. Response
`rates of 0 to 33% have been reported in five trials of combi(cid:173)
`nation IL-2fflL in patients with metastatic renal cell car(cid:173)
`cinoma.
`
`Other Renal Tumors
`
`Renal Oncocytoma
`Oncocytomas constitute approximately 5% of solid renal
`neoplasms and invariably pursue a benign course. Micro(cid:173)
`scopically these tumors are composed of polygonal cells
`with intense eosinophilia, granular cytoplasm, and abun(cid:173)
`dant mitochondria. Grossly, on cut section, these tumors
`have brown pigmentation and are often associated with a
`central scar. The origin of these tumors is thought to be
`the distal collecting tubule. Because preoperative diagnosis
`is difficult and because oncocytomas can coexist with renal
`
`cell carcinoma, the treatment of choice is radical ne(cid:173)
`phrectomy.
`
`Angiomyolipoma
`Angiomyolipomas are hamartomas composed of blood
`vessels, adipocytes, and abundant smooth muscle. They are
`seen commonly in patients with tuberous sclerosis and have
`a tendency to multiplicity and bilaterality. The fat content
`of these lesions often permits radiographic diagnosis with
`CT imaging. Asymptomatic tumors under 4 cm may be
`observed with radiographic monitoring. Symptomatic le(cid:173)
`sions can often be treated with angioinfarction. If surgery
`is required, excision of the lesion using renal parenchymal
`sparing techniques should be attempted because of the
`tendency toward multiplicity and bilaterality.
`
`Sarcomas
`Sarcomas represent less than 5% of all malignant tumors
`of the kidney. The most common sarcoma is leiomyosar(cid:173)
`coma. Others include osteogenic sarcoma, liposarcoma,
`carcinosarcoma, fibrosarcoma, rhabdomyosarcoma, and
`malignant fibrous histiocytoma. The treatment of choice
`for all of these tumors is radical nephrectomy, if possible.
`
`Metastatic Tumors
`Because of their rich vascularity, the kidneys are fre(cid:173)
`quently the site of metastatic spread. These tumors are
`often asymptomatic and discovered· only at autopsy.
`Lymphoma is probably the _most common metastatic neo(cid:173)
`plasm of the kidney; it may involve the renal parenchyma
`diffusely. With the exception of lymphomatous involve(cid:173)
`ment which may respond to systemic therapy, treatment is
`usually unnecessary since the patient's prognosis from their
`primary tumor is almost uniformly poor.
`
`RENAL PELVIC AND URETERAL TUMORS
`
`Epithelial tumors of the upper urinary tract are uncom(cid:173)
`mon. They show a male to female·predo_minance of roughly
`2: 1 and are more common among whites than African(cid:173)
`Americans. Tumors of the upper urinary tracts are common
`in patients with Balkan nephropathy and are more fre(cid:173)
`quently bilateral. These upper tract tumors are commonly
`associated with bladder tumors which occur in 40 to 75%
`of patients at some point in time. Patients with bladder
`tumors have a slight (2 to 13%) chance of developing ure(cid:173)
`teral or renal pelvic tumors.
`
`Etiology
`An increased risk of renal pelvic and ureteral tumors
`has been reported for patients who smoke, abuse analgesics
`(particularly phenacetin), and who have been occupation(cid:173)
`ally exposed to chemicals, petrochemicals, plastics, coke,
`coal, asphalt, and tar. Among these, cigarette smoking is the
`major risk factor for carcinoma of the upper urinary tract.
`
`Pathology
`Transitional cell carcinoma accounts for more than 90%
`of all upper tract urothelial tumors. The remaining 10%
`
`I
`-~
`
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`374
`
`Robert R. Bahnsen
`
`TABLE l
`The St.aging of Kidney Cancer
`
`Primary tumor (T)
`TX
`Primary tumor cannot be assessed
`TO
`· No evidence of primary tumor
`Tl
`Tumor 2.5 cm or less in greatest dimension, limited to the kidney
`Tumor more than 2.5 cm in greatest dimension, limited to the kidney
`T2
`T3
`Tumor extends into major veins or invades adrenal gland or
`perinephric tissues, but not beyond Gerota's fascia
`T3a Tumor invades adrenal gland or perinephric tissues, but not
`beyond Gerota 's fascia
`·
`T3b Tumor grossly extends into renal vein(s) or vena cava
`Tumor invades beyond Gerotas fascia
`T4
`Regional lymph nodes (N)
`The regional lymph nodes are the abdominal para-aortic, paracaval, and renal
`hilar. Laterality does not affect the N classification. The significance of the
`regional lymph node metastasis in staging kidney cancer lies in the number
`and size and not in whether unilateral or contralateral.
`NX Regional lymph nodes cannot be assessed
`NO No regional lymph node metastasis
`Nl Metastasis in a single lymph node, 2 cm or less in greatest dimension
`N2 Metastasis in a single lymph node, more than 2 cm but not more than
`5. cm in greatest dimension, or multiple lymph nodes, none more
`than 5 cm in greatest dimension
`N3 Metastasis in a lymph node more than 5 cm in greatest dimension
`Distant metastasis (M)
`MX
`Presence of distant metastasis cannot be assessed
`MO
`No distant metastasis
`Ml
`Distant metastasis
`AJCC/UICC stage grouping
`Stage I
`Stage II
`Stage III
`
`MO
`MO
`MO
`MO
`MO
`MO
`MO
`MO
`MO
`MO
`MO
`Ml
`
`n
`
`Tl
`T2
`Tl
`T2
`T3a
`T3a
`T3b
`T3b
`T4
`AnyT
`AnyT
`AnyT
`
`NO
`NO
`Nl
`Nl
`NO
`Nl
`NO
`Nl
`AnyN
`N2
`N3
`AnyN
`
`Stage IV
`
`consists of adenocarcinoma, squamous cell carcinomas, and
`inverted papillomas. Nonurothelial tumors are exceed(cid:173)
`ingly rare.
`
`Diagnosis
`The most common presentation of upper tract tumors
`is gross, total (i.e., bloody throughout mict~rition), painless
`hematuria. The presence of string-like clots is suggestive
`of an upper tract origin of the bleeding. The diagnosis is
`confirmed by radiologic imaging, most often with excretory
`or retrograde urography. At the time that retrograde py(cid:173)
`elography is undertaken, saline barbotage and/or brush
`biopsy of the lesion can be performed. Cellular material
`obtained by such maneuvers can be examined cytopatho(cid:173)
`logically to confirm the diagnosis.
`
`Staging
`Metastatic evaluation is best performed utilizing CT
`scanning to assess the presence and degree of local, re(cid:173)
`gional, and distant disease. Staging is illustrated in Table 4.
`
`Treatment
`The treatment of upper tract urothelial tumors almost
`always involves surgical excision. Neither radiotherapy nor
`chemotherapy has been shown in large series to have a
`substantial impact on response or survival. Renal pelvic
`tumors are treated by nephroureterectomy with bladder
`cuff excision because the risk of ipsilateral ureteral or blad(cid:173)
`der tumor recurrence is high (30 to 75%). Upper and mid(cid:173)
`ureteral tumors are best treated by segmental resection if
`the tumors are solitary or low grade, and by nephroureter-
`
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`58. Renal and Urinary Tract Neoplasia
`
`375
`
`TABLE 4
`Staging Systems of Upper Tract Urothelial Tumors
`
`Finding
`Carcinoma in situ
`Noninvasive papillary tumor
`Tumor involving submucosa
`Muscle-invasive tumor
`Tumor invading renal parenchyma
`Tumor invading peripelvic or
`periureteral soft tissue
`Invasion of contiguous organs
`Lymph node metastases
`Distant metastases
`
`Grabstald-
`Cummings
`Stage
`I
`I
`II
`III
`III
`III
`
`IV
`IV
`IV
`
`1987 UICC
`Stage
`Tis
`Ta
`Tl
`T2
`T3
`T3
`
`T4
`(Nl-3)
`Ml
`
`ectomy if they are multiple or high grade. Distal ureteral
`tumors are most effectively treated with distal ureterec(cid:173)
`tomy and ureteroneocystostomy.
`
`BLADDER NEOPLASMS
`
`Bladder cancer is a common urologic tumor that is
`broadly divided into two biologically meaningful subtypes.
`The first is superficial low grade transitional cell carcinoma
`which has as its greatest risk a tendency for frequent recur(cid:173)
`rence within the bladder. The second is invasive high grade
`cancer which often presents in advanced stages and is asso(cid:173)
`ciated with substantial mortality.
`
`Etiology
`Bladder tumors are more frequent in men than women
`(approximately 3: 1) and in older patients. The peak inci(cid:173)
`dence of the disease is the seventh decade of life. Environ(cid:173)
`mental carcinogens have been postulated as the major caus(cid:173)
`ative factor in this cancer. There is a clear causal
`relationship between cigarette smoking and bladder cancer.
`Smokers have at least a fourfold increased risk of develop(cid:173)
`ing bladder tumors, and it is estimated that smoking is
`responsible for the development of one third of all bladder
`tumors. Occupational exposure to aromatic amines is simi(cid:173)
`larly known to predispose a patient to the development of
`bladder cancer. In particular, a high prevalence of bladder
`. tumors has been shown in individuals exposed to aniline
`dyes. Other occupations linked to bladder cancer develop-
`ment include truck driving, painting, and leather working,
`as well as others in which there has been chronic exposure
`to volatile chemicals such as dry cleaning. Similar to upper
`tract urothelial cancers, analgesic abuse is associated with
`an increased risk of bladder tumors. Other putative carcino(cid:173)
`gens include radiation therapy and cyclophosphamide che(cid:173)
`motherapy.
`Bladder irritation from chronic infection or a long-term
`indwelling foley catheter is associated with the develop(cid:173)
`ment of squamous .cell carcinoma. From 2 to 10% of para(cid:173)
`plegics with chronic indwelling catheters develop bladder
`cancer, and approximately 80% are of squamous histology .
`
`In the Nile River Valley, schistosomal infestation of the
`bladder (bilharziasis) is associated with the development
`of squamous cell carcinoma.
`
`Pathology
`The overwhelming majority of bladder tumors are transi(cid:173)
`tional cell carcinomas. Although most bladder tumors arise
`de novo, a number of proliferative lesions of the bladder
`have been identified. These include atypical hyperplasia,
`Von Brunn's nests, cystitis cystica, cystitis follicularis, cysti(cid:173)
`tis glandularis, inverted papilloma, nephrogenic adenoma,
`squamous metaplasia, and leukoplakia.
`Bo~h uroepithelial dysplasia and carcinoma in situ (CIS)
`of the bladder have been documented as preneoplastic
`lesions. Dysplasia is characterized as mild, moderate, and
`severe, and is intermediate between normal uroepithelium
`and carcinoma in situ. CIS is a term reserved for poorly
`differentiated transitional cell carcinoma confined to the
`surface uroepithelium. It may be asymptomatic or associ(cid:173)
`ated with symptoms of bladder irritability such as fre(cid:173)
`quency, urgency, or dysuria. At cystoscopy, it often appears
`as a velvety patch of erythematous mucosa. CIS is fre- ·
`quently (20 to 75%) noted to coexist (in adjacent or distant
`mucosa) with muscle invasive transitional cell carcinomas
`of the bladder. Although the natural history of this disease
`is not fully known, it is of interest that 20% of patients who
`underwent cystectomy for treatment of carcinoma in situ
`were found to have micro~copically invasive cancer. At
`present, the treatment of choice for CIS is intravesical
`instillation of BCG which produces complete regression in
`approximately 50 to 65% of patients.
`As mentioned previously, more than 90% of bladder
`cancers are transitional cell carcinoma. These tumors arise
`most commonly at the bladder neck and lateral bladder
`walls. Roughly 70% are low-grade superficial tumors. While
`the majority of patients will develop a recurrence, only a
`small percentage of these tumors (10 to 15%) will progress
`to the more serious muscle invading tumors. Unfortunatelyt
`80 to 90% of the patients with muscle invasive tumors have
`the diagnosis made at their first presentation. Even more
`sobering is the fact that nearly 50% of this group will already
`have occult distant metastases.
`Much less common are squamous cell carcinoma and
`adenocarcinomas. Squamous cell carcinomas are frequent
`in Egypt because of chronic infection with Schistosoma
`haematobium. In the United States they constitute 3 to 7%
`of tumors and afflict patients with chronic irritation from
`infection, stones, or indwelling catheters. Treatment con(cid:173)
`sists of radical cystectomy, since radiation and chemother(cid:173)
`apy are ineffective. Adenocarcinomas represent less than
`2% of bladder tumors and are most often seen in patients
`born with extrophic bladders or in urachal tumors that
`invade the dome of the bladder. Adenocarcinomas respond
`poorly to radiotherapy or cytotoxic chemotherapy and are
`best treated by exenterative surgery.
`
`Diagnosis
`Patients with carcinoma of the bladder usually (85%)
`present with gross painless hematuria. Although conven-
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`West-Ward Exhibit 1044
`Bahnson 1998
`Page 007
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`376
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`Robert R. Bahnsen
`
`tional cytology, flow cytometry, and quantitative fluores(cid:173)
`cent image analysis have all been -utilized to diagnose blad(cid:173)
`der tumors, the diagnosis is most reliably confirmed by
`cystoscopy and biopsy. Excretory urography is used to rule
`out involvement of the upper tract_s by tumor and to detect
`ureteral obstruction which is almost always a sign of muscle
`invasive cancer ..
`Early detection studies have reported the favorable ex(cid:173)
`perience of using chemical reagent strips to test for hematu(cid:173)
`ria. Approximately 20% of the population was positive and
`8 to 22% of those further evaluated were found to have
`urinary malignancies. Two thirds of the detected tumors
`were bladder cancers. Further studies are necessary before
`screening can be recommended.
`
`Staging
`Clinical staging of bladder patients is essential for plan(cid:173)
`ning therapy. The most important information is the patho(cid:173)
`logic evaluation of the transurethral bladder tumor resec(cid:173)
`tion. Grade and depth of penetration of the tumor into
`the bladder wall determine if the patient has a low-grade,
`superficial or high-grade, infiltrating tumor. Superficial tu(cid:173)
`mors do not require further staging evaluation. Muscle
`infiltrating tumors are best staged with CT scanning to rule
`out lymph node or visceral metastases. Chest radiography
`and serum chemistries should also be performed and if the
`alkaline phosphatase is elevated a bone scan should be
`considered. The most accurate means of detecting lymph
`node metastases is pelvic lymphadenectomy but this is usu(cid:173)
`ally performed at the same time as radical cystectomy. The
`TNM classification of bladder tumors is best utilized for
`staging and is illustrated in Table 5.
`
`Treatment
`Patients with superficial tumors can be managed effec(cid:173)
`tively by transurethral resection. Patients should have fol(cid:173)
`low-up cystoscopy at 3 month intervals for 2 years, then
`every 6 months for 2 years and annually thereafter. This
`can usually be performed in the office using flexible cysto(cid:173)
`scopes. The troublesome feature of superficial tumors is
`their 70% recurrence rate.
`Patients who are judged to have a high risk of recurrent
`tumor because of increased grade or stage, multiple tumors,
`or a history of recurrence can be treated with intravesical
`chemotherapy or immunotherapy. Thiotepa, doxorubicin,
`and mitomycin Care cytotoxic agents commonly employed
`in patients with superficial transitional cell carcinoma. They
`have been shown to reduce recurrence rates to 30 to 44%.
`Intravesical BCG has been shown in prospective trials to
`be highly effective in reducing recurrence rates (0 to 41 % ),
`and is currently the favored method of prophylaxis.
`Patients who present with muscle invasive bladder cancer
`can be treated with surgery, radiation therapy, or chemo(cid:173)
`therapy. At present, the most effective local therapy is
`radical cystectomy. Pelvic recurrence rates are 10 to 20%,
`compared to 50 to 70% with radiation therapy, chemother-
`
`apy, or combination of both. The disadvantage of radical
`surgery is the loss of normal bladder function. Radical
`cystectomy in men consists of removal of the pelvic lymph
`nodes, bladder, and prostate. If the tumor is associated
`with diffuse CIS of the bladder or involvement of the pros(cid:173)
`tate, total urethrectomy is included. In women the opera(cid:173)
`tion is commonly called an anterior exenteration and in(cid:173)
`cludes excision of pelvic lymph nodes, bladder, urethra,
`ovary, fallopian tubes, uterus, aµd the anterior wall of the
`vagina. Bladder reconstru.ction usually consists of a ilea]
`conduit or a continent urinary reservoir. The continent
`diversions may be cutaneous, or in eligible men, brought
`down to the urethra. The morbidity of radical cystectomy
`and bladder reconstruction is 25 to 35% and mortality rate
`is 1 to 2%. Five-year survivals of 75% have been reported
`for patients with T2, T3a disease, 44% for T3a, T3b tumors,
`and 36% for T4 lesions.
`Radiation as monotherapy has· not been shown to have
`high cure rates in patients with invasive disease. Five-year
`survival rates have averaged 20 to 35%. Bladder sparing
`protocols utilizing chemotherapy with cisplatin, metho(cid:173)
`trexate and vinblastine (CMV), and radiation therapy
`( 4000 cGy) have been reported. If the patients have a
`comple~e response from this treatment, further radiother(cid:173)
`apy to a total dose of 6480 cGy is given. Patients with only
`a partial response are advised to have a cystectomy.
`Chemotherapy has been utilized primarily in metastatic
`disease but more recently has been used as an adjunct to
`surgery or radiotherapy. Cisplatin is the single most active
`agent, but combination chemotherapy· with methotrexate,
`vinblastinet doxorubicin, and cisplatin (M-VAC) has been
`shown in patients with metastatic disease to be superior in
`a multicenter randomized trial. However, the complete
`response rates are still low and of relatively short duration.
`Chemotherapy prior to planned surgery (neoadjuvant)
`has been advocated to reduce the risk of disease recurrence
`after cystectomy. Proponents of this approach argue that;
`(1) micrometastases may be present at the time of diagno(cid:173)
`sis; (2) micrometastases are eliminated most efficiently
`when the volume of tumor is small (3) downstaging of the
`tumor prior to surgery can occur, and (4) there may be a
`reduction in the chemotherapy access to tumor as a conse(cid:173)
`quence of surgery. As yet, there is no evidence from prop(cid:173)
`erly designed trials to favor this approach. Similarly, no
`well-designed properly executed trials have been per(cid:173)
`formed which show a definite advantage to the use of adju(cid:173)
`vant chemotherapy following surgery. Neverthelesst the
`increased effectiveness of combination chemotherapy
`makes the concept of adjuvant therapy app