Received February 23, 1990; accepted after revision May 20, 1990.

I Both authors: Department of Radiology, Box 3808, Duke University Medical Center, Durham, NC 27710. Address reprint requests to A. A. Leder.

AJR 155:713-722, October 1990 0361-803X/90/1554-0713 C American Roentgen Ray Society

713

Review Article

‘‘. I

Transitional Cell Carcinoma of the Pelvicalices and UreterRichard A. Leder1 and N. Reed Dunnick

Transitional cell carcinoma accounts for about 90% of all can-cers of the renal pelvis and more than 90% of all cancers of theureter. Its clinical presentation is nonspecific. Radiology plays acritical role in detection, evaluation, and disease monitoring. We

reviewed the pathologic and clinical features of transitional cellcarcinoma of the upper urinary tract, with attention to its radio-logic appearance, staging, and treatment.

Primary tumors of the renal pelvis and collecting systemare relatively uncommon. They are less common than renaladenocarcinomas by a ratio of 1 :4 to 1 :5. They are two tothree times more common than ureteral neoplasms. Bladdercarcinomas are 50 times more common than renal pelvictumors, reflecting the larger surface area of the bladdermucosa. Transitional cell carcinoma accounts for approxi-mately 9O% of all cancers of the renal pelvis and over 90%of all cancers of the ureter [1]. The clinical presentation oftransitional cell carcinoma of the pelvicaliceal system andureter is nonspecific. The radiologic evaluation is critical forboth initial detection and subsequent evaluation and diseasemonitoring. The pathologic and clinical features of transitionalcell carcinoma of the upper urinary tract are reviewed, withattention to its radiologic appearance, staging, and treatment.

Pelvicaliceal Transitional Cell Carcinoma

Pathology

Transitional cell mucosa can differentiate into either squa-mous or glandular tissue. Eighty-five percent to 95% of uro-epithelial carcinomas are transitional cell tumors, approxi-mately 1 0% are squamous cell carcinomas, and less than 1%

are adenocarcinomas. Of the transitional cell carcinomas,85% or more are papillary; the rest are nonpapillary.

Grabstald et al. [2] divide the renal pelvic tumors into fourgroups on the basis ofhistologic stage and degree of invasion.

Group I tumors are histologically benign papillomas. They arecomposed of delicate fronds, each with a central fibrovascularcore and usually five to 1 0 cell layers of epithelium. Theindividual epithelial cells are cytologically benign. These cellsclosely resemble normal epithelial cells except for a spindlingtendency. Group II tumors are noninvasive or focally invasivepapillary carcinomas. Group Ill tumors are fully invasive, butconfined to the kidney. Invasion outside the kidney or renalpelvis constitutes a group IV tumor. Each group is furthersubclassified into those without (A) and those with (B) othertumors in the bladder and/or ureter. Modifications to thisstaging system have been made that are analogous to theJewett-Marshall-Strong system for bladder cancer. Higherstage reflects greater depth of tumor invasion [1].

Dow

nloa

ded

from

ww

w.a

jron

line.

org

by 2

7.72

.237

.148

on

09/2

7/14

fro

m I

P ad

dres

s 27

.72.

237.

148.

Cop

yrig

ht A

RR

S. F

or p

erso

nal u

se o

nly;

all

righ

ts r

eser

ved

714 LEDER AND DUNNICK AJA:155, October 1990

Papillary transitional cell carcinomas are exophytic polypoidlesions that are attached by a stalk to the mucosa. Thepapillary type of carcinoma tends to be a low-grade malignantlesion that is slow to infiltrate, is late to metastasize, andfollows a relatively benign course. Nonpapillary carcinomaspresent as nodular or flat tumors. The noninfiltrating, non-

papillary tumors may show only slight thickening of the renalpelvis. Nonpapillary tumors do not produce well-defined fillingdefects. They are typically high-grade malignant tumors andare infiltrative [1-3].

Histologic grading of transitional cell neoplasms is basedon the degree of cellular anaplasia. Grade I tumor cells displaysome anaplasia but are well differentiated and closely resem-ble normal epithelial tissue. Grade II cells are still recognizableas being of transitional origin, however, the number of celllayers is increased, as are the number of mitoses. Tumor cellsof grade III are barely recognizable as being of transitionalorigin, and there are exaggerated layers of cells and morefrequent mitoses. The cells are disarrayed, and superficial celllayers are loosened and fragmented [4].

Etiology

A number of chemical agents may play an important role inthe development of urothelial neoplasms. Occupational ex-posure to beta-naphthylamine, 4-aminobiphenyl, 4-nitrobi-phenyl, or 4,4-diaminobiphenyl is carcinogenic. These com-

pounds are used in the synthesis of azo dyes and pigmentsused in the textile, printing, and plastic industries. N-hydrox-ylation produces even more carcinogenic compounds. Blad-der tumors are more common than upper tract transitionalcell carcinomas because of the time required for hydrolyzingenzymes to become activated. Stasis in the upper tracts mayprovide increased exposure time and therefore upper tracttumors [5]. For example, renal pelvic tumors occur in horse-shoe kidneys at least three times as often as in nonfusedkidneys. The urine stasis present in the horseshoe kidneyprolongs the contact of carcinogens with the collecting sys-tem. In addition, calculi in horseshoe kidneys have beenreported in 21 -60% of cases, and an association may existbetween hydronephrosis, renal calculi, renal infection, andrenal pelvic tumors [6, 7]. No clear interrelationship has beenestablished between these factors, although it could be pos-tulated that metaplasia as a response to inflammation orcalculi may then progress to carcinoma [3].

Other chemical agents have been associated with urothelialmalignant neoplasms. Cyclophosphamide is a biologically in-

active nitrogen mustard that is metabolized by liver micro-somes to several biproducts, at least two of which are cyto-toxic. The upper tract urothelial malignant tumors associatedwith cyclophosphamide therapy are high-grade and extremelyaggressive. It is unclear whether these tumors are due to theimmunosuppressive character of cyclophosphamide or to in-herent carcinogenic properties. Additional urologic effects ofcyclophosphamide include hemorrhagic cystitis and bladderfibrosis with contracture [8, 9].

Thorotrast, a 25% colloidal thorium dioxide suspension,also has been associated with transitional cell carcinoma. The

compound can spread subepithelially because of pyelointer-stitial backflow during retrograde pyelography. This results inpermanent retention in the wall of the renal pelvis and in therenal sinus surrounding fornices and intrarenal vessels. Thefrequency of tumor induction after Thorotrast retrograde pye-lography is 50%, with a latent period ranging from 21 to 35years [10].

Numerous reports have described the association of highlyinvasive transitional cell carcinomas and phenacetin abuse.Phenacetin is an aniline derivative and its major metabolite,N-acetyl-para-aminophenol, is excreted in the urine [1 1]. Thevast majority of these neoplasms have been in the renal pelvis[1 2]. Patients with analgesic nephropathy have widespreadurothelial dysplasia, which predisposes to neoplasia [13].

Ureteral pseudodiverticulosis is associated with epithelialcarcinoma of the urinary tract. Although this may be coinci-dental, it suggests that patients with ureteral pseudodiverti-culosis are predisposed to the development of malignantepithelial tumors. It is unlikely that pseudodiverticula are pre-malignant by themselves. The presence of pseudodiverticulamay increase the susceptibility of the ureteral mucosa tocarcinogenesis, perhaps by serving as multiple small pools ofstagnant urine [14].

Transitional cell carcinoma is more prevalent in patients

from the Balkan states (Yugoslavia, Greece, Rumania, Bul-garia). In these areas, an endemic nephropathy developsslowly (approximately 20 years) and there is no acute phase.In the later phases of the disease, renal failure develops andis accompanied by high urine output. The cause of this formof the disease is obscure, although it may be related todrinking water. It is part of a degenerative interstitial disease.The renal pelvic and ureteral tumors that develop are usuallyof low grade, and of relatively slow evolution. Bilateral tumorsare found in 1 0%, and multiplicity is common [15].

Clinical Findings

The average age at diagnosis of patients with transitionalcell carcinoma is 65 years; approximately 70% of patients aremore than 60 years old at presentation (range, 32-88 years).Males predominate by a ratio of4:1 [1 6]. Gross or microscopichematuria is the most common symptom in patients withrenal pelvic or ureteral tumors. It is present in more than 75%of patients. Flank pain, precipitated by ureteral or ureteropel-vic junction obstruction caused by a tumor mass, occurs inapproximately one fourth of patients. Approximately 1 0% ofpatients have lost weight and less than 5% have other symp-toms. A tumor will be discovered incidentally in less than 5%

of patients [17].

Urine Cytology

Urine cytology can be used in the diagnosis of transitionalcell carcinomas, although the technique is inaccurate and hasa high false-negative rate. Nocks et al. [1 8] reported positivefindings on urine cytology in no patients with grade I tumors,29% with grade II tumors, and 79% with grade Ill tumors.Positive urine cytology was found in 14% of patients with

Dow

nloa

ded

from

ww

w.a

jron

line.

org

by 2

7.72

.237

.148

on

09/2

7/14

fro

m I

P ad

dres

s 27

.72.

237.

148.

Cop

yrig

ht A

RR

S. F

or p

erso

nal u

se o

nly;

all

righ

ts r

eser

ved

Fig. 1.-Low-grade, low-stage transitional cell carcinoma of left renal pelvis. Fig. 2.-Infiltrating renal pelvic transitional cellA, Excretory urogram shows small, smooth filling defect in renal pelvis (arrowhead). carcinoma. Excretory urogram shows large nodu-B, CT scan shows intrapelvic soft-tissue mass (arrow). lar filling defect in renal pelvis with multiple infun-

dibular extensions (arrowheads).

AJR:155, October 1990 URINARY TRANSITIONAL CELL CARCINOMA 715

lesions confined to the renal pelvis, mucosa, or submucosa(stage A); 33% with tumor extending into the renal paren-

chyma or invading the renal pelvis wall but still confined tothe kidney (stage B); 80% with tumor penetrating into theperipelvic or perirenal fat (stage C); and 89% with metastatictumor (stage D). Cytologic samples obtained by barbotage(repeated washings) provide a more reliable sampling of the

upper tract when neoplasia is present. In these instances, theaccuracy of cytologic diagnosis increases from 35% to 60%with voided urine, from 60% to 70% with urine collected

passively by catheter, and from 80% to 90% with lavagedsamples [19].

An improved technique in the diagnosis of upper urinarytract transitional cell carcinomas is fluoroscopically guidedretrograde brush biopsy. Appropriate catheter placement isconfirmed by injecting a small amount of contrast material,and the area of abnormality is brushed vigorously. Maximalsensitivity of the procedure is achieved by using fluoroscopicguidance and dilute contrast material. Water-soluble contrastmaterial may cause changes in the cellular structure of theepithelium on routine cytologic techniques. This appears tobe concentration dependent and is probably related to thehypertonic nature of the contrast media. Because of thepossibility of cellular distortion, the contrast material shouldbe washed away with saline. Alternatively, low-osmolar, non-ionic contrast material or dilute standard 60% diatrizoate maybe used. Contact smears on glass slides are made immedi-ately after withdrawal of the brush guidewire, placed in 95%ethyl alcohol, and sent for subsequent Papanicolaou staining.Brush tips are cut off and sent in carboxymethylcellulosefixative solution for cell-block analysis. A recently reportedschema grading cells from grade I (normal transitional epithe-hum) to grade V (conclusive evidence of malignancy) showeda brush biopsy diagnosis of atypical cells to be stronglysuggestive of malignancy (75% positive predictive value)[20].

Although retrograde brush biopsy has a high diagnosticaccuracy compared with urine cytology, it is not without risk.This consists mainly of flank pain, infection, and gross he-matuna. Mechanical trauma has been reported as a cause ofspread of a ureteral transitional cell tumor. However, this isunusual and seldom pertinent because therapy usually in-cludes nephroureterectomy [21].

When cytology or brush biopsy is inconclusive, uretero-scopic techniques are available to the urologist. Under anes-thesia, the ureteral ostium is dilated and a 12-French, 50-cm-long ureterorenoscope is inserted. Five-French biopsy forcepsand an electroresectoscope can be inserted. This techniqueallows the unequivocal diagnosis of urothelial carcinoma en-doscopically with the ability to obtain biopsy specimens [22].

Plain Films

Plain abdominal radiographs are seldom useful in makingthe diagnosis of transitional cell carcinoma. Rarely, a renalmass may be detected. Renal calculi or tumoral calcification

can be present, although it is uncommon. The prevalence ofcalcification in transitional cell tumor ranges from less than1% to approximately 7% [23]. Detection of calcification isimproved greatly on CT examination.

Excretory Urography

Excretory urography is the most commonly performed initialexamination in patients with transitional cell carcinomas. Fivecategories of abnormality were described by Lowe and Roy-lance [24]: (1) a discrete filling defect within the renal collectingstructures (35%) (Fig. 1); (2) filling defects within distendedcalices (26%) (Fig. 2); (3) caliceal obliteration and calicealamputation (19%); (4) hydronephrosis with renal enlargementand a “soap-bubble” nephrogram (6%); and (5) reduced func-

Dow

nloa

ded

from

ww

w.a

jron

line.

org

by 2

7.72

.237

.148

on

09/2

7/14

fro

m I

P ad

dres

s 27

.72.

237.

148.

Cop

yrig

ht A

RR

S. F

or p

erso

nal u

se o

nly;

all

righ

ts r

eser

ved

716 LEDER AND DUNNICK AJR:155, October 1990

tion without renal enlargement (1 3%). In this category, nopyelogram is evident. Although transitional cell carcinoma canpresent in any of these fashions, multiple other disorders cancause each of these urographic appearances (Table 1) [24].

The surface of a pelvicaliceal or ureteral filling defect maybe smooth, irregular, or stippled. The “stipple sign” refers totrapping of contrast material within the interstices of a papil-lary lesion. The vast majority of urothelial tumors are papillarytransitional cell carcinomas; these tumors exist as multiplebranching fronds emanating from a central core. This signmay be seen anywhere in the urinary tract and is helpful indifferentiating a tumor from inflammation or blood clot. Bloodclots within the collecting system may trap contrast materialirregularly; however, the pattern is much coarser than that oftumors. Contrast material trapped in a fungus ball has alamellar pattern [25].

Transitional cell tumors also may appear as a distendedtumor-filled calix (oncocalix) or tumor obstructing a calicealinfundibulum (phantom calix). In the ureter, a transitional cell

carcinoma may appear as a goblet or “champagne glass”(Fig. 3). In this situation, the ureter is dilated distal to the fillingdefect. This may be caused by accommodation of the ureterto the intraluminal tumor growth or by repeated tumoralprolapse during ureteral peristalsis [26]. This is distinct fromureteral calculi that cause proximal ureteral dilatation anddistal ureteral narrowing due to spasm and/or edema.

The hallmark of analgesic nephropathy is necrosis of therenal papillae. Changes on excretory urography are variableand can be subtle. Parenchymal scarring characterized by a“wavy” renal outline may be found. Cortical depressions maybe located directly over a calix or between calices. Withcontinued use of analgesics, indentations develop and resultin discrete renal cortical depressions. This scarring patternmay be unilateral, but frequently is bilateral. When transitionalcell carcinoma is associated with analgesic abuse, 5% have

demonstrated simultaneous bilateral renal pelvic tumors [27].

Retrograde Pyelography

Retrograde pyelography can be used to show morphologicfeatures of tumors found on excretory urography. In particu-lar, a fixed filling defect suggests neoplasm rather than bloodclots and mycetoma, which move with change in position ofthe patient. Tumors arising from the anterior wall of the renal

pelvis may be missed if only radiographs of the supine patientare obtained [28]. Retrograde examination allows evaluationof a nonfunctioning kidney, which occurs when the kidney isextensively invaded by tumor without associated hydrone-phrosis or renal vein involvement [29]. A change in orientationof a ureteral filling defect demonstrated first with retrogradeinjection of contrast material, and subsequently with ante-grade flow of contrast material, is diagnostic of an intraluminallesion rather than a vascular impression [30]. Other intralu-minal lesions, such as a fibroepithelial polyp of the ureter,also may demonstrate this pyelographic sign.

Son ography

Sonography is useful in differentiating nonopaque calculifrom blood clots, tumors, and other soft-tissue masses. Themost common appearance of a renal transitional cell carci-noma is a discrete, solid, hypoechoic mass separating thecentral echo complex (Fig. 4). Less common presentationsare disruption of a portion of the central echo complex withnormal surrounding parenchyma or an appearance resemblinghydronephrosis [31]. A centrally located mass in the renalsinus may resemble mild hydronephrosis, but the solid natureof the lesion is discernible on careful examination [32]. Whentumor resides within a kidney that is obstructed by someother process, the sonographic appearance may be confus-ing. Tumor may be discovered coincidentally in an obstructedsystem, rather than causing the obstruction itself.

The sonographic characteristics of a renal mass are notsufficiently specific to allow confident differentiation of tran-

sitional cell carcinoma from adenocarcinoma, metastasis, lym-phoma, or inflammatory disease. Transitional cell carcinoma,however, can be suggested when a mass is seen in a centrallocation; focal enlargement of the adjacent renal cortex sug-gests cortical infiltration. Hypernephromas cause more corti-

cal disruption associated with a renal mass. Inflammatorymasses usually do not involve the central echo complex [31].Pyelocaliceal mucosal thickening is nonspecific and may becaused by infection or chronic obstruction; potentially it couldmimic a nonpapillary transitional cell carcinoma on sonogra-phy. In this setting, appropriate clinical history and retrogradepyelography with cytology would be necessary.

Transitional cell carcinoma occasionally mimics a renalstone on sonography. High-grade transitional cell carcinomascan exhibit areas of squamous metaplasia. These metaplastic

TABLE 1: Differential Diagnoses in Transitional Cell Carcinoma on Excretory Urography

Type of Abnormality Differential Diagnosis

Discrete filling defect within renal Stone, clot, pyelitis/uretentis cystica, intramural hemorrhage

collecting structuresFilling defects within distended cal- Tuberculosis, papillary necrosis

icesCaliceal obliteration and caliceal Hypernephrorna, abscess, focal xanthogranulornatous pyelonephritis, metastasis, tuberculosis

amputation

Hydronephrosis with renal enlarge- Hydronephrosis, pyonephrosis

ment and soap-bubble appear-

ance on nephrogramReduced function without renal en- Ureteral/bladder carcinoma, renal artery stenosis, diffuse xanthogranulomatous pyelonephritis

largement

Note-Adapted from Lowe and Roylance [24].

Dow

nloa

ded

from

ww

w.a

jron

line.

org

by 2

7.72

.237

.148

on

09/2

7/14

fro

m I

P ad

dres

s 27

.72.

237.

148.

Cop

yrig

ht A

RR

S. F

or p

erso

nal u

se o

nly;

all

righ

ts r

eser

ved

A B

AJR:1 55, October1990 URINARY TRANSITIONAL CELL CARCINOMA 717

Fig. 3.-Ureteral transitional cell carcinoma.A, Excretory urogram shows hydroureter with

obstruction by mass In mid ureter.B, Retrograde pyelogram shows intraluminal fill-

ing defect with distal ureteral widening, the cham-pagne-glass sign.

Fig. 4.-Renal pelvic transitional cell tumor.A, Sonogram shows mass separating central

echo complex of left kidney.B, CT scan shows soft-tissue mass (arrow)

within renal pelvis.

areas are characterized by the abundant formation of keratinpearls. This hard and smooth surface produces dense echoessimilar to those seen in calculi. This rare pitfall has beenreported in a high-grade transitional cell tumor and serves asa reminder that tumor may be mimicked by renal stones [33].

CT

CT provides excellent detail of the kidney and urinary tract.Transitional cell carcinomas have CT densities ranging from8 to 30 H, in comparison with fat in the renal sinus (-60 to1 20 H), renal cysts (-1 0 to +1 0 H), and calculi (1 00 to 250H) (Fig. 5). The density of sinus fat remains in the negative

range on contrast-enhanced CT; renal cysts remain un-changed. Transitional cell carcinomas can be detected asmasses of density greater than that of urine, but less thanthat of the renal parenchyma. After injection of contrastmaterial, these tumors increase in density to 1 8-55 H [34].

The density of a transitional cell carcinoma on CT is suffi-ciently different from other causes of pelvicaliceal filling de-fects (renal calculi, blood clot) to make CT scans useful [35].The attenuation value of a blood clot, which ranges from 50to 65 H, is higher than that of a soft-tissue tumor and lower

than that of a renal calculus (Fig. 6). Blood clots do not showcontrast enhancement. When it is difficult to differentiatebetween a blood clot and a neoplasm, a second study canbe performed. At that time, a blood clot most likely will havelysed, changed configuration, or decreased in attenuation[36].

CT is also useful in determining the site of origin of a lesion.Finely collimated images may allow distinction between pel-vicaliceal, extracaliceal, or parenchymal lesions.

CT patterns in transitional cell tumors include a caliceal orrenal pelvic filling defect, pelvicaliceal irregularity, infundibular

stenosis, caliceal cutoff, caliceal expansion, and focal or globalnonvisualization [34]. Differentiation of transitional cell carci-noma from renal cell carcinoma is aided by the lesser enhance-ment of a transitional cell tumor as opposed to the hypervas-cular, nonnecrotic, noncystic, and noncalcified renal cell tu-mor. The typical transitional cell tumor is centrally located,and its centrifugal expansion and/or invasion of the kidney isdifferent from the eccentric origin and invasion of the renalsinus seen in hypernephromas. Transitional cell tumors donot distort the shape of the kidney. A central mass that isslightly less dense than normal renal parenchyma and showsminimal tumor enhancement strongly suggests a transitional

Dow

nloa

ded

from

ww

w.a

jron

line.

org

by 2

7.72

.237

.148

on

09/2

7/14

fro

m I

P ad

dres

s 27

.72.

237.

148.

Cop

yrig

ht A

RR

S. F

or p

erso

nal u

se o

nly;

all

righ

ts r

eser

ved

.4

718 LEDER AND DUNNICK AJR:155, October 1990

‘9’.

A

cell tumor. A delayed nephrogram with accentuated late pa-renchymal opacification occasionally exhibiting a striatednephrogram also may be seen. The centrifugal expansionpattern of transitional carcinoma can result in any combinationof findings including compression, displacement, and/or dis-appearance of the renal sinus fat; trapping of contrast materialin narrowed and compressed caliceal spaces or obstructedand slightly dilated calices; or thinning of the surroundingrenal parenchyma with focal enlargement of the kidney and

centrifugal, uneven invasion of the renal parenchyma. A massthat preserves the uniform contour of the kidney and shows

extrarenal spread at and through the renal hilum are allpossible findings on the CT examination of transitional cellcarcinoma [37].

The hydronephrotic form of transitional cell tumor is due toureteropelvic junction obstruction and may present a diag-

nostic dilemma. Although urography and/or pyelography maybe used to make the diagnosis, CT occasionally may providea definitive diagnosis. An enhancing soft-tissue mass at theapex of a dilated renal pelvis on CT indicates a tumor causingureteropelvic junction obstruction. Nodular thickening of thewall of the renal pelvis may occur (Fig. 7), or the mass maybe bulky and grow to fill the renal pelvis and extend intodilated calices. The proximal ureter may be thickened andfilled from invasion by the neoplasm. This is in distinction topatients with congenital ureteropelvic junction obstruction,where CT examination will show an enlarged fluid-filled renalpelvis. The wall in this case will be thin, smooth, and uniform;the renal pelvis is dilated to a greater degree than the calices.The pelvic walls are stretched and are barely discernible onCT. An abrupt transition from the engorged pelvis to thecollapsed proximal ureter will be noted [38].

Carcinoma of the renal pelvis can be mimicked on CT byother conditions including chronic xanthogranulomatous pye-lonephritis, chronic ureteropelvic junction obstruction withsuperimposed infection, eosinophilic ureteritis, and pyelitis.Urothelial neoplasms and inflammation can coexist in thesame kidney. CT is useful in these confusing cases, asdisease-such as liver metastases, regional lymphadenop-athy, or synchronous contralateral or ipsilateral tumor-maybe found elsewhere, which aids in diagnosis.

Fig. 5.-Uric acid stone.A, Excretory urogram shows triangular filling

defect (arrow) in collecting system of left kidney.B, Unenhanced CT scan shows high-density

calculus (arrowhead) in left renal pelvis.

CT can provide valuable information in staging disease inpatients with transitional cell carcinoma. Baron et al. [39]described three patterns of transitional cell carcinoma. Half oftheir patients had a sessile mass, approximately one fifth hadureteral wall thickening, and about a third had an infiltratingrenal mass. Of 24 lesions, 1 6 had localized disease (stage Ior II), four had stage Ill disease, and four had stage IV disease.CT correctly characterized the extent of disease in 20 of 24cases. CT was successful in differentiating tumors confinedto the wall from those with local extension or distant metas-tasis. In their experience, CT was not useful for differentiating

tumors limited to the uroepithelial mucosa (stage l)from thosewith muscle wall invasion (stage II). In this region of the body,as elsewhere, CT may underestimate the extent of diseaseby failing to detect metastases in normal-sized lymph nodes.The pathologic staging (Table 2) is paralleled by a preoperative

staging system based on CT examination that divides staginginto (A) tumor confined to the pelvicaliceal system, (B) exten-sion to the renal parenchyma but still confined to the kidney,(C) transpelvic or transparenchymal invasion into the peripel-vic and perirenal fat without gross extension and withoutnodal involvement, and (D) gross local extrarenal extensionand/or nodal metastases [36]. CT can document metastaticdisease to the lungs, retroperitoneal and distant lymph nodes,and liver. Bone metastases may be found but are best eval-uated on radionuclide bone scans or plain films.

MR Imaging

MR imaging is not used frequently in the diagnosis andmanagement of transitional cell tumors. Detection of tumor isbetter accomplished with other techniques. Small lesions maybe missed on MR imaging because of motion artifacts. OnTi -weighted images, the tumor has similar or slightly lesssignal intensity than normal renal parenchyma. T2-weightedimages show a slight increase in signal intensity [40]. MR isuseful in its ability to detect vascular extension [41].

Angiography

Most urothelial neoplasms are hypovascular on arteriog-raphy. In cases of small, noninvasive tumor, no angiographic

Dow

nloa

ded

from

ww

w.a

jron

line.

org

by 2

7.72

.237

.148

on

09/2

7/14

fro

m I

P ad

dres

s 27

.72.

237.

148.

Cop

yrig

ht A

RR

S. F

or p

erso

nal u

se o

nly;

all

righ

ts r

eser

ved

Fig. 6.-Blood clot.A, CT scan after IV administration of contrast material shows filling defect (arrowhead) in renal

pelvis.B, Unenhanced CT scan reveals high-density mass (arrow) due to recent blood clot.

Fig. 7.-Hydronephrosis of right kidney due totransitional cell carcinoma of renal pelvis. Rightkidney is enlarged and renal pelvis is markedlythickened (arrow). Renal pelvis and calices aredilated.

AJR:155, October1990 URINARY TRANSITIONAL CELL CARCINOMA 719

TABLE 2: Staging of Transitional Cell Carcinoma

Stage Description

A or I Limited to uroepithelial mucosa and lamina

propria

B or II Invasion to, but not beyond, pelvic/ureteralmuscularis

C or Ill Invasion beyond muscularis into adventitial

fat or renal parenchymaD or IV Distant metastasis

abnormality can be identified. Invasive tumors may showarterial encasement and occlusion. Neovascularity with en-larged pelvic and ureteric arteries can be seen in the regionof a tumor. Arteriography does not allow urothelial tumors tobe differentiated from xanthogranulomatous pyelonephritis,which may show similar venous encasement, occlusion, andfine neovascularity [42]. Arteriography is seldom used fordiagnosis or staging of transitional cell carcinoma.

Invasion of transitional cell carcinoma into the renal vein is

an uncommon, late finding [43-45]. Hartman et al. [46] re-ported a 7% prevalence of venous involvement in cases seenat the Armed Forces Institute of Pathology. Patients withrenal vein involvement and carcinoma of the renal pelvis havea reduced 5-year survival rate (5% vs 43% without renal veininvasion). Venous invasion of transitional cell carcinoma is nota contraindication to surgery. If tumor completely fills the renal

vein or extends into the inferior vena cava, the surgicalapproach will be altered to avoid transecting tumor [47].

Ureteral Transitional Cell Carcinoma

Primary carcinoma of the ureter is rare; it accounts for only1 % of all cancers of the upper urinary tract. The peak preva-lence of these tumors is between the fifth and seventh de-cades and males predominate in a ratio of 3:1 . Ureteral tumorsare more common on the left side (63%) and are found most

frequently in the lower third of the ureter (70%). Most patientspresent with hematuria or flank pain [48]. Metastases from

ureteral transitional cell carcinoma include retroperitoneallymph nodes (34%), distant lymph nodes (1 7%), liver (1 7%),lumbar vertebrae (1 3%), lungs (9%), kidneys (8%), and infre-

quently other sites [26].Pathologic staging of ureteral tumors includes grades 0,

papilloma; A, submucosal infiltration; B, muscular invasion; C,periureteral fat invasion; and D, tumor outside the ureter,regional lymphadenopathy, and distant metastasis. Patientswith stage 0 lesions have an excellent prognosis. Eightypercent of patients with stage A disease live more than 5years after diagnosis. The overall 5-year survival rate withstage B lesions is 50% and with stage C disease is 33.3%;stage D disease has a dismal prognosis [49]. Most ureteralcarcinomas are superficial; 93% are transitional cell types,5% are squamous cell, and 2% are glandular cell types [50].Most are papillary; approximately 40% are nonpapillary.

Excretory urography is the primary tool used in diagnosingureteral neoplasms. Excretory urography may show a non-functioning kidney (46%), hydronephrosis with or withouthydroureter (34%), or a ureteral filling defect with or withouthydronephrosis or hydroureter (1 9%) (Fig. 8) [50]. In approx-imately 70% of cases, hydronephrosis or nonvisualization isassociated with invasive ureteral tumor. When chronic ob-struction causes nonfunction of the kidney, urography is notdiagnostic. In these cases, pyelography, either retrograde orantegrade, may be used. However, antegrade pyelography isan invasive procedure, and occasionally retrograde pyelog-raphy is impossible because of inability to catheterize the

ureter. CT is able to visualize the entire ureter and candistinguish between renal calculus and tumor. CT is usefulfor identification of both the intraluminal mass and extraure-teral tumor extension, thereby helping to stage disease. Ure-teral neoplasms may appear as soft-tissue filling defectswithin the ureter or thickening of the ureteral wall [51 ]. Thefinding of a soft-tissue filling defect or thickening of the wall

Dow

nloa

ded

from

ww

w.a

jron

line.

org

by 2

7.72

.237

.148

on

09/2

7/14

fro

m I

P ad

dres

s 27

.72.

237.

148.

Cop

yrig

ht A

RR

S. F

or p

erso

nal u

se o

nly;

all

righ

ts r

eser

ved

Fig. 8.-Transitional cell carcinoma of ureterdraining lower-pole moiety in patient with completeduplication of collecting system of right kidney.

A, Retrograde pyelogram shows bibbed mass(arrow) in ureter.

B, CT scan shows intraluminal soft-tissue mass(arrowhead).

is nonspecific and can be mimicked by inflammatory condi-tions (including inspissated pus) [52] or ureteral metastases[53].

Multiplicity

An important feature of transitional cell carcinoma is itspropensity for multicentricity, both synchronous and metach-ronous lesions (Fig. 9). Metachronous bladder carcinomaoccurs in 20-37% of patients with transitional cell carcinomaof the ureter. Transitional cell carcinoma of the upper tract ismulticentric in 20-44% of patients (Fig. 1 0). Unsuspectedrenal pelvic tumors have been found in patients with ureteraltumors. This fact emphasizes the need for complete evalua-tion of the entire urinary tract when a lesion is discovered.Furthermore, there is a high prevalence, 1 0-40%, of ipsilateralrecurrence after partial ureterectomy for transitional cell tumor(Fig. 1 1) [54]. Additionally, tumor may be found in the upperurinary tract in patients with a history of transitional cell tumorof the bladder (Fig. 1 2). The upper tract recurrence rate has

been reported to be less than lOb in patients treated bytransurethral resection for transitional cell carcinoma of thebladder [55].

Since metachronous transitional cell carcinoma of the blad-der occurs after renal and ureteral transitional cell carcinomain 20-55% of patients, close follow-up evaluation of the lowerurinary tracts is necessary. Bladder lesions typically occur1 5-48 months (renal transitional cell carcinoma) and 10-24months (ureteral transitional cell carcinoma) after initial diag-nosis [56]. In these patients, cystoscopic evaluation of thebladder should be done at 3-month intervals for a period of 2years, just as it is done in the follow-up of primary bladdercancer [1 9]. The reported prevalence of bilateral synchronousand/or metachronous upper tract transitional cell carcinomaranges from 1 % to 1 0%. Therefore, annual follow-up excre-tory urography and, if necessary, retrograde pyelography,performed at the time of cystoscopy, is recommended. Me-tachronous upper tract lesions develop in 0-6#{176}hof patients,at an average delay of 77 months, after diagnosis of a primarytransitional cell carcinoma of the bladder. Urine cytologicexaminations should be performed semiannually for 2 yearsin these patients and at least annually thereafter. Annual

excretory or retrograde urography, or both, for the first 2years after diagnosis of transitional cell Carcinoma of the

bladder, followed by biennial examinations, is recommended.

Closer surveillance is required in patients at increased risk.This includes patients with Balkan nephropathy, vesicoure-teral reflex, multifocal recurrent transitional cell carcinoma ofthe bladder, high-grade bladder carcinoma, carcinoma in situin the distal ureter resected during cystectomy, history ofanalgesic abuse, history of heavy smoking, exposure to car-cinogens, and treatment with cyclophosphamide [56]. Anadditional site of transitional cell carcinoma is in bowel con-duits used for urinary diversions in patients after cystectomyfor bladder carcinoma (recurrent tumor) or for benign bladderconditions (primary tumor) [57, 58].

Treatment

Treatment of renal pelvic transitional cell carcinoma con-sists of total nephroureterectomy with excision of a cuff ofbladder. In selected cases, nephrectomy can be performedwithout removal of the entire ureter, either because standardtotal nephroureterectomy with removal of a cuff of bladder iscontraindicated by the age or physical debility of the patient

or because the tumor is so extensive that such an additionto the operation would be futile [59]. Parenchyma-sparing

operations include partial nephrectomy and open pyelotomywith tumor excision and fulguration. Operative pyeloscopy isuseful for a thorough examination of the entire intrarenalcollecting system. Transurethral ureteropyeloscopy can beused as an endoscopic method for diagnosis and treatmentof renal pelvic transitional cell carcinoma. There is only verylimited experience in the ureteroscopic treatment of uppertract tumors. It does appear that low-grade, localized, distalureteral tumors can be managed effectively by ureteroscopicmeans [60]. In addition to retrograde access to the uppertracts, antegrade, percutaneous resection techniques are alsoavailable to the urologist. Small, well-localized, superficialtumors can be removed percutaneously. A cure can be pro-vided in selected patients, including those with a normalcontralateral kidney and with small (no more than 2 cm),single, low-grade, papillary tumors that are confined to themucosa, who, in addition, have negative cytologic results,negative results of random biopsies of contiguous mucosa,

and no history of concurrent transitional cell carcinoma else-where in the urinary tract [61].

Destruction of tumor can be accomplished with either anargon or neodymium-yttrium aluminum garnet laser placed

through a flexible ureteroscope. Topical use of chemothera-

Dow

nloa

ded

from

ww

w.a

jron

line.

org

by 2

7.72

.237

.148

on

09/2

7/14

fro

m I

P ad

dres

s 27

.72.

237.

148.

Cop

yrig

ht A

RR

S. F

or p

erso

nal u

se o

nly;

all

righ

ts r

eser

ved

Fig. 9.-Multifocal transitional cell carcinoma. Fig. 10.-Soft-tissue masses (arrowheads) in renal pel-A, CT scan shows soft-tissue mass (arrow) at apex of hydronephrotic right kidney. Small vis bilaterally. Selective urine cytologic studies confirmed

calcification is present centrally. bilateral transitional cell carcinoma.B, Second mass at right ureterovesical junction (black arrowhead). Normal distal left ureter

(whIte arrowhead).

Fig. I 1.-Recurrent transitional cell carcinoma in patient who had had right nephrectomy andsubtotal ureterectomy for transitional cell carcinoma.

A, Retrograde pyebogram shows extreme nodubarity (arrowhead) in right ureteral stump.B, CT scan shows soft-tissue density (black arrow) in remaining right ureter. Note normal left

ureter (white arrow).

Fig. 12.-Multiple filling defects (arrows) in pel-vis and collecting system of left kidney seen onIoop-o-gram of patient who had prior cystectomyfor transitional cell carcinoma of bladder.

peutic agents, such as bacillus Calmette-Gu#{233}rin instilled di-rectly into the upper urinary tract, also may be efficacious inthe conservative management of renal pelvic transitional cellcarcinoma [62]. Intracavitary therapy administered through anephrostomy tube also may consist of mitomycin C [63].Thiotepa has been used successfully for low-grade, low-stagebladder tumors and can be delivered topically for ureteralcarcinoma [64].

Proximal ureteral neoplasms are generally treated with totalnephroureterectomy. Low-grade, noninvasive tumors of thedistal ureter may be treated by partial ureterectomy andureteroneocystostomy. Segmental resections can be consid-ered in cases of solitary kidney with a ureteral tumor, bilateralsynchronous ureteral tumors, patients with poor renal func-tion, and high-risk patients [65]. Patients who have segmentalresection will require close follow-up surveillance for the pos-sibility of ipsilateral recurrence. The role of adjuvant radiationtherapy is under investigation. Postoperative radiation maybe used for advanced ureteral carcinomas and in patients

with renal pelvic carcinoma with recurrent or gross disease.Radiation therapy can be delivered postoperatively to patientsat high risk for local and regional failure [66].

REFERENCES

1 . Richie JP. Carcinoma of the renal pelvis and ureter. In: Skinner DG,Lieskovsky G. eds. Diagnosis and management of genitourinary cancer.Philadelphia: Saunders, 1988:323-336

2. Grabstald H, Whitmore WF, Melamed MA. Renal pelvic tumors. JAMA

1971;218:845-8543. Bennington JL, Beckwith JB. Tumors of the kidney, renal pelvis, and

ureter. In: At!as of tumor pathology, 2nd series, fasc 1 2. Washington, DC:

Armed Forces Institute of Pathology, 19754. Highman WJ. Transitional carcinoma of the upper urinary tract: a histolog-

ical and cytopathological study. J Clin Patho! 1986:39:297-305

5. Robbins SL, Cotran AS. Pathologic basis of disease, 2nd ed. Philadelphia:

Saunders, 1979:1186-12096. Reed HM, Robinson ND. Horseshoe kidney with simultaneous occurrence

of calculi, transitional cell and squamous cell carcinoma. Urology 1984;23:62-64

Dow

nloa

ded

from

ww

w.a

jron

line.

org

by 2

7.72

.237

.148

on

09/2

7/14

fro

m I

P ad

dres

s 27

.72.

237.

148.

Cop

yrig

ht A

RR

S. F

or p

erso

nal u

se o

nly;

all

righ

ts r

eser

ved

722 LEDER AND DUNNICK AJR:155, October 1990

7. Murphy DM, Zincke H. Transitional cell carcinoma in the horseshoe kidney:report of 3 cases and review of the literature. Br J Urol 1982:54:484-485

8. Brenner DW, Schellhammer PF. Upper tract urothelial malignancy after

cyclophosphamide therapy: a case report and literature review. J Urol1987;137:1226-1 227

9. Shetty SD, Tabacqchali MA. Cyclosphosphamide and ureteric carcinoma.Br J Uro! 1987:60:274

10. Oyen RH, Gielen JL, Van Poppel HP, et al. Renal thorium deposition

associated with transitional cell carcinoma: radiologic demonstration in two

patients. Radiology 1988:169:705-707

1 1 . Bengtsson U, Angervall L, Ekman H, Lehman L. Transitional cell tumors ofthe renal pelvis in analgesic abusers. Scand J Uro! Nephro! 1968:2:145-1 50

1 2. Burnett KR, Miller JB, Greenbaum El. Transitional cell carcinoma: rapid

development in phenacetin abuse. AiR 1980:134:1259-126113. Chapple CA, Newman J, O’Brien JM, Considine J. Analgesic nephropathy

complicated by transitional cell carcinoma of the renal pelvis. Br J Uro!1987:59:89-96

14. Kenney PJ, Wasserman NF. Ureteral pseudodiverticulosis associated with

carcinoma of renal pelvis. UrolRadiol 1987:9:161-16315. Petkovic SD. Epidemiology and treatment of renal pelvic and ureteral

tumors. J Urol 1975:114:858-86516. Latham HS, Kay S. Malignant tumors of the renal pelvis. Surg Gynecol

Obstet 1974:138:613-62217. Aubenstein MA, WaIz BJ, Bucy JG. Transitional cell carcinoma of the

kidney: 25-year experience. J Uro! 1978:119:594-597

18. Nocks BN, Heney NM, Daly JJ, Perrone TA, Griffin PP. Prout GA. Transi-tional cell carcinoma of renal pelvis. Urology 1982;19:472-477

19. Droller MJ. Transitional cell cancer: upper tracts and bladder. In: Walsh

PC, Gittes AF, Perimutter AD, Stamey TA, eds. Campbeil’s urology, 5th

ed. Philadelphia: Saunders, 1986;1343-144020. Sheline M, Amendola MA, Pollack HM, Banner MP, de las Morenas A,

Wein AJ. Fluoroscopically guided retrograde brush biopsy in the diagnosis

of transitional cell carcinoma of the upper urinary tract: results in 45patients. AiR 1989:153:313-316

21 . Farkas A, Moriel EZ, Prat 0. Rapid spread of transitional ureteral tumor: aserious unusual complication of ureteral brush biopsy. J Urol 1983;129:1229-1230

22. Papadopouios I, Figge M, Weissbach L, Merkel KHH. Diagnosis of uro-thelial tumor by ureterorenoscopy. Eur Urol 1987:13:296-299

23. Dinsmore BJ, Pollack HM, Banner MP. Calcified transitional cell carcinomaof the renal pelvis. Radiology 1988;1 67:401-404

24. Lowe PP, Roylance J. Transitional cell carcinoma of the kidney. Ciln Radio!

1976:27:503-512

25. McLean GK, Pollack HM, Banner MP. The stipple sign”-urographicharbinger of transitional cell neoplasms. Urol Radio! 1979:1:77-79

26. Pollack HM. Clinical urography. Philadelphia: Saunders, 1990:1292-135227. Hattery AR, Hartman GW, Williamson B. General case of the day.

RadioGraphics 1986;6:1091-1095

28. Pearson AC, Cope V. Costello CB. A potential pitfall with lesions of therenal pelvis. Br J Uro! 1987;60:86-88

29. Becker JA. Transitional cell carcinoma of the renal pelivs: causes of non-visualization on excretory urography. J Urol 1969:101:280-282

30. Swanson SK, zincke H. “Flip-fiop phenomenon on retrograde ureterog-raphy establishes diagnosis of ureteral tumor. Urology 1983:21:542-543

31 . Ostrovsky PD, Carr L, Goodman J. litrasound of transitional cell carci-noma. JCU 1985:13:35-36

32. Cunningham JJ. Ultrasonic demonstration of renal collecting system inva-

sion by transitional cell cancer. JCU 1982:10:339-34133. Janetschek G, Putz A, Feichtinger H. Renal transitional cell carcinoma

mimicking stone echoes. J Ultrasound Med 1988:7:83-8634. Gatewood 0MB. Goldman SM, Marshall FF, S�g&man 55. Computed

tomography of transitional cell carcinoma of the kidney. In: Siegelman 55,

Gatewood 0MB, Goldman SM, eds. Computed tomography of the kidneysand adrenals, vol. 3. New York: Churchill-Livingstone, 1984:81-111

35. Parienty RA, Ducellier A, Pradel J, Lubrano JM, Coquille F, Richard F.Diagnostic value of CT numbers in pelvocalyceal filling defects. Radiology1982:145:743-747

36. CholankerilJV, Freundlich A, Ketyer 5, Spirito AL, NapolitanoJ. Computedtomography in urothelial tumors of renal pelvis and related filling defects.

CT 1986:10:263-272

37. Gatewood 0MB, Goldman SM, Marshall FF, Siegelman 55. Computerized

tomography in the diagnosis of transitional cell carcinoma of the kidney.J Uro! 1982:127:876-887

38. Schwartz JM, Bosniak MA, Hulnick DH, Megibow AJ. The use of computedtomography in the diagnosis of carcinoma of the renal pelvis causing

ureteropelvic junction obstruction. Uro! Radio! 1988:9:204-20939. Baron AL, McClennan BL, Lee JKT, Lawson TL. Computed tomography

of transitional-cell carcinoma of the renal pelvis and ureter. Radiology1982;144:125-1 30

40. Jaffe J, Friedman AC, Seidmon EJ, Aadecki PD, Lev-Toaft AS, CarolineDF. Diagnosis of ureteral stump transitional cell carcinoma by CT and MAimaging. AJR 1987:149:741-742

41. Hricak H, Theoni AF, Carroll PF, Demas BE, Marotti M, Tanagho EA.

Detection and staging of renal neoplasms: a reassessment of MA imaging.

Radio!ogy 1988:166:643-64942. Kadir S. Diagnostic angiography. Philadelphia: Saunders, 1986:445-495

43. Aenert WA, Audin U, Casarella WJ. Aenal vein thrombosis in carcinoma

of the renal pelvis. AiR 1972:114:735-74044. Jitsukawa 5, Nakamura K, Nakayama M, Osawa A, Matsui K. Transitional

cell carcinoma of kidney extending into renal vein and inferior vena cava.

Urology 1985:25:310-31245. Geiger J, Fong 0, Fay A. Transitional cell carcinoma of renal pelvis with

invasion of renal vein and thrombosis of subhepatic inferior vena cava.Urology 1986:28:52-54

46. Hartman DS, Pyatt AS, Dailey E. Transitional cell carcinoma of the kidneywith invasion into the renal vein. Urol Radio! 1983;5:83-87

47. McCullough DL, Talner LB. Inferior vena caval extension of renal carci-

noma: a lost cause? AJR 1974:121:819-826

48. Bloom NA, Vidone RA, Lytton B. Primary carcinoma of the ureter: a report

of 102 new cases. J Uro! 1970:103:590-59849. Mills C, Vaughan ED. Carcinoma ofthe ureter: natural history, management

and 5-year survival. J Uro! 1983:129:275-27750. Batata MA, Whitmore WF, Hilaris BS, Tokita N, Grabstald H. Primary

carcinoma of the ureter: a prognostic study. Cancer 1975:35:1626-163251 . Kenney PJ, Stanley AJ. Computed tomography of ureteral tumors.

J Comput Assist Tomogr 1987;1 1 :102-1 0752. Bosniak MA. Case records of the Massachusetts General Hospital. Case

11-1981 . N Eng! J Med 1981:304:657-66353. Winalski CS, Lipman JC, Tumeh 55. Ureteral neoplasms. RadioGraphics

1990:10:271-28354. Ghazi MA, Morales PA, Al-Askan S. Primary carcinoma of ureter. Urology

1979:14:18-2155. Hatch TA, Hefty TA, Barry JM. Time-related recurrence rates in patients

with upper tract transitional cell carcinoma. J Urol 1988:140:40-4156. Yousem DM, Gatewood 0MB, Goldman SM, Marshall FF. Synchronous

and metachronous transitional cell carcinoma of the urinary tract: preva-lence, incidence, and radiographic detection. Radiology 1988:167:

613-61857. Roberts SD, Williams HJ, Aesnick Ml. Metastatic transitional cell carcinoma

in an ileal conduit following cystectomy. J Uro! 1987:137:734-73558. Higgs B, Ineson NA. Transitional cell carcinoma arising at the site of

ureterosigmoidostomy. Br J Uro! 1983:55:451-45259. Mufti GA, Gove JAW, Badenoch DF, et al. Transitional cell carcinoma of

the renal pelvis and ureter. Br J Uro! 1989:63:135-140

60. Huffman JL. Ureteroscopic management of transitional cell carcinoma ofthe upper urinary tract. Uro! Clin North Am 1988;1 5:419-424

61 . Onhuela E, Smith AD. Percutaneous treatment of transitional cell carci-noma of the upper urinary tract. Uro! Ciln North Am 1988:15:425-431

62. Ziegelbaum M, Novick AC, Streem SB, Montie JE, Pontes JE, StraffonRA. Conservative surgery for transitional cell carcinoma of the renal pelvis.

J Uro! 1987:138:1146-114963. Smith AY, Vitale PJ, Lowe BA, Woodside JR. Treatment of superficial

papillary transitional cell carcinoma of the ureter by vesicoureteral refluxof mitomycin C. J Uro! 1987:138:1231-1233

64. Powder JA, Mosberg WH, Pierpont AZ, Tatoyan KB, Young JD. Bilateralprimary carcinoma of the ureter: topical intraureteral thiotepa. J Urol

1984:132:349-35265. Zoretic 5, Gonzales J. Primary carcinoma of ureters. Urology 1983:21:

354-35666. Brookland AK, Richter MP. The postoperative irradiation of transitional cell

carcinoma of the renal pelvis and ureter. J Uro! 1985:133:952-955

Dow

nloa

ded

from

ww

w.a

jron

line.

org

by 2

7.72

.237

.148

on

09/2

7/14

fro

m I

P ad

dres

s 27

.72.

237.

148.

Cop

yrig

ht A

RR

S. F

or p

erso

nal u

se o

nly;

all

righ

ts r

eser

ved