Transitional Cell Carcinoma of the Kidney

Background

This rare tumor characteristically arises within the pelvis of the kidney. It has a similar histologic and gross appearance to transitional cell carcinomas occurring elsewhere in the urinary tract.

OUTLINE

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Differential Diagnosis

Prognosis and Treatment

Commonly Used Terms

Internet Links

DISEASE ASSOCIATIONS CHARACTERIZATION

ANALGESICS

Morphologic evidence that analgesic-induced kidney pathology contributes to the progression of tumors of the renal pelvis.

Stewart JH, Hobbs JB, McCredie MR.

Department of Medicine, University of Otago, and Dunedin Hospital, Dunedin, New Zealand.

Cancer 1999 Oct 15;86(8):1576-82 Abstract quote
BACKGROUND: Whether phenacetin-containing analgesics cause renal pelvic tumors by virtue of the weak mutagenicity of phenacetin, or indirectly through local effects of analgesic-induced renal papillary scarring, is debated. Because phenacetin consumption ceased in New South Wales, Australia in 1975, cases of renal pelvic carcinoma seen 14-15 years later (many of which were associated with long-standing analgesic-induced renal papillary pathology) provided an opportunity to examine the temporal relation between phenacetin exposure and those histologic characteristics of the tumors and adjacent renal tissue that may implicate analgesics in their etiology.

METHODS: The authors conducted a "blinded" histopathologic review of tumors of the renal pelvis and adjacent noncancerous renal tissue from 100 cases for which epidemiologic data regarding risk factor exposure (specifically phenacetin-containing analgesics, tobacco, infection, and kidney stones) had been obtained in a population-based case-control study from New South Wales in 1989 and 1990.

RESULTS: A history of consumption of phenacetin-containing analgesics was associated strongly with the presence and severity of diffuse renal papillary scarring, and less strongly with papillary calcification. The histologic grade of the renal pelvic tumors tended to rise significantly with consumption of phenacetin-containing analgesics in a dose-dependent fashion and with the degree of papillary scarring, but was not related to smoking. In multivariate analysis it was the degree of papillary scarring (to a greater extent than the amount of phenacetin consumption) that was associated significantly and strongly with a higher histologic grade. Only diffuse papillary calcification was associated significantly with squamous change in the renal pelvic tumors.

CONCLUSIONS: Based on the results of the current study, the authors conclude that 1) in phenacetin-related tumors of the renal pelvis, the presence and severity of analgesic-induced renal papillary scarring correlates with tumor progression and 2) papillary calcification is a risk factor for squamous change in renal pelvic urothelioma.

BLADDER CANCER, PRIOR

Upper tract transitional cell carcinoma following cystectomy for bladder cancer.

Huguet-Perez J, Palou J, Millan-Rodriguez F, Salvador-Bayarri J, Villavicencio-Mavrich H, Vicente-Rodriguez J.

Department of Urology, Fundacio Puigvert, Barcelona, Spain.

Eur Urol 2001 Sep;40(3):318-23 Abstract quote
PURPOSE: We assessed the incidence of upper urinary tract tumors (UUTTs) after cystectomy for invasive or superficial transitional cell carcinoma (TCC) of the bladder. The risk factors, patients' characteristics and evolution of those who developed UUTTs are analyzed.

MATERIALS AND METHODS: From August 1980 to February 1994, 568 radical cystectomies were performed for TCC of the bladder: in 469 instances (82.5%) due to invasive tumor (T2-T4), and in 99 cases (17.5%) for superficial tumor (Ta, T1, Tis). All patients were followed for at least 5 years or until death. A retrospective study of patients who developed UUTTs has been performed. A revision of bladder tumor and UUTT characteristics, and the intervals between both is also evaluated.

RESULTS: 26 patients (4.5%) developed UUTTs: 11 of the 99 patients cystectomized for superficial TCCs (11.1%); 6 of the 392 patients with primary invasive TCC (1.5%), and 9 of the 77 (11.6%) patients with invasive tumors and a prior history of superficial TCC. The interval to the development of UUTT was higher after cystectomy for superficial tumor. TCCs of the bladder that subsequently developed UUTTs were high grade in 84%, multifocal in 80%, or had carcinoma in situ in 65%, tumor in the prostatic urethra in 52%, and involvement of the distal ureter in 57%. Twenty-two UUTTs (84%) were located in the calyces or the renal pelvis, 3 were bilateral (11.5%), 14 multiple (58%) and 4 superficial (16%). With a median follow-up time of 18 (range 3-103) months, 14 patients (53.8%) died of tumor, 2 were alive with disease, 2 were lost for follow-up, and 8 (30%) were alive and free of disease.

CONCLUSIONS: We found that patients cystectomized for superficial or invasive TCC with a prior history of superficial TCC have a higher incidence of UUTTs. These cases require follow-up with annual urography or loopography.

CHRONIC PYELITIS

UROLITHIASIS

PATHOGENESIS CHARACTERIZATION

APOPTOSIS

Apoptotic cell death and Smad4 expression in transitional cell carcinoma of the renal pelvis and ureter.

Kong C, Zhang X, Takenaka I.

Department of Urology, Kagawa Medical University, Kagawa, Japan.

Int J Urol 2001 Jul;8(7):386-90 Abstract quote

PURPOSE: To investigate the frequency of apoptosis and the expression of Smad4 protein as well as their roles in transitional cell carcinoma (TCC) of the renal pelvis and ureter.

METHODS: Apoptosis was detected by using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) technique in 34 formalin-fixed and paraffin-embedded specimens of renal pelvic and ureteral TCC. The expression of Smad4 was immunohistochemically studied.

RESULTS: The incidence of apoptosis ranged from 1.10 to 3.75% with a median of 2.50% in TCC of the renal pelvis and ureter. The incidence of apoptosis was noted to be closely related to histologic grade but not to pathologic stage of the cancer. The expression of Smad4 was detected in six of 34 cases (17.6%). Regarding subcellular distribution, Smad4 protein was localized both in cytoplasm and nucleus of the cancer cells. In comparing the incidence of apoptosis with the expression of Smad4, no significant associations were seen between them. The expression of Smad4 was not related to the tumor grade nor stage of the cancer.

CONCLUSIONS: The present study demonstrated close association of the incidence of apoptosis with the tumor grade of TCC of the renal pelvis and ureter. Significance of Smad4 expression was not noted in the study. It suggests that apoptotic cell death may play an important role in the tumor progression of renal pelvic and ureteral TCC.

CHROMOSOMAL ABNORMALITIES

Comparative genomic hybridization analysis of transitional cell carcinomas of the renal pelvis.

Rigola MA, Fuster C, Casadevall C, Bernues M, Caballin MR, Gelabert A, Egozcue J, Miro R.

Departament de Biologia Cel-lular, Fisiologia, Immunologia, Universitat Autonoma de Barcelona, Bellaterra E-08193, Spain. progression of this type of tumors.

Cancer Genet Cytogenet 2001 May;127(1):59-63 Abstract quote

We used comparative genomic hybridization to analyze 10 primary tumor samples from patients with transitional cell carcinoma of the renal pelvis.

The most frequent loss was located at 9q, that is, in 50% of the tumors. Gains of DNA sequences were most frequently observed in chromosome regions 1q21 approximately q23, 2p23 approximately p25, 8q21.1 approximately q22 and in the whole chromosome 20. High level amplifications at 1q21 approximately q25, 6p22 approximately p23, 8q21 approximately q22, 8q22 approximately q24.1, 11q13, and 12q14 approximately q21 were detected.

Most of these regions have previously been reported to be involved in transitional cell carcinoma of the bladder, thus confirming the importance of an increasing number of chromosome imbalances in the development and progression of this type of tumors.

Upper tract urothelial carcinoma: a clinicopathologic study including microsatellite instability analysis.

Blaszyk H, Wang L, Dietmaier W, Hofstadter F, Burgart LJ, Cheville JC, Hartmann A.

Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota (HB, LW, LJB, JCC)
Mod Pathol 2002 Aug;15(8):790-7 Abstract quote
Urothelial carcinoma of the renal pelvis and ureter may develop as a manifestation of the hereditary nonpolyposis colorectal cancer syndrome that is characterized by mutations in a number of DNA mismatch repair genes and detectable as microsatellite instability.

In this study, we examined microsatellite instability and the clinicopathologic features of urothelial carcinoma of the renal pelvis (n = 61) and ureter (n = 53) from 114 consecutive patients surgically treated from 1985-1992. Clinical data were obtained through chart review. Matched normal and tumor DNA was extracted from paraffin-embedded tissue, and a panel of six microsatellite loci was analyzed. The male-female ratio was 2.8:1 with a median age of 70 years (range, 28 to 92 y). Microsatellite analysis was successful in 67 tumors, and 21 (31.3%) patients had tumors that exhibited microsatellite instability. Patients with microsatellite-unstable tumors were significantly more likely to have additional nonurologic cancers (P =.015) including colorectal carcinoma (P =.001) compared with patients with tumors that did not exhibit microsatellite instability. In addition, patients with microsatellite-unstable tumors showed more colorectal cancers in their family (P =.026) and were more likely to have higher grade urothelial carcinoma of the upper tract (P =.028). Grade and stage, but not microsatellite status, were the strongest predictors of cancer-specific survival.

This study found the highest frequency of microsatellite instability in upper urothelial tract carcinomas reported to date and highlights upper tract urothelial carcinoma as a marker of the hereditary nonpolyposis colorectal cancer syndrome in some patients. These findings reinforce the importance of obtaining cancer histories in patients with upper tract urothelial carcinoma to subsequently identify individuals with the hereditary nonpolyposis colorectal cancer syndrome and at-risk relatives for surveillance and management programs.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

Transitional cell carcinoma of the renal pelvis: a retrospective look at CT staging with pathologic correlation.

Buckley JA, Urban BA, Soyer P, Scherrer A, Fishman EK.

Department of Radiology, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
Radiology 1996 Oct;201(1):194-8 Abstract quote
PURPOSE: To identify the reasons for the discrepancies between computed tomographic (CT) and pathologic staging of transitional cell carcinoma of the renal pelvis and to develop new criteria to increase the accuracy of CT in staging.

MATERIALS AND METHODS: CT scans of 31 consecutive patients with renal pelvic transitional cell carcinoma were evaluated. CT and pathologic staging were compared.

RESULTS: Pathologic staging revealed four stage 0 tumors, three stage I, five stage II, 10 stage III, and nine stage IV. The initial overall CT staging accuracy was 52% (16 of 31 patients). The sensitivity for minimal invasion was 17% (two of 12 patients). Two-thirds (10 of 15 patients) of the misinterpreted cases were overstaged as stage III. Proximal hydronephrosis was present in 80% of overstaged cases (eight of 10 patients). Reevaluation of the CT studies by using proximal hydronephrosis as a criterion for minimal invasion improved overall CT staging accuracy (77%). The revised staging yielded a sensitivity of 83% and specificity of 95% for minimal invasion and improved the specificity for deep invasion (17% to 92%).

CONCLUSION: In a patient with transitional cell carcinoma of the renal pelvis, hydronephrosis proximal to the tumor may cause overstaging of stage 0-II disease and may not indicate more advanced disease.

LABORATORY MARKERS

CA19-9

CA19-9-producing transitional cell carcinoma of the renal pelvis: a case report.

Taki T, Honda N, Yamada Y, Hibi H, Mitsui K, Matsuura O, Yoshikawa K.

Department of Urology, Aichi Medical University.

Hinyokika Kiyo 2001 Mar;47(3):191-4 Abstract quote

We report a case of CA19-9-producing transitional cell carcinoma of the renal pelvis.

A 59-year-old male patient with left hydronephrosis was referred to us from a local physician. Retrograde pyelogram revealed irregular filling defects involving calices, pelvis and proximal ureter. The serum CA19-9 level was elevated. Under the diagnosis of renal pelvic tumor, we performed radical left nephroureterectomy. The tumor was histologically diagnosed as transitional cell carcinoma. The tumor cells showed positive immunostaining for CA19-9. The serum CA19-9 level was normalized after the operation.

To our knowledge, this is the 28th case of a CA19-9-producing tumor in the Japanese literature.

PELVIC WASHINGS

Transitional cell carcinoma of the renal pelvis the diagnostic role of pelvic washings.

Witte D, Truong LD, Ramzy I.

Department of Pathology, Baylor College of Medicine and the Methodist Hospital, Houston, TX 77030, USA.
Am J Clin Pathol 2002 Mar;117(3):444-50 Abstract quote
One hundred renal pelvic washings were reviewed blindly for 12 cytologic features. Of 52 washings with tissue confirmation, the cytologic diagnosis suggestive of or positive for transitional cell carcinoma (TCC) was made in 36 cases; 11 were negative, and 5 were unsatisfactory.

Of 36 positive washings, histology confirmed the TCC diagnosis in 35 but revealed only reactive changes in 1. Of 11 negative washings, 9 were histologically negative for TCC, and 2 were positive for high-grade TCC. Among 48 washings without tissue confirmation, 33 were negative for TCC or showed reactive changes, 12 were negative for high-grade dysplasia or malignancy, but low-grade TCC could not be ruled out, 1 was suggestive of malignancy, and 2 were unsatisfactory. Clinical follow-up revealed no TCC. Predictive cytologic features of high-grade TCC were high nuclear/cytoplasmic ratio, isolated cells, anisonucleosis, nuclear hyperchromasia, and coarse chromatin; for low-grade they were presence of more than 5 papillary groups, cellular overlapping, anisonucleosis, and hyperchromasia.

The sensitivity and specificity for the cytologic diagnosis were 89% and 97% for high-grade TCC and 100% and 78% for low-grade TCC, respectively. Renal pelvic washings can be used to accurately diagnose TCC of the renal pelvis. The positive predictive value for high-grade TCC is 93%, but for low-grade tumors it is 43%.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

VARIANTS

MYELOMA KIDNEY

Renal pelvic carcinoma with unusual appearance simulating amyloidosis (myeloma kidney): a report of five cases.

Hes O, Michal M, Kinkor Z, Curik R, Baumruk L.

Department of Pathology, Faculty Hospital, Pilsen, Czech Republic.
Int J Surg Pathol 2002 Jan;10(1):41-5 Abstract quote
We describe 5 cases of urothelial carcinoma (UC) of the renal pelvis, which grew in a distinctive gross and microscopical pattern into the renal parenchyma. Five patients (2 men and 3 women, mean age 67.4 years) underwent nephrectomy for vague clinical findings. The cut surface of the tumor was white to light gray and the consistency was elastic. The corticomedullary border was indistinct, resulting in an appearance that suggested amyloidosis or myeloma.

The renal pelvis showed normal mucosa with areas of dysplastic changes. The tumors spread from the renal pelvis in a diffuse and irregular, infiltrative pattern and surrounded intact glomeruli. Detailed sampling of invasive tumor component showed foci of UC with transitions to clear squamous cells. The predominant clear squamous neoplastic cells had foci of granular eosinophilic cytoplasm and resembled conventional renal cell carcinoma. Four patients were alive and without signs of the disease for 5 months to 4 years after nephrectomy; 1 died of generalized tumor 7 months after nephrectomy.

The unusual gross and microscopic features result in varied problems in differential diagnosis, which are discussed herein.

THROMBUS IN VENA CAVA

Transitional cell carcinoma of the renal pelvis forming tumor thrombus in the vena cava.

Miyazato M, Yonou H, Sugaya K, Koyama Y, Hatano T, Ogawa Y.

Department of Urology, University of the Ryukyu, Okinawa, Japan.
Int J Urol 2001 Oct;8(10):575-7 Abstract quote
A 47-year-old man presented with a left renal incidentaloma without hematuria.

The tumor was complicated by inferior vena cava (IVC) thrombus extending from Th11 to L4. A temporary IVC filter was introduced prior to surgery. A midline incision was used to perform a left radical nephrectomy and en bloc lymphadenectomy with excision of the inferior vena cava from above the level of the left renal vein to 2.5 cm above the confluence of the common iliac veins. The pathological diagnosis was invasive transitional cell carcinoma. The tumor thrombus consisted of transitional cell carcinoma that histologically invaded the walls of the IVC. He died of cancer 17 months after the operation for the liver metastases.

This is the 18th case report of such a presentation in the literature.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

VARIANTS

SARCOMATOID CARCINOMA

Sarcomatoid transitional cell carcinoma of the renal pelvis. A report of five cases with clinical, pathological, immunohistochemical and DNA ploidy analysis.

Lopez-Beltran A, Escudero AL, Cavazzana AO, Spagnoli LG, Vicioso-Recio L.

Department of Pathology, Cordoba University Medical School, Spain.

Pathol Res Pract 1996 Dec;192(12):1218-24 Abstract quote
Sarcomatoid transitional cell carcinoma of the renal pelvis is a rare neoplasm with only 7 well illustrated examples reported. These tumours can assume a partial or complete spindle cell pattern of growth, leading to the erroneous classification as sarcomas.

We describe the clinic-pathologic features of five additional examples of sarcomatoid carcinoma of the renal pelvis observed in three males and two females. The age ranged from 65-to-82 years-old (mean 71.6). All these patients were treated by nephrectomy and died of disease between 6 and 20 months (mean 11.2) after the onset of symptoms. An immunohistochemical study demonstrated coexpression of keratins, epithelial membrane antigen and vimentin. The image DNA ploidy of all the tumours showed an aneuploid pattern.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

COLLECTING DUCT CARCINOMA

Cytopathology of retrograde renal pelvis brush specimens: an analysis of 40 cases with emphasis on collecting duct carcinoma and low-intermediate grade transitional cell carcinoma.

Zaman SS, Sack MJ, Ramchandani P, Tomaszewski JE, Gupta PK.

Department of Pathology, University of Pennsylvania Medical Center, Philadelphia 19104, USA.

Diagn Cytopathol 1996 Nov;15(4):312-21 Abstract quote
We report our experience with 40 retrograde renal brush samples of pelvic-calyceal lesions with confirmatory tissue studies.

On-site cytopathologic evaluation was performed in 38 of these specimens. The final histologic diagnoses included 24 cases of transitional cell carcinoma (TCC), 17 of which were low-intermediate grade tumors. All 24 cases were diagnosed cytologically as TCC (22), or as suspicious for TCC (2). Three cases classified as collecting duct carcinomas were resected; the cytologic specimens in 2 of these cases were interpreted as TCC, and one as reactive change. There were three renal cell carcinomas (RCC); cytologically, one was considered a papillary neoplasm, one suspicious for malignancy, and one as reactive. Two cases of atypical renal cysts were reported as suspicious for malignancy in both cytologic and histologic material. There was one case of metastatic colon carcinoma identified in the brush specimen. Finally, tissue studies in the remaining 7 cases showed reactive/inflammatory changes; however, four of the corresponding pelvic brush specimens were considered abnormal.

A review of the above cases is reported with the objective of presenting the cytologic features seen in collecting duct carcinoma, low-intermediate grade TCC, and diagnostically difficult cases with cyto/histomorphologic discrepancies. The contribution of on-site assessment to diagnostic accuracy is also discussed.

FIBROEPITHELIAL POLYP

Fibroepithelial polyp of the renal pelvis: nephron-sparing surgery after false-positive biopsy for transitional cell carcinoma.

Brady JD, Korman HJ, Civantos F, Soloway MS.

Department of Urology, University of Miami School of Medicine, Florida 33101, USA.
Urology 1997 Mar;49(3):460-4 Abstract quote
Benign fibroepithelial polyps of the renal pelvis are extremely rare, with only 23 cases previously reported. The diagnosis is usually made following nephrectomy or nephroureterectomy for an assumed malignancy. This case involves a 66-year-old woman referred with presumed biopsy-proven transitional cell carcinoma of the renal pelvis. Radiographic findings were suggestive of a benign lesion. Pyelotomy and frozen section confirmed these suspicions.

The polyp was excised and the kidney spared. The diagnosis and management of fibroepithelial polyps are discussed and the literature reviewed.

HEMANGIOPERICYTOMA

Hemangiopericytoma of renal sinus expanding to the renal hilum: an unusual presentation causes misinterpretation as transitional cell carcinoma.

Choi YJ, Hwang TK, Kang SJ, Kim BK, Shim SI.

Department of Clinical Pathology and Urology, Catholic University Medical College, Seoul, Korea.
J Korean Med Sci 1996 Aug;11(4):351-5 Abstract quote
We report a case of renal hemangiopericytoma occurring in renal sinus and expanding to the renal hilum. This unusual presentation caused misinterpretation of this tumor as transitional cell carcinoma of the renal pelvis clinically.

The patient who was a 30-year-old woman had a relatively well demarcated solid tumor, 8 x 6 cm, in the renal sinus of the left kidney.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

Renal pelvic neoplasms and atypical urothelium in patients with end-stage analgesic nephropathy.

Blohme I, Johansson S.
Kidney Int 1981 Nov;20(5):671-5 Abstract quote
In a series of 772 renal transplant patients, 84 had analgesic nephropathy (AN). Four of them had renal pelvic carcinoma.

The incidence of atypical urothelial changes of the renal pelvis was studied in 56 AN patients, the majority nephrectomized before or shortly after the renal transplantation. Urothelial atypia, usually bilaterally, was found in 27 patients. Multiple sections resulted in an even higher incidence (8/9). No atypical changes were found in normal kidneys or in end-stage diseased kidneys with other diseases, or in chronically rejected renal allografts.

These findings further strengthen the association between intake of phenacetin-containing analgesics and the development of renal pelvic tumors. Patients with end-stage analgesic nephropathy are a high-risk group for developing urinary tract tumors and should be subjected to endoscopic and cytologic surveillance. After renal transplantation, prophylactic bilateral nephroureterectomy is advocated.

Ki-67

Prognostic significance of Ki-67 labeling index in urothelial tumors of the renal pelvis and ureter.

Masuda M, Iki M, Takano Y, Asakura T, Noguchi S, Ikeda I, Kubota Y, Hosaka M.

Department of Urology, Yokohama City University School of Medicine, Japan.
J Urol 1996 Jun;155(6):1877-80 Abstract quote
PURPOSE: We evaluated the prognostic significance of the Ki-67 labeling index in 70 patients with primary urothelial tumors of the renal pelvis and ureter.

MATERIALS AND METHODS: Immunohistochemical staining for Ki-67 in archival tumor materials was done by the streptavidin-biotin method.

RESULTS: Univariate survival analysis showed that the prognosis of patients with a high Ki-67 labeling index of 21.7 or more was significantly worse than that of patients with an intermediate labeling index of 13.3 to less than 21.7 (p < 0.01) or a low labeling index of less than 13.3 (p < 0.001). Multivariate survival analysis showed that staining for Ki-67 labeling index was significantly correlated with prognosis (p < 0.01).

CONCLUSIONS: Analysis of Ki-67 labeling index provides useful prognostic information about patients with primary urothelial tumors of the renal pelvis and ureter.

p27

Prognostic significance of p27Kip1 and Ki-67 expression in carcinoma of the renal pelvis and ureter.

Kamai T, Takagi K, Asami H, Ito Y, Arai K, Yoshida KI.

Department of Urology, Dokkyo University School of Medicine, Tochigi, Japan.

BJU Int 2000 Jul;86(1):14-9 Abstract quote

OBJECTIVE: To determine the significance of p27(Kip1) (p27) for tumour behaviour and prognosis of patients with transitional cell carcinoma (TCC) of the renal pelvis and ureter.

PATIENTS AND METHODS: Using immunohistochemical staining, the relationship was evaluated between p27 protein level (low < 50%, high > 50%) and the Ki-67 labelling index (low < 30%, high > 30%) and clinicopathological features of 37 consecutive Japanese patients with TCC of the renal pelvis and ureter.

RESULTS: Low levels of p27 correlated with higher tumour stage (P < 0.05) and positive lymph node metastases (P < 0.05). There was no significant association between p27 staining and the grade and tumour proliferation as assessed by the Ki-67 index. A high Ki-67 index correlated with higher grade and stage (P < 0.05). Kaplan-Meier plots of survival rate in patients with low or high p27 staining showed that low levels correlated with a shorter disease-free and overall survival (P < 0.001 and P < 0.01, respectively). Similarly, patients with a high Ki-67 index had lower disease-free and overall survival than those with a low Ki-67 index (P < 0.01 and P < 0.05, respectively). The Cox proportional hazards model showed that a low level of p27 was an independent predictor of a shorter disease-free (P < 0.01) and overall survival (P < 0.05) on univariate analysis, but not of overall survival on multivariate analysis. A high Ki-67 index was an independent prognostic marker for shorter disease-free survival on univariate and multivariate analysis (P < 0.01) and for overall survival on multivariate analysis (P < 0.05). In those with a high Ki-67 index, increased p27 staining was associated with a better prognosis than decreased staining for disease-free and overall survival (log-rank test, P < 0. 01 and P < 0.05, respectively).

CONCLUSIONS: The finding that a low level of p27 is associated with tumour invasion and unfavourable prognosis indicates that p27 may be a useful prognostic marker for survival in upper urinary tract cancer.

p53

Roles of p53 and MDM2 in tumor proliferation and determination of the prognosis of transitional cell carcinoma of the renal pelvis and ureter.

Hashimoto H, Sue Y, Saga Y, Tokumitsu M, Yachiku S.

Department of Urology, Asahikawa Medical College, Japan.

Int J Urol 2000 Dec;7(12):457-63 Abstract quote

BACKGROUND: The significance of p53 overexpression for the prognosis of transitional cell carcinoma (TCC) of the renal pelvis and ureter remains controversial. Simultaneous evaluation of p53 and MDM2 may enable better prediction of tumor proliferation and patient prognosis than that obtained with evaluation of p53 alone.

METHODS: Immunohistochemical detection of p53 protein, MDM2 protein and Ki-67 antigen as proliferation markers was performed for tissue samples obtained from 74 patients with TCC of the renal pelvis and ureter. The correlations of p53/MDM2 overexpression with conventional pathological features, Ki-67 labelling index (LI) and patient survival were studied.

RESULTS: Overexpression of p53 was related to progression of each of the pathological features examined (grade, stage, type of infiltration, vascular invasion and lymphatic invasion) and Ki-67 LI was significantly higher with high p53 expression than with low p53 expression. However, overexpression of MDM2 was related to neither disease progression nor Ki-67 LI. Survival analyses were performed for 66 patients. Univariate analysis showed p53 to be a useful prognostic indicator, but in a multivariate analysis only type of infiltration and Ki-67 LI were independent survival markers, while p53 was not. Overexpression of MDM2 was unrelated to patient survival, and the combination of p53 and MDM2 for survival indication was found not to be useful.

CONCLUSIONS: Overexpression of p53 is related to disease progression, increased tumor proliferation and patient survival for TCC of the renal pelvis and ureter, but the independent prognostic value of p53 did not reach statistical significance. Combined analysis of MDM2 with p53 cannot be recommended for examination of the malignant potential of TCC of the renal pelvis and ureter.

TREATMENT

SURGERY

Long-term follow-up of endoscopically treated upper urinary tract transitional cell carcinoma.

Elliott DS, Blute ML, Patterson DE, Bergstralh EJ, Segura JW.

Department of Urology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.

Urology 1996 Jun;47(6):819-25 Abstract quote
OBJECTIVES: This report focuses on the long-term follow-up of patients with endoscopically treated upper tract transitional cell carcinoma (TCC) to determine the effectiveness of endoscopic therapy.

METHODS: From May 1983 to April 1994, 44 patients with TCC of the upper urinary tract underwent conservative endourologic treatment with either electrocautery fulguration or neodymium:yttrium-aluminum-garnet laser at our institution. The mean follow-up period was 5 years (range, 3 months to 11 years).

RESULTS: Renal pelvic tumor sizes ranged from 0.4 to 4.0 cm (mean, 1.5) and ureteral tumors from 0.2 to 1.0 cm (mean, 0.5).The majority of tumors were of pathologic grade 3 or less, and all were Stage T2 or less. Seventeen of 44 patients (38.6%) had local tumor recurrence (mean time to recurrence, 12.8 months; range 1.5 to 64). Mean recurrence time was 7.3 months for renal pelvic tumors and 17.8 months for ureteral tumors. Nineteen of 44 patients (43.2%) developed bladder tumors. The overall 5-year disease-free rate was 57%. No recurrent tumor was shown to have increased in grade, and one recurrent tumor was proved to have progressed in stage. Six patients (14%) ultimately required a nephroureterectomy for recurrence. There were no major complications as a result of endoscopic therapy. Six patients (14%) died of the effects of metastatic TCC, 5 of whom had known muscle invasive bladder TCC.

CONCLUSIONS: Endourologic techniques and the conservative treatment of upper urinary tract TCC is an evolving field and can be safely and effectively used as a first-line treatment for upper tract TCC in selected patients.

Ureteroscopic treatment and surveillance of upper urinary tract transitional cell carcinoma.

Keeley FX Jr, Bibbo M, Bagley DH.

Department of Urology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

J Urol 1997 May;157(5):1560-5 Abstract quote
PURPOSE: We determined the efficacy of ureteroscopic treatment of upper urinary tract transitional cell carcinoma.

MATERIALS AND METHODS: Of 92 patients diagnosed with upper urinary tract transitional cell carcinoma at our institution from 1985 to 1995, 38 (41 kidneys) underwent ureteroscopic treatment and followup. Semirigid and flexible ureteroscopes were used to examine the collecting system. Tumors were biopsied, and treated with fulguration, the neodymium:YAG laser and/or the holmium:YAG laser. Patients were treated every 6 to 12 weeks until tumor-free and then followed on a strict endoscopic protocol.

RESULTS: Mean and median followup was 35.1 and 26 months, respectively (range 3 to 116). Grading of ureteroscopic biopsies was possible in 40 of 41 cases. Initial grading of tumors was low (grade 1 or 1 to 2) in 21 kidneys, grade 2 in 14 and grade 3 in 5. Of 41 kidneys 28 (68%) were documented as tumor-free ureteroscopically at some time following treatment, including 8 (29%) with subsequent recurrences that were treated endoscopically and 24 (86%) with no evidence of disease at the most recent followup. No patient to date has had progression of disease during endoscopic followup. High tumor grade, size and multifocality were significantly associated with tumor persistence and recurrence. Location in the kidney versus ureter was not a significant prognostic factor. Of the recurrent tumors 75% were not identified radiographically but were only discovered endoscopically. Two of 8 kidneys removed after endoscopic treatment had no tumor stage (pT0).

CONCLUSIONS: Endoscopic treatment of upper urinary tract transitional cell carcinoma is a reasonable method to treat carefully select patients based on strict indications. Complete endoscopic followup at regular intervals is essential to rule out recurrences.

Laparoscopic radical nephroureterectomy for upper tract transitional cell carcinoma: the Cleveland Clinic experience.

Gill IS, Sung GT, Hobart MG, Savage SJ, Meraney AM, Schweizer DK, Klein EA, Novick AC.

Section of Laparoscopic and Minimally Invasive Surgery, Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA

J Urol 2000 Nov;164(5):1513-22 Abstract quote

PURPOSE: We report our single institutional experience with retroperitoneal laparoscopic radical nephroureterectomy in patients with upper tract transitional cell carcinoma and compare results to those achieved by the open technique.

MATERIALS AND METHODS: A total of 77 patients underwent radical nephroureterectomy for pathologically confirmed upper tract transitional cell carcinoma. Of these patients 42 underwent laparoscopic nephroureterectomy from September 1997 through January 2000 and 35 underwent open surgery. All specimens were extracted intact. Of the laparoscopic group the juxtavesical ureter and bladder cuff were excised by our novel transvesical needlescopic technique in 27 and radical nephrectomy was performed retroperitoneoscopically in all 42. Data were compared retrospectively with 35 patients undergoing open radical nephroureterectomy from February 1991 through December 1999.

RESULTS: Laparoscopy was superior in regard to surgical time (3.7 versus 4.7 hours, p = 0.003), blood loss (242 versus 696 cc, p <0. 0001), specimen weight (559 versus 388 gm., p = 0.04), resumption of oral intake (1.6 versus 3.2 days, p = 0.0004), narcotic analgesia requirements (26 versus 228 mg., p <0.0001), hospital stay (2.3 versus 6.6 days, p <0.0001), normal activities (4.7 versus 8.2 weeks, p = 0.002) and convalescence (8 versus 14.1 weeks, p = 0.007). Complications occurred in 5 patients (12%) in the laparoscopic group, including open conversions in 2, and in 10 (29%) in the open group (p = 0.07). Followup was shorter in the laparoscopic group (11.1 versus 34.4 months, p <0.0001). The 2 groups were similar in regard to bladder recurrence (23% versus 37%, p = 0.42), local retroperitoneal or port site recurrence (0% versus 0%) and metastatic disease (8.6% versus 13%, p = 1.00). Mortality occurred in 2 patients (6%) in the laparoscopic group and 9 (30%) in the open group. Cancer specific survival (97% versus 87%) and crude survival (97% versus 94%) were similar between both groups (p = 0.59).

CONCLUSIONS: In patients with upper tract transitional cell carcinoma who are candidates for radical nephroureterectomy the retroperitoneal laparoscopic approach satisfactorily duplicates established technical principles of traditional open oncological surgery, while significantly decreasing morbidity from this major procedure. Short-term oncological and survival data of the laparoscopic technique are comparable to open surgery. Although long-term followup data are not yet available, it appears that laparoscopic radical nephroureterectomy may supplant open surgery as the standard of care in patients with muscle invasive or high grade upper tract transitional cell carcinoma.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.

Commonly Used Terms

Kidney-Renal Cell Carcinoma

Urinary Bladder Carcinoma

Last Updated 8/26/2002

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PATHOGENESIS	CHARACTERIZATION
APOPTOSIS
Apoptotic cell death and Smad4 expression in transitional cell carcinoma of the renal pelvis and ureter. Kong C, Zhang X, Takenaka I. Department of Urology, Kagawa Medical University, Kagawa, Japan.	Int J Urol 2001 Jul;8(7):386-90 Abstract quote PURPOSE: To investigate the frequency of apoptosis and the expression of Smad4 protein as well as their roles in transitional cell carcinoma (TCC) of the renal pelvis and ureter. METHODS: Apoptosis was detected by using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) technique in 34 formalin-fixed and paraffin-embedded specimens of renal pelvic and ureteral TCC. The expression of Smad4 was immunohistochemically studied. RESULTS: The incidence of apoptosis ranged from 1.10 to 3.75% with a median of 2.50% in TCC of the renal pelvis and ureter. The incidence of apoptosis was noted to be closely related to histologic grade but not to pathologic stage of the cancer. The expression of Smad4 was detected in six of 34 cases (17.6%). Regarding subcellular distribution, Smad4 protein was localized both in cytoplasm and nucleus of the cancer cells. In comparing the incidence of apoptosis with the expression of Smad4, no significant associations were seen between them. The expression of Smad4 was not related to the tumor grade nor stage of the cancer. CONCLUSIONS: The present study demonstrated close association of the incidence of apoptosis with the tumor grade of TCC of the renal pelvis and ureter. Significance of Smad4 expression was not noted in the study. It suggests that apoptotic cell death may play an important role in the tumor progression of renal pelvic and ureteral TCC.
CHROMOSOMAL ABNORMALITIES
Comparative genomic hybridization analysis of transitional cell carcinomas of the renal pelvis. Rigola MA, Fuster C, Casadevall C, Bernues M, Caballin MR, Gelabert A, Egozcue J, Miro R. Departament de Biologia Cel-lular, Fisiologia, Immunologia, Universitat Autonoma de Barcelona, Bellaterra E-08193, Spain. progression of this type of tumors.	Cancer Genet Cytogenet 2001 May;127(1):59-63 Abstract quote We used comparative genomic hybridization to analyze 10 primary tumor samples from patients with transitional cell carcinoma of the renal pelvis. The most frequent loss was located at 9q, that is, in 50% of the tumors. Gains of DNA sequences were most frequently observed in chromosome regions 1q21 approximately q23, 2p23 approximately p25, 8q21.1 approximately q22 and in the whole chromosome 20. High level amplifications at 1q21 approximately q25, 6p22 approximately p23, 8q21 approximately q22, 8q22 approximately q24.1, 11q13, and 12q14 approximately q21 were detected. Most of these regions have previously been reported to be involved in transitional cell carcinoma of the bladder, thus confirming the importance of an increasing number of chromosome imbalances in the development and progression of this type of tumors.
Upper tract urothelial carcinoma: a clinicopathologic study including microsatellite instability analysis. Blaszyk H, Wang L, Dietmaier W, Hofstadter F, Burgart LJ, Cheville JC, Hartmann A. Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota (HB, LW, LJB, JCC)	Mod Pathol 2002 Aug;15(8):790-7 Abstract quote Urothelial carcinoma of the renal pelvis and ureter may develop as a manifestation of the hereditary nonpolyposis colorectal cancer syndrome that is characterized by mutations in a number of DNA mismatch repair genes and detectable as microsatellite instability. In this study, we examined microsatellite instability and the clinicopathologic features of urothelial carcinoma of the renal pelvis (n = 61) and ureter (n = 53) from 114 consecutive patients surgically treated from 1985-1992. Clinical data were obtained through chart review. Matched normal and tumor DNA was extracted from paraffin-embedded tissue, and a panel of six microsatellite loci was analyzed. The male-female ratio was 2.8:1 with a median age of 70 years (range, 28 to 92 y). Microsatellite analysis was successful in 67 tumors, and 21 (31.3%) patients had tumors that exhibited microsatellite instability. Patients with microsatellite-unstable tumors were significantly more likely to have additional nonurologic cancers (P =.015) including colorectal carcinoma (P =.001) compared with patients with tumors that did not exhibit microsatellite instability. In addition, patients with microsatellite-unstable tumors showed more colorectal cancers in their family (P =.026) and were more likely to have higher grade urothelial carcinoma of the upper tract (P =.028). Grade and stage, but not microsatellite status, were the strongest predictors of cancer-specific survival. This study found the highest frequency of microsatellite instability in upper urothelial tract carcinomas reported to date and highlights upper tract urothelial carcinoma as a marker of the hereditary nonpolyposis colorectal cancer syndrome in some patients. These findings reinforce the importance of obtaining cancer histories in patients with upper tract urothelial carcinoma to subsequently identify individuals with the hereditary nonpolyposis colorectal cancer syndrome and at-risk relatives for surveillance and management programs.

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Transitional cell carcinoma of the renal pelvis: a retrospective look at CT staging with pathologic correlation. Buckley JA, Urban BA, Soyer P, Scherrer A, Fishman EK. Department of Radiology, Johns Hopkins Hospital, Baltimore, MD 21287, USA.	Radiology 1996 Oct;201(1):194-8 Abstract quote PURPOSE: To identify the reasons for the discrepancies between computed tomographic (CT) and pathologic staging of transitional cell carcinoma of the renal pelvis and to develop new criteria to increase the accuracy of CT in staging. MATERIALS AND METHODS: CT scans of 31 consecutive patients with renal pelvic transitional cell carcinoma were evaluated. CT and pathologic staging were compared. RESULTS: Pathologic staging revealed four stage 0 tumors, three stage I, five stage II, 10 stage III, and nine stage IV. The initial overall CT staging accuracy was 52% (16 of 31 patients). The sensitivity for minimal invasion was 17% (two of 12 patients). Two-thirds (10 of 15 patients) of the misinterpreted cases were overstaged as stage III. Proximal hydronephrosis was present in 80% of overstaged cases (eight of 10 patients). Reevaluation of the CT studies by using proximal hydronephrosis as a criterion for minimal invasion improved overall CT staging accuracy (77%). The revised staging yielded a sensitivity of 83% and specificity of 95% for minimal invasion and improved the specificity for deep invasion (17% to 92%). CONCLUSION: In a patient with transitional cell carcinoma of the renal pelvis, hydronephrosis proximal to the tumor may cause overstaging of stage 0-II disease and may not indicate more advanced disease.
LABORATORY MARKERS
CA19-9
CA19-9-producing transitional cell carcinoma of the renal pelvis: a case report. Taki T, Honda N, Yamada Y, Hibi H, Mitsui K, Matsuura O, Yoshikawa K. Department of Urology, Aichi Medical University.	Hinyokika Kiyo 2001 Mar;47(3):191-4 Abstract quote We report a case of CA19-9-producing transitional cell carcinoma of the renal pelvis. A 59-year-old male patient with left hydronephrosis was referred to us from a local physician. Retrograde pyelogram revealed irregular filling defects involving calices, pelvis and proximal ureter. The serum CA19-9 level was elevated. Under the diagnosis of renal pelvic tumor, we performed radical left nephroureterectomy. The tumor was histologically diagnosed as transitional cell carcinoma. The tumor cells showed positive immunostaining for CA19-9. The serum CA19-9 level was normalized after the operation. To our knowledge, this is the 28th case of a CA19-9-producing tumor in the Japanese literature.
PELVIC WASHINGS
Transitional cell carcinoma of the renal pelvis the diagnostic role of pelvic washings. Witte D, Truong LD, Ramzy I. Department of Pathology, Baylor College of Medicine and the Methodist Hospital, Houston, TX 77030, USA.	Am J Clin Pathol 2002 Mar;117(3):444-50 Abstract quote One hundred renal pelvic washings were reviewed blindly for 12 cytologic features. Of 52 washings with tissue confirmation, the cytologic diagnosis suggestive of or positive for transitional cell carcinoma (TCC) was made in 36 cases; 11 were negative, and 5 were unsatisfactory. Of 36 positive washings, histology confirmed the TCC diagnosis in 35 but revealed only reactive changes in 1. Of 11 negative washings, 9 were histologically negative for TCC, and 2 were positive for high-grade TCC. Among 48 washings without tissue confirmation, 33 were negative for TCC or showed reactive changes, 12 were negative for high-grade dysplasia or malignancy, but low-grade TCC could not be ruled out, 1 was suggestive of malignancy, and 2 were unsatisfactory. Clinical follow-up revealed no TCC. Predictive cytologic features of high-grade TCC were high nuclear/cytoplasmic ratio, isolated cells, anisonucleosis, nuclear hyperchromasia, and coarse chromatin; for low-grade they were presence of more than 5 papillary groups, cellular overlapping, anisonucleosis, and hyperchromasia. The sensitivity and specificity for the cytologic diagnosis were 89% and 97% for high-grade TCC and 100% and 78% for low-grade TCC, respectively. Renal pelvic washings can be used to accurately diagnose TCC of the renal pelvis. The positive predictive value for high-grade TCC is 93%, but for low-grade tumors it is 43%.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
COLLECTING DUCT CARCINOMA
Cytopathology of retrograde renal pelvis brush specimens: an analysis of 40 cases with emphasis on collecting duct carcinoma and low-intermediate grade transitional cell carcinoma. Zaman SS, Sack MJ, Ramchandani P, Tomaszewski JE, Gupta PK. Department of Pathology, University of Pennsylvania Medical Center, Philadelphia 19104, USA.	Diagn Cytopathol 1996 Nov;15(4):312-21 Abstract quote We report our experience with 40 retrograde renal brush samples of pelvic-calyceal lesions with confirmatory tissue studies. On-site cytopathologic evaluation was performed in 38 of these specimens. The final histologic diagnoses included 24 cases of transitional cell carcinoma (TCC), 17 of which were low-intermediate grade tumors. All 24 cases were diagnosed cytologically as TCC (22), or as suspicious for TCC (2). Three cases classified as collecting duct carcinomas were resected; the cytologic specimens in 2 of these cases were interpreted as TCC, and one as reactive change. There were three renal cell carcinomas (RCC); cytologically, one was considered a papillary neoplasm, one suspicious for malignancy, and one as reactive. Two cases of atypical renal cysts were reported as suspicious for malignancy in both cytologic and histologic material. There was one case of metastatic colon carcinoma identified in the brush specimen. Finally, tissue studies in the remaining 7 cases showed reactive/inflammatory changes; however, four of the corresponding pelvic brush specimens were considered abnormal. A review of the above cases is reported with the objective of presenting the cytologic features seen in collecting duct carcinoma, low-intermediate grade TCC, and diagnostically difficult cases with cyto/histomorphologic discrepancies. The contribution of on-site assessment to diagnostic accuracy is also discussed.
FIBROEPITHELIAL POLYP
Fibroepithelial polyp of the renal pelvis: nephron-sparing surgery after false-positive biopsy for transitional cell carcinoma. Brady JD, Korman HJ, Civantos F, Soloway MS. Department of Urology, University of Miami School of Medicine, Florida 33101, USA.	Urology 1997 Mar;49(3):460-4 Abstract quote Benign fibroepithelial polyps of the renal pelvis are extremely rare, with only 23 cases previously reported. The diagnosis is usually made following nephrectomy or nephroureterectomy for an assumed malignancy. This case involves a 66-year-old woman referred with presumed biopsy-proven transitional cell carcinoma of the renal pelvis. Radiographic findings were suggestive of a benign lesion. Pyelotomy and frozen section confirmed these suspicions. The polyp was excised and the kidney spared. The diagnosis and management of fibroepithelial polyps are discussed and the literature reviewed.
HEMANGIOPERICYTOMA
Hemangiopericytoma of renal sinus expanding to the renal hilum: an unusual presentation causes misinterpretation as transitional cell carcinoma. Choi YJ, Hwang TK, Kang SJ, Kim BK, Shim SI. Department of Clinical Pathology and Urology, Catholic University Medical College, Seoul, Korea.	J Korean Med Sci 1996 Aug;11(4):351-5 Abstract quote We report a case of renal hemangiopericytoma occurring in renal sinus and expanding to the renal hilum. This unusual presentation caused misinterpretation of this tumor as transitional cell carcinoma of the renal pelvis clinically. The patient who was a 30-year-old woman had a relatively well demarcated solid tumor, 8 x 6 cm, in the renal sinus of the left kidney.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
Renal pelvic neoplasms and atypical urothelium in patients with end-stage analgesic nephropathy. Blohme I, Johansson S.	Kidney Int 1981 Nov;20(5):671-5 Abstract quote In a series of 772 renal transplant patients, 84 had analgesic nephropathy (AN). Four of them had renal pelvic carcinoma. The incidence of atypical urothelial changes of the renal pelvis was studied in 56 AN patients, the majority nephrectomized before or shortly after the renal transplantation. Urothelial atypia, usually bilaterally, was found in 27 patients. Multiple sections resulted in an even higher incidence (8/9). No atypical changes were found in normal kidneys or in end-stage diseased kidneys with other diseases, or in chronically rejected renal allografts. These findings further strengthen the association between intake of phenacetin-containing analgesics and the development of renal pelvic tumors. Patients with end-stage analgesic nephropathy are a high-risk group for developing urinary tract tumors and should be subjected to endoscopic and cytologic surveillance. After renal transplantation, prophylactic bilateral nephroureterectomy is advocated.
Ki-67
Prognostic significance of Ki-67 labeling index in urothelial tumors of the renal pelvis and ureter. Masuda M, Iki M, Takano Y, Asakura T, Noguchi S, Ikeda I, Kubota Y, Hosaka M. Department of Urology, Yokohama City University School of Medicine, Japan.	J Urol 1996 Jun;155(6):1877-80 Abstract quote PURPOSE: We evaluated the prognostic significance of the Ki-67 labeling index in 70 patients with primary urothelial tumors of the renal pelvis and ureter. MATERIALS AND METHODS: Immunohistochemical staining for Ki-67 in archival tumor materials was done by the streptavidin-biotin method. RESULTS: Univariate survival analysis showed that the prognosis of patients with a high Ki-67 labeling index of 21.7 or more was significantly worse than that of patients with an intermediate labeling index of 13.3 to less than 21.7 (p < 0.01) or a low labeling index of less than 13.3 (p < 0.001). Multivariate survival analysis showed that staining for Ki-67 labeling index was significantly correlated with prognosis (p < 0.01). CONCLUSIONS: Analysis of Ki-67 labeling index provides useful prognostic information about patients with primary urothelial tumors of the renal pelvis and ureter.
p27
Prognostic significance of p27Kip1 and Ki-67 expression in carcinoma of the renal pelvis and ureter. Kamai T, Takagi K, Asami H, Ito Y, Arai K, Yoshida KI. Department of Urology, Dokkyo University School of Medicine, Tochigi, Japan.	BJU Int 2000 Jul;86(1):14-9 Abstract quote OBJECTIVE: To determine the significance of p27(Kip1) (p27) for tumour behaviour and prognosis of patients with transitional cell carcinoma (TCC) of the renal pelvis and ureter. PATIENTS AND METHODS: Using immunohistochemical staining, the relationship was evaluated between p27 protein level (low < 50%, high > 50%) and the Ki-67 labelling index (low < 30%, high > 30%) and clinicopathological features of 37 consecutive Japanese patients with TCC of the renal pelvis and ureter. RESULTS: Low levels of p27 correlated with higher tumour stage (P < 0.05) and positive lymph node metastases (P < 0.05). There was no significant association between p27 staining and the grade and tumour proliferation as assessed by the Ki-67 index. A high Ki-67 index correlated with higher grade and stage (P < 0.05). Kaplan-Meier plots of survival rate in patients with low or high p27 staining showed that low levels correlated with a shorter disease-free and overall survival (P < 0.001 and P < 0.01, respectively). Similarly, patients with a high Ki-67 index had lower disease-free and overall survival than those with a low Ki-67 index (P < 0.01 and P < 0.05, respectively). The Cox proportional hazards model showed that a low level of p27 was an independent predictor of a shorter disease-free (P < 0.01) and overall survival (P < 0.05) on univariate analysis, but not of overall survival on multivariate analysis. A high Ki-67 index was an independent prognostic marker for shorter disease-free survival on univariate and multivariate analysis (P < 0.01) and for overall survival on multivariate analysis (P < 0.05). In those with a high Ki-67 index, increased p27 staining was associated with a better prognosis than decreased staining for disease-free and overall survival (log-rank test, P < 0. 01 and P < 0.05, respectively). CONCLUSIONS: The finding that a low level of p27 is associated with tumour invasion and unfavourable prognosis indicates that p27 may be a useful prognostic marker for survival in upper urinary tract cancer.
p53
Roles of p53 and MDM2 in tumor proliferation and determination of the prognosis of transitional cell carcinoma of the renal pelvis and ureter. Hashimoto H, Sue Y, Saga Y, Tokumitsu M, Yachiku S. Department of Urology, Asahikawa Medical College, Japan.	Int J Urol 2000 Dec;7(12):457-63 Abstract quote BACKGROUND: The significance of p53 overexpression for the prognosis of transitional cell carcinoma (TCC) of the renal pelvis and ureter remains controversial. Simultaneous evaluation of p53 and MDM2 may enable better prediction of tumor proliferation and patient prognosis than that obtained with evaluation of p53 alone. METHODS: Immunohistochemical detection of p53 protein, MDM2 protein and Ki-67 antigen as proliferation markers was performed for tissue samples obtained from 74 patients with TCC of the renal pelvis and ureter. The correlations of p53/MDM2 overexpression with conventional pathological features, Ki-67 labelling index (LI) and patient survival were studied. RESULTS: Overexpression of p53 was related to progression of each of the pathological features examined (grade, stage, type of infiltration, vascular invasion and lymphatic invasion) and Ki-67 LI was significantly higher with high p53 expression than with low p53 expression. However, overexpression of MDM2 was related to neither disease progression nor Ki-67 LI. Survival analyses were performed for 66 patients. Univariate analysis showed p53 to be a useful prognostic indicator, but in a multivariate analysis only type of infiltration and Ki-67 LI were independent survival markers, while p53 was not. Overexpression of MDM2 was unrelated to patient survival, and the combination of p53 and MDM2 for survival indication was found not to be useful. CONCLUSIONS: Overexpression of p53 is related to disease progression, increased tumor proliferation and patient survival for TCC of the renal pelvis and ureter, but the independent prognostic value of p53 did not reach statistical significance. Combined analysis of MDM2 with p53 cannot be recommended for examination of the malignant potential of TCC of the renal pelvis and ureter.
TREATMENT
SURGERY
Long-term follow-up of endoscopically treated upper urinary tract transitional cell carcinoma. Elliott DS, Blute ML, Patterson DE, Bergstralh EJ, Segura JW. Department of Urology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.	Urology 1996 Jun;47(6):819-25 Abstract quote OBJECTIVES: This report focuses on the long-term follow-up of patients with endoscopically treated upper tract transitional cell carcinoma (TCC) to determine the effectiveness of endoscopic therapy. METHODS: From May 1983 to April 1994, 44 patients with TCC of the upper urinary tract underwent conservative endourologic treatment with either electrocautery fulguration or neodymium:yttrium-aluminum-garnet laser at our institution. The mean follow-up period was 5 years (range, 3 months to 11 years). RESULTS: Renal pelvic tumor sizes ranged from 0.4 to 4.0 cm (mean, 1.5) and ureteral tumors from 0.2 to 1.0 cm (mean, 0.5).The majority of tumors were of pathologic grade 3 or less, and all were Stage T2 or less. Seventeen of 44 patients (38.6%) had local tumor recurrence (mean time to recurrence, 12.8 months; range 1.5 to 64). Mean recurrence time was 7.3 months for renal pelvic tumors and 17.8 months for ureteral tumors. Nineteen of 44 patients (43.2%) developed bladder tumors. The overall 5-year disease-free rate was 57%. No recurrent tumor was shown to have increased in grade, and one recurrent tumor was proved to have progressed in stage. Six patients (14%) ultimately required a nephroureterectomy for recurrence. There were no major complications as a result of endoscopic therapy. Six patients (14%) died of the effects of metastatic TCC, 5 of whom had known muscle invasive bladder TCC. CONCLUSIONS: Endourologic techniques and the conservative treatment of upper urinary tract TCC is an evolving field and can be safely and effectively used as a first-line treatment for upper tract TCC in selected patients.
Ureteroscopic treatment and surveillance of upper urinary tract transitional cell carcinoma. Keeley FX Jr, Bibbo M, Bagley DH. Department of Urology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.	J Urol 1997 May;157(5):1560-5 Abstract quote PURPOSE: We determined the efficacy of ureteroscopic treatment of upper urinary tract transitional cell carcinoma. MATERIALS AND METHODS: Of 92 patients diagnosed with upper urinary tract transitional cell carcinoma at our institution from 1985 to 1995, 38 (41 kidneys) underwent ureteroscopic treatment and followup. Semirigid and flexible ureteroscopes were used to examine the collecting system. Tumors were biopsied, and treated with fulguration, the neodymium:YAG laser and/or the holmium:YAG laser. Patients were treated every 6 to 12 weeks until tumor-free and then followed on a strict endoscopic protocol. RESULTS: Mean and median followup was 35.1 and 26 months, respectively (range 3 to 116). Grading of ureteroscopic biopsies was possible in 40 of 41 cases. Initial grading of tumors was low (grade 1 or 1 to 2) in 21 kidneys, grade 2 in 14 and grade 3 in 5. Of 41 kidneys 28 (68%) were documented as tumor-free ureteroscopically at some time following treatment, including 8 (29%) with subsequent recurrences that were treated endoscopically and 24 (86%) with no evidence of disease at the most recent followup. No patient to date has had progression of disease during endoscopic followup. High tumor grade, size and multifocality were significantly associated with tumor persistence and recurrence. Location in the kidney versus ureter was not a significant prognostic factor. Of the recurrent tumors 75% were not identified radiographically but were only discovered endoscopically. Two of 8 kidneys removed after endoscopic treatment had no tumor stage (pT0). CONCLUSIONS: Endoscopic treatment of upper urinary tract transitional cell carcinoma is a reasonable method to treat carefully select patients based on strict indications. Complete endoscopic followup at regular intervals is essential to rule out recurrences.
Laparoscopic radical nephroureterectomy for upper tract transitional cell carcinoma: the Cleveland Clinic experience. Gill IS, Sung GT, Hobart MG, Savage SJ, Meraney AM, Schweizer DK, Klein EA, Novick AC. Section of Laparoscopic and Minimally Invasive Surgery, Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA	J Urol 2000 Nov;164(5):1513-22 Abstract quote PURPOSE: We report our single institutional experience with retroperitoneal laparoscopic radical nephroureterectomy in patients with upper tract transitional cell carcinoma and compare results to those achieved by the open technique. MATERIALS AND METHODS: A total of 77 patients underwent radical nephroureterectomy for pathologically confirmed upper tract transitional cell carcinoma. Of these patients 42 underwent laparoscopic nephroureterectomy from September 1997 through January 2000 and 35 underwent open surgery. All specimens were extracted intact. Of the laparoscopic group the juxtavesical ureter and bladder cuff were excised by our novel transvesical needlescopic technique in 27 and radical nephrectomy was performed retroperitoneoscopically in all 42. Data were compared retrospectively with 35 patients undergoing open radical nephroureterectomy from February 1991 through December 1999. RESULTS: Laparoscopy was superior in regard to surgical time (3.7 versus 4.7 hours, p = 0.003), blood loss (242 versus 696 cc, p <0. 0001), specimen weight (559 versus 388 gm., p = 0.04), resumption of oral intake (1.6 versus 3.2 days, p = 0.0004), narcotic analgesia requirements (26 versus 228 mg., p <0.0001), hospital stay (2.3 versus 6.6 days, p <0.0001), normal activities (4.7 versus 8.2 weeks, p = 0.002) and convalescence (8 versus 14.1 weeks, p = 0.007). Complications occurred in 5 patients (12%) in the laparoscopic group, including open conversions in 2, and in 10 (29%) in the open group (p = 0.07). Followup was shorter in the laparoscopic group (11.1 versus 34.4 months, p <0.0001). The 2 groups were similar in regard to bladder recurrence (23% versus 37%, p = 0.42), local retroperitoneal or port site recurrence (0% versus 0%) and metastatic disease (8.6% versus 13%, p = 1.00). Mortality occurred in 2 patients (6%) in the laparoscopic group and 9 (30%) in the open group. Cancer specific survival (97% versus 87%) and crude survival (97% versus 94%) were similar between both groups (p = 0.59). CONCLUSIONS: In patients with upper tract transitional cell carcinoma who are candidates for radical nephroureterectomy the retroperitoneal laparoscopic approach satisfactorily duplicates established technical principles of traditional open oncological surgery, while significantly decreasing morbidity from this major procedure. Short-term oncological and survival data of the laparoscopic technique are comparable to open surgery. Although long-term followup data are not yet available, it appears that laparoscopic radical nephroureterectomy may supplant open surgery as the standard of care in patients with muscle invasive or high grade upper tract transitional cell carcinoma.

Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms
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DISEASE ASSOCIATIONS	CHARACTERIZATION
ANALGESICS
Morphologic evidence that analgesic-induced kidney pathology contributes to the progression of tumors of the renal pelvis. Stewart JH, Hobbs JB, McCredie MR. Department of Medicine, University of Otago, and Dunedin Hospital, Dunedin, New Zealand.	Cancer 1999 Oct 15;86(8):1576-82 Abstract quote BACKGROUND: Whether phenacetin-containing analgesics cause renal pelvic tumors by virtue of the weak mutagenicity of phenacetin, or indirectly through local effects of analgesic-induced renal papillary scarring, is debated. Because phenacetin consumption ceased in New South Wales, Australia in 1975, cases of renal pelvic carcinoma seen 14-15 years later (many of which were associated with long-standing analgesic-induced renal papillary pathology) provided an opportunity to examine the temporal relation between phenacetin exposure and those histologic characteristics of the tumors and adjacent renal tissue that may implicate analgesics in their etiology. METHODS: The authors conducted a "blinded" histopathologic review of tumors of the renal pelvis and adjacent noncancerous renal tissue from 100 cases for which epidemiologic data regarding risk factor exposure (specifically phenacetin-containing analgesics, tobacco, infection, and kidney stones) had been obtained in a population-based case-control study from New South Wales in 1989 and 1990. RESULTS: A history of consumption of phenacetin-containing analgesics was associated strongly with the presence and severity of diffuse renal papillary scarring, and less strongly with papillary calcification. The histologic grade of the renal pelvic tumors tended to rise significantly with consumption of phenacetin-containing analgesics in a dose-dependent fashion and with the degree of papillary scarring, but was not related to smoking. In multivariate analysis it was the degree of papillary scarring (to a greater extent than the amount of phenacetin consumption) that was associated significantly and strongly with a higher histologic grade. Only diffuse papillary calcification was associated significantly with squamous change in the renal pelvic tumors. CONCLUSIONS: Based on the results of the current study, the authors conclude that 1) in phenacetin-related tumors of the renal pelvis, the presence and severity of analgesic-induced renal papillary scarring correlates with tumor progression and 2) papillary calcification is a risk factor for squamous change in renal pelvic urothelioma.
BLADDER CANCER, PRIOR
Upper tract transitional cell carcinoma following cystectomy for bladder cancer. Huguet-Perez J, Palou J, Millan-Rodriguez F, Salvador-Bayarri J, Villavicencio-Mavrich H, Vicente-Rodriguez J. Department of Urology, Fundacio Puigvert, Barcelona, Spain.	Eur Urol 2001 Sep;40(3):318-23 Abstract quote PURPOSE: We assessed the incidence of upper urinary tract tumors (UUTTs) after cystectomy for invasive or superficial transitional cell carcinoma (TCC) of the bladder. The risk factors, patients' characteristics and evolution of those who developed UUTTs are analyzed. MATERIALS AND METHODS: From August 1980 to February 1994, 568 radical cystectomies were performed for TCC of the bladder: in 469 instances (82.5%) due to invasive tumor (T2-T4), and in 99 cases (17.5%) for superficial tumor (Ta, T1, Tis). All patients were followed for at least 5 years or until death. A retrospective study of patients who developed UUTTs has been performed. A revision of bladder tumor and UUTT characteristics, and the intervals between both is also evaluated. RESULTS: 26 patients (4.5%) developed UUTTs: 11 of the 99 patients cystectomized for superficial TCCs (11.1%); 6 of the 392 patients with primary invasive TCC (1.5%), and 9 of the 77 (11.6%) patients with invasive tumors and a prior history of superficial TCC. The interval to the development of UUTT was higher after cystectomy for superficial tumor. TCCs of the bladder that subsequently developed UUTTs were high grade in 84%, multifocal in 80%, or had carcinoma in situ in 65%, tumor in the prostatic urethra in 52%, and involvement of the distal ureter in 57%. Twenty-two UUTTs (84%) were located in the calyces or the renal pelvis, 3 were bilateral (11.5%), 14 multiple (58%) and 4 superficial (16%). With a median follow-up time of 18 (range 3-103) months, 14 patients (53.8%) died of tumor, 2 were alive with disease, 2 were lost for follow-up, and 8 (30%) were alive and free of disease. CONCLUSIONS: We found that patients cystectomized for superficial or invasive TCC with a prior history of superficial TCC have a higher incidence of UUTTs. These cases require follow-up with annual urography or loopography.
CHRONIC PYELITIS
UROLITHIASIS

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
MYELOMA KIDNEY
Renal pelvic carcinoma with unusual appearance simulating amyloidosis (myeloma kidney): a report of five cases. Hes O, Michal M, Kinkor Z, Curik R, Baumruk L. Department of Pathology, Faculty Hospital, Pilsen, Czech Republic.	Int J Surg Pathol 2002 Jan;10(1):41-5 Abstract quote We describe 5 cases of urothelial carcinoma (UC) of the renal pelvis, which grew in a distinctive gross and microscopical pattern into the renal parenchyma. Five patients (2 men and 3 women, mean age 67.4 years) underwent nephrectomy for vague clinical findings. The cut surface of the tumor was white to light gray and the consistency was elastic. The corticomedullary border was indistinct, resulting in an appearance that suggested amyloidosis or myeloma. The renal pelvis showed normal mucosa with areas of dysplastic changes. The tumors spread from the renal pelvis in a diffuse and irregular, infiltrative pattern and surrounded intact glomeruli. Detailed sampling of invasive tumor component showed foci of UC with transitions to clear squamous cells. The predominant clear squamous neoplastic cells had foci of granular eosinophilic cytoplasm and resembled conventional renal cell carcinoma. Four patients were alive and without signs of the disease for 5 months to 4 years after nephrectomy; 1 died of generalized tumor 7 months after nephrectomy. The unusual gross and microscopic features result in varied problems in differential diagnosis, which are discussed herein.
THROMBUS IN VENA CAVA
Transitional cell carcinoma of the renal pelvis forming tumor thrombus in the vena cava. Miyazato M, Yonou H, Sugaya K, Koyama Y, Hatano T, Ogawa Y. Department of Urology, University of the Ryukyu, Okinawa, Japan.	Int J Urol 2001 Oct;8(10):575-7 Abstract quote A 47-year-old man presented with a left renal incidentaloma without hematuria. The tumor was complicated by inferior vena cava (IVC) thrombus extending from Th11 to L4. A temporary IVC filter was introduced prior to surgery. A midline incision was used to perform a left radical nephrectomy and en bloc lymphadenectomy with excision of the inferior vena cava from above the level of the left renal vein to 2.5 cm above the confluence of the common iliac veins. The pathological diagnosis was invasive transitional cell carcinoma. The tumor thrombus consisted of transitional cell carcinoma that histologically invaded the walls of the IVC. He died of cancer 17 months after the operation for the liver metastases. This is the 18th case report of such a presentation in the literature.

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
VARIANTS
SARCOMATOID CARCINOMA
Sarcomatoid transitional cell carcinoma of the renal pelvis. A report of five cases with clinical, pathological, immunohistochemical and DNA ploidy analysis. Lopez-Beltran A, Escudero AL, Cavazzana AO, Spagnoli LG, Vicioso-Recio L. Department of Pathology, Cordoba University Medical School, Spain.	Pathol Res Pract 1996 Dec;192(12):1218-24 Abstract quote Sarcomatoid transitional cell carcinoma of the renal pelvis is a rare neoplasm with only 7 well illustrated examples reported. These tumours can assume a partial or complete spindle cell pattern of growth, leading to the erroneous classification as sarcomas. We describe the clinic-pathologic features of five additional examples of sarcomatoid carcinoma of the renal pelvis observed in three males and two females. The age ranged from 65-to-82 years-old (mean 71.6). All these patients were treated by nephrectomy and died of disease between 6 and 20 months (mean 11.2) after the onset of symptoms. An immunohistochemical study demonstrated coexpression of keratins, epithelial membrane antigen and vimentin. The image DNA ploidy of all the tumours showed an aneuploid pattern.