Papillary transitional-cell carcinoma of the upper urinary tract: a cytological review

Urinary cytology is a well-accepted diagnostic procedure for bladder carcinomas but it is utilized less frequently for diagnosis of upper urinary tract tumors. Accurate diagnosis depends on a suitable specimen as well as knowledge of diagnostic traps. This review article with several case studies emphasizes the various techniques used to obtain optimal samples, correct interpretative criteria, and diagnostic pitfalls. Technological advances for objective grading and predicting the biological behavior of tumors are also discussed.     

Patterns of invasion and histological growth as prognostic indicators in urothelial carcinoma of the upper urinary tract

The biological significance of squamous and glandular differentiation and different patterns of invasion in upper urinary tract urothelial carcinoma is unclear. We reviewed 268 cases of consecutive upper urinary tract carcinomas with respect to the presence of squamous and/or glandular differentiation and different patterns of invasion (nodular, trabecular, and infiltrative) and correlated data with patient outcome. Squamous or glandular differentiation occurred in 47/268 (18%) tumors and its presence correlated with high tumor stage (P<0.001) and grade (P<0.001). Invasive patterns were nodular in 49/227 (22%), trabecular in 95/227 (42%), and infiltrative in 83/227 (37%) tumors. The nodular pattern prevailed in low stage (P<0.001) and low-grade (P<0.001) tumors, whereas the infiltrative pattern prevailed in high stage (P<0.001) and high-grade (P<0.001) tumors. Multivariate analysis proved that tumor stage (P<0.001) and the infiltrative pattern (P<0.001) are independent predictors of metastasis-free survival, whereas tumor grade and squamous and glandular differentiation lacked independent influence on patient outcome. In conclusion, the infiltrative pattern of invasion significantly correlated with advanced disease and poor patient outcome. In contrast, the presence of squamous and/or glandular invasion did not prove independent influence on patient outcome. The pattern of invasion should be commented upon separately in the pathology report.     

Micropapillary urothelial carcinoma of the upper urinary tract: Clinicopathologic study of five cases

We report 5 cases of micropapillary urothelial carcinoma (MPUC) involving the renal pelvis (2), renal pelvis and ureter (2), and proximal ureter (1). The patients were 2 women and 3 men, ages 65 to 92 years (mean, 76.0 years). All tumors showed a high-grade transitional cell carcinoma component, and in 3 cases, there also were areas of in situ carcinoma. The case involving only the ureter occurred in a 65-year-old man with a history of nephrectomy 12 years previously for urothelial carcinoma of the renal pelvis. The tumor recurred in the ureteral stump. In all cases, areas displaying micropapillary architecture were observed. In 2 cases the micropapillary areas were noninvasive; in 1 case a pure invasive pattern was seen; and in 2 cases a mixed invasive and noninvasive pattern was present. the micropapillary pattern was invasive; and the case involving the ureteral stump contained invasive and noninvasive micropapillary carcinoma. All patients died of their tumors from 3 to 24 months after initial diagnosis. MPUC involving the renal pelvis and ureter is associated closely with advanced stages of disease and has highly aggressive behavior. Recognition of this growth pattern is important for prognosis and avoiding misdiagnosis with papillary renal cell carcinoma and other tumors.     

Sarcomatoid carcinoma of the upper urinary tract: clinical outcome and molecular characterization

Sarcomatoid carcinoma (carcinosarcoma) of the upper urinary collecting system is a rare aggressive malignancy composed of malignant epithelial and stromal components. Because of the paucity of reported cases, the clinical behavior, molecular alterations, and potential therapies for this malignancy are not well understood. Eight cases of sarcomatoid carcinoma involving the upper urinary tract were studied. Clinicopathologic characteristics were reviewed. Immunohistochemical expression of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2)/neu, c-kit, and p53 was analyzed in each case. Evaluation for amplification of EGFR and HER2 genes was performed by interphase fluorescence in situ hybridization (FISH). Each tumor was also examined for gains of chromosomes 3, 7, and 17 and for loss of chromosome 9p21 by UroVysion FISH (Vysis, Downers Grove, IL). The patients we studied were 5 females and 3 males, ranging in age from 56 to 78 years (mean age, 69 years). Presenting symptoms included gross hematuria, flank mass, urinary obstruction, fever, or sepsis. Radical nephroureterectomy was performed on all patients. Tumor size ranged from 2 to 13 cm. Coexisting urothelial carcinoma was present in all 8 cases. Heterologous osteosarcoma was identified in 2 cases. Pathologic stage was pT4 in 5 cases and pT3 in 3 cases. Lymph node metastases were present in 5 patients at the time of surgery. Of 8 patients, 7 died within 2 years after surgery. EGFR immunostaining had moderately to strongly positive results in 6 of 8 cases. Both HER2/neu and c-kit immunostaining had negative results in all cases. p53 immunostaining had positive results in 5 of 8 cases. The EGFR polysomy was demonstrated in 7 of 8 cases. No amplification of HER2/neu was present in any case. UroVysion FISH showed abnormalities typical of urothelial carcinoma in all 8 cases. In conclusion, the prognosis of sarcomatoid carcinoma of the upper urinary tract is extremely poor, most patients died within 2 years (7/8 patients). Gains of chromosome 3, 7, and 17 and loss of chromosome 9p21 were commonly observed in these tumors. Our findings suggest that targeted therapy may be a rational strategy in the management of these patients.     

Squamous differentiation and prognosis in upper urinary tract urothelial carcinoma

Squamous differentiation is the most common histological variation in urothelial carcinoma (UC). However, the clinical significance of squamous differentiation in upper urinary tract UC is unclear. To investigate the significance of squamous differentiation, hematoxylin and eosin stained slides from 140 patients with upper urinary tract UC who underwent nephroureterectomy were reviewed by a single pathologist and the presence of squamous differentiation was recorded. Squamous differentiation was observed in 23 out of 140 studied cases (16%). Squamous differentiation significantly correlated with several adverse prognostic factors including histological grade 3 tumors, presence of lymphovascular invasion, concomitant carcinoma in situ, advanced tumor stage, and occurrence of lymph node metastasis. The Kaplan-Meier and univariate Cox regression analyses revealed that the presence of squamous differentiation was significantly associated with shorter metastasis-free survival [log-rank P = 0.030; univariate hazard ratio (HR), 2.30; 95% confidence interval (CI), 1.06-4.99], cancer-specific survival (log-rank P = 0.0024; univariate HR 3.34; 95% CI, 1.47-7.85), and overall survival (log-rank P = 0.018; univariate HR 2.39; 95% CI, 1.13-5.06) after nephroureterectomy. However, in multivariate analyses, squamous differentiation was not significantly associated with patient outcomes. These findings suggest that squamous differentiation is associated with disease progression, but is not an independent predictor of a worse prognosis in patients with upper urinary tract UC.     

Transitional cell carcinoma with sarcomatous elements in the urinary tract. Six cases examined by immunohistochemistry.

We report six cases of carcinoma showing sarcomatous change in the urinary tract examined by conventional histochemistry and immunohistochemistry. All of the cases were transitional cell carcinoma with or without focal squamous cell carcinoma. Sarcomatous components resembling spindle cell sarcoma with a marked myxoid stroma or chondrosarcomatous element were also observed in all cases. The sarcomatous elements were closely associated with the areas of squamous cell carcinoma in three cases. Various histochemical staining procedures demonstrated mesenchymal features in the stroma of sarcomatous areas. By immunohistochemical examination, the epithelial components showed positive reactions for keratin, epithelial membrane antigen and, focally, carcinoembryonic antigen. The sarcomatous components revealed a positive immunoreaction for keratin but lacked other epithelial markers in all cases. Chondrosarcomatous elements in two cases were positive for both keratin and S-100 protein. These findings indicate that sarcomatous elements in carcinoma may represent mesenchymal metaplasia with partial or complete loss of epithelial features. However, further study will be necessary in order to determine whether heterogeneous elements, such as chondrosarcomatous areas, are epithelial or truly mesenchymal in origin.     

Pacemaker activity in the upper urinary tract.

Ureteral peristaltic activity begins with the origin of electrical activity at pacemaker sites. These sites are located in the proximal portion of the urinary collecting system. The 'atypical' smooth muscle cells at these sites fire 'pacemaker' potentials at a frequency higher than the 'driven' action potentials recorded from typical smooth muscle cells. In contrast to typical smooth muscle cells, these atypical pacemaker cells have less than 40% of their cellular area occupied by contractile filaments and demonstrate a sparse immunoreactivity for alpha-smooth muscle actin. Expression of c-Kit, a tyrosine kinase receptor, correlates with the onset of organized ureteral peristalsis in the embryo. Capsaicin-sensitive sensory afferents and the endogenous release of tachykinins and prostaglandins are involved in the maintenance of normal ureteral peristalsis.     

Lymphoepithelioma-like carcinoma of the urinary tract: a clinicopathological study of 30 pure and mixed cases.

We studied 28 cases of lymphoepithelioma-like carcinoma of the bladder, one case in the renal pelvis, and one in the urethra. The mean age of the patients was 67.6 years with 21 (70%) males. Seventeen cases (56.7%) were pure with the remaining mixed with other patterns of carcinoma, including invasive urothelial carcinoma (n=10), invasive adenocarcinoma (n=3), and squamous cell carcinoma (n=2). The surface demonstrated carcinoma in situ (CIS) in six cases, noninvasive high-grade papillary urothelial carcinoma in three cases, and in situ adenocarcinoma in one case. In 19/30 (66%) cases, there was a heavy lymphocytic infiltrate and in the remaining 11/30 (34%) cases a mixed inflammatory infiltrate. None of the 26 cases labeled for EBV-encoded RNA by in situ hybridization. Tumor stages at presentation were: seven cases T1 (23%); 14 cases T2 (47%); seven cases T3 (23%); and two cases T4 (7%). Treatment consisted of radical cystectomy in 13/30 cases (43%); partial cystectomy in 4/30 cases (13%); nephrectomy in one case (3%), and transurethral resection often followed by radiation or chemotherapy in 12/30 (40%) cases. The mean follow up for patients without progression was 31 months. Eight of 27 cases with follow-up (30%) cases had tumor recurrence, with seven patients having metastases. In cases treated with cystectomy, the 5-year actuarial recurrence-free risk was 59% (62 and 57%, for pure and mixed cases, respectively). Lymphoepithelioma-like carcinoma, whether in pure or mixed form, has a similar prognosis to ordinary urothelial carcinoma when treated by cystectomy. Of the three pure cases treated by chemotherapy, two were free of disease at 4 and 65 months and the third had recurrent disease at 17 months. Given the association of lymphoepithelioma-like carcinoma with urothelial carcinoma in 47% of our cases and its propensity for multifocality, partial cystectomy would typically be ill advised for lymphoepithelioma-like carcinoma.     

Radiation disease of the urinary tract: histological features of 18 cases.

AIMS: To study the spectrum of histological changes in the urinary tract caused by pelvic irradiation. METHODS: Biopsy specimens of ureter and bladder and cystectomy specimens from 18 patients who had received pelvic irradiation were studied and the histological features were arbitrarily grouped into early and late changes. RESULTS: A wide range of histological changes were noted of which submucosal inflammation, fibrosis, and epithelial damage were the commonest. Other less common features were interstitial haemorrhage, ureteritis and cystitis cystica, squamous metaplasia of vaginal type and perineural inflammation. CONCLUSIONS: Although epithelial changes were most prominent in early cases and stromal changes in the late cases, there was a continuing spectrum of epithelial damage which persisted many years after initial radiation. Similarly, submucosal fibrosis was equally prominent in early and late phases.     

Clinicopathologic study of basaloid squamous carcinoma of the upper aerodigestive tract.

The clinicopathologic and immunohistochemical characteristics of nine cases of basaloid squamous carcinoma (BSC) of the upper aerodigestive tract are reported, along with the results of an in situ hybridization for human papilloma virus (HPV) DNA. The cases were selected through a review of 237 head and neck carcinomas, and were located in the supraglottic larynx (5), hypopharynx (2), and the base of tongue (2). The patients were 7 males and 2 females with the mean age of 62. BSCs were histologically characterized by lobules and nests of basaloid cells with scanty cytoplasm, comedonecrosis and adenoid features, and by concomitant presence of squamous cell carcinoma. Immunohistochemically, all BSCs showed positivity for high molecular weight cytokeratin (HMW CK) with heterogeneous or diffuse staining pattern, but lacked reactivity for neuroendocrine markers and bcl-2 oncoprotein. No HPV DNA was detected in BSCs. This study reaffirms that BSC is a rare carcinoma with a peculiar topographic distribution and distinct pathologic features.     

Scanning electron microscopy of the upper urinary tract in transitional cell carcinoma of the renal pelvis.

Three nephrectomy specimens with transitional cell carcinoma (TCC) of the renal pelvis were thoroughly examined by both light and scanning electron microscopy. The tumours as well as the urothelium of the upper urinary tract were studied. In all three cases, extensive areas of the urothelium, even in places remote from the tumours, were found by scanning electron microscopy (SEM) to be covered by pleomorphic microvilli. This suggests that there is a widespread failure of differentiation of the urothelium to a much greater extent than can be appreciated by conventional light microscopy.     

Unsuspected analgesic nephropathy in transitional cell carcinoma of the upper tract: a morphological study

Analgesic nephropathy is known to have a high incidence in Australia where, following the experience in Scandinavia, reports have been published for some time recording the association between analgesic nephropathy and urothelial malignancies. The morbid anatomical features of analgesic nephropathy are now sufficiently well accepted to allow a retrospective study of unselected nephrectomies for transitional cell carcinoma of the renal pelvis and ureter, in order to assess the incidence of analgesic-type changes in this well defined group of malignancies. The records of a large general histopathology department between 1972–1978 were searched and 24 consecutive transitional cell carcinomas in these sites treated by nephrectomy were selected for study. Of these, 21 were suitable for assessment and on review were shown to comprise 11 cases with papillary changes acceptable as analgesic in type and five which were suggestive of early analgesic change. Of these 16, seven were female, only two were known analgesic abusers and five were recorded as consuming analgesics on a regular basis. These findings suggest that analgesics may play a significant role in the pathogenesis of urothelial malignancy in the general population.     

Urothelial carcinoma of the upper urinary tract: inverted growth pattern is predictive of microsatellite instability

Urothelial carcinoma of the renal pelvis and ureter may develop as a manifestation of hereditary nonpolyposis colorectal cancer syndrome (HNPCC), a disorder characterized by mutation or inactivation of a number of DNA mismatch repair genes and detectable as microsatellite instability (MSI). Some urothelial carcinomas display areas of endophytic, or inverted, growth. In this study, urothelial cancers of the upper urinary tract (n = 132) from patients treated at 2 tertiary care centers were studied to identify an association between growth pattern and MSI. Thirty-five neoplasms were microsatellite unstable (26.5%), and MSI was more frequent in papillary lesions than in sessile urothelial cancers (P = .033). The amount of inverted growth was estimated as a percentage of the total tumor. The interobserver and intraobserver concordance in recognizing inverted growth was good, and 65.7% of microsatellite-unstable tumors exhibited at least 20% of an inverted growth component, compared with only 17.5% of microsatellite-stable tumors (P < .0001). In this series, inverted growth predicted MSI with a sensitivity and specificity of .82. Inverted growth in urothelial carcinomas of the upper urinary tract may serve as a marker lesion for MSI and may help identify patients who should be offered testing for HNPCC.     

Prognostic significance of epithelial-mesenchymal transition phenotypes in upper urinary tract urothelial carcinoma

Epithelial-mesenchymal transition (EMT) is a process which epithelial cells gain mesenchymal phenotype such as motility and invasiveness. We investigated the role of EMT in upper urinary tract urothelial carcinoma (UTUC). The patient cohort included 93 cases of UTUC treated with radical nephroureterectomy. Tissue microarrays were constructed from formalin-fixed paraffin-embedded tissue blocks. Immunohistochemical staining was performed for E-cadherin, vimentin, and smooth muscle actin to evaluate the EMT status. Interpretation criteria were defined for the staining results and EMT phenotypes were assigned as wild type, incomplete type (loss of E-cadherin and negative for vimentin), and complete type (loss of E-cadherin and positive for vimentin). The loss of E-cadherin and vimentin-expression was observed in 76 (81.7%) and 10 (10.8%) cases, respectively, yielding EMT phenotypes comprised of 17 cases (18.3%) of wild type, 66 cases (71.0%) of incomplete type, and 10 cases (10.8%) of complete types. In survival analyses, wild type showed statistically significant association with longer extra-bladder recurrence free survival (p?<?.001) and overall survival (p?<?.001). In multivariate analyses, complete type was an independent prognostic factor for extra-bladder recurrence free survival and overall survival. EMT phenotype based on the combination of EMT-related markers may provide a useful prognostic marker for UTUC patients.     

Production of beta-human chorionic gonadotropin by prostatic adenocarcinoma and transitional cell carcinoma of the upper urinary tract.

Ectopic production and secretion of hormones by a wide variety of tumours has been known for many years. Recently human chorionic gonadotropin (HCG) production and/or secretion have been noted in 15 cases with prostatic adenocarcinoma (Fukutani et al. 1983; Papapetrou et al. 1980: Broder et al. 1977; Menon & Stefani 1980; McManus et al. 1976) and in two with upper urinary tract transitional cell carcinoma (Fukutani et al. 1983; McManus et al. 1976). In this study we utilised the indirect immunoperoxidate technique to demonstrate beta-HCG production in prostatic adenocarcinoma and upper urinary tract urothelial tumours. Of 100 cases of prostatic adenocarcinoma beta-HCG production was demonstrated in nine cases, eight of which were poorly differentiated, and of 14 urothelial tumours of the upper urinary tract beta-HCG production was present in two high grade transitional cell carcinomas.