Spindle cell carcinoma progressed from transitional cell carcinoma of the urinary bladder

The author reports a very rare case of spindle cell carcinoma (SpCC) of the urinary bladder progressed from ordinary papillary transitional cell carcinoma (TCC). A 63-year-old man complained of hematuria. A transurethral endoscopic examination revealed a papillary tumor, and transuthetral resection of bladder tumor (TUR-BT) was performed and was diagnosed as ordinary papillary urothelial TCC. Since then, he was treated with TUR-BT eight times. Chemotherapy, radiation, radical cystectomy and lymph nodes dissection were performed 16 years after the first TUR-BT. However, he developed rectal mucosal metastasis. He is now alive 17 years after the first presentation. All the TUR-BT specimens were ordinary papillary TCCs without invasion (pTa). Immunohistochemically, the TUR-BT specimens were positive for pancytokeratin, high molecular weight cytokeratin (CK), CK 5/6, CK 7, CK 18, CK 19, CK 20, p53, p63, Ki-67 (10%), and negative for other antigens examined including vimentin. The cystectomy bladder specimens show broad ulcers and polypoid lesions, and malignant spindle cells (SpCC) invading into muscular layer were present. No TCC elements were recognized. The tumor cells were positive strongly for vimentin, and less strongly for pancytokeratin, high molecular weight cytokeratin, CK 5/6, CK 14, CK 18, p53, p63 and Ki-67 (95%), and negative for other antigens examined. The rectal metastatic lesion showed SpCC without TCC elements, and were strongly positive for vimentin, and weakly positive for pancytokeratin, S100 protein, p53, p63, Ki-67 (90%), neuron-specific enolase, CD56, KIT and PDGFRA. It was negative for other antigen examined. It is strongly suggested that the present SpCC were progressed from ordinary TCC.     

Association between the expression pattern of p16, pRb and p53 and the response to intravesical bacillus Calmette-Guerin therapy in patients with urothelial carcinoma in situ of the urinary bladder

There is limited data regarding the association between the expression of cell cycle-regulating molecules and the response of patients with urothelial carcinoma in situ (CIS) to bacillus Calmette-Guerin (BCG) therapy. To examine the relationship between p16, pRb and p53 expression in bladder CIS and patient response to initial BCG therapy, we performed immunohistochemical studies for 27 patients with bladder CIS. Overexpression of p16, pRb, and p53 was observed in 37%, 41%, and 48% of patients, respectively. Initial BCG therapy was effective in 21 patients (78%). Coexistence of papillary urothelial carcinoma, depth (pTa or pT1) and grade of coexisting papillary carcinoma did not affect the response to BCG therapy. pRb overexpression had a significant relationship to poor response to BCG therapy (P= 0.027). The results of this study indicate that overexpression of pRb in bladder CIS predicts poor response of intravesical BCG instillation and status of p16 and p53 may not be predictive of initial BCG failure.     

E-cadherin expression in urothelial carcinoma in situ,superficial papillary transitional cell carcinoma,and invasive transitional cell carcinoma

Flat urothelial carcinoma in situ (CIS) is a precursor of invasive transitional cell carcinoma (TCC). High-grade TCCs frequently are accompanied by CIS in surrounding urothelium. In contrast, superficial, noninvasive papillary TCCs are often low grade and generally are unaccompanied by CIS. E-cadherin (E-CD) is a member of a family of transmembrane glycoproteins involved in intercellular adhesion. Loss or decreased expression of E-CD has been linked to the invasive phenotype of a wide variety of human neoplasms, including bladder tumors. The objective of this study was to compare the expression of E-CD in high-grade urothelial dysplasia (HD)/CIS, superficial papillary TCC, benign urothelium, and invasive TCC. Staining for E-CD was performed in formalin-fixed, paraffin-embedded sections using a Ventana NexES immunostainer (Tuscon, AZ). Percentage and intensity of cell membrane staining for E-CD was calculated for the 4 groups using the quantitative Automatic Cellular Imaging System (ChromaVision, San Juan Capistrano, CA). The results were as follows: The CIS group (n = 23) had percentage and intensity (92.8%, 120.0 U) of E-CD expression similar to the superficial noninvasive papillary TCC group (n = 16, 97.8%, 123.0 U) and the benign urothelium group (n = 17, 87.9%, 104.6 U), but it had statistically significant higher percentage and intensity than the invasive TCC group (n = 15, 45.4%, and 39.2 U, P <.05). Our data indicate that CIS and superficial, noninvasive papillary TCCs strongly express E-CD. In contrast, loss of E-CD expression is associated with the invasive TCC phenotype. Only when TCCs become invasive does E-CD expression decrease in directly proportion to the depth of invasion.     

CK5, CK5/6, and Double-Stains CK7/CK5 and p53/CK5 Discriminate In Situ vs Invasive Urothelial Cancer in the Prostate

For primary bladder tumors, distinguishing urothelial carcinoma (UC) invading the fibromuscular stroma of the prostate (pT4a) from in situ UC involving prostatic ducts can be difficult. Immunohistochemical markers (cytokeratin [CK]5/6, CK5, CK7, CK20, p53, p63, high-molecular-weight keratin [HMWK], androgen receptor, prostate-specific antigen [PSA], prostate specific acid phosphatase [PSAP], laminin, CD44s, CD141) were assessed for their usefulness in determining depth of UC invasion in the prostate. In cystoprostatectomy specimens containing in situ UC in prostatic ducts, both CK5/6 and CK5 clearly differentiated prostatic basal cells from in situ UC. The remaining markers were not effective in determining depth of tumor invasion. Double-stain combinations CK7/CK5 and p53/CK5 were performed and robustly color contrasted in situ tumor from surrounding basal cells. The use of CK5/6, CK5, CK7/CK5, or p53/CK5 is recommended to assist in determining the depth of UC invasion in the prostate when histologic findings are equivocal.     

Flat urothelial carcinoma in situ of the bladder with glandular differentiation

We present the clinicopathologic and immunonohistochemical features of 25 cases of flat urothelial carcinoma in situ with glandular differentiation. Previously, cases on this category have been reported as in situ adenocarcinoma (a term not currently preferred). Fourteen of 25 cases had concurrent conventional urothelial carcinoma in situ. Five of the cases were primary carcinoma in situ with glandular differentiation; twenty cases of secondary carcinoma in situ with glandular differentiation were associated with urothelial carcinoma alone (n = 11) or with glandular differentiation (n = 7), discohesive (n = 1) or micropapillary carcinoma (n = 1). The individual tumor cells were columnar. The architectural pattern of the carcinoma in situ with glandular differentiation consisted of 1 or more papillary, flat or cribriform glandular patterns. Univariate statistical analysis showed no survival differences between urothelial carcinoma in situ with glandular differentiation and conventional urothelial carcinoma in situ (log-rank 0.810; P = .368). Carcinoma in situ with glandular differentiation showed high ki-67 index and p53 accumulation, high nuclear and cytoplasmic p16 expression and diffuse PTEN expression, a phenotype that also characterized concurrent conventional carcinoma in situ. MUC5A, MUC2, CK20, and c-erbB2 were positive in all 25 cases of urothelial carcinoma in situ with glandular differentiation, and CDX-2 was present in 19 cases; MUC1, CK7, or 34βE12 was focally present in 21, 19, and 18 cases, respectively. MUC1core was negative in all cases. We concluded that urothelial carcinoma in situ with glandular differentiation is a variant of carcinoma in situ that follows the natural history of conventional urothelial carcinoma in situ. The immunophenotype suggests urothelial origin with the expression of MUC5A and CDX2 as signature for glandular differentiation.     

Iatrogenic pathology of the urinary bladder

Intravesical immunotherapy, chemotherapy, and neoadjuvant systemic chemotherapy are among the most frequent therapeutic procedures to treat malignancies of the urinary bladder. These treatment modalities produce reactive morphologic changes in the urothelium that can mimic urothelial carcinoma in situ, urothelial dysplasia or true invasive urothelial neoplasia. Mitomycin C used after transurethral resection of bladder tumor to reduce recurrences, BCG intravesical immunotherapy to treat high risk non-muscle invasive bladder cancer and urothelial carcinoma in situ, and platinum-based systemic chemotherapy to improve post-cystectomy disease-specific survival some of the causes of therapy related atypia in urinary bladder. In addition, a number of systemic drugs in use to treat other systemic diseases, such as cyclophosphamide used to treat certain auto-immune disorders or hematologic malignancies, or the anesthetics ketamine increasingly used as illegal recreational drug, may produce similarly relevant atypical changes in the urothelium, and therefore, need to be differentiated from intraepithelial neoplasia. Immunohistochemical approach to reactive urothelium from CIS using CK20, p53, and CD44 may also be of utility in the pos-therapy scenario.     

Effects of alanine cluster mutations in the D12 subunit of vaccinia virus mRNA (guanine-N7) methyltransferase

The SV40 large T-antigen (TAg) has proven useful in studying pathways involved with cell division and tissue homeostasis. TAg disrupts the normal action of tumor suppressors pRb and p53. It is unclear whether T-antigen inhibition of p53 and pRb is sufficient for oncogenic transformation or if additional T-antigen activities are required. To pursue this question, cell lines were generated that coexpress an amino-terminal fragment of T-antigen (TAgN136), which has been shown to be sufficient to block pRb function, together with a dominant-negative p53. Neither focus formation nor saturation density was enhanced by coexpression of the dominant-negative p53 molecule, p53DD, along with TAgN136. Furthermore, a full-length TAg mutant incapable of binding p53 was capable of relieving contact inhibition, a hallmark of transformation. These results suggest the presence of a novel transforming activity in addition to the binding and inactivation of p53, requiring TAg amino acids 137 to 708.     

Correlation of cytokeratin patterns with histopathology during neoplastic progression in the rat urinary bladder.

The discrimination of atypical (premalignant) cells from invasive neoplastic cells in primary bladder lesions is a major diagnostic problem in cytopathology and surgical pathology. We have used an animal model of urinary bladder carcinogenesis to determine the specific changes which occur in the expression of certain cytokeratins (CK) during the progression of lesions from regenerative hyperplasia and carcinoma in situ to transitional cell carcinomas. At sequential time points following exposure of the rat bladder epithelium to N-methyl-N-nitrosourea in vivo, immunohistochemical staining of CKs was evaluated in ethanol-fixed samples from the induced urothelial lesions using commercially available anti-CK mouse monoclonal antibodies. Specific changes were found in the expression of CKs 13, 18, and 19 during the neoplastic progression of induced urothelial lesions in the rat. These changes included the reciprocal loss of expression of CK 19 and the reappearance of CK 18 as malignant tumors developed. Invasive cells also did not express CK 13. Our results, based on the rat model, are similar to those reported by others on CK expression in human bladder tumors. Because these changes in CK expression occurred at specific points in the progression of urothelial lesions, the antibodies utilized in this study may be helpful in predicting the invasive potential of cells present in cytopathological specimens and tissue biopsies from human urothelial lesions.     

Mixed papillary adenocarcinoma and transitional cell carcinoma of the uterine cervix

A mixed papillary adenocarcinoma and transitional cell carcinoma (MAcTcc) was discovered in the uterine cervix of a 38-year-old woman. A condylomatous papillary lesion was found in the uterine cervix during a colposcopic study and histopathological examination showed that the tumor was composed of two different neoplastic subtypes. One was an adenocarcinoma (AC) component showing papillary and tubular structure with endocervical and intestinal differentiation; the other was a transitional cell carcinoma (TCC) component showing papillary excrescence mimicking papillary TCC of urothelial origin. To characterize the tumor, an immunohistochemical study of cytokeratins (CK) was performed. The AC component showed immunoreactivities similar to conventional adenocarcinomas: positive immunoreactivity of low-molecular-weight cytokeratins 7, 8 and 19, and negative immunoreactivity of CK20 and high-molecular-weight cytokeratin (34βE12). The lower epithelial layer of the TCC component showed different immunoreactivity, but the superficial epithelial layer had similar immunohistochemical findings to the AC component. These findings indicate that the TCC component had the cellular character of AC rather than that of TCC or squamous cell carcinomas. This is thought to be the first report of a MAcTcc of the uterine cervix.     

Molecular and kinetic features of transitional cell carcinomas of the bladder: biological and clinical implications

Molecular and kinetic analyses have contributed to our understanding of the biology of transitional cell carcinomas (TCC) of the bladder. The concordant pattern of X-chromosome inactivation of multiple TCCs appearing at different times and at different sites and concordant genetic abnormalities in a subset of muscle-invasive TCC strongly support a monoclonal origin and a homogeneous tumor cell selection throughout the neoplasm. However, topographic intratumor heterogeneity results from the accumulation of genetic lesions in tumor suppressor genes, predominantly neurofibromatosis (NF)-1-defective in the superficial compartment and tumor protein p53 (TP53)-defective in the deep one, with lower proliferation and down-regulation of apoptosis in the latter. TCCs follow the general concept of multistep carcinogenesis and proceed through two distinct genetic pathways responsible for generating different TCC morphologies. These are the inactivation of cyclin-dependent kinase inhibitors (p15, p16, and p21WAF/CIP1) in low-grade TCC and early TP53-mediated abnormalities in high-grade TCC. TCC progression correlates with genetic instability and accumulation of collaborative genetic lesions mainly involving TP53, retinoblastoma (RB)-1, and growth factors. Distinctive genetic (low incidence of RB-1 and NF-1 abnormalities) and kinetic (slower cell turnover) profiles also correlate with a "single-file" infiltration pattern and poor survival in muscle-invasive TCCs. The underlying molecular changes of carcinoma in situ involve multiple and more extensive deletions (normally TP53-defective) than coexistent invasive TCC, suggesting an independent genetic evolution, while low-grade dysplasia is mainly polyclonal and shows a low rate of gene deletions.     

Correlation of DNA ploidy levels with altered cytokeratin patterns in rat bladder tumors.

Flow cytometry analysis of primary bladder carcinoma cells is appropriate for demonstrating the association between the presence of aneuploid cells and increased malignant potential for transitional cell carcinoma (TCC). Our laboratory previously has reported a specific alteration in the cytokeratin (CK) pattern of experimentally induced bladder carcinomas in rats. Unique immunohistochemically detectable changes in CK expression were the loss of CK 13 expression in invasive TCC cells and the loss of CK 19 expression in induced TCC. We now report the correlation of these changes in CK expression with cellular aneuploidy of the induced bladder carcinomas. Bladder carcinomas were induced in rats by direct instillation of N-methyl-N-nitrosourea. Immunohistochemistry was performed on the induced tumors using four commercially available monoclonal antibodies specific for CK 18 (TR1031), CK 13 (K8.12), CK 19 (K4.62), and the CKs 5, 7, and 8 (K8.13). Flow cytometry data from the induced bladder carcinomas was analyzed and the DNA index, proliferative index, and percent aneuploid cells were calculated for each time point. The percent aneuploid cells and CK 19 staining were tested statistically and were shown to be negatively correlated. We therefore hypothesize that the combination of the loss of CK 19 as detected by the antibody K4.62 coupled with the presence of aneuploid cells in histopathologically diagnosed invasive TCC is a significant factor in predicting the prognosis for any given diagnosis.     

Prognostic significance of atypical papillary urothelial hyperplasia

Typical papillary hyperplasia, a recently recognized precursor lesion to low-grade papillary urothelial neoplasms, consists of undulating folds of cytologically benign urothelium. Well-developed, branching fibrovascular cores of a papillary neoplasm are not evident. We have noted lesions with the architectural pattern of papillary hyperplasia; however, the overlying urothelium demonstrated varying degrees of cytologic atypia. We identified 15 cases of atypical papillary hyperplasia (13 males, 2 females, age 55 to 92) with overlying urothelium showing cytologic atypia. Of these cases, 8 (53%) were received in consultation. Of the 15 cases, 8 exhibited overlying flat carcinoma in situ (CIS), 4 had overlying dysplasia, and 3 were transitional between papillary hyperplasia with atypia and the earliest lesions of papillary neoplasia. Of these cases, 5 patients had multiple specimens with atypical papillary hyperplasia (range, 2 to 8) over time. Concurrent to the diagnosis of atypical papillary hyperplasia, there were 25 different urothelial lesions: CIS (n = 11), papilloma (n = 1), papillary neoplasm of low malignant potential with CIS (n = 1), high-grade papillary urothelial carcinoma (n = 10; 3 with CIS), small-cell carcinoma (n = 1), and infiltrating urothelial carcinoma (n = 1). Of 11 patients with known prior history, 2 had 12 prior urothelial neoplasms (9 low-grade papillary neoplasms, 2 papillary urothelial neoplasms of low malignant potential, and 1 high-grade papillary cancer). Of 10 patients with atypical papillary hyperplasia and a minimum of 1 year of follow-up, 9 had 19 recurrences: CIS (n = 4), papilloma (n = 1), papillary neoplasm of low malignant potential (n = 1), infiltrating urothelial carcinoma (n = 3; 1 with CIS), and high-grade papillary urothelial carcinoma (n = 10; 5 with invasion and 2 with CIS). Whether the papillary hyperplasia had overlying CIS or dysplasia did not affect the correlation with urothelial neoplasms. Immunohistochemical analysis of p53 and Ki-67 expression in 8 cases demonstrated overexpression of p53 (n = 2; 1 with overlying dysplasia and 1 with overlying CIS), and Ki-67 (n = 5; 2 with overlying dysplasia and 3 with overlying CIS). Taken together, these results suggest that atypical papillary hyperplasia is most frequently associated with CIS and high-grade papillary cancer. In some cases, CIS or dysplasia may evolve into atypical papillary hyperplasia, with further progression to high-grade papillary cancer. This process may be analogous to papillary hyperplasia without cytologic atypia progressing to low-grade papillary urothelial neoplasms.     

Expression of pRb, p53, p16 and cyclin D1 and their clinical implications in urothelial carcinoma

The aim of this study was to assess immunohistochemical expression of p53, pRb, p16, and cyclin D1, alone or in combination, as prognostic indicators and to investigate their correlation with clinocopathologic features of urothelial carcinoma. Immunohistochemical staining for p53, pRb, p16, and cyclin D1 was performed on a tissue microarray from 103 patients with urothelial carcinoma who underwent radical cystectomy. Of the patient samples analyzed, 36 (35%), 61 (59%), 47 (46%) and 30 (29%) had altered expression of p53, pRb, p16, and cyclin D1, respectively. Abnormal expression of p53 and pRb correlated with depth of invasion (P=0.040 and P=0.044, respectively). Cyclin D1 expression was associated with tumor stage and recurrence (P=0.017 and P=0.036, respectively). Altered pRb was significantly correlated with overall survival (P=0.040). According to the expression pattern of pRb and p53, p53/pRb (altered/normal) had worse survival than p53/pRb (normal/altered) (P=0.022). Alteration of all markers had worse survival than all normal (P=0.029). As determined by multivariate analysis, tumor stage, lymph node metastasis and the combined expression of p53 and pRb are independent prognostic factors. In conclusion, immunohistochemical evaluation of cell cycle regulators, especially the p53/pRb combination, might be useful in planning appropriate treatment strategies.     

Poorly differentiated adenocarcinomas of prostate versus high-grade urothelial carcinoma of the bladder: a diagnostic dilemma with immunohistochemical evaluation of 2 cases

The differential diagnosis between carcinoma of the urinary bladder and adenocarcinoma of the prostate can be difficult, especially in the poorly differentiated forms infiltrating the neighboring organs. In this article, the authors report 2 cases that pose a diagnostic dilemma to the pathologist. The first is an infiltration of the bladder by a poorly differentiated adenocarcinoma of the prostate, which was clinically suspected as a papillary urothelial neoplasm. The second is a collision tumor composed of prostatic adenocarcinoma and urothelial carcinoma observed on a core needle biopsy of the prostate. In both cases, a large panel of immunohistochemical markers were used and demonstrated positivity for prostate-specific antigen and alpha methyl racemase in the prostatic carcinomas and immunoreactivity for CK7, CK20, Ag 34betaE12, and p53 in the urothelial carcinoma. The differentiating histological and immunohistochemical findings are discussed.     

Correlation of Ki-67 and p53 with the new World Health Organization/International Society of Urological Pathology Classification System for Urothelial Neoplasia

OBJECTIVE: The present study examines p53 and Ki-67 staining patterns of the diagnostic entities included within the new World Health Organization/International Society of Urological Pathology (WHO/ISUP) classification of urothelial neoplasms. DESIGN: We retrospectively studied 151 bladder biopsies from 81 patients with the following neoplasms: normal urothelium (n = 34 biopsies); low-grade intraurothelial neoplasia (LGIUN; n = 19); high-grade intraurothelial neoplasia (HGIUN; n = 20); papillary hyperplasia (n = 4); papilloma (n = 3); papillary neoplasm of low malignant potential (LMP; n = 12); low-grade papillary carcinoma (n = 28); and high-grade papillary carcinoma (n = 31). Sections were labeled immunohistochemically with antibodies to p53 and Ki-67 (MIB-1). Two hundred cells from each lesion were visually counted, and the percentage of positive cells was tabulated without knowledge of the WHO/ISUP diagnosis. RESULTS: In flat lesions, p53 positivity was of limited diagnostic utility; the marker was present in 6 of 34 benign biopsies, 6 of 19 LGIUNs, and 10 of 20 HGIUNs. In one case in which HGIUN was present elsewhere in the bladder, 29% of the benign urothelial cells were p53 positive. In papillary lesions, p53 positivity was not seen in 4 of 4 cases of papillary hyperplasia, 3 of 3 papillomas, and 8 of 12 LMP tumors. In contrast, p53 was detected in 18 of 28 low-grade and 26 of 31 high-grade papillary urothelial carcinomas. A p53 labeling index (LI) greater than 30% was only seen in HGIUNs and high-grade papillary carcinomas. In flat lesions, an increased Ki-67 LI separated out benign urothelium (mean LI, 0.62%) from dysplasia (mean LI, 3.3%) and HGIUN (mean LI, 11.6%). In papillary lesions, Ki-67 positivity was as follows: papillary hyperplasia (mean LI, 1.1%); papilloma (mean LI, 4.3%); LMP tumors (mean LI, 2.5%), low-grade papillary carcinoma (mean LI, 7.3%); and high-grade carcinoma (mean LI, 15.7%). A Ki-67 LI greater than 10% was seen only in low- and high-grade papillary carcinomas, HGIUN, and single cases of LGIUN and papillary neoplasm of LMP. CONCLUSIONS: An increased proliferative index as demonstrated by immunohistochemical staining for Ki-67 (MIB-1) is most often seen in papillary carcinoma and HGIUN. Marked p53 positivity is also characteristic of carcinoma but may be seen in benign-appearing urothelium, suggesting a "field effect" with occult molecular aberration.     

Expression of RNA-binding protein IMP3 (KOC) in benign urothelium and urothelial tumors

RNA-binding protein IMP3 is a KH-domain-containing protein and a member of the insulin-like growth factor messenger RNA-binding protein family. It is identical to K-homology protein overexpressed in cancer that was identified through screening for genes differentially expressed between benign pancreatic tissue and pancreatic cancer. Several studies have shown that IMP3 is associated with aggressive and advanced tumors in various organs. We studied the expression of IMP3 in benign urothelium and urothelial tumors by immunohistochemistry. The expression pattern of IMP3 was further compared with that of p53 and p16. Our study shows that IMP3 is generally not expressed in benign urothelium or low-grade urothelial tumors including urothelial dysplasia, papillary urothelial neoplasm of low malignant potential, and low-grade papillary urothelial carcinoma. The expression of IMP3 is significantly increased in high-grade urothelial tumors including high-grade papillary urothelial carcinoma, urothelial carcinoma in situ, and invasive urothelial carcinoma. Expression of IMP3 in urothelial tumors parallels the accumulation of nuclear p53, although there is not always a one to one correlation. In contrast, expression of p16 in the different groups of urothelial tumors is more variable. Urothelial carcinomas with invasion of muscularis propria appear to express IMP3 more frequently than lower-stage tumors. These findings suggest that IMP3 may be involved in the progression of urothelial tumors from low grade to high grade in both papillary and flat lesions. Immunohistochemical detection of the combined expression of IMP3 and p53 is useful in the diagnosis of high-grade urothelial tumors, particularly in small, superficial materials.     

Relationship between expression of the KAI1 metastasis suppressor and other markers of advanced bladder cancer

Expression of a newly described inhibitor of tumour metastasis, KAI1, was examined in bladder cancer progression and compared with the expression of p53 and pRb, which are markers of advanced disease. KAI1 mRNA (by in situ hybridization) and protein levels (by immunohistochemistry) were examined in 135 paraffin-embedded bladder tissue sections. Significant decreases in KAI1 mRNA and protein levels were detected between normal and tumour tissue (p<0.001 and p=0.026, respectively), and between non-invasive and invasive tumours (p=0.046 and p<0.001, respectively). Loss of KAI1 protein expression was accompanied by a shift in staining pattern from a uniform distribution to a weaker, membranous or heterogeneous pattern. Normal tissue and low-grade tumours showed little p53 protein staining. High level staining (indicative of mutant p53) was associated with increased grade in non-invasive tumours (p=0.031) but was not significantly higher in invasive tumours. Whilst p53 protein staining increased with malignant progression and KAI1 mRNA expression decreased, there was no significant correlation between the two patterns (p=0.33, adjusted for group, p=0.18) or when only cancer samples were analysed (p=0.065, adjusted for group, p=0.26), even when taking into account overexpression of MDM-2 protein as a pathway for inactivation of p53. There was no correlation between loss of KAI1 mRNA expression and gain of abnormal pRb staining (p=0. 30, or adjusted for tumour samples only, p=0.59). These results suggest that loss of KAI1 expression is associated with invasive bladder cancer, but is not related to mutation of p53 or to loss of normal pRb expression.     

Assessment of basal cell status and proliferative patterns in flat and papillary urothelial lesions: a contribution to the new WHO classification of the urothelial tumors of the urinary bladder

In 1999, the World Health Organization (WHO) published a new classification of papillary urothelial tumors of the urinary bladder. Intended to represent a reproducible, easy-to-use classification system that better separates patients with true malignancies (bladder cancer) from those patients who are at an increased risk for developing bladder cancer, problems in the differential diagnosis of various lesions remained. Probably the most critical distinction is between papillomas, papillary urothelial neoplasms of low malignant potential (lmp), and grade I papillary carcinomas. Conversely, problems in the distinction between reactive atypia, atypia of unknown significance, and dysplasia, as well as the distinction of dysplasia from carcinoma in situ (CIS), are unresolved. Whether urothelial basal cell status assessment on hematoxylin and eosin-stained slides completed by cytokeratin immunohistochemistry with anticytokeratin clone 34betaE12 may help to improve some of the previously mentioned diagnostic dilemmas was investigated. Basal cell status assessment was helpful in the differentiation between dysplasia and CIS. In dysplasia, CK IHC showed a predominantly basal labeling pattern, whereas in CIS, labeling of all urothelial layers was seen. Basal cell status assessment could separate 2 groups of pTa GIb papillary carcinoma. Group 1 with a continuous basal CK labeling and a low MIB-1 labeling index (LI) was compared with group 2, with a diffuse labeling pattern and a significantly higher MIB-1 LI. Whether group 1 carcinomas should better be assigned to the group of papillary urothelial neoplasms of lmp is discussed.     

Invasive urothelial carcinoma with squamous differentiation and associated high-risk human papilloma virus infection: Clinical,cytologic, and histologic features of a rare entity

We correlate the fine needle aspiration (FNA) cytologic findings with the histologic features of an invasive high-grade urothelial carcinoma showing squamous differentiation in the setting of high-risk Human Papilloma Virus (hrHPV) infection. To our knowledge, only extensive urinary bladder catheterization has been associated with hrHPV-positive urothelial carcinoma with squamous differentiation, and rarely at that. Herein, we present a case arising in a patient with only sparse and intermittent catheterization. A 69-year-old woman presented with voiding difficulties, and after continued symptoms, a Foley catheter was placed, and a cystoscopy procedure revealed two 1–2 cm inflammatory masses. Excisional biopsies were interpreted as papillary urothelial carcinoma. One month follow-up pelvic imaging demonstrated a new mass involving the urinary bladder neck, with irregular wall thickening and perivesical fat stranding, as well as probable vaginal involvement. CT-guided FNA (CT-FNA) to collect smears and core biopsies revealed an invasive urothelial carcinoma with squamous differentiation. HPV-cytopathic changes amid squamous metaplasia and dysplasia were noted on FNA smears with HPV E6/E7 RNA in situ hybridization (ISH) showing on the FNA core biopsy specimen. Immunostains showed that the tumor cells were positive for P16 (strong, diffuse), CK7, p63, ER, and GATA3 (patchy). Subsequent radical cystectomy revealed the extent of the patient's carcinoma, with direct extension to the vaginal wall, and involvement of the radial soft tissue resection margins. Describing the cytomorphologic features of a hrHPV positive urothelial carcinoma with squamous differentiation, without an extensive history of urinary catheterization or prior known history of HPV infection, emphasizes the role of cytopathology as a powerful diagnostic tool for recognizing a unique and unexpected lesion.     

膀胱尿路上皮癌MMP-2表达及其与FAK、p53、bcl-2、Ki-67的关系

目的 比较不同分化和浸润程度膀胱尿路上皮癌MMP—2表达及其与FAK、p53、bcl—2和Ki—67的关系。方法 采用免疫组化EnVision法对83例膀胱尿路上皮癌和68例非肿瘤尿路上皮，进行MMP—2、FAK、p53、bcl—2和Ki—67的表达检测。结果 MMP—2在肿瘤组织中的表达显著高于非肿瘤性移行上皮，其表达强度随肿瘤分化程度降低和浸润深度增加而显著增强。分化差和浸润性膀胱癌中FAK和p53表达增强，并与MMP—2表达呈正相关；分化差膀胱癌中Ki—67表达增强而bcl—2表达丢失，Ki—67与MMP—2表达呈正相关。结论 在膀胱尿路上皮癌的进展和分化过程中，肿瘤分化程度越低，肿瘤细胞分泌MMP—2越多，其浸润和转移的能力也越强。FAK、p53、Ki—67和bcl—2不但与肿瘤细胞的生长密切相关，还可能直接或间接地参与了MMP—2的调控。