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PURPOSE: Current first-line treatment options in patients with metastatic urothelial carcinoma (mUC) unfit to receive cisplatin-containing chemotherapy include PD-1/L1 inhibitors and carboplatin-containing chemotherapy. However, the optimal sequencing of these therapies remains unclear. MATERIAL AND METHODS: We conducted a multicenter retrospective analysis. Consecutive cisplatin-ineligible patients with mUC treated with first-line carboplatin-containing chemotherapy followed sequentially by second-line PD-1/L1 inhibitor, or the reverse order, were included. Patient demographics, objective response, time to treatment failure for first-line (TTF1) and second-line (TTF2) therapy, interval between end of first-line and initiation of second-line treatment (Interval(1L-2L)), and overall survival (OS) were collected. Multivariate analysis was conducted to examine the association of sequencing on OS. RESULTS: In this multicenter retrospective study, we identified 146 cisplatin-ineligible patients with mUC treated with first-line (1L) PD-1/L1 inhibitor therapy followed by second-line (2L) carboplatin-containing chemotherapy (Group 1, n=43) or the reverse sequence (Group 2, n=103). In the overall cohort, median age was 72, 76% were men, and 18% had liver metastasis. In both groups, objective response rates were higher with carboplatin-containing chemotherapy (45.6% 1L, 44.2% 2L) compared to PD-1/L1 inhibitors (9.3% 1L, 21.3% 2L). On multivariate analysis, treatment sequence was not associated with overall survival (HR 1.05, p=0.85). Site of metastasis was the only factor significantly associated with overall survival (p=0.002). CONCLUSIONS: In this biomarker-unselected cohort of cisplatin-ineligible patients with mUC, PD-1/L1 inhibitor followed by carboplatin-containing chemotherapy and the reverse sequence had comparable OS.

Pilomatrixoma, an uncommon, usually benign cutaneous appendageal tumor, shows differentiation toward the hair follicle matrix cell. It undergoes various histopathologic stages, early on displaying epithelial and shadow cells along with granulomatous inflammation. In later stages, illustrated by this unusual case, epithelial cells disappear and are replaced by calcification and ossification. Immunohistochemistry in the current case showed transitional cell reactivity for β-catenin, probably linking the tumor to a mutation in the β-catenin gene CTNNB1. There was also transitional cell positivity for cyclin D1, a marker found in matrical cells of the human hair follicle. While pilomatrixoma occurs occasionally in the eyelid, the ossified eyelid variant in the current case is very rare, with only one preceding description in the literature.

Treatment failure, recurrence, and metastasis in bladder cancer are attributed to a subset of tumor cells expressing cancer stem cell (CSC) markers. This study aimed to explore the expression levels and the clinical significance of putative CSC markers OCT4 and CD133 in bladder cancer.Tissue microarray-based immunohistochemical analysis was applied to investigate the expression patterns of potential CSC markers OCT4 and CD133 in bladder cancer samples. The correlation between the expressions of each marker and clinicopathologic parameters was then analyzed.There was a significant association between OCT4 expression and the TNM stage of bladder cancer (P0.001). Our analysis demonstrated a significant association between the intensity of staining and the presence of lamina propria and muscularis propria invasion (P=0.02 and 0.02, respectively), whereas a relative inverse correlation was found between CD133 expression with lamina propria invasion (P=0.051) and muscularis propria invasion (P=0.07).The correlation of OCT4, but not CD133, with the invasiveness of bladder cancer revealed that OCT4 can be considered as a key regulator of tumor progression, aggressive behavior, and metastasis; therefore, OCT4 can be a potential marker for targeted therapy of bladder cancer.

Purpose We developed a prognostic nomogram for patients with high grade urothelial carcinoma of the upper urinary tract after extirpative surgery. Materials and Methods Clinical data were available for 2,926 patients diagnosed with high grade urothelial carcinoma of the upper urinary tract who underwent extirpative surgery. Cox proportional hazard regression models identified independent prognosticators of relapse in the development cohort (838). A backward step-down selection process was applied to achieve the most informative nomogram with the least number of variables. The L2-regularized logistic regression was applied to generate the novel nomogram. Harrell's concordance indices were calculated to estimate the discriminative accuracy of the model. Internal validation processes were performed using bootstrapping, random sampling, tenfold cross-validation, LOOCV, Brier score, information score and F1 score. External validation was performed on an external cohort (2,088). Decision tree analysis was used to develop a risk classification model. Kaplan-Meier curves were applied to estimate the relapse rate for each category. Results Overall 35.3% and 30.7% of patients experienced relapse in the development and external validation cohort. The final nomogram included age, pT stage, pN stage and architecture. It achieved a discriminative accuracy of 0.71 and 0.76, and the AUC was 0.78 and 0.77 in the development and external validation cohort, respectively. Rigorous testing showed constant results. The 5-year relapse-free survival rates were 88.6%, 68.1%, 40.2% and 12.5% for the patients with low risk, intermediate risk, high risk and very high risk disease, respectively. Conclusions The current nomogram, consisting of only 4 variables, shows high prognostic accuracy and risk stratification for patients with high grade urothelial carcinoma of the upper urinary tract following extirpative surgery, thereby adding meaningful information for clinical decision making.

Most non-neoplastic lesions of the ovaries have not been comprehensively examined in the contemporary literature. We evaluated completely embedded ovaries from 403 unselected, consecutive patients who had grossly normal adnexa. These included prophylactic specimens in high-risk women with BRCA mutations (38 women) and women with a personal history of breast cancer or a family history of breast and/or ovarian cancer (79 women). Transitional cell (Brenner) nests were found in 9.1%; 31% of these lesions were smaller than 1 mm, and 8 were solitary nests. Cortical granulomas were found in 20.5%, fatty metaplasia in 5.3%, mucinous metaplasia of surface epithelial inclusions in 5.5%, and smooth muscle stromal metaplasia in 2%. One or more types of stromal hyperplasia were found in 24.3%. Endometriosis was found in 22% of adnexa. There were no significant differences in the findings in high-risk women compared with non-high-risk except those attributable to age differences between the groups. These findings establish baseline frequencies for non-neoplastic ovarian lesions, and suggest that transitional cell nests are so common that they can be regarded as a normal finding.

Although it is common to find metastases of transitional cell carcinoma of the bladder to the lymph nodes, lung, bone, and liver, cardiac metastases have only been rarely reported. We report a case of symptomatic metastasis of transitional cell cancer to the right ventricle. A 59-year-old man with a history of transitional cell bladder cancer status post cystectomy and chemotherapy, with neobladder placement, presented with hematuria, shortness of breath, murmur, and evidence of right-sided heart failure. On imaging workup, including transthoracic echocardiography and cardiac computed tomography, we found a large right ventricular mass. A review of the literature showed that there are only 9 cases of cardiac metastasis from transitional cell cancer reported; however, our case is unique because it is the only reported case of symptomatic improvement due to effective treatment with chemotherapy.

We have investigated the morphology of the sinus node of the human cardiac conduction system. Until today the sinus node (SN) is described as a heterogeneous system composed of 2 types of cells, namely, P or pale and T or transitional cells which are immersed in the matrix around the sinus nodal artery. T cells are said to share characteristics of P cells and of peripheral working atrial myocardial cells. This study was carried out on autoptic and explanted specimens using histochemical, immunohistochemical, and electron microscopic methods.Our investigations show that SN tissue has a quite different cellular composition, ie, spherical and/or star-shaped cells organized in clusters with long cytoplasmic processes (type P), transitional cells, similar to myocytes but with a reduced number of sarcomeres (type T) and, finally, as yet not described in the literature, fibroblast-like cells with long bi-tripolar extensions contacting cells. Interestingly, SN is squared by connective and elastic fibers geometrically arranged. Immunohistochemistry shows that the 3 cell types of the SN node express mesenchymal markers revelatory of their embryological origin. Innervation appears to be more complex than previously thought; we identified a system of synaptophysin-positive cholinergic vesicles dependent on the sympathetic system and parasympathetic fibers expressing S100 protein.Overall results indicate that the SN has an unexpected, systematic architecture.

Since changes in protein phosphorylation are a common feature of cancer cells, we analyzed phosphoproteins in the tissue and urine of patients with bladder cancer and assessed the diagnostic relevance of abnormally phosphorylated proteins as tumor markers.Enrolled in this study were 66 patients and 82 healthy volunteers. From the first 14 patients with bladder cancer we obtained samples of malignant and normal bladder tissue. All patients and volunteers provided a urine sample. Protein extracts of tissue specimens were separated by 2-dimensional gel electrophoresis for comparative analysis of neoplastic and normal tissue. Phosphoproteins were studied by Western blot and characterized by mass spectrometry. Urine samples were analyzed by 1-dimensional gel electrophoresis. Phosphoproteins were measured by affinity dot blotting.Profound changes in the pattern of protein tyrosine phosphorylation were consistently, reproducibly observed in bladder cancer tissues. A total of 24 phosphorylated proteins were differentially expressed in cancer tissue and identified by mass spectrometry. Phosphoproteins were fairly stable in urine samples, leading to accumulation. Urinary tyrosine phosphoproteins showed the most remarkable changes in patients with cancer with an approximately 5-fold increase compared to levels in healthy controls.To our knowledge we investigated for the first time the diagnostic potential of tissue and urinary tyrosine phosphoproteins for bladder carcinoma. Results indicate that phosphorylated proteins may represent a new, valuable class of urinary biomarkers for bladder cancer.

Pediatric transitional cell carcinomas of the bladder are typically characterized by low-grade histology, adolescent and young adult age, and cure with surgical resection. Here, we report a high-grade transitional cell carcinoma of the bladder in a 5-year-old boy treated with a partial cystectomy and adjuvant intravesical Bacillus Calmette-Guerin.

Fluorescence in situ hybridization is gaining popularity for transitional cell carcinoma screening. We determined the accuracy of fluorescence in situ hybridization for identifying upper tract transitional cell carcinoma.A retrospective review of our upper tract transitional cell carcinoma database from 2005 to 2008 identified 35 patients with upper tract transitional cell carcinoma who submitted voided urine specimens for fluorescence in situ hybridization at commercial laboratory during a routine office visit. Each patient was evaluated endoscopically in the operating room within 3 months of sampling. Suspicious lesions were biopsied and treated. Transitional cell carcinoma in the lower or upper tract was proved by direct visualization, positive biopsy or upper tract cytology read as positive or highly suspicious for malignancy.Of the patients 35 satisfied study inclusion criteria. A total of 67 fluorescence in situ hybridization specimens were submitted. Upper tract transitional cell carcinoma was identified on 51 operative evaluations, of which 23 showed concurrent bladder tumor. For all encounters the sensitivity of fluorescence in situ hybridization was 56% and specificity was 80%. Sensitivity for low and high grade lesions was 68% and 67%, respectively. Only upper tract tumors were noted in 28 patients, in whom there were 2 false-positive and 13 false-negative voided fluorescence in situ hybridization results. In these cases sensitivity was 54% and specificity was 78% compared to the 18% sensitivity and 100% specificity of bladder cytology. Sensitivity for low and high grade upper tract transitional cell carcinoma was 60% and 50%, respectively.Voided fluorescence in situ hybridization has become an adjunct for bladder transitional cell carcinoma surveillance. However, it has limited value for upper tract tumor surveillance.

Purpose: We evaluated the association of soft tissue surgical margins with characteristics and outcomes of patients treated with radical cystectomy for urothelial carcinoma of the bladder.Materials and Methods: We retrospectively collected the data of 4,410 patients treated with radical cystectomy and pelvic lymphadenectomy without neoadjuvant chemotherapy at 12 academic centers in the United States, Canada and Europe. A positive soft tissue surgical margin was defined as presence of tumor at inked areas of soft tissue on the radical cystectomy specimen.Results: Positive soft tissue surgical margins were identified in 278 patients (6.3%). On univariate analysis positive soft tissue surgical margin was significantly associated with advanced pT stage, higher tumor grade, lymphovascular invasion and lymph node metastasis (p

To compare long-term overall survival (OS) in patients with G1 and G2 grade Ta bladder cancer after transurethral resection of bladder tumors (TURBTs). Secondary aim was to investigate clinical and pathologic prognostic factors for OS of Ta patients, except G3/high grade (HG). A total of 243 patients, retrospectively selected, with Ta nonmuscle invasive bladder cancer (NMIBC) underwent TURBT between January 2006 and December 2008 (median follow-up 109 months). Inclusion criteria were: Ta at first manifestation, G1 or G2 grade with no associated carcinoma in situ (CIS). Seventy-nine patients were excluded due to concomitant CIS (1), G3/HG tumors (47), and lost to follow-up (31). Ethical approval was obtained from the Ethical Committee of the Mures County Hospital. Statistical analysis was performed using STATA 11.0. Following inclusion criteria, 164 patients with primary G1 or G2 Ta tumors, were enrolled. Recurrence was observed in 26 (15.8%) and progression in 5 (3%) patients. Ten-year survival in G1 patients was 67.8% (CI 54.3–78.1) and in G2 patients 59% (CI 49–67.3) (P = .31). Univariable and multivariable logistic regression analysis underlined that advanced age at diagnosis (hazard ratio [HR] 1.10) and no Bacillus Calmette–Guerin (BCG) treatment (HR 0.24 and 0.29) were independent predictors for death at 10 years after diagnosis. Long-term analysis confirms that patients with well differentiated (G1) and moderately well differentiated (G2) Ta tumors have similar OS. A longer OS was even reported in those who underwent BCG adjuvant therapy.

Bladder transitional cell carcinoma is the second most common urological malignancy, of which 80% are superficial disease limited to the bladder. Superficial bladder transitional cell carcinoma has a high propensity for recurrence and progression after initial resection, necessitating adjuvant intravesical therapy. TRAIL (tumor necrosis factor-related apoptosis inducing ligand) can selectively induce apoptosis in most tumor cells while sparing normal cells. TRAIL drives not only the death receptor pathway, but also the mitochondrial pathway through Bid. Due to the anti-apoptotic functions of Bcl-2 and clusterin on the mitochondrial apoptotic pathway the effects of down-regulating these proteins were examined in partially TRAIL resistant bladder transitional cell carcinoma cell lines.Antisense oligonucleotides targeting Bcl-2 and clusterin were used alone or combined with TRAIL and cytotoxicity was examined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolim bromide) proliferation assay. Apoptotic pathway signals were detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis/Western blotting after the various combination treatments. All statistical tests were 2 sided.Although no direct correlation between TRAIL sensitivity and the relative expression levels of Bcl-2 and clusterin was found in the bladder transitional cell carcinoma cell lines examined, antisense oligonucleotide mediated the down-regulation of Bcl-2 and clusterin, increasing the sensitivity of the partially resistant cells to TRAIL. This was mediated through increased apoptotic signaling of the mitochondrial pathway, as evident by the increased activation of caspase-9 and 3, and cleaved DFF45. There was no benefit of combined antisense oligonucleotide therapy.This study provides proof of principle that TRAIL combined with antisense oligonucleotide-Bcl-2 may have potential as a novel future treatment strategy for bladder transitional cell carcinoma.

Objective To describe computed tomographic (CT) and magnetic resonance (MR) imaging findings of transitional cell tumors, including newly established transitional cell carcinoma, according to tumor type with pathological correlation. Methods We retrospectively reviewed the CT and MR images of 22 patients with transitional cell tumors of ovary (14 benign Brenner, 2 borderline Brenner, 2 malignant Brenner, and 4 transitional cell carcinomas) for the following factors: size, location, configuration, signal intensity, staging, and accompanying ovarian tumors. Results Sixteen tumors were detected on CT or MRI (8 benign, 2 borderline, and 6 malignant tumors), and the mean size of measurable tumors was 8.8 cm. Benign Brenner tumors were homogeneous solid (n = 6) or unilocular cystic (n = 2). Two borderline Brenner tumors were multilocular cystic. Malignant tumors, including malignant Brenner tumors and transitional cell carcinomas, were heterogeneous solid (n = 3) or multilocular cystic (n = 3). The signal intensity of solid components on T2-weighted images was isointense compared with that of muscle in benign and borderline Brenner tumors and hyperintense in malignant tumors. Conclusions The CT and MR appearance of transitional cell tumors varied according to tumor type. Benign Brenner tumors were homogeneous solid or unilocular cystic pattern, and malignant tumors were heterogeneous solid or multilocular cystic.

To review the systemic treatment, patient selection and treatment outcome of transitional cell carcinoma of the urinary bladder, squamous cell carcinoma and adenocarcinoma, focusing on advances and findings within the last year.Cisplatin-based chemotherapy is considered to be the standard treatment for transitional cell carcinoma. In recent updates of randomized trials, patients with favorable prognostic factors were shown to have a chance of long-term disease-free survival even after chemotherapy for metastatic disease. Patient selection for cisplatin, newer drugs or alternative combinations is crucial. New genetic markers like excision repair cross-complementing 1 expression were developed and tested for this purpose. Adequate evaluation of renal function plays an important role for treatment selection, especially in the elderly population. Newer chemotherapeutics like oxaliplatin, vinflunine and pemetrexed have been studied in the first- or second-line settings. Their efficacy is promising, but there is still a need for further testing. Only few data are available on the systemic treatment of squamous cell carcinoma and adenocarcinoma. Complete resection seems to be more important than chemotherapy in the rare cases of adenocarcinoma of the urinary tract.In locally advanced and metastatic disease patient- and tumor-related prognostic factors and predictive factors for response to treatment will guide treatment decisions in the future.

We compared the differential expression of cyclooxygenase-2 in normal bladder tissue, primary bladder transitional cell carcinoma and transitional cell carcinoma metastases to lymph nodes, and determined whether cyclooxygenase-2 expression is associated with molecular alterations commonly found in bladder transitional cell carcinoma and clinical outcomes after radical cystectomy.Immunohistochemical staining for cyclooxygenase-2, survivin (Novus Biologicals, Littleton, Colorado), p21, p27, pRB, p53, MIB-1, Bax, Bcl-2, cyclin D(1) (Dakotrade mark), cyclin E (Oncogene, Cambridge, Massachusetts) and caspase-3 (Cell Signaling, Beverley, Massachusetts) was performed on archival bladder specimens from 9 subjects who underwent cystectomy for benign causes, 21 patients who underwent transurethral resection and 157 consecutive patients after radical cystectomy, and on 41 positive lymph nodes.Cyclooxygenase-2 was expressed in none of the 9 normal bladder specimens (0%), 52% of transurethral resection specimens, 62% of cystectomy specimens and 80% of lymph nodes involved with transitional cell carcinoma. Cyclooxygenase-2 expression was associated with higher pathological stage, lymphovascular invasion and metastases to lymph nodes (p=0.001, 0.045 and 0.002, respectively). Cyclooxygenase-2 expression was associated with altered expression of p53 (p=0.039), pRB (p=0.025), cyclin D1 (p=0.034) and caspase-3 (p=0.014). On univariate analysis cyclooxygenase-2 expression was associated with an increased risk of disease recurrence and bladder cancer specific mortality (p=0.0189 and 0.0472, respectively). However, on multivariate analysis only pathological stage and metastases to lymph nodes were associated with disease recurrence (p0.001 and0.001) and survival (p0.001 and 0.015, respectively).Cyclooxygenase-2 is not expressed in normal bladder urothelium. Cyclooxygenase-2 over expression is associated with pathological and molecular features of biologically aggressive disease, suggesting a role for cyclooxygenase-2 in bladder cancer development and invasion.

Superficial bladder transitional cell carcinoma has a high recurrence rate following endoscopic resection. Most parameters used to predict recurrence are associated with high grade transitional cell carcinoma. However, there are few valid parameters for predicting low grade transitional cell carcinoma recurrence. We elucidated the prime factor in recurrent superficial low grade bladder transitional cell carcinoma.A total of 40 cases of superficial low grade bladder transitional cell carcinoma were analyzed, including 20 recurrent and 20 nonrecurrent cases. Fresh frozen tumor and normal tissues were used. Real-time reverse transcriptase-polymerase chain reaction and Western blots were performed subsequently to evaluate the validity of molecules identified by 0.12K cDNA array composed of matrix metalloproteinase, oncogenes and cell cycle related genes.On cDNA microarray analysis matrix metalloproteinase-1, 2, 9, 12 and 15, transforming growth factor-beta1, vascular endothelial growth factor and fos were found to be significantly up-regulated in recurrent cases. On real-time reverse transcriptase-polymerase chain reaction to validate those molecules matrix metalloproteinase-1 and 12, transforming growth factor-beta1, vascular endothelial growth factor and fos were significantly over expressed in recurrent cases. Western blot showed significant over expression of matrix metalloproteinase-1 and 12, transforming growth factor-beta1, vascular endothelial growth factor and fos in recurrent cases.Over expression of matrix metalloproteinase-1 and 12, transforming growth factor-beta1, vascular endothelial growth factor and fos may be associated with the recurrence of superficial low grade bladder transitional cell carcinoma.

BACKGROUND The morphological and electrophysiological characteristics of cardiac cells in Koch triangle are still disputed. We studied the appearance and electrical properties of these diverse myocytes to elucidate their complex electrophysiological phenomena. METHODS Experiments were conducted using cooled charge coupling device (CCD) system and whole cell, patch clamp technique to determine the morphology, action potential and sodium current density of single viable myocytes enzymatically isolated from the Koch triangle of rabbit hearts. RESULTS Morphologically, cardiac cells in shape of spider, tiny spindle, slender spindle, rod and strip were observed in percentage of 3.0 +/- 0.3, 35.0 +/- 5.0, 15.0 +/- 2.0, 40.0 +/- 5.0 and 6.0 +/- 0.7 respectively. The cellular dimensions and capacitance gradually increased in the above order (all P < 0.05). Electrophysiologically, action potential configurations recorded from them were similar respectively to nodal (N), atrial nodal (AN), nodal Hisian (NH), atrial (A) and Hisian like potentials obtained from the intact atrioventricular nodal preparations. Diastolic depolarization appeared in all myocytes except for rod cells. Sodium current density increased in the order of tiny spindle, strip, rod, slender spindle cell (all P < 0.05), but could not be detected in spider-shaped cells. Linear regression analysis revealed that membrane capacitance was correlated negatively to the rate of diastolic depolarization r = -0.70, P < 0.001, but positively to maximum depolarization potential, amplitude of action potential, upstroke velocity and maximum peak value of sodium current density r = 0.84, 0.80, 0.87 and 0.75, respectively; all P < 0.001. CONCLUSIONS The results demonstrated that spider-shaped, spindle, rod and strip cells in Koch triangle might correspond to pacemaking, transitional, atrial and Purkinje like cells, respectively. Furthermore, tiny spindle and slender spindle cells were referred to transitional cell alpha (TCalpha) and beta (TCbeta) accordingly considering their distinctive electrical properties. Different myocytes with diverse electrical properties constituted the infrastructure of sophisticated electrophysiological phenomena in Koch triangle. In view of the prominent percentage and electrical properties, tiny spindle and slender spindle cells were presumed to play important roles.

The clinicopathological features predictive of outcome in patients with upper urinary tract transitional cell carcinoma are not clearly established. We analyzed the prognostic impact of tumor necrosis with respect to metastasis-free survival.The presence of focal (10% or less of the tumor area) and extensive (greater than 10% of the tumor area) coagulative tumor necrosis was retrospectively reevaluated in 268 cases of consecutive upper urinary tract transitional cell carcinoma and correlated with outcome.Overall tumor necrosis was noted in 113 of 268 (42.2%) cases of transitional cell carcinoma with 63 (23.5%) showing focal and 50 (18.7%) showing extensive necrosis, respectively. Tumor necrosis was associated with high tumor stage (p0.001) and high tumor grade (p0.001). In addition, tumor necrosis was more common in pelvic tumors compared with ureteral tumors (p0.001). Actuarial 5-year metastasis-free survival rates for patients with transitional cell carcinoma with extensive, focal and lacking necrosis were 24%, 45% and 78%, respectively (log rank test p0.001). Multivariate analysis proved pT stage greater than 1 (p0.001, RR 6.04, 95% CI 2.82-12.93), high tumor grade (p0.001, RR 3.37, 95% CI 1.65-6.89) and extensive tumor necrosis as independent predictors of poor patient outcome (p = 0.02, RR 1.82, 95% CI 1.09-3.05).The presence of extensive tumor necrosis proved to be an additional histological variable with an independent influence on metastasis-free survival in patients with upper urinary tract transitional cell carcinoma. Its assessment is readily applicable in routine sections and should thus be commented upon separately in the pathology report.

We characterized initial relapse patterns in patients who underwent cystectomy for transitional cell carcinoma of the bladder at our institution.Between June 1995 and December 2001 a total of 417 patients underwent radical cystectomy for transitional cell carcinoma. Of the 399 patients treated with orthotopic diversion or incontinent cutaneous diversion, recurrent TCC developed in 86 (21.6%). We retrospectively examined this population to determine if any perioperative variables influenced the first site of disease recurrence.Of the 86 patients in whom metastatic disease developed after cystectomy, the mean followup was 22.1 months. Mean time to disease recurrence was 15.1 months. Recurrence was most commonly initially in the pelvis (30.2%). Other common sites of first recurrence included the viscera (26.7%), the retroperitoneum (16.3%) and the skeletal system (16.3%). The site of first recurrence did not correlate significantly with gender, age, diversion type, pathological stage, nodal status, prostatic involvement or the presence of a positive surgical margin. Lymphovascular invasion was more prevalent in the pelvic recurrence group (62%) than in the retroperitoneal (36%), visceral (22%) or skeletal metastases (29%) groups (p = 0.03).While the pelvis is the most common site of disease recurrence following radical cystectomy, TCC of the bladder recurs in an unpredictable pattern and aggressive surveillance is indicated. Patients with local pelvic recurrence had a higher percentage of lymphovascular invasion on cystectomy than the other recurrence site groups.

We studied the effects of insufflation gas and pressure on the adhesion, growth, apoptosis and necrosis of transitional cell carcinoma (TCC) in an in vitro model.Tumor adhesion and cell growth of AY-27 rat TCC was measured after 3-hour incubation with CO2, N2 and He insufflation at different pressures (0, 10 and 15 mm Hg) in vitro. The effects of these gases on the rate of tumor cell apoptosis and necrosis were compared.In vitro the tumor adhesion rate was lowest with CO2 and highest with N2. Higher gas pressures resulted in decreased adhesion rates for CO2 and He but increased adhesion rates for N2. N2 enhanced tumor cell proliferation at all pressures studied. He and CO2 resulted in an initial increase in cell proliferation in the first 24 hours, followed by a decrease in tumor growth. Extracellular medium turned acidic in CO2 (pH 6.27 to 6.39) but basic in N2 and He (pH 8.39 to 8.84). At all insufflation pressures studied apoptosis and necrosis rates were increased in the first 24 hours, followed by a decrease for CO2 and N2. He resulted in increasing apoptosis and necrosis throughout the study period.The type of gas and insufflation pressure affects cell adhesion and tumor growth. There was a significant increase in tumor adhesion and proliferation with N2 insufflation compared with CO2 and He at 0 to 15 mm Hg pressures. CO2 demonstrated the greatest decrease in TCC adhesion and proliferation at 15 mm Hg pressure. Apoptosis and necrosis were highest for He compared with the other gases.

Background— The 3D structure of the atrioventricular conduction axis incorporating detailed cellular and molecular composition, especially that relating to gap-junctional proteins, is still unclear, impeding mechanistic understanding of cardiac rhythmic disorders. Methods and Results— A 3D model of the rabbit atrioventricular conduction axis was reconstructed by combining histological and immunofluorescence staining on serial sections. The exact cellular boundaries, especially those between transitional cells and atrial myocardium, were demarcated by a dense and irregular desmin-labeling pattern in conductive myocardium. The model demonstrates that the atrioventricular conduction axis is segregated into 2 connecting compartments, 1 predominantly expressing connexin45 (compact node and transitional cells) and the other predominantly coexpressing connexin43 and connexin45 (His bundle, lower nodal cells, and posterior nodal extension). The transitional zone shows unique features of spatial complexity, including a bridging bilayer structure (a deep transitional zone connecting with a superficial atrial-transitional overlay) and asymmetrical continuity (wider atrial-transitional interfaces and shorter atrial-axial distances in the hisian portion than in the ostial portion). In the latter compartment, the His bundle, lower nodal cells, and posterior nodal extension form a continual axis and longitudinal transitional-axial interface. Conclusions— Key findings of the present study are the demonstration of a distinct anatomical border between transitional and atrial cells, connection between transitional cells and both lower nodal cells and posterior nodal extension, and distinctive connexin expression patterns in different compartments of the rabbit atrioventricular conduction axis. These features, synthesized in a novel 3D model, provide a structural framework for the interpretation of nodal function.

Purpose: Proliferative epithelial metaplasia that develops in the anastomotic line after gastrocystoplasty has unknown malignant potential. Flow cytometry analysis of cell cycle profiles is used to predict the neoplastic progression of metaplastic lesions in other proliferative epithelium. We used this technique to evaluate transitional cell metaplasia in rat gastrocystoplasty specimens.Materials and Methods: A total of 50 prepubescent female Long-Evans rats were randomly assigned to an experimental group (gastrocystoplasty) or a control group (sham operation). At 21 to 27 months (mean 24.9) after operation 12 rats per group survived to sacrifice. Metaplastic lesions were microdissected to yield a minimum of 104 cells for DNA flow cytometry and cell cycle analysis. Transitional cell epithelium from sham specimens and gastric epithelium from experimental animals served as controls.Results: Transitional cell hyperplasia and metaplasia with cyst formation were found in the anastomotic line in all 12 ...

In the current study, the immunohistochemical localization of survivin was correlated with the histologic diagnosis in healthy transitional cell epithelium, transitional cell carcinoma (TCC) in situ, and TCC of the urinary bladder. Forty-five TCCs (grades 1-3, 15 of each), 14 cases of TCC in situ, and II healthy bladder mucosal specimens were selected from archival collections of formalin-fixed bladder tissues. Slides were reacted with an anti-survivin antibody using a conventional immunohistochemical method and then were scored for nuclear and cytoplasmic staining. Statistical analysis of survivin expression was performed to evaluate the correlation of staining pattern with histologic diagnosis and clinical outcome. Nuclear staining for survivin was detected in 26 of 45 TCCs and in 2 of 14 cases of TCC in situ, but was not detected in healthy bladder mucosa. The association of nuclear staining with TCC versus both healthy bladder mucosa and TCC in situ was statistically significant (P < 0.001). Patients with TCC and a nuclear pattern of survivin localization had a greater period of disease-free survival (27.2 months) than was observed in patients with TCC that showed no nuclear staining for survivin (9.9 months); however, the differences were not statistically significant. Nuclear localization of survivin is a marker of TCC but is rarely present in premalignant or benign bladder mucosal specimens.

Carcinomas of the bladder that resemble clear cell carcinoma of mullerian type are rare. Whether such neoplasms 1) arise from mullerian elements in the bladder and are histogenetically identical to the female genital tract cancer, 2) are a peculiar variant of vesical adenocarcinoma of nonmullerian derivation, or 3) represent a peculiar morphologic expression of transitional cell (urothelial) carcinoma with gland differentiation is often uncertain. We reviewed the clinical, conventional pathologic, and immunohistochemical features of 13 neoplasms with exclusive, or predominant, morphologic features of clear cell carcinoma. The 11 female and two male patients were 22-83 (mean 57) years of age. The clinical and gross features had no unique aspects. On microscopic examination the most common pattern, present in all cases, was tubulocystic, with a papillary pattern, present in six tumors and a predominant solid growth in one. Cells with abundant clear cytoplasm were conspicuous in nine tumors and hobnail cells were seen in eight. Four tumors showed focally recognizable patterns of transitional cell (urothelial) carcinoma in the available material. In five other tumors pseudostratified epithelium reminiscent of transitional epithelium was present focally. Endometriosis was present in two cases. In two other cases benign cysts focally lined by ciliated epithelium and surrounded by elastosis were interpreted as most likely mullerian. Immunohistochemistry was performed in 10 cases. All tumors stained for CA 125 (usually strong, ranging from focal to diffuse) and nine tumors stained for CK7 (usually strong and diffuse). CK20 was focally and weakly positive in four tumors and extensively positive in another. The same immunohistochemical panel was performed on 10 typical transitional cell carcinomas, 4 transitional cell carcinomas with gland differentiation, not otherwise specified, and 5 pure adenocarcinomas of the bladder (one of urachal origin). Minimal CA 125 positivity was seen in two transitional cell carcinomas. CA 125 staining was seen in the areas of gland differentiation in three of four transitional cell carcinomas and three of five pure adenocarcinomas but was focal in most cases. All transitional cell carcinomas and transitional cell carcinomas with gland differentiation showed extensive CK7 positivity. In contrast, only one of four positive pure adenocarcinomas showed >5% CK7-positive cells. Although all groups showed CK20 positivity, the percentage of CK20 positive cells was higher in pure adenocarcinomas. Prostate specific antigen was negative in all tumors. The cytokeratin immunoprofile of clear cell carcinomas of the bladder is closer to transitional cell carcinomas and transitional cell carcinomas with gland differentiation than pure adenocarcinomas arguing against an unusual form of adenocarcinoma. Our finding of CA 125 expression in bladder tumors of apparent urothelial origin contrasts with some studies that have regarded CA 125 expression as evidence for a mullerian origin. The frequency of gland differentiation in transitional cell carcinomas and the rarity of vesical endometriosis could be taken to suggest that these tumors are mostly of urothelial derivation, but the strong female preponderance in our series argues for a mullerian origin in at least some cases, and this is almost certain in the four cases with benign mullerian components. In the absence of endometriosis or conventional foci of transitional cell carcinoma, it may be impossible to determine whether a tumor with the morphology of clear cell carcinoma is of mullerian or transitional (urothelial) cell lineage, and at this time immunochemistry does not solve this problem.

To describe the clinical characteristics, treatment patterns and outcomes in advanced small cell bladder cancer (aSCBC) patients and compare to those with urothelial carcinoma (UC). Individuals in the National Cancer Data Base with a diagnosis of either nodal (TxN+M0) or distant metastatic (TxNxM1) disease were identified from 1998 to 2010. We assessed the relationships between stage, treatment modalities and survival in the aSCBC cohort and compared these to UC patients. In the 960 patient aSCBC cohort (62% M1), 50% received palliative therapy alone, 68% in M1 versus 21% in M0 groups (P

Purpose: Recent data imply that 3-dimensional (D) p53 protein modeling provides more specific information on its function in patients with pancreatic adenocarcinoma. In addition to immunohistochemical and single strand conformational polymorphism analysis, we performed 3-D p53 protein modeling and correlated our results with the disease-free survival of patients with muscle invasive transitional cell carcinoma of the bladder who underwent surgery.Materials and Methods: We identified 43 patients and analyzed p53 status in each by immunohistochemical testing, single strand conformational polymorphism and DNA sequencing with 3-D protein modeling. Median followup was 38 months (range 4 to 92). The results of each analysis were compared and correlated with cancer specific survival. Statistical analysis was performed using the log rank test on Kaplan-Meier survival curves.Results: The population included 30 men and 13 women 35 to 84 years old (median age 65). Nuclear over expression of p53 protein was observed ...

Loss of DNA mismatch repair due to diminished expression or mutation of hMLH1 is associated with genomic instability followed by cancer. We performed genetic analyses of hMLH1 to determine whether hMLH1 alterations have a role in urothelial tumorigenesis.We examined genomic DNA from 118 sporadic transitional cell carcinomas, including 83 bladder and 35 renal pelvis or ureter cases, for aberrant promoter methylation and mutation in the hMLH1 gene. Immunohistochemical reactivity to hMLH1 protein and genome instability in these transitional cell carcinomas were also studied.Two of the 118 cases (1.7%) had microsatellite instability and hMLH1 promoter methylation with loss of or reduced hMLH1 protein expression. A single transitional cell carcinoma (0.8%) without microsatellite instability had an hMLH1 missense mutation with a C-to-T transition, resulting in the substitution Arg217 --Cys. Immunostaining with antihMLH1 antibody was found in this transitional cell carcinoma.To our knowledge these findings provide the first in vivo evidence for the type and frequency of possible involvement of promoter methylation and mutation of hMLH1 in sporadic urothelial transitional cell carcinoma. They also suggest that hMLH1 alterations may not account for many cases of sporadic transitional cell carcinoma tumorigenesis.

We determined whether expression levels of matrix metalloproteinase (MMP)-2, MMP-9, membrane-type MMP-1 (MT1-MMP), tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 messenger (m) RNA in superficial transitional cell carcinoma of the bladder may be used as predictors of tumor recurrence.Total RNA was extracted from 51 superficial transitional cell carcinomas of the bladder, and expression levels of MMP-2, MMP-9, MT1-MMP, TIMP-1 and TIMP-2 messenger mRNA in these specimens were measured by Northern blot analysis. Results were evaluated in regard to tumor recurrence.Mean MMP-9 and TIMP-2 mRNA expression in the tumors of patients with recurrence were 2.5 and 3-fold higher, respectively, than in those of patients without recurrence despite no significant differences in MMP-2, MT1-MMP or TIMP-1 expression. The recurrence-free survival rate of patients with elevated MMP-9 and TIMP-2 mRNA expression was significantly lower than that of patients with normal MMP-9 and TIMP-2 expression, respectively. In addition, Cox's multivariate analysis revealed that elevated MMP-9 and TIMP-2 were strongly associated with a high incidence of intravesical recurrence of superficial bladder cancer.These results indicate that MMP-9 and TIMP-2 are strongly expressed in the tumors of patients with recurrence compared with those without recurrence and elevated MMP-9 and TIMP-2 may be used as predictors of recurrence in patients with superficial transitional cell carcinoma.

Purpose: In this study, we employed similar techniques to detail dendritic cell subsets within bladder transitional cell carcinoma and kidney transitional cell carcinoma.Materials and Methods: To identify both the CD1a+ and CD1a- antigen-expressing dendritic cell populations we employed a double labeling technique to identify non-lineage-expressing leukocytes similar to that employed to isolate blood dendritic cells.Results: Dendritic cells were found in significant numbers within both bladder and kidney derived transitional cell carcinoma. Almost all the dendritic cells among the tumor cells belonged to the CD1a+ subset of epithelial dendritic cells. Similar numbers of dendritic cells were observed in the lamina propria adjacent to the tumor. These dendritic cells belonged predominantly to the CD1a- subset. These differences appear to reflect the different dendritic cell phenotypes reported for the epidermis and dermis.Conclusions: The number of dendritic cells increased as the grade of the tumor...

Purpose: The limitations of cytology and the invasiveness of cystoscopy for detecting bladder cancer generate increasing interest in noninvasive, urine bound diagnostic tools. We assessed the diagnostic value of the newly developed immunocytochemical test, Immunocyt, which detects cellular markers specific for transitional cell cancer in the voided urine of patients with bladder cancer.Materials and Methods: Participating in our prospective study were 264 consecutive patients with a mean age of 65.9 years, including 114 in whom symptoms were suggestive of bladder cancer and 150 who were being followed after complete transurethral resection of superficial transitional cell carcinoma. Voided urine specimens were evaluated by standard cytology and the Immunocyt test, which traces the monoclonal antibodies M344, LDQ10 and 19A211 against transitional cell carcinoma in exfoliated urothelial cells. In all cases cystoscopy was subsequently performed and any suspicious lesion was evaluated by biopsy.Result...

Since squamous cell differs from transitional cell cancer regarding histopathology, clinical outcome and etiology, the underlying genetic effects of these 2 tumor types may also be different. We compared numerical aberrations of chromosomes 7, 9 and 17 in bilharzial squamous cell carcinoma, and bilharzial and nonbilharzial transitional cell carcinoma by fluorescence in situ hybridization, and correlated the findings to p53 positivity of the 3 tumor types.Cystectomy for invasive bladder cancer was performed in 169 men and 51 women with a mean age of 54.8 years (range 28 to 83). Of the 220 patients 100 (45.4%) had histologically verified bilharzial squamous cell carcinoma, 61 (27.7%) bilharzial transitional cell carcinoma and 59 (26.8%) nonbilharzial transitional cell carcinoma. Using fluorescence in situ hybridization cystectomy specimens were evaluated for numerical aberrations of chromosomes 7, 9 and 17, and p53 detection was performed by immunohistochemistry.Aberrations of chromosome 7 were observed in 79% of the bilharzial squamous cell carcinoma specimens, and 100% and 93.2% of bilharzial and nonbilharzial transitional cell carcinoma specimens, respectively (p = 0.00011). Aberrations of chromosome 9 were seen in 92% of squamous cell carcinoma specimens but in only 52.4% and 60.9% of bilharzial and nonbilharzial transitional cell carcinoma, respectively (p0.00001). Aberrations of chromosome 17 were found in only 29% of squamous cell carcinoma specimens, compared to 83.6% and 84.7% aberrations of chromosome 17 in both transitional cell carcinoma groups, respectively (p0.00001). The p53 over expression was similar in all 3 tumor types with 82% for squamous cell carcinoma, and 73.7% for bilharzial and 81.3% for nonbilharzial transitional cell carcinoma (not significant, p = 0.5285).Our data show clear differences between chromosomal patterns of invasive bilharzial squamous cell carcinoma and invasive bilharzial or nonbilharzial transitional cell carcinoma but similar frequencies of p53 over expression in all 3 tumor types. However, aberrations of chromosome 9 were observed in all analyzed groups, which confirms the 2 pathways in the oncogenesis of squamous cell and transitional cell carcinoma at the cytogenetic level as suggested by molecular studies.

Most papillary transitional cell carcinomas (TCC) are characterized architecturally by an exophytic growth of fingerlike papillae, but some exhibit a prominent endophytic growth pattern resulting in considerable difficulty in assessing invasion. We report on 18 cases of TCC (17 urinary bladder, one pelvicalyceal system) in which endophytic growth was evident either as interanastomosing cords and columns of urothelium, often with a striking resemblance to inverted papilloma (inverted papilloma-like pattern), or as broad, pushing bulbous invaginations into the lamina propria (broad-front pattern). The mean age of the patients was 68 years (range, 32-94 years), with a male preponderance (3.5:1). In four cases, the endophytic pattern was exclusively inverted papilloma-like, 10 cases had only the broad-front pattern, and four cases showed both patterns. Exophytic papillary TCC of the usual type was present in all but two cases, varying from focal (five cases) to moderate (five cases) to extensive (six cases). In spite of the extensive incursion into the lamina propria resulting from the inverted growth, only nine cases (50%) had unequivocal destructive invasion (lamina propria invasion, eight cases; muscularis propria invasion, one case). Follow-up data, available in 14 cases (1-48 months; mean, 15.5 months), revealed one patient alive with disease, 11 patients with no evidence of disease, and two patients dead of other causes. The limited follow-up does not permit evaluation of the impact of the endophytic patterns on outcome. Because the phenomenon of endophytic growth in TCC has received little attention, we present detailed morphologic descriptions of our cases and review the problems associated with assessment of invasion and the different patterns of invasion by TCC.

Papillary carcinomas of the uterine cervix with transitional or squamous differentiation are rare tumors that often resemble transitional cell carcinomas of the urinary tract. We reviewed 32 such cases of papillary cervical carcinoma and divided them into three groups: 1) predominantly (> 90%) squamous (nine cases), 2) mixed squamous and transitional (16 cases), and 3) predominantly transitional (seven cases). Overall, the patients ranged in age from 22 to 93 years (mean 50), and the most common clinical presentation was abnormal bleeding (15 patients) and an abnormal Papanicolaou smear (nine patients). The tumors ranged in size from 0.7 to 6.0 cm (mean 3.0). All cases demonstrated a papillary architecture with fibrovascular cores lined by a multilayered, atypical epithelium resembling a high-grade squamous intraepithelial lesion of the cervix. Underlying superficial to deep stromal invasion was seen in 18 of 20 cases (90%); in the remaining 12 cases, the specimen was too superficial to assess invasion. Eighteen (86%) of the 21 cases examined immunohistochemically demonstrated immunoreactivity for cytokeratin 7, whereas only two of the 21 (9.5%) showed positivity for cytokeratin 20. Of the 12 women for whom follow-up information was available, three were treated by simple hysterectomy, two underwent radical hysterectomy, one was treated with radiation alone, and one with combination chemotherapy and radiotherapy. Three patients died of disease (two in the squamous group and one transitional) within an average of 13 months after diagnosis. Local recurrence developed in two women, and one of these, a vaginal recurrence, occurred 12 years after the original diagnosis. Based on the above findings, we believe that these tumors are a clinicopathologically distinct, homogeneous group that display a morphologic spectrum. Nevertheless, because some tumors may show a purely squamous or purely transitional appearance, we propose retaining the above three separate designations for these tumors with the understanding that there is often a substantial degree of subjectivity in deciding whether a tumor is squamous or transitional. The most distinctive, objective, and easily recognizable feature of these tumors is their surface papillary architecture rather than their superficial resemblance to transitional cell carcinomas of the urinary tract, and we emphasize the need to distinguish these potentially aggressive malignant tumors from the far more common and benign papillary lesions of the cervix.

We investigated the relationships between the degradation of basement membrane underlying superficial urothelial carcinomas, including carcinoma in situ and the functional p53 loss caused by inactivation of p53 and the overexpression of mdm2 oncoprotein.Nuclear accumulations of p53 and mdm2 were examined immunohistochemically for 60 transitional cell carcinomas (primary lesions) and 13 accompanying (concomitant) carcinoma in situ lesions. Degradation of the basement membrane was defined as the reduction or total loss of type IV collagen expression. Whether there was up-regulation of MMP-1, MMP-2, and MMP-9 was analyzed immunohistochemically.The frequency of the degradation of basement membrane underlying grade 1 pTa tumors was 0%, grade 2-3 pTa tumors 57.1%, and primary CIS lesions 83.3%. Nuclear over-accumulation of p53 was found in 48.3% and of mdm2 in 23.3% of the primary tumors. In pTa-pT1 carcinomas, nuclear staining of p53, mdm2, or both was highly correlated with degradation of the basement membrane underlying carcinomas (p = 0.00002). In the CIS lesions, the association of p53 nuclear staining with the destruction of type IV collagen expression was of borderline significance (p = 0.03). When mdm2 overexpression was considered as a molecular abnormality together with p53 inactivation, the correlation with the degradation of the basement membrane was highly significant (p = 0.00006). Moreover, the functional p53 loss was strongly associated with the up-regulation of matrix metalloproteinases (MMPs) (p = 0.0005). This finding was well correlated with the strong association of basement membrane degradation with up-regulation of MMPs (p = 0.000004).Degradation of basement membranes underlying superficial carcinomas or CIS of the urothelium was significantly related to p53 inactivation, mdm2 overexpression, or both. The expression status of mdm2 should provide better information about the progression of superficial urothelial carcinomas than the status of p53 alone.

Sixty-three examples of transitional cell metaplasia of the cervix or vagina from patients 50 to 84 (average 67.6) years of age are described. Fifty-seven of the 59 patients were postmenopausal and two perimenopausal. Only four patients were documented to have received hormonal therapy. The lesion was an incidental microscopic finding in all patients and was found in 29 hysterectomy specimens, 18 endocervical or endometrial curettage specimens, 11 cervical biopsy or cone biopsy specimens, and five vaginal biopsy specimens. The sites involved by transitional cell metaplasia were the exocervix (n = 14), transformation zone (n = 33), vagina (n = 10), or a combination (n = 4). The cervical and vaginal specimens most commonly showed involvement of the surface epithelium by transitional cell metaplasia. Other transitional cell patterns were isolated stromal nests (n = 9) and invagination of surface epithelium into the underlying stroma (n = 2). The typical appearance of transitional cell metaplasia was a hyperplastic epithelium with lack of maturation, consisting of spindled nuclei with tapered ends and frequent longitudinal nuclear grooves. The nuclei were typically oriented vertically in the deeper layers, and horizontally with a streaming pattern superficially. The cells had low nuclear to cytoplasmic ratios, perinuclear halos, and absent to rare mitotic figures. Mild to moderate atypia was seen in only two cases. Many of the cases could have been confused with squamous dysplasia due to the lack of apparent maturation. However, in most cases, attention to cytologic detail disclosed the typical features of transitional cell metaplasia. This process, usually seen in older women, has not been emphasized and can be overdiagnosed as dysplasia, leading to unnecessary treatment.

Purpose: The purpose of this trial was to evaluate an immunoassay for urinary nuclear matrix protein, NMP22,* *Matritech, Inc., Newton, Massachusetts. as an indicator for transitional cell carcinoma of the urinary tract.Materials and Methods: Three groups of subjects participated in this trial of NMP22: 1--175 with transitional cell carcinoma, 2--117 with benign urinary tract conditions and 3--375 healthy volunteers. Each subject provided a single (3 voids) urine sample for analysis at the time of study entry. Each sample was assayed for the level of NMP22.Results: In normal healthy volunteers and in subjects with benign conditions median NMP22 levels were 2.9 and 3.3 units per ml., respectively. Median urinary NMP22 levels in patients with transitional cell carcinoma were significantly greater than in comparison subjects. Patients with active transitional cell carcinoma had significantly greater median urinary NMP22 levels than those with no evidence of disease (6.04 versus 4.11 units per ml., p ...

Pilomatricoma is a benign epidermal appendage tumor with differentiation toward hair cortex cells. It is composed of varying percentages of basophilic cells, shadow cells, and transitional cells. Transitional cells seem to be apoptotic cells as evidenced by their morphological and ultrastructural characteristics. We investigated apoptosis in ten specimens of pilomatricoma by the transferase-mediated dUTP-biotin nick end labeling (TUNEL) technique. TUNEL-positive structures were detected in both transitional cell and amorphous debris zones, but not in either basophilic cell or shadow cell zones. In the transitional cell zone, apoptotic cells were found either in groups or bands, while in the amorphous debris zone, apoptotic bodies of varying sizes were seen diffusely. These findings indicate that transitional cells, due to the fact that they are dying cells, may not differentiate into the shadow cells. This view is supported by the facts that the transition of basophilic cells into the shadow cells is abrupt in some areas and that tumor cells, with or without ultrastructural characteristics of apoptosis, are found in the transitional cell zone. Furthermore, ultrastructural nuclear changes in shadow cells are different from those seen in apoptosis. Therefore, we propose that the name of transitional cells should be changed to "condensed cells." Although it has been conventionally though that basophilic cells in pilomatricoma differentiate directly and/or via transitional cells into shadow cells, we demonstrate that basophilic cells undergo two different processes. The first is differentiation directly into shadow cells, an the second is passage, via "condensed cells" (transitional cells), into the amorphous debris that results from tumor kinetics.

The origin of rarely encountered transitional cell carcinomas of the fallopian tubes has, to date, been ascribed to transitional cell metaplasia of the tubal serosa or subserosal Walthard rests. We report here three examples of transitional cell metaplasia of the mucosa of the fallopian tubes--in each instance an incidental finding--and propose this lesion as a hitherto unreported possible precursor for such tumors.

CD44 is a widely expressed cell surface adhesion molecule in which various isoforms arise from alternative RNA splicing mechanism during cancer initiation. We assessed whether multifocal transitional cell carcinoma of the urothelium is due to field change and/or intraluminal seeding and implantation.In a series of 24 patients with synchronous and/or metachronous multiple urothelial cancers we performed reverse transcription-polymerase chain reaction analysis using a set of primers capable of amplifying all CD44 splice variant isoforms. After polymerase chain reaction products were electrophoresed band intensities with areas corresponding to the major isoforms (that is CD44s, CD44v10 and CD44v8-10) were quantified, and CD44v10-to-CD44s and CD44v8-10-to-CD44s ratios were calculated. Moreover, p53 gene mutations in exons 4 to 11 were screened by direct DNA sequencing.Of these 24 cases 18 showed similar CD44v10-to-CD44s and CD44v8-10-to-CD44s ratios in among multiple urothelial cancers in each case. However, in the remaining 6 cases these ratios were quite different among multiple cancer lesions. Furthermore, different types of p53 mutation were detected among multiple cancer lesions in only 2 of 24 cases, which also indicated different patterns of CD44 alternative splicing.These findings suggest that at least some multiple transitional cell carcinomas of the urothelium seem to be of independent origin based on the analysis of alternative RNA splicing of CD44. Moreover, this hypothesis was further supported by the evaluation of p53 gene mutation.

We report five transitional cell neoplasms of the uterine cervix: three infiltrating high-grade transitional cell carcinomas and two inverted transitional cell papillomas. The patients with TCCs were aged 34, 73, and 81 years, two presented with vaginal bleeding and the third with a large cystic ovarian mass. The three transitional cell carcinomas had a superficial noninvasive papillary component. Two tumors metastasized, one to the pelvic lymph nodes, the other to the ovary. The two patients with metastasis are alive after radical hysterectomy or total abdominal hysterectomy and chemotherapy, but follow-up is short. The third patient is currently receiving radiotherapy. Microscopically, the transitional cell carcinomas were similar to those originating in the urinary bladder or ovary. The inverted transitional cell papillomas were discovered in the cervixes of young adult women, one of whom had atypical squamous cells on a cervical smear at her presentation. The second patient had a slightly raised lesion in the cervix noted when routine smears were obtained. The microscopic features of the inverted transitional cell papillomas were similar to those of the corresponding tumor of the urinary bladder. It is important to separate transitional cell carcinomas from other papillary cancers of the cervix to delineate their clinical and pathological features and establish the prognostic differences, if any, from squamous cell carcinoma. Inverted transitional cell papilloma of the cervix represents a hitherto undescribed benign neoplasm arising at this site. These cases illustrate that cervical epithelium, which is known to undergo benign transitional cell metaplasia, may also give rise to benign and malignant transitional cell neoplasms.

We report the clinical and morphologic features of a transitional cell carcinoma (TCC) that arose within a paratubal cyst of the right broad ligament. This case represents only the second report of a TCC arising in the broad ligament and the first with documented origin within a paratubal cyst. A possible explanation for this tumor's histogenesis as it relates to the more common transitional cell neoplasms of the ovary is presented.

The success of radiofrequency catheter ablation in the treatment of atrioventricular junctional, or atrioventricular nodal, reentrant tachycardia has rekindled interest in the electrophysiological and anatomical characteristics of the reentrant circuit. We conclude that there is no evidence that within the atrioventricular nodal area, which contains both the compact node and transitional cells, there are anatomically delineated dual or multiple pathways. Rather, the two main atrial inputs into the atrioventricular nodal area (posterior and anterior) seem to be the anatomically relevant structures for "slow" and "fast" pathways. Two other inputs (sinus septum and left atrial) may be the cause for multiple pathways in some individuals. Nonuniform anisotropic properties of the zone of transitional cells may account for slow or fast conduction in the same area, depending on directional differences of wavefronts. We prefer the term atrioventricular junctional reentrant tachycardia rather than atrioventricular nodal reentrant tachycardia because of mounting evidence that perinodal tissue is involved in the reentrant circuit. Finally, the role and origin of double extracellular electrograms is discussed. Further research is required to establish whether an anatomical or an electrogram-guided approach for catheter ablation is preferred.