The remnant urothelium after reconstructive bladder surgery

The pathology of the remnant urinary tract in an increasing population of cystectomy patients with orthotopic and heterotopic bladder substitution due to primary bladder carcinoma, and its management is discussed. The incidence of urethral tumours in primary or recurrent bladder cancer in long-term studies is approximately 6% for male and 2% for female patients. Risk factors for urethral tumour occurrence are tumours at the bladder neck and recurrent multifocal tumours. CIS of the bladder not involving the bladder neck, and muscle invasive tumours with or without lymph node involvement are not significantly correlated with urethral cancer. Those patients at risk for urethral tumours need additional work-up (multiple urethral biopsies and/or urethral brushings, frozen section of the membranous urethra) before an orthotopic lower urinary tract reconstruction to the urethra should be considered. In a large series of male patients, the majority of patients with urethral tumours had a single conservative treatment session, and did not recur thereafter demonstrating the feasibility of a conservative approach for superficial urethral tumour recurrences in patients with an orthotopic neo-bladder to the urethra. The incidence of upper tract tumours following cystectomy and lower urinary tract reconstruction lies between 2.4-17%. In a group of 258 patients with an orthotopic bladder substitution, we have seen an incidence of 3.5%. Tumour multifocality, carcinoma in situ in the bladder and/or distal ureter, locally advanced bladder tumour stage, and invasion of the intramural ureter were seen as risk factors in some series. A tendency for a higher incidence can be seen in those series with longer follow-up. The median time between cystectomy and diagnosis of upper tract tumours lies between 8 and 69 months in most series. A longer observation period in larger numbers of patients with an orthotopic neo-bladder and longer survival rates in general after cystectomy may reveal an increase in the incidence of upper tract tumours over the next decade.     

Carcinoma in situ and dysplasia of the bladder urothelium

Summary Urothelial carcinoma in situ (CIS) is a high grade noninvasive malignant tumor which involves most commonly but not exclusively the transitional epithelium of the urinary bladder. Despite its relatively innocuous cystoscopic appearance, CIS is rarely an incidental finding and most patients present with symptoms of urinary tract disease. The majority have previous or concurrent bladder cancer; primary CIS does occur but is uncommon. Detection of CIS is best accomplished by urinary cytologic examination. Experimental studies have shed light on the development of CIS, but its biological potential in the spectrum of neoplastic transformation remains unclear. The prognosis of patients with CIS is variable: many develop invasive carcinoma while others continue for years without disease progression. Urothelial dysplasia represents a distinctive pattern of morphologic alteration characterized histologically and cytologically as atypia which deviates from normal to a mild or a moderate degree. Like CIS, most information concerning urothelial dysplasia has been obtained from experimental studies in laboratory animals or from patients with bladder cancer. Preliminary evidence indicates that dysplasia may be a precursor lesion in the spectrum of developing carcinoma. While both experimental studies and clinical observations suggest that urothelial carcinoma arises through a series of progressively severe cytologic and histologic changes, these events are not necessarily an inevitable continuum in human patients and further definition of the relationship of dysplasia and CIS to invasive urothelial cancer is required.     

Dysfunction of bladder urothelium and bladder urothelial cells in interstitial cystitis

The human bladder urothelium (BU) and bladder urothelial cells (BUCs) play an important role in the normal functioning of bladder including bladder storage. Current evidence in interstitial cystitis (IC) supports multiple abnormalities in bladder urothelial physiology. These data have come primarily from human studies. The discovery of a novel protein termed the antiproliferative factor (APF) uniquely expressed by IC BUCs is extremely important. APF induces increased permeability of normal BUCs grown in culture. Furthermore, APF regulates expression of other cytokines, including upregulating heparin-binding epidermal growth factor-like growth factor and downregulating epidermal growth factor by BUCs. These cytokine abnormalities were also related to increases in purinergic (adenosine triphosphate) signaling, which could mediate increased bladder sensation. Recent studies of uroplakins, which are specialized proteins expressed only in the apical urothelial cells, suggest that uroplakins play a role in the barrier function of the BU. It is also conceivable that alterations in uroplakins may result in bladder symptoms related to increased permeability or decreased protective function. As the body of knowledge about BU and BUC function increases, novel therapies targeting urothelial cells should become clinically feasible.     

Multifocal pigmentation of prostatic and bladder urothelium

Multifocal pigmentation of the bladder and prostatic urothelium is described in 2 white men. The light microscopic, electron microscopic and histochemical characterization of these foci identified the contained pigment as melanin.     

Effects of formalin on bladder urothelium.

Formalin instillation into canine bladders was followed by serial radiographic and histologic evaluation. A generalized slough of epithelial tissue was seen with the deposition of an amorphous substance. Telangiectasia resulted in moderate bleeding. No ureterovesical junction obstruction was seen and reflux occurring in 60 per cent of the animals reverted to normal. Correlation with clinical experience is made.     

Effect of urothelium on bladder contractility in diabetic rats

AIM: It is known that physiopathological changes in diabetes affect the function of the bladder. In this study, we aimed to demonstrate the possible effects of diabetes on the urothelium during this physiopathological process. METHODS: Diabetes was induced in rats by tail vein injection of 35 mg/kg streptozotocin. Eight weeks later, intact and denuded bladder strips were prepared from these rats. Electrical field stimulation (EFS; 0.5-32 Hz), carbachol (10(-8)-10(-3) mol/L; cumulative dosage-response curves) and KCl (120 mmol/L) were used for the evaluation of the contractile responses. All responses were expressed as mg tension developed per mg of bladder tissue. Weights of rats and of their bladders, blood glucose levels, and frequency- and concentration-response curves were compared using anova, the paired t-test and the independent t-test. Differences were considered significant at P<0.05. RESULTS: Although no differences related to the weight of bladders of the control and diabetic groups were observed, there were differences in blood glucose levels and body weights between the two groups. Similarly, although there were no differences between the data obtained with EFS and KCl from tissues with intact and denuded strips in the control group, carbachol responses significantly differed between intact and denuded strips in the non-diabetic group. These differences were not observed in the diabetic group. In the control groups, in the presence of additional strips with intact urothelium placed in the medium containing denuded tissue, the differences in contractile responses between the intact control strip and the denuded strip disappeared. CONCLUSIONS: Diabetes possibly changes the interaction between the relaxant factors that are released from urothelium and muscarinic stimulation, but these interactions are not completely understood yet. Consequently, the response of the bladder to contractile stimulants is also affected. Further studies are required to reveal the mechanism by which diabetes influences the urothelium.     

Gene expression in normal urothelium depends on location within the bladder: a possible link to bladder carcinogenesis

OBJECTIVES: Clinical studies have shown that more than 70% of primary bladder tumours arise in the area around the ureteric orifice. In this study a genomic approach was taken to explore the molecular mechanisms that may influence this phenomenon. METHODS: RNA was isolated from each individual normal ureteric orifice and the dome biopsy from 33 male patients. Equal amounts of the pooled ureteric orifice and dome mRNAs were labelled with Cy3 and Cy5, respectively before hybridising to the gene chip (UniGEM 2.0, Incyte Genomics Inc., Wilmington, Delaware, USA). Results: Significant changes (more than a twofold difference) in gene expression were observed in 3.1% (312) of the 10,176 gene array: 211 genes upregulated and 101 downregulated. Analysis of Cdc25B, TK1, PKM, and PDGFra with RT-PCR supported the reliability of the microarray result. Seladin-1 was the most upregulated gene in the ureteric orifice: 8.3-fold on the microarray and 11.4-fold by real time PCR. CONCLUSIONS: Overall, this study suggests significant altered gene expression between these two anatomically distinct areas of the normal human bladder. Of particular note is Seladin-1, whose significance in cancer is yet to be clarified. Further studies of the genes discovered by this work will help clarify which of these differences influence primary bladder carcinogenesis.     

Mechanisms of disease: involvement of the urothelium in bladder dysfunction

Although the urinary bladder urothelium has classically been thought of as a passive barrier to ions and solutes, a number of novel properties have been recently attributed to urothelial cells. Studies have revealed that the urothelium is involved in sensory mechanisms (i.e. the ability to express a number of sensor molecules or respond to thermal, mechanical and chemical stimuli) and can release chemical mediators. Localization of afferent nerves next to the urothelium suggests that urothelial cells could be targets for neurotransmitters released from bladder nerves or that chemicals released by urothelial cells could alter afferent nerve excitability. Taken together, these and other findings highlighted in this article suggest a sensory function for the urothelium. Elucidation of mechanisms that influence urothelial function might provide insights into the pathology of bladder dysfunction.     

The role of fibrinogen in mediating staphylococcal adherence to fibers

The use of tampons and surgical gauze pads and colonization with Staphylococcus aureus have been established as risk factors for the development of toxic shock syndrome. To elucidate the role of blood factors in the mediation of staphylococcal adherence to fibers used in tampons and surgical packing, an adherence assay with cotton fibers was developed. Results demonstrated that cotton disks precoated with fibrinogen in the presence of human serum albumin bound a significant percentage of the inoculum for both staphylococcal strains tested when compared to human serum albumin controls. Likewise, fibers pretreated with plasma or defibrinated blood containing a small amount of fibrin revealed comparable staphylococcal adherence to that of fibrinogen. In contrast, fibers pretreated with serum, fibronectin, or vitronectin did not exhibit significant augmentation in staphylococcal attachment in comparison to human serum albumin controls. The attachment of staphylococci to fibrinogen and/or fibrin appeared to be specific and is blocked by goat anti-human fibrinogen antibody, but not fibronectin, vitronectin, or nonimmune goat IgG. Thus, our data indicate that fibrinogen/fibrin is the dominant blood component in the mediation of staphylococcal adherence to fibers used in tampons and surgical gauze pads.     

Crystal retention by injured urothelium of the rat urinary bladder

Injuries caused by hydrochloric acid or Triton X 100 application to the rat bladder urothelium, and the effects on calcium oxalate crystal retention, were examined by light and scanning electron microscopy. Damage due to either compound resulted in desquamation of urothelial cells. The crystals appeared to be retained by a fibrillar material, some of which was identified as fibrin. Heparin treatment of injured urothelium was found to prevent crystal retention.     

Observations on the ultrastructure of human urothelium: The response of normal bladder of elderly subjects to hyperthermia

Summary An electron microscopic study of normal bladder urothelium of elderly subjects treated by hyperthermic perfusions has shown that the tissue responds, sooner or later, in every instance by desquamation. There is no evidence of cell death prior to desquamation although various organelles undergo structural alterations. Mitochondria are especially prone to suffer varying degrees of damage. A short heat shock has revealed differences in the initial response of the thick and thin regions of bladder urothelium known to occur in elderly subjects. After a long, fractionated treatment, regeneration is evident within 3 daysof the end of treatment, and follow-up biopsies have revealed a hyperplastic urothelium within 10 to 12 weeks. The constituent cells show signs of cytodifferentiation at this time but it remains unknown when an ultrastructurally normal urothelium with characteristic cell layers will be restored. The various treatments in this study suggest that the stem cells in the epithelium are unaffected by the levels of hyperthermia employed and that their unimpaired proliferative capacity ensures regeneration of the urothelium.     

The role of the mucosa in modulation of evoked responses in the spinal cord injured rat bladder

Aims

Mounting evidence indicates that a variety of factors released from the urothelium or suburothelium can modulate smooth muscle activity. Although the relationship between the mucosa and smooth muscle has been investigated, little is known about the pathophysiologic changes in detrusor‐mucosa interactions in neurogenic bladders. The goal of the study was to determine the impact of the mucosa on evoked responses in spinal cord injured (SCI) bladders.

Methods

Urinary bladders were obtained from 6wk SCI rats or age‐matched uninjured controls. Ex vivo isometric tension studies were performed and muscarinic receptor expression was measured in bladder tissue with and without mucosa.

Results

The magnitude and area of nerve evoked responses in SCI tissue with mucosa was higher than without mucosa. The duration and decay time of nerve‐evoked responses were longer in SCI than control tissue irrespective of the mucosa. The level of the muscarinic M₂ receptor was decreased in the mucosa of SCI bladders.

Conclusions

Detrusor‐mucosa interactions are substantially altered in the neurogenic bladder. After spinal cord injury, an excitatory modulation of smooth muscle contraction by the mucosa emerges, and could be targeted via intravesical treatment in the context of neurogenic bladder dysfunction.