Detrusor Mastocytosis Research Articles

MP07-11 INTERSTITIAL CYSTITIS / BLADDER PAIN SYNDROME - DETRUSOR MAST CELL COUNT IS ASSOCIATED WITH HYDRODISTENTION CLINICAL RESPONSE

INTRODUCTION AND OBJECTIVE: Interstitial Cystitis / Bladder Pain Syndrome (IC/BPS) is, presumably, an umbrella term for several disorders, with hypothesized differences in pathomechanisms and response to treatment. Clinical guidelines are disputed whether bladder biopsies are indicated as a part of standard IC/BPS patient evaluation or only for ruling out differential diagnoses. Abnormal mast cell activation in the detrusor has long been suggested as a mechanism for IC/BPS symptoms, but their role in patient evaluation is unclear. Our aim was to find out if detrusor mastocytosis in bladder biopsies has clinical implications, specifically if it can predict clinical symptom improvement and its duration, following treatment with hydrodistention. METHODS: In a retrospective study, we examined bladder biopsies taken from patients with complaints concordant with IC/BPS during cystoscopy and hydrodistention under anesthesia. We correlated pathological findings with patient reported symptom improvement or resolution and its duration. We used t-test, chi-square, and multivariate linear regression to define the relations between detrusor mastocytosis (≥20 mast cells / mm2) and symptom improvement. RESULTS: 31 Patients, 27 female and 4 male, mean age 59±17.6 years, underwent cystoscopy under anesthesia for suspected IC/BPS between 2013 and 2019. For 24 patients (21 female, 3 male, mean age 59±17.5 years), bladder biopsies with mast cell count were available. Eight (33%) had detrusor mastocytosis. The median follow-up was 9.6 [range: 2.3-61.4] months. Mastocytosis was associated with symptom improvement (p=0.03) and patients with detrusor mastocytosis experienced an average additional 6.8 months (95% CI 1.6-12.1, p=0.014) of improvement, compared with patients without. In a univariate regression model, improvement duration was positively correlated with detrusor mastocytosis (p=0.005), age (p=0.047) and follow-up duration (0.002), but not with gender (p=0.25), Charlson comorbidity score (p=0.61), Hunner lesion presence (p=0.14) or bladder capacity under anesthesia (p=0.20). In a multivariate model, mastocytosis was the only factor correlated with improvement duration (p=0.025). CONCLUSIONS: Detrusor mastocytosis in bladder biopsies was associated with symptom improvement after hydrodistention in IC/BPS patients. This finding may improve disease phenotyping and treatment choice direction. Mast cell activity may be a target for future research on noninvasive test development for IC/BPS phenotyping. Source of Funding: none.

Hunner lesion versus non-Hunner lesion interstitial cystitis/bladder pain syndrome.

Global consensus on the standardization of terminology for interstitial cystitis/bladder pain syndrome is lacking and is in the formative stages. The Workshop on Hunner lesion versus non-Hunner lesion at the 2018 International Consultation on Interstitial Cystitis Japan discussed prevalence, performance and outcome of endoscopy, the role of histopathology, and markers. A panel of experts reviewed the literature regarding Hunner lesion vs. non-Hunner lesion interstitial cystitis/bladder pain syndrome. The prevalence of Hunner lesion has been reported to be 5-57%. Older age and smaller anatomic bladder capacity were associated with Hunner lesions. Cystoscopy using local anesthesia is not adequate in diagnosing interstitial cystitis but is needed to rule out confusable diseases. Cystoscopy with hydrodistention and redistention of the bladder is considered standard. A Hunner lesion is visualized as a quite typical inflammatory reaction: a reddened mucosal area with small vessels radiating towards a central scar, splitting at distension, usually associated with a waterfall bleeding pattern. Biopsies from the inflamed area show inflammatory infiltrates, granulation tissue, detrusor mastocytosis, and fibrin deposits. Ablation of Hunner lesions includes transurethral resection of lesions, fulguration, laser ablation, and cortical steroid injections. Mast cell density is a somewhat controversial matter, described differently in different studies: marked increase in Hunner lesion vs. non-Hunner lesion in the majority of studies, no difference in a few. Nitric oxide appears to be a definitive marker in distinguishing Hunner lesion vs. non-Hunner lesion disease. Macrophage migration inhibitory factor is elevated in Hunner lesion patients. Increased level of urinary proinflammatory genes expression has also been found in Hunner lesion subjects. Hunner lesion patients are clinically and pathologically distinct from non-Hunner lesion bladder pain syndrome patients.

Management of Bladder Pain Syndrome: Green-top Guideline No. 70.

Management of Bladder Pain Syndrome: Green-top Guideline No. 70.

Are Mast Cells Still Good Biomarkers for Bladder Pain Syndrome/Interstitial Cystitis?

ESSIC identifies mast cell infiltrates of detrusor muscle as a diagnostic criterion for bladder pain syndrome/interstitial cystitis. However, an increased mast cell count is also characteristic of overactive bladder syndrome. The lack of uniformity in mast cell detection methods hampers data comparison. Using state-of-the-art techniques we investigated whether mast cells differ among bladder conditions. We analyzed bladder biopsies from 56 patients, including 31 with bladder pain syndrome/interstitial cystitis with (12) or without (19) Hunner lesions, 13 with overactive bladder syndrome and 12 without bladder symptoms to determine the quantity, location, distribution and activation of mast cells using immunohistochemistry with anti-mast cell tryptase. Patients were allocated to study groups by key bladder symptoms commonly used to define conditions (pain and major urgency). Subepithelial mast cell localization (p <0.001) and an increased detrusor mast cell count (p = 0.029) were characteristic of bladder pain syndrome/interstitial cystitis with Hunner lesions. The optimal cutoff of 32 detrusor mast cells per mm(2) achieved only 68% accuracy with 38% positive predictive value. No difference was observed between bladder pain syndrome/interstitial cystitis without Hunner lesions and overactive bladder syndrome. Patient groups differed in lymphocyte infiltration (p = 0.001), nodular lymphocyte aggregates (p <0.001) and urothelium integrity (p <0.001). Subepithelial mast cell distribution was characteristic of bladder pain syndrome/interstitial cystitis with Hunner lesions. Detrusor mastocytosis had poor predictive value for bladder pain syndrome/interstitial cystitis. Mast cell assessment did not distinguish bladder pain syndrome/interstitial cystitis without Hunner lesions from overactive bladder syndrome.

Bladder pain syndrome: do the different morphological and cystoscopic features correlate?

For the diagnosis of bladder pain syndrome (BPS), the International Society for the Study of Bladder Pain Syndrome (ESSIC) recommends a specific diagnostic work-up using cystoscopy with hydrodistension and bladder biopsies. This study evaluates the correlation between the histological findings in bladder biopsies handled following ESSIC recommendations, as well as the importance of the histological features in BPS compared with the cystoscopic findings. The study included 15 men and 93 women. All patients underwent cystoscopy with hydrodistension, and at least three deep biopsies including detrusor muscle were taken. For the cell count the Leder stain was used most frequently. A cut-off point of 28 mast cells/mm(2) was used for detrusor mastocytosis. Significant correlations were found between urothelial damage and inflammatory infiltrate (p < 0.001). Detrusor mastocytosis was significantly more elevated in biopsies with normal urinary epithelium (Tukey corrected p < 0.0001) than in biopsies where the urothelium was damaged. No other correlations were found between histological findings or between histological and cystoscopic findings. Both cystoscopy with hydrodistension and histology can be used to illustrate different pathophysiological mechanisms in patients with BPS. These results favour the use of both in the classification of BPS patients.

Bladder pain syndrome/interstitial cystitis in a Danish population: a study using the 2008 criteria of the European Society for the Study of Interstitial Cystitis

To characterize and evaluate a Danish patient population with bladder pain syndrome/interstitial cystitis (BPS/IC), using a working definition for BPS/IC incorporating six variables, and a set of criteria defined by the European Society for the Study of Interstitial Cystitis (ESSIC); to describe the clinical course and treatment intensity in relation to these variables. Clinical data were obtained retrospectively from medical records for 349 consecutive patients with IC referred to the Department of Urology, Copenhagen University Hospital Herlev, Denmark between 1966 and 2008. The median (range) age at diagnosis was 53 (16-88) years; 64% were followed for at least 2 years. The outcome was expressed in terms of treatment intensity and was correlated with clinical data (pain, nocturnal frequency, bladder capacity, mucosal glomerulations, detrusor mastocytosis, detrusor intrafascicular fibrosis, IFF). All patients had pain and 75% had nocturia at least twice. The bladder capacity estimated under general anaesthesia was <500 mL in 42%; 53% presented with detrusor mastocytosis (> or =28 mast cells/mm(2)) and 50% with IFF. The detrusor mast cell count (P < 0.001), IFF (P = 0.004) and nocturnal frequency (P = 0.043) had statistically significant prognostic value for treatment intensity, whereas bladder capacity and glomerulations were not significant. Nocturia, detrusor mastocytosis and IFF are associated with multiple treatments and presumed failure of standard urological therapy in patients with BPS/IC, while bladder capacity and glomerulations are not. Valid conclusions cannot be drawn because of numerous limitations to the study.

Proteomic Investigation on Chronic Bladder Irritation in the Rat

Interstitial cystitis (IC) is a painful bladder syndrome associated with urinary frequency and urgency. Elusive cause of IC makes its diagnosis only possible by exclusion in many cases. In this study, we used proteomics for identifying disease-associated proteins in a rat model of chronic bladder irritation. Chronic irritation of the rat bladder was caused by a brief (90 seconds) intravesical instillation of 0.2 mL of 0.4 N HCl. Whole bladders were collected at different time points after treatment, snap frozen, and nuclear and cytosolic protein extracts were obtained. Samples were resolved in standard 2-dimensional (2D) gels stained with an improved Coomasie stain or by differential gel electrophoresis (DIGE). Differentially expressed spots were excised and identified by MALDI-TOF MS/MS. Histologic and Western blot analyses were also performed. Bladder morphology and histologic appearance of bladder sections after HCl treatment reflected hemorrhage, edema, epithelial denudation, detrusor mastocytosis, and eosinophilia. Proteomic analysis of irritated rat bladder revealed marked overexpression of 4 nuclear proteins and marked underexpression of 1 nuclear protein compared with normal rat bladders. Among these proteins, inflammation-associated calgranulin A (over) and smooth muscle protein-22/transgelin (under) showed opposed expression patterns after bladder irritation. Presence of mast cells and eosinophils and overexpression of calgranulin A confirm the inflammatory component of HCl-irritated bladder. Altered expression of nuclear proteins is of particular interest because of their possible role as a prognostic marker in inflammatory bladder disorders. However, more studies are needed before clinical application of these findings can be established.

Interstitial cystitis in a woman with systemic mastocytosis

Studies have reported detrusor mastocytosis in patients with interstitial cystitis. The author describes a patient with systemic mastocytosis who was confirmed to have detrusor mastocytosis and interstitial cystitis. She responded to therapy with pentosanpolysulfate. The literature on systemic mastocytosis and the role of mast cells in the pathophysiology of interstitial cystitis are reviewed.

Interleukin-4 and 13 Induce the Expression and Release of Monocyte Chemoattractant Protein 1, Interleukin-6 and Stem Cell Factor From Human Detrusor Smooth Muscle Cells: Synergy With Interleukin-1β and Tumor Necrosis Factor-α

Interstitial cystitis is characterized by an increased number of activated MCs in the detrusor muscle. However, to our knowledge the factors that influence the anatomical relationship between MCs and HDSMCs are unknown. MCP-1, IL-6 and SCF have a critical role in the regulation of MC development, signaling and function. We investigated whether HDSMCs are capable of expressing and releasing MCP-1, IL-6 and SCF in response to IL-4, IL-13, IL-1beta and tumor necrosis factor-alpha. HDSMCs were isolated and cultured using an explant technique. Protein expression, and the secretion of MCP-1, IL-6 and SCF were assayed by semiquantitative reverse transcriptase-polymerase chain reaction and specific enzyme-linked immunosorbent assay. Unstimulated cells released low amounts of MCP-1, IL-6 and SCF. In cells stimulated by IL-4 MCP-1 mRNA was up-regulated by a mean factor +/- SD of 3.5 +/- 1.3, IL-6 mRNA was up-regulated by 3.8 +/- 1.3, the soluble form of SCF was up-regulated by 3.2 +/- 0.6 and the membrane bound form of SCF was up-regulated by 7.9 +/- 5.6. For IL-13 stimulated cells the values were 2.6 +/- 1.5, 3.6 +/- 2.1, 2.9 +/- 1.6 and 5.7 +/- 3.7, respectively. Soluble SCF mRNA expression was 5 times higher than the expression of mSCF mRNA. IL-4 and IL-13 given separately stimulated MCP-1, IL-6 and SCF secretion in a concentration (0.01 to 100 ng/ml) and time (0 to 24 hours) dependent manner. Furthermore, IL-1beta and tumor necrosis factor-alpha alone induced significant release of MCP-1, IL-6 and SCF but in combination with IL-4 or IL-13 it induced greater secretion of MCP-1, IL-6 and SCF. To our knowledge these findings demonstrate for the first time that HDSMCs express and release MCP-1 and IL-6, and show relatively high expression of soluble SCF. This supports our hypothesis that HDSMCs may have an active role by orchestrating the local inflammatory response in the bladder wall with possible implications for the pathophysiology of detrusor mastocytosis.

INCREASED URINARY LEUKOTRIENE E4 AND EOSINOPHIL PROTEIN X EXCRETION IN PATIENTS WITH INTERSTITIAL CYSTITIS

The role of cysteinyl containing leukotriene C4, D4 and E4, and eosinophil protein X in interstitial cystitis is unknown. Leukotriene E4, the end product of cysteinyl containing leukotrienes, and eosinophil protein X are markers of the activation of mast cells and eosinophils, respectively. Cysteinyl containing leukotrienes are potent and specific chemoattractants for eosinophils. We compared the urinary excretion of leukotriene E4 and eosinophil protein X in patients with interstitial cystitis and in healthy controls. Morning spot urine samples from nine patients with interstitial cystitis who fulfilled National Institute of Diabetes and Digestive and Kidney Diseases criteria were collected on the day of cystoscopy with biopsies. Aliquots of urine specimens were immediately centrifuged and the supernatants were stored at -80C until use. Urine samples from 9 healthy women served as controls. Urinary leukotriene E4 and eosinophil protein X were measured by enzyme immunoassay and radioimmunoassay, respectively. All determinations were performed in duplicate and normalized to urine creatinine. Leukotriene E4 and eosinophil protein X were significantly increased in the morning urine of patients with interstitial cystitis compared with controls. The mean urinary excretion of leukotriene E4 plus or minus standard deviation was 148.8 +/- 62.5 and 62.2 +/- 17.5 ng./mmol. creatinine in patients and controls (p = 0.003), while the mean urinary excretion of eosinophil protein X was 109.7 +/- 70.4 and 43.7 +/- 22.0 microg./mmol. creatinine, respectively (p = 0.01). All urine cultures were negative. The mean mast cell count in detrusor biopsies in the interstitial cystitis group was 41 cells per mm.2 (range 5 to 84). Eosinophilic granulocytes were occasionally observed in the submucosa but not in the detrusor. Our study shows that patients with interstitial cystitis and detrusor mastocytosis have increased urinary leukotriene E4 and eosinophil protein X. It is possible that cysteinyl containing leukotrienes and eosinophil protein X are involved in the pathogenesis of interstitial cystitis. Urinary leukotriene E4 and eosinophil protein X may be useful markers for assessing the grade of activation of mast cells and eosinophils in patients with interstitial cystitis and/or for confirming the diagnosis. However, it remains to be investigated whether the increase in urinary leukotriene E4 and eosinophil protein X correlates with interstitial cystitis symptoms.

THE CYSTEINYL LEUKOTRIENE D4 RECEPTOR ANTAGONIST MONTELUKAST FOR THE TREATMENT OF INTERSTITIAL CYSTITIS

The presence of leukotriene D4 receptors in human detrusor myocytes and increased urinary leukotriene E4 in patients with interstitial cystitis and detrusor mastocytosis imply a role for cysteinyl containing leukotrienes as proinflammatory mediators in this disease. We examined the efficacy of the cysteinyl leukotriene 1 receptor antagonist montelukast for treating patients with interstitial cystitis and detrusor mastocytosis. Ten women in whom interstitial cystitis was diagnosed according to National Institute of Diabetes and Digestive and Kidney Diseases criteria and who also had detrusor mastocytosis with a minimum of 28 mast cells per mm.2 muscle tissue were included in this study. Patients received a single dose of montelukast daily for 3 months. The efficacy of treatment was determined by 24-hour urinary frequency, nocturia and pain using visual analog scales. After 1 month of montelukast treatment there was a statistically significant decrease in 24-hour urinary frequency, nocturia and pain which persisted during the 3 months of treatment. After 3 months 24-hour urinary frequency had decreased from 17.4 to 12 voidings (p = 0.009), nocturia had decreased from 4.5 to 2.8 (p = 0.019) and pain had decreased from 46.8 to 19.6 mm. on a visual analog scale (p = 0.006). No side effects were observed during treatment. Montelukast treatment resulted in significant improvement in urinary frequency and pain. Its efficacy for decreasing urinary frequency and pain imply a role of leukotriene receptor antagonists for managing interstitial cystitis but further placebo controlled clinical studies are needed.

Treatment of interstitial cystitis with montelukast, a leukotriene D 4 receptor antagonist

Cysteinyl-containing leukotrienes (CysLTs) are lipid mediators known to possess potent proinflammatory action. We have recently shown the presence of CysLT1 receptors in primary cultures of human detrusor muscle cells. In this pilot study we investigated whether the CysLT1 receptor antagonist montelukast (Singulair ), currently used to treat asthma, had any effect as a new therapy in the treatment of interstitial cystitis (IC). Ten women with diagnosed IC according to National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria and detrusor mastocytosis (with a minimum of 28 mast cells/mm2 muscle tissue) were included in the study. The patients were treated with 10 mg montelukast daily for 2 months. The efficacy of the treatment was determined by the following parameters: 24-hour urinary frequency, pain using visual analog scales (VAS), and use of analgesics. After 2 months of treatment, 24-hour urinary frequency decreased significantly from 17.38 to 12.58 times (P = 0.005) and pain from 46.8 mm to 23.36 mm (P = 0.01) according to VAS. We observed no side effects of montelukast during the study. Only 3 patients used analgesics and there was no change in their use during the study. We conclude that treatment of IC patients with montelukast resulted in a significant improvement of urinary frequency and pain. Additional placebo controlled clinical studies will eventually lead to a better understanding of the pathological and physiological role of CysLTs and the role of CysLT1 receptor antagonists in the treatment of IC.

Mast cell involvement in interstitial cystitis: a review of human and experimental evidence

Interstitial cystitis (IC) is a heterogeneous syndrome of unknown etiology. Altered bladder glycosaminoglycans lining and bladder mastocytosis have been documented in IC. The objective of this article is to critically examine the published data on bladder mastocytosis in clinical, experimental, and animal studies, with particular emphasis on morphologic evidence of mast cell increase and activation. The literature on bladder mastocytosis and mast cell activation in IC is critically reviewed with particular reference to staining methodology, tryptase immunoreactivity, and electron microscopy. Data from humans and animal models of IC are included. Mastocytosis in IC is best documented by tryptase immunocytochemical staining. Standard surgical stains such as Giemsa and toluidine blue routinely underestimate the degree of mastocytosis. Mast cells are 6- to 8-fold higher in the detrusor compared with controls in “classic IC,” and 2- to 3-fold higher in “nonulcerative” IC. Detrusor mastocytosis occurs in both classic and nonulcer IC. Mucosal mast cell increase is present in nonulcerative IC. Mast cell activation without typical exocytosis occurs in the mucosa and submucosa. Activation of mast cells, irrespective of bladder location or degree of mastocytosis, is significant. Mast cell-derived vasoactive and proinflammatory molecules may contribute to the pathogenesis of IC.

Significance of hematuria in patients with interstitial cystitis: review of radiographic and endoscopic findings

Objectives. Hematuria may be found in up to 30% of patients with interstitial cystitis (IC). However, few studies have described its etiology based on the findings of a complete evaluation. We reviewed the clinical significance of hematuria in the setting of IC. Methods. We retrospectively reviewed the records of 148 patients fulfilling the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases inclusion criteria for IC. Patients with gross or microscopic hematuria were identified. Evaluation consisted of urine culture and cytology, cystoscopy, and intravenous urography (or retrograde pyelography plus renal ultrasound). Patients with urinary tract infections were excluded. Results. Of 148 patients, 60 (41%) were found to have had at least one episode of hematuria during a mean follow-up of 18 months. Of 56 patients who agreed to be evaluated, 8 (14%) had positive urologic findings. Of these, none were highly significant; five were simple renal cysts (8.9%), one was a renal stone (1.8%), one was reflux nephropathy (1.8%), and one was medullary sponge kidney (1.8%). Cystoscopy, cytology, and bladder biopsy did not demonstrate malignancy in any patient. No statistically significant differences were found in age (49.9 versus 46.7 years), sex (90% versus 91% female), bladder capacity (792 versus 808 mL), and the presence of Hunner’s ulcers (5% versus 2.4%), glomerulations (60% versus 59.9%), or detrusor mastocytosis (55% versus 47.6%) between patients with hematuria and those without ( P >0.05). Conclusions. The incidence of hematuria in patients with IC may be higher than previously reported. Nevertheless, although many of these patients present with pelvic pain and irritative voiding symptoms, the hematuria evaluation is unlikely to reveal a life-threatening urologic condition.

A Molecular Marker for the Development of Interstitial Cystitis in a Rat Model: Isoactin Gene Expression

Purpose To determine whether the differential expression of bladder smooth muscle isoactin can be used as a molecular marker for the development of interstitial cystitis (IC). Methods Three groups of five female Sprague-Dawley rats each underwent urethral catheterization and intravesical instillation of 0.5 ml. of 0.4N HCl. One group was sacrificed one, two, and four weeks after the application of HCl, and their bladders harvested for histologic examination and evaluation using northern blot analysis of bladder smooth muscle isoactins. Five control animals were sacrificed and their bladders harvested to establish isoactin gene expression of bladder smooth muscle in the normal state. The bladders of the rats in each group were excised, immediately frozen in liquid nitrogen, pooled, then stored at -70C until needed for RNA isolation. Isoactin cDNA probes have been developed, therefore isoactin specific cDNA insert fragments were isolated and insert DNA was purified by gel electrophoresis. Total cellular RNA was isolated from 1.0 gm. of bladder smooth muscle from each group. After spectrophotometric quantification, Northern Blot analysis was performed using 2% agarose-formaldehyde gels and Biotrans nylon membranes. Two complete Northern Blot series were run on a single gel and blotted to a single membrane to eliminate gel and blotting discrepancies. Results Microscopic histologic analysis revealed detrusor mastocystosis and eosinophilia as has been noted in humans with chronic interstitial cystitis. Two weeks after the intravesical application of hydrochloric acid, the relative expression of gamma-smooth muscle isoactin was noted to increase by 1.7-fold, while alpha-smooth muscle isoactin expression increased by a factor of 9. These effects were seen to stabilize four weeks after acid application. Conclusions The intravesical application of dilute HCl in rats results in a histologic appearance which mimics that seen in humans with interstitial cystitis. The appearance of detrusor mastocytosis and eosinophilia was accompanied by a relative decrease in the expression of gamma- and a relative increase in alpha-smooth muscle isoactin gene expression. This pattern of smooth muscle isoactin expression is consistent with a more immature and possibly synthetic smooth muscle phenotype, which may be responsible for the clinical presentation of those with IC. Northern blot analysis of bladder smooth muscle cells may serve as an effective marker for the development of interstitial cystitis in humans.

Histological changes in interstitial cystitis

Various aspects of the histological appearance of the bladder wall in interstitial cystitis have been emphasized over the 75 years since Hunner described the condition. The major focus of interest in this disease during the last decade has been the study of the relative significance of detrusor mastocytosis. Although this was for some years considered pivotal in establishing a diagnosis of interstitial cystitis, most recent studies have not shown mastocytosis to be a consistent feature of the disease. The histological picture of this condition is now considered to be that of a chronic inflammatory infiltrate of the lamina propria, possibly with fibrosis of the detrusor or lamina propria. The authors attempted to determine if there is a correlation between the severity of inflammation and fibrosis, and detrusor mastocytosis, on initial biopsy and the response of symptoms to conservative treatment. Of 39 patients, 10 required major surgical intervention. Although not reaching statistical significance, most cases with mild disease responded to conservative management. However, over 50% of cases showing severe histological disease also responded well to this type of treatment. Histological assessment of the interstitial cystitis bladder is more useful in ruling out other diseases than in allowing the demonstration of specifical diagnostic features of this condition. A severely abnormal microscopic picture does not necessarily indicate a poor prognosis.

Prolongation of response to dmso by heparin maintenance

Dimethylsulfoxide (DMSO) is an effective treatment of symptomatic patients with detrusor mastocytosis but it is associated with frequent relapses. A group of patients (N = 25) followed for twelve months showed a relapse rate of 59 percent. Our experience with a combination of DMSO and heparin has suggested that the relapse rate may be lower. Heparin is a glycosaminoglycan that may afford protection to the urothelium and may reduce the relapse rate. It is better tolerated than DMSO or a combination of DMSO and heparin and does not produce garlic halitus. It is not associated with coagulation anomalies when administered intravesically. To determine whether or not maintenance therapy with intravesical heparin may reduce relapses we have treated a similar cohort of 25 patients with monthly instillations of 10,0001 U of heparin over a twelve-month period. Both groups were comparable in age, duration of symptoms, severity of symptoms, and response to DMSO. At twelve months only 20 percent of the heparin-treated group had relapsed versus 52 percent of the control group. Furthermore 6 patients (24%) in the follow-up group failed to respond to retreatment with DMSO while all of the heparin maintenance group continued to respond to one or more treatments with DMSO. Thus, it seems that heparin maintenance produces a significant reduction in the relapse rate of patients who respond to DMSO and reduces the number of patients requiring alternative therapy.

Do Women with Idiopathic Sensory Urgency have Early Interstitial Cystitis?

Interstitial cystitis is rarely considered as a cause of urinary symptoms in referrals to gynaecology clinics. Recent concepts in the diagnosis of this condition mean that it is emerging as a much more common entity, with both early and late forms of the disease being described. Mast cell density in the detrusor muscle has been reported to be useful as a disease marker to substantiate the diagnosis of interstitial cystitis where no classical diagnostic features exist. We assessed mast cell counts in bladder biopsies from 27 women with idiopathic sensory urgency and 10 control patients about to undergo a colposuspension procedure for pure genuine stress incontinence; 30% of the study group had a clear increase in the detrusor muscle mast cell population (detrusor mastocytosis). No control patient showed such an increase. Early interstitial cystitis should be considered as a possible cause of lower urinary tract symptoms in patients with apparently idiopathic sensory urgency.

Diagnosis of Interstitial Cystitis

We reviewed clinical and histological findings in 55 patients with interstitial cystitis and 21 with voiding dysfunction secondary to other pathological conditions. Of our interstitial cystitis patients 36% would fail to meet the research definition proposed at a recent National Institutes of Health workshop. Detrusor mastocytosis was present in 64% of our interstitial cystitis patients compared to 80% of the noninterstitial cystitis group. There was no statistically significant difference in mean detrusor mast cell counts between interstitial cystitis and noninterstitial cystitis patients. Biopsies of 12 patients who did meet the proposed National Institutes of Health research definition were evaluated by immunohistochemical techniques. Early results are inconclusive.These studies indicate that interstitial cystitis is a complex disease whose diagnosis presently still must be made from a symptom complex rather than from objective histological criteria, including mastocytosis or the presence of any specific immunoreactive cell. (J. Urol., 143: 278–281, 1990).

Autorosette Inhibition Factor: A Positive Acute Phase Reactant in Interstitial Cystitis

Autorosette inhibition factor (AIF), complement C3d and eosinophil cationic protein (ECP) in urine were determined in 28 patients with painful bladder disease. In patients with interstitial cystitis (IC), diagnosed by the demonstration of detrusor mastocytosis, a positive correlation (r = 0.73, p less than 0.01) between AIF and C3d was found, whereas no reliable correlation was found in the remaining patients. The median concentration of urinary ECP was significantly elevated in the group of patients with IC whereas the median concentration of C3d was significantly elevated in both groups. AIF seems to behave as a positive acute phase reactant in IC. It is hypothesized that AIF may play a role in the pathogenesis of IC by influencing the normal barrier function of the epithelium of the bladder.