Abstract

Bladder pain syndrome/interstitial cystitis is a condition with the leading clinical symptoms related to the bladder, such as pain and voiding frequency. The present understanding is that there are a variety of presentations representing different pathological entities, even though sharing similar symptomatology and the same chronic course. Only a subset of patients has bleeding lesions as seen in the cystoscope with bladder distension, previously described as ulcers, and microscopic changes with interstitial inflammation, fibrosis and mastocytosis. These findings are nowadays consistent with classic IC with Hunner’s lesions also designated as type 3C.

Summary of recommendations

Patients with bladder pain symptoms can be hard to treat. Studies over the years have shown that it is important to identify classic interstitial cystitis (IC) with Hunner’s lesions since this is a well treatable disease. Cystoscopic examination is mandatory; in classic IC typical changes, as discussed in this paper, includes an inflamed area with central vulnerable scars which rupture with increasing bladder distension while non-ulcer BPS displays a normal bladder mucosa at initial cystoscopy.

To make an unquestionable diagnosis, histopathology is required, too. Deep biopsies including bladder muscle is needed to diagnose classic IC, since the disease process involves superficial as well as deeper layers of the bladder wall. Important features to consider when making the histopathologic diagnosis are: denudation, ulceration, granulation tissue, fibrosis and mast cells in the urothelium as well as counts in the detrusor muscle.

1 What is interstitial cystitis?

Much has changed since the term interstitial cystitis (IC) was first introduced by Skene in 1887 [1]. An important step came almost exactly 100 years ago when Guy L. Hunner described a symptom complex of bladder pain associated with peculiar cystoscopic findings, later denominated the Hunner’s ulcers [2], at that time being tantamount to IC. A first stage in a change came 1949, when John Hand presented a large series of IC patients observing that IC did not comprise just the single entity with Hunner’s ulcers, claiming that other clinical presentations could be met [3]. Later on, in 1978, Messing and Stamey suggested that there might be an early form of the disease characterized by small submucosal bleedings, so-called glomerulations, potentially progressing into the well-known classic disease with Hunner’s ulcers [4], and after that extent, the diagnose became even wider. However, subsequent observations have not been able to confirm the progression of the ‘early form’ presentation into the classic ulcerous form, including the end stage disease (bladder contracture). Currently, we are continuing a circle of development again to realize that Hunner’s disease is a unique entity. The present understanding is that different presentations stand for different pathological entities, even though sharing similar symptomatology and the same chronic course [5], [6], [7], [8]. For example, a recent report by Killinger et al. failed to disclose any striking differences in pain patterns between the two subtypes [9]. Between the two main clinical (and cystoscopic) presentations, the differences are reflected in clinical manifestation and age distribution [7], [8], and it has also been reported that the two subtypes respond differently to many treatment procedures [8]. The notion of heterogeneity of the disease concept IC [5] was supported by observations by Koziol et al. based on US epidemiological data relating to demographics, risk factors, symptoms, pain and psychosocial factors [6]. Quite recently, Peters et al. demonstrated remarkable differences between the two subtypes in the number of comorbid diagnoses as well as symptoms [10].

In the last few years, important changes have taken place in ideas on cornerstones in IC diagnostics. During decades, the distribution of classic IC versus non-ulcer disease has been debated. Messing and Stamey stated that classic interstitial cystitis could account for about half of all patients with interstitial cystitis [4] in agreement with our notions [5], [6], [7], [8] while others found Hunner’s type to be a rare finding, accounting for 5–10% of cases of interstitial cystitis [11].

On the other hand, in their very large series. Koziol et al. noted classic interstitial cystitis in approximately 20 percent of cases [6]. That opinion of Hunner’s lesions disease being rare is a reasonable explanation of leaving identification out and to omit separation of this entity in clinical research, leading to doubtful usefulness of results, during several decades. Now, an increasing number of reports indicate that there is every reason to pay attention to this entity.

Cystoscopically, classic IC displays typical reddened mucosal areas often associated with small vessels radiating towards a central scar which ruptures with increasing bladder distension while non-ulcer IC displays a normal bladder mucosa at initial cystoscopy [5], [6], [7], [8]. Since the time of Hand, the finding of glomerulations has been regarded as a positive diagnostic sign. However remarkably, according to a recent critical review the finding of glomerulations is of little diagnostic consequence [12].

2 Bladder pain syndrome (BPS)

During the last decades, the nomenclature of the disease called interstitial cystitis has been debated. The leading clinical symptoms are pain related to the bladder and voiding frequency while inflammation of the bladder interstitium is found only in a subset of patients; in many cases it is hard to find the cause of origin of complaints. Therefore, a new terminology was needed, and several organisations (the European Society for the Study of Interstitial Cystitis/ESSIC, later International Society for the Study of Bladder Pain Syndrome, the European Association of Urology/EAU and the American Association of Urology/AUA) have agreed to the general term bladder pain syndrome (BPS) including interstitial cystitis, BPS/IC. In addition, the ESSIC has constructed a classification system with classical IC with Hunner’s lesions designated as type 3C.

3 General role of histopathological examination in BPS/IC

The primary role of histopathology in the diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC) is one of excluding other possible diagnoses. Confusing and harmful conditions must be ruled out; carcinoma and carcinoma in situ, eosinophilic cystitis, tuberculous cystitis, as well as any other entities with a specific tissue diagnosis, such as metaplastic changes like enteric metaplasia, squamous cell metaplasia and nephrogenic metaplasia.

However, it is worth noting that biopsy retrieval and histopathological examination is also needed when it comes to diagnosing BPS/IC. Although most histopathology features are not distinctive in non-Hunner’s diseases, certain findings are specific for classic IC. The understanding of the properties of various cell systems has developed dramatically in recent decades and the diagnosis with standard staining procedures and light microscopy can now be reinforced and further refined with immunohistochemistry and even more sophisticated ancillary techniques.

4 What happens to the biopsy in the pathology laboratory?

If the clinician wants to get a correct histopathological diagnosis of BPS/IC, biopsies should preferably be obtained by transurethral resection of large and deep strips of the bladder wall, including the detrusor muscle; however, deep cold cup biopsies is also an acceptable option. The choice of biopsy technique is mostly depending on local routines, but the choice of biopsy retrieval technique is also influenced by the clinically suspected pathology and thus the pathology the clinician finds important to verify or exclude.

Formaldehyde fixation (4%, 10%) is compulsory and the fixation rate is approximately 1 mm per hour, meaning that small biopsies are fixated by the time they reach the pathology laboratory. Then the specimen is dehydrated, paraffin or wax embedded, and cut into series of 4 µm sections. Thereafter, the specimen is deparaffinized and stained with hematoxylin/eosin (Htx-Eo) and mounted with coverslips. Other staining are often performed to make it easier for the pathologist. For instance, Van Gieson or Sirius can be used to demonstrate fibrosis. The specific antibody mast cell tryptase is nowadays preferred to visualise tryptase in mast cells. Toluidin Blue, a metachromatic dye, may also be used to stain mast cells but the staining procedure with Toluidin blue is tricky. This method is very dependent on low pH, mast cell containing heparin and chondroitin-sulfate to be visualized. Additional chemicals in this method like HCl, citric acid, as well as the dye Toludin blue is unhealthy for people handling the dying process. This method has now, in many laboratories, been replaced with a mast cell tryptase antibody capable of reveal an increased number of mast cells in the mucosa and the detrusor muscle (Figure 1).