By Bahram Robert Oliai, M.D.
In this newsletter we are going to “shift gears” away from neoplastic diaseases of the prostate and “focus” instead on medical disease of the bladder, specifically interstitial cystitis (IC). Occasionally a bladder biopsy is submitted to our practice, taken from a patient in whom the differential diagnosis includes IC. In the majority of such cases the requisition includes a request for either a mast cell stain, mast cell count, or at least a comment on the presence of mast cells.
What exactly is interstitial cystitis? Are mast cells in a bladder biopsy really helpful in making the diagnosis of IC? Are there other features which we as pathologists can comment on which can help our clinical colleagues/friends in making this diagnosis? Are there any new laboratory tests which may help in the diagnosis of IC? These are some of the questions which I hope to address in this month’s newsletter.
As the diagnosis of IC should enter the differential of any patient (especially female) experiencing pelvic pain, this disease may well be encountered by many different specialties (including but certainly not limited to Urologists, Gynecologists, Internists, and Family Practitioners). Acknowledging this varied audience I will begin with a basic description of IC.
What is Interstitial Cystitis?
Interstitial cystitis is a chronic, poorly understood, and most likely under diagnosed disorder of the bladder characterized by marked urinary frequency, urgency, pelvic/suprapubic/perineal pain, and nocturia in the absence of another identifiable cause (i.e. infection, stones, obstruction, carcinoma). This is a disorder which primarily affects middle aged Caucasian women; however, men and rarely even children can suffer from IC. Patients may also show a history of autoimmune disease.
Although there have been clinical criteria set forth by the NIH-NIDDK (National Institute of Diabetes and Digestive and Kidney Disease – Table 1), these were originally designed as criteria for research study inclusion and may not be suitable for clinical diagnosis, as many patients with IC will be missed when strictly adhering to the NIH-NIDDK guidelines.
Clinically, the differential is that of chronic pelvic pain and would include entities such as endometriosis and pelvic inflammatory disease. Patients may seek the help of several different specialists before this diagnosis is made.
Interstitial cystitis is a medical enigma with no known etiology; however, several theories have been advanced, some seemingly more plausible than others.
One theory holds that some kind of toxic urine component is present in these patients which somehow leaches into the bladder interstitium, resulting in a chronic inflammatory response. This possibly natural occurring substance may cause this response in susceptible individuals. Some believe that the development of recurrent IC in a pouch post urinary diversion lends support to this theory (5, 8).
Perhaps IC is really just another type of autoimmune disease. In support of this theory, it has been shown that some patients with IC demonstrate anti-bladder antibodies and may have high ANA titers (8).
Others believe that mast cell activation is the driving force behind IC and much has been written about the role of mast cells in IC. Mast cells may represent a conspicuous component of the inflammatory infiltrate in IC especially if noted in the detrusor muscle. Indeed it has even been proposed that IC be referred to as “detrusor mastocytosis (4).” Electron microscopy studies have also shown that the granules in the mast cells of IC patients may be more activated and likely to degranulate than those of patients with other conditions (8).
Yet another pathogenic mechanism proposes that IC results from a decrease or disruption of the normal glycosaminoglycan (GAG) coating of the urothelium. This results in increased bladder permeability allowing noxious substances from the urine to permeate and irritate the bladder wall (8). Interestingly, immunohistochemical staining has shown decreased staining for GP51 (glycoprotein 51, a component of the GAG urothelial coat) as compared to controls (1). This mechanism may be supported by studies using various urine markers to support the clinical diagnosis of IC. Studies have shown that a decreased urinary GP51 and Heparin Binding Epidermal Factor and increased urinary anti-proliferative factor and Epidermal Growth factor is a pattern associated with IC (1, 3, 7). Finally one of the treatments for IC, intravesical heparin, is thought to have properties similar to the bladder’s own GAG lining (8).
Diagnosis of Interstitial Cystitis
The key point is that the diagnosis of IC is essentially a clinical one often based on a constellation of clinical and cystoscopic findings and by ruling out other disease entities. The evaluation may include urine analysis, urine microscopic evaluation, urine culture, urine cytology, and cystoscopy under anesthesia with bladder distension at 80 cm of water for 2 minutes. At cystoscopy cardinal findings include either bladder ulcer (known as Hunner’s ulcer, present in <10% of cases, FIG 1, 9) and so-called “glomerulations,” which correspond microscopically to submucosal hemorrhages which become especially prominent on bladder distension. Histologic findings in non-ulcer cases can be very subtle, but generally biopsies show suburothelial edema, telangectasias, lamina propria hemorrhages, mucosal tears, and denudation (FIG 2). Sometimes chronic inflammatory infiltrates, fibrosis, and rarely even vasculitis can be noted. Additionally, nerve proliferation can be seen on occasion (2).
The utility of biopsy in the diagnosis of IC is somewhat unclear and this practice seems to vary among different practice settings (6); however, I personally believe that biopsy and urinary cytology do have a role in the evaluation of IC. The primary role in this setting is to rule out flat urothelial carcinoma in situ which can clinically and cystoscopically mimic IC. Additionally, with biopsy material the pathologist may be able to help exclude other forms of cystitis such as hemorrhagic cystitis, radiation cystitis (hopefully a history of radiation would be provided), and eosinophilic cystitis. In the classic ulcerative form of IC, Hunner’s ulcer(s) are seen on biopsy and given the clinical history can be rather specific. As an aside, these ulcers seem to always remind me of the serpiginious ulcers of inflammatory bowel disease. Crohn’s colitis can also show nerve hypertrophy; perhaps there are other parallels which may be drawn between these diseases.
Role of Mast Cell Counts
There is conflicting data regarding the utility of quantifying mast cells to help make the diagnosis of IC. Although some studies have suggested that the presence of mast cells in the detrusor muscle is somewhat specific for IC (4, 9, 10), some data suggests this is not the case (2, 6, 7). Some advocate performing a mast cell tryptase stain and counting the number of mast cells per mm squared with counts above 28 cells supporting a diagnosis of IC. This is problematic for several reasons. First, histologic sections are two dimensional and counts may vary from section (level) to section (level). Furthermore, marking an exact mm squared field is very difficult to do microscopically. The results of mast cell counts will vary depending on the stain used, the staining technique, and where the mast cells are counted (urothelium, lamina propria, detrusor muscle).
In situations in which biopsies are performed for possible IC, I personally report on the following:
1. The presence of ulcer(s)
2. The presence or absence of malignancy
3. The presence of significant fibrosis
4. The presence of muscularis propria in the specimen (I report this on all bladder biopsies)
5. The presence of significant urothelial denudation
6. Any other specific findings that may suggest another diagnosis
Although I prefer not to (for the reasons explained above), if requested I can make a comment regarding the presence of mast cells, whether or not they appear prominent, and their location. In doing this I prefer to use a C-KIT (CD117) immunoperoxidase stain to mark the cells, because I find that this stain shows a cleaner background and is technically less problematic than many of the other mast cell stains I have used.