Specimens from patients with BPS/IC type 3C (classic IC) as a rule display striking histologic alterations from normal mucosa (Fig. 8.2), with prominent ulcerations that may be covered by fibrin mixed with inflammatory cells, in particular neutrophils (Fig. 8.3). The ulcerations are often wedge shaped and involve the superficial part of the lamina propria, not seldom extending all the way into the lamina muscularis mucosae. Underlying granulation tissue is present in the vast majority of the subjects [13]. These findings tally with those reported already 100 years ago by Hunner, who reported the abundance of granulation tissue formation as well as chronic inflammation involving all coats of the bladder [14]. There is an abnormal microvascularity in the lamina propria which may result in petechial bleeding or glomerulations, and possibly also ulceration as a consequence of ischemia, this in turn may bring about hemorrhage in the entire lamina propria. BPS/IC type 3C (classic IC) hence displays marked inflammatory changes in the lamina propria, including the presence of lymphocytes, plasma cells, mast cells and neutrophils. Eosinophils are generally few. Germinal centre formation may be seen. Fibrosis is commonly displayed in BPS/IC and especially inter and intra lamellar fibrosis in the detrusor muscle should be evaluated and reported (Fig. 8.4a, b).

The counting of mast cells in the detrusor muscle, using a grid, is mandatory in diagnosing BPS/IC. The mast cell count is usually high above 25 per mm² (Fig. 8.1).

The aforementioned light microscopic features differ markedly from what can be seen in nonulcer IC. Lepinard reported that whereas pancystitis affected the three layers of bladder wall, this was not the case in nonulcerative disease [15]. In another report, comprising 64 patients with ulcerative disease and 44 with nonulcerative IC, ulcerative disease had mucosal ulceration and hemorrhage, granulation tissue, severe inflammatory infiltrates, high mast cell counts, and perineural infiltrates. The nonulcer group, despite sharing a similar sympomatology and the same chronic course, had an impervious mucosa with a meagre inflammatory response, the main feature being numerous, mucosal ruptures and suburothelial hemorrhages [16]. Not seldom, biopsies can be perfectly normal in nonulcer IC.

Electron microscopy has not been very successful in diagnosing BPS/IC. In an early paper on this topic, Collan et al. stated that there was a considerable similarity of the ultrastructure of epithelial cells between controls and IC patients [17], and some 10 years later Dixon et al. also failed to discover any differences in the morphologic appearances of urothelial cells in patients with IC as compared to controls [18]. Neither could Anderström et al. see any unambiguous ultrastructural surface characteristics for IC, however, the proportion of cells covered by round, uniform and pleomorphic microvilli was higher in the IC patients than in controls [19].

At variance with these reports on lack of diagnostic positive histopathologic signs in nonulcer IC, Elbadawi and Light concluded that ultrastructural changes appear to be sufficiently distinctive to be diagnostic in specimens submitted for pathologic confirmation of nonulcer interstitial cystitis. They performed a detailed ultrastructural study on patients with nonulcer IC [20]. A distinctive combination of peculiar muscle cell profiles, injury of intrinsic vessels and nerves in muscularis and suburothelium, and discohesive urothelium was observed in lesional and less markedly in nonlesional samples of all specimens. Marked edema of various tissue elements and cells appeared to be a common denominator of many observed changes. Urothelial changes disrupted the true permeability barrier. Neural changes included a combination of degenerative and regenerative features.

Mast cells are regarded not only as cells involved in allergic tissue reactions but as multifunctional immunocompetent cells involved in a variety of tissue reactions such as chronic inflammation, examples of which are classic IC and rheumatoid arthritis as well as fibrosis [21]. It has thus been shown that the mast cell, in addition to histamine and heparin, also contains other highly potent inflammatory mediators such as leucotrienes, cytokines and the angiogenic and fibroblast stimulatory factor bFGF (basic fibroblast growth factor) [22, 23]. In addition to allergen binding, nerve-derived mediators may also stimulate mast cell secretion. Several lines of evidence support the concept of a neuroimmune connection [24] and morphological association between mast cells and neuropeptide-containing nerves has been demonstrated [25–27].

It was demonstrated, in bladder specimens from patients with classic IC, non-ulcer IC and controls, that mast cells were visualised in terms of metachromasia, reflecting glycosaminoglycan content, and immunohistochemically, visualising tryptase, chymase and IL-6 as well as the surface markers CD 117 and stem cell factor (SCF) [28]. In this report, classic IC displayed a 6–10-fold increase of mast cells in terms of proteinase positivity while nonulcer IC revealed twice as many mast cells as controls. In contrast to non-ulcer IC and controls, classic IC displayed an abundance of epithelial mast cells.

There are numerous reports on autoantibodies in patients with IC [29–31] and, moreover, some of the common clinical and histopathological characteristics present in IC patients show certain similarities with other known autoimmune phenomena. This is the background to the theory that IC may arise from autoimmune disturbances. The role of autoimmunity in IC is controversial and the disease is not thought to originate from a direct autoimmune attack on the bladder. Rather, some of the autoimmune symptoms and pathologic findings in IC arise indirectly as a result of tissue destruction and inflammation from other, as yet unknown, causes.

In a study of 47 IC patients, Mattila et al. found immune deposits in the vessel walls of 33 patients [32] and in a subsequent study, electron microscopy evidence of endothelial injury was found in 14 out of 20 IC patients [33]. There is, no doubt, an inflammatory response in classic IC, of a chronic nature, and this makes it possible that there is a cell-mediated autoimmune response at hand. In a report encompassing 24 classic IC patients, nine nonulcer patients and ten controls [34] it was found that the classic IC patients displayed aggregates of T-cells as well as B-nodules with focal germinal centres. There was a decreased or normal helper/suppressor ratio and suppressor cytotoxic cells were present in the germinal centres. The nonulcer patients, conversely, had only slightly increased numbers of lymphoid cells, dominated by T-helper cells, the nonulcer group not differing significantly from the controls.

In the very recent publication by Maeda et al. patients with Hunner type interstitial cystitis (HIC) and non-Hunner type interstitial cystitis (NHIC) were compared [35]. Using immunohistochemical quantification of infiltrating T-lymphocytes, B-lymphocytes and plasma cells, the authors were able to demonstrate that lymphoplasmacytic infiltration was significantly more severe in HIC specimens than in NHIC specimens. They moreover disclosed that the loss of residual epithelium was considerably decreased in HIC specimens but not in NHIC specimens. Finally, in situ hybridization of the light chains was performed to examine clonal B-cell expansion and the authors demonstrated that such expansion of light-chain-restricted B-cells was observed in 31% of cases of HIC. The authors concluded that NHIC and HIC appear to be divergent pathological entities, the latter being characterized by pancystitis, frequent clonal B-cell expansion and epithelial denudation. The very same research group also used double-immunofluorescence for CXCR3 and CD138 to detect CXCR3 expression in plasma cells from subjects with HIC and NHIC, respectively. Correlations between CXCR3 positivity and lymphocytic and plasma cell numbers and clinical parameters were explored. The density of CXCR3-positive cells showed no significant differences between HIC and non-IC cystitis specimens. However, distribution of CXCR3-positivity in plasma cells indicated co-localization of CXCR3 with CD138 in HIC specimens, but not in non-IC cystitis specimens [36].