Other histopathological criteria turned out to be better markers for the diagnosis of BPS/IC [9]. Dense to medium lymphocytic infiltrates, frequently combined with the presence of nodular lymphocyte aggregates (Fig. 10.1a) or lymph follicles were characteristic for BPS/IC with and without Hunner’s lesion, with 86% accuracy and an 85% positive prediction value. Also an absent or defective urothelium (Fig. 10.1a) was a strong criterion for separating BPS/IC from OAB, with 88% accuracy and an 83% positive prediction value. Moreover, immunohistochemical staining with antibodies to PGP9.5, a marker for unmyelinated nociceptive sensory nerve fibers, showed submucosal sensory hyperinnervation (Fig. 10.1d) in cases of BPS/IC, but not in OAB, with 88% accuracy and an 83% positive prediction value. Typically, these nerve fibers are not present in the submucosa of healthy patients, but under pathological conditions they proliferate, partly under the influence of neurotrophins, such as nerve growth factor (NGF). Immunohistochemical staining of the NGF-receptor p75^NTR in basal urothelial cells was a sign for urothelial regeneration and thus a further evidence for BPS/IC.

Similar to 30 years ago, biopsy evaluation plays a central and important role for the diagnosis of BPS/IC. Mast cell hyperplasia and migration towards the ulcer bed or beneath the epithelium were evidently characteristic for BPS/IC with Hunner’s lesion. BPS/IC without Hunner’s lesion and OAB, however, could not be distinguished by mast cell counts, activation or localization. Therefore, mast cell evaluation is not helpful for the diagnosis of BPS/IC, especially because BPS/IC with Hunner’s lesion can already be identified by cystoscopy. Other histological features, such as the sensory hyperinnervation, urothelial defects and lymphocytic infiltration are better histopathological criteria to differentiate between BPS/IC and OAB.

The origin of BPS/IC still remains unknown. Thirty years ago, Aldenborg et al. ended their article by suggesting an infection or an allergic reaction as possible causes. These assumptions still remain valid, and very likely, causes are multifactorial. To find out, further studies are required. Research will also focus on the identification and adequate therapy of early forms to prevent disease progression. A good diagnosis and treatment monitoring, e.g. based on robust objective histopathological markers, is mandatory to achieve these goals.