Interstitial cystitis: a critique of current concepts with a new proposal for pathologic diagnosis and pathogenesis

Abstract

Interstitial cystitis (IC) has continued to be an unresolved problem in clinical urology despite intense investigation over the past 16 or more years. Its etiology and pathogenesis are still undetermined, and its pathologic diagnosis is essentially one of exclusion, with no specific or clear criteria. In this review, current concepts of the etiology/pathogenesis and pathology are critically analyzed, new pathologic observations summarized, and a proposal of neurogenic inflammation as the primary pathogenetic factor is presented in the context of all currently available information. The popular postulate attributing IC to a deficient or defective glycosaminoglycan urothelial surface layer is not substantiated by morphologic, experimental, clinical, or therapeutic observations. Although the consensus seems to discount an infectious etiology, there is sufficient evidence that a microbial factor—short of a bona fide clinical infection—may have a role. Both auto-immunity and mast cell infiltration also appear to have a role, despite the lack of evidence that either is involved as the primary etiologic factor. Claims that the so-called feline urologic syndrome may represent a natural animal model of IC are shaky. As it now stands, there is no natural or induced animal model that duplicates IC as it occurs in humans. No specific or diagnostic light microscopic pathologic features are provided by either routine histopathology or immunohistochemistry. Increasingly, it has been recognized that detrusor mast cell count has little or no diagnostic value. On the other hand, electron microscopy has provided important new observations: (a) presence of mast cells, activated by piecemeal degranulation, in close proximity to intrinsic nerves—particularly in suburothelium; (b) distinctive pathologic changes in urothelium, suburothelium, and muscularis in biopsy samples obtained after diagnostic bladder hydrodistension; (c) constant associated changes in venules, capillaries, and neural elements in the same biopsy samples; and (d) diffuse involvement of bladder wall, with the most evident and profound pathologic changes in posthydrodistension biopsy samples obtained from cystoscopically obvious lesions (glomerulations). These features are sufficiently distinctive to allow definitive pathologic diagnosis of IC, and provide a firm basis for primary involvement of neurogenic inflammation in its pathogenesis. A proposal is presented regarding the mechanisms invoked by neurogenic inflammation. This proposal revolves around sensory nerve excitation, the release of neuropeptides, and activated differential secretion of potent mast cell mediators. This proposal can account for the heterogeneity and variability of observed pathologic features, and upholds the tacit acceptance of IC as a disease of pluricausal etiology and multifactorial pathogenesis.