Hunner-Type (Classic) Interstitial Cystitis: A Distinct Inflammatory Disorder Characterized by Pancystitis, with Frequent Expansion of Clonal B-Cells and Epithelial Denudation

Abstract

Interstitial cystitis (IC) is a chronic bladder disease with urinary frequency, bladder discomfort or bladder pain of unknown etiology. Based on cystoscopic findings, patients with IC are classified as either Hunner-type/classic IC (HIC), presenting with a specific Hunner lesion, or non-Hunner-type IC (NHIC), presenting with no Hunner lesion, but post-hydrodistension mucosal bleeding. Inflammatory cell infiltration, composed predominantly of lymphocytes, plasma cells and epithelial denudation, has in the past been documented as a major pathological IC finding. However, the significance of the pathological evaluation of IC, especially with regard to the difference between HIC and NHIC, has been downplayed in recent years. In this study, we performed immunohistochemical quantification of infiltrating T-lymphocytes, B-lymphocytes and plasma cells, and measured the amount of residual epithelium in urinary bladder biopsy specimens taken from patients with HIC and NHIC, and those with no IC, using image analysis software. In addition, in situ hybridization of the light chains was performed to examine clonal B-cell expansion. Lymphoplasmacytic infiltration was significantly more severe in HIC specimens than in NHIC specimens (P <0.0001). Substantial lymphoplasmacytic inflammation (≥200 cells/mm2) was observed in 93% of HIC specimens, whereas only 8% of NHIC specimens were inflamed. Plasmacytic infiltration was more prominent in HIC specimens compared with NHIC and non-IC cystitis specimens (P <0.005). Furthermore, expansion of light-chain-restricted B-cells was observed in 31% of cases of HIC. The amount of residual epithelium was decreased in HIC specimens compared with NHIC specimens and non-IC cystitis specimens (P <0.0001). These results suggest that NHIC and HIC are distinct pathological entities, with the latter characterized by pancystitis, frequent clonal B-cell expansion and epithelial denudation. An abnormality in the B-cell population may be involved in the pathogenesis of HIC.

Clinical guidelines for interstitial cystitis and hypersensitive bladder updated in 2015

“…Bladder biopsy might not be essential for diagnosis. However, Hunner type IC shows epithelial denudation and dense inflammatory infiltrates in the bladder, which are totally different from non‐Hunner type IC or HSB …”

“…Alterations of urothelial differentiation and homeostasis are shown by denudation of the epithelium, low expression of interleukin‐8, increased levels of apoptosis with decreased proliferation, or abnormal expression of APF, uroplakin, chondroitin sulfate and tight junctional proteins. Dysregulated urothelium can result in increased permeability, generating hypersensitive bladder symptoms .…”

“…Bladders with Hunner type IC show diffuse and intense inflammation and overexpression of pro‐inflammatory genes . Light‐chain restriction in infiltrated plasma cells suggests involvement of specific immunological reactions . Bladder inflammation is likely to induce afferent nerve overactivity …”

Protease activated‐receptor 4 activation as a model of persistent bladder pain: Essential role of macrophage migration inhibitory factor and high mobility group box 1

“…IC/BPS is a debilitating chronic disease characterized by bladder‐related pain or discomfort with some urinary symptoms . Classic IC/BPS patients show bladder inflammation with Hunner's lesions . However, most IC/BPS patients do not show urinary infections, inflammation or other obvious bladder pathologies .…”

Time of symptom onset and histologic findings in bladder pain syndrome/interstitial cystitis: new findings on useful correlations

“…The results of some studies 27 suggest that NHIC and HIC are distinct pathological entities, with the latter characterized by pancystitis, frequent clonal B-cell expansion and epithelial denudation. An abnormality in the B-cell population was found as a relevant feature in the pathogenesis of HIC.…”