ICCs serve as pacemaker cells regulating coordinated ureteral peristalsis and several studies have demonstrated reduced ICC density and disrupted spatial organization in resected PUJ segments from children with obstruction compared with controls [1,2]. Importantly, such alterations are often identified in specimens lacking significant fibrosis, inflammation, or fixed luminal narrowing, supporting a neuromuscular basis for obstruction. While biologically plausible, translation of this concept into routine diagnostic practice is hindered by the absence of standardized evaluation criteria. Foremost among these is age-related variability [1-3]. ICCs undergo postnatal maturation, with increasing density and network complexity during early childhood. Consequently, ICC counts that may be physiologically appropriate in infants could represent a true pathological reduction in older children. Reduced ICC counts in a 4- to 6-year-old child are more likely to be pathological than developmental, whereas similar findings in infants may fall within physiological limits. Despite this, most published studies lack robust age-stratified reference data, limiting their applicability to individual cases.
Another important consideration during microscopic assessment of ICCs is the precise site of biopsy, especially in cases of severe obstruction, as investigators have reported differential density of ICC in regions above the PUJ, at the PUJ, and below the PUJ [3,4].
Technical issues further complicate assessment. ICCs are typically highlighted using c-Kit (CD117) immunohistochemistry, but mast cells, which also express CD117, are abundant in the ureteric wall and represent a major interpretative pitfall (Figure 1A-D). Importantly, this diagnostic pitfall of CD117+ mast cells may persist even in specimens showing secondary tissue remodeling or mild fibrosis and should not be interpreted as evidence against a functional neuromuscular contribution to the obstruction. Without careful morphological correlation, mast cells may be erroneously included in ICC counts, leading to overestimation. Accurate identification, therefore, requires strict morphological correlation, limiting counts to spindle-shaped intermuscular cells with cytoplasmic processes and avoiding reliance on staining alone. DOG1, which shows cytoplasmic and membranous positivity in gastrointestinal ICCs, has been proposed as an adjunct marker, but its role in routine PUJ diagnostics remains limited [5]. Equally important is the lack of standardized reporting criteria. Absolute ICC counts per high-power field, though commonly used in research, lack validated diagnostic cut-offs. In routine practice, a semi-quantitative approach that assesses ICC density (preserved vs reduced), distribution (uniform vs patchy), and continuity (intact vs disrupted networks), is more reproducible and functionally meaningful. ICC findings on immunohistochemistry should not be interpreted in isolation. Smooth muscle architecture, neural elements, and fibrosis must be evaluated concurrently to avoid attributing obstruction solely to ICC paucity. From a diagnostic standpoint, ICC assessment should be regarded as supportive evidence that may explain functional obstruction, rather than a standalone criterion for PUJ obstruction (Figure 2). In conclusion, ICC evaluation offers valuable insight into the functional pathology of PUJ obstruction but currently occupies a supplementary role in diagnostic histopathology. Adoption of age-aware interpretation, careful morphological validation, and standardized semi-quantitative reporting would enhance consistency and clinical relevance. Future multicentric studies aimed at defining age-matched reference patterns and reproducible scoring systems are necessary before ICC assessment can be fully integrated into routine PUJ pathology reporting.
1) Nandan R, Jain V, Agarwala S, Das P, Goel P, Kalaivani M, Yadav DK. Evaluation of interstitial cells of cajal-like cells at the pelviureteric junction in children with pelviureteric junction obstruction: a prospective study and review of literature. J Indian Assoc Pediatr Surg. 2022;27(4):395-401. doi: 10.4103/jiaps. jiaps_103_21 Figure 2: Interpretative framework for assessing interstitial cells of Cajal (ICC) in pelvi-ureteric junction (PUJ) obstruction
2) Yang X, Zhang Y, Hu J. The expression of Cajal cells at the obstruction site of congenital pelviureteric junction obstruction and quantitative image analysis. J Pediatr Surg. 2009;44(12):2339-42. doi: 10.1016/j.jpedsurg.2009.07.061
3) Samaranayake UMJE, Mathangasinghe Y, Liyanage UA, de Silva MVC, Samarasinghe MC, Abeygunasekera S, Lamahewage AK, Malalasekera AP. Variations in the density and distribution of cajal like cells associated with the pathogenesis of ureteropelvic junction obstruction: a systematic review and meta-analysis. Front Surg. 2021;8:721143. doi: 10.3389/fsurg.2021.721143
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