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Altered expression of interstitial cells of Cajal in primary obstructive megaureter
Journal of Pediatric Urology (2013) 9, 1028e1031
Altered expression of interstitial cells of Cajal in primary obstructive megaureter Yeliz Kart a, Osman Z. Karakus‚ b,*, Oguz Ates‚ b, ¨r b ¨lce Hakgu ¨der b, Mustafa Olguner b, Feza M. Akgu Gu a b
Clinics of Pediatric Surgery, Private Reyap Hospital, Tekirdag, Turkey Department of Pediatric Surgery, Dokuz Eylu¨l University, Faculty of Medicine, Izmir, Turkey
Received 27 November 2012; accepted 6 February 2013 Available online 15 March 2013
KEYWORDS Interstitial cells of Cajal; Ureterovesical junction obstruction; Megaureter
Abstract Objective: A marked decrease in the density of interstitial cells of Cajal (ICC) has been shown in patients with ureteropelvic junction obstruction. ICC may also play a role in primary obstructive megaureter (POM). An immunohistochemical study was conducted to investigate the density of ICC in ureterovesical junction (UVJ) segments resected from patients with POM and from control autopsy specimens. Materials and methods: Resected UVJ segments from 11 patients operated for POM comprised the study group. Control UVJs were obtained from autopsy specimens of 7 children who died from causes other than urogenital pathology. The UVJs including the narrowest parts were studied using immunohistochemical staining for C-kit positive cells. Results: The number of ICC was significantly lower in the UVJs of the POM compared to the control group. The UVJs of the POM group had 1.75 1.14 ICC (mean 1SD), whereas the control group had 5.76 2.99 ICC (mean 1SD). Conclusion: The number of ICC was decreased in the UVJs of the patients with POM compared to the normal control group. As dilation of the ureter during fetal life is a common condition and ureteral dilation is often self limiting, we hypothesize that ureteral peristalsis is a maturational event including the maturational development of ICC. Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company.
Introduction The etiology of primary obstructive megaureter (POM) is still obscure. Two layers of muscle, a circular outer and
longitudinal inner layer, are present at the ureterovesical junction (UVJ). There is little collagen in the connective tissue between these two muscle layers. Transportation of urine occurs by means of peristalsis of these muscles. An
_ _ ¨ niversitesi, Tıp Faku * Corresponding author. Dokuz Eylu ¸ ocuk Cerrahisi Anabilim Dalı, 35340 Inciraltı, Izmir, Turkey. Tel.: þ90 232 ¨l U ¨ltesi, C 4123002; fax: þ90 232 2792101. E-mail addresses: [email protected], [email protected] (O.Z. Karakus‚). 1477-5131/$36 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company. http://dx.doi.org/10.1016/j.jpurol.2013.02.003
Altered expression of interstitial cells of Cajal increase in collagen is a common finding in all research regarding the etiology of POM. Hypertrophy of the circular muscle and atrophy of the inner muscle accompany the increase in collagen. It has been postulated that these changes cause deterioration of urine flow at the UVJ [1e5]. Interstitial cells of Cajal (ICC) are important cells for organs with peristaltic function. ICC produce signals for rhythmic contractions and their absence is associated with peristaltic dysfunction. The role of ICC in the motility of the gastrointestinal system has been extensively studied [6]. A lack of expression of c-kit immunoreactive ICC has been shown in childhood intestinal motility disorders such as Hirschsprung’s disease and internal sphincter achalasia [7,8]. ICC have been shown to be present in the human and porcine upper urinary tract [9e12]. ICC are distributed throughout the ureter, including the proximal and distal part in the human and porcine ureter [9,11]. Additionally, Solari et al. have shown a marked decrease in the density of ICC in ureteropelvic junction (UPJ) specimens obtained from patients with UPJ obstruction (UPJO) [12]. This ubiquitous distribution of ICC in the human ureter and relationship with peristalsis indicate that ICC might contribute to the intrinsic pacemaker activity of the urinary tract. ICC may also play a role in human POM. The distribution of ICC at the UVJ of patients with POM has been studied [13], but this distribution in normal children has not been studied. We planned an immunohistochemical study to investigate the density of ICC in UVJ segments resected from patients with POM, and from children with a normal urinary tract who died from causes other than urogenital pathology.
Material and methods Operation specimens (including narrowest “intramural” part of the ureter) of 11 patients operated for POM (8 girls, 3 boys) comprised the study group. Mean age of the patients was 46.2 31.6 months (8 monthse10 years). Diagnosis of POM was established by voiding cystourethrography, ultrasonography and radionuclide study, and confirmed by surgical findings. Control UVJs were obtained from autopsy specimens of children who died from causes other than urogenital pathology. There were 7 children (5 boys, 2 girls) in the control group. Mean age of the children was 42.7 45.1 months (1 monthe14 years). The specimens were resected in the same manner as in the surgical procedure, and the same region of ureter as in the POM group was used for histopathological examination. No gross renal pathologies were detected during autopsy in any child in the control group. The ureters of the control group were narrower than 7 mm and the UVJ could easily be catheterized with a 6 F catheter, and the luminal patency was confirmed in all control specimens.
1029 (Novacastra, Newcastle, UK) primary antibody in a 1:40 dilution and an anti-rabbit immuno-conjugate secondary antibody incubated with horseradish peroxide (HRP)streptavidin solution (LSAB2 System-HRP, Code K0675; Dako Cytomation, Glostrup, Denmark). Slides were developed with 3-30 -diaminobenzidine (DAB; D4293; Sigma Aldrich), counterstained with Mayer’s hematoxylin, and examined by light microscopy (Olympus BX-51). Negative control samples were identically stained with study samples without primary antibodies.
Light microscopy Tissues were examined by two blinded pathologists. The distribution of ICC in different regions was assessed semiquantitatively by applying morphological criteria [14]. ICCs were c-kit-positive spindle-shaped cells with long cytoplasmic processes located in the muscular layer, while mast cells were spherical cells with a central nucleus located in the mucosa and submucosa. The ICC were counted separately in ten randomly selected high-power fields (100). Mean numbers of ICC were compared using ANOVA followed by Tukey’s test. p values lower than 0.01 were accepted as significant.
Results ICC located in the muscular layer had a fusiform cell body, thin cytoplasm, wide ovoid nucleus and two dendritic processes (Fig. 1). In contrast, mast cells were located in the submucosa, muscularis mucosa and mucosa with a centralized round nucleus (Fig. 2). The number of ICC was significantly lower in the UVJ of the POM compared with the control group (p < 0.01). The UVJ of the POM group had 1.75 1.14 ICC (mean 1SD), whereas the control group had 5.76 2.99 ICC (mean 1SD) (Table 1).
Discussion Accumulation of collagen and hypertrophy of the muscular layer of the ureter have been postulated as the cause of
Immunohistochemical staining Longitudinal 4 mm serial sections of formalin fixed, paraffin embedded tissue samples were heated in 0.01 mol/l citrate buffer (pH 6.0) in a microwave oven for antigen retrieval. Then, tissue samples were treated with Liquid Mouse Monoclonal Antibody C-kit Oncoprotein (CD117)
Figure 1 ICC located in the muscular layer had a fusiform cell body, thin cytoplasm, wide ovoid nucleus and two dendritic processes (black arrow).
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Figure 2 Mast cells located in the mucosa and submucosa had a spherical cell body with central nucleus (black arrow).
POM [1e5]. However, samples obtained from different parts of the ureter show different histopathological properties [15]. While the UVJ in POM has a collagen and elastin distribution similar to the normal ureter, the dilated proximal part has muscular hypertrophy and increased collagen and elastin, under either light or electron microscopy [2,15,16]. Therefore, the accumulation of collagen and elastin in the proximal ureteral wall in POM does not seem to be the cause of the obstruction but as the result of the obstruction; thus the etiology of POM is obscure. ICC were first described in the gastrointestinal tract. They are important pacemaker cells in human peristaltic organs. ICC have tyrosine kinase surface receptors. By means of these receptors ICC show C-kit positivity. Hypoplasia or aplasia of these cells was shown to be closely related to peristaltic dysfunction in hollow organs. Lack or hypoplasia of the ICC has been shown in several diseases with peristaltic dysfunction, such as Hirschsprung’s disease and internal anal sphincter achalasia [6e8]. McCloskey and Gurney first described ICC in the urinary system in guinea pigs [17]. ICC have also been shown to be present in the human urinary system [12]. Solari et al. showed that human urinary ICC were microscopically identical to the gastrointestinal system ICC. They also hypothesized that urinary functional obstructive disorders of the human urinary system might be related with the aplasia or hypoplasia of the ICC as seen in the gastrointestinal system. They and others showed that ICC were sparse or
Table 1 group.
Number of interstitial cells of Cajal in each
Group
Interstitial cells of Cajal (mean 1SD)
Primary obstructive megaureter Control
1.75 1.14* 5.76 2.99
Mean number of interstitial cells of Cajal examined under 100 magnification counted in 10 random areas. *p < 0.01 compared to control group.
absent in the UPJ segments of patients who were operated for UPJO [12,18]. The absence or scarcity of ICC at the UVJ may cause the cessation of peristaltic waves and local dysmotility, which result in obstruction or an impaired ureteral valve mechanism. Therefore, ICC have been shown to play a role in VUR, and a decrease in ICC has been shown at the UVJ of patients with VUR [13,16]. However, whether the decrease or absence of ICC at the UVJ of patients with VUR is a primary or secondary phenomenon is debatable. Oberritter et al. have shown that a decrease in ICC occurred at the UVJ of pigs with surgically created VUR. They suggested that this is a secondary phenomenon [19]. A similar debate may also be valid for POM. A decrease in ICC at the UVJ of patients with POM has been shown [13,20]. Kang et al. have shown that the number of ICC was significantly lower in the UVJ of refluxing megaureter compared with obstructive megaureter [13]. As they did not have a normal healthy control group they could only compare refluxing and obstructed UVJs. They also showed that the proportion of smooth muscle and number of apoptotic cells were significantly increased in the proximal ureter of the obstructive megaureter [13]. Similar results were observed in experimental ureteral obstruction, indicating that smooth muscle cell proliferation and apoptosis in proximal ureter in POM might be a secondary phenomenon [21]. The authors proposed that proliferation and apoptosis is a response of the fibrous and smooth muscle layers to increased wall tension of the ureter which impairs blood flow [21]. The decrease in ICC in POM may also be explained by the ischemia theory [13]. However, Kuzgunbay et al. have shown that the number of ICC was increased in the proximal ureter after acute obstruction of the ureter [22]. They suggested that this increase was related to increased ureteral peristaltic activity. They stated that the results are representative of the acute acquired condition, which differs from congenital conditions such as UPJO and POM in which ICC were absent or decreased. In the present study we have shown that the number of ICC was decreased in the UVJ of patients with POM compared with to the normal control group. Considering that dilation of the ureter during fetal life is a common condition compared with newborns, and ureteral dilation is often a self-limiting condition, we hypothesize that ureteral peristalsis is a maturational event including the maturational development of the ICC [23]. In the minority of patients who manifest the symptoms of POM, the problem might be related to the number of mature ICC that provide adequate peristalsis for urine flow. Otherwise, even borderline insufficiency of ICC may initiate an obstructioneproliferationeischemia cascade that results in manifest POM. Further studies are needed to evaluate the maturation of ICC in the fetus and restoration of the ICC after the obstruction is relieved in POM.
Funding None.
Conflict of interest None.
Altered expression of interstitial cells of Cajal
Ethical approval This study was approved by the Local Ethical Committee of Dokuz Eylu ¨l University.
References [1] Escala JM, Keating MA, Boyd G, Pierce A, Hutton JL, Lister J. Development of elastic fibres in the upper urinary tract. J Urol 1989;141:969e73. [2] Gosling JA, Dixon JS. Functional obstruction of the ureter and renal pelvis: a histological and electron microscopic study. Br J Urol 1978;50:145e52. [3] Hanna MK, Jeffs RD, Sturgess JM, Barkin M. Ureteral structure and ultrastructure. Part III. The congenitally dilated ureter (megaureter). J Urol 1977;117:24e7. [4] Nicotina PA, Romeo C, Arena F, Romeo G. Segmental upregulation of transforming growth factor-beta in the pathogenesis of primary megaureter. An immunocytochemical study. Br J Urol 1997;80:946e9. [5] Notley RG. Electron microscopy of the primary obstructive megaureter. Br J Urol 1972;44:229e34. [6] Rolle U, Piaseczna-Piotrowska A, Puri P. Interstitial cells of Cajal in the normal gut and in intestinal motility disorders of childhood. Pediatr Surg Int 2007;23:1139e52. [7] Piotrowska AP, Solari V, Puri P. Distribution of interstitial cells of Cajal in the internal anal sphincter of patients with internal anal sphincter achalasia and Hirschsprung disease. Arch Pathol Lab Med 2003;127:1192e5. [8] Rolle U, Piotrowska AP, Nemeth L, Puri P. Altered distribution of interstitial cells of Cajal in Hirschsprung disease. Arch Pathol Lab Med 2002;126:928e33. [9] Metzger R, Neugebauer A, Rolle U, Bo ¨hling L, Till H. C-Kit receptor (CD117) in the porcine urinary tract. Pediatr Surg Int 2008;24:67e76. [10] Metzger R, Schuster T, Till H, Franke FE, Dietz HG. Cajal-like cells in the upper urinary tract: comparative study in various species. Pediatr Surg Int 2005;21:169e74. [11] Metzger R, Schuster T, Till H, Stehr M, Franke FE, Dietz HG. Cajal-like cells in the human upper urinary tract. J Urol 2004; 172:769e72.
1031 [12] Solari V, Piotrowska AP, Puri P. Altered expression of interstitial cells of Cajal in congenital ureteropelvic junction obstruction. J Urol 2003;170:2420e2. [13] Kang HJ, Lee HY, Jin MH, Jeong HT, Han SW. Decreased interstitial cells of Cajal-like cells, possible cause of congenital refluxing megaureters: histopathologic differences in refluxing and obstructive megaureters. Urology 2009;74: 318e23. [14] Ahmadi O, Nicholson Mde L, Gould ML, Mitchell A, Stringer MDA. Interstitial cells of Cajal are present in human extrahepatic bile ducts. J Gastroenterol Hepatol 2010;25: 277e85. [15] Lee BR, Partin AW, Epstein JI, Quinlan DM, Gosling JA, Gearhart JP. A quantitative histological analysis of the dilated ureter of childhood. J Urol 1992;148:1482e6. [16] Schwentner C, Oswald J, Lunacek A, Fritsch H, Deibl M, Bartsch G, et al. Loss of interstitial cells of Cajal and gap junction protein connexin 43 at the vesicoureteral junction in children with vesicoureteral reflux. J Urol 2005;174:1981e6. [17] McCloskey KD, Gurney AM. Kit positive cells in the guinea pig bladder. J Urol 2002;168:832e6. [18] 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: 2339e42. [19] Oberritter Z, Rolle U, Juhasz Z, Cserni T, Puri P. Altered expression of c-kit-positive cells in the ureterovesical junction after surgically created vesicoureteral reflux. Pediatr Surg Int 2009;25:1103e7. [20] Arena F, Nico `tina PA, Arena S, Romeo C, Zuccarello B, Romeo G. C-kit positive interstitial cells of Cajal network in primary obstructive megaureter. Minerva Pediatr 2007;59: 7e11. [21] Kim HG, Paick SH, Kwak C, Kim HH, Uno YS. Serial microscopic changes in cell proliferation and apoptosis in obstructed ureter of rat. J Endourol 2006;20:590e7. [22] Kuzgunbay B, Doran F, Bayazit Y, Turunc ¸ T, Satar N, Kayis AA. The effects of ureteral obstruction on Cajal-like cells in rats. J Pediatr Urol 2009;5:269e73. [23] Shokeir AA, Nijman RJ. Antenatal hydronephrosis: changing concepts in diagnosis and subsequent management. BJU Int 2000;85:987e94.
Altered expression of interstitial cells of Cajal in primary obstructive megaureter Yeliz Kart a, Osman Z. Karakus‚ b,*, Oguz Ates‚ b, ¨r b ¨lce Hakgu ¨der b, Mustafa Olguner b, Feza M. Akgu Gu a b
Clinics of Pediatric Surgery, Private Reyap Hospital, Tekirdag, Turkey Department of Pediatric Surgery, Dokuz Eylu¨l University, Faculty of Medicine, Izmir, Turkey
Received 27 November 2012; accepted 6 February 2013 Available online 15 March 2013
KEYWORDS Interstitial cells of Cajal; Ureterovesical junction obstruction; Megaureter
Abstract Objective: A marked decrease in the density of interstitial cells of Cajal (ICC) has been shown in patients with ureteropelvic junction obstruction. ICC may also play a role in primary obstructive megaureter (POM). An immunohistochemical study was conducted to investigate the density of ICC in ureterovesical junction (UVJ) segments resected from patients with POM and from control autopsy specimens. Materials and methods: Resected UVJ segments from 11 patients operated for POM comprised the study group. Control UVJs were obtained from autopsy specimens of 7 children who died from causes other than urogenital pathology. The UVJs including the narrowest parts were studied using immunohistochemical staining for C-kit positive cells. Results: The number of ICC was significantly lower in the UVJs of the POM compared to the control group. The UVJs of the POM group had 1.75 1.14 ICC (mean 1SD), whereas the control group had 5.76 2.99 ICC (mean 1SD). Conclusion: The number of ICC was decreased in the UVJs of the patients with POM compared to the normal control group. As dilation of the ureter during fetal life is a common condition and ureteral dilation is often self limiting, we hypothesize that ureteral peristalsis is a maturational event including the maturational development of ICC. Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company.
Introduction The etiology of primary obstructive megaureter (POM) is still obscure. Two layers of muscle, a circular outer and
longitudinal inner layer, are present at the ureterovesical junction (UVJ). There is little collagen in the connective tissue between these two muscle layers. Transportation of urine occurs by means of peristalsis of these muscles. An
_ _ ¨ niversitesi, Tıp Faku * Corresponding author. Dokuz Eylu ¸ ocuk Cerrahisi Anabilim Dalı, 35340 Inciraltı, Izmir, Turkey. Tel.: þ90 232 ¨l U ¨ltesi, C 4123002; fax: þ90 232 2792101. E-mail addresses: [email protected], [email protected] (O.Z. Karakus‚). 1477-5131/$36 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company. http://dx.doi.org/10.1016/j.jpurol.2013.02.003
Altered expression of interstitial cells of Cajal increase in collagen is a common finding in all research regarding the etiology of POM. Hypertrophy of the circular muscle and atrophy of the inner muscle accompany the increase in collagen. It has been postulated that these changes cause deterioration of urine flow at the UVJ [1e5]. Interstitial cells of Cajal (ICC) are important cells for organs with peristaltic function. ICC produce signals for rhythmic contractions and their absence is associated with peristaltic dysfunction. The role of ICC in the motility of the gastrointestinal system has been extensively studied [6]. A lack of expression of c-kit immunoreactive ICC has been shown in childhood intestinal motility disorders such as Hirschsprung’s disease and internal sphincter achalasia [7,8]. ICC have been shown to be present in the human and porcine upper urinary tract [9e12]. ICC are distributed throughout the ureter, including the proximal and distal part in the human and porcine ureter [9,11]. Additionally, Solari et al. have shown a marked decrease in the density of ICC in ureteropelvic junction (UPJ) specimens obtained from patients with UPJ obstruction (UPJO) [12]. This ubiquitous distribution of ICC in the human ureter and relationship with peristalsis indicate that ICC might contribute to the intrinsic pacemaker activity of the urinary tract. ICC may also play a role in human POM. The distribution of ICC at the UVJ of patients with POM has been studied [13], but this distribution in normal children has not been studied. We planned an immunohistochemical study to investigate the density of ICC in UVJ segments resected from patients with POM, and from children with a normal urinary tract who died from causes other than urogenital pathology.
Material and methods Operation specimens (including narrowest “intramural” part of the ureter) of 11 patients operated for POM (8 girls, 3 boys) comprised the study group. Mean age of the patients was 46.2 31.6 months (8 monthse10 years). Diagnosis of POM was established by voiding cystourethrography, ultrasonography and radionuclide study, and confirmed by surgical findings. Control UVJs were obtained from autopsy specimens of children who died from causes other than urogenital pathology. There were 7 children (5 boys, 2 girls) in the control group. Mean age of the children was 42.7 45.1 months (1 monthe14 years). The specimens were resected in the same manner as in the surgical procedure, and the same region of ureter as in the POM group was used for histopathological examination. No gross renal pathologies were detected during autopsy in any child in the control group. The ureters of the control group were narrower than 7 mm and the UVJ could easily be catheterized with a 6 F catheter, and the luminal patency was confirmed in all control specimens.
1029 (Novacastra, Newcastle, UK) primary antibody in a 1:40 dilution and an anti-rabbit immuno-conjugate secondary antibody incubated with horseradish peroxide (HRP)streptavidin solution (LSAB2 System-HRP, Code K0675; Dako Cytomation, Glostrup, Denmark). Slides were developed with 3-30 -diaminobenzidine (DAB; D4293; Sigma Aldrich), counterstained with Mayer’s hematoxylin, and examined by light microscopy (Olympus BX-51). Negative control samples were identically stained with study samples without primary antibodies.
Light microscopy Tissues were examined by two blinded pathologists. The distribution of ICC in different regions was assessed semiquantitatively by applying morphological criteria [14]. ICCs were c-kit-positive spindle-shaped cells with long cytoplasmic processes located in the muscular layer, while mast cells were spherical cells with a central nucleus located in the mucosa and submucosa. The ICC were counted separately in ten randomly selected high-power fields (100). Mean numbers of ICC were compared using ANOVA followed by Tukey’s test. p values lower than 0.01 were accepted as significant.
Results ICC located in the muscular layer had a fusiform cell body, thin cytoplasm, wide ovoid nucleus and two dendritic processes (Fig. 1). In contrast, mast cells were located in the submucosa, muscularis mucosa and mucosa with a centralized round nucleus (Fig. 2). The number of ICC was significantly lower in the UVJ of the POM compared with the control group (p < 0.01). The UVJ of the POM group had 1.75 1.14 ICC (mean 1SD), whereas the control group had 5.76 2.99 ICC (mean 1SD) (Table 1).
Discussion Accumulation of collagen and hypertrophy of the muscular layer of the ureter have been postulated as the cause of
Immunohistochemical staining Longitudinal 4 mm serial sections of formalin fixed, paraffin embedded tissue samples were heated in 0.01 mol/l citrate buffer (pH 6.0) in a microwave oven for antigen retrieval. Then, tissue samples were treated with Liquid Mouse Monoclonal Antibody C-kit Oncoprotein (CD117)
Figure 1 ICC located in the muscular layer had a fusiform cell body, thin cytoplasm, wide ovoid nucleus and two dendritic processes (black arrow).
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Y. Kart et al.
Figure 2 Mast cells located in the mucosa and submucosa had a spherical cell body with central nucleus (black arrow).
POM [1e5]. However, samples obtained from different parts of the ureter show different histopathological properties [15]. While the UVJ in POM has a collagen and elastin distribution similar to the normal ureter, the dilated proximal part has muscular hypertrophy and increased collagen and elastin, under either light or electron microscopy [2,15,16]. Therefore, the accumulation of collagen and elastin in the proximal ureteral wall in POM does not seem to be the cause of the obstruction but as the result of the obstruction; thus the etiology of POM is obscure. ICC were first described in the gastrointestinal tract. They are important pacemaker cells in human peristaltic organs. ICC have tyrosine kinase surface receptors. By means of these receptors ICC show C-kit positivity. Hypoplasia or aplasia of these cells was shown to be closely related to peristaltic dysfunction in hollow organs. Lack or hypoplasia of the ICC has been shown in several diseases with peristaltic dysfunction, such as Hirschsprung’s disease and internal anal sphincter achalasia [6e8]. McCloskey and Gurney first described ICC in the urinary system in guinea pigs [17]. ICC have also been shown to be present in the human urinary system [12]. Solari et al. showed that human urinary ICC were microscopically identical to the gastrointestinal system ICC. They also hypothesized that urinary functional obstructive disorders of the human urinary system might be related with the aplasia or hypoplasia of the ICC as seen in the gastrointestinal system. They and others showed that ICC were sparse or
Table 1 group.
Number of interstitial cells of Cajal in each
Group
Interstitial cells of Cajal (mean 1SD)
Primary obstructive megaureter Control
1.75 1.14* 5.76 2.99
Mean number of interstitial cells of Cajal examined under 100 magnification counted in 10 random areas. *p < 0.01 compared to control group.
absent in the UPJ segments of patients who were operated for UPJO [12,18]. The absence or scarcity of ICC at the UVJ may cause the cessation of peristaltic waves and local dysmotility, which result in obstruction or an impaired ureteral valve mechanism. Therefore, ICC have been shown to play a role in VUR, and a decrease in ICC has been shown at the UVJ of patients with VUR [13,16]. However, whether the decrease or absence of ICC at the UVJ of patients with VUR is a primary or secondary phenomenon is debatable. Oberritter et al. have shown that a decrease in ICC occurred at the UVJ of pigs with surgically created VUR. They suggested that this is a secondary phenomenon [19]. A similar debate may also be valid for POM. A decrease in ICC at the UVJ of patients with POM has been shown [13,20]. Kang et al. have shown that the number of ICC was significantly lower in the UVJ of refluxing megaureter compared with obstructive megaureter [13]. As they did not have a normal healthy control group they could only compare refluxing and obstructed UVJs. They also showed that the proportion of smooth muscle and number of apoptotic cells were significantly increased in the proximal ureter of the obstructive megaureter [13]. Similar results were observed in experimental ureteral obstruction, indicating that smooth muscle cell proliferation and apoptosis in proximal ureter in POM might be a secondary phenomenon [21]. The authors proposed that proliferation and apoptosis is a response of the fibrous and smooth muscle layers to increased wall tension of the ureter which impairs blood flow [21]. The decrease in ICC in POM may also be explained by the ischemia theory [13]. However, Kuzgunbay et al. have shown that the number of ICC was increased in the proximal ureter after acute obstruction of the ureter [22]. They suggested that this increase was related to increased ureteral peristaltic activity. They stated that the results are representative of the acute acquired condition, which differs from congenital conditions such as UPJO and POM in which ICC were absent or decreased. In the present study we have shown that the number of ICC was decreased in the UVJ of patients with POM compared with to the normal control group. Considering that dilation of the ureter during fetal life is a common condition compared with newborns, and ureteral dilation is often a self-limiting condition, we hypothesize that ureteral peristalsis is a maturational event including the maturational development of the ICC [23]. In the minority of patients who manifest the symptoms of POM, the problem might be related to the number of mature ICC that provide adequate peristalsis for urine flow. Otherwise, even borderline insufficiency of ICC may initiate an obstructioneproliferationeischemia cascade that results in manifest POM. Further studies are needed to evaluate the maturation of ICC in the fetus and restoration of the ICC after the obstruction is relieved in POM.
Funding None.
Conflict of interest None.
Altered expression of interstitial cells of Cajal
Ethical approval This study was approved by the Local Ethical Committee of Dokuz Eylu ¨l University.
References [1] Escala JM, Keating MA, Boyd G, Pierce A, Hutton JL, Lister J. Development of elastic fibres in the upper urinary tract. J Urol 1989;141:969e73. [2] Gosling JA, Dixon JS. Functional obstruction of the ureter and renal pelvis: a histological and electron microscopic study. Br J Urol 1978;50:145e52. [3] Hanna MK, Jeffs RD, Sturgess JM, Barkin M. Ureteral structure and ultrastructure. Part III. The congenitally dilated ureter (megaureter). J Urol 1977;117:24e7. [4] Nicotina PA, Romeo C, Arena F, Romeo G. Segmental upregulation of transforming growth factor-beta in the pathogenesis of primary megaureter. An immunocytochemical study. Br J Urol 1997;80:946e9. [5] Notley RG. Electron microscopy of the primary obstructive megaureter. Br J Urol 1972;44:229e34. [6] Rolle U, Piaseczna-Piotrowska A, Puri P. Interstitial cells of Cajal in the normal gut and in intestinal motility disorders of childhood. Pediatr Surg Int 2007;23:1139e52. [7] Piotrowska AP, Solari V, Puri P. Distribution of interstitial cells of Cajal in the internal anal sphincter of patients with internal anal sphincter achalasia and Hirschsprung disease. Arch Pathol Lab Med 2003;127:1192e5. [8] Rolle U, Piotrowska AP, Nemeth L, Puri P. Altered distribution of interstitial cells of Cajal in Hirschsprung disease. Arch Pathol Lab Med 2002;126:928e33. [9] Metzger R, Neugebauer A, Rolle U, Bo ¨hling L, Till H. C-Kit receptor (CD117) in the porcine urinary tract. Pediatr Surg Int 2008;24:67e76. [10] Metzger R, Schuster T, Till H, Franke FE, Dietz HG. Cajal-like cells in the upper urinary tract: comparative study in various species. Pediatr Surg Int 2005;21:169e74. [11] Metzger R, Schuster T, Till H, Stehr M, Franke FE, Dietz HG. Cajal-like cells in the human upper urinary tract. J Urol 2004; 172:769e72.
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