Secondary Logo

Journal Logo

Value of Fecal Calprotectin as a Biomarker for Juvenile Polyps in Children Investigated With Colonoscopy

Olafsdottir, Ingunn; Nemeth, Artur; Lörinc, Ester; Toth, Ervin; Agardh, Daniel

Journal of Pediatric Gastroenterology and Nutrition: January 2016 - Volume 62 - Issue 1 - p 43–46
doi: 10.1097/MPG.0000000000000893
Original Articles: Gastroenterology
Free

Objectives: The clinical presentation of colonic juvenile polyps with abdominal discomfort and occult rectal bleedings make them difficult to recognize. The aim of this study was to report the clinical features of colonic juvenile polyps in children referred to colonoscopy and evaluate fecal calprotectin (FCP) as a screening biomarker for their diagnosis.

Methods: The study included a total of 266 children (range 3.1–19.0 years, median age 15.8 years) investigated with ileocolonoscopy; of whom, 239 (89%) were investigated for inflammatory bowel disease (IBD). FCPs were analyzed as a marker of colonic inflammation, and levels <50 mg/kg was considered to be negative.

Results: Juvenile polyps were detected in 12 (4.5%) children; the remaining 67 (25.2%) had Crohn disease, 57 (21.4%) ulcerative colitis, 5 (1.9%) unclassified IBD, 4 (1.5%) allergic colitis, bleeding source was localized in 6 (2.3%), and 115 (43.2%) had unspecific or normal findings. FCP was available in 203 (76.3%) children before colonoscopy; levels of FCP were higher in children with juvenile polyps (range 28–2287 mg/kg, median 844 mg/kg) compared with those with normal colonoscopies (range <20–2443 mg/kg, median 130 mg/kg, P < 0.0001), but not compared with those with active IBD (range <20–7780 mg/kg, median 962 mg/kg, P = 0.6299). FCPs were available in 9 of 12 children after polypectomy, of whom all had their FCP levels significantly reduced (range 0–281 mg/kg, median 49 mg/kg, P < 0.0001).

Conclusions: Colonic juvenile polyps are frequently found in pediatric patients presenting with hematochezia and elevated FCP levels. Colonic juvenile polyps are difficult to differentiate from pediatric IBD without a colonoscopy.

*Pediatric Gastroenterology Unit, Department of Pediatrics

Endoscopy Unit, Department of Gastroenterology, Skåne University Hospital, Malmö

Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.

Address correspondence and reprint requests to Daniel Agardh, MD, PhD, Department of Clinical Sciences, Lund University/CRC, Jan Waldenströmsgata 35, Skåne University Hospital SUS, SE-205 02 Malmoe, Sweden (e-mail: daniel.agardh@med.lu.se).

Received 13 April, 2015

Accepted 16 June, 2015

The authors report no conflicts of interest.

What Is Known

  • Prevalence of colonic juvenile polyps is probably underestimated because of their occult clinical presentation.
  • Fecal calprotectin is a useful marker of intestinal inflammation and associated with inflammatory bowel disease.

What Is New

  • Children with colonic juvenile polyps also have strongly elevated fecal calprotectin levels before colonoscopy and subsequently normalize after polypectomy.
  • Colonic juvenile polyps should be considered to be a differential diagnosis to pediatric inflammatory bowel disease.

Juvenile polyps are found in children investigated for rectal bleedings (hematochezia), colitis or are accidently detected during colonoscopy. The reported prevalence ranges between 0.08% and 3.7% among children and most frequently diagnosed in children between 3 and 10 years of age with a male predominance (1). The occurrence of juvenile polyps is, however, probably underestimated because of their occult clinical presentation with atypical symptoms such as abdominal discomfort with or without moderate painless hematochezia. In one-third of the children, the clinical presentation is a microcytic anemia as a result of chronic blood loss, which often misleads a clinician to suspicion of inflammatory bowel disease (IBD) (2,3).

Calprotectin is an intracellular calcium and zinc binding protein found in the cytosol of neutrophils with bacteriostatic and fungistatic properties (4,5). The detection of calprotectin from stool samples can be seen as directly proportional to neutrophil migration toward the gastrointestinal tract and that fecal calprotectin (FCP) concentration closely correlate with the excretion of leucocytes in the feces (5,6). FCP is therefore used as a noninvasive biomarker for intestinal inflammation and has mainly been associated with active IBD (7). Hitherto, only a few conditions other than IBD have been reported with elevated FCP (5). To date no diagnostic noninvasive markers have been evaluated for screening of individuals for juvenile polyps, although sporadic case reports have been published on children with solitary juvenile polyps and elevated levels of FCP (8–10). A noninvasive screening biomarker, similar to how FCP has been used for the diagnosis of IBD, would be thus a valuable tool in clinical practice for detecting juvenile polyps.

In this study, we describe the clinical features and outcome of a subset of children treated for juvenile polyps at a single pediatric gastroenterology unit. More specifically, we evaluated the clinical value of FCP as a screening biomarker for juvenile polyps in relation to other common colonic disorders detected by endoscopy.

Back to Top | Article Outline

METHODS

Study Cohort

In this study, clinical data and diagnostic outcome of colonoscopies were retrospectively retrieved from children referred to colonoscopy at the Gastroenterology Unit at the Department of Paediatrics, Skåne University Hospital, Malmö, Sweden. During the study period of January 2006 to November 2012, 266 children (128 girls, 138 boys) were consecutively investigated with colonoscopy at a median age of 5.8 (3.1–19.0) years. Indications for colonoscopy were according to the international pediatric guidelines for performing a colonoscopy were included (2,3). This study was performed according to the principles of the Declaration of Helsinki. Informed consents were obtained for all study participants from a parent or legal guardian, before endoscopic procedures and the analysis of FCP.

Back to Top | Article Outline

Endoscopic Procedure and Preparation of the Biopsy Specimens

Standard ileocolonoscopy with biopsy and polypectomy, if appropriate, was performed in general anesthesia or deep sedation with propofol. All biopsies were after sampling oriented on a tissue paper before being fixed in formalin and thereafter embedded in paraffin. Each specimen was cut serially in 4 μm sections and stained with hematoxylin and eosin according to standard procedure protocol. After routine laboratory processing the specimens were assessed by light microscopy. Histological diagnosis was based on the pathologist's statement in the medical record retrieved from the Department of Pathology, Skåne University Hospital, Malmö, Sweden.

Back to Top | Article Outline

FCP

FCP was analyzed with a commercial enzyme-linked immunosorbent assay (CALPRO, Oslo, Norway). According to the manufacturer, the detection limit for FCP is 20 mg/kg and the cutoff for a positive value set to ≥50 mg/kg. No separate cutoff levels are given for children. Patients with active a symptomatic IBD typically have levels between 200 and 40,000 mg/kg (http://www.calpro.no/products/calprotectin-elisa-test-alp).

Back to Top | Article Outline

Statistical Analysis

Levels of FCP were expressed as median with range and differences between groups were compared using the Kruskal-Wallis test and the Wilcoxon signed-rank test for pairwise comparisons of levels before and after polypectomy. P-values <0.05 was considered statistical significant. The GraphPad Prism version 6.01 software (GraphPad Software, San Diego, CA) was used for statistical analysis.

Back to Top | Article Outline

RESULTS

Demographics of Study Population

The vast majority of patients were investigated for a clinical suspicion of IBD in 239/266 (90.0%) children. The remaining 9/266 (3.4%) were investigated to localize bleeding source from vascular malformations or from a Meckel diverticulum, 7/266 (2.6%) for polyps (either as solitary polyp or because of familial adenomatous polyposis), 3/266 (1.1%) for the indication of allergic colitis and 8/266 were investigated because of other rare reasons (tuberculosis, malignancy, malrotation, solitary ulcus, etc).

Back to Top | Article Outline

Outcome of Colonoscopy and Histology

A bleeding source from vascular malformations, such as congenital angiodysplasias, hemangiomas, or blue rubber bleb nevus syndrome, was detected in 6/266 (2.3%) children. Among the children investigated with colonoscopy and serial biopsies, the histological diagnosis of Crohn disease was established in 67/266 (25.2%), ulcerative colitis in 57/266 (21.4%), unclassified IBD in 5/266 (1.9%), and allergic colitis in 4/266 (1.5%) children. The remaining 115/266 (43.2%) had unspecific or normal findings in which no specific diagnosis could be established. A solitary juvenile polyp were detected and sent for histological evaluation in 12/266 (4.5%) children.

Back to Top | Article Outline

Detection and Diagnosis of Juvenile Polyps

Among those children diagnosed as having a solitary juvenile polyp, 8/12 (67%) were detected in the sigmoid colon and the remaining 4 in the cecum, ascending- and descending colon and rectum, respectively (Table 1). All polyps were protruding type with a wide and/or long stalk with irregular surface and all were removed by snare resection without any complications (Fig. 1). All but 2 of children with juvenile polyps had complaints of rectal bleedings before colonoscopy, which disappeared completely after polypectomy at the follow-up visit. One child had a small mucosal bleeding in the sigmoid colon during resection of the polyp that stopped after fixation with clips. There was no other complication related to colonoscopy. Histology confirmed diagnosis of inflamed hyperplastic juvenile polyp in all patients (Fig. 2).

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

Back to Top | Article Outline

FCP Before and After Polypectomy

Levels of FCP were available in 203/266 (76.3%) of the investigated children before colonoscopy at median 571 (range <20–7780) mg/kg. Among those 203 children, FCP were analyzed in 108 children with active children with IBD at median 962 (range <20–7780) mg/kg, which was higher than in the 83 children with a normal colonoscopy at median 130 (range <20–2443) mg/kg (P < 0.0001), but not as compared with the 12 children diagnosed as having juvenile polyps at median 844 (range 28–2287) mg/kg (P = 0.6299) (Fig. 3). At 3 months after polypectomy, levels of FCP had decreased to a median 49 (<20–281) mg/kg measured in 9 of the 12 children (P = 0.0078) (Fig. 3).

FIGURE 3

FIGURE 3

Back to Top | Article Outline

DISCUSSION

In this study, we report a frequency of juvenile polyps in near 5% of children consecutively investigated with colonoscopy. Although the study population and number of patients detected were few to make general assumptions on the overall prevalence of juvenile polyps in children, the frequency was unexpectedly high as compared with what have been reported previously (1). The main explanation for this finding is most likely because of an accelerating numbers of performed colonoscopies the past 10 years at our pediatric gastroenterology unit. The rising incidence of pediatric Crohn disease in Sweden (11,12) along with the introduction of FCP has resulted in an increase of colonoscopies in which the majority of the children with elevated FCP are further investigated with a primary clinical suspicion of IBD.

Still, many children with juvenile polyps present with subtle symptoms and moderate rectal bleedings are therefore expected to remain undiagnosed because of insufficient investigations. Strategies for detecting colonic juvenile polyps are therefore warranted, especially in children in whom symptoms and clinical signs can be difficult to distinguish from more common gastrointestinal conditions such as constipation wherein invasive methods such as colonoscopy should be avoided for the diagnosis. Less invasive methods for imaging of the gastrointestinal tract other than endoscopy have been evaluated for the diagnosis of colonic juvenile polyps. Ultrasonography seems both valid and safe to be used as a first-line investigation in children (13,14). The ultrasound technique is, however, observer-dependent and small polyps may be missed by less experienced investigators. Another noninvasive screening method of polyps is to image the colonic lumen is the second-generation of colon capsules that seem promising in adults (15), but there is paucity of studies to recommend it in children.

We have found that the children with juvenile polyps also had strongly elevated levels of FCP before colonoscopy, which subsequently normalized after polypectomy. FCP is strongly associated with active IBD (16) and moderately elevated in gastrointestinal bleedings, gastroenteritis, celiac disease, microscopic colitis, nonsteroidal anti-inflammatory drug enteropathy and diverticular disease as well as colon polyps in adults (5,17). The associations between FCP and juvenile polyps have only been described in children with juvenile polyps in a few case reports before (8,9), but there is no publication on direct comparisons of FCP levels between juvenile polyps before and after polypectomy and IBD. FCP is a useful marker of intestinal inflammation, particularly because its levels seem to be unaffected by inflammation outside the gastrointestinal tract. Thereby, it can be considered as a sensitive marker for intestinal inflammation but not specific because it is associated with various conditions that cause intestinal inflammation (6). The histological features of a solitary juvenile polyps shows typical nonadenomatous structures containing dilated cystic spaces, exuberant lamina propria with marked vascularity, areas of ulcerations, and increased numbers of inflammatory cells including neutrophilic granulocytes (5,18). Considering the inflammatory characteristics of the histological features of juvenile polyps typically showing crypts filled mucus rich of neutrophils and eosinophil's and a surface layer that is covered with intraepithelial neutrophils, it is not surprising why patients with solitary juvenile polyps also secrete high concentrations of FCP.

In our study cohort, 75% the juvenile polyps were found in the sigmoid colon or rectum. These results are similar to previous findings that show that majority of polyps are localized in distal part of the left colon (19). This typical localization also explains why most of the children clinically present with hematochezia. If levels of FCP are also found strongly elevated, it will be clinically difficult to distinguish a patient with distal colitis from one with an inflammatory juvenile polyp without performing a proper investigation of the colon. A solitary juvenile polyp should therefore always be reconsidered as a differential diagnosis to IBD and a colonoscopy recommended when a child is presenting under these circumstances.

Juvenile polyps belong to the group of benign hamartomas, which are the most common of gastrointestinal tumors during childhood and can be presented as a solitary polyp or as multiple polyps in the juvenile polyposis syndrome (20). Although juvenile polyposis syndrome is a premalignant condition, solitary polyps are generally considered as being sporadic with small to no risk for malignancy. To date, there is no surveillance program for children diagnosed as having juvenile polyps. At our pediatric gastroenterology unit, there is a follow-up 1 month after the investigation and levels of FCP are measured again 3 months after polypectomy and if being reduced to normal levels, parents are generally instructed to return in case of symptoms arise again. Recent data reveal that the recurrence rate for solitary juvenile polyps in children was 17% and there exist case reports of neoplasia in children with solitary juvenile polyps (21,22). Because none of the included children with juvenile polyps in this study had a follow-up colonoscopy, it cannot be excluded that there was an incomplete remission of the juvenile polyp. None of them, however, had presented with recurrent symptoms during clinical follow-up.

A weakness of this study is its retrospective design with incomplete collection of stool samples for FCP analysis. Also, the size of the study cohort was too low for adequate calculations of sensitivity, specificity negative and positive predictive values for FCP in children with juvenile polyps. Because an indication for a colonoscopy was already biased by the level of FCP, patients with juvenile polyps that may present with normal FCP levels may be underestimated. More important, it cannot be excluded that other variables such as clinical presentation, duration of symptoms, or other inflammatory markers would lead to similar results. The diagnostic performance of FCP in juvenile polyps from this study thus needs to be regarded with caution.

In conclusion, solitary colonic juvenile polyps may frequently be found in pediatric patients investigated with colonoscopy. Solitary colonic juvenile polyps are associated with increased level of FCP and may thus be difficult to discern from IBD without a diagnostic colonoscopy. Colonic juvenile polyps should therefore be considered as a differential diagnosis to pediatric IBD, although normal levels of FCP do not exclude a juvenile polyp. Larger studies are warranted to further evaluate if FCP can be recommended as a noninvasive screening biomarker for colonic juvenile polyps.

Back to Top | Article Outline

REFERENCES

1. Thakkar K, Alsarraj A, Fong E, et al Prevalence of colorectal polyps in pediatric colonoscopy. Dig Dis Sci 2012; 57:1050–1055.
2. IBD Working Group of the European Society for Paediatric Gastroenterology H. Nutrition Inflammatory bowel disease in children and adolescents: recommendations for diagnosis—the Porto criteria. J Pediatr Gastroenterol Nutr 2005; 41:1–7.
3. Levine A, Koletzko S, Turner D, et al ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr 2014; 58:795–806.
4. Konikoff MR, Denson LA. Role of fecal calprotectin as a biomarker of intestinal inflammation in inflammatory bowel disease. Inflamm Bowel Dis 2006; 12:524–534.
5. Montalto M, Gallo A, Santoro L, et al Role of fecal calprotectin in gastrointestinal disorders. Eur Rev Med Pharmacol Sci 2013; 17:1569–1582.
6. Vermeire S, Van Assche G, Rutgeerts P. Laboratory markers in IBD: useful, magic, or unnecessary toys? Gut 2006; 55:426–431.
7. Fagerberg UL, Loof L, Merzoug RD, et al Fecal calprotectin levels in healthy children studied with an improved assay. J Pediatr Gastroenterol Nutr 2003; 37:468–472.
8. Teitelbaum JE, Adu-Darko MA. Fecal calprotectin in juvenile polyposis coli. J Clin Gastroenterol 2010; 44:593.
9. Pauley-Hunter RJ, Kunnath S, Wolff K, et al Fecal calprotectin and pediatric juvenile polyps. J Pediatr Gastroenterol Nutr 2015; 60:e30–e31.
10. Kolho KL, Raivio T, Lindahl H, et al Fecal calprotectin remains high during glucocorticoid therapy in children with inflammatory bowel disease. Scand J Gastroenterol 2006; 41:720–725.
11. Askling J, Grahnquist L, Ekbom A, et al Incidence of paediatric Crohn's disease in Stockholm, Sweden. Lancet 1999; 354:1179.
12. Malmborg P, Grahnquist L, Lindholm J, et al Increasing incidence of paediatric inflammatory bowel disease in northern Stockholm County, 2002-2007. J Pediatr Gastroenterol Nutr 2013; 57:29–34.
13. Wang X, Jia C, Yang H, et al Sonographic features of a juvenile polyp: a case report and literature review. Clin Imaging 2014; 38:215–217.
14. Wei C, Dayong W, Liqun J, et al Colorectal polyps in children: a retrospective study of clinical features and the value of ultrasonography in their diagnosis. J Pediatr Surg 2012; 47:1853–1858.
15. Parker CE, Spada C, McAlindon M, et al Capsule endoscopy—not just for the small bowel: a review. Expert Rev Gastroenterol Hepatol 2015; 9:79–89.
16. Fagerberg UL, Loof L, Myrdal U, et al Colorectal inflammation is well predicted by fecal calprotectin in children with gastrointestinal symptoms. J Pediatr Gastroenterol Nutr 2005; 40:450–455.
17. Pezzilli R, Barassi A, Morselli Labate AM, et al Fecal calprotectin levels in patients with colonic polyposis. Dig Dis Sci 2008; 53:47–51.
18. Adolph VR, Bernabe K. Polyps in children. Clin Colon Rectal Surg 2008; 21:280–285.
19. Lee BG, Shin SH, Lee YA, et al Juvenile polyp and colonoscopic polypectomy in childhood. Pediatr Gastroenterol Hepatol Nutr 2012; 15:250–255.
20. Fox VL, Perros S, Jiang H, et al Juvenile polyps: recurrence in patients with multiple and solitary polyps. Clin Gastroenterol Hepatol 2010; 8:795–799.
21. Thakkar K, Fishman DS, Gilger MA. Colorectal polyps in childhood. Curr Opin Pediatr 2012; 24:632–637.
22. Giardiello FM, Hamilton SR, Kern SE, et al Colorectal neoplasia in juvenile polyposis or juvenile polyps. Arch Dis Child 1991; 66:971–975.
Keywords:

calprotectin; inflammatory bowel disease; juvenile polyp

© 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,