Role of molecular imaging in the management of patients affected by inflammatory bowel disease: State-of-the-art

Table 1 Studies on planar scintigraphy and single photon emission tomography included in the present review

Ref.	Year of pub	Journal	n of pts	Indication	Imaging technique	Gold standard	Conclusion
Rowe et al[14]	1995	Am J Gastroenterol	11	The measurement of the severity colitis	111In-labelled leukocyte planar scintigraphy	Truelove and Witts criteria	The disappearance of radioactivity from the spleen or whole body during 24 h is likely to be a useful and accurate index of disease severity in inflammatory colitis Scintigraphy is useful for patients with CD, but not for ulcerative colitis. Leukocyte scintigraphy is more useful for the reassessment than initial diagnosis (particularly in case of structuring and fistulising CD). 99mTc-Leukoscan cannot be useful for the evaluation of IBD
Lachter et al[8]	2003	Hepato-Gastroenterology	46	Diagnosis of suspected inflammatory bowel disease	99mTc-HMPAO planar scintigraphy	Histology
Kerry et al[10]	2005	Nuclear Medicine Communication	22	Diagnosis of IBD and comparison between 99mTc-HMPAO and 99mTc-Leukoscan	99mTc-HMPAO planar scintigraphy 99mTc-Leukoscan planar scintigraphy 99mTc-Leukoscan SPECT	Histology Radiology Response to treatment
Biancone et al[11]	2005	Am J Gastroenterol	22	Comparison between 99mTc-HMPAO planar and SPECT for the assessment of intestinal infiltration in CD	99mTc-HMPAO planar and SPECT	Histology	SPECT images may better discriminate between intestinal and bone marrow uptake, thus allowing a better visualization of CD lesions in the pelvis (especially for perianal and enterovesical disease)
Cheow et al[15]	2005	Eur J Nucl Med Mol Imaging	30	To quantify disease activity in IBD	99mTc-granulocytes planar scintigraphy and 111In-granulocytes	NA	A dedicated whole-body counting using 111In can be useful to quantify inflammatory disease, especially IBD
Van den Brande et al[16]	2007	Gut	14	To predict the efficacy of anti-TNF treatment in IBD	99mTc-annexin V	Histology	The uptake of 99mTc-annexin V correlates with clinical benefit of anti-TNF treatment
Mota et al[13]	2010	World J Gastroenterol	20	To evaluate inflammatory activity in CD patients	99mTc-HMPAO	NA	Scintigraphy with radiolabeled HMPAO could be useful for the evaluation of intestinal activity in CD
Paredes et al[9]	2010	Journal of Crohn’s and Colitis	40	To assess the accuracy of abdominal ultrasonography, 99mTc-HMPAO in recurrent CD	99mTc-HMPAO	Histology	99mTc-HMPAO can be used in case of postsurgical recurrence in CD, in particular for those patients who reject endoscopic examination or for the assessment of neoterminal ileum
Hillel et al[12]	2011	Nuclear Medicine Communication	99	To compare planar and SPECT imaging in IBD	99mTc-HMPAO	NA	SPECT improves interoperator variability and probably sensitivity for IBD. The size of lesion suggest that planar images underestimates the extent of active disease
Aarntzen et al[19]	2015	J Nucl Med	30	To assess the accuracy of 99mTc-CXCL8 SPECT to detect and to localize disease activity	99mTc-CXCL8	Histology	99mTc-CXCL8 is a novel target for neutrophil recruitment to the intestinal wall, especially in moderate to severe exacerbations of IBD

CD: Crohn’s disease; IBD: Inflammatory bowel disease; TNF: Tumor necrosis factor; NA: Not available; SPECT: Single photon emission tomography; pts: Patients.

Table 2 Diagnostic accuracies in some selected studies on single photon emission tomography

Ref.	Year of pub	Tracer	Sensitivity	Specificity
Lachter et al[8]	2003	99mTc-HMPAO	58%	100%
Kerry et al[10]	2005
99mTc-HMPAO (2 h)		99mTc-HMPAO	87%	86%
99mTc-Leukoscan (1 h)		99mTc-Leukoscan	20%	86%
99mTc-Leukoscan (2 h)			40%	100%
99mTc-Leukoscan (4 h)			73%	57%
99mTc-Leukoscan (4 h-SPECT)			87%	57%
Paredes et al[9]	2010	99mTc-HMPAO
Endoscopic recurrence			88%	42.9%
Scintigraphic recurrence			73.3%	88.2%
Aarntzen et al[19]	2015	99mTc-CXCL8	95%	44%

SPECT: Single photon emission tomography.

Table 3 Overview of the selected studies on the role of positron emission tomography in diagnosing inflammatory bowel disease

Ref.	Year of pub	Journal	n of pts	Indication	Imaging technique	Gold standard	Conclusions
Meisner et al[6]	2007	Inflamm Bowel Dis	12	To identify regions of active inflammation in patients with known and at least moderate UC or CD	18F-FDG-PET/CT	Clinical evaluation including colonoscopy and radiologic imaging	There is high correlation between 18F-FDG-PET activity and clinical disease activity CT is necessary for anatomical identification of different bowel segments in CD patients with small bowel involvement or surgically treated
Das et al[1]	2010	Eur J Nucl Med Mol Imaging	15	To assess the extent and severity of disease in patients with active, mild to moderate UC	18F-FDG-PET/CT colonography	Colonoscopy	18F-FDG-PET/CT colonography is a useful tool for the assessment of extent and activity of UC
Ahmadi et al[7]	2010	Inflamm Bowel Dis	41	To identify disease activity in patients with known or suspected active CD of the small intestine To find out possible risk factors for therapy failure	Localized 18F-FDG-PET/CTe	NA	18F-FDG-PET scan does not increase CTe in detection of active disease A low 18F-FDG uptake in at least one small bowel segment, resulted to be pathological on CTe, represent a risk factor for medical treatment failure
Groshar et al[20]	2010	J Nucl Med	28	To evaluate disease activity in patients with known or suspected active CD	18F-FDG-PET/CTe	NA	SUVmax correlates well with CTe findings of active disease. It might be a reliable objective method for quantifying CD’s activity
Shyn et al[21]	2010	J Nucl Med	13	To detect active disease and assess severity of inflammation in patients with clinically suspected active CD	18F-FDG-PET/CTe	Histology after surgery or after biopsy performed during endoscopy	18F-FDG-PET added to CTe may improve the detection of active disease
Holtmann et al[2]	2012	Dig Dis Sci	43	To detect bowel segments with active CD	18F-FDG-PET	Endoscopy for distal ileum and colon, hydro-MRI for proximal ileum	18F-FDG-PET diagnostic performance in the detection of bowel segments with active disease is high. Compared to 18F-FDG-PET, hydro-MRI shows much lower sensitivity but higher specificity for all colon segments, higher sensitivity and the same specificity for terminal ileum and same performance for proximal ileum. Both methods seem to have high accuracy in strictures detection and characterization of their nature
Lenze et al[4]	2012	Inflamm Bowel Dis	30	To detect CD strictures and differentiate inflammatory from fibrotic ones	18F-FDG-PET/CT enteroclysis, MR enteroclysis, transabdominal ultrasound	Endoscopy + hystology	All the three studied techniques have good strictures detection rates relating to the gold standard, but none of them can accurately differentiate strictures’ nature. However, a combination of methods allows the detection of all strictures requiring surgery
Catalano et al[5]	2016	Radiology	19	To differentiate fibrotic from inflammatory strictures in CD patients	18F-FDG-PET/MR enterography	Post-surgical histology	18F-FDG-PET/MR enterography offers valid biomarkers for stricture evaluation

SPECT: Single photon emission tomography; CD: Crohn’s disease; UC: Ulcerative colitis; NA: Not available; ¹⁸F-FDG-PET: Positron emission tomography with ¹⁸F-Fluorodehoxiglucose; CT: Computed tomography; MRI: Magnetic resonance imaging; SUV: Standardized uptake value; CTe: CT esensitivity; pts: Patients.

Table 4 Diagnostic accuracies in some selected studies on positron emission tomography

Ref.	Year of pub	Tracer	Sensitivity	Specificity
Meisner et al[6]	2007	18F-FDG
UC			95.8%	NA
CD			81.3%	NA
Das et al[1]	2010	18F-FDG	98.5%	NA
Ahmadi et al[7]	2010	18F-FDG	NA	NA
Groshar et al[20]	2010	18F-FDG	NA	NA
Shyn et al[21]	2010	18F-FDG
Detection of bowel segments with active CD
Using a threshold > 1 (at least mild activity)			63.3%	100%
Using a threshold > 2 (at least moderate activity)			100%	89.7%
Holtmann et al[2]	2012	18F-FDG
Detection of active CD
In the terminal ileum + colon (on a per segment-based analysis)			90%	92.6%
In the proximal ileum (on a per patient-based analysis)			100%	100%
Lenze et al[4]	2012	18F-FDG
Detection of CD strictures			81%	NA
Differentiation of the nature of
All strictures			53%
Only inflammatory ones			83%
Only fibromatous ones			11%
Only mixed ones			0%
Treglia et al[65] (meta-analysis) (on a per segment-based analysis)	2013	18F-FDG	85%	87%
Zhang et al[3] (meta-analysis) 18F-FDG On per-bowel-segment basis On per-patient basis	2014	18F-FDG, 99mTc-HMPAO, 99mTc-monoclonal antigranulocyteantibody	0.84 0.59	0.86 1
99mTc-HMPAO			0.86	0.50
On per-bowel-segment basis			0.79	0.76
On per-patient basis			0.91	0.85
99mTc-monoclonal antigranulocyte antibody on per-bowel-segment basis			0.45	0.94
Catalano et al[5]	2016	18F-FDG	(Mean)	(Mean)
Detection of fibrotic CD strictures by
ADC × SUVmax < 3000			0.67	0.73
SI on T2-weightedimages × SUVmax < 2000			0.77	0.57
SUVmax < 2.5			0.79	0.61
ADC < 1250 × 10-3 mm2/s			0.84	0.26
SI on T2-weightedimages < 750			0.73	0.13

SPECT: Single photon emission tomography; CD: Crohn’s disease; UC: Ulcerative colitis; NA: Not available; ¹⁸F-FDG: ¹⁸F-Fluorodehoxiglucose; SUV: Standardized uptake value; ADC: Apparent diffusion coefficient; SI: Scintigraphic indices.

Table 5 Studies on molecular imaging in paediatric patients included in the present review

Ref.	Year	Pts (n)	Age (range)	Type of study	Clinical setting	Principal results	Technique	Segments evaluated (n)	Criterion for positivity
Papós et al[48]	1996	20	4-18	Prospective	IBD	sensitivity, specificity, and accuracy of LS were 93%, 88% and 91%, respectively	99mTc-HMPAO-WBC planar scintigraphy (30 min and 2 and 3 h)		Scored relative to the normal bone marrow uptake (0, no uptake; 1 < bone marrow uptake; 2 = bone marrow uptake; and 3 > bone marrow uptake)
Charron et al[36]	1998	178	n.r.	Retrospective		Useful in distinguishing discontinuous from continuous colitis	99mTc-HMPAO-WBC planar scintigraphy + SPECT (0.5-1 h, 2-4 h)
Cucchiara et al[35]	1999	48	2-17	Prospective	suspected IBD	significant correlation between results of scintigraphy and endoscopy for the intensity of inflammation	99mTc-HMPAO-WBC planar scintigraphy (dynamic + 30, 60, 120 and 180 min)	9	Abnormal if activity was seen in the gut within the first hour. 0 = no labeling; 1 = less than bone marrow; 2 = greater than bone marrow, less than liver; and 3 = greater than or equal to liver
Del Rosario et al[50]	1999	35	2-20	Retrospective	IBD	83% sensitivity which prompted more aggressive management in 75% of cases	99mTc-HMPAO-WBC planar scintigraphy (30 min + 2 h)
Charron et al[33]	1999	184	n.r.	Retrospective		Sensitivity = 90%, specificity = 97%, overall accuracy = 93%	99mTc-HMPAO-WBC planar scintigraphy + SPECT (0.5-1 h, 2-4 h ± 6 h ± 24 h)
Charron et al[37]	2000	262	n.r.	Retrospective	IBD	Useful as initial screening modality to exclude IBD	99mTc-HMPAO-WBC planar scintigraphy + SPECT (0.5-1 h, 2-4 h)
Alberini et al[32]	2001	28	2-15	Retrospective		Sensitivity and specificity were 75% and 92% for 99mTc-HMPAO-WBC	99mTc-HMPAO-WBC planar scintigraphy (1 + 3 h, p.i.)
Davison et al[38]	2001	10	n.r.	Prosepctive	CD	99mTc-HMPAO leucocyte scintigraphy should not be depended upon as a screening test for Crohn’s disease	99mTc-HMPAO-WBC planar scintigraphy + (45 min + 3.5 h)		Abdominal isotope uptake equal to or greater than that associated with the bone marrow was considered to indicate significant inflammation
Bruno et al[41]	2002	66	4-19	Prospective		Sensitivity of immunoscitigraphy was 94% for CD and 85% for UC with a relative low specificity	99mTc-BW250/183 planar scintigraphy (4 + 24 h, p.i.)
Grahnquist et al[39]	2003	95	2-16	Prospective	Suspected IBD (screening test)	As a screening test for children with suspected IBD the calculated sensitivity was 75%, and the specificity was 82%	99mTc-HMPAO-WBC planar scintigraphy (45 min + 3.5 h)	6
Peacock et al[40]	2004	64	2-19	Retrospective	Suspected IBD	99mTc-Stannous colloid LS had an 88% sensitivity, 90% specificity	99mTc-stannous colloid WCS planar + SPECT (1 h, 3 h)
Chroustova et al[47]	2009	40	5-18		Monitoring IBD (17 = UC, 23 = CD)	99mTc-HMPAO-WBC provided good information about the current stage of disease in IBD monitoring	99mTc-HMPAO-WBC planar scintigraphy + SPECT (30-45 min, 2 h, 3 h)		Graded 1-3 according to the uptake intensity. Grade 1 = a barely detectable abnormal uptake, grade 3 = an abnormal uptake at least as intense as that in the bone marrow and grade 2 was between these extremes. The extent of the abnormal uptake was subjectively classified as A (restricted to a single small focus), C (diffuse, such as in pancolitis) or B (between these extremes)
Caobelli et al[34]	2011	52	2-17	Prospective		Sensitivity of 94%, specificity of 86%, and negative predictive value of 96% to diagnose IBD. During the follow-up, all relapses and remissions were correctly recognized	99mTc-HMPAO-WBC planar scintigraphy (0.5 h, 3 h, p.i.)		Disease severity was graded by the focal uptake intensity vs iliac bone uptake (Scan Activity Index) and compared with Endoscopy Mayo Score

SPECT: Single photon emission tomography; CD: Crohn’s disease; UC: Ulcerative colitis; IBD: Inflammatory bowel disease; WBC: White blood cell; LS: Leukocyte scintigraphy; pts: Patients.