Imaging of colorectal cancer liver metastases using contrast-enhanced US,multidetector CT,MRI,and FDG PET/CT: a meta-analysis

Abstract

Background

Imaging of colorectal cancer liver metastases (CRCLMs) has improved in recent years. Therefore, the role of current imaging techniques needs to be defined.

Purpose

To assess the diagnostic performance of contrast-enhanced ultrasound (CEUS), multidetector computed tomography (MDCT), magnetic resonance imaging (MRI), and fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in the detection of CRCLMs.

Material and Methods

PubMed database was searched for articles published during 2000–2019. Inclusion criteria were as follows: diagnosis/suspicion of CRCLMs; CEUS, MDCT, MRI, or FDG PET/CT performed for the detection of CRCLMs; prospective study design; histopathologic examination, intraoperative findings and/or follow-up used as reference standard; and data for calculating sensitivity and specificity reported.

Results

Twelve prospective studies were assessed, including 536 patients with CRCLMs (n = 1335). On a per-lesion basis, the sensitivity of CEUS, MDCT, MRI, and FDG PET/CT was 86%, 84%, 89%, and 62%, respectively. MRI had the highest sensitivity on a per-lesion analysis. CEUS and MDCT had comparable sensitivities. On a per-patient basis, the sensitivity and specificity of CEUS, MDCT, MRI, and FDG PET/CT was 80% and 97%, 87% and 95%, 87% and 94%, and 96% and 97%, respectively. The per-patient sensitivities for MRI and MDCT were similar. The sensitivity for MRI was higher than that for CEUS, MDCT, and FDG PET/CT for lesions <10 mm and lesions at least 10 mm in size. Hepatospecific contrast agent did not improve diagnostic performances.

Conclusion

MRI is the preferred imaging modality for evaluating CRCLMs. Both MDCT and CEUS can be used as alternatives.

Keywords

Computed tomography magnetic resonance imaging positron emission tomography liver metastases

Introduction

Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death (1). Liver metastases are a common consequence of CRC. Surgical resection is the only definitive treatment for colorectal cancer liver metastases (CRCLMs), increasing the five-year survival rate to 25%–50% (1 –4). Preoperative selection of patients with CRCLMs who are most likely to benefit from surgery is essential and challenging.

At present, several non-invasive imaging modalities including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and fluorine-18-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) are available for the detection of CRCLMs (2 –13). However, the optimal imaging strategy has not yet been defined.

Recently, contrast-enhanced US (CEUS) has progressively gained a significant role in the evaluation of liver lesions, with accuracy comparable to that of multidetector CT (MDCT) in some studies (2 –4,14,15). CT is currently regarded as the standard imaging modality for one-session whole-body staging, including the liver, for patients initially diagnosed with CRC (2 –4,7,13,16). MRI has also been proved useful in the preoperative assessment of CRCLMs, providing a high detection rate, even for lesions <10 mm (2 –4,7,17 –22). Recently, the sensitivity of MRI in the diagnosis of liver metastases has improved, as a result of two innovations: diffusion-weighted imaging (DWI) and hepatospecific contrast agents (2,3,11,12,17 –22). Liver-specific contrast agents are currently recommended for MRI of the liver, with hepatobiliary phase improving the detection and characterization of liver lesions (18). However, it is not yet clear which patients with CRC should have an MRI scan of the liver in addition to standard staging CT. The role of 18F-FDG PET/CT in metastatic CRC is evolving, mainly due to the capacity of PET/CT to detect additional sites of extrahepatic disease. PET/CT is highly sensitive in detecting liver metastases >10 mm, but its sensitivity drops for lesions <10 mm (2,3,7,8,23 –25).

A number of meta-analyses on the performances of various imaging modalities in the diagnosis of CRCLMs are available. However, some of them include data on imaging modalities used in the past, and others are characterized by significant heterogeneity of the study design (7 –13,15,19,24,26 –28).

Taking into account the progress that has been made in the application of imaging techniques during the last years, the aim of the present systematic review is to update the analysis of published prospective studies on this topic, focusing on the diagnostic accuracy of CEUS, MDCT, MRI, and FDG PET/CT in the diagnosis of CRCLMs.

Material and Methods

This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendations (29).

Search strategy

A systematic and comprehensive literature search of studies on human subjects was performed by two researchers (CN and GA, the second researcher with previous experience on data extraction from meta-analyses) to identify articles about the diagnostic performance of CEUS, MDCT, MRI, and FDG PET/CT in the diagnosis of CRCLMs. Data were obtained from the PubMed database and included articles published from January 2000 up to December 2019. The key words were as follows: “liver metastases” OR “hepatic metastases” OR “colorectal” OR “contrast-enhanced ultrasound” OR “CEUS” OR “multidetector CT” OR “MDCT” OR “magnetic resonance imaging” OR “MRI” OR “fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)” and “FDG PET/CT.” Only articles in the English language were assessed. Abstracts, reports of meetings, editorial comments, case reports, reviews, letters to the editor, and articles that did not include raw data were excluded. Articles found to be suitable on the basis of their title and abstract were subsequently selected to further determine appropriateness for inclusion in this meta-analysis.

Study inclusion and exclusion criteria

All eligible articles were independently reviewed by the two researchers. The following inclusion criteria were used: CEUS, MDCT, MRI, and/or FDG PET/CT used to identify and characterize CRCLMs; prospective study design; histopathologic analysis (surgical specimen, core biopsy, or positive cytological findings), intraoperative observation (manual palpation, intraoperative US/IOUS) and/or clinical and imaging follow-up used as the reference standard; for per-patient or per-lesion statistics, sufficient data presented to calculate the true-positive (TP) and false-negative (FN) values for imaging techniques. Disagreements were resolved by consensus.

Studies were excluded if results for different imaging modalities were presented in combination and data on the performance of each individual technique could not be extracted. Studies including patients with diagnosis or suspicion of metastases from solid tumors other than CRC were considered eligible only if it was possible to extrapolate results obtained on CRCLMs. Studies including patients who had previously undergone treatment (surgery, radiation therapy, and/or chemotherapy) were also excluded.

Data extraction and quality assessment

The following study design characteristics were recorded: first author and year of publication; characteristics of study population, including number of patients with CRC, age, male-to-female ratio, number of patients with CRCLMs, number of liver lesions; number and size of liver metastases; imaging modality, including CEUS, MDCT, MRI or FDG PET/CT; and, report of the reference standard.

The numbers of TP, FN, false-positive (FP) and true-negative (TN) results for the detection of CRCLMs were extracted on a per-lesion and per-patient basis.

When at least two datasets were available for the four imaging techniques, subgroup analyses were performed. The following subgroups were created: (i) different liver metastases sizes (lesions <10 mm vs. those ≥10 mm); (ii) MDCT studies performed on the portal phase alone and those performed on both arterial and portal phases; and (iii) for MRI, MRI performed with gadolinium-based contrast agents (gadolinium-diethylenetriamine pentaacetic acid, Gd-DTPA), DWI, and gadoxetic acid-enhanced MRI (gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid, Gd-EOB-DTA).

To investigate for possible publication bias on CT and MRI studies, we used the Egger regression test. The quality of the included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool by two independent reviewers (GA and CN) and all emerging conflicts were resolved by consensus (30).

Results

Included studies

The literature search found a total of 2001 articles, of which 136 were potentially relevant based on their title and/or abstract. From 75 prospective studies, 12 articles fulfilled the inclusion criteria (14,31 –41). The flow chart of the selection process is shown in Fig. 1.

Fig. 1.

Flow chart showing study selection.

A total of 536 patients with CRCLMs were included in this meta-analysis (mean age = 64 years; age range = 23–93 years); the male-to-female ratio was referred in all studies, including 749 male and 500 female patients (Table 1).

Table 1.

Characteristics of the eligible studies.

Author (year)	Patients with CRC	Mean age (years)	M/F ratio	Patients with CRCLMs	Liver lesions	CRCLMs	CRCLMs<10 mm
Rafaelsen (2011)	271	68	1.16:1	21		>68
Bohm (2004)	24		1.1:1	24	174	74
Larsen (2009)	331	67	1.3:1	54
Mainenti (2010)	34	63	1.4:1	6	57	16	8
Cantisani (2010)	110	62	1.4:1	95	460	430	120
Kim (2015)	51	62	3.25:1	47		104	28
Arita (2015)	100	64.5	2.8:1	100	293	280
Schulz (2015)	46	67	1.7:1	42	336	140	43
Achiam (2016)	20	64 ± 17	4:01	2	9	9
Shiozawa (2016)	69	66	2:01	69	133	109
Asato (2017)	158	66	3.25:1	68	147	105	25
Koh (2018)	30	59.5	2:01	8

CRC, colorectal cancer; CRCLM, colorectal cancer liver metastasis.

Characteristic of studies

CEUS was included in six studies (14,32 –34,36,39). MDCT was used in 11 studies (14,31 –38,40,41). MRI was used in nine studies (31,33,35 –41), including seven 1.5-T studies (31,33,35 –39), one 3-T study (40), and one study using both 1.5-T and 3-T magnets (41). Gd-DTPA was administered in three studies (31,33,38) and Gd-EOB-DTPA in five studies (35 –37,39,40). DWI (35 –37,39,41) was performed in five studies, including four studies with combined reading of DWI and EOB-MRI (35 –37,39) and one study with combined reading of DWI and Gd-MRI (41). FDG PET/CT was included in two studies (Table 2) (33,37).

Table 2.

Characteristics of imaging modalities.

Author (year)	Standard of reference	Imaging modality
Rafaelsen (2011)	Histopathology, IOUS, follow-up	CEUS, MDCT
Bohm (2004)	Histopathology, FNA, IOUS	MDCT, MRI (Gd)
Larsen (2009)	Histopathology, FNA, IOUS, intraoperative palpation, imaging findings, follow-up	CEUS, MDCT
Mainenti (2010)	Histopathology, IOUS, intraoperative palpation, follow-up	CEUS, MDCT, MRI (Gd), PET/CT
Cantisani (2010)	Histopathology, IOUS, manual palpation, follow-up	CEUS, MDCT
Kim (2015)	Histopathology, imaging findings, follow-up	MDCT, MRI (EOB), DWI, DWI + EOB
Arita (2015)	Histopathology, follow-up	CEUS, MDCT, MRI (EOB), DWI + EOB
Schulz (2015)	Histopathology, follow-up	MDCT, MRI (EOB), DWI, DWI + EOB, PET/CT
Achiam (2016)	Histopathology, imaging findings, follow-up	MDCT, MRI (Gd)
Shiozawa (2016)	Histopathology, follow-up	CEUS, MRI (EOB), DWI + EOB
Asato (2017)	Histopathology, IOUS	MDCT, MRI (EOB)
Koh (2018)	Histopathology, follow-up	MDCT, DWI

CEUS, contrast-enhanced ultrasound; DWI, diffusion-weighted imaging; FDG-PET/CT, fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography; FNA, fine-needle aspiration; Gd-DTPA, gadolinium-diethylenetriamine pentaacetic acid; Gd-EOB-DTPA, gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid; IOUS, intraoperative ultrasound; MDCT, multidetector computed tomography; MRI, magnetic resonance imaging.

The following reference tests were used: histopathologic examination (n = 12); follow-up, mostly for at least 3–6 months (n = 10); intraoperative observation (n = 6, including intraoperative US and/or palpation); typical imaging findings (n = 3); and fine-needle aspiration (n = 2) (Table 2).

Study quality grading using QUADAS II scores showed that the majority of studies were of good quality (Fig. 2).

Fig. 2.

The quality assessment of the included studies.

Pooled diagnostic accuracy

The sensitivity estimates for CEUS, MDCT, MRI, and PET/CT on a per-lesion basis were 86% (95% confidence interval [CI] = 83.88%), 84% (95% CI = 82.86%), 89% (95% CI = 87.91%), and 62% (95% CI = 53.69%), respectively. The per-lesion diagnostic performances, including TP, FN, FP, and TN findings, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for each imaging modality are presented in Table 3. Four, nine, nine, and two datasets for CEUS (33,34,36,39), MDCT (31,33 –38,40,41), MRI (31,33,35 –41), and FDG PET/CT (33,37), respectively, were included in the analysis. The sensitivity estimates for MRI were significantly higher than that for MDCT (P = 0.03), CEUS (P = 0.049) and FDG PET/CT (P < 0.001). CEUS had higher sensitivity compared to MDCT, although non-significant (P = 0.14).

Table 3.

Results of the per-lesion analysis for CEUS, MDCT, MRI, and PET/CT.

Author (year)	Study	TP	FN	FP	TN	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)
Bohm (2004)	MDCT	64	9	1	0	88	0	98	0
	MRI (Gd)	42	4	0	0	91		100
Mainenti (2010)	CEUS	8	8	5	36	50	87.8	61	81.8
	MDCT	11	5	7	34	69	0.82	61	75.5
	MRI (Gd)	13	3	0	41	81	100	100	75.9
	PET/CT	11	5	1	40	69	87.8	92	76.5
Cantisani (2010)	CEUS	399	31	5	25	92.8	83.3	98.7	44.6
	CEUS	367	63	7	23	85.3	76.7	98	26.7
	MDCT	396	34	4	26	92.8	86.7	99	43
	MDCT	384	46	5	25	89.3	83.3	98.7	35
Kim (2015)	MDCT	90	14	40		87		69
	MRI (DWI)	92	12	14		88		87
	MRI (EOB)	102	2	9		98		92
	MRI (DWI + EOB)	103	1	11		99		90
Arita (2015)	CEUS	210	70	4		75		98
	MDCT	227	53	3		81		99
	MRI (DWI + EOB)	232	48	2		82		99
Schulz (2015)	MDCT	95	45	12	184	68	94	89	81
	MRI (DWI + EOB)	126	14	27	169	90	87	82	93
	PET/CT	85	55	3	193	61	99	97	78
Achiam (2016)	MDCT	2	7	0		22		100
	MRI (Gd + DWI)	8	1	1		89		89
	MRI (Gd + DWI)	8	1	0		89		100
Shiozawa (2016)	CEUS	99	10	3	21	90.8	84.5	97.1	67.7
	MRI (DWI + EOB)	104	5	7	17	95.4	70.8	93.7	77.3
Asato (2017)	MDCT	86	19			82		95
	MRI (EOB)	87	8			92		96
Koh (2018)	MDCT					93.9		93.9
	MRI (DWI)					100		100

CEUS, contrast-enhanced ultrasound; DWI, diffusion-weighted imaging; EOB, ethoxybenzyl; FN, false negative; FP, false positive; MDCT, multidetector computed tomography; MRI, magnetic resonance imaging; NPV, negative predictive value; PET/CT, positron emission tomography/computed tomography; PPV, positive predictive value; TN, true negative; TP, true positive.

The sensitivity estimates for CEUS, MDCT, MRI, and PET/CT on a per-patient basis were 80% (95% CI = 77.84%), 87% (95% CI = 84.90%), 87% (95% CI = 83.90%), and 96% (95% CI = 86.99%), respectively. The specificity estimates for CEUS, MDCT, MRI, and PET/CT on a per-patient analysis were 97% (95% CI = 95.98%), 95% (95% CI = 93.96%), 94% (95% CI = 83.99%), and 97% (95% CI = 86.100%), respectively. The per-patient diagnostic performances are presented in Table 4. Five, nine, six, and two datasets for CEUS (14,32 –34,36), MDCT (14,32 –38,41), MRI (33,35 –38,41), and FDG PET/CT (33,37), respectively, were included. In three studies, the specificity and negative predictive value could not be evaluated, due to limited data. MRI and MDCT had comparable sensitivity estimates. Both MRI and MDCT had higher sensitivity compared to CEUS, although non-significant (P = 0.85 and P = 0.20, respectively). Although sensitivity was higher for FDG PET/CT, data were too limited for comparison with other modalities. Specificity in the available studies was comparable among imaging modalities.

Table 4.

Results of the per-patient analysis for CEUS, MDCT, MRI, and PET/CT.

Author (year)	Study	TP	FN	FP	TN	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)
Rafaelsen (2011)	CEUS	18	3	6	244	85.7	97.6	75	98.8
	MDCT	18	3	11	239	85.7	95.6	62.1	98.8
Larsen (2009)	CEUS	43	11	7	304	79.6	97.7	86	96
	MDCT	48	6	18	293	88.9	94.2	72	98
Mainenti (2010)	CEUS	5	1	4	24	83	86	56	96
	MDCT	5	1	1	27	83	96	83	96
	MRI (Gd)	5	1	0	28	83	100	100	97
	PET/CT	6	0	1	27	100	96	86	100
Cantisani (2010)	CEUS	91	4			95.8
	CEUS	89	6			93.4
	MDCT	92	3			96.8
	MDCT	91	4			95.8
Kim (2015)	MDCT	47	0			100
	MDCT	47	0			100
	MRI (DWI)	47	0			100
	MRI (DWI + EOB)	47	0			100
Arita (2015)	CEUS	210	70	4		75		98
	MDCT	227	53	2		81		99
	MRI (DWI + EOB)	232	48	2		82		99
Schulz (2015)	MDCT	39	3	2	2	93	50	95	40
	MRI (DWI + EOB)	42	0	3	1	100	25	93	100
	PET/CT	40	2	0	4	95	100	100	67
Achiam (2016)	MDCT	1	1	0	18	50	100	100	95
	MRI (Gd + DWI)	2	0	1	17	100	94	67	100
	MRI (Gd + DWI)	2	0	0	18	100	100	100	100
Koh (2018)	MDCT	7	1			87.5	95.5
	MRI (DWI)	8	0	0	22	100	100	100	100

Datasets for CEUS (33,34), MDCT (33 –35,37,40), MRI (33,35,37,40), and FDG PET/CT (33,37) were adequate to calculate sensitivity for CRCLMs <10 mm. Datasets for MDCT (33,37,40), MRI (33,37,40), and FDG PET/CT (33,37) were adequate to calculate sensitivity for CRCLMs ≥10 mm, separately. Data for CEUS were inadequate to assess sensitivity for lesions ≥10 mm. The sensitivity estimates for CEUS, MDCT, MRI, and PET/CT on a per-lesion basis for CRCLMs < 10 mm were 74% (95% CI = 66.82%), 60% (95% CI = 54.67%), 80% (95% CI = 71.87%), and 16% (95% CI = 7.29%), respectively. The sensitivity estimates for MDCT, MRI, and PET/CT for CRCLMs at least 10 mm were 90% (95% CI = 85.94%), 97% (95% CI = 94.99%), and 84% (95% CI = 75.90%), respectively. The per-lesion diagnostic performances for each imaging modality are presented in Tables 5 and 6. The sensitivity for MRI for lesions < 10 mm was significantly higher than that for MDCT (P < 0.0001). Data for CEUS and FDG PET/CT were too limited to allow comparison with other techniques. The sensitivity for MRI for lesions at least 10 mm was higher than that for MDCT, although non-significant (P = 0.028). Comparison with FDG PET/CT data was not possible due to the small number of studies.

Table 5.

Diagnostic performance values of CEUS, MDCT, MRI, and PET/CT for CRCLMs < 10 mm.

Author (year)	Study	TP	FN	FP	TN	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)
Mainenti (2010)	CEUS	3	5	3		37		50
	MDCT	5	3	6		63		45
	MRI (Gd)	5	3	0		63		100
	PET/CT	4	4	1		50		80
Cantisani (2010)	CEUS	92	28			76.7
	CEUS	76	44			63.3
	MDCT	91	29			75.8
	MDCT	88	31			73.3
Kim (2015)	MDCT	16	12	35		57		31
	MRI (DWI)	23	5	19		82		55
	MRI (EOB)	26	2	7		93		79
	MRI (DWI + EOB)	27	1	9		96		76
Schulz (2015)	MDCT	7	36	6	144	16	96	54	80
	MRI (DWI + EOB)	32	11	18	132	74	88	64	93
	PET/CT	4	39	3	147	9	98	64	93
Asato (2017)	MDCT	16	9	3		60		84
	MRI (EOB)	19	6	3		76		86.3

Table 6.

Diagnostic performance values of MDCT, MRI, and PET/CT for CRCLMs ≥10 mm.

Author (year)	Study	TP	FN	FP	TN	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)
Mainenti (2010)	CEUS	5	3	2		62		71
	MDCT	6	2	1		75		86
	MRI (Gd)	8	0	0		100		100
	PET/CT	7	1			88		100
Schulz (2015)	MDCT	88	9	5	43	91	88	94	83
	MRI (DWI + EOB)	94	3	9	39	97	82	91	93
	PET/CT	81	16		48	84	100	100	75
Asato (2017)	MDCT	3	7	3		90		96.5
	MRI (EOB)	78	2	1		97		98.5

Five MDCT datasets were performed on portal phase (33 –35,38,41) and on both arterial and portal phases (14,32,36,37,40). The sensitivity estimates for portal-phase MDCT and MDCT performed on arterial and portal phases on a per-lesion basis were 89% (95% CI = 86.92%) and 78% (95% CI = 74.81%), respectively. The sensitivity estimates for portal-phase MDCT and MDCT performed on arterial and portal phases on a per-patient basis were 96% (95% CI = 92.99%) and 84% (95% CI = 80.87%), respectively. Portal-phase MDCT had higher sensitivity than that for MDCT obtained on arterial and portal phases, although differences were not significant both on a per-lesion (P = 0.85) and on a per-patient analysis (P = 0.8).

The sensitivities for Gd-MRI (31,33,38) (89%, 95% CI = 79.95%) and EOB-MRI (35 –37,39,40) (88%, 95% CI = 86.90%) on a per-lesion analysis were similar (P = 0.70). The sensitivity for EOB-MRI (35 –37) on a per-patient analysis was 87% (95% CI = 83.90%). No adequate data for sensitivity estimates on a per-patient analysis for Gd-MRI were extracted.

The sensitivity for DWI combined with EOB-MRI (35 –37,39) on a per-lesion analysis was 89% (95% CI = 86.91%). Data for DWI alone were limited to allow calculation of sensitivity estimates on a per-lesion basis. DWI (35,41) (100%, 95% CI = 94.100%) had higher sensitivity than the combined reading (37 –39) (87%, 95% CI = 83.90%) on a per-patient analysis, although data for DWI were limited.

No publication bias was found using the Egger regression test.

Discussion

This meta-analysis assesses the diagnostic performances of CEUS, MDCT, MRI, and FDG PET/CT in the detection of known or suspected CRCLMs in patients that have not previously undergone treatment. Twelve prospective studies published during 2000–2019 were included. On a per-lesion analysis, MRI had the highest sensitivity (89%) when compared to CEUS (86%), MDCT (84%), and FDG PET/CT (62%). No differences in sensitivity estimates between CEUS and MDCT were noted.

On a per-patient basis, MRI and MDCT were comparable in sensitivity (87% and 87%, respectively). CEUS had lower sensitivity estimates (80%), but without statistically significant differences. Specificity estimates were comparably high for all imaging modalities. FDG PET/CT had the highest sensitivity (96%) on a per-patient analysis, but data were limited to allow comparison with other imaging techniques.

MRI proved the most sensitive technique (80%) for the detection of CRCLMs < 10 mm when compared to CEUS (74%) and MDCT (60%). The sensitivity estimates for CEUS were significantly higher than that for MDCT.

Portal phase MDCT had a higher sensitivity both on a per-lesion (89%) and on a per-patient analysis (96%) when compared to MDCT performed on arterial and portal phases (78% and 84%, respectively), although differences were not statistically significant.

EOB-MRI did not improve sensitivity when compared to Gd-MRI and DWI. On a per-lesion basis, Gd-MRI and EOB-MRI had comparably high sensitivities (89% and 88%, respectively). DWI had higher sensitivity (100%) when compared to DWI combined with EOB-MRI (87%) on a per-patient analysis, although data were based on a small number of studies.

MRI has been reported as the first-line modality for the evaluation of CRCLMs, with a high detection rate for lesions < 10 mm, in patients who have not undergone therapy also in a previous meta-analysis, which included prospective studies published during 1990–2010 (27). The authors of this review suggested that FDG PET can be used as s second-line technique. Thirty-nine articles fulfilled the inclusion criteria in this analysis, including 25 CT studies (nine with MDCT), seven contrast-enhanced MRI studies (four with Gd-MRI, nine with superparamagnetic iron oxide-enhanced MRI, and three with mangafodipir trisodium enhanced-MRI), and nine studies with FDG PET. The sensitivity estimates for CT, MRI, and FDG PET on a per-lesion basis were 74.4%, 80.3%, and 81.4%, respectively. The sensitivity for CT, MRI, and FDG PET on a per-patient basis was 83.6%, 88.2%, and 94.1%, respectively. The authors also reported that the use of liver-speciﬁc contrast agents and MDCT scanners did not provide improvement of their results (27). Our analysis including also prospective studies and patients without previous treatment updated the role of the current imaging techniques used in the investigation of CRCLMs, namely CEUS, MDCT, MRI, including DWI and EOB-MRI and FDG PET/CT.

In recent years, CEUS has represented an alternative option for the evaluation of liver metastases, with accuracies comparable to that of CT and MRI, when scanning allows a complete evaluation of all liver segments (2,14,15,42). In the present meta-analysis, no statistically significant differences in the detection of CRCLMs were observed between CEUS and MDCT on a per-lesion basis and between CEUS and both MRI and MDCT on a per-patient basis. Westwood et al. (15) reported no differences in the diagnostic performances between CEUS, CT and MRI in the detection of liver metastases. However, this review is limited by the low number of studies, including one study with CRCLMs and a study with various primary malignancies, the majority with CRC (15). A recently published meta-analysis compared the diagnostic efficacy of CEUS, DWI, and contrast-enhanced MRI in the detection of CRCLMs (9). This review included 47 studies published during 2003–2008 to 2018, including 18 studies with CEUS, six with DWI, 16 with contrast-enhanced MRI, five using both CEUS and contrast-enhanced MRI, and two using both DWI and contrast-enhanced MRI. The authors concluded that CEUS performs similarly to DWI and contrast-enhanced MRI, especially for lesions ≥10 mm in maximal diameter. Specifically, in a per-lesion analysis the sensitivity estimates for CEUS, DWI and contrast-enhanced MRI were 85.3%, 83.0%, and 90.1%, respectively, and for lesions ≥10 mm, the sensitivities were 93.1%, 92.9%, and 94.5%, respectively. However, the present review is limited due to considerable heterogeneity, related to the variability in study design characteristics, patient characteristics technical aspects, and reference standard used (9).

Nowadays, DWI and EOB-MRI have been reported to improve the efficacy of MRI in the preoperative diagnosis of CRCLMs (17 –22). This was not proved in the current analysis and it was somewhat surprising. We found that both Gd-MRI and EOB-MRI had comparably high sensitivities on a per-lesion basis.

A recently published systematic review and meta-analysis (11) assessed the diagnostic performances of MDCT, EOB-MRI, and PET/CT in the detection of CRCLMs. EOB-MRI proved the most sensitive technique (93.1%), and EOB-MRI and PET/CT had similar specificities. Thirty-six studies were included in this analysis, assessing both prospective and retrospective data as well as patients after chemotherapy (11).

Vilgrain et al. (12) through a comprehensive search of articles up to June 2015 assessed the diagnostic performance of DWI, EOB-MRI, and combined MRI in the detection of liver metastases. This meta-analysis was based on 39 articles, with a large heterogeneous population, including 1105 patients with CRCLMs, both prospective and retrospective studies and also patients after treatment. The authors showed that DWI combined with EOB-MRI was more sensitive (95.5%) than DWI (87.1%) and EOB-MRI alone (90.6%) on a per-lesion basis (12). The above were not met in the current report. Specifically, DWI proved more sensitive (100%) compared to DWI combined with EOB-MRI (87%) on a per-patient basis, although the number of eligible studies was small. Interestingly, Hwang et al. (43) in a recently published retrospective study, found no significant differences between conventional MRI including DWI with or without MDCT and EOB-MRI in the detection and characterization of CRCLMs.

FDG PET/CT proved a sensitive technique in the detection of CRCLMs on a per-patient basis, although our results are limited, due to the small number of studies. Maffione et al. (8) assessed the role of FDG PET and FDG PET/CT in a review of 18 studies published from 2004 to 2014. This analysis reported FDG PET/CT as highly accurate for the detection of liver metastases on a per-patient basis, but less accurate on a per-lesion basis. Compared to MRI and CT, PET had a lower sensitivity on a per-patient basis and a per-lesion basis, but a higher specificity, affecting patient management in about 25% of cases. The limitations of this review included heterogeneity in population, assessment of prospective and retrospective studies, data on contrast-enhanced PET/CT and patients after therapy (8).

The present meta-analysis has some inherent limitations, including selection bias, study heterogeneity, and differences in population. First, our search was limited to the PubMed database, including only published articles, meaning studies that report a “positive result” and therefore not resulting in a representative sample. Differences among eligible studies existed. An important bias was that we included both patients suspected of having CRCLMs and those with known metastatic disease. Subgroup analysis was not performed due to lack of relevant data. The use of different reference standards and the lack of any analysis assessing the effect of each reference test on diagnostic accuracy represent another limitation. Finally, the number of studies eligible for this review, especially in the subgroup analysis was very small. However, a meta-analysis representing a powerful statistical tool is usually based on heterogeneous, often small studies, as in this review.

In conclusion, based on the results of the present meta-analysis, MRI represents the most sensitive imaging modality for the detection of CRCLMs. Both MDCT and CEUS can be used as second-line diagnostic techniques. Data on FDG PET/CT were limited to justify the role of the technique in the investigation of CRCLMs.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Athina C Tsili

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