Whole-body MRI versus 18F-FDG PET/CT for pretherapeutic assessment and staging of lymphoma: a meta-analysis.

PURPOSE: 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is the reference standard in staging of 18F-FDG-avid lymphomas; however, there is no recommended functional imaging modality for indolent lymphomas. Therefore, we aimed to compare the performance of whole-body magnetic resonance imaging (WB-MRI) with that of 18F-FDG PET/CT for lesion detection and initial staging in patients with aggressive or indolent lymphoma.
MATERIALS AND METHODS: We searched the MEDLINE, EMBASE, and CENTRAL databases for studies that compared WB-MRI with 18F-FDG PET/CT for lymphoma staging or lesion detection. The methodological quality of the studies was assessed using version 2 of the "Quality Assessment of Diagnostic Accuracy Studies" tool. The pooled staging accuracy (μ) of WB-MRI and 18F-FDG PET/CT for initial staging and for assessing possible heterogeneity (χ2) across studies were calculated using commercially available software.
RESULTS: Eight studies comprising 338 patients were included. In terms of staging, the meta-analytic staging accuracies of WB-MRI and 18F-FDG PET/CT for Hodgkin lymphoma and aggressive non-Hodgkin lymphoma (NHL) were 98% (95% CI, 94%-100%) and 98% (95% CI, 94%-100%), respectively. The pooled staging accuracy of 18F-FDG PET/CT dropped to 87% (95% CI, 72%-97%) for staging in patients with indolent lymphoma, whereas that of WB-MRI remained 96% (95% CI, 91%-100%). Subgroup analysis indicated an even lower staging accuracy of 18F-FDG PET/CT for staging of less FDG-avid indolent NHLs (60%; 95% CI, 23%-92%), in contrast to the superior performance of WB-MRI (98%; 95% CI, 88%-100%).
CONCLUSION: WB-MRI is a promising radiation-free imaging technique that may serve as a viable alternative to 18F-FDG PET/CT for staging of 18FDG-avid lymphomas, where 18F-FDG PET/CT remains the standard of care. Additionally, WB-MRI seems a less histology-dependent functional imaging test than 18F-FDG PET/CT and may be the imaging test of choice for staging of indolent NHLs with low 18F-FDG avidity.

Introduction

Malignant lymphoma is the most common primary hematopoietic malignancy, which is also considered as one of the most curable forms of cancer. The two main categories of lymphomas are Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (NHLs). Accurate staging at the initial diagnosis of lymphoma is crucial to appropriate treatment planning and prognostication. The current staging system for malignant lymphoma, the Cotswolds modification of the Ann Arbor staging system, is applied to both HL and NHL. Staging according to the Ann Arbor system is based on the number of lesions and the extent of nodal or extra-nodal involvement, whereas the Cotswolds modification put forward tumor burden as a complementary factor. Therefore, several imaging modalities have been used for noninvasive staging of lymphoma, including computed tomography (CT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). Compared with CT, 18F-FDG PET/CT is more sensitive in the detection of nodal and extra-nodal lymphomatous involvement, for it can provide both metabolic and morphologic information.1 However, the diagnostic accuracy of 18F-FDG PET/CT depends on 18F-FDG avidities of tumor lesions which vary for different histologic subtypes.2,3 18F-FDG PET/CT has been proven to be highly sensitive and regarded as the standard method in staging of HL, aggressive NHLs, and follicular lymphoma (FL),1 but its diagnostic accuracy is unstable in staging of indolent lymphomas.4–7 Besides, the need for initial staging, restaging, and therapy monitoring requires multiple 18F-FDG PET/CT examinations for a single patient, which lead to concerns of radiation-induced secondary malignancies, especially in younger patients.8–10

In recent years, whole-body magnetic resonance imaging (WB-MRI) has emerged as a radiation-free alternative to 18F-FDG PET/CT for obtaining both anatomic and functional images. Conventional WB-MRI comprises a T1-weighted sequence, a T2-weighted sequence, and fat-suppression techniques such as short-tau inversion recovery. This sequence has been reported to be particularly effective for detecting bone marrow metastases, but its use is restricted by its limited ability to detect small lesions in the abdomen and pelvis.11–13 Diffusion-weighted imaging is being increasingly applied in the evaluation of patients with malignant disease.14 Through its ability to measure the Brownian motion of water molecules in tissue, diffusion-weighted imaging can be used to detect tumors with restricted diffusion and provide superior visualization of lymph nodes.15 Even though 18F-FDG PET/CT is the current reference standard in the staging of HL and high-grade lymphomas, there is hitherto no recommended functional imaging modality for staging of some indolent histologic subtypes. Therefore, in order to determine the diagnostic value of WB-MRI for initial lymphoma staging, especially for indolent subtypes, this study systematically compared the diagnostic accuracy of WB-MRI with that of 18F-FDG PET/CT in staging of aggressive and indolent lymphomas.

Materials and methods

Literature search

We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for studies comparing the diagnostic accuracy of WB-MRI and 18F-FDG PET/CT in lymphoma. The database search was without language or date limits. The search terms were designed to capture the concepts of lymphoma, WB-MRI, and diffusion-weighted imaging. The search was performed over the span of 2 months and terminated in June 2016. The detailed electronic search strategies applied to each database are shown in Table S1.

Study selection

Studies evaluating the diagnostic accuracy of WB-MRI using 18F-FDG PET/CT as the comparator test in patients with histologically proven lymphoma were included. Studies were excluded if they 1) lacked a diffusion-weighted sequence, 2) included previously reported cases, 3) reported only on the detection of bone marrow involvement, 4) focused only on restaging or response assessment, 5) used 18F-FDG PET/CT as the only reference standard, 6) had a sample size smaller than 10, or 7) included patients with other malignancies or hematologic disorders.

Two reviewers (YLD and YLH) separately screened the titles and abstract of every record retrieved, and the full texts were obtained for potentially eligible studies. YLD and YLH then independently applied the inclusion and exclusion criteria to the full text and together resolved any disagreement.

Methodological quality assessment

The methodological quality of the studies was assessed using version 2 of the “Quality Assessment of Diagnostic Accuracy Studies” tool. The tool comprises four domains: patient selection, index test, reference standard, and flow and timing.16 Two reviewers (DYW and XCZ) independently applied the signaling questions for each domain to the content of the studies and reached a consensus on adding or omitting certain signaling questions to develop a guide specifically for quality assessment. In accord with the guide, each domain was assessed in terms of risk of bias, and the first three domains were assessed in terms of concerns about applicability. The bias risk or applicability concerns were described as low, high, or unclear.

Reference standard

The pathologic diagnosis was regarded as the most reliable evidence of tumor involvement. However, when pathologic evidence was inadequate for disease assessment, the reference standard of staging was based on the integrated interpretation of 18F-FDG PET/CT and WB-MRI images, with the confirmation of clinical and imaging follow-up or bone marrow biopsy.

Staging was performed according to the Cotswolds modification of the Ann Arbor system.

Data extraction and statistical analysis

Data of all included studies were independently extracted by two reviewers (DYW and YLH) and any disagreement was resolved through discussion. The data extracted from the articles included: authors, date, study type, population description, sample size and characteristics, 18F-FDG PET/CT and WB-MRI protocols, image interpretation methods, reference standards, sensitivities and specificities of 18F-FDG PET/CT or WB-MRI for lesion detection, stages according to 18F-FDG PET/CT or WB-MRI findings, final stages according to histopathology or imaging follow-ups.

The agreements between 18F-FDG PET/CT and WB-MRI for lesion detection were calculated with Cohen’s kappa statistic, defined as poor (κ≤0.4), moderate (0.4<κ≤0.6), good (0.6<κ≤0.8), and excellent (0.8<κ≤1) agreement. To access the diagnostic accuracy of initial staging, we split the study populations into two groups according to pathologic subtypes, including HL or aggressive NHL groups and indolent NHL groups. The staging accuracy estimates were defined as the proportion of the patients who were correctly staged by 18F-FDG PET/CT or WB-MRI in each group. In order to stabilize the variance, we calculated the staging accuracies with Freeman–Tukey double arcsine transformation17 before calculating the pooled estimates. The 95% CI of these estimates were calculated in accordance with the Wilson score CI method.18 Statistical heterogeneity was assessed by visually inspecting the forest plots and using the χ2-test (with a p-value of 0.10 indicating statistical significance). The I2 statistic was used to measure the degree of inconsistency across studies, with I2 values of 25%, 50%, and 75% representing low, moderate, and high substantial heterogeneity.19,20 We used random-effects model to calculate meta-analytic estimates (μ) because moderately high inconsistency was found in one group (I2=49.8%). Publication bias was weighed using Egger’s test, with a p-value of 0.05 indicating statistical significance.21 All data were analyzed using Stata (version 14.0).

Results

We identified a total of 3,453 records through database searches (845 articles from MEDLINE, 2,598 from EMBASE, and 10 from CENTRAL). Figure 1 shows the flow of studies through the screening and selection process. After primary screening of the titles and abstracts and removal of duplicates, 69 articles were selected for full-text analysis. Two of these articles did not provide sufficient information: one did not provide the histologic subtype of each patient;22 the other had incomplete follow-up data and we could not determine the standard stage.23 Of the remaining 67 articles, 8 met our inclusion criteria. Table 1 summarizes the main features of the included studies.

Figure 1

Flow diagram of study selection.

Abbreviations: DTA, diagnostic test accuracy; DW, diffusion-weighted; WB-MRI, whole-body magnetic resonance imaging.

Table 1

Main features of studies included in meta-analysis

Study, year	Study type	Patients (n)	Mean age and range (years)	Sex, M/F	Lymphoma subtype
Albano et al,24 2016	Cohort, prospective	68	42, 15–86	37/31	HL, DLBCL, FL, MCL
Stecco et al,25 2015	Cohort, retrospective	17	63.1, 34–82	12/5	DLBCL, FL, MALTL
Ferrari et al,5 2014	Cohort, prospective	27	40.6, 23–78	15/12	HL, DLBCL, MCL, FL, MZL, SLL
Stéphane et al,26 2013	Cohort, prospective	23	51, 18–84	11/12	HL, DLBCL, BL
Gu et al,27 2011	Cohort, prospective	17	20–80	11/6	HL, FL, DLBCL, NKTCL, AITCL
Mayerhoefer et al,28 2014	Cohort, prospective	140	57.6, 19–88	70/70	HL, MALTL, DLBCL, FL, nMZL, MCL, SLL/CLL
Lin et al,29 2010	Cohort, prospective	15	48, 23–79	9/6	DLBCL
Abdulqadhr et al,30 2011	Cohort, prospective	31	47.2, 18–78	20/11	HL, DLBCL, ALCL, AITCL, PMBL

Abbreviations: AITCL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MALTL, mucosa-associated lymphoid tissue lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NKTCL, natural killer T-cell lymphoma; nMZL, nodal marginal zone lymphoma; NR, not reported; PMBL, primary mediastinal B-cell lymphoma; SLL, small lymphocytic lymphoma; BL, Burkitt lymphoma; HL, Hodgkin lymphoma.

Methodological quality of studies

Figure 2 presents our risk of bias and applicability concerns ratings for each study, and Figure 3 summarizes the overall methodological quality of the studies.

Figure 2

Summary of risk of bias and applicability concerns: reviewers’ judgments about each domain for each included study.

Figure 3

Risk of bias and applicability concerns: reviewers’ judgments about each domain, presented as percentages across included studies.

In the participant-selection domain, the risk of bias in five studies was judged to be unclear because it was not clear whether a consecutive sample of patients had been enrolled.25,30 In the index-test domain, all studies were considered to be at low risk of bias. In the reference-standard domain, the study by Ferrari et al5 was at high risk of bias because the reference standard had not been clearly described. We considered the remaining eight studies to be at low risk of bias. In the flow-and-timing domain, all studies were considered to be at low risk of bias.

In our assessment of applicability concerns, we were highly concerned that in one study5 the target condition as defined by the reference standard did not match the review question.

Agreement between WB-MRI and 18F-FDG PET/CT for lesion detection

Five studies reported the results on the comparison between WB-MRI and 18F-FDG PET/CT on a per-lesion basis.5,24–26,29 Among them, three studies analyzed the agreement between WB-MRI and 18F-FDG PET/CT for the detection of both nodal and extra-nodal lesions, and two studies only provided the information of nodal regions. All five studies reported excellent agreement between the two imaging modalities (Table 2).

Table 2

Agreement between WB-MRI and 18F-FDG PET/CT for nodal and extra-nodal lymphoma involvement

Study	Nodal		Extra-nodal
	Kappa value (95% CI)	Agreement	Kappa value (95% CI)	Agreement
Lin et al29	0.84 (0.77–0.91)	Excellent	1.00 (1.00–1.00)	Excellent
Stéphane et al26	0.92 (0.88–0.96)	Excellent	0.93 (0.85–1.00)	Excellent
Ferrari et al5	0.82 (0.73–0.90)	Excellent	0.83 (0.61–1.00)	Excellent
Stecco et al25	0.87 (0.82–0.92)	Excellent	NR	NR
Albano et al24	0.95 (0.93–0.97)	Excellent	NR	NR

Abbreviations: 18F-FDG, 18F-fluorodeoxyglucose; PET/CT, positron emission tomography/computed tomography; NR, not reported; WB-MRI, whole-body MRI.

Separated staging accuracy of WB-MRI and 18F-FDG PET/CT for initial lymphoma staging

Of the eight studies reported on the performance of WB-MRI and 18F-FDG PET/CT for initial lymphoma staging, two included data for HL and aggressive NHL patients,26,29 and the other six included mixed histologic subtypes of aggressive and indolent lymphomas.5,24,25,27,28,30 Table 3 summarized the staging accuracies of WB-MRI and 18F-FDG PET/CT in both groups. In staging of HL and aggressive NHLs, both WB-MRI and 18F-FDG PET/CT were reported to be highly sensitive with the staging accuracy of 90%–100%, except that one study25 reported a staging accuracy of 75% for staging with 18F-FDG PET/CT. In indolent NHL group, the staging accuracies of WB-MRI were higher than that of 18F-FDG PET/CT in two studies.28,30

Table 3

WB-MRI vs 18F-FDG PET/CT for initial lymphoma staging: variables extracted by groups

Study	Patients (n)	Staging accuracy of WB-MRI	Staging accuracy of PET/CT	ADC calculated
HL and aggressive NHL
Abdulqadhr et al30	26	1.00	1.00	No
Lin et al29	15	1.00	0.93	Yes
Gu et al27	11	0.91	1.00	No
Stéphane et al26	23	1.00	1.00	Yes
Ferrari et al5	20	1.00	0.95	Yes
Mayerhoefer et al28	62	0.90	0.94	Yes
Stecco et al25	4	1.00	0.75	No
Albano et al24	58	0.91	0.95	Yes
Indolent NHL
Abdulqadhr et al30	5	1.00	0.40	No
Gu et al27	6	0.83	0.83	No
Ferrari et al5	7	1.00	1.00	Yes
Mayerhoefer et al28	78	0.94	0.79	Yes
Stecco et al25	13	0.85	0.85	No
Albano et al24	10	1.00	1.00	Yes

Abbreviations: 18F-FDG, 18F-fluorodeoxyglucose; PET/CT, positron emission tomo graphy/computed tomography; ADC, apparent diffusion coefficient; HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; WB-MRI, whole-body magnetic resonance imaging.

Assessment of heterogeneity and publication bias

When analyzing the staging accuracy of WB-MRI, the studies in both the HL and aggressive NHL group and the indolent NHL group showed good homogeneity, according to the χ2-test (p=0.20 and 0.64, respectively). In the analyses of 18F-FDG PET/CT, no statistically significant heterogeneity was found in the HL and aggressive NHL group (p=0.45; I2=0.00%). However, moderately high heterogeneity was observed in the indolent NHL group (I2=49.78%), so we used random effect models for the calculation of pooled estimates.

For both 18F-FDG PET/CT and WB-MRI, Egger’s test showed no indications of small-study effects and publication bias in the HL and aggressive NHL group (p=0.099 and 0.659, respectively) and the indolent lymphoma group (p=0.968 and 0.890, respectively). We did not perform a funnel plot because this meta-analysis included a limited number (<10) of relevant studies.

Pooled staging accuracy of WB-MRI and 18F-FDG PET/CT for initial lymphoma staging

Table 4 lists the pooled staging accuracies derived from the meta-analysis, and Figures 4 and 5 present forest plots of the individual and meta-analytic staging accuracies of the two imaging modalities. In terms of staging, the meta-analytic staging accuracies of WB-MRI and 18F-FDG PET/CT for HL and aggressive NHL were 98% (95% CI, 94%–100%) and 98% (95% CI, 94%–100%), respectively. The pooled staging accuracies of 18F-FDG PET/CT dropped to 87% (95% CI, 72%–97%) for indolent lymphoma, whereas that of WB-MRI remained at 96% (95% CI, 91%–100%).

Table 4

Pooled staging accuracies: WB-MRI vs 18F-FDG PET/CT

Series	Modality	μa	95% CIb	χ2c	dfd	p-value	I2e
HL and aggressive NHL	WB-MRI	0.98	0.94–1.00	9.78	7	0.20	28.42%
	18F-FDG PET/CT	0.98	0.94–1.00	3.42	5	0.45	0.00%
Indolent NHL	WB-MRI	0.96	0.91–1.00	6.79	7	0.64	0.00%
	18F-FDG PET/CT	0.87	0.72–0.97	9.96	5	0.08	49.78%

Notes:

μ is meta-analysis derived pooled staging accuracy across all groups.

95% CIs are for μ.

χ2 is measure of homogeneity.

df indicates degrees of freedom.

I2 indicates variation in μ attributable to heterogeneity.

Abbreviations: 18F-FDG, 18F-fluorodeoxyglucose; PET/CT, positron emission tomography/computed tomography; HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; WB-MRI, whole-body magnetic resonance imaging.

Figure 4

Individual and meta-analytic (μ) sensitivity of WB-MRI vs 18F-FDG PET/CT for initial staging in patients with HD and aggressive NHL. 95% CIs are indicated by horizontal bars.

Abbreviations: 18F-FDG, 18F-fluorodeoxyglucose; PET/CT, positron emission tomography/computed tomography; ES, effect size; HD, Hodgkin disease; NHL, non-Hodgkin lymphoma; WB-MRI, whole-body MRI.

Figure 5

Individual and meta-analytic (μ) sensitivity of WB-MRIvs 18F-FDG PET/CT for initial staging in patients with indolent NHL. 95% CIs are indicated by horizontal bars.

Abbreviations: 18F-FDG, 18F-fluorodeoxyglucose; PET/CT, positron emission tomography/computed tomography; ES, effect size; HD, Hodgkin disease; NHL, non-Hodgkin lymphoma; WB-MRI, whole-body MRI.

Subgroup analysis of indolent NHLs in accordance with 18F-FDG avidity

The diagnostic accuracy of 18F-FDG PET/CT relies on the 18F-FDG avidity of lymphoma lesions. The indolent series comprised a heterogeneous group of lymphoma subtypes with variable FDG avidities, which may potentially contribute to the heterogeneity in the indolent group. Thereby, a subgroup analysis was conducted and the patients with indolent NHLs were assigned into two subgroups in view of the FDG avidity: group A, histological subtypes with generally high FDG avidities, including FL and nodal marginal zone lymphoma (nMZL); group B, subtypes in which FDG-avid lesions were less common, including small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and mucosa-associated lymphoid tissue lymphoma (MALTL). The meta-analytic staging accuracies of 18F-FDG PET/CT in group A and group B were 99% (95% CI, 93%–100%) and 60% (95% CI, 23%–92%), respectively. Significant difference was found between the above two estimates according to the test for heterogeneity between subgroups (p<0.001). In contrast to 18F-FDG PET/CT, the meta-analytic staging accuracies of WB-MRI in group A (99%; 95% CI, 93%–100%) and group B (98%; 95% CI, 88%–100%) were comparable (p=0.35).

Discussion

This systematic review included eight studies, five of which5,24–26,29 reported the agreement between WB-MRI and 18F-FDG PET/CT using a region-based scoring system. Regarding lesion detection, excellent agreement between WB-MRI and 18F-FDG PET/CT was reported. We did not perform the meta-analysis on a per-lesion basis because the studies differed widely in design, with several potential sources of heterogeneity. The largest source of variability between studies was most likely the application and interpretation of WB-MRI. In accordance with the stated objectives of the studies, they differed in the sequence, acquisition plane, and slice thickness used and in the body area imaged (Table 5). Additionally, in the process of image interpretation, the criteria for identifying potentially involved nodal or extra-nodal sites also differed across studies, and the cutoffs for lymph node size were not standardized as well. Similarly, the differences in reference standard would also contribute to heterogeneity.

Table 5

WB-MRI protocols of included studies

Study	Protocol		Parameters		Extent
	Sequence	Plane	S,a mm	b value, s/mm2
Abdulqadhr et al30	T1WI, T2W-STIR	Coronal	6	–	NR
	DWIBS	Axial	6	0 and 1,000
Lin et al29	DWI	Axial	5	50, 400, and 800	Head, neck, chest, abdomen, pelvis, proximal thigh
Gu et al27	T2WI, T2W SPAIR	Axial	5	–	Head to distal thigh
	DWI	Axial	6	0 and 1,000
Stéphane et al26	T1WI, STIR	NR	NR	NR	Head to thigh
	DWIBS	Axial	4	0 and 1,000
Ferrari et al5	T1WI, STIR	Coronal	6	–	Head to thigh
	DWIBS	Axial	6	0, 500, and 1,000
Mayerhoefer et al28	T1W-TSE, FLASH	NR	NR	NR	Vertex to upper thigh
	DWI	Axial	5	50 and 1,000
Klenk et al31	T1W-SPGR	Axial	4–5	–	NR
	DWI	Axial	4–5	0 and 600
Stecco et al25	T1W-TSE, T2W-STIR	Axial	6	–	Head to feet
	DWIBS	Axial	6	0 and 1,000
Albano et al24	T1WI, STIR	Coronal	4–5	–	Vertex to toes
	DWI	Axial	4–5	0 and 800

Notes:

S indicates slice thickness. b value is a parameter of diffusion weighted sequence. “–” indicates not applicable.

Abbreviations: DWI, diffusion-weighted imaging; DWIBS, diffusion-weighted wholebody imaging with background body signal suppression; FLASH, fast low-angle shot; NR, not reported; SPAIR, spectral attenuated inversion recovery; SPGR, spoiled gradient; STIR, short-tau recovery; T1W, T1-weighted imaging; T2W, T2-weighted inversion imaging; TSE, turbo spin echo; WB-MRI, whole-body MRI.

In the evaluation of staging accuracy, the patients were categorized by histologic subtype and were divided into two groups, including with HL or aggressive NHL group and indolent NHL group. WB-MRI has been previously shown to have high accuracy for initial lymphoma staging, compared with 18F-FDG PET/CT, by meta-analysis.32 But the value of 18F-FDG PET/CT for lymphoma staging depends on the 18F-FDG avidities of the lesions, which vary for different histologic subtypes. According to the literature, HL and most forms of aggressive NHL – such as diffuse large B-cell lymphoma, Burkitt lymphoma, mantle cell lymphoma (MCL), natural killer T-cell lymphoma, and angioimmunoblastic T-cell lymphoma – are 18F-FDG-avid in more than 95% of patients and thus can be easily detected by 18F-FDG PET/CT.2,3 Indolent lymphomas, however, demonstrate a variety of 18F-FDG avidities. FL, the most common form of indolent NHLs, discloses positive 18F-FDG uptake in 95% of patients,2 but the uptake is less than that in high-grade lymphomas.33 nMZL is highly 18F-FDG-avid, whereas extra-nMZL and SLL show a much lower 18F-FDG avidity of 55% and 83%, respectively.2 Moderate 18F-FDG avidity was observed in patients with MALTL, ranging from 54% to 82%.2,34,35 Therefore, to determine the role of WB-MRI in the management of different lymphoma subtypes, we compared the staging accuracy of WB-MRI with that of 18F-FDG PET/CT for lymphomas subtypes with high 18F-FDG avidity versus those for which variable 18F-FDG avidity has been reported.

In our study, the pooled staging accuracies of WB-MRI and 18F-FDG PET/CT were high and similar for initial staging and lesion detection in HL and aggressive NHL; 219 patients with these types of lymphoma underwent both WB-MRI and 18F-FDG PET/CT. WB-MRI stage agreed with the reference standard in 207 patients, and 18F-FDG PET/CT in 209 patients. As the present recommended standard imaging method for 18F-FDG-avid lymphoma, 18F-FDG PET/CT has several disadvantages. Radiation, for one, is of most concern. Since patients will require numerous examinations over the course of their treatment and postremission surveillance, the risk of secondary malignancies will increase, especially in younger patients.36 Even though more than one study has reported that breathing-motion artifacts degenerated images and led to false-negative results in corresponding nodal regions,28,30 our results showed that, in terms of staging, diffusion-weighted MRI performed as well as 18F-FDG PET/CT, with an overall staging accuracy of 98% (95% CI, 94%–100%). Therefore, WB-MRI may serve as a viable alternative for initial staging in patients with HL and aggressive NHL.

In total, 119 patients with indolent NHL were included in our meta-analysis. With regard to staging, WB-MRI agreed with the reference standard in 111 patients, and 18F-FDG PET/CT, in 97 patients. Moderately high heterogeneity was found in the indolent NHL group for staging with 18F-FDG PET/CT. It may due in part to the differences in the distribution of histological subtypes of the study population which consequently resulted in the diversity of 18F-FDG avidity among the studies. Compared with diagnostic performance in HL and aggressive NHLs, the meta-analytic staging accuracy of WB-MRI in the indolent series (96%; 95% CI, 91%–100%) remained high, whereas that of 18F-FDG PET/CT (87%; 95% CI, 72%–97%) decreased significantly. Moderately high heterogeneity was observed in the indolent NHL group; thereby, a subgroup analysis was performed in view of 18F-FDG avidity. The results of the subgroup analysis revealed that 18F-FDG PET/CT remained highly sensitive in staging of 18F-FDG avid indolent lymphomas, and the less favorable staging accuracy of 18F-FDG PET/CT for indolent series was primarily caused by the inclusion of less 18F-FDG avid lymphoma subtypes (ie, SLL/CLL and MALTL) in the indolent group. In contrast, the staging performance of WB-MRI was stable and excellent, regardless of the variety of histological subtypes. These results indicate that WB-MRI, as a functional imaging method, may be less histology-dependent than 18F-FDG PET/CT, as is consistent with a previous study.28 Such results may be explained by the hypothesis that high cellular density, which can be detected by diffusion-weighted imaging, is a more general feature of lymphoma than elevated glucose metabolism. For many types of indolent lymphomas, such as MALTL and SLL/CLL, no functional imaging modality has yet been recommended for staging or for treatment response assessment. Our results showed that WB-MRI may be the imaging method of choice for staging of these subtypes of indolent lymphomas.

Our meta-analysis had several limitations. First, we did not perform subgroup analyses according to every NHL subtype because the studies included a wide spectrum of subtypes, some of which (eg, small lymphocytic lymphoma/chronic lymphocytic leukemia, MZL, and MCL) were represented by only a few patients. Larger sample sizes are essential for evaluating the staging performance of WB-MRI. Second, the differences in WB-MRI protocols (Table 5) and image interpretation methods may have contributed to a large part of the heterogeneity. Even though WB-MRI seems a promising and radiation-free imaging method for initial staging of lymphoma patients, there is no agreement concerning the sequence protocol applied, especially for the choice of b values (a parameter of diffusion weighted sequence), which may compromise the reproducibility of the results among different studies included in the meta-analysis.37 Indeed, lack of reproducibility may also be one of the major obstacles against the demonstration of the potential merits of WB-MRI for lymphoma staging, which calls for multicenter prospective studies to address the degree to which the diagnostic performance of WB-MRI depends on the sequence protocol or the method of acquisition. Third, the differences in reference standards may have increased the clinical heterogeneity. Only one study used histopathology aided by clinical and imaging follow-up as the standard of reference.31 Although a pathologic diagnosis is regarded as the most reliable evidence of tumor involvement, invasive exploration of all potential sites for pathologic analysis is ethically and practically infeasible since lymphoma is often diffuse. On that account, most studies based the reference standard on the integrated interpretation of 18F-FDG PET/CT and WB-MRI images, and confirmed the stage by clinical and imaging follow-up or bone marrow biopsy, especially when the results of WB-MRI and 18F-FDG PET/CT were discordant.26–30 Inclusion of an index test (WB-MRI) as part of the reference standard may increase the risk of incorporation bias and, thus, lead to an overestimation of diagnostic accuracy.

Conclusion

WB-MRI is a promising radiation-free imaging technique that may serve as a viable alternative to 18F-FDG PET/CT for staging of 18FDG-avid lymphomas, where 18F-FDG PET/CT remains the standard of care. Additionally, WB-MRI seems a less histology-dependent functional imaging test than 18F-FDG PET/CT and may be the imaging test of choice for staging of indolent lymphomas with low 18F-FDG avidity. Larger-scaled or multicenter prospective studies are needed to further confirm the usefulness of WB-MRI for staging of lymphoma.

Table S1

Search strategy

Source	Search strategy	Hits retrieved
1. MEDLINE In-process and other nonindexed citations and MEDLINE 1946–present (Ovid SP)	1. “Positron emission tomography”.ti,ab.	December 2016: 845
	2. exp Positron-emission Tomography/
	3. “FDG-PET”.ti,ab.
	4. PET.ti,ab.
	5. (“18F-FDG” or “FDG uptake”).ti,ab.
	6. fluodeoxyglucose*.ti,ab.
	7. fluorodeoxyglucose*.ti,ab.
	8. or/1-7
	9. exp Magnetic Resonance Imaging/
	10. (MRI or MRIs).ti,ab.
	11. ((“magnetic resonance” or MR) adj2 (imag* or tomograph* or scan*)).ti,ab.
	12. ((WB or “whole body”) adj2 (“magnetic resonance” or MR or MRI)).ti,ab.
	13. “diffusion weighted imag*”.ti,ab.
	14. DWI.ti,ab.
	15. ((DW or “diffusion weighted”) adj2 (“magnetic resonance” or MR or MRI)).ti,ab.
	16. or/9-15
	17. exp lymphoma/
	18. lymphom*.ti,ab.
	19. (Hodgkin or Hodgkins or Hodgkin’s).ti,ab.
	20. (“non-Hodgkin” or “non-Hodgkins” or “non-Hodgkin’s”).ti,ab.
	21. (HD or HL).ti,ab.
	22. (NHD or NHL).ti,ab.
	23. (AITCL or CLL or DLBCL or FL or MALTL or MCL or MZL or NKTCL or nMZL or PMBL or SLL).ti,ab.
	24. or/17-23
	25. 8 and 16 and 24
2. EMBASE	#1 ‘positron emission tomography’/exp	December 2016: 2,598
	#2 ‘positron emission tomography’:ab,ti
	#3 pet:ab,ti
	#4 ‘fdg pet’:ab,ti
	#5 ‘18f-fdg’:ab,ti OR ‘fdg uptake’:ab,ti
	#6 fluodeoxyglucose*:ab,ti
	#7 fluorodeoxyglucose*:ab,ti
	#8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7
	#9 ‘magnetic resonance imaging’/exp
	#10 ‘magnetic resonance imaging’:ab,ti
	#11 mri:ab,ti OR mris:ab,ti
	#12 ((‘magnetic resonance’ OR mr) NEAR/2 (imag* OR tomograph* OR scan*)):ab,ti
	#13 ((wb OR ‘whole body’) NEAR/2 (‘magnetic resonance’ OR mr OR mri)):ab,ti
	#14 ‘diffusion weighted imag*’:ab,ti
	#15 dwi:ab,ti
	#16 ((dw OR ‘diffusion weighted’) NEAR/2 (‘magnetic resonance’ OR mr OR mri)):ab,ti
	#17 #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16
	#18 ‘lymphoma’/exp
	#19 lymphoma:ab,ti
	#20 hodgkin*:ab,ti
	#21 ‘non hodgkin*’:ab,ti
	#22 hd:ab,ti OR hl:ab,ti
	#23 nhd:ab,ti OR nhl:ab,ti
	#24 aitcl:ab,ti OR cll:ab,ti OR dlbcl:ab,ti OR fl:ab,ti OR maltl:ab,ti OR mcl:ab,ti OR mzl:ab,ti OR nktcl:ab,ti OR nmzl:ab,ti OR pmbl:ab,ti OR sll:ab,ti
	#25 #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24
	#26 #8 AND #17 AND #25
3. CENTRAL	1. MeSH descriptor Lymphoma explode all trees	December 2016: 10
	2. MeSH descriptor Hodgkin Disease explode all trees
	3. (hodgkin* or hogkin* or hodkin* or hodgin*):ti,ab,kw
	4. (“non hodgkin*” or “non hogkin*” or “non hodkin*” or “non hodgin*”):ti,ab,kw
	5. (AITCL or CLL or DLBCL or FL or MALTL or MCL or MZL or NKTCL or nMZL or PMBL or SLL):ti,ab,kw
	6. (NHD or NHL):ti,ab,kw
	7. (HD or HL):ti,ab,kw
	8. (#1 or #2 or #3 or #4 or #5 or #6 or #7)
	9. MeSH descriptor Positron-Emission Tomography explode all trees
	10. MeSH descriptor Tomography, Emission-Computed explode all trees
	11. (pet* or petscan* or (Positron* and emission*) or (Positron* and tomography*)):ti,ab,kw
	12. (pet* and (deoxy* or fluor* or 18fluor* or fdg* or 18fdg* or fludeoxy*)):ti,ab,kw
	13. (pet* or petscan*):ti,ab,kw
	14. (tomograph* or tomographs* or tomographic* or tomography* or tomographies*):ti,ab,kw
	15. emission*:ti,ab,kw
	16. (#14 and #15)
	17. (#9 or #10 or #11 or #12 or #13 or #16)
	18. MeSH descriptor Magnetic Resonance Imaging explode all trees
	19. “diffusion weighted imag*”:ti,ab,kw
	20. DWI:ti,ab,kw
	21. (DW or “diffusion weighted”):ti,ab
	22. (“magnetic resonance” or MR or MRI):ti,ab
	23. (#21 and #22)
	24. (#18 or #19 or #20 or #23)
	25. (#8 and #17 and #24)