- Email: [email protected]
CT in Mantle Cell Lymphoma.
Journal Pre-proof 18
F-FDG PET or PET/CT in Mantle Cell Lymphoma.
Domenico Albano, Giorgio Treglia, Marina Gazzilli, Elisabetta Cerudelli, Raffaele Giubbini, Francesco Bertagna PII:
S2152-2650(20)30065-3
DOI:
https://doi.org/10.1016/j.clml.2020.01.018
Reference:
CLML 1528
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 20 December 2019 Accepted Date: 25 January 2020
18 Please cite this article as: Albano D, Treglia G, Gazzilli M, Cerudelli E, Giubbini R, Bertagna F, F-FDG PET or PET/CT in Mantle Cell Lymphoma., Clinical Lymphoma, Myeloma and Leukemia (2020), doi: https://doi.org/10.1016/j.clml.2020.01.018. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
18
F-FDG PET or PET/CT in Mantle Cell Lymphoma.
Domenico Albano1, Giorgio Treglia2,3, Marina Gazzilli1, Elisabetta Cerudelli1, Raffaele Giubbini1, Francesco Bertagna1. 1
Nuclear Medicine, University of Brescia and Spedali Civili Brescia, Brescia, Italy.
2
Clinic of Nuclear Medicine and Molecular Imaging, Imaging Institute of Southern Switzerland Bellinzona and
Lugano, Switzerland. 3
Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of
Lausanne Lausanne, Switzerland.
Corresponding author: Domenico Albano, M.D. Nuclear Medicine, Spedali Civili di Brescia, P.le Spedali Civili 1; 25123 Brescia Italy e-mail: [email protected] Tel.: +39-30-3995468
Fax: +39-30-3995420
ORCID: 0000-0003-0810-6494
Conflict of interest: The authors declare that they have no conflict of interest.
1
ABSTRACT Purpose: The aim of this systematic review was to examine published data about the potential role of Fluorine-18fluorodeoxyglucose positron emission tomography or positron emission tomography/computed tomography (18F-FDG PET or PET/CT) in patients affected by mantle cell lymphoma (MCL). Methods: A comprehensive computer literature search of Scopus, PubMed/MEDLINE and Embase databases was conducted including articles indexed up to November 2019; 25 studies or subsets in studies analyzing the value of 18FFDG PET or PET/CT in patients with MCL were eligible for inclusion. Results: From the analyses of the selected studies, the following main findings have been found: 1) MCL are 18F-FDGavid in most of cases, especially nodal lesions, instead bone marrow (BM) and gastrointestinal (GI) disease localizations have low 18F-FDG avidity; 2) 18F-FDG PET/CT seems to be helpful in staging setting, showing a better diagnostic performance than conventional imaging and a positive impact on clinical stage; 3) 18F-FDG PET/CT is useful in evaluating treatment response, especially after chemotherapy and transplantation; 4) metabolic response after therapy seems to have a prognostic role. Conclusions: Despite several limitations affect this analysis, especially related to the heterogeneity of the studies included, MCL is an 18F-FDG-avid lymphoma in most of the cases, with the exception of BM and GI disease. Moreover, 18F-FDG PET/CT seems to be useful in evaluating treatment response and prognosis.
KEYWORDS: PET/CT; MCL; 18F-FDG; mantle cell lymphoma; review.
2
INTRODUCTION Mantle cell lymphoma (MCL) is a B-cell non Hodgkin’s lymphoma (NHL) representing about 5–10% of all NHLs [1]. Pathogenesis of MCL seems to be related to a translocation t (11;14) that leads to an over-expression of cyclin D, that may be used as a marker of the disease [2]. MCL usually presents poor prognosis due to the high risk of relapse and the frequent involvement of extranodal sites. Nowadays no shared biological, pathological, or imaging markers to identify this subset of NHL are available as well as prognostic indexes [2,3]. A correct staging and identification of validated prognostic criteria could be crucial because it could modify patient management and treatment. More sophisticated prognostic stratification are required to identify subgroups of MCL patients who might benefit from more aggressive treatments, or in whom the prognosis is already sufficiently good to obviate more conservative treatment approaches. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a noninvasive imaging tool used for staging, restaging and evaluation of treatment response in 18F-FDG-avid HL and NHL [4,5], like Diffuse Large B cell lymphoma (DLBCL) and follicular lymphoma (FL); but its value in MCL is still under debate due to the lacking of strong evidences in the literature [6,7,8]. The major topic investigated in literature about 18F-FDG PET/CT in MCL is its metabolic behavior and, therefore, its 18
F-FDG-avidity, related to the nodal and extranodal sites of disease. MCL frequently affects extranodal localizations
like bone marrow (BM) and gastrointestinal (GI) tract and the potential usefulness of 18F-FDG PET/CT in detecting disease in these sites is not yet completely understood. This metabolic behavior reflects intrinsically the possible role of 18
F-FDG PET/CT in evaluating treatment response and prognostication.
The aim of our systemic review was to analyze the published data about the potential role of 18F-FDG PET and PET/CT in patients affected by MCL.
3
MATERIALS AND METHODS Search strategy A comprehensive literature search of Scopus, PubMed/MEDLINE and Embase databases was conducted to find relevant published articles about the role of 18F-FDG PET or PET/CT in patients with MCL. We used a search algorithm based on a combination of the following terms: (a) “PET” OR "PET/CT" OR “positron emission tomography” OR “positron emission tomography/computed tomography” AND (b) “MCL” OR “mantle cell lymphoma”. No beginning date limit was used for our literature search which was updated until November 30, 2019. Only articles in the English language were selected. To enlarge our research, references of the retrieved articles were also screened for searching additional papers. All reports collected were managed using EndNote®Basic (ThompsonReuters). Study selection Studies or subsets in studies investigating the value of 18F-FDG PET or PET/CT in patients with MCL were eligible for inclusion. Instead, exclusion criteria were: (a) articles not in the field of interest; (b) review articles, meta-analyses, letters, conference proceedings, editorials, and (c) case reports or small case series (less than 10 patients with MCL included). Two researchers (FB and DA) independently reviewed the titles and abstracts of the articles, applying the above-mentioned inclusion and exclusion criteria and the same two researchers then independently reviewed the fulltext version of the papers to evaluate their suitability. In case of disagreements, a third opinion (GT) was asked. Data abstraction For each included study, data were collected concerning the basic study features (author names, year of publication, study design), the main clinical patients features (age, gender, purpose), technical variables (PET device used, radiotracer injected activity, image analysis), number of patients evaluated and diagnostic accuracy data expressed. The main findings of the articles included in this review were reported in the “Results” section.
4
RESULTS Literature search The comprehensive computer literature search from the Scopus, PubMed/MEDLINE and Embase databases revealed 122 articles collected and managed by EndNote®Basic (ThompsonReuters). Reviewing titles and abstracts, 77 studies were excluded because reported data were not within the field of interest of this review; 19 articles were excluded as case reports, small case series, editorials, comments, reviews or conference proceedings; one paper was excluded because it was not in the English language. Lastly, 25 articles were selected and screened in the full-text version [9-33]. No additional studies were found screening the references of these papers (Figure 1). Eleven papers assessed the 18FFDG avidity of MCL and the diagnostic accuracy in detecting disease at PET or PET/CT [9-13,15,17,27-29,33], fifteen papers were focused on treatment response evaluation [9,10,16,18-22,24-26,29,30,32,33], fourteen papers on possible prognostic role [10-12,14,15,18,20,24,26,29-33] and four studies evaluated the impact on follow-up [9,10,15,23]. The main features of the included studies are summarized in Table 1-2.
Qualitative analysis Among 25 papers that included globally 1799 patients [9-33], 21 were of retrospective nature [9-14,16-20,22,23,25,2733] and the remaining 4 of prospective [15,21,24,26]. In all studies hybrid PET/CT was used, with the exception of one paper [17] where only PET was used and four where both PET and PET/CT scanners were considered [9,11,12,15]. PET/CT images were analyzed visually in all papers, and semiquantitative analysis was performed also in 11 [9-12,1416,27,29-31]. Maximum standardized uptake value (SUVmax) was the most frequent semiquantitative metabolic parameter evaluated. Only one study considered texture analysis [31].
18
F-FDG avidity and staging
The overall accuracy of 18F-FDG PET or PET/CT in patients with MCL on a per-patient-based analysis of nodal disease was very high with an average sensitivity of 97.5% (range 90-100%), and an average specificity of 100% (Table 3). The type of tomograph used (only PET versus PET/CT) seems to not influence the diagnostic performance (p>0.05). About the GI involvement of MCL [12,15,28,33], considering GI endoscopy and/or biopsy as gold reference standard, the diagnostic accuracy of 18F-FDG PET/CT decreased with an average sensitivity of 39% (range 11-60%) and an average specificity of 98% (range 92-100%). In a recent paper [28], the authors compared the diagnostic performances of 18F-FDG PET/CT in studying GI disease in all MCL patients and subsequently excluding diabetic patients with metformin therapy and the diagnostic performances increased (sensitivity passed from 64% to 78%; specificity from 92% to 92%). Instead for BM disease [10,12,15,27,28,33] and considering BM biopsy as gold reference standard, average sensitivity and specificity of 18F-FDG PET or PET/CT were 36% (12-100%) and 98% (87.5-100%), respectively. Only one paper [27] found a very high accuracy of 18F-FDG PET/CT in BM with a sensitivity of 100%; in this work, the authors proposed a voxel-based analysis of the iliac bones which improved the analyses. Comparing 18F-FDG PET/CT with conventional imaging studies (especially CT) [9,10,15,17,28], PET/CT had higher detection rate recognizing more lesions in a significant number of cases and allowing to change the stage of patients in 41/209 (20%) patients evaluated (Table 4). In most cases (36 of 41), 18F-FDG PET/CT allowed to upstage the disease.
5
Treatment response evaluation and follow-up Several studies have assessed the role of 18F-FDG PET or PET/CT in evaluating the response to therapy (Table 5). Firstly, Gill et al. [9] among 24 patients who underwent PET scan after therapy showed a higher diagnostic accuracy of PET/CT compared to conventional imaging in detecting treatment response. Good performance of 18F-FDG PET/CT in evaluating treatment response was demonstrated by subsequent other papers using different criteria of response: European Organisation for Research and Treatment of Cancer (EORTC) [10], International Harmonization Project (IHP) [16,18,19,20,26] and Deauville criteria [21,24,29,30,32,33]. In few papers metabolic criteria response was not reported specifically [22,25]. 18F-FDG PET/CT metabolic response after therapy showed also to have a prognostic role. Complete metabolic response was significantly correlated with progression free survival (PFS) [10,26], with disease free survival (DFS) [20], with overall survival (OS) [18,21] or with both PFS and OS [24,32]. On the other hand, few studies denied these evidences showing no prognostic impact of 18F-FDG PET/CT results on PFS [18,19] and on OS [19,31,33]. 18F-FDG PET/CT results at interim were evaluated only in two articles [19,32] with controversial results: according to Kedmi et al. [19] interim PET/CT results were not associated with PFS and OS, whilst for Jeon et al. [32] significant correlation between metabolic response and PFS and OS was showed. Considering follow-up, only four studies were available [9,10,15,23] and all agreed that follow-up 18F-FDG PET/CT scans had no significant impact in the management of the MCL patients.
Prognostic role of baseline 18F-FDG PET/CT About prognostic role of 18F-FDG PET/CT in MCL, 13 papers are present in literature reporting controversial results (Table 6). Firstly, Karam et al. [11] in 81 patients demonstrated that SUVmax using a cutoff of 5 could predict poorer OS and FFS (failure free survival), but subsequent works [12,15] using a threshold of 6 of SUVmax did not show any correlation with outcome survival. Other two papers evaluated SUVmax with opposite results: in the first [29] with a cutoff of 10.3 a significant correlation with both PFS and OS was reported; in the second [30] with a cutoff of 4.7 no significant association was demonstrated. Metabolic tumor volumes parameters, like MTV and TLG, were studied in only two papers [29,30] showing significant correlation with outcome survival, but confirmed at multivariate analysis only in the second one [30]. In a recent study, Albano et al. [30] studied for first time other baseline metabolic parameters (SUVbsa, SUVlbm, lesion to liver SUV ratio and lesion-to blood pool SUV ratio) and demonstrated no correlation with PFS and OS. Texture analysis was studied only in one paper [31] with promising results: a combination of SUVmean and Entropy features resulted significantly correlated with 2-year PFS.
6
DISCUSSION The value of 18F-FDG PET/CT in evaluating MCL is still under debate because it is not yet understood if this lymphoma histotype is 18F-FDG avid or not. This doubt derived also by the low number of studied and patients evaluated in literature, in comparison with other more diffuse lymphomas, like HL, DLBCL and FL. In our review, detection rate of MCL nodal disease at 18F-FDG PET/CT was good with an average sensitivity of 97.5% and an average specificity of 100% [9,10,12,13,17,28,29,33]. The accuracy in studying MCL disease is quite low considering BM and GI involvement (Table 3). The detection of extranodal disease is very important for staging accurately MCL patients as advanced stage. Both BM and GI tract are difficult setting to investigate with 18F-FDG due to the presence of physiological uptake of this radiotracer in several inflammatory and functional conditions. Accurate analysis of BM involvement in patients affected by lymphoma is fundamental but it may be a challenge owing to sampling errors; it has been previously demonstrated that 30% of patients will show unilateral positive BM that could have been missed [34]. Moreover, the BM biopsy is considered the reference standard for assessment of BM disease by lymphoma, but it presents some limitations: the invasive nature of the procedure, the unilateral analysis, the possible complications related to the procedure, and the very small part of BM studied sometimes not representative of the global disease. These difficulties reflect the controversial results present in literature about the detection of BM disease in NHL and HL [35,36]. It is quite shared that in DLBCL a focal 18F-FDG uptake in BM has to be considered a true positive finding and BM biopsy can be avoided; instead, in case of negative 18F-FDG PET/CT in BM the presence of BM disease cannot be excluded. For MCL the role of 18F-FDG PET/CT in studying BM involvement is limited and not well studied; only six papers [10,12,15,27,28,33] analyzed this topic. With the exception of one study [27], all other studied reported very low sensitivity and high specificity, underlying the potential usefulness of PET/CT in selecting patients with no need of BM biopsy. Also for GI evaluation with
18
F-FDG PET/CT, some issues are present. It is
possible to have not homogeneous moderate uptake in bowel and stomach due to different inflammatory and physiological states. Moreover, diabetic patients, especially in therapy with oral hypoglycemic drugs, may present an increased 18F-FDG uptake in the bowel which affect and limit the evaluation of the scan in the GI tract [37,38]. This evidence is true not only for lymphoma but for every kind of cancer. In our review, we demonstrated a low sensitivity of PET/CT in detecting GI disease and an optimal specificity. Of course the property to be 18F-FDG-avid influences the possible impact of 18F-FDG PET/CT in staging, treatment response evaluation and prognostication field. Considering MCL as an 18F-FDG-avid lymphoma, different treatment response criteria based on PET/CT were used in MCL as IHP and Deauville criteria. According to IHP criteria [39], visual analysis alone is adequate for interpreting PET findings as positive or negative after completion of therapy. For residual mass with transversal diameter more than 2 cm, mediastinal blood pool activity is recommended as the reference background activity to define PET positivity, while for smaller residual mass should be considered positive if its activity is above that of the surrounding background. But the IHP criteria was upgraded in 2009, when an alternative criteria called Deauville criteria based on the application of a five-point scale using the mediastinum and liver activity as the reference standard was proposed [40]; this scale has been recommended for reporting end of treatment PET for tracer avid lymphoma HL and several NHL, as DLBCL and FL [20,21]. Also in MCL, Deauville criteria seems to be accurate in evaluating treatment response and be correlated with outcome survival. About interim PET, many open questions remain. The potential role of baseline
18
F-FDG PET/CT parameters in prognostication is yet an open issue with controversial
results [11,12,15,29-31]. The analysis of this role is limited by several points: the first limitation is the difficulty to
7
compare the studies due to the heterogeneous population evaluated (different sample, kind of therapy, different baseline features), other limitations are the small sample of patients included and the different semiquantitative metabolic parameters studied (SUVs, ratios, MTV and TLG). So far, no strong evidence about the positive prognostic impact of 18
F-FDG PET/CT for survival outcome is available and more studies are needed to confirm or controvert these results.
SUV is the most widely utilized and generally accepted parameter in the current published literature for evaluating disease activity in lymphoma and also in MCL: it has been commonly investigated with promising results but not shared. In fact, different threshold have been proposed to discriminate between responders and not reresponders. This is probably due to the fact that it is potentially influenced by several variables, like blood glucose level, extravasation of tracer, technological features, uptake time, decay of radiotracer and partial volume effect. For these reason, other metabolic parameters (like MTV and TLG) has been introduced with the aim to overcome these issues. These parameters are considered a compromise between morphological and metabolic/functional variables because include both volumetric and metabolic characteristics and seem to be useful in predicting treatment response and prognosis in other lymphoma histotypes [41-45]. In MCL, it is premature to declare the same evidence because only two papers [29,30] investigated these parameters with controversial results.
Limitations of the studies Some limitations affect the quality of this review like the absence of multicentric and prospective studies, the low number of patients studied and the heterogeneity among the analyzed papers. This heterogeneity arises from diversity in features of the patients included, methodological aspects, reference standard used and global quality of the study.
8
CONCLUSION Despite several limitations, MCL may be considered an 18F-FDG-avid histotype lymphoma in nodal localizations; on the other hand, 18F-FDG PET/CT has low accuracy for GI and BM involvement of MCL. Also in staging and treatment response evaluation 18F-FDG PET/CT seems to be helpful, changing the stage and the subsequent management in some cases. Instead the prognostic value of 18F-FDG PET/CT, despite promising preliminary results, is not yet clear. More extensive studies, maybe prospective and multicentric, are desirable to suggest its possible introduction in the diagnostic flow chart.
9
COMPLIANCE WITH ETHICAL STANDARDS Conflict of interest The authors declare they have no conflict of interest.
Author contributions Domenico Albano: study design, data analysis, article writing, and final approval of the manuscript. Maria Gazzilli, Elisabetta Cerudelli: literature search, data analysis and final approval of the manuscript. Giorgio Treglia, Raffaele Giubbini: study design, article writing, and final approval of the manuscript. Francesco Bertagna: data analysis, article writing, and final approval of the manuscript
10
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26 Klener P, Fronkova E, Belada D, et al. Alternating R CHOP and R cytarabine is a safe and effective regimen for transplant ineligible patients with a newly diagnosed mantle cell lymphoma. Hematol Oncol 2018 36;110115.
27 Morgan R, Perry M, Kwak J, et al. Positron emission tomography-based analysis can accurately predict bone marrow involvement with Mantle Cell Lymphoma. Clin Lymphoma Myeloma Leuk 2018;18:731-736.
28 Albano D, Ferro P, Bosio G, et al. Diagnostic and Clinical Impact of Staging 18F-FDG PET/CT in Mantle-Cell
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14
FIGURE LEGENDS Figure 1 Literature search flow-chart
15
Table 1: the main features of papers selected
First Author Gil [9]
Year 2008
Country Australia
Study design Retrospective
N° MCL patients 28
M:F 20:8
Age mean (range) 59* (33-82)
Brepoels [10]
2008
Belgium
Retrospective
37
28:9
58* (36-77)
Karam [11] Bodet-Milin [12] Weiler-Sagie [13] Mato [14] Hosein [15] Tateishi [16] Alavi [17] Cohen [18] Kedmi [19] Magnusson [20] Czuczman [21] Htet [22] Guidot [23] Lamonica [24] Mei [25] Klener [26]
2009 2010 2010 2011 2011 2011 2011 2013 2014 2014 2016 2016 2017 2017 2017 2018
Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Prospective Retrospective Prospective
81 44 14 53 52 10 20 29 58 66 45 12 204 32 191 73
na 29:15 na na 40:12 6:4 13:7 25:4 49:9 63:13 32:13 10:2 Na 22:10 142:49 49:24
na 62* (43-80) na 58 (35-74) 58* (39-92) 71* (59-75) 59 60* (37-73) 59* (41-88) 58 (34-73) 70* (48-88) 57* (42-69) na 68 (52-78) 59* (33-76) 70 (58-83)
Morgan [27] Albano [28] Bailly [29]
2018 2019 2019
USA-Belgium France Israel USA USA Japan USA USA Israel USA USA Australia USA USA USA Czech Republic USA Italy France
Retrospective Retrospective Retrospective
11 123 104
8:3 91:31 78:26
60.5 66 (29-88) 57* (41-65)
Albano [30] Mayerhoefer [31] Jeon [32] Albano [33]
2019 2019 2019 2019
Italy USA Korea Italy
Retrospective Retrospective Retrospective Retrospective
87 107 89 229
65:22 72:35 72:17 172:57
65 (29-88) 64.5 (na) 64* (26-84) 65 (29-88)
Purpose Staging, treatment response, followup Staging, treatment response, prognosis, follow-up Staging, Prognosis Staging, Prognosis Staging Prognosis Staging, Prognosis, Follow-up Treatment response Staging Treatment response, prognosis Treatment response Treatment response, prognosis Treatment response Treatment response Follow-up Treatment response, prognosis Treatment response Treatment response, prognosis Staging Staging Staging, treatment response, prognosis Treatment response, prognosis Prognosis Treatment response, prognosis Staging, treatment response and prognosis
*median value MCL: Mantle Cell lymphoma; M: male; F: female; na: not available
Table 4: summary of main evidences of literature about staging purpose of 18F-FDG PET/CT in MCL comparing with conventional imaging Author
N° upstage (%)
N° downstage (%)
Change of stage acc. Ann Arbor
Gill [9]
1/9 (11%)
0/9 (0%)
II→ III
Brepoels [10]
9/24 (37.5%)
2/24 (8%)
na
Hosein [15]
1/34 (4%)
0/34 (0%)
III → IV n 1
Alavi [17]
4/19 (21%)
1/19 (5%)
na
Albano [28]
21/123 (17%)
2/123 (2%)
I or II → III n 19 III → IV n 2 III → II n 2
Na: not available
n1
Table 2: main technical aspects First Author
Device
18F-FDG mean injected dose Uptake time Image analysis min MBq
Semiquantitative parameters
Gil [9]
PET & PET/CT
na
60
Visual and semiquantitative SUVmax
Brepoels [10]
PET/CT
na
na
Visual and semiquantitative SUVmax
Karam [11]
PET & PET/CT
444-666
60-75
Visual and semiquantitative SUVmax
Bodet-Milin [12]
PET & PET/CT
5-7 MBq/Kg
60-80
Visual and semiquantitative SUVmax
Weiler-Sagie [13]
PET/CT
370-555
60-90
Visual
Mato [14]
PET/CT
na
na
Visual and semiquantitative SUVmax
Hosein [15]
PET & PET/CT
1.65-5.1 MBq/Kg
60-90
Visual and semiquantitative SUVmax
Tateishi [16]
PET/CT
3.5-5 MBq/Kg
60
Visual and semiquantitative SUVmax
Alavi [17]
PET
1,.5-5.1 MBq/Kg
60
Visual
Cohen [18]
PET/CT
na
na
Visual
Kedmi [19]
PET/CT
na
na
Visual
Magnusson [20]
PET/CT
na
na
Visual
Czuczman [21]
PET/CT
na
na
Visual
Htet [22]
PET/CT
na
na
Visual
Guidot [23]
PET/CT
na
na
Visual
Lamonica [24]
PET/CT
370-740
50-70
Visual
Mei [25]
PET/CT
na
na
Visual
Klener [26]
PET/CT
na
na
Visual
Morgan [27]
PET/CT
na
na
Visual and semiquantitative SUVmax, SUVmean
Albano [28]
PET/CT
3.5-4.5 MBq/Kg
60 ± 10
Visual
Bailly [29]
PET/CT
na
na
Visual and semiquantitative SUVmax, SUVpeak, MTV and TLG
Albano [30]
PET/CT
3.5-4.5 MBq/Kg
60 ± 10
Visual and semiquantitative SUVbw, SUVlbm, SUVbsa, Lesion-to-liver SUVmax ratio, Lesion-toblood pool SUVmax ratio, MTV, TLG
Mayerhoefer [31]
PET/CT
444-552
60
Visual, semiquantitative and SUVmax, SUVmean, radiomics SUVpeak, MTV, TLG, + 17 radiomic features
Jeon [32]
PET/CT
na
na
Visual
Albano [33] PET/CT 3.5-4.5 MBq/Kg 60 ± 10 Visual MBq: megabecquerel; SUV: standardized uptake value; bw: body weight; lbm: lean body mass; bsa: body surface area; MTV: metabolic tumour volume; TLG: total lesion glycolysis; na: not available
Table 3: summary of main evidences concerning 18F-FDG-avidity in staging MCL Nodal disease Specificity
Gastrointestinal disease
PPV
NPV
Sensitivity
Author
Sensitivity
Gil [9]
100%
/
100%
/
na
na
na
na
na
na
na
na
Brepoels [10]
100%
/
100%
/
na
na
na
na
12.5%
100%
80%
100%
Bodet-Milin [12]
90%
100%
100%
92%
11%
100%
100%
81%
12%
100%
100%
64%
Weiler-Sagie [13] 100%
/
100%
/
na
na
na
na
na
na
na
na
Hosein [15]
na
na
na
na
20%
100%
100%
64%
12%
100%
100%
26%
Alavi [17]
90%°
100%°
na
na
na
na
na
na
na
na
na
na
Morgan [27]
na
na
na
na
na
na
na
na
100%
87.5%
85%
100%
Albano [28]
100%
/
100%
/
64% 78%*
92% 92%*
69% 72%*
90% 94%*
52%
98%
97%
65%
Bailly [29]
100%
/
100%
/
na
na
na
na
na
na
na
na
99%
93%
90%
27%
100%
100%
48%
Albano [33] 100% / 100% / 60% *excluding patients with diabetes mellitus type 2 ° global accuracy (considering both nodal and extranodal disease) na: not available; PPV: positive predictive value; NPV: negative predictive value.
Specificity
Bone marrow disease
PPV
NPV
Sensitivity
Specificity
PPV
NPV
Table 5: summary of papers evaluated treatment response Authors
Criteria of PET/CT response
Type of therapy
Main findings
Gil [9]
nr
Different CMT regimens (+6 ASCT)
High accuracy in evaluating treatment response
Brepoels [10]
EORTC
Different CMT regimens (+5 ASCT)
Significant impact on PFS
Tateishi [16]
IHP
Bendamustine
High accuracy in evaluating relapse
Cohen [18]
IHP
Pre ASCT
Significant impact on OS (p 0.007); no impact on PFS (p 0.054)
Kedmi [19]
IHP
35 R-CHOP or R-CHOP like CMT 24 + BEAM and ASCT
No impact on OS and PFS
Magnusson [20] IHP
Pre allogenic SCT and ASCT
Significant impact on DFS
Czuczman [21]
Deauville criteria
Bendamustine + Rituximab
Significant impact on OS
Htet [22]
nr
R-hyper-CVAD
Combination of PET/CT and BMB results may predict response therapy.
Lamonica [24]
Deauville criteria
Bendamustine + Rituximab
Significant impact on PFS, OS and DOR
Mei [25]
nr
Pre ASCT
PET/CT helped to stratify patients response
Klener [26]
IHP
Alternating R-CHOP/R-HDAC
Significant impact on PFS
Albano [30]
Deauville criteria
21 R-BAC, 56 R-CHOP or alternating Significant impact on PFS, not on OS R-CHOP/R-HDAC, 10 R-ASCT
Jeon [32]
Deauville criteria
R-CHOP
Albano [33]
Deauville criteria
Significant impact on PFS and OS of interim PET/CT
82 R-CHOP, 68 R-DHAP, 39 RSignificant impact on PFS, not on OS Bendamustina, 24 BCVPP, 12 MBVD nr: not reported; IHP: International Harmonization Project; EORTC: European Organisation for research and Treatment of Cancer; CMT: chemotherapy; ASCT: autologous stem cell transplant; PFS: progression free survival; OS: overall survival; DFS: disease free survival; DOR: duration of response
Table 6: summary of studied evaluating prognostic role of 18F-FDG PET/CT First author
Total patients Parameters considered evaluated
Main findings
Karam [11]
81
pretreatment SUVmax ≤5; >5
Correlation with OS and FFS
Bodet-Milin [12]
44
pretreatment SUVmax<6; ≥6
No correlation with OS and EFS
Hosein [15]
52
pretreatment SUVmax ≤6; >6
No correlation with OS and PFS
Bailly [29]
104
pretreatment SUVmax (≤10.3; >10.3), MTV (≤41.47; >41.47) and TLG
SUVmax correlated with PFS and OS MTV correlated with PFS and OS only at univariate analysis
Albano [30]
81
pretreatment SUVbw, SUVlbm, SUVbsa, LBP SUV R, L-L SUV R, MTV & TLG*
MTV and LTG correlated with end of treatment response, OS and PFS
Mayerhoefer [31]
107
pretreatment radiomic signature includng SUVmean and Entropy * dichotomized using ROC curve analysis OS: overall survival; EFS: event free survival; FFS: failure free survival
Correlation with PFS
F-FDG PET or PET/CT in Mantle Cell Lymphoma.
Domenico Albano, Giorgio Treglia, Marina Gazzilli, Elisabetta Cerudelli, Raffaele Giubbini, Francesco Bertagna PII:
S2152-2650(20)30065-3
DOI:
https://doi.org/10.1016/j.clml.2020.01.018
Reference:
CLML 1528
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 20 December 2019 Accepted Date: 25 January 2020
18 Please cite this article as: Albano D, Treglia G, Gazzilli M, Cerudelli E, Giubbini R, Bertagna F, F-FDG PET or PET/CT in Mantle Cell Lymphoma., Clinical Lymphoma, Myeloma and Leukemia (2020), doi: https://doi.org/10.1016/j.clml.2020.01.018. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
18
F-FDG PET or PET/CT in Mantle Cell Lymphoma.
Domenico Albano1, Giorgio Treglia2,3, Marina Gazzilli1, Elisabetta Cerudelli1, Raffaele Giubbini1, Francesco Bertagna1. 1
Nuclear Medicine, University of Brescia and Spedali Civili Brescia, Brescia, Italy.
2
Clinic of Nuclear Medicine and Molecular Imaging, Imaging Institute of Southern Switzerland Bellinzona and
Lugano, Switzerland. 3
Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of
Lausanne Lausanne, Switzerland.
Corresponding author: Domenico Albano, M.D. Nuclear Medicine, Spedali Civili di Brescia, P.le Spedali Civili 1; 25123 Brescia Italy e-mail: [email protected] Tel.: +39-30-3995468
Fax: +39-30-3995420
ORCID: 0000-0003-0810-6494
Conflict of interest: The authors declare that they have no conflict of interest.
1
ABSTRACT Purpose: The aim of this systematic review was to examine published data about the potential role of Fluorine-18fluorodeoxyglucose positron emission tomography or positron emission tomography/computed tomography (18F-FDG PET or PET/CT) in patients affected by mantle cell lymphoma (MCL). Methods: A comprehensive computer literature search of Scopus, PubMed/MEDLINE and Embase databases was conducted including articles indexed up to November 2019; 25 studies or subsets in studies analyzing the value of 18FFDG PET or PET/CT in patients with MCL were eligible for inclusion. Results: From the analyses of the selected studies, the following main findings have been found: 1) MCL are 18F-FDGavid in most of cases, especially nodal lesions, instead bone marrow (BM) and gastrointestinal (GI) disease localizations have low 18F-FDG avidity; 2) 18F-FDG PET/CT seems to be helpful in staging setting, showing a better diagnostic performance than conventional imaging and a positive impact on clinical stage; 3) 18F-FDG PET/CT is useful in evaluating treatment response, especially after chemotherapy and transplantation; 4) metabolic response after therapy seems to have a prognostic role. Conclusions: Despite several limitations affect this analysis, especially related to the heterogeneity of the studies included, MCL is an 18F-FDG-avid lymphoma in most of the cases, with the exception of BM and GI disease. Moreover, 18F-FDG PET/CT seems to be useful in evaluating treatment response and prognosis.
KEYWORDS: PET/CT; MCL; 18F-FDG; mantle cell lymphoma; review.
2
INTRODUCTION Mantle cell lymphoma (MCL) is a B-cell non Hodgkin’s lymphoma (NHL) representing about 5–10% of all NHLs [1]. Pathogenesis of MCL seems to be related to a translocation t (11;14) that leads to an over-expression of cyclin D, that may be used as a marker of the disease [2]. MCL usually presents poor prognosis due to the high risk of relapse and the frequent involvement of extranodal sites. Nowadays no shared biological, pathological, or imaging markers to identify this subset of NHL are available as well as prognostic indexes [2,3]. A correct staging and identification of validated prognostic criteria could be crucial because it could modify patient management and treatment. More sophisticated prognostic stratification are required to identify subgroups of MCL patients who might benefit from more aggressive treatments, or in whom the prognosis is already sufficiently good to obviate more conservative treatment approaches. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a noninvasive imaging tool used for staging, restaging and evaluation of treatment response in 18F-FDG-avid HL and NHL [4,5], like Diffuse Large B cell lymphoma (DLBCL) and follicular lymphoma (FL); but its value in MCL is still under debate due to the lacking of strong evidences in the literature [6,7,8]. The major topic investigated in literature about 18F-FDG PET/CT in MCL is its metabolic behavior and, therefore, its 18
F-FDG-avidity, related to the nodal and extranodal sites of disease. MCL frequently affects extranodal localizations
like bone marrow (BM) and gastrointestinal (GI) tract and the potential usefulness of 18F-FDG PET/CT in detecting disease in these sites is not yet completely understood. This metabolic behavior reflects intrinsically the possible role of 18
F-FDG PET/CT in evaluating treatment response and prognostication.
The aim of our systemic review was to analyze the published data about the potential role of 18F-FDG PET and PET/CT in patients affected by MCL.
3
MATERIALS AND METHODS Search strategy A comprehensive literature search of Scopus, PubMed/MEDLINE and Embase databases was conducted to find relevant published articles about the role of 18F-FDG PET or PET/CT in patients with MCL. We used a search algorithm based on a combination of the following terms: (a) “PET” OR "PET/CT" OR “positron emission tomography” OR “positron emission tomography/computed tomography” AND (b) “MCL” OR “mantle cell lymphoma”. No beginning date limit was used for our literature search which was updated until November 30, 2019. Only articles in the English language were selected. To enlarge our research, references of the retrieved articles were also screened for searching additional papers. All reports collected were managed using EndNote®Basic (ThompsonReuters). Study selection Studies or subsets in studies investigating the value of 18F-FDG PET or PET/CT in patients with MCL were eligible for inclusion. Instead, exclusion criteria were: (a) articles not in the field of interest; (b) review articles, meta-analyses, letters, conference proceedings, editorials, and (c) case reports or small case series (less than 10 patients with MCL included). Two researchers (FB and DA) independently reviewed the titles and abstracts of the articles, applying the above-mentioned inclusion and exclusion criteria and the same two researchers then independently reviewed the fulltext version of the papers to evaluate their suitability. In case of disagreements, a third opinion (GT) was asked. Data abstraction For each included study, data were collected concerning the basic study features (author names, year of publication, study design), the main clinical patients features (age, gender, purpose), technical variables (PET device used, radiotracer injected activity, image analysis), number of patients evaluated and diagnostic accuracy data expressed. The main findings of the articles included in this review were reported in the “Results” section.
4
RESULTS Literature search The comprehensive computer literature search from the Scopus, PubMed/MEDLINE and Embase databases revealed 122 articles collected and managed by EndNote®Basic (ThompsonReuters). Reviewing titles and abstracts, 77 studies were excluded because reported data were not within the field of interest of this review; 19 articles were excluded as case reports, small case series, editorials, comments, reviews or conference proceedings; one paper was excluded because it was not in the English language. Lastly, 25 articles were selected and screened in the full-text version [9-33]. No additional studies were found screening the references of these papers (Figure 1). Eleven papers assessed the 18FFDG avidity of MCL and the diagnostic accuracy in detecting disease at PET or PET/CT [9-13,15,17,27-29,33], fifteen papers were focused on treatment response evaluation [9,10,16,18-22,24-26,29,30,32,33], fourteen papers on possible prognostic role [10-12,14,15,18,20,24,26,29-33] and four studies evaluated the impact on follow-up [9,10,15,23]. The main features of the included studies are summarized in Table 1-2.
Qualitative analysis Among 25 papers that included globally 1799 patients [9-33], 21 were of retrospective nature [9-14,16-20,22,23,25,2733] and the remaining 4 of prospective [15,21,24,26]. In all studies hybrid PET/CT was used, with the exception of one paper [17] where only PET was used and four where both PET and PET/CT scanners were considered [9,11,12,15]. PET/CT images were analyzed visually in all papers, and semiquantitative analysis was performed also in 11 [9-12,1416,27,29-31]. Maximum standardized uptake value (SUVmax) was the most frequent semiquantitative metabolic parameter evaluated. Only one study considered texture analysis [31].
18
F-FDG avidity and staging
The overall accuracy of 18F-FDG PET or PET/CT in patients with MCL on a per-patient-based analysis of nodal disease was very high with an average sensitivity of 97.5% (range 90-100%), and an average specificity of 100% (Table 3). The type of tomograph used (only PET versus PET/CT) seems to not influence the diagnostic performance (p>0.05). About the GI involvement of MCL [12,15,28,33], considering GI endoscopy and/or biopsy as gold reference standard, the diagnostic accuracy of 18F-FDG PET/CT decreased with an average sensitivity of 39% (range 11-60%) and an average specificity of 98% (range 92-100%). In a recent paper [28], the authors compared the diagnostic performances of 18F-FDG PET/CT in studying GI disease in all MCL patients and subsequently excluding diabetic patients with metformin therapy and the diagnostic performances increased (sensitivity passed from 64% to 78%; specificity from 92% to 92%). Instead for BM disease [10,12,15,27,28,33] and considering BM biopsy as gold reference standard, average sensitivity and specificity of 18F-FDG PET or PET/CT were 36% (12-100%) and 98% (87.5-100%), respectively. Only one paper [27] found a very high accuracy of 18F-FDG PET/CT in BM with a sensitivity of 100%; in this work, the authors proposed a voxel-based analysis of the iliac bones which improved the analyses. Comparing 18F-FDG PET/CT with conventional imaging studies (especially CT) [9,10,15,17,28], PET/CT had higher detection rate recognizing more lesions in a significant number of cases and allowing to change the stage of patients in 41/209 (20%) patients evaluated (Table 4). In most cases (36 of 41), 18F-FDG PET/CT allowed to upstage the disease.
5
Treatment response evaluation and follow-up Several studies have assessed the role of 18F-FDG PET or PET/CT in evaluating the response to therapy (Table 5). Firstly, Gill et al. [9] among 24 patients who underwent PET scan after therapy showed a higher diagnostic accuracy of PET/CT compared to conventional imaging in detecting treatment response. Good performance of 18F-FDG PET/CT in evaluating treatment response was demonstrated by subsequent other papers using different criteria of response: European Organisation for Research and Treatment of Cancer (EORTC) [10], International Harmonization Project (IHP) [16,18,19,20,26] and Deauville criteria [21,24,29,30,32,33]. In few papers metabolic criteria response was not reported specifically [22,25]. 18F-FDG PET/CT metabolic response after therapy showed also to have a prognostic role. Complete metabolic response was significantly correlated with progression free survival (PFS) [10,26], with disease free survival (DFS) [20], with overall survival (OS) [18,21] or with both PFS and OS [24,32]. On the other hand, few studies denied these evidences showing no prognostic impact of 18F-FDG PET/CT results on PFS [18,19] and on OS [19,31,33]. 18F-FDG PET/CT results at interim were evaluated only in two articles [19,32] with controversial results: according to Kedmi et al. [19] interim PET/CT results were not associated with PFS and OS, whilst for Jeon et al. [32] significant correlation between metabolic response and PFS and OS was showed. Considering follow-up, only four studies were available [9,10,15,23] and all agreed that follow-up 18F-FDG PET/CT scans had no significant impact in the management of the MCL patients.
Prognostic role of baseline 18F-FDG PET/CT About prognostic role of 18F-FDG PET/CT in MCL, 13 papers are present in literature reporting controversial results (Table 6). Firstly, Karam et al. [11] in 81 patients demonstrated that SUVmax using a cutoff of 5 could predict poorer OS and FFS (failure free survival), but subsequent works [12,15] using a threshold of 6 of SUVmax did not show any correlation with outcome survival. Other two papers evaluated SUVmax with opposite results: in the first [29] with a cutoff of 10.3 a significant correlation with both PFS and OS was reported; in the second [30] with a cutoff of 4.7 no significant association was demonstrated. Metabolic tumor volumes parameters, like MTV and TLG, were studied in only two papers [29,30] showing significant correlation with outcome survival, but confirmed at multivariate analysis only in the second one [30]. In a recent study, Albano et al. [30] studied for first time other baseline metabolic parameters (SUVbsa, SUVlbm, lesion to liver SUV ratio and lesion-to blood pool SUV ratio) and demonstrated no correlation with PFS and OS. Texture analysis was studied only in one paper [31] with promising results: a combination of SUVmean and Entropy features resulted significantly correlated with 2-year PFS.
6
DISCUSSION The value of 18F-FDG PET/CT in evaluating MCL is still under debate because it is not yet understood if this lymphoma histotype is 18F-FDG avid or not. This doubt derived also by the low number of studied and patients evaluated in literature, in comparison with other more diffuse lymphomas, like HL, DLBCL and FL. In our review, detection rate of MCL nodal disease at 18F-FDG PET/CT was good with an average sensitivity of 97.5% and an average specificity of 100% [9,10,12,13,17,28,29,33]. The accuracy in studying MCL disease is quite low considering BM and GI involvement (Table 3). The detection of extranodal disease is very important for staging accurately MCL patients as advanced stage. Both BM and GI tract are difficult setting to investigate with 18F-FDG due to the presence of physiological uptake of this radiotracer in several inflammatory and functional conditions. Accurate analysis of BM involvement in patients affected by lymphoma is fundamental but it may be a challenge owing to sampling errors; it has been previously demonstrated that 30% of patients will show unilateral positive BM that could have been missed [34]. Moreover, the BM biopsy is considered the reference standard for assessment of BM disease by lymphoma, but it presents some limitations: the invasive nature of the procedure, the unilateral analysis, the possible complications related to the procedure, and the very small part of BM studied sometimes not representative of the global disease. These difficulties reflect the controversial results present in literature about the detection of BM disease in NHL and HL [35,36]. It is quite shared that in DLBCL a focal 18F-FDG uptake in BM has to be considered a true positive finding and BM biopsy can be avoided; instead, in case of negative 18F-FDG PET/CT in BM the presence of BM disease cannot be excluded. For MCL the role of 18F-FDG PET/CT in studying BM involvement is limited and not well studied; only six papers [10,12,15,27,28,33] analyzed this topic. With the exception of one study [27], all other studied reported very low sensitivity and high specificity, underlying the potential usefulness of PET/CT in selecting patients with no need of BM biopsy. Also for GI evaluation with
18
F-FDG PET/CT, some issues are present. It is
possible to have not homogeneous moderate uptake in bowel and stomach due to different inflammatory and physiological states. Moreover, diabetic patients, especially in therapy with oral hypoglycemic drugs, may present an increased 18F-FDG uptake in the bowel which affect and limit the evaluation of the scan in the GI tract [37,38]. This evidence is true not only for lymphoma but for every kind of cancer. In our review, we demonstrated a low sensitivity of PET/CT in detecting GI disease and an optimal specificity. Of course the property to be 18F-FDG-avid influences the possible impact of 18F-FDG PET/CT in staging, treatment response evaluation and prognostication field. Considering MCL as an 18F-FDG-avid lymphoma, different treatment response criteria based on PET/CT were used in MCL as IHP and Deauville criteria. According to IHP criteria [39], visual analysis alone is adequate for interpreting PET findings as positive or negative after completion of therapy. For residual mass with transversal diameter more than 2 cm, mediastinal blood pool activity is recommended as the reference background activity to define PET positivity, while for smaller residual mass should be considered positive if its activity is above that of the surrounding background. But the IHP criteria was upgraded in 2009, when an alternative criteria called Deauville criteria based on the application of a five-point scale using the mediastinum and liver activity as the reference standard was proposed [40]; this scale has been recommended for reporting end of treatment PET for tracer avid lymphoma HL and several NHL, as DLBCL and FL [20,21]. Also in MCL, Deauville criteria seems to be accurate in evaluating treatment response and be correlated with outcome survival. About interim PET, many open questions remain. The potential role of baseline
18
F-FDG PET/CT parameters in prognostication is yet an open issue with controversial
results [11,12,15,29-31]. The analysis of this role is limited by several points: the first limitation is the difficulty to
7
compare the studies due to the heterogeneous population evaluated (different sample, kind of therapy, different baseline features), other limitations are the small sample of patients included and the different semiquantitative metabolic parameters studied (SUVs, ratios, MTV and TLG). So far, no strong evidence about the positive prognostic impact of 18
F-FDG PET/CT for survival outcome is available and more studies are needed to confirm or controvert these results.
SUV is the most widely utilized and generally accepted parameter in the current published literature for evaluating disease activity in lymphoma and also in MCL: it has been commonly investigated with promising results but not shared. In fact, different threshold have been proposed to discriminate between responders and not reresponders. This is probably due to the fact that it is potentially influenced by several variables, like blood glucose level, extravasation of tracer, technological features, uptake time, decay of radiotracer and partial volume effect. For these reason, other metabolic parameters (like MTV and TLG) has been introduced with the aim to overcome these issues. These parameters are considered a compromise between morphological and metabolic/functional variables because include both volumetric and metabolic characteristics and seem to be useful in predicting treatment response and prognosis in other lymphoma histotypes [41-45]. In MCL, it is premature to declare the same evidence because only two papers [29,30] investigated these parameters with controversial results.
Limitations of the studies Some limitations affect the quality of this review like the absence of multicentric and prospective studies, the low number of patients studied and the heterogeneity among the analyzed papers. This heterogeneity arises from diversity in features of the patients included, methodological aspects, reference standard used and global quality of the study.
8
CONCLUSION Despite several limitations, MCL may be considered an 18F-FDG-avid histotype lymphoma in nodal localizations; on the other hand, 18F-FDG PET/CT has low accuracy for GI and BM involvement of MCL. Also in staging and treatment response evaluation 18F-FDG PET/CT seems to be helpful, changing the stage and the subsequent management in some cases. Instead the prognostic value of 18F-FDG PET/CT, despite promising preliminary results, is not yet clear. More extensive studies, maybe prospective and multicentric, are desirable to suggest its possible introduction in the diagnostic flow chart.
9
COMPLIANCE WITH ETHICAL STANDARDS Conflict of interest The authors declare they have no conflict of interest.
Author contributions Domenico Albano: study design, data analysis, article writing, and final approval of the manuscript. Maria Gazzilli, Elisabetta Cerudelli: literature search, data analysis and final approval of the manuscript. Giorgio Treglia, Raffaele Giubbini: study design, article writing, and final approval of the manuscript. Francesco Bertagna: data analysis, article writing, and final approval of the manuscript
10
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Gill S, Wolf M, Miles Prince H, et al. 18F Fluorodeoxyglucose positron emission tomography scanning for staging, response assessment, and disease surveillance in patients with Mantle cell lymphoma. Clin Lymphoma Myeloma Leuk 2008;8:158-165.
10 Brepoels L, Stroobants S, De Wever W, et al. Positron emission tomography in mantle cell lymphoma. Leuk Lymphoma 2008;49:1693-1701.
11 Karam M, Ata A, Irish K, et al. FDG positron emission tomography/computed tomography scan may identify mantle cell lymphoma patients with unusually favorable outcome. Nucl Med Comm 2009;30:770-778.
12 Bodet-Milin C, Touzeau C, Leux C, et al. Prognostic impact of 18F-fluorodeoxyglucose positron emission tomography in untreated mantle cell lymphoma: a retrospective study from GOELAMS group. Eur J Nucl Med Mol Imaging 2010;37:1633-1642.
13 Weiler-Sagie M, Bushelev O, Epelbaum R, et al. (18)F-FDG avidity in lymphoma readdressed: a study of 766 patients. J Nucl Med. 2010;51:25–30.
14 Mato AR, Svodoba J, Feldman T, et al. Post-treatment (not interim) positron emission tomography-computed tomography scan status is highly predictive of outcome in Mantle Cell Lymphoma patients treated with RHyperCVAD. Cancer 2012;118:3565-3570.
15 Hosein PJ, Pastorini VH, Paes FM, et al. Utility of positron emission tomography scans in mantle cell lymphoma. Am J Hematol 2011;86:841-845.
11
16 Tateishi U, Tatsumi M, Terauchi T, et al. Relevance of monitoring metabolic reduction in patients with relapsed or refractory follicular and mantle cell lymphoma receiving bendamustine: a multicenter study. Cancer Sci 2011;102:414-418.
17 Alavi A, Shrikanthan S, Aydin A, et al. Fluorodeoxyglucose-positron-emission tomography findings in Mantle cell lymphoma. Clin Lymphoma Myeloma Leuk 2011;11:261-266.
18 Cohen JB, Hall NC, Ruppert AS, et al. Association of pre-transplantation positron emission tomography/computed tomography and outcome in mantle cell lymphoma. Bone Marrow Transplant 2013;48:1212-1217.
19 Kedmi M, Avivi I, Ribakovsky E, et al. Is there a role for therapy response assessment with 2-[fluorine-18] fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in mantle cell lymphoma? Leuk Lymphoma 2014;55:2484-2489.
20 Magnusson E, Cao Q, Linden MA, et al. Hematopoietic cell transplantation for mantle cell lymphoma: predictive value of pretransplant positron emission tomography/computed tomography and bone marrow evaluations for outcomes. Clin Lymphoma Myeloma Leuk 201;14:114-121.
21 Czuczman MS, Goy A, Lamonica D, et al. Phase II study of bendamustine combined with rituximab in relapsed/refractory mantle cell lymphoma: efficacy, tolerability, and safety findings. Ann Hematol 2015;94:2025-2032.
22 Htet S, Lane S, Kipp D, et al. PET-CT confirmed complete remission and MRD negativity in mantle cell lymphoma patients treated with R-hyper-CVAD results in excellent outcome in the absence of autologous stem cell transplantation: a singlecentre case for a transplant-free approach. Intern Med J 2016;46:1113-1114.
23 Guidot DM, Switchenko JM, Nastoupil LJ, et al. Surveillance imaging in mantle cell lymphoma in first remission lacks clinical utility. Leukemia Lymphoma 2017;59:888-895.
24 Lamonica D, Graf AD, Munteanu MC, et al. 18F-FDG PET for Measurement of Response and Prediction of Outcome to Relapsed or Refractory Mantle Cell Lymphoma Therapy with Bendamustine–Rituximab. J Nucl Med 2017;58:62-68.
25 Mei MG, Cao TM, Chen L, et al. Long-Term Results of High-Dose Therapy and Autologous Stem Cell Transplantation for Mantle Cell Lymphoma: Effectiveness of Maintenance Rituximab. Biol Blood Marrow Transplant 2017;23:1861-1869.
26 Klener P, Fronkova E, Belada D, et al. Alternating R CHOP and R cytarabine is a safe and effective regimen for transplant ineligible patients with a newly diagnosed mantle cell lymphoma. Hematol Oncol 2018 36;110115.
27 Morgan R, Perry M, Kwak J, et al. Positron emission tomography-based analysis can accurately predict bone marrow involvement with Mantle Cell Lymphoma. Clin Lymphoma Myeloma Leuk 2018;18:731-736.
28 Albano D, Ferro P, Bosio G, et al. Diagnostic and Clinical Impact of Staging 18F-FDG PET/CT in Mantle-Cell
12
Lymphoma: A Two-Center Experience.Clin Lymphoma Myeloma Leuk. 2019;19:e457-e464.
29 Bailly C, Carlier T, Berriolo-Riedinger A, et al. Prognostic value of FDG-PET in patients with mantle cell lymphoma: results from the LyMa-PET Project. Haematologica. 2019 doi: 10.3324/haematol.2019.223016.
30 Albano D, Bosio G, Bianchetti N, et al. Prognostic role of baseline 18F-FDG PET/CT metabolic parameters in mantle cell lymphoma. Ann Nucl Med 2019. Doi 10.1007/s12149-019-01354-9
31 Mayerhoefer ME, Riedl CC, Kumar A, et al. Radiomic features of glucose metabolism enable prediction of outcome in mantle cell lymphoma. Eur J Nucl Med Mol Imaging. 2019 doi: 10.1007/s00259-019-04420-6
32 Jeon YW, O JH, Park KS, et al. Prognostic impact of interim positron emission tomography in mantle cell lymphoma patients treated with frontline R-CHOP. Br J Haematol 2019; doi: 10.1111/bjh.16257
33 Albano D, Laudicella R, Ferro P, et al. The Role of 18F-FDG PET/CT in Staging and Prognostication of Mantle Cell Lymphoma: An Italian Multicentric Study. Cancers (Basel) 2019;21:11.
34 Juneja SK, Wolf MM, Cooper IA. Value of bilateral bone marrow biopsy specimens in non-Hodgkin’s lymphoma. J Clin Pathol 1990; 43:630-2.
35 Adams HJA, Kwee TC, de Keizer B, et al. Systematic review and meta-analysis on the diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary? Ann Oncol 2014; 25:921-7.
36 Adams HJA, Kwee TC, de Keizer B, et al. FDG PET/CT for the detection of bone marrow involvement in diffuse large B cell lymphoma: systematic review and meta-analysis. Eur J Nucl Med Mol Imaging 2014; 41:565-74.
37 Gontier E, Fourme E, Wartski M, et al. High and typical 18F-FDG bowel uptake in patients treated with metformin. Eur J Nucl Med Mol Imaging 2008;35:95–9.
38 Bybel B, Greenberg ID, Paterson J, et al. Increased F-18 FDG intestinal uptake in diabetic patients on metformin: a matched case-control analysis. Clin Nucl Med 2011;36:452–6.
39 Juweid ME, Stroobants S, Hoekstra OS, et al. Imaging Subcommittee of International Harmonization Project in Lymphoma. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 2007;25:571–578.
40 Meignan M, Gallamini A, Haioun C. et al. Report on the Second International Workshop on interim positron emission tomography in lymphoma held in Menton, France, 8–9 April 2010. Leuk Lymphoma. 2010;51:2171–2180.
41 Albano D, Bosio G, Camoni L, et al. Prognostic role of baseline 18F-FDG PET/CT parameters in MALT lymphoma. Hematol Oncol 2019;37:39-46.
42 Cottereau AS, Lanic H, Mareschal S, et al. Molecular Profile and FDG-PET/CT Total Metabolic Tumor Volume Improve Risk Classification at Diagnosis for Patients with Diffuse Large B-Cell Lymphoma. Clin Cancer Res 2016;22:3801-3809.
43 Toledano MN, Desbordes P, Banjar A, et al. Combination of baseline FDG PET/CT total metabolic tumour volume and gene expression profile have a robust predictive value in patients with diffuse large B-cell lymphoma. Eur J Nucl Med Mol Imaging 2018;45:680-688.
44 Albano D, Bosio G, Pagani C, et al. Prognostic role of baseline 18F-FDG PET/CT metabolic parameters in Burkitt lymphoma. Eur J Nucl Med Mol Imaging 2019;46:87-96.
13
45 Albano D, Bertoli M, Battistotti M, et al. Prognostic role of pretreatment 18F-FDG PET/CT in primary brain lymphoma. Ann Nucl Med 2018;32:532-541.
14
FIGURE LEGENDS Figure 1 Literature search flow-chart
15
Table 1: the main features of papers selected
First Author Gil [9]
Year 2008
Country Australia
Study design Retrospective
N° MCL patients 28
M:F 20:8
Age mean (range) 59* (33-82)
Brepoels [10]
2008
Belgium
Retrospective
37
28:9
58* (36-77)
Karam [11] Bodet-Milin [12] Weiler-Sagie [13] Mato [14] Hosein [15] Tateishi [16] Alavi [17] Cohen [18] Kedmi [19] Magnusson [20] Czuczman [21] Htet [22] Guidot [23] Lamonica [24] Mei [25] Klener [26]
2009 2010 2010 2011 2011 2011 2011 2013 2014 2014 2016 2016 2017 2017 2017 2018
Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Prospective Retrospective Prospective
81 44 14 53 52 10 20 29 58 66 45 12 204 32 191 73
na 29:15 na na 40:12 6:4 13:7 25:4 49:9 63:13 32:13 10:2 Na 22:10 142:49 49:24
na 62* (43-80) na 58 (35-74) 58* (39-92) 71* (59-75) 59 60* (37-73) 59* (41-88) 58 (34-73) 70* (48-88) 57* (42-69) na 68 (52-78) 59* (33-76) 70 (58-83)
Morgan [27] Albano [28] Bailly [29]
2018 2019 2019
USA-Belgium France Israel USA USA Japan USA USA Israel USA USA Australia USA USA USA Czech Republic USA Italy France
Retrospective Retrospective Retrospective
11 123 104
8:3 91:31 78:26
60.5 66 (29-88) 57* (41-65)
Albano [30] Mayerhoefer [31] Jeon [32] Albano [33]
2019 2019 2019 2019
Italy USA Korea Italy
Retrospective Retrospective Retrospective Retrospective
87 107 89 229
65:22 72:35 72:17 172:57
65 (29-88) 64.5 (na) 64* (26-84) 65 (29-88)
Purpose Staging, treatment response, followup Staging, treatment response, prognosis, follow-up Staging, Prognosis Staging, Prognosis Staging Prognosis Staging, Prognosis, Follow-up Treatment response Staging Treatment response, prognosis Treatment response Treatment response, prognosis Treatment response Treatment response Follow-up Treatment response, prognosis Treatment response Treatment response, prognosis Staging Staging Staging, treatment response, prognosis Treatment response, prognosis Prognosis Treatment response, prognosis Staging, treatment response and prognosis
*median value MCL: Mantle Cell lymphoma; M: male; F: female; na: not available
Table 4: summary of main evidences of literature about staging purpose of 18F-FDG PET/CT in MCL comparing with conventional imaging Author
N° upstage (%)
N° downstage (%)
Change of stage acc. Ann Arbor
Gill [9]
1/9 (11%)
0/9 (0%)
II→ III
Brepoels [10]
9/24 (37.5%)
2/24 (8%)
na
Hosein [15]
1/34 (4%)
0/34 (0%)
III → IV n 1
Alavi [17]
4/19 (21%)
1/19 (5%)
na
Albano [28]
21/123 (17%)
2/123 (2%)
I or II → III n 19 III → IV n 2 III → II n 2
Na: not available
n1
Table 2: main technical aspects First Author
Device
18F-FDG mean injected dose Uptake time Image analysis min MBq
Semiquantitative parameters
Gil [9]
PET & PET/CT
na
60
Visual and semiquantitative SUVmax
Brepoels [10]
PET/CT
na
na
Visual and semiquantitative SUVmax
Karam [11]
PET & PET/CT
444-666
60-75
Visual and semiquantitative SUVmax
Bodet-Milin [12]
PET & PET/CT
5-7 MBq/Kg
60-80
Visual and semiquantitative SUVmax
Weiler-Sagie [13]
PET/CT
370-555
60-90
Visual
Mato [14]
PET/CT
na
na
Visual and semiquantitative SUVmax
Hosein [15]
PET & PET/CT
1.65-5.1 MBq/Kg
60-90
Visual and semiquantitative SUVmax
Tateishi [16]
PET/CT
3.5-5 MBq/Kg
60
Visual and semiquantitative SUVmax
Alavi [17]
PET
1,.5-5.1 MBq/Kg
60
Visual
Cohen [18]
PET/CT
na
na
Visual
Kedmi [19]
PET/CT
na
na
Visual
Magnusson [20]
PET/CT
na
na
Visual
Czuczman [21]
PET/CT
na
na
Visual
Htet [22]
PET/CT
na
na
Visual
Guidot [23]
PET/CT
na
na
Visual
Lamonica [24]
PET/CT
370-740
50-70
Visual
Mei [25]
PET/CT
na
na
Visual
Klener [26]
PET/CT
na
na
Visual
Morgan [27]
PET/CT
na
na
Visual and semiquantitative SUVmax, SUVmean
Albano [28]
PET/CT
3.5-4.5 MBq/Kg
60 ± 10
Visual
Bailly [29]
PET/CT
na
na
Visual and semiquantitative SUVmax, SUVpeak, MTV and TLG
Albano [30]
PET/CT
3.5-4.5 MBq/Kg
60 ± 10
Visual and semiquantitative SUVbw, SUVlbm, SUVbsa, Lesion-to-liver SUVmax ratio, Lesion-toblood pool SUVmax ratio, MTV, TLG
Mayerhoefer [31]
PET/CT
444-552
60
Visual, semiquantitative and SUVmax, SUVmean, radiomics SUVpeak, MTV, TLG, + 17 radiomic features
Jeon [32]
PET/CT
na
na
Visual
Albano [33] PET/CT 3.5-4.5 MBq/Kg 60 ± 10 Visual MBq: megabecquerel; SUV: standardized uptake value; bw: body weight; lbm: lean body mass; bsa: body surface area; MTV: metabolic tumour volume; TLG: total lesion glycolysis; na: not available
Table 3: summary of main evidences concerning 18F-FDG-avidity in staging MCL Nodal disease Specificity
Gastrointestinal disease
PPV
NPV
Sensitivity
Author
Sensitivity
Gil [9]
100%
/
100%
/
na
na
na
na
na
na
na
na
Brepoels [10]
100%
/
100%
/
na
na
na
na
12.5%
100%
80%
100%
Bodet-Milin [12]
90%
100%
100%
92%
11%
100%
100%
81%
12%
100%
100%
64%
Weiler-Sagie [13] 100%
/
100%
/
na
na
na
na
na
na
na
na
Hosein [15]
na
na
na
na
20%
100%
100%
64%
12%
100%
100%
26%
Alavi [17]
90%°
100%°
na
na
na
na
na
na
na
na
na
na
Morgan [27]
na
na
na
na
na
na
na
na
100%
87.5%
85%
100%
Albano [28]
100%
/
100%
/
64% 78%*
92% 92%*
69% 72%*
90% 94%*
52%
98%
97%
65%
Bailly [29]
100%
/
100%
/
na
na
na
na
na
na
na
na
99%
93%
90%
27%
100%
100%
48%
Albano [33] 100% / 100% / 60% *excluding patients with diabetes mellitus type 2 ° global accuracy (considering both nodal and extranodal disease) na: not available; PPV: positive predictive value; NPV: negative predictive value.
Specificity
Bone marrow disease
PPV
NPV
Sensitivity
Specificity
PPV
NPV
Table 5: summary of papers evaluated treatment response Authors
Criteria of PET/CT response
Type of therapy
Main findings
Gil [9]
nr
Different CMT regimens (+6 ASCT)
High accuracy in evaluating treatment response
Brepoels [10]
EORTC
Different CMT regimens (+5 ASCT)
Significant impact on PFS
Tateishi [16]
IHP
Bendamustine
High accuracy in evaluating relapse
Cohen [18]
IHP
Pre ASCT
Significant impact on OS (p 0.007); no impact on PFS (p 0.054)
Kedmi [19]
IHP
35 R-CHOP or R-CHOP like CMT 24 + BEAM and ASCT
No impact on OS and PFS
Magnusson [20] IHP
Pre allogenic SCT and ASCT
Significant impact on DFS
Czuczman [21]
Deauville criteria
Bendamustine + Rituximab
Significant impact on OS
Htet [22]
nr
R-hyper-CVAD
Combination of PET/CT and BMB results may predict response therapy.
Lamonica [24]
Deauville criteria
Bendamustine + Rituximab
Significant impact on PFS, OS and DOR
Mei [25]
nr
Pre ASCT
PET/CT helped to stratify patients response
Klener [26]
IHP
Alternating R-CHOP/R-HDAC
Significant impact on PFS
Albano [30]
Deauville criteria
21 R-BAC, 56 R-CHOP or alternating Significant impact on PFS, not on OS R-CHOP/R-HDAC, 10 R-ASCT
Jeon [32]
Deauville criteria
R-CHOP
Albano [33]
Deauville criteria
Significant impact on PFS and OS of interim PET/CT
82 R-CHOP, 68 R-DHAP, 39 RSignificant impact on PFS, not on OS Bendamustina, 24 BCVPP, 12 MBVD nr: not reported; IHP: International Harmonization Project; EORTC: European Organisation for research and Treatment of Cancer; CMT: chemotherapy; ASCT: autologous stem cell transplant; PFS: progression free survival; OS: overall survival; DFS: disease free survival; DOR: duration of response
Table 6: summary of studied evaluating prognostic role of 18F-FDG PET/CT First author
Total patients Parameters considered evaluated
Main findings
Karam [11]
81
pretreatment SUVmax ≤5; >5
Correlation with OS and FFS
Bodet-Milin [12]
44
pretreatment SUVmax<6; ≥6
No correlation with OS and EFS
Hosein [15]
52
pretreatment SUVmax ≤6; >6
No correlation with OS and PFS
Bailly [29]
104
pretreatment SUVmax (≤10.3; >10.3), MTV (≤41.47; >41.47) and TLG
SUVmax correlated with PFS and OS MTV correlated with PFS and OS only at univariate analysis
Albano [30]
81
pretreatment SUVbw, SUVlbm, SUVbsa, LBP SUV R, L-L SUV R, MTV & TLG*
MTV and LTG correlated with end of treatment response, OS and PFS
Mayerhoefer [31]
107
pretreatment radiomic signature includng SUVmean and Entropy * dichotomized using ROC curve analysis OS: overall survival; EFS: event free survival; FFS: failure free survival
Correlation with PFS