Annals of Oncology Advance Access originally published online on September 15, 2006
Annals of Oncology 2006 17(12):1761-1765; doi:10.1093/annonc/mdl295
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© 2006 European Society for Medical Oncology
hematologic malignancies |
18F-Fluoro-deoxy-glucose positron emission tomography in lymphoma of mucosa-associated lymphoid tissue: histology makes the difference
1 Department of Nuclear Medicine, Medical University Vienna, Vienna, Austria
2 Department of Pathology, Medical University Vienna, Vienna, Austria
3 Department of Internal Medicine I, Medical University Vienna, Vienna, Austria
* Correspondence to: Dr M. Hoffmann, Department of Nuclear Medicine, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel: +43 (0)1 40400 5274; Fax: +43 (0)1 40400 5552; E-mail: martha.hoffmann{at}meduniwien.ac.at
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Abstract |
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Background: The usefulness of 2-[fluorine-18]fluoro-2-deoxy-D-glucose Positron emission tomography (18F-FDG–PET) in lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is still a matter of debate, and conflicting results have been reported. We have evaluated whether the histological feature of plasmacytic differentiation (PD) might explain the heterogeneous behavior of MALT lymphoma regarding 18F-FDG uptake.
Patients and methods: A total of 35 patients with a diagnosis of MALT lymphoma referred to our PET unit were studied. Whole-body 18F-FDG–PET scans were carried out on a General Electrics advanced PET scanner 40 min after i.v. injection of 300–380 MBq 18F-FDG. Images were reconstructed iteratively. In areas with focally elevated FDG uptake, standard uptake values (SUVs) were calculated.
Results: A total of 19 patients had MALT lymphoma with plasmacytic differentiation (pMALT), while MALT lymphoma without plasmacytic features was diagnosed in 16 patients. Sixteen of 19 patients with PD showed significant 18F-FDG uptake in involved sites (SUV: 3.5–11.7). By contrast, 13 of 16 patients with normal MALT lymphoma showed a false-negative 18F-FDG–PET result. Two of these patients disclosed no tracer uptake in the majority of involved sites apart from one single lesions, while three had a true-positive 18F-FDG–PET scan (SUV: 3.4–6.0).
Conclusions: 18F-FDG–PET visualizes pMALT in a high proportion of patients, whereas FDG–PET results are significantly less reliable in typical MALT (P = 0.001). This finding may partly account for the heterogeneous results of 18F-FDG–PET-studies in MALT lymphoma.
Key words: 18F-FDG–PET, imaging, MALT lymphoma, plasmacytic differentiation
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Extranodal marginal zone (MZ) B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a distinct clinicopathological entity initially defined by Isaacson and Wright [1], which has been incorporated into the World Health Organization (WHO) classification of hematological malignancies [2]. Due to its unique clinical properties and the presence of a common mucosal immunity linking the various organs involved in mucosal immunity [3], MALT lymphoma requires an extensive staging routine to assess the extent of the disease before initiation of treatment [4].
Positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) is a widely accepted imaging tool for staging and follow-up of non-Hodgkin lymphomas irrespective of indolent or aggressive behavior [5–9]. Divergent results, however, have been reported for imaging of MALT lymphoma using 18F-FDG–PET [10–12].
The postulated cell of origin of MALT lymphoma is the MZ B cell, which corresponds to a post-germinal-center B cell with rearranged and mutated immunoglobulin heavy and light chain genes. These MZ B cells apparently display the capacity to differentiate into plasma cells. In keeping with this hypothesis, MALT lymphomas often include high numbers of plasma cells, a phenomenon termed plasmacytic differentiation (PD). This feature is found in up to 30% of MALT lymphomas [2, 13], but is especially prominent in a special, albeit rare type of MALT lymphoma termed immunoproliferative small intestinal disease [14, 15]. It may also explain cases initially described as extramedullary plasmacytoma within classical MALT organs, such as the gastrointestinal (GI)-tract, which might in fact be MALT lymphomas with extreme PD. In a recent report, we have found high focal uptake of 18F-FDG in a patient with MALT lymphoma having undergone prior treatment with the anti-CD20 antibody (Ab) rituximab [13]. In case of this patient, Ab treatment had resulted in a clonal selection by totally eliminating CD20-positive MZ cells with subsequent overgrowth of the plasmacytic component, as verified by multiple biopsies. The finding of high 18F-FDG uptake in this patient with exclusive plasma cell histology is in keeping with reports suggesting 18F-FDG–PET as a reliable staging method for multiple myeloma [16, 17]. While no information on the presence of PD in patients with MALT lymphoma included in studies on 18F-FDG–PET so far has been provided, one might hypothesize that the ongoing discussion about 18F-FDG–PET in MALT lymphoma may, in part, be due to the variable histology of MALT lymphoma and a potential influence of PD on 18F-FDG–PET imaging results.
We have therefore initiated a study to evaluate 18F-FDG–PET for imaging of plasmacytically differentiated MALT lymphoma (pMALT) as compared to a control group of consecutive MALT lymphoma patients without plasmacytic features imaged at our institution. In addition, we have also assessed the influence of proliferative activity and MALT lymphoma-specific genetic changes including t(11;18)(q21;q21), t(14;18) involving IGH and MALT1, t(1;14)(p22;q32) and trisomies 3 and 18 on imaging results.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Patients with a diagnosis of pMALT were studied, and patients with typical MALT lymphoma referred for 18F-FDG–PET imaging at our institution during the same time span were retrospectively evaluated as a control group. In all patients identified, reassessment of histological specimens was carried out by a reference hematopathologist (AC). Histopathological diagnosis was established according to the criteria defined in the recent WHO classification for MALT lymphoma [2]. In all patients, immunologic phenotyping on paraffin sections was done for demonstration of heavy and light chain restriction and for the phenotype CD20+CD5-CD10-cyclinD1- which, in context with the microscopic appearance, is consistent with MALT lymphoma. PD was defined as the presence of sheets of light chain-restricted plasma cells. In addition, assessment of MALT lymphoma-specific translocations was carried out in all patients on paraffin-embedded biopsy sections. Paraffin-embedded biopsy samples were tested for MALT lymphoma-specific genetic aberrations including t(11;18)(q21;q21), t(14;18)(q32;q21) involving IGH and MALT1, t(1;14)(p22;q32) and trisomies 3 and 18. t(11;18)(q21;q21) involving API2 and MALT1 was assessed by RT-PCR, t(14;18)(q32;q21) involving IGH and MALT1, t(1;14)(p22;q32) involving BCL10 and IGH and trisomies 3 and 18 were investigated by fluorescence in situ hybridization.
All patients underwent staging including gastroscopy with multiple biopsies, endosonography of the upper GI-tract, computed tomography (CT) of thorax and abdomen, lymph-node sonography, colonoscopy with multiple biopsies, otorhinolarnygologic assessment, magnetic resonance imaging of salivary and lacrimal glands and bone marrow biopsy according to our standard protocol [4].
Whole-body-18F-FDG–PET scans were carried out using a dedicated full-ring PET scanner (Advance; General Electric Medical Systems, Milwaukee, WI) with an axial field of view of 15.2 cm. Patients were asked to fast for at least 4 h before 18F-FDG-application. 18F-FDG–PET scans were started not earlier than 40 min following the i.v. bolus injection of 
380 MBq of 18F-FDG. In case of lymphoma involvement of the orbit, the patients were asked to close their eyes and a blindfold was administered to avoid eyeball movements. In most patients, the following scan parameters were used: Emission scans of 5-min acquisition time per table position and subsequent transmission scans with 75 000 000 counts per bed position using the built-in 67Ge/68Ga rod sources were obtained. The images were reconstructed iteratively with ordered-subset expectation maximization. The images were assessed visually on axial, coronary and sagittal reconstruction and the multi-intensity projection image by identifying regions with significantly elevated nonphysiologic 18F-FDG uptake. In addition, we applied a semiquatitative analysis using the max standard uptake value (SUV) as activity in the region of interest (ROI) standardized to body weight. ROIs were drawn manually around areas of abnormal 18F-FDG uptake. The highest SUV per patient was used for statistical analyses. The 18F-FDG–PET scans were compared with conventional staging results and clinical outcome for each patient and the findings were classified as true positive, true negative, false positive or false negative.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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A total of 19 patients with pMALT were imaged, while 16 consecutive patients with typical MALT lymphoma also underwent 18F-FDG–PET imaging during the same time span (for patient characteristics see Table 1). Eight patients presented with gastric MALT lymphoma, while the remaining 27 cases had been diagnosed with extragastric MALT lymphoma. The exact details of disease extent are given in Table 1. The majority of patients (23 of 35; 66%) underwent 18F-FDG–PET at initial diagnosis and 12 patients (34%) at relapse.
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MALT lymphoma-specific genetic aberrations were detected in 14 patients (for details see Table 1), with six of 19 pMALT patients harboring a chromosomal aberration.
Overall, a sensitivity of 54% was found, with 19 of 35 patients rated true positive with max SUV levels of 3.5–11.7 in involved sites (Figure 1), while 16 were found to be false negative on 18F-FDG–PET (Table 2). Among the patients rated false negative, two patients showed mixed results with 18F-FDG–PET negativity in the majority of documented lesions apart from one single focal 18F-FDG-accumulation (Table 1, Patients No. 30 and 31). Eleven of the 27 patients with extragastric MALT lymphoma had their primary site in the orbit. In this largest subgroup of patients, only five of 11 patients showed 18F-FDG–PET results corresponding to histology and conventional imaging (four true positive and one true negative). Diverging results were found for the two groups of patients, with 16 of 19 pMALT patients rated positive (Figure 1) as opposed to three of 16 patients with normal MALT histology (P = 0.001). Thus, a sensitivity of 84% versus 19% was found in the two groups. Apart from PD, none of the parameters studied was found to significantly influence 18F-FDG–PET results, including t(11;18)(q21;q21) (P = 1.0), t(14;18) involving IGH/MALT1 (P = 0.15), trisomy 3 (P = 0.9) and trisomy 18 (P = 0.9). In addition, the proliferative activity in terms of Ki67 staining was not significantly different between the two groups (P = 0.27), and no influence of the localization (i.e. gastric versus extragastric) and imaging at primary diagnosis versus relapse on imaging findings was detected.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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18F-FDG–PET is a widely accepted imaging tool for staging and follow-up of non-Hodgkin lymphomas irrespective of indolent or aggressive behavior [5–9]. Nevertheless, the results for MALT lymphoma are still divergent concerning the reliability of 18F-FDG. In initial series carried out at our institution, we found 18F-FDG–PET not to be a reliable method for visualizing MALT lymphoma as opposed to its nodal counterpart [10, 11]. By contrast, Beal and co-workers have recently published a series of 42 Patients with MALT lymphoma showing 18F-FDG-avidity in 80%. While the discrepancies between these reports appear remarkable, there are in fact various potential explanations that should be considered.
As also discussed by Beal and co-workers [12], one major drawback concerning our previously published series is the technique applied for imaging. All patients in our first report [10] and some included in the second series [11] were scanned without whole-body attenuation resulting in lower imaging quality. While technical possibilities resulting in higher image quality have evolved in the meantime, however, this was the best possible technique available at our institution at that time. As opposed to this, the present study has been carried out using the currently applied standards in 18F-FDG–PET-scanning. The advances of PET concerning hardware and software and the more widespread access to PET/CT will probably continue to improve imaging results. In terms of MALT lymphoma, however, a recent series investigating MALT lymphoma and reported in abstract form [18] has still shown serious shortcomings in reliably detecting MALT lymphoma sites. These findings are in keeping with our present series which suggests only a slight improvement for imaging of typical MALT lymphoma and argues against a mere ‘technical’ explanation.
Another important point when interpreting 18F-FDG–PET results is the fact that MALT lymphoma is a disease arising in an inflammatory/infectious background. In view of this, one should be extremely cautious in setting the threshold to define tracer uptake-intensity suggestive of malignancy. In addition, interpretation of 18F-FDG–PET images might vary greatly in blinded versus unblinded series, i.e. with beforehand knowledge of histology and exact localization of histologically verified sites, where also lower tracer accumulations might be accepted as positive results. In the series by Beal, the authors reported a SUV of 5.5 (range 1.4–26.0) in 34 patients rated positive. Actually a SUV of 1.4 seems to be rather low to be specific or even suspicious for malignancy, as MALT lymphoma often arises within inflammatory sites, such as the stomach or especially the orbit. For SUV levels in the orbit, results might additionally be influenced by orbital muscle activity. In our series, 11 patients with MALT lymphoma of the orbital region were included, five with pMALT showing four true-positive results and one false-negative result, respectively. The seven typical orbital MALT lymphomas showed a false-negative result in six and a true-positive result in one patient.
Due to our prior finding of impressive 18F-FDG uptake in a patient with transformation to pure plasma cell histology following rituximab [13] and in view of the positive findings reported with 18F-FDG–PET in multiple myeloma [16, 17], we have hypothesized that the feature of PD might influence 18F-FDG–PET results. In fact, a statistically significant difference was found for the sensitivity in pMALT (83%) versus typical MALT (20%). Apart from PD, no parameter investigated was found to affect imaging findings, including imaging at initial diagnosis versus relapsed patients, genetic aberrations, localization and proliferative activity in terms of Ki67 staining, which was not different between the two groups. While no information on PD was given in the series by Beal et al., our findings allow the speculation that this feature might indeed be an important contributor to positive 18F-FDG–PET imaging in MALT lymphoma. However, a note of caution should still be added when considering widespread use of 18F-FDG–PET in pMALT, as a substantial amount of lesions still remain undetected in such patients.
Taken together, our findings add a potential piece to the puzzle in order to unravel the optimal use of 18F-FDG–PET in patients with MALT lymphoma. In spite of a significantly higher sensitivity in patients with pMALT, the data obtained so far still do not justify an uncritical routine use of 18F-FDG–PET in patients with MALT lymphoma.
Received for publication July 9, 2006. Accepted for publication July 11, 2006.
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