Reply to H.J adams et al: “Is <scp>FDG‐PET/CT</scp> a sensitive and specific method for the detection of extranodal involvement in diffuse large <scp>B</scp>‐cell lymphoma?”
Authors: Tarec Christoffer El‐Galaly, Martin Hutchings, Diego Villa
Journal: American Journal of Hematology (2015)

To the Editor: We thank Adams et al. for their interest in our article “Outcome prediction by extranodal involvement, IPI, R-IPI, and NCCN-IPI in the PET/CT and rituximab era: A Danish-Canadian study of 443 patients with diffuse-large B-cell lymphoma” 1. The purpose of our study was to examine the prognostic value of PET/CT-detected extranodal disease in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP (-CHOP-like) and to validate prognostic scores 2-4. We conclude that the IPI, R-IPI, and NCCN-IPI (in modified form) remain highly prognostic in PET/CT staged DLBCL, and that the number of extranodal sites in itself appears to be a valuable discriminator of outcome 1. In the correspondence, Adams et al. share views on PET/CT for evaluation of extranodal lymphoma and reiterate relevant concerns regarding PET/CT for bone marrow evaluation as well as the prognostic role of PET/CT-ascertained bone marrow involvement 5-8. While the latter is a topic of discussion in our article, the first two topics fall outside its scope. The first question is whether PET/CT has high sensitivity to detect extranodal disease/bone marrow involvement. This statement was based on earlier studies reporting an upstaging by PET/CT in up to 41% of patients with non-Hodgkin lymphoma (mainly DLBCL), which was often caused by detection of additional extranodal disease 9, 10. Adams et al. suggest that our data do not support a high sensitivity for extranodal DLBCL. We fully agree with this, since our study, as discussed in the limitations section, does not include a comparison between PET/CT and CT staged patient. We also agree with Adams et al. that the true nature of most extranodal lesions detected by PET/CT is unknown and that FDG-accumulation is no ultimate proof of malignancy. For this study (and for daily clinical purposes), however, we chose a pragmatic approach in which we assume that abnormal FDG-uptake found suspicious for lymphoma represents DLBCL. Confirmatory biopsies of FDG-avid lesions over and above what is required for standard of care are neither ethically nor logistically feasible. Schaefer et al. found non-Hodgkin lymphoma (including DLBCL) in biopsies targeting FDG-avid lesions in the bone marrow 11. Adams et al. reported poor concordance between iliac crest FDG-uptake and routine bone marrow biopsy (BMB) from the site in DLBCL 12. Specifically targeting the bone marrow site with highest FDG-uptake for biopsy, however, would be more reasonable when evaluating clinically relevant concordance between PET/CT and BMB. How would the sensitivity of BMB change if bone marrow lesions with the highest FDG uptake were consequently selected for biopsy site and as the reference standard? We can only speculate. The second point to which Adams et al. disagree is the prognostic value of PET/CT-ascertained bone marrow involvement in DLBCL (focal PET/CT lesions), which, as clearly stated in our paper, remains ambiguous. Still Adams et al. feel we discussed the part inappropriately. Khan et al. reported that the outcome of patients with focal PET/CT lesions in the bone marrow was similar to that of other patients with stage IV disease without bone marrow involvement 10. Outcome was worse for patients with positive BMB, but these patients often had other high-risk features 10. Berthet el al found independent prognostic value of PET/CT-ascertained bone marrow involvement in multivariate analysis, while Cerci et al. (not cited in our article) reported adverse outcome in patients with PET/CT-ascertained bone marrow involvement only when BMB was concordantly positive, and vice versa 13, 14. The results of Cerci et al. clearly question the prognostic relevance of searching for bone marrow involvement in PET/CT negative cases 13. In a retrospective cohort study by Adams’ own group, focally increased FDG uptake in the bone marrow was not prognostic for PFS or OS. However, because of the small number of patients the analysis is likely underpowered and 34/78(44%) of patients had PET/CT-detected bone marrow involvement, which is higher than usually reported 1, 10, 13-16. Our study supports an independent prognostic value of PET/CT-ascertained bone marrow involvement, but we do not “claim” prognostic irrelevance of BMB, as accused by Adams et al. The fact that positive BMB was only prognostic in univariate analysis rather reflects the interplay with other important prognostic factors. As in a previous letter, Adams et al. indicate that failure to include imaging-detected bone marrow disease in the NCCN-IPI in contrast to BMB-ascertained bone marrow disease supports prognostic irrelevance of imaging-detected bone marrow disease 3, 5. However, it is worth noting that PET/CT staging was not mandatory in the cohorts that gave rise to the NCCN-IPI 3, 17. At present, we are evaluating the prognostic role of focal PET/CT lesions in further analyses to add further clarity to this ambiguity of PET/CT-ascertained bone marrow lesions in DLBCL. In our discussion, we state that our data may suggest that BMB is not necessary in PET/CT-staged patients, but conclude that more comprehensive exploration is needed. This evokes the third objection by Adams et al. We are aware that some previous studies, including large series and our own data, have shown suboptimal sensitivities of PET/CT to detect bone marrow involvement by BMB 13, 16, 18. The Lugano classification recommends BMB in patients without evidence of bone marrow involvement by PET/CT and only if finding of a discordant histology is relevant for patient management 19. We acknowledge the risk of missing DLBCL and discordant indolent histology in the bone marrow if routine BMB is not performed as part of the routine staging work-up 14, 18, 20. However, the guidelines apply a critical view on the added diagnostic value of an invasive diagnostic procedure like BMB. For many patients BMBs are associated with anxiety and pain 21. Thus, the discussion of PET/CT versus BMB in DLBCL should not be a discussion of sensitivities alone, but need to include all aspects 5. Staging does not serve its own purpose, but guides treatment decisions and provides baseline information for treatment response assessment. In the current landscape of R-CHOP(-like) therapy for DLBCL, it seems unlikely that indiscriminate use of BMB will alter treatment in a relevant number of patients. Last but not least, future treatment decisions will hopefully be guided by the biological heterogeneity of DLBCL rather than by bone marrow disease detected by BMB (or PET/CT) 22. Tarec Christoffer El-Galaly1* Martin Hutchings2 Diego Villa3 1Department of Hematology, Aalborg University Hospital, Aalborg, Denmark; 2Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 3Division of Medical Oncology, British Columbia Cancer Agency Centre for Lymphoid Cancer and the University of British Columbia, Vancouver BC, Canada