Overestimated value of FDG-PET based bone marrow evaluation in lymphoma: Response to Adams and Kwee.

Abstract

We would like to thank Adams and Kwee for their interest in and comments on our recently published article (Ujjani et al, 2016). We would also like thank the editors of the journal for the opportunity to continue the discussion in this issue. The purpose of our retrospective study was to confirm the role of positron emission tomography-computerized tomography (PET-CT) in detecting bone marrow involvement (BMI) in diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL) and to explore its usefulness in other types of lymphomas. We concluded that PET-CT is appropriate for DLBCL and HL, whereas bone marrow biopsy remains the standard for follicular lymphoma (FL). While Adams and Kwee do not agree with the use of FDG-PET in determining BMI for DLBCL, several published studies support this modality (Carr et al, 1998; Berthet et al, 2013; Khan et al, 2013). Furthermore, the 2014 Lugano Classification recommends PET-CT for the staging of DLBCL based on an extensive body of literature (Cheson et al, 2014). Bone marrow biopsy should only be performed if evaluating for a discordant histology, with which our findings are consistent. Adams and Kwee claim that the presence of BMI determined by FDG-PET lacks prognostic value. We would like to clarify that the combined modality of FDG-PET and CT was used to determine BMI in our analysis; FDG-uptake in the bone marrow greater than the liver and not otherwise explained by CT findings or clinical history was considered positive. Furthermore, the conclusion that FDG-PET-detected BMI has no prognostic value is premature and has yet to be prospectively analysed. In a large retrospective review of HL patients with skeletal lesions on FDG-PET, El-Galaly et al (2012) noted an inferior progression-free survival (PFS) and overall survival (OS) compared to those who did not. Berthet et al (2013) found that DLBCL patients with a negative bone marrow biopsy and FDG-uptake in the marrow had a worse PFS and OS than those who did not. Similarly, patients without BMI on PET-CT had a better PFS and OS than patients with BMI on PET-CT. BMI determined by PET-CT was an independent predictive factor of PFS in the multivariate analysis. Adams and Kwee note that the significance of diffusely increased FDG-uptake in the bone marrow varies amongst lymphomas and may bias our study results. We recognize that diffuse uptake in HL can represent reactive hyperplasia; Adams et al (2015a) have previously demonstrated that a bone marrow biopsy is likely to be negative in HL patients with these findings. Therefore, HL patients with diffuse FDG-uptake in the marrow were not empirically considered to have BMI in our analysis. Adams et al (2015a) also demonstrated that a bone marrow biopsy in non-Hodgkin lymphoma with diffuse uptake would likely be positive for BMI, therefore these patients were concluded to have BMI based on PET-CT. Adams and Kwee state that the occurrence of relapse in FL or DLBCL patients who achieve a complete remission (CR) via FDG-PET may be due to its inferiority in assessing residual lymphoma after chemoimmunotherapy. We concur that a bone marrow biopsy should be used to assess residual BMI in FL patients previously known to have BMI. It should be noted, however, that in a pooled analysis of three phase III randomized FL trials, the achievement of a PET-negative CR was associated an improvement in PFS and OS, suggesting appropriate assessment of disease status (Trotman et al, 2014). We disagree with Adams and Kwee's statement that there is a higher than expected rate of relapse in DLBCL patients who achieve a CR by PET-CT. The expected rate of relapse in DLBCL varies considerably, from 73% in the germinal centre B-cell subtype to 48% in the activated B-cell subtype (Scott et al, 2015). Adams et al (2015b) have previously demonstrated that the relapse rate in this population with FDG-PET is 7–20%, although they did not include data regarding cell of origin. Nevertheless, these results are less than previously reported with traditional methods of response and contradicts their statement. Our study did not include data regarding the additional value of FDG-PET to CT as its superiority is well-established in FDG-avid, nodal lymphomas; FDG-PET is the current standard of care for staging these malignancies. If a patient with DLBCL or HL is unable to receive a FDG-PET for treatment planning, a bone marrow biopsy would be indicated. As the procedure is painful, anxiety-provoking and can result in false-positive FDG-PET results if performed prior to imaging, we recommend that practitioners be judicious with its use.