Prognostic value of metabolic tumor volume of extranodal involvement in diffuse large B cell lymphoma

Annals of Hematology https://doi.org/10.1007/s00277-023-05165-x ORIGINAL ARTICLE Prognostic value of metabolic tumor volume of extranodal involvement in diffuse large B cell lymphoma Kana Oiwa1,2 · Kei Fujita1,3 · Shin Lee1,3 · Tetsuji Morishita4,5 · Tetsuya Tsujikawa6 · Eiju Negoro1,7 · Takeshi Hara3 · Hisashi Tsurumi3 · Takanori Ueda1 · Takahiro Yamauchi1 Received: 15 September 2022 / Accepted: 15 December 2022 © The Author(s) 2023 Abstract Extranodal involvement predicts poor outcomes of diffuse large B cell lymphoma (DLBCL), but the impact of the metabolic tumor burden (MTV) of extranodal sites using positron emission tomography has not been clarified. This study aimed to assess the impact of extranodal MTV on overall survival (OS). We retrospectively analyzed 145 newly diagnosed DLBCL patients and verified the prognostic impact of each extranodal and nodal MTV. Multivariate Cox hazards modelling using both extranodal and nodal MTV as covariables identified extranodal MTV as a significant factor for OS (hazard ratio [HR] 1.072, 95% confidence interval [CI] 1.019–1.129, P = 0.008), but not nodal MTV. Multivariate Cox modelling using restricted cubic splines demonstrated that the impact of total MTV depends on the MTV of extranodal sites, not of nodal sites. When both the number and MTV of extranodal involvements were used as covariables, extranodal MTV remained a significant predictor of OS (HR 1.070, 95%CI 1.017–1.127, P = 0.009), but the number of extranodal sites did not. Extranodal MTV potentially had a more significant role on prognosis than nodal MTV. When considering prognostic impacts, the MTV of extranodal involvement is significantly more important than the number. Keywords Extranodal involvement · Metabolic tumor burden · Positron emission tomography · Prognosis · Diffuse large B cell lymphoma Introduction Kana Oiwa and Kei Fujita contributed equally to this work. * Shin Lee 1 Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan 2 Department of Hematology and Oncology, Nagoya City University, Aichi, Japan 3 Department of Hematology and Oncology, Matsunami General Hospital, Dendai 185‑1 Kasamatsu‑Cho, Hashima‑Gun, Gifu 501‑6062, Japan 4 Department of Internal Medicine, Matsunami General Hospital, Gifu, Japan 5 Department of Healthcare Economics and Quality Management, Graduate School of Medicine, Kyoto University, Yoshida Konoe‑Cho, Kyoto, Japan 6 Department of Radiology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan 7 Department of Cancer Care Promotion Center, University of Fukui, Fukui, Japan Diffuse large B cell lymphoma (DLBCL) is the most common subtype of lymphoma, and is categorized as aggressive [1, 2]. Given the high chemosensitivity and potential curability of the disease, providing optimal treatment for each individual patient is indispensable [3, 4]. The heterogeneity of DLBCL has been identified both clinically and molecularly [5]. DLBCL with an extranodal presentation is genetically and clinically different from nodal DLBCL, showing a negative influence on prognosis [6–10]. The presence of bulky disease or elevated levels of lactate dehydrogenase (LDH) represent a high tumor burden and are also associated with adverse outcomes [11–13]. Positron emission tomography (PET) with 2-[ 18 F] fluoro-2-deoxy-D-glucose (FDG) plays an important role in the evaluation of baseline extranodal DLBCL [14, 15]. Metabolic tumor volume (MTV) measured by FDG-PET is a parameter reflecting the tumor burden, taking into account the metabolic activity of the tumor. Previous studies have demonstrated that pretreatment total MTV 13 Vol.:(0123456789) Annals of Hematology affects survival outcomes in DLBCL [16–18]. Recently, a new prognostic indicator using MTV, age, and stage has been shown to outperform the prognostic ability of the IPI (International Prognostic Index), leading to greater attention being paid to the prognostic utility of the MTV in DLBCL [19]. However, the prognostic impact of MTV in DLBCL can be expected to differ widely depending on whether extranodal or nodal disease is present. Few reports have focused on the MTV of extranodal involvement in the pretreatment assessment of DLBCL patients, despite its likely importance. The present study investigated the impact of the baseline MTV of extranodal involvement as measured by FDGPET on overall survival (OS) in patients with de novo DLBCL using multivariate Cox hazards modelling with restricted cubic splines (RCS). Furthermore, the prognostic impacts of MTV of nodal and total involvement sites were evaluated using Cox hazards modelling. Methods Patient selection We performed a retrospective, single-centre observational study from 2007 to 2017 at University of Fukui Hospital, Japan. Lymphomas were classified according to the Revised European American Lymphoma classification and the World Health Organization classification [2, 20]. Patients comprised individuals with newly diagnosed, histologically confirmed DLBCL, who were ≥ 18 years old at diagnosis and who underwent FDG-PET before treatment. Patients with post-transplant lymphoproliferative disorder, central nervous system involvement, composite disease consisting of DLBCL plus indolent non-Hodgkin’s lymphoma, human immunodeficiency virus or unassessable FDG-PET due to hyperglycaemia were excluded. To avoid bias when assessing the survival outcome, the primary transformation from indolent lymphoma was excluded in the present study. Patients who had most tumors surgically removed before the initiation of chemotherapy were also excluded. The baseline demographics and disease characteristics of patients were collected by retrospective chart review. Baseline characteristics including Eastern Cooperative Oncology Group performance status (PS), number of extranodal sites, elevated LDH level (> 222 IU/L), soluble interleukin-2 receptor (sIL-2R) level, serum albumin level, bulky mass (maximum diameter > 7.5 cm), B symptoms, bone marrow involvement, and the IPI were extracted. Comorbidities at diagnosis were assessed using the Charlson Comorbidity Index (CCI) [21]. 13 FDG‑PET and measurement of MTV All whole-body PET scans with FDG were performed using a combined PET/CT scanner (Discovery LS; GE Medical Systems), which permits simultaneous acquisition of 35 image slices in 3-dimensional acquisition mode with interslice spacing of 4.25 mm. The PET/CT scanner incorporates an integrated four-slice multidetector CT scanner, which was used for attenuation correction. CT scanning parameters were as follows: Auto mA (upper limit, 40 mA; noise index, 20); 140 kV; section thickness, 5 mm; table feed, 15 mm; and pitch, 4 mm. After fasting for at least 4 h, patients received intravenous injection of 185 MBq of FDG and image acquisition began 50 min after injection. A whole-body emission scan was performed from the head to the inguinal region, with 2 min per bed position (7–8 bed p (...truncated)