Role of Bone Marrow Biopsy in the Staging of Diffuse Large B-Cell Lymphoma in the PET/CT Era
Authors: Alzahrani Musa F. , El-Galaly Tarec Christoffer , Hutchings Martin , Hansen Jakob Werner , Brown Peter de Nully , Loft Annika , Johnsen Hans E , Iyer Victor , Wilson Don , Sehn Laurie H. , Savage Kerry J. , Connors Joseph M. , Villa Diego 
Published: November 2019

Abstract
Background
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL) and bone marrow involvement by lymphoma is seen in up to one third of cases, as assessed by iliac crest bone marrow biopsy (BMB) at the time of diagnosis. Traditionally, BMB has been the gold standard test to detect bone marrow infiltration by lymphoma. 18-Fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET/CT), has become standard in the initial staging of DLBCL. Prior studies have suggested that PET/CT staging may obviate the need for staging BMB in patients with Hodgkin lymphoma. However, because of limited evidence, this approach has not been adopted in patients with DLBCL. We investigated whether BMB adds useful information to PET/CT staging in patients with an initial diagnosis of DLBCL.
Patients and Methods
Patients with a new diagnosis of DLBCL who underwent both staging PET/CT and BMB were retrospectively identified across three institutions: British Columbia Cancer Agency (n=149, 2011-2013), Aalborg University Hospital (n=179, 2007-2013), and Copenhagen University Hospital (n=202, 2009-2012). We reviewed the reports of PET/CT scans and BMBs from each academic institution performed at the time of diagnosis prior to treatment of DLBCL. Ann Arbor stage was determined including PET/CT with and without the contribution of BMB, and the proportion of stage IV cases by each method was calculated.
Results
530 patients were identified: median age 65 years (range 16-90), 294 (56%) male, 137 (26%) largest mass >10cm, 263 (50%) elevated LDH, 105 (20%) performance status >2, and 149 (28%) with more than one extranodal site. International Prognostic Index score was 0-1 in 159 (30%), 2 in 145 (27%), 3 in 119 (23%), and 4-5 in 107 (20%) patients. 520 (98%) received rituximab-containing chemotherapy, 130 (25%) radiotherapy, and 3 (<1%) consolidative autologous stem cell transplantation.
A total of 181 (34%) patients had bone marrow involvement established by either PET/CT (n=146, 28%), BMB (n=87, 16%), or both (n=52, 10%). Focal skeletal lesions on PET/CT were unifocal (n=42), bifocal (n=15), multifocal/diffuse (n=89). 52 of the 146 patients (36%) with positive PET/CT had a positive BMB (39 DLBCL, 13 iNHL), while 35 of the 384 patients (9%) with negative PET/CT had a positive BMB (12 DLBCL, 23 iNHL). Table 1 shows the distribution of Ann Arbor staging as defined by PET/CT alone and with inclusion of BMB results. BMB upstaged 12/209 (6%) stage I/II patients to stage IV, including 3 patients with DLBCL and 9 patients with iNHL in the bone marrow.
Focal skeletal lesions on PET/CT identified bone marrow involvement by lymphoma (DLBCL or iNHL) with sensitivity 60%, specificity 79%, positive predictive value 36%, and negative predictive value 91%. In a subgroup analysis excluding the 36 patients with iNHL in the bone marrow, focal skeletal lesions on PET/CT identified bone marrow involvement by DLBCL with sensitivity 78%, specificity 79%, positive predictive value 29%, and negative predictive value 97%.
Conclusions
In patients with DLBCL, staging PET/CT does not identify all cases with bone marrow involvement. BMB upstaged 6% of patients with stage I/II who had a PET/CT negative for any skeletal involvement. However, the majority had indolent histologies in the bone marrow, and only 1% were upstaged due to involvement of the bone marrow with DLBCL. Although PET/CT has a high negative predictive value for ruling out bone marrow involvement by high grade lymphoma, BMB remains a necessary component in the evaluation of patients with a new diagnosis of DLBCL mainly because of its ability to detect iNHL that was missed by PET/CT which may have implications in the post-treatment surveillance setting.
Table 1. Clinical staging by PET/CT alone and with inclusion of bone marrow biopsy results. Clinical Stage Staging Modality Patients upstaged to stage IV by bone marrow biopsy PET/CT alone PET/CT and bone marrow biopsy N (%) N (%) N I 121 (23) 114 (21) 7 (2 DLBCL, 5 iNHL) II 88 (17) 83 (16) 5 (1 DLBCL, 4 iNHL) III 92 (17) 77 (15) 15 (5 DLBCL, 10 iNHL) IV 229 (43) 256 (48) Not applicable

Disclosures
No relevant conflicts of interest to declare.