Primary Diffuse Large B-Cell Lymphoma of the Bone

Case Study 

Presentation and Diagnosis 

ML is a 74-year-old male retired rancher from a rural area with a past medical history of hypertension and obesity. He developed progressive right hip pain and swelling in the area, which acutely worsened after a fall from his horse, prompting him to go to the ED.  

Imaging showed a right hip fracture with multiple ill-defined lytic lesions throughout the femoral neck and intertrochanteric region, raising concern for a pathologic hip fracture. Hip MRI showed areas of marrow replacement with enhancement throughout the proximal right femur as well as marrow enhancement within the superior and inferior pubic ramus, right sacrum, right iliac bone, and pubic symphysis. CT scan of the chest, abdomen, and pelvis proved no lymphadenopathy but did show osseous destructive lesions with pathologic fractures at L2 and L4, as well as ill-defined hypodensities within the spleen. Laboratory findings were unremarkable except for hemoglobin 11.0 g/dL, lactate dehydrogenase (LDH) 350 IU/L (upper limit of normal [ULN] 200 IU/L), calcium 12.3 mg/dL (ULN 10.2 mg/dL), and alkaline phosphatase 200 IU/L (ULN 150 IU/L). 

Treatment 

He underwent emergent open reduction and internal fixation with biopsy of the bone lesion. Pathology revealed diffuse large B-cell lymphoma (DLBCL) germinal center B-cell (GCB) subtype, stage IV. The neoplastic cells showed a lymphoid phenotype and expressed CD20 and PAX5, as well as BCL-6, but were negative for CD10 and MUM1. Ki-67 staining was noted in more than 95% of the viable specimen. Tumor cells were negative for BCL-2 and cMYC. Bone marrow core biopsy showed 95% cellularity with extensive diffuse pattern proliferation of neoplastic lymphocytes, consistent with large B-cell lymphoma infiltration of the bone marrow. 

He was treated for his mild hypercalcemia through vigorous hydration and chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for 6 cycles followed by 45 Gy of involved field radiation. PET/CTs at both the interim (after 4 cycles of chemoimmunotherapy) and the end of treatment (EOT) showed Deauville 2. He tolerated treatment well except for grade 1 peripheral neuropathy in his feet. 

Ongoing surveillance consists of laboratory and clinical examinations, every 3 months for the first 2 years and then every 6 months and annually at 5 years or as clinically shown. He also will undergo surveillance imaging annually for the first 2 years.  

Discussion 

DLBCL is the most common pathological type in primary bone DLBCL (PB-DLBCL). The main clinical manifestations of PB-DLBCL are bone pain (82%–92%) and swelling (34%–45%).¹ It is also slightly more common in males than females.² Other less common presentations include pathological fractures and systemic “B-type” symptoms such as fevers, weight loss, and night sweats. Any skeletal site can be involved, and femurs are affected in approximately 20%–38% of cases.¹ Spread to lymph nodes and bone marrow occurs in about 28% and 35% of cases, respectively.³ 

Diagnostic Evaluation 

Laboratory results are usually unremarkable and do not aid in the diagnosis of PB-DLBCL. Initial diagnostic workup includes radiographic imaging of the affected area. However, radiographic findings for cases of PB-DLBCL can be difficult to distinguish from other primary bone tumors such as osteosarcoma, Ewing sarcoma, and chondrosarcoma. Plain X-ray films are the first diagnostic test of choice.  

PB-DLBCL most commonly presents as osteolytic or osteoblastic lesions with disease involvement of the cortex and reactive periosteal changes.⁴ CT scan can be used to further delineate these lesions and define the tumor boundaries to detect evidence of extraosseous extension as well as cortical breakthrough.⁴ MRI further aids in diagnosis by revealing the extent of disease in greater detail through demonstration of abnormal signal intensity areas on T1- and T2-weighted images with minimal contrast enhancement. Despite the minimal availability of data, PET-CT is recommended as a standard tool for the initial evaluation, staging, and response assessment of FDG-avid lymphomas by the recent Lugano classification system.⁵ 

Clinical and radiological suspicion for PB-DLBCL should be further assessed by pathology via bone biopsy. It is recommended to avoid excisional biopsies and minimize the amount of resected tissue to reduce the risk of pathological fractures in these cases.¹ 

Staging and Prognostic Factors 

The most commonly used staging criteria for PB-DLBCL is the Lugano classification system.⁵ Stage IE represents disease confined to an extranodal site, such as a solitary bone lesion. If there is evidence of regional lymph node involvement with a single bone lesion, the disease is then classified as stage IIE. Multifocal disease that is strictly limited to the skeletal system is classified as stage IV.⁶ 

The prognosis of patients with PB-DLBCL is directly correlated to the stage of disease. Five-year overall survival (OS) varies from 82% for patients with stage IE disease to 38% for cases of disseminated DLBCL with skeletal involvement.¹ Conventional prognostic factors, such as the International Prognostic Index (IPI), have proven to be ineffective in predicting the prognosis for PB-DLBCL as staging and the number of extranodal sites have no variability in PB-DLBCL.⁷ Furthermore, the GCB subtype is associated with favorable outcomes in primary bone DLBCL.⁸ 

Treatment 

Due to the rarity of PB-DLBCL, there is no uniform standard for the current treatment scheme. The mainstays of therapy are radiotherapy, chemotherapy, and surgery. Although surgery plays an important role in bone stabilization and resolution of fracture, PB-DLBCL treatment typically consists of anti-CD20 (rituximab) and CHOP-based therapies, with the possible addition of radiotherapy (RT) if necessary.⁹ Although rituximab in combination with chemotherapy showed significant improvements in the prognosis of patients with PB-DLBCL, the risk-benefit profile of radiotherapy as a consolidative therapy remains controversial.^9,10 

Follow-Up 

Interim restaging is performed to determine whether a patient’s disease has not responded to or has progressed on induction therapy. A negative PET scan after 2 to 4 cycles of induction therapy has been associated with significantly higher event-free survival and OS rates in several studies.^11-14 A PET-guided treatment approach is helpful to minimize the use of RT in selected patients with limited-stage DLBCL.^15-17 If treatment modifications are considered based on interim PET scan results, a repeat biopsy of residual masses should be strongly considered to confirm PET positivity prior to more therapy.  

EOT restaging is performed upon completion of treatment. The best time for EOT restaging is not known. However, NCCN guidelines recommend waiting for 6 to 8 weeks after completion of therapy before repeating PET scans.¹⁸ Surveillance imaging is used for monitoring asymptomatic patients. When a disease can only be visualized on PET/CT scan (ie, bone), it is proper to continue with PET/CT scans for surveillance. 

References 

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2. Jawad MU, Schneiderbauer MM, Min ES, Cheung MC, Koniaris LG, Scully SP. Primary lymphoma of bone in adult patients. Cancer. 2010;116(4):871-879.  
3. Li J, Li X, Gao T, Zhou C, Guo Q, Liu D. Primary diffuse large B-cell lymphoma of bone in adults: a SEER population-based study. Medicine (Baltimore). 2024;103(43):e40071.  
4. Mulligan ME, Kransdorf MJ. Sequestra in primary lymphoma of bone: prevalence and radiologic features. Am J Roentgenol. 1993;160(6):1245-1248.  
5. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for first evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3067.  
6. Paes FM, Kalkanis DG, Sideras PA, Serafini AN. FDG PET/CT of extranodal involvement in non-Hodgkin lymphoma and Hodgkin disease. Radiographics. 2010;30(1):269-291.  
7. Held G, Zeynalova S, Murawski N, et al. Impact of rituximab and radiotherapy on outcome of patients with aggressive B-cell lymphoma and skeletal involvement. J Clin Oncol. 2013;31(32):4115-4122.  
8. Heyning FH, Hogendoorn PCW, Kramer MHH, Holland CTQ, Dreef E, Jansen PM. Primary lymphoma of bone: extranodal lymphoma with favourable survival independent of germinal centre, post-germinal centre or indeterminate phenotype. J Clin Pathol. 2009;62(9):820-824.  
9. Held G, Zeynalova S, Murawski N, et al. Impact of rituximab and radiotherapy on outcome of patients with aggressive B-cell lymphoma and skeletal involvement. J Clin Oncol. 2013;31(32):4115-4122.  
10. Held G, Murawski N, Ziepert M, et al. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014;32(11):1112-1118. 
11. Mikhaeel NG, Timothy AR, O'Doherty MJ, et al. 18-FDG-PET as a prognostic indicator in the treatment of aggressive non-Hodgkin's lymphoma—comparison with CT. Leuk Lymphoma. 2000;39(5-6):543-553.  
12. Spaepen K, Stroobants S, Dupont P, et al. Early restaging positron emission tomography with (18)F-fluorodeoxyglucose predicts outcome in patients with aggressive non-Hodgkin's lymphoma. Ann Oncol. 2002;13(9):1356-1363. 
13. Haioun C, Itti E, Rahmouni A, et al. [18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcomes. Blood. 2005;106(4):1376-1381. 
14. Dupuis J, Itti E, Rahmouni A, et al. Response assessment after an inductive CHOP or CHOP-like regimen with or without rituximab in 103 patients with diffuse large B-cell lymphoma: integrating 18-fluorodeoxyglucose positron emission tomography to the International Workshop Criteria. Ann Oncol. 2009;20(3):503-507. 
15. Poeschel V, Held G, Ziepert M, et al. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2019;394(10216):2271-2281.  
16. Persky DO, Li H, Stephens DM, et al. Positron emission tomography-directed therapy for patients with limited-stage diffuse large B-cell lymphoma: results of Intergroup National Clinical Trials Network Study S1001. J Clin Oncol. 2020;38(26):3003-3011.  
17. Freeman CL, Savage KJ, Villa DR, et al. Long-term results of PET-guided radiation in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2021;137(7):929-938. 
18. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 2.2025. February 10, 2025. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf