Primary Bone Lymphoma

Primary bone lymphoma is a lymphoma that arises in bone, with or without regional lymph node or soft tissue involvement, and no distant spread at presentation. About 90% are diffuse large B-cell lymphoma; the rest include follicular, Hodgkin and T-cell types.

It accounts for under 1% of all non-Hodgkin lymphomas, about 3 to 5% of extranodal lymphomas and 3 to 7% of primary malignant bone tumours. It occurs at any age, with a peak at 45 to 60 years (and a second peak in children), and is more common in males (1.5 to 2 to 1). Common sites are the femur, pelvis, humerus, spine, tibia and skull.

The commonest presentation is persistent bone pain with a soft tissue mass. Constitutional (B) symptoms occur in under 20%. Complications are pathological fracture (in 10 to 20%), spinal cord compression, hypercalcaemia, and relapse (central nervous system relapse in a minority). With modern treatment, 5-year overall survival is 80 to 90%.

Pathophysiology.

Malignant B cells infiltrate marrow and cortex and spread through the Haversian system, which explains why large soft tissue masses can exist with little cortical destruction on imaging. Most cases are of germinal centre or non-germinal centre phenotype, with MYC, BCL2 and BCL6 alterations that decide prognosis. Immunosuppression, Epstein-Barr virus, and previous radiation are risk factors.

Localised, persistent bone pain (often present for months, worse at night), a swelling or palpable mass, pathological fracture, restricted motion, and sometimes neurological deficits from spinal or pelvic involvement. Fever, night sweats and weight loss are uncommon.

Examine the affected bone and joints, soft tissue mass, regional lymph nodes, abdomen (liver and spleen), skin and neurological function.

• Radiographs: a lytic, permeative or "moth eaten" lesion (or mixed), often with little cortical destruction despite extensive marrow replacement, with sclerosis in about a third; periosteal reaction may be laminated or absent. Radiographs may be normal early.
• MRI: shows the intramedullary extent and a large soft tissue mass with cortical preservation (a characteristic mismatch), with low T1 and intermediate to high T2 signal and homogeneous enhancement.
• Positron emission tomography with CT: for staging, since it separates solitary from multifocal and nodal disease, and for response assessment.
• Biopsy: image directed core biopsy or open biopsy by a specialist team, before any surgery, with enough tissue for immunohistochemistry (CD20, CD79a, CD10, BCL6, MUM1, Ki-67), and molecular tests (MYC, BCL2, BCL6 rearrangement). Do not use frozen section alone.
• Blood tests: full blood count, lactate dehydrogenase (raised in about half), calcium, urea and creatinine, liver function, uric acid, beta-2 microglobulin, protein electrophoresis, HIV, hepatitis B and C serology.
• Bone marrow biopsy (when PET is not conclusive) and cerebrospinal fluid assessment if there is a skull or spine lesion, high risk features, or neurological symptoms.

Differential diagnosis.

• Ewing sarcoma and osteomyelitis.
• Myeloma and plasmacytoma.
• Metastatic carcinoma and Langerhans cell histiocytosis.
• Osteosarcoma and small round cell tumours.

Treatment is chemotherapy with an anti-CD20 antibody, with or without radiotherapy, led by haematology. Surgery is used only for diagnosis and for stabilisation of impending or actual fracture.

Immunochemotherapy (diffuse large B-cell lymphoma). R-CHOP every 21 days for 6 cycles (4 cycles followed by radiotherapy in limited disease in some centres):

• Rituximab 375 mg/m2 intravenously on day 1. Start the first infusion at 50 mg/hour and increase by 50 mg/hour every 30 minutes to a maximum of 400 mg/hour; give premedication with paracetamol 1 g orally, chlorphenamine 10 mg orally or intravenously and hydrocortisone 100 mg intravenously. Screen for hepatitis B (surface antigen and core antibody) before the first dose; avoid with active severe infection; monitor for infusion reactions, hepatitis B reactivation and progressive multifocal leukoencephalopathy.
• Cyclophosphamide 750 mg/m2 intravenously on day 1; ensure hydration; reduce for renal or hepatic impairment; monitor blood count and watch for haemorrhagic cystitis.
• Doxorubicin 50 mg/m2 intravenously on day 1 (maximum lifetime dose 450 mg/m2 to reduce cardiotoxicity); check echocardiography or a multigated scan before treatment and after 3 cycles; avoid with left ventricular ejection fraction under 50% and severe hepatic impairment.
• Vincristine 1.4 mg/m2 (maximum 2 mg) intravenously on day 1, fatal if given intrathecally; monitor for neuropathy and constipation.
• Prednisolone 100 mg orally once daily on days 1 to 5; monitor glucose and mood.
• Pegfilgrastim 6 mg subcutaneously once on day 2 of each cycle (24 to 72 hours after chemotherapy) for primary prophylaxis of neutropenia when the risk of febrile neutropenia is over 20% or the patient is older than 60 years; avoid within 14 days before the next cycle; check blood count.
• Antiemetic prophylaxis: ondansetron 8 mg orally or intravenously before chemotherapy and every 12 hours for 2 days (maximum 16 mg in a single intravenous dose; avoid with prolonged QT).
• Hepatitis B prophylaxis for carriers or core antibody positive patients: entecavir 0.5 mg orally once daily on an empty stomach, starting before chemotherapy and continuing for 12 months after the last dose of rituximab; reduce at creatinine clearance under 50 mL/min.
• Tumour lysis risk is low in solitary disease; maintain hydration and check uric acid, potassium and creatinine in the first cycle.

Radiotherapy. Involved site radiotherapy to the bone, 30 to 40 Gy in 15 to 20 fractions, after chemotherapy for a bulky or partial response disease, to reduce local relapse. Weigh long term risks in younger patients.

Orthopaedic management. Prophylactic fixation for a lesion with a high fracture risk, and fixation of a pathological fracture, ideally after biopsy; most fractures heal with chemotherapy and radiotherapy. Spinal cord compression: urgent steroid, radiotherapy or chemotherapy, and decompression when unstable.

Analgesia.

• Paracetamol 1 g orally every 6 hours as needed for up to 5 to 7 days (maximum 4 g daily; 3 g daily when weight is under 50 kg, with chronic alcohol use or hepatic impairment).
• Oral morphine 5 to 10 mg every 4 hours as needed for severe pain for up to 3 days (start 2.5 to 5 mg with age over 75 or eGFR under 30 mL/min/1.73 m2; avoid exceeding 60 mg in 24 hours without senior review); monitor sedation and respiration and prescribe a laxative. Review the regimen as the lymphoma responds.
• Avoid NSAIDs during chemotherapy with thrombocytopenia or kidney impairment.

Monitoring. Blood count, creatinine, liver function and lactate dehydrogenase before each cycle. Interim PET-CT after 2 to 4 cycles and at the end of treatment. Echocardiography before treatment and after 3 cycles. Clinic review every 3 months for 2 years, then every 6 months to 5 years; late effects including cardiac disease and second malignancy.

Referral and escalation. Refer every suspected primary bone lymphoma urgently to haematology or a sarcoma and lymphoma service before surgery. Emergency referral for spinal cord compression, febrile neutropenia, hypercalcaemia, tumour lysis, superior vena cava obstruction or an impending fracture.

Special groups.

• Older adults: dose reduced R-miniCHOP in frail patients; geriatric assessment.
• Children and young adults: managed in paediatric or adolescent oncology units, with regimens for Burkitt and other types.
• Immunosuppressed and HIV: treat the underlying cause and give antiretroviral therapy; consider Epstein-Barr virus related disease.
• Pregnancy: urgent haematology and obstetric planning; chemotherapy in the second and third trimester is possible, while rituximab and radiotherapy are avoided.
• Kidney impairment: adjust cyclophosphamide, avoid NSAIDs, reduce morphine doses and enoxaparin.