Primary Bone Lymphoma

What it is. Primary bone lymphoma (PBL) is a malignant lymphoma that arises within bone, with no evidence of nodal or other extraskeletal disease at presentation. It is a non-Hodgkin lymphoma that happens to live in the skeleton, and over 80% are diffuse large B-cell lymphoma (DLBCL), a high-grade B-cell malignancy. Because it is a haematological cancer rather than a true bone-forming tumour, it is staged and treated largely with the lymphoma toolkit (Ann Arbor stage, International Prognostic Index, chemotherapy), while the orthopaedic surgeon manages the biopsy and the mechanical consequences in bone.

What counts as primary. The tumour must arise within the skeleton, not in a node. It may involve one bone, or more than one while remaining bone-limited, and staging away from the skeleton must be negative; classically there is no distant disease within about 6 months of diagnosis. A lymphoma that fails these tests is secondary skeletal lymphoma, in which bone is one site of widespread nodal or systemic disease, and that is a different staging and treatment conversation.

Why the distinction matters. PBL sits in the differential of an aggressive, permeative round cell lesion in an adult, alongside Ewing sarcoma, metastatic carcinoma, multiple myeloma and infection. Telling them apart matters enormously because the treatment and prognosis are completely different.

Frequency. A genuinely rare tumour: less than 5% of all primary bone tumours and roughly 3-7% of extranodal lymphomas. Most of what is known comes from registry and single-centre series.

Who. Adults, with a broad peak around 45-60 years, older than the typical Ewing sarcoma patient. Most series report a slight male predominance, but large registry data show no strong sex preponderance.

Where. The long-bone metadiaphysis, the femur most commonly, plus the pelvis and spine.

The cell and how it grows. PBL is a clonal proliferation of malignant lymphocytes within the marrow space. In DLBCL, diffuse sheets of large, atypical lymphoid cells (centroblast-like or immunoblast-like) efface the marrow and permeate between the bony trabeculae, forming neither bone nor cartilage. This permeative growth, through the marrow and the Haversian canals, explains the imaging signature: extensive marrow and soft-tissue disease with a relatively preserved cortex.

Immunophenotype. Immunohistochemistry and flow cytometry identify the cell and subtype the lymphoma.

• B-cell markers in DLBCL: CD20, CD19, CD79a, PAX5
• A high proliferation index (Ki-67)
• Cell-of-origin profiling, germinal-centre versus activated B-cell, by the Hans algorithm
• Flow cytometry on fresh tissue confirms clonality rapidly

Place in the WHO classification. Within the WHO classification of haematolymphoid tumours, PBL is not a separate entity: it is a primary extranodal presentation of an established lymphoma type. Most often that is DLBCL, with smaller numbers of follicular, marginal zone, T-cell rich B-cell, anaplastic large cell and, in children, lymphoblastic lymphomas. The histological subtype, defined by morphology plus immunophenotype, drives treatment more than the fact that the tumour is in bone.

PBL is staged with two parallel systems. The musculoskeletal frameworks (Enneking, AJCC) are the ones used for any bone tumour; the lymphoma-specific Ann Arbor stage and International Prognostic Index are the ones that actually drive treatment and prognosis.

Ann Arbor stage, adapted for extranodal and bone disease, is the working staging system.

• Stage IE - single extranodal (bone) site only
• Stage IIE - bone site plus regional nodes on the same side of the diaphragm
• Stage IIIE - involvement on both sides of the diaphragm
• Stage IV - disseminated or multifocal extranodal disease

The International Prognostic Index (IPI) risk-stratifies and predicts survival from five factors, remembered as APLES.

• Age over 60
• Poor performance status, ECOG 2 or worse
• Elevated LDH, which reflects tumour burden
• More than one extranodal site
• Advanced stage, Ann Arbor III-IV

The age-adjusted IPI is the single strongest predictor of long-term survival in bone DLBCL.

Enneking. The surgical staging system for musculoskeletal tumours divides by grade, compartment and metastasis.

• Stage I - low grade (A intracompartmental, B extracompartmental)
• Stage II - high grade (A intracompartmental, B extracompartmental)
• Stage III - any grade with regional or distant metastasis

Bone lymphoma is high grade and typically extracompartmental at presentation, so in surgical terms it behaves as Enneking IIB. Unlike osteosarcoma, that does not mandate wide resection, because the disease is treated systemically.

AJCC. The AJCC system for bone tumours uses tumour size (T, with 8 cm as a key cut-off), nodal status (N), metastasis (M) and histological grade (G). It is here because examiners may ask you to name the bone-tumour staging systems. For management decisions in bone lymphoma the Ann Arbor stage and IPI take precedence: this is a lymphoma being staged, not a sarcoma.

The usual story. Localised bone pain, often present for weeks to months and frequently worse at night, in a patient who is otherwise relatively well. There may be a palpable mass or soft-tissue swelling over the bone, and reduced function of the adjacent joint. A minority present acutely with a pathological fracture.

The spine. Vertebral involvement brings back pain, radiculopathy from nerve root compression, and spinal cord compression, which is an emergency. In some series half of spinal cases present with cord compression.

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Systemic symptoms. The lymphoma B-symptoms (fever, drenching night sweats, weight loss) are often absent in truly bone-limited disease. Their presence should prompt a search for systemic spread.

Why it matters most here. Biopsy is the single most important orthopaedic step, and it is easy to get wrong in lymphoma. The tumour is chemosensitive and rarely resected, so the biopsy is more than a staging step: it is essentially the only tissue you may take.

Why small samples fail. Lymphoid cells are fragile and crush easily, crush artefact is frequent, and reactive fibrosis can make a small sample look non-specific. A small core that is crushed, or one sent only in formalin, frequently returns as "small round blue cell tumour, non-diagnostic", and the patient faces a repeat procedure.

What the pathologist needs. A generous core or open biopsy, with fresh tissue split off for flow cytometry before fixation, adequate material for immunohistochemistry and molecular studies, and a warning that lymphoma is on the differential. That is what allows the lymphoma to be subtyped. The operative steps, including where to place the tract, are under Surgical Technique.

The aggressive permeative bone lesion in an adult has a short, high-stakes differential. The distinction is ultimately made on the immunohistochemistry panel, which is exactly why the biopsy must be generous and the right stains requested.

The principle. Systemic chemotherapy first, radiotherapy as consolidation in selected cases, and surgery reserved for biopsy and mechanical problems. Bone lymphoma is exquisitely chemosensitive, and wide resection is not part of standard treatment.

Chemotherapy. The backbone is R-CHOP: rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone, the standard for DLBCL, which most cases are. The number of cycles is guided by Ann Arbor stage, IPI and PET response, and CNS prophylaxis is considered in high-risk disease (see Complications). In the SEER registry, chemotherapy was an independent favourable prognostic factor (DOI).

Why rituximab. In primary bone lymphoma, adding rituximab to CHOP markedly improved 3-year progression-free survival, 88% with R-CHOP against 52% with CHOP-like therapy (DOI). That British Columbia comparison is between sequential treatment eras rather than randomised arms, so the direction is more secure than the size of the gap.

Radiotherapy. Consolidation, not sole treatment. It is often added after chemotherapy for residual disease, bulky sites, or following cord compression, and a French PB-DLBCL series suggested it may be useful as a consolidation modality alongside immunochemotherapy (DOI). Combined-modality therapy is balanced against late toxicity, especially in younger patients.

Surgery. Supportive, not curative. It has three roles:

• Biopsy to establish the diagnosis
• Fixation of an impending or actual pathological fracture
• Spinal cord decompression and stabilisation when there is neurological compromise not amenable to urgent radiotherapy

Relapsed or refractory disease. Salvage chemotherapy, with consideration of autologous stem-cell transplant in fit patients. CAR T-cell therapy (tisagenlecleucel) produces durable responses in relapsed or refractory DLBCL, with a best overall response rate of 52% and 40% complete responses (DOI). These decisions are made within a haematology-led multidisciplinary team.

Managing the bone itself. The orthopaedic decision follows from the mechanical problem in front of you.

Although bone lymphoma is a medical disease, the orthopaedic surgeon performs two operations in it that must be done well.

The diagnostic biopsy. Plan it as though later surgery might be needed, even though the tumour is rarely resected.

1. Plan the approach with the surgeon who would do any later definitive surgery, and place the tract so it can be excised later if needed
2. Use a longitudinal incision in line with the limb, avoiding contamination of multiple compartments and neurovascular structures; transverse incisions and poorly placed tracts compromise later surgery
3. Take a generous core or open sample of representative tumour, avoiding the necrotic centre
4. Split off fresh tissue for flow cytometry, send adequate material for histology, immunohistochemistry, molecular studies and microbiology (infection is a key differential), and tell the pathologist lymphoma is suspected
5. Achieve meticulous haemostasis - a haematoma spreads tumour through tissue planes

Stabilising an impending or actual fracture. The goal is stability while systemic treatment works.

1. Confirm a tissue diagnosis where possible before definitive fixation
2. For long bones, intramedullary fixation gives durable load-sharing stability that tolerates chemotherapy and allows early function
3. Consider the whole bone at risk - tumour may extend beyond the obvious lesion, so protect the entire bone
4. Coordinate timing with the haematology team around chemotherapy cycles and marrow nadir
5. Avoid the temptation to resect

From the disease. Pathological fracture of the affected bone, spinal cord or nerve root compression, relapsed or refractory lymphoma, and CNS relapse, for which bone or extranodal involvement is a recognised risk factor.

CNS relapse. In diffuse large B-cell lymphoma, bone involvement is an independent risk factor for central nervous system relapse (hazard ratio around 4), and rituximab reduces overall CNS relapse rates (DOI). This is why CNS-directed risk assessment and, in selected cases, prophylaxis are part of the haematology plan.

From treatment.

• Chemotherapy toxicity - myelosuppression, neutropenic sepsis, cardiotoxicity (doxorubicin), neuropathy (vincristine)
• Tumour lysis syndrome with rapid response to chemotherapy
• Radiotherapy late effects - including second malignancy and growth disturbance in the young
• Surgical complications - infection, fixation failure, wound problems compounded by immunosuppression

Because treatment is led by chemotherapy, care after biopsy or fixation runs in parallel with systemic therapy.

Early recovery. Watch the wound, especially during chemotherapy-related immunosuppression. Mobilise early after stabilisation to preserve function, and coordinate analgesia with the oncology team.

During chemotherapy. Monitor for neutropenic sepsis and treat it promptly. Protect the operated or affected limb until the bone consolidates, while PET-CT response assessment guides ongoing treatment.

Long-term surveillance. Regular clinical and imaging follow-up for relapse, a watch for the late effects of chemotherapy and radiotherapy, and functional rehabilitation of the affected limb or spine.

Survival. Primary bone lymphoma has a substantially better prognosis than osteosarcoma or Ewing sarcoma of bone. The largest population-based analysis, SEER (2558 patients), confirmed DLBCL as the dominant histology and reported 5- and 10-year overall survival of approximately 66% and 54% (DOI). The British Columbia cohort showed 62% and 41% for bone DLBCL, rising to a 5-year survival of 90% in younger patients with a good IPI (DOI).

Site and fracture. The two large cohorts do not agree on site. SEER found that appendicular and craniofacial primaries carried a survival advantage over axial ones, whereas in the British Columbia series neither primary site nor pathological fracture at presentation independently affected overall survival; there, outcome was driven by age and IPI.

Global Picture

Primary bone lymphoma is rare, so practice rests on registry and cohort data rather than randomised trials specific to bone. The principles below are consistent across major lymphoma and bone-tumour frameworks worldwide.

Practice Points That Travel

• Multidisciplinary care (haematology, radiation oncology, orthopaedic/spinal surgery, pathology, radiology) is standard everywhere.
• R-CHOP is the global backbone for DLBCL bone lymphoma, with rituximab availability being the main source of practice variation in lower-resource settings.
• Surgery is supportive - biopsy and stabilisation - across all settings; wide resection is not standard anywhere.
• Prognosis is favourable relative to other malignant bone tumours, a message that holds across registries.

High-Yield Points to Drill