Lymphoma of Bone

  • Red marrow of the long bones and axial skeleton is most frequently involved.

  • Less common locations include the skull and craniofacial bones.

  • Involvement of the small bones in hands and feet is extremely rare.

In the long bones:

  • The femur is the most commonly affected single bone, followed by the humerus.

  • Lesser numbers occur in the tibia and fibula.

  • Occasional cases occur in the radius and ulna.

In the axial skeleton:

  • The spine and pelvis predominate.

  • Occasional cases occur in the ribs, clavicle, sternum, and scapula.

Clinical Signs and Symptoms

  • Localized bone pain occurs in 70–80 % of patients.

  • Approximately 20–30 % have swelling or a palpable mass.

  • Duration of symptoms is usually of the order of several months.

  • Lymphoma of the spine commonly presents with neurological deficit.

  • Pathologic fracture of long bones occurs in approximately 15 % of cases.

  • Systemic symptoms are rare, seen in approximately 5 % of cases.

  • Paraneoplastic phenomena, e.g., hypercalcemia, are very rare.

Image Features

  • Findings are variable and overall nonspecific.

  • Plain radiographs show a spectrum of changes varying from normal or minimal subtle changes to diffuse permeative destruction of the bone.

  • Multiple modality imaging is most informative (i.e., combined x-ray, CT, MRI, and bone scan) although each is essentially nonspecific.

  • Multiple bone involvement is noted in approximately 20 % of cases.

Radiographic Features

  • Seventy percent are lytic.

  • Twenty-eight percent are of mixed lytic and sclerotic appearance.

  • Two percent are totally sclerotic.

  • In most cases (75 %) a permeative/moth-eaten appearance is seen representing multiple small poorly defined radiolucencies within the affected area of the bone which overall is poorly marginated.

  • In 60 % a periosteal reaction is noted which has an aggressive appearance characterized by a single- or multiple-layered appearance (onion skin), usually with interrupted or discontinuous areas.

  • In 50–75 % of cases a soft tissue mass of variable size occurs (optimally identified by CT in 80 % of these and by MRI in all cases).

  • In 22 % pathological fracture is present.

  • In 16 % sequestrum can be identified (best seen on CT).

  • In 4 % of cases the tumor crosses joints (particularly in the vertebral column and sacroiliac joints).

  • In 5 % of cases the changes are either very subtle or not identifiable on plain radiograph.

The MRI, CT, and bone scan findings are essentially nonspecific in nature. FDG PET scan characteristically shows increased glucose avidity in the affected area, is useful for identifying disease elsewhere, and helps evaluate response to therapy.

Bone scan usually shows increased isotope uptake that is:

  • Marked in 65 %

  • Moderate in 35 %

  • Negative in less than 2 % of cases

CT scan is useful for identification of:

  • Permeative pattern

  • Areas of cortical destruction

  • Soft tissue mass

  • Sequestrum formation

MRI Features

  • Will confirm lesional tissue in cases with subtle radiographic changes.

  • Helps identify cortical destruction.

  • Clarifies the intra- and extraosseous extent of the lesion.

  • Lesional tissue is usually:

    • Low or intermediate signal intensity on T1-weighted imaging

    • High signal intensity on T2-weighted imaging

    • Shows homogeneous and diffuse enhancement of soft tissue component

    • Shows homogeneous or heterogeneous enhancement of intraosseous component (depending on intermingled marrow elements and stromal fibrosis)

    • MRI also allows identification of peritumoral and marrow edema which are T2 hyperintense.

    • With stromal fibrosis both T1- and T2-weighted images may be of lower signal intensity.

Less common imaging findings are documented including:

  • Cortical distribution only

  • Lesions confined to the mid-diaphysis

  • Lesions with geographic margins

  • Lesions with aneurysmal features

  • Joint extension

General Comments

Most cases of primary lymphoma of bone:

  • Are solitary in nature (80 %).

  • Occur in the metadiaphysis of long bones.

  • Extensive involvement of the bone is not unusual.

  • Are characterized by radiolucencies with a permeative pattern.

  • With minimal or mild cortical destruction.

  • With a layered periosteal reaction.

  • And with an associated soft tissue mass.

Features highly suggestive of lymphoma:

  • Identification of a soft tissue mass on CT or on MR associated with marrow disease without excessive cortical destruction

  • An abnormal bone scan, MRI, or CT with marrow replacement in a setting of a virtually normal radiograph

Image Differential Diagnosis

  • The imaging findings of lymphoma are similar to that seen in other small round blue cell tumors (including Ewing tumor) in all of which tumor cells percolate through the Haversian system gaining access to the soft tissue component but leaving the cortex virtually intact.

  • The differential diagnosis therefore includes all the other forms of small round blue cell tumors which can be seen in various age groups.

    In children

    • Ewing tumor

    • Neuroblastoma

    • Leukemia

    • Langerhans cell histiocytosis

    • Osteomyelitis

    In teens and young adults

    • Ewing tumor

    • Leukemia

    • Lytic osteosarcoma

    • Langerhans cell histiocytosis

    • Osteomyelitis

    In adults

    • Myeloma/plasmacytoma

    • Metastasis

    • Langerhans cell histiocytosis

    • Osteomyelitis

  • In general, sequestrum formation is seen in a setting of osteomyelitis, Langerhans cell histiocytosis, and lymphoma and occasionally in bone sarcomas and desmoplastic fibroma.

Given that the imaging findings are essentially nonspecific for lymphoma, histological confirmation for accurate diagnosis is always required.


Gross Features

  • Excision specimens are extremely rare as therapy usually comprises chemotherapy and/or radiotherapy after biopsy. Occasionally, surgical excision may be done in a setting of pathologic fracture or other complicating processes.

  • In excision specimens, the tumor usually has a fish-flesh appearance similar to that seen in nodal lymphoma:

    • The intraosseous component has poorly defined margins with intermingled residual bone trabeculae imparting a gritty consistency. Permeation by tumor through the Haversian system with destruction of the cortex may be seen.

    • If reactive sclerosis is present, the gross specimen may be very hard.

  • Biopsy material (which is the more common specimen received) is similar:

    • Comprising of soft friable pale fleshy tissue which may be hemorrhagic.

    • It may be firm related to fibrosis.

    • It may be hard related to sclerosis.

Handling of Tissue

Sampling of fleshy tissue in areas without bone and avoiding necrotic areas will optimize morphological examination, immunophenotyping, and other ancillary techniques including molecular and genetic studies:

  • In hard specimens, the fleshy fragments should be gently teased out in order to avoid prolonged decalcification with consequent suboptimal morphology and immunophenotyping.

  • If the tissue can be handled in the intraoperative setting or as soon as possible in the fresh state, cytological touch preparations can be performed which helps to optimize assessment of the cytological features, particularly in a setting of accompanying sclerosis and fibrosis.

  • Flow cytometric analysis of fresh lesional tissue should always be performed:

    • Although flow cytometry can be performed on tissue fragments retrieved from core biopsy, the cells have to be released from the accompanying stroma.

    • In our experience, direct aspiration of the lesional tissue in an intraoperative or intrabiopsy setting improves the cell yield and surface antibody retrieval.

Biopsy material must be handled with care in order to:

  • Avoid crushing artifact which is common particularly in the setting of stromal fibrosis

  • Retrieve material for flow cytometric analysis

  • Retrieve material for accurate morphological assessment

  • Retrieve material for accurate immunohistochemical testing

  • Retrieve material for genetic studies

Harder biopsies may require significant decalcification. After attempting to retrieve and tease out the soft tissue component and prepare touch smears, gentler methods of decalcification (e.g., EDTA) are optimal.


  • A diffuse growth pattern is usual.

  • Permeation of marrow spaces occurs, the cells surrounding and entrapping the host bone which usually remains otherwise intact. Residual marrow fat is also often present.

  • Accompanying reactive bone sclerosis may occur which in some has a pagetoid appearance.

  • Crush artifact is very common, more so than in all other small round blue cell tumors. In some this is extensive making morphological assessment challenging and sometimes precluding it (hence the value of cytology smears).

  • Variable stromal fibrosis is seen with fine reticulin fibers surrounding individual cells.

  • In some, more prominent fibrosis of the stroma is noted in which crushed and distorted cells are embedded:

    • The fibrosis may have a fasciculated or storiform architecture imparting a spindling appearance to the cells and simulating sarcoma.

    • Occasionally the cells are arranged in a linear single file manner within the fibrous tissue simulating metastatic carcinoma.

  • Clustering of cells with a pseudo-organoid or alveolar pattern may be seen simulating carcinoma, and in some this impression is accentuated by clearing of the cytoplasm or even signet-ring change.

  • Accompanying inflammatory cells are common occasionally masking the neoplastic cells:

    • Intermingled nonneoplastic lymphocytes are common in which T cells predominate.

    • In some instances eosinophils may be seen prompting consideration of Langerhans cell histiocytosis and Hodgkin lymphoma.

    • Neutrophils may even occur, leading to misinterpretation as osteomyelitis.

  • Morphologically most diffuse large B-cell lymphomas have a centroblastic morphology in which the cells have a polymorphous appearance:

    • Variation and shape and size are common.

    • Nuclei are large and irregular and often cleaved and may be mono- and/or multilobulated.

    • Nuclear chromatin is usually finely clumped.

    • Nucleoli may be prominent and two or three may be seen.

    • The cytoplasm is amphophilic and usually inconspicuous with tendency to smearing.

  • Occasionally mixed centroblastic and centrocytic forms are seen with a mixture of small intermediate and larger lymphoid cells.

  • Occasionally immunoblastic forms predominate:

    • The cells have distinct round nuclear borders and a single prominent nucleolus.

    • Abundant amphophilic cytoplasm may be seen.

  • Necrosis may be extensive making interpretation difficult; however, in many cases retention of CD20 immunoreactivity can be demonstrated.

  • In rarer primary bone lymphomas, specific morphological features may be seen similar to that expected in nodal disease:

    • Anaplastic large cell lymphoma:

      • Is characterized by marked nuclear variability in size and shape

      • Has large cells with horseshoe- or kidney-shaped nuclei known as “hallmark” cells

    • Lymphoblastic lymphoma, most often seen in children:

      • Is usually characterized by sheets of cells with rounded nuclei and a fine stippled chromatin pattern

      • Simulates Ewing sarcoma in particular

    • T-cell lymphomas have irregular cleaving of nuclei.

    • Burkitt lymphoma comprises:

      • A monotonous population of medium-sized cells

      • Round nuclei with finely clumped dispersed chromatin

      • Multiple basophilic medium-sized nucleoli

      • Deeply basophilic cytoplasm with lipid vacuoles

      • Brisk proliferation with frequent mitoses and apoptosis resulting in a starry sky pattern

    • Low-grade lymphomas are rare, most cases reflecting secondary involvement rather than primary bone lymphoma. Findings include:

      • Sheets of small- to intermediate-sized lymphoid cells with nuclear irregularities. Nucleoli are usually inconspicuous. Mitotic activity is low and cellular apoptosis not expected.

      • Occasional documented cases include:

        • Follicular lymphoma

        • Mantle cell lymphoma

        • Marginal lymphoma

        • Well-differentiated lymphocytic lymphoma

    • Osseous Hodgkin disease as a primary presenting phenomenon is extremely rare:

      • Most cases represent secondary involvement.

      • Nodular sclerosing and mixed cellularity subtypes are most common.

      • Bone marrow fibrosis with a mixed infiltrate including eosinophils, lymphocytes, histiocytes (sometimes with granuloma formation), and in some instances admixed neutrophils may be seen.

      • Intermingled large cells with prominent nucleoli representing lacunar cells or Reed-Sternberg cells/Reed-Sternberg variants are variably distributed.

Appropriate immunophenotyping is necessary in all cases for adequate clarification. In addition, immunophenotype allows differentiation from other mimics including small round blue cell tumors of the bone.

Flow cytometric analysis for B- and T-cell clonal abnormalities should be undertaken.

Genetic studies may be needed to establish the diagnosis in some cases.

Cytological Findings

  • FNA cytology is very useful in differentiating small round blue cell tumors from other primary bone malignancies and from metastatic carcinoma and melanoma.

  • This technique is best used as an adjunct to histological assessment and in combination with flow cytometry and genetic testing if necessary.

  • As the majority of lymphomas of the bone are of large cell type, aspirates are usually highly cellular.

  • Tumor cells usually comprise naked nuclei with marked nuclear variability in shape and size with irregular nuclear borders.

  • Distinct nucleoli and scattered mitotic figures may be seen.

  • Lymphoglandular bodies representing cytoplasmic fragments are identifiable in the background and allow confirmation of lymphoid origin.

Ancillary techniques

Immunohistochemical Findings

Primary bone lymphomas should be assessed with an immunohistochemical profile as would be performed in their nodal counterparts. The panel of antibodies therefore will depend on the morphological findings.

Most Are Mature B-Cell Neoplasms

  • Cells express CD45 and CD20 in most cases.

  • CD19 and CD79a are positive.

  • PAX5 expression is variable, decorating multilobated cells in particular.

  • Approximately 50 % are of germinal center B-cell type:

    • CD10 and BCL6 positive

    • CD10 negative, BCL6 positive, MUM1 negative

  • Some are indeterminate:

    • CD10 negative, BCL6 positive, MUM1 unknown

  • Some are of post-germinal center phenotype:

    • CD10 negative, BCL6 negative

    • CD10 negative, BCL6 positive, MUM1 positive

  • BCL2, MUM1, P53, and CD44 expression is variable.

  • Intermingled small mature T cells are decorated by CD3.

  • MIB1 proliferation rate varies but is usually high and greater than 40 % and may be more than 90 % in some cases.

  • Cyclin D1 is negative.

Anaplastic Large Cell Lymphoma

Jan 2, 2017 | Posted by in ORTHOPEDIC | Comments Off on Lymphoma of Bone

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