Malignant Lymphoma 

Primary lymphoma of bone is an uncommon disease and must be separated from skeletal involvement in systemic lymphoma. Primary lymphoma of bone is stage IE (extranodal) disease and may present to the orthopedic surgeon prior to biopsy as a solitary bone lesion simulating a bone sarcoma. Skeletal involvement in systemic lymphoma is, by definition, is stage IV disease and is usually not initially seen by the orthopedic surgeon except when a patient is being treated for complications of systemic lymphoma, such as pathologic fracture.

Bone lymphoma is depicted in the images below.

The definition of primary lymphoma of bone continues to be debated. Most authors exclude disseminated or recurrent disease in which the bone is only 1 of many sites of involvement. To be considered primary lymphoma of bone, the following criteria should be met:

• Histologic documentation of lymphoma in the bone
• Solitary bone lesion or multiple skeletal lesions with no prior involvement of lymph nodes or other lymphoid tissue
• No lymph node involvement or involvement of regional lymph nodes only

Soft-tissue extension from the bone lesion is acceptable; the involved soft tissue may be sampled to document malignant lymphoma.

Involved bones are those that normally contain red marrow. Common sites, in order of decreasing frequency, include the following:

• Femur
• Humerus
• Tibia
• Spine
• Pelvis
• Sternum
• Ribs
• Bones of the skull and face

Involvement of the small bones of the hands and feet is rare. The results from some series have suggested that the mandible and maxilla are the most frequently affected sites, but in these studies, documentation of bone as the primary site of disease was not well supported.

Characteristics of primary bone lymphoma

Bhagavathi et al reported clinical, pathologic, immunohistochemical, and molecular features of 21 cases of primary bone diffuse large B-cell lymphoma. The tumors consisted of diffuse sheets of large atypical cells or a polymorphous mixture of small-to-large cells with large, multilobated nuclei; fine chromatin; and inconspicuous to prominent nucleoli. BCL-2 was positive in 17 cases, and TP53 was positive in 11 cases. Polymerase chain reaction showed 10 cases with immunoglobulin heavy-chain and 4 cases with IGH/BCL-2 gene rearrangement. Fluorescence in-situ hybridization showed 14% of cases with BCL-6, 19% of cases with BCL-2, and 9% of cases with C-MYC gene rearrangement.^[1]

Frequency

Primary lymphoma of bone constitutes 3% of primary bone tumors and 5% of extranodal lymphomas (or approximately 2% of all primary non-Hodgkin lymphomas).^[2]

Secondary involvement of bone marrow is seen in 5-15% of patients with Hodgkin disease and 30-53% of patients with non-Hodgkin lymphoma. Up to 50% of patients with acquired immunodeficiency syndrome (AIDS)–associated Hodgkin disease have secondary bone marrow involvement.^[3]

Sex and age predilections

Males are affected more frequently than are females by primary lymphoma of bone, the male-to-female ratio being 1.8:1. All ages are affected, although lymphoma of bone is uncommon in childhood. Most patients are in the fifth to seventh decade of life.

Diagnostic and classification modalities

The proper diagnosis, classification, and management of malignant lymphomas involve the following:

• Histopathology
• Immunohistochemistry
• Immunophenotyping (flow cytometry) studies
• Cytogenetic studies
• Molecular pathology studies

Current state of research

The relative rarity of primary lymphoma of bone has resulted in the absence of therapeutic trials and of standardized definitions of the disease. Most studies in the literature are retrospective, and the number of patients reported on is usually too small for subgroup analysis. Prospective studies are needed to clarify the impact that specific histologic subtypes and therapeutic modalities have on outcome.

Compared with other malignant tumors of bone, primary lymphoma of bone has a good overall prognosis.^[4] With effective chemotherapy and radiation therapy, most series site an overall 5-year survival of 60% or higher.^[5]

In the pediatric population, aggressive chemotherapy has led to 5-year survival rates of greater than 90%. One study found no statistically significant difference in survival between patients with primary lymphoma of bone (stage IE) and persons who had nodal lymphoma with bone metastasis (stage IV). This may reflect the overall improvement in survival statistics for non-Hodgkin lymphoma.

In a study by Jawad et al of 1500 adult patients with primary lymphoma of bone, the 5- and 10-year survival rates were 58% and 45%, respectively. Younger age and localized disease were found to be independent predictors of survival. According to the authors, it was noteworthy that the incidence of disease increased during the study period (1973-2005).^[6]

In another study, Bhagavathi et al reported that age less than 60 years and complete response to initial treatment were significant predictors of survival outcome in primary bone diffuse large B-cell lymphoma.^[1]

In a retrospective study by Alencar et al of 53 patients with primary lymphoma of bone, in whom the most common histologic type was diffuse large B-cell lymphoma (83%), 44 out of 46 patients who underwent chemotherapy and/or radiation achieved a complete response. Progression-free survival was 83% at 4 years, and no difference was seen between patients treated with chemotherapy or combined chemotherapy plus radiation. There was a trend toward improved progression-free survival in patients with diffuse large B-cell lymphoma who were treated with rituximab plus chemotherapy.^[7]

Most patients who relapse do so early. Local recurrence and distant spread are observed. Radiation therapy helps to decrease the incidence of local recurrence. Therefore, series appearing in the literature have portrayed a relatively higher incidence of distant spread.

No prognostic significance has been attached to the sex of the patient, the histologic type of lymphoma, the size of the primary lesion, and the treatment modality employed.

Adverse prognostic factors are as follows:

• Higher stage at diagnosis (lymph node and/or soft-tissue involvement)
• Advanced age (>60 y)
• Poor performance index

One study noted higher local recurrence rates in lesions of the jaw, and another study found lower survival rates in patients with lesions involving the pelvic bones. In children, hypercalcemia is associated with a poorer prognosis.

The etiology of bone lymphoma is unknown. Viral agents and immunosuppression have been implicated in some cases. Primary lymphoma of bone has been documented as a posttransplant lymphoproliferative disorder in patients who have been immunosuppressed. Bone has also been documented as a site for primary lymphoma in patients with AIDS. Rarely, patients with Paget disease of bone may develop malignant lymphoma in the involved bone. However, these associations are not commonly documented, although they are the subject of a few case reports in the literature.

Genetic considerations

Cytogenetic and molecular abnormalities are associated with many different lymphomas. These can be documented in the setting of primary bone lymphoma as well.

Some common recurrent abnormalities are as follows:

• t(14;18)(q32;q21) - Overexpression of Bcl-2 protein, seen in 80-90% of follicular B-cell lymphomas and in 20% of diffuse large B-cell lymphomas
• Rearrangements involving band 3q27 - Rearrangement of BCL-6 gene, seen in 35% of diffuse large B-cell lymphomas
• t(8:14)(q24;q32) - Overexpression of Myc protein, seen in 80% of Burkitt lymphomas; variant translocations t(2;8)(p11;q24) or t(8;22)(q24;q11), found in the remaining 20% of cases
• t(2;5)(p23;q35) - Formation of nucleophosmin–anaplastic lymphoma kinase (NPM-ALK) fusion protein, seen in T-cell anaplastic large cell lymphoma
• t(11;14)(q13;q32) - Overexpression of cyclin D1, seen in mantle cell lymphoma (not reported as a primary bone lymphoma)

Systemic symptoms (B symptoms), such as weight loss, fever, and night sweats, are seen in fewer than 10% of patients in true stage IE lymphoma of bone. Hypercalcemia is seen in some pediatric patients and has been associated with a poorer prognosis. As mentioned above, primary lymphoma of bone has in rare instances been associated with AIDS, immunosuppression, and Paget disease of bone.

The most common presenting feature of bony lymphoma is bone pain, which occurs in 60-100% of patients. Other presenting characteristics are a palpable swelling or mass, as well as a pathologic fracture (see the image below). Pediatric patients may present with functional deficits in involved limbs.

Differential diagnosis based on radiographic examination, depending on a lesion's exact radiographic appearance and on the age of the patient, includes the following:

• Metastatic carcinoma
• Osteosarcoma
• Ewing sarcoma^[8]
• Malignant fibrous histiocytoma or fibrosarcoma of bone
• Neuroblastoma and other small round cell tumors
• Osteomyelitis
• Langerhans cell histiocytosis
• Multiple myeloma
• Leukemic infiltrate
• Paget disease
• Giant cell tumor

Obtain a complete blood count (CBC) with differential white blood cell (WBC) count to evaluate peripheral blood for evidence of leukemia, because leukemic deposits may mimic primary lymphoma of bone.

Serum chemistry studies, including of the patient's calcium level, may reveal hypercalcemia in some individuals.

Most patients have elevated lactate dehydrogenase (LDH) levels, although this is directly proportionate to the disease load. In patients with truly isolated stage IE bone disease involving smaller bones, the LDH may be within normal limits.

The erythrocyte sedimentation rate also is frequently elevated when there is systemic disease involvement.

In most cases, these studies depict lytic lesions, which appear as a moth-eaten or permeative pattern of bone destruction.^[9] A mixed lytic-sclerotic reaction is evident in approximately 30% of cases, with less than 5% of lesions being purely sclerotic. Sclerotic lesions are uncommon in primary non-Hodgkin lymphoma of bone but are seen more frequently in disseminated Hodgkin disease.

An associated soft-tissue mass extending from the involved bone is apparent in 50-85% of cases. Periosteal reaction is less common, but it may lead to confusion with other aggressive lesions when present.

Lymphomas of bone often are large and may involve the entire bone. Lymphomas may involve the entire end of a bone, including the adjoining metaphysis and epiphysis, down to the subchondral bone, an appearance that may be confused with Paget disease or a benign giant cell tumor of bone. Sequestra are apparent in up to 11% of cases.^[10] These are unusual in malignant bone tumors, with the exception of fibrosarcomas and similar tumors.

Radiographic images of malignant lymphoma are provided below.

Most lesions appear homogeneous and hypointense on T1-weighted magnetic resonance imaging (MRI) scans and enhance with the administration of contrast.^{[11, 12]} The appearance on T2-weighted images is inhomogeneous and may be hypointense, isointense, or hyperintense with respect to fat. MRI has high sensitivity in the detection of lesions and in the demonstration of soft-tissue extension. Extension across a joint is rarely seen.

Primary lymphoma of bone can be suspected based on MRI if an intact cortex is seen, even in the face of soft-tissue extension, although this finding is by no means specific to lymphoma. In one study, hypointense lesions on T2-weighted images correlated with histologic evidence of intralesional fibrosis.

Lesions of osteosarcoma, Ewing sarcoma, multiple myeloma, and neuroblastoma, as well as other small round cell tumors, are always hyperintense on T2-weighted images and typically have destructive cortical penetration if soft-tissue extension is present. (See the images below.)

Technetium-99m Bone Scan

This technique has very good sensitivity, with increased uptake of technetium-99m (^99m Tc) usually being noted (98% of patients), particularly at the periphery of the lesions (see the images below). However, a central cold area may be present, representing necrotic tumor.

Gallium scan

Increased uptake is noted most commonly throughout the lesions, and the scan is frequently used for initial staging and follow-up.^[13] This technique has comparable sensitivity to a^99m Tc scan and can reveal soft-tissue lesions as well.

Flow cytometry studies

This technique uses fresh tissue to document cell-surface markers that identify cell lineage.

Identification of the immunophenotype of malignant lymphoma is essential to proper diagnosis, classification, and treatment.

Tissue should be submitted to the laboratory fresh or in a tissue culture medium, such as RPMI1640.

Cytogenetic studies

Cytogenetic abnormalities are common in lymphomas and have diagnostic, therapeutic, and prognostic significance.

Submit tissue specimens for cytogenetic studies to the laboratory fresh or in tissue culture medium, such as RPMI 1640 or Ham's F-10.

Bone marrow aspirate and peripheral blood specimens collected with sodium heparin anticoagulant also may be submitted for cytogenetic analysis.

Molecular pathology studies

For molecular studies, fresh tissue should be frozen and kept at -70°C.

Paraffin-embedded tissue from histopathology also is acceptable for some molecular tests.

Bone marrow aspirate and peripheral blood specimens collected with ethylenediamine tetra-acetic acid (EDTA) anticoagulant also may be submitted for molecular pathology studies.

Diagnostic procedures are indicated most frequently in the presence of a solitary bone lesion with a differential diagnosis that includes lymphoma and metastatic disease, myeloma, and/or primary bone sarcoma.

The following diagnostic procedures can be employed:

• Fine-needle aspiration
• Core-needle biopsy
• Open biopsy

In most instances, a needle biopsy is adequate to diagnose lymphoma of bone, but specific subtyping may necessitate open biopsy when inadequate tissue is present from the fine-needle procedure.^[14]

Whenever soft-tissue extension from the bone lesion is apparent on prebiopsy imaging studies, a biopsy should be taken of the soft-tissue extent in order to avoid further weakening of the bone (which could lead to pathologic fracture).

Similarly, in disseminated disease with bone involvement, as when concurrent lymphadenopathy is present, the lymph nodes are usually the most accessible and, therefore, the most desirable site for biopsy. In these latter instances, bone biopsy can usually be avoided if the radiologic features are consistent with the disseminated disease.

The possibility of a nonlymphoid primary bone tumor cannot be excluded until the biopsy has been evaluated. It is important that the biopsy be carried out in a manner that allows for excision of the biopsy tract with a subsequent en bloc resection, if necessary. Therefore, such biopsies are best performed by surgeons trained in oncologic resection. Obtaining sufficient tissue for ancillary studies in order to avoid repeat procedures is imperative. Consultation with the pathologist and/or laboratory personnel before performing a diagnostic procedure is essential if lymphoma is being considered as a differential diagnosis of a bone lesion. This communication should continue at the time of biopsy. Frozen section confirmation of tissue viability and adequacy should be requested.

In many centers, it is possible to submit fresh tissue to the pathologist, who then distributes it to various sections for ancillary studies as deemed appropriate. The pathologist may also perform intraoperative studies to determine the adequacy of the specimen. If these guidelines are not followed, at least 50% of patients will require additional diagnostic procedures before treatment is initiated.

Malignant lymphomas are classified based on the Revised European American Lymphoma (REAL) classification or on the proposed World Health Organization (WHO) classification. These systems are similar, being based on immunophenotype and morphology.

In adults, diffuse large B-cell lymphoma is the most common subtype of malignant lymphoma to appear as primary lymphoma of bone, accounting for 60-90% of such cases. These cases show a diffuse population of large lymphoid cells, sometimes with convoluted nuclear contours. Admixed fibrosis is present with a background population of small, reactive lymphocytes.

Other types of lymphoma that are seen in primary bone lesions include follicular lymphoma, Burkitt lymphoma, precursor B-lymphoblastic lymphoma, and B-cell small lymphocytic lymphoma. T-cell lymphomas are distinctly uncommon. Cases of anaplastic large cell lymphoma, peripheral T-cell lymphoma, and adult T-cell lymphoma have been reported, with adult T-cell lymphoma having been associated with human T-cell lymphotrophic virus type I (HTLV-I) infection.^[15]

Histologic differential diagnosis includes Ewing sarcoma, neuroblastoma and other types of small round cell tumors, granulocytic sarcoma, and Langerhans cell histiocytosis.

Immunohistochemical images of malignant lymphoma are provided below.

Most primary lymphomas of bone are considered stage IE or IIE in the Ann Arbor staging system. This system is suboptimal for staging primary bone lymphoma and is applied inconsistently in the published literature. The following modification of the Ann Arbor system has been proposed:

• Stage I - One bony lesion with or without soft-tissue extension
• Stage II - Two bony lesions on the same side of the diaphragm or 1 bony lesion with regional lymph node involvement
• Stage III - Involvement on both sides of the diaphragm
• Stage IV - Involvement of the central or peripheral nervous system or of bone marrow on staging biopsy

In addition to employing images of the primary lesion (in the form of plain radiographs, CT scans, or MRI scans) and physical examination, staging studies use^99m Tc bone scans, bilateral iliac crest bone marrow biopsy, and CT scans of the chest, abdomen, and pelvis.^[16] In children, examination of cerebrospinal fluid also is recommended, to exclude central nervous system involvement.

Medical treatment is the mainstay therapy for primary lymphoma of bone. Chemotherapy and radiation therapy are used in conjunction in most cases.

The usual chemotherapy utilizes CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) or another, similar regimen for several cycles.^{[17, 18]} This may be combined with radiation therapy to the affected bone in a 40-60 Gy dose, fractionated over several weeks.

Some studies indicate that the results of combined modality therapy (chemotherapy and radiation therapy) are better than those from radiation therapy alone, while other studies have not documented any statistically significant difference.^{[17, 5, 19, 20, 21]} Because of the relative rarity of this disease, standard treatment protocols have not been developed and followed, and the data in the literature are retrospective.

In children, aggressive chemotherapy alone appears to be as effective as combined modality therapy. Because radiation therapy in children is associated with an increased incidence of adverse, growth-related consequences, it should be avoided in this population.

Therapeutic agents, such as rituximab (an anti-CD20 antibody), have been employed against B-cell lymphomas.^[22] Refractory cases have been treated with allogeneic bone marrow transplantation.

No standard role for surgery exists in the primary management of bone lymphomas, beyond its use as a means of obtaining tissue for diagnosis and of treating complications, such as pathologic fracture. Before the advent of radiation and chemotherapy, some patients were treated with amputation, but with current medical treatment, amputation is generally not necessary.

Indications for the operative involvement of orthopedic surgeons in bone lymphoma most commonly fall into 1 of the following 3 categories:

• Diagnosis
• Treatment of pathologic or impending pathologic fractures
• Decompression of spinal canal compromise

No clear role for surgical debulking procedures or resection currently exists for primary bone lymphoma.

Indications for prophylactic stabilization of impending pathologic fractures

Because lymphomas involving bone may result in pathologic fractures, appropriate steps should be taken to prevent such fractures before they occur. In most patients, particularly those who are younger and compliant, protective weight bearing through the treatment period and until radiologic appearance improves will suffice. However, prophylactic stabilization may be indicated in selected patients who are either unable or unwilling to take such measures to avoid fracture during this often protracted period.

Essentially, the evaluation for impending pathologic fracture is the same for bone lymphoma as it is for metastatic bone lesions. The highest-risk lesions are those of a lytic nature that involve more than one half to two thirds of the involved bone's diameter. This is particularly true of lesions that are located in the peritrochanteric region or, to a lesser extent, elsewhere in the lower extremity, and that are accompanied by pain caused by functional weight bearing.

However, whenever prophylactic stabilization is considered prior to potential radiotherapy treatment, close communication with the radiation oncologist is an important way to ensure that the implant will not hamper the planned treatment course to a great degree.

Age, health status, and willingness to comply with protected weight bearing are important considerations in the setting of what appears to be an impending pathologic fracture resulting from bone involvement by lymphoma. Generally, changes that are initially lytic on radiograph will, following radiotherapy, fill in over time. If patients with lower extremity lesions are willing and able to use ambulatory aids to limit weight bearing, the avoidance of internal fixation is sometimes desirable.

Indications for fixation of pathologic fractures

Once pathologic fracture occurs through bone involved by lymphoma, operative stabilization is generally indicated, particularly in the lower extremities, in the long bones of the upper extremities, and in unstable spine fractures.

When internal fixation is needed at the time of diagnosis or prior to irradiation, close communication with the radiation oncologist is needed to determine how the internal fixation will affect radiotherapy treatment options. In most cases, however, if the radiation employs anteroposterior and posteroanterior fields, the scatter created by the internal fixation in each direction will cancel out and so will not create a great problem.

Excision

Operative excision is rarely indicated in the primary treatment of bone lymphoma. Increasing evidence suggests that the prognosis for even isolated stage IE bone lymphoma may not be significantly better than that for disseminated lymphoma with bone involvement, further underscoring the importance of systemic management for local disease treatment.

In rare cases in which there is recalcitrant symptomatic local disease, limited extremity function, or nonunion of pathologic fracture through irradiated bone previously involved by lymphoma, excision of the involved bone may be considered.

Decompression of spinal canal compromise

Occasionally, lymphoma involves the spine. In these cases, a tumor may extend from the bone into the spinal canal. When this soft-tissue extension results in progressive neurologic deficit, decompression may be necessary. The need for concomitant fusion is determined in large part by the extent of the instability created by the decompressive procedure.

Contraindications

Because surgical intervention is only used to establish a diagnosis (biopsy) and for managing complications, no specific contraindications to surgery exist.

Complications from malignant bone lymphoma and its treatment can include the following:

• Fracture
• Fracture nonunion
• Wound infection
• Osteonecrosis
• Secondary arthritis following collapse of osteonecrotic bone
• Neuropathy
• Toxicity of chemotherapy
• Thrombophlebitis

Fractures are most common in weight-bearing bones and have been associated with the primary disease, with radiation therapy, and with avascular necrosis following chemotherapy.