Primary (Malignant) Lymphoma of Bone (PLB)

The definition of PLB includes the following criteria:

• Histologic documentation of lymphoma in the bone
• A solitary bone lesion or multiple skeletal lesions
• No involvement of lymph nodes (except regional lymph nodes) or other lymphoid tissue

Soft-tissue extension from the bone is a common feature of PLB.

Commonly involved bones in PLB, in order of decreasing frequency, include the following:

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

The metadiaphyseal portion of bone is the most common site of disease. Involvement of the small bones of the hands and feet is rare. Some studies have suggested that the mandible and maxilla are frequently affected sites, but confirmation that bone is the primary site of disease in these cases has not been well documented.

The etiology of PLB is unknown. Viral agents and immunosuppression have been implicated in some cases. PLB 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.

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

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 BCL6 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)

PLB accounts for fewer than 5% of primary bone tumors and fewer than 5% of extranodal lymphomas (or ~1% 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. As many as 50% of patients with AIDS-associated Hodgkin disease have secondary bone-marrow involvement.[3, 4]

PLB may occur at any age, but it is most commonly diagnosed between the ages of 45 and 60 years; it is rare in children.[5] Males are affected more frequently than females (male-to-female ratio, 1.2-1.8:1).

In general, PLB has a better prognosis than most primary bone sarcomas or metastatic lesions do. The Surveillance, Epidemiology, and End Results (SEER) database reported 5- and 10-year survival rates of 58% and 45%, respectively, including patients from 1973-2005.[6] These rates were lower than those reported in most other literature.

A study from Memorial Sloan-Kettering Cancer Center reported a 5-year overall survival rate of 95% with chemoradiation and 78% with single-modality treatment.[7] The patients treated with only chemotherapy, however, tended to have more advanced-stage disease. The University of Miami reported a progression-free survival rate of 83% at 4 years.[8] Demircay et al reported a disease-free 5-year survival rate for patients younger than 60 years and older than 60 years of 90% and 62%, respectively.[9]

Positive prognostic factors for outcome include younger age at diagnosis, multimodal treatment, and localized disease; inclusion of rituximab in the treatment regimen may improve the prognosis.[10] Other factors (eg, type of lymphoma, sex, and lesion size) have not been shown to be significant on multivariate analysis.

The most common presentation of primary lymphoma of bone (PLB; also referred to as reticulum cell sarcoma, malignant lymphoma of bone, or osteolymphoma) consists of several months of bone pain and the appearance of a soft-tissue mass. Constitutional symptoms (B symptoms), such as weight loss, fever, and night sweats, are present in fewer than 10% of patients with PLB. Hypercalcemia is seen in some pediatric patients and has been associated with a poorer prognosis. PLB may be rarely seen in patients with AIDS, immunosuppression, and Paget disease of bone.

The severity of bone pain should be ascertained, particularly with weightbearing. Activity-related pain that subsides with rest or worsening pain despite adjuvant chemoradiation may be indicative of structural insufficiency and the need for prophylactic fixation.

Patients with PLB may present with a prominent mass, even with minimal radiographic changes. All lymph nodes should be palpated. Nodal involvement is rare with primary soft-tissue or bone sarcomas, but is an important factor in managing lymphoma. (See the image below.)

Routine laboratory testing, including a complete blood count (CBC) with differential and a basic metabolic panel with calcium levels, should be obtained. As with any workup of an aggressive-appearing bone lesion in an adult, additional laboratory testing includes the following:

• Alkaline phosphatase (ALP), which can be elevated in Paget disease and osteosarcoma
• Lactate dehydrogenase (LDH), which can be elevated in lymphoma and Ewing sarcoma
• Prostate-specific antigen (PSA) for prostate cancer
• Liver function tests (LFTs) for liver disease
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for infection
• Urine and serum protein electrophoresis for multiple myeloma

There is a wide variability in the plain radiographic appearance of primary lymphoma of bone (PLB). Potential presentations include the following[12] :

• Essentially normal-appearing bone with only a subtle shadow from an associated soft-tissue extension
• Focal, well-circumscribed, lucent lesion
• Permeative destructive lesion with an aggressive periosteal reaction

These patterns and variability in appearance are similar to other round cell tumors, such as Ewing sarcoma. Subtle findings on radiographs, unless they are pathognomonic for well-known benign entities, should always be further investigated with advanced imaging or at least monitored for stability over time. (See the images below.)

Although PLB can appear subtle on plain radiographs, its appearance on magnetic resonance imaging (MRI) is usually more dramatic. PLB is a marrow-replacing process, and this is evident on T1-weighted series as low signal intensity within the medullary space. On T2-weighted and short tau-inversion recovery (STIR) series, these reactive and edematous areas produce high signal intensity. Typically, the lesions demonstrate areas of intravenous contrast uptake.

Many instances of PLB have an extensive soft-tissue component with minimal cortical destruction. It is hypothesized that the malignant cells extravasate from the bone through small vascular channels in the cortex. (See the images below.)

Technetium Tc-99m and gallium scans have very good sensitivity, with increased radionuclide uptake in 98% of PLBs, particularly at the periphery of the lesions. A central cold area representing necrotic tumor may be present. (See the images below.)

A study by Pu et al suggested that fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) could play a substantial role in diagnosing PLB and assessing the efficacy of treatment.[13] Relevant parameters included standardized uptake value (SUV), metabolic tumor volume, and total lesion glycolysis.

After a full imaging workup has been completed, a biopsy is typically necessary to establish a diagnosis. Fine-needle aspiration biopsy (FNAB) relies on cytologic interpretation and is controversial for primary lesions. Core needle biopsy (CNB) provides more tissue than FNAB and allows histologic analysis, but it may not provide enough tissue for a battery of ancillary studies.

If the lesion does not have a soft-tissue extension that can be sampled or a cortical defect that can be used to access the medullary canal, an open biopsy with a bone trephine or even a cortical window may be necessary.[14]  All surgical biopsies should be performed by a trained orthopedic oncologist. There are many pitfalls, including unnecessary contamination of other compartments and ill-advised incisions detrimental to future operations.

If lymph nodes are enlarged, they also should undergo biopsy for staging and further evaluation of the disease process.

Obtaining sufficient tissue for ancillary studies is imperative. Consultation with the pathologist and/or laboratory personnel before performing a diagnostic procedure is essential if lymphoma is being considered in the 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 performed.

Generally, it is best to send the tissue specimen as fresh, on a saline-soaked Telfa pad, rather than in formalin. This allows for chromosome studies, flow cytometry, and immunohistochemistry. The pathology laboratory generally places specimens as necessary into diluted formalin fixative.

The Revised European American Lymphoma (REAL) classification separated lymphomas into the following three main categories:

• B-cell lymphoma
• T-cell and natural killer (NK) cell neoplasms
• Hodgkin disease

Within the B-cell and T-cell/NK types, lymphomas may be further divided into precursor and peripheral (mature) subtypes.

The vast majority (~80%) of PLB cases are diffuse large B-cell lymphoma (DLBCL),[5] one of the more common non-Hodgkin lymphomas. On histology, it is characterized by large cells that are centroblastic, immunoblastic, or anaplastic. The centroblastic variant is most common and has the appearance of large lymphocytes with scant cytoplasm.

Histologic differential diagnosis includes Ewing sarcoma, neuroblastoma and other types of small round cell tumors, granulocytic sarcoma, and Langerhans cell histiocytosis. (See the images below.)

Distinguishing lymphoma from Ewing sarcoma can be challenging. An immunohistochemical panel that includes consistent markers for Ewing (CD99) and for lymphoma (terminal deoxynucleotidyl transferase [TdT]) should be performed. Other markers, such as CD43, CD79a, CD20, and leukocyte common antigen (LCA), are inconsistently present in lymphoma but should be absent in Ewing sarcoma. Vimentin is positive in the majority of Ewing sarcoma cases and a minority of lymphoma cases.[15, 16]

Staging studies include the following:

• Radiography and MRI of the primary lesion
• Whole-body bone scan
• Bilateral iliac crest bone marrow biopsy
• CT of the chest, abdomen, and pelvis
• In children, cerebrospinal fluid (CSF) analysis to exclude central nervous system (CNS) involvement

18F-FDG PET/CT has also been employed in staging and restaging PLB.[17, 18]

A solitary bone lesion with PLB is classified as stage IE according to the Ann Arbor system. This represents one extranodal site of involvement. If regional lymph nodes are involved, it is stage IIE. Disseminated disease is deemed stage IV.

Radiation therapy (RT) for primary lymphoma of bone (PLB; also referred to as reticulum cell sarcoma, malignant lymphoma of bone, or osteolymphoma) provides adequate local control rates; however, when used alone, it results in high rates of systemic failure. The addition of chemotherapy provides superior overall survival and a decreased incidence of relapse.[19, 20]  Multimodal chemoradiation can often even allow bone healing. Only approximately one third of patients with PLB ultimately require surgery for impending pathologic fractures.[9]

Patients should be monitored radiographically and clinically during chemoradiation for bone healing. Those with persistent activity-related pain should be evaluated for surgery before progressing to less restrictive weightbearing precautions.

Chemotherapy typically consists of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone (CHOP), either with (RCHOP) or without the anti-CD-20 antibody rituximab. Intrathecal methotrexate may be given for central nervous system (CNS) prophylaxis. RT of 40-60 Gy, fractionated over several weeks, usually follows chemotherapy.[21, 22, 23]  Refractory cases have been treated with allogeneic bone marrow transplantation.[24]

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

Surgery is not a primary modality of treatment for PLB, aside from biopsy and treatment of skeletal complications. Before the advent of effective RT and chemotherapy, some patients were treated with amputation. Indications for the operative involvement of orthopedic surgeons in PLB most commonly fall into one of the following three categories:

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

No clear role for surgical debulking or wide resection currently exists for PLB.

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, protected weightbearing and use of a gait-aid devices suffice during chemoradiation and until there is improvement of the radiographic appearance. Prophylactic stabilization may be indicated in selected patients who are either unable or unwilling to take such measures to avoid fracture, or if there is an increase in activity-related pain indicating structural insufficiency and microfractures.

The evaluation for impending pathologic fracture in PLB is similar to that 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 bone diameter. This is particularly true for lesions that are located in the peritrochanteric region and cause pain with weightbearing. Lesions that have cortical destruction are at higher risk than those that are primarily marrow-replacing.

Prophylactic stabilization typically involves curettage, cementation, and augmentation of the lesion with internal fixation. An adjuvant such as cryotherapy may be used.

Indications for fixation of pathologic fractures

If a pathologic fracture occurs, the surgical decision-making changes. On average, approximately one third of all pathologic fractures from metastases to bone heal after surgical fixation. This rate varies depending on the type of primary malignancy. There are no published rates for PLB, but with the addition of radiation therapy that further hinders bone healing, the surgeon should assume that the fracture will not heal.

Because the survival for PLB is fairly high, the construct chosen should be very durable. Several trauma studies have demonstrated the ability of a statically locked intramedullary nail at least 12 mm in diameter to support early weightbearing of an average adult male, even with comminution or a segmental bone defect. Nevertheless, the bone stock in patients with malignancy may be compromised, and it is likely that long-term weightbearing on a nail with no bony support will result in hardware failure.

If the pathologic fracture occurs in an area amenable to bone resection and replacement with a megaprosthesis, this should be strongly considered. Cemented endoprostheses provide immediate stability and early resumption of activity.

Surgery for spinal involvement

Lymphoma can occur in the spine and cause nerve or cord compression. In cases of foraminal or central stenosis from soft-tissue extension of PLB, decompression may be necessary to prevent progressive neurologic deficit. If there is spinal instability either from the decompression or from a lytic lesion, spinal fusion also may be necessary.

Contraindications

Contraindications for surgery are similar to those noted in other conditions and are not specific to PLB. Needle biopsies are often adequate and can obviate the need for surgical biopsy. Because RT and chemotherapy are effective modalities of treatment, a cure can be achieved without surgical intervention.

Complications from PLB and its treatment can include the following:

• Fracture ^[25]
• Fracture nonunion
• Wound infection
• Failure of prophylactic fixation
• Secondary arthritis following collapse of osteonecrotic bone
• Toxicity of chemotherapy
• Thrombophlebitis
• Avascular necrosis (AVN) of bone
• Secondary malignancy from chemotherapy or RT