Laboratory Studies
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:
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Alkaline phosphatase (ALP), which can be elevated in Paget disease and osteosarcoma
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Lactate dehydrogenase (LDH), which can be elevated in lymphoma and Ewing sarcoma
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Prostate-specific antigen (PSA) for prostate cancer
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Liver function tests (LFTs) for liver disease
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Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for infection
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Urine and serum protein electrophoresis for multiple myeloma
Plain Radiography
There is a wide variability in the plain radiographic appearance of primary lymphoma of bone (PLB). Potential presentations include the following [12] :
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Essentially normal-appearing bone with only a subtle shadow from an associated soft-tissue extension
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Focal, well-circumscribed, lucent lesion
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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.)
An elderly woman presents with complaints of left shoulder pain of several months duration. A plain radiograph of the left shoulder (glenoid view) reveals a destructive lytic process eroding the cortical margins of the acromial process.
A woman who is in the early part of her fifth decade presents with progressive left thigh pain and a limp. An anteroposterior radiograph of her left proximal femur reveals a lytic destructive process involving the subtrochanteric region, with medical cortical erosion, soft-tissue extension, and an associated lesser trochanteric avulsion fracture. The proximal femur is the most common site for primary bone lymphoma.
Anteroposterior radiograph of the left clavicle reveals a mixed lytic and sclerotic destructive process within the midportion of the bone, with indistinct, permeative borders.
Magnetic Resonance Imaging
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.)
Coronal, T1-weighted magnetic resonance imaging (MRI) scan of the left shoulder reveals the replacement of the left acromion by a low-signal process extending into the surrounding soft tissue.
Coronal, T2-weighted magnetic resonance imaging (MRI) scan of the left shoulder reveals a high-signal process involving the left acromion and extending to the surrounding soft tissue. The MRI scan's features are suggestive only of a very high cellularity fluid-containing process, but they are nonspecific. Biopsy is required for a specific diagnosis.
Coronal, T1-weighted magnetic resonance imaging (MRI) scan of the upper thorax and bilateral shoulders reveals a marrow replacement low-signal process involving the entire right proximal humerus. The corresponding T2-weighted MRI scan showed a high-signal process in this area. This MRI scan was produced after plain radiographs were interpreted as normal and an MRI scan of the cervical spine and brachial plexus revealed the unsuspected findings in the humerus.
Bone Scanning
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.)
Total skeleton technetium-99m (99mTc) nuclear medicine scan shows increased uptake in the left acromion, the site of bony involvement by lymphoma in this patient. The initial differential diagnosis suggested metastatic disease to bone in addition to multiple myeloma and lymphoma, in that order.
Total skeleton technetium-99m (99mTc) nuclear medicine scan reveals an isolated increased uptake in the left proximal femur at the site of this patient's bone lymphoma.
Technetium-99m (99mTc) total skeleton nuclear medicine scan shows increased uptake in the midportion of the left clavicle, an area corresponding to the clinical site of bone enlargement.
PET/CT
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.
Biopsy
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.
Histologic Findings
The Revised European American Lymphoma (REAL) classification separated lymphomas into the following three main categories:
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B-cell lymphoma
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T-cell and natural killer (NK) cell neoplasms
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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.)
Sections of the biopsy show a diffuse infiltrate of atypical large lymphoid cells with vesicular nuclei, small nucleoli, and moderate cytoplasm. Small reactive lymphocytes are in the background.
An immunohistochemical stain using an antibody directed against CD20 (B-cell marker) shows strong positivity in the large lymphoid cells. This is an example of a diffuse large B-cell lymphoma.
Diffuse infiltrate of large lymphoid cells is present, with cleared cytoplasm and hyperchromatic nuclei. Admixed small, reactive lymphocytes also are noted.
Immunohistochemical stain using an antibody against CD20 is positive in the large cells; this is a diffuse large B-cell lymphoma.
Another example of a diffuse large cell lymphoma. In addition to the large lymphoid cells with moderate cytoplasm, a few cells with lobate nuclei also are seen. Such cells are often observed in large cell lymphoma of the bone.
Histologic sections reveal a highly cellular neoplasm composed of cells with a high nucleus-to-cytoplasm ratio, scant cytoplasm, and fine nuclear chromatin. The cells showed immunohistochemical evidence of B-cell lineage and expressed terminal deoxynucleotidyl transferase (TdT), consistent with a precursor B-lymphoblastic lymphoma.
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
Staging studies include the following:
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Radiography and MRI of the primary lesion
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Whole-body bone scan
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Bilateral iliac crest bone marrow biopsy
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CT of the chest, abdomen, and pelvis
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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.
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Total skeleton technetium-99m (99mTc) nuclear medicine scan reveals an isolated increased uptake in the left proximal femur at the site of this patient's bone lymphoma.
-
Total skeleton technetium-99m (99mTc) nuclear medicine scan shows increased uptake in the left acromion, the site of bony involvement by lymphoma in this patient. The initial differential diagnosis suggested metastatic disease to bone in addition to multiple myeloma and lymphoma, in that order.
-
Coronal, T1-weighted magnetic resonance imaging (MRI) scan of the left shoulder reveals the replacement of the left acromion by a low-signal process extending into the surrounding soft tissue.
-
Coronal, T2-weighted magnetic resonance imaging (MRI) scan of the left shoulder reveals a high-signal process involving the left acromion and extending to the surrounding soft tissue. The MRI scan's features are suggestive only of a very high cellularity fluid-containing process, but they are nonspecific. Biopsy is required for a specific diagnosis.
-
Sections of the biopsy show a diffuse infiltrate of atypical large lymphoid cells with vesicular nuclei, small nucleoli, and moderate cytoplasm. Small reactive lymphocytes are in the background.
-
An immunohistochemical stain using an antibody directed against CD20 (B-cell marker) shows strong positivity in the large lymphoid cells. This is an example of a diffuse large B-cell lymphoma.
-
A woman who is in the early part of her fifth decade presents with progressive left thigh pain and a limp. An anteroposterior radiograph of her left proximal femur reveals a lytic destructive process involving the subtrochanteric region, with medical cortical erosion, soft-tissue extension, and an associated lesser trochanteric avulsion fracture. The proximal femur is the most common site for primary bone lymphoma.
-
An elderly woman presents with complaints of left shoulder pain of several months duration. A plain radiograph of the left shoulder (glenoid view) reveals a destructive lytic process eroding the cortical margins of the acromial process.
-
Diffuse infiltrate of large lymphoid cells is present, with cleared cytoplasm and hyperchromatic nuclei. Admixed small, reactive lymphocytes also are noted.
-
Immunohistochemical stain using an antibody against CD20 is positive in the large cells; this is a diffuse large B-cell lymphoma.
-
Clinical photo of a left shoulder shows a prominence in the midportion of the left clavicle. This 45-year-old man was suffering from local pain and tenderness but had no history of prior trauma.
-
Technetium-99m (99mTc) total skeleton nuclear medicine scan shows increased uptake in the midportion of the left clavicle, an area corresponding to the clinical site of bone enlargement.
-
Anteroposterior radiograph of the left clavicle reveals a mixed lytic and sclerotic destructive process within the midportion of the bone, with indistinct, permeative borders.
-
Another example of a diffuse large cell lymphoma. In addition to the large lymphoid cells with moderate cytoplasm, a few cells with lobate nuclei also are seen. Such cells are often observed in large cell lymphoma of the bone.
-
Plain radiographs in this 12-year-old patient with severely progressive right shoulder pain were interpreted as being normal. At most, they showed the existence of localized osteopenia in the right proximal humerus, but they did not demonstrate the presence of a discrete lesion within the bone. Based on the initial evaluation and plain radiographs, the patient was thought to have referred pain from the cervical region or brachial plexus.
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Coronal, T1-weighted magnetic resonance imaging (MRI) scan of the upper thorax and bilateral shoulders reveals a marrow replacement low-signal process involving the entire right proximal humerus. The corresponding T2-weighted MRI scan showed a high-signal process in this area. This MRI scan was produced after plain radiographs were interpreted as normal and an MRI scan of the cervical spine and brachial plexus revealed the unsuspected findings in the humerus.
-
Histologic sections reveal a highly cellular neoplasm composed of cells with a high nucleus-to-cytoplasm ratio, scant cytoplasm, and fine nuclear chromatin. The cells showed immunohistochemical evidence of B-cell lineage and expressed terminal deoxynucleotidyl transferase (TdT), consistent with a precursor B-lymphoblastic lymphoma.
