Pathology of Primary Bone Lymphoma
The term non-Hodgkin lymphoma (NHL) encompasses a heterogeneous mix of lymphomas, which are either of a B- or T-cell phenotype and that meet the diagnostic criteria for one of the subtypes detailed in the 2008 World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues.  Most primary lymphomas of the bone are of the NHL type and of the diffuse large B-cell lymphoma (DLBCL) subtype. [2, 3, 4, 5, 6, 7]
Primary NHL of bone (primary bone lymphoma) is a rare condition, accounting for less than 1-2% of adult NHL and less than 7-10% primary bone tumors. [2, 3, 4, 5, 6, 7, 8, 9] The majority of the cases are limited disease by the Ann Arbor staging system and occur in adults of age 45-60 years. [2, 4, 5, 6, 7] Rare cases occur in children with a mean age of 12 years.  The male–to-female ratio is either equal or shows a slight male predominance. [2, 3, 4, 5, 6, 7, 9]
The etiology of primary NHL of bone is not currently known. Certain subtypes of NHL have been shown to be associated with a virus (Epstein-Barr virus [EBV], human immunodeficiency virus [HIV], human herpes virus-6 [HHV-6]).  However, viral etiology has not been studied to any great extent in primary NHL of bone.
Due to its rare occurrence, the optimal treatment for primary NHL of bone is not known. Radiation, the traditional standard of care, may be given alone or, more commonly, combined with chemotherapy as a multimodality approach. The sequence of radiation and chemotherapy varies in the literature, and the optimal sequence of treatments is not currently known. [2, 4, 5, 6, 7, 9] CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisolone, rituximab) is a commonly utilized regimen. As necessary, stabilization of a pathologic fracture or laminectomy will occur before the initiation of other therapies. [2, 9] The use of bisphosphonates in primary NHL of bone has not been explored to any great extent. 
The following image depicts a radiograph with lytic lesions in an adult long bone.
Primary non-Hodgkin lymphoma (NHL) of bone can be a difficult to diagnosis without a high level of suspicion.  The most common presenting symptom is pain without antecedent trauma that is unrelieved by rest. [2, 8, 9, 6, 7] This condition can present as monostotic or polystotic disease, [4, 5, 6, 7, 8, 9] most often in the long bones of adults, with the femur being the most common location.
Other common locations include the vertebral column and pelvis. [2, 4, 5, 6, 8, 9] In children, cases appear with a similar frequency in the pelvis, vertebral column, and long bones and present most commonly in early adolescence with a predominance in males.  Regardless of age, presentations in the mandible, rib, palate, clavicle and scapula have also been reported. 
Patients can also present with a palpable mass, swelling, limp, night pain, pathologic fractures, spinal cord compression, and systemic B symptoms (fever, night sweats, weight loss). [2, 4, 5, 6, 7, 8, 9]
Anemia and/or elevated lactate dehydrogenase (LDH), alkaline phosphatase (ALP), erythrocyte sedimentation rates (ESRs), platelet counts, and calcium levels have been reported with primary non-Hodgkin lymphoma (NHL) of bone. [2, 9] Diagnostic testing typically includes, but is not limited to, the following laboratory and radiologic studies:
Complete blood cell (CBC) count
Peripheral blood smear
Routine serum chemistries
Serum lactate dehydrogenase (LDH) level
Bone marrow aspirate and biopsy
Bone biopsy (core needle, incisional or excisional)
Computed tomography (CT) scanning
Magnetic resonance imaging (MRI)
No specific radiologic findings are seen, and when detectable, primary NHL of bone can have a heterogeneous appearance with lytic, blastic, and mixed lesions reported (see the following image). [6, 7, 9] Additional imaging features include periosteal reaction, soft-tissue extension, pathologic fracture, and cord compression.  The radiologic differential diagnosis includes benign entities (reactive conditions, osteomyelitis) and malignant entities (Hodgkin lymphoma, sarcoma, neuroblastoma, metastatic disease).
Go to Malignant Lymphoma for complete information on this topic.
Grossly the lesions of primary non-Hodgkin lymphoma (NHL) of bone are usually yellow-tan and fleshy in appearance. There are usually no gross morphologic features that lend themselves to a specific characterization. Although no specific morphologic features have been seen in primary NHL of bone, sheets to clusters of small to large lymphocytes, with variable nuclear and cytoplasmic features, are typically seen (see the images below). In a review of primary NHL of bone, 103 of 131 reported cases (age range, 18-87 y) were diffuse large B-cell lymphoma (DLBCL).  DLBCL typically shows a polymorphic lymphoid infiltrate with conspicuous large cells, demonstrating vesicular chromatin and one of the following well described morphologic patterns: centroblastic, immunoblastic, T-cell histiocyte rich or anaplastic. 
Other subtypes of NHL have been reported to a lesser extent in adults, including follicular lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, mantle cell lymphoma, and Burkitt lymphoma. [4, 5, 6, 7] In children, DLBCL is the most common subtype, followed by lymphoblastic lymphoma. 
No specific immunophenotype has been reported for primary non-Hodgkin lymphoma (NHL) of bone, and immunophenotypic findings will depend on the subtype of NHL present. The majority of the cases are of the diffuse large B-cell lymphoma (DLBCL) subtype, and can be divided into cases of a germinal-center phenotype (CD10+, BCL-6+, MUM-1-) or cases of a nongerminal center phenotype (CD10-, BCL-6-, MUM-1+) by immunophenotyping (immunohistochemistry alone or in combination with flow cytometry). Of the non-DLBCL cases, the majority are of a B-cell phenotype. [4, 5, 6, 7] Occasional cases will show a T-cell phenotype, a finding that is more commonly seen outside the Western world.  See the following images.
The ability to perform a large-scale study of molecular findings in primary non-Hodgkin lymphoma (NHL) of bone is precluded both by the rarity of this entity and the effects of specimen decalcification (ie, nucleic acid degradation). To date, molecular findings in primary NHL of bone have been reviewed on a limited basis and have shown disparate results.
Lima and colleagues reviewed the molecular findings of 63 cases of primary diffuse large B-cell lymphoma (DLBCL) of bone by multiple modalities and found rearrangements of BCL-2 and c-MYC in a portion of their cases.  No case showed rearrangements of BCL-6, PAX-5, cyclin-D1, or ALK. Of note, one of their cases showed a dual rearrangement of c-MYC and BCL-2, a molecular finding more classically seen in nodal DLBCL. 
Due to the rarity of this disease, it is difficult to determine long-term prognosis in primary non-Hodgkin lymphoma (NHL) of bone. Factors such as age, sex, stage of disease, type of bone, number of bones involved, histologic subtype, lactate dehydrogenase (LDH) level, and the presence or absence of either pathologic fractures or spinal cord compression have been investigated. 
In an effort to clarify lymphoma staging, the International Prognostic Index (IPI) was designed to predict the risk of disease recurrence and overall survival, by taking into account factors such as age, stage of disease, performance status, number of extranodal sites, and the presence or absence of an elevated LDH.
Current understanding has shown that the overall survival (OS) of patients with primary bone lymphoma is better than that seen in nodal diffuse large B-cell lymphoma (DLBCL) and nonosseous extranodal lymphoma.  In a large-scale review of adult primary NHL of bone, 5- and 10-year OS was reported to be 62% and 41%, respectively, findings that were similar to previously reported survival data. [4, 5] OS rates of 40-100% have been reported in children. 
Disease progression or relapse of disease appears to confer a poor prognosis, in contrast to pathologic fracture, spinal cord compression, and/or multifocal disease. [2, 4] Using univariate analysis, a review of 15 pediatric cases showed a worse prognosis in children younger than 9 years and a negative trend with non–large cell histology, bone marrow involvement, elevated calcium and female sex. 
Conclusions regarding prognosis must be made with the understanding that current reported cases have a bias toward low-stage disease, low IPI score, and DLBCL.  In addition, prognosis depends on the inclusion criteria (ie, whether polyostotic disease and/or cases with bone marrow involvement are included). [2, 9]
A study reported that multifocal bone diffuse large B-cell lymphoma patients exhibit a significantly better prognosis compared to patients with advanced-stage diffuse large B-cell lymphoma. 
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Messina C, Ferreri AJ, Govi S, for the International Extranodal Lymphoma Study Group (I.E.L.S.G.). Clinical features, management and prognosis of multifocal primary bone lymphoma: a retrospective study of the international extranodal lymphoma study group (the IELSG 14 study). Br J Haematol. 2014 Mar. 164(6):834-40. [Medline].
Chisholm KM, Ohgami RS, Tan B, Hasserjian RP, Weinberg OK. Primary lymphoma of bone in the pediatric and young adult population. Hum Pathol. 2016 Aug 20 [Epub ahead of print]. [Medline].
Lesley Elizabeth Fox, MD Pathologist, ReitPath Pathology, Austin, Texas
Lesley Elizabeth Fox, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, Texas Medical Association, United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.
Francis H Gannon, MD Associate Professor of Pathology and Orthopedic Surgery, Director of Residency and Fellowship Programs, Department of Pathology, Baylor College of Medicine; Staff Pathologist, Department of Pathology, Texas Children’s Hospital, Ben Taub General Hospital and Debakey Veterans Affairs Medical Center
Francis H Gannon, MD is a member of the following medical societies: American Society for Bone and Mineral Research, International Academy of Pathology, International Skeletal Society, Texas Medical Association
Disclosure: Nothing to disclose.
Pathology of Primary Bone Lymphoma
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