Primary bone lymphoma.
Abstract: * Primary bone lymphomas are rare, even though secondary involvement of the bone marrow is a common event in systemic lymphomas. Most primary bone lymphomas are primary bone diffuse large B-cell lymphomas (PBDLBCLs) with a rare occurrence of follicular, marginal zone, anaplastic large cell, Hodgkin, and T-cell lymphomas. The PBDLBCL affects the middle-aged to elderly population, with a slight predominance in men. The patients present with bone pain, palpable mass, fractures, or neurologic symptoms. The metaphysis of bones is a common location of PBDLBCL. Morphologically, the lymphoma consists of a polymorphous mixture of small to large cells with multilobated nuclei, fine chromatin, and inconspicuous to prominent nucleoli. Differential diagnoses for PBDLBCL include chronic osteomyelitis, primary bone sarcoma, leukemic infiltrate, Ewing sarcoma, metastatic sarcomas, and carcinoma. Most PBDLBCLs are treated with combined radiotherapy and chemotherapy with good prognosis.
Article Type: Report
Subject: Lymphomas (Diagnosis)
Lymphomas (Care and treatment)
Bone cancer (Diagnosis)
Bone cancer (Care and treatment)
Chemotherapy (Usage)
Chemotherapy (Standards)
Cancer (Chemotherapy)
Cancer (Usage)
Cancer (Standards)
Authors: Bhagavathi, Sharathkumar
Fu, Kai
Pub Date: 11/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: Nov, 2009 Source Volume: 133 Source Issue: 11
Topic: Event Code: 350 Product standards, safety, & recalls
Accession Number: 230152099
Full Text: Lymphomas commonly occur in the lymph nodes, and extranodal sites are a less frequent origin of lymphomas. Primary bone lymphomas (PBLs) are rare, even though secondary involvement of the bone marrow is a common event in systemic lymphomas. Primary bone lymphoma was first described by Oberling in 1928.1 Parker and Jackson reported a PBL series in 19392 under the designation reticulum cell sarcoma of bone, establishing PBL as a distinct entity. The lymphoid and B-cell origin was subsequently proved by immunohistochemistry. (3,4) Primary bone lymphoma is defined as a lymphoma that is confined to the bone or bone marrow without evidence of concurrent systemic involvement. According to the 2002 World Health Organization classification of tumors of soft tissue and bone, the criteria for a diagnosis of PBL are (1) a single skeletal tumor without regional lymph node involvement, and (2) multiple bone lesions without visceral or lymph node involvement. (5)

Primary bone lymphomas account for less than 1% of all malignant lymphomas, 7% of malignant bone tumors, and 4% to 5% of extra nodal lymphomas. (5,6) Most PBLs are primary bone diffuse large B-cell lymphomas (PBDLBCL) with a rare occurrence of follicular, marginal zone, anaplastic large cell, Hodgkin, and T-cell lymphomas. (5)

Herein, we reviewed the clinical features, gross and microscopic findings, ancillary studies, differential diagnoses, prognostic markers, and treatment of PBDLBCL. Rare variants of PBL are also described briefly.

PRIMARY BONE DIFFUSE LARGE B-CELL LYMPHOMA

Clinical Features

This disease commonly affects the middle-aged to elderly population, with a median age of 48 years. However, it has also been described in pediatric patients as well. (7,8) Most reports in the literature suggest a slight male predominance of 1.5:1. The most common presentation of patients with PBDLBCL is bone pain, and less-frequent presentations include a palpable mass and bone fracture. Very rarely, patients have presented with neurologic symptoms, such as paraplegia from compression. Compared with systemic lymphomas, the systemic or B symptoms occur less frequently with PBDLBCL. Rarely, symptoms caused by hypercalcemia (eg, lethargy, constipation, and somnolence) may be present. (6)

Anatomic Location

Beal et al (9) reported a series of PBDLBCL that included 82 patients. In that series, the frequency of different bone involvement was femur (27%), pelvis (15%), tibia/fibula (13%), polyostotic (13%), humerus (12%), spine (9%), other (5%), mandible (2%), radius/ulna (1%), scapula (1%), and skull (1%). Rarely, small bones of the hands and feet are involved in PBDLBCL.

Radiographic Findings

The metaphysis is the most common site of occurrence in long bones. The lesion shows varying areas of sclerosis and osteolysis, producing a "moth-eaten" appearance. (10) After cortical bone destruction, the tumor extends into the soft tissue. Sclerotic PBL may be mistaken for osteoblastic metastasis or Paget disease. (10)

Staging

After bone biopsy confirms the diagnosis of PBDLBCL, computed tomography examinations of the chest, abdomen, and pelvis are usually performed to exclude a primary nodal origin or distant disease. A magnetic resonance imaging scan is conducted to stage the extent of the disease within the affected bone.

Macroscopic Features

In most patients, the diagnosis of PBDLBCL is verified by needle biopsy. Rarely, a portion of the bone may be resected because of a fracture, and it may grossly show extraosseous extension, indistinct margins, and a soft fleshly appearance, similar to that of systemic lymphoma. (5)

Microscopic Features

Most PBDLBCLs show a diffuse growth pattern. The bone trabeculae may be normal or thickened. The lymphoma cells permeate between the trabeculae and medullary fat. The lymphoma consists 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 (Figure 1, A). Occasionally, the lymphoma shows immunoblastic morphology with round nuclei, abundant amphophilic cytoplasm, and prominent nucleoli. (11) The background shows an infiltration by mature T cells. Fine reticular fibers and occasional diffuse fibrosis are seen between the cells. The prominent fibrosis may lead to spindling of the lymphoma cells, which gives a sarcomatous appearance. Rarely, clear cytoplasm and signet ring cells mimic metastatic adenocarcinoma. (10) The tumor cells may be crushed during a biopsy procedure, which may lead to difficulty in diagnosis. Prolonged decalcification may affect both cytologic features and immunohistochemical staining. (10)

Differential Diagnosis

Differential diagnoses for PBL include chronic osteomyelitis, primary bone sarcoma, leukemic infiltrate, small blue round cell tumors (including Ewing sarcoma/primitive neuroectodermal tumor, rhabdomyosarcoma, metastatic neuroblastoma, and small-cell osteosarcoma), metastatic sarcomas, mesenchymal chondrosarcoma, and metastatic carcinoma.

The polymorphous morphology of PBL simulates chronic osteomyelitis. Apart from immunohistochemical staining, clinical history and nuclear features help to differentiate lymphoma from chronic osteomyelitis. The large, neoplastic cells with a background of small lymphocytes, a positive lymphoid (CD20), and molecular markers (immunoglobulin heavy chain [IgH] gene rearrangement) facilitate the arrival at a lymphoma diagnosis.10 However, molecular studies may not be possible sometimes because of decalcification. Thus, a sample sent for flow cytometry study and well-prepared, unstained touch-imprint smears may be helpful. The latter can be sent for molecular studies, if needed.

Granulocytic sarcomas are occasionally present as bone tumors. They show eosinophilic, granulocytic maturation and lack atypical large lymphoid cells. Histochemical staining for myeloperoxidase and lysozyme in the neoplastic cells helps to confirm the diagnosis of granulocytic sarcoma.

Primary bone diffuse large B-cell lymphomas may show a sarcomatous appearance because of fibrosis. Apart from the multicentric origin and diffuse bone marrow involvement, immunohistochemical staining for CD45, B-cell markers, and T-cell markers helps to differentiate lymphoma from sarcomas. (5)

The cells of Ewing sarcoma/primitive neuroectodermal tumor are monomorphic and express vimentin, CD99 (MIC2), and FLI1. They may be positive for neural markers, such as neuron-specific enolase, chromogranin, and synaptophysin. The neoplastic cells of lymphoblastic lymphoma are usually positive for terminal deoxynucleotidyl transferase.

The metastatic carcinomas are positive for cytokeratins and negative for lymphoid markers. Clinical history may be helpful as well.

Ancillary Studies

The tumor cells in DLBCL are positive for CD45, CD20, CD79a, and PAX5 (B-cell markers) and negative for CD3 and CD5 (T-cell markers). Primary bone lymphoma can be further divided into germinal-center B-cell type and non-germinal-center B-cell type by using CD10, BCL6, and MUM1 antibodies (Figure 1, B through D). (12) It has been shown in nodal lymphomas that the germinal-center B-cell subtype has a better prognosis than the non-germinal-center B-cell subtype, even with the addition of rituximab. (13)

Cytogenetic and Molecular Studies

In the literature, cytogenetic and molecular studies of PBDLBCL are limited. In the study by Huebner-Chan et al, (11) 72% (13 of 18) of the cases showed IgH gene rearrangement (Figure 1). However, none of these cases in their series showed BCL2 /IgH rearrangement. In the study by de Level et al, (14) only 1 out of 23 cases (4%) showed BCL2/IgH rearrangement. Even though BCL2 protein was expressed in 55%11 and 70% of cases (14) in both studies, the low to absent incidence of BCL2/IgH rearrangements indicates that other mechanisms (eg, amplification of the BCL2 gene)may be responsible for the overexpression of the BCL2 protein. The most recent study using fluorescence in situ hybridization (15) has shown 28% of BCL2 (9 of 32) and 9% of c-MYC (3 of 32) translocations in PBDLBCL. However, none of these cases showed BCL6, PAX5, ALK, and CCND1 rearrangements. (15) The authors conclude that PBDLBCL represents a specific group among extranodal B-cell lymphomas. To date, there are no published studies evaluating gene expression profiles in PBDLBCL.

Treatment and Prognosis

Most PBDLBCLs are treated with combined radiotherapy and chemotherapy. The radiotherapy dose ranges from 2000-6150 centigrays (cGy) with a median dose of 4400 cGy. The chemotherapy regimen usually consists of cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab. A study by Beal et [al.sup.9] has illustrated the various treatment strategies for PBDLBCL and their outcomes. Among 81 patients with available follow-up information, 46 patients (56%) received combined treatment with chemotherapy and radiotherapy, 24 patients (29%) received chemotherapy, and 11 patients (13%) received radiotherapy alone. The 5-year overall survival, disease-specific survival, and freedom from treatment failure were 88%, 96%, and 81%, respectively. In a study by Ramadan et al, (16) 3-year progression-free survival in patients who received rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone was 88% compared with 52% for those who received only cyclophosphamide, doxorubicin, vincristine, and prednisone. (16) Age greater than 60 years at presentation, with higher international prognostic index scores (4-5), are associated with poorer prognosis.

PRIMARY BONE LYMPHOMAS OTHER THAN PBDLBCL T-Cell Lymphomas

T-cell PBLs are extremely rare. Only case reports and small case series, to our knowledge, have been described in the literature. In a study by Ostrowski et al, (17) 1 case of T-cell PBL was reported out of 422 bone lymphomas (0.2%). This study also included systemic lymphomas that spread to bone. A Japanese series by Ueda et al (18) reported an incidence of 8.8% (3 of 34). This could be a function of the higher prevalence of T-cell lymphoma in Japan in comparison to Western countries. T-cell origin was ascertained mainly by immunophenotyping and, rarely, by T-cell receptor gene rearrangement. The lymphoma exhibited a cell size from small to medium in 50% of the cases and either pleomorphic or medium to large cells in the other 50% of cases.

[FIGURE OMITTED]

Anaplastic Large Cell Lymphoma

Primary bone anaplastic large cell lymphomas are uncommon, and to our knowledge, only a few case reports and a small case series have been reported in the literature. (19) The mean patient age is 33 years, with a range of 4 to 63 years. This lymphoma mainly involves the axial bones. Differential diagnoses include small blue round cell tumors, eosinophilic granuloma and osteomyelitis in children, and metastatic tumors, sarcoma, and melanoma in elderly patients. The tumor consists of large cells with pleomorphic nuclei and multiple prominent nucleoli. Most lymphomas are positive for CD30 and some of the T-cell markers, and staining for CD45 and epithelial membrane antigen is variable. The expression of cytotoxic proteins, TIA-1, perforin, and granzyme B is also variable. Most anaplastic large cell lymphomas show the t(2:5) that fuses ALK (anaplastic lymphoma kinase) on chromosome 2 with the NPM (nucleophosmin) on chromosome 5. This can be detected immunohistochemically by reactivity with an ALK-1 antibody. Morphologic variants include lymphohistocytic and small cell types, and variability makes diagnosis a challenge. Immunohistochemical markers, such as epithelial membrane antigen, cytokeratin, S100, CD1a, CD99, FLI1, neuron-specific enolase, and lymphoid markers, are used to differentiate anaplastic large cell lymphomas from other tumors. T-cell receptor gene rearrangement studies are useful for confirming T-cell lymphoma. (20) Multifocal disease, ALK-1 negativity, tumor necrosis, and advanced age are associated with poorer prognosis.

Hodgkin Lymphoma

Hodgkin lymphoma (HL) is typically a systemic disease in which 10% to 20% of cases show involvement of the bone during the progression of the disease. Primary HL of bone is even rarer than primary non-Hodgkin lymphoma of bone. Few case reports of primary bone HL involving either single or multiple bones have, to our knowledge, been described in the literature. (21,22) The bones frequently involved are the pelvic bones, humerus, vertebra, and femur. Hodgkin lymphoma of bone is often misdiagnosed as osteomyelitis because of the similar clinical and radiologic features. (20) Radiologically, HL of bone shows osteolysis, osteosclerosis, or mixed osteosclerosis/osteolysis. Differential diagnoses include osteomyelitis, non-Hodgkin lymphoma, metastasis, leukemia, and primary bone sarcoma.

Mixed cellularity and nodular sclerosis are commonly observed subtypes of HL. Identification of Reed-Sternberg cells or their variants in the appropriate nonneoplastic background, consisting of lymphocytes, granulocytes, histiocytes, plasma cells, and fibroblasts, is required for the diagnosis. Immunoreactivity of Reed-Sternberg cells for CD30 and CD15 confirms the diagnosis. Solitary osseous HLs are treated with local radiotherapy alone and show a good prognosis. (22)

Other Lymphomas

Primary follicular, small lymphocytic, marginal zone, and lymphoplasmacytic lymphomas of bone are extremely rare.

CONCLUSION

Diffuse large B-cell lymphoma is the most common type of PBL. The molecular mechanisms involved in the pathogenesis of PBDLBCL are not yet fully understood. The difference between PBDLBCL and other extranodal DLBCL is still controversial. Addition of rituximab to the standard chemotherapy significantly improves the overall survival in patients with PBDLBCL.

References

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(8.) Bakshi NA, Ross CW, Finn WG, et al. ALK-positive anaplastic large cell lymphoma with primary bone involvement in children. Am J Clin Pathol. 2006; 125(1):57-63.

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Sharathkumar Bhagavathi, MD; Kai Fu, MD, PhD

Accepted for publication December 2, 2008.

From the Department of Hematopathology, Indiana University, Indianapolis, Indiana (Dr Bhagavathi); and the Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska (Dr Fu).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Kai Fu, MD, PhD, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198 (e-mail: kfu@unmc.edu).
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