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Kanavos, T.; Birbas, E.; Papoudou-Bai, A.; Hatzimichael, E.; Kitsouli, A.; Karpathiou, G.; Kanavaros, P. Primary Bone Lymphoma. Encyclopedia. Available online: (accessed on 23 June 2024).
Kanavos T, Birbas E, Papoudou-Bai A, Hatzimichael E, Kitsouli A, Karpathiou G, et al. Primary Bone Lymphoma. Encyclopedia. Available at: Accessed June 23, 2024.
Kanavos, Theofilos, Effrosyni Birbas, Alexandra Papoudou-Bai, Eleftheria Hatzimichael, Aikaterini Kitsouli, Georgia Karpathiou, Panagiotis Kanavaros. "Primary Bone Lymphoma" Encyclopedia, (accessed June 23, 2024).
Kanavos, T., Birbas, E., Papoudou-Bai, A., Hatzimichael, E., Kitsouli, A., Karpathiou, G., & Kanavaros, P. (2023, March 17). Primary Bone Lymphoma. In Encyclopedia.
Kanavos, Theofilos, et al. "Primary Bone Lymphoma." Encyclopedia. Web. 17 March, 2023.
Primary Bone Lymphoma

Primary bone lymphoma is a rare neoplasm of malignant lymphoid cells presenting with one or more bone lesions without nodal or other extranodal involvement. It accounts for approximately 1% of all lymphomas and 7% of malignant primary bone tumors.

bone lymphomas B-cells immunohistochemistry

1. Introduction

Primary bone lymphoma (PBL) is currently defined as a neoplasm composed of malignant lymphoid cells that presents with one or more bone lesions without nodal involvement or other extranodal lesions, according to the 2020 World Health Organization (WHO) classification of soft tissue and bone tumors [1][2]. The majority of PBLs represent non-Hodgkin lymphoma (NHL) and diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is by far the most common histological type [3]. PBL must be distinguished from the secondary bone involvement of systemic lymphomas, which occurs in 16–20% of lymphoma patients and carries a poor prognosis, whereas PBL is considered to have the most favorable prognosis of all malignant primary bone tumors [4][5][6]. Diagnosis of PBL, which is frequently delayed due to its non-specific clinical manifestations and equivocal radiographic findings, is based on the combination of clinical examination and imaging studies and confirmed by histopathological examination with immunohistochemical staining [7][8][9]. The present research summarizes the epidemiological, clinical, radiological and histological features, as well as the etiology, histogenesis, treatment and prognosis of PBL.

2. Epidemiology

PBL is a rare neoplastic disease and accounts for approximately 1% of all lymphomas, 3–7% of extranodal lymphomas and 7% of malignant primary bone tumors [4][10][11][12]. NHL constitutes the vast majority of PBLs with DLBCL, NOS, representing over 80% of all cases [10][13][14]. PBL of T-cell origin is extremely uncommon, but has a higher relative frequency in Japan and Taiwan compared to the West [15][16]. PBL may occur at all ages, with a typical diagnosis age of 45–60 years [10][15][17]. In addition, men are affected more than women, with a male/female ratio of 1.2–1.8 [3].

3. Clinical Findings

The clinical features of PBL are generally unspecific, frequently leading to a delay in diagnosis, and, thus, a high index of suspicion is required [18] [19]. The most common symptom of PBL is local bone pain in the affected area, which is not relieved by rest and has been characterized as insidious, intermittent and progressively worsening [20] [21] [22] [18] [23] [24] [19] [25] [26] [27] [28] [29]. Other less common manifestations include soft tissue edema, palpable mass, pathological fracture, restricted range of motion in the involved articulation and “B” symptoms, namely fever, night sweats and unintentional weight loss  [20] [21] [22] [30] [31] [19] [25] [28] [29] [32] [33]. The latter are present in a minority of patients and are less frequent in PBL compared to systemic lymphomas [20] [32]. Nonetheless, PBL should be considered in cases of fever of unknown origin, especially in the presence of bone pain [ [26]. Spinal cord compression and hypercalcemia due to osteolysis with related symptoms, such as lethargy, somnolence and constipation, are two major complications [20] [23] [28] [29] [32]. Cases of PBL involving the mandible or maxilla can manifest with toothache, loose teeth, gingiva edema and local numbness and are, therefore, often misdiagnosed as oral diseases [34] [35]. Cases with a history of preceding trauma in the affected area have also been reported [19] [36] [37] [38]. The average time between the onset of symptoms and the diagnosis is 8 months [20] [18].
PBL can develop in any part of the skeleton, although is most common in the femur, humerus, tibia, spine and pelvis [20] [21] [22] [18] [30] [23] [39] [40] [26] [27] [28] [32] [41]. Other less common sites of occurrence include the skull, forearm, scapula, clavicle, patella, hands and feet [21] [22] [23] [39] [40] [27] [33]. Interestingly, younger age has been associated with an appendicular location of PBL, which could be explained by the active bone marrow present in the long bones of younger patients [32]. In the case of long bones, PBL most frequently occurs in the metaphysis [40].

4. Treatment and Prognosis

As already mentioned, PBL is a heterogenous and uncommon disease, hindering the conduction of randomized clinical trials. Therefore, there is no standard treatment for this condition and the recommended strategies are derived from retrospective studies. Treatment options include chemotherapy or immunochemotherapy, radiotherapy and surgery [2][10]. Pain management in patients with bone tumors is of great significance. The supportive care for pain should be multimodal with the use of multiple complementary pharmacological and non-pharmacological approaches [42][43].
The role of surgery in the management of PBL is generally limited. Due to the progress of chemotherapy and radiotherapy, most surgical procedures have been performed for diagnostic purposes, namely biopsy [2][4][8][9][10][44]. Indications for surgical treatment of PBL include impeding or actual pathological fractures, neurological complications, such as spinal cord compression, segmental defects in long bones and skeletal or articular collapse caused by avascular necrosis following treatment [2][4][7][8][9][10][45]. Early surgical treatment of lower extremity pathological fractures before chemotherapy provides a better quality of life and helps the patient endure subsequent treatment and hospitalization. In the case of an upper extremity fracture, however, given the minor disability resulting from the use of a brace, surgical treatment can be delayed, allowing for early initiation of chemotherapy and radiotherapy [45]. Orthopedic care is significant during treatment and the recovery period, as the risk for fracture persists until complete bone healing. Patients with involvement of weight-bearing bones may rarely require internal stabilization or bracing until bone healing is achieved [9]. In a study conducted by Yang et al. [10], surgical treatment of primary bone DLBCL (PB-DLBCL), NOS did not affect survival.
Treatment of PBL is based on systemic therapy and the current modalities include chemotherapy or immunochemotherapy with or without radiotherapy, resulting in a 5-year overall survival (OS) of approximately 70% [2][7][8][9][10][46][47][48][49]. Anthracycline-based, multiagent chemotherapy comprising cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with or without the addition of rituximab (R-CHOP) is the preferred modality [2][9][10][44][45][46][47][49][50]. According to Ramadan et al. [51] the addition of rituximab to CHOP increased the 3-year progression-free survival (PFS) of patients with PBL from 52% to 88%, although Müller et al. [7] reported no difference in the OS between patients treated with CHOP and R-CHOP. Additionally, chemotherapy may decrease the risk of local recurrence in PBL and improve the prognosis of children and adults with disseminated disease [7]. Bruno Ventre et al. [50] reported a favorable prognosis of patients with PB-DLBCL, NOS who underwent chemotherapy with or without radiotherapy and claimed that chemotherapy is more effective than radiotherapy in PB-DLBCL, NOS cases. Indeed, chemotherapy has proven to be superior to radiotherapy for the treatment of PBL with a 10-year OS of 56 and 25%, respectively. However, various studies have shown improved OS with combined chemoradiotherapy compared to chemotherapy or radiotherapy alone [44]. Christie et al. [52] reported a 5-year OS of 90% in PBL patients treated with both chemotherapy with three cycles of CHOP and radiotherapy to a dose of 45 Gy in 25 fractions, whereas Müller et al. [7] reported a trend for better OS with chemotherapy combined with 4-6 cycles of CHOP and radiotherapy to a typical dose of 46 Gy, which was, however, statistically insignificant. Furthermore, Beal et al. [53] found that PBL patients managed with a combined modality versus a single modality therapy presented a significantly superior outcome, with a 5-year OS of 95 and 78%, respectively. Hence, chemotherapy and radiotherapy are usually combined for the treatment of PBL, achieving a 5-year OS of 80–90% [48]. The choice of chemotherapy regimen is based on the histology of PBL. R-CHOP is the preferred regimen when the PBL is of B-cell origin and CHOP when of T-cell origin. When anthracyclines are contraindicated, etoposide or gemcitabine can be used instead.
Radiotherapy was once the standard treatment of PBL with appropriate local disease control, but produced disappointing relapse rates, which led to the introduction of chemotherapy for the management of this neoplasm [9][44][49]. In a study conducted by Ma et al. [54], consolidation radiotherapy significantly improved the prognosis in early stage PB-DLBCL, NOS patients compared to chemotherapy alone, with a 5-year OS of 84.2 and 72.7%, respectively, but not in those with advanced stage disease. The same study reported a significantly increased long-term risk for second primary malignancies in early-stage patients with an age at diagnosis of 18–39 years or appendicular skeleton involvement, but not in advanced stage patients. Furthermore, neither early stage nor advanced stage cases were associated with an increased short-term risk for second primary malignancies. These findings can be partly explained by the fact that early stage, younger age and appendicular site of bone involvement were associated with remarkably extended survival time [54]. Various studies suggest that radiotherapy should only be performed as a consolidation modality [10]. When PBL involves areas associated with significant bone marrow production, such as the pelvis, application of radiotherapy should be carefully considered to avoid hematopoiesis-related complications [9][44].
PBL presents a generally favorable prognosis [8][10][14][46][48][55][56][57][58]. In fact, it is considered to possess the best prognosis of all primary malignant bone tumors and better prognosis than secondary bone lymphoma [4][5]. In a study conducted by Li et al. [56], patients with PB-DLBCL, NOS showed significantly better survival compared to those with secondary bone DLBCL, NOS and non-osseous DLBCL, NOS. The prognosis of PBL in the pediatric population is even better, despite the rapid progression, elevated incidence of micrometastasis and tendency to spread to the central nervous system that characterize PBL in children [14][46]. Suryanarayan et al. [59] studied 31 cases of pediatric PBL and reported a 5-year PFS and OS of 95 and 100%, respectively. In cases of complete response, even elderly people may have a long-term survival [58].
Advanced age is an important, unfavorable predictor of survival in patients with PBL [2][7][10][44][45][51][60][61][62]. Specifically, Demicray et al. [61] reported a 5-year disease-free survival of 90% in patients younger than 60 years and 62% in patients aged 60 years old or older. Furthermore, Jawad et al. [13] found 5-year disease-specific survival rates of 87, 74 and 45% in patients with diagnosis age of less than 30, 30–59 and 60 or more years old, respectively. Other adverse prognostic factors include advanced stage determined by either the Ann Arbor or Lugano classification system, declining performance status, high International Prognostic Index (IPI) score, raised lactate dehydrogenase (LDH) levels, multifocality, soft tissue extension and local relapse, which occurs in approximately 10% of patients [2][5][7][8][44][46][51][63][64][65]. Furthermore, Yang et al. [10] reported a significantly lower survival for tumors in the spine compared to the extremity bones, which may be related to the compression of nerves and the complications of this phenomenon, while Liu et al. [63] found a significant survival disadvantage for axial compared to appendicular or craniofacial lesions. In addition, PBLs of T-cell origin exhibited worse prognosis than their B-cell counterparts in a study conducted by Hsieh et al. [15]. In contrast, complete response to treatment has been identified as a favorable prognostic marker of PBL [62][66].


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