Primary bone lymphoma

Primary bone lymphoma (PBL) is a malignant neoplasm of lymphoid cells arising within bone without significant lymph node or other extranodal involvement.[1] It is classified among extranodal non-Hodgkin lymphomas and accounts for 1–2% of all lymphomas and 3–7% of malignant bone tumors.[1][2] The vast majority are diffuse large B-cell lymphomas (DLBCL).[3][4] In the jaws, PBL is uncommon but clinically important because it frequently mimics periapical inflammatory disease or squamous cell carcinoma, leading to diagnostic delay.[5][6] The characteristic imaging pattern is an ill-defined radiolucency with a permeative or moth-eaten pattern of bone destruction, often accompanied by a soft-tissue mass that appears disproportionately large relative to the degree of cortical destruction.[2][7] Management is nonsurgical, relying on immunochemotherapy with or without radiation therapy, distinguishing it fundamentally from carcinomas and sarcomas of the jaws.[5][8]

Current Classification

The WHO Classification of Haematolymphoid Tumours (5th edition, 2024) and the International Consensus Classification (ICC, 2022) both recognize DLBCL, not otherwise specified (DLBCL-NOS) as the entity encompassing most primary bone lymphomas.[9][10] PBL is listed in the WHO Classification of Tumours of Soft Tissue and Bone as "primary non-Hodgkin lymphoma of bone" but is not designated as a separate lymphoma entity or subentity in either the WHO-HAEM5 or ICC lymphoid neoplasm classifications.[1]

Historical and Obsolete Terms

• Reticulum cell sarcoma — the original designation used from the 1930s through the 1970s, based on the erroneous assumption that these tumors arose from reticular (histiocytic) cells rather than lymphocytes.[11][12][13]
• Histiocytic lymphoma — the Rappaport classification term that replaced "reticulum cell sarcoma," also now obsolete.[11][14]
• Both terms were abandoned after immunophenotyping demonstrated that the overwhelming majority of these tumors are of B-lymphocyte origin.[15][16]

Awareness of these obsolete names remains important when interpreting older literature and archival pathology reports.

• Incidence: 1–2 per million per year worldwide.[1]
• Age: Predominantly affects middle-aged to elderly adults (median approximately 50–55 years), though cases span from childhood to the ninth decade.[2][4]
• Sex: Slight male predominance (male-to-female ratio approximately 1.6–1.8:1).[2][4]
• Skeletal distribution: Long bones (femur, tibia, humerus) are the most common sites overall; the jaws are infrequently involved. Among jaw lymphomas, the maxilla is affected more often than the mandible, and the posterior alveolar regions are the most common intraoral sites.[2][17][18][19]
• Jaw lymphomas in context: Lymphomas are the second most common non-epithelial malignancy of the oral and maxillofacial region after squamous cell carcinoma. Jaw involvement accounts for less than 1% of all non-Hodgkin lymphomas.[6][20][21]

A distinct epidemiologic variant is endemic Burkitt lymphoma, which classically presents as a jaw mass in young children (peak 3–7 years) in equatorial Africa and Papua New Guinea, driven by EBV and Plasmodium falciparum co-infection.[22][23]

Presentation and Symptoms

• Pain and swelling are the most common presenting complaints; pain is often dull, persistent, and poorly localized, mimicking odontogenic infection.[6][24]
• Tooth mobility and spontaneous loosening of teeth occur when the alveolar process is infiltrated.[6][25]
• Paresthesia or numbness of the inferior alveolar nerve distribution (numb chin/lip) is a characteristic finding that should raise suspicion for malignancy, particularly when no obvious dental cause is identified.[6][26][27]
• Gingival or alveolar swelling may present as a broad-based, firm, non-tender mass, sometimes with mucosal ulceration.[6][20]
• Non-healing extraction socket — failure of a socket to heal after tooth removal is a recognized red flag.[6][24]

Tempo and Diagnostic Pitfalls

Jaw lymphomas frequently follow a rapid clinical course, with maxillary alveolar lesions in particular showing a short interval between symptom onset and presentation.[5] Approximately half of jaw lymphomas are initially misdiagnosed as periapical inflammatory disease or periodontal disease, and the other half as carcinoma.[5][24] Diagnostic delay is common and is typically associated with initial misdiagnosis as an odontogenic lesion that fails to respond to endodontic or periodontal treatment.[26][28][29]

Systemic Symptoms

Constitutional B symptoms (fever, night sweats, weight loss) are occasionally present but are less common in localized PBL than in systemic lymphoma.[17][30]

Location and Distribution

In the jaws, PBL most commonly involves the posterior body and ramus of the mandible or the posterior maxillary alveolus.[5][18] Maxillary involvement is reported more frequently than mandibular involvement in jaw lymphoma case series.[18][19] Lesions may be centered in the alveolar process, body, or ramus, and can extend across anatomic boundaries into the maxillary sinus, nasal cavity, or infratemporal fossa.[21][31]

Periphery and Shape

• The margins are characteristically ill-defined and diffuse, lacking a corticated border.[6]
• The outline is irregular and does not conform to a recognizable geometric shape, distinguishing it from most odontogenic cysts and benign tumors.[6]
• On panoramic radiographs, the lesion may appear as a poorly demarcated radiolucency that blends imperceptibly into surrounding normal bone.[6][32]

Internal Architecture

• The dominant pattern is radiolucent, with a permeative or moth-eaten pattern of bone destruction being the most common appearance.[2]
• A mixed radiolucent-radiopaque (mixed-density) pattern is occasionally seen.[2][33]
• Rarely, a predominantly sclerotic (radio-opaque) pattern occurs, which can mimic osteomyelitis or osteosarcoma; this atypical presentation has been documented in the maxilla on CBCT.[34]
• No internal calcification, septation, or tooth-like structures are present.

Effects on Teeth and Adjacent Structures

• Periapical radiolucencies mimicking inflammatory periapical lesions are a common and diagnostically treacherous presentation; the involved teeth may test vital on pulp testing.[26][29][35]
• Widening of the periodontal ligament space around involved teeth, sometimes progressing to a "floating teeth" appearance, is a recognized finding that should prompt consideration of malignancy.[25][31]
• Tooth displacement may occur, and loss of the lamina dura around affected teeth is common.[6][36]
• Root resorption is generally uncommon in jaw lymphoma, which can help distinguish it from some odontogenic lesions, though it is not a reliable exclusionary finding.[19]
• Destruction of developing tooth crypts is characteristic of Burkitt lymphoma in children.[36]
• Enlargement of the inferior alveolar canal on panoramic radiography is an occasional finding that correlates with perineural tumor infiltration and clinical paresthesia.[27]

Cortical Involvement and Extent

A hallmark feature of bone lymphoma is the disproportion between the extent of marrow involvement and the degree of cortical destruction — the soft-tissue component and marrow infiltration are often far more extensive than the cortical breach would suggest.[7][32][37] This finding, when identified on cross-sectional imaging, is considered the most critical radiologic clue to the diagnosis.[7][37]

• Cortical destruction, when present, tends to be mild to moderate relative to the overall tumor volume.[32][38]
• Periosteal reaction is occasionally seen in mandibular lesions, typically as a layered or interrupted pattern along the lingual or buccal cortex.[2][39]
• Sequestra (islands of devitalized bone within the destructive lesion) occur occasionally in bone lymphoma and, when present, can mimic osteomyelitis.[40]
• Extension into the maxillary sinus with destruction of the sinus floor is common in maxillary lesions.[21][34]
• Pathologic fracture is rare in jaw lesions but is a recognized complication in long-bone PBL.[2]

Variants and Special Patterns

• Burkitt lymphoma of the jaws produces rapidly destructive, poorly circumscribed osteolytic lesions, often near the angle of the mandible or in the posterior maxilla, with large associated soft-tissue masses and destruction of developing tooth buds in children.[36][38]
• Lesions mimicking periapical pathology — small, localized radiolucencies at the apices of teeth that are indistinguishable from periapical granulomas or cysts on conventional radiographs represent a well-documented diagnostic trap.[26][28][29]
• Normal-appearing radiographs — early or small lesions may produce no detectable abnormality on panoramic or periapical radiographs, necessitating advanced imaging when clinical suspicion is high.[7][32]

MRI

MRI is the preferred modality for evaluating the extent of marrow infiltration and soft-tissue involvement.[7][41] Lesions typically appear isointense to hypointense on T1-weighted images and isointense to slightly hyperintense on T2-weighted sequences, with moderate homogeneous enhancement.[7][30] The relative homogeneity and absence of central necrosis can help distinguish lymphoma from squamous cell carcinoma, which tends to show more heterogeneous signal and necrosis.[31][38] MRI is also superior for assessing skull base invasion, perineural spread, and orbital involvement.[41]

Medical CT

Contrast-enhanced CT demonstrates a soft-tissue density mass with bone destruction and is useful for evaluating cortical integrity and sinus involvement.[21][39] The soft-tissue component typically enhances mildly and homogeneously, without the marked necrosis seen in carcinomas.[38] CT is complementary to MRI for assessing cortical bone erosion.[41]

PET/CT

FDG-PET/CT is essential for staging, as it identifies additional skeletal and extraskeletal sites of disease, distinguishes primary from secondary bone lymphoma, and is used for treatment response assessment.[33] DLBCL is characteristically FDG-avid.[19]

Primary bone lymphoma of the jaws must be distinguished from other aggressive radiolucent lesions and from conditions that produce periapical or alveolar radiolucencies. The ill-defined, permeative destruction with disproportionately preserved cortex and associated soft-tissue mass, particularly in a middle-aged or older adult with paresthesia, should raise suspicion for lymphoma.

The highest-risk diagnostic pitfall is misidentification of lymphoma as a periapical inflammatory lesion, leading to unnecessary endodontic treatment and delayed diagnosis. Any periapical radiolucency associated with vital teeth, unexplained paresthesia, progressive tooth mobility without periodontal disease, or failure to resolve after appropriate dental treatment warrants biopsy.[6][24][26]

Microscopic Features

The vast majority of primary bone lymphomas are DLBCL-NOS.[3][4] The tumor consists of diffuse sheets of large atypical lymphoid cells with round to irregular or multilobated nuclei, fine to vesicular chromatin, and inconspicuous to prominent nucleoli.[3][4] A polymorphous mixture of small and large cells may be present.[3] Mitotic figures are frequent. The bone marrow spaces are diffusely replaced by tumor, with permeation through Haversian canals explaining the characteristic imaging pattern of marrow infiltration with relatively preserved cortex.[7]

Immunophenotype

• Pan-B-cell markers are positive: CD20, CD19, CD79a, PAX5.[4][43]
• Cell-of-origin subtyping uses the Hans algorithm: CD10, BCL6, and IRF4/MUM1 distinguish germinal center B-cell (GCB) from non-GCB subtypes.[4][42]
• Approximately half of primary bone DLBCL cases show a GCB immunophenotype, which is associated with a more favorable prognosis.[1][42]
• BCL2 protein is expressed in the majority of cases; MYC rearrangement should be assessed by FISH, as dual MYC/BCL2 rearrangement (double-hit) identifies high-grade B-cell lymphoma with a worse prognosis.[4][43][44]
• Ki-67 proliferation index is variable but often high.[4]

Molecular Features

Recent genomic profiling has demonstrated that primary bone DLBCL frequently harbors an EZB-like mutational profile (enriched for EZH2, KMT2D, CREBBP, and TNFRSF14 mutations), supporting a germinal center origin and potentially explaining the favorable prognosis relative to nodal DLBCL.[1]

Radiologic-Pathologic Correlation

The permeative growth through marrow spaces and Haversian canals, with relative preservation of cortical bone, directly accounts for the imaging hallmark of a large soft-tissue mass with surprisingly little cortical destruction.[7] Sequestra result from tumor encasement and devascularization of cortical bone fragments.[40]

Other Histologic Subtypes

Rare subtypes arising as PBL include follicular lymphoma, marginal zone lymphoma, anaplastic large cell lymphoma, Hodgkin lymphoma, and T-cell lymphomas.[3] Burkitt lymphoma of the jaws shows sheets of intermediate-sized cells with a "starry sky" pattern from tingible body macrophages, a Ki-67 index approaching 100%, and the hallmark t(8;14) MYC translocation.[22][45]

Workup and Referral

When jaw lymphoma is suspected based on clinical and imaging findings, incisional or core biopsy with immunohistochemistry and flow cytometry is essential for definitive diagnosis.[5][43] Fine-needle aspiration alone is insufficient.[43] Once lymphoma is confirmed, referral to hematology-oncology is mandatory. Staging with FDG-PET/CT is required to distinguish primary from secondary bone involvement and to determine disease extent.[33] The Ann Arbor staging system (modified Lugano classification) is used for staging.[12][17]

Treatment

• Immunochemotherapy is the cornerstone of treatment. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is the standard first-line regimen for DLBCL, including primary bone DLBCL.[8][21][43]
• Consolidative radiation therapy (typically 30–45 Gy) to the involved bone site has historically been added after chemotherapy. A large single-institution series demonstrated improved progression-free and overall survival with the addition of consolidative RT. However, a multicenter retrospective study in the rituximab era found that consolidative RT did not significantly improve outcomes in patients achieving complete metabolic response after rituximab-based immunochemotherapy, suggesting RT may be reserved for patients with partial response.[8][46]
• Radical surgical resection is not indicated — this is a critical distinction from jaw carcinomas and sarcomas.[5][18]

Prognosis

PBL carries a more favorable prognosis than many other primary malignant bone tumors and than nodal or other extranodal DLBCL:[1][7]

• Five-year overall survival is approximately 70–82% with modern immunochemotherapy-based regimens.[8][47]
• Complete response to initial treatment is achieved in approximately 73% of patients.[47]
• Ten-year overall survival is approximately 60–77%.[8][47]

Prognostic Factors

• Age >60 years and polyostotic disease are associated with worse outcomes.[47]
• GCB immunophenotype is associated with longer overall survival compared with non-GCB.[42]
• Stage (localized IE/IIE vs. advanced) remains the most important clinical prognostic variable.[12][17]
• Skeletal involvement in DLBCL may confer a worse prognosis with rituximab-based therapy compared with non-skeletal extranodal sites, and additive radiotherapy to bone sites may partially mitigate this effect.[48]

Surveillance

Follow-up includes clinical examination and laboratory studies every 3–6 months for 5 years, with CT imaging no more often than every 6 months for 2 years; PET/CT is appropriate for surveillance when disease is only visualized on PET.[43]

Burkitt Lymphoma of the Jaws

Endemic Burkitt lymphoma represents a distinct clinical scenario in the maxillofacial region. It is the most common childhood malignancy in sub-Saharan Africa, classically presenting as a rapidly growing jaw mass in children aged 3–7 years.[22][23] EBV is present in virtually all endemic cases, and Plasmodium falciparum malaria is a critical co-factor.[22] Contemporary data suggest that abdominal presentation is now more common than jaw involvement even in endemic regions.[22][49] Treatment is chemotherapy-based, and localized disease carries a favorable prognosis.[36][50] Sporadic Burkitt lymphoma rarely involves the jaws.[23]

Immunodeficiency-Associated Lymphoma

Patients with HIV/AIDS or iatrogenic immunosuppression are at increased risk for aggressive B-cell lymphomas, including DLBCL and Burkitt lymphoma, which may present in the jaws.[22] Plasmablastic lymphoma, a rare aggressive variant strongly associated with HIV and EBV, has a predilection for the oral cavity and jaws.[19]