Non-Hodgkin lymphoma

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignant clonal proliferations of lymphoid cells; roughly 85–90% are of B-cell origin, with the remainder arising from T cells or natural killer (NK) cells.[1][2] In the jaws, NHL is predominantly an aggressive, high-grade, extranodal process, most commonly diffuse large B-cell lymphoma (DLBCL), followed by Burkitt lymphoma, plasmablastic lymphoma, and extranodal NK/T-cell lymphoma, nasal type[3][4]; indolent MALT and follicular lymphomas occur mainly in oral soft tissues and minor salivary glands.

• Biologic behavior: rapidly growing and locally destructive; frequently misread clinically and radiographically as an odontogenic infection or reactive process, producing diagnostic delay.[3][6]
• Usual site: soft-tissue predominance (gingiva, palate, buccal mucosa) with secondary bone invasion; true intraosseous (primary bone) lymphoma of the jaws is less common but well recognized.[7][8]
• Etiology/pathogenesis (when established): germinal-center and post-germinal-center B-cell transformation driven by error-prone somatic hypermutation and class-switch recombination; a subset is virus-associated (Epstein-Barr virus, human herpesvirus-8), particularly in immunosuppressed hosts.[2][9]
• Signature imaging pattern: an ill-defined osteolytic lesion with disproportionately mild cortical destruction relative to tumor extent.[3][10]
• Management direction: tissue diagnosis followed by systemic chemoimmunotherapy, not surgical resection.[11][12]

NHL is defined in contrast to Hodgkin lymphoma and encompasses all mature and precursor B-cell, T-cell, and NK-cell neoplasms. Current classification follows two parallel, largely concordant 2022–2024 frameworks: the WHO Classification of Haematolymphoid Tumours (WHO-HAEM5, 2022; print 2024) and the International Consensus Classification (ICC, 2022).[2][11][40] Both integrate morphology, immunophenotype, and molecular genetics, and differ only in selected nomenclature and provisional entities.[2]

• Accepted entity names relevant to the jaws: DLBCL, not otherwise specified (NOS); Burkitt lymphoma; plasmablastic lymphoma; high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements; extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma); and extranodal NK/T-cell lymphoma, nasal type.[11] WHO-HAEM5 names two of these differently, "extranodal NK/T-cell lymphoma" (dropping "nasal type") and "DLBCL/HGBL with MYC and BCL2 rearrangements," whereas the ICC retains HGBL terminology for double-hit lymphoma.[2][40]
• Useful aliases: "non-Hodgkin's lymphoma"; "double-hit/triple-hit lymphoma" is informal shorthand for HGBL with concurrent MYC plus BCL2/BCL6 rearrangements.[11]
• Obsolete usage: "MALToma" and the older term "histiocytic lymphoma" (an outdated designation for large-cell lymphoma) should be avoided to prevent confusion.

Oral lymphomas are uncommon, representing less than 5% of all lymphomas, but rank among the more frequent oral malignancies after squamous cell carcinoma and salivary gland carcinoma.[9] Primary aggressive oral lymphomas account for only about 2–3% of all lymphomas.[4]

• Age: broad range spanning childhood to the ninth decade; the pooled mean age is approximately 52 years, and DLBCL most often presents in the sixth to seventh decades. Burkitt lymphoma skews markedly younger.[8]
• Sex: a modest male predominance (roughly 1.6:1) is reported across oral series.[8]
• Subtype frequency: DLBCL is the single most common oral and maxillofacial NHL, accounting for around 60% of oral cavity cases, with Burkitt and T-cell lymphomas less frequent. When the jawbones specifically are involved, reported cases are overwhelmingly high-grade: DLBCL, Burkitt lymphoma, plasmablastic lymphoma, NK/T-cell lymphoma, and leukemic infiltrates.[3][8]
• Anatomic distribution: soft-tissue sites (gingiva, palate, buccal mucosa, tongue) predominate; among intraosseous disease both jaws are affected, and high-grade subtypes involve the mandible and maxilla with roughly equal frequency.[7][8]

Presentation is nonspecific and frequently mistaken for dental disease, which is the central clinical pitfall. The most common finding is a broad-based swelling or bulging mass, with or without surface ulceration, and often relatively rapid growth.[6][7]

• Symptoms: swelling/mass is reported in roughly 80% of cases, variably accompanied by pain, mucosal ulceration, and tooth mobility. Many patients are initially treated for periodontal or endodontic disease or for a non-healing extraction socket.[6][7][8][14]
• Neurosensory findings: paresthesia or numbness ("numb chin") is a characteristic feature of intraosseous mandibular involvement and should prompt evaluation for malignancy when no dental cause is evident.[6][15]
• Tempo and red flags: aggressive growth, a short interval of prior awareness, ulceration with necrosis, bilateral palatal involvement, inadequate healing after extraction, and persistent numbness or pain without dental origin all warrant prompt biopsy. High-grade and medium/large-cell subtypes are significantly more associated with painful, ulcerative, necrotic, and bone-destructive presentations.[16][17]
• Complications/systemic clues: cervical or generalized lymphadenopathy, B symptoms, elevated serum lactate dehydrogenase (LDH), and poor response to empiric dental therapy suggest disseminated disease and poorer prognosis.[18]

NHL of the jaws most often produces an ill-defined, osteolytic (radiolucent) lesion, and its appearance closely simulates an inflammatory or infectious process; nearly half of reported cases carry an initial presumptive diagnosis of dental infection.[3] A critical and recurring observation is that bone destruction visible on imaging is often mild relative to the true extent of marrow and soft-tissue involvement, so apparently unremarkable or subtle films do not exclude the diagnosis.[10]

Location and distribution

• Occurs in both jaws; high-grade subtypes affect mandible and maxilla with comparable frequency.[3][8]
• Lesions are frequently centered on the alveolar process and are often intimately associated with teeth, contributing to misdiagnosis as periodontal or periapical disease. Plasmablastic lymphoma favors the posterior maxillary and alveolar regions and is primarily a soft-tissue tumor with adjacent bone invasion.[3][13][14]

Periphery and shape

• Borders are predominantly ill-defined (reported in roughly 80% of cases).[3]
• A minority—approximately one-third of Burkitt lymphomas and some other subtypes—show relatively well-defined margins, occasionally mimicking a cyst or a benign unilocular radiolucency.[3][19]

Internal architecture

• Almost always purely radiolucent/osteolytic (around 86%).[3]
• Mixed or osteogenic (radiopaque foci) appearances are rare and, when present, largely reflect reactive bone, superimposed soft-tissue opacification, or sinus involvement rather than tumor matrix; only DLBCL and leukemic infiltrates have been described with an osteogenic appearance.[3]

Effects on teeth and alveolar process

• Periodontal ligament space widening, with or without loss of the lamina dura, is a useful alert feature and should raise suspicion of a hematolymphoid (or other malignant) process when unexplained by periodontitis.[3][8]
• A "floating tooth" appearance—teeth suspended in a radiolucent destruction with loss of supporting alveolar bone—is classically associated with Burkitt lymphoma but is also seen in DLBCL and plasmablastic lymphoma.[3][13]
• Root resorption is uncommon; neoplastic cells tend to permeate around dental structures rather than resorb them, a helpful discriminator from some benign aggressive lesions.[3][13]

Effects on adjacent structures

• Diffuse, uniform enlargement of the mandibular (inferior alveolar) canal has been reported as an early and relatively characteristic feature, correlating with perineural permeation and clinical numbness.[15]
• Maxillary disease may encroach upon and opacify the maxillary sinus and erode the orbital floor and nasal walls; NK/T-cell lymphoma, nasal type characteristically produces midline palatal and sinonasal destruction.[3][20]

Growth pattern, cortical involvement, and extent

• Growth is permeative and locally aggressive, yet cortical erosion is often disproportionately mild for the tumor volume, with marrow replacement and extraosseous soft-tissue spread exceeding the degree of cortical breakdown.[10]
• Tumor may extend into surrounding soft tissue without overt cortical destruction, sometimes obscuring the primary site of origin.[3]

Periosteal reaction and variants

• Periosteal reaction is uncommon in jaw lymphoma; when present it may be spiculated and is more often seen with leukemic infiltrates. Lamellated periosteal reaction can occur in primary bone lymphoma of the long bones but is infrequent in the jaws.[3][21]

Cross-sectional and functional imaging materially change characterization and staging and are routinely obtained once lymphoma is suspected or confirmed.

Marrow and soft-tissue assessment

Magnetic resonance imaging best demonstrates the hallmark discordance of lymphoma: extensive marrow replacement and a soft-tissue mass with relatively preserved cortex.[21][22] Lesions are typically hypointense to isointense on T1-weighted images and iso- to hyperintense on T2-weighted/STIR sequences, with homogeneous but nonspecific enhancement that overlaps other tumors.[23][24] MRI is preferred for evaluating marrow invasion and skull base, perineural, and intracranial extension.[25]

Metabolic imaging and staging

NHL, including DLBCL and plasmablastic lymphoma, is strongly FDG-avid, and FDG PET/CT is central to staging, response assessment, and surveillance.[13][26] CT remains complementary for defining cortical erosion and for guiding biopsy of the most representative, non-necrotic tissue.[25][26]

The dominant reasoning task is distinguishing an aggressive-appearing, ill-defined jaw radiolucency of lymphoma from inflammatory disease and from other malignancies—especially because lymphoma so often masquerades as dental infection and because imaging features alone cannot reliably separate lymphoma subtypes.[3] The following highest-yield alternatives should be actively excluded.

The highest-risk pitfall is anchoring on an inflammatory or endodontic explanation and treating empirically: a non-healing socket, unexplained numbness, or a periapical radiolucency that fails to respond should trigger incisional/excisional or core-needle biopsy with immunohistochemistry and molecular studies, because fine-needle aspiration alone is insufficient for diagnosis or grading of lymphoma.[11][18]

Definitive diagnosis rests on biopsy with integrated morphology, immunophenotyping, and molecular testing; a hematopathology review of representative tissue is standard.[11] DLBCL shows diffuse sheets of large atypical lymphoid cells with nuclei equal to or exceeding a macrophage nucleus (centroblastic, immunoblastic, T-cell/histiocyte-rich, and anaplastic morphologic patterns), and is subclassified by cell of origin into germinal-center B-cell (GCB) and activated B-cell/non-GCB types, the latter predominating in head and neck disease and carrying a less favorable prognosis.[5]

• Immunophenotype: B-cell lineage markers (CD20, PAX5) are the diagnostic anchor for DLBCL; a focused panel of CD5, CD10, BCL2, BCL6, IRF4/MUM1, cyclin D1, and Ki-67 resolves differential categories and establishes GCB versus non-GCB status.[11]
• Molecular findings that affect classification/behavior: concurrent MYC with BCL2 and/or BCL6 rearrangements define high-grade "double-hit/triple-hit" lymphoma, which behaves more aggressively than DLBCL, NOS and alters therapy; MYC-driven Burkitt lymphoma shows medium-sized cells, a "starry-sky" pattern, and Ki-67 near 100%.[11]
• Subtype-specific correlates: extranodal NK/T-cell lymphoma, nasal type is angiocentric and angiodestructive with coagulative necrosis, expresses CD56 and cytotoxic markers, and is EBV-positive (EBER)—explaining the midfacial/palatal destruction seen clinically. Plasmablastic lymphoma is a large B-cell neoplasm with plasmacytic immunophenotype (often CD20-negative, CD138-positive, frequently EBV-associated) and recurrent MYC, JAK-STAT, and NOTCH pathway alterations.[11][30][31]
• Radiologic-pathologic correlation: the tendency of tumor to permeate marrow and escape through vascular channels with limited cortical breach accounts for the characteristic imaging discordance between extensive disease and mild cortical destruction.[10][22]

Management is medical, not surgical: the oral and maxillofacial team's role is early recognition, representative biopsy, and prompt referral, after which treatment is directed by hematology-oncology and staged with PET/CT.[11][13] Surgery is diagnostic rather than definitive; radical resection is inappropriate and distinguishes lymphoma from carcinoma, where resection is standard.[16]

• Workup: excisional or incisional biopsy (or multiple core biopsies) with immunohistochemistry, flow cytometry, immunoglobulin gene rearrangement studies, and FISH for major translocations; FNA alone is inadequate. Staging includes PET/CT, marrow evaluation, LDH, and HIV/viral serologies when relevant.[11][13]
• Definitive treatment (DLBCL, the dominant subtype): anthracycline-based chemoimmunotherapy, most commonly R-CHOP; substitution of polatuzumab vedotin for vincristine (Pola-R-CHP) benefits higher-risk advanced disease. Limited-stage disease may be treated with abbreviated chemoimmunotherapy with or without involved-site radiotherapy, whereas advanced disease generally requires six cycles.[11][12][32]
• Selection factors and other subtypes: high-grade "double-hit" lymphoma is often managed with DA-EPOCH-R; Burkitt lymphoma requires intensive regimens; plasmablastic and NK/T-cell lymphomas are treated with subtype-specific protocols and have poorer outcomes. Radiotherapy added after R-CHOP achieves excellent local control for head and neck DLBCL.[11][31][33]
• Recurrence and surveillance: recurrence after initial therapy is substantial (reported around 31% in craniofacial series), supporting structured clinical and imaging follow-up.[34]
• Prognosis: DLBCL is curable in roughly two-thirds of patients, and those without relapse by 24 months approach general-population life expectancy; the NCCN-IPI (age, LDH, stage, performance status, extranodal sites) stratifies risk. Indolent MALT lymphoma of the oral/maxillofacial region carries a markedly better outcome than DLBCL. Extranodal oral cavity/maxillofacial DLBCL behaves more aggressively, with lower response rates and inferior survival than Waldeyer ring disease, underscoring the value of early diagnosis.[2][12][35][36]

Immunodeficiency and viral drivers

In HIV-positive and transplant/iatrogenically immunosuppressed patients, oral NHL is frequently virus-driven—EBV in plasmablastic and many aggressive B-cell lymphomas, and HHV-8 in specific entities—and may require immune-status optimization alongside chemotherapy.[4][9][31] Plasmablastic lymphoma in particular is strongly associated with HIV and carries a poor prognosis, with historically short median survival.[31]

Pediatric considerations

Jaw NHL in children is dominated by Burkitt lymphoma, which classically produces rapidly enlarging destructive maxillary and mandibular masses with floating teeth; it is highly chemosensitive and curable with intensive regimens, making prompt recognition essential.[19][37]