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Periapical radiolucent lesions are commonly of endodontic origin; however, some persistent cases may indicate non-endodontic pathologies, including malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of lymphoma affecting the oral and maxillofacial region, yet its primary occurrence in the jaws is rare. This case report highlights the diagnostic challenges in differentiating endodontic lesions from periapical lymphomas and includes a literature review of documented cases.

A 44-year-old male presented with a persistent periapical lesion in the anterior maxilla, unresponsive to endodontic and periodontal treatments. Clinical examination revealed facial asymmetry, gingival edema, palatal swelling, and dental mobility. Imaging showed an ill-defined hypodense lesion extending beyond the periapical region. Fine needle aspiration and incisional biopsy confirmed DLBCL through histopathology and immunohistochemistry. The patient underwent six cycles of R-CHOP chemotherapy.

After treatment, intraoral examination revealed mucosal integrity, absence of swelling, and stabilization of dental mobility. Cone-beam computed tomography demonstrated bone regeneration, and PET/CT imaging confirmed complete remission.

This case underscores the importance of considering malignancies in the differential diagnosis of persistent periapical lesions. Accurate clinicoradiographic assessment, histopathological confirmation, and interdisciplinary collaboration are essential for timely diagnosis and improved patient outcomes.