Extranodal NK/T-Cell Lymphoma, Nasal Type, Presenting as an Isolated Oral Manifestation

<b>Background/Objectives</b>: Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), is a rare and extremely aggressive subtype of non-Hodgkin lymphoma that most frequently involves the nasal cavity and upper aerodigestive tract. Primary isolated oral manifestation is exceptionally uncommon and may mimic odontogenic or infectious diseases, delaying diagnosis. We report a case of ENKTCL-NT presenting initially as a destructive oral lesion without sinonasal involvement at diagnosis. <b>Methods</b>: A 32-year-old man with progressive palatal ulceration underwent clinical and imaging assessment (panoramic radiography and staging ^18F-FDG PET-CT) and repeated biopsies. Diagnosis was established using histopathology (H&E), immunohistochemistry (T-cell markers and cytotoxic profile), EBV detection by EBER in situ hybridization, and T-cell receptor gamma (TCRG) gene rearrangement analysis. <b>Results</b>: The lesion presented as a hemorrhagic, ulcerative palatal destruction covered by pseudomembranous exudate and was complicated by fungal infection, periostitis, and severe dental inflammatory foci, contributing to diagnostic delay. Histopathological examination revealed extensive necrosis with a dense atypical lymphoid infiltrate; angiocentric and angiodestructive growth was identified in one biopsy specimen. Tumor cells expressed T-cell markers (CD2, CD3, CD5, CD7; heterogeneous) and cytotoxic markers (TIA-1) and showed CD30 and CD56 positivity, with EBV positivity confirmed by EBER in situ hybridization. Molecular analysis demonstrated monoclonal TCRG rearrangement, and Ki-67 indicated high proliferative activity. Initial PET-CT demonstrated an intensely FDG-avid, locally invasive lesion without distant organ involvement. The patient was treated with L-asparaginase-based SMILE chemotherapy followed by radiotherapy (50 Gy), achieving marked initial clinical improvement and partial metabolic response; however, systemic relapse subsequently occurred with refractory disease despite salvage therapy and immunotherapy. <b>Conclusions</b>: This case highlights the substantial diagnostic challenge posed by isolated oral extranodal NK/T-cell lymphoma, nasal type, which may closely mimic benign inflammatory or infectious conditions and lead to significant diagnostic delay. Persistent, progressive, or therapy-resistant oral ulcerations should prompt early consideration of hematologic malignancy. Timely biopsy with comprehensive immunophenotyping, EBV testing, and close multidisciplinary collaboration are essential for accurate diagnosis and may contribute to earlier diagnosis and improved patient outcomes in these rare and atypical presentations.