Rare eye lymphoma case shows limits of local therapy in NK/T-cell disease

A 61-year-old woman whose rare Epstein–Barr virus-associated lymphoma first appeared on the skin of her left thigh has become the subject of a newly published case report documenting an unusual and aggressive course of disease: a relapse inside her left eye, followed by spread to the optic nerve and nasal cavity despite weeks of locally targeted treatment. The report, published in Frontiers in Oncology by ophthalmologists and hematologists affiliated with the Bascom Palmer Eye Institute, the Medical University of South Carolina, and the H. Lee Moffitt Cancer Center, describes in detail how the malignancy evaded both imaging and local therapy, and why the authors argue that early systemic evaluation and treatment matter enormously in this uncommon cancer.

The patient’s story began six months before her eye emergency, when a skin biopsy from her left thigh led to a diagnosis of EBV-positive extranodal natural killer/T-cell lymphoma, an aggressive cancer of immune cells that almost always arises outside lymph nodes. Staging scans with positron emission tomography and computed tomography showed stage IV disease, marked by fluorodeoxyglucose-avid masses in the skin and tissue beneath it, along with numerous smaller cutaneous nodules. Flow cytometric analysis of her bone marrow aspirate and peripheral blood revealed low-level involvement by the lymphoma. She received two cycles of SMILE-based chemotherapy, a combination of dexamethasone, methotrexate, ifosfamide, etoposide, and pegaspargase, with the pegaspargase omitted from the second cycle. When that chemotherapy was completed, roughly three months before her eye symptoms brought her to the emergency department, repeat PET/CT showed no evidence of metabolically active disease.

Her oncologists, following contemporary guideline-based recommendations, advised additional cycles of chemotherapy even though the scans looked clear. The patient declined, citing the normal imaging findings and her wish not to continue treatment. That decision, made with what imaging could show at the time, became a pivotal point in the case. Extranodal NK/T-cell lymphoma is strongly associated with Epstein–Barr virus, most commonly involves the nasal cavity and upper respiratory tract, and is encountered predominantly in people from Asia and Latin America, a pattern the authors attribute to possible genetic predisposition and geographic variation in viral strains. It is characterized by rapid progression, a high propensity for tissue necrosis, and frequent spread to extranodal sites, and intraocular involvement generally signals advanced systemic disease with a poor prognosis.

The woman arrived at the Bascom Palmer Eye Institute emergency department with six months of progressive, painless vision loss in her left eye. An outside ophthalmologist had already started her on difluprednate and atropine for suspected vitritis, an inflammation of the eye’s gel-like interior, and although she initially improved, the vision loss gradually returned and worsened. At presentation, her right eye saw 20/25 while the left could only count fingers at two feet. Intraocular pressures were normal, and dilated examination revealed vitritis in the left eye; ultrasound showed moderately dense, mobile vitreous opacities. Laboratory testing for syphilis and tuberculosis came back negative, narrowing the differential diagnosis.

A diagnostic pars plana vitrectomy provided the answer. Cytopathologic examination showed a diffuse infiltrate of atypical, moderately sized lymphoid cells with irregular nuclei, coarse chromatin, and scant cytoplasm. Immunohistochemical staining revealed the cells were positive for CD3, CD7, and CD56 and negative for CD20, and in situ hybridization for Epstein–Barr virus-encoded RNA was positive, confirming EBV within the tumor cells. Together, the morphology and immunophenotype established a diagnosis of secondary intraocular extranodal NK/T-cell lymphoma, a presentation so rare that intraocular T-cell lymphomas of any kind account for only about 1.3 percent of intraocular lymphomas, most of which are B-cell malignancies, and NK/T-cell lymphomas represent fewer than 2 percent of all T-cell lymphomas.

An urgent repeat PET/CT scan found no disease foci outside the eye, but the care team still recommended systemic chemotherapy and external beam radiation therapy, warning that a negative scan could not exclude occult systemic or central nervous system involvement. The patient declined both, concerned about side effects and reassured by the clean imaging. Instead, she elected weekly intravitreal methotrexate injections at 400 micrograms in 0.1 milliliters, a local therapy delivered directly into the eye. After the first injection, her visual acuity improved to 20/150 and the vitreous cleared. But with the fundus now visible, clinicians observed vessel whitening and sheathing in the inferotemporal periphery, a retinal vasculitis that had not been present at the time of vitrectomy. It was presumed secondary to the underlying lymphoma, though occlusive vasculitis caused by methotrexate itself could not be completely ruled out. Systemic chemotherapy and radiation were recommended again; the patient chose observation.

A week later, optical coherence tomography of the inferior mid-periphery showed new sub-retinal pigment epithelium infiltrates that had not appeared on baseline imaging a few weeks earlier. After further discussion, with the patient still refusing systemic therapy, the intravitreal methotrexate injections resumed, and an additional injection resolved the vasculitis. But three months after her initial presentation, she developed a new abducens nerve palsy in the right eye, impairing lateral gaze. By then she had received six injections rather than the planned twelve, because missed and delayed appointments had disrupted the weekly schedule. Her left-eye vision was 20/80, though examination was severely limited by a dense posterior subcapsular cataract, and repeat OCT showed worsening sub-RPE infiltrates. Brain MRI found no extraocular disease or central nervous system involvement, but the authors note that because of the lymphoma’s neurotropism, initial imaging can be falsely negative in patients presenting with cranial nerve palsies, so follow-up MRI was advised.

A week later, the left eye’s vision acutely dropped to 20/400 with a new afferent pupillary defect. Ultrasound showed a new fullness of the optic nerve head, and OCT of the retinal nerve fiber layer confirmed optic nerve head edema. An urgent repeat MRI of the brain and orbits revealed abnormal T2 hyperintense signal in the posterior intraorbital and intracanalicular left optic nerve and its sheath, along with an enlarging T2 hypointense lesion in the posterior left nasal cavity. The rest of the brain showed no leptomeningeal enhancement, parenchymal lesions, or other intracranial involvement. Faced with optic nerve and nasal cavity disease, the patient finally agreed to more aggressive treatment: two more intravitreal methotrexate injections, for a total of eight, and systemic and intrathecal chemotherapy with a SMILE regimen modified to include high-dose methotrexate.

After two cycles, her systemic symptoms improved and the abducens palsy resolved, but vision in the left eye deteriorated to no light perception. A cataract obscured the posterior segment, preventing OCT assessment of the sub-RPE infiltrates, though ultrasound showed the optic nerve head no longer appeared swollen. Over the following sixteen months she received two doses of intrathecal cytarabine, with cerebrospinal fluid cytology and flow cytometry showing no malignant involvement, completed four cycles of a modified DDGP regimen of dexamethasone, cisplatin, and gemcitabine, and, after disease recurrence, an additional cycle plus pembrolizumab. She underwent radiation therapy to the bilateral orbits, paranasal sinuses, and skull base, totaling 36 Gy in 20 fractions. At final follow-up, approximately 23 months after presentation, the lymphoma was in remission. The right eye saw 20/30 with a mild abduction deficit and moderate cataract; the left eye remained no light perception with a large white cataract and low pressure.

The authors emphasize that most reported cases of intraocular NK/T-cell lymphoma arise from direct extension from the nasal cavity, with only a handful documented from distant sites such as the testes, retroperitoneum, and skin or soft tissue. This case, originating in the thigh and later involving the nasal cavity and optic nerve, is exceptionally rare. Prognosis for advanced-stage relapsed or refractory disease remains poor, with median overall survival often under one year and no universally accepted standard of care, although National Comprehensive Cancer Network guidelines recommend non-anthracycline chemotherapy combined with L-asparaginase, such as four to six cycles of SMILE-HD-MTX, for all patients with advanced disease. Whether the optic nerve invasion occurred through contiguous spread from the eye, extension from occult central nervous system disease, or systemic reseeding remains unclear. The authors suggest that earlier systemic therapy and radiation, potentially followed by consolidation with allogeneic stem cell transplantation, might have altered the disease trajectory, while acknowledging that respecting patient autonomy is essential even when recommended treatment is declined. As a single case report, the account cannot establish treatment effects, but it underscores the diagnostic challenge of a malignancy that can masquerade as ordinary eye inflammation, and the limitations of local therapy alone against a cancer with neurotropic potential.

Subject of Research: A case report of secondary intraocular extranodal NK/T-cell lymphoma with optic nerve involvement following local therapy

Article Title: Secondary intraocular extranodal natural killer/T-cell lymphoma with optic nerve involvement: a case report

Article References: Ersan, S., Zhang, C., Miguez, S. M., Idarraga, M. A., Sokol, L., Dubovy, S. R., Mendoza-Santiesteban, C. E., & Williams, B. K., Jr. (2026). Secondary intraocular extranodal natural killer/T-cell lymphoma with optic nerve involvement: a case report. Frontiers in Oncology, 16, Article 1954795. https://doi.org/10.3389/fonc.2026.1954795

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1954795

Keywords: NK/T-cell lymphoma, intraocular lymphoma, Epstein-Barr virus, optic nerve, intravitreal methotrexate, case report, ophthalmology, hematologic malignancies, vitritis, chemotherapy, radiation therapy, SMILE regimen