Report of a case of nasal-type extranodal NK/T-cell lymphoma with ciliary body involvement and literature review of interleukin-10 and interleukin-6 in intraocular T-cell lymphoma

Abstract

Purpose

To present a presumed case of NK/T-cell lymphoma with ciliary body involvement, emphasizing key clinical findings and diagnostic testing that facilitated differentiation from anterior uveitis.

Methods

Retrospective case report and review of the literature.

Results

A 47-year-old man with a history of nasal-type extranodal NK/T-cell lymphoma (ENKL) presented with cloudy vision in the left eye and was initially diagnosed with anterior uveitis. Work-up initially included aqueous interleukin-10 (IL-10) and interleukin-6 (IL-6) ratio determination, and later B-scan and ultrasound biomicroscopy (UBM). The IL-10/IL-6 ratio was less than 1, but ultrasound imaging revealed peripheral subretinal fluid and ciliary body thickening. The patient underwent five cycles of intravitreal methotrexate for presumed uveal lymphoma involving the ciliary body with pseudo-keratic precipitates before a nasal biopsy confirmed recurrent ENKL. A review of the literature regarding IL-10/IL-6 ratios showed that 71 % of published cases of intraocular T-cell lymphoma had ratios less than 1.

Conclusion

ENKL, nasal type, is an aggressive and uncommon disease, and its ocular involvement, though infrequent, can resemble anterior uveitis. The IL-10/IL-6 ratio is of limited value in the diagnosis of T-cell lymphoma affecting intraocular structures. This case highlights the critical role of UBM in identifying ciliary body involvement of intraocular malignancies.

Highlights

• •Overlapping clinical presentations between extranodal NK/T-cell lymphoma and anterior uveitis can complicate diagnosis.
• •Ultrasound biomicroscopy is an effective tool to determine ciliary body involvement in extranodal NK/T-cell lymphoma.
• •Using the interleukin-10 to interleukin-6 ratio as a diagnostic tool for intraocular T-celllymphoma has limitations.

Glossary

Extranodal NK/T-cell lymphoma (ENKL)

rare and aggressive form of non-Hodgkin's lymphoma, commonly presenting with nasal mass, nasal obstruction, hoarseness of voice, dysphagia, and airway obstruction

Intraocular lymphoma

type of lymphoma that occurs inside the eye, either originating from the central nervous system or systemic lymphoma with ocular extranodal involvement

Ciliary body

structure behind the iris that is involved in aqueous humor production and accommodation

Ultrasound biomicroscopy (UBM)

high-resolution ultrasound imaging used to visualize the anterior segment

Interleukin-10 (IL-10)

cytokine involved in growth and differentiation of B-cells, with elevated levels associated with B-cell lymphoma

Interleukin-6 (IL-6)

cytokine involved in inflammatory processes and marker of inflammation in uveitis

Interleukin-10 to interleukin-6 ratio

diagnostic tool used to differentiate between intraocular lymphoma and other ocular diseases

Methotrexate

antimetabolite commonly administered to treat cancers and autoimmune diseases

1. Introduction

Extranodal natural killer/T-cell lymphoma (ENKL), nasal type, is a rare form of non-Hodgkin's lymphoma. It commonly presents with a nasal mass, nasal obstruction, hoarseness of voice, dysphagia, and airway obstruction. ENKL is more prevalent in Asian and Latin American populations and is strongly associated with the Epstein-Barr Virus.^1,2 Compared to B-cell lymphoma, ENKL tends to be more aggressive and carries a poorer prognosis.³

We present a case of ENKL with secondary ciliary body involvement. This report underscores the challenges in diagnosing lymphoma affecting intraocular structures due to overlapping clinical manifestations with uveitis. While an interleukin-10 (IL-10) to interleukin-6 (IL-6) ratio greater than 1 is a suggestive biomarker for B-cell lymphoma,4, 5, 6, 7, 8 it may be of limited value for ENKL, as the ratio was less than 1. We include a review of literature of IL-10 and IL-6 values in intraocular T-cell lymphoma cases to assess their diagnostic value. Ultrasound biomicroscopy (UBM) proved to be a crucial diagnostic tool in identifying involvement in the ciliary body and establishing the diagnosis.

2. Case presentation

A 47-year-old Asian male presented with three weeks of cloudy vision and foreign body sensation in his left eye. He had been previously diagnosed with uveitis by an outside ophthalmologist and was started on prednisolone acetate 1 % ophthalmic solution six times daily and cyclopentolate twice a day in his left eye. The patient has a history of biopsy-proven nasal-type ENKL in his left nasal cavity, diagnosed 15 months prior. Treatment initially included four cycles of modified SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy, followed by radiation therapy over the course of 1 month. The ENKL was deemed in remission upon completion of therapy.

On initial examination, the best corrected visual acuity (BCVA) was 20/15 in his right eye and 20/20 in his left eye. The intraocular pressure (IOP) was 14 mmHg in his right eye and 13 mmHg in his left eye. The slit-lamp examination of the left eye showed mutton-fat keratic precipitates (KP) and 2+ anterior chamber (AC) flare, but no cell (Fig. 1). The right eye was unremarkable.

Fig. 1.

Slit lamp photo of the left eye showing keratic precipitates.

Two weeks later, persistent KPs despite corticosteroid treatment raised suspicion for lymphoma, and prednisolone was tapered to three times daily. The patient was on valacyclovir for oral herpes simplex virus and stopped during chemotherapy. Valacyclovir 1 g three times a day was resumed at four weeks due to recurrent oral cold sores. Additional diagnostic testing was completed. Antinuclear antibody (ANA) was positive at 1:160, while HLA-B27, rheumatoid factor, c-ANCA, p-ANCA, RPR/TPPA, QuantiFERON-TB Gold, lysozyme, angiotensin cESR, CRP, and EBV titers were all negative.

Six weeks after the patient's initial visit, a uveitis specialist was consulted. The exam revealed 1+ AC cell with new KPs. Prednisolone was tapered to twice a day. Valacyclovir was discontinued to maximize the yield of an AC tap for viral labs. AC tap was later repeated for flow cytometry and cytokine analysis. PCR testing for HSV, CMV, and VZV was negative. Cytology showed a paucicellular specimen with rare small lymphocytes, histiocytes, and red blood cells. High levels of IL-10 (8.9 pg/mL and 9.3 pg/mL) and IL-6 (77.3pg/mL and 135.5pg/mL) were obtained, yielding IL-10/IL-6 ratios of 0.11 and 0.06, respectively.

B-scan and UBM were performed revealing peripheral subretinal fluid (SRF), vitritis (Fig. 2), and ciliary body thickening with a maximum height of 3.37 mm inferiorly (Fig. 3A), respectively. In the setting of SRF and ciliary body thickening, it was now presumed that the eye disease represented uveal lymphoma involving the ciliary body with pseudo-KPs.

Fig. 2.

B-scan of the left eye showing serous choroidal detachment with surrounding subretinal fluid (white circle).

Fig. 3.

(A) UBM of the left eye showing thickening of the ciliary body (white circle). (B) Resolved ciliary body thickening after intravitreal methotrexate injections and systemic immunotherapy, taken approximately 7 months later (white arrow).

The patient subsequently underwent five cycles of intravitreal injections, each consisting of four injections of 400 μg (0.05 cc) of methotrexate administered every 3–4 days, followed by a two-week recovery period to allow the ocular surface to recover. Treatment was complicated by diffused epitheliopathy and elevated IOP, managed with punctal plugs, aggressive lubrication, cyclosporine 0.05 %, and a short course of brimonidine 0.15 % and dorzolamide-timolol 22.3–6.8 mg/mL.

Initial computed tomography (CT) and magnetic resonance imaging (MRI) of the brain and orbits showed hyperenhancement of the left iris and ciliary body that was consistent with uveitis. This imaging showed no evidence of active lymphoproliferative disease or an intracranial or orbital mass at the time. During intravitreal methotrexate treatment, new imaging demonstrated a nasopharyngeal mass lesion that proved to be recurrent ENKL on biopsy. In response, systemic immunotherapy (brentuximab and nivolumab) was initiated, and intravitreal methotrexate was paused. The lymphoma had responded to therapy, and ciliary body thickening resolved (Fig. 3B).

At one year, after eight cycles of immunotherapy, the patient's BCVA was 20/60 in the left eye with a newly developed posterior subcapsular cataract. The ocular surface was stabilized and the IOP was within normal limits without topical therapy. The ciliary body mass, subretinal fluid, and vitritis remained resolved. Following phacoemulsification and intraocular lens placement 18 months after initial presentation, the BCVA in the left eye improved to 20/25. The patient has continued to receive immunotherapy for 22 months since initiation of treatment.

3. Methods

A literature search was performed using the National Library of Medicine PubMed interface (www.pubmed.gov). Articles from April 1980 to February 2025 containing the keywords “intraocular”, “T-cell”, and “lymphoma”, inclusive were identified (Search Date: March 18, 2025). Only articles published in peer-reviewed journals in English with primary data from human subjects were reviewed. To be included in this report, articles had to include interleukin-10, interleukin-6, or interleukin-10 to interleukin-6 ratio values in patients who presented with intraocular T-cell lymphomas.

4. Results

The literature search returned a total of 144 articles. 135 articles were excluded because they failed to meet the aforementioned inclusion criteria. One additional article was excluded because it presented duplicate interleukin data from a patient presented in one of the included studies. Eight studies total are presented in this review, representing interleukin data from 15 separate patients with intraocular T-cell lymphoma. Of the 15 patients identified, 14 included data on IL-10/IL-6 ratios, with 10 of 14 having IL-10/IL-6 ratios less than one and 4 of 14 having ratios greater than one. All values are displayed in Table 1.

Table 1.

Literature review of interleukin-10 and interleukin-6 values reported in intraocular T-cell lymphoma cases.

Patient/Study	IL-10 (pg/mL)	IL-6 (pg/mL)	IL-10/IL-6
Patient 118	8	Not Reported	Not Reported
Patient 219	137	146	0.93 < 1
Patient 320	137	143	0.95 < 1
Patient 420	743	311	2.38 > 1
Patient 520	203	843	0.24 < 1
Patient 621	Not Reported	Not Reported	>1
Patient 721	Not Reported	Not Reported	>1
Patient 821	Not Reported	Not Reported	<1
Patient 921	Not reported	Not Reported	<1
Patient 1021	Not Reported	Not Reported	<1
Patient 1122	Not Reported	Not Reported	<1
Patient 1222	Not Reported	Not Reported	<1
Patient 1323	5.5	27.1	0.20 < 1
Patient 1424	27.2	299.5	0.09 < 1
Patient 1525	39.4	37.5	1.05 > 1

5. Discussion

The presented case is an example of a rare ocular malignancy with a presumed diagnosis of uveal ENKL involving the ciliary body with pseudo-KPs supported by UBM findings in the absence of histopathologic confirmation. Challenges included the lack of cell burden in the vitreous or anterior chamber that might have facilitated appropriate diagnosis by biopsy. Additionally, the IL-10 to IL-6 ratio was less than 1; the ratio has been shown to be a useful marker for the presence of at least B-cell lymphomas when greater than 1.4, 5, 6, 7, 8 Immunohistochemistry may have aided in diagnosis, but its utility is often constrained by limited cellular yield. A serous retinal detachment did not develop until later in the course.

This case parallels previous reports of ENKL ocular involvement, which is rare and often presents a diagnostic challenge, as its clinical presentation can closely resemble uveitis. Several reports describe cases where ENKL was initially treated as uveitis with corticosteroids, leading to delays in appropriate therapy.9, 10, 11 While Han et al. reported a case of nasal-type ENKL involving the conjunctiva, ciliary body, vitreous and retina,¹² intraocular manifestations of ENKL, particularly with ciliary body involvement, are exceedingly rare. Comprehensive multi-modal imaging, including UBM imaging of the ciliary body, may be best employed early in the course of the disease if there is any suspicion of lymphoma or question of the diagnosis.

When evaluating for intraocular lymphoma, a comprehensive systemic workup, including whole-body imaging, is essential, as the eye is typically a secondary site of disease. While the gold standard for diagnosis is an intraocular biopsy, obtaining an adequate specimen can be very challenging. Therefore, non-tissue biopsy testing is important. IL-10 has been identified as a biomarker for B-cell lymphoma; although not definitive, IL-10/IL-6 ratios greater than 1 may aid in differentiating from other conditions, especially uveitis.4, 5, 6, 7, 8 For intraocular T-cell lymphomas, this test is less helpful, as 71 % of the published cases (Table 1) have IL-10/IL-6 ratios that are less than 1, consistent with current literature.¹³ This is somewhat surprising as ENKL has been shown to overexpress IL-10.¹⁴ In this report, despite a low IL-10/IL-6 ratio, the patient was ultimately diagnosed and treated for presumed uveal ENKL involving the ciliary body.

UBM provides high-resolution imaging of the anterior ocular segment, allowing for detailed views of ciliary structures that are otherwise difficult to visualize. UBM imaging of anterior uveitis often showed exudates, fibrosis tissue, and edema,¹⁵ whereas cases of ciliary body lymphoma demonstrated solid infiltration, low homogeneous internal reflectivity, and 360° thickening.¹⁶ UBM provided critical support in establishing the uveal ENKL diagnosis in this case.

Given the rarity of ENKL with ciliary body involvement, there is no standardized treatment protocol. However, studies have shown the effectiveness of intravitreal methotrexate injections and external beam radiotherapy in treating intraocular lymphoma.¹⁷ In this case, the presumed uveal ENKL was successfully treated with methotrexate injections.

This case report underscores the importance of a systematic diagnostic approach when evaluating suspected uveitis that fails to respond to corticosteroids. When autoimmune and infectious etiologies are ruled out, intraocular lymphoma should be considered. The IL-10/IL-6 ratio was not a helpful biomarker for making a diagnosis in this case and may have limited diagnostic utility for intraocular T-cell lymphomas. UBM, however, proved to be a crucial tool in identifying the ciliary body mass, supporting a diagnosis of presumed uveal lymphoma in a patient with known history of systemic ENKL, and leading to successful treatment.

CRediT authorship contribution statement

Madeline S. Louie: Writing – review & editing, Writing – original draft, Visualization, Investigation. Nathan A. Brice: Writing – review & editing, Writing – original draft, Data curation. Edmund Tsui: Writing – review & editing, Conceptualization. Judy L. Chen: Writing – review & editing, Conceptualization. Colin A. McCannel: Writing – review & editing, Supervision, Conceptualization.

Patient consent

Written consent from the patient has been obtained.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.