Discussion
Extranodal NK/T cell lymphoma (ENKL) is a rare and aggressive form of lymphoma accounting for approximately 10% of peripheral T cell lymphoma cases internationally and 1% of lymphoma overall. 4The typical clinical presentation is of a destructive lesion in the upper aerodigestive tract, usually in patients of Asian descent, responding well to radiotherapy in the early stages. Important adverse prognostic factors for ENKL treated with non-anthracycline based regimens are age greater than 60 years, stage III or IV disease, distant lymph-node involvement, non-nasal type disease and detectable EBV viral DNA titre. 9 While localised nasal disease typically responds to initial treatment with chemoradiotherapy, extranasal disease has consistently been shown to confer a worse prognosis and is generally treated with intensive chemotherapy. 9,10This case describes an Australian woman of Italian ancestry who presented with cutaneous and ocular ENKL, without any nasal disease. The histology and immunohistochemistry are consistent with classically described cases, with NK cell markers, EBV positivity, cytotoxic profile and angioinvasion all present. CD3 positivity on immunohistochemistry in this case reflects cytoplasmic CD3 epsilon expression which unlike surface CD3 is usually positive in ENKL. 1
Primary cutaneous ENKL is rare, fewer than 100 cases have been described in the literature with the majority of these being Asian patients.11-15 The dermatological findings are varied and include subcutaneous nodules, erythematous papules, cellulitis and ulcerations which can occur at any site but appear more common at the extremities. 11-15 Radiotherapy alone is a successful treatment in localised cutaneous disease, with 80% of patients responding. For more advanced stage cutaneous disease, radiotherapy is not feasible and systemic chemotherapy is indicated.11 The skin manifestations in this case were consistent with those described in previous case reports of primary cutaneous ENKL, with erythematous nodules and plaques predominantly in the legs. There was widespread skin involvement in more than two non-contiguous skin regions, conferring a T3 designation on the TNM staging system and significantly worse prognosis. 14
ENKL with ocular involvement is extremely rare and only four biopsy proven case reports were identified in the medical literature.16-19 There have been other cases described which likely represent ocular involvement, without histological evidence. 20,21 All cases described have occurred in patients with nasal ENKL as opposed to extranasal. Uveitis was the primary finding in all cases of previously described ocular ENKL, with or without retinal/choroidal detachments. 16-22 In the current case, the patient presented with recurrent uveitis and vitreous hypercellularity, with no other cause found. True CNS ENKL is extremely rare and the optimal therapy is unknown. The use of CNS penetrating agents such as high-dose methotrexate and cytarabine are the mainstay of therapy in B-cell lymphoma with CNS involvement, although these agents are challenging to deliver in very elderly patients, as highlighted by this report.
The frontline management of ENKL has moved towards asparaginase based chemotherapy. 23-27 SMILE was evaluated in a phase 2 trial of 38 patients with stage IV, relapsed or refractory ENKL demonstrating a complete response rate of 45% after 2 cycles and 1 year OS of 55%. 28 SMILE results in considerable toxicity and is challenging to deliver in elderly patients.28,29 There is emerging evidence of the efficacy and safety of other asparaginase containing regimens such as DDGP (cisplatin, dexamethasone, gemcitabine, pegaspargase) and P-GEMOX (pegaspargase, gemcitabine and oxaliplatin) in the treatment of ENKL.29-34 A recent randomized trial showing superior disease control and favourable toxicity for DDGP relative to SMILE represents a welcome advance for patients with this aggressive disease.35
The management of refractory ENKL is challenging in any patient, but particularly so in the very elderly. We elected to use the immune checkpoint inhibitor pembrolizumab on the basis of encouraging data from case reports and small case series 36-38. Unfortunately, our patient did not derive benefit from the agent, and was effectively refractory to every therapeutic intervention apart from a brief symptomatic improvement from binocular radiotherapy. Reduced dose SMILE was poorly tolerated and limited therapy to two cycles. Based on recent randomized trial data, DDGP appears both more active and better tolerated and should be considered a preferred frontline approach. Further trials incorporating novel agents such as pembrolizumab are required to improve outcomes for patients with ENKL.
Consent: Informed consent was obtained from the patient for inclusion in this case report.
Disclosures: CYC: consulting/advisory/honoraria – Roche, Janssen, MSD, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics; research funding – Celgene, Roche, Abbvie; travel expenses – Roche.
Conflict of interest: The authors declare no conflicts of interest
Funding statement: There was no funding for the writing of this case report
Acknowledgements: N/A
Author contributions: Dr Benhur Ammanuel contributed the pathology section and second figure. Dr Rohen White contributed the radiotherapy section. Dr Chris Kennedy contributed the ophthalmology section. Dr Peter Mallal and Dr Chan Cheah completed the remainder of the case report as well as the editing.