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.