Extranodal natural killer (NK)/T cell lymphoma (ENKTL), nasal type is a subtype of non-Hodgkin’s lymphoma characterized by an association with Epstein–Barr virus (EBV) infection and extranodal involvement [1, 2]. The lymphoma cells originate from either NK cells or γδ T cells [3]. T cell receptor gene rearrangement is observed in 10–35% of patients [4]. Therefore, in the latest World Health Organization classification, these lymphomas are referred to as ENKTLs, to reflect their putative cellular origins from NK cells and T cells [5]. The invariable association of ENKTL with EBV and its pathogenic role were recognized in earlier studies [6-8]. EBV exists in a clonal episomal form and is not integrated into the host genome in ENKTL [9]. The distribution of normal NK cells along barrier surfaces explains the extranodal property of ENKTL. The incidence of ENKTL varies significantly among regions, being the highest in East Asia and Latin America where early childhood EBV infection is prevalent [10-12]. Clinically, ENKTL shows unique features and predominantly involves the nasal area as a progressive necrotic lesion; thus, it was previously referred to as “lethal midline granuloma”. Pathologically, ENKTL had been referred to as polymorphic reticulosis or angiocentric lymphoma, because angiocentric and angio-invasive infiltrates are commonly present [13]. In this article, we summarize the current diagnosis and treatment of ENKTL and emerging treatment options.

ENKTL usually manifests as progressive ulceration and necrotic granuloma in the nasal cavity, palate, and nasopharynx, frequently causing palatal perforation [6, 7]. The tumor frequently invades around tissues such as facial skin, paranasal sinus, and orbits, and results in extensive destruction of midline lesions [1]. At presentation, the disease is often localized in the nose, nasopharynx, oropharynx, Waldeyer’s ring, and upper aerodigestive tract; however, advanced disease may involve the skin, lymph node, liver, spleen, bone marrow, and peripheral blood [1]. The most common symptoms at the time of diagnosis are nasal obstruction and bloody rhinorrhea [8]. Swelling of the cheek or orbit, sore throat, and hoarseness are also major symptoms of ENKTL [8, 14]. In addition, systemic symptoms such as prolonged fever and weight loss are common [8]. ENKTL usually affects individuals aged about 40–50 years without gender predilection [1, 8].

Endoscopic examination and biopsy are crucial for the diagnosis of ENKTL [15]. Typically, the tumor lesion has extensive angioinvasion and necrosis, which often makes an accurate diagnosis difficult. Therefore, multiple biopsy samples are needed for better diagnosis. The tumor lesion is composed of a polymorphic population of atypical lymphoid cells, inflammatory cells, and eosinophils [10]. ENKTL cells express CD2, cytoplasmic CD3 (but not surface CD3), and CD45, as well as the NK cell marker CD56. Perforin, Fas ligand, and intercellular adhesion molecule-1 (ICAM-1) are also expressed in the tumor cells [13]. To diagnose ENKTL, the presence of EBV-encoded RNA by in situ hybridization should be confirmed along with either CD56 or cytotoxic molecules (granzyme B, perforin, or TIA1). In the absence of both, the diagnosis becomes EBV-positive peripheral T cell lymphoma, not otherwise specified [5].

A measurement of plasma EBV DNA titer by polymerase chain reaction is recommended at diagnosis. EBV DNA fragments are released into the blood when ENKTL cells undergo apoptosis [16]. This characteristic makes a measurement of plasma EBV DNA useful in determining tumor burden [17], real-time monitoring of treatment response [18], and prediction of recurrence during follow-up [19].

ENKTL is typically a fluorodeoxyglucose-avid lymphoma, and an analysis demonstrated that positron emission tomography/computed tomography (PET/CT) is superior to conventional staging methods (physical examination, CT with intravenous contrast, biopsies from primary sites, and bone marrow examinations) in detecting malignant lesions [20]. Therefore, PET/CT is currently regarded as the standard imaging modality for ENKTL. In addition, end of treatment PET/CT is useful for prognostication [19]. Thus, it should be performed for newly diagnosed patients as a baseline study.

Unlike other NHLs, the international prognostic index (IPI) does not discriminate among risk groups clearly in ENKTL. Most patients (81%) are classified into the low or intermediate risk group based on the IPI, because ENKTL has very unique clinical features presenting localized disease (76%), with rare involvement of bone marrow (6%), and high occurrence of constitutional symptoms even in localized disease (29%) [21]. Thus, a different prognostic model composed of four clinical prognostic factors (B symptoms, stage III/IV, elevated LDH, and regional LN involvement) was proposed for ENKTL (NK prognostic index) [1, 21]. This model had balanced distribution in each group (group 1, 27%; group 2, 31%; group 3, 20%; group 4, 22%) and predicted treatment outcomes better than did IPI. However, this prognostic model was based on the outcomes with anthracycline-containing regimens, so it is outdated. Since EBV DNA titer has been recognized as a clinical progression/recurrence marker [22], another prognostic model based on post-treatment Deauville score on PET-CT scan and the presence of EBV DNA was evaluated [19]. In that study, both Deauville score 3 or 4 [progression-free survival (PFS) hazard ratio (HR), 3.607; 95% confidence interval (CI), 1.772–7.341; univariable P<0.0001] and EBV DNA positivity (PFS HR, 3.595; 95% CI, 1.598–8.089; univariable P<0.0001) were significantly associated with PFS and overall survival (OS). By combining the two prognostic factors, the model predicted PFS even better (for low risk vs. high risk, HR, 7.761; 95% CI, 2.592–23.233; P<0.0001; for low risk vs. failure, HR, 18.546; 95% CI, 5.997–57.353; P<0.0001). The most recently proposed prognostic index of NK lymphoma (PINK/PINK-E) was built from the clinical data of Asian patients, which uses EBV DNA titer as well as clinical parameters (age >60 yr, advanced stage, non-nasal type disease, and distant lymph node involvement) for risk stratification [23]. With the above mentioned models, a risk-adapted approach according to the risk groups should be evaluated with further studies.

Standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by involved field radiotherapy (RT) showed disappointing outcomes as front-line treatment for ENKTL [24]. This is mainly attributed to the high expression of the multidrug resistance (MDR) related P-glycoprotein on ENKTL cells, which makes chemotherapeutic agents (doxorubicin and cyclophosphamide) ineffective [25, 26]. In addition, other MDR related proteins such as MDR-associated protein (MRP), and lung resistance-related protein are also expressed in ENKTL cells [27]. Poor drug penetration due to extensive tissue necrosis also hampers the effect of chemotherapy [28]. Therefore, non-anthracycline based combinations including agents such as methotrexate, ifosfamide, etoposide, gemcitabine, platinum, and L-asparaginase are used as front-line therapy.

L-asparaginase induced rapid apoptosis of neoplastic NK cells ex vivo due to their inability to synthesize asparagine [29]. L-asparaginase as a single agent was found to be effective for relapsed/refractory ENKTL [30]. Based on this finding, L-asparaginase combinations were tested as front-line treatment [31, 32]. A meta-analysis showed that the use of L-asparaginase was associated with better overall response rate (ORR) and complete remission (CR) rates in both localized and systemic ENKL [33].

RT showed better treatment outcomes as front-line therapy than CHOP [28], and the importance of radiation dosage was also shown in many studies [34-36]. Radiation dose less than 50 Gy produced inferior outcomes. However, RT alone is also not enough due to the high risk of systemic relapse [37]. Thus, combined chemotherapy and radiotherapy (concurrent or sequential) is currently considered as the standard treatment for patients with limited disease.

L-asparaginase containing regimens are currently most widely used in the treatment of advanced ENKTL. In the initial study of SMILE, 20 patients with advanced ENKTL were included [45]. After 2 cycles of SMILE, the ORR and CR rate were 80 and 40%, respectively. With a median follow-up of 24 months, the 1-year OS and PFS rates were both 45%. All the patients developed grade III/IV neutropenia and there was a treatment-related mortality rate of 10%. This result was reproduced outside clinical trials. In a retrospective analysis including 26 patients with newly diagnosed stage IV ENKTL, SMILE induced CR in 53.8% of the patients. Grade III/IV neutropenia occurred in 65.5% of patients and there were 5 sepsis-related deaths. The 5-year OS rate was 47% and the 4-year disease-free survival rate was 60% [46]. In the application of SMILE to patients with ENKTL, the risk of hematological toxicities was a major concern. A retrospective analysis reported that GDP (gemcitabine, dexamethasone, and cisplatin) induced an ORR of 83% after a median of 6 cycles among patients with disseminated ENKL without causing grade III/IV febrile neutropenia [55]. In terms of treatment-related toxicities, the GDP regimen showed an advantage over the previous regimens.

Another L-asparaginase-containing regimen was evaluated in a phase II study that included 19 patients with relapsed/refractory ENKL [56]. After three cycles of AspaMetDex (L-asparaginase, methotrexate, and dexamethasone) chemotherapy, the CR rate and ORR were 61% and 78%, respectively. With a median follow-up of 26 months, the estimated 2-year OS and PFS rates were both around 40%. Only one patient experienced grade IV neutropenia.

Pegylated asparaginase containing regimens have been explored in ENKTL. In a retrospective study, MEDA (methotrexate, etoposide, dexamethasone, and pegaspargase) was evaluated among 13 patients with advanced stage and relapsed/refractory disease [57]. The reported CR rate and ORR were 62% and 77%, respectively, after 6 cycles. With a median follow-up of 20 months, the 1-year OS and PFS rates were 69% and 62%, respectively. Another study evaluated P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) among 21 patients with relapsed/refractory disease (9 patients with advanced stage) [58]. In the study, the CR rate and ORR were 52% and 81%, respectively. With a median follow-up of 17 months, the 3-year OS and PFS rates were 58% and 24%, respectively. In a randomized trial, DDGP (dexamethasone, gemcitabine, cisplatin, and pegaspargase) was compared with SMILE among patients with newly diagnosed advanced stage ENKTL [59]. Twenty-one patients in each group received 6 cycles of DDGP or SMILE. The 1-year PFS and 2-year OS rates were better in the DDGP group than in the SMILE group (86% vs. 38% for 1-year PFS, P=0.006; 74% vs. 45% for 2-year OS, P=0.027). The CR rate and ORR were higher in the DDGP group than in the SMILE group (71% vs. 29%, P=0.005 for CR rate; 95% vs. 67%, P=0.018 for ORR) with less hematological toxicities.

The role of hematopoietic stem cell transplantation (HSCT) in the treatment of ENKTL has been explored in many studies. However, as most of these studies were small phase I, II, or retrospective analyses including very heterogeneous clinical settings with diverse protocols, interpreting the results is complicated.

The clinical outcomes of upfront auto-HSCT were analyzed in a retrospective study conducted in Korea [60]. The study included 62 patients with ENKTL (31 patients with advanced disease), and reported that at a median follow-up of 43.3 months, the 3-year PFS and OS rates were 52.4% and 60.0%, respectively. Among patients with localized disease, the 3-year PFS and OS rates were 64.5% and 67.6%, respectively. Another European study reported that the 2-year OS and PFS rates of the 28 ENKTL patients who received upfront auto-HSCT were 40% and 33%, respectively [61]. Those results were not significantly better as compared with current treatments. Thus, the major expert consensus is that consolidative auto-HSCT is not recommended in patients with localized disease when they achieve a CR with a front-line therapy [62]. For patients with advanced disease and relapsed disease, the role of auto-HSCT is unclear. Auto-HSCT could be considered for consolidation among patients who achieved complete remission, but is not indicated for refractory disease or patients who fail to achieve CR.

With regard to allo-HSCT, an analysis from Japan reported the feasibility of allo-HSCT in NK/T cell lymphoma [63]. In the study including 22 patients with ENKTL, the 2-year PFS and OS rates were 34% and 40%, respectively (median follow-up, 34 mo). A multicenter analysis performed by the Asia Lymphoma Study Group reported favorable outcomes with allo-HSCT [64]. The analysis included 18 patients who underwent allo-HSCT. At a median follow-up of 21 months, the estimated 5-year PFS and OS rates were 51% and 57%, respectively. The use of L-asparaginase containing regimen (SMILE) and achieving CR prior to HSCT were the most important prognostic factors. A retrospective analysis performed by the Center for International Blood and Marrow Transplant Research reported clinical outcomes of allo-HSCT in ENKTL [65]. At a median follow-up of 36 months, the 3-year OS and PFS rates were 34% and 28%, respectively, with a non-relapse mortality rate of 30%. Recently, a retrospective analysis from Korea reported a possible role of allo-SCT in refractory/relapsed disease [66]. At a median follow-up of 28.5 months, one third (5/15) of the patients with ENKTL remained in CR after salvage allo-HSCT, although eight of them had experienced disease progression after auto-HSCT. However, since there is no clear evidence supporting allo-HSCT in ENKTL so far, the advantage of HSCT should be evaluated in each patient and further studies should be conducted to elucidate when to perform which type of HSCT in ENKTL.

The treatment outcomes of refractory/relapsed ENKTL after L-asparaginase containing regimens remain poor. In a retrospective study, with a median follow-up of 58.6 months (range, 27.9–89.2), the median second (PFS) was 4.1 months (95% CI, 3.04–5.16) and the OS was 6.4 months (95% CI, 4.36–8.51) [67]. Therefore, a new treatment approach is needed for these patients.

The treatment of ENKTL has evolved rapidly in the last decade. For localized disease, current combined chemotherapy and radiotherapy cures the majority of patients. However, the treatment outcomes among patients with advanced or refractory/relapsed disease remain unsatisfactory. Recent advances in the immunotherapy and targeted therapy for ENKTL shed light on better treatment for those patients (Table 2). Future studies of promising new drugs and their combination with currently used strategies should be conducted in a collaborative way given the rarity of ENKTL.