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Pathogenesis and Treatment of Extranodal Natural Killer/T-Cell Lymphoma

Seminars in Hematology, 1, 51, pages 42 - 51

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL) is one of the uncommon subtypes of malignant lymphoma, and predominantly occurs in the nasal or paranasal areas and less frequently in the skin. Previously, its prognosis was poor due to the expression of P-glycoprotein, which actively exports several anticancer agents outside the lymphoma cells. However, in recent years, novel therapeutic approaches such as simultaneous chemoradiotherapy or l-asparaginase–based regimens including SMILE (steroid, methotrexate, ifosfamide, l-asparaginase, and etoposide) improved the response to therapy and survival of ENKL patients. Epstein-Barr virus (EBV) is present in lymphoma cells of almost all patients, accounting for the pathogenesis of ENKL. Fragmented EBV-DNA is released from tumor cells, and can be detected in the peripheral blood of patients. The EBV-DNA copy numbers are associated with tumor burden, and can predict the prognosis of ENKL, as well as the toxicity against chemotherapy. Based on this recent progress, ENKL is currently categorized as a lymphoma with intermediate prognosis, but the overall treatment results are not satisfactory. Further improvement of the prognosis of ENKL is therefore warranted, including the optimal use of hematopoietic stem cell transplantation (HSCT).

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL) is a predominantly extranodal lymphoma, mainly occurring in the nasal/paranasal area, skin/soft tissue, or gastrointestinal tract.1 and 2 The clinical course is aggressive, and the prognosis is poor.3, 4, 5, and 6 The most important issue considering the treatment of ENKL is the expression of P-glycoprotein, which mediates multidrug resistance (MDR).7, 8, and 9 Therefore, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or other anthracycline-based chemotherapy is usually not effective for ENKL.5 and 10

However, in recent years, novel agents have been identified for the treatment of ENKL.11 and 12 Chemotherapeutic agents not affected by P-glycoprotein, such as methotrexate and/or l-asparaginase, are effective against NK cell tumors. 12 In this article, novel treatment strategies for NK/T-cell neoplasms are reviewed.

Pathogenesis Of Nk/T-Cell Lymphoma

The genetic mechanism of lymphomagenesis specific for NK/T-cell lymphoma has long remained undetermined. With regard to chromosomal abnormalities, deletion of the long arm of chromosome 6 was reported to be the most frequent cytogenetic aberration.13 and 14 Complementary genetic hybridization (CGH) and array-based CGH analyses have confirmed that this is the most frequently affected region.15, 16, 17, and 18 From this region, two genes—PRDM1 and FOXO3—were identified to be mutated and responsible for lymphomagenesis.17 and 19 The FOXO3 aberration is specific for ENKL, but PRDM1 mutations are also found in other types of lymphoma,20 and 21 suggesting that PRDM1 is a common tumor-suppressor for lymphoma. 22 Other oncogenes or tumor-suppressors active in other types of lymphoma include TP53, CDKN2A, FAS, SHP1, TP73, and KIT, 23 but little is known about the novel specific genetic aberrations. Further studies using next-generation sequencing are required to clarify the genetic pathogenesis of ENKL.

The most important factor for lymphomagenesis of ENKL is the Epstein-Barr virus (EBV), which is detected in almost all ENKLs.2 and 24 Currently, EBV infection is regarded as a hallmark of this type of lymphoma, and can be detected by means of in situ hybridization (ISH) or Southern blotting. Since EBV has a transforming activity on lymphocytes, it is believed to play an important role in lymphomagenesis. 25

Pathology Of Nk/T-Cell Neoplasms

Histological specimens of ENKL show diffuse proliferation of lymphoma cells with an angiocentric or angiodestructive growth pattern. Varying degrees of infiltration of inflammatory cells are presented and sometimes accompany necrotic changes. These factors caused the misclassification of this tumor as a non-neoplastic condition, in particular as regards nasal lymphomas. 26 Repeat biopsies are important for precise diagnosis. The lymphoma cells express NK cell markers, including CD2, cytoplasmic CD3 (cyCD3), CD7, and CD56. 27 Surface CD3 (sCD3), CD5, and T-cell receptor (TCR) are negative, and TCR genes show germline configurations. 28 Cytotoxic molecules such as TIA-1, granzyme B, and perforin are also positive in this lymphoma.29 and 30

Disease Features Of Nk/T-Cell Lymphoma

The nose and paranasal area including the upper aerodigestive tract are the most commonly affected sites of origin for ENKL, followed by skin and gastrointestinal tract.3, 4, 5, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40 Table 1 shows the clinical features of patients with ENKL from various countries. Approximately half of the patients present with stage I disease, and one fourth with stage II. Some cases show long-term limitation to the original site. However, once the tumor develops outside the original site, the disease rapidly progresses and disseminates with fever, hemophagocytosis, and disseminated intravascular coagulation. With regard to the site of origin, nasal ENKL more frequently presents as a localized disease (ratio 4:1), whereas extranasal ENKL is more frequently detected at an advanced stage (ratio 2:3). 5 The prognosis for the latter is poorer than the former, 6 mainly due to differences in stage distribution. 41 The current World Health Organization (WHO) classification includes both nasal and extranasal ENKLs in the same category of disease. 2 On the other hand, peripheral T-cell lymphomas are separated to entities from each affected organ: cutaneous, hepatosplenic, and intestinal. 42 Because the treatment approach for localized disease is different between nasal and extranasal ENKLs, these two entities should be separated in the forthcoming version of the classification.

Table 1 Clinicopathologic Characteristics of ENKL From Different Countries

Investigators Suzuki et al 5 Chim et al 3 Kim et al 31 Lee et al 4 Li et al 32 Li et al 33 Ng et al 34 Cuadra-Garcia et al 35 Aviles et al 36 Barrionuevo et al 37 Gualco et al. 38 Chauchet et al 39 Pongpruttipan et al 40
Country Japan Hong Kong Korea Korea China Taiwan Singapore USA Mexico Peru Brazil France Thailand
No. of patients 123 (nasal) 27 (extranasal) 67 114 262 175 77 42 17 108 78 122 36 67
Median age (range) 52 yr (14-89) 57 yr (23-89) 49 yr (17-84) 47 yr - 44 yr (11-79) 45 yr (16-86) 49 c (20-80) 48 yr (27-78) 42 yr (27-69) 43 yr (10-94) - 49 yr (22-80) 44 yr (11-83)
M/F ratio 81/42 12/15 52/15 72/42 170/92 115/60 56/21 34/8 10/7 67/41 51/27 85/37 24/11 54/13
Stage I 55 6 51 83 200 133 56 20 12 108 44 23/30 10 26/40
II 29 4 5 31   28   12 0   14 2/30 6  
III 8 1 5 - 62 4 21 1 0 (20) 5 2/30 0 14/40
IV 31 16 6 -   10   6 1   7 4/30 20  
Age > 60 yr 38 (31%) 11 (41%) 23 (35%) * 20 (18%) 55 (21%) - 18 (23%) 14 (33%) - 8 (7%) - - 9 (25%) -
Stage I/II 68% 37% 84% - 76% 92% 73% 82% 92% 84% 83% 83% 44% 65%
PS 0-1 98 (80%) 16 (59%) 52 (78%) 108 (95%) 26 (72%) - - - - 43 (40%) - - 27 (75%) -
LDH > normal 52 (43%) 19 (70%) 39 (59%) * 75 (69%) 166 (63%) - - - - 88 (81%) § - - 14 (39%) -
B symptoms 56 (46%) 17 (63%) 23 (35%) * 78 (69%) 92 (35%) - 22 (29%) - - 50 (46%) 30 (38%) - 14 (39%) -
IPI L/LI 92 (75%) 13 (49%) 59 (88%) 100 (89%) 212 (81%) - 60 (78%) 21 (60%) - 23 (21%) - - 24 (68%) 22 (59%)

lowast Excluding one patient with operative resection.

Mean.

§ >2-fold.

Treatment Of Extranodal Nk/T-Cell Lymphoma

Limited Stages

Because of the chemo-refractoriness mediated by P-glycoprotein, radiotherapy has been the mainstay for treatment of ENKL. Radiation monotherapy was previously applied but was not effective for occult lesions outside the radiation field.43 and 44 Chemotherapy followed by radiotherapy does not provide satisfactory results, with 5-year overall survival (OS) rates less than 50%.45 and 46 Therefore, radiotherapy followed by chemotherapy became the standard for the limited-stage ENKL.32 and 47 In recent years, two clinical trials from Japan and Korea were conducted using a strategy of simultaneous chemoradiotherapy (SCRT).48 and 49 In the Japanese study, patients were treated with 50 Gy of radiotherapy accompanied by the two-thirds dose of DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin) regimen ( Figure 1A ). 11 Two-thirds DeVIC was repeated for three cycles, and the total treatment period was 9 weeks. The Korean study adopted a cisplatin monotherapy for SCRT followed by three cycles of VIPD (etoposide, ifosfamide, cisplatin, and dexamethasone) chemotherapy ( Figure 1B ). 12 Both studies showed satisfactory results, with 2-year OS of approximately 80% ( Table 2 ), and the long-term follow-up study confirmed the durable efficacy with 5-year OS of 70%. 50 However, no comparative trials have been conducted for limited-stage ENKL. Therefore, sequential radio-chemotherapy still remains as an option for the initial treatment of limited-stage ENKL.

gr1

Figure 1 Simultaneous chemoradiotherapy for localized NK/T-cell lymphoma. (A) RT-2/3 DeVIC regimen by Japan Clinical Oncology Group. The two-thirds dose of DeVIC regimen is given for three cycles simultaneously with radiotherapy. (B) CCRT (concurrent chemoradiotherapy)-VIPD regimen from Korea. Cisplatin monotherapy is administered in the period of radiotherapy. Three cycles of the VIPD regimen are supplemented.

Table 2 Simultaneous Chemoradiotherapy (SCRT) Studies for Localized NK/T-Cell Lymphoma

  JCOG0211-DI Korean CCRT
Treatment period 9 weeks 16-20 weeks
Radiation dose 50 Gy 40-50.8 Gy (median: 40 Gy)
Cytotoxic agents CBDCA CDDP
  ETP ETP
  IFM IFM
  Dexa Dexa
Chemotherapy 3 courses SCRT + 3 courses
No. of patients 27 30
Stage I ratio 67% 50%
     
CR rate 77% 73% → 90% (best response)
ORR 81% 100%
2-yr OS 78% 86%
 Median f/u 32 mo 23.7 mo
 Range (24-62 mo) (17.3-37 mo)

Abbreviations: JCOG, Japan Clinical Oncology Group; CCRT, concurent chemoradiotherapy; CBDCA, carboplatin; ETP, etoposide; IFM, ifosfamide; Dexa, dexamethasone; CDDP, cisplatin; CR, complete response; ORR, overall response rate; OS, overall survival; f/u, follow-up.

Advanced Stages, Relapsed or Refractory State

The prognosis of advanced-stage ENKL was poor in the era of anthracycline-based chemotherapy. 5 l-Asparaginase was found to be effective for ENKL,51, 52, and 53 and in vitro studies verified the efficacy. 54 l-Asparaginase is an enzyme that digests serum l-asparagine and acts as an anti-tumor agent through asparagine starvation of tumors with low expression levels of asparagine synthetase. The NK Cell Tumor Study Group conducted clinical trials for a new regimen termed SMILE, which consists of steroid, methotrexate, ifosfamide, l-asparaginase, and etoposide ( Figure 2A ). 55 The phase II SMILE study showed an excellent anti-tumor activity in ENKL, with an overall response rate (ORR) of 79% (90% confidence interval [CI], 65%–89%) and a 1-year survival rate of 55% (95% CI, 38%–69%). 56 The superior OS of patients who received SMILE over historical controls is shown in Figure 3 . The efficacy was further verified by long-term follow-up, with a 3-year OS of 50% (95% CI, 33%–65%). 57

gr2

Figure 2 Adverse reaction of l-asparaginase by age. (A) SMILE regimen by the NK Cell Tumor Study Group. Methotrexate is given alone on the initial day, followed by a 3-day course of ifosfamide, etoposide, and dexamethasone. These four agents constitute the SMILE head. From day 8 to day 20, l-asparaginase is given every other days as a long tail.<<perm not needed>> (B) AspaMetDex regimen by GELA/GOELAMS. Methotrexate is given on day 1, and then l-asparaginase is given on days 2, 4, 6, and 8.

gr3

Figure 3 Overall survival of newly diagnosed stage IV, or relapsed/refractory ENKL. The survival curve of SMILE phase II study 56 is overlaid on those of historical controls. Note that the curves are not exactly comparable because of background differences.

The French GELA and GOELAMS groups developed another l-asparaginase–containing regimen, AspaMetDex (l-asparaginase, methotrexate, and dexamethasone, Figure 2B ). 58 The phase II study of AspaMetDex for relapsed or refractory ENKL also showed a good ORR of 74% and 1-year OS of 47%. 59 SMILE and AspaMetDex are compared in Table 3 . Results of a later study for newly diagnosed ENKL patients were disappointing. 60 Although more than half of the patients were in localized stage, the ORR was 55% (95% CI, 32%–77%) and OS was <50%. All patients examined had anti-asparaginase antibody, suggesting a need for further refinement.

Table 3 L-Asparaginase–Containing Studies for Advanced/Relapsed/Refractory NK/T-Cell Lymphoma

  NKTSG 56 GELA and GOELAMS 59
Regimen SMILE AspaMetDex
Cytotoxic agents MTX MTX
  L-asp L-asp
  Dexa Dexa
  ETP  
  IFM  
No. of patients 38 19
Course 2 courses 3 courses
Chemotherapy intrval 28 days 21 days
Stage III/IV ratio 71% 37%
CR rate 45% 61% (1 patient excluded)
ORR 79% 78%
2-yr OS 51% 41%
 Median f/u 24 mo 26 mo
 Range (13-35 mo) (17-49 mo)
In case of L-asparaginase allergy SMILE head is strong enough MTX monotherapy

Abbreviations: NKTSG, NK-cell Tumor Study Group; MTX, methotrexate; L-asp, L-asparaginase; Dexa, dexamethasone; ETP, etoposide; IFM, ifosfamide; CR, complete response; ORR, overall response rate; OS, overall survival; f/u, follow-up.

Hematopoietic Stem Cell Transplantation

In a previous era when ENKL was defined by a poor prognosis even in limited-stage disease, both autologous and allogeneic HSCTs were the treatments of choice. 23 Upfront autologous HSCT was given to eligible patients, with a long-term survival rate ranging from 50%–70% reported in studies from Taiwan, Japan, and Korea.61, 62, and 63 A matched-control study comparing autologous HSCT and traditional chemotherapy revealed that the advantage of autologous HSCT was limited to patients with a high-risk prognostic index. 64 On the other hand, allogeneic HSCT showed a long-term survival rate ranging from 30%–40%,62 and 65 but the patient background characters were worse than those of autologous HSCT. Patients who received allogeneic HSCT were more likely to be in non–complete remission condition, and to have higher clinical stage at diagnosis, although their median age was lower. 66 To date, no superiority of either autologous or allogeneic HSCT has been identified; the same is true for the conditioning intensity of reduced versus myeloablative conditioning. 66 In the current decade, the treatment modality was changed and prognosis was improved by the introduction of SCRT and l-asparaginase–containing chemotherapy; hence, new questions have been raised regarding the significance and methodology of HSCT for ENKL. Further investigations and prospective evaluations are needed to clarify the indication of HSCT for NK/T-cell lymphoma.

Role Of Ebv-Dna

Clonal EBV is found in virtually all ENKLs. EBV-DNA is linear in the viral particles, but circularizes as an episomal form with unique size of terminal repeat in tumor cells. 67 Cell-free fragmented EBV-DNA is released from lymphoma cells during apoptotic proliferation. 68 In the peripheral blood of ENKL patients, as well as in other EBV-positive tumors, the EBV-DNA can be detected to varying degrees by polymerase chain reaction ( Figure 4 ). The amount of EBV-DNA represents tumor volume, and therefore can predict the prognosis.69 and 70 The usefulness of EBV-DNA was also confirmed in prospective studies.71 and 72 Among patients in the SMILE phase II study, the amount of EBV-DNA further predicted the degree of adverse reactions. 72 This is particularly important for patient care and further clinical studies because the toxicity of SMILE is higher than that of other regimens. There are several choices of source tissue for analysis, including plasma, total blood, and mononuclear cells, and each choice represents a different outcome. 73 Our studies have shown the advantage of choosing whole blood plasma over other components.71 and 72

gr4

Figure 4 Mechanism of detection of fragmented EBV-DNA in peripheral blood. Episomal EBV-DNA exists in lymphoma cells. In the process of tumor growth some lymphoma cells are induced to apoptosis. Cell-free fragments of EBV-DNA, as well as human DNA, are released from the apoptotic lymphoma cells, and are leaked into peripheral blood.

In addition to ENKL, at least three diseases are recognized as systemic or local proliferation of NK cells: aggressive NK-cell leukemia (ANKL), lymphomatoid gastroenteropathy, and chronic NK cell lymphocytosis (CNKL). The disease features are summarized in Table 4 .

Table 4 Features of NK Cell Lineage Diseases

  Extranodal NK Cell Lymphoma, Nasal Type Aggressive NK Cell Leukemia Lymphomatoid Gastroenteropathy (Takeuchi's disease) Chronic NK Cell Lymphocytosis
Limited Stage Advanced Stage
Morphology LGL LGL LGL LGL
Azurophilic granule (Giemsa) + + + +
Eosinophilic granule (HE) - - + -
Median age 40s - 50s 50s 30s - 40s 50s 60s
Sex distribution M > F M > F M = F F > M M = F
Lynphnode involvement - +/- + - -
Extranodal involvement Nose, skin Nose, skin, bone marrow, blood, GI tract Bone marrow, blood, liver, spleen Stomach, intestine Bone marrow, blood
B-symptom Rare Frequent Frequent No No
Surface marker CD2+, cyCD3+, CD16-/+, CD56+ CD2+, CD16+, CD56+ CD2+, cyCD3+, CD16-, CD56+ CD2+, CD16+, CD56+/-
EBV + + (/-) - -
Clinical course Sometimes indolent Aggressive Aggressive Spontaneous regression Indolent
Therapy Radiotherapy followed by chemotherapy No standard therapy No standard therapy Observation Observation
Prognosis Fair Poor Extremely poor Good Good (depends on underlying disease)

Abbreviations: HE, hematoxylin-eosin; LGL, large granular lymphocyte; EBV, Epstein-Barr virus; M, male; F, female.

Aggressive NK Cell Leukemia

ANKL is a rare leukemic form of N cell neoplasm that accounts for <1% of the lymphoid malignancies. ANKL predominantly occurs in younger patients with a median age of approximately 40 years without any sex predilection.74 and 75 Patients frequently present with B-symptoms, such as fever, night sweats, or body weight loss. Hematologic manifestation of ANKL is that of leukemia, which includes circulating and bone marrow leukemic cells, neutropenia, anemia, and thrombocytopenia but hepatosplenomegaly is also frequently recognized. Cutaneous or central nervous system involvement is uncommon. Leukemic cells show morphology of large granular lymphocytes and expression of NK cell antigens, including CD2+, cytoplasmic CD3, CD7, and CD56. EBV is usually present in ANKL but not exclusively. 74 Expression of CD16 is characteristic for ANKL in comparison to ENKL, suggesting a distinct differentiation stage of NK cells. 76 ANKL originates from cytotoxic NK cells, which are more mature than immunoregulatory NK cells. The genetic differences of ANKL and ENKL, including genomic gain and loss, were revealed by array-based comparative genomic hybridization. 16 Clinical course of ANKL is rapid and progressive. Although anthracycline-based chemotherapy shows only limited response, l-asparaginase is useful. However, due to systemic organ damage, the SMILE regimen is not appropriate for this disease. Dose-reduced SMILE or l-asparaginase monotherapy is suitable for treatment.12 and 77

Lymphomatoid Gastroenteropathy (Takeuchi's disease)

The first documentation of lymphomatoid gastroenteropathy or NK cell enteropathy was in 2006. 78 Later, in 2010, a total of 10 patients were reported, and the disease concept has been established by Takeuchi et al. 79 This disease is characterized by a localized proliferation of NK cells, mostly in the stomach, but less frequently in the intestine.79 and 80 Patients do not show specific symptoms, and most are found by chance. Many of them accompany gastric cancer, but this is a result of selection by follow-up endoscopy. Macroscopic findings show protruded lesion(s) in the stomach of approximately 1 cm diameter with or without depression or ulcers. A sheet proliferation of NK cells is found in biopsy specimens but necrotic pictures are not seen. EBV is negative, and can be a hallmark of differential diagnosis from ENKL. Lymphoepithelioid lesions are occasionally observed. Eosinophilic granules are found in proliferating NK cells, but their nature is uncertain. Association with Helicobacter pylori, which is often recognized, remains unclear. The lesions usually disappear without any medications, but infrequently experience recurrence. The most important point for this disease is to avoid chemotherapy for lymphoma and to watchfully observe.

Chronic NK Cell Lymphocytosis

CNKL is characterized by a chronic increase of peripheral blood NK cells without lymphadenopathy or organomegaly. 81 This disease is essentially non-neoplastic nature, and does not show any cytogenetic abnormalities. However, peripheral blood counts and morphology of leukemic cells are analogous to ANKL. EBV is usually undetectable in CNKL, hence the examination of EBV may help the differential diagnosis. 82 Rare cases of CNKL were reported to develop into ANKL, but these may represent occult ANKLs in the category of CNKL rather than transformation. Consequently, careful observation is needed for CNKL patients, since a part of ANKL is EBV-negative. CNKL is sometimes associated with reactive conditions against viral infections or underlying solid tumors. 81 Whole-body examinations are thus recommended for clinical management of CNKL.

Conclusion

Several new insights have been developed for ENKL. The disease is currently recognized to have an intermediate prognosis. Further improvements for diagnosis and treatment should be explored in prospective clinical studies.

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Footnotes

Department of HSCT Data Management and Biostatistics, Nagoya University, Graduate School of Medicine, Nagoya, Japan

lowast Address correspondence to Ritsuro Suzuki, MD, Department of HSCT Data Management and Biostatistics, Nagoya University, Graduate School of Medicine, 1-1-20 Daiko-Minami, Higashi-ku, Nagoya, 461-0047 Japan

Conflicts of interest: none.