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Clinical features of extranodal nasal-type NK/T-cell lymphoma in children and adolescents
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Extranodal nasal-type natural killer (NK)/T-cell lymphoma is rarely observed in children and adolescents. We aim to investigate the clinical features, prognosis, and treatment outcomes in these patients. Thirty-seven patients were reviewed. There were 19, 14, 2, and 2 patients with stage I, stage II, stage III, and stage IV diseases, respectively....
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... Since then, efforts were shifted towards studying the effectivity of radiotherapy in treating NKTL (12)(13)(14). Many retrospective analysis and prospective clinical trials were published in the Far East supporting the use of radiotherapy as the primary treatment (13,(15)(16)(17)(18). Radiotherapy has been found to be the most important modality for treating ENKTL since the 1990s when NKTL was still referred to as angiocentric lymphoma (13). ...
Extranodal Natural Killer/T-cell lymphoma (ENKTL) is an extremely rare type of lymphoma which is highly lethal. It mainly affects the midline area unfolding as a necrotic granulomatous and extremely disfiguring lesion. There are two subtypes of (NKTL); the most common one is nasal which appears in the nasal cavity including the nasopharynx, oropharynx, parts of the aero digestive tract and Waldeyer’s ring. While the other rarer subtype, appears in sites like the skin, testis, gastrointestinal tract, salivary glands and muscle. ENKTL is popular for the expression of multidrug resistance-associated P-glycoprotein, which not only plays the main role at exporting many antitumor agents outside tumor cells, but also makes the disease hard to treat. It is commonly associated with Epstein-Barr virus (EBV) infection and commonly occurs in Asian populations. However, there is no single unified consensus yet as to what is the standardized treatment for ENKTL. Radiotherapy alone treatment, has been considered as a first-line therapy for localized ENKTL, which later on was found to be insufficient for improving survival rates. Thus, the combination of chemotherapy and radiotherapy has been recommended as a therapeutic modality for localized ENKTL. Several combination modalities of radiotherapy and chemotherapy have been advised in clinical practice including concurrent, sequential and sandwich chemo radiotherapy. For the best treatment outcome, only patients with localized nasal ENKTL and low risk of treatment failure are eligible for radiotherapy. Both radiotherapy and hematopoietic stem cell transplantation (HSCT) have been used as treatment modalities in ENKTL patients. Upfront HSCT was performed for ENKTL, but it was associated with a very poor prognosis even for the limited-stage disease. The evidence supporting the use of HSCT to treat ENKTL was derived from the results of a series of phase 1 and 2 trials along with retrospective studies. The end result was a unified consensus that consolidative HSCT is not necessary in patients with newly diagnosed localized ENKTL who achieved complete response after treatment with any of the modern chemo radiotherapy regimens. Hence, HSCT is solely advised for advanced and relapsed NKTL. The main debate remains over which HSCT is the most suitable for patients with newly diagnosed advanced NKTL and relapsed NKTL.
... According to Ann Arbor staging system, approximately 70% of the NKTCL patients are classified as early-stage cases who are promising to be cured [3]. Considering NKTCL is sensitive to radiation but may be resistant to chemotherapy, the radiotherapy is considered to be the most important treatment for some early-stage patients with a satisfactory local control rate and could be used alone [4]. However, systemic recurrence after radiotherapy in a portion of NKTCL patients seriously affects their long-term survival, and the first-line treatment combined with radiotherapy and chemotherapy is considered necessary. ...
The therapeutic modalities of early-stage and advanced extranodal natural killer/T-cell lymphoma (NKTCL) patients are completely different. The former is mainly radiotherapy with or without chemotherapy, while the latter relies on chemotherapy-based systemic treatment.1,2 According to Ann Arbor staging system, approximately 70% of the NKTCL patients are classified as early-stage cases who are promising to be cured.3 Considering NKTCL is sensitive to radiation but may be resistant to chemotherapy, the radiotherapy is considered to be the most important treatment for some early-stage patients with a satisfactory local control rate and could be used alone.4 However, systemic recurrence after radiotherapy in a portion of NKTCL patients seriously affects their long-term survival, and the first-line treatment combined with radiotherapy and chemotherapy is considered necessary. Therefore, the use of radiotherapy alone in early-stage NKTCL is still a controversial issue.5,6
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... [1] The prevalence of PTCL varies prominently in regions, in which the prevalence of PTCL-NOS is about 25-36% in all PTCL, 22% in Asian and 15% in China. [2,7] A study [8] has discovered that ENKL occurs more frequently in Asian, especially south China and Southeast Asia, with prevalence of > 4 folds than that in western countries. This study disclosed that in the PTCL subtypes, PTCL-NOS was still the most common, followed by ALCL and AITL. ...
Background:
This study aimed to explore the clinical characteristics, therapeutic efficacy and prognostic factors of peripheral T-cell lymphoma (PTCL).
Methods:
The clinical data of 119 PTCL patients who were admitted to the Xinjiang Medical University Affiliated Tumor Hospital from January 2010 to December 2017 were retrospectively analyzed, including the clinical characteristics, therapeutic efficacy, prognosis-related factors and treatments. Among the patients, 98 patients received antharcyclines-based therapeutic protocols, including Cyclophosphamide, Pirarubicin, Vincristine, Prednisone (CHOP) protocol and Cyclophosphamide, Pirarubicin, Vincristine, Prednisone, Etoposide (CHOPE) protocol, with median follow-up time of 32.5 months (2-166 months). The patients' clinical characteristics were analyzed, and COX ratio risk regression model was adopted to analyze the prognostic factors related with the survival rate of PTCL patients.
Results:
The 5-year overall survival (OS) rate was 46.4% and progression-free survival (PFS) rate was 42.7% in the 98 patients, and there were insignificant differences between patients with CHOP protocol and those with CHOPE protocol in the 5-year OS and PFS rates (OS: P = 0.197, PFS: P = 0.663). The univariate analysis results showed that different pathological types, Ann Arbor stage, Eastern Cooperative Oncology Group (ECOG) score ≥ 2, the number of extranodal lymphomas involved, Lactic dehydrogenase (LDH) level, presence/absence of bone marrow involved, international prognostic index (IPI) score, β2 microglobulin (β2-MG) level and hemoglobin (Hb) level were poor prognosis factors influencing patients' OS and PFS rates (P all < .05). Multivariate analysis demonstrated that different pathological types, Ann Arbor stage, presence/absence of bone marrow involved and Hb level were independent prognostic indicators influencing patients' OS and PFS rates (P all < .05).
Conclusion:
PTCL is poor in therapeutic efficacy and prognosis, and different pathological types, Ann Arbor stage, presence/absence of bone marrow involved and Hb level are related with the prognosis of PTCL patients. Anemia occurring before the treatment is an important predictive indicator influencing the prognosis of PTCL patients and patients who experience anemia will be poor in prognosis.
... The 5-year OS and progression-free survival rates for all patients were 77.0% and 68.5%, similar to that in adult patients. 25 At present, the outcome in early-stage ENKTL patients is excellent after comprehensive treatment. In this cohort, the 5-year EFS and OS rates of patients with ENKTL were 66.2% and 94.7%, respectively. ...
Purpose
As extranodal natural killer/T‐cell lymphoma (ENKTL) occurs rarely in children and adolescents, standardized therapy is yet to be determined. This study aimed to describe the clinical features and determine the optimal chemotherapy regimen for childhood ENKTL.
Methods
The treatment outcomes of radiotherapy combined with asparaginase‐based (P‐GEMOX or P‐GMED) or asparaginase‐absent chemotherapy regimens (CHOP, EPOCH, or NHL‐BFM‐90/95) in patients aged ≤18 years with newly diagnosed ENKTL from December 2006 to December 2018 were compared.
Results
Among the 34 patients included in the study, 21 had stage I/II disease. The overall response rates of chemotherapy with or without asparaginase were 85.0% and 78.6%, respectively. With a median follow‐up of 54 months, the 5‐year event‐free survival (EFS) rates of patients with stage I/II and III/IV disease were 66.2 ± 11.3% and 26.0 ± 12.8%, respectively (P = .027). In stage III/IV patients treated with asparaginase‐based or asparaginase‐absent regimens, the 5‐year EFS rates were 40.0 ± 17.4% and 0%, respectively (P = .236). The 5‐year EFS rates of stage III/IV patients who received or did not receive hematopoietic stem cell transplant were 66.7 ± 27.2% and 11.1 ± 10.5%, respectively (P = .054). In addition, chemotherapy‐associated side effects were significantly less in patients treated with asparaginase‐based regimens as compared to asparaginase‐absent regimens in this cohort.
Conclusion
P‐GEMOX and P‐GMED regimens are effective and safe for treating childhood ENKTL.
... Only a few cases of ENKTL occurring in children and adolescents have been reported. [6,7,12] It tends to have a male predominance and the clinical symptoms are not specific. Most patients present as stage I/II and frequently with B symptoms. ...
... Additionally, ENKTL commonly occurs in the nasal cavity and/or paranasal region, [7] extremely rarely in the skin, orbit, liver, spleen and lung. [6,12] Up to now, ENKTL of children and adolescents, occurring in the GI tract was never reported before. To the best of our knowledge, this is the first reported case of ENKTL of childhood in the GI tract. ...
Rationale:
Primary extranodal natural killer (NK)/T-cell lymphoma (ENKTL) rarely occurs in childhood and adolescence. To the best of our knowledge, ENKTL of childhood in the gastrointestinal (GI) tract has not been reported yet.
Patient concerns:
A 12-year-old Chinese boy complained of abdominal pain and persistent fever for 1 month.
Diagnosis:
Grossly an ulcerated tumor with perforation was located at the proximal ascending colon, 5 cm × 4 cm × 1.5 cm in diameter. The tumor was poorly circumscribed, tan-white and solid. Histological evaluation revealed medium-sized atypical lymphoid cells with large areas of necrosis distributed throughout all layers of the colon. Small blood vessels with destroyed walls were surrounded by lymphoid cells. Immunohistochemistry (IHC) highlighted tumor cells as strongly positive for CD3, CD56, CD5, CD2, CD8, CD4, CD43, T-cell restricted intracellular antigen 1 (TIA-1) and granzyme B. The proliferation index, measured by Ki-67 expression was high with 60%. The In situ hybridization (ISH) for EBER was positive. TCR was negative. Therefore, the final diagnosis was ENKTL of childhood in the colon.
Interventions:
The patient underwent right hemicolectomy and ileocolostomy.
Outcomes:
We recommended further evaluation and treatment, but the patient and patient family rejected further treatment of his condition. The patient died within 1 month after being discharged from hospital as a result of his disease.
Lessons:
ENKTL of childhood in the GI tract is extremely rare. Due to the non-specific clinical symptoms, it is easy it is easy not to think of this differential diagnosis at early stage. If patients have GI symptoms, ENKTL cannot easily be ignored. It is necessary to diagnose ENKTL of childhood in the GI tract by morphology and immunohistochemistry, and to differentiate from the GI T-cell lymphomas. We hope this case may serve as a reference improving clinical diagnosis and treatment.
... (Swerdlow et al., 2017;Sánchez-Romero et al., 2019) (Table 2) Rarely, it can affect children and adolescents, and most of the cases reported are from China, Japan and Guatemala. (Sánchez-Romero et al., 2019;Huang et al., 2016;Wang et al., 2009) ...
Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT) is an aggressive malignancy associated with Epstein-Barr virus infection, with a geographic and racial predilection for some Asian and Latin American countries. ENKTCL-NT manifests as a necrotic process affecting nasal or upper aerodigestive structures and, rarely, extranasal sites such as skin, and the gastrointestinal tract. ENKTCL-NT was characterized by its poor prognosis irrespective of clinical stage and therapy. However, during the last two decades, advances in its clinicopathologic, genetic and molecular characterization have been achieved, as have changes in the chemotherapy regimens that, in combination with radiotherapy, are significantly improving the survival of these patients, especially in initial stages. For these reasons, we present an overview of the historical background of ENKTCL-NT along with an updated review of its potential etiological factors, clinicopathologic and molecular features, as well as its prognostic models, current treatment protocols, and future directions on potential promising therapeutic approaches.
... According to the PINK-E, the OS was: 81% for low, 55% for intermediate, and 28% for high risk patients at 3 years [4]. Despite the absence of a standard of care for ENKL, for localized disease it appears that non-anthracycline based regimens like mSMILE, achieve a higher rate of durable response then seen in series with radiotherapy alone (25-49% relapse rate [19,20]) or other anthracycline-based chemotherapy (5 year OS, 73,3% vs 60,9%, p < 0.001; 5 year PFS, 64,0% vs 47.6%, p < 0.001) [21]. Consistent with these data, other non-anthracycline containing regimens have shown good results. ...
A modification of the SMILE regimen with dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) followed by Intensity-Modulated Radiotherapy (IMRT) at lower than usual dose, has been adopted as standard of care for extranodal NK-/T-cell lymphoma (ENKL) at our institution. mSMILE is a short course, intensive regimen incorporating pegylated asparaginase. Here, we describe clinical details, outcome and safety of patients receiving mSMILE. Among 28 patients with ENKL treated, response post-mSMILE was 93% (CR 68%), response post IMRT was 95% (CR 87.5%). Among early-stage patients/low PINK-E (n = 13), overall survival (OS) was 100% at the median follow-up of 31 months; progression-free survival (PFS) was 92%. Advanced-stage and intermediate/high PINK-E patients fared similarly (OS 43%, PFS 33.3% at the median follow-up). Thirty-two percent of the patients experienced G3-4 non-hematologic toxicity, all experienced hematologic toxicity. Most localized-stage patients achieved long-term disease control. Despite high response rates, most of the advanced stage patients relapsed quickly.
... 9 Risk-adapted therapy with RT alone for the low-risk group and RT followed by chemotherapy (CT) for the high-risk group yields favorable outcomes in the anthracycline (ANT)-based CT era. 10 Over the last decade, early-stage ENKTCL treatments have evolved with the utilization of first-line new-regimen CT and radiotherapy. 5,[11][12][13] Phase I/II trials or single-arm retrospective studies have reported improved survival with concurrent or sequential non-ANT-based CT and RT for early-stage patients. [14][15][16][17][18][19] In recent pooled studies from the China Lymphoma Collaborative Group (CLCG), new CT regimens significantly improved survival compared with ANT-based regimens, regardless of stage and age. ...
We aimed to determine the survival benefits of chemotherapy (CT) added to radiotherapy (RT) in different risk groups of patients with early‐stage extranodal nasal‐type NK/T‐cell lymphoma (ENKTCL), and to investigate the risk of postponing RT based on induction CT responses. A total of 1360 patients who received RT with or without new‐regimen CT from 20 institutions were retrospectively reviewed. The patients had received RT alone, RT followed by CT (RT + CT), or CT followed by RT (CT + RT). The patients were stratified into different risk groups using the nomogram‐revised risk index (NRI). A comparative study was performed using propensity score‐matched (PSM) analysis. Adding new‐regimen CT to RT (vs RT alone) significantly improved overall survival (OS, 73.2% vs 60.9%, P < .001) and progression‐free survival (PFS, 63.5% vs 54.2%, P < .001) for intermediate‐risk/high‐risk patients, but not for low‐risk patients. For intermediate‐risk/high‐risk patients, RT + CT and CT + RT resulted in non‐significantly different OS (77.7% vs 72.4%; P = .290) and PFS (67.1% vs 63.1%; P = .592). For patients with complete response (CR) after induction CT, initiation of RT within or beyond three cycles of CT resulted in similar OS (78.2% vs 81.7%, P = .915) and PFS (68.2% vs 69.9%, P = .519). For patients without CR, early RT resulted in better PFS (63.4% vs 47.6%, P = .019) than late RT. Risk‐based, response‐adapted therapy involving early RT combined with CT is a viable, effective strategy for intermediate‐risk/high‐risk early‐stage patients with ENKTCL in the modern treatment era.
... The CR rate of radiotherapy alone ranged from 60% to 80% for stages IE to IIE nasal ENKTL [4,6,27,28]. Therefore, sample size was calculated to be adequate to reject a 70% CR rate in support of a target CR rate of 90% on the basis of Simon's optimal two-stage design. ...
... In our study, the CR rate was 100%, and the 2-year OS and PFS rates were 90.9% and 92.8%. Besides, the CR rate after CCRT was 90.0% in our study, which is considerably higher than the rates reported in previous studies on CCRT, radiotherapy alone, and chemotherapy followed by radiotherapy [7,11,12,27,28,31,32]. Therefore, we considered our therapeutic regimen to be highly effective for the treatment of localized nasal ENKTL. ...
Background:
Concurrent chemoradiotherapy (CCRT) is expected to improve local and systemic disease control and has been established as a standard therapy for several types of solid tumors. Considering the benefits of frontline radiation and pegaspargase in localized extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL), we conducted a phase II study on pegaspargase-based CCRT to explore an effective treatment.
Methods:
In this study, 30 patients with newly diagnosed nasal ENKTL in stages IE to IIE received CCRT (radiation 50 Gy and two cycles of pegaspargase 2500 unit/m2 every 3 weeks). Four courses of pegaspargase were performed after CCRT.
Results:
The patients completed CCRT and four cycles of pegaspargase. The complete remission (CR) rate was 90% with a 95% confidential interval (CI ) of 73.5% to 97.9% after CCRT. The CR rate was 100% (95% CI, 88.4 % to 100%) at the end of the treatment. The 2-year overall survival and progression-free survival rates were 90.9% (95% CI, 78.4 % to 100%) and 92.8% (95% CI, 83.2% to 100%), respectively. The major adverse events (AEs) were in grades 1-2.
Conclusion:
Preliminary data indicate that pegaspargase combined with concurrent radiotherapy for newly diagnosed patients with nasal ENKTL was efficacious and well tolerated. (This study was registered at www.chictr.org, the Clinical Trial Registration Number was ChiCTR-OIC-15007662.) IMPLICATIONS FOR PRACTICE: This clinical trial, evaluating the efficacy and toxicity of concurrent chemoradiotherapy by using single-drug pegaspargase for patients with ENKTL in stage IE to IIE,showed pegaspargase combined with concurrent radiotherapy was efficacious and well tolerated. Pegaspargase has a long half-life and is easy to administer via intramuscular injection. Consequently, pegaspargase combined with concurrent radiotherapy for ENKTL patients can be completed in the outpatient clinic.
... Although there are scarce studies with data specific to age, it seems that treatment response is increased in young patients. The result is a higher survival rate (between 73-77%) when compared to adults [61,62]. This finding is maintained even in patients in early stages of disease treated with radiotherapy alone [61,62]. ...
... The result is a higher survival rate (between 73-77%) when compared to adults [61,62]. This finding is maintained even in patients in early stages of disease treated with radiotherapy alone [61,62]. ...
Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT) is a lymphoid malignancy that mainly affects the nasopharynx and is associated with the Epstein-Barr virus (EBV). Increased incidence is seen in some Latin American and Asian countries. In this study, we describe a case series of 86 Guatemalan patients with ENKTCL-NT from a single diagnostic head and neck center. We emphasize the distinctive clinical, microscopic, and immunohistochemical (IHC) features, as well as EBV positivity by in situ hybridization (ISH). Most of the patients (90.6%) were of Mayan descent and low socioeconomic status (SES). Males were more often affected than females, comprising 68.3% of cases. Patient age ranged from 8 to 71, with a mean of 34.7 years. All cases arose in the upper aerodigestive tract and mainly presented as a rapidly progressive, necrotizing midfacial process affecting the nasal, nasopharyngeal, sinonasal, palatal, and oropharyngeal structures. Microscopically, ENKTCL-NT showed a diffuse polymorphic and atypical lymphoid infiltrate. Angiocentric and angiodestructive growth patterns were present with associated necrosis. Peripheral hyaline necrosis of blood vessels was a histologic hallmark. The ISH and IHC profiles included positivity of EBV, LCA, CD3, CD45RO, CD30 (focal in 39.2%), granzyme-B, TIA-1, perforin (in 82.3%), and CD56 (in 83.7%). CD20 was negative, and the Ki-67 index ranged from 70 to 90%. In Guatemala, this lymphoma is strongly associated with people of low SES and indigenous ethnicity. When affected, the palatal mucosa provides the best site to obtain a representative biopsy. Since ENKTCL-NT is highly aggressive, it is extremely important to recognize the spectrum of clinical presentations and microscopic features in order to avoid misdiagnosis and treatment delay.
