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ORIGINAL ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 1  |  Page : 20-25

Extranodal NK/T-cell lymphoma-nasal type: Experience from a regional cancer center in India


Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Date of Submission14-Oct-2019
Date of Acceptance11-Feb-2020
Date of Web Publication23-Dec-2020

Correspondence Address:
Dr. Pravin Ashok Khandare
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Dr. M H Marigowda Road, Bengaluru - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjmsr.mjmsr_39_19

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  Abstract 


Introduction: Extranodal natural killer/T-cell lymphoma-nasal type (ENKTL-NT) is an aggressive rare non-Hodgkin's lymphoma (NHL) subtype. It presents with involvement of the nasal and upper aerodigestive region causing extensive destruction of these midline structures. It has a predilection for the Asian population. Most cases present in the early-stage disease. Treatment outcomes are usually poor, and no consensus for optimal treatment strategy exists. Patients and Methods: This is a retrospective analysis of ENKTL-NT, diagnosed in a regional cancer center in India during the period of 2013–2018. The demographic and clinical features, laboratory parameters, radiological, histopathological features, and treatment outcomes were studied. Patients were treated with SMILE or AspaMetDex regimes sandwiched with radiotherapy. Statistical analysis was performed using software “Epi Info” Version 7.2, (CDC, Atlanta, Georgia, USA). Results: Fourteen patients were diagnosed with ENKTL-NT during this period. Eight patients received SMILE, and six patients have received AspaMetDex as induction chemotherapy. Ten (71.42%) of 14 patients have achieved CR. At the median follow-up of 30 months (4–47 months), nine patients relapsed with median progression-free survival of 22 months. The median overall survival was not reached. There were two induction deaths, one in AspaMetDex and one in the SMILE group. All patients receiving SMILE experienced at least one episode of Grade 3/4 hematological toxicity. Patients receiving AspaMetDex did not have any Grade 3/4 hematological toxicity. Discussion: ENKTL-NT in India is not as common as reported in other Asian countries. Patients usually present at an earlier stage because of the peculiar site of affection. It has high response rates, but relapses are common. Most of the relapses occur within the first 2 years of follow-up. Conclusion: ENKTL-NT is rare aggressive NHL subtype with good response to L-asparaginase-based chemotherapy sandwiched with radiation therapy. SMILE is a more toxic regime than AspaMetDex but can be managed with proper supportive care.

Keywords: Extranodal NK/T-cell lymphoma, L-asparaginase, nasal type


How to cite this article:
Saldanha SC, Khandare PA, Dasappa L, Jacob LA, Babu M C, Lokesh K N, Suma M N. Extranodal NK/T-cell lymphoma-nasal type: Experience from a regional cancer center in India. Muller J Med Sci Res 2020;11:20-5

How to cite this URL:
Saldanha SC, Khandare PA, Dasappa L, Jacob LA, Babu M C, Lokesh K N, Suma M N. Extranodal NK/T-cell lymphoma-nasal type: Experience from a regional cancer center in India. Muller J Med Sci Res [serial online] 2020 [cited 2021 Mar 5];11:20-5. Available from: https://www.mjmsr.net/text.asp?2020/11/1/20/304595




  Introduction Top


Natural killer (NK) cells are large granular lymphocytes comprising 10%–15% of circulating lymphocytes and are critical components of the innate immune system. They act as cytolytic cells targeting tumor cells and cells infected with bacteria or viruses. The World Health Organization classifies NK cell lymphomas into aggressive NK cell leukemia and extranodal NK/T-cell lymphoma-nasal type (ENKTL-NT).[1] It is previously known as angiocentric T-cell lymphomas or polymorphic reticulosis, and they are prevalent in Asia and South America. ENKTL-NT has a strong geographical predilection for the Asian population from China, Korea, Japan, and Southeast Asia.[2] Various case series and retrospective analyses have reported a 5%–15% incidence of NK/T-cell malignancies from these regions, of all lymphomas. Indian data are scarce for this non-Hodgkin's lymphoma (NHL) subtype. A recent study from South India showed ENKTL-NT contributed to 1.16% of all NHL.[3] The present study was conducted to study the demographic, clinicopathological, and radiological profile of ENKTL-NT and treatment outcomes from a regional cancer center in India.


  Patients and Methods Top


This is a retrospective analysis of ENKTL-NT, diagnosed and treated at a regional cancer center in India, during the period of January 2013–December 2018.

Written informed consent was obtained from all patients before the clinical examination, any procedure, and before starting treatment. Data were recorded for demographic details, clinical history, and physical examination, with a detailed head-and-neck region examination. Laboratory tests included complete blood counts, organ function tests (liver function test [LFT] and renal function test [RFT]), and serological tests for HIV, Hepatitis B, and C. Other procedures included cerebrospinal fluid (CSF) examination, unilateral bone marrow aspiration, and biopsy. Radiological assessment was done using the contrast-enhanced CT scans (CECT) of the neck, paranasal sinuses, thorax, abdomen, and pelvis for evaluating the extent of disease. The diagnosis was confirmed by the histopathological examinations of biopsy tissues, by using immunohistochemistry (IHC) and EBER-ISH testing.

Patients were treated with L-Asparaginase-based chemotherapy regimens, either SMILE or AspaMetDex sandwiched with radiation therapy (RT) after three cycles [Table 1] and [Table 2]. Patients were reassessed at regular intervals by physical examination with detailed head-and-neck evaluation. Response to treatment was evaluated by repeat CECT scans at regular intervals usually, post 3 cycles and again at the completion of treatment, or earlier if clinically indicated. Data were recorded for the type of chemotherapy regime, response, the toxicity profile of treatment, and survival analysis.
Table 1: SMILE protocol

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Table 2: AspaMetDex protocol

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  Results Top


A total of 1133 lymphoma cases were registered at our center from the period of January 2013 to December 2018, including Hodgkin's and NHL. Fourteen patients were diagnosed with ENKTL-NT, constituting 1.23% of all lymphomas and 1.5% of NHL. Ten were male and four were female (M:F ratio: 2.5:1). Age ranged from 31 to 60 years, with a median of 37 years. All patients presented with clinical features of nasal obstruction, either with nasal stuffiness, or difficulty breathing through nose. The median duration of symptoms was 3 months (range: 1–12 months).

Clinical examinations revealed polypoidal growth in the nasal cavity without any evident external swelling in four patients, four patients had maxillary and parotid region swelling, four patients had externally visible ulceroproliferative growth involving nose, and two patients had a destructive ulcerative lesion with foul-smelling discharge involving the nasal alae and nasal cartilage [Figure 1]. One patient had palatal perforation at presentation while two others developed during treatment [Figure 2]. None of the patients had clinically palpable peripheral lymphadenopathy or hepatosplenomegaly. Other baseline characteristics of patients are listed in [Table 3].
Figure 1: Patient presenting with an extensive destructive lesion of the nose

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Figure 2: Patient with palatal perforation after 1st chemotherapy with SMILE

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Table 3: Baseline clinical features of patients with Extranodal Natural killer/T-cell lymphoma-nasal type

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Laboratory testing showed a mean hemoglobin of 13.1 g/dl for males and 11.6 g/dl for females. Total leukocyte and platelet count were within the normal limits for all cases. Organ function testing included liver and RFTs (LFTs and RFTs), which were within the normal limits for all patients. All patients tested nonreactive for HIV, Hepatitis B, and C serology.

Histopathological examination from nasal biopsies of all patients had tissues with an extensive amount of necrosis along with interspersed sheets of atypical lymphoid cells. IHC was done which was positive for polyclonal CD 3, CD 56, and leukocyte common antigen and negative for CK, CD 10, CD 20, epithelial membrane antigen, and Tdt. Ki-67 index ranged from 30% to 80%. EBER-ISH was positive in 12 cases and in the other two cases not done, because of insufficient tissue [Figure 3].
Figure 3: Histopathology and immunohistochemistry

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Radiological assessment was done by CECT of the neck, paranasal sinuses, thorax, abdomen, and pelvis at baseline. A majority (78.5%) of patients had early-stage disease (Stage IE and IIE). Positron emission tomography-computed tomography (PET-CT) scan was done in only one patient for staging and response assessment. None of the cases had bone marrow involvement by lymphoma. One patient had intracranial extension with CSF positivity for atypical lymphoid cells.

All patients were treated with L-asparaginase-based chemotherapy. Eight patients received SMILE and six received AspaMetDex as initial induction regime. Ten patients (71.42%) achieved CR, based on the radiological assessment. One patient had partial response, and one had refractory disease post 3 cycles of SMILE and was later enrolled in a clinical trial at different center and we could not follow him after that. One patient died in each chemotherapy group during induction. At a median follow-up of 30 months (4–47 months), nine patients relapsed with median progression-free survival of 22 months. At the time of relapse, patients were treated with salvage regime-containing L-asparaginase. Of six patients on AspaMetDex as initial treatment, four patients relapsed who were subsequently salvaged with SMILE and achieved CR, while only one patient progressed on SMILE and subsequently received immunotherapy under clinical trial. Median OS was not reached, with only two other deaths during follow-up. The Kaplan–Meier survival graphs are shown in [Figure 4] and [Figure 5]. Even though the number of patients was low in each chemotherapy group, there were no significant differences in survival outcomes in two groups.
Figure 4: Kaplan–Meier graph for overall survival

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Figure 5: Kaplan–Meier graph for progression-free survival

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All adverse events were recorded and graded as per the common terminology criteria for adverse events version 4.0 and are tabulated in [Table 4]. At least one event of Grade 3 or 4 hematological toxicity was observed by all patients receiving SMILE. Patients receiving AspaMetDex did not experience any Grade 3 or 4 hematological toxicity. [Table 5] shows comparison of toxicity profile between the two regimens. None of the patients had a delay in chemotherapy or radiotherapy schedule related to hematological toxicity.
Table 4: Adverse events graded according to common terminology criteria for adverse events version 4.0

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Table 5: Comparison between SMILE and AspaMetDex protocols toxicity

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  Discussion Top


NK/T-cell malignancies are rare aggressive NHL subtypes with specific geographical predilection. The median age at presentation is the fifth decade, according to published literature which includes various case series and single-institution experiences.[4],[5],[6] ENKTL accounts for 5%–15% of all NHL in certain Asian and few Central and South American countries.[4] Our institute is a regional cancer center, and cases are referred from across the home state as well as from nearby states. In our study, it represented 1.5% of all NHL, which is quite low compared to reported rates in other Asian countries. The median age was 37 years in this study, which is a decade earlier. This may be due to geographical variation or the small number of patients studied. The current study had a male-to-female ratio of 2.5:1 which is in concordance with the available literature, showing male-to-female ratio varying from 2:1 to 3:1.

Clinically, NK/T-cell malignancies may be divided into nasal, nonnasal, and aggressive lymphoma/leukemia subtype. Nasal-type NK/T-cell lymphoma usually presents with a localized disease which in advanced stage may disseminate to skin, gastrointestinal tract, and testes. Non-NT NK/T-cell lymphoma by strict definition requires the absence of nasal involvement, shown by random nasopharyngeal region biopsies and/or PET/CT scan.[7] Most non-NT have primaries, which are a common site for dissemination of NT. A stringent definition was not used for non-NT in prior series, which may have described many cases of disseminated NT as non-NT. Aggressive lymphoma/leukemia subtype has a very aggressive course with survival measured only in weeks to months.

Imaging modalities used in most published studies of ENKTL were CECT and/or magnetic resonance imaging (MRI). CT and MRI, though give valuable information about the local extent of disease, recent literature suggests fluorine-18-fluorodeoxyglucose PET scan should be standard for staging and response assessment in NK/T-cell lymphoma.[8] As ENKTL is associated with extensive necrosis, PET-CT gives a better evaluation of functional tumor burden compared to CT or MRI, which might aid in planning RT. Interim and end-of-treatment responses based on PET-CT was shown to have prognostic significance in ENKTL.[9] The facility for PET-CT is not available at our center and has to be outsourced on as needed basis. Majority of patients taking treatment at our center belong to low socioeconomic strata and receive therapy under various government schemes. Only one patient in our study cohort underwent PET-CT for staging and response assessment, while CECT was used in rest.

Conventionally, RT was treatment modality for localized ENKTL. Response rates for localized stage I/II disease with radiotherapy alone ranged between 60% and 80%, with a median 5-year overall survival (OS) of 40%–59%.[10] The most common nonhematologic toxicity associated with RT was Grade 1 and 2 radiation-induced mucositis and skin changes (25%–30%). RT alone is associated with an unacceptably high relapse rate in a range of up to 40%.[11] Some initial reports suggested no benefit of adding chemotherapy to RT.[12] These reports were based on studies which used cyclophosphamide, doxorubicin, vincristine, and prednisone-like chemotherapy. Conventional anthracycline-based chemotherapy which is a backbone of the treatment for the majority of high-grade NHL is not effective in NK/T-cell malignancies due to the high expression of P-glycoprotein, which result in multidrug-resistance phenotype.[13],[14] Localized Stage I/II NT disease can be cured with regimes using chemotherapy sandwiched with radiotherapy, whereas chemotherapy is the treatment modality for patients with Stage III/IV nasal, nonnasal, and aggressive subtype.[15]

In this study, the majority of patients were in localized stages IE or IIE, which may explain the high overall response rate of 78.57% of treatment. In patients receiving the SMILE regime, all patients experienced Grade 3/4 hematological toxicities. This adverse effect data are similar to that of Asia lymphoma study group.[16] Patients treated with AspaMetDex did not have any Grade 3/4 hematological toxicity, which is less than reported in the earlier report evaluating the efficacy of the AspaMetDex regimen.[17]


  Conclusion Top


ENKTL-NT is a rare aggressive NHL subtype with good response to L-asparaginase-based chemotherapy sandwiched with RT with good tolerability and manageable toxicity profile for early-stage disease.

Acknowledgment

The authors would like to thank the Department of Pathology and the Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India for their assistance in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Burad DK, Therese MM, Nair S. Peripheral T-cell lymphoma: Frequency and distribution in a tertiary referral center in South India. Indian J Pathol Microbiol 2012;55:429-32.  Back to cited text no. 3
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Au WY, Weisenburger DD, Intragumtornchai T, Nakamura S, Kim WS, Sng I, et al. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: A study of 136 cases from the international peripheral T-cell lymphoma project. Blood 2009;113:3931-7.  Back to cited text no. 4
    
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Lee J, Suh C, Park YH, Ko YH, Bang SM, Lee JH, et al. Extranodal natural killer T-cell lymphoma, nasal-type: A prognostic model from a retrospective multicenter study. J Clin Oncol 2006;24:612-8.  Back to cited text no. 5
    
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Kwong YL, Anderson BO, Advani R, Kim WS, Levine AM, Lim ST, et al. Management of T-cell and natural-killer-cell neoplasms in Asia: Consensus statement from the Asian Oncology Summit 2009. Lancet Oncol 2009;10:1093-101.  Back to cited text no. 7
    
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Khong PL, Huang B, Lee EY, Chan WK, Kwong YL. Midtreatment 18F-FDG PET/CT scan for early response assessment of smile therapy in natural killer/T-cell lymphoma: A prospective study from a single center. J Nucl Med 2014;55:911-6.  Back to cited text no. 9
    
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You JY, Chi KH, Yang MH, Chen CC, Ho CH, Chau WK, et al. Radiation therapy versus chemotherapy as initial treatment for localized nasal natural killer (NK)/T-cell lymphoma: A single institute survey in Taiwan. Ann Oncol 2004;15:618-25.  Back to cited text no. 10
    
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Kim SJ, Kim WS. Treatment of localized extranodal NK/T cell lymphoma, nasal type. Int J Hematol 2010;92:690-6.  Back to cited text no. 11
    
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Wang L, Xia ZJ, Huang HQ, Lu Y, Zhang YJ. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the treatment of stage IE/IIE extranodal natural killer/T cell lymphoma, nasal type: 13-year follow-up in 135 patients. Int J Hematol 2012;96:617-23.  Back to cited text no. 12
    
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Yamaguchi M, Kita K, Miwa H, Nishii K, Oka K, Ohno T, et al. Frequent expression of P-glycoprotein/MDR1 by nasal T-cell lymphoma cells. Cancer 1995;76:2351-6.  Back to cited text no. 13
    
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Drénou B, Lamy T, Amiot L, Fardel O, Caulet-Maugendre S, Sasportes M, et al. CD3- CD56+ non-Hodgkin's lymphomas with an aggressive behavior related to multidrug resistance. Blood 1997;89:2966-74.  Back to cited text no. 14
    
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Jaccard A, Gachard N, Marin B, Rogez S, Audrain M, Suarez F, et al. Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood 2011;117:1834-9.  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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