NK cells target tumour cells and bacteria or virus-infected cells and kill them by cytolysis [10]. NK cells and T cells share a common ontogeny, and thus, both express CD2 and CD7 [10]. Unlike T cells, NK cells are negative for surface CD3 but express cytoplasmic CD3. NK cells also express CD56, CD57 and CD16, with CD56 being the most consistently expressed [10].

NNKTL is characterized by distinct extranodal distribution [1]. It is a relatively rare NHL. It was first described in 1897 by McBride who observed destruction of the midline (nose and face) and coined the term “lethal midline granuloma” [11]. In the late twentieth century, it was called nasal T-cell lymphoma [6]. Later, the tumour cells were found to have the NK-cell marker CD56; hence, the term NNKTL was adopted [6]. The association of NNKTL and EBV was described by Harabuchi et al. in Japan in 1990 [12].

As discussed earlier, there is a geographic variation of NNKTL prevalence. Much is still being unveiled about the reasons for the variation [6]. It has been postulated that certain human leukocyte antigen (HLA) types have the disadvantage of presenting EBV-associated proteins to T cells, similar to HLA-B46 that is a risk factor for nasopharyngeal cancer, which is also an EBV-associated cancer [6]. Another postulation for the geographic variation is that of the differences in EBV strains and their potential to cause NNKTL [6]. Environmental factors may also play a role in the differences [6]. Some authors have postulated that the low documented NNKTL figures in Africa are also due to lack of requisite immunohistochemical and molecular diagnostic techniques to diagnose NNKTL [8].

The NNKTL lymphoma cells comprise a polymorphous population of atypical small, intermediate and large lymphocytes, admixed with eosinophils; histiocytes and plasma cells [6]. The tumour infiltrate is angio-centric and angio-invasive, with resultant coagulative necrosis [5].The presence of EBV in the tumour cells is detected most reliably by EBER-ISH, which is a diagnostic requisite [5].

NNKTL is initially found as a necrotic granuloma in the nasal cavity, palate and nasopharynx [6]. The symptoms of this stage of the lymphoma are nasal congestion and/or bloody rhinorrhoea [6]. Other symptoms include fever, weight loss, sore throat, swelling of the buccal area or orbits and a hoarse voice [6]. Although usually locally aggressive, NNKTL may spread to the skin, salivary glands, bone marrow, testes and gastrointestinal tract [5]. Tumour-associated haemophagocytic lymphohistiocytosis (HLH) can also occur [5]. There is no difference in distribution between the genders, and the lymphoma develops around the ages of 40 to 50 years [6].

There are benign histopathological and phenotypical mimickers of extranodal NK/T-cell lymphomas that need to be differentiated from the lymphoma. These include chronic active EBV infection, mosquito-bite hypersensitivity, lymphomatoid gastropathy and NK-cell enteropathy [5].

Regardless of the initial site of presentation of NNKTL, a nasal panendoscopy must be performed, and biopsy of suspicious lesions is taken [6]. Bone marrow biopsies must include EBER-ISH to exclude bone marrow involvement. Positron emission tomography-computed tomography (PET/CT) is the recommended imaging modality [6]. In settings where PET/CT is not readily available, magnetic resonance imaging (MRI) or computed tomography (CT) can be used.

Measurement of serum-free circulating EBV deoxyribonucleic acid (DNA) by PCR is an accurate surrogate biomarker of lymphoma load [12].

The extranodal pattern of disease of NNKTL renders the Ann-Arbour staging system of limited use in prognostication and treatment guidelines. Rather, a TNM staging was suggested by Yan et al. in 2015. This TNM staging system was found to be very effective in stratification of tumour burden and survival risk [13].

NNKTL are radiosensitive [5]. Recurrence is high with radiation alone, so chemoradiation is the recommended standard of treatment [6]. Anthracycline-based regimens with radiotherapy showed unsatisfactory results to a multidrug resistance phenotype of NNKTL cells [6]. Different chemotherapy regimens can be used including DeVIC (dexamethasone, etoposide, ifosfamide and carboplatin), SMILE and others with limited success [6]. A multicentre study by Yang et al. in 2015 looked at a prognostic nomogram for overall survival in previously untreated patients with NNKTL. The finding was that the overall survival (OS) rate was 60.3% [14]. The role of stem cell transplantation is unknown but may be beneficial in the relapsed setting [15, 16].

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