Non-Hodgkin lymphoma is one of the top ten cancer localizations by incidence and mortality. It was responsible for 544 000 new cases and 260 000 deaths worldwide in 2020. In the USA, Lymphoid neoplasms are 34.4/100 000. Extranodal Natural Killers/T Cell´s Lymphoma (ENKTL) is a rare subtype of lymphoma with a higher incidence in East Asia and Central and South America and is more frequent in males than in females. In the USA, the reported incidence of ENKTL increased from 0.4 in 2001 to 0.8 in 2014 per 1 000 000 individuals.^{1,7,8,9,10,11,12} To the best knowledge of the author, this paper constitutes the first report of an ENKTL in Cuba and according to the registry of the National Institute of Oncology and Radiobiology, this is the first case diagnosed in this institution at least in the last decade.

Multiple factors have been implicated in the development of ENKTL. Among them, the infection with EBV has been strongly associated with this lymphoma and is implicated in its pathogenesis. Viral LMP activate MYC and NF-κB. MYC epigenetically induce EZH2 and thus proliferation, while NF-κB also induce proliferation and stimulate PDL1 and hence immune evasion.^6,13,14,15

Genetic risk factors have only been spotted in recent years. Some loci have been associated with ENKTL like IL18RAP promotor and 47F-67I, 47Y-67L, and rs9277378. Those loci control inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation, involving HLA-DRB1 and HLA-DPB1.^16,17

Molecular studies have shown several genetic and epigenetic alterations in ENKTL. Mutation analysis revealed frequent activation of oncogenic pathway and alterations in tumour suppressor genes (TSGs). Mutations mainly affect JAK/STAT pathway, TP53, PRDM1 and DDX3X, which also activate MYC and NF-κB. Moreover, mutations in genes associated with epigenomic regulation, as well as miRNA and histone methylation (H3K27me3) dysregulation have been reported. Altogether, these stimulate proliferation, immune evasion and inhibits apoptosis. Genomic and transcriptomic profiling have shown to be useful to identify distinct genetic subtypes and potential therapeutic personalization in ENKTL.^{15,18,19,20,21}

Clinical Characteristics

ENKTCL usually affects the nasal/upper aerodigestive tract, most frequently the nasal cavity, paranasal sinuses, and nasopharynges. Less frequent, non-nasal, and metastatic localizations include the gastrointestinal tract, skin, testis, adrenal glands, kidney, breast, and eyes. Lymphadenopathy and bone marrow involvement are less frequent but observable in nearly 20% of cases. The clinical symptoms include nasal obstruction, nasal drainage, facial swelling, and B-symptoms.^22,23,24

Diagnosis/morphology

ENKTLs are lymphoid tumors, histologically characterized by a diffuse angiocentric and angio-destructive growth pattern with ischemia and necrosis. Cells may be variable in size but mid or mixed small and large are the most frequent. The neoplastic cells express CD2, and cytoplasmatic CD3 (but not surface CD3) and CD56 and do not express CD20, which is useful for immunohistochemistry (IHC) diagnosis. The proliferation index assessed by the Ki-67 antibody is usually high and is associated with bad prognosis. ENKTL is closely associated with EBV, therefore EBV markers are also detected by IHC.^3,4,22,25,26

Treatment and clinical outcome Survival/Prognosis

The treatments usually used for Lymphomas such as Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapies have failed to show sufficient efficacy in ENKTL as they express MDR/ABCB1.^27,28 Consequently, other treatments have been adopted: Radiotherapy (50-54 Gy) plus dexamethasone, etoposide, ifosfamide, and dexamethasone (RT-DeVIC) and radiotherapy with cisplatin once per week followed by etoposide, ifosfamide, cisplatin, and dexamethasone (CCRT-VIPD). Considering the high expression of P-glycoprotein/MDR in ENKTL, corticosteroid, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) and L-asparaginase, methotrexate, and dexamethasone (AspaMetDex) have been used with better results. But L-asparaginase-containing chemotherapies have a higher incidence of adverse reactions such as liver damage, bone marrow suppression and infection, and death. Also, DDGP (cisplatin, dexamethasone, gemcitabine, and pegaspargase) chemotherapy show improved response and survival compared with SMILE.^22,23,28,29

Therefore, in view of the general status of the patient we decide to start treatment with RT-VIPD and not with an L-asparaginase-containing chemotherapy. Even those, the patient continued to decline his status and perished two months after the diagnosis. The overall survival (OS) rate reported for localized stage I/II ENKTL at 5 years is near 70% meanwhile, the OS rate at 5 years for advanced stage IV ENKTL is close to 20% where nearly half of patients die within the first six months. Conditions that increase hazard ratio and decrease OS and progression-free survival (PFS) are B-symptoms Hb <11 g/dL, low platelet, high LDH, involvement of lymphadenopathies, Ki-67 > 60%, stage IV.^22,23 Several of those conditions were present in our patient.