Typically, the viral infection, which affects >90% of the world population, occurs years before evidence of ENKTCL-NT, is carried in cells in a latent, asymptomatic form, and for unclear reasons becomes active in causing the disease.

Following the virus's activation, the infected cells acquire numerous genetic abnormalities which may play an important role in the development and/or progression of ENKTCL-NT.

However, EBV+ nodal NKTCL is manifested primarily by its involvement in lymph nodes; it also has clinical, pathological, pathophysiological, and genetic features that differ significantly from those of ENKTCL-NT.

Clinical studies have found that newer chemotherapeutic regimens greatly improved survival in cases of early disease.

Affected patients (median age 50–60 years old; males predominate) most often (~80% of cases) present with nasal bleeding, upper airway obstruction, perforation of the hard palate, and/or disfiguring, necrotic lesions of the nasal cavity, nasopharynx (including Waldeyer's tonsillar ring), paranasal sinuses, palate,[13] and/or eye socket.

[16] Also in rare cases, patients evidence a widespread disease that includes malignant cell infiltrations in the liver, spleen, lymph nodes, bone marrow, and/or blood.

[14] Rarely, patients show laboratory evidence of hemophagocytic lymphohistiocytosis such as: decreased circulating red blood cells, leukocytes, and/or platelets; increased serum levels of liver-derived enzymes, ferritin, and/or triglycerides; decreased serum levels of fibrinogen; and/or hemophagocytosis, i.e. engulfment of blood cells by tissue histiocytes in the liver, spleen, bone morrow, and/or other tissues.

[19] In consequence, the EBV latency II genes force infected cells to become immortal, proliferate excessively, invade tissues, and avoid attack by the hosts' immune system.

Due at least in part to these imposed factors, the infected cells may acquire other genetic abnormalities that further promote their malignant behavior.

[citation needed] Deletions in the long (i.e. "q") arm at position 21–25 (notated as 6q21–25) from one of the two chromosome 6's was an early finding in occasional cases of ENKTCL-NT.

Studies suggest that overactive VEGF receptor and Protein kinase B signaling pathways may also play a role in the pathogenesis of ENKTCL-NT.

[12]) Studies on cultured malignant NK cells and/or patient tissue specimens find that numerous genes are hypermethylated at their promoter sites and therefore are silenced, i.e. make less or none of their protein products.

This silencing has been detected in numerous proteins expressed by cultured NK cells (e.g. BCL2L11, DAPK1, PTPN6, TET2, SOCS6, PRDM1, AIM1, HACE, p15, p16, p73, MLH1, RARB, and ASNS) and the MIR146A gene for its miR-146a microRNA product.

These cells exhibit evidence of EBV infection as determined by in situ hybridization assays to detect one of the virus's latent products, typically EBER-1/2 micoRNAs.

[14] The diagnosis of ENKTCL-NT depends on histological findings that biopsied tissue infiltrates contain lymphocytes that express CD3ε, cytotoxic molecules (granzyme B, perforin, TIA1), and EBV.

Whole body PET-CT scans are recommended to determine the extent of disease at presentation as well as to follow the effects of therapeutic interventions.

Patients presenting with ENKTCL-NT that does not involve the head area typically have a disseminated and aggressively progressive disease with a very poor prognosis.

[25] Patients, particularly those in the advanced poor risk groups may develop hemophagocytic lymphohistiocytosis or have their disease progress to aggressive NK-cell leukemia.

The following regimens are recommended by many studies and the European Society for Medical Oncology Clinical Practice guidelines[16] or National Comprehensive Cancer Network:[31] There are numerous regimens that use non-chemotherapeutic agents to target specific elements known or thought to be involved in the survival of the malignant cells in a significant percentage of ENKTCL-NT cases.

[16] The targets, therapeutic agents, and some phase 1 clinical trials (testing for appropriate dosages, safety, and side effects) and/or phase 2 clinical trials (testing for efficacy and safety) include: Small molecule inhibitors of JAK3 (e.g. tofacitinib), JAK1/JAK2 (e.g. AZD1480), STAT3 (e.g. WP1066), and DDX3X (e.g. RK-33) are being study in pre-clinical in vitro experiments as potential inhibitors of malignant NK/T cell proliferation and survival.