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An aggressive lymphoma of natural killer cells, always driven by Epstein-Barr virus, that destroys the tissues in the middle of the face: the nose, the palate and the sinuses. It is common in east Asia and Latin America and uncommon in Europe, and it is the one lymphoma in which ordinary anthracycline chemotherapy does not work at all.
What it is. A lymphoma of natural killer cells, and in a minority of cases of cytotoxic T cells, in which every tumour cell carries Epstein-Barr virus. The virus is part of the definition: a tumour with this appearance that does not carry it is a different disease. The cells grow around and into blood vessels, which cuts off the blood supply to the tissue they sit in, and that is why the disease destroys what it grows in rather than simply displacing it.
Where it starts and what it does. Most often in the nose and the structures around it: the nasal cavity, the sinuses, the hard palate, the back of the throat. It presents as blockage, bleeding, crusting or a hole in the palate, and it is often treated as sinusitis for months before anybody biopsies it. Extranasal sites include the skin, the gut, the testis and the soft tissues, and disease starting outside the nose behaves worse. WHO-HAEM5 dropped the qualifier nasal type from the name in 2022 for exactly that reason, because the disease is recognised at several extranodal sites; the International Consensus Classification kept it, so a report in 2026 may carry either name.
How it differs from the rest of the T-cell family, and this is the most important thing on the page. The tumour expresses P-glycoprotein, a pump that throws anthracyclines back out of the cell. Chemotherapy built around doxorubicin, which is the backbone of almost every other lymphoma regimen, therefore does not work here and must not be used. What does work is asparaginase, an enzyme that strips the amino acid asparagine out of the blood; the tumour cannot make its own and dies. WHO-HAEM5 records the consequence plainly: introducing asparaginase-based chemotherapy with radiotherapy markedly improved outcomes in this disease.
Two near neighbours it is separated from. Intravascular NK/T-cell lymphoma was counted as a form of this disease in the previous classification; in 2022 it was moved to be described alongside aggressive NK-cell leukaemia, because it does not form masses, favours the skin and the central nervous system, is not invariably positive for the virus, and its place is not yet clear. In the other direction, an indolent NK-cell lymphoproliferative disorder of the gut has almost the same surface markers and regresses on its own; what separates them is the virus, which that condition does not carry. WHO-HAEM5 says it is most important not to mistake one for the other.
How the outlook is estimated. The index in current use is PINK, built from 527 patients treated at 38 hospitals in 11 countries with regimens that contained no anthracycline. Four features predicted survival: age over 60, stage III or IV, involvement of distant lymph nodes, and disease starting outside the nose. Three-year overall survival was 81 per cent with none of them, 62 per cent with one, and 25 per cent with two or more. Adding the level of Epstein-Barr virus DNA in the blood, which is also an independent predictor, gives a second version of the index.
The treatment is on this page, moved here from the peripheral T-cell lymphoma page once this record existed. Radiotherapy matters more in early disease than in almost any other lymphoma, and delaying it worsens the outcome.
Uncommon everywhere outside east Asia and Latin America. In Taiwan, 872 new diagnoses were recorded between 2008 and 2021 and the age-adjusted incidence fell over that period, with an average annual change of minus 2.47 per cent; the age-specific rate in people aged 45 to 64 fell from 0.46 to 0.32 per 100,000 person-years. In the United States it is commoner among Asian and Pacific Islander and Hispanic people than among non-Hispanic white people, and the published North American and European data are described by the specialists who collected them as very limited. The United Kingdom population series that reports lymphoma by subtype does not list it separately.
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma), Mediastinal grey zone lymphoma, Primary effusion lymphoma, Plasmablastic lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, EBV-positive diffuse large B-cell lymphoma, Primary large B-cell lymphoma of the testis, Gastric MALT lymphoma, Ocular adnexal MALT lymphoma, Adult T-cell leukaemia/lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous anaplastic large cell lymphoma, Lymphomatoid papulosis, Mycosis fungoides, Enteropathy-associated T-cell lymphoma, Monomorphic epitheliotropic intestinal T-cell lymphoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Splenic marginal zone lymphoma, Nodal marginal zone lymphoma, Primary cutaneous marginal zone lymphoma, Primary cutaneous follicle centre lymphoma, Sezary syndrome, Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma), Hepatosplenic T-cell lymphoma, Intravascular large B-cell lymphoma, Lymphomatoid granulomatosis, T-cell prolymphocytic leukaemia, Splenic B-cell lymphoma/leukaemia with prominent nucleoli (formerly B-cell prolymphocytic leukaemia and hairy cell leukaemia variant), T-cell large granular lymphocytic leukaemia, Mixed-phenotype acute leukaemia, Myeloid leukaemia of Down syndrome, Burkitt leukaemia, Marginal zone lymphoma, Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome), Primary mediastinal (thymic) large B-cell lymphoma, Leukaemia (all types), Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Non-Hodgkin lymphoma (all types), Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Polycythaemia vera (PV), Essential thrombocythaemia (ET), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Systemic mastocytosis, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD), FLT3-mutated acute myeloid leukaemia, IDH1- and IDH2-mutated acute myeloid leukaemia, NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, Secondary and therapy-related acute myeloid leukaemia, Acute promyelocytic leukaemia, Acute myeloid leukaemia in older or unfit patients, Smouldering multiple myeloma, Newly diagnosed multiple myeloma, transplant-eligible, Newly diagnosed multiple myeloma, transplant-ineligible, Relapsed or refractory multiple myeloma, Plasma cell leukaemia, Lower-risk myelodysplastic syndromes, Higher-risk myelodysplastic syndromes, Chronic lymphocytic leukaemia, first treatment, Relapsed or refractory chronic lymphocytic leukaemia, Richter transformation of chronic lymphocytic leukaemia, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase, Primary myelofibrosis, Standard-risk B-cell acute lymphoblastic leukaemia in children, High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL), Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL), Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL), Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year), Relapsed and refractory acute lymphoblastic leukaemia in children, Acute myeloid leukaemia in children, Erdheim-Chester disease, Rosai-Dorfman-Destombes disease, Single-system Langerhans cell histiocytosis (bone, skin or one other organ), Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement), Indolent and smouldering systemic mastocytosis, Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia), Early-stage classical Hodgkin lymphoma (stage I to II), Advanced-stage classical Hodgkin lymphoma (stage III to IV), Nodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma), Relapsed and refractory classical Hodgkin lymphoma
The presentation looks like sinusitis: blockage, bleeding, crusting and pain in the nose, often treated with antibiotics and steroids for months. A biopsy taken through the nose is often necrotic and non-diagnostic, so repeat biopsies are common and are not a failure. The diagnosis needs in situ hybridisation for Epstein-Barr-encoded RNA, which is positive in every tumour cell by definition, together with an NK-cell phenotype: CD56 positive, surface CD3 negative with cytoplasmic CD3-epsilon positive, and cytotoxic granule proteins present. A gut lesion with the same markers but no virus is the indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, which regresses on its own; WHO-HAEM5 says it is most important not to mistake one for the other.
PET-CT of the whole body, magnetic resonance imaging of the face and sinuses to map local destruction, examination of the nose and throat, and a measurement of Epstein-Barr virus DNA in the blood, which tracks the disease and is an independent predictor of survival. The index in use is PINK, built from 527 patients treated without anthracyclines at 38 hospitals in 11 countries, which counts age over 60, stage III or IV, involvement of distant lymph nodes, and disease starting outside the nose: three-year overall survival was 81 per cent with none of those, 62 per cent with one and 25 per cent with two or more. Adding the viral DNA level gives a second version, PINK-E.
An Epstein-Barr virus-driven lymphoma that destroys the midline structures of the face, common in east Asia and Latin America and uncommon in Europe. It expresses P-glycoprotein, which pumps anthracyclines out of the cell, so CHOP is ineffective and must not be used. Every effective regimen contains asparaginase, which the tumour cannot resist because it lacks asparagine synthetase. Early-stage disease (stage I and II, confined to the upper aerodigestive tract) is treated with radiotherapy at a relatively high dose of about 50 Gy, given concurrently with or sandwiched between asparaginase-containing chemotherapy. Radiotherapy is the single most important component in early disease and delaying it worsens outcome. Advanced and relapsed disease is treated with an asparaginase-containing regimen. SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) was tested in 38 patients with newly diagnosed stage IV, relapsed or refractory disease: the overall response rate after two cycles was 79 per cent, complete response 45 per cent, and one-year overall survival 55 per cent, with grade 4 neutropenia in 92 per cent and grade 3 or 4 infection in 61 per cent. Nineteen of the 28 who completed treatment went on to a stem cell transplant. Gentler asparaginase-based regimens such as P-GEMOX and DDGP are widely used in China. Pegylated asparaginase has largely replaced native L-asparaginase. Plasma Epstein-Barr virus DNA is used to monitor response. PD-1 blockade has substantial activity in relapsed disease and is used where available.
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Query for this cancer: (TITLE:"Extranodal NK/T-cell lymphoma" OR ABSTRACT:"Extranodal NK/T-cell lymphoma" OR TITLE:"Extranodal NK/T-cell lymphoma, nasal type" OR ABSTRACT:"Extranodal NK/T-cell lymphoma, nasal type" OR TITLE:"ENKTL" OR ABSTRACT:"ENKTL" OR TITLE:"ENKTCL" OR ABSTRACT:"ENKTCL" OR TITLE:"Nasal type NK/T-cell lymphoma" OR ABSTRACT:"Nasal type NK/T-cell lymphoma" OR TITLE:"NK/T-cell lymphoma" OR ABSTRACT:"NK/T-cell lymphoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Extranodal NK/T-cell lymphoma, not a curated reading list.
The SMILE regimen, built around asparaginase and deliberately free of anthracyclines, was tested in newly diagnosed stage IV, relapsed and refractory disease and established asparaginase as the backbone of treatment.
Built from 527 patients treated without anthracyclines at 38 hospitals in 11 countries: age over 60, stage III or IV, distant lymph node involvement and non-nasal disease gave three-year overall survival of 81, 62 and 25 per cent across the three risk groups.
WHO-HAEM5 renamed the entity extranodal NK/T-cell lymphoma, recognising its presentation at several extranodal sites; the International Consensus Classification kept the nasal type qualifier.
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Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
Cold-triggered acute neuropathy: avoid cold drinks and air for days after infusion.
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
Possible QT prolongation. QT prolongation and torsades reported post-marketing; correct electrolytes.
Reduce to 75% for CrCl 15-50.
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