# Extranodal NK/T-cell lymphoma

Source: https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/  
OnCo record `extranodal-nk-t-cell-lymphoma` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-29
- Also known as: Extranodal NK/T-cell lymphoma, nasal type; ENKTL; ENKTCL; Nasal type NK/T-cell lymphoma; NK/T-cell lymphoma; Lethal midline granuloma; Angiocentric lymphoma; Extranodal NK/T-cell lymphoma (EBV)
- Tags: heme; lymphoma; subtype-page
- Group: haematologic
- Burden: 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.
- Subtypes: Nasal, arising in the nasal cavity, sinuses or palate, which is an extranodal site; Extranasal, arising in the skin, gut, testis or soft tissue, which carries a worse outlook and is a risk factor in the PINK index
- Biomarkers: Epstein-Barr virus in every tumour cell by EBER in situ hybridisation, which is part of the definition; An NK-cell phenotype: CD56 positive, surface CD3 negative with cytoplasmic CD3-epsilon positive, and cytotoxic granule proteins present; P-glycoprotein expression, which is why anthracycline chemotherapy does not work; Plasma Epstein-Barr virus DNA, which tracks the disease and is an independent predictor of survival; The PINK index: age over 60, stage III or IV, distant lymph node involvement and non-nasal disease; Deletion of 6q21-25, and mutations of the JAK-STAT pathway, epigenetic regulators, TP53, MGA and DDX3X

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/extranodal-nk-t-cell-lymphoma/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/#overview
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/#what-it-is [2 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/#finding-it [6 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/#treating-it [3 settings, 1 decision with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/#evidence [3 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/#science [2 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/#living-with-it [12 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/coming/ [9 medicines, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/extranodal-nk-t-cell-lymphoma/data/ [38 connected records]

## Standard of care

- Making the diagnosis, and why it is usually late: 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. ([Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Epstein-Barr virus (EBV) in cancer](https://onco.cc/terms/ebv-term/), [Endoscopy (EGD, EUS, ERCP)](https://onco.cc/terms/endoscopy/), [The two lymphoma classifications of 2022 (WHO-HAEM5 and ICC)](https://onco.cc/terms/lymphoma-classification-2022/))
- Staging and the risk score: 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. ([FDG PET](https://onco.cc/technologies/fdg-pet/), [Plasma EBV DNA](https://onco.cc/terms/plasma-ebv-dna/), [Lugano classification / Ann Arbor staging](https://onco.cc/terms/lugano-classification/), [Epstein-Barr virus (EBV) in cancer](https://onco.cc/terms/ebv-term/))
- Extranodal NK/T-cell lymphoma, nasal type: asparaginase, and why anthracyclines do not work: 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. ([Asparaginase (pegaspargase, calaspargase pegol, Erwinia asparaginase)](https://onco.cc/drugs/asparaginase/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Ifosfamide](https://onco.cc/drugs/ifosfamide/), [Etoposide](https://onco.cc/drugs/etoposide/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Gemcitabine](https://onco.cc/drugs/gemcitabine/), [Oxaliplatin](https://onco.cc/drugs/oxaliplatin/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Radiotherapy in lymphoma: involved-site fields, 24 Gy, 4 Gy and total skin electron therapy](https://onco.cc/terms/lymphoma-tx-radiotherapy/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Epstein-Barr virus (EBV) in cancer](https://onco.cc/terms/ebv-term/), [Plasma EBV DNA](https://onco.cc/terms/plasma-ebv-dna/), [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/))

## Open problems

- The disease is common in east Asia and Latin America and rare in the countries that run most randomised trials, so the regimens that work best were developed where most of the patients are and are least familiar where the rest of them are treated.
- There is no randomised comparison between the asparaginase-containing regimens in use, and they differ substantially in toxicity.
- PD-1 blockade produces responses in relapsed disease and has never been tested against anything in a randomised trial in this disease.
- The commonest clinical failure is delay: the presentation looks like sinusitis, and the biopsy is often taken months after the symptoms began.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Extranodal_NK/T-cell_lymphoma,_nasal_type
- WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022): https://doi.org/10.1038/s41375-022-01620-2
- International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022): https://doi.org/10.1182/blood.2022015851
- A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment, 527 patients from 38 hospitals in 11 countries (Kim, Lancet Oncology 2016): https://doi.org/10.1016/S1470-2045(15)00533-1
- Extranodal NK/T cell lymphoma, nasal type: an update on epidemiology, clinical presentation and natural history in North American and European cases (Current Hematologic Malignancy Reports 2016): https://doi.org/10.1007/s11899-016-0355-9
- Trends in the incidence of the Epstein-Barr virus-associated malignancies extranodal NK/T-cell lymphoma and nasopharyngeal carcinoma in Taiwan (PLoS One 2024): https://doi.org/10.1371/journal.pone.0315380
- NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version): https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq

## Connected records

- cancers: [Adult T-cell leukaemia/lymphoma](https://onco.cc/cancers/adult-t-cell-leukaemia-lymphoma/), [Hepatosplenic T-cell lymphoma](https://onco.cc/cancers/hepatosplenic-t-cell-lymphoma/), [Monomorphic epitheliotropic intestinal T-cell lymphoma](https://onco.cc/cancers/monomorphic-epitheliotropic-intestinal-t-cell-lymphoma/), [Nasopharyngeal carcinoma](https://onco.cc/cancers/nasopharyngeal/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma)](https://onco.cc/cancers/peripheral-t-cell-lymphoma/)
- technologies: [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [FDG PET](https://onco.cc/technologies/fdg-pet/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/)
- drugs: [Asparaginase (pegaspargase, calaspargase pegol, Erwinia asparaginase)](https://onco.cc/drugs/asparaginase/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Etoposide](https://onco.cc/drugs/etoposide/), [Gemcitabine](https://onco.cc/drugs/gemcitabine/), [Ifosfamide](https://onco.cc/drugs/ifosfamide/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Oxaliplatin](https://onco.cc/drugs/oxaliplatin/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- terms: [B-cell, T-cell and NK-cell lymphoma](https://onco.cc/terms/lymphoma-b-versus-t-cell/), [Endoscopy (EGD, EUS, ERCP)](https://onco.cc/terms/endoscopy/), [Epstein-Barr virus (EBV) in cancer](https://onco.cc/terms/ebv-term/), [Lugano classification / Ann Arbor staging](https://onco.cc/terms/lugano-classification/), [Nodal and extranodal lymphoma](https://onco.cc/terms/lymphoma-nodal-versus-extranodal/), [Plasma EBV DNA](https://onco.cc/terms/plasma-ebv-dna/), [Prognostic Index for T-cell lymphoma (PIT)](https://onco.cc/terms/lymphoma-pit-score/), [Radiotherapy in lymphoma: involved-site fields, 24 Gy, 4 Gy and total skin electron therapy](https://onco.cc/terms/lymphoma-tx-radiotherapy/), [The lymphoma regimen alphabet: R-CHOP, pola-R-CHP, DA-EPOCH-R, ABVD, BEACOPP and the rest](https://onco.cc/terms/lymphoma-tx-regimen-alphabet/), [The two lymphoma classifications of 2022 (WHO-HAEM5 and ICC)](https://onco.cc/terms/lymphoma-classification-2022/)

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JSON: https://onco.cc/api/v1/entities/extranodal-nk-t-cell-lymphoma.json