Extranodal NK/T-cell lymphoma
ENKTCL; previously "extranodal NK/T-cell lymphoma, nasal type" (WHO 2017 4R; the "nasal type" qualifier was dropped in WHO-HAEM5 2022 because extranasal disease is well recognised and the qualifier had become misleading); "lethal midline granuloma" (older descriptive term — now obsolete); polymorphic reticulosis (older); angiocentric T-cell lymphoma (older)
Extranodal NK/T-cell lymphoma is an aggressive Epstein-Barr-virus-driven mature NK-cell or cytotoxic T-cell lymphoma with a striking predilection for the midline upper aerodigestive tract (nasal cavity, paranasal sinuses, palate, pharynx) where it produces destructive, ulcerating, often necrotic disease. WHO-HAEM5 (2022) dropped the historic "nasal type" qualifier and now uses "extranodal NK/T-cell lymphoma" as a single entity, reflecting that ~20% of cases arise at extranasal sites including the skin, GI tract, testis and soft tissue. The skin is the second most common site of involvement (~10–15%), presenting as multiple subcutaneous nodules, plaques or panniculitis-like infiltrates, with secondary haemophagocytic lymphohistiocytosis a frequent and life-threatening complication. The disease is over-represented in East Asian, Central American and Mexican populations; in UK practice it is uncommon but seen with disproportionate frequency in patients of Chinese, Korean and Japanese descent. EBV (EBER) positivity is the diagnostic hallmark; the disease is also characterised by angiocentric and angiodestructive growth. Asparaginase-based combination chemotherapy (SMILE, DDGP, P-GEMOX) and concurrent / sandwich radiotherapy are the modern standards of care.
Clinical features
- Upper aerodigestive / nasal presentation (~80%) — destructive, ulcerating, foul-smelling midfacial mass involving the nasal cavity, palate, sinuses; nasal obstruction, epistaxis, septal perforation, palatal perforation; "lethal midline granuloma" was the historical descriptive term.
- Extranasal presentation (~20%) — skin (second commonest site), GI tract, testis, soft tissue.
- Cutaneous involvement — multiple subcutaneous nodules, plaques, panniculitis-like infiltrates, ulcerated tumours; often on face, trunk, extremities.
- Median age 40–60; M:F ~3:1.
- B symptoms (fever, weight loss, night sweats) common.
- Haemophagocytic lymphohistiocytosis (HLH) — frequent (10–30%) and life-threatening; hyperferritinaemia, cytopenias, hepatosplenomegaly.
- Differential — chronic granulomatous infection (TB, leishmaniasis, deep fungus), GPA / vasculitis, cocaine-induced midline destruction, other lymphomas.
Histology & immunophenotype
- Diffuse atypical lymphoid infiltrate with marked angiocentric and angiodestructive growth, ischaemic necrosis and ulceration.
- Atypical lymphoid cells of variable size with irregular nuclei.
- Phenotype:
- CD2+, CD3-cytoplasmic+ (surface CD3 negative or weak), CD56+, CD8 variable.
- Cytotoxic markers (TIA-1, granzyme B, perforin) strongly positive.
- EBV (EBER in situ hybridisation) strongly positive — diagnostic hallmark.
- Negative — surface CD3 (in NK-cell variants), CD4, CD20, ALK, βF1 (αβ TCR usually negative; some γδ).
- Clonal T-cell receptor rearrangement variable (NK-cell origin lacks TCR rearrangement; T-cell variants show TCRγ rearrangement).
- Differential by histology — primary cutaneous γδ T-cell lymphoma (TCRγδ+, EBV negative); cutaneous CD8+ aggressive epidermotropic CTCL (αβ phenotype); angioimmunoblastic T-cell lymphoma; primary cutaneous ALCL.
Staging
- CT chest/abdomen/pelvis ± PET-CT.
- MRI of head and neck for nasal disease.
- Bone marrow biopsy.
- Lumbar puncture if neurological involvement.
- EBV plasma DNA quantification — useful prognostic marker; trend during treatment correlates with response.
- HLH screen (FBC, LDH, ferritin, fibrinogen, triglycerides).
- Refer to specialist haematology / cutaneous lymphoma MDT (UK: Guy's, St George's, Manchester, NCRI Lymphoma Group).
Management
- Localised nasal disease (Ann Arbor I–II) — concurrent or sandwich chemoradiotherapy.
- Concurrent chemoradiotherapy with cisplatin-based regimens.
- Sandwich chemotherapy (asparaginase-based) before / after RT.
- Advanced / disseminated / extranasal disease — asparaginase-based combination chemotherapy:
- SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, etoposide).
- DDGP (dexamethasone, cisplatin, gemcitabine, pegaspargase).
- P-GEMOX (pegaspargase, gemcitabine, oxaliplatin).
- Allogeneic haematopoietic stem-cell transplantation in selected patients with chemo-sensitive disease.
- Anti-PD-1 immunotherapy (pembrolizumab, sintilimab, tislelizumab) — emerging activity in relapsed / refractory disease; particularly effective in this EBV-driven disease.
- Haemophagocytic lymphohistiocytosis — urgent HLH-94 / HLH-2004 protocol; etoposide / dexamethasone / cyclosporine.
- Avoid CHOP-type regimens — historically poor response in this MDR1-positive lymphoma.
Prognosis
Variable by stage and subtype. Localised nasal disease — 5-year overall survival 50–70% with modern chemoradiotherapy. Disseminated / extranasal disease — 5-year overall survival 20–40%. Adverse factors — extranasal involvement, advanced stage, HLH at presentation, high EBV plasma DNA, age >60, B symptoms.
References
- Yamaguchi M et al. Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type. J Clin Oncol; 2011.
- Tse E, Kwong YL. The diagnosis and management of NK/T-cell lymphomas. J Hematol Oncol; 2017.
- WHO Classification of Haematolymphoid Tumours, 5th edition (WHO-HAEM5); 2022. International Consensus Classification of Mature Lymphoid Neoplasms; 2022.
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