{"entity":{"id":"alk-negative-anaplastic-large-cell-lymphoma","kind":"cancer","name":"ALK-negative anaplastic large cell lymphoma","aka":["ALK-negative ALCL","ALK- ALCL","Anaplastic large cell lymphoma, ALK-negative","ALK-negative ALCL (DUSP22, TP63 subsets)","Systemic ALK-negative anaplastic large cell lymphoma"],"tldr":"An aggressive T-cell lymphoma that looks like its ALK-positive sibling under the microscope and carries the same CD30 marker, but lacks the broken ALK gene. It affects older people and is cured less often, and several genetic changes inside it predict very different outcomes.","summary":"What it is. A lymphoma of T cells that looks anaplastic, carries uniform strong CD30 and has no ALK rearrangement. The definition is therefore partly negative, which is why WHO-HAEM5 describes it as a heterogeneous entity: it is what is left when ALK-positive disease, breast implant-associated disease and the skin lymphomas have been excluded.\n\nHow it differs from its ALK-positive sibling. In age, and in outcome. ALK-positive disease affects people in their twenties and thirties; this affects people around 70. Both carry CD30, both are treated with the same first-line regimen, and ALK-positive disease is cured considerably more often. Where the appearance is identical, only the ALK stain tells them apart, which is why it is done on every anaplastic lymphoma.\n\nWhat is inside it, and what that is worth. Sequencing has found several genetic contexts within ALK-negative disease, and WHO-HAEM5 is careful about how much weight to put on them: it says there are not currently enough data to decide whether they are prognostic markers or genuine molecular subtypes. Rearrangement of TP63, loss of TP53 and overexpression of the interleukin-2 receptor alpha chain are each associated with worse outcomes. DUSP22 rearrangement was initially reported to carry a five-year survival as good as ALK-positive disease, and WHO-HAEM5 notes that more recent studies have not confirmed that association, which is the sort of reversal worth knowing about before a prognosis is given on the strength of it.\n\nSome of the genetics show in the appearance. Tumours with a DUSP22 rearrangement have cells with a doughnut-like shape and grow in sheets with less variation in size, and LEF1 staining may be a surrogate for the rearrangement. A group with a Hodgkin-like appearance shows aberrant ERBB4 protein, and the cells look more anaplastic where JAK2 is rearranged.\n\nHow it is treated. The same as the other CD30-positive nodal T-cell lymphomas: brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone, on the strength of ECHELON-2, and consolidation of a first remission with an autologous stem cell transplant in people fit for it, which is convention rather than demonstrated benefit. The detail is on the peripheral T-cell lymphoma page and in the treatment layer of this family.","asOf":"2026-09-29","wikipedia":"https://en.wikipedia.org/wiki/Anaplastic_large-cell_lymphoma","links":[{"label":"WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms (Alaggio, Leukemia 2022)","url":"https://doi.org/10.1038/s41375-022-01620-2"},{"label":"International Consensus Classification of Mature Lymphoid Neoplasms (Campo, Blood 2022)","url":"https://doi.org/10.1182/blood.2022015851"},{"label":"ECHELON-2: brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma, five-year results (Horwitz, Annals of Oncology 2022)","url":"https://doi.org/10.1016/j.annonc.2021.12.002"},{"label":"Lymphoma incidence, survival and prevalence 2004 to 2014, subtype analyses from the UK Haematological Malignancy Research Network (Smith, Br J Cancer 2015)","url":"https://doi.org/10.1038/bjc.2015.94"},{"label":"NCI PDQ: adult non-Hodgkin lymphoma treatment (health professional version)","url":"https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq"}],"tags":["heme","lymphoma","subtype-page"],"related":["alk-positive-anaplastic-large-cell-lymphoma","primary-cutaneous-anaplastic-large-cell-lymphoma","breast-implant-associated-alcl","peripheral-t-cell-lymphoma","non-hodgkin-lymphoma"],"cancers":[],"sections":[],"technologies":["histopathology-ihc","fdg-pet","adc","autologous-stem-cell-transplant"],"targets":["cd30","tp53"],"drugs":["brentuximab-vedotin"],"companies":[],"institutions":[],"pathways":[],"terms":["lymphoma-classification-2022","lymphoma-pit-score","ipi-score","lymphoma-tx-regimen-alphabet","lymphoma-tx-transplant-role","lymphoma-b-versus-t-cell"],"trials":["echelon-2"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"In the United Kingdom population series that reports lymphoma by subtype, 27 of 5,796 lymphomas were ALK-negative anaplastic large cell lymphoma, a European age-standardised rate of 0.08 per 100,000 a year, with a median age at diagnosis of 69.0 years, more than thirty years older than the ALK-positive form. Across all anaplastic large cell lymphomas in that series, five-year relative survival was 50.8 per cent; the published table's figure for the ALK-negative subgroup alone is internally inconsistent and is not quoted here.","subtypes":["With DUSP22 rearrangement","With TP63 rearrangement, which is associated with worse outcomes","With JAK2 rearrangement","Not otherwise characterised"],"biomarkers":["Uniform strong CD30 on every tumour cell","Absence of ALK protein by immunohistochemistry, which is the defining negative","DUSP22 rearrangement, whose prognostic meaning is disputed; WHO-HAEM5 records that the favourable association first reported has not been confirmed","TP63 rearrangement, loss of TP53 and overexpression of the interleukin-2 receptor alpha chain, each associated with worse outcomes","The Prognostic Index for T-cell lymphoma and the International Prognostic Index"],"standardOfCare":[{"setting":"Making the diagnosis","approach":"CD30 and ALK immunohistochemistry on the biopsy. The diagnosis is partly a negative one: uniform strong CD30 with an anaplastic appearance and no ALK, in a lymphoma that is not confined to the skin and is not associated with a breast implant. Those two exclusions matter because both of them are treated very differently. Testing for DUSP22 and TP63 rearrangements is done where it is available, with the caution that WHO-HAEM5 does not regard the resulting groups as established subtypes.","refs":["histopathology-ihc","cd30","alk","lymphoma-classification-2022","fdg-pet"],"guideline":{"version":"WHO Classification of Haematolymphoid Tumours, 5th edition (2022), with the International Consensus Classification (2022) where they differ","url":"https://doi.org/10.1038/s41375-022-01620-2"}},{"setting":"First-line treatment","approach":"Brentuximab vedotin with cyclophosphamide, doxorubicin and prednisone, the same regimen as for ALK-positive disease and on the same trial: in ECHELON-2, five-year progression-free survival was 51.4 per cent against 43.0 with chemotherapy alone and overall survival 70.1 against 61.0. Consolidating a first remission with high-dose therapy and an autologous stem cell transplant is standard practice here, unlike in ALK-positive disease, and it rests on a single-arm study and registry comparisons rather than on a randomised trial; a patient is entitled to be told that. The regimens are on the peripheral T-cell lymphoma page.","refs":["echelon-2","brentuximab-vedotin","cyclophosphamide","doxorubicin","prednisone","autologous-stem-cell-transplant","lymphoma-tx-transplant-role","peripheral-t-cell-lymphoma"],"guideline":{"version":"ECHELON-2 five-year results (Annals of Oncology 2022); NCCN T-Cell Lymphomas; NCI PDQ","url":"https://doi.org/10.1016/j.annonc.2021.12.002"}}],"stateOfArt":[],"history":[{"year":2008,"title":"Separated from ALK-positive disease","note":"The fourth edition of the WHO classification made ALK-negative anaplastic large cell lymphoma a distinct entity rather than a variant, on the strength of its different biology and clinical course.","refs":["alk"]},{"year":2014,"title":"Genetic subgroups described","note":"Rearrangements of DUSP22 and TP63 were identified within ALK-negative disease and reported to carry very different outcomes, which raised the question of whether the entity should be split again.","refs":[]},{"year":2022,"title":"The classification declines to split it, and records a reversal","note":"WHO-HAEM5 states that there are not yet enough data to decide whether the genetic contexts are prognostic markers or molecular subtypes, and that the favourable outcome first reported for DUSP22 rearrangement has not been confirmed by more recent studies.","refs":["lymphoma-classification-2022"]}],"pipeline":[],"openProblems":["The entity is defined by what it is not, and WHO-HAEM5 says so. Whether its genetic subgroups are real subtypes or prognostic markers is unresolved.","The prognostic meaning of DUSP22 rearrangement reversed between the first reports and the later ones, and treatment decisions have been made on the earlier version.","Autologous transplant consolidation in first remission is standard practice here on the strength of registry comparisons and a single-arm study, and has never been tested against continuing observation."],"parent":"peripheral-t-cell-lymphoma"},"route":"/cancers/alk-negative-anaplastic-large-cell-lymphoma/","neighbours":{"cancer":[{"id":"alk-positive-anaplastic-large-cell-lymphoma","kind":"cancer","name":"ALK-positive anaplastic large cell lymphoma","route":"/cancers/alk-positive-anaplastic-large-cell-lymphoma/"},{"id":"breast-implant-associated-alcl","kind":"cancer","name":"Breast implant-associated anaplastic large cell lymphoma","route":"/cancers/breast-implant-associated-alcl/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"peripheral-t-cell-lymphoma","kind":"cancer","name":"Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma)","route":"/cancers/peripheral-t-cell-lymphoma/"},{"id":"primary-cutaneous-anaplastic-large-cell-lymphoma","kind":"cancer","name":"Primary cutaneous anaplastic large cell lymphoma","route":"/cancers/primary-cutaneous-anaplastic-large-cell-lymphoma/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"autologous-stem-cell-transplant","kind":"technology","name":"Autologous stem cell transplant (high-dose therapy)","route":"/technologies/autologous-stem-cell-transplant/"},{"id":"fdg-pet","kind":"technology","name":"FDG PET","route":"/technologies/fdg-pet/"},{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"},{"id":"cd30","kind":"target","name":"CD30","route":"/targets/cd30/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"brentuximab-vedotin","kind":"drug","name":"Brentuximab vedotin","route":"/drugs/brentuximab-vedotin/"},{"id":"cyclophosphamide","kind":"drug","name":"Cyclophosphamide","route":"/drugs/cyclophosphamide/"},{"id":"doxorubicin","kind":"drug","name":"Doxorubicin","route":"/drugs/doxorubicin/"},{"id":"prednisone","kind":"drug","name":"Prednisone","route":"/drugs/prednisone/"}],"term":[{"id":"lymphoma-b-versus-t-cell","kind":"term","name":"B-cell, T-cell and NK-cell lymphoma","route":"/terms/lymphoma-b-versus-t-cell/"},{"id":"ipi-score","kind":"term","name":"International Prognostic Index (IPI)","route":"/terms/ipi-score/"},{"id":"lymphoma-pit-score","kind":"term","name":"Prognostic Index for T-cell lymphoma (PIT)","route":"/terms/lymphoma-pit-score/"},{"id":"lymphoma-tx-transplant-role","kind":"term","name":"Stem cell transplant in lymphoma: what it is still for","route":"/terms/lymphoma-tx-transplant-role/"},{"id":"lymphoma-tx-regimen-alphabet","kind":"term","name":"The lymphoma regimen alphabet: R-CHOP, pola-R-CHP, DA-EPOCH-R, ABVD, BEACOPP and the rest","route":"/terms/lymphoma-tx-regimen-alphabet/"},{"id":"lymphoma-classification-2022","kind":"term","name":"The two lymphoma classifications of 2022 (WHO-HAEM5 and ICC)","route":"/terms/lymphoma-classification-2022/"}],"trial":[{"id":"echelon-2","kind":"trial","name":"ECHELON-2","route":"/trials/echelon-2/"}]}}