Anaplastic Large Cell Lymphoma

Cancer MONDO:0020325 Pathograph 8 Lymphoma

Anaplastic large cell lymphoma (ALCL) is a CD30-positive mature T-cell lymphoma family that includes systemic ALK-positive disease, systemic ALK-negative disease, primary cutaneous disease, and breast implant-associated disease. This entry models ALCL as a single disease-level mechanism graph with subtype-scoped mechanisms, phenotypes, biomarkers, and treatments rather than splitting every ontology subclass into a separate dismech page.

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1
Mappings
1
Definitions
6
Pathophys.
1
Histopath.
3
Phenotypes
8
Pathograph
5
Genes
6
Treatments
4
Subtypes
1
Deep Research
🔗

Mappings

MONDO
MONDO:0020325 anaplastic large cell lymphoma
skos:exactMatch MONDO
Primary MONDO disease identifier for this ALCL entry.
📘

Definitions

1
Pathologic definition of anaplastic large cell lymphoma
ALCL is a mature T-cell lymphoma family unified by strong CD30 expression and subdivided into systemic ALK-positive, systemic ALK-negative, primary cutaneous, and breast implant-associated entities.
CASE_DEFINITION General pathologic and molecular definition of anaplastic large cell lymphoma
Show evidence (1 reference)
PMID:40565334 SUPPORT Other
"Anaplastic Large Cell Lymphoma (ALCL) represents a diverse group of mature T-Cell Lymphomas unified by strong CD30 expression but with different molecular and clinical subtypes."
This review provides a concise disease-level definition that fits the dismech page as the shared ALCL mechanism unit.
◆

Subtypes

4
molecular
Systemic ALK-Positive Anaplastic Large Cell Lymphoma MONDO:0017602
Systemic ALCL subtype driven by ALK rearrangement or fusion, usually affecting younger patients and often presenting with advanced-stage disease. It is the most treatment-responsive systemic ALCL subtype.
Show evidence (2 references)
PMID:37655119 SUPPORT Other
"This subtype contains a translocation between the ALK gene on chromosome 2 and one of several other genes that together form an oncogene."
This review defines systemic ALK-positive ALCL by its ALK translocation-driven oncogene.
PMID:37655119 SUPPORT Other
"This lymphoma has a median age of 34 years, is more common in males, and is in advanced stage at the time of diagnosis in most patients."
This supports the typical younger age distribution and advanced-stage presentation of systemic ALK-positive ALCL.
Systemic ALK-Negative Anaplastic Large Cell Lymphoma MONDO:0017603
Systemic ALCL subtype lacking ALK rearrangement and showing marked genetic heterogeneity, including DUSP22-rearranged, TP63-rearranged, and triple-negative cases with different outcomes.
Show evidence (2 references)
PMID:24894770 SUPPORT Human Clinical
"Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy."
This multicenter study supports modeling systemic ALK-negative ALCL as one subtype with clinically important internal genetic heterogeneity.
PMID:24894770 SUPPORT Human Clinical
"Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively."
This provides the core genomic subgrouping used inside the systemic ALK-negative ALCL facet.
anatomical site
Primary Cutaneous Anaplastic Large Cell Lymphoma MONDO:0017598
CD30-positive cutaneous ALCL caused by skin-homing malignant T cells. It typically presents with solitary or multifocal ulcerative nodules and has a more localized clinical program than systemic ALCL.
Show evidence (2 references)
PMID:34382383 SUPPORT Human Clinical
"Primary cutaneous anaplastic large cell lymphoma (pcALCL), a hematological neoplasm caused by skin-homing CD30+ malignant T cells, is part of the spectrum of primary cutaneous CD30+ lymphoproliferative disorders."
This genomic study directly supports primary cutaneous ALCL as a skin-homing CD30-positive malignant T-cell process.
PMID:24346900 SUPPORT Human Clinical
"Primary cutaneous anaplastic large-cell lymphoma is part of the spectrum of CD30+ lymphoproliferative cutaneous processes, characterized by single or multifocal nodules that ulcerate, are autoregressive and recurrent."
This case-based abstract supports the characteristic cutaneous clinical presentation used for this subtype facet.
exposure associated
Breast Implant-Associated Anaplastic Large Cell Lymphoma MONDO:0850112
Exposure-associated ALCL subtype that arises in the capsule around textured breast implants, usually as a delayed seroma and less commonly as a capsular mass. Limited-stage seroma-confined disease is managed primarily with complete surgery.
Show evidence (1 reference)
PMID:38102324 SUPPORT Human Clinical
"Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a subtype of ALCL that arises as a seroma or a mass in the capsule surrounding textured breast implants."
This cohort abstract directly defines breast implant-associated ALCL as a capsule-based seroma or mass around textured implants.
⚙

Pathophysiology

6
ALK Fusion Oncogene Formation
Systemic ALK-positive ALCL is initiated by chromosomal rearrangements that generate ALK fusion oncogenes, most commonly NPM1::ALK.
ALK link NPM1 link
Downstream
ALK-Driven STAT3 Activation ALK fusion proteins signal constitutively to STAT3.
Show evidence (1 reference)
PMID:29617304 SUPPORT Other
"ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1"
This review supports ALK rearrangement, most often with NPM1, as the core initiating lesion in systemic ALK-positive ALCL.
ALK-Driven STAT3 Activation
Activated ALK constitutively phosphorylates and activates STAT3 in systemic ALK-positive ALCL, establishing a central survival and growth program.
ALK link STAT3 link
cell surface receptor signaling pathway via JAK-STAT link ↑ INCREASED cell surface receptor protein tyrosine kinase signaling pathway link ↑ INCREASED
Downstream
BCL2L1-Mediated Apoptosis Resistance STAT3 activity sustains anti-apoptotic transcriptional output.
PD-L1-Mediated Immune Evasion STAT3 activity promotes checkpoint-ligand upregulation.
Show evidence (2 references)
PMID:11850821 SUPPORT In Vitro
"We show here that expression of activated ALK induces the constitutive phosphorylation of Stat3 in transfected cells as well as in primary human ALCLs."
This mechanistic study directly supports constitutive STAT3 activation as a consequence of activated ALK in ALCL.
PMID:40565334 SUPPORT Other
"In ALK-positive ALCL, ALK fusion proteins drive oncogenesis via constitutive activation of STAT3 and other signaling pathways."
This review independently supports STAT3 as a central ALK-driven oncogenic signaling hub in ALK-positive ALCL.
BCL2L1-Mediated Apoptosis Resistance
ALK-positive ALCL uses STAT3-dependent BCL2L1 transcription to resist cell death and support clonal outgrowth.
BCL2L1 link
apoptotic process link ↓ DECREASED
Show evidence (1 reference)
PMID:11850821 SUPPORT In Vitro
"These studies support a pathogenic mechanism whereby stimulation of anti-apoptotic signals through activation of Stat3 contributes to the successful outgrowth of ALK positive tumor cells."
This directly supports a discrete apoptosis-resistance node downstream of ALK-driven STAT3 activation.
PD-L1-Mediated Immune Evasion
ALK-positive ALCL can upregulate PD-L1/CD274 through STAT3, adding an immune-suppressive phenotype to the malignant T-cell program.
CD274 link
negative regulation of T cell mediated immunity link ↑ INCREASED
Show evidence (2 references)
PMID:19088198 SUPPORT In Vitro
"NPM/ALK induces CD274 expression by activating its key signal transmitter, transcription factor STAT3."
This directly supports PD-L1 upregulation as a STAT3-dependent immune-evasion mechanism in ALK-positive ALCL cells.
PMID:24404580 SUPPORT In Vitro
"These unique features, which are strictly dependent on NPM-ALK activity and expression, include perpetual cell growth, proliferation, and survival; activation of the key signal transduction pathways STAT3 and mTORC1; and expression of CD30 (the hallmark of anaplastic large-cell lymphoma) and of..."
This transformation model independently links NPM-ALK to PD-L1 expression in a malignant ALCL-like T-cell state.
JAK/STAT3 Pathway Alteration in ALK-Negative ALCL
Many ALK-negative ALCLs activate JAK/STAT signaling through JAK1 and/or STAT3 mutations instead of ALK fusion signaling. Similar lesions are also seen in breast implant-associated ALCL.
JAK1 link STAT3 link
cell surface receptor signaling pathway via JAK-STAT link ↑ INCREASED
Show evidence (2 references)
PMID:34572893 SUPPORT Other
"Additionally, systemic ALK- ALCL-apart from DUSP22-rearranged cases-harbors JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT signaling pathway. The JAK1/3 and STAT3 mutations have also been identified in BIA-ALCL but not in pc-ALCL."
This review directly supports subtype-scoped JAK/STAT pathway activation in systemic ALK-negative and breast implant-associated ALCL.
PMID:40565334 SUPPORT Other
"ALK-negative ALCL comprises heterogeneous genetic subtypes, in which JAK/STAT3 pathway alterations and novel gene fusions are gaining recognition as potential therapeutic targets."
This disease-level review supports JAK/STAT3 alteration as a mechanistically important branch of ALK-negative ALCL biology.
PI3K-AKT and MAPK Signaling Upregulation in Primary Cutaneous ALCL
Primary cutaneous ALCL shows recurrent genomic and transcriptomic changes affecting PI3K/AKT, MAPK, and related signaling routes that can support proliferation in skin-homing malignant T cells.
PIK3R1 link
Show evidence (1 reference)
PMID:34382383 SUPPORT Human Clinical
"Consistent with the genomic data, transcriptome analysis uncovered upregulation of signal transduction routes associated with the PI-3-K, MAPK and G-protein pathways (e.g., ERK, phospholipase C, AKT)."
This genomic and transcriptomic study supports a distinct signaling program in primary cutaneous ALCL centered on PI3K/AKT and MAPK pathways.
✶

Histopathology

1
Hallmark Cell Morphology VERY_FREQUENT
Across ALCL subtypes, pleomorphic tumor cells with hallmark-cell morphology are a key tissue-level feature used to recognize the disease family.
Show evidence (1 reference)
PMID:28975123 SUPPORT Human Clinical
"Histologically, all the subtypes showed pleomorphic and "hallmark" cells with strong CD30 expression and variable loss of T-cell antigens."
This abstract directly supports hallmark-cell morphology as a shared histopathologic feature across ALCL subtypes.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Anaplastic Large Cell Lymphoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Breast 1
Capsular Mass OCCASIONAL Breast mass (HP:0032408)
Show evidence (1 reference)
PMID:38102324 SUPPORT Human Clinical
"Patients presented with clinically evident effusion in 78% of cases and a mass in 17% of cases, and 83% of patients presented with stage 1 BIA-ALCL."
This cohort quantifies the less-common mass-presenting phenotype in breast implant-associated ALCL.
Cardiovascular 1
Regional Lymph Node Involvement OCCASIONAL Lymphadenopathy (HP:0002716)
Show evidence (1 reference)
PMID:24346900 SUPPORT Human Clinical
"Extracutaneous dissemination may occur, especially to regional lymph nodes."
This abstract supports regional lymph-node involvement as an occasional extracutaneous phenotype of primary cutaneous ALCL.
Integument 1
Ulcerating Skin Nodules VERY_FREQUENT Skin nodule (HP:0200036)
Show evidence (1 reference)
PMID:24346900 SUPPORT Human Clinical
"Primary cutaneous anaplastic large-cell lymphoma is part of the spectrum of CD30+ lymphoproliferative cutaneous processes, characterized by single or multifocal nodules that ulcerate, are autoregressive and recurrent."
This abstract directly supports ulcerating cutaneous nodules as the defining clinical presentation of primary cutaneous ALCL.
🧬

Genetic Associations

5
ALK Rearrangement (Defining Rearrangement)
Show evidence (1 reference)
PMID:29617304 SUPPORT Other
"ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1"
This review directly supports ALK rearrangement as the defining genetic event of systemic ALK-positive ALCL.
DUSP22 Rearrangement (Molecular Subgroup)
Show evidence (1 reference)
PMID:24894770 SUPPORT Human Clinical
"Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively."
This study directly supports DUSP22 rearrangement as a recurrent molecular subgroup within systemic ALK-negative ALCL.
TP63 Rearrangement (Molecular Subgroup)
Show evidence (1 reference)
PMID:24894770 SUPPORT Human Clinical
"Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively."
This study directly supports TP63 rearrangement as a recurrent molecular subgroup within systemic ALK-negative ALCL.
JAK1 Mutation (JAK/STAT Pathway Activation)
Show evidence (1 reference)
PMID:34572893 SUPPORT Other
"Additionally, systemic ALK- ALCL-apart from DUSP22-rearranged cases-harbors JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT signaling pathway."
This review supports JAK1 mutation as a recurrent route to JAK/STAT pathway activation in systemic ALK-negative ALCL.
STAT3 Mutation (JAK/STAT Pathway Activation)
Show evidence (1 reference)
PMID:34572893 SUPPORT Other
"Additionally, systemic ALK- ALCL-apart from DUSP22-rearranged cases-harbors JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT signaling pathway."
This review supports STAT3 mutation as a recurrent route to JAK/STAT pathway activation in systemic ALK-negative ALCL.
💊

Treatments

6
Anthracycline-Based Combination Chemotherapy
Action: cancer chemotherapy MAXO:0000646
Agent: cyclophosphamide ↗ doxorubicin ↗ vincristine ↗ prednisone ↗
Anthracycline-containing multiagent chemotherapy remains a core systemic treatment backbone for ALK-positive systemic ALCL.
Show evidence (1 reference)
PMID:29279550 SUPPORT Other
"Patients with ALK-positive ALCL are usually treated with anthracycline-based regimens, such as combination cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOEP (CHOP plus etoposide)"
This review supports anthracycline-based multiagent chemotherapy as a core systemic treatment backbone in ALK-positive ALCL.
Brentuximab Vedotin Plus CHP
Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262
Agent: brentuximab vedotin ↗
Frontline brentuximab vedotin plus CHP improved progression-free and overall survival over CHOP in previously untreated systemic ALCL and other CD30-positive PTCL.
Show evidence (2 references)
PMID:30914464 SUPPORT Human Clinical
"In November 2018, the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin (BV) for the treatment of adult patients with previously untreated systemic anaplastic large cell lymphoma"
This FDA summary directly supports brentuximab vedotin plus CHP as a frontline systemic ALCL regimen.
PMID:30914464 SUPPORT Human Clinical
"The median PFS was 48.2 months with BV+CHP versus 20.8 months with CHOP, resulting in a hazard ratio (HR) of 0.71"
This directly supports superior frontline disease control with BV+CHP over CHOP in the ECHELON-2 approval-setting trial.
Single-Agent Brentuximab Vedotin
Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262
Agent: brentuximab vedotin ↗
In relapsed or refractory systemic ALCL, single-agent brentuximab vedotin can produce durable complete remissions in a subset of patients.
Show evidence (1 reference)
PMID:28974506 SUPPORT Human Clinical
"These final results, which demonstrated a high rate of peripheral neuropathy resolution, and durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab vedotin may be a potentially curative treatment option."
This phase 2 follow-up study directly supports durable disease control with single-agent brentuximab vedotin in relapsed or refractory systemic ALCL.
Crizotinib
Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352
Agent: crizotinib ↗
ALK inhibition with crizotinib has meaningful activity in relapsed or refractory systemic ALK-positive ALCL.
Show evidence (1 reference)
PMID:37549532 SUPPORT Human Clinical
"CONCLUSION: Crizotinib shows efficacy and an acceptable safety profile in ALK+ ALCL relapsed/refractory patients."
This phase 2 study directly supports crizotinib as an active targeted agent in relapsed or refractory ALK-positive systemic ALCL.
Radiation Therapy
Action: radiation therapy MAXO:0000014
Localized primary cutaneous ALCL can be treated with skin-directed radiation therapy.
Show evidence (1 reference)
PMID:24346900 SUPPORT Human Clinical
"Radiotherapy, removal of the lesion and/or low-dose methotrexate are the treatments of choice."
This abstract directly supports radiation therapy as a standard local treatment option in primary cutaneous ALCL.
Complete Surgical Excision with Implant Removal
Action: surgical procedure MAXO:0000004
Breast implant-associated ALCL is primarily managed with complete surgical excision, including total capsulectomy and implant removal.
Show evidence (1 reference)
PMID:26628470 SUPPORT Human Clinical
"Patients who underwent a complete surgical excision that consisted of total capsulectomy with breast implant removal had better OS (P = .022) and EFS (P = .014)"
This multi-institutional cohort directly supports complete capsulectomy with implant removal as the key treatment for breast implant-associated ALCL.
🔬

Biochemical Markers

2
CD30/TNFRSF8 Expression (strong diffuse tumor-cell expression)
Show evidence (1 reference)
PMID:29617304 SUPPORT Other
"Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers"
This review supports strong CD30 expression as the defining biomarker of the ALCL disease family.
ALK Fusion Protein Expression (immunohistochemically detectable surrogate for ALK rearrangement)
Show evidence (1 reference)
PMID:35941721 SUPPORT Human Clinical
"ALK immunohistochemistry is an excellent surrogate for ALK- R"
This pathology study directly supports ALK protein expression by immunohistochemistry as the biomarker surrogate for ALK-rearranged ALCL.
{ }

Source YAML

click to show 
name: Anaplastic Large Cell Lymphoma
creation_date: "2026-04-13T05:41:42Z"
updated_date: "2026-04-22T20:13:21Z"
category: Cancer
categories:
- Hematologic Malignancy
- T-cell Neoplasm
- Non-Hodgkin Lymphoma
synonyms:
- ALCL
- anaplastic large-cell lymphoma
description: >-
  Anaplastic large cell lymphoma (ALCL) is a CD30-positive mature T-cell lymphoma
  family that includes systemic ALK-positive disease, systemic ALK-negative
  disease, primary cutaneous disease, and breast implant-associated disease.
  This entry models ALCL as a single disease-level mechanism graph with
  subtype-scoped mechanisms, phenotypes, biomarkers, and treatments rather than
  splitting every ontology subclass into a separate dismech page.
definitions:
- name: Pathologic definition of anaplastic large cell lymphoma
  definition_type: CASE_DEFINITION
  description: >-
    ALCL is a mature T-cell lymphoma family unified by strong CD30 expression
    and subdivided into systemic ALK-positive, systemic ALK-negative, primary
    cutaneous, and breast implant-associated entities.
  scope: General pathologic and molecular definition of anaplastic large cell lymphoma
  evidence:
  - reference: PMID:40565334
    reference_title: "Molecular Insights into the Diagnosis of Anaplastic Large Cell Lymphoma: Beyond Morphology and Immunophenotype."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Anaplastic Large Cell Lymphoma (ALCL) represents a diverse group of mature
      T-Cell Lymphomas unified by strong CD30 expression but with different molecular
      and clinical subtypes.
    explanation: >-
      This review provides a concise disease-level definition that fits the
      dismech page as the shared ALCL mechanism unit.
disease_term:
  preferred_term: anaplastic large cell lymphoma
  term:
    id: MONDO:0020325
    label: anaplastic large cell lymphoma
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0020325
      label: anaplastic large cell lymphoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this ALCL entry.
parents:
- Lymphoma
has_subtypes:
- name: Systemic ALK-Positive
  display_name: Systemic ALK-Positive Anaplastic Large Cell Lymphoma
  description: >-
    Systemic ALCL subtype driven by ALK rearrangement or fusion, usually
    affecting younger patients and often presenting with advanced-stage disease.
    It is the most treatment-responsive systemic ALCL subtype.
  classification: molecular
  subtype_term:
    preferred_term: ALK-positive anaplastic large cell lymphoma
    term:
      id: MONDO:0017602
      label: ALK-positive anaplastic large cell lymphoma
  evidence:
  - reference: PMID:37655119
    reference_title: "ALK-positive anaplastic large cell lymphoma in adults."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This subtype contains a translocation between the ALK gene on chromosome 2
      and one of several other genes that together form an oncogene.
    explanation: >-
      This review defines systemic ALK-positive ALCL by its ALK translocation-driven
      oncogene.
  - reference: PMID:37655119
    reference_title: "ALK-positive anaplastic large cell lymphoma in adults."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This lymphoma has a median age of 34 years, is more common in males, and is
      in advanced stage at the time of diagnosis in most patients.
    explanation: >-
      This supports the typical younger age distribution and advanced-stage
      presentation of systemic ALK-positive ALCL.
- name: Systemic ALK-Negative
  display_name: Systemic ALK-Negative Anaplastic Large Cell Lymphoma
  description: >-
    Systemic ALCL subtype lacking ALK rearrangement and showing marked genetic
    heterogeneity, including DUSP22-rearranged, TP63-rearranged, and triple-negative
    cases with different outcomes.
  classification: molecular
  subtype_term:
    preferred_term: ALK-negative anaplastic large cell lymphoma
    term:
      id: MONDO:0017603
      label: ALK-negative anaplastic large cell lymphoma
  evidence:
  - reference: PMID:24894770
    reference_title: "ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely
      disparate outcomes following standard therapy.
    explanation: >-
      This multicenter study supports modeling systemic ALK-negative ALCL as one
      subtype with clinically important internal genetic heterogeneity.
  - reference: PMID:24894770
    reference_title: "ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8%
      of ALK-negative ALCLs, respectively.
    explanation: >-
      This provides the core genomic subgrouping used inside the systemic
      ALK-negative ALCL facet.
- name: Primary Cutaneous
  display_name: Primary Cutaneous Anaplastic Large Cell Lymphoma
  description: >-
    CD30-positive cutaneous ALCL caused by skin-homing malignant T cells. It
    typically presents with solitary or multifocal ulcerative nodules and has a
    more localized clinical program than systemic ALCL.
  classification: anatomical_site
  subtype_term:
    preferred_term: primary cutaneous anaplastic large cell lymphoma
    term:
      id: MONDO:0017598
      label: primary cutaneous anaplastic large cell lymphoma
  evidence:
  - reference: PMID:34382383
    reference_title: "Whole-genome profiling of primary cutaneous anaplastic large cell lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Primary cutaneous anaplastic large cell lymphoma (pcALCL), a hematological
      neoplasm caused by skin-homing CD30+ malignant T cells, is part of the spectrum
      of primary cutaneous CD30+ lymphoproliferative disorders.
    explanation: >-
      This genomic study directly supports primary cutaneous ALCL as a skin-homing
      CD30-positive malignant T-cell process.
  - reference: PMID:24346900
    reference_title: "Primary cutaneous anaplastic large-cell lymphoma--case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Primary cutaneous anaplastic large-cell lymphoma is part of the spectrum of
      CD30+ lymphoproliferative cutaneous processes, characterized by single or
      multifocal nodules that ulcerate, are autoregressive and recurrent.
    explanation: >-
      This case-based abstract supports the characteristic cutaneous clinical
      presentation used for this subtype facet.
- name: Breast Implant-Associated
  display_name: Breast Implant-Associated Anaplastic Large Cell Lymphoma
  description: >-
    Exposure-associated ALCL subtype that arises in the capsule around textured
    breast implants, usually as a delayed seroma and less commonly as a capsular
    mass. Limited-stage seroma-confined disease is managed primarily with complete
    surgery.
  classification: exposure_associated
  subtype_term:
    preferred_term: breast implant-associated anaplastic large cell lymphoma
    term:
      id: MONDO:0850112
      label: breast implant-associated anaplastic large cell lymphoma
  evidence:
  - reference: PMID:38102324
    reference_title: "Surgical Management and Long-Term Outcomes of BIA-ALCL: A Multidisciplinary Approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a
      subtype of ALCL that arises as a seroma or a mass in the capsule surrounding
      textured breast implants.
    explanation: >-
      This cohort abstract directly defines breast implant-associated ALCL as a
      capsule-based seroma or mass around textured implants.
pathophysiology:
- name: ALK Fusion Oncogene Formation
  description: >-
    Systemic ALK-positive ALCL is initiated by chromosomal rearrangements that
    generate ALK fusion oncogenes, most commonly NPM1::ALK.
  genes:
  - preferred_term: ALK
    term:
      id: hgnc:427
      label: ALK
  - preferred_term: NPM1
    term:
      id: hgnc:7910
      label: NPM1
  subtypes:
  - Systemic ALK-Positive
  evidence:
  - reference: PMID:29617304
    reference_title: "The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ALK is rearranged in approximately 80% of systemic ALCL cases with one of
      its partner genes, most commonly NPM1
    explanation: >-
      This review supports ALK rearrangement, most often with NPM1, as the core
      initiating lesion in systemic ALK-positive ALCL.
  downstream:
  - target: ALK-Driven STAT3 Activation
    description: ALK fusion proteins signal constitutively to STAT3.
- name: ALK-Driven STAT3 Activation
  description: >-
    Activated ALK constitutively phosphorylates and activates STAT3 in systemic
    ALK-positive ALCL, establishing a central survival and growth program.
  genes:
  - preferred_term: ALK
    term:
      id: hgnc:427
      label: ALK
  - preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  biological_processes:
  - preferred_term: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
  - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007169
      label: cell surface receptor protein tyrosine kinase signaling pathway
  subtypes:
  - Systemic ALK-Positive
  evidence:
  - reference: PMID:11850821
    reference_title: "Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show here that expression of activated ALK induces the constitutive
      phosphorylation of Stat3 in transfected cells as well as in primary human ALCLs.
    explanation: >-
      This mechanistic study directly supports constitutive STAT3 activation as
      a consequence of activated ALK in ALCL.
  - reference: PMID:40565334
    reference_title: "Molecular Insights into the Diagnosis of Anaplastic Large Cell Lymphoma: Beyond Morphology and Immunophenotype."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In ALK-positive ALCL, ALK fusion proteins drive oncogenesis via constitutive
      activation of STAT3 and other signaling pathways.
    explanation: >-
      This review independently supports STAT3 as a central ALK-driven oncogenic
      signaling hub in ALK-positive ALCL.
  downstream:
  - target: BCL2L1-Mediated Apoptosis Resistance
    description: STAT3 activity sustains anti-apoptotic transcriptional output.
  - target: PD-L1-Mediated Immune Evasion
    description: STAT3 activity promotes checkpoint-ligand upregulation.
- name: BCL2L1-Mediated Apoptosis Resistance
  description: >-
    ALK-positive ALCL uses STAT3-dependent BCL2L1 transcription to resist cell
    death and support clonal outgrowth.
  genes:
  - preferred_term: BCL2L1
    term:
      id: hgnc:992
      label: BCL2L1
  biological_processes:
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
  subtypes:
  - Systemic ALK-Positive
  evidence:
  - reference: PMID:11850821
    reference_title: "Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These studies support a pathogenic mechanism whereby stimulation of
      anti-apoptotic signals through activation of Stat3 contributes to the successful
      outgrowth of ALK positive tumor cells.
    explanation: >-
      This directly supports a discrete apoptosis-resistance node downstream of
      ALK-driven STAT3 activation.
- name: PD-L1-Mediated Immune Evasion
  description: >-
    ALK-positive ALCL can upregulate PD-L1/CD274 through STAT3, adding an
    immune-suppressive phenotype to the malignant T-cell program.
  genes:
  - preferred_term: CD274
    term:
      id: hgnc:17635
      label: CD274
  biological_processes:
  - preferred_term: negative regulation of T cell mediated immunity
    modifier: INCREASED
    term:
      id: GO:0002710
      label: negative regulation of T cell mediated immunity
  subtypes:
  - Systemic ALK-Positive
  evidence:
  - reference: PMID:19088198
    reference_title: "Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      NPM/ALK induces CD274 expression by activating its key signal transmitter,
      transcription factor STAT3.
    explanation: >-
      This directly supports PD-L1 upregulation as a STAT3-dependent immune-evasion
      mechanism in ALK-positive ALCL cells.
  - reference: PMID:24404580
    reference_title: "The potent oncogene NPM-ALK mediates malignant transformation of normal human CD4(+) T lymphocytes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These unique features, which are strictly dependent on NPM-ALK activity and
      expression, include perpetual cell growth, proliferation, and survival;
      activation of the key signal transduction pathways STAT3 and mTORC1; and
      expression of CD30 (the hallmark of anaplastic large-cell lymphoma) and of
      immunosuppressive cytokine IL-10 and cell-surface protein PD-L1/CD274.
    explanation: >-
      This transformation model independently links NPM-ALK to PD-L1 expression
      in a malignant ALCL-like T-cell state.
- name: JAK/STAT3 Pathway Alteration in ALK-Negative ALCL
  description: >-
    Many ALK-negative ALCLs activate JAK/STAT signaling through JAK1 and/or
    STAT3 mutations instead of ALK fusion signaling. Similar lesions are also
    seen in breast implant-associated ALCL.
  genes:
  - preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  - preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  biological_processes:
  - preferred_term: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
  subtypes:
  - Systemic ALK-Negative
  - Breast Implant-Associated
  evidence:
  - reference: PMID:34572893
    reference_title: "ALK-Negative Anaplastic Large Cell Lymphoma: Current Concepts and Molecular Pathogenesis of a Heterogeneous Group of Large T-Cell Lymphomas."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additionally, systemic ALK- ALCL-apart from DUSP22-rearranged cases-harbors
      JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT
      signaling pathway. The JAK1/3 and STAT3 mutations have also been identified in
      BIA-ALCL but not in pc-ALCL.
    explanation: >-
      This review directly supports subtype-scoped JAK/STAT pathway activation in
      systemic ALK-negative and breast implant-associated ALCL.
  - reference: PMID:40565334
    reference_title: "Molecular Insights into the Diagnosis of Anaplastic Large Cell Lymphoma: Beyond Morphology and Immunophenotype."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ALK-negative ALCL comprises heterogeneous genetic subtypes, in which JAK/STAT3
      pathway alterations and novel gene fusions are gaining recognition as potential
      therapeutic targets.
    explanation: >-
      This disease-level review supports JAK/STAT3 alteration as a mechanistically
      important branch of ALK-negative ALCL biology.
- name: PI3K-AKT and MAPK Signaling Upregulation in Primary Cutaneous ALCL
  description: >-
    Primary cutaneous ALCL shows recurrent genomic and transcriptomic changes
    affecting PI3K/AKT, MAPK, and related signaling routes that can support
    proliferation in skin-homing malignant T cells.
  genes:
  - preferred_term: PIK3R1
    term:
      id: hgnc:8979
      label: PIK3R1
  subtypes:
  - Primary Cutaneous
  evidence:
  - reference: PMID:34382383
    reference_title: "Whole-genome profiling of primary cutaneous anaplastic large cell lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consistent with the genomic data, transcriptome analysis uncovered
      upregulation of signal transduction routes associated with the PI-3-K, MAPK
      and G-protein pathways (e.g., ERK, phospholipase C, AKT).
    explanation: >-
      This genomic and transcriptomic study supports a distinct signaling program
      in primary cutaneous ALCL centered on PI3K/AKT and MAPK pathways.
histopathology:
- name: Hallmark Cell Morphology
  finding_term:
    preferred_term: Abnormal cell morphology
    term:
      id: HP:0025461
      label: Abnormal cell morphology
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Across ALCL subtypes, pleomorphic tumor cells with hallmark-cell morphology
    are a key tissue-level feature used to recognize the disease family.
  evidence:
  - reference: PMID:28975123
    reference_title: "Systemic and primary cutaneous anaplastic large cell lymphoma: Clinical features, morphological spectrum, and immunohistochemical profile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histologically, all the subtypes showed pleomorphic and "hallmark" cells
      with strong CD30 expression and variable loss of T-cell antigens.
    explanation: >-
      This abstract directly supports hallmark-cell morphology as a shared
      histopathologic feature across ALCL subtypes.
phenotypes:
- category: Cutaneous
  name: Ulcerating Skin Nodules
  subtype: Primary Cutaneous
  frequency: VERY_FREQUENT
  description: >-
    Primary cutaneous ALCL typically presents with solitary or multifocal skin
    nodules that may ulcerate and recur.
  phenotype_term:
    preferred_term: Skin nodule
    term:
      id: HP:0200036
      label: Skin nodule
  evidence:
  - reference: PMID:24346900
    reference_title: "Primary cutaneous anaplastic large-cell lymphoma--case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Primary cutaneous anaplastic large-cell lymphoma is part of the spectrum of
      CD30+ lymphoproliferative cutaneous processes, characterized by single or
      multifocal nodules that ulcerate, are autoregressive and recurrent.
    explanation: >-
      This abstract directly supports ulcerating cutaneous nodules as the
      defining clinical presentation of primary cutaneous ALCL.
- category: Lymphatic
  name: Regional Lymph Node Involvement
  subtype: Primary Cutaneous
  frequency: OCCASIONAL
  description: >-
    Primary cutaneous ALCL can disseminate to regional lymph nodes.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:24346900
    reference_title: "Primary cutaneous anaplastic large-cell lymphoma--case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extracutaneous dissemination may occur, especially to regional lymph nodes.
    explanation: >-
      This abstract supports regional lymph-node involvement as an occasional
      extracutaneous phenotype of primary cutaneous ALCL.
- category: Device-associated mass
  name: Capsular Mass
  subtype: Breast Implant-Associated
  frequency: OCCASIONAL
  description: >-
    A minority of breast implant-associated ALCL cases present as a capsule-based
    mass rather than isolated seroma.
  phenotype_term:
    preferred_term: Breast mass
    term:
      id: HP:0032408
      label: Breast mass
  evidence:
  - reference: PMID:38102324
    reference_title: "Surgical Management and Long-Term Outcomes of BIA-ALCL: A Multidisciplinary Approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients presented with clinically evident effusion in 78% of cases and a
      mass in 17% of cases, and 83% of patients presented with stage 1 BIA-ALCL.
    explanation: >-
      This cohort quantifies the less-common mass-presenting phenotype in
      breast implant-associated ALCL.
biochemical:
- name: CD30/TNFRSF8 Expression
  biomarker_term:
    preferred_term: Tumor Necrosis Factor Receptor Superfamily Member 8
    term:
      id: NCIT:C38906
      label: Tumor Necrosis Factor Receptor Superfamily Member 8
  presence: strong diffuse tumor-cell expression
  frequency: VERY_FREQUENT
  notes: >-
    Strong CD30 expression is the shared biomarker that unifies ALCL as a disease
    family and enables CD30-directed therapy.
  evidence:
  - reference: PMID:29617304
    reference_title: "The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell
      lymphoproliferations that share morphological and immunophenotypical features,
      namely strong CD30 expression and variable loss of T-cell markers
    explanation: >-
      This review supports strong CD30 expression as the defining biomarker of
      the ALCL disease family.
- name: ALK Fusion Protein Expression
  subtype: Systemic ALK-Positive
  biomarker_term:
    preferred_term: ALK Fusion Protein Expression
    term:
      id: NCIT:C81946
      label: ALK Fusion Protein Expression
  presence: immunohistochemically detectable surrogate for ALK rearrangement
  notes: >-
    ALK immunohistochemistry is a practical surrogate for ALK rearrangement in
    systemic ALK-positive ALCL.
  evidence:
  - reference: PMID:35941721
    reference_title: "Immunohistochemical Approach to Genetic Subtyping of Anaplastic Large Cell Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ALK immunohistochemistry is an excellent surrogate for ALK- R
    explanation: >-
      This pathology study directly supports ALK protein expression by
      immunohistochemistry as the biomarker surrogate for ALK-rearranged ALCL.
genetic:
- name: ALK Rearrangement
  subtype: Systemic ALK-Positive
  association: Defining Rearrangement
  gene_term:
    preferred_term: ALK
    term:
      id: hgnc:427
      label: ALK
  notes: >-
    ALK rearrangement defines systemic ALK-positive ALCL and creates an oncogenic
    tyrosine kinase program.
  evidence:
  - reference: PMID:29617304
    reference_title: "The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ALK is rearranged in approximately 80% of systemic ALCL cases with one of
      its partner genes, most commonly NPM1
    explanation: >-
      This review directly supports ALK rearrangement as the defining genetic
      event of systemic ALK-positive ALCL.
- name: DUSP22 Rearrangement
  subtype: Systemic ALK-Negative
  association: Molecular Subgroup
  gene_term:
    preferred_term: DUSP22
    term:
      id: hgnc:16077
      label: DUSP22
  notes: >-
    DUSP22 rearrangement identifies a major molecular subgroup within systemic
    ALK-negative ALCL.
  evidence:
  - reference: PMID:24894770
    reference_title: "ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8%
      of ALK-negative ALCLs, respectively.
    explanation: >-
      This study directly supports DUSP22 rearrangement as a recurrent molecular
      subgroup within systemic ALK-negative ALCL.
- name: TP63 Rearrangement
  subtype: Systemic ALK-Negative
  association: Molecular Subgroup
  gene_term:
    preferred_term: TP63
    term:
      id: hgnc:15979
      label: TP63
  notes: >-
    TP63 rearrangement defines a smaller systemic ALK-negative ALCL subgroup
    with poor outcomes under standard therapy.
  evidence:
  - reference: PMID:24894770
    reference_title: "ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8%
      of ALK-negative ALCLs, respectively.
    explanation: >-
      This study directly supports TP63 rearrangement as a recurrent molecular
      subgroup within systemic ALK-negative ALCL.
- name: JAK1 Mutation
  subtype: Systemic ALK-Negative
  association: JAK/STAT Pathway Activation
  gene_term:
    preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  notes: >-
    JAK1 mutation is one route to constitutive JAK/STAT signaling in systemic
    ALK-negative ALCL.
  evidence:
  - reference: PMID:34572893
    reference_title: "ALK-Negative Anaplastic Large Cell Lymphoma: Current Concepts and Molecular Pathogenesis of a Heterogeneous Group of Large T-Cell Lymphomas."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additionally, systemic ALK- ALCL-apart from DUSP22-rearranged cases-harbors
      JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT
      signaling pathway.
    explanation: >-
      This review supports JAK1 mutation as a recurrent route to JAK/STAT pathway
      activation in systemic ALK-negative ALCL.
- name: STAT3 Mutation
  subtype: Systemic ALK-Negative
  association: JAK/STAT Pathway Activation
  gene_term:
    preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  notes: >-
    STAT3 mutation is another recurrent route to constitutive JAK/STAT signaling
    in systemic ALK-negative ALCL.
  evidence:
  - reference: PMID:34572893
    reference_title: "ALK-Negative Anaplastic Large Cell Lymphoma: Current Concepts and Molecular Pathogenesis of a Heterogeneous Group of Large T-Cell Lymphomas."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additionally, systemic ALK- ALCL-apart from DUSP22-rearranged cases-harbors
      JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT
      signaling pathway.
    explanation: >-
      This review supports STAT3 mutation as a recurrent route to JAK/STAT pathway
      activation in systemic ALK-negative ALCL.
diagnosis:
- name: Tissue diagnosis with morphology and immunohistochemistry
  description: >-
    Diagnosis relies on recognizing hallmark-cell morphology and confirming the
    ALCL immunophenotype with immunohistochemistry, including CD30 in the initial
    panel.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  markers: CD30, ALK, CD2, CD3, CD5, CD20, PAX5, CD15
  evidence:
  - reference: PMID:28975123
    reference_title: "Systemic and primary cutaneous anaplastic large cell lymphoma: Clinical features, morphological spectrum, and immunohistochemical profile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnosis of ALCL is based on recognizing the key morphological features,
      especially the presence of "hallmark" cells. IHC is essential for confirmation
      of diagnosis and excluding other malignancies with anaplastic morphology. The
      inclusion of CD30 in the initial IHC panel will help identify LCA negative cases
      and avoid misdiagnosis.
    explanation: >-
      This abstract directly supports morphology-plus-IHC as the core diagnostic
      workflow for ALCL.
- name: Molecular genetic subtyping
  description: >-
    Genetic subtyping uses ALK immunohistochemistry plus targeted ancillary
    testing to sort ALCL into ALK-rearranged, TP63-rearranged, DUSP22-rearranged,
    and related groups.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  markers: ALK, DUSP22, TP63, LEF1, TIA1, phospho-STAT3 Y705, p63
  evidence:
  - reference: PMID:35941721
    reference_title: "Immunohistochemical Approach to Genetic Subtyping of Anaplastic Large Cell Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Together with previous data, these findings support a 4-marker
      immunohistochemistry algorithm using ALK, LEF1, TIA1, and p63 for genetic
      subtyping of ALCL.
    explanation: >-
      This study directly supports ancillary testing for molecular subgrouping
      within the unified ALCL disease page.
treatments:
- name: Anthracycline-Based Combination Chemotherapy
  description: >-
    Anthracycline-containing multiagent chemotherapy remains a core systemic
    treatment backbone for ALK-positive systemic ALCL.
  context: Systemic ALK-Positive disease
  treatment_term:
    preferred_term: cancer chemotherapy
    term:
      id: MAXO:0000646
      label: cancer chemotherapy
    therapeutic_agent:
    - preferred_term: cyclophosphamide
      term:
        id: CHEBI:4027
        label: cyclophosphamide
    - preferred_term: doxorubicin
      term:
        id: CHEBI:28748
        label: doxorubicin
    - preferred_term: vincristine
      term:
        id: CHEBI:28445
        label: vincristine
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  evidence:
  - reference: PMID:29279550
    reference_title: "Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients with ALK-positive ALCL are usually treated with anthracycline-based
      regimens, such as combination cyclophosphamide, doxorubicin, vincristine, and
      prednisolone (CHOP) or CHOEP (CHOP plus etoposide)
    explanation: >-
      This review supports anthracycline-based multiagent chemotherapy as a core
      systemic treatment backbone in ALK-positive ALCL.
- name: Brentuximab Vedotin Plus CHP
  description: >-
    Frontline brentuximab vedotin plus CHP improved progression-free and overall
    survival over CHOP in previously untreated systemic ALCL and other CD30-positive
    PTCL.
  context: Previously untreated systemic ALCL
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: brentuximab vedotin
      term:
        id: NCIT:C66944
        label: Brentuximab Vedotin
  evidence:
  - reference: PMID:30914464
    reference_title: "FDA Approval Summary: Brentuximab Vedotin in First-Line Treatment of Peripheral T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In November 2018, the U.S. Food and Drug Administration (FDA) approved
      brentuximab vedotin (BV) for the treatment of adult patients with previously
      untreated systemic anaplastic large cell lymphoma
    explanation: >-
      This FDA summary directly supports brentuximab vedotin plus CHP as a
      frontline systemic ALCL regimen.
  - reference: PMID:30914464
    reference_title: "FDA Approval Summary: Brentuximab Vedotin in First-Line Treatment of Peripheral T-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median PFS was 48.2 months with BV+CHP versus 20.8 months with CHOP,
      resulting in a hazard ratio (HR) of 0.71
    explanation: >-
      This directly supports superior frontline disease control with BV+CHP over
      CHOP in the ECHELON-2 approval-setting trial.
- name: Single-Agent Brentuximab Vedotin
  description: >-
    In relapsed or refractory systemic ALCL, single-agent brentuximab vedotin
    can produce durable complete remissions in a subset of patients.
  context: Relapsed or refractory systemic ALCL
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: brentuximab vedotin
      term:
        id: NCIT:C66944
        label: Brentuximab Vedotin
  evidence:
  - reference: PMID:28974506
    reference_title: "Five-year results of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These final results, which demonstrated a high rate of peripheral neuropathy
      resolution, and durable remissions in a subset of patients with relapsed or
      refractory systemic ALCL, provide evidence that single-agent brentuximab
      vedotin may be a potentially curative treatment option.
    explanation: >-
      This phase 2 follow-up study directly supports durable disease control with
      single-agent brentuximab vedotin in relapsed or refractory systemic ALCL.
- name: Crizotinib
  description: >-
    ALK inhibition with crizotinib has meaningful activity in relapsed or
    refractory systemic ALK-positive ALCL.
  context: Relapsed or refractory systemic ALK-Positive disease
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: crizotinib
      term:
        id: CHEBI:64310
        label: crizotinib
  evidence:
  - reference: PMID:37549532
    reference_title: "Efficacy and safety of crizotinib in ALK-positive systemic anaplastic large-cell lymphoma in children, adolescents, and adult patients: results of the French AcSé-crizotinib trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CONCLUSION: Crizotinib shows efficacy and an acceptable safety profile in
      ALK+ ALCL relapsed/refractory patients.
    explanation: >-
      This phase 2 study directly supports crizotinib as an active targeted agent
      in relapsed or refractory ALK-positive systemic ALCL.
- name: Radiation Therapy
  description: >-
    Localized primary cutaneous ALCL can be treated with skin-directed radiation
    therapy.
  context: Localized primary cutaneous disease
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: MAXO:0000014
      label: radiation therapy
  evidence:
  - reference: PMID:24346900
    reference_title: "Primary cutaneous anaplastic large-cell lymphoma--case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiotherapy, removal of the lesion and/or low-dose methotrexate are the
      treatments of choice.
    explanation: >-
      This abstract directly supports radiation therapy as a standard local
      treatment option in primary cutaneous ALCL.
- name: Complete Surgical Excision with Implant Removal
  description: >-
    Breast implant-associated ALCL is primarily managed with complete surgical
    excision, including total capsulectomy and implant removal.
  context: Breast Implant-Associated disease
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:26628470
    reference_title: "Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant-Associated Anaplastic Large-Cell Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients who underwent a complete surgical excision that consisted of total
      capsulectomy with breast implant removal had better OS (P = .022) and EFS
      (P = .014)
    explanation: >-
      This multi-institutional cohort directly supports complete capsulectomy
      with implant removal as the key treatment for breast implant-associated ALCL.
📚

References & Deep Research

Deep Research

1
OpenAI ▸
Anaplastic Large Cell Lymphoma Curation Notes
gpt-5

Anaplastic Large Cell Lymphoma Curation Notes

Modeling Decision

This curation follows the cancer modeling guidance from dismech issue #1198 and the Wilms tumor pattern:

  • The dismech page is the disease-level mechanism graph for ALCL, not a one-page-per-ontology-subclass expansion.
  • disease_term stays MONDO-first at MONDO:0020325 (anaplastic large cell lymphoma).
  • Major ALCL entities are represented as flat subtype facets under one page:
  • Systemic ALK-positive
  • Systemic ALK-negative
  • Primary cutaneous
  • Breast implant-associated
  • Genetic subgroups such as DUSP22-rearranged and TP63-rearranged ALK-negative ALCL are modeled as mechanism/genetic facts inside the unified disease page, not as separate dismech pages.
  • Current schema only provides Subtype.subtype_term as a MONDO-grounded slot and does not expose a disease-level ncit_mappings slot. Because of that, NCIT grounding was carried through histopathology findings, biomarkers, and treatment regimens/agents rather than by inventing non-schema subtype mapping structures.

Ontology Anchors

Disease

  • MONDO disease anchor: MONDO:0020325 anaplastic large cell lymphoma
  • NCIT companion cancer concept: NCIT:C3720 Anaplastic Large Cell Lymphoma

MONDO subtype anchors used in YAML

  • MONDO:0017602 ALK-positive anaplastic large cell lymphoma
  • MONDO:0017603 ALK-negative anaplastic large cell lymphoma
  • MONDO:0017598 primary cutaneous anaplastic large cell lymphoma
  • MONDO:0850112 breast implant-associated anaplastic large cell lymphoma

NCIT companion subtype concepts used in interpretation

  • NCIT:C37195 Systemic Anaplastic Large Cell Lymphoma, ALK-Positive
  • NCIT:C37196 Systemic Anaplastic Large Cell Lymphoma, ALK-Negative
  • NCIT:C6860 Primary Cutaneous Anaplastic Large Cell Lymphoma
  • NCIT:C139012 Breast Implant-Associated Anaplastic Large Cell Lymphoma

Histopathology / biomarker / treatment grounding

  • NCIT:C39679 Hallmark Cell
  • NCIT:C193484 CD30 Antigen [Presence] in Tissue by Immune Stain
  • NCIT:C38906 Tumor Necrosis Factor Receptor Superfamily Member 8
  • NCIT:C81946 ALK Fusion Protein Expression
  • NCIT:C66944 Brentuximab Vedotin
  • NCIT:C159558 CHP-Brentuximab Vedotin Regimen
  • NCIT:C160013 Crizotinib Regimen

PMID-Backed Evidence Used

Disease framing and subtype axes

  • PMID:40565334
  • Quote: Anaplastic Large Cell Lymphoma (ALCL) represents a diverse group of mature T-Cell Lymphomas unified by strong CD30 expression but with different molecular and clinical subtypes.
  • Use: disease-level definition and justification for one unified ALCL page.
  • PMID:40565334
  • Quote: ALCL comprises four major entities: systemic ALK-positive ALCL, systemic ALK-negative ALCL, Breast Implant-Associated ALCL (BIA-ALCL), and primary cutaneous ALCL.
  • Use: flat subtype facet structure.
  • PMID:24894770
  • Quote: Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy.
  • Use: ALK-negative modeled as one subtype with internal genetic heterogeneity, not split into multiple pages.

Histopathology and diagnosis

  • PMID:28975123
  • Quote: Histologically, all the subtypes showed pleomorphic and "hallmark" cells with strong CD30 expression and variable loss of T-cell antigens.
  • Use: hallmark-cell histopathology and diffuse CD30-positive tissue phenotype.
  • PMID:28975123
  • Quote: Diagnosis of ALCL is based on recognizing the key morphological features, especially the presence of "hallmark" cells.
  • Use: diagnostic emphasis on morphology.
  • PMID:28975123
  • Quote: The inclusion of CD30 in the initial IHC panel will help identify LCA negative cases and avoid misdiagnosis.
  • Use: diagnostic workflow and IHC panel design.
  • PMID:35941721
  • Quote: Together with previous data, these findings support a 4-marker immunohistochemistry algorithm using ALK, LEF1, TIA1, and p63 for genetic subtyping of ALCL.
  • Use: ancillary subtype-specific diagnostic testing.

Mechanism notes kept atomic in YAML

  • PMID:29617304
  • Quote: ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1
  • Use: discrete ALK Fusion Oncogene Formation node.
  • PMID:11850821
  • Quote: We show here that expression of activated ALK induces the constitutive phosphorylation of Stat3 in transfected cells as well as in primary human ALCLs.
  • Use: separate ALK-Driven STAT3 Activation node.
  • PMID:11850821
  • Quote: These studies support a pathogenic mechanism whereby stimulation of anti-apoptotic signals through activation of Stat3 contributes to the successful outgrowth of ALK positive tumor cells.
  • Use: separate BCL2L1-Mediated Apoptosis Resistance node.
  • PMID:19088198
  • Quote: NPM/ALK induces CD274 expression by activating its key signal transmitter, transcription factor STAT3.
  • Use: separate PD-L1-Mediated Immune Evasion node.
  • PMID:34572893
  • Quote: Additionally, systemic ALK- ALCL-apart from DUSP22-rearranged cases-harbors JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT signaling pathway.
  • Use: subtype-scoped JAK/STAT3 Pathway Alteration in ALK-Negative ALCL.
  • PMID:34382383
  • Quote: Consistent with the genomic data, transcriptome analysis uncovered upregulation of signal transduction routes associated with the PI-3-K, MAPK and G-protein pathways (e.g., ERK, phospholipase C, AKT).
  • Use: distinct primary-cutaneous signaling node rather than collapsing all non-ALK biology together.

Phenotypes and treatment

  • PMID:37655119
  • Quote: This lymphoma has a median age of 34 years, is more common in males, and is in advanced stage at the time of diagnosis in most patients.
  • Use: advanced-stage presentation phenotype for systemic ALK-positive disease.
  • PMID:24346900
  • Quote: Primary cutaneous anaplastic large-cell lymphoma is part of the spectrum of CD30+ lymphoproliferative cutaneous processes, characterized by single or multifocal nodules that ulcerate, are autoregressive and recurrent.
  • Use: skin-nodule phenotype for primary cutaneous ALCL.
  • PMID:38102324
  • Quote: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a subtype of ALCL that arises as a seroma or a mass in the capsule surrounding textured breast implants.
  • Use: seroma and capsule-mass phenotypes for BIA-ALCL.
  • PMID:30914464
  • Quote: In November 2018, the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin (BV) for the treatment of adult patients with previously untreated systemic anaplastic large cell lymphoma
  • Use: frontline brentuximab vedotin plus CHP.
  • PMID:28974506
  • Quote: These final results, which demonstrated ... durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab vedotin may be a potentially curative treatment option.
  • Use: relapsed/refractory brentuximab vedotin.
  • PMID:37549532
  • Quote: CONCLUSION: Crizotinib shows efficacy and an acceptable safety profile in ALK+ ALCL relapsed/refractory patients.
  • Use: targeted ALK inhibition.
  • PMID:26628470
  • Quote: Patients who underwent a complete surgical excision that consisted of total capsulectomy with breast implant removal had better OS (P = .022) and EFS (P = .014)
  • Use: surgery-first management for BIA-ALCL.

Why Separate Pages Were Not Created

Separate disease files were not created for ALK-positive ALCL, ALK-negative ALCL, primary cutaneous ALCL, or BIA-ALCL because:

  • the user explicitly requested application of the #1198 cancer-guideline pattern;
  • ALCL is represented in current disease ontology usage as one disease family with major subtype entities;
  • the important modeling burden here is subtype-scoped mechanism and treatment separation inside one page, not proliferating disease pages; and
  • only some branches, especially ALK-positive systemic disease and cutaneous/BIA disease, show clearly different mechanistic programs, which are captured by atomic nodes and subtype-scoped evidence inside the single page.

Cached References Added for This Slice

  • PMID:40565334
  • PMID:29617304
  • PMID:37655119
  • PMID:24894770
  • PMID:35941721
  • PMID:34382383
  • PMID:34572893
  • PMID:24404580
  • PMID:19088198
  • PMID:11850821
  • PMID:30914464
  • PMID:28974506
  • PMID:37549532
  • PMID:24346900
  • PMID:26628470
  • PMID:38102324