Anaplastic Large Cell Lymphoma

Cancer MONDO:0020325 Pathograph 32 Show in embeddings browser Mature T-cell and NK-cell non-Hodgkin lymphoma

Anaplastic large cell lymphoma (ALCL) is a CD30-positive mature T-cell lymphoma family comprising systemic ALK-positive, systemic ALK-negative, and primary cutaneous disease. Breast implant-associated ALCL is represented in its own MONDO:0850112 disorder entry because it is an exposure-associated entity outside the MONDO:0020325 descendant branch.

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1
Mappings
2
Definitions
9
Pathophys.
2
Histopath.
8
Phenotypes
4
Hypotheses
4
Gaps
32
Pathograph
6
Genes
9
Medical Actions
3
Subtypes
5
Differentials
6
Datasets
3
Trials
3
Models
1
Deep Research
🔗

Mappings

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

Definitions

2
Pathologic definition of anaplastic large cell lymphoma
ALCL is a mature T-cell lymphoma family unified by strong CD30 expression and subdivided here into systemic ALK-positive, systemic ALK-negative, and primary cutaneous 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."
The review provides the shared disease-family definition used by this entry.
International consensus classification framework
The entry follows the modern mature-lymphoid-neoplasm framework in which genomic findings refine entity definitions and diagnostic criteria.
OTHER Classification context for mature T-cell lymphoma entities
Show evidence (1 reference)
PMID:35653592 SUPPORT Other
"Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities."
The International Consensus Classification provides the genomic and diagnostic framework used to keep mature lymphoma entities distinct.
◆

Subtypes

3
molecular
Systemic ALK-Positive Anaplastic Large Cell Lymphoma MONDO:0017602
Systemic ALCL defined by an ALK fusion oncogene, often presenting at advanced stage in children, adolescents, and younger adults.
Show evidence (3 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."
The review defines the subtype by its ALK translocation-derived 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."
The review supports the younger adult distribution and frequent advanced-stage presentation.
PMID:36907641 SUPPORT Other
"Most children and adolescents present in advanced stages, often with extranodal disease and B symptoms."
The pediatric review directly supports the age-specific advanced-stage, extranodal, and constitutional presentation.
Systemic ALK-Negative Anaplastic Large Cell Lymphoma MONDO:0017603
Systemic ALCL lacking ALK rearrangement and containing genetically distinct DUSP22-rearranged, TP63-rearranged, and two triple-negative molecular groups (TN-I and TN-II).
Show evidence (3 references)
PMID:24894770 SUPPORT Human Clinical
"Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy."
The multicenter study supports a systemic ALK-negative subtype with clinically meaningful internal heterogeneity.
PMID:24894770 SUPPORT Human Clinical
"Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively."
The study defines two recurrent genomic subgroups within ALK-negative disease.
PMID:41329859 SUPPORT Human Clinical
"We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies 4 molecularly distinct ALK- ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II)."
The large molecular-profiling study refines triple-negative ALK-negative disease into TN-I and TN-II groups.
anatomical site
Primary Cutaneous Anaplastic Large Cell Lymphoma MONDO:0017598
A primary cutaneous CD30-positive lymphoproliferative disorder produced by skin-homing malignant T cells and requiring separation from systemic ALCL with secondary skin involvement.
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."
The genomic study directly supports the skin-homing malignant T-cell boundary.
PMID:21841159 SUPPORT Other
"Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma."
International consensus places primary cutaneous ALCL within the cutaneous CD30-positive lymphoproliferative-disorder spectrum.
◈

Mechanistic Hypotheses

4
ALK fusion to STAT3 survival model
alk_fusion_stat3_model CANONICAL Systemic ALK-Positive
Evidence balance 1 support
Constitutive ALK fusion kinase activity activates STAT3, which drives anti-apoptotic and immune-evasion programs supporting the ALK-positive malignant clone.
Pathograph links
Constitutive ALK Fusion Kinase Activity -> ALK-Driven STAT3 Activation DIRECT Activated ALK constitutively phosphorylates STAT3.
ALK-Driven STAT3 Activation -> BCL2L1-Mediated Apoptosis Resistance DIRECT STAT3 enhances transcription of the anti-apoptotic BCL2L1 product Bcl-xL.
ALK-Driven STAT3 Activation -> PD-L1-Mediated Immune Evasion DIRECT STAT3 directly induces expression of CD274/PD-L1.
BCL2L1-Mediated Apoptosis Resistance -> Systemic CD30-Positive Malignant T-Cell Expansion INDIRECT KNOWN INTERMEDIATES Apoptosis resistance permits survival and outgrowth of the malignant clone. Intermediates: survival selection and accumulation of ALK-positive tumor cells
PD-L1-Mediated Immune Evasion -> Systemic CD30-Positive Malignant T-Cell Expansion INDIRECT KNOWN INTERMEDIATES PD-L1-mediated immune suppression permits persistence and outgrowth of the malignant clone. Intermediates: reduced antitumor T-cell activity and immune clearance
Systemic CD30-Positive Malignant T-Cell Expansion -> Advanced-Stage Systemic Presentation INDIRECT UNKNOWN INTERMEDIATES Systemic clonal expansion can produce disseminated advanced-stage disease.
Show evidence (1 reference)
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."
The study directly establishes the central ALK-to-STAT3 link.
JAK/STAT-driven systemic ALK-negative subset
systemic_alk_negative_jak_stat_model EMERGING Systemic ALK-Negative
Evidence balance 1 support
In a subset of systemic ALK-negative ALCL, somatic JAK1 and STAT3 alterations replace ALK fusion signaling as a route to constitutive JAK/STAT activation.
Pathograph links
JAK/STAT3 Activation in Systemic ALK-Negative ALCL -> Systemic CD30-Positive Malignant T-Cell Expansion INDIRECT KNOWN INTERMEDIATES Constitutive JAK/STAT signaling supports malignant-clone expansion. Intermediates: JAK/STAT transcriptional programs for tumor-cell survival and proliferation
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."
The review supports a mutation-driven JAK/STAT branch in systemic ALK-negative disease.
pSTAT3-defined type I and epigenetic type II molecular model
alcl_type_i_type_ii_molecular_model EMERGING Systemic ALK-Positive Systemic ALK-Negative
Evidence balance 1 support
Integrated profiling separates ALCL into pSTAT3-positive type I disease, including ALK-positive and TN-I tumors, and pSTAT3-negative type II disease, including DUSP22-rearranged, TP63-rearranged, and TN-II tumors. Type II disease is enriched for non-tyrosine-kinase and epigenetic-regulator programs.
Pathograph links
EZH2-Associated Epigenetic Program in Type II ALK-Negative ALCL -> Systemic CD30-Positive Malignant T-Cell Expansion INDIRECT UNKNOWN INTERMEDIATES Epigenetic-regulator activity is modeled as supporting malignant-cell transcriptional state and expansion.
Show evidence (1 reference)
PMID:41329859 SUPPORT Human Clinical
"Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II)."
The large molecular-profiling study directly defines the two-type model and its constituent groups.
PI3K/AKT and MAPK signaling in primary cutaneous ALCL
primary_cutaneous_pi3k_mapk_model EMERGING Primary Cutaneous
Evidence balance 1 support
Recurrent genomic and transcriptomic alterations converge on proliferation-promoting PI3K/AKT, MAPK, and G-protein pathways in primary cutaneous ALCL.
Pathograph links
PI3K-AKT and MAPK Signaling Upregulation in Primary Cutaneous ALCL -> Skin-Homing CD30-Positive Malignant T-Cell Expansion INDIRECT KNOWN INTERMEDIATES Proliferation-promoting signaling supports the skin-homing malignant clone. Intermediates: altered proliferation and survival programs in skin-homing malignant T cells
Skin-Homing CD30-Positive Malignant T-Cell Expansion -> Ulcerating Skin Nodules INDIRECT KNOWN INTERMEDIATES Skin-localized malignant-cell expansion produces nodular lesions that may ulcerate. Intermediates: dermal tumor-cell accumulation and tissue injury
Skin-Homing CD30-Positive Malignant T-Cell Expansion -> Regional Lymph Node Involvement INDIRECT KNOWN INTERMEDIATES Cutaneous disease can disseminate to draining regional lymph nodes. Intermediates: lymphatic dissemination from cutaneous tumor sites
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)."
Integrated genomic and transcriptomic analysis supports the signaling model while leaving individual driver sufficiency unresolved.
?

Discussions and Knowledge Gaps

4
Which primary cutaneous ALCL treatment strategies have comparative prospective evidence sufficient to replace case-series-driven selection?
KNOWLEDGE GAP OPEN gap_primary_cutaneous_treatment_evidence
Attached to
treatments#Radiation Therapy treatments#Surgical Excision treatments#Low-Dose Methotrexate for Primary Cutaneous ALCL treatments#Brentuximab Vedotin for Primary Cutaneous ALCL has_subtypes#Primary Cutaneous
Prospective brentuximab data and modern reviews improve the evidence base, but most management evidence remains non-randomized. Comparative sequencing, risk stratification, and uncommon aggressive variants remain unresolved.
Posed 2026-07-21T02:53:02Z
Show evidence (2 references)
PMID:21841159 SUPPORT Other
"Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies."
The consensus explicitly identifies the comparative-treatment evidence gap.
PMID:42192920 SUPPORT Other
"Overall, current management is supported largely by non-randomized data, and key gaps remain in risk stratification, optimal sequencing of therapies, and management of uncommon aggressive variants."
The current review explicitly confirms the remaining evidence gaps.
Which clinical and molecular contexts explain the conflicting survival estimates for DUSP22-rearranged systemic ALK-negative ALCL?
KNOWLEDGE GAP OPEN gap_dusp22_prognostic_reproducibility
Attached to
genetic#DUSP22 Rearrangement has_subtypes#Systemic ALK-Negative
Two multicenter molecular cohorts, including the largest integrated series, report survival comparable to ALK-positive disease, whereas an independent cohort found no advantage over DUSP22-nonrearranged ALK-negative ALCL. Prospective, treatment-annotated molecular cohorts are needed before DUSP22 alone can determine treatment intensity.
Posed 2026-08-04T00:00:00Z
Show evidence (3 references)
PMID:24894770 SUPPORT Human Clinical
"Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001)."
This cohort reported a strongly favorable DUSP22-associated outcome.
PMID:41329859 SUPPORT Human Clinical
"Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%)."
The largest integrated cohort supports the favorable DUSP22 signal while resolving TN-I, TN-II, and TP63 outcomes.
PMID:36453104 SUPPORT Human Clinical
"However, in this cohort DUSP22-R was not associated with a better clinical outcome."
This independent cohort directly establishes non-reproduction of the favorable association.
How faithfully does the T-cell-targeted NPM-ALK transgenic mouse reproduce mature human ALK-positive ALCL rather than a broader lineage-promiscuous lymphoid transformation phenotype?
HUMAN MODEL MISMATCH OPEN gap_npm_alk_mouse_lineage_fidelity
Attached to
animal_models#Mus musculus pathophysiology#Constitutive ALK Fusion Kinase Activity
The model provides in-vivo evidence that NPM-ALK is oncogenic, but its tumors arise largely as immature-thymocyte lymphomas and some mice develop clonal plasma-cell neoplasms. Those outputs do not precisely reproduce a mature T-cell ALCL entity and bound translational interpretation.
Posed 2026-08-04T00:00:00Z
Show evidence (1 reference)
PMID:12424201 SUPPORT Model Organism
"NPM-ALK Tg thymic lymphomas displayed a T-cell phenotype characteristic of immature thymocytes and frequently coexpressed surface CD30. A subset of the NPM-ALK Tg mice also developed clonal B-cell plasma cell neoplasms."
The observed immature and B-lineage tumors directly define the fidelity mismatch.
Can checkpoint blockade or prolonged ALK inhibition replace allogeneic transplantation for selected relapsed pediatric ALK-positive ALCL?
KNOWLEDGE GAP OPEN gap_relapse_consolidation_sequencing
Attached to
treatments#Crizotinib treatments#Allogeneic Hematopoietic Stem Cell Transplantation
Multiple agents can reinduce remission, but comparative prospective evidence is insufficient to determine which patients require transplantation and which can safely continue less intensive targeted or immune therapy.
Posed 2026-08-04T00:00:00Z
Show evidence (1 reference)
PMID:36907641 SUPPORT Other
"It needs to be shown whether check-point inhibitors or long-term ALK-inhibition may substitute for transplantation."
The pediatric management review explicitly states the unresolved comparison.
⚙

Pathophysiology

9
Constitutive ALK Fusion Kinase Activity
ALK rearrangement, most often NPM1::ALK, creates a constitutively active fusion tyrosine kinase in systemic ALK-positive ALCL.
ALK fusion to STAT3 survival model
ALK hgnc:427 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALK (hgnc:427). hgnc:427 is a gene from the HUGO Gene Nomenclature Committee. NPM1 hgnc:7910 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NPM1 (hgnc:7910). hgnc:7910 is a gene from the HUGO Gene Nomenclature Committee.
protein tyrosine kinase activity GO:0004713 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased protein tyrosine kinase activity (GO:0004713). GO:0004713 is a molecular function from the Gene Ontology. ↑ INCREASED
Computational models
NPM-ALK Signaling-Network Sensitivity Model KINETIC Models signal flow from NPM-ALK through interacting survival and proliferation pathways.
Downstream
ALK-Driven STAT3 Activation Activated ALK constitutively phosphorylates STAT3. ALK fusion to STAT3 survival model
Show evidence (3 references)
PMID:37655119 SUPPORT Other
"The most frequent translocation is t(2;5) which combines ALK with NPM1."
The review identifies NPM1 as the most frequent ALK fusion partner.
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 quantifies the frequency of ALK rearrangement in systemic ALCL and identifies NPM1 as the most common fusion partner.
PMID:11850821 SUPPORT In Vitro
"The anaplastic lymphoma kinase (ALK) gene is characteristically translocated in Anaplastic Large Cell Lymphomas (ALCL) and the juxtaposition of the ALK gene to multiple partners results in its constitutive protein tyrosine kinase activity."
The experimental study directly supports constitutive kinase activity of ALK fusions.
ALK-Driven STAT3 Activation
Constitutive STAT3 activation is the central transcriptional signaling hub downstream of the ALK fusion kinase.
ALK fusion to STAT3 survival model
ALK hgnc:427 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALK (hgnc:427). hgnc:427 is a gene from the HUGO Gene Nomenclature Committee.
cell surface receptor signaling pathway via JAK-STAT GO:0007259 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
Dominant-Negative STAT3 in Karpas 299 and SU-DHL-1 Cells CELL LINE Selectively inhibits STAT3 signaling downstream of NPM-ALK.
Computational models
NPM-ALK Signaling-Network Sensitivity Model KINETIC Models JAK3-STAT3 as one control branch of the NPM-ALK network.
Downstream
BCL2L1-Mediated Apoptosis Resistance STAT3 enhances transcription of the anti-apoptotic BCL2L1 product Bcl-xL. ALK fusion to STAT3 survival model
PD-L1-Mediated Immune Evasion STAT3 directly induces expression of CD274/PD-L1. ALK fusion to STAT3 survival model
Show evidence (1 reference)
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."
The study directly supports constitutive STAT3 activation downstream of activated ALK.
BCL2L1-Mediated Apoptosis Resistance
STAT3-dependent BCL2L1 transcription protects ALK-positive tumor cells from cell death and supports clonal outgrowth.
ALK fusion to STAT3 survival model
BCL2L1 hgnc:992 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BCL2L1 (hgnc:992). hgnc:992 is a gene from the HUGO Gene Nomenclature Committee.
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Systemic CD30-Positive Malignant T-Cell Expansion Apoptosis resistance permits survival and outgrowth of the malignant clone. ALK fusion to STAT3 survival model
Show evidence (1 reference)
PMID:11850821 SUPPORT In Vitro
"Increased expression of Bcl-x(L) provided sufficient anti-apoptotic signals to protect cells from treatment with specific inhibitors of the Jaks/Stat pathway or the Brc-Abl kinase."
The experiment directly supports Bcl-xL-mediated apoptosis resistance.
PD-L1-Mediated Immune Evasion
STAT3-dependent CD274/PD-L1 expression adds an immunosuppressive program to ALK-positive malignant T cells.
ALK fusion to STAT3 survival model
CD274 hgnc:17635 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CD274 (hgnc:17635). hgnc:17635 is a gene from the HUGO Gene Nomenclature Committee.
negative regulation of T cell mediated immunity GO:0002710 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased negative regulation of T cell mediated immunity (GO:0002710). GO:0002710 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Systemic CD30-Positive Malignant T-Cell Expansion PD-L1-mediated immune suppression permits persistence and outgrowth of the malignant clone. ALK fusion to STAT3 survival model
Show evidence (1 reference)
PMID:19088198 SUPPORT In Vitro
"These findings identify an additional cell-transforming property of NPM/ALK and describe a direct link between an oncoprotein and an immunosuppressive cell-surface protein."
The study characterizes ALK-induced PD-L1 as an immunosuppressive cell-surface program.
JAK/STAT3 Activation in Systemic ALK-Negative ALCL
Somatic JAK1 and STAT3 mutations activate JAK/STAT signaling in a subset of systemic ALK-negative ALCL, excluding the DUSP22-rearranged subset in the cited review.
JAK/STAT-driven systemic ALK-negative subset
JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee. STAT3 hgnc:11364 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STAT3 (hgnc:11364). hgnc:11364 is a gene from the HUGO Gene Nomenclature Committee.
cell surface receptor signaling pathway via JAK-STAT GO:0007259 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Systemic CD30-Positive Malignant T-Cell Expansion Constitutive JAK/STAT signaling supports malignant-clone expansion. JAK/STAT-driven systemic ALK-negative subset
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."
The review directly links JAK1/STAT3 mutations to pathway activation in a systemic ALK-negative subset.
EZH2-Associated Epigenetic Program in Type II ALK-Negative ALCL
DUSP22-rearranged, TP63-rearranged, and TN-II ALK-negative tumors fall within a pSTAT3-negative type II molecular group enriched for non-tyrosine-kinase pathways and epigenetic regulators, particularly EZH2, with EZH2 and H3K27me3 overexpression demonstrated immunohistochemically.
pSTAT3-defined type I and epigenetic type II molecular model
EZH2 hgnc:3527 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EZH2 (hgnc:3527). hgnc:3527 is a gene from the HUGO Gene Nomenclature Committee.
histone H3K27 methyltransferase activity GO:0046976 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased histone H3K27 methyltransferase activity (GO:0046976). GO:0046976 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Systemic CD30-Positive Malignant T-Cell Expansion Epigenetic-regulator activity is modeled as supporting malignant-cell transcriptional state and expansion. pSTAT3-defined type I and epigenetic type II molecular model
Show evidence (1 reference)
PMID:41329859 SUPPORT Human Clinical
"Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched for non-tyrosine kinase pathways, particularly epigenetic regulators such as EZH2. Immunohistochemistry showed overexpression of EZH2 and its trimethylated substrate H3K27."
The human profiling and immunohistochemistry directly support the type II epigenetic program and EZH2/H3K27me3 overexpression.
Systemic CD30-Positive Malignant T-Cell Expansion
Systemic ALCL consists of an expanding CD30-positive malignant T-cell clone; ALK fusion signaling and mutation-driven JAK/STAT signaling are distinct upstream routes into this shared disease compartment.
ALK fusion to STAT3 survival model
mature T cell CL:0002419 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mature T cell (CL:0002419). CL:0002419 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Advanced-Stage Systemic Presentation Systemic clonal expansion can produce disseminated advanced-stage disease. ALK fusion to STAT3 survival model
Systemic Lymphadenopathy Systemic malignant-cell expansion commonly produces enlarged lymph nodes.
Fever Systemic lymphoma can produce fever as part of the B-symptom complex.
Night Sweats Systemic lymphoma can produce night sweats as part of the B-symptom complex.
Weight Loss Systemic lymphoma can produce weight loss as part of the B-symptom complex.
Extranodal Disease Systemic clonal dissemination can involve sites outside lymph nodes.
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."
The review supports a shared CD30-positive mature T-cell malignant compartment across systemic molecular subtypes.
PI3K-AKT and MAPK Signaling Upregulation in Primary Cutaneous ALCL
Primary cutaneous ALCL shows transcriptomic upregulation of PI3K/AKT, MAPK, and G-protein signal-transduction routes without assigning a single universal causal gene.
PI3K/AKT and MAPK signaling in primary cutaneous ALCL
Downstream
Skin-Homing CD30-Positive Malignant T-Cell Expansion Proliferation-promoting signaling supports the skin-homing malignant clone. PI3K/AKT and MAPK signaling in primary cutaneous ALCL
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)."
Integrated transcriptome analysis directly supports pathway-level upregulation.
Skin-Homing CD30-Positive Malignant T-Cell Expansion
The primary cutaneous branch is an expansion of skin-homing CD30-positive malignant T cells that produces localized or multifocal cutaneous lesions and can extend to regional lymph nodes.
PI3K/AKT and MAPK signaling in primary cutaneous ALCL
mature T cell CL:0002419 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mature T cell (CL:0002419). CL:0002419 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Ulcerating Skin Nodules Skin-localized malignant-cell expansion produces nodular lesions that may ulcerate. PI3K/AKT and MAPK signaling in primary cutaneous ALCL
Regional Lymph Node Involvement Cutaneous disease can disseminate to draining regional lymph nodes. PI3K/AKT and MAPK signaling in primary cutaneous ALCL
Show evidence (1 reference)
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."
The study directly defines pcALCL as a skin-homing CD30-positive malignant T-cell neoplasm.
✶

Histopathology

2
Hallmark Cells
ALCL includes characteristic hallmark cells with strong CD30 expression and variable loss of T-cell antigens.
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."
The clinicopathologic series directly supports the shared hallmark-cell morphology and immunophenotype.
Nuclear Pleomorphism
Large neoplastic cells show pleomorphic nuclear morphology across ALCL subtypes.
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."
The clinicopathologic series directly supports pleomorphic tumor-cell morphology.
⬡

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

8
Cardiovascular 2
Regional Lymph Node Involvement Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24346900 SUPPORT Human Clinical
"Extracutaneous dissemination may occur, especially to regional lymph nodes."
The report directly supports regional lymph-node involvement without justifying a numerical frequency.
Systemic Lymphadenopathy HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39551572 SUPPORT Other
"It usually causes lymphadenopathy and B symptoms; however, diverse cutaneous manifestations can also be observed."
The review directly identifies lymphadenopathy as a usual manifestation.
Integument 1
Ulcerating Skin Nodules HP:0200036 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin nodule (HP:0200036). HP:0200036 is a phenotype from the Human Phenotype Ontology.
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."
The report supports the morphology and behavior of the cutaneous lesions; no population frequency is inferred from the case-based source.
Metabolism 1
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32311892 SUPPORT Human Clinical
"25 patients (62.5%) had B symptoms, such as fever, emaciation and night sweat."
The retrospective systemic cohort explicitly includes fever.
Constitutional 1
Night Sweats HP:0030166 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Night sweats (HP:0030166). HP:0030166 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32311892 SUPPORT Human Clinical
"25 patients (62.5%) had B symptoms, such as fever, emaciation and night sweat."
The retrospective systemic cohort explicitly includes night sweats.
Growth 1
Weight Loss HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32311892 SUPPORT Human Clinical
"25 patients (62.5%) had B symptoms, such as fever, emaciation and night sweat."
Emaciation supports weight loss, but the cohort gives no formal weight threshold.
Other 2
Advanced-Stage Systemic Presentation FREQUENT
Show evidence (1 reference)
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."
"Most patients" supports placement in the FREQUENT band without assigning a more precise prevalence.
Extranodal Disease
Show evidence (1 reference)
PMID:36907641 SUPPORT Other
"Most children and adolescents present in advanced stages, often with extranodal disease and B symptoms."
The pediatric review directly supports extranodal presentation.
🧬

Genetic Associations

6
ALK Rearrangement (Defining somatic ALK fusion driver)
Gene: ALK hgnc:427 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALK (hgnc:427). hgnc:427 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
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."
The review directly identifies the defining somatic ALK translocation.
NPM1 Fusion Partner (Recurrent partner in the defining somatic NPM1::ALK fusion driver)
Gene: NPM1 hgnc:7910 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NPM1 (hgnc:7910). hgnc:7910 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Show evidence (1 reference)
PMID:37655119 SUPPORT Other
"The most frequent translocation is t(2;5) which combines ALK with NPM1."
The review directly identifies NPM1 as the most frequent ALK fusion partner.
DUSP22 Rearrangement (Molecular subgroup and cohort-dependent prognostic biomarker)
Gene: DUSP22 hgnc:16077 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DUSP22 (hgnc:16077). hgnc:16077 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: BIOMARKER variant_origin: SOMATIC
Show evidence (4 references)
PMID:24894770 SUPPORT Human Clinical
"Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively."
The study establishes DUSP22 rearrangement as a recurrent molecular subgroup.
PMID:24894770 SUPPORT Human Clinical
"Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001)."
This initial multicenter cohort supports a favorable outcome association, which is retained as one cohort-specific estimate.
PMID:41329859 SUPPORT Human Clinical
"Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%)."
The largest integrated molecular cohort independently supports a favorable DUSP22-associated survival estimate.
+ 1 more reference
TP63 Rearrangement (Molecular subgroup and adverse prognostic biomarker)
Gene: TP63 hgnc:15979 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TP63 (hgnc:15979). hgnc:15979 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: BIOMARKER variant_origin: SOMATIC
Show evidence (3 references)
PMID:24894770 SUPPORT Human Clinical
"Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively."
The study establishes TP63 rearrangement as a recurrent molecular subgroup.
PMID:24894770 SUPPORT Human Clinical
"Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001)."
The outcome association supports adverse prognostic-biomarker classification.
PMID:41329859 SUPPORT Human Clinical
"Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%)."
The large molecular cohort independently supports the adverse TP63-rearranged outcome association.
JAK1 Mutation (Somatic JAK/STAT-pathway driver alteration)
Gene: JAK1 hgnc:6190 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is JAK1 (hgnc:6190). hgnc:6190 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
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."
The review supports JAK1 mutation as a somatic pathway driver in the defined subset.
STAT3 Mutation (Somatic JAK/STAT-pathway driver alteration)
Gene: STAT3 hgnc:11364 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STAT3 (hgnc:11364). hgnc:11364 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
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."
The review supports STAT3 mutation as a somatic pathway driver in the defined subset.
💊

Medical Actions

9
CHOP-Based Anthracycline Chemotherapy
Category: Therapeutic Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632 Regimen: CHOP regimenNCI Thesaurus (NCIT) Relation: this regimen component is this clinical intervention This regimen component is CHOP regimen (NCIT:C9549). NCIT:C9549 is a clinical intervention from the NCI Thesaurus. Ontology label: CHOP Regimen NCIT:C9549
CHOP or CHOEP has been a systemic treatment backbone, especially for ALK-positive disease.
Mechanism Target:
INHIBITS Systemic CD30-Positive Malignant T-Cell Expansion — Multiagent cytotoxic therapy reduces the proliferating systemic malignant T-cell compartment.
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)"
The review supports use of cytotoxic combination therapy against systemic ALK-positive disease; it does not isolate one graph-node mechanism.
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)"
The review directly supports CHOP/CHOEP use in systemic ALK-positive ALCL.
Brentuximab Vedotin Plus CHP
Category: Therapeutic Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632 Regimen: CHP-Brentuximab Vedotin RegimenNCI Thesaurus (NCIT) Relation: this regimen component is this clinical intervention This regimen component is CHP-Brentuximab Vedotin Regimen (NCIT:C159558). NCIT:C159558 is a clinical intervention from the NCI Thesaurus. NCIT:C159558
Agent: brentuximab vedotin NCIT:C66944 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses brentuximab vedotin (NCIT:C66944). NCIT:C66944 is a therapeutic agent from the NCI Thesaurus. cyclophosphamide CHEBI:4027 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cyclophosphamide (CHEBI:4027). CHEBI:4027 is a therapeutic agent from Chemical Entities of Biological Interest. doxorubicin CHEBI:28748 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxorubicin (CHEBI:28748). CHEBI:28748 is a therapeutic agent from Chemical Entities of Biological Interest. prednisone CHEBI:8382 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses prednisone (CHEBI:8382). CHEBI:8382 is a therapeutic agent from Chemical Entities of Biological Interest.
Frontline brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone improves progression-free and overall survival over CHOP in previously untreated CD30-positive peripheral T-cell lymphomas, with the trial population targeted to include 75% systemic ALCL.
Mechanism Target:
INHIBITS Systemic CD30-Positive Malignant T-Cell Expansion — The anti-CD30 conjugate delivers an antimitotic payload to the CD30-positive malignant-cell compartment; CHP supplies complementary cytotoxic activity.
Show evidence (1 reference)
PMID:29279550 SUPPORT Other
"For targeted therapies, an anti-CD30 monoclonal antibody linked to a synthetic antimitotic agent (brentuximab vedotin) and ALK inhibitors (crizotinib, alectinib, and ceritinib) are being used in clinical settings."
The review directly supports CD30-directed delivery of an antimitotic payload rather than an incorrect ALK-STAT3 target assignment.
Show evidence (3 references)
PMID:30522922 SUPPORT Human Clinical
"METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma)..."
The phase 3 design directly establishes the intended systemic-ALCL-rich frontline population and randomized comparator.
PMID:30522922 SUPPORT Human Clinical
"Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group"
The randomized trial directly supports improved progression-free survival with A+CHP.
PMID:40750774 SUPPORT Human Clinical
"median PFS per investigator was not reached in the A + CHP arm and was 54.2 months in the CHOP arm, with estimated 5-year PFS rates of 61% versus 48%, respectively"
The ALCL-specific five-year analysis directly supports durable PFS benefit in the systemic ALCL subgroup.
Single-Agent Brentuximab Vedotin
Category: Therapeutic Action: immunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Agent: brentuximab vedotin NCIT:C66944 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses brentuximab vedotin (NCIT:C66944). NCIT:C66944 is a therapeutic agent from the NCI Thesaurus.
Single-agent brentuximab vedotin can produce durable remissions in relapsed or refractory systemic ALCL.
Mechanism Target:
INHIBITS Systemic CD30-Positive Malignant T-Cell Expansion — Brentuximab vedotin delivers an antimitotic payload to CD30-positive malignant cells.
Show evidence (1 reference)
PMID:29279550 SUPPORT Other
"For targeted therapies, an anti-CD30 monoclonal antibody linked to a synthetic antimitotic agent (brentuximab vedotin) and ALK inhibitors (crizotinib, alectinib, and ceritinib) are being used in clinical settings."
The review directly supports the CD30-directed antimitotic mechanism.
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."
The phase 2 follow-up directly supports durable remissions in relapsed or refractory systemic ALCL.
Crizotinib
Category: Therapeutic Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
Agent: crizotinib CHEBI:64310 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses crizotinib (CHEBI:64310). CHEBI:64310 is a therapeutic agent from Chemical Entities of Biological Interest.
Crizotinib is an ALK inhibitor with clinical activity in relapsed or refractory systemic ALK-positive ALCL.
Mechanism Target:
INHIBITS Constitutive ALK Fusion Kinase Activity — Crizotinib directly targets ALK fusion kinase activity upstream of STAT3.
Show evidence (1 reference)
PMID:29279550 SUPPORT Other
"For targeted therapies, an anti-CD30 monoclonal antibody linked to a synthetic antimitotic agent (brentuximab vedotin) and ALK inhibitors (crizotinib, alectinib, and ceritinib) are being used in clinical settings."
The review identifies crizotinib as an ALK inhibitor, anchoring it to fusion kinase activity rather than to a downstream nonspecific node.
Show evidence (1 reference)
PMID:37549532 SUPPORT Human Clinical
"CONCLUSION: Crizotinib shows efficacy and an acceptable safety profile in ALK+ ALCL relapsed/refractory patients."
The phase 2 trial directly supports clinical activity in the intended ALK-positive setting.
Radiation Therapy
Category: Therapeutic Action: Radiation TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Radiation Therapy (NCIT:C15313). NCIT:C15313 is a clinical intervention from the NCI Thesaurus. NCIT:C15313
Skin-directed radiation is a local treatment option for primary cutaneous ALCL lesions.
Mechanism Target:
INHIBITS Skin-Homing CD30-Positive Malignant T-Cell Expansion — Local radiation reduces the skin-localized malignant T-cell compartment in the treated field.
Show evidence (1 reference)
PMID:24346900 SUPPORT Human Clinical
"Radiotherapy, removal of the lesion and/or low-dose methotrexate are the treatments of choice."
The report supports local radiotherapy use; it does not experimentally isolate the graph-node mechanism.
Show evidence (1 reference)
PMID:24346900 SUPPORT Human Clinical
"Radiotherapy, removal of the lesion and/or low-dose methotrexate are the treatments of choice."
The abstract directly supports radiotherapy as a local treatment option.
Surgical Excision
Category: Therapeutic Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Surgical removal is a local option for a localized primary cutaneous ALCL lesion.
Mechanism Target:
INHIBITS Skin-Homing CD30-Positive Malignant T-Cell Expansion — Excision physically removes the localized cutaneous tumor-cell compartment.
Show evidence (1 reference)
PMID:24346900 SUPPORT Human Clinical
"Radiotherapy, removal of the lesion and/or low-dose methotrexate are the treatments of choice."
The report supports lesion removal but does not compare local modalities.
Show evidence (1 reference)
PMID:24346900 SUPPORT Human Clinical
"Radiotherapy, removal of the lesion and/or low-dose methotrexate are the treatments of choice."
The source explicitly supports removal of a localized lesion.
Low-Dose Methotrexate for Primary Cutaneous ALCL
Category: Therapeutic Action: ChemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. NCIT:C15632
Agent: methotrexate CHEBI:44185 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses methotrexate (CHEBI:44185). CHEBI:44185 is a therapeutic agent from Chemical Entities of Biological Interest.
Low-dose methotrexate is a systemic option for selected primary cutaneous ALCL patients.
Mechanism Target:
INHIBITS Skin-Homing CD30-Positive Malignant T-Cell Expansion — Antimetabolite therapy suppresses the proliferating cutaneous malignant-cell compartment.
Show evidence (1 reference)
PMID:42192920 SUPPORT Other
"alternative systemic therapies, including methotrexate and retinoids, remain relevant in selected patients."
The review supports selected clinical use, not a uniquely isolated graph-node mechanism.
Show evidence (1 reference)
PMID:42192920 SUPPORT Other
"alternative systemic therapies, including methotrexate and retinoids, remain relevant in selected patients."
The current review directly supports methotrexate for selected patients.
Brentuximab Vedotin for Primary Cutaneous ALCL
Category: Therapeutic Action: ImmunotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. NCIT:C15262
Agent: brentuximab vedotin NCIT:C66944 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses brentuximab vedotin (NCIT:C66944). NCIT:C66944 is a therapeutic agent from the NCI Thesaurus.
Brentuximab vedotin has the strongest prospective systemic-therapy evidence for multifocal or relapsed primary cutaneous ALCL.
Mechanism Target:
INHIBITS Skin-Homing CD30-Positive Malignant T-Cell Expansion — The CD30-directed conjugate delivers an antimitotic payload to cutaneous malignant cells.
Show evidence (1 reference)
PMID:42192920 SUPPORT Other
"For multifocal or relapsed disease, brentuximab vedotin demonstrates the most robust prospective data and has reshaped the treatment landscape"
The review supports the disease context; CD30-directed payload delivery is established elsewhere in this entry.
Show evidence (1 reference)
PMID:42192920 SUPPORT Other
"For multifocal or relapsed disease, brentuximab vedotin demonstrates the most robust prospective data and has reshaped the treatment landscape"
The current review directly supports this context-specific use.
Allogeneic Hematopoietic Stem Cell Transplantation
Category: Therapeutic Action: Hematopoietic Cell TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. NCIT:C15431
Allogeneic transplantation is a consolidation option after reinduction for selected relapsed pediatric ALK-positive ALCL.
Mechanism Target:
INHIBITS Systemic CD30-Positive Malignant T-Cell Expansion — Conditioning and donor immune effects consolidate control of the systemic malignant clone after reinduction.
Show evidence (1 reference)
PMID:36907641 SUPPORT Other
"Survival at relapse exceeds 60-70% with consolidation according to the time of relapse (Vinblastine monotherapy or allogeneic hematopoietic stem cell transplantation)"
The review supports consolidation but does not isolate conditioning and donor immune mechanisms.
Show evidence (1 reference)
PMID:36907641 SUPPORT Other
"Survival at relapse exceeds 60-70% with consolidation according to the time of relapse (Vinblastine monotherapy or allogeneic hematopoietic stem cell transplantation)"
The pediatric review directly supports allogeneic transplantation as relapse consolidation.
🔬

Biochemical Markers

3
CD30/TNFRSF8 Expression (strong diffuse tumor-cell expression)
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."
The review supports strong CD30 expression as the unifying family biomarker.
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"
The pathology study directly supports ALK immunohistochemistry as a rearrangement surrogate.
Phosphorylated STAT3 Y705 Expression (present in type I and absent in type II molecular ALCL)
Show evidence (1 reference)
PMID:41329859 SUPPORT Human Clinical
"RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression."
The cohort directly supports pSTAT3-Y705 as a molecular-type classifier.
🔬

Diagnosis

3
Tissue Morphology and Immunohistochemistry
Diagnosis relies on hallmark-cell morphology plus immunohistochemistry, including CD30 and ALK, while excluding other anaplastic malignancies.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Markers: CD30, ALK, CD2, CD3, CD5, CD20, PAX5, CD15
Show evidence (1 reference)
PMID:28975123 SUPPORT Human Clinical
"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..."
The clinicopathologic study directly supports the morphology-plus-IHC diagnostic workflow.
Molecular Genetic Subtyping
ALK immunohistochemistry and ancillary markers guide molecular subtyping; rearrangement testing can resolve ALK, DUSP22, and TP63 groups.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Markers: ALK, DUSP22, TP63, LEF1, TIA1, phospho-STAT3 Y705, p63
Show evidence (2 references)
PMID:35941721 SUPPORT Human Clinical
"Together with previous data, these findings support a 4-marker immunohistochemistry algorithm using ALK, LEF1, TIA1, and p63 for genetic subtyping of ALCL."
The pathology study directly supports ancillary-marker-based genetic subtyping.
PMID:41329859 SUPPORT Human Clinical
"RNA sequencing with unsupervised gene expression profiling in 393 patients identified 2 main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (type I) or absence (type II) of phosphorylated STAT3Y705 expression."
The molecular cohort directly supports phospho-STAT3 Y705 as a subtyping marker.
Clinicopathologic Confirmation of Primary Cutaneous Disease
Primary cutaneous ALCL must be interpreted within the cutaneous CD30-positive lymphoproliferative-disorder spectrum and correlated with clinical staging to exclude systemic disease involving skin.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:21841159 SUPPORT Other
"Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma."
The consensus establishes the relevant disease spectrum; the cached abstract does not enumerate the entire staging workflow.
📊

Prevalence

1
General population
Annual Incidence 0.25 per 100,000 1–9 per 1,000,000
A recent clinical literature review reports an annual incidence estimate of 0.25 cases per 100,000 people; this is an incidence rate, not point prevalence.
Show evidence (1 reference)
PMID:39551572 SUPPORT Human Clinical
"The incidence of anaplastic large cell lymphoma is 0.25 cases per 100,000 people."
The literature review supplies the explicit population incidence estimate.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Anaplastic Large Cell Lymphoma:

Classic Hodgkin Lymphoma
Overlapping Features Hodgkin lymphoma can show overlapping anaplastic morphology and CD30 expression.
Distinguishing Features
  • Integrate lineage markers, PAX5, CD15, ALK, and the broader immunophenotypic pattern.
  • Confirm that the morphology and clinical distribution fit an ALCL entity.
Show evidence (1 reference)
PMID:28975123 SUPPORT Human Clinical
"However, other entities such as diffuse large B-cell lymphoma, peripheral T-cell lymphoma, Hodgkin lymphoma, and undifferentiated carcinoma can also show similar anaplastic features."
The clinicopathologic study explicitly includes Hodgkin lymphoma among mimics with similar anaplastic features.
Peripheral T-Cell Lymphoma, Not Otherwise Specified
Overlapping Features Other peripheral T-cell lymphomas can show anaplastic cytology and variable CD30 expression.
Distinguishing Features
  • Require the coherent ALCL hallmark-cell and strong diffuse CD30 phenotype.
  • Use ALK and ancillary molecular subgrouping where appropriate.
Show evidence (1 reference)
PMID:28975123 SUPPORT Human Clinical
"However, other entities such as diffuse large B-cell lymphoma, peripheral T-cell lymphoma, Hodgkin lymphoma, and undifferentiated carcinoma can also show similar anaplastic features."
The study explicitly includes peripheral T-cell lymphoma among the anaplastic morphologic mimics.
Diffuse Large B-Cell Lymphoma
Overlapping Features Diffuse large B-cell lymphoma can resemble ALCL morphologically.
Distinguishing Features
  • Establish B-cell versus T-cell lineage with an appropriate immunohistochemical panel.
  • Interpret CD30 in the full lineage and molecular context.
Show evidence (1 reference)
PMID:28975123 SUPPORT Human Clinical
"However, other entities such as diffuse large B-cell lymphoma, peripheral T-cell lymphoma, Hodgkin lymphoma, and undifferentiated carcinoma can also show similar anaplastic features."
The study explicitly includes diffuse large B-cell lymphoma among the morphologic mimics.
Undifferentiated Carcinoma
Overlapping Features Undifferentiated carcinoma can mimic the large pleomorphic morphology of ALCL.
Distinguishing Features
  • Use leukocyte, epithelial, and lineage markers to establish tumor origin.
  • Retain CD30 in the initial panel when leukocyte common antigen is negative.
Show evidence (1 reference)
PMID:28975123 SUPPORT Human Clinical
"However, other entities such as diffuse large B-cell lymphoma, peripheral T-cell lymphoma, Hodgkin lymphoma, and undifferentiated carcinoma can also show similar anaplastic features."
The study explicitly includes undifferentiated carcinoma among the anaplastic morphologic mimics.
Lymphomatoid Papulosis
Overlapping Features Lymphomatoid papulosis shares the primary cutaneous CD30-positive lymphoproliferative-disorder spectrum with primary cutaneous ALCL.
Distinguishing Features
  • Correlate morphology with the longitudinal lesion pattern and clinical distribution.
  • Exclude systemic ALCL before assigning a primary cutaneous diagnosis.
Show evidence (1 reference)
PMID:21841159 SUPPORT Other
"Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma."
The consensus directly establishes the close classification boundary; the cached abstract does not enumerate all distinguishing clinical criteria.
📊

Related Datasets

6
Expression signature characteristic of Anaplastic Large Cell Lymphoma (ALCL) patients geo:GSE217426
RNA extracted from tumor biopsies of 44 patients affected by ALCL was analyzed on the nCounter system using a custom panel called VF_150921 (Nanostring Technologies).
human MICROARRAY n=44
PMID:37381763
Identified by GEO DataSets index search for Anaplastic Large Cell Lymphoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Plasma small-extracellular vesicles enriched in miR-122-5p promote disease aggressiveness in pediatric Anaplastic Large Cell Lymphoma geo:GSE209838
Emerging evidence shows that small extracellular vesicles (S-EVs) play a critical role in cancer biology. However, the role of S-EVs in pediatric anaplastic large cell lymphoma (ALCL) is still largely unknown. Small RNA sequencing of plasma S-EVs revealed a peculiar microRNA profile in pediatric ALCL patients compared to healthy donors (HD). In particular, the liver-specific miR-122-5p was more abundant in ALCL plasma S-EVs compared to HD. Elevated levels of miR-122-5p correlated with advanced stage disease and impaired hepatic function in ALCL patients.
human BULK RNA SEQ n=50
PMID:37014813
Identified by GEO DataSets index search for Anaplastic Large Cell Lymphoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Peripheral T-cell lymphomas expressing CD30 and CD15 expand the spectrum of anaplastic large cell lymphoma, ALK-negative geo:GSE115917
RNAseq of 14 samples of human primary T cell lymphoma
human BULK RNA SEQ n=14
PMID:38613165
Identified by GEO DataSets index search for Anaplastic Large Cell Lymphoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Breast implant-associated anaplastic large cell lymphoma shallow whole genome sequencing for copy number analysis and Whole exome sequencing data. ega:EGAS00001003962
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) shallow whole genome sequencing of 29 BIA-ALCL patients for copy number analysis and 24 Alk-negative ALCL samples as control cohort. 7 Whole exome sequencing BIA-ALCL samples.
human
PMID:32898861
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Anaplastic Large Cell Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Integrative molecular analysis of pediatric Anaplastic large cell lymphoma reveals subtypes with distinct immune suppression signatures. ega:EGAS00001004189
Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma accounting for 10–15% of all childhood lymphomas. While more than 90% of the ALCL cases contain ALK-rearrangement, these tumors possess significant inter-tumor molecular heterogeneity that contributes to distinct morphologic differences and clinical impact. To gain insight into the molecular heterogeneity within ALK+ ALCL, we performed whole-exome sequencing, RNA-sequencing, and methylome analysis of 42 primary pediatric ALK+ ALCL patients. Our data showed that ALK+ALCLs was subclassified into two subtypes based on ALK gene expression, methylation profiles, and somatic mutation patterns.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Anaplastic Large Cell Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
The genomic landscape of primary cutaneous anaplastic large cell lymphoma (pcALCL) ega:EGAS00001004429
Primary cutaneous anaplastic large cell lymphoma (pcALCL) is the second most common variant of cutaneous T-cell lymphoma. We subjected tumor biopsies from patients with pcALCL to whole-genome sequencing, whole-exome sequencing and RNA-sequencing to investigate genomic alterations and deregulated gene expression in the disease.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Anaplastic Large Cell Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
🔬

Clinical Trials

3
NCT01777152 PHASE_III COMPLETED
ECHELON-2 was the randomized, double-blind phase 3 comparison of frontline brentuximab vedotin plus CHP against CHOP in CD30-positive mature T-cell lymphomas, with systemic ALCL forming the principal disease population. ClinicalTrials.gov listed COMPLETED status when checked on 2026-08-04.
Show evidence (1 reference)
clinicaltrials:NCT01777152 SUPPORT Human Clinical
"This is a double-blind, randomized, multicenter, phase 3 clinical trial to compare the efficacy and safety of brentuximab vedotin in combination with CHP with the standard-of-care CHOP in patients with CD30-positive mature T-cell lymphomas."
The registry directly supports the phase, design, population, and comparison.
NCT00866047 PHASE_II COMPLETED
This single-arm phase 2 study evaluated single-agent brentuximab vedotin in relapsed or refractory systemic ALCL. ClinicalTrials.gov listed COMPLETED status when checked on 2026-08-04.
Show evidence (1 reference)
clinicaltrials:NCT00866047 SUPPORT Human Clinical
"This is a single-arm, open-label, multicenter, clinical trial to evaluate the efficacy and safety of brentuximab vedotin (SGN-35) as a single agent in patients with relapsed or refractory ALCL."
The registry directly supports the study design, agent, and relapsed/refractory ALCL population.
NCT02034981 PHASE_II COMPLETED
AcSé-crizotinib was a biology-driven multicohort phase 2 study that included an ALK-positive relapsed or refractory ALCL cohort. ClinicalTrials.gov listed COMPLETED status when checked on 2026-08-04.
Show evidence (2 references)
clinicaltrials:NCT02034981 SUPPORT Human Clinical
"This is a biology driven, trans-tumoral, multicentric phase II trial assessing the efficacy and the safety of the targeted agent crizotinib as a monotherapy in 23 cohorts of patients with identified activating molecular alterations in the crizotinib target genes."
The registry supports the umbrella design and intervention but does not name the ALCL cohort in its summary.
PMID:37549532 SUPPORT Human Clinical
"CONCLUSION: Crizotinib shows efficacy and an acceptable safety profile in ALK+ ALCL relapsed/refractory patients."
The trial publication independently confirms the ALK-positive ALCL cohort and clinical activity.
🧫

Experimental Models

1
Dominant-Negative STAT3 in Karpas 299 and SU-DHL-1 Cells CELL_LINE
Two human ALK-positive ALCL cell lines infected with an adenoviral dominant-negative STAT3 construct test whether ongoing STAT3 activity is required for tumor-cell survival and cell-cycle progression.
AdSTAT3DN infection control adenoviral infection
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Karpas 299 and SU-DHL-1 ALK-positive ALCL cell lines
Culture
Adenoviral dominant-negative STAT3 perturbation in monolayer cell culture
Publication
PMID:15184887
Pathograph links
ALK-Driven STAT3 Activation Selectively inhibits STAT3 signaling downstream of NPM-ALK.
Show evidence (1 reference)
PMID:15184887 SUPPORT In Vitro
"we further examined its biological significance in ALCL using two ALK(+) ALCL cell lines (Karpas 299 and SU-DHL-1) and an adenoviral vector that carries dominant-negative STAT3 (AdSTAT3DN)."
The experiment directly defines the cell-line perturbation model.
Findings
Dominant-negative STAT3 induced apoptosis and G1 cell-cycle arrest.
"Introduction of STAT3DN induced apoptosis and G(1) cell cycle arrest."
Show evidence (1 reference)
PMID:15184887 SUPPORT In Vitro
"Introduction of STAT3DN induced apoptosis and G(1) cell cycle arrest."
The perturbation result directly supports STAT3 dependence in these lines.
Show evidence (1 reference)
PMID:15184887 SUPPORT In Vitro
"we further examined its biological significance in ALCL using two ALK(+) ALCL cell lines (Karpas 299 and SU-DHL-1) and an adenoviral vector that carries dominant-negative STAT3 (AdSTAT3DN)."
The publication explicitly defines the two-line experimental system.
🐁

Animal Models

1
T-cell-targeted human NPM-ALK transgene Mus musculus
Mice expressing human NPM-ALK in T cells develop malignant lymphoproliferative disease after a short latency. The thymic lymphomas have an immature T-cell phenotype and often express surface CD30, while a subset of mice also develops plasma-cell neoplasms.
Malignant lymphoproliferative disease Immature T-cell thymic lymphoma Surface CD30 expression Plasma-cell neoplasms in a subset
Species
Mus musculus
Genotype
T-cell-targeted human NPM-ALK transgene
Genes
ALK hgnc:427 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns ALK (hgnc:427). hgnc:427 is a gene from the HUGO Gene Nomenclature Committee. NPM1 hgnc:7910 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns NPM1 (hgnc:7910). hgnc:7910 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:12424201 SUPPORT Model Organism
"However, after a short period of latency, all NPM-ALK Tg mice developed malignant lymphoproliferative disorders (mean survival, 18 weeks)."
The transgenic study directly establishes penetrant lymphoproliferative disease.
PMID:12424201 SUPPORT Model Organism
"NPM-ALK Tg thymic lymphomas displayed a T-cell phenotype characteristic of immature thymocytes and frequently coexpressed surface CD30. A subset of the NPM-ALK Tg mice also developed clonal B-cell plasma cell neoplasms."
The source directly supports both lymphoma phenotype and lineage-fidelity limitations.
🧮

Computational Models

1
NPM-ALK Signaling-Network Sensitivity Model KINETIC
A quantitative phenomenological ODE network uses Hill-type transfer functions and steady-state sensitivity analysis to rank control points for NPM-ALK-driven survival and proliferation. It predicts a predominant VAV1-CDC42 contribution to proliferation and RAS-MEK-ERK contribution to survival; these predictions require experimental validation.
PMID:27669408
Pathograph links
Constitutive ALK Fusion Kinase Activity Models signal flow from NPM-ALK through interacting survival and proliferation pathways.
Show evidence (1 reference)
PMID:27669408 SUPPORT Computational
"We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK"
The model explicitly starts from NPM-ALK-driven signal flow.
ALK-Driven STAT3 Activation Models JAK3-STAT3 as one control branch of the NPM-ALK network.
Show evidence (1 reference)
PMID:27669408 SUPPORT Computational
"Our results also highlight the importance of a group of interleukins together with the Janus kinase 3 (JAK3) / signal transducer and activator of transcription 3 (STAT3) signalling in the development of NPM-ALK derived ALCL."
The simulation explicitly includes and prioritizes the JAK3-STAT3 branch.
The model is literature-derived rather than patient-specific and reports relative steady-state activities, not validated clinical response predictions.
Show evidence (1 reference)
PMID:27669408 SUPPORT Computational
"We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK to identify therapeutically targetable nodes through which it may be possible to regain control of the tumourigenic process."
The publication directly defines the computational scope and purpose.
{ }

Source YAML

click to show 
name: Anaplastic Large Cell Lymphoma
creation_date: "2026-04-13T05:41:42Z"
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 comprising systemic ALK-positive, systemic ALK-negative, and
  primary cutaneous disease. Breast implant-associated ALCL is represented in
  its own MONDO:0850112 disorder entry because it is an exposure-associated
  entity outside the MONDO:0020325 descendant branch.
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 here into systemic ALK-positive, systemic ALK-negative, and
    primary cutaneous 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: >-
      The review provides the shared disease-family definition used by this
      entry.
- name: International consensus classification framework
  definition_type: OTHER
  description: >-
    The entry follows the modern mature-lymphoid-neoplasm framework in which
    genomic findings refine entity definitions and diagnostic criteria.
  scope: Classification context for mature T-cell lymphoma entities
  evidence:
  - reference: PMID:35653592
    reference_title: "The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Major findings from recent genomic studies have impacted the conceptual
      framework and diagnostic criteria for many disease entities.
    explanation: >-
      The International Consensus Classification provides the genomic and
      diagnostic framework used to keep mature lymphoma entities distinct.
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:
- Mature T-cell and NK-cell non-Hodgkin lymphoma
prevalence:
- population: General population
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.25
  notes: >-
    A recent clinical literature review reports an annual incidence estimate of
    0.25 cases per 100,000 people; this is an incidence rate, not point
    prevalence.
  evidence:
  - reference: PMID:39551572
    reference_title: "Anaplastic lymphoma kinase-negative primary systemic anaplastic large cell lymphoma mimicking a ruptured epidermal cyst of the scalp: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The incidence of anaplastic large cell lymphoma is 0.25 cases per 100,000 people.
    explanation: The literature review supplies the explicit population incidence estimate.
has_subtypes:
- name: Systemic ALK-Positive
  display_name: Systemic ALK-Positive Anaplastic Large Cell Lymphoma
  description: >-
    Systemic ALCL defined by an ALK fusion oncogene, often presenting at
    advanced stage in children, adolescents, and younger adults.
  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: >-
      The review defines the subtype by its ALK translocation-derived 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: >-
      The review supports the younger adult distribution and frequent
      advanced-stage presentation.
  - reference: PMID:36907641
    reference_title: Diagnosis and management of ALK-positive anaplastic large cell lymphoma in children and adolescents.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most children and adolescents present in advanced stages, often with
      extranodal disease and B symptoms.
    explanation: >-
      The pediatric review directly supports the age-specific advanced-stage,
      extranodal, and constitutional presentation.
- name: Systemic ALK-Negative
  display_name: Systemic ALK-Negative Anaplastic Large Cell Lymphoma
  description: >-
    Systemic ALCL lacking ALK rearrangement and containing genetically distinct
    DUSP22-rearranged, TP63-rearranged, and two triple-negative molecular groups
    (TN-I and TN-II).
  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: >-
      The multicenter study supports a systemic ALK-negative subtype with
      clinically meaningful internal 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: >-
      The study defines two recurrent genomic subgroups within ALK-negative
      disease.
  - reference: PMID:41329859
    reference_title: "Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We introduce an integrated molecular classification that preserves
      currently diagnosed ALCL entities but identifies 4 molecularly distinct
      ALK- ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II).
    explanation: >-
      The large molecular-profiling study refines triple-negative ALK-negative
      disease into TN-I and TN-II groups.
- name: Primary Cutaneous
  display_name: Primary Cutaneous Anaplastic Large Cell Lymphoma
  description: >-
    A primary cutaneous CD30-positive lymphoproliferative disorder produced by
    skin-homing malignant T cells and requiring separation from systemic ALCL
    with secondary skin involvement.
  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: >-
      The genomic study directly supports the skin-homing malignant T-cell
      boundary.
  - reference: PMID:21841159
    reference_title: "EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs)
      are the second most common form of cutaneous T-cell lymphomas and include
      lymphomatoid papulosis and primary cutaneous anaplastic large-cell
      lymphoma.
    explanation: >-
      International consensus places primary cutaneous ALCL within the
      cutaneous CD30-positive lymphoproliferative-disorder spectrum.
mechanistic_hypotheses:
- hypothesis_group_id: alk_fusion_stat3_model
  hypothesis_label: ALK fusion to STAT3 survival model
  status: CANONICAL
  description: >-
    Constitutive ALK fusion kinase activity activates STAT3, which drives
    anti-apoptotic and immune-evasion programs supporting the ALK-positive
    malignant clone.
  applies_to_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: >-
      The study directly establishes the central ALK-to-STAT3 link.
- hypothesis_group_id: systemic_alk_negative_jak_stat_model
  hypothesis_label: JAK/STAT-driven systemic ALK-negative subset
  status: EMERGING
  description: >-
    In a subset of systemic ALK-negative ALCL, somatic JAK1 and STAT3
    alterations replace ALK fusion signaling as a route to constitutive
    JAK/STAT activation.
  applies_to_subtypes:
  - Systemic ALK-Negative
  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: >-
      The review supports a mutation-driven JAK/STAT branch in systemic
      ALK-negative disease.
- hypothesis_group_id: alcl_type_i_type_ii_molecular_model
  hypothesis_label: pSTAT3-defined type I and epigenetic type II molecular model
  status: EMERGING
  description: >-
    Integrated profiling separates ALCL into pSTAT3-positive type I disease,
    including ALK-positive and TN-I tumors, and pSTAT3-negative type II disease,
    including DUSP22-rearranged, TP63-rearranged, and TN-II tumors. Type II
    disease is enriched for non-tyrosine-kinase and epigenetic-regulator programs.
  applies_to_subtypes:
  - Systemic ALK-Positive
  - Systemic ALK-Negative
  evidence:
  - reference: PMID:41329859
    reference_title: "Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs
      (TN-I); type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements
      and the remaining triple-negative ALCLs (TN-II).
    explanation: The large molecular-profiling study directly defines the two-type model and its constituent groups.
- hypothesis_group_id: primary_cutaneous_pi3k_mapk_model
  hypothesis_label: PI3K/AKT and MAPK signaling in primary cutaneous ALCL
  status: EMERGING
  description: >-
    Recurrent genomic and transcriptomic alterations converge on
    proliferation-promoting PI3K/AKT, MAPK, and G-protein pathways in primary
    cutaneous ALCL.
  applies_to_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: >-
      Integrated genomic and transcriptomic analysis supports the signaling
      model while leaving individual driver sufficiency unresolved.
pathophysiology:
- name: Constitutive ALK Fusion Kinase Activity
  description: >-
    ALK rearrangement, most often NPM1::ALK, creates a constitutively active
    fusion tyrosine kinase in systemic ALK-positive ALCL.
  genes:
  - preferred_term: ALK
    term:
      id: hgnc:427
      label: ALK
  - preferred_term: NPM1
    term:
      id: hgnc:7910
      label: NPM1
  molecular_functions:
  - preferred_term: protein tyrosine kinase activity
    modifier: INCREASED
    term:
      id: GO:0004713
      label: protein tyrosine kinase activity
  subtypes:
  - Systemic ALK-Positive
  evidence:
  - reference: PMID:37655119
    reference_title: ALK-positive anaplastic large cell lymphoma in adults.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most frequent translocation is t(2;5) which combines ALK with NPM1.
    explanation: >-
      The review identifies NPM1 as the most frequent ALK fusion partner.
  - 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 quantifies the frequency of ALK rearrangement in systemic
      ALCL and identifies NPM1 as the most common fusion partner.
  - 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: >-
      The anaplastic lymphoma kinase (ALK) gene is characteristically
      translocated in Anaplastic Large Cell Lymphomas (ALCL) and the
      juxtaposition of the ALK gene to multiple partners results in its
      constitutive protein tyrosine kinase activity.
    explanation: >-
      The experimental study directly supports constitutive kinase activity of
      ALK fusions.
  downstream:
  - target: ALK-Driven STAT3 Activation
    description: Activated ALK constitutively phosphorylates STAT3.
    causal_link_type: DIRECT
    hypothesis_groups:
    - alk_fusion_stat3_model
    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: >-
        Activated ALK directly induces constitutive STAT3 phosphorylation.
- name: ALK-Driven STAT3 Activation
  description: >-
    Constitutive STAT3 activation is the central transcriptional signaling hub
    downstream of the ALK fusion kinase.
  genes:
  - preferred_term: ALK
    term:
      id: hgnc:427
      label: ALK
  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-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: >-
      The study directly supports constitutive STAT3 activation downstream of
      activated ALK.
  downstream:
  - target: BCL2L1-Mediated Apoptosis Resistance
    description: STAT3 enhances transcription of the anti-apoptotic BCL2L1 product Bcl-xL.
    causal_link_type: DIRECT
    hypothesis_groups:
    - alk_fusion_stat3_model
    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: >-
        NPM-ALK expression caused enhanced Bcl-x(L) transcription, largely
        mediated by Stat3.
      explanation: >-
        The study directly links NPM-ALK/STAT3 activity to enhanced Bcl-xL
        transcription.
  - target: PD-L1-Mediated Immune Evasion
    description: STAT3 directly induces expression of CD274/PD-L1.
    causal_link_type: DIRECT
    hypothesis_groups:
    - alk_fusion_stat3_model
    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: >-
        The study directly supports STAT3-dependent induction of PD-L1.
- name: BCL2L1-Mediated Apoptosis Resistance
  description: >-
    STAT3-dependent BCL2L1 transcription protects ALK-positive tumor cells from
    cell death and supports 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: >-
      Increased expression of Bcl-x(L) provided sufficient anti-apoptotic
      signals to protect cells from treatment with specific inhibitors of the
      Jaks/Stat pathway or the Brc-Abl kinase.
    explanation: >-
      The experiment directly supports Bcl-xL-mediated apoptosis resistance.
  downstream:
  - target: Systemic CD30-Positive Malignant T-Cell Expansion
    description: Apoptosis resistance permits survival and outgrowth of the malignant clone.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - survival selection and accumulation of ALK-positive tumor cells
    hypothesis_groups:
    - alk_fusion_stat3_model
    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: >-
        The authors directly connect STAT3-mediated anti-apoptotic signaling to
        ALK-positive tumor-cell outgrowth.
- name: PD-L1-Mediated Immune Evasion
  conforms_to: "immune_checkpoint_blockade#Adaptive Immune Resistance"
  description: >-
    STAT3-dependent CD274/PD-L1 expression adds an immunosuppressive program to
    ALK-positive malignant T cells.
  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: >-
      These findings identify an additional cell-transforming property of
      NPM/ALK and describe a direct link between an oncoprotein and an
      immunosuppressive cell-surface protein.
    explanation: >-
      The study characterizes ALK-induced PD-L1 as an immunosuppressive
      cell-surface program.
  downstream:
  - target: Systemic CD30-Positive Malignant T-Cell Expansion
    description: PD-L1-mediated immune suppression permits persistence and outgrowth of the malignant clone.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced antitumor T-cell activity and immune clearance
    hypothesis_groups:
    - alk_fusion_stat3_model
    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: >-
        These findings identify an additional cell-transforming property of
        NPM/ALK and describe a direct link between an oncoprotein and an
        immunosuppressive cell-surface protein.
      explanation: The study supports the immune-evasion program; reduced immune clearance is represented as an explicit intermediate.
- name: JAK/STAT3 Activation in Systemic ALK-Negative ALCL
  description: >-
    Somatic JAK1 and STAT3 mutations activate JAK/STAT signaling in a subset of
    systemic ALK-negative ALCL, excluding the DUSP22-rearranged subset in the
    cited review.
  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
  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: >-
      The review directly links JAK1/STAT3 mutations to pathway activation in a
      systemic ALK-negative subset.
  downstream:
  - target: Systemic CD30-Positive Malignant T-Cell Expansion
    description: Constitutive JAK/STAT signaling supports malignant-clone expansion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - JAK/STAT transcriptional programs for tumor-cell survival and proliferation
    hypothesis_groups:
    - systemic_alk_negative_jak_stat_model
    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: >-
        The review supports mutation-driven pathway activation; the
        transcriptional survival and proliferation intermediates are modeled
        explicitly as omitted.
- name: EZH2-Associated Epigenetic Program in Type II ALK-Negative ALCL
  description: >-
    DUSP22-rearranged, TP63-rearranged, and TN-II ALK-negative tumors fall within
    a pSTAT3-negative type II molecular group enriched for non-tyrosine-kinase
    pathways and epigenetic regulators, particularly EZH2, with EZH2 and H3K27me3
    overexpression demonstrated immunohistochemically.
  genes:
  - preferred_term: EZH2
    term:
      id: hgnc:3527
      label: EZH2
  molecular_functions:
  - preferred_term: histone H3K27 methyltransferase activity
    modifier: INCREASED
    term:
      id: GO:0046976
      label: histone H3K27 methyltransferase activity
  subtypes:
  - Systemic ALK-Negative
  evidence:
  - reference: PMID:41329859
    reference_title: "Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched
      for non-tyrosine kinase pathways, particularly epigenetic regulators such as
      EZH2. Immunohistochemistry showed overexpression of EZH2 and its
      trimethylated substrate H3K27.
    explanation: The human profiling and immunohistochemistry directly support the type II epigenetic program and EZH2/H3K27me3 overexpression.
  downstream:
  - target: Systemic CD30-Positive Malignant T-Cell Expansion
    description: Epigenetic-regulator activity is modeled as supporting malignant-cell transcriptional state and expansion.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - alcl_type_i_type_ii_molecular_model
    evidence:
    - reference: PMID:41329859
      reference_title: "Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Type I ALCLs were enriched for JAK-STAT3, whereas type II ALCLs were enriched
        for non-tyrosine kinase pathways, particularly epigenetic regulators such as
        EZH2.
      explanation: The cohort supports pathway enrichment, while the causal transcriptional intermediates remain unresolved.
- name: Systemic CD30-Positive Malignant T-Cell Expansion
  description: >-
    Systemic ALCL consists of an expanding CD30-positive malignant T-cell clone;
    ALK fusion signaling and mutation-driven JAK/STAT signaling are distinct
    upstream routes into this shared disease compartment.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  cell_types:
  - preferred_term: mature T cell
    term:
      id: CL:0002419
      label: mature T cell
  subtypes:
  - Systemic ALK-Positive
  - Systemic ALK-Negative
  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: >-
      The review supports a shared CD30-positive mature T-cell malignant
      compartment across systemic molecular subtypes.
  downstream:
  - target: Advanced-Stage Systemic Presentation
    description: Systemic clonal expansion can produce disseminated advanced-stage disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - alk_fusion_stat3_model
    evidence:
    - 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: >-
        The review directly supports advanced-stage presentation in most
        systemic ALK-positive cases; the dissemination intermediates are not
        resolved by the cited abstract.
  - target: Systemic Lymphadenopathy
    description: Systemic malignant-cell expansion commonly produces enlarged lymph nodes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39551572
      reference_title: "Anaplastic lymphoma kinase-negative primary systemic anaplastic large cell lymphoma mimicking a ruptured epidermal cyst of the scalp: a case report and literature review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It usually causes lymphadenopathy and B symptoms; however, diverse
        cutaneous manifestations can also be observed.
      explanation: >-
        The review directly identifies lymphadenopathy as a usual systemic ALCL
        manifestation; intervening anatomic steps are not specified.
  - target: Fever
    description: Systemic lymphoma can produce fever as part of the B-symptom complex.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32311892
      reference_title: "[Clinical characteristics and prognostic factors of 40 cases of primary systemic anaplastic large cell lymphoma]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        25 patients (62.5%) had B symptoms, such as fever, emaciation and night
        sweat.
      explanation: The systemic cohort explicitly includes fever among B symptoms.
  - target: Night Sweats
    description: Systemic lymphoma can produce night sweats as part of the B-symptom complex.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32311892
      reference_title: "[Clinical characteristics and prognostic factors of 40 cases of primary systemic anaplastic large cell lymphoma]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        25 patients (62.5%) had B symptoms, such as fever, emaciation and night
        sweat.
      explanation: The systemic cohort explicitly includes night sweats among B symptoms.
  - target: Weight Loss
    description: Systemic lymphoma can produce weight loss as part of the B-symptom complex.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32311892
      reference_title: "[Clinical characteristics and prognostic factors of 40 cases of primary systemic anaplastic large cell lymphoma]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        25 patients (62.5%) had B symptoms, such as fever, emaciation and night
        sweat.
      explanation: Emaciation supports constitutional weight loss, although the cohort does not define a weight threshold.
  - target: Extranodal Disease
    description: Systemic clonal dissemination can involve sites outside lymph nodes.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36907641
      reference_title: Diagnosis and management of ALK-positive anaplastic large cell lymphoma in children and adolescents.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Most children and adolescents present in advanced stages, often with
        extranodal disease and B symptoms.
      explanation: >-
        The pediatric review directly supports extranodal disease in systemic
        ALK-positive ALCL; the dissemination route is not resolved.
- name: PI3K-AKT and MAPK Signaling Upregulation in Primary Cutaneous ALCL
  description: >-
    Primary cutaneous ALCL shows transcriptomic upregulation of PI3K/AKT,
    MAPK, and G-protein signal-transduction routes without assigning a single
    universal causal gene.
  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: >-
      Integrated transcriptome analysis directly supports pathway-level
      upregulation.
  downstream:
  - target: Skin-Homing CD30-Positive Malignant T-Cell Expansion
    description: Proliferation-promoting signaling supports the skin-homing malignant clone.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered proliferation and survival programs in skin-homing malignant T cells
    hypothesis_groups:
    - primary_cutaneous_pi3k_mapk_model
    evidence:
    - reference: PMID:34382383
      reference_title: Whole-genome profiling of primary cutaneous anaplastic large cell lymphoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our molecular findings suggest that inhibition of
        proliferation-promoting pathways altered in pcALCL (particularly
        PI-3-K/AKT signaling) should be explored as potential alternative
        therapy for patients with this lymphoma
      explanation: >-
        The genomic study describes the pathways as proliferation-promoting;
        the cellular intermediates are intentionally represented as omitted.
- name: Skin-Homing CD30-Positive Malignant T-Cell Expansion
  description: >-
    The primary cutaneous branch is an expansion of skin-homing CD30-positive
    malignant T cells that produces localized or multifocal cutaneous lesions
    and can extend to regional lymph nodes.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  cell_types:
  - preferred_term: mature T cell
    term:
      id: CL:0002419
      label: mature T cell
  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: >-
      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: >-
      The study directly defines pcALCL as a skin-homing CD30-positive
      malignant T-cell neoplasm.
  downstream:
  - target: Ulcerating Skin Nodules
    description: Skin-localized malignant-cell expansion produces nodular lesions that may ulcerate.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - dermal tumor-cell accumulation and tissue injury
    hypothesis_groups:
    - primary_cutaneous_pi3k_mapk_model
    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: >-
        The report directly supports nodular and ulcerating manifestations of
        the cutaneous malignant process.
  - target: Regional Lymph Node Involvement
    description: Cutaneous disease can disseminate to draining regional lymph nodes.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - lymphatic dissemination from cutaneous tumor sites
    hypothesis_groups:
    - primary_cutaneous_pi3k_mapk_model
    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: >-
        The report directly supports regional-node dissemination.
histopathology:
- name: Hallmark Cells
  finding_term:
    preferred_term: Hallmark Cell
  description: >-
    ALCL includes characteristic hallmark cells with strong CD30 expression and
    variable loss of T-cell antigens.
  diagnostic: true
  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: >-
      The clinicopathologic series directly supports the shared hallmark-cell
      morphology and immunophenotype.
- name: Nuclear Pleomorphism
  finding_term:
    preferred_term: Nuclear Pleomorphism
    term:
      id: NCIT:C38721
      label: Nuclear Pleomorphism
  description: Large neoplastic cells show pleomorphic nuclear morphology across ALCL subtypes.
  diagnostic: true
  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: The clinicopathologic series directly supports pleomorphic tumor-cell morphology.
phenotypes:
- category: General
  name: Advanced-Stage Systemic Presentation
  subtype: Systemic ALK-Positive
  frequency: FREQUENT
  description: >-
    Systemic ALK-positive ALCL commonly presents at advanced stage.
  phenotype_term:
    preferred_term: Advanced-stage systemic lymphoma presentation
  evidence:
  - 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: >-
      "Most patients" supports placement in the FREQUENT band without assigning
      a more precise prevalence.
- category: Cutaneous
  name: Ulcerating Skin Nodules
  subtype: Primary Cutaneous
  description: >-
    Primary cutaneous ALCL may present with solitary or multifocal nodules that
    ulcerate, regress, 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: >-
      The report supports the morphology and behavior of the cutaneous lesions;
      no population frequency is inferred from the case-based source.
- category: Lymphatic
  name: Regional Lymph Node Involvement
  subtype: Primary Cutaneous
  description: >-
    Primary cutaneous ALCL can disseminate beyond skin 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: >-
      The report directly supports regional lymph-node involvement without
      justifying a numerical frequency.
- category: Lymphatic
  name: Systemic Lymphadenopathy
  description: Systemic ALCL usually causes lymph-node enlargement.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:39551572
    reference_title: "Anaplastic lymphoma kinase-negative primary systemic anaplastic large cell lymphoma mimicking a ruptured epidermal cyst of the scalp: a case report and literature review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It usually causes lymphadenopathy and B symptoms; however, diverse
      cutaneous manifestations can also be observed.
    explanation: The review directly identifies lymphadenopathy as a usual manifestation.
- category: Constitutional
  name: Fever
  description: Fever may occur within the systemic B-symptom complex.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:32311892
    reference_title: "[Clinical characteristics and prognostic factors of 40 cases of primary systemic anaplastic large cell lymphoma]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      25 patients (62.5%) had B symptoms, such as fever, emaciation and night
      sweat.
    explanation: The retrospective systemic cohort explicitly includes fever.
- category: Constitutional
  name: Night Sweats
  description: Night sweats may occur within the systemic B-symptom complex.
  phenotype_term:
    preferred_term: Night sweats
    term:
      id: HP:0030166
      label: Night sweats
  evidence:
  - reference: PMID:32311892
    reference_title: "[Clinical characteristics and prognostic factors of 40 cases of primary systemic anaplastic large cell lymphoma]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      25 patients (62.5%) had B symptoms, such as fever, emaciation and night
      sweat.
    explanation: The retrospective systemic cohort explicitly includes night sweats.
- category: Constitutional
  name: Weight Loss
  description: Constitutional weight loss may occur within the systemic B-symptom complex.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:32311892
    reference_title: "[Clinical characteristics and prognostic factors of 40 cases of primary systemic anaplastic large cell lymphoma]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      25 patients (62.5%) had B symptoms, such as fever, emaciation and night
      sweat.
    explanation: Emaciation supports weight loss, but the cohort gives no formal weight threshold.
- category: General
  name: Extranodal Disease
  description: Systemic ALCL can involve sites outside lymph nodes, especially in pediatric ALK-positive disease.
  phenotype_term:
    preferred_term: Extranodal disease
  evidence:
  - reference: PMID:36907641
    reference_title: Diagnosis and management of ALK-positive anaplastic large cell lymphoma in children and adolescents.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most children and adolescents present in advanced stages, often with
      extranodal disease and B symptoms.
    explanation: The pediatric review directly supports extranodal presentation.
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 ALCL-family biomarker and the target
    recognized by brentuximab vedotin.
  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: >-
      The review supports strong CD30 expression as the unifying family
      biomarker.
- 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 an 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: >-
      The pathology study directly supports ALK immunohistochemistry as a
      rearrangement surrogate.
- name: Phosphorylated STAT3 Y705 Expression
  subtype: Systemic ALK-Negative
  biomarker_term:
    preferred_term: phosphorylated STAT3 Y705 expression
  presence: present in type I and absent in type II molecular ALCL
  notes: >-
    pSTAT3-Y705 immunohistochemistry discriminated two overarching molecular
    types with high predictive accuracy in the LLMPP cohort; it is a classifier,
    not by itself a disease-defining genetic alteration.
  evidence:
  - reference: PMID:41329859
    reference_title: "Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNA sequencing with unsupervised gene expression profiling in 393 patients
      identified 2 main molecular types of ALCL that could be predicted with 91%
      accuracy based on the presence (type I) or absence (type II) of
      phosphorylated STAT3Y705 expression.
    explanation: The cohort directly supports pSTAT3-Y705 as a molecular-type classifier.
genetic:
- name: ALK Rearrangement
  subtype: Systemic ALK-Positive
  association: Defining somatic ALK fusion driver
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: ALK
    term:
      id: hgnc:427
      label: ALK
  notes: >-
    ALK rearrangement defines systemic ALK-positive ALCL and creates a
    constitutively active fusion kinase.
  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: >-
      The review directly identifies the defining somatic ALK translocation.
- name: NPM1 Fusion Partner
  subtype: Systemic ALK-Positive
  association: Recurrent partner in the defining somatic NPM1::ALK fusion driver
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: NPM1
    term:
      id: hgnc:7910
      label: NPM1
  notes: >-
    NPM1 is the most frequent fusion partner of ALK in systemic ALK-positive
    ALCL.
  evidence:
  - reference: PMID:37655119
    reference_title: ALK-positive anaplastic large cell lymphoma in adults.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most frequent translocation is t(2;5) which combines ALK with NPM1.
    explanation: >-
      The review directly identifies NPM1 as the most frequent ALK fusion
      partner.
- name: DUSP22 Rearrangement
  subtype: Systemic ALK-Negative
  association: Molecular subgroup and cohort-dependent prognostic biomarker
  relationship_type: BIOMARKER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: DUSP22
    term:
      id: hgnc:16077
      label: DUSP22
  notes: >-
    DUSP22 rearrangement identifies a recurrent ALK-negative subgroup, but its
    favorable prognostic association has not reproduced consistently across
    cohorts. It is represented as a biomarker rather than forced into an
    unsupported causal edge.
  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: >-
      The study establishes DUSP22 rearrangement as a recurrent molecular
      subgroup.
  - 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: >-
      Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for
      DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases
      lacking all 3 genetic markers (P < .0001).
    explanation: >-
      This initial multicenter cohort supports a favorable outcome association,
      which is retained as one cohort-specific estimate.
  - reference: PMID:41329859
    reference_title: "Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year
      overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative
      ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%).
    explanation: The largest integrated molecular cohort independently supports a favorable DUSP22-associated survival estimate.
  - reference: PMID:36453104
    reference_title: DUSP22 rearrangement is associated with a distinctive immunophenotype but not outcome in patients with systemic ALK-negative anaplastic large cell lymphoma.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, in this cohort DUSP22-R was not associated with a better clinical
      outcome.
    explanation: >-
      A later independent cohort directly contradicts a general
      favorable-prognosis interpretation, so prognostic use is explicitly
      cohort-dependent.
- name: TP63 Rearrangement
  subtype: Systemic ALK-Negative
  association: Molecular subgroup and adverse prognostic biomarker
  relationship_type: BIOMARKER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: TP63
    term:
      id: hgnc:15979
      label: TP63
  notes: >-
    TP63 rearrangement identifies a smaller ALK-negative subgroup associated
    with poor outcome; it is not asserted as a sufficient causal driver here.
  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: >-
      The study establishes TP63 rearrangement as a recurrent molecular subgroup.
  - 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: >-
      Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for
      DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases
      lacking all 3 genetic markers (P < .0001).
    explanation: >-
      The outcome association supports adverse prognostic-biomarker
      classification.
  - reference: PMID:41329859
    reference_title: "Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year
      overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative
      ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%).
    explanation: The large molecular cohort independently supports the adverse TP63-rearranged outcome association.
- name: JAK1 Mutation
  subtype: Systemic ALK-Negative
  association: Somatic JAK/STAT-pathway driver alteration
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: JAK1
    term:
      id: hgnc:6190
      label: JAK1
  notes: >-
    JAK1 mutation is one route to constitutive JAK/STAT signaling in a subset of
    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: >-
      The review supports JAK1 mutation as a somatic pathway driver in the
      defined subset.
- name: STAT3 Mutation
  subtype: Systemic ALK-Negative
  association: Somatic JAK/STAT-pathway driver alteration
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  notes: >-
    STAT3 mutation is another route to constitutive JAK/STAT signaling in a
    subset of 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: >-
      The review supports STAT3 mutation as a somatic pathway driver in the
      defined subset.
diagnosis:
- name: Tissue Morphology and Immunohistochemistry
  description: >-
    Diagnosis relies on hallmark-cell morphology plus immunohistochemistry,
    including CD30 and ALK, while excluding other anaplastic malignancies.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      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: >-
      The clinicopathologic study directly supports the morphology-plus-IHC
      diagnostic workflow.
- name: Molecular Genetic Subtyping
  description: >-
    ALK immunohistochemistry and ancillary markers guide molecular subtyping;
    rearrangement testing can resolve ALK, DUSP22, and TP63 groups.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  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: >-
      The pathology study directly supports ancillary-marker-based genetic
      subtyping.
  - reference: PMID:41329859
    reference_title: "Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RNA sequencing with unsupervised gene expression profiling in 393 patients
      identified 2 main molecular types of ALCL that could be predicted with 91%
      accuracy based on the presence (type I) or absence (type II) of
      phosphorylated STAT3Y705 expression.
    explanation: The molecular cohort directly supports phospho-STAT3 Y705 as a subtyping marker.
- name: Clinicopathologic Confirmation of Primary Cutaneous Disease
  description: >-
    Primary cutaneous ALCL must be interpreted within the cutaneous CD30-positive
    lymphoproliferative-disorder spectrum and correlated with clinical staging
    to exclude systemic disease involving skin.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:21841159
    reference_title: "EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs)
      are the second most common form of cutaneous T-cell lymphomas and include
      lymphomatoid papulosis and primary cutaneous anaplastic large-cell
      lymphoma.
    explanation: >-
      The consensus establishes the relevant disease spectrum; the cached
      abstract does not enumerate the entire staging workflow.
differential_diagnoses:
- name: Classic Hodgkin Lymphoma
  description: >-
    Hodgkin lymphoma can show overlapping anaplastic morphology and CD30
    expression.
  distinguishing_features:
  - Integrate lineage markers, PAX5, CD15, ALK, and the broader immunophenotypic pattern.
  - Confirm that the morphology and clinical distribution fit an ALCL entity.
  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: >-
      However, other entities such as diffuse large B-cell lymphoma, peripheral
      T-cell lymphoma, Hodgkin lymphoma, and undifferentiated carcinoma can also
      show similar anaplastic features.
    explanation: >-
      The clinicopathologic study explicitly includes Hodgkin lymphoma among
      mimics with similar anaplastic features.
- name: Peripheral T-Cell Lymphoma, Not Otherwise Specified
  description: >-
    Other peripheral T-cell lymphomas can show anaplastic cytology and variable
    CD30 expression.
  distinguishing_features:
  - Require the coherent ALCL hallmark-cell and strong diffuse CD30 phenotype.
  - Use ALK and ancillary molecular subgrouping where appropriate.
  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: >-
      However, other entities such as diffuse large B-cell lymphoma, peripheral
      T-cell lymphoma, Hodgkin lymphoma, and undifferentiated carcinoma can also
      show similar anaplastic features.
    explanation: >-
      The study explicitly includes peripheral T-cell lymphoma among the
      anaplastic morphologic mimics.
- name: Diffuse Large B-Cell Lymphoma
  description: >-
    Diffuse large B-cell lymphoma can resemble ALCL morphologically.
  distinguishing_features:
  - Establish B-cell versus T-cell lineage with an appropriate immunohistochemical panel.
  - Interpret CD30 in the full lineage and molecular context.
  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: >-
      However, other entities such as diffuse large B-cell lymphoma, peripheral
      T-cell lymphoma, Hodgkin lymphoma, and undifferentiated carcinoma can also
      show similar anaplastic features.
    explanation: >-
      The study explicitly includes diffuse large B-cell lymphoma among the
      morphologic mimics.
- name: Undifferentiated Carcinoma
  description: >-
    Undifferentiated carcinoma can mimic the large pleomorphic morphology of
    ALCL.
  distinguishing_features:
  - Use leukocyte, epithelial, and lineage markers to establish tumor origin.
  - Retain CD30 in the initial panel when leukocyte common antigen is negative.
  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: >-
      However, other entities such as diffuse large B-cell lymphoma, peripheral
      T-cell lymphoma, Hodgkin lymphoma, and undifferentiated carcinoma can also
      show similar anaplastic features.
    explanation: >-
      The study explicitly includes undifferentiated carcinoma among the
      anaplastic morphologic mimics.
- name: Lymphomatoid Papulosis
  description: >-
    Lymphomatoid papulosis shares the primary cutaneous CD30-positive
    lymphoproliferative-disorder spectrum with primary cutaneous ALCL.
  distinguishing_features:
  - Correlate morphology with the longitudinal lesion pattern and clinical distribution.
  - Exclude systemic ALCL before assigning a primary cutaneous diagnosis.
  evidence:
  - reference: PMID:21841159
    reference_title: "EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs)
      are the second most common form of cutaneous T-cell lymphomas and include
      lymphomatoid papulosis and primary cutaneous anaplastic large-cell
      lymphoma.
    explanation: >-
      The consensus directly establishes the close classification boundary;
      the cached abstract does not enumerate all distinguishing clinical
      criteria.
treatments:
- name: CHOP-Based Anthracycline Chemotherapy
  action_category: THERAPEUTIC
  description: >-
    CHOP or CHOEP has been a systemic treatment backbone, especially for
    ALK-positive disease.
  context: Systemic ALCL
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  regimen_term:
    preferred_term: CHOP regimen
    term:
      id: NCIT:C9549
      label: CHOP Regimen
  target_mechanisms:
  - target: Systemic CD30-Positive Malignant T-Cell Expansion
    treatment_effect: INHIBITS
    description: >-
      Multiagent cytotoxic therapy reduces the proliferating systemic malignant
      T-cell compartment.
    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: >-
        The review supports use of cytotoxic combination therapy against
        systemic ALK-positive disease; it does not isolate one graph-node
        mechanism.
  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: >-
      The review directly supports CHOP/CHOEP use in systemic ALK-positive ALCL.
- name: Brentuximab Vedotin Plus CHP
  action_category: THERAPEUTIC
  description: >-
    Frontline brentuximab vedotin plus cyclophosphamide, doxorubicin, and
    prednisone improves progression-free and overall survival over CHOP in
    previously untreated CD30-positive peripheral T-cell lymphomas, with the
    trial population targeted to include 75% systemic ALCL.
  context: Previously untreated systemic ALCL
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: brentuximab vedotin
      term:
        id: NCIT:C66944
        label: Brentuximab Vedotin
    - preferred_term: cyclophosphamide
      term:
        id: CHEBI:4027
        label: cyclophosphamide
    - preferred_term: doxorubicin
      term:
        id: CHEBI:28748
        label: doxorubicin
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  regimen_term:
    preferred_term: CHP-Brentuximab Vedotin Regimen
    term:
      id: NCIT:C159558
      label: CHP-Brentuximab Vedotin Regimen
  target_mechanisms:
  - target: Systemic CD30-Positive Malignant T-Cell Expansion
    treatment_effect: INHIBITS
    description: >-
      The anti-CD30 conjugate delivers an antimitotic payload to the
      CD30-positive malignant-cell compartment; CHP supplies complementary
      cytotoxic activity.
    evidence:
    - reference: PMID:29279550
      reference_title: "Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        For targeted therapies, an anti-CD30 monoclonal antibody linked to a
        synthetic antimitotic agent (brentuximab vedotin) and ALK inhibitors
        (crizotinib, alectinib, and ceritinib) are being used in clinical
        settings.
      explanation: >-
        The review directly supports CD30-directed delivery of an antimitotic
        payload rather than an incorrect ALK-STAT3 target assignment.
  evidence:
  - reference: PMID:30522922
    reference_title: "Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      METHODS: ECHELON-2 is a double-blind, double-dummy, randomised,
      placebo-controlled, active-comparator phase 3 study. Eligible adults from
      132 sites in 17 countries with previously untreated CD30-positive
      peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large
      cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP
      for six or eight 21-day cycles.
    explanation: >-
      The phase 3 design directly establishes the intended systemic-ALCL-rich
      frontline population and randomized comparator.
  - reference: PMID:30522922
    reference_title: "Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Median progression-free survival was 48·2 months (95% CI 35·2-not
      evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP
      group
    explanation: >-
      The randomized trial directly supports improved progression-free survival
      with A+CHP.
  - reference: PMID:40750774
    reference_title: "Brentuximab vedotin plus chemotherapy for the treatment of front-line systemic anaplastic large cell lymphoma: subgroup analysis of the ECHELON-2 study at 5 years' follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      median PFS per investigator was not reached in the A + CHP arm and was
      54.2 months in the CHOP arm, with estimated 5-year PFS rates of 61% versus
      48%, respectively
    explanation: >-
      The ALCL-specific five-year analysis directly supports durable PFS benefit
      in the systemic ALCL subgroup.
- name: Single-Agent Brentuximab Vedotin
  action_category: THERAPEUTIC
  description: >-
    Single-agent brentuximab vedotin can produce durable remissions in relapsed
    or refractory systemic ALCL.
  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
  target_mechanisms:
  - target: Systemic CD30-Positive Malignant T-Cell Expansion
    treatment_effect: INHIBITS
    description: >-
      Brentuximab vedotin delivers an antimitotic payload to CD30-positive
      malignant cells.
    evidence:
    - reference: PMID:29279550
      reference_title: "Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        For targeted therapies, an anti-CD30 monoclonal antibody linked to a
        synthetic antimitotic agent (brentuximab vedotin) and ALK inhibitors
        (crizotinib, alectinib, and ceritinib) are being used in clinical
        settings.
      explanation: >-
        The review directly supports the CD30-directed antimitotic mechanism.
  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: >-
      The phase 2 follow-up directly supports durable remissions in relapsed or
      refractory systemic ALCL.
- name: Crizotinib
  action_category: THERAPEUTIC
  description: >-
    Crizotinib is an ALK inhibitor with clinical activity in relapsed or
    refractory systemic ALK-positive ALCL.
  context: Relapsed or refractory systemic ALK-positive ALCL
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: crizotinib
      term:
        id: CHEBI:64310
        label: crizotinib
  target_mechanisms:
  - target: Constitutive ALK Fusion Kinase Activity
    treatment_effect: INHIBITS
    description: >-
      Crizotinib directly targets ALK fusion kinase activity upstream of STAT3.
    evidence:
    - reference: PMID:29279550
      reference_title: "Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        For targeted therapies, an anti-CD30 monoclonal antibody linked to a
        synthetic antimitotic agent (brentuximab vedotin) and ALK inhibitors
        (crizotinib, alectinib, and ceritinib) are being used in clinical
        settings.
      explanation: >-
        The review identifies crizotinib as an ALK inhibitor, anchoring it to
        fusion kinase activity rather than to a downstream nonspecific node.
  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: >-
      The phase 2 trial directly supports clinical activity in the intended
      ALK-positive setting.
- name: Radiation Therapy
  therapeutic_modality: RADIOTHERAPY
  action_category: THERAPEUTIC
  description: >-
    Skin-directed radiation is a local treatment option for primary cutaneous
    ALCL lesions.
  context: Localized primary cutaneous ALCL
  treatment_term:
    preferred_term: Radiation Therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  target_mechanisms:
  - target: Skin-Homing CD30-Positive Malignant T-Cell Expansion
    treatment_effect: INHIBITS
    description: >-
      Local radiation reduces the skin-localized malignant T-cell compartment
      in the treated field.
    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: >-
        The report supports local radiotherapy use; it does not experimentally
        isolate the graph-node mechanism.
  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: >-
      The abstract directly supports radiotherapy as a local treatment option.
- name: Surgical Excision
  therapeutic_modality: SURGERY
  action_category: THERAPEUTIC
  description: Surgical removal is a local option for a localized primary cutaneous ALCL lesion.
  context: Localized primary cutaneous ALCL
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Skin-Homing CD30-Positive Malignant T-Cell Expansion
    treatment_effect: INHIBITS
    description: Excision physically removes the localized cutaneous tumor-cell compartment.
    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: The report supports lesion removal but does not compare local modalities.
  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: The source explicitly supports removal of a localized lesion.
- name: Low-Dose Methotrexate for Primary Cutaneous ALCL
  action_category: THERAPEUTIC
  description: Low-dose methotrexate is a systemic option for selected primary cutaneous ALCL patients.
  context: Selected multifocal or recurrent primary cutaneous ALCL
  treatment_term:
    preferred_term: Chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: methotrexate
      term:
        id: CHEBI:44185
        label: methotrexate
  target_mechanisms:
  - target: Skin-Homing CD30-Positive Malignant T-Cell Expansion
    treatment_effect: INHIBITS
    description: Antimetabolite therapy suppresses the proliferating cutaneous malignant-cell compartment.
    evidence:
    - reference: PMID:42192920
      reference_title: "Primary Cutaneous Anaplastic Large Cell Lymphoma: A Review of Diagnosis and Treatment for the General Oncologist."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        alternative systemic therapies, including methotrexate and retinoids,
        remain relevant in selected patients.
      explanation: The review supports selected clinical use, not a uniquely isolated graph-node mechanism.
  evidence:
  - reference: PMID:42192920
    reference_title: "Primary Cutaneous Anaplastic Large Cell Lymphoma: A Review of Diagnosis and Treatment for the General Oncologist."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      alternative systemic therapies, including methotrexate and retinoids,
      remain relevant in selected patients.
    explanation: The current review directly supports methotrexate for selected patients.
- name: Brentuximab Vedotin for Primary Cutaneous ALCL
  action_category: THERAPEUTIC
  description: Brentuximab vedotin has the strongest prospective systemic-therapy evidence for multifocal or relapsed primary cutaneous ALCL.
  context: Multifocal or relapsed primary cutaneous 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
  target_mechanisms:
  - target: Skin-Homing CD30-Positive Malignant T-Cell Expansion
    treatment_effect: INHIBITS
    description: The CD30-directed conjugate delivers an antimitotic payload to cutaneous malignant cells.
    evidence:
    - reference: PMID:42192920
      reference_title: "Primary Cutaneous Anaplastic Large Cell Lymphoma: A Review of Diagnosis and Treatment for the General Oncologist."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        For multifocal or relapsed disease, brentuximab vedotin demonstrates the
        most robust prospective data and has reshaped the treatment landscape
      explanation: The review supports the disease context; CD30-directed payload delivery is established elsewhere in this entry.
  evidence:
  - reference: PMID:42192920
    reference_title: "Primary Cutaneous Anaplastic Large Cell Lymphoma: A Review of Diagnosis and Treatment for the General Oncologist."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For multifocal or relapsed disease, brentuximab vedotin demonstrates the
      most robust prospective data and has reshaped the treatment landscape
    explanation: The current review directly supports this context-specific use.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  action_category: THERAPEUTIC
  description: Allogeneic transplantation is a consolidation option after reinduction for selected relapsed pediatric ALK-positive ALCL.
  context: Selected children and adolescents with relapsed systemic ALK-positive ALCL
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Systemic CD30-Positive Malignant T-Cell Expansion
    treatment_effect: INHIBITS
    description: Conditioning and donor immune effects consolidate control of the systemic malignant clone after reinduction.
    evidence:
    - reference: PMID:36907641
      reference_title: Diagnosis and management of ALK-positive anaplastic large cell lymphoma in children and adolescents.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Survival at relapse exceeds 60-70% with consolidation according to the
        time of relapse (Vinblastine monotherapy or allogeneic hematopoietic stem
        cell transplantation)
      explanation: The review supports consolidation but does not isolate conditioning and donor immune mechanisms.
  evidence:
  - reference: PMID:36907641
    reference_title: Diagnosis and management of ALK-positive anaplastic large cell lymphoma in children and adolescents.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Survival at relapse exceeds 60-70% with consolidation according to the
      time of relapse (Vinblastine monotherapy or allogeneic hematopoietic stem
      cell transplantation)
    explanation: The pediatric review directly supports allogeneic transplantation as relapse consolidation.
clinical_trials:
- name: NCT01777152
  phase: PHASE_III
  status: COMPLETED
  description: >-
    ECHELON-2 was the randomized, double-blind phase 3 comparison of frontline
    brentuximab vedotin plus CHP against CHOP in CD30-positive mature T-cell
    lymphomas, with systemic ALCL forming the principal disease population.
    ClinicalTrials.gov listed COMPLETED status when checked on 2026-08-04.
  evidence:
  - reference: clinicaltrials:NCT01777152
    reference_title: "A Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Versus CHOP in the Frontline Treatment of Patients With CD30-positive Mature T-cell Lymphomas"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a double-blind, randomized, multicenter, phase 3 clinical trial to
      compare the efficacy and safety of brentuximab vedotin in combination with
      CHP with the standard-of-care CHOP in patients with CD30-positive mature
      T-cell lymphomas.
    explanation: The registry directly supports the phase, design, population, and comparison.
- name: NCT00866047
  phase: PHASE_II
  status: COMPLETED
  description: >-
    This single-arm phase 2 study evaluated single-agent brentuximab vedotin in
    relapsed or refractory systemic ALCL. ClinicalTrials.gov listed COMPLETED
    status when checked on 2026-08-04.
  evidence:
  - reference: clinicaltrials:NCT00866047
    reference_title: A Phase 2 Study of SGN-35 in Treatment of Patients With Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma (ALCL)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a single-arm, open-label, multicenter, clinical trial to evaluate
      the efficacy and safety of brentuximab vedotin (SGN-35) as a single agent
      in patients with relapsed or refractory ALCL.
    explanation: The registry directly supports the study design, agent, and relapsed/refractory ALCL population.
- name: NCT02034981
  phase: PHASE_II
  status: COMPLETED
  description: >-
    AcSé-crizotinib was a biology-driven multicohort phase 2 study that included
    an ALK-positive relapsed or refractory ALCL cohort. ClinicalTrials.gov
    listed COMPLETED status when checked on 2026-08-04.
  evidence:
  - reference: clinicaltrials:NCT02034981
    reference_title: "AcSé CRIZOTINIB : Secured Access to Crizotinib for Patients With Tumors Harboring a Genomic Alteration on One of the Biological Targets of the Drug."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a biology driven, trans-tumoral, multicentric phase II trial
      assessing the efficacy and the safety of the targeted agent crizotinib as
      a monotherapy in 23 cohorts of patients with identified activating
      molecular alterations in the crizotinib target genes.
    explanation: The registry supports the umbrella design and intervention but does not name the ALCL cohort in its summary.
  - 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: The trial publication independently confirms the ALK-positive ALCL cohort and clinical activity.
animal_models:
- species: Mus musculus
  genotype: T-cell-targeted human NPM-ALK transgene
  genes:
  - preferred_term: ALK
    term:
      id: hgnc:427
      label: ALK
  - preferred_term: NPM1
    term:
      id: hgnc:7910
      label: NPM1
  description: >-
    Mice expressing human NPM-ALK in T cells develop malignant
    lymphoproliferative disease after a short latency. The thymic lymphomas have
    an immature T-cell phenotype and often express surface CD30, while a subset
    of mice also develops plasma-cell neoplasms.
  associated_phenotypes:
  - Malignant lymphoproliferative disease
  - Immature T-cell thymic lymphoma
  - Surface CD30 expression
  - Plasma-cell neoplasms in a subset
  evidence:
  - reference: PMID:12424201
    reference_title: NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, after a short period of latency, all NPM-ALK Tg mice developed
      malignant lymphoproliferative disorders (mean survival, 18 weeks).
    explanation: The transgenic study directly establishes penetrant lymphoproliferative disease.
  - reference: PMID:12424201
    reference_title: NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      NPM-ALK Tg thymic lymphomas displayed a T-cell phenotype characteristic of
      immature thymocytes and frequently coexpressed surface CD30. A subset of
      the NPM-ALK Tg mice also developed clonal B-cell plasma cell neoplasms.
    explanation: The source directly supports both lymphoma phenotype and lineage-fidelity limitations.
experimental_models:
- name: Dominant-Negative STAT3 in Karpas 299 and SU-DHL-1 Cells
  description: >-
    Two human ALK-positive ALCL cell lines infected with an adenoviral
    dominant-negative STAT3 construct test whether ongoing STAT3 activity is
    required for tumor-cell survival and cell-cycle progression.
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Karpas 299 and SU-DHL-1 ALK-positive ALCL cell lines
  culture_system: Adenoviral dominant-negative STAT3 perturbation in monolayer cell culture
  conditions:
  - AdSTAT3DN infection
  - control adenoviral infection
  publication: PMID:15184887
  modeled_mechanisms:
  - target: ALK-Driven STAT3 Activation
    description: Selectively inhibits STAT3 signaling downstream of NPM-ALK.
    evidence:
    - reference: PMID:15184887
      reference_title: Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastic large cell lymphoma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we further examined its biological significance in ALCL using two
        ALK(+) ALCL cell lines (Karpas 299 and SU-DHL-1) and an adenoviral vector
        that carries dominant-negative STAT3 (AdSTAT3DN).
      explanation: The experiment directly defines the cell-line perturbation model.
  findings:
  - statement: Dominant-negative STAT3 induced apoptosis and G1 cell-cycle arrest.
    supporting_text: Introduction of STAT3DN induced apoptosis and G(1) cell cycle arrest.
    evidence:
    - reference: PMID:15184887
      reference_title: Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastic large cell lymphoma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Introduction of STAT3DN induced apoptosis and G(1) cell cycle arrest.
      explanation: The perturbation result directly supports STAT3 dependence in these lines.
  evidence:
  - reference: PMID:15184887
    reference_title: Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastic large cell lymphoma.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we further examined its biological significance in ALCL using two
      ALK(+) ALCL cell lines (Karpas 299 and SU-DHL-1) and an adenoviral vector
      that carries dominant-negative STAT3 (AdSTAT3DN).
    explanation: The publication explicitly defines the two-line experimental system.
computational_models:
- name: NPM-ALK Signaling-Network Sensitivity Model
  description: >-
    A quantitative phenomenological ODE network uses Hill-type transfer
    functions and steady-state sensitivity analysis to rank control points for
    NPM-ALK-driven survival and proliferation. It predicts a predominant
    VAV1-CDC42 contribution to proliferation and RAS-MEK-ERK contribution to
    survival; these predictions require experimental validation.
  modeled_mechanisms:
  - target: Constitutive ALK Fusion Kinase Activity
    description: Models signal flow from NPM-ALK through interacting survival and proliferation pathways.
    evidence:
    - reference: PMID:27669408
      reference_title: Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        We computationally simulated the signalling network which mediates
        pathological cell survival and proliferation through NPM-ALK
      explanation: The model explicitly starts from NPM-ALK-driven signal flow.
  - target: ALK-Driven STAT3 Activation
    description: Models JAK3-STAT3 as one control branch of the NPM-ALK network.
    evidence:
    - reference: PMID:27669408
      reference_title: Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy.
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Our results also highlight the importance of a group of interleukins
        together with the Janus kinase 3 (JAK3) / signal transducer and
        activator of transcription 3 (STAT3) signalling in the development of
        NPM-ALK derived ALCL.
      explanation: The simulation explicitly includes and prioritizes the JAK3-STAT3 branch.
  model_type: KINETIC
  publication: PMID:27669408
  notes: >-
    The model is literature-derived rather than patient-specific and reports
    relative steady-state activities, not validated clinical response predictions.
  evidence:
  - reference: PMID:27669408
    reference_title: Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      We computationally simulated the signalling network which mediates
      pathological cell survival and proliferation through NPM-ALK to identify
      therapeutically targetable nodes through which it may be possible to
      regain control of the tumourigenic process.
    explanation: The publication directly defines the computational scope and purpose.
discussions:
- discussion_id: gap_primary_cutaneous_treatment_evidence
  prompt: >-
    Which primary cutaneous ALCL treatment strategies have comparative
    prospective evidence sufficient to replace case-series-driven selection?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Radiation Therapy
  - treatments#Surgical Excision
  - treatments#Low-Dose Methotrexate for Primary Cutaneous ALCL
  - treatments#Brentuximab Vedotin for Primary Cutaneous ALCL
  - has_subtypes#Primary Cutaneous
  rationale: >-
    Prospective brentuximab data and modern reviews improve the evidence base,
    but most management evidence remains non-randomized. Comparative sequencing,
    risk stratification, and uncommon aggressive variants remain unresolved.
  evidence:
  - reference: PMID:21841159
    reference_title: "EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although a broad spectrum of therapeutic strategies has been reported,
      these have been limited mostly to small retrospective cohort series or
      case reports, and only very few prospective controlled or multicenter
      studies have been performed, which results in a low level of evidence for
      most therapies.
    explanation: >-
      The consensus explicitly identifies the comparative-treatment evidence
      gap.
  - reference: PMID:42192920
    reference_title: "Primary Cutaneous Anaplastic Large Cell Lymphoma: A Review of Diagnosis and Treatment for the General Oncologist."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Overall, current management is supported largely by non-randomized data,
      and key gaps remain in risk stratification, optimal sequencing of
      therapies, and management of uncommon aggressive variants.
    explanation: The current review explicitly confirms the remaining evidence gaps.
  posed_date: "2026-07-21T02:53:02Z"
- discussion_id: gap_dusp22_prognostic_reproducibility
  prompt: >-
    Which clinical and molecular contexts explain the conflicting survival
    estimates for DUSP22-rearranged systemic ALK-negative ALCL?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#DUSP22 Rearrangement
  - has_subtypes#Systemic ALK-Negative
  rationale: >-
    Two multicenter molecular cohorts, including the largest integrated series,
    report survival comparable to ALK-positive disease, whereas an independent
    cohort found no advantage over DUSP22-nonrearranged ALK-negative ALCL.
    Prospective, treatment-annotated molecular cohorts are needed before DUSP22
    alone can determine treatment intensity.
  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: >-
      Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for
      DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases
      lacking all 3 genetic markers (P < .0001).
    explanation: This cohort reported a strongly favorable DUSP22-associated outcome.
  - reference: PMID:41329859
    reference_title: "Gene expression profiling reveals 2 overarching types of ALCL with distinct targetable biology: an LLMPP study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year
      overall survival, 95%) and ALK+ ALCL (88%), intermediate for triple-negative
      ALCL (TN-I, 52% and TN-II, 37%), and poor for TP63-rearranged ALCL (0%).
    explanation: The largest integrated cohort supports the favorable DUSP22 signal while resolving TN-I, TN-II, and TP63 outcomes.
  - reference: PMID:36453104
    reference_title: DUSP22 rearrangement is associated with a distinctive immunophenotype but not outcome in patients with systemic ALK-negative anaplastic large cell lymphoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, in this cohort DUSP22-R was not associated with a better clinical
      outcome.
    explanation: This independent cohort directly establishes non-reproduction of the favorable association.
  posed_date: "2026-08-04T00:00:00Z"
- discussion_id: gap_npm_alk_mouse_lineage_fidelity
  prompt: >-
    How faithfully does the T-cell-targeted NPM-ALK transgenic mouse reproduce
    mature human ALK-positive ALCL rather than a broader lineage-promiscuous
    lymphoid transformation phenotype?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Mus musculus
  - pathophysiology#Constitutive ALK Fusion Kinase Activity
  rationale: >-
    The model provides in-vivo evidence that NPM-ALK is oncogenic, but its tumors
    arise largely as immature-thymocyte lymphomas and some mice develop clonal
    plasma-cell neoplasms. Those outputs do not precisely reproduce a mature
    T-cell ALCL entity and bound translational interpretation.
  evidence:
  - reference: PMID:12424201
    reference_title: NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      NPM-ALK Tg thymic lymphomas displayed a T-cell phenotype characteristic of
      immature thymocytes and frequently coexpressed surface CD30. A subset of
      the NPM-ALK Tg mice also developed clonal B-cell plasma cell neoplasms.
    explanation: The observed immature and B-lineage tumors directly define the fidelity mismatch.
  posed_date: "2026-08-04T00:00:00Z"
- discussion_id: gap_relapse_consolidation_sequencing
  prompt: >-
    Can checkpoint blockade or prolonged ALK inhibition replace allogeneic
    transplantation for selected relapsed pediatric ALK-positive ALCL?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Crizotinib
  - treatments#Allogeneic Hematopoietic Stem Cell Transplantation
  rationale: >-
    Multiple agents can reinduce remission, but comparative prospective evidence
    is insufficient to determine which patients require transplantation and
    which can safely continue less intensive targeted or immune therapy.
  evidence:
  - reference: PMID:36907641
    reference_title: Diagnosis and management of ALK-positive anaplastic large cell lymphoma in children and adolescents.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It needs to be shown whether check-point inhibitors or long-term
      ALK-inhibition may substitute for transplantation.
    explanation: The pediatric management review explicitly states the unresolved comparison.
  posed_date: "2026-08-04T00:00:00Z"
datasets:
- accession: geo:GSE217426
  title: Expression signature characteristic of Anaplastic Large Cell Lymphoma (ALCL) patients
  description: RNA extracted from tumor biopsies of 44 patients affected by ALCL was analyzed on the nCounter system using a custom panel called VF_150921 (Nanostring Technologies).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 44
  publication: PMID:37381763
  notes: Identified by GEO DataSets index search for Anaplastic Large Cell Lymphoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE209838
  title: Plasma small-extracellular vesicles enriched in miR-122-5p promote disease aggressiveness in pediatric Anaplastic Large Cell Lymphoma
  description: Emerging evidence shows that small extracellular vesicles (S-EVs) play a critical role in cancer biology. However, the role of S-EVs in pediatric anaplastic large cell lymphoma (ALCL) is still largely unknown. Small RNA sequencing of plasma S-EVs revealed a peculiar microRNA profile in pediatric ALCL patients compared to healthy donors (HD). In particular, the liver-specific miR-122-5p was more abundant in ALCL plasma S-EVs compared to HD. Elevated levels of miR-122-5p correlated with advanced stage disease and impaired hepatic function in ALCL patients.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 50
  publication: PMID:37014813
  notes: Identified by GEO DataSets index search for Anaplastic Large Cell Lymphoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE115917
  title: Peripheral T-cell lymphomas expressing CD30 and CD15 expand the spectrum of anaplastic large cell lymphoma, ALK-negative
  description: RNAseq of 14 samples of human primary T cell lymphoma
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 14
  publication: PMID:38613165
  notes: Identified by GEO DataSets index search for Anaplastic Large Cell Lymphoma (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001003962
  title: Breast implant-associated anaplastic large cell lymphoma shallow whole genome sequencing for copy number analysis and Whole exome sequencing data.
  description: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) shallow whole genome sequencing of 29 BIA-ALCL patients for copy number analysis and 24 Alk-negative ALCL samples as control cohort. 7 Whole exome sequencing BIA-ALCL samples.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:32898861
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Anaplastic Large Cell Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001004189
  title: Integrative molecular analysis of pediatric Anaplastic large cell lymphoma reveals subtypes with distinct immune suppression signatures.
  description: Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma accounting for 10–15% of all childhood lymphomas. While more than 90% of the ALCL cases contain ALK-rearrangement, these tumors possess significant inter-tumor molecular heterogeneity that contributes to distinct morphologic differences and clinical impact. To gain insight into the molecular heterogeneity within ALK+ ALCL, we performed whole-exome sequencing, RNA-sequencing, and methylome analysis of 42 primary pediatric ALK+ ALCL patients. Our data showed that ALK+ALCLs was subclassified into two subtypes based on ALK gene expression, methylation profiles, and somatic mutation patterns.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Anaplastic Large Cell Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001004429
  title: The genomic landscape of primary cutaneous anaplastic large cell lymphoma (pcALCL)
  description: Primary cutaneous anaplastic large cell lymphoma (pcALCL) is the second most common variant of cutaneous T-cell lymphoma. We subjected tumor biopsies from patients with pcALCL to whole-genome sequencing, whole-exome sequencing and RNA-sequencing to investigate genomic alterations and deregulated gene expression in the disease.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Anaplastic Large Cell Lymphoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
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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