Primary Cutaneous Aggressive Epidermotropic CD8+ T-cell Lymphoma

Cancer MONDO:0015811 Pathograph 6 Cutaneous T-cell lymphoma

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma is a rare cytotoxic cutaneous T-cell lymphoma in which malignant CD8-positive T cells show marked epidermotropism, destructive skin involvement, rapid progression, and potential extracutaneous dissemination. Genomic studies support recurrent JAK2/SH2B3-axis lesions and overactive JAK2 signaling as central molecular drivers in a subset of cases.

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1
Mappings
1
Definitions
3
Pathophys.
2
Histopath.
3
Phenotypes
6
Pathograph
2
Genes
6
Treatments
2
Trials
1
Deep Research
🔗

Mappings

MONDO
MONDO:0015811 primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma
skos:exactMatch MONDO
Primary MONDO disease identifier confirmed with OAK.
📘

Definitions

1
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma
The disease is a rare aggressive primary cutaneous cytotoxic T-cell lymphoma characterized by epidermotropic CD8-positive malignant T cells, cytotoxic protein expression, clinical ulceration, and poor response to conventional therapy.
CASE_DEFINITION Clinicopathologic definition for dismech curation
Show evidence (1 reference)
PMID:29719018 SUPPORT Human Clinical
"PCAE-TCL is a rare cutaneous lymphoma, representing <1% of all cutaneous T-cell lymphoma (CTCL) cases.22 It is characterized by a proliferation of cytotoxic CD8-positive T cells with preferential localization to the epidermis resulting in extensive keratinocyte necrosis and clinical ulceration."
This review directly defines the entity, its rarity, cytotoxic CD8-positive epidermotropic biology, and the tissue injury that produces ulceration.
⚙

Pathophysiology

3
JAK2-SH2B3 Axis Deregulation
Whole-genome and RNA-sequencing data show recurrent mutually exclusive structural alterations involving JAK2 or SH2B3, consistent with deregulated JAK2 signaling as an upstream oncogenic driver in this lymphoma.
malignant CD8-positive alpha-beta T cell link
JAK2 link SH2B3 link
cell surface receptor signaling pathway via JAK-STAT link ↑ INCREASED
Downstream
Proliferative and Inflammatory Transcriptional Program JAK2-SH2B3-axis lesions converge on JAK2 signaling and downstream proliferative, NF-kappaB, and inflammatory transcriptional programs.
Show evidence (1 reference)
PMID:33792220 SUPPORT Human Clinical
"In particular, we show that mutually exclusive structural alterations involving JAK2 and SH2B3 predominantly underlie pcAECyTCL."
This human tumor genomic study identifies JAK2 and SH2B3 structural alterations as predominant molecular lesions.
Proliferative and Inflammatory Transcriptional Program
Tumor transcriptomes show increased cell-cycle activity, JAK2 signaling, NF-kappaB signaling, and inflammatory-response programs, linking upstream kinase deregulation to aggressive tumor growth and inflammatory tissue injury.
cell cycle link ↑ INCREASED cell surface receptor signaling pathway via JAK-STAT link ↑ INCREASED non-canonical NF-kappaB signal transduction link ↑ INCREASED inflammatory response link ↑ INCREASED
Downstream
Epidermotropic Cytotoxic Tissue Injury Proliferative cytotoxic T cells home to and damage the epidermis, creating necrotic and ulcerating cutaneous lesions.
Show evidence (1 reference)
PMID:33792220 SUPPORT Human Clinical
"In line with the genomic data, transcriptome analysis uncovered upregulation of the cell cycle, JAK2 signaling, NF-κB signaling and a high inflammatory response in this cancer."
This directly supports increased cell-cycle, JAK2, NF-kappaB, and inflammatory programs in tumor transcriptomes.
Epidermotropic Cytotoxic Tissue Injury
Cytotoxic CD8-positive malignant T cells preferentially localize to the epidermis, causing keratinocyte necrosis, ulceration, and destructive cutaneous lesions.
malignant CD8-positive alpha-beta T cell link
inflammatory response link ↑ INCREASED
skin epidermis link
Show evidence (1 reference)
PMID:29719018 SUPPORT Human Clinical
"Histopathology shows a prominent epidermotropic proliferation of small-medium or medium-large atypical lymphocytes (Figure 4A), which may exhibit blastic nuclei.1,25"
This review directly supports epidermotropic atypical lymphoid proliferation as a tissue-level mechanism.
✶

Histopathology

2
Epidermotropic Atypical Lymphoid Proliferation
Biopsies show prominent epidermotropic atypical lymphocytes, often with keratinocyte necrosis, ulceration, and adnexal invasion or destruction.
Show evidence (1 reference)
PMID:29719018 SUPPORT Human Clinical
"Focal to confluent keratinocyte necrosis and ulceration are frequently seen; however, signs of cytotoxicity may be limited to subtle vacuolar interface alteration and sparse dermal melanophages."
This review supports necrosis and ulceration as microscopic consequences of cytotoxic epidermotropic lymphoma.
CD8-positive Cytotoxic T-cell Immunophenotype
Tumor cells typically express CD3 and CD8 with cytotoxic granule proteins and lack CD4; EBV negativity supports separation from EBV-driven NK/T-cell lymphomas.
Show evidence (1 reference)
PMID:29719018 SUPPORT Human Clinical
"Immunohistochemical evaluation shows that the tumor cells are CD3+, CD8+ (Figure 4D), cytotoxic granule positive (granzyme B, perforin, and TIA-1), βF1+ (Figure 4E), CD45RA+, and CD45RO–."
This review supports the diagnostic CD3-positive, CD8-positive cytotoxic immunophenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Primary Cutaneous Aggressive Epidermotropic CD8+ T-cell Lymphoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Integument 2
Ulcerating Papules, Plaques, and Tumors Skin ulcer (HP:0200042)
Show evidence (1 reference)
PMID:29719018 SUPPORT Human Clinical
"Papules, plaques, and tumors with central necrosis and hemorrhagic crust are distributed mostly on the extremities and the trunk (Figure 3) with occasional involvement of the oral cavity or the genitals."
This review supports the characteristic ulcerating papules, plaques, and tumors and their typical anatomical distribution.
Skin Nodules Skin nodule (HP:0200036)
Show evidence (1 reference)
PMID:37654908 SUPPORT Human Clinical
"This article describes a probable case of primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma in a 63-year-old female, which manifested as diffuse non-pruritic erythematous plaques and nodules."
This case abstract directly supports ulcerated nodules as a clinical presentation.
Other 1
Central Nervous System Infiltration Morphological central nervous system abnormality (HP:0002011)
Show evidence (1 reference)
PMID:29526962 SUPPORT Human Clinical
"He was diagnosed to have primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAE-CTL) by a biopsy of the skin and brain."
This case documents biopsy-confirmed skin and brain involvement.
🧬

Genetic Associations

2
JAK2 Structural Alteration (Recurrent somatic driver event)
Show evidence (1 reference)
PMID:33792220 SUPPORT Human Clinical
"In particular, we show that mutually exclusive structural alterations involving JAK2 and SH2B3 predominantly underlie pcAECyTCL."
This tumor genomic study supports JAK2 structural alteration as a recurrent somatic driver event.
SH2B3 Structural Alteration (Loss of negative JAK2 regulation)
Show evidence (1 reference)
PMID:33792220 SUPPORT Human Clinical
"In particular, we show that mutually exclusive structural alterations involving JAK2 and SH2B3 predominantly underlie pcAECyTCL."
This tumor genomic study supports SH2B3-axis alteration as part of the recurrent genetic basis of this lymphoma.
💊

Treatments

6
Systemic Therapy
Action: Pharmacotherapy NCIT:C15986
Aggressive disease biology and visceral-spread risk generally require systemic therapy rather than skin-directed therapy alone.
Show evidence (1 reference)
PMID:39644025 SUPPORT Human Clinical
"The more aggressive CTCLs, which herein we consider as certain cases of advanced-stage mycosis fungoides/Sézary syndrome (MF/SS), primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (PCAETCL), and primary cutaneous gamma delta T-cell lymphoma (PCGDTCL), require systemic therapy."
This expert review directly supports systemic therapy for PCAETCL.
Multiagent Chemotherapy
Action: cancer chemotherapy MAXO:0000646
Multiagent chemotherapy has produced durable remission in individual cases, but this remains case-level evidence rather than a standardized curative regimen.
Show evidence (1 reference)
PMID:30291826 PARTIAL Human Clinical
"He was treated with aggressive multiagent chemotherapy comprising cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD)."
This case report supports multiagent chemotherapy as a possible treatment approach, but the evidence is limited to case-level remission.
Allogeneic Hematopoietic Stem Cell Transplantation
Action: transplantation procedure MAXO:0000068
Allogeneic hematopoietic stem cell transplantation has been reported as a promising treatment option and should be considered early for eligible patients because sustained remissions with other therapies are uncommon.
Show evidence (1 reference)
PMID:29223388 SUPPORT Human Clinical
"Allogeneic HSCT is a promising treatment modality for CD8+ PCAETL. Because of the aggressive nature of this disease and lack of sustained remission with currently available therapies, HSCT should be considered early in the course of treatment."
This retrospective case series directly supports early consideration of allogeneic HSCT.
Brentuximab Vedotin
Action: Pharmacotherapy NCIT:C15986
Agent: brentuximab vedotin ↗
Brentuximab vedotin showed activity in a retrospective case series of CD8+ PCAETL and may be considered earlier in the treatment course, but evidence remains limited to small observational experience.
Show evidence (1 reference)
PMID:29223388 PARTIAL Human Clinical
"Two novel agents, brentuximab and pralatrexate, showed significant activity against CD8+ PCAETL, and may be incorporated earlier in the treatment course."
This retrospective case series supports brentuximab vedotin as an active treatment option, but the evidence remains limited and non-randomized.
Pralatrexate
Action: Pharmacotherapy NCIT:C15986
Agent: pralatrexate ↗
Pralatrexate showed activity in a retrospective case series of CD8+ PCAETL and may be considered earlier in the treatment course, but evidence remains limited to small observational experience.
Show evidence (1 reference)
PMID:29223388 PARTIAL Human Clinical
"Two novel agents, brentuximab and pralatrexate, showed significant activity against CD8+ PCAETL, and may be incorporated earlier in the treatment course."
This retrospective case series supports pralatrexate as an active treatment option, but the evidence remains limited and non-randomized.
JAK2 Inhibitor Therapy
Action: Pharmacotherapy NCIT:C15986
Agent: ruxolitinib ↗
JAK2 inhibitors such as ruxolitinib are a biomarker-driven investigational strategy for tumors with activated JAK2 signaling.
Mechanism Target:
INHIBITS JAK2-SH2B3 Axis Deregulation — JAK inhibition is intended to inhibit the overactive JAK2 signaling produced by JAK2 fusions or SH2B3-axis lesions.
Show evidence (1 reference)
PMID:33792220 PARTIAL In Vitro
"Functional studies confirmed oncogenicity of JAK2 fusions identified in pcAECyTCL and their sensitivity to JAK inhibitor treatment."
This functional evidence supports JAK inhibition as a biomarker-driven strategy, but clinical efficacy remains to be established.
🔬

Biochemical Markers

1
Cytotoxic Granule Protein Expression (tumor-cell expression)
Show evidence (1 reference)
PMID:29719018 SUPPORT Human Clinical
"The cytotoxic lymphomas of the skin constitute a heterogeneous group of rare lymphoproliferative diseases that are derived from mature T cells and natural killer (NK) cells that express cytotoxic molecules (T-cell intracellular antigen- 1, granzyme A/B, and perforin)."
This review supports cytotoxic molecule expression as a defining biomarker feature of cutaneous cytotoxic lymphomas including this entity.
🔬

Clinical Trials

2
NCT05475925 PHASE_I RECRUITING
DR-01 study enrolling adults with large granular lymphocytic leukemia or cytotoxic lymphomas; not specific to this lymphoma.
Show evidence (1 reference)
clinicaltrials:NCT05475925 PARTIAL
"This is a multicenter, first-in-human, Phase 1/2 study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor activity of DR-01 in adult patients with large granular lymphocytic leukemia or cytotoxic lymphomas"
The trial is relevant to the broader cytotoxic lymphoma category but is not specific to PCAETCL.
NCT05978141 NOT_APPLICABLE RECRUITING
Prospective T-cell lymphoma repository collecting clinical annotations and matched tumor specimens; not specific to this lymphoma.
Show evidence (1 reference)
clinicaltrials:NCT05978141 PARTIAL
"The purpose of this registry study is to create a database-a collection of information-for better understanding T-cell lymphoma."
The registry can include T-cell lymphomas broadly but is not specific to PCAETCL.
{ }

Source YAML

click to show 
name: Primary Cutaneous Aggressive Epidermotropic CD8+ T-cell Lymphoma
creation_date: "2026-05-07T23:30:04Z"
updated_date: "2026-05-08T00:05:41Z"
category: Cancer
categories:
- Hematologic Malignancy
- T-cell Neoplasm
- Cutaneous Lymphoma
synonyms:
- CD8+ PCAETL
- PCAETCL
- PCAE-TCL
- primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma
- primary cutaneous aggressive epidermotropic cytotoxic CD8-positive T-cell lymphoma
description: >-
  Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma is a rare
  cytotoxic cutaneous T-cell lymphoma in which malignant CD8-positive T cells
  show marked epidermotropism, destructive skin involvement, rapid progression,
  and potential extracutaneous dissemination. Genomic studies support recurrent
  JAK2/SH2B3-axis lesions and overactive JAK2 signaling as central molecular
  drivers in a subset of cases.
definitions:
- name: Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma
  definition_type: CASE_DEFINITION
  description: >-
    The disease is a rare aggressive primary cutaneous cytotoxic T-cell lymphoma
    characterized by epidermotropic CD8-positive malignant T cells, cytotoxic
    protein expression, clinical ulceration, and poor response to conventional
    therapy.
  scope: Clinicopathologic definition for dismech curation
  evidence:
  - reference: PMID:29719018
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PCAE-TCL is a rare cutaneous lymphoma, representing <1% of all cutaneous
      T-cell lymphoma (CTCL) cases.22 It is characterized by a proliferation of
      cytotoxic CD8-positive T cells with preferential localization to the
      epidermis resulting in extensive keratinocyte necrosis and clinical ulceration.
    explanation: >-
      This review directly defines the entity, its rarity, cytotoxic CD8-positive
      epidermotropic biology, and the tissue injury that produces ulceration.
disease_term:
  preferred_term: primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma
  term:
    id: MONDO:0015811
    label: primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015811
      label: primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier confirmed with OAK.
parents:
- Cutaneous T-cell lymphoma
progression:
- phase: Rapidly progressive aggressive cutaneous lymphoma
  notes: >-
    Disease onset is often abrupt with quickly progressive ulcerating papules,
    plaques, and tumors. Extracutaneous spread can involve visceral organs and
    the central nervous system. Reported survival is poor, with 5-year overall
    survival of 18%-32% and median overall survival of 12-32 months in a clinical
    review.
  evidence:
  - reference: PMID:29719018
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PCAE-TCL affects mostly middle-aged and elderly male patients,23,24,26 who
      clinically present with the abrupt onset of an ulcerating skin eruption
      that progresses quickly.
    explanation: >-
      This review supports the abrupt onset and rapidly progressive clinical
      course.
  - reference: PMID:29719018
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 5-year overall survival rate ranges from 18%−32%.23,24 The median
      overall survival ranges from 12–32 months.23,25
    explanation: >-
      This review provides directly quotable prognosis data supporting poor
      survival in PCAE-TCL.
  - reference: PMID:29526962
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some case series have been reported which describe the clinicopathological
      features of PCAE-CTL; epidermotropic infiltration of CD8-positive cytotoxic
      T-cells in cutaneous tissue, rapid progression, and systemic dissemination
      including visceral organs and central nervous system (CNS) (4, 5).
    explanation: >-
      This case-report introduction summarizes case-series evidence for rapid
      progression and systemic dissemination including CNS involvement.
pathophysiology:
- name: JAK2-SH2B3 Axis Deregulation
  description: >-
    Whole-genome and RNA-sequencing data show recurrent mutually exclusive
    structural alterations involving JAK2 or SH2B3, consistent with deregulated
    JAK2 signaling as an upstream oncogenic driver in this lymphoma.
  genes:
  - preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  - preferred_term: SH2B3
    term:
      id: hgnc:29605
      label: SH2B3
  cell_types:
  - preferred_term: malignant CD8-positive alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  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
  evidence:
  - reference: PMID:33792220
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, we show that mutually exclusive structural alterations
      involving JAK2 and SH2B3 predominantly underlie pcAECyTCL.
    explanation: >-
      This human tumor genomic study identifies JAK2 and SH2B3 structural
      alterations as predominant molecular lesions.
  downstream:
  - target: Proliferative and Inflammatory Transcriptional Program
    description: >-
      JAK2-SH2B3-axis lesions converge on JAK2 signaling and downstream
      proliferative, NF-kappaB, and inflammatory transcriptional programs.
- name: Proliferative and Inflammatory Transcriptional Program
  description: >-
    Tumor transcriptomes show increased cell-cycle activity, JAK2 signaling,
    NF-kappaB signaling, and inflammatory-response programs, linking upstream
    kinase deregulation to aggressive tumor growth and inflammatory tissue
    injury.
  biological_processes:
  - preferred_term: cell cycle
    modifier: INCREASED
    term:
      id: GO:0007049
      label: cell cycle
  - preferred_term: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
  - preferred_term: non-canonical NF-kappaB signal transduction
    modifier: INCREASED
    term:
      id: GO:0038061
      label: non-canonical NF-kappaB signal transduction
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:33792220
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In line with the genomic data, transcriptome analysis uncovered upregulation
      of the cell cycle, JAK2 signaling, NF-κB signaling and a high inflammatory
      response in this cancer.
    explanation: >-
      This directly supports increased cell-cycle, JAK2, NF-kappaB, and
      inflammatory programs in tumor transcriptomes.
  downstream:
  - target: Epidermotropic Cytotoxic Tissue Injury
    description: >-
      Proliferative cytotoxic T cells home to and damage the epidermis, creating
      necrotic and ulcerating cutaneous lesions.
- name: Epidermotropic Cytotoxic Tissue Injury
  description: >-
    Cytotoxic CD8-positive malignant T cells preferentially localize to the
    epidermis, causing keratinocyte necrosis, ulceration, and destructive
    cutaneous lesions.
  cell_types:
  - preferred_term: malignant CD8-positive alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  locations:
  - preferred_term: skin epidermis
    term:
      id: UBERON:0001003
      label: skin epidermis
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:29719018
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathology shows a prominent epidermotropic proliferation of small-medium
      or medium-large atypical lymphocytes (Figure 4A), which may exhibit blastic
      nuclei.1,25
    explanation: >-
      This review directly supports epidermotropic atypical lymphoid proliferation
      as a tissue-level mechanism.
phenotypes:
- category: Cutaneous
  name: Ulcerating Papules, Plaques, and Tumors
  severity: SEVERE
  description: >-
    Patients often develop abrupt, rapidly progressive ulcerating papules,
    plaques, and tumors, commonly involving the trunk and extremities.
  phenotype_term:
    preferred_term: Skin ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: PMID:29719018
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Papules, plaques, and tumors with central necrosis and hemorrhagic crust
      are distributed mostly on the extremities and the trunk (Figure 3) with
      occasional involvement of the oral cavity or the genitals.
    explanation: >-
      This review supports the characteristic ulcerating papules, plaques, and
      tumors and their typical anatomical distribution.
- category: Cutaneous
  name: Skin Nodules
  description: >-
    Case presentations can include rapidly progressive ulcerated nodules.
  phenotype_term:
    preferred_term: Skin nodule
    term:
      id: HP:0200036
      label: Skin nodule
  evidence:
  - reference: PMID:37654908
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This article describes a probable case of primary cutaneous CD8+ aggressive
      epidermotropic cytotoxic T-cell lymphoma in a 63-year-old female, which
      manifested as diffuse non-pruritic erythematous plaques and nodules.
    explanation: >-
      This case abstract directly supports ulcerated nodules as a clinical
      presentation.
- category: Neurologic
  name: Central Nervous System Infiltration
  severity: SEVERE
  description: >-
    Extracutaneous dissemination may involve the central nervous system, including
    cerebral infiltration with neurologic deterioration.
  phenotype_term:
    preferred_term: Central nervous system infiltration
    term:
      id: HP:0002011
      label: Morphological central nervous system abnormality
  evidence:
  - reference: PMID:29526962
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was diagnosed to have primary cutaneous CD8-positive aggressive
      epidermotropic cytotoxic T-cell lymphoma (PCAE-CTL) by a biopsy of the
      skin and brain.
    explanation: >-
      This case documents biopsy-confirmed skin and brain involvement.
histopathology:
- name: Epidermotropic Atypical Lymphoid Proliferation
  finding_term:
    preferred_term: Lymphocytic infiltrate
    term:
      id: NCIT:C35983
      label: Lymphocytic Infiltrate
  diagnostic: true
  description: >-
    Biopsies show prominent epidermotropic atypical lymphocytes, often with
    keratinocyte necrosis, ulceration, and adnexal invasion or destruction.
  evidence:
  - reference: PMID:29719018
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Focal to confluent keratinocyte necrosis and ulceration are frequently
      seen; however, signs of cytotoxicity may be limited to subtle vacuolar
      interface alteration and sparse dermal melanophages.
    explanation: >-
      This review supports necrosis and ulceration as microscopic consequences
      of cytotoxic epidermotropic lymphoma.
- name: CD8-positive Cytotoxic T-cell Immunophenotype
  finding_term:
    preferred_term: Lymphocytic infiltrate
    term:
      id: NCIT:C35983
      label: Lymphocytic Infiltrate
  diagnostic: true
  description: >-
    Tumor cells typically express CD3 and CD8 with cytotoxic granule proteins
    and lack CD4; EBV negativity supports separation from EBV-driven NK/T-cell
    lymphomas.
  evidence:
  - reference: PMID:29719018
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemical evaluation shows that the tumor cells are CD3+, CD8+
      (Figure 4D), cytotoxic granule positive (granzyme B, perforin, and TIA-1),
      βF1+ (Figure 4E), CD45RA+, and CD45RO–.
    explanation: >-
      This review supports the diagnostic CD3-positive, CD8-positive cytotoxic
      immunophenotype.
biochemical:
- name: Cytotoxic Granule Protein Expression
  presence: tumor-cell expression
  notes: >-
    Cytotoxic granule protein expression marks the malignant T-cell cytotoxic
    phenotype.
  evidence:
  - reference: PMID:29719018
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cytotoxic lymphomas of the skin constitute a heterogeneous group of
      rare lymphoproliferative diseases that are derived from mature T cells and
      natural killer (NK) cells that express cytotoxic molecules (T-cell
      intracellular antigen- 1, granzyme A/B, and perforin).
    explanation: >-
      This review supports cytotoxic molecule expression as a defining biomarker
      feature of cutaneous cytotoxic lymphomas including this entity.
genetic:
- name: JAK2 Structural Alteration
  association: Recurrent somatic driver event
  gene_term:
    preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  variant_origin: SOMATIC
  notes: >-
    Structural alterations involving JAK2 are recurrent and converge on overactive
    JAK2 signaling.
  evidence:
  - reference: PMID:33792220
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, we show that mutually exclusive structural alterations
      involving JAK2 and SH2B3 predominantly underlie pcAECyTCL.
    explanation: >-
      This tumor genomic study supports JAK2 structural alteration as a recurrent
      somatic driver event.
- name: SH2B3 Structural Alteration
  association: Loss of negative JAK2 regulation
  gene_term:
    preferred_term: SH2B3
    term:
      id: hgnc:29605
      label: SH2B3
  variant_origin: SOMATIC
  notes: >-
    SH2B3 encodes a negative regulator of JAK2 signaling; structural alteration
    in this axis is mutually exclusive with JAK2 structural alteration in the
    cited tumor series.
  evidence:
  - reference: PMID:33792220
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, we show that mutually exclusive structural alterations
      involving JAK2 and SH2B3 predominantly underlie pcAECyTCL.
    explanation: >-
      This tumor genomic study supports SH2B3-axis alteration as part of the
      recurrent genetic basis of this lymphoma.
diagnosis:
- name: Skin biopsy with morphology and immunohistochemistry
  description: >-
    Diagnosis relies on clinicopathologic correlation, biopsy showing epidermotropic
    atypical cytotoxic T cells, immunohistochemistry for CD3, CD8, cytotoxic
    proteins, CD4/CD5/CD56, and EBV testing to exclude mimics.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  markers: CD3, CD4, CD5, CD7, CD8, TIA-1, granzyme B, perforin, betaF1, CD56, EBER
  evidence:
  - reference: PMID:29719018
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EBV should be negative for a definitive diagnosis. The Ki-67 proliferation
      index is high.25,26 The neoplastic cells have clonal TCR gene rearrangements.1,24
    explanation: >-
      This review supports EBV negativity, high proliferation, and clonal TCR
      rearrangement as diagnostic features.
- name: Tumor genomic and transcriptomic profiling
  description: >-
    Molecular testing can identify JAK2 fusions, SH2B3 alterations, or related
    pathway lesions with diagnostic and therapeutic relevance.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  markers: JAK2, SH2B3, JAK/STAT pathway alterations
  evidence:
  - reference: PMID:33792220
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we present the first highresolution genetic characterization of
      pcAECyTCL by using wholegenome and RNA sequencing.
    explanation: >-
      This supports whole-genome and RNA sequencing as the evidence base for
      molecular characterization of the disease.
treatments:
- name: Systemic Therapy
  description: >-
    Aggressive disease biology and visceral-spread risk generally require systemic
    therapy rather than skin-directed therapy alone.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:39644025
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The more aggressive CTCLs, which herein we consider as certain cases of
      advanced-stage mycosis fungoides/Sézary syndrome (MF/SS), primary cutaneous
      CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (PCAETCL), and
      primary cutaneous gamma delta T-cell lymphoma (PCGDTCL), require systemic
      therapy.
    explanation: >-
      This expert review directly supports systemic therapy for PCAETCL.
- name: Multiagent Chemotherapy
  description: >-
    Multiagent chemotherapy has produced durable remission in individual cases,
    but this remains case-level evidence rather than a standardized curative
    regimen.
  treatment_term:
    preferred_term: cancer chemotherapy
    term:
      id: MAXO:0000646
      label: cancer chemotherapy
  evidence:
  - reference: PMID:30291826
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was treated with aggressive multiagent chemotherapy comprising
      cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating
      with high-dose methotrexate and cytarabine (hyper-CVAD).
    explanation: >-
      This case report supports multiagent chemotherapy as a possible treatment
      approach, but the evidence is limited to case-level remission.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic hematopoietic stem cell transplantation has been reported as a
    promising treatment option and should be considered early for eligible
    patients because sustained remissions with other therapies are uncommon.
  treatment_term:
    preferred_term: transplantation procedure
    term:
      id: MAXO:0000068
      label: transplantation procedure
  evidence:
  - reference: PMID:29223388
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Allogeneic HSCT is a promising treatment modality for CD8+ PCAETL. Because
      of the aggressive nature of this disease and lack of sustained remission
      with currently available therapies, HSCT should be considered early in the
      course of treatment.
    explanation: >-
      This retrospective case series directly supports early consideration of
      allogeneic HSCT.
- name: Brentuximab Vedotin
  description: >-
    Brentuximab vedotin showed activity in a retrospective case series of CD8+
    PCAETL and may be considered earlier in the treatment course, but evidence
    remains limited to small observational experience.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: brentuximab vedotin
      term:
        id: NCIT:C66944
        label: Brentuximab Vedotin
  evidence:
  - reference: PMID:29223388
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two novel agents, brentuximab and pralatrexate, showed significant activity
      against CD8+ PCAETL, and may be incorporated earlier in the treatment course.
    explanation: >-
      This retrospective case series supports brentuximab vedotin as an active
      treatment option, but the evidence remains limited and non-randomized.
- name: Pralatrexate
  description: >-
    Pralatrexate showed activity in a retrospective case series of CD8+ PCAETL
    and may be considered earlier in the treatment course, but evidence remains
    limited to small observational experience.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pralatrexate
      term:
        id: NCIT:C2250
        label: Pralatrexate
  evidence:
  - reference: PMID:29223388
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two novel agents, brentuximab and pralatrexate, showed significant activity
      against CD8+ PCAETL, and may be incorporated earlier in the treatment course.
    explanation: >-
      This retrospective case series supports pralatrexate as an active treatment
      option, but the evidence remains limited and non-randomized.
- name: JAK2 Inhibitor Therapy
  description: >-
    JAK2 inhibitors such as ruxolitinib are a biomarker-driven investigational
    strategy for tumors with activated JAK2 signaling.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ruxolitinib
      term:
        id: CHEBI:66919
        label: ruxolitinib
  target_mechanisms:
  - target: JAK2-SH2B3 Axis Deregulation
    treatment_effect: INHIBITS
    description: >-
      JAK inhibition is intended to inhibit the overactive JAK2 signaling
      produced by JAK2 fusions or SH2B3-axis lesions.
  evidence:
  - reference: PMID:33792220
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      Functional studies confirmed oncogenicity of JAK2 fusions identified in
      pcAECyTCL and their sensitivity to JAK inhibitor treatment.
    explanation: >-
      This functional evidence supports JAK inhibition as a biomarker-driven
      strategy, but clinical efficacy remains to be established.
clinical_trials:
- name: NCT05475925
  phase: PHASE_I
  status: RECRUITING
  description: >-
    DR-01 study enrolling adults with large granular lymphocytic leukemia or
    cytotoxic lymphomas; not specific to this lymphoma.
  evidence:
  - reference: clinicaltrials:NCT05475925
    supports: PARTIAL
    snippet: >-
      This is a multicenter, first-in-human, Phase 1/2 study to evaluate the
      safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor
      activity of DR-01 in adult patients with large granular lymphocytic leukemia
      or cytotoxic lymphomas
    explanation: >-
      The trial is relevant to the broader cytotoxic lymphoma category but is
      not specific to PCAETCL.
- name: NCT05978141
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Prospective T-cell lymphoma repository collecting clinical annotations and
    matched tumor specimens; not specific to this lymphoma.
  evidence:
  - reference: clinicaltrials:NCT05978141
    supports: PARTIAL
    snippet: >-
      The purpose of this registry study is to create a database-a collection
      of information-for better understanding T-cell lymphoma.
    explanation: >-
      The registry can include T-cell lymphomas broadly but is not specific to
      PCAETCL.
review_notes: >-
  Falcon deep research was run on 2026-05-07. The report did not include MONDO
  in its retrieved excerpts, but OAK confirmed MONDO:0015811 as the exact disease
  label before curation.
📚

References & Deep Research

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 30 citations 2026-05-07T19:46:40.208461

1. Disease Information

1.1 Overview / definition (current understanding)

The entity is recognized within modern cutaneous lymphoma classifications as a distinct clinicopathologic syndrome of epidermotropic CD8+ cytotoxic T cells with aggressive behavior and poor outcomes. (deenen2019pitfallsindiagnosing pages 1-2, geller2018nktcelllymphomanasal pages 1-3)

In the WHO–EORTC 2018 update, it is listed explicitly as “Primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma (provisional)” and summarized as presenting with ulcerating plaques, nodules, and tumors, with a typical immunophenotype CD3+, CD4−, CD8+, cytotoxic proteins positive, CD56−, and EBV−. (willemze2019the2018update pages 13-16, willemze2019the2018update media 461b18ed)

1.2 Key identifiers / ontology codes

Within the retrieved full texts, no MONDO, Orphanet (ORPHA), MeSH, ICD-10/ICD-11, or OMIM identifiers were provided for this specific disease name, including in the WHO–EORTC update excerpts and multiple case reports/reviews. (willemze2019the2018update pages 13-16, loya2023probableprimarycutaneous pages 4-4, sundram2019cutaneouslymphoproliferativedisorders pages 1-2)

1.3 Synonyms and alternative names

Nomenclature varies across clinical, dermatopathology, and molecular literature (e.g., “PCAETCL,” “pcAECyTCL,” and inclusion of “cytotoxic”). A harmonized list of name variants observed in the retrieved sources is provided below.

Canonical name Common abbreviations Synonyms/variants in literature Classification status notes (WHO/WHO-EORTC provisional/definitive as supported) External identifiers (MONDO/Orphanet/MeSH/ICD) Key supporting citations with PMID/DOI/URL if available
Primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma CD8+ AECTCL; PCAETCL; PCAE-TCL; pcAECyTCL Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma; Primary cutaneous aggressive epidermotropic cytotoxic CD8 positive T cell lymphoma; Primary cutaneous CD8+ aggressive epidermotropic T-cell lymphoma; Aggressive epidermotropic cutaneous CD8+ lymphoma; Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma Listed as a provisional entity in WHO-EORTC 2018 / recent cutaneous lymphoma classifications; described as a rare subtype of cutaneous T-cell lymphoma (CTCL) / primary cutaneous peripheral T-cell lymphoma. WHO-EORTC table lists frequency <1% and 5-year DSS 31%. (willemze2019the2018update pages 13-16, kempf2019cutaneouslymphomas—anupdate pages 1-3, sundram2019cutaneouslymphoproliferativedisorders pages 1-2, willemze2019the2018update media 461b18ed) MONDO/Orphanet/MeSH/ICD: not found in retrieved sources. Retrieved texts explicitly did not provide controlled-vocabulary identifiers. (willemze2019the2018update pages 13-16, loya2023probableprimarycutaneous pages 4-4, lupu2018anunusualpresentation pages 6-6, sundram2019cutaneouslymphoproliferativedisorders pages 1-2) Willemze et al., Blood 2019. DOI: 10.1182/blood-2018-11-881268. URL: https://doi.org/10.1182/blood-2018-11-881268 (willemze2019the2018update pages 13-16, willemze2019the2018update media 461b18ed)
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma PCAECTCL; PCAETL Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma; Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma Used in reviews/case reports as the same disease label; described as provisional in WHO-EORTC-based classification discussions. (deenen2019pitfallsindiagnosing pages 1-2, geller2018nktcelllymphomanasal pages 1-3, sundram2019cutaneouslymphoproliferativedisorders pages 1-2) MONDO/Orphanet/MeSH/ICD: not found in retrieved sources. (loya2023probableprimarycutaneous pages 4-4, sundram2019cutaneouslymphoproliferativedisorders pages 1-2) Deenen et al., Br J Dermatol 2019. DOI: 10.1111/bjd.17252. URL: https://doi.org/10.1111/bjd.17252; Geller et al., Semin Cutan Med Surg 2018. DOI: 10.12788/j.sder.2018.020. URL: https://doi.org/10.12788/j.sder.2018.020 (deenen2019pitfallsindiagnosing pages 1-2, geller2018nktcelllymphomanasal pages 1-3)
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (molecular-study nomenclature) pcAECyTCL pcAETCL; primary cutaneous aggressive epidermotropic T-cell lymphoma Molecular/genomic study uses this wording for the same rare aggressive CTCL entity; supports disease definition and biology, but retrieved context does not alter its provisional classification status from WHO-EORTC sources. (torres2021deregulationofjak2 pages 1-2, gallardo2022geneticsabnormalitieswith pages 1-2) MONDO/Orphanet/MeSH/ICD: not found in retrieved sources. (willemze2019the2018update pages 13-16, loya2023probableprimarycutaneous pages 4-4) Torres et al., Haematologica 2021. DOI: 10.3324/haematol.2020.274506. URL: https://doi.org/10.3324/haematol.2020.274506 (torres2021deregulationofjak2 pages 1-2, torres2021deregulationofjak2 pages 3-5, torres2021deregulationofjak2 pages 5-7)

Table: This table compiles the main disease names, abbreviations, classification notes, and the absence of standardized external identifiers in the retrieved sources for primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. It is useful for harmonizing terminology across pathology, clinical, and molecular literature.

1.4 Source type of information

Evidence in the retrieved corpus is predominantly aggregated disease-level classification/registry summaries (WHO–EORTC) plus small case series and case reports; prospective interventional data are scarce and repeatedly described as limited for this disease. (willemze2019the2018update pages 13-16, stuver2024throughthickand pages 1-2, cyrenne2018transplantationinthe pages 4-5)

2. Etiology

2.1 Disease causal factors

Primary driver biology (current evidence): JAK2/JAK–STAT pathway deregulation. A whole-genome and RNA-sequencing study provides evidence that structural and mutational alterations converging on JAK2 signaling are central in this lymphoma, including recurrent JAK2 fusions and loss of negative regulation via SH2B3. (torres2021deregulationofjak2 pages 1-2, torres2021deregulationofjak2 pages 3-5)

Direct quote (abstract evidence): “we show that mutually exclusive structural alterations involving JAK2 and SH2B3 predominantly underlie pcAECyTCL… Functional studies confirmed oncogenicity of JAK2 fusions… and their sensitivity to JAK inhibitor treatment.” (Haematologica; published online 2021; DOI https://doi.org/10.3324/haematol.2020.274506). (torres2021deregulationofjak2 pages 1-2)

2.2 Risk factors

No validated environmental, infectious, or inherited germline predisposition factors were identified in the retrieved sources. The current literature base is dominated by somatic tumor profiling and clinicopathologic case descriptions. (torres2021deregulationofjak2 pages 1-2, deenen2019pitfallsindiagnosing pages 1-2)

2.3 Protective factors / gene–environment interactions

No protective factors or gene–environment interaction evidence was identified in the retrieved sources. (willemze2019the2018update pages 13-16)

3. Phenotypes

3.1 Clinical phenotypes (signs/symptoms)

Common presentation includes rapidly progressive papules/plaques/nodules/tumors, often ulcerated or necrotic, with potential extracutaneous spread (reported sites include lung, testis, CNS, oral mucosa in case-based literature). (loya2023probableprimarycutaneous pages 3-4, kempf2021cutaneoust‐celllymphomas—an pages 1-2)

In WHO–EORTC tabulations, the typical presentation is ulcerating plaques, nodules and tumors. (willemze2019the2018update media 461b18ed)

3.2 Age of onset, severity, and progression

This is generally described as aggressive and rapidly progressive, with poor survival. (kempf2021cutaneoust‐celllymphomas—an pages 1-2, loya2023probableprimarycutaneous pages 3-4)

3.3 Differential diagnosis / diagnostic pitfalls

It can clinically and histologically mimic inflammatory or indolent lymphoproliferative disorders; a documented pitfall is resemblance to pyoderma gangrenosum or lymphomatoid papulosis (LyP) type D, necessitating close clinicopathologic correlation and appropriate immunophenotyping. (deenen2019pitfallsindiagnosing pages 1-2)

3.4 Suggested HPO terms (for knowledge base annotation; not exhaustive)

  • Skin ulcer (HP:0001050)
  • Cutaneous nodule (HP:0100749)
  • Skin plaque (HP:0200035)
  • Erythematous skin lesion (HP:0010783)
  • Necrosis (HP:0000966)
  • Central nervous system involvement (phenotype depends on manifestation; e.g., seizures HP:0001250)

(These are ontology suggestions; the retrieved sources support the underlying clinical concepts but do not provide HPO mappings.) (loya2023probableprimarycutaneous pages 3-4, willemze2019the2018update media 461b18ed)

4. Genetic / Molecular Information

4.1 Recurrent somatic alterations (primary literature)

High-resolution genomics (WGS/RNA-seq; n=12 tumors) identified: (i) recurrent JAK2 fusions (e.g., PCM1::JAK2, KHDRBS1::JAK2, TFG::JAK2) and (ii) mutually exclusive focal inactivation of SH2B3, a negative regulator of JAK2 signaling. Together, alterations affecting the JAK2–SH2B3 axis predominated. (torres2021deregulationofjak2 pages 5-7, torres2021deregulationofjak2 pages 2-3)

Mechanistically, JAK2 fusion architecture is consistent with constitutive activation: the fusions join the JAK2 kinase domain to partner oligomerization domains, predicted to “self-oligo/dimerize and become activated without the need of cytokine-mediated receptor stimulation.” (torres2021deregulationofjak2 pages 3-5)

Additional recurrent cooperating lesions reported include frequent disruption of CDKN2A/B (9p21) and deletions of chromatin regulators (e.g., ARID1A, EED), consistent with cell-cycle checkpoint loss and chromatin dysregulation as cooperating hallmarks. (torres2021deregulationofjak2 pages 3-5, torres2021deregulationofjak2 pages 2-3)

A review summarizing genetic abnormalities across primary cutaneous lymphomas also reports recurrent targetable fusions in this entity, including CAPRIN1::JAK2 and SELENOI::ABL1, reinforcing the theme of kinase-fusion-driven oncogenic signaling. (gallardo2022geneticsabnormalitieswith pages 7-9)

4.2 Functional consequences and therapeutic implications

Functional assays showed JAK2 fusions to be oncogenic and sensitive to JAK inhibition, supporting biomarker-driven consideration of JAK inhibitors (e.g., ruxolitinib) when an activated JAK2 axis is detected. (torres2021deregulationofjak2 pages 1-2, torres2021deregulationofjak2 pages 5-7)

4.3 Suggested GO biological process terms (mechanism annotation)

  • JAK-STAT cascade (GO:0007259)
  • Regulation of cytokine-mediated signaling pathway (GO:0001959)
  • Positive regulation of cell population proliferation (GO:0008284)
  • Cell cycle checkpoint (GO:0000075)
  • NF-kappaB signaling (e.g., GO:0043122)

4.4 Suggested cell types (Cell Ontology; mechanism annotation)

  • CD8-positive, alpha-beta T cell (CL:0000625)
  • Cytotoxic T cell (CL:0000910)

(These are ontology suggestions aligned to the immunophenotype and lineage reported in WHO–EORTC tables and molecular studies.) (willemze2019the2018update media 461b18ed, willemze2019the2018update pages 13-16)

5. Environmental Information

No specific environmental, lifestyle, occupational, or infectious triggers were identified in the retrieved sources for this entity. (willemze2019the2018update pages 13-16)

6. Mechanism / Pathophysiology

6.1 Causal chain (integrated model)

  1. Initiating oncogenic lesions: recurrent JAK2 gene fusions or loss of negative regulation via SH2B3 produce persistent JAK2 signaling. (torres2021deregulationofjak2 pages 3-5, torres2021deregulationofjak2 pages 5-7)
  2. Signal transduction and transcriptional programs: transcriptome analysis shows upregulation of JAK2 signaling, cell-cycle programs, and TNF-α/NF-κB signaling, plus a high inflammatory response signature. (torres2021deregulationofjak2 pages 1-2, torres2021deregulationofjak2 pages 5-7)
  3. Tumor expansion and tissue phenotype: malignant CD8+ cytotoxic T cells infiltrate the epidermis (marked epidermotropism), producing clinically aggressive ulcerating plaques/tumors with capacity for extracutaneous dissemination. (willemze2019the2018update media 461b18ed, loya2023probableprimarycutaneous pages 3-4)

6.2 Molecular profiling technologies

The most disease-specific mechanistic evidence in the retrieved set comes from whole-genome sequencing and RNA sequencing in pcAECyTCL tumors. (torres2021deregulationofjak2 pages 1-2, torres2021deregulationofjak2 pages 2-3)

7. Anatomical Structures Affected

7.1 Organ/tissue level

  • Primary site: skin (cutaneous lymphoma by definition; no extracutaneous disease at diagnosis in classification frameworks). (willemze2019the2018update pages 13-16)
  • Clinical morphology: ulcerating plaques/nodules/tumors. (willemze2019the2018update media 461b18ed)

7.2 Suggested UBERON terms

  • Skin of body (UBERON:0002097)
  • Epidermis (UBERON:0001003)

8. Temporal Development

8.1 Onset and progression

The disease is described as having rapid onset of necrotic/ulcerated plaques and tumors and an aggressive course. (kempf2021cutaneoust‐celllymphomas—an pages 1-2)

9. Inheritance and Population

9.1 Epidemiology (rarity)

WHO–EORTC tabulated frequency is <1% among primary cutaneous lymphomas in registry-based summaries. (willemze2019the2018update media 461b18ed)

A 2023 case report summarizes the rarity as “about 1% of cutaneous T-cell lymphomas” and notes that “slightly more than 30 cases” had been reported in the literature at that time (case-report-level secondary summary). (loya2023probableprimarycutaneous pages 3-4)

9.2 Inheritance

No germline inheritance pattern was identified in the retrieved sources; available evidence supports a predominantly somatic oncogenic process (e.g., JAK2 fusions, SH2B3 deletions). (torres2021deregulationofjak2 pages 3-5)

10. Diagnostics

10.1 Diagnostic approach (clinicopathologic)

Diagnosis relies on combined clinical and histopathologic evaluation because of overlap with other CD8+ cutaneous lymphomas and inflammatory mimics. (lupu2018anunusualpresentation pages 6-6, deenen2019pitfallsindiagnosing pages 1-2)

WHO–EORTC immunophenotype snapshot (Table data): CD3+, CD4−, CD8+, cytotoxic proteins positive, CD56−, EBV−, lineage αβ T-cell. (willemze2019the2018update media 461b18ed)

10.2 Biomarkers and molecular tests

Given the recurrent JAK2 fusions and SH2B3 alterations, contemporary molecular profiling (e.g., RNA-seq fusion detection and/or DNA-based profiling) can identify actionable lesions and support classification in challenging cases. (torres2021deregulationofjak2 pages 5-7, gallardo2022geneticsabnormalitieswith pages 7-9)

10.3 Differential diagnosis (examples supported in retrieved sources)

  • Pyoderma gangrenosum (clinical mimic)
  • Lymphomatoid papulosis type D
  • CD8+ mycosis fungoides
  • Cutaneous γδ T-cell lymphoma
  • Primary cutaneous peripheral T-cell lymphoma, NOS

(deenen2019pitfallsindiagnosing pages 1-2, loya2023probableprimarycutaneous pages 3-4)

11. Outcome / Prognosis

11.1 Registry-level survival statistics

WHO–EORTC table data report 5-year disease-specific survival (DSS) ~31% for this provisional entity. (willemze2019the2018update media 461b18ed)

11.2 Case-based prognosis estimates

A 2023 case report states a “survival time of 32 months from the commencement of skin lesions” (secondary summary of prior literature). (loya2023probableprimarycutaneous pages 3-4)

12. Treatment

12.1 Current practice patterns and real-world implementations

Because prospective trials are scarce, real-world management often follows aggressive lymphoma paradigms and institutional experience.

Systemic chemotherapy and radiation: A multi-institution case series reported use of multiagent regimens (e.g., CHOP, EPOCH, gemcitabine-based regimens, ICE/DHAP), plus radiotherapy including localized XRT and total skin electron beam therapy (TSEBT). (cyrenne2018transplantationinthe pages 4-5, cyrenne2018transplantationinthe pages 7-9)

Transplantation: The same series emphasizes that durable responses were observed mainly with allogeneic stem cell transplantation (allo-SCT) or brentuximab vedotin in selected settings. (cyrenne2018transplantationinthe pages 4-5)

Targeted / biomarker-driven therapy: Genomic evidence supporting JAK2 pathway targeting has enabled off-label or investigational use of JAK inhibitors (e.g., ruxolitinib), including use after relapse post-transplant in a 2023 case report. (sopena2023hematopoieticstemcell pages 2-3, torres2021deregulationofjak2 pages 1-2)

12.2 Expert opinion (2023–2024 priority)

A 2024 ASH Hematology expert review stresses that PCAETCL has “few prospective studies to guide treatment,” and that “recent genomic insights… such as the presence of JAK2 fusions in PCAETCL… have created options for new biomarker-driven strategies.” (Hematology; Dec 2024; DOI https://doi.org/10.1182/hematology.2024000529). (stuver2024throughthickand pages 1-2)

12.3 Treatment outcomes and statistics (available)

In the 2018 case series, outcomes included multiple complete responses in individuals receiving allo-SCT and brentuximab; at last follow-up, transplanted patients were alive, with median follow-up around 40 months (range reported). (cyrenne2018transplantationinthe pages 4-5)

A 2023 case report reiterates poor baseline prognosis (“5-year survival rate of less than 40%”) and describes multi-line therapy culminating in allo-HSCT, followed by relapse treated with ruxolitinib. (sopena2023hematopoieticstemcell pages 1-2, sopena2023hematopoieticstemcell pages 2-3)

12.4 MAXO terms (treatment action ontology; suggested)

  • Chemotherapy (MAXO:0000058)
  • Radiation therapy (MAXO:0000014)
  • Allogeneic hematopoietic stem cell transplantation (MAXO term; concept supported by clinical text)
  • Janus kinase inhibitor therapy (MAXO concept)

(These are ontology suggestions; supporting evidence for modalities is in cited clinical series/case reports.) (cyrenne2018transplantationinthe pages 7-9, sopena2023hematopoieticstemcell pages 2-3)

12.5 Ongoing clinical trials / registries (not disease-specific but relevant to cytotoxic/T-cell lymphoma populations)

  • NCT05475925 (Phase 1/2; cytotoxic lymphomas / large granular lymphocytic leukemia; recruiting). (tool-retrieved trial record; not PCAETCL-specific) (stuver2024throughthickand pages 1-2)
  • NCT05978141 (Observational registry for people with T-cell lymphoma; recruiting). (stuver2024throughthickand pages 1-2)

13. Prevention

No primary prevention strategy is supported in the retrieved sources. Secondary prevention is limited to early recognition and accurate diagnosis, given frequent diagnostic pitfalls and aggressive progression. (deenen2019pitfallsindiagnosing pages 1-2, lupu2018anunusualpresentation pages 6-6)

14. Other Species / Natural Disease

No naturally occurring veterinary/other-species analog was identified in the retrieved sources. (willemze2019the2018update pages 13-16)

15. Model Organisms

No dedicated in vivo model organism systems were identified in the retrieved sources. Mechanistic functional work in the key molecular study used cell-based assays to validate oncogenicity of JAK2 fusions and their inhibitor sensitivity. (torres2021deregulationofjak2 pages 5-7)

Notes on evidence gaps

  1. Standard identifiers (MONDO/Orphanet/ICD/MeSH) were not present in the retrieved full-text excerpts; mapping will require dedicated queries to those ontology resources using the synonyms listed. (willemze2019the2018update pages 13-16, loya2023probableprimarycutaneous pages 4-4)
  2. Many clinical outcome statistics remain based on registry summaries and small case series, reflecting the rarity and the limited prospective trial evidence base. (stuver2024throughthickand pages 1-2, cyrenne2018transplantationinthe pages 4-5)

References

  1. (deenen2019pitfallsindiagnosing pages 1-2): N. J. Deenen, L. Koens, E. H. Jaspars, M. Vermeer, R. Willemze, M. D. de Rie, and M. Bekkenk. Pitfalls in diagnosing primary cutaneous aggressive epidermotropic cd8+ t‐cell lymphoma. British Journal of Dermatology, 180:411-412, Oct 2019. URL: https://doi.org/10.1111/bjd.17252, doi:10.1111/bjd.17252. This article has 13 citations and is from a highest quality peer-reviewed journal.

  2. (geller2018nktcelllymphomanasal pages 1-3): Shamir Geller, Patricia L Myskowski, and Melissa Pulitzer. Nk/t-cell lymphoma, nasal type, γδ t-cell lymphoma, and cd8-positive epidermotropic t-cell lymphoma—clinical and histopathologic features, differential diagnosis, and treatment. Seminars in Cutaneous Medicine and Surgery, 37:30-38, Mar 2018. URL: https://doi.org/10.12788/j.sder.2018.020, doi:10.12788/j.sder.2018.020. This article has 53 citations and is from a peer-reviewed journal.

  3. (willemze2019the2018update pages 13-16): Rein Willemze, Lorenzo Cerroni, Werner Kempf, Emilio Berti, Fabio Facchetti, Steven H. Swerdlow, and Elaine S. Jaffe. The 2018 update of the who-eortc classification for primary cutaneous lymphomas. Blood, 133 16:1703-1714, Apr 2019. URL: https://doi.org/10.1182/blood-2018-11-881268, doi:10.1182/blood-2018-11-881268. This article has 1674 citations and is from a highest quality peer-reviewed journal.

  4. (willemze2019the2018update media 461b18ed): Rein Willemze, Lorenzo Cerroni, Werner Kempf, Emilio Berti, Fabio Facchetti, Steven H. Swerdlow, and Elaine S. Jaffe. The 2018 update of the who-eortc classification for primary cutaneous lymphomas. Blood, 133 16:1703-1714, Apr 2019. URL: https://doi.org/10.1182/blood-2018-11-881268, doi:10.1182/blood-2018-11-881268. This article has 1674 citations and is from a highest quality peer-reviewed journal.

  5. (loya2023probableprimarycutaneous pages 4-4): Marcela Velarde Loya, Monica G Millan Reza, Mariana Olaya Cordova, and Zaira D Chavéz López. Probable primary cutaneous cd8+ aggressive epidermotropic cytotoxic t-cell lymphoma: a case report of a diagnostic challenge. Cureus, Aug 2023. URL: https://doi.org/10.7759/cureus.44375, doi:10.7759/cureus.44375. This article has 1 citations.

  6. (sundram2019cutaneouslymphoproliferativedisorders pages 1-2): Uma Sundram. Cutaneous lymphoproliferative disorders: what’s new in the revised 4th edition of the world health organization (who) classification of lymphoid neoplasms. Advances in Anatomic Pathology, 26:93-113, Mar 2019. URL: https://doi.org/10.1097/pap.0000000000000208, doi:10.1097/pap.0000000000000208. This article has 21 citations and is from a domain leading peer-reviewed journal.

  7. (kempf2019cutaneouslymphomas—anupdate pages 1-3): Werner Kempf, Anne‐Katrin Zimmermann, and Christina Mitteldorf. Cutaneous lymphomas—an update 2019. Hematological Oncology, 37:43-47, Jun 2019. URL: https://doi.org/10.1002/hon.2584, doi:10.1002/hon.2584. This article has 110 citations and is from a peer-reviewed journal.

  8. (lupu2018anunusualpresentation pages 6-6): M Lupu, V Voiculescu, and L Papagheorghe. An unusual presentation of primary cutaneous aggressive epidermotropic cd8+ t cell lymphoma. Unknown journal, 2018.

  9. (torres2021deregulationofjak2 pages 1-2): Armando N. Bastidas Torres, Davy Cats, Jacoba J. Out-Luiting, Daniele Fanoni, Hailiang Mei, Luigia Venegoni, Rein Willemze, Maarten H. Vermeer, Emilio Berti, and Cornelis P. Tensen. Deregulation of jak2 signaling underlies primary cutaneous cd8+ aggressive epidermotropic cytotoxic t-cell lymphoma. Haematologica, 107:702-714, Apr 2021. URL: https://doi.org/10.3324/haematol.2020.274506, doi:10.3324/haematol.2020.274506. This article has 61 citations.

  10. (gallardo2022geneticsabnormalitieswith pages 1-2): Fernando Gallardo and Ramon M. Pujol. Genetics abnormalities with clinical impact in primary cutaneous lymphomas. Cancers, 14:4972, Oct 2022. URL: https://doi.org/10.3390/cancers14204972, doi:10.3390/cancers14204972. This article has 22 citations.

  11. (torres2021deregulationofjak2 pages 3-5): Armando N. Bastidas Torres, Davy Cats, Jacoba J. Out-Luiting, Daniele Fanoni, Hailiang Mei, Luigia Venegoni, Rein Willemze, Maarten H. Vermeer, Emilio Berti, and Cornelis P. Tensen. Deregulation of jak2 signaling underlies primary cutaneous cd8+ aggressive epidermotropic cytotoxic t-cell lymphoma. Haematologica, 107:702-714, Apr 2021. URL: https://doi.org/10.3324/haematol.2020.274506, doi:10.3324/haematol.2020.274506. This article has 61 citations.

  12. (torres2021deregulationofjak2 pages 5-7): Armando N. Bastidas Torres, Davy Cats, Jacoba J. Out-Luiting, Daniele Fanoni, Hailiang Mei, Luigia Venegoni, Rein Willemze, Maarten H. Vermeer, Emilio Berti, and Cornelis P. Tensen. Deregulation of jak2 signaling underlies primary cutaneous cd8+ aggressive epidermotropic cytotoxic t-cell lymphoma. Haematologica, 107:702-714, Apr 2021. URL: https://doi.org/10.3324/haematol.2020.274506, doi:10.3324/haematol.2020.274506. This article has 61 citations.

  13. (stuver2024throughthickand pages 1-2): Robert Stuver and Steven M. Horwitz. Through thick and thin: confronting the aggressive cutaneous t-cell lymphomas. Hematology, 2024:62-68, Dec 2024. URL: https://doi.org/10.1182/hematology.2024000529, doi:10.1182/hematology.2024000529. This article has 0 citations and is from a peer-reviewed journal.

  14. (cyrenne2018transplantationinthe pages 4-5): Benoit M. Cyrenne, Juliet Fraser Gibson, Antonio Subtil, Michael Girardi, Iris Isufi, Stuart Seropian, and Francine Foss. Transplantation in the treatment of primary cutaneous aggressive epidermotropic cytotoxic cd8‐positive t‐cell lymphoma. Clinical Lymphoma, Myeloma & Leukemia, 18:e85–e93, Jan 2018. URL: https://doi.org/10.1016/j.clml.2017.11.004, doi:10.1016/j.clml.2017.11.004. This article has 21 citations.

  15. (loya2023probableprimarycutaneous pages 3-4): Marcela Velarde Loya, Monica G Millan Reza, Mariana Olaya Cordova, and Zaira D Chavéz López. Probable primary cutaneous cd8+ aggressive epidermotropic cytotoxic t-cell lymphoma: a case report of a diagnostic challenge. Cureus, Aug 2023. URL: https://doi.org/10.7759/cureus.44375, doi:10.7759/cureus.44375. This article has 1 citations.

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  18. (gallardo2022geneticsabnormalitieswith pages 7-9): Fernando Gallardo and Ramon M. Pujol. Genetics abnormalities with clinical impact in primary cutaneous lymphomas. Cancers, 14:4972, Oct 2022. URL: https://doi.org/10.3390/cancers14204972, doi:10.3390/cancers14204972. This article has 22 citations.

  19. (cyrenne2018transplantationinthe pages 7-9): Benoit M. Cyrenne, Juliet Fraser Gibson, Antonio Subtil, Michael Girardi, Iris Isufi, Stuart Seropian, and Francine Foss. Transplantation in the treatment of primary cutaneous aggressive epidermotropic cytotoxic cd8‐positive t‐cell lymphoma. Clinical Lymphoma, Myeloma & Leukemia, 18:e85–e93, Jan 2018. URL: https://doi.org/10.1016/j.clml.2017.11.004, doi:10.1016/j.clml.2017.11.004. This article has 21 citations.

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  21. (sopena2023hematopoieticstemcell pages 1-2): L Sopena, M Merchante, MA Alcácera, and I Varela. Hematopoietic stem cell transplantation in primary cutaneous aggressive epidermotropic cd8+ t-cell lymphoma: a case report. Journal of Clinical Images and Medical Case Reports, Oct 2023. URL: https://doi.org/10.52768/2766-7820/2646, doi:10.52768/2766-7820/2646. This article has 0 citations.