(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)
In PCAETL, recurrent genomic events affecting genes involved in the cell cycle, chromatin regulation, and the JAK/STAT pathway have been reported, including complex genomic rearrangements and diverse JAK2 fusions. Upregulated JAK2 signaling is a consistent finding in nearly all cases, distinguishing PCAETL from other cytotoxic cutaneous T-cell lymphomas. Cases without JAK2 fusions often exhibit gain-of-function mutations in JAK2, STAT3, and STAT5B, alongside loss of negative regulators of the JAK/STAT pathway, particularly SH2B3.[1]
Driver Gene
Fusion(s) and Common Partner Genes
Molecular Pathogenesis
Typical Chromosomal Alteration(s)
Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
Established Clinical Significance Per Guidelines - Yes or No (Source)
Clinical Relevance Details/Other Notes
JAK2 fusion
KHDRBS1-JAK2
PCM1-JAK2
TFG-JAK2
Fusion retains the JAK2 tyrosine kinase domain, tethered to partner oligomerization domains → self-oligo/dimerization → cytokine-independent activation and overactivation of JAK2 signaling
Common (~25%), (3 of 12 patients)
D: Identifies a JAK2-deregulated subset; JAK-STAT activation supported by pSTAT3/5 IHC and RNA-seq. T: Preclinical sensitivity to JAK1/2 inhibition (ruxolitinib IC₅₀ ≈ 9–15 nM) and AZD1480; oncogenic activity inhibited by JAK inhibition.
Potential therapeutic target with JAK inhibitors.[1]
MYC fusion
ACTB-MYC
NPM1-MYC
Fusions involve MYC, a transcriptional regulator driving proliferation. Partner genes (ACTB, NPM1) contribute strong promoters, likely leading to MYC overexpression and deregulated cell-cycle progression.
Structural (inter- or intrachromosomal) rearrangements
Recurrent (2 of 12 patients)
D: Supports presence of a high-grade proliferative (cell-cycle deregulated) molecular subtype; MYC rearrangements co-occurred with JAK2 fusions
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)
Chr #
Gain, Loss, Amp, LOH
Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]
Relevant Gene(s)
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
Established Clinical Significance Per Guidelines - Yes or No (Source)
The most frequently affected locus, shows losses in the MTAP, CDKN2A, and CDKN2B regions (12/20 patients).[4] It was also the most common in another study (10/12 patients).[1]
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
EXAMPLE:
8
EXAMPLE: Gain
EXAMPLE:
chr8
EXAMPLE:
Unknown
EXAMPLE: D, P
EXAMPLE:
Common recurrent secondary finding for t(8;21) (add references).
Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
The most frequently affected locus, shows losses in the MTAP, CDKN2A, and CDKN2B regions (12/20 patients).[4] It was also the most common in another study (10/12 patients).[1]
All the genes found in these regions are implicated in several pathways associated with lymphoma and tumor development, including T-cell signaling, DNA damage response, the JAK-STAT pathway, and epigenetic modifications.[4]
Characteristic Chromosomal or Other Global Mutational Patterns
Although PCAETL exhibit multiple copy number alterations (CNAs), they lack a distinct signature or genomic profile, as their recurrent CNAs partially or entirely overlap with those found in other aggressive cutaneous T cell lymphomas.[4]
Chromosomal Pattern
Molecular Pathogenesis
Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
Established Clinical Significance Per Guidelines - Yes or No (Source)
Clinical Relevance Details/Other Notes
Gene Mutations (SNV/INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
Gene
Genetic Alteration
Tumor Suppressor Gene, Oncogene, Other
Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
Established Clinical Significance Per Guidelines - Yes or No (Source)
Clinical Relevance Details/Other Notes
JAK3; p.R657W, p.M511I
Gain-of-function mutations
Oncogene
Unknown
Unknown
JAK2; p.L393V
Germline SNV renders JAK2 hypersensitive to cytokine stimulation
Oncogene
Unknown
Unknown
STAT3; p.H19R, p.G604A
Gain-of-function mutations
Oncogene
Unknown
Unknown
STAT5B; p.N642H, p.P702S, p.Y665F, p.S434L
Gain-of-function mutations
Oncogene
Unknown
Unknown
SH2B3; p.L201Sfs78, p.V35Afs154
Frameshift mutations leading to loss of function
Tumor Suppressor Gene (TSG)
Unknown
Unknown
SOCS1; p.S71Rfs*14
Frameshift mutation leading to a premature stop codon[1]
Tumor Suppressor Gene (TSG)
Unknown
Unknown
EXAMPLE:EGFR
EXAMPLE: Exon 18-21 activating mutations
EXAMPLE: Oncogene
EXAMPLE: Common (lung cancer)
EXAMPLE: T
EXAMPLE: Yes (NCCN)
EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE:TP53; Variable LOF mutations
EXAMPLE: Variable LOF mutations
EXAMPLE: Tumor Supressor Gene
EXAMPLE: Common (breast cancer)
EXAMPLE: P
EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE:BRAF; Activating mutations
EXAMPLE: Activating mutations
EXAMPLE: Oncogene
EXAMPLE: Common (melanoma)
EXAMPLE: T
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Germline SNV renders JAK2 hypersensitive to cytokine stimulation
STAT3; p.H19R, p.G604A
Oncogene
JAK2 fusions, SH2B3 deletions
None specified
No
Unknown
No
Gain-of-function mutations
STAT5B; p.N642H, p.P702S, p.Y665F, p.S434L
Oncogene
SH2B3 deletions
None specified
No
Unknown
No
Gain-of-function mutations
SH2B3; p.L201Sfs78, p.V35Afs154
Tumor Suppressor Gene (TSG)
STAT5B mutations, JAK or STAT gene mutations
JAK2 fusions
No
Unknown
No
Frameshift mutations leading to loss of function
SOCS1; p.S71Rfs*14
Tumor Suppressor Gene (TSG)
JAK or STAT gene mutations
None specified
No
Unknown
No
Frameshift mutation leading to a premature stop codon[1]
Many SNVs and deletions in other genes are also detected and are predicted to be deleterious.[1]
Epigenomic Alterations
Alteration in LIN28, ARID1A, PARP10, MLL3, and MLL5 have been described and may play a role in the pathogenesis.[4]
Genes and Main Pathways Involved
Gene; Genetic Alteration
Pathway
Pathophysiologic Outcome
JAK2; Fusion
JAK-STAT
Constitutive activation leading to cytokine-independent cell survival and proliferation. Overactivation of signaling pathways due to self-oligo/dimerization of the chimeric proteins.
SH2B3; Deletion
JAK-STAT
Loss of negative feedback regulation on JAK2 signaling, resulting in enhanced JAK2 pathway activation.
PTPRC; Deletion
JAK-STAT
Disruption of negative regulation of the JAK-STAT pathway, contributing to overactivation of JAK2 signaling.
STAT3; SNV
JAK-STAT
Gain-of-function mutations resulting in enhanced signaling and cell survival.
STAT5; SNV
JAK-STAT
Gain-of-function mutations leading to overactivation of the pathway, promoting cell proliferation.
MYC; Fusions
Cell Cycle Regulation
Dysregulation of cell cycle processes, contributing to uncontrolled cell proliferation.
CDKN2A/B; Deletions
Cell Cycle Regulation
Inactivation of tumor suppressor genes leading to disruptions in cell cycle control.
TP53; Truncating Mutations (nonsense, frameshift)
Cell Cycle Regulation
Loss of p53 function leading to impaired DNA repair and increased genomic instability.
ARID1A; Deletions
Chromatin Regulation
Loss of chromatin remodeling activity affecting gene expression and cell growth regulation.
KMT2D; Truncating Mutations
Chromatin Regulation
Disruption in histone methylation, affecting gene expression and cell differentiation.
NCOR1; Truncating Mutations
Chromatin Regulation
Loss of corepressor function, leading to altered gene expression and potentially contributing to oncogenesis.[1]
Genetic Diagnostic Testing Methods
Fluorescence In Situ Hybridization (FISH): Detects chromosomal rearrangements and specific gene fusions, such as JAK2 fusions.
Polymerase Chain Reaction (PCR): Amplifies specific regions of DNA to identify genetic alterations, including gene fusions and specific mutations.
Next-Generation Sequencing (NGS): Identifies pathogenic small-scale mutations (SNVs and INDELs) and structural alterations. NGS can analyze multiple genes and pathways simultaneously, which is useful for comprehensive genetic profiling.[1]
Familial Forms
Unknown
Additional Information
PCAETL has an aggressive clinical course, with a median survival time of 12 months. The prognosis is similar regardless of whether the morphology is small or large cell, or whether the lesions are localized or diffuse.[5]
This disease is defined/characterized as detailed below:
Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAETL) is a rare and poorly characterized neoplastic proliferation of T lymphocytes with CD8 and cytotoxic molecule expression. PCAETL is marked by epidermal necrosis, a high proliferation index, and aggressive clinical behavior. It should be distinguished from other rare epidermotropic subtypes of cutaneous gamma-delta T-cell lymphomas (such as gamma-delta mycosis fungoides), CD8+ mycosis fungoides, localized pagetoid reticulosis, and type D lymphomatoid papulosis.[6][5][7]
The epidemiology/prevalence of this disease is detailed below:
PCAETL is rare, comprising less than 1% of all cutaneous T-cell lymphomas. It typically occurs in adults and shows a predilection for males.[6][7]
The clinical features of this disease are detailed below:
Signs and symptoms - Diffusely distributed papules (common); Localized papules (less common); Ulcerated nodules, tumors, and plaques; Erosion or central necrosis; Preceded by chronic, poorly defined patches (subset); Disseminated to visceral sites (lungs, testes, CNS); Lymph nodes spared; No association with immunosuppression [6][5][7]
Laboratory findings - None
The sites of involvement of this disease are detailed below:
PCAETL can present with either localized or generalized skin lesions and may affect the oral mucosa.[8]
The morphologic features of this disease are detailed below:
Pagetoid epithelial involvement (epidermal and adnexal) is typically observed; however, the infiltrate may involve the entire dermis.[7][9] Lymphocyte morphology ranges from monomorphic to pleomorphic. Rimming of subcutaneous fat spaces has been reported. Spongiosis can result in blister formation.[10]
The tumor cells typically consist of atypical small to large lymphocytes with indented nuclei, minimal cytoplasm, and occasional immunoblastic features. Histological signs of cytotoxicity are evident, including epidermal necrosis or ulceration, dermal necrosis, karyorrhexis, and rare angiocentric destruction.[5][7][10] Ulceration can resemble pyoderma gangrenosum.[11] There is often pronounced pagetoid epidermotropism, particularly in cases with widespread lesions.[6][12]
The immunophenotype of this disease is detailed below:
Positive - CD3, TIA1, granzyme B, perforin, CCR4
CD4/CD8 - CD8+/CD4-; rare cases of double positivity or double negativity have been reported
CD2/CD5/CD7 - CD2(+/-), CD5(-), CD7(-/+)
TCR - TCR-βF1+, rarely TCRγδ+; rare cases of double positive and null type have been reported
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References
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Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
Prior Author(s):
*Citation of this Page: “Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 11/8/2025, https://ccga.io/index.php/HAEM5:Primary_cutaneous_CD8-positive_aggressive_epidermotropic_cytotoxic_T-cell_lymphoma.
