Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma

Haematolymphoid Tumours (WHO Classification, 5th ed.)

(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.)

Primary Author(s)*

Ahmed Eladely, MBBCh. Andrew Siref, MD.

Creighton University, Omaha, NE.

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	T-cell and NK-cell lymphoid proliferations and lymphomas
Family	Mature T-cell and NK-cell neoplasms
Type	Primary cutaneous T-cell lymphoid proliferations and lymphomas
Subtype(s)	Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma

Related Terminology

Acceptable	N/A
Not Recommended	Berti lymphoma; Ketron–Goodman / disseminated pagetoid reticulosis

Gene Rearrangements

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.

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

Individual Region Genomic Gain/Loss/LOH

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.)

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.

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.

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.)

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.

Many SNVs and deletions in other genes are also detected and are predicted to be deleterious.

Epigenomic Alterations

Alteration in LIN28, ARID1A, PARP10, MLL3, and MLL5 have been described and may play a role in the pathogenesis.

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.

Familial Forms

Unknown