Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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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.[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%), (3/12 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 (2/12 patients) | D: Supports presence of a high-grade proliferative (cell-cycle deregulated) molecular subtype; MYC rearrangements co-occurred with JAK2 fusions | Both patients had JAK2 fusions.[1] | |
| ABL1 fusion[2] | SELENO1-ABL1 | Retained its catalytic tyrosine kinase domain but lost its N-terminal SH2 and SH3 regulatory domains | Recurrent (1/6 patients) | Potential therapeutic target with Imatinib.[3] | |||
| BAZ1A rearrangement[1] | None specified | Encodes a chromatin-remodeling factor; rearrangements likely cause chromatin dysregulation and transcriptional mis-regulation. The gene is grouped with other drivers of chromatin regulation and cell-cycle control. | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| PTPRC rearrangement[1] | None specified | Negative regulator of JAK-STAT signaling; rearrangements disrupt this phosphatase, removing inhibition of JAK2 → persistent STAT activation and T-cell proliferation. | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| RB1 rearrangement[1] | None specified | Tumor suppressor controlling G1/S checkpoint. Recurrent rearrangements likely disrupt RB1, leading to deregulated cell-cycle progression and cooperation with other oncogenic events | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| MTAP rearrangement[1] | None specified | None specified | Structural (inter- or intrachromosomal) rearrangements | Common (~25%), (3/12 patients) | |||
| SH2B3 rearrangement[1] | None specified | A negative regulator of JAK2 signaling. Alterations in SH2B3 result in inactivation of this inhibitory adaptor protein. | Focal interstitial deletions at 12q24.12 | Recurrent (2/12 patients) | D: Identifies cases with loss of negative regulation in the JAK-STAT pathway. | ||
| CLEC16A rearrangement[1] | None specified | None specified | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| PIP4K2A rearrangement[1] | None specified | None specified | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| DLEU1 rearrangement[1] | None specified | None specified | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| SLC24A2 rearrangement[1] | None specified | None specified | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| ABR
rearrangement[1] |
None specified | None specified | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| GNA14 rearrangement[1] | None specified | None specified | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| RHCE rearrangement[1] | None specified | None specified | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| RHD rearrangement[1] | None specified | None specified | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| DLG2 rearrangement[1] | None specified | None specified | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) | |||
| FRMD4A rearrangement[1] | None specified | None specified | Structural (inter- or intrachromosomal) rearrangements | Recurrent (2/12 patients) |
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.)
| 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) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| 1 | Loss | p36.11[1] [4] | Unknown | Unknown | ||
| 1 | Loss | 1p36.22[1] | Unknown | Unknown | ||
| 1 | Loss | 1p36.32-p36.33[1][4] | Unknown | Unknown | ||
| 2 | Loss | q37.3[4] | Unknown | Unknown | ||
| 4 | Loss | q13.2[1] | Unknown | Unknown | ||
| 7 | Gain | q21.11-q22.3[4] | Unknown | Unknown | ||
| 7 | Gain | q22.1[1] | Unknown | Unknown | ||
| 7 | Gain | q32.1-q36.1[4] | Unknown | Unknown | ||
| 7 | Gain | q35[1] | Unknown | Unknown | ||
| 7 | Gain | q36.1-q36.3[1][4] | Unknown | Unknown | ||
| 7 | Loss | p14.1[1] | Unknown | Unknown | ||
| 7 | Loss | q34[1][4] | Unknown | Unknown | ||
| 8 | Loss | p12[4] | Unknown | Unknown | ||
| 8 | Gain | q24.3[4] | Unknown | Unknown | ||
| 9 | Loss | p21.3[1][4] | Unknown | Unknown | 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] | |
| 10 | Loss | p11.22[1] | Unknown | Unknown | ||
| 11 | Loss | q23.2[1] | Unknown | Unknown | ||
| 12 | Loss | q24.12[1] | Unknown | Unknown | ||
| 13 | Loss | q14.11[1][4] | Unknown | Unknown | ||
| 14 | Loss | q11.2[1][4] | Unknown | Unknown | ||
| 16 | Loss | p13.13[1] | Unknown | Unknown | ||
| 17 | Loss | p13.2[4] | Unknown | Unknown | ||
| 17 | Loss | p13.3[1] | Unknown | Unknown | No cancer genes.[1] | |
| 17 | Gain | q21.31[4] | Unknown | Unknown | ||
| 17 | Gain | q21.33-q22[1][4] | Unknown | Unknown | ||
| 17 | Gain | q22[1] | Unknown | Unknown | ||
| 17 | Gain | q25.3[4] | Unknown | Unknown | ||
| 19 | Loss | p13.3[1] | Unknown | Unknown | ||
| 21 | Gain | q22.12[4] | Unknown | Unknown | ||
| X | Gain | p11.23-p11.22[4] | Unknown | Unknown | ||
| X | Gain | q28[4] | Unknown | Unknown |
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 | Rare (1/12 patients,1/12 patients) | Unknown | Unknown | |
| JAK2; p.L393V | Germline SNV renders JAK2 hypersensitive to cytokine stimulation | Oncogene | Rare (1/12 patients) | Unknown | Unknown | |
| STAT3; p.H19R, p.G604A | Gain-of-function mutations | Oncogene | Rare (each 1/12 patients) | Unknown | Unknown | |
| STAT5B; p.N642H, p.P702S, p.Y665F, p.S434L | Gain-of-function mutations | Oncogene | p.N642H, Recurrent (2 /12)
p.P702S, p.Y665F, p.S434L, Rare (each 1/12 patients) |
Unknown | Unknown | |
| SH2B3; p.L201Sfs78, p.V35Afs154 | Frameshift mutations leading to loss of function | Tumor Suppressor Gene (TSG) | Rare (each 1/12 patients) | Unknown | Unknown | |
| SOCS1; p.S71Rfs*14 | Frameshift mutation leading to a premature stop codon[1] | Tumor Suppressor Gene (TSG) | Rare (1/12 patients) | Unknown | Unknown |
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.[5][6][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.[5][6][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
- Ki67 % - >75%
- Negative - EBER, CD1a, CD30, CD25, ALK1, EMA
- Variable - CD45RA(+/-), CD15(-/+)[1][2][4]
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34 1.35 1.36 1.37 1.38 1.39 1.40 1.41 1.42 1.43 1.44 Bastidas Torres, Armando N.; et al. (2022-03-01). "Deregulation of JAK2 signaling underlies primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma". Haematologica. 107 (3): 702–714. doi:10.3324/haematol.2020.274506. ISSN 1592-8721. PMC 8883537 Check
|pmc=value (help). PMID 33792220 Check|pmid=value (help). - ↑ 2.0 2.1 Lee, Katie; et al. (2021-12-09). "Primary cytotoxic T-cell lymphomas harbor recurrent targetable alterations in the JAK-STAT pathway". Blood. 138 (23): 2435–2440. doi:10.1182/blood.2021012536. ISSN 1528-0020. PMC 8662071 Check
|pmc=value (help). PMID 34432866 Check|pmid=value (help). - ↑ Buus, Terkild B.; et al. (2021-12-09). "Oncogenic fusions JAK up CD8+ cytotoxic CTCL". Blood. 138 (23): 2311–2312. doi:10.1182/blood.2021013619. ISSN 0006-4971.
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 4.23 Fanoni, Daniele; et al. (2018-12). "Array‐based CGH of primary cutaneous CD8+ aggressive EPIDERMO‐tropic cytotoxic T‐cell lymphoma". Genes, Chromosomes and Cancer. 57 (12): 622–629. doi:10.1002/gcc.22673. ISSN 1045-2257. Check date values in:
|date=(help) - ↑ 5.0 5.1 5.2 5.3 Guitart, Joan; et al. (2017-05). "Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas". Modern Pathology. 30 (5): 761–772. doi:10.1038/modpathol.2016.240. Check date values in:
|date=(help) - ↑ 6.0 6.1 6.2 6.3 Berti, Emilio; et al. (1999-08). "Primary Cutaneous CD8-Positive Epidermotropic Cytotoxic T Cell Lymphomas". The American Journal of Pathology. 155 (2): 483–492. doi:10.1016/S0002-9440(10)65144-9. Check date values in:
|date=(help) - ↑ 7.0 7.1 7.2 7.3 7.4 Robson, Alistair; et al. (2015-10). "Aggressive epidermotropic cutaneous CD 8 + lymphoma: a cutaneous lymphoma with distinct clinical and pathological features. Report of an EORTC Cutaneous Lymphoma Task Force Workshop". Histopathology. 67 (4): 425–441. doi:10.1111/his.12371. ISSN 0309-0167. Check date values in:
|date=(help) - ↑ Travassos, Daphine Caxias; et al. (2022-06). "Primary cutaneous CD8 + cytotoxic T‐cell lymphoma of the face with intraoral involvement, resulting in facial nerve palsy after chemotherapy". Journal of Cutaneous Pathology. 49 (6): 560–564. doi:10.1111/cup.14199. ISSN 0303-6987. Check date values in:
|date=(help) - ↑ Saruta, Hiroshi; et al. (2017-09). "Hematopoietic stem cell transplantation in advanced cutaneous T‐cell lymphoma". The Journal of Dermatology. 44 (9): 1038–1042. doi:10.1111/1346-8138.13848. ISSN 0385-2407. Check date values in:
|date=(help) - ↑ 10.0 10.1 Nofal, Ahmad; et al. (2012-10). "Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: Proposed diagnostic criteria and therapeutic evaluation". Journal of the American Academy of Dermatology. 67 (4): 748–759. doi:10.1016/j.jaad.2011.07.043. Check date values in:
|date=(help) - ↑ Deenen, N.J.; et al. (2019-02). "Pitfalls in diagnosing primary cutaneous aggressive epidermotropic CD 8 + T‐cell lymphoma". British Journal of Dermatology. 180 (2): 411–412. doi:10.1111/bjd.17252. ISSN 0007-0963. Check date values in:
|date=(help) - ↑ Willemze, R. (2005-05-15). "WHO-EORTC classification for cutaneous lymphomas". Blood. 105 (10): 3768–3785. doi:10.1182/blood-2004-09-3502. ISSN 0006-4971.