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PubMed2026

Genomic Diversity and Clinical Variability in Pediatric Primary Cutaneous Anaplastic Large Cell Lymphoma: A Case Series.

Primary cutaneous anaplastic large cell lymphoma (pcALCL) is a rare pediatric CD30-positive T-cell lymphoproliferative disorder with an excellent prognosis, but its genomic drivers are poorly defined. We report three children with skin-limited disease demonstrating striking molecular heterogeneity, including NPM::ALK, NUP214::FRK, and a novel PICALM::JAK2 fusion not previously described in pcALCL. Clinical courses ranged from spontaneous regression to systemic therapy, yet all achieved durable complete remission without progression over 31-50 months. These findings highlight previously unrecognized genomic diversity and expand the molecular landscape of pediatric pcALCL.

Humans↗
PubMed2026

Multiomic study of cutaneous T-cell lymphoma reveals single-cell clonal evolution in progression and therapy resistance.

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multiomics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. Here, we present a comprehensive multiomics view of CTCL clonal evolution, incorporating exome, whole-genome, epigenome, bulk, single-cell T-cell receptor, and single-cell RNA sequencing of 99 clinically annotated serial skin, peripheral blood, and lymph node samples from 34 patients with CTCL. We leveraged this extensive data set to define the molecular underpinnings of CTCL progression in individual patients at single-cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, phosphoinositide 3-kinase inhibitor signaling, and programmed cell death protein 1 (PD-1) checkpoint pathways as evasion tactics deployed by malignant T cells. We identified a gain-of-function mutation in STAT3 (D661Y) and demonstrated, using cleavage under targets and release using nuclease (CUT&RUN) and RNA sequencing, that it enhances binding to and transcription of genes in Rho GTPase pathways. With our previous work implicating this pathway in histone deacetylase inhibitor-resistant CTCL, these data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL. Our findings support an approach in which genomic analysis is widely used for improved disease monitoring, biomarker-informed clinical trial design, and genome-guided therapeutic decision-making. Moreover, these molecular changes present new opportunities for therapeutic targeting in this challenging and incurable cancer.

Multiomics↗
PubMed2026

Real-World Experience With TRBC1 Immunohistochemistry Across Cutaneous T-Cell Lymphoma Subtypes: A Large Cohort Study.

T-cell receptor &#x3b2;-chain constant region 1 (TRBC1) immunohistochemistry identifies clonal &#x3b1;&#x3b2; T-cell populations on tissue sections, but its real-world performance across cutaneous T-cell lymphoma (CTCL) and related infiltrates is uncharacterized. The analytic cohort comprised 665 biopsies (566 patients) with paired T-cell receptor (TCR) clonality testing, classified clinicopathologically as mycosis fungoides (MF; MF-Patch, MF-Plaque, MF-Tumor, and MF-Folliculotropic); MF or S&#xe9;zary syndrome; primary cutaneous small or medium T-cell lymphoproliferative disorders (LPDs); other CTCL-cutaneous LPDs; or reactive. At the primary <15%/>85% threshold, TRBC1 IHC achieved 85.8% sensitivity (337/393), 79.8% specificity (217/272), 86.0% positive and 79.5% negative predictive value, and 83.3% accuracy. Sensitivity was lowest in MF-Patch (84.2%). Three-reader agreement (Fleiss &#x3ba; = 0.943) fell to &#x3ba; = 0.776 in 176 reflexed biopsies, with disagreement concentrated on MF-Patch and CD30-positive LPDs. Monotypic TRBC1 predicted neoplasia, with odds rising with infiltrate density: MF-Patch (odds ratio, 5.41), MF-Plaque (10.40), MF/S&#xe9;zary syndrome with MF-Tumor (15.19), and CTCL-cutaneous LPD (18.16). Polytypic TRBC1 was associated with reactive disease (odds ratio, 53.65), effectively excluded clonality (negative likelihood ratio, 0.18), and was uniformly observed in an independent 270-biopsy reactive cohort. For observer-independent validation, digital image analysis-derived TRBC1 quantification (QuPath) was applied to a stratified random subset of 250 biopsies representative of the cohort's tumor-burden distribution. The digital read-tracked molecular clonality (85.1% sensitivity, 80.1% specificity against TCR; area under the curve, 0.842) agreed with the dermatopathologist's manual read in 87.6% of cases (&#x3ba; = 0.752), with the data-derived cutoff matching the prespecified <15%/>85% threshold value. Discordance was directional for both manual scoring and digital quantification: in MF-Patch, 25 of 38 (65.8%) and 12 of 17 (70.6%) cases were polytypic with monoclonal TCR (false-negative-dominant); in reactive biopsies, 34 of 45 (75.6%) and 19 of 20 (95%) were monotypic with polyclonal TCR (false-positive-dominant). These findings support a TRBC1-first approach, reserving reflex TCR testing for borderline expression or clinicopathologic discordance, preserving diagnostic accuracy while reducing molecular testing and reimbursement-based costs.

S&#xe9;zary syndrome↗
PubMed2026

Established and emerging prognostic factors in mycosis fungoides and S&#xe9;zary syndrome.

Mycosis fungoides (MF) and S&#xe9;zary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL), characterized by heterogeneous clinical behavior and variable prognosis. Accurate prognostication is essential for risk-adapted management. This review synthesizes emerging evidence on prognostic factors in MF and SS, with a focus on recent genomic advances. Traditional prognostic frameworks are outlined, highlighting the prognostic impact of demographics, stage, clinical features, and histologic findings. More advanced prognostics are then outlined, including genomic alterations and impact of the tumor microenvironment. We highlight realms in which integration of traditional and more biological prognostic frameworks can support more individualized treatment strategies.

S&#xe9;zary syndrome↗
PubMed2026

Mycosis Fungoides-Like Atopic Dermatitis Represents a Th22-Dominant Inflammatory Endotype.

BACKGROUND: Early-stage mycosis fungoides (MF) often presents diagnostic challenges because of its clinical overlap with atopic dermatitis (AD). In clinical practice, we encountered a subset of patients with severe AD who fulfilled the MF diagnostic criteria yet remained clinically indistinguishable from AD and presented refractoriness to advanced therapies. We termed this ambiguous entity "mycosis fungoides-like AD" (mfAD) and sought to determine whether it represents malignant transformation or a distinct inflammatory endotype of AD. METHODS: Skin biopsies were obtained from 7 patients with AD and 11 patients with mfAD. We performed paired single-cell RNA sequencing and single-cell T-cell receptor sequencing analyses. Publicly available MF and AD datasets were integrated for comparative analysis. Spatial transcriptomic profiling was used to contextualize single-cell findings within the tissue architecture. RESULTS: Comparative transcriptomic analysis revealed that T cells in mfAD were aligned with those in AD and lacked genomic instability. High-resolution profiling showed that mfAD was characterized by oligoclonal Th22 expansion rather than a single dominant malignant clone. Notably, all patients with mfAD achieved rapid clinical remission with selective JAK1 inhibition, indicating the therapeutic response characteristics of inflammatory dermatoses. CONCLUSION: Our findings demonstrate that mfAD is not a true malignancy, but rather a Th22-driven inflammatory endotype of AD. These results redefine mfAD as an inflammatory subtype within the AD spectrum, providing a mechanistic explanation for both the "pseudo-monoclonality" that leads to MF misdiagnosis and the failure of dupilumab. This study establishes a rationale for the use of JAK inhibitors in precision medicine for this patient population.

JAK inhibitor↗