Pediatric Mature T/NK-cell neoplasms
2023-05-14 Sheng Xiao, MD , Chunxiao Yang Affiliation1.Brigham and Women's Hospital, Boston, MA
Classification
Definition
Pediatric mature T/NK-cell neoplasms are a heterogeneous group of lymphomas, with anaplastic large cell lymphoma (ALCL) being the most common subtype, accounting for about 10% of pediatric non-Hodgkin lymphomas. ALCL is divided into ALK+ and ALK- subgroups, with ALK+ patients having a worse prognosis. However, they can respond well to next-generation ALK inhibitors such as Lorlatinib.1 The genomic profile can help in the diagnosis of this group of tumors. For example, peripheral T-cell lymphomas can exhibit TET2 and DNMT3A mutations, while hepatosplenic cell lymphomas can present with isochromosome 7q.2 Additionally, TCR clonality assays are important in diagnosing T-cell lymphoma due to the inefficiency of establishing clonality by flow cytometry (unlike in B-cell lymphoma). It is worth noting that TCR is typically polyclonal in NK-cell lymphoma.
| Mature T/NK-cell neoplasms | Genetic marker(s) | |
|---|---|---|
| Peripheral T-cell lymphoma NOS | PTCL-NOS is a diverse group of mature T-cell lymphomas that do not fit into any specific PTCL category and is typically exhibiting an aggressive clinical course. ID2, RHOA, TET2, CDKN2A, CDKN2B, and TP53 are mutated in pediatric PTCL, NOS, although are less frequent as compared to their adult counterparts. Chromosome aberrations include complex karyotypes with both numerical and structural changes.3,4 | |
| Aggressive NK-cell leukemia | ANKL is neoplastic NK cell proliferation with an acute presentation. Activation of the JAK/STAT and the RAS/MAPK signaling plays a central role in tumorigenesis of aggressive NK cell leukemia. Common mutations include TP53 (34%), DDX3X (29%), TET2 (28%), CREBBP (21%), KMT2D (21%), STAT3(17%-21%).5-8 TCR clonality is typically negative. Recurrent cytogenetic aberrations include del(6q), del(11q), del(7p), del(17p), and 1q gain.9,10 | |
| Mycosis fungoides | MF is a cutaneous T-cell lymphoma with clonal small to medium-sized mature T cells. Mutated genes are enriched in JAK3/STAT3 signaling, MAPK signaling, and epigenetic regulation. Common mutations include TNFRSF1B, KMT2C, TP53, KRAS, PLCG1, DNMT3A.11 | |
| Primary cutaneous CD30-positive T-cell lymphoproliferative disorders | Primary cutaneous CD30+ lymphoproliferative disorders include lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma (C-ALCL), with a good prognosis for both subtypes. Chromosome rearrangements/ gene fusions are dominant drivers, including NPM1::ALK from t(2;5)(p23;q35), DUSP22::FRA7H from t(6;7)(p25.3;q32.3), TP63::TBL1XR1 from inv(3)(q26q28), and NPM1::TYK2 from t(5;19)(q35;p13). Additional frequently mutated genes include STAT3, H3K4, KMT2D, KMT2A, SETD2, CREBBP, TP53.12-15 | |
| Subcutaneous panniculitis-like T-cell lymphoma | SPTCL is a CD8+ cytotoxic α/β T-cell lymphoma mimicking panniculitis. PI3K/AKT/mTOR and JAK‐STAT signaling are involved in tumorigenesis.16,17 Germline mutation in HAVCR2 (encoding T-cell immunoglobulin mucin 3) is a genetic factor that predisposes to this disease. Additional frequently mutated genes include UNC13D, PIAS3, KMT2D.18 | |
| Anaplastic large cell lymphoma, ALK-positive | ALK+ ALCL is one of the more common NHLs in children, with ALK rearrangement being a dominant driver, including NPM1::ALK from t(2;5)(p23;q35) and TPM3::ALK from t(1;2)(q25;p23). The oligomerization domain from NPM1 or TPM3 is fused to the kinase domain of ALK, leading to ligand-independent ALK activation.19-27 | |
| Hepatosplenic T-cell lymphoma | iso(7q) is a common finding in HPTL, leading to a gain of 7q including ABCB1 at 7q22.28,29 Trisomy 8 is also seen in some cases. Mutations of SETD2, STAT5B, INO80, TET3, SMARCA2, STAT3 are frequently observed.30,31 These tumors mostly express TCR γ/δ. | |
| Systemic EBV-positive T-cell lymphoma of childhood | Systemic EBV-positive T-cell lymphoma of childhood is a rapidly progressing disease characterized by multiorgan failure, sepsis, and ultimately death and is caused by the clonal proliferation of T cells infected with the EBV. There are currently no consistent chromosome or gene alterations that have been identified in association with this disease. | |
| Hydroa vacciniforme lymphoproliferative disorder | No consistent chromosome/gene alterations are described. TCR is usually clonal but does not correlate with the severity of the disease. |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 35802834 | 2022 | Next-generation ALK inhibitors are highly active in ALK-positive large B-cell lymphoma. | Soumerai JD et al |
| 2 | 35330161 | 2022 | Genetic Landscape of Peripheral T-Cell Lymphoma. | Hathuc V et al |
| 3 | 34363798 | 2021 | Clinicopathological features and prognostic significance of programmed death ligand 1 in pediatric ALK-positive anaplastic large cell lymphoma: results of the ALCL99 treatment in Japan. | Iwafuchi H et al |
| 4 | 34390161 | 2021 | Molecular features of non-anaplastic peripheral T-cell lymphoma in children and adolescents. | Au-Yeung RKH et al |
| 5 | 27631517 | 2017 | EBV-negative Aggressive NK-cell Leukemia/Lymphoma: Clinical, Pathologic, and Genetic Features. | Nicolae A et al |
| 6 | 29263771 | 2017 | The Cost of Hematopoietic Stem-Cell Transplantation in the United States. | Broder MS et al |
| 7 | 29148541 | 2018 | Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia. | Huang L et al |
| 8 | 32590457 | 2020 | Genomic and Immunophenotypic Landscape of Aggressive NK-Cell Leukemia. | El Hussein S et al |
| 9 | 17261497 | 2007 | Aggressive natural killer cell leukemia: report of a Chinese series and review of the literature. | Ryder J et al |
| 10 | 16049916 | 2005 | Genome-wide array-based comparative genomic hybridization of natural killer cell lymphoma/leukemia: different genomic alteration patterns of aggressive NK-cell leukemia and extranodal Nk/T-cell lymphoma, nasal type. | Nakashima Y et al |
| 11 | 32039026 | 2019 | An Update on Molecular Biology of Cutaneous T Cell Lymphoma. | Walia R et al |
| 12 | 32049976 | 2020 | Evidence linking atopy and staphylococcal superantigens to the pathogenesis of lymphomatoid papulosis, a recurrent CD30+ cutaneous lymphoproliferative disorder. | Kadin ME et al |
| 13 | 15165197 | 2004 | Three children with CD30 cutaneous anaplastic large cell lymphomas bearing the t(2;5)(p23;q35) translocation. | Hinshaw M et al |
| 14 | 34977845 | 2022 | Genomic Analysis of Cutaneous CD30-Positive Lymphoproliferative Disorders. | Abdulla FR et al |
| 15 | 30630983 | 2019 | CD30-positive primary cutaneous lymphoproliferative disorders: molecular alterations and targeted therapies. | Prieto-Torres L et al |
| 16 | 28294301 | 2018 | Recurrent mutations in epigenetic modifiers and the PI3K/AKT/mTOR pathway in subcutaneous panniculitis-like T-cell lymphoma. | Li Z et al |
| 17 | 30792187 | 2019 | Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma. | Polprasert C et al |
| 18 | 30374066 | 2018 | Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome. | Gayden T et al |
| 19 | 9819383 | 1998 | Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity. | Bai RY et al |
| 20 | 11110708 | 2000 | Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. | Bai RY et al |
| 21 | 17416736 | 2007 | NPM-ALK oncogenic kinase promotes cell-cycle progression through activation of JNK/cJun signaling in anaplastic large-cell lymphoma. | Leventaki V et al |
| 22 | 16909118 | 2007 | Oncogenic tyrosine kinase NPM/ALK induces activation of the MEK/ERK signaling pathway independently of c-Raf. | Marzec M et al |
| 23 | 11280786 | 2001 | Role of phosphatidylinositol 3-kinase-Akt pathway in nucleophosmin/anaplastic lymphoma kinase-mediated lymphomagenesis. | Slupianek A et al |
| 24 | 16482213 | 2006 | Fusion tyrosine kinase mediated signalling pathways in the transformation of haematopoietic cells. | Turner SD et al |
| 25 | 12934099 | 2003 | Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma. | Amin HM et al |
| 26 | 15184887 | 2004 | Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastic large cell lymphoma. | Amin HM et al |
| 27 | 15895073 | 2005 | Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. | Chiarle R et al |
| 28 | 11807981 | 2002 | Fluorescence in situ hybridization study of chromosome 7 aberrations in hepatosplenic T-cell lymphoma: isochromosome 7q as a common abnormality accumulating in forms with features of cytologic progression. | Wlodarska I et al |
| 29 | 25057852 | 2014 | Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma. | Finalet Ferreiro J et al |
| 30 | 24947020 | 2014 | Frequent STAT5B mutations in γδ hepatosplenic T-cell lymphomas. | Nicolae A et al |
| 31 | 28122867 | 2017 | The Genetic Basis of Hepatosplenic T-cell Lymphoma. | McKinney M et al |
Citation
Sheng Xiao, MD ; Chunxiao Yang
Pediatric Mature T/NK-cell neoplasms
Atlas Genet Cytogenet Oncol Haematol. 2023-05-14
Online version: http://atlasgeneticsoncology.org/solid-tumor/209159/pediatric-mature-t-nk-cell-neoplasms
