Background ALK gene rearrangements have been described in a variety of mesenchymal neoplasms. Recently, a new subset of ALK-rearranged epithelioid mesenchymal neoplasms was described. As the spectrum of ALK-rearranged neoplasms has been expanding, the true nature of the neoplasms, clinical behavior, and relatedness has yet to be determined. We utilized methylation profiling to examine our cohort of these neoplasms to determine how these tumors relate to each other, and to other mesenchymal neoplasms both with and without ALK rearrangements, which may help with further classification of these rare tumors. Design DNA was bisulfite converted (Zymo EZ DNA Methylation), treated with a restoration process, amplified and fragmented. Hybridization was performed using the Infinium MethylationEPIC BeadChip v2 (Illumina), and scanning and processing were performed using the NextSeq 550 or iScan (Illumina). Data were first analyzed using the Heidelberg Epignostix Sarcoma Methylation Classifier (version 12.3). To explore the epigenetic landscape, we performed t-distributed stochastic neighbor embedding (t-SNE) analysis incorporating our cohort and all reference tumors published by Koelsche et al., followed by unsupervised clustering of the t-SNE coordinates using hierarchical density-based spatial clustering of applications with noise (HDBSCAN). Clinicopathologic and molecular data were also reviewed and integrated with the methylation results. Results We identified 5 cases of ALK-rearranged epithelioid mesenchymal neoplasms in 3 females and 2 males, with an age ranging from 1 month to 28 years. One infant case corresponded to the infantile fibrosarcoma (IFS) methylation class, whereas the remaining cases did not achieve a high-calibrated match to any established class using the Heidelberg Epignostix sarcoma methylation classifier. On t-SNE analysis, the cases did not form a distinct cluster but rather intermingled with other tumor types, including infantile fibrosarcoma (n = 2), EGFR-altered tumors (n = 1), giant cell tumor of bone (n = 1), and dermatofibrosarcoma protuberans (n = 1) (Figure 1). Conclusions While all the cases in our cohort demonstrated ALK fusions and epithelioid morphology, they did not cluster together on methylation analysis. They exhibited a diverse epigenetic profile and may represent a heterogenous group. Two of our cases occurred in infants and clustered near IFS, suggesting that in young children, these may represent an epithelioid variant of IFS-like tumors.
1554 ALK-rearranged Epithelioid Mesenchymal Neoplasms in Children and Young Adults Represent an Epigenetically Diverse Group of Tumors
Evelina Miele;
2026-01-01
Abstract
Background ALK gene rearrangements have been described in a variety of mesenchymal neoplasms. Recently, a new subset of ALK-rearranged epithelioid mesenchymal neoplasms was described. As the spectrum of ALK-rearranged neoplasms has been expanding, the true nature of the neoplasms, clinical behavior, and relatedness has yet to be determined. We utilized methylation profiling to examine our cohort of these neoplasms to determine how these tumors relate to each other, and to other mesenchymal neoplasms both with and without ALK rearrangements, which may help with further classification of these rare tumors. Design DNA was bisulfite converted (Zymo EZ DNA Methylation), treated with a restoration process, amplified and fragmented. Hybridization was performed using the Infinium MethylationEPIC BeadChip v2 (Illumina), and scanning and processing were performed using the NextSeq 550 or iScan (Illumina). Data were first analyzed using the Heidelberg Epignostix Sarcoma Methylation Classifier (version 12.3). To explore the epigenetic landscape, we performed t-distributed stochastic neighbor embedding (t-SNE) analysis incorporating our cohort and all reference tumors published by Koelsche et al., followed by unsupervised clustering of the t-SNE coordinates using hierarchical density-based spatial clustering of applications with noise (HDBSCAN). Clinicopathologic and molecular data were also reviewed and integrated with the methylation results. Results We identified 5 cases of ALK-rearranged epithelioid mesenchymal neoplasms in 3 females and 2 males, with an age ranging from 1 month to 28 years. One infant case corresponded to the infantile fibrosarcoma (IFS) methylation class, whereas the remaining cases did not achieve a high-calibrated match to any established class using the Heidelberg Epignostix sarcoma methylation classifier. On t-SNE analysis, the cases did not form a distinct cluster but rather intermingled with other tumor types, including infantile fibrosarcoma (n = 2), EGFR-altered tumors (n = 1), giant cell tumor of bone (n = 1), and dermatofibrosarcoma protuberans (n = 1) (Figure 1). Conclusions While all the cases in our cohort demonstrated ALK fusions and epithelioid morphology, they did not cluster together on methylation analysis. They exhibited a diverse epigenetic profile and may represent a heterogenous group. Two of our cases occurred in infants and clustered near IFS, suggesting that in young children, these may represent an epithelioid variant of IFS-like tumors.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
