ABSTRACT Objective Alveolar rhabdomyosarcoma (ARMS) is a distinct histologic subtype of rhabdomyosarcoma, associated with the presence of a PAX3 or PAX7::FOXO1 gene fusion in approximately 80% of cases. Adverse outcomes for patients with ARMS are associated with the presence of a FOXO1 gene fusion; however, additional genetic markers are necessary to better characterize FOXO1 ‐fusion negative ARMS. Methods We reviewed the histology of 306 diagnostic biopsies from participants enrolled in the recent Children's Oncology Group (COG) trial ARST1431. Ultra‐low pass whole genome sequencing and custom panel sequencing were performed on all diagnostic biopsies with available material. Results Histologic review of diagnostic specimens from ARST1431 identified two cases with predominantly ARMS histology (small round cells with uniform, round nuclei) that were distinctive compared to other cases with ARMS histology due to the presence of: (a) distinctive large nucleoli with coarse chromatin, (b) amphophilic cytoplasm, (c) abundant karyorrhexis, and (d) admixed tingible body macrophages—all strongly resembling the histologic features of Burkitt lymphoma. Each case showed diffuse myogenin reactivity and lacked evidence of a FOXO1 gene rearrangement by FISH and expanded molecular testing. Tumor sites included the perianal region (2‐year‐old male) and upper extremity (1‐year‐old female). Sequencing studies identified high amplification (> 50 copies) of the MYCL proto‐oncogene in both cases. Retrospective analysis of the amplification data available for ARST1431 identified one additional case in a 15‐year‐old male with high amplification of MYCL and similar histologic features that were more difficult to identify in a limited biopsy sample. The two former patients experienced recurrence and died of disease, while the third patient was alive without recurrence. Conclusions We hypothesize that the distinctive histologic phenotype of these three cases is driven by high‐level MYCL amplification (> 50 copies). With an incidence of 1.6% in this series, these unique histologic features may be useful to further identify and characterize FOXO1 ‐fusion negative ARMS. Review of additional cases will be required to determine the clinical significance of this unique histologic pattern with MYCL amplification.
ABSTRACT This retrospective study involving 155 patients from the Düsseldorf MDS Registry compared cytogenetic banding from peripheral blood (PB) and bone marrow (BM) in patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). For 63 of these patients, paired PB and BM cytogenetic analyses were available that were conducted no more than 3 months apart. Concordant ISCN results were found in 81%, with no significant differences in the total number of metaphases or aberrant metaphases between PB and BM. Furthermore, IPSS‐R/‐M scorings, derived from PB and BM, turned out to be comparable, with only 7 out of 63 patients classified into a different cytogenetic risk category. This implies that aberrant clones are not underrepresented in PB and that cytogenetic findings from PB can reliably reflect those obtained from BM.
ABSTRACT Primary pericardial SMARCB1 ‐deficient tumors with rhabdoid morphology are exceptionally rare. We present an adult case of a primary SMARCB1 ‐deficient pericardial tumor showing concurrent loss of INI1 ( SMARCB1 ) and BRG1 ( SMARCA4 ) expression, representing the third documented tumor with co‐loss of these SWI/SNF subunits across tumor sites. Targeted RNA sequencing detected no pathogenic sequence variants or fusion transcripts and showed reduced SMARCB1 and SMARCA4 transcript abundance. DNA‐based whole‐exome sequencing (WES) identified no pathogenic or likely pathogenic sequence variants in either gene. High‐resolution SNP microarray demonstrated a homozygous SMARCB1 deletion with intact SMARCA4 , establishing biallelic SMARCB1 inactivation; BRG1 loss was accompanied by marked SMARCA4 transcript downregulation in the absence of a detectable SMARCA4 genomic alteration. In the clinicopathological context, the overall findings supported classification as a SMARCB1 ‐deficient pericardial tumor with rhabdoid morphology. Following resection, postoperative imaging suggested residual or recurrent disease. Combined doxorubicin–ifosfamide chemotherapy and radical radiotherapy achieved a complete radiologic response. However, imaging 18 months after resection suggested multifocal pericardial recurrence, with disease control regained following similar treatment. This course is hypothesis‐generating and may suggest sensitivity to DNA‐damaging therapy in the setting of dual SWI/SNF deficiency.
ABSTRACT MN1::BEND2 fusion is well established in CNS tumors but exceptionally rare in extracranial mesenchymal neoplasms. We report a subcutaneous upper‐back tumor in a 41‐year‐old woman, composed of bland round‐to‐epithelioid cells with branching capillary vasculature and focal infiltrative growth. The tumor recurred 42 months after excision. Targeted RNA sequencing identified an in‐frame MN1 exon 1:: BEND2 exon 9 fusion, supported by Sanger sequencing and MN1 break‐apart FISH; Nuclear BEND2 immunoreactivity was an ancillary finding. Unlike two previously reported extracranial MN1::BEND2 ‐harboring tumors with high‐grade spindle‐cell morphology and myofibroblastic differentiation, this tumor lacked overt high‐grade nuclear features and myoid differentiation. This case broadens the morphologic spectrum of MN1::BEND2 mesenchymal neoplasms. Limited reported cases, no meaningful follow‐up after re‐excision, and unsuccessful methylation profiling preclude conclusions regarding biologic behavior. BEND2 immunohistochemistry may serve an ancillary screen marker, but its sensitivity and specificity remain to be established, and molecular confirmation is required.
ABSTRACT The molecular interpretation of eosinophilic neoplasms harboring t (5;12) may be challenging because cytogenetic breakpoint assignments can suggest a PDGFRB rearrangement without identifying the underlying fusion. We retrospectively investigated a woman with a chronic eosinophilic myeloid neoplasm initially investigated in 2002, in whom a subsequent t (5;12)(q31 ~ q33;p13) raised suspicion of PDGFRB involvement. Contemporary molecular investigations failed to identify the rearrangement, and an empiric trial of imatinib produced no meaningful hematologic response. Seventeen years later, blast transformation was accompanied by persistence of t (5;12) and acquisition of del(9)(q22). Fluorescence in situ hybridization demonstrated ETV6 rearrangement but no PDGFRB break‐apart pattern, indicating en bloc translocation of the PDGFRB locus. Targeted RNA sequencing of archived RNA extracted from cryopreserved peripheral blood cells collected in 2004 subsequently identified a strong‐evidence ETV6::ACSL6 fusion joining exon 2 of ETV6 to exon 2 of ACSL6 , supported by 1847 reads and 218 unique start sites. Targeted myeloid DNA sequencing detected no mutation within the regions analyzed. Identification of ETV6::ACSL6 shifted the biological interpretation away from presumed constitutive tyrosine kinase activation toward a proposed cytokine regulatory rewiring involving the 5q31 cytokine locus, consistent with published experimental evidence and the absence of response to imatinib. This case illustrates how contemporary RNA‐based fusion detection can resolve a historically uncharacterized structural rearrangement and refine biological interpretation and therapeutic expectations, while documenting an unusually prolonged natural history of an ETV6::ACSL6 ‐associated eosinophilic myeloid neoplasm.
