Genes, Chromosomes & Cancer最新文献

Conventional high-grade osteosarcomas are characterized by aggressive radiologic features, cytologic pleomorphism, and complex genomics. However, rare examples of osteosarcomas remain challenging due to unusual histology, such as sclerosing or osteoblastoma-like features, which may require molecular confirmation of their complex genetic alterations. We have encountered such a case in a 17-year-old man, who presented with a third metatarsal sclerotic bone lesion, found incidentally in the work-up of a foot trauma. The initial imaging revealed a lesion with sclerotic/blastic features proximally and lucent/lytic portion distally, findings interpreted consistent with osteoblastoma. The lesion was managed intra-lesionally with curettings and cryoablation; however, the microscopic findings were non-specific, showing a bland osteoblastic proliferation embedded in a densely sclerotic matrix. Subsequently, the patient developed two rapid recurrences; the first recurrence was treated similarly despite its associated soft tissue extension radiographically, and the histologic findings remained non-specific. The 2nd recurrence showed a large mass, with bone destruction and soft tissue extension and an open biopsy revealed features of osteosarcoma with lace-like osteoid deposition, albeit with uniform cytomorphology. The subsequent below knee amputation showed features compatible with high-grade osteosarcoma, including solid growth of uniform epithelioid cells, with vesicular nuclei and scant cytoplasm, set in a lace-like meshwork of osteoid matrix. There was significant mitotic activity and tumor necrosis. Tumor cells were positive for SATB2. Further molecular work-up was performed showing an unexpected NIPBL::BEND2 fusion, which has been previously reported in two cases of phosphaturic mesenchymal tumor (PMT). FGF23 (ISH) was performed and was negative. By DNA methylation profiling, unsupervised clustering and UMAP dimensionality reduction revealed grouping with high-grade osteosarcomas and not with the PMT group. The patient received chemotherapy post-amputation and is alive without evidence of disease, with 10-month follow-up. We report an aggressive, overtly malignant acral bone-forming tumor, harboring a NIPBL::BEND2 fusion. Further studies are needed to evaluate the recurrent potential of this fusion in osteosarcomas and its relationship with PMT.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm that can locally recur and potentially metastasize. Approximately 50% of IMTs harbor rearrangements in the gene encoding anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase that can be therapeutically targeted with tyrosine kinase inhibitors (TKIs). With successful application of TKI in ALK-positive nonsmall cell carcinoma (NSCLC), ALK inhibitors are often first-line treatments for patients with unresectable or metastatic IMTs. Although acquired resistance to these agents may develop, resistance mechanisms are sparsely reported for IMTs. Here we report a case of a 71 year-old man with metastatic pulmonary IMT harboring a DCTN1::ALK fusion that progressed during alectinib TKI treatment. Whole exome sequencing of an enlarging metastatic lesion in right 4th rib revealed a novel p.V1180L mutation in the ALK tyrosine kinase domain as the mechanism of acquired resistance. To our knowledge, this is the first report of acquired p. V1180L mutation in IMTs treated with TKIs. In cases of ALK-positive IMTs that progress on TKI therapy, targeted sequencing for acquired ALK mutations may inform clinical decisions to adopt second-line therapeutic strategies.

Xanthogranulomatous epithelial tumor (XGET)/Keratin-positive giant cell tumor (KP-GCT) represents a spectrum of recently described neoplasms characterized by a proliferation of distinctive mononuclear cells expressing keratin within a background of osteoclast-like giant cells, mixed inflammatory cells, and a variably prominent xanthogranulomatous component. Recent studies demonstrated a recurrent HMGA2::NCOR2 fusion in many cases. We herein describe a case of XGET/KP-GCT arising in the right femoral head of a 19-year-old male harboring a rare novel HMGA2::COL14A1 fusion.

MN1 fusion is emerging as oncogenic in soft-tissue tumors. Here, we provided detailed clinicopathological documentation of a tumor with MN1::TAF3 fusion. The tumor developed on the face of an 8-year-old boy and did not recur or metastasize for 5 years after surgery without adjuvant therapy. Histologically, the tumor predominantly comprised sheets and nests of atypical, mildly pleomorphic epithelioid cells. Mallory body-like eosinophilic cytoplasmic inclusions, small round cells, and fascicles of spindle cells were focally observed. Mitotic activity was high, and focal necrosis was present. Immunohistochemically, the tumor was positive for cytokeratin AE1/AE3 in the epithelioid cell component but otherwise showed nonspecific phenotypes. Targeted RNA sequencing identified an in-frame MN1 (exon 1)::TAF3 (exon 3) fusion transcript. We validated the transcript with reverse transcription-polymerase chain reaction, Sanger sequencing, and MN1 break-apart fluorescence in situ hybridization. MN1::TAF3 was previously listed without details in a large-scale sequencing study involving a pediatric round cell sarcoma in the orbit, raising the possibility that these tumors might form a coherent group.