Myoepithelial Tumors of Bone With EWSR1::PBX3 Fusion: A Spectrum From Benign to Malignant.

The EWSR1::PBX3 fusion gene, commonly associated with cutaneous syncytial myoepitheliomas, is also found in myoepithelial tumors (METs) of bone and soft tissue. These tumors typically demonstrate benign histology and favorable outcomes. This study examines 6 previously unreported intraosseous METs harboring the EWSR1::PBX3 fusion, focusing on their histopathologic characteristics, immunophenotype, clinical and radiographic profiles, and patient outcomes. The cohort comprised 5 men and 1 woman, aged 25 to 65 years (median age: 31 years), with tumors located in the proximal tibia (3 cases), distal radius (2 cases), and ilium (1 case) and sizes between 3.2 and 12.2 cm (median size: 3.9 cm). Imaging showed osteolytic lesions with varying degrees of cortical involvement and soft tissue extension in 3 cases. Histologically, 4 tumors showed mainly uniform oval-to-spindled cells in syncytial or fascicular arrangements within a collagenous matrix, displaying either bland nuclear features or mild atypia, and low to slightly elevated mitotic activity (≤1 per 10 high-power fields in 3 cases and 6 per 10 high-power fields in 1), classifying them as benign or atypical METs. In contrast, 2 tumors exhibited pronounced nuclear atypia with ovoid, spindled, epithelioid and round cells, hyperchromatic nuclei, inconspicuous nucleoli, increased N/C ratios, high mitotic rates (17 and 19 per 10 high-power fields), and extensive necrosis. Both tumors behaved aggressively-one patient underwent amputation after neoadjuvant chemotherapy and radiation, and the other died within 7 months with the disease still present. Immunohistochemically, the tumors consistently expressed epithelial membrane antigen and S100 but lacked keratin (AE1/AE3) expression. Our study demonstrated that bone METs with EWSR1::PBX3 fusions encompass a histologic continuum from benign to malignant, with benign/atypical METs mirroring their cutaneous analogs in morphology, and malignant variants distinguished by heterogeneous cytologic and architectural features, pronounced nuclear atypia, and high mitotic rates.

DNA Methylation Profiling Distinguishes Adamantinoma-Like Ewing Sarcoma From Conventional Ewing Sarcoma.

Adamantinoma-like Ewing sarcoma (ALES) has traditionally been considered a variant of Ewing sarcoma because it generally harbors EWSR1::FLI1 fusions despite showing diffuse positivity for keratins and p40. However, it has become increasingly recognized that different tumors can have identical translocations, including shared fusions between carcinomas and sarcomas, raising questions as to whether ALES might represent a separate entity. Using methylation profiling, we further explored the relationship between Ewing sarcoma and ALES. The archives of multiple institutions were searched for candidate cases of ALES. DNA methylation profiling was performed and results were compared to corresponding data from conventional Ewing sarcoma. Twelve cases of ALES (5 previously reported) were identified in 10 men and 2 women (aged 20-72 years; median age, 41.5 years). Cases included tumors arising in the parotid gland (3), sinonasal cavity (2), submandibular gland (2), thyroid gland (1), neck (1), gingiva (1), hypopharynx (1), and mandible (1). Histologic review consistently showed sheets and nests of basaloid cells within a fibromyxoid or hyalinized stroma. All tumors were positive for at least 1 keratin and CD99 expression, whereas all 10 cases tested were positive for p63 or p40; S100 protein expression was noted in 2 cases. Cases harbored either EWSR1::FLI1 fusions (n = 6), FUS::FLI1 fusions (n = 1), and/or EWSR1 rearrangements (n = 6). Methylation profiling was successful in 11/12 cases evaluated. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) of DNA methylation data revealed a distinct methylation cluster for all 11 cases, including the tumor with the FUS::FLI1 fusion, which clearly segregated them from the conventional Ewing sarcoma. Follow-up (n = 11, 1-154 months) revealed that 4 patients experienced recurrence and 6 developed metastatic disease. ALES demonstrates a distinct methylation signature from conventional Ewing sarcoma. This finding adds to the distinctive immunoprofile of ALES, suggesting that these 2 tumors should be considered distinct entities rather than histologic extremes of the same disease.

Lipoblastoma-Like Tumor and Fibrosarcoma-Like Lipomatous Neoplasm Represent the Same Entity: A Clinicopathologic and Molecular Genetic Study of 23 Cases Occurring in Both Men and Women at Diverse Locations.

Lipoblastoma-like tumor (LLT) is a benign soft tissue tumor demonstrating mixed morphologic features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma but lacking genetic alterations associated with those tumors. LLT was originally thought to be specific to the vulva but has since been reported in the paratesticular region. The morphologic features of LLT overlap with those of "fibrosarcoma-like lipomatous neoplasm" (FLLN), a rare, indolent adipocytic neoplasm considered by some to form part of the spectrum of atypical spindle cell and pleomorphic lipomatous tumor. We compared the morphologic, immunohistochemical, and genetic features of 23 tumors previously classified as LLT (n = 17) and FLLN (n = 6). The 23 tumors occurred in 13 women and 10 men (mean age, 42 years; range, 17 to 80 years). Eighteen (78%) cases arose in the inguinogenital region, whereas 5 tumors (22%) involved noninguinogenital soft tissue, including the flank (n = 1), shoulder (n = 1), foot (n = 1), forearm (n = 1), and chest wall (n = 1). Microscopically, the tumors were lobulated and septated, with variably collagenized fibromyxoid stroma, prominent thin-walled vessels, scattered univacuolated or bivacuolated lipoblasts, and a minor component of mature adipose tissue. Using immunohistochemistry, 5 tumors (42%) showed complete RB1 loss, with partial loss in 7 cases (58%). RNA sequencing, chromosomal microarray, and DNA next-generation sequencing study results were negative for significant alterations. There were no clinical, morphologic, immunohistochemical, or molecular genetic differences between cases previously classified as LLT or FLLN. Clinical follow-up (11 patients [48%]; range, 2-276 months; mean, 48.2 months) showed all patients were alive without disease, and only one patient had experienced a single local recurrence. We conclude that LLT and FLLN represent the same entity, for which "LLT" seems most appropriate. LLT may occur in either sex and any superficial soft tissue location. Careful morphologic study and appropriate ancillary testing should allow for the distinction of LLT from its potential mimics.

Pleomorphic Liposarcoma: A Series of 120 Cases With Emphasis on Morphologic Variants.

Pleomorphic liposarcoma (PLPS) is a highly aggressive sarcoma comprising variable numbers of pleomorphic lipoblasts mixed with undifferentiated pleomorphic sarcoma (UPS)-like areas. Morphologic variants, such as myxofibrosarcoma-like or epithelioid, may cause diagnostic confusion, especially on a core biopsy, but there are few data on the prognostic significance of these features. A total of 120 PLPS biopsies and resection specimens were reviewed and catalogued based on the presence of myxofibrosarcoma-like, UPS-like, and epithelioid foci, in 10% increments. The clinical parameters were collected. Cases occurred in 75 males and 45 females, ranging from 8 to 98 years (median, 62.5 y). Cases arose in the extremities (n=72), trunk (n=32), head/neck (n=10), bone (n=4), mediastinum (n=1), or viscera (colon polyp, n=1). Of those with known depth (n=81), 40 were intramuscular, 34 were subcutaneous, and 7 arose in the dermis. Their sizes ranged from 1 to 24.5 cm (median, 7 cm). Of the patients with ≥1 month of follow-up (n=70), 5 had recurrence and 15 had metastasis. The 5-year overall survival and event-free survival rates were 66.2% and 63.1%, respectively. Tumors ≥5 cm had inferior overall survival compared with tumors <5 cm. The presence of epithelioid areas was also statistically significant in terms of poorer overall survival and event-free survival, while tumors with ≥50% undifferentiated pleomorphic-like areas had better overall survival. There was a trend towards poorer outcomes in tumors with necrosis (≥1%). PLPS is an aggressive adipocytic malignancy that is most commonly present in the extremities of older adults. The morphologic features of these tumors are diverse, and they may be mistaken for UPS or myxofibrosarcoma, carcinoma, and melanomas, particularly on biopsies. Tumor size, necrosis, and epithelioid morphology are associated with adverse prognosis.