👤 Cristina R Antonescu

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare, low-grade sarcoma affecting with predilection the acral soft tissues of middle-aged adults. Clinically, MIFS is associated with a high rate of local recurrence but infrequent distant metastases. The diagnosis remains challenging due to their wide histologic spectrum and overlap with reactive, benign, and low-grade malignant lesions. Moreover, a significant limitation is that molecular confirmation is achieved in only a subset of cases, due to its broad range of genetic alterations which requires a multiplatform approach. Thus, a definitive diagnosis, especially at nonacral sites and in molecularly negative cases, remains uncertain. Our goal was to perform a detailed clinicopathologic and molecular reappraisal of MIFS managed at a single tertiary cancer center with dedicated orthopedic oncology expertise. Additionally, we examined potential outcomes correlating with specific genetic alterations. A cohort of 33 patients (12 males, 21 females, median age 52 years) was selected. Tumors were tested by FISH, Archer, and/or targeted NGS. VGLL3 amplification was detected in 84%, BRAF fusions in 33% and combined TGFBR3/MGEA5 rearrangements in 32% of cases. Two novel fusions were detected, RRAGB::CCNB3 and FGFR1::ZBTB47. Other events included a YAP1::MAML2 fusion in two cases, one co-existing with a BRAF fusion. Overall, 8 (24%) patients recurred, 4 more than once, while 4 (12%) patients developed metastasis (3 locoregional, 1 pulmonary), all associated with VGLL3 gene amplification. Positive margin status was associated with increased recurrence and reduced disease-free survival (DFS, p = 0.02). Moreover, it emphasizes the impact of multiplatform molecular testing in confirming the diagnosis. The lack of both local recurrence and metastatic potential outside VGLL3 amplifications requires further investigation. Show less

We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans. We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion. Thirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%-90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response. Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes. See related commentary by Weiss et al., p. 649. Show less

The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3/7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel FGFR1::ANK1 fusion, we reviewed our molecular files for cases harboring FGFR1-related fusions. One additional case with an FGFR1::TACC1 fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in TP53 or DICER1 on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic TP53 and TET2 mutations. Two additional RMS cases (one unclassified, one ERMS) with FGFR1 overexpression but lacking FGFR1 fusions were identified by RNA sequencing. These two cases and the FGFR1::TACC1-positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent FGFR1 fusions. However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy. Show less

Composite hemangioendothelioma is a rare, locally aggressive, and rarely metastasizing vascular neoplasm which affects both children and adults. Recently, a number of gene fusions including YAP1::MAML2, PTBP1::MAML2, and EPC1::PHC2 have been detected in a small subset of cases with or without neuroendocrine expression. Herein, we present four additional cases with novel in-frame fusions. The cohort comprises two females and two males with a wide age range at diagnosis (24-80 years). Two tumors were deep involving the right brachial plexus and mediastinum, while the remaining were superficial (right plantar foot and abdominal wall). The size ranged from 1.5 to 4.8 cm in greatest dimension. Morphologically, all tumors had an admixture of at least two architectural patterns including retiform hemangioendothelioma, hemangioma, epithelioid hemangioendothelioma, or angiosarcoma. The tumors were positive for endothelial markers CD31 (3/3), ERG (4/4), and D2-40 (1/4, focal), while SMA was expressed in 2/3 highlighting the surrounding pericytes. Synaptophysin showed immunoreactivity in 2/3 cases. One patient had a local recurrence after 40 months, while two patients had no evidence of disease 4 months post-resection. Targeted RNA sequencing detected novel in-frame fusions in each of the cases: HSPG2::FGFR1, YAP1::FOXR1, ACTB::MAML2, and ARID1B::MAML2. The two cases with neuroendocrine expression occurred as superficial lesions and harbored YAP1::FOXR1 and ARID1B::MAML2 fusions. Our study expands on the molecular spectrum of this enigmatic tumor, further enhancing our current understanding of the disease. Show less

With the widespread application of next-generation sequencing, the genetic landscape of uterine mesenchymal neoplasms has been evolving rapidly to include several recently identified fusion genes. Although chromosomal rearrangements involving the 10q22 and 17q21.31 loci have been reported in occasional uterine leiomyomas decades ago, the corresponding KAT6B::KANSL1 fusion has been only recently identified in 2 uterine tumors diagnosed as leiomyoma and leiomyosarcoma. We herein describe 13 uterine stromal neoplasms carrying a KAT6B::KANSL1 (n=11) and KAT6A::KANSL1 (n=2) fusion. Patient ages ranged from 33 to 81 years (median, 49 y). Tumor size was 2.6 to 23.5 cm (median, 8.2 cm). Nine tumors were myometrium-centered, and 3 had an intracavitary component. Original diagnoses were mostly low-grade endometrial stromal sarcoma (LG-ESS; 10 cases) with atypical features (limited CD10 expression, sex cord-like features, pericytic vasculature, and frequent myxoid changes). Treatment was hysterectomy±bilateral salpingo-oophorectomy (10), myomectomy (1), and curettage (2). Five patients were disease-free at 6 to 34 months, 3 (27%) died of disease at 2 to 47 months, and 3 were alive with disease at 2, 17, and 17 years. Histologically, most tumors showed variable overlap with LG-ESS, but they were generally well-circumscribed lacking the extensive permeative and angioinvasive growth typical of LG-ESS. They were composed of monotonous medium-sized oval and spindle cells arranged into diffuse sheets with prominent spiral-type arterioles and frequent pericytoma-like vascular pattern. Variable myxoid stromal changes were frequent. Mitotic activity ranged from 1 to >20 in 10 HPFs. Immunohistochemistry showed variable expression of CD10 (12/13), estrogen receptor (8/11), progesterone receptor (8/11), smooth muscle actin (9/11), desmin (4/12), h-caldesmon (2/10), calretinin (3/8), inhibin (1/7), WT1 (4/7), cyclin D1 (5/11; diffuse in only 1 case), and pankeratin (5/10). This series characterizes a KAT6B/A::KANSL1 fusion-positive uterine stromal neoplasm within the morphologic spectrum of LG-ESS but with atypical features. The relationship of these neoplasms to genuine LG-ESS remains unclear. This molecular subtype of uterine endometrial stromal sarcoma has the potential for an unfavorable clinical course despite the absence of widely invasive growth; nevertheless, analysis of more cases is necessary to delineate the phenotypic spectrum and biological potential of this tumor. Show less