High-grade Sarcoma Research Articles

GLI1 gene alterations including fusions and amplifications compromise a subset of malignant mesenchymal tumors exhibiting characteristic monomorphic nested morphology and frequent S100 positivity, which mimic glomus tumors or well differentiated neuroendocrine tumors. We report four high-grade uterine endometrial stromal sarcomas (ESS) harboring GLI1 and MDM2/CDK4 co-amplifications with a median age of 51.5 years (range 43 ~ 72 years). Histologically, tumors showed a heterogenous morphology, including ovoid to spindle cells, showing nested/nodular arrangement (4/4). Myxoid background was observed at least partially in 4 tumors with prominent capillary networks. Mitoses index was 2 to 20/10 HPF (median 9.5/10 HPF). Immunochemically, tumors showed diffuse staining of CD10 (3/4) with frequently positive CyclinD1(2/4 tested) and mostly negative S100 protein (3/4). Next-generationsequencing (NGS) studies revealed GLI1 and MDM2/CDK4 co-amplification in all cases (4/4) and GLI1 fusion in 1 case (1/4), which were validated by fluorescence in situ hybridization (FISH) analysis. BCOR fusions were firstly identified with GLI1 and MDM2/CDK4 co-amplification in 2 cases (2/4). Copy number (CN) segmentation data showed GLI1 co-amplified cases present generally a single peak at the 12q13.3-15 locus. Follow-up (range:3 to 112 months; median 37.5 months) showed recurrence and/or metastasis in all cases (4/4), in which 1 patient developed lungs and liver metastasis. Relapse-free survival (RFS) analysis showed similar median RFS between GLI1 co-amplified HGESS and GLI1 non-amplified HGESS groups, which were shorter than LGESS group. Unusual clinicopathologic features of these HGESS with GLI1 and MDM2/CDK4 co-amplification mimicked other neoplasms, which caused significant diagnostic challenge and pitfalls. However, identification of GLI1 alterations in these tumors is beneficial for diagnosis and potential use of targeted GLI1 inhibitors.

This study aimed to evaluate temporal trends in treatment patterns for localized soft tissue sarcomas (STSs) and identify factors associated with relapse-free survival (RFS) and overall survival (OS). A retrospective cohort study was conducted using the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD) and electronic health records from a high-volume sarcoma unit. Patients aged ≥18 years with grade 3, localized STS ≥5cm diagnosed between 2013 and 2023 were included. The cohort was divided into two periods (2013-2017 and 2018-2023) to assess changes in treatment practices. Kaplan-Meier and Cox proportional hazards models evaluated RFS and OS. Among 202 patients, radiation use decreased in the late period (79%vs. 64%, p = 0.03), with a trend toward increased systemic therapy (8%vs. 16%, p = 0.13). Median RFS was 19 months (95% confidence interval [CI]: 14.9-26.0), with no significant difference between periods (hazard ratio [HR] 1.30, 95% CI: 0.93-1.82, p = 0.13). Median OS was 48 months (95% CI: 38.1-62.9), also showing no difference (HR 1.20, 95% CI: 0.80-1.78, p = 0.38). Radiotherapy improved RFS (HR 0.69, 95% CI: 0.49-0.98, p = 0.04) but not OS. Systemic therapy showed no RFS or OS benefit. Exploratory analyses identified age, tumor size, FDG-PET SUVmax, site, and Sarculator risk as prognostic factors. Treatment patterns evolved over time, reflecting emerging evidence, but no significant RFS or OS differences were observed. Further research is needed, including exploring prognostic factors like elevated baseline FDG-PET SUVmax.

Introduction: Patients with malignancy, especially high-grade uterine sarcomas, are at elevated risk for venous thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary embolism (PE), and intracardiac thrombi. The coexistence of thrombi in the inferior vena cava (IVC), pulmonary arteries, and right heart is rare and potentially life-threatening, even in asymptomatic individuals. Early recognition and intervention are crucial to prevent catastrophic embolic events. Case Presentation: A 48-year-old female with a recent total abdominal hysterectomy for high-grade uterine stromal sarcoma presented for outpatient CT imaging to evaluate disease extent. Imaging revealed extensive IVC thrombus, a small pulmonary embolism, and a possible right atrial thrombus. The patient, who was on prophylactic-dose low molecular weight heparin (Lovenox) and had taken her morning dose, denied leg swelling or pelvic pain. Notably, she had a prior right lower extremity DVT six months earlier following an ankle fracture, treated with a three-month course of anticoagulation. She was referred to the emergency department, where transthoracic echocardiography (TTE) showed a large, mobile thrombus extending into the right atrium and ventricle. She underwent emergent mechanical thrombectomy, with complete removal of the thrombus. Post-procedure transesophageal echocardiography (TEE) confirmed no residual thrombus. Discussion: This case highlights the thrombotic potential in patients with uterine stromal sarcoma, particularly in the postoperative period despite prophylaxis. The development of extensive VTE in the absence of symptoms is a dangerous diagnostic blind spot. The presence of a right heart thrombus, although rare, carries a high mortality risk if left untreated. Prompt use of imaging and mechanical thrombectomy can be life-saving. This case also calls attention to the potential need for therapeutic rather than prophylactic anticoagulation in select high-risk cancer patients. Conclusion: Asymptomatic patients with high-risk malignancies may harbor extensive and life-threatening thrombi despite appropriate prophylaxis. This case underscores the importance of vigilance, comprehensive imaging, and timely intervention in preventing fatal embolic events in oncologic populations.

Uterine Sarcomas With Recurrent KDM2B Gene Fusions: Three Cases of a Possible Novel Subtype of High-Grade Endometrial Stromal Sarcoma.

Introduction CIC-rearranged sarcoma (CRS) is a rare type of high-grade undifferentiated small round cell sarcoma characterized by a range of possible CIC gene rearrangements. It develops predominantly in the deep soft tissues of the limbs and trunk in young individuals (total range, 0.5–83 years; mean, 27–37 years; median, 24.5–33 years), and less commonly in bone and viscera. The occurrence of this sarcoma in the female reproductive tract is very rare, and it has not yet been described in the ovary. Case presentation We report a CRS case that arose from the left ovary in a 5-year-old girl. Histologically, the tumor was lobulated or leaf-shaped, with a fibrotic septum composed of closely arranged small- to medium-sized round cells and short spindle-shaped cells. In addition, the neoplastic cells exhibited multifocal membrane positivity for CD99 and diffuse positivity for WT1, TLE1, FLI‑1, P53, INI-1, and Calretinin, CD56 focal positive, while it was negative for ETV4. Fluorescent in situ hybridization analysis showed CIC-positive split signals. Conclusion CRSs are highly aggressive tumors. Rare CRSs have been reported in the female genital tract, and they are often difficult to diagnose. Especially in cases with atypical morphology and immunohistochemistry, it is necessary to integrate molecular features in the diagnosis of undifferentiated neoplasms.

Cardiac undifferentiated pleomorphic sarcomas are rare primary malignant tumors of the heart and constitute a significant portion of cardiac sarcomas. We present the diagnostic approach in a case of high-grade undifferentiated pleomorphic cardiac sarcoma with an unusual location in a 70-year-old woman.

A Rare Case of High-Grade Undifferentiated Pleomorphic Sarcoma of the Terminal Ileum in a 40-Year-Old Man: Successful Outcome and Prolonged Survival After Surgical Resection and Adjuvant Chemotherapy

In this report, we present a 51-year-old woman with months of heavy vaginal discharge, pain, nausea, and vomiting. Magnetic resonance imaging showed a large necrotic mass expanding the uterus with extension through the myometrium. Initial biopsy showed a malignant spindle cell neoplasm with high mitotic activity and necrosis. Immunohistochemistry (IHC) suggested a high-grade sarcoma, and further surgical resection confirmed a diagnosis of primary uterine angiosarcoma with positive ERG and CD31. Whole exome and whole transcriptome sequencing revealed pathogenic variants for CDKN2A (p.W110*; c.330G > A) and TP53 (c.782 + 1G > T; c.782 + 1G > T). Unfortunately, despite aggressive surgical management, the patient experienced rapid progression and succumbed to her disease within 5 months. Primary uterine angiosarcomas are exceedingly rare and clinically aggressive mesenchymal malignancies, with fewer than 30 tumors reported in the English literature. This report highlights the diagnostic challenges posed by primary uterine angiosarcomas, particularly due to their nonspecific high-grade morphology and focal vascular features. A broad IHC panel and molecular analysis can aid in accurate diagnosis.

Undifferentiated embryonal sarcoma(UES) is a rare, highly malignant tumor mainly originating from the liver, composed of primitive undifferentiated mesenchymal cells. Undifferentiated embryonal sarcoma of the liver(UESL) is a rare entity. Here, we report a case of abdominal mass in a young female that morphologically resembles UES without liver involved. Notably, the mass was located from the abdominal cavity to the retroperitoneum without any correlation with the liver. The patient had no history of prior tumors, and detailed examinations of the liver revealed no definite lesions. In addition, we propose undifferentiated high-grade sarcoma with UES-like features in the retroperitoneum, in which TP53 gene mutation may serve as the initiating factor for tumorigenesis.

Rethinking tumor viability as prognostic factor in soft tissue sarcoma.

Management of peripheral-vein leiomyosarcomas, recurrence patterns and individualised treatment strategy.

ERBB2/ERBB3‑mutated S100/SOX10‑positive uterine sarcoma is a recently described entity with distinct morphological, immunophenotypic, and molecular features, representing a subset of high-grade uterine sarcomas. This tumor is characterized by ERBB2/ERBB3 mutations or ERBB2 amplification, which leads to the overexpression or constitutive activation of HER2. The presence of HER2 amplification represents a potential target for the treatment with HER2 inhibitors. Here we present a case of high-grade uterine cervix sarcoma with ERBB2 amplification and S100/SOX10 expression in a 58-year-old patient. The tumor measured 50mm at its largest dimension and recurred two years after surgery. Histologically, the tumor was composed of round and spindle cell, showing diffuse nuclear expression of SOX10 and both nuclear and cytoplasm expression of S100. It also demonstrated ERBB2 amplification, as well as mutations in ATRX and BACH1. Accurate recognition of such tumors is crucial due to their propensity for aggressive behavior and the availability of potential targeted therapeutic options.

High-grade endometrial stromal sarcoma is a rare and aggressive subtype of uterine sarcoma, characterized by a poor prognosis. While typical initial manifestations include gynecological symptoms such as abnormal vaginal bleeding (for example, postmenopausal bleeding, intermenstrual bleeding, or menorrhagia), abdominal pain, and abdominal distension, an initial presentation involving distant metastases, particularly to the brain, is exceptionally uncommon. This case highlights a highly atypical initial presentation of this rare and challenging disease. This report details a unique clinical scenario of high-grade endometrial stromal sarcoma in a 58-year-old Japanese woman. She presented with left hemiparesis and unexplained weight loss, leading to the discovery of multiple brain tumors on cranial computed tomography. Following craniotomy and tumor resection, pathology suggested metastatic sarcoma. Positron emission tomography-computed tomography subsequently identified the uterus as the most probable primary site. Despite initial negative endometrial biopsy results, a targeted transabdominal computed tomography-guided biopsy ultimately confirmed the diagnosis of high-grade endometrial stromal sarcoma. Furthermore, detailed imaging and pathological findings raised the intriguing possibility that the high-grade endometrial stromal sarcoma may have originated from pre-existing adenomyosis. Despite initial chemotherapy and Gamma Knife radiosurgery for brain metastases, the patient's condition rapidly deteriorated, leading to her death approximately 4months after initial presentation, highlighting the aggressive nature and poor prognosis of this disease. The inherent rarity of high-grade endometrial stromal sarcoma, combined with its highly unusual initial presentation as neurological symptoms, significantly contributed to the diagnostic delay in this case. This report critically underscores the vital importance for clinicians to maintain a high index of suspicion for high-grade endometrial stromal sarcoma in the differential diagnosis of patients presenting with brain metastases, even when typical gynecological complaints are absent.

A woman in her 30s diagnosed with high-grade soft tissue sarcoma with pulmonary metastases began treatment with ifosfamide-epirubicin, netupitant/palonosetron and dexamethasone. Shortly after, she developed dizziness and dysarthria, raising suspicion of ifosfamide-induced encephalopathy. Ifosfamide was immediately discontinued before the first dose was completed, and treatment with methylene blue was initiated the following day as the clinical condition continued to worsen. Due to her clinical condition, she was transferred to the intensive care unit, where she was started on thiamine and dexmedetomidine combined with methylene blue. Three days later, her neurological status improved, allowing methylene blue and thiamine to be discontinued. Several publications have reported cases of ifosfamide-related encephalopathy in patients receiving concomitant aprepitant, a CYP3A4 substrate and inhibitor that may increase the levels of ifosfamide's toxic metabolites. However, no cases of ifosfamide-induced encephalopathy have been reported with the use of netupitant/palonosetron for antiemetic prophylaxis. In light of our patient's condition, it is possible that the concomitant use of ifosfamide and netupitant/palonosetron contributed to an earlier onset and increased severity of ifosfamide-related neurotoxicity.

There is a wide range of tissue changes that may arise after exposition to ionizing radiation. Most of these changes fall in the non-neoplastic category. Nevertheless, due to the damaging effect radiation has on the DNA, there is a risk of developing secondary tumours, usually high-grade sarcomas. Here, we present a case of an elderly man who developed recurrent fibroepithelial polyps of the pharyngeal mucosa. He had a history of ipsilateralsquamous cell carcinoma of the tonsil 17years before treated by complete surgical resection followed by adjuvant radiotherapy. Histologically, these polyps consisted of relatively well-defined, partially eroded mucosal projections with a fibro-myxoid and inflamed stroma lacking evident signs of malignancy. The 4th recurrence was submitted to DNA panel sequencing, which identified three pathogenic variants in the PTEN, DNMT3A, and TERT genes that were not present in the local normal tissue before radiotherapy. On further analysis, well-known and established radiation induced changes such as copy number (CN)alterations or a radiation signature were not detected. The clinical presentation and the mutations detected argue against a purely reactive, but rather a likely benign neoplastic process that is thought to have developed post-actinically, without clear evidence of malignancy (absence of atypia, no invasive growth,flat CN profile). This case report raises awareness of a possible association between radiotherapy and the subsequent development of a benign-appearing low-grade mucosal soft tissue neoplasm.

To evaluate multiparametric MRI features of pediatric soft-tissue sarcomas, comparing pre-treatment and post-treatment features, and assessing correlation with clinical outcomes. Retrospective cohort study, including pediatric patients (≤ 18years) with histologically-confirmed soft-tissue sarcomas who underwent MRI with anatomic and functional sequences in consecutive series. Post-treatment MRI was available for a subset, and features were recorded by two readers. Pre-treatment and post-treatment features were compared using Wilcoxon signed-rank test with Hodges-Lehmann estimator. Inter-reader agreement was assessed with intraclass correlation coefficient, and Mann-Whitney and Cox regression tests were used to correlate the features with clinical outcome. There were 27 patients. Pre-treatment we measured tumor size, ADCminimum (mean: 507 × 10-6mm2/s) and ADCaverage (mean: 690 × 10-6mm2/s). Post-treatment (10 patients) included a reduction in tumor size (p = 0.002) and higher ADCminimum (mean: 1116 × 10-6mm2/s) and ADCaverage (mean: 1344 × 10-6mm2/s) values. Pre-treatment size was larger in patients with metastasis at baseline (p = 0.004) and progression (p = 0.002), but size change after treatment did not correlate with progression. Baseline ADC​​ did not correlate with progression, but the group with progression showed less difference between pre- and post-treatment ADCminimum (p = 0.019) and ADCaverage (p = 0.032). There was excellent agreement between the readers measuring ADCminimum (ICC = 0.991) and ADCaverage (ICC = 0.978). For high-grade pediatric soft-tissue sarcomas, the pre-treatment size is an important prognostic factor, and a reduction in tumor size was observed after treatment, but did not correlate with progression. However, changes to ADC values between pre-treatment and post-treatment MRI correlated with disease progression, suggesting that ADC is a potentially useful biomarker of clinical outcome.

Malignant chondroblastoma is a recently described variant of chondroblastoma showing a distinct age/site distribution and morphology along with the typical H3-3B p.K36M mutation. We sought to further compare conventional and malignant chondroblastoma. Malignant chondroblastomas were collected. H3-3 K36M immunohistochemistry, as well as DNA methylation and copy number profiling, were performed and compared with conventional chondroblastoma. Forty-one samples from 26 patients were identified (20 males, 6 females; age: 19-62 years; median: 39 years). Anatomical sites included rib (7), pelvis (4), acromion (4), scapula (4), spine (2), long bone (3), calcaneus (1), and talus (1). Imaging showed an expansile mass with variable cortical erosion and/or breakthrough. Most patients (n = 17) showed sheets of atypical ovoid cells deposited in a myxoid stroma. Osteoclast-like giant cells/matrix formation was scarce. Six patients had tumors with features of conventional chondroblastoma but significant cytologic atypia. Three tumors demonstrated a morphology indistinguishable from conventional chondroblastoma except for extensive permeation, and one of these cases showed a transition to high-grade sarcoma. The final case was composed only of high-grade pleomorphic sarcoma that harbored an H3F3A p.K36M mutation. When an adjacent host bone was present, permeative growth through the cortex and native trabeculae was noted. All samples tested positive for the H3-3 K36M-specific antibody (26 of 26). Methylome profiling of 28 specimens from 24 patients revealed that 26 of these specimens formed a distinct cluster on a uniform manifold approximation and projection dimension reduction plot separate from conventional chondroblastoma and high-grade osteosarcoma. Of 26 methylomes from which interpretable copy number profiles can be derived, 12 had no variations, whereas 14 had copy number changes. Of 22 patients, 11 experienced local recurrence, 8 patients developed metastasis, and 3 patients died of disease. Malignant chondroblastoma is a rare, clinically and epigentically distinct variant of chondroblastoma with a predilection for the flat bones of skeletally mature individuals and high rates of local recurrence and distant metastases. A subset transforms into high-grade pleomorphic sarcoma, either de novo or in subsequent recurrences. Malignant chondroblastoma with high-grade features and/or copy number variations appears to have a higher propensity for adverse events, including death from disease.

Undifferentiated Small Round Cell Sarcomas of Bone.

Rationale:High-grade myofibroblastic sarcoma (HGMS) is a rare mesenchymal tumor with a high recurrence and metastatic rate. Few cases of high-grade myofibroblastic sarcomas have been reported. Herein, we report the first case of HGMS originating from the thyroid.Diagnosis and patient concerns:Based on the findings of thyroid, pathological examination, and immunohistochemical staining, grade III myofibroblastic sarcoma (MS) was diagnosed. Meanwhile, systemic imaging revealed multiple metastases in the scalp, lung, bone, liver, spleen, pancreas.Interventions and outcome:The patient had not received any treatment and expired 28 days after admission.Lessons:HGMS of thyroid shows high invasiveness and metastatic potential, often leading to rapid disease progression and poor survival outcomes. Early diagnosis and intervention guided by clinical evaluation, pathological findings, and imaging are essential to improve patient prognosis.

To report our personal experience in hindfoot reconstruction using an anterolateral thigh (ALT) free flap following radical resection of a high-grade synovial sarcoma. Methods The patient underwent clinical and imaging assessments, and a biopsy of the lesion confirmed the diagnosis of synovial sarcoma (SS) of the hindfoot. A multidisciplinary team was involved to define the most appropriate therapeutic strategy. Results After radical resection of the tumor mass, soft tissue coverage of the extensive skin defect was achieved using an ALT free flap. No local recurrences were observed during the follow-up period. At approximately twenty-four months after surgical treatment, the patient is able to ambulate independently, with no significant limitations in daily activities. Conclusion The complex management of this rare disease requires a dedicated reference center for foot and ankle surgery, supported by a multidisciplinary team including expert orthopedic and plastic surgeons, as well as specialized oncologists, to ensure accurate diagnosis and appropriate treatment.