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Aneurysmal bone cyst (ABC) is a locally aggressive, expansile, typically multilocular cystic bone tumor. ABC was previously thought to be a non-neoplastic lesion; however, it is now considered to be neoplasm that features recurrent chromosomal translocations resulting in gene fusions between ubiquitin specific peptidase 6 ( USP6 ) and multiple partners, including COL1A1 , CDH11 , TRAP150 , ZNF90 and OMD . Using next generation sequencing (NGS), we uncovered two fusion partners of USP6 in two ABCs: platelet activating factor acetylhydrolase 1b regulatory subunit 1 ( PAFAH1B1 ), which is known to contribute to tumorigenesis in lung cancer, and runt-related transcription factor 2 ( RUNX2 ), which is known to regulate osteoblastic differentiation, osteosarcoma tumorigenesis and its metastasis. In our study, the PAFAH1B1 – USP6 fusion consisted of the promoter of PAFAH1B1 fused to the 5′-untranslated region (5′-UTR) of USP6 and was discovered in a typical ABC. The RUNX2 – USP6 fusion had the promoter and a short coding region of RUNX2 fused to the translation start codon of USP6 and was detected in an unusually aggressive ABC with an osteosarcoma-like soft tissue extension. Our findings not only expanded the repertoire of the partner genes of USP6 in ABC but also can serve as a reference for future studies to better understand the correlation between various gene fusions and the progression of ABC. [ABSTRACT FROM AUTHOR]

Lipoblastoma is a benign myxoid neoplasm arising in young children that typically demonstrates adipose differentiation. It is often morphologically indistinguishable from primitive myxoid mesenchymal tumor of infancy (PMMTI), which is characterized by a well-circumscribed myxoid mass with a proliferation of primitive mesenchymal cells with mild cytologic atypia. PMMTI occurs in the first year of life and is known to have locally aggressive behavior. No specific genetic rearrangements have been reported to date. In contrast, the presence of PLAG1 (Pleomorphic Adenoma Gene 1) rearrangement is diagnostic for lipoblastoma. We hereby demonstrate the combined application of multiple approaches to tackle the diagnostic challenges of a rapidly growing neck tumor in a 3-month-old female. An incisional tumor biopsy had features of an undifferentiated, myxoid mesenchymal neoplasm mimicking PMMTI. However, tumor cells showed diffuse nuclear expression by immunohistochemical (IHC) stain. Conventional cytogenetic and fluorescence in situ hybridization (FISH) analyses as well as next generation sequencing (NGS) demonstrated evidence of PLAG1 rearrangement, confirming the diagnosis of lipoblastoma. This experience warrants that undifferentiated myxoid lipoblastoma can mimic PMMTI, and the combination of cytogenetic and molecular approaches is essential to distinguish these two myxoid neoplasms. Literature on lipoblastomas with relevant molecular and cytogenetic findings is summarized. Our case is the first lipoblastoma diagnosed with a PLAG1 fusion defined by NGS technology. [ABSTRACT FROM AUTHOR]

High-risk transplantation-associated thrombotic microangiopathy (TMA) can present with multisystem involvement and is associated with a poor outcome after hematopoietic stem cell transplantation (HSCT), with < 20% 1-year survival. TMA may involve the intestinal vasculature and can present with bleeding and ischemic colitis. There are no established pathologic criteria for the diagnosis of intestinal TMA (iTMA). The goal of our study was to identify histologic features of iTMA and describe associated clinical features. We evaluated endoscopic samples from 50 consecutive HSCT patients for 8 histopathologic signs of iTMA and compared findings in 3 clinical groups based on the presence or absence of systemic high-risk TMA (hrTMA) and the presence or absence of clinically staged intestinal graft-versus-host disease (iGVHD): TMA/iGVHD, no TMA/iGVHD, and no TMA/no iGVHD. Thirty percent of the study subjects had a clinical diagnosis of systemic hrTMA. On histology, loss of glands, intraluminal schistocytes, intraluminal fibrin, intraluminal microthrombi, endothelial cell separation, and total denudation of mucosa were significantly more common in the hrTMA group ( P < .05). Intravascular thrombi were seen exclusively in patients with hrTMA. Mucosal hemorrhages and endothelial cell swelling were more common in hrTMA patients but this difference did not reach statistical significance. Patients with hrTMA were more likely to experience significant abdominal pain and gastrointestinal bleeding requiring multiple blood transfusions ( P < .05). Our study shows that HSCT patients with systemic hrTMA can have significant bowel vascular injury that can be identified using defined histologic criteria. Recognition of these histologic signs in post-transplantation patients with significant gastrointestinal symptoms may guide clinical decisions. [ABSTRACT FROM AUTHOR]

Meckel's diverticula are common congenital gastrointestinal malformations that most often present with bloody stool or bowel obstruction. Occasionally these diverticula may become inverted and serve as a lead point for the development of intussusception. Herein, we report the case of a 10-year old female presenting with abdominal pain and non-bloody, non-bilious emesis and suspicion of intussusception. Upon performing an exploratory laparotomy, the intussusception lead point was found to be an inverted Meckel's diverticulum obstructing the lumen of the intestine. [ABSTRACT FROM AUTHOR]

Ewing sarcoma (ES) is an aggressive malignant small round cell tumor that arises in bone or soft tissue of adolescents and young adults. A characteristic molecular finding in ES is EWSR1 gene fusion with ETS (erythroblast transformation-specific) family genes including FLI1 (~90%) and ERG (>5%). Here we report our experience using integrated clinicopathologic, cytogenetic, fluorescence in situ hybridization (FISH), and reverse transcriptase polymerase chain reaction (RT-PCR) analyses of 32 pediatric patients with ES diagnosed in a single institution between 2005 and 2011. Diagnostic EWSR1 rearrangements were detected in 30 (93.8%) of 32 patients. Cytogenetics detected t(11;22) (n = 14) and t(21;22) (n = 1) in 15 (46.9%) patients. FISH detected EWSR1 rearrangements in 27 (96.4%) of 28 patients tested. RT-PCR was positive in 27 (84.4%) of 32 patients, including 24 EWSR1-FLI1 and 3 EWSR1-ERG. RT-PCR defined breakpoints and fusion partners in 7 cases with EWSR1 rearrangements detected by FISH. Sanger sequencing further delineated breakpoints in 21 (77.8%) of 27 RT-PCR positive cases. In summary, conventional cytogenetic analysis provided a global view but had a lower detection rate and longer turnaround time than other methods. FISH is a rapid method and theoretically can detect all EWSR1 rearrangements, but it cannot identify all partners and is not completely specific for ES. RT-PCR and sequencing are more sensitive and useful in identifying fusion partners and refining breakpoints; however, these methods can be compromised by poor RNA preservation and primer design. In conclusion, an integrated approach that uses all methods capable of detecting EWSR1 rearrangements has value in the workup of suspected cases of ES. [ABSTRACT FROM AUTHOR]

Overactivated complement is a high-risk feature in HSCT recipients with transplant associated thrombotic microangiopathy (TA-TMA) and untreated patients have dismal outcomes. We present our experience in 64 pediatric HSCT recipients with high risk TA-TMA and multi-organ injury treated with the complement blocker eculizumab. • To evaluate the impact of high risk TA-TMA on clinical outcomes. • To determine high risk TA-TMA response to complement blocking therapy with eculizumab. • To gain clinical knowledge in this high-risk population for future study planning. We performed retrospective chart review of all patients receiving eculizumab therapy for high risk TA-TMA at our institution (2012-2018). All patients were prospectively screened for TA-TMA and received PK/PD guided eculizumab dosing. We demonstrate a significant improvement in 1 year post-HSCT survival to 66% in treated patients from our previously reported untreated cohort with the same high-risk TA-TMA features that had 1 year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive eculizumab therapy course using PK/PD guided drug dosing, requiring a median of 11 doses of eculizumab (IQR 7-20), and were off therapy in median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of therapy were less likely to respond to treatment (OR =0.15, p-value 0.0014) and required more doses of eculizumab [r = 0.43, p-value = 0.0004]. Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9, p=0.0015) and had lower 1y survival (44% vs 78%, p=0.01). Over 70% of survivors had mild proteinuria on long term follow up. The best CystC GFR recovery in survivors was a median 20% lower (IQR 7.3-40.3%) than their pre-HSCT CystC GFR. Complement blockade with eculizumab is an effective therapeutic strategy for high risk TA-TMA, but some patients with severe disease lack a complete response, prompting us to propose early intervention strategies and search for additional targetable endothelial injury pathways. [ABSTRACT FROM AUTHOR]