Anastomosing haemangioma of the mediastinum: Clinicopathological series with radiological and genetic characterisation.

AIMS: Anastomosing haemangiomas are benign tumours with anastomosing vascular channels that may mimic angiosarcoma. While anastomosing haemangiomas have been described in diverse locations, particularly the abdominal/paraspinal region, data on anastomosing haemangiomas in the mediastinum remain limited. We report the clinicopathological, radiological and molecular characteristics of the largest single-institutional series of mediastinal anastomosing haemangiomas. METHODS AND RESULTS: In our pathology archives in 2011-23, we reviewed all vascular lesions involving the mediastinum and identified seven anastomosing haemangiomas. Clinical information was abstracted from medical charts; available radiological imaging was reviewed. Targeted DNA-based next-generation sequencing (447 genes, including GNAQ and GNA11) was performed on five cases. The seven patients included five women and two men, with an age range of 55-77 (median = 72) years. Of the six tumours with available radiology, two each were in the prevascular, visceral and paravertebral mediastinum, with lobulated peripheral enhancement in all tumours examined with contrast enhancement. Six patients underwent tumour resection; one patient received proton radiotherapy. Microscopically, each tumour was solitary and characterised by anastomosing capillary-sized vessels lined by hobnail endothelial cells. Fibrin microthrombi, hyaline globules and extramedullary haematopoiesis were common. In the five tumours analysed by next-generation sequencing, GNAQ p.Q209P was identified in one tumour; no additional reportable alterations were identified in the remaining cases. No recurrence was noted in the four patients with available follow-up of 3-58 (median = 9.5) months after resection. CONCLUSION: While mediastinal anastomosing haemangiomas can microscopically mimic angiosarcoma, awareness of this entity and radiological correlation may help to circumvent this diagnostic pitfall.

Complete tumor necrosis after neoadjuvant chemotherapy defines good responders in patients with Ewing sarcoma.

BACKGROUND: Survival in patients who have Ewing sarcoma is correlated with postchemotherapy response (tumor necrosis). This treatment response has been categorized as the response rate, similar to what has been used in osteosarcoma. There is controversy regarding whether this is appropriate or whether it should be a dichotomy of complete versus incomplete response, given how important a complete response is for in overall survival of patients with Ewing sarcoma. The purpose of this study was to evaluate the impact that the amount of chemotherapy-induced necrosis has on (1) overall survival, (2) local recurrence-free survival, (3) metastasis-free survival, and (4) event-free survival in patients with Ewing sarcoma. METHODS: In total, 427 patients who had Ewing sarcoma or tumors in the Ewing sarcoma family and received treatment with preoperative chemotherapy and surgery at 10 international institutions were included. Multivariate Cox proportional-hazards analyses were used to assess the associations between tumor necrosis and all four outcomes while controlling for clinical factors identified in bivariate analysis, including age, tumor volume, location, surgical margins, metastatic disease at presentation, and preoperative radiotherapy. RESULTS: Patients who had a complete (100%) tumor response to chemotherapy had increased overall survival (hazard ratio [HR], 0.26; 95% CI, 0.14-0.48; p < .01), recurrence-free survival (HR, 0.40; 95% CI, 0.20-0.82; p = .01), metastasis-free survival (HR, 0.27; 95% CI, 0.15-0.46; p ≤ .01), and event-free survival (HR, 0.26; 95% CI, 0.16-0.41; p ≤ .01) compared with patients who had a partial (0%-99%) response. CONCLUSIONS: Complete tumor necrosis should be the index parameter to grade response to treatment as satisfactory in patients with Ewing sarcoma. Any viable tumor in these patients after neoadjuvant treatment should be of oncologic concern. These findings can affect the design of new clinical trials and the risk-stratified application of conventional or novel treatments.

Prognostic Significance of Percentage and Size of Dedifferentiation in Dedifferentiated Chondrosarcoma.

Dedifferentiated chondrosarcoma is rare, aggressive, and microscopically bimorphic. How pathologic features such as the amounts of dedifferentiation affect prognosis remains unclear. We evaluated the percentages and sizes of dedifferentiation in a consecutive institutional series of dedifferentiated chondrosarcomas from 1999 to 2021. The statistical analysis included cox proportional hazard models and log-rank tests. Of the 67 patients (26 women, 41 men; age, 39 to >89 [median 61] years; 2 with Ollier disease), 58 presented de novo; 9 were identified with conventional chondrosarcomas 0.6-13.2 years (median, 5.5 years) prior. Pathologic fracture and distant metastases were noted in 27 and 7 patients at presentation. The tumors involved the femur (n = 27), pelvis (n = 22), humerus (n = 7), tibia (n = 4), scapula/ribs (n = 4), spine (n = 2), and clivus (n = 1). In the 56 resections, the tumors ranged in size from 3.5 to 46.0 cm (median, 11.5 cm) and contained 1%-99.5% (median, 70%) dedifferentiated components that ranged in size from 0.6 to 24.0 cm (median, 7.3 cm). No correlation was noted between total size and percentage of dedifferentiation. The dedifferentiated components were typically fibrosarcomatous or osteosarcomatous, whereas the associated cartilaginous components were predominantly grade 1-2, rarely enchondromas or grade 3. The entire cohort's median overall survival and progression-free survival were 11.8 and 5.4 months, respectively. In the resected cohort, although the total size was not prognostic, the percentage of dedifferentiation ≥20% and size of dedifferentiation >3.0 cm each predicted worse overall survival (9.9 vs 72.5 months; HR, 3.76; 95% CI, 1.27-11.14; P = .02; 8.7 vs 58.9 months; HR, 3.03; 95% CI, 1.21-7.57; P = .02, respectively) and progression-free survival (5.3 vs 62.1 months; HR, 3.05; 95% CI, 1.13-8.28; P = .03; 5.3 vs 56.6 months; HR, 2.50; 95% CI, 1.06-5.88; P = .04, respectively). In conclusion, both the percentages and sizes of dedifferentiation were better prognostic predictors than total tumor sizes in dedifferentiated chondrosarcomas, highlighting the utility of their pathologic evaluations.

Vasculopathy and Increased Vascular Congestion in Fatal COVID-19 and Acute Respiratory Distress Syndrome.

Rationale: The leading cause of death in coronavirus disease 2019 (COVID-19) is severe pneumonia, with many patients developing acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD). Whether DAD in fatal COVID-19 is distinct from other causes of DAD remains unknown. Objective: To compare lung parenchymal and vascular alterations between patients with fatal COVID-19 pneumonia and other DAD-causing etiologies using a multidimensional approach. Methods: This autopsy cohort consisted of consecutive patients with COVID-19 pneumonia (n = 20) and with respiratory failure and histologic DAD (n = 21; non-COVID-19 viral and nonviral etiologies). Premortem chest computed tomography (CT) scans were evaluated for vascular changes. Postmortem lung tissues were compared using histopathological and computational analyses. Machine-learning-derived morphometric analysis of the microvasculature was performed, with a random forest classifier quantifying vascular congestion (CVasc) in different microscopic compartments. Respiratory mechanics and gas-exchange parameters were evaluated longitudinally in patients with ARDS. Measurements and Main Results: In premortem CT, patients with COVID-19 showed more dilated vasculature when all lung segments were evaluated (P = 0.001) compared with controls with DAD. Histopathology revealed vasculopathic changes, including hemangiomatosis-like changes (P = 0.043), thromboemboli (P = 0.0038), pulmonary infarcts (P = 0.047), and perivascular inflammation (P < 0.001). Generalized estimating equations revealed significant regional differences in the lung microarchitecture among all DAD-causing entities. COVID-19 showed a larger overall CVasc range (P = 0.002). Alveolar-septal congestion was associated with a significantly shorter time to death from symptom onset (P = 0.03), length of hospital stay (P = 0.02), and increased ventilatory ratio [an estimate for pulmonary dead space fraction (Vd); p = 0.043] in all cases of ARDS. Conclusions: Severe COVID-19 pneumonia is characterized by significant vasculopathy and aberrant alveolar-septal congestion. Our findings also highlight the role that vascular alterations may play in Vd and clinical outcomes in ARDS in general.

Assessing the Safety and Utility of Wound VAC Temporization of the Sarcoma or Benign Aggressive Tumor Bed Until Final Margins Are Achieved.

BACKGROUND: Local recurrence of microinvasive sarcoma or benign aggressive pathologies can be limb- and life-threatening. Although frozen pathology is reliable, tumor microinvasion can be subtle or missed, having an impact on surgical margins and postoperative radiation planning. The authors' service has begun to temporize the tumor bed after primary tumor excision with a wound vacuum-assisted closure (VAC) pending formal margin analysis, with coverage performed in the setting of final negative margins. METHODS: This retrospective analysis included all patients managed at a tertiary referral cancer center with VAC temporization after soft tissue sarcoma or benign aggressive tumor excision from 1 January 2000 to 1 January 2019 and at least 2 years of oncologic follow-up evaluation. The primary outcome was local recurrence. The secondary outcomes were distant recurrence, unplanned return to the operating room for wound/infectious indications, thromboembolic events, and tumor-related deaths. RESULTS: For 62 patients, VAC temporization was performed. The mean age of the patients was 62.2 ± 22.3 years (median 66.5 years; 95% confidence interval [CI] 61.7-72.5 years), and the mean age-adjusted Charlson Comorbidity Index was 5.3 ± 1.9. The most common tumor histology was myxofibrosarcoma (51.6%, 32/62). The mean volume was 124.8 ± 324.1 cm3, and 35.5% (22/62) of the cases were subfascial. Local recurrences occurred for 8.1% (5/62) of the patients. Three of these five patients had planned positive margins, and 17.7% (11/62) of the patients had an unplanned return to the operating room. No demographic or tumor factors were associated with unplanned surgery. CONCLUSIONS: The findings showed that VAC-temporized management of microinvasive sarcoma and benign aggressive pathologies yields favorable local recurrence and unplanned operating room rates suggestive of oncologic and technical safety. These findings will need validation in a future randomized controlled trial.

Sclerostin immunohistochemical staining in surgically treated giant cell tumor of bone.

BACKGROUND: Giant cell tumor of bone (GCTB) is a destructive lesion with a high potential for recurrence. RANK-ligand targeted therapy has provided promising, yet mixed results. Sclerostin (SOST) inhibition results in a net anabolic response and is currently used in the treatment of osteoporosis. The application to GCTB is unknown. OBJECTIVES: We sought to determine if GCTB stained for SOST on immunohistochemistry and correlate its expression with predictor variables. METHODS: All patients at a single institution undergoing surgery for GCTB between 1993 and 2008 with a minimum of 6 months follow-up were included. Primary outcomes included the presence of SOST staining, secondary outcomes included the correlation of patient and tumor-specific predictor variables. RESULTS: SOST antibody staining of any cell type was present in 47 of 48 cases (97.9%). Positivity of the stromal cells was present in 39 of 48 cases (81.3%) and was associated with radiographic aggressiveness (p = 0.023), symptomatic presentation (p = 0.032), prior surgery (p = 0.005), and patient age (p = 0.034). Positivity of giant cells was present in 41 of 48 cases (85.4%) and was not significant with predictive factors. CONCLUSIONS: Sclerostin staining in GCTB is a novel finding and warrants further research to define the role of sclerostin as a prognostic factor and therapeutic target.

Sclerostin Immunohistochemical Staining in Aggressive Maxillofacial Giant Cell Lesions: Initial Results and Potential Therapeutic Target.

INTRODUCTION: Maxillofacial (MF) giant cell lesions (GCLs) are benign, often locally aggressive lesions with potential for recurrence. Systemic treatments have included interferon alpha, calcitonin, bisphosphonates, and denosumab. Sclerostin (SOST) is typically thought to be a negative regulator of bone metabolism and anti-SOST agents have been used to treat osteoporosis; however, its role in central giant cell granuloma is unknown. The purpose of this study was to evaluate the expression of SOST in MF GCLs. MATERIALS AND METHODS: This was a retrospective study of patients with MF GCLs treated at a single institution between 1993 and 2008 with a minimum follow-up of 6 months. Representative tissue was used to create a tissue microarray and SOST immunohistochemical (IHC) staining and grading was performed. The primary outcomes were IHC staining of the stromal cells and giant cells. The secondary outcomes included correlation of IHC staining and patient predictor variables including clinically benign and aggressive lesions. All analyses were completed using univariate statistical tests. RESULTS: A total of 37 subjects were included (29 clinically aggressive and 8 clinically benign). Sclerostin staining was present in 30 of 37 subjects (81%). Of these, 22 (60%) had stromal cell staining and 28 (76%) had giant cell staining. The presence or absence of staining, of either cell type, was not associated with aggressiveness, presence of clinical symptoms, tumor size, previous interferon therapy, previous surgery, or the race or age of the patient. DISCUSSION: Maxillofacial GCLs have an overall high level of SOST staining; however, the role of SOST in treatment and prognosis is unknown and warrants further study.

Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19.

COVID-19 has been associated with cardiac injury and dysfunction. While both myocardial inflammatory cell infiltration and myocarditis with myocyte injury have been reported in patients with fatal COVID-19, clinical-pathologic correlations remain limited. The objective was to determine the relationships between cardiac pathological changes in patients dying from COVID-19 and cardiac infection by SARS-CoV-2, laboratory measurements, clinical features, and treatments. In a retrospective study, 41 consecutive autopsies of patients with fatal COVID-19 were analyzed for the associations between cardiac inflammation, myocarditis, cardiac infection by SARS-CoV-2, clinical features, laboratory measurements, and treatments. Cardiac infection was assessed by in situ hybridization and NanoString transcriptomic profiling. Cardiac infection by SARS-CoV-2 was present in 30/41 cases: virus+ with myocarditis (n = 4), virus+ without myocarditis (n = 26), and virus- without myocarditis (n = 11). In the cases with cardiac infection, SARS-CoV-2+ cells in the myocardium were rare, with a median density of 1 cell/cm2. Virus+ cases showed higher densities of myocardial CD68+ macrophages and CD3+ lymphocytes, as well as more electrocardiographic changes (23/27 vs 4/10; P = 0.01). Myocarditis was more prevalent with IL-6 blockade than with nonbiologic immunosuppression, primarily glucocorticoids (2/3 vs 0/14; P = 0.02). Overall, SARS-CoV-2 cardiac infection was less prevalent in patients treated with nonbiologic immunosuppression (7/14 vs 21/24; P = 0.02). Myocardial macrophage and lymphocyte densities overall were positively correlated with the duration of symptoms but not with underlying comorbidities. In summary, cardiac infection with SARS-CoV-2 is common among patients dying from COVID-19 but often with only rare infected cells. Cardiac infection by SARS-CoV-2 is associated with more cardiac inflammation and electrocardiographic changes. Nonbiologic immunosuppression is associated with lower incidences of myocarditis and cardiac infection by SARS-CoV-2.

Surface osteosarcoma: Predictors of outcomes.

BACKGROUND AND OBJECTIVES: The subtypes of surface osteosarcomas include well-differentiated, low-grade parosteal osteosarcoma (POS), intermediate-grade periosteal osteosarcoma (PerOS), high-grade surface osteosarcoma (HGSO), and high-grade, dedifferentiated POS (dPOS). We aimed to determine disease progression, defined as local recurrence and metastatic disease, and overall (OS) and disease-specific survival (DSS). We identify outcome predictive factors and report functional results. METHODS: This retrospective study evaluated patients with primary surface osteosarcoma at our hospital from 1992 to 2019. Fifty-one patients had a median follow-up of 6.1 years (range: 0.1-25.2). Histologic subtypes included 32 POS, 11 PerOS, 4 HGSO, and 3 dPOS. Bone and soft tissue margins were classified using the American Joint Committee on Cancer residual tumor classification (Rx = Not evaluable; R0 = negative margin; R1 = microscopic positive margin; and R2 = macroscopic positive margin) and the modified R classification (mRx = not evaluable; mR0 = negative margin >1 mm; mR1 = negative margin ≤1 mm; mR1-dir: Positive microscopic margin locally; mR2a: Positive macroscopic margin locally; mR2b: positive macroscopic margin distally; and mR2C: positive macroscopic margin locally and distally). Forty-one patients had functional outcomes. RESULTS: Three POS patients developed recurrence: two had R0 margins and one an intralesional resection. Five patients developed lung metastases (POS: 3, dPOS: 2). Four patients died. The only significant disease progression predictor was age. OS at 10 years was 97%. 48 patients had negative bone margins (R0 or mR0 and mR1) and 47 patients had negative soft-tissue margins (R0 or mR0 and mR1). The average MSTS score was 88.43 (range: 34.29-100). CONCLUSIONS: We advocate surgery for POS and believe R0 (mR0 and mR1 resections) or planned R1 (mR1-dir) to preserve function are acceptable. We favor chemotherapy and surgery for PerOS, though a chemotherapeutic response is highly variable. High-grade tumors are the most infrequent subtype, but HGSO and dPOS seem to portend a poorer prognosis. Good function can be obtained.

Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1-KMT2A-YAP1 and VIM-KMT2A fusions.

Sarcomas are driven by diverse pathogenic mechanisms, including gene rearrangements in a subset of cases. Rare soft tissue sarcomas containing KMT2A fusions have recently been reported, characterized by a predilection for young adults, sclerosing epithelioid fibrosarcoma-like morphology, and an often aggressive course. Nonetheless, clinicopathologic and molecular descriptions of KMT2A-rearranged sarcomas remain limited. In this study, we identified by targeted next-generation RNA sequencing an index patient with KMT2A fusion-positive soft tissue sarcoma. In addition, we systematically searched for KMT2A structural variants in a comprehensive genomic profiling database of 14,680 sarcomas interrogated by targeted next-generation DNA and/or RNA sequencing. We characterized the clinicopathologic and molecular features of KMT2A fusion-positive sarcomas, including KMT2A breakpoints, rearrangement partners, and concurrent genetic alterations. Collectively, we identified a cohort of 34 sarcomas with KMT2A fusions (0.2%), and YAP1 was the predominant partner (n = 16 [47%]). Notably, a complex rearrangement with YAP1 consistent with YAP1-KMT2A-YAP1 fusion was detected in most cases, with preservation of KMT2A CxxC-binding domain in the YAP1-KMT2A-YAP1 fusion and concurrent deletions of corresponding exons in KMT2A. The tumors often affected younger adults (age 20-66 [median 40] years) and histologically showed variably monomorphic epithelioid-to-spindle shaped cells embedded in a dense collagenous stroma. Ultrastructural evidence of fibroblastic differentiation was noted in one tumor examined. Our cohort also included two sarcomas with VIM-KMT2A fusions, each harboring concurrent mutations in CTNNB1, SMARCB1, and ARID1A and characterized histologically by sheets of spindle-to-round blue cells. The remaining 16 KMT2A-rearranged sarcomas in our cohort exhibited diverse histologic subtypes, each with unique novel fusion partners. In summary, KMT2A-fusion-positive sarcomas most commonly exhibit sclerosing epithelioid fibrosarcoma-like morphology and complex YAP1-KMT2A-YAP1 fusions. Cases also include rare spindle-to-round cell sarcomas with VIM-KMT2A fusions and tumors of diverse histologic subtypes with unique KMT2A fusions to non-YAP1 non-VIM partners.

Molecular characteristics of poorly differentiated chordoma.

Pediatric poorly differentiated chordoma is a subtype of chordoma with a much more aggressive clinical course and has been characterized by loss of SMARCB1. This study characterizes the molecular features of these tumors in comparison to conventional chordoma. A search of records between 1990 and 2017 at Massachusetts General Hospital identified two patients with sufficient excess tissue for molecular analysis and a third patient diagnosed with a highly cellular conventional chordoma. The three tumors were sent for array comparative genomic hybridization for genome-wide copy number variants; multiplex PCR for single-nucleotide variants; and RNA-sequencing for fusions. Poorly differentiated chordoma showed chromosome 22q loss, including SMARCB1, with no identifiable mutations on multiplex PCR. The cellular conventional chordoma showed a complex pattern of chromosomal gains and losses involving 12 chromosomes, and an RB1 mutation at low allelic frequency. RNA-Seq identified no disease-defining gene fusion events. Poorly differentiated chordoma appears to represent a distinct type of tumor that is genetically unrelated to conventional chordoma. Recognition of this subtype is important because these malignancies should be treated aggressively with multimodality therapy, and possibly targeted therapy.

Histone H3K27 dimethyl loss is highly specific for malignant peripheral nerve sheath tumor and distinguishes true PRC2 loss from isolated H3K27 trimethyl loss.

Malignant peripheral nerve sheath tumors contain loss of histone H3K27 trimethylation (H3K27me3) due to driver mutations affecting the polycomb repressive complex 2 (PRC2). Consequently, loss of H3K27me3 staining has served as a diagnostic marker for this tumor type. However, recent reports demonstrate H3K27me3 loss in numerous other tumors, including some in the differential diagnosis of malignant peripheral nerve sheath tumor. Since these tumors lose H3K27me3 through mechanisms distinct from PRC2 loss, we set out to determine whether loss of dimethylation of H3K27, which is also catalyzed by PRC2, might be a more specific marker of PRC2 loss and malignant peripheral nerve sheath tumor. Using mass spectrometry, we identify a near complete loss of H3K27me2 in malignant peripheral nerve sheath tumors and cell lines. Immunohistochemical analysis of 72 malignant peripheral nerve sheath tumors, seven K27M-mutant gliomas, 43 ependymomas, and 10 Merkel cell carcinomas demonstrates that while H3K27me3 loss is common across these tumor types, H3K27me2 loss is limited to malignant peripheral nerve sheath tumors and is highly concordant with H3K27me3 loss (33/34 cases). Thus, increased specificity does not come at the cost of greatly reduced sensitivity. To further compare H3K27me2 and H3K27me3 immunohistochemistry, we investigated 42 melanomas and 54 synovial sarcomas, histologic mimics of malignant peripheral nerve sheath tumor with varying degrees of H3K27me3 loss in prior reports. While global H3K27me3 loss was not seen in these tumors, weak and limited H3K27me3 staining was common. By contrast, H3K27me2 staining was more clearly retained in all cases, making it a superior binary classifier. This was confirmed by digital image analysis of stained slides. Our findings indicate that H3K27me2 loss is highly specific for PRC2 loss and that PRC2 loss is a rarer phenomenon than H3K27me3 loss. Consequently, H3K27me2 loss is a superior diagnostic marker for malignant peripheral nerve sheath tumor.

Clinical and Molecular Analysis of Pathologic Fracture-associated Osteosarcoma: MicroRNA profile Is Different and Correlates with Prognosis.

BACKGROUND: MicroRNAs are small, noncoding RNAs that regulate the expression of posttranslational genes. The presence of some specific microRNAs has been associated with increased risk of both local recurrence and metastasis and worse survival in patients with osteosarcoma. Pathologic fractures in osteosarcoma are considered to be more the manifestation of a neoplasm with a more aggressive biological behavior than the cause itself of worse prognosis. However, this has not been proved at the biological or molecular level. Currently, there has not been a microRNA profiling study of patients who have osteosarcoma with and without pathologic fractures that has described differences in terms of microRNA profiling between these two groups and their correlation with biologic behavior. QUESTIONS/PURPOSES: (1) In patients with osteosarcoma of the extremities, how do the microRNA profiles of those with and without pathologic fractures compare? (2) What relationship do microRNAs have with local recurrence, risk of metastasis, disease-specific survival, and overall survival in osteosarcoma patients with pathologic fractures? METHODS: Between 1994 and 2013, 217 patients were diagnosed and treated at our institution for osteosarcoma of the extremities. Patients were excluded if (1) they underwent oncologic resection of the osteosarcoma at an outside institution (two patients) or (2) they were diagnosed with an extraskeletal osteosarcoma (29 patients) or (3) they had less than 1 year of clinical follow-up and no oncologic outcome (local recurrence, metastasis, or death) (four patients). A total of 182 patients were eligible. Of those, 143 were high-grade osteosarcomas. After evaluation of tumor samples before chemotherapy treatment, a total of 80 consecutive samples were selected for sequencing. Demographic and clinical comparison between the sequenced and non-sequenced patients did not demonstrate any differences, confirming that both groups were comparable. Diagnostic samples from the extremities of 80 patients with high-grade extremity osteosarcomas who had not yet received chemotherapy underwent microRNA sequencing for an ongoing large-scale osteosarcoma genome profiling project at our institution. Six samples were removed after a second look by a musculoskeletal pathologist who verified cellularity and quality of samples to be sequenced, leaving a total of 74 patients. Of these, two samples were removed as they were confirmed to be pelvic tumors in a second check after sequencing. The final study sample was 72 patients (11 patients with pathologic fractures and 61 without). Sequencing data were correlated with fractures and local recurrence, risk of metastasis, disease-specific survival, and overall survival through Kaplan-Meier analyses. RESULTS: Several microRNAs were expressed differently between the two groups. Among the markers with the highest differential expression (edgeR and DESeq algorithms), Hsa-mIR 656-3p, hsa-miR 493-5p, and hsa-miR 381-3p were upregulated in patients with pathologic fractures, whereas hsa-miR 363, hsa-miR 885-5p, and has-miR 20b-5p were downregulated. The highest differential expression fracture and nonfracture-associated microRNA markers also distinguished groups of patients with different metastasis risk, a well as different disease-specific and overall survival. Furthermore, the profile of pathologic fractures demonstrated a higher differential expression for microRNA markers that were previously associated with a higher risk of metastasis and lower survival rates in patients with osteosarcoma. CONCLUSIONS: In patients who have osteosarcoma, the microRNA profiles of those with pathologic fractures are different than of patients without pathologic fractures. The highest differential expression mircroRNA molecules in patients with pathologic fractures predict also higher risk of metastatic disease as well as worse disease-specific survival and overall survival. Furthermore, we found higher differential expression of microRNAs in the pathologic fracture group previously associated with poor prognosis. The higher risk of metastasis and poorer overall survival in patients with pathologic fractures is inherent to tumor aggressive biologic behavior. It is plausible that the fracture itself is not the direct cause of worse prognosis but another manifestation of tumor biologic aggressiveness. Identification of these molecules through liquid biopsies may help to determine which patients may benefit from surgery before fractures occur. The same technology can be applied to identify patterns of response to conventional chemotherapy, assisting in more specific and accurate systemic therapy. LEVEL OF EVIDENCE LEVEL: III, prognostic study.

Multiple calcifying fibrous pseudotumors of the pleura: ultrastructural analysis provides insight on mechanism of dissemination.

Calcifying fibrous pseudotumor (CFP) is a rare, benign soft tissue tumor that may uncommonly arise in the pleura. These tumors can show multifocal dissemination across the pleural surface, but the mechanism underlying this dissemination is unclear. Review of previously reported cases of pleural CFP demonstrates a strong predilection for basal and diaphragmatic pleural surfaces, and a significantly higher rate of multifocality compared with other locations. We present a 59-year-old male with multiple CFP of the pleura. Reactive-appearing adhesions spanning the pleural surfaces were present, and by electron microscopy, were involved by tumor. We suggest this is the likely mode of dissemination across the pleural surfaces.

Clinicopathologic characteristics of poorly differentiated chordoma.

Chordoma is a rare malignant tumor of bone with high morbidity and mortality. Recently, aggressive pediatric poorly differentiated chordoma with SMARCB1 loss has been described. This study summarizes the clinicopathologic features of poorly differentiated chordoma with SMARCB1 loss in the largest series to date. A search of records between 1990-2017 at MGH identified 19 patients with poorly differentiated chordoma. Immunohistochemical stains were evaluated. Kaplan-Meier survival statistics and log-rank (Mantel Cox) tests compared survival with other subtypes. The patients (n = 19) were diagnosed at a median age of 11 years (range: 1-29). Tumors arose in the skull base and clivus (n = 10/19; 53%); cervical spine (n = 6/19; 32%); and sacrum or coccyx (n = 3/19; 16%). The clinical stage of these patients (AJCC 7e) was stage 2A (n = 7/16; 44%); stage 2B (n = 6/16; 38%); stage 4A (n = 1/16; 6%); and stage 4B (n = 2/16; 13%). The tumors were composed of sheets of epithelioid cells with nuclear pleomorphism, abundant eosinophilic cytoplasm, and increased mitoses. Tumors were positive for cytokeratin (n = 18/18; 100%) and brachyury (n = 18/18; 100%). Patients were treated with a combination of excision, radiation therapy, and chemotherapy. No difference in overall survival, progression free survival, local control time, and metastasis free survival was identified between poorly differentiated chordoma of the skull base and of the spine. Compared to other chordoma subtypes, poorly differentiated chordoma has a significantly decreased mean overall survival after stratification by site (p = 0.037). Pediatric poorly differentiated chordoma has a distinct clinical and immunohistochemical profile, with characteristic SMARCB1 loss and decreased survival compared to conventional/chondroid chordoma. Recognition of this subtype is important because these malignancies should be treated aggressively with multimodality therapy.

Histopathology of synovial cysts of the spine.

AIMS: Cystic lesions derived from the synovial and ligamentous structures of the spine have varied histological appearances. Not uncommonly, there is discrepancy between the clinicoradiological diagnosis and histology. Therefore, we sought to characterise the histological features of tissue submitted as 'synovial cysts' of the spine. METHODS AND RESULTS: Resected specimens of the spine labelled 'synovial cysts' and 'lumbar cysts' were histologically evaluated and classified on the basis of histopathological features. Seventy-five histological samples of spinal cysts were identified. Thirty-one were classified as synovial cysts (definite synovial lining), 28 showed pseudocystic degeneration of the ligamentum flavum, seven showed pseudocyst formation without evidence of a synovial lining or degeneration of the ligamentum flavum, and eight showed cyst contents only or no histological evidence of cyst wall for evaluation. Twenty-five cases (33%), especially those showing pseudocystic degeneration of the ligamentum flavum, were associated with very characteristic tumour calcinosis-like calcium deposition with a surrounding foreign-body giant-cell reaction. CONCLUSION: Histology of 'synovial cysts' of the spine shows varied types of cyst; a large proportion are not synovial-lined cysts, but rather show pseudocystic degenerative changes of the ligamentum flavum, often associated with very characteristic finely granular calcifications and a foreign-body giant-cell reaction. This may have implications not only for understanding the pathogenesis of these lesions, but also for their varied responses to non-surgical interventions.

YWHAE Rearrangement in a Purely Conventional Low-grade Endometrial Stromal Sarcoma that Transformed Over Time to High-grade Sarcoma: Importance of Molecular Testing.

Low and high-grade endometrial stromal sarcomas (ESS) can be distinguished on a morphologic basis. Low-grade ESS is composed of oval cells that resemble normal proliferative-phase endometrial stroma, while the well-known high-grade ESS is composed of round cells growing in nests separated by delicate sinusoidal vasculature. Recurrent JAZF1 rearrangements have been reported to be most frequent in low-grade stromal sarcomas (up to 60%), while YWHAE rearrangements are characteristic of high-grade ESS. Herein, we report a case of a 45-yr-old woman with stage IA typical low-grade ESS who developed multiple abdominopelvic recurrences and lung metastases 15 mo after her primary tumor was resected. The unusual morphology (without high-grade areas) as well as the aggressive behavior of the tumor prompted molecular testing which showed YWHAE rearrangement in her abdominopelvic recurrence and her primary tumor. Five years after her primary tumor was resected, she developed scalp metastases with a typical morphology of a high-grade ESS associated with t(10;17) and died of her disease. Our case highlights the potential value of molecular testing in all low-grade ESS at time of initial diagnosis to stratify patients at higher risk for developing high-grade ESS with the goal of offering closer follow-up for early detection and treatment if transformation occurs.

Clinical, radiological, and pathological features of extraskeletal osteosarcoma.

OBJECTIVE: To evaluate clinical and radiological features of pathology-proven extraskeletal osteosarcomas. METHODS: This retrospective study was IRB-approved and HIPAA-compliant. Our pathology database was queried for cases of extraskeletal osteosarcoma. Tumor location, size, imaging appearance, presence of metastases, and clinical outcome were documented. RESULTS: Nineteen patients met inclusion criteria (age 59 ± 15 (range 28-85) years; 15 male, 4 female). Tumors occurred in the lower extremities (12 out of 19, 63%), pelvis/gluteal region (3 out of 19, 16%), upper extremity (2 out of 19, 5%), thorax (1 out of 19, 5%), and neck (1 out of 19, 5%). Two out of 19 (11%) patients had undergone radiation to the tumor site previously. According to pathology, 16 out of 19 tumors were high-grade (84%). Tumors presented as soft-tissue masses measuring 9.5 ± 6.8 (2-29) cm. Tumor mineralization was present in 5 out of 19 cases (26%) and local invasion was found in 1 out of 19 cases (6%). On MRI, tumors typically appeared hyperintense on T2-weighted sequences with enhancement in 15 out of 15 (100%) contrast-enhanced studies, and with central necrosis in 10 out of 19 (53%) cases. Low-grade tumors were smaller (<4 cm; 3 out of 3, 100%) and lacked central necrosis (3 out of 3, 100%). 8 out of 19 patients (42%) had metastases, most commonly to the lung (7 out of 19, 37%) and bone (2 out of 19,11%). Two out of 8 patients (25%) with metastases and 8 out of 11 (73%) without metastases achieved recurrence-free survival (mean follow-up 3.8 ± 4.0 [0.2-14.2]) years. No metastases or deaths occurred in patients with low-grade histology. CONCLUSIONS: Extraskeletal osteosarcomas are rare, typically high-grade malignancies that commonly metastasize to lung and bones. Low-grade tumors and those without metastases have a good prognosis. MRI appearance is nonspecific, with T2 hyperintense signal and heterogeneous enhancement. Unlike conventional osteosarcoma, mineralization is rare.

Synovial sarcoma mimicking benign peripheral nerve sheath tumor.

OBJECTIVE: To assess the radiographic and clinicopathologic features of synovial sarcoma of the nerve that were clinically or radiologically interpreted as benign peripheral nerve sheath tumor. MATERIALS AND METHODS: Five patients with synovial sarcoma arising from the peripheral nerve and interpreted clinically and radiologically as peripheral nerve sheath tumors were identified. Clinicopathologic and imaging features were evaluated. RESULTS: There were three females and two males, ranging in age from 28 to 50 (mean 35.8) years. Most patients (4/5) complained of a mass, discomfort or pain. MR images demonstrated a heterogeneous, enhancing, soft tissue mass contiguous with the neurovascular bundle. On histologic examination, most tumors were monophasic synovial sarcoma (4/5). At the time of surgery, all tumors were noted to arise along or within a peripheral nerve. All patients were alive with no evidence of disease with median follow-up of 44 (range 32-237) months. For comparison, approximately 775 benign peripheral nerve sheath tumors of the extremities were identified during the same time period. CONCLUSIONS: Primary synovial sarcoma of the nerve can mimic peripheral nerve sheath tumors clinically and on imaging and should be included in the differential diagnosis for tumors arising from peripheral nerves.

Osseous metastases of chordoma: imaging and clinical findings.

PURPOSE: To describe the imaging and clinical characteristics of chordoma osseous metastases (COM). MATERIALS AND METHODS: Our study was IRB approved and HIPAA compliant. A retrospective search of our pathology database for pathology-proven COM yielded 15 patients who had undergone MRI, CT, bone scan, and/or FDG-PET/CT. The imaging and clinical features of the COMs were recorded. A control group of age and gender matched chordoma patients without osseous metastasis was evaluated. RESULTS: The COM mean maximal dimension was 6.4 ± 4.0 cm. The majority (60%) of patients had one lesion. Extra-osseous soft tissue component was present in 85% and was larger than intra-osseous component in 76%. On MRI the lesions were heterogeneous but predominantly T2 hyperintense with hypointense septae, and with variable enhancement. On CT the lesions were typically destructive or permeative; calcifications were rare. The extent of the soft tissue component was isodense to muscle on CT and therefore better evaluated on MRI. COM was in a body part contiguous to the site of the primary tumor. Compared to the controls, COM patients were more likely to have local recurrence (P = 0.0009) and positive resection margins (P = 0.002). At 1 year, 33% of COM patients were deceased and 13% had progressive metastases. CONCLUSION: COM are associated with large extra-osseous soft tissue components, which are better visualized by MRI. They are often located in a body part contiguous to the site of the primary tumor, portend poor prognosis, and are associated with positive resection margins and local recurrence.