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* Context.--The incidence, distribution, and significance of calcium pyrophosphate dihydrate deposition (CPPD) disease have not been extensively compared among various total joint resections. Objective.--To investigate and define the clinical and pathologic features of CPPD in hip, shoulder, and knee arthroplasties. Design.--We retrospectively reviewed consecutive total hip, knee, and shoulder arthroplasty cases (N = 3195) confirmed pathologically between January 1, 2017, and October 10, 2018, comparing clinical and pathologic data. Results.--Among 2004 hip arthroplasties, 61 (3%) had CPPD on pathologic examination; the majority had a histologic diagnosis of osteoarthritis, followed by fracture and avascular necrosis. Of 1113 knee arthroplasties, 98 (9%) had CPPD; all had a histologic diagnosis of osteoarthritis. Among 78 shoulder arthroplasties, 10 (13%) had CPPD; all but one had a histologic diagnosis of osteoarthritis. Patients with hip and knee CPPD were significantly older than those without CPPD. Of the 169 pathologically detected CPPD cases, only 35 (21%) were documented on preoperative radiologic images or by other clinical means; radiology reports were significantly more likely to document chondrocalcinosis in the knees than in the hips. Histologically, CPPD was noted almost exclusively in the separately submitted soft tissues/joint capsule, concomitantly involving the articular cartilage surface in only 3.0% (5 of 169) of cases. Conclusions.--Calcium pyrophosphate dihydrate deposition is more than twice as likely to occur in the knees and shoulders compared with the hips. Patients with CPPD in the knees or hips are usually not recognized preoperatively/radiologically and constitute a significantly older population. Reliably establishing the diagnosis of CPPD requires pathologic examination of the submitted soft tissue/joint capsule., Calcium pyrophosphate dihydrate deposition (CPPD) disease is a metabolic arthritis produced by the deposition of calcium pyrophosphate (CPP) dihydrate crystals in the synovium, joint capsule, and periarticular soft tissues, including [...]

* Context.--Bone and soft tissue tumors are heterogeneous, diagnostically challenging, and often defined by gene fusions. Objective.--To present our experience using a custom 34-gene targeted sequencing fusion panel. Design.--Total nucleic acid extracted from formalin-fixed, paraffin-embedded (FFPE) tumor specimens was subjected to open-ended, nested anchored multiplex polymerase chain reaction and enrichment of 34 gene targets, thus enabling detection of known and novel fusion partners. Results.--During a 12-month period, 147 patients were tested as part of routine clinical care. Tumor percentage ranged from 10% to 100% and turnaround time ranged from 3 to 15 (median, 7.9) days. The most common diagnostic groups were small round blue cell tumors, tumors of uncertain differentiation, fibroblastic/myofibroblastic tumors, and adipocytic tumors. In-frame fusion transcripts were identified in 64 of 142 cases sequenced (45%): in 62 cases, the detection of a disease-defining fusion confirmed the morphologic impression; in 2 cases, a germline TFG-GPR128 polymorphic fusion variant was detected. Several genes in the panel partnered with multiple fusion partners specific for different diagnoses, for example, EWSR1, NR4A3, FUS, NCOA2, and TFE3. Interesting examples are presented to highlight how fusion detection or lack thereof was instrumental in establishing accurate diagnoses. Novel fusion partners were detected for 2 cases of solid aneurysmal bone cysts (PTBP1-USP6, SLC38A2-USP6). Conclusions.--Multiplex detection of fusions in total nucleic acid purified from FFPE specimens facilitates diagnosis of bone and soft tissue tumors. This technology is particularly useful for morphologically challenging entities and in the absence of prior knowledge of fusion partners, and has the potential to discover novel fusion partners. (Arch Pathol Lab Med. 2021;145:851-863; doi: 10.5858/arpa.2020-0336-OA), Gene fusions occur frequently in bone and soft tissue (BST) neoplasms and, less frequently, in other kinds of solid tumors. (1-3) The observation of these fusions in patient specimens can [...]

CREB gene family (ATF1, CREB1, CREM) fusions with either EWSR1 or FUS gene partners drive the pathogenesis of a wide range of neoplasms, including various soft tissue tumors, intracranial myxoid mesenchymal tumors (IMMTs), hyalinizing clear cell carcinoma (HCCC), and rare mesotheliomas. Recently, a SMARCA2::CREM fusion was reported in one case each of IMMT and HCCC. In this study, we expand the clinicopathologic and molecular spectrum of these neoplasms by describing three additional cases with SMARCA2::CREM and one with a novel SMARCA4::CREM fusion, highlighting the recurrent potential of additional CREB gene fusion partners beyond FET family members. To evaluate if these fusions define a new pathologic entity, we performed a comprehensive genomic and methylation analysis and compared the results to other related tumors. Tumors occurred in children and young adults (median age 20 years) and spanned a broad anatomic distribution, including soft tissue, intracranial, head and neck, and prostatic urethra. Microscopically, the tumors shared an undifferentiated round to epithelioid cell phenotype and a hyalinized fibrous stroma. Immunohistochemically, a polyphenotypic profile was observed, with variable expression of SOX10, desmin, and/or epithelial markers. No targetable genomic alterations were found using panel‐based DNA sequencing. By DNA methylation and transcriptomic analyses, tumors grouped closely to FET::CREB entities, but not with SMARCA4/SMARCB1‐deficient tumors. High expression of CREM by immunohistochemistry was also documented in these tumors. Patients experienced local recurrence (n = 2), locoregional lymph node metastases (n = 2), and an isolated visceral metastasis (n = 1). Overall, our study suggests that SMARCA2/4::CREM fusions define a distinct group of neoplasms with round cell to epithelioid histology, a variable immunoprofile, and a definite risk of malignancy. Larger studies are needed to further explore the pathogenetic relationship with the FET::CREB family of tumors. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Chondromyxoid fibroma (CMF) is a rare, benign bone tumour which arises primarily in young adults and is occasionally diagnostically challenging. Glutamate metabotropic receptor 1 (GRM1) gene encodes a metabotropic glutamate receptor and was recently shown to be up‐regulated in chondromyxoid fibroma through gene fusion and promoter swapping. The aim of this study was to interrogate cases of CMF for the presence of GRM1 gene rearrangements, gene fusions and GRM1 protein overexpression.Selected cases were subjected to testing by fluorescent in‐situ hybridisation (FISH) with a GRM1 break‐apart probe, a targeted RNA sequencing method and immunohistochemical study with an antibody to GRM1 protein. Two cases were subjected to whole transcriptomic sequencing. In 13 of 13 cases, GRM1 protein overexpression was detected by immunohistochemistry using the GRM1 antibody. Of the 12 cases successfully tested by FISH, nine of 12 showed GRM1 rearrangements by break‐apart probe assay. Targeted RNA sequencing analysis did not detect gene fusions in any of the eight cases tested, but there was an increase in GRM1 mRNA expression in all eight cases. Two cases subjected to whole transcriptomic sequencing (WTS) showed elevated GRM1 expression and no gene fusions.GRM1 gene rearrangements can be detected using FISH break‐apart probes in approximately 75% of cases, and immunohistochemical detection of GRM1 protein over‐expression is a sensitive diagnostic method. The gene fusion was not detected by targeted RNA sequencing, due most probably to the complexity of fusion mechanism, and is not yet a reliable method for confirming a diagnosis of CMF in the clinical setting. [ABSTRACT FROM AUTHOR]

Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK‐rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene‐altered spindle cell neoplasms affecting both pediatric and adult patients. Follow‐up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co‐expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high‐grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low‐ and intermediate‐grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]