Biphenotypic sinonasal sarcoma (BSS) is a rare mesenchymal neoplasm characterized by dual neural and myogenic differentiation, recurrent PAX3 gene rearrangements, and low-grade morphology. High-grade transformation has been described, posing significant diagnostic challenges due to overlap among sinonasal tumors. DNA methylation profiling has emerged as a powerful diagnostic tool for sinonasal neoplasms, although BSS was not included in previous cohorts. In this study, we investigated the DNA methylation profile of BSS and its relationship with fusion type and high-grade transformation. Fourteen BSS samples were retrospectively collected from four academic institutions. All cases underwent genome-wide methylation profiling using the Illumina Infinium MethylationEPIC array, and available clinical, radiological, histopathologic, and immunohistochemical data were reviewed. RNA sequencing was performed when sufficient material was available. Methylation profiles were analyzed using t-distributed stochastic neighbor embedding (t-SNE) and compared with a reference cohort of sinonasal tumors. The median patient age was 52.7 years, with a female predominance (M:F ratio 1:2.25). The most common fusion was PAX3::MAML3 (6/12, 50.0%), followed by PAX3::FOXO1 and other rare rearrangements, including PAX3::NCOA2, PAX3::YAP1, and FUS::POU2AF3, detected in one case each (1/12, 8.3%). Most importantly, all BSS samples formed a cohesive epigenetic group upon dimensionality reduction, clearly separated from other sinonasal tumors. No specific clustering was seen among different fusion types or tumor grade. Our findings support that BSS represents a unique and molecularly distinct sinonasal sarcoma with a characteristic DNA methylation signature, independent of gene fusion partners or histologic progression, providing a valuable tool for the classification of challenging cases.

Primary renal angiosarcoma is an exceedingly rare tumor with dismal prognosis. Herein we describe a case with relatively indolent clinical course. A 67-year-old male underwent imaging studies for left abdominal discomfort and was found to have a 12cm left upper pole renal mass with multiple bony and hepatic lesions. Initial renal biopsy was extremely scant, showing rare lesional cells in papillary configuration, raising possibility of papillary renal cell carcinoma. Repeat biopsy showed proliferation of anastomosing vascular channels lined with highly atypical endothelial cells. Papillary-like structures composed of collagen lined by lesional endothelial cells were also noted. Lesional cells were positive for ERG and CD31, while negative for pancytokeratin and PAX-8. Diagnosis of angiosarcoma was rendered. Patient received multiple cycles of chemotherapy and immunotherapy, showed treatment response on restaging scans; however, showed enlargement of the primary site. He subsequently underwent cytoreductive nephrectomy which showed a ypT3 Angiosarcoma, NOS with 80% necrosis (therapy effect) and mitotic activity of 11/mm2. NA Patient is alive with evidence of residual disease on most recent scans 9 months after cytoreductive surgery and 41 months after initial diagnosis.

Renal leiomyosarcoma is a rare and aggressive mesenchymal tumor, accounting for 1–2% malignant renal neoplasms, with strong predilection for females. Due to overlapping features with more conventional renal tumors, accurate diagnosis can be challenging and relies on detailed histopathologic and immunohistochemical analysis. A 59-year-old male presented with two-week history of right flank pain. Imaging revealed a large, heterogeneous enhancing mass centered in the right kidney with focal cystic elements. Radical nephrectomy showed a 10.6cm tan-white, whorled mass arising from the renal sinus and hilum. Microscopy revealed intersecting fascicles of spindle cells with moderate pleomorphism, 16-mitoses/10HPF, and 10% necrosis. Immunohistochemistry was positive for SMA and desmin, and negative for epithelial, melanocytic, and histiocytic markers, excluding the differential diagnoses of sarcomatoid carcinoma, angiomyolipoma, and malignant fibrous histiocytoma. Diagnosis of primary renal leiomyosarcoma FNLCC grade 2 was rendered. The tumor was staged pT3 with negative margins and no nodal involvement. On follow-up the patient remains disease-free 14-months post-surgery. NA This case highlights the role of detailed morphologic and immunohistochemical evaluation in diagnosing renal leiomyosarcoma and importance of radiologic assessment to confirm the tumor’s primary renal origin rather than extension from retroperitoneum. Early surgical intervention plays key role in long-term disease control.

Inflammatory myofibroblastic tumor (IMT) is a neoplasm of uncertain etiology that predominantly occurs as an abdominal or pulmonary lesion in children and young adults. Histologic patterns include myxoid, hypercellular, and hypocellular fibrous. While hypercellular IMT is well-established, immunohistochemical evidence of rhabdomyoblastic differentiation within these tumors has not been reported previously. We report a cellular IMT with rhabdomyoblastic differentiation in left cheek of a 24-year-old male. The patient presented to oral surgery for a 3.5 cm cheek lesion with ulceration. The wide excision specimen revealed a variably cellular proliferation of spindle cells with eosinophilic cytoplasm arranged in short fascicles, with a partially myxoid matrix, chronic inflammatory infiltrate, minimal atypia, and low mitotic activity. This morphology is interrupted by a sharp transition to areas of increased cellularity and mitotic rate. Immunohistochemically, the tumor showed reactivity for SMA, desmin, and ALK1. Transitional areas of increased cellularity showed evidence of rhabdomyoblastic differentiation in their additional expression of myogenin and Myo D1. Gene fusion panel identified CLTC-ALK fusion, supporting the diagnosis. The patient is alive without evidence of recurrence two months after reresection. NA Our case presents previously unreported immunohistochemical findings in an IMT, which may have implications for therapeutic and diagnostic approaches to myofibroblastic tumors.

Tenosynovitis with psammomatous calcifications (TPC) is a rare, benign condition currently regarded as a pseudotumor possibly related to repetitive use and/or trauma with a predilection for females at acral sites. Thirty-five cases have been reported, with the largest series comprising 23 patients; yet, TPC remains poorly recognized by pathologists and clinicians alike. We report a series of eighteen additional cases along with radiology and clinical follow-up. Our cohort demonstrated a strong female sex predilection (14 females and 4 males), with ages ranging from 12 to 71 years (mean 50 years) and involved the hand/finger (10), toes/foot (5), wrist (2), or elbow (1). More than half (56

As Artificial Intelligence (AI) making advancements in medical decision-making, there is a growing need to ensure doctors develop appropriate reliance on AI to avoid adverse outcomes. However, existing methods in enabling appropriate AI reliance might encounter challenges while being applied in the medical domain. With this regard, this work employs and provides the validation of an alternative approach -- majority voting -- to facilitate appropriate reliance on AI in medical decision-making. This is achieved by a multi-institutional user study involving 32 medical professionals with various backgrounds, focusing on the pathology task of visually detecting a pattern, mitoses, in tumor images. Here, the majority voting process was conducted by synthesizing decisions under AI assistance from a group of pathology doctors (pathologists). Two metrics were used to evaluate the appropriateness of AI reliance: Relative AI Reliance (RAIR) and Relative Self-Reliance (RSR). Results showed that even with groups of three pathologists, majority-voted decisions significantly increased both RAIR and RSR -- by approximately 9% and 31%, respectively -- compared to decisions made by one pathologist collaborating with AI. This increased appropriateness resulted in better precision and recall in the detection of mitoses. While our study is centered on pathology, we believe these insights can be extended to general high-stakes decision-making processes involving similar visual tasks.

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.

Calcified chondroid mesenchymal neoplasm is a term proposed for tumors with a spectrum of morphologic features, including cartilage/chondroid matrix formation, that frequently harbor FN1 gene fusions. We report a series of 33 cases of putative calcified chondroid mesenchymal neoplasms, mostly referred for expert consultation out of concern for malignancy. Patients included 17 males and 16 females, with a mean age of 51.3 years. Anatomic locations include the hands and fingers, feet and toes, head and neck, and temporomandibular joint; 1 patient presented with multifocal disease. Radiologic review showed soft tissue masses with variable internal calcification, which occasionally scalloped bone but in all cases appeared indolent/benign. Tumors had a mean gross size of 2.1 cm and a homogenous rubbery to fibrous/gritty tan-white cut surface. Histology demonstrated multinodular architecture with a prominent chondroid matrix and increased cellularity towards the periphery of the nodules. The tumor cells were polygonal with eccentric nuclei and bland cytologic features and showed a variable amount of increased spindled / fibroblastic forms in the perinodular septa. The majority of cases had notable grungy and/or lacy calcifications. A subset of cases demonstrated at least focal areas of increased cellularity and osteoclast-like giant cells. Herein, we confirm the distinct morphologic and clinicopathologic features associated with this entity with the largest series to date, with a focus on practical diagnostic separation from similar chondroid neoplasms. Awareness of these features is critical in avoiding pitfalls, including a malignant diagnosis of chondrosarcoma.

This study aims to develop a comprehensive and easily executable histopathologic grading scheme for murine knee osteoarthritis (OA) using specific scoring criteria for both cartilage and periarticular changes, which may overcome important limitations of the existing grading systems. The new grading scheme was developed based on mouse knee OA models with observation periods up to 24 months of age (spontaneous OA) or 24-week post-injury (posttraumatic OA). Semi-quantitative assessments of the histopathologic OA changes were applied to all four quadrants per femorotibial joint for 50 joints (200 quadrants) using specific scoring criteria rather than mild to severe grades. Scoring elements per quadrant were as follows: cartilage lesion (0-7), osteophyte (0-3), subchondral bone change (0-3), synovitis (0-3), and ectopic periarticular soft-tissue chondrogenesis and ossification (0-3). The new histopathologic grading scheme had high intra- and interobserver reproducibility (correlation coefficients r > 0.95) across experienced and novice observers. Sensitivity and reliability analyses confirmed the ability of the new scheme to detect minimal but significant OA progression (p < 0.01) within a 2-week interval and to accurately identify tissue- and quadrant-specific OA severity within the joints. In conclusion, this study presents the first whole-joint histopathologic grading scheme for murine knee OA that covers all-stage osteoarthritic changes in all major joint tissues, including periarticular soft-tissue ossification that is not included in any of the existing OA grading systems. This reproducible scheme is easy to execute and sensitive to minimal OA progression without using computer software, suitable for quick OA severity assessments of the entire femorotibial joint.

We report a case of a 67-year-old male patient with a sinonasal tumor that showed areas of classic biphenotypic sinonasal sarcoma (BSNS) which in some sections sharply transitioned into high-grade rhabdomyosarcoma. Immunohistochemically, the conventional BSNS parts showed S100 protein, SMA, PAX7, and focal MyoD1 expression, whereas desmin and myogenin were negative. In contrast, the cells in high-grade areas expressed desmin, MyoD1, myogenin, and PAX7, while being negative for S100 protein and SMA. Using the Archer FusionPlex assay, the classical PAX3::MAML3 gene fusion was detected. FISH for PAX3 and MAML3 confirmed a break of these genes in both components. Despite aggressive therapy, the tumor progression resulted in the patient's death. The herein presented case, together with 2 previously published cases of BSNS with high-grade transformation, helps to better understand this novel phenomenon. Although the risk for such transformation appears low, it has important clinical and diagnostic implications which are discussed.

Calcified chondroid mesenchymal neoplasm is a term proposed for tumors with a spectrum of morphologic features, including cartilage/chondroid matrix formation, that frequently harbor FN1 gene fusions. We report a series of 33 cases of putative calcified chondroid mesenchymal neoplasms, mostly referred for expert consultation out of concern for malignancy. Patients included 17 males and 16 females, with a mean age of 51.3 years. Anatomic locations include the hands and fingers, feet and toes, head and neck, and temporomandibular joint; 1 patient presented with multifocal disease. Radiologic review showed soft tissue masses with variable internal calcification, which occasionally scalloped bone but in all cases appeared indolent/benign. Tumors had a mean gross size of 2.1 cm and a homogenous rubbery to fibrous/gritty tan-white cut surface. Histology demonstrated multinodular architecture with a prominent chondroid matrix and increased cellularity towards the periphery of the nodules. The tumor cells were polygonal with eccentric nuclei and bland cytologic features and showed a variable amount of increased spindled / fibroblastic forms in the perinodular septa. The majority of cases had notable grungy and/or lacy calcifications. A subset of cases demonstrated at least focal areas of increased cellularity and osteoclast-like giant cells. Herein, we confirm the distinct morphologic and clinicopathologic features associated with this entity with the largest series to date, with a focus on practical diagnostic separation from similar chondroid neoplasms. Awareness of these features is critical in avoiding pitfalls, including a malignant diagnosis of chondrosarcoma.

Papillary hemangioma (PH) is a recently described vascular tumor with a predilection for the skin of the head and neck. Histopathologically, it is characterized by a bland endothelial proliferation arranged in a papillary configuration, bearing resemblance to glomeruloid hemangioma seen in the context of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes syndrome. The largest cutaneous PH reported to date measured 1.5 cm in greatest dimension. Here, we report a case of PH with an alarming size of 10 cm. We present this case to add to the limited literature on this rare tumor, highlight the histopathologic differences between PH and its mimics, and emphasize the variable nature of PH tumor size.

Spindle cell/pleomorphic lipoma has a wide range of histologic appearances and frequently presents diagnostic difficulties. All but the most common cases can be easily confused for locally aggressive or malignant entities. Recently, a family of related tumors resembling SCPL but with unusual clinical features and an atypical and aggressive histologic appearance has been described under the umbrella term of atypical spindle cell pleomorphic lipomatous tumors (ASCPLT). Proper identification of these tumors is critical to prevent unwarranted aggressive surgical and medical therapy. This review focuses on the clinical and histopathologic features of SCL and ASCPLT as well as the challenging differential diagnoses these tumors present.

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.

Paget’s disease of bone is a rare diagnosis in patients under 40 years of age. We report a case diagnosed in a 35-year-old patient with suspected symptomatic presentation at the age of 30 years during pregnancy. This report details the course of the patient’s evaluation toward diagnosis and includes previously suspected etiologies, significant radiologic features and conclusive histologic findings. This case is relevant to the existing literature because it demonstrates that Paget’s disease of bone should be included in the differential diagnosis of younger patients outside the traditional disease demographic who present with diagnostic radiologic findings and elevated serum alkaline phosphatase.