Uncertain Differentiation Research Articles

Trojan Horse Strategy for Wireless Electrical Stimulation-Induced Zn2+ Release to Regulate Neural Stem Cell Differentiation for Spinal Cord Injury Repair.

Due to the uncertain differentiation of neural stem cells (NSCs), replenishing lost neurons by endogenous neural differentiation to repair spinal cord injury (SCI) remains challenging. The electrical stimulation-induced drug release is a promising approach for the localized and controlled release of drugs to regulate the differentiation of NSCs into neurons. Here, we developed Zn-PDA@BT nanoparticles acted as Trojan Horse to enter cells through endocytosis for Zn2+-controlled release therapy by the potentials generated by the piezoelectric effect. Due to the presence of polydopamine (PDA), under ultrasound stimulation, the electrical signal derived from the piezoelectric effect of barium titanate nanoparticles can be attracted to the surface of Trojan Horse nanoparticles to facilitate the controlled release of Zn2+. And Zn2+ bonded with PDA can increase the intracellular Zn2+ concentration within mouse-derived NSCs (mNSCs) to regulate the differentiation of mNSCs, which could enhance excitatory neuronal differentiation and inhibit astrocyte differentiation of mNSCs by activating the TGF-β and p53 pathways. More importantly, this Trojan Horse therapy allowed mNSCs to differentiate into mature neurons in 5 days, while the natural differentiation process took 10 days. Moreover, the transplantation of mNSC-ingested Zn-PDA@BT nanoparticles effectively replenished lost neurons at the damaged site and promoted function recovery after SCI in vivo, demonstrating the great potential of electrical stimulation-induced Zn2+ release for SCI repair.

Synchronous endometrial and minor salivary gland carcinomas – role of molecular diagnostics amid lack of clinical suspicion

Abstract Introduction/Objective Synchronous malignancies account for 3-5% of all tumor diagnoses but can be challenging to detect if one or both tumors are rare histologic subtypes and clinical suspicion is lacking. Molecular diagnostics are critical for accurate diagnosis in these difficult cases to guide appropriate patient care. Methods/Case Report We report the case of a 49-year-old female who was diagnosed with a high-grade, mixed- histology endometrial adenocarcinoma a few years back. She was found to have hilar and mediastinal nodal carcinoma of uncertain differentiation a couple of months after her initial diagnosis, clinically labelled as metastatic endometrial carcinoma. Following neoadjuvant chemotherapy, her hysterectomy showed complete pathologic response, and was found to be POLE ultramutated on NGS. Follow-up PET scan in 2023 showed progression of hilar/endobronchial thickening, as well as interval increase in size of mediastinal nodes, again presumed to be endometrial metastases, despite the POLE mutant status. Repeat sampling was performed from both the sites, along with comprehensive molecular profiling. Cytology from the nodes and surgical pathology from the endobronchial lesion showed similar morphology consisting of hyperchromatic basaloid cells in cribriform arrangement with tubular structures containing myxoid stromal material, negative for PAX-8, ER, p40, and TTF1 immunostains, inconsistent with endometrial metastasis. Molecular studies including FISH and NGS showed MYB1::NFIB fusion characteristic of adenoid cystic carcinoma and absence of POLE mutation, definitively refuting the clinically suspected progression of endometrial metastasis. Molecular testing confirmed that the endobronchial tumor and mediastinal nodal involvement were caused by a second primary, distinct from her POLE-ultramutated endometrial carcinoma which disappeared with chemotherapy. Her extended molecular workup also revealed a pathogenic mutation in BRIP1, suggesting a genetic cancer predisposition syndrome requiring referral for genetic counseling. Results (if a Case Study enter NA) NA Conclusion Molecular pathology is an invaluable tool for unravelling diagnostic complexity. Pathologists must integrate cytomorphology, molecular genetics and knowledge of cancer biology to steer the clinical teams towards the best patient care.

Mesenchymal Non-Meningothelial Tumors of the CNS: Evolving Molecular Landscape and Implications for Neuroradiologists.

The World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5) significantly revised the terminology and diagnostic criteria of "mesenchymal non-meningothelial" tumors of CNS to better align with the classification of these soft tissue tumors outside the CNS. The CNS chapter only covers the entities with distinct histological or molecular characteristics that occur exclusively or primarily in the CNS. These tumors usually arise from the meninges and are rarely intraparenchymal in origin, mainly in the supratentorial compartment. These tumors are grouped into three main categories: soft tissue, chondro-osseous, and notochordal. Soft tissue tumors, the largest group, are further divided into fibroblastic, vascular, and skeletal muscle subtypes. Notably, a new subcategory for "tumors of uncertain differentiation" has been introduced, encompassing three new histomolecular entities: FET::CREB fusion-positive, CIC-rearranged sarcoma, and primary intracranial sarcoma, DICER1-mutant. Emerging entities like dural angioleiomyomas and spindle cell neoplasms with NTRK-rearrangements have been reviewed, although not introduced in WHO CNS5. Given the often non-specific histology and immunophenotype of mesenchymal nonmeningothelial tumors of uncertain differentiation, molecular techniques have become indispensable for accurate diagnosis. This review provides a comprehensive overview of primary mesenchymal non-meningothelial CNS tumors, including their clinical, radiological, histopathological, and molecular characteristics and treatment strategies.ABBREVIATIONS: ALK: Anaplastic lymphoma kinase; ATF1: activating transcriptase factor-1; CREB: cAMP response element-binding protein; CREM: cAMP response element modulator; CIC: Capicua transcriptional receptor; EWSR1: Ewing sarcoma RNA binding protein; FUS: fused in sarcoma; NAB2: nerve growth factor-inducible protein A binding protein 2; STAT6: signal transducer and activator of transcription 6; WHO: World Health Organization WHO CNS5: World Health Organization Classification of Tumors of the Central Nervous System, fifth edition.

Malignant transformation of craniofacial fibrous dysplasia: A clinicopathological, immunohistochemical and molecular analysis of 15 cases in one single institution

ObjectiveMalignant transformation of craniofacial fibrous dysplasia (FD) is not common and its clinicopathological as well as molecular characteristics remain largely unknown with limited literature reports. Study designPatients diagnosed with FD including McCune-Albright syndrome (MAS), polyostotic fibrous dysplasia (PFD), and monostotic fibrous dysplasia (MFD), accompanied by malignant transformation at our institution over the past 18 years (2005–2023) were retrospectively screened and analyzed to investigate the epidemiology and clinicopathological features of these tumors. ResultsThree hundred and five patients were diagnosed as FD in our hospital from 2005 to 2023, with 176 females (57.7 %) and 129 males (42.3 %). The average age at diagnosis was 28.35 years, ranging from 7 to 70 years. A total number of 15 (4. 9 %) cases of FD with malignant transformation were selected. Among these 15 patients, the age of the initial diagnosis of FD ranged from 6 to 54 years (mean age 28.87 ± 16.77), and the ages when malignant transformation occurred ranged from 18 to 57 years (mean age 38.53 ± 13.05). Among 15 patients, 12 patients were female (80 %) and 3 were male (20 %). Fifteen cases included MSA in 2 patients, PFD in 4 patients, and MFD in 9 patients. Of the anatomical sites in craniofacial bones, the most common site of the lesion was the maxilla, followed by the mandible. Malignant neoplasm arising in FD were osteosarcoma (12/15), chondrosarcoma (1/15) and high-grade sarcoma of uncertain differentiation (2/15). The 3- and 5-year overall survival rate was 33.3 % (5/15) and 20 % (3/15) respectively. In secondary osteosarcoma from FD, MDM2 and CDK4 positivity were 33.3 % and 41.7 % respectively, and only one case was MDM2-amplified and CDK4-amplified. ConclusionMalignant transformation in fibrous dysplasia was an exceedingly rare event and with a female predominance. The overall survival rate was poor. Osteosarcoma was the most common malignant neoplasm arising in FD. MDM2 and CDK4 expression may aid in the diagnosis of secondary osteosarcoma in FD.

Innovations in the classification of soft tissue tumors

Soft tissue tumors are avery heterogeneous group of tumors. Their classification is regularly updated by the World Health Organization (WHO), most recently in 2020. The current classification of soft tissue tumors emphasizes molecular biological tumor characteristics, which enable tumor-specific treatment. In addition to Ewing's sarcoma, which occurs as bone as well as extra-skeletal soft tissue tumors as asmall round cell sarcoma, three other subtypes of undifferentiated, small and round cell sarcomas have been introduced. Some names of the new sarcomas can be derived from the gene mutations. The groups of adipocytic and (myo)fibroblastic tumors have been extended by three further entities. There were further additions to vascular soft tissue tumors, smooth muscle cell tumors, peripheral nerve sheath tumors and tumors of uncertain differentiation. Adistinction is made between benign, intermediate locally aggressive, intermediate rarely metastatic and malignant soft tissue tumors.

Clinical and pathological analyses of 14 cases of angiomatoid fibrous histiocytoma.

Angiomatoid fibrous histiocytoma (AFH) is a soft tissue tumor of uncertain differentiation. Although its prognosis is good, its diagnosis and differential diagnosis remain a challenge, particularly for tumors with an atypical morphology. We evaluated the clinicopathological characteristics of 14 AFH cases and examined the key factors in its diagnosis or differential diagnosis. The cohort comprised 6 men and 8 women aged 9-65years (average age: 31.2years). Most of the tumors (11/14, 79%) were located in soft tissues, whereas 3/14 (21%) were located in the lung (1 case) and brain (2 cases). Tumor cells were spindle-shaped to epithelioid, with a visible fibrous capsule (9/14, 64%), hemorrhagic gap (9/14, 64%), lymphocyte sleeve (7/14, 50%), necrosis (3/14, 21%), and infiltrative boundary (4/14, 29%). The tumors expressed desmin (10/14, 71%) and exhibited low levels of Ki-67. 13 cases (93%) displayed ESWSR1 gene rearrangement. At follow-up, 1 case (7%) experienced local tumor recurrence. AFH is a rare intermediate tumor. Its pathological diagnosis requires a comprehensive analysis of histological, immunophenotypic, and molecular genetic features to avoid misdiagnosis. Our study has further enriched the histological features of AFH, emphasizing the importance of differential diagnosis and providing a reference for clinical practice.

TRPS1 Expression Is Frequently Seen in a Subset of Cutaneous Mesenchymal Neoplasms and Tumors of Uncertain Differentiation: A Potential Diagnostic Pitfall.

Although extensively studied in cutaneous epithelial neoplasms, the TRPS1 immunoreactivity in cutaneous mesenchymal neoplasms and tumors of uncertain differentiation (CMNTUDs), such as atypical fibroxanthoma (AFX), remains largely unexplored. We assessed TRPS1 immunoreactivity in 135 CMNTUDs, comprising 46 fibrohistiocytic/fibroblastic tumors, 28 vascular tumors, 24 peripheral nerve sheath tumors (PNSTs), 21 tumors of uncertain differentiation, and 16 smooth muscle tumors. Additionally, we included selected cases of melanoma with spindled cell morphology or desmoplastic features (n = 9) and sarcomatoid squamous cell carcinoma (SSCC) (n = 5) to compare TRPS1 expression patterns with those of AFX. TRPS1 expression was prevalent in dermatofibromas (24/24), leiomyomas (8/8), AFXs/pleomorphic dermal sarcoma (PDS) (20/21), dermatofibrosarcomas protuberans (14/22), and leiomyosarcomas (6/8). It was uncommon in angiosarcomas (3/20), Kaposi sarcomas (2/8), and neurofibromas (5/17) and absent in perineuriomas (0/2). AFXs/PDS exhibited the highest median H-score of 240, contrasting with minimal TRPS1 immunoreactivity in vascular neoplasms and PNSTs, with median H-scores consistently below 10. Significant differences in H-score were observed between AFXs/PDS and angiosarcomas (p < 0.001), melanomas (p < 0.001), and leiomyosarcomas (p = 0.029). However, no significant difference was found compared to SSCCs, suggesting limited discriminatory power of TRPS1 in this context. This study sheds light on TRPS1 expression patterns in a subset of CMNTUDs, extending beyond prior studies primarily focused on epithelial tumors, while underscoring potential pitfalls associated with TRPS1 immunohistochemistry.

Epidemiología de los tumores musculoesqueléticos en una unidad de referencia

ObjectiveThe objective of this study was to perform an epidemiological analysis of patients presented to the Musculoskeletal Tumors Committee of a reference hospital. Material and methodA retrospective analysis of patients with sarcomas treated in a reference Sarcoma Unit between 2009 and 2022 was carried out. ResultsA total of 1978 patients were analyzed, of which 1477 (74.67%) were diagnosed as sarcomas. They were divided into 446 (30.20%) bone tumors and 1.031 (69.80%) soft tissue tumors. The most common benign bone tumor was enchondroma (27.23%), giant cell tumor (59.21%) was the most common tumor of intermediate malignancy and the malignant one was osteosarcoma (24.78%). The most frequently observed benign soft tissue tumor was lipoma (50.74%), the atypical lipomatous tumor (53.25%) was the most frequent tumor of intermediate malignancy and the malignant one was sarcoma of uncertain differentiation (38.10%). ConclusionOur study represents the first work on the epidemiology of sarcomas and other musculoskeletal tumors in our country, being very useful to adapt the resources destined for their diagnosis and treatment.

#2339 All-trans retinoic acid enhances the efficacy of mesenchymal stem cells in acute kidney injury

Abstract Background and Aims Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy for acute kidney injury (AKI), but still suffer from the drawbacks of low survival rate, low homing rate, and uncertain differentiation. In search of better therapeutic strategies, we explored all-trans retinoic acid (ATRA) pretreatment of MSCs to observe whether it could improve the therapeutic efficacy on AKI. Method We established a renal ischemia/reperfusion (I/R) injury model induced by clamping of left renal artery for 30 minutes and contralateral nephrectomy. C57BL/6 mice were randomly divided into 4 groups: sham group, IRI group, MSCs group, and ATRA-MSCs group. MSCs or ATRA-pretreated MSCs were injected via tail vein. GFR was measured by transcutaneous monitoring the clearance of FITC-sinistrin. These mice were sacrificed 3 days after surgery, and the serum creatinine (SCr) and blood urea nitrogen (BUN) levels were measured. The renal pathological changes were examined by Periodic Acid-Schiff staining (PAS). The in vitro hypoxia/reoxygenation (H/R) model was established using human proximal tubular epithelial cells (HK-2 cells). Co-culturing HK-2 cells with MSCs or ATRA-pretreated MSCs. Western blot, quantitative real time-PCR (qRT-PCR), and immunohistochemistry were used to detect mRNA or protein expression. We performed RNA sequencing (RNA-seq) analysis in ATRA-pretreated MSCs. The content of hyaluronic acid (HA) in the supernatant of ATRA-pretreated MSCs culture was detected by ELISA. Hyaluronan synthase mRNA expression level in ATRA-pretreated MSCs assessed by qRT-PCR analysis. The HAS2 promoter-binding transcription factors were forecasted by the JASPAR Transcription Factor Binding Site database. Western blot was used to detect whether P13K/AKT pathway was activated by ATRA-pretreated MSCs. Whether this nephroprotective effect could be reversed were explored by silencing HAS2 or CD44 antibodies. Results The AKI mice showed a significant decrease in GFR and even complete loss of renal function. Administration of MSCs significantly increased GFR, and MSCs pretreated with ATRA further increased GFR. Mice injected with ATRA-pretreated MSCs had significantly lower levels of SCr, BUN and ATN scores compared with untreated MSCs. Western blot, quantitative real-time PCR (qRT-PCR), and immunohistochemistry showed that ATRA pretreated MSCs were more effective in reducing AKI inflammation and apoptosis and promoting proliferative repair than untreated MSCs. GO enrichment analysis demonstrated that the hyaluronan biosynthetic process may be a significantly expressed. HAS2 expression and HA content of MSCS were significantly increased after the addition of ATRA. Analysis for potential transcription factor binding sites revealed that the HAS2 promoter region has multiple potential binding sites for the retinoic acid receptor. Based on the predictions from the JASPAR database, the RXR-RAR heterodimer had the highest prediction score. We then performed ChIP analysis to experimentally verify the binding of RXR-RAR heterodimer transcription factor to HAS2 promoters. We further found that ATRA-pretreated MSCs activated the PI3K/AKT signaling pathway in AKI. As expected, we found that ATRA-pretreated MSCs anti-inflammatory, anti-apoptosis, and pro-proliferation effects were substantially reversed by silencing HAS2 or blocking CD44. Conclusion ATRA promotes HA secretion from MSCs and activates the PI3K/AKT pathway, which in turn enhances the therapeutic efficacy of MSCs on AKI.

A rare case of superficial vulvar angiomyxoma

Abstract Angiomyxoma is a rare, slow growing mesenchymal neoplasm that occurs almost exclusively in the genital, perineal and pelvic regions of adult women of reproductive age. We present the case of a 52-year-old female with asymptomatic lesion over the vulva since 6 months which gradually increased in size. On examination single, well circumscribed, erythematous to skin coloured, pedunculated mass was seen over the right side of the vulva measuring approximately 10 x 5cms. On palpation it was mobile, soft to firm in consistency with a smooth surface. Complete Excision under aseptic precaution was done and sent for histopathological examination which showed features suggestive of Angiomyxoma, a very rare gynaecologic tumour and classified as “tumors of uncertain differentiation “with estrogen and progesterone receptors. We present this case to highlight the importance of Histopathology in dermatology to diagnose rare cases and improve patient care.

Mesenchymal and Non-meningothelial Tumors Involving the Central Nervous System

In the World Health Organization Classification of Brain Tumors Fifth Edition, mesenchymal non-meningothelial tumors involving the central nervous system are divided into three major categories: soft tissue tumors, chondro-osseous tumors, and notochordal tumors. Soft tissue tumors are classified into four groups: fibroblastic and myofibroblastic tumors, vascular tumors, skeletal muscle tumors, and tumors of uncertain differentiation. This article will focus on solitary fibrous tumors(SFTs), which are frequently encountered clinically and continue to undergo classification revisions in the 5th edition, and outline the three newly added histological diagnoses. Although SFTs and hemangiopericytomas occur throughout the body, including the central nervous system, nomenclatures have been different between the classifications of "Tumours of Soft Tissue and Bone" and "Tumours of the Central Nervous System." The latest nomenclature is "SFT" in accordance with the nomenclature of bone and soft-tissue tumors. In addition, three new diagnoses, which are intracranial mesenchymal tumor FET-CREB fusion-positive, CIC-rearranged sarcoma, and primary intracranial sarcoma DICER1-mutant, have been defined based on genetic abnormalities in tumors of uncertain differentiation.

Do the Histological Differences of Soft Tissue Sarcomas Affect the Rate of Skin Defect Reconstruction?

In soft tissue sarcoma (STS) resection, flap reconstruction and/or skin grafting is frequently required. However, it is not clear whether the histological difference affects the rate of reconstruction. The present study aimed to investigate it. This study compared in 5 classifications (105 adipocytic tumors, 102 fibroblastic tumors, 39 muscle tumors, 31 peripheral nerve sheath tumors, and 178 tumors of uncertain differentiation). In addition, the reconstruction rates of detailed tumor sites were compared. The median and case number (percentage) were calculated. Tumor size (adipocytic 112 mm vs fibroblastic 79 mm, muscle 72 mm, nerve 90 mm, uncertain 74 mm, P < 0.0001 in all comparisons), histological low-grade rates (adipocytic 43.8% vs uncertain 3.9%, P < 0.0001; fibroblastic 46.1% vs muscle 15.4%, P = 0.003; fibroblastic vs uncertain, P < 0.0001; nerve 19.4% vs uncertain, P = 0.003) and reconstruction rates (adipocytic 5.7% vs fibroblastic 42.2%, muscle 33.3%, nerve 32.3%, uncertain 25.8%, P < 0.0001 in all comparisons) were significantly different. In the region of lower extremity, the regions of thigh [adipocytic 1/62 (1.6%) vs fibroblastic 7/32 (21.9%), P = 0.002], and lower leg [adipocytic 1/16 (6.3%) vs fibroblastic 11/19 (57.9%), P = 0.002] were significantly different. In adipocytic tumors, the tumor size was significantly large; however, the skin defect reconstruction rate was significantly lower than that of the other STS. Histologically, the reconstruction rate of STS derived from superficial tissue increases, whereas the reconstruction rate derived from deep tissue such as adipocytic tumor decreases.

TAF15::NR4A3 gene fusion identifies a morphologically distinct subset of extraskeletal myxoid chondrosarcoma mimicking myoepithelial tumors.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain differentiation predominantly arising in deep soft tissue. Its conventional morphologic appearance manifests as a relatively well-circumscribed, multilobular tumor composed of uniform short spindle-to-ovoid primitive mesenchymal cells with deeply eosinophilic cytoplasm arranged in anastomosing cords within abundant myxoid matrix. The genetic hallmark of EMC has long been considered to be pathognomonic gene rearrangements involving NR4A3, which when fused to TAF15, often have high-grade morphology with increased cellularity, moderate to severe cytologic atypia, and rhabdoid cytomorphology. Herein, we describe two cases of EMC with TAF15::NR4A3 fusion that appear morphologically distinct from both conventional and high-grade EMC. Both cases had an unusual biphasic appearance and showed diffuse positivity for p63, mimicking myoepithelial tumors. DNA methylation profiling demonstrated that both cases clearly cluster with EMC, indicating that they most likely represent morphologically distinct variants of EMC. The clinical significance and prognostic impact of this morphologic variance remains to be determined. Molecular testing, including DNA methylation profiling, can help to confirm the diagnosis and avoid confusion with mimics; it adds another layer of data to support expanding the morphologic spectrum of EMC.

New established cell lines from undifferentiated pleomorphic sarcoma for in vivo study

As a high-grade soft-tissue sarcoma(STS), undifferentiated pleomorphic sarcoma(UPS) is highly recurrent and malignant. UPS is categorized as a tumor of uncertain differentiation and has few options for treatment due to its lack of targetable genetic alterations. There are also few cell lines that provide a representative model for UPS, leading to a dearth of experimental research. Here, we established and characterized new cell lines derived from two recurrent UPS tissues. Cells were obtained from UPS tissues by mincing, followed by extraction or dissociation using enzymes and culture in a standard culture environment. Cells were maintained for several months without artificial treatment, and some cell clones were found to be tumorigenic in an immunodeficient mouse model. Interestingly, some cells formed tumors in vivo when injected after aggregation in a non-adherent culture system for 24 h. The tissues from in vivo study and tissues from patients shared common histological characteristics. Pathways related to the cell cycle, such as DNA replication, were enriched in both cell clones. Pathways related to cell-cell adhesion and cell-cell signaling were also enriched, suggesting a role of the mesenchymal-to-epithelial transition for tumorigenicity in vivo. These new UPS cell lines may facilitate research to identify therapeutic strategies for UPS.

Establishment, characterization and functional testing of two novel ex vivo extraskeletal myxoid chondrosarcoma (EMC) cell models

Extraskeletal myxoid chondrosarcoma (EMC) is a malignant mesenchymal neoplasm of uncertain differentiation as classified by the WHO Classification of Tumours 2020. Although often associated with pronlonged survival, EMC has high rates of distant recurrences and disease-associated death. EMCs are translocation sarcomas and harbor in > 90% of the cases an NR4A3 rearrangement. The molecular consequences of the NR4A3 gene fusions are not yet fully elucidated as well-characterized ex vivo cell models for EMC are lacking. Patient-derived ex vivo models are important and essential tools for investigating disease mechanisms associated with diseases that are rare, that exhibit poor prognosis and for the identification of potential novel treatment options. We established two novel EMC ex vivo models (USZ20-EMC1 and USZ22-EMC2) for functional testing and research purposes. USZ20-EMC1 and USZ22-EMC2 were established and maintained as sarco-sphere cell models for several months in culture. The cells were molecularly characterized using DNA sequencing and methylation profiling. Both cell models represent their native tumor tissue as confirmed by histomorphology and their molecular profiles, suggesting that native tumor cell function can be recapitulated in the ex vivo models. Using a functional screening approach, novel anti-cancer drug sensitivities including potential synergistic combinations were identified. In conclusion, two novel EMC ex vivo cell models (USZ20-EMC1 and USZ22-EMC2) were successfully established and characterized from native tumor tissues. Both cell models will be useful tools for further investigating disease mechanisms and for answering basic and translational research questions.

Angiomatoid Fibrous Histiocytoma: A Tumor With Uncertain Behavior and Various Clinicopathological Presentations.

BackgroundAngiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of uncertain differentiation, which has various clinical and morphological presentations. Although it behaves in a benign manner, it has malignant potential.AimTo share various histological patterns and survival data in our population of this rare entity.Materials and methodsWe studied 25 patients who reported AFH from January 2011 to December 2021. Clinical information, gross and histological features, immunohistochemical results, and survival data were compiled and analyzed.ResultsAmong 25 cases reported as AFH, the majority (68%) were males with a mean age of 31.8 years at the time of diagnosis. The most common location was the lower extremity, especially the thigh (56%), and the mean size of the lesion was 55 mm. Most of the lesions were superficial (84%). Grossly, the majority of lesions (76%) had a solid appearance. Microscopically, classic spindle cell morphology was the most common (76%) with a lymphoid cuff and intralesional hemorrhage. Mild cellular atypia was seen in most (92%) of the cases, while some biopsies (8%) had a high-grade morphology. The majority of patients were alive, while one patient died of the disease.ConclusionAFH is an under-recognized entity with various clinical and histological presentations and a low malignant potential.

A 73-Year-Old Man with an Incidental Diagnosis of Deltoid Intramuscular Myxoma Following a History of Trauma

Patient: Male, 73-year-old Final Diagnosis: Intramuscular myxoma Symptoms: Shoulder pain Medication:— Clinical Procedure: — Specialty: General and Internal Medicine • Orthopedics and Traumatology Objective: Rare disease Background:Intramuscular myxomas are rare and benign soft-tissue tumors of uncertain differentiation. Predisposing or precipitating factors have not yet been reported. Activating mutation in GNAS (exons 8 and 9) is detected in >90% of sporadic cases. The role of chronic myopathy, tendinopathy, or trauma to muscles in the etiology of these neoplasms is not known. We report an unusual case of a deltoid mass found following longstanding rotator cuff tendinopathy and a recent fall, later confirmed to be an intramuscular myxoma on biopsy.Case Report:A 73-year-old man with a 5-year history of left shoulder pain and rotator cuff tear presented with intractable pain in his left shoulder after a recent fall at home. Physical examination was suggestive of a rotator cuff injury and magnetic resonance imaging (MRI) of the left shoulder revealed a 2.7×2.5×3.7cm T1 hypo- and T2 hyperin-tense oblong mass-like signal abnormality with heterogeneous, predominantly peripheral enhancement within the deltoid muscle concerning for a malignant mass. Surgical resection was carried out along with left reverse total shoulder replacement, and histopathology revealed findings consistent with an intramuscular myxoma.Conclusions:Intramuscular myxomas are rare, benign tumors. This case report presents one such myxoma incidentally found in a patient with longstanding rotator cuff tendinopathy and a recent fall. Although this co-occurrence is likely incidental, further research and case series review of similar presentations may influence postulations of the pathophysiology of myxomas.

Ossifying fibromyxoid tumour with an unusually prominent central ossification harbouring EPC1-PHF1 gene fusion: A case report and literature review

Ossifying fibromyxoid tumour (OFMT) is a soft tissue neoplasm of uncertain differentiation, with potential for recurrences and metastases depending on the presence of atypical or malignant histological features. Most cases show an incomplete shell of mature bone in the periphery of the lesion. Recurrent PHF1 gene rearrangements were also recently reported in OFMTs, with the most common rearrangement involving a fusion to EP400. We report a case of a 75-year-old male that was diagnosed with an OFMT showing an unusually prominent central ossification. Further, this lesion also harboured the less commonly reported EPC1-PHF1 gene fusion, thus further characterising the morphological features that are associated with this molecular event in this entity. Differential diagnoses of lesions with prominent ossification and emerging molecular findings associated with this entity are discussed.

NTRK Fusions Detection in Paediatric Sarcomas to Expand the Morphological Spectrum and Clinical Relevance of Selected Entities.

Undifferentiated round cell sarcomas (URCS) of soft tissue and bone and tumours of uncertain differentiation (TUD) are commonly ascribed to a subset of neoplasms with low frequency of NTRK gene fusions. However, more recently NTRK-rearranged round and spindle cell tumours have been noted in case reports and in limited or heterogeneous cohorts. The aim of our study was to investigate the presence of NTRK gene fusions in a large retrospective cohort of paediatric URCS and TUD after a systematic review of the diagnosis, according to the recently updated WHO classification scheme. One-hundred and five patients with diagnosis of URCS or TUD, involving the bone or soft tissue, were retrospectively evaluated. After the case selection and the histopathological review of the case cohort, pan-Trk immunohistochemistry (IHC) testing was performed on formalin-fixed paraffin-embedded (FFPE) tissues. Tumour RNA was extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation, using a 10-gene NGS fusion panel, sequenced on an Illumina MiSeq. The NGS-positive cases were further confirmed by real-time PCR. On immunohistochemical screening, 12/105 (11.4%) cases were positive using the pan-Trk antibody, showing three different staining patterns with the cytoplasmic distribution being most common. Molecular analysis using NGS and confirmed by the real-rime PCR detected two positive cases for the ETV6-NTRK3 fusion. The histological pattern of the two positive cases, together with the demonstration of the NTRK rearrangement, leaded to re-classify these previously not otherwise specified sarcomas with uncertain differentiation into the emerging category of NTRK-rearranged neoplasms. In addition, we found the two NTRK fused neoplasms showing a clinical indolent course, in contrast with literature.

Metastatic spindle cell sarcoma: A rare type of undifferentiated soft tissue neoplasm

Sarcomas are rare and characterised by an incidence of approximately 5 cases/100.000 people. Primary spindle cell sarcomas are a subclassification of soft tissue sarcomas, known as uncertain differentiation tumours, based on their unspecific line of differentiation. It might begin in layers of connective tissue under the skin, between muscles or surrounding organs. Diagnosis can be challenging and delayed due to the often-painless nature of these cancers and the common assumption of an underlying benign condition. The presence of distant metastatic disease at the time of the initial diagnosis is not frequent, but is more likely in large, deep and high-grade malignancy sarcomas. Our case describes an elderly patient diagnosed with an asymptomatic undifferentiated spindle cell sarcoma in the lower limb that developed metastatic disease after intentional curative therapy. Keywords: CT/MRI LI-RADS; CEUS LI-RADS; gadolinium contrast; MRI contrast agents; congenital heart disease; contrast enhanced ultrasound.