Multimodality Imaging of Intimal Sarcoma Causing Both Severe Mitral Stenosis and Mitral Regurgitation.

Intimal sarcomas (IS) are rare, malignant, rapidly progressive mesenchymal tumors that typically occur in the tunica intima of larger vessels, and they rarely involve the heart. IS are frequently misdiagnosed during the initial clinical presentation. This case report describes an uncommonly located IS, highlighting specific findings obtained through multimodality imaging.

A 50-Year-Old Man Presenting with Multiple Bone Lesions and a Diagnosis of Phosphaturic Mesenchymal Tumor of the Femur.

BACKGROUND Phosphaturic mesenchymal tumor (PMT) is an extremely rare mesenchymal neoplasm that is commonly seen in bone and soft tissue. It is associated with a paraneoplastic syndrome, oncogenic osteomalacia, due to tumor-induced urinary phosphate wasting. It is demonstrated to be predominantly mediated by fibroblast growth factor 23 (FGF23)/fibroblast growth factor receptor 1 (FGFR1) axis. Clinically, PMT usually presents as a solitary lesion in the bone. The diagnosis of PMT is challenging due to its non-specific clinical manifestation, radiologic findings, and morphological features. CASE REPORT We report the case of a 50-year-old man presenting with multiple lytic bone lesions and associated pathologic fracture of the right femur, clinically suspicious for multiple myeloma or other metastatic malignant process. Resection from the right femur showed a hypercellular lesion composed of oval-to-spindled cells infiltrating the native trabecular bone with admixed multinucleated giant cells. Immunohistochemical (IHC) staining and in situ hybridization (ISH) demonstrated the tumor cells were positive for SATB2, ERG, FGFR1, and FGF23 ISH. DNA and RNA next-generation sequencing showed marked increases in mRNA levels of FGF23 and FGFR1. The constellation of clinicoradiologic, histomorphologic, IHC, and molecular findings supported a diagnosis of primary benign PMT. CONCLUSIONS This case report discusses a patient with PMT presenting with multifocal lesions due to tumor-induced osteomalacia at initial presentation. We hope that this report will increase the awareness of clinician and pathologists of PMT as a differential diagnosis in patients presenting with multifocal lytic bone lesions. In turn, this will prevent misdiagnosis and overtreatment of a typically benign process.

Intracranial Phosphaturic Mesenchymal Tumor Detected by 68 Ga-DOTATATE PET/CT.

ABSTRACT: A 68 Ga-DOTATATE PET/CT scan was conducted to locate the causative tumor responsible for suspected tumor-induced osteomalacia in a 56-year-old woman. The PET/CT images showed a focus in the right occipital region. Subsequent MRI showed an extra-axial nodule in the right occipital region, mimicking a meningioma. Although rare, an intracranial phosphaturic mesenchymal tumor was still suspected because of the typical clinical settings. Finally, phosphaturic mesenchymal tumor was confirmed by the postoperative pathology.

Treatment and Diagnose of Spinal Phosphaturic Mesenchymal Tumor: A Case Report and a Systematic Literature Review.

BACKGROUND: Spinal phosphaturic mesenchymal tumor (PMT) is a rare disorder but can be cured once the diagnosis is clear and a complete removal by surgery is performed. To the best of our knowledge, only 22 cases in the spine have been described, and we report a case with the largest number of spinal segments (T12-L5) affected among spine PMT cases. METHODS: A comprehensive literature search was performed until May 23, 2023, following the Preferred Reporting Items for Systematic Reviews guidelines. Studies were chosen through relevant PubMed, Web of Science, and EMBASE searches to prioritize obtaining the largest studies. The Medical Subject Headings and Boolean operators employed for this search were ("PMT" or "TIO" or "Tumor-induced osteomalacia" or "phosphaturic mesenchymal tumor") and ("spine" or "spinal"). Two researchers (L.S.Z. and D.B.C) independently reviewed and evaluated the included articles. Any differing opinions were discussed until a consensus was reached. A total of 18 studies were included. A case report is also presented. RESULTS: We report a case of spinal PMT. The full text of the relevant articles was construed. A total of 18 studies were reviewed and consolidated. These articles are roughly divided into the following 5 subcategories: 1) clinical features and baseline distribution, 2) laboratory and imaging findings, 3) pathological manifestations, and 4) surgical methods and treatment options. CONCLUSIONS: Spinal PMT is very rare with a high rate of misdiagnosis and debilitating complications, so it is of significance to increase awareness of the disease among spine surgeons consulted by patients with spinal PMT. 68Ga-DOTATOC-PET/CT shows very high sensitivity to the spinal PMT but there is no way to exactly determine the location of the tumor. PMT has unique immunohistochemical characteristics and malignant PMT is rare. Once diagnosed, complete surgical excision is the recommended treatment. Burosumab is one of the available options, especially in cases that are recurrent and difficult to surgically resect.

Cytological findings of phosphaturic mesenchymal tumor: Report of a case with summary of prior published cases.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm causing tumor-induced osteomalacia (TIO) and is characterized by secretion of FGF23, renal phosphate wasting and hypophosphataemia. It can be completely cured by resection and therefore its diagnosis is of utmost importance. Although the histology is well described, there is sparse literature on cytology of PMT and only three cases have been described so far. A 45-year-old lady presented with a non-tender mass in hard palate for 2 years from which fine-needle aspiration was done. The smears were paucicellular and showed bland spindle cells embedded in osteoid-like stromal matrix in a hemorrhagic background. Here we take the opportunity to describe the cytological findings of PMT along with its cytological differentials and a summary of prior published cases.

Tumor-induced osteomalacia: An overview.

Tumor-induced osteomalacia (TIO) is rare paraneoplastic syndrome of hypophosphatemic osteomalacia, caused by phosphaturic factors secreted by small mesenchymal origin tumors with distinct pathological features, called 'phosphaturic mesenchymal tumors'. FGF23 is the most well-characterized of the phosphaturic factors. Tumors are often small and located anywhere in the body from head to toe, which makes the localisation challenging. Functional imaging by somatostatin receptor-based PET imaging is the first line investigation, which should be followed with CT or MRI based anatomical imaging. Once localised, complete surgical excision is the treatment of choice, which brings dramatic resolution of symptoms. Medical management in the form of phosphate and active vitamin D supplements is given as a bridge to surgical management or in inoperable/non-localised patients. This review provides an overview of the epidemiology, pathophysiology, pathology, clinical features, diagnosis, and treatment of TIO, including the recent advances and directions for future research in this field.

Clinical Characteristics of Malignant Phosphaturic Mesenchymal Tumor Causing Tumor-Induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by oversecretion of fibroblast growth factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). PMTs are usually benign neoplasms but some of them show malignant characteristics. OBJECTIVE: The aim of this study was to compare the clinical characteristics of benign and malignant PMTs inducing TIO. METHODS: On March 31, 2023, we performed a systematic review of individual patient data analysis in Medline, Google Scholar, Google book, and Cochrane Library using the terms "tumor induced osteomalacia," "oncogenic osteomalacia," "hypophosphatemia," with no language restrictions and according to Preferred Reporting Items for Systematic reviews and Meta-Analyses criteria. RESULTS: Overall, we collected data from 837 patients with TIO in which the diagnosis of benign and malignant PMT was specified. Of them, 89 were affected by malignant PMT and 748 by benign PMT. Patients with malignant PMTs were younger and presented bone pain, functional impairment, and bone deformities more frequently. Malignant PMTs showed higher values of intact FGF23 and a higher mortality rate. CONCLUSION: The study results identify the clinical characteristics of patients with malignant TIO, permitting the early identification of patients with PMT at increased risk of malignancy. This may significantly improve the diagnostic approach to disease. Further experimental studies are mandatory to clarify the role of FGF23 in the pathogenesis of malignancy in PMTs.

Cirugía radioguiada de tumores mesenquimales con semilla de 125I / Radioguided surgery of mesenchymal tumors with 125I seeds

Introducción La cirugía radioguiada emplea fuentes radioactivas para identificar y extirpar lesiones de difícil localización. Los tumores mesenquimales constituyen un grupo heterogéneo de neoplasias derivados del mesodermo, incluyendo lesiones benignas y sarcomas malignos. El objetivo de este estudio fue evaluar la capacidad de la semilla radioactiva de 125I para guiar la localización intraoperatoria de tumores mesenquimales, analizando sus tasas de complicación y evaluando los márgenes de las piezas quirúrgicas recuperadas. Métodos Estudio observacional retrospectivo de todos los pacientes consecutivos sometidos a cirugía radioguiada de un tumor mesenquimal con semilla radioactiva de 125I desde enero de 2012 hasta enero de 2020 en un centro de referencia terciario en España. La semilla fue insertada mediante punción percutánea guiada con ecografía o tomografía computarizada de forma ambulatoria. Resultados Se extirparon 15 lesiones en 11 cirugías a 11 pacientes, recuperando todas las lesiones marcadas (100%) con semilla de 125I. Las lesiones incluyeron áreas de fibrosis benigna (26,7%), angiofibroma celular (6,7%), tumor desmoide (20%), tumor fibroso solitario (13,3%), condrosarcoma (6,7%) y sarcoma pleomórfico (26,7%), con una tasa elevada de tumores recurrentes (60%). Solo hubo una complicación (6,7%) por caída de la semilla dentro del lecho quirúrgico. Según la clasificación de la Union for International Cancer Control de tumor residual, el 80% de las lesiones resultaron en una resección R0, el 6,7% fueron una resección R1 y el 13,3% fueron una resección R2. Conclusión La cirugía radioguiada fue una técnica precisa para la extirpación de tumores mesenquimales de difícil localización (AU)

Introduction Radioguided surgery uses radioactive substances to identify and remove hard-to-locate lesions. Mesenchymal tumors constitute a heterogeneous group of neoplasms derived from the mesoderm, including benign lesions and malignant sarcomas. The aim of this study was to evaluate the ability of the 125I radioactive seed to guide intraoperative localization of mesenchymal tumors, analyzing its complication rates and evaluating the margins of the surgical specimens retrieved. Methods Retrospective observational study of all consecutive patients undergoing radioguided surgery of a mesenchymal tumor with a 125I radioactive seed from January 2012 to January 2020 at a tertiary referral center in Spain. The seed was inserted percutaneously guided by ultrasound or computed tomography on an outpatient setting. Results Fifteen lesions were removed in 11 surgeries on 11 patients, recovering all marked lesions (100%) with a 125I seed. The lesions included areas of benign fibrosis (26.7%), cellular angiofibroma (6.7%), desmoid tumor (20%), solitary fibrous tumor (13.3%), chondrosarcoma (6.7%), and pleomorphic sarcoma (26.7%), with a high rate of recurrent tumors (60%). There was only one complication (6.7%) due to the seed falling within the surgical bed. According to the UICC classification of residual tumor, 80% of the lesions resulted in an R0 resection, 6.7% were an R1 resection, and 13.3% were an R2 resection. Conclusion Radioguided surgery was a precise technique for the removal of hard-to-locate mesenchymal tumors (AU)

Sinonasal phosphaturic mesenchymal tumour: radiation oncologist's perspective.

Tumour-induced osteomalacia is a rare cause of osteomalacia, the majority of which is of mesenchymal origin. Oncogenic osteomalacia is a potentially curable condition caused by phosphaturic mesenchymal tumours. We present the case of a woman in her 30s with a sinonasal phosphaturic mesenchymal tumour, treated with surgical excision followed by adjuvant intensity-modulated radiotherapy and subsequent adjuvant chemotherapy. The patient experienced minimal adverse effects during radiation. There was good local control and cosmetic outcomes with no radiation-related toxicity at a follow-up period of 32 months.

Klotho Overexpression Is Frequently Associated With Upstream Rearrangements in Fusion-Negative Phosphaturic Mesenchymal Tumors of Bone and Sinonasal Tract.

Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs.

Phosphaturic mesenchymal tumor: A chondromyxoid fibroma-like type.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that causes tumor-induced osteomalasia (TIO) in most affected patients, usually through the production of fibroblast growth factor 23 (FGF23). This tumor is often misdiagnosed due to its relative rarity and its widely varied histomorphologic spectrum. Here we describe a case of a 78-year-old woman who presented with a left middle tumor without symptoms of TIO. The histological features resembled chondromyxoid fibroma with smudgy calcification in the tumor matrix. In addition, we evaluated FGF23 expression through immunohistochemical study and reverse transcription polymerase chain reaction. PMT with chondromyxoid fibroma features are extremely rare. Examining the expression of FGF23 is useful in the diagnosis of PMT.

[Fibrocartilaginous mesenchymoma: a clinicopathological analysis of four cases].

Objective: To investigate the clinical, radiological, histological and molecular features and the differential diagnosis of fibrocartilaginous mesenchymoma (FM). Methods: Four cases of FM diagnosed in the Department of Pathology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine from 2020 to 2022 were analyzed. Related literature was also reviewed. Results: Case 1 was a 10-year-old girl with bone destruction in the sacrum and L5 articular processes revealed by CT scan. Case 2 was a 7-year-old girl with an aggressive lesion in her right distal ulna. Case 3 was an 11-year-old boy with a lesion in the metaphysis of his left proximal tibia. Case 4 was an 11-year-old boy with bone destruction in the distal portion of a radius. Microscopically, the four tumors all consisted of numerous spindle cells, hyaline cartilage nodules, and bone trabeculae. The hypocellular to moderately cellular spindle cell component contained elongated cells with slightly hyperchromatic, mildly atypical nuclei arranged in bundles or intersecting fascicles. Benign-appearing cartilaginous nodules of various sizes and shapes were scattered throughout the tumors. There were areas mimicking epiphyseal growth-plate characterized by chondrocytes arranged in parallel columns and areas of enchondral ossification. The stroma was rich in mucus in case 1. Mutation of GNAS and IDH1/IDH2 and amplification of MDM2 gene were not found in any of the three tested cases. Conclusions: FM is very rare and tends to affect young patients. It most frequently occurs in the metaphysis of long tubular bones, followed by the iliac-pubic bones and vertebrae. FM is characterized by a mixed population of spindle cells, hyaline cartilage nodules and trabeculae of bone, without specific immunophenotypes and molecular alternations. As a borderline, locally aggressive neoplasm, surgical removal with a wide margin is generally the treatment of choice for FM.

Phosphaturic Mesenchymal Tumor Along the Hallux side Inducing a Chronic non-Healing Wound: A Case Report with Literature Review.

Phosphaturic mesenchymal tumor (PMT) is a rare paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia, and bone calcification disorders. Complete surgical resection of the tumor is believed to be the most effective treatment measure. However, the diagnosis of PMT is very difficult because of its insidious and small size, especially, when it appears in subcutaneous tissue with a chronic non-healing wound. We report a rare case of a 38-year-old man with a chronic non-healing wound on the left hallux for approximately eight months. Plain radiographic images and magnetic resonance imaging (MRI) revealed a cystic radiolucent shadow in the left distal phalanx. Bone scan observations also showed increased uptake in the same location. Histologically, this tumor was composed of numerous spindle cells with clusters of giant cells. The serum FGF23 level was significantly higher before surgery, with higher FGF23 levels closer to the tumor. Reverse transcription polymerase chain reaction and immunohistochemistry further confirmed the high expression of FGF23 in tumors. These data suggest that FGF23 may be a potential causative factor of PMT. The serum FGF23 levels might be useful for the diagnosis of PMT and localization of the tumor. The tumor was CD56- and D2 to 40-positive and CD31-negative. The non-healing wound caused by PMT might be attributed to the invasive growth of the tumor, destruction of intercellular junctions, and decrease in the number of endothelial cells.

Superficial GLI1-amplified mesenchymal neoplasms: Expanding the spectrum of an emerging entity which reaches the realm of dermatopathology.

Mesenchymal neoplasms with GLI1 alterations (rearrangements and/or amplification) have been reported recently in several anatomic locations, which include head and neck, soft tissue, and gastrointestinal tract. Herein, to the best of our knowledge, we describe the first three cases of superficial/subcutaneous mesenchymal neoplasm with GLI1 amplification. The neoplasms exhibited low-grade cytologic features with predominant round cell morphology, glomangioma-like areas and a rich background capillary network. There were two to three mitotic figures per 10 HPF and focal necrosis in one case. The tumors exhibited variable expression of CDK4, MDM2, STAT6, D2-40, CD56 and cyclin D1. p16 had strong and diffuse nuclear and cytoplasmic expression in two cases. Numerous other stains were negative. Fluorescence in situ hybridization detected GLI1, DDIT3, and CDK4 coamplification in all cases, while next generation sequencing did not detect a GLI1 gene fusion. The overall features were compatible with a GLI1-amplified mesenchymal neoplasm. In Case 1 a new distant skin lesion appeared 1 month after the surgery exhibiting similar morphology albeit with a higher mitotic index. In Cases 2 and 3, there is no evidence of local recurrence or systemic disease after 8 years and 1 month of follow-up, respectively. These new cases of superficial GLI1-amplified neoplasm expand its clinical spectrum and enter the realm of dermatopathology. The combination of CDK4, cyclin D1, D2-40, and p16 expression with variable MDM2, STAT6, CD56, and S100 immunoreactivity in a low-grade neoplasm with round/ovoid cytomorphology resembling a vascular or adnexal neoplasm may suggest the possibility of GLI1-amplified neoplasm.

Fibrocartilaginous mesenchymoma of pelvis-a potential diagnostic pitfall.

Fibrocartilaginous mesenchymoma (FM) is a rare bone tumor mimicking other fibrocartilaginous lesions on imaging and histologically. Hence, it is difficult to diagnose this entity especially on small biopsies. In this article, we report a case of FM mimicking desmoplastic fibroma on biopsy. A 36-year-old male presented with pain in the left hip. Imaging showed a large expansile lytic lesion involving the acetabulum and pubis. The differential diagnosis was suggestive of giant cell tumor, aneurysmal bone cyst, intraosseous desmoplastic fibroma, and chondrosarcoma. Biopsy revealed a low-grade spindle cell lesion with no evidence of osteoid or chondroid matrix. The lack of cartilaginous nodules in the biopsy prompted a preoperative diagnosis of desmoplastic fibroma. The excised mass showed bland spindle cell proliferation, benign cartilage nodules, and epiphyseal plate-like enchondral ossification suggestive of fibrocartilaginous mesenchymoma. Negative immunostaining for SATB2, CDK4, and MDM2 ruled out low-grade central osteosarcoma. Though GNAS mutations were not performed in this case, rimming of the bony trabeculae at the periphery of the epiphyseal growth plate-like cartilaginous nodule ruled out fibrous dysplasia. The absence of cartilaginous component misleads the diagnosis preoperatively in small biopsies.