Ossifying fibromyxoid tumors (OFMT) are rare tumors with an intermediate risk of malignancy that are usually found in the extremities. To date, only three cases of OFMTs involving the paraspinal musculature have been reported in the literature. Two of these previously reported cases demonstrated poorly circumscribed tumors with involvement of adjacent osseous and soft tissue structures. We report the first case of a well-circumscribed OFMT involving the paraspinal musculature with extrinsic erosion of bone but otherwise no significant soft tissue extension. Specifically, we review the CT and MRI findings, immunohistopathology, and genetics used to confirm the diagnosis of OFMT.

Ossifying fibromyxoid tumor (OFMT) is a rare mesenchymal neoplasm first described in 1989. It typically arises in the superficial soft tissues of the extremities as a slow-growing, painless mass. Histologically, it is commonly characterized by a multilobular architecture composed of uniform epithelioid cells embedded in a fibromyxoid matrix, often surrounded by a rim of metaplastic bone. While classic cases are readily identifiable, the tumor's histopathological heterogeneity can mimic a range of benign and malignant neoplasms, posing significant diagnostic challenges. Molecularly, most OFMTs harbor PHF1 rearrangements, commonly involving fusion partners such as EP400, MEAF6, or TFE3. This review underscores the importance of an integrated diagnostic approach- incorporating histopathological, immunohistochemical, and molecular data- to accurately classify OFMT and distinguish it from its mimics. Expanding awareness of its morphologic and molecular spectrum is essential for precise diagnosis, optimal patient management, and a deeper understanding of this enigmatic neoplasm.

Objective: To investigate the clinicopathological characteristics of ossifying fibromyxoid tumor (OFMT) with rare fusion subtypes. Methods: Three cases of OFMT with rare fusion subtypes, diagnosed and consulted in the Zhejiang Hospital, Zhejiang Provincial People's Hospital, Hangzhou, China and Ningbo Clinical Pathology Diagnosis Center, Ningbo, China from January 2016 to December 2024 were collected. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and targeted RNA sequencing were performed to analyze the immunohistochemical and molecular genetic characteristics of these OFMT. Literature review was also conducted. Results: All three patients were male, with ages of 50, 74, and 58 years, respectively. The tumors were located in the left foot, left thigh, and left lumbar region, respectively, and all presented as slowly growing, painless masses in the skin or subcutaneous tissue. Grossly, the tumors measured 3.5 cm, 6.3 cm, and 5.0 cm in maximum diameter, respectively, with a grayish-white to grayish-yellow, solid, lobulated cut surface. One case exhibited a noticeable myxoid texture. Microscopically, one tumor was located in the superficial dermis, while the other two were in the subcutaneous tissue. The tumors were well-demarcated and showed a lobulated or multinodular growth pattern. None of the cases had a complete surrounding bony shell (only one case had very focal ossification). The tumor cells were monomorphic, short spindle-shaped, oval to epithelioid, and arranged in solid sheets, trabeculae, and small nests within a variably fibromyxoid stroma. Case 1 exhibited abundant pseudorosette-like structures formed by short spindle cells surrounding acellular fibrous stroma. Case 2 showed focal transition of epithelioid tumor cells into fasciculately arranged spindle cells, with extensive stromal hyalinization. Case 3 had a predominantly myxoid stroma with a rich network of thin-walled blood vessels. The tumor cells exhibited mild nuclear atypia with 1-3 mitotic figures per 50 high-power fields. All three cases showed diffuse and strong expression of CD10. Two of the three cases showed nuclear expression of TFE3, while one case showed diffuse and strong expression of desmin and S-100. Targeted RNA sequencing revealed PHF1 (ex12)::TFE3 (ex7) fusion in two cases and MEAF6 (ex5)::PHF1 (5'UTR) fusion in one case, which were further confirmed by FISH study. All three patients underwent tumor resection. Two showed no recurrence during follow-up periods of 98 months and 15 months, respectively, while one experienced local recurrence at 12 months postoperatively. Conclusions: OFMT with rare fusion subtypes often exhibits atypical histological and immunophenotypic features, and lacks a characteristic bony shell. Incorporating TFE3 into the diagnostic IHC panel greatly aids in screening for the cases with rare PHF1::TFE3 fusions. Familiarity with the histological and immunophenotypic characteristics, and differential diagnostic points of these rare OFMT subtypes, is essential for judicious use of molecular genetic tools in achieving a definitive diagnosis.

Ossifying Spindled and Epithelioid Tumor: A Novel Soft Tissue Tumor.

Abstract Introduction/Objective Ossifying fibromyxoid tumor (OFMT) represents a rare mesenchymal neoplasm of uncertain differentiation which harbors PHF1 fusion with various partner genes, notably EP400, MEAF6, EPC1, and TFE3. Herein we report a case of OFMT with a novel NBPF10::PHF1 fusion. Methods/Case Report The patient is a 41-year-old female who presented initially for evaluation of subarachnoid hemorrhage secondary to a ruptured cerebral aneurysm. Incidentally, imaging identified a 2.8 cm heterogeneously calcified mass in the left supraclavicular region. Biopsy of this mass demonstrated spindled to ovoid cells within a variably myxoid and densely collagenous stroma, lacking classic bone formation and typical lobular architecture. The lesion exhibited prominent staghorn vessels and minimal cytologic pleomorphism. Immunohistochemical staining revealed diffuse CD10 positivity, focal desmin positivity, and cytoplasmic localization of beta-catenin, while markers such as S100, MUC4, SMA, SOX10, CD34, STAT6, and TLE1 were negative. Mayo Clinic Sarcoma targeted gene fusion/rearrangement next-generation sequencing panel (SARCP) was performed and identified an NBPF10::PHF1 fusion, confirming the diagnosis of OFMT. Results NA Conclusion This case expands the spectrum of PHF1 gene fusion partners in OFMT. It highlights metaplastic bone is not always present in OFMT, especially in small biopsies, and underscores the importance of molecular testing in diagnosing this rare mesenchymal neoplasm.

enlargement (Figs 2 and3).Chest X-ray and CT chest showed no abnormality.Core needle biopsy performed twice from the lesion was inconclusive.The case was discussed in a multidisciplinary tumor board, and in view of clinical and radiological features suspicious of malignancy, surgical intervention was planned.Intraoperatively, the tumor was of rubbery consistency, resembling sarcoma, with skin and bone (right lower alveolus) involvement and intact FOM mucosa.The tongue was not involved.Based on the extent of the tumor, right composite resection with dual flap (pectoralis major myocutaneous flap and deltopectoral flap) reconstruction was done (Fig. 4).Postoperative recovery was uneventful.Postoperative histopathology revealed OFMT with free resected margins.No cervical lymph node involvement was noted (IHC study: S100, desmin focal positive).

Ossifying fibromyxoid tumor (OFMT) is a soft tissue neoplasm of uncertain differentiation, characterized by peripheral ossification within a fibromyxoid stroma and typically occurring in the extremities and trunk. However, OFMT arising from the submandibular gland is extremely rare. A 40-year-old male presented with a progressively enlarging painless mass in the left submandibular region over two years. Radiological examination revealed a well-demarcated, round lesion measuring 1.3cm in maximal diameter. Histopathology demonstrated nodular/lobular growth of uniform round-to-oval tumor cells with abundant eosinophilic cytoplasm, focal epithelioid features, and minimal atypia. Prominent myxoid stroma containing vascular networks was also observed in tumor. While peripheral infiltration was noted in small nests, resection margins were clear and perineural invasion absent. Immunohistochemistry showed diffuse S-100/vimentin positivity, focal weak desmin reactivity, and cytokeratin/CD34/SMA negativity. Next-generation sequencing (NGS) identified a pathogenic PHF1::EP400 fusion, confirming OFMT diagnosis despite absent calcification. The presence of infiltrative tumor cell growth warrants a diagnosis of atypical OFMT in this case. No recurrence occurred at 18-month follow-up. In this report, we present a rare case of OFMT arising in the submandibular region without histological evidence of ossification. This case give prominence to molecular detection in diagnosing morphologically ambiguous tumors and expands the clinicopathological spectrum of OFMT regarding anatomical distribution and histological variants.

We report an unusual uterine polypoid mesenchymal tumor in a 52-year-old resembling the soft tissue neoplasm ossifying fibromyxoid tumor (OFMT). The neoplasm was morphologically low-grade with hypocellular areas containing bland spindle cells in a fibromyxoid stroma, cellular areas resembling typical low-grade endometrial stromal sarcoma (LGESS), and abundant mature bone. The cellular areas were ER and CD10 positive and cyclin D1 negative, and the hypocellular areas were ER and CD10 negative, with approximately 50% of the nuclei being cyclin D1 positive. The tumor harbored a BRD8::PHF1 fusion. This fusion has been reported rarely in uterine mesenchymal neoplasms, which have been designated as LGESS or high-grade endometrial stromal sarcoma. In reporting this case, we review previously reported uterine mesenchymal neoplasms with a BRD8::PHF1 fusion. Since OFMT commonly contains PHF1 fusions, we discuss the most appropriate terminology for the neoplasm we report and suggest that it is best classified as an LGESS with OFMT-like morphology.

Skeletal muscle marker expression in ossifying fibromyxoid tumor: A study of 44 tumors.

Background: Ossifying fibromyxoid tumors (OFMTs) are rare mesenchymal neoplasms with behaviors ranging from benign to malignant. Although most occur in the extremities and trunk, 9-13% are found in the head and neck, such as the oral cavity, scalp, and calvarium. Diagnosis is challenging due to their rarity and histological similarity to other neoplasms. This review synthesizes evidence on the clinical presentation, diagnostic features, and treatment outcomes of OFMTs in the head and neck, focusing on surgical management and adjuvant therapies. Methods: A systematic review was conducted according to PRISMA guidelines, with searches in PubMed/MEDLINE, Embase, Scopus, and Web of Science. Studies from 1989 to 2024 reporting OFMTs in the head and neck with clinical, histopathological, and treatment data were included. Extracted data encompassed demographics, tumor features, surgical margins, adjuvant therapy, and outcomes. Results: Forty studies with 99 patients were included. Patient ages ranged from 3 weeks to 88 years (median 47), with a male predominance (63.64%). The most common presentation was a slow-growing, painless mass. Tumors were most often found in the neck, oral cavity, scalp, and calvarium. Histopathology revealed encapsulated tumors with fibromyxoid stroma, spindle-shaped cells, and a peripheral rim of metaplastic bone in 70% of cases. Immunohistochemistry showed positivity for S-100, vimentin, and SOX10. Surgical excision was the main treatment, used in 28.28% of cases, with recurrence in 9.09% and no metastases. Adjuvant therapies, mainly radiotherapy, were employed in 15.15% of cases. Conclusions: OFMTs of the head and neck are rare neoplasms requiring multidisciplinary care. Imaging, histopathology, and immunohistochemistry are key to diagnosis. Surgical excision with clear margins remains the primary treatment, with a low recurrence rate. Adjuvant therapy may be needed for malignant or incompletely excised cases. Further research is needed to optimize follow-up protocols and assess molecular profiling for risk stratification.

Benign ossifying fibromyxoid tumor: A case in disguise - ACHR- Print ISSN No: - 2581-5725 Online ISSN No:- 2456-9267 Article DOI No:- 10.18231/j.achr.2025.007, IP Archives of Cytology and Histopathology Research-IP Arch Cytol Histopathol Res

Ossifying fibromyxoid tumor is a rare soft tissue mesenchymal neoplasm of unclear lineage and intermediate malignant potential, primarily arising in subcutaneous tissues of the limbs, head and neck, or trunk. Ossifying fibromyxoid tumors can be classified as typical, atypical, or malignant. While, most ossifying fibromyxoid tumors exhibit benign behavior, a subset demonstrates malignant tendencies, with a potential for local recurrence and distant metastasis. We report a case of an atypical ossifying fibromyxoid tumor in the soft tissue of the right elbow, characterized by multiple local recurrences and pulmonary metastases. This report details the clinical presentation, radiological findings, histopathological features, and therapeutic interventions, highlighting the challenges in managing this aggressive variant.

TFE3-rearranged ossifying fibromyxoid tumors are uniquely negative for glycoprotein non-metastatic melanoma protein B: A study of 13 TFE3-rearranged mesenchymal tumors.

92 TFE3-Rearranged Ossifying Fibromyxoid Tumors are Uniquely Negative for Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB): A Study of 12 TFE3-rearranged Mesenchymal Tumors

54 Ossifying Fibromyxoid Tumors Harbor a Distinct Methylation Signature Regardless of the Fusion Type and Share an Epigenetic Relationship with Myoepithelial Tumors

Ossifying fibromyxoid tumour is a rare mesenchymal soft tissue sarcoma with uncertain differentiation and variable metastatic potential. This study offers a retrospective analysis of 23 patients diagnosed with OFMT between 1993 and 2024. The tumours most commonly arose in the extremities and trunk, with all patients undergoing surgical resection of the primary tumour. Immunohistochemical analysis frequently revealed the expression of S100 protein and desmin, while next-generation sequencing identified PHF1 rearrangements in 83 % of patients with available NGS, notably PHF1::EP400 and PHF1::TFE3 fusions. Five patients experienced local recurrence, and four developed metastatic disease. There is no prospective data to guide decision making with regards to systemic therapy, and doxorubicin-based regimens demonstrate limited efficacy. However, the potential role of epigenetic dysregulation in OFMT tumorigenesis opens exciting avenues for treatment. In this cohort, one patient exhibited a remarkably durable response to a combination of gemcitabine, which inhibits DNA methylation, and dacarbazine, following rapid tumour progression on doxorubicin. Given the limited clinical experience with OFMT, multidisciplinary tumour boards are crucial for tailoring individualized treatment strategies. This study contributes to the growing body of literature on OFMT, providing a foundation for future research.

BCOR-rearranged sarcomas constitute ultra-rare tumors. Among these, ZC3H7A/B::BCOR sarcomas are less common and are primarily reported as a subset of high-grade endometrial stromal sarcomas, as well as in the spectrum of malignant ossifying fibromyxoid tumors (OFMTs). Herein, we present the clinicopathological, immunohistochemical, and molecular profiles of seven soft tissue tumors exhibiting ZC3H7A/B::BCOR fusions. The patient’s age ranged from 13 to 65 years (median = 38). Locations were neck (2) and one case each in the paraspinal region, scalp, gluteal region, chest wall, and thigh. Histologically, the tumors were composed of round to polygonal or spindle-shaped cells with a variable amount of fibromyxoid stroma, lacking bone shell or ossification, leading to a range of initial differential diagnoses. Immunohistochemically, the tumor cells were positive for S100 (5/6), cyclin D1 (2/3), SATB2 (2/3), BCOR (2/4), and TLE1 (1/3) while negative for MUC4 (0/6), keratin (0/5), EMA (0/4), desmin (0/6), CD34 (0/6), SMA (0/5), SOX10 (0/5), and melanoma cocktail (0/2). Targeted RNA sequencing revealed ZC3H7B::BCOR fusions in six tumors (four with ZC3H7Bex10::BCORex6 and one each ZC3H7Bex12::BCORex7 and ZC3H7Bex12::BCORex6). One tumor revealed a ZC3H7Aex10::BCORex6 fusion. All seven tumors were resected, mostly with clear margins (5/7), including two patients who received adjuvant therapy. Three of four patients with available follow-up (mean = 45 months) died of disease, while one patient was alive with multiple bone metastases. This series comprises seven additional ZC3H7A/B::BCOR soft tissue sarcomas associated with aggressive clinical outcomes. Whether this aggressive sarcoma represents a molecular subtype of malignant OFMT or a genetic variant of BCOR-rearranged sarcomas remains to be further verified.

Ossifying fibromyxoid tumour is a rare mesenchymal neoplasm predominantly affecting adults characterised by a multinodular growth pattern and the presence of a fibrous pseudocapsule with areas of ossification. Prompted by the recognition of a non-ossifying ossifying fibromyxoid tumour with lipomatous differentiation which caused diagnostic difficulty, we sought to further explore cases of ossifying fibromyxoid tumour with non-osseous heterologous elements. A search of our institutional and consultation archives revealed three additional cases that demonstrated lipomatous components and two cases with cartilaginous differentiation. RNA-sequencing revealed fusions involving PHF1 (n = 4) or EPC1 (n = 1) in all (five of five) cases tested, including EPC1::PHC1 and JAZF1::PHF1 fusions, which have not been reported before in ossifying fibromyxoid tumour. These six cases expand the histomorphological spectrum of ossifying fibromyxoid tumour, introducing lipomatous differentiation as a hitherto undocumented feature. Awareness of these rare variants will ensure appropriate diagnosis and clinical management.

TFE3 rearrangements characterize histogenetically, topographically, and biologically diverse neoplasms. Besides being a universal defining feature in alveolar soft part sarcoma (ASPS) and clear cell stromal tumor of the lung, TFE3 fusions have been reported in subsets of renal cell carcinoma, perivascular epithelioid cell tumor (PEComa), epithelioid hemangioendothelioma and ossifying fibromyxoid tumors. TFE3 -related neoplasms are rare in the head and neck and may pose diagnostic challenges. We herein describe 22 TFE3 fusion neoplasms affecting 11 males and 11 females aged 4 to 79 years (median, 25) and involving different head and neck sites: sinonasal cavities (n = 8), tongue (n = 4), oral cavity/oropharynx (n = 3), salivary glands (n = 2), orbit (n = 2), and soft tissue or unspecified sites (n = 3). Based on morphology and myomelanocytic immunophenotype, 10 tumors qualified as ASPS, 7 as PEComas (3 melanotic; all sinonasal), and 5 showed intermediate (indeterminate) histology overlapping with ASPS and PEComa. Immunohistochemistry for TFE3 was homogeneously strongly positive in all cases. Targeted RNA sequencing/FISH testing confirmed TFE3 fusions in 14 of 16 successfully tested cases (88%). ASPSCR1 was the most frequent fusion partner in ASPS (4 of 5 cases); one ASPS had a rare VCP::TFE3 fusion. The 6 successfully tested PEComas had known fusion partners as reported in renal cell carcinoma and PEComas ( NONO, PRCC, SFPQ , and PSPC1 ). The indeterminate tumors harbored ASPSCR1::TFE3 (n = 2) and U2AF2::TFE3 (n = 1) fusions, respectively. This large series devoted to TFE3-positive head and neck tumors illustrates the recently proposed morphologic overlap in the spectrum of TFE3 -associated mesenchymal neoplasms. While all PEComas were sinonasal, ASPS was never sinonasal and occurred in diverse head and neck sites with a predilection for the tongue. The indeterminate (PEComa-like) category is molecularly more akin to ASPS but shows different age, sex, and anatomic distribution compared with classic ASPS. We report VCP as a novel fusion partner in ASPS and PSPC1 as a novel TFE3 fusion partner in PEComa (detected in one PEComa). Future studies should shed light on the most appropriate terminological subtyping of these highly overlapping tumors.

Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain origin, exhibiting a wide clinical and morphological spectrum. It ranges from benign forms, which typically behave indolently, to malignant lesions with significant recurrence and metastatic potential. The majority of OFMTs harbor PHF1 gene rearrangements, with EP400 being the most common fusion partner. Herein, we present a patient with malignant metastatic OFMT, with the very rare PHF1::FOXR2 fusion, and discuss the potential clinical implications of this genetic alteration.