Fibroblastic Sarcoma Research Articles

Myxoinflammatory fibroblastic sarcoma of the liver: Case report and literature review.

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade malignant soft tissue sarcoma that primarily affects the distal extremities in adults, with the highest incidence in patients in their 40s and 50s. It has a high local recurrence rate and a low metastasis rate. Although MIFSs have been documented in other sites, an MIFS in the liver is highly unusual. Herein, we present a case of a patient with hepatic MIFS. The patient was a 58-year-old Chinese man with abdominal pain as the primary symptom. Abdominal computed tomography and magnetic resonance imaging revealed a mass in the right posterior lobe of the liver. The patient underwent surgical excision, and the excised specimen was identified as MIFS. Three years later, the patient returned to our hospital for abdominal pain. Computed tomography and magnetic resonance imaging revealed a mass in liver segments 2/3/4. Postoperative pathological examination of the tumor revealed the recurrence of MIFS. The patient underwent surgical resection of the MIFS. The patient received multiple pirarubicin-based chemotherapy treatments and an ALK inhibitor (anlotinib) within 6 months after surgery, but the tumor recurred. MIFS can not only occur in the proximal limbs, trunk, head, and neck but can also affect the abdominal organs. Surgical resection remains the primary treatment option for MIFS in the absence of any contraindications. Because the recurrence rate of MIFS is high, meticulous long-term monitoring is required.

Flexor Digitorum Superficialis to Flexor Digitorum Profundus Tendon Transfer after Wide Excision of Myxoinflammatory Fibroblastic Sarcoma: A Case Report

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare, low-grade soft tissue neoplasm that typically arises in the extremities. A 72-yearold woman presented with recurrent masses on her left forearm. Four years prior, she underwent an excisional biopsy, diagnosed as MIFS, followed by wide excision and split-thickness skin graft coverage. Preoperative magnetic resonance imaging was conducted for the recurrent mass, revealing multiple tumors invading the flexor digitorum profundus (FDP) muscle and fascia. The tumors including most of the FDP muscle were therefore excised. The third flexor digitorum superficialis (FDS) tendon was harvested, divided in half, and connected to the second and fifth FDP tendons. The same procedure was performed for the third and fourth FDP tendons with fourth FDS tendon. An anterolateral thigh free flap was used to reconstruct the skin and soft tissue defect of the left forearm. Adjuvant radiation therapy was performed. At 12 weeks postoperatively, the patient exhibited no wound complications and achieved spontaneous partial flexion of the metacarpophalangeal and proximal interphalangeal joints.

Optical Genome Mapping for Comprehensive Cytogenetic Analysis of Soft-Tissue and Bone Tumors for Diagnostic Purposes

Soft tissue and bone tumours represent a heterogeneous group of tumours encompassing more than 100 histological subtypes today. Identifying genetic aberrations is increasingly important in these tumours for accurate diagnosis. While gene mutations are typically detected by second generation sequencing, the identification of structural variants (SVs) and copy number alterations (CNAs) remains challenging and requires various cytogenetic techniques including karyotyping, fluorescent in situ hybridisation and arrays, each having important limitations.We applied Optical Genome Mapping (OGM), a non-sequencing-based technique for high-resolution detection of SVs and CNAs in a retrospective series of diagnostic soft tissue and bone tumour samples. Sample preparation was successful in 38 out of 53 cases, with the highest success rate in non-adipocytic soft tissue tumours (24/27 cases, 89%). In 32 out of 35 cases carrying a diagnostic SV or CNA, OGM identified the aberration (91%) including a POU2AF3::EWSR1 fusion in a round cell sarcoma and a translocation t(1;5)(p22;p15) in a myxoinflammatory fibroblastic sarcoma. Interestingly, OGM shed light on the genomic complexity underlying the various aberrations. In five samples OGM showed that chains of rearrangements generated the diagnostic fusion, three of which involved chromoplexy. Additionally, in nine samples chromothripsis was causal to the formation of giant marker/ring/double minute chromosomes. Finally, compared to standard-of-care cytogenetics, OGM revealed additional aberrations, requiring further investigation of their potential clinical relevance.

Recent Advances in the Diagnosis, Pathogenesis, and Management of Myxoinflammatory Fibroblastic Sarcoma.

Myxoinflammatory fibroblastic sarcoma (MIFS) is an infiltrative, locally aggressive fibroblastic neoplasm of intermediate malignancy that typically arises in the distal extremities of middle-aged adults. It can histologically be confused with a number of benign and malignant conditions. Recently, high-grade examples of MIFS have been described. Immunohistochemistry plays a very limited role in the diagnosis of MIFS. Several genetic alterations have been identified in MIFS, including a t(1;10)(p22;q24) translocation with TGFBR3 and/or OGA rearrangements, BRAF rearrangement, and VGLL3 amplification. Although it appears that VGLL3 amplification is the most consistent alteration, the molecular pathogenesis of MIFS remains poorly understood. A wide resection is considered the standard treatment for MIFS. Radiotherapy may be a viable option in cases with inadequate surgical margins or cases where surgery is likely to cause significant functional impairment. The systemic treatment options for advanced or metastatic disease are very limited. This review provides an updated overview of the clinicoradiological features, pathogenesis, histopathology, and treatment of MIFS.

PRAME immunohistochemistry in soft tissue tumors and mimics: a study of 350 cases highlighting its imperfect specificity but potentially useful diagnostic applications.

Preferentially expressed antigen in melanoma (PRAME) immunohistochemistry is currently used in pathology for the assessment of melanocytic neoplasms; however, knowledge of its expression patterns in soft tissue tumors is limited. PRAME immunohistochemistry (clone QR005) was assessed on whole tissue sections of 350 soft-tissue tumors and mimics (> 50 histotypes). PRAME immunoreactivity was evaluated as follows: 0 "negative" (0% positive cells); 1+ (1-25% positive cells); 2+ (26-50% positive cells); 3+ (51-75% positive cells), and 4+ "diffuse" (> 75% positive cells). PRAME was expressed in 111 lesions (0 benign, 6 intermediate malignancy, and 105 malignant), including fibrosarcomatous dermatofibrosarcoma protuberans (2/4, 0 diffuse), NTRK-rearranged spindle cell neoplasm (2/4, 0 diffuse), atypical fibroxanthoma (1/7, 0 diffuse), Kaposi sarcoma (1/5, 0 diffuse), myxoid liposarcoma (11/11, 9 diffuse), synovial sarcoma (11/11, 6 diffuse), intimal sarcoma (7/7, 5 diffuse), biphenotypic sinonasal sarcoma (3/3, 1 diffuse), angiosarcoma (10/15, 6 diffuse), malignant peripheral nerve sheath tumor (9/12, 4 diffuse), pleomorphic rhabdomyosarcoma (2/3, 2 diffuse), alveolar rhabdomyosarcoma (2/6, 0 diffuse), embryonal rhabdomyosarcoma (7/7, 4 diffuse), undifferentiated pleomorphic sarcoma (2/12, 1 diffuse), leiomyosarcoma (2/15, 1 diffuse), clear cell sarcoma of soft tissue (1/10, 0 diffuse), low-grade fibromyxoid sarcoma (1/5, 0 diffuse), Ewing sarcoma (2/10, 1 diffuse), CIC-rearranged sarcoma (8/8, 4 diffuse), BCOR-sarcoma (2/5, 1 diffuse), melanoma (20/20, 14 diffuse), and thoracic SMARCA4-deficient undifferentiated tumor (5/5, all diffuse). All tested cases of spindle cell lipoma, dedifferentiated/pleomorphic liposarcoma, dermatofibrosarcoma protuberans, solitary fibrous tumor, inflammatory myofibroblastic tumor, myxoinflammatory fibroblastic sarcoma, nodular fasciitis, myxofibrosarcoma, epithelioid hemangioendothelioma, atypical vascular lesion, hemangioma, lymphangioma, vascular malformation, papillary endothelial hyperplasia, GIST, gastrointestinal clear-cell sarcoma, malignant melanotic nerve sheath tumor, neurofibroma, schwannoma, granular cell tumor, alveolar soft part sarcoma, epithelioid sarcoma, extraskeletal myxoid chondrosarcoma, myoepithelioma, ossifying fibromyxoid tumor, angiomatoid fibrous histiocytoma, PEComa, dermatofibroma, pleomorphic dermal sarcoma, and chordoma were negative. PRAME shows imperfect specificity in soft-tissue pathology but may serve as a diagnostic adjunct in selected differential diagnoses that show contrasting expression patterns.

Report of an Unusual Case of Hemosiderotic Fibrohistiocytic Lipomatous Tumor with Systematic Review of Clinicopathological Characteristics and Differential Diagnosis

The spectrum of lipomatous lesions ranges from benign to highly malignant disease. Differentiation between these mesenchymal lesions is important for pathologist as well as clinician to indicate prognosis and choose the most appropriate treatment. Hemosiderotic firohistiocytic lipomatous tumor (HFLT) is a rare subtype of lipomatous tumor. The diagnosis is usually based on clinical, histological, and immunohistochemical (IHC) information. We reported a case of 56 years old man with a painful mass in the dorsal aspect of the thigh showing an unusal clinical presentation but a characteristic histological and IHC features. In this article we have retrospectively reviewed the 67 cases of HFLT reported in literature so far along with one case reported at our institution. The review focuses on clinicopathological and histomorphological characteristics of HFLT and the related entities. The hallmark of HFLT and its related lesions is complex admixture of mature adipose tissue, spindle tumor cells with striking deposition of hemosiderin pigment. Even though HFLT shows marked predeliction for the distal extremeties especially the foot/ ankle with a female preponderance, they can occur at uncommon site such as thigh and also in males as seen in our case. Keywords: Pleomorphic hyalinizing angiectatic tumor, Hemosiderotic fibrolipomatous tumor, Myxoinflammatory Fibroblastic Sarcoma, Hemosiderin, Lipoma

Myxoinflammatory Fibroblastic Sarcoma of the Hand

Myxoinflammatory fibroblastic sarcoma is an ultra-rare tumor type with a prevalence of fewer than two per 100,000 people. The tumor poses a challenge because it can be misdiagnosed as a benign lesion in clinical and radiological investigations, causing serious morbidity in patients. We present the case of a 33-year-old patient who presented with painless hand swelling that was misdiagnosed as lymphaticovenous malformation based on magnetic resonance imaging. The patient underwent surgical excision, and myxoinflammatory fibroblastic sarcoma was diagnosed postoperatively. All surgical interventions failed to achieve negative margin. A decision to start radiotherapy was made, and tissue convergence was done temporally using acellular dermal matrix and split-thickness skin graft. On patient follow-up, the graft had taken well, and the patient was undergoing radiotherapy sessions with a plan for permanent hand reconstruction after negative margins are achieved. Based on this case report, we identified that magnetic resonance imaging is not yet a reliable method to diagnose myxoinflammatory fibroblastic sarcoma. Therefore, implementing a multidisciplinary team approach, a preoperative core needle biopsy, planned surgical intervention, and early involvement of radiotherapy is recommended to minimize morbidity. We strongly urge establishing a sarcoma specialized treatment center in the region to limit patient morbidity.

Malignant undifferentiated epithelioid neoplasms with MAML2 rearrangements: A clinicopathologic study of seven cases demonstrating a heterogenous entity.

Among mesenchymal tumors, MAML2 gene rearrangements have been described in a subset of composite hemangioendothelioma and myxoinflammatory fibroblastic sarcoma (MIFS). However, we have recently encountered MAML2-related fusions in a group of seven undifferentiated malignant epithelioid neoplasms that do not fit well to any established pathologic entities. The patients included five males and two female, aged 41-71 years old (median 65 years). The tumors involved the deep soft tissue of extremities (hip, knee, arm, hand), abdominal wall, and the retroperitoneum. Microscopically, the tumors consisted of solid sheets of atypical epithelioid to histiocytoid cells with abundant cytoplasm. Prominent mitotic activity and necrosis were present in 4 cases. In 3 cases, the cells displayed hyperchromatic nuclei or conspicuous macronucleoli, and were admixed with background histiocytoid cells and a lymphoplasmacytic infiltrate. By immunohistochemistry (IHC), the neoplastic cells had a nonspecific phenotype. On targeted RNA sequencing, MAML2 was the 3' partner and fused to YAP1 (4 cases), ARHGAP42 (2 cases), and ENDOD1 (1 case). Two cases with YAP1::MAML2 harbored concurrent RAF kinase fusions (RBMS3::RAF1 and AGK::BRAF, respectively). In 2 cases with targeted DNA sequencing, mutations in TP53, RB1 and PTEN were detected in 1 case, and PDGFRB mutations, CCNE1 amplifications and CDKN2A/2B deletion were detected in another case, which showed strong and diffuse PDGFRB expression by IHC. Of the 4 cases with detailed clinical history (median follow-up period 8months), three developed distant metastatic disease (one of which died of disease); one case remained free of disease 3 years following surgical excision. In conclusion, we describe a heterogeneous series of MAML2-rearranged undifferentiated malignant epithelioid neoplasms, a subset of which may overlap with a recently described MIFS variant with YAP1::MAML2 fusions, further expanding the clinicopathologic spectrum of mesenchymal neoplasms with recurrent MAML2 gene rearrangements.

Unexpected Clinical Outcome for Myxoinflammatory Fibroblastic Sarcoma, When Should They Be Considered High Grade?

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare tumor of soft tissue. It typically presents as a low-grade sarcoma with myxoid stroma, has a predilection for distal extremities, and displays a high propensity for local recurrence, but low metastatic potential. The risk factors associated with high-risk lesions metastasizing are poorly defined. In cases where the tumor metastasizes, therapeutic options are few, and death is rare. Our case discusses an aggressive MIFS that progressed from a painless lesion on a patient's calf, to her death from a malignant pleural effusion within 21 months. The 58-year-old woman presented with a mass on her left calf. It was excised and was originally thought to be a benign process. It re-grew quickly after the initial resection, and she underwent re-excision of the mass. The pathologic examination was consistent with an MIFS. Despite negative margins on her second resection and an attempt at local control with radiotherapy, it metastasized to her lungs within less than 2 years. This resulted in a malignant pleural effusion that caused her death. An MIFS is typically benign but can metastasize in atypical cases. Even if the disease is metastatic, it is unlikely to be the cause of death. Treatment of metastatic MIFS is poorly defined, but there are suggested therapies beyond surgical resection and radiotherapy. Successful treatment of an MIFS should include a high index of suspicion in extremity lesions, screening for metastasis, and possible targeted therapies based on tumor genomics.

Usefulness of SynCAM3 and cyclin D1 immunohistochemistry in distinguishing superficial CD34-positive fibroblastic tumor from its histological mimics.

Superficial CD34-positive fibroblastic tumor (SCPFT) is a fibroblastic/myofibroblastic soft tissue tumor of rarely metastasizing intermediate malignancy. Some recent studies have described a relationship between SCPFT and PRDM10-rearranged soft tissue tumor (PRT) based on SynCAM3 and PRDM10 expression on immunohistochemistry. We performed CD34, cytokeratin AE1/AE3, SynCAM3, and PRDM10 immunohistochemistry in SCPFT and its histological mimics, including myxoinflammatory fibroblastic sarcoma (MIFS), superficially localized myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma. We also examined cyclin D1 expression because it is expressed in MIFS and MFS. We conducted fluorescence in situ hybridization (FISH) of PRDM10 rearrangement in SCPFT cases. On immunohistochemistry, only SCPFT showed strong and diffuse SynCAM3 expression. SCPFT also exhibited strong nuclear and weak cytoplasmic cyclin D1 expression, which was similar to that observed in MIFS. Two of five SCPFT cases exhibited nuclear PRDM10 expression. FISH revealed PRDM10 split signals in 44% and 24% of tumor cells in two SCPFT cases showing nuclear PRDM10 expression on immunohistochemistry, respectively. A minority of non-SCPFT cases showed focal SynCAM3 expression, but a combination of SynCAM3 and cyclin D1 in addition to CD34 and cytokeratin AE1/AE3 may be useful for the differential diagnosis of SCPFT and its histological mimics.

Recurrent YAP1::MAML2 fusions in “nodular necrotizing” variants of myxoinflammatory fibroblastic sarcoma: a comprehensive study of 7 cases

AbstractMyxoinflammatory fibroblastic sarcoma (MIFS) is a rare soft tissue tumor with a predilection for the distal extremities and a tendency for local recurrence. Morphologically, MIFS consists of spindle and bizarre epithelioid cells resembling virocytes embedded in a fibrous to myxoid stroma with an abundant inflammatory infiltrate. Importantly, the molecular landscape of MIFS is wide and includes: VGLL3 amplification, BRAF fusion/amplification and OGA/TGFBR3 rearrangements. In this study, we describe a variant of MIFS showing a frequent nodular configuration associated with necrosis and recurrent YAP1::MAML2 fusions. The cohort consisted of 7 patients (4 females and 3 males) ranging in age from 21 to 71 years (median: 47 years). Two tumors (28%) occurred in acral locations while the remaining cases were more widely distributed (thigh, n = 2; arm, n = 1; neck; n = 1; chest-wall, n = 1). Tumor size ranged from 10 to 38 mm (median: 20 mm). Histologically, lesions frequently presented as nodules with central areas of necrosis, and were predominantly composed of sheets of epithelioid cells with large vesicular nuclei and prominent nucleoli (Reed-Sternberg-like cells or virocytes). The stroma was mostly fibrous and showed a polymorphous inflammatory infiltrate. Myxoid stromal changes were focally seen in one case, and pseudolipoblasts were absent. The immunophenotype was nonspecific, with only pan-keratin (AE1-AE3) and cyclin D1 expression in a subset of cases. RNA-Sequencing detected YAP1::MAML2 fusions in 3/7 cases; aCGH showed no significant gene copy number variations in 4 tested cases, and FISH analysis showed no VGLL3 amplification in 1 tested case. Follow-up was available for 6 cases, ranging from 7 to 63 months (median: 42 months). Local recurrence and metastasis were not seen and one tumor showed spontaneous regression following initial biopsy. In conclusion, we describe a novel variant of MIFS with distinctive clinicopathological and molecular features for which we propose the term “nodular necrotizing” MIFS.

Recurrent VGLL3 fusions define a distinctive subset of spindle cell rhabdomyosarcoma with an indolent clinical course and striking predilection for the head and neck.

The mammalian Vestigial-like (VGLL) transcriptional cofactor family of proteins VGLL1-4 has recently emerged as an important player in the tumorigenesis of diverse neoplasms. The role of VGLL3 in soft tissue tumors is exemplified by its amplification in myxoinflammatory fibroblastic sarcoma and its rearrangement (fused to CHD7, CHD9, or MAMLD1) in hybrid schwannoma-perineurioma. This study characterizes a distinctive low-grade myogenic neoplasm with a striking predilection for the head and neck, characterized by VGLL3 fusions. The study includes five males and one female patient, aged 30-71 years (median, 56). Three tumors originated in the tongue, with one case each in the nasopharynx, oral cavity, and oropharynx. The VGLL3 fusion partners included TCF12 (n= 3), EP300 (n= 2), and PPARGC1A (n= 1). The tumor size range was 0.8-1.6cm (all, but one, was <1cm). Histologically, all tumors displayed bland spindle to ovoid cells arranged into vague fascicular and diffuse patterns. Mitotic activity ranged from 1 to 7 per 10 HPFs. Five tumors were muscle-centered and infiltrative, and one was centered beneath nasopharyngeal mucosa. Immunohistochemistry revealed consistent expression of desmin (diffuse in four and patchy in two cases) associated with patchy smooth muscle actin expression (4/6), and focal reactivity for myogenin (5/6) and myoD1 (1/3). All patients were managed surgically; one patient each received adjuvant radio- or chemotherapy. Three patients with follow-up were without disease at 8, 19, and 60 months and one was alive with unknown disease status at 24 months. All VGLL3 fusions were in-frame and involved exon 2, fused with either TCF12 exon 16, EP300 exon 31, or PPARGC1A exon 5, respectively. This series characterizes a distinctive subset of spindle cell rhabdomyosarcoma (RMS) with a predilection for the head and neck in adults, defined by VGLL3 fusions, likely indolent behavior and limited rhabdomyoblastic differentiation. Further delineation of this entity and differentiation from more aggressive molecular subtypes of spindle cell RMS is mandatory to define the most appropriate therapeutic strategy and avoid overtreatment.

RNA-sequencing of myxoinflammatory fibroblastic sarcomas reveals a novel SND1::BRAF fusion and 3 different molecular aberrations with the potential to upregulate the TEAD1 gene including SEC23IP::VGLL3 and TEAD1::MRTFB gene fusions.

Myxoinflammatory fibroblastic sarcoma (MIFS) has been shown to harbor various recurrent molecular aberrations; most of which, however, seem to be present in only a minority of cases. In order to better characterize the molecular underpinnings of MIFS, fourteen cases were analyzed by targeted RNA-sequencing (RNA-seq), VGLL3 enumeration FISH probe, and BRAF break-apart and enumeration probes. Neither t(1;10)(p22;q24) nor BRAF gene amplifications were found. However, VGLL3 gene amplification was detected in 5 cases by FISH which corresponded with an increase in VGLL3 expression detected by RNA-seq. In 1 of these cases, RNA-seq additionally revealed a novel SND1::BRAF fusion. Two of the 9 cases lacking VGLL3 amplification harbored either a SEC23IP::VGLL3 or a TEAD1::MRTFB rearrangement by RNA-seq, both confirmed by RT-PCR and Sanger sequencing. The detected molecular aberrations have a potential to either activate the expression of genes regulated by the transcription factors of the TEAD family, which are involved in tumor initiation and progression, or switch on the MEK/ERK signaling cascade, which plays an important role in cell cycle progression. Our results broaden the molecular genetic spectrum of MIFS and point toward the importance of the VGLL3-TEAD interaction, as well as the deregulation of the MEK/ERK pathway in the pathogenesis of MIFS, and may represent a potential target for therapy of recurrent or advanced disease.

Abstract 3100: XenoSarc: patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization

Abstract STS constitutes a family of rare mesenchymal tumors with more than 70 subtypes described. The limited treatment options available for advanced STS patients underline the need for reliable preclinical models to test new therapeutic approaches. We established a panel of PDX models (XenoSarc) by subcutaneous implantation of fresh tumor specimens in athymic mice (nu/nu NRMI). Once tumor growth was observed, pieces of tumor were re-transplanted to next generations of animals. At each passage tumor fragments were collected for histopathological and molecular characterization. In an ongoing effort 493 STS samples from 414 consenting patients treated at the University Hospitals, Leuven (Belgium) have been transplanted. A total of 67 PDX models from 20 STS subtypes have been established, meaning they have stable morphological, immunohistochemical and genetic characteristics over at least 2 passages. The PDX platform includes more common STS subtypes such as myxofibrosarcoma (n=12 models), gastrointestinal stromal tumors (9), dedifferentiated liposarcoma (10), and leiomyosarcoma (8), as well as models from ultra-rare subtypes, e.g. pulmonary intimal sarcoma, extraskeletal osteosarcoma, mesenchymal chondrosarcoma, myxoinflammatory fibroblastic sarcoma and others. All relevant details about the donor patient and tumor characteristics, including sensitivity to the standard treatments, are known for every model. The models are well-characterized, with availability of molecular information on genomic profile (by low-coverage whole genome sequencing), and expression profile (by RNA sequencing). Xenografts are accompanied by ready to use tissue microarrays (TMA) from the models, which can be exploited for target identification and model selection for preclinical studies. Ex-mouse material can also be used to establish primary cell cultures and 3D organoids for in vitro screening purposes. The XenoSarc platform offers opportunities for studying the biology of various sarcoma subtypes including ultra-rare entities and was found to be a very reliable tool for early drug screening in STS in preparation of clinical testing of novel compounds. The platform is available for collaborative preclinical projects with academic and industrial partners. Citation Format: Agnieszka Wozniak, Luna De Sutter, Lore De Cock, Britt Van Renterghem, Che-Jui Lee, Yannick Wang, Ulla Vanleeuw, Kimberly Verbeeck, Daphne Hompes, Friedl Sinnaeve, Hazem Wafa, Baki Topal, Joris Jaekers, Dirk Van Raemdonck, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski. XenoSarc: patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3100.

Abstract 2777: Characterizing the molecular underpinnings of sorafenib sensitivity in desmoid tumors

Abstract Background: Desmoid tumors (DT) are rare fibroblastic sarcomas that have high recurrence rates. Though we know mutations in the beta-catenin (CTNNB1) gene are commonly observed with dysregulation of the Wnt signaling pathway in patients with DT, the molecular mechanisms driving DT growth remain poorly understood. There is currently no standard systemic treatment for DT. The multi-kinase inhibitor, sorafenib, has been identified as a potential front-line agent for DT after a recent clinical trial demonstrated an objective response in one third of patients. The mechanism for how sorafenib inhibits DT progression is still unclear, so it is unknown which characteristics predict response to the drug. Our work has identified the early growth response-1 (EGR1) gene as a downstream target of sorafenib. Methods: Nine DT cell lines have previously been brought into culture with stable passage. These cell lines were treated with sorafenib at 10 μM. RNA was collected from parental and treated cells and subsequent RNA sequencing was performed. Differential gene expression was performed using R. Appropriate comparisons for multiplicity were performed. Western blots were performed to confirm changes in expression of key genes at the protein level. EGR1 overexpression vector was introduced to the 2 DT cell lines and further treated with sorafenib. Additional banked patient desmoid tumor samples were sequenced to assess EGR1 levels and correlation with the CTNNB1. Results: We first evaluated the effect of sorafenib on CTNNB1 in the DT models. Western blot demonstrated no changes in protein levels of CTNNB1 in the 4 cell lines tested at 72 hours post-treatment. This was further confirmed on RNA-sequencing. To identify additional gene targets of sorafenib, additional differential gene expression analysis was performed resulting in 13 altered genes at an adjusted p &amp;lt; 0.01. The most significantly altered gene, both by p-value and by fold change, was the EGR1 mRNA transcript. EGR1 transcript levels were significantly attenuated by sorafenib treatment (logFC = 2.720, adjusted p-value &amp;lt;&amp;lt; 0.0001). Western blot analysis confirmed this decrease. EGR1-high DT cell line models exhibited faster growth rates and also higher sensitivity to sorafenib. Fifteen additional patient desmoid tumor samples confirmed the steady state of CTNNB1 and high variability of the EGR1 transcript. There was no correlation between the EGR1 and CTNNB1 transcript. Conclusion: This study found that sorafenib does not directly modulate CTNNB1, but does decrease EGR1 expression at both the mRNA and protein level. This suggests that EGR1 expression may be associated with aggressive DT and may also predict responsiveness to treatment with sorafenib. Confirmatory EGR1 modulation experiments are underway and will be provided at time of presentation. Citation Format: Max Devine, Joy Tang, Colin Stets, John Hays, James L. Chen. Characterizing the molecular underpinnings of sorafenib sensitivity in desmoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2777.

First dorsal interosseous muscle transfer to restore opposition of the new thumb after index pollicization: anatomical description of an original technique and case report

Index pollicization in severe thumb hypoplasia or aplasia in children or for the reconstruction of a mutilated thumb in adults is a rare and technically demanding procedure. Weakness of the new thumb is routinely reported after index pollicization. An inappropriate position of the first dorsal interosseous muscle (FDIM) can partly explain this strength deficit. Here, we report an original anatomical study on FDIM transfer for reanimation of the new thumb’s opposition function and its clinical application. An anatomical study was carried out on three upper limbs from fresh, non-embalmed adult cadavers. We demonstrated the feasibility of an FDIM transfer pedicled on the proper FDIM artery and the deep branch of the ulnar nerve. The proximal FDIM insertions were sutured to the lateral border of the flexor retinaculum to recreate the superficial thenar musculature. This procedure was performed on a 52-year-old man who was referred to us with swelling on his hand. We discovered a myxoid inflammatory fibroblastic sarcoma of the thumb that required proximal thumb amputation while preserving the base of the first metacarpal. To our knowledge, this is the first description of FDIM pedicled flap transfer during an index pollicization procedure among an adult population. However, in severe thumb hypoplasia or aplasia cases, this procedure is limited by the size and anatomical variations of the neurovascular structures among a population affected by radial longitudinal deficiency.

Myxoinflammatory Fibroblastic Sarcoma: New Case Report of a Rare Entity

Myxoinflammatory fibroblastic sarcoma (MIFS) is a malignant mesenchymal tumor most commonly occurring in the distal extremities of adults, it generally behaves like a low-grade tumor but is still able to progress locally and metastasize to distant sites, rarely resulting in death. It is a tumor whose unusual morphology can lead to misdiagnosis, either in the non-neoplastic sense (infectious or inflammatory) or as another sometimes malignant tumor entity. The genetic abnormalities detected in MIFS are the t(1;10)(p22:q24) translocation, with rearrangements of TGFBR3 and MGEA5 genes associated with increased levels of FGF8, with chromosome 3 marker/ring formation, and amplification of the VGLL3 locus.

Myxoinflammatory fibroblastic sarcoma of the submandibular gland

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade soft tissue tumor, it usually affecting the distal extremities. Upon conducting a literature review, we could not find a case of MIFS in the submandibular gland. In this study, we described a 44-year-old female patient who presented to our clinic with a complaint of swelling under the left side of her submandibular region that had persisted for eight months. Due to an initial diagnosis of submandibular gland neoplasm, the gland was totally excised. The pathological examination report indicated MIFS, and therefore, the patient was recommended to attend periodic follow-up visits.

Dermatofibrosarcoma protuberans in a 5-year-old child.

Dermatofibrosarcoma protuberans (DFSP) is a rare, slow-growing but progressive soft tissue fibroblastic sarcoma with a high tendency to relapse, but with very low metastatic potential. In children it is even rarer than in adults with an estimated incidence of 1 per million per year (5). How-ever, there are also congenital cases (3). In the child there is no different distribution between the two sexes and it is localized in the limbs in two thirds of cases, in the trunk in a third (4). The histological examination is decisive for the diagnosis, which is based on the presence of a proliferation of fibroblastic appearance with a storiform arrangement, poor peripheral delimitation, invasion of the subcutaneous tissue, positivity of proliferating cells with CD-34, low mitotic index. The histological examination also serves to differentiate DFSP from fibrosaroma, which has a worse prognosis due to its ability to metastasize. Once the histological examination has confirmed the clinical suspicion of DFSP, the therapeutic problem arises. After evaluating the extent of the neoplasm with MRI or CT scan, it is still necessary to remove the tumor, if a biopsy has been done, or to reoperate on the scar if the tumor has been already removed, with a margin of 2 cm (1). Relapses are less frequent in the child. However, they occur between 9 (2) and 15% (4) after complete remission, attested by imaging and histologically free margins. For this reason, even after a complete remission, it is necessary to monitor the child for years. In advanced, unresectable or metastasizing cases, therapy with imatinib has been tried (2). The latter is a monoclonal antibody directed against the platelet-derived growth factor (PDGF), which is characteristically dysregulated in DFSP, due to a chromosomal translocation t(17;22), whereby the PDGF-beta gene on chromosome 22 fuses with the alpha collagen gene of type 1 (COL1A1) on chromosome 17. The translocation is also used in diagnosis because it is almost constantly present in DFSP (4). The prognosis of DFSP is good especially in children with 100% survival at 5 years (4).

Pleomorphic Hyalinizing Angiectatic Tumor (PHAT): Review of the Literature with Case Presentation.

Pleomorphic hyalinizing angiectatic tumor (PHAT) is a very rare entity of soft tissue considered a “neoplasm of uncertain behaviour of connective or other soft tissue” by the World Health Organization (2020). It develops in subcutaneous tissue of the lower extremities, more frequently in the region of the ankle and foot, and rarely as a deep-seated soft tissue mass in locations such as the perineum, buttock, arms, head and neck, and viscera. Although inconsistent cytogenetic data have been reported on PHAT so far, there are potential morphological and genetic overlaps with hemosiderotic fibrolipomatous tumor (HFLT) and myxoinflammatory fibroblastic sarcoma (MIFS). Here we report a case of PHAT at the level of the upper third of the right thigh in a 48-year-old patient and we also focus on the differential diagnoses of these entities and conduct a literature review of reported cases.