Desmoid Fibromatosis Research Articles

Desmoid fibromatosis (DF) is a locally aggressive soft tissue neoplasm with frequent recurrences. DF is characterized by alterations in the Wnt/β-catenin pathway, with the majority showing sporadic mutations in CTNNB1 , whereas others have germline mutations in APC . Immunohistochemical staining for β-catenin is often difficult to interpret and can be negative in up to 30% of cases. Prior studies have shown that some DFs lacking nuclear expression of β-catenin may carry activating CTNNB1 mutations. Droplet digital polymerase chain reaction (ddPCR) has been used effectively in detecting mutations in formalin-fixed, paraffin-embedded (FFPE) samples of various cancer types. In this study, we assess the diagnostic utility of ddPCR to detect CTNNB1 mutations in DF with β-catenin expression on immunohistochemistry (IHC), as well as in diagnostically challenging cases. Of the 28 DFs with nuclear β-catenin expression by IHC, 24 cases showed a CTNNB1 mutation by ddPCR using primers against the most common point mutations in CTNNB1 . The most frequent mutation was T41A (n=14; 50%), followed by S45F (n=8; 33%) and S45P (n=3;12%). We identified 8 additional (myo)fibroblastic lesions of uncertain classification, which were negative for nuclear β-catenin expression by IHC. We detected CTNNB1 mutations in 3 unknown lesions, including S45F (n=2) and S45P (n=1). ddPCR is a sensitive, rapid and cost-efficient methodology to detect common CTNNB1 mutations in DF, especially in diagnostically challenging cases.

Abstract Introduction: While activation of beta-catenin is associated with desmoid fibromatosis (DF), mechanisms by which this oncogene initiates tumorigenesis are unclear as are factors underlying variable biologic behavior in the disease and vulnerability to targeted therapies. This study sought to define downstream pathways dysregulated by beta-catenin that may be modulated to potentially affect patient outcome. Methods: Multiple primary DF cell lines were developed from surgical specimens, validated by Sanger sequencing, and immortalized by ectopic expression of TERT. Gene expression was assessed in DF tumors (n=45) with U133A arrays and by RNA-seq in cells. Direct targets of beta-catenin were identified by CHIP-seq. Lentiviral systems were used to deliver shRNA (or scramble control) and overexpression constructs. Cell proliferation, protein levels/phosphorylation and gene expression were assessed by CyQuant DNA quantification, immunoblot, and RT-PCR, respectively. Endothelial cell (HUVEC) tube formation was quantitated using light microscopy. Results: Gene set enrichment analysis performed on RNA-seq data comparing DF cells treated with shRNA directed against CTNNB1 showed downregulation of hypoxia-regulated genes, and unsupervised analysis clustered 45 DF tumors separately from normal mesenchymal tissue based on the expression levels of these genes. CTNNB1 knockdown (KD) was associated with reduction in HIF1A and ability of DF cells to induced endothelial tube formation in HUVEC co-cultures (71%, p<0.001); ectopic expression of HIF1A in CTNNB1 KDs rescued this effect. HIF1A KD itself inhibited DF induction of HUVEC tube formation (49%, p<0.001), but did not affect DF cell proliferation. CHIP-seq nominated ABL1, a known regulator of HIF1 translation, as a direct target of beta-catenin. CTNNB1 KD caused 65% (p=0.01) decrease in ABL1 expression, and reduction in levels of c-ABL, its downstream target p-CRKL, and HIF1-alpha. Unlike HIF1A, ABL1 KD also reduced proliferation in multiple DF cell lines (up to 90%) as did direct inhibition of c-ABL with its inhibitor dasatinib (IC50 <50nM). Dasatinib and sorafenib, a PDGFR-beta inhibitor of clinical benefit in DF, both reduced cellular levels of p-ABL, p-CRKL and HIF1a expression in DF cells. Sorafenib also inhibited HUVEC tube-formation (59% at 1uM, p<0.05) induced by DF. Conversely, exogenous PDGF-BB stimulated DF proliferation (53% increase at 20ng/ml, p<0.05), increased p-ABL, p-CRKL and HIF1a in DF and promoted endothelial cell tube formation (2-fold, p<0.05) when added to DF and HUVEC co-cultures but not HUVEC cell cultures alone. Conclusion: ABL1 is a transcriptional target of beta-catenin in DF cells and is necessary for proliferation and maintenance of HIF1-alpha levels. Regulation of c-ABL activity by PDGFR-beta and targeted therapies modulates DF cell proliferation and paracrine signaling, suggesting a reason for variable biologic behavior between tumors and a mechanism for sorafenib activity in DF. This finding may point to markers predictive of outcome in patients. Citation Format: Jia Hu, Anthony Villano, Rachael O'Connor, Yuliy Rozenberg, Alankrta Venkatesh, Mrinal Gounder, Nicholas Socci, Samuel Singer, Meera Hameed, Aimee M. Crago. Growth factor signaling and kinase inhibitors regulate oncogenesis in desmoid fibromatosis by modulating activity of the beta-catenin transcription target ABL1 [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A028.

Abstract Cancer cells rewire metabolic pathways and energy production to support the enhanced proliferation, invasion and resistance to treatment. The three main glucose metabolism pathways that support growth of cancer cells are: a) the glycolysis pathway for energy production; b) the pentose phosphate pathway for biomass production; and c) the hexosamine biosynthesis pathway (HBP) for protein glycosylation. It is known that the activation of HBP leads to altered glycosylation of oncogenes, transcription factors and kinases in many types of cancer. These aberrations may lead to increased proliferation and survival of tumor cells, and may be associated with resistance to therapy. A better understanding of the role of HBP in malignancies has the potential for clinical implications. Several studies demonstrated that pharmacological inhibition of GFPT2 (glutamine-fructose-6-phosphate transaminase 2, the first and rate-limiting enzyme in HBP) and the enzymes that act downstream of HBP may exhibit anti-tumorigenic effect both in vitro and in vivo, and may modulate sensitivity to chemo-, radio- and immunotherapy. Most of these studies focused on carcinomas and the role of HPB in sarcoma has not been studied. We recently reported a remarkable enrichment of genes involved in HBP in a subset of leiomyosarcoma (LMS) and demonstrated that expression of GFPT2 in LMS is associated with poor clinical outcome. We identified the c-Myc oncoprotein as a potential target of HPB that may be stabilized by aberrant glycosylation in LMS. Here we show the results of a large-scale screening of 260 primary specimens of 33 types of soft tissue lesions. In addition to expression in a subset of LMS, we observed near universal expression of GFPT2 in 34 of 35 desmoid type fibromatosis (DTF), independent of the mutation type of the CTNNB1 gene. Gene Set Enrichment Analysis of a previously published 3SEQ transcriptomic dataset composed of DTF and 9 other types of fibrotic lesions identified significant enrichment of other genes implicated in HBP and multiple glycosylation-associated pathways in DTF compared to the other types of fibrotic lesions. Our analysis identified ATF6 (activating transcription factor 6) as a possible target regulated by aberrant glycosylation as a consequence of HBP activation in DTF. ATF6 is a glycoprotein that has been demonstrated to underlie the resistance to chemotherapy in osteosarcoma, to have a pro-oncogenic role in primary liver cancers and has been proposed as a therapeutic target in cystic fibrosis. Others have shown that targeting HBP can provide therapeutic benefit in a number of preclinical models of carcinoma. Our studies offer new insights into the mechanisms of DTF tumorigenesis and, when confirmed by in vitro studies, will provide a rationale to explore the potential of therapeutic targeting of HBP in DTF. Citation Format: Joanna Przybyl, Angela Tolwani, Sushama Varma, Matt van de Rijn. Targeting hexosamine biosynthesis pathway for the treatment of desmoid tumors [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B015.

Rationale:Desmoid fibromatosis is a rare benign tumor, but due to its rarity and diverse clinical course, treatment guidelines have not been established. However, since a good prognosis can be expected, an accurate diagnosis and appropriate treatment are required. We describe a rare case of desmoid fibromatosis on young female that presented as huge abdominal mass.Patients concerns:A 28-year-old female with left upper abdominal pain 1 month ago was referred.Diagnoses:Abdominal computed tomography and magnetic resonance imaging revealed a heterogeneous soft tissue mass approximately 29 × 17 cm in size in the left abdomen with abdominal wall invasion and pathological fracture in costochondral junction of the left 8th to 10th ribs.Interventions:Surgical resection was performed.Outcomes:33 × 23 × 6 cm sized tumorous mass showed proliferation of bland fibromatosis and myofibroblast with nuclear β-catenin expression on pathological examination. Desmoid fibromatosis arising from intra-abdominal soft tissue with ribs and pericardium invasion was diagnosed.Lessons:The mainstay of treatment of symptomatic desmoid fibromatosis is surgical resection, and in the case of abdominal tumor, it can be more dangerous when it invades adjacent organ. We report a case that required additionally multidisciplinary approach for surgery and postoperative treatment of huge abdominal desmoid tumor which infiltrate bone and pericardium beyond abdominal cavity.

1511P Efficacy and toxicity of sorafenib in desmoid type fibromatosis: A real-world experience

1512P Pain in patients with desmoid fibromatosis (DF)

Medulloblastoma is the most common pediatric embryonal brain tumor, and may occur in cancer predisposition syndromes. We describe novel associations of medulloblastoma with atypical prolactinoma and dural high-grade sarcoma in Li-Fraumeni syndrome (LFS), and epidural desmoid fibromatosis in familial adenomatous polyposis (FAP)/Turcot syndrome. Genomic analysis showing XRCC3 alterations suggested radiotherapy as contributing factor to the progression of LFS-associated medulloblastoma, and demonstrated different mechanisms of APC inactivation in the FAP-associated tumors. The integrated genomic-transcriptomic analysis uncovered the growth pathways driving tumorigenesis, including the prolactin-prolactin receptor (PRLR) autocrine loop and Shh pathway in the LFS-associated prolactinoma and medulloblastoma, respectively, the Wnt pathway in both FAP-associated neoplasms, and the TGFβ and Hippo pathways in the soft tissue tumors, regardless of germline predisposition. In addition, the comparative analysis of paired syndromic neoplasms revealed several growth pathways susceptible to therapeutic intervention by PARP, PRLR, and selective receptor tyrosine kinase (RTK) inhibitors. These could target the defective DNA damage repair in the LFS-associated medulloblastoma, the prolactin autocrine loop in the atypical prolactinoma, the EPHA3/7 and ALK overexpression in the FAP-associated medulloblastoma, and the multi-RTK upregulation in the soft tissue neoplasms. This study presents the spatiotemporal evolution of novel neoplastic associations in syndromic medulloblastoma, and discusses the post-radiotherapy risk for secondary malignancies in syndromic pediatric patients, with important implications for the biology, diagnosis, and therapy of these tumors.-9uTLpjCeHFTYhThd81HRBVideo

Desmoid fibromatosis involving the pancreas: A retrospective case series with clinical, cytopathologic and radiologic correlation

Percutaneous cryoablation for desmoid fibromatosis: initial experience at a UK centre

IntroductionSorafenib is a tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, thyroid carcinoma, and desmoid fibromatosis. As high inter-individual variability exists in exposure, there is a scientific rationale to pursue therapeutic drug monitoring (TDM). We investigated the feasibility of TDM in patients on sorafenib and tried to identify sub-groups in whom pharmacokinetically (PK) guided-dosing might be of added value. MethodsWe included patients who started on sorafenib (between October 2017 and June 2020) at the recommended dose of 400 mg BID or with a step-up dosing schedule. Plasma trough levels (Ctrough) were measured at pre-specified time-points. Increasing the dose was advised if Ctrough was below the target of 3750 ng/mL and toxicity was manageable. ResultsA total of 150 samples from 36 patients were collected. Thirty patients (83 %) had a Ctrough below the prespecified target concentration at a certain time point during treatment. Toxicity from sorafenib hampered dosing according to target Ctrough in almost half of the patients. In 11 patients, dosing was adjusted based on Ctrough. In three patients, this resulted in an adequate Ctrough without additional toxicity four weeks after the dose increase. In the remaining eight patients, dose adjustment based on Ctrough did not result in a Ctrough above the target or caused excessive toxicity. ConclusionsTDM for sorafenib is not of added value in daily clinical practice. In most cases, toxicity restricts the possibility of dose escalations.

A collision tumor is a neoplastic lesion comprised of two or more distinct cell populations with distinct borders. Desmoid fibromatosis (DF) is a rare musculoaponeurotic tissue tumor that grows deep in the connective tissue and shows locally aggressive behavior. Only two cases of collision tumors with desmoid fibromatosis are reported in the English literature, albeit papillary thyroid carcinoma with desmoid fibromatosis-like stroma is regarded as a variant rather than a collision tumor. We present a unique case of collision tumor with desmoid fibromatosis surrounding intra-abdominal metastasis from urothelial carcinoma. A 65-year-old white male with history of bladder and left renal pelvis high-grade papillary urothelial carcinoma status post-nephrectomy was found to have a small bowel obstruction due to a soft tissue mass. Histology of the mass showed multiple matted lymph nodes with metastatic urothelial carcinoma admixed with a proliferation of spindle cells positive for nuclear beta-catenin, consistent with desmoid fibromatosis. While the prior surgical site likely acted as a nidus for development of desmoid fibromatosis, we also hypothesize that a dysregulation of beta-catenin signaling pathways within the cancer cells might have attributed to the spindle cell proliferation in the stroma surrounding the tumor. Our case emphasized the importance of clinical suspicion of desmoid fibromatosis in patients with metastatic cancer, requiring a prompt diagnosis and treatment to decrease the risk of complications and local recurrence.

Meigs syndrome is defined by the presence of a benign ovarian tumor, ascites, and pleural effusion (predominantly on the right side). A characteristic sign of Meigs syndrome is the complete disappearance of exudate after surgical resection of the ovarian tumor.We present a case report of a 58-year-old patient admitted for an advanced ovarian tumor with pleural effusion, ascites, and tumor marker elevation typical for ovarian cancer. Cytological examination of ascites and pleural effusion was repeatedly negative for malignancy. Histopathological examination of the bio-psied tissue was concluded as low-grade mesenchymal neoplasia. The second opinion of histopathological examination was concluded as low grade fibroblastic pelvic tumor without the possibility of exact specification. Dia-gnoses of desmoid fibromatosis and low-grade fibromyxiod sarcoma (less likely) were considered. Surgical resection was indicated, and a large tumor with numerous adhesions to the uterus, bladder, and thin loops with a noticeably thickened peritoneum were perioperatively described. Histologically, left ovarian fibroma with productive peritonitis and sanguine-induced ascites was dia-gnosed. Due to the clinical findings and the result of the histopathological examination, the case was classified as Meigs syndrome. Two months after the surgery, the ascites and pleural effusion disappeared, and the tumor marker levels normalized.The present case report documents that it is always necessary to consider diseases other than those most likely at the outset, as the treatment algorithm and prognosis of these rare diseases may differ significantly.

Desmoid fibromatosis in thyroid bed: a case report

Setting the international research agenda for sarcoma together with patients and carers: first results of the Sarcoma Patient EuroNet (SPAEN) priority setting partnership

Desmoid fibromatosis of the breast is extremely rare. It is characterized by high locally aggressive potential but does not have a metastatic power. We report the case of a 52-year-old patient with a breast desmoid tumor on a ground of rectocolic polyposis. MRI has an important place in the diagnostic strategy while confirmation is done by pathological examination. The initial treatment is surgical excision but other therapeutic choices (radiotherapy) are being evaluated.

Extra-abdominal desmoid fibromatosis: Cryoablation versus traditional therapies

BackgroundDesmoid fibromatosis (DF) is a rare clonal proliferation of fibroblasts and myofibroblasts. It develops in the connective tissues and does not metastasize but may infiltrate adjacent structures. Because of the rarity of these tumors and the unpredictable natural history of the disease, well-defined and precise guidelines of the optimal treatment for DF have not been formulated.Case PresentationHere, we present a giant abdominal DF that invaded the right spermatic cord and iliac vessels. The lesion was excised with external iliac artery dissection; however, the vein was sacrificed. The abdominal wall defect was then repaired with a polypropylene mesh. The lesional cells are positive for β-catenin.ConclusionsIn the past decades, there has been a change in the treatment of DF. The “wait and see” policy has been considered initially in most cases. Surgical intervention remains a valid option for symptomatic lesions. The optimal regimes of the tumor should not take the risk of making the patient more symptomatic than the lesion itself.

Introduction and importanceDesmoid Fibromatosis (DF) represents a rare neoplasm developing from fascial and musculoaponeurotic structures. Preoperative diagnosis of DF is a challenge because of its rarity and nonspecific presentation. Imaging may be helpful for determining the correct diagnosis. Currently there are different clinical treatments of DF including surgical treatment, drug treatment and radiotherapy.Case presentationA 43-year-old Caucasian male presented to the Emergency Department with a 6-month history of recurrence of post-traumatic chest wall hematoma. Physical examination revealed a partially solid, painless mass on the right anterior chest wall. Laboratory tests reported and neutrophilic leukocytosis. Thoracic contrast-enhanced computed tomography showed a smooth contour, heterogeneous and hypodense subcutaneous soft tissue mass anterior to the right pectoral muscles and to the right 4th–7th rib. The patient underwent surgery: a solid suprafascial neoplasm was completely excised. The postoperative course of the patient was uneventful.Clinical discussionDF is a soft tissue neoplasm with a tendency for local invasion and recurrence. The course of DF cannot be predicted, being fatal if DF infiltrates vital structures. Diagnosis of DF is difficult and imaging may be helpful for determining the correct diagnosis. Currently the treatment for DF has shifted from surgery (post-operative recurrence rates of 20%–70%) to conservative therapy including watchful waiting.ConclusionDF is a myofibroblastic proliferative soft tissue tumor and classified as an intermediate malignancy. Preoperative diagnosis of DF needs a high index of suspicion and is facilitated by imaging. Surgery, among different treatments, represents a potentially curative treatment of DF.

In the following report, we present the case of a 31-year-old patient examined for a suspected small bowel tumour. Small bowel tumours are relatively rare and definitive diagnosis is often preceded by surgical resection. The same was true for our patient examined for a soft tissue lesion found with imaging techniques in close proximity to the small intestine. After ruling out hormonal activity, diagnostic laparotomy was performed. Desmoid fibromatosis, a rare tumour of the mesentery, was confirmed histopathologically. Although without metastatic potential, desmoid fibromatosis is a tumour with moderately malignant potential for aggressive growth into surrounding structures and organs and a large percentage of local recurrences.

Introduction: Desmoid tumors are rare cases that arise from aponeurotic tissue. Parasitic leiomyoma is a rare type of leiomyoma that grows in reproductive age, but differential diagnostics have something in common.Case report: A case of a 34-year-old Asian woman, secundigravida, outpatient clinic, referred from surgery division with chief complaint of a lump in the stomach that has become bigger in the past 4 years. There was no menstrual complaint, and the patient had a history of one previous cesarean section. Computed Tomography (CT) revealed a mass on the abdominal wall that extends to the abdominal cavity, and the patient underwent a mass biopsy and the histopathology results were obtained in the form of uterine leiomyoma or fibroid. During the operation, the mass was obtained from the abdominal wall and had no connection to internal reproductive organs, and due to the large mass, we consulted to digestive surgery division for mass resection, and a mesh graft was placed. Based on the results of tissue examination, the desmoid fibromatosis tumor was obtained from histological findings.Conclusion: Preoperative management by performing magnetic resonance imaging (MRI) can be useful to evaluate the difference between both diseases. Immunohistochemistry stain should be performed to differentiate between both diseases in case the MRI unavailable.