Molecular Pathogenesis of Sporadic Desmoid Tumours and Its Implications for Novel Therapies: A Systematised Narrative Review.

Sporadic desmoid-type fibromatosis is a rare, fibroblastic soft-tissue neoplasm with local aggressiveness but no metastatic potential. Aberrant Wnt/ß-catenin signalling has been extensively linked to desmoid pathogenesis, although little is known about other molecular drivers and no established treatment approach exists. We aimed to summarise the current literature regarding the molecular pathogenesis of sporadic desmoid-type fibromatosis and to discuss the effects of both current and emerging novel therapies targeting these mechanisms. A literature search was conducted of MEDLINE® ALL and EMBASE databases for published studies (2000-August 2021) using keywords related to 'fibromatosis aggressive', 'immunohistochemistry', 'polymerase chain reaction' and 'mutation'. Articles were included if they examined the role of proteins in sporadic or extra-abdominal human desmoid-type fibromatosis pathogenesis. Searching identified 1684 articles. Following duplicate removal and eligibility screening, 36 were identified. After a full-text screen, 22 were included in the final review. At least 47% of desmoid-type fibromatosis cases displayed aberrant ß-catenin immunoreactivity amongst ten studies. Cyclin D1 overexpression occurred in at least 40% of cases across five studies. Six studies reported oestrogen receptor-ß expression with a range of 7.4-90%. Three studies implicated matrix metalloproteinases, with one study demonstrating vascular endothelial growth factor overexpression. One study explored the positive relationship between cyclooxygenase-2 and platelet-derived growth factor receptor-ß. Aberrant Wnt/ß-catenin signalling is a well-established pathogenic driver that may be targeted via downstream modulation. Growth factor signalling is best appreciated through the clinical trial effects of multi-targeted tyrosine kinase inhibitors, whilst oestrogen receptor expression data may only offer a superficial insight into oestrogen signalling. Finally, the tumour microenvironment presents multiple potential novel therapeutic targets.

Sporadic desmoid tumours are rare soft-tissue neoplasms that arise from connective tissues in the chest wall, head, neck and limbs. Whilst lacking metastatic potential, uncertainty surrounding their locally aggressive growth and unpredictable recurrence complicates treatment approaches. At the molecular level, alterations in the Wnt/ß-catenin signalling pathway, a fundamental coordinator of cell growth and development, have been strongly linked to desmoid tumour development. Beyond this, however, little is known about other molecular drivers. In the case of progressive or life-threatening disease, complex treatment decisions are made regarding the use of surgery, radiotherapy or systemic treatment modalities. Of the targeted systemic therapies, a lack of comparative clinical studies further complicates medical treatment decision making as no definitive treatment approach exists. Therefore, this review aimed to summarise the literature regarding the molecular drivers of desmoid tumour pathogenesis and to discuss the current and emerging novel therapies targeting such mechanisms. Utilising findings from human desmoid tissue samples, we present the rationale for targeting downstream mediators of the central Wnt/ß-catenin pathway and outline potential treatment targets in the tumour microenvironment. We also highlight the knowledge gained from clinical drug trials targeting desmoid growth factor signalling and present the potentially superficial insight provided by oestrogen receptor expression profiles on the role of oestrogen signalling in desmoid pathogenesis. In doing so, this work may assist in the eventual development of an evidence-based treatment approach for sporadic desmoid tumours.

Less-invasive fascia-preserving surgery for abdominal wall desmoid.

The mainstay of treatment for desmoid has been shifted to active surveillance (AS). However, surgery is still being performed on abdominal wall desmoid with a wide surgical margin. The purposes of this study are to clarify the treatment results of less-invasive, fascia preserving surgery for patients with abdominal wall desmoid, and to propose a new treatment modality. Since 2009, 34 patients with abdominal desmoid have been treated in our institution. Among them, as a final treatment modality, 15 (44%) were successful with AS, 15 were subjected to less-invasive surgery, and 4 methotrexate and vinblastine treatment. The clinical results of less-invasive surgery were clarified. In the surgical group, although the surgical margin was all microscopic positive (R1), only one patient (6.7%), who has the S45F mutation type of CTNNB1, showed recurrence, at a mean follow-up of 45 months. There were no patients with familial adenomatous polyposis (FAP)-related desmoid in this cohort. Only two patients (13%) required fascia lata patch reconstruction after removal of the tumor. In patients with non FAP-related abdominal wall desmoid, less-invasive, fascia preserving surgery is recommended as a favorable option as active treatment. Based on the results of this study, multi-institutional further research is warranted with an increased number of patients.

Clinicopathological features of 70 desmoid-type fibromatoses confirmed by ß-catenin immunohistochemical staining and CTNNB1 mutation analysis.

Desmoid-type fibromatosis (DF) is a locally aggressive neoplasm characterized by mutations in the CTNNB1 gene, which encodes the ß-catenin protein. We reviewed 85 cases of DF and performed Sanger sequencing for detecting mutations in CTNNB1 and immunostaining for detecting ß-catenin localization. We included 70 DF samples, of which 56 cases demonstrated nuclear ß-catenin localization and 43 cases harboured CTNNB1 mutations. CTNNB1-mutant DF samples consistently displayed nuclear ß-catenin expression and were derived from larger-sized tumours compared to samples with wild-type CTNNB1. When we further classified DF cases into 2 subgroups based on the type of specimen, excised specimens with nuclear ß-catenin expression frequently displayed CTNNB1 mutation and no statistical correlation between nuclear ß-catenin expression and CTNNB1 mutation was observed in biopsies. When we classified CTNNB1 mutation cases into 2 subgroups (DF with T41A or T41I, and DF with S45F or S45P), T41A or T41I mutations were observed more frequently in males than in females. Additionally, DF tumours harbouring S45F or S45P mutations were located more frequently in the abdominal wall than tumours with T41A or T41I mutations. In conclusion, CTNNB1 mutation correlates with nuclear ß-catenin expression in larger or excised DF tumours, and DF harbouring CTNNB1 mutations manifest variable clinical presentations.

Incidental 18F-Fluciclovine Uptake in a Desmoid Tumor Detected in a Patient Undergoing PET/CT Imaging for Prostate Cancer.

ABSTRACT: A 74-year-old man with biochemical recurrent prostate cancer underwent 18F-fluciclovine PET/CT for restaging to determine subsequent treatment strategy. 18F-fluciclovine PET/CT imaging demonstrated incidental focal heterogeneous increased 18F-fluciclovine uptake corresponding to a soft tissue nodule within the musculature of the left anterior abdominal wall. Subsequent ultrasound-guided biopsy of the lesion revealed histopathology compatible with a desmoid tumor. Consequently, the patient underwent surgical resection with wide local excision of the lesion.

A rare sporadic pancreatic desmoid fibromatosis diagnosed by endoscopic ultrasound-guided fine-needle aspiration: Case report and literature review.

Intra-abdominal desmoid fibromatosis (also known as desmoid tumor) is a rare benign but often locally aggressive infiltrative fibrous proliferation. Pancreatic desmoid fibromatosis is even rarer, with only 31 cases previously reported in the English-language literature. These tumors present a distinct diagnostic challenge due to their rarity and non-specific image findings and presentation, with most cases diagnosed as desmoid fibromatosis only after surgical resection. This report presents a rare case of pancreatic desmoid fibromatosis in a 72 year old man, who on a follow-up CT for a previously diagnosed angiomyolipoma of the kidney was found to have a 4.0 cm pancreatic tail mass. This was sampled pre-operatively by endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA). Examination of the cytology material showed a low-grade spindle cell lesion. Immunohistochemistry (IHC) performed on FNA cell block showed the lesional cells to be positive for beta-catenin, consistent with fibromatosis. Additional mutational analysis on cell block material revealed the characteristic CTNNB1 gene mutation (T41A), confirming the diagnosis. The mass was then surgically resected and again confirmed to be desmoid fibromatosis on histopathologic examination. On review of previously published cases of pancreatic desmoid fibromatosis, most were initially suspected to be some type of pancreatic neoplasm and were not biopsied prior to surgical resection. This case suggests a potential key role for fine-needle aspiration cytology in the preoperative diagnosis of pancreatic and other intra-abdominal desmoid tumors, particularly as evidence emerges that non-surgical treatment may be a viable first option for some cases.

ß-catenin S45F mutation results in apoptotic resistance.

Wnt/ß-catenin signaling is one of the key cascades regulating embryogenesis and tissue homeostasis; it has also been intimately associated with carcinogenesis. This pathway is deregulated in several tumors, including colorectal cancer, breast cancer, and desmoid tumors. It has been shown that CTNNB1 exon 3 mutations are associated with an aggressive phenotype in several of these tumor types and may be associated with therapeutic tolerance. Desmoid tumors typically have a stable genome with ß-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of ß-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in ß-catenin S45F mutants, resulting in decreased induction of apoptosis in these cells. Our findings also demonstrate that RUNX3 plays a pivotal role in the inhibition of apoptosis found in the ß-catenin S45F mutants. Restoration of RUNX3 overcomes this inhibition in the S45F mutants, highlighting it as a potential therapeutic target for malignancies harboring this specific CTNNB1 mutation. While the regulatory effect of RUNX3 in ß-catenin is already known, our results suggest the possibility of a feedback loop involving these two genes, with the CTNNB1 S45F mutation downregulating expression of RUNX3, thus providing additional possible novel therapeutic targets for tumors having deregulated Wnt/ß-catenin signaling induced by this mutation.

[Biology and signaling pathways involved in the oncogenesis of desmoid tumors]. / Biologie et voies de signalisations impliquées dans l'oncogenèse des tumeurs desmoïdes.

Desmoid tumors (TDs) are derived from mesenchymal stem cells and their pathogenesis is strongly linked to the Wingless/Wnt cascade where the deregulation of ß-catenin plays a major role. A mutation of the CTNNB1 encoding ß-catenin is found in the majority of sporadic TD cases and constitutional mutations of APC have been described in heritable forms in patients with familial adenomatous polyposis (FAP). Estrogens could also play a role in pathogenesis and this is the basis for the use of hormone therapy. Other signaling pathways have been involved in the development of TDs such as Notch, Hedgehog, JAK/STAT, PI3 Kinase/AKT and mTOR. Metalloproteases are expressed in TDs and play a role in invasiveness. TGF-ß, as a growth factor, stimulates the transcriptional activity of ß-catenin. Future studies will need to focus on better describing and understanding the immune environment of TDs. One of the major difficulties for the experimental study of TDs is the virtual absence of a preclinical model, either in vitro or in vivo. This is partly why the interactions between the different signaling pathways presented here and their consequences for the development of TDs are still poorly understood.

PARP-1 expression as a prognostic factor in Desmoid-type fibromatosis.

Desmoid-type fibromatoses (or desmoid tumors) are entities of intermediate biological potential and are locally invasive. Radical surgery, as state of the art therapy, is frequently limited by incomplete resections. Hormone modifying therapies are promising but further research is required. Poly Adenosine Diphosphate Ribose Polymerase-1 (PARP-1), a DNA repairing enzyme, might be a pathogenetic factor and could become a potential target for therapy as shown by the successful treatment of selected carcinomas and sarcomas by PARP-inhibition. In this study, we investigated the expression of estrogen receptors (ER) α (1) and ß (2), progesterone receptor (PR), androgen receptor (AR), as well as PARP-1 via immunohistochemistry and quantitative RT-PCR in 69 tissue samples of desmoid tumors. Immunohistochemistry was quantified using the Immunoreactivity Score (IRS). Overall expression patterns were correlated with clinical-pathologic parameters to determine their value as a prognostic factor. Among the investigated hormone receptors only ERß showed partial cytoplasmic reactivity. PARP-1 revealed variable nuclear positivity with IRS ranging from 0 to 6. Univariate survival analysis showed that higher expression of estrogen receptor 1 was associated with shorter disease-free survival (p = 0.005). Uni- (p = 0.03) and multivariate (p = 0.003) analyses of mRNA data revealed that higher PARP-1 expression correlated with earlier recurrence. According to this study PARP-1 expression is associated with poorer prognosis, that is faster recurrence, highlighting the possibility of PARP-1-targeting agents as a therapeutic option. Hormone receptors were of minor prognostic relevance in this study.

Estrogen receptor beta expression correlates with proliferation in desmoid tumors.

BACKGROUND AND OBJECTIVES: Estrogen receptor signaling and cyclin D1 have a major role in tumor cell proliferation in breast cancer. Desmoid tumors are rare neoplasms that may respond to endocrine treatment. The present study aimed to investigate the expression levels and the clinical relevance of estrogen receptor beta (ERß) and cyclin D1 in desmoid tumors. METHODS: This study consists of 83 patients with a surgically treated desmoid tumor. ERß and cyclin D1 expression was examined by immunohistochemistry in tissue microarrays. Cyclin A and Ki67 were studied in our previous work. RESULTS: Median ERß expression was 10.8%. ERß expression correlated with expression of the proliferation antigens Ki67 (rp = 0.35, P = 0.003), cyclin D1 (rp = 0.34, P = 0.004), and cyclin A (rp = 0.34, P = 0.004). ERß immunoexpression showed a trend towards predictive impact for recurrence as a continuous variable. Further explorative analysis indicated that very high ERß expression was related to high risk of relapse (hazard ratio [HR] 2.6; P = 0.02). Median cyclin D1 expression was 15.6%. High cyclin D1 expression was associated with high Ki67 and cyclin A expression. Cyclin D1 was not associated with time to recurrence. CONCLUSIONS: ERß and cyclin D1 immunopositivity correlated with high proliferation in desmoid tumors. High ERß expression might be predictive for postoperative recurrence.

Growth rate and myofibroblast differentiation of desmoid fibroblast-like cells are modulated by TGF-ß signaling.

Desmoid-like fibromatosis (DF) is a rare myofibroblastic benign tumor, often associated with local and repeated injuries, spontaneous regression and stabilization of disease progression suggesting the involvement of altered Wnt/ß-catenin signaling activation and/or aberrant response of the DF cells to external environmental stimuli. The aim of this study was to investigate the response of DF cells to microenvironmental factors such as inflammatory and growth factors or hormones. We observed that the inflammatory cytokine, transforming growth factor-ß (TGF-ß1) stimulated cell growth and myofibroblast differentiation of DF cells regardless of the presence of a ß-catenin mutation. The role of TGF-ß1 in cell growth and myogenic differentiation of in vitro cultures of primary DF cells and normal fibroblasts was investigated by gene and protein expression analyses. We demonstrated that TGF-ß1 exerted its role via the canonical Smad pathway with the phosphorylation of Smad3 being crucial for TGF-ß1 dependent DF cell growth and myofibroblastic differentiation. Furthermore we demonstrated that cell confluence is a critical determinant of TGF-ß1 inducing the DF myofibroblast differentiation, implying that the intercellular communications have an important role on the DF myofibroblast behavior. We observed the formation of an increased stress-fiber pattern in DF cells with increased projected cell area and stronger cell-cell contacts in presence of TGF-ß1. These results demonstrated that TGF-ß1 plays a crucial role in the DF cells growth and, together with cell-cell interactions, in DF myofibroblast conversion; we also highlighted that the cellular sensitivity to this cytokine was an intrinsic feature of the DF cells.

Sino-orbital desmoid tumor in a pediatric patient - Case report with review of literature.

We report a case of a 2-year-old female who presented with bilateral progressive proptosis, visual loss, nasal obstruction, and breathing difficulty. Magnetic resonance imaging revealed a large sino-orbital mass that was extending to the orbital apex and skull base. An initial diagnosis of rhabdomyosarcoma was made elsewhere on the basis of the presence of round and spindle cell tumor. Subsequent biopsy with immunohistochemical staining was positive for nuclear staining with ß-catenin, shifting the diagnosis to a myofibroblastic tumor, favoring desmoid-type fibromatosis. With image guidance, near complete excision of tumor was performed by a multidisciplinary team, while respecting danger zones such as the skull base and the optic nerve. Following a recurrence over 2 months, additional excision was performed with a 6-month treatment of methotrexate and vinblastine. Desmoid tumor is a rare form of soft tissue tumor uncommonly seen in the orbital area. Although benign, it is known to be recurrent and infiltrative. Few data are known and further information will aid in the management of these tumors.

Novel intra-genic large deletions of CTNNB1 gene identified in WT desmoid-type fibromatosis.

A wait and see approach for desmoid tumors (DT) has become part of the routine treatment strategy. However, predictive factors to select the risk of progressive disease are still lacking. A translational project was run in order to identify genomic signatures in patients enrolled within an Italian prospective observational study. Among 12 DT patients (10 CTNNB1-mutated and 2 wild type) enrolled from our institution only two patients (17%) showed a progressive disease. Tumor biopsies were collected for whole exome sequencing. Overall, DT exhibited low somatic sequence mutation rate and no additional recurrent mutation was found. In the two wild type (WT) cases, two novel alterations were detected: a complex deletion of APC and a pathogenic mutation of LAMTOR2. Focusing on WT DT subtype, deep sequencing of CTNNB1, APC and LAMTOR2 was conducted on a retrospective series of 11 WT DT using a targeted approach. No other mutation of LAMTOR2 was detected, while APC was mutated in two cases. Low-frequency (mean reads of 16%) CTNNB1 mutations were discovered in five samples (45%) and two novel intra-genic deletions in CTNNB1 were detected in two cases. Both deletions and low frequency mutations of CTNNB1 were highly expressed. In conclusion, a minority of DT is WT for either CTNNB1, APC or any other gene involved in the WNT pathway. In this subgroup novel and hard to be detected molecular alterations in APC and CTNNB1 were discovered, contributing to explain a portion of the allegedly WT DT cases.

High cyclin A expression, but not Ki67, is associated with early recurrence in desmoid tumors.

BACKGROUND AND OBJECTIVES: Desmoid tumors are soft-tissue tumors originating from myofibroblasts with a tendency to recur after surgery. High expression of proliferation markers is associated with shortened progression-free and/or overall survival in many neoplasms, including soft-tissue sarcomas. We investigated the prognostic role of cyclin A and Ki67 in desmoid tumors by immunohistochemistry. METHODS: The study included 76 patients with desmoid tumor operated at Helsinki University Hospital between 1987 and 2011. A tissue micro array (TMA) was constructed and the TMA sections were immunostained with cyclin A and Ki67 antibodies. A computer-assisted image analysis was performed. RESULTS: Cyclin A expression was evaluable in 74 and Ki67 in 70 patients. Cyclin A immunopositivity varied from 0% to 9.9%, with a mean of 1.9%. Cyclin A expression correlated significantly with Ki67. Cyclin A expression was associated with recurrence-free survival (HR 1.9, 95% CI = 1.1-3.2, P = .02), as were positive margin (HR 6.0, 95% CI = 1.6-22.5, P = .008) and extremity location (HR 5.3, 95% CI = 1.7-16.8, P = 0.005). Ki67 immunopositivity varied from 0.33% to 13.8%, with a mean of 4.6%, but had no significant prognostic impact (HR 1.1, P = .2). CONCLUSIONS: Our study indicates that cyclin A may be a new prognostic biomarker in surgically treated desmoid tumors.

A Metabolomics Pilot Study on Desmoid Tumors and Novel Drug Candidates.

Desmoid tumors (aggressive fibromatosis) are locally invasive soft tissue tumors that lack the ability to metastasize. There are no directed therapies or standard treatment plan, and chemotherapeutics, radiation, and surgery often have temporary effects. The majority of desmoid tumors are related to T41A and S45F mutations of the beta-catenin encoding gene (CTNNB1). Using broad spectrum metabolomics, differences were investigated between paired normal fibroblast and desmoid tumor cells from affected patients. There were differences identified, also, in the metabolomics profiles associated with the two beta-catenin mutations, T41A and S45F. Ongoing drug screening has identified currently available compounds which inhibited desmoid tumor cellular growth by more than 50% but did not affect normal fibroblast proliferation. Two drugs were investigated in this study, and Dasatinib and FAK Inhibitor 14 treatments resulted in unique metabolomics profiles for the normal fibroblast and desmoid tumor cells, in addition to the T41A and S45F. The biochemical pathways that differentiated the cell lines were aminoacyl-tRNA biosynthesis in mitochondria and cytoplasm and signal transduction amino acid-dependent mTORC1 activation. This study provides preliminary understanding of the metabolic differences of paired normal and desmoid tumors cells, their response to desmoid tumor therapeutics, and new pathways to target for therapy.

Comparison of ß-Catenin and LEF1 Immunohistochemical Stains in Desmoid-type Fibromatosis and its Selected Mimickers, With Unexpected Finding of LEF1 Positivity in Scars.

ß-catenin immunohistochemical stain can be useful in the diagnosis of many tumors including desmoid-type fibromatosis (DTF). Lymphoid enhancer-factor 1 (LEF1), a recently emerged marker, is part of the Wnt pathway with ß-catenin but has not been studied in DTF. We performed LEF1 and ß-catenin immunohistochemistry in DTF (n=26), superficial fibromatosis (n=19), sclerosing mesenteritis (n=12), gastrointestinal stromal tumor (n=17), and cutaneous scar (n=14) using tissue microarray and whole sections. The staining intensity was scored as strong (visible at ×2 objective, value of 3), moderate (visible at ×4, value of 2), weak (visible at ×10, value of 1), and negative (not visible at ×10, value of 0). The percentage of positive nuclei was recorded in 10% increment. Histologic scores were generated by multiplying numerical value of intensity and percentage of positive nuclei. A score of at least 10 was defined as positive. Eighteen of the 25 DTF were positive for LEF1 while 12 of 25 were positive for ß-catenin (1 excluded due to loss of tissue). Gastrointestinal stromal tumor cases were negative for both markers. All superficial fibromatoses were negative except 2 cases with weak positivity for LEF1 but not ß-catenin. Only 2 case of sclerosing mesenteritis were weakly positive for LEF1 but negative for ß-catenin. Ten of 14 scars were positive for LEF1 but only 1 of them was weakly positive for ß-catenin. In conclusion, this study demonstrated that LEF1 may be a useful marker in the differential diagnosis of DTF in certain contexts. However, caution should be exercised since LEF1 positivity can also be seen in scars.

Papillary thyroid carcinoma with desmoid-type fibromatosis: A clinical, pathological, and immunohistochemical study of 14 cases.

Papillary thyroid carcinoma (PTC) with desmoid-type fibromatosis (DTF) is characterized by genetic alterations of the fibroblasts. PTC-DTF is extremely rare, and the reports on such cases have been sporadic. Immunohistochemical staining using the antibody for beta-catenin is useful in diagnosing the variant. This report aims to describe the clinical, pathological, and immunohistochemical findings in 14 cases of PTC-DTF and to clarify the diagnostic significance of the variant. The patients included 9 women and 5 men, with a mean age of 49.3 years. PTCs with focal DTF components and with extensive DTF components included 7 cases each. No significant differences were noted in terms of age, gender, and serum thyroglobulin levels between extensive and focal DTF cases. On aspiration cytology, 12 cases were reported as suspicious for malignancy or malignant, and schwannoma or fibroma was suggested in 1 case each. The DTF components were histologically classified into 4 types, namely, central (4 cases), peripheral (1 case), mixed (7 cases), and diffuse type (2 cases). The stromal components were consistent with those of DTF. Immunohistochemically, fibroblasts in the DTF components showed nuclear and cytoplasmic expression for beta-catenin in 12 cases. The features are observed even in cases in which stromal components focally exist. Neither carcinoma cells nor the fibroblasts with Ki-67 labeling index >5% were found in all cases. We agree that PTC with nodular fasciitis-like stroma should be renamed to PTC-DTF.

Comparison of sporadic and FAP-associated desmoid-type fibromatoses.

BACKGROUND AND OBJECTIVES: Desmoid-type fibromatosis is a rare disease of which 7.5-16% have been reported to be related to familial adenomatous polyposis (FAP). We sought to compare the characteristics and treatment of sporadic and FAP-related desmoid-type fibromatoses. METHODS: Altogether 220 patients were included in the study after receiving a diagnosis of desmoid-type fibromatosis by the Pathology Department of Helsinki University Hospital, with adequate follow-up. Patients were included from January 1, 1980 until April 30, 2015. RESULTS: FAP-related tumors were found in 22 (10%) patients. FAP-related desmoid-type fibromatoses were larger, more commonly multiple, and more often intra-abdominally situated. Surgery was the treatment of choice for 179 (90%) of the sporadic patients and for 18 (82%) of FAP-related patients. Resections with non-involved margins (R0) were more common in sporadic desmoid-type fibromatoses (55% vs. 23%, P = 0.048). The risk of recurrence was 25% in sporadic- and 44% in the FAP-related group. Three (14%) patients with FAP-related desmoid-type fibromatoses died from the disease. CONCLUSIONS: The predictors for FAP occurrence among desmoid tumor patients are large tumor size, intra-abdominal location, multiple tumors, and patient's young age. Desmoid-type fibromatosis patients suffer a high recurrence rate, also among those experiencing sporadic tumors, but the risk of death due to the tumor is low. Conversely, desmoid disease represents a substantial cause of death among FAP patients.

Human microRNA expression in sporadic and FAP-associated desmoid tumors and correlation with beta-catenin mutations.

Desmoid tumors (DT) are rare, benign, fibroblastic neoplasm with challenging histological diagnosis. DTs can occur sporadically or associated with the familial adenomatous polyposis coli (FAP). Most sporadic DTs are associated with ß-catenin gene (CTNNB1) mutations, while mutated APC gene causes FAP disease. microRNAs (miRNAs) are involved in many human carcinogenesis.The miRNA profile was analyzed by microarray in formalin-fixed, paraffin-embedded (FFPE) specimens of 12 patients (8 sporadic, 4 FAP-associated) and 4 healthy controls. One hundred and one mRNAs resulted dysregulated, of which 98 in sporadic DTs and 8 in FAP-associated DTs, 5 were shared by both tumors. Twenty-six miRNAs were then validated by RT-qPCR in 23 sporadic and 7 FAP-associated DT samples matched with healthy controls. The qPCR method was also used to evaluate the CTNNB1 mutational status in sporadic DTs. The correlation between sporadic DTs and miRNA expression showed that miR-21-3p increased in mutated versus wild-type DTs, while miR-197-3p was decreased. The mRNA expression of Tetraspanin3 and Serpin family A member 3, as miR-21-3p targets, and L1 Cell Adhesion Molecule, as miR-197-3p target, was also evaluate. CTNNB1 mutations associated to miRNA dysregulation could affect the genesis and the progression of this disease and help histological diagnosis of sporadic DTs.

TGF-ß and CTGF are Mitogenic Output Mediators of Wnt/ß-Catenin Signaling in Desmoid Fibromatosis.

Desmoid fibromatosis is a locally aggressive clonal fibroblastic proliferation with high recurrence rates and no metastatic potential. Implicated molecular aberrations occur within the Wnt/ß-catenin pathway (APC and ß-catenin gene mutations). Transforming growth factor-ß (TGF-ß) and connective tissue growth factor (CTGF) are profibrotic growth factors, downstream from nuclear translocation of ß-catenin, that lead to increased fibrogenesis. CTGF (a downstream effector of TGF-ß) is a matricellular protein that modulates the activity of growth factors, adhesion molecules, integrins, and extracellular matrix thus playing a central role in tissue remodeling and fibrosis. Recently there has been growing interest in use of extracellular matrix inhibitors for treatment of various fibrogenic diseases. Desmoid fibromatosis samples (n=15) were evaluated for expression of ß-catenin, TGF-ß, and CTGF using immunohistochemistry on formalin paraffin-embedded material. A control group comprising scar tissue and adjacent normal skin (n=10) were simultaneously immunostained with above mentioned markers. Real-time polymerase chain reaction was performed on frozen specimens of desmoid fibromatosis (n=6) and normal skin (n=2). All 15 desmoid tumors were positive for ß-catenin (surrogate marker of Wnt/ß-catenin pathway dysregulation) which was negative in control normal skin and scar samples. TGF-ß and CTGF were negative in 9 of 10 normal skin controls. TGF-ß and CTGF were positive in all cases of scar tissue. All 15 cases of desmoid tumors were positive for TGF-ß and CTGF. The real-time polymerase chain reaction showed higher expression levels of TGF-ß and CTGF in desmoid fibromatosis compared with normal skin. The high constitutive expression of ß-catenin downstream effectors; TGF-ß, CTGF has the potential for enabling targeted therapy.