Current Update on Desmoid Fibromatosis.

Multimodality imaging including ultrasound, computed tomography (CT) and magnetic resonance (MR) play a key role in the diagnosis, staging and follow up of DF [ 31 – 34 ]. Ultrasound is helpful for delineating the tumor, especially DF occurring in the abdominal wall and extremities ( Fig. 1 ). DF can present as well defined or poorly defined infiltrative heterogeneous solid mass [ 33 , 35 – 37 ]. Tumors have variable echogenicity depending upon the amount of collagen, fibrosis and cellular components within the lesion [ 36 ]. A recent study reported that presence of stellar-type configuration with multiple irregular sun-burst like extensions along fascial planes may be a useful diagnostic feature of superficial extra-abdominal DF but larger prospective studies would be helpful to validate this finding [ 35 ]. CT is commonly used for imaging DF and is particularly helpful for intra-abdominal lesions. Tumors occurring within the abdominal cavity tend to most commonly involve the mesentery, although other sites may be affected (Fig. 2 , 7 ). Intra-abdominal tumors may present as well defined soft tissue masses with variable attenuation, or occur as poorly defined infiltrative lesions (30–32). Similar to ultrasound, the CT appearance of the tumor may be dictated by the amount of collagenous and myxoid contents. In general, myxoid portions of the tumor tend to be hypodense compared to skeletal muscle, while collagenous and fibrotic components can be isodense or hyperdense (30–32). DF typically enhances following intravenous contrast administration; however, the degree of enhancement is usually mild to moderate, owing to the presence of varying myxoid and collagenous material within the tumor [ 33 , 38 ]. Necrosis is typically absent [ 34 ]. CT can provide critical information required for treatment planning, including relationship of the tumor to the major vessels and adjacent organs ( Fig. 7 ). Complications such as bowel obstruction, bowel ischemia and hydronephrosis are readily identified on CT [ 38 ]. Given its excellent soft tissue resolution, MR is very useful for imaging DF, especially the extra-abdominal lesions occurring in the extremities, head and neck, abdominal and chest wall (Fig. 3 , 4 , 8 ). MR may also be useful for monitoring mesenteric DF, particularly in those with allergy to iodinated contrast media as well as in young patients in whom it is desirable to reduce radiation exposure ( Fig. 7 ). MR characteristics of DF depend upon the histological components of the tumor ( Fig 3 – 4 , 7 – 8 ) [ 32 , 39 – 41 ]. Fibrotic and collagenous portions of DF typically demonstrate low signal intensity on T2 weighted sequences and demonstrate mild to moderate enhancement, especially on the delayed phase post contrast enhanced images; in contrast, prominent cellular stroma and myxoid matrix in DF manifests as heterogeneous T2 hyperintense areas and demonstrate moderate to intense enhancement following intravenous contrast administration. Presence of linear, non-enhancing, T1- and T2-hypointense bands seen within the tumor (band sign) is reported to a characteristic MR finding seen in 60–90% of DF ( Fig. 4 ) [ 39 ]. However, it should be noted that band sign is not pathognomonic of DF as other musculoskeletal soft tissue tumors such as malignant fibrous histiocytoma may also demonstrate this imaging feature [ 39 , 40 ]. Fascial tail sign refers to the presence of a linear infiltrative border extending from the tumor along the fascial plane and may be seen in up to 83 % of DF ( Fig. 3 – 4 ) [ 39 ]. A recent study reported that the mean apparent diffusion coefficient (ADC) of DF was significantly higher than the malignant soft tissue sarcomas, implying that diffusion weighted imaging may be helpful in differentiating DF from the malignant tumors [ 42 ]. CT and MR imaging features can aid decision on patient management. The relationship of the tumor to the adjacent structures (especially the major neurovascular structures and vital organs) should be carefully evaluated and reported as this can help decide the feasibility of surgery. Also, CT and MR play a critical role in the follow up as these tumors tend to have a high recurrence rate. Furthermore, imaging is important in evaluating response to non-surgical therapy. Conventionally, response to therapy is evaluated using tumor response criteria RECIST 1.1, which is based on decrease in tumor size. However, this can significantly underestimate response to therapy, especially when systemic targeted therapies are used. Hence alternate tumor response criteria has been proposed in DF which takes into account changes in tumor size as well as interval changes in tumor attenuation (on CT) and changes in T2 signal intensity and degree of tumor enhancement ( on MR), following systemic therapy (31). Even in the absence of change in tumor size, reduction in CT attenuation, decrease in T2 signal intensity and decrease in enhancement of the tumor are reported to be findings suggestive of modified response to therapy (31). These imaging findings may reflect response in the form of increased fibrous component and decreased active inflammatory component within DF. The role of fluoro-de-oxy-glucose positron emission tomography (FDG PET/ CT) in DF is not yet fully defined. There is limited literature regarding the utility of PET CT in DF, with most of the current evidence coming from small case series and case reports [ 43 – 47 ]. DF tends to demonstrate mild FDG avidity ( Fig. 9 ) [ 43 – 47 ]. Few small studies indicate that PET CT may be useful for monitoring efficacy of systemic therapy in DF as reduction in FDG uptake correlated with pathological features such as fibrosis and decrease in tumor mitosis [ 44 , 47 ]. Larger, prospective studies would be required for validation before PET CT can be used in the routine clinical practice for DF.

The clinical presentation in DF is highly variable and may be influenced by the tumor location [ 26 , 27 ]. Most DF in the abdominal wall and extra-abdominal locations may present as painless mass. However, larger lesions and those adjacent to neurovascular structures may be associated with pain and functional impairment (Fig 4 , 5 ) [ 26 , 27 ]. Intra-abdominal DF can result in various complications such as bowel obstruction, hydronephrosis and rarely intestinal perforation [ 28 – 30 ] ( Fig 7 ).

Awareness of the molecular cytogenetics of DF has provided an insight in the pathogenesis of both the familial and sporadic DF. Wnt/ β-catenin pathway is believed to play a key role in the pathogenesis of DF ( Fig 10 ) [ 5 , 11 ]. β-catenin is an important molecule with multiple cellular functions including serving as cell adhesion molecule in adherens junctions in the mesenchyme cells. Intra-cellular levels of β-catenin are regulated by the adenomatous polyposis coli (APC) gene and the Wnt pathway [ 5 ]. APC gene plays a key role in the phosphorylation and subsequent proteasomal degradation of the β-catenin. On the other hand, Wnt pathway inhibits this APC-dependent phosphorylation of β-catenin ( Fig 10 ) [ 11 ]. Besides APC, another important gene complex playing a vital role in the downstream regulation and degradation of the β-catenin is the catenin beta 1 (CTNNB1) gene [ 5 , 11 ]. Genetic alterations in the APC and CTNNB1 gene are thought to be vital events resulting in the hereditary and sporadic DF. All patients with FAP syndrome inherit a single mutant defective allele of the APC gene; DF develops in FAP when the second allele also becomes defective due to somatic inactivation such as mutation 3’ in codon 1444 of the APC gene (Knudson’s two-hit hypothesis). Non-functional APC gene results in excessive accumulation of intra-cellular β-catenin; high levels of β-catenin may cause over stimulation of various genes such as cyclin-D1 and c-myc, resulting in a cascade of events leading to excessive cell proliferation & differentiation, with resultant DF tumor development in FAP. Sporadic DF is associated with a high incidence (85%) of mutations in CTNNB1 gene, which may lead to uninhibited activation of Wnt pathway, leading to accumulation of excessive cytoplasmic β-catenin, ultimately resulting in development of the tumor [ 12 ]. Trisomy 8 and trisomy 20 has also been reported in sporadic DF [ 13 ]. Mutations in other genes such as AKT1, BRAF and TP53 have also been reported in DF [ 14 ]. Better understanding of the molecular cytogenetics of DF has also enhanced our knowledge of the molecular biology and tumor behavior of this rare condition. For example, in patients with FAP-related DF, presence of mutation in 5’ of codon 400 in APC gene is associated with a significantly better prognosis compared to mutation 3” of codon 1400 [ 15 ]. Similarly, S45 mutation of CTNNB1 mutation has been associated with a higher risk of local recurrence in sporadic DF, compared to other types of mutation in beta-catenin gene [ 16 , 17 ]. Studies analyzing gene-expression profiles in DF have also identified specific gene-expression signatures which can help predict progression fee survival and time to recurrence [ 18 , 19 ]. Unravelling cytogenetics of DF may also pave way for improved management of this tumor. For example, recent studies indicate that targeting Wnt/ β-catenin pathway and Notch pathway with PF-03084014, a potent γ secretase inhibitor, may be a potential alternative therapy for managing DF [ 20 ]. Further, tumor genotype may also be useful to predict response to therapy and treatment efficacy. For example, CTNNB1 mutation status may help to identify patients who are most likely to benefit from targeted therapy with imatinib [ 21 ]. Similarly, identification of CTNNB1 S45 mutation status may be helpful in predicting treatment efficacy of meloxicam in DF [ 22 ].

Traditionally, DF was managed by surgical resection. However, surgical resection of these tumors may be associated with significant morbidity and mortality. Resection of tumors located close to major neurovascular structures might result in significant functional impairment. Also, optimal removal of intra-abdominal mesenteric DF might warrant extensive surgery, including resection of significant portions of bowel, major vascular structures and adjacent abdominal organs, which may lead to significant postoperative complications. Furthermore, DF has a high incidence of local recurrence (20–39%) [ 50 ]. In view of the unpredictable tumor behavior and the significant morbidity associated with surgery, a more conservative, step-wise approach is currently preferred in the management of DF [ 7 , 8 , 51 ]. Newly diagnosed, asymptomatic DF may be managed with “wait and see” approach. Studies have shown that patients with asymptomatic DF may be initially managed with active surveillance as a significant percentage of these tumors show long term stability without treatment [ 8 , 52 ]. In one study involving 83 DF patients placed on active surveillance, the 5 year progression free survival (PFS) was 50% and the median time to progression (TTP) was 14 months [ 8 ]. Another study reported that 16 out of 27 patients placed on active surveillance had stable disease during a median follow up of 52 months, with a TTP of 19 months [ 52 ]. Further, some of the DF may undergo spontaneous regression. Bonvalot et al. reported that 29 out of 102 patients (28%) with abdominal wall DF had spontaneous tumor regression [ 53 ]. Similarly, another study reported 20% spontaneous regression rate in extra-abdominal wall DF managed non-surgically [ 54 ]. However, treatment should be offered to patients who decline observation. Also, tumors showing interval increase in size and/ or causing symptoms (including those resulting in cosmetic disfigurement) may require active management. Factors associated with a higher risk of post-operative recurrence include large tumor size, younger patient age, and location of the tumors in the extremities and mesentery [ 55 , 56 ]. In general, optimal resection with negative surgical margin should be the primary goal of the surgery for best oncological outcome [ 55 , 57 , 58 ]. However, some studies reported no significant difference in the 5 year PFS in patients with positive versus negative surgical margin [ 56 , 59 , 60 ]. Given these conflicting findings, it is currently unclear if patients with positive surgical margin warrant 2 nd look surgery or can be managed conservatively. Radiotherapy may be useful for unresectable or recurrent DF as well as in patients who are at high risk for surgery [ 61 – 64 ]. Further, adjuvant radiotherapy following surgery may also be considered in DF, especially those with positive surgical margins [ 64 ]. A recent meta-analysis reported that combination of surgery and radiotherapy had a lower local failure rate compared to surgery alone [ 65 ]. However, it has to be noted that radiation therapy is also associated with significant morbidity and hence careful risk versus benefit analysis should be performed and therapeutic doses kept to as low as reasonably possible [ 65 , 66 ]. Another treatment option includes radiofrequency tumor ablation, although this is not well established. Systemic therapy also plays an important part in the management of DF. Various therapeutic agents including anti-estrogenic drugs (tamoxifen and toremifene), non-steroidal anti-inflammatory drugs (meloxicam, indomethacin, sulindac and celecoxib), cytotoxic chemotherapy (doxorubicin, methotrexate and vinblastine) and tyrosine kinase inhibitors (imatinib, sunitinib, pazopanib, sorafenib, sirolimus) have been reported to be useful for achieving disease stability in DF [ 4 , 21 , 55 , 67 – 69 ]. Given the high toxicity profile of some of these agents, patients should be closely monitored for any potential treatment induced complications [ 55 , 70 ]. In summary, DF is a rare, locally aggressive soft tissue tumor with variable tumor behavior. DF may develop at any site but is particularly more common in the extremities, abdominal wall and mesentery. Management of desmoid tumors mandates multidisciplinary approach including watchful waiting, surgery, radiation and systemic therapy. Multimodality imaging including ultrasound, CT and MR is useful in the diagnosis, evaluation of treatment response and surveillance of these tumors.

Abdominal DF: Various pathological processes can result in abdominal wall masses include infection, inflammation, endometriosis, hematoma and neoplasm [ 48 , 49 ]. Clinical history and imaging features are often helpful in narrowing the differential diagnoses [ Table 1 ]. Mesenteric DF: Mesenteric DF typically occurs in patients with history of FAP. However, colorectal cancers in FAP patients can result in mesenteric metastases, mimicking DF. Further, it has to be noted that DF may develop in the mesentery even in patients without a known history of FAP. In such circumstances, other disease processes which can result in mesenteric masses should be considered in the differential diagnoses, including carcinoid tumor, lymphoma, retractile sclerosing mesenteritis, gastrointestinal stromal tumor and mesenteric metastases [ Table 2 ] [ 34 ]. Extra-abdominal DF: Various soft tissue tumors may mimic extra-abdominal DF occurring in extremities, head and neck and trunk. Although the imaging features described previously can help to narrow the differential diagnoses and point towards a preliminary diagnosis of DF, definitive diagnosis requires histopathological confirmation.

Desmoid fibromatosis (DF) is a locally aggressive, deep seated connective tissue malignancy developing in musculoaponeurotic tissues. It is also known as aggressive fibromatosis, deep fibromatosis, musculoaponeurotic fibromatosis and desmoid tumor. DF is a rare tumor, with reported incidence of 2–4 per million population and account for 0.03% of all neoplasms [ 1 , 2 ]. DF most commonly develops between the age of 15 and 60 years, and tends to be more common in females [ 3 ]. DF may affect any site but is commonly seen in the extremities, abdominal wall and abdominal mesentery [ 4 ]. Although DF lacks metastatic potential, it has a high propensity for recurrence. Therefore, DF has now been classified as “intermediate, locally aggressive” tumor in the WHO classification of soft tissue tumors. In the past, DF was typically managed with surgical resection. However, recent advances in the molecular cytogenetics and tumor biology of DF have led to a paradigm shift in the management of this condition. In this article, we illustrate the multimodality imaging features of DF. We also review the etiopathogenesis, molecular cytogenetics, histopathology & clinical features of DF and discuss the recent advances in the management.

Histopathologically, DF is characterized by proliferation of uniform spindle cells resembling myofibroblasts, in the background of abundant collagenous stroma and vascular network [ 23 ]. Histological features such as hyperchromatasia and atypia are absent. Tumor cells are similar to the myofibroblasts seen during the proliferative stage of wound healing. Cells may have nuclei containing euchromatin or heterochromatin [ 24 ]. Large amounts of myxoid stroma may be seen in some tumors, especially those that develop in mesentery. On immunohistochemistry, DF stains positive for nuclear B-catenin, vimentin, cyclooxygenase 2, tyrosine kinase PDGFRb, androgen receptor and estrogen receptor beta but negative for desmin, S-100, h-caldesmon, CD34 and c-KIT [ 25 ].

The etiopathogenesis of DF is not yet clear but is believed to be multifactorial [ 4 – 8 ]. DF may be sporadic or familial in nature. Trauma, pregnancy and use of oral contraceptives have been implicated in the etiopathogenesis [ 4 – 8 ]. DF has a high proclivity to develop at sites of surgical scar, especially in those after cesarean section and intra-abdominal resections ( Fig. 1 ). While pregnancy and use of oral contraceptives have been shown to be associated with development of DF, the exact role of hormonal influence is not fully understood. Although the vast majority of these tumors are sporadic, DF may also be hereditary. Familial DF develops predominantly in patients with familial adenomatosis polyposis (FAP) ( Fig.2 ). Patients with FAP have 1000 fold higher risk of developing DF [ 9 ]. Studies report that DF may be seen in 5–16 % of FAP [ 2 , 6 , 9 , 10 ]. The sporadic tumors occur more frequently in the extra-abdominal location (Fig 3 – 5 ). In contrast, majority of the FAP-associated DF develop intra-abdominally within the mesentery and/ or in the abdominal wall (Fig 2 , 6 – 9 ). Further, FAP-associated DF tends to be larger, multifocal and occur more commonly in the younger patients [ 2 , 6 , 9 , 10 ].