Desmoid Tumors

Desmoid tumors: Epidemiology, risk factors, molecular pathogenesis, clinical presentation, diagnosis, and local therapy Authors Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Sep 2013. | This topic last updated: oct 7, 2013.

INTRODUCTION — Desmoid tumors (also called aggressive fibromatosis, deep musculoaponeurotic fibromatosis, and also formerly termed fibrosarcoma grade I of the desmoid type) are locally aggressive tumors with no known potential for metastasis or dedifferentiation. The term "desmoid" originates from the Greek word "desmos", meaning band or tendon-like, and was first applied in the 1800s to describe tumors with a tendon-like consistency.

Although they lack the capacity to establish metastases, desmoids are locally aggressive and have a high rate of recurrence even after complete resection. Tumor-related destruction of vital structures and/or organs can be fatal, particularly when these tumors arise in patients with familial adenomatous polyposis (FAP, Gardner's syndrome).

This topic review will discuss the epidemiology, risk factors, molecular pathogenesis, clinical presentation, and local treatment options for desmoid tumors. Systemic therapy is discussed elsewhere, as are other miscellaneous benign diseases affecting soft tissue and bone, such as Gorham's disease, desmoplastic fibroma of bone, pigmented villonodular synovitis, keloids and ganglia. (See "Desmoid tumors: Systemic therapy" and "Antineoplastic therapy for miscellaneous benign diseases affecting soft tissue and bone" and "Keloids" and "Ganglia and nodules".)

EPIDEMIOLOGY AND RISK FACTORS — Desmoid tumors are rare; they account for about 0.03 percent of all neoplasms and less than 3 percent of all soft tissue tumors. The estimated incidence in the general population is two to four per million population per year [1].

Individuals between the ages of 15 and 60 are most commonly affected; desmoids are rare in the young and in the elderly. They are slightly more common in women than in men [2], and there is no significant racial or ethnic predilection.

Gardner's syndrome — Most desmoids arise sporadically, although between 5 and 15 percent are associated with familial adenomatous polyposis (FAP) [3,4]. FAP is caused by mutations in the APC (adenomatous polyposis coli) gene, located on chromosome 5q21-q22. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Genetics'.)

The development of desmoid tumors in patients with FAP was first described by Gardner in 1951 and is now designated Gardner's syndrome (image 1). Desmoid tumors affect between 10 to 20 percent of patients with FAP [5-13]. The risk of developing a desmoid in a patient with FAP is 852 times that of the general population [7]. Although extremity desmoids can also occur, most of these patients develop abdominal tumors, one-half of which are intraabdominal, the remainder involving the abdominal wall [13]. Other prominent extraintestinal lesions in these patients include osteomas and cysts. Families have been described who exhibit desmoids as the only manifestation of an APC mutation [14,15]. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Gardner syndrome'.)

Until early elective colectomy became routine in patients with FAP, the dominant cause of death in these patients was carcinoma of the colon at a relatively young age. With the increasing use of prophylactic colectomy, desmoid tumors have become an important cause of morbidity and mortality [16-21]. Desmoids are the cause of death in up to 11 percent of patients with FAP [20,22]. However, progression is often

gradual and approximately 60 percent are still alive 10 years after the diagnosis, some with advanced disease [5,6,21,23].

Prognosis varies according to disease extent, although there is no consensus on the best way to quantify disease extent. (See 'Mortality associated with desmoids' below.) The desmoids that arise in patients with FAP have a particular predilection for surgical sites (eg, the mesentery or abdominal wall following colectomy, the site of an ileal pouch-anal anastomosis), and prior surgery is a risk factor for the development of desmoids in these families [13,16-18,24-27]. In one series, prior abdominal surgery had been performed in 68 percent of patients with FAP and abdominal desmoid tumors; lesions developed within five years after surgery in approximately one-half [25]. One patient in particular dramatically demonstrated this association with surgery. She had been treated, apparently successfully, with chemotherapy for an intraabdominal desmoid tumor. To confirm the response, laparoscopy was performed. Within months, desmoid tumors began developing in each of the three trocar sites; the tumors became massive and inoperable and led to the death of the patient.

The only other described risk factors in these kindreds are a family history of desmoid tumor, pregnancy, and the specific location of the APC mutation (3’ of codon 1444 [13,27]). (See 'APC mutations' below.)

The intraabdominal desmoids that develop in patients with FAP are often unresectable because they diffusely infiltrate the mesentery. Furthermore, recurrences tend to become more frequent and aggressive with each surgical intervention. For these reasons, a multidisciplinary approach that includes systemic therapy is typically required to achieve optimal outcomes for these patients. (See 'Issues specific to intraabdominal desmoids' below.)

Pregnancy — Desmoid tumors have been associated with high estrogen states. Extraabdominal and abdominal desmoids tend to occur in women during or following pregnancy. The classic presentation is that of an abdominal mass that is separate from the uterus [28]. Trauma related to the pregnancy (including a scar from a prior Cesarean section [29]) and exposure to elevated hormone levels may both be contributory, although the evidence linking high estrogen levels and desmoid tumors is largely based on anecdotal and retrospective reports [30]. Subsequent pregnancy is not necessarily a risk factor for recurrence or development of new disease in a woman with a pregnancy-related desmoid, although the data are quite limited (three cases described in which there was no recurrence with subsequent pregnancy) [31,32].

Antecedent trauma — Desmoid tumors have also been associated with episodes of antecedent trauma. Up to 30 percent of patients with desmoid tumors have a history that involves antecedent trauma [33,34], particularly, as noted above, surgical trauma in patients with FAP. A similar relationship has been observed in some sporadically occurring desmoid tumors. In one series, an antecedent history of trauma at the tumor site was elicited in 28 percent of 32 primary desmoid tumors [35].

The association between antecedent trauma and the development of desmoids is particularly compelling in view of emerging data implicating a molecular connection between wound healing processes and fibroproliferative disorders of mesenchymal tissue. (See 'Etiology and molecular pathogenesis' below.)

ETIOLOGY AND MOLECULAR PATHOGENESIS — The etiology of desmoid tumors is unknown. However, the identification of clonal chromosomal changes in a significant fraction of cases supports the neoplastic nature of these tumors [36,37]. In addition, as noted above, emerging evidence implicates dysregulated wound healing in the pathogenesis of these and other fibroblastic lesions.

Understanding molecular pathogenesis is of considerable interest in this disease given its highly variable clinical course. Lesions can range from stable or spontaneously regressing to slow growing to rapidly progressive with varying propensity to recur after definitive therapy. Identifying the molecular aberrations

that predict the clinical course can be very useful from a therapeutic standpoint and is a subject of active investigation.

The molecular events that lead to desmoid tumor formation are incompletely understood. However, increasing evidence points to involvement of the APC gene and beta-catenin (both components of the Wnt signaling pathway) in the molecular pathogenesis of desmoids both in Gardner’s syndrome as well as in sporadic desmoids [38]. Desmoids in FAP arise from APC inactivation and subsequent accumulation of beta-catenin in cells [39]. In contrast, APC mutations are uncommon in sporadic desmoids, which usually arise from mutations in the gene for beta-catenin, CTNNB1 [38,40].

Wnt/beta-catenin pathway and its role in desmoid tumors — The Wnt/beta-catenin signaling pathway is thought to play a key role in the molecular pathogenesis of desmoid tumors, both those associated with FAP, and sporadic tumors. The basic features of the Wnt signaling pathway are depicted in the figure (figure 1).

Beta-catenin plays an active role in transcription within mesenchymal cells [41]. The adenomatous polyposis coli (APC) complex tightly regulates levels of beta-catenin in the cell by phosphorylation, which results in destruction of beta-catenin in the proteosome. Activation of the Wnt pathway initiated by binding of an external ligand causes inhibition of the kinase activity of the APC complex resulting in greater levels of beta-catenin in the cell. This non-phosphorylated beta-catenin translocates to the nucleus where it acts with other proteins to activate the transcription of genes such as CYCD1 and MYC, thereby promoting proliferation and enhanced survival [42]. Mutations in either the APC gene or the beta-catenin gene (CTNNB1) can result in dysregulation of the levels of beta-catenin in the cell that leads to its accumulation in the nucleus.

The importance of the Wnt signaling pathway to the molecular pathogenesis of fibroblastic tumors such as desmoids is suggested by the following observations:

Somatic APC mutations as well as activating mutations of CTNNB1 (both of which result in accumulation of beta-catenin) have been discovered in the majority of sporadic desmoids [43-47].

Beta-catenin protein levels and tcf transcriptional activity are elevated in fibroblasts during the proliferative phase of wound healing [45,48,49].

In preclinical models, stabilization of intracellular beta-catenin leads to dysregulation of mesenchymal cell proliferation, motility and invasiveness, and in transgenic mice, induces the development of desmoid tumors [45].

It is hoped that the elucidation of the central role of beta-catenin in the pathogenesis of desmoid tumors will lead to future therapeutic advances targeting this molecule [50].

APC mutations — A normal APC protein prevents the accumulation of beta-catenin, a cytosolic and nuclear protein, by mediating its phosphorylation and resultant degradation. The majority of germline as well as sporadic mutations in the APC gene lead to premature truncation of the APC protein and loss of the beta-catenin regulatory domain. This allows beta catenin to accumulate, bind to, and activate the transcription factor tcf-4 [39]. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Genetics'.)

Mutations of the APC gene on chromosome 5q are responsible for FAP. More than 300 mutations have been described, most of which lead to frame shifts or premature stop codons, resulting in a truncated APC gene product. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Genetics'.)

As noted above, between 10 and 20 percent of patients with FAP develop a desmoid tumor. This variant of FAP is referred to as Gardner’s syndrome. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Gardner syndrome'.)

Although desmoids can occur with mutations in any APC gene location, the specific location of the mutation within the APC gene seems to correlate with the occurrence of desmoid tumors in patients with FAP [51]. In general, desmoid tumors occur more frequently when mutations are in the 3' end of the APC gene, specifically between codons 1445 and 1580 [11,27,51-56]:

In one series of 36 patients from 20 families with FAP and mutations in codons 1445 to 1578, all developed desmoid tumors with the exception of three prepubertal children [53].

In another study of 953 FAP patients from 187 families, mutations between codons 1310 and 2011 were associated with a sixfold risk of desmoid tumors relative to the low-risk reference region (159 to 495) [54].

Another study of 269 patients found that desmoid tumors were present in 61 percent of patients with mutations between codons 1445 and 1580 compared with 18 percent of patients with mutations at sites 3' to that region [55].

How the abnormal gene that is responsible for FAP promotes the formation of tumors such as desmoids is incompletely understood. However, increasing evidence points to involvement of the APC gene and beta-catenin (both components of the Wnt signaling pathway) in the molecular pathogenesis of inherited desmoids (Gardner's syndrome) as well as in sporadic cases [40,57]. Sex hormones may also be actively involved in this process [58].

Mutations in the beta-catenin gene — Mutations in CTNNB1 have been found in sporadic desmoid tumors with variable prevalence (39 to 87 percent); however, larger and more recent studies place the prevalence estimate at around 85 percent [42]. CTNNB1 gene mutations are therefore the most common route of Wnt pathway activation in desmoids. Phosphorylation of beta-catenin is mediated by a portion of the protein encoded by exon 3 of CTNNB1 gene. Three specific mutations are encountered in desmoid tumors: T41A, S45F and S45P. At least some data suggest that S45F mutations are associated with a higher rate of recurrence after surgical resection of a primary desmoid tumor [59].

Sporadic tumors and trisomy 8 and 20 — Other genetic aberrations have been described in sporadic desmoids. As an example, nonrandom clonal chromosomal changes, particularly trisomy 8 and/or 20, occur in one-third or more of sporadic desmoid tumors [60-64]. Similar nonrandom genetic aberrations have been found in benign fibrous bone lesions (such as fibrous dysplasia), suggesting a similar pathogenesis [62]. Although the clinical relevance of these genetic abnormalities is unclear, their presence has been associated with a higher risk of local recurrence in some reports [60,61].

The finding of individual trisomies and their association in the same cell is rare in solid tumors, particularly mesenchymal tumors [62,63]. However, these aberrations are known to occur in related benign, fibrous lesions arising in both soft tissue and bone tumors (eg, Dupuytren's contracture, plantar fibrosis, Peyronie's disease, carpal tunnel syndrome and infantile fibrosarcoma) [62-64]. Trisomy 8 is also a frequent finding in hematologic malignancies but is remarkably infrequent in nonfibrous solid tumors.

CLINICAL PRESENTATION AND DIAGNOSIS — Most desmoid tumors present as a deeply seated painless or minimally painful mass with a history of slow growth. Intraabdominal desmoids can present with intestinal obstruction, bowel ischemia, or functional deterioration in an ileoanal anastomosis (typically in a patient who has undergone colectomy for FAP [16-18]).

Desmoid tumors can develop at virtually any body site, but three main anatomic sites are described: trunk/extremity, abdominal wall, and intraabdominal (bowel and mesentery). In patients with FAP, intraabdominal desmoids predominate. (See 'Gardner's syndrome' above.)

In non-FAP-associated cases, the most commonly involved areas are the shoulder girdle, hip-buttock region and the extremities, where the location is usually deep in the muscles or along fascial planes [33]. Desmoid tumors may be multifocal at one site (typically the extremity [65]), but they rarely occur at different regions in the same patient.

Breast desmoids — Desmoid tumors are an unusual cause of a breast mass, and they may be mistaken for a primary or recurrent breast cancer. Many patients have a history of breast cancer or breast surgery. In a series of 32 patients with a breast desmoid, eight (25 percent) had a previous history of breast cancer, and 14 (44 percent) had prior breast surgery [66]. All patients had a palpable mass, which was seen on mammography in six of 16 and MRI in all eight patients who had the test. Following resection, eight (29 percent) had a recurrence at a median of 15 months, and there was a trend toward more local recurrences in the setting of positive margins (5 of 9 versus 3 of 19 with negative margins) [66]. (See 'Local recurrence and the importance of resection margins' below.)

The spectrum of molecular abnormalities seen in breast desmoids is similar to that described for desmoid tumors of the abdomen, trunk and extremities [46].

Radiographic studies — Cross-sectional imaging of the affected area with CT or MRI is needed to define the relationship of the tumor to adjacent structures in order to assess resectability and the need for treatment. There are no radiographic characteristics that can reliably distinguish desmoids from malignant soft tissue tumors. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Radiographic studies'.)

Although desmoids can be adequately evaluated by CT (image 1), we prefer MRI, especially for truncal and extremity tumors. MRI characteristics of desmoid tumors are variable and relate to their cellularity and fibrous content. Desmoids may be hypointense or isointense to muscle on T1-weighted images; they are predominantly hyperintense on T2-weighted images, but hypointense bands may be seen that represent dense collections of collagen bundles [67]. T2 hyperintensity may diminish over time as tumor cellularity decreases and collagen deposition increases [68]. With the administration of gadolinium, desmoids typically show moderate to marked enhancement, and the hypointense bands may become more apparent because collagen bundles are not enhanced by contrast material [69].

Histologic diagnosis — The diagnosis of a desmoid tumor can only be established by histological examination of a biopsy specimen. Incisional biopsy generally yields more tissue than a core needle biopsy to help distinguish between a benign and malignant process. However, in the hands of experienced pathologists, tissue from a core biopsy may be sufficient to make the diagnosis.

Histologically, desmoids are characterized by a monoclonal [70] fibroblastic proliferation appearing as small bundles of spindle cells in an abundant fibrous stroma. The fibroblasts have a propensity to concentrate at the periphery of the lesion, and the cellularity is low. The infiltrative connective tissue process may resemble that of a low-grade fibrosarcoma, but the cells lack nuclear and cytoplasmic features of malignancy. There are usually few mitotic figures and necrosis is absent. Histologically, sporadic and FAP-associated desmoids are indistinguishable.

Immunohistochemistry may aid the histologic diagnosis. The spindle cells usually stain for vimentin and smooth muscle actin and nuclear beta-catenin but are generally negative for desmin, cytokeratins, and S-100. (See 'APC mutations' above and 'Mutations in the beta-catenin gene' above.)

Nuclear beta-catenin immunoreactivity supports the diagnosis of a desmoid tumor; positive staining was identified in 80 and 67 percent of sporadic and FAP-associated desmoids in one large series [71]. However, it is not definitive because other entities (superficial fibromatoses, low grade myofibroblastic sarcomas, solitary fibrous tumors) also stain for nuclear beta-catenin [71]. Furthermore, beta-catenin negativity does not preclude the diagnosis of fibromatosis.

Staging — There is no need to obtain staging radiographic studies of any other site because desmoids lack the propensity for regional or distant spread.

There is no commonly used or agreed upon staging system for desmoids. The 7th edition of the American Joint Committee on Cancer (AJCC) TNM staging system for soft tissue sarcomas specifically excludes desmoids. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Staging'.)

A novel classification for staging intraabdominal desmoids in patients with FAP has been developed, but is not in widespread use. Its prognostic utility is unclear. (See 'Mortality associated with desmoids' below.)

Endoscopy — Given the association of desmoids and FAP, it is important to obtain an accurate family history, particularly of colon cancer, during the initial evaluation. At some institutions, colonoscopy is recommended for all patients diagnosed with a desmoid tumor, particularly an intraabdominal desmoid. (See 'Gardner's syndrome' above.)

NATURAL HISTORY — Desmoids are characterized by variable clinical behavior. Although most grow progressively larger over time, growth is indolent, and periods of growth arrest are not uncommon. The following data are available regarding the natural history of untreated desmoids:

In a series of 54 patients with a primary or recurrent desmoid who were not treated initially with surgery, radiotherapy (RT), or systemic therapy, the five-year progression-free survival rate was 50 percent [72].

In a second report, 27 patients with newly diagnosed sporadic desmoids underwent initial attentive medical surveillance rather than active therapy [73]. Patients were chosen for this approach according to the site of progression, which could not be life-threatening or at risk for mutilation (adjacent nerves or vessels). At a median follow-up of 52 months, only six progressed (22 percent). Sixteen patients had stable disease and five had spontaneous tumor regression.

These data suggest that an initial “wait and see” approach to therapy is a reasonable option for some patients, although the features that identify those patients at low risk of disease progression are not established. (See 'Treatment' below.)

The factors suggested to influence disease recurrence rate are anatomic site of disease (tumors of the extremity have the worst prognosis, particularly in distal locations; trunk/abdominal wall tumors have a lower rate of recurrence than either intraabdominal or extraabdominal disease sites [74]), size (particularly >7 cm [73]), gender (women have a higher rate of local recurrence than men), and age (younger patients [under age 37 in one series [73]] have a higher recurrence rate than older individuals) [2,73,75]. The influence of positive resection margins is controversial and discussed below. (See 'Local recurrence and the importance of resection margins' below.)

How these factors should be used to select treatment is unclear.

Molecular markers of biologic behavior — Emerging data suggest that specific molecular factors (such as specific mutations within the beta-catenin gene) may correlate with recurrence risk [59,76,77]. In a study of

gene expression profiles of 14 patients with sporadic desmoids, expression of the midkine gene was correlated with a higher likelihood of recurrence and shorter time to recurrence [78]. However, this work is in its infancy, and validation in a prospective clinical trial will be necessary prior to clinical application.

Mortality associated with desmoids — Despite being histologically benign and neither associated with the capacity for metastatic spread nor malignant degeneration into a fibrosarcoma, desmoids are locally infiltrative and can cause death via destruction of adjacent vital structures and organs. Most centers report a cause-specific mortality rate of 1 percent or less in patients with desmoid tumors at other than intraabdominal sites [79-81]. As an example, in a report of 189 patients treated for a desmoid tumor at M. D. Anderson from 1995 to 2005 and followed for a median 63 months, only five died, four of non-desmoid causes [81].

Desmoids are more often fatal in patients with intraabdominal tumors, particularly in the setting of FAP. As noted above, desmoids are the cause of death in up to 11 percent of patients with this syndrome [20].

The factors that influence survival have not been well characterized, particularly for sporadic tumors. A prognostic stratification system for FAP-associated desmoids has been proposed that was derived from a series of 154 such patients seen at the Cleveland Clinic; five-year survival rates according to stage were as follows [21]:

Stage I (asymptomatic, <10 cm maximum diameter and not growing) – 95 percent

Stage II (mildly symptomatic [sensation of mass or pain but no restriction], <10 cm in maximum diameter, and not growing) – 100 percent

Stage III (moderately symptomatic [sensation of mass, pain, restrictive but not hospitalized], or bowel/ureteric obstruction, or 10 to 20 cm or slowly growing) – 89 percent

Stage IV (severely symptomatic [sensation of mass, pain, restrictive and hospitalized], septic complications such as fistula and abscess, or >20 cm and rapidly growing) – 76 percent

The prognostic value of this proposed staging system has not been independently validated. Treatment was variable within each group. With median follow-up ranging from 44 to 81 months depending on the group, there were no deaths among patients with stage I or II disease, while four patients with stage III disease (15 percent) and eight of those with stage IV disease (44 percent) died from their desmoids.

TREATMENT — The locally aggressive nature of desmoid tumors renders anatomic site the major factor in treatment planning and overall management strategy.

Initial observation — Desmoids have an unpredictable clinical course, and close observation is an acceptable strategy for stable, asymptomatic primary or recurrent desmoids, particularly if resection would entail major morbidity [30,72,73,82]. In one series of 142 patients presenting with a primary (n = 74) or recurrent (n = 68), 83 were treated with observation only, while 59 were initially offered medical therapy (hormone therapy or chemotherapy) [72]. The five-year progression-free survival rate was 50 versus 41 percent for the observation and medically-treated patients, respectively. (See 'Natural history' above.)

Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) suggest that patients with desmoid tumors can be followed carefully if the tumors are small and not located on the trunk, and if surgery would lead to excessive morbidity [83].

Treatment of an extraabdominal desmoid is indicated for symptomatic patients, and patients with progressively enlarging tumors irrespective of symptoms, if there is imminent risk to adjacent structures or if the tumor creates cosmetic concerns.

Surgery — When medically and technically feasible, desmoid tumors are treated by surgical resection with a negative margin [79,84]. Complete resection of the tumor with negative microscopic margins is the standard surgical goal but is often constrained by anatomic boundaries and the infiltrative nature of desmoids.

Due to the size and infiltrative nature of extraabdominal desmoids, resection may require skin grafting or flap reconstruction. Resection of abdominal wall desmoids may require reconstruction of the abdominal wall to close the defect and minimize the risk of hernias. Intraabdominal desmoid tumors typically involve the mesentery, and resection generally requires concomitant bowel resection. During resection, the surgeon must take care not to compromise the superior mesenteric artery or vein. Given the propensity of desmoids to recur, reconstruction should allow for the possibility of future resections and reconstructions.

Desmoid tumors have a high rate of recurrence following even complete surgical removal, and the contribution of incomplete resection to local recurrence rates is unclear. Furthermore, resection does not appear to affect survival, which is not surprising in view of the histologically benign nature of desmoids. Given these issues, the overall surgical strategy should be an attempt at complete removal using function-preserving surgical approaches to minimize major morbidity (functional and/or cosmetic).

Local recurrence and the importance of resection margins — The relationship between surgical margin status and local recurrence rates is unclear, as evidenced by the following:

Even patients who undergo aggressive resection with widely negative margins have recurrence rates of 16 to 39 percent [75,79,81,85-89].

While some series show higher recurrence rates with close or positive resection margins [24,75,79,86,88-90], many report that the risk of recurrence is independent of margin status [49,74,81,91-94]. In one of the largest series of 426 newly diagnosed desmoid tumors, 370 had initial surgical resection, and 252 had histologic assessment of surgical margins [73]. The two and five-year progression-free survival rates for the 110 patients with microscopically complete (R0) resection (77 and 63 percent) were not significantly different from those of the 107 patients with a microscopically positive (R1) resection margin (74 and 61 percent), but they were markedly lower among the 37 patients with a macroscopically positive (R2) resection margin (43 and 22 percent). Similar findings have been noted in other large series [81,91].

These data, combined with the fact that recurrence only develops in fewer of one-half of those with positive margins [89], have led some to conclude that aggressive attempts to achieve negative resection margins are not warranted if they result in excessive morbidity [30,49,89,95]. Moreover, uncertainty as to the importance of positive resection margins has led to controversy with regard to the utility of postoperative RT for patients with incompletely resected disease. These data are discussed below.

Radiation therapy — RT is an effective primary therapeutic option for desmoid tumors in patients who are not good surgical candidates, those who decline surgery, and those for whom surgical morbidity would be excessive. The time to regression after RT alone is often quite long and several years may elapse before regression is complete [96,97].

In a number of reports, RT alone (50 to 60 Gy) or combined with surgery in patients with incomplete resection achieves long-term local control in approximately 70 to 80 percent of desmoids [85,86,93,97-106]. The volume of disease does not appear to influence the probability of local control.

The contribution of primary RT to the management of desmoid tumors can be illustrated by the following reports:

One report included 107 patients with desmoid tumors who were treated with surgery alone (n = 51), RT alone (n = 15), or surgery followed by RT (n = 41) [86]. The five-year actuarial local control rates were 69, 93, and 72 percent in the three groups, respectively. The five-year rate of local control with surgery alone was 50 percent (three of six) if gross residual disease was left behind, 56 percent for microscopically positive margins, and 77 percent for negative margins. In contrast, local control was achieved in all five patients treated with RT alone for a primary tumor and in 9 of 10 treated at the time of recurrence.

Similar conclusions were reached in a comparative review of published experience with treatment of desmoid tumors [85]. Local control rates after surgery alone (n = 381) were 61 percent overall, and they were 72 and 41 percent for those with negative or positive margins, respectively. For patients undergoing surgery plus RT (n = 297), the local control rate was 75 percent overall, and it was 94 and 75 percent for cases with negative and positive margins, respectively. The overall local control rate for RT alone (n = 102) was 78 percent, and it was 83 and 73 percent for those treated for primary or recurrent tumors, respectively.

Remarkably similar local control rates (81 percent at three years) were noted in a pilot phase II trial of moderate dose RT (56 Gy) in 44 patients with inoperable progressive primary, recurrent, or incompletely resected desmoid tumors [97].

It can be concluded from these data that despite their non-metastatic nature, desmoids are radiosensitive tumors. Although RT is an option for nonsurgical definitive therapy of desmoids, its use must be balanced against the potential for late radiation effects such as secondary malignancies, particularly in younger patients, and RT-related fibrosis. In general, primary RT could be considered an appropriate option for patients who are symptomatic or otherwise in need of treatment, who are not good surgical candidates, or decline surgery, and those for whom surgical morbidity would be excessive.

The recommended dose of RT for definitive therapy is 50 to 60 Gy in five to seven weeks at 1.8 to 2 Gy per fraction. Local recurrence rates do not appear to be reduced by the use of higher doses [93]

Postoperative RT — There are no data to support the use of RT in the adjuvant setting after complete surgical resection, and it is generally not recommended [86,107].

The utility of postoperative RT for patients with positive resection margins is controversial for the following reasons:

While improved recurrence-free survival in patients with irradiated microscopically margin-positive tumors was shown in an early report from M. D. Anderson [79], a large series from Massachusetts General Hospital [86], and a comparative review of published experience with treatment of desmoid tumors [85], at least three other large series (including a later cohort of patients treated at M. D. Anderson) have failed to demonstrate benefit from RT in this setting [49,81,91].

As noted previously, the status of the resection margins has not consistently been shown to correlate with the risk of recurrence [49,81,91-94,108]. Even in those series that show a higher rate of recurrence in patients with positive margins in the absence of RT, recurrence is not inevitable in patients with positive resection margins [86,109]. Furthermore, successful salvage therapy at the time of recurrence has been possible in the majority of patients, particularly those with extremity or truncal tumors. (See 'Management of recurrent disease' below.)

The potential for late radiation effects such as secondary malignancies is of concern, particularly in younger patients.

From these data, many clinicians conclude that deferring RT is an acceptable option for patients with microscopically positive margins as long as local progression, if it occurred, would not risk significant morbidity. However, we and others recommend postoperative RT for patients with gross or macroscopic

residual disease after initial resection, as well as for those with microscopically positive margins after resection of recurrent disease [110]. (See 'Management of recurrent disease' below.)

Others disagree with this approach, advocating postoperative RT regardless of the surgical margins (or RT alone) because of the importance of local control to cure of this nonmetastatic condition. [85]. Guidelines from the NCCN suggest that postoperative RT be considered in patients with a large tumor, although they provide no definition for what constitutes a "large" tumor [83].

Neoadjuvant RT — One approach to increasing resectability and reducing rates of local recurrence in extraabdominal desmoids is the use of neoadjuvant (preoperative) radiotherapy. Experience with this approach is limited:

In the largest report, 58 patients underwent preoperative RT and were followed for a median of 69 months [111]. There were 11 local recurrences (19 percent), and two patients had major wound complications (3.4 percent). This wound complication rate was lower than the authors' historical experience with a similar preoperative RT dose and schedule for soft tissue sarcomas, leading them to speculate that patients with fibromatosis might have an inherent wound healing advantage over those with soft tissue sarcoma.

In two other small series from the same institution, a total of 43 patients with potentially resectable desmoid tumors received doxorubicin 30 mg by continuous infusion daily for three days concurrent with RT (10 x 3 Gy fractions); resection was performed four to eight weeks later [112]. In the later study, 16 of 30 patients received one year of postoperative therapy with high-dose tamoxifen and an NSAID [113]. With a median follow-up of 71 and 45 months in the two studies, respectively, there were only five local recurrences (11 percent).

While these results are promising, confirmation with larger, prospective, randomized trials is needed before this approach can be considered standard.

Neoadjuvant systemic therapy — The concept of using systemic therapy with or without RT to reduce tumor size/bulk prior to an attempt at surgical resection of desmoid tumors is relatively new, and there are few data on the utility of this approach. However, interest in multimodality approaches to avoid debilitating local therapy is increasing [113], particularly in view of the demonstration that several chemotherapy regimens are active, at least in the setting of advanced disease. (See "Desmoid tumors: Systemic therapy".)

At least some data suggest that the improved outcomes seen in contemporary series of patients treated for desmoid tumors might be at least partly attributable to the increased use of multimodality therapy applied both in the neoadjuvant and adjuvant setting [81]. However, no prospective data are available. Further experience with neoadjuvant systemic therapy is needed in order to address optimal patient selection criteria and the best way to sequence surgery, systemic therapy, and RT.

Issues specific to intraabdominal desmoids — Intraabdominal desmoids are less often resectable than are extraabdominal and abdominal wall desmoids. Surgery may be difficult and even impossible for intraabdominal desmoids, particularly when they arise in the setting of FAP, although it is an important option for selected patients [5,114,115]. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Gardner syndrome'.)

The intraabdominal desmoids that develop in patients with FAP are often unresectable because they diffusely infiltrate the mesentery and are often multiple. Morbidity after attempted resection, which often necessitates removal of part of the small intestine, is substantial and includes bowel ischemia, adhesions and resultant obstruction, and fistula formation [116]. Moreover, the rate of recurrence is high after attempted resection, and the recurrent disease is often more aggressive than the initial desmoid [19,23,80].

In one report, as an example, tumor debulking led to aggressive progression of desmoids in four of six patients [19].

These observations have led the American Society of Colon and Rectal Surgeons and a joint task force of the American Society of Clinical Oncology/Society of Surgical Oncology to advocate conservative management rather than initial resection for patients with Gardner's syndrome and intraabdominal desmoid tumors that are large, slow-growing, involve the mesentery, or encase vessels and/or organs [117,118].

At many institutions, a multimodality approach that includes initial medical therapy is preferred for these patients [119,120]. Options for systemic therapy include noncytotoxic therapy (a nonsteroidal antiinflammatory agent [NSAID], tamoxifen), radiation therapy, targeted therapy with imatinib, or cytotoxic chemotherapy. (See "Desmoid tumors: Systemic therapy", section on 'Management of desmoid tumors in FAP patients'.)

POSTTREATMENT SURVEILLANCE — There are no evidence-based protocols for surveillance following treatment. We typically follow patients by clinical examination and radiographic studies (where appropriate) every six months for the first three years, every 12 months to year 6, and then every other year. Consensus-based guidelines from the NCCN suggest a history and physical examination with appropriate imaging every three to six months for two to three years, then annually [83].

MANAGEMENT OF RECURRENT DISEASE — Successful salvage therapy is possible in the majority of patients who have a local recurrence [79,85,98,121]. If it is feasible and can be carried out using a function-preserving approach, surgical resection is preferred for a recurrent extraabdominal desmoid tumor. We recommend postoperative RT if the margins are positive.

However, RT alone is a reasonable alternative due to the higher morbidity of repeat operation and the increased probability of positive margins. In a comparative review of the literature, the overall local control rate for RT alone (n = 102) was 78 percent, and it was 83 and 73 percent for those treated for primary or recurrent tumors, respectively [85]. In one series, local control was achieved in all 9 of 10 patients receiving RT for recurrent desmoid [86].

Patients who develop a recurrence in a previously irradiated area where successful surgical salvage is not possible can be treated with systemic therapy. Cytotoxic and non-cytotoxic agents can be considered for treatment based upon the clinical setting and symptoms experienced by the patient (algorithm 1). (See "Desmoid tumors: Systemic therapy".)

FAP patients — The decision to proceed with surgery in patients with recurrent intraabdominal desmoid in the setting of FAP is more difficult. Recurrences can become more frequent and aggressive with each surgical intervention. Optimal management must be individualized depending on symptomatology and the clinical circumstances. For most of these patients, initial medical therapy is a reasonable approach. (See "Desmoid tumors: Systemic therapy".)

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(See "Patient information: Familial adenomatous polyposis (The Basics)".)

SUMMARY AND RECOMMENDATIONS — Desmoid tumors (also called aggressive fibromatosis) are benign, slowly growing fibroblastic neoplasms with no metastatic potential but a propensity for local recurrence, even after complete surgical resection. Despite being histologically benign, they are locally infiltrative and can cause death through destruction of adjacent vital structures and organs. (See 'Introduction' above.)

The risk of desmoids is increased in patients with familial adenomatous polyposis (FAP). The occurrence of desmoid tumors in the setting of FAP is designated Gardner's syndrome. Given the association with FAP, at some institutions, colonoscopy is recommended for all patients with desmoid tumors, particularly intraabdominal. (See 'Gardner's syndrome' above.)

Treatment of desmoids is a clinical challenge, particularly in patients with FAP who tend to develop intraabdominal desmoids at sites of prior surgery. Because of their locally aggressive behavior and tendency to relapse with more aggressive disease, multimodality treatment is often required for these benign lesions and is best delivered within the context of a multidisciplinary team specializing in sarcoma treatment.

Treatment — The natural history of desmoid tumors is prolonged, variable, and unpredictable, and it is not clear that any intervention improves survival. (See 'Natural history' above.)

Extraabdominal and abdominal wall tumors

Observation is an appropriate option in asymptomatic patients who may be reliably followed. If desmoids remain unchanged or shrink, observation may be continued. If the tumor increases in size or becomes symptomatic, if there is imminent risk to adjacent structures, or if the desmoid creates cosmetic concerns, treatment should be pursued. (See 'Initial observation' above.)

We suggest complete surgical excision as the treatment of choice for a potentially resectable extraabdominal (extremity, trunk, breast) or abdominal wall desmoids in a patient who is medically able to tolerate surgery and if resection can be accomplished without major functional or cosmetic deficit (Grade 2B). Controversy remains as a number of patients will fare well without surgical intervention, so a more conservative approach appears rational for relatively static lesions. (See 'Surgery' above.)

Primary radiation therapy (RT) is an appropriate option for patients who need treatment but are not good surgical candidates, those who decline surgery, and those for whom surgical morbidity would be excessive. An alternative approach is initiation of systemic treatment in these patients, especially if they are young and there are concerns about the potential for late toxicity from RT. (See 'Radiation therapy' above.)

We recommend not pursuing adjuvant RT in patients with microscopically negative surgical margins, regardless of tumor size (Grade 1C). We suggest not pursuing adjunctive RT following resection of a primary desmoid tumor with microscopically positive margins (Grade 2C). Since fewer than 50 percent of these patients will develop a recurrence, patients who remain progression-free will be spared the long-term sequelae of RT. (See 'Postoperative RT' above.)

For gross residual disease of a primary desmoid, we suggest observation or RT rather than more radical resection (Grade 2B). Due to the very high local control rates with RT, additional surgery is warranted only if there is strong confidence in obtaining clear margins, and functional loss is minimal and acceptable.

For a recurrent desmoid tumor, our preference is observation or surgical resection. However, systemic therapy or RT alone are reasonable alternative treatments in selected patients who are thought to have a higher morbidity from repeat operation and an increased probability of positive margins. For patients who undergo surgery for a recurrent desmoid, we suggest observation or postoperative RT if the margins are positive (Grade 2C). (See 'Management of recurrent disease' above.)

Intraabdominal desmoid, Gardner's syndrome

For patients who have large intraabdominal desmoid tumors, particularly in the setting of Gardner's syndrome, surgery is still a standard approach for resectable tumors. However, the infiltrative nature of the desmoid in this situation often precludes surgery, and the surgical margins are often positive. Medical therapy in lieu of surgery is a viable option for patients with more difficult tumors such as those involving the mesentery, major vessels, or other critical structures. (See 'Issues specific to intraabdominal desmoids' above and "Desmoid tumors: Systemic therapy".)

Surgery with or without RT is an appropriate option if there is no response to medical therapy. In this situation, consideration should be given to use of intraoperative electron beam therapy as a component of the treatment [122].

Management of recurrence of an intraabdominal tumor in patients with Gardner's syndrome is challenging because recurrences tend to become more frequent and aggressive with each surgical intervention. Most of these patients are managed with systemic therapy rather than additional local measures. (See 'Management of recurrent disease' above and "Desmoid tumors: Systemic therapy".)

Posttreatment surveillance

There is no standard protocol for follow-up of patients with desmoid tumors. However, we typically follow patients by clinical examination and radiographic studies (where appropriate) every six months for the first three years, every 12 months to year 6, and then biannually. (See 'Posttreatment surveillance' above.)

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