Version May 2024
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 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 ganglion cysts. (See "Desmoid tumors: Systemic therapy" and "Treatment for tenosynovial giant cell tumor and other benign neoplasms affecting soft tissue and bone" and "Keloids and hypertrophic scars" and "Ganglion cysts of the wrist and hand".)
EPIDEMIOLOGY AND RISK FACTORS — Desmoid tumors are rare; they account for approximately 0.03 percent of all neoplasms and fewer 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 older adults. They are slightly more common in females than in males [2], and there is no significant racial or ethnic predilection.
Familial adenomatous polyposis and Gardner syndrome — Most desmoids arise sporadically, although between 5 and 15 percent are associated with familial adenomatous polyposis (FAP) [3-5]. FAP is caused by mutations in the APC (adenomatous polyposis coli) gene, located on chromosome 5q21-q22. Given that most desmoids that occur in the setting of FAP are abdominal (intra-abdominal or abdominal wall [6]), some authors recommend screening for FAP (colonoscopy, genetic screening) in patients with intra-abdominal or truncal desmoid tumors [5]. However, the chance of discovering FAP in patients who develop a desmoid without a prior history of FAP is relatively low (4 to 5 percent in two separate series [5,7]), and in our view, this does not justify screening for FAP in all individuals with an intra-abdominal or truncal desmoid tumor.
Screening might be more useful in the setting of multiple desmoids, which seem to cluster in the FAP group. We and others restrict screening for FAP to an "enriched population" of individuals with desmoid tumors who have a higher risk of having FAP because of age <40 years (11 percent yield), intra-abdominal or retroperitoneal tumors (5.4 percent yield), multifocal disease (29 percent yield), and family history (8 percent yield) [7]. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Genetics' and 'Endoscopy' below.)
The development of desmoid tumors in patients with FAP was first described by Gardner in 1951 (image 1). Desmoid tumors affect between 10 to 20 percent of patients with FAP [6,8-15]. The risk of developing a desmoid in a patient with FAP is 852 times that of the general population [10]. Although extremity desmoids can also occur, most of these patients develop abdominal tumors, one-half of which are intra-abdominal, the remainder involving the abdominal wall [6]. Other prominent extraintestinal lesions in these patients include osteomas and dermoid cysts. Families have been described who exhibit desmoids as the only manifestation of an APC mutation [16,17].
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 [18-23]. Desmoids are the cause of death in up to 11 percent of patients with FAP [22,24]. However, progression is often gradual and approximately 60 percent are still alive 10 years after the diagnosis, some with advanced disease [8,9,23,25].
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 [6,18-20,26-29]. 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 [27]. One patient in particular dramatically demonstrated this association with surgery. She had been treated, apparently successfully, with chemotherapy for an intra-abdominal 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 [6,29]). (See 'Adenomatous polyposis coli (APC) mutations' below.)
The intra-abdominal 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 'Intra-abdominal desmoids' below.)
Pregnancy — Desmoid tumors have been associated with high estrogen states. Extra-abdominal and abdominal desmoids tend to occur in females during or following pregnancy. The classic presentation is that of an abdominal mass that is separate from the uterus [30]. Trauma related to the pregnancy (including a scar from a prior Cesarean section [31]) 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 [32].
If a woman had a desmoid arise during a prior pregnancy and the desmoid was resected, the recurrence risk during future pregnancies is low. If a woman had an existing desmoid (pregnancy associated or predating any pregnancy) that was managed with watchful waiting, that desmoid can grow during a subsequent pregnancy, but not always. The risk to the pregnancy is very low, and the course of the pregnancy may be relatively normal.
The best data on sporadic desmoids developing during or shortly after pregnancy, and the natural history of females with a history of desmoid fibromatosis prior to conception come from a multi-institutional retrospective series of 92 females with both desmoids and pregnancy; 44 (48 percent) had a pregnancy-related desmoid (diagnosed during pregnancy [n = 24] or within six months of delivery [n = 20]), while 48 (52 percent) had a history of desmoid tumor previously diagnosed before conception and either still in situ (n = 29, including previous partial resection) or completely resected (n = 19) [33]. Initial treatment was resection in 48 percent, medical therapy (cytotoxic chemotherapy with any regimen of agents, antiestrogens or luteinizing hormone releasing hormone inhibitors, other hormonal therapy, anti-inflammatory drugs, and targeted biologic therapy) in 9 percent, and watchful waiting in 43 percent. The following were noted:
●Pregnancy-associated desmoid fibromatosis is associated with good outcomes overall.
●No obstetric complications were directly attributable to the presence of desmoid fibromatosis.
●Among the 24 females who presented with a desmoid during pregnancy, 12 of the 15 patients initially managed with watchful waiting had progressive tumor growth during or after pregnancy; however, of the 16 patients who were initially managed conservatively (which included one patient treated with medical therapy), only four eventually required resection. The risk of relapse after initial surgery was 13 percent. Spontaneous regression occurred in three (13 percent).
●Among the 20 patients who developed a desmoid within six months of delivery, 5 of the 13 patients initially managed conservatively (medical therapy or watchful waiting) progressed; however, only 2 of the 13 eventually required resection. Spontaneous regression occurred in two (10 percent).
●Among the 48 females with a history of desmoid fibromatosis prior to pregnancy, 42 percent had relapse/progression. Of these, 94 percent were successfully managed with either resection or watchful waiting; 6 percent required multiple lines of therapy. Eight experienced spontaneous regression after pregnancy, four complete.
●Among 15 further pregnancies in all groups, only four (27 percent) progressed, all initially managed by watchful waiting; three were subsequently resected.
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 [34,35], particularly, as noted above, surgical intervention 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 [36].
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 [37,38]. 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 syndrome as well as in sporadic desmoids [39]. Desmoids in familial adenomatous polyposis (FAP) arise from APC inactivation and subsequent accumulation of beta-catenin in cells [40]. In contrast, APC mutations are uncommon in sporadic desmoids, which usually arise from mutations in the gene for beta-catenin, CTNNB1 [39,41].
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 [42]. 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 proteasome. 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 [43]. 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. Whole exome sequencing and genomic analysis identify alterations in CTNNB1 and Wnt pathway regulators in nearly all patient samples [44].
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 [45-49].
●Beta-catenin protein levels and tcf transcriptional activity are elevated in fibroblasts during the proliferative phase of wound healing [47,50,51].
●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 [47].
Activation of Wnt signaling through constitutively active beta-catenin has been shown to increase expression of midkine (also known as neurite growth-promoting factor 2 [NEGF2], a protein encoded by the MDK gene), which may have a role in pathogenesis in desmoid tumors. Midkine expression has been associated with recurrence of desmoids in one study [52], but this awaits further confirmation. 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 [53].
Adenomatous polyposis coli (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 [40]. (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 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 [54]. In general, desmoid tumors occur more frequently when mutations are in the 3' end of the APC gene, specifically between codons 1445 and 1580 [14,29,54-60]:
●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 [56].
●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) [57].
●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 [58].
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 syndrome) as well as in sporadic cases [41,61]. Sex hormones may also be actively involved in this process [62].
Mutations in the beta-catenin gene — Mutations in CTNNB1 have been found in sporadic desmoid tumors with variable prevalence (39 to 87 percent); however, other studies place the prevalence estimate at around 85 percent [43]. 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 [63], although other data do not support a statistically significant difference in recurrence risk according to either CTNNB1 mutation status or the specific CTNNB1 mutation [64].
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 [65-69]. Similar nonrandom genetic aberrations have been found in benign fibrous bone lesions (such as fibrous dysplasia), suggesting a similar pathogenesis [67]. 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 [65,66].
The finding of individual trisomies and their association in the same cell is rare in solid tumors, particularly mesenchymal tumors [67,68]. 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) [67-69]. Trisomy 8 is also a frequent finding in hematologic malignancies but is remarkably infrequent in nonfibrous solid tumors.
Mutations in AKT1, BRAF, and TP53 — While adult desmoid tumors are exclusively driven by Wnt/beta-catenin activation [70], pediatric desmoids can harbor additional mutations, suggesting a more complex molecular pathogenesis in this population. In addition to CTNNB1 mutations (64 percent), alterations were identified in AKT1 E17K (31 percent), BRAF V600E (19 percent), and TP53 R273H (9 percent) in a 28-patient study of pediatric desmoids [71]. These mutations can be present in pediatric desmoids that are CTNNB1 wild type (36 percent) or in combination with CTNNB1 mutations (64 percent).
CLINICAL PRESENTATION AND DIAGNOSIS — Most desmoid tumors present as a deeply seated painless or minimally painful mass with a history of slow growth. Intra-abdominal desmoids can present with nausea, early satiety [72], intestinal obstruction, bowel ischemia, or functional deterioration in an ileoanal anastomosis (typically in a patient who has undergone colectomy for familial adenomatous polyposis [FAP]) [18-20].
Desmoid tumors can develop at virtually any body site, but three main anatomic sites are described: trunk/extremity, abdominal wall, and intra-abdominal (bowel and mesentery). In patients with FAP, intra-abdominal desmoids predominate. (See 'Familial adenomatous polyposis and Gardner 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 [34]. Desmoid tumors may be multifocal at one site (typically the extremity [73]), 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 [74]. All patients had a palpable mass, which was seen on mammography in six of 16 and magnetic resonance imaging (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) [74]. (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 [48].
Radiographic studies — Cross-sectional imaging of the affected area with computed tomography (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 [75]. T2 hyperintensity may diminish over time as tumor cellularity decreases and collagen deposition increases [76]. 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 [77].
Ultrasound may also be a useful diagnostic study, particularly with desmoids involving the chest or abdominal wall [78,79]. Desmoids frequently appear as oval, well or poorly defined solid soft tissue masses with variable echogenicity, and no central necrosis or calcifications. However, there are no pathognomonic sonographic features.
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 [80] 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 'Adenomatous polyposis coli (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 [81]. However, it is not definitive because other entities (superficial fibromatoses, low grade myofibroblastic sarcomas, solitary fibrous tumors) also stain for nuclear beta-catenin [81]. Furthermore, beta-catenin negativity does not preclude the diagnosis of fibromatosis. Next-generation sequencing is reported to be highly sensitive for the detection of CTNNB1 mutations in desmoid-type fibromatoses [44]. Even in true CTNNB1 wild-type tumors (by next-generation sequencing), genomic alterations that result in Wnt activation (such as chromosome 6 loss/BMI1 mutation) may be present [70] and can aid molecular evaluation of these tumors.
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 eighth edition of the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (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 intra-abdominal desmoids in patients with FAP has been developed, but it 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 intra-abdominal desmoid. However, the yield of identifying FAP is low (3.7 percent in one series [7]). An enrichment strategy for screening for FAP (both by genetic testing and colonoscopy) is suggested above. (See 'Familial adenomatous polyposis and Gardner syndrome' above.)
NATURAL HISTORY — Desmoids are characterized by variable clinical behavior. Although most grow progressively larger over time, growth is usually indolent, and periods of growth arrest/spontaneous regression are not uncommon [82-87]. 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, radiation therapy (RT), or systemic therapy, the five-year progression-free survival rate was 50 percent [82].
●In a second report, 27 patients with newly diagnosed sporadic desmoids underwent initial attentive medical surveillance rather than active therapy [83]. Patients were chosen for this approach according to the site of tumor where progression could not be life-threatening or pose a 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.
●An even higher rate of spontaneous regression was seen in a series of 102 patients with primary abdominal wall desmoid tumors who were initially observed [84]. Over a median follow-up period of 32 months, 29 experienced spontaneous regression. The median size decrease was 66 percent, with 12 patients having no tumor detectable.
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 intra-abdominal or extra-abdominal disease sites [88,89]), size (particularly >7 cm [83,89]), sex (females have a higher rate of local recurrence than males), and age (younger patients [under age 37 in one series [83] and under age 30 in another series [90]] have a higher recurrence rate than older individuals) [2,83,91]. 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 from many (but not all [64]) institutions suggest that molecular factors (such as specific mutations within the beta-catenin gene) may correlate with recurrence risk [63,92-96]. Expression of estrogen receptor beta and cyclin D1 correlates with high proliferation in desmoid tumors, and in at least one report, estrogen receptor beta expression showed a trend towards greater risk of postoperative recurrence [97]. Although it is hoped that molecular analysis will eventually be used to guide the treatment strategy, 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 intra-abdominal sites [98-100]. 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 [100].
Desmoids are more often fatal in patients with intra-abdominal tumors, particularly in the setting of familial adenomatous polyposis (FAP). As noted above, desmoids are the cause of death in up to 11 percent of patients with this syndrome [22].
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 [23]:
●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 anatomic site of the desmoid tumor is the major factor that impacts management. 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.
Extra-abdominal and abdominal wall desmoids
Initial observation — Desmoids have an unpredictable clinical course, and close observation is the preferred strategy for stable, asymptomatic primary or recurrent desmoids, particularly if resection would entail major morbidity [32,82-84,101,102]. In one series of 142 patients presenting with a primary (n = 74) or recurrent (n = 68) desmoid tumor, 83 were treated with observation only, while 59 were initially offered medical therapy (hormone therapy or chemotherapy) [82]. The five-year progression-free survival rate was 50 versus 41 percent for the observation and medically treated patients, respectively. (See 'Natural history' above.)
In another report of 106 primary abdominal wall desmoid tumors initially managed without surgery (four with medical treatment and 102 with initial observation only), the one- and three-year incidences of a final switch to surgery were 14 and 16 percent, respectively [84]. Of the 102 patients who were initially observed, 29 experienced spontaneous tumor regression over a median follow-up period of 32 months. Only an initial tumor size of >7 cm was associated with a higher risk of requiring a change in the treatment strategy. All second intent resections were macroscopically complete, and 82 percent were microscopically complete (R0).
Perhaps the most convincing data supporting observation for patients with desmoid fibromatosis come from the phase III placebo-controlled trial of sorafenib, in which the placebo arm had a 20 percent response rate (all partial responses), suggesting the importance of observation, especially in patients where symptoms are mild or absent [103]. (See "Desmoid tumors: Systemic therapy", section on 'Sorafenib'.)
Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [104] suggest observation as a primary therapeutic option for patients with desmoid tumors that are potentially resectable but asymptomatic, non-life threatening, and not causing significant impairment, and includes observation as an option for tumors that are unresectable or if surgery would lead to unacceptable morbidity.
Treatment of an extra-abdominal or abdominal wall desmoid is indicated for symptomatic patients, and for those with progressively enlarging tumors irrespective of symptoms, if there is imminent risk to adjacent structures or if the tumor creates cosmetic concerns.
Surgery — The role of surgery has evolved for desmoid tumors. Initial observation is preferred for patients who are asymptomatic or only minimally symptomatic. (See 'Initial observation' above.)
For symptomatic patients, systemic therapy is often used as an alternative to surgery, particularly if resection would be associated with significant morbidity. (See "Desmoid tumors: Systemic therapy".)
When surgery is indicated, complete resection of the tumor with negative microscopic margins is the standard goal, but positive margins are acceptable if necessary to maintain function. The overall surgical strategy should also use function-preserving surgical approaches to minimize major morbidity (functional and/or cosmetic). Truly radical resections are not indicated.
Due to the size and infiltrative nature of extra-abdominal 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. Intra-abdominal 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.
Historically, desmoid tumors were treated by surgical resection with a negative margin, when medically and technically feasible [98,105]. However, 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.
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 [91,98,100,106-110].
●While some series [26,91,98,107,109-111] show higher recurrence rates with close or positive resection margins, many series report that the risk of recurrence is independent of margin status [51,88,100,112-115]. 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 [83]. 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).
●A meta-analysis of 16 retrospective reports (1295 patients with extra-abdominal or abdominal wall desmoids) concluded that patients with microscopically positive margins had a significantly higher recurrence risk (risk ratio [RR] 1.78, 95% CI 1.40-2.26) [116]. However, the extent of tumor clearance (distance from the tumor to the resection margin) was not reported in most studies. Further, the group with negative resection margins might represent patients in whom resection was technically easier, which could explain their lower recurrence rate. These issues preclude definitive conclusions.
These data, combined with the fact that recurrence only develops in fewer than one-half of those with positive margins [110], have led some to conclude that aggressive attempts to achieve negative resection margins are not warranted if they result in excessive morbidity [32,51,110,117]. Moreover, uncertainty as to the importance of positive resection margins has led to controversy with regard to the utility of postoperative radiation therapy (RT) for patients with incompletely resected disease. These data are discussed below.
Radiation therapy — Observation is often the preferred initial strategy for desmoid tumors (see 'Initial observation' above). For situations where the desmoid tumor is causing significant symptoms, systemic therapy, surgery, and RT should all be considered as potential treatment options. Multimodality evaluation and discussion is the optimal forum to make such management decisions. RT is an effective primary therapeutic option for 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 [118,119].
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 [106,107,114,119-128]. 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) [107]. 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 [106]. 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 [119].
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 is an appropriate option for patients who are symptomatic or otherwise in need of treatment; who are not good surgical candidates or decline surgery; those for whom surgical morbidity would be excessive; and those for whom systemic therapy is not recommended.
The recommended dose of RT for definitive therapy is 50 to 56 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 [114].
Postoperative radiation therapy — There are no data to support a benefit for RT in the adjuvant setting after complete surgical resection, and it is generally not recommended [107,129].
Deferring RT is the preferred option for patients with microscopically positive margins as well as for those with gross or macroscopic residual disease after initial resection. Our preference in these situations is to withhold RT and proceed with surveillance, which is a successful strategy for this nonmetastatic condition.
Postoperative RT can be reserved for symptomatic recurrences or local recurrence that are difficult to manage. Guidelines from the NCCN [104] suggest that postoperative RT be considered after R2 resection or in the setting of disease progression or recurrence, with or without additional surgery. (See 'Management of recurrent disease' below.)
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 [98], a large series from Massachusetts General Hospital [107], and a comparative review of published experience with treatment of desmoid tumors [106], 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 [51,100,112]. A meta-analysis of 16 reports (1295 patients, all retrospective observational studies) concluded that adjuvant RT improved recurrence rates after incomplete surgical resection for patients with primary extra-abdominal and abdominal wall tumors (RR 1.54, 95% CI 1.05-2.27) and in those with recurrent disease (RR 1.60, 95% CI 1.12 to 2.28) [116]. However, the lack of randomization in any of these reports and the missing information on tumor size and anatomic location compromise interpretation of the results.
●As noted previously, the status of the resection margins has not consistently been shown to correlate with the risk of recurrence [51,100,112-115,130]. 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 [107,131]. 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.
Neoadjuvant radiation therapy — One approach to increasing resectability and reducing rates of local recurrence in extra-abdominal desmoids is the use of neoadjuvant (preoperative) RT. Experience with this approach is limited:
●In the largest report, 58 patients underwent preoperative RT and were followed for a median of 69 months [132]. 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 [133]. In the later study, 16 of 30 patients received one year of postoperative therapy with high-dose tamoxifen and a nonsteroidal antiinflammatory drug (NSAID) [134]. 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. Furthermore, neoadjuvant systemic therapy may be preferred in order to avoid the risk of subsequent tumors related to RT.
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 [134], particularly in view of the demonstration that several chemotherapy regimens are active in the setting of advanced or unresectable disease. (See "Desmoid tumors: Systemic therapy".)
Data supporting the efficacy of targeted therapies, such as sorafenib and pazopanib, for unresectable desmoid tumors leave a gap in evidence about their impact on outcomes of subsequent surgery. Considering that these agents suppress angiogenesis, their impact on wound healing should be addressed if patients with previously unresectable desmoids are considered for subsequent surgery due to their response to a molecularly targeted agent. (See "Desmoid tumors: Systemic therapy", section on 'Tyrosine kinase inhibitors'.)
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 [100]. 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.
Intra-abdominal desmoids — Intra-abdominal desmoids are less often resectable than are extra-abdominal and abdominal wall desmoids. Surgery may be difficult or even impossible for intra-abdominal desmoids, particularly when they arise in the setting of familial adenomatous polyposis (FAP), although it is an important option for selected patients [8,135,136].
The intra-abdominal 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 [137]. Moreover, the rate of recurrence is high after attempted resection, and the recurrent disease is often more aggressive than the initial desmoid [21,25,99,117]. In one report, as an example, tumor debulking led to aggressive progression of desmoids in four of six patients [21]. A retrospective evaluation of outcomes in 62 patents with FAP and intra-abdominal desmoids tumors showed that conservative management and surgery produced comparable outcomes to upfront surgery (10-year rate of progression-free survival 49 versus 33 percent) [138].
These observations have led the American Society of Colon and Rectal Surgeons and a joint task force of the American Society of Clinical Oncology/the Society of Surgical Oncology to advocate conservative management rather than initial resection for patients with Gardner syndrome and intra-abdominal desmoid tumors that are large, slow growing, involve the mesentery, or encase vessels and/or organs [139,140].
At many institutions, a multimodality approach that includes initial systemic therapy is preferred for these patients [141,142]. Options for systemic therapy include noncytotoxic therapy (an NSAID, tamoxifen), targeted therapy with imatinib, or cytotoxic chemotherapy. (See "Desmoid tumors: Systemic therapy".)
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 National Comprehensive Cancer Network (NCCN) [104] suggest a history and physical examination with appropriate imaging every three to six months for two to three years, then annually.
MANAGEMENT OF RECURRENT DISEASE — Successful salvage therapy is possible in the majority of patients who have a local recurrence [98,106,120,143]. Surveillance is an acceptable initial approach, with treatment for symptoms and/or tumor growth. Multimodality input is important as systemic therapy, surgery, and radiation therapy (RT) are all potential treatment options. If it is feasible and can be carried out using a function-preserving approach, surgical resection is often acceptable for a recurrent extra-abdominal desmoid tumor.
However, RT alone is a reasonable alternative for tumors felt to be at risk for higher morbidity with repeat operation. 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 [106]. In one series, local control was achieved in 9 of 10 patients receiving RT for recurrent desmoid [107].
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 on the clinical setting and symptoms experienced by the patient (algorithm 1). (See "Desmoid tumors: Systemic therapy".)
Familial adenomatous polyposis patients — The decision to proceed with surgery in patients with recurrent intra-abdominal desmoid in the setting of familial adenomatous polyposis (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".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Soft tissue sarcoma (The Basics)" and "Patient education: Familial adenomatous polyposis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Natural history – 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. The natural history of desmoid tumors is prolonged, variable, and unpredictable. Despite being histologically benign, they are locally infiltrative and, uncommonly, can cause death through destruction of adjacent vital structures and organs. (See 'Introduction' above and 'Natural history' above.)
●Risk factors – Risk factors for desmoid tumors include the following:
•Familial adenomatous polyposis – The risk of desmoids is increased in patients with familial adenomatous polyposis (FAP). However, the diagnostic yield of FAP among patients who have desmoid fibromatosis is low. (See 'Familial adenomatous polyposis and Gardner syndrome' above and "Familial adenomatous polyposis: Screening and management of patients and families".)
•Desmoid tumors and pregnancy – Extra-abdominal and abdominal desmoids tend to occur in females during or following pregnancy. The risk to the pregnancy is very low, and the course of the pregnancy may be relatively normal. (See 'Pregnancy' above.)
-If a patient had a desmoid arise during a prior pregnancy and the desmoid was resected, the recurrence risk during future pregnancies is low.
-If a patient had an existing desmoid (pregnancy associated or predating any pregnancy) that was managed with watchful waiting, that desmoid can grow during a subsequent pregnancy, but not always.
●Principles of treatment – The anatomic site of the desmoid tumor is the major factor that impacts management, due to the locally aggressive nature of the disease. (See 'Treatment' above.)
•Treatment of desmoids can be a clinical challenge, particularly in patients with FAP, who tend to develop intra-abdominal desmoids at sites of prior surgery. (See 'Familial adenomatous polyposis patients' above.)
•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.
●Extra-abdominal and abdominal wall tumors – Observation is an appropriate option in asymptomatic or minimally symptomatic patients who may be reliably followed. If desmoids grow only very slowly, remain unchanged, or shrink, observation may be continued. Treatment should be pursued if the tumor significantly increases in size, becomes moderately to severely symptomatic, if there is imminent risk to adjacent structures, or if the desmoid creates cosmetic concerns. (See 'Initial observation' above.)
•Complete surgical excision is often the treatment of choice for a potentially resectable extra-abdominal (extremity, trunk, breast) or abdominal wall desmoid in a patient who is medically able to tolerate surgery and if resection can be accomplished without major functional or cosmetic deficit. (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. (See 'Radiation therapy' above.)
-Systemic treatment is an alternative approach in these patients, especially if they are young and there are concerns about the potential for late toxicity from RT including but not limited to radiation-associated malignancies. (See "Desmoid tumors: Systemic therapy".)
•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 radiation therapy' 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. Systemic therapy is also effective in controlling extremity desmoids in a number of patients, precluding the need for further surgery.
●Intra-abdominal desmoid, Gardner syndrome - For patients who have large intra-abdominal desmoid tumors, particularly in the setting of Gardner 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 often the preferred option for patients with more difficult tumors, such as those involving the mesentery, major vessels, or other critical structures. (See 'Intra-abdominal desmoids' above and "Desmoid tumors: Systemic therapy".)
•Surgery is an appropriate option if there is no response to medical therapy.
•Management of recurrence of an intra-abdominal tumor in patients with Gardner 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.)
●Recurrent disease – For a recurrent desmoid tumor, multimodality evaluation should be used to determine treatment options, which include observation, systemic therapy, RT alone or repeat surgical resection. (See 'Management of recurrent disease' above.)
•Observation is preferred if the tumor is asymptomatic or minimally symptomatic.
•For patients who undergo surgery for a recurrent desmoid, we suggest observation or postoperative RT if the margins are positive (Grade 2C).
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas F DeLaney, MD, who contributed to an earlier version of this topic review.
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