Desmoid tumors are fibrous mesenchymal neoplasms that arise from deep musculoaponeurotic structures. They may occur sporadically or in association with familial adenomatous polyposis (FAP). Though desmoid tumors lack the ability to metastasize, they are locally invasive, often behaving clinically like low-grade fibrosarcomas. This local tissue destruction can lead to significant morbidity, disfigurement, functional deficit, and death. Desmoid tumors have an unpredictable natural history, with some exhibiting the ability to grow rapidly to large size, while other tumors may remain stable for years, and still others may regress completely without treatment. They have a propensity to recur despite complete surgical resection. Treatment consists of surgery, radiation therapy (RT), and systemic therapies, in varying combinations. The rarity of desmoid tumors, combined with their highly variable clinical course, has made formulating consensus guidelines for treatmentdifficult, and considerable controversy still exists regarding many aspects of management. This chapter will provide an overview of the clinicopathologic features of desmoid tumors and will address the diversity of options available in their treatment.

Desmoid tumors occur only rarely in the general population, with an estimated annual incidence of two to four cases per million individuals.¹ In contrast, in patients with FAP, desmoid tumors are much more common, occurring in approximately 10% to 25% of patients.^2–4 Studies with higher estimates may reflect the fact that patients with desmoid tumors are often referred to tertiary care centers with expertise in FAP, where many of these studies are performed. Patients with FAP have a risk of developing a desmoid tumor at least 800 times that of the general population.^4,5 Of all patients presenting with a desmoid tumor, at least 7.5% will ultimately be diagnosed with FAP.⁴

FAP is a cancer predisposition syndrome inherited in an autosomal dominant fashion, caused by a mutation in the adenomatous polyposis coli (APC) tumor suppressor gene. FAP is characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, beginning in adolescence. Without prophylactic colectomy, patients will almost inevitably develop colorectal cancer, usually by the age of 40 years. In addition to colorectal polyps, various extracolonic manifestations are commonly seen in patients with FAP. In 1953, Gardner described patients with a hereditary triad of intestinal polyposis, osteomas, and cutaneous or subcutaneous lesions. This constellation of findings became known as “Gardner syndrome.”⁶ Since that time, it has become clear that almost all families with FAP demonstrate some combination of extracolonic manifestations in addition to polyposis, and these associated extracolonic findings are now grouped under the umbrella of FAP. Various cancers and lesions with malignant potential are more common in patients with FAP, including papillary thyroid carcinoma, hepatoblastoma, brain tumors, pancreatic cancer, adrenal adenomas, duodenal and small bowel adenomas, duodenal cancer, gastric fundic gland polyps, gastric antrum adenomas, and gastric cancer, and desmoid tumors. Additionally, various benign abnormalities are also commonly seen in FAP patients, including congenital hypertrophy of the retinal pigment epithelium (CHRPE), osteomas, supernumerary teeth and other dental abnormalities, epidermoid cysts, sebaceous cysts, fibromas, and lipomas.^7–10

Within FAP, there is a range of phenotypes observed in patients, including classical FAP, profuse FAP, and attenuated FAP. In classical FAP, patients are found to have at least 100 colorectal polyps developing in adolescence, and they often develop some of the extracolonic manifestations listed above. In profuse FAP, patients develop greater than 1000 polyps, with many developing more than 5000, and the disease begins in the first or second decade of life.^9,11 In a mild phenotype, known as attenuated FAP (AFAP), patients develop fewer adenomas, on the order of 10 to 100 adenomas.¹² Adenomas typically develop at a later age in life, usually between the ages of 20 to 25 years, with colorectal cancers more likely to develop at a later age.¹² Though some extracolonic findings are less common in AFAP, upper gastrointestinal findings, thyroid, and duodenal cancer risks appear to be similar to those of classical FAP.^9,12 While some studies have found desmoid tumors to be less common in AFAP than in FAP, this prevalence may depend on the location of the APC mutation in each patient. Knudsen et al¹² identified desmoid tumors in only 5% of patients with AFAP. In contrast, Lefevre et al examined and genotyped AFAP patients, grouping them based on the location of their APC mutation, and found that between 23% and 39% of AFAP patients had desmoid tumors.

Studies comparing sporadic and FAP-associated desmoid tumors have identified various differences in clinical features between the two disease groups. While sporadic desmoid tumors occur more commonly in women, in FAP patients there is a more even distribution between the sexes. Nieuwenhuis et al⁴ found that 70% of sporadic desmoid patients occurred in women, whereas only 54% of FAP-associated desmoids were noted in women. Similarly, a study of desmoid patients seen at the Mayo Clinic found a female/male ratio of 1.71 in sporadic cases, compared to a female/male ratio in FAP cases of 1.12.² Patients with FAP are often younger at the time of diagnosis of their desmoid tumors, with a mean age of 36 years versus 42 years for sporadic patients.² In either sporadic or FAP-associated desmoids, however, tumors can occur at any age and have been documented from infancy through the ninth decade of life.^4,5 The frequency of disease site also differs between sporadic and FAP-associated desmoids. The Mayo Clinic group found that 54.4% of sporadic desmoids are located on the trunk, 34.7% on the limbs, and only 10.9% within the abdomen. In FAP patients, 31.4% were located on the trunk, 1.4% on the limbs, and 67.1% within the abdomen.²

Risk factors for developing a desmoid tumor include a positive family history of desmoid tumors, an APC mutation on the 3’ side of codon 1399, and previous abdominal surgery.^13,14 Some studies have implicated female sex as a risk factor for desmoid tumors, though this finding is controversial.^13,14 Patients with FAP have a 25% risk of developing a desmoid tumor if such tumors are present in a first-degree relative, and this risk decreases to 11% if desmoids are present in a second-degree relative and 8% for disease in third-degree relatives.⁵

Desmoid tumors represent a significant cause of morbidity and mortality for select patients. Aggressive intra-abdominal disease, often involving the mesentery, is common in patients with FAP, and patients are often affected at a young age. In a study from the St. Mark’s Hospital in London, in FAP patients who had undergone colectomy and ileorectal anastomosis, desmoid tumors were the third most common cause of death after duodenal cancer and metastases of unknown primary, and death from desmoid tumor occurred at an average age of 27 years and a median of 3 years after colectomy.¹⁵ In a study from the Italian Registry of Familial Polyposis, desmoids represented the second most common cause of death in FAP patients after colorectal cancer.⁷ A study from the Cleveland Clinic found desmoid tumors to be the second leading cause of death in FAP patients after colorectal cancer. Moreover, desmoid tumors were noted to be the leading cause of death in patients with FAP who had undergone prophylactic colectomy, with patients dying an average of 6.6 years after colectomy, at a mean age of 35.3 years.¹⁶

The molecular biology underlying desmoid tumorigenesis is increasingly becoming better understood. It is clear that dysregulation of the Wnt/β-catenin pathway is seen in both sporadic and FAP-associated desmoid tumors, though the mechanism underlying this dysregulation is driven by different but related cellular processes. FAP is caused by germline mutations in the tumor suppressor gene APC, which lies on chromosome 5q21-22.¹⁷ Consistent with Knudson’s two-hit hypothesis,¹⁸ a germline mutation in the APC gene results in a null allele, and when this germline mutation is followed by somatic inactivation of the wild-type allele by either mutation or deletion, a homozygous functional knockout of the APC gene is created.^19–21 APC is broadly expressed throughout the body, though its important tumor suppressor function is the regulation of the Wnt/β-catenin pathway. One function of APC is to form a complex that regulates the level of β-catenin within the cell. β-catenin is a cellular protein that plays a role in both cell–cell interactions in adherens junctions, as well as in the regulation of gene expression through the Wnt signaling pathway. Under normal conditions, levels of β-catenin are closely regulated by the APC complex, which is formed by several proteins, including APC, glycogen synthase kinase (GSK)-3β, and axin.²² When β-catenin is present at high levels, the APC complex marks β-catenin for destruction by sequential phosphorylation at four critical sites—serines 45, 37, and 33, and threonine 41—all of which are encoded by exon 3 of the β-catenin gene, CTNNB1.²³ Any disruption in this process allows β-catenin to accumulate within the cell.

The majority of FAP-associated desmoid tumors are caused by mutations in the APC gene that result in a truncated, nonfunctional APC protein, which cannot degrade β-catenin properly.²⁴ Genetic testing can typically identify an APC mutation in approximately 80% of patients with FAP.²⁵ It is important to note that up to 25% of FAP patients have a de novo APC mutation, meaning these patients will display the genotype and phenotype commonly observed in FAP and yet not report a family history of this disease.²⁶ In approximately 85% of cases of sporadic desmoid tumors, the mutations lie not in the APC gene, but in the CTNNB1 gene at threonine 41 (T41A) or serine 45 (S45F, S45P, and S45C).^27,28 These mutations prohibit appropriate β-catenin phosphorylation, leading to increased levels of stabilized β-catenin within the cell.²⁹ Somatic APC mutations have also been observed in sporadic desmoid tumors.³⁰ In the case of either APC or CTNNB1 mutations, the Wnt/β-catenin pathway becomes constitutively active. Unphosphorylated, active β-catenin accumulates in the cytoplasm and then translocates to the nucleus, where it acts with transcription factors in the T-cell factor/lymphoid enhancing factor (Tcf/LEF) family to activate transcription of genes such as CYCD1 and c-MYC, ultimately promoting tumorigenesis through increased cell proliferation, survival, and differentiation.

Cytogenetic analysis of desmoid tumor specimens reveals recurrent chromosome aberrations, including loss of 6q, loss of 5q, gain of 20q, and gain of chromosome 8.^31–35 The significance of these findings is unclear. Fletcher et al³² found trisomy 8 to be a predictor of recurrence, though this finding was not supported by Salas et al.³⁴

The APC gene consists of 15 exons, encoding 2843 amino acids. Several studies have demonstrated a spectrum of disease that correlates disease phenotype with genotype. The number of polyps, age of onset of colorectal cancer, and number of extracolonic manifestations, including CHRPE, desmoid tumors, upper GI polyps, gastric adenomas, duodenal adenomas, and the finding of multiple extracolonic manifestations have been shown to correlate with specific mutation sites and regions of the APC gene.^8,9,36 In addition, the severity of colorectal disease has been found to correlate with specific regions. The variant profuse FAP correlates with a truncating mutation between codons 1250 and 1464, while mutations associated with attenuated FAP generally fall at either end of the APC gene.^9,36 The finding of desmoid tumors in FAP has been linked to mutations toward the 3’ end of the APC gene, generally downstream of codon 1400.³⁷

In sporadic desmoid tumors, recent studies have identified a correlation between the specific mutation site in the CTNNB1 gene and the risk of local recurrence. Lazar et al³⁸ reported that 5-year recurrence-free survival (RFS) was significantly worse in desmoids harboring the S45F mutation (23%) compared to those with mutations at T41A (57%) or wild-type tumors (67%). Likewise, Colombo et al³⁹ found that primary, completely resected sporadic desmoid tumors with the S45F mutation had a higher rate of local recurrence than desmoids with other mutations or wild-type tumors. However, these results are controversial as Mullen et al⁴⁰ did not find a correlation between specific CTNNB1 codon mutation and risk of recurrence. It is clear that further studies are needed to refine our understanding of the molecular determinants of outcome for desmoid tumors. Given these findings, targeting the Wnt/β-catenin pathway is certainly an attractive potential therapeutic option in the future treatment of desmoid tumors.

On gross examination, desmoid tumors are firm and rubbery and white to tan in color. The cut surface reveals a glistening, whorled, trabeculated surface resembling scar tissue. There is usually little evidence of hemorrhage or necrosis. Histologically, uniform stellate to spindle cells resembling fibroblasts are arranged in long fascicles or whirling patterns, surrounded by a dense collagenous matrix. Nuclei are small and sharply defined, with no nuclear atypia or hyperchromasia, and the cytoplasm is eosinophilic.^41–43

On immunohistochemical staining, cells typically stain strongly positive for vimentin, have focal or patchy positivity for smooth muscle actin (SMA), and typically stain negative for desmin, h-caldesmon, and S100.^41–43 Expression of c-KIT in desmoid tumors is generally variable, but always lower than that seen in gastrointestinal stromal tumors (GISTs).^44,45 Between 70% and 100% of desmoid tumors will display high-level nuclear β-catenin expression.^46–48 Very few other mesenchymal or spindle cell neoplasms stain positive for this marker, including solitary fibrous tumor, synovial sarcoma, endometrial stromal sarcoma, and low-grade myofibroblastic sarcomas. GISTs and sclerosing mesenteritis will typically stain negative for nuclear β-catenin.⁴⁷ While nuclear immunostaining for β-catenin is not definitive for the diagnosis of desmoid tumors, it is strongly supportive of this diagnosis.

Recent studies have also attempted to better characterize other biomarkers expressed in desmoid tumors. In a study of FAP desmoid tumor samples, Colombo et al⁴⁵ demonstrated that COX2, β-catenin, PDGFR-β, and PDGF-β were expressed in all samples examined, while PDGFR-α, estrogen receptor (ER)-β, PDGF-α, p53, and nuclear cyclin D1 were expressed in a variable percentage of samples.

Since desmoid tumors tend to be slow growing, they may remain undetected for years. Tumors can develop at virtually any anatomic site, though the abdominal wall, mesentery, trunk, shoulder, and thigh are the most common sites of disease.³⁵ Solitary lesions are most common, though multifocal disease can be present, typically in the same anatomic region. Desmoids usually present as an asymptomatic, firm mass. Tumors tend to be firm and fixed to underlying structures due to their invasive pattern of growth. Symptoms are variable and depend on tumor location. Intra-abdominal desmoids located in the mesentery can present with small bowel obstruction or symptoms due to compression of adjacent organs. These small bowel obstructions are often recurrent and frequently require surgical intervention.⁴⁹ Patients may occasionally present with bleeding or an acute abdomen due to bowel perforation. Retroperitoneal desmoid tumors may cause ureteral obstruction, which frequently requires ureteral stenting or percutaneous nephrostomy tube placement for complete obstructions.⁵⁰ Pelvic desmoids may present as a slow-growing pelvic mass that may be mistaken for an ovarian neoplasm. Extremity desmoids may cause pain or restricted range of motion if joint involvement exists. Upon physical examination, the clinician should assess the size and relationship of the tumor to nearby structures as well as evaluate for evidence of functional compromise.

Any patient presenting with a desmoid tumor should have a thorough history taken, including a detailed family history. Although familial tumors represent a small proportion of patients with desmoid tumors, any patient with a desmoid tumor and a personal or family history of colon polyps or colorectal cancer should raise suspicion for FAP. Current NCCN Guidelines recommend that any patient diagnosed with a desmoid tumor, even in the absence of a family history of FAP, should undergo genetic testing for an APC mutation.⁵¹

Currently there is no consensus staging system for desmoid tumors. However, in 2005 a staging system for intra-abdominal desmoid tumors in FAP patients was proposed by the Cleveland Clinic group, based on tumor size and behavior.⁵² According to this classification, stage I tumors measure less than 10 cm, are not growing, and are asymptomatic; stage II tumors measure less than 10 cm, are not growing, and are mildly symptomatic; stage III tumors measure between 10 cm and 20 cm, are slowly growing, are moderately symptomatic, or are causing bowel or ureteric obstruction; and stage IV tumors measure greater than 20 cm, are rapidly growing, or are severely symptomatic. While this staging system is not yet widely used, it was formulated with the goal of stratifying FAP patients with intra-abdominal desmoid tumors in order to allow for a more standardized classification of these tumors to enable better multicenter, prospective studies of their treatment.

Imaging

Either computed tomography (CT) scans or magnetic resonance imaging (MRI) scans may be used to evaluate desmoid tumors. MRI is particularly beneficial for extra-abdominal desmoids owing to its excellent soft tissue resolution, helping to delineate the extent of the tumor and its relationship to adjacent neurovascular structures. Desmoid tumors lack a capsule, tend to be firmly fixed to adjacent structures, and often infiltrate beyond the borders seen on imaging studies.

On CT scan, the attenuation of desmoid tumors is variable. Some lesions demonstrate patchy contrast enhancement, while other lesions are nonenhancing. In patients with multifocal disease, lesions may have inconsistent enhancement—some lesions will appear hypodense while other lesions in the same patient will appear hyperdense. There is no correlation on CT scan between the size of a desmoid tumor and its density. Intra-abdominal desmoids often appear as poorly defined areas of infiltration, with whorled soft-tissue thickening within the fat of the mesentery.⁵³ On T1-weighted MRI scan, tumors have low or intermediate signal intensity. Masses on T2-weighted images may have low, intermediate, or high signal intensity. In general, a desmoid tumor has a signal intensity between that of skeletal muscle and subcutaneous fat. The majority of lesions will demonstrate some degree of heterogeneity. Most tumors will demonstrate contrast enhancement on MRI.⁵⁴

Studies reviewing both MRI findings and histologic sections of the same tumors have demonstrated good correlation between signal intensity, tumor cellularity, and collagen content.⁵⁵ Tumors with high intensity on T2-weighted images generally are more cellular, with less collagen on histologic exam. Those tumors exhibiting more rapid growth tend to be more cellular and thus have higher T2 signal intensity.

While both CT and MRI are commonly used to evaluate desmoid tumors; a recent study by the St. Mark’s group compared 1.5T MRI with 64-slice multidetector CT (MDCT) to determine if MRI was equivalent or superior in the assessment of desmoid tumors in patients with FAP.⁵⁶ In this study, in patients with known desmoid tumors who underwent imaging studies by both modalities, MRI identified 23 desmoid tumors, while MDCT identified only 21 desmoids, missing two that were detectable by MRI. The modalities were equivalent in their ability to define the local extent of tumor. MRI may be useful in young patients with desmoid tumors, who require ongoing surveillance, since this modality allows for adequate monitoring of disease while avoiding radiation.

In general, MRI scans are most useful in the assessment and operative planning of extremity and girdle desmoid tumors, as MRI offers unparalleled soft tissue contrast and demonstrates well the relationship of tumor to nerves and adjacent soft tissue structures. CT scan is primarily used in the assessment and operative planning of intra-abdominal desmoid tumors, in order to best define the relationship of the tumor to adjacent viscera and other anatomic structures. For mesenteric desmoid tumors, in particular, it is important to delineate the spatial relationship of the tumor to the mesenteric vasculature, especially the superior mesenteric artery (SMA) and vein, in order to define the resectability of the tumor and/or the need for vascular resection and reconstruction. Some centers utilize CT scans with triple-phase contrast and 3D imaging to enable beautiful reconstructions of the mesenteric arteries and veins for precise preoperative planning.⁵⁷

Biopsy

It is absolutely critical to obtain a histologic diagnosis of desmoid tumor by as limited an interventional means as possible prior to the initiation of any treatment (especially surgery), since the optimal treatment approach for a given desmoid tumor may in fact be “no treatment.” Core needle biopsy (CNB) is the most convenient and efficient means of establishing a histologic diagnosis. Fine needle aspiration (FNA) biopsy is much less likely than a CNB to establish the diagnosis of a desmoid tumor given the more limited amount of tissue obtained in a FNA biopsy. For easily palpable tumors, CNB can be done in the office under local anesthesia. Generally, five to six cores of tissue are obtained from different areas of the tumor. Image-guided CNB should be considered for more deeply situated tumors and for heterogeneous tumors where sampling of a specific area is desired. In addition, percutaneous, CT-guided CNB should be arranged for an intra-abdominal or retroperitoneal mass for which desmoid tumor is considered in the differential.

Laboratory Studies

There are no known serum tumor markers that can be used to distinguish desmoid tumors from other soft tissue tumors. Baseline laboratory studies should be obtained prior to contrast imaging and therapy, but they otherwise have a limited role. The diagnosis of desmoid tumor is typically made on the basis of cross-sectional imaging and biopsy.

Due to the rarity of desmoid tumors and the complexity of their management, the diagnosis of a desmoid tumor in a patient should prompt referral to a multidisciplinary team with expertise in the management of connective tissue tumors. Given that desmoid tumors exhibit an unpredictable natural history and are prone to recur even after complete resection, a diversity of management options exist, and resection is frequently not the optimal choice for initial management. A strategy of “watchful waiting” or definitive RT may be preferable for some patients. Patients who do undergo resection may recur many years later. Regardless of the treatment strategy chosen, patients with desmoid tumors require close follow-up, which can be best accomplished in a multidisciplinary setting.