Excerpt from Desmoid Tumor

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Background

Desmoid tumors are histologically benign fibrous neoplasms originating from the musculoaponeurotic structures throughout the body. The term desmoid, coined by Muller in 1838, is derived from the Greek word desmos, which means tendonlike.

Desmoid tumors often appear as infiltrative, usually well-differentiated, firm overgrowths of fibrous tissue, and they are locally aggressive. The synonym aggressive fibromatosis describes the marked cellularity and aggressive local behavior. This course and the tendency for recurrence make the treatment of these relatively rare fibrous tumors challenging.

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Pathophysiology

Although desmoid tumors most commonly arise from the rectus abdominis muscle in postpartum women and in scars due to abdominal surgery, they may arise in any skeletal muscle. The tumors tend to infiltrate adjacent muscle bundles, frequently entrapping them and causing their degeneration. Although fixation to musculoaponeurotic structures is apparent, the overlying skin is normal. The myofibroblast is the cell considered to be responsible for the development of desmoid tumors (see Procedures).

Gardner syndrome or familial adenomatous polyposis (FAP) is characterized by colorectal adenomatous polyps and soft and hard tissue neoplasms. The former may number in the hundreds to thousands. Gardner syndrome was regarded as a separate disease until the identification of the APC (adenomatous polyposis coli) gene, at which point mutations in the APC gene were recognized as the underlying cause of both Gardner syndrome and FAP. Some authors regard Gardner syndrome as a subset of FAP, and some have even suggested that the term Gardner syndrome be replaced by FAP. Additionally, evidence also exists for a genetic predisposition to desmoid tumors in FAP, independent of the APC mutation.

Desmoid tumors occur at a rate of 10-15% in patients with FAP, an autosomal inherited disease caused by germline mutations in the APC gene. Sporadic forms have no hereditary background.¹ Desmoid tumors show biallelic APC mutation, with one change usually occurring distal to the second beta-catenin binding/degradation repeat of the gene (3' to codon 1399).^{2, 3} The relationship between extracolonic manifestations and the site of the APC mutation suggests a specific role of the APC protein in different tissues. However, unknown genetic factors independent of APC may be important in the susceptibility to desmoid tumors in patients with FAP.

In desmoid tumors, 1 of the 2 mutations usually occurs distal to the second beta-catenin binding/degradation repeat of the gene (3' to codon 1399). Catenin and catenin-binding genes have been found to be associated with neoplastic processes in a number of ways. Independent predictors of increased desmoid risk in one study were said to be (1) germline mutation distal to codon 1399, (2) any family history of gastrointestinal disease, and (3) a strong family history of desmoid tumors.

The relationship between certain extracolonic manifestations and sites of the APC mutation suggests specific roles of the APC protein in different tissues. These different roles may correspond to specific sites of missense mutations in the APC gene. For example, dental manifestations of Gardner syndrome have been suggested to be associated with mutations at or near codon 1556. However, the influence of unknown genetic factors independent of APC in susceptibility to desmoid tumors in FAP needs to be explored.

FAP results from a germline mutation in the APC gene. Desmoid tumors are associated with a biallelic APC mutation in the affected tissue. This usually results from a spontaneous somatic mutation in the unaffected APC gene of a single cell in a patient with the FAP syndrome. This process is an example of the Knudsen "two hit" hypothesis, in which a tumor suppressor gene, such as APC, must be biallelically mutated in order for a specific type of tumor to occur.

In genetically normal individuals, with normal germline genes, this necessitates a rare combination of events, such that at least 2 somatic mutations must occur in both alleles of a single tumor suppressor gene, in this case the APC gene. In FAP syndrome patients, one APC germline gene is already mutated in every cell in the body (barring a rare reverse somatic mutation in some cells), and, therefore, only one new somatic mutation is required in the opposite APC gene for the tumor to develop.

FAP may be associated with mutations in the APC gene, but mutations in several other genes, particularly mismatch DNA repair genes, which are primarily responsible for ensuring integrity of polymerases responsible for DNA replication, may also result in familial colonic polyposis. These patients with familial colonic polyposis typically do not show other manifestations of Gardner syndrome. Conversely, extracolonic manifestations characteristic of Gardner syndrome may occur independent of intestinal polyps or a mutation in the APC gene.

Frequency

International

Overall, desmoid tumors are reported to account for 0.03% of all neoplasms.⁴ When present in patients with familial polyposis of the colon, the prevalence of desmoid tumors is as high as 13%.⁵

Mortality/Morbidity

Despite their benign histologic appearance and negligible metastatic potential, the tendency of desmoid tumors to cause local infiltration is significant in terms of (1) deformity, morbidity, and mortality resulting from pressure effects and (2) potential obstruction of vital structures and organs.

Sex

Desmoid tumors most commonly occur in women after childbirth. Desmoid tumors are twice as common in females than in males; however, 60 patients were described,⁶ and the female-to-male ratio was 1.2:1. In children, the sex incidence is equal.

Age

Although desmoid tumors are more common in persons aged 10-40 years than in others, they do occur in young children and older adults. Sixty patients were described by Lee et al⁶ in 2006, with an average age at diagnosis of 41.3 years.

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