Desmoid Tumor

Desmoid tumors are cytologically bland 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.[1]

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. Desmoid tumors tend to infiltrate adjacent muscle bundles, frequently entrapping them and causing their degeneration.[2] They may be derived from mesenchymal stem cells.[3] 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.[4] 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).[5, 6] 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, one of the two 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. Most sporadic desmoid tumors are linked with β-catenin gene mutations.[7]

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. Nuclear localization of β-catenin may be evident in pediatric desmoids regardless of mutation status, with most showing somatic mutations in CTNNB1.[8] However, many harbor germline mutations in APC. CTNNB1 mutations are common in sporadic desmoid tumors.[9] CTNNB1 mutations and APC mutations are mutually exclusive in this entity; accordingly, the presence of a somatic CTNNB1 mutation facilitates exclusion of a syndromic disorder.[10]

The cause of desmoid tumors is uncertain and may be related to trauma or hormonal factors, or they may have a genetic association.

The familial polyposis gene on chromosome 5 has been extensively studied.[6, 11]

An endocrine etiology is suggested. Desmoid tumors most commonly appear in young women during or after pregnancy. The tumors regress during menopause[12] and after tamoxifen treatment.[13] Desmoid tumors may regress after exposure to oral contraceptives.[14]

The proliferative response of fibroblasts to estrogen has been established.[15]

Frequency

Overall, desmoid tumors are reported to account for 0.03% of all neoplasms.[16] When present in patients with familial polyposis of the colon, the prevalence of desmoid tumors is as high as 13%.[17]

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,[18] 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 al in 2006, with an average age at diagnosis of 41.3 years.[18]

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.

Local desmoid tumor recurrence rates are reported to be as high as 70%. A positive surgical margin is a significant risk factor for recurrence.[19, 20]  The prognostic value of miRNA expression profiling has been suggested as a way to delineate surgical candidates from those who might be monitored without treatment.[21]

Intra-abdominal desmoid tumors may kill patients with familial adenomatous polyposis.[22] Five-year survival rates of such patients with stage I, II, III, and IV intra-abdominal desmoid tumors were found to be 95%, 100%, 89%, and 76%, respectively. The 5-year survival rate of stage IV patients with severe pain/narcotic dependency, tumor size larger than 10 cm, and need for total parenteral nutrition was only 53%.

A study of 179 patients with primary, sporadic desmoid tumors who had complete surgical resection found that those with the S45F mutation had a greater tendency for local recurrence than those without it.[23]

Although desmoid tumors can arise in any skeletal muscle, they most commonly develop in the anterior abdominal wall and shoulder girdle.

Retroperitoneal neoplasms are more common in familial polyposis coli and Gardner syndrome after abdominal surgery than in other conditions.[24]

Clusters of cases in families without evidence of any associated syndromes have also been reported.[25]

A history of trauma (often surgical) to the site of the desmoid tumor is elicited in 1 in 4 cases.[26] . Implant-associated breast desmoid tumors may occur.[27]

Peripheral desmoid tumors

Peripheral desmoid tumors are firm, smooth, and mobile. They often adhere to surrounding structures. The overlying skin is usually unaffected. The presence of such a soft tissue growth should alert the clinician to delve more deeply into the family history for evidence of familial polyposis coli and Gardner syndrome. Extra-abdominal desmoid tumors are rare and may be first evident as gradually increasing leg swelling.[28] Desmoid tumors may rarely appear on the foot.[29]

Intra-abdominal and extra-abdominal desmoid tumors

Intra-abdominal desmoid tumors may be seen. Extra-abdominal desmoid tumors may also be seen (rarely) in the urological system, including in the bladder and scrotum.[30, 31] Intra-abdominal desmoid tumors remain asymptomatic until their growth and infiltration cause visceral compression. Symptoms of intestinal, vascular, ureteric, or neural involvement may be the initial manifestations. An ethmoidal desmoid tumor has been described in a pediatric patient.[32]

Breast desmoid tumors

Desmoid tumors account for 0.2% of primary breast tumors, developing from muscular fasciae and aponeuroses.[33] Desmoid tumors may mimic breast cancer.[34]

Immunostaining with vimentin, alpha smooth muscle actin, muscle actin, and desmin are helpful in distinguishing the tumors in the differential diagnosis of desmoid tumors.

APC germline mutations in apparently sporadic desmoid tumor patients who have no clinical or familial signs of familial adenomatous polyposis (FAP) but have a family history of colorectal carcinoma in at least one family member were evaluated by Brueckl et al[4] in 2005. They reported that patients with sporadic desmoid tumors and no clinical or laboratory signs of FAP may not need to be routinely tested for germline mutations of the APC gene. However, performing an APC mutational analysis instead of other tests (eg, esophagogastroduodenoscopy, complete colonoscopy) may be a more time- and cost-effective plan.

CT scanning and MRI are used for the diagnosis and follow-up of desmoid tumors. They can help determine the extent of the tumor and its relationship to nearby structures, especially prior to surgical removal. MRI is superior to CT scanning in defining the pattern and the extent of involvement as well as in determining if recurrence has occurred after surgery.

The preferred diagnostic test is biopsy of the tumor. A fine-needle aspiration biopsy specimen may be considered.[35]

Electron microscopy may be performed. On electron microscopic examination, the spindle cells of desmoid tumors appear to be myofibroblasts. This finding is thought to represent an abnormal proliferation of myofibroblasts, which normally disappear gradually during the later stages of wound healing.

Colonoscopy and fundal examination are indicated to investigate for the presence of Gardner syndrome.

The tumors are composed of abundant collagen surrounding poorly circumscribed bundles of spindle cells. The dense bundles of eosinophilic spindle cells contain regular nuclei and pale cytoplasm with neither mitoses nor giant cells. Macrophages, giant cells, and lymphocytes are present peripherally.

The aforementioned features are in contrast to those in a fibrosarcoma, which has greater mitotic activity, an increased nuclear-to-cytoplasm ratio, greater vascularity, less collagen production, and a paucity of immune cells.[16]

Bland fibrocytic cells of a desmoid tumor growing in a haphazard-to-storiform manner and producing collagen (hematoxylin-eosin, original magnification X100).

Desmoid tumor spindle cells invading skeletal muscle (hematoxylin-eosin, original magnification X100).

Dermoid tumor spindle cells surrounding and destroying skeletal muscle cells (hematoxylin-eosin, original magnification X100)

Primary surgery with negative surgical margins is the most successful primary treatment modality for desmoid tumors. Positive margins after surgery reflect a high risk for recurrence.[36]  Surgery plus the administration of nonsteroidal anti-inflammatory medication, hormonal therapy, and cytotoxic chemotherapy is sometimes used, the latter being the most effective pharmacological approach.[37]  Since desmoid tumors do not metastasize, many approaches are nonoperative in nature.[38] Since desmoid tumors may stabilize and regress, active observation is an option.

In those patients who refuse surgery or are not surgical candidates, the options below may be considered.

Radiation therapy may be used as a treatment for recurrent disease or as primary therapy to avoid mutilating surgical resection. It may be used postoperatively, preoperatively, or as the sole treatment.[39]

Pharmacologic therapy with antiestrogens and prostaglandin inhibitors may also be used. Pharmacologic agents result in objective response rates of approximately 40-50%; the duration of response is variable.[40]

In cases of recurrent extra-abdominal desmoid tumors in which surgery is contraindicated or in cases of recurrence, a chemotherapeutic regimen of doxorubicin, dacarbazine, and carboplatin may be effective. Intra-abdominal desmoid tumors as a part of Gardner syndrome may respond to systemic doxorubicin, and ifosfamide can be useful for patients with complications from the tumor.[41] Polychemotherapy has been used[42] and can be combined with targeted therapy with imatinib.[43]

Expanded knowledge of familial adenomatosis polyposis–desmoid tumor molecular underpinnings may aid in the development of novel therapeutic strategies.[44]

Magnetic resonance‒guided high-intensity focused ultrasound may prove a safe and effective option for selected desmoid tumors.[45, 46]

Systemic therapy is appropriate if a primary complete resection is not feasible or if there is relapse or progression after resection.[47] There are a number of novel drug therapy candidates for desmoid tumors.[48] Pazopanib, a potent tyrosine kinase inhibitor, represents a promising new therapy for desmoid tumors in adolescent and young adult patients.[49]

Split-course radiotherapy in patients with desmoid tumors was well tolerated with good outcomes.[50]

Aggressive, wide surgical resection is the treatment of choice.[51, 52] Complete surgical excision of desmoid tumors is the most effective method of cure. This sometimes necessitates removal of most of an anterior compartment of a leg. Extensive cases may require excision plus adjuvant treatment including chemotherapy and repeat surgery.[53] In selected patients, radical resection with intraoperative margin evaluation by frozen sections followed by immediate mesh reconstruction may be a safe and effective procedure providing definitive cure yet minimizing functional limitations.[54]  However, there has been a recent tendency to more conservative management.[10] Active surveillance MRI has become a popular option.[55]

Evidence suggests that pregnancy does not adversely affect surgical outcomes.[56]

Lesions involving the extremities and deep soft tissues of the trunk have a higher risk of recurrence, as do Gardner syndrome–associated lesions in other locations.[57]

For tumors that are asymptomatic or nonprogressive, some prefer a wait-and-see approach.[51]

After surgery, MRI may be useful for monitoring desmoid tumor recurrence.

The goals of pharmacotherapy are to induce remission, to prevent complications, and to reduce morbidity.[40] Local recurrences are frequent after surgery, particularly if margins are positive. Radiotherapy alone for gross disease or after a microscopically incomplete resection yields local control rates of approximately 75-80%.

Class Summary

These agents inhibit cell growth and proliferation. Pharmacologic agents result in objective response rates of approximately 40-50%; the duration of response is variable.

Doxorubicin (Adriamycin, Rubex)

Doxorubicin inhibits topoisomerase II and produces free radicals, which may cause the destruction of DNA. The combination of these 2 events, in turn, can inhibit the growth of neoplastic cells.

Dacarbazine (DTIC-Dome)

Dacarbazine inhibits DNA, RNA, and protein synthesis. It inhibits cell replication throughout all phases of the cell cycle.

Carboplatin (Paraplatin)

Carboplatin is an analog of cisplatin. It has the same efficacy as cisplatin but with a better toxicity profile.