Desmoid Tumors

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Desmoid tumors (DTs) are benign fibrous growths which do not metastasize, but tend to invade locally. Although rare in the general population, DTs are not rare in FAP. They may arise in musculoaponeurotic structures throughout the body, but are most common in the abdomen. Desmoid tumors (DTs) affect between 4 and 20% of FAP patients. Within 10 years after colectomy, the cumulative risk of developing DTs is 16% [61], and the cumulative lifetime risk is 21% [62]. The peak incidence is between 28 and 31 years, although they may occur at any age [61,63, 64].

Bertario et al. [65] described independent predictors of DTs in FAP patients: APC mutations beyond codon 1444, family history of desmoids, female gender, and the presence of osteomas. The female-tomale ratio of DTs in FAP is 1.4 [62, 63, 66]. In first-degree relatives of FAP patients with DTs, the relative risk of developing DTs is 2.5, when compared to FAP kindreds with no family history of DTs [61, 63]. Eleven to thirteen percent of patients are diagnosed with DTs before diagnosis of FAP, while 8-19% have a simultaneous diagnosis, and 68-82 % develop DTs after the diagnosis of FAP [63,67].

Desmoid tumors (DTs) in FAP seem to occur on the basis of APC gene inactivation and accumulation of P-catenin in the cells. There is evidence to suggest that a mutation near or beyond codon 1444 may influence the process [68, 69].

A model of DT development has been suggested that is analogous to the adenoma-carcinoma sequence: mesenteric plaque-like precursor lesions progress to mesenteric fibromatosis that can give rise to desmoid tumors [70]. Desmoid tumors often develop in surgical scars, leading to the theory that surgical trauma is a potential initiating factor. Abdominal surgery precedes development of DTs in 68-83% of FAP patients, and in most cases a colectomy has been performed [63, 66, 71, 72]. There is no evidence to suggest that the extent or type of surgery influences DT development [62, 70, 73, 74]. Estrogen is considered to influence the development and growth of DTs [63]. Therefore, estrogen-blocking drugs are part of the usual treatment of these tumors.

Desmoid tumors are homogeneous, firm lesions that have no capsule. They vary in size from multiple small plaques to large tumors. Histological sections show highly differentiated fibroblasts and myofi-broblasts, embedded in a matrix of collagen, with a normal number of mitoses and a lack of atypia. Desmoid tumors invade muscles and aponeuroses, attach to and erode bone and engulf rather than invade blood vessels, nerves, ureters and other hollow organs.

The histological diagnosis might be difficult. Occasional confusion with highly differentiated sarcoma may exist [75]. Transformation to sarcoma is extremely rare [76]. In FAP patients, 50% of DTs are intra-abdominal, 40% occur in the abdominal wall, and 10% on the extremities. Among the intraabdominal DTs, 85-100% are located in the mesentery and 15% in the retroperitoneum [62, 67]. Desmoid tumors often present as a slow growing , non-tender, abdominal mass, although rapid growth has been reported [77] and they rarely regress spontaneously [66, 78]. Intra-abdominal DTs are often asymptomatic. The most common symptom is abdominal pain, which occurs in only about one third of patients. Discomfort, nausea, vomiting, diarrhea and hematochezia are less common. Desmoid tumors may cause small-bowel obstruction and hydronephrosis as a result of intestinal or ureteric compression [79]. Fistula between the tumor and the ureters or intestine [80, 81], abscess formation or intestinal perforation with peritonitis are infrequent complications [66]. Mesenteric vessels encasement may lead to ischaemia of the small bowel [82]. Development of DTs often impairs the outcome of patients with an ileal pouch-anal anastomosis, and it might become necessary to remove the pouch or create a permanent diverting stoma [74, 82]. A rapidly growing tumor might cause symptoms during pregnancy and interfere with normal maturation and delivery of the fetus prompting surgical resection [83]. The relation between FAP and mesenteric DTs is well established, and therefore it is recommended to perform a sigmoidoscopy whenever a mesenteric DT is diagnosed. [84-87]. Incidental intra-abdominal DTs were identified in 3% of FAP patients during the first laparotomy, and in 30% during a second laparotomy. Interestingly, an incidental finding of DTs influenced the intended procedure (e.g., ileal pouch anal anastomosis) in only 13 and 30% of the first and second laparotomy, respectively [88]. In addition, the incidental finding of desmoid reaction during laparoto-my may have little bearing on the subsequent development of clinically significant intra-abdominal DTs [88].

Diagnosis

Desmoid tumors (DTs) in the abdominal wall are diagnosed by histological examination of a percutaneous biopsy; a CT scan is done to obtain accurate information on the extension of the abdominal tumor and to monitor the outcome of treatment [89]. Magnetic resonance imaging (MRI) has proved valuable in the diagnosis of DTs on the extremities [90]. When surgery is being considered, mesenteric angiography or MR angiography are useful in demonstrating the possible relationships to major mesenteric vessels [84].

Treatment

Medical treatment of DTs is still almost empirical as large prospective randomized studies are lacking. Sulindac, a COX inhibitor with prolonged effect is frequently used either alone or in combination with an anti-estrogen [66, 85, 91]. Desmoid tumors response rates to treatment with Sulindac alone or in combination with anti-estrogen or Warfarin were 33-50% in several studies [66, 84, 92, 93]; however, others have reported less encouraging results [72]. COX 2 inhibitors (Celecoxib) were also suggested, although clinical benefit has not yet been demonstrated [94, 95].

Anti-estrogens are frequently used in combination with a NSAID as first-line treatment in patients with non-complicated DTs [84, 85, 91, 96]. The choice is between tamoxifen or its analogues (toremifene, raloxifen). Several small studies demonstrate estrogen receptors in 33-75% of DTs [91, 97]. However, the effect of anti-estrogen therapy is not exclusively mediated through estrogen receptors, as some DT swithout estrogen receptors also responds to anti-estrogen [86, 97]. An overall response to this treatment is seen in about 50% of the patients [84,86,92]. Other reports were less optimistic [66, 93, 94].

Cytotoxic chemotherapy had proven valuable in the treatment of fibrosarcomas and, because of this, several studies have investigated its effect on DTs [72, 75,98-101]. Some have demonstrated partial or complete response to a combination of doxorubicin and dacarbazine in 46-100% of patients [72, 98,99]. Oth ers could not reproduce similar results [100]. In addition, the morbidity and mortality related to cytotoxic chemotherapy is considerable [98-100]. Most authors therefore recommend that the use of cyto-toxic chemotherapy should be limited to patients with large unresectable mesenteric or retroperitoneal DTs which do not respond to treatment with sulindac and anti-estrogen [75, 98-100, 102]. Other combinations of chemotherapeutic agents have been suggested for treating patients who had previously failed medical treatment or to those with inoperable aggressive fibromatosis [103,104].

Radiotherapy is not recommended by most authors, since DTs are frequently located in the mesenterium, where irradiation might cause unacceptable complications [64-72]. In addition, its efficacy is questionable. Nevertheless, some do recommend radiotherapy for inoperable aggressive fibro-matosis.

Other treatment modality has been reported

Small studies have reported remission with a combination of warfarin and sulindac. Others showed successful treatment with interferon, LHRH analogues, progesterons, ascorbic acid, prednisolone, testosterone, pirfenidone, imatinib mesylate and hyperthermia [92, 105-111]. Some patients with recurrent DTs of the extremities were successfully treated using isolated limb perfusion with tumor necrosis factor-alpha and melphalan [112].

Surgery for DTs of the abdominal wall or the extremities includes wide excision with tumor-free margins. Complications are few, but the reported recurrence rate is 10-68% [62, 78, 87, 113]. Mesenteric or retroperitoneal DTs usually exhibit expansive growth around parts of the small intestine and/or larger mesenteric vessels, and this often renders radical surgical excision impossible. Major complications such as abscess formation, fistulas or short-bowel syndrome were seen in up to 47% of patients after curative or palliative resection with postoperative mortality of 10-60% [64, 71, 72, 84]. Recurrence was seen at a mean interval of 5 years in 78% of the patients after presumed excision for cure [71]. On this basis, excision of a large DTs located in the mesentery or retroperitoneum should not be attempted in non-complicated cases, but only in patients with imminent or manifest bowel obstruction, intestinal ischaemia or hydronephrosis [64, 82, 102]. Surgery is usually targeted to relieve symptoms by performing intestinal bypass or segmental resection rather then tumor excision. Intestinal or multi-visceral allograft or autograft transplantation has been proposed as a lifesaving procedure for other wise untreatable patients with complicated DTs [114, 115].

A staging system that stratifies patients by disease severity of intra-abdominal DTs was recently suggested by the Collaborative Group of the Americas on Inherited Colorectal Cancer [116]. Size of tumor, presence of symptoms, and rate of growth mainly determine the staging and the treatment that is required. They recommend surgery for small symptomatic tumors that are not growing and can be resected with minimal sequela. Surgery should also be considered, when urgent treatment is required for large tumors, rapid growth or life threatening complications. Alternatives in these difficult situations are combination chemotherapy (adriamycin and dacarbazine) and radiation [116]. Intra-abdominal DTs may compromise ileoanal pouch function after restorative proctocolectomy, particularly if the pouch mesentery is involved. This may require a diverting stoma or pouch excision. Pouch salvage is possible in isolated cases with either surgical excision of the tumor or combination chemotherapy [117-119].

Prognosis

About 4-6% of DTs resolve spontaneously [66, 78]. In cases of unresectable mesenteric DTs, the mortality rate has been reported to be as high as 30% [120]. The overall survival rate after 10 years is 63% [84]. Death occurs 3-6 years after being diagnosed with DTs and at an age of 30-40 years [120]. Death due to colorectal cancer is still the most frequent cause of death in FAP patients, but among the EM, DTs are a frequent cause of death [120, 121]. In general, a tumor diameter >10 cm, multiple mesenteric DTs, bilateral hydronephrosis, and extensive mesenteric growth are considered to be bad prognostic signs. Low proliferation of Ki-67 in DTs is associated with RO resection, and has significant positive prognostic value [122].

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