Familial adenomatous polyposis (FAP) is a hereditary condition transmitted in an autosomal dominant fashion. It is characterized by development of hundreds to thousands of adenomatous polyps in the colon and rectum, leading to a nearly 100% risk of cancer by the age of 40 [1]. The condition results from mutation of the APC gene on chromosome 5, and accounts for 1% or less of all colorectal cancers (CRCs) [2]. The risk of death due to CRC is decreased after prophylactic total proctocolectomy. Therefore, the extra-colonic manifestations of FAP are becoming more clinically significant [3]. Among these, desmoid tumors (DTs) and periampullary cancers are currently the most common causes of death after CRC [4].

DTs are poorly understood, frequently aggressive, tumors of mesenchymal origin, which arise in musculoaponeurotic structures. Intra-abdominal desmoids often appear to be surgically-induced, typically by prophylactic colectomy, but can arise in the absence of surgery [5]. DTs are rare soft tissue tumors which can arise sporadically or in association with FAP. The DT is an extra-colonic manifestation of FAP. Despite their inability to metastasize, DTs are frequently locally invasive and may compress surrounding structures. In contrast to sporadic tumors, FAP-associated desmoids usually arise in the abdomen, and are a major cause of morbidity and mortality in patients who have undergone prophylactic colonic surgery. Despite recent research, they remain poorly understood entities, and current treatments generally lack evidence of efficacy.

In the current study, we retrospectively examined the clincopathologic characteristics and outcomes of FAP patients with and without DTs, as well as the risk factors for progression of FAP-related DTs in patients undergoing surgical and pharmacological therapies in a single center.

DTs are rare, with an estimated incidence of 2-5 per million population. The prevalence of DTs in FAP patients is probably between 10% and 15%, approximately 1,000 times that in the general population [6,7]. However, the etiology, behavior, and tumor biology of DT in patients with FAP remain poorly understood. Surgical trauma, pregnancy, and other hormonal influences have been implicated in the development of DT [6,8]. In addition, presence of an APC mutation at the 3′ end of the APC gene is more likely to result in development of DT [9,10]. Some studies [8,11] reported that multiple desmoids are more likely to occur in women. However, in this study, there was no difference in the proportion of multiple desmoids by gender. In general, DT affects 10-15% of patients with FAP. However, in this study, the incidence was 24%, greater than previously reported in the literature. Five out of 18 desmoid patients were referred from other hospitals after the FAP operation or recurrence of DTs. Therefore, the relatively greater incidence of DT observed in our study may be due to the reputation of our center as a higher referral center in Korea.

Some studies have compared sporadic and FAP-related desmoids tumors [12,13]. Patients with FAP related DTs were younger at the time of diagnosis and had CRC more often than patients with sporadic DTs. The proportion of female patients with sporadic DTs was higher than that of males, and half of sporadic DTs were located extra-abdominally, whereas FAP-related DTs were generally intra-abdominal.

The optimal treatment for DTs in FAP patients has not been established; medical and surgical treatments have not been standardized, owing to a lack of understanding of the tumor biology, the rarity of the disease, and the lack of predictably effective agents.

Previous studies reported high recurrence rates and high morbidity rates after surgical resection [7,14]. On the other hand, surgery for intra-abdominal desmoids as well as for abdominal wall and extra-abdominal tumors has been shown to be safe in selected patients [11]. Comparable outcomes were recently reported for surgery and conservative treatment for intra-abdominal desmoids [15]. Surgical treatment is generally more suitable for extra-abdominal and abdominal wall DTs than for mesenteric desmoids [8,11,15].

Commonly used pharmacological agents are NSAIDs and hormonal agents. One systematic review reported favorable outcomes after using NSAIDs, hormonal agents, and cytotoxic chemotherapies [16]. Another study suggested that high-dose tamoxifen (120 mg) and sulindac (300 mg) were the primary treatment for patients with FAP-associated DTs [17]. A recent study found no significant difference in progression-free survival between NSAIDs, hormonal treatment, and a combination of the two [15]. In the current study, four of the six patients who underwent palliative surgery were treated with NSAIDs and hormonal treatment after surgery, and the DTs were stabilized in three patients. Hormonal treatment with NSAIDs also appeared to have a positive effect on unresectable DTs.

Preliminary results for use of imatinib mesylate in treatment of DTs have been encouraging, with partial response rates of 10-15%, and one-year tumor control rates of 36-50% [18,19]. In another study imatinib had no evident positive effect [15]. In our study, in two of the three patients treated with imatinib, this treatment was effective against DTs. Doxorubicin based chemotherapy has recently been reported to be an effective and safe treatment for FAPassociated DTs [15,20-22]. In our study, the DTs were stabilized in one of two patients treated with doxorubicinbased chemotherapy.

There is increasing evidence supporting the use of radiotherapy either before surgery or in combination with surgery, to reduce local recurrence of abdominal wall and extra-abdominal desmoids [23,24]. However, radiotherapy is rarely used for intra-abdominal desmoids because of the risk of radiation enteritis.

A recent study proposed a staging system based on tumor size, symptoms, behavior (growth), and the presence of complications, and the authors tailored their treatment of intra-abdominal DTs according to the stage. Stage I desmoids were watched carefully, and the patients were only occasionally started on NSAID. If a stage I desmoid was found incidentally during surgery and was easily resectable, resection was performed. Stage II tumors were treated by surgery (if resectable with minimal sequelae), and anti-estrogens or NSAIDs were also used whenever possible in order to obtain a faster and more consistent response with a low risk of adverse effects. Stage III desmoids were treated with a combination of NSAID, anti-estrogens, and cytotoxic agents, and patients with stage IV disease received urgent treatment, including major exenterative surgery whenever possible, as well as cytotoxic agents and radiation [25].

In our study, no difference in mortality and progression rate was observed between the curative resection group and the palliative resection group. Intra-abdominal DTs were a sign of locally aggressive tumors with unpredictable behavior requiring multidisciplinary treatment. Due to the possibility of massive small bowel resection, we recommend medical treatment in cases of mesentery DTs. In cases of abdominal wall DTs, we recommend surgical resection. Surgical intervention was also required in cases of bowel obstruction, fistula, and tumor rupture. We believe that the role of surgery is limited to resectable tumors and tumors with complications such as fistulae and bowel obstructions. Although there was no established strategy for medical therapy of DT in our center, we usually started the treatment with sulindac and tamoxifen or tamoxifen and goserelin acetate. We consider treatment with a cytotoxic agent such as doxorubicin-based chemotherapy or imatinib mesylate after failure of primary treatment.

Surgical trauma is a well-known risk factor for desmoids in patients with FAP. Some authors recommend delayed prophylactic surgery for female patients with 3′ APC mutations, since development of DTs is quite likely in these patients [3,24]. In the current study, we found that patients with DTs that were not the consequence of surgical trauma were at increased risk of tumor progression and this showed an association with tumor-related death. DTs unrelated to surgical trauma appeared to relapse despite curative resection. However, this was a small study and a large-scale multicenter study is needed in order to confirm our conclusions.

DTs in patients with FAP are mainly intra-abdominal, particularly mesenteric. A multidisciplinary approach to DT treatment that includes NSAIDs, anti-estrogens, cytotoxic agents, and surgery is needed. However, the role of surgery may be limited to resectable tumors and tumors with complications. Patients with DTs unrelated to surgical trauma appear to have a relatively poor prognosis.