INTRODUCTION — Desmoid tumors are deep-seated, benign, slowly growing fibroblastic neoplasms that arise from musculoaponeurotic stromal elements. The term desmoid originates from the Greek word "desmos", meaning band or tendon-like and was first applied in the 1800s to describe tumors with a tendon-like consistency.
Although they are locally aggressive, desmoids do not have the capacity to establish metastatic lesions. Nevertheless, tumor-related destruction of vital structures and/or organs can be fatal, particularly when they arise in patients with familial adenomatous polyposis (FAP, Gardner's syndrome).
|Desmoid tumors are generally classified as intraabdominal
or extraabdominal. The extraabdominal tumors, which are usually sporadic,
are effectively treated with local therapy. Despite their benign
character, desmoid tumors have a high rate of recurrence with surgery
alone. Patients with multiple local recurrences despite adequate local
therapy are considered for systemic therapy. In contrast, intraabdominal
desmoids, particularly those arising in the setting of FAP, are often
unresectable because they are characterized by diffuse infiltration of the
mesentery. In addition, recurrences tend to become more frequent and
aggressive with each surgical intervention. Systemic therapy options for
these patients include antiinflammatory agents, hormonal agents (eg,
tamoxifen), and cytotoxic chemotherapy.
Thus, desmoid tumors (particularly when they arise in FAP) defy at least two general dogmas that are prevalent in clinical oncology: that low-grade tumors with no known metastatic potential do not kill patients, and that they should not respond to chemotherapy.
EPIDEMIOLOGY — Desmoid tumors are uncommon; they account for about 0.03 percent of all neoplasms, and less than 3 percent of all soft tissue tumors. The estimated incidence in the general population is two to four per million population per year, which in the United States, translates into approximately 900 new tumors annually
Individuals between the ages of 15 and 60 are most often affected; desmoids are rare in the young and in the elderly. They are slightly more common in women than in men and there is no significant racial or ethnic distribution.
The incidence of desmoids is higher in patients with FAP. Desmoids affect from 4 to 20 percent of patients with FAP . The simultaneous appearance of FAP and desmoid tumors was described by Gardner in 1951, and is now designated as Gardner's syndrome Until early elective colectomy became routine in patients with FAP, the dominant cause of death in these patients was carcinoma of the colon. With the increasing use of prophylactic colectomy, desmoid tumors have become an important cause of morbidity and in some instances, mortality Desmoids are responsible for death in up to 11 percent of patients with FAP
HISTOLOGY — Desmoids tend to be large bulky tumors that lack pseudoencapsulation, and locally infiltrate adjacent tissue structures. Histologically, they are characterized by small bundles of spindle cells in an abundant fibrous stroma. The fibroblasts have a propensity to concentrate at the periphery of the lesion, and the cellularity is low. There are usually few mitotic figures and necrosis is absent.
ETIOLOGY AND PATHOGENESIS — The etiology of desmoid tumors is unknown. However, the identification of clonal chromosomal changes in a significant fraction of cases supports the neoplastic nature of these tumors and emerging evidence implicates dysregulated wound healing in the pathogenesis of these and other fibroblastic lesions.
Trisomy 8 and 20 — Nonrandom clonal chromosomal changes, particularly trisomy 8 and/or 20, occur in one-third or more of sporadic desmoid tumors Similar nonrandom genetic aberrations have been found in benign fibrous bone lesions (such as fibrous dysplasia), suggesting a similar pathogenesis Although the clinical relevance of these genetic abnormalities is unclear, their presence appears to be associated with a higher risk of recurrence
As an example, in one report, trisomy 8 and/or trisomy 20 were observed in cells cultured from 6 of 13 desmoid tumors FISH (fluorescence in situ hybridization) analysis performed on the nuclei from 25 desmoid tumors from paraffin blocks or frozen tissue indicated that local recurrence was more likely in desmoids with trisomy. Among patients followed for more than one year, local recurrence was more frequent in tumors with trisomy 8 (four of six as compared to 2 of 17 recurrences in trisomy 8-negative tumors).
The finding of individual trisomies and their association in the same cell is rare in solid tumors, particularly mesenchymal tumors However, these aberrations are known to occur in related benign, fibrous lesions arising in both soft tissue and bone tumors, (eg, Dupuytren's contracture, plantar fibrosis, Peyronie's disease, carpal tunnel syndrome and infantile fibrosarcoma) Trisomy 8 is also a frequent finding in hematologic malignancies, but is remarkably infrequent in nonfibrous solid tumors.
Gardner's syndrome — Gardner's syndrome is a variant of FAP that is distinguished by the presence of prominent extraintestinal lesions, such as desmoid tumors, osteomas, and cysts. When in any member of an FAP family, the family has traditionally been said to have Gardner's syndrome rather than FAP, since all members of the family segregate the same mutation in the adenomatous polyposis coli (APC) gene. Desmoids may be the first manifestation of Gardner's syndrome. Families have also been reported that exhibit desmoids as the only manifestation of an APC mutation.
The estimated risk of developing a desmoid tumor in patients with FAP is between 4 and 20 percent They have a particular predilection for surgical sites (eg, the mesentery or abdominal wall following colectomy, the site of an ileal pouch-anal anastomosis).
In one series, prior abdominal surgery had been performed in 68 percent of patients with FAP and abdominal desmoid tumors; lesions develop within five years after surgery in approximately one-half . One patient dramatically demonstrated this association with surgery. She had been treated, apparently successfully with chemotherapy for an intraabdominal desmoid tumor. To confirm the response, laparoscopy was performed. Within months, desmoid tumors began developing in each of the three trocar sites; the tumors became massive and inoperable and led to the death of the patient.
APC mutations and beta-catenin — Mutations of the APC gene on chromosome 5q are responsible for FAP. More than 300 mutations have been described, most of which lead to frame shifts or premature stop codons, resulting in a truncated APC gene product. Several studies have attempted to correlate specific APC mutations with the clinical phenotype. As a general rule, mutations between codons 169 to 1393 are associated with the classic form of FAP while mutations that are more 3' or 5' are associated with the attenuated form of FAP.
The site of the germline mutation in patients with FAP may be important for the risk of developing a desmoid tumor. Mutations between codons 1445 and 1578 have been associated with desmoid tumors in some reports although others have not found this association
How the abnormal gene promotes the formation of tumors such as desmoids is incompletely understood. However, increasing evidence points to involvement of germline APC mutations in the molecular pathogenesis of desmoids in patients with Gardner's syndrome The normal APC protein prevents the accumulation of beta-catenin, a cytosolic and nuclear protein, by mediating its phosphorylation and resultant degradation. The loss of the beta-catenin regulatory domain in the truncated protein allows beta catenin to accumulate, bind to and activate the transcription factor Tcf-4
Trauma and pregnancy — Up to 30 percent of patients with desmoid tumors have a history that involves antecedent trauma particularly, surgical trauma in patients with FAP (see above). A similar relationship has been observed in some sporadically occurring desmoid tumors. In one series, an antecedent history of trauma at the tumor site was elicited in 28 percent of 32 primary desmoid tumors
Abdominal desmoids tend to occur in women during or following pregnancy. The classic presentation is that of an abdominal mass that is separate from the uterus Trauma related to pregnancy and exposure to elevated hormone levels may both be contributory. As an example, one case report describes a desmoid tumor that developed at the site of a prior cesarean section scar during a subsequent pregnancy . Subsequent pregnancy is not necessarily a risk factor for recurrence or development of new disease in a woman who develops a pregnancy-related desmoid
CLINICAL PRESENTATION AND DIAGNOSIS — Most desmoid tumors present as a painless or minimally painful mass with a history of slow growth. Intraabdominal desmoids can be associated with intestinal obstruction, mucosal ischemia, or functional deterioration in an ileoanal anastomoses (typically in a patient who has undergone colectomy for FAP
Desmoid tumors can develop at virtually any body site; they most commonly arise in the torso (shoulder girdle and hip-buttock region) and the extremities. The location is usually deep in the muscles or along fascial planes. Desmoid tumors may be multifocal on an extremity, but they rarely occur at different regions in the same patient.
Diagnosis — Ultrasound is often the first method of examination of a soft tissue lesion on the torso or extremity. If the mass is solid, CT or MRI are needed to determine adherence to adjacent structures and resectability. Although desmoids can be adequately evaluated by CT, we prefer MRI for definition of the pattern and extent of involvement. There are no radiographic characteristics that can reliably distinguish desmoids from malignant soft tissue tumors.
The diagnosis of a desmoid tumor can only be established by histological examination of a biopsy specimen. Incisional biopsy is often preferred over a needle biopsy because of the need to distinguish between a benign and malignant process with very high confidence.
There is no accepted staging system for desmoid tumors.
Natural history — Although benign, desmoid tumors are locally infiltrative and can be fatal by causing destruction of adjacent vital structures and organs. In a report of 138 patients managed at one institution between 1965 and 1984, 11 died of their disease Factors associated with a poor outcome in this study were: age 18 to 30 years, presentation with locally recurrent disease, incomplete excision, and no postoperative radiation therapy (RT). However, this series may not be representative since many patients had advanced disease at the time of diagnosis. Other centers report an overall mortality rate <1 percent in patients with desmoid tumors at other than intraabdominal sites
Thus, even though desmoids are benign in the sense that they cannot produce distant metastases, the disease process may be devastating, and occasionally fatal. Fortunately, the pace of progression is usually relatively slow, with periods of comparative stability or even temporary regression. Regrowth is not an inevitable consequence following grossly incomplete surgical resection
TREATMENT — Treatment of desmoid tumors is indicated when they cause symptoms, if there is imminent risk to adjacent structures, or if they create cosmetic concerns.
Surgery — Because of their locally infiltrative nature, desmoid tumors are treated by surgical resection with a wide margin when medically and technically feasible. Since these are benign tumors, the treatment strategy should be to obtain tumor-free margins using function-preserving approaches to minimize major morbidity (functional and/or cosmetic).
Extraabdominal and abdominal wall desmoids are more often resectable than are intraabdominal tumors. Surgery may be difficult and even impossible for intraabdominal desmoids, although it may be an important option for selected patients. Medical therapy may be considered as a first-line option, particularly for tumors that involve the mesentery or encase vessels and organs (see below).
Despite their benign character, desmoid tumors have a high rate of recurrence with surgery alone. Even patients who undergo aggressive resection with wide margins have recurrence rates of 23 to 39 percent When they recur, salvage therapy with RT and/or repeat excision is usually successful.
Intraabdominal desmoids that arise in the setting of Gardner's syndrome have a greater tendency for local recurrence and multiple lesions. Moreover, they may be relatively refractory to RT and may be rendered more aggressive after surgical intervention . In one report, as an example, tumor debulking led to aggressive progression of desmoids in four of six patients This has led some clinicians to advocate conservative management with noncytotoxic therapy as opposed to resection and/or RT in these patients although this is controversial
Importance of resection margins — The available data are conflicting with regard to the importance of complete resection. Some authors report that the risk of recurrence is independent of margin status while others demonstrate higher recurrence rates with close or positive resection margins As an example, in one series of 203 patients undergoing surgery for either primary or recurrent desmoid tumors over a 35 year period, margins were microscopically positive in 57 and negative in 146. As expected, the disease-free survival rate was significantly better in patients with primary disease (76 versus 59 percent at 10 years), but it was not significantly worse for those with microscopically positive versus negative margins at primary surgery (five year disease-free survival rate for those with positive and negative margins, 79 versus 82 percent; at 10 years, 74 versus 77 percent).
These data have led some to conclude that aggressive attempts to achieve negative resection margins are not warranted if they result in excessive morbidity. Moreover, uncertainty as to the importance of positive resection margins has led to controversy with regard to the utility of postoperative RT for patients with incompletely resected disease. These data are discussed below.
Radiation therapy — RT is an effective primary therapeutic option for patients who are not good surgical candidates, those who decline surgery, and those for whom surgical morbidity would be excessive. The time to regression after RT alone is often quite long and several years may elapse before regression is complete
In a number of reports, RT alone (50 to 60 Gy) or combined with surgery in patients with positive resection margins achieves long-term control in approximately 70 to 80 percent of desmoids. The volume of disease does not appear to affect the probability of local control.
The contribution of RT to the management of desmoid tumors can be illustrated by the following reports:
The recommended dose of RT for definitive therapy is 50 to 60 Gy in six to seven weeks at 1.8 to 2 Gy per fraction. Local recurrence rates do not appear to be reduced by the use of higher doses. In one study, for example, 23 patients were treated with RT for unresectable disease; the relapse rate at five years was 31 percent. Radiation doses above 56 Gy did not improve outcome, and were associated with more complications (30 versus 5 percent with lower doses at 15 years). Positive resection margins were not an adverse prognostic factor in this report.
Postoperative RT — Postoperative RT is generally not recommended for patients with uninvolved resection margins. The benefit of postoperative RT for those with positive resection margins is controversial. As noted previously, the status of the resection margins has not been shown to significantly increase the risk of recurrence in several retrospective series. Furthermore, even in those series that did show a higher rate of recurrence in patients with positive margins in the absence of RT, successful salvage therapy at the time of recurrence has been possible in the majority of patients
These issues were illustrated in a retrospective analysis of 189 patients treated for desmoid tumors at MD Anderson Cancer Center, 122 with surgery alone, 46 with surgery and RT, and 21 with RT alone. Ten-year local recurrence rates were significantly higher in surgically treated patients who had positive as compared to negative resection margins (54 versus 27 percent), and surgical margin status was the single most significant determinant of recurrence in surgically treated patients. Among the 40 patients with incompletely resected desmoids, local recurrence rates were significantly lower if postoperative RT was added (10-year recurrence rates 31 versus 54 percent). However, salvage treatment with surgery or RT was successful in 43 of the 58 patients who recurred (including 7 of the 10 with positive initial resection margins), and no patients died of aggressive fibromatosis.
The benefit of RT plus surgery was further addressed in a comparative review of published experience with treatment of desmoid tumors. Local control rates after surgery alone (n = 381) were 61 percent overall, and were 72 and 41 percent for those with negative or positive margins, respectively. For patients undergoing surgery plus RT (n = 297), the local control rate was 75 percent overall, and it was 94 and 75 percent for cases with negative and positive margins, respectively. The overall local control rate for RT alone (n = 102) was 78 percent, and was 83 and 73 percent for those treated for primary or recurrent tumors, respectively.
From these data, many clinicians (including our group) conclude that local failure is not inevitable if residual tumor is left in situ. Deferring radiation is an acceptable option for patients with microscopically positive margins as long as local progression, if it occurred, would not risk significant morbidity. However, we and others recommend postoperative irradiation for microscopically positive margins after resection of recurrent disease, and for patients with gross or macroscopic residual disease.
Others disagree, citing the importance of local control to cure of this nonmetastatic condition, and the greater likelihood of local control with either RT alone or surgery followed by RT for incompletely resected disease. A prospective randomized trial is currently underway by the American College of Surgeons Oncology Group (ACOSOG trial Z9031), in which patients with retroperitoneal sarcomas (including desmoid tumors) are randomly assigned to surgery with or without preoperative RT . Eligible patients should be encouraged to participate.
Neoadjuvant therapy — A novel approach to reducing the rate of local recurrence is the use of neoadjuvant (preoperative) radiotherapy with or without chemotherapy:
While these results are promising, confirmation with larger, prospective, randomized trials is needed.
Systemic therapy — Patients with extraabdominal desmoids and multiple locoregional recurrences despite adequate local therapy are generally considered for systemic therapy. Other indications for systemic therapy include unresectable tumors, and intraabdominal desmoids, especially those associated with familial adenomatous polyposis (FAP). In such patients, early and aggressive systemic therapy is important to avoid life-threatening complications.
A variety of agents are active, including noncytotoxic therapy (NSAIDs, hormone manipulation, pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone), an antifibroblast agent) and cytotoxic chemotherapy. Most of the reported data come from isolated case reports, limiting the conclusions that can be drawn as to the relative effectiveness of these agents in the treatment of desmoid tumors.
An important point is that clinical situations without any impending threat to life or function can be treated with less toxic approaches, such as hormone therapy or NSAIDs. Cytotoxic chemotherapy is a more appropriate choice for patients with rapidly growing tumors, or those who are highly symptomatic.
Noncytotoxic systemic therapy — Clinical and experimental evidence suggest the hormone dependency of desmoid growth. Particularly in patients who do not have good options for surgery or radiation, therapy is often begun with a hormonal agent such as tamoxifen; there is less published experience with the antiestrogen toremifene, raloxifene, or progestational agents
Clinical benefit (symptomatic improvement with shrinkage or stabilization of disease) is reported in approximately 50 percent of patients, with most of the objective responses being partial rather than complete. Tumors are slow to manifest an actual reduction in size, not infrequently, shrinkage lags behind discontinuation of therapy by months or even years. Response durations range from seven months to 12 years
The mechanism underlying benefit is unclear since responses to tamoxifen have been seen in desmoids that do not express hormone receptors. The latency of the therapeutic response has led some to suggest that the mechanism of action could be deprivation of a growth signal or cytokine, which results in prolonged and continued regression long after treatment discontinuation.
There are also documented responses to NSAIDs (most often sulindac), both alone and in combination with tamoxifen. Although response rates as high as 70 percent are reported with combined therapy, regression is usually partial and may take many months after an initial period of tumor enlargement. In one report, 10 of 13 patients with FAP-associated desmoids responded to daily tamoxifen (120 mg daily) and sulindac (300 mg daily), as did two of eight recurrent sporadic tumors.
The contribution of tamoxifen to these results is unclear. At least one report documents the resolution of a desmoid tumor being treated with indomethacin and ascorbic acid for 14 months. NSAIDs alone represent a potentially attractive treatment option, particularly since they also appear to protect against colon cancer.
Several case reports describe objective response or prolonged periods of disease stabilization with interferon alfa, in some cases following failure of sulindac and tamoxifen
An important point is that many of the above clinical studies using noncytotoxic agents predate the widespread use of objective response criteria such as the RECIST criteria. Most experts treating large numbers of these recurrent tumors find that the true objective regression rates with these agents is in the range of 10 to 15 percent range with another 25 percent of patients experiencing minor shrinkage or tumor stabilization (clinical benefit rate 50 percent).
Chemotherapy — As noted previously, desmoid tumors, particularly those arising in the setting of FAP, defy a prevalent dogma in clinical oncology that slow-growing tumors without metastatic potential should not respond to chemotherapy. In fact, several regimens are active, and in all cases, durable response lasting years have been reported, clearly establishing the efficacy of chemotherapy in this disease
Since randomized trials are not available, the optimal regimen is uncertain . In general, an approach which matches the expected toxicity of systemic therapy with the degree of symptoms caused by the tumor or the rate of tumor growth appears to be the most reasonable.
Imatinib — At least one case report suggests clinical and radiographic benefit from the tyrosine kinase inhibitor imatinib (Gleevec®), an effect that is presumably due to tumor expression of activated receptor tyrosine kinases c-kit and/or platelet-derived growth factor receptor (PDGFR) . A study of imatinib in 50 patients with recurrent desmoid tumors was completed by the Sarcoma Alliance for Research through Collaboration, and preliminary data presented at the 2004 meeting of the American Society of Clinical Oncology. The two and four month the progression free survival rates were 91 and 78 percent, respectively. Polymorphisms and mutations were found in exon 18 of PDGFR-alpha in some patients. Maturation of these data will be needed to determine the true clinical efficacy of imatinib in patients with desmoid tumors.
Antifibrotic agents — Antifibrotic agents seem to represent a rational choice for therapy. Experience with one such agent, pirfenidone, is limited to a pilot trial of 14 patients. Two of the seven patients who continued therapy for at least 18 months had partial tumor regression. This agent is not approved for use in the United States or Europe.
Percutaneous chemical ablation — At least one report suggests that percutaneous injection of acetic acid into the desmoid can achieve objective tumor shrinkage and prolonged periods of disease stabilization. Further experience with this approach is needed.
SUMMARY AND RECOMMENDATIONS — Desmoid tumors (also called aggressive fibromatosis) are benign slowly growing fibroblastic neoplasms. Although desmoids do not have the capacity to establish metastatic lesions they infiltrate adjacent tissues, causing destruction of structures and/or organs that can be fatal. Nevertheless, the likelihood of dying from aggressive fibromatosis is very low (<1 percent).
Treatment of desmoids is a clinical challenge. Although these are benign tumors, because of their locally aggressive behavior and tendency to relapse, multimodality treatment is often required, and best delivered within the context of a multidisciplinary team specializing in sarcoma treatment. Treatment recommendations should be based upon analysis of the risk-to-benefit ratio because of the inconsistent nature and response to treatment of this tumor.