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Acta Orthop. Belg., 2004, 70, 199-203
Treatment of aggressive fibromatosis :
A multidisciplinary approach
predilection for patients between 20 and 40 years(5, 24, 28). AF is a fibroproliferative disorder charac- Desmoid tumours are dense fibroblastic tumours terised by a monoclonal proliferation of fibroblast- occurring in any mesenchymal tissue at the site of like cells. A similar excessive proliferative stage is a fascia. It is usual to distinguish extra-abdominal also observed in wound healing. AF occurs most and abdominal forms, although they are micro- frequently as a sporadic lesion, but it may also scopically similar. The extra-abdominal variety is occur as part of familial adenomatous polyposis also called aggressive fibromatosis (AF). Ab- coli, a rare disease caused by an autosomal heredi- dominal desmoid involves either the abdominal tary condition due to mutation of the adenomatous wall, particularly the lower part of the rectus abdo- polyposis coli (APC) gene on chromosome 5. The minis muscle, or the abdominal cavity where it disease is associated with osteoma, aggressive arises in the mesentery or from any muscular struc- fibromatosis and other soft tissue tumours, and ture. The abdominal variety tends to occur more polyposis of the colon. Interestingly, the APC gene frequently in women of child-bearing age. This helps regulate the cellular level of beta-catenin, a review will only focus on the extra-abdominal vari- signal protein secreted by fibroblasts, which binds transcription factors. In AF, beta-catenin is elevated AF is a tumour with many contrasts: it is a pure- and causes cell proliferation. In a transgenic mouse ly benign process but it may infiltrate vital struc- strain having a genetically modified beta-catenin tures and cause severe morbidity. The growth metabolism, AF will develop (6). AF may also potential can be high in some cases, with early develop after removal of a Gardner’s fibroma recurrence, whereas spontaneous regression can be which appears as a first symptom of a Gardner’s syndrome (30). AF displays various chromosomal Owing to such a disconcerting tumoral behav- alterations with trisomies in chromosome 8 and 20 iour, the treatment has been a matter for debate and and deletion on parts of chromosome 5 (8). Fifteen EPIDEMIOLOGICAL, GENETIC and CLINI-
From Cliniques Universitaires Saint-Luc, Brussels, Belgium. CAL ASPECTS
Christian Delloye, MD, PhD, Professor and Chairman.
Didier Viejo-Fuertes, MD, Senior Registrar.
AF is a rare occurrence with a prevalence of Department of Orthopaedics and Trauma Surgery.
Pierre Scalliet, MD, Professor and Chairman.
about three persons per million individuals (4, 25).
Radiotherapy Department and Center for Cancer. There is no racial predisposition. It occurs slightly Cliniques Universitaires Saint-Luc, 10 avenue Hippocrate ; more frequently in females and may concern a broad age range from 3 to 70 years but with a Acta Orthopædica Belgica, Vol. 70 - 3 - 2004 C. DELLOYE, D. VIEJO-FUERTES, P. SCALLIET percent of sporadic cases of AF display somatic tions are based on retrospective studies or reviews. APC mutations and 60 % of those without APC Even more, the aggressiveness of the disease alteration have a mutation in the beta-catenin genes appears highly variable : spontaneous regressions that impair its degradation (1, 29).
have been reported (3, 7) whereas some patients left Cyclooxygenase-2 (Cox-2) is an enzyme in- with contaminated margins after surgery did not volved in prostaglandin synthesis and is dependent experience recurrence. No one single treatment on the presence of beta-catenin. Cox-2 is overex- emerges as most effective and modern trends rely pressed in AF. Cox-blocking drugs might decrease on a customised algorithm for treatment. the cell proliferation in AF (22).
AF has been observed appearing in surgical Surgery alone
scars (14) or in a previously traumatised area (12).
Clinically, the most frequent complaint is a non Because of its marked propensity to recur, wide painful deep mass that is slowly growing. Symp- local excision has been the preferred treatment. It is toms may be caused by compression on adjacent meant that surgery will remove the pathologic tis- structures. The tumour is firm on physical exami- sue with a margin of at least 10 mm of healthy tis- nation. It is a plain mass. AF may affect the limbs, sue. In a non encapsulated and infiltrative patholo- the head, the neck and the trunk. In the limbs, it gy, the surgical achievement of a healthy, unconta- shows a predilection for the shoulder and the but- minated margin is of importance. One of the diffi- tock. More rarely, AF may be multicentric. AF is culties associated with surgery is the adequate benign with a strong propensity to recur locally, assessment of the extent of AF. The infiltrative even after wide resection. It can cause significant nature of the tumour makes it difficult to assess morbidity owing to its ability to infiltrate any during surgery the true microscopic extent of the anatomical structure. Desmoid tumour is a benign pathologic process. Reflecting this difficulty, the tumour but not a benign disease (23). reported rate of a contaminated margin after Magnetic resonance imaging (MRI) is the most surgery is high, ranging from 44 % (31) to 61 % (17).
appropriate imaging modality to demonstrate the However, achieving wide surgical resection does not necessarily ensure control of the disease andconversely, a positive margin does not imply a HISTOLOGY
recurrence, emphasising the highly variable behav-iour of the process. Recurrence rates ranging from AF is a proliferation of well-differentiated zero to 28 % after wide excision with non contam- fibroblasts arranged in parallel rows separated by inated margins have been reported (3, 19, 31). Such variable amounts of collagen. It is a dense fibrous occurrence becomes significantly higher when the tumour which lacks a capsule and which infiltrates resected specimen has contaminated limits, with along fascial planes and may invade any adjacent recurrence rates in the range of 40 to 60 % (3, 19, structures. Mitoses, cellular atypia and necrosis are 31). Most but not all studies (11, 18, 25) agree that a positive margin at surgery will cause a higherrecurrence rate. This finding has stimulated the TREATMENT OPTIONS
combined use of radiotherapy as an adjuvant tocontrol the disease. Recurrent disease has a worse Desmoid tumours can be frustrating to manage prognosis than primary lesions with respect to the because no one treatment offers a high likelihood of achieving remission. There are several options totreat desmoid tumours : surgery, radiotherapy, Radiotherapy alone
chemotherapy, isolated tumour perfusion and hor-monal therapy. Randomised studies on treatment Radiation is an effective option to treat AF, alone modalities are lacking and current recommenda- or combined with surgery. Radiation alone is at Acta Orthopædica Belgica, Vol. 70 - 3 - 2004 least equal in controlling the disease to surgery vitro studies indicate however that this molecule alone with negative margins when assessed with has a growth inhibitory effect on these cells rather the 5- and 10-year relapse rate (3, 19, 31). The aver- than an anti-oestrogen effect (27). This tumour lacks age dose is 50-60 Gy, whereas exceeding this range the oestrogen receptors when assayed by immuno- will cause a significant rise in radiation complica- tion (3). Approximately 20 % of the patients treated Chemotherapy has been advocated sporadically with radiation will develop complications (3, 19).
in desmoid tumours not amenable to surgery or Fibrosis is the main complication but secondary radiation. Vinblastine-methotrexate or doxoru- sarcoma (0.7 %) has also been reported as a late bicine-dacabarzine are the most frequently report- complication (19). Another problem is the delin- ed regimens (2, 4, 20, 26, 28).
eation of the irradiation volume for a non encapsu- Isolated limb perfusion appears to be one of the lated disease that propagates along the main axis of promising treatments of AF in the limbs. The iso- muscles and fascia. A margin of 5-8 cm in the main lated limb is perfused with melphalan and tumour axis should be included in the radiation field (3).
necrosis factor, a potent anti-neoangiogenic mole-cule. Successful results have been reported at short Combined surgery and radiotherapy
term in recurrent desmoid tumours but need to befurther confirmed (9). This association appears to be the most effective in controlling the disease. In cases with negative PROGNOSTIC FACTORS
margins, the value of radiotherapy remains ques-tionable whereas in cases with positive margins, There is no general agreement on the signifi- the impact of external beam radiation is significant, cance of various parameters. Among the reported with a recurrence rate falling from 52 % with significant factors for recurrence are: recurrent pre- surgery alone to 26 % with both treatments com- sentation (23, 31, 29), positive margin (2, 16, 18, 31) and age below 18 years (31). Among most reportednon significant variables are : age, gender, site and Pharmacological agents
A large variety of molecules have been tried in STRATEGY
the conservative treatment of AF. Most concernpatients with a contraindication to surgery or radi- Once confirmed with biopsy, the behaviour of ation, or with relapsing disease. A review of this the tumour should be monitored with MRI. Stable mode of treatment has been made recently (4, 13, lesions can be observed at regular intervals with 26). No conclusive results have emerged so far from imaging studies. Anti-cox 2 drugs should be given.
the literature. The most commonly reported agents A progressing tumour needs to be treated. If AF is are : anti-inflammatory drugs, hormonal therapy, amenable to surgery, surgery with the aim of achieving negative margins should be the treatment Anti-inflammatory agents have been used suc- of choice. When considering surgery, if an impor- cessfully but conclusive results are lacking so far.
tant functional deficit is anticipated for achieving Since two years, the role of cox-2 in the AF prolif- negative margins, radiotherapy alone should be eration has been emphasised (22). The use of anti- given. Mutilating or ablative surgery will be ex- Cox 2 nonsteroidal antiinflammatory drugs in AF cluded. If the surgical margins appear contaminat- appears relevant and should be tried as an adjuvant ed, then postoperative radiotherapy should be given therapy to slow down the tumour growth.
at a dose range of 50-60 Gy. In case of recurrence, Tamoxifen, an oestrogen antagonist has often surgery when possible will be associated with been used in unoperable cases on the assumption radiotherapy or radiotherapy alone can be per- that this tumour can display oestrogen receptors. In formed. In case of recurrence after irradiation, iso- Acta Orthopædica Belgica, Vol. 70 - 3 - 2004 C. DELLOYE, D. VIEJO-FUERTES, P. SCALLIET lated limb perfusion will be considered. Medical 7. Dalen B, Bergh P, Gunterberg B. Desmoid tumors : a
treatment can be given after these first three lines clinical review of 30 patients with more than 20 years fol- low-up. Acta Orthop Scand 2003 ; 74 : 455-459.
8. De Wever I, Dal Cin P, Fletcher C et al. Cytogenetic,
clinical and morphologic correlations in 78 cases of fibro- CONCLUSIONS
matosis : a report from the CHAMP study group. ModPathol 2000 ; 13 : 1080-1085.
AF should be managed with a multidisciplinary 9. Eggermont A, de Wilt JH, ten Hagen T. Current uses of
isolated limb perfusion in the clinic and a model system for approach. Although curative surgery should be new strategies. Lancet Oncol 2003 ; 4 : 429-437.
advocated first, the location, the size of the tumour, 10. Fernberg J, Brosjö O, Larsson O, Soderlund V,
the patient history should be taken into considera- Strander H. Interferon-induced remission in aggressive
tion to decide which modality is most appropriate.
fibromatosis of the lower extremity. Acta Oncol 1999 ; 38 : The natural history of this benign tumour remains unclear. Some continue to grow while others are 11. Gronchi A, Casali P, Mariani L et al. Quality of surgery
and outcome in extra-abdominal aggressive fibromatosis : easily controlled. The growing capacity of the a series of patients surgically treated at a single institution.
tumour should be documented with MRI.
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Contemporary views still set surgery as a first 12. Icard P, Le Rochais JP, Galateau E, Evrard C. Desmoid
line when appropriate. Radiotherapy should be fibromatosis of the shoulder and of the upper chest wall used when doubt persists about the quality of the after a clavicular fracture. Eur J Card Thorac Surg 1999 ; margin after surgical treatment. Isolated limb per- 13. Janinis J, Patriki M, Vini L, Aravantinos G, Whelan J.
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laparoscopic trocar site. Ann Surg 1998 ; 64 : 388-390.
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treatment options should be based on a risk/benefit ment of extraabdominal desmoid tumors with interferon-alpha with or without tretinoin. J Surg Oncol 2000 ; 73 : 16. McCollough M, Parsons J, Van Der Griend R,
Enneking W, Heare T. Radiation therapy for aggressive
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1. Alman B, Pajerski M, Diaz-Cano S, Wolfe H. Increased
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2. Azarelli A, Gronchi A, Bertulli R et al. Low-dose chemo-
18. Merchant N, Lewis J, Woodruff J, Leung D, Brennan
therapy with methotrexate and vinblastine for patients with M. Extremity and trunk desmoid tumors. A multifactorial
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19. Nuyttens J, Rust P, Thomas C, Turrisi A. Surgery versus
3. Ballo M, Zagars G, Pollack A. Radiation therapy in the
radiation therapy for patients with AF or desmoid tumors.
management of desmoid tumors. Int J Radiation Oncology Cancer 2000 ; 88 : 1517-1523.
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20. Okuno S, Edmonson J. Combination chemotherapy for
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Clevers H, Alman B. Beta-catenin stabilization dysregu-
2) modulates proliferation in aggressive fibromatosis lates mesenchymal cell proliferation, motility, and inva- (desmoid tumor). Oncogene 2001 ; 20 : 451-460.
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28. Spear M, Jennings C, Mankin H et al. Individualizing
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