CTOS Op Ed

Extra-abdominal Primary Fibromatosis:
Strategy According to Molecular Findings?

An ESUN Article

Sylvie Bonvalot, MD, PhD
Department of Surgery
Institut Gustave Roussy
Villejuif, France

Editor's Note: This editorial is part of an ongoing series of Op Ed pieces written by one of the members of the Board of Directors of the Connective Tissue Oncology Society (CTOS). Dr. Sylvie Bonvalot was a member of the CTOS Board until 2007. She will present her clinical experience as a sarcoma surgeon on "wait-and-see" protocols for fibromatosis at the upcoming CTOS meeting in London (November 13-15, 2008). These These editorials are intended to address important and controversial issues in the field. The "Questions, Comments & Counterpoint" column allows readers to express their opinions in response to these Op Ed pieces. Click here to send in an opinion.

Sporadic aggressive fibromatosis has a high tendency for local recurrence, even after apparently adequate resection. In institutional retrospective studies, local failure rates range between 25-60% at 5 years. This wide range shows the great variability of accrual, treatments and follow-up in such a rare disease which has never been investigated in a controlled randomized study. Traditionally, patients undergo standard surgery approaches with the primary goal always being complete resection with negative margins, as indicated for sarcomas.

However, differences in the aggressive nature of these tumours exist and surgical indications change over time. During the last 10 years, the following concepts evolved from individual series. In 1998, the standard treatment was primary resection with negative margins when feasible, and exclusive radiotherapy was proposed in situations where surgery would result in major functional or cosmetic defects (1). After that, authors (2) advocated function-sparing operations, and concluded that attempting to achieve the goal of negative margins could result in unnecessary morbidity. Thus, function-sparing surgery became a "reasonable" choice when feasible without leaving macroscopic residual disease. Medical observation alone was first proposed for recurrent but stable lesions (3). After that, an initial period of expectant observation was proposed in case of irresectable primary tumour (4). In 2007, neoadjuvant treatments were introduced since they could be associated with improved patient outcome (5). Some tumours respond to chemotherapy (6) or other systemic treatments, thereby avoiding the functional consequences of surgery. More recently, Imatinib has been tested on advanced aggressive fibromatosis (7). Presently, authors address the question whether surgery and other aggressive treatments should systematically be part of first-line treatment (8). In this last study, a subset of patients with extra abdominal primary fibromatosis was managed with a systematic, non-aggressive protocol, and growth arrest occurred in 2/3 of non-operated patients. This "non-aggressive" protocol was applied on a larger multi-institutional series of patients (9) and its implementation avoided aggressive surgery or radiotherapy on the majority of primary tumours.

Discrepancies between the results of the impact of the quality of surgery suggest that additional factors may influence the natural history of these tumours. Among these factors, intrinsic biological characteristics of tumour cells and the host microenvironment could account for highly diverse outcomes. The subgroup of progressive or recurrent tumours might have the same aggressive biological characteristics, whatever their treatment. Molecular determinants of fibromatosis recurrence or progression remain obscure. Recently (10), the prevalence of the mutations of the gene encoding beta-catenin was evaluated in a large cohort of sporadic desmoids (180 patients). Mutations were observed in 85% of the specimens. Four mutations in two codons of exon 3 were identified: T41A (41%), S45F (36%), and S45P (4%), AA 45 (3%). In another retrospective study (11), five-year recurrence-free survival was significantly poorer in S45F-mutated desmoids (23%, P < 0.0001) versus either T41A (57%) or non-mutated tumors (65%). Nuclear beta-catenin expression was observed in 98% of specimens and intensity was inversely correlated with incidence of desmoid recurrence (P < 0.01).

Clearly, we need prospective studies to understand the molecular mechanisms behind desmoid tumorigenesis and progression, and to confirm whether some mutations are at particular risk for recurrence or progression. The final objective is to use molecular findings of tumours to individualize the selection of management protocols. This application of personalized medicine in fibromatosis could lead to the right treatment at the right time for the optimal outcome.

References

  1. Spear MA, Jennings LC, Mankin HJ et al. Individualizing management of aggressive fibromatoses. Int J Radiat Oncol Biol Phys. 1998; 40(3):637-45.

  2. Merchant NB, Lewis JJ, Woodruff JM, et al. Extremity and trunk desmoid tumors: a multifactorial analysis of outcome. Cancer 1999; 86(10):2045-52.

  3. Pignatti G, Barbanti-Brodano G, Ferrari D et al. Extraabdominal desmoid tumor. A study of 83 cases. Orthop Relat Res. 2000;(375):207-13

  4. Phillips SR, A'Hern R, Thomas JM. Aggressive fibromatosis of the abdominal wall, limbs and limb girdles. Br J Surg. 2004; 91(12):1624-9.

  5. Lev D, Kotilingam D, Wei C, et al.Optimizing treatment of desmoid tumors.J Clin Oncol. 2007 May 1;25(13):1785-91.

  6. Patel SR, Benjamin RS. Desmoid tumors respond to chemotherapy: defying the dogma in oncology. J Clin Oncol. 2006 Jan 1; 24(1):11-2.

  7. Heinrich MC, McArthur GA, Demetri GD, et al. Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). J Clin Oncol. 2006 Mar 1; 24(7):1195-203.

  8. Bonvalot S, Eldweny H, Haddad V, et al. Extra-abdominal primary fibromatosis: Aggressive management could be avoided in a subgroup of patients. Eur J Surg Oncol. 2008 Apr; 34(4):462-8.

  9. Fiore M, Perego A, Pennacchioli E, et al. Alternative clinical approach in aggressive fibromatosis: wait and see frontline policy. A multi-institutional retrospective review (CTOS 2008).

  10. J. Domont, J. Bénard, L. Lacroix, et al. Detection of β-catenin mutations in primary extra-abdominal fibromatosis (EAF): An ancillary diagnostic tool. J Clin Oncol 26: 2008 (May 20 suppl; abstr 10518)

  11. Lazar AJ, Tuvin D, Hajibashi S,et al.Specific Mutations in the {beta}-Catenin Gene (CTNNB1) Correlate with Local Recurrence in Sporadic Desmoid Tumors. Am J Pathol. 2008 Oct 2.

 

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