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Quality of Surgery and Outcome in Extra-Abdominal Aggressive Fibromatosis: A Series of Patients Surgically Treated at a Single Institution

From the Departments of Surgery, Medical Oncology, Biostatistics, Pathology, and Radiation Oncology, Istituto Nazionale per lo studio e la cura dei Tumori, Milan, Italy.

Address reprint requests to Alessandro Gronchi, MD, Department of Surgery, Istituto Nazionale per lo studio e la cura dei Tumori, via Venezian 1, 20133 Milano, Italy; email: alessandro.gronchi{at}istitutotumori.mi.it.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To explore prognostic factors in surgically treated aggressive fibromatosis (extra-abdominal desmoid tumor).

Patients and Methods: A total of 203 consecutive patients treated with surgery over a 35-year period at a single referral center were retrospectively reviewed. One hundred twenty-eight were first seen at our institution with primary disease, whereas 75 had a recurrent tumor. All patients underwent macroscopically complete resection. Margins were rated as negative in 146 (97 with primary tumors, 49 with recurrences) and positive in 57 (31 in primary, 26 in recurrences) patients. Median follow-up was 135 months.

Results: Patients with primary disease had a better disease-free survival rate than those with recurrence (76% v 59% at 10 years). Presenting with a recurrence was also the strongest predictor of local failure in the multivariate analysis. In patients first treated for primary disease, size and site had prognostic significance, whereas microscopically positive surgical margins did not. In contrast, in patients with recurrence, there was a trend toward better prognosis if margins were negative (although this was not significant at multivariate analysis).

Conclusion: Presence of microscopic disease does not necessarily affect long-term disease-free survival in patients with primary presentation of extra-abdominal desmoid tumors. Thus, function-sparing surgery may be a reasonable choice when feasible without leaving macroscopic residual disease. In patients with recurrences, positive margins may more clearly affect prognosis, potentially necessitating adjuvant radiation in selected cases.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
FIBROMATOSES ARE a group of rare fibrous tissue proliferations of intermediate malignancy that display local aggressiveness but no propensity to metastasize.^1–4 However, unlike superficial fibromatosis, deep fibromatoses are aggressive tumors (hence the term aggressive fibromatosis) that may cause serious clinical problems.^5,6 Deep fibromatoses (desmoid tumor) include extra-abdominal and intra-abdominal (mainly mesenteric) fibromatosis. Intra-abdominal fibromatosis has a distinct behavior, being primarily associated with familial adenomatous polyposis.^7–11

Extra-abdominal fibromatoses are monoclonal fibroblastic proliferations arising in musculo-aponeurotic structures.^2–4 It is a relatively common entity among soft tissue lesions, with an incidence averaging 0.2 to 0.4 per 100,000/yr. Local growth with tissue invasion often results in pain, deformity, organ dysfunction, and eventually, albeit rarely, death owing to invasion of vital organs. It can occur anywhere in the body but is mainly found in extremities and girdles, chest and abdominal wall, and neck. Optimal management has not been clearly defined. Surgery is generally considered the treatment mainstay. However, despite wide surgical margins, a high local recurrence rate is reported by several series, ranging from 24% to 77% at 10 years.^1,6,12–21 Despite a well-known clinical history, prognostic factors have not been clearly identified. This was because most series have neither distinguished between intra- and extra-abdominal fibromatosis, nor have they distinguished between primary and recurrent presentation of the disease. In particular, the prognostic significance of positive surgical margins and the indications to radiation therapy in extra-abdominal fibromatosis are still debated.^12–31

To assess the value of prognostic factors and particularly the effect of surgical quality on final outcome, we conducted a retrospective case series analysis of patients treated at our institution over a 35-year period.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between May 1966 and February 2001, 293 patients with aggressive fibromatosis were treated at the Istituto Nazionale per lo studio e la cura dei Tumori, Milan, Italy.

Among these patients, 81 were affected by intra-abdominal tumors or associated with Gardner syndrome and were excluded from this analysis. Two hundred twelve patients presented with extra-abdominal aggressive fibromatosis and were operated with eradicating intent. Five patients had a macroscopically incomplete resection, three were lost to follow-up soon after surgery, and one died as a result of postoperative complications. These patients were also excluded from this analysis. Thus, the outcome of the remaining 203 patients was evaluated for this article (Table 1). The median follow-up time for the entire group is 135 months (range, 1 to 360 months).

All surgical resections were macroscopically complete, and a single pathologist retrospectively reviewed the marginal status. Margins were classified as negative if they were microscopically clear. This was the case in 146 patients (97 with primary tumors and 49 with recurrences). Margins were microscopically positive in 57 patients (31 with primary tumors and 26 with recurrences).

Radiation therapy was delivered as an adjunct in selected cases (40 patients; 20 with primary tumors and 20 with recurrences). The indication to radiation therapy was given by both the operating surgeon and the radiation oncologist when a higher risk of recurrence was predicted on clinical grounds. However, no prospectively selected criteria were used to this end. External-beam radiation was used in all such cases, and doses ranged from 45 to 65 Gy (median, 57 Gy).

Time to local failure and recurrence-free survival were calculated from the time of surgery at our institution. Disease-free survival curves were calculated using the Kaplan-Meier method,³² and comparisons between curves were made using the log-rank test. Site (classified as extremities, girdles, walls, and others), size (< 5 cm v 5 cm), marginal status, and phase of disease (primary v recurrent) were tested as possible prognostic factors, following recent case series analyses. Multivariate analysis was performed using the Cox proportional hazards model. We considered as covariates the tumor presentation (primary v recurrence), site (extremities/girdles v walls/other), tumor size ( 5 cm v < 5 cm), surgical margins (positive v negative), and interaction terms between presentation and the remaining covariates. To avoid biases from retrospective evaluations, we stratified Cox models analysis according to the time when surgery was performed (before 1980, 1980 to 1989, and after 1989). All P values reported are two-sided. P values less than .05 were considered significant.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Overall, 198 conservative surgical procedures were performed (14 of which were re-excisions after a primary operation performed elsewhere), and five major demolitions were undertaken (one amputation, two disarticulations, and two forequarter amputations). The last amputation was performed in August 1982. All following patients with locally advanced disease were not surgically treated and were addressed to medical therapy.

Most patients (165) underwent operation after January 1980 and were prospectively followed-up in a consistent fashion. The distribution of the patients by decade is shown in Fig 1. At the time of last follow-up, 14 patients were dead (five patients as a result of local progression and nine patients as a result of other causes). The overall survival rate was 98% at 5 years and 94% at 10 years (Fig 2).

View larger version (67K): [in this window] [in a new window]   Fig 1. Patient distribution by decade.

View larger version (15K): [in this window] [in a new window]   Fig 2. Overall survival (OS) and disease-free survival (DFS) of the entire series (203 patients). Tick marks overlapping survival curves denote censored times.

Patients with primary lesions at first surgery at our institution had a better outcome, with an 81% (95% CI, 74% to 88%) disease-free survival rate at 5 years and a 76% (95% CI, 69% to 84%) disease-free survival rate at 10 years. The 5-year disease-free survival rate for patients with recurrences at surgery was 59% (95% CI, 47% to 71%), which did not change for 10 years. This difference in outcome depending on the previous surgical history at definitive surgery was statistically significant (P < .01; Fig 3).

View larger version (13K): [in this window] [in a new window]   Fig 3. Disease-free survival (DFS) by phase at presentation at our institution (128 primary cases and 75 recurrences). Tick marks overlapping survival curves denote censored times.

Primary Disease
Patients having tumors less than 5 cm in diameter had a significantly better outcome, with a 5-year disease-free survival rate of 94% (95% CI, 87% to 100%), unchanged at 10 years, whereas patients with tumors 5 cm in diameter had a 72% (95% CI, 62% to 83%) disease-free survival rate at 5 years and a 66% (95% CI, 55% to 78%) disease-free survival rate at 10 years (P < .01).

Regarding site, patients with extremity/girdles tumors had a 72% (95% CI, 60% to 84%) disease-free survival rate at 5 years and a 62% (95% CI, 49% to 76%) disease-free survival rate at 10 years, whereas patients with wall/other tumors had an 88% (95% CI, 80% to 96%) disease-free survival rate at 5 years, unchanged at 10 years (P < .01).

Marginal status was not a significant prognostic factor in this subset of tumors. Patients with positive margins had a 5-year disease-free survival rate of 79% (95% CI, 64% to 94%) and a 10-year disease-free survival rate of 74% (95% CI, 57% to 91%), whereas those with negative margins had a 5-year disease-free survival rate of 82% (95% CI, 74% to 90%) and a 10-year disease-free survival rate of 77% (95% CI, 69% to 86%; P = .5; Fig 4).

View larger version (13K): [in this window] [in a new window]   Fig 4. Disease-free survival (DFS) of primary cases (128 patients) by quality of surgical margins. Tick marks overlapping survival curves denote censored times.

Patients with extremity/girdles tumors had a 60% (95% CI, 46% to 75%) disease-free survival rate at 5 years (unchanged at 10 years), and patients with wall/other tumors had a 56% (95% CI, 36% to 77%) disease-free survival rate at 5 years (unchanged at 10 years; P = .85).

Though not statistically significant, a trend was detected depending on marginal status: Patients with positive margins had a 47% (95% CI, 26% to 68%) disease-free survival rate at 5 years (unchanged at 10 years), whereas patients with negative margins had a 65% (95% CI, 51% to 79%) disease-free survival rate at 5 and 10 years (P = .17; Fig 5).

View larger version (13K): [in this window] [in a new window]   Fig 5. Disease-free survival (DFS) of recurrences (75 patients) by quality of surgical margins. Tick marks overlapping survival curves denote censored times.

Multivariate Analysis
Regression coefficient estimates and corresponding SEs and Wald’s P values obtained from the Cox regression model are reported in Table 2. Hazard ratios (HRs) and corresponding 95% CIs derived from the above coefficients for primaries and recurrences are reported in Table 3.

The overall test on interactions achieved statistical significance (P < .01). Considering the single interaction terms, significant results were obtained for tumor size (P < .01), but not for site (P = .20) and marginal status (P = .14). Taken together, the above findings indicate that the prognostic effect of tumor site, size, and margin status is different between primary lesions and recurrences. In particular, by looking at the HRs shown in Table 3, it seems that in patients with primary tumors, disease location at extremities/girdles and size 5 cm, but not margin status, are unfavorable prognostic factors (HR > 1). On the contrary, in patients with recurrences, none of the factors explored had a clear prognostic effect, but a negative trend was detected for microscopically positive surgical margins.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this series of 200-plus patients with deep, nonmesenteric aggressive fibromatosis who were surgically treated at the same institution over a 35-year time period, overall survival at 10 years after definitive surgery was in excess of 90%, whereas the disease-free survival rate was approximately 70%. Risk of recurrence clearly was correlated with whether surgery was undertaken for primary or recurrent disease, whereas quality of surgical margins seemed to adversely affect prognosis only in patients with an already recurring disease. In primary presentations, microscopically positive surgical margins did not seem to substantially decrease the 75% long-term disease-free survival rate.

Optimal management of aggressive fibromatosis has not yet been defined, but surgery, if feasible, remains the treatment mainstay, albeit followed by a significant local failure rate.^12–31 The propensity of aggressive fibromatosis to locally recur is related to its infiltrative nature, which makes it difficult for the surgeon to grossly identify the true extent of disease. These tumors lack a pseudocapsule and display nonpalpable diffusion along muscle bundles and fascial planes. This may justify the high recurrence rate of the disease after adequate surgery. If so, however, surgical margins should be correlated with the final outcome at least in terms of recurrence rate, although not of survival, given the essentially local aggressiveness of the disease.

Indeed, Posner et al,¹ in their multivariate analysis of 138 patients, identified positive resection margins as the most important independent predictive factor of local recurrence. Their series included 19 patients with intra-abdominal disease. Similar results were obtained by Goy et al¹⁶ in a series of 68 patients, by Spear et al¹⁸ in a series of 107 patients, by Ballo et al¹⁹ in a series of 189 patients, and by a recent review.²⁹ Despite their reproducibility, however, these results may have been biased by some factors, such as the inclusion in the same series of intra- and extra-abdominal tumors, as well as both primary lesions and recurrences (Table 4). In addition, these patients may have received disparate treatments.

That surgical margins could be relevant in patients with an already recurrent disease but not in those with primary lesions, as our series would seem to suggest, is intriguing. Indeed, Merchant et al²⁰ analyzed a series of 105 patients affected only by primary aggressive fibromatosis and made our same observation, like other authors as well, though Miralbell et al,¹² Reitamo et al,⁵ and Kiel et al³¹ analyzed small series (Table 4). One may well speculate that the recurrence rate highly depends on inherent characteristics of the disease, which might be more or less aggressive on its own, so that it might recur or not rather independent of the fine quality of surgery. However, one should not overlook the fact that all patients in our series were operated on in a consistent fashion by surgeons with experience in the disease. In addition, microscopically positive margins may not differ substantially from microscopically negative margins falling close to the tumor. At any rate, the difference in terms of disease-free survival does not exceed 15% (over a rough 50%) also in these selected patients.

Conversely, the risk of relapse was highly dependant on site and size. Patients with large tumors located at the extremities or girdles had a higher risk of recurrence, regardless of whether they were excised with positive or negative resection margins.

Conceptually, a positive margin in sarcomas means that active tumor has been left behind, and this should be avoided in principle. What these observations may indicate is that attempts to achieve negative resection margins through aggressive, possibly demolitive surgical resections may not be desirable, at least not in most instances, in aggressive fibromatosis.

The natural history of this disease is that of a slow and locally invasive growth. This growth is not constant. There can be partial regressions as well as periods of rapid growth.^33,34 Most important, there can be long periods of stable disease. These variations in tumor growth may be rather independent of any medical treatment, though several drugs, from nonsteroidal anti-inflammatory agents to biologic agents, from hormones to more or less aggressive chemotherapy, have been suggested to actually affect the disease.^35–39 As a matter of fact, roughly 75% of patients surgically treated for primary aggressive fibromatosis are cured regardless of the appearance of microscopic surgical margins.

All this contributes to the ongoing debate over adjuvant therapies. It is possible that the issue of whether the disease has already recurred might indicate adjuvant radiation more than marginal status. Likewise, if demolitive surgery is the only way to achieve a reasonably complete excision of the disease, a wait-and-see approach or a medical therapy may be reasonable.

However, wide surgery may become more important in the presence of a recurrent lesion. Likewise, our data indicate that adjuvant radiation therapy in the case of positive margins might be more required in this patient setting, though in the absence of randomized data, it is difficult to state whether any adjuvant treatment really has a potential effect on this disease. In this regard, several studies have reported on the effectiveness of radiation therapy in terms of gross tumor control. This is why many authors have considered the role of radiation therapy as adjuvant treatment.^{14,16–19,23–30} Indeed, the adverse effect of positive resection margins would seem to be offset by the addition of radiation in several reports.^18,19,29,30 Forty patients in our series received adjuvant radiation at the discretion of the operating surgeon and the radiation oncologist without a significant difference in local recurrence, independent of the resection margins and of whether the disease was primary or recurrent. Aside from the obviously limited patient sample, because patients were arbitrarily selected in the lack of any prospectively specified criteria over a 20-year time period, nothing can be said about the effectiveness of adjuvant radiation therapy in our series. That patients considered to be at high risk of recurrence achieved the same (slightly higher) disease-free survival may also imply that adjuvant radiation has been effective. Therefore, our data leave entirely open the question of whether adjuvant radiation therapy may be effective in the disease. They may just suggest that, if radiation therapy is to be used as an adjuvant treatment, it might be more useful in patients with recurrences, because in this setting, local radicality may be prognostically more important. Of course, the role of adjuvant radiation therapy in this disease could be best assessed through a randomized trial. Randomized trials are difficult in such a rare disease, and even more so if one is willing to select only a subset of patients.

In conclusion, surgery remains the mainstay of treatment of aggressive fibromatosis. Best surgery is obviously the goal, with at least a macroscopically complete excision as an end point. Even if microscopic surgical margins may not make a difference in primary lesions, surgery should nonetheless be planned carefully in this insidious, highly aggressive, local malignancy. However, the surgeon must often decide whether to preserve organs and function. Based on our data, one might say that the pathologic finding of unexpected positive margins does not necessarily dictate demolitive operations. If feasible, surgery remains the treatment mainstay in patients with recurrences. A higher risk of further local relapse must be anticipated in this patient setting. Moreover, positive surgical margins might be a critical factor. Possibly, adjuvant radiation therapy may thus have a role in this patient setting, albeit in the absence of formal evidence of efficacy owing to the unfeasibility, thus far, of prospective randomized trials in this disease. Finally, one should consider medical options in all cases in which surgery is clearly unfeasible at a reasonable price in terms of organs and functions.

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Submitted May 22, 2002; accepted December 18, 2002.

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