Myxofibrosarcoma is a soft tissue sarcoma with a mucoid nodular appearance that occurs most commonly in the extremities of elderly patients.1,11,16 Local recurrence rates range from 22% to 79%1,9,15,16 irrespective of grade, depth, and size.15 With local failure, 42% of patients may progress to higher grade disease.5,9,15 Distant disease is rarely seen in the low grade variant.9,15,16
Myxofibrosarcoma, historically, was classified as a myxoid variant of malignant fibrous histiocytoma.27 Due to myxofibrosarcoma's characteristic plexiform pattern of capillary-like vessels,1,12 histochemical staining patterns,1 its ultrastructural features that are similar to ordinary fibroblasts,11 and its clinicopathological features,16,17 it is now felt by many authors to be a clinically distinct entity.9,14,15,19,23
We asked whether modern imaging techniques with magnetic resonance imaging improved understanding of margin status and thus the local failure and survival rates of myxofibrosarcoma as compared to historically reported local failure and survival rates in the literature. We hypothesized a biopsy prior to referral would have a negative impact on local recurrence and survival. During MR analysis, two growth patterns were identified in our patient population; therefore we also questioned whether the diffuse growth pattern had a negative impact on local recurrence and disease free survival as compared to a centrifugal growth pattern. Finally, we asked whether radiation therapy reduces local recurrence.
MATERIALS AND METHODS
We retrospectively reviewed the records of patients treated between 1990 and 2004 who were entered prospectively into an orthopaedic database with a diagnosis of myxofibrosarcoma (Fig 1). The patient group formed a cohort that would be compared to historical reports in the literature for local recurrence and survival analysis.1,15,16 For analysis of MR growth patterns, prereferral biopsy, and the efficacy of radiation therapy, patients were divided into two cohorts for analysis of each question. Twenty-one patients were treated for upper extremity myxofibrosarcomas. There were 10 men and 11 women with a median age of 63 years (interquartile distance [IQD], 53-76 years). The median follow-up was 52 months (IQD, 29-73 months; range, 18-122 months in survivors). No patients were lost to followup. We obtained information from patient medical records, radiographic imaging, and pathologic reports. Extended follow-up consisted of annual physical examination and chest radiographs.
All patients presented with localized disease. The anatomical locations are depicted in Table 1. Fourteen patients had an outside biopsy before referral, with 13 having been unplanned sarcoma excisions. According to the staging system of the American Joint Committee on Cancer 6th edition,7 six patients had Stage I, six had Stage II, and nine had Stage III disease. Fourteen patients had lesions deep to the fascia, and seven had lesions that were superficial. Histological grade was low in six and high in fifteen on a two tiered grading system.9 The median tumor size was 6 cm (IQD, 4-10 cm).
Magnetic resonance imaging (MRI) was performed on all patients before the definitive resection for preoperative planning. Three patients did not have a preoperative MRI performed by the referring physician prior to the outside procedure. At the time of retrospective review, only nineteen of the preoperative MRIs were available for review. Therefore, sixteen patients had a pre- manipulation MR for analysis of growth patterns. All patients had T1 and T2-weighted images on file, but only four patients had MR images with gadolinium enhancement; therefore, analysis of T1 and T2-weighted images were used for this study. T1-weighted images showed the extent of disease poorly. Magnetic resonance T2-weighted images were evaluated for a pattern of extensive spread along the fascial planes that extended more than the width of the tumor away from the primary site of disease (Fig 2). The growth pattern as depicted on the MRI was as a thin film along the surface of the fascia, as opposed to the typical centrifugal growth pattern4 of a sarcoma mass. Ten of the 21 patients showed the pattern of extensive spread on preprocedural MR images.
All patients were surgically treated, with 19 receiving limb- sparing surgery. Primary amputations were performed in two patients because of extensive contamination after a prior outside marginal excision in one patient, and the second because of the initial extent of disease. Five patients had microscopically positive margins without residual gross disease after the definitive resection. All five positive margins occurred in patients who underwent an outside biopsy. Two of the five patients with positive margins underwent re-excision to negative margins. Two patients underwent re-excision for narrow negative margins (margin of 1 mm or less). Seventeen patients, including all patients with high-grade disease and all patients with positive margins, received adjuvant radiotherapy. Adjuvant therapy consisted of postoperative external beam radiotherapy in 15 patients, brachytherapy in only one, and the preoperative radiotherapy with a brachytherapy boost in one patient. The median dose was 6300 cGy (IQD, 6000-6600). Two patients with Stage III disease received adjuvant chemotherapy.
We conducted an analysis of the effects of patient factors (age, sex, and site), tumor characteristics (size, grade, depth, and MRI pattern), and treatment factors (prior procedure, margin status, and adjuvant radiotherapy) to determine risk factors for local recurrence. Univariate analysis was performed with Fisher's exact test, and multivariate analysis was performed with logistical regression. Disease-free survival and disease-specific survival were estimated by the methods of Kaplan-Meier.10 An event for disease-free survival was defined as a local or systemic recurrence of disease. An event for disease-specific survival was death related to disease. We used the log-rank test to evaluate the significance of the previously mentioned patient, disease, and treatment related factors on disease-free and disease-specific survival. Significant (p < 0.05) prognostic factors on univariate analysis were evaluated with the Cox regression model. Statistical analysis was performed with SPSS 12.0 for Windows (SPSS Corporation, Chicago, IL). Confidence intervals (CI) of 95% were calculated for statistical parameters.
Prior outside procedures and distinct anatomic growth patterns as seen on MRI had a negative impact on the local recurrence rate (47% for the group of 9). The median time to local failure was 18 months (IQD, 9-43). Four patients developed multiple recurrences (n = 2, 3, 4, and 6), and three of them eventually underwent an amputation for local control. Patient factors of age, sex and anatomical location had no impact on the local failure rates (Table 2). Tumor factors of depth, size, and grade did not affect the rate of local failure (Table 2). At the time of presentation to the referral center, a prior outside unplanned excision increased (p = 0.04; hazard ratio, 2.3; 95% CI, 1.1-4.7) the local recurrence rate to 62% (8 of 13) versus a local failure rate of 14% (1 of 7) in patients with no prior treatment (one patient with an outside incisional biopsy removed from this analysis). On preoperative MRI, the presence of an increased perifascial T2 signal pattern increased (p = 0.007; hazard ratio 5.0, 95% CI, 1.5-17.3) the local failure rate to 80% (8 of 10) versus the local failure rate of 0% (0 of 6) for patients with a centrifugal growth pattern. The cohort with a preoperative MRI pattern of diffuse increased perifascial T2 signal was different from the outside unplanned excision cohort. The treatment-related factor of a positive margin after definitive resection had a trend toward increased (p = 0.07; hazard ratio, 1.6; 95% CI, 0.9-3.0) local failure with a rate of 80% (4 of 5) versus a rate of 33% (5 of 16) for a negative margin. On multivariate analysis, the local recurrence rates did not differ. Therefore, grossly negative en bloc tumor and tumor bed excision achieved the same degree of local control whether or not a negative histological margin was obtained.
A diffuse spreading growth pattern as seen on MR had a negative impact on disease-free survival due to poor local failure rates, while disease specific survival remained high across all grades. A diffuse spreading growth pattern reduced (p = 0.009) the disease-free survival (median survival, 14 months; 95% CI, 4-59 months) as compared with centrifugal growth (no events) (Table 3) (Fig 3). The disease free survival at 5 years was 43% (SE, 22%) for low-grade disease and 39% (SE, 18%) for high-grade disease (Fig 4). Distant disease developed in five of the 10 patients with the diffuse pattern. The sites of metastases were the lungs in four, soft tissue satellite lesions outside of the involved extremity in three, and the spine in one patient. Although disease-free survival was uniformly poor due to the high local failure rate, disease specific survival for the cohort remained high across all grades. Disease specific survival at 5 years was 100% (no deaths) for low-grade disease and 75% (SE, 13%) for high grade disease (median survival, 100 months; 95% CI, 78-122). A local recurrence had a trend (p = 0.07) toward decreased disease specific survival, with a median survival of 91 months (95% CI, 62-120). The only factor to decrease (p = 0.009) the disease specific survival for the group was the development of metastases with a median survival of 43 months (95% CI, 35-69). Disease-free survival was not different between the outside biopsy cohort and the tertiary referral center biopsy cohort. The factors were not different on multivariate analysis for disease specific survival.
Radiation therapy had no appreciable effect on local recurrence (Table 4). All local recurrences were in field failures at the surgical margin. No local failures occurred at the margin of the field or outside the field of radiation. The local failure rate for all patients receiving radiotherapy was 53% (9 of 17) as compared with the 0% (0 of 4) recurrence rate in patients with no adjuvant treatment. The local failure rate in patients with microscopically positive margins, who received radiotherapy without re-excision, was 100% (3 of 3) as compared with the 50% (1 of 2) failure rate for patients who underwent a second re- excision to negative margins and radiotherapy.
Our primary questions were whether modern imaging improved our surgical margins, reduced local recurrences, and enhanced survival in myxofibrosarcoma. The large series in the literature were predominantly from the pre- MR era and have reported a substantial local failure rate as high as 79%.1,15,16 Similarly, historical overall survival has been as low as 65% at five years.1,16 In evaluating MR images, distinctly different diffuse patterns and centrifugal patterns of growth were observed. This has not been reported in the literature. Additionally, during review of the patient series we sought to evaluate the efficacy of radiation therapy in our small series.
The major limitation of our series is the small patient population for this rare disease. We lacked the power to evaluate minor differences in the treatment groups. Additionally, 14 patients had outside biopsies prior to referral. The prior surgical procedures appear to be one reason for the high local failure rate. However, prereferral procedures did not correlate with growth patterns, thus they are separate risk factors for local failure. Another limitation was the nonrandom use of radiotherapy. Selection bias caused the radiation group to receive all the patients with the greatest risk of recurrence.
The local failure rate for the group after wide resection was 47%, which is similar to prior studies of extremity myxofibrosarcoma (Table 5). Local failure has been reported to be between 22 and 79%.1,9,15,16 Though we did not find factors common in other sarcomas predicted local failures, such as size, grade, and margin status,2,3,21,22,24,25 our series corroborates the findings of Mentzel et al15 who reported local recurrence in myxofibrosarcoma was independent of grade, size, and depth. Before the main stream use of conservative surgery, Merck et al found margin status and prior treatments to increase local recurrence.16 Radical compartmental resections were found to have a local failure rate of 17%, while nonradical excisions had a 79% local failure rate.16 If a nonradical excision preceded a radical resection, the local failure rate was 33%.16 We confirmed the higher rate of local failure when patients undergo an unplanned excision of a soft tissue sarcoma before referral and definitive resection. The trend of increased local failure after prior procedures mirrors other soft tissue sarcomas.6,13,18 In our small group, no low grade recurrences progressed to high grade disease contrary to the progression frequency reported in the literature5,15 to be as high as 42%.9
Though local failure rates and disease-free survival for high and low grade disease were poor, the disease specific survival for the high grade disease was 75% (SE, 13%). The literature reveals survival rates of 89% to 100% for low grade disease at 5 years,1,9,16 and as low as 54% for high grade disease.16 Similar to other reports, our low- grade disease group had no deaths and no metastases. Though mortality rates are minimal with low-grade disease, this entity must be treated appropriately because of the reported risk of progression to high-grade disease and the risk of metastases with recurrence.
An infiltrative growth pattern in myxofibrosarcoma has been identified in the literature.15,26 Mentzel et al found the growth pattern occurred more frequently in superficial lesions, but found no correlation with local failure,15 while Wada reported a patient with diffuse disease without a discrete mass in the thigh who underwent amputation.26 We observed the infiltrative pattern was strongly associated with local recurrence. The radiologists at the referring institution reported the thin film of increased signal along the fascial planes as peritumoral edema changes and not as tumor extension. This anatomic pattern must be recognized as tumor growth as seen histologically in our series, not dismissed as edema on pre-treatment MR images. It seems prudent to resect the entire area of increased signal on T2-weighted MR images whenever possible to obtain an adequate wide margin. Theoretically, gadolinium enhancement should be able to detect the difference between edema and hypervascularized neoplastic tissue. We could not assess this since only four patients had Gadolinium studies. Postoperative use may preclude its utility due to regional postoperative inflammatory changes. Gadolinium is now currently used in our soft tissue sarcoma patients.
Our final question was whether adjuvant radiotherapy influenced outcome. Radiotherapy has been shown to decrease local failure rates after limb-sparing surgery for high-grade soft tissue sarcomas in a prospective trial20 and in retrospective studies.3,8 In our series, radiotherapy had no appreciable effect on local failure rates. Radiation for patients with microscopically positive surgical margins did not seem to improve local control when re-excision was not performed. Our series lacks the power to give a definitive answer to the original question.
Myxofibrosarcoma can show a diffuse infiltrative growth pattern that must be appreciated during presurgical planning. High quality T2-weighted MR images were found to depict the infiltrative pattern the best, but gadolinium enhanced images may provide even greater detail. Because of the apparent lack of response to radiotherapy, we recommend re-excision to negative margins to minimize the local recurrence rates. Additionally, we recommend against intralesional resections before referral to a tertiary care facility.
The authors thank Dr. Cristina R. Antonescu for her verification of the pathological specimens and Kristy Simmons, Orthopaedic Research Assistant, for her help with data collection and management.
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