Abstract
Background: Several variables have been reported as being prognostic with regard to the outcomes of soft-tissue sarcomas. Although the tumors are subjectively ominous, no prior study has been performed to evaluate the treatment or prognosis of fungating soft-tissue sarcomas.
Methods: We performed a retrospective review of all soft-tissue sarcomas treated at our institution between 1989 and 2004 that had been followed for a minimum of two years or until the death of the patient. Our study group consisted of twenty-four patients with a primary high-grade fungating tumor, and our control group consisted of 146 consecutive patients with a primary high-grade non-fungating tumor. The study cohorts were compared with regard to disease presentation, treatment, and oncologic outcomes.
Results: There were no significant differences in tumor size, tumor depth, or histopathologic diagnoses between the cohorts, although the patients with a fungating tumor tended to be older (mean, sixty-five years compared with fifty-five years in the control group; p = 0.004) and have shorter postoperative follow-up (mean, thirty-eight months compared with sixty-five months in the control group; p = 0.03). The proportion of patients presenting with metastases was significantly greater in the group with a fungating tumor (33% compared with 9% in the control group; p = 0.003). Significantly more patients with a fungating tumor underwent amputation (35% compared with 12% in the control group; p = 0.01), while a greater proportion of control patients received radiation therapy (68% compared with 39% in the group with a fungating tumor; p = 0.02). There was no difference in the proportions of patients receiving chemotherapy or in the local recurrence rates between the two cohorts. The Kaplan-Meier five-year overall survival estimates were 20% in the group with a fungating tumor compared with 63% (p < 0.0001) in the control group. The Kaplan-Meier five-year disease-specific survival estimates for patients presenting with localized disease was 58% in the group with a fungating tumor and 74% in the control group (p = 0.05). Multivariate analysis demonstrated that disease stage, fungation, and a tumor size of =10 cm were significant independent negative prognostic factors for disease-specific survival.
Conclusions: Malignant tumor ulceration is an independent predictor of a poor prognosis for patients with a high-grade soft-tissue sarcoma. Despite the discouraging overall prognosis, aggressive multidisciplinary treatment can lead to long-term survival in an important subgroup of patients with fungating lesions.
Level of Evidence: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.
Excluding Kaposi sarcoma1 and dermatofibrosarcoma protuberans2, two disease processes that nearly always originate in the skin and subcutaneous tissues, direct cutaneous involvement by soft-tissue sarcomas is relatively rare. Cutaneous involvement due to soft-tissue metastases also occurs more commonly in patients with primary carcinomas than in those with sarcomas3.
"Fungate" means "to grow rapidly like a fungus." In the field of oncology, this term has become synonymous with malignant tumor ulceration, referring to a process of locally aggressive growth whereby a malignant tumor erodes through and occasionally protrudes from the skin (Fig. 1). The presence of malignant ulceration has proven prognostic value for carcinomas such as breast cancer4 and melanoma5. To our knowledge, only nine previous cases of fungating soft-tissue sarcoma have been reported, with the majority of these being Marjolin-type ulcers6 with underlying chronic osteomyelitis7-13. Seven of these nine patients died of the disease within the relatively short follow-up periods preceding publication.
Patients with high-grade soft-tissue sarcoma have a relatively poor prognosis. In historical series, up to 50% of patients eventually had distant metastases and died of the disease14-16. Local disease control had been similarly difficult, with local recurrence rates ranging from 33% to 92% in previous studies17. The advent of advanced preoperative soft-tissue assessment afforded by magnetic resonance imaging coupled with frequent utilization of adjuvant radiation therapy has dramatically improved local recurrence rates, which have ranged from 0% to 25% in more recent series18-25. Simultaneously, the standard of care for local disease control has evolved, in most instances from radical resection or amputation26 to wide local excision supplemented with the judicious use of radiation therapy25. The impact of improved local disease control on overall survival remains controversial, with various series suggesting that local recurrence may20,27,28 or may not19,23 be prognostic. Additional reported prognostic factors for overall survival following management of soft-tissue sarcoma include tumor stage, grade, size, site, depth, and histopathologic diagnosis14,20-23,26-31.
Although fungation is ostensibly an indicator of a poor prognosis as a result of the apparent aggressive and advanced nature of the disease process, the potential prognostic importance and the treatment implications of soft-tissue-sarcoma fungation have not been previously assessed, to our knowledge. The purpose of the present study was to evaluate the impact of malignant tumor ulceration, with or without associated external intumescence, on treatment and prognosis by comparing a group with a high-grade fungating soft-tissue sarcoma with a contemporaneous control group with a high-grade non-fungating soft-tissue sarcoma.
Following institutional review board approval, we performed a retrospective review of the inpatient and outpatient medical records, radiologic studies, and pathology reports of all patients with soft-tissue sarcoma of the pelvis or an extremity treated at a tertiary referral musculoskeletal oncology center between 1989 and 2004. The primary study group consisted of twenty-four patients with a fungating soft-tissue sarcoma in whom malignant ulceration had occurred prior to the initial presentation at our facility. Histopathologic analysis demonstrated that all fungating tumors were high-grade. Four additional patients who presented with a fungating local recurrence after an initial excision of a non-fungating primary soft-tissue sarcoma at outside facilities were excluded from further analysis. Likewise, patients with dermatofibrosarcoma protuberans or Kaposi sarcoma were excluded, regardless of the histologic grade, as were all patients with an intermediate or low-grade soft-tissue sarcoma. Tumors were considered "fungating" in the present series if frank necrosis and ulceration of the overlying skin (Fig. 1) had occurred, with or without concomitant extracorporeal tumor growth and regardless of the lesion depth. This group was compared with a contemporaneous control cohort consisting of 146 consecutive patients treated for a primary, non-fungating, high-grade soft-tissue sarcoma during the same period. All patients in both groups had been followed for a minimum of two years postoperatively or until death.
Scrutinized variables included patient age and sex, tumor depth and size, disease site, duration of symptoms, histopathologic diagnosis, and Musculoskeletal Tumor Society (MSTS) stage32. The surgical treatment and the use of adjuvant therapy, including chemotherapy and radiation therapy, were analyzed for each patient. Outcome measures included local recurrence of disease; metastases; and disease-free, disease-specific, and overall survival.
Surgical Procedures
The goal of surgical treatment was complete removal of each tumor with an appropriately wide or radical margin of resection. The decision to perform a limb-sparing procedure rather than an amputation was determined by the anticipated ability, based on lesion depth, size, and involvement of critical neurovascular structures, to achieve adequate operative margins while maintaining a functional limb.
Adjuvant Treatment
Because of the fifteen-year span of the study, the administration of chemotherapy and radiation therapy was not uniform. Patients with larger, deeper tumors and more advanced stages of disease were more likely to receive chemotherapy. Preoperative neoadjuvant doxorubicin-based chemotherapy has been recommended to all patients with a large, high-grade sarcoma since 1999, and it was utilized sporadically before that time. Patients who had >90% tumor necrosis following neoadjuvant chemotherapy had additional postoperative adjuvant chemotherapy. Patients with <90% tumor necrosis underwent a modified postoperative chemotherapeutic regimen or were treated with radiation therapy alone. Adjuvant external beam radiation therapy was recommended to most patients following wide resection but was preferentially administered to patients with close wide, wide-contaminated, or histologically positive margins. The radiation therapy was given at a minimum of three weeks after the resection, following complete wound-healing. Patients did not routinely receive radiation therapy following radical resection or amputation, wide excision associated with adequate margins and an excellent response to neoadjuvant chemotherapy33, or wide resection of a small (<4-cm) superficial soft-tissue sarcoma21. Patients presenting with fulminant metastatic disease also did not receive radiation therapy. Preoperative radiation therapy had been utilized in a small minority (five) of the 108 radiation-therapy-treated patients in this series.
Postoperative Surveillance
Magnetic resonance imaging was used for surveillance for local tumor recurrence three months after the surgery, every three to four months for two years, and every six months for up to five years. Annual clinical examinations were performed thereafter. Surveillance for distant metastases included alternate chest radiographs and computed tomography scans every six months postoperatively for five years and annual chest radiographs thereafter. Follow-up data were tabulated on the basis of the patients' last office visit either with us or with their treating medical oncologist. For the few patients lacking recent follow-up data and not known to have died, the U.S. Social Security Death Index was queried to confirm patient survival (in which case the follow-up duration was determined by the date of the last clinic visit) or death (in which case the family was contacted and/or public records were utilized to determine the cause of death). We thus believe that our findings represent a worst-case analysis of disease-specific and overall patient survival relative to the reported duration of follow-up.
Statistical Analysis
Descriptive statistics were analyzed for both cohorts. The Student t test was utilized to compare continuous variables (e.g., tumor size and duration of symptoms), and potential differences between rates and proportions of occurrences (e.g., of amputation and radiation therapy) were assessed with chi-square analysis or the Fisher exact test as appropriate. Disease-free, disease-specific, and overall survival rates were analyzed with the Kaplan-Meier method, with differences in survivorship between cohorts assessed with the log-rank (Mantel-Cox) test. Multivariate analysis of disease-specific survival was performed with use of Cox regression (proportional hazards) analysis, for factors that had an apparently significant effect in the Kaplan-Meier analysis. The censoring variables in this analysis were termination of follow-up (loss to or most recent follow-up) and death due to other causes, while the outcome of interest was death secondary to soft-tissue sarcoma. By convention, differences were considered significant for a type-I error rate of p < 0.05, and all alpha values presented are two-tailed.
Source of Funding
There was no external funding for this study.
Eight male and sixteen female patients with an average age of 64.9 years (range, twenty-nine to eighty-seven years) had a fungating tumor (Table I). The control group consisted of eighty-six male and sixty female patients with an average age of 54.6 years (range, ten to ninety years). The patients with malignant tumor ulceration were significantly older than the control patients (p = 0.004). The mean duration of postoperative follow-up of the surviving patients was thirty-eight months (range, twenty-four to fifty-five months) in the group with a fungating tumor and 65.1 months (range, twenty-four to 212 months) in the group with a non-fungating tumor; this difference was significant (p = 0.03). The duration of symptoms prior to presentation averaged 13.8 months (median, eight months; range, two to 132 months) in the group with a fungating tumor and 10.2 months (median, five months; range, 0.5 to 108 months) in the control group (p = 0.37). The size of the fungating tumors averaged 9.9 cm (range, 2 to 25 cm) and that of the non-fungating tumors, 11.1 cm (range, 1 to 35 cm) (p = 0.40). Thirteen fungating tumors (54%) originated in the subcutaneous tissues, and eleven (46%) were deep. In the control cohort, ninety lesions (62%) were deep and fifty-six (38%) were superficial (p = 0.18). The most common histopathologic diagnoses in both groups were high-grade pleomorphic undifferentiated sarcoma (formerly known as malignant fibrous histiocytoma), liposarcoma, synovial sarcoma, and leiomyosarcoma (p = 0.47). As noted, all lesions were considered to be high-grade sarcomas by the interpreting musculoskeletal pathologists.
Surgical and Adjuvant Treatment
Fifteen patients (65%) with a fungating sarcoma underwent a limb-sparing procedure, and eight patients (35%) underwent amputation (Table II). One elderly patient with a fungating sarcoma and advanced metastatic disease at presentation died prior to the planned operative treatment. In the control group, 128 patients (88%) had a limb-salvage procedure and eighteen (12%) underwent amputation. The difference in amputation rates between the two groups was significant (p = 0.01). Nine patients (39%) with a fungating tumor and ninety-nine (68%) in the control group received radiation therapy, a significant difference (chi square = 5.9; p = 0.02) that was clearly influenced by the higher rate of amputations within the group with a fungating tumor. Fourteen patients (61%) with a fungating tumor initially received chemotherapy compared with seventy-three (50%) in the control group (p = 0.38). There were no chemotherapy-related deaths in either group.
Oncologic Outcomes
Eight patients (33%) with a fungating tumor and thirteen patients (9%) in the control group presented with pulmonary metastatic disease. The disease stages at presentation are shown in Table I. Significantly more patients with fungating soft-tissue sarcoma than controls presented with metastases (p = 0.003). Of the twenty-three patients with operative treatment of the primary fungating sarcoma, three (13%) had local recurrence of the disease—two following a limb salvage procedure and one following an amputation at our facility. Twenty (14%) of the 146 patients in the control group had local recurrence of the disease. The Kaplan-Meier five-year disease-free survival estimate was 34.6% (95% confidence interval, 27.1% to 42.0%) in the group with a fungating tumor and 52.8% (95% confidence interval, 44.0% to 61.6%) in the control group (Fig. 2-A). This difference was significant (chi square = 12.3; p = 0.03).
At the time of final follow-up, eight patients (33%) with a fungating tumor were alive, six with no evidence of disease and two with disease. Thus, sixteen patients with a fungating sarcoma died during the follow-up period. Thirteen patients died of the disease at a mean of 10.2 months (range, zero to thirty-one months postoperatively), and three patients (two with no evidence of disease and one with metastatic disease) died of other causes at a mean of fifty-nine months (range, sixteen to fifty-seven months). In the control group, eighty-eight patients (60%) were alive at the time of final follow-up; eighty-three had no evidence of disease and five had disease. Of the fifty-eight patients in the control group who died, forty-eight died of the disease at a mean of 39.0 months (range, three to 175 months) postoperatively and ten patients died of other causes at a mean of 29.1 months (range, five to seventy-four months). The mean duration of survival of the patients who died of the disease was significantly shorter (p = 0.01) in the group with a fungating tumor (mean, 10.2 months) than it was in the control group (mean, 39.0 months). The Kaplan-Meier five-year overall survival estimate was 19.6% (95% confidence interval, 0% to 39.2%) in the group with a fungating sarcoma and 63.2% (95% confidence interval, 54.4% to 72.2%) in the control group (Fig. 2-B). This difference was significant (chi square = 19.5; p < 0.0001).
With exclusion of patients with MSTS stage-III (metastatic) disease at presentation, it was found that metastases had developed in the follow-up period in seven (44%) of the sixteen patients with malignant ulceration compared with thirty-nine (29%) of the 133 patients in the control group (p = 0.18). When the patients presenting with MSTS stage-II disease were analyzed, the Kaplan-Meier five-year disease-specific survival estimate was found to be 58.0% (95% confidence interval, 50.6% to 65.4%) in the group with a fungating tumor and 74.1% (95% confidence interval, 66.3% to 81.8%) in the control group (Fig. 2-C). This was a significant difference (chi square = 3.7; p = 0.05).
Multivariate analysis demonstrated that stage-III disease at presentation (p < 0.0001), fungating soft-tissue sarcoma (p = 0.006), and a tumor size of =10 cm (p = 0.01) were significant independent prognostic variables for decreased disease-specific survival (Table III), while the disease site and lesion depth were not. Duration of symptoms, age, sex, local recurrence, and tumor size of <5 cm were not included in the Cox model because of the absence of any apparent effect. The use of chemotherapy or radiation therapy also did not affect disease-specific survival; however, this study was not designed to assess the effectiveness of these modalities as their utilization was not standardized over the study time frame. Despite the putative bias toward utilizing radiation therapy for patients thought to be at risk for local recurrence, we noted a trend toward improved local control among patients who received radiation therapy (p = 0.11). The impact of the histopathologic grade on prognosis was not analyzed, as all sarcomas were considered to be high-grade.
As the present study suggests, malignant ulceration and fungation of soft-tissue sarcoma is probably an underreported phenomenon. To our knowledge, only nine cases of fungating soft-tissue sarcoma have been reported previously, with an early survival rate of only 22%7-13. Three series34-36 with a total of twenty-eight subcutaneous infiltrating high-grade pleomorphic undifferentiated sarcomas have been reported in the dermatologic literature; in these series, only seven patients either died of the disease or had systemic failure within the published follow-up periods. However, it is unclear from these reports how many, if any, of these lesions were actually fungating masses as opposed to mere subcutaneous disease with or without associated skin changes. In the largest of these series, the authors did not find an infiltrative growth pattern associated with subcutaneous tumors to be prognostic34. We did not find a difference in survival of patients with fungating soft-tissue sarcoma based on lesion depth.
In the present study, we found protruding malignant ulceration of a high-grade soft-tissue sarcoma to be a significant (p < 0.0001) negative prognostic indicator. Fungation of a soft-tissue sarcoma has striking clinical relevance, with Kaplan-Meier five-year overall survival estimates of 19.6% and 63.2% for the fungating-sarcoma and control groups, respectively. While the survival in our large control group of patients with a high-grade soft-tissue sarcoma was somewhat more favorable than might be anticipated on the basis of historical findings14-16, our findings are consistent with those in several more recent series, in which survival rates were reported to range from 63% to 75%20-22,24. Direct comparisons are complicated by variations in surgical and adjuvant treatments, differences in the duration of follow-up and spectrum of disease, and mixed histopathologic grades in other studies19,21-24,26,30,31.
Fungating malignant ulceration of soft-tissue sarcoma was also a significant independent negative prognostic variable as determined with multivariate oncologic survival analysis (p = 0.006). An advanced disease stage at presentation (p < 0.0001) and a tumor size of =10 cm (p = 0.01) were additional independent negative prognostic indicators. While we found no difference in the mean size of the lesions between the cohorts, patients with a fungating soft-tissue sarcoma were significantly more likely to present with systemic disease (p = 0.003). However, analyses that either controlled for the stage at presentation (the multivariate analysis) or excluded patients presenting with metastases (i.e., included only patients with stage-II disease) demonstrated a persistent disease-specific survival effect attributable to fungation. These collective findings indicate that malignant ulceration is prognostic in and of itself. We therefore believe fungation of soft-tissue sarcoma to be an overt reflection of a locally and systemically aggressive sarcoma phenotype.
Despite the poor outcomes associated with malignant ulceration of soft-tissue sarcoma, the treatment of patients with fungating soft-tissue sarcoma should not be one of resigned palliation. Rather, we advocate expeditious multidisciplinary clinical and radiologic evaluation, aggressive multimodality treatment, and diligent clinical and radiographic surveillance of these tumors for evidence of local or systemic recurrence. When patients who presented with metastases were excluded, the Kaplan-Meier five-year disease-specific survival estimate for patients with a fungating soft-tissue sarcoma was 58%, including one patient who was alive with metastatic disease.
Long-term success of sarcoma treatment requires local disease control. In our series, there was no difference in local recurrence rates between patients in whom the fungating lesion had been treated with limb salvage and those in whom it had been treated with amputation, although the percentage of patients who underwent amputation in the fungating-sarcoma cohort was significantly higher than that in the control group. The nonrandomized, retrospective nature of this study makes extrapolation of these data difficult because of the obvious bias toward amputation for larger tumors involving critical neurovascular structures. However, our study does suggest that amputation is not required in all patients with a fungating mass. Rather, patients should undergo appropriate systemic staging and radiographic evaluation of the lesion, followed by detailed counseling regarding the feasibility, risks, and benefits of the various surgical alternatives.
Numerous studies have now provided convincing evidence that radiation therapy improves local control rates and permits, when necessary, more conservative operative treatment that can spare critical structures or salvage functional joint levels18-25. Radiation therapy therefore should be considered to be a treatment option for all patients with high-grade soft-tissue sarcoma, particularly those with close wide, wide-contaminated, or histologically positive margins. We believe that preoperative radiation therapy is generally contraindicated for patients with fungating soft-tissue sarcoma, as it is unlikely to have a beneficial effect on the already ulcerated skin in candidates for limb salvage and it is not generally necessary prior to amputation. Although studies have demonstrated that preoperative and postoperative radiation regimens result in equivalent local control rates, preoperative treatment regimens have been associated with a substantially increased wound complication rate, with lower, more tightly focused radiation doses having a potential benefit18,25. Two patients in our series with a relatively small fungating lesion received preoperative radiation therapy, and postoperative wound complications developed in both.
Routine use of chemotherapy in the management of soft-tissue sarcomas remains controversial37, but a growing body of evidence suggests that there are small but measurable and significant (p < 0.05) benefits for patients with regard to disease-free and overall survival, and that toxicity-related deaths are rare19,20,38,39. Not all patients with fungating soft-tissue sarcoma in our study were treated with chemotherapy because of the broad time frame encompassed by the study, lower levels of evidence supporting chemotherapy earlier in the study, limitations imposed by the patient's functional status, patients' refusal, and our own evolving understanding of both the severity of and the potential salvageability of limbs involved by these disease processes.
Because of the rarity of soft-tissue sarcoma in general and fungating soft-tissue sarcoma in particular, this retrospective review encompassed a large time span in order to amass sufficient numbers of patients and achieve sufficient follow-up to permit meaningful analysis. Thus, the management of some patients, particularly with regard to chemotherapeutic and radiation treatments, has evolved over the time period of the study, and management was not standardized either between or within the study cohorts. Neither the Kaplan-Meier nor the Cox regression analysis that we utilized accounts for the possible effect of competing risks of death from other causes on that from malignant disease. Thus, while we believe that the general conclusions reached in our study are valid, we cannot comment on the potential impact of comorbidities and patient age on disease-specific survival (that is, whether patients who are more likely to die of other causes would also be more likely to die of soft-tissue sarcoma), and our disease-free and overall survival curves cross at fifty-six months for the fungating-sarcoma cohort. Furthermore, we limited the control group to patients with high-grade soft-tissue sarcoma in an effort to construct histopathologic parity, as all of the fungating sarcomas were high-grade. Both groups were restricted to patients who had been followed for a minimum of two years postoperatively, or until death, in an effort to allow reasonable analyses regarding local recurrence rates and disease prognosis. The duration of postoperative follow-up was significantly longer in our control group, but this discrepancy would theoretically bias oncologic outcomes in favor of the cohort with fungating sarcoma, as patients with late local recurrences, metastases, or death from disease would ostensibly be more likely to be captured in the former group. We thus believe that our control group of patients with non-fungating sarcoma was adequate as formulated for the comparative data analyses performed and that the general conclusions that were reached in this study are valid despite the limitations described above.
In conclusion, protruding malignant ulceration of high-grade soft-tissue sarcomas portends a poor prognosis in terms of disease-specific and overall survival as compared with the absence of ulceration of tumors of identical grade and similar histopathologic characteristics. Although they are more likely to require amputation, fungating soft-tissue sarcomas can be treated successfully with limb salvage and, following appropriate treatment, the local recurrence rates of these tumors appear to be similar to those of non-fungating sarcomas. Aggressive treatment with judicious use of multimodal adjuvant therapies is indicated and can lead to relatively long survival in an important minority of these challenging cases, particularly when the patient presents without detectable systemic disease. 
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