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© 2002 American Society for Clinical Oncology Extraosseous Osteosarcoma: Response to Treatment and Long-Term OutcomeByFrom the Multidisciplinary Sarcoma Center and Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Peter W.T. Pisters, MD, Department of Surgical Oncology, Box 444, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; email: ppisters{at}mdanderson.org
PURPOSE: To evaluate the clinicopathologic features of extraosseous osteosarcoma (EOO), a rare soft tissue form of osteosarcoma, and to examine its response to multimodality therapy. PATIENTS AND METHODS: The medical records of all patients with EOO evaluated at The University of Texas M.D. Anderson Cancer Center between 1960 and 1999 were reviewed for clinicopathologic factors, treatment, and outcome. RESULTS: Sixty consecutive patients with EOO were identified, including 38 patients with localized (American Joint Committee on Cancer stages I to III) disease. The majority of patients presented with T2 tumors (n = 35, 58%), and 90% of tumors were located beneath the investing fascia. Twenty-seven patients with measurable and assessable disease were treated with doxorubicin-based chemotherapy (median doxorubicin starting dose, 75 mg/m2; median number of cycles, four). The overall response rate was 19%, with two complete and three partial responses; one (6%) of 18 doxorubicin-treated patients who underwent subsequent surgery had a pathologic complete response. For the subset of 30 patients with localized disease treated at M.D. Anderson, the 5-year actuarial local recurrence–free, distant recurrence–free, event-free, and disease-specific survival rates were 82% (95% confidence interval [CI], 70% to 98%), 64% (95% CI, 43% to 93%), 47% (95% CI, 30% to 70%), and 46% (95% CI, 26% to 80%), respectively. CONCLUSION: EOO should be considered clinically and therapeutically distinct from osseous osteosarcoma. Radiographic response rates and pathologic complete response rates to doxorubicin-based systemic therapy are low.
EXTRAOSSEOUS osteosarcoma (EOO) is a malignant mesenchymal neoplasm that is located in the soft tissues without direct attachment to the skeletal system and that produces osteoid, bone, or chondroid material. The first reported case of EOO was described by Wilson in 1941.1 Subsequently, Fine and Stout2 reported on 12 patients with EOO and combined their findings with 34 cases culled from the literature before 1956. Fine and Stout emphasized that EOO had clinical and pathologic features distinct from myositis ossificans and suggested that EOO might be similar in clinical behavior to osteosarcoma of bone origin. Notwithstanding increased awareness of the condition among pathologists after these preliminary reports, EOO remains rare, with fewer than 300 reported cases.3-8 As a consequence, there are few reliable data on the incidence and clinical behavior of this tumor in the literature. The rarity of EOO has prevented accurate and consistent documentation of clinicopathologic factors or of responses to various therapeutic approaches. The present study was undertaken to evaluate the clinicopathologic features of EOO and its response to therapy.
The University of Texas M.D. Anderson Cancer Center Tumor Registry and the M.D. Anderson Prospective Sarcoma Database were queried to identify all patients with EOO evaluated at M.D. Anderson from 1960 to 1999. Sixty consecutive patients diagnosed with EOO between January 1, 1960, and December 31, 1999, were identified. A comprehensive retrospective review of the medical records of these patients was performed. Data on clinicopathologic factors, treatment, outcome, and patterns of treatment failure were recorded. The diagnosis of EOO was confirmed at the time of initial evaluation by review of relevant pathology slides at M.D. Anderson. The following definitions were used. A tumor was considered to be a localized primary tumor if there was no evidence of metastasis and the lesion had not been treated or only a biopsy had been performed within 2 months of presentation. Locally recurrent disease was defined as tumor occurrence at a site previously treated for an EOO. The tumor was considered to be in the upper extremity if it was at or beyond the shoulder joint and in the lower extremity if it was in the groin or leg. The anatomic depth of the tumor was characterized as either superficial or deep relative to the investing fascia of the extremity or trunk. Tumor size was defined as the maximum dimension measured by pathologic evaluation, pretreatment cross-sectional imaging (computed tomography, magnetic resonance imaging, or ultrasonography), or physical examination. An operation was considered to be an R0 resection if the entire tumor was removed with microscopically negative surgical margins, an R1 resection if surgical margins were microscopically positive, an R2 resection if there was gross residual tumor, or an RX resection if the microscopic status of surgical margins could not be ascertained. A late recurrence was defined as any recurrence 5 years or more after treatment. All patients were retrospectively staged according to the American Joint Committee on Cancer staging system (5th edition).9
For the subset of patients treated with doxorubicin- and/or cisplatin-based chemotherapy during the era of cross-sectional imaging (n = 36), response assessment was based on comparison of the pretreatment and posttreatment radiographic tumor size; four patients treated before the availability of routine cross-sectional imaging had response assessment based on physical examination. The following definitions of radiographic response were used. A complete response (CR) was defined as complete disappearance of tumor on immediate postchemotherapy imaging studies. A partial response (PR) was defined as a
Summary statistics were obtained using established methods. Differences in proportions were assessed using Fisher’s exact test. Overall survival was defined as the time from the date of initiation of therapy at M.D. Anderson to the date of death from any cause. Differences between the entire cohort and the subset of patients with localized disease were assessed by the Long-term outcome was evaluated separately for the subgroup with localized (stage I to III) disease treated at M.D. Anderson and the subgroup with advanced disease (stage IV). Local and distant were considered as two competing sites of first recurrence. In the presence of dependent competing risks, the Kaplan-Meier approach will produce an overestimate of the cause-specific failure probability. Therefore, for each competing site, cause-specific cumulative incidence functions were estimated and differences between groups were tested.11 Event-free survival was evaluated considering any form of recurrence or treatment-related death as events. P values of less than .05 were considered to be statistically significant.
Clinicopathologic Factors The clinicopathologic characteristics for the entire cohort of 60 patients are outlined in Table 1. The median age of patients presenting to M.D. Anderson with EOO was 55 years (range, 13 to 85 years); 41 patients (78%) were older than 50 years. There were 37 male patients (62%) and 23 female patients (38%). Thirty patients (50%) presented with localized primary disease. Thirty-one patients (52%) presented with EOO of the lower extremity, 16 patients (27%) had primary tumors in the trunk or thorax, and eight (13%) had EOO arising in the abdomen/retroperitoneum. The majority of patients presented with T2 tumors (n = 35, 58%), and 54 (90%) had tumors located beneath the investing fascia. The most common disease stage was stage III (n = 26, 43%). Three patients (5%) were believed to have radiation-induced EOO because their tumors were located within radiation fields treated 8, 10, and 19 years before the diagnosis of in-field EOO. Thirty-eight (88%) of 41 patients with localized (stage I to III) EOO were treated and followed-up at M.D. Anderson. These 38 patients constitute the subgroup hereafter referred to as the subgroup with localized EOO.
The clinicopathologic factors for the subgroup of 38 patients with localized EOO are outlined in Table 1. The median age of patients with localized EOO was also 55 years (range, 13 to 85 years). There were 26 male patients (68%). Twenty-four patients (63%) presented with localized primary disease. Twenty-two patients (58%) presented with T2 tumors. The distribution of patient age, tumor site, tumor size, and tumor depth in the subgroup with localized disease were similar to those of the entire cohort.
Treatment of Localized EOO Fourteen patients (37%) with localized EOO underwent initial surgery at M.D. Anderson. The initial surgery consisted of wide excision (n = 11), above-knee amputation (n = 1), or hemipelvectomy (n = 2). Twenty-one patients (55%) had undergone prereferral surgery, including six R0 resections, five R1 resections, and three R2 resections. The microscopic status of prereferral surgical margins was uncertain in seven patients (RX). Five of the eight patients who underwent R1 or R2 resections underwent reoperative surgery at M.D. Anderson in an effort to achieve R0 status. The reoperative procedures consisted of re-excision (n = 2), hemipelvectomy (n = 1), hip disarticulation (n = 1), or laryngectomy (n = 1). The other three patients did not undergo reoperative surgery; two had thoracic tumors (R2 resection) and were treated with radiation and chemotherapy, and one had a retroperitoneal tumor (R1 resection) and was treated with radiation. None of the seven patients who underwent prereferral RX resection underwent a second surgery after multidisciplinary review of their cases; all had tumors located in anatomic sites not amenable to further surgery. Seven patients (18%) with localized EOO were treated with external-beam radiation, in conjunction with surgery and chemotherapy (n = 6) or with chemotherapy (n = 1). Four (57%) of these patients received preoperative radiotherapy (median total dose, 50 Gy; range, 30 to 50 Gy), and three patients (43%) received postoperative radiotherapy (total doses of 44, 45, and 60 Gy).
Outcomes for Patients With Localized EOO Local recurrences. A total of six local recurrences (20%) were observed among the 30 patients who were grossly free of disease after surgery. Five of the patients had a local recurrence as their first recurrence; one patient developed a local recurrence as a second recurrence after treatment for pulmonary metastases. The median time to first local recurrence was 15.3 months (range, 2 to 60 months). Assuming competing sites of recurrence (local v regional/distant) to be independent, the 5-year actuarial local recurrence–free survival rate for the 30 patients with localized disease was 82% (95% confidence interval [CI], 70% to 98%) (Fig 1). Alternatively, without assuming independence of competing sites of recurrence, the 5-year cumulative local recurrence rate was 18% (95% CI, 3% to 33%), and the 5-year local recurrence–free survival rate was 82% (95% CI, 67% to 97%). By univariate analysis, sex, depth of tumor, microscopic status of surgical margin, tumor-node-metastasis (TNM) stage, and tumor size were not associated with the development of local recurrence.
Regional/distant recurrences. Among the 30 patients who were grossly free of disease after surgery, nine patients developed a distant recurrence as a first site of recurrence. One patient developed a regional lymphatic recurrence as a first recurrence. Two patients developed a distant recurrence after an initial local recurrence. The median time to development of regional/distant disease was 13 months (range, 2 to 72 months). Assuming independence of competing sites of recurrence, the 5-year actuarial regional/distant recurrence–free survival rate for the 30 patients with localized disease was 64% (95% CI, 43% to 93%) (Fig 2). Alternatively, without assuming independence of competing sites of recurrence, the 5-year cumulative regional/distant recurrence rate was 32% (95% CI, 12% to 52%), and the 5-year distant recurrence–free survival rate was 68% (95% CI, 48% to 88%). For patients with distant recurrences, the median survival duration was 16 months from the date of identification of M1 disease. Univariate analysis indicated that patient sex, tumor depth, microscopic status of surgical margin, TNM stage, and tumor size were not associated with distant failure.
Late recurrences. A late recurrence (beyond 5 years) occurred in one patient. This patient presented with a primary lower-extremity EOO that was treated with limb-sparing R0 resection without adjuvant chemotherapy or radiotherapy. He presented with a distant recurrence (in the pancreas) 72 months later. After pancreatectomy for ostensibly solitary M1 disease, he presented with lung metastases 18 months later. This patient remains alive with pulmonary disease 11 years after initial treatment and 3 years after the diagnosis of pulmonary metastases. Event-free survival. Among the 30 patients who were grossly free of disease after surgery, 15 (50%) remained event-free after completion of all therapy. The remaining 15 patients experienced recurrences; the median time to recurrence of any type was 11 months (range, 2 to 72 months). The 5-year actuarial event-free survival rate for the 30 patients with localized disease was 47% (95% CI, 30% to 70%) (Fig 3). By univariate analysis, patient sex, tumor depth, microscopic status of surgical margin, TNM stage, and tumor size were not related to event-free survival.
Disease-specific survival. Of the 38 patients with localized disease, 22 patients (58%) died during the follow-up period: 17 died of progressive sarcoma, one of chemotherapy toxicity, and four other causes. Eleven (69%) of 16 patients were alive at their last follow-up, and 11 (29%) of 38 of them had no evidence of disease. The estimated 5-year disease-specific survival rate for the subset of 30 patients rendered grossly free of disease after surgery was 46% (95% CI, 26% to 80%) (Fig 4). By univariate analysis, the clinicopathologic factors associated with statistically significant differences in disease-specific survival were tumor size greater than 10 cm (P = .012), microscopically positive surgical margin (P = .007), and TNM stage greater than stage II (P = .0005). In a Cox regression model, none of these factors were significant for disease-specific survival.
Outcomes for Patients With Advanced EOO Of the 55 patients treated at M.D. Anderson Cancer Center, 17 patients (31%) presented with synchronous metastatic disease (stage IV). The majority of these patients had primary EOO originating in an extremity (n = 13); the remaining had primaries in the breast, head or neck, thorax, or retroperitoneum. Most stage IV patients (n = 16, 94%) presented with only one site of metastasis. The most common site of metastasis was the lung (n = 15, 88%). One patient had brain metastases, and one had brain and lung metastases. Sixteen (94%) of the 17 patients presenting with stage IV EOO died; the median time from presentation to death was 8 months. Fourteen of these patients died of EOO, and two patients died of neutropenic sepsis during chemotherapy administration. Of the 17 patients who presented with stage IV disease, six (35%) were rendered grossly free of tumor by a combination of metastasectomy and chemotherapy; only one of these patients remained disease-free at 8 years of follow-up. The other five patients had recurrences at distant sites and died of recurrent EOO. The estimated 5-year disease-specific survival rate was 10% (95% CI, 2% to 63%) (Fig 4); the median survival duration of patients with stage IV EOO was 8 months.
Outcomes for Patients With Extremity EOO
Chemotherapy for EOO Eight of the 27 patients also received ifosfamide (median starting dose, 10 g/m2; median number of cycles, three) as part of doxorubicin, ifosfamide, and mesna (n = 7) or mesna, doxorubicin, ifosfamide, and dacarbazine (n = 1). Two (25%) of these patients responded (one CR and one PR), and four patients (50%) had PD during ifosfamide-based treatment. Fifteen patients with measurable and nonmeasurable but assessable disease were treated with cisplatin-containing regimens (median cisplatin starting dose, 120 mg/m2; range, 100 to 180 mg/m2; median number of cycles, three; range, one to five cycles); 13 received cisplatin combined with doxorubicin (and are included in the subset of 27 patients described above), and two patients were treated with cisplatin alone. The overall objective response rate was 13%, with two PRs. Seven patients (47%) had SD (n = 4) or a minor response (n = 3). PD was noted in six patients (40%) treated with cisplatin-based chemotherapy.
Herein we report long-term event-free survival and responses to therapy for a relatively large cohort of patients with EOO. The current findings demonstrate that localized EOO has an overall prognosis similar to that of other forms of high-grade soft tissue sarcoma.12,13 The 5-year actuarial event-free and disease-specific survival rates for the subset of patients with localized EOO were 47% and 46%, respectively. For patients with metastatic EOO, the median survival duration was 8 months, with a 5-year actuarial disease-specific survival rate of 10%. The median survival time in patients with advanced EOO is somewhat shorter than that reported for patients with metastatic soft tissue sarcoma.14,15 In contrast to EOO’s similarities to high-grade soft tissue sarcoma, the clinicopathologic features of EOO, response to chemotherapy, and risk for relapse seem different from those for osseous osteosarcoma. First, the median age of patients presenting with EOO is several decades older than that of patients with osseous osteosarcoma, a disease that is usually manifest within the first two decades of life.16 Second, the distribution of anatomic sites observed in our series of patients with EOO differs substantially from that of osseous osteosarcoma, which is found predominantly in the lower extremities.16,17 Third, EOO seems relatively chemoresistant, whereas osteosarcoma of bone is generally viewed as a relatively chemosensitive form of sarcoma.16 We observed a radiographic CR plus PR rate of 19% with doxorubicin-based chemotherapy for EOO. Although it is difficult or impossible to assess the response of osseous osteosarcoma radiographically because osseous lesions rarely change in size after chemotherapy, pathologic CR rates for osseous osteosarcoma are in the 25% to 60% range.18-20 Because imaging may also be an unreliable means of evaluating treatment response of EOO, we examined the pathologic CR rate for EOO after preoperative chemotherapy. The 6% pathologic CR rate observed in our EOO patients treated with doxorubicin-based chemotherapy is lower than the rates reported in patients receiving doxorubicin-based treatment for osseous osteosarcoma.21,22 As such, EOO seems relatively more chemoresistant than osseous osteosarcoma. Our current multidisciplinary approach for EOO is similar to that used for high-risk soft tissue sarcoma. We do not treat EOO patients with platinum-based chemotherapy regimens as we do osseous osteosarcoma patients because preliminary experience with cisplatin-based treatment suggested that it is not active against EOO.23 This initial impression is supported by the 13% response rate noted in the current report among 15 patients treated with cisplatin-based chemotherapy. Given the absence of compelling evidence to support the continued use of cisplatin-based regimens in patients with EOO, we believe that these patients may be more optimally treated with ifosfamide-containing regimens or other investigational agents. It should be noted that only a small number of patients with EOO have been treated with our current therapeutic approach using dose-intensive doxorubicin and ifosfamide or high-dose ifosfamide alone. Consequently, the specific contribution of ifosfamide needs to be studied further. We currently enroll patients with EOO who are candidates for systemic therapy onto our ongoing trials of ifosfamide-containing regimens. Our experience with doxorubicin-based systemic therapy for EOO merits further comment. Twenty-seven patients with measurable and nonmeasurable but assessable disease were treated with doxorubicin-based systemic therapy at a median doxorubicin starting dose of 75 mg/m2. The radiographic CR plus PR rate and the pathologic CR rate were 19% and 6%, respectively. PD was noted radiographically in 48% of patients. This relatively low pathologic CR rate (compared with osseous osteosarcoma) and high PD rate emphasize the relative anthracycline resistance of EOO. The role for limb-sparing surgery for patients with extremity and limb-girdle EOO has been questioned. In 1971, Allan and Soule reported on 26 patients with EOO.3 Their report suggested improved survival and decreased local recurrence rates with amputation as compared with wide local excision. However, since their report, there has been a general migration away from ablative procedures and toward limb-sparing approaches for patients with extremity sarcomas. The superior functional outcome and comparable survival (v amputation) observed with limb-sparing approaches for other sarcomas24 have provided the foundation for our own policy to use limb-sparing approaches for EOO. We use the same clinical and anatomic criteria in selecting EOO patients for limb-sparing surgery as used for patients with other types of extremity soft tissue sarcoma. The 82% 5-year local recurrence–free survival rate noted herein is comparable to that reported in large series of patients with extremity soft tissue sarcoma treated with limb-sparing approaches.13,25-27 On this basis, we currently continue to recommend a limb-sparing approach for patients with extremity EOO. In summary, the current findings demonstrate that EOO is a relatively doxorubicin-resistant, poor-prognosis form of soft tissue sarcoma that should be viewed by clinicians as clinically and therapeutically distinct from osseous osteosarcoma. The local recurrence–free survival rates observed with long-term follow-up suggest that patients with extremity EOO can be treated with limb salvage approaches similar to those currently used for patients with non-EOO soft tissue sarcoma. Notwithstanding the rarity of EOO and other uncommon soft tissue sarcoma subtypes, advances in the care of these patients will require disease-specific clinical trials.
We thank Vivian Z. Garcia and Melissa Burkett for assistance in preparing the manuscript.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50% decrease in the three-dimensional tumor volume without the appearance of new lesions. A minor response was defined as a 15% to 49% decrease in the three-dimensional volume of the primary lesion. Progressive disease (PD) was defined as a 
2 test or Wilcoxon rank sum test, depending on the type of variable (ie, categorical, dichotomous, or continuous). Fisher’s exact test was used in place of the 
