Hindawi Publishing Corporation Sarcoma Volume 2014, Article ID 902620, 8 pages http://dx.doi.org/10.1155/2014/902620
Research Article Clinical Features and Outcomes Differ between Skeletal and Extraskeletal Osteosarcoma Sheila Thampi,1 Katherine K. Matthay,1 W. John Boscardin,2 Robert Goldsby,1 and Steven G. DuBois1 1
Department of Pediatrics, UCSF School of Medicine and UCSF Benioff Childrenβs Hospital, 505 Parnassus Avenue M649, P.O. Box 0106, San Francisco, CA 94143, USA 2 Department of Medicine and Epidemiology and Biostatistics, UCSF School of Medicine 505 Parnassus Avenue, San Francisco, CA 94143, USA Correspondence should be addressed to Steven G. DuBois; [email protected] Received 23 May 2014; Revised 21 August 2014; Accepted 26 August 2014; Published 9 September 2014 Academic Editor: Clement Trovik Copyright Β© 2014 Sheila Thampi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Extraskeletal osteosarcoma (ESOS) is a rare subtype of osteosarcoma. We investigated patient characteristics, overall survival, and prognostic factors in ESOS. Methods. We identified cases of high-grade osteosarcoma with known tissue of origin in the Surveillance, Epidemiology, and End Results database from 1973 to 2009. Demographics were compared using univariate tests. Overall survival was compared with log-rank tests and multivariate analysis using Cox proportional hazards methods. Results. 256/4,173 (6%) patients with high-grade osteosarcoma had ESOS. Patients with ESOS were older, were more likely to have an axial tumor and regional lymph node involvement, and were female. Multivariate analysis showed ESOS to be favorable after controlling for stage, age, tumor site, gender, and year of diagnosis [hazard ratio 0.75 (95% CI 0.62 to 0.90); π = 0.002]. There was an interaction between age and tissue of origin such that older patients with ESOS had superior outcomes compared to older patients with skeletal osteosarcoma. Adverse prognostic factors in ESOS included metastatic disease, larger tumor size, older age, and axial tumor site. Conclusion. Patients with ESOS have distinct clinical features but similar prognostic factors compared to skeletal osteosarcoma. Older patients with ESOS have superior outcomes compared to older patients with skeletal osteosarcoma.
1. Introduction Extraskeletal osteosarcoma (ESOS) is a rare malignant soft tissue sarcoma with histologic similarities to primary bone osteosarcoma but without attachment to the bone or periosteum. ESOS accounts for 1% of all soft tissue sarcomas and 4% of osteogenic osteosarcomas [1]. Multiple case series ranging from 10 to 88 patients have described this rare and unique tumor, with distinct clinical features between ESOS and primary bone osteosarcoma [2, 3]. ESOS is a tumor primarily of older age with a mean age of 47.5 to 61 years [1]. The majority of case series describe a male predominance [1, 3β7]. An early report described an overall survival rate of 38% at 5 years [5]. However, more recent groups that have used multiagent chemotherapy and wide resection during surgical procedures have described overall survival rates of 66 to 77%, similar to skeletal osteosarcoma
[7, 8]. Reported adverse prognostic factors include metastatic disease at presentation, large tumor size, and inability to achieve complete surgical resection [1, 4, 5, 7, 9]. In order to further characterize this rare malignancy and compare it statistically to primary skeletal osteosarcoma, we used a large registry to analyze the largest known cohort of patients with ESOS. We define patient and tumor characteristics, estimated overall survival rates, and prognostic factors specifically for patients with ESOS.
2. Methods 2.1. Patients. In this cohort study, the analytic cohort included patients with osteosarcoma of skeletal or extraskeletal origin reported to the US National Cancer Instituteβs SEER (Surveillance, Epidemiology, and End Results;
2 http://seer.cancer.gov/data/) system from 1973 to 2009. This registry captures clinical data and outcomes from approximately one-quarter of the US population. Data are collected from a variety of sources, including health providers, pathology reports, laboratories, autopsy reports, and death certificates. Standard data quality measures are employed. We included a convenience sample of patients in SEER with histologically confirmed high-grade osteosarcoma of any age at time of diagnosis. Given their low metastatic potential, we excluded patients with low-grade osteosarcoma (e.g., parosteal and intraosseous subtypes). The SEER database included 4,178 cases of high-grade osteosarcoma. We excluded five patients with unknown tissue of origin, which resulted in an analytic cohort of the remaining 4,173 patients. 2.2. Predictor Variable. We evaluated patient characteristics and outcomes according to tissue of origin (skeletal versus extraskeletal). Primary site was identified in SEER based on ICD-O-3 topography codes, which was then used to code each patient as having a skeletal or extraskeletal primary tumor. As only tumors with the histology code for osteosarcoma were included, primary tumors reported to arise in a soft tissue site were defined as extraskeletal osteosarcoma. Imaging materials (scans and/or scan reports) were not available to confirm skeletal or extraskeletal tissue origin. 2.3. Outcome Variables. Patient characteristics and overall survival were evaluated based on extraskeletal versus skeletal disease. Analyzed variables included age at diagnosis (continuous variable and age categorized in tertiles with exclusion of the youngest patients, age β€ 17 years), sex, year of diagnosis (in 10-year increments), race, primary tumor location (evaluated as distinct sites and also dichotomized with tumors of the head, neck, and trunk defined as axial versus tumors of the extremity defined as appendicular), presence of regional lymph nodes, histologic subtype, tumor size (dichotomized at 10 cm), use of radiation therapy, and stage of disease, defined as either localized or metastatic. Patients with only regional node involvement outside of the primary site of disease were determined to have localized disease. To determine overall survival, we used total months of follow-up and patient vital status at the time of last follow-up. To determine competing events, we used the variables vital status and cause-specific death, which describes death related to cancer and noncancer causes. 2.4. Statistical Methods. We compared patient characteristics between groups with skeletal osteosarcoma or ESOS using chi-squared tests (for categorical variables) or Studentβs ttest (for continuous variables). Overall survival was estimated using Kaplan-Meier (KM) methods with 95% confidence intervals. Potential differences in overall survival between groups were evaluated with log-rank tests. The median follow-up time for the analytic cohort was 102 months. We also performed competing risk analysis using the Fine-Gray proportional subhazard model to focus on death
Sarcoma due to malignancy. Death due to causes other than osteosarcoma was coded as a competing event. If cause of death was unknown, then those patients were not included in the competing risk analysis. Cox proportional hazard methods were used to determine the effect of extraskeletal disease on overall survival while controlling for other differences in patient characteristics between the groups. Time dependent covariates were used to test the proportional hazards assumption. The SEER database was accessed using SEERβ Stat version 7.1.0.
3. Results 3.1. Patient Characteristics Differ between Extraskeletal and Skeletal Osteosarcoma. Of the 4,173 patients in the analytic cohort, 256 (6.1%) patients had ESOS. Table 1 provides patient characteristics according to tissue of origin. The mean age for patients with ESOS was 60.7 years compared to 31.4 years for those with skeletal osteosarcoma (π < 0.0001). Patients with extraskeletal involvement were more likely to be female (54.3% versus 44.5%, π = 0.002), have an axial tumor (61.1% versus 25.1%, π < 0.0001), and have regional lymph node involvement (7.7% versus 2.4%, π < 0.0001). There was a statistically significant difference in distribution in primary tumor sites (π < 0.0001), most notable in comparing the frequency of primary tumors arising in the lower extremity (32.7% for extraskeletal versus 62.6% for skeletal). Patients with extraskeletal tumors were more likely to receive radiation treatment than patients with skeletal tumors (25.3% versus 12.3%, π < 0.0001). Whether radiation was instituted prior to diagnosis of osteosarcoma is unknown. About 30% of ESOS were found in the thorax, which includes involvement of the chest wall, breast, heart, and soft tissue. However, 6 cases were primary lung lesions, 4 were primary pleural lesions, and all are without documented skeletal involvement. Almost all ESOS were reported to have conventional osteosarcoma histology, rather than other histologic subtypes of high-grade osteosarcoma. There were no statistically significant differences in patient race, tumor size, or stage of disease based upon tissue of origin. 3.2. Overall Survival Differs between Extraskeletal and Skeletal Osteosarcoma. On Kaplan-Meier testing of the entire analytic cohort, without accounting for competing risks, overall survival was inferior for patients with ESOS as compared to those with skeletal osteosarcoma (Figure 1(a)). The estimated fiveyear overall survival for those with extraskeletal disease was 37% (95% CI 30.6 to 43.3) compared to 50.8% (95%CI 49.1 to 52.5; π < 0.0001) for those with skeletal disease. Differential overall survival was also seen according to tissue of origin when looking exclusively at patients with localized disease, but a statistically significant difference in overall survival according to tissue of origin was not seen in the cohort of patients with metastatic disease (see Supplemental Figure available online at http://dx.doi.org/10.1155/2014/902620). Specifically, the estimated five-year overall survival for those with localized extraskeletal disease was 47% (95% CI 39.8 to 54.6) compared to 63% (95% CI 60.8 to 64.7) for patients with
Sarcoma
3 1.00 P < 0.0001
Estimated overall survival
Estimated overall survival
1.00 0.75 0.50 0.25
P = 0.32 0.75 0.50 0.25 0.00
0.00 0
12
24
36 48 60 72 84 96 108 120 Months from initial diagnosis
Number at risk Extraskeletal 250 169 131 101 83 67 55 46 41 34 29 Skeletal 3848 2932 2237 1855 1586 1384 1221 1077 931 833 729
0
12
24
36 48 60 72 84 96 108 120 Months from initial diagnosis
Number at risk Extraskeletal 6 6 6 2 2 2 1 1 1 1 1 1653 1413 1124 933 803 710 632 558 475 425 375 Skeletal
(a)
(b)
1.00 Estimated overall survival
Estimated overall survival
1.00 P = 0.908 0.75 0.50 0.25
P = 0.320 0.75 0.50 0.25 0.00
0.00 0
12
24
0
36 48 60 72 84 96 108 120 Months from initial diagnosis
12
24
36 48 60 72 84 96 108 120 Months from initial diagnosis
Number at risk 8 8 6 3 3 Extraskeletal 23 19 15 12 10 8 820 698 555 473 410 368 325 292 254 224 199 Skeletal
Number at risk Extraskeletal 72 56 48 40 33 27 21 18 17 16 14 Skeletal 740 559 406 340 294 243 208 179 159 144 118
(c)
(d)
Estimated overall survival
1.00 P < 0.0001 0.75 0.50 0.25 0.00 0
12
24
36 48 60 72 84 96 108 120 Months from initial diagnosis
Number at risk Extraskeletal 149 88 62 47 38 Skeletal 635 262 152 109 79
30 63
25 56
19 48
17 43
14 40
11 37
Extraskeletal Skeletal (e)
Figure 1: (a) Kaplan-Meier estimates of overall survival from the time of diagnosis according to tumor tissue of origin in all patients with high-grade osteosarcoma [π = 4,173 (256 with extraskeletal involvement and 3,917 with skeletal involvement)]. (b) Kaplan-Meier estimates of overall survival from the time of diagnosis according to tumor tissue of origin in patients aged from 0 to 17 years [π = 1,672 (6 with extraskeletal involvement and 1,666 with skeletal involvement)]. (c) Kaplan-Meier estimates of overall survival from the time of diagnosis according to tumor tissue of origin in patients aged from 18 to 32 years [π = 849 (24 with extraskeletal involvement and 825 with skeletal involvement)]. (d) Kaplan-Meier estimates of overall survival from the time of diagnosis according to tumor tissue of origin in patients aged from 33 to 59 years [π = 824 (72 with extraskeletal involvement and 752 with skeletal involvement)]. (e) Kaplan-Meier estimates of overall survival from the time of diagnosis according to tumor tissue of origin in patients aged from 60 to 99 years [π = 828 (154 with extraskeletal involvement and 674 with skeletal involvement)].
4
Sarcoma Table 1: Characteristics of 4,173 patients with osteosarcoma according to tissue of origin.
Characteristic Mean age (range) Sex Male Female Year of diagnosis 1973β1979 1980β1989 1990β1999 2000β2009 Race Caucasian African American Asian Native American Primary site Lower extremity Upper extremity Head Spine Ribs/sternum Pelvis Thorax Abdomen/retroperitoneum Primary tumor location Axial Appendicular Regional lymph node Present Absent Stage Distant metastasis No distant metastasis Tumor size
Research Article Clinical Features and Outcomes Differ between Skeletal and Extraskeletal Osteosarcoma Sheila Thampi,1 Katherine K. Matthay,1 W. John Boscardin,2 Robert Goldsby,1 and Steven G. DuBois1 1
Department of Pediatrics, UCSF School of Medicine and UCSF Benioff Childrenβs Hospital, 505 Parnassus Avenue M649, P.O. Box 0106, San Francisco, CA 94143, USA 2 Department of Medicine and Epidemiology and Biostatistics, UCSF School of Medicine 505 Parnassus Avenue, San Francisco, CA 94143, USA Correspondence should be addressed to Steven G. DuBois; [email protected] Received 23 May 2014; Revised 21 August 2014; Accepted 26 August 2014; Published 9 September 2014 Academic Editor: Clement Trovik Copyright Β© 2014 Sheila Thampi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Extraskeletal osteosarcoma (ESOS) is a rare subtype of osteosarcoma. We investigated patient characteristics, overall survival, and prognostic factors in ESOS. Methods. We identified cases of high-grade osteosarcoma with known tissue of origin in the Surveillance, Epidemiology, and End Results database from 1973 to 2009. Demographics were compared using univariate tests. Overall survival was compared with log-rank tests and multivariate analysis using Cox proportional hazards methods. Results. 256/4,173 (6%) patients with high-grade osteosarcoma had ESOS. Patients with ESOS were older, were more likely to have an axial tumor and regional lymph node involvement, and were female. Multivariate analysis showed ESOS to be favorable after controlling for stage, age, tumor site, gender, and year of diagnosis [hazard ratio 0.75 (95% CI 0.62 to 0.90); π = 0.002]. There was an interaction between age and tissue of origin such that older patients with ESOS had superior outcomes compared to older patients with skeletal osteosarcoma. Adverse prognostic factors in ESOS included metastatic disease, larger tumor size, older age, and axial tumor site. Conclusion. Patients with ESOS have distinct clinical features but similar prognostic factors compared to skeletal osteosarcoma. Older patients with ESOS have superior outcomes compared to older patients with skeletal osteosarcoma.
1. Introduction Extraskeletal osteosarcoma (ESOS) is a rare malignant soft tissue sarcoma with histologic similarities to primary bone osteosarcoma but without attachment to the bone or periosteum. ESOS accounts for 1% of all soft tissue sarcomas and 4% of osteogenic osteosarcomas [1]. Multiple case series ranging from 10 to 88 patients have described this rare and unique tumor, with distinct clinical features between ESOS and primary bone osteosarcoma [2, 3]. ESOS is a tumor primarily of older age with a mean age of 47.5 to 61 years [1]. The majority of case series describe a male predominance [1, 3β7]. An early report described an overall survival rate of 38% at 5 years [5]. However, more recent groups that have used multiagent chemotherapy and wide resection during surgical procedures have described overall survival rates of 66 to 77%, similar to skeletal osteosarcoma
[7, 8]. Reported adverse prognostic factors include metastatic disease at presentation, large tumor size, and inability to achieve complete surgical resection [1, 4, 5, 7, 9]. In order to further characterize this rare malignancy and compare it statistically to primary skeletal osteosarcoma, we used a large registry to analyze the largest known cohort of patients with ESOS. We define patient and tumor characteristics, estimated overall survival rates, and prognostic factors specifically for patients with ESOS.
2. Methods 2.1. Patients. In this cohort study, the analytic cohort included patients with osteosarcoma of skeletal or extraskeletal origin reported to the US National Cancer Instituteβs SEER (Surveillance, Epidemiology, and End Results;
2 http://seer.cancer.gov/data/) system from 1973 to 2009. This registry captures clinical data and outcomes from approximately one-quarter of the US population. Data are collected from a variety of sources, including health providers, pathology reports, laboratories, autopsy reports, and death certificates. Standard data quality measures are employed. We included a convenience sample of patients in SEER with histologically confirmed high-grade osteosarcoma of any age at time of diagnosis. Given their low metastatic potential, we excluded patients with low-grade osteosarcoma (e.g., parosteal and intraosseous subtypes). The SEER database included 4,178 cases of high-grade osteosarcoma. We excluded five patients with unknown tissue of origin, which resulted in an analytic cohort of the remaining 4,173 patients. 2.2. Predictor Variable. We evaluated patient characteristics and outcomes according to tissue of origin (skeletal versus extraskeletal). Primary site was identified in SEER based on ICD-O-3 topography codes, which was then used to code each patient as having a skeletal or extraskeletal primary tumor. As only tumors with the histology code for osteosarcoma were included, primary tumors reported to arise in a soft tissue site were defined as extraskeletal osteosarcoma. Imaging materials (scans and/or scan reports) were not available to confirm skeletal or extraskeletal tissue origin. 2.3. Outcome Variables. Patient characteristics and overall survival were evaluated based on extraskeletal versus skeletal disease. Analyzed variables included age at diagnosis (continuous variable and age categorized in tertiles with exclusion of the youngest patients, age β€ 17 years), sex, year of diagnosis (in 10-year increments), race, primary tumor location (evaluated as distinct sites and also dichotomized with tumors of the head, neck, and trunk defined as axial versus tumors of the extremity defined as appendicular), presence of regional lymph nodes, histologic subtype, tumor size (dichotomized at 10 cm), use of radiation therapy, and stage of disease, defined as either localized or metastatic. Patients with only regional node involvement outside of the primary site of disease were determined to have localized disease. To determine overall survival, we used total months of follow-up and patient vital status at the time of last follow-up. To determine competing events, we used the variables vital status and cause-specific death, which describes death related to cancer and noncancer causes. 2.4. Statistical Methods. We compared patient characteristics between groups with skeletal osteosarcoma or ESOS using chi-squared tests (for categorical variables) or Studentβs ttest (for continuous variables). Overall survival was estimated using Kaplan-Meier (KM) methods with 95% confidence intervals. Potential differences in overall survival between groups were evaluated with log-rank tests. The median follow-up time for the analytic cohort was 102 months. We also performed competing risk analysis using the Fine-Gray proportional subhazard model to focus on death
Sarcoma due to malignancy. Death due to causes other than osteosarcoma was coded as a competing event. If cause of death was unknown, then those patients were not included in the competing risk analysis. Cox proportional hazard methods were used to determine the effect of extraskeletal disease on overall survival while controlling for other differences in patient characteristics between the groups. Time dependent covariates were used to test the proportional hazards assumption. The SEER database was accessed using SEERβ Stat version 7.1.0.
3. Results 3.1. Patient Characteristics Differ between Extraskeletal and Skeletal Osteosarcoma. Of the 4,173 patients in the analytic cohort, 256 (6.1%) patients had ESOS. Table 1 provides patient characteristics according to tissue of origin. The mean age for patients with ESOS was 60.7 years compared to 31.4 years for those with skeletal osteosarcoma (π < 0.0001). Patients with extraskeletal involvement were more likely to be female (54.3% versus 44.5%, π = 0.002), have an axial tumor (61.1% versus 25.1%, π < 0.0001), and have regional lymph node involvement (7.7% versus 2.4%, π < 0.0001). There was a statistically significant difference in distribution in primary tumor sites (π < 0.0001), most notable in comparing the frequency of primary tumors arising in the lower extremity (32.7% for extraskeletal versus 62.6% for skeletal). Patients with extraskeletal tumors were more likely to receive radiation treatment than patients with skeletal tumors (25.3% versus 12.3%, π < 0.0001). Whether radiation was instituted prior to diagnosis of osteosarcoma is unknown. About 30% of ESOS were found in the thorax, which includes involvement of the chest wall, breast, heart, and soft tissue. However, 6 cases were primary lung lesions, 4 were primary pleural lesions, and all are without documented skeletal involvement. Almost all ESOS were reported to have conventional osteosarcoma histology, rather than other histologic subtypes of high-grade osteosarcoma. There were no statistically significant differences in patient race, tumor size, or stage of disease based upon tissue of origin. 3.2. Overall Survival Differs between Extraskeletal and Skeletal Osteosarcoma. On Kaplan-Meier testing of the entire analytic cohort, without accounting for competing risks, overall survival was inferior for patients with ESOS as compared to those with skeletal osteosarcoma (Figure 1(a)). The estimated fiveyear overall survival for those with extraskeletal disease was 37% (95% CI 30.6 to 43.3) compared to 50.8% (95%CI 49.1 to 52.5; π < 0.0001) for those with skeletal disease. Differential overall survival was also seen according to tissue of origin when looking exclusively at patients with localized disease, but a statistically significant difference in overall survival according to tissue of origin was not seen in the cohort of patients with metastatic disease (see Supplemental Figure available online at http://dx.doi.org/10.1155/2014/902620). Specifically, the estimated five-year overall survival for those with localized extraskeletal disease was 47% (95% CI 39.8 to 54.6) compared to 63% (95% CI 60.8 to 64.7) for patients with
Sarcoma
3 1.00 P < 0.0001
Estimated overall survival
Estimated overall survival
1.00 0.75 0.50 0.25
P = 0.32 0.75 0.50 0.25 0.00
0.00 0
12
24
36 48 60 72 84 96 108 120 Months from initial diagnosis
Number at risk Extraskeletal 250 169 131 101 83 67 55 46 41 34 29 Skeletal 3848 2932 2237 1855 1586 1384 1221 1077 931 833 729
0
12
24
36 48 60 72 84 96 108 120 Months from initial diagnosis
Number at risk Extraskeletal 6 6 6 2 2 2 1 1 1 1 1 1653 1413 1124 933 803 710 632 558 475 425 375 Skeletal
(a)
(b)
1.00 Estimated overall survival
Estimated overall survival
1.00 P = 0.908 0.75 0.50 0.25
P = 0.320 0.75 0.50 0.25 0.00
0.00 0
12
24
0
36 48 60 72 84 96 108 120 Months from initial diagnosis
12
24
36 48 60 72 84 96 108 120 Months from initial diagnosis
Number at risk 8 8 6 3 3 Extraskeletal 23 19 15 12 10 8 820 698 555 473 410 368 325 292 254 224 199 Skeletal
Number at risk Extraskeletal 72 56 48 40 33 27 21 18 17 16 14 Skeletal 740 559 406 340 294 243 208 179 159 144 118
(c)
(d)
Estimated overall survival
1.00 P < 0.0001 0.75 0.50 0.25 0.00 0
12
24
36 48 60 72 84 96 108 120 Months from initial diagnosis
Number at risk Extraskeletal 149 88 62 47 38 Skeletal 635 262 152 109 79
30 63
25 56
19 48
17 43
14 40
11 37
Extraskeletal Skeletal (e)
Figure 1: (a) Kaplan-Meier estimates of overall survival from the time of diagnosis according to tumor tissue of origin in all patients with high-grade osteosarcoma [π = 4,173 (256 with extraskeletal involvement and 3,917 with skeletal involvement)]. (b) Kaplan-Meier estimates of overall survival from the time of diagnosis according to tumor tissue of origin in patients aged from 0 to 17 years [π = 1,672 (6 with extraskeletal involvement and 1,666 with skeletal involvement)]. (c) Kaplan-Meier estimates of overall survival from the time of diagnosis according to tumor tissue of origin in patients aged from 18 to 32 years [π = 849 (24 with extraskeletal involvement and 825 with skeletal involvement)]. (d) Kaplan-Meier estimates of overall survival from the time of diagnosis according to tumor tissue of origin in patients aged from 33 to 59 years [π = 824 (72 with extraskeletal involvement and 752 with skeletal involvement)]. (e) Kaplan-Meier estimates of overall survival from the time of diagnosis according to tumor tissue of origin in patients aged from 60 to 99 years [π = 828 (154 with extraskeletal involvement and 674 with skeletal involvement)].
4
Sarcoma Table 1: Characteristics of 4,173 patients with osteosarcoma according to tissue of origin.
Characteristic Mean age (range) Sex Male Female Year of diagnosis 1973β1979 1980β1989 1990β1999 2000β2009 Race Caucasian African American Asian Native American Primary site Lower extremity Upper extremity Head Spine Ribs/sternum Pelvis Thorax Abdomen/retroperitoneum Primary tumor location Axial Appendicular Regional lymph node Present Absent Stage Distant metastasis No distant metastasis Tumor size
