Pediatric-type sarcomas such as rhabdomyosarcoma (RMS), Ewing sarcoma (EWS), primitive neuroectodermal tumor (PNET), and desmoplastic small round-cell tumor (DSRCT) are rare in adults, with limited studies on their prognosis and optimal treatment strategies. We aimed to examine the outcome of children and adult patients with RMS, EWS, PNET, and DSRCT and relevant prognostic factors.
We retrospectively reviewed 220 pediatric-type sarcoma patients at a single institution between 1985 and 2011. Comparisons were made in order to examine differences in demographics, disease characteristics, and survival. Survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards models.
A total of 220 consecutive patients were identified at our institute. Median age was 15.6 years (range, 0 to 81 years) and there were 108 children (49%) and 112 adult patients (51%). According to histological classification, 106 patients (48.2%) had RMS, 60 (27.3%) had EWS, 50 (22.7%) had PNET, and 4 (1.8%) had DSRCT. With a median follow-up period of 6.6 years, the estimated median overall survival (OS) of all patients was 75 months (95% confidence interval [CI], 27.2 to 122.8 months) and median event-free survival (EFS) for all patients was 11 months (95% CI, 8.8 to 13.2 months). No significant difference in OS and EFS was observed between adults and children. In multivariate analysis, distant metastasis (hazard ratio [HR], 1.617; 95% CI, 1.022 to 2.557; p=0.040) and no debulking surgery (HR, 1.443; 95% CI, 1.104 to 1.812; p=0.012) showed independent association with worse OS.
Metastatic disease and no surgical treatment are poor prognostic factors for OS among pediatric-type sarcomas for both adults and children.
Soft tissue sarcomas (STS) form a set of heterogeneous neoplasms originating from mesenchymal cells. They are rare tumors comprising approximately 1% of all adult malignancies and 12% of pediatric cancers [
RMS is the most frequent tumor in children, accounting for more than 50% of cases [
Previous studies on treatment outcome of pediatric-type sarcoma reported controversial results on age as a predictor of poor prognosis. A study comparing adult and pediatric RMS from 1973 to 2005 reported that adults had worse survival than children with similar tumors [
In this study, we will compare features of four types of pediatric sarcomas that occur in both adults and children, characterize clinical outcome, and identify the prognostic factors associated with survival.
The clinical and survival outcome data of patients with a reported diagnosis of RMS, EWS, PNET, and DSRCT between 1985 and 2011 were obtained from the database at Severance Hospital. All patients were treated with a multidisciplinary approach, including surgery, chemotherapy, or radiotherapy. Clinical data of these patients were reviewed retrospectively. The following clinical parameters were collected: demographic data, pathology, primary anatomic site, tumor extent at diagnosis, chemotherapy, radiotherapy, surgery, recurrence or progression, and survival. The following prognostic factors were analyzed: age, sex, tumor histology, primary site, tumor extent, primary tumor size, surgery, chemotherapy, and radiotherapy. Favorable tumor sites were defined as nonparameningeal head and neck, genitourinary sites except bladder and prostate, and orbit. Unfavorable sites included the parameningeal head and neck region, bladder, prostate, limb, and other sites. Tumor extent was defined using the Intergroup Rhabdomyosarcoma Study Group.
Most study patients (90.4%) received chemotherapy and the most common chemotherapy regimen was VP16/adriamycin/cyclophosphamide. Additional regimens included combinations of adriamycin, ifosphamide, vincristine, actinomycin-D, and cisplatin.
Radiotherapy (RT) techniques and methods evolved with technology over the course of the study; however, the basic principles were applied to all patients as follows. Patients’ extremities were immobilized for simulation and treatment in custom molds. The target volume encompassed the entire affected compartment, but was longitudinally extended 5 to 8 cm beyond the tumor. If necessary, additional magnetic resonance imaging was used for enhanced target definition. Most patients received a consistent dose/fractionation schedule of 50.4 Gy at 1.2 Gy fractions. The median RT dose was 45 Gy (range, 14 to 85 Gy).
Debulking surgery, or wide excision, was performed in 129 patients (58.6%). Wide excision refers to a dissection plane through unaffected normal tissue within the involved compartment, as defined by the criteria of Enneking et al. [
Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method. OS was calculated from the date of diagnosis to the date of death from the disease or the last follow-up. EFS was calculated from the date of treatment to the first documented relapse or progression. Survival estimates were calculated using the Kaplan-Meier method and log-rank test was used for comparison of survival curves. The chi-squared test was used for comparison of clinical parameters. Multivariate survival analyses using a Cox’s proportional hazard model were performed in order to characterize prognostic factors for OS and EFS.
Results of comparison of the clinical findings in children and adult patients are shown in
For 108 children, with a median age of 6 years (range, 0 to 6 years), 74 patients (68.5%) had tumors located in unfavorable sites, 49 patients (45.4%) had tumor size equal to or greater than 5 cm, and 26 patients (24.1%) had metastatic disease. Sixty-one patients (56.5%) had undergone debulking surgery, 55 patients (50.9%) had received radiotherapy, and 95 patients (87.9%) had received chemotherapy. By histopathology, 56 patients (51.8%) had RMS, 30 (27.8%) had EWS, 18 (16.7%) had PNET, and 4 (3.7%) had DSRCT.
For 112 adults, with a median age of 26 years (range, 16 to 81 years), 77 patients (68.7%) had tumors located in unfavorable sites, 59 patients (52.7%) had tumor size equal to or greater than 5 cm, and 33 patients (29.5%) had metastatic disease. Thirty-nine patients (34.8%) had undergone debulking surgery, 63 patients (56.3%) had received radiotherapy, and 100 patients (89.3%) had received chemotherapy. By histopathology, 50 patients (44.6%) had RMS, 30 (26.8%) had EWS, 32 (28.6%) had PNET, and none (0%) had DSRCT.
Among 220 patients, 115 (52.3%) had died at the time of analysis with a median follow-up period of 6.6 years (range, 0.1 to 29.0 years). Estimated median OS of all patients was 75 months (95% CI, 27.2 to 122.8 months), and the median EFS of all patients was 11 months (95% CI 8.8 to 13.2 months). No significant difference in OS was observed between adults and children (60 months [95% CI, 1.9 to 132.1] vs. 75 months [95% CI, 11.6 to 104.3], p=0.859) (
We performed univariate and multivariate analyses using the log-rank test for analysis of prognostic factors in adults and children (
Next, we compared OS of patients according to number of poor prognostic factors. Poor prognostic factors were scored as follows: no distant metastasis=0, distant metastasis=1; tumor size less than 5 cm=0, tumor size equal or greater than 5 cm=1; surgery=0, no surgery=1. The Kaplan-Meier curve of four stratified scores showed a significant difference in survival (0 [not reached] vs. 1 [81 months] vs. 2 [58 months] vs. 3 [18 months], p < 0.001) (
In a subgroup analysis of 158 patients with localized disease, 52 patients (32.9%) showed recurrence: 21 patients (13.3%) with local recurrence and 31 patients (19.6%) with distant recurrence. The most frequent sites of distant recurrence were lung (15%), brain (7%), bone (6%), spine (2%), and liver (1%), in the order of frequency.
Using data during a 26-year period, we described 220 adult and pediatric patients with a reported diagnosis of RMS, EWS, PNET, and DSRCT. To the best of our knowledge, our work represents the first study examining the survival and prognostic factors in both pediatric and adult patients in the Asian population. While there were no significant differences in baseline characteristics in the study population, no significant differences in OS and EFS were observed between adults and children. In children, large tumor size (> 5 cm), metastatic disease, no surgical treatment, and PNET histology showed an association with shorter OS, whereas in adults, only no debulking surgery showed an association with shorter OS.
The effect of age on survival of sarcoma patients has been a subject of debate, with different conflicting results from different studies. In a few retrospective studies, survival in adults was reported to be dramatically worse than that reported for children [
In the multivariate model, we compared prognostic factors of survival between adults and children. In all patients, surgical intervention was found to show significant association with improved survival when compared with no surgical intervention. Surgery is the mainstay of treatment of STS, and the rate of local recurrence following wide resection with negative margins is usually below 20% [
We reviewed previous studies of pediatric-type sarcoma in adults and children, as shown in
Recently, increased understanding of the molecular biology of sarcomas has led to advances in molecular diagnostics and clinical management of certain sarcomas [
Our study has a few limitations. First, it is retrospective and the data collected often lacked detailed information on treatment. A lack of details of systemic chemotherapy and a few missing data are major limitations of our findings. Second, as it spanned a long period of time from 1985 until now, the heterogeneity in treatment strategies could result in different survival outcomes regardless of initial disease presentation. Third, due to the heterogeneity of histologic subtypes, it may be difficult to draw a common conclusion from the analysis of prognostic factors. Despite these limitations, our study is unique in that we have compared the survival outcome of a large number of adults and children with similar baseline characteristics.
Our study adds relevant data on clinical features and outcome of pediatric tumor in adult patients. No significant difference in survival outcome was observed between adults and children. Metastatic disease and no surgical treatment are poor prognostic factors for OS among pediatric-type sarcomas for both adults and children. Additional studies on treatment outcomes and molecular biology are clearly needed in order to further clarify differences between adult and pediatric sarcoma.
Conflict of interest relevant to this article was not reported.
(A) Comparison of overall survival (OS) in adults and children. (B) Comparison of event-free survival (EFS) in adults and children. (C) Comparison of OS according to histology in all patients. (D) Comparison of EFS according to histology in children. RMS, rhabdomyosarcoma; EWS, Ewing sarcoma; PNET, primitive neuroectodermal tumor; DSRCT, desmoplastic small round-cell tumor.
Overall survival (OS) according to number of poor prognostic factors.
Baseline characteristics of patients
Characteristic | Total (n=220) | Children (n=108) | Adults (n=112) | p-value |
---|---|---|---|---|
Gender Male | 121 (55) | 50 (46.3) | 71 (63.4) | 0.010 |
Female | 99 (45) | 58 (53.7) | 41 (36.6) | |
Age | ||||
Median age (range, yr) | 15.6 (0-81) | 6(0-16) | 26 (18-81) | |
Adult (≥ 18 yr) | 112 (50.9) | - | - | |
≥ 30 yr | - | - | 43 (38.4) | |
< 30 yr | - | - | 69 (61.6) | |
Child (< 18 yr) | 108 (49.1) | - | - | |
Primary site | 0.446 | |||
Favorable | 69 (30.5) | 34 (31.5) | 35 (31.3) | |
Nonparameningeal | 36 (16.4) | 19 (17.6) | 19 (17) | |
Genitourinary (nonbladder, nonprostate) | 23 (10.5) | 11 (10.2) | 12 (10.7) | |
Orbit | 8 (3.6) | 4 (3.7) | 4 (3.6) | |
Nonfavorable | 151 (68.2) | 74 (68.5) | 77 (68.7) | |
Parameningeal | 46 (20.9) | 23 (21.3) | 27 (20.5) | |
Bladder/prostate | 9 (4.1) | 5 (4.6) | 5 (4.4) | |
Limb | 46 (20.9) | 21 (19.4) | 25 (22.3) | |
Others | 49 (22.3) | 25 (23.1) | 24 (21.4) | |
Tumor size (cm) | 0.278 | |||
< 5 | 108 (49.1) | 57 (52.8) | 51 (46.4) | |
≥ 5 | 108 (49.1) | 49 (45.4) | 59 (52.7) | |
Nonevaluable | 4 (1.8) | 2 (1.9) | 2 (1.8) | |
Distant metastasis | 0.446 | |||
M0 | 158 (71.8) | 81 (75) | 77 (68.8) | |
M1 | 59 (26.8) | 26 (24.1) | 33 (29.5) | |
Nonevaluable | 3 (1.4) | 1 (0.9) | 2 (1.8) | |
Debulking surgery | 0.482 | |||
Yes | 129 (58.6) | 61 (56.5) | 39 (34.8) | |
No | 82 (37.3) | 43 (39.8) | 68 (63.6) | |
Nonevaluable | 9 (4.1) | 4 (3.7) | 5 (4.5) | |
Radiotherapy | 118 (53.6) | 55 (50.9) | 63 (56.3) | 0.687 |
Chemotherapy | 199 (90.4) | 99 (91.7) | 100 (89.3) | 1.000 |
Histopathology | 0.381 | |||
Rhabdomyosarcoma | 106 (48.2) | 56 (51.8) | 50 (44.6) | |
Ewing's sarcoma | 60 (27.3) | 30 (27.8) | 30 (26.8) | |
Primary neuroectodermal tumor | 50 (22.7) | 18 (16.7) | 32 (28.6) | |
Desmoplastic small round cell tumor | 4 (1.8) | 4 (3.7) | 0 (0) |
Values are presented as number (%).
Multivariate analysis of prognostic factors
All |
Children |
Adults |
||||
---|---|---|---|---|---|---|
HR | p-value | HR | p-value | HR | p-value | |
Gender | ||||||
Male | 1.00 | 1.00 | 1.00 | |||
Female | 1.023 (0.693-1.511) | 0.908 | 1.001 (0.693-1.446) | 0.995 | 1.000 (0.790-1.231) | 0.999 |
Age | ||||||
Adult (≥ 18 yr) | 1.00 | - | - | - | - | |
Child (< 18 yr) | 1.051 (0.713-1.547) | 0.802 | - | - | - | - |
Primary site | ||||||
Favorable | 1.00 | 1.00 | 1.00 | |||
Non-favorable | 1.262 (0.751-1.798) | 0.500 | 1.316 (0.695-2.491) | 0.399 | 1.181 (0.702-1.763) | 0.392 |
Tumor size (cm) | ||||||
< 5 | 1.00 | 1.00 | 1.00 | |||
≥ 5 | 1.179 (0.766-1.813) | 0.454 | 1.540 (1.06-2.24) | 0.024 | 1.560 (0.798-3.050) | 0.193 |
Distant metastasis | ||||||
M0 | 1.00 | 1.00 | 1.00 | |||
M1 | 1.617 (1.022-2.557) | 0.040 | 1.851 (1.249-2.745) | 0.001 | 1.261 (0.659-2.411) | 0.484 |
Debulking surgery | ||||||
Yes | 1.00 | 1.00 | 1.00 | |||
No | 1.443 (1.104-1.812) | 0.012 | 1.811 (1.467-1.958) | 0.006 | 1.605 (1.349-1.910) | 0.003 |
Chemotherapy | ||||||
Yes | 1.00 | 1.00 | 1.00 | |||
No | 1.009 (0.575-1.770) | 0.975 | 1.243 (0.583-2.647) | 0.573 | 1.279 (0.548-2.987) | 0.570 |
Radiotherapy | ||||||
Yes | 1.00 | 1.00 | 1.00 | |||
No | 1.012 (0.696-1.471) | 0.951 | 1.078 (0.626-1.858) | 0.787 | 0.978 (0.582-1.642) | 0.932 |
Histopathology | 0.043 | 0.007 | 0.969 | |||
RMS | 1.00 | 1.00 | 1.00 | |||
EWS | 1.300 (0.843-2.004) | 0.236 | 1.756 (0.923-3.341) | 0.086 | 0.955 (0.530-1.721) | 0.879 |
PNET | 1.562 (0.990-2.465) | 0.055 | 2.387 (1.230-4.631) | 0.010 | 1.023 (0.543-1.927) | 0.944 |
DSRCT | 1.560 (0.485-5.013) | 0.456 | 2.523 (0.339-18.768) | 0.366 | 1.063 (0.251-4.496) | 0.934 |
HR, hazard ratio; RMS, rhabdomyosarcoma; EWS, Ewing sarcoma; PNET, primitive neuroectodermal tumor; DSCRT, desmoplastic small round-cell tumor.
Previously reported pediatric-type sarcoma in adults and children
Type | No. | Study years | Results | Reference |
---|---|---|---|---|
Western | ||||
RMS | ||||
Adults | 1,071 | 1973-2005 | Adults with RMS had significantly worse outcome than children, tumors were more likely to be at unfavorable site; 5-year survival rate 27% vs. 61% | Sultan et al., 2009 [ |
Children | 1,529 | |||
Adults | 171 | 1975-2001 | Overall rate of response to chemotherapy was 85%; 5-year event-free survival was 28% and 5-year overall survival was 61% | Ferrari et al., 2003 [ |
Adults | 113 | 5-Year survival rate 26% | Ariel and Briceno, 1975 [ |
|
EWS/PNET | ||||
Age ≤ 14 | 190 | 1972-1992 | Rate of relapse ≤ 14 years vs. >14 years: 15.9 vs. 13.8 (p < 0.94) | Bacci et al., 2004 [ |
Age > 14 | 212 | |||
Adults Children | 19 | 1995-2003 | Median OS of patients ≤ 20 years vs. > 20 years did not differ (p=0.27) | Yamada et al., 2006 [ |
Adults | 372 | 1989-2007 | Adult age, hispanic race, metastatic disease, large tumor size, low socioeconomic status are poor prognostic factors for overall survival | Lee et al., 2010 [ |
Children | 353 | |||
Adults | 24 | 1990-2005 | Localized disease: 3-year survival 59% | Gupta et al., 2010 [ |
Adults | 27 | 1979-2002 | 5-Year survival rate 58% | Smorenburg et al., 2007 [ |
Adults | 25 | 1991-2002 | Axial location: 2-year survival 33% | Argon et al., 2004 [ |
Children | 220 | 1979-2004 | 5-Year survival rate 63.5% | Rodriguez-Galindo et al., 2007 [ |
DSRCT | ||||
Adults | 18 | 1998-2006 | 5-Year survival rate 27.9% | Liping et al., 2008 [ |
Asian | ||||
Adults | 84 | 1995-2009 | Median OS 33.1 months | Ahn et al., 2011 [ |
Median EFS 14.4 months | ||||
Localized disease was a significant independent prognostic factor for longer OS, and favorable primary tumor sites were associated with longer EFS |
Comparison of event-free survival (EFS) (A) and overall survival (OS) (B) of adolescents and young adults (AYA) population with the rest of the population.