Sarcomas Across the Age Spectrum
Article Outline
In most cancers, the age of the affected patient has a significant influence on how that cancer is approached. This is less often the case in sarcomas in that both children and adults are treated similarly. However, different types of sarcomas are most typical in these populations, and our understanding of these cancers in one group has provided direction for understanding them in the other group. For example, advances at the molecular level in Ewing sarcoma, a disease that affects predominantly children, helped spearhead the uncovering of several signature translocations in adult sarcomas, such as synovial sarcoma and myxoid liposarcomas. The success of chemotherapy in pediatric sarcomas continues to be a benchmark for adult sarcomas to emulate. Conversely, the demonstration of the viability of limb-sparing surgery combined with adjuvant radiation in adult extremity sarcomas helped advance that treatment approach in pediatric sarcomas. To illustrate some of these concepts and to enhance our understanding of sarcomas across the age spectrum, 4 types of sarcoma are discussed. The first 2 are Ewing sarcoma and rhabdomyosarcoma seen mainly, but not exclusively, in children. The other 2 are synovial sarcoma, which can be looked at as a bridge between pediatric and adult sarcomas as it affects mainly young adults, and liposarcoma that is almost exclusively an adult sarcoma.
Sarcomas are one of the most notable examples of cancer crossing the age spectrum. Pediatric sarcomas frequently occur during infancy and can even be congenital. Conversely, the incidence of adult-type sarcomas increases during the final decades of life. Sarcomas compromise a heterogeneous group of malignancies, with dramatically different biologies and clinical behaviors. The more our understanding of sarcomas has grown, the more aware we have become of these distinct differences. In general, the pediatric-type sarcomas tend to be relatively sensitive to chemotherapy and radiotherapy, whereas the adult sarcomas are less so. These distinctions have led to different treatment algorithms for pediatric and adult sarcomas. In addition, the long-term risk to benefit ratio of different treatment modalities differs between children and adults. This also influences our approach to treating sarcomas across the age spectrum.
To illustrate the similarities and differences between pediatric and adult sarcomas, this article will review 2 of the most common pediatric sarcomas, rhabdomyosarcoma (RMS) and Ewing sarcoma (ES), and compare these with an overview of typical adult sarcoma types, such as synovial sarcoma and liposarcoma.
Rhabdomyosarcoma
Although RMS is the most common pediatric sarcoma, there are only 350 cases annually in the United States (Fig. 1). This illustrates the dramatically lower incidence of solid tumors in children compared with older adults. RMS is truly a tumor of the young, with two-thirds of cases occurring in children aged <7 years. There is a slight male predominance (1.3:1) and the disease is less common in children of African or Asian ancestry.1
Figure 1.
Incidence of rhabdomyosarcoma (RMS) and non-RMS soft-tissue sarcomas in the pediatric age ranges from the SEER Program 1975-95, NCI.1. (Color version of figure is available online.)
RMS is one of the many small, round, blue cell tumors of childhood, with skeletal myogenic lineage. There are 2 primary histologic subtypes, the more common embryonal and the less common alveolar. The latter is characterized by a PAX/FKHR translocation between chromosomes 2;13 or 1;13.2 RMS can arise nearly anywhere in the body but has a predilection for certain sites, such as the head and neck (36%) and genitourinary organs (24%). One of the unique characteristics of this disease is the strong influence of primary site on prognosis (Fig. 2). Indeed, primary tumor site is one of the most powerful predictors of survival in RMS. Tumors arising in the orbit have the best outcomes and those arising in an extremity have the worst.3 This is in distinct contrast with the finding that extremity is the most favorable site for adult-type sarcomas.
Figure 2.
Failure-free survival for local and/or regional RMS by primary site in IRS IV. Reprinted with permission from Crist et al.3 (Color version of figure is available online.)
Pediatric sarcomas are much more likely to have regional lymph node involvement than adult sarcomas, and RMS has the highest rate of all. However, risk of nodal involvement varies significantly with primary site from <1% for orbit tumors to as high as 30%-35% for extremity and paratesticular tumors. Tumors of alveolar histology are more likely to spread to lymph nodes than embryonal tumors.4 Slightly <25% of patients have overt distant metastases at diagnosis. As with other sarcomas, the most common sites of spread are lung, bone, and bone marrow. Although the presence of distant metastases typically renders the adult sarcoma patient incurable, this is not always the case with RMS. Patients aged 2-10 years with embryonal histology have an estimated long-term disease-free survival of 40% because of the tumor's excellent response to systemic chemotherapy.4
The treatment algorithms for RMS are complex and vary depending on patient's risk status and other variables. This disease has been more thoroughly studied in systematic, consecutive clinical investigations than any other sarcoma. The Intergroup Rhabdomyosarcoma Study Group has conducted many large-scale international trials since 1972. As a result, we have learned a tremendous amount about tailoring treatment for subgroups of patients to maximize cure rates and minimize long-term toxicity. The paradigm of multimodality treatment is the rule for RMS, with all patients receiving multiagent chemotherapy with the addition of surgery and/or radiotherapy.
Because RMS is typically exquisitely sensitive to chemotherapy, large up-front surgery that could sacrifice form or function is discouraged. Because most tumors are large and infiltrative, initial surgery is not recommended for most patients. Today, approximately 15% of patients in the United States undergo complete resection of their primary tumors at diagnosis. Irrespective of having had initial resection or biopsy only, all patients then begin chemotherapy. The conventional standard agents are vincristine, dactinomycin, and cyclophosphamide. However, most patients are enrolled in clinical trials that may offer a variation on this theme. Current efforts are directed at reducing exposures to chemotherapy for the most favorable patients and augmenting therapy for those with poorer prognostic variables, such as metastatic disease. The current Children's Oncology Group (COG) protocol for intermediate-risk RMS (ARST0531) includes 14 cycles of chemotherapy over 42 weeks.
In conjunction with this long course of systemic therapy, patients require surgery and/or radiation therapy for local control. Unlike adult-type sarcomas, RMS and ES can be successfully treated with definitive radiation therapy without surgical resection. Definitive radiotherapy doses for RMS are moderate compared with doses used for adult-type sarcomas: 45 Gy for orbital tumors to 50 Gy for other unresected sites. The local control rates following definitive radiotherapy are excellent, ranging from 84% for parameningeal tumors to 96% for extremity tumors.5 When negative margins are achieved on initial surgery for embryonal tumors, radiotherapy is not indicated. All alveolar and embryonal tumors with positive margins require postoperative radiation doses of 36-41 Gy.6 These doses are significantly lower than the 63-66 Gy used for postoperative radiation in adult sarcomas.
The timing of radiotherapy for RMS has varied over the years and across protocols. The current COG protocols call for radiotherapy to begin at week 4 of chemotherapy for intermediate-risk tumors and at week 20 for high-risk disease. There are data indicating that a delay in radiotherapy decreases local control, yet the temptation to delay radiation exists because of the dramatic tumor shrinkage that often occurs with chemotherapy. In addition, the delay in starting RT for patients with high risk (and metastatic) disease permits additional cycles of chemotherapy to be administered. In certain cases, this may allow for smaller radiation target volumes or doses. In infants aged <2 years, the current COG protocols allow more flexibility in the timing and design of radiotherapy because of concern about late effects.
Unlike adult sarcomas, the radiosensitivity of RMS and ES has led to the use of whole lung radiotherapy for patients with lung metastases. The use of fractionated low-dose radiation (15 Gy) to the entire thoracic cavity is the standard of care for this common pattern of metastatic disease. Although there are no conclusive data proving a reduction in lung failures, some data have suggested an increase in overall survival.7 Because the cure rates for stage IV patients remain unacceptably low, there is little enthusiasm for withholding this potentially effective therapy at this time. Radiotherapy is also routinely recommended to treat sites of regional nodal involvement of RMS as well as focal distant metastases to bone.
Pediatric cooperative groups in Europe have conducted their own impressive series of trials in pediatric sarcomas, including RMS. Their approach has been to avoid radiotherapy more aggressively by switching to second- and third-line chemotherapy regimens before sending children for definitive surgery or radiotherapy. Although this approach has allowed some patients to avoid radiotherapy, the overall rates of local control and survival are notably lower than those achieved in the United States.8
Although it is ironic that pediatric sarcomas are so much more radiosensitive than adult sarcomas, we must aim to minimize exposure to this modality because of the potential long-term toxicity. Advances in imaging and radiation delivery promise to improve the therapeutic ratio for all sarcomas, but the advantages will be especially important in pediatric cases. Positron emission tomography scans have quickly become recognized as a valuable tool in the staging of RMS because of the high sensitivity rate.9 Positron emission tomography imaging is currently being studied prospectively on COG ARST0531 to determine its utility for staging and for response assessment. Intensity-modulated radiation therapy has been highly beneficial in treating many different sarcomas but may be most useful for the most challenging cases, such as head and neck RMS. Results from our center show that very high rates of local control can be achieved with reduced margins using intensity-modulated radiation therapy.10 Similarly, proton therapy holds much promise for treating pediatric sarcomas.11
A recent article confirms that adults with RMS have significantly worse outcomes than children.12 Part of the difference may be attributed to a higher percentage of adult patients having poor prognostic features, such as unfavorable site or histology (Table 1). However, the explanation for this is not known. The incidence of extremity primary site is 26% in adults as compared with 14% in children (P < 0.0001). Adults also have notably higher rates of pleomorphic subtype, 19% versus 1%, and not otherwise specified histology, 43% versus 13% (P < 0.0001). However, alveolar subtype and unfavorable primary site lost significance when the analysis was restricted to adults. Regional and distant metastases were not more common in adults. Given the dramatic difference in 5-year survival for localized disease, 47% for adults versus 82% for children (P < 0.0001), it is clear that age itself is a strong prognostic factor. It remains unknown how much of this is due to less adequate treatment of adults and how much is due to inherent biological differences.
Table 1. Data Collected from the SEER Database from 1973 to 2005. Modified from Sultan et al12
| Children | Adults | P | |
|---|---|---|---|
| Incidence (per million) | 4.3 | <1 | <0.0001 |
| Favorable histology (embryonal) | 57% | 20% | <0.0001 |
| Favorable site (orbit, H&N, GU) | 39% | 27% | <0.0001 |
| Distant metastases at diagnosis | 27% | 28% | NS |
| 5-Year survival | 61% | 27% | <0.0001 |
Ewing Sarcoma
Despite there being many similarities between RMS and ES, there are some differences also. ES occurs at a similar rate, 300 cases per year in the United States, but is more common in the second decade (10-20 years of age) than in younger children.13 The tumor is most common in Caucasians but has a very low incidence in Chinese children and especially African ancestry.14 ES may arise from either bone or soft tissue, and like RMS, can occur in a wide variety of anatomical sites, but has a much lower incidence in the head and neck. Also, ES does not tend to arise in organ sites, such as the genitourinary system. ES tumors are common in both the axial and appendicular skeleton as well as in skeletal muscle throughout the body. ES is also a small, round, blue cell tumor and most cases exhibit a characteristic EWS-FLI1, t(11;22) translocation.15
ES has not been quite as extensively studied as RMS, yet co-operative group protocols have resulted in very important discoveries. It is clear that all patients with ES benefit from systemic chemotherapy, and the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin has been shown to increase survival.16 Like RMS patients, ES patients require surgery and/or radiotherapy for local control. Although surgical resection may be performed at diagnosis, most experts in the field agree that it is preferred to give several cycles of induction chemotherapy before considering surgery or radiotherapy because the response may be profound, and in some cases can facilitate a more complete or less morbid resection. In addition, chemotherapy immediately addresses the micrometastatic disease likely to be present. If surgery can be performed with acceptable negative margins, radiotherapy is not generally indicated. However, when margins are positive or close, postoperative radiation should be delivered using doses of 45-50 Gy. As with RMS, and unlike all adult-type sarcomas, definitive radiotherapy is an alternative to surgery for ES. The recommended dose is 55.8 Gy, which is higher than the dose for RMS but lower than the doses used for adult-type sarcomas. Local control rates range from approximately 75%-85% in the published data.10, 11, 17, 18, 19, 20
There continues to be a debate in the preference for surgery versus radiotherapy for ES. Those in favor of surgery cite a lower rate of local failure in many series. Opponents counter that there is typically a significant selection bias, with the most favorable patients receiving surgery. For radiotherapy, there are data from co-operative group studies showing equivalent disease-free survival with a surgical or radiation approach and equivalent local control in some series. At our center, decisions regarding the mode or modes of local therapy are made on an individual basis for each patient. When surgery can be performed without much risk of long-term disability, then it is usually recommended. However, when surgery would result in loss of form or function, radiation would be preferred. The option of using planned preoperative and postoperative radiotherapy with surgery should also be considered, but often the morbidity of both modalities is expected to be worse than one or the other.
When deciding whether to use radiotherapy for a child with ES, one must consider a variety of potential late effects that may not be a significant consideration in the older adult patient. Growth of bone and soft tissue can be severely impaired when treating young patients. This problem is much less of a concern for a mature teen than for the younger child, but even muscle development seems more impaired in teens than in adults. Patient with ES who are treated with radiotherapy are known to have an increased risk of secondary tumors, especially other sarcomas. The incidence of secondary sarcomas ranges in various reports, but seems to be in the range of 2%-5% with contemporary radiation doses.21, 22 The risk of secondary cancers is not as significant a concern in older adult patients because their tissues are less susceptible to the carcinogenic effects of radiation, and older patients are not expected to live as many decades as pediatric patients because of competing risks.
It is well established that older age is a negative prognostic factor for patients with sarcomas. With the exception of infants, younger children with RMS have better outcomes than teenagers. Adult RMS patients have even worse reported survivals. Similarly, older adults with ES are reported to have poorer outcomes than their pediatric and young adult counterparts.23 It is noted that older patients cannot tolerate intensive chemotherapy as well as pediatric patients and therefore often do not receive the same aggressive treatment. However, the poorer prognosis seems also to be due to increased tumor resistance in older patients.
Synovial Sarcoma
Most reports in the published data show that synovial sarcoma tends to occur in young adults with a mean age of 30-40 years. The classical, albeit not universal, presentation as a painful mass near joint spaces with focal calcifications seen on plain x-rays tends to set synovial sarcoma apart from other soft-tissue sarcomas. Histologically, there are 2 types of synovial sarcomas. One is called biphasic because of the presence of epithelial cells as well as spindle cells, and the other is called monophasic, characterized by a tumor predominantly made of spindle cells. There have been significant strides in our understanding of the molecular biology of synovial sarcoma. There is a signature reciprocal translocation, t(X; 18) (p11; q11) that is seen in almost all synovial sarcomas. The translocation involves the SYT gene on chromosome 18 and the SSX gene on the X chromosome, resulting in SYT-SSX fusion with at least 2 subtypes: SYT-SSX1 and SYT-SSX2, depending on the location of the breakpoint in the SSX gene.
The prognostic factors for synovial sarcoma are similar to other sarcomas. In a review of 128 patients with localized primary synovial sarcoma, Trassard et al24 demonstrated that on multivariate analysis, stage (P = 0.001), male sex (P = 0.007), and truncal locations (P = 0.006) were associated with poor disease-specific survival. Lewis et al25 reported on 112 patients with similar characteristics and found large tumor size (P = 0.003, relative risk = 2.3) and the presence of bone or neurovascular invasion (P = 0.3, relative risk = 2.7) to be independent predictors of death from sarcoma. The subtype of fusion gene has been shown to be of prognostic importance as well. Landanyi, et al26 evaluated a subset of patients with synovial sarcoma who presented with localized disease (n = 133) and found that SYT-SSX1 was the only independent predictor (P = 0.04) of poor overall survival. Canter et al27 constructed a nomogram on 255 patients with localized synovial sarcoma for whom increasing tumor size (5 versus 5-10 versus >10 cm) and location (upper extremity versus lower extremity versus other locations) were the most important predictors of mortality from sarcoma. However, tumor depth (superficial versus deep) and histology variant (monophasic versus biphasic) were incorporated in the nomogram to enhance the nomogram's individualized patient-survival estimates.
Synovial sarcomas have not been identified as having radioresistant histology. Italiano et al28 reviewed the French Sarcoma Group experience in synovial sarcoma. There were 237 patients with nonmetastatic disease; 112 received adjuvant radiotherapy and 125 did not. On multivariate analysis, the use of radiotherapy was associated with significant reduction in local recurrence (P = 0.026, hazard ratio [HR] = 0.43). Palmerini et al29 found that in patients with inadequate margins, the 5 year local-recurrence–free survival was only 25% with no radiotherapy compared with 70% for those who received adjuvant radiotherapy (P = 0.025). The benefit of adjuvant radiotherapy in that study affected event-free survival (P = 0.02) in the subset of patients (n = 204) with localized disease. One of the largest studies on conservative surgery and adjuvant radiotherapy was reported by Guadagnolo et al30 from MD Anderson Cancer Center. There were 150 patients (mean age, 35 years) with nonmetastatic disease treated between 1960 and 2003. With a median follow-up of 13.2 years, the 10-year local recurrence rate was 18%. In the subset of patients with lower extremity location (n = 58), the 10-year local recurrence rate was 20%, compared with 14% for upper extremities, but that difference was not statistically significant. The only predictor of increase risk of local recurrence was margin status. For patients with negative margin, the 10-year local recurrence rate was 12% as compared with 32% for positive or unknown-status margins (P < 0.05). By 10 years, 44% of patients developed distant metastasis. This high rate of distant spread, coupled with the relatively young age of patients with synovial sarcoma at the time of presentation, explains the great deal of interest in trying to find an effective systemic therapy for this disease. Eilber et al31 found in a review of 101 patients with primary synovial sarcoma from 2 institutions that ifosfamide-based chemotherapy was effective. With a median follow-up of 58 months, the 4 year disease-specific survival was 88% for those who received adjuvant chemotherapy, compared with 67% for those who did not (P = 0.01). The use of chemotherapy was an independent predictor of improved disease-specific survival on multivariate analysis (P = 0.007, HR, 0.3). The experience of the French Sarcoma Group, however, differs. Neither neoadjuvant nor adjuvant chemotherapy affected overall survival (P = 0.725 and P = 0.999, respectively) in that study.28 One of the reasons for the discrepancy could be an early survival benefit of chemotherapy that may dissipate over time.27
In a recent report comparing the clinical features and outcomes of synovial sarcoma in 213 children and 1055 adults, no major differences in stage distribution were observed (Table 2).32 The estimated 5-year cancer-specific survival was 83% for those aged <18 years and 62% for adults (P < 0.001). Factors associated with better survival were female sex, non-black race, tumors located in extremities, localized tumors, and tumors <5 cm in size. In multivariate analysis, after adjusting for other variables, adults had significantly higher mortality rates than children despite their similar clinical presentations. It is supposed that factors other than unfavorable clinical features might be involved in the poorer outcome of adult patients with synovial sarcoma.
Table 2. Data Collected from the SEER Database from 1983 to 2005. Modified from Sultan et al32
| Children | Adults | P | |
|---|---|---|---|
| Age | 0-9 (15%) | 19-29 (28%) | — |
| 10-18 (85%) | 30-39 (26%) | ||
| 40-49 (20%) | |||
| ≥50 (27%) | |||
| Histology | 41% | 52% | <0.001 |
 NOS | 24% | 28% | |
| Spindle cell | 0% | 1% | |
| Epithelioid cell | 35% | 19% | |
| Biphasic | |||
| Location | 6% | 8% | 0.027 |
| Head and neck | 76% | 68% | |
| Extremity | 1% | 5% | |
| Lungs and pleura | 16% | 15% | |
| Trunk | 2% | 4% | |
| Others⁎ | |||
| 5-Year survival | 83% | 62% | <0.001 |
⁎Other locations include retroperitoneum, kidney, adrenal gland, liver, ileum, thymus, heart, unknown, and NOS. |
Liposarcoma
Liposarcoma is the most common histology in soft-tissue sarcoma, accounting for about 20% of all adult sarcoma cases. There are 5 histologic subtypes of liposarcoma: well-differentiated (48%), myxoid (18%), round cell (10%), de-differentiated (18%), and pleomorphic (8%), with each having different biology and pattern of behavior.33 For example, myxoid liposarcoma often occurs in patients aged 25-45 years and has a high incidence of osseous metastases, especially to spine.34 In contrast, well-differentiated liposarcoma occurs more often in the 50-70 years of age group and has practically no risk of distant spread. In addition, despite the strikingly different morphologic characteristics of myxoid liposarcoma and round-cell liposarcoma, both subtypes have signature translocation t(12;16)(q13;p11) in more than 90% of cases. The translocation leads to the fusion of the CHOP gene on chromosome 12, with the TLS gene on chromosome 16 and the generation of the TLS-CHOP fusion gene.33 A nomogram was devised at Memorial Sloan-Kettering Cancer Center to better predict the prognosis of patients with liposarcoma. In this nomogram, age, sex, presentation status, site, histologic variant, tumor size, depth, and margin status were incorporated to provide more accurate survival predictions and help identify patients appropriate for adjuvant therapy.35 Although well-differentiated and de-differentiated liposarcomas do not have the signature translocation that myxoid and round-cell liposarcomas have, gene expression profiling is showing encouraging signs of being able to identify potential therapeutic targets. Singer et al36 found that activation of cell cycle and checkpoint pathways in well-differentiated and de-differentiated liposarcoma combined with MDM2 overexpression in these subtypes identified MDM2 (a protein that promotes p53 degradation) as a promising drug target.
The role of adjuvant radiation is linked to the histologic subtype and tumor site. For patients with well-differentiated liposarcoma of the extremity, observation after an oncological resection is recommended. In a review of 91 cases of well-differentiated liposarcoma and atypical lipomatous tumor (2 histologic subtypes that are closely linked) of the extremity, Kooby et al37 reported a 100% local control rate at 5 years. Adjuvant radiotherapy was given to only 17 patients. Of the 91 patients, 5 ultimately developed local recurrence and had significant components of sclerosing morphology, positive margin of resection, and recurrence after 5 years (range, 60-120 months). The recommendation from that study was that patients with atypical lipomatous tumor and/or well-differentiated liposarcoma without sclerosing components, even in the presence of positive margin, are best managed by surgery alone. In the nomogram developed for primary-extremity sarcoma treated with limb-sparing surgery alone (n = 684) in an effort to predict local recurrence (Fig. 3) having atypical lipomatous tumor or well-differentiated liposarcoma was associated with a very low risk of local recurrence, further justifying this policy.38 For patients with retroperitoneal liposarcoma, those with well-differentiated or de-differentiated liposarcoma have a risk of local recurrence significantly higher than for the extremities; thus, adjuvant radiotherapy should be considered but weighted against the potential toxicity of radiotherapy, especially if given postoperatively. Zagars et al39 reviewed 112 patients from MD Anderson Cancer Center who were treated with conservative surgery and adjuvant radiotherapy. The 10-year local recurrence rate was 7% for myxoid (n = 71) and 37% for pleomorphic liposarcoma (n = 26, P < 0.05). This exquisite radiosensitivity of myxoid liposarcoma was demonstrated by others (Fig. 4). Chung et al40 compared 88 patients with myxoid liposarcoma to 603 with other sarcoma histology, all treated with surgery and adjuvant radiation. The 5-ear local recurrence–free survival was 97.7% for myxoid tumor compared with 89.6% for other histologies (P = 0.008). Eilber et al41 reviewed the role of ifosfamide chemotherapy in 245 patients with primary liposarcoma of the extremity and found significant improvement in disease-specific survival with its use (P = 0.01, HR = 0.3).
Figure 3.
Nomogram to predict local recurrence in primary extremity sarcoma treated with limb-sparing surgery alone.
Figure 4.
Response of myxoid liposarcoma to preoperative radiotherapy. (Color version of figure is available online.)
In summary, sarcomas represent a heterogeneous group of tumors with distinct biologies and natural histories. Although some sarcomas are much more common in children and others in adults, all types occur across the age spectrum. Much progress has been made treating pediatric sarcomas in children and adult sarcomas in adults, but we do not yet understand how to optimally treat these tumors when they occur at uncharacteristic ages. The COG is currently conducting a trial (ARST 0332) for non-RMS soft-tissue sarcomas in an effort to meet this clinical challenge. Likewise, additional work is needed in adult oncology to understand and potentially narrow the gap in survival for adults with pediatric-type tumors, such as RMS. Our hope for future progress will depend on collaboration of pediatric and adult oncologists to study sarcomas across the age spectrum.
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PII: S1053-4296(09)00064-2
doi:10.1016/j.semradonc.2009.09.003
© 2010 Elsevier Inc. All rights reserved.
