Discussion
Lymph node metastases in pediatric patients with NRSTS are associated with a poor prognosis.3,6,9,11 Adult studies suggest that CCS and epithelioid sarcoma have a higher risk of lymph node metastasis as compared to synovial sarcoma6,9, however this association remains unconfirmed in children. Clarifying the incidence and impact of nodal metastasis for these histologic subtypes is important as locoregional control measures for nodal disease can reduce tumor recurrence.9,11,12 We therefore sought to examine trends in incident lymph node metastasis and lymph node sampling in a pediatric and young adult cohort.
We conducted a retrospective survival analysis of 1303 pediatric patients with CCS, epithelioid, and synovial sarcoma in the National Cancer Database. Our results confirm that children and young adults with synovial sarcoma have infrequent lymph node metastasis (2.2%), while nodal involvement is more common in patients with CCS (14.6%) and epithelioid sarcoma (15.0%). These frequencies are comparable to those reported in the adult literature6,9 and support that synovial sarcoma does not have a strong proclivity for lymphatic spread in children.
By utilizing a national database, our study was able to examine the associations between lymph node sampling and overall survival for individual NRSTS histologic subtypes of CCS, epithelioid, and synovial sarcoma. Previous research on lymph node sampling in pediatric NRSTS has relied on single center studies8,17,18, cohorts of adults and children6,19,20, or analyses that group histologic subtypes.3,5 Given the known heterogeneity in treatment and outcomes of NRSTS subtypes7,9 as well as the differences in survival between older adults and pediatric patients with NRSTS20, our study results add clarity to the significance of lymph node metastasis in pediatric patients with CCS, epithelioid, and synovial sarcoma subtypes.
This study supports lymph node metastasis as an independent risk factor for OS in pediatric patients with CCS, epithelioid, and synovial sarcoma, but we found tumor histology did not significantly modify this relationship. This finding contrasts with results from a NCDB study of adults with NRSTS, which showed the associated impact of lymph node metastasis on OS was worse in histologic subtypes with good overall prognoses, such as epithelioid sarcoma11. With the rarity of lymph node metastasis seen for each histological subtype in our cohort, it is possible that our study was underpowered to detect this difference.
Current Children’s Oncology Group (COG) and European Society for Medical Oncology (ESMO) practice guidelines recommend routine lymph node sampling for pediatric patients with CCS and epithelioid sarcoma, but not synovial sarcoma.21,22 We found lymph node sampling occurred in only half of patients with CCS and epithelioid sarcoma, and this trend was stable across the 12-year study period. We speculate that the inconsistent practice of lymph node sampling may be due to variation in practice patterns. For example, center-specific variation in routine use of FDG-PET scans or other patient-specific factors which limit the ability to obtain FDG-PET scans may differentially drive staging procedures. Improved adherence to lymph node sampling recommendations may be an important goal for future quality improvement studies.
Our results show an associated survival benefit to lymph node sampling in pediatric patients with CCS. We speculate that sampling procedures more accurately identified lymph node metastases in patients with CSS, leading to augmented treatment plans and ultimately improved patient survival. Unfortunately, database constraints prevented us from detecting if augmented treatment plans were in fact implemented for these patients. However, in support of this theory, we found that children with CCS who did not undergo lymph node sampling had inferior survival rates, which were similar to the 2-year OS seen in those with lymph node metastasis. Given the higher incidence of lymph node metastasis in CCS as seen in this study, our findings support the recommendation for routine lymph node sampling in this histologic subtype.
Our findings also support the recommendation to avoid routine lymph node sampling in patients with synovial sarcoma without clinical or radiographic concern for nodal involvement. As previously mentioned, our study found that lymph node metastasis was rare in children and young adults with synovial sarcoma. Additionally, children with synovial sarcoma who underwent lymph node sampling had an associated decreased survival, likely because those for whom sampling procedures were recommended were at higher risk for advanced disease. Conversely, patients with synovial sarcoma who had negative lymph nodes had similar 2-year OS to those who did not undergo a lymph node sampling procedure.
The benefits of lymph node sampling for epithelioid sarcoma in children remains unclear. Our results showed that confirming lymph node involvement by sampling was not significantly associated with improved OS, and 2-year OS for patients with epithelioid sarcoma were similar between those who had negative nodes and those who did not undergo a sampling procedure. However, our study corroborates that epithelioid sarcoma does have a high propensity for lymph node involvement. Locoregional staging may remain important for treatment planning for patients with epithelioid sarcoma, as previous literature suggests that imaging underestimates nodal involvement in soft tissue sarcomas.23
We acknowledge there were several limitations to our study. First, we utilized a retrospective database with limited granularity. For example, we could not accurately analyze disease-free survival or distinguish timing or technique for lymph node sampling. Second, our inclusion criteria restricted the study cohort to patients who underwent primary surgical resection or primary site radiation. Therefore, our study results may not extrapolate to patients with unresectable or advanced metastatic disease. Finally, there may exist differential sampling bias in our results: in patients with no clinical suspicion for nodal involvement, it is probable that physicians were more likely to sample lymph nodes in those with CCS or epithelioid sarcoma as compared to synovial sarcoma because of current COG and ESMO practice guidelines.
Despite these limitations, our results suggest that pediatric patients with CCS and epithelioid sarcoma, but not synovial sarcoma, are at substantial risk of lymph node metastasis. Lymph node sampling was associated with improved survival in patients with CCS, yet it was inconsistently performed in patients with this subtype. Additionally, the impact of lymph node sampling in patients with epithelioid sarcoma remains unclear. Future research could focus on determining the significance of lymph node sampling in pediatric patients with epithelioid sarcoma, as lymph node metastasis is common in this subtype.
Conflict of Interest Statement: The authors have no potential conflicts of interest.
Acknowledgments: None