The prognosis of STS with metastasis is poor, and the main metastasis sites of STS are lung and bone, LNM is relatively rare. The latest AJCC staging system defines lymph node involvement as being stage IV disease for sarcomas of the trunk and extremities[1]. This indicates that LNM is a significant prognostic factor. Therefore, it is necessary to study the risk factors and prognosis of LNM in STS. At present, most studies have included all types of STS or site-specific, patient-specific STS. For example, Gusho et al. studied the LNM rate and prognosis of all STS of the extremities[11]. Sherman et al. studied the LNM rate and predictors of adult STS of extremities. Our study included six types of STS with the highest risk of LNM in the head, neck and extremities. We analyzed the prognosis of 2,756 patients with STS without LNM and who were treated surgically. Also, we further clarified the impact of NLND on the prognosis of these patients.
In our cohort, rhabdomyosarcoma (25.3%), clear cell sarcoma (16.8%) and epithelioid sarcoma (12.4%) had the highest rates of LNM, while leiomyosarcoma had the lowest rate of LNM at 1.3%. This is consistent with previously reported rates of lymph node positive of different STS (26.7% for rhabdomyosarcoma, 16-18.8% for clear cell sarcoma, and 13-14.5% for epithelioid sarcoma) from several large cohort studies[8, 11, 13]. In children and adolescents (< 19 years), rhabdomyosarcoma has the highest positive rate of lymph node, while in adults (≥ 19 years) is clear cell sarcoma. The results are similar to previous studies[8, 14]. This may be related to differences in the histological subtypes of STS in different populations of age, rhabdomyosarcoma was the most common STS in children and adolescents and accounts for one-half of pediatric STS[15]. We identified independent risk factors for LNM using the multivariate Cox proportional risk model. Male, head and neck, high grade (III + IV), tumor size greater than 4 cm, non-leiomyosarcomas are more likely to have LNM. Several studies have reported similar results. Miccio et al. found that high-grade and clear cell/ angiosarcoma/ rhabdomyosarcoma/ epithelioid (CARE) histology are associated with LNM in STS[7]. In another study, Behranwala et al. examined 2,127 STS, finding a 70% association between high-grade tumors and lymph nodes spread, and LNM are more likely to appear in the proximal location of the sarcoma[6]. Sherman et al. included 27,536 patients of extremity soft tissue sarcoma (ESTS) from the National Cancer Data Base (2000–2009) and found that the risk factors for LNM were histologic subtype, tumor size, and grade[14]. In addition, some studies have shown that LNM is also related to age and primary site[10, 16]. However, no studies have reported an association between gender and LNM. Our results suggest that male is at higher risk of LNM compared to female (OR: 1.291, 95% CI, 1.012–1.646; P = 0.040). The literature reports that males have historically been associated with a higher predisposition to STS than females, but the extent to which gender affects lymph node metastasis has not been established [17].
We performed a prognostic analysis of 2,756 patients without LNM and who had undergone surgery. Age, grade, stage, size, histology and marital status were found to be independent prognostic factors for cancer-specific survival. This result is similar to previous studies. A study with patient data also from the SEER database showed that for the historically high-risk extremity STS, age, grade, size, surgery, and regional lymph node status were independent disease-specific prognostic factors[11]. Another study found that for epithelial sarcoma, tumor site was a prognostic factor for event-free survival and overall survival, and extremities site had a better prognosis than proximal-type variant[18]. Understanding these characteristics of STS can help us to better provide clinical counseling and personalized treatment for patients.
The current study further investigated the association between NLND and prognosis. After PSM, we found that NLND was an independent prognosis factor for patients with a high risk of LNM such as rhabdomyosarcomas, angiosarcomas, Ewing sarcomas, epithelioid sarcomas, and clear cell sarcomas. Surprisingly, NLND can not improve the prognosis of leiomyosarcoma before and after PSM. We further analyzed the leiomyosarcoma cohort and found that most of the leiomyosarcoma patients were older than the rest five types of sarcomas (median age: 61 years vs. 41 years, P < 0.001) and only a small proportion of the population (6.81%) received NLND compared with 21.2% of other tumors. Moreover, we can't get information from the SEER database of the reasons why these patients did not have lymph node dissection. It may be that these patients are older, have comorbidities or have treatment contraindications. And the SEER database did not record the treatment information of these patients about adjuvant treatments such as radiotherapy and chemotherapy. Above all of these factors may affect the accuracy of the results and cause confounding bias. Therefore, further clinical validation is needed.
At present, some studies have reported the prognosis of lymph node examination/dissection for STS with LNM, but the result remains controversial. Al-Refaie et al suggest that regional lymph node dissection may prolong survival time[19]. Ecker et al support regional lymph node examination for patients with epithelioid and possibly clear cell sarcoma[20]. Brady et al found that lymph node sampling was associated with improved disease-specific survival in patients with extremity rhabdomyosarcoma (64% versus 49%, P = 0.005)[21]. Riad et al show that resection of involved lymph nodes had an estimated 5-year survival of 57%, whereas nine patients treated without surgery all died within 30 months[22]. In another study, NLND was proved to be an independent risk factor for cancer-specific survival in non-metastatic colorectal sarcomas patients[23]. However, some studies have found that lymph node examination/dissection has no effect on prognosis. A study of epithelioid sarcoma found that lymphadenectomy did not improve overall survival in patients with LNM[24]. Another study found that resection of the metastatic lymph node had better survival at 1.5 years, but did not improve the long-term survival of patients with STS[9]. Some studies think the management of positive lymph nodes remains uncertain, and the effect of lymphadenectomy on the overall survival of STS with LNM needs to be further clarified [3, 10]. In summary, our study suggests that NLND is appropriate treatment for specific patients with STS, such as those who have a high risk of LNM. Nevertheless, we still recommend that patients' treatment decisions should be based on the clinical reality of the patient, because lymph node dissection may have some acute and chronic complications, such as lymphorrhea, chylous ascites, seroma, delayed wound healing and chronic lymphedema[25].
Our study has some limitations which need to be considered. First, this is a retrospective study and may have inherent limitations, so our results must be validated in prospective studies. Second, the SEER database does not record detailed information about chemotherapy, radiotherapy, comorbidities, complications, and recurrence, which may have a potential impact on the results. Despite these limitations, our findings are of significance.