Due to its rarity, lymph node metastasis (LNM) in soft tissue sarcoma (STS) is still insufficiently characterized. It is associated with a severe course of disease, and certain subtypes like clear cell sarcoma, angiosarcoma, rhabdomyosarcoma and epithelioid sarcoma seem to be more likely to present LNM. There is limited evidence for clinical management of LNM, including the value of lymphadenectomy and sentinel lymph node biopsy (SLNB) [16].
To our knowledge, this is the first study to compare STS patients with suspicious lymph nodes in imaging and histological confirmation (pN1) or exclusion of LNM (pN0). To date, no radiological criteria for LNM in STS have been established. Our results demonstrate a significant association of LN size in terms of long and short axis diameter (LAD and SAD) with LNM. ROC analysis suggests an SAD of 17mm and an LAD of 24mm as possible predictive cut-off values for LNM.
Enlargement of LN commonly leads to suspicion, but nodal size criteria vary depending on location and entity [17]. Further, in other entities like non-small cell lung cancer (NSCLC) and gastric cancer, a lack of correlation between lymph node size and metastatic infiltration has been reported [18, 19]. Considering the low sample size and the heterogeneity of our cohort, LN in different locations were reviewed together being a limitation of this study. The SAD/LAD ratio tended to be higher in our metastatic patients (p = 0.076) being in line with previous literature across entities [20, 21]. Based on the observation that malignant LN lose their oval shape and become more circular, a high SAD/LAD ratio has been recognized as a potential criterion for LNM across different LN regions. Historically, central necrosis is considered as the best criterion in CT scan for cervical LNM with an accuracy of nearly 100% [15]. In our cohort, we could confirm a strong association with LNM. However, 11.5% (n = 3) of benign patients did also present a central necrosis while 40% (n = 12) of metastatic patients did not. It should be noted that one of the benign patients did receive a neoadjuvant chemotherapy after initial imaging and before histological examination. In this case, a complete regression might have led to the benign histological finding.
While CT and magnetic resonance imaging (MRI) serve as the standard-of-care in staging of STS, FDG-PET-CT is individually used to exclude distant metastasis by including metabolic characteristics [13]. In previous studies a high sensitivity and specificity of 90–100% for FDG-PET-CT in detecting LNM in bone and soft tissue sarcoma has been demonstrated. However, the positive predictive value varied and tended to be rather low due to FDG uptake in inflammatory tissue [22, 23]. In our cohort, only 14 patients received an FDG-PET-CT, and SUVmax was significantly higher in LNM patients with a predictive cut-off value of 6.38 after ROC analysis. The large range of SUVmax in benign and malignant LN suggests a weak predictive value of this modality.
When histological examination is not performed, size development of LN under systemic therapy might provide further information about its dignity. In our study, we analyzed the follow-up imaging of 41 patients. As expected, metastatic LN showed size progression without therapy while benign LN remained rather stable. Under systemic therapy, benign and metastatic LN behaved similarly and showed a slight median size regression. This might be a result of the immunosuppressive effect of chemotherapy, leading not only to a reaction of malignant but also of reactive tissue.
To find more predictive parameters beyond imaging, blood serum parameters including leukocyte counts, CRP and LDH around the time of initial suspicion were reviewed. In our cohort, LDH and CRP were significantly higher in LNM patients being in line with previous reports about high LDH and CRP values in an advanced tumor stage [24, 25]. Due to volatile nature of CRP and leukocyte counts and possible impact from concomitant infections or other stress situations, these results must be interpreted with caution.
Our study does not necessarily provide valid information about the subtypes with the highest incidence of LNM due to sole inclusion of patients with histologically examined LN. To some extent, STS at high risk of LNM might have directly received a systemic therapy without histological examination of lymph nodes. Undifferentiated pleomorphic sarcoma (UPS) constituted the most common subtype of our patients with benign and metastatic lymph nodes (LN, 27 and 20% respectively). Besides its heterogenous and aggressive profile, the immunogenic nature of UPS might be a reason for a high incidence of suspicious LN in this subtype [26]. However, rare subtypes at high risk for LNM like rhabdomyosarcoma, clear cell sarcoma and epithelioid sarcoma were are also part of our cohort. As implied by our results, male gender has been associated with LNM in extremity STS in previous literature [27].
Limitations of our study include the small size of our cohort and the retrospective design. Typically for STS studies, the patient cohort is very heterogenous including many different subtypes and locations. Furthermore, a high selection bias must be assumed as only patients with biopsy were included.