Differentiation of benign and metastatic lymph nodes in soft tissue sarcoma

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Berclaz, Markus Albertsmeier, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3402984/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Feb, 2024 Read the published version in Clinical & Experimental Metastasis → Version 1 posted 9 You are reading this latest preprint version Abstract Introduction: Lymph node metastasis (LNM) occurs in less than 5% of soft tissue sarcoma (STS) patients and indicates an aggressive course of disease. Suspicious lymph nodes in staging imaging are a frequent matter of discussion in multidisciplinary tumor boards. Predictive markers are needed to enable stratification and improve treatment of STS patients. Materials and Methods In this study, 56 STS patients with radiologically suspicious and subsequently histologically examined lymph nodes (LN) were reviewed. Patients with benign (n = 26) and metastatic (n = 30) LN were analyzed with regard to clinical, laboratory and radiological parameters. Results Short axis diameter (SAD) and long axis diameter (LAD) of LN were significantly larger in patients with LNM (median 22.5 vs. 14mm, p < 0.001 and median 29.5 vs. 21mm, p = 0.003, respectively). In addition, presence of central necrosis and high maximal standardized uptake value (SUVmax) in FDG-PET-CT scan were significantly associated with LNM (60 vs. 11.5% of patients, p < 0.001 and median 8.59 vs. 3.96, p = 0.013, respectively). With systemic therapy, a slight median size regression per time was observed in both metastatic and benign LN. Serum LDH and CRP levels were significantly higher in patients with LNM (median 247 vs. 187.5U/l, p = 0.005 and 1.5 vs. 0.55mg/dl, p = 0.039, respectively). Conclusion This study shows significant associations between LNM and imaging features as well as laboratory parameters of STS patients. The largest SAD, SUVmax in FDG-PET-CT scan, the presence of central necrosis, and high serum LDH level are the most important parameters to distinguish benign from metastatic LNs. Soft tissue sarcoma lymph node metastasis predictive parameters staging imaging Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Soft tissue sarcoma (STS) refers to a heterogenous group of mesenchymal malignancies accounting for approximately 1% of all malignancies in adults [ 1 ]. Up to half of STS patients will develop metastatic disease, mainly to the lungs [ 2 ]. With survival rates of one to two years despite optimal treatment, prognosis remains dismal for advanced and metastatic STS patients [ 3 , 4 ]. While hematogenous spread is commonly observed, lymph node metastases (LNM) are exceptionally rare with an incidence of 2.6–5.3% reported for STS [ 5 – 9 ]. Certain subtypes like synovial sarcoma, clear cell sarcoma, angiosarcoma, rhabdomyosarcoma and epithelioid sarcoma (acronym: SCARE) were found to be more likely to develop LNM, although latest reports exclude synovial sarcoma from this list [ 9 ]. Regional LNM, potentially indicating a disseminated disease and a high biological aggressiveness, is associated with a poor survival. A comprehensive analysis of the American National Cancer Database demonstrated an overall survival of 28 months in STS patients with pN1M0 disease varying by histology, approximating the prognosis of a metastatic STS disease [ 6 ]. According to the current American Joint Committee on Cancer (AJCC) classification, any N1M0 STS in the trunk and extremities is classified as stage IV, such as a M1 metastatic STS [ 10 ]. However, the significance of regional LNM remains controversial and patients with extremity STS and isolated LNM might have a better prognosis than the AJCC classification suggests [ 11 ]. Depending on pathological, radiological and clinical assessment, STS patients are treated with either a potentially curative or palliative intent. In non-metastatic stages, complete surgical resection can be coupled with radio- and chemotherapy plus regional hyperthermia to reduce local and distant recurrence. For metastatic patients, palliative anthracycline-based chemotherapy remains the standard treatment [ 12 , 13 ]. Frequently, STS patients present with suspicious lymph nodes in staging imaging, based on non-sarcoma specific criteria, like pathological enlargement and the presence of a central necrosis [ 14 , 15 ]. As nodal involvement indicates a more advanced stage, it might change the treatment strategy towards an extended surgical intervention or a palliative therapy. Considering the strong impact on the therapeutic approach in these patients, it is important to carefully interpret suspicious lymph nodes in staging imaging and, if appropriate, to examine them histologically. So far, there are no accurate radiologic or clinical criteria for the evaluation of lymph node involvement in STS. This study aimed to identify predictive parameters for LNM in STS patients in a German large-volume sarcoma center. 2. Materials and Methods 2.1 Patient selection Patients who underwent histological examination of radiologically suspicious LN with either histologically confirmed or excluded LNM of STS between 2006 and 2022 were included. Histological examination was either performed as a LN biopsy or in the context of a tumor resection. Clinical, radiological and outcomes data were extracted from our hospital database. Tumor or lymph node size were recorded from the imaging analysis and/or pathological report. Due to the anonymized nature of the study, an informed consent was not required. 2.2 Imaging Analysis Computed tomography (CT), magnetic resonance (MR) and positron emission tomography with 18-fluorodeoxyglucose (FDG-PET-CT) images were reviewed by one radiologist with subspecialty training in oncological imaging (WGK). Size of lymph nodes in terms of long axis diameter (LAD) and short axis diameter (SAD) as well as number and the presence of a central necrosis were evaluated. Lymph node central necrosis is defined as a central area of low attenuation surrounded by an irregular periphery of enhancing tissue [15]. FDG uptake was quantified by calculating maximal standardized uptake value (SUVmax) which indicates the degree of tumor metabolism. 2.3 Histopathology Histopathology was performed according to standard procedures at the LMU Munich pathology department by a specialized sarcoma pathologist. The pathologists’ original report served as specification of tumor grade and lymph node histology. 2.4 Statistics Continuous variables were compared with the Mann–Whitney U test, and categorical variables with the Fisher’s exact test. Receiver operating characteristic (ROC) curves were analyzed and compared for those variables that demonstrated significant association with lymph node status. Optimal cut-off values from ROC curve analyses were determined by the highest Youden Index.  Overall survival was analyzed using the Kaplan–Meier method and the log-rank test. The results with a p-value of less than 0.05 were considered statistically significant. Statistical analysis was performed using R software version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria). 3. Results 3.1 Patient cohort The clinicopathologic characteristics of the study cohort are summarized in Table 1 . A total of 56 STS patients with radiologically suspicious LN and either benign LN (group B , n = 26) or metastatic LN (group M , n = 30) evaluated by histological examination were included in our study. These two groups of patients were compared with regard to clinical parameters. Median age was similar in both groups ( B : median 60 years, range 13–78 years vs. M : median 54 years, range 25–79 years), and a male predominance was observed in both groups ( B : 62% and M : 70% of patients in each group). Undifferentiated pleomorphic sarcoma (UPS) represented the most common subtype in both groups ( B : n = 7, 27%, M : n = 6, 20%) along with leiomyosarcoma in group B (n = 7, 27%), and followed by clear cell sarcoma in group M (n = 3, 10%). For patients with benign and metastatic LN, high tumor grade (G2/3; B : 81%, M : 73%), localization of the primary tumor on the extremities ( B : 42%, M : 67%), regional ( B : 69%, M : 80%) and synchronous occurrence (at initial diagnosis) of LN ( B : 62%, M : 60%) were common characteristics. Primary tumor size did not differ significantly regarding the dignity of LN ( B : median 9cm, range 3.8-13.3cm, M : median 7.1cm, range 0.8-15cm; p = 0.447). Histopathological examination revealed LN and sarcoma tissue in 18 patients (60% of group M ) and only sarcoma tissue in 12 patients (40%). For patients with benign LN, LN tissue without specification (n = 9, 34.6% of group B ), reactive LN (n = 7, 23.3%), granulomatous inflammation (n = 4, 15.4%), sinus histiocytosis/anthracosis (n = 3, 11.5%) and fibrosclerotic tissue (n = 3, 11.5%) were reported. Median overall survival (OS) from initial suspicion of LNM was 8.74 years for patients with benign LN and 3.16 years for patients with metastatic LN (p = 0.006). Table 1 Characteristics of patients with benign and metastatic lymph nodes Factor Benign LN (n = 26) Metastatic LN (n = 30) p-value Histological subtype - UPS - Leiomyosarcoma - Clear Cell Sarcoma - Fibrosarcoma - Dediff. Liposarcoma - Synovial Sarcoma - EHE - Rhabdomyosarcoma - Other (all STS ≤ 2 patients) 7 (27%) 7 (27%) 2 (8%) 2 (8%) 2 (8%) 2 (8%) 0 (0%) 0 (0%) 4 (15%) 6 (20%) 2 (7%) 3 (10%) 2 (7%) 1 (3%) 1 (3%) 3 (10%) 3 (10%) 9 (30%) 0.180 Grading according to FNCLCC - 1 - 2 - 3 - Not available/ applicable 1 (4%) 8 (31%) 13 (50%) 4 (15%) 3 (10%) 7 (23%) 15 (50%) 5 (17%) 0.845 Localization of primary tumor - Extremities - Retroperitoneal/Abdominal - Trunk - Head/Neck - Pleural/pulmonary - Other 11 (42%) 6 (23%) 3 (12%) 1 (4%) 2 (8%) 3 (12%) 20 (67%) 1 (3%) 2 (7%) 1 (3%) 3 (10%) 3 (10%) 0.238 Localization of suspicious lymph nodes - Regional - Distant 18 (69%) 8 (31%) 24 (80%) 6 (20%) 0.375 Date of occurrence of suspicious lymph nodes - Synchronous - Metachronous 16 (62%) 10 (38%) 18 (60%) 12 (40%) > 0.999 UPS: Undifferentiated pleomorphic sarcoma, EHE: Epithelioid haemangioendothelioma, FNCLCC: Fédération Nationale des Centres de Lutte Contre le Cancer 3.2 Radiological characteristics In staging imaging, number of suspicious LN did not differ in metastatic and benign patients (p = 0.770). However, a significantly larger short axis diameter (SAD; B : median 14mm, range 7-27mm vs. M : median 22.5mm, range 10-51mm, p < 0.001) and long axis diameter (LAD; B : median 21mm, range 11-38mm vs. M : median 29.5mm, range 13-86mm, p = 0.003) were observed in metastatic LN. The SAD/LAD ratio tended to be higher for metastatic LN ( B : median 0.68, range 0.5-1 vs. M : median 0.8, range 0.5–0.94, p = 0.076) (Fig. 1 ). Receiver operating characteristics (ROC) analysis revealed an AUC of 0.81 for SAD and an AUC of 0.73 for LAD. Sensitivity and specificity were 73.3%, 76.9% for SAD with a cut-off value of 17mm and 73.3%, 65.4% for LAD with a cut-off value of 24mm (Fig. 3 ). A central necrosis was detected in 60% (n = 18) of patients with metastatic LN, compared to only 11.5% (n = 3) of patients with benign LN (p < 0.001). PET-CT imaging at initial suspicion was performed in 25% of patients ( B : n = 8, M : n = 6). SUVmax was significantly higher for patients with metastatic LN ( B : median 3.96, range 1.74–7.78 vs. M : median 8.59, range 4.68–17.8, p = 0.013) (Fig. 2 ). ROC analysis could determine an AUC of 0.9 with a sensitivity and specificity of 83.3%, 87.5% for a cut-off value of 6.38 (Fig. 3 ). 3.3 Blood parameters Of our patient cohort, routine blood parameters were available in 45 patients (80.4% of all patients, B : n = 22, M : n = 23). Date of included blood sampling ranged from ten days before to 53 days after the first radiological suspicion. Serum lactate dehydrogenase (LDH) levels were significantly higher in the patient cohort with metastatic LN ( B : median 187.5U/l, range 122-279U/l vs. M : median 247U/l, range 163-468U/l, p = 0.005). C-reactive protein (CRP) levels also proved to be higher in these patients ( B : median 0.55mg/dl, range 0.1-5.8mg/dl vs. M : median 1.5mg/dl, range 0.1-24.4mg/dl, p = 0.039), whereas leukocytes did not differ between the two groups ( B : median 7.57G/l, range 3.4-12.6G/l vs. M : median 8.7G/l, range 3.6-21.4G/l, p = 0.218). AUC for LDH was 0.75 with a sensitivity and specificity of 72.7%, 68.2% for a cut-off value of 226 U/l (Fig. 3 ). 3.4 Radiological Follow-Up For 41 patients, follow-up imaging was available in a range of 1.7–76 weeks (median 9.8 weeks). Of these patients, 61% (n = 25) received a systemic therapy between initial and follow-up imaging ( B : n = 13, M : n = 12), and 36.6% ( B : n = 7, M : n = 8) did not undergo a therapy in this time interval. One patient with metastatic LN was treated with radiotherapy. As the time interval between radiological examinations varies between patients, size difference per week was calculated. Without therapy, benign LN presented a median SAD difference of 0.0mm/week (range − 0.21–0.47) while metastatic LN showed a median growth of 1.92mm/week (range − 0.85–3.18). Under systemic therapy, a slight SAD regression of LN was equally observed in benign and metastatic patients ( B : median − 0.17mm/week, range − 0.46-0.27mm/week vs. M : median − 0.11mm/week, range − 1.86-0.67mm/week) (Fig. 4 ). New suspicious lymph nodes in follow-up imaging were only observed in two metastatic patients (one with and one without therapy). 4. Discussion 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. 5. Conclusion To our knowledge, this study is the first attempt to predict lymph node status for patients with soft tissue sarcoma. We found that a large lymph node size in terms of short axis diameter, the presence of central necrosis and a high SUVmax are strong imaging features associated with lymph node positivity for patients with soft tissue sarcoma. High serum LDH values could also serve as a predictive parameter of LNM. Lymph node size regression with systemic therapy should not routinely be interpreted as a response to therapy and evidence of malignancy. As ranges of all parameters overlap in benign and metastatic LN, biopsy should always be performed in case of doubt. Declarations Compliance with Ethical Standards The authors have no potential conflicts of interest to disclose. Due to anonymized nature of this study an informed consent was not required. Competing Interests The authors have no competing interests to declare that are relevant to the content of this article. This research received no external funding. Ethics Approval The Internal Review Board and the Ethical Review Committee at the Ludwig Maximilians University (LMU) Hospital, Munich, Germany, approved the protocol of this research project (Protocol Nr. 23-0236). All data were irreversibly anonymized. Data Availability The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Author Contributions Conceptualization A.B.-M., W.G.K. and L.H.L.; data curation A.B.-M., V.J. and W.G.K.; formal analysis A.B.-M. and V.J.; investigation A.B.-M., V.J. and W.G.K.; methodology A.B.-M., V.J., L.H.L. and W.G.K.; project administration L.H.L. and W.G.K.; resources L.H.L. and W.G.K.; software V.J.; supervision L.H.L. and W.G.K.; validation L.H.L. and W.G.K.; visualization V.J.; writing—original draft A.B.-M.; writing—review and editing V.J., L.H.L., W.G.K., L.M.B., D.D.G., H.R.D., A.K., M.A., L.M.U., M.v.B.-B., J.R., N.-S.S.-H., T.K. All authors have read and agreed to the published version of the manuscript. The work reported in the paper has been performed by the authors, unless clearly specified in the text. References Beckingsale TB, Shaw C (2017) Epidemiology of bone and soft-tissue sarcomas. 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Cite Share Download PDF Status: Published Journal Publication published 29 Feb, 2024 Read the published version in Clinical & Experimental Metastasis → Version 1 posted Editorial decision: Revision requested 18 Dec, 2023 Reviews received at journal 17 Dec, 2023 Reviewers agreed at journal 27 Nov, 2023 Reviews received at journal 16 Oct, 2023 Reviewers agreed at journal 09 Oct, 2023 Reviewers invited by journal 06 Oct, 2023 Editor assigned by journal 05 Oct, 2023 Submission checks completed at journal 05 Oct, 2023 First submitted to journal 01 Oct, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3402984","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":238066079,"identity":"109a0817-3656-4e01-a1e7-e0295b200f1b","order_by":0,"name":"Anton Burkhard-Meier","email":"data:image/png;base64,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","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Anton","middleName":"","lastName":"Burkhard-Meier","suffix":""},{"id":238066080,"identity":"b51c5904-9bc1-4299-8f7b-ebd8c3bc3266","order_by":1,"name":"Vindi Jurinovic","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vindi","middleName":"","lastName":"Jurinovic","suffix":""},{"id":238066081,"identity":"475889a6-92f0-4e83-b3ce-a9b99b304d94","order_by":2,"name":"Luc M. Berclaz","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Luc","middleName":"M.","lastName":"Berclaz","suffix":""},{"id":238066082,"identity":"d675b06f-a37f-408f-ba4e-449ea528e21a","order_by":3,"name":"Markus Albertsmeier","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Markus","middleName":"","lastName":"Albertsmeier","suffix":""},{"id":238066083,"identity":"f6280a06-6b52-4f4f-aefb-c696334a7960","order_by":4,"name":"Hans Roland Dürr","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hans","middleName":"Roland","lastName":"Dürr","suffix":""},{"id":238066084,"identity":"830a1052-d227-4f40-93e9-f7e2ac8cf6ad","order_by":5,"name":"Alexander Klein","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Klein","suffix":""},{"id":238066085,"identity":"a323453a-5cef-49db-bf87-86a23d90dd01","order_by":6,"name":"Thomas Knösel","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Knösel","suffix":""},{"id":238066086,"identity":"e930f287-9ff4-43eb-88f1-aa9d23105c47","order_by":7,"name":"Dorit Di Gioia","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dorit","middleName":"Di","lastName":"Gioia","suffix":""},{"id":238066087,"identity":"c94772db-5609-4d0b-9ec8-15eb5c732e50","order_by":8,"name":"Lena M. Unterrainer","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lena","middleName":"M.","lastName":"Unterrainer","suffix":""},{"id":238066088,"identity":"b24ed65e-f0ec-4a7b-b8d9-4f4f6bf92ccd","order_by":9,"name":"Nina-Sophie Schmidt-Hegemann","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nina-Sophie","middleName":"","lastName":"Schmidt-Hegemann","suffix":""},{"id":238066089,"identity":"66b96868-e270-4b05-8d65-ab242d16a1ce","order_by":10,"name":"Jens Ricke","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jens","middleName":"","lastName":"Ricke","suffix":""},{"id":238066090,"identity":"e1292998-a50d-47f8-8dab-578f5fe3d4dd","order_by":11,"name":"Michael Bergwelt-Baildon","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Bergwelt-Baildon","suffix":""},{"id":238066091,"identity":"6fcb6212-c7f5-445a-bcbe-a85befd00105","order_by":12,"name":"Wolfgang G. Kunz","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wolfgang","middleName":"G.","lastName":"Kunz","suffix":""},{"id":238066092,"identity":"53ea37cc-a91c-4789-b961-797b00ed97f1","order_by":13,"name":"Lars H. Lindner","email":"","orcid":"","institution":"University Hospital, LMU Munich","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lars","middleName":"H.","lastName":"Lindner","suffix":""}],"badges":[],"createdAt":"2023-10-01 16:29:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3402984/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3402984/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10585-024-10273-7","type":"published","date":"2024-02-29T15:01:46+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":44364755,"identity":"f78cb9f5-908d-4aa1-a7dd-737c2eee3387","added_by":"auto","created_at":"2023-10-10 14:14:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":141150,"visible":true,"origin":"","legend":"\u003cp\u003eRadiological characteristics: Size in terms of short axis diameter (SAD) and long axis diameter (LAD) in mm (a,b), SAD/LAD ratio (c) and number of lymph nodes (d) in benign (n=26) and metastatic (n=30) lymph nodes in soft tissue sarcoma patients\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3402984/v1/0c7f000fa9aff2c26d67ab18.png"},{"id":44364756,"identity":"8986f603-9031-4072-8d50-736a48404b68","added_by":"auto","created_at":"2023-10-10 14:14:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":103176,"visible":true,"origin":"","legend":"\u003cp\u003eRadiological characteristics: Presence of central necrosis and maximal standardized uptake value (SUVmax) in FDG-PET-CT in benign (n=26 and n=8, respectively) and metastatic (n=30 and n=6, respectively) lymph nodes in soft tissue sarcoma patients\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3402984/v1/beb85be60f4c96aacf41f0bc.png"},{"id":44364757,"identity":"4d2a7a20-664d-4402-a648-106443fa5185","added_by":"auto","created_at":"2023-10-10 14:14:13","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":96525,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristic curve for short axis diameter (SAD), long axis diameter (LAD), maximal standardized uptake value (SUVmax) and lactate dehydrogenase (LDH)\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3402984/v1/ff9906ecce49b7d178a86484.png"},{"id":44364754,"identity":"3dbe7082-3854-4feb-955a-9c04f8ad5fdb","added_by":"auto","created_at":"2023-10-10 14:14:13","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":64029,"visible":true,"origin":"","legend":"\u003cp\u003eRadiological follow-up: Difference of short axis diameter of lymph nodes in mm per week under systemic therapy (benign: n=13, metastatic: n=12) or without therapy (benign: n=7, metastatic: n=8)\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-3402984/v1/11fe9def6ceb95a1412e25b5.png"},{"id":44364758,"identity":"b5bd263d-e1ac-4917-b391-073b442bc7f5","added_by":"auto","created_at":"2023-10-10 14:14:13","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1388726,"visible":true,"origin":"","legend":"\u003cp\u003ea) CT staging imaging at baseline of a 59-year-old female patient with an undifferentiated pleomorphic sarcoma in the right thigh region and metastasis to iliac and inguinal lymph nodes. A central necrosis is identified in the detected metastatic lymph nodes. b) CT follow-up staging of a 65-year-old female patient three months after curative resection of a uterine leiomyosarcoma. Suspicious bihilar lymph nodes proved to be epithelioid cell granuloma without necrosis compatible with a sarcoid-like reaction.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-3402984/v1/c7b33ea89f98cdb7b2882048.png"},{"id":51958278,"identity":"e7ecc2d9-7ac6-4f42-ac30-49f34a662605","added_by":"auto","created_at":"2024-03-04 15:14:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1471242,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3402984/v1/11d54bb2-21c1-4b69-8469-0cbaa63aa0fc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Differentiation of benign and metastatic lymph nodes in soft tissue sarcoma","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSoft tissue sarcoma (STS) refers to a heterogenous group of mesenchymal malignancies accounting for approximately 1% of all malignancies in adults [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Up to half of STS patients will develop metastatic disease, mainly to the lungs [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. With survival rates of one to two years despite optimal treatment, prognosis remains dismal for advanced and metastatic STS patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile hematogenous spread is commonly observed, lymph node metastases (LNM) are exceptionally rare with an incidence of 2.6\u0026ndash;5.3% reported for STS [\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Certain subtypes like synovial sarcoma, clear cell sarcoma, angiosarcoma, rhabdomyosarcoma and epithelioid sarcoma (acronym: SCARE) were found to be more likely to develop LNM, although latest reports exclude synovial sarcoma from this list [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Regional LNM, potentially indicating a disseminated disease and a high biological aggressiveness, is associated with a poor survival. A comprehensive analysis of the American \u003cem\u003eNational Cancer Database\u003c/em\u003e demonstrated an overall survival of 28 months in STS patients with \u003cem\u003epN1M0\u003c/em\u003e disease varying by histology, approximating the prognosis of a metastatic STS disease [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. According to the current \u003cem\u003eAmerican Joint Committee on Cancer\u003c/em\u003e (AJCC) classification, any \u003cem\u003eN1M0\u003c/em\u003e STS in the trunk and extremities is classified as stage IV, such as a M1 metastatic STS [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, the significance of regional LNM remains controversial and patients with extremity STS and isolated LNM might have a better prognosis than the AJCC classification suggests [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDepending on pathological, radiological and clinical assessment, STS patients are treated with either a potentially curative or palliative intent. In non-metastatic stages, complete surgical resection can be coupled with radio- and chemotherapy plus regional hyperthermia to reduce local and distant recurrence. For metastatic patients, palliative anthracycline-based chemotherapy remains the standard treatment [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFrequently, STS patients present with suspicious lymph nodes in staging imaging, based on non-sarcoma specific criteria, like pathological enlargement and the presence of a central necrosis [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. As nodal involvement indicates a more advanced stage, it might change the treatment strategy towards an extended surgical intervention or a palliative therapy. Considering the strong impact on the therapeutic approach in these patients, it is important to carefully interpret suspicious lymph nodes in staging imaging and, if appropriate, to examine them histologically. So far, there are no accurate radiologic or clinical criteria for the evaluation of lymph node involvement in STS. This study aimed to identify predictive parameters for LNM in STS patients in a German large-volume sarcoma center.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Patient selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients who underwent histological examination of radiologically suspicious LN with either histologically confirmed or excluded LNM of STS between 2006 and 2022 were included. Histological examination was either performed as a LN biopsy or in the context of a tumor resection. Clinical, radiological and outcomes data were extracted from our hospital database. Tumor or lymph node size were recorded from the imaging analysis and/or pathological report. Due to the anonymized nature of the study, an informed consent was not required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Imaging Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComputed tomography (CT), magnetic resonance (MR) and positron emission tomography with 18-fluorodeoxyglucose (FDG-PET-CT) images were reviewed by one radiologist with subspecialty training in oncological imaging (WGK). Size of lymph nodes in terms of long axis diameter (LAD) and short axis diameter (SAD) as well as number and the presence of a central necrosis were evaluated. Lymph node central necrosis is defined as a central area of low attenuation surrounded by an irregular periphery of enhancing tissue [15]. FDG uptake was quantified by calculating maximal standardized uptake value (SUVmax) which indicates the degree of tumor metabolism.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Histopathology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHistopathology was performed according to standard procedures at the LMU Munich pathology department by a specialized sarcoma pathologist. The pathologists\u0026rsquo; original report served as specification of tumor grade and lymph node histology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Statistics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables were compared with the Mann\u0026ndash;Whitney U test, and categorical variables with the Fisher\u0026rsquo;s exact test. Receiver operating characteristic (ROC) curves were analyzed and compared for those variables that demonstrated significant association with lymph node status. Optimal cut-off values from ROC curve analyses were determined by the highest Youden Index.  Overall survival was analyzed using the Kaplan\u0026ndash;Meier method and the log-rank test. The results with a p-value of less than 0.05 were considered statistically significant. Statistical analysis was performed using R software version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).\u0026nbsp;\u003c/p\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Patient cohort\u003c/h2\u003e \u003cp\u003eThe clinicopathologic characteristics of the study cohort are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A total of 56 STS patients with radiologically suspicious LN and either benign LN (group \u003cem\u003eB\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;26) or metastatic LN (group \u003cem\u003eM\u003c/em\u003e, n\u0026thinsp;=\u0026thinsp;30) evaluated by histological examination were included in our study. These two groups of patients were compared with regard to clinical parameters.\u003c/p\u003e \u003cp\u003eMedian age was similar in both groups (\u003cem\u003eB\u003c/em\u003e: median 60 years, range 13\u0026ndash;78 years vs. \u003cem\u003eM\u003c/em\u003e: median 54 years, range 25\u0026ndash;79 years), and a male predominance was observed in both groups (\u003cem\u003eB\u003c/em\u003e: 62% and \u003cem\u003eM\u003c/em\u003e: 70% of patients in each group). Undifferentiated pleomorphic sarcoma (UPS) represented the most common subtype in both groups (\u003cem\u003eB\u003c/em\u003e: n\u0026thinsp;=\u0026thinsp;7, 27%, \u003cem\u003eM\u003c/em\u003e: n\u0026thinsp;=\u0026thinsp;6, 20%) along with leiomyosarcoma in group \u003cem\u003eB\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;7, 27%), and followed by clear cell sarcoma in group \u003cem\u003eM\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;3, 10%). For patients with benign and metastatic LN, high tumor grade (G2/3; \u003cem\u003eB\u003c/em\u003e: 81%, \u003cem\u003eM\u003c/em\u003e: 73%), localization of the primary tumor on the extremities (\u003cem\u003eB\u003c/em\u003e: 42%, \u003cem\u003eM\u003c/em\u003e: 67%), regional (\u003cem\u003eB\u003c/em\u003e: 69%, \u003cem\u003eM\u003c/em\u003e: 80%) and synchronous occurrence (at initial diagnosis) of LN (\u003cem\u003eB\u003c/em\u003e: 62%, \u003cem\u003eM\u003c/em\u003e: 60%) were common characteristics. Primary tumor size did not differ significantly regarding the dignity of LN (\u003cem\u003eB\u003c/em\u003e: median 9cm, range 3.8-13.3cm, \u003cem\u003eM\u003c/em\u003e: median 7.1cm, range 0.8-15cm; p\u0026thinsp;=\u0026thinsp;0.447).\u003c/p\u003e \u003cp\u003eHistopathological examination revealed LN \u003cem\u003eand\u003c/em\u003e sarcoma tissue in 18 patients (60% of group \u003cem\u003eM\u003c/em\u003e) and only sarcoma tissue in 12 patients (40%). For patients with benign LN, LN tissue without specification (n\u0026thinsp;=\u0026thinsp;9, 34.6% of group \u003cem\u003eB\u003c/em\u003e), reactive LN (n\u0026thinsp;=\u0026thinsp;7, 23.3%), granulomatous inflammation (n\u0026thinsp;=\u0026thinsp;4, 15.4%), sinus histiocytosis/anthracosis (n\u0026thinsp;=\u0026thinsp;3, 11.5%) and fibrosclerotic tissue (n\u0026thinsp;=\u0026thinsp;3, 11.5%) were reported.\u003c/p\u003e \u003cp\u003eMedian overall survival (OS) from initial suspicion of LNM was 8.74 years for patients with benign LN and 3.16 years for patients with metastatic LN (p\u0026thinsp;=\u0026thinsp;0.006).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients with benign and metastatic lymph nodes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBenign LN (n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMetastatic LN (n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eHistological subtype\u003c/span\u003e\u003c/p\u003e \u003cp\u003e- UPS\u003c/p\u003e \u003cp\u003e- Leiomyosarcoma\u003c/p\u003e \u003cp\u003e- Clear Cell Sarcoma\u003c/p\u003e \u003cp\u003e- Fibrosarcoma\u003c/p\u003e \u003cp\u003e- Dediff. Liposarcoma\u003c/p\u003e \u003cp\u003e- Synovial Sarcoma\u003c/p\u003e \u003cp\u003e- EHE\u003c/p\u003e \u003cp\u003e- Rhabdomyosarcoma\u003c/p\u003e \u003cp\u003e- Other (all STS\u0026thinsp;\u0026le;\u0026thinsp;2 patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (27%)\u003c/p\u003e \u003cp\u003e7 (27%)\u003c/p\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e4 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (20%)\u003c/p\u003e \u003cp\u003e2 (7%)\u003c/p\u003e \u003cp\u003e3 (10%)\u003c/p\u003e \u003cp\u003e2 (7%)\u003c/p\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003cp\u003e3 (10%)\u003c/p\u003e \u003cp\u003e3 (10%)\u003c/p\u003e \u003cp\u003e9 (30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.180\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eGrading according to FNCLCC\u003c/span\u003e\u003c/p\u003e \u003cp\u003e- 1\u003c/p\u003e \u003cp\u003e- 2\u003c/p\u003e \u003cp\u003e- 3\u003c/p\u003e \u003cp\u003e- Not available/ applicable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003cp\u003e8 (31%)\u003c/p\u003e \u003cp\u003e13 (50%)\u003c/p\u003e \u003cp\u003e4 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (10%)\u003c/p\u003e \u003cp\u003e7 (23%)\u003c/p\u003e \u003cp\u003e15 (50%)\u003c/p\u003e \u003cp\u003e5 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.845\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eLocalization of primary tumor\u003c/span\u003e\u003c/p\u003e \u003cp\u003e- Extremities\u003c/p\u003e \u003cp\u003e- Retroperitoneal/Abdominal\u003c/p\u003e \u003cp\u003e- Trunk\u003c/p\u003e \u003cp\u003e- Head/Neck\u003c/p\u003e \u003cp\u003e- Pleural/pulmonary\u003c/p\u003e \u003cp\u003e- Other\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (42%)\u003c/p\u003e \u003cp\u003e6 (23%)\u003c/p\u003e \u003cp\u003e3 (12%)\u003c/p\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003cp\u003e3 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (67%)\u003c/p\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003cp\u003e2 (7%)\u003c/p\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003cp\u003e3 (10%)\u003c/p\u003e \u003cp\u003e3 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.238\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eLocalization of suspicious lymph nodes\u003c/span\u003e\u003c/p\u003e \u003cp\u003e- Regional\u003c/p\u003e \u003cp\u003e- Distant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (69%)\u003c/p\u003e \u003cp\u003e8 (31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (80%)\u003c/p\u003e \u003cp\u003e6 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.375\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eDate of occurrence of suspicious lymph nodes\u003c/span\u003e\u003c/p\u003e \u003cp\u003e- Synchronous\u003c/p\u003e \u003cp\u003e- Metachronous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (62%)\u003c/p\u003e \u003cp\u003e10 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (60%)\u003c/p\u003e \u003cp\u003e12 (40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eUPS: Undifferentiated pleomorphic sarcoma, EHE: Epithelioid haemangioendothelioma, FNCLCC: F\u0026eacute;d\u0026eacute;ration Nationale des Centres de Lutte Contre le Cancer\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Radiological characteristics\u003c/h2\u003e \u003cp\u003eIn staging imaging, number of suspicious LN did not differ in metastatic and benign patients (p\u0026thinsp;=\u0026thinsp;0.770). However, a significantly larger short axis diameter (SAD; \u003cem\u003eB\u003c/em\u003e: median 14mm, range 7-27mm vs. \u003cem\u003eM\u003c/em\u003e: median 22.5mm, range 10-51mm, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and long axis diameter (LAD; \u003cem\u003eB\u003c/em\u003e: median 21mm, range 11-38mm vs. \u003cem\u003eM\u003c/em\u003e: median 29.5mm, range 13-86mm, p\u0026thinsp;=\u0026thinsp;0.003) were observed in metastatic LN. The SAD/LAD ratio tended to be higher for metastatic LN (\u003cem\u003eB\u003c/em\u003e: median 0.68, range 0.5-1 vs. \u003cem\u003eM\u003c/em\u003e: median 0.8, range 0.5\u0026ndash;0.94, p\u0026thinsp;=\u0026thinsp;0.076) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eReceiver operating characteristics (ROC) analysis revealed an AUC of 0.81 for SAD and an AUC of 0.73 for LAD. Sensitivity and specificity were 73.3%, 76.9% for SAD with a cut-off value of 17mm and 73.3%, 65.4% for LAD with a cut-off value of 24mm (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA central necrosis was detected in 60% (n\u0026thinsp;=\u0026thinsp;18) of patients with metastatic LN, compared to only 11.5% (n\u0026thinsp;=\u0026thinsp;3) of patients with benign LN (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). PET-CT imaging at initial suspicion was performed in 25% of patients (\u003cem\u003eB\u003c/em\u003e: n\u0026thinsp;=\u0026thinsp;8, \u003cem\u003eM\u003c/em\u003e: n\u0026thinsp;=\u0026thinsp;6). SUVmax was significantly higher for patients with metastatic LN (\u003cem\u003eB\u003c/em\u003e: median 3.96, range 1.74\u0026ndash;7.78 vs. \u003cem\u003eM\u003c/em\u003e: median 8.59, range 4.68\u0026ndash;17.8, p\u0026thinsp;=\u0026thinsp;0.013) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). ROC analysis could determine an AUC of 0.9 with a sensitivity and specificity of 83.3%, 87.5% for a cut-off value of 6.38 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Blood parameters\u003c/h2\u003e \u003cp\u003eOf our patient cohort, routine blood parameters were available in 45 patients (80.4% of all patients, \u003cem\u003eB\u003c/em\u003e: n\u0026thinsp;=\u0026thinsp;22, \u003cem\u003eM\u003c/em\u003e: n\u0026thinsp;=\u0026thinsp;23). Date of included blood sampling ranged from ten days before to 53 days after the first radiological suspicion. Serum lactate dehydrogenase (LDH) levels were significantly higher in the patient cohort with metastatic LN (\u003cem\u003eB\u003c/em\u003e: median 187.5U/l, range 122-279U/l vs. \u003cem\u003eM\u003c/em\u003e: median 247U/l, range 163-468U/l, p\u0026thinsp;=\u0026thinsp;0.005). C-reactive protein (CRP) levels also proved to be higher in these patients (\u003cem\u003eB\u003c/em\u003e: median 0.55mg/dl, range 0.1-5.8mg/dl vs. \u003cem\u003eM\u003c/em\u003e: median 1.5mg/dl, range 0.1-24.4mg/dl, p\u0026thinsp;=\u0026thinsp;0.039), whereas leukocytes did not differ between the two groups (\u003cem\u003eB\u003c/em\u003e: median 7.57G/l, range 3.4-12.6G/l vs. \u003cem\u003eM\u003c/em\u003e: median 8.7G/l, range 3.6-21.4G/l, p\u0026thinsp;=\u0026thinsp;0.218). AUC for LDH was 0.75 with a sensitivity and specificity of 72.7%, 68.2% for a cut-off value of 226 U/l (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Radiological Follow-Up\u003c/h2\u003e \u003cp\u003eFor 41 patients, follow-up imaging was available in a range of 1.7\u0026ndash;76 weeks (median 9.8 weeks). Of these patients, 61% (n\u0026thinsp;=\u0026thinsp;25) received a systemic therapy between initial and follow-up imaging (\u003cem\u003eB\u003c/em\u003e: n\u0026thinsp;=\u0026thinsp;13, \u003cem\u003eM\u003c/em\u003e: n\u0026thinsp;=\u0026thinsp;12), and 36.6% (\u003cem\u003eB\u003c/em\u003e: n\u0026thinsp;=\u0026thinsp;7, \u003cem\u003eM\u003c/em\u003e: n\u0026thinsp;=\u0026thinsp;8) did not undergo a therapy in this time interval. One patient with metastatic LN was treated with radiotherapy. As the time interval between radiological examinations varies between patients, size difference per week was calculated. Without therapy, benign LN presented a median SAD difference of 0.0mm/week (range \u0026minus;\u0026thinsp;0.21\u0026ndash;0.47) while metastatic LN showed a median growth of 1.92mm/week (range \u0026minus;\u0026thinsp;0.85\u0026ndash;3.18). Under systemic therapy, a slight SAD regression of LN was equally observed in benign and metastatic patients (\u003cem\u003eB\u003c/em\u003e: median \u0026minus;\u0026thinsp;0.17mm/week, range \u0026minus;\u0026thinsp;0.46-0.27mm/week vs. \u003cem\u003eM\u003c/em\u003e: median \u0026minus;\u0026thinsp;0.11mm/week, range \u0026minus;\u0026thinsp;1.86-0.67mm/week) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNew suspicious lymph nodes in follow-up imaging were only observed in two metastatic patients (one with and one without therapy).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eDue 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) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first study to compare STS patients with suspicious lymph nodes in imaging and histological confirmation (\u003cem\u003epN1\u003c/em\u003e) or exclusion of LNM (\u003cem\u003epN0\u003c/em\u003e). 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.\u003c/p\u003e \u003cp\u003eEnlargement of LN commonly leads to suspicion, but nodal size criteria vary depending on location and entity [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. 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\u0026thinsp;=\u0026thinsp;0.076) being in line with previous literature across entities [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. 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% [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In our cohort, we could confirm a strong association with LNM. However, 11.5% (n\u0026thinsp;=\u0026thinsp;3) of benign patients did also present a central necrosis while 40% (n\u0026thinsp;=\u0026thinsp;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.\u003c/p\u003e \u003cp\u003eWhile 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 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In previous studies a high sensitivity and specificity of 90\u0026ndash;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 [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eWhen 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.\u003c/p\u003e \u003cp\u003eTo 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 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eOur 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 [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLimitations 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.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eTo our knowledge, this study is the first attempt to predict lymph node status for patients with soft tissue sarcoma. We found that a large lymph node size in terms of short axis diameter, the presence of central necrosis and a high SUVmax are strong imaging features associated with lymph node positivity for patients with soft tissue sarcoma. High serum LDH values could also serve as a predictive parameter of LNM. Lymph node size regression with systemic therapy should not routinely be interpreted as a response to therapy and evidence of malignancy. As ranges of all parameters overlap in benign and metastatic LN, biopsy should always be performed in case of doubt.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no potential conflicts of interest to disclose. Due to anonymized nature of this study an informed consent was not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article. This research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Internal Review Board and the Ethical Review Committee at the Ludwig Maximilians University (LMU) Hospital, Munich, Germany, approved the protocol of this research project (Protocol Nr. 23-0236). All data were irreversibly anonymized.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization A.B.-M., W.G.K. and L.H.L.; data curation A.B.-M., V.J. and W.G.K.; formal analysis A.B.-M. and V.J.; investigation A.B.-M., V.J. and W.G.K.; methodology A.B.-M., V.J., L.H.L. and W.G.K.; project administration L.H.L. and W.G.K.; resources L.H.L. and W.G.K.; software V.J.; supervision L.H.L. and W.G.K.; validation L.H.L. and W.G.K.; visualization V.J.; writing\u0026mdash;original draft A.B.-M.; writing\u0026mdash;review and editing V.J., L.H.L., W.G.K., L.M.B., D.D.G., H.R.D., A.K., M.A., L.M.U., M.v.B.-B., J.R., N.-S.S.-H., T.K. All authors have read and agreed to the published version of the manuscript. The work reported in the paper has been performed by the authors, unless clearly specified in the text.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBeckingsale TB, Shaw C (2017) Epidemiology of bone and soft-tissue sarcomas. Orthop Trauma 31:144\u0026ndash;150. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.mporth.2017.03.005\u003c/span\u003e\u003cspan address=\"10.1016/j.mporth.2017.03.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eItaliano A, Mathoulin-Pelissier S, Le Cesne A, Terrier P, Bonvalot S, Collin F et al (2011) Trends in survival for patients with metastatic soft-tissue sarcoma. 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J Orthop Surg Res 17:1\u0026ndash;16. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13018-022-03050-3\u003c/span\u003e\u003cspan address=\"10.1186/s13018-022-03050-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-and-experimental-metastasis","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clin","sideBox":"Learn more about [Clinical \u0026 Experimental Metastasis](http://link.springer.com/journal/10585)","snPcode":"10585","submissionUrl":"https://submission.nature.com/new-submission/10585/3","title":"Clinical \u0026 Experimental Metastasis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Soft tissue sarcoma, lymph node metastasis, predictive parameters, staging imaging","lastPublishedDoi":"10.21203/rs.3.rs-3402984/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3402984/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003eLymph node metastasis (LNM) occurs in less than 5% of soft tissue sarcoma (STS) patients and indicates an aggressive course of disease. Suspicious lymph nodes in staging imaging are a frequent matter of discussion in multidisciplinary tumor boards. Predictive markers are needed to enable stratification and improve treatment of STS patients.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e \u003cp\u003eIn this study, 56 STS patients with radiologically suspicious and subsequently histologically examined lymph nodes (LN) were reviewed. Patients with benign (n\u0026thinsp;=\u0026thinsp;26) and metastatic (n\u0026thinsp;=\u0026thinsp;30) LN were analyzed with regard to clinical, laboratory and radiological parameters.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eShort axis diameter (SAD) and long axis diameter (LAD) of LN were significantly larger in patients with LNM (median 22.5 vs. 14mm, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and median 29.5 vs. 21mm, p\u0026thinsp;=\u0026thinsp;0.003, respectively). In addition, presence of central necrosis and high maximal standardized uptake value (SUVmax) in FDG-PET-CT scan were significantly associated with LNM (60 vs. 11.5% of patients, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and median 8.59 vs. 3.96, p\u0026thinsp;=\u0026thinsp;0.013, respectively). With systemic therapy, a slight median size regression per time was observed in both metastatic and benign LN. Serum LDH and CRP levels were significantly higher in patients with LNM (median 247 vs. 187.5U/l, p\u0026thinsp;=\u0026thinsp;0.005 and 1.5 vs. 0.55mg/dl, p\u0026thinsp;=\u0026thinsp;0.039, respectively).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study shows significant associations between LNM and imaging features as well as laboratory parameters of STS patients. The largest SAD, SUVmax in FDG-PET-CT scan, the presence of central necrosis, and high serum LDH level are the most important parameters to distinguish benign from metastatic LNs.\u003c/p\u003e","manuscriptTitle":"Differentiation of benign and metastatic lymph nodes in soft tissue sarcoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-10 14:14:08","doi":"10.21203/rs.3.rs-3402984/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2023-12-18T18:57:25+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-12-17T20:56:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"0c3d29dd-2756-43a7-808d-ec3a735e664d","date":"2023-11-27T16:12:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-10-16T10:15:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5fc5afbe-c67a-444e-8f7d-dfee75e35bf8","date":"2023-10-09T13:51:40+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-10-06T07:20:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-10-05T11:15:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-10-05T11:15:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical \u0026 Experimental Metastasis","date":"2023-10-01T16:15:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-and-experimental-metastasis","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clin","sideBox":"Learn more about [Clinical \u0026 Experimental Metastasis](http://link.springer.com/journal/10585)","snPcode":"10585","submissionUrl":"https://submission.nature.com/new-submission/10585/3","title":"Clinical \u0026 Experimental Metastasis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"72babe44-f9fc-4e8b-ae97-480adb2d28d8","owner":[],"postedDate":"October 10th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-03-04T15:07:41+00:00","versionOfRecord":{"articleIdentity":"rs-3402984","link":"https://doi.org/10.1007/s10585-024-10273-7","journal":{"identity":"clinical-and-experimental-metastasis","isVorOnly":false,"title":"Clinical \u0026 Experimental Metastasis"},"publishedOn":"2024-02-29 15:01:46","publishedOnDateReadable":"February 29th, 2024"},"versionCreatedAt":"2023-10-10 14:14:08","video":"","vorDoi":"10.1007/s10585-024-10273-7","vorDoiUrl":"https://doi.org/10.1007/s10585-024-10273-7","workflowStages":[]},"version":"v1","identity":"rs-3402984","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3402984","identity":"rs-3402984","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}