Soft tissue sarcoma is a collection of rare malignancies, which presents inherent challenges to risk stratification and our understanding of this heterogeneous group of diseases. In an analysis of the risk, prognostic importance, and surgical treatment considerations regarding nodal metastases, the current analysis demonstrated that 5.3% of all adults with soft tissue sarcomas will develop lymph node metastases. Nodal involvement was associated with histologic subtype and overall survival. In patients who develop lymph node metastasis, this analysis demonstrates an association between lymphadenectomy and overall survival.
This study is limited by its retrospective approach and missing lymph node status for some patients who would be otherwise appropriate for inclusion. Although data for female and nonwhite patients have been shown to be less complete than those for other patients in large cancer databases, the SEER database has been shown to be representative of the general cancer population of the United States and to have a higher degree of completeness than other cancer registries. It is impossible to know the reasons for not examining or recording node status in these patients. Given the nature of the database, there may be differences in individual or institutional use of investigation for lymphatic disease. The SEER database coding guidelines allow for clinical, surgical, or pathologic adjudication of the presence of nodal metastasis. The true incidence of lymph node metastasis in soft tissue sarcoma is otherwise difficult to determine. Physical examination may show nodal sites of disease. PET can detect regional and distant lymph node involvement, although it is not routinely performed as part of sarcoma staging. Sentinel node biopsy is commonly performed in the staging of rhabdomyosarcoma and epithelioid sarcoma but is most commonly performed in tertiary cancer centers or in the setting of a clinical trial, potentially excluding many patients in the SEER database. Interestingly, the utility of sentinel node biopsy, even for histologic subtypes that are presumed to be at increased risk for nodal metastasis, remains to be fully clarified .
The distribution of histologic subtypes of soft tissue sarcomas would be expected to differ between adults and children, and the current analysis was limited to adults. Although there is little reason to believe that the risk of lymph node metastasis would differ according to patient age, we would expect a larger representation of patients with rhabdomyosarcoma among children and adolescents, which could skew the overall proportion of patients with nodal metastasis across the population of patients with soft tissue sarcomas. Therefore, we felt that excluding children and adolescents would more accurately represent the adult sarcoma population as a whole. In contrast to adults, a larger proportion of pediatric patients with sarcoma may be treated within large multicenter cooperative group studies, which may dictate surveillance and treatment strategies and may provide more granular detail on the management of nodal metastases in their respective cohorts.
We found that 5.3% of patients in the SEER database had lymph node metastases and 12% had distant metastases. Only 9% of patients were missing data on lymph node status. Exclusion of these patients with incomplete data yielded a proportion with nodal metastasis of 5.3%. Previous studies of soft tissue sarcoma have varied widely in their reported incidence of lymph node metastasis [3, 7, 13, 17, 22]. Even in our most conservative estimation, if all patients with unknown lymph node status were presumed to be negative for nodal disease, the proportion would be 4.8%, which is still markedly greater than the largest single-institution analysis . This difference likely reflects improved collection of data on these uncommon events in a rare tumor with the use of a large national database. Although our proportions are nearly double those suggested in some reports, this relatively low rate is unlikely to alter current surveillance protocols for soft tissue sarcomas. However, our findings can help physicians better advise patients and their families regarding their risk of nodal spread of disease.
A recent analysis of patients with metastatic sarcoma noted that more than 88% of patients with metastatic disease developed metastasis to only one site . In that report, however, the proportion of patients with metastatic sarcoma to the lung was 4.6 times higher than the proportion of patients with metastasis to lymph nodes. The current study from the SEER database, in contrast, suggests that the relative proportion of metastasis to lymph nodes is greater. The reason for this discrepancy is unclear and may be related to different methods of identifying patients with nodal involvement.
This study’s results confirm an association between the histologic subtype or soft tissue sarcoma and overall survival. The 5-year overall survival was lower in patients who developed lymph node metastasis than in those who did not. Prior reports have suggested that the 5-year overall survival rate of patients with soft tissue sarcoma with lymph node metastasis was approximately 13% to 34% [5, 8], which is consistent with our finding of 20% 5-year overall survival.
In our investigation, the highest overall survival for patients with lymph node metastases was in those who underwent excision of the primary tumor with lymphadenectomy. The role of lymphadenectomy in the treatment of soft tissue sarcoma has been debated [2-4, 6]. Although we are unable to determine causality in this study, and the proportion with nodal metastasis was still relatively low across the entire cohort, this association may reflect better survival in patients who undergo a more aggressive approach to tumor control. However, this may also reflect selection bias, because those deemed to be healthier or with a lesser metastatic burden may be more likely to undergo aggressive surgical excision. Furthermore, the SEER database is unable to establish whether the addition of chemotherapy can explain this unexpected finding. There were no differences in 5-year overall survival between patients who had only lymph node biopsy compared with those who did not undergo lymph node biopsy. This may indicate a low yield of biopsy or nodal sampling in the overall soft tissue sarcoma population. A recent prospective trial of a subset of soft tissue sarcoma histologic types showed a strong correlation between positive sentinel lymph node biopsy and decreased survival . Although these findings support the potential role for lymphadenectomy in the setting of nodal metastasis, further investigation is necessary to fully elucidate its clinical benefit. However, the current analysis suggests that properly selected patients may be appropriate for lymphadenectomy for management of lymph node metastasis from soft tissue sarcoma.
We thank Rachel Box, Jenni Weems, and Eileen Martin for their outstanding editorial assistance in the preparation of this manuscript.
1. Andreou D, Boldt H, Werner M, Hamann C, Pink D, Tunn PU. Sentinel node biopsy in soft tissue sarcoma subtypes with a high propensity for regional lymphatic spread: results of a large prospective trial. Ann Oncol. 2013;24:1400–1405.
2. Baratti D, Pennacchioli E, Casali PG, Bertulli R, Lozza L, Olmi P, Collini P, Radaelli S, Fiore M, Gronchi A. Epithelioid sarcoma: prognostic factors and survival in a series of patients treated at a single institution. Ann Surg Oncol. 2007;14:3542–3551.
3. Behranwala KA, A'Hern R, Omar AM, Thomas JM. Prognosis of lymph node metastasis in soft tissue sarcoma. Ann Surg Oncol. 2004;11:714–719.
4. Blazer DG 3rd, Sabel MS, Sondak VK. Is there a role for sentinel lymph node biopsy in the management of sarcoma? Surg Oncol. 2003;12:201–206.
5. Daigeler A, Kuhnen C, Moritz R, Stricker I, Goertz O, Tilkorn D, Steinstraesser L, Steinau HU, Lehnhardt M. Lymph node metastases in soft tissue sarcomas: a single center analysis of 1,597 patients. Langenbecks Arch Surg. 2009;394:321–329.
6. de Visscher SA, van Ginkel RJ, Wobbes T, Veth RP, Ten Heuvel SE, Suurmeijer AJ, Hoekstra HJ. Epithelioid sarcoma: still an only surgically curable disease. Cancer. 2006;107:606–612.
7. Deenik W, Mooi WJ, Rutgers EJ, Peterse JL, Hart AA, Kroon BB. Clear cell sarcoma (malignant melanoma) of soft parts: a clinicopathologic study of 30 cases. Cancer. 1999;86:969–975.
8. Fong Y, Coit DG, Woodruff JM, Brennan MF. Lymph node metastasis from soft tissue sarcoma in adults. Analysis of data from a prospective database of 1772 sarcoma patients. Ann Surg. 1993;217:72–77.
9. Kane JM, Finley JW, Driscoll D, Kraybill WG, Gibbs JF. The treatment and outcome of patients with soft tissue sarcomas and synchronous metastases. Sarcoma. 2002;6:69–73.
10. Lewis JJ, Brennan MF. Soft tissue sarcomas. Curr Probl Surg. 1996;33:817–872.
11. Loya AC, Prayaga AK, Arora A, Sundaram C, Rao IS, Uppin SG, Raju GS, Surath A, Rajappa RS. Lymph node metastasis of soft tissue tumors: a cytomorphologic study. Acta Cytol. 2007;51:153–160.
12. Maduekwe UN, Hornicek FJ, Springfield DS, Raskin KA, Harmon DC, Choy E, Rosenberg AE, Nielsen GP, DeLaney TF, Chen YL, Ott MJ, Yoon SS. Role of sentinel lymph node biopsy in the staging of synovial, epithelioid, and clear cell sarcomas. Ann Surg Oncol. 2009;16:1356–1363.
13. Mazeron JJ, Suit HD. Lymph nodes as sites of metastases from sarcomas of soft tissue. Cancer. 1987;60:1800–1808.
16. National Institutes of Health, National Cancer Institute. SEER as a research resource. Available at: seer.cancer.gov/about/factsheets/. Accessed August 25, 2016.
17. Nelen SD, Vogelaar FJ, Gilissen F, Van der Linden JC, Bosscha K. Lymph node metastasis after a soft tissue sarcoma of the leg: a case report and a review of the literature. Case Rep Surg. 2013;2113:930361.
18. Pinheiro PS, Morris CR, Liu L, Bungum TJ, Altekruse SF. The impact of follow-up type and missed deaths on population-based cancer survival studies for Hispanics and Asians. J Natl Cancer Inst Monogr. 2014;2014:210–217.
19. Savina M, Le Cesne A, Blay JY, Ray-Coquard I, Mir O, Toulmonde M, Cousin S, Terrier P, Ranchere-Vince D, Meeus P, Stoeckle E, Honoré C, Sargos P, Sunyach MP, Le Péchoux C, Giraud A, Bellera C, Le Loarer F, Italiano A. Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study. BMC Med. 2017;15:78.
20. Skinner KA, Eilber FR. Soft tissue sarcoma nodal metastases: biologic significance and therapeutic considerations. Surg Oncol Clin N Am. 1996;5:121–127.
21. Wagner W, Willich N, Rube C, Prott FJ, Micke O. [Treatment results of soft tissue sarcomas in adults] [in German]. Strahlenther Onkol. 1994;170:91–99.
22. Weingrad DN, Rosenberg SA. Early lymphatic spread of osteogenic and soft-tissue sarcomas. Surgery. 1978;84:231–240.