Rare, rarer, rarest: lessons from the largest retrospective study to date on mediastinal sarcomas

Physicians concerned with the diagnosis and management of patients with mediastinal tumors are used to the fact that they have to rely on hardly any secured data and little evidence-based knowledge for their decisions. But even by these standards, primary mediastinal sarcomas are extremely rare tumors that account for no more than 5% of mediastinal neoplasms. Less than 1% of soft tissue sarcomas are located in the mediastinum.

Therefore, a recent study published by Engelhardt et al., in The Annals of Thoracic Surgery (1) is an unprecedented effort to gather and organize available information on mediastinal sarcomas. Taking advantage of the National Cancer Database (NCDB), one of the largest cancer registries worldwide, the authors were able to analyze retrospective data of 976 patients with mediastinal sarcomas. The limitations of such studies are well known and weigh heavily, since they have the potential to erroneously bias our conception and approach to a given disease. However, in the case of extremely rare cancers, such data are probably the best one can expect in a long time. Searches in cancer registries make it necessary to categorize and to simplify variables and are heavily dependent on the accuracy of the input, which may explain some surprising findings of the study, such as the fact that liposarcomas, a group that made up a substantial or even the predominant proportion in most previous studies (2), are not mentioned at all. This may in part be explained by the exclusion of thymic tumors from the dataset, where these tumors are frequently located. Similarly, the frequency of sarcoma subtypes is almost certainly skewed by the inclusion of cardiac sarcomas, which may explain why angiosarcomas were the most common histological subtype in this study. Setting such details aside, the authors have generated relevant and robust information, which will help define the major lines guiding the therapeutic approach to mediastinal sarcomas. Not surprisingly, five-year overall survival was poor (14.8%) for the entire cohort and only slightly better for younger patients with fewer comorbidities. In this largest study to date, the results clearly confirm previous findings from other studies that radical surgery with R0 margins is the only curative approach and is superior to all other treatment modalities (3-5). A combination of surgery followed by radiation resulted in the best overall survival, while the benefit of chemotherapy remained unclear (similar to the situation in other anatomic locations) (6-8). The impact of surgery is also highlighted by the fact that even debulking surgery (R1/R2) resulted in better five-year overall survival than non-surgical treatments (radiation and/or chemotherapy) (1).

It should be noted in brackets that the listed entities in this study (angiosarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, sarcoma not otherwise specified) all belong to the unfortunate group of tumors that have so far not benefited from precision medicine, in contrast to some other soft tissue sarcomas such as gastrointestinal stroma tumors (GIST) (9) or inflammatory myofibroblastic tumors (IMFT) (10), to name a few. In summary, while the mediastinum may be a highly challenging anatomical compartment, mediastinal sarcomas seem to follow the general rules elsewhere in the body with respect to treatment. From the data presented by Engelhardt et al., it appears safe to conclude that radical surgery, in combination with radiotherapy, is currently the best hope for cure. This general statement should not ignore the possibility that specific single entities with targetable molecular alterations might well benefit from recent developments in precision medicine and immunotherapy.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Luigi Ventura (Thoracic Surgery, Surgical Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/med.2019.08.04). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Engelhardt KE, DeCamp MM, Yang AD, et al. Treatment Approaches and Outcomes for Primary Mediastinal Sarcoma: Analysis of 976 Patients. Ann Thorac Surg 2018;106:333-9. [Crossref] [PubMed]
2. den Bakker MA, Marx A, Mukai K, et al. Mesenchymal tumours of the mediastinum--part I. Virchows Arch 2015;467:487-500. [Crossref] [PubMed]
3. Paquette M, Truong PT, Hart J, et al. Primary sarcoma of the mediastinum: a report of 16 cases referred to the British Columbia Cancer Agency. J Thorac Oncol 2010;5:898-906. [Crossref] [PubMed]
4. Luo DX, Huang MJ, Xiong B, et al. Primary mediastinal sarcoma: surgical outcomes of 21 cases. Interact Cardiovasc Thorac Surg 2013;17:982-6. [Crossref] [PubMed]
5. Abdel-Rahman O. An analysis of clinical characteristics and patient outcomes in primary mediastinal sarcomas. Expert Rev Anticancer Ther 2017;17:1071-6. [Crossref] [PubMed]
6. Zaidi MY, Ethun CG, Tran TB, et al. Assessing the Role of Neoadjuvant Chemotherapy in Primary High-Risk Truncal/Extremity Soft Tissue Sarcomas: An Analysis of the Multi-institutional U.S. Sarcoma Collaborative. Ann Surg Oncol 2019; [Epub ahead of print]. [PubMed]
7. Milgrom DP, Sehdev A, Kays JK, et al. Integrating therapies for surgical adult soft tissue sarcoma patients. Transl Gastroenterol Hepatol 2018;3:88. [Crossref] [PubMed]
8. Baldini EH, Le Cesne A, Trent JC. Neoadjuvant Chemotherapy, Concurrent Chemoradiation, and Adjuvant Chemotherapy for High-Risk Extremity Soft Tissue Sarcoma. Am Soc Clin Oncol Educ Book 2018;38:910-5. [Crossref] [PubMed]
9. Laurent M, Brahmi M, Dufresne A, et al. Adjuvant therapy with imatinib in gastrointestinal stromal tumors (GISTs)-review and perspectives. Transl Gastroenterol Hepatol 2019;4:24. [Crossref] [PubMed]
10. Theilen TM, Soerensen J, Bochennek K, et al. Crizotinib in ALK+ inflammatory myofibroblastic tumors-Current experience and future perspectives. Pediatr Blood Cancer 2018; [Crossref] [PubMed]