Multiple Recurrence of Primary Orbital Synovial Sarcoma: Report of Two Cases and Literature Review
Department of Ophthalmology, Ophthalmic Laboratory, West China Hospital, Sichuan University, Chengdu, 610041, China
* Corresponding Author: Weimin He. Email:
Oncologie 2022, 24(4), 927-935. https://doi.org/10.32604/oncologie.2022.026720
Received 21 September 2022; Accepted 21 November 2022; Issue published 31 December 2022
AbstractSynovial sarcoma (SS) is typically an aggressive malignant soft tissue tumor that mostly affects adolescents and young adults. It is extremely rare in orbit and carries a high risk of recurrence and metastasis, posing a challenge to ophthalmologists in diagnosing and managing. We present two primary orbital synovial sarcoma cases with unilateral exophthalmos and limited motility. Both male patients underwent reoperation in our hospital since tumor recurrence; the pathologic diagnoses were biphasic type and occult type, respectively. Both cases were positive for EMA and CK, and SOX-9 and INI-1 were newly discovered immune markers. Fluorescence in situ hybridization analysis (FISH) revealed a translocation of t (X; 18) (p11.2; q11.2) that was detected in case 1 but not in case 2. Both patients initially refused adjuvant therapy, developed multiple recurrences and metastasis, and eventually died of distant metastasis. We provided clinical features, imaging findings, histopathology, treatments, outcomes of these very rare cases, and a literature review, underlining the timely diagnosis and management.
Synovial sarcoma (SS) is a highly malignant soft tissue sarcoma that differentiates into mesenchymal tissue and epithelium. It accounts for approximately 10% of all soft tissue tumors and has an unknown source and cell of origin, variable clinical behavior, and unique genetic features . It can develop at any age and location, most commonly in the extremities of adolescents and young adults; males are more commonly afflicted . SS involving orbit is exceedingly rare; only 13 cases have been well documented to date, and SS from all sites has a high risk of recurrence and metastasis . However, a correct diagnosis and systemic management pose a challenge for an ophthalmologist. Here, we present two primary orbital SS to expand the medical literature about this rare condition. To our knowledge, case 2 is the first case of occult SS in orbit. In addition, we also review the literature of previously published SS cases, with an emphasis on timely diagnosis and treatment.
Two cases of orbital SS have been reviewed, which were accessioned in the database of the Ophthalmology Department and Pathology Department of West China Hospital of Sichuan University from 2009 to 2021.
A 56-year-old man presented with a 2-year history of proptosis of the right eye (Fig. 1A). He underwent surgery in another hospital one year ago, and the pathologic diagnosis was SS. On ophthalmologic examination, the visual acuity was light perception in the right eye and count finger/40 cm in the left eye. A poorly defined, nonmobile soft mass in the nasal region of the right orbit was palpated, and proptosis was identified. The edema of the inferior bulbar conjunctiva, the disappeared pupillary reaction, and limited ocular motility in all directions were presented. The computed tomography (CT) imaging indicated a 4.8 cm × 2.6 cm soft tissue mass in the right medial orbit in close relation to ocular muscles and optic nerve without invading the eyeball and orbital wall (Figs. 1C and 1D). A routine orbitotomy was performed from the upper edge of the orbit and the tumor was removed as completely as possible (Fig. 2A). Subsequently, the hematoxylin-eosin (HE) and immunohistochemical staining indicated the tumor was mainly composed of spindle-shaped cells and epithelioid cells with positive staining of TLE-1, EMA and CK (Figs. 2A–2F). The histopathology confirmed the diagnosis of biphasic SS with molecular translocation t (X; 18) (p11.2; q11.2) of the SS18-SSX gene. Although adjuvant radiation and chemotherapy were recommended, the patient refused. Since then, the patient has had five relapses, accepted five tumor resections and one gamma knife radiosurgery over three years, and finally received chemotherapy and radiotherapy. Nevertheless, he died of lung metastases 11 months after adjuvant therapy, as reported by telephone follow-up.
A 28-year-old man sought treatment for tumor recurrence of the right orbit. Three years and eight months ago, he underwent two operations and adjuvant radiation in another hospital. The pathologic diagnosis was mesenchymal chondrosarcoma. His best corrected visual acuity was 20/20 in both eyes, and the right eye showed an obvious proptosis with limited motility in horizontal directions. The remainders of the ophthalmic examination results were normal. An orbital CT scan revealed a right retrobulbar soft mass near the lateral wall with calcification and bone involvement (Fig. 3A). A lateral orbitotomy and complete tumor resection were performed. Histological examination showed a small round spindle cell proliferation with positive staining of CD99, EMA, CK19, INI-1 and SOX-9, but without the translocation of t (X; 18) (p11.2; q11.2). Thus, the final diagnosis is occult SS. After the operation, the patient did not receive radiotherapy or chemotherapy. Since then, he has had four relapses (Figs. 3B–3F). The malignant tumor developed intracranial extension at the fourth relapse, and then he accepted tumor resections in orbit and brain combined with regular adjuvant radiotherapy and chemotherapy (gemcitabine, pirarubicin and ifosfamide). Unfortunately, he died of brain metastases after a two-month follow-up.
Orbital SS is a very rare malignant entity. Among the 13 current reports of orbital SS (including our cases), 11 were primary SS (Appendix A) and 2 were metastatic SS [4,5]. The age of patients ranged from 1.5 to 56 years (median: 26.9 years), and the female was more susceptible, unlike any other part of the body. However, orbital lesions in these reported cases do not have any distinguishing characteristics.
SS is categorized into 3 main types: the monophasic type contains only spindle cells, the biphasic type contains epithelial and spindle cell components in varying proportions, and the poorly differentiated type contains monophasic and biphasic regions as well as poorly differentiated areas . Of 13 cases with available histopathological information, the biphasic type is the most common and the poorly differentiated type is the rarest. It is worth noting that we reported a rarer type; this is the first case of occult SS occurring in orbit.
As observed in case 2, SS is commonly missed or misdiagnosed; the patient was initially considered to have mesenchymal chondrosarcoma. The pathologic differential diagnosis of SS includes malignant peripheral nerve sheath tumor, fibrosarcoma, leiomyosarcoma, mesenchymal chondrosarcoma and other small round blue cell tumors. Traditionally, the diagnosis of biphasic SS depends on its unique histological morphology, but other types need to be supported by immunohistochemical and molecular genetic studies.
Positivity for EMA, CK, and Vimentin is the most valuable and sensitive marker for the diagnosis of SS. TLE-1 is highly sensitive but not specific to SS . Other positive expressions include Calponin, Bcl-2, CD-99, S-100, collagen IV, Synaptophysin, SOX10 and AE1/AE3, and negative stains for α-SMA, desmin, Factor VIII, CD34 and MPO could also be helpful to rule out other mesenchymal tumors. Interestingly, we found the tumor in our case 2 positive staining for SOX-9 and INI-1, which has never been reported. Currently, the newly discovered translocation t (X;18) (p11.2; q11.2) is diagnostic and is present in more than 90% of SS and does not occur in other forms of sarcomas [6,8].
SS carries a high risk of local recurrence and distant metastasis that most often occur in the lungs, brain, lymph, and bone marrow [5,9]. Some favorable prognosis factors include younger patient age, smaller tumor size (<5 cm), combined with chemoradiotherapy, negative surgical margin, extremity location, and SS18-SSX2 fusion gene, while unfavorable prognosis factors include the poorly differentiated subtype, the presence of metastasis, lymph node positivity and SS18-SSX1 fusion gene [3,9–11].
Surgical resection with a negative margin remains the standard initial treatment for SS; however, it is difficult to obtain negative surgical margins due to the poorly defined form of the tumor and its adherence to critical issues such as the extraocular muscles or optic nerve. Exenteration could be considered if the tumor is large or if tumor-free margins are difficult to identify. Postoperative radiotherapy is recommended for patients with positive margins to prevent tumor relapse or metastasis. Palmerini et al.  retrospectively studied radiotherapy and prognosis in 250 adult SS patients. They found that patients who received radiotherapy had a higher 5-year local control rate than those who received surgery alone (85% vs. 67%). The role of chemotherapy for SS is controversial. Several studies suggested that neoadjuvant/adjuvant chemotherapy does not significantly improve the survival of soft tissue sarcoma patients [13,14]; other studies suggested that chemotherapy is not recommended for low-risk SS but is recommended for high-risk patients . Among the 11 patients reported previously, 8 cases had no recurrences or metastasis with follow-up time ranging from 6 to 84 months, possibly due to negative surgical margin or incomplete resection with adjuvant therapy. In our cases, both patients underwent multiple operations with adjuvant chemoradiotherapy; however, they initially refused chemoradiation and eventually died of metastasis. Thus, only surgical resection is not enough, timely postoperative adjuvant therapy is essential for local control and distant metastasis. Some clinical trials focusing on immunotherapeutic strategies are underway, including SS18-SSX specific vaccine and genetically engineered lymphocytes treating patients with NY-ESO-1 positive tumors [16,17]. With the discovery of potential therapeutic targets, molecular-targeted drugs are increasing and have shown good efficacy, tyrosine kinase inhibitors such as Pazopanib and Apatinib are inhibiting VEGF1, VEGF2, VEGF3 and PDGFRα, PDGFRβ, c-Kit to inhibit tumor growth activity [18,19].
Orbital SS is extremely rare and easily misdiagnosed. The diagnosis should be made by combining histopathology, immunohistochemistry, and molecular genetics. SS18-SSX fusion gene testing is the golden standard of diagnosis, however, due to the current high cost, high equipment requirements and failure to detect SS18-SSX in a few SS cases, exploring more economical and effective methods for SS identification is still necessary. Patients with orbital SS need to be treated with free-marginal surgery combined with adjuvant radiotherapy or chemotherapy, the latter should be added for high-risk SS or metastasis SS. However, we also need further studies to explore new immunotherapy and gene therapy to improve the survival rate.
Acknowledgement: The authors thank the patients who agreed to be included in this study.
Author’s Contribution: YW: Conceptualization, methodology, data collection, writing original draft and review and editing, YJW: Investigation, review and editing, WMH: Surgery, conceptualization, supervision, review and editing.
Ethics Approval and Informed Consent Statement: Informed written consent has been obtained from the patients in this case report to publish this paper. The present study involved human participants, and it was conducted considering ethical responsibilities according to the World Medical Association and the Declaration of Helsinki.
Availability of Data and Materials: There is no additional data regarding this study and all available data and materials have been shared within the case report.
Funding Statement: The authors received no specific funding for this study.
Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present study.
- Speth, B. M., Krieg, A. H., Kaelin, A., Exner, G. U., & Guillou, L. (2011). Synovial sarcoma in patients under 20 years of age: A multicenter study with a minimum follow-up of 10 years. Journal of Children’s Orthopaedics, 5(5), 335-342. [Google Scholar] [CrossRef]
- Thway, K., & Fisher, C. (2014). Synovial sarcoma: Defining features and diagnostic evolution. Annals of Diagnostic Pathology, 18(6), 369-380. [Google Scholar] [CrossRef]
- Aytekin, M. N., Öztürk, R., Amer, K., & Yapar, A. (2020). Epidemiology, incidence, and survival of synovial sarcoma subtypes: SEER database analysis. Journal of Orthopaedics Surgery, 28(2), [Google Scholar] [CrossRef]
- Buono, L. M., Silberschmidt, A., Foroozan, R., & Savino, P. J. (2002). Metastatic synovial sarcoma to the skull base and orbit. American Journal of Ophthalmology, 134(5), 785-787. [Google Scholar] [CrossRef]
- Wladis, E. J., Farber, M. G., & Nepo, A. G. (2012). Metastatic synovial sarcoma to the orbit. Ophthalmic Plastic Reconstructive Surgery, 28(6), e131-e132. [Google Scholar] [CrossRef]
- Helman, L. J., & Meltzer, P. (2003). Mechanisms of sarcoma development. Nature Reviews Cancer, 3(9), 685-694. [Google Scholar] [CrossRef]
- Terry, J., Saito, T., Subramanian, S., Ruttan, C., & Antonescu, C. R. (2007). TLE1 as a diagnostic immunohistochemical marker for synovial sarcoma emerging from gene expression profiling studies. The American Journal of Surgical Pathology, 31(2), 240-246. [Google Scholar] [CrossRef]
- Garcia, C. B., Shaffer, C. M., Alfaro, M. P., Smith, A. L., & Sun, J. (2012). Reprogramming of mesenchymal stem cells by the synovial sarcoma-associated oncogene SYT-SSX2. Oncogene, 31(18), 2323-2334. [Google Scholar] [CrossRef]
- Stagner, A. M., Jakobiec, F. A., & Fay, A. (2017). Primary orbital synovial sarcoma: A clinicopathologic review with a differential diagnosis and discussion of molecular genetics. Survey of Ophthalmology, 62(2), 227-236. [Google Scholar] [CrossRef]
- Shukla, P. N., Pathy, S., Sen, S., Purohit, A., & Julka, P. K. (2003). Primary orbital calcified synovial sarcoma: A case report. Orbit, 22(4), 299-303. [Google Scholar] [CrossRef]
- Hartstein, M. E., Silver, F. L., Ludwig, O. J., & O’Connor, D. M. (2006). Primary synovial sarcoma. Ophthalmology, 113(11), 2093-2096. [Google Scholar] [CrossRef]
- Palmerini, E., Staals, E. L., Alberghini, M., Zanella, L., & Ferrari, C. (2009). Synovial sarcoma: Retrospective analysis of 250 patients treated at a single institution. Cancer, 115(13), 2988-2998. [Google Scholar] [CrossRef]
- Pervaiz, N., Colterjohn, N., Farrokhyar, F., Tozer, R., & Figueredo, A. (2008). A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer, 113(3), 573-581. [Google Scholar] [CrossRef]
- Woll, P. J., Reichardt, P., Le Cesne, A., Bonvalot, S., & Azzarelli, A. (2012). Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): A multicentre randomised controlled trial. The Lancet Oncology, 13(10), 1045-1054. [Google Scholar] [CrossRef]
- von Mehren, M., Randall, R. L., Benjamin, R. S., Boles, S., & Bui, M. M. (2018). Soft tissue sarcoma, version 2.2018, NCCN clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network, 16(5), 536-563. [Google Scholar]
- Robbins, P. F., Kassim, S. H., Tran, T. L., Crystal, J. S., & Morgan, R. A. (2015). A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: Long-term follow-up and correlates with response. Clinical Cancer Research, 21(5), 1019-1027. [Google Scholar] [CrossRef]
- Kawaguchi, S., Tsukahara, T., Ida, K., Kimura, S., & Murase, M. (2012). SYT-SSX breakpoint peptide vaccines in patients with synovial sarcoma: A study from the Japanese musculoskeletal oncology group. Cancer Science, 103(9), 1625-1630. [Google Scholar] [CrossRef]
- Miyamoto, S., Kakutani, S., Sato, Y., Hanashi, A., & Kinoshita, Y. (2018). Drug review: Pazopanib. Japanese Journal of Clinical Oncology, 48(6), 503-513. [Google Scholar] [CrossRef]
- Scott, L. J. (2018). Apatinib: A review in advanced gastric cancer and other advanced cancers. Drugs, 78(7), 747-758. [Google Scholar] [CrossRef]