What is soft tissue sarcoma?

Sarcoma is a rare cancer in adults (1% of all adult cancers), but rather prevalent in children (about 15% of all childhood cancers). It is made up of many “subtypes” because it can arise from a variety of tissue structures (nerves, muscles, joints, bone, fat, blood vessels – collectively referred to as the body’s “connective tissues”). Because these tissues are found everywhere on the body, Sarcomas can arise anywhere. Thus, within each site of the more “common” cancers there is the occasional surprise sarcoma diagnosis (e.g., breast sarcoma, stomach sarcoma, lung sarcoma, ovarian sarcoma, etc.). The most frequent location are the limbs since this is where the majority of the body’s connective tissue resides. They are commonly hidden deep in the body, so sarcoma is often diagnosed when it has already become too large to expect a hope of being cured. Although a lot of the lumps and bumps we get are benign, people should have them looked at by a doctor at an early stage in case it is sarcoma.

Sarcoma is sometimes curable by surgery (about 20% of the time), or by surgery with chemotherapy and/or radiation (another 50-55%), but about half the time they are totally resistant to all of these approaches—thus the extreme need for new therapeutic approaches. At any one time, more than 50,000 patients and their families are struggling with sarcoma. More than 17,000 new cases are diagnosed each year and nearly 7,000 people die each year from sarcoma in the United States.

How is Sarcoma Diagnosed?

The only reliable way to determine whether a tumor is benign or malignant is through a surgical biopsy. Therefore, all soft tissue and bone lumps that persist or grow should be biopsied. During this procedure, a doctor makes an incision or uses a special needle to remove a sample of tumor tissue. A pathologist examines the tissue under a microscope. If cancer is present, the pathologist can usually determine the type of cancer and its grade. The grade of the tumor is determined by how abnormal the cancer cells appear when examined under a microscope. The grade predicts the probable growth rate of the tumor and its tendency to spread. Low-grade sarcomas, although cancerous, are unlikely to metastasize. High-grade sarcomas are more likely to spread to other parts of the body.

Synovial Sarcoma

Synovial sarcoma most commonly affects adolescents and young adults in age 15-40. It originates from mesenchymal cells, but not from the synovium as the name implies. More than 90% of synovial sarcomas demonstrate t(X:18) translocation involving SYT and SSX genes, resulting in abnormal fusion (chimeric) protein (SYT-SSX). The fusion protein has altered function and represents the initiating molecular event leading to tumor formation. Synovial sarcoma can spread to other part of body mainly through blood circulation, sometimes through lymph node. Metastasis occurs in half of all cases, months to years after the initial diagnosis, or presents at the time of diagnosis.

Epidemiology

Synovial sarcoma is the fourth most commonly occurring sarcoma, accounting for 8-10 % of all sarcoma. The incidence is estimated to be 900 new cases a year in US. There is 2-4 fold predilection of development of synovial sarcoma for males over females. People with Li-Fraumeni syndrome (loss of p53 gene function) and neurofibromatosis (altered function of NF1 gene) are associated with higher risk. The poor prognostic factors include (1) distant metastasis, (2) age older than 25 years, (3) tumor size of greater than 5 cm, (4) poorly differentiated area seen in histology.

Clinical Features

Synovial sarcoma most commonly presents in lower extremities, but can also present in upper extremities and represents one of the three most common sarcomas in upper extremities. It can present in trunk, head & neck, infrequently in lungs. Synovial sarcoma usually presents with a mass, often deep-seated, rapidly growing with or without pain. Other presentations depend on the specific anatomical location(s), i.e. pneumothorax (punctured lung) or hemoptysis (coughing blood) or cough due to lung metastasis, bone pain or pathological fracture due to bone metastasis, G.I. symptoms due to metastasis to liver, abdomen or pelvis. The 5-, 10-, and 20-year overall survival rates for the non-metastatic adult group are approximately 66%, 48%, and 38%. The Pediatric multi-center study show the estimated 5-year overall survival and event-free survival rates for the entire group were 80% and 72%, respectively.

Treatment and Follow-up for Localized Disease

For tumor size of 5 cm or less, limb-saving surgical resection with generous margin with or without radiation therapy is recommended. For tumor greater than 5 cm, multi-disciplinary approach using pre-operative (neoadjuvant) chemotherapy, plus pre-operative radiation treatment, followed by surgery is recommended, although the role of chemotherapy continues to be debated.

Treatment and Follow-up for Metastatic Disease

Multi-disciplinary approach utilizing chemotherapy, radiation treatment and limb-sparing surgery is recommended. The goals are to control disease as well as preserve quality of life.

Targeted Therapies

Currently, there is no targeted therapy yet. More than 90% of synovial sarcoma show specific translocation t(X:18) involving SYT and SSX genes. SYT and SSX and the abnormal fusion (chimeric) protein (SYT-SSX) represent tumor-specific abnormal molecules and are ideal targets for drug therapy and vaccine/immunotherapy.

Sarcoma Treatments

Treatment for Soft Tissue Sarcoma

While the conventional approaches to managing most sarcomas, such as surgery, chemotherapy, and radiotherapy, have remained in use for an extended period.

Nonetheless, the 21st century has ushered in a new era of understanding through advanced research methodologies, revealing numerous genetic targets specific to sarcomas. In response, scientists are diligently crafting inhibitor drugs and pioneering immunotherapies tailored to combat these targets. While there is still room for enhanced treatments across the spectrum of sarcomas, it's heartening to witness the burgeoning array of newly approved agents. A concise chronological account of FDA approvals is presented below:

2001 - the first targeted treatment for sarcoma was approved by the FDA. Imatinib mesylate (Gleevec®) is an inhibitor of the KIT gene, which is present in most gastrointestinal stromal tumors (GIST), a type of sarcoma. This treatment showed that it was possible to treat sarcomas by targeting specific genes that are mutated or over-expressed in tumor cells as compared to normal cells.
2006 - Sunitinib malate (Sutent®) for GIST
2012 - Pazopanib (Votrient®) for certain soft-tissue sarcomas
2013 - Regorafenib (Stivargo®) for GIST
2013 - Denosumab (Xgeva®) for giant cell tumor of bone (similar to sarcoma)
2015 - Eribulin mesylate (Halaven®) for liposarcoma
2015 - Trabectedin (Yondelis®) for liposarcoma and leiomyosarcoma
2018 – Larotrectinib (Vitrakvi®) for infantile fibrosarcoma and other sarcomas with NTRK fusions
2019 – Pexidartinib hydrochloride (Turalio®) for tenosynovial giant cell tumor (TGCT)
2020 - Tazemetostat hydrobromide (Tazverik®) for epithelioid sarcoma
2020 - Avapritinib (Ayvakit®) for GIST
2020 - Ripretinib (Qinlock®) for GIST
2021- Nab-sirolimus (Fyarro®) for perivascular epithelioid cell tumor (PEComa)
2022 – Atezolizumab (Tecentriq®) for alveolar soft part sarcoma (ASPS)

Note that the drugs above might also be useful for other sarcoma sub-types with specific gene characteristics. In addition, certain treatments approved for other cancers, such as pembrolizumab (Keytruda®), have also proven effective for some sarcomas.

What is soft tissue sarcoma?

How is Sarcoma Diagnosed?

Synovial Sarcoma

Sarcoma Treatments

Treatment for Soft Tissue Sarcoma

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