Synovial sarcoma

Summarize

1. General

OVERVIEW: Synovial sarcoma (SS) is a common soft-tissue sarcoma in adolescents and young adults, usually occurring around joints. The t(X;18)(p11.2;q11.2) chromosome translocation and the resulting SYT-SSX fusion gene are present in almost all synovial sarcomas. Synovial sarcoma does not run in families.
Presentation: It is most common in the extremities and trunk, especially near the joints, and initially presents as a slow-growing, unexplained, painless mass that may cause pain or interfere with function as it progresses.
Treatment: The preferred treatment option for synovial sarcoma is surgical resection, which is often combined with chemotherapy and radiation therapy.
Prognosis: Generally, synovial sarcoma has a five-year survival rate of 50-60% and a ten-year survival rate of 40-50%.

Definition of Disease

Synovial sarcoma is a malignant tumor that is a soft-tissue sarcoma and usually occurs around the joints of the limbs and trunk. Synovial sarcoma is not a familial disease, and the t(X;18)(p11.2;q11.2) chromosomal translocation, and the resulting SYT-SSX fusion gene, is present in almost all synovial sarcomas.

Epidemiological

epidemiological

According to U.S. statistics, synovial sarcoma affects approximately 1.55 people per million, and accounts for 9% of soft tissue sarcomas in patients under 20 years of age with an incidence rate of approximately 0.7 per million. More than 90% of synovial sarcoma cases occur in the extremities, and about half of the cases develop distant metastases, most often to the lungs.
Synovial sarcoma can occur in all age groups, most often in adolescents and young adults between the ages of 15 and 29, and more often in males than females, with a male to female ratio of 1.2:1.

Etiolog & Risk factors

1. General

Synovial sarcoma has no apparent environmental trigger and is primarily caused by translocations of the X chromosome and chromosome 18.

2. Underlying causes

More than 90% of patients with synovial sarcoma have a translocation between the X chromosome and chromosome 18 t(X;18)(p11.2;q11.2). In simple terms, two segments on these two chromosomes exchange places: the SYT gene on chromosome 18 is fused to SSX1, SSX2, or SSX4 on the X chromosome, resulting in the creation of a new mutant gene called the SYT-SSX fusion gene. It has been shown that the class of the fusion gene (SYT-SSX1 or SYT-SSX2) has an impact on the tissue typing and prognosis of the disease. In particular, the five-year metastasis-free survival rate of patients harboring SYT-SSX2 mutations is significantly higher than that of patients harboring SYT-SSX1.
The vast majority of synovial sarcomas are incidental and do not run in families.

predisposing factor

There are no clear triggers for this disease.

Classification & Stage

Type of disease

(1) Disease typing
Synovial sarcomas can be divided into three distinct histologic subtypes based on the type of cells in the tumor sample:
● Monophasic: only one characteristic cell, usually a spindle cell.
● Biphasic: two characteristic cell types can be recognized, spindle cells and epithelial cells, and is the most common type of synovial sarcoma.
● De-differentiated type: on the basis of the morphology of the monophasic or biphasic type, some areas of undifferentiated pleomorphic or small rounded cell components are visible microscopically, and nuclear schizophrenic phases are common.
(2) Disease classification
● Grading of synovial sarcoma in children and adolescents (under 18 years of age)
The U.S. Children's Cancer Collaborative Group (COG) classifies non-rhabdomyosarcoma soft tissue sarcomas (including synovial sarcomas) in children and adolescents into 3 different grades based on histologic subtypes, extent of necrosis of the tumor tissue, the number of nuclear divisions, and tumor pleomorphism. Of these, all synovial sarcomas are grade 3.
● Grades of synovial sarcoma in adults
Adult synovial sarcomas can be graded according to the French National Confederation of Cancer Centers (FNCLCC) Histologic and Pathologic Grading System, a scoring-based grading system that scores tumors according to differentiation, mitosis, and the degree of necrosis of the tumor cells and divides them into 3 grades based on the total score.
Due to the characteristic tumor differentiation of synovial sarcoma, its grading is at least 2 levels.
(3) Disease staging
● Staging synovial sarcoma in children and adolescents (under 18 years of age)
● Synovial sarcoma in children and adolescents is staged according to the TNM staging system before treatment:
Stage I: no local lymph node metastasis, no distant metastasis, and pathological grading of 1 or 2.
Stage II: superficial tumor or deep tumor with maximum tumor diameter ≤5 cm, no local lymph node metastasis, no distant metastasis, and pathological grading of grade 3.
Stage III: deep tumors with maximum tumor diameter >5 cm, no local lymph node metastasis, no distant metastasis, and pathological grading of grade 3.
Stage IV: Regardless of the size of the primary tumor and regardless of the pathological grading, once local lymph node metastasis or distant metastasis occurs, it belongs to stage IV.
Since all synovial sarcomas in children and adolescents have a pathologic grade of 3, they are all staged as stage II or above.
● Postoperative pathologic staging of synovial sarcoma in children and adolescents:
Stage I: Limited lesion with complete resection of the tumor and pathology confirms complete resection;
Or tumor confined to the primary muscle or primary organ;
or the tumor invades into adjacent tissues other than the primary muscle or organ, such as through the fascial layer.
Stage II: complete resection of the tumor as seen by the naked eye, and the tumor has local infiltration or regional lymph node metastasis;
Or the tumor is completely resected as seen by the naked eye, but there is residue under the microscope, and there is no metastasis in the regional lymph nodes;
or complete resection of the tumor as seen by the naked eye, with no residue under the microscope, but with regional lymph node metastasis;
or complete resection of the tumor as far as the naked eye can see, with microscopic residue and regional lymph node metastasis.
Stage III: Tumor not completely resected or biopsy sampling only, with residual tumor to the naked eye with biopsy sampling only;
Or most of the tumor is excised as seen by the naked eye, but there is obvious residual tumor by the naked eye.
Stage IV: Distant metastasis is present at the beginning of the disease;
or presence of lung, liver, bone, bone marrow, brain, distant muscle or lymph node metastases;
Or the presence of positive cerebrospinal fluid cytology, pleural or peritoneal effusion, and implantation of tumor foci in the pleura or peritoneum.
● Staging synovial sarcoma in adults (18 years of age or older)
The American Joint Committee on Cancer (AJCC) has established a TNM staging system for all adult soft tissue sarcomas, including synovial sarcoma, based on the size of the primary tumor, invasion of adjacent lymph nodes, presence of distant metastases, and pathologic grading. The specific staging is as follows:
Stage ⅠA: superficial or deep tumor, maximum diameter of tumor ≤5 cm, no local lymph node metastasis, no distant metastasis, pathological grading cannot be evaluated or pathological grading is grade 1.
Stage IB: superficial or deep tumor, tumor maximum diameter >5 cm, no local lymph node metastasis, no distant metastasis, pathological grading cannot be evaluated or pathological grading is grade 1.
Stage IIA: superficial or deep tumor, tumor maximum diameter ≤5 cm, no local lymph node metastasis, no distant metastasis, pathological grading cannot be evaluated or pathological grading is grade 2 or 3.
Stage IIB: superficial or deep tumor, tumor maximum diameter >5 cm, no local lymph node metastasis, no distant metastasis, pathological grading cannot be evaluated or pathological grading is grade 2.
Stage III: superficial or deep tumors with maximum tumor diameter >5 cm, no local lymph node metastasis, no distant metastasis, pathological grading cannot be evaluated or pathological grading is grade 3; in addition, any tumor with local lymph node metastasis but no distant metastasis is classified as Stage III, regardless of the size of the primary tumor and pathological grading.
Stage IV: Regardless of the size of the primary tumor and pathological grading, once distant metastasis occurs, it is classified as stage IV.
Since the pathological grading of synovial sarcoma is at least grade 2, it is staged as stage IIA or above.
(4) Disease risk grouping
Synovial sarcoma in children and adolescents (under 18 years of age) is categorized into low-risk, intermediate-risk, and high-risk groups based on risk:
● Low-risk group: tumors without distant metastasis, completely resectable, with tumor pathological grade 1 or 2, or with tumor pathological grade 3 but maximum diameter ≤ 5 cm.
● Intermediate-risk group: tumors without distant metastases that can be completely resected, with a pathological grade of 3 and a maximum diameter of >5 cm; or tumors without distant metastases that cannot be completely resected.
● High-risk group: all tumors with distant metastases.
No risk grouping is performed for synovial sarcoma in adults (18 years of age or older).

Clinical manifestations

1. General

Synovial sarcoma is usually a painless mass in its early stages and is more difficult to detect; its symptoms depend on the size and location of the tumor. Sometimes, the symptoms are similar to arthritis, bursitis or synovitis. However, when it develops, the mass often interferes with body functions. For example, the mass appears in the head and neck, thus affecting swallowing and breathing or altering vocalizations. Also, the lump may affect the nerves, resulting in pain.

2. Typical symptoms

Synovial sarcoma most commonly occurs in the extremities and trunk, with a few cases occurring in the head and neck, retroperitoneal cavity and mediastinum, lungs and pleura, kidneys, heart, and stomach. In its early stages, synovial sarcoma usually presents as a painless, slow-growing mass and is therefore easily overlooked. Common symptoms are:
● Swelling or lumps (usually located deep within) The most common site is the thigh near the knee, but synovial sarcoma can occur near other joints as well, mainly in the arms and legs, and rarely within a joint.
● Lumps may or may not be accompanied by pain .
● Claudication or difficulty using the leg, arm, hand, or foot.

Clinical Department

1. General

Common tests for synovial sarcoma include: history interview, physical examination, biochemical tests, imaging, cytopathology, immunohistochemistry, and molecular genetics.

2. Departments attended

Pediatrics (pediatric patients), Oncology, Orthopedics, Bone Oncology

Examination & Diagnosis

1. Relevant inspections

(1) Laboratory Tests
Blood routine, liver function (alanine aminotransferase, direct bilirubin, Hepatitis B antibody, Hepatitis C antibody), pre-transfusion STD screening (syphilis, HIV), renal function (urea nitrogen, creatinine, uric acid), electrolyte and blood amylase measurement, lactate dehydrogenase, coagulation function.
(2) Imaging tests
● Ultrasound: Because ultrasound is convenient and easy to perform, it is often used as a preliminary examination to determine the nature of the mass (cystic or solid), to understand the blood flow that provides the mass, and to check whether there is regional lymph node metastasis. It can also be used to guide puncture biopsy, which takes less time and is as accurate as CT guidance.
● CT: The localization effect and qualitative diagnostic ability of CT are more ideal. Enhanced CT can clearly show the size of the mass, its boundaries and its relationship with adjacent tissues in the surrounding area.CT is not as good as MRI in resolving soft tissues, but it is better than MRI in displaying fine calcification, ossification and bone destruction, and can show whether there is any bone destruction in the bone near the tumor and the destruction situation. Chest CT is the imaging test of choice for early detection of lung metastasis and pleural effusion. Meanwhile, CT can be used to guide puncture biopsy, which is characterized by less damage, low cost and high accuracy.
● Magnetic resonance imaging (MRI): MRI has a better resolution of soft tissues than CT and can accurately show the location of the lesion and its relationship with the surrounding structures from a variety of different angles and directions. It can also be used to clarify the blood supply of the lesion and its relationship with the neighboring blood vessels and nerves through enhancement scanning or magnetic resonance angiography. At the same time, MRI can help determine the pathological nature of the mass. Therefore, MRI is currently the imaging method of choice for tumors of the extremities and trunk, spine and other parts of the body, and is one of the important bases for developing surgical plans. Meanwhile, MRI can also be used to guide puncture biopsy, which is more accurate than ultrasound or CT in its localization, and can avoid puncturing into necrotic, cystic degeneration and hemorrhagic areas, thus improving the success rate of biopsy, but the cost is relatively high.
● X-ray: Calcification can be observed in synovial sarcoma under X-ray, which can be used to assist in diagnosis. Also, X-rays clearly show changes in the bone adjacent to the tumor and can help show the relationship of the soft tissue mass to adjacent bone and joints, which can be used to rule out bone tumors and to assess the risk of pathological fracture in cases of bone invasion.
● Positron Emission Computed Tomography (PET-CT): PET-CT can show the exact location of the tumor and its metabolic status, and can be used to evaluate the patient's general condition. However, it is also inferior to CT and MRI in terms of local details. It is not recommended as a routine pre-surgical examination, and is mainly used to determine postoperative residual tumor, recurrence and distant metastasis, and can help to find the primary lesion of metastatic tumor.
● Whole-body bone radionuclide imaging (commonly known as bone scanning): it is the preferred method for early detection of tumor bone metastasis, but it has a high false-positive rate and cannot be used as a basis for diagnosis, and can be used for disease staging, prognosis judgment and observation of therapeutic effect.
(3) Histopathological examination
Pathologic tissue specimens are usually obtained by puncture biopsy or biopsy.
Basic histopathologic examination mainly includes histomorphology, immunocytochemistry, light and electron microscopy, cytogenetics, molecular biology examination and so on.
Almost all synovial sarcomas have a characteristic t(X;18)(p11.2;q11.2) chromosomal translocation and a resulting SYT-SSX1 or SYT-SSX2 fusion gene, and therefore the diagnosis of synovial sarcoma can be confirmed if the associated chromosomal abnormality or fusion gene is detected.

2. Differential diagnosis

In adolescents or children, pain associated with bones and joints is often mistaken for "growing pains," but growing pains tend to be bilateral and symmetrical. In patients with synovial sarcoma, the pain progresses to a palpable soft tissue mass.
Also, synovial sarcoma has a similar histologic pattern to certain other tumors, making case diagnosis difficult. Currently, pathomorphologic evaluation is the gold standard for synovial sarcoma diagnosis. Also molecular genetics (SYT-SSX fusion gene) and immunohistochemical tests play an important role.

Clinical Management

1. General

Overall, the treatment options for synovial sarcoma need to be determined by the extent and location of the disease, the patient's tolerance for treatment, and the prognosis for the disease. The preferred treatment option for primary synovial sarcoma is surgical resection.

2. Surgery

Surgery involves a biopsy and surgical removal of the entire tumor, adjacent muscles and lymph nodes. Depending on the location and size of the tumor, all or part of the limb may need to be removed. The principle of surgical resection is to ensure a complete removal of the tumor based on a safe surgical border (1 cm outside the tumor margin or reaction zone) while preserving as many organs and limbs as possible. If ensuring a safe surgical border conflicts with limb preservation, limb function is usually sacrificed.
If the tumor is growing on an extremity, interstitial resection, wide resection, or amputation may be performed depending on the specific condition. Interstitial resection and wide resection are usually recommended in preference to interstitial resection because of their potential to preserve all or part of the function of the limb. In general, interstitial resection or wide resection requires that the patient has no involvement of vital vascular nerve bundles, that soft tissue coverage is intact, and that preservation of limb function is expected to be superior to that of a prosthesis. Following surgery, it may take up to a year for the patient to regain full use of the limb.
Amputation may be considered if the patient requires amputation, or if the patient has significant vascular or nerve bundle involvement, or lacks bone or soft tissue reconstruction after limb preservation, or if prosthetic function is expected to be superior to limb preservation. The advantages of amputation are the relative simplicity of the procedure, the low chance of surgical complications, and the thoroughness of local tumor resection.
If the tumor is large (maximum diameter >5 cm), deep, or invades the surrounding tissues, nerves, or large blood vessels, and resection is more difficult, or if complete resection is expected to be difficult, neoadjuvant chemotherapy can be administered first, and surgery can be performed after the tumor has shrunk.

3. Radiation therapy

Surgical resection + adjuvant radiation therapy (radiotherapy) is currently the standard treatment modality for surgically resectable synovial sarcoma. If the tumor is large (maximum diameter > 5 cm), deep, or invades surrounding tissues, nerves, or large blood vessels, and resection is more difficult, or if complete resection is expected to be difficult, preoperative radiotherapy may be performed to shrink the tumor.
If the tumor is not completely removed at the time of surgery, or if the tumor is large at the time of removal (maximum diameter > 5 cm), postoperative adjuvant radiotherapy is required to generally kill residual tumor cells.

4. Chemotherapy

Synovial sarcoma is more sensitive to chemotherapy (chemo) and therefore chemotherapy is an important adjuvant treatment. It can be divided into neoadjuvant chemotherapy, adjuvant chemotherapy and palliative chemotherapy.
(1) Neoadjuvant chemotherapy
Neoadjuvant chemotherapy can be considered before surgery to help shrink the tumor in these cases below:
● The tumor is large (maximum diameter > 5 cm) and deeper
● Invasion of surrounding tissues, nerves or large blood vessels, making resection more difficult
● Difficulty of complete resection is anticipated
Local recurrence requiring a second resection
Distant metastases before palliative surgery
Neoadjuvant chemotherapy may be given in conjunction with preoperative adjuvant radiotherapy. Neoadjuvant chemotherapy for synovial sarcoma in children and adolescents is currently not standardized, with VAC (cyclophosphamide + vincristine + actinomycin D) regimen, VDC (vincristine + adriamycin + cyclophosphamide) regimen, and IE (isocyclophosphamide + etoposide) regimen recommended. Preoperative neoadjuvant chemotherapy in adults is usually recommended as adriamycin (ADM) ± isocyclophosphamide (IFO), or the MAID regimen (mesylate + adriamycin + isocyclophosphamide + dacarbazine).
For preoperative neoadjuvant chemotherapy for extremity tumors, isolated limb heat-perfusion chemotherapy may be considered; however, the ability of isolated limb heat-perfusion chemotherapy to provide a survival benefit is inconclusive and is not recommended for routine use. If the patient's physical condition permits, isolated limb perfusion chemotherapy can also be used in conjunction with or in sequence with radiotherapy and intravenous chemotherapy. Isolated limb heat infusion chemotherapy not only can make the tumor local get higher drug concentration, but also can use the local thermal effect (38-39 ℃) to further kill the tumor cells, improve the rate of extensive resection of the tumor, and increase the chances of limb-saving treatment.
(2) Adjuvant chemotherapy
Adjuvant chemotherapy refers to the use of chemotherapeutic drugs after surgical resection of the tumor to eliminate the remaining tiny metastatic foci as much as possible, to reduce the chance of tumor recurrence and metastasis, and to improve the cure rate.
For children and adolescents, if the tumor is small (≤5 cm) and there is no residue on the margins after total resection, no subsequent chemotherapy is needed, but deep tumors over 5 cm require at least 6 cycles of adjuvant chemotherapy. Currently, there is no consensus on the postoperative adjuvant chemotherapy regimen for synovial sarcoma in children and adolescents, and the VAC (cyclophosphamide + vincristine + actinomycin D) regimen, VDC (vincristine + adriamycin + cyclophosphamide) regimen, and IE (isocyclophosphamide + etoposide) regimen are recommended.
For adult synovial sarcoma, postoperative radiotherapy combined with adjuvant chemotherapy may be considered. Postoperative adjuvant chemotherapy is strongly recommended if the patient has the following conditions:
● The tumor is deep, with a maximum diameter of >5 cm
● The tumor is not completely resected
● Local recurrence with secondary resection
Adjuvant chemotherapy for synovial sarcoma in adults is usually recommended as the ADM±IFO regimen, with 6 cycles of chemotherapy suggested.
(3) Palliative chemotherapy
For unresectable locally advanced or metastatic synovial sarcoma, aggressive and effective chemotherapy is beneficial to alleviate symptoms, prolong survival and improve quality of life.
Re-chemotherapy is not recommended if the patient has failed multiple lines of chemotherapy, has demonstrated difficulty in benefiting from chemotherapy, and has an Eastern Cooperative Oncology Group Performance Statu(ECOG-PS) score >1.

5. Cutting-edge therapies

Targeted Therapies
In recent years, there have been other clinical trials attempting to use Olaratumab for first-line treatment of synovial sarcoma, or Pazopanib and Trabectedin for second-line treatment, but they were all ineffective, with patient response rates of less than 18%.
Anti-VEGFR targeted drugs are effective in advanced synovial sarcoma and are an option to consider.
(2) Immunotherapy
Immunotherapies such as PD-1 and CTLA4 are less effective in synovial sarcoma.
Up to 76% of synovial sarcomas express NY-ESO-1 protein, and TCR-T cell immunotherapy targeting the related gene is currently undergoing clinical trials. Some synovial sarcomas with advanced lung metastases have a significant reduction in the volume of lung tumors after treatment, which is therefore considered the most promising method for a breakthrough. A number of manufacturers are currently developing this therapy.

6. Treatment of subdivided carcinomas

1. Tumors of adipose tissue - liposarcoma

Treatment for liposarcoma may include the following:

:: Surgery to completely remove the tumor. If the cancer is not completely removed, a second surgery may be needed;

● Chemotherapy to shrink the tumor, followed by surgery;

:: Radiation therapy before and after surgery;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

2. Bone tumors - extraosseous mesenchymal chondrosarcoma

Treatment of extraosseous mesenchymal chondrosarcoma may include the following:

:: Surgery to completely remove the tumor. Radiation therapy may be given before and/or after surgery;

:: Chemotherapy followed by surgery. Surgery followed by chemotherapy with/without radiation therapy;

● Clinical trials such as targeted therapy clinical trials, radiotherapy clinical trials, or clinical trials of surgery with or without radiotherapy.

3. Bone tumors - extraosseous osteosarcoma

Treatment of extraskeletal osteosarcoma may include the following:

● Surgery to completely remove the tumor, followed by chemotherapy;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

4. Tumors of fibrous (connective) tissue - sclerofibromas

Treatment for sclerofibromas may include the following:

4.1 Surgery to completely remove the tumor, pre-surgical treatment may include the following:

:: Observation

:: Chemotherapy

:: Radiotherapy

:: Anti-estrogen medication

:: Non-steroidal anti-inflammatory drug (NSAID) therapy

4.2 If the tumor is not completely removed by surgery, the following treatments may be considered:

:: Observation, if no other treatment options are available

● Radiation therapy or chemotherapy, if the tumor cannot be removed by surgery

:: Clinical trials consisting of targeted therapy, radiotherapy and surgery with/without radiotherapy participation

4.3 For the treatment of recurrent sclerofibromatous fibromatosis, the following options may be considered:

:: Observe and consider surgery after a period of time

:: Chemotherapy

5. Fibrous (connective) tissue tumors - rhabdomyosarcomas

Treatment of rhabdomyosarcoma may include the following:

:: Surgery to remove the tumor as completely as possible. Surgery may include Mohs surgery;

:: Radiation therapy before and after surgery;

● Radiation therapy and targeted therapy (imatinib) if the tumor cannot be removed or recurrence occurs;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

6. Fibrosarcoma - Infantile fibrosarcoma

Treatment for infantile fibrosarcoma may include the following:

:: Surgical removal of the tumor, if possible, followed by observation;

● Chemotherapy after surgery;

● Chemotherapy to shrink the tumor, followed by surgery;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation;

● Clinical trials of targeted therapies (tyrosine kinase inhibitors).

7. Fibrosarcoma - adult-type fibrosarcoma

Treatment for adult-type fibrosarcoma may include the following:

● Surgery to remove the tumor as completely as possible.

8. Fibrosarcoma - Inflammatory myofibroblastoma

Treatment for inflammatory myofibroblastoma may include the following:

● Surgery to remove the tumor as completely as possible;

● Chemotherapy;

● Steroid therapy;

● Non-steroidal anti-inflammatory drug (NSAID) therapy;

● Targeted therapy (ALK inhibitors);

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

9. Fibrosarcoma - low-grade fibromucinous sarcoma

Treatment of low-grade fibromucinous sarcoma may include:

:: Surgery to completely remove the tumor;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

10. Fibrosarcoma - Mucinous fibrosarcoma

Treatment for mucinous fibrosarcoma may include the following:

:: Surgery to completely remove the tumor;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

11. Fibrosarcoma - sclerosing epithelioid fibrosarcoma

Treatment for sclerosing epithelioid fibrosarcoma may include the following:

:: Surgery to completely remove the tumor;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

12. Skeletal muscle tumors - rhabdomyosarcoma

See Children Rhabdomyosarcoma in the Treatment section.

13. Smooth muscle tumors - smooth muscle sarcomas

Treatment of smooth muscle sarcoma may include the following:

● Chemotherapy;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

14. Fibrous histiocytoma - plexiform fibrous histiocytoma

Treatment of tufted fibrous histiocyte tumors may include the following:

:: Surgery to completely remove the tumor;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

15. Peripheral nervous system tumors - ectodermal macrophage tumors

Treatment of ectodermal macrophage tumors may include the following:

:: Surgery and chemotherapy;

:: Radiation therapy.

16. Peripheral nervous system tumors - malignant peripheral nerve sheath tumors

Treatment of malignant peripheral nerve sheath tumors may include the following:

● Surgery to remove the tumor as completely as possible;

:: Pre/post-surgical radiation therapy;

:: Chemotherapy for tumors that cannot be removed by surgery;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation;

:: Clinical trials of targeted therapies (histone methyltransferase inhibitors) for tumors that cannot be removed by surgery;

:: Clinical trials of antibody-drug couplings.

It is unclear whether radiation therapy or chemotherapy after surgery improves tumor outcomes.

17. Peripheral nervous system tumors - malignant salamander tumors

Malignant salamander tumors may be considered for the same treatment options as rhabdomyosarcoma, including surgery, chemotherapy, or radiation. Targeted therapy, radiation therapy, and surgical treatment options with/without chemotherapy involvement are under investigation.

18. Peripheral (perivascular) tumors - Infantile angioepithelioma

Treatment of vascular ectodermal cell tumors in infants may include the following:

● Chemotherapy.

19. Peripheral (perivascular) tumors - infantile myofibromatosis

Treatment for infantile myofibromatosis may include the following:

● Combination chemotherapy.

20. Tumor of unknown origin (location of first tumor formation unknown) - Adenovascular soft tissue sarcoma

Treatment of alveolar soft tissue sarcoma may include the following:

● Surgery to remove the tumor as completely as possible;

● Pre/post-surgical radiation therapy if the tumor cannot be completely removed by surgery;

● Targeted therapy (angiogenesis inhibitors);

● Clinical trials of targeted therapies (angiogenesis inhibitors) for children;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

21. Tumors of unknown origin (location of first tumor formation unknown) - Clear cell sarcoma of soft tissue

Treatment of clear cell sarcoma of soft tissue may include the following:

:: Surgical removal of tumors when possible;

:: Pre/post-surgical radiation therapy;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

22. Tumor of unknown origin (location of first tumor formation unknown) - proliferative small round cell tumor

There is no standard treatment for pro-connective proliferative small round cell tumors. Treatment may include the following:

● Surgery to remove the tumor as completely as possible;

● Chemotherapy followed by surgery;

● Chemotherapy and targeted therapy (mTOR inhibitors);

:: Radiation therapy.

23. Tumor of unknown origin (location of first tumor formation unknown) - Epithelioid sarcoma

Treatment of epithelioid sarcoma may include the following:

:: Surgical removal of tumors when possible;

:: Pre/post-surgical chemotherapy;

:: Pre/post-surgical radiation therapy;

:: Clinical trials of targeted therapies (histone methyltransferase inhibitors).

24. Tumor of unknown origin (location of first tumor formation unknown) - Extra-renal malignant rhabdomyosarcoma

Treatment of extrarenal malignant rhabdomyosarcoma may include the following:

:: Hybrid therapy, including surgical removal of the tumor if possible, chemotherapy and radiotherapy treatment;

:: Clinical trials of targeted therapies (histone methyltransferase inhibitors).

25. Tumor of unknown origin (location of first tumor formation unknown) - Extraosseous mucinous chondrosarcoma

Treatment of extraskeletal mucinous chondrosarcoma may include the following:

:: Surgical removal of tumors when possible;

:: Radiation therapy;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation;

:: Clinical trials of targeted therapies (histone methyltransferase inhibitors).

26. Tumors of unknown origin (location of first tumor formation unknown) - Perivascular epithelioid cell tumor (PEComa)

Treatment of perivascular epithelioid cell tumors may include the following:

:: Surgical removal of the tumor;

:: Observation followed by surgery;

● Targeted therapy (mTOR inhibitors) for tumors that produce specific genetic changes and cannot be removed by surgery;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

27. Tumors of unknown origin (location of first tumor formation unknown) - Primitive Neuroectodermal Tumor (PNET)

See summary on Ewing's sarcoma treatment.

28. Tumor of unknown origin (location of first tumor formation unknown) - synovial sarcoma

Synovium Treatment may include the following:

● Surgery. Radiation therapy and/or chemotherapy may be given before or after surgery;

● Chemotherapy;

● Clinical trials of gene therapy;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation;

:: Clinical trials of targeted therapies (histone methyltransferase inhibitors);

:: Clinical trials of antibody-drug couplings.

29. Tumor of unknown origin (location of first tumor formation unknown) - Undifferentiated/unclassified sarcoma

These tumors include undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (high grade stage). There is no standard treatment for these tumors. Treatment may include the following:

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

30. Vascular tumors - soft tissue angiosarcoma

Treatment of hemangiosarcoma may include the following:

:: Surgery to completely remove the tumor;

:: Combination of surgery, chemotherapy and radiation for hemangiosarcoma that has spread;

● Targeted therapy (bevacizumab) and chemotherapy for hemangiosarcoma starting in infancy;

● Clinical trials consisting of targeted therapy, radiation therapy, and surgery with/without radiation therapy participation.

31. Vascular tumors - epithelioid hemangioendothelioma

Treatment of epithelioid hemangioendothelioma may include the following:

:: Surgical removal of tumors when possible;

● Immunotherapy (interferon) and targeted therapy (thalidomide, sorafenib, pazopanib, sirolimus) for tumors that may have spread;

● Chemotherapy;

● Total hepatectomy and liver transplantation when the tumor is in the liver;

● Clinical trials of targeted therapy (trametinib).

32. Metastatic childhood soft tissue sarcoma

Treatment for children with soft tissue sarcomas that are diagnosed and found to have spread to other parts of the body may include the following:

● Chemotherapy and radiation. Tumors that can have spread to the lungs may be considered for surgical removal;

● Stereotactic radiation therapy, for tumors that have spread to the lungs.

33. Vascular tumors - recurrent and progressive childhood soft tissue sarcomas

Treatment of recurrent or progressive childhood-onset soft tissue sarcomas may include the following:

:: Surgery to remove cancers that have recurred at the site of initial formation or have spread to the lungs;

● External or internal radiation therapy after surgery, if not already performed;

● Surgery to remove an arm or leg with a tumor, if radiation therapy has been given;

● Chemotherapy;

● Targeted therapy (pazopanib);

● A new chemotherapy clinical trial with/without targeted therapy (pazopanib) together;

● A type of clinical trial that examines specific gene changes in a sample of a patient's tumor. The type of targeted therapy that will be given to the patient depends on the type of gene change.

References:

https://www.cancer.gov/types/soft-tissue-sarcoma/patient/child-soft-tissue-treatment-pdq?from=singlemessage&isappinstalled=0

Prognosis

1. General

Overall, the five-year survival rate for synovial sarcoma is more than 50% and the ten-year survival rate is 40-50%. The prognosis of synovial sarcoma is mainly affected by the following factors:
● Tumor size: this is the most significant factor affecting the prognosis of the tumor. Larger tumors (maximum diameter >5 cm) at diagnosis are relatively more difficult to remove completely, are more likely to metastasize, and have a relatively poorer prognosis.
● Patient age: pediatric patients have a better prognosis than adults, and children under 10 years of age have a better prognosis.
● Primary site: Distal limb tumors have a better prognosis than proximal limb or trunk tumors.
● Histologic type: the undifferentiated/poorly differentiated type of synovial sarcoma has a less favorable prognosis than other types.
● Metastatic status: If the patient has already developed metastases at the time of diagnosis, the prognosis will be relatively unsatisfactory.
● Surgical status: The prognosis is better if the first surgical resection is able to remove the tumor completely and secure surgical boundaries are ensured.

2. Complications

(1) Cardiotoxicity
Anthracycline chemotherapeutic drugs have cardiotoxicity, which may lead to acute myocardial injury and chronic cardiac impairment. The former is transient and reversible local ischemia of the myocardium, which may be manifested as panic, shortness of breath, chest tightness and discomfort in the precordial region. The latter is irreversible congestive heart failure and is related to the cumulative dose of the drug. If cardiac function tests suggest abnormal cardiac function and are not due to infection, anthracyclines need to be suspended until cardiac function recovers. If myocardial injury occurs, drugs such as dexpropylenimine (Zinecard) may be selected for treatment according to the condition. If possible, cardiology consultation can be invited to assist the treatment.
(2) Elevated transaminases
Certain chemotherapeutic agents can cause transaminases to rise. If the simple aminotransferase markers (ALT/AST) are 10 times or more above the normal limit, chemotherapy may be delayed. If abnormalities persist after 1 week, chemotherapy may be given under close observation.
(3) Neurotoxicity
The chemotherapeutic drug vincristine is neurotoxic, and a single dose should not exceed 2 mg. Common mild neurotoxic side effects of vincristine can be manifested as jaw pain, constipation, weakened deep reflexes, and sometimes vocal disturbances. If obvious signs of toxicity such as persistent abdominal colic, unsteady gait, severe pain, and abnormal secretion of the antidiuretic hormone urokinetic hormone (SIADH) are present, the dosage should be reduced or switched to the less neurotoxic vincristine. If appendicitis develops, the drug should be discontinued and switched to vincristine after recovery. Vinpocetine and vinblastine have not been studied for efficacy, but the internationally recognized drug is vinpocetine. Therefore, if there are no obvious symptoms of toxicity, vincristine is recommended to be preferred.
(4) Pneumocystis carinii infection
Patients are at risk of Pneumocystis carinii infection, so long-term administration of cotrimoxazole (SMZco) is usually recommended for prevention.
(5) Anemia
If the patient develops anemia, it can usually be relieved by transfusion of red blood cells, which is mandatory for hematocrits below 60 g/L.
(6) Thrombocytopenia
Platelets should be transfused if the platelet count is less than 20×109 /L. If the child has obvious bleeding symptoms or infections, the transfusion indication can be relaxed appropriately.
(7) Neutropenia
If it is expected that the patient may suffer from neutrophil deficiency for a long time, granulocyte colony-stimulating factor (commonly known as leukocyte boosting injection) can be used.
(8) Long-term effects of radiotherapy
The use of radiotherapy and high-dose chemotherapeutic agents may result in long-term toxic side effects, especially in pediatric patients.
Cranial radiotherapy may cause functional deficits in the sensory nerves of children, which are manifested as decreased function in executive function, sustained attention, memory, processing rate, and visuomotor integration, and learning disabilities, lower IQ, and behavioral changes.
Systemic radiotherapy may affect the eyes, neck, and orbits and can cause visual impairment, cataracts, tear duct atrophy, dry eye, retinopathy, and glaucoma.
Radiotherapy and chemotherapy can also cause pulmonary fibrosis, interstitial pneumonia and other chronic severe lung lesions, and also increase the risk of secondary tumors.
Therefore, patients need to pay attention to review and follow-up. If relevant symptoms are observed, they should seek medical treatment promptly.

3. Recurrence

Synovial sarcomas have some potential for recurrence. Undifferentiated/poorly differentiated types of synovial sarcoma are more likely to experience recurrence than other types.
Surgical resection of locally recurrent synovial sarcoma, with or without distant metastases, may be considered for removal of the recurrent lesion and requires removal of the recurrent tumor along with the scar tissue, including the skin incision. Adjuvant radiotherapy is given before and after surgery.

Follow-up & Review

1. General

Complete treatment as prescribed and maintain good lifestyle habits. Regular follow-up should be done after finishing the treatment in order to detect recurrence and long-term effects.

2. Review and follow-up

(1) Follow-up for children and adolescents (under 18 years of age)
Year 1: Review every 3 months for physical examination, blood routine, blood biochemistry, chest X-ray and lesion imaging.
Year 2 to 3: every 4 to 6 months for physical examination, routine blood tests, blood biochemistry, chest X-ray and imaging of the lesion.
Year 4 to 5: review every 12 months, physical examination, blood routine, blood biochemistry, chest X-ray and lesion imaging.
Years 6 to 10: annual physical examination, blood routine, biochemistry.
After 10 years, the patient should be rechecked annually as much as possible, and the status of secondary tumors should be noted.
(2) Follow-up for adults (18 years old and above)
Year 1~3: review every 3~4 months.
Year 4 to 5: every 6 months.
After 5 years: annual review.
In addition to the routine questioning of relevant medical history and physical examination, appropriate imaging tests are selected according to the different parts of the body.

Routine

1. Management of daily life

(1) Rest and exercise
Patients need to be guaranteed a sleep schedule. Regular and quality sleep is helpful for physical recovery and immunity. A suitable sleeping environment (usually dimly lit, quiet and at a suitable temperature) may be helpful in improving the quality of sleep.
If the patient's physical condition permits, simple activities can be encouraged and assisted. Moderate exercise is helpful in preventing muscle atrophy, enhancing physical strength and endurance, and promoting appetite.
(2) Diet
It is recommended to provide patients with a nutritious and balanced diet, guaranteeing the intake of high-quality proteins (e.g. meat, eggs, milk, poultry, fish and shrimp, soybeans and soybean products, quinoa, etc.), as well as more grains and cereals, vegetables and fruits to ensure the intake of other nutrients. Patients with reduced immunity during treatment should avoid expired, spoiled, unclean and potentially food-safe foods. Specific dietary advice can be obtained from the dietitian at your hospital.

2. Special considerations

Keep all the consultation and treatment records of the patient for future review and medical consultation as reference.
If the tumor of a pediatric patient is located in the limbs, he/she should pay attention to the development of the limbs after treatment, and go to the orthopedic department in time if there are any developmental problems such as short and long legs.

3. Daily disease monitoring

Post-operative complications, chemotherapy-induced side effects (e.g., hair loss, fatigue, vomiting, etc.), recurrence of tumor metastasis, and growth and development problems should be noted in pediatric patients. Consult your doctor when fever, worsening symptoms, new symptoms, and treatment-induced side effects occur.

4. Prevention

There is no better way to prevent the development of synovial sarcoma, but regular follow-up and maintenance of good lifestyle habits can help prevent and detect early recurrence of the disease or the emergence of long-term effects.

Cutting-edge Therapeutic & Clinical Research

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References

1.The diagnosis and treatment standard of non-rhabdomyosarcoma soft tissue sarcoma in children and adolescents (2019 edition)
2. Chinese expert consensus on the diagnosis and treatment of soft tissue sarcoma (2015 edition)
3.2014 Expert Consensus on Clinical Diagnosis and Treatment of Soft Tissue Sarcoma of the Extremities
4.2014 Interpretation of Expert Consensus on Clinical Diagnosis and Treatment of Soft Tissue Sarcoma of the Limb
5. http://www.danafarberbostonchildrens.org/conditions/solid-tumors/synovial-sarcoma.aspx
6.Kawai A, Woodrliff J, Healey JH, et al. SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med 1998; 338: 153- 160.
7. https://rarediseases.info.nih.gov/diseases/7721/synovial-sarcoma
8. 2017 AJCC 8th Edition Distal Extremity Soft Tissue Sarcoma Classification System
9. https://path.upmc.edu/cases/case292/dx.html
10. https://www.cancer.gov/types/soft-tissue-sarcoma/hp/child-soft-tissue-treatment- pdq
11. http://surgpathcriteria.stanford.edu/softmisc/synovial_sarcoma/
12. Palmerini, E., Staals, E.L., Alberghini, M., Zanella, L., Ferrari C., Benassi, M.S., Picci, P., Mercuri, M., Bacci, G. and Ferrari, S. Synovial sarcoma. Cancer, 2009, 115: 2988-2998. doi:10.1002/cncr.24370

Audit specialists

Zhengdong Cai, Director, Department of Orthopedics, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
Personal introduction:
https://baike.baidu.com/item/%E8%94%A1%E9%83%91%E4%B8%9C