Abstract
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Synovial sarcoma is a rare and highly malignant soft tissue sarcoma. The inconspicuous and diversity of its early symptoms make it a highly misdiagnosed disease.
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The management of synovial sarcomas is challenging as they are rare and have a poor prognosis. Early and correct diagnosis and treatment are critical for clinical outcomes. Misdiagnosis or delayed diagnosis can have devastating consequences for the patient.
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The detection of SS18 gene rearrangement is considered a powerful tool in establishing the diagnosis of synovial sarcomas. Biopsies and testing for gene rearrangements are recommended for all patients in whom SS cannot be excluded.
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Surgery is the mainstay of treatment for synovial sarcomas. Neoadjuvant/adjuvant radiotherapy is recommended for patients with big tumors (>5 cm) or positive resection margins, and neoadjuvant/adjuvant chemotherapy is recommended for patients with high-risk tumors or advanced diseases.
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This article reviews synovial sarcomas from the perspectives of clinical and radiological presentation, histological and cytogenetic analysis, differential diagnosis, treatment, and prognosis.
Introduction
Synovial sarcoma (SS) is a relatively rare malignancy, accounting for 5–10% of all soft tissue sarcomas (STS) (1). All SSs are considered to be high-grade STS, characterized by local invasiveness and a propensity to metastasize, affecting pediatric, adolescent, and adult populations. The peak incidence is observed in the third decade of life. The inconspicuousness and diversity of early symptoms and the rarity of SSs pose a certain influence on patient presentation and clinical diagnosis. This makes the disease highly susceptible to delayed awareness and misdiagnosis. A study performed by Chotel et al. found that only half of SS patients had typical STS symptoms and the mean duration of symptoms before diagnosis was 98 weeks. Presenting a mean diagnosis delay caused by patients (from the time at which symptoms were first noted until the time when the patient first consulted a doctor) of 43 weeks and a mean diagnosis delay caused by doctors (from the first medical visit until an accurate diagnosis was established) of 50 weeks (2). More importantly, the delay did not improve significantly over the study’s 21-year period.
Cases of SS being misdiagnosed as other diseases are reported frequently (3, 4, 5, 6). SS is reportedly misdiagnosed most frequently as a benign lesion by magnetic resonance imaging (MRI) (7, 8). Studies by Chotel et al., Luczyńska et al., and Berquist et al. all suggest a misdiagnosis rate of up to 50% when SS is diagnosed based on an MRI (2, 7, 9). In another study by Choi et al. which included 90 patients with SS, it was reported that a sarcoma was not considered at initial diagnosis in 42% of the patients (10). Furthermore, the common misdiagnoses due to nonspecific imaging features differed according to tumor location. SSs were most commonly mistaken for neurogenic tumors in the upper limbs (56%) and cystic masses in the lower limbs (47%) (10). This happened because the relatively small-sized SS tended to be more homogenous on MRI scans, making it difficult to discern them from neurogenic tumors in the upper limbs (11). In contrast, relatively large-sized SSs (>5 cm) were usually heterogeneous with cystic or necrotic components, making them likely to be diagnosed as cystic masses in the lower limbs (12). However, even when biopsies are performed, the misdiagnosis rate of SS is as high as 9–17% when combined with histological and cytological findings for diagnosis (13, 14, 15). One study on SSs based on cytology and histology even reported a misdiagnosis rate of 53.7% with initial cytology reports (16).
SS is considered to be a high-grade STS with a tendency to be locally aggressive and metastatic; therefore, early diagnosis and treatment is crucial for the patient’s prognosis. However, the high rate of delay and misdiagnosis of SS in current clinical diagnosis has negative consequences for patients. Therefore, we have narrative-reviewed SS from the perspectives of clinical and radiologic presentation, histological and cytogenetic analysis, differential diagnosis, treatment, and prognosis so that our readers can have a comprehensive understanding of SS and reduce the delay and misdiagnosis rate of this sarcoma.
Clinical presentation
SS is predominant in young adults between the ages of 15 and 40 years, with a peak incidence in the third decade and 90% occurring before the age of 60 (17). SSs are most commonly present as soft tissue masses, but cases of primary SS of the bone have been reported (18). These lesions can occur anywhere in the body, with the majority arising in the extremities, particularly in the lower extremity in juxta-articular locations (1, 19, 20). In the early stages, small SSs may cause insignificant signs or symptoms. As the tumor grows larger, the patient may notice a mass or swelling of the affected region. In some cases, the tumor can limit the range of motion or cause numbness and/or pain if it located next to nerves. The common clinical appearance is a slow-growing, painless mass and may give the false impression of being benign. So, SS is frequently initially misdiagnosed as a benign lesion (also as hematoma) because of its small size, slow growth rate, well-defined circumscription, insidious onset, younger age at presentation, and atypical presenting symptoms (1, 21).
Radiologic presentation
MRI is the imaging gold standard for soft tissue masses and the optimal imaging modality to assess the extent and intrinsic characteristics of SSs. Further, MRI imaging also facilitates staging and therapy planning. MRI is, therefore, a fundamental part of the clinical patient work-up. In the following, we will discuss the role of the different imaging modalities, including MRI, and potential features suggesting the diagnosis of SS in the appropriate clinical context.
Radiography
The primary role of radiographs in the context of SS is to identify calcifications within a previously identified mass (Fig. 1). These may be present in up to 30% of tumors. A juxta-articular, but not intra-articular, mass in a young adult (15–40 years) with dystrophic calcifications should raise suspicion for SS. Calcifications may be focal or disseminated throughout most of the tumor and may have a fine, stippled, or opaque appearance, which can mimic bone forming tumors, including osteosarcoma and myositis ossificans (22, 23). Radiographs may be able to show underlying bone erosion and periosteal reaction; however, an MRI possesses a greater sensitivity for the detection of bone involvement. Overall, radiographs should be considered to supplement MRI information, supporting the diagnosis of SS.
Synovial sarcoma of the right plantar in a 36-year-old man. X-rays showed very subtle interdigital calcification and a corresponding large mass on MRI. (A, B) X-rays of the right foot; (C, D) T2 fat-saturated axial and coronal; (E) T1 sagittal.
Citation: EFORT Open Reviews 9, 3; 10.1530/EOR-23-0193
Magnetic resonance imaging
MRI is the modality of choice because of its excellent soft tissue contrast and its ability to depict the full lesion extent and potential neighboring tissue invasion in multiple planes (21). Consequently, we consider MRI an essential part for the work-up and clinical decision-making. It needs to be noted that SS may display suggestive MRI features but ultimately these are not pathognomonic, and therefore, tissue sampling is required.
SSs are heterogeneous sarcomas and imaging characteristics differ between different tumors, but in most cases, SSs appear as heterogeneous, multilobulated masses with a low T1-signal intensity, similar to muscle and mostly high T2-signal intensity in comparison to muscle tissue. A characteristic but not mandatory feature is a high degree of signal heterogeneity on fluid-sensitive sequences, with areas of high, intermediate, and low signal intensity, which is called the ‘triple sign’ and can suggest the diagnosis of SS (9, 23, 24). It is assumed to be the result of a simultaneous presence of cellular, viable sarcoma tissue, hemorrhage, and necrosis, as well as calcified and fibrotic areas. The triple sign was reported in circa 50% of SSs but can also be identified in other soft tissue tumors. It is important to note, that a heterogeneous MRI appearance is a feature of larger SSs (>5 cm), while smaller tumors may show a homogenous signal intensity on all MRI sequences.
A SS, especially when small, appears sharply demarcated. Larger lesions are often cystic or multi-lobulated, with various degrees of internal septation (24). Hemorrhage and consecutive fluid-fluid levels are common.
SSs typically show heterogeneous enhancement, after application of IV contrast, reflecting the different sarcoma components responsible for the triple sign (25). The cellular components are enhanced avidly, showing high signal intensity on T1w fat-suppressed sequences, while the necrotic, hemorrhagic, fibrotic, and calcified areas show no or little enhancement. The application of IV contrast is especially important in SS with predominantly cystic features on non-contrast T1 and fluid-sensitive MRI. Thick enhancing septations and nodules suggest malignancy in these cases. We are not aware, nor are there any reported cases in the literature of a purely cystic SS without significant soft tissue component. Moreover, application of IV contrast is important to guide biopsies to these viable tumor components.
MRI may also be used to monitor chemo- or radiation therapy. Increasing areas of high signal intensity on fluid-sensitive MRI sequences suggest necrosis and a favorable response, while a reduction in size can be present.
Overall, larger SS usually show features typical for a malignant soft tissue tumor with potentially suggestive characteristics such as the triple sign, while smaller lesions may be homogenous and less conspicuous with smooth contours, leading to diagnostic uncertainty (26).
Computed tomography
The primary roles of CT in the context of SS are the detection of soft tissue calcifications and staging for detection of metastatic disease. The metastases, mostly found in the lungs, can also show dystrophic calcifications.
The CT appearance of a local tumor reflects the MRI characteristics described above but lacks the MRI’s superior soft tissue contrast. Consequently, SSs appear heterogeneous, often hypointense with avid contrast enhancement, in the above described patterns. The presence of a hemorrhage or necrosis can result in a multiloculated appearance with heterogeneous enhancement, after iodine contrast application (22, 27). CT can play a role if the bone involvement is equivocal on the MRI (28).
Ultrasonography
Ultrasonography may be the first line imaging modality in patients who present with a new palpable lump. We suggest these patients to be transferred to a dedicated sarcoma center as per current guidelines. The ultrasound of a SS is not specific, usually showing a hypoechogenic mass with a varying degree of heterogeneity. An ultrasound can suggest the presence of calcifications and distinguish between solid and cystic lesions. In superficial lesions, ultrasound guidance is useful for a needle biopsy, targeting previously identified cellular and viable tumor components.
Fluorodeoxyglucose positron emission tomography/computed tomography
FDG PET-CT is rarely used as a finding modality for a masse concerning for a SS. FDG PET/CT imaging provides comprehensive information on tumor metabolism and morphology and is currently used primarily to guide biopsies assess treatment response and stage tumors (29, 30, 31). Some studies have also combined the standardized uptake value (SUVmax) to make prognostic predictions for SS but the results are controversial which may be due to the lower uptake of glucose in SS (31, 32, 33).
Histological presentation
Histological subtypes
According to the World Health Organization classification of soft tissue tumors (20), two distinct histological subtypes of SS are described: (i) monophasic, which contains predominantly spindle cells (Fig. 2A); and (ii) biphasic, which contains spindle and epithelial cell components in varying proportions (Fig. 2B). Of the two histological subtypes, monophasic tumors account for the majority, while biphasic tumors account for one-quarter to one-third of all cases. Furthermore, it is necessary to emphasize that the term ‘SS’ is a histological error and a misnomer, as it neither arises nor differentiates from synovium.
Histological images of synovial sarcoma. (A) Monophasic synovial sarcoma showing spindle cells arranged in a haphazard pattern (H&E staining, 50×); (B) Biphasic synovial sarcoma comprising a mixture of spindle cells and pseudoacinic epithelial proliferations (H&E staining, 100×).
Citation: EFORT Open Reviews 9, 3; 10.1530/EOR-23-0193
Immunohistochemical markers
All types of SS display a positivity for cytokeratin and epithelial membrane antigen (EMA) in most cases, but the expression of EMA is more frequent and broader than that of cytokeratin (34, 35). In particular, poorly differentiated areas of a SS almost always contain focal EMA, whereas the cytokeratin expression only reaches about 50% (36), a diffuse expression of BCL2, and a focal positivity for CD99. Further, S100 proteins are also found in some types, although, these markers are not specific (34, 35, 37). CD34 is almost always negative in monophasic SSs, which is useful in the exclusion of solitary fibrous tumors, as the immunophenotypes of these two tumors can otherwise overlap (13). TLE1, an antibody derived from gene expression profiling studies, is emerging as a highly sensitive marker for SSs of all types, with moderate or strong nuclear staining in the vast majority of SSs (38, 39). Nonetheless, it is not sufficiently specific enough, as occasional examples of malignant peripheral nerve sheath tumor and solitary fibrous tumor can also display a positivity (40, 41). However, its sensitivity serves useful in excluding SS as the diagnosis when the result is negative. In addition, h-caldesmon is always negative in SSs (35).
Cytologic presentation
The typical pattern is a mixture of tumor cells with high cellularity composed of varying spindle, oval, or round cells with low-grade atypia (13). The monophasic SS consists mainly of blue spindle cells of uniform size, sparse cytoplasm, an ovoid and highly pigmented nuclei with inconspicuous nucleoli and regular granular chromatin (20). The spindle cells are typically arranged in dense cellular sheets or vague fascicles. The biphasic SS contains both epithelial and spindle cell components, where the spindle cells are similar to the monophasic SS. For biphasic SSs, gland-like structures can be seen in most cases and the glandular lumina contains epithelial mucin. In glandular areas, cuboidal or columnar epithelial cells with ovoid vesicular nuclei are observed, often containing abundantly more palely eosinophilic cytoplasm than the surrounding spindle cells (20). Focally myxoid changes and areas of calcification and/or ossification are also found in SSs (42, 43). In addition, many SSs often have branching, vascular networks mimicking hemangiomas and fibromas (44). Signs of mitosis and varying numbers of mast cells are visible under high magnification (44). Furthermore, in some SSs, there are poorly differentiated areas, which are mainly composed of polymorphic clusters of cells that vary in size and shape. These cells can be fascicular spindle cells, small round hyperchromatic tumor cells, or epithelioid cells (45). The nuclei of these cells are also irregular and reveal high mitotic activity (>6 mitoses/mm2) (46). Necrotic areas, branching vascular patterns, and thin fibrovascular septa are more often seen in poorly differentiated areas (47).
In conclusion, monomorphic blue spindle cells showing variable epithelial differentiation as well as diffuse and strong nuclear immunostaining for TLE1 is the essential histologic diagnostic criterion for SS (20).
Cytogenetic presentation
A SS is characterized by a pathognomonic translocation t(X;18) which is present in >95% of the cases (48). This translocation leads to the expression of different SS18:SSX oncogenic fusion proteins, which drive the sarcoma genesis. Subtypes include SS18:SSX1 and SS18:SSX2 and less commonly SS18:SSX4 (49).
Some studies have shown that SS18-SSX1 is associated with the biphasic subtype, whereas SS18-SSX2 is seen mostly in the monophasic subtype (50, 51, 52). However, there are studies that have expressed a different view. Amary et al. found that there was no statistically significant association between biphasic, monophasic, and fusion types (53).
Both, fluorescence in situ hybridization (FISH) and RT-PCR testing have been validated in the diagnosis of this translocation (53). Detection of SS18 gene rearrangement is now considered to be a powerful diagnostic tool for diagnosing SS and can significantly reduce the rate of misdiagnosis.
Differential diagnosis
The differential diagnosis of SS is very broad. Cysts can be difficult to distinguish from small SSs. As small SSs can present as well-defined, homogeneous, fluid-sensitive sequence high signal lesions or distinct cystic lesions and can mimic benign entities such as ganglia (Fig. 3) or bursae (54). Peripheral nerve sheath tumors also have a variety of morphological patterns, which are difficult to distinguish from SSs. Especially, the expression of TLE1 is also common in peripheral nerve sheath tumors, such as neurofibroma, schwannomas, and MPNST (40). SSs can also show a ‘split fat’ sign on the MRI, which is the classic description of peripheral nerve sheath tumors and shown by almost all tumors arising within skeletal muscles. Other STSs are also a major differential diagnosis for extremity SS. Leiomyosarcomas may be confused with SSs as it can show focal dot keratin and rare EMA expression. Undifferentiated pleomorphic sarcomas and fibrosarcomas may share many imaging characteristics, including the ‘triple sign’, which is often seen in SSs (54). However, in general, other STSs usually present later in life, while the age of onset of SS is earlier. SSs can closely resemble Ewing sarcomas or primitive neuroectodermal tumors (PNETs), especially, the poorly differentiated SSs (1). In particular, they can both stain positive for CD99. The difference is that a poorly differentiated SS does not show a membrane pattern, while more than 90% of PNETs show a strong membrane immunoreactivity (55). Moreover, small round cell neoplasms in general rarely test positive for TLE1, which can help distinguish them from SSs. In addition, in some very rare cases, SS can exhibit extensive intratumoral hemorrhage, making it difficult to differentiate it from a hematoma (56). Especially, in patients presenting after trauma or injury, it can be easily misdiagnosed as a hematoma (57, 58). For these patients, whenever the clinical findings are inadequate regarding the mode of injury and initial treatment fails to relieve symptoms, physicians should consider the differential diagnosis of malignancy (see Fig. 4 with case).
2.4 × 2 cm synovial sarcoma of the right anterior tibial tendon in a 63-year-old man, which was initially suspected to be a ganglion without the application of contrast. (A–C) T2 fat-saturated axial, sagittal, and coronal; (D) T1 paraaxial.
Citation: EFORT Open Reviews 9, 3; 10.1530/EOR-23-0193
10 × 7 cm synovial sarcoma of the left thigh in a 34-year-old man. (A, B) T1 coronal and axial; (C) T2 fat-saturated coronal; (D) T2 axial; (E, F) T1 fat-saturated coronal and axial after contract administration; (G, H): enhanced subtraction coronal and axial. This case initially presented with left thigh swelling and tenderness and MRI revealed a heterogeneous mass. A tumor or intramuscular hematoma was suspected. The initial biopsy suggested skeletal muscles without histopathological findings, which increased the suspicion of a hematoma. However, given that the patient was not clearly traumatized, it was insufficient to explain the extensive hemorrhage within the lesion. Therefore, a second biopsy was conducted promptly, revealing a synovial sarcoma with extensive hemorrhage and necrosis. Neoadjuvant chemotherapy, neoadjuvant radiotherapy, and tumor resection were implemented. At the time of writing this article, the patient is 15 months postoperative with no local or distant recurrence.
Citation: EFORT Open Reviews 9, 3; 10.1530/EOR-23-0193
Treatment
Surgical treatment
Surgery is the mainstay of treatment for SS, and the principles are similar to those that apply to STS in general. After a definitive diagnosis, wide surgical excision with a margin of healthy tissue is the surgical intervention of choice for patients with the primary localized disease. If present, the incisional biopsy site should be resected en bloc with the specimen. Pathological specimens need to be free of tumors at least at the margins, preferably with margins of normal tissue, because noncurative procedures such as incomplete excision or intralesional resection are not useful for treatment (59). For larger tumors in deeper, more unfavorable locations, radiotherapy in combination with surgery is often required. For more advanced diseases, especially in metastatic SS, surgery has a much more limited role and multimodal treatment that entails surgery, radiotherapy, and systemic chemotherapy may be indicated (60, 61).
In addition, although limb-preserving surgery to preserve limb function is the main trend in surgical protocols, amputation is still reserved as a surgical option for some specific SS patients, especially with very distal tumor locations. Examples include patients with tumor location that necessitates the excision of vital structures, older patients, or those with extensive medical comorbidities who cannot tolerate a major surgery (62).
Radiotherapy
Neoadjuvant/adjuvant radiotherapy has shown to improve local control and may have an overall survival (OS) benefit in patients with SS (63, 64). As SSs are all considered high grade sarcomas, radiotherapy is recommended for larger tumors (>5 cm), or in any case where a close margin may be required to preserve the major neurovascular structure or bone (65). Gingrich et al. (63) even suggested a routine implementation of radiotherapy in the treatment of patients with SS, including those receiving aggressive multimodal and trimodal care. Radiotherapy can be administered through a variety of modalities, including external beam therapy, brachytherapy, and intensity-modulated radiation therapy (IMRT). None of these modalities have specifically shown to be better for SS, though (59). But when compared, IMRT allows for a higher dose of radiation to more closely contour the tumor and reduce the volume of radiation to the surrounding, normal tissues, which has been shown to reduce wound complications and need for reconstructive soft tissue flaps (66). However, some recent studies have controverted the benefits of radiotherapy. A multicenter retrospective study showed that radiotherapy does not provide additional benefit for SS patients who achieved R0 resection. Further, given the adverse effects of radiotherapy, it is recommended that adjuvant radiotherapy be avoided for patients with SS for whom an R0 margin has been achieved (67). Moreover, other reports also suggested that adjuvant radiotherapy is unnecessary, even for high-grade sarcoma, after the excision at the reference center (68, 69). Nevertheless, given the local control effect of radiotherapy, we still recommend the application of neoadjuvant radiotherapy and/or adjuvant radiotherapy to SS patients with big tumors (>5 cm) or positive resection margins.
Chemotherapy
Since early studies confirmed that neoadjuvant chemotherapy based on ifosfamide had an impressive response to treatment of metastatic and pediatric SS, SS was considered to be a particularly chemosensitive STS (70, 71). In general, chemotherapy is reserved for patients with high-risk tumors or advanced diseases and is considered to be more effective in younger patients (72). Nowadays, anthracycline, alone or combined with ifosfamide, represents first-line therapy for SS and the combination is believed to be more effective with a remission rate of 58% for the combination of doxorubicin and ifosfamide (73, 74). In addition to the aforementioned agents, trabectedin and pazopanib are also effective with remission rates of approximately 15–20% and represent the approved second/third-line treatment options that should be favored (75). However, for patients who cannot take anthracyclines, single-agent high-dose ifosfamide is available as a second-line option. It is also effective in patients who have already received pretreatment with ifosfamide (76). In addition, a combination regimen of gemcitabine and doxorubicin may be used for patients who are intolerant or resistant to first or second-line chemotherapy. However, this protocol seems more suitable for keeping the disease in a stable state than providing additional clinical benefits (77).
It should be noted that the role of chemotherapy in adult SS patients is less clear (78, 79, 80). However, in recent years, many oncologists and even EMSO guidelines have begun to favor recommending chemotherapy for SS in adults, given that systemic treatment with the combination of doxorubicin and ifosfamide could reduce the risk of distant metastases and that preoperative chemotherapy could increase the probability of conservative resection in locally advanced cases (81, 82). The EMSO guidelines recommend chemotherapy as an option for limb-preserving surgery, and recommend at least three cycles of adjuvant or neoadjuvant chemotherapy for patients at a high risk of death (82). Furthermore, in a retrospective analysis of 15 clinical trials (on a total of 3330 patients with advanced STS, including 330 cases of SS), the EORTC Soft Tissue and Bone Sarcoma Study Group found SSs formed a distinct subgroup of STS with certain properties. SSs presented a better response to chemotherapy (no particular regimen seemed superior, though ifosfamide did seem to be more active), a longer progression-free survival (PFS) (6.3 months vs 3.7 months), and a longer OS period (15.0 vs 11.7 months) (72). This further prompted many adult sarcoma experts to also recommend chemotherapy, even in the neoadjuvant setting, for adult patients with high-risk SSs.
Targeted therapy
In the field of research on targeted therapies for SS, new agents including receptor tyrosine kinase inhibitors, epigenetic modifiers, and immunotherapies have been investigated in clinical trials. However, only pazopanib, a receptor tyrosine kinase inhibitor, is approved for clinical use. Pazopanib is a multitargeting tyrosine kinase inhibitor directed against the receptor tyrosine kinases, vascular endothelial growth factor receptors 1/2/3, platelet-derived growth factor receptors, and c-Kit, whereby blocking tumor growth and inhibiting angiogenesis (83). Recent phase II and III studies have suggested that pazopanib is an active agent in metastatic and refractory SS (84, 85). The retrospective SPIRE study (on 211 patients with STS, including 24 cases of SS) additionally demonstrates the activity of pazopanib in SS. The mean OS period was 13.8 months, with a median treatment duration on the drug of 5.1 months (86). Regorafenib is another tyrosine kinase inhibitor under investigation, which has shown to improve the progression-free survival time in SS patients. In the synovial sarcoma cohort of the REGOSARC trial, the PFS was 5.6 months with regorafenib versus 1.0 month with placebo (87). Enhancer of zest homolog 2 (EZH2) inhibitors are a new class of agents targeting the epigenetics. EZH2 is altered in SS due to the SS18–SSX fusion. But studies have generally shown that EZH2 inhibitors have very limited antitumor effects (88, 89). Histone deacetylase (HDAC) is another pathway to target the epigenetics in SS. Similar to EZH2, although HDAC showed preclinical activity in SS (90), it did not show any observed responses in clinical trials in SS patients (91). New York esophageal squamous cell carcinoma 1 (NYESO-1), a hydrophobic cancer-testis antigen, is expressed in approximately 80% of tumor specimens from patients with SS (92). A targeted therapy against NYESO-1, using genetically modified T cells, seemed promising in HLA-A2-positive patients with SS, with an overall objective response rate of 61% and OS rate of 38% at 3 years, and 14% at 5 years (93). Additionally, the WNT–β-catenin, protein kinase B (AKT)–mammalian target of rapamycin (mTOR) pathways, palbociclib and other CD4/6 inhibitors, arginosuccinate synthetase 1, and malic enzyme 1 (ME1) have also been investigated by scholars as actionable targets but have been more limited to the preclinical stage and have not provided much clinical benefit.
Prognosis
SS is often considered a high-grade sarcoma with a poor prognosis. Gazendam et al. mentioned that the 5-year survival rate for SS in the 1960s was shown to be at 25–51% only (94). However, there was a trend toward an improved survival rate over time. Krieg et al. (2011) demonstrated that the 5-year survival rate was at 74.2%, the 10-year at 61.2%, and the 15-year rate at 46.5% respectively (95). Venkatramani et al. (2021) showed that the 5-year survival rate was at 97.67% in low-risk patients, at 88.83% in intermediate-risk patients, and at 12.5% in high-risk patients at a median follow-up of 6.8 years (96).
Regarding the prognostic factors, the most important ones are the grading and staging (usually according to the FNCLCC grading system and AJCC staging system) of the tumor at the time of diagnosis or treatment. They override the influence of other prognostic factors (97). According to the survival analysis done by Krieg et al. (95), for grade 2 tumors, the median survival time (MST) was about 18 years, and for grade 3 tumors, the MST was about 2.5 years. Guillou et al. demonstrated similar results, with a median disease-specific survival (DSS) of 176 months for grade 2 SS, and 48 months for grade 3 SS (46). It should be noted that the FNCLCC grading system used in these two studies is still the old classification, not the most recent version. More recently, Bianchi et al. (98) also confirmed that grade 3 tumors had worse 10-year survival rates compared to grade 2 tumors (42.8% vs 49.5%). For the tumor staging, patients who did not have metastases at diagnosis (stage II or III) the MST was 28.9 months compared to 17.1 months for patients who were metastatic at diagnosis (stage IV) (99).
Age is an independent prognostic factor for SS patients. Sultan et al. demonstrated the 5-year survival rate for children and adolescents to be at 83% compared to 62% in adults (100). Similarly, the results of the studies by Smolle et al. (101) and Fice et al. (102) confirmed this observation. In addition, tumor size and tumor location are also associated with the prognosis. Large tumor size and primary tumors located toward the trunk have been reported to be associated with a worse prognosis (103, 104). Moreover, some scholars have proposed that the histological subtype is also a prognostic factor. Xiong et al. reported higher 5- and 10-year survival rates for the biphasic subtype compared to the monophasic subtype (69% vs 59% and 60% vs 49%, respectively) (105). The same results were shown in a retrospective study with 196 patients by Bianchi et al. (98) who similarly observed that patients with monophasic subtype had a worse prognosis (42.3% vs 59.7% OS at 10 years). Some studies, on the other hand, have shown that neither the histological subtype nor the fusion type (SS18:SSX) had any significant effect on the prognosis (95, 106).
Moreover, Sarculator (107) and Memorial Sloan Kettering (MSKCC) (108) are two of the most widely adopted contemporary prognostic prediction models based on clinical and pathological characteristics for patients with STS. Both of them have shown to hold good prognostic ability for survival outcomes in STS (109, 110). Proper application of them can improve the clinicians' ability to assess the prognosis of a SS patient, strengthen prognosis-based decision-making, and patient stratification.
Conclusion
SS is a high-grade malignant STS characterized by a pathognomonic translocation of the t(X;18) chromosome, displaying genetic abnormalities. Further, it has a propensity for localized aggressiveness and metastasis and a poor prognosis. The diagnosis of SS is difficult and often subject to misdiagnosis due to its atypical features, wide morphological and immunophenotypical variation, and tendency to occur at any anatomical site. A misdiagnosis combined with the resulting fallacious treatment will amplify the scarce prognosis of the disease, leading to extremely serious consequences. Therefore, we recommend that orthopedic physicians perform biopsies and testing for the SS18 gene rearrangements in all patients in whom a SS cannot be excluded, especially those located in the extremities and joints, to minimize misdiagnosis.
ICMJE Conflict of Interest Statement
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported here.
Funding Statement
This work was in part supported by the China Scholarship Council (CSC, 202308170024) granted to CL.
Author contribution statement
AHK and CL have contributed to the study design. CL has contributed to the manuscript preparation. AHK, FK, DR, and CK have contributed to the manuscript revision. All authors have read and agreed to the final version of the manuscript.
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