Synovial Sarcoma of the Extremities: a Literature Review

applied sciences

Review Synovial Sarcoma of the Extremities: A Literature Review

Cosmin Ioan Faur 1, Daniel Laurentiu Pop 1, Ahmed Abu Awwad 1, Carmen Lacramioara Zamﬁr 2,*, Roxana Folescu 3,†, Daniela Gurgus 3,†, Andrei Gheorghe Marius Motoc 4,†, Jenel Marian Patrascu 1, Sorin Bogdan Motoi 5,*, Oana Belei 6 and Ana Maria Ungureanu 5

1 Department of Orthopedics, “Victor Babes”, University of Medicine and Pharmacy, Eftimie Murgu Sq. Nr.2, 300041 Timisoara, Romania; [email protected] (C.I.F.); [email protected] (D.L.P.); [email protected] (A.A.A.); [email protected] (J.M.P.) 2 Department of Morpho-Functional Sciences I, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iasi, Romania 3 Department of Balneology, Medical Recovery and Rheumatology, Centre for Preventive Medicine, “Victor Babes”, University of Medicine and Pharmacy, Eftimie Murgu Sq. Nr.2, 300041 Timisoara, Romania; [email protected] (R.F.); [email protected] (D.G.) 4 Department of Anatomy and Embryology, “Victor Babes”, University of Medicine and Pharmacy, Eftimie Murgu Sq. Nr.2, 300041 Timisoara, Romania; [email protected] 5 Department of Radiology and Medical Imaging, University of Medicine and Pharmacy “Victor Babes”, 300736 Timisoara, Romania; [email protected] 6 Department of Pediatrics, First Pediatric Clinic, Disturbances of Growth and Development on Children Research Center, Victor Babes University of Medicine and Pharmacy, No 2 Eftimie Murgu Square, 30041 Timisoara, Romania; [email protected] * Correspondence: carmen.zamﬁr@umﬁasi.ro (C.L.Z.); [email protected] (S.B.M.); Tel.: +40-744-571-673 (C.L.Z.) † These authors contributed equally to this work.

Citation: Faur, C.I.; Pop, D.L.; Abu Abstract: Synovial sarcoma (SS) is a rare and highly malignant tumor and a type of soft tissue Awwad, A.; Zamﬁr, C.L.; Folescu, R.; sarcoma (STS), for which survival has not improved signiﬁcantly in recent years. Synovial sarcomas Gurgus, D.; Motoc, A.G.M.; Patrascu, occur mostly in adolescents and young adults (15–35 years old), usually affecting the deep soft J.M.; Motoi, S.B.; Belei, O.; et al. tissues near the large joints of the extremities, with males being at a slightly higher risk. Despite its Synovial Sarcoma of the Extremities: name, synovial sarcoma is neither related to the synovial tissues that are a part of the joints, i.e., the A Literature Review. Appl. Sci. 2021, synovium, nor does it express synovial markers; however, the periarticular synovial sarcomas can 11, 7407. https://doi.org/10.3390/ app11167407 spread as a secondary tumor to the joint capsule. SS was initially described as a biphasic neoplasm comprising of both epithelial and uniform spindle cell components. Synovial sarcoma is characterized

Academic Editor: Ipsita Banerjee by the presence of the pathognomonic t (X; 18) (p11.2; q11.2) translocation, involving a fusion of the SS18 (formerly SYT) gene on chromosome 18 to one of the synovial sarcoma X (SSX) genes on Received: 13 July 2021 chromosome X (usually SSX1 or SSX2), which is seen in more than 90% of SSs and results in the Accepted: 9 August 2021 formation of SS18-SSX fusion oncogenes. Published: 12 August 2021 Keywords: synovial sarcoma; imaging diagnosis; immunophenotyping Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional afﬁl- iations. 1. Introduction Soft tissue sarcomas in general and synovial sarcoma (SS) in particular are highly malignant tumors, and still represent an unsolved problem for musculoskeletal oncologists in terms of local recurrence and survival rate. Synovial sarcomas of the extremities are the Copyright: © 2021 by the authors. most frequent (80–90%), occurring mostly in adolescents and young adults (15–35 years old, Licensee MDPI, Basel, Switzerland. AYA generation), usually affecting the deep soft tissues near the large joints of the extrem- This article is an open access article ities, with males being at a slightly higher risk [1]. The origin of the synovial sarcoma distributed under the terms and comes not from the articular synovial tissue. However, the occurrence of synovial sarcoma conditions of the Creative Commons originating from an intraarticular location is suspected to be rare [2]. The main localizations Attribution (CC BY) license (https:// are in the legs or arms, especially thigh, popliteal fossa and foot, but SS can appear in creativecommons.org/licenses/by/ any part of the body [3]. The incidence of synovial sarcoma has been estimated to be 4.0/).

Appl. Sci. 2021, 11, 7407. https://doi.org/10.3390/app11167407 https://www.mdpi.com/journal/applsci Appl. Sci. 2021, 11, 7407 2 of 10

2.75 per 100,000, with an incidence of cases by age of 74% for the group aged 20–64 years old and 16% for those 65 years and older [4]. SS was initially described as a biphasic neoplasm containing both epithelial and uniform spindle cell components. Synovial sarcoma is characterized by the presence of the pathognomonic t (X;18) (p11.2; q11.2) translocation, involving a fusion of the SS18 (formerly SYT) gene on chromosome 18 to one of the synovial sarcoma X (SSX) genes on chromosome X (usually SSX1 or SSX2), which is seen in more than 90% of SSs and results in the formation of SS18-SSX fusion oncogenes [5,6]. These tests may include imaging studies, such as an X-ray, CT scan and/or MRI scan; genetic testing to detect the specific chromosomal translocation between chromosome 18 and chromosome X that is identified in most cases of synovial sarcoma; and a biopsy of the tumor [7]. About 50% of cases showed normal X-rays because of the small size of the lesion or because of the location of the synovial sarcoma in regions with complex neuro-vascular anatomical structures. The CT scan may commonly identify the tumor as a heterogeneous soft-tissue mass with a density that is similar to or slightly lower to that of the muscles. In the evaluation of synovial sarcoma, an MRI exam is the procedure of choice. Three histological subtypes of synovial sarcomas are described: biphasic (20–30% of lesions); monophasic (50–60%), especially mesenchymal spindle-cell elements; and the poorly differentiated subtype. The lesion is usually well defined and may be surrounded by a pseudocapsule (mainly in small dimension masses), but it also may appear with poorly defined margins and polilobulated, and with areas of intratumoral hemorrhage, necrosis and cystic zones alternating with calcification areas [8]. Surgery is the mainstay of treatment for synovial sarcoma. The goal is to remove the malignant tissue with a margin of healthy tissue around it. This can sometimes involve the removal of an entire muscle or muscle group, or even amputation. Although treatment is focused on surgery, adjuvant radiation and/or chemotherapy may be beneficial, particularly in high-risk patients and in order to decrease the chances of recurrence. Significant prognostic factors include: size > 5 cm, deep-seated localization, adequacy of surgical margins and history of recurrence [9].

2. Diagnosis 2.1. Clinical Presentation Soft tissue sarcomas may appear anywhere in the body, with the majority of them being located at the level of the lower limb, mostly around the knee or hip joint. The nomenclature of synovial sarcoma might be confusing since their origin is not the synovial tissue but the primitive mesenchymal cells [10]. In the early stages, small synovial sarcomas 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 presses on nearby nerves [11]. The common clinical appearance is a slow-growing painless mass and may give the false impression of being benign. Based on the tumor location, some functional impairment may appear. Sometimes, the symptoms of a synovial sarcoma can be mistaken with other inflammatory conditions, such as bursitis and synovitis, or it may go unnoticed for a long time. Plain radiographs often show small calcifications within the mass. This finding should alert the physician to the diagnosis [12]. Synovial sarcoma may first be suspected in the presence of characteristic signs and symptoms. Additional tests may be required in order to determine the correct diagnosis and the severity of the condition.

2.2. Imaging Examinations X-ray: Simple X-rays are not sensitive enough for the diagnosis of SS. Usually, an X-ray is the first imaging study performed as a routine procedure in the presence of an overgrown tumoral mass in an extremity. Calcifications, which can mimic myositis ossificans, and bone involvement (erosions, osteolysis) may be observed on plain X-rays (Figure1). Appl. Sci. 2021, 11, x FOR PEER REVIEW 3 of 11

Appl. Sci. 2021, 11, x FOR PEER REVIEW 3 of 11

overgrown tumoral mass in an extremity. Calcifications, which can mimic myositis ossificans, and bone involvement (erosions, osteolysis) may be observed on plain x-rays (Figure overgrown tumoral mass in an extremity. Calcifications, which can mimic myositis ossifi- Appl. Sci. 2021, 11, 7407 1). 3 of 10 cans, and bone involvement (erosions, osteolysis) may be observed on plain x-rays (Figure 1).

Figure 1. Synovial sarcoma, F, 40 YO—radiological AP view of the right hip and proximal thigh (prior to CT exam) reveals the presence of soft tissue calcifications medial to the lesser trochanter. FigureFigure 1. 1.Synovial Synovial sarcoma, sarcoma, F, 40F, YO—radiological40 YO—radiological AP view AP ofview the rightof the hip right and hip proximal and proximal thigh thigh (prior(priorMagnetic to to CT CT exam) exam) resonance reveals reveals the the presence imaging presence of soft(MRI) of tissuesoft with tiss calcificationsue contrast calcifications medial should tomedial the be lesser consideredto the trochanter. lesser trochanter.for tumors exceeding 2–3 cm and is probably the imaging method of choice for synovial sarcomas. MagneticMagnetic resonance resonance imaging imaging (MRI) (MRI) with with contrast contrast should should be considered be considered for tumors for tumors exceedingMRI will 2–3provide cm and valuable is probably information the imaging regarding method of the choice extent for synovialof the tumor sarcomas. and MRIthe relation- exceeding 2–3 cm and is probably the imaging method of choice for synovial sarcomas. willship provide with the valuable surrounding information anatomical regarding structures; the extent ofthe the use tumor of a and gadolinium the relationship contrast will MRI will provide valuable information regarding the extent of the tumor and the relation- withenhance the surrounding the amount anatomical of information structures; that the can use be of aobtained gadolinium since contrast it is able will enhanceto differentiate ship with the surrounding anatomical structures; the use of a gadolinium contrast will thebetween amount hemorrhagic of information areas that and can solid be obtained tumoral since tissue. it is able to differentiate between enhance the amount of information that can be obtained since it is able to differentiate hemorrhagicThe T2 areassequences and solid are tumoralmore specific tissue. for the diagnosis of soft tissue sarcomas and can betweenThe T2hemorrhagic sequences are areas more and specific solid tumoral for the diagnosis tissue. of soft tissue sarcomas and reveal an inhomogeneous tumor, mainly with a hyperintense signal, in contrast with mus- can revealThe T2 an inhomogeneoussequences are more tumor, specific mainly for with the a hyperintensediagnosis of signal, soft tissue in contrast sarcomas with and can cles, and the specific “triple sign” is present, representing a mixture of solid parts (me- muscles,reveal an and inhomogeneous the specific “triple tumor, sign” mainly is present, with a representing hyperintense a mixture signal, in of contrast solid parts with mus- dium hemorrhage and/or necrosis (high signal intensity) and calcifications or/and fibrotic (mediumcles, and hemorrhagethe specific and/or “triple necrosis sign” is (high presen signalt, representing intensity) and a calcificationsmixture of solid or/and parts (me- fibroticareas (low areas signal (low signal intensity). intensity). The The heterogeneity heterogeneity is is completed completed by thethe presence presence of of cystic cystic parts dium hemorrhage and/or necrosis (high signal intensity) and calcifications or/and fibrotic partswith withan aspect an aspect of fluid–fluid of fluid–fluid levels levels due due to to blood blood sedimentatio sedimentationn (Figures (Figures2 and 2 and3). 3). areas (low signal intensity). The heterogeneity is completed by the presence of cystic parts with an aspect of fluid–fluid levels due to blood sedimentation (Figures 2 and 3).

Figure 2. 2.A A 40-year 40-year old old female female patient patient with with synovial synovial sarcoma. sarcoma. Image Image represents represents an axial MRIan axial of the MRI of the proximalproximal right right thigh—axial thigh—axial T2 FSE T2 (fastFSE spin (fast echo) spin and echo FATSAT) and (fat FATSAT saturation). (fat Theresaturation). is an increased There is an in- diametercreasedFigure 2. diameter of A the 40-year right of thigholdthe femaleright because thigh patient of because a soft with tissue ofsynovial a mass soft tissue (thinsarcoma. arrows), mass Image (thin where representsarrows), an inhomogeneous where an axial an inhomoge-MRI of the mixtureneousproximal mixture of solidright and ofthigh—axial solid cystic and areas cystic T2 is shownFSE areas (fast (block is shownspin arrow). echo (block) and arrow). FATSAT (fat saturation). There is an increased diameter of the right thigh because of a soft tissue mass (thin arrows), where an inhomogeneous mixture of solid and cystic areas is shown (block arrow). Appl. Sci. 11 Appl. Sci. 20212021,, 11,, 7407x FOR PEER REVIEW 44 of 1011 Appl. Sci. 2021, 11, x FOR PEER REVIEW 4 of 11

Figure 3. SameSame patient patient as as in in Figures Figures 11 andand 22,, MR image, image, coronal coronal T2 T2 STIR STIR (short-time (short-time inversion inversion re- Figure 3. Same patient as in Figures 1 and 2, MR image, coronal T2 STIR (short-time inversion re- recovery):covery): heterogeneous heterogeneous soft soft tissue tissue mass mass showing showing a a mixture mixture of of solid solid areas areas (line arrow), hemorrhage covery): heterogeneous soft tissue mass showing a mixture of solid areas (line arrow), hemorrhage and/or necrosis (block arrow), calcifications or fibrosis, cystic elements and infiltration of adjacent and/orand/or necrosis necrosis (block (block arrow), calcifications calcifications or fibrosis,fibrosis, cystic elementselements andand infiltrationinfiltration ofof adjacentadjacent fat. Furthermore, fluid–fluid levels (block arrow) can be observed in this figure. fat.fat. Furthermore, fluid–fluidfluid–fluid levelslevels (block(block arrow)arrow) cancan bebe observedobserved inin thisthis figure.figure. Computed tomography (CT) is usually performed either if the MRI is contraindicated Computed tomographytomography (CT)(CT) isis usuallyusually performedperformed eithereither ifif thethe MRIMRI is contraindicated (e.g.,(e.g., duedue toto thethe presencepresence ofof orthopedicorthopedic implants),implants), isis unavailableunavailable oror ifif thethe radiologistsradiologists needneed (e.g., due to the presence of orthopedic implants), is unavailable or if the radiologists need additional informationinformation regardingregarding thethe locallocal bonebone involvementinvolvement oror betterbetter visualizationvisualization ofof thethe additional information regarding the local bone involvement or better visualization of the intratumoralintratumoral calcificationscalcifications (Figures(Figures4 4–6).–6). intratumoral calcifications (Figures 4–6).

Figure 4. Axial CT-scan: evident enlargement of the right thigh; heterogeneous soft-tissue mass with Figure 4. Axial CT-scan: evident enlargement of the right thigh; heterogeneous soft-tissuesoft-tissue massmass withwith calcifications, adjacent fat infiltration and skin thickening—synovial sarcoma, M, 26 YO patient. calciﬁcations,calcifications, adjacentadjacent fatfat inﬁltrationinfiltration andand skinskin thickening—synovialthickening—synovial sarcoma,sarcoma, M,M, 2626YO YOpatient. patient.

Figure 5. Synovial sarcoma, F, 31 YO patient—CT image, axial section: soft-tissue mass with heter- Figure 5. SynovialSynovial sarcoma, sarcoma, F, F,31 31YO YO patient—CT patient—CT image, image, axial axial section: section: soft-tissue soft-tissue mass masswith heter- with ogeneous content, showing necrotic areas alternating with calcifications and cystic areas. heterogeneousogeneous content, content, showing showing necrotic necrotic areas areas alternating alternating with withcalcifications calciﬁcations and cystic and cystic areas. areas. Appl. Sci. 2021, 11, 7407 5 of 10 Appl. Sci. 2021, 11, x FOR PEER REVIEW 5 of 11

FigureFigure 6.6. Synovial sarcoma, F, 3131 YOYO patient, CT image,image, axial section, with contrast—bone window: osteolyticosteolytic areaarea inin thethe rightright ischio-pubicischio-pubic rami.rami.

OtherOther imagingimaging examinationsexaminations may may be be required. required. For For example, example, a bonea bone scan scan may may be be useful use- inful detecting in detecting possible possible metastatic metastatic lesions lesions or an or Angio-CT an Angio-CT may may be requested be requested by the by oncologic the onco- surgeon,logic surgeon, especially especially for deep for deep synovial synovial sarcomas sarcomas in order in order to understand to understand the relationshipthe relation- ofship the of tumor the tumor with with the neurovascular the neurovascular structures structures for appropriate for appropriate preoperative preoperative planning plan- (Figurening (Figure7). 7).

FigureFigure 7.7. Angio-CT with 3D reconstruction indicatingindicating thethe relationship ofof thethe synovialsynovial sarcomasarcoma withwith thethe majormajor arterialarterial vesselsvessels andand thethe tumoraltumoral vascularization.vascularization.

2.3.2.3. Biopsy AA biopsybiopsy isis mandatorymandatory forfor aa properproper diagnosisdiagnosis inin patientspatients withwith synovialsynovial sarcoma;sarcoma; moreover,moreover, itit willwill allowallow thethe morphopathologistmorphopathologist toto differentiatedifferentiate thisthis tumor,tumor, especiallyespecially fromfrom otherother softsoft tissuetissue sarcomas,sarcomas, andand toto definedefine thethe tumortumor staging.staging. InIn orderorder toto harvest harvest a a representative representative sample sample of tumoralof tumoral tissue, tissue, there there are severalare several options op- available,tions available, including: including: a fine needlea fine needle aspiration, aspiration, a core needle a corebiopsy needle (with biopsy or without(with or imagingwithout guidance)imaging guidance) and an incisional and an incisional biopsy. biopsy. AtAt this point, point, a acore core needle needle biopsy biopsy is cons is consideredidered to probably to probably be the be best the choice, best choice, espe- especiallycially if it is if performed it is performed under under ultrasonographic ultrasonographic or tomographic or tomographic guidance guidance for deep, for deep, non- nonpalpablepalpable tumors. tumors. The major The majoradvantage advantage of a core of needle a core biopsy needle is biopsy the amount is the of amount tissue that of tissuecan be thatretrieved can be compared retrieved to compared a fine needle to a aspiration fine needle and aspiration the small and rate the of complications small rate of complicationscompared to an compared incisional to biopsy an incisional [11,13]. biopsy [11,13]. An incisional biopsy should be performed by a musculoskeletal oncologist or after An incisional biopsy should be performed by a musculoskeletal oncologist or after consulting them, where the size of the incision should be as small as possible and it should consulting them, where the size of the incision should be as small as possible and it should Appl.Appl. Sci.Sci.2021 2021,,11 11,, 7407x FOR PEER REVIEW 66 of 1011 Appl. Sci. 2021, 11, x FOR PEER REVIEW 6 of 11

bebe inin lineline withwith thethe plannedplanned incisionincision forfor thethe tumoraltumoral excision.excision. AA goodgood surgicalsurgical techniquetechnique isis be in line with the planned incision for the tumoral excision. A good surgical technique is requiredrequired withwith carefulcareful hemostasishemostasis inin orderorder toto avoidavoid hematomahematoma formation.formation. required with careful hemostasis in order to avoid hematoma formation. TheThe microscopicmicroscopic examexam ofof thethe synovialsynovial sarcomasarcoma willwill indicateindicate oneone ofof thethe threethree possiblepossible The microscopic exam of the synovial sarcoma will indicate one of the three possible variants:variants: monophasic,monophasic, biphasicbiphasic or or poorly poorly differentiated. differentiated. For For the the first first variant, variant, the the cellularity cellular- variants: monophasic, biphasic or poorly differentiated. For the first variant, the cellular- isity represented is represented by spindleby spindle cells, cells, whereas whereas in a in biphasic a biphasic synovial synovial sarcoma, sarcoma, there there may may also also be ity is represented by spindle cells, whereas in a biphasic synovial sarcoma, there may also epithelialbe epithelial cells cells present present (Figures (Figures8 and 8 9and). Furthermore, 9). Furthermore, the microscopic the microscopic exam exam may revealmay re- be epithelial cells present (Figures 8 and 9). Furthermore, the microscopic exam may re- theveal presence the presence of calcifications/ossification of calcifications/ossification areas areas in up in to up one-third to one-third of cases. of cases. veal the presence of calcifications/ossification areas in up to one-third of cases.

FigureFigure 8.8. MicroscopicMicroscopic ﬁndings—classicalfindings—classical synovialsynovial sarcomasarcoma withwith twotwo mainmain subtypes:subtypes: biphasicbiphasic andand Figure 8. Microscopic findings—classical synovial sarcoma with two main subtypes: biphasic and monophasic appearance, and with two typical cell types: spindle cells and epithelial cells (fusocel- monophasicmonophasic appearance,appearance, and and with with two two typical typical cell cell types: types: spindle spindle cells cells and and epithelial epithelial cells cells (fusocellular (fusocellular proliferation with myxoid areas, detail), which is rare (HE staining, 20×). proliferationlular proliferation with myxoidwith myxoid areas, areas, detail), detail), which which is rare is (HE rare staining, (HE staining, 20×). 20×).

Figure 9. Microscopic finding—monophasic subtype of a synovial sarcoma with mesenchymal spin- Figure 9. Microscopic finding—monophasic subtype of a synovial sarcoma with mesenchymal spin- Figuredle cell 9.elementsMicroscopic and fusocellular finding—monophasic proliferationsubtype (HE staining, of a synovial 40×). sarcoma with mesenchymal spindledle cell cellelements elements and andfusocellular fusocellular proliferation proliferation (HE (HE staining, staining, 40×). 40 ×). 3. Treatment 3.3. Treatment For the vast majority of the lower limb synovial sarcomas, surgical treatment and ForFor thethe vastvast majoritymajority ofof thethe lowerlower limblimb synovialsynovial sarcomas,sarcomas, surgicalsurgical treatmenttreatment andand adjuvant radiotherapy represent the gold standard of treatment. adjuvantadjuvant radiotherapyradiotherapy representrepresent thethe goldgold standardstandard ofof treatment.treatment. 3.1. Surgical Treatment 3.1.3.1. Surgical TreatmentTreatment In the past, the main surgical procedure that was used for the removal of a soft tissue InIn thethe past,past, thethe mainmain surgicalsurgical procedureprocedure thatthat waswas usedused forfor thethe removalremoval ofof aa softsoft tissuetissue sarcomasarcoma of the the lower lower limb limb was was amputation, amputation, which which provided provided low low recurrence recurrence rates rates but butsac- sarcoma of the lower limb was amputation, which provided low recurrence rates but sac- sacrificedrificed functional functional integrity. integrity. rificed functional integrity. TheThe recentrecent evolutionevolution ofof thethe surgicalsurgical techniques,techniques, togethertogether withwith thethe adjuvantadjuvant methods,methods, The recent evolution of the surgical techniques, together with the adjuvant methods, especiallyespecially radiotherapy,radiotherapy, made made the the so-called so-called conservative conservative surgery surgery possible possible for thefor treatmentthe treat- especially radiotherapy, made the so-called conservative surgery possible for the treat- ofment synovial of synovial sarcomas sarcomas of the of extremities. the extremities. A wide A surgicalwide surgical excision excision with negative with negative margins mar- is ment of synovial sarcomas of the extremities. A wide surgical excision with negative mar- thegins procedure is the procedure of choice. of Negativechoice. Negative margins margins are extremely are extremely important important in order toin decreaseorder to gins is the procedure of choice. Negative margins are extremely important in order to thedecrease rate of the local rate recurrenceof local recurrence and the and overall the survivaloverall survival rate. No rate. specific No specific guidelines guidelines exist decrease the rate of local recurrence and the overall survival rate. No specific guidelines regardingexist regarding the ideal the dimensionideal dimension of the of margin the margin that should that should be resected be resected around around the tumoral the tu- exist regarding the ideal dimension of the margin that should be resected around the tu- massmoral for mass synovial for synovial sarcoma. sarcom Usually,a. Usually, for small for (<5 small cm), (<5 superficial cm), superficial tumors, atumors, wide excision a wide moral mass for synovial sarcoma. Usually, for small (<5 cm), superficial tumors, a wide Appl. Sci. 2021, 11, 7407 7 of 10

with negative margins of approximately 1–2 cm is considered sufficient. In large synovial sarcomas with difficult localizations, achieving a proper negative margin without affecting important neurovascular structures may be difficult. In these situations, very close or microscopically positive margins may occur and the use of adjuvant therapies becomes mandatory in order to avoid local recurrences. Several methods of tissue reconstruction are available now in order to preserve a satisfactory functional status of the limb following excision. Use of non-vascularized or vascularized bone grafts, bulk allografts and oncologic endoprosthetic implants are now available for skeletal reconstruction following large osteoarticular resections. Sacrificing the major vessels may be required for sarcomas that are surrounding these structures. Following this, arterial reconstruction with an autologous saphenous vein or synthetic grafts is mandatory in order to maintain the viability of the limb. Soft tissue reconstruction may also be required following the excision of synovial sarcoma. Several technical options are available in the surgeon’s armamentarium, such as skin grafts, loco-regional and free flaps for coverage of the residual defect or tendon and muscle transfers for the restoration of motor function. Coordinated multidisciplinary surgical work is usually needed, especially for large sarcomas with problematic localizations in order to achieve a satisfactory resection, together with a good functional result and a satisfactory cosmesis of the limb.

3.2. Radiotherapy Adjuvant radiation therapy was shown to facilitate local control in the management of synovial sarcomas. It is usually recommended for high-grade, larger tumors (>5 cm). Radiotherapy may be administered pre- or postoperatively, with a lack of a generally accepted protocol at this time. The timing of radiotherapy is still controversial, with advocates of both pre- or post-surgical radiation. Several complications, such as a fracture, ﬁbrosis, edema and joint stiffness, are reported following radiation therapy for synovial sarcomas [14]. In order to reduce the volume of radiation and the incidence of complications, intensity-modulated radiation therapy was proposed for adjuvant treatment of soft tissue sarcomas. This technique allows for the use of a higher dose of radiation closer to the core of the tumor, which will reduce the amount of exposure for the surrounding normal tissues.

3.3. Chemotherapy The use of adjuvant chemotherapy in the treatment of soft tissue sarcoma in general and synovial sarcoma in particular is controversial. Unlike other sarcomas, it seems that there are some subgroups of synovial sarcomas that might benefit from systemic therapy with cytotoxic chemical agents. Usually, chemotherapy is reserved for high-risk, large and deep tumors that have at least an approximately 50% risk of developing metastatic lesions. Based on the existing literature, there is no indication for perioperative chemotherapy in young or adolescent patients with a small SS (<5 cm) when appropriate oncologic margins can be obtained following surgical excision [15]. Preoperative chemotherapy might also be beneficial by reducing the size of large tumors and causing necrosis and hence allow for easier and complete resection of the tumoral tissue. However, there are several randomized studies that showed limited or no overall survival benefit with adjuvant chemotherapy [12,16].

3.4. Other Therapeutical Options There is evidence of angiogenesis playing a critical role in the progression of soft tissue sarcomas and, hence, the anti-angiogenic factors might be useful in reducing the tumoral mass. Tyrosine kinase inhibitors, such as endothelial growth factor receptor inhibitors (e.g., sorafenib, pazopanib and sunitinib), were investigated in clinical trials. The most Appl. Sci. 2021, 11, x FOR PEER REVIEW 8 of 11

Appl. Sci. 2021, 11, 7407 8 of 10 inhibitors (e.g., sorafenib, pazopanib and sunitinib), were investigated in clinical trials. The most suitable candidates that are considered useful in the treatment of synovial sar- comasuitable might candidates be sorafenib that and are consideredpazopanib useful[9,17,18]. in the(Figure treatment 10) of synovial sarcoma might be sorafenib and pazopanib [9,17,18]. (Figure 10).

Figure 10. Therapeutic algorithm in synovial sarcoma of extremities. Figure 10. Therapeutic algorithm in synovial sarcoma of extremities. TheThe role role of of immunotherapy, immunotherapy, especially especially in th thee treatment ofof metastaticmetastatic softsoft tissuetissue sarco-sarcomas,mas, was was evaluated. evaluated. SynovialSynovial sarcomassarcomas havehave a high expression of cancer/testis antigen, antigen, especiallyespecially NY-ESO-1, NY-ESO-1, which is highlyhighly immunogenic.immunogenic. The The safety safety and and activity activity of of immunother- immuno- therapyapy with with genetically genetically engineered engineered targeted targeted T-lymphocytes T-lymphocytes to to this this antigen antigen (autologous (autologous T Tcells cells expressingexpressing NY-ESO-1NY-ESO-1c259c259,, which which is is an an affinity-enhanced afﬁnity-enhanced T-cell T-cell receptor receptor (TCR) (TCR) that that recognizesrecognizes an an HLA-A2-restricted HLA-A2-restricted NY-ESO-1/LAGE1a-derived NY-ESO-1/LAGE1a-derived peptide) peptide) in in patients patients with with metastaticmetastatic synovial synovial sarcoma sarcoma was was evaluated evaluated and indicated aa clinicallyclinically signiﬁcantsignificant antitu-anti- tumoralmoral effect effect [ 10[10,19].,19].

4.4. Discussion Discussion TheThe potential potential aggressive aggressive behavior behavior of of syno synovialvial sarcoma sarcoma makes makes the the pathological pathological and and radiological evaluations very important for an appropriate staging and an adequate thera- radiological evaluations very important for an appropriate staging and an adequate ther- peutical decision. apeutical decision. Additional testing has to be performed in order to confirm the diagnosis and the Additional testing has to be performed in order to confirm the diagnosis and the se- severity of the condition and to decide on the appropriate treatment options. These tests verity of the condition and to decide on the appropriate treatment options. These tests may include imaging studies, such as an X-ray, CT scan and/or MRI scan; genetic testing to may include imaging studies, such as an x-ray, CT scan and/or MRI scan; genetic testing detect the specific chromosomal translocation between chromosome 18 and chromosome to detect the specific chromosomal translocation between chromosome 18 and chromo- X that is identified in most cases of synovial sarcoma; and a biopsy of the tumor. Cross- some X that is identified in most cases of synovial sarcoma; and a biopsy of the tumor. sectional images are suggestive, but not specific, for synovial sarcoma, and the main sign Cross-sectional images are suggestive, but not specific, for synovial sarcoma, and the main is the polilobulated aspect, with a “triple sign”, i.e., hemorrhage, fluid levels and septa sign is the polilobulated aspect, with a “triple sign”, i.e., hemorrhage, fluid levels and (“bowl of grapes” sign) [20–22]. septa (“bowl of grapes” sign) [20-22]. Usually, the tumor presents as a palpable soft-tissue mass or swelling, with a long periodUsually, between the clinicaltumor onsetpresents and as the a diagnosis,palpable soft-tissue particularly mass due or to swelling, the initial with slow a growth long periodof the between lesion (average clinical 2–4onset years). and the diagnosis, particularly due to the initial slow growth of the Moreover,lesion (ave therage presented 2–4 years). case displayed the same elements of positive and differential diagnosis,Moreover, but withthe presented a final diagnosis case displayed that was the established same elements only via of apositive biopsy. and differential diagnosis,The certain but diagnosiswith a final of diagnosis synovial sarcomathat was remainsestablished a challenge only via a and biopsy. the recognition of theThe disease certain shoulddiagnosis be of based synovial upon sarcoma a combination remains a of challenge findings, and including the recognition traditional of themorphology, disease should detection be based of the upon chromosomal a combination t (X; 18) of translocationfindings, including and a paneltraditional of immuno- mor- phology,histochemical detection markers of the [23 chromosomal,24]. t (X; 18) translocation and a panel of immuno- histochemicalThe potential markers prognostic [23,24]. values were determined by studying many clinical factors. For example, some authors found age to predict survival, where young patients have a better prognosis than the elderly [25,26]. Most studies reported no effect of gender, except for one study that found worse survival rates for males [27]. The tumor size frequently Appl. Sci. 2021, 11, 7407 9 of 10

predicted local recurrence and survival in many studies [6,25]. Central locations seem to have a worse prognosis than peripheral locations [6,28]. Histopathological features, such as undifferentiated tumors, necrosis, high histologic grades and increased mitotic rates, were associated with a worse prognosis [16–18,29]. Furthermore, local recurrence was associated with a greater risk of metastasis and shorter survival [13,30]. The proper therapeutic algorithm takes both the staging of the tumor and the prognostic factors into account. Surgical techniques are similar to those recommended for soft tissue sarcomas in general, consisting of a large tumoral resection that includes the whole compartment [31,32].

5. Conclusions Synovial sarcoma is a malignant disease that frequently manifests in the extremities of young adults but can occur anywhere and in any age group, with a tendency toward late recurrences and metastases, particularly with large tumors. A soft tissue mass near a joint of a young patient that is evident on a plain film with calcifications should always raise suspicion for synovial sarcoma. The most common differential diagnosis described in the literature we need to consider are the tumor-like lesions and intramuscular hematomas; extreme obesity and increased body mass index (especially, constitutional high thigh diameter) make it difficult to establish a presumptive diagnosis of synovial sarcoma. For an adequate treatment and a precise staging, it is very important to evaluate the potential aggressive behavior of a synovial sarcoma via paraclinical investigations (using radiological, CT and MRI methods). Current multimodal treatment includes radiation, surgical resection and chemotherapy. Surgery is the mainstay of treatment for synovial sarcoma. The goal is to remove the malignant tissue, together with a margin of healthy tissue around it.

Author Contributions: Conceptualization, A.M.U. and C.I.F.; methodology, D.G.; software, R.F., S.B.M. and O.B.; validation, A.A.A. and D.G.; formal analysis, D.G.; investigation, A.M.U.; resources, J.M.P. and D.G.; data curation, D.L.P.; writing—original draft preparation, C.I.F. and A.M.U.; writing— review and editing, C.L.Z.; visualization, A.G.M.M.; supervision, S.B.M.; project administration, A.M.U. and C.I.F. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References 1. Kransdorf, M.J. Malignant soft-tissue tumors in a large referral population: Distribution of diagnoses by age, sex, and location. AJR Am. J. Roentgenol. 1995, 164, 129–134. [CrossRef] 2. Sistla, R.; Tameem, A.; Vidyasagar, J.V. Intra articular synovial sarcoma. Indian J. Pathol. Microbiol. 2010, 53, 115–116. [CrossRef] [PubMed] 3. Murphey, M.D.; Gibson, M.S.; Jennings, B.T.; Crespo-Rodríguez, A.M.; Fanburg-Smith, J.; Gajewski, D.A. Imaging of Synovial Sarcoma with Radiologic-Pathologic Correlation. RadioGraphics 2006, 26, 1543–1565. [CrossRef][PubMed] 4. Joseph, N.; Laurent, S.; Zheng, S.; Stirnadel-Farrant, H.; Dharmani, C. Epidemiology of synovial sarcoma in EU28 countries. Sarcoma 2019, 30, 706–707. [CrossRef] 5. Smith, M.; Fisher, C.; Wilkinson, L.; Edwards, J. Synovial sarcomas lack synovial differentiation. Histopathology 1995, 26, 279–281. [CrossRef][PubMed] 6. Thway, K.; Fisher, C. Synovial sarcoma: Deﬁning features and diagnostic evolution. Ann. Diagn. Pathol. 2014, 18, 369–380. [CrossRef][PubMed] 7. Ryan, C.W.; Meyer, J. Clinical Presentation, Histopathology, Diagnostic Evaluation, and Staging of Soft Tissue Sarcoma. UpTo- Date. January 2015. Available online: https://www.uptodate.com/contents/clinical-presentation-histopathology-diagnostic- evaluation-and-staging-of-soft-tissue-sarcoma (accessed on 1 November 2020). 8. Folpe, A.L.; Schmidt, R.A.; Chapman, D.; Gown, A.M. Poorly Differentiated Synovial Sarcoma: Immunohistochemical Distinction From Primitive Neuroectodermal Tumors and High-Grade Malignant Peripheral Nerve Sheath Tumors. Am. J. Surg. Pathol. 1998, 22, 673–682. [CrossRef] Appl. Sci. 2021, 11, 7407 10 of 10

9. Siegel, H.J.; Sessions, W.; Casillas, M.A., Jr.; Said-Al-Naief, N.; Lander, P.H.; Lopez-Ben, R. Synovial sarcoma: Clinicopathologic features, treatment, and prognosis. Orthopedics 2007, 30, 1020–1025. [CrossRef] 10. Robbins, P.F.; Morgan, R.A.; Feldman, S.A.; Yang, J.C.; Sherry, R.M.; Dudley, M.E.; Wunderlich, J.R.; Nahvi, A.V.; Helman, L.J.; Mackall, C.L.; et al. Tumor Regression in Patients with Metastatic Synovial Cell Sarcoma and Melanoma Using Genetically Engineered Lymphocytes Reactive With NY-ESO-1. J. Clin. Oncol. 2011, 29, 917–924. [CrossRef][PubMed] 11. Vargas, B. Synovial Cell Sarcoma. Medscape Ref. 2014. Available online: https://emedicine.medscape.com/article/1257131- overview (accessed on 1 November 2020). 12. Palmerini, E.; Paioli, A.; Ferrari, S. Emerging therapeutic targets for synovial sarcoma. Expert Rev. Anticancer Ther. 2014, 14, 791–806. [CrossRef] 13. Jo, V.Y.; Fletcher, C.D. WHO classification of soft tissue tumors: An update based on the 2013 (4th) edition. Pathology 2014, 46, 95–140. [CrossRef] 14. Song, S.; Park, J.; Kim, H.J.; Kim, I.H.; Han, I.; Kim, H.-S.; Kim, S. Effects of Adjuvant Radiotherapy in Patients with Synovial Sarcoma. Am. J. Clin. Oncol. 2017, 40, 306–311. [CrossRef] 15. Nakamura, T.; Saito, Y.; Tsuchiya, K.; Miyachi, M.; Iwata, S.; Sudo, A.; Kawai, A. Is perioperative chemotherapy recommended in childhood and adolescent patients with synovial sarcoma? A systematic review. Jpn. J. Clin. Oncol. 2021, 51, 927–931. [CrossRef] 16. Casali, P.G.; Picci, P. Adjuvant chemotherapy for soft tissue sarcoma. Curr. Opin. Oncol. 2005, 17, 361–365. [CrossRef] 17. Chao, C.; Al-Saleem, T.; Brooks, J.J.; Kraybill, W.G.; Eisenberg, B. Vascular Endothelial Growth Factor and Soft Tissue Sarcomas: Tumor Expression Correlates With Grade. Ann. Surg. Oncol. 2001, 8, 260–267. [CrossRef][PubMed] 18. Martín-Liberal, J.; Pousa, A.L.; Martin-Broto, J.; Cubedo, R.; Gallego, O.; Brendel, E.; Tirado, O.M.; Del Muro, X.G. Phase I trial of sorafenib in combination with ifosfamide in patients with advanced sarcoma: A Spanish group for research on sarcomas (GEIS) study. Investig. New Drugs 2014, 32, 287–294. [CrossRef][PubMed] 19. D’Angelo, S.P.; Melchiori, L.; Merchant, M.S.; Bernstein, D.; Glod, J.; Kaplan, R.; Grupp, S.; Tap, W.D.; Chagin, K.; Binder, G.K.; et al. Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma. Cancer Discov. 2018, 8, 944–957. [CrossRef] 20. Alvegård, T.A.; Berg, N.O. Histopathology peer review of high-grade soft tissue sarcoma: The Scandinavian Sarcoma Group experience. J. Clin. Oncol. 2016, 7, 1845–1851. [CrossRef][PubMed] 21. Pop, D.L.; Nodi¸ti,G.; Abu-Awwad, A.; Mali¸ta,D.C.; Zamfir, C.L.; Grigora¸s,M.L.; Verme¸san,D.; Prejbeanu, R.; Faur, C.I.; H˘ar˘agu¸s, H.G.; et al. Alveolar rhabdomyosarcoma in an adolescent male patient—Case report and current perspectives. Rom. J. Morphol. Embryol. 2018, 59, 1247–1252. [PubMed] 22. Abu-Awwad, A.; Folescu, R.; Pop, D.L.; Motoc, A.G.M.; Oprea, D.M.; Tudoran, M.; Zamfir, C.; Faur, C.I.; Verme¸san,D.; Deleanu, B.N.; et al. Morphometric characteristics of fibrocartilaginous tissue in the herniated intervertebral disc. Rom. J. Morphol. Embryol. 2019, 60, 629–634. [PubMed] 23. Nielsen, T.O.; Poulin, N.M.; Ladanyi, M. Synovial Sarcoma: Recent Discoveries as a Roadmap to New Avenues for Therapy. Cancer Discov. 2015, 5, 124–134. [CrossRef] 24. Guillou, L.; Benhattar, J.; Bonichon, F.; Gallagher, G.; Terrier, P.; Stauffer, E.; Somerhausen, N.D.S.A.; Michels, J.-J.; Jundt, G.; Vince, D.R.; et al. Histologic Grade, But Not SYT-SSX Fusion Type, Is an Important Prognostic Factor in Patients with Synovial Sarcoma: A Multicenter, Retrospective Analysis. J. Clin. Oncol. 2004, 22, 4040–4050. [CrossRef] 25. Przybyl, J.; Sciot, R.; Wo´zniak,A.; Schöffski, P.; Vanspauwen, V.; Samson, I.; Siedlecki, J.A.; Rutkowski, P.; Debiec-Rychter, M. Metastatic potential is determined early in synovial sarcoma development and reflected by tumor molecular features. Int. J. Biochem. Cell Biol. 2014, 53, 505–513. [CrossRef] 26. Shi, W.; Indelicato, D.J.; Morris, C.G.; Scarborough, M.T.; Gibbs, C.P.; Zlotecki, R.A. Long-term treatment outcomes for patients with synovial sarcoma: A 40-year experience at the University of Florida. Am. J. Clin. Oncol. 2013, 36, 83–88. [CrossRef][PubMed] 27. Spillane, A.J.; A’Hern, R.; Judson, I.R.; Fisher, C.; Thomas, J.M. Synovial Sarcoma: A Clinicopathologic, Staging, and Prognostic Assessment. J. Clin. Oncol. 2000, 18, 3794–3803. [CrossRef][PubMed] 28. Ferrari, A.; Gronchi, A.; Casanova, M.; Meazza, C.; Gandola, L.; Collini, P.; Lozza, L.; Bertulli, R.M.; Olmi, P.; Casali, P.G. Synovial sarcoma: A retrospective analysis of 271 patients of all ages treated at a single institution. Cancer 2004, 101, 627–634. [CrossRef] 29. Spurrell, E.L.; Fisher, C.; Thomas, J.M.; Judson, I.R. Prognostic factors in advanced synovial sarcoma: An analysis of 104 patients treated at the Royal Marsden Hospital. Ann. Oncol. 2005, 16, 437–444. [CrossRef] 30. Guadagnolo, B.A.; Zagars, G.K.; Ballo, M.; Patel, S.R.; Lewis, V.O.; Pisters, P.W.; Benjamin, R.S.; Pollock, R. Long-Term Outcomes for Synovial Sarcoma Treated With Conservation Surgery and Radiotherapy. Int. J. Radiat. Oncol. 2007, 69, 1173–1180. [CrossRef] 31. Radaelli, S.; Stacchiotti, S.; Casali, P.G.; Gronchi, A. Emerging therapies for adult soft tissue sarcoma. Expert Rev. Anticancer Ther. 2014, 14, 689–704. [CrossRef] 32. Mitsuyoshi, G.; Naito, N.; Kawai, A.; Kunisada, T.; Yoshida, A.; Yanai, H.; Dendo, S.; Yoshino, T.; Kanazawa, S.; Ozaki, T. Accurate diagnosis of musculoskeletal lesions by core needle biopsy. J. Surg. Oncol. 2006, 94, 21–27. [CrossRef]