Synovial sarcoma from imaging to immunohistochemistry

INTRODUCTION

Synovial sarcoma is the most common non-rhabdomyosarcomatous soft tissue sarcoma in the pediatric population and the fourth most common primary soft tissue malignancy overall, classified under malignant tumor of uncertain differentiation, according to the 5^th World Health Organization (WHO) classification of soft tissue tumors 2020.^[1,2] It is a misnomer since neither the tumor arises from the synovium nor synovial structures such as tendons, bursae, or sheaths; rather, it arises from the primitive mesenchymal cells adjacent to the joints. Due to their indolent nature, these tumors are often clinically misinterpreted as benign entities such as synovitis, myositis, or bursitis.^[3] However, this tumor is invariably a high-grade malignancy that requires a long-term follow-up due to a high propensity of recurrence or metastasis, even after a complete surgical resection.^[1] It is relatively sensitive to chemotherapeutic agents despite being an aggressive tumor.^[4]

CASE REPORT

A woman in her late 20 s was referred to our institute with complaints of pain and swelling in her right elbow for 1-year duration [Figure 1]. On examination, the swelling was firm to hard, warm on touch, and associated with blackish skin discoloration. She had pallor along with palpable right-sided axillary lymph nodes. She underwent a preliminary radiological investigation.

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Figure 1:

A woman in her late 20s presented with pain and swelling in the right elbow and was diagnosed with synovial sarcoma. Clinical image showing a large swelling in the right elbow (arrow), firm to hard in consistency, warm on touch, and associated with blackish discoloration of the overlying skin.

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Right elbow radiographs [Figure 2] showed a large well-defined, soft tissue lesion with indistinct margins extending from the distal third humeral shaft to the proximal third forearm without calcification or lucencies. There was an associated cortical irregularity and periosteal reaction in the humeral condyles, radial head, and medial aspect of the proximal ulna with periarticular osteopenia. An ultrasound was performed to assess the solid-cystic nature of the lesion. Ultrasonogram of the right forearm [Figure 3a] in the transverse plane showed isoechoic to hyperechoic soft tissue mass in the muscular plane with numerous cystic spaces and necrotic areas. On color and spectral Doppler imaging [Figure 3b and c], there was internal vascularity and low-flow monophasic waveform. Panoramic imaging [Figure 3d] demonstrates the entire extent of the lesion. To characterize and narrow down the differentials, an magnetic resonance imaging (MRI) was ordered. Preceding an MRI, the differentials considered were juxtacortical osteosarcoma, synovial sarcoma, any other high-grade sarcoma, and metastasis from an unknown primary. Right elbow MRI [Figure 4a-e] showed a multi-lobulated soft tissue mass in the proximal meta-diaphyseal region of the right radius and ulna in the anterior and medial compartment, measuring 10.8 cm × 10.5 cm × 18.4 cm. The mass was predominantly solid with numerous cystic and necrotic areas. It was hyperintense T2W sequence and heterogeneous on the T1W sequence and showed heterogeneous enhancement on the post-contrast sequence. The mass extended into the medulla with cortical erosion of the bone underneath and altered marrow signal intensity in the distal third of the humeral shaft and proximal third of the radial and ulnar shaft. There was no joint space involvement.

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Figure 2:

A woman in her late 20s presented with pain and swelling in the right elbow and was diagnosed with synovial sarcoma. (a and b) Anteroposterior radiographs of the right elbow show a large well-defined soft tissue lesion (arrow) with indistinct margins extending from the distal third humeral shaft to the proximal third forearm without calcification or lucencies within it. There is cortical irregularity and periosteal reaction (arrowhead) in the humeral condyles, radial head, and medial aspect of the proximal ulna with periarticular osteopenia. (c) Lateral view shows a large well-defined soft tissue lesion (arrow) with indistinct margins extending from the distal third humeral shaft to the proximal third forearm without calcification or lucencies within it.

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Figure 3:

A woman in her late 20s presented with pain and swelling in the right elbow and was diagnosed with synovial sarcoma. Ultrasonography of the right forearm in axial view (a) shows isoechoic to hyperechoic soft tissue mass in the muscular plane of the right forearm with numerous cystic spaces and necrotic areas. On color and spectral Doppler (b and c), there was internal vascularity and low-flow monophasic waveform. Panoramic imaging (d) demonstrates the entire extent of the lesion.

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Figure 4:

A woman in her late 20s presented with pain and swelling in the right elbow and was diagnosed with synovial sarcoma. (a) Magnetic resonance imaging HASTE axial shows a multi-lobulated soft tissue mass (arrow) with numerous cystic and necrotic areas (asterisk), in the anterior and medial compartment. (b) T2W sagittal shows a multi-lobulated soft tissue mass (arrow) with numerous cystic and necrotic areas in the anterior and medial compartment. (c) Axial PDFS sequence of the right elbow on the axial plane shows a multi-lobulated hyperintense soft tissue mass (arrow) with altered marrow signal intensity in the distal third of the humeral shaft and proximal third of the radial and ulnar shaft (thick arrow). There is no joint space involvement. (d) Sagittal T1W of the right elbow shows heterogeneous intensity multi-lobulated soft tissue mass (arrow) arising from the proximal meta-diaphyseal region of the right radius and ulna with extension into the medullary cavity with cortical erosion of the underlying bone (arrowhead). (e) Sagittal post-contrast T1W sequence shows heterogeneous post-contrast enhancement (black arrow) of the mass lesion with involvement of the capitulum of the humerus (white curved arrow).

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Before the patient was taken up for an image-guided biopsy, the treating physician performed a freehand tru-cut biopsy from the palpable mass; however, the histopathology was inconclusive. A decision was therefore made to go ahead with an ultrasound-guided axillary lymph node biopsy. Histopathology of the biopsy on lower-power magnification showed a malignant tumor composed of oval to short spindle cells arranged in non-descript sheets with geographic areas of necrosis, suggestive of a poorly differentiated type [Figure 5a-e]. On immunohistochemistry, the tumor was positive for transducin-like enhancer (TLE1) (diffusely) and Antibody Epithelial 1/Antibody Epithelial 3 (AE1/AE3) (very focal) while negative for Natural Killer 2 (NK2) homeobox 2 (NKX2.2) and epithelial membrane antigen (EMA). Integrase interactor (INI1)/SWItch defective/Sucrose Non Fermenting (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1) showed weak to absent staining. Synovial sarcoma was finally diagnosed with the help of the immunostains mentioned above.

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Figure 5:

A woman in her late 20s presented with pain and swelling in the right elbow and was diagnosed with synovial sarcoma. (a) Hematoxylin and eosin stain on x10 (lower magnification) shows a malignant tumor composed of oval-to-short spindle-shaped cells arranged in sheets with interspersed thin-walled branching blood vessels. (b) x45 (higher magnification) shows monomorphic cells with round to oval to short spindle -shaped nuclei that suggest a poorly diffferentiated tpye. (c) On immunohistochemistry, tumor cells showing focal expression of AE1/AE3, (d) tumor cells showing diffuse, intense positivity for transducin-like enhancer 1, (e) tumor cells showing weak to absent staining pattern for integrase interactor 1/subfamily B member 1.

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DISCUSSION

As compared to soft tissue sarcoma of other types that have exponentially increased risk in the sixth decade of life, synovial sarcoma usually presents in children and young adults, with a mean age of 35 years.^[1,5] Patients often complain of indolent swelling with or without pain for a long duration.^[3,5]

On radiographs, the mass shows nonspecific juxta-articular soft tissue opacity with lobulated margins. There is remodeling of the underlying bone in the form of superficial erosion, periosteal reaction, and osteoporosis. Punctate peripheral or eccentric calcification is seen in 30% of cases.^[1,3,6] Similar to a plain radiograph, computed tomography is also a rare diagnostic modality due to its poor soft tissue resolution. The attenuation of mass is similar to or lower than a muscle.^[4] Multiplanar reconstruction, 3D reconstruction, and higher spatial resolution help the treating physician in surgical planning. On ultrasonogram, the mass is heterogeneous with intermediate echogenicity.^[1] Soft tissue sarcomas are best evaluated on MRI.^[1,7] The mass is round or lobulated with intervening septa.^[1] On T1W, the mass is iso to hyperintense and heterogeneously hyperintense on T2W. The pattern of enhancement can be diffuse, heterogeneous, or peripheral. Enhancing solid areas helps in recognizing cellular areas that should be biopsied. The cystic, necrotic, and hemorrhagic areas are hyperintense; cellular tissue is isointense; and calcified and fibrous tissue is hypointense, this pattern is called “triple sign” on T2W imaging.^[1,3] Multiple cystic areas with hemorrhage form a picture similar to the “bowl of grapes.”^[1] Smaller lesions (<5 cm) are homogeneously T2 bright, which might be difficult to differentiate from benign lesions such as nerve sheath tumors and vascular malformations.^[8]

Demonstration of cytological abnormality t (X;18) (p11; q11) is highly specific for this tumor, which leads to SS18::SSX gene fusion. This gene can be detected on fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction, which constitutes the diagnostic gold standard for the diagnosis. However, this can have practical limitations related to cost and expertise.^[1,3,9] The tumor shows mesenchymal and epithelial differentiation, and on histology, it is divided into three subtypes – monophasic, biphasic, and poorly differentiated.^[1] Diagnosing synovial sarcoma solely on histopathological examination and with small biopsies can be challenging as monophasic synovial sarcoma resembles malignant peripheral nerve sheath tumor, solitary fibrous tumor, and dermatofibrosarcoma protuberans. Ewing’s sarcoma is a close differential of poorly differentiated type.^[9]

Immunostains to substantiate synovial sarcoma diagnosis include EMA, cytokeratin 7 (CK7), AE1/AE3, Microneme protein 2, B-cell lymphoma 2, cluster of differentiation (CD34), INI1, and TLE1.^{[4, 7, 10]} CK7, pan-keratin, and EMA are positive in 90% of cases of synovial sarcoma. Other soft tissue tumors such as solitary fibrous tumors show positivity for CD34, which is negative in synovial sarcoma. TLE 1, an immunohistochemical marker, is a highly sensitive, although not very specific immunohistochemical marker for a synovial sarcoma diagnosis.^[9] Positive immune expression of TLE1 is included in the acceptable criteria for diagnosing synovial sarcoma as per the recent WHO classification of bone and soft tissue tumor 5^th edition 2020. Its sensitivity is 95.2%, while specificity concerning the close differentials of synovial sarcoma is 72%^[4] TLE1 is cost-effective and efficient and it gives quick results when compared with the FISH technique.^[4] A weak to absent (mosaic) of INI1/SMARCB1 is also seen in synovial sarcoma, wherein most other sarcomas retain INI expression with 88% sensitivity and 97% specificity.^[10] Lately, SS18-SSX fusion antibody has been identified for the diagnosis of a synovial sarcoma, with a sensitivity of 95% and specificity of 100%. This in combination with SSX antibody ( SSX C-terminus) is a surrogate for the molecular diagnosis of synovial sarcoma.^[11]

Juxtacortical osteosarcoma is a close mimic of synovial sarcoma on imaging. Both tumors show cortical erosion, medullary invasion, and large heterogeneously enhancing soft tissue mass. Table 1 differentiates both of them.

CONCLUSION

Young adults presenting with painless soft tissue swelling in the extremity should be suspected of soft tissue sarcoma. Both radiological and pathological findings along with immunohistochemical markers are useful in narrowing down the differentials as either of them is non-specific.