Synovial sarcoma

Tumor biology and incidence

Malignant soft tissue sarcoma that usually involves tendon sheaths, bursae, and joint capsule; rarely invades joint itself
- Joint cavity involvement has been reported to occur in 5-10% of patients
Commonly found in close proximity to large joints of extremities
May arise from the pluripotential mesenchyme of the limb bud
Fourth most common sarcoma (primary three being MFH, liposarcoma, and rhabdomyosarcoma)
- Most common soft tissue sarcoma of foot and second most common malignant soft-tissue tumor in pediatric patients
- Accounts for 5-10% of all soft tissue sarcomas; approximately 800 new cases diagnosed each year in the US

Age

Adolescents and young adults between ages 15 and 40

Gender

M:F = 1.2:1

Presentation

Roughly >50% of cases present with a palpable, deep swelling or mass; may be associated with pain or tenderness
- Unusual for pain/tenderness to be only presenting symptom
Radiating or referred pain and paresthesias as secondary symptoms due to local mass effect on nerves
Typically a delayed presentation, often confused with recent or remote history of injury to extremity
May be confounded by mechanical symptoms at involved joint (ie, snapping, locking, JLT at knee joint)

Physical findings

Tenderness or pain associated with a deep tissue mass
Tissue mass may be mobile or fixed and of variable size
Masses are generally located in the extremities
Typically chronic symptoms specific to involved joint
Mechanical symptoms involving joint not uncommon
Paresthesias may be involved as well

Plain films

X-ray essential - roughly 25% of patients present with images containing evidence of calcification of tumor mass, varying from stippling to dense/amorphous deposition
Tumors may present with lobulated, round, or oval radiographic shadow on X-ray

Site

Knee most common site, followed by ankle/foot, elbow, and upper arm/shoulder

Size

May grow to >15 cm, but on average measure 3 to 5 cm
Lesions <1 cm have been reported.

Tumor effect on bone

Underlying bone tends to be uninvolved, although 15-20% of patients have bone erosion, invasion, or periosteal reaction
Massive bony destruction uncommon and seen only with large, extensive, poorly differentiated tumors
Changes in bone are secondary to pressure atrophy

CT scan

Useful to delineate size, calcification, and bony invasion/destruction (if present)

MRI

Nonspecific; has appearance of a benign lesion
Seen in extra-articular locations
Usually shows heterogeneous septated mass of low to intermediate signal on T1-weighted sequences and high signal on T2 images
High signal on T1 and T2 images has been reported, hemorrhage within tumor may be evident as fluid levels

Differential diagnosis

Myositis
Hematoma
Synovitis
Tendonitis
Bursitis

Natural history

Insidious, slow growth of tumor with potential for metastasis
Primary location for metastasis is lungs; however, lymph node involvement occurs in 3-27% of patients
Time to surgery from onset of symptoms generally 2-4 years
Poor prognosis; some molecular markers can be used to as prognostic indicators to predict course of disease

Pathology

Initially named due to a similar appearance to normal synovium microscopically; however, the tumor bears no resemblance to synovium, either ultrastructurally or immunohistochemically
Gross: Yellow to gray-white
Four distinct histologic types: classic biphasic, monophasic fibrous, monophasic epithelial, and poorly differentiated
- Classic biphasic
  - Epithelial cells characterized by large, round, or oval vesicular nuclei and abundant pale-staining cytoplasm with distinctly outlined cellular borders
  - Cells present in solid cords, whorls, or nests
  - Spaces lined by single layer of epithelial cells bearing close resemblance to normal synovium
  - Surrounding component consists mostly of well-oriented, spindle-shaped cells of uniform appearance with small amounts of indistinct cytoplasm and oval dark-staining nuclei
  - Generally indistinguishable from fibrosarcoma except for absence of herringbone pattern
- Monophasic fibrous
  - Positive immunostaining of spindle cells for keratin and epithelial membrane antigen
  - Shares identical morphological features to spindle-cell portion of the biphasic type
- Monophasic epithelial
  - Exhibits glandular structures lined with epithelial cells
  - Differential diagnosis includes metastatic and adnexal carcinoma, malignant melanoma, malignant epithelioid schwannoma, and epithelioid sarcoma
- Poorly differentiated
  - Solidly packed oval or spindle-shaped cells of small size that seem to be intermediate in appearance between epithelial and spindle cells
Less-differentiated variants grow more rapidly and tend to be poorly circumscribed, with multiple areas of hemorrhage, necrosis, and cystic formation
- Implies a worse prognosis; however, large studies have not shown that the histologic analysis of synovial sarcoma has a significant prognostic or therapeutic importance
Distinguishing feature from other sarcomas is potential presence of two distinct cell types: epithelial (seen in carcinoma) and fibrosarcoma-like spindle cells

Immunohistochemistry and cytogenetics

Both cellular elements show reactivity for cytokeratins and, less intensely, for epithelial membrane antigen
Positive immunostaining for keratin seen in nearly all biphasic synovial sarcomas and many of the monophasic fibrous type
Other positive stains include desmoplakin, Leu-7, and S-100 protein
Characteristic balanced translocation between chromosomes X and 18, t(X;18)(p11.2;q11.2) in most cases
- Translocation fuses the SYT gene from chromosome 18 to either of two highly homologous genes at Xp11, SSX1, or SSX2
- SYT-SSX1 and SYT-SSX2 function in aberrant transcriptional regulation.
- Translocation occurs in all histological variants

Diagnosis and treatment

Most commonly misdiagnosed soft tissue tumor, due to variable size, slow growth, benign appearance on imaging studies, and similarity of pain symptoms seen with simple trauma
Imaging relatively non-specific; biopsy needed to confirm diagnosis
Diagnosis based on clinical and imaging information such as patient age, symptoms, location of the tumor, presence of calcification or ossification, and MRI appearance
Treatment is includes surgical wide resection
- No minimal acceptable margin has been established
- However, there is susceptibility for microscopic infiltration of tumor cells into pseudocapsule of tumor
- Suggested margins include 1-3 cm in adults (may be impossible in most children and in deep-seated tumors adjacent to bone or important neurovascular structures)
Adjuvant chemotherapy controversial, not standard practice
- However, preoperative systemic or isolated limb perfusion chemotherapy may enable limb-sparing surgery in most patients
Local control may be improved with perioperative radiation, especially in patients with marginal rather than wide-resection
- Recommendations for radiation depend on primary site and size of tumor, histology, patient age, and extent of disease before and after surgical resection
- In general, with conventional fractionation (1×1.8 to 2 Gy/day), radiotherapy doses between 50 and 70 Gy should be administered
- In most cases, the radiation field includes the initial tumor plus 2- to 3-cm margins
Chemotherapy and/or radiation typically reserved for high risk patients

Prognosis

Factors determining high risk and associated with a worse prognosis include:
- Size >5 cm
- Deep seated
- Inadequate surgical resection
- Local recurrence
- Patient age >20 years
- Monophasic subtype
- Mitotic activity of >10 per high power field
Variant of translocation may imply prognostic value: Two studies with cohorts of 104 and 243 synovial sarcoma patients showed the overall 5-year metastasis-free survival for patients with SYT-SSX1 ranged from 42% to 53%, versus 73% to 89% for those with SYT-SSX2.
Non-metastatic synovial sarcoma: 5-year disease-specific survival rate was 62.9% in one study of 128 patient . 5-year overall survival and the 5-year metastatic-free survival rate in another study of 271 patients was 71% and 51%, respectively.