SS, predominately arising in the soft tissue, can also occur primarily at intrathoracic sites such as lung, pleura, mediastinum, and heart. It was historically believed to arise from synovium (hence the name synovial sarcoma), but this concept has largely been abandoned and significant debate exists over the true cell of origin. Therefore, the newest World Health Organization soft tissue classification categorizes SS as a “tumor of uncertain differentiation.”
Definition
• A mesenchymal spindle cell neoplasm that demonstrates variable epithelial differentiation and possesses a specific chromosomal translocation, t(X;18)(p11;q11), resulting in the fusion of SYT and SSX genes
Clinical features
Epidemiology
• Primary intrathoracic sarcomas are exceedingly rare; the vast majority are metastatic from primary soft tissue sites. Because of diagnostic challenges and continued reclassification, it is difficult to accurately report meaningful epidemiological data for intrathoracic SS
Presentation
• Common signs and symptoms (dyspnea, coughing, chest pain, hemoptysis, and incidental radiographic findings) are similar to other lung tumors and correlate with location
• There is no gender bias
• Age range shows wide variation; large studies reveal an older mean age than soft tissue SS
Macroscopy and location
• Primary pulmonary SSs can arise in any segment of any pulmonary lobe but are most often peripheral, well-circumscribed, nonencapsulated lesions
• Size range is wide: 0.6 to 17 cm in greatest dimension
• Gross morphological features are similar to its soft tissue counterpart, demonstrating a soft tan, multinodular cut surface often with cystic degeneration and necrosis
Tumor spreading and staging
• Recurrence and local spreading occurs to chest wall, pericardium, diaphragm, and paraspinal soft tissues
• Systemic metastases occur in approximately 25% of patients, whereas metastases to mediastinal lymph nodes are uncommon
Prognosis and treatment
• SS, intrathoracic and soft tissue, is considered an aggressive tumor; most are seen as grade II (Fédération Nationale des Centres de Lutte Contre le Cancer)
• Primary pulmonary SS has a poor prognosis with an overall 5-year survival range between 36% and 76%. Many criteria have been purported to influence prognosis; however, the main prognostic factor continues to be complete surgical resection
• SYT–SSX fusion type has been correlated with prognosis in soft tissue SS; however, this remains controversial and unproven
• Because of its rarity, no clear guidelines exist for the optimal treatment of intrathoracic or soft tissue SS. Current treatment includes lobectomy or pneumonectomy, followed by adjuvant radiation or chemotherapy or both
• Compared with other sarcomas, SS is moderately chemosensitive: it has a 50% response rate to ifosfamide- and doxorubicin-based regimens. Therapy for soft tissue SS results in improved time to local recurrence and recurrence-free survival, with an overall trend toward increased survival rate
Pathology
Histology
• Intrathoracic and extrathoracic SS are histologically identical, displaying two major subtypes, biphasic and monophasic
• Biphasic tumors contain both epithelial and spindle cells
• The epithelial component can form glands, cords, or nests, and the tumor cells are characterized by ovoid nuclei and abundant cytoplasm. Limited biopsies may only sample the glandular component, leading to an erroneous diagnosis of adenocarcinoma
• The spindle cell component is arranged in dense cellular sheets or vague fascicles, and most display prominent hemangiopericytoma-like vessels. A variable amount of stromal and focal myxoid change is often observed. Microcyst formation is not uncommon, and mast cells may be abundant. The spindled tumor cells have uniform, oval to round nuclei, sparse cytoplasm, and indistinct cell borders, which creates the appearance of overlapping nuclei
• Primary pulmonary SS predominately is seen as the monophasic spindle cell subtype, lacking the glandular structures
• The monophasic glandular subtype is remarkably rare
Immunopathology/special stains
• The current gold standard for diagnosis of SS is the demonstration of t(X;18), or SYT–SSX fusion product, by FISH, RT-PCR, or cytogenetics combined with morphological features. However, immunohistochemical analysis can be useful in narrowing the differential diagnosis
• In SS, the most useful positive markers are cytokeratins, epithelial membrane antigen (EMA), CD99, BCL2, and transducin like enhancer-1 (TLE-1), whereas some key negative markers are used to rule out other entities
• Cytokeratins are expressed in 90% of the epithelial component and occasionally in spindle cells. CK7 and CK19 are often used because these markers are usually negative in malignant peripheral nerve sheath tumor and Ewing sarcoma
• EMA is more widely expressed than cytokeratins, particularly in the poorly differentiated subtype
• CD99 cytoplasmic expression in epithelial tumor cells and membranous expression in spindle cells is seen in greater than 50% of SS. Ewing sarcomas are also positive for CD99 and may enter the differential for undifferentiated subtypes of SS
• BCL2 is positive in both epithelial and spindle component in the majority of SS
• TLE-1 has recently been described to be positive (nuclear) in more than 90% of SS; however, it is also positive in a significant number of peripheral nerve sheath tumors but is rare to absent in other tumors
• CD34 is usually absent, in contrast to strong and diffuse positivity in solitary fibrous tumors
• Muscle markers: calponin is usually positive, desmin is usually negative, and muscle-specific or smooth muscle actin can be observed focally; vimentin is positive in spindle cells
Cytogenetics and molecular genetics
• t(X;18)(p11;q11) is specific for SS and can be detected cytogenetically in more than 90% of cases
• The translocation results in a fusion gene composed of SYT, from chromosome 18, and either SSX1 or SSX2, from chromosome X. By careful FISH or PCR analysis the fusion transcript can be detected in close to 100% of cases
• SYT and SSX genes encode nuclear proteins, which lack DNA-binding domains but have the capacity for protein–protein interactions. The fusion product is thought to mediate binding of transcriptional regulators, possibly playing a role in important epigenetic modifications such as methylation
Main differential diagnoses
• Metastatic SS of the lung: clinical correlation is essential
• Spindle cell carcinoma, malignant mesothelioma, small-cell carcinoma, thymoma, pleuropulmonary blastoma, solitary fibrous tumor, Ewing sarcoma, and other mesenchymal spindle cell tumors
Fig 1 Pulmonary synovial sarcoma. A, Low power shows a highly cellular tumor. B, Higher power shows tumor infiltrating lung parenchyma.
Fig 2 Pulmonary synovial sarcoma. A, Tumor cells have scant cytoplasm and oval-to-spindled nuclei. B, Nuclear crowding and overlap, as seen here, is a characteristic feature.
Fig 3 Pulmonary synovial sarcoma. Immunohistochemistry is positive for CAM5.2 (cytoplasmic) (A) and EMA (B). C, TLE-1 shows nuclear positivity in the majority of tumor cells. Note negative endothelial cells.