SYT-SSX2 Variant of Primary Pulmonary Synovial Sarcoma With Focal Expression of CD117 (c-Kit) Protein and a Poor Clinical Outcome

Primary synovial sarcoma of the lung is an extremely rare tumor that has been recently described and characterized.1 These tumors may be monophasic or biphasic, the former being spindle cell type, and must be differentiated from sarcomatoid carcinoma and metastatic sarcomas to the lung that have similar histologic features. The largest reported series of primary pulmonary synovial sarcoma comprised 25 cases, with up to 20 years of follow-up.1 Ten of the 25 patients died of the disease, with metastasis to the liver or invasion of adjacent organs; one patient died 2 years after diagnosis with metastasis to the central nervous system and bone. A characteristic chromosome t(X;18) translocation found in soft tissue synovial sarcomas was reported to also be present in a primary pulmonary synovial sarcoma.2 We report a case of primary sarcoma of the lung with the characteristic histologic and immunophenotypic features of synovial sarcoma, and the t(X;18) translocation for the SYT-SSX2 variant. Additionally, the tumor was focally positive for CD117 (c-Kit) protein. The patient had a rapidly progressive course despite treatment; she developed brain, lung, and adrenal metastasis within 6 months of initial presentation and died from fulminant disease.

A 45-year-old woman with a 20 pack-year smoking history presented to an outside facility with a 1-month history of progressive, intermittent left-sided chest pain. Chest radiography and computed tomography scans revealed a left infrahilar mass with a loculated pleural effusion. Thoracoscopy revealed several pleural-based pulmonary masses, and biopsies of these masses were interpreted as carcinosarcoma of the lung. The patient received endolumenal brachytherapy and one cycle of therapy with ifosfamide (with mesna), carboplatin, etoposide, 5-fluorouracil, and leucovorin. She tolerated that poorly and was referred to the University of Texas Medical Branch Oncology Clinic. She subsequently received 4 cycles of gemcitabine with carboplatin and experienced a slight reduction in the size of the metastases. After completing this chemotherapy, she underwent a left pneumonectomy. After resection, the tumor was reclassified as a monophasic synovial sarcoma, based on the results of histologic, immunophenotypic, and molecular genetic studies. Two months later, the patient presented with a 2-week history of progressive, severe headache, nausea, and vomiting. A computed tomography scan showed a 7.0-mm right occipital brain lesion, and a biopsy of this lesion was found to be consistent with a metastasis from the primary pulmonary lesion. Additional staging evaluation also demonstrated new right lung and adrenal lesions. Because the patient's tumor was found to express c-Kit protein, she was started on imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corporation, East Hanover, NJ). However, despite this therapy, her clinical status deteriorated rapidly. The imatinib was discontinued after only 2 weeks, and she was discharged to a hospice facility, where she later died.

Paraffin blocks of the tumor were cut at a thickness of 4 μm and stained with hematoxylin-eosin. Additional sections were cut for immunohistochemical studies, which were performed using the standard avidin-biotin peroxidase technique and a heat-activated epitope-retrieval buffer. Briefly, the sections were heated in a microwave oven 3 times for a total of 5 minutes in 0.01M sodium citrate buffer, pH 6.0. The color reaction was developed with the substrate 3,3′-diaminobenzidine tetrahydrochloride (Sigma, St Louis, Mo). The primary antibodies used are listed in the Table.

Grossly, the left lower lobe showed a well-circumscribed, nonencapsulated, subpleural mass with pushing borders; it measured 9.0 × 6.5 × 6.0 cm. The cut surface was solid tan-white with areas of necrosis. The tumor was not connected with the bronchial tract in any way. The overlying pleura was puckered.

Histologically, the tumor appeared to be a fascicular spindle cell neoplasm with uniform, tapering nuclei; pale and poorly defined cytoplasm; and a collagenous stroma (Figure, a). The tumor contained focal areas that were markedly hyalinized and myxoid. The mitotic count was less than 5 per 10 high-power fields; however, the tumor showed extensive areas of necrosis, possibly related to the previous chemotherapy.

The neoplastic cells stained strongly and diffusely positive for vimentin, Bcl-2 (Figure, b), and CD99 (Figure, c). In addition, focal positivity for EMA, AE1/AE3, and cytokeratin 7 was present. Tumor cells were negative for CAM 5.2, cytokeratin 20, cytokeratin 31, cytokeratin 34, CD45, desmin, smooth muscle actin, thyroid transcription factor 1, and S100 protein. Tumor cells were focally positive for CD117 (Figure, d).

Molecular genetic study performed at the Armed Forces Institute of Pathology (AFIP), Division of Pulmonary and Mediastinal Pathology, using a reverse transcriptase polymerase chain reaction assay showed evidence of a gene fusion resulting in the SYT-SSX2 variant. This gene fusion is usually caused by the t(X;18) translocation between the short arm of the chromosome X and the long arm of chromosome 18.

Primary pulmonary synovial sarcomas are very rare tumors, and their clinical course is largely unknown. The only large series of patients from the AFIP reports an almost equal gender distribution and a mortality rate of 55% in 18 of the 25 patients who had follow-up from 1 to 20 years.1 Six of the 10 patients who died had metastatic disease, and 4 died of unrelated causes and had no evidence of disease at death. Four of the patients who were alive had either recurrence or metastasis from 1 to 7 years after diagnosis, and 4 were well without evidence of disease from 2 to 20 years after diagnosis. Since that study, there have been a few more case reports of primary pulmonary synovial sarcoma.2–4 Synovial sarcoma is a morphologically distinct entity. Of the 2 histologic types, the biphasic type is easily diagnosed based on the presence of both epithelial and spindle cell components. The monophasic type is difficult to diagnose because it has a uniform spindle cell pattern and thus may be confused with other malignant spindle cell neoplasms, such as fibrosarcoma, hemangiopericytoma, leiomyosarcoma, and spindle cell carcinoma or carcinosarcoma. The initial diagnosis in the patient we describe was sarcomatoid carcinoma, but she had no response to the standard therapy used for lung carcinomas. Immunohistochemical, electron microscopy, and molecular genetic studies have been extremely useful in the diagnosis of this tumor.

Synovial sarcomas of soft tissue may occur at any age; however, the peak incidence is between 10 and 35 years. More than 60% of soft tissue synovial sarcomas arise in the lower limbs, especially the thigh. A small number of cases have been reported to occur in the abdominal wall, head and neck, mediastinum, and lung or pleura.5 Although many of these tumors occur close to articular structures, it is no longer believed that they arise from the synovium. It is interesting that many patients with soft tissue synovial sarcoma report pain, sometimes long standing, and often preceding the appearance of a palpable mass in the soft tissues. In the AFIP series of primary pulmonary sarcomas, 7 of the 25 patients reported chest pain, and 9 patients had hemoptysis, shortness of breath, cough, or fever; 9 patients were asymptomatic.1 Our patient also presented with progressively severe chest pain. The reason for chest pain in patients with lung lesions is not clear, but it may be due to pleural irritation or possibly due to production of humoral factors such as cytokines.

Synovial sarcomas can now be diagnosed with confidence because of recent demonstration of a tumor-specific chromosome t(X;18)(p11.2;icq11.2) translocation that results in the production of 2 principal fusion genes, SYT-SSX1 and SYT-SSX2.5,6 The balanced reciprocal translocation of t(X;18)(p11.2;icq11.2), which we also found in this case, has been reported in 90% of all synovial sarcomas. This translocation involves the SYT gene on chromosome 18 and either the SSX1 or SSX2 gene on the X chromosome. The function of the fusion protein remains uncertain; the SYT protein appears to function as a transcriptional activator, whereas the SSX proteins appear to function as transcriptional corepressors.7 It is not known if one or both functions persist in the fusion protein. The SYT-SSX fusion messenger RNA can be detected by using reverse transcriptase polymerase chain reaction or fluorescence in situ hybridization methodology. Both monophasic and biphasic tumor types have fusion genes; however, the biphasic tumors have only the SYT-SSX1 fusion gene, whereas the monophasic tumors can have either one of the 2 fusion genes. This gene expression pattern is of interest not only in diagnosing synovial sarcoma, but also in predicting the prognosis. Soft tissue synovial sarcomas that express the SYT-SSX1 fusion protein (irrespective of the histologic type) have a poorer prognosis than those expressing the SYT-SSX2 fusion protein, with respective 5-year progression-free survival rates of 42% versus 89%.8,9 Whether expression pattern has the same prognostic significance in the pulmonary synovial sarcomas remains to be seen. In the present case, the fusion gene type was SYX-SSX2, but the patient had a poor response to therapy and developed brain and adrenal metastases within 6 months of diagnosis.

A recent report of strong c-Kit expression in several pediatric soft tissue sarcomas, including synovial sarcomas,10 prompted us to look for c-Kit expression in our case since therapeutic modalities are available for treating c-Kit–expressing tumors with good results. In the case presented here, the pulmonary tumor showed only focal c-Kit positivity, and there was no c-Kit expression in the metastatic brain tumor. The lack of expression in the brain tumor may be related to the treatments given before the lung tumor was removed, or it may represent the aggressiveness of the tumor. The patient had no response to treatment with imatinib, although it was given for only a short period of time, and at that point her status had begun to deteriorate. It is also unclear if the c-Kit expressed in this patient's lesion was actually functional, was merely an epiphenomenon, or was expressed only in the primary tumor because the subsequent metastatic lesions were derived from a clone that did not express c-Kit. In any of these situations, one must expect that the imatinib therapy would in all likelihood be ineffective.

Primary pulmonary synovial sarcoma is a rare entity that has been characterized on the basis of its immunophenotype and a distinct chromosome translocation. An early and definitive diagnosis may provide the opportunity for new and specific target-based treatment. Further studies of this tumor, including follow-up and treatment responses, would help in defining the clinical course and survival of patients with this rare malignancy, and may provide a better understanding of this disease.