Clear cell sarcoma of soft tissue (CCSST) is an exceedingly rare tumor that originates from neural crest cells and is histologically characterized by clear cells that represent intracellular glycogen accumulation. These tumors share histological and immunohistochemical characteristics with malignant melanoma (MM). They commonly arise from tendinous sheaths and aponeuroses, with the majority described in the lower limbs, particularly around the ankles. Tumors arising in the upper extremities are rare and very few cases of primary CCSST have been described in arising in the chest wall and scapular soft tissues.
While the major cause of these tumors remains unknown, several risks have been described for soft tissue sarcomas, such as genetic predisposition, radiation therapy, lymphedema, gene mutations, and chemotherapy.
Clear cell sarcoma was initially described as “malignant melanoma of soft parts” due to their histological similarities. Both share immunohistochemical markers, and their gene expression profiling suggests that CCSST are a genomic subtype of MM. Unlike MM, however, most clear cell sarcomas are associated with a t(12;22)(q13-14;q12) translocation.
The true incidence of this tumor remains unknown. It is more common in Caucasians and estimated that men and women are equally affected with a median age of 39 years, with rare cases reported in children. It typically arises in the lower extremities, particularly around the foot and ankle, however, rare presentations in the kidney, trunk, penis, gastrointestinal tract, head and neck have been described. The 5- and 10-year overall survival for clear cell sarcoma is estimated to be 50% and 38% respectively, with later stages (III and IV) having a worse survival rate.
Clear-cell sarcoma of soft tissue appears as a macroscopically tan-gray firm mass. With a size that may range from 0.4 to 14.5 cm, it commonly shows infiltration along the tendons and aponeuroses. Immunohistochemical studies commonly show neoplastic cells positive with HMB-45, S100 protein, and Melan-A. Most cases exhibit a t(12;22)(q13;q12) translocation causing an EWSR1/ATF1 gene fusion, a finding that helps differentiate these lesions from MM.
On microscopy, the neoplastic cells show abundant cytoplasm containing numerous mitochondria. Cells are commonly polygonal and fusiform with clear cytoplasm and a centrally located round nucleus. The "clear-cell" appearance represents intracellular glycogen accumulation, as demonstrated by periodic acid-Schiff stain. Pigmented and unpigmented melanosomes, scattered multinucleated giant cells, and areas of focal necrosis are also commonly present.
CCSST commonly show highly infiltrative cells, haphazardly organized into compact nests and fascicles that dissect along dense fibrous connective tissue.
Immunohistochemistry shows antigens commonly associated with melanin synthesis, including HMB-45 and S100 within the cytoplasm and nucleus. It may also show positivity for CD99, Melan-A, neuron-specific enolase, and vimentin.
Most patients present in their thirties and forties. While CCSST commonly appears in the legs or thighs as a small tender spot or swelling, some patients may present involvement of the subcutaneous tissue and adjacent dermis and may present with ulceration of the overlying skin.
Initial evaluation should include a complete history and physical examination. As previously discussed, most patients will present with a small swelling or tender spot in the lower extremities particularly in an ankle. Patients should be asked about when the mass was noticed, the pattern of growth and evaluated for signs and symptoms that may help in early staging. Physical examination should be focused on determining size, depth, fixation to adjacent tissues, edema or possible neurovascular compromise.
In addition to plain radiographs, which is useful to evaluate for possible masses arising from bone, or to detect intralesional calcifications, cross-sectional imaging with magnetic resonance imaging (MRI) is commonly preferred for masses that arise in the extremities. MRI, unlike CT, delineates different muscle groups and may provide more information regarding the extent of these tumors. CT may provide useful information on metastatic disease, particularly if the patient has a large (greater than 5 cm) or deep-seated tumor.
Histology is essential for planning further workup and treatment. Tissue may be obtained through incisional biopsy, fine needle aspiration, or core needle biopsy. The latter has a lower incidence of complications, is highly accurate and usually preferred.
Further pathological workup for CCSST, should include immunohistochemistry. Confirmation of CCSST and differentiating this tumor from MM will also require fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR).
After treatment, discussed below, postoperative imaging is commonly performed 3 months after treatment. For lesions that are high-grade on presentation, 3- to 6-month interval imaging is preferred while low-grade lesions may be followed with annual imaging.
For localized lesions, the treatment of choice is wide surgical resection with negative margins. If complete excision is achieved, adjuvant therapy is typically unnecessary as there is no significant improvement in survival. Intralesional excision has been associated with higher recurrence rates.
Radiotherapy may improve outcome in patients who undergo close resection margins. Chemotherapy is primarily employed in patients with metastatic disease. Cisplatin-based and caffeine-assisted chemotherapy with doxorubicin and cisplatin may be beneficial in patients with metastatic disease or large tumors on presentation.
After surgical excision, patients should be followed closely due to the high rates of recurrence. Patients with higher risk may benefit from close interval imaging, while lower risk patients may be followed with yearly imaging.
The differential diagnoses of a tumor located in the proximity of tendons and aponeurosis should include paraganglioma-like dermal melanocytic tumor, MM, malignant peripheral nerve sheath tumor, synovial sarcoma and clear cell myomelanocytic tumor.
Compared to MM, CCSST usually occurs in the younger patient population, is located in deeper tissues, associated with aponeuroses or tendons, and commonly lacks epidermal involvement. Additionally, the t(12;22) translocation seen in CCSST has not been observed in malignant MM. However, there may be a significant histologic overlap.
Paraganglioma-like dermal melanocytic tumor primarily presents in the extremities of female patients, as a dermal nodule. On microscopy, it shows oval-cells arranged in packet-like groups.
Clear cell myomelanocytic tumor belongs to a family of tumors known as perivascular epithelioid cell family of tumors, which present commonly in the abdomen, usually in the ligamentum teres of the liver of young patients. Malignant peripheral nerve sheath tumor usually arises within large peripheral nerves and is negative for HMB-45.
CCSST is associated with an overall poor prognosis. A study with 75 patients showed a 69% and 21% rate of metastatic disease and local recurrence, respectively. The overall 5-year survival rate was 47% and 36% for 10-years. Furthermore, for patients who presented localized disease, the overall survival was 55% and 41% at 5 and 10 years, respectively. A case series with 52 patients showed a survival rate of 59% and 41% at 5 years and 10 years.
Another study showed 10% to 14% of patients developing regional lymph node metastasis, and a majority of all patients with CCSST eventually developing distant metastasis, most commonly to lung and bone tissue, in addition to regional lymph nodes.
Overall, the course of CCSST is regarded as relentless and progressive, usually terminating in widespread metastatic disease.
While a large percentage of patients present with indolently growing mass in the lower extremity, around 30% to 60% of patients may present pain or tenderness. A minority of patients may present with ulceration of the overlying skin.
Untreated CCSST will most likely progress to a widespread deadly metastatic disease.
Although most patients present in their 30s or 40s, the overall prognosis for CCSST is generally regarded as poor. Some patients may appear disease-free after treatment for some time and posteriorly develop local recurrence or late metastatic disease with a rapidly fatal progression. Patients should be educated about the overall poor prognosis of CCSST, individual risk factors for local or metastatic recurrence, and be provided with tumor staging before and after treatment. They should also be encouraged to follow-up closely with their healthcare providers.
Patient-centered management should include counseling on diagnostic work-up and treatment choices, individualizing patients with different risk factors for local or distant recurrence. Tumor staging should be done early, and repeated with more information, commonly after excision biopsy, and using the tumor, node, metastasis (TNM) system for patients with soft tissue sarcomas that arise in extremity/trunk.
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