Clear cell sarcoma with aggressive transformation to intra-abdominal metastasis after carbon ion radiotherapyTo the Editor:Clear cell sarcoma (CCS) is an extremely rare malignancy accounting for less than 1% of all soft tissue sarcomas.1 It typically arises in the extremities of young adults and often takes longer to diagnose because of its slow progression.2,3.4 Chemotherapy and radiation therapy have limited efficacy in CCS, but surgery is an option for localized disease. However, due to its risk of recurrence and metastasis, CCS heralds a poor prognosis.3 We report the case of a 13-year-old male with CCS on the chest wall. Carbon ion radiotherapy effectively shrunk the primary tumor. Six months after treatment, however, multiple metastatic lesions were found in the liver, and the patient eventually succumbed due to hemorrhagic shock.The patient is a 13-year-old male who initially consulted for a 1-month history of left chest and back pain. Plain chest x ray and chest computed tomography (CT) revealed a mass in the left middle thorax which extended over four ribs and the chest wall (Fig. 1A-C). The mass extended into the spinal canal but without spinal cord compression (Fig. 1C). The left axillary lymph node was enlarged with calcification (Fig. 1B). Positron emission tomography (PET)-CT demonstrated a maximum standardized uptake value (SUV) of 17.7 without evidence of distant metastasis. Histopathological examination of the lymph node biopsy revealed epithelioid to spindle-shaped cells arranged in nests, separated by fibrous septa. The tumor cells exhibited clear to amphophilic cytoplasm and oval nuclei with prominent nucleoli (Figure 1D). On immunohistochemistry, the tumor cells were positive for HMB-45, MelanA, SOX-10, and S-100 protein. Fluorescence in situ hybridization analysis demonstrated a break-apart pattern with separated red and green signals within a single cell, confirming the presence of an EWSR1 rearrangement and leading to the diagnosis of clear cell sarcoma. Furthermore, EWSR1::ATF1 was detected on comprehensive genomic profiling tests.The case was deemed inoperable because of the high risk of flail chest and spinal cord damage. Although conventional chemotherapy and radiation therapy were reported to have no significant effect on CCS, recent reports have demonstrated the efficacy of carbon ion radiotherapy (C-ion RT) for bone and soft tissue tumors.5 This case was considered to be a good candidate for C-ion RT due to the unresectable tumor and absence of distant metastasis.For the C-ion RT setup, the initial treatment was two courses of chemotherapy with doxorubicin and ifosfamide. However, the patient was not responsive to conventional chemotherapy. Afterward, he underwent C-ion RT. A detailed irradiation plan was made to minimize radiation exposure to vital organs near the tumor, such as the heart, lungs, and the spinal canal (Fig. 1E-G). The clinical radiation dose (in Gy) of C-ion RT was based on the relative biological effectiveness (RBE), calculated by multiplying the physical dose with the RBE of C-ion beams. A common protocol for soft tissue sarcoma involves a total set dose of 64.0, 67.2, or 70.4 Gy in 16 fractions.6 In this case, due to the proximity of the tumor to the spinal cord, 64 Gy of C-ion RT in 16 fractions was administered over a 4-week period with 4 consecutive days in a week. The entire tumor was irradiated over a single period to avoid the increased risk of side effects. Three months after C-ion RT, the tumor shrunk from 50 to 40 mm, and the area of hypointensities on diffusion-weighted Magnetic resonance imaging (MRI) was also localized. PET-CT showed a decrease in maximum SUV from 17.7 to 7.1 (Fig. 2A-F). None of the common side effects of C-ion RT were observed during and after treatment, including interstitial pneumonia, rib fracture, and lower limb paresthesia.Repeat MRI and PET-CT indicated that C-ion RT was effective against the primary tumor. However, 5 months after C-ion RT, the patient experienced intermittent abdominal pain, and abdominal CT revealed multiple masses in the liver and intra-abdominal lymph nodes (Fig. 2G-I). Further laboratory work-up indicated disseminated intravascular coagulation. A relapse of CCS was suspected, but the patient died of hemorrhagic shock from a ruptured tumor on the day of admission before any further examinations could be done.This case was managed with C-ion RT as an alternative to surgery. C-ion RT is known for its high-precision dose distribution and high biological effectiveness. The 5-year local control rate of C-ion RT for all inoperable bone and soft tissue tumors is 68% in Japan, and it is expected to be as effective as surgery.5 The patient’s posttreatment MRI and PET-CT suggested that C-ion RT can be a good option for treating the primary tumor of CCS. However, the patient developed distant metastasis and died a few months after C-ion RT. CCS is prone to relapse (40%) and metastasis (20%–50%), resulting in a poor prognosis.4 Some indicators of poor prognosis include a tumor size more than 5 cm, presence of regional lymph node metastasis, and necrosis.2 The patient in this report had a large tumor size with lymph node metastasis, which indicate a high risk of relapse. Recently, new drugs such as histone deacetylase inhibitors, BRD4 inhibitors, and PRMT5 inhibitors reportedly exert an antiproliferation effect with the reduced expression of EWSR1-ATF1, the oncogenic driver fusion gene of CCS.7,8 In conclusion, C-ion RT was demonstrated to have a potent therapeutic effect on the primary tumor of CCS, and its combination with novel drugs can potentially improve the long-term prognosis of CCS with metastasis.
