Late metastasis in Ewing sarcoma

To the editor. Ewing sarcoma (EWS) is the second most common malign bone tumor of adolescence and young adulthood after osteosarcoma.1,2 Up to 40% of patients suffering from localized primary EWS sustain a relapse.3,4 The median time from initial diagnosis to relapse is 1.3 to 2.3 years. Only 10% will experience tumor recurrence beyond five years.3,5–8 In the early 1990s, a 21-year-old female patient was diagnosed with EWS of the right femur and received perioperative chemotherapy with VAIA (vincristine, adriamycin, ifosfamide, actinomycin D) according toCESS86,9 wide tumor resection, implantationof an allograftwith intramedullary nailing, and postoperative radiotherapy. Twenty-nine years later, the patientwas referred to our department due to a pulmonary lesion that had been found incidentally on standard chest X-ray. Chest computed tomography (CT) revealed a subpleural lesion with blurred contours and a maximum diameter of 2.4 cm. F-18 flouro-deoxy-glucose-positron emission tomography showed solitary increased and polymorphous tracer uptake in the apicoposterior segment of the left upper lobe. Upon CT-guided fine-needle biopsy, hypercellular round cell tumor tissue was obtained. Immunohistochemistry revealed CD99 expression in 100% of tumor cells and nuclear expression with NKX2.2. Molecular analysis using the Archer Fusion Plex Sarcoma Panel revealed EWSR1-FLI1 gene fusion. Interdisciplinary consensus yielded the diagnosis of a solitary, very late metastasis of EWS. Preoperative chemotherapy with irinotecan and temozolomide was administered, achieving stable disease according to the current RECIST 1.1 criteria in chest CT scan after 2 cycles. Wedge resection of the metastasis was performed via lateral minithoracotomy. Histological examination revealedwide parenchymatous margins but diffuse infiltration of the pleura. The patient underwent postoperative radiotherapy. Six months after surgery, she presented with a fluidothorax caused by pleural sarcomatosis with malignant cells containing EWSR1-FLI1. Further chemotherapy was offered but refused by the patient. Paulussen et al. compared event-free survival in patients with localized EWS receiving VAIA (as in our case) or EVAIA (etoposide+ VAIA), with the latter being introduced in the 1990s. Recurrence risk reduction of 17% was observed in patients treated with EVAIA in comparison to VAIA.10 Thus, late tumor recurrence is likely to be higher among patients treated before the 1990s.11 While mechanisms of tumor dormancy are relatively well known in many sarcomas, they still remain to be explored in EWS.12 Antiangiogenic signals play an important role in maintaining dormancy in dormant osteosarcoma cells, whereas proangiogenic signals promote renewed increase of activity and growth in micrometastases. Major operations seem tobe linked to awakeningof dormantmicrometastatic lesions,whichmost likely is basedon considerable cytokine release due to surgery.12 However, the patient described herein had last undergone surgery eight years before pulmonarymetastasis was discovered. With29years, this casedescribes the longest time spanbetween initial EWS diagnosis and relapse in the literature, raising awareness that EWS can develop very late metastases.