CASE REPORT
In April 2019, a 22 year old male with no past medical history presented with increasing pain in the right pelvis and inferior limb. Pain was at first managed by his general practitioner with nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids with no clear clinical benefit. In February 2020, a magnetic resonance (MRI) of right hip bone was performed, which detected a 9cm lesion extended from the femoral head to the bone neck, hyperintense on T2-weighted images suggesting intraspongious edema. A computed-tomography (CT) scan subsequently performed confirmed the presence of a vast, irregular osteolytic area and a hyperdense tissue in the great trochanter region, with a maximum depth of 15mm. In March 2020, a biopsy of the osteolytic area was performed: the histological specimen showed a proliferation of undifferentiated, small round cell positive for CD99, FLI1, vimentin and focal CD56, suggestive of Ewing sarcoma. The molecular analysis confirmed the presence of EWSR1-ERG rearrangement (21q22.2). Staging chest and abdomen CT and PET-CT scan did not detect any distant metastases; right femur head, neck, intertrochanteric region and proximal diaphysis showed a pathological hypermetabolism (SUV max 7.16), but bone marrow fine needle aspiration was negative for neoplastic cells. From April to June 2020, patient received four courses of induction chemotherapy: two cycles of vincristine, doxorubicin and cyclophosphamide (VDC), one cycle of vincristine, actinomycin-D and ifosfamide (VAI) and one cycle of etoposide and ifosfamide (IE). The following radiological assessment (chest, abdomen and right inferior limb CT scan and right hip MRI) showed disease stability. In July 2020, patient underwent surgical resection of right femur and global modular replacement system prosthesis implant. Pathological response was good, although not complete, with a 95% necrosis rate and 5% of residual sarcomatous cells. Between August 2020 and March 2021, the patient received adjuvant chemotherapy: 3 cycles of VDC, 3 cycles of VAI and 3 cycles of IE. Afterwards, follow up was started with trimestral chest, abdomen and right inferior limb CT scan and blood tests. Radiological assessments didn’t detect any signs of disease relapse; blood samples showed persistently stable G2 neutropenia, G1 anemia and G1 lymphocytopenia, consistent with recent chemotherapy. The patient experienced slowly increasing pain at his right thigh, refractory to analgesics and opioids. After one year, in August 2022, blood tests showed pancytopenia, with neutropenia G1 (N 1750 /mm3), lymphocytopenia G1 (LYMPH 0.97/mm3), thrombocytopenia G2 (PLT 74000/mm3) and anemia G1 (11.4 g/dl). Lactate dehydrogenase (655 U/L) and ferritin (1505 ug/l) levels were increased. Peripheral blood smear identified the presence of immature cells (myelocytes 4%, metamyelocytes 0.5%). Lymphocytes flow cytometry analysis, vitamin B12, protein electrophoresis, alkaline phosphatase, renal and hepatic function were preserved. At this time, MRI of right inferior limb displayed intraspongious edema of iliopubic branch, CT scan was persistently negative. No signs of recent bleeding were objectifiable. A bone marrow fine needle aspiration and a biopsy were then performed. The myelogram showed the presence of big, pleomorphic non hematopoietic cells. Ewing sarcoma bone marrow relapse was confirmed by the biopsy, where most bone marrow space was occupied by a high-grade neoplasm composed of small round cells, arranged in sheets, characterized by monotonous nuclear appearance and scant cytoplasm with focal areas of cytoplasmic clearing. Brisk mitotic activity, areas of hemorrhage and necrosis were present throughout the biopsy specimen. By immunohistochemistry, the neoplastic cells showed strong crisp membranous CD99 immunostaining and diffuse NKX2.2 nuclear immunopositivity. Conversely, terminal deoxynucleotidyl transferase (TdT), desmin and myogenin (Myf4) were negative. [Figure 1] A PET-CT was then performed, showing an intense bone marrow glucidic hypermetabolism in spine, scapulae, sternum, ribs, hipbone, humeri and femurs. At the end of August 2022 blood cell counts rapidly dropped (in particular, Hb 8 g/dL, PLT 33.000/mm3). Given the low blood cell counts which contraindicated standard polychemotherapy regimens, we decided to start first line chemotherapy with high dose ifosfamide at the dose of 1g/m2 per day, administered as a continuous infusion over 14 days, followed by a 14 days pause. The first course of such chemotherapy was started on August 24, 2022, with a 50% precautionary dose-reduction (total dose: 7 g/m2 over 2 weeks). A strict, daily monitoring of blood count was performed both during infusion and in the 2 weeks off; toxicity nadir was reached on day 17, with anemia G3 (7.3 g/dl) and thrombocytopenia G4 (PLT 21000 /mm3). Persistent hematological toxicity required one platelet and multiple red blood cells transfusions. At the beginning of the second course, blood counts improved with neutrophil count back to normal, improved hemoglobin (10.3 g/dl) and lymphocyte count (0.82 /mm3) but persisting severe thrombocytopenia (32000 /mm3). Following the second course, administered at the same reduced dose, platelet count started to slowly increase; no platelet and less red blood cell transfusions were needed. On the third cycle, thrombocytopenia was restored to G1 level (85000 /mm3), and chemotherapy dosage was increased to 80% (total dose 11 g/m2), with a good hematological and subjective tolerance. [Figure 2] After three cycles, PET-CT scan showed metabolic response. [Figure 3] Due to the persistently improved blood tests, and the normalization of platelet count, chemotherapy was prosecuted at full dose for three more cycles. Metabolic and hematological responses were associated with clinical benefit on pain and deambulation. In February 2023, after six total courses of high-dose ifosfamide, PET-CT showed progressive bone marrow disease and once again blood tests abruptly dropped, with G3 neutropenia, G2 lymphocytopenia, G1 anemia and G1 thrombocytopenia. Moreover, the patient developed vision problems, hyposthenia and hypoesthesia of lower limbs, and a brain MRI demonstrated a diffuse meningeal invasion. In March 2023, a new line of chemotherapy with Irinotecan and Temozolomide was started. Although it was administered at a reduced dose, therapy was complicated by persistent neutropenia G3 needing frequent treatment delays and dose adjustments. In July 2023, the patient was hospitalized due to paraparesis, acute urinary retention and pain; a CT scan confirmed new bone progression. He received palliative radiotherapy on painful sites and was started on oral etoposide with only minor benefits. Palliative care team was then involved, and the patient died two months later at home.