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.