Results:
A 13-year-old girl without relevant medical antecedents presented with a
4-week history of worsening pain, swelling and loss of strength in her
left upper limb. Plain radiography showed an osteolytic lesion involving
the proximal humerus, and magnetic resonance imaging (MRI) revealed a
bone lesion with characteristics of aggressiveness and associated soft
tissue mass (Fig. 1a and b). Trucut biopsy showed a heterogeneous
neoplastic proliferation with round cell nests on a collagen stroma and
osteoid foci, compatible with conventional osteosarcoma. The bone scan
and thoracic computed tomography (CT) ruled out distant metastases but
revealed two left axillary and supraclavicular nodular lesions of 17 and
21 mm, respectively (Fig. 1c). An axillary lymph node biopsy was
compatible with metastasis of osteosarcoma.
The patient started chemotherapy treatment according to Spanish Society
of Pediatric Hematology and Oncology protocol for localized osteosarcoma
(SEHOP 2010) (based on methotrexate, cisplatin, doxorubicin, and
ifosfamide) presenting a significant decrease in swelling, pain and
normalization of analytical parameters in the first weeks of treatment.
During induction chemotherapy she suffered from a spontaneous
pathological fracture. On week 11 she developed local swelling, pain and
increased levels of LDH (lactate dehydrogenase) and alkaline
phosphatase. The evaluation carried out on week 12, prior to the
loco-regional surgical treatment, showed signs of local progression with
increase of the soft tissue mass, increased diaphyseal extension and
full infiltration of the epiphysis. Local lymph nodes showed
radiological stability. The extension work-up ruled out metastatic
progression. The patient underwent upper limb amputation and lymph node
dissection, since limb sparing surgery was deemed unlikely to achieve
optimal local control after discussion in our local multidisciplinary
tumour board. The surgical specimen showed a neoplastic proliferation
with 30% post-chemotherapy necrosis and free surgical margins (R0
Ennekin). Atypical cells with epithelioid and focal rhabdoid habit were
observed, with positivity for myogenin and desmin. In other areas there
were foci of cartilage and fine osteoid (Fig. 2). The neoplasm was
reclassified as an osteosarcoma with a focal component of
rhabdomyosarcoma. Among the multiple lymph nodes resected, only two of
them showed neoplastic infiltration with similar characteristics to
those described at bone specimen.
PET-CT performed three weeks after surgery showed new cervical
adenopathies, multiple bilateral pulmonary nodules and bone lesions
compatible with metastatic progression. She received two cycles of the
VIT regimen [vincristine (1.5 mg / m2 / day, days +1
and +8), irinotecan (50 mg / m2 / day x 5 days) and
temozolomide (150 mg / m2 / day x 5 days)] in a
21-day interval. She progressed after these two cycles and ultimately
died of disease progression.
An extensive molecular analysis was performed on surgical material at
progression, including tumour whole exome sequencing (WES), RNA
sequencing and methylation profiling. It revealed 21 homologous
recombination defects that resulted in a high genomic rearrangement but
with a low mutational burden. Mutational disruption ofTSC2 (stop-gain mutation), TP53 (stop-gain mutation),CCNE1 (focal duplication and mRNA overexpression) andSETD2 (missense mutation) were revealed. A DNA Methylation-Based
Classifier for sarcomas was inconclusive. This analysis was only
available after the patient passed away and could not be used for
therapeutic purposes.