A 11-year-old male patient presented with a history of a painless mass involving the first metatarsal of the left foot that was gradually enlarging over the preceding year. A local examination confirmed a firm, 80 × 30 mm mass involving the first metatarsal of the left foot. Ankle’s range of motion was full and painless. Systemic examination did not reveal any abnormalities and laboratory investigations were unremarkable.
Plain radiographs showed mixed lytic and sclerotic changes involving the entire first metatarsal, with an indistinct permeative appearance of the cortex, associated periosteal reaction, and a subtle soft-tissue component (Figure 1A). A magnetic resonance imaging (MRI) scan showed a diffuse aggressive destructive process involving the entire first metatarsal, with heterogeneous medullary cavity enhancement, an aggressive periosteal reaction, and breach of the cortices. The lesion appeared heterogeneous, hypointense, and isointense on T1-weighted images and heterogeneous hyperintense on T2-weighted images. An associated soft-tissue component encased the metatarsal and illustrated postcontrast enhancement (Figure 1B). Systemic staging included a fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) scan that showed several skeletal lesions including the left humerus, lumbar spine, and the pelvis. An incisional biopsy confirmed the diagnosis of EWS with EWSR1 rearrangement with fluorescence in situ hybridization (FISH).
The patient received emergency radiotherapy of the spinal column prior to commencement of neoadjuvant chemotherapy after developing symptoms related to spinal cord compression secondary to skeletal metastases. After radiotherapy, neoadjuvant chemotherapy was started according to the Children’s Oncology Group EWS Protocol (AEWS0031). The duration of this chemotherapy regimen spans 48 weeks and comprises courses of vincristine (V) (1.5 mg/m2 /dose), doxorubicin (D) (75 mg/m2 / dose), cyclophosphamide (C) (1.2 g/m2 /dose) (VDC) alternating at intervals with courses of ifosfamide (1.8 g/m2 /day for 5 days per course) and etoposide 100 mg/m2 /day for 5 days per course) (IE). The patient received 5 cycles of neoadjuvant chemotherapy comprising VDC/IE before local and systemic staging was repeated to assess response to the chemotherapy. A repeat MRI scan confirmed the permeative destructive process of the first metatarsal with an interval decrease in the size of the associated soft-tissue component (Figure 1C). The follow-up positron emission tomography/computed tomography (PET/CT) showed evidence of residual disease in the known primary of the left foot with no evidence of disease elsewhere.
Definitive surgical management consisted of wide excision of the first metatarsal through a dorsomedial approach, including resection of the biopsy tract (Figure 2A). Reconstruction of the bone and soft-tissue defect was accomplished by an ipsilateral pedicled osteocutaneous fibula flap (Figure 2B). Although amputation was considered given the high risk of positive margins, the decision to perform wide resection and reconstruction was based on an extensive discussion between the patient, orthopedic oncological surgeon, and pediatric oncologist. Another contributing factor was that the patient presented with several skeletal metastases that showed an interval decrease in size on the repeat MRI. Once all wounds had healed, adjuvant chemotherapy, consisting of VDC and IE, was recommenced and weight bearing was allowed in a supportive boot. Clinical review at 3 months found a plantigrade sensate foot with no instability of the hallux (Figure 2C). On completion of the chemotherapy regimen, the patient will receive adjuvant radiotherapy for positive surgical margins.
Histology
Initial biopsy:
The pretreatment incisional biopsy consisted of a single fragment measuring 16 × 9 × 7 mm and showed a lesion composed of invasive nests of uniform small round cells with round nuclei containing finely stippled chromatin and inconspicuous nucleoli, scant clear to eosinophilic cytoplasm, and indistinct cytoplasmic membranes (Figure 3A). Immunohistochemical studies showed membranous expression of cluster of differentiation 99 (CD99) (Figure 3C) and nuclear expression of FLI1 (Figure 3D) in the tumor cells. FISH revealed rearrangement of the EWSR1 gene.
Resection specimen:
Macroscopically, the specimen consisted of the left first metatarsal with overlying skin and surrounding soft tissue and measured 60 × 50 × 35 mm. On the cut section, a white-gray lesion was present in the periosteal soft tissue with areas of hemorrhage. Microscopically, the residual tumor was mostly present in the soft-tissue infero-medial to the metatarsal with scant microscopic foci of residual tumor in the medullary cavity of the metatarsus. Histologically, it showed typical features of EWS as seen on the initial biopsy, but now with widespread squamous differentiation in the form of prominent eosinophilic cytoplasm and frank keratin pearl formation (Figure 3B). Areas of necrosis, hemosiderin-laden macrophages, foamy macrophages, calcification, and stromal fibrosis were observed, related to treatment effect/response. Immunohistochemical studies have shown CD99 and FLI1 expression as seen in the previous biopsy. Additional immunohistochemical stains were performed on both (prechemotherapy and postchemotherapy) specimens and included AE1/AE3, cytokeratin 5 (CK5), 34βE12, P63, and P40 (Table 1). AE1/AE3 showed positive staining in both specimens, but P63 and P40 (Figure 4) were only positive in the resection specimen on both decalcified and nondecalcified tissues. CK5 and 34βE12 showed reactivity in single isolated cells in the initial biopsy but were diffusely positive in the resection specimen. Desmin, erythroblast transformation-specific related gene (ERG), and S100 immunohistochemical stains were negative and argues against the possibility of other small round cell lesions such as a desmoplastic small round cell tumor that can also express CD99 and cytokeratins.
Table 1. Immunohistochemical staining profile: + (positive in single cells), ++ (diffusely positive), - (negative).
Immunohistochemical stain
|
Initial biopsy
|
Resection specimen
|
CD99
|
++
|
++
|
FLI-1
|
++
|
++
|
AE1/AE3
|
++
|
++
|
P63
|
-
|
++
|
P40
|
-
|
++
|
CK5
|
+
|
++
|
34βE12
|
+
|
++
|