A 55-year-old male presents to his primary care physician complaining of right hip pain for the past eight months. He also reports progressive loss of hearing over the same time period. Radiographic imaging reveals multiple areas of expanded bony cortices and coarsened trabeculae in his right hip and skull. Laboratory analysis reveals an isolated elevation in alkaline phosphatase with normal levels of serum calcium and phosphate. Which of the following histologic findings is most likely to be seen if one of the lesions were biopsied?

Immature woven bone with collagen fibers arranged irregularly

Mature lamellar bone with collagen fibers arranged in lamellae

Chondroblasts and chondrocytes forming a cartilaginous matrix

Sheets of monotonous round blue cells

Large pleomorphic cells with numerous atypical mitotic figures and “lacey” osteoid formation

An investigator is studying DNA repair processes in an experimental animal. The investigator inactivates a gene encoding a protein that physiologically excises nucleotides from damaged, bulky, helix-distorting DNA strands. A patient with a similar defect in this gene is most likely to present with which of the following findings?

Dry skin and increased photosensitivity

Ataxic gait and facial telangiectasias

Malignant breast and ovarian growths

Leukocoria and a painful bone mass

Colorectal and endometrial cancers

A 5-year-old boy is brought to the pediatric clinic for evaluation of fever, pain, swelling in the left leg, and limping. Review of systems and history is otherwise unremarkable. The vital signs include: pulse 110/min, temperature 38.1°C (100.6°F), and blood pressure 100/70 mm Hg. On examination, there is a tender swelling over the lower part of his left leg. Which 1 of the following X-ray findings is most suggestive of Ewing’s sarcoma?

X-ray showing lytic bone lesion with periosteal reaction

Mixed lytic and blastic appearance in the X-ray

X-ray showing broad-based projections from the surface of the bone

X-ray showing a sharply marginated radiolucent area within the apophysis

X-ray showing deep muscle plane displacement from the metaphysis

An 18-month-old boy is brought to the doctor’s office for evaluation of abdominal pain. The boy looks emaciated and he is now significantly below his growth chart predicted weight. The family history is non-contributory. The vital signs are unremarkable. On physical examination, a non-tender mass is felt in the upper part of the abdomen. A magnetic resonance image (MRI) scan of his abdomen demonstrates a mass in his right adrenal gland. Biopsy of the mass demonstrates an abundance of small round blue cells. With this biopsy result, which 1 of the following findings would confirm the diagnosis?

Elevation of vanillylmandelic acid in the urine

MRI showing the intrarenal origin of the mass

Radiograph of the bone showing the presence of lytic bone lesion with periosteal reaction

A 4-year-old boy with Down syndrome presents with fatigue and recurrent infections. CBC shows WBC 150,000/μL with 90% myeloblasts, hemoglobin 6.5 g/dL, platelets 15,000/μL. Flow cytometry confirms acute myeloid leukemia with megakaryoblastic features (AMKL). The parents are concerned about treatment intensity given their child's baseline developmental delays and increased treatment-related toxicity risk in Down syndrome. Evaluate the treatment approach considering the unique biology and competing risks.

Modified chemotherapy protocol with dose reductions of cytarabine but standard anthracyclines, given Down syndrome-associated AML excellent prognosis

Bone marrow transplantation as first-line therapy

Palliative care approach given poor baseline function and high treatment toxicity

Reduced-intensity chemotherapy due to Down syndrome and baseline developmental concerns

Standard AML chemotherapy protocol without modification

A 15-year-old boy presents with right distal femur pain and a palpable mass. X-ray shows a mixed lytic-sclerotic lesion with periosteal elevation creating a Codman triangle and sunburst pattern. Biopsy confirms osteosarcoma. Staging shows pulmonary micrometastases. Alkaline phosphatase is markedly elevated. The family requests consideration of alternative therapies and limb salvage options. Synthesize the treatment plan addressing oncologic outcomes and functional preservation.

Neoadjuvant chemotherapy, tumor necrosis assessment, limb salvage with endoprosthesis, and adjuvant chemotherapy with potential pulmonary metastasectomy

Limb salvage surgery without chemotherapy followed by observation

Radiation therapy alone as primary treatment

Palliative care focus given metastatic disease at presentation

Immediate amputation without chemotherapy due to metastatic disease

A 2-year-old girl presents with a large abdominal mass, aniridia, and developmental delay. Family history reveals a sibling who died of Wilms tumor at age 3. Genetic testing shows a germline WT1 mutation. Ultrasound reveals bilateral renal masses. The parents are concerned about treatment options that preserve renal function. Evaluate the optimal management strategy considering long-term outcomes.

Bilateral renal biopsy followed by neoadjuvant chemotherapy and bilateral nephron-sparing surgery

Chemotherapy followed by bilateral nephrectomy and immediate transplantation

Close surveillance with delayed intervention until symptoms develop

Immediate bilateral nephrectomy with dialysis and future transplantation

Unilateral nephrectomy of the larger tumor followed by observation of contralateral kidney

Ewing sarcoma for USMLE Step 3: High-Yield Pediatrics Lessons

Basics - Blue Cell Tumour

Small round blue cell tumour (SRBCT) of bone and soft tissue.
Origin: Believed to be of neural crest cell / neuroectodermal origin.
Microscopy:
- Sheets of uniform, small cells with round nuclei and scant, clear cytoplasm.
- Homer-Wright pseudorosettes (cells around a fibrillary meshwork) may be seen.
- Cytoplasm is PAS-positive due to glycogen, which is diastase-sensitive.
IHC Marker: CD99 (MIC2) is the most sensitive marker.

⭐ Genetic Hallmark: Translocation t(11;22)(q24;q12), resulting in the EWS-FLI1 fusion gene.

Ewing sarcoma histology: small round blue cells

Pathogenesis - Translocation Tango

Primary Driver: Specific chromosomal translocations.
Classic Translocation: t(11;22)(q24;q12) is the hallmark, found in ~85% of cases.
- Fuses the EWSR1 gene on chromosome 22 with the FLI1 gene on chromosome 11.
- Creates the EWSR1-FLI1 fusion oncogene.
Fusion Protein: The resulting chimeric protein acts as an aberrant transcription factor, driving oncogenesis.
📌 Mnemonic: Think of basketballer Patrick Ewing (jersey #33): 11 + 22 = 33.

⭐ The EWSR1-FLI1 fusion is the most common type. Other partners for EWSR1 exist (e.g., ERG), but are less frequent.

chromosomal translocation diagram)

Diagnosis - Onion Skin & Codman

X-ray Findings: The initial imaging modality.
- Location: Most commonly affects the diaphysis of long bones (femur, tibia, humerus) and the pelvis.
- Appearance: Poorly-defined, lytic lesion with a permeative or "moth-eaten" pattern of bone destruction.
Periosteal Reaction: Key diagnostic signs.
- "Onion skin" appearance: A lamellated, layered reaction.
- Codman triangle: A triangular area of new subperiosteal bone.
- A "sunburst" or "hair-on-end" pattern can also occur.

⭐ Exam Favourite: The classic description is a destructive lesion in the diaphysis of a long bone with an "onion skin" periosteal reaction.

Multilayer periosteal reaction (onion skin) on X-ray

Management - Chemo Sandwich

Overall Strategy: A multi-modal approach combining chemotherapy and local control measures, structured like a sandwich.

Neoadjuvant (Induction) Chemotherapy:
- Pre-operative treatment to shrink the primary tumor.
- Regimen: VDC/IE (Vincristine, Doxorubicin, Cyclophosphamide alternating with Ifosfamide, Etoposide).
Local Control:
- Surgery: Wide local excision / limb salvage is preferred.
- Radiotherapy: For unresectable tumors or positive surgical margins.
Adjuvant Chemotherapy:
- Post-local control to eradicate micrometastases.

⭐ The VDC/IE regimen, administered over 9-12 months, is the standard of care and a major factor in improved survival rates for Ewing sarcoma.

High‑Yield Points - ⚡ Biggest Takeaways

Second most common primary malignant bone tumor in children, after osteosarcoma.

A small round blue cell tumor of neuroectodermal origin.

Characteristic translocation is t(11;22), resulting in the EWS-FLI1 fusion gene.

Most commonly involves the diaphysis of long bones (like the femur) and the pelvis.

X-ray findings include lytic lesions with an "onion skin" periosteal reaction.

Histology may show Homer-Wright rosettes.

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Ewing sarcoma