What are the differential diagnoses and management options for a pediatric patient presenting with symptoms suggestive of round cell tumors?

Round Cell Tumors in Children: Differential Diagnoses

The differential diagnosis of pediatric round cell tumors includes Ewing sarcoma (most common malignant bone tumor after osteosarcoma), rhabdomyosarcoma, neuroblastoma, lymphoma, nephroblastoma (Wilms tumor), desmoplastic small round cell tumor, poorly differentiated synovial sarcoma, small cell osteosarcoma, mesenchymal chondrosarcoma, and the recently recognized CIC-rearranged and BCOR-rearranged sarcomas. 1, 2, 3, 4

Primary Diagnostic Approach

Immediate referral to a specialized sarcoma center before biopsy is mandatory to prevent tissue plane contamination and optimize outcomes. 5, 2 The definitive diagnosis requires core needle biopsy (multiple samples) providing sufficient material for three essential components: 1

• Conventional histology to assess morphologic patterns 6, 1
• Immunohistochemistry panels including CD99/MIC2, desmin, myogenin, and cytokeratin markers 1
• Molecular genetic testing (FISH or RT-PCR) for specific translocations that determine both diagnosis and prognosis 1, 4

Major Differential Diagnoses by Molecular Classification

Ewing Sarcoma Family

• Classic presentation: Adolescents (median age 15 years), predominantly Caucasian males (1.5:1 ratio), with diaphyseal or metadiaphyseal bone involvement showing "onion skin" periosteal reaction and mottled bone appearance 6, 5, 2
• Molecular hallmark: t(11;22)(q24;q12) creating EWSR1::FLI1 fusion in 85% of cases; alternative translocations include t(21;22), t(7;22), t(17;22), t(2;22), and inv(22) 6, 1
• Immunophenotype: Small blue round cells that are PAS-positive and strongly CD99 (MIC2)-positive 6, 2
• Common sites: Pelvic bones (20%), extremities (50%), with 20-25% presenting with metastatic disease 6, 2

CIC-Rearranged Sarcomas

• Distinguishing features: Focal pleomorphism and epithelioid morphology can predominate, despite round cell appearance 4
• Molecular signature: CIC::DUX4 fusion from t(4;19)(q35;q13) or t(10;19)(q26;q13) 1
• Clinical behavior: Distinct biology but treated with Ewing sarcoma protocols 1

BCOR-Rearranged Sarcomas

• Morphologic clue: Often exhibit spindled neoplastic cell population rather than purely round cells 4
• Molecular hallmark: BCOR::CCNB3 fusion, mainly found in bone and pediatric patients 1
• Treatment approach: Multiagent chemotherapy for at least 9 weeks prior to local therapy 1

Rhabdomyosarcoma (Alveolar Type)

• Key differential feature: Desmin and myogenin positivity on immunohistochemistry distinguishes from Ewing sarcoma 3, 7
• Clinical context: Most common soft tissue sarcoma in children, requires different chemotherapy regimen than Ewing sarcoma 8

Neuroblastoma

• Age distribution: Typically younger children than Ewing sarcoma 7
• Immunophenotype: Distinct from Ewing sarcoma with different marker profile 7

Lymphoma

• Critical distinction: Requires different treatment paradigm entirely; immunophenotyping essential 7

Other Rare Entities

• NFATC2 sarcoma: Remarkable epithelioid features 4
• PATZ1 sarcoma: Sclerotic background pattern 4
• Desmoplastic small round cell tumor: Distinct molecular profile requiring specific identification 3, 4
• Poorly differentiated synovial sarcoma: Round cell variant in differential 4
• Small cell osteosarcoma: Distinguished by malignant osteoid production 2, 4
• Mesenchymal chondrosarcoma: Rare round cell variant 4

Complete Staging Workbook (Before Any Treatment)

The following studies must be completed before initiating therapy: 6, 1, 2

• Local imaging: MRI of primary site with contrast to define precise involvement of bone, bone marrow, soft tissues, and relationship to critical neurovascular structures 6, 1
• Metastatic workup: Chest CT with or without contrast for lung/pleural metastases 6, 1, 2
• Skeletal assessment: 99mTc bone scintigraphy and whole body FDG-PET/CT 6, 1, 2
• Bone marrow evaluation: Biopsy and aspirate from sites distant from primary tumor 6, 1, 2
• Additional imaging: Plain radiographs in two planes of entire involved bone including adjacent joints 6, 2

Critical Diagnostic Pitfalls to Avoid

Morphologic overlap is extensive among round cell tumors—diagnosis cannot be made on cytomorphology alone. 3, 4, 7 Common errors include:

• Assuming CD99 positivity equals Ewing sarcoma: Cross-reactivity exists between different round cell tumors; molecular confirmation of EWSR1 rearrangement is mandatory 5, 7
• Inadequate tissue sampling: Insufficient material for all three diagnostic modalities (histology, immunohistochemistry, molecular testing) leads to diagnostic failure 1, 7
• Biopsy before referral: Contamination of tissue planes compromises subsequent surgical resection 5
• Relying on immunohistochemistry alone: Poorly differentiated tumors may lose specific antigens, and unstandardized ICC performance yields unreliable results 7
• Ignoring molecular classification: The category of "undifferentiated round cell sarcoma" has significantly shrunk with molecular advances; specific genetic diagnosis determines treatment and prognosis 4

Treatment Implications by Diagnosis

Immediate multiagent chemotherapy is the cornerstone for most round cell sarcomas, but specific regimens differ substantially by molecular subtype. 1

• Ewing sarcoma: VDC/IE (vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide) demonstrates superiority; local control requires surgery, radiotherapy, or both 1
• High-risk localized Ewing sarcoma: Consolidation with melphalan-based high-dose chemotherapy with autologous stem cell transplant conveys survival benefit 1
• CIC-rearranged and BCOR-rearranged sarcomas: Treated with Ewing sarcoma protocols despite distinct biology 1
• Rhabdomyosarcoma: Standard multiagent chemotherapy without proven benefit from high-dose chemotherapy/stem cell transplant 1

Prognostic Stratification

Survival with surgery or radiotherapy alone is less than 10%; multimodality treatment achieves 60-70% survival in localized disease and 20-40% in metastatic disease. 6 Key prognostic factors include:

• Metastatic disease at presentation: 10% lung, 10% bone/bone marrow, 5% combinations or other sites 6, 2
• Site of metastases: Bone/bone marrow metastases confer worse prognosis (<20% 5-year survival) than pulmonary metastases (20-40% 5-year survival) 2
• Age, tumor size, location: Age >15 years, axial location, large tumor volume, and elevated serum LDH are adverse factors 2

Surveillance Requirements

Prolonged surveillance is mandatory as round cell tumors can recur years after initial treatment. 1 For relapsed disease, second-line options include topotecan/cyclophosphamide, irinotecan/temozolomide, high-dose ifosfamide, or multi-targeted tyrosine kinase inhibitors (pazopanib, cabozantinib, regorafenib), though median overall survival is approximately one year. 1 Clinical trial enrollment is strongly prioritized for relapsed disease. 1