Askin Tumor: Comprehensive Overview

Definition

Askin tumor is a primitive neuroectodermal tumor (PNET) of the thoracopulmonary region, specifically arising from the soft tissues of the chest wall, and is now classified within the Ewing sarcoma family of tumors. 1, 2 This malignancy is treated identically to Ewing sarcoma according to current NCCN guidelines, which explicitly state that "Ewing sarcoma can be treated using this algorithm, including primitive neuroectodermal tumor of bone, Askin tumor, and extraosseous Ewing sarcoma." 1

Etiology

The underlying cause involves chromosomal translocations, most commonly t(11;22)(q24;q12), which is present in >90% of cases and results in EWSR1 gene rearrangements. 1
Approximately 90% of Ewing sarcoma family tumors (including Askin tumor) will have one of four specific cytogenetic translocations, with EWSR1::FLI1 being the most common fusion. 1
Rare cases may harbor FUS gene rearrangements (FUS::ERG or FUS::FEV fusion transcripts) instead of EWSR1. 1

Risk Factors

Age: Predominantly affects children, adolescents, and young adults, with median age around 14 years and 90% of patients <20 years. 1
Sex: Unlike adult presentations, there appears to be no clear sex predominance in the pediatric/young adult population. 2, 3
Prior radiation exposure: Not typically associated with Askin tumor, unlike some other sarcomas. 1

Pathogenesis (Stepwise)

Initial genetic event: Chromosomal translocation t(11;22)(q24;q12) occurs, creating an EWSR1::FLI1 fusion gene (or alternative fusions involving EWSR1 or FUS with other ETS family transcription factors). 1
Oncogenic fusion protein formation: The fusion protein acts as an aberrant transcription factor, dysregulating gene expression programs. 1
Cellular transformation: Primitive neural crest-derived cells in the chest wall soft tissues undergo malignant transformation. 1, 2
Tumor development: Rapidly growing small round cell tumor develops in the thoracopulmonary region with aggressive local invasion. 2, 4
Local invasion: Tumor invades adjacent structures including ribs, pleura, and lung parenchyma. 2, 4
Metastatic spread: Hematogenous dissemination occurs, most commonly to lungs, bones, and bone marrow; approximately 20% have detectable metastases at diagnosis. 1

Gross Pathology

Appearance: Large, soft tissue mass arising from the chest wall with a fleshy, tan-white cut surface. 2, 4
Size: Typically presents as a large mass, often >8-10 cm at diagnosis. 1, 4
Location: Originates in the thoracopulmonary region, specifically the chest wall soft tissues, with frequent involvement of ribs and pleura. 2, 3
Associated findings: Local rib erosion/destruction, pleural effusion, and invasion into adjacent lung parenchyma are common. 2, 4

Microscopic Pathology

Cellular composition: Sheets of uniform small round blue cells with scant cytoplasm, round nuclei, and fine chromatin. 1, 5
Architecture: Diffuse growth pattern with areas of necrosis; may show Homer-Wright rosettes (pseudorosettes). 1
Immunohistochemistry:
- Positive markers: CD99 (MIC2 gene product, membranous pattern - highly characteristic), neuron-specific enolase, synaptophysin, chromogranin (variable), vimentin. 1, 5, 6
- Negative markers: Cytokeratin (typically negative, distinguishing from desmoplastic small round cell tumor), desmin, S100 (helps exclude neuroblastoma). 5
Molecular confirmation: EWSR1 gene rearrangement detected by FISH, RT-PCR, or next-generation sequencing is diagnostic. 1, 6

Molecular Mechanisms

Primary driver: EWSR1::FLI1 fusion (in ~85% of cases) or other EWSR1::ETS fusions create chimeric transcription factors. 1
Alternative fusions: FUS::ERG or FUS::FEV in rare EWSR1-negative cases. 1
Prognostic implications: Preliminary reports suggest EWSR1::FLI1 translocation may be associated with better prognosis than other variants, though recent large studies (EURO-EWING 99, Children's Oncology Group) suggest similar outcomes across fusion subtypes with modern therapy. 1
Diagnostic testing: Comprehensive genomic profiling or fusion panels should be considered if initial targeted PCR, FISH, or cytogenetics are negative. 1

Clinical Features

Presenting Symptoms

Chest wall mass: Palpable, often painful swelling is the most common presentation. 2, 4, 7
Pain: Localized chest wall pain, often progressive. 2, 4, 8
Respiratory symptoms: Dyspnea, cough, or respiratory distress due to mass effect. 7, 8
Constitutional symptoms: Fever, weight loss, malaise. 2
Pleural effusion symptoms: If present, may cause additional dyspnea. 2

Physical Examination Findings

Visible or palpable chest wall mass. 3, 4
Tenderness over the affected area. 4
Decreased breath sounds if large pleural effusion or lung compression present. 7

Complications

Local Complications

Rib destruction: Progressive erosion and destruction of adjacent ribs. 2, 4
Pleural effusion: Often malignant, causing respiratory compromise. 2
Lung invasion: Direct extension into pulmonary parenchyma. 4, 8
Mediastinal compression: Large tumors may compress mediastinal structures. 7

Systemic Complications

Pulmonary metastases: Most common site of distant spread. 1
Skeletal metastases: Bone and bone marrow involvement. 1
Local recurrence: High rate of local chest wall recurrence despite treatment. 2, 4

Treatment-Related Complications

Chemotherapy toxicity: Myelosuppression, cardiotoxicity (from doxorubicin), hemorrhagic cystitis (from cyclophosphamide/ifosfamide). 1
Radiation toxicity: Pulmonary fibrosis, cardiac toxicity, secondary malignancies. 1
Surgical morbidity: Chest wall instability, respiratory compromise. 4, 7

Investigations

Initial Diagnostic Workup

Imaging of primary site:
- Contrast-enhanced MRI ± CT of chest (preferred for soft tissue detail). 1
- Plain radiographs show chest wall mass with rib erosion. 2
- CT demonstrates large soft tissue mass, local rib destruction, and pleural effusion. 2, 4
Metastatic evaluation:
- Chest CT (can be with or without contrast; low-dose non-contrast for restaging). 1
- FDG-PET/CT head-to-toe (preferred) and/or bone scan. 1
- Bone marrow biopsy and/or screening MRI of spine and pelvis. 1
Tissue diagnosis:
- Core needle biopsy or open surgical biopsy (patients should be referred to specialized bone sarcoma centers BEFORE biopsy to prevent tissue plane contamination). 1, 6
- Histopathology with immunohistochemistry (CD99, NSE). 1, 5
- Cytogenetics and/or molecular studies for EWSR1 rearrangement (FISH, RT-PCR, or comprehensive genomic profiling). 1, 6

Laboratory Studies

Serum lactate dehydrogenase (LDH): Prognostic tumor marker; elevated levels associated with worse outcomes. 1
Complete blood count: Baseline and to detect bone marrow involvement. 1

Fertility Preservation

Fertility consultation: Should be considered before initiating chemotherapy, as recommended by American Society for Reproductive Medicine and NCCN. 1

Differential Diagnosis

The diagnosis must be confirmed with biopsy showing small round cells that are CD99-positive and molecular testing demonstrating EWSR1 gene rearrangements, as radiographic features alone are not distinctive. 6

Key Differentials

Desmoplastic small round cell tumor (DSRCT): Distinguished by polyphenotypic immunoprofile with cytokeratin, desmin, and WT-1 positivity; has EWSR1::WT1 fusion (different from Askin tumor's EWSR1::FLI1). 5
Neuroblastoma: Chromogranin and synaptophysin strongly positive; lacks CD99 positivity; lacks epithelial markers; different age distribution (younger children). 5
Rhabdomyosarcoma: Desmin positive but lacks cytokeratin and WT-1; different immunoprofile from Askin tumor. 5
Lymphoma: CD45 positive with B-cell or T-cell markers; CD99 negative. 5
Small cell carcinoma: TTF-1 positive if lung origin; neuroendocrine markers positive; typically older patients; CD99 negative. 5
Ewing sarcoma of bone: Same tumor family but arises from bone rather than chest wall soft tissue; treated identically. 1
Merkel cell carcinoma: CK20 and TTF-1 positive; typically cutaneous origin; older patients. 5

Management

Askin tumor requires comprehensive multimodal therapy including complete surgical resection, multiagent chemotherapy, and radiotherapy, following the same treatment algorithm as Ewing sarcoma. 1, 5, 4

Treatment Algorithm

1. Initial Chemotherapy (Neoadjuvant)

Multiagent chemotherapy (Category 1) for at least 9 weeks prior to local therapy. 1
Regimen: VDC (vincristine, doxorubicin, cyclophosphamide) alternating with IE (ifosfamide and etoposide). 1
Duration: Total of 12-15 courses over 8-12 months. 1
Rationale: Shrinks tumor, treats micrometastatic disease, allows assessment of chemosensitivity. 1, 4

2. Restaging After Induction Chemotherapy

Chest CT. 1
Contrast-enhanced MRI ± CT of primary site. 1
X-rays of primary site. 1
Consider FDG-PET/CT (head-to-toe) or bone scan. 1
Repeat other abnormal studies. 1

3. Local Control Therapy

Surgery is the preferred treatment for local control whenever feasible. 1, 4

Surgical resection: Wide surgical margin should be attempted; may require chest wall resection with rib removal and reconstruction. 1, 4, 7
Radiotherapy indications:
- Marginal or intralesional surgery. 1
- Inoperable tumors. 1
- Macroscopic residual disease. 1
Radiation dosing:
- 40-45 Gy for microscopic residual disease. 1
- 50-60 Gy for macroscopic disease. 1

4. Consolidation Chemotherapy

Continue multiagent chemotherapy (8-10 additional courses) after local control. 1
Total treatment duration: 8-12 months. 1

Management of Metastatic Disease at Diagnosis

Same standardized chemotherapy as localized disease. 1
For lung metastases in complete remission: Consider total lung irradiation. 1
For limited residual macroscopic lung disease: Consider thoracotomy. 1
Bone metastases: Supplemental irradiation usually indicated. 1
Longer treatment prior to local control can be considered based on response. 1

Management of Recurrent Disease

Re-operation and/or re-irradiation when possible. 1
Chemotherapy: For patients no longer eligible for local treatments or with good performance status. 1
Clinical trials: Should be strongly considered. 4, 7

Critical Pitfalls to Avoid

Do NOT perform biopsy before referral to specialized bone sarcoma center - tissue plane contamination can compromise subsequent surgical resection. 1, 6
Do NOT use radiotherapy as sole local treatment when surgery is feasible - surgery is preferred despite radiosensitivity. 1
Do NOT omit molecular testing - EWSR1 rearrangement confirmation is essential for accurate diagnosis. 1, 6
Do NOT forget fertility preservation counseling before starting chemotherapy. 1

Prognosis

Overall Survival

Historical outcomes: Poor prognosis with high mortality rates. 2, 8
Modern multimodal therapy: Improved outcomes, with localized disease achieving approximately 60% 5-year survival. 1
Metastatic disease: Significantly worse prognosis; lung metastases alone have better prognosis (30% 5-year survival) than skeletal metastases (10% 5-year survival). 1

Prognostic Factors

Adverse prognostic factors include: 1, 4

Metastatic disease at presentation. 1
Large tumor size (>8-10 cm). 1, 4
Pelvic localization (though Askin tumor is thoracic by definition). 1
Age >15 years. 1
Elevated serum LDH. 1, 4
Poor histological response to preoperative chemotherapy. 1
Radiotherapy as only local treatment (without surgery). 1
Advanced tumor stage. 4

Recurrence Patterns

Local chest wall recurrence: Common pattern. 2, 4
Pulmonary metastases: Frequent site of recurrence. 2
Skeletal metastases: Secondary bone involvement. 2

Fusion Subtype and Prognosis

While EWSR1::FLI1 translocation was preliminarily associated with better prognosis, recent large studies (EURO-EWING 99, Children's Oncology Group) demonstrate similar outcomes across fusion subtypes with current effective therapies. 1

What is Askin's tumor, its definition, etiology, risk factors, pathogenesis, pathology, molecular mechanisms, clinical features, complications, investigations, differential diagnosis, management, and prognosis in children and young adults?

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