What is the diagnosis for a 22-year-old female with a 9-month history of a growing 8x8 cm palpable right anterior thigh mass, ill-defined soft tissue characteristics, possible femoral infiltration, reactive inguinal lymphadenopathy, and hepatoid features on histopathology, but negative hepatitis profile and alpha-fetoprotein (AFP) levels?

Diagnosis: High-Grade Soft Tissue Sarcoma with Hepatoid Differentiation

This 22-year-old female most likely has a high-grade soft tissue sarcoma with hepatoid features, requiring urgent referral to a specialized sarcoma multidisciplinary team (MDT) for core needle biopsy and definitive surgical planning. 1, 2

Clinical Reasoning

The constellation of findings strongly suggests malignancy rather than a benign process:

Features Indicating Sarcoma

• Size >5 cm (8x8 cm mass) is a critical red flag that mandates specialist evaluation, as masses exceeding this threshold have significantly higher malignancy risk 1, 3
• Progressive growth over 9 months with ill-defined borders on imaging represents concerning behavior inconsistent with typical benign lesions 1, 2
• Possible femoral infiltration indicates aggressive local invasion, a hallmark of high-grade sarcomas that can involve adjacent bone structures 1, 2
• Deep location in the anterior thigh compartment substantially increases malignancy probability compared to superficial masses 1, 3
• Reactive inguinal lymphadenopathy suggests regional disease spread, which occurs in certain sarcoma subtypes and represents an adverse prognostic factor requiring more aggressive treatment planning 1

Hepatoid Histopathology Interpretation

• Hepatoid features with negative AFP and hepatitis markers effectively exclude hepatocellular carcinoma or metastatic liver disease 4, 5
• This histologic pattern can occur in rare soft tissue sarcomas with hepatoid differentiation, representing an unusual morphologic variant rather than a primary hepatic process 1
• The negative AFP (normal threshold <20 ng/mL for non-hepatic tumors) further supports a primary soft tissue origin rather than AFP-producing hepatocellular carcinoma 4

Immediate Management Algorithm

Step 1: Urgent Specialist Referral (Within 2 Weeks)

• Refer immediately to a specialized sarcoma MDT before any biopsy attempt, as improper biopsy technique outside reference centers can contaminate tissues and compromise limb-salvage surgery 1, 2, 6
• All patients with suspected soft tissue sarcoma must be managed by specialist teams per NICE guidance to optimize morbidity and mortality outcomes 1, 2

Step 2: Complete Staging at Sarcoma Center

Advanced Imaging Protocol:

• MRI of the right thigh with contrast is mandatory as it provides the most accurate information for diagnosis, surgical planning, and radiotherapy planning for extremity soft tissue tumors 1, 2, 3
• CT chest must be performed to exclude pulmonary metastases, as soft tissue sarcomas predominantly metastasize to the lungs 1, 2
• CT abdomen and pelvis should be included given the high-grade features and lower extremity location 2
• Ultrasound or cross-sectional imaging of inguinal lymph nodes is essential given the reactive lymphadenopathy, particularly important for certain sarcoma subtypes (synovial sarcoma, epithelioid sarcoma, clear cell sarcoma, angiosarcoma) 1, 2

Step 3: Tissue Diagnosis at Reference Center

• Percutaneous core needle biopsy under image guidance is the standard approach, with multiple cores taken to maximize diagnostic yield 1, 2, 3
• The biopsy tract must be planned so it can be safely removed during definitive surgery 2
• Fine needle aspiration is not recommended as the primary diagnostic modality due to insufficient tissue for accurate grading and subtyping 2
• Histological diagnosis must follow the 2020 WHO Classification of Soft Tissue and Bone to determine grade and stage 2
• Specialist pathology review is mandatory given the unusual hepatoid features and high discrepancy rates (8-11% major discordance, 16-35% minor discordance) when biopsies are performed outside sarcoma centers 2

Step 4: Grading and Molecular Assessment

• FNCLCC grading system should be applied, which distinguishes three malignancy grades based on differentiation, necrosis, and mitotic rate 1
• Molecular pathology (FISH, RT-PCR) should complement morphology and immunohistochemistry, especially given the unusual hepatoid presentation 1
• Tumor size, depth (relative to muscular fascia), and grade must be documented as they carry prognostic value 1

Treatment Approach Based on Staging

For Localized High-Grade Disease

• Wide surgical excision with negative margins (R0) is standard treatment, requiring removal of the tumor with a rim of normal tissue (minimum 1 cm where feasible, though margins can be minimal against resistant anatomical barriers like muscular fasciae) 1, 3
• Adjuvant radiotherapy will likely be required given the size >5 cm, high grade, and deep location 1
• Adjuvant chemotherapy may be considered as an option for high-risk patients (G2-3, deep, >5 cm) through shared decision-making, though it is not standard treatment in adult-type soft tissue sarcomas 1

For Regional Lymph Node Involvement

• Aggressive treatment planning is appropriate given the adverse prognostic significance of regional lymph node metastases in adult-type soft tissue sarcomas 1
• Surgery through wide excision coupled with adjuvant radiation therapy and consideration of adjuvant chemotherapy for sensitive histological types represents standard treatment 1
• The context should be viewed as likely systemic disease rather than truly "adjuvant" therapy 1

Critical Pitfalls to Avoid

• Never perform biopsy outside a specialized sarcoma center, as this can contaminate normal tissues and compromise limb-salvage options, directly impacting morbidity 1, 2, 6
• Do not delay referral for additional imaging at non-specialist centers, as timely diagnosis enables curative treatments with significantly improved survival (84% overall survival with timely MPNST diagnosis) 1
• Do not assume benign disease based on young age alone—soft tissue sarcomas occur across all age groups, and the 9-month growth history with concerning imaging features overrides age considerations 1
• Do not rely on ultrasound alone for deep masses, as ultrasound accuracy is considerably lower for deep-seated lesions compared to superficial ones 1, 3

Prognostic Considerations

• Size >5 cm, high grade, deep location, and possible lymph node involvement represent multiple adverse prognostic factors that necessitate aggressive multimodal treatment 1
• The hepatoid differentiation pattern is unusual and may require specialized pathologic interpretation to determine the exact sarcoma subtype and guide chemotherapy sensitivity predictions 1
• Timely referral to a specialized center is the single most important factor affecting both morbidity (limb preservation) and mortality outcomes in extremity soft tissue sarcomas 1, 2