What are the diagnostic criteria and management strategies for a young patient suspected of having Li-Fraumeni syndrome based on their family history and personal medical history of cancer, using the Chompret criteria?

Chompret Criteria for Li-Fraumeni Syndrome

The Chompret criteria identify four specific clinical scenarios that warrant TP53 genetic testing, demonstrating 95% sensitivity when combined with classic LFS criteria and serving as the primary framework for identifying candidates for genetic testing. 1

The Four Clinical Scenarios Triggering TP53 Testing

The National Comprehensive Cancer Network defines these specific situations that mandate TP53 genetic testing 1:

1. Early-Onset Breast Cancer

• Premenopausal breast cancer diagnosed before age 31 years as a standalone criterion 1
• Breast cancer before age 46 years when combined with a family history of LFS-spectrum tumors 1
• This represents the most common presentation in adult women with LFS 2

2. Multiple Primary Tumors

• Patient with multiple primary tumors, at least two of which are LFS core cancers, with the first occurring before age 36 3, 4
• Approximately half of LFS patients develop simultaneous or metachronous multiple cancers 5

3. Rare Tumors Warranting Testing Regardless of Age or Family History

• Adrenocortical carcinoma at any age 1, 3
• Choroid plexus carcinoma 1
• Embryonal anaplastic subtype rhabdomyosarcoma 1
• Low-hypodiploid acute lymphoblastic leukemia (40% harbor germline TP53 mutations) 1

4. Familial Presentation

• Proband with an LFS core tumor before age 46 years AND at least one first- or second-degree relative with an LFS core tumor before age 56 years (or any age for core tumors) 3, 4

Core LFS Spectrum Tumors

The following cancers constitute the primary tumor spectrum for applying Chompret criteria 1, 5:

• Soft tissue sarcomas (particularly rhabdomyosarcoma) 1
• Osteosarcoma and bone tumors (up to 10% of pediatric osteosarcoma cases have germline TP53 mutations) 1
• Brain tumors (choroid plexus carcinoma, gliomas, Sonic Hedgehog medulloblastoma) 1
• Premenopausal breast cancer 1
• Adrenocortical carcinoma 1

Broader Tumor Spectrum Beyond Core Criteria

Additional cancers associated with LFS that should raise clinical suspicion 1, 3:

• Hematologic malignancies (leukemias, particularly low-hypodiploid ALL) 1
• Colorectal cancer (significantly elevated risk in mutation carriers) 3
• Pancreatic cancer (elevated risk documented) 3
• Lung, kidney, thyroid, gastrointestinal, and skin cancers 1
• Neuroblastoma in children 1

Clinical Performance and Limitations

The Chompret criteria demonstrate 95% sensitivity when combined with classic LFS criteria, compared to only 40% sensitivity for classic criteria alone, with a positive predictive value of 20-35%. 1

Critical Pitfall to Avoid

Do not rely solely on Chompret criteria to exclude LFS—if clinical suspicion exists based on tumor pattern or multiple primaries, proceed with TP53 testing even when criteria are not fully met. 5, 6 A documented case exists of a 50-year-old woman with four primary cancers (breast, lung, colorectal, tongue) who did not meet revised Chompret criteria but was ultimately found to have a TP53 mutation 6.

When to Test Outside Formal Criteria

Consider TP53 testing in these additional scenarios 5, 3:

• Any childhood sarcoma, regardless of family history 3
• Breast cancer before age 30 years, even without family history 3
• Any patient with multiple primary cancers where at least one is an LFS-associated tumor 6

Special Population Considerations

Brazilian Founder Mutation (R337H)

In patients of Brazilian descent (particularly South/Southeastern regions), the c.1010G>A (p.R337H) founder mutation occurs in 0.3% of the population and presents with distinct characteristics 2, 7:

• Lower penetrance before age 30 years 2
• Later onset of adult tumors compared to DNA-binding domain mutations 2
• Median age at first tumor diagnosis of 22 years for R337H carriers versus 2 years for DNA-binding domain mutations 7

Genotype-Phenotype Correlations

Dominant-negative missense mutations within the DNA-binding domain carry the highest cancer risk, particularly for brain tumors, osteosarcoma, and rhabdomyosarcoma. 2 Twenty percent of LFS families harbor one of six hotspot mutations (p.R175H, p.G245S, p.R248Q, p.R248W, p.R273H, p.R282W) 2.

Immediate Actions Upon Meeting Criteria

Once Chompret criteria are met or TP53 mutation is confirmed, immediately initiate comprehensive cancer surveillance regardless of patient age, using the modified Toronto Protocol. 8 This includes:

• Whole-body MRI annually 8
• Brain MRI annually 8
• Breast MRI annually starting age 20-25 years for women 8
• Abdominal/pelvic ultrasound every 3-4 months in children 8
• Complete blood count monitoring 8
• Comprehensive physical examination every 6 months 8

Genetic counseling and psychological support must accompany all testing given the near-100% lifetime cancer risk in women and 75% in men. 2, 8, 5