Li-Fraumeni Syndrome Workup

Updated: Nov 29, 2023
  • Author: Avanthi Tayi Shah, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Approach Considerations

Evaluation for constitutional TP53 mutation in patients with a cancer presentation or cancer and a family history suggestive of potential Li-Fraumeni syndrome (LFS) is warranted to aid in predicting future risk of other primary malignancies for the patient as well as for other family members.

Considerations should be made regarding the use of testing for germline TP53 mutations. The National Comprehensive Cancer Network (NCCN) Guidelines Testing Criteria should be used as a guide. Patients and families with histories consistent with Li-Fraumeni syndrome or with presentations of cancer suggestive of a possible germline TP53 mutation should be counseled regarding genetic testing.

Initially, testing should be limited to an affected individual (ie, in whom cancer has been diagnosed) to determine if a TP53 mutation is present. Then, subsequent testing of at-risk family members can be limited to the specific mutation previously documented.

Prior to testing, ensure that the significance of either a positive or a negative result is clear to all patients and relatives. Explain that no simple screening or intervention exists that can eliminate the potential of developing cancer for those who carry the mutation.

Family members whose test results are negative for the TP53 mutation but for whom the mutation was previously established in an affected relative can be reasonably reassured of a low risk of developing cancer at an early age. However, they should understand that this does not mean they are immune to developing a malignancy at some point. Generally, cancer is a multifactorial condition, and the risk may depend on health-related behaviors (eg, smoking, environmental exposures, diet) and other potential genetic factors.


Laboratory Studies

Although most reported Li-Fraumeni syndrome–related TP53 mutations occur in exons 5-8, optimal DNA analysis should include evaluation of the entire coding and noncoding portions of the gene (exons 1-11) by automated sequencing methods. Because TP53 mutations are constitutional (ie, germline), DNA derived from any clinical source can potentially be evaluated. Peripheral blood leukocytes are the most easily obtained source and are typically collected in citrate or heparin anticoagulant tubes.

In those patients diagnosed with Li-Fraumeni syndrome, some groups advocate for routine laboratory surveillance with complete blood cell counts for leukemia/lymphoma screening and hormone levels (17-OH-progesterone, total testosterone, DHEAS, androstenedione) for adrenal cortical carcinoma screening.



Imaging Studies

Surveillance guidelines have been proposed from the United States, Australia, and Canada with the goal of early detection of cancer and reduction in morbidity and mortality. [36, 37, 29] ​  

Breast cancer screening

Annual breast MRI screening (preferred) or mammogram (if MRI is unavailable), at age 20-29 years. [36]

Annual mammogram and breast MRI screening, at age 30-75 years. [36]

Consider management on an individual basis after age 75 years. [36]

Gastrointestinal cancer screening

Colonoscopy and upper endoscopy should be performed every 2-5 years starting at age 25 years or 5 years before the earliest known colon or gastric cance in the family. [36]

Use of other imaging modalities

Annual whole body MRI and annual brain MRI, as part of the whole body MRI or as a separate exam. [36]

Abdominal ultrasound every 3-4 months.  [29, 37]

Example of a surveillance program 

A clinical surveillance protocol, the Toronto protocol, for TP53 mutation carriers was implemented at the Hospital for Sick Children in Toronto in 2004. The protocol includes frequent laboratory and radiographic screening for adrenocortical carcinoma, brain tumors, soft-tissue and bone sarcoma, leukemia/lymphoma, breast cancer, and colon cancer. Long-term feasibility and outcomes data were available over an 11-year period.

It was demonstrated that the protocol was feasible, with >90% compliance with key components of the protocol in those patients who chose to undergo surveillance. Forty asymptomatic tumors were detected in 19/59 patients who underwent surveilance, in contrast to 61 symptomatic tumors that were diagnosed in 43/49 patients on the non-surveillance arm. Twenty-five of 40 tumors on the surveillance arm were low-grade or premalignant at the time of detection and among those diagnosed with a cancer, survival was better in the surveillance group than in the non-surveillance group. Different screening modalities identified the observed tumors, but it is important to note that there were 2 false negatives (cancers diagnosed between surveillance studies) and 2 biopsy-proven false positives. Importantly, 5-year overall survival was improved in the surveillance group (88.8%) compared to the non-surveillance group (59.6%).