Li-Fraumeni Syndrome Workup

Updated: Nov 13, 2018
  • Author: Avanthi Tayi Shah, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Laboratory Studies

Evaluation for constitutional TP53 mutation in patients with cancer and a family history or presentation 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.

Some authors have advocated for genetic screening in children who are diagnosed with specific cancers, irrespective of family history, including adrenocortical carcinoma and choroid plexus carcinoma at any age, rhabdomyosarcoma before age 3 years, and possibly osteosarcoma before age 10 years, as several groups have documented a 50-100% rate of germline TP53 mutations in these subsets. [9, 6, 32]

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.

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.


Imaging Studies

Breast cancer screening

Annual breast MRI screening (preferred) or mammogram (if MRI is unavailable), at age 20-29 years. [31]

Annual mammogram and breast MRI screening, at age 30-75 years. [31]

Consider management on an individual basis after age 75 years. [31]

Colorectal cancer screening

Colonoscopy should be performed every 2-5 years starting no later than age 25 years. [31]

Use of other imaging modalities

The utility of whole body MRI, as a screening tool, is being investigated in several international trials. [31]

Example of a surveillance program  [32]

A clinical surveillance protocol (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.

The study included 33 TP53 mutation carriers from 8 families; 18 self-elected to be in the surveillance group, and 15 self-elected to not have surveillance. Of the 18 patients in the surveillance group, 10 asymptomatic tumors were detected in 7 patients. Five tumors were malignant and 5 were low-grade or premalignant. All 7 patients were alive at the end of 24-month follow-up. Of the 16 patients in the nonsurveillance group, 12 symptomatic, high-grade, high-stage tumors were found in 10 patients. Only 2 of the 10 patients were alive at the end of follow-up.

Three-year overall survival was 100% in the surveillance group and 21% in the nonsurveillance group (P = .0155).

Among those diagnosed with a cancer, survival was better in the surveillance group than in the nonsurveillance group (100% vs 20%, respectively; P = .0417).