Friday, December 9, 2011

Li-Fraumeni Syndrome

Li-Fraumeni syndrome is an autosomal-dominant familial cancer syndrome that results in an increased lifelong risk of what are considered Li-Fraumeni syndrome spectrum tumors (e.g., soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer), among others. About 3/4 of patients have a mutation in the gene encoding the p53 tumor suppressor protein (TP53). The cancers aren't limited to those listed above, however, and patients can have a wide range of malignancies, including melanoma, germ-cell tumors, gastric carcinoma, Wilms tumor, lymphoma, and lung, laryngeal, prostate, and pancreatic cancers.

The 2009 Chompret (after Agnès Chompret) criteria for germline TP53 mutation screening are as follows:
  • [A Li-Fraumeni syndrome spectrum tumor before age 46 years.] AND [At least one first- or second-degree relative with a Li-Fraumeni syndrome spectrum tumor (except breast cancer if the proband has breast cancer) before the age of 56 years or with multiple tumors.]
  • [Multiple tumors (except multiple breast tumors), two of which belong to the Li-Fraumeni syndrome tumor spectrum.] AND [The first tumor occurred before the age of 46 years.]
  • [Adrenocortical carcinoma or choroid plexus tumor (irrespective of family history).]
These criteria result in a mutation detection rate of ~30-35% and sensitivity and specificity of ~80-90% and ~50-60%, respectively.

These screening criteria and the availability of genetic testing raise the question of how best to manage patients, asymptomatic carriers, and relatives of patients with Li-Fraumeni syndrome.

Regarding the patient with Li-Fraumeni syndrome and a known malignancy: Radiation must be carefully applied (if at all), as second malignant tumors frequently arise in the radiotherapy field in these patients.

It has been suggested that women begin breast cancer screening in their mid-20s (the average age of onset is ~30 years in these patients). Beyond that, there are currently no clear clinical surveillance, preventive, or treatment recommendations for patients with Li-Fraumeni syndrome.

The situation seems even less clear when it comes to management of asymptomatic relatives of patients with p53 germline mutations. This is because of the variable expressivity of the mutation, the diverse range of tumors, and, as noted above, absence of clear surveillance, preventative, and treatment recommendations.

PET-CT has been put forward as a surveillance modality for identifying presymptomatic malignancies. In a study of members of Li-Fraumeni syndrome families with germline TP53 mutations, FDG-PET/CT screening resulted in cancer detection in 20% (3 out of 15 subjects).

Prenatal genetic testing can also be offered after careful screening and thorough counseling of parents.

The images above are from a patient with a history of right adrenal cortical carcinoma (note the clips on the right, pink arrow), who developed an anterior mediastinal sarcoma. A p53 mutation was found.


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