Li-Fraumeni Syndrome

Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome associated with TP53 mutation.

Description

Li-Fraumeni Syndrome (LFS) is an inherited genetic disorder associated with a significant predisposition to a broad range of cancers. The syndrome is named after American physicians Frederick Li and Joseph Fraumeni, who first identified the syndrome in 1969. It’s marked by the early onset of multiple primary cancers, often during childhood and early adulthood.

Pathogenesis

Li-Fraumeni Syndrome is caused by germline mutations in the TP53 tumour suppressor gene on chromosome 17p13.1. This gene codes for the p53 protein, often referred to as the “guardian of the genome” due to its role in controlling cell division and preventing tumourigenesis. Mutations in TP53 disrupt the function of the p53 protein, leading to unchecked cell growth and division, and a greatly increased risk of developing various forms of cancer.

Epidemiology, Risk Factors & Associations

• Li-Fraumeni Syndrome is a rare condition, with an estimated prevalence of 1 in 20,000 individuals.
• The disease follows an autosomal dominant inheritance pattern. An affected individual has a 50% chance of passing the mutation to their offspring.
• Females with LFS are at a significantly increased risk of developing breast cancer. The lifetime risk is estimated to be up to 85% (as compared to around 12% in the general population).
• Adrenocortical carcinoma is an especially indicative cancer type for LFS, given its rareness in the general population and increased prevalence in individuals with LFS.

Clinical Features

The five cancer types which account for the majority of LFS tumours include: adrenocortical carcinomas, breast cancer, central nervous system tumours, osteosarcomas, and soft-tissue sarcomas.

• Breast cancer: Women with LFS have up to an 85% lifetime risk of developing breast cancer. Most commonly, these cancers are diagnosed before the age of 30 and are of the triple-negative subtype (lacking expression of ER, PR, and HER2).
• Sarcomas: The incidence of soft-tissue and bone sarcomas in LFS is significantly elevated, with approximately 20% of affected individuals developing a sarcoma. The most common types are osteosarcoma and soft-tissue sarcomas (such as leiomyosarcoma and rhabdomyosarcoma), which are often diagnosed in the first two decades of life.
• Brain tumours: Brain tumours occur in approximately 15% of individuals with LFS and can occur at any age. The most common types are glioblastomas and medulloblastomas, which are frequently diagnosed during childhood or adolescence.
• Adrenocortical carcinomas (ACC): ACC is a rare cancer that is significantly overrepresented in LFS, making it an indicative cancer type for this syndrome. ACC usually occurs in the first decade of life and represents about 3-5% of all LFS-related cancers.

Other associated cancers include:

• Leukaemia: Individuals with LFS have a significantly increased risk of developing leukaemia, with a lifetime risk of about 5-10%. The most common types are acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), typically presenting in early childhood. Clinical features may include fatigue, pallor, bleeding or bruising easily, and recurrent infections.
• Lung cancer: Though less common, LFS patients also have an elevated risk of lung cancer, particularly adenocarcinoma and small cell lung cancer. It is estimated that 6% of LFS individuals may develop lung cancer, often at an earlier age than the general population (typically before age 50). Patients may experience persistent cough, chest pain, shortness of breath, or recurrent respiratory infections.
• Gastrointestinal tumours: Gastrointestinal (GI) cancers occur in about 4-6% of LFS individuals. The most common types are colorectal cancer and gastric cancer. The age of onset varies but can occur as early as the second decade of life. Symptoms are often nonspecific but may include changes in bowel habits, blood in the stool, persistent abdominal discomfort, or unexplained weight loss.
• Other cancers: LFS individuals may develop other less common types of cancer, such as melanoma, pancreatic cancer, and renal cell carcinoma. The lifetime risk for these cancers is less well-defined, but it is clearly higher than that of the general population. Symptoms will be dependent on the type and location of the specific cancer. As with all malignancies in LFS, these cancers often present at an earlier age than typically seen in the general population.

Pathological Features

Histopathology

Features are variable and reflect the wide range of potential malignancies. Examples include invasive ductal carcinomas in the case of breast cancer, or spindle cell morphology in sarcomas. For adrenocortical carcinomas, there can be diffuse proliferation of atypical adrenal cortical cells.

Biochemistry

There is no specific biochemical marker for LFS, but tumour markers such as CA-125, PSA, or alpha-fetoprotein may be elevated, depending on the type of cancer.

Genetics

The presence of a germline mutation in the TP53 gene is the key genetic feature of LFS. About 70% of families that meet the classic LFS criteria have identifiable TP53 mutations.

Radiological Features

General Features

• Breast MRI: In breast cancer cases, lesions often appear as high signal intensity masses on T2-weighted images and show rapid initial enhancement followed by a washout pattern on dynamic contrast-enhanced sequences.
• Brain MRI: Brain tumours, such as gliomas, may present as a heterogeneous mass with variable enhancement and possible necrosis or haemorrhage.
• CT Abdomen: Adrenocortical carcinomas may appear as large, heterogeneous adrenal masses with areas of necrosis or haemorrhage.
• Bone scan / MRI: Sarcomas, such as osteosarcomas, may appear as destructive, moth-eaten appearing bone lesions with soft tissue mass and new bone formation.

Grading and Staging

Grading and staging of tumours in Li-Fraumeni Syndrome follows the standard protocols for the specific cancer type.

Diagnosis

Diagnosis of LFS is established when all three classic clinical criteria are met or when there is a heterozygous germline pathogenic variant in TP53.

Classical Criteria

1. An individual with a sarcoma diagnosed before the age of 45 years.
2. A first-degree relative with any cancer diagnosed before the age of 45 years.
3. A first- or second-degree relative with any cancer diagnosed before the age of 45 years or a sarcoma diagnosed at any age.

Differential Diagnosis

Differential diagnoses include other hereditary cancer syndromes, such as:

• Lynch Syndrome: Characterised by a high risk of colorectal and endometrial cancer. Differentiated by the absence of mutations in the TP53 gene and the presence of mutations in mismatch repair genes.
• Familial Atypical Multiple Mole Melanoma Syndrome: This syndrome also presents with a predisposition to multiple cancers, including melanoma and pancreatic cancer, but typically lacks the diverse range of sarcomas seen in LFS.

Management

Management in Li-Fraumeni Syndrome is centred around regular surveillance for early detection of malignancies and may include:

• A comprehensive physical examination annually or biannually.
• Annual whole-body MRI starting in childhood.
• Annual breast MRI and mammography for women starting at age 20-25.
• Consideration of bilateral mastectomy in women due to high lifetime risk of breast cancer.
• Annual brain MRI starting in infancy.
• Education about self-examination for testicular cancer in males.
• Genetic counselling for the affected individual and their family.