Introduction

Li-Fraumeni Syndrome (LFS) is a rare inherited disorder that greatly increases the risk of developing cancer, especially in younger ages. It has an autosomal dominant inheritance pattern, meaning if one single copy of a mutated gene was inherited, then Li-Fraumeni Syndrome would result. LFS is caused by mutations in the TP53 tumour suppressor gene, which normally functions to prevent abnormal cell growth.^1,3 LFS affects an estimated 1 in 5000 to 1 in 20,000 people, with women having up to a 90% lifetime risk of cancer and men around 70%. Also, about half of all cancers in affected individuals occur before the age of 40, and many develop more than one primary cancer in their lifetime. ^1,2 People with LFS have a 15 to 35 times greater risk of developing cancer at a young age compared to the general population.¹ 

LFS can involve many different types of cancer, but some are more common. These common types of cancer associated with LFS are soft tissue sarcomas, osteosarcomas, breast cancer, brain tumours and adrenocortical carcinomas. These are referred to as the core cancers of LFS.^1-3 Other cancers like leukaemia, colorectal, lung, stomach and melanoma may also present at a higher rate in those with LFS compared to those without.^1,2  As the risk of developing these cancers is early onset, early detection through genetic testing and regular surveillance is key. Modern strategies, like whole body magnetic resonance imaging, are helpful in identifying cancers earlier and thus improving outcomes and survival for those with LFS.³ Understanding the common types of cancers associated with LFS is important for patients, family and healthcare workers to make informed decisions and better survival. 

Soft tissue sarcomas

Soft tissue sarcomas are among the earliest and most common cancers seen in LFS.^1,4 They account for more than one third of cancers diagnosed before 20 years old. These tumours can develop in many parts of the body, including the arms and legs, internal organs, the area behind the abdominal organs and the head and neck.⁴ Historically, a diagnosis of sarcoma before the age of 45 years old was one of the key clinical features for identifying LFS. As the diagnosis of the syndrome often happens only after the first cancer is found, getting a complete family history at the time the sarcoma is diagnosed is crucial to help identify families who may carry TP53 mutations.⁴

Soft tissue sarcomas, in particular rhabdomyosarcoma, are the most common cancer types in children with LFS. 17% to 27% of all cancers in children with LFS are rhabdomyosarcomas. Research shows that these tumours are relatively frequent, with roughly 15% in women and 22% in men with LFS developing a soft tissue sarcoma in their lifetime.² Moreover, data shows that sarcomas make up 17.4% of all cancers in people who carry TP53 mutations and 36.8% of cancers in patients who are younger than 20 years old.⁴ 

Common subtypes

Rhabdomyosarcoma is the most frequent soft tissue sarcoma in children with LFS.^2,4,5 The highest risk is between the ages of 0 and 15, though cases can occur in older children and teenagers.² There are 2 types of rhabdomyosarcomas: embryonal and alveolar.  Embryonal rhabdomyosarcoma is most common in young children and typically affects the head and neck or the urinary and reproductive system. Most cases are within the first 10 years of life. Alveolar rhabdomyosarcoma is more common in older children and teenagers and typically affects the hands and feet.⁴ In a French study, 31 patients with rhabdomyosarcoma and a TP53 mutation were studied, and it was found that most children were diagnosed around the age of 2.⁵ This highlights how early this type of soft tissue sarcoma develops in LFS.  

Leiomyosarcoma and liposarcoma are other soft tissue sarcomas which are more commonly diagnosed in adults with LFS. Leiomyosarcoma accounts for 9% and liposarcoma accounts for about 5% in people with sarcomas who carry TP53 mutations. Some tumours are classified as sarcoma not otherwise specified, and these make up 17% of cases.⁴  

Osteosarcomas

Osteosarcoma is the most common primary bone cancer and a hallmark tumour in LFS.^4,7 These tumours form new bone tissue called osteoid, and they account for up to 16% of all cancers in LFS. It is one of the most common cancer types in LFS after breast cancer and soft tissue sarcomas.^2,6,7 Osteosarcoma can develop at any age, but it is most common in childhood and adolescence. Older adults can also develop osteosarcomas due to factors like radiation or bone conditions like Paget’s disease.⁴ These childhood onset tumours are important for early detection of TP53 mutations.^4,6,7 In a study of 52 LFS patients, the age of diagnosis was mostly around 13 years old, emphasising early teenage onset.^6,7 Men have a higher risk of bone cancer with 11% by 70 years old, whereas for women it is 5%.²  

Osteosarcomas typically develop in the long bones, especially the distal femur, but in LFS patients, they also happen in unusual sites like the axial skeleton or jaw.^4,6,7 Tumours in these sites should be a sign for genetic testing for LFS.⁷ Some tumours seen in LFS include periosteal or high-grade osteosarcomas, which are more common in children and teenagers.^6,7 Compared with sporadic cases, LFS osteosarcomas are more likely to appear in children under 10, develop in the axial skeleton or jaw and can present with more than one tumour. In addition, about a quarter of patients already have their cancer spreading in their body, which is known as metastasis, when diagnosed.⁶   

Early identification of TP53 mutations is critical for guiding treatment and cancer treatment since LFS patients are at high risk for multiple primary cancers, especially if they have cancer at a young age. Structured surveillance programs, like the Toronto Protocol, call for regular physical exams, ultrasounds and skin checks as well as endoscopies for adults. Doctors also monitor women’s breasts using an MRI. After any cancer diagnosis, yearly whole body and brain MRIs are recommended.⁸ These surveillance approaches allow cancer to be detected earlier, and when they are in their early stages, so patients have a better survival rate. Some patients have been found to have a 5 year higher survival rate compared to those who are not monitored.⁸  

Brain Tumours

People with LFS have an increased risk of brain tumours, though these are less common than sarcomas, breast, or bone cancers. The most common types are choroid plexus carcinoma, medulloblastoma and gliomas. About one third of choroid plexus carcinomas happen in people with LFS. Medulloblastomas usually appear in teenagers and tend to be more aggressive.⁹ Gliomas can also develop, with some being slower growing and others more aggressive. Regular check ups and brain scans can help detect tumours early.⁸ 

Adenocortical Carcinoma (ACC)

ACC is a key cancer in LFS. It most often develops in children but can also appear in adults under 40.^2,10,11 Some TP53 gene changes can increase the risk of ACC in children.² Everyone with ACC should be offered genetic testing, no matter their age or family history.^10,11  Early identification helps guide care and monitoring for future cancers.

Breast Cancer 

Breast cancer is the most common cancer in women with LFS, with a lifetime risk of 80% to 90%.² These cancers usually occur before menopause and are often the type that responds to hormones or certain therapies^.2,12 Some women may also develop less common breast tumours. Men rarely get breast cancer, but it has been reported. Women with LFS may have higher chances of cancer in the same or opposite breast, so monitoring is important.²

Other cancers

LFS can also increase the risk of other cancers. This includes lung cancer, skin cancer such as melanoma, lymphoma, prostate cancer, kidney, ovary, testis, thyroid and larynx cancers.² These cancers are less common but are still important for doctors to watch for.

Screening and Prevention

As people with LFS can develop multiple cancers at a young age, regular screening is crucial.⁸ Children are recommended to have frequent physical exams and ultrasounds. When it comes to adults, they should undergo physical exams every six months. Annual imaging, including full body scans and brain scans, is recommended after a cancer diagnosis.⁸ Women should start breast exams and imaging in their early twenties. Studies show that following these screening schedules helps to detect cancer earlier and improves patient outcomes. For example, 5 year survival was 88.8% for those who underwent regular monitoring compared to 59.6% for those who did not.⁸ Genetic testing is essential to identify people carrying TP53 mutations, guide treatment and help family members take preventative measures.^4,8  

Summary

Li-Fraumeni Syndrome (LFS) is a rare inherited condition that increases the risk of several cancers, often at young ages. People with LFS carry changes in the TP53 gene, which normally helps protect the body from cancer. The most common cancers in LFS are soft tissue sarcomas, bone cancers, breast cancer, brain tumours, and adrenal gland cancers, though other cancers, such as lung, melanoma, lymphoma, kidney, thyroid, and reproductive organ cancers, can also develop. As LFS can cause multiple cancers in one person or family, early detection is very important. Regular check-ups, imaging scans, and age-appropriate screenings, especially for children and women, help detect cancers early and improve outcomes by making informed treatment decisions.