Li-Fraumeni syndrome (LFS), also known as the sarcoma, breast, leukaemia and adrenal gland (SBLA) cancer syndrome, is a rare genetic disorder that causes the development of multiple malignant (cancerous) tumours throughout the body at a very young age. It is caused by a genetic mutation in the p53 gene, also known as the TP53 gene, which acts as a tumour suppressor in the body.
Familial cancer syndromes, also known as hereditary cancer syndromes, are rare conditions that cause an increased risk of cancer as the result of inherited genetic mutations in certain cancer-related genes. They can affect both adults and children, however they generally develop in people at a younger age than normal. While familial cancer syndromes are not classified as cancer, they are equally as severe and can be life-threatening as they are associated with the development of various tumours throughout the body. Having a familial cancer syndrome does not guarantee the development of cancer, however the risk of developing cancer is higher than those who do not have a familial cancer syndrome.
LFS is slightly more common in females, and tends to develop before the age of 40 (often in childhood before the age of 10). However, anyone can develop this disease.
Types of Tumours Associated with Li-Fraumeni Syndrome
LFS is most commonly associated with the development of various sarcomas, breast cancers, leukaemia’s, and adrenal gland cancers. However, it has also been linked to other types of tumours, such as brain tumours. Some examples include:
Rarely, other types of tumours may develop as a result of LFS, such as:
Treatment
When cancers are detected, they are staged and graded based on size, metastasis (whether the cancer has spread to other parts of the body) and how the cancer cells look under the microscope. Staging and grading helps your doctors determine the best treatment for you. However, each patient with LFS will present with a unique disease behaviour, with varying cancer locations and symptoms. As such, there is no one treatment method that will work for everyone, and there is no standard staging system for this disease. Instead of staging and grading, your doctor will recommend a treatment plan based on the following factors:
- Type of cancer present
- Cancer location
- Whether or not the cancer has metastasised
- Your age
- General health
- Your treatment preferences.
Your doctor may also recommend genetic testing, which analyses your tumour DNA and can help determine which treatment has the greatest chance of success. They will then discuss the most appropriate treatment option for you.
Treatment options for tumours associated with LFS may include:
- Surgery to remove as much of the tumour(s) as possible – these will vary based on tumour type and location.
- Chemotherapy.
- Immunotherapy.
- Targeted therapy.
- Cryotherapy.
- Hormone blocking therapy (for certain receptor positive breast cancers).
- Stem cell transplant (common with leukaemia).
- Clinical trials.
- Palliative care.
For more information on the treatment options, please refer to the Rare Cancers Australia treatment options page.
Li-Fraumeni Syndrome and Radiation Therapy
Radiation therapy, or radiotherapy, uses controlled doses of radiation to damage or kill cancer cells. This is one of the more commonly known cancer treatments, however, there is evidence to suggest that patients with LFS are more sensitive to radiation, and have a higher risk of developing radiation-induced tumours. Patients with this condition may be advised to be cautious about the use of radiotherapy as a treatment option.
Risk factors
While the cause of LFS remains unknown, the following factors may increase the likelihood of developing the disease:
- Certain genetic mutations, such as TP53 and CHEK2 (another tumour suppressor gene).
- Having a family history of Li-Fraumeni syndrome.
Individuals with LFS may also be prone to carcinogenic risks (a substance that has the potential to cause cancer), such as tobacco smoking or radiation exposure.
Not everyone with these risk factors will develop the disease, and some people who have the disease may have none of these risk factors. See your general practitioner (GP) if you are concerned.
Early symptoms
The symptoms of LFS often vary by the types of tumours present.
Symptoms of Sarcomas
Symptoms of sarcomas associated with LFS often vary by subtype:
Symptoms of Breast Cancer
In the early stages of LFS breast cancer, the disease may be asymptomatic. As the cancer progresses, some of the following symptoms may appear:
- A lump or lumpiness in the breast(s).
- A change in the size and/or shape of the breast.
- Swollen breasts.
- Changes to the nipple, potentially including:
- Changes in shape.
- Crusting, sores and/or ulcers.
- Unusual redness.
- Pain.
- Clear or bloody discharge.
- Inverted nipple (nipple turns inward when it used to face outward).
- Dimpling or indentation on the skin of the breast.
- A rash and/or itchiness of the breast.
- A scaly appearance and/or changes in the colour of the breast.
- Swelling or discomfort in the armpit or near the collarbone.
- Persistent, unusual pain not associated with the menstrual cycle.
Symptoms of Leukaemia’s
Symptoms of LFS leukaemia often vary by subtype.
Symptoms of Acute Lymphoblastic Leukaemia
Symptoms of LFS ALL are similar between adult and paediatric subtypes.
In the early stages of disease, some patients may appear symptomatic. As the cancer progresses, some of the following symptoms may appear:
- Anaemia, which carries its own set of symptoms:
- Fatigue.
- Dizziness.
- Paleness.
- Shortness of breath.
- Frequent or persistent infections.
- Easy bruising and/or bleeding.
- Bone and/or joint pain.
- Swollen lymph nodes (painless lumps) in the neck, underarms, stomach, and/or groin.
- Abdominal discomfort, potentially caused by a swollen liver, thymus, and/or spleen.
- Purpura or petechiae (a rash of small, red dots due to small superficial capillary bleeds).
- Unexplainable weight loss and/or loss of appetite.
- Fever and/or drenching night sweats.
- Heavy menstrual periods.
Symptoms of Acute Myeloid Leukaemia
In the early stages of disease, some patients may appear symptomatic. As the cancer progresses, some of the following symptoms may appear:
- Anaemia, which carries its own set of symptoms:
- Fatigue.
- Dizziness.
- Paleness.
- Shortness of breath.
- Frequent or persistent infections.
- Easy bruising and/or bleeding.
- Bone and/or joint pain.
- Swollen lymph nodes (painless lumps) in the neck, underarms, stomach, and/or groin.
- Abdominal discomfort, potentially caused by a swollen liver, thymus, and/or spleen.
- Purpura or petechiae (a rash of small, red dots due to small superficial capillary bleeds).
- Unexplainable weight loss and/or loss of appetite.
- Fever and/or drenching night sweats.
- Unusually heavy menstrual periods.
- Leukostasis, which carries its own set of symptoms:
- Headache.
- Weakness on one side of the body.
- Slurred speech.
- Confusion.
- Fatigue.
- Problems with blood clotting.
Symptoms of Adrenocortical Carcinomas
Symptoms of adrenocortical carcinoma will vary between adults and children, as well as between functional and non-functional tumours.
Paediatric symptoms
Most children with adrenocortical carcinoma have functioning tumours. However, children can also develop non-functional tumours.
The symptoms of childhood adrenocortical carcinomas are:
- Abdominal or back pain.
- A lump in the abdomen.
- A feeling of fullness in the abdomen.
- High blood pressure.
- Acne.
- Growing of body hair not associated with regular puberty.
- Deepening of the voice not associated with regular puberty.
- Accelerated growth rate.
- Enlarged genitalia (caused by excess androgen hormone).
- Growth of breast tissue in males (caused by excess oestrogen in males).
- Cushing’s syndrome (caused by excess cortisol).
Non-functional adrenocortical carcinoma in adults
Early stages of a non-functional adrenocortical carcinoma may not cause any symptoms in early stages. As the tumour progresses, symptoms may occur, including:
- Abdominal or back pain.
- A lump in the abdomen.
- A feeling of fullness in the abdomen.
Functional adrenocortical carcinoma in adults
The symptoms of functional adrenocortical carcinomas will vary based on the hormone that is being produced in excess.
Excess cortisol
Excess cortisol production may cause following symptoms:
- Unexplained weight gain (specifically in the face, neck, trunk, and limbs).
- Growth of facial, back or arm hair.
- A round, red, full, face.
- Deepening of the voice.
- Muscle weakness.
- High blood pressure and/or blood sugar.
Excess aldosterone
Excess aldosterone production may cause the following symptoms:
- High blood pressure.
- Muscle weakness and/or cramping.
- Frequent urination.
- Constantly feeling thirsty.
Excess testosterone
Excess testosterone production in men will usually present as asymptomatic.
Excess testosterone production in women may cause the following symptoms:
- Growth of facial, back or arm hair.
- Acne.
- Hair loss/balding.
- Deepening of the voice.
- Absence of menstrual periods.
Excess oestrogen
Symptoms of excess oestrogen production will vary between men and women.
In women, the following symptoms may appear:
- Irregular menstrual periods.
- Vaginal bleeding in women who have gone through menopause.
- Unexplained weight gain.
In men, the following symptoms may appear:
- Growth of breast tissue.
- Decreased or absent sex drive.
- Impotence (inability to develop and/or maintain an erection).
Symptoms of Brain Tumours
The symptoms of LFS brain tumours often vary by subtype:
Not everyone with the symptoms above will have cancer, but see your general practitioner (GP) if you are concerned.
Diagnosis/diagnosing
If your doctor suspects you have LFS, they may order some of the following tests to confirm the diagnosis and refer you to a specialist for treatment. The tests required for diagnosis will often vary based on the symptoms present, and where the tumour(s) are suspected to be located.
Physical examination
Your doctor will collect your overall medical history, as well as your current symptoms. Following this, they may examine your body to check for any abnormalities.
Genetic testing
In addition to guiding treatment, genetic testing can be used to help diagnose certain conditions. LFS has been linked to mutations in the TP53 gene, which changes specific protein functions. These changes can lead to cell abnormalities and, in extreme cases, cancer. Your doctor may perform genetic testing to better understand your condition.
Neurological examination
A neurological examination assesses sensory and motor functions, and can generally be done in your GPs office. The doctor may check your vision, hearing, balance, coordination, strength, and reflexes, depending on the signs and symptoms you have described. Any problem that is detected in this exam can help determine which portion of the CNS needs further investigation.
Endocrine studies & blood tests
Endocrine studies involve blood and/or urine tests and imaging tests (see below) to analyse your hormone levels and detect any abnormalities. Some of these tests may include:
- General blood test to assess overall health.
- Blood catecholamine studies, which measure levels of certain catecholamine levels in your blood.
- 24-hour urine test, which measures levels of catecholamine levels in your urine.
Imaging tests
The doctor will take images of your body using magnetic resonance imaging (MRI), a computed tomography scan (CT scan), ultrasounds, and/or positron emission tomography (PET scan), depending on where it is suspected the cancer is. The doctor may also look at other parts of the body and look for signs of metastasis. Your doctor may also recommend a somatostatin receptor scintigraphy scan, which involves injecting a radioactive substance into the bloodstream which attaches to the tumour and shows where the tumour(s) are located in the body.
Lumbar puncture
A lumbar puncture, or spinal tap, involves inserting a needle between two vertebrae in the lower spine and extracting a sample of cerebral spinal fluid (CSF) for analysis. A local anaesthetic or sedative is given prior to the procedure. Your doctor will discuss any risks and possible complications with you prior to the procedure.
Bone Marrow Aspiration
A bone marrow aspiration is a process that involves inserting the needle into the hipbone (or breastbone in some cases) to remove samples of solid and liquid bone marrow. These samples will then be analysed for cancer cells.
Biopsy
Once the location of the cancer has been identified, the doctor will perform a biopsy to remove a section of tissue using a needle. This tissue will then be sent to the lab and analysed for cancer cells.
Prognosis (Certain factors affect the prognosis and treatment options)
While it is not possible to predict the exact course of the disease, your doctor may be able to give you a general idea based on the extent of the disease, susceptibility to treatment, age, overall fitness, and medical history. It is very important to discuss your individual circumstances with your doctor to better understand your prognosis.
References
Some references are to overseas websites. There may be references to drugs and clinical trials that are not available here in Australia.