P Hendry, P Whitford
Department of Surgery, Crosshouse Hospital, Kilmarnock
Correspondence to: Mr P Hendry, Department of Surgery, Crosshouse Hospital, Kilmarnock. Tel: 07989 859339 Email: paulhendry77@btinternet.com
SMJ 2005 50(3): 130-131
Abstract
Li-Fraumeni syndrome is a rare cause of breast cancer. It should be considered in cancer cases where a genetic link is suspected. It impacts dramatically on treatment and has major implications for the patient and their family.
Keywords: Li-Fraumeni, breast cancer
Case report
A 29-year-old female was seen urgently at our breast clinic in September of 2002 having noticed a lump in her right breast. This was described, by her GP, as a hard mass on the lateral aspect of her right breast along with retraction of her nipple. She was a generally well non-smoker, Para 3+0, with no allergies or regular medications. Past medical history included a left mastectomy in 1994 for an aggressive cystosarcoma Phylloides tumour and a benign lumpectomy from the right breast.
Examination confirmed tender nodularity in the right breast with distortion of the ipsilateral nipple and a small, firm mobile nodule was palpable near the right axilla. Ultrasounds demonstrated an ill-defined, 1.5-cm lobulated region, of decreased echogenicity behind and lateral to the old scar. FNA was carried out, under US guidance, confirming malignant cells.
Mammography illustrated malignant type microcalcification throughout the upper outer quadrant of the right breast and suspicious lymph nodes in the axilla. Core biopsies confirmed invasive breast carcinoma though staging did not demonstrate any evidence of distant metastases.
Following an uncomplicated mastectomy and level III axillary node clearance, pathology reported a 46-mm, grade 3 ductal carcinoma with surrounding DCIS. 23 of 27 nodes were positive with extensive lymphovascular invasion. ER and PR receptors were negative but HER2 receptor was 3+.
Such an aggressive secondary cancer at such a young age with a previous history of a phylloides tumour was suspicious of a genetic abnormality. Further questioning about her family revealed that her daughter died of adrenal cancer at the age of four years. Her father had died at the age of 42 with no clear diagnosis but with a history compatible with cerebral malignancy. Her paternal grandfather also died of bowel cancer in his early 50s. This supported the idea of a genetic link. In late 2002 the patient had genetic testing. Blood tests showed a germline mutation in the p53 gene and confirmed the diagnosis of Li-Fraumeni syndrome.
Adjuvant chemotherapy was commenced. Due to the risk of radiation induced sarcoma, radiotherapy is undesirable with these patients. However due to the aggressive nature of her disease 3-field radiotherapy was scheduled in the interest of short-term disease control.
The patient was unfortunately lost to follow up for about a year as she repeatedly missed appointments despite numerous phone calls from staff. She presented in early 2004 with right upper quadrant pain and hepatomegally. Ultrasound confirmed liver metastases. CT also raised the suspicion of thoracic and lumbar vertebral metastases, but this was not confirmed on bone scan or plain x-ray. In April 2004 she commenced palliative chemotherapy and was reviewed by the palliative care team in June 2004.
In Sept 2004 despite worsening headaches and papiloedema a CT scan failed to show cerebral metastases, however MRI confirmed the presence of widespread miliary deposits in the brain. A deposit in the spinal cord at level of T11 was also discovered. She then moved out of the area to be with her mother, palliative treatment continued and she passed away in early 2005.
Discussion
Breast cancer is one of the commonest cancers in Scotland with an estimated lifetime risk of 8%,1 up to 10% of these cases are the result of genetic predisposition. 2,3 Li-Fraumeni syndrome (LFS) accounts for less than 0.1% of breast cancers but should be considered with early onset breast cancers, soft tissue sarcomas, leaukaemia, primary brain tumours and adreno-cortical carcinomas. There are fewer than 400 families worldwide reported to have LFS, 3-5 although rare it has major implications for treatment and follow-up.
LFS is inherited in an autosomal dominant pattern and is caused by a defect in the tp53 gene, which is known to control the cell cycle and DNA replication. The tp53 gene was identified in 1979 and is considered the “guardian of the genome”. It plays a major role as a checkpoint and determines whether cells undergo DNA repair or cell death (apoptosis). Following recognition of damaged DNA; the normal cellular tumour antigen p53 protein either activates downstream genes to promote DNA repair or signals a “sensor” molecule to confirm damage and commence cell death. The protein may also have a more specific role in the DNA repair process. 4
A mutated form of the tumour antigen p53 can work in the opposite direction and cooperate with the RAS oncogene products to block the checkpoint of normal cellular tumour antigen p53. These leads to an inability to set off the appropriate chain of events and therefore damaged DNA can lead to the uncontrolled development or growth of diverse tumour types. 4
Clinically the diagnosis of LFS or Li-Fraumeni like syndrome (LFL) should be considered when a sarcoma is diagnosed before the age of 45 years and family members have cancers at a young age.3 Often childhood or early adulthood cancers have been diagnosed within the family and multiple primary tumours are not uncommon. Within LFS families breast cancer accounts for approximately a third of the cancer cases and usually occurs in the fourth decade. With LFS cancer risk is 50% by age 40 and up to 90% by age 60.4
An adequate family history is the key to identifying women with a genetic cancer predisposition. Patients in families with LFS who are treated for cancer must be offered counselling regarding the significant risk of developing other primary malignancies and appropriate follow-up monitoring. Diagnosis has major implications for the patient, their treatment and their family.
Surveillance for other cancers in this group has been shown to be ineffective in reducing morbidity or mortality however close attention to any lingering symptoms is recommended.4 Women who are identified to carry the germline TP53 have the option of breast surveillance or prophylactic mastectomy. Experimental evidence suggests potential increased sarcoma risk due to increased adverse effects of ionizing radiation on LFS cells with TP53 defects and radiation induced second malignancies have been reported among individuals with tp-53 mutations. Mammographic surveillance remains controversial due to the associated risk of radiation induced malignancy.3 This is also significant in the use of radiotherapy for treatment of breast cancer. Children in families with LFS who survive an initial cancer have a relative risk of developing a second cancer that is 83 times greater than that of the general population. Cumulative probability of a family member affected by LFS developing a second cancer is 57% at 30 years after developing the first cancer
In summary this case reflects a rare condition accounting for less than 0.1% of breast cancer cases but which is very significant to the patient and has major implications for their family. In a younger age group conservative surgery and radiotherapy is often the preferred treatment path, however radiation treatment may promote further malignancy. Radical surgery should therefore be considered to treat this group of patients. When there is a high incidence or an unusual type of cancer within a family a thorough family history should be taken and the diagnosis of Li- Fraumeni Syndrome considered. Although the incidence of Li-Fraumeni syndrome is very low, its early identification allows a more tailored and hopefully more effective treatment for individuals affected.
REFERENCES
1 Breast cancer in women. A national clinical guideline SIGN Guideline number 29. http://www.sign.ac.uk/guidelines/fulltext/29/index.html
2 McPherson K, Steel C M, Dixon JM. Breast cancer-epidemiology, risk factors, and genetics. Br Med J 2000; 321:624-628
3 Thull DL, Vogel VG. Recognition and management of hereditary breast cancer syndromes. The Oncologist 2004;9:13-24
4 Schneider KA, Li F. Li-Fraumeni Syndrome. http://www.geneclinics.org/profiles/ li-fraumeni/details.html
5 Levine AJ. P53, the cellular gatekeeper for growth and division. Cell 1997;88:323- 331