What Is A Phyllodes Tumour of The Breast? 

Introduction

Breast cancer is one of the most prevalent neoplasms in the human population. Neoplasm is an abnormal growth of cells, which can be either benign or malignant. Phyllodes tumours are a type of breast tumour that is less prevalent than ductal and glandular tumour types. The phyllodes tumour starts in the stroma, which is the connective tissue of the breast. In 2020, 11.7% of all diagnosed cancers were female breast cancer, making it the most prevalent neoplasm in the world.1  Phyllodes tumours are a rare type of breast cancer called a sarcoma. However, they are also a significant subtype with different morphological and histological differences to ductal carcinoma and other types of breast cancer. Phyllodes tumours account for 1% of all breast cancer cases. Read on to find out all you need to know about phyllodes tumours and how they are diagnosed and treated.⁹

Aetiology and pathogenesis - what causes the disease? how does the disease progress?

Stroma (connective tissue) associated with breast tumours has different characteristics than the stroma of the breast without tumour cells. The density of the capillaries is also increased, as well as a higher amount of fibrin and collagen deposits. A greater amount of fibroblasts and immune cells are a typical signal of malignancy.⁴ In the breast tissue, there are epithelial cells dispersed within stromal cells. The epithelial parenchyma and stromal parenchyma give rise to different types of tumours. 

Phyllodes tumours are more prevalent in women than men due to the hormonal influences of oestrogen and progesterone. Men who suffer from gynecomastia are at an increased risk of developing phyllodes tumours, and this is possibly due to a hormone imbalance.¹² Li-Fraumeni syndrome is a genetic condition linked to an increased risk of developing phyllodes tumours. It is caused by a mutation in the TP53 gene and is inherited from your parents. This condition is associated with cancer at a younger age of onset when compared to the general population. ⁵

Classification of phyllodes tumours

What are some of the different morphological changes in phyllodes tumours? 

• Atypical nucleus 
• Increased cellularity of the stroma 
• Increased mitotic activity 

To determine mitotic activity (the rate at which cells divide), a Biomedical Scientist will look at the sample under the microscope and count the number of cells dividing within a given area. This is then used as a parameter for deciding if the tissue has a higher-than-normal level of cells that are dividing. The criteria used for determining if a sample has a high mitotic activity are as follows. “10 mitoses per 10 HPF (compared with 3 mitosis/10 HPF for a benign Phyllodes Tumour” ^7,8

• Changes to the margin around the tumour 

If there are abnormal cells in the margin around an excised tumour, then this is indicative that the whole tumour has not been removed effectively. Abnormal margins around the tumour can also suggest the potential for metastasis, for example, when the cells have lost their normal shape and orientation. 

• Increased stromal growth ⁵ 

Three main categories: benign, malignant, and borderline malignant

• Benign tumours don’t spread to other organs. 
• Borderline tumours have some signs of changes in the cells but have not changed significantly enough to be deemed malignant. 
• Malignant tumours have significant changes in the architecture of the cells, and there is a strong risk of metastasis.

Clinical presentation

• Usually, phyllode tumours are found on a mammogram without any symptoms as part of routine screening.
• Painless breast mass with rapid growth. 
• The tumour may grow significantly over several weeks, but then the tumour is unlikely to metastasise to other locations if it is benign. 
• Common in women who already have fibroadenomas.
• Skin changes (increased prominence of veins). 

Diagnosis

Family history and clinical presentation

A doctor will take a detailed account of your family and any familiar cancers. This is because if you have first-degree relatives with breast cancer, there is an increased risk that a benign phyllodes tumour may become malignant.

Mammogram

A mammogram is an imaging technique that is used to determine any lumps or abnormalities in the breast. The breast is placed between two plates, and images are taken to determine the location and consistency of the lump based on its white appearance on the film. These images will then be taken to a Multi-Disciplinary  Meeting of histologists and doctors to determine an appropriate course of action.

Histology

A biopsy is taken and processed in the laboratory. The sample is made into a microscope slide and stained with haematoxylin and eosin for the pathologist to visualise the cellular architecture. A leaf-like pattern is observed in the case of a phyllodes tumour, with areas that are hyper-cellular.¹³

Fine-needle aspiration (FNA)

A needle is inserted into the breast tumour to remove a small sample. This is a less invasive method than the core biopsy. ²

Core needle biopsy (CNB)

A slightly larger needle is used to remove a biopsy from the breast tumour. Both the fine-needle aspiration and core needle biopsy will be completed with the help of ultrasound to visualise the tumour as it is being biopsied. If the FNA or  CNB show any histological signs of malignancy, then an excision of the tumour will be needed for further histological testing.

Surgery and further histological tests 

Treatment strategies

Chemotherapy is only needed if the phyllodes tumour is malignant.³

• Treatment options for phyllodes tumours are based on tumour characteristics and the patient’s health. For example, if a patient is frail, chemotherapy may not be recommended if the  doctor believes  the body won’t  tolerate it
• Clear margins on excision are important to reduce the likelihood of tumour cells being left behind. Any tumour cells left behind can regrow the tumour. 
• Mastectomy is required in cases of malignant tumours where the tumour grows into nearby tissues such as lymph nodes. A mastectomy is the removal of one or both breasts. Reconstruction of the breast can be completed by a plastic surgeon with synthetic implants.
• Radiotherapy is needed if there is an incomplete excision or in the case of a high risk of the tumour becoming malignant. 

Prognosis and follow-up

• The prognosis and follow-up depend on the classification of the tumour⁶
• Regular follow-up appointments, clinical examinations, and imaging such as MRI, CT and mammogram are necessary. An  MRI scan is needed in pre-menopausal women due to the higher breast tissue density. Some tumours in pre-menopausal women will not show up on a mammogram but will be visible on an MRI
• In the case of a malignant phyllodes tumour, monitoring for signs of recurrence once the tumour has been removed is essential. If the tumour is benign, monitoring is required to detect signs of it becoming malignant and for any signs of metastasis.

Research and future directions

There are numerous genetic and molecular aspects of phyllodes tumours. More information is being generated from research every day. Some of the main areas of research into the genetic basis of phyllodes tumours are as follows.

• MED12 is a common mutation in patients with phyllodes tumours³

MED12 is a gene that encodes a protein within our cells, essential for cell growth and cell migration. It also regulates cell division; therefore, a mutation in MED12 can lead to increased cell division in tumour cells.¹¹

• Loss of function in p53^6,3

P53 is a nuclear transcription factor associated with apoptosis (cell death). The loss of function of p53 can result in tumour cells avoiding apoptosis, thereby promoting tumour. Some patients with a p53 mutation exhibit chemotherapy resistance. ¹⁰

• Amplification of genes in IGF1R and EGFR³
• SETD2, BRCA2, and TSC1 mutations ³

Research is used to aid in the diagnosis of breast cancer, such as including AI in the diagnosis of breast tumours. Targeted therapies like immunotherapy can be used to treat phyllode tumours. This is applicable when a patient has a specific genetic mutation that can be targeted by immunotherapy drugs. For example, if a patient has an EGFR mutation, they can have tyrosine kinase inhibitors or monoclonal antibody treatment. Many immunotherapy drugs may only be available as part of a clinical trial. 

Conclusion

Understanding phyllodes tumours is an area in which we need to better comprehend the metastatic potential of a normally benign tumour. A multidisciplinary approach is needed for the effective management and treatment of all breast cancer cases. It is also important to look for any signs of recurrence with imaging and follow-up appointments. Overall, it is increasingly important to raise awareness about this rare subtype of breast tumour and to educate people on the importance of attending breast cancer screening appointments.