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Multi-centric breast cancer is a type of extensive breast cancer that has two or more tumour foci within different quadrants of the same breast. Typical signs and symptoms for this cancer are the presence of lumps, changes in size of the breast, form of the nipple and blood discharge from the breast. This type of cancer is one of the leading cause of death among all diseases. It was first discovered in early 1920s, and was later named as multi centric breast cancer. The mechanisms involved behind this cancer are the mutations in BRAC, PI3K and PTEN genes, which results in the uncontrollable cell growth, eventually contributing to breast cancer tumours formation.

There are various common diagnosis methods including clinical breast examination, mammogram, ultrasound, magnetic resonance imaging (MRI) and biopsy for this type of breast cancer. Patients with multi centric breast cancer can receive different treatment methods depending on the severity and own will. There is a higher likelihood that patients will receive a more invasive surgical treatment, such as mastectomy, to prevent the risk of recurrence. However, patients can choose to receive double lumpectomies to remove the tumour, along with radiation therapy as their treatment method to conserve their breast. An informed consent must be provided, and patients must attain full understanding of the risks and outcome

s prior to proceeding with the treatment.

Signs and Symptoms
The symptoms of multi centric breast cancer can vary depending on the severity and other factors. One of the most common symptoms is the presence of two or more lumps within the same breast, which can be detected through self examination. The likelihood of early detection of multi centric breast cancer is higher by combining monthly breast self-examination (BSE) with regular physical exams, mammography and magnetic resonance imaging (MRI). Changes of the breast shape can also be an identification of the disease, in which one breast may appear bigger or lower than the other breast. Other early signs of multi centric breast cancer can be changes of the nipple shape, breast skin texture and abnormal nipple discharge. Examples include nipple inversion, breast skin dimpling and blood stained liquid discharge from nipple. Other than the changes in the form of the breast and nipple, pain in the breast area, also known as mastodynia, is also an indication of the presence of breast carcinoma.

Incidence
There are different types of cancer such as lung cancer and skin cancer. Among these cancers, breast cancer is one of the most fatal type of disease around the world. There were 268,600 cases of breast cancer in American women followed by 41,760 deaths in 2019. Discovery of different focus of breast cancer was reported in early 1920 and this was further elaborated to define Multifocal and Multi centric Breast Cancer. As there is continuous increase in incidence of this cancer and upon developing technology of mammography, more people are defined as multifocal and Multi centric Breast Cancer (MMBC). Incidence of MMBC is between 9-75% in developed countries but this depends on different criteria. For instance, China reported that only 2% of patients are defined as MMBC. The reason for this huge difference is due to lack of uniformity in diagnosis. Therefore, standardised method and criteria should be made in order to define the incidence of MMBC correctly.

BRAC1 and BRAC2 Mutations
There are two types of BRAC genes 一 BRAC1 and BRAC2 that play crucial roles in the maintenance of genome stability. These genes are also tumour suppressor genes that prevent cell from dividing uncontrollably. Inactivating mutations in BRAC1 and BRAC2 can therefore contribute to genome instability and increased risk of multi centric breast cancer. The causes of BRCA genes mutations can be attributed to predisposing factors, precipitating factors and etiology (which is still currently unknown). Predisposing factors include gender, genetics and age, whereas precipitation factors can be diet, immunosuppression and even non-compliance to treatment. Consequently, this leads to unregulated differentiation of cancer cells in the breast or milk ducts, resulting in the growth of the malignant tumour cells in the breast.

PI3K and PTEN Mutations
In a healthy individual, programmed cell death, commonly known as apoptosis, is a biological process that occurs every once in a while when cells are are no longer needed for metabolism for the maintenance of tissue homeostasis. Until then, there are protective pathways that protect cells from apoptosis, which includes the PI3K/AKT pathway. In the pathway, activated receptor tyrosine kinase (RTK) by growth factors causes the phosphorylation of PIP2 into PIP3. PIP3 then subsequently leads to the activation of protein kinase B (AKT). AKT is a protein that plays an essential role in the regulation of cell growth, cell cycle proliferation and decrease apoptosis. PTEN gene is responsible for preventing the over-activation of AKT by dephosphorylating PIP3. In normal conditions, PI3K gene is not expressed, however mutations of the PI3K and PTEN genes are often encountered in multi centric breast cancer patients, causing hyperactivity of the PI3K/AKT pathway, resulting in the formation of breast cancer tumours.

Diagnosis
There are different methodologies for diagnosis of Multi centric Breast Cancer.

Clinical Breast Examination
Clinical Breast Examination is physical diagnosis of breast cancer. Patient could be uncomfortable with this examination as doctors physically diagnose by checking abnormality on patient’s breast and lymph nodes. This examination is often done during the regular check up.

Mammogram
Mammogram is the use of X-rays on breast to picture it. Use of mammogram helps doctor to detect early signal of the breast cancer. With this advantage, doctors recommend patients to go for regular mammograms for early detection and surgery. This technique requires flattening of breasts while taking a picture and therefore this is uncomfortable and women often find this painful. Pain does not last for long and it depends on the size of breasts and how skilled the technologists are.

Ultrasound
Ultrasound is use of sound wave to find any abnormal changes on your breast tissues. This technique is often not used for diagnosis of breast cancer but this is useful to detect changes in breasts.

Magnetic Resonance Imaging (MRI)
This method uses magnetic field and radio waves to generate specific structure of breast. Some studies confirmed that MRI has higher sensitivity over traditional imaging in detecting Multi centric Breast Cancer. Recent studies showed that MRI detected additional tumors in 20% of studied women with 66% of reliability. But this also indicates that there are 34% chances of false-positive result so there are still higher rate of misdiagnosis of Multi centric Breast Cancer.

Biopsy
Biopsy is used to confirm patient’s breast cancer status. Doctor uses needle and insert it into the breast or lymph node and remove tissues or lymph node. Lymph nodes have higher chances of having cancerous tissues. These collected tissues are analysed in the lab for justification.

Based on the techniques provided above, different classification of breast cancer could be determined. For multiple tumours, if there are more than one definite tumour on the same quadrant of the breast it is interpreted as multifocal and when there are multiple tumours on multiple quadrants of breast it is defined as multi centric breast cancer.

Case
57 years old woman was diagnosed with Multi centric Breast Cancer. She found out that her left side of breast was continuing to increase size. This increase was not the cause of any hormonal therapy or contraceptives. Also, there was clearly no family history of breast cancer. First, clinical breast examination was done and there was swelling of left breast but fortunately her right breast was clear. After the clinical breast Examination, ultrasound technique and biopsy confirmed that she has invasive multi centric breast cancer. Different diagnosis was taken and she was also confirmed with skeletal metastasis. She refused treatment because there are wide spread of cancerous cell throughout the body due to late diagnosis. This case shows that early detection of breast cancer is important and should be treated before the metastasis so that the chances of survival increase.

Surgical Treatments
There are multiple types of surgical treatments for multi centric breast cancer. The choice of surgical treatment is depended on several factors including stage of the cancer and size of the tumours. Patients with higher stages of breast cancer (stage 3 or 4) and larger tumour sizes have a higher likelihood to receive mastectomy than lumpectomy to prevent the risk of recurrence.

Mastectomy
Mastectomy is the standard surgical treatment for multi centric breast cancer patients, which is the removal of the entire breast. The benefits of mastectomy are low rate of recurrence, less likely to receive radiotherapy and no need for further surgical procedures, if not wound infection has been encountered. If the patient has any concerns for their body image, an original breast appearance can be restored by breast reconstruction surgery.

Double Lumpectomies
Double lumpectomies, also labelled as breast conservative therapy (BCT), is an alternative and preferred surgical treatment to mastectomy for early stage multi centric breast cancer patients. The procedure of double lumpectomies involves the surgical ablation of the cancerous tumour foci and the surrounding breast tissues in different quadrant of the same breast. The application of moderate-dose radiotherapy (RT) is essential for the eradication of any minimal residual disease after BCT. The main difference between BCT and mastectomy is that BCT is a breast-conserving surgical procedure, whereas mastectomy requires the removal of the entire breast. The benefits of double lumpectomies are the avoidance of breast reconstruction surgery and minimal breast scarring. However, this surgical treatment is not preferable for patients with over two breast tumours within the same breast due to difficulty in removing all cancer cells.

Neoadjuvant Chemotherapy
Neoadjuvant chemotherapy is a type of chemotherapy that the patient may receive prior to the surgical procedure. The function of this therapy is to reduce the size of the cancer tumours, so that BCT can be conducted rather than mastectomy. Common side effects that are associated with this type of chemotherapy are hair loss, nausea and extreme fatigue.

Adjuvant Chemotherapy
This is another type of chemotherapy that is commonly conducted after the surgical treatment. The chances of recurrence is minimised by adjuvant chemotherapy as cancer cells that are remained after the surgery are destroyed during the chemotherapy sessions. Likewise, the associated risks and side effects of this type of chemotherapy are also similar to neoadjuvant chemotherapy.