Essay: How epithelial ovarian cancer arises and develops

There are three forms of ovarian cancer – the most common being epithelial OC (~90% of cases), stromal OC (~7%) and germ line OC (~1-2%). This essay will focus particularly on how epithelial ovarian cancer arises and develops, as this is the form of OC that Abbi has. As confirmed by pathologists, the mass on Abbi’s ovary is an ovarian adenocarcinoma (a malignant tumour that forms in the epithelial lining of glandular structures), which indicates epithelial OC. Possible sites of tumour origin include the ovarian surface, fallopian tube or the epithelium of the peritoneal cavity, called the mesothelium. These tumours can be classified as type I, where the tumour begins as a cystadenoma (a benign ovarian growth) that develops into a proliferative or borderline tumour and eventually into an invasive tumour. This is considered to be a slower, less aggressive process and tumours ordinarily have low malignant potential with mutations most frequently occurring in BRAF, KRAS, ERBB2. These are oncogenes, which regulate mitogen-activated protein kinase (MAPK) and mutations in these genes causes the MAPK signal transduction pathway to become and remain activated, leading to uncontrolled cell proliferation. In contrast, type II tumours are characterised as high-grade; they evolve and metastasise rapidly. It is estimated that nearly 80% have mutations in p53 (a tumour suppressor gene), 20-67% show overexpression of ERBB2. Genetic instability is characteristic of type II tumours due to chromosomal rearrangement, with 90% of cases showing mutations in BRCA1 and BRCA2. These mutations cause uncontrolled proliferation and the build-up of these cells forms a mass called a tumour. Could insert table showing % mutations according to type?
The cells in ovarian tumours undergo a transformation called epithelial-to-mesenchymal transition (EMT) before they detach and start to metastasise. This process allows the epithelial cells to loosen its attachment to each other and to the basement membrane. A loss of a glycoprotein, E-cadherin, has been identified to correlate with the tumour becoming invasive and these transformed cells now proliferate. Cells detach from the tumour either singly or as multicellular ‘spheroids’ and passively travel in the peritoneal fluid to the secondary sites: the peritoneum (a serous membrane lining the abdominal cavity) and omentum (a peritoneal layer surrounding the abdominal organs). The cancer cells then undergo mesenchymal-to-epithelial transition (MET) to transform back into the epithelial phenotype where it is believed to regain its epithelial properties such as responding to paracrine growth factors in order for the continued growth of the tumour and integration into the new site.
Symptoms and Diagnosis
Unfortunately, OC has developed a reputation of being a ‘silent killer’ as symptoms often go unnoticed until the cancer has developed significantly. Symptoms include persistent abdominal pain, persistent bloatedness (for ~3 weeks), feeling full, frequent urination, changes in bowel movements (including diarrhoea/constipation), fatigue. When patients begin to recognise these changes in their bodies, they should approach their general practitioner. The GP will ordinarily examine internally by inserting fingers into the vagina and applying pressure on the abdomen to check for any abnormalities. A referral to the gynaecologist will include taking a medical history, recording symptoms and possibly another internal examination. If it is likely they have OC, the CA125 test will be arranged, as well as a CT scan or ultrasound. The CA125 (cancer antigen 125) blood test measures the level of ca125, a protein produced by some ovarian cancer cells, in the blood. A reading of greater than 35U/ml suggests there is some inflammation in the area, but it is not a conclusive test for OC as elevated CA125 levels can be indicative of many different diseases, including endometriosis and pelvic inflammatory disease. The test is also used as a means of monitoring treatment progress. Abbi’s test results were extremely high – 500U/ml and 650U/ml, which she was referred to a specialist gynaecological cancer surgeon. An ultrasound is performed to check for abnormalities in the size and texture of the ovaries, and whether there are any cysts. CT scans are sometimes used for a clearer view of the ovaries. Doctors use the risk of malignancy index (RMI), which combines the results of the ultrasound, CA125 level and menopausal status – women with high scores are then referred to a multidisciplinary team who decide on what happens next. Once diagnosis of OC is confirmed, the cancer must then be staged (how far the cancer has spread) and graded (the appearance of cells). Talk about Abbi here?
Figure 1 shows the different stages of Ovarian Cancer.
Treatments for OC
The typical treatment pathway for an advanced OC patient is cytoreductive surgery (tumour removal) followed by platinum-based chemotherapy. The treatment options depend on the stage of the cancer, whether fertility is an issue and the general health of the patient. The most effective treatment for OC is surgery (find a stat). It should be noted that sometimes it is unable to determine what stage the patient is at without surgery. Surgery can include a hysterectomy (removal of uterus), a unilateral/bilateral salphingo-oophorectomy (removal of one/both ovaries and fallopian tube) and omentectomy (removal of omentum), which are the procedures Abbi had. It is common that tissues and lymph nodes from pelvis and abdomen are biopsied to detect if the cancer has spread. It is vital that the gynaecologic oncologist properly stages and ‘debulks’ the cancer optimally for the highest possible survival rate of the patient. Studies show that patients who have undergone optimal cytoreduction have approximately a 22-month median survival advantage compared to patient with suboptimal cytoreduction (those left with tumours larger than 1cm in diameter).
Chemotherapy kills cancer cells by halting cell division and is usually the second step in managing the treatment of an OC patient. Adjuvant chemotherapy is administered, either intravenously (infusion into veins) or orally (swallowed), post-surgery to kill any remaining cancerous cells. The combination of cytotoxic, platinum-based drugs commonly given are carboplatin and paclitaxel. Carboplatin is an alkylating agent (alkyl group is added), which binds to DNA and inhibits DNA replication, transcription and causes cell death.