Ovarian cancer

Ovarian cancers are numerous in their cell types as there are a wide array of cell types to be found within the ovary. It is the 5th most common cancer in women (after breast, lung, colon and uterine), however, it carries the highest mortality rate of all gynaecological cancers in the UK. It has a peak age of incidence at 60 years old and generally carries a poor prognosis, especially considering 80% of women present with advanced disease.

🔢 Pathophysiology and classification

Ovarian cancer may occur due to inherited mutations of certain genes such as BRCA1 or BRCA2. Lynch syndrome of course also pose a risk with its associated genes (MLH1, MSH2, EPCAM). Although the cancers involve the ovaries, it is also the fallopian tube that is the site of origin in many of these patients, with the distal fimbriae being the most common origin site. Cancer cells that break off from the origin site follow the peritoneal fluid to the sub-diaphragmatic space, for this reason the diaphragm, right liver edge and omentum are among the most common sites of implantation.

Let’s discuss the types of ovarian cancers based on the cell type from which they derive

• Epithelial ovarian tumours (90%)

These tumours arise from the epithelial cells of the ovary and fallopian tube. Most are believed to derive from the fimbria of the fallopian tube.

They may be benign (adenomas), intermediate (borderline malignant) or malignant:

1. Serous cystadenocarcinoma - the most common subtype (i.e. the most common type of ovarian cancer altogether). It is characterised by psammoma bodies which are round microscopic calcium collections. It is a benign tumour.
2. Endometrioid carcinomas - endometrioid ovarian cancer is the 2nd most common type of epithelial ovarian tumour. It is linked to endometriosis. Most cases are diagnosed at an early stage and are low-grade. It is possible to have an endometrioid ovarian cancer as well as a separate endometrial cancer.

3. cystadenocarcinoma - mucinous ovarian cancer is rare and is difficult to diagnose. It is characterised by mucin vacuoles. It may be a primary tumour or it may be a Krukenberg tumour (a metastasis to the ovaries from another primary site - most commonly the GI tract), which is made up of mucin-rich signet ring cells.
4. Clear cell ovarian cancer - another rare ovarian cancer. It is also linked to endometriosis. Clear cells are cells that have a clear or pale cytoplasm on histology.
5. Brenner’s tumour - these are a subtype of transitional cell tumour within the ovaries. The majority are benign but it is possible for them to become malignant. They are solid, well defined and pale yellow in colour. 10-15% are bilateral.

Some eptihelial ovarian cancers are undifferentiated or unclassifiable as they have cells that are underdeveloped and so it is not possible to distinguish where the cells derive from.

• Non-epithelial ovarian tumours (10%)
1. Germ cell tumours/dermoid cysts - these originate from the reproductive germ cells and as such often present in premenopausal women. The tumours arise from totipotent germ cells. These are cells that contain all 3 layers of embryonic tissue (ectoderm, endoderm and mesoderm) and may give rise to any tissue type. They contain hair, teeth, bone, intestinal tissue etc.

There are different types of dermoid tumours that may form such as:

1. Immature teratomas
2. Dysgerminomas
3. Yolk sac tumours
4. Choriocarcinomas
5. Embryonal carcinomas
2. Sex cord-stromal tumours - these are rare benign or malignant tumours that may arise from the stromal tissue (connective tissue) or sex cords (the embryonic structures that later form the ovarian follicles).

There are 3 main groups of sex cord-stromal tumours:

1. Pure stromal tumours - such as fibromas. They are mostly benign.
2. Pure sex cord tumours - such as granulosa cell tumours. These are malignant and are the most common type of sex cord-stromal tumours. They produce hormones such as oestrogen and are therefore called functioning tumours. The release of oestrogen can lead to symptoms such as abnormal vaginal bleeding or breast tenderness.
3. Mixed sex cord-stromal tumours - such as sertoli-leydig tumours. These can be benign or may be cancerous.

📊 Staging

🤷‍♀️

Summary of FIGO staging of ovarian cancer:

1. Stage I - confined to the ovary.
2. Stage II - extra-ovarian involvement, but confined to the pelvis.
3. Stage III - extra-pelvic involvement, but confined to the abdomen
4. Stage IV - distant metastasis.

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Detailed FIGO staging classification for ovarian cancer:

😷 Presentation

Unfortunately ovarian cancer can present with vague and non-specific symptoms which can be dismissed as menopausal symptoms and therefore the woman does not even address them with the GP. It is therefore important to consider ovarian cancer when treating women over 50 years old with the following symptoms:

• Bloating
• Early satiety and loss of appetite
• Weight loss
• Urinary symptoms - such as frequency and urgency.
• Postmenopausal vaginal bleeding
• Constipation or diarrhoea
• “Tired all the time”

Advanced disease may present with:

• Hip or groin pain - this is referred pain due to compression of the obturator nerve. The obturator nerve forms from branches of L2-L4 and is responsible for the hip adductors, obturator externus and gracilis. It provides sensation to the medial portion of the thigh too (adductor region).
• Pelvic pain
• Abdominal/pelvic mass
• Ascites - this is because vascular growth factors are released that increase vascular permeability. It is important to consider Meig’s syndrome (triad of benign ovarian mass, ascites and pleural effusion), although this occurs with benign ovarian masses and not ovarian cancer.

🔍 Investigations

1. 🥇 CA-125 - a CA-125 of >35IU/mL is significant and warrants a referral and USS of the abdomen and pelvis.
2. 🥇 Ultrasound abdomen and pelvis - a raised CA-125 should prompt this.
3. 🏆 Diagnostic laparoscopy + biopsy
4. Calculate the risk of malignancy index (RMI)

We can also consider the following tests:

• CT scan - for staging.
• Ascitic tap (paracentesis) - to test the ascitic fluid for cancer cells.

⚠️ Women <40 years old with complex ovarian masses should have the following tumour markers to assess for possible dermoid cysts/germ cell tumours:

1. Lactate dehydrogenase
2. Alpha-fetoprotein
3. Human chorionic gonadotrophin (hCG)

💡

CA-125 is an antigen that is elevated in times of peritoneal irritation. It is not specific to malignant ovarian masses in premenopausal women as there is an increased rate of false positives. This is because it may be raised in cases of:

• Endometriosis
• Adenomyosis
• Pelvic infection

• Liver disease
• Pregnancy

🧰 Management