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Contents
Abstract
- Ovarian cancer is a key differential diagnosis in any woman with persistent or frequent abdominal symptoms such as bloating, urinary or gastrointestinal changes, especially in those aged 50 or over. Ovarian cancer is linked to mutations (harmful changes) in the BRCA1 and BRCA2 genes (BReast CAncer genes 1 and 2), which are also linked to breast cancer. This means that it is important to be wary of any symptoms of ovarian cancer in patients with those mutations.
- There are three main types of ovarian cancer, depending on the type of cell the cancer starts in: epithelial (the cells covering the ovary), germ cell (the cells that develop into eggs) and sex cord stromal (the supporting tissue of the ovary). Each of these types has many subtypes. Treatment depends on the exact type of cancer, how far it has spread (the stage) and how abnormal the cells look under the microscope (the grade).
- The uterus has two main tissue layers. The myometrium (the muscle wall) mostly forms benign fibroids, also known as leiomyomas (non-cancerous growths of smooth muscle). Cancer of the myometrium is rare. The endometrium (the lining) can form malignant adenocarcinomas (cancers of glandular tissue).
- Cell division in the uterus is driven by the hormone oestrogen. Therefore, oestrogen that is not balanced by enough progesterone (unopposed oestrogen) increases the chance of developing endometrial cancer. Fibroids also depend on oestrogen and progesterone to grow. The mainstay of curative management of uterine cancer currently is surgical removal.
- The cervix is the neck of the uterus, where it joins the vagina. It is lined by two types of epithelium: stratified squamous epithelium (flat cells in many layers) on the vaginal side, and columnar epithelium (tall, column-shaped cells) on the uterine side. The transformation zone is the area around the join between them, where columnar epithelium is replaced by squamous epithelium. Precancerous change, and most squamous cancers of the cervix, most often start here because the cell type is changing.
- Human papillomavirus (HPV) is found in almost all cervical cancers. Strains 16 and 18 cause about 70% of them, and also contribute toward the risk of oral, vulval, anal and penile cancer. The HPV vaccine protects against these strains and is offered to all 12 to 13 year olds in the UK.
- In England, routine cervical screening is offered to people with a cervix aged 25 to 64, normally every five years after a negative high-risk HPV result. Some people are invited sooner, for example after a positive HPV test or if they were given a due date under the old three-year schedule. Screening aims to find HPV and precancerous cervical changes before cancer develops.
- The vulva is part of the external genitalia of women, and is covered by squamous epithelium (flat skin-type cells), so the most common cancer of this organ is squamous cell carcinoma. Risk factors for development include HPV 16/18 infection and lichen sclerosus, a chronic inflammatory skin condition that often affects the vulva.
Core
This article focuses on cancers of the female reproductive tract, and so includes information on cancers of the vulva, cervix, uterus and ovaries.
For information on cancers of the male reproductive tract (including prostate and testicular), see our article here.
For information on cancers of the breast, see our article here.
Ovarian cancer is a cancer which is infamously hard to detect. Ovarian cancer is usually associated with only very vague abdominal symptoms such as bloating, distension (a swollen abdomen), abdominal or pelvic pain, feeling full quickly (early satiety), loss of appetite, and urinary or gastrointestinal changes (e.g. constipation or urinary urgency). These symptoms may be mild. They may be misdiagnosed as irritable bowel syndrome (IBS, a common bowel condition) or gastroenteritis, or not assumed to be associated with one another. As a result, ovarian cancer commonly goes undiagnosed and is usually in later stages on detection.
Ovarian cancer is associated with mutations in the BRCA1 and BRCA2 genes both of which are also associated with breast cancer. As a result any patients with known gene mutations presenting with the vague abdominal symptoms mentioned above should be investigated for ovarian cancer with a high level of suspicion.
CA-125 is a tumour marker (a protein in the blood that can be raised when a cancer is present). It is measured with a blood test if ovarian cancer is suspected. NICE advises measuring CA-125 in primary care (for example at the GP surgery) in people with ovaries who are aged 40 or over and have persistent symptoms that suggest ovarian cancer. An urgent ultrasound scan of the abdomen and pelvis is then arranged if the level reaches an age-based threshold, which ranges from 24 to 35 IU/ml (international units per millilitre). In those aged 39 or under, CA-125 is not used on its own, because it is not an accurate indicator of ovarian cancer risk at this age. An urgent ultrasound scan is considered instead. CA-125 can be raised in ovarian cancer and in other neoplastic (tumour) and non-neoplastic conditions, including endometriosis (womb-lining tissue growing outside the uterus), fibroids and even pregnancy. CA-125 may also be normal in early stages of ovarian cancer, so a normal result does not exclude disease and further assessment, including imaging, may be required.
Remembering the lymphatic drainage of the ovaries is important when removing ovarian masses. Lymphatic drainage of the ovaries is to the para-aortic lymph nodes (the nodes beside the aorta, at the back of the abdomen). It also drains to the pelvic lymph nodes, and by a minor route to the inguinal nodes in the groin.
There are three main cell types in the ovaries, and therefore three possible origins of cancer. There are many subtypes beyond the scope of this article so only the main subtypes are discussed here.
Epithelial ovarian cancer is the most common category of ovarian cancer and is a carcinoma, a malignant tumour of epithelial cells. These cancers do not always start on the surface of the ovary. Most high-grade serous cancers are thought to begin in the fimbriae, the finger-like ends of the fallopian tubes, before involving the ovary. High-grade (fast-growing) serous cancers of the ovary, the fallopian tube and the peritoneum (the lining of the abdominal cavity) are closely related.
There are multiple subtypes:
- Serous - the most common subtype. Serous tumours are often cystic (fluid-filled), but solid areas or papillary projections (finger-like growths) suggest a borderline (between benign and malignant) or malignant tumour. High-grade serous cancer is generally thought to be solid, or a mix of solid and cystic areas.
- Endometrioid: the second most common subtype, which can be linked to endometriosis (womb-lining tissue growing outside the uterus).
- Mucinous (mucus-producing): a rare subtype. It can be difficult to diagnose, because doctors have to check whether it started in the ovary or spread there from the digestive system.
Cancer of the epithelium of the fallopian tubes is similar to epithelial cancer of the ovaries.
Germ cell tumours of the ovary stem from the ova (egg cells) present in the ovary, and can be benign or malignant. They occur most commonly before the age of 30.
There are multiple subtypes:
- Benign: mature teratomas (often called dermoid cysts, which are growths containing a mixture of tissue types). They can differentiate into multiple tissue types so may contain structures such as teeth and hair. Mature teratomas are the most common ovarian germ cell tumour.
- Malignant:
- Dysgerminomas (the most common malignant germ cell tumour).
- Immature teratomas (teratomas that contain immature tissue).
- Yolk sac tumours (germ cell tumours that often form a mixed solid and cystic mass).
- Choriocarcinomas - these are tumours derived from placental-type cells.
Sex Cord Stromal (Ovarian stromal)
Sex cord stromal tumours are derived from the granulosa and theca interna cells (the cells around the developing egg that support it). Granulosa cell tumours are the most common type. They often make the hormone oestrogen. Symptoms of sex cord stromal tumours can include irregular or heavy periods and bleeding after the menopause.
The uterus is a secondary sex organ, which means that it matures only once puberty has begun. Anatomically, it is made up of the fundus (superior) and body. It has two main components:
The myometrium is the smooth muscle layer of the uterus which is used to expel the fetus during labour or the menstrual blood during a period.
Fibroids (also known as leiomyomas) are common, benign, well circumscribed tumours (tumours with a clear edge) that are oestrogen and progesterone dependent. This means they may enlarge in early pregnancy, and they usually shrink after the menopause. They are normally asymptomatic, unless large, when they may present with heavy periods (menorrhagia), urinary frequency, pelvic pain and fertility issues.
Malignant tumours of the myometrium such as leiomyosarcoma are possible, but rare.
Endometrial cancer is the commonest gynaecological cancer in the UK (source), and has peak incidence in post-menopausal women. It is an adenocarcinoma (derived from glandular tissue). It is responsive to oestrogen, so anything that increases oestrogen exposure raises the risk of developing endometrial cancer. Examples are being overweight, early menarche (first period at a young age), late menopause, tamoxifen use (tamoxifen is a breast cancer drug) and oestrogen-only hormone replacement therapy.
The presentation of endometrial cancer is normally abnormal bleeding patterns. This is usually bleeding between periods (intermenstrual) or, because most patients are older, post-menopausal bleeding (bleeding after the periods have stopped). NICE advises a suspected cancer pathway referral (an urgent referral to a specialist) for anyone with a uterus who is aged 55 or over and has unexplained post-menopausal bleeding that cannot be explained by hormone replacement therapy, and says to consider one under the age of 55. The specialist tests can include a transvaginal ultrasound scan (a probe placed in the vagina), a hysteroscopy (a thin camera passed into the uterus) and a biopsy of the lining of the uterus. A thickened endometrium warrants further investigation.
Treatment of endometrial cancer is commonly by hysterectomy (surgical removal of the uterus). In a few carefully selected women who want to have children, and whose cancer is early, low grade (grade 1) and confined to the lining of the uterus, hormone treatment can be tried instead. Progestogens (hormones similar to progesterone) are given by mouth or through a hormone-releasing coil in the uterus (the levonorgestrel-releasing intrauterine system, LNG-IUS). This needs close monitoring, and surgery may still be needed later.
The cervix is the point of connection between the vaginal canal and the uterus. It is made up of two regions: the endocervix and the ectocervix.
The ectocervix is the portion of the cervix that extends into the vagina. It has a stratified squamous (flat cells in many layers) epithelium that is non-keratinised, meaning it has no tough outer layer of keratin. The opening of the ectocervix is called the external os.
The endocervix (endocervical canal), is the inner part of the cervix, between the external os (vaginal end) and internal os (uterine end). It is lined by simple columnar epithelium (a single layer of tall, column-shaped cells) that secretes cervical mucus.
These two cell types mean that cervical cancers can be squamous cell carcinomas or adenocarcinomas (cancers of the mucus-producing cells).
The join between the stratified squamous epithelium of the ectocervix and the columnar epithelium of the endocervix is called the squamocolumnar junction. The transformation zone is the area around this join where columnar epithelium has changed, or can change, into squamous epithelium (squamous metaplasia). This area is of extra concern in the development of cancers, because most squamous cancers of the cervix start here.
Areas of abnormal cells called cervical intraepithelial neoplasia (CIN, precancerous change in the lining of the cervix) are pre-malignant lesions. Some will progress to cervical cancer if they are not treated, but many regress (go away) without treatment. The more severe the grade, the higher the risk of progression. Abnormal cells from CIN can be detected by cervical screening (once called a smear test), so pre-cancerous lesions can be detected before cancer has set in.
The human papillomavirus is a virus that infects the skin, commonly of the genitals, mouth or anus. Most infections are asymptomatic. Some strains of HPV can cause genital warts (strains 6 and 11) and some strains (strains 16 and 18) can predispose to cancers including cervical, vulval, penile, anal and oral cancer. Approximately 99% of cervical cancers are associated with HPV infection, with strains 16 or 18 being associated with about 70% (Cancer Research UK; NHS).
In the UK, 12-13 year old males and females are routinely offered the HPV vaccine, which protects against multiple high-risk and wart-associated strains, including 6, 11, 16 and 18. This helps to reduce the incidence of cancers associated with HPV infection and the incidence of genital warts.
In England, cervical screening is offered to people with a cervix aged 25 to 64. Routine recall is normally every five years following a negative high-risk HPV result. Some people are invited sooner, for example after a positive HPV test or if they were given a due date under the old three-year schedule. This describes England only, because Scotland, Wales and Northern Ireland run their own screening programmes. Symptoms such as bleeding after sex require clinical assessment; do not wait for a screening invitation.
During the examination, a small sample of cells is taken from the cervix and first tested for HPV. If HPV is detected, the sample is then examined with cytology (a microscope test) to look for abnormal cells. This looks for cell changes that may be pre-malignant (CIN). The NHS in England also offers some people an HPV self-test kit as an alternative way to take part. It can be done at home or in a private space, and it is the next best option for people who were invited for screening but did not attend.
If the sample is found to be HPV negative, there is low risk of cervical cancer and the patient would be invited for another regular screening 5 years later.
If the sample is found to be HPV positive, but there are no abnormal cells found, the risk of cervical cancer is increased slightly. This patient would be invited for repeat screening in 1 year, and again 1 year later if HPV is still found. If HPV is still present after 2 years, they are asked to have a colposcopy.
If the sample is found to be HPV positive and there are abnormal cells found, the risk of cervical cancer is high. This patient would be invited for a colposcopy (visualisation of the cervix) to further investigate the abnormalities. At colposcopy, the patient may undergo further biopsy or procedures to remove the abnormal cells to help prevent them progressing into cancer.
The vulva is the external genitalia of a woman, made up of the labia majora (outer lips), labia minora (inner lips) and clitoris. Like other skin on the body, it is covered by a keratinised squamous epithelium (flat cells with a tough outer layer of keratin). This helps the skin resist friction. As a result, most of the cancers that occur in the vulval region are squamous cell carcinomas. However, because it is skin, malignant melanomas or basal cell carcinomas can also occur.
Risks for vulval cancer include smoking, a weakened immune system and long-term skin conditions that cause chronic inflammation, such as lichen sclerosus. This condition does not have a known cause, but results in the development of white patches of itchy, cracked skin. As this occurs in the genital area, the skin can split and heal repeatedly, resulting in chronic inflammation and an increased risk of developing vulval cancer, although this risk is low.
Another risk factor for vulval cancer is HPV infection, most often strain 16, followed by strains 33 and 18. Strains 16 and 18 are the two most strongly linked to cervical cancer. They can cause vulval intraepithelial neoplasia (VIN, precancerous change in the skin cells of the vulva) in a similar way to the development of cervical intraepithelial neoplasia.
It is important to note that HPV strains 6 and 11, which cause genital warts, are not directly associated with the development of carcinomas.
The management of vulval cancer is usually surgery. This is local excision (cutting out the cancer with an area of normal tissue around it), sometimes with lymph node removal (removing lymph nodes in the groin, the inguinal nodes). Radiotherapy or chemotherapy may also be used. If the cancer has spread locally, the typical pattern is extension into the urethra (the tube that carries urine out of the body), vagina and anus, and less commonly the bladder.
Edited by: Dr. Ben Appleby
Reviewed by: Dr. Thomas Burnell and Dr. Marcus Judge
Quiz
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