Cancer of the cervix tends to affect younger women, peaking in the reproductive years. 80% of cervical cancers are squamous cell carcinoma. Adenocarcinoma is the next most common type. Very rarely there are other types, such as small cell cancer.
Cervical cancer is strongly associated with human papillomavirus. Children aged 12 – 13 years are vaccinated against certain strains of HPV to reduce the risk of cervical cancer.
Cervical screening with smear tests is used to screen for precancerous and cancerous changes to the cells of the cervix. Early detection of precancerous changes enables prompt treatment to prevent the development of cervical cancer.
Human Papilloma Virus
The most common cause of cervical cancer is infection with human papillomavirus (HPV). HPV is also associated with anal, vulval, vaginal, penis, mouth and throat cancers. HPV is primarily a sexually transmitted infection.
There are over 100 strains of HPV. The important ones to remember are type 16 and 18, as they are responsible for around 70% of cervical cancers and also the strains targeted with the HPV vaccine. There is no treatment for infection with HPV. Most cases resolve spontaneously within two years, while some will persist.
P53 and pRb are tumour suppressor genes. They have a role in suppressing cancers from developing. HPV produces two proteins (E6 and E7) that inhibit these tumour suppressor genes. The E6 protein inhibits p53, and the E7 protein inhibits pRb. Therefore, HPV promotes the development of cancer by inhibiting tumour suppressor genes.
Risk Factors
You can think of the risk factors for cervical cancer in terms of:
- Increased risk of catching HPV
- Later detection of precancerous and cancerous changes (non-engagement with screening)
- Other risk factors
Increased risk of catching HPV occurs with:
- Early sexual activity
- Increased number of sexual partners
- Sexual partners who have had more partners
- Not using condoms
Non-engagement with cervical screening is a significant risk factor. Many cases of cervical cancer are preventable with early detection and treatment of precancerous changes.
Other risk factors are:
- Smoking
- HIV (patients with HIV are offered yearly smear tests)
- Combined contraceptive pill use for more than five years
- Increased number of full-term pregnancies
- Family history
- Exposure to diethylstilbestrol during fetal development (this was previously used to prevent miscarriages before 1971)
TOM TIP: When you are performing a history in your exams and considering cancer, always ask about risk factors to show your examiners you are assessing that patient’s risk of having cancer. Ask about attendance to smears, number of sexual partners, family history and smoking.
Presentation
Cervical cancer may be detected during cervical smears in otherwise asymptomatic women.
The presenting symptoms that should make you consider cervical cancer as a differential are:
- Abnormal vaginal bleeding (intermenstrual, postcoital or post-menopausal bleeding)
- Vaginal discharge
- Pelvic pain
- Dyspareunia (pain or discomfort with sex)
These symptoms are non-specific, and in most cases, not caused by cervical cancer. The next step is to examine the cervix with a speculum. During examination, swabs can be taken to exclude infection.
Where there is an abnormal appearance of the cervix suggestive of cancer, an urgent cancer referral for colposcopy should be made to assess further. Appearances that may suggest cervical cancer are:
- Ulceration
- Inflammation
- Bleeding
- Visible tumour
The NICE Clinical Knowledge Summaries (2017) recommend against unscheduled cervical screening with a smear test. They also advise against using the result of cervical screening to exclude cervical cancer where it is suspected for another reason, even if the smear result was normal.
Cervical Intraepithelial Neoplasia
Cervical intraepithelial neoplasia (CIN) is a grading system for the level of dysplasia (premalignant change) in the cells of the cervix. CIN is diagnosed at colposcopy (not with cervical screening). The grades are:
- CIN I: mild dysplasia, affecting 1/3 the thickness of the epithelial layer, likely to return to normal without treatment
- CIN II: moderate dysplasia, affecting 2/3 the thickness of the epithelial layer, likely to progress to cancer if untreated
- CIN III: severe dysplasia, very likely to progress to cancer if untreated
CIN III is sometimes called cervical carcinoma in situ.
TOM TIP: Try not to get mixed up between dysplasia found during colposcopy and dyskaryosis on smear results.
Screening
Screening for cervical cancer aims to pick up precancerous changes in the epithelial cells of the cervix. It involves a cervical smear test, performed by a qualified person, often a practice nurse. The test consists of a speculum examination and collection of cells from the cervix using a small brush. The cells are deposited from the brush into a preservation fluid. This fluid is transported to a lab where the cells are examined under a microscope for precancerous changes (dyskaryosis). This way of transporting the cells is called liquid-based cytology.
The samples are initially tested for high-risk HPV before the cells are examined. If the HPV test is negative (the person does not have HPV), the cells are not examined, the smear is considered negative, and the woman is returned to the routine screening program.
The cervical screening program involves performing a smear for women (and transgender men that still have a cervix):
- Every three years aged 25 – 49
- Every five years aged 50 – 64
There are some notable exceptions to the program:
- Women with HIV are screened annually
- Women over 65 may request a smear if they have not had one since aged 50
- Women with previous CIN may require additional tests (e.g. test of cure after treatment)
- Certain groups of immunocompromised women may have additional screening (e.g. women on dialysis, cytotoxic drugs or undergoing an organ transplant)
- Pregnant women due a routine smear should wait until 12 weeks post-partum
Cytology results:
- Inadequate
- Normal
- Borderline changes
- Low-grade dyskaryosis
- High-grade dyskaryosis (moderate)
- High-grade dyskaryosis (severe)
- Possible invasive squamous cell carcinoma
- Possible glandular neoplasia
Infections such as bacterial vaginosis, candidiasis and trichomoniasis may be identified and reported on the smear result.
Actinomyces-like organisms are often discovered in women with an intrauterine device (coil). These do not require treatment unless they are symptomatic. Where the woman is symptomatic (e.g. pelvic pain or abnormal bleeding), removal of the intrauterine device may be considered.
A summary of the management of smear results based on the Public Health England guidelines from 2019 is:
- Inadequate sample – repeat the smear after at least three months
- HPV negative – continue routine screening
- HPV positive with normal cytology – repeat the HPV test after 12 months
- HPV positive with abnormal cytology – refer for colposcopy
Colposcopy
A specialist performs colposcopy. It involves inserting a speculum and using equipment (a colposcope) to magnify the cervix. This allows the epithelial lining of the cervix to be examined in detail. During colposcopy, stains such as acetic acid and iodine solution can be used to differentiate abnormal areas.
Acetic acid causes abnormal cells to appear white. This appearance is described as acetowhite. This occurs in cells with an increased nuclear to cytoplasmic ratio (more nuclear material), such as cervical intraepithelial neoplasia and cervical cancer cells.
Schiller’s iodine test involves using an iodine solution to stain the cells of the cervix. Iodine will stain healthy cells a brown colour. Abnormal areas will not stain.
A punch biopsy or large loop excision of the transformational zone can be performed during the colposcopy procedure to get a tissue sample.
Large Loop Excision of the Transformation Zone (LLETZ)
A large loop excision of the transformation zone (LLETZ) procedure is also called a loop biopsy. It can be performed with a local anaesthetic during a colposcopy procedure. It involves using a loop of wire with electrical current (diathermy) to remove abnormal epithelial tissue on the cervix. The electrical current cauterises the tissue and stops bleeding.
Bleeding and abnormal discharge can occur for several weeks following a LLETZ procedure. This varies between women. Intercourse and tampon use should be avoided after the procedure to reduce the risk of infection. Depending on the depth of the tissue removed from the cervix, the procedure may increase the risk of preterm labour.
Cone Biopsy
A cone biopsy is a treatment for cervical intraepithelial neoplasia (CIN) and very early-stage cervical cancer. It involves a general anaesthetic. The surgeon removes a cone-shaped piece of the cervix using a scalpel. This sample is sent for histology to assess for malignancy.
The main risks of a cone biopsy are:
- Pain
- Bleeding
- Infection
- Scar formation with stenosis of the cervix
- Increased risk of miscarriage and premature labour
Staging
The International Federation of Gynaecology and Obstetrics (FIGO) staging system is used to stage cervical cancer:
- Stage 1: Confined to the cervix
- Stage 2: Invades the uterus or upper 2/3 of the vagina
- Stage 3: Invades the pelvic wall or lower 1/3 of the vagina
- Stage 4: Invades the bladder, rectum or beyond the pelvis
Management
Management of cervical cancer depends on the stage and the individual situation. The usual treatments are:
- Cervical intraepithelial neoplasia and early-stage 1A: LLETZ or cone biopsy
- Stage 1B – 2A: Radical hysterectomy and removal of local lymph nodes with chemotherapy and radiotherapy
- Stage 2B – 4A: Chemotherapy and radiotherapy
- Stage 4B: Management may involve a combination of surgery, radiotherapy, chemotherapy and palliative care
The 5-year survival drops significantly with more advanced cervical cancer, from around 98% with stage 1A to around 15% with stage 4. Early detection makes a significant difference, which is one reason the screening program is so valuable and important.
Pelvic exenteration is an operation that may be used in advanced cervical cancer. It involves removing most or all of the pelvic organs, including the vagina, cervix, uterus, fallopian tubes, ovaries, bladder and rectum. It is a vast operation and has significant implications on quality of life.
Bevacizumab (Avastin) is a monoclonal antibody that may be used in combination with other chemotherapies in the treatment of metastatic or recurrent cervical cancer. It is also used in several other types of cancer. It targets vascular endothelial growth factor A (VEGF-A), which is responsible for the development of new blood vessels. Therefore, it reduces the development of new blood vessels. You may also come across this medication as a treatment for wet age-related macular degeneration, where it is injected directly into the patient eye to stop new blood vessels forming on the retina.
Human Papillomavirus (HPV) Vaccine
The HPV vaccine is ideally given to girls and boys before they become sexually active. The intention is to prevent them contracting and spreading HPV once they become sexually active. The current NHS vaccine is Gardasil, which protects against strains 6, 11, 16 and 18:
- Strains 6 and 11 cause genital warts
- Strains 16 and 18 cause cervical cancer
TOM TIP: A common exam task is to counsel parents about their child receiving the HPV vaccine. They are upset because they believe this implies their daughter or son is sexually promiscuous. Focus on the fact it needs to be given before they become sexually active and that it protects them from cervical cancer and genital warts. HPV is very common and infection is the number one risk factor for cervical cancer.
Last updated July 2020