Cervical cancer screening

NHS Cervical Screening Programme (NHSCSP) that screens women and transgender men (with retained cervix) aged 24.5-64.

Cervical cancer is a common malignancy whose aetiology is intimately related to human papillomavirus. There are around 3,200 cases of cervical cancer in the UK each year and in 2017 it was the 14th most common cancer in women. The NHSCSP aims to prevent the development of cervical cancer through the early identification and treatment of premalignant lesions.

The cervix

The cervix, derived from the Latin cervix meaning neck, is a fibromuscular structure that sits at the lower portion of the uterus. It has an external os, continuous with the vaginal canal, and an internal os continuous with the uterine cavity. Between the two os lies the endocervical canal which is lined by simple columnar epithelium. The ectocervix is the vaginal canal facing portion of the cervix and is lined by stratified squamous non-keratinised epithelium.

The interface between the columnar and squamous epithelium is called the squamocolumnar junction. The exact position of this varies depending on age, menstrual status, pregnancy status and other factors (e.g. hormonal contraceptives).

Ectropion refers to the eversion of endocervical columnar epithelium onto the ectocervix. This is a normal physiological process that occurs at different stages of life (e.g. post menarche, during pregnancy). The replacement of this newly formed columnar epithelium with squamous epithelium is referred to as squamous metaplasia. Again, this is a normal physiological process. The region where this occurs is called the transformation zone – this is the zone in which most cervical cancers arise.

Pre-malignant lesions

Invasive squamous cell carcinoma is the most common form of cervical cancer. It tends to be preceded by a long period of non-invasive disease termed cervical intraepithelial neoplasia (CIN). Whilst low-grade CIN may spontaneously regress, high-grade lesions have a greater risk of developing into invasive cancer and as such is a significant target of the screening process. The primary cause of CIN is the human papillomavirus (HPV), and testing for the presence of this virus now forms the first stage of cervical cancer screening.

Cervical glandular intraepithelial neoplasia (CGIN) may also be identified during the screening process. This is a non-invasive lesion that can develop into adenocarcinoma of the cervix.

For more information on Cervical Cancer itself check out our notes.

Screening involves a cervical smear.

The NHSCSP offers screening from 24.5 to 64 years old to women, transgender men (with a retained cervix) and non-binary individuals (assigned female at birth). The frequency of screening depends on the age of the patient:

• 24.5 years old: first appointment sent to ensure they can be screened before turning 25.
• 25-49 years old: screening every three years.
• 50-64 years old: screening every five years.
• 65 years or older: may request screening if they have not had screening since turning 50. Screening will also be arranged if they have had recent abnormal cytology.

The cervix should be visualised with a speculum (abnormal macroscopic appearances should be urgently referred to gynaecology on a cancer pathway). The cytology sample is taken from the transformation zone. Liquid-based cytology (LBC) is now the method of choice, replacing older methods like the Papanicolaou smear (colloquially known as the ‘Pap smear’).

1. Primary hrHPV screening

Human papillomavirus (HPV) is implicated in the development of approximately 99.7% of cervical cancers. There are more than 100 types though less than 20 have been strongly linked to cervical cancer, so-called high-risk HPV (hrHPV). The two most important subtypes are HPV 16 and 18 – they are responsible for 70-75% of cervical cancers.

Cervical cells from a smear test are reviewed for the presence of high-risk HPV. If they are present, cytology will be completed.

2. Cytology

If hrHPV is found on screening then cytology of cervical cells will be completed. The findings can be normal, abnormal or inadequate:

• Abnormal cytology:
  • Borderline changes in endocervical cells: changes that don’t meet the criteria of other abnormalities. Patients should be referred and have a colposcopy within 2 weeks.
  • Borderline changes in squamous cells: changes that don’t meet the criteria of other abnormalities. Patients should be referred and offered a colposcopy within 6 weeks.
  • Low-grade dyskaryosis: dyskaryosis refers to abnormal appearing cells. Low-grade dyskaryosis has a lower risk of invasive cancer. Patients should be referred and offered a colposcopy within 6 weeks.
  • High-grade dyskaryosis: may be moderate or severe, which tends to correlate with CIN 2 and CIN 3. Patients should be referred and have a colposcopy within 2 weeks.
  • Suspected invasive cancer: patients should be referred and have a colposcopy within 2 weeks.
  • Glandular neoplasia: patients should be referred and have a colposcopy within 2 weeks.
• Inadequate cytology: inadequate samples should be repeated within 3 months. If two are inadequate the patients are referred for colposcopy. The same is true if hrHPV tests are unavailable recurrently.
• hrHPV positive, cytology negative: Screening should be repeated at 12 months in patients who are hrHPV positive with negative cytology. If negative they may return to the normal screening programme. If still hrHPV positive at 12 months (and cytology negative), repeat again at 12 months (i.e. 24 months after initial smear). If positive again (even if the cytology is negative or inadequate) the patient should be referred for colposcopy.

Colposcopy is a procedure that allows optimal visualisation of the cervix.

It is completed as a day-case procedure and typically takes 20-30 minutes. As with the cervical smear a speculum is placed in the vaginal vault and the cervix identified. A colposcope (which remains external) is then used to offer a magnified view of the cervix. After examining the cervix, chemicals may be applied and biopsies taken:

• Liquid tests: Schiller’s (Lugol’s) iodine test involves the application of an iodine-based solution. As the iodine solution is glycophilic, normal glycogen containing squamous epithelium stains brown or black. CIN and invasive cancer has little glycogen and does not stain. Columnar epithelium is also deficient in glycogen so does not stain. Acetic acid may also be applied, causing some abnormal cells to become white (so-called ‘acetowhite’).
• Biopsy: a sample of tissue may be taken to allow further analysis to be performed.

According to figures from the NHS around 40% of patients will have normal colposcopies. The remaining 60% have abnormal results that often require further treatment. There are a number of possible biopsy results including:

• Normal tissue
• Cervical intraepithelial neoplasia (CIN, discussed in more detail below)
• Cervical glandular intraepithelial neoplasia (CGIN)

During colposcopy, a ‘see and treat’ policy may be offered in those referred with high-grade changes. This allows patients to be treated for suspected high-grade CIN during their first visit. Caution must be used to avoid over-treating patients and the decision to offer such a service must be made by a senior clinician.

There are a number of scenarios where screening may be delayed or be performed with greater frequency.

Reasons to delay

Cervical screening may be temporarily delayed in a number of circumstances. Reasons to delay include:

• Currently menstruating
• Abnormal vaginal discharge / pelvic infection
• Less than 12 weeks postnatal
• Less than 12 weeks after a termination of pregnancy or miscarriage

In certain situations, it may be felt unlikely the patient will return for follow-up, a decision will have to be made about taking the sample whilst acknowledging the context.

Pregnancy

In pregnant women normally a routine screen will often be rescheduled to 3 months post-partum. If a woman has had an abnormal screen and subsequently falls pregnant, management should be guided by specialists.

Post-hysterectomy

The need for cervical screening following hysterectomy depends on several factors:

• Type of hysterectomy: total (cervix removed) versus subtotal (cervix remains)
• Reason for the hysterectomy
• Presence of CIN on hysterectomy specimen

Patients who have undergone a subtotal hysterectomy will need to continue on the National Cervical Screening Programme. Patients who have undergone a total hysterectomy may need to continue screening depending on the presence of CIN because of the risk of developing vaginal intraepithelial neoplasia. This involves taking vault cytology from the top of the vagina at specified time intervals.

Additional screening

Under certain circumstances, additional screening may be indicated. In appropriate patients aged 25-64, offer additional screening if:

• Renal failure requiring dialysis (or any other disease with a high chance of needing organ transplantation): Screen at time of diagnosis
• If planned to have organ transplantation: Screen within a year before transplantation.
• HIV: Screening at diagnosis, then yearly is advised.

Additional screening guidelines may exist for patients with various conditions or taking immunosuppressants. This tends to follow local guidelines and is managed by specialists.

There are numerous unique cases. Daughters of women exposed to diethylstilbestrol (DES, a synthetic oestrogen used from 1940 to 1970, exposure in utero was shown to increase the risk of clear cell adenocarcinoma affecting the vagina and cervix) may undergo more frequent screening or colposcopy.

Cervical intraepithelial neoplasia (CIN) refers to pre-malignant cervical dysplasia.

CIN are premalignant epithelial lesions that may progress to cancer.

• CIN 1: Mild dysplasia, malignant progression unlikely, most self resolve.
• CIN 2: Moderate dysplasia, higher risk of progression to malignancy.
• CIN 3: Severe dysplasia, highest risk of progression to malignancy.

Figures vary from study to study but CIN 3 is associated with around an 18% risk of progressing to invasive cancer over 10 years.

Patients with CIN 1 will typically be brought back for repeat review at 12 months. CIN 2 may resolve but risk of cancer is increased and removal is typically indicated. In CIN 3 removal is always advised.

Surgical management options include knife cone biopsy, laser conisation, large loop excision of the transformation zone (LLETZ), l and cryocautery amongst others.