Cervical intraepithelial neoplasia (CIN) is a premalignant dysplasia of the cervical epithelium caused by human papillomavirus (HPV). It can, over time, progress to cervical cancer, necessitating chemoradiation and potential surgery.
Cervical cancer is a preventable and common cancer.
This article is designed to provide medical students with an understanding of CIN and cervical cancer, including prevention methods.
Cervical cancer is the 4th most common female cancer worldwide, with an annual incidence of 604,000 and mortality of 342,000 in 2020. It is caused by HPV-16 and HPV-18 in over 70% of cases, with other high-risk types responsible for an additional 20%.
In the UK, cervical cancer is the 14th most common cancer among women of all ages, and the 2nd most common cancer among women aged 15-44. There are around 3,200 new cases and 850 deaths each year. This cancer occurs in around 50% of women under the age of 45 and the incidence increases from age 15, peaking at 30-34 before decreasing with age (Figure 1).
Almost all cases of Cervical Intraepithelial Neoplasia (CIN) and cervical cancer are driven by infection with Human Papillomavirus (HPV). High-risk types include HPV-16 and HPV-18, which contribute to over 70% of cervical cancer cases, and 31, 33, 35, 45, 52 and 58, which account for an additional 20% of cervical cancers.
The cervix is an anatomical region that facilitates the passage of sperm into the uterine cavity while maintaining sterility of the upper female reproductive tract. It is composed of two regions: the endocervical canal and the ectocervix.
The endocervical canal is lined by mucus-secreting simple columnar epithelium and ends at a narrowing called the internal os, which marks the beginning of the uterine cavity. The ectocervix is the distal part of the cervix which projects into the vagina and is lined by stratified squamous non-keratinized epithelium which is resistant to the low pH of the vagina. The external os marks the transition from the ectocervix to the endocervical canal.
The squamocolumnar junction (SCJ) marks the location where the squamous epithelium of the ectocervix and columnar epithelium of the endocervix meet. When the columnar epithelium of the endocervix is exposed to the acidic environment in the vagina, it undergoes squamous metaplasia, and the area between the original SCJ and the new SCJ is known as the transformation zone.
Microtrauma to the epithelial cells of the transformation zone provides HPV with access to basal keratinocytes. HPV infects these cells with its surface proteins and uses its E6 and E7 oncoproteins to inhibit the tumour suppressors p53 and pRb, resulting in uncontrolled cellular proliferation. The ensuing accumulation of mutations results in pre-malignant cellular abnormalities, known as Cervical Intraepithelial Neoplasia (CIN).
Cervical Intraepithelial Neoplasia (CIN) can, in some cases, progress to invasive carcinomas. 80% of cervical cancers are squamous cell carcinomas of the epithelial lining of the ectocervix, while 20% are adenocarcinomas of the glands within the lining of the cervix.
HPV is most commonly spread through direct skin-skin contact during sexual intercourse, although other, rarer routes of transmission include contact with contaminated surfaces or objects, oro-genital transmission, perinatal vertical transmission, and autoinoculation.
The greatest risk factor for developing cervical cancer is HPV infection. Other risk factors include smoking, inadequate cervical screening, high parity, oral contraceptive use, lower socioeconomic status, co-infection with other sexually transmitted infections such as HIV, herpes simplex, and chlamydia, and previous cancers of the vagina, vulva, kidneys, and urinary tract.
Most HPV infections are asymptomatic and cleared within 2 years, and many women are diagnosed through routine screening. However, any woman presenting with abnormal vaginal bleeding (intermenstrual, postcoital, postmenopausal), vaginal discharge (blood-stained, mucoid, or purulent), or pelvic pain/dyspareunia should be checked for cervical cancer. Other important areas to cover in the history include previous screening, and any other relevant medical history.
When collecting clinical data for suspected cervical cancer, several key pieces of information should be gathered. This includes:
A speculum examination should be performed and may show a cervical mass or an inflamed cervix which may bleed on contact. For more information on performing a speculum examination and a cervical smear test, refer to relevant medical literature.
Table 1 outlines the differential diagnoses to consider in the context of symptoms of suspected cervical cancer.
Differential diagnosis
Clinical summary
Cervicitis
Inflamed, friable cervix prone to bleeding
Commonly caused by chlamydia trachomatis
Ectropion
Red cervix (Figure 5)
A benign condition involving the presence of columnar epithelium on the outside of the cervix
Endometrial cancer
May present with abnormal vaginal bleeding
Most cases of cervical ectropion are diagnosed during cervical screening.
Women with visible signs of cervical cancer, persistent unexplained cervical symptoms or bleeding for more than 3 months should be offered fast-track colposcopy or a gynaecology 2-week wait referral.
Premenopausal women with persistent abnormal bleeding may benefit from referral to gynaecology or genitourinary services.
Relevant bedside investigations include:
Relevant laboratory investigations include:
Relevant imaging investigations include:
Other relevant investigations include:
The NHS cervical screening program (NHSCP) is offered to all women aged 24.5 - 64 years. At age 24.5, women should receive an invitation for screening before the age of 25. At ages 25-49, women should be offered screening every 3 years. At ages 50-64 years, women should be offered screening every 5 years. At ages 65 and over, women should be screened if recent cervical cytology is normal, or if they haven’t had a cervical screening test since 50 and they request one.
The NHSCP requires a sample to be taken from the cervix. Three investigations are involved in the NHSCP:
Colposcopy involves inserting a speculum and using a colposcope (a microscope with a light) to visualize the cervix in detail.
Primary HR-HPV testing was fully implemented in 2019 and replaced the Papanicolaou test (‘pap smear’) as the first step of screening. The NHSCP protocol is shown in Figure 7.
Cervical Intraepithelial Neoplasia (CIN) is an abnormal growth of pre-malignant cells on the cervix. It is classified according to the thickness of the affected skin:
When high-grade precancerous cells invade the basement membrane, they are staged using the FIGO classification system.
Treatment decisions are based on the stage of the disease:
Treatment decisions are based on the stage of the disease:
Women with advanced or incurable cervical cancer should be managed on an individual basis with input from a multi-disciplinary team, focusing on pain, renal failure, bleeding and thrombosis, malodour and lymphoedema.
Women should be encouraged to participate in the national screening programme and receive the HPV vaccine. They should also be given advice on safer sex to reduce the risk of acquiring HPV, including using condoms and limiting the number of sexual partners.
HPV vaccines contain particles from the major protein of the viral capsid. Currently, the following groups are eligible:
The bivalent vaccine against HPV 16 and 18 was introduced in 2008 and replaced in 2012 by Gardasil, the quadrivalent vaccine against HPV 6, 11, 16 and 18. This is planned to be replaced in 2022 by Gardasil 9, the 9-valent vaccine against HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58 to provide more protection against cancer and genital warts. The immunisation programme was initially aimed at girls before the onset of sexual activity but Was expanded in 2019 to include boys. As of 2020, there is 85% coverage for girls and 53% for boys.
For individuals aged 15-25 who did not receive the vaccine, a schedule of three doses within 12 months is recommended. From April 2022, this has changed to two doses, six months apart.
Following diagnosis and treatment, people may experience a range of sexual complications such as loss of libido, vaginal stenosis, vaginal dryness, dyspareunia, atrophic vaginitis, and pain. Medical complications of advanced disease may include pain, renal failure, thromboembolism, haemorrhage, malodour, and fistula formations. Iatrogenic complications may include lymphoedema, and symptoms relating to late radiation effects on the bladder, ureter, and rectum.
Those diagnosed with cervical cancer are more likely to experience psychological problems associated with the diagnosis, pain, nausea, fatigue, potential guilt for not attending follow-up, and stigma.
HPV infection takes an average of 10 years or longer to progress to invasive carcinoma. CIN progression is not linear:
Mortality from cervical cancer has decreased dramatically in the last 40 years due to improved screening and treatment. A good prognostic outlook is associated with an earlier stage of disease at diagnosis and an earlier age of diagnosis. For example, women aged 15-39 surviving their diagnosis for five years or more is around 90%, while only 25% of those aged 80 or over do the same.
Early stage diagnosis has a one year survival rate of 96%, compared to 50% for the latest stages. On average, over 80% of women survive their diagnosis for more than a year, over 60% survive for more than five years and over 50% survive for more than 10 years.
