Cervical cancer is a malignant neoplasm of the uterine cervix and the 4th most common cancer in ♀ worldwide. 85% of cases occur in developing countries. An estimated 266,000 deaths from cervical cancer occurred worldwide in 2012, which accounts for 7.5% of ♀ cancer deaths. Cervical screening and treatment of high-grade cervical intraepithelial neoplasia HGCIN aims to prevent development of invasive cervical cancer (ICC).
The vagina and ectocervix are lined with stratified squamous epithelium, and the endocervix with columnar epithelium. The position of the squamo-columnar junction (SCJ) varies throughout life. Hormonal changes (puberty, pregnancy) lead to enlarging of the cervix and eversion of the endocervical columnar epithelium, moving the SCJ distally. This is counterbalanced by squamous metaplasia (the normal process of reversion to squamous epithelium). The area between the original and receding SCJ is known as the transformation zone (TZ), which is susceptible to malignant change when exposed to oncogenic stimuli.
• Atypia: epithelial cells showing nuclear or cytoplasmic abnormalities that are not considered to be malignant or premalignant. Koilocytic atypia describes atypical cells with a perinuclear halo associated with HPV infection.
• Dyskaryosis: nuclear abnormality of cervical epithelial cells, graded as low or high grade. This is examined for during cytological cervical screening programmes.
• CIN: squamous cell premalignant lesion (also known as dysplasia). Architectural and cytological changes in squamous epithelial cells; a histological diagnosis. Grades of CIN are based on depth of epithelial involvement. The basement membrane is always intact.
• CIN1—lowest 1/3 only (mild dysplasia)
• CIN2—lower 2/3 (moderate dysplasia)
• CIN3—>2/3 of epithelial cells abnormal (severe dysplasia).
• Cervical glandular intra-epithelial neoplasia (CGIN): columnar cell premalignant lesion, less common than CIN; also a histological diagnosis. Nuclear, nucleolar, and glandular structural abnormalities are seen in columnar epithelial cells. Low-grade (LCGIN) is also known as endocervical gland dysplasia. HCGIN is also known as adenocarcinoma in situ.
• ICC: penetration of basement membrane by malignant epithelial cells.
• HPV (
Chapter 23, ‘Aetiology’, p. 292): High risk HPV (HR-HPV) is implicated in both SCC and adenocarcinoma, although only a small number of ♀ infected with HR-HPV develop cervical cancer. HPV DNA is detected in 95% of cervical cancer precursors. HPV 16 and 18 have been associated with around 70% of cervical cancers.
• CIN: has the potential to develop into cervical cancer, but may regress or persist as CIN. The oncogenic potential of the HPV type and environmental factors (e.g. smoking, immunosuppression) will influence risk of progression, as well as histological grade of CIN. Estimates of progression from CIN 3 to ICC range 12–40%.
• CGIN: pre-invasive stage of adenocarcinoma.
• Other STIs: may 
risk of progression of HPV infection to dyskaryosis, probably 2° to cervicitis.
• Sexual activity: relative risk 2.5 if coitarche <18 years compared with >21 years. ≥5 lifetime partners confers a relative risk of 2.8.
• Parity and age at first pregnancy: risk with parity, independent of other risk factors. risk with 
age at 1st pregnancy.
• Smoking: appears to risk of ICC two-fold.
• Lower socioeconomic class: linked to risk of ICC.
• Combined oral contraception: long-term use (>10 years).
• Immunosuppression: persistence of HPV infection.
• CIN is typically asymptomatic, but should be considered in those with PCB or IMB.
• ICC can have a variety of clinical presentations. Women may be asymptomatic, present with irregular vaginal bleeding or, if advanced, with symptoms of a mass or metastatic disease.
• If ICC presents with symptoms, it is usually more advanced so signs are often evident, e.g. fixed uterus and parametrial/posterior pelvic induration, hepatosplenomegaly or inguinal/supraclavicular lymph node enlargement. Subtle signs of early stages of ICC may be missed, e.g. pronounced cervical contact bleeding, hard or irregular and enlarged or ulcerated cervix, profuse offensive vaginal discharge.
Cytological screening involves collection, staining, and microscopic examination of epithelial cells from the cervix, looking for dyskaryosis
• The newer technique of liquid-based cytology (LBC) has replaced Papinacolaou smears (see Box 30.1).
• Advantages include less unsatisfactory samples, easier analysis, and the ability for the sample to be tested for HPV DNA and other biomarkers.
• ‘Unsatisfactory’ results (usually <2%) are due to insufficient epithelial cells, or the presence of blood or pus cells.
• False-negative results may be found in established ICC because of cell necrosis.
• Closer correlation between cytological and histological findings occurs with higher degrees of abnormality.
• Cytology laboratories will advise on the correct management and follow-up of abnormal cytology. (See Box 30.2 for English guidance).
• Coincidental findings (including Trichomonas vaginalis (TV), Candida spp., Neisseria gonorrhoeae, genital herpes, and Actinomyces-like organisms) may be seen during microscopy. Most would require clinical evaluation and confirmation before treatment. It should be noted, however, that the specificity for the finding of TV probably exceeds 98% on LBC samples.
Box 30.1 Cervical cytology technique
• Take cervical smear before cleaning the cervix and taking any endocervical swabs.
• Note macroscopic appearance of the cervix. Defer cytology if marked cervicitis.
• Sweep 360° around the cervix ×5 in a clockwise direction, ensuring TZ sampling.
• For LBC, the end of the sampling brush is rinsed or broken off into the preservative medium.
Box 30.2 Cervical cytology guidance in England
A computerized call–recall system invites ♀ registered with a GP for screening:
• ♀ aged 65+, only if not screened since age 50 or a recent abnormality).
Screening can be done in GUM, sexual health, and primary care. A copy of the result should go to the patient’s GP. In the UK, screening commences at age 25. Below this age, most low-grade abnormalities due to HR-HPV resolves spontaneously and, where identified, may result in over-investigation and/or treatment with potential adverse reproductive outcomes. Furthermore, the rate of cervical cancer is extremely low, with cytology screening not having any impact.
The British Association for Cytopathology (BAC)/NHS Cervical Screening Program (NHSCSP) 2013 classification of cervical cytology is used in the UK, and the Bethesda system is used more widely worldwide (Tables 30.1 and 30.2).
Table 30.1 Classification of CIN: squamous lesions
| BAC/NHSCSP (2013) | Bethesda system (2015) | |
| Cytology | Histology | |
| Borderline changes in squamous cells | Atypical squamous cells of uncertain significance (ASCUS) Atypical squamous cells cannot exclude HSIL | HPV |
| Low-grade dyskaryosis | LSIL | CIN1 |
| High-grade dyskaryosis (moderate) | HSIL | CIN2 |
| High-grade dyskaryosis (severe) | HSIL | CIN3 |
| High-grade dyskaryosis/invasive SCC | HSIL SCC | SCC |
Data from: NHS Cervical Screening Programme (2013) Achievable standards, benchmarks for reporting, and criteria for evaluating cervical cytopathology, and Nayar and Wilbur (2015) The Bethesda System for Reporting Cervical Cytology. Berlin, Springer.
Table 30.2 Classification of glandular lesions
| BAC/NHSCSP (2013) | Bethesda system (2015) |
| Borderline nuclear changes, endocervical | Atypical glandular cells (endocervical/endometrial/glandular) |
| Glandular neoplasia of endocervical type or glandular neoplasia of non-cervical type | Atypical glandular cells (endocervical/glandular) favour neoplastic |
| Endocervical adenocarcinoma in situ | |
| Adenocarcinoma (endocervical, endometrial, extra-uterine, other) |
Data from: NHS Cervical Screening Programme (2013) Achievable standards, Benchmarks for reporting, and Criteria for evaluating cervical cytopathology, and Nayar and Wilbur (2015) The Bethesda System for Reporting Cervical Cytology. Berlin: Springer.
The NHSCSP has introduced HPV triage to discriminate between ♀ at increased risk of high-grade CIN requiring colposcopic diagnosis and low risk ♀, who may return to routine screening ( Chapter 30, ‘Cytological indications for colposcopy’, p. 362).
Any trans person with a cervix should be offered cervical screening. This may fall outside of the national call/recall system if their gender identity on their NHS records is male. A local arrangement for reminders may need to be sought. ( Chapter 3, ‘Other issues’, p. 46).
Colposcopy is an investigation of cervical premalignancy. It uses up to ×40 magnification and acetic acid +/– iodine, to visually grade CIN, and highlight optimal sites for biopsy for histopathological assessment.
The entire SCJ should be visualized and abnormalities graded by:
• appearances of acetowhite epithelium
• vascular pattern, e.g. mosaicism, punctuation.
• suspected ICC or glandular neoplasia: urgent
• high grade dyskaryosis (moderate or severe)
• low grade dyskaryosis/borderline nuclear changes if the sample is HR-HPV positive or if ♀ is HIV positive
• unsatisfactory/inadequate samples: indicated if three consecutive unsatisfactory smears (taken at 3-monthly intervals).
Symptoms raising suspicion of cancer after excluding infection (e.g. persistent vaginal discharge, IMB, PCB in ♀ >40 years, post-menopausal bleeding).
Atypical glandular cytology may indicate invasive cervical adenocarcinoma, CGIN, CIN, or endometrial pathology. Endometrial cells on cytology in post-menopausal ♀ raises suspicion of endometrial disease and should be investigated. If borderline glandular cells are present, colposcopy is recommended for cervical biopsies and endometrial sampling. Punch biopsy not reliable for atypical glandular cytology. Excisional conization for diagnosis +/– treatment is recommended.
A suspicious-looking cervix may warrant further investigation. Speculum examination may reveal an obvious cervical tumour, requiring biopsy to confirm the diagnosis.
Aims of treatment are to eradicate intraepithelial lesions, while minimizing associated morbidity and adverse reproductive outcomes.
CIN is managed by accredited colposcopists and ♀ should receive clear information and have access to appropriate counselling.
Options include:
• Ablation: by cryotherapy (only for small size CIN1) or laser vaporization (unless suspected invasion, glandular disease, SCJ not visualized, or previous treatment for CIN).
• Excision: has largely replaced ablation because of better results, greater applicability, more rapid treatment with less bleeding, and lower cost of equipment.
• Cone biopsy: preferred method for adenocarcinoma in situ.
CGIN can be managed with local excision and surveillance if excision margins are free from disease. If family is complete, hysterectomy should be considered.
There is risk of residual or recurrent disease after CIN and CGIN treatment. HPV DNA as a ‘test of cure’ reduces the duration of surveillance following treatment by safely returning women who test negative to routine recall at an earlier date.
Histological diagnosis and clinical staging guide treatment decisions. Age, fertility requirements, and general fitness influence management. As for all cancer treatments, these may be curative or palliative.
Treatment options include cone biopsy/loop excision/trachelectomy (removal of cervix only), total/radical hysterectomy, radiotherapy, and chemotherapy.
The treatment of ICC and its associated effects include early menopause, loss of fertility, and vaginal stenosis causing dyspareunia.
HPV vaccination aims to prevent CIN, ICC and other HPV related disease. Both bivalent and quadrivalent vaccines have been shown in large randomized control trials to be highly efficacious at reducing CIN and also provide herd immunity against other HPV types.
Routine cervical screening should be deferred if pregnant until postpartum unless the ♀ has missed or defaulted her appointment prior to pregnancy. Colposcopic assessment of the pregnant ♀ requires a high degree of skill. The aim is to exclude invasive disease and where possible to defer biopsy or treatment until postpartum.
Cervical cancer is ~5× more common in women living with HIV. Advanced HIV disease is the strongest independent risk factor for developing cervical abnormalities. All ♀ with a new HIV diagnosis should ideally have a baseline colposcopy and thereafter, annual cervical screening. Subsequent colposcopy should follow national screening guidance. The recommended age range for screening is the same as for all women (although clinicians may make local arrangements for younger women). Invasive cervical cancer is AIDS defining.