Cervical intraepithelial neoplasia, cervical screening and cervical cancer

Overview

Cervical cancer is a preventable cancer: it has a known cause (high-risk HPV), a long pre-cancer stage (CIN) that can be found by screening, and a vaccine. In high-income countries screening has made it uncommon. In low- and middle-income countries, including Pakistan, it remains a major killer of women in their reproductive years because organised screening and vaccination are limited.

This chapter covers: HPV and the transformation zone, CIN, screening and colposcopy, treatment of CIN, HPV vaccination, and invasive cervical cancer (presentation, FIGO staging and treatment).

Aetiology: human papillomavirus

• HPV is a small double-stranded DNA virus, spread by sexual contact. Infection is very common after sexual activity starts and usually clears on its own.
• Low-risk types 6 and 11: genital warts (condylomata acuminata).
• High-risk types: 16 and 18 (the main ones), also 31, 33, 45 and others. HPV 16 and 18 together cause over 70% of cervical cancers.
• Only persistent high-risk infection leads to CIN and cancer.
• Viral proteins E6 and E7 inactivate the tumour suppressors p53 and Rb, letting infected cells divide without control.

Risk factors (all point to HPV exposure or persistence)

• Early first intercourse, multiple sexual partners, a partner with many partners.
• Smoking (reduces viral clearance).
• Immunosuppression: HIV, transplant drugs.
• Never or rarely screened: the single biggest factor in women who develop cancer.

The transformation zone

• The ectocervix has stratified squamous epithelium; the endocervix has columnar epithelium. They meet at the squamocolumnar junction (SCJ).
• The SCJ moves: it lies at the os in childhood, moves out onto the ectocervix at puberty, in pregnancy and on the pill (ectropion), then returns.
• Exposed columnar cells turn into squamous cells by metaplasia. The area between the original and the current SCJ is the transformation zone.
• Dividing metaplastic cells are vulnerable to HPV, so the transformation zone is where CIN and cancer arise. Screening samples must include it.

Cervical intraepithelial neoplasia (CIN)

CIN is dysplasia confined to the epithelium: immature, dark-staining cells with large nuclei and abnormal mitoses. Once cells break through the basement membrane, it is cancer.

• Koilocytes (cells with a halo around a wrinkled nucleus) are the hallmark of HPV infection.
• Progression from CIN to cancer is slow, usually taking years, which is why screening works.
• The glandular precursor is cervical glandular intraepithelial neoplasia (CGIN); it lies in the canal and is harder to find.

Cervical screening

Tests

• Cytology grades: low grade (borderline change, mild dyskaryosis) and high grade (moderate or severe dyskaryosis).
• A single smear misses some high-grade CIN (sensitivity about 40-70%), but repeated screening catches it because progression is slow.
• UK programme: women aged 25-64, invited every 3-5 years. Women under 25 are not screened because CIN at that age often regresses and treatment would harm future pregnancies.
• WHO recommends HPV DNA testing as the preferred screening test, from age 30, every 5-10 years (from 25, every 3-5 years, for women living with HIV) (WHO, 6 July 2021, checked 11 Nov 2026).

Colposcopy

Examination of the cervix under 5-20× magnification, used for diagnosis and treatment after an abnormal screening test.

• Acetic acid: abnormal areas with many nuclei turn white (acetowhite).
• Lugol's iodine (Schiller test): normal squamous cells contain glycogen and stain brown; CIN lacks glycogen and stays pale (iodine-negative).
• Abnormal vessels (punctation, mosaic) show new vessel growth.
• Biopsy the worst area if unsure ("select and treat"); clearly high-grade lesions can be treated at the same visit ("see and treat").

Treatment of CIN

• CIN 1: observe with repeat testing (often in 12 months); much of it regresses.
• CIN 2 and 3: treat.

• Follow-up: "test of cure" HPV test at 6 months; if negative, back to routine screening in 3 years.
• Large or repeated excisions raise the risk of mid-trimester miscarriage and preterm birth.

HPV vaccination

• Prevents persistent infection, CIN and cancer if given before exposure; best given to girls (and boys) at 12-13 years, before sexual activity.
• Bivalent: 16, 18. Quadrivalent: 6, 11, 16, 18 (adds wart protection). Nonavalent: 6, 11, 16, 18 plus five more high-risk types (including 31, 33 and 45).
• It is prophylactic, not therapeutic: it does not treat existing CIN.
• Vaccinated women still need screening, because the vaccine does not cover every high-risk type.

Invasive cervical cancer

Pathology and spread

• Squamous cell carcinoma: about 70-80%; adenocarcinoma makes up most of the rest (it is less well detected by cytology, so its share rises where screening is good).
• Spreads directly: laterally to the parametria (and ureters), anteriorly to the bladder, posteriorly to the rectum, down the vagina.
• Lymphatic spread to pelvic nodes (obturator, internal and external iliac), then para-aortic nodes.
• Blood spread (lungs, liver, bone) is late.
• Death in advanced disease often comes from ureteric obstruction and renal failure (uraemia).

Clinical features

• Postcoital bleeding (classic), intermenstrual or postmenopausal bleeding, offensive blood-stained discharge.
• Early microscopic disease may have no symptoms and be found on a LLETZ specimen.
• Advanced disease: pelvic and back pain (nerve invasion), leg oedema, continuous leak of urine or faeces (vesicovaginal or rectovaginal fistula), anaemia, renal failure from blocked ureters.
• Examination: a friable, exophytic mass that bleeds on touch, or a hard, ulcerated cervix (endophytic tumours can look deceptively normal). Rectovaginal examination assesses parametrial thickening.

Investigations and staging

• Biopsy confirms the diagnosis and type.
• MRI pelvis and abdomen: tumour size, parametria, nodes. Chest X-ray.
• Examination under anaesthesia (with cystoscopy, sometimes sigmoidoscopy) if operability is unclear.
• IVU or ultrasound for ureteric obstruction where MRI is not available.
• Cervical cancer is staged clinically (FIGO), with imaging, unlike endometrial and ovarian cancer, which are staged surgically. This allows staging in low-resource settings where most patients receive radiotherapy.

FIGO staging (2018) and treatment

Treatment details

• Radical (Wertheim) hysterectomy: removes the uterus, cervix, parametria and upper third of the vagina with pelvic nodes; ovaries can be kept in young women (squamous cancer rarely spreads to them). Open surgery has better survival than the laparoscopic route. Complications: bladder atony (needing self-catheterisation for a time), sexual problems from a shorter vagina, lymphoedema, ureteric injury.
• Radiotherapy: external beam to the pelvis plus brachytherapy (internal source placed in the uterus and vagina). Cisplatin given with it (chemoradiotherapy) improves cure.
  • Early effects: tiredness, diarrhoea, bladder irritation, skin redness.
  • Late effects: vaginal stenosis, radiation cystitis and proctitis, bowel damage, fistula; ovarian failure (early menopause).
• Surgery is preferred for early disease in young women because it keeps the ovaries and avoids long-term radiation damage; once disease is beyond the cervix, radiotherapy is better than surgery.
• Palliative care: pain control, management of bleeding, fistulae and renal failure; palliative radiotherapy for bone pain.

Quick revision

• Persistent high-risk HPV (16, 18) causes CIN and cancer; smoking and HIV help it persist.
• Transformation zone = site of CIN; screening must sample it.
• CIN 1 = lower third (watch); CIN 2-3 = two-thirds to full thickness (treat with LLETZ).
• Abnormal screen: colposcopy (acetowhite, iodine-negative areas) and biopsy.
• HPV vaccine at 12-13 years; prophylactic only; screening still needed.
• Cancer: postcoital bleeding; squamous 70-80%; spreads to parametria and pelvic nodes.
• FIGO clinical staging: IB radical hysterectomy; IIB-IVA chemoradiotherapy (cisplatin + external beam + brachytherapy).
• Hydronephrosis = IIIB; bladder or rectal mucosa = IVA.

Written by The House Job from standard references (Gynaecology by Ten Teachers).

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