Oxford Handbook of Genitourinary Medicine, HIV, and Sexual
Health (2 edn)
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Introduction
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 in puberty and pregnancy (or the use of hormonal contraception) lead to 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 transformation zone (TZ), which is susceptible to malignant change when exposed to oncogenic stimuli, especially high-risk human papilloma virus (HPV).
Atypia Cells in the epithelium show nuclear or cytoplasmic abnormalities not considered to be malignant or premalignant. Koilocytotic atypia or koiloctytosis refers to the presence of cells with a perinuclear halo associated with HPV infection.
Cervical intra-epithelial neoplasia (CIN) Squamous cell premalignant lesion also known as dysplasia. Identified by architectural and cytological changes in the epithelium with the underlying basement membrane intact (essential feature). Three grades of CIN based on the level of epithelial involvement:
CIN1—lowest third (mild dysplasia)
CIN2—lower two-thirds (moderate dysplasia)
CIN3—more than two-thirds (severe dysplasia or carcinoma in situ).
Cervical glandular intra-epithelial neoplasia (CGIN) Columnar cell premalignant lesions. Less common than CIN. Identified by nuclear, nucleolar, and gland structure abnormalities. Low-grade (LCGIN) is also known as endocervical gland dysplasia (EGD) and high-grade (HCGIN) as adenocarcinoma in situ (AIS).
Invasive cervical carcinoma (ICC) Penetration of the basement membrane by malignant epithelial cells. 85–90% are squamous cell carcinoma (SCC) and the remainder are adeno/adenosquamous.
Epidemiology
Cervical carcinoma is the second most common malignancy in ♀ worldwide. ~80% of cases arise in developing countries (rates 25–45/100,000). Variations between and within countries occur because of differing HPV infection rates, other aetiological factors, and uptake of screening (2%of all ♀ cancers in UK). Most frequently diagnosed in those aged 40–50 years. The reciprocal association between vaginal/anal and cervical SCC demonstrates the multifocal nature of high-risk HPV infection.
Natural history
Untreated, 25–60% of CIN3 will progress to ICC over 20 years, and ~20% of CIN1 and ~30% of CIN2 to higher-grade lesions. 25–50% of CIN1 may regress to normal, especially in younger ♀. Persistence of high-risk HPV infection is associated with progression to CIN2–3 (10–40% in 2 years).
Risk factors
Infection
Human papilloma virus (HPV): high-risk HPV in >99% of SCC (usually 16 (50%) and 18 (20%), also 31, 35, 39, 45, 51, 52, 56, and 58). The relative risk of SCC is ↑ 15×. However, the probability of an individual with high-risk HPV developing SCC is <2% with other factors important for malignant transformation. In adeno/adenosquamous carcinoma HPV 18 (50%), 16 (30%).
Other genital infections: cervicitis is considered to be a reason for the association between Chlamydia trachomatis and CIN3/SCC (2-fold ↑). Conflicting evidence implicating herpes simplex virus 2, Neisseria gonorrhoeae and Trichomonas vaginalis.
Sexual activity: age of coitarche is linked to ↑ risk of SCC, e.g. relative risk 2.5 if <18 years compared with >21 years. Risk ↑ by multiple sexual partners e.g. ↑ 14-fold if >5 lifetime partners.
Parity: incidence of SCC ↑ with parity independent of other risks. Young age at first pregnancy also appears to be a risk marker.
Male factor: ↑ incidence of CIN and ICC in partners of ♂ with high-risk HPV infection or a history of multiple sexual contacts.
Smoking: appears to ↑ risk of CIN and SCC.
Oral contraception: long-term use (>5 years) is associated with ↑ risk of ICC/CIN (3× if >5 and 4× if >10 years).
Immunosuppression: ↑ risk with immunodeficiency, e.g. HIV infection, Hodgkin’s disease, treatment causing immunosuppression.
Condoms offer some protection especially in delaying CIN progression.
Clinical features
CIN is typically asymptomatic but is important to exclude in those with post-coital bleeding (PCB) or intermenstrual bleeding (IMB).
ICC diagnosed in up to 4% of ♂ with PCB and 1.5% with post-menopausal bleeding. If symptomatic, it is usually more advanced so signs are generally evident (pronounced cervical contact bleeding, hard, irregular, and enlarged or ulcerated cervix, profuse offensive vaginal discharge) but subtle signs of early stages may be missed.
In advanced ICC:
bimanual and rectal examination may demonstrate a fixed uterus and parametrial/posterior pelvic induration
general examination may show hepatosplenomegaly or inguinal/supraclavicular lymph node enlargement.
Screening
Introduced in the 1940s to screen for premalignant exfoliated cervical cells. Adequate sampling of TZ is achieved by visualizing the full circumference of the cervix. If incomplete, it can lead to false-negative results (2–25%). ‘Unsatisfactory’ results are due to insufficient epithelial cells or presence of blood or pus cells (~10% with slide preparations, <2% using liquid-based cytology).
Exfoliated cells display nuclear and cytoplasmic characteristics which correspond to the underlying pathology. Dyskaryosis is the nuclear abnormality of exfoliated cells, graded as mild, moderate, and severe. This indicates the minimum degree of cin likely to be present as 1, 2, and 3, respectively. Cells suggesting possible invasive carcinoma show coarse chromatin clumps and extensive keratinization with bizarre forms. 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.
High-risk HPV DNA detection
Role in 1° screening unproven although more sensitive than cytology in predicting CIN2/3. Low specificity, especially in those <30 years, because of the high prevalence of transient HPV infection.
A computerized call–recall system is used to invite ♀ who are registered with a GP for screening every 3 years if aged 25–49 and every 5 years if aged 50–64. (♀ aged 65+, only if not screened since age 50 or have had a recent abnormality).
It is important not to commence routine screening below the age of 25 because much of the low-grade abnormality due to high hpv prevalence resolves spontaneously and the rate of cervical carcinoma is extremely low, with cytology screening not having any impact. Screening is best provided in primary care but if taken in gum, arrangements should be made for a copy of the result to go to the patient’s GP.
| BSCC | Bethesda system (2001) |
|---|---|
Borderline nuclear changes | Atypical squamous cells of uncertain significance (ASCUS) |
Borderline nuclear changes with koiloctytosis Mild dyskaryosis | Low-grade squamous intra-epithelial lesion |
Moderate dyskaryosis Severe dyskaryosis | High-grade squamous intra-epithelial lesion |
Suspected invasive carcinoma | Squamous cell carcinoma |
Borderline nuclear changes, endocervical | Atypical glandular cells (endocervical/endometrial/glandular) |
Suspected glandular neoplasia (in Scotland ‘adenocarcinoma’ if invasive adenocarcinoma suggested, otherwise ‘glandular neoplasia’) | Atypical glandular cells (endocervical/glandular) favour neoplastic |
Endocervical adenocarcinoma in situ | |
Adenocarcinoma (endocervical, endometrial, extra-uterine, other) |
| BSCC | Bethesda system (2001) |
|---|---|
Borderline nuclear changes | Atypical squamous cells of uncertain significance (ASCUS) |
Borderline nuclear changes with koiloctytosis Mild dyskaryosis | Low-grade squamous intra-epithelial lesion |
Moderate dyskaryosis Severe dyskaryosis | High-grade squamous intra-epithelial lesion |
Suspected invasive carcinoma | Squamous cell carcinoma |
Borderline nuclear changes, endocervical | Atypical glandular cells (endocervical/endometrial/glandular) |
Suspected glandular neoplasia (in Scotland ‘adenocarcinoma’ if invasive adenocarcinoma suggested, otherwise ‘glandular neoplasia’) | Atypical glandular cells (endocervical/glandular) favour neoplastic |
Endocervical adenocarcinoma in situ | |
Adenocarcinoma (endocervical, endometrial, extra-uterine, other) |
Take cervical smear before cleaning the cervix and taking endocervical swabs for N.gonorrhoeae and C.trachomatis.
Note the macroscopic appearance of the cervix. Defer cytology if in menses or there is marked cervicitis.
Sweep 360° around the cervix, being sure to sample the transitional zone:
liquid-based cytology—the end of the sampling brush is rinsed or broken off into the preservative medium
alcohol-fixed smear—Aylesbury spatula (if the SCJ is within the endocervical canal, a spatula/endocervical brush combination is recommended).
Diagnosis
CIN
Colposcopy is an essential investigation of cervical premalignancy. Using up to 40× magnification and acetic acid ± iodine, it enables visual grading of CIN and highlights optimal sites for biopsy.
Cytological indications for colposcopy:
suspected invasive carcinoma or glandular
neoplasia—urgent.
moderate/severe dyskaryosis or borderline endocervical changes
mild dyskaryosis/borderline nuclear changes—indicated if any repeat cytology at 6, 12, or 24 months is abnormal (if mild dyskaryosis, initial colposcopy rather than repeat cytology may be advised)
unsatisfactory/inadequate samples—indicated if three consecutive unsatisfactory smears (3 monthly intervals)
any dyskaryosis with a history of CIN.
Clinical indications for colposcopy/gynaecological assessment:
symptoms raising suspicion of carcinoma after excluding infection (e.g. postcoital/intermenstrual bleeding in ♀ >40 years, post-menopausal bleeding).
ICC
Biopsy, loop, or needle excision depending on appearance.
For staging:
bimanual vaginal and rectal examination under anaesthesia (EUA) with proctoscopy and sigmoidoscopy if rectal spread suspected
chest and skeletal radiographs, IV urogram, and barium enema.
Routine general haematological assessment and other investigations to exclude or gauge metastases, e.g. MRI with a transvaginal coil, lymph node dissection.
Management
CIN
CIN should be managed by accredited colposcopists following clear policies and protocols. Multidisciplinary links are essential. ♀ with CIN should receive clear information and have access to appropriate counselling. Treatment options are as follows.
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 AIS.
Histology report should indicate if any excision is complete. If not, repeat is required. Cytological follow-up is recommended, with repeat colposcopy for abnormal results (at 6 and 12 months followed by annual repeat for 10 years after treatment of CIN2/3 and 2 years after CIN1).
Carcinoma
Histological diagnosis and clinical staging are the basis of treatment decision ranging from cone biopsy to surgery, radiotherapy, and chemo-therapy in various combinations. Age, fertility requirements, and general fitness are individual factors influencing management. 5 year survival rates vary from ~100% (3mm micro-invasion) to 5–15% (extension beyond pelvis).
Pregnancy
Routine cervical cytology should be postponed until after delivery, but repeat following a previous abnormality may be taken in mid-trimester. Incidence of ICC is low and pregnancy does not have an adverse impact. Management of CIN (biopsy and treatment) can be deferred until the postpartum period, but colposcopic suggestion of ICC requires urgent biopsy. Treatment of ICC will entail termination or preterm delivery.
Prevention
Screening prevents ~5000 cases a year in the UK by reducing the lifetime risk of SCC from 1.7% to 0.7%.
Recently introduced bivalent and quadrivalent vacaccines against types 6, 11, 16, and 18, if given before the onset of sexual activity and exposure to HPV, are expected to prevent ~70% of invasive cervical cancers and ~60% of high-grade CIN. However, the introduction of the immunization programme does not remove the need for cervical screening since there are no data on the long-term efficacy of the vaccines and the epidemiological impact of immunization on the less common oncogenic HPV types and cervical cervical cancer incidence is not known.
HIV and cervical carcinoma
↑ high-risk HPV infection and persistence
↑ in incidence (>4-fold) of CIN2/3
Annual cervical cytology recommended
Colposcopy and biopsy recommended for borderline changes, mild dyskaryosis
↑ recurrence of CIN after treatment (which should be by excision)
Cervical carcinoma is an AIDS-defining condition
