Chapter 37 Premalignant and malignant conditions of the female genital tract
CERVICAL PRECANCER AND CANCER
The cervical epithelium undergoes changes throughout the menstrual cycle and is readily accessible for examination. The epithelium covering the ectocervix is stratified and identical to that of the vagina (Fig. 37.1). It is separated from the underlying stroma by an apparent basement membrane. Superior to this is a layer of basal cells from which the other cell layers differentiate. Above the basal layer are five or six layers of parabasal cells. Above these are intermediate and superficial cell layers. The intermediate cell layer consists of large cells, each with reticulated nuclei and vacuoles of glycogen in the cytoplasm. The superficial cell layer varies in thickness, depending on the oestradiol : progesterone ratio. The superficial cells are flattened and have small nuclei, the cytoplasm containing glycogen (Fig. 37.2). A small amount of keratin is produced in some of the cells, which becomes ‘cornified’. During the reproductive years the superficial cells are constantly shed or exfoliated into the vagina, and differentiation of cells from the basal layer also proceeds constantly.
The characteristics of the superficial cells can be studied by taking a smear from the cervix and staining it with Papanicolaou’s stain. In some women the nuclei become abnormally shaped or dyskaryotic, which may indicate a precancerous change; this can be detected by cervical smears.
Epidemiology of cervical cancer
Cervical cancer occurs almost exclusively in women who are or have been sexually active. There is strong molecular biological and epidemiological evidence that the predominant cause of cervical cancer is sexually transmitted human papilloma virus (HPV). There are four HPV types that are considered to be high risk (16, 18, 45 and 56), a further 11 types that are intermediate risk (31, 33, 35, 39, 51, 52, 55, 58, 59, 66 and 68) and eight that are low risk (6, 11, 26, 42, 44, 54, 70 and 73) By the age of 35, 60% of sexually active women have acquired HPV infection of the genital tract (including the vulva). This proportion is higher if the woman or her partner has had several sexual partners. In most cases the infection is symptomless and disappears within a few months (see p. 258).
Cervical exfoliative cytology
The development of cervical carcinoma is preceded by the appearance of abnormal (dyskaryotic) cervical cells. These can be detected by microscopically examining an exfoliative cervical smear, stained using the Papanicolaou stain (the Pap test). As this is a screening test false negatives may occur, estimated at 5–15%. The proportion of false-negative smears will be reduced if strict criteria are adopted for taking and for examining the smear.
A further refinement is liquid-based cytology that involves taking cervical cells with a Cervex sampler brush and rinsing the brush into a vial of fixative. The cells are not obscured by blood or mucus and are all fixed properly. In the laboratory, a monolayer of cells is made which is easier to interpret. If the result is inconclusive, the remaining cells in the vial can be used to make a hybrid capture test, which will detect the presence of oncogenic HPV. This methodology reduces the unsatisfactory/inconclusive smear rate by 80% and has been shown to be cost-effective. A further advantage of this test is that it is likely to reduce the number of colposcopies that gynaecologists make when an inconclusive Pap smear abnormality is found. The technique has the potential to be used for the detection of other sexually transmitted diseases, such as chlamydia and gonorrhoea.
The recommended smear regimen is summarised in Box 37.1. In women aged 30 and over, the doctor or nurse taking the smear should also examine the woman’s breasts, teach her breast self-examination, and after the age of 40 measure her blood pressure.
Technique for taking a cervical smear
A tray is provided on which a bivalve vaginal speculum, some slides, a spray-on fixative plastic, a modified Ayre spatula and an endocervical brush are placed. Before performing a vaginal examination, the warmed speculum is inserted to expose the cervix. The cytobrush is inserted into the cervical canal and rotated. The sample is smeared on to the slide. The ectocervix is sampled with the Ayre spatula or Cervex brush by rotating it twice through 360° and the sample is smeared on to a slide (Fig. 37.3). If liquid-based cytology is being used the brush is placed in the liquid medium.

Fig. 37.3 Methods of obtaining cells from the cervix for cytological examination, using (1) a special wooden spatula, (2) an Ayre spatula, and (3) a Cervex sampler.
The smears are sent to a reliable, quality assured cytological laboratory for examination.
REPORTING ON SMEARS
Cytologists have agreed that nuclear abnormalities should form the basis of a cytological diagnosis. They have agreed to report smears as follows:
The Bethesda Classification
An alternative classification is used in the USA (the Bethesda Classification). Smears showing abnormal cells are categorized as:
Squamous cell
New cervical screening techniques
Meta-analysis of conventional screening found a sensitivity of 58%, a specificity of 69% and a false-negative rate of 20%. This has led to the exploration of other technologies to improve diagnostic accuracy. In the ThinPrep method, the sample is placed into a 20 mL vial of buffered alcohol, which is then prepared for automated image analysis. A study by Duke University and the American Association of Obstetrics and Gynaecology reported that this technique was cost-effective and would reduce cancer cases, deaths and serious interventions, including hysterectomy, by 57% if screening was performed every 2 years.
HPV-negative women should have repeat cervical cytology at recommended intervals. HPV-positive women should be offered colposcopic evaluation.
Telling the patient
The result of the smear should be reported to the woman by phone or by letter. This applies to all smears, not just abnormal ones. If an abnormal smear is reported, the need to counsel and explain is imperative.
To many women, the finding of a dyskaryotic smear suggests the presence of cancer. If HPV is found, many women question their own and their partner’s previous sexual behaviour. Either finding can lead to guilt, misery and anxiety. Doctors should be aware of this and should talk with the woman, explaining the meaning of the result and that HPV is not always sexually transmitted. The woman should also be told, in clear non-jargon language, what procedures may be needed. In one reported study, the term ‘precancer’ was perceived as threatening and the authors suggested that a better term would be ‘early warning cells’.
Management of abnormal cervical smears
Approaches to the management of abnormal cervical smears are summarized in Table 37.1.
HPV infection with no evidence of dyskaryosis
Smears should be taken at 6-monthly intervals until they are negative for HPV, then annually for 2 years. If there is no evidence of HPV at this time, the patient should return to having a smear every 2 years. If dyskaryosis appears in any smear, treat as recommended below.
Mild dyskaryosis (predictive of CIN 1) with or without HPV
There are three potential management options:
Consequently the National Health and Medical research Council of Australia recommends option 1.

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