Diseases of the Cervix

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Chapter 10 Diseases of the Cervix

Normal Cervical Epithelium 174

Anatomy of the Cervix 174

Benign Squamous Metaplasia 174

The Role of Human Papilloma Virus in Cervical Disease 175

Risk Factors 175

Screening for Cervical Cancer 176

Screening Process 176

Cervical Smears 177

Interpretation of Cervical Smears 177

Premalignant and Malignant Cervical Disease 178

Dysplasia 178

Microinvasive Cervical Carcinoma 178

Risk of Progression of Cervical Intraepithelial Neoplasia 178

Colposcopy 179

Identification of Atypical Epithelium 179

Treatment of Cervical Intraepithelial Neoplasia 180

Ablative Techniques 180

Excisional Techniques 181

Carcinoma of the Cervix 183

Clinical Findings 183

Symptoms 183

Carcinoma of the Cervix 184

Squamous Cell Carcinoma 184

Spread 185

Diagnosis of Cervical Carcinoma 186

Staging of Cervical Carcinoma 187

Radiotherapy and Chemotherapy in Cervical Carcinoma 189

Brachytherapy 189

External Beam Therapy 189

Complications 189

Surgery for Cervical Carcinoma 190

Microinvasive Cervical Carcinoma 190

Radical Hysterectomy and Node Dissection 190

Radical Surgery for Cervical Cancer 192

Treatment of Cervical Carcinoma: Surgery or Radiotherapy? 193

Prognosis 193

Normal cervical epithelium

Anatomy of the cervix

The cervix constitutes the lower third of the uterus.

It is in two parts, the endocervix and the ectocervix. Before puberty, the dividing line between the endo- and ectocervix is sharp, and is determined by the character of the lining epithelium: the ectocervix is covered with squamous epithelium and the endocervix is covered with columnar epithelium.

Benign squamous metaplasia

Stratification well defined with:

Under the influence of oestrogen (e.g. at puberty, during pregnancy or when the combined pill is taken), the cervix enlarges, so that the columnar epithelium of the endocervix can be seen on the ectocervix. This region, formerly the endocervix, which is now anatomically the ectocervix, is known as the ‘transformation zone’. The transformation zone is a dynamic area that responds to changes in endogenous or exogenous oestrogen. As it undergoes changes, it becomes a squamous metaplasia, which is a benign condition. The transformation zone is important as it is susceptible to infection with the human papilloma virus (HPV), which is known to lead to possible dysplastic change, and this in turn may lead to cervical cancer.

The role of human papilloma virus in cervical disease

Risk factors

Human Papilloma Virus (HPV) Infection

HPV infection is now known to be the viral agent required for the development of, initially, cervical intraepithelial neoplasia (CIN), and, ultimately, a cervical carcinoma. Approximately 80% of women will be infected with at least one of the more than 100 genotypes of HPV. 70–90% of women infected with HPV will clear the infection spontaneously within 1–3 years.

HPV is a DNA virus that can integrate into the human genome, and each genotype has a number. The most prevalent HPV genotypes in cervical carcinoma are 16 and 18. They are responsible for at least 70% of all cervical cancers.

The HPV genome encodes early (E) proteins that are responsible for viral regulation, cell transformation and late (L) proteins that make the viral capsule. HPV infects the basal cells and the expression of genes E6, E7 in high risk genotypes allows them to act as oncogenes via a variety of mechanisms to cause unregulated cell growth that may lead to dysplasia and cancer. Two tumour suppressor proteins that are affected by the E6/E7 gene products are p53 and retinoblastoma.

Screening for cervical cancer

Screening for cervical intraepithelial neoplasia (CIN) can be done by performing cervical smears and offering subsequent colposcopic assessment if significant dyskaryotic change is found. Treatment of CIN significantly reduces the incidence of and mortality associated with cervical cancer. For these reasons, many countries, including the UK, have set up a national screening programme.

Screening process

The Cervical Smear

A cervical smear is taken by a trained healthcare professional, often in their local practice. The cervix is visualised using a speculum. A wooden spatula or small plastic broom is placed in the cervical canal and rotated through 360°. The superficial layer of cells overlying the squamocolumnar junction is removed. If a wooden spatula is used, it is then smeared on a slide and fixed. If the broom is used, it is placed into a vial of liquid fixative (liquid-based cytology – LBC). Both methods then stain the specimen using Papanicolou’s method and the cells are examined under a microscope. The LBC technique is automated once the sample is sent for processing and this method produces cleaner specimens for analysis, thus reducing the number of unsatisfactory slides. If abnormal cells, dyskaryosis, are identified, the patients are referred for colposcopy.

In Scotland, the current cervical screening programme includes the following:

– All women between 20 and 60 years are invited for a smear test every 3 years.

– Immunocompromised/immunosuppressed women are offered annual screening.

– A national electronic database records and monitors the cervical smear process from the point of invitation to the completion of a colposcopic assessment. This is the Scottish Cervical Call-Recall System (SCCRS).

An abnormal smear is usually an indication for colposcopy (see p. 179).

Cervix brush and pot

Cervical Smears

Interpretation of cervical smears

Smears are reported in the following categories:

Normal

Inflammatory changes

Borderline nuclear change

Glandular abnormality

The smear shows a mixture of normal cells and dyskaryotic (abnormal nuclei) cells.

The cells are almost all abnormal and show larger nuclei with coarse chromatin.

In general, the more severe the dyskaryosis, the more likely the patient is to have high grade CIN. However, even in women with a mildly dyskaryotic smear, the incidence of high grade CIN can be 50%.

A referral for colposcopy is made for all women with, moderate or severe dyskaryosis. A repeat smear is justified in women with inflammatory or borderline nuclear changes. However, if these abnormalities persist, colposcopy is indicated. Colposcopy is also indicated if there are three or more abnormal smear tests of any grade in a 10-year interval.

Premalignant and malignant cervical disease

Dysplasia

Dysplasia occurs when the epithelium shows changes such as nuclear enlargement, increased nucleocytoplasmic ratio and abnormal mitoses. It is regarded as the first step in a series of changes that may lead to cervical intraepithelial neoplasia (CIN) and subsequently to invasive carcinoma. The pathological features of mild, moderate and severe dysplasia are shown. In practice there can be inter- and intra-observer variation between these categories.

CIN 1 ≡ low grade dysplasia

CIN 2 ≡ high grade dysplasia

CIN 3 ≡ high grade dysplasia

Microinvasive cervical carcinoma

The histological appearance of an early cervical invasion with spread through the basement membrane is shown here.

Risk of progression of cervical intraepithelial neoplasia

CIN has the potential to develop into a malignant cervical disease but it may also regress or persist as CIN without undergoing any malignant change. The risk of developing cervical cancer following dysplasia is 10–20%. The risk is also influenced by the grade of CIN, oncogenic potential of the HPV type, and environmental factors such as smoking and the immune status of a patient.

Colposcopy

Colposcopy means binocular inspection of the cervix with magnification.

The colposcopist recognises two kinds of epithelium, the ‘native’ epithelium which may be squamous or columnar; and the metaplastic squamous epithelium which arises in the physiological transformation zone.

Identification of atypical epithelium

Following the insertion of a speculum, the cervix is swabbed with 3% or 5% acetic acid. This dehydrates cells and the abnormal areas with larger and denser nuclei reflect light, appearing white. The vascular pattern within the white area can also be examined. Any changes are described with terms such as mosaicism and punctation. Trained colposcopists establish areas of abnormality and perform a small biopsy. Those patients with a high grade smear and an abnormal colposcopic appearance may be offered treatment at their first visit. Other patients requiring treatment will usually return as an outpatient.

Patients can find the whole process stressful and this is taken into account when seeing patients in the clinic and arranging management for the patient.

Treatment of cervical intraepithelial neoplasia

There is a high rate of spontaneous regression within the first 2 years after a diagnosis of low grade CIN (CIN1). For this reason, the majority of CIN1 cases are usually kept under review to establish if the changes regress cytologically and colposcopically.

High grade CIN (CIN2/3) has a lower rate of regression and is associated with a malignant transformation rate of up to 22%. Treatment is therefore offered to women with high grade CIN. This is usually done as an outpatient, under local anaesthetic, but some women may require admission for a general anaesthetic. The method of treatment chosen will depend on training, availability of technique and the need to minimise morbidity.

Ablative techniques

All these techniques destroy abnormal cervical tissue. In contrast to the excisional methods, there is no tissue for analysis after treatment and any occult invasive disease may not be recognised. Hence it is essential to have:

Excluded invasive disease by colposcopically directed biopsy, prior to treatment.

No discrepancy between cytology/colposcopy/histology.

No evidence of microinvasion/invasion.

No evidence of a glandular lesion.

Satisfactory colposcopy.

Morbidity with these techniques is often lower compared to the excisional techniques and there is less bleeding and no increased risk of adverse pregnancy outcomes such as preterm delivery and preterm rupture of the membranes.

Excisional techniques

Excisional techniques have a major advantage over ablative methods in that tissue is obtained and can be examined histologically. The diagnosis can be confirmed and the completeness of excision can be assessed.

Many operators prefer to perform excisional techniques on all patients. However, increasingly, in response to the data concerning pregnancy-related morbidity, some individuals are more selective and offer excision rather than ablation when they

1. Suspect invasive disease

2. Are treating a glandular abnormality

3. Cannot visualise the squamocolumnar junction

4. Are managing a patient with previous cervical surgery

The following techniques are currently in use:

Large Loop Excision of the Transformation Zone (LLETZ)

This has become one of the most popular methods for treating premalignant cervical disease. A thin wire loop is used to excise the transformation zone using a blended diathermy current. It is also known as a LEEP (Loop Electrosurgical Excision Procedure). Ball diathermy is applied for haemostasis at the treated the excision base.

Knife Cone Biopsy

This technique was extremely popular prior to the introduction of LLETZ. However, it requires a general anaesthetic and is now less commonly used. Complications include bleeding, infection, and cervical stenosis or incompetence during a subsequent pregnancy.

Laser Cone Biopsy

In a laser cone biopsy, a cone of tissue is removed as above. However, the procedure may be done under local anaesthesia. The costs of the equipment and the training required have reduced its potential popularity. Laser does have the advantage that co-existing VAIN may be treated at the same time.

Follow-Up

The above techniques are effective in treating CIN but recurrence can occur in 5% of the patients. All women who have had CIN should be followed up with increased smear cytology surveillance for a minimum of 5–10 years; there is regional variation within the UK.

Carcinoma of the cervix

Worldwide, carcinoma of the cervix is the commonest malignancy of the female genital tract. Its incidence varies from country to country and is significantly reduced where there is an organised screening programme. In developed countries, such as the UK, cervical cancer is the twelfth most common malignancy in females.

Clinical findings

The cervix becomes very indurated; necrosis and ulceration commonly follow quickly.

Later, a large fungating mass is produced. Sloughing may leave an excavated crater.

The tumour may form a proliferating growth which protrudes into the vagina – a ‘cauliflower’, ‘exophytic’, ‘everting’ growth. This tumour type bleeds easily and soon becomes ulcerated.

Sometimes the spread is in the substance of the cervix – called ‘excavating’, ‘endophytic’, ‘inverting’ growth. The cervix becomes stony, hard and enlarged – the ‘barrel-shaped’ cervix.

Symptoms

Cervical cancer may present with no symptoms or may be detected at the microscopic stage through a screening programme. If symptoms are present, then, they may include:

1. Irregular vaginal bleeding. It is not often due to carcinoma but the possibility must be kept in mind. The bleeding may be due to intermenstrual bleeding, postcoital bleeding or postmenopausal bleeding.

2. Vaginal discharge. The growth may become infected and produce offensive discharge.

3. Symptoms of advanced disease. Pain, bladder/bowel pressure symptoms, haematuria and cachexia.

Carcinoma of the cervix

The two commonest cancers are squamous cell carcinomas and adenocarcinomas. 70% are squamous cell carcinomas and 15% are adenocarcinomas with the remainder being the less common types.

Squamous cell carcinoma

The appearances are typical, but cell nests are absent and keratinisation is rarely seen.

Adenocarcinoma

This less common form of cervical malignancy usually arises from the columnar epithelium of the endocervix.

The appearances in this form are typical of adenocarcinomas in other organs.

Low power. Tubular processes spread out from the lumina of the glands. The characteristic pattern is an aggressive adenomatous formation with very little fibrous stroma.

Many indeterminate patterns are seen on microscopic examination. Sometimes, both glandular and squamous malignant cells appear together – an adenocanthoma – and squamous metaplasia is common.

High power appearance of squamous epithelium, which appears to originate by metaplasia of the columnar epithelium.

Spread

Direct spread into adjacent tissues such as the vagina or parametrium can occur. In postmenopausal women, it can also lead to a uterine outlet obstruction and pyometra. Its spread to the parametrium may induce pain and tenderness.

Spread downwards into the vaginal wall, if not diagnosed or treated, may involve the bladder or rectum and lead to the formation of fistulae. A backwards spread along the uterosacral ligaments can lead to an involvement of the sacral plexus causing intractable sciatic pain that can be felt in the hip or the leg.

Lymphatic spread also occurs and may precede direct spread. This is why lymphadenectomy is still important in the assessment of cervical cancers. From the cervical lymphatics, the spread is usually along the paracervical lymph tract to the iliac and obturator nodes. Blood borne spread is less likely to occur in early stage disease but may be significant in advanced disease. Ovarian involvement is rare.

Diagnosis of cervical carcinoma

Biopsy is necessary for histological confirmation of the carcinoma. If the growth is early, some normal tissue should be removed as well, and a diagram provided to show the pathologist from where the biopsy was taken. It should be no bigger than necessary and a punch biopsy, millimetres in size, may be sufficient. LLETZ biopsy can be performed for diagnosis but is generally not performed in the presence of evidence of malignant growth that is visible to the naked eye. Very occasionally, what appears to be a definite malignant lesion turns out to be benign.

Some differential diagnoses include:

Cervicitis with ectopy, the commonest cervical lesion and, if florid, can be most misleading.

Mucous cervical polyps, when infected, can present with a very suspicious appearance. (But all polyps require examination.)

Tuberculosis is rare in the cervix. There is nearly always a history of genital tuberculosis.

A primary chancre (syphilis) can appear in the cervix and is ulcerated, hard and indurated. In the United Kingdom, this is rare.

Staging of cervical carcinoma

Each growth is allocated to a stage according to the extent of spread (FIGO).

Stage IA Microscopic Cervical Cancer.

Stage 1A1

Stromal invasion ≤3.0 mm in depth and ≤7.0 mm in horizontal spread.

Stage 1A2

Stromal invasion ≤5.0 mm in depth and ≤7.0 mm horizontal spread.

Stage IB The growth is confined to the cervix.

Stage 1B1

Clinically visible lesion ≤4.0 cm dimension.

Stage 1B2

Clinically visible lesion >4 cm in greatest dimension.

Stage II Tumour invades beyond the uterus but not to pelvic wall or to lower third of the vagina.

IIA Without parametrial invasion.

IIA1 Clinically visible lesion ≤4 cm greatest dimension.

IIA2 Clinically visible lesion >4 cm greatest dimension.

IIB Extension into the parametrium but not as far as the pelvic wall.

Stage III Extension to lower third of vagina or to pelvic wall.

IIIa Carcinoma involving the lower third of the vagina.

IIIb Carcinoma extending to the pelvic side wall and/or hydronephrosis due to tumour.

Stage IV Extension through vagina into bladder or outside the pelvis.

IVa Carcinoma involving adjacent organs.

IVb Carcinoma extending to distant organs.

Staging is clinicopathological and, currently, imaging that demonstrates hydronephrosis due to tumour involvement can be used for staging purposes. Whilst magnetic resonance imaging (MRI) is commonly available in developed countries, it is less so in developing countries. Therefore, although MRI is useful in assessing the local spread of disease and may be used in clinical decision, it is not included in the FIGO staging.

Radiotherapy and chemotherapy in cervical carcinoma

Chemotherapy combined with radiotherapy is equivalent in terms of treatment efficacy, compared to radical surgery, for early stage cervical cancers. The choice of treatment will depend upon patient fitness, size of tumour and likelihood of requiring adjuvant treatment based on preoperative factors; the aim being to deliver the most effective combination of treatments to minimise morbidity.

Chemotherapy given along with radiotherapy has been shown to improve treatment outcomes, with chemotherapy given at the same time as radiotherapy further sensitising tumours to radiotherapy. A haemoglobin >11 g/dl will also increase efficacy.

The radiotherapy is delivered by two modes – external beam therapy and brachytherapy (delivered close to tumour site).

Brachytherapy

Hollow carriers are placed in the uterus and vaginal fornices under general anaesthesia. Radioactive sources can then be loaded into these tubes for treatment at a later date. Intracavity therapy allows high doses of radioactivity to be targeted to the cervix. The activity falls with increasing distance from the source, therefore the tissues around the cervix (bladder, bowel, etc.) receive a lower dose.

External beam therapy

External beam therapy is applied to the pelvis to control spread outside the cervix. The total radiotherapy dose is divided into smaller doses or fractions that are delivered over short daily treatments, usually as 20–25 fractions. Treatment, therefore, lasts for 4–5 weeks.

Complications

Short term	Long term
Diarrhoea	Persistent bowel and bladder symptoms
Urinary frequency	Radiation menopause
Nausea	Vaginal stenosis/scarring/dryness
Vulval inflammation	Late secondary tumours

Surgery for cervical carcinoma

Microinvasive cervical carcinoma

This may be treated with a LLETZ biopsy or if the patient has completed her family, by a simple hysterectomy.

Radical hysterectomy and node dissection

This consists of removal of the uterus, upper 2 cm of the vagina, the tissues/ligaments adjacent to the cervix (parametrium) and the lymph glands overlying the iliac vessels and the obturator nerve at the sides of the pelvis. It can be performed abdominally, vaginally or laparoscopically, with robots being increasingly used for laparoscopic dissection.

The broad ligament is opened up and the ureter dissected off the uterus and cervix. This is a vascular area. This diagram shows the ureter being identified by palpation but it is also directly visualised and dissected.

The ureter is identified at the common iliac division and followed downwards. The ureter has to be mobilised to protect it, but this does lead to the possibility of a fistula due to avascular necrosis.

The ureter has been dissected clearly down to the bladder and the uterine vessels, divided at their origin, form the internal iliac artery.

After division of the ligamentous attachments (uterosacral and cardinal) of the uterus, the vagina is transected. The vaginal opening may then be over sewn around its margin to provide haemostasis and allow fluid to drain. This will seal within a short time following surgery.

In this description the hysterectomy is shown first, followed by the lymphadenectomy; but many surgeons carry out the lymphadenectomy first followed by the block dissection of the radical hysterectomy.

The vagina is severed below the Wertheim clamp in this example but similar clamps may also be used.

Dissecting out the fatty tissue and glands from the obturator fossa.

Dissecting out the external iliac glands. (Other accessible groups of nodes are also removed.)

Radical surgery for cervical cancer

Special Circumstances

Fertility sparing surgery

Removal of the uterus leads to loss of fertility and many women in the age range for the development of cervical cancer may not have any children or have completed their family. Daniel Dargent, Lyon, France, has developed a technique for a radical vaginal excision of the cervix and retaining the uterine body. This technique has the potential to preserve fertility. Lymph node spread is assessed by laparoscopic lymphadenectomy. This is now an accepted technique and is being performed in specialist centres. Pregnancies have been recorded but there are potential pregnancy-related complications such as pre-term labour, pre-term rupture of the membranes and late miscarriages.

Exenteration for relapsed disease

Localised, central, pelvic relapsed carcinoma can be salvaged by radical excision of the pelvic tumour. Due to the proximity of the bladder and the rectum to the vagina, such surgery may involve – in addition to removal of the vagina – removal of the bladder (anterior exenteration), bowel (posterior exenteration) or both (total exenteration). This is a long and complex procedure that may require urinary diversion, colostomy formation and the creation of a new vagina.

Surgical complications of surgical treatment for cervical cancer

Early	Late
Haemorrhage	Atonic bladder
Infection	Lymphoedema
Damage to ureters or bladder	Ureteric/bladder fistulae (1–2%)
Venous thromboembolic disease	Ureteric/bladder fistulae (1–2%)