Gynaecological oncology

Management

It is important to establish the diagnosis by biopsy ( Fig. 20.2 ) and to search for intraepithelial neoplasia in other sites like the cervix and vagina, particularly when usual VIN is found. Treatment of usual VIN includes imiquimod, an immune modifier, laser therapy and superficial excision of the skin lesion. There is no role for medical treatment in d-VIN, and surgical excision tends to be more radical than that for usual VIN. Recurrence is common, and because there is a risk of malignant progression, especially in d-VIN, long-term follow-up is essential.

Symptoms

The patient with vulval carcinoma experiences pruritus and notices a raised lesion on the vulva, which may ulcerate and bleed ( Fig. 20.3 ). Malignant melanomas are usually single, hyperpigmented and ulcerated. Vulval carcinoma most frequently develops on the labia majora (50% of cases) but may also grow on the prepuce of the clitoris, the labia minora, Bartholin’s glands and in the vestibule of the vagina.

Mode of spread

Spread occurs both locally and through the lymphatic system. The lymph nodes involved are the superficial and deep inguinal nodes and the femoral nodes ( Fig. 20.4 ). Pelvic lymph nodes, except in primary lesions involving the clitoris, have usually only secondary involvement. Vascular spread is late and rare. The disease usually progresses slowly, and the terminal stages are accompanied by extensive ulceration, infection, haemorrhage and remote metastatic disease. In some 30% of cases, lymph nodes are involved on both sides. Stages are defined by the International Federation of Obstetrics and Gynaecology (FIGO) on the basis of surgical rather than clinical findings ( Table 20.1 ).

Treatment

Stage IA disease can be treated by wide local excision. Stage IB lesions that are at least 2cm lateral to the midline are treated by wide local excision and unilateral groin node dissection. All other stages are treated by wide radical local excisions or radical vulvectomy and bilateral groin node dissection. Sentinel node dissection may replace conventional node dissection in centres with experience in the technique. Postoperative radiotherapy has a role in patients where the tumour extends close to the excision margin or there is involvement of the groin nodes. Preoperative radiotherapy, with or without chemotherapy, may be used in cases of extensive disease to reduce the tumour volume. Complications of radical vulvectomy and groin node dissection include wound breakdown, lymphocyst and lymphoedema (30%), secondary bleeding, thromboembolism, sexual dysfunction and psychological morbidity. Response to chemotherapy is generally poor. Patients are followed up at intervals of 3–6 months for 5 years.

Prognosis

Prognosis is determined by the size of the primary lesion and lymph node involvement. The overall survival rate in operable cases without lymph node involvement is 90% and is up to 98% where the primary lesion is less than 2cm in size. This falls to 50–60% with node involvement and is less than 30% in patients with bilateral lymph node involvement. Malignant melanoma and adenocarcinoma have a poor prognosis, with a 5-year survival of 5%.

Symptoms

The symptoms include irregular vaginal bleeding and offensive vaginal discharge when the tumour becomes necrotic and infection supervenes. Local spread into the rectum, bladder or urethra may result in fistula formation. The tumour may appear as an exophytic lesion or as an ulcerated, indurated mass.

Method of spread

Tumour spread, as previously stated, occurs by direct infiltration or by lymphatic extension. Lesions involving the upper half of the vagina follow a pattern of spread similar to that of carcinoma of the cervix. Tumours of the lower half of the vagina follow a similar pattern of spread to that of carcinoma of the vulva.

Treatment

The diagnosis is established by biopsy of the tumour. Staging is made before commencing treatment ( Table 20.2 ).

The primary method of treatment is by radiotherapy – both by external beam therapy and brachytherapy.

Surgical treatment can also be considered in selected patients. For example, radical hysterectomy or vaginectomy and pelvic lymph node dissection can be considered in patients with stage I disease in the upper vagina, radical vulvectomy may be needed in stage I disease in the lower vagina and pelvic exenteration may be considered in patients with localized invasion to the bladder or rectum without parametrial or lymph node metastasis.

Prognosis

Results of treatment depend on the initial staging and on the method of therapy. Stages I and II have a 5-year survival of around 60% but this figure falls to 30–40% for stages III and IV. Adenocarcinoma of the vagina, which often occurs in young females, also responds well to irradiation.

HPV infection and cervical cancer

Almost all cases of cervical cancer (over 99%) are caused by high-risk HPV infection. There are more than 100 subtypes of HPV infection. HPV infection can infect genital and non-genital sites. The subtypes are classified as high risk or low risk. High-risk subtypes are associated with cancer, while the low-risk types cause warts. Amongst the 14 high-risk subtypes, HPV 16 and 18 cause about 70% of cervical cancer. HPV infection is mainly transmitted via close skin-to-skin contact, such as genital-to-genital contact and anal, vaginal and oral sex. It is a very common infection, where the majority of sexually active women would have been infected sometime during their lifetime. However, most infections are transient and are cleared by the body’s natural immunity. Only persistent infections lead to cancer. Apart from cervical cancer, HPV infection also causes other cancers such as vulval, vaginal, anal and oropharyngeal cancers.

Primary prevention – HPV vaccination

Since we now know that the main cause for cervical cancer is HPV infection, preventing HPV infections would be the best primary preventive measure. Prophylactic HPV vaccines have been developed. Bivalent and quadrivalent vaccines have been in the market for about a decade. The bivalent vaccine targets the two high-risk subtypes, HPV 16 and 18, while the quadrivalent vaccine covers HPV 16 and 18 as well as two low-risk subtypes, HPV 6 and 11, which cause genital warts. The prevention of HPV 16 and 18 infections could theoretically prevent more than 70% of cervical cancer cases, and indeed evidence from Australia after a decade of use has shown a 77% reduction in high-risk HPV serotypes in women aged 18–24 and 30–50% reaction in HSIL with a 90% reduction in genital warts. These vaccines are most effective when given before any exposure to the virus, i.e. before sexual debut. Vaccination using the quadrivalent vaccine was introduced for girls in Australia in 2007. In the UK, a national vaccination programme against HPV 16 and 18 infections was introduced in 2008. Since 2012, girls aged 12–13 years have been routinely offered the quadrivalent vaccine, with the first HPV vaccination given when they are in school year 8, and the second dose is offered 6–12 months after the first. In some other countries, e.g. Australia, the vaccination programme has extended to boys. Although boys do not get cervical cancer, they benefit from protection from other HPV-related cancers and genital warts, and their vaccination helps reduce the risk of transmission to their future partners by increasing her immunity to the virus. The HPV vaccine has been shown to offer protection for at least 10 years, and it is likely that the protection will be lifelong. Recently, a new nanovalent vaccine has been introduced. In addition to HPV 16 and 18, the nine-valent vaccine protects against five other oncogenic types (31, 33, 45, 52, 58) which, together with 16 and 18, account for nearly 90% of cervical cancers.

Secondary prevention – screening for premalignant lesions

The aim of cervical screening programmes is to detect the non-invasive precursor of cervical cancer, CIN, in the asymptomatic population in order to reduce mortality and morbidity. The National Health Service (NHS) national cervical screening programme was introduced in England and Wales in 1988, and by 1991, 80% of all women between the ages of 20 and 65 were being tested on a 5-yearly basis. Since then mortality from cervical cancer has fallen by 7% a year. Currently all women aged between 25 and 49 are invited for screening every 3 years, and those between 50 and 64 are invited every 5 years. Conventionally, cervical cytology is taken from the cervix. This is often referred to as a cervical smear or a Pap smear, named after the inventor of the test, Georgios Papanicolaou. Conventional smears involve taking cells from the cervix on the whole of the transformation zone with a 360-degree sweep using an Ayres or Aylesbury spatula and smeared onto a glass slide. In recent years, liquid-based cytology (LBC) has largely replaced the conventional smears. For LBC, the cells from the transformation zone are taken with a plastic cervical brush. The brush is rotated in the same direction for five turns and transferred into a container of transport medium (see Chapter 15 ). LBC allows automated processing of the smears, and it reduces the rate of unsatisfactory smears. The sample can also be used for additional tests such as HPV testing. Cervical cytology ( Figs 20.6 and 20.7 ) is primarily for screening for squamous lesions and cannot reliably exclude endocervical disease. In 2017 screening in Australia was changed to an HPV-based test collected in the same way as the Pap smear support by LBC only in women identified as being positive for one of a number of high-risk HPV serotypes. As in the UK screening begins at age 25; if negative, it is repeated at 5-year intervals until age 75.

HPV testing

High-risk HPV testing has a sensitivity of about 90% for high-grade CIN, which is 25% more sensitive than cytology. One of the most commonly used HPV tests is the Hybrid Capture II (HCII) test, which tests for a pool of 13 high-risk HPV subtypes. Some HPV tests can not only test for the presence of any high-risk HPV subtypes (similar to the HC II) but also give individual results for HPV 16 and 18, which carry a particularly high risk for a high-grade lesion. HPV testing in conjunction with cervical cytology (co-test) or as a stand-alone test as a primary screening method has been evaluated. Co-testing is recommended in the United States for women over the age of 30, while HPV testing alone is recommended for women over age 25. High-risk HPV testing also has a very high negative predictive value, which allows a longer screening interval for women with a negative test, and it may be a more appropriate primary screening test for vaccinated women. However, high-risk HPV tests have lower specificity, since not all HPV infection would cause premalignant changes. Without a good triage system for high-risk HPV-positive results, more women would need to be referred for colposcopy (see later section) and result in more unnecessary interventions. Therefore, some areas in the UK have adopted the HPV test as the primary cervical screening method, and this would be gradually introduced across the country. Women testing positive for high-risk HPV would have cytology triage (i.e. have an LBC done). If the woman has a positive high-risk–positive test and an abnormal cytology result (borderline or worse), she would be referred for colposcopy. In Australia, the primary HPV test with genotyping for 16 and 18 has replaced cytology in its cervical screening programme (see earlier section).

Principles of colposcopy

At colposcopy, the colposcopist adds acetic acid, followed by Lugol’s iodine, to identify the most abnormal areas to take biopsies. Neoplastic cells have an increased amount of nuclear material in relation to cytoplasm and less surface glycogen than normal squamous epithelium. They are associated with a degree of hypertrophy of the underlying vasculature. When exposed to 5% acetic acid, the nuclear protein will coagulate, giving the neoplastic cells a characteristic white appearance ( Fig. 20.10 ). Small blood vessels beneath the epithelium may be seen as dots (punctation) or a crazy paving pattern (mosaicism) due to the increased capillary vasculature. The neoplastic cells do not react with Lugol’s iodine (Schiller’s test), unlike the normal squamous epithelium that will stain dark brown ( Fig. 20.11 ). Early invasive cancer is characterized by a raised or ulcerated area with abnormal vessels, friable tissue and coarse punctation with marked mosaicism. It feels hard on palpation and often bleeds on contact. In more advanced disease, the cervix becomes fixed or replaced by a friable warty-looking mass ( Fig. 20.12 ).

Treatment of high-grade preinvasive lesions

If the colposcopic-directed biopsy shows a low-grade lesion, only regular surveillance would be required in most cases. However, if the biopsy shows a high-grade lesion, treatment by excision or destruction of the affected area (usually the whole of the transformation zone) is required.

Destructive/ablative methods such as laser ablation, cryocautery and coagulation diathermy are only suitable when the entire transformation zone can be visualized, there is no evidence of glandular abnormality or invasive disease and there is no major discrepancy between the cytology and histology results. Excision instead of ablation is the preferred treatment because the excised specimen can be sent for a histological diagnosis to confirm the biopsy result. The commonest excisional method is the large loop excision of the transformation zone (LLETZ) ( Fig. 20.13 ), which is excision with a diathermy wire loop, which can be done under local anaesthetic in the outpatient clinic. When the SCJ cannot be seen or a lesion of the glandular epithelium is suspected, a deeper ‘cone’ biopsy is required to ensure that all of the endocervix is sampled ( Fig. 20.14 ). About 5% of women will have persistent or recurrent disease following treatment; therefore, follow-up is important. Follow-up protocols vary in different countries. For example, in the UK, women are usually invited to return for repeat cytology ± HPV test as a test of cure 6 months later. If both cytology and high-risk HPV are negative, the woman can return in 3 years. If high-risk HPV is positive, she will need to have colposcopy again. If HPV is not available, then she needs to have repeat cytology.