Lower Genital Tract Neoplasia - study group statement

Recommendations fall into three categories:

1. Recommendations for clinical practice (principally aimed at Fellows and Members of the Royal College of Obstetricians and Gynaecologists) based upon research evidence (where available) and the consensus view of the Group. The clinical practice recommendations have been graded from 'A' to 'C' according to the strength of evidence on which each is based (Table 35.1). The scheme for the grading of recommendations is based on the system adopted by both the NHS Executive and the Scottish Intercollegiate Guidelines Network.
2. Recommendations for future research in those clinical areas where the Group identified a need for further evidence on which to base practice.
3. Recommendations relating to health education and health policy.

Table 35.1. Grading of recommendations

Recommendations for clinical practice

Cervical neoplasia

1. Both conventional and liquid-based smear samples are best taken with either a single ectocervical broom or a combination of spatula and endocervical brush. (Grade A)
2. Excisional methods to treat cervical intraepithelial neoplasia grade 2 (CIN2 and CIN3) are superior to destructive methods. The resultant histology reduces the risk of inappropriate treatment of occult carcinoma. (Grade B)
3. Loop excision and laser excision of the transformation zone appear to be equally effective, but loop excision has advantages of cost, short duration of treatment and less pain. (Grade A)
4. Conisation, i.e. laser, knife or loop, appears to be adequate management for cervical glandular intraepithelial neoplasia providing the cone margins are clear, there is no pathological suspicion of invasion and long-term follow-up is agreed. (Grade C)
5. Older patients with atypical glandular cells of uncertain significance (AGUS) must be considered for possible lesions higher in the genital tract. (Grade C)
6. Microinvasive cervical glandular neoplasia is not an accepted definition; management of apparent early invasive adenocarcinoma of the cervix requires careful histological review and assessment by a gynaecological oncologist. (Grade C)
7. Individualisation of patient care with a multidisciplinary review should be undertaken for all patients with invasive cervical cancer. (Grade C)
8. Surgery for cervical cancer may be considered as an option for old and young alike. (Grade C)
9. Young women with early-stage cervical cancer desirous of fertility should be considered for locally radical fertility-sparing surgery. (Grade C)
10. Expert imaging of the cervix, e.g. with magnetic resonance imaging, is essential before deciding on treatment of early cervical cancer. (Grade C)
11. A number of women with disease resistant to standard treatment may be suitable for ultra-radical surgery. Quality-of-life issues and reconstruction of pelvic structures should be considered. (Grade C)
12. All patients with high-risk or advanced (stage Ib2 or greater) cervical cancer should be considered for chemoradiation. (Grade C)
13. Participation of patients with cervical cancer in clinical trials to determine optimal regimen for chemoradiation is desirable. (Grade C)

Vaginal neoplasia

1. Treatment by excision is the preferred option for vaginal intraepithelial neoplasia grade 3 (VAIN3), especially if the uterus has been removed previously. (Grade C)
2. 5-fluorouracil has no place in the management of vaginal intraepithelial neoplasia. (Grade C)

Vulval neoplasia

1. 16. Examination of the vulva is a significant part of the physical examination of adult women. Clinically abnormal vulval skin requires a biopsy and histopathological examination for appropriate diagnosis and clinical management. (Grade C)
2. Untreated vulval intraepithelial neoplasia (VIN) has a significant invasive potential. The increasing frequency of VIN in young women has been associated with an increased incidence of VIN-related cancer. While most VIN-related cancers occur in the first decade following diagnosis and treatment, later cases occur and therefore the patients need long-term follow up. (Grade C)
3. Long-term follow-up of patients with lichen sclerosus is required because a small proportion will develop vulval cancer. The risk is increased where there is clinical or histological evidence of hyperplastic changes. (Grade C)
4. The radicality of the vulval excision must now be individualised according to the extent of the cancer (and not the adjacent epithelial changes). (Grade C)
5. Sentinel node identification may allow management to reduce the morbidity of lymphadenectomy without increasing the risk of groin node recurrence. (Grade C)
6. Patients with vulval cancer who are not suitable for radical surgery because of poor medical condition or advanced local disease should be considered for chemoradiation by an expert multidisciplinary team. (Grade C)
7. If vulval or perianal intraepithelial neoplasia extends to within 1.5 cm of the anus, the anal canal should be examined for anal intraepithelial neoplasia (AIN). (Grade C)

Anal neoplasia

1. The morbidity following the treatment of high-grade AIN is significant. Surgery may be required for symptoms and to exclude invasion, but otherwise observation is thought to be appropriate. (Grade C)
2. Chemoradiation is the treatment of choice for anal carcinoma. (Grade C)

General

1. Issues of patient consent and management of women who test positive for human papillomavirus (HPV) must be considered before performing HPV testing. (Grade C)

Recommendations for research

1. The combination of high-risk HPV DNA testing and cytology offers a greater than 99% negative predictive value. Both adjunctive HPV DNA testing and primary HPV DNA testing may offer significant benefits to a cervical neoplasia screening programme.
2. Other markers, such as HPV RNA and the use of chip technology, should also be evaluated.
3. Further assessment of p16 and minichromosome maintenance proteins as markers of cervical neoplasia should be carried out.
4. Further research is required to understand how keratinocytes with HPV genomic material escape immune surveillance, and how immune response to such altered keratinocytes can be enhanced.
5. The results of several studies on the contribution of HPV testing to cervical screening for borderline or mildly dyskaryotic changes are awaited before definitive recommendations can be made to guide UK practice.
6. HPV testing may be useful in avoiding both unnecessary treatment and prolonged surveillance. Data will be available in the next few years from large prospective studies (ALTS, TOMBOLA, HART, LBC, HPV pilots) on HPV testing, psychological effects and health economies.
7. Liquid-based cytology preparation systems differ in their technology and methodology used. New liquid-based cytology systems require technical and qualitative evaluations before implementation with the National Health Service Cervical Screening Programme. These should include an assessment of the equipment, risk assessments, professionally led evaluation of the end product and also of the utility and limitations as a common platform for new technologies such as HPV testing and automated scanners. Criteria should be developed and published for these evaluations as soon as possible.
8. The techniques of visual inspection with acetic acid (VIA) and opticoelectric devices need further evaluation.
9. Research should be encouraged into whether solutions of fixatives other than acetic acid might provide better definition of cervical neoplasia.
10. The use of video colposcopy in various clinical settings should be studied.
11. There is a need for an appropriately designed trial on which method to use to treat type III transformation zones, i.e. when the endocervical lesion is not colposcopically visible in its entirety.
12. The Study Group recognises the need to undertake further studies of therapeutic immunotherapy and recommends that these be evaluated in patients with (HPV-16+) high-grade VIN and AIN (high-grade anogenital neoplasia, AGIN) as the preferred model.
13. Consideration should be given to the use of intralesional or mucosally delivered vaccines and the possibility of administering a topical adjuvant in the management of lower genital tract neoplasia.
14. Collaborations between centres are to be encouraged in order to recruit sufficient numbers of patients for treatment within an appropriate time frame. This could include clinical, immunological and genetic collaborations.
15. Incorporation of immunotherapy into surgical or chemoradiation treatment protocols should be considered for invasive cervical carcinoma.
16. Funding is required to support trials of therapeutic immunotherapy and consideration given to support of a coordinating body.
17. Gene immunotherapy with HLA-A2 or HLA-B13 is safe and has demonstrated interesting biological response in cervical and ovarian cancer. Further research in randomised control trials to assess benefits in local and distant recurrence and survival when used in conventional modality of therapy is recommended.
18. Further research is desirable to understand what molecular pathological inheritance factors increase the risk of lichen sclerosus progressing to cancer.
19. Participation of patients with cervical cancer in clinical trails to determine optimal regimen for chemoradiation is desirable.

Recommendations for health policy and education

1. HPV infection is extremely common and approximately 80% of sexually active women in the UK will be infected with HPV at some point before the age of 30 years.
2. Although HPV infection is required for the development of cervical cancer, fewer than 10% of those with persisting infection would develop cervical cancer even if they were never treated.
3. Progression to invasive cancer is extremely rare within ten years of HPV infection and in most cases could be prevented by treatment of early precancerous stages.
4. The presence of oncogenic high risk HPV DNA is, at present, the best molecular marker for assessing the risk of cervical neoplasia.
5. Cell-cycle control proteins show significant promise as markers of oncogenic HPV infection.
6. Women need clear and up-to-date information about the significance of HPV. In association with this Study Group, patient information sheets should be designed and made available.
7. National cytology societies should seek convergence for the descriptions and terms adopted within current cytological terminologies.
8. Subject to cost considerations, liquid-based cytology should be implemented as the routine screening test because it provides a better sample for cytology assessment , thereby reducing the rate of unsatisfactory smears, and also because it provides a common platform to which other new technologies can be added.
9. Different collection devices and methods are required for liquid-based cytology systems. Training of all smear takers is important in the optimal use of sampling devices in order to obtain samples of appropriate quality for cervical screening.
10. Numerous historical studies describe something of the natural history of lower genital tract precancers. It is no longer ethical to postpone any treatment indefinitely, so studies of the natural history are no longer possible.
11. VIA and opticoelectrical devices may have an advantage of almost instant clinical diagnosis.
12. It appears that VIA/direct visual inspection may contribute to cervical cancer screening but false negatives will mean missed diagnosis and false positives will lead to either over-treatment or the need for further triage.
13. Early results in respect of one of the opticoelectrical devices shows results comparable with cytology, i.e. 70% sensitivity in detection of high-grade cervical disease. When combined with cytology, the sensitivity is in excess of 90%.
14. All individuals undertaking colposcopy should have completed or be undertaking the British Society for Colposcopy and Cervical Pathology/RCOG certification for colposcopy.
15. Colposcopic index usage improves the diagnostic accuracy. There may be the potential to include other parameters such as HPV test results (if known) in these indices.
16. Colposcopists should understand why acetowhite epithelium does not always represent cervical neoplasia.
17. Low-grade lesions cannot be identified on cytology alone. Cytology, colposcopy and histology of targeted biopsies all have limitations and should be considered together in managing low grade lesions.
18. Conservative management avoids over treatment and 60-70% of low-grade intraepithelial lesions will regress spontaneously within 10-23 months.
19. The psychological impact of cervical disease is significant and is not related to the degree of abnormality.
20. Because of the difficulties in interpreting cervical glandular pathology, referral for review by a gynaecological cancer centre pathologist is recommended.
21. Vulval Paget's disease is usually of cutaneous origin but may be a manifestation of urothelial or anorectal neoplasia. Histopathological study and clinical assessment can distinguish these.
22. VIN has a significant invasive potential.
23. A VIN lesion may be associated with invasive squamous cell carcinoma. Biopsy and histopathological evaluation of representative lesions is required for diagnosis and evaluation of possible invasion.
24. Invasive vulval carcinoma requires management by clinicians skilled and experienced in the management of such cases. For proper clinical and pathological staging it is necessary to measure tumour diameter, thickness, depth of invasion and status of the inguinofemoral lymph nodes. The term 'microinvasion' is not recommended in referring to superficially invasive vulval carcinomas. International Federation of Obstetrics and Gynaecology (FIGO) staging is recommended in all cases.
25. The contribution of the gynaecologist to managing vulval disease must be encouraged by providing further educational meetings.
26. Delays in the management of vulval cancer still occur because of patient delay and clinician misdiagnosis of suspicious vulval lesions.
27. The term AIN is preferred to Bowen's disease.