high‐risk HPV (HRHPV) positive, low‐grade dyskaryosis.
Case History 2: A 30‐year‐old woman with unexplained infertility is referred via her GP to the infertility clinic. As part of a routine appointment, it is discovered this patient has never undergone cervical screening. Screening is offered and performed and is reported as HRHPV with severe dyskaryosis.
Case History 3: A 33‐year‐old woman with infertility is part way through her infertility investigations when she undergoes a routine cervical screening. This is reported as HRHPV and possible glandular abnormality. She is referred to the colposcopy clinic.
Background
Cervical screening programs around the world vary significantly, with vast differences in the frequency and age of commencement of screening, if programs exist at all. Within the UK, the NHS cervical screening is currently offered to all women between the ages of 25–64 years on a 3‐year basis until the age of 50 and then every 5 years until 64 years of age. The screening program has recently changed to offer primary HPV screening first, with cytology testing only in those who are high‐risk HPV positive. The aim of all cervical screening programs is to detect precancerous lesions early to avoid the progression to cervical cancer.
Around the world several countries have introduced the HPV vaccination program, with the aim of immunizing girls against the most common oncogenic HPV strains. In the UK this was introduced in 2008 [1] initially with girls alone, and later boys also. The vaccine consists of two injections over 6 months which offer protection against HPV 16 and 18, which are the most common high‐risk oncogenic strains, and 6 and 11 which are associated with genital warts. This offers protection against approximately 70% of the cervical cancers.
Early detection and treatment of cervical abnormalities can prevent 75% of cervical cancers [1]. For those who have normal HPV screening reports the chances of developing cervical cancer in the subsequent 3 to 5 years is low [1]. It is estimated that approximately 4% of those attending for cervical screening will have an abnormality detected. Those reported as low grade should all ideally be seen within the colposcopy service within 6 weeks or as soon as practicable. Those reported as high grade (moderate or severe dyskaryosis, glandular, or possible invasion) should all be seen within 2 weeks [2].
UK practice and the practice in the wider world have changed over the last few years with a drive towards more conservative management, particularly in those who wish to have children. Several studies have evaluated the rates of preterm birth and miscarriage following cervical treatment. It appears those with abnormal cervical screening have a higher rate of preterm birth compared with those with normal cervical screening even without treatment. This could be due to confounding issues such as smoking status and comorbidities although further research in this field is ongoing.
Research suggests 2.5% of all preterm births in the UK are due to cervical treatment with cervical depths of >10mm or more [3].
A 2017 Cochrane review found that those undergoing excisional treatment, whether large loop excision of transformation zone (LLETZ) or cold knife cone, had a higher preterm birth rate than those undergoing ablative treatments. However, these results should be interpreted with caution due to the low quality of the included studies [4].
Management options
Good practice would be to ensure all patients referred to fertility clinics are up to date with their local cervical screening program, and if they are not, they should be encouraged to take up this opportunity to have the screening. This also includes couples in same sex female relationships. This should ideally have been done in primary care prior to referring the patient, but if it has not been done, this should again be encouraged to be undertaken before undergoing fertility investigations and treatment. All patients should be strongly encouraged to stop smoking, as those who persist with smoking are less likely to find their precancerous cells resolve.
Women who are attending for consideration for assisted reproduction techniques (ART) are often stressed because of their fertility issues. Any additional issues will only compound this. Women with abnormal cervical cytology, who are referred for colposcopy, are also at increased stress, often comparable to levels seen prior to major surgery. There are currently no national recommendations for clinical situations where the cervical sample shows an abnormality and the woman is considering treatment for infertility.
Women should be seen and assessed but not necessarily treated. To avoid overtreatment, women should not be seen on a “see and treat” basis. In women being considered for ART, it would be prudent to undertake immediate colposcopy. The advantage of this approach is that if the colposcopic assessment is normal, then no further action needs to take place apart from repeating the cervical sample in 6 months.
Low‐grade lesions
HRHPV positive result with low‐grade dyskaryosis (as in Case History 1) warrants referral to the colposcopy clinic with the aim of the patient being seen within 6 weeks. If the colposcopy is deemed to be low grade changes on colposcopic impression alone, or on biopsy of cervical intraepithelial neoplasia (CIN) 1 at most, the patient would be returned to the primary care setting for a cervical screening sample to be repeated in 12 months. If this low‐grade abnormality persists for more than 2 years, then consideration of treatment should be offered.
A low‐grade abnormity alone with reassuring colposcopic features should not delay fertility investigations or treatment, with the proviso that should the patient develop symptoms which raise the suspicion of cervical cancer such as post coital or intermenstrual bleeding, she should be reviewed in an appropriate clinical setting.
High‐grade lesions
On the other hand, severe dyskaryosis (as in Case History 2) warrants an urgent referral to colposcopy. This patient should be seen within 2 weeks. A colposcopic examination should be performed with the aim of establishing a diagnosis. Careful counseling should be offered to the patient with a discussion around the option of see and treat (excisional LLETZ) versus punch biopsy with the options of observation alone, or treatment once the diagnosis has been established. Treatment options include excisional LLETZ or ablative treatments such as cold coagulation, acknowledging the increasing preterm birth rates associated with deeper excisions. If CIN 1–2 is diagnosed it is reasonable to have these cases reviewed, both histology and cytology at the local colposcopy multidisciplinary team (MDT) meeting with the option of conservative management in the form of 6 monthly colposcopy attendance and cervical screening, progressing to treatment should the patient develop symptoms suspicious of cancer or the CIN rises to CIN 3 or 2 years have elapsed with no cytological resolution.
If CIN 3 is detected along with any suggestion of a glandular abnormality or cancer, then excisional rather than ablative treatment should be offered promptly.
In those with CIN, the aim is to keep the depth of excision to >7 mm but <10 mm where possible. All patients with CIN should be offered HPV test of cure testing with their general practitioner 6 months following treatment, and ideally fertility treatment should be deferred until this result is known.
Glandular abnormalities
Glandular abnormalities (as in Case History 3) warrant a prompt direct referral to colposcopy and should be seen within 2 weeks [2]. There is a high prevalence of invasive adenocarcinoma, cervical glandular intraepithelial neoplasia (CGIN) and CIN in this population of patients [2]. Cervical biopsy alone in this setting lacks adequate sensitivity and excisional treatment such as a LLETZ is preferable to
