Is mRNA indeed Useful in Clinical Management of Cervical Pathology?

Introdcution

Personalised medicine and precision medicine are being applied in more and more medical fields in the last years. The need for personalisation is especially pronounced in cervical pathology, since in the majority of cases an abnormal screening test does not necessarily imply high-grade lesion, regardless of whether the screening test is cytology or HPV testing.

Deviation from the principles of personalised medicine leads unavoidably to overtreatment, with both clinical and psychological side effects. As far as the clinical side effects are concerned, CIN treatments have been associated with an increased risk of reproductive morbidity, such as miscarriage in the second trimester, preterm birth (PTB) (overall less than 37 weeks of gestation, but also more severe prematurity including less than 34 or 28 weeks of gestation) and perinatal mortality (Kyrgiou, 2006;Arby, 2008;Kyrgiou, 2014; Kyrgiou, 2015; Kyrgiou, 2016;Kyrgiou, 2017). This risk is more pronounced with more radical treatments and increasing cone depth. For example, relative risk (RR) of PTB is 1.54 (1.09, 2.18) for cone depth less than 10/12mm, compared to general population, but RR increases to 1.93 (1.62, 2.31) for cone depths more than 10/12mm, 2.77 (1.95, 3.93) for cone depths more than 15/17mm and 4.91 (2.06, 11.68) for cone depths more than 20mm (Kyrgiou, 2016). Psychological consequences should also not be neglected. Informing the patient that she needs treatment causes anxiety and panic, not only in the same patient but also in her family.

For this reason, CIN1 lesions should be managed conservatively, and only CIN2+ lesions should be treated, as a rule of thumb. In young women wishing further fertility, conservative management of CIN2 lesions is also acceptable (Massad, 2013), as long as colposcopy is satisfactory and patient is not expected to be lost to follow-up. Expectant management of CIN2 lesions is justified, because a high percentage of CIN2 lesions regress spontaneously, especially in younger women. According to a recent meta-analysis (BMJ, 2018), regression rate of CIN2 is 60% (57-63%) for women aged less than 30 years, and only 11% (5-19%) of CIN2 will progress to CIN3+ in this age group.

Although histology/biopsy is considered to be the gold standard in most medical fields, this is not very clear in cervical pathology. Sensitivity of colposcopically-directed punch biopsies (PBs) is not always high. According to a meta-analysis (Underwood, 2012), when cone histology was CIN3+, pre-treatment PBs had shown <CIN1 in 8.9% of cases, and <CIN2 in 19.9% of cases. In addition, PBs showing CIN2 are not informative of whether this lesion has a high likelihood of spontaneous regression in the future, similar to most CIN2 lesions (thus treatment is not necessary), or whether it might persist or progress (thus treatment might be warranted). For this reason, apart from PB results, more information is needed to help us in the personalised management.