Page 31 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman
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Introduction
High-grade cervical intraepithelial neoplasia (CIN) is considered to be the precursor of cervical 2 cancer, which is currently the fourth most common malignancy in women worldwide.(1) Cervical
cancer, and high-grade CIN as its precursor, are caused by infection with human papillomavirus
(HPV).(2) The incidence of cervical cancer has declined in developed countries as a result of
screening programs and early treatment of precursor lesions.(3) Currently, standard therapy for high-grade CIN lesions is surgical excision: this is usually done by large loop excision of the transformation zone (LLETZ). The rationale for this generalized treatment is that the natural history of the individual CIN lesion is unpredictable: whereas a subset of high-grade lesions will progress to cervical cancer, another subset will regress spontaneously. Approximately 30% of high-grade CIN progresses to cervical cancer.(4, 5) On the contrary, recent evidence suggests that spontaneous regression of high-grade CIN occurs in approximately 20-40% of high-grade lesions.(6-9) Current histopathological assessment is unable to differentiate between lesions that will progress to cervical cancer and those that will regress spontaneously. In the light of these findings, treatment of all high-grade CIN leads to overtreatment and unnecessary complications as a result.(10) LLETZ is an invasive procedure with several short term and long term side effects. Two important long term adverse effects of LLETZ treatment are a potentially increased risk of subfertility and increased risk of premature birth in subsequent pregnancies, most probably as a result of cervical insufficiency.(11-14) Ideally, those lesions that will regress spontaneously should be differentiated from those that will not do so, allowing for watchful waiting instead of invasive treatment in the subgroup of patients in which spontaneous regression is expected. Individual regression risk prediction of high-grade CIN is essential for this strategy. As current histopathological assessment is not suited for this purpose, other markers are needed: individual or combined markers that predict the natural course of individual high-grade CIN lesions.
Such prognostic biomarkers are clinical or biological characteristics that are objectively measurable and provide information on the likely outcome of disease outcome in an individual. (15) Prognostic biomarkers define the effects of patient or disease characteristics on disease outcome in patients. As such, prognostic biomarkers may be helpful for the identification of patients with high risk of disease progression thereby guiding the choice to select those who will benefit from treatment.
The natural history of CIN was historically assumed a sequence of steps through histopathological classification. More recent insights indicate that the natural history of CIN should rather reflect HPV infection status: it is hypothesized that HPV infections are either productive or transforming. Productive infections lead to the production of new viruses and are histologically characterized by minor cellular changes, diagnosed as CIN 1 or less. On the contrary, high-grade CIN is caused by a transforming infection, leading to more extensive cellular changes.(16) The development of CIN is determined by a complex interaction between the immune system, viral factors and functional cellular mechanisms. Potential prognostic biomarkers may be identified at these different levels of interaction.(17-19) This review aims to identify biomarkers that have been associated with the natural history of high-grade CIN or are considered promising in this regard. Before biomarker
A review of prognostic biomarkers
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