Page 43 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

occurred significantly more often in HPV L1 negative patients than in L1 positive patients (25.9%
vs 9.4%). The positive predictive value for no progression to a higher disease grade was 90,6% in
L1 positive women. The negative predictive value for progression in L1 negative women was 26%. 2 No subgroup analysis for patients with CIN 2 was made.(68) Sarmadi et al. followed 65 women,
43 with histologically confirmed LSIL and 22 with HSIL during 24 months.(65) Disease regression
was significantly less frequent in L1 negative LSIL patients (33.3%) than in L1 positive patients
(60.7%), while disease progression was more frequent. The sensitivity of L1 positivity for lack of
disease progression in LSIL was 70,2%, the specificity 100% and the PPV 100%. All cases of HSIL
were L1-negative.The study by Sarmadi et al. shows that L1-expression is lost in high-grade CIN.
This is a logical consequence of early gene overexpression and loss of late gene expression in high-
grade CIN. L1 therefore does not seem to be a logical prognostic biomarker in the natural history
of high-grade CIN.
Wang et al. and Kim et al. found an association between HPV viral load at baseline and progression of low-grade CIN.(69, 70) However, this may also reflect the development of a new high-grade lesion in addition to a low-grade lesion, instead of true progression of the low-grade lesion. Furthermore, an association was found between a decreasing viral load over time and regression of high-grade CIN, but this study does not provide information on the prognostic value of baseline viral load.(8) Kadish et al. and Peng et al. found an association between T-cell epitopes in the HPV16 E7 proteins and disease regression of LSIL and HSIL, but both studies were performed in small populations and the effect sizes seem to be limited.(71, 72)
Viral integration has been identified as a promising diagnostic biomarker in CIN, but the evidence on its prognostic value is limited. Manawapat et al. found an association between increased viral integration and persistence of HPV16 infection, but not disease progression to CIN 3.(73) Li et al. showed that persistent virus infection and progression of LSIL was more common in cases with integrated HPV16 than in cases with episomal HPV16.(74) The study was performed in a very limited number of patients.
Cell cycle regulatory factors
Understanding of the cellular processes involved in cervical carcinogenesis provides a basis for biomarker selection. The HPV oncoproteins Rb and p53, tumour suppressor protein p16 and proliferation marker Ki67 are probably the most well-known markers of cellular processes in cervical oncogenesis. Several cell cycle proteins have been identified and implemented in CIN diagnosis and others have been identified as potential biomarkers in CIN diagnosis.(75) Much less evidence exist on potential prognostic biomarkers.
p53 and Rb/pRb
Decreased Rb was identified as a strong independent predictor of CIN 1/2 progression by Kruse et al., in a prognostic study in 90 patients.(76) pRb was not found predictive for the progression of histologically proven LSIL in 101 cases by Quint et al., who also found no association with p53. (77) One author studied the prognostic value of pRb in high-grade CIN: Munk et al. followed 162 patients with CIN 2-3 during an mean of 16 weeks.(6) Increased pRb was the strongest predictor
A review of prognostic biomarkers
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