Impact of utilizing p16INK4A immunohistochemistry on estimated performance of three cervical cancer screening tests

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Abstract
The histopathological diagnosis of cervical intraepithelial neoplasia grade 2,3 (CIN 2,3) is subjective and prone to variability. In our study, we analyzed the impact of utilizing a biomarker (p16INK4A) together with histopathology to refine the “gold standard” utilized for evaluating the performance of 3 different cervical cancer screening tests: cervical cytology, human papillomavirus (HPV) DNA testing and visual inspection with acetic acid (VIA). Cervical biopsies from 2 South African cervical cancer screening studies originally diagnosed by a single pathologist were reevaluated by a second pathologist and a consensus pathology diagnosis obtained. Immunohistochemical staining for p16INK4A was then performed. The estimated sensitivity of some cervical cancer screening tests was markedly impacted by the criteria utilized to define CIN 2,3. Use of routine histopathology markedly underestimated the sensitivity of both conventional cytology and HPV DNA testing compared to an improved gold standard of consensus pathology and p16INK4A positivity. In contrast, routine histopathology overestimated the sensitivity of VIA. Our results demonstrate that refining the diagnosis of CIN 2,3 through the use of consensus pathology and immunohistochemical staining for p16INK4A has an important impact on measurement of the performance of cervical cancer screening tests. The sensitivity of screening tests such as HPV DNA testing and conventional cytology may be underestimated when an imperfect gold standard (routine histopathology) is used. In contrast, the sensitivity of other tests, such as VIA, may be overestimated with an imperfect gold standard.

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