Diagnostic Challenge of Cervical Intraepithelial Neoplasia with Concurrent Follicular Cervicitis: Histomorphological Features and P16 Immunostaining as a Diagnostic Adjunct

The literature acknowledges difficulties in diagnosing cervical intraepithelial neoplasia (CIN) when it is closely associated with a dense chronic inflammatory infiltrate within the superficial cervical stroma. This is due to atypical reactive and regenerative epithelial changes such as nuclear enlargement/overlap and impaired maturation, mimicking some of the cytological and architectural features found in CIN [1,2]. Follicular cervicitis (FC), a form of chronic cervicitis with prominent lymphoid follicles containing well-formed germinal centres, is usually easily identifiable but has led to misdiagnoses in gynecologic cytology [3], and we propose also in cervical histology. p16INK4a tumour-suppressor protein over expression has been shown to detect integrated high-risk human papilloma virus (hrHPV), with p16INK4a immunohistochemistry (p16 IHC) acting as a surrogate biomarker for oncogenic hrHPV infection [4,5]. In the supporting literature and the authors’ experience, p16 immunoreactivity tends to be weak and patchy in low grade CIN (CIN1) and reactive mimickers, such as atrophy and squamous metaplasia. Conversely strong and diffuse (so-called “block-positive” staining) p16 immunoreactivity strongly favours an interpretation of high grade CIN (CIN2 and CIN3) [1-7]. Consensus recommendations from the Lower Anogenital Squamous Terminology (LAST) project from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology advise pathologists to consider using p16 IHC for equivocal lesions only; when the H&E morphologic differential diagnosis is between a high grade disease and either a high grade mimic, such as immature squamous metaplasia or low grade disease. They state that although the grade of CIN should be based on the H&E histomorphology of the lesion, if a biomarker such as p16 IHC is used, the results may override the original H&E interpretation. Routine use of p16 IHC is not recommended, especially when the H&E morphologic differential diagnosis is between low grade disease and negative. Overuse of p16 IHC might lead to the potential overtreatment of patients following overinterpretation of staining patterns in low grade lesions [8]. The aim of this study was to identify common histomorphological features in coexisting CIN and FC, which to our best knowledge have not been previously demonstrated.