Cervical intraepithelial neoplasia: the expanding spectrum of cervical squamous intraepithelial lesions with focus on morphologic and molecular nuances.

Cervical squamous cell carcinoma (SCC) is classified by the World Health Organization based on its association with human papillomavirus (HPV) into HPV-associated (HPVA) and HPV-independent (HPVI) categories. HPVI SCCs can be p53 wild-type or p53 abnormal, the latter harboring a driver alteration in TP53 and portending worse survival. Recent developments have expanded the spectrum of squamous intraepithelial lesions (SILs) in the cervix. In the HPVA category, seborrheic keratosis-like lesions are now established as having an aetiological association with HPV42, a common low-risk HPV type. Papillary immature metaplasia, a further low-risk HPVA lesion, also falls into this category. More recently, potential HPVI squamous precursor lesions have been described; these form a wide morphologic spectrum and are difficult to diagnose, with the use of p16, p53, and HPV testing mandatory. When these ancillary tests are used, the HPVI SILs, similar to their invasive counterparts, stratify into p53 abnormal and p53 wild-type categories. Different genomic alterations are seen within the two groups, supporting their neoplastic nature. In this review, we provide a historical perspective and comprehensive description of all cervical SILs, with a focus on emerging entities and premalignant lesions, and appraise the terminology used over past years and that recently proposed for new entities. Key clinical, colposcopic, and morphologic features, differential diagnosis, treatment, follow-up, and prognosis are discussed. Special attention is paid to ancillary studies that assist in resolving differential diagnoses and their interpretation in light of recent scientific publications and international guidelines. We also discuss the clinical impact of a pathologic diagnosis of HPVA versus HPVI SILs.