Cervical intraepithelial neoplasia

The classification of cervical precancerous lesions has evolved over time and the terms from the different classification systems are currently used interchangeably. Hence a brief review of the terminology is warranted. The oldest classification system classified lesions as having mild dysplasia on one end and severe dysplasia/carcinoma in situ on the other. This was followed by cervical intraepithelial neoplasia (CIN) classification, with mild dysplasia termed CIN I, moderate dysplasia CIN II, and severe dysplasia termed CIN III. Because the decision with regard to patient management is two-tiered (observation versus surgical treatment), the three-tier classification system has been recently simplified to a two-tiered system, with CIN I renamed low-grade squamous intraepithelial lesion (LSIL) and CIN II and CIN III combined into one category referred to as high-grade squamous intraepithelial lesion (HSIL) Table 22-1. Classification Systems for Premalignant Squamous Cervical Lesions

Dysplasia/Carcinoma in Situ	Cervical Intraepithelial Neoplasia (CIN)	Squamous Intraepithelial Lesion (SIL), Current Classification
Mild dysplasia	CIN I	Low-grade SIL (LSIL)
Moderate dysplasia	CIN II	High-grade SIL (HSIL)
Severe dysplasia	CIN III	High-grade SIL (HSIL)
Carcinoma in situ	CIN III	High-grade SIL (HSIL)

LSILs are associated with productive HPV infection, but show no significant disruption or alteration of the host cell cycle. Most LSILs regress spontaneously, with only a small percentage progressing to HSIL. LSIL does not progress directly to invasive carcinoma. For these reasons LSIL is not treated like a premalignant lesion. In HSIL, there is a progressive deregulation of the cell cycle by HPV, which results in increased cellular proliferation, decreased or arrested epithelial maturation, and a lower rate of viral replication, as compared with LSIL. HSILs are one tenth as common as LSILs.

Morphology. Figure 22-17 illustrates a spectrum of morphologic alterations that range from normal to high grade dysplasia. The diagnosis of SIL is based on identification of nuclear atypia characterized by nuclear enlargement, hyperchromasia (dark staining), presence of coarse chromatin granules, and variation of nuclear sizes and shapes. The nuclear changes may be accompanied by cytoplasmic halos indicating disruption of the cytoskeleton before release of the virus into the environment. Nuclear alterations and perinuclear halo are termed koilocytic atypia. The grading of SIL into low or high grade is based on expansion of the immature cell layer from its normal, basal location. If the atypical, immature squamous cells are confined to the lower one third of the epithelium, the lesion is graded as LSIL; if they expand to two thirds of the epithelial thickness, it is graded as HSIL.

F igure 22-18A illustrates the histologic features of LSIL. The adjacent panel, Figure 22-18B, shows detection of HPV DNA using an in situ hybridization test. The staining is most intense in the superficial layers of the epithelium, which contain the highest viral load. Figures 22-18C and D show immunostaining for Ki-67 and p16. Ki-67 is a marker of cellular proliferation, and in normal squamous mucosa is confined to the basal layer of the epithelium. In contrast, in SILs, Ki-67 positivity is seen throughout the entire thickness of epithelium, indicating abnormal expansion of the epithelial proliferative zone (see Fig. 22-18C). p16, a cyclin kinase inhibitor, is a cell cycle-regulatory protein, which inhibits the cell cycle by preventing the phosphorylation of RB. It has been shown that in cells infected with oncogenic HPVs, there is overexpression of p16 (see Fig. 22-18D). Despite high levels of p16, however, the HPV-infected cells continue to proliferate because RB, the target of p16 inhibitory activity, is inactivated by the E7 HPV oncoprotein. Both Ki-67 and p16 staining are highly correlated with HPV infection and are useful for confirmation of the diagnosis in equivocal cases of SIL.

More than 80% of LSILs and 100% of HSILs are associated with high oncogenic risk HPVs. HPV 16 is the single most common HPV type detected in both categories of lesions. Table 22-2 shows rates of regression and progression of SILs within 2-year follow-up.25 Although the majority of HSILs develop from LSILs, approximately 20% of cases of HSIL develop de novo, without the preexisting LSIL.26 The rates of progression are by no means uniform, and although HPV type-especially HPV 16-is associated with increased risk, it is difficult to predict the outcome in an individual patient. These findings underscore that the risk of developing precancer and cancer is conferred only in part by HPV type, and depends also on immune status and environmental factors. Progression to invasive carcinoma, when it occurs, may take place in a few months to more than a decade.