Pathology of hpv infection at the cytologic and histologic levels

International Journal of Gynecology and Obstetrics (2006) 94 (Supplement 1), S22--S31 -

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CHAPTER 3

Pathology of HPV infection at the cytologic and histologic levels: Basis for a 2-tiered morphologic classification system
Thomas C. Wright, Jr.

KEYWORDS
Squamous intraepithelial lesion (SIL); Cervical intraepithelial neoplasia (CIN); Cervix; Cancerprecursors; Human papillomavirus (HPV)

Abstract Over the last 2 decades the pathogenesis and natural history of cervical cancer has become clearer. As a result, the cytologic and histologic terminology used to refer to cervical cancer precursors has needed to change. Today we recognize that almost all cervical cancers are due to infection with specific highrisk types of human papillomavirus (HPV). Mostwomen become infected with these viruses within several years of initiating sexual intercourse and a productive HPV infection frequently results in characteristic morphologic changes within the infected cervical squamous cells. Cells demonstrating the morphologic changes associated with a productive HPV infection are referred to as low-grade squamous intraepithelial lesions (LSIL) when observed incytologic specimens and low-grade cervical intraepithelial neoplasia (CIN 1) when observed in histologic specimens. In some women, HPV gene expression becomes unlinked to the state of differentiation of the infected epithelial cells and deregulated expression of the early region of the viral genome results in a dramatic increase in expression of two HPV oncoproteins (E6 and E7). This results inloss of normal cell cycle control of the epithelium and genetic instability. When this occurs the epithelium develops characteristic morphologic features, with immature “basaloid-type” squamous cells and mitotic figures in the upper half of the cervical epithelium. Such lesions are felt to represent “true” neoplasia and are referred to as high-grade squamous intraepithelial lesions (HSIL) whenobserved in cytologic specimens and high-grade cervical intraepithelial neoplasia (CIN 2,3) when observed in histologic specimens. © 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction
The histopathologic and cytopathologic classification of a disease should reflect both its clinical behavior and the current conceptsregarding its pathogenesis. Over the last 2 decades our understand-

ing of the pathogenesis of cervical cancer and its precursor lesions has increased dramatically. As a result, the old terminology is being discarded and replaced by a new terminology that more accurately reflects both clinical behavior and pathogenesis. Changes in terminology are frequently disrup-

0020-7292/$ -- see frontmatter © 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Pathology of HPV infection at the cytologic and histologic levels tive. Inevitably, many will question the need for the change and it takes years for training resources such as textbooks and management guidelines to be updated. The recent change in the histopathologic andcytopathologic classification of cervical cancer precursors seems to have been particularly disruptive, perhaps because so many clinicians are involved in different aspects of cervical cancer prevention. In this article we review the pathogenesis of cervical cancer as well as the histopathologic and cytopathologic classification and features of cervical cancer precursors.

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2. Olderterminologies
From the 1930s though the 1960s, noninvasive intraepithelial lesions of the cervix were classified using a 4-tiered terminology [1]. The 4 categories of precursor were mild dysplasia, moderate dysplasia, severe dysplasia, and carcinoma in situ (Figure 1). It was not widely accepted that dysplastic lesions were cervical cancer precursors, and carcinoma in situ was believed to be the only...