CHAPTER 3. Squamous intraepithelial lesions: cytology–histology CHAPTER 3 CHAPTER correlation CHAPTER 1 CHAPTER This chapter discusses the nat- 3.2 Historical context but were confined to the epithelium. ural history of cervical precancer, The term “dysplasia” was coined HPV and oncogenesis, cytology no- The precursor phase of the natural about 20 years later by Reagan and menclature, and the cytological and history of cervical cancer is char- Hicks (1953), and dysplasia was cat- histological recognition of cervical acterized by cellular changes within egorized as being mild, moderate, precancer. the epithelial lining of the cervix; in or severe depending on the propor- other words, the abnormality is en- tion of the epithelial layers involved 3.1 Current understanding of tirely intraepithelial. John Williams in the dysplastic process. Carcino- the natural history of cervical first described intraepithelial cellular ma in situ was considered to have precancer changes in tissue adjacent to inva- a greater degree of abnormality and sive cancer more than 125 years to be the final precancerous state. Cervical cancer has a long precursor ago (Williams, 1888). During the The term “koilocyte” (halo or vac- stage. The cervix is accessible and early decades of the 20th centu- uolated cytoplasm or empty space sheds exfoliated cells easily, and cy- ry, the concept of intraepithelial cytoplasm) was coined by Koss and tological examination of these cells dysplasia gained acceptance (Cul- Durfee (1956). Meisels and Fortin reveals precancerous changes that len, 1900; Rubin, 1910). It implied (1976) first recognized these cells as are easily eradicated. The essential cancerous-looking cells confined being infected with HPV. causative agent of cervical cancer to the epithelium above the base- Richart (1968) introduced the is the presence of high-risk HPV, ment membrane and led to the term concept of a continuum and subdi- which is easily detectable. Cervical “carcinoma in situ” (Broders, 1932), vided the spectrum of abnormality cancer is a completely preventable which was defined as full-thickness into three categories, called CIN disease. This is quite apart from the cellular changes that looked mor- grades 1 (mild dysplasia), 2 (moder- availability of an effective vaccina- phologically similar to undifferenti- ate dysplasia), and 3 (severe dyspla- tion. The disease should not exist. ated invasive carcinomatous cells sia). In this classification, carcinoma Chapter 3. Squamous intraepithelial lesions: cytology–histology correlation 23 in situ was combined with severe Fig. 3.1. Changing terminology and treatment trends for cervical precancer dysplasia. The cytological classifi- over the past century. CKC, cold-knife conization; Cryo, cryotherapy; LEEP, cation was similar in that mild, mod- loop electrosurgical excision procedure; Rx, treatment. erate, and severe dyskaryosis were suggestive (but not diagnostic) of CIN1, 2, and 3, respectively. The relative ease of treatment afforded by outpatient therapy, which had begun to replace hysterectomy and cold-knife conization in the 1970s and 1980s, lowered the threshold for treatment of cervical lesions. In an attempt to simplify the classifi- cation and because it had become clear that minor-grade lesions did not often progress to cancer, Richart (1990) proposed a two-tier classifi- cation system. High-grade lesions were thought to be much more likely to be genuinely precancerous. Low- grade lesions were considered to be transient and rarely precancerous. Many low-grade lesions were asso- These lesions have limited, if any, and major numerical and structural ciated with koilocytosis and recog- precancerous potential for progres- alterations of the host cell chromo- nized as being HPV-related. Howev- sion to cancer. This type of infection somes. This leads to uneven distri- er, this classification system was not is called a productive infection. The bution of the overall DNA content universally used. Also, moderate ab- key step in the pathogenesis of HPV- (aneuploidy) and is reflected by shifts normalities, some of which were un- linked cancers is the activation of the of the nuclear staining pattern (the doubtedly low-grade in nature, were viral oncogenes E6 and E7 in the bas- staining intensity). This type of infec- included in the high-grade category al and parabasal cells of the infect- tion is more readily recognized cyto- and perhaps treated too readily. The ed epithelium (Bergeron et al., 2015; logically, colposcopically, and histo- different classifications are repre- Doorbar et al., 2012; Duensing and logically and is called a transforming sented in the diagram in Fig. 3.1, with Münger, 2004). If these viral genes are infection (see Chapter 4). treatment patterns included below. expressed in basal or parabasal cells, Sometimes moderate dyskary- The traditional “screen, diagnose, they trigger chromosomal instability osis (at cytology) or moderate and treat” pathway (Fig. 3.2) worked reasonably well when the threshold Fig. 3.2. Traditional process of screening test, colposcopic assessment, his- for referral to colposcopy was set tological diagnosis, and treatment. high. The concept of a continuum persisted until relatively recently. A greater understanding of the biology of oncogenic HPV and its different effects in squamous epithelium of the lower genital tract has led to a differ- ent concept. It now seems clear that there are two different types of HPV infection. The first type is an innocent and transient infection, which may produce mild or low-grade lesions that are recognizable cytological- ly, colposcopically, or histologically. 24 dysplasia (at histology) may contain Fig. 3.3. Different HPV infection stages. both types of infection, and these are difficult to distinguish using cytology or histology. Fortunately, develop- ments in molecular biology have led to specific biomarkers of cell biol- ogy that can discriminate between these types where doubt exists (see Chapter 4). 3.3 HPV and the genesis of cervical cancer Several different risk factors have CHAPTER 3 CHAPTER been implicated for cervical cancer and precancer. These include smok- ing, early age at first intercourse, nutritional deficiency, chlamydial infection, multiple sexual partners, multiple pregnancies, and long-term use of oral contraceptives (Bosch et the epithelial cell nuclei and chang- the past 25 years. These revisions al., 1995; Franco et al., 1999; IARC, es from a latent to a transforming in- reflect the changing understanding 2007, Schiffman et al., 1996; Wal- fection. It is in those cases that the of risk associated with different cy- boomers et al., 1999). However, the risk of progression is high. It is not tological and histological reporting fundamental and essential causative known what distinguishes those cas- and a greater understanding of the agent is the persistence of oncogen- es in which the virus becomes inte- role of oncogenic HPV. The United ic HPV in the epithelium of the TZ grated and transforming from those Kingdom classification now reflects and/or adjacent glandular epitheli- in which the infection is transient and the Bethesda two-tier classification. um. The relationship between onco- harmless. The relationship between To help clinicians manage their pa- genic HPV and cervical precancer oncogenic HPV infection and the risk tients with different grades of ab- appears, at first, paradoxical. Cervi- of progression or clearance is dis- normality, the ASCCP developed a cal cancer is always associated with cussed in Chapter 4. The crucial step series of clinical guidelines linked to oncogenic HPV, but oncogenic HPV is that of the HPV infection becoming the Bethesda classification (Wright is a normal and usually transient in- a transforming infection. et al., 2003). In the United Kingdom, fection that most healthy sexually the NHS Cervical Screening Pro- active women will encounter in early 3.4 Cytology nomenclature gramme (NHS, 2010) produced an reproductive life. The current think- evidence-based guidelines docu- ing is that the oncogenic HPV gains To this day, there are several dif- ment, which linked management to entry to the cervical epithelium at the ferent cytological classifications for the degree of cytological abnormal- new SCJ, possibly associated with cervical precancer. The German ity and other relevant case charac- minor abrasions, and that this allows classification is used in Germany, teristics (e.g. HPV test result, age, the virus to access reserve cells un- Austria, and some countries in east- and smoking history). It has recently derneath the single layer of columnar ern Europe. The United Kingdom been updated (NHS, 2016). Fig. 3.1 epithelium (Fig. 3.3). has its own classification, as do Aus- attempts to relate some of the pre- Most women will be infected tralia and New Zealand. Perhaps the vious cytology nomenclatures to with oncogenic HPV, and the great most widely used classification is the current Bethesda classification, majority will clear the infection with- the Bethesda terminology system, which is probably the most widely out any residual harm or increased first introduced in 1988 by the United used system today. risk of cervical cancer. In a small States National Cancer Institute (Sol- There has always been an in- percentage of women, the infection omon, 1989). It embraced the con- terdisciplinary dependency in man- persists, and in a small proportion cept of a two-tier gradation and has agement of cervical precancer. of those, it becomes integrated into undergone