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Precancerous Lesions of the Cervix
This chapter covers the epidemiology, pathogenesis, current nomenclature, and histological appearances of precancerous lesions of the cervix. For over 20 years, it has been evident that specific types of human papillomavirus (HPV) cause almost all squamous cell carcinomas of the cervix as well as the vast majority of adenocarcinomas of the cervix. However, much remains to be learned regarding the precise molecular pathways by which these DNA tumor viruses produce tumors and why only a small minority of HPV- infected individuals develop disease. The chapter discusses the current terminology used to refer to precancerous lesions including both squamous and glandular lesions. The chapter then provides an in- depth description of the histological features of both squamous intraepithelial lesions and glandular neoplasia. This includes both their differential diagnoses and the use of adjunctive histological methods including p16.
Precursors of Squamous Cell Carcinoma
Terminology and Historical Perspective
The histopathological classification of a disease should reflect both current concepts of its pathogenesis and its clinical behavior. Over the last 50 years, our understanding of the pathobiology and behavior of cervical cancer precursors has evolved considerably. As a result, the terminology used to classify preinvasive lesions of the cervix has frequently changed. Although these changes in nomenclature and the resulting lack of a uniform terminology have been an ongoing source of confusion to both gynecologists and pathologists, each change has actually reduced the number of specific pathological categories and has made clinical decision-making more straightforward.
The existence of precursor lesions for invasive cervical cancer has been recognized for over a century. As early as 1886, Sir John Williams commented on the presence of noninvasive epithelial abnormalities adjacent to invasive squamous cell carcinomas of the cervix (Williams 1888). The spatial relationships and histologic appearance of these noninvasive epithelial lesions were better described by Cullen in 1900 who recognized that these intraepithelial lesions histologically resembled the adjacent invasive cancers (Cullen 1900). In the 1930s, Broders reintroduced the term carcinoma in situ that was first used by Schottlander and Kermauner to refer to these intraepithelial cervical lesions (Broders 1932). A temporal relationship between carcinoma in situ and invasive cancer was subsequently reported by Smith and Pemberton, as well as by Galvin, Jones, and Telinde, who diagnosed carcinoma in situ in several patients months to years before the development of invasive cervical cancer (Pemberton and Smith 1929). The recognition that there was both a spatial and temporal relationship between carcinoma in situ and invasive squamous cell carcinoma led to the hypothesis that invasive squamous cell carcinoma develops from a histologically well-defined precursor lesion (Broders 1932). This hypothesis was subsequently substantiated by long-term follow-up studies, which clearly demonstrated that a significant proportion of untreated patients with carcinoma in situ subsequently develop invasive squamous cell carcinoma (Kolstad and Klem 1976; Koss et al. 1963).
Once it was accepted that carcinoma in situ was a precursor to invasive squamous cell carcinoma, population-based cytological screening programs were begun to detect and treat precursor lesions prior to the actual development of cancer. As large numbers of women began to be screened for cervical disease, it became apparent that many women had cervical epithelial abnormalities that were cytologically/histologically less severe than carcinoma in situ. These lesions formed a histologic spectrum that ranged from lesions in which the majority of the cells had the cytological features of carcinoma in situ to those in which the degree of atypicality was much less. A variety of confusing terms were used to refer to the spectrum of cervical abnormalities with features intermediate between those of carcinoma in situ and normal cervical epithelium including anaplasia, basal cell hyperplasia, and atypical hyperplasia, but the term that came to be most widely used was dysplasia. Dysplasia is derived from the Greek word "dys" that translates to "bad" and "plasia" that translates to "molding" and is a term that has been widely used in many areas of pathology to describe nonmalignant processes. Dysplasia was usually graded as mild, moderate, or severe. The key distinguishing feature of dysplasia was that the atypical cells did not extend through the full thickness of the epithelium or invade the basement membrane. In the cytological nomenclature, dysplasia was considered to be a benign to possibly malignant squamous epithelial atypia, whereas carcinoma in situ was designated as positive for malignant cells.
The separation of noninvasive cervical lesions into two groups, dysplasia and carcinoma in situ, implied that there was a biologic distinction between these two entities and that the two could be reproducibly distinguished from each other. In most centers, dysplasia was considered to be a potentially reversible process and therefore was either ignored, followed, or treated depending on a variety of clinical factors, whereas carcinoma in situ was considered to be a highly significant lesion and patients with this diagnosis were usually treated with hysterectomy. This classification of noninvasive precursor lesions into dysplastic and carcinoma in situ lesions was based solely on arbitrary histologic differences which were often quite subtle (Burghardt 1991; Koss 1978). In the 1960s, several studies of inter- and intraobserver variability of histologic diagnosis demonstrated that pathologists could not reproducibly distinguish between severe dysplasia and carcinoma in situ (Crocker et al. 1968; Kirkland 1963).
A number of studies in the late 1960s suggested that the cellular changes of dysplasia and carcinoma in situ were qualitatively similar and remained constant throughout the histologic spectrum. Both dysplasia and carcinoma in situ were found to be monoclonal proliferations of abnormal squamous epithelial cells with an aneuploid nuclear DNA content (Fu et al. 1983). On the basis of these descriptive biologic studies, Richart introduced the concept that all types of precursor lesions to squamous cell carcinoma of cervix represented a single disease process which he termed cervical intraepithelial neoplasia (CIN) (Richart 1973).
Terminologies for cervical cancer precursor lesions
Older classification
CIN classification
WHO/Bethesda System classification
Mild dysplasia
Moderate dysplasia
Severe dysplasia
Carcinoma in situ
General Features
Vaccination against HPV is already causing dramatic reductions in the rates of cytological abnormalities and histologic HSIL in countries such as Australia and Denmark that have achieved high vaccine coverage. The Australia national vaccination program was carried out between 2007 and 2009 and resulted in over half of women 12–26 years being vaccinated with the quadrivalent HPV vaccine (HPV 6, 11, 16, 18) (Brotherton 2016). By 2013 the Victorian Cervical Cytology Registry showed a significant reduction in both high-grade cytological abnormalities and histologic HSIL among women who had been vaccinated in school-based programs between ages 12 and 17 years. The prevalence rate of HSIL+ was 4.8 per 1000 person years in vaccinated women compared to 6.4 per 1000 in unvaccinated women (Gertig et al. 2013). By 2016 this same registry reported that the prevalence rate of HSIL+ among women 25–29 years had declined by 17% compared to the preceding 2 years (Brotherton et al. 2016). A Danish registry study found that between 2010 and 2013 there was a markedly decreasing trend in the incidence of HSIL+ for young women 12–20 years who had been targeted by the Danish HPV vaccination program (Baldur-Felskov et al. 2014).
Risk factors associated with SIL in various epidemiological studies
Sexual activity
Number of sexual partners
Early sexual activity (especially less than 16 years of age)
Sexually transmitted diseases
Human papillomavirus
Herpes simplex virus
Chlamydia trachomatis
Early age of first pregnancy
Low socioeconomic class
Cigarette smoking
Human immunodeficiency virus
Immunosuppression from any cause
Interval since last Pap smear
Oral contraceptive use
Human Papillomaviruses
In the late 1970s based on theoretical considerations, Dr. Harald zur Hausen suggested that there might be an association between HPV and cervical cancer, an achievement for which he received the Nobel Prize in Medicine in 2008 (Hausen 1977, 2009). A large number of epidemiological, clinicopathological, and molecular studies subsequently linked the presence of specific types of HPV to the development of anogenital cancers and their precursors, and it is now accepted that infection with high-risk HPVs plays a critical role in the pathogenesis of most cervical cancers and their precursor lesions (Human Papillomaviruses 2007).
Classification of HPV and Association with Specific Types of Anogenital Lesions
Papillomaviruses are classified as members of the family Papillomaviridae (Human Papillomaviruses 2007). The papillomaviruses are double-standard DNA tumor viruses that have a DNA genome of approximately 8,000 base pairs in length, a nonenveloped virion that measures 45–55 nm in diameter, and an icosahedral capsid composed of 72 capsomers. Papillomaviruses are widely distributed throughout nature. There are bovine, canine, avian, rabbit, deer, and human papillomaviruses. They are all highly species specific viruses which infect only one species. This suggests an evolutionary history spanning over 300 hundred millions years (Herbst et al. 2009). Within a given species, many types and subtypes of papillomaviruses may exist. Unlike many other viruses in which specific viral isolates have capsid proteins with different antigenic structures, the capsid proteins of papillomavirus are highly conserved and antibodies directed against bovine papillomavirus (BPV) capsid proteins cross-react with human papillomaviruses (Jenson et al. 1980). Therefore, DNA sequence is used to classify different viral types (genotypes).
Papillomaviruses are epitheliotrophic viruses which predominantly infect skin and mucous membranes and produce characteristic epithelial proliferations at the sites of infection. These benign epithelial proliferations or papillomas have the capacity to undergo malignant transformation under certain circumstances. Examples of this in animals include the papillomas induced in domestic rabbits by the cottontailed rabbit papillomavirus (CRPV) which can progress to invasive squamous cell carcinomas when treated with topical applications of methylcholantrene and alimentary tract papillomas induced in cattle by bovine papillomavirus (BPV) which undergo malignant transformation when the animals eat radiomimetic bracken ferns. In humans, HPV infections occur on the skin and mucous membranes, on the conjunctiva, oral cavity, larynx, tracheobronchial tree, esophagus, bladder, anus, and genital tract of both sexes. HPVs appear to be fastidious in their growth requirements and replicate only in the nucleus of infected cells. In addition to being species specific, papillomaviruses are also relatively tissue and site specific.
Oncogenic risk of common types of anogenital human papillomavirus
Low oncogenic risk:a
6, 11, 42, 43, 44, 53
High oncogenic risk
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68
Unclear oncogenic risk:
26, 66, 73, 82
The distribution of HPV types in invasive cervical cancers shows an even stronger enrichment for HPV 16 and 18 that is observed in women with HSIL, Fig. 10b (Smith et al. 2007). One study used a sensitive PCR method to identify and type HPV in paraffin-embedded samples from over 10,000 women with invasive cervical cancer (de Sanjose et al. 2010). The most common HPV types were 16, 18, 31, 33, 35, 45, 52, and 58. These genotypes combined accounted for 91% of the HPV positive cases. HPV 16 was the single most commonly identified genotype and was found in 61% of cervical cancers. HPV 16 was more commonly found in squamous cell carcinomas (62%) than in adenocarcinomas (50%). In contrast, HPV 18 and 45 are more commonly found in adenocarcinomas (32% and 12%, respectively) than in squamous cell carcinomas (8% and 5%, respectively). HPV 16, 18, and 45 combined accounted for 94% of cervical adenocarcinomas. HPV 31, 33, and 52 are each found in 3–4% of cervical cancers (de Sanjose et al. 2010). None of the other high-risk types are found in more than 2% of cervical cancers and most are found in 1% or less. As with HSIL, multiple HPV types are rarely found in association with invasive cervical cancers.
Genomic Organization of HPV
The early region open reading frames (ORFs) encode for proteins required for viral replication and maintenance of a high viral copy number in infected cells (Doorbar et al. 2012). The early region also includes the transforming regions of the HPV genome: E5, E6, and E7. The E6 and E7 ORFs encode the major transforming genes of HPV (Hausen 2002). The E5 ORF encodes a protein with weak transforming capacity. Both the E6 and E7 proteins are small zinc-binding proteins that lack endogenous enzymatic activity and exert their transforming activity through binding to cell regulatory proteins (Doorbar 2007, 2018). E6 can bind to p53 and results in rapid proteolytic degradation of p53 through an ubiquitin-dependent pathway, thus blocking apoptosis. E7 binds to the retinoblastoma (Rb) gene product, as well as other "Rb-like proteins." Binding of E7 to Rb blocks the cell proliferation inhibiting function of these endogenous tumor suppressors. E7 can also activate cyclins A and E as well as block the cell proliferation inhibiting functions of WAF-1 and p27, two cyclin-dependent kinase inhibitors. The end result of overexpression of E6 and E7 within cells is unrestricted cell proliferation and a blockage of apoptosis.
The late region of HPV is downstream of the early region and contains two ORFs termed L1 and L2 which encode capsid proteins. The L1-encoded protein is the major capsid protein and is highly conserved among papillomaviruses from all species. The L2-encoded protein is a minor capsid protein which is much more variable among viral types. Transcription from the L1 and L2 ORFs occurs as a late event in the viral life cycle at a time when infectious virus is being produced. L1 capsid proteins produced in in vitro culture systems are capable of associating and forming viral-like particles (VLPs) that are similar to native virions, but lack the viral genome. VLPs composed of L1 capsid proteins are the antigens used in the prophylactic HPV vaccines.
Life Cycle of HPV
In order for a HPV infection to persist and progress to HPV-associated precancerous and cancerous lesions, it is important that it avoids the host immune response (de Sanjose et al. 2018). One strategy that is used to avoid the host immune response is to maintain a low profile (Stanley 2012). All of the HPV life-cycle takes place in differentiating keratinocytes that are programed to undergo cell death and be released from the epithelial surface remote from immune activity. HPV does not cause virus-induced cell death and hence there is no inflammation or danger signal made to the immune system. Langerhans cells are not recruited to the sites of HPV infection. Although keratinocytes normally have the capacity to respond to cell injury and the presence of pathogens and mediate immune response, HPV infections downregulate innate immune sensors on the keratinocytes and suppress the type 1 interferon response as well as downregulates cytokine responses (Stanley 2012). Through these and other mechanisms, HPV evades the innate immune response and there is a delay in activation of adaptive immunity.
Epidemiology of HPV Infections
Anogenital HPV infections are primarily transmitted by direct skin-to-skin or mucosa-to-mucosa contact. Based on prevalence studies among both men and women in the population, it appears that although sexual intercourse is the most common route of infection, intercourse is not required for transmission (Burchell et al. 2006; Gravitt 2011). The efficiency of transmission during sexual intercourse is unknown, but clearly quite high with some estimates indicating a 40% transmission risk per act of intercourse (Burchell et al. 2006). Infection with multiple types of HPV is seen in 20%-30% of infected young men and women. Condom use reduces but does not eliminate the risk of transmission to women. It also appears that male circumcision reduces transmission and carriage of HPV (Winer et al. 2006).
Most women become infected with HPV within several years of initiating sexual activity (Winer et al. 2003; Brown et al. 2005). Cumulative exposure is difficult to measure because most infections are transient and relatively short-lived and serology is an insensitive indicator of exposure since many infected women do not produce measurable levels of antibody (Ho et al. 2004). However, prospective follow-up studies of female college students report that after 5 years of follow-up 80% have been infected at some point with HPV (Winer et al. 2003). Follow-up studies indicate that a frequent pattern of infection in sexually active young women is multiple serial infections with different types of HPV with each infectious episodes being of relatively short duration (Brown et al. 2005).
Development of Cervical Disease After HPV Infection
About one-third of the HPV-DNA-positive women will have a cytological abnormality (Schiffman et al. 2007). The cumulative incidence of minor cytological abnormalities in HPV-infected women with initial normal cytology is 25–50% within 1–2 years. The risk of a cytological abnormality declines to baseline level in the population by 4 years (Castle et al. 2002; Moscicki et al. 2001). Risk factors for HPV persistence and the subsequent development of HSIL are not yet well characterized; however, HPV type is clearly important. HPV 16 infections are especially oncogenic. The 3 year cumulative risk for CIN 3 is approximately 25% for women 25 years and older with a prevalent HPV 16 infection, and the 12 year cumulative risk for CIN 3 is approximately 50% in women with a persistent HPV 16 infection for 2 years (Kjaer et al. 2010; Wright et al. 2015). Risks of persistence and subsequent development of HSIL are also increased for HIV-infected and other immunosuppressed women (Wright and Kuhn 2006).
Because of the insensitivity of colposcopy to detect small lesions, there are limited data on how long it takes for a persistent HPV infection to develop into a HSIL or invasive cancer. Some authors hold the belief that the subsequent development of HSIL and invasive cervical cancer in persistently infected women takes an average of 5–14 years if undetected and not treated (Woodman et al. 2007). Others believe that persistence of a high-risk HPV infection for more than 7 years without the development of HSIL (CIN 3) is uncommon (Moscicki et al. 2012; Castle et al. 2011). The peak prevalence of HPV infection in the population is in the late teens/early 20s, whereas cervical cancer incidence in unscreened populations plateaus from around 35 to 55 years of age. HSIL is consistently more common than are invasive squamous cell carcinomas in unscreened populations, suggesting that only a minority of HSIL develops the capacity to become invasive cancers (Holowaty et al. 1999; Gravitt 2011). Long-term follow-up studies of untreated or partially treated HSIL have found that 30–50% progress to invasive cancer over a 30 year follow-up period (McCredie et al. 2008).
Other Risk Factors
It should be stressed that although infection with specific high-risk types of HPV is necessary for the development of invasive cervical cancer, it is not sufficient for the development of cervical cancer. The long latency between the initial exposure to HPV and the development of cervical cancer as well as the fact that only a small fraction of women exposed to HPV develop cervical disease suggest that additional steps and perhaps other co-factors are necessary in the pathogenesis of cervical neoplasia. It should also be recognized that because of the strength of the association between HPV infection and cervical disease, it is difficult to evaluate the role of other risk factors (Gravitt 2011).
Cigarette smoking has been associated with the development of cervical cancer (Bosch and de Sanjose 2007). In a comprehensive review of the literature, Szarewski concluded that a positive association between cigarette smoking and the development of cervical cancer had been reported by the majority of studies designed to address this question (Szarewski and Cuzick 1998). There are a number of possible mechanisms that could account for an association between cervical cancer and cigarette smoking. One is the secretion of cigarette smoke by-products, including nicotine and cotinine, in cervical mucous of tobacco users and women passively exposed to cigarette smoke (McCann et al. 1992). Another possible mechanism that could account for the association is the effect of cervical smoke by-products on the number and distribution of immune effector and regulatory cells such as Langerhans cells in the cervix (Szarewski et al. 2001).
Multiparity and the use of combined oral contraceptives are also recognized as a significant risk factor for the development of both cervical cancer precursors and invasive cervical cancers. A meta-analysis of 28 studies evaluating the risk of cervical cancer in women on oral contraceptives demonstrated that the relative risk of invasive cervical cancer increased with increasing duration of contraceptive use. After 10 years of use, the summary relative risks for were 2.2 (95% CI. 1.9–2.2) for all women and 2.5 (95% CI. 1.6–3.9) for HPV positive women (Smith et al. 2003). A recent analysis of the 308,036 women enrolled and followed up to 9 years in the European Prospective Investigation into Cancer and Nutrition Study (EPIC) found that increasing number of pregnancies was associated with an increased risk of CIN 3 (Roura et al. 2016). In the EPIC study, the use of oral contraceptives for ≥15 years versus never used was associated with a significant increase in risk of both CIN 3 and invasive cervical cancer (Roura et al. 2016).
Cellular immune responses against HPV clearly play an important role in determining whether HPV infections are ultimately cleared or whether they persist and can develop into cervical neoplasia (Stanley 2012). Immunosuppression is a well-established risk factor for the development of both SIL and cervical cancer. Renal transplant recipients have a relative risk of 13.6 for the development of cervical carcinoma in situ compared to women in the general population (Wright and Kuhn 2006). Infection with human immunodeficiency virus (HIV) is also an important risk factor for SIL and invasive cervical cancer (Denslow et al. 2014). HPV infections are more prevalent and tend to be more persistent in HIV-infected women (McDonald et al. 2014). Numerous studies have documented a higher prevalence of cervical neoplasia including invasive cancer among HIV-infected women compared to various control groups of HIV-uninfected women (Denny et al. 2012). A recent meta-analysis found that prolonged use of antiretrovirals (ART) in HIV-infected women reduces their risk of acquiring HPV as well as reduces their risk of SIL (Kelly et al. 2018).
Clinical Features
SIL appears to be somewhat more frequently detected on the posterior lip of the cervix compared to the anterior lip of the cervix and is rarely seen at the lateral cervical angles (Pretorius et al. 2006; Guido et al. 2005). SIL may expand horizontally and involve the entire transformation zone, but it usually does not extend onto the native portio epithelium. The endocervical extension of SIL is not restricted and extension along the entire endocervical canal and into the uterus can rarely occur. The size and endocervical distribution of SIL tend to vary directly with increasing severity of lesion grade. HSIL usually has the largest surface area and more frequently involves the endocervical canal.
Pathologic Findings
SIL is characterized by abnormal cellular proliferation, abnormal maturation, and cytologic atypia. The cytologic abnormalities include hyperchromatic nuclei, abnormal chromatin distribution, nuclear pleomorphism, and increased nuclear: cytoplasmic ratio. Nuclear atypia is the hallmark of SIL. The nuclear borders are irregular, and the chromatin is coarse, granular (salt and pepper), or filamentous throughout the nuclear mass.
Low-Grade Squamous Intraepithelial Lesion
Differential Diagnosis
Variability in histopathological diagnoses in ALTS
Quality control panel review diagnosis
Initial Dx
LAST recommendations for the use of p16 immunostaining (Darragh et al. 2012)
1. p16 IHC is recommended when the H&E differential diagnosis is between HSIL and a mimic of HSIL (such as immature squamous metaplasia, atrophy, reactive epithelial changes, tangential cutting)
Positive p16 staining supports a diagnosis of HSIL
2. Whenever a pathologist is entertaining a H&E diagnosis of HSIL (CIN 2), p16 IHC is recommended to help clarify the diagnosis
Positive p16 staining supports a diagnosis of HSIL. Negative staining supports a diagnosis of LSIL or a non-HPV associated lesion
3. p16 IHC is recommended as an adjudication tool for cases in which there is professional disagreement in histologic specimen interpretation
With the caveat that the disagreement includes HSIL
4. It is recommended against the use of p16 IHC as a routine adjunct to histological assessment of biopsy specimens with morphologic interpretations of normal, LSIL, and HSIL (CIN 3)
LAST also reviewed the clinical utility of other potential biomarkers including IHC with Ki-67 and a less widely used biomarker ProEx C. They concluded that there was insufficient evidence to recommend the routine use of these markers when diagnosing cervical tissue samples (Darragh et al. 2012). When used in combination with p16 IHC, the overall improvement in performance obtained by combining additional biomarkers was minimal compared to p16 alone. Nevertheless, many pathologists use Ki-67 IHC when interpreting difficult cervical biopsies. Ki-67 is a marker of cellular proliferation which shows staining in the upper two-thirds of the epithelium in SIL, whereas normal squamous epithelium typically shows only limited staining in the parabasal cell layers, Figs. 26c and 27c (Queiroz et al. 2006b; Isacson et al. 1996). However, unlike p16, Ki-67 staining may be positive in HPV-negative squamous metaplasia and reactive/reparative conditions which reduces its usefulness in differentiating these conditions from SIL.
High-Grade Squamous Intraepithelial Lesion
Distinguishing features of LSIL and HSIL
Lower third
Upper two-thirds
HPV types
Any anogenital HPV
High-risk typesa
Frequently present
Occasionally present
Mostly diploid or polyploid
Usually aneuploid
Abnormal mitotic figures
Location of undifferentiated cells and mitotic figures
Lower third
Upper two-thirds
Differential Diagnosis
Behavior of SIL
Before discussing the behavior of SIL, it is important to emphasize that most natural history studies were conducted in the 1970s and 1980s prior to our enhanced understanding of the role of HPV in the pathogenesis of cervical cancer and the realization that LSIL is simply a cytological and histological marker for a productive HPV infection. Moreover, over the last decade we have come to realize that not only is the interpretation of cervical biopsies and cytology subjective and prone to considerable error, but also that colposcopy is much less accurate than previously thought (Massad 2006; Waxman et al. 2017; Pretorius et al. 2011). Nevertheless, the older natural history studies remain important because they provide insight into both the likelihood that a woman with SIL will spontaneously clear her lesion and the likelihood that she will develop an invasive cervical cancer. Since these studies used the dysplasia/CIS or CIN terminology, in this section those terms will be retained in order to accurately describe the findings from these studies. Two approaches have been used to determine the natural history of SIL. These are prospective, clinical follow-up studies of individual women with cervical lesions and epidemiological studies linking cytology records with cancer registries. Prospective clinical follow-up studies of the "natural history" or behavior of SIL have provided widely varying estimates of the rate of progression and regression the different lesions. This is not surprising since various studies have used different entry criteria, different diagnostic criteria for categorizing lesions as SIL, and different study designs. For example, some studies have used punch biopsy and endocervical curettage to establish the diagnosis. These diagnostic methods may remove (treat) lesions and therefore may interfere with long-term analysis by increasing the frequency of spontaneous regression and decreasing the frequency of progression (Nasiell et al. 1983).
Natural history of CIN is dependent of lesional grade
% Regression
% Persist
Progress to CIS
Toronto long-term follow-up of abnormal cervical cytology
Grade of lesion
2 years (%)
10 years (%)
Regression ratesa
Mild dysplasia
Moderate dysplasia
Progression ratesb
Mild dysplasia
Moderate dysplasia
Severe dysplasia
What these studies show is that the vast majority of LSIL spontaneously regress in the absence of treatment and the risk that a woman with a LSIL will be subsequently diagnosed with either carcinoma in situ or invasive cervical cancer is relatively low. They also demonstrate that the likelihood that HSIL will regress in the absence of treatment is higher than many clinicians realize and that it generally takes many years for a HSIL to progress to an invasive carcinoma.
Precursors of Cervical Adenocarcinoma
Terminology and Historical Perspective
The first indication that precursor lesions for invasive endocervical adenocarcinomas exist came in 1952 when Helper described highly atypical neoplastic cells lining architecturally normal endocervical glands adjacent to frankly invasive endocervical adenocarcinomas (Helper et al. 1952). Shortly thereafter, Friedell and McKay described two patients with atypical glandular lesions of the cervix and designated these lesions adenocarcinoma in situ (AIS) because of their histologic resemblance to invasive endocervical adenocarcinoma (Friedell and McKay 1953). One of these patients had a coexistent invasive adenocarcinoma of the cervix and one, squamous "carcinoma in situ."
By analogy to squamous cell cervical cancer precursors, some authors have proposed parallel classification schemas for endocervical adenocarcinoma precursors which include lesions with a lesser degree of abnormality than AIS (Bousfield et al. 1980; Brown and Wells 1986; Genest et al. 1993; Luesley et al. 1987). Such low-grade putative glandular precursor lesions were originally termed endocervical dysplasia by Bousfield et al., but other terms such as atypical hyperplasia are also used to refer to lesions which resemble AIS, but have a somewhat lesser degree of nuclear atypia and mitotic activity (Hopkins et al. 1988; Bousfield et al. 1980). Gloor and associates suggested that the term cervical intraepithelial glandular neoplasia (CIGN) be used to refer to both endocervical glandular dysplasia and AIS and that endocervical glandular dysplasia be classified as either CIGN grade 1 or 2 and AIS be classified as CIGN grade 3 (Genest et al. 1993). The term endocervical glandular dysplasia has been used to describe a "glandular lesion characterized by significant nuclear abnormalities that are more striking than those in glandular atypia, but fall short of the criteria for adenocarcinoma in situ" (Tavassoli and Devilee 2003). However, several different diagnostic criteria have been proposed for this entity and there is not widespread acceptance of any of them (Ioffe et al. 2003; Gloor and Hurlimann 1986a; Jaworski 1990). Because of the relative rarity of endocervical glandular dysplasia, the subjective nature of the morphologic criteria used to distinguish it from AIS, and the infrequent coexistence of endocervical glandular dysplasia with AIS, the significance of endocervical glandular dysplasia is not known and a number of authors question that it even exists as a discrete entity (Goldstein et al. 1998; Lee 2003; Loureiro and Oliva 2014). A number of studies have utilized objective biomarkers including HPV DNA positivity, proliferation markers such as Ki-67/MIB-1, p16, and selective mucin staining to determine whether endocervical glandular dysplasia acts as a precursor to AIS or invasive endocervical adenocarcinoma (Anciaux et al. 1997; Lee et al. 2000; Gloor and Hurlimann 1986b; Riethdorf et al. 2002; Tase et al. 1989a; Baker et al. 2006; Murphy et al. 2004; Leary et al. 1991; Higgins et al. 1992). Although some of these studies have shown a similar pattern of biomarker expression in both endocervical glandular dysplasia and AIS, most studies have not (Lee 2003; Ioffe et al. 2003; Goldstein et al. 1998; Riethdorf et al. 2002). Investigators who advocate the use of endocervical glandular dysplasia do so under the misguided notion that there is a similar relationship of glandular precursors to HPV infection as there is for squamous precursor lesions. As previously discussed the histologic manifestation of productive viral infection is LSIL. Productive HPV infection is tightly linked to squamous differentiation. Glandular epithelium does not support productive infection. Accordingly, there is no comparable low-grade lesion in glandular epithelium. Since the term glandular dysplasia implies a relationship to AIS and invasive carcinoma which does not exist, the use of this term should be discontinued. Instead atypical glandular proliferations that fall short of AIS should be evaluated using biomarkers such as p16 and Ki-67 and classified as reparative changes if they are p16 negative and show a low Ki-67 labeling index. In contrast, if they express p16 strongly and diffusely and show a high Ki-67 proliferation index, they are classified as AIS. The 2014 World Health Organization classification discusses the term endocervical glandular dysplasia which it states is synonymous with low-grade CIGNA but further comments that it is a poorly reproducible diagnosis for which criteria are not well defined (Kurman et al. 2014). It also recommends that IHC be performed and if the profile matches that AIS that the lesion be classified as AIS for management purposes.
Epidemiology and Etiology
Over the last three decades, endocervical glandular lesions have received increasing attention. This is attributable to a variety of factors. One is a perception that the prevalence of adenocarcinomas of the cervix and its precursor lesions is increasing. There has been a documented absolute increase in the prevalence of invasive adenocarcinomas in specific groups of women in both the United States and Europe. This may be due, in part, to the routine use of cytobrushes and HPV testing in screening and the widespread adoption of excisional methods for treating SIL such as the loop electrosurgical excision procedure (LEEP) which permit pathological examination of the entire transformation zone. In addition, there is an increased awareness of these lesions by pathologists and an awareness by colposcopists that certain types of glandular lesions are difficult to recognize colposcopically.
The prevalence of AIS is not well understood, but it is considerably less common than SIL. In most registry series, the ratio between AIS and HSIL has ranged from 1:26 to 1:237. Estimates for the United States as a whole are available in the Surveillance Epidemiology and End Results (SEER) public database that contains data from patients entered into the database between 1976 and 1995, which is the last year that in-situ carcinomas were reported to the database (SEER 2001; Wang et al. 2004a). In the SEER registry, there were a total of 149,178 women with either in situ or invasive cervical cancer. Of these, 96% had squamous lesions and 4% had glandular lesions. 121,793 (82%) of all cervical lesions were classified as in situ and of these, 120,317 (99%) were squamous cell carcinoma in situ, and only 1,476 (1%) were adenocarcinoma in situ. For comparison, of the 27,385 women with invasive cervical cancer, 4,369 (16%) had invasive adenocarcinoma. In 1991–1995 the age-adjusted incidence rate in the SEER database for squamous carcinoma in situ in White women was 27.93 cases per 100,000, whereas the age-adjusted incidence rate for AIS was only 1.25 per 100,000 (Plaxe and Saltzstein 1999; Wang et al. 2004a). Although the overall incidence of AIS remains quite low, the incidence increased approximately six fold in the USA from the 1970s to the 1990s (Wang et al. 2004a). Because AIS is no longer reported, we do not know if the incidence has continued to increase over the last two decades. However, a recent registry study from the Netherlands has reported a significant increase in the incidence of AIS between 2004 and 2013 (van der Horst et al. 2017). The increase in incidence occurred predominantly in women 25–39 years of age and 59% of the cases had a concomitant SIL. Recently, baseline data from two large US cervical cancer screening studies have been published (Wright et al. 2012; Stoler et al. 2018). Both studies referred all women 25 years and older who were HPV or cytology positive to colposcopy and required that a cervical biopsy and/or endocervical curettage be obtained. In one study 16 cases of adjudicated AIS were detected among the 42,695 subjects (37.5 cases per 100,000 women); in the other study 9 cases were detected among the 28,110 subjects (32.0 per 100,000 women). For comparison, the rate of adjudicated HSIL (CIN 3) in the two studies was 594.9 per 100,000 and 569.2 per 100,000, respectively, which gives an AIS to HSIL (CIN 3) ratio in the range of 1:15. The rates of AIS in these two contemporary studies are an order of magnitude higher than rates reported in the 1990s from SEER which is not unexpected given the perception of many pathologists that they have been diagnosing increasing numbers of AIS over the last two decades. Moreover, these two studies are unique in that they referred all HPV-positive women to colposcopy and included histologic sampling in all women.
The age relationship between AIS and invasive adenocarcinoma is similar to that of HSIL and invasive squamous cell carcinoma, suggesting that AIS is a precursor lesion (Plaxe and Saltzstein 1999). AIS rates peak at age 35–44 years in both White and Black women (Wang et al. 2004a). However, unlike squamous lesions of the cervix in which high-grade precursors occur more frequently than invasive cancer, exactly the opposite relationship exists for AIS and invasive adenocarcinoma of the cervix. The incidence of invasive glandular lesions is higher than that of noninvasive glandular lesions in all age groups (Plaxe and Saltzstein 1999). A number of reasons have been proposed for this apparent discrepancy including the fact that AIS is more difficult to detect both cytologically and colposcopically than is SIL and, therefore, might not be detected prior to the development of invasive adenocarcinoma. Additional support implicating AIS as a precursor of invasive adenocarcinoma comes from several anecdotal case reports and two small series of patients who had cytologic or histologic evidence of AIS several years prior to the detection of invasive adenocarcinoma (Boddington et al. 1976; Boon et al. 1981; Kashimura et al. 1990). Although these studies have been interpreted as indicating that AIS is a precursor lesion, it is conceivable that an unrecognized invasive cancer was present at the time of the original Pap test or cervical biopsy.
Clinical Features
The average of women with AIS is 37 years based on a meta-analysis of multiple studies that included 1278 women undergoing treatment (Salani et al. 2009). Most women with AIS are asymptomatic and the lesions are detected either during screening or fortuitously on an endocervical curettage, cervical punch biopsy, cone or loop excisional biopsy performed during the workup for SIL. In women who are symptomatic, the most common complaint is abnormal vaginal bleeding, either postcoital, postmenopausal, or out of phase. Rarely, symptomatic patients present with an abnormal discharge. AIS is difficult to detect both cytologically and colposcopically (Duska 2009; Renshaw et al. 2004). In one early study of 42 women with histologically confirmed AIS, only 45% of the women had atypical glandular cells detected on the preceding cervical cytology (Denehy et al. 1997). The other cases were detected fortuitously on biopsies taken to evaluate SIL. A similar sensitivity of about 50% was found in a retrospective review of previous cytology specimens in histologically confirmed cases of AIS reported to the Australian cancer registry (Ruba et al. 2004). In the Gardasil HPV vaccine trials, a total of 22 subjects with AIS were identified and only 2 of the 22 (10%) had a preceding cervical cytology suggestive of glandular neoplasia (Ault et al. 2011). In the largest study to date, Umezawa et al. reviewed 140 prior cervical cytology specimens from 74 women with AIS (Umezawa et al. 2015). The sensitivity of the original cytology was only 45%. After review by 6 independent cytopathologists diagnostic accuracy increased to 79%. Almost identical results were found in an European multicenter treatment trial of AIS in which only 40% of the referral cytology results were consistent with a glandular lesion (Costa et al. 2012). In that trial 24% of the colposcopies in women with AIS were considered negative.
The distribution of AIS in the cervix is important for determining the clinical management. AIS typically involves both the epithelial surface and endocervical glands or crypts, but in some cases it can be limited to the glands and rarely it can be limited to the surface epithelium (Witkiewicz et al. 2005). Cases confined to the surface epithelium present at a younger average age than cases that involve endocervical glands or crypts, and it has been postulated that they may represent the earliest form of AIS (Witkiewicz et al. 2005). AIS confined to the surface can be quite easily overlooked since they are often small and have less pronounced cytologic atypia and mitoses than the AIS that involves endocervical glands or crypts. In 65% of cases, AIS involves the transformation zone (Andersen and Arffmann 1989; Bertrand et al. 1987) and in the majority of cases it is unifocal. However, AIS can extend for a distance of up to 3 cm. into the endocervical canal and occasionally it can be multicentric with skip lesions in the endocervical canal where foci of AIS are separated from each other by normal endocervical tissue (Bertrand et al. 1987; Cullimore et al. 1992).
The identification of AIS in biopsies and on endocervical curettage can be challenging. One of the first large case series of AIS found that despite colposcopy, cervical biopsy, and endocervical, curettage almost a third of the cases were only identified after conization (Andersen and Arffmann 1989). In the recent European multicenter study that evaluated specimens from 3979 women originally diagnosed with high-grade precancer, 65 cases were diagnosed as AIS at the original institution (Holl et al. 2015). However, only 26 (40%) of these cases were confirmed as AIS by expert pathology review. Moreover, an additional 23 cases of AIS that had not been diagnosed at the original institution were identified during expert review.
Pathologic Findings
Differential Diagnosis
Invasion should be suspected if the involved glands extend beyond the glandular field or beyond the deepest uninvolved endocervical crypt. In addition, in AIS there should be no desmoplasia or stromal reaction around the involved glands. Other worrisome features that can be associated with invasion are exuberant glandular budding, an extensive cribriform pattern, foci in which the glands become confluent or back-to-back and the formation of papillary projections from the endocervical surface (Kudo et al. 1991; Ostor et al. 2000).
Clinical Behavior and Treatment
Due to the relative rarity of AIS, no natural history studies have been published and therefore the evidence that these lesions are precursors for invasive endocervical adenocarcinoma remains circumstantial. Despite this, until recently it was believed that women with AIS should undergo hysterectomy because there were numerous reports in the literature of persistent AIS or invasive disease occurring after conservative management of AIS with conization (Kennedy and Biscotti 2002; Muntz 1996). Because AIS most often occurs in young women who may be desirous of preserving their fertility, there has been a movement towards managing these women conservatively with conization, either cold-knife, large loop electrosurgical excision (LEEP), or laser (Massad et al. 2013a; Costa et al. 2012; Munro et al. 2017). There have been a number of series of patients with AIS who have been followed after cone biopsy. These studies have generally shown low rates of recurrence among women treated by means of a cone biopsy, provided the endocervical margin is negative. In the European multicenter trial of treatment of AIS with conization, 12.6% of patients were diagnosed during follow-up with AIS/SIL or invasive carcinoma (Costa et al. 2012). The most important risk factor for recurrence after conization is margin status (Munro et al. 2017; Costa et al. 2012; Goldstein and Mani 1998; Wolf et al. 1996; Salani et al. 2009). Women with positive endocervical margins are at significant risk for having an undiagnosed invasive cervical adenocarcinoma or for developing recurrent AIS. Although residual disease has been reported in up to 40% of patients with uninvolved margins, this can increase to up to 80% if the margin is involved (Costa et al. 2012). A 2009 meta-analysis found that of 671 patients followed after conization with surveillance only, 26% of women with negative margins developed recurrent disease, but only 0.1% developed invasive adenocarcinoma (Salani et al. 2009). The meta-analysis found that invasive adenocarcinoma was detected in 5.2% of patients with positive margins. Other factors for residual or recurrent disease are age >30 years, pure AIS (e.g., no coexistent HSIL), and larger lesions (>8 mm) (Munro et al. 2017; Costa et al. 2012). Based on these studies, conservative management by cone biopsy alone is now considered to be an option in women with AIS desirous of maintaining their fertility, if the cone biopsy margins are negative.
Cervical Cytology
Strengths and Limitations of Cervical Cytology
Although it was introduced over a half century ago, cervical cytologic screening continues to be one of the most effective cancer prevention test available. Over the half century since it was introduced, so much epidemiological and modeling data have accumulated demonstrating the effectiveness of cytology that it has become the index by which all other cancer screening tests are compared. Cytologic screening performed only twice in a woman's lifetime can reduce her risk for invasive cervical cancer by up to 43% and yearly screening is estimated to reduce a woman's risk by over 90% (Parkin 1991; Goldie et al. 2004). However, despite the effectiveness of cytologic screening, it is important to remember that no screening, diagnostic, or therapeutic technique used in medicine is perfect, and cervical cytology is no exception. Some women will develop invasive cervical cancer, despite routine cytologic screening.
Over the last decades numerous advances have been made in cervical cytology collection techniques, how cytological preparations are evaluated, and the classification systems used for reporting cytologic diagnosis. One of the most important advances has been the introduction of liquid-based cytology. With liquid-based cytology, the cells collected from the cervix are transferred directly to a liquid fixation solution that is shipped to the cytology laboratory where the slide is prepared. One of the primary advantages of liquid-based cytology is that molecular testing for sexually transmitted infections such as HPV DNA, chlamydia, N. gonorrhea can be performed directly from liquid-based specimens. HPV testing is particularly useful when a diagnosis of ASC-US is made (i.e., "reflex" HPV DNA testing).
The Bethesda System (TBS) Terminology
The Bethesda System 2014 Classification (Nayar and Wilbur 2015)
Specimen type:
Indicate conventional smear (Pap smear) versus liquid-based preparation versus other
Specimen adequacy:
Satisfactory for evaluation
Unsatisfactory for evaluation (specify reason)
General categorization (optional)
Negative for intraepithelial lesion or malignancy
Other: See interpretation/result
Epithelial cell abnormality: See interpretation/result (specify "squamous" or "glandular" as appropriate)
Negative for intraepithelial lesion or malignancy
Nonneoplastic findings (optional to report)
Nonneoplastic cellular variations
Reactive cellular changes
Glandular cells status posthysterectomy
Endometrial cells (in a women > 45 yrs of age)
Epithelial cell abnormalities
Squamous cell
Atypical squamous cells
– Of undetermined significance (ASC-US)
– Cannot exclude HSIL (ASC-H)
Low-grade squamous intraepithelial lesion (LSIL) (encompassing: HPV/milddysplasia/CIN1)
High-grade squamous intraepithelial lesion (HSIL) (encompassing: moderate and severe dysplasia, CIS: CIN 2 and CIN 3)
Squamous cell carcinoma
Glandular cell
– Endocervical cells (NOS or specify in comments)
– Endometrial cells (NOS or specify in comments)
– Glandular cells (NOS or specify in comments)
– Endocervical cells, favor neoplastic
– Glandular cells, favor neoplastic
Endocervical adenocarcinoma in situ
– Endocervical
– Endometrial
– Extrauterine
– Not otherwise specified (NOS)
Other malignant neoplasms: (specify)
Adjunctive testing:
Provide a brief description of the test method(s) and report the result so that it is easily understood by the clinician
Computer-assisted interpretation of cervical cytology
If case examined by an automated device, specify device, and result
Educational notes and comments appended to cytology reports (optional)
Cytological Appearance of Cervical Cancer Precursors
The Bethesda System classification categorizes precursors to cervical cancer as "epithelial cell abnormalities." The category "epithelial cell abnormalities" is subdivided into abnormalities of squamous cells and abnormalities involving glandular cells, either endocervical or endometrial. Cytological changes previously classified as mild squamous cytological atypia and atypical endocervical cells are also included in this category.
Squamous Cell Abnormalities
Atypical Squamous Cells (ASC)
The ASC category is used to designate cytological changes suggestive of a squamous intraepithelial lesion (SIL) that are quantitatively or qualitatively insufficient for a definitive diagnosis of SIL (Workshop 1991; Solomon et al. 2002; Nayar and Wilbur 2015). There are several points that need to be made with respect to ASC. First, a diagnosis of ASC is one of exclusion; the cells are abnormal, but they do not warrant a diagnosis of SIL. Second, a diagnosis of ASC should not be used when the underlying process is inflammatory or reactive, such slides should be carefully reviewed and classified as "negative for intraepithelial lesion or malignancy" whenever possible rather than ASC. Third, although the ASC category is sometimes disparagingly referred to as a "cytological wastebasket," there are specific criteria that should be used for making this diagnosis. If these criteria are adhered to, the median rate of ASC in US laboratories is approximately 5% of all cytology specimens and the ASC rate should be no more than twice the SIL rate (Eversole et al. 2010).
The 2014 Bethesda System subdivides the ASC category into two subdivisions: Atypical Squamous Cells – Undetermined Significance (ASC-US) refers to samples in which the cytological changes are suggestive of LSIL but lack sufficient cytological abnormalities to allow a definitive diagnosis, and Atypical Squamous Cells – Cannot Exclude an HSIL (ASC-H) refers to samples in which the cytological changes are suggestive of HSIL, but the cytological abnormalities are insufficient to allow a definitive interpretation (Sherman et al. 1999).
Criteria used to diagnosis atypical squamous cells (ASC)
Atypical squamous cells – undetermined significance (ASC-US)
Cells resemble superficial or intermediate squamous cells in size and configuration
Nuclei are 2.5–3 times the size of a normal intermediate cell nuclei or 2 times the size of a metaplastic cell nucleus
Nuclei are round to oval with minimal irregularities
Nuclei are normochromatic to slightly hyperchromatic
Atypical squamous cells – cannot exclude HSIL (ASC-H)
Small cells with high N/C ratios
Cells resemble parabasal or basal cells in size and configuration, but the nucleus is 1.5–2.5 times larger resulting in a high N/C ratio
Cells occur singularly or in small groups
Nuclei often have uneven chromatin and are hyperchromatic
Nuclear contour is often irregular
Crowded sheet pattern
Crowded clusters of cells resembling parabasal or basal cells with atypical nuclear features including hyperchromasia and high N/C ratios
Cells have a loss of polarity and can be difficult to visualize
It should be emphasized that the degree of nuclear changes considered sufficient to warrant a diagnosis of ASC-US is highly subjective and varies between cytologists. This introduces a degree of uncertainty with respect to a diagnosis of ASC-US, and studies have shown that a diagnosis of ASC-US is the least reproducible of all cytological diagnoses (Confortini et al. 2003, 2007; Gatscha et al. 2001). Approximately 3–5% of women with a diagnosis of ASC-US will have histologic HSIL (CIN 3) when colposcopy is performed (Stoler et al. 2013; Stoler et al. 2011; Tewari et al. 2017).
ASC-H is an uncommon finding and typically accounts for less than 10% of all ASC diagnoses. The median reporting rate of ASC-H in the US laboratories in 2006 was 0.3% according to the College of American Pathologists (CAP) survey (Eversole et al. 2010). The majority of women with ASC-H are high-risk HPV DNA positive, and histologic HSIL is identified at the time of colposcopy in 12–68% of women with ASC-H (Sherman et al. 1999; Bandyopadhyay et al. 2008; Liman et al. 2005). Because of the high prevalence of histologic HSIL in women with ASC-H, it has been suggested that ASC-H would be more appropriately referred to as "equivocal HSIL" (Wright et al. 2007).
Low-Grade Squamous Intraepithelial Lesions (LSIL)
With cytology methods such as liquid-based cytology and computerized imaging systems, the rate of LSIL appears to be increasing in the USA. In surveys taken in the 1990s the median reporting rate of LSIL in US laboratories was 1.6%, but by 2006 this has increased to 3% (Jones and Davey 2000; Eversole et al. 2010). A recent report of the impact of implementing a computerized cytology imaging system in a tertiary military center reported that after implementation the rate of LSIL increased from 2.6% to 3.9% (Duby and DiFurio 2009). Age is an important factor in determining the prevalence of LSIL. In a large US screening trial, the prevalence of LSIL decreased from 6.5% in women 21–24 years of age to 3.8% in women 25–29 years and then to 1.4% in women 40–49 years (Wright et al. 2012).
High-Grade Squamous Intraepithelial Lesions (HSIL)
Criteria used to diagnosed squamous epithelial cell abnormalities
Bethesda System
CIN terminology
Older terminology
Mild dysplasia
Mod. dysplasia
Severe dysplasia
Cell type
Superficial or intermediate
Basal, spindle, pleomorphic
Cell arrangement
Singly or sheets
Singly or sheets
Singly or sheets
Singly or sheets or syncitia
Number abnormal cells
Nuclear size
Nuclear:cytoplasmic ratio
The number of abnormal cells that are present can vary dramatically case to case. When only a few small HSIL cells of the basal cell type are present, it can be quite challenging to correctly classify the case as a HSIL, and these cases account for a disproportionate percentage of false negative cervical cytology. According to the College of American Pathologists (CAP) 2006 survey, the median reporting rate of HSIL in US laboratories was 0.6% (Eversole et al. 2010). The rate of HSIL varies with age. In a large US screening trial, the prevalence of HSIL decreased from 0.7% in women 21–24 years of age to 0.4% in women 25–29 years and then to 0.2% in women 40–49 years (Wright et al. 2012). A diagnosis of HSIL connotes a high risk for significant cervical disease. Histologic HSIL is found in approximately 60% of women with HSIL (Massad et al. 2013b).
Invasive Squamous Cell Carcinoma
Glandular Cell Abnormalities
In the 2014 Bethesda System, all types of glandular cell abnormalities, including both atypical endocervical and endometrial cells, are combined together in a single entity referred to as glandular cell abnormalities. Benign appearing endometrial cells occurring in postmenopausal women are classified as "other." Glandular cell abnormalities are divided into three categories: atypical glandular cells, either unqualified or favor neoplastic; adenocarcinoma in situ; and invasive adenocarcinoma.
Atypical Glandular Cells (AGC)
All atypical glandular cells lacking the diagnostic features of adenocarcinoma, irrespective of whether they are of endometrial or endocervical origin, are classified by the 2014 Bethesda System as atypical glandular cells with a specification as to whether they are endocervical, endometrial, or of uncertain origin. There are two categories of AGC. The first is atypical glandular cells (either endocervical, endometrial, or unclassified) that are not qualified and the second is atypical glandular cells; favor neoplastic.
Glandular cytological abnormalities are considerably less common than squamous abnormalities, and most cytologists tend to be less comfortable recognizing and diagnosing them. In addition, the criteria used to differentiate reactive endocervical changes, endocervical dysplasia, endocervical adenocarcinoma in situ and invasive endocervical adenocarcinoma are less well established than those used for squamous lesions. Cytologists even have difficulty in differentiating atypical endocervical cells from cases of HSIL that have extended into endocervical crypts. This accounts for the high prevalence of squamous abnormalities (approximately 30%) detected in women referred for AGC to colposcopy (Kim et al. 1999; Ronnett et al. 1999).
Adenocarcinoma In Situ
Management of Cytologic Abnormalities and Cervical Cancer Precursors
In 2012 the American Society for Colposcopy and Cervical Pathology sponsored a consensus workshop to update prior Consensus Guidelines for the Management of Women with Cytological Abnormalities and Cervical Cancer Precursors (Wright et al. 2007; Massad et al. 2013a). These guidelines are widely used in the USA and are evidence-based with each recommendation accompanied by a grading of both the strength of the recommendation and the strength of the data supporting the recommendation. What follows is a brief synopsis of the guidelines. The complete recommendations and management algorithms are available at www.asccp.org.
Atypical Squamous Cells (ASC)
The prevalence of biopsy-confirmed HSIL among women undergoing colposcopy for an ASC cytology varies from 5% to 17% (Wright et al. 2007; Stoler et al. 2011, 2013). The prevalence of HSIL in women with ASC depends on a number of factors including the patient's age, history, and the subclassification of the ASC result. Overall, it appears that approximately half of women with histologic HSIL have ASC as their initial abnormal cervical cytology result (Lonky et al. 1999; Kinney et al. 1998). However, it should be noted that the risk that a woman with ASC has invasive cervical cancer is quite low (about one per thousand).
Atypical Squamous Cells: Undetermined Significance (ASC-US)
Atypical Squamous Cells: Cannot Exclude HSIL (ASC-H)
ASC-H is a much more concerning cytology result than ASC-US since biopsy-confirmed HSIL is identified in 13% to 66% of women with ASC-H (Xu et al. 2016). Thus for the purposes of management, ASC-H should be considered to be an equivocal HSIL result and all women with ASC-H should be referred for a colposcopic evaluation (Massad et al. 2013a). If after colposcopy the patient has histologic LSIL or less, follow-up utilizing either repeat cotesting at 12 and 24 months, a loop electrosurgical excision (LEEP), or review of the cytological, histological, and colposcopic findings is acceptable.
Low-Grade Squamous Intraepithelial Lesions (LSIL)
High-Grade Squamous Intraepithelial Lesions (HSIL)
Histologic LSIL
Histologic HSIL
Women with histologic HSIL (CIN 3) are at significantly high risk of progressing to invasive cervical cancer and therefore treatment is recommended. Provided the colposcopic examination is satisfactory and there is no suggestion of invasive disease (e.g., by either colposcopy, cytology, or histology), both ablative or excisional treatment modalities are considered acceptable forms of treatment (Massad et al. 2013a). A diagnostic excisional procedure is recommended for all women with histological HSIL and unsatisfactory colposcopic examination or with recurrent disease. The management of women with histologic HSIL (CIN 2) is controversial and recommendations vary between countries. It is clear that regression rates and progression rates to invasive cervical cancer are lower in women with histologic HSIL (CIN 2) than in women with HSIL (CIN 3) (Tainio et al. 2018; Ostor 1993; Moscicki et al. 2010; Silver et al. 2018). In the USA follow-up is recommended for women desirous of maintaining childbearing capacity with histologic HSIL or HSIL (CIN 2), but treatment is considered acceptable (Massad et al. 2013a). For all other women, treatment is recommended.
Endocervical Curettage
In most instances, when atypical epithelium is detected in the endocervical curettage, it lacks underlying stroma and orientation is not possible. As a result, the pathologist can neither rule out underlying invasion nor grade an intraepithelial lesion. In other cases, where the atypical epithelium is well oriented, the pathologist is able to grade the lesion and can, if desired. It is also helpful if the pathologist conveys an estimate of the amount of atypical epithelium that is present in the endocervical curettage. If only a few small fragments of atypical epithelium are present in the endocervical curettage, these may represent "pick-ups" from a lesion that is actually confined to the portio and does not extend into the endocervical canal. In such cases it may be preferable to reexamine the patient with the colposcope rather than proceeding directly with a diagnostic excisional procedure. Frequently the second, carefully performed curettage yields no atypical epithelium and the patient may be managed on a conservative, outpatient basis. Conversely, the pathologist should be careful not to discount or overlook a few or even a single fragment of atypical epithelium in an endocervical curettage. In a review of 21 women who developed invasive cancer after cryotherapy, 7 out of 18 endocervical curettages taken before cryotherapy were found on review to contain SIL that had been missed at the time of original diagnosis (Schmidt et al. 1992).
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