Berek and Hacker's Gynecologic Oncology - (Section II Disease Sites)

low resource settings are likely to result from the lack of organized cervical screening
and inadequate access to treatment. In many developed countries, screening with cervical
cytology has resulted in large-scale reductions in cervical cancer incidence and mortality
over time (4,5).
The primary goal of cervical screening is to prevent cervical cancer. This is achieved by
the detection, treatment and follow-up of preinvasive cervical lesions (6,7). Modern
understanding that almost all cervical cancers are caused by persistent infection with
approximately 15 types of HPV has led to important new approaches to primary and
secondary prevention via prophylactic HPV vaccination (8,9) and primary HPV-based
screening (9,10).
Classification of Preinvasive Cervical Disease

The proposal that invasive squamous carcinoma of the cervix arises through progression of a
preinvasive lesion, as opposed to a de novo event, was initially postulated by Schauenstein in
1908 (11). The term “carcinoma in situ” was later introduced to describe cancerous changes
confined to the epithelium (12). It is now understood that precancerous lesions arise from
persisting HPV infection of the cervix, even though the majority of HPV infections regress
(13).
The Dysplasia Terminology

Although referred to earlier by Papanicolaou and Traut (14), Reagan and Hamonic (15)
described cytologic differences between “carcinoma in situ” and a group of “less anaplastic”
lesions in 1956 and introduced the term dysplasia in 1962 (16). In 1975, the World Health
Organization (WHO) defined dysplasia as a “lesion in which part of the epithelium was
replaced by cells showing varying degrees of atypia.” Dysplastic changes were graded as
mild, moderate, and severe, but precise guidelines for these subdivisions were not defined
and grading always remained highly subjective (17–19).
A dual terminology developed, leading to inconsistencies in treatment policies. If a diagnosis

Copyright © 2020. Wolters Kluwer Health. All rights reserved.
of “dysplasia” was made, this was considered a nonspecific change and the patient was
subjected to a cone biopsy. If the diagnosis of “carcinoma in situ” was made, this was
considered a “preinvasive cancer” and the patient underwent an obligatory hysterectomy
(20).
Cervical Intraepithelial Neoplasia

In 1969, invasive squamous cell carcinoma of the cervix was demonstrated to be the
result of progressive intraepithelial dysplastic atypia occurring within the metaplastic
Berek, J, & Hacker, NF 2020, Berek and Hacker's Gynecologic Oncology, Wolters Kluwer Health, Philadelphia. Available from: ProQuest Ebook Central. [15 December 2023].
Created from cvtisr-ebooks on 2023-12-15 12:39:21.
epithelium of the cervical transformation zone (TZ) (21). The classification of lesions
from mild dysplasia to carcinoma in situ did not truly reflect either the morphologic or
biologic continuum of preinvasive cervical disease. The diagnosis was highly subjective and
was not reproducible.
After pioneering research into the natural history of cervical cancer precursors, Richart (22)
proposed the term “cervical intraepithelial neoplasia” (CIN) in 1973 to describe the
biologic spectrum of cervical preinvasive squamous disease. Three grades of CIN were
described, CIN 1 (mild dysplasia), CIN 2 (moderate dysplasia), and CIN 3 (severe
dysplasia/carcinoma in situ). This system was consistent with biologic evidence that strongly
implied a single process of cervical squamous carcinogenesis (23–28).
Fifty years’ experience with the CIN terminology, coupled with advanced understanding of
the role of HPV in the causation of cervical neoplasia (29–34), has led to a critical reappraisal
of this model and to further reclassification of the terminology for reporting cytologic
abnormalities consistent with preinvasive disease (35–40).
The CIN grading is very subjective. No reproducible cytologic or histologic distinction

at the lower end of the CIN continuum exists between CIN 1 and HPV infection alone.
Both inter- and intraobserver consistency in diagnosis are poor (37,38,41,42). Separating
CIN 2 from CIN 3 is often not reproducible (43–45). The two critical questions in the
assessment of the cervical epithelium are: (i) do the changes represent a genuine cancer
precursor; and (ii) is the lesion invasive cancer?
In histologic terms, CIN 3 is clearly established as a bona fide cancer precursor,

although there are few identified risk factors for progression of CIN 3 to cancer other
than time (46). CIN 3 is a reliable and more highly reproducible morphologic diagnosis,
with undifferentiated cells having fixed genetic abnormalities replacing almost the full
thickness of the cervical epithelium. It is reliably distinguished from recently acquired HPV
infection and is a genuine surrogate marker of subsequent cancer risk. Uncertainty still exists
in relation to the progressive potential of less severe dysplastic lesions including CIN 2
(47–49).
CIN 1 is increasingly viewed as an insensitive histologic marker of HPV infection. The

diagnosis includes errors of processing and interpretation of colposcopically directed
biopsies. Standardized for positivity of a given high-risk HPV type, a diagnosis of CIN 1
does not predict a meaningfully higher risk of CIN 3 than does a negative biopsy (50).
By contrast, longitudinal outcomes after HPV infection have demonstrated higher risk of
CIN 2+ and CIN 3+ in HPV-positive versus HPV-negative women, with follow-up times
up to 18 years (51). HPV types 16 and 18 are associated with a higher risk of subsequent
high-grade CIN than the other oncogenic types (51,52).
There appears to be considerable heterogeneity in the microscopic diagnosis, biology,
and clinical behavior of CIN 2 lesions (48,49,53). CIN 2 can sometimes be produced by
noncarcinogenic HPV types and is equivocal in its cancer potential (53). Some CIN 2 lesions
represent acute HPV infection with a more severe microscopic appearance that are destined
to regress. Others are incipient precancer (CIN 3) that will persist and progress with an
attendant high risk of future invasion if left untreated.
The risk factor profiles (53–55) and distributions of HPV genotype (56) in CIN 2 and CIN 3
are different. CIN 2 is more likely to spontaneously regress than CIN 3 (49,57,58). There
is an increasing tendency to follow CIN 2 lesions prospectively rather than treat, particularly
among young, nulliparous women, providing they are good candidates for prospective
follow-up (59,60). The clinical dilemma remains the inability to reliably predict those
lesions less severe than CIN 3 that are at greatest risk of progression to cancer.
New molecular markers hold promise in this regard (61–65) and there is evidence that
technologies such as dual immunohistochemical (IHC) staining for the markers Ki-67
and p16 can improve histologic classification of CIN 3 abnormalities (66–70) and
resolve CIN 2 diagnoses (71). The Lower Anogenital Squamous Terminology
Standardization Project (LAST nomenclature) relies on p16 IHC staining to triage CIN 2
(72); p16 is a biomarker for disruption of the Rb pathway by HPV (68,72). CIN 2 that is p16
positive is combined with CIN 3 as a high-grade lesion. CIN 2 that is p16 negative is
combined with CIN 1 as a low-grade lesion, the histologic diagnosis of HPV infection (Fig.
8.1).
Cervical Precancer—Modern Concepts

HPV infection is a necessary precursor of true precancer (73,74). A defined precancerous
lesion remains the target of screening and preventive treatment programs and represents a
genuine surrogate for cancer risk (75–77). CIN 3 is the most certain histologic surrogate
marker of cancer risk. CIN 3 lesions demonstrate the same aneuploid DNA (78) content
and genetic instability (79) as is seen in invasive cancer. Some CIN 3 lesions are small and a
proportion may regress, particularly after biopsy, but at this time, all CIN 3 lesions should be
managed as definite precancer lesions.
CIN 2 has the poorest interobserver reproducibility of any cervical histologic diagnosis
(42). Despite the emergence of biomarkers such as p16 IHC staining, it is often
recommended that CIN 2 lesions should be treated to provide a further safety margin against
the development of cancer. No biomarker yet denes the distinct intermediate state of CIN 2.
Current consensus is that CIN 2 is a mix of CIN 1 (productive infection) and CIN 3
(precancer) (80). In order to permit the possibility of regression of CIN 2 lesions under
careful clinical follow-up for selected younger women of low-parity, clinicians may request
distinction of CIN 2 from CIN 3.
Infection with oncogenic HPV types is strongly predictive of future risk of high-grade
abnormalities/precancer (51,52,81). HPV infection might not be associated with any
microscopic abnormality, while most low-grade abnormalities will regress (82,83),
particularly among young women (84). LSIL should be managed conservatively by
observation without treatment with an expectation of regression within 2 years.
Persistence longer than 2 years correlates with an increased HSIL risk.
Figure 8.1 Changes to the terminology and number of tiers used to describe cervical
precancer over time with corresponding management options (procedure). CKC, cold-
knife conization; Cryo, cryotherapy; Rx, treatment. (Modified with permission. Courtesy of J.
Thomas Cox. From Darragh TM, Colgan TJ, Cox JT, et al. The Lower Anogenital Squamous
Terminology Standardization Project for HPV-associated Lesions: Background and consensus
recommendations from the College of American Pathologists and the American Society for
Colposcopy and Cervical Pathology. Arch Pathol Lab Med 2012;136:1266–1297.)
HSIL, particularly CIN 3, should be treated, usually by electrosurgical excision.

Balancing the benefits of screening and treatment against the potential harm of over
diagnosis and over treatment is the clinical challenge (85,86). Many women must be treated
to prevent one cancer.
Primary prevention of cervical precancer and cancer through HPV vaccination means
the diagnosis and management of CIN are now part of a secondary prevention
program.
High-grade lesions are commonly found within a broader field of low-grade disease,
suggesting that CIN 3 may develop in high-risk HPV-infected epithelium independent of, and
within a CIN 1 lesion, rather than as a classical stepwise progression. The reported
progressive potential of histologically confirmed low-grade lesions to CIN 3 varies from
12–33% (20,21,87,88). Traditional models of cervical carcinogenesis suggested that
persistent HPV infection would progressively lead to CIN 1, CIN 2, CIN 3 and finally cancer
(89). An alternative model was that CIN 1 may not be necessary for the development of CIN
3 (90,91). CIN 3 could evolve directly and rapidly from normal epithelium infected by HPV
following a “molecular switch” model (92). Invasive cancer may then take 10–12 years to
develop from CIN 3 (93,94). Little is known about specific genetic and epigenetic mutations
that underpin the evolution of CIN 3. It is not possible to accurately predict whether a
woman will develop cervical cancer.
When low- and high-grade CIN lesions coexist, genetic alterations that accumulate during
cervical neoplastic transformation indicate a common cellular origin for such multifocal
lesions. This suggests different intraepithelial lesions arise from the same or clonally related
progenitor cells (91). Recent research has demonstrated simultaneous development of
multifocal CIN lesions of different grades. This suggests the “molecular switch” model might
be more likely than the “sequential progression” model (91,95).
Manipulation of host cell DNA methylation machinery is an important mechanism by which

HPV influences cellular and viral gene expression and is likely to be one of the mechanisms
by which HPV evades antiviral immunity (96). DNA methylation is a potent epigenetic
regulator of gene expression. Hypermethylation of promoter regions of tumor suppressor
genes, resulting from the upregulation of DNA methyltransferase (DNMT) expression caused
by the viral oncogenes E6 and E7, leads to gene silencing and this is known to be involved in
cervical carcinogenesis (97–99). Some methylation patterns have been shown to be HPV
type–specific (100,101), which may reflect a capacity of specific HPV types to dominate the
methylation machinery of the host.
If a CIN 3 lesion arose from coexisting adjacent CIN 1, methylation in the adjacent CIN 1
lesion should demonstrate a bridging pattern similar to or the same as the nearby CIN 3. It
should be distinctly different from a separate primary CIN 1 lesion. This has recently been
demonstrated to be not the case, which is consistent with a model where CIN 3 can emerge
directly from normal epithelium, possibly simultaneously to CIN 1 (95).
Persistent lesions can enlarge over time but retain characteristic epigenotypes. Initial
rapid progression to CIN 3 may be driven by a series of epigenetic changes happening both
before and during HPV infection. Distinct epigenotypes may underpin the distinct
morphologic patterns in CIN 1 and CIN 3 lesions, explaining, in part, different progression
characteristics of these lesions (95).
Adjacent CIN lesions of different grades usually contain the same hrHPV type(s) but
methylation patterns within the different lesions will usually be significantly different and
characteristic of the lesion grade. Methylation testing may be an effective future triage
tool to detect and characterize women at higher risk of developing CIN 3 and cancer.
Lower Anogenital Squamous Terminology Standardization Project for

HPV-Associated Lesions (LAST Project)
HPV interacts with genital tract squamous epithelia in two basic ways. Firstly, HPV
infection may produce transient lesions, which support virion production. Such lesions
have been variously described as low-grade lesions, intraepithelial neoplasia grade 1, mild
dysplasia or condylomata. Such lesions may be undetected clinically. Secondly, HPV-
epithelial interaction may produce lesions classified as precancerous. Viral oncogene
overexpression drives cell proliferation to produce a clonal expansion of undifferentiated
cells, characterized clinically by persistent viral detection, persistent and advancing
colposcopic abnormalities, and increasing risk of malignant transformation. These
precancerous lesions are not reliably distinguishable by routine histology, regardless of the
site of the lesion or the sex of the individual (102,103).
On the basis of specified principles of HPV-associated disease (Table 8.1) and issues related
to terminology, a consensus process was sponsored by the College of American Pathologists
(CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP). In 2012,
the Lower Anogenital Squamous Terminology (LAST Project) published a
comprehensive re-evaluation of the terminology of HPV-associated lesions of the lower
anogenital tract including the cervix, vagina, vulva, perianal area, anus, penis, and scrotum
(72).
Table 8.1 General Principles Underlying the LAST Project
1. There is unified epithelial biology to HPV-related squamous disease

2. Each cytologic or histologic sample is only a statistical representation of the patient’s true biology
3. The more samples or data points available, the more accurate the assessment of the patient’s true
biology
4. The true biology represents the risk for cancer at the current time and, to a lesser extent, the risk for
cancer over time
5. Diagnostic variation can be improved by:
a. Aligning the number of diagnostic terms with the number of biologically relevant categories and
b. The use of biologic markers
Reproduced from Darragh TM, Colgan TJ, Cox JT, et al. The Lower Anogenital Squamous Terminology
Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the
College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit
Tract Dis 2012;16:205–242.
The LAST Project recommendations include:
1. There should be a unified histopathologic nomenclature with a single set of diagnostic
terms. A two-tiered nomenclature was recommended for noninvasive HPV-associated
squamous proliferations of the lower anogenital tract, which may be further qualified
with the appropriate –IN terminology. (–IN refers to the generic intraepithelial neoplasia
terminology without specifying location.)
2. HPV-associated squamous lesions of the lower anogenital tract should be classified
as low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous
intraepithelial lesion (HSIL), which may be further classified by the –IN classification.
3. The biomarker p16 immunohistochemical (IHC) staining should be used when the
hematoxylin and eosin (H&E) morphologic diagnosis is between precancer (–IN 2 or
–IN 3) and a mimic of precancer (e.g., processes known to be unrelated to neoplastic
risk, such as immature squamous metaplasia, atrophy, reparative epithelial changes,
tangential cutting). Strong and diffuse block-positive p16 results would support a
categorization of precancerous disease.
4. If the pathologist is entertaining an H&E morphologic interpretation of –IN 2 (under
the old terminology, which is a biologically equivocal lesion falling between the
morphologic changes of HPV infection and precancer), p16 IHC is recommended to
help clarify the situation. Strong and diffuse block-positive p16 results support a
categorization of precancer. Negative or non–block-positive staining strongly favors an
interpretation of low-grade disease or a non–HPV-associated pathology.
5. p16 IHC should be used as an adjudication tool for cases in which there is a
professional disagreement in histologic specimen interpretation with the caveat that
the differential diagnosis should include a precancerous lesion (–IN 2 or –IN 3).
6. p16 IHC should not be used as a routine adjunct to histologic assessment of biopsy
specimens with morphologic interpretations of negative, –IN 1, and –IN 3.
The LAST terminology for squamous HPV-associated lesions and associated p16
biomarker usage reflects modern clinical practice (Fig. 8.2A,B). If the LAST terminology
is broadly accepted, squamous histology and cytologic reporting should be indistinguishable
and consistent in the United States. Potential reconciliation of LAST terminology and the
three-tiered CIN system in cytologic and histologic diagnoses is represented in Table 8.2.
As a result of implementation of the recommendations of the LAST WG4, p16 use has
increased considerably, which has resulted in an increase in the HSIL diagnosis rate,
particularly in young women (104). To avoid overtreating young women, observation may
be recommended for HSIL requiring p16 immunohistochemistry for confirmation, as this
would correspond closely to CIN 2. This flexibility afforded to treating physicians reduces
the likelihood that overcalling HSIL, based on p16-positive results, would have negative
consequences for younger patients.
Figure 8.2 A: Pathologic diagnoses using p16 and potential clinical management
options for cervical biopsies. (a) Use of p16 to evaluate the differential diagnosis of HSIL
versus a mimic, such as immature squamous metaplasia and atrophy. (Modified with
permission. Courtesy of Philip E. Castle.) (b) Use of p16 to evaluate morphologic CIN 2. The
choice of clinical management for HSIL depends on the entire clinical scenario including
patient’s age, colposcopic findings, and biopsy diagnosis. (Modified with permission. Courtesy
of Philip E. Castle.) B: Cervical biopsy with SIL showing partial maturation. Grading is difficult
(? CIN 2). H&E morphology at medium power shows atypical parabasal-like cells extending
into the middle third of the epithelium. Corresponding p16 IHC stains reveals diffuse strong
staining meeting the definition of p16 strong diffuse block-positive. This case is best interpreted
as HSIL. (Reproduced with permission from Darragh TM, Colgan TJ, Cox JT, et al. The
Lower Anogenital Squamous Terminology Standardization Project for HPV-associated lesions:
Background and consensus recommendations from the College of American Pathologists and
the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med
2012;136:1266–1297, with permission from Archives of Pathology & Laboratory Medicine.
Copyright © 2012 College of American Pathologists.)

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Berek and Hacker's Gynecologic Oncology - (Section II Disease Sites)

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low resource settings are likely to result from the lack of organized cervical screening

Classification of Preinvasive Cervical Disease

The Dysplasia Terminology

A dual terminology developed, leading to inconsistencies in treatment policies. If a diagnosis

Cervical Intraepithelial Neoplasia

The CIN grading is very subjective. No reproducible cytologic or histologic distinction

In histologic terms, CIN 3 is clearly established as a bona fide cancer precursor,

CIN 1 is increasingly viewed as an insensitive histologic marker of HPV infection. The

Cervical Precancer—Modern Concepts

managed as definite precancer lesions.

HSIL, particularly CIN 3, should be treated, usually by electrosurgical excision.

Manipulation of host cell DNA methylation machinery is an important mechanism by which

Lower Anogenital Squamous Terminology Standardization Project for

Table 8.1 General Principles Underlying the LAST Project

1. There is unified epithelial biology to HPV-related squamous disease

Copyright © 2012 College of American Pathologists.)

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