Pathology of HPV infection at the cytologic and histologic

International Journal of Gynecology and Obstetrics (2006) 94 (Supplement 1), S22---S31
www.elsevier.com/locate/ijgo
CHAPTER 3
Pathology of HPV infection at the cytologic and
histologic levels: Basis for a 2-tiered morphologic
classification system
Thomas C. Wright, Jr.
KEYWORDS
Squamous intraepithelial
lesion (SIL);
Cervical intraepithelial
neoplasia (CIN);
Cervix;
Cancer precursors;
Human papillomavirus
(HPV)
Abstract Over the last 2 decades the pathogenesis and natural history of cervical cancer has become clearer. As a result, the cytologic and histologic terminology used to refer to cervical cancer precursors has needed to change. Today we
recognize that almost all cervical cancers are due to infection with specific highrisk types of human papillomavirus (HPV). Most women become infected with these
viruses within several years of initiating sexual intercourse and a productive HPV infection frequently results in characteristic morphologic changes within the infected
cervical squamous cells. Cells demonstrating the morphologic changes associated
with a productive HPV infection are referred to as low-grade squamous intraepithelial lesions (LSIL) when observed in cytologic specimens and low-grade cervical
intraepithelial neoplasia (CIN 1) when observed in histologic specimens. In some
women, HPV gene expression becomes unlinked to the state of differentiation of
the infected epithelial cells and deregulated expression of the early region of the
viral genome results in a dramatic increase in expression of two HPV oncoproteins
(E6 and E7). This results in loss of normal cell cycle control of the epithelium and
genetic instability. When this occurs the epithelium develops characteristic morphologic features, with immature “basaloid-type” squamous cells and mitotic figures in the upper half of the cervical epithelium. Such lesions are felt to represent
“true” neoplasia and are referred to as high-grade squamous intraepithelial lesions
(HSIL) when observed in cytologic specimens and high-grade cervical intraepithelial
neoplasia (CIN 2,3) when observed in histologic specimens.
© 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier
Ireland Ltd. All rights reserved.
1. Introduction
The histopathologic and cytopathologic classification of a disease should reflect both its clinical behavior and the current concepts regarding its pathogenesis. Over the last 2 decades our understand-
ing of the pathogenesis of cervical cancer and its
precursor lesions has increased dramatically. As a
result, the old terminology is being discarded and
replaced by a new terminology that more accurately reflects both clinical behavior and pathogenesis. Changes in terminology are frequently disrup-
0020-7292/$ --- see front matter © 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.
All rights reserved.
Pathology of HPV infection at the cytologic and histologic levels
tive. Inevitably, many will question the need for the
change and it takes years for training resources such
as textbooks and management guidelines to be updated. The recent change in the histopathologic and
cytopathologic classification of cervical cancer precursors seems to have been particularly disruptive,
perhaps because so many clinicians are involved in
different aspects of cervical cancer prevention. In
this article we review the pathogenesis of cervical
cancer as well as the histopathologic and cytopathologic classification and features of cervical cancer
precursors.
2. Older terminologies
From the 1930s though the 1960s, noninvasive intraepithelial lesions of the cervix were classified using a 4-tiered terminology [1]. The 4 categories of
precursor were mild dysplasia, moderate dysplasia,
severe dysplasia, and carcinoma in situ (Figure 1).
It was not widely accepted that dysplastic lesions
were cervical cancer precursors, and carcinoma in
situ was believed to be the only “true” precursor. Therefore, women with dysplasias of all grades
tended to be followed up cytologically, whereas
treatment for those with carcinoma in situ was frequently a cone biopsy or a hysterectomy. By the
early 1970s, laboratory studies as well as prospective clinical follow-up studies showed that the dysplasia/carcinoma in-situ terminology reflected neither the clinical behavior nor the pathogenesis of
cervical cancer precursors [2]. The laboratory studies available at that time indicated that the cellular
Figure 1 Dysplasia and carcinoma in situ terminology
compared with the CIN terminology. From the 1950s
through the 1960s the terms dysplasia and carcinoma in
situ were widely used to describe noninvasive intraepithelial lesions of the cervix. They were replaced in the
1970s with the CIN terminology, which combined severe
dysplasia and carcinoma in situ into CIN 3.
S23
changes observed in dysplasia and carcinoma in situ
were qualitatively similar and remained rather constant throughout the histologic spectrum of putative precursor lesions. Both dysplasia and carcinoma
in situ could be monoclonal proliferations of abnormal squamous epithelial cells, and both were frequently aneuploid [3]. By electron microscopy and
time-lapse cinematography, all grades of dysplasia
and carcinoma in situ shared features [4]. Moreover,
studies of intraobserver and interobserver variability in the histologic diagnosis of severe dysplasia and
carcinoma in situ demonstrated that pathologists
could not reproducibly differentiate the 2 entities
[5]. Perhaps most importantly, prospective followup studies demonstrated that dysplastic lesions of
all grades could progress to carcinoma in situ, and
that all, therefore, could progress to cervical cancer. Based on the information available in the early
1970s, Richart [6] introduced the concept that all
types of precursor lesions to squamous carcinomas
of the cervix represented a single disease process.
He termed this process cervical intraepithelial neoplasia (CIN).
At the time of its introduction, CIN was believed
to describe a spectrum of histologic and cytologic
changes that shared a common etiology, biology,
and natural history. Although the CIN terminology
divided the precursor lesions into 3 groups --- CIN
1 for mild dysplasia; CIN 2 for moderate dysplasia; and CIN 3 for both severe dysplasia and carcinoma in situ (Figure 1) --- these groups were considered to represent different stages of a single biological continuum. Therefore, inherent in the CIN
terminology was the belief that CIN lesions of all
grades were “true” cancer precursors and that all,
even CIN 1 lesions, had the potential to progress to
invasive cancer if untreated. The CIN terminology
was introduced concordantly with the development
of simple outpatient ablative techniques for treating CIN lesions, such as cryotherapy and electrofulguration. Because of this convergence it became
widely recommended that CIN lesions of all grades,
including CIN 1, be treated. The CIN terminology became widely adopted for use in both histopathology and cytopathology. Yet, as our understanding of
the pathogenesis of cervical cancer and its precursor lesions improved, it became clear that the basic
premise underlying the CIN terminology was incorrect.
3. Pathogenesis of cervical cancer
Today it is recognized that human papillomavirus
(HPV) infection plays an essential role in the pathogenesis of cervical cancer [7]. Most women become
S24
exposed to and infected with HPV shortly after initiating sexual activity. The target cells for an initial
HPV infection are the immature basal cells of the
epithelium, and HPV is thought to reach these cells
through microabrasions or cracks within the epithelium. Viral replication is tightly linked to the differentiation state of the virally infected epithelial
cells [8,9]. Replication of the HPV genome is tightly
controlled by cellular mechanisms within the basal
cells, and appears to be linked to cellular replication so that the viral DNA replicates with the
host' s genome. The number of copies of the HPV
genome, as a circular or episomal form, is thus low
in the basal cell' s nucleus, and virally encoded proteins are expressed at very low levels. As a result,
HPV-infected basal cells show no specific cytologic
or histologic changes and cannot be distinguished
from uninfected cells. This stage of an HPV infection is referred to as a “latent” or “clinically unapparent” infection since the woman is HPV DNA
positive, but no lesions can be detected, even by
microscopy.
As HPV-infected epithelial cells differentiate and
move upwards in the epithelium, viral transcription
of the early region of the HPV genome dramatically
increases [8,9]. The early region encodes for a number of proteins, including E1, E2, E6, and E7, which
are important for viral replication. The HPV genome
is relatively small (approximately 8000 base pairs)
and does not encode the enzymes required for viral DNA replication. The only proteins provided by
the viral genome that are directly involved in viral
replication are 2 regulatory proteins, E1 and E2, and
HPV must therefore rely on the host' s DNA replication machinery for viral DNA synthesis [10]. However, as the epithelial cells differentiate, the cellular DNA replication machinery is normally inactivated. In order to undergo vegetative DNA amplification in the differentiating epithelial cells, the
virus needs to reactivate the cellular DNA replication machinery. Studies of cultured human keratinocytes have shown that the viral E7 protein is
capable of reactivating the cellular DNA replication machinery in differentiated cells [11]. The viral
E6 protein also appears to play an important role
by blocking the apoptosis that would normally occur in the differentiated cells [12]. Together, these
changes provide in the cell the synthetic phase environment necessary for vegetative viral DNA replication and complete virion formation. Infectious virus
is eventually released as the differentiated cells are
shed from the epithelium. In most women immunity develops against HPV after a period of months
or years, and productive viral infection ceases [13].
These women eventually become HPV DNA negative.
T.C. Wright, Jr.
In some HPV-infected women viral gene expression becomes unlinked to the state of differentiation of the infected epithelial cells, resulting in a
change in the topography of viral gene expression
within the epithelium (see Chapter 1) [8,9]. One of
the results of this other mode of viral infection is
the dramatic increase in the expression of E6 and E7
HPV in the lower layers of the epithelium due to the
proteins' deregulated expression [8,9]. The deregulated expression of HPV proteins E6 and E7 results in
the disruption of normal cell cycle regulation; abrogation of apoptosis mechanisms; and genetic instability. Genetic instability, which is a characteristic
feature of most malignant neoplasms, occurs early
in the development of precancers, thereby allowing for the stepwise acquisition of multiple mutations. Produced by alterations in the mitotic spindle apparatus, genetic instability permits aberrant
mitotic events that can produce a disequilibrium in
the distribution of chromosomes, leading to changes
in the number and structure of chromosomes. It can
eventually produce a change in the overall DNA content, referred to as aneuploidy. Genetic instability
is thought to play a critical role in the development
of cervical cancer [14].
The association between infection with high-risk
types of HPV and high-grade cervical cancer precursors as well as cervical cancer is so strong that it
has prompted the use of HPV DNA testing in the
clinical management of women with the “borderline” cytologic abnormalities referred to as atypical
squamous cells of undetermined significance (ASCUS), and as an adjunct to the cytologic evaluation of
women aged 30 years and older who undergo routine
cervical screening [15,16]. When HPV DNA testing
is used in the management of women with ASC-US,
molecular testing for high-risk types of HPV is performed, typically with residual fluid after a liquidbased cytologic specimen is processed. If a woman
tests positive for high-risk HPV DNA she is referred
for colposcopy; and if she tests negative, routine
screening is resumed [16,17]. In women who test
positive for high-risk HPV DNA but are found to be
cytologically negative, both tests are repeated 6 to
12 months after the initial screening. Because the
negative predictive value of being both cytologically
negative and testing negative for high-risk HPV DNA
is greater than 98.8% in all studies, and 99.9% or
100% in most, women for whom the results of both
tests are negative do not require rescreening for 3
years [15].
Pathology of HPV infection at the cytologic and histologic levels
4. Two-tiered morphologic classification
system of noninvasive HPV-associated
cervical lesions
It used to be believed that the multistep nature of
the pathogenesis of cervical cancer described above
was mirrored by a defined sequence of morphologic changes, identified as CIN 1, CIN 2, and CIN
3, and that these changes reflected the natural history of CIN lesions. Numerous studies have demonstrated over the past several decades that a higher
CIN grade correlated with a greater risk that lesions
progress to a higher grade or to invasive cervical
cancer. A comprehensive review of natural history
studies of CIN lesions was conducted by Ostor (Table 1) [18]. The investigator concluded that spontaneous regression during the different follow-up
studies occurred in 57%, 43%, and 32% of cases for
CIN 1, CIN 2, and CIN 3 lesions, respectively, and
that persistence occurred in 32%, 35%, and 56% of
these lesions. Only 1% of CIN 1 lesions and 5% of CIN
2 lesions, but more than 12% of CIN 3 lesions, progressed to invasive cervical cancer during follow-up.
Moreover, it is now recognized that lesions that
would in previous days have been considered highgrade CINs (CIN 2,3) often develop quickly after initial infection with high-risk types of HPV, and that
such lesions are not necessarily preceded by lesions
with the morphological appearance of a CIN 1 [19].
For example, in a long-term follow-up study of college students, it was found that the median time
Table 1 Summary of the natural history of CIN
lesions *
CIN 1
CIN 2
CIN 3
Regress
Persist
Progress to
to CIS
Progress to
to invasion
57%
43%
32%
32%
35%
56%
11%
22%
1%
5%
>12%
Abbreviations: CIN, cervical intraepithelial neoplasia; CIS,
carcinoma in situ.
* Adapted from reference [18].
Table 2
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from first detection of HPV DNA to identification of
a histologically confirmed CIN 2,3 lesion was only
14.1 months [19]. Similarly, in a long-term followup study of a prophylactic vaccine against HPV-16,
most CIN 2,3 lesions associated with HPV-16 in the
placebo arm appeared to develop rapidly after the
initial infection with HPV-16 [20]. Therefore, the
older concept that it took years to progress from
a CIN 1 to a CIN 2 or CIN 3 lesion appears to be incorrect.
We thus recognize that high-grade CINs (CIN 2,3)
often develop quickly after an incident infection
with high-risk types of HPV, and that most CIN 1 lesions are not “neoplasia” but simply virus-producing
lesions. Moreover, a lesion with the morphologic appearance of CIN 2 does not necessarily have fewer
chromosomal alterations than a lesion with the morphologic appearance of CIN 3. Therefore, the terminology used for noninvasive HPV-associated cervical
lesions needs to be changed to better reflect the biology of HPV infections. Instead of classifying noninvasive HPV-associated cervical lesions as a continuum of lesions (CIN 1, CIN 2, and CIN 3) reflecting
a single underlying biological process at different
stages of development, we need to represent noninvasive HPV-associated cervical lesions as 2 distinct
biological entities (Figure 2) [21]. One represents a
productive viral infection caused by oncogenically
low- or high-risk types of HPV. These lesions are usually self-limited and spontaneously resolve when the
patient stops shedding HPV. The other represents a
true neoplastic process confined to the epithelium,
but with the capacity to progress to invasive cervical
cancer if not treated. These neoplastic lesions are
usually histologically high grade; they almost always
are associated with high-risk types of HPV; and they
show deregulation of E6 and E7 expression. They
also are monoclonal and have chromosomal alterations.
The 2-tiered classification system can account for
all noninvasive HPV-associated cervical lesions. Lesions that are most likely the manifestation of a
productive viral infection are referred to as “lowgrade” and those that potentially represent a cervi-
Comparison of terminologies used for cytologic and histologic findings
Dysplasia/carcinoma
in situ
CIN terminology
Bethesda System
for cytologic studies
Modified CIN terminology
for histologic studies
Mild dysplasia
Moderate dysplasia
Severe dysplasia
Carcinoma in situ
Invasive cancer
CIN 1
CIN 2
CIN 3
LSIL
HSIL
Low-grade CIN (CIN 1)
High-grade CIN (CIN 2,3)
Invasive cancer
Invasive cancer
Invasive cancer
Abbreviations: CIN, cervical intraepithelial neoplasia; HSIL, high-grade squamous intraepithelial lesions; LSIL, low-grade
squamous intraepithelial lesions.
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T.C. Wright, Jr.
Figure 2 Low-grade/high-grade terminology for noninvasive HPV-associated epithelial lesions. This terminology is
based on the realization that morphologically low-grade lesions generally represent productive HPV infections and do
not act as precursors to invasive cervical cancer. In contrast, morphologically high-grade lesions tend to be neoplastic
and have the potential to act as precursors to invasive cancer. Low-grade and high-grade lesions are separated on the
diagram to emphasize the fact that high-grade lesions can develop de novo.
cal cancer precursor are referred to as “high grade”
(Figure 2). However, whether these lesions should
be referred to as squamous intraepithelial lesions
(SILs) or should remain known as CINs is subject
to controversy among proponents of a 2-tiered terminology system. In the United States, where 2tiered terminology and the Bethesda System have
been widely adopted for cytologic determination,
the terms low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial
lesion (HSIL) are used in cytologic diagnosis [22].
However, most pathologists continue to use CIN 1
to refer to lesions likely to manifest a productive viral infection and CIN 2,3 for lesions that manifest a
neoplastic process [23].
It is important for clinicians to recognize that
histopathologic and cytologic appearance are, unfortunately, relatively poor predictors of the biologic potential of a given lesion. Based on both
biomarkers and biologic behavior over long-term
follow-up, it is now clear that some histologically
and cytologically low-grade lesions have the biologic characteristics of a high-grade lesion [24]. This
is particularly true for low-grade lesions associated
with high-risk types of HPV. For example, low-grade
lesions associated with HPV-16 and HPV-18 are invariably monoclonal proliferations of cells, a feature of neoplasia and not of a productive viral infection [25]. Conversely, some lesions that could be
classified as “high-grade” based on their histologic
and cytologic appearance have the biologic characteristics of low-grade lesions. This is especially true
for lesions with the histologic appearance of CIN 2.
Almost half of these lesions are self-limited, and
have been observed to regress spontaneously within
short periods without any treatment [24]. However,
most of these lesions are associated with high-risk
types of HPV and many are aneupoloid and demonstrate loss of heterozygosity (LOH) at specific chromosomal loci. These are characteristic features of
CIN 3 lesions and invasive cervical cancer [26]. A
histopathologic diagnosis of CIN 2 is also poorly reproducible. Because a considerable proportion of lesions with the histologic features of CIN 2 have the
biologic features of neoplasia, they are classified as
high-grade in the 2-tiered terminology [21,22,26].
5. Histologic and cytologic features of
noninvasive HPV-associated cervical lesions
5.1. Low-grade productive HPV infections
During the productive viral infection stage, large
numbers of complete viral genomes are produced,
which are subsequently packaged with the capsid
proteins into infectious virions. Characteristic cytologic changes occur in the squamous cells in which
productive HPV infection is taking place. These are
multinucleation, nuclear enlargement, nuclear hyperchromasia, irregular nuclear outlines, and perinuclear halos. Squamous epithelial cells demonstrating these cytologic features are referred to as koilocytes, a word derived from the Greek koilos, which
means hole (Figure 3). These changes are recognizable in both cytologic and histologic specimens. In
Pathology of HPV infection at the cytologic and histologic levels
S27
Classic cytologic features low-grade CIN:
• Cellular enlargement
• Multinucleation
• Nuclear hyperchromasia
• Nuclear irregularity
• Presence of perinuclear halos
Classic cytologic and histologic features high-grade CIN:
• Immature basaloid-type cells with high nucleus to cytoplasm ratio
• Immature basaloid-type cells in the upper half of the epithelium
• Mitoses occurring in the upper half of the epithelium
• Irregular, hyperchromatic nuclei
• Abnormal mitotic figures
addition to the cytologic changes occurring in individual squamous cells, architectural changes also
occur in a squamous epithelium in which productive HPV infection is taking place. The squamous
epithelium then frequently becomes acanthotic (or
thickened), and sometimes forms papillary projections with central fibrovascular cores (Figure 4A and
B). Lesions with this histologic appearance are referred to as low-grade CINs (CIN 1), whereas specimens showing the cytologic features of HPV effects
are referred to as LSILs.
In-situ hybridization techniques can demonstrate
the presence of HPV DNA in koilocytes within tis-
Figure 3 Low-grade squamous intraepithelial lesion
(LSIL). Epithelial cells removed using a spatula or broom
from the more differentiated layers of the squamous
epithelium of the cervix demonstrate the characteristic
features of a productive human papillomavirus (HPV) infection. They show multinucleation, perinuclear halos,
nuclear enlargement, and hyperchromasia. Cells with
these features are frequently referred to as koilocytes.
Figure 4 Low-grade cervical intraepithelial neoplasia
(CIN 1). (A) During productive HPV infection the cervical squamous epithelium becomes somewhat thickened,
or acanthotic. (B) At higher magnification the cytologic
effects of a productive HPV infection are obvious, with
multiple koilocytes.
S28
T.C. Wright, Jr.
HPV and those associated with “high oncogenic risk”
types of HPV [26]. Since clinical and histologic criteria do not allow differentiation among low-grade
lesions on the basis of their oncogenic potential,
distinctions between flat cervical condylomas and
low-grade CIN (CIN 1) lesions are no longer clinically
meaningful and have been dropped.
Over a period of several months, the vast majority of HPV-infected persons develop an effective
immune response against the type of HPV that they
harbor [13]. The shedding of HPV DNA spontaneously
stops once the immune response has developed.
This occurs within 2 years of infection in approximately 90% of women. When the shedding stops,
the cytopathic effects of productive HPV infection
disappear. In natural history studies, women have
tended to remain HPV DNA negative after they have
stopped shedding a given type of HPV. However, it
is still unknown what proportion of the women who
spontaneously stop shedding HPV DNA actually clear
the infection from their bodies, and in what proportion HPV is maintained in an episomal form and low
copy numbers in the basal cells of the mucosa.
Figure 5 In-situ hybridization of HPV in a low-grade
CIN (CIN 1). In-situ hybridization has been performed
with a probe against the DNA of high-risk types of HPV.
Cells that have blue nuclei have large numbers of HPV
genomes indicating that a productive viral infection is
taking place. Most of the productively infected cells are
in the more differentiated layers of the epithelium. Although this lesion has the morphologic features of a lowgrade lesion, it is caused by infection with a high-risk
type of HPV.
sue sections (Figure 5), and electron microscopic
studies have confirmed the presence of completely
formed viruses in koilocytes [27]. However, the presence of perinuclear clearing, or halos, in cells without significant nuclear atypia is seen in a variety of non-neoplastic disorders as well as in HPV
infection. These disorders include infections with
Trichomonas organisms, Gardnerella vaginalis, and
Candida organisms. Moreover, perinuclear clearing
can occasionally be a feature of the atrophic epithelial changes found in the cervices of postmenopausal
women or of women with immature squamous metaplasia. Before the recognition that all CINs are associated with HPV infection, cervical condylomas
and low-grade CINs (CIN 1) were generally classified as separate histopathologic entities. With the
widespread application of HPV typing to cervical lesions, it has become evident that it is impossible
to distinguish, on histologic grounds alone, between
flat cervical condylomas and low-grade CIN (CIN 1)
lesions associated with “low oncogenic risk” types of
5.2. High-grade neoplastic HPV-associated lesions
Lesions that have the histologic features of a neoplasia and may be precursor lesions are referred
to as high-grade CINs (CIN 2,3), whereas cytological specimens with these features are referred to
as HSILs. Although HPV-induced cytopathic effects
are often present, they are usually less prominent
in high-grade CIN (CIN 2,3) than in low-grade CIN
(CIN 1). High-grade CIN (CIN 2,3) is characterized
by immature basaloid cells and mitotic figures that
extend into the upper half of the epithelium (Figure
6). The immature basaloid cells usually have nuclear
crowding, pleomorphism, and loss of normal cell polarity. They have a minimal amount of cytoplasm
and therefore a high nucleus to cytoplasm ratio.
Another feature found in most high-grade lesions
is the presence of abnormal mitotic figures (Figure
7). Most invasive cervical cancers have chromosomal
abnormalities and LOH at specific chromosomal loci.
In addition, many are aneuploid. This suggests that
aneuploid intraepithelial lesions with LOH at these
loci are at risk for progressing to invasive carcinomas if left untreated, and studies have documented
that the percentage of aneuploid CIN lesions with
LOH at the specific sites increases with CIN grade
[28---30]. In one study that used an imaging system
to measure the DNA content of Feulgen-stained cervical cells, it was found that 33% of mildly dysplastic
lesions were aneuploid [28]. The percentage of aneuploid lesions increased to 75% for moderate dysplasias and 90% for severe dysplasias and carcino-
Pathology of HPV infection at the cytologic and histologic levels
Figure 6 High-grade cervical intraepithelial neoplasia
(CIN 2,3). Immature basaloid-type cells extend into the
middle layers of the epithelium. These cells have enlarged hyperchromatic nuclei giving them a high nucleus
to cytoplasm ratio. Mitoses are also occurring in the upper half of the epithelium.
mas in situ. Similar results have been obtained using other techniques to assess DNA content. As 85%
of CINs with aneuploid DNA patterns contain abnormal mitotic figures, the best histologic predictor of
an aneuploid lesion is the presence of abnormal mitotic figures [31].
Another characteristic feature of high-grade
lesions is overexpression of p16INK, a cyclindependent kinase inhibitor involved in the control
of the cell cycle [32]. The intracellular expression
of p16INK is increased upon the binding of high-risk,
HPV-derived E7 oncoproteins to the retinoblastoma
gene product. A number of studies have demonstrated that staining with p16INK is very uncommon
in normal cervical squamous epithelium, but that
a small proportion of CIN 1 lesions, a higher proportion of CIN 2 lesions, and the vast majority of
CIN 3 lesions and cancers stain positively for p16INK
(Figure 8) [33---36]. Moreover, prospective follow-up
studies suggest that p16INK-positive lesions behave
as precursor lesions. In one prospective study with
women having low-grade CINs (CIN 1), the rate of
regression of p16INK-negative lesions was found to
be higher (71%) than that of p16 INK-positive lesions
(38%) [37]. Although some of the p16INK-negative
S29
Figure 7 Abnormal mitotic figure. A characteristic feature of high-grade CIN (CIN 2,3) is aneuploidy. Abnormal
mitotic figures are good markers for aneuploidy; their
presence in a lesion indicates that the lesion is neoplastic.
Figure 8: Immunohistochemical staining for p16INK.
High-grade CIN (CIN 2,3) lesions almost invariably
demonstrate overexpression of p16INK. p16INK overexpression is shown by the dark-brown staining of the epithelium.
low-grade CINs (CIN 1) progressed to high-grade
CINs (CIN 2,3) in that study, the p16INK-positive lesions were much more likely to progress. In another
prospective study, 44% of the women with lesions
found to be p16INK positive on biopsy and classified as “not CIN 2,3” by consensus histopathologic
diagnosis were subsequently diagnosed with CIN 2,3
[33]. Therefore, there is considerable data suggesting that p16INK immunostaining can help identify
which high-grade CIN (CIN 2,3) lesions will behave
as precursor lesions.
S30
T.C. Wright, Jr.
6. Conclusions
Over a decade ago, S.J. Gould thus described the
significance of taxonomy to the sciences:
[9]
“The much maligned science of taxonomy,
the ordering and classification of organisms,
takes a culturally imposed backseat to the
more interventionist and generalizing work
style of experimentation and quantification.
But taxonomy should be viewed as one of the
most fundamental, and probably most noble,
of scientific pursuits --- for what can be more
basic than the parsing of nature' s rich and
confusing complexity? Our categories, moreover,
record our modes of thought, and taxonomy
therefore teaches us as much about our mental
functioning as about nature' s variety.” [38]
[10]
[11]
[12]
[13]
[14]
[15]
This review of the evolution of the terminologies used for noninvasive HPV-associated lesions of
the cervix provides greater insight into how pathologists, clinicians, and scientists view the pathogenesis of cervical cancer than into the actual morphologic expression of the lesions. While the latter have
remained stable, each change in terminology, from
the dysplasia/carcinoma in situ terminology of the
1950s, through the spectrum of CIN introduced by
Richart in the late 1960s, to the Bethesda System' s
low-grade/high-grade lesion terminology, has been
based on new scientific information that has altered
our fundamental views of the pathogenesis of cervical cancer.
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