29. Preinvasive Lesions of the Lower Genital Tract. Will Gyn.

 Preinvasive Lesions of the Lower Genital Tract

BS. Nguyễn Hồng Anh

O ce gynecology requently involves the diagnosis and management o preinvasive lower genital tract disease, most o ten

involving the uterine cervix. Since widespread introduction o the

Papanicolaou (Pap) test in the 1950s, cervical cancer screening

has reduced the incidence o and mortality rate rom invasive

cervical cancer by more than 70 percent (Howlader, 2014).

T is is true despite a continued rise in the incidence o preinvasive

lesions (Kurdgelashvili, 2013). Approximately 7 percent o U.S.

women who undergo Pap testing will have an abnormal result

(Wright, 2012). An abnormal screening test prompts urther

patient evaluation, usually with colposcopy and biopsy. Histologic

results are more de nitive and in orm appropriate management.

LOWER GENITAL TRACT NEOPLASIA

In the lower genital tract (LG ), the term intraepithelial neoplasia re ers to squamous epithelial lesions that are potential

precursors o invasive cancer. T ese lesions demonstrate a

range o histologic abnormality rom mild to severe based on

cytoplasmic, nuclear, and histologic changes. T e severity o a

squamous intraepithelial lesion is graded by the proportion o

epithelium with abnormal cells rom the basement membrane

upward toward the sur ace. In the case o cervical intraepithelial

neoplasia (CIN), abnormal cells con ned to the lower third

o the squamous epithelium are re erred to as mild dysplasia
or CIN 1, extending into the middle third as moderate dysplasia or CIN 2, into the upper third as severe dysplasia or CIN
3, and ull-thickness involvement as carcinoma in situ (CIS)
(Fig. 29-1). Squamous neoplasia o the vagina, vulva, perianal,
and anal squamous epithelia (VaIN, VIN, PAIN, and AIN,
respectively) are graded similarly with the caveat that VIN 1
is no longer recognized (p. 647). T e natural history o these
extracervical lesions is less understood than or CIN. In contrast, the cervical columnar epithelium does not demonstrate
an analogous neoplastic disease spectrum because it is only one
cell-layer thick. Histologic abnormalities are there ore limited
to either adenocarcinoma in situ (AIS) or adenocarcinoma.
T e concept o cervical neoplasia as a spectrum has come
under question with increasing insight into human papillomavirus (HPV) in ection. Mild squamous dysplasia is now recognized as evidence o HPV in ection, most o which is transient
and unlikely to progress. Moderate to severe dysplastic squamous
lesions are considered to be true cancer precursors. Current cytology reporting re ects this two-tier concept (Solomon, 2002). In
1989, the Bethesda System nomenclature replaced CIN with
squamous intraepithelial lesion (SIL). Because cytologic and histologic changes o HPV in ection and CIN 1 cannot be distinguished reliably and because o their like natural histories, they
are categorized together as low-grade squamous intraepithelial
lesions (LSIL). Similarly, CIN 2, CIN 3, and CIS are di cult to
distinguish, are truer cancer precursors, and are all designated as
high-grade squamous intraepithelial lesions (HSIL). T e diagnostic distinction between LSIL and HSIL is more reliable, biologically plausible, and clinically meaning ul than diagnoses using
the CIN system. T is two-tiered nomenclature is now recommended, and guidelines or the management o these lesions are
grouped accordingly (Darragh, 2012).
ANATOMIC CONSIDERATIONS
■ External Genitalia
Precancerous lesions o the emale LG are o ten multi ocal,
can involve any o its structures, and may appear similar to
benign processes. For example, micropapillomatosis labialis is
a benign anatomic variant characterized by minute epithelial
projections on the inner labia minora (Fig. 29-2). T is condition can be easily mistaken or HPV-related lesions, but true
HPV lesions tend to be multi ocal and asymmetric, and to have
multiple papillations arising rom a single base (Ferris, 2004).
Micropapillomatosis o ten shows spontaneous regression, and
treatment is not indicated (Bergeron, 1990).
FIGURE 29-1 A. Normal ectocervical epithelium is a nonkeratinizing, stratified squamous epithelium. Mitoses are normally confined
to the lower layers, namely, the basal and parabasal epithelial layers.
B. Low-grade squamous intraepithelial lesion (LSIL). This biopsy’s
location at the transformation zone is indicated by the presence
of both columnar epithelium (asterisk) and squamous epithelium.
Low-grade SIL has a disordered proliferation of squamous cells and
increased mitotic activity confined to the basal one third of the
epithelium. Koilocytotic atypia, which is indicative of proliferative
HPV infection, involves the more superficial epithelium. Koilocytosis
is typified by nuclear enlargement, coarse chromatin, nuclear
“wrinkling,” and perinuclear halos. C. This high-grade SIL shows disordered, highly atypical squamous cells and increased mitotic activity
involving the full thickness of the epithelium. Note the mitotic figure
located close to epithelial surface (yellow arrow). (Used with permission
from Dr. Kelley Carrick.)

■ Vagina

T e vagina is lined by nonkeratinized squamous epithelium,

and glands are absent. However, areas o columnar epithelium

are occasionally ound within the vaginal squamous mucosa, a

condition termed adenosis. It is o ten attributable to in utero

exposure to exogenous estrogen, particularly diethylstilbestrol

(DES) ( rimble, 2001). T ese areas are red patches within the

squamous epithelium and can be mistaken or ulcers or other

lesions. With DES-related adenosis, care ul palpation o the

vagina is warranted in addition to visual inspection, as clear

cell adenocarcinoma may be palpable be ore becoming visible.

■ Cervix

Squamocolumnar Junction

During embryogenesis, upward migration o strati ed squamous

epithelium rom the urogenital sinus and vaginal plate is thought

to replace müllerian epithelium (Ul elder, 1976). T is process

usually terminates near the external cervical os, orming the original (congenital) squamocolumnar junction (SCJ). When visible

on the ectocervix, the SCJ is a pink, smooth squamous epithelium juxtaposed against the red, velvety columnar epithelium

surrounding the external cervical os. Rarely, this migration is

incomplete resulting in an SCJ in the upper vaginal ornices. T is

is a normal variant and also seen with in utero DES exposure.

T e columnar epithelium is commonly re erred to as “glandular.” T is is because it produces mucus, and its deep in oldings appear histologically similar to glandular tissue (Fig. 29-3).

However, true glands, consisting o acini and ducts, are not

present on the cervix (Ul elder, 1976).

T e location o the SCJ varies with age and hormonal status

(Fig. 29-4). During the reproductive years, it everts outward onto

the ectocervix, especially during adolescence, pregnancy, and

with combination hormonal contraceptive use. It regresses into

the endocervical canal during the natural process o squamous

metaplasia and in low-estrogen states such as menopause, prolonged lactation, and long-term progestin-only contraceptive use.

Squamous Metaplasia

At puberty, the rise in estrogen levels leads to increased glycogenation o the LG nonkeratinized squamous epithelium. In

providing a carbohydrate source, glycogen allows vaginal ora

to be dominated by lactobacilli, which produce lactic acid. T e

resultant acidic vaginal pH is the suspected stimulus or squamous metaplasia, which is the normal replacement o columnar by

squamous epithelium on the cervix. Relatively undif erentiated

reserve cells underlying the cervical epithelia are the apparent

precursors o the new metaplastic cells, which dif erentiate urther

into squamous epithelium. T is normal process creates a progressively widening band o metaplastic and maturing squamous

epithelium, termed the trans ormation zone ( Z), between the

congenital (original) columnar epithelium and the squamous

epithelium (Fig. 29-5)

FIGURE 29-2 Benign lower genital tract lesions. A. Condylomata

tend to be multifocal, asymmetric, and have multiple papillations

arising from a single base. B. Micropapillomatosis labialis is a normal variant of vulvar anatomy encountered along the inner aspects

of the labia minora and lower vagina. In contrast to condylomata,

projections are uniform in size and shape and arise singly from

their base attachments

FIGURE 29-3 Endocervical anatomy. A. Sagittal view of the cervix. In

this drawing, a portion of the endocervical canal is boxed. (Modified

with permission from Eastman NJ, Hellman LM: Williams Obstetrics

12th ed., New York: Appleton-Century-Crofts, Inc; 1961.) B. The

endocervix is lined by a simple columnar, mucin-secreting epithelium.

Crypts and small exophytic projections appear pseudopapillary when

viewed in cross section. (Used with permission from Dr. Kelley Carrick.)

FIGURE 29-4 The location of the squamocolumnar junction (SCJ) is variable. A. The SCJ is located on the ectocervix and is fully visualized.

B. The SCJ is located within the endocervical canal and is not visible.

FIGURE 29-5 Schematic describing relevant cervical landmarks.

The original squamocolumnar junction (SCJ) marks the terminal

site of the upward migration of squamous epithelium during

embryonic development. The SCJ location moves with age and

hormonal status. With higher estrogen states, the SCJ everts outward. With low-estrogen states and with squamous metaplasia,

the SCJ moves closer to the cervical os. The transformation zone

consists of the band of squamous metaplasia lying between the

original SCJ and new (current) SCJ. As the metaplastic epithelium

matures, it moves outward relative to the newer, less mature areas

of metaplasia and can become indistinguishable from the original

squamous epithelium.

FIGURE 29-6 The human papillomavirus life cycle is completed in
synchrony with squamous epithelium differentiation. Early genes,
including the E6 and E7 oncogenes, are expressed most strongly
within the basal and parabasal layers. The late genes encoding capsid proteins are expressed later in the superficial layers. Intact virus
is shed during normal desquamation of superficial squames. Late
genes are not strongly expressed in high-grade neoplastic lesions.

Transformation Zone and Cervical Neoplasia

Nearly all cervical neoplasia, both squamous and columnar,

develops within the Z, usually adjacent to the new or current

SCJ. Cervical reserve and immature metaplastic cells appear

particularly vulnerable to the oncogenic ef ects o HPV and

cocarcinogens (Stanley, 2010a). Squamous metaplasia is most

active during adolescence and pregnancy. T is may explain why

early ages o rst sexual activity and o rst pregnancy are cervical cancer risk actors.

h UMAN PAPILLOMAVIRUS

■ Basic Virology

T e causative role o HPV in nearly all cervical neoplasia and a

signi cant proportion o vulvar, vaginal, and anal neoplasia is

rmly established. HPV primarily in ects human squamous or

metaplastic epithelial cells. It is a double-stranded DNA virus

with a protein capsid unique to each viral type. More than 150

genetically distinct HPV types have been identi ed, and o

these, approximately 40 types in ect the LG (Doorbar, 2012).

T e circular HPV genome consists o only nine identi ed

open reading rames (Stanley, 2010a). In addition to one regulatory region, the six “early” (E) genes govern unctions early

in the viral li e cycle, including DNA maintenance, replication,

and transcription. Early genes are expressed in the lower squamous epithelial layers (Fig. 29-6). T e two “late” genes encode

the major (L1) and minor (L2) capsid proteins. T ese proteins

are expressed in the super cial epithelial layers late in the viral li e

cycle and during the assemblage o new, in ectious viral particles.

Sequential HPV gene expression is synchronous with and dependent on squamous epithelial dif erentiation. T us, completion

o the viral li e cycle takes place only within an intact, ully di -

erentiating squamous epithelium (Doorbar, 2012). T is makes

it nearly impossible to culture HPV in vitro. HPV is a nonlytic

virus, and there ore in ectiousness depends on normal desquamation o in ected epithelial cells. A new in ection is initiated

when the L1 and L2 capsid proteins bind to the epithelial basement membrane and/or basal cells, permitting entry o HPV

viral particles into cells o a new host (Sapp, 2009).

Genital HPV is the most common sexually transmitted

disease (S D) in the United States, and most sexually active

adults are in ected at some time (Dunne, 2014). Most incident HPV in ections develop in women younger than 25 years.

T e point prevalence in U.S. emales aged 14 to 59 years is 27

percent. It is highest in those aged 20 to 24 years (45 percent)

and becomes less prevalent with increasing age (Dunne, 2007).

Clinically, HPV types are classi ed as high-risk (HR) or lowrisk (LR) based on their strength o association with cervical

cancer. LR HPV types 6 and 11 cause nearly all genital warts,

laryngeal papillomas, and a minority o subclinical HPV in ections. LR HPV in ections are rarely, i ever, oncogenic.

In contrast, persistent HR HPV in ection is now viewed

as required or the development o cervical cancer. HR HPV

types, including 16, 18, 31, 33, 35, 45, and 58, along with a

ew less common types, account or approximately 95 percent

o cervical cancer cases worldwide (Muñoz, 2003). HPV 16 is

the most oncogenic, accounting or the largest percentage of

CIN 3 lesions (45 percent) and cervical cancers (55 percent)

worldwide. It is also the dominant type in other HPV-related

anogenital and oropharyngeal cancers (Schif man, 2010; Smith,

2007). Although the prevalence o HPV 18 is much lower than

that o HPV 16 in the general population, it is ound in 13

percent o cervical squamous cell carcinomas, and in an even

higher proportion o cervical adenocarcinomas and adenosquamous carcinomas (approximately 40 percent) (Bruni, 2010;

Smith, 2007). ogether, HPVs 16 and 18 account or approximately 70 percent o cervical cancers worldwide, 68 percent o

squamous cell carcinomas, and 85 percent o adenocarcinomas

(Bosch, 2008). HPV type 45 is the third most common ound

in cervical cancers (de Sanjose, 2010). HPV 16 accounts or

more than 1 in 5 cervical HPV in ections and is the most common HPV ound among low-grade lesions and in women without neoplasia (Bruni, 2010; Herrero, 2000). T us, HR HPV

in ection does not cause neoplasia in most in ected women,

and additional host, viral, and environmental actors determine

progression to LG neoplasia.

■ Transmission

T e most important risk actors or the acquisition o genital

HPV in ection are the number o li etime and recent sexual partners and early age at rst sexual intercourse (Burk, 1996; Fairley,

1994; Franco, 1995). Genital HPV is transmitted by direct,

usually sexual, contact with the genital skin, mucous membranes,

or body uids o an individual with either warts or subclinical

HPV in ection. T e in ectivity o inapparent (subclinical) HPV

is assumed to be high. HPV is thought to access to the basal

cell layer and basement membrane through microabrasions o

the genital epithelium during sexual contact. Once in ected,

these basal cells may become a viral reservoir (Stanley, 2010b).

Cervical HR HPV in ection generally requires penetrative

intercourse. Oral-genital and hand-genital HPV transmissions

are possible but are much less common than with genitalgenital transmission (Winer, 2003). Women who have sex with

women have rates o HR HPV positivity, abnormal cervical

cytology, and high-grade cervical neoplasia similar to those o

heterosexual women, but undergo cervical cancer screening less

o ten. Women with or without past sexual experiences with

men have a similar risk, implying that digital, oral, and perhaps object contact places them at risk o HR HPV in ection

(Marrazzo, 2000). T us, all women who are sexually active

should undergo cervical cancer screening according to current

recommendations regardless o sexual orientation.

Genital HPV detection, including HR HPV, has been

reported in apparently sexually naïve girls and young women

(Doer er, 2009; Winer, 2003). Nonetheless, genital warts that

develop in children a ter in ancy are always reason to consider the

possibility o sexual abuse. HPV in ection by nonsexual contact,

autoinoculation, or omite trans er appears possible. T is is

supported by reports o nongenital HPV types in a signi cant

minority o pediatric and adolescent genital wart cases (Cohen,

1990; Obalek, 1990; Sieg ried, 1997).

Congenital HPV in ection rom vertical transmission

(mother to etus or newborn) beyond transient skin colonization is rare. Conjunctival, laryngeal, vulvar, or perianal warts present at birth or that develop within 1 to 3 years o birth are

most likely due to perinatal exposure to maternal HPV (Cohen,

1990). In ection is not linked to maternal genital warts or route

o delivery (Silverberg, 2003; Syrjänen, 2010). Accordingly,

cesarean delivery generally is not recommended or maternal

HPV in ection. Exceptions include cases o large genital warts

that would obstruct delivery or might avulse and bleed with

cervical dilation or vaginal delivery.

FIGURE 29-7 The natural history of genital human papillomavirus

(HPV) infection varies between individuals and over time. Most

infections are subclinical. Spontaneous resolution is the most common outcome. Neoplasia is the least common manifestation of

HPV infection, developing as the result of persistent infection with

integration of HPV DNA

■ Infection Outcomes

Genital HPV in ection causes variable outcomes (Fig. 29-7).

T ese can be broadly grouped as latent or expressed in ections.

In ection expression may be productive, that is, creating in ectious viral particles, or it may be neoplastic, causing preinvasive

disease or malignancy. Most productive in ections are subclinical, but a smaller percentage yields clinically apparent genital

warts. Last, HPV in ection can be transient or can become

persistent. High-grade neoplasia (CIN 3 or worse) is the least

common outcome o genital HPV in ection, requiring HPV

persistence.

Latent in ection re ers to that in which cells are in ected, but

HPV remains quiescent. T ere are no detectable tissue ef ects,

as the virus is not actively replicating. T e virus is present below

detectable levels. T us, it is uncertain whether apparent clearance o the HPV constitutes true eradication o HPV rom

in ected tissues or whether it re ects latency.

Productive in ections are characterized by viral li e-cycle

completion and plenti ul production o in ectious viral particles (Stanley, 2010a). Viral gene expression and assemblage are

completed in synchrony with terminal squamous dif erentiation, concluding with desquamation o in ected squames. T ese

in ections have little or no malignant potential because the

HPV genome remains episomal and its oncogenes are expressed

at very low levels (Durst, 1985; Stoler, 1996).

In both emale and male genital tracts, productive HPV

in ections cause either visible genital warts (condyloma acuminata) or much more commonly, subclinical in ections.

Subclinical in ections may be indirectly identi ed as low-grade

cytologic, colposcopic, or histologic abnormalities. However,

all these observational diagnoses are subjective and poorly

reproducible. HPV testing more accurately re ects HPV in ection but is limited to speci c HPV types and viral loads.

With neoplastic in ection (CIN 3 and cervical cancer),

the circular HPV genome is disrupted and integrates at random locations into a host chromosome (Fig. 30-1, p. 659).

Unrestrained transcription o the E6 and E7 oncogenes ollows (Durst, 1985; Stoler, 1996). T e E6 and E7 oncoproteins

produced inter ere with and accelerate degradation o p53 and

pRb, which are key tumor suppressor proteins produced by the

host (Fig. 30-2, p. 659). T is leaves the in ected cell vulnerable to malignant trans ormation by loss o cell-cycle control,

cellular proli eration, and accumulation o DNA mutations

over time (Doorbar, 2012).

In resultant preinvasive lesions, normal epithelial dif erentiation is disrupted and incomplete. T e degree o disruption

is used to grade histology as low-grade (encompassing HPV

changes and CIN 1) or high-grade (CIN 2, CIN 3, and CIS).

T e average age at diagnosis o low-grade cervical disease is

younger than that o high-grade lesions and invasive cancers.

T us, disease was thought to progress rom milder- to highergrade lesions over time. An alternative theory now proposes

that low-grade lesions are generally acute, transient, and not

oncogenic. High-grade lesions and cancers are monoclonal and

arise de novo rather than rom preexistent low-grade disease

(Baseman, 2005; Kiviat, 1996).

T e pathogenesis o HPV-related neoplasia at other anogenital sires is thought to be similar to that o the cervix. Genital

HPV in ection is usually multi ocal and involves the cervix

most o ten. Neoplasia at one site increases the risk o neoplasia

elsewhere in the LG (Spitzer, 1989).

■ Natural history of Infection

In ection with HPV, predominantly HR types, is very common

soon a ter initiation o sexual activity (Brown, 2005; Winer,

2003). T is in ection o ten accompanies sexual debut and is

not evidence o promiscuity (Collins, 2002).

Most HPV in ection and related lesions, whether clinical or

subclinical, spontaneously resolve, especially in adolescents and

young women (Ho, 1998; Moscicki, 1998). Questions have

been raised as to whether apparent clearance re ects true resolution or limited testing sensitivity (Winer, 2011). Several studies

show that LR HPV in ections resolve aster than those involving HR HPV (Moscicki, 2004; Schlecht, 2003; Woodman,

2001). Younger women requently change HPV types, re ecting transience o in ection and sequential rein ection by new

partners rather than persistence (Ho, 1998; Rosen eld, 1992).

Simultaneous or sequential in ection with multiple HPV types

is common (Schif man, 2010).

Persistent HR HPV in ection is necessary or the development o cervical neoplasia. A minority o HPV in ections

become persistent, but most young women (65 percent) with

HPV 16/18 in ections lasting more than 6 months will develop

SIL ( rottier, 2009). T e risk o progression to high-grade neoplasia increases with age, as HPV in ection in older women

is more likely to re ect persistence (Hildesheim, 1999). Cellmediated immunity likely plays the largest role in HPV in ection persistence and in progression or regression o benign and

neoplastic lesions.

■ Infection Diagnosis

HPV in ection is suspected based on clinical lesions or results

o cytology, histology, and colposcopy, all o which are subjective and o ten inaccurate. Moreover, serology is unreliable and

cannot distinguish past rom current in ection (Dillner, 1999).

As noted, culture o HPV is not easible. T us, diagnosis is

con rmed only by the direct detection o HPV nucleic acids by

methods that include in situ hybridization, nucleic acid amplication testing (NAA ), polymerase chain reaction (PCR),

or others (Molijn, 2005). Currently, our HR HPV tests are

approved by the Food and Drug Administration (FDA) or

clinical use, and all use NAA to detect any o 13 or 14 HR

HPV types. wo o these tests report speci cally the presence

o HPV 16 or HPV 18 to aid risk strati cation and customized

management. Due to clinical test limitations, a negative test

result does not exclude HPV in ection. T ere ore, these tests

are not indicated or use ul or routine S D screening. LR HPV

testing has no indication and can lead to inappropriate expense,

urther evaluation, and unnecessary treatment.

T e clinical role o HR HPV testing or cervical cancer

screening and or surveillance o SIL continues to evolve. It is

not of ered as a screen or HPV in ection outside o current

guidelines. Namely, appropriate clinical uses or HR HPV

testing include: cotesting with cervical cytology screening in

women aged 30 years or older, triage or surveillance o certain

abnormal cytology results and untreated CIN, and posttreatment surveillance (Davey, 2014). One HR HPV test (cobas

HPV est) was recently FDA approved as a stand-alone screening test or cervical cancer or women 25 years o age and older

(p. 634).

I typical genital warts are ound in a young woman or i

high-grade cervical neoplasia or invasive cancer is identi ed

by cytology or histology, then HPV in ection is assumed, and

HPV testing is unnecessary. Because o high HPV prevalence

in young women (less than age 25), HR HPV testing or cervical cancer screening is not recommended. HPV testing is not

FDA approved or use in women a ter complete hysterectomy,

and there are no guidelines or managing HPV test results in

these women.

■ Infection Treatment

T e indications to treat HPV-related LG disease are symptomatic warts, high-grade neoplasia, or invasive cancer. No

ef ective treatment resolves subclinical or latent HPV in ection. Needless physical LG damage may result rom unrealistic attempts to eradicate HPV in ections, which are usually

sel -limited. Encouragement o positive health behaviors and

optimal management o immune compromise seems sensible.

reatment o cervical LSIL (HPV changes or CIN 1) is not

necessary and is considered only a ter observation or at least

2 years.

Various treatment modalities are available or genital warts

and are chosen according to lesion size, location, and number

(Rosales, 2014). Mechanical removal or destruction, topical

immunomodulators, and chemical or thermal coagulation can

be used ( able 3-15, p. 71). Examination o a male partner

does not bene t a emale partner either by in uencing rein ection or by altering the clinical course or treatment outcome or

genital warts or LG neoplasia (Centers or Disease Control

and Prevention, 2010).

■ Infection Prevention

Behavior

Sexual abstinence, delaying coitarche, and limiting the number

o sexual partners are logical strategies to avoid genital HPV

in ection and its adverse ef ects. However, evidence is lacking rom trials o counseling and sexual practice modi cation.

Condoms do not cover all potentially HPV-in ected anogenital

skin. T ere ore, condoms may not be completely protective but

are likely to reduce acquisition and transmission o HPV. Winer

and associates (2003) conducted the rst prospective study o

male condom use and showed reductions in HPV in ection rates

in young women even i condoms were used inconsistently.

Vaccines

T ese of er the greatest promise or prevention and possibly reversal o its sequelae in those already in ected. Local and humoral

immunity likely protect against incident in ection, and prophylactic vaccines elicit type-speci c humoral antibody production

that prevents new HPV in ection by blocking its entry into host

cells (Stanley, 2010b). T ey do not prevent transient HPV positivity or resolve preexistent in ection. HPV vaccines have the

potential to prevent malignancies at least six body sites that

include cervix, vulva, vagina, penis, anal canal, and oropharynx.

Currently, three HPV vaccines are FDA approved or prevention o incident HPV in ection and cervical neoplasia.

T ey use recombinant technologies or the synthetic production o the L1 capsid proteins o each HPV type included

in the vaccine. T e resultant virus-like particles are highly

immunogenic but are not in ectious as they lack viral DNA

(Stanley, 2010b).

Cervarix (HPV2) is a bivalent vaccine against HPVs 16 and

18. Gardasil (HPV4) is a quadrivalent vaccine against HPV types

6, 11, 16, and 18. HPV4 is being replaced by Gardasil 9 (HPV9),

a nonavalent vaccine. HPV9 protects against all HPV types in

HPV4 plus types 31, 33, 45, 52, and 58. Coverage o these

additional HR HPV types will bring the theoretical percentage

o cervical cancers prevented rom 65 percent to approximately

80 percent. All three vaccines contain adjuvants that boost the

immune response to vaccine antigens. T ey are administered in

three intramuscular doses during a 6-month period. Speci cally,

the second dose is given 1 to 2 months a ter the rst dose, and

the third dose is given 6 months a ter the rst dose. Prolongation

o the dosing schedule does not appear to diminish immunogenicity. Optimal vaccination strategies administer these prior

to sexual activity initiation, when the potential bene t is great

est. However, a history o prior sexual activity, HPV-related

disease, or HPV-test positivity should not deter vaccine administration. esting or HPV is not recommended prior to vaccination (American College o Obstetricians and Gynecologists,

2014a). T e Advisory Committee on Immunization Practices

(ACIP) currently recommends that HPV vaccine be administered routinely to girls aged 11 to 12 years (as early as age 9

years). Vaccination is also recommended or 13- to 26-year-old

women not previously vaccinated (Markowitz, 2014; Petrosky,

2015). Vaccination can be given during lactation but is avoided

during pregnancy (American College o Obstetricians and

Gynecologists, 2014a). Immune compromised women are candidates to receive the vaccine and show high seroconversion

rates despite the theoretical risk o a blunted immune response.

All three vaccines show nearly 100-percent e cacy in preventing incident in ection and high-grade cervical neoplasia

rom HPV types included in the vaccines (Future II Study

Group, 2007; Paavonen, 2009; Joura, 2015). HPV4 and HPV9

additionally protect against HPV types 6 and 11, which cause

nearly all genital warts, laryngeal papillomatosis, and many lowgrade cytologic abnormalities. HPV4 and HPV9 are approved

or genital wart prevention in both males and emales. T ey are

also FDA approved or the prevention o vaginal, vulvar, and

anal neoplasia. HPV2 does not prevent genital warts. It is not

approved or extracervical LG disease prevention, although

theoretically it should.

HPV vaccines are highly immunogenic with maintenance

o protection or at least 5 to 8 years a ter vaccination (Ferris,

2014; Harper, 2006). No evidence supports the need or later

booster dosing. T ey have excellent sa ety pro les, are welltolerated, and can be administered along with other recommended vaccinations.

Because HPV vaccines prevent most, but not all, HPVrelated cervical cancers, cervical cancer screening should continue per current guidelines. Countries with high vaccination

rates have seen dramatic reductions in anogenital warts, and

reductions in Pap abnormalities and cervical neoplasia are

expected (Ali, 2013). Despite suboptimal vaccination rates in

the United States, HPV4 vaccine-type in ections among U.S.

adolescents have decreased by 56 percent since vaccine introduction in 2006 (Stokley, 2014).

CERVICAL INTRAEPITh ELIAL NEOPLASIA

■ Risk Factors

Henk and associates (2010) estimated that 412,000 cases o

CIN are diagnosed in the United State annually. Risk actors

are similar to those o invasive cervical cancer, and CIN is most

strongly related to persistent genital HR HPV in ection and

increasing age (Table 29-1) (Ho, 1995; Kjaer, 2002; Remmink,

1995).

T e median age o cervical cancer diagnosis in the United

States (late th decade) is approximately a decade later than

or CIN. In an older woman, HPV in ection is more likely to

persist than resolve. Older age is linked with waning immune

competence and also allows accumulation o genetic mutations

over time that can lead to malignant cellular trans ormation.

Additionally, adverse socioeconomic actors and decreased need

or prenatal care and contraception cause older women to be

screened less o ten.

Behavioral risk actors or CIN mirror those or HPV acquisition and include early onset o sexual activity, multiple sexual

partners, and male partner promiscuity (Buckley, 1981; de Vet,

1994; Kjaer, 1991). A ter adjustments or HPV positivity and

lower socioeconomic status, tobacco use also increases the preinvasive disease risk (Castle, 2004; Plummer, 2003).

Dietary de ciencies o certain vitamins such as A, C, E, beta

carotene, and olic acid may alter cellular immunity to HPV

in ection. T is may promote viral in ection persistence and

cervical neoplasia (Paavonen, 1990). However, in the United

States, lack o association between dietary de ciencies and cervical disease may re ect the relatively su cient nutritional status o even lower-income women (Amburgey, 1993).

Combination oral contraceptives (COCs) have been linked with

an increased risk o cervical cancer in current users (International

Collaboration o Epidemiological studies o Cervical Cancer,

2007). Possible mechanisms include increased persistence o HPV

in ection and oncogene expression (de Villiers, 2003). Conversely,

multiple studies have ailed to nd an increased CIN risk in users

o hormonal contraceptives or postmenopausal hormone therapy

(Castle, 2005; Harris, 2009; Yasmeen, 2006). DES exposure in

utero appears to double the risk o developing high-grade cervical

disease in addition to an increased risk o cervical and vaginal clear

cell adenocarcinoma (Hoover, 2011).

Increasing parity has been correlated with cervical cancer

risk, but it is unclear i this is related to earlier sexual activity,

a progestin-exposure ef ect, or other actors. Immune suppression during pregnancy, hormonal in uences on cervical epithelium, and physical trauma related to vaginal deliveries have all

been suggested (Brinton, 1989; Muñoz, 2002).

Immunosuppressed women in general show increased risks

or CIN and or greater lesion severity, multi ocal lesion pattern, and lesions at multiple LG sites. T ey also experience

higher rates o treatment ailure, persistence, and recurrence o

LG disease compared with those who are immunocompetent.

Speci cally, human immunode ciency virus (HIV)-positive

women have higher rates o abnormal Pap results and CIN compared with HIV-negative women (p. 651). ransplant recipients have an increased risk o developing a malignancy a ter

transplantation, including neoplasms o the LG and anal canal

(Gomez-Lobo, 2009). Women on immunosuppressive medications or other disorders have higher rates o LG neoplasia.

Inadequate screening is another risk actor. O women diagnosed with cervical cancer in the United States, approximately

60 percent either have never been screened (50 percent) or have

not had a Pap test during the previous 5 years (10 percent)

(American College o Obstetricians and Gynecologists, 2012b).

Lack o screening is a major contributor to higher rates o cervical cancer in socioeconomically disadvantaged women, particularly those o minority ethnicity, rural residence, or older age,

and those who are recent immigrants (Benard, 2007).

■ Natural history

Preinvasive lesions can spontaneously regress, remain stable, or

progress. T e risk o progression to invasive cancer increases

with the severity o CIN. Estimates o CIN progression, persistence, and regression are provided in a review by Ostor (1993)

and shown in Table 29-2. Low-grade lesions are thought to be

mani estations o acute HPV in ection, and most spontaneously

regress within a ew years. High-grade lesions are less likely to

do so. Castle and coworkers (2009b) calculated that approximately 40 percent o CIN 2 regresses spontaneously within

2 years. T is is even more requent (greater than 60 percent)

in young, healthy women (Moscicki, 2010). CIN 2 is thought

to be a mixture o low- and high-grade lesions that are di cult

to distinguish histologically, rather than an intermediate step

in the progression rom CIN 1 to CIN 3. T e risk o progression to invasive cancer o biopsied but otherwise untreated CIN

3 lesions approximates 30 percent over 30 years (McCredie,

2008).

CERVICAL NEOPLASIA DIAGNOSIS

Cervical cancer screening ideally nds preinvasive lesions that

can be eradicated or nds early-stage cervical cancer that can

be treated success ully. Cervical cancer screening was previously

limited to cervical cytology. But, during the past decade, HR

HPV testing has also become an important screening tool.

In general, LG preinvasive lesions are visible only with

aided inspection. One exception is VIN, which is generally visible, palpable, or both. Only cervical lesions at either end o the

neoplastic disease spectrum are grossly visible, namely, condylomata and invasive cancers. Accordingly, all symptoms suspicious or cervical neoplasia and grossly visible cervical lesions

require prompt biopsy.

■ Cervical Cytology

Cervical cytologic screening is one o modern medicine’s

great success stories. It detects most cervical neoplasia during

the typically prolonged premalignant or early occult invasive

phases, when treatment outcomes are optimal. Conventional

glass slides (traditionally called the Pap smear) and liquid-based

Pap tests are considered equally acceptable or screening by

all current guidelines (American College o Obstetricians and

Gynecologists, 2012b; Saslow, 2012; U.S. Preventive Services

ask Force, 2012).

Introduced in the 1940s, cervical cytology has never been

evaluated in a randomized, controlled, or masked trial (Koss,

1989). However, countries with organized screening programs

have consistently realized dramatic declines in both cervical

cancer incidence and mortality rates. T e Pap test’s speci city is consistently high, approximating 98 percent. However,

estimates o its sensitivity or detection o CIN 2 or worse

are lower, are more variable, and range rom 45 to 65 percent (Whitlock, 2011). T is imper ect sensitivity is balanced

by recommendations or repetitive screening throughout a

woman’s li e. Although the incidence o cervical squamous

carcinoma continues to decline, both the relative and absolute

incidences o adenocarcinoma have increased, particularly in

women younger than 50 (Herzog, 2007). Adenocarcinoma and

adenosquamous carcinoma now account or at least 20 percent

o cervical cancers. T is increase may be due in part to the Pap

test’s lower sensitivity or detection o adenocarcinoma than or

squamous cancers and their precursor lesions.

False-negative Pap test results may ollow sampling error,

in which abnormal cells are not present in the Pap test, or by

screening error, in which the cells are present but missed or

misclassi ed by the screener (Wilkinson, 1990). Mandated

quality assurance measures and computerized slide-screening

technologies address screening errors. Suboptimal management

o abnormal results by providers and ailure o patient ollow up

also contribute to avoidable cases o cervical cancer. Clinicians

can maximize the bene t o screening by obtaining an optimal

cytologic specimen and by adhering to current evidence-based

guidelines or the management o abnormal test results.

Performing a Pap Test

Ideally, Pap tests are scheduled to avoid menstruation. Patients

should abstain rom vaginal intercourse, douching, vaginal tampon use, and intravaginal medicinal or contraceptive creams

or a minimum o 24 to 48 hours be ore a test. reatment o

cervicitis or vaginitis prior to Pap testing is optimal. However,

Pap testing is not de erred due to unexplained discharge or

unscheduled bleeding, as these may be signs o cervical or other

genital tract cancers.

As shown in Figure 21-9 (p. 488), the appearance o cervical

squamous cells varies throughout the menstrual cycle and with

hormonal status. T us, clinical in ormation aids accurate Pap

interpretation and o ten includes: date o last menstrual period,

current pregnancy, exogenous hormone use, menopausal status,

complaints o abnormal bleeding, and prior abnormal Pap test

results, CIN, or other LG neoplasia. Additionally, intrauterine devices (IUDs) can cause reactive cellular changes, and their

presence is noted. Full visualization o the cervix is essential

or detection o gross lesions and SCJ identi cation. Speculum

placement should be as com ortable as possible. A thin coating

o water-based lubricant can be used on the outside o the

speculum blades without compromising Pap test quality or

interpretation (Gri th, 2005; Harmanli, 2010). ouching the

cervix prior to per orming a Pap test is avoided, as dysplastic epithelium may be inadvertently removed with minimal trauma.

Discharge covering the cervix may be care ully absorbed by a

large swab, with care not to contact the cervix. Vigorous blotting

or rubbing may cause scant cellularity or a alse-negative Pap

test result. When indicated, additional sampling to detect other

cervical or vaginal in ection may ollow Pap test collection.

Sampling o the trans ormation zone at the SCJ is paramount to the sensitivity o the Pap test. echniques are adapted

and sampling devices chosen according to SCJ location, which

varies widely with age, obstetric trauma, and hormonal status.

Women known or suspected o in utero DES exposure may also

bene t rom a separate Pap test o the upper vagina, as these

women carry an additional risk or vaginal cancer.

T ree types o plastic devices are commonly used to sample

the cervix: the spatula, broom, and endocervical brush (also

known as a cytobrush) (Fig. 29-8). A spatula predominantly

samples the ectocervix. An endocervical brush samples the

endocervical canal and is used in combination with a spatula.

A broom samples both endo- and ectocervical epithelia simultaneously but can be supplemented by an endocervical brush.

Wooden collection devices and cotton swabs are no longer recommended due to their in erior collection and release o cells.

A spatula is oriented to best t the cervical contour, straddle

the squamocolumnar junction, and sample the distal endocervical canal. A clinician rmly scrapes the cervical sur ace,

completing at least one ull rotation. A ter the spatula sample

is obtained, the endocervical brush, with its conical shape and

plastic bristles, is inserted into the endocervical canal only until

the outermost bristles remain visible just within the external os.

T is prevents inadvertent sampling o lower uterine segment

cells, which can be mistaken or atypical cervical cells. o avoid