CERVICAL CANCER SCREENING OVERVIEW - The Papanicolaou Smear (Pap Test) Is A Test
CERVICAL CANCER SCREENING OVERVIEW - The Papanicolaou Smear (Pap Test) Is A Test
CERVICAL CANCER SCREENING OVERVIEW - The Papanicolaou Smear (Pap Test) Is A Test
A vaccine is available to help prevent infection with some types of HPV (types 6, 11, 16, and 18)
and is recommended for girls or women between the ages of 9 and 26 years and for boys or men
between the ages of 9 and 21 years, but can be given up to 26 years of age. Smoking cessation is
recommended for those who smoke.
CERVICAL CANCER SCREENING TESTS There are several ways to screen for cervical
cancer. The traditional screening test is called a Pap test.
Pap smear The Pap test is a method of examining cells from the cervix (picture 1). The cervix is
located at the lower end of the uterus (figure 1).
To perform a Pap test, a doctor or other health care provider will perform a pelvic exam and use a
small brush or spatula to collect cells from the cervix. The cells are smeared on a glass slide (called
a traditional Pap smear) or added to a preservative fluid (called liquid-based, thin layer testing).
Studies that have compared the traditional Pap smear to liquid-based cytology do not prove one
test to be more accurate than another.
HPV testing An HPV test can be done along with a Pap test or as a separate test. Like a Pap
test, the HPV test is done during a pelvic exam, using a small brush to collect a sample from the
cervix. Women who are under age 30 are not usually tested for HPV because many women in this
age group have temporary infections, which will go away without treatment.
WHO SHOULD HAVE HPV TESTING? If you are 30 years or older, your doctor or nurse may
recommend HPV testing in addition to a Pap test. If your HPV test and Pap test are negative, repeat
testing is not usually needed for five years. HPV testing may also be done if the results of your Pap
test results are unclear.
WHO SHOULD HAVE A PAP SMEAR?
Younger women In the United States, the first Pap test is recommended at age 21; some other
countries suggest that screening begin at age 25. Cervical cancer is very rare in younger women.
Pap smear screening before age 21 in girls and women who are sexually active is not
recommended because of the very high risk of false-positive results (that is, do not indicate a
precancerous condition) because many HPV infections in this group are temporary. There is
concern that procedures done to follow-up on these results may impair a young womans future
fertility.
In the past, experts recommended that every woman have a Pap test every year. This has changed,
and Pap testing is suggested every three years for most women over age 21. More frequent testing
may be needed if test results are not normal, or for women with HIV disease or other specific
immune system conditions.
Even if you have had a vaccine for human papillomavirus, you will still need cervical cancer
screening. (See "Patient information: Human papillomavirus (HPV) vaccine (Beyond the Basics)".)
Older women Most experts feel that women who are 65 years or older can stop having Pap
tests if:
You have had Pap tests on a regular basis in the past
You have had at least three normal Pap tests in a row (or two tests with combination Pap and
HPV test) over the past 10 years, with the most recent within the past five years
After hysterectomy Women who have had a total hysterectomy (your uterus and cervix were
removed) do not need a Pap test, unless:
The hysterectomy did not remove your cervix (eg, if the hysterectomy was "subtotal")
Your hysterectomy was done because of cervical cancer or precancer
You were exposed to diethylstilbestrol (DES) during your mother's pregnancy
PREPARING FOR YOUR PAP SMEAR A Pap test can be done at any time during your
menstrual cycle.
PAP SMEAR RESULTS The results from your Pap test will be available a few weeks after your
visit. Pap test results may be reported as:
Negative Pap tests that have no abnormal, precancerous, or cancerous cells are labeled as
"Negative for intraepithelial lesion or malignancy.
Abnormal results Cervical cells may appear abnormal for a variety of reasons. For example,
you may have a cervical infection, or you may have a precancerous area or even cervical cancer.
Follow-up testing If your Pap test is abnormal, or if your Pap test is normal but your HPV test is
abnormal (positive), you may need follow-up testing; the best strategy depends on several
individual factors.
The epidemiology and disease associations of HPV infections will be reviewed here. The clinical
manifestations, diagnosis, treatment, and prevention of these infections and their association with
malignancy are discussed separately. (See "Virology of human papillomavirus infections and the
link to cancer" and "Recommendations for the use of human papillomavirus vaccines".)
TISSUE TROPISM Different human papillomavirus (HPV) types have a propensity to infect
different body sites (table 1).
Cutaneous Certain HPV types have a predilection for cutaneous epithelium and are found in
plantar warts, common warts, flat warts, and butcher's warts [1]. HPV types associated with plantar
and common warts include type 1 and types 2 and 4, respectively. Flat warts are most often caused
by HPV types 3 and 10, while butcher's warts (common warts that tend to occur in meat, poultry,
and fish handlers) are most often associated with HPV types 7 and 2 [2].
Bowen's disease, a form of high-grade intraepithelial neoplasia, has both genital and extragenital
forms [3]. It can occur on the fingers, toes, palms, feet, and on the genital mucosa. Multiple HPV
types have been isolated from these lesions; including HPV types 16, 18, 31, 32, 34, and others
[1,3,4].
Epidermodysplasia verruciformis is a rare, probably autosomal recessive condition, characterized
by the appearance of HPV-induced wart-like lesions early in childhood, with malignant
transformation in approximately half of patients during adulthood, often in skin surfaces with sun
exposure. Multiple HPV types have been isolated from these lesions, but HPV types 5 and 8 appear
to have the most malignant potential in these individuals [5].
Anogenital epithelium HPV types with a predilection for anogenital keratinized skin and
mucous membrane infection also exist. Common sites for infection include: the penis, scrotum,
perineum, anal canal, perianal region, vaginal introitus, vulva, and cervix. The major manifestations
of anogenital HPV include:
Genital warts (condyloma acuminatum) Condylomata acuminata (also known as genital or
venereal warts) are benign anogenital warts, caused most often by HPV types 6 and 11 [6,7].
(See "Condylomata acuminata (anogenital warts) in adults".)
Squamous intraepithelial lesions and/or carcinoma of the vagina, vulva, cervix, anus or penis
HPV infection has been clearly linked to all or nearly all squamous intraepithelial lesions and
cancers of the cervix and anus. HPV is also linked to a subset of penile, vulvar, and vaginal
cancers. Of the 14 most common oncogenic HPV types associated with these cancers, HPV
16 is the most common and associated with the highest risk of progression to cancer [2,4,6,810].
The presence of a cervical transformation zone is not necessary for oncogenic HPV to infect the
female genital tract. As a result, the prevalence of oncogenic HPV subtypes in the vagina is similar
in women who have and have not undergone hysterectomy [11]. Similarly, HPV may infect not only
the anal canal in the anal transformation zone, but also more distal sites, including the keratinized
skin of the anal verge and perianal region [12,13]. (See "Virology of human papillomavirus infections
and the link to cancer" and "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis,
and prevention" and "Anal squamous intraepithelial lesions: Diagnosis, screening, prevention, and
treatment" and "Vaginal intraepithelial neoplasia" and "Vulvar intraepithelial
neoplasia" and "Carcinoma of the penis: Epidemiology, risk factors, staging, and prognosis".)
Other mucosal surfaces An increasing body of evidence suggests a relationship between HPV
infection, particularly with HPV type 16, and squamous cell carcinoma of the oral cavity, especially
in those less than 50 years of age [14,15]. Infection of the respiratory mucosa with HPV types 6 and
11 also occurs, particularly but not exclusively in young children and infants [6].
DETECTION OF HPV HPV infection can be detected by several molecular methods, but only
testing of cervical cytological or biopsy specimens is currently clinically available. Staining of
histology specimens for HPV antigens such as capsid proteins or early region proteins such as E6
or E7 (ie, from tumor resection) can also be performed, but their clinical utility is uncertain and these
tests are not readily available. In the United States, there are no FDA-approved tests clinically
available to detect HPV infection of oropharyngeal, anal, or male genital specimens. There are also
no FDA-approved serological or blood tests to detect HPV infection.
HPV testing on cervical specimens and molecular testing methods are discussed in detail
elsewhere. (See "Cervical cancer screening tests: Techniques for cervical cytology and human
papillomavirus testing", section on 'HPV testing' and "Virology of human papillomavirus infections
and the link to cancer", section on 'Detecting HPV'.)
DISEASE ASSOCIATIONS
Nongenital warts Cutaneous human papillomavirus (HPV) infections are widespread throughout
the general population. Warts occur in 10 percent of children, with a peak incidence between the
ages of 12 and 16 [16]. Nongenital warts are not confined solely to the pediatric population; as
many as 3.5 percent of adults have nongenital warts at any given time [6]. Common warts represent
up to 71 percent of all cutaneous warts followed in frequency by plantar warts and flat warts (34 and
4 percent, respectively) [2]. Cutaneous warts can present in patients in ages ranging from 2 to 80
years. Only 16 percent of patients are over the age of 35, but in one report accounted for 11
referrals per 1000 patients annually [17].
Genital warts Population-based studies in sexually active individuals suggest that the burden of
genital warts is high, with a prevalence ranging from 1 percent in the United States to approximately
10 percent in Scandinavian countries [16,18-20]. The peak prevalence occurs in persons between
the ages of 17 and 33 years of age, and the peak incidence is in those from ages 20 to 24 years.
The incidence of HPV infection was evaluated in 8702 women who were enrolled in the placebo
arms of two randomized trials of HPV quadrivalent vaccine [21]. Approximately 3 percent developed
genital warts over four years. In a multinational cohort of 2487 healthy men, 4.5 percent developed
genital warts over a median of 18 months [22]. Risk factors for genital warts in women and men
included baseline and incident infection with HPV types 6 and 11, acquisition of new sexual
partners, and a higher number of sexual partners.
Men and women with anogenital warts frequently experience psychological distress and disruption
of sexual relationships [23,24]. (See "Condylomata acuminata (anogenital warts) in adults".)
Cervical cancer Worldwide, an estimated 500,000 cases of invasive cervical carcinoma are
diagnosed annually [25]. Cervical carcinoma was the most frequent malignancy among women in
developing countries until it was surpassed by breast cancer in the early 1990s [4]. (See "Virology
of human papillomavirus infections and the link to cancer" and "Cervical intraepithelial neoplasia:
Terminology, incidence, pathogenesis, and prevention" and "Invasive cervical cancer: Epidemiology,
risk factors, clinical manifestations, and diagnosis".)
Evidence linking HPV to cervical carcinoma is extensive [2,4,8,26], with HPV 16 accounting for
approximately 50 percent of cases and HPV 18 for 20 percent [27]. The epidemiology of high-risk
types can be illustrated by the following observations:
A study of paraffin-embedded samples representing 10,575 cases of invasive cervical cancer
from 38 countries spanning five continents demonstrated that the most common HPV types
were 16, 18, 31, 33, 35, 45, 52 and 58; HPV types 16 and 18 represented 71 percent of the
cases overall.
A pooled analysis of 11 case-control studies from nine countries involving 1918 women with
histologically confirmed squamous-cell cervical cancer and 1928 controls was performed to
better determine the risk associated with various HPV genotypes [28]. HPV DNA was found in
90 percent of the women with cervical cancer and 13 percent of controls. Fifteen HPV types
were classified as high risk (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and
82).
The prevalence of antibodies against HPV 16, the most commonly identified high-risk type,
was evaluated in almost 1600 men and women attending sexually transmitted diseases clinics
in the United States [29]. The seroprevalence of HPV 16 was 19 percent in men and 30
percent in women.
The high frequency of infection with high-risk types illustrates the potential significance of
vaccination efforts against HPV. (See "The life cycle, natural history, and immunology of human
papillomaviruses".)
A detailed discussion of other risk factors for cervical cancer is found elsewhere. (See "Invasive
cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on
'Epidemiology and risk factors'.)
Anal cancer Although a relatively uncommon cancer, the incidence of anal cancer in the United
States has increased substantially in the last three decades [30]. Most of these cases are
attributable to HPV infection, with similar high-risk types as found in cervical cancer, particularly 16
and 18 (see above). The epidemiological link of HPV infection to anal cancer is discussed in detail
elsewhere. (See "Classification and epidemiology of anal cancer", section on 'Human
papillomavirus infection'.)
Cancer of the external genitalia HPV is also linked to penile, vulvar, and vaginal cancers.
Unlike cervical and anal cancer, however, not all cancers of the external genitalia are associated
with HPV infection. In contrast to HPV-negative cancers, which are often associated with chronic
inflammation or lichen sclerosis, HPV-associated penile and vulvar cancers occur at a younger age,
exhibit basaloid instead of keratinizing pathology, do not have p53 mutations, and are associated
with sexual risk factors [31,32].
Oropharyngeal cancer HPV infection may also play a role in the pathogenesis of squamous cell
carcinomas of the head and neck. However, there are currently no clinically available tests for
detection of oropharyngeal HPV infection. Furthermore, it is as yet uncertain what the actual risk for
cancer of an individual HPV infection is and whether detecting infection would be clinically useful.
The available data on oropharyngeal HPV infection highlight that it is associated with sexual risk
factors, that it is not as common as genital HPV infection, and that detecting oropharyngeal HPV
infection at a single time-point likely has little value in assessing the risk for cancer development.
Like penile and vulvar cancer, oropharyngeal cancers consist of two broad categories of disease:
HPV-associated and non-HPV-associated. HPV-associated oropharyngeal cancers are primarily
found in the oropharynx and base of the tongue and tonsil [33-35]. HPV has also been linked to
cancer of the larynx [36]. (See"Human papillomavirus associated head and neck cancer".)
HPV-related oropharyngeal cancers occur in a younger population than the non-HPV-associated
cancers and are primarily associated with sexual risk factors [37,38]. In contrast, the non-HPVassociated cancers are associated primarily with alcohol and tobacco use and often have p53
mutations. In the United States, the incidence of HPV-associated cancers has been rising and the
incidence of non-HPV-associated cancers has been declining, such that the incidence of the former
now exceeds that of the latter [30,38]. In an age and gender-matched case-control study of 130
patients with newly diagnosed squamous cell carcinoma of the head and neck, oropharyngeal
malignancy was associated with high-risk sexual behaviors, oropharyngeal HPV infection, and HPV
16 seropositivity [33].
The prevalence of oropharyngeal HPV is generally lower than that of anogenital HPV infection
[35,39-41]. The prevalence of oropharyngeal HPV infection was evaluated in a cross-sectional
study of 5579 women and men who provided an oral sample for HPV DNA sampling [35]. The
overall prevalence of any HPV DNA was 6.9 percent, and the prevalence of HPV type 16 was 1
percent. HPV prevalence was approximately threefold more common in men compared with women
(10.1 versus 3.6 percent), consistent with the observed sex distribution for HPV-associated
oropharyngeal cancer. Oropharyngeal HPV prevalence has been associated with a greater number
of sexual (including oral sex) and open-mouthed kissing partners in both men and women, as well
as with older age and smoking [35,39,42,43].
Similarly, the incidence of oropharyngeal HPV is lower than that of anogenital HPV infection. In a
study of 1626 men aged 18 to 70 years (88 percent men who have sex with women only) without a
prior history of HPV-associated disease and with a median follow-up of 13 months, 4.4 percent
acquired an oropharyngeal infection with any HPV type and 1.7 percent with an oncogenic HPV
type [44]. The incidence of oropharyngeal HPV infection was 5.6 and 2.5 cases per 1000 personmonths for any and oncogenic types, respectively, and was constant across all age groups. In
multivariate analysis, acquisition of a new oncogenic oropharyngeal HPV infection was associated
with former or current smoking and single/divorced/separated/widowed marital status, but not with
number of sexual partners or oral sex partners. Of the infections with enough longitudinal follow-up,
45 of 81 (56 percent) oral infections with any type and 18 of 24 (75 percent) infections with
oncogenic types spontaneously cleared, at a median of six to seven months.
There is emerging evidence that HPV vaccination can also protect against oropharyngeal HPV
infection [45]. (See "Recommendations for the use of human papillomavirus vaccines", section on
'Oral disease'.)
Recurrent respiratory papillomatosis Recurrent respiratory papillomatosis (RRP) is the most
common benign laryngeal tumor in children and is thought to be caused by HPV acquired during
passage through the birth canal of an infected mother [46]. HPV 6 and 11 are the types most
commonly involved. The incidence is uncertain but has been estimated at 4.5 per 100,000 children
and 1.8 per 100,000 adults in the United States. Although benign, substantial morbidity arises from
obstruction of the larynx by the warts, and many affected children require multiple ablative
procedures [46,47]. In addition, the papillomatous lesions can rarely grow aggressively, spread into
the lungs, and undergo malignant transformation.
This condition is discussed in further detail elsewhere. (See "Hoarseness in children: Etiology and
management", section on 'Papillomatosis (HPV)'.)
RISK FACTORS FOR INFECTION Human papillomavirus (HPV) is spread from skin surface to
skin surface. Close personal contact is assumed to be of importance for the transmission of
cutaneous warts [2], while anogenital warts and HPV infection of the cervix are primarily transmitted
by genital-genital, oral-genital, anal-genital, or oral-anal contact [2,26]. However, HPV types
typically isolated from common warts (types 1 and 2) have been isolated from anogenital warts in
children, and infection of the respiratory tract mucosa (recurrent respiratory papillomatosis) is
thought to occur during passage of the fetus through an infected birth canal. (See "Hoarseness in
children: Etiology and management", section on 'Papillomatosis (HPV)'.)
The most consistent predictor of genital HPV infection has been sexual activity [48,49]. Most studies
have been performed in young women in whom the following findings have been noted:
The risk of HPV infection in women is directly related to the number of male sex partners
[18,48,50-55] and to the male partners' number of female sex partners [48].
As with other sexually transmitted infections, sex with a new partner is a stronger risk factor
than sex with a steady partner [51,54]. In a prospective cohort study of young women in San
Francisco, for example, the relative hazard was 10.1 per new partner per month [54].
Both vaginal and anal intercourse are major risk factors for HPV infection [48]. Although penetrating
vaginal intercourse is not required for transmission [51], the prevalence of HPV infection is much
lower among virgins (4 versus 22 percent in sexually active women in a report from Sweden) [53].
In one study of adolescent females with no reported history of sex, genital HPV infection was noted
in 8 percent and was associated with intravaginal cleansing, but this observation could simply
reflect unreported or nonpenetrating sexual activity [56,57]. Anal intercourse is likely an efficient
means of spread of HPV to the anal canal but it is similarly not required for transmission; other
types of contact may also play a role in transmission, such as spread through fingers or toys, or
from other genital organs infected with HPV [51,58,59].
Among heterosexual couples, type-specific concordance (ie, both partners infected with the same
HPV type) is common, almost 25 percent in one series [60]. Additionally, among discordant
heterosexual couples, female to male transmission may occur at a higher rate than male to female
transmission [61]. Transmission in either direction is typically asymptomatic [18,62].
In several studies of women, the presence of anti-HPV antibodies, indicative of prior infection, has
been associated with a decreased risk of subsequent infection with HPV of the same type,
particularly for type 16, suggesting the potential for protective immunity following natural infection
[63-65]. However, the extent and duration of such protection is unknown, and many women do not
develop antibodies following infection [66-68].
EPIDEMIOLOGY IN FEMALES A meta-analysis in 157,879 women with normal cervical cytology
demonstrated that the worldwide point-prevalence of human papillomavirus (HPV) is approximately
10 percent [69]. The highest regional prevalence was found to be in Africa, where 22 percent of
women had evidence of HPV infection. The most common types worldwide were HPV 16 and 18,
both of which are preventable by vaccination. (See "The life cycle, natural history, and immunology
of human papillomaviruses".)
The prevalence of cervical HPV infection decreases sharply in women after the age of 30 [70].
Those with persistent infection are at the highest risk for the development of high-grade squamous
intraepithelial lesions or invasive cervical cancer [70]. (See 'Cervical cancer' above.)
United States The estimated prevalence of anogenital tract HPV infections in the United States
is 20 million, with an annual incidence of 5.5 million. It has been estimated that 75 to 80 percent of
sexually active adults will acquire a genital tract HPV infection before the age of 50 [71]. Two
longitudinal studies have also demonstrated that acquisition of cervical HPV infection also predicted
acquisition of an anal HPV infection [72,73].
Genital HPV infection is common in young sexually active women in the United States, as illustrated
by the following observations among different age groups [48,50,51,74-76]:
The National Health and Nutrition Examination Survey (NHANES) assessed the prevalence
of HPV infection in the United States by collecting vaginal swabs for HPV DNA in 1921 women
[74]. The overall prevalence was 27 percent and was highest among females aged 20 to 24
years (45 percent). The prevalence of the specific types contained within the quadrivalent HPV
vaccine (ie, types 6, 11, 16, and 18) was 17, 7, 16, and 7 percent, respectively [77]. (See "The
life cycle, natural history, and immunology of human papillomaviruses".)
In a series of 312 urban adolescent girls (mean age 16) with a median of two years of sexual
activity and four lifetime sex partners, cervical HPV was detected in 64 percent using
polymerase chain reaction (PCR)-based testing [50]. Another study demonstrated that the
one-year cumulative incidence of initial HPV infection in 244 female college students was 29
percent after their first male sexual partner [75].
A prospective study evaluated 608 female college students at six-month intervals for three
years; the evaluation included cervicovaginal lavage that was tested for HPV DNA [48]. At
entry, 26 percent were HPV-positive. Among those who were HPV-negative, 43 percent
acquired HPV during the three-year follow-up. A similar rate of new disease acquisition (32
percent in two years) was noted in another report of 603 female university students [51]. Longterm follow-up of a subset of these patients with HPV infection at baseline (n = 156)
demonstrated persistence of the same HPV type in 4.8 percent (over an average of four
years) in association with pathologic changes [78].
In a review of over 3800 women 18 to 40 years of age, the overall HPV prevalence was 39
percent [52]. Detection of high-risk and low-risk HPV genotypes declined with increasing age.
In a seroepidemiologic study of injection and noninjection drug users (median age 24 years),
HPV 16 seroprevalence was 38 percent and HPV 18 seroprevalence was 42 percent [79].
The above data reflect the overall prevalence of HPV infection. However, many sexually active
young women have sequential infections with different oncogenic types of HPV. These infections
are usually detected transiently, although they frequently produce reversible cytologic changes.
There may be racial differences in the type and turnover of HPV infection in women [80-82]. These
differences are illustrated by the findings of a longitudinal study of 467 college-age women in the
United States [80]. The overall incidence of HPV infection was similar between black and white
women, but black women had a slightly higher incidence of infection with high-risk HPV types. Two
years after the incident high-risk HPV infection, more black women had persistent infection (56
versus 24 percent of white women). These findings might contribute to the higher incidence of
cervical cancer in black women in the United States. (See "Invasive cervical cancer: Epidemiology,
risk factors, clinical manifestations, and diagnosis", section on 'Incidence and mortality'.)
Among older women, the prevalence of HPV detection may be related more to reactivation of
infection acquired previously than to new, recent infections. In a cohort of over 800 women aged 35
to 60 years, the attributable risk for high-risk HPV detection associated with a history of more than
five lifetime sexual partners was greater than that associated with a new sexual partner among
women older than 50 years (87 versus 8 percent) [83]. In contrast, among women 35 to 49 years,
the attributable risks associated with lifetime and recent sexual partners were the same (28
percent). That this reflects reactivation of infection in older women is only one interpretation of the
data, but raises important questions about the cause and importance of reactivation HPV [84,85].
Reactivation has also been proposed as a major source of newly detected HPV infection among
HIV-infected women. In a prospective study of 1848 HIV-infected women (the Womens Interagency
HIV Study), more than half of the women with newly detected cervical HPV infection had reported
no new sexual partners since the prior visit [86].
Studies of anal HPV infection in women suggest that it is far more common than originally thought
[87-89]. In studies of high-risk women, including HIV-infected women and women with a history of
commercial sex work or injection drug use, anal HPV infection is more common than cervical HPV
infection [90]. In studies of lower-risk women, the prevalence and incidence of anal HPV infection is
similar to that of cervical HPV infection [72,88]. Women with a history of vulvar or cervical highgrade squamous intraepithelial lesions or cancer are also at increased risk of anal HPV infection
and HPV-related disease. In one study of women with cervical or vulvar high-grade squamous
intraepithelial lesions, 12 percent had an anal squamous intraepithelial lesion and 9 percent had an
anal high-grade squamous intraepithelial lesion [91]. In these studies anal intercourse was not a
consistent risk factor for either anal HPV infection or anal squamous intraepithelial lesions.
Despite the frequency of anal HPV infections in women, they are often detected only transiently
[87,92]. In one study of 431 sexually active women, half of whom had incident anal HPV infections,
more than 58 percent became HPV DNA test-negative over a 15-month period of follow-up [87].
This observation may help explain why the incidence of anal cancer is much lower than that of
cervical cancer [93].
EFFECT OF HPV VACCINE Bivalent and quadrivalent human papillomavirus (HPV) vaccines
are available for the prevention of HPV genital infection in women and men; the bivalent vaccine is
effective against HPV types 16 and 18 and the quadrivalent vaccine is effective against HPV types
6, 11, 16, and 18. Clinical trial data have demonstrated efficacy against acquisition of vaccineassociated HPV types with declines in incident and persistent cervical and vulvovaginal infection
and abnormalities in women [117-119]. The quadrivalent vaccine has also been shown to be
effective in men at reducing persistent external genital and anal HPV infection as well as lesions
that occur at these sites, including condyloma and squamous intraepithelial lesions [120]. No trials
have directly evaluated the efficacy of the bivalent vaccine in men or for anal disease in women.
However, in a post-hoc analysis of women who had participated in a trial of the bivalent vaccine,
there were fewer persistent anal HPV infections in the vaccinated group compared with the placebo
group [121].
Several studies have reported declining HPV prevalence and incidence of HPV-related disease
following the introduction of HPV vaccination [122-131]. As an example, in the United States, the
prevalence of HPV 6, 11, 16, and 18 in cervical samples from females aged 14 to 19 years
decreased by 56 percent, from 11.5 percent in the pre-vaccine era (2003 to 2006) to 5.1 percent in
the post-vaccine era (2007-2010) [126]. This observation was made in the setting of estimated
vaccine coverage with at least one dose of 25 to 49 percent among adolescent girls between 2007
and 2010 [132]. In Australia, the 2007 implementation of a national program to administer the
quadrivalent vaccine to women aged 12 to 26 years led to high rates of vaccine coverage,
particularly among females under 18 years old [122-125]. In one study of the cervical cytology
registry in Victoria, Australia, there was a progressive decrease in the incidence of high-grade
cervical squamous intraepithelial lesions among girls 18 years of age or younger in the two years
after the vaccination program compared with the four years preceding it [122]. HPV vaccination is
also associated with decreases in the burden of genital warts. In a study of nearly 400,000 females
born between 1989 and 1999 in Denmark, vaccination was associated with a substantially lower
risk of developing genital warts (229 cases among 248,403 vaccinated versus 2241 cases among
151,367 unvaccinated individuals after an average of 3.5 years of follow-up) [133]. Declines in the
incidence of genital warts have also been temporally associated with vaccine availability in both
young women and heterosexual men in Australia [124,125] and in the United States [134].
Although many of these studies did not formally link individual vaccination status or implicated HPV
type with disease occurrence, they suggest an association between widespread vaccination and
population decreases in HPV-related disease that is consistent with the efficacy observed in clinical
trials of the HPV vaccines and that may reflect vaccine-associated herd immunity.
(See "Recommendations for the use of human papillomavirus vaccines", section on
'Efficacy' and "Recommendations for the use of human papillomavirus vaccines", section on
'Efficacy'.)
Routine HPV immunization is recommended by multiple guideline committees for female
adolescents and adults 9 to 26 years of age and male adolescents and adults 11 to 21 years of age;
HPV vaccine is most effective when given before the onset of sexual debut.
(See "Recommendations for the use of human papillomavirus vaccines", section on
'Recommendations for HPV immunization in females' and "Recommendations for the use of human
papillomavirus vaccines", section on 'Recommendations for HPV immunization in males'.)
VIRAL INTERACTIONS BETWEEN HIV AND HPV HIV and human papillomavirus (HPV)
infections appear to affect the epidemiology of these two viruses bidirectionally.
Effect of HIV infection on HPV Several studies have shown that HPV infection is more common
among HIV-infected than uninfected men and women [103,135-138]. In a study of 486 heterosexual
South African couples followed for up to 24 months, new HPV infection was detected more
frequently in HIV-infected women (57 versus 27 events per 1000 person-months) and men (80
versus 52 events per 1000 person-months) compared with HIV-uninfected individuals [137].
Furthermore, HIV infection was independently associated with a decreased likelihood of clearance
of HPV infection over time.
Another study evaluated the concordance of HPV infection among 254 heterosexually active
couples and the impact of HIV coinfection on the prevalence of HPV [136]. The following
observations were made:
HPV detection was significantly more common among HIV-infected women than among HIVuninfected women (68 versus 31 percent, respectively).
Similarly, HPV detection was significantly more common among HIV-infected men than
among HIV-uninfected men (72 versus 43 percent, respectively).
HIV coinfection in one partner had a significant impact on the prevalence of HPV infection in
the other partner. For example, HIV-uninfected male partners of HIV-infected women had a
greater prevalence of HPV than did HIV-uninfected male partners of HIV-uninfected women
(58 percent versus 32 percent, respectively).
Concordance of the same HPV genotypes was more commonly found among couples where
one or both partners were HIV-infected, compared with HIV-uninfected couples.
Among men who have sex with men (MSM), HPV prevalence is similarly increased in the setting of
HIV infection [103,139-141]. In a meta-analysis of 53 studies, the pooled prevalence of anal HPV
infection was considerably higher in HIV-infected men (93 and 74 percent for any type and any
high-risk type, respectively, compared with 64 and 37 percent in HIV-uninfected MSM) [103].
The use of effective antiretroviral therapy (ART) may attenuate the risk of HPV infection and
persistence among HIV-infected patients [138,142-144], although data are conflicting [145]. As an
example, in a study of 652 HIV-infected women, among whom the baseline prevalence of high-risk
HPV was 42 percent, ART use and HIV RNA suppression for more than two years were each
independently associated with a lower risk of high-risk HPV infection [142]. Sustained HIV RNA
suppression was also marginally associated with clearance of high-risk HPV infection (OR 1.02,
95% CI 1.001-1.04). Other studies have not shown an association between ART use and decreased
HPV risk [146]. The effect of ART on the risk of HPV-associated neoplasia is discussed elsewhere.
(See "Preinvasive and invasive cervical neoplasia in HIV-infected women", section on 'Highly active
antiretroviral therapy' and "Anal squamous intraepithelial lesions: Diagnosis, screening, prevention,
and treatment", section on 'HIV infection'.)
Effect of HPV on HIV acquisition The first evidence for an association between HPV infection
and increased risk of HIV acquisition came from studies of MSM. In a cohort of HIV-uninfected
MSM, infection with more than one anal HPV type was significantly associated with HIV
seroconversion (adjusted hazard ratio [HR] 3.5; 95% CI 1.210.6) [147]. Subsequent studies
suggest that penile HPV infection is also a risk factor for subsequent HIV infection [148]. HIVuninfected men in Kenya (n = 2168) who were participating in a randomized trial of male
circumcision underwent HPV DNA sampling of their glans/coronal sulcus and were followed up for
42 months for evidence of HIV acquisition [148]. Approximately 50 percent of the men had evidence
of HPV DNA at baseline. After controlling for subsequent circumcision status, baseline herpes
simplex virus type 2 serostatus, and other sexual risk factors, those men who were infected with
HPV at baseline had a significantly higher risk of HIV acquisition compared with men without HPV
infection (HR 1.8; 95% CI 1.1-2.9).
In contrast, in a case-control study of 44 men who acquired HIV infection and 787 HIV-uninfected
men who had been followed in a circumcision trial, penile HPV acquisition was not associated with
HIV acquisition after controlling for other HIV transmission risks [149]. However, an association
between clearance of HPV infection and subsequent HIV infection was observed in this study and
postulated to be related to changes in local immune responses that might predispose to HIV
infection.
The presence of HPV infection also appears to be associated with an increased risk of HIV
acquisition among women. In a meta-analysis of prospective studies of women who underwent HPV
testing, HIV acquisition was associated with baseline HPV infection of any and high-risk type (HRs
2.06 [95% CI 1.44-2.94] and 1.99 [95% CI 1.54-2.56], respectively) when compared with no
baseline HPV infection [150]. Of note, several included studies did not assess or adjust for sexual
behavior or other coincident sexually transmitted infections, which are significant potential
confounders in the association between HPV and HIV. In a separate study of women from
Zimbabwe, clearance of cervical HPV infection was associated with risk of HIV acquisition [151],
similar to the association with clearance of penile HPV infection described in the study above.
Whether HPV infection itself predisposes to subsequent HIV infection or is simply a marker of
increased HIV risk remains unknown. It is also unclear whether prevalent HPV infection or the
immune response associated with clearing that HPV infection, or both, plays a role in potentiating
HIV acquisition.
SUMMARY AND RECOMMENDATIONS
Human papillomaviruses are double-stranded DNA viruses that only infect humans.
(See 'Introduction' above.)
Different human papillomavirus (HPV) types have a propensity to infect different body sites.
As examples, HPV types 1, 2, and 4 have a predilection for cutaneous epithelium while HPV
types 6, 11, 16, and 18 have a predilection for mucous membrane infection. (See 'Tissue
tropism' above.)
Cutaneous infection with HPV types 1 and 2 is frequently associated with plantar or common
hand warts. Mucocutaneous infection with HPV types 6, 11, 16, and 18 is often associated
with genital warts and precancerous and cancerous lesions of the cervix, vulva, vagina, penis,
anus, and oropharynx. Evidence linking HPV to cervical carcinoma is extensive, with HPV 16
accounting for approximately 60 percent of cases and HPV 18 for 10 percent. (See 'Disease
associations' above.)
Close personal contact is assumed to be of importance for the transmission of cutaneous
warts, while anogenital and cervical infection are primarily transmitted through sexual contact.
Both of these represent transmission from one epithelial surface to another. As with other
sexually transmitted infections, persons with multiple sex partners are at greater risk for HPV
infection compared with those in a monogamous relationship, and individuals with a new sex
partner are at greater risk than those with a long-term sex partner. (See 'Risk factors for
infection' above.)
The worldwide prevalence of HPV infection among females is approximately 10 percent. The
highest regional prevalence is in Africa, where 22 percent of women have evidence of HPV
infection. Worldwide, the most serious HPV infections are caused by high-risk types HPV 16
and 18, both of which are preventable by vaccination. (See 'Epidemiology in females' above.)
Rates of anal cancer are rising among men and women in the United States. Studies in men
who have sex with men (MSM) and heterosexual men demonstrate that HPV infection is
highly prevalent among men, including high-risk type HPV 16. Some observational studies
suggest that male circumcision is associated with lower rates of HPV infection than those
observed in uncircumcised men. (See 'Epidemiology in males' above.)
Bivalent and quadrivalent HPV vaccines are available for the prevention of HPV genital
infection in women and men; the bivalent vaccine is effective against HPV types 16 and 18
and the quadrivalent vaccine is effective against HPV types 6, 11, 16, and 18. Clinical trial
data have demonstrated efficacy against acquisition of vaccine-associated HPV types with
declines in incident and persistent HPV infections and decreasing rates of cervical and anal
squamous intraepithelial lesions. (See 'Effect of HPV vaccine' above and "Recommendations
for the use of human papillomavirus vaccines".)
HPV detection is more common among HIV-infected men and women than among men and
women who are HIV-uninfected. Among HIV-uninfected men and women, HPV infection is
associated with an increased risk of HIV acquisition compared with those without HPV
infection. (See 'Viral interactions between HIV and HPV' above.)
times greater than that of men reporting no such history. (See "Carcinoma of the penis:
Epidemiology, risk factors, staging, and prognosis".)
MOLECULAR PATHOGENESIS The role of human papillomavirus (HPV) infections in the
etiology of epithelial cancers has been supported by the following observations [14]:
HPV DNA is commonly present in anogenital pre-cancer and invasive cancers, as well as
oral cancers
Expression of the viral oncogenes E6 and E7 is consistently demonstrated in lesional tissue
The E6 and E7 gene products have transforming properties by their interaction with growthregulating host cell proteins
In cervical carcinoma cell lines, continued E6 and E7 expression is necessary to maintain the
malignant phenotype
Epidemiologic studies indicate HPV infections as the major factor for the development of
cervical cancer
HPV proteins The HPV genome encodes DNA sequences for six early (E) proteins associated
with viral gene regulation and cell transformation, two late (L) proteins that form the shell of the
virus, and a region of regulatory DNA sequences known as the long control region or upstream
regulatory region [15,16].
The two most important HPV proteins in the pathogenesis of malignant disease are E6 and E7.
Both E6 and E7 proteins are consistently expressed in HPV-carrying anogenital malignant tumors,
and they act in a cooperative manner to immortalize epithelial cells [17]. At the molecular level, the
ability of E6 and E7 proteins to transform cells relates in part to their interaction with two intracellular
proteins, p53 and retinoblastoma (Rb), respectively. (See "Anal squamous intraepithelial lesions:
Diagnosis, screening, prevention, and treatment" and "Vaginal intraepithelial
neoplasia" and "Preinvasive and invasive cervical neoplasia in HIV-infected women".)
Role of p53 protein In the normal cell, the p53 protein is a negative regulator of cell growth,
controlling cell cycle transit from G0/G1 to S phase, and also functions as a tumor suppressor
protein by halting cell growth after chromosomal damage and allowing DNA repair enzymes to
function [18-21]. Following E6 binding of p53, p53 is degraded in the presence of E6-associated
protein [22]. This allows unchecked cellular cycling, and has an anti-apoptotic effect, permitting the
accumulation of chromosomal mutations without DNA repair [23,24]. This leads to chromosomal
instability in high-risk HPV-containing cells. The interaction of E6 with p53 may also affect
regulation and/or degradation of the Src family of nonreceptor tyrosine kinases, potentially playing a
role in the stimulation of mitotic activity in infected cells [14,25].
In contrast to the E6 protein, E7 protein sensitizes wild-type p53-containing cells to apoptosis, but
exerts an anti-apoptotic effect in cells with mutated p53 [26,27]. The possible significance of this
viral oncoprotein expression may be regulated in this manner via the retinoic acid receptor
[41], or by cytokines such as transforming growth factor beta [42,43], interferon-alpha [44], or
tumor necrosis factor-alpha [45].
Alterations in host cell DNA (eg, p53 mutations) may interact with viral oncoproteins by acting
in concert with the oncogenes to permit progression from immortalization to transformation
[46]. Alternatively, genetically unmodified, high-risk, HPV-infected human cells may be blocked
from immortalization by intracellular control of viral oncoprotein function [47].
These data suggest that intercellular cytokine-mediated control plays an important role in
suppression of malignant transformation. Progression to the malignant phenotype probably involves
a genetic change in the pathways controlling intracellular or intercellular signaling [14]. The
chromosomal instability that characterizes HPV infection may be one mechanism leading to these
genetic modifications.
RISK FACTORS FOR HPV INFECTION Genital human papillomavirus (HPV) infections are
considered to be spread by unprotected penetrative intercourse or close skin-to-skin physical
contact involving an infected area [48]. Digital/anal and digital/vaginal contact probably can also
spread the virus, as may fomites [48]. (See"Epidemiology of human papillomavirus infections".)
Both primary (eg, the WHIM syndrome, described as Warts, Hypogammaglobulinemia, Infections,
and Myelokathexis [a congenital disorder of the white blood cells that results in chronic leukopenia
and neutropenia]) and secondary immunodeficiency disorders (eg, human immunodeficiency virus
[HIV] infection) may predispose patients to HPV infections and to the development of malignancies
in affected tissues. Although primary immunodeficiencies are rare, the possibility of an underlying
immune disorder should be considered in patients with particularly severe or refractory HPV
infections. (See "Malignancy in primary immunodeficiency", section on 'HPV'.)
DETECTING HPV The detection of human papillomavirus (HPV) is facilitated by recent
advances in molecular biology. HPV testing is increasingly being used in clinical management of
patients. HPV testing falls into three main categories [49]:
HPV DNA testing HPV DNA testing was the first approach developed for routine clinical
testing. Many studies showed that the addition of HPV DNA testing to cervical cytology
improved the sensitivity for detection of cervical cancer precursors, such as cervical
intraepithelial neoplasia (CIN) 2 and 3. However, the specificity also decreased, resulting in
the potential unnecessary referral of women for colposcopy.
HPV RNA testing HPV RNA testing, looking for expression of E6 and/or E7 RNA, may be
performed with the expectation that active HPV oncogene expression would provide better
sensitivity and specificity than HPV DNA testing. This test has recently received US Food and
Drug Administration (FDA) approval for cervical HPV testing, as it significantly improves the
specificity of detecting CIN2+, thereby decreasing the number of "false-positive" HPV tests
compared with HPV DNA testing.
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The
Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language,
at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are written at the 10 th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
Cancer cervical
PATHOGENESIS Human papillomavirus (HPV) is central to the development of cervical
neoplasia and can be detected in 99.7 percent of cervical cancers [3]. The virology and molecular
pathogenesis of HPV-associated malignancies are discussed in detail separately. (See "Virology,
pathogenesis, and epidemiology of human herpesvirus 6 infection".)
There are four major steps in cervical cancer development [34]:
Oncogenic HPV infection of the metaplastic epithelium at the cervical transformation zone
(the junction between the squamous epithelium of the ectocervix and the glandular epithelium
of the endocervical canal)
Persistence of the HPV infection
Progression of a clone of epithelial cells from persistent viral infection to precancer
Development of carcinoma and invasion through the basement membrane
Genital tract HPV infection is extremely common but results in cervical cancer in only a small
proportion of infected women. It has been estimated that 75 to 80 percent of sexually active adults
will acquire genital tract HPV before the age of 50 [35,36]. The disease burden of genital HPV
infection includes conditions other than cervical cancer, including anogenital warts, and cancer of
the vulva, vagina, anus, and penis [37,38]. (See "Virology of human papillomavirus infections and
the link to cancer"and "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and
prevention", section on 'Role of human papillomavirus'.)
Among the more than 40 genital mucosal HPV types identified, approximately 15 are known to be
oncogenic (table 1). Subtypes HPV 16 and 18 are found in over 70 percent of all cervical cancers.
HPV plays a role primarily in the two most common histologic types of cervical cancer: squamous
cell (69 percent of cervical cancers) and adenocarcinoma (25 percent) (see 'Histopathology' below).
The HPV subtypes associated with squamous cancer are different from those associated with
adenocarcinoma. In an international study of over 30,000 cervical cancers, the distribution of HPV
subtypes was [39]:
Squamous cell carcinoma HPV 16 (59 percent of cases), 18 (13 percent), 58 (5 percent),
33 (5 percent), 45 (4 percent)
Adenocarcinoma HPV 16 (36 percent), 18 (37 percent), 45 (5 percent), 31 (2 percent), 33
(2 percent)
Most HPV infections are transient, and the virus alone is not sufficient to cause cervical neoplasia.
When HPV infection persists, the time from initial infection to development of high grade cervical
intraepithelial neoplasia and, finally, invasive cancer takes an average of 15 years, although more
rapid courses have been reported [40].
Herpes simplex virus-2 infection as a cofactor in cervical cancer pathogenesis has been reported in
some, but not all studies [41-44]. Further investigation of this issue is needed.
HISTOPATHOLOGY The histopathologic types of cervical cancer are listed in the table (table 2)
[45]. In the United States from 2001 to 2004, the distribution of histologic types was [4]:
Squamous cell carcinoma 69 percent
Adenocarcinoma (including adenosquamous) 25 percent
Other histologies 6 percent
The incidence of invasive cervical adenocarcinoma and its variants has increased dramatically over
the past few decades, particularly in younger women [46,47]. Several causative factors have been
proposed to explain this trend, including increased prevalence of specific HPV-16 and 18 variants
that are associated more with adenocarcinoma than with squamous cell carcinoma as well as
exposure to estrogens, both endogenous (eg, obesity) and exogenous (eg, hormonal contraception,
postmenopausal estrogen therapy).
Adenosquamous tumors exhibit both glandular and squamous differentiation. They may be
associated with a poorer outcome than squamous cell cancers or adenocarcinomas [48-50].
Neuroendocrine or small cell carcinomas can originate in the cervix in women, but are infrequent
[51]. Rhabdomyosarcoma of the cervix is rare; it typically occurs in adolescents and young women
[52,53]. Primary cervical lymphoma and cervical sarcoma are also rare [54-56].
(See "Rhabdomyosarcoma in childhood and adolescence: Clinical presentation, diagnostic
evaluation, and staging" and "Small cell neuroendocrine carcinoma of the cervix", section on
'Introduction' and "Invasive cervical adenocarcinoma".)
ROUTES OF SPREAD Cervical cancer can spread by direct extension or by lymphatic or
hematogenous dissemination. Direct extension may involve the uterine corpus, vagina, parametria,
peritoneal cavity, bladder, or rectum. Ovarian involvement by direct extension of cervical cancer is
rare; ovarian metastases occur in approximately 0.5 percent of squamous cell carcinomas and 1.7
percent of adenocarcinomas [57]. The most common sites for hematogenous spread are the lungs,
liver, and bone; the bowel, adrenal glands, spleen, and brain are less frequent sites.
Historically, obturator lymph nodes were thought to be the most frequent site of nodal metastases in
women with cervical cancer [58]. It was also thought that lymphatic spread advanced in an orderly
fashion from the lymph nodes on the pelvic sidewall to the common iliac, and then the paraaortic
group (figure 1). However, subsequent studies, including those utilizing the sentinel lymph node
mapping technique, emphasize that any of the pelvic lymph node groups, and even paraaortic
lymph nodes, may contain the first draining lymph node and may be the first site of nodal
metastasis [59,60]. This was illustrated in a large retrospective study (n = 619) that evaluated
women with cervical cancer who had solitary (one or two) positive lymph nodes discovered via
radical hysterectomy and complete lymphadenectomy [61]. The distribution of sites of nodal
metastasis were: external iliac (43 percent), obturator (26 percent), parametrial (21 percent),
common iliac (7 percent), presacral (1 percent), and paraaortic (1 percent).
Sentinel node biopsy in cervical cancer is discussed in detail separately.
The risk of pelvic lymph node metastasis increases with increasing depth of invasion, according to
the International Federation of Gynecology and Obstetrics (FIGO) staging system (table 3)
(see "Invasive cervical cancer: Staging and evaluation of lymph nodes") [62-66]:
Stage IA1 0.6 percent
Stage IA2 7 percent
The risk of paraaortic nodal involvement increases as the local disease extent increases:
Stage IB 8 percent
Stage IIA 12 percent
Stage IIB 29 percent
Stage IIIA 17 percent
Stage IIIB 27 percent
Stage IVA 47 percent
CLINICAL MANIFESTATIONS Early cervical cancer is frequently asymptomatic, underscoring
the importance of screening. The most common symptoms at presentation are [67]:
Irregular or heavy vaginal bleeding
Postcoital bleeding
Some women present with a vaginal discharge that may be watery, mucoid, or purulent and
malodorous. This is a nonspecific finding and may be mistaken for vaginitis or cervicitis.
Advanced disease may present with pelvic or lower back pain, which may radiate along the
posterior side of the lower extremities. Bowel or urinary symptoms, such as pressure-related
complaints, hematuria, hematochezia, or vaginal passage of urine or stool, are uncommon and
suggest advanced disease.
In asymptomatic women, cervical cancer may be discovered as a result of cervical cancer
screening or incidentally, if a visible lesion is discovered upon pelvic examination. (See "Screening
for cervical cancer" and 'Physical examination' below.)
DIAGNOSIS The diagnosis of cervical cancer is made based upon histologic evaluation of a
cervical biopsy.
Physical examination A pelvic examination should be performed in any woman with symptoms
suggestive of cervical cancer. Visualization of the cervix upon speculum examination may reveal a
normal appearance or a visible cervical lesion; large tumors may appear to replace the cervix
entirely. Any lesion that is raised, friable, or has the appearance of condyloma should be biopsied,
regardless of previous benign cervical cytology results [68]. The only visible lesions that do not
require biopsy are Nabothian cysts, and only when this diagnosis is confirmed by an experienced
examiner. (See "Congenital cervical anomalies and benign cervical lesions", section on 'Nabothian
cysts'.)
Cervical cancer usually originates at the transformation zone (the junction between the squamous
epithelium of the ectocervix and the glandular epithelium of the endocervical canal). The lesion may
manifest as superficial ulceration, exophytic tumor in the exocervix, or infiltration of the endocervix.
Endophytic tumors can result in an enlarged, indurated cervix whose surface is smooth, referred to
as a "barrel shaped cervix." Among cervical adenocarcinomas, approximately one-half are
exophytic, others diffusely enlarge or ulcerate the cervix, and about 15 percent have no visible
lesion because the carcinoma is within the endocervical canal.
A thorough pelvic examination including rectovaginal examination with assessment of tumor size
and vaginal or parametrial involvement is required for staging cervical cancer. This is discussed in
detail separately. (See "Invasive cervical cancer: Staging and evaluation of lymph nodes", section
on 'Staging procedure'.)
Other suspicious physical examination findings are palpable groin or supraclavicular lymph nodes.
Cervical cytology Cervical cytology is the principal method for cervical cancer screening.
Cytology should also be performed for women with suspected cervical cancer.
Cervical cancer screening, techniques for cervical cytology testing, and interpretation of results are
discussed in detail separately. (See "Screening for cervical cancer"and "Cervical cancer screening
tests: Techniques for cervical cytology and human papillomavirus testing" and "Cervical and vaginal
cytology: Interpretation of results".)
Human papillomavirus (HPV) testing is used in combination with cervical cytology for cervical
cancer screening and helps to determine which women with abnormal cytology results require
further evaluation. However, it does not play a role in the diagnosis of malignancy in women with
symptoms or a visible lesion suggestive of cervical cancer. (See "Screening for cervical cancer",
section on 'Co-testing (Pap test and HPV testing)'.)
Cervical biopsy and colposcopy Cervical biopsy may be performed as part of an initial
evaluation or along with a full staging procedure, depending on the level of suspicion of malignancy
and the patient's access to health care. The approach to cervical biopsy differs depending upon the
patient's presentation and findings on pelvic examination:
In women with a grossly visible lesion, a suspected diagnosis of cancer must be confirmed
by a biopsy of the lesion. We prefer to take the biopsy from the area of the lesion that looks
most suspicious with care to avoid grossly necrotic areas, as these are often non-diagnostic.
Any cervix that is unusually firm or expanded should be sampled by punch biopsy and
endocervical curettage, even if the cervical cytology test does not show evidence of neoplasia.
Biopsy in women with gross lesions may result in significant bleeding and even hemorrhage,
and practitioners should be adequately prepared with hemostatic agents such Monsel solution
and the ability to pack the vagina should bleeding be significant.
Women without a visible lesion (eg, symptomatic, abnormal cervical cytology) should
undergo colposcopy with directed biopsy.
Symptomatic women without a visible lesion and those who have only abnormal cervical
cytology should undergo colposcopy with directed biopsy. An adequate colposcopy requires
that the entire squamocolumnar junction and all lesions be completely visualized and that
biopsies of the lesions explain the abnormal cytology. Women in settings in which colposcopy
is not available may undergo directed biopsy with the aid of visual inspection methods.
(See "Colposcopy" and"Screening for cervical cancer in resource-limited settings", section on
'Visual inspection methods'.)
Cervical conization is necessary if malignancy is suspected but is not found with directed
cervical biopsies (eg, some women with high grade cervical intraepithelial neoplasia,
inadequate colposcopy, and in women with an endocervical curettage that is positive for
moderate to severe dysplasia). Conization is also required in the setting of microinvasive
cancer to determine whether conservative or radical surgery is required for treatment.
Techniques for colposcopy and cervical biopsy and the staging evaluation for cervical cancer
are discussed in detail separately. (See "Colposcopy" and "Invasive cervical cancer: Staging
and evaluation of lymph nodes".)
Other diagnostic modalities Imaging studies are not typically part of cervical cancer diagnosis,
although some are used for staging and evaluation of women with known malignancy.
(See "Invasive cervical cancer: Staging and evaluation of lymph nodes", section on 'Staging
procedure' and "Invasive cervical cancer: Staging and evaluation of lymph nodes", section on
'Further evaluation'.)
Differential diagnosis The differential diagnosis of cervical cancer includes other conditions that
result in irregular or heavy vaginal bleeding, vaginal discharge, or a visible cervical lesion.
Genital tract bleeding and vaginal discharge may be caused by a variety of conditions. Post-coital
bleeding, which is the most specific presentation of cervical cancer, may also result from cervicitis.
Evaluation of women with these conditions is discussed in detail separately. (See "Approach to
abnormal uterine bleeding in nonpregnant reproductive-age women" and "Postmenopausal uterine
bleeding" and "Approach to women with symptoms of vaginitis".)
Benign tumor-like lesions that may mimic cervical cancer include Nabothian cysts, mesonephric
cysts, cervical ectropion, ulcers associated with sexually transmitted infections, reactive glandular
changes from inflammation, and endometriosis. (See "Congenital cervical anomalies and benign
cervical lesions".)
SCREENING AND PREVENTION The rate of cervical cancer has declined significantly in
settings in which cervical cancer screening is employed. In addition, human papillomavirus (HPV)
vaccination had been introduced to reduce the incidence of cervical neoplasia. (See "Screening for
cervical cancer" and "Recommendations for the use of human papillomavirus vaccines".)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The
Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language,
at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are written at the 10 th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
Basics topics (see "Patient information: Cervical cancer (The Basics)")
Beyond the Basics topics (see "Patient information: Cervical cancer treatment; early stage
cancer (Beyond the Basics)" and "Patient information: Fertility preservation in women with
early stage cervical cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Cancer of the uterine cervix is the third most common cancer diagnosis and cause of death
among gynecologic cancers in the United States. In countries that do not have access to
cervical cancer screening and prevention programs, cervical cancer remains the second most
common type of cancer and cause of cancer deaths among all types of cancer in women.
(See 'Incidence and mortality' above.)
The lifetime risk of developing cervical cancer for United States women is 0.76 percent. The
mean age at diagnosis of cervical cancer in the United States is 48 years old. (See 'Age
distribution' above.)
Human papillomavirus (HPV) is central to the development of cervical neoplasia and can be
detected in 99.7 percent of cervical cancers. Subtypes HPV 16 and 18 are found in over 70
percent of all cervical cancers. (See 'Pathogenesis' above.)
Risk factors for cervical cancer are mostly associated with an increased risk of acquiring or
having a compromised immune response to HPV infection; these include: early onset of
sexual activity, multiple sexual partners, a high-risk sexual partner, history of sexually
transmitted infections, history of vulvar or vaginal squamous intraepithelial neoplasia or
cancer, and immunosuppression. Oral contraceptive use appears to be associated with an
increased risk of cervical cancer. Cigarette smoking appears to be associated with an
increased risk of squamous cell cancer, but not adenocarcinoma. (See 'Risk factors' above.)
The most common histologic types of cervical cancer are squamous cell (69 percent of
cervical cancers) and adenocarcinoma (25 percent). The histopathologic types of cervical
cancer are listed in the table (table 2). (See 'Histopathology' above.)
Early cervical cancer is frequently asymptomatic, emphasizing the importance of screening.
The most common symptoms at presentation are: abnormal vaginal bleeding (including
postcoital bleeding) and vaginal discharge. A lesion may or may not be visible or palpable on
physical examination. (See 'Clinical manifestations'above and 'Physical examination' above.).
The diagnosis of cervical cancer is established by biopsy. Symptomatic women without a
visible lesion and those who have only abnormal cervical cytology should undergo colposcopy
with directed biopsy and, if necessary, diagnostic conization. (See 'Diagnosis' above.).