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Practice Essentials

Cervical cancer (see the image below) is the third most common malignancy
in women worldwide, and it remains a leading cause of cancer-related death
for women in developing countries. In the United States, cervical cancer is
relatively uncommon.
Inline figure

Cervical carcinoma with adnexa.

/Inline figure
Essential update: FDA approves bevacizumab for late-stage cervical
cancer
In August 2014, the US Food and Drug Administration (FDA) approved
bevacizumab (Avastin) for the management of persistent, recurrent or latestage (metastatic) carcinoma of the cervix.[1, 2] This agent is approved for
combination chemotherapy with paclitaxel and cisplatin or with paclitaxel and
topotecan.[1, 2]
Approval was based on the GOG-0240 study (n = 452) that assessed the
efficacy and safety of bevacizumab plus chemotherapy (paclitaxel and
cisplatin or paclitaxel and topotecan) in women with persistent, recurrent or
metastatic carcinoma of the cervix.[1, 3] A statistically significant improvement in
overall survival (OS) and an increase in the rate of tumor shrinkage was
shown in women treated with bevacizumab plus chemotherapy compared with
chemotherapy alone. However, hypertension, thromboembolic events, and
gastrointestinal fistulas were higher in the bevacizumab group.[1, 3]
Signs and symptoms
The most common finding in patients with cervical cancer is an abnormal
Papanicolaou (Pap) test result.
Physical symptoms of cervical cancer may include the following:
Abnormal vaginal bleeding
Vaginal discomfort

Malodorous discharge
Dysuria
Diagnosis
Human papillomavirus (HPV) infection must be present for cervical cancer to
occur. Complete evaluation starts with Papanicolaou (Pap) testing.

Screening recommendations
Current screening recommendations for specific age groups, based on
guidelines from the American Cancer Society (ACS), the American Society for
Colposcopy and Cervical Pathology (ASCCP), the American Society for
Clinical Pathology (ASCP), the US Preventive Services Task Force (USPSTF),
and the American College of Obstetricians and Gynecologists (ACOG), are as
follows[4, 5, 6, 7] :
< 21 years: No screening recommended
21-29 years: Cytology (Pap smear) alone every 3 years
30-65 years: Human papillomavirus (HPV) and cytology cotesting every 5
years (preferred) or cytology alone every 3 years (acceptable)
>65 years: No screening recommended if adequate prior screening has been
negative and high risk is not present
Management
Immunization
Evidence suggests that HPV vaccines prevent HPV infection.[8] The following 2
HPV vaccines are approved by the FDA:
Gardasil (Merck, Whitehouse Station, NJ): This quadrivalent vaccine is
approved for girls and women 9-26 years of age to prevent cervical cancer
(and also genital warts and anal cancer) caused by HPV types 6, 11, 16, and
18; it is also approved for males 9-26 years of age [9]
Cervarix (GlaxoSmithKline, Research Triangle Park, NC): This bivalent
vaccine is approved for girls and women 9-25 years of age to prevent cervical
cancer caused by HPV types 16 and 18 [10]
The Advisory Committee on Immunization Practices (ACIP) recommendations
for vaccination are as follows:
Routine vaccination of females aged 11-12 years of age with 3 doses of either
HPV2 or HPV4
Routine vaccination with HPV4 for boys aged 11-12 years of age, as well as
males aged 13-21 years of age who have not been vaccinated previously
Vaccination with HPV4 in males aged 9-26 years of age for prevention of
genital warts; routine use not recommended
Stage-based treatment
The treatment of cervical cancer varies with the stage of the disease, as
follows:
Stage 0: Carcinoma in situ (stage 0) is treated with local ablative or excisional
measures such as cryosurgery, laser ablation, and loop excision; surgical
removal is preferred

Stage IA1: The treatment of choice for stage IA1 disease is surgery; total
hysterectomy, radical hysterectomy, and conization are accepted procedures
Stage IA2, IB, or IIA: Combined external beam radiation with brachytherapy
and radical hysterectomy with bilateral pelvic lymphadenectomy for patients
with stage IB or IIA disease; radical vaginal trachelectomy with pelvic lymph
node dissection is appropriate for fertility preservation in women with stage
IA2 disease and those with stage IB1 disease whose lesions are 2 cm or
smaller
Stage IIB, III, or IVA: Cisplatin-based chemotherapy with radiation is the
standard of care [11]
Stage IVB and recurrent cancer: Individualized therapy is used on a palliative
basis; radiation therapy is used alone for control of bleeding and pain;
systemic chemotherapy is used for disseminated disease [11]

Background
Cervical cancer is the third most common malignancy in women worldwide,
and it remains a leading cause of cancer-related death for women in
developing countries. In the United States, cervical cancer is relatively
uncommon. (See Epidemiology.)
The incidence of invasive cervical cancer has declined steadily in the United
States over the past few decades; however, it remains at high levels in many
developing countries. The change in the epidemiologic trend in the United
States has been attributed to mass screening with Papanicolaou (Pap) tests,
which permits detection and treatment of pre-invasive disease.
Recognition of the etiologic role of human papillomavirus (HPV) infection in
cervical cancer has led to the recommendation of adding HPV testing to the
screening regimen in women 30-65 years of age (see Workup). However,
women who have symptoms, abnormal screening test results, or a gross
lesion of the cervix are best evaluated with colposcopy and biopsy.
For further recommendations concerning cervical cancer evaluation and
management of abnormal Pap test results, and treatment of cervical
intraepithelial neoplasia (CIN), see the American Society for Colposcopy and
Cervical Pathology (ASCCP) guidelines.[12] (See also Presentation and
Workup.)
The treatment of cervical cancer varies with the stage of the disease. For early
invasive cancer, surgery is the treatment of choice. In more advanced cases,
radiation combined with chemotherapy is the current standard of care. In
patients with disseminated disease, chemotherapy or radiation provides
symptom palliation. (See Treatment and Medication.)

Pathophysiology
Human papillomavirus (HPV) infection must be present for cervical cancer to
occur. HPV infection occurs in a high percentage of sexually active women.
However, approximately 90% of HPV infections clear on their own within

months to a few years and with no sequelae, although cytology reports in the
2 years following infection may show a low-grade squamous intraepithelial
lesion.
On average, only 5% of HPV infections will result in the development of CIN
grade 2 or 3 lesions (the recognized cervical cancer precursor) within 3 years
of infection. Only 20% of CIN 3 lesions progress to invasive cervical cancer
within 5 years, and only 40% of CIN 3 lesions progress to invasive cervical
cancer with 30 years.
Because only a small proportion of HPV infections progress to cancer, other
factors must be involved in the process of carcinogenesis. The following
factors have been postulated to influence the development of CIN 3 lesions:
The type and duration of viral infection, with high-risk HPV type and persistent
infection predicting a higher risk for progression; low-risk HPV types do not
cause cervical cancer
Host conditions that compromise immunity (eg, poor nutritional status,
immunocompromise, and HIV infection)
Environmental factors (eg, smoking and vitamin deficiencies)
Lack of access to routine cytology screening
In addition, various gynecologic factors significantly increase the risk of HPV
infection. These include early age of first intercourse and higher number of
sexual partners.
Although use of oral contraceptives for 5 years or longer has been associated
with an increased risk of cervical cancer, the increased risk may reflect a
higher risk for HPV infection among sexually active women. However, a
possible direct interaction between oral contraceptives and HPV infection has
not been disproved.[13]
Genetic susceptibility
Genetic susceptibility to cervical cancers caused by HPV infection has been
identified via studies of twins and other first-degree relatives, as well as
genome-wide association studies. Women who have an affected first-degree
biologic relative have a 2-fold relative risk of developing a cervical tumor
compared with women who have a nonbiologic first-degree relative with a
cervical tumor.[14, 15] Genetic susceptibility accounts for fewer than 1% of
cervical cancers.
Genetic changes in several classes of genes have been linked to cervical
cancer. Tumor necrosis factor (TNF) is involved in initiating the cell
commitment to apoptosis, and the genes TNFa-8, TNFa-572, TNFa-857,
TNFa-863, and TNF G-308A have been associated with a higher incidence of
cervical cancer.[16, 17, 18, 19] Polymorphisms in another gene involved in apoptosis
and gene repair, Tp53, have been associated with an increased rate of HPV
infection progressing to cervical cancer.[20, 21, 22, 23, 24]
Human leukocyte antigen (HLA) genes are involved in various ways. Some
HLA gene anomalies are associated with an increased risk of HPV infection
progressing to cancer,[25, 26] others with a protective effect.[27, 28] The chemokine
receptor-2 (CCR2) gene on chromosome 3p21[29, 30] and the Fas gene on

chromosome 10q24.1[26, 31] may also influence genetic susceptibility to cervical


cancer, perhaps by disrupting the immune response to HPV. The CASP8 gene
(also known as FLICE or MCH5) has a polymorphism in the promoter region
that has been associated with a decreased risk of cervical cancer.[32]
Epigenetic modifications may also be involved in cervical cancer. Methylation
is the best understood and probably the most common mechanism of
epigenetic DNA modeling in cancer. Aberrant DNA methylation patterns have
been associated with the development of cervical cancer and may harbor
important clues for developing treatment.[33, 34]
Human papillomavirus
HPV comprises a heterogeneous group of viruses that contain closed circular
double-stranded DNA. The viral genome encodes 6 early open reading frame
proteins (ie, E1, E2, E3, E4, E6, and E7), which function as regulatory
proteins, and 2 late open reading frame proteins (ie, L1 and L2), which make
up the viral capsid.
To date, more than 115 different genotypes of HPV have been identified and
cloned. A large multinational cervical cancer study found that more than 90%
of all cervical cancers worldwide are caused by 8 HPV types: 16, 18, 31, 33,
35, 45, 52, and 58. Three types16, 18, and 45cause 94% of cervical
adenocarcinomas.[35] HVP type 16 may pose a risk of cancer that is an order of
magnitude higher than that posed by other high-risk HPV types.[36]
The World Health Organization (WHO) International Agency for Research on
Cancer Monograph Working Group has grouped HPV types of the
mucosotropic alpha genus according to the evidence supporting their
association with cervical cancer (see Table 1, below).[36]
Inline table
Table 1. Human Papillomavirus Types Associated With Cervical Cancer (Open
Table in a new window)
HPV
Alpha
Group

Types

Evidence for Cervical Cancer Causation

16

Most carcinogenic HPV type, known to cause cancer at several


sites

18,31,33,35,39,45,51,52,56,
58, 59

Sufficient evidence

68

Limited evidence in humans and strong mechanistic evidence

26,53,66,67,70,73,82

Limited evidence in humans

30,34,69,85,97

Classified by phylogenetic analogy to HPV types with sufficient or


limited evidence in humans

6,11

Inadequate epidemiological evidence and absence of carcinogenic


potential in mechanistic studies

2A

2B

HPV = human papillomavirus.

The HPVs that infect the human cervix fall into 2 broad risk categories. The

low-risk types (eg, HPV 6 and 11) are associated with condylomata and a very
small number of low-grade squamous epithelial lesions (SILs) but are never
found in invasive cancer. The high-risk types (eg, HPV 16) vary in prevalence
according to the cervical disease state.
Upon integration into the human genome, the linearization of high-risk HPV
DNA places the E6 and E7 genes in a position of enhanced replication. E7
binds and inactivates the Rb protein while E6 binds p53 and directs its
degradation, and the functional loss of the TP53 and RB genes leads to
resistance to apoptosis, causing uncensored cell growth after DNA damage.
This ultimately results in progression to malignancy.
Human immunodeficiency virus
The role of HIV infection in the pathogenesis of cervical cancer is not fully
understood. However, HIV infection is known to suppress the already low level
of immune recognition of HPV infection, allowing HPV to cause more damage
than it would in immunocompetent women.
Cervical cancer is at least 5 times more common in HIV-infected women, and
this increased prevalence has remained essentially unchanged with the use of
highly active antiretroviral therapy.[37] Studies have shown a higher prevalence
of HPV infection in HIV-seropositive women than in seronegative women, and
the HPV prevalence was directly proportional to the severity of
immunosuppression as measured by CD4+ T-cell counts.

Etiology

With rare exceptions, cervical cancer results from genital infection with HPV,
which is a known human carcinogen.[36, 38, 39, 40, 41] Although HPV infections can be
transmitted via nonsexual routes, the majority result from sexual contact.
Consequently, major risk factors identified in epidemiologic studies are as
follows:
Sex at a young age
Multiple sexual partners
Promiscuous male partners
History of sexually transmitted diseases
HIV infection is associated with a 5-fold increase in the risk of cervical cancer,
presumably because of an impaired immune response to HPV infection.[37]
Exposure to diethylstilbestrol in utero has been associated with an increased
risk of CIN grade 2 or higher.[42]

Epidemiology
Cervical cancer is the third most common malignancy in women worldwide.
The frequency varies considerably between developed and developing
countries, however: Cervical cancer is the second most common cancer in
developing countries, but only the tenth most common in developed countries.
Similarly, cervical cancer is the second most common cause of cancer-related
deaths in women in developing countries but is not even among the top 10
causes in developed countries.[43]

In the United States, cervical cancer is relatively uncommon. The incidence of


invasive cervical cancer has declined steadily in the US over the past few
decades; for example, since 2004, rates have decreased by 2.1% per year in
women younger than 50 years and by 3.1% per year in women 50 years of
age and older.[44] This trend has been attributed to mass screening with Pap
tests.[45] Cervical cancer rates continue to rise in many developing countries,
however.
The American Cancer Society (ACS) estimated that in the United States,
12,170 new cases of cervical cancer would be diagnosed in 2012.[44]
Internationally, more than 500,000 new cases are diagnosed each year; rates
vary widely, ranging from an annual incidence of 4.5 cases per 100,000 in
Western Asia to 34.5 per 100,000 women in Eastern Africa.[46] In industrialized
countries with well-established cytology screening programs, the incidence of
cervical cancer ranges from 4 to 10 per 100,000 women.
The incidence of CIN 2/3 disease in the US is about 150 per 100,000 women,
with the peak incidence around 800 per 100,000 women in the 25-29 year age
group. The incidence of abnormal cytology screens for all ages is an order of
magnitude larger, at 7800 per 100,000 women.
Forouzanfar et al performed annual age-specific assessments of cervical
cancer in 187 countries from 1980 to 2010. The global cervical cancer
incidence increased from 378,000 cases per year in 1980 to 454,000 cases
per year in 2010 (annual rate of increase, 0.6%). Cervical cancer death rates
have been decreasing, but the disease still accounted for 200,000 deaths in
2010; in developing countries, 46,000 of these women were aged 15-49
years, and 109,000 were aged 50 years or older.[47]
Age-related demographics
The Centers for Disease Control and Prevention (CDC) surveillance of
screening-detected cancers (colon and rectum, breast, and cervix) in the
United States from 2004 to 2006 reported that the incidence of late-stage
cervical cancer was highest among women aged 50-79 years.[48] However,
cervical cancer may be diagnosed in any woman of reproductive age.
Indeed, rates of cervical adenocarcinoma have been increasing in women
under 40 years of age.[49] These cases are less easily detected with Pap test
screening, and survivorship is low because cases tend to be detected at a late
stage. Moreover, the HPV types causing adenocarcinoma are different from
the types causing squamous carcinoma. HPV 16, which is a stronger
carcinogen than other HPV types, has been found more frequently in younger
women than in older ones.[50, 51]
Race-related demographics
Racial variation in cervical cancer rates per 100,000 women in the United
States, according to Surveillance Epidemiology and End Results (SEER) data
from 2005-2009, was as follows:
Hispanic - 11.8
African American - 9.8
American Indian/Alaska Native - 8.1
White - 8.0

Asian/Pacific Islander - 7.2


Except for Asian/Pacific Islanders, women of other races have higher mortality
from cervical cancers than their white counterparts in the United States do.[52]
Death rates from cervical cancer have been highest among African
Americans; however, death rates in African-American women decreased by
2.6% per year from 2004 to 2008 while remaining stable in white women.[44]

Prognosis

The prognosis in patients with cervical cancer depends on the disease stage.
In general, the 5-year survival rates are as follows:
Stage I - Greater than 90%
Stage II - 60-80%
Stage III - Approximately 50%
Stage IV - Less than 30%
The ACS estimated that 4220 women would die of cervical cancer in the
United States in 2012.[44] This represents 1.3% of all cancer deaths and 6.5%
of deaths from gynecologic cancers.

Patient Education

Cervical cancer is overrepresented among underserved and minority groups


in the United States. It is imperative to increase awareness about the benefit
of Pap test screening for preventing cervical cancer among women in these
groups. Education about the benefit of HPV vaccination is also important but
must be accompanied by the information that vaccination does not substitute
for regular screening.
A Cochrane review found that the best approach to encourage women to
undergo cervical screening involved invitations.[53] These may take any of the
following forms:
Appointments (fixed or open)
Letters
Telephone calls
Verbal recommendations
Prompts
Follow-up letters
These findings relate to screening in developed countries, however, and their
relevance to developing countries is unclear. Further studies are required to
determine the effectiveness of promising interventions, such as revealing in an
invitation letter the gender of the smear taker, using a health promotion nurse,
employing lay outreach health workers, and carrying out intensive attempts at
recruitment.

History
Because many women are screened routinely, the most common finding is an
abnormal Papanicolaou (Pap) test result. Typically, these patients are
asymptomatic.
Clinically, the first symptom of cervical cancer is abnormal vaginal bleeding,

usually post coital. Vaginal discomfort, malodorous discharge, and dysuria are
not uncommon.
The tumor grows by extending along the epithelial surfaces, both squamous
and glandular, upward to the endometrial cavity, throughout the vaginal
epithelium, and laterally to the pelvic wall. It can invade the bladder and
rectum directly, leading to constipation, hematuria, fistula, and ureteral
obstruction, with or without hydroureter or hydronephrosis. The triad of leg
edema, pain, and hydronephrosis suggests pelvic wall involvement. The
common sites for distant metastasis include extrapelvic lymph nodes, liver,
lung, and bone.

Physical Examination
In patients with early-stage cervical cancer, physical examination findings can
be relatively normal. As the disease progresses, the cervix may become
abnormal in appearance, with gross erosion, ulcer, or mass. These
abnormalities can extend to the vagina. Rectal examination may reveal an
external mass or gross blood from tumor erosion.
Bimanual pelvic examination findings often reveal pelvic or parametrial
metastasis. If the disease involves the liver, hepatomegaly may develop.
Pulmonary metastasis usually is difficult to detect on physical examination
unless pleural effusion or bronchial obstruction becomes apparent. Leg
edema suggests lymphatic or vascular obstruction caused by tumor.

Approach Considerations

Complete evaluation starts with Papanicolaou (Pap) testing. Positive results


should prompt colposcopy and biopsies with further workup of cervical
intraepithelial neoplasia (CIN), including excisional procedures. If pathologic
evaluation after loop electrosurgical excision or conization suggests invasive
cancer with positive margins, the patient should be referred to a gynecologic
oncologist. Patients with suspicious or grossly abnormal cervical lesions on
physical examination should undergo biopsy regardless of the cytologic
findings.
Once the diagnosis is established, a complete blood count (CBC) and serum
chemistries for renal and hepatic function should be ordered to look for
abnormalities from possible metastatic disease, and imaging studies should
be performed for staging purposes. In the International Federation of
Gynecology and Obstetrics (Federation Internationale de Gynecologie et
dObstetrique [FIGO]) guidelines for staging, procedures are limited to the
following[54] :
Colposcopy
Biopsy
Conization of cervix
Cystoscopy

Proctosigmoidoscopy
Chest x-ray
Cystoscopy and proctoscopy should be performed in patients with a bulky
primary tumor to help rule out local invasion of the bladder and the colon.
Barium enema studies can be used to evaluate extrinsic rectal compression
from the cervical mass.
In the United States, more complex radiologic imaging studies are often done
to guide the choice of therapeutic options. These may include computed
tomography (CT), magnetic resonance imaging (MRI), and positron-emission
tomography (PET), as well as surgical staging. (See also Cervical Cancer
Imaging.)

Screening Recommendations

In 2014, the American College of Physicians (ACP) issued a new clinical


guideline that does not recommend routine screening pelvic examinations in
asymptomatic, nonpregnant adult women.[55, 56] The expert panel cited not only
a lack of strong evidence to support such screening but also the potential
psychological/physical harms of false-positive results.[55, 56, 57] Moreover, it noted
that screening pelvic examinations have a low diagnostic accuracy for
detecting ovarian cancer or bacterial vaginosis.[55] The ACP recommends that
screening examinations for cervical cancer should be limited to visual
inspection of the cervix and to the use of cervical swabs for human
papillomavirus.[55]
Although the American College of Obstetricians and Gynecologists (ACOG)
recommends routine annual pelvic examination in all women aged 21 years
and older,[4, 5] it recognizes that there are no data to support such examinations
in low-risk asymptomatic patients.[56, 57]
Previously, the American Cancer Society (ACS), the American Society for
Colposcopy and Cervical Pathology (ASCCP), and the American Society for
Clinical Pathology (ASCP) issued joint guidelines for cervical cancer
screening.[6] In 2012, the US Preventive Services Task Force (USPSTF) issued
updated guidelines whose recommendations are consistent with those of the
ACS, ASCCP, and ASCP.[7]
Screening recommendations for specific patient age groups are as follows[4, 5, 6,
7]
:
<25 years No screening recommended
21-29 years Cytology (Pap smear) alone every 3 years
30-65 years Human papillomavirus (HPV) and cytology cotesting every 5
years (preferred) or cytology alone every 3 years (acceptable)
>65 years No screening recommended if adequate prior screening has been
negative and high risk is not present
In January 2016, the ACOG issued screening guidelines following 2015
interim guidelines from the American Society for Colposcopy and Cervical
Pathology and the Society of Gynecologic Oncology.[102, 5] The new
guidelines are largely consistent with the above recommendations.[5] However,
the guidelines state that HPV testing alone can be considered an alternative to

cytology testing in women aged 25 years and older.[5]


The USPSTF cautions that positive screening results are more likely with
HPV-based strategies than with cytology alone and that some women may
have persistently positive HPV results and require prolonged surveillance with
additional frequent testing. Similarly, women who would otherwise be advised
to end screening at age 65 years on the basis of previously normal cytology
results may undergo continued testing because of positive HPV test results.[7]
In March 2013, the American Society for Colposcopy and Cervical Pathology
(ASCCP) issued updated guidelines for managing women with abnormal
cervical cancer screening results and diagnosed cancer precursors. The
Updated Consensus Guidelines for Managing Abnormal Cervical Cancer
Screening Tests and Cancer Precursors include the following[58, 59] :
Guidance for the management of discordant co-tests: If results of either Pap
smear or HPV testing are positive, but not both, co-testing is integrated into
follow-up care. Colposcopy, HPV DNA typing, or both may be indicated.
Routine screening: A recommendation for a return to "routine" screening in
women treated for cervical cancer is specified.
Adolescent screening: Screening is no longer recommended for adolescents.
Women aged 21-24 years are at low risk for invasive cervical cancer;
however, they are at high risk for HPV exposure and associated lesions. The
recommended workup varies according to findings of atypical squamous cells
of undetermined significance or low-grade or high-grade squamous
intraepithelial lesion; this may include colposcopy.
Neoplasia guidance: The guidelines address whether cervical intraepithelial
neoplasia grade 1 (CIN1) on endocervical canal curettage (ECC) should be
treated as positive ECC or CIN1.
Guidance for the management of women with unsatisfactory cytologic findings
and specimens that are missing endocervical or transformation zone
components: Colposcopy may be required for women with positive HPV
results or with repeated unsatisfactory cytologic findings.
Current US guidelines advise against using HPV testing to screen for cervical
cancer in women younger than 30 years; the ACS advises that for screening
in women 30-65 years of age, HPV testing alone is not currently
recommended for most clinical settings in the US. Annual screening is not
recommended at any age or with any method.
Women who have had a total hysterectomy may stop undergoing cervical
cancer screening. Exceptions are as follows:
Women who had a hysterectomy without removal of the cervix
Women who have had a CIN grade 2 or 3 lesion treated in the past 20 years
Women who have had cervical carcinoma at any time
Women in whom co-testing shows a negative Pap smear but a positive HPV
test should have 12-month follow-up cotesting. Women with atypical
squamous cells of undetermined significance (ASCUS) on Pap smear but a
negative HPV test can be rescreened with cotesting in 5 years or with cytology
alone in 3 years.[6]

The ACOG also issued the following recommendations on cervical cancer


screening in HIV-positive women[4, 5] :
HIV-positive women younger than 30 yr can undergo cytology testing once
every 3 yr instead of annually if they have had thre3 consecutive normal
annual cytology tests; ACOG recommends against cotesting for women
younger than 30 yr
Women with HIV who are aged 30 yr or older can undergo either testing with
cytology alone or cotesting; those with three consecutive normal annual
cytology tests can then be screened annually, and those with one normal
cotest result can also be screened annually
ACOG recommends against starting screening before age 21 yr unless a
woman is HIV-positive, regardless of the age of onset of sexual intercourse,
as only 0.1% of cases of cervical cancer occur before age 20 yr, and evidence
that screening is effective in this age group is lacking

Papanicolaou Testing
For many years, the Pap test has been the standard method for cervical
cancer screening. Retrospective data have shown that screening with a Pap
test reduces the incidence of cervical cancer by 60-90% and the death rate by
90%.
Because of false negatives, the best that a Pap test can do is to reduce the
incidence of cervical cancer to 2-3 per 100,000 women. False-negative tests
mostly result from sampling error, which can be reduced by ensuring that
adequate material is taken from both the endocervical canal and the
ectocervix. Smears without endocervical or metaplastic cells should be
repeated. (See Pap Smear.)
The limitations of the conventional Pap test include limited sensitivity (51%)
and a significant proportion of inadequate specimens. In addition, accurate
interpretation of conventional Pap tests is often compromised by the presence
of artifacts (eg, blood, mucus, obscuring inflammation, scant cellular material,
or air-drying artifact).
Newer liquid-based Pap test technologies have become available. In a
randomized, controlled trial from the Netherlands that compared liquid-based
and conventional cervical cytology, liquid-based cytology reduced the
proportion of unsatisfactory specimens from 1.1% to 0.3% and eliminated
obscuring blood, poor fixation, cytolysis, and insufficient spreading of cells as
causes of unsatisfactory results.[60]
With liquid-based cytology, however, older women (primarily those 55-60
years of age) were more likely to have a sample called unsatisfactory.
Nevertheless, 18-month follow-up showed that women with unsatisfactory
results by either method were not at higher risk for cervical abnormalities.[60]
ThinPrep Papanicolaou test
Test samples for the ThinPrep Pap test are collected the same way as those
for the conventional Pap test. However, the specimen is placed in a
preservative solution rather than on a slide. An automated processor prepares
the sample and makes a uniform slide for review. Mucus and blood are

removed in the process. The ThinPrep Papanicolaou test was approved in


1996 by the US Food and Drug Administration (FDA) as an alternative to the
traditional conventional smear.

Human Papillomavirus Testing


The Hybrid Capture II assay for HPV was approved by the FDA in 2003 as a
new approach for cervical cancer. This test is useful for interpreting equivocal
results from a Pap test. If a woman has a Pap test result showing ASCUS but
a subsequent HPV test is negative, she can be rescreened with Pap testing in
3 years; if the HPV test is positive, then additional workup with a colposcopy is
indicated.
The ACS guidelines favor using HPV testing with cytology in women aged 30
years and older. If both tests are negative, then the next Pap test can be
delayed for 5 years.

Imaging Studies for Metastasis


A routine chest radiograph is obtained to help rule out pulmonary metastasis.
Chest radiography may be considered optional for disease that is stage IB1 or
lower.[11]
A CT scan of the abdomen and pelvis is performed to look for metastasis in
the liver, lymph nodes, or other organs (see the image below) and to help rule
out hydronephrosis or hydroureter. MRI or positron-emission tomography
(PET) scanning is an alternative to CT scanning; in fact, PET scanning is now
recommended for patients with stage IB2 disease or higher.[11]
Inline figure

CT scan of cervical cell carcinoma demonstrates markedly enlarged lymph node at left pelvic
sidewall. This is consistent with pelvic lymph node metastasis, which is indicative of stage
IIIB disease. Cystic consistency is not unusual for metastatic cervical carcinoma. Primary

tumor is well depicted as hypoattenuating circumscribed mass. Cyst is present in anteriorly


located left ovary.

Magnetic resonance whole-body diffusion-weighted imaging scanning has


been used to distinguish uterine cervical carcinoma from normal uterine
cervix. This technique can also differentiate metastatic nodes from benign
nodes.[61] (See also Cervical Cancer Imaging.)

Surgical Staging
Clinical staging protocols can fail to demonstrate pelvic and aortic lymph node
involvement in 20-50% and 6-30% of patients, respectively. For that reason,
surgical staging sometimes is recommended.
Pretreatment surgical staging is the most accurate method of determining the
extent of disease. However, there is little evidence to suggest that routine
surgical staging yields any significant improvement in overall survival.
Therefore, the decision whether to perform pretreatment surgical staging
should be made on an individual basis after a thorough nonsurgical workup,
including fine-needle aspiration of lymph nodes, has failed to demonstrate
metastatic disease.

Histologic Findings
Precancerous lesions of the cervix usually are detected via a Pap test. The
Pap test classification system has evolved over the years. Standardized Pap
test reporting emerged from a 1988 workshop sponsored by the National
Cancer Institute. Currently, cervical cytology results are reported according to
the 2001 Bethesda System.[62]
2001 Bethesda System for reporting cervical cytologic diagnoses
Specimen adequacy may be the single most important quality assurance
component of the system.

Specimen classifications are as follows:


Satisfactory for evaluation (note presence/absence of
endocervical/transformation zone component)
Unsatisfactory for evaluation (specify reason)
Specimen rejected/not processed (specify reason)
Specimen processed and examined, but unsatisfactory for evaluation of
epithelial abnormality because of (specify reason)
General categorization (optional) is as follows:
Negative for intraepithelial lesion or malignancy
Epithelial cell abnormality
Other
Possible interpretations or results are as follows:
Negative for intraepithelial lesion or malignancy
Observed organisms (eg, Trichomonas, Candida, bacteria) and cellular
changes consistent with herpes simplex virus are reported
Reporting other nonneoplastic findings (ie, inflammation and atrophy) is
optional

Epithelial cell abnormalities


Squamous cell
Atypical squamous cells (ASC)
ASCUS
ASC where a high-grade squamous intraepithelial lesion (HSIL) cannot be
excluded (ASC-H)
Low-grade squamous intraepithelial lesion (LSIL)
Encompassing HPV, mild dysplasia, and CIN 1 (see the first image below)
HSIL
Encompassing moderate and severe dysplasia, carcinoma in situ, CIN 2, and
CIN 3 (see the second image below)
Squamous cell carcinoma (see the third image below)
Glandular cell
Atypical glandular cells (AGC) (specify endocervical, endometrial, or not
otherwise specified)
AGC favoring neoplastic (specify endocervical or not otherwise specified)
Endocervical adenocarcinoma in situ (AIS)
Adenocarcinoma
Other (list not comprehensive)
Endometrial cells in a woman aged 40 years or older Inline figure

Cervical intraepithelial neoplasia grade I. /Inline figure Inline figure

Cervical intraepithelial neoplasia grade III. /Inline figure Inline figure

Squamous cell cervical carcinoma. /Inline figure

Automated review and ancillary testing are included as appropriate.


Educational notes and suggestions are optional.
The histology of cervical malignancy is predominantly that of squamous cell
carcinoma, which represents approximately 80% of cases, with
adenocarcinomas representing almost 20%. Less common histologies include
small cell carcinoma, melanoma, and lymphoma.
A study by Wang et al reported that atypical glandular cells found at cervical
screening is associated with increased risk of cervical cancer for up to 15
years, particularly for cervical adenocarcinoma and women with atypical
glandular cells at age 30-39.[63]

FIGO and TNM Staging


There are 2 major staging systems that are frequently used in cervical cancer
(see Table 2, below and Cervical Cancer Staging):

The FIGO system, developed in collaboration with the World Health


Organization (WHO) [54]
The TNM system, developed by the International Union Against Cancer
(UICC) and the American Joint Committee on Cancer (AJCC) [64]
Inline table
Table 2. Cervical Cancer Staging: Primary Tumor (T) (Open Table in a new
window)

TNM
Stage

FIGO
Stage

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Cervical carcinoma confined to uterus (extension to corpus should be disregarded)

T1a

IA

Invasive carcinoma diagnosed only by microscopy. All macroscopically visible lesions


even with superficial invasionare T1b/1B. Stromal invasion with a maximal depth
of 5.0 mm measured from the base of the epithelium and a horizontal spread of 7.0
mm or less. Vascular space involvement, venous or lymphatic, does not affect
classification.

T1a1

IA1

Measured stromal invasion 3 mm or less in depth and 7 mm or less in lateral spread

T1a2

IA2

Measured stromal invasion more than 3 mm but not more than 5 mm with a horizontal
spread 7 mm or less

T1b

IB

Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2

T1b1

IB1

Clinically visible lesion 4 cm or less in greatest dimension

IB2

Clinically visible lesion more than 4 cm

T2

II

Cervical carcinoma extends beyond the cervix but not to the pelvic sidewall or to the
lower third of vagina

T2a

IIA

Tumor without parametrial invasion

T2b

IIB

Tumor with parametrial invasion

T3

III

Tumor extends to the pelvic wall and/or involves the lower third of the vagina and/or
causes hydronephrosis or nonfunctioning kidney

T3a

IIIA

Tumor involves lower third of vagina; no extension to pelvic sidewall

T3b

IIIB

Tumor extends to pelvic sidewall and/or causes hydronephrosis or nonfunctioning


kidney

IV

Cervical carcinoma has extended beyond the true pelvis or has involved (biopsy
proven) the bladder mucosa or rectal mucosa. Bullous edema does not qualify as a
criteria for stage IV disease.

T4

IVA

Spread to mucosa of adjacent organs (bladder, rectum, or both)

M1

IVB

Distant metastasis

In the UICC/AJCC system, regional lymph node (N) involvementincluding


paracervical, parametrial, hypogastric (obturator), common, internal and
external iliac, and presacral and sacral nodesis graded as follows.

NX: Regional lymph nodes cannot be assessed


N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
The T and N grades are combined with the grade for distant metastasis (M) to
yield the staging for the cancer (see Table 3, below).
Inline table
Table 3. UICC/AJCC Staging for Cervical Cancer
Stage

Tumor

Node

Metastasis

Tis

N0

M0

IA1

T1a1

N0

M0

IA2

T1a2

N0

M0

IB1

T1b1

N0

M0

IIA

T2a

N0

M0

IIB

T2b

N0

M0

IIIA

T3a

N0

M0

IIIB

T1

N1

M0

T2

N1

M0

T3a

N1

M0

T3b

Any N

M0

IVA

T4

Any N

M0

IVB

Any T

Any N

M1

Approach Considerations
Intravaginal application of 5% 5-fluorouracil (5-FU) was found to be an
effective treatment for cervical intraepithelial neoplasia (CIN) 2 in a
prospective, nonblinded, randomized controlled study of 60 women.[65, 66] At 6month follow-up, disease regression was observed in 26 of 28 women (93%)
who were treated with 5-FU and in 15 of 27 women (56%) in an observationonly group. Normal cervical biopsy, a normal Pap smear, and a negative
human papillomavirus (HPV) test were seen in 14 of the 28 patients in the
treatment group at 6-month follow-up, compared with 6 of the 17 patients in
the observation group.[65, 66] Topical 5-FU was well tolerated.
The treatment of cervical cancer varies with the stage of the disease (see
Cervical Cancer Staging). For early invasive cancer, surgery is the treatment

of choice. In more advanced cases, radiation combined with chemotherapy is


the current standard of care. In patients with disseminated disease,
chemotherapy or radiation provides symptom palliation. (See also Cervical
Cancer Treatment Protocols.)
The treatment of cervical cancer frequently requires a multidisciplinary
approach. Involvement of a gynecologic oncologist, radiation oncologist, and
medical oncologist may be necessary.

Stage-Based Therapy
Stage 0 cancer
Carcinoma in situ (stage 0) is treated with local ablative or excisional
measures such as cryosurgery, laser ablation, and loop excision. Surgical
removal is preferred in that it allows further pathologic evaluation to rule out
microinvasive disease. After treatment, these patients require lifelong
surveillance.
Stage IA1 cancer
The treatment of choice for stage IA1 disease is surgery. Total hysterectomy,
radical hysterectomy, and conization are accepted procedures. Lymph node
dissection is not required if the depth of invasion is less than 3 mm and no
lymphovascular invasion is noted.
Selected patients with stage IA1 disease but no lympho-vascular space
invasion who desire to maintain fertility may undergo therapeutic conization
with close follow-up, including cytology, colposcopy, and endocervical
curettage. Patients with comorbid medical conditions who are not surgical
candidates can be successfully treated with radiation.
According to National Comprehensive Cancer Network (NCCN) guidelines,
pelvic radiation therapy is currently a category 1 recommendation for women
with stage IA disease and negative lymph nodes after surgery who have highrisk factors (eg, a large primary tumor, deep stromal invasion, or
lymphovascular space invasion).[11]

Stage IA2, IB, or IIA cancer


For patients with stage IB or IIA disease, there are 2 treatment options:
Combined externa l beam radiation with brachytherapy
Radical hysterectomy with bilateral pelvic lymphadenectomy
Radical vaginal trachelectomy with pelvic lymph node dissection is appropriate
for fertility preservation in women with stage IA2 disease and those with stage
IB1 disease whose lesions are 2 cm or smaller.[11] The principal problems with
pregnancy after trachelectomy are premature labor and the need to undergo
cesarean section for delivery.[67]
In a retrospective review of 62 patients with stage IB1 cervical carcinoma who
underwent attempted radical trachelectomy and underwent preoperative
magnetic resonance imaging (MRI), Lakhman et al found that
pretrachelectomy MRI helped identify high-risk patients who were likely to
need radical hysterectomy and helped confirm the absence of residual tumor
after a cone biopsy with negative margins.[68] A tumor size of 2 cm or larger and
deep cervical stromal invasion on MRI were associated with an increased

chance of radical hysterectomy.


Most retrospective studies have shown equivalent survival rates for
trachelectomy and hysterectomy, though such studies usually are flawed
because of patient selection bias and other compounding factors. However, a
2008 study showed identical overall and disease-free survival rates for the 2
procedures.[69]
Current surgical guidelines for stage IA2 to IIA cervical cancers allow for
minimally invasive techniques, such as traditional laparoscopic and robotically
assisted laparoscopic techniques, in the surgical management of these
tumors. Indeed, it has been shown that these less morbid procedures are
equally effective in achieving adequate surgical margins and lymph node
dissection while possessing the added advantage of shorter postoperative
recovery times.[70, 71, 72]
An analysis of women from the Surveillance, Epidemiology, and End Results
(SEER) database who underwent radical hysterectomy with
lymphadenectomy revealed that patients with node-negative early-stage
cervical cancer who underwent a more extensive lymphadenectomy had
improved survival.[73] Compared with patients who had fewer than 10 nodes
removed, patients who had 21-30 nodes removed were 24% less likely to die
of their tumors, and those who had more than 30 nodes removed were 37%
less likely to die.
Postoperative irradiation of the pelvis reduces the risk of local recurrence in
patients with high-risk factors (ie, positive pelvic nodes, positive surgical
margins, and residual parametrial disease).[74] A randomized trial showed that
patients with parametrial involvement, positive pelvic nodes, or positive
surgical margins benefit from a postoperative combination of cisplatincontaining chemotherapy and pelvic irradiation.[75]
Postoperative radiation therapy is also recommended in patients who have at
least 2 intermediate risk factors (including tumor size greater than 2 cm, deep
stromal invasion, or lymphovascular space invasion). For patients with IB2 or
IIA cancer and tumors larger than 4 cm, radiation and chemotherapy is
selected in most cases. Risks are associated with combined therapy, but
many of these patients will meet either intermediate- or high-risk criteria after
radical hysterectomy and therefore are strong candidates for this approach.
Stage IIB, III, or IVA cancer
For locally advanced cervical carcinoma (stages IIB, III, and IVA), radiation
therapy was the treatment of choice for many years. Radiation therapy begins
with a course of external beam radiation to reduce tumor mass and thereby
enable subsequent intracavitary application. Brachytherapy is delivered by
means of afterloading applicators that are placed in the uterine cavity and
vagina.
Additionally, the results from large, well-conducted, prospective randomized
clinical trials have demonstrated a dramatic improvement in survival when
chemotherapy is combined with radiation therapy.[76, 77, 78] Consequently, the use

of cisplatin-based chemotherapy in combination with radiation has become the


standard of care for primary management of patients with locally advanced
cervical cancer.[11]
Stage IVB and recurrent cancer
Individualized therapy is used on a palliative basis. Radiation therapy is used
alone for control of bleeding and pain, whereas systemic chemotherapy is
used for disseminated disease.[11] For recurrent disease, the choice of therapy
is influenced by the treatments previously employed.
Treatment of pelvic recurrences after primary surgical management should
include single-agent chemotherapy and radiation, and treatment for
recurrences elsewhere should include combination chemotherapy.[79, 80, 81] For
central pelvic recurrence after radiation therapy, modified radical hysterectomy
(if the recurrence is smaller than 2 cm) or pelvic exenteration should be
undertaken.[82, 83]
For disease recurring after chemotherapy and radiation therapy, a diseasefree interval of more than 16 months is considered to designate the tumor as
platinum-sensitive.[84] The standard of care in these cases is chemotherapy
with a platinum-based doublet of paclitaxel and cisplatin.[80, 81, 85, 86]
The NCCN also recommends docetaxel, gemcitabine, ifosfamide, 5fluorouracil, mitomycin, irinotecan, and topotecan as possible candidates for
second-line therapy (category 2B recommendation), as well as pemetrexed
and vinorelbine (category 3 recommendation). In addition, bevacizumab as
single-agent therapy is also acceptable.[11]
Treatment with bevacizumab plus cisplatin and paclitaxel or topotecan and
paclitaxel was approved by the FDA in August 2014 for persistent, recurrent,
or metastatic cervical cancer.[1, 2] A statistically significant improvement in
overall survival (OS) and an increase in the rate of tumor shrinkage was
shown in women treated with bevacizumab plus chemotherapy compared with
chemotherapy alone.[1, 3] However, hypertension, thromboembolic events, and
GI fistulas were higher in the bevacizumab group.[3]
Bevacizumab/paclitaxel/cisplatin or topotecan is considered a first-line
regimen for recurrent or metastatic cervical cancer.[11]
In a randomized study of 452 women with advanced cervical cancer
(recurrent, persistent, or metastatic disease), Tewari et al reported that adding
bevacizumab to combination chemotherapy prolonged survival in these
women by about 3.7 months compared with chemotherapy alone (topotecan
plus paclitaxel; cisplatin plus paclitaxel).[3, 87, 88, 89] Because topotecan-paclitaxel
was not superior to cisplatin-paclitaxel, the data from the groups treated with
these combination regimens were combined.[3, 87]
Median overall survival was 17.0 months with bevacizumab and
chemotherapy, whereas it was 13.3 months with chemotherapy alone.[3, 87, 88, 89]
At a median follow-up of 20.8 months, 60% of the patients died.[87] Progressionfree survival was 8.2 months with bevacizumab plus chemotherapy but 5.9
months with chemotherapy alone. The response rate was 48% with

bevacizumab and chemotherapy compared with 36% in the group receiving


chemotherapy alone.[3, 87, 88, 89] However, the addition bevacizumab also led to an
increased incidence of adverse effects such as hypertension of grade 2 or
higher (25% vs 2%), thromboembolic events of grade 3 or higher (8% vs 1%),
and gastrointestinal fistulas of grade 3 or higher (3% vs 0%) compared with
chemotherapy alone.[3, 87]
Recurrences arising in a previously irradiated field or after a disease-free
interval of less than 16 months are less likely to respond to subsequent
therapies. Consequently, patients with such recurrences should be strongly
encouraged to participate in clinical trials. Special efforts should be made to
ensure that they receive comprehensive palliative care, including adequate
pain control.

Complications of Therapy
Radiation-related complications
During the acute phase of pelvic radiation therapy, the surrounding normal
tissues (eg, intestines, bladder, and perineal skin) often are affected. Acute
adverse gastrointestinal (GI) effects include diarrhea, abdominal cramping,
rectal discomfort, and bleeding. Diarrhea can usually be controlled by giving
either loperamide or atropine sulfate. Small steroid-containing enemas are
prescribed to alleviate symptoms from proctitis.
Cystourethritis also can occur, leading to dysuria, frequency, and nocturia.
Antispasmodics often are helpful for symptom relief. Urine should be
examined for possible infection. If urinary tract infection (UTI) is diagnosed,
therapy should be instituted without delay.
Proper skin hygiene should be maintained for the perineum. Topical lotion
should be used if erythema or desquamation occurs.
Late sequelae of radiation therapy usually appear 1-4 years after treatment.
The major sequelae include rectal or vaginal stenosis, small bowel
obstruction, malabsorption, radiation enteritis, and chronic cystitis.
Surgical complications
The most frequent complication of radical hysterectomy is urinary dysfunction
resulting from partial denervation of the detrusor muscle. Other complications
include foreshortened vagina, ureterovaginal fistula, hemorrhage, infection,
bowel obstruction, stricture and fibrosis of the intestine or rectosigmoid colon,
and bladder and rectovaginal fistulas. Invasive procedures (eg, nephrostomy
or diverting colostomy) sometimes are performed in this group of patients to
improve their quality of life.

Nutrition
Proper nutrition is important for patients with cervical cancer. Every attempt
should be made to encourage and provide adequate oral food intake.
Nutritional supplements (eg, Ensure [Abbott Nutrition, Columbus, OH] or
Boost [Nestl HealthCare Nutrition, Fremont, MI]) are used when patients
have had significant weight loss or cannot tolerate regular food because of
nausea caused by radiation or chemotherapy. In patients with severe

anorexia, appetite stimulants such as megestrol can be prescribed.


For patients who are unable to tolerate any oral intake, percutaneous
endoscopic gastrostomy tubes are placed for nutritional supplementation. In
patients with extensive bowel obstruction as a result of metastatic cancer,
hyperalimentation sometimes is used.

Prevention of Human Papillomavirus Infection

Human papillomavirus (HPV) infection is usually transmitted sexually, though


rare cases have been reported in virgins.[90] Condom use may not prevent
transmission.[90, 91] A study in a mouse model by Roberts et al found that a
widely used vaginal spermicide, nonoxynol-9, greatly increased susceptibility
to HPV infection, whereas carrageenan, a polysaccharide present in some
vaginal lubricants, prevented infection.[92]
Evidence suggests that HPV vaccines prevent HPV infection.[8] PATRICIA
(PApilloma TRIal against Cancer In young Adults) found HPV 16/18 vaccine to
be efficacious against cervical intraepithelial neoplasia (CIN) grade 2 or 3 and
adenocarcinoma in situ, irrespective of the HPV type in the lesion.[93] Crossprotective efficacy was demonstrated against 4 oncogenic HPV types not
included in the vaccine.[94] Use of an HPV 6/11/16/18 vaccine reduced the risk
of any high-grade cervical lesions by 19.0% overall, irrespective of causal
HPV type.[92]
The following three HPV vaccines are approved by the US Food and Drug
Administration (FDA):
Gardasil (Merck, Whitehouse Station, NJ) This quadrivalent vaccine is
approved for girls and women 9 to 26 years of age to prevent cervical cancer
(and also genital warts and anal cancer) caused by HPV types 6, 11, 16, and
18; it is also approved for males 9 to 26 years of age [9]
Gardasil 9 (Merck, Whitehouse Station, NJ) This nine-valent vaccine is
approved for girls and women 9 to 26 years of age to prevent cervical cancer
(and also genital warts and anal cancer); in addition to coverage of HPV types
6, 11, 16, and 18, it covers HPV types 31, 33, 45, 52, and 58; it is also
approved for males 9 to 15 years of age [95]
Cervarix (GlaxoSmithKline, Research Triangle Park, NC) This bivalent
vaccine is approved for girls and women 9 through 25 years of age to prevent
cervical cancer caused by HPV types 16 and 18 [10]
The Advisory Committee on Immunization Practices (ACIP) recommends
routine HPV vaccination of girls aged 11-12 years with 3 doses of either HPV
vaccine. The vaccination series can be started as young as age 9 years.
Catch-up vaccination is recommended for females aged 13-26 years who
have not been previously vaccinated or who have not completed the full
series.[96]
The ACIP also recommends routine use of quadrivalent HPV vaccine in boys
aged 11-12 years, as well as in males aged 13-21 years who have not been
vaccinated previously or who have not completed the 3-dose series. Males
aged 22-26 years may also be vaccinated.[97]
In the Costa Rica Vaccine Trial, researchers documented durable antibody
responses after 1 dose (as opposed to the standard 3 doses) of the bivalent

human papillomavirus (HPV) 16/18 L1 viruslike particle vaccine Cervarix.[98, 99]


The investigators evaluated 78 women who received 1 dose of the vaccine,
192 who received 2 doses, and 120 who received all 3 doses. These women
were compared with 113 women who did not receive vaccine but had
antibodies against the viruses. All subjects in the 3 vaccine groups had
antibodies against HPV 16 and 18 for as long as 4 years.[99] Although antibody
titers in women who received 1 dose were lower than those in women who
received 3 doses, they remained stable over 4 years.
Screening for cervical cancer should continue in vaccinated women, following
the same guidelines as in unvaccinated women.[6] These vaccines do not
provide complete protection against cervical cancer; oncogenic HPV types
other than 16 and 18 account for about 30% of cases, and cross-protection
may be only partial. In addition, not all vaccinated patients may mount an
effective response to the vaccine, particularly if they do not receive all 3 doses
or if they get the doses at time intervals that are not associated with efficacy.
Finally, the duration of protection with these vaccines has not yet been
determined. The available evidence suggests that immunity from infection with
the HPV types covered by these vaccines will persist for at least 6-8 years,[100]
but continuing follow-up will be required to determine whether revaccination
will be necessary.
The safety of HPV vaccines is a deeply controversial topic. Follow-up of large
patient populations who participated in phase 3 clinical trials has documented
that both FDA-approved HPV vaccines are extremely safe. Articles in the
popular media, however, have detailed cases of young women with
devastating illness attributed to the vaccines.
In post licensure safety surveillance for the quadrivalent HPV vaccine, 6.2% of
all reports to the Vaccine Adverse Event Reporting System (VAERS)
described serious adverse events, including neurologic injury (eg, GuillainBarr syndrome) and 32 reports of death. In comparison with other vaccines,
rates of most of these adverse events were no greater than the background
rates, but there was disproportional reporting of syncope and venous
thromboembolic events

Metaplastic change in the cervix and


its physiological basis
Metaplasia is the name given to the process by which one fully
differentiated type of epithelium appears to transform into another
differentiated type. It is usually an adaptive change that occurs in in
reaction to chronic irritation, or in response to hormonal stimuli. As
the female goes through puberty and reaches maturation, hormonal

changes cause the cervix to evert, which in turn causes the fragile
glandular epithelium to be exposed to a harsher, more acidic
environment in the vagina. A similar process occurs during
pregnancy.
This eversion, or ectropion, is sometimes incorrectly referred to as a
cervical erosion because of its appearance as a red rim
surrounding the cervical os.

Three histological stages have been identified:

Stage 1: Reserve cell hyperplasia - the reserve cells in the


endocervical epithelium start to divide.
Stage 2: Immature squamous metaplasia - the reserve cells
proliferate to form a multilayer of immature parabasal cells. A
surface layer of mucinous columnar cells can often be seen on the
surface.
Stage 3: Mature squamous metaplasia the immature cells have
differentiated into mature squamous epithelium, which is
nearly indistinguishable from the original squamous epithelium.
Endocervical crypts may be seen deep to the surface epithelium
identifying its origin from squamous metaplasia.
Figure 2.5. Residual endocervical glands beneath squamous
metaplasia in the transformation zone

(a) Immature squamous metaplasia with underlying endocervical crypt

From birth until puberty, the endocervical epithelium is composed of


columnar cells and the ectocervical epithelium of native squamous
cells. The interface between the two is termed the original
squamocolumnar junction.
During puberty and at the first pregnancy the cervix increases in
volume in response to hormonal changes. The endocervical
epithelium everts onto the ectocervix (portio vaginalis) exposing it to
the acid pH of the vagina. This provides a stimulus for metaplastic
change of the columnar epithelium.
The process of metaplasia is a patchy one: it starts initially in the
crypts and at the tips of the endocervical villae, which gradually
fuse. Eventually the whole of the everted endocervical epithelium
may be replaced by squamous epithelium.
Figure 2.6 Development of squamous metaplasia

Squamocolumnar junction prior to puberty.

Key:
1.
2.
3.
4.
5.

Native squamous epithelium


Columnar epithelium of endocervix
Squamocolumnar junction (SCJ)
Eversion of endocervical epithelium
Metaplastic change in transformation zone

Clinical significance of squamous metaplasia


in the cervix
In the cervix, the area of the epithelium that has undergone
metaplastic change is called the transformation zone (TZ).
Numerous studies have shown that high-grade CIN primarily
involves the immature metaplastic epithelial cells of the TZ where
most, if not all cervical cancers arise.

Specimen Collection, Adequacy & Requisition


Cervical Cytology Practice Guideline
Approved by the ASC Executive Board November 10, 2000

III. Specimen Collection and Submission


The importance of proper specimen collection and submission cannot be
overemphasized. At least one half to two thirds of false negatives are
the result of patient conditions present at the time of sample collection
and submission and the skill and knowledge of the individual who
obtains the specimen.39, 40, 41 The clinical community is responsible for

training health care personnel to assure that adequate cervical cytology


samples are collected and submitted to the laboratory with appropriate
clinical information. The laboratory provides feedback on sample
adequacy via individual reports, and may elect to provide summary
information regarding patient sampling to its clients.

III.A. Patient Preparation

To optimize collection conditions, a woman should: 42


Schedule an appointment approximately two weeks (10-18 days) after
the first day of her last menstrual period.
Not douche 48 hours prior to the test.
Not use tampons, birth control foams, jellies or other vaginal creams or
vaginal medications for 48 hours prior to the test.
Refrain from intercourse 48 hours prior to the test.

III.B. Test Requisition

Under the supervision and guidance of the physician, a laboratory


requisition must be legibly and accurately filled out before obtaining the
cellular sample. The laboratory requisition is the main communication
link between the physician and the laboratory. The requisition should
request the following information as required by CLIA 88. 43
Patients name (any name change in the past 5 years should be noted.)
Age and/or date of birth.
Menstrual status (LMP, hysterectomy, pregnant, postpartum, hormone
therapy.)
Previous abnormal cervical cytology result, previous treatment, biopsy or
surgical procedure.
Patients risk status for developing cervical cancer, e.g. high risk. The
clinician should expect that the laboratory would rely upon the
information provided on the current requisition in arriving at an
assessment of risk status. (See section IIB.)
Source of specimen, e.g. cervical, vaginal.
Appropriate clinical history provided by the physician on the requisition
should include:
Hormone/contraceptive use.
Relevant clinical findings (abnormal bleeding, grossly visible lesion, etc.)

III.C. Labeling the Sample

The glass slide or specimen vial must be labeled with a unique identifier,
usually the patients first and last names, at the time of the collection of
the cellular sample. Individual laboratories may require a second
identifier such as date of birth, medical record number, social security
number or collection date. The lab must have a written procedure that
specifies the requirements for proper specimen identification. For glass

slides, the required information is written in solvent resistant pen or


pencil on the frosted end of the slide. For liquid based samples, the
required information must be affixed to the vial.

III.D. Visualization of the Cervix for Collection of


an Adequate Sample
Collection of a cervical cytology specimen is usually performed with the
patient in the dorsolithotomy position. A sterile, or single-use bivalve
speculum of appropriate size is inserted into the vagina without
lubrication. Warm water may be used to facilitate insertion of the
speculum. The position of the speculum should allow for complete
visualization of the os and ectocervix.
The transformation zone is the site of origin for most cervical neoplasia
and should be the focus of cytology specimen collection. 44 The
transformation zone may be easily visualized or may be high in the
endocervical canal. Location varies not only from patient to patient, but
in an individual over time. Factors producing variation include changes
in vaginal pH, hormonal changes including pregnancy, childbirth, and
menopausal status, and hormonal therapy. In postmenopausal patients
or women who have received radiation therapy, cervical stenosis may
prevent visualization of the transformation zone. It remains important to
sample the endocervix in these patients. This may require more
extensive clinical procedures. If a patient has had a hysterectomy, a
vaginal sample is sufficient, with particular attention to sampling the
vaginal cuff.

III.E. Collection Devices

There are a variety of collection devices available for sampling the


endocervix, transformation zone and ectocervix. They include
endocervical brushes, wooden and plastic spatulas, and plastic broomtype samplers. Plastic spatulas are preferred over wooden since the
wooden spatulas retain cellular material.45 The use of a cotton-tipped
swab is NOT recommended, even if the swab is moistened. 41 Cells
adhere to the cotton and do not transfer well to the glass slide, which
results in an incomplete specimen. Analysis of different sampling
methods has shown that overall, the cytobrush and spatula together
provide the best specimen for cervical cytology.46 However, the choice
of a particular device is dependent on variations in the size and shape of
the cervix and the clinical situation. As stated in III.D., age, parity, and
hormonal status of the patient can affect the exposure of the
transformation zone. Previous therapy, such as conization, laser therapy
or cryotherapy, can also change the features of the cervix. The clinician
ought to consider these factors when choosing a collection device. 41

Liquid based methods require the use of collection devices that have
been approved by the FDA for use with the particular specimen
preparation instrument.

III.F. Techniques for Sample Collection

III.F.1. Collection of cervical/vaginal specimens for


conventional smear preparation using the spatula
and endocervical brush
The vaginal fornix and ectocervix should be sampled before the
endocervix/transformation zone. First, a sample of the ectocervix is
taken using a plastic (or wooden) spatula. The notched end
of the spatula that corresponds to the contour of the cervix is rotated
360 around the circumference of the cervical os, retaining the sample
on the upper surface of the spatula. Grossly visible lesions, including
irregular, discolored or friable areas should be directly sampled and can
be placed on a separate slide, especially if the lesion is distant from
other collection areas. The spatula is held with the specimen face up
while the endocervical sample is collected.
Sampling of the endocervix requires insertion of the endocervical brush
into the endocervical canal until only the bristles closest to the hand are
visible. The brush is rotated 45-90 and removed. At this time, the
sample on the spatula is spread evenly and thinly lengthwise down one
half of the labeled slide surface, using a single uniform motion. The
endocervical brush is then rolled along the remaining half of the labeled
slide surface by turning the brush handle and slightly bending the bristles
with gentle pressure. The brush should not be smeared with force or in
multiple directions.41,47 The entire slide is then rapidly fixed by
immersion or spray and the collection devices are discarded. Note: use
of the endocervical brush may be contraindicated in pregnant patients.
Refer to the package insert. If the above-described sampling order is
reversed, bleeding secondary to abrasion from the brush may obscure
the cellular material.

III.F.2. Collection of cervical/vaginal specimens for


liquid-based preparations using the spatula and
endocervical brush
For liquid based preparations, the ectocervix should be sampled using
the same procedure as for conventional Pap smears. However, the

spatula with the cellular material is rinsed in the specimen vial and then
discarded. The endocervical specimen is collected using the same
technique as for conventional Pap smears. However, the endocervical
brush is rinsed in the vial and then discarded. Manufacturers directions
must be followed.48

III.F.3. Collection of cervical/vaginal specimens for


conventional smear preparation using the broomlike device
The ectocervix and endocervix are collected simultaneously with the
broom-like device. The central bristles of the broom are inserted into
the endocervical canal until the lateral bristles bend fully against the
ectocervix. The sampling device is rotated 360 in the same direction
five (5) times while maintaining gentle pressure. The broom is removed
and with a single paint stroke motion the cellular sample is transferred
down the long axis of the labeled surface of the slide. The broom is
turned over and the paint stroke motion is repeated over the same area.
The slide is rapidly fixed either by immersion or spray and the device is
then discarded.

III.F.4. Collection of cervical/vaginal specimens for


liquid-based preparations using the broom-like
device
The ectocervical and endocervical specimens are collected with the
broom-like device simultaneously. The central bristles of the device
are inserted into the endocervical canal until the lateral bristles fully bend
against the ectocervix. Maintaining gentle pressure, the broom is rotated
in a clockwise direction 360 for a total of five (5) times. The broom is
then rinsed in the specimen vial. Manufacturers directions vary and
must be referred to and followed. 48,49

III.G. Cell Fixation for Conventional Cervical


Cytology

Immediate fixation of the cellular sample, within seconds of specimen


collection, is necessary to prevent air-drying. Air-drying obscures cellular
detail and compromises specimen evaluation. Immersing the slide in
alcohol or spraying with fixative can prevent air-drying artifact.
If the specimen is immersed in alcohol, it may remain in the alcohol for
transport to the laboratory. Alternatively, the specimen can be immersed
in alcohol for 20-30 minutes, removed and allowed to air dry, then placed

in a container/mailer for transport to the laboratory.50 The immersion


technique requires use of a separate container for each specimen and
changing or filtering the alcohol between specimens.
If a specimen is spray fixed, only quality controlled cytology fixatives
should be used. Hair spray should NOT be used. Whether using a
pump spray, aerosol fixative or single application packet, the
manufacturers instructions on the container and package insert should
be followed. Generally, spray fixatives should be 6-10 inches (15-25 cm)
from the glass slide when applied.41

III.H. Variability in Specimen Collection and


Submission Practices

Variations in specimen collection include the use of conventional Pap


smear collection on a glass slide/slides or collection in a liquid fixative.
Additional variation is encountered in rinsing the collection devices and
handling of the devices after the specimen has been collected.
Manufacturers instructions and/or package inserts should be consulted
and recommendations followed.
Other variations include the use of different collection devices. The
plastic spatula is preferred to the wooden spatula. The endocervical
brush is preferred for sampling of the endocervix. The broom-like
device is also available. Clinical judgment is required to determine the
appropriate device, as there is no single sampling device that is optimal
for all clinical circumstances.
There is variation in placement of the vaginal, ectocervical and
endocervical samples on the glass slide. For VCE slides, the vaginal
sample is collected first and placed on the slide near the frosted end
within the section labeled V. The ectocervical specimen is then
collected and smeared within the section of the slide labeled C. The
endocervical specimen is collected last, and smeared within the section
of the slide labeled E. The slide is then rapidly fixed. Another option is
to mix a vaginal pool sample with the cervical specimen. This somewhat
protects the cellular material from air-drying prior to fixation. Yet another
option is to smear the ectocervical specimen on the slide, and then
directly roll the endocervical brush on top followed by fixation.
No consensus has been reached on the clinical benefit of one slide
versus two slides for cervical cytology. Several comparative studies
have been performed and concluded that the single slide method is an
acceptable alternative to the double slide method. The single slide
method decreases the number of slides screened in the laboratory,
reduces costs for glass slides, and requires less space for storage. 51, 52
While this section discusses the consensus of the cytologic community

regarding the most appropriate and effective methods of specimen


collection and submission, it is not intended to supplant or establish the
gynecologic communitys standard of care and practice regarding these
issues. Nor is this Guideline intended to diminish the responsibility of
clinicians to be aware of and apply the standards applicable to their
medical specialty and their individual patients.
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