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
/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
Types
16
18,31,33,35,39,45,51,52,56,
58, 59
Sufficient evidence
68
26,53,66,67,70,73,82
30,34,69,85,97
6,11
2A
2B
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]
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
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
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
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
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
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.
TNM
Stage
FIGO
Stage
TX
T0
Tis
Carcinoma in situ
T1
T1a
IA
T1a1
IA1
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
IB2
T2
II
Cervical carcinoma extends beyond the cervix but not to the pelvic sidewall or to the
lower third of vagina
T2a
IIA
T2b
IIB
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
T3b
IIIB
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
M1
IVB
Distant metastasis
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
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]
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
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.
Key:
1.
2.
3.
4.
5.
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
Liquid based methods require the use of collection devices that have
been approved by the FDA for use with the particular specimen
preparation instrument.
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
Bibliography/References
39 McGoogan E, Colgan TJ, Ramzy I et al. Cell preparation methods
and criteria for sample adequacy: IAC Task Force Summary. Acta Cytol
1998; 42:25-32.
40 Vooijs GP, Elias A, Van der Graaf Y, Poelen-van de Berg M. The
influence of sample takers on the cellular composition of cervical
smears. Acta Cytol 1986; 35:251-257.
41 Thompson D. Adequate Pap Smears: A guide for sampling
techniques in screening for abnormalities of the uterine cervix.
Laboratory Proficiency Testing Program of Canada, 1989.
42 American Cancer Society, Atlanta, Georgia. Web site:
http:\www.cancer.org
43 Clinical Laboratory Improvement Amendments of 1988; Final Rule.
Federal Register. Feb. 28, 1992; Vol. 57: 493.1105.
44 NCCLS. Papanicolaou Technique; Approved Guideline. NCCLS
Document 15-A (ISBN 1-56238-238-1) Villanova, Pennsylvania:
NCCLS; 1994; 14: no. 8.
45 Rubio CA. The false negative smear. Obstet and Gynecol 97;
49:576-580.
46 Boon ME, Guilloud JC, Rietverd WJ. Analysis of five sampling
methods for the preparation of cervical smears. Acta Cytol 1989; 33:
843-848.
47 Luzzatto R, Boon ME. Contribution of the endocervical cytobrush
sample to the diagnosis of cervical lesions. Acta Cytol 1996; 40:11431147.
48 Cytyc Corporation, 85 Swanson Road, Boxborough, Massachusetts,
01719
49 TriPath Imaging, Inc. 700 Plantation Drive, Burlington, North
Carolina, 27215
50 Somrak TM, Sorensen K, Abdul-Karim F. Pap smear: Collection,
handling and quality assurance. Chicago: ASCP Press; 1990.
51 Saitas VL, Hawthorne C, Cater J, Bibbo M. Single slide versus