Cervical cancer is the 3rd most common gynecologic cancer and

the 8th most common cancer among women in the US. Mean age
at diagnosis is 50, but the cancer can occur as early as age 20.
The American Cancer Society estimates that in the US, 13,170
new cases of invasive cervical cancer and 4,250 deaths from
cervical cancer will occur in 2019.

Cervical cancer results from cervical intraepithelial neoplasia (CIN),

which appears to be caused by infection with human
papillomavirus (HPV) type 16, 18, 31, 33, 35, or 39.
Risk factors for cervical cancer include
 Younger age at first intercourse

 A high lifetime number of sex partners

 Cigarette smoking

 Immunodeficiency

Regardless of sexual history, clinicians should assume that women

have been exposed to someone with HPV because it is ubiquitous.

Pathology
CIN is graded as

 1: Mild cervical dysplasia

  2: Moderate dysplasia

 3: Severe dysplasia and carcinoma in situ

CIN 3 is unlikely to regress spontaneously; if untreated, it may,

over months or years, penetrate the basement membrane,
becoming invasive carcinoma.

About 80 to 85% of all cervical cancers are squamous cell

carcinoma; most of the rest are adenocarcinomas. Sarcomas and
small cell neuroendocrine tumors are rare.

Invasive cervical cancer usually spreads by direct extension into

surrounding tissues or via the lymphatics to the pelvic and para-
aortic lymph nodes. Hematogenous spread is possible but rare.

If cervical cancer spreads to the pelvic or para-aortic lymph nodes,

the prognosis is worse, and the location and size of the radiation
therapy field is affected.

Symptoms and Signs

Early cervical cancer can be asymptomatic.

When symptoms occur, they usually include irregular vaginal

bleeding, which is most often postcoital but may occur
spontaneously between menses. Larger cancers are more likely to
bleed spontaneously and may cause a foul-smelling vaginal
discharge or pelvic pain. More widespread cancer may cause
obstructive uropathy, back pain, and leg swelling due to venous or
lymphatic obstruction.

Pelvic examination may detect an exophytic necrotic tumor in the

cervix.

Diagnosis
 Papanicolaou (Pap) test

 Biopsy

 Clinical staging, usually by biopsy, pelvic examination, and

chest x-ray

Cervical cancer may be suspected during a routine gynecologic

examination. It is considered in women with

 Visible cervical lesions

 Abnormal routine Pap test results

 Abnormal vaginal bleeding

Reporting of cervical cytology results is standardized (see

table Bethesda Classification of Cervical Cytology  [1]). Further
evaluation is indicated if atypical or cancerous cells are found,
particularly in women at risk. If cytology does not show any obvious
cancer, colposcopy (examination of the vagina and cervix with a
magnifying lens) can be used to identify areas that require biopsy.
Colposcopy-directed biopsy with endocervical curettage is usually
diagnostic. If not, cone biopsy (conization) is required; a cone of
tissue is removed using a loop electrical excision procedure
(LEEP), laser, or cold knife.
Cervical Cancer

SCIENCE PHOTO LIBRARY

Loop Electrosurgical Excision Procedure (LEEP)

TABLE
Staging
Cervical cancers are clinically staged based on biopsy, physical
examination, and chest x-ray results (see table Bethesda
Classification of Cervical Cytology ). In the International Federation
of Gynecology and Obstetrics (FIGO) staging system, stage does
not include information about lymph node status. Although not
included as staging, lymph node status is one of the most
important prognostic factors in early-stage cervical cancer (stages
IA1 to IB1); it is required for treatment planning and affects the
radiation therapy field.
If the stage is > IA2, CT or MRI of the abdomen and pelvis is
typically done to identify metastases, although results are not used
for staging. PET with CT (PET/CT) is being used more commonly
to check for spread beyond the cervix. If PET/CT, MRI, or CT is not
available, cystoscopy, sigmoidoscopy, and IV urography, when
clinically indicated, may be used for staging.

The purpose of this staging system is to establish a consistent

standard and uniform classification of diagnosis in all regions of the
world. The system excludes results of tests that are less likely to
be available worldwide (eg, MRI) because most cases of cervical
cancer occur in developing countries. Because such tests are not
used, findings such as parametrial invasion and lymph node
metastases are often missed, and thus understaging is possible.
When imaging tests suggest that pelvic or para-aortic lymph nodes
are grossly enlarged (> 2 cm), surgical exploration, typically with a
retroperitoneal approach, is occasionally indicated. Its sole
purpose is to remove enlarged lymph nodes so that radiation
therapy can be more precisely targeted and more effective.
Prognosis
In squamous cell carcinoma, distant metastases usually occur only
when the cancer is advanced or recurrent. The 5-year survival
rates are as follows:

 Stage I: 80 to 90%

 Stage II: 60 to 75%

 Stage III: 30 to 40%

 Stage IV: 0 to 15%

Nearly 80% of recurrences manifest within 2 years.

Adverse prognostic factors include

 Lymph node involvement

 Large tumor size and volume

 Deep cervical stromal invasion

  Parametrial invasion

 Lymphovascular space invasion (LVSI)

 Nonsquamous histology

Treatment
 Excision or curative radiation therapy if there is no spread to
parametria or beyond

 Radiation therapy and chemotherapy if there is spread to

parametria or beyond

 Chemotherapy for metastatic and recurrent cancer

Treatment of cervical cancer may include surgery, radiation

therapy, and chemotherapy. If hysterectomy is indicated but
patients cannot tolerate it, radiation therapy plus chemotherapy is
used.

Cervical intraepithelial neoplasia (CIN) and

squamous cell carcinoma stage IA1
Treatment involves

 Conization or simple hysterectomy

Microinvasive cervical cancer, defined as FIGO stage IA1 with no
lymphovascular space invasion (LVSI), has a < 1% risk of lymph
node metastases and may be managed conservatively with
conization using LEEP, laser, or cold knife. Conization is indicated
for patients who are interested in preserving fertility. Simple
hysterectomy should be done if patients are not interested in
preserving fertility or if margins are positive after conization.

In cases of stage IA1 with lymphovascular space invasion,

conization (with negative margins) and laparoscopic pelvic sentinel
lymph node (SLN) mapping  plus lymphadenectomy (lymph node
dissection) is a reasonable strategy.

Stages IA2 to IIA

For stage IA2 or IB1 cervical cancer, the standard
recommendation is
 Radical hysterectomy with bilateral pelvic lymphadenectomy
(with or without SLN mapping)

Radical hysterectomy includes resection of the uterus (including

the cervix), parts of the cardinal and uterosacral ligaments, the
upper 1 to 2 cm of the vagina, and the pelvic lymph nodes. Recent
results from a phase III prospective randomized trial (1) show that
minimally invasive surgery (MIS) resulted in a lower overall survival
rate and a higher recurrence rate than total abdominal radical
hysterectomy (TARH). Therefore, practice patterns now show a
preference for an open approach rather than MIS.
The Querleu & Morrow classification system describes 4 basic
types of radical hysterectomy, with a few subtypes that take nerve
preservation and paracervical lymphadenectomy into account (2).
For stage IB2 to IIA cervical cancer, the most common approach
is
 Combined chemotherapy and pelvic radiation

Another treatment option is radical hysterectomy and bilateral

pelvic lymphadenectomy, sometimes with radiation therapy (see
table Sedlis Criteria for External Pelvic Radiation After Radical
Hysterectomy).
If extracervical spread is noted during surgery, radical
hysterectomy is not done, and postoperative radiation therapy with
concurrent chemotherapy is recommended to prevent local
recurrence.

In some patients who have early-stage cervical cancer and who

wish to preserve fertility, a radical trachelectomy may be done. An
abdominal, vaginal, laparoscopic, or robotic-assisted approach can
be used. In this procedure, the cervix, parametria immediately
adjacent to the cervix, upper 2 cm of the vagina, and pelvic lymph
nodes are removed. The remaining uterus is reattached to the
upper vagina, preserving the potential for fertility. Ideal candidates
for this procedure are patients with the following:

 Histologic subtypes such as squamous cell carcinoma,

adenocarcinoma, or adenosquamous carcinoma
  Stage IA1/grade 2 or 3 with lymphovascular space invasion

 Stage IA2

 Stage IB1 with lesions < 2 cm in size

Invasion of the upper cervix and lower uterine segment should be
excluded by MRI before surgery. Rates of recurrence and death
are similar to those after radical hysterectomy. If patients who have
this procedure plan to have children, delivery must be cesarean.
After a radical trachelectomy, fertility rates range from 50 to 70%,
and the recurrence rate is about 5 to 10%.

Stages IIB to IVA

For stages IIB to IVA cervical cancer, the standard therapy is

 Radiation therapy plus chemotherapy (eg, cisplatin)

Surgical staging should be considered to determine whether para-
aortic lymph nodes are involved and thus whether extended-field
radiation therapy is indicated, particularly in patients with positive
pelvic lymph nodes identified during pretreatment imaging. A
laparoscopic retroperitoneal approach is recommended.

When cancer is limited to the cervix and/or pelvic lymph nodes, the
standard recommendation is

 External beam radiation therapy, followed by brachytherapy

(local radioactive implants, usually using cesium) to the cervix
Radiation therapy may cause acute complications (eg, radiation
proctitis and cystitis) and, occasionally, late complications (eg,
vaginal stenosis, intestinal obstruction, rectovaginal and
vesicovaginal fistula formation).

Chemotherapy is usually given with radiation therapy, often to

sensitize the tumor to radiation.

Although stage IVA cancers are usually treated with radiation

therapy initially, pelvic exenteration (excision of all pelvic organs)
may be considered. If after radiation therapy, cancer remains but is
confined to the central pelvis, exenteration is indicated and cures
up to 40% of patients. The procedure may include continent or
incontinent urostomy, low anterior rectal anastomosis without
colostomy or with an end-descending colostomy, omental carpet to
close the pelvic floor (J-flap), and vaginal reconstruction with
gracilis or rectus abdominis myocutaneous flaps.

Stage IVB and recurrent cancer

Chemotherapy is the primary treatment, but only 15 to 25% of
patients respond to it.

In a recent study, adding bevacizumab to combination

chemotherapy
(cisplatin plus paclitaxel or topotecan plus paclitaxel) resulted in an
improvement of 3.7 months in median overall survival in patients
with recurrent, persistent, or metastatic cervical cancer (3).
Metastases outside the radiation field appear to respond better to
chemotherapy than does previously irradiated cancer or
metastases in the pelvis.

Sentinel lymph node mapping for cervical cancer

Sentinel lymph node (SLN) mapping is an alternative to full pelvic
lymphadenectomy for patients with early-stage (IA1 with
lymphovascular space invasion or IB1) cervical cancer (4) because
only 15 to 20% of these patients have positive nodes. SLN
mapping therefore decreases the number of full pelvic
lymphadenectomies, which can have adverse effects (eg,
lymphedema, nerve damage).
For SLN mapping, blue dye or technetium-99 ( 99Tc) is directly
injected into the cervix, usually at 3 and 9 o’clock. More recently,
indocyanine green (ICG) can be used as the tracer when open or
minimally invasive surgery is done. During surgery, SLNs are
identified by direct visualization of blue dye, by a camera to detect
the fluorescence of ICG, or by a gamma probe to detect 99Tc. SLNs
are commonly located medial to the external iliac vessels, ventral
to the hypogastric vessels, or in the superior part of the obturator
space.
Ultrastaging of all SLNs is done to detect micrometastasis and
isolated tumor cells. Any suspicious node must be removed
regardless of mapping. If there is no mapping on a hemipelvis, a
side-specific lymphadenectomy is done.
Detection rates for sentinel node lymph mapping are best for
tumors < 2 cm.

Criteria for radiation therapy after radical

hysterectomy
Criteria used to determine whether pelvic radiation with concurrent
chemotherapy should be done after radical hysterectomy include
the following (see table Sedlis Criteria for External Pelvic Radiation
After Radical Hysterectomy ):
 Presence of lymphovascular space invasion

 Depth of invasion

 Tumor size

Prevention

Screening tests
Two types of screening tests for cervical abnormalities are used:

 Pap test

 HPV test

Routine cervical cancer screening tests are recommended as

follows (1):
  From age 21 to 29: Usually every 3 years for the Pap test
(HPV testing is not generally recommended)

 Age 30 to 65: Every 3 years if only a Pap test is done or every

5 years if only an HPV test is done or if both tests are done
(more frequently in women at high risk of cervical cancer)

 After age 65: No more testing if test results have been normal
in the preceding 10 years

If women have had a hysterectomy for a disorder other than cancer

and have not had abnormal Pap test results, screening is not
indicated. (See also Cervical Cancer Screening Guidelines .)
HPV testing is the preferred method of follow-up evaluation for all
women with ASCUS (atypical squamous cells of undetermined
significance), an inconclusive finding detected by Pap tests. If HPV
testing shows that the woman does not have HPV, screening
should continue at the routinely scheduled intervals. If HPV is
present, colposcopy should be done.

HPV vaccine
Preventive HPV vaccines include
 A bivalent vaccine that protects against subtypes 16 and 18
(which cause most cervical cancers)

 A quadrivalent vaccine that protects against subtypes 16 and

18 plus 6 and 11
  A 9-valent vaccine that protects against the same subtypes as
the quadrivalent plus subtypes 31, 33, 45, 52, and 58 (which
cause about 15% of cervical cancers)

Subtypes 6 and 11 cause > 90% of visible genital warts.

The vaccines aim to prevent cervical cancer but do not treat it.

For patients ≥ 15 years, three doses are given over 6 months (at 0,
1 to 2, and 6 months). For patients < 15 years, two doses are given
6 to 12 months apart.

The HPV vaccine is recommended for boys and girls, ideally

before they become sexually active. The standard recommendation
is to vaccinate boys and girls beginning at age 11 to 12 years, but
vaccination can begin at age 9