Treatment Modalities for Cervical
Pre-Invasive Lesions
10
Gokhan Tulunay, MD
Nejat Ozgul, MD
Most practitioners use a three minute freeze, a five minute
thaw and then another three minute freeze. It is the least
expensive and easiest treatment to perform. Local anesthetic
is usually not necessary but will make the procedure less
painful.
Complications are rare. The procedure does cause mild
cramping, watery discharge for several weeks and in rare
cases, freeze burn of the vagina, mild bleeding or infection.
Pelvic inflammatory disease (PID) may occur if there is
cervicitis and there is some risk of stenosis in adolescents.
Cryotherapy sometimes moves the squamacolumnar (SCJ)
into the os, which may decrease cervicitis but increase
problems with accurate follow-up. Stenosis or hidden SCJ
can be avoided if a flat tip or a tip with a minimal nipple is
used.
Cryotherapy is best for smaller lesions. There is a renewed
interest and a recent trend back to using cryotherapy which
fell somewhat into disfavor after LEEP became popular.
Cryotherapy equipment and technique are shown at Figures
1, 2 and 3.
Introduction
Treatment of cervical preinvasive lesions is divided into
ablative and excisional techniques. Ablative therapy destroys
the abnormal cells and the surface of the transformation zone.
Excisional therapy also provides a surgical specimen that is
examined in the laboratory to evaluate the severity of the
diseased tissue removed and if possible, the completeness
of the procedure. The cure rate for each type of outpatient
therapy is about 80% to 90% with one treatment and 95%
with repeated treatment, if the method is properly selected.
The cure rate with loop electrosurgical excision procedure
(LEEP) is similar to cryotherapy or laser.
An excision procedure is preferred if there is evidence of
multi-quadrant disease, AGC, crypt (glandular) involvement
or AIS. However, LEEP also has a higher failure rate if there
is multi-quadrant disease or crypt involvement. Often the
decision is made by the preferences of the clinician. However,
the woman must be informed about all choices in a balanced
manner as part of informed consent.
All treatment procedures destroy some cervix. Cervical
stenosis can result in amenorrhea, severe dysmenorrhea,
infertility and inadequate colposcopy. Treatment may shorten
the cervix and decrease mucus production from cervical
glands that also could compromise fertility. Treatment may
cause increased risk of premature delivery and any type
of conization (laser, LEEP, cold-knife) increases cervical
incompetence. Cervical incompetence can cause late
spontaneous abortions, premature rupture of membranes
and premature delivery. Although fertility problems are
believed to be low with the less invasive procedures, the
frequency and severity of these changes and the comparative
risk with each of the different treatment modalities has not
been clearly defined. The studies, especially for LEEP, have
been small, observational, lacked adequate controls and of
short duration. More studies are needed on the impact of
the various treatment modalities on pregnancy. Clinicians
should inform women about the concern and lack of definite
evidence on future fertility and pregnancy outcomes as part
of the education process and informed consent procedure.
Laser
Diseased tissue is removed with a CO2 laser. Energy is
converted into light which is focused by mirrors and lenses on
(1) Probe, (2) Trigger, (3) Handle grip (fibreglass) (4) Yoke, (5)
Instrument inlet of gas from cylinder, (6) Tightening knob, (7) Pressure
gauge showing cylinder pressure, (8) Silencer (outlet), (9) Gasconveying tube, (10) Probe tip
Ablative Techniques
Cryotherapy
Figure 1. Components of cryotherapy equipment (Reproduced from
IARC Manual (1) under permission).
Cryotherapy involves freezing the cervix to about -60°C to
-80°C to a depth of 4 to 5 millimeters with a liquid NO2 probe.
49
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u Treatment Modalities for Cervical Pre-Invasive Lesions
Figure 2. Positioning of the cryoprobe tip on the cervix (Reproduced
from IARC Manual (1) under permission).
Figure 3. (a) The iceball on the cervix immediately after cryotherapy, (b)
Appearance 2 weeks after cryotherapy. (c) 3 months after cryotherapy.
(d) 1 year after cryotherapy (Reproduced from IARC Manual (1) under
permission).
a small area where it vaporizes the tissue. The procedure is
precise because it is colposcope-directed to the problematic
area and it has a measured depth of about six to seven
millimeters. It is also possible to do a contoured conization
with laser. Other advantages include more rapid healing, less
disagreeable discharge and in most cases, better visibility of
the SCJ after the procedure. Laser is used for the vulva and
vagina and is best for multifocal cervical disease, lesions wide
on the cervix or if the vagina is involved.
Disadvantages include greater expense and the need
for anesthesia. The procedure takes longer for large
lesions. Laser causes an unpleasant (burning flesh) odor
and sometimes significant intraoperative and postoperative
bleeding. There are risks of burns to the vagina, pain,
menstrual cramps, vaginal adenosis and cervical stenosis.
Cervical stenosis occurs in over 10% of laser cones and
can result in amenorrhea, severe dysmenorrhea, infertility
and inadequate colposcopy. The equipment is expensive
compared to other treatment modalities. It takes a long time
to learn good laser skills. Laser ablation is less used now
and more colposcopists treat with LEEP instead. Laser is still
frequently used for conization and for VAIN and VIN.
Requirements for ablative therapy are shown at Table 1.
Excisional Techniques
Whenever treatment is done that does not meet all the criteria
for ablative therapy (above), an excisional technique must be
used.
Loop Electrosurgical Excision Procedure (LEEP)
Loop Electrosurgical Excision Procedure (LEEP), also called
Large Loop Excision of the Transformation Zone (LLETZ),
cuts off the surface of the cervix to a depth of six to ten
millimeters with a low voltage, high frequency radio signal in
a tungsten wire. It uses blended cutting and coagulation, so
the area is cauterized as well. Often, all of the transformation
zone is removed for pathology to rule out cancer, which could
be missed with other treatment methods. LEEP is easier to
learn, easier to perform and faster than ablative laser therapy
or cold-knife or laser conization. Expert colposcopists may
diagnose and treat HSIL at the same visit, but there is a
significant chance of over treatment so this should be limited
to women with clear evidence of CIN-3. Disadvantages of
LEEP include greater expense than cryotherapy, the need
for anesthesia, and being unable to stop during cutting
so the specimen may be removed in pieces. The clinician
must be very steady and the client must not move. There
are risks of burns to the vagina or the area of the grounding
pad, pain, significant bleeding during the procedure (36%),
postoperative bleeding, infection, urinary tract infections,
toxic shock, menstrual cramps, cervical stenosis, and excess
depth of tissue removal or even amputation of cervix. There
is significant risk (perhaps 50%) of leaving disease at the
margins, which increases the risk of persistent disease.
Complications are higher in very young women, during the
postpartum period and in postmenopausal women with
atrophy.
An advantage of LEEP is that there is histological
evaluation of the entire sample removed (unless heat
Table 1.
•
•
•
•
•
•
Requirements for ablative therapy.
Evaluation by a skilled colposcopist
Satisfactory colposcopy
Colposcopy, cytology and histology correlate
Lesion <3 quadrants, <10 mm radially
No deep crypt (glandular) involvement
No evidence of AGC or invasive cancer
Treatment Modalities for Cervical Pre-Invasive Lesions u
51
Figure 4. Excision of an ectocervical lesion with one pass (Reproduced
from IARC Manual (1) under permission).
damage makes it unreadable). Several studies indicated that
conization (LEEP, laser or cold-knife) resulted in the detection
of unsuspected microinvasive carcinoma that was missed on
the colposcopic biopsy. However, the cure rate has been very
good with ablative therapy such as cryocautery or laser. This
detection of “missed cancer” probably indicates that ablative
therapy also cures microinvasive cancers and may also be a
reflection of the 50% over-diagnosis of microinvasive cancer.
Furthermore, conization does not remove the entire lesion
in about 40% to 60% of the time, yet still usually cures the
disease.
Conization
Conization is therapeutic as well as diagnostic. Conization
involves using a knife (coldknife), LEEP/LLETZ (top-hat) or
laser, to cut out the area of the cervix around the cervical
os, removing the entire transformation zone and much of the
endocervical canal. A coldknife cone uses a regular surgical
blade to remove a conical area from the surface of the cervix
into the cervical canal. The cold-knife cone has the advantage
of removing a single surgical specimen, without “burned”
edges, thus facilitating evaluation of the margins for complete
management of the disease. LEEP is now the most common
means of conization, since it is faster and easier and has
fewer immediate complications than laser or cold-knife cones.
Different techniques for excision of an ectocervical lesion
may be used (Figures 4, 5 and 6). In addition to the regular
Figure 6. Excision of an ectocervical lesion with multiple passes
(Reproduced from IARC Manual (1) under permission).
Figure 5. Excision of an ectocervical lesion with one pass. Note the
excised specimen in place; the excised specimen is removed and the
appearance of the cervix after the removal of the excised specimen
(Reproduced from IARC Manual (1) under permission).
removal of the surface area, a smaller wire loop is used to
remove one or more deeper areas above the cervical canal
(called top-hat). Laser conization cuts out a cylinder shaped
block of tissue around the cervical canal (Figures 7 and 8).
Conization usually gives a complete tissue sample for
microscopic analysis. The pathologic evaluation of the cone
specimen is again subjective and also subject to sampling
error, since selected blocks are taken from the specimen
for pathological analysis. Both laser and LEEP cones have
a significant risk of thermal damage sufficient to impede
the pathologic diagnosis. LEEP cone usually results in
several pieces making it harder to evaluate the margins for
residual disease. The cure rate for HSIL and probably even
microinvasive cancer is as good or better than hysterectomy.
Cold-knife cone has a better cure rate than LEEP and is
Figure 7. Excision of ectocervical plus endocervical lesions
(Reproduced from IARC Manual (1) under permission).
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u Treatment Modalities for Cervical Pre-Invasive Lesions
Figure 8. Excision of an ectocervical lesion
extending into the endocervical canal by a twolayer excisional method; (a) appearance of the
CIN 3 lesion after 5% acetic acid application;
(b) appearance after Lugol’s iodine application;
(c) excision of the ectocervical lesion in
progress; (d) ectocervical cut completed; (e)
endocervical cut completed and the specimen
in place (narrow arrows); (f) endocervical cut
specimen removed and the bleeding points in
the floor of the crater are being fulgurated to
achieve haemostasis (Reproduced from IARC
Manual (1) under permission).
preferred for possible AIS, cancer and adenocarcinoma.
However, no conization by any method (or other treatment)
will “cure” HPV infection.
In a recent meta-analysis, one prospective cohort and 19
retrospective studies were retrieved. Cold knife conization
was associated with a significantly increased risk of perinatal
mortality (relative risk 2.87, 95% confidence interval 1.42
to 5.81) and a significantly higher risk of severe preterm
delivery (2.78, 1.72 to 4.51), extreme preterm delivery (5.33,
1.63 to 17.40), and low birth weight of <2000 g (2.86, 1.37
to 5.97). Laser conization, described in only one study, was
also followed by a significantly increased chance of low birth
weight of <2000g and <1500 g. Large loop excision of the
transformation zone and ablative treatment with cryotherapy
or laser were not associated with a significantly increased risk
of serious adverse pregnancy outcomes (2).
The Indications for Conization Include the Following
•
•
•
•
•
•
•
•
•
HSIL (not LSIL) and unsatisfactory colposcopy (the limits
of the lesion were not visible by colposcopy or the SCJ
was not visualized in entirety).
The endocervical sample (ECC) contained HSIL or cancer
cells, or contained any SIL with a HSIL Pap or biopsy and
unsatisfactory colposcopy.
Significant discrepancy in cytology.
HSIL or cancer not explained by colposcopy and biopsy.
A very large, severe CIN-3 lesion should probably have
conization by LEEP or other modalities.
Presence of microinvasion on the biopsy.
Diagnosis and sometimes treatment of microinvasive
cervical cancer.
Cytology or biopsy evidence suggesting AIS or invasion
need cold-knife (or laser) conization.
Persistent CIN-3 that was not effectively treated by other
treatment methods.
Conization has “the highest complication rate of any
type of gynaecologic surgery.” The complications are about
the same with cold-knife, laser, and LEEP cones. Risks
of conization include costs (including hospitalization, if
necessary), intraoperative and postoperative bleeding;
infection, cervical stenosis, loss of cervical mucus-secreting
glands causing infertility and cervical incompetence. There
is a possibility of residual disease, but this usually can be
detected by evaluation of the surgical margins. Positive
margins on conization is increased with more severe lesions
but does not necessarily indicate need for further treatment,
and negative margins does not prove cure. Follow-up Paps
are essential to document cure.
Hysterectomy
Hysterectomy should only be used for invasive cancer of
the cervix (squamous carcinoma or adenocarcinoma and
sometimes AIS), uterus (endometrium), or adnexa (tubes or
ovaries) or for other significant pelvic pathology that does
not respond to conservative treatment. It should not be used
for SIL alone. Hysterectomy often constitutes over-treatment
for women without invasive cancer. Unfortunately, it is still
advocated for precancerous changes (CIN-3) by some
authorities.
References
1.
2.
Sellors John W, Sankaranarayanan R. Colposcopy and
Treatment of Cervical Intraepithelial Neoplasia: A Beginners’
Manual. Published by IARC, Lyon, 2003.
Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, MartinHirsch P, Prendiville W, Paraskevaidis E. Perinatal mortality and
other severe adverse pregnancy outcomes associated with
treatment of cervical intraepithelial neoplasia: meta-analysis.
BMJ 2008 Sep 18;337:a1284. doi: 10.1136/bmj.a1284. Review.