NFOG - Nordic Federation of Societies of Obstetrics and Gynecology

55. Premalignant lesions of the uterine cervix

Take home messages

Oncogenic human papillomavirus (HPV) is considered a necessary, but not a sufficient, cause of cervical cancer.
Persistent HPV infection may lead to development of premalignant lesions that may progress to cervical cancer if left undetected and
untreated.
Women with abnormal screening results are typically referred for colposcopy which enables the procurement of colposcopy-directed
biopsies.
Diagnosis of premalignant lesions of the cervix is made based on histopathological examination of biopsies from the cervix.
Treatment of premalignant lesions of the cervix depends on the severity of the disease and is normally performed by surgical removal of
the lesion under local anesthesia.

Introduction
The uterine cervix is the lower cylindrical portion of the uterus that projects into the vagina. It consists of fibromuscular tissue, is covered
by the ectocervical lining and contains the endocervical canal which connects the external opening (os) with the uterine cavity at the
internal os. The canal is lined by single layer columnar mucus-producing epithelium. The ectocervix, often referred to as the “portio
vaginalis”, is covered by non-keratinized multilayer squamous cell epithelium, illustrated in Figure 1. The endocervical and ectocervical
linings join at the squamo-columnar junction (SCJ). The site of the SCJ near the external os and on the ectocervix varies with age and
hormonal changes. Prior to menarche, the SCJ is located closely to or at the external os, but during reproductive age the SCJ is located
further out on the ectocervix at a variable distance from the external os. After menopause, the SCJ retracts into the cervical canal and is
to a lesser extent or not at all longer visible at a gynecological speculum examination. The transformation zone (TZ) is the shifting area
where the original and the constantly renewed SCJ meet. This is where premalignant lesions of the cervix usually arise.

Figure 1. Illustration of the uterine cervix with the squamocolumnar junction (SCJ) and transformation zone (TZ), the area where
premalignant lesions of the cervix usually arise. Copyright K.C. Toverud CMI (Click to enlarge)

Etiology and pathogenesis

Premalignant lesions of the cervix, often referred to as cervical precancer or cervical dysplasia, arise as a result of an infection with
human papillomavirus (HPV). HPV is the most common sexually transmitted infection, affecting most women at some point in their lives.
So far more than 150 HPV genotypes have been identified. The prevalence of HPV infection peaks around the age of 20 when 40-50% of
women have acquired HPV, after which the prevalence rates gradually decline with advancing age, down to 5-10% in older women. HPV
types can be divided into low- and high-risk types depending on their oncogenic potential. Low-risk types may also cause anogenital
wart formation, whereas the high-risk types can lead to cervical precancer and possibly cancer. Upon infection most women (80-90%
within five years) are able to mount an effective immune response, resulting in gradual clearance of the infection, but some women fail
to clear the infection, which leads to persistent infection. A persistent HPV infection with one of the high-risk HPV types may lead to
cervical precancer, which can subsequently progress to cervical cancer if left undetected and untreated. It is estimated that it takes 10-
20 years for cervical cancer to develop from the time of HPV infection. There are differences among HPV types in how often and how fast
they progress to high-grade dysplasia and cancer, with HPV16 being the most aggressive genotype.
Premalignant lesions of the cervix may arise from the squamous or the glandular columnar epithelium, - in some cases from both. A
precancer arising from columnar epithelium is referred to as adenocarcinoma-in-situ (AIS), whereas precancer arising from squamous
epithelium is referred to as cervical intraepithelial neoplasia (CIN). The diagnosis is made by histopathological examination of tissue
samples from the cervix. The classification of CIN, the most common histologic subtype, depends among other things on the proportion
of the thickness of the cervical squamous epithelium that is made up of dysplastic cells (Figure 2). In CIN1 (histological LSIL in the WHO
2014 classification system), dysplastic cells are confined to the outer 1/3 of the epithelium, whereas dysplastic cells are confined to 1/3-
2/3 of the thickness in CIN2 (histological HSIL) and from 2/3 up to the entire thickness of the epithelium in CIN3 (histological HSIL). As
the columnar epithelial is only one layer of cells, precancers arising there will always be AIS. For both histological subtypes there is no
invasion through the basement membrane at the precancer stage.

Figure 2. Classification of premalignant lesions arising from squamous cell epithelium. (Click to enlarge)

Cervical cancer prevention

Cervical cancer is largely preventable through screening and HPV vaccination. Screening for cervical cancer at the population level
enables both detection of premalignant lesions and undiagnosed cancer at an early stage in individuals with no signs or symptoms of
disease. Vaccination against a subset of high-risk HPV genotypes prevents to a very large degree the development of premalignant
lesions and cervical cancer that are causally related to the genotypes included in the vaccine.

Vaccination against human papillomavirus

Prophylactic vaccines have been developed for primary prevention of HPV-related cervical precancer and cancer. Three prophylactic
vaccines have been or are currently commercially available. The bivalent vaccine (Cervarix®) targets HPV16 and 18 that account for ~70%
of cervical cancer cases, and the quadrivalent vaccine (Gardasil®) targets the former two and HPV6 and 11, the most common causes of
genital warts. The nonavalent vaccine (Gardasil-9®) targets nine HPV types, i.e. 31, 33, 45, 52, and 58 in addition to the previously
mentioned HPV types. HPV types included in the nonavalent vaccine account for an estimated 90% of cervical cancer cases. Recently, the
quadrivalent vaccine was replaced by the nonavalent vaccine in many vaccination programs worldwide.

The antibody response after a natural HPV infection is poor and does not confer protection against reinfection. The magnitude of
antibody response after vaccination is up to 100-fold higher than after a natural HPV infection and remains elevated for a very long time.
Vaccines are typically administered in a two-dose regimen with a 6-month interval. A three-dose regimen is recommended after
adolescence and in immunocompromised individuals. Protection against HPV infection and cervical precursor lesions appears to remain
high in the late teens and early adulthood despite a lower serum antibody level.

The prophylactic HPV vaccines have been shown to be highly efficacious (>95%) against HPV infection and cervical precancer attributed
to the HPV-types covered by the vaccine. First proof of protection against invasive cancer from a randomised setting has also been
reported. In the Nordic countries and many other countries, the implementation of HPV vaccination in national childhood vaccination
programs has resulted in a reduced incidence of anogenital warts and cervical precancer (up to 90% reduction of high-grade lesions),
particularly among those vaccinated. Unvaccinated individuals may receive protection against HPV and HPV-related disease when a large
fraction of the population is vaccinated. This phenomenon is called herd immunity. There is also some evidence of cross-protection
against high-risk genotypes not targeted by the bivalent and quadrivalent vaccines. HPV vaccination offers greatest protection against
HPV-related disease in women who are HPV negative with no evidence of prior infection compared to women who are already infected
with HPV.

In many countries HPV vaccination is recommended for adolescent girls only, but some countries recommend vaccination of adolescent
boys as well, resulting in an increased herd immunity. In recent years, campaigning from anti-vaccine groups and fear of serious adverse
events after HPV vaccination have affected HPV vaccine uptake in some countries. There is, however, no indication or evidence that HPV
vaccination is associated with increased long-term risks of serious disease or adverse pregnancy outcomes.

Screening for cervical cancer

Screening for cervical cancer was introduced in the Nordic countries in the 1960’s (Denmark, Finland, Iceland, and Sweden) and 1970’s
(Norway). Both the incidence of and mortality from cervical cancer have declined drastically since then. Organized screening for cervical
cancer enables detection of premalignant lesions, thereby reducing the risk of cervical cancer by successful treatment of the
premalignant lesions and may also result in cancer being detected at an early stage, thereby reducing morbidity and mortality from the
disease.
Figure 3. Broom shaped brush used to collect cells for liquid based cervical cytology. Copyright K.C. Toverud CMI (Click to enlarge)

Figure 4. Photo of liquid based cervical cytology brush and container. (Click to enlarge)

Screening for cervical cancer is performed in primary care or at screening clinics, starting in the Nordic countries when a woman turns 23
or 25 years and ending at age 65, with minor variations across countries (Table 1). The examiner (trained midwife, nurse or physician)
collects a cell sample from the cervix at a speculum examination. Epithelial cells are collected from the SCJ on the ectocervix using a
spatula and from the endocervical canal using a brush, or by a combined brush/spatula that enables simultaneous collection of endo-
and ectocervical cells (Figure 3 and 4. See also Performing cervical cytology part in Approach to the patient chapter).

Fixed and stained cervical cytology specimens are evaluated using light microscopy by which epithelial cells are assessed for dysplastic
features, such as hyperchromatic changes and enlarged nuclei. In the Nordic countries and several other middle and high-income
countries, cervical cytology samples are classified according to the Bethesda classification, with some national variations.

Cell samples can also be analyzed for the presence of HPV. Screening with HPV is the primary recommendation for screening of women
≥30 years; however, not all countries have switched to primary HPV screening yet. Screening for HPV is more sensitive for detecting
cervical precancer and cancer compared to screening with cytology. The improved sensitivity means that switching to HPV-based
screening will result in fewer screening failures (i.e. false negative sampling) and more women will be diagnosed with a precancerous
lesion that can be easily treated. This should decrease the incidence of cervical cancer, assuming that 85-90% of women will participate
in organized screening. As HPV is a common infection among young women, and most HPV-positive women will have a transient
infection, additional testing (i.e. triage testing) of all HPV-positive samples is required to identify those with the highest immediate risk of
dysplasia. In the Nordic countries, the recommended triage test to be performed on HPV-positive samples is cytology. In some countries
and in specific research settings, partial or complete HPV typing is used to identify women with the highest risk for cervical cancer, as it
is well established that the HPV type with the highest associated cancer risk is HPV16, followed by HPV18.

Table 1. Cervical screening programs in each of the Nordic countries.

Age
Country Interval Method Comment
group
 Age
Country Interval Method Comment
group

23 –
49: 23 – 59:
3 years cytology In 2020, HPV screening will be evaluated within the Danish screening program for
Denmark 23 – 64 women aged 30 years and older.
50 – 60 – 64:
64: HPV
5 years

25 – 29:
30 – 60
cytology 1Some municipalities screen from age 25 until age 65.
Finland (25 – 5 years
30 – 65:
65)1
HPV

Iceland 23 – 65 3 years Cytology

23 –
34: 23 – 34:
23 – 3 years cytology
Norway
69 35 – 35 – 69:
69: HPV
5 years

23 –
50: 23 – 29: 2One last smear should be offered after age 63. Age up to 70, dependent on the
23 – 3 years cytology previous smear. Seven year-interval for women who are HPV negative in the
Sweden
70 51– 70: 30 – 70: previous screening round.
7 HPV2
years2

Cervical cancer screening has been very successful. In the Nordic countries, incidence and mortality rates of cervical cancer have
decreased by 80% during the screening era (See also the Gynecological Cancer chapter). With HPV-based screening the protection against
cervical cancer for those who participate at the regular recommended intervals is estimated to be more than 90%, and protection from
cervical cancer death is even higher. The most crucial factor for the success of screening is a high coverage. Thus, encouraging and
facilitating regular participation is important. Invitation to fixed appointments with easy rescheduling and reminder electronic/postal
have proven to be effective measures in sustaining a high participation rate. Non-attenders may respond to telephone reminders and
self-sampling for HPV testing, which is now part of screening programs in some Nordic countries.

Diagnostics

Colposcopy
If cervical screening reveal pathology (abnormal cytology and/or HPV positive) the woman should be referred to a gynaecologist for
further investigation.

A colposcope is a binocular microscope with a 6-40 times magnification. Its main use is for triage and treatment of women who have
abnormal smears in order to identify those with high-grade lesions (CIN 2/3 and AIS) who are in need of treatment to prevent
progression of a precancerous lesion to invasive cancer.

The procedure is performed by a gynecologist using a two-bladed self-retracting speculum to enable the upper part of the vagina and
the cervix to be adequately visualized. The main focus of the procedure is to inspect the transformation zone (TZ), which is where
precancerous lesions are most frequently found. Initially, a systematic inspection of the cervix is performed at low magnification. Areas
of particular interest are subsequently evaluated in greater detail at a higher magnification. It is important to note that the TZ may also
be located inside the cervical canal and may therefore not be completely visible by colposcopy (inadequate colposcopy). This is
particularly common in postmenopausal women.

Since colposcopy is an in vivo examination useful information is typically achieved using different types of dying. Acetic acid 3-5% makes
columnar epithelium and dysplastic squamous epithelium edematous and it will appear opaque and white (acetowhitening) (Figures 1, 5,
6 and 7). Lugol´s fluid (iodine staining) stains the glycogen in mature normal squamous cells so they will appear dark brown. Degrees of
acetowhitening and the shape of the margins are important predictors of high-grade lesions. The examination also focuses on capillary
patterns, extension of the lesion under examination, and it´s surface. Using a green filter allows the vessels to be more clearly defined.
Based on the colposcopic evaluation, colposcopy-directed biopsies are obtained from the areas on the ectocervix that appear most
abnormal. Collection of cervical punch biopsies can be performed with or without local anesthetics. High-quality colposcopy is essential
for good results in cervical cancer prevention. Thus, dedicated colposcopy training and education programs are important.

Colposcopy is a subjective method like histopathological examination. In order to increase reproducibility and improve standardization,
different scoring systems have been developed. It is important to note that management and treatment decisions should be based on a
combined evaluation of all information available: colposcopic diagnosis, cytopathology, HPV status, and histopathology together. It
should also include patient history and patient preferences.

Figure 5. The photo illustrates a normal cervix during colposcopy. (Click to enlarge)

Figure 6. The photo illustrates the cervix during colposcopy. Acetowhitening is seen on the anterior part of the portio. (Click to enlarge)

Clinical management and follow-up

There is an international agreement that high-grade precursor lesions (CIN2/3 and AIS) should be treated. In recent years, there has been
a trend toward expectant management in young women with a CIN2 diagnosis, as surgical treatment increases the risk of preterm birth
and late abortions. Additionally, given that it typically takes an average of 10-15 years to progress from HPV acquisition to invasive
cancer, an observational approach of CIN2 lesions is considered safe in the youngest women. Another important factor is that a large
fraction of CIN2 lesions in women <30 will resolve without treatment. For CIN3 it is estimated that, if left untreated, one-third of CIN3
lesions will progress to cancer, one-third will regress, and one-third will remain unchanged over time. Thus, only one of three patients
are in need of treatment, but as no progression marker or method is available to predict which lesions will progress there is consensus to
treat all, as the risk of cancer is considered too high with expectant management. Treatment is generally not performed in pregnancy, but
close surveillance should be performed to reduce the risk of progression to invasive cancer. After pregnancy follow-up is required.

The treatment is surgical (excisional), and the most used method today is LLETZ (Large Loop Excision of the Transformation Zone), which
is typically performed in local anesthesia at an outpatient clinic, using a colposcope to identify the lesion. A wire loop, heated with a high-
frequency electrical current, enables the removal of the transformation zone, including the lesion, by simultaneously cutting and
coagulating the tissue (Figure 2, Video clip 1). The method is relatively easy to learn but also has some limitations and risks, such as
bleeding and damage to the vaginal wall. Additionally, the cone may be incomplete or destroyed with regard to histopathologic
evaluation if the wrong technique is applied, and the cone biopsy may be too big, too small or charred. Laser surgery requires more
expensive equipment and experience. For all these procedures, the size of the cone should be adapted to the size and localization of the
lesion as well as the age of the woman. Treatment success with these methods should be at least 95%. An estimated 5-10% of women
experience treatment failure, which is a result of incomplete resection or recurrence. Destructive methods (cryosurgery and
electrocoagulation) are not primary methods, have the disadvantage of lower success rates and do not enable histopathological
evaluation, as no cervical tissue is removed.

Figure 7. The picture illustrates the female genitals. The magnified parts illustrate an excision of the transformation zone (LLETZ). The
procedure is also demonstrated in Video clip 1. (Click to enlarge)
 Conisation
NFOG textbook

01:48

Recommendations for follow-up after treatment depends on histopathological examination of the cone biopsy (margin status and grade
of the lesion) and subsequent HPV-status and cytopathology. At present, most guidelines recommend HPV-test and Papanicoulau (Pap)-
smear 6 months after treatment. If both tests are negative a woman can return to routine screening or a repeated HPV and cytology co-
test can be performed at 24 months after treatment. Some screening programs offer life-long screening for women once treated for a
high-grade lesion, as these women have a long-term increased risk for cervical cancer and other HPV-related cancers (for more than 20
years). There is no indication that surgical treatment has a negative impact on fertility, besides the observed (slight) increased risk of
preterm delivery and late abortions.

Keywords: Human papillomavirus, screening, vaccination, precancerous lesions, colposcopy, cervical cancer, cone biopsy.

Test yourself
Click at NFOG-MCQ  and then at chapter 55

References

Literature
 The Bethesda System for Reporting Cervical Cytology: Definition, Criteria, and Explanatory Notes 
1. 3rd Edition ed., 2015
2. Atlas of colposcopy - principles and practice.
World Health Organization .
3. IARC Monographs on the evaluation of Carcinogenic Risks to Huhans
Biological Agents, Volume 100B 

Authors
Anne Hammer , MD, PhD, Associate Professor, Denmark
Björn Strander , MD, Associate Professor, Sweden.
Joakim Dillner , MD, Professor, Sweden
Ole Erik Iversen , MD, PhD, Professor Emeritus, Norway
Pekka Nieminen, MD, Associate Professor, Finland.
Last edited 21.08.2020

Published by:
NFOG - Nordic Federation of Societies of Obstetrics and Gynecology
Ole Mogensen Department of Obstetrics and Gynecology - Aarhus University Hospital
8200 Århus N

Telephone: +45 30 71 45 62
[email protected]