Aboud Srour

Universitatea de Medicin i Farmacie
Iuliu Haieganu Cluj-Napoca

Facultatea de Medicin
LUCRARE DE LICEN
Conization: Diagnostic and Treatment
method in Cervical Cancer
Indrumator tiinific
Conf. Dr. Dan Mihu
Absolvent
Aboud Srour
2012
1
Acknowledgments
In our times, knowledge and information are easily accessed by the fortunate in world;
Schools, Universities, and other educational circuits. I should be thankful for being one of those
fortunate people. Consequently, i want to thank my father Shokry Srour Aboud, for far more
wisdom than given in all the knowledge sources I have encountered, and my mother Noha Fozy
Aboud, and the rest of my family for their unconditional support, no matter the conditions.
I wish to thank also Mrs. Juganariu Monica, our year secretary and coordinator, for being
excellent in her job, being an address at all times, and for worm handling that can only be described
as motherly.
Thanks to Dr. Pop Daria, for helping in forming this thesis, when she didnt have to, And
for pushing me for more, when needed.
Last but not least, thanks to Conf. Dr. Dan Mihu, for supervising my work and guiding.
Contents
Acknowledgments ................................................................................................................................ 2
Part 1 .................................................................................................................................................... 5
Chapter 1 .............................................................................................................................................. 5
1.
Anatomy ....................................................................................................................................... 5
2.
Histology ...................................................................................................................................... 8
2.1
Squamous Epithelium ............................................................................................................ 8
2.2.
Glandular Epithelium ............................................................................................................ 9
2.3.
Squamocolumnar Junction .................................................................................................. 10
2.4.
Transformation Zone ........................................................................................................... 10
2.5.
Colposcopic and Neoplastic significance of the transformation zone ................................. 12
2.6.
Histology and colposcopy of the transformation zone ........................................................ 12
Chapter 2 ............................................................................................................................................ 14
Cervical Cancer .................................................................................................................................. 14
1. Pathophysiology ...................................................................................................................... 14
1.1.
Genetic susceptibility ....................................................................................................... 15
1.2.
Human papillomavirus ..................................................................................................... 16
1.3.
Human immunodeficiency virus ...................................................................................... 17
2. Etiology ................................................................................................................................... 18
3. Prognosis ................................................................................................................................. 18
4. Epidemiology .......................................................................................................................... 18
5. History ..................................................................................................................................... 20
6. Physical Examination .............................................................................................................. 20
7. Diagnosis and Evaluation ........................................................................................................ 20
8. Screening Recommendations .................................................................................................. 21
8.1.
Papanicolaou Smear Testing ............................................................................................ 22
8.2.
ThinPrep Papanicolaou test.............................................................................................. 23
8.3.
Human Papillomavirus Testing........................................................................................ 23
8.4.
Imaging Studies for Metastasis ........................................................................................ 24
9. Surgical Staging ...................................................................................................................... 24

10.
Histologic Findings.............................................................................................................. 24
3
10.1.
2001 Bethesda System for reporting cervical cytologic diagnoses .............................. 24
Chapter 3 ............................................................................................................................................ 28
Conization .......................................................................................................................................... 28
1. History of conization: .............................................................................................................. 29
2. Techniques: ............................................................................................................................. 30
2.1.
Cold-Knife Conization ..................................................................................................... 30
2.2.
Loop Electrosurgical Excision Procedure (LEEP)........................................................... 31
2.3.
Laser Conization .............................................................................................................. 36
Part 2 .................................................................................................................................................. 37
1.
Introduction ................................................................................................................................ 37
2.
Material and methods ................................................................................................................. 38
3.
Results ........................................................................................................................................ 39
3.1.
Incidence in Age Groups ..................................................................................................... 39
3.2.
Smoking ............................................................................................................................ 44
3.3.
Cytology and Biopsy results ................................................................................................ 45
3.3.
Environmental background.................................................................................................. 48
3.4.
Method of Conization .......................................................................................................... 49
3.5.
Hemostasis Method ............................................................................................................. 50
4.
Discussion .................................................................................................................................. 51
5.
Conclusion .................................................................................................................................. 54
Bibliography ....................................................................................................................................... 55
Part 1
Chapter 1
1. Anatomy
The Uterus (Fig. 1) is a hollow, thick-walled, muscular organ situated deeply in the pelvic
cavity between the bladder and rectum. Into its upper part the uterine tubes open, one on either side,
while below, its cavity communicates with that of the vagina. When the ova are discharged from the
ovaries they are carried to the uterine cavity through the uterine tubes. If an ovum be fertilized it
imbeds itself in the uterine wall and is normally retained in the uterus until prenatal development is
completed, the uterus undergoing changes in size and structure to accommodate itself to the needs of
the growing embryo. After parturition the uterus returns almost to its former condition, but certain
traces of its enlargement remains. It is necessary, therefore, to describe as the type-form the adult
virgin uterus, and then to consider the modifications which are effected as a result of pregnancy.
Figure 1
In the virgin state the uterus is flattened antero-posteriorly and is pyriform in shape, with the
apex directed downward and backward. It lies between the bladder in front and the pelvic or sigmoid
colon and rectum behind, and is completely within the pelvis, so that its base is below the level of
the superior pelvic aperture. Its upper part is suspended by the broad and the round ligaments, while
its lower portion is imbedded in the fibrous tissue of the pelvis.
The long axis of the uterus usually lies approximately in the axis of the superior pelvic
aperture, but as the organ is freely movable its position varies with the state of distension of the
bladder and rectum. Except when much displaced by a fully distended bladder, it forms a forward
angle with the vagina, since the axis of the vagina corresponds to the axes of the cavity and inferior
aperture of the pelvis.
The uterus measures about 7.5 cm. in length, 5 cm. in breadth, at its upper part, and nearly
2.5 cm. in thickness; it weighs from 30 to 40 gm. It is divisible into two portions. On the surface,
about midway between the apex and base, is a slight constriction, known as the isthmus, and
corresponding to this in the interior is a narrowing of the uterine cavity, the internal orifice of the
uterus. The portion above the isthmus is termed the body, and that below, the cervix. The part of the
body which lies above a plane passing through the points of entrance of the uterine tubes is known
as the fundus.
Cervix (cervix uteri; neck): The cervix is the lower constricted segment of the uterus. It is
somewhat conical in shape, with its truncated apex directed downward and backward, but is slightly
wider in the middle than either above or below. Owing to its relationships, it is less freely movable
than the body, so that the latter may bend on it. The long axis of the cervix is therefore seldom in the
same straight line as the long axis of the body. The long axis of the uterus as a whole presents the
form of a curved line with its concavity forward, or in extreme cases may present an angular bend at
the region of the isthmus.
The cervix projects through the anterior wall of the vagina, which divides it into an upper,
supravaginal portion, and a lower, vaginal portion.
The supravaginal portion (portio supravaginalis [cervicis]) is separated in front from the
bladder by fibrous tissue (parametrium), which extends also on to its sides and lateralward between
the layers of the broad ligaments. The uterine arteries reach the margins of the cervix in this fibrous
tissue, while on either side the ureter runs downward and forward in it at a distance of about 2 cm.
6
from the cervix. Posteriorly, the supravaginal cervix is covered by peritoneum, which is
prolonged below on to the posterior vaginal wall, when it is reflected on to the rectum, forming the
rectouterine excavation. It is in relation with the rectum, from which it may be separated by coils of
small intestine.
The vaginal portion (portio vaginalis [cervicis]) of the cervix projects free into the anterior
wall of the vagina between the anterior and posterior fornices. On its rounded extremity is a small,
depressed, somewhat circular aperture, the external orifice of the uterus, through which the cavity of
the cervix communicates with that of the vagina. The external orifice is bounded by two lips, an
anterior and a posterior, of which the anterior is the shorter and thicker, although, on account of the
slope of the cervix, it projects lower than the posterior. Normally, both lips are in contact with the
posterior vaginal wall.
Interior of the Uterus- The cavity of the uterus is small in comparison with the size of the
organ.
The Cavity of the Body (cavum uteri) is a mere slit, flattened antero-posteriorly. It is
triangular in shape, the base being formed by the internal surface of the fundus between the orifices
of the uterine tubes, the apex by the internal orifice of the uterus through which the cavity of the
body communicates with the canal of the cervix.
The Canal of the Cervix (canalis cervicis uteri) is somewhat fusiform, flattened from before
backward, and broader at the middle than at either extremity. It communicates above through the
internal orifice with the cavity of the body, and below through the external orifice with the vaginal
cavity. The wall of the canal presents an anterior and a posterior longitudinal ridge, from each of
which proceed a number of small oblique columns, thepalmate folds, giving the appearance of
branches from the stem of a tree; to this arrangement the name arbor vit uterina is applied. The
folds on the two walls are not exactly opposed, but fit between one another so as to close the
cervical canal.
The total length of the uterine cavity from the external orifice to the fundus is about 6.25 cm.
The mucous membrane (tunica mucosa) is smooth, and closely adherent to the subjacent
tissue. It is continuous through the fimbriated extremity of the uterine tubes, with the peritoneum;
and, through the external uterine orifice, with the lining of the vagina.
In the cervix the mucous membrane is sharply differentiated from that of the uterine cavity.
It is thrown into numerous oblique ridges, which diverge from an anterior and posterior longitudinal
raph. In the upper two-thirds of the canal, the mucous membrane is provided with numerous deep
glandular follicles, which secrete a clear viscid alkaline mucus; and, in addition, extending through
the whole length of the canal is a variable number of little cysts, presumably follicles which have
become occluded and distended with retained secretion. They are called the ovula Nabothi. The
mucous membrane covering the lower half of the cervical canal presents numerous papill. The
epithelium of the upper two-thirds is cylindrical and ciliated, but below this it loses its cilia, and
gradually changes to stratified squamous epithelium close to the external orifice. On the vaginal
surface of the cervix the epithelium is similar to that lining the vagina, viz., stratified squamous. [1]
2. Histology
An understanding of the histology of the cervix is critical to the use of effective cytologic
screening, colposcopy, and biopsy results in the management and treatment of cervical neoplasia.
The stroma of the cervix, which accounts for most of its mass and shape, is composed of dense,
fibromuscular tissue made up of collagenous connective tissue (smooth muscle and elastic tissue)
and ground substance (mucopolysaccharide). Through the stroma course the vascular, lymphatic,
and nervous supplies of the cervix. While of great importance to the structure and obstetrical
functioning of the cervix, the stroma plays little role in cervical neoplasia. Rather, it is the
epithelium of the cervix which gives rise to cervical neoplasia. Therefore, this section will focus on
the cervical epithelium.
The cervix is covered by both columnar and stratified non-keratinising squamous epithelia. The
squamocolumnar junction, where these two meet, is the most important cytologic and colposcopic
landmark, as this is where over 90% of lower genital tract neoplasia arises. This junction is
presumed, but not proven, to be the embryologic junction of the Mllerian and urogenital sinus
epithelia. [2, 3, 4]
2.1 Squamous Epithelium
The squamous epithelium (Fig.2) of the cervical portio is similar to that of the vagina, except
that it is generally smooth and lacks rete pegs. Colposcopically, it appears featureless except for a
fine network of vessels which is sometimes visible. The relative opacity and pale pink coloration of
8
the squamous epithelium derives from its multi-layered histology and the location of its supporting
vessels below the basement membrane. [2, 3, 4]
Figure 2
2.2. Glandular Epithelium

The glandular or columnar epithelium of the cervix is located cephalad to the
squamocolumnar junction. It covers a variable amount of the ectocervix and lines the endocervical
canal. It is comprised of a single layer of mucin-secreting cells. The epithelium is thrown into
longitudinal folds and invaginations that make up the so-called endocervical glands (they are not
true glands). These infolding crypts and channels make the cytologic and colposcopic detection of
neoplasia less reliable and more problematic. The complex architecture of the endocervical glands
gives the columnar epithelium a papillary appearance through the colposcope and a grainy
appearance upon gross visual inspection. The single cell layer allows the coloration of the
underlying vasculature to be seen more easily. Therefore, the columnar epithelium appears more red
in comparison with the more opaque squamous epithelium. [2, 3, 4]
2.3. Squamocolumnar Junction

The squamocolumnar junction (SCJ) is defined as the junction between the squamous
epithelium and the glandular epithelium. It is often marked by a line of metaplasia and its location is
variable. Age and hormonal status are the most important factors influencing its location. During the
perimenarche, the SCJ is located at or very close to the external os. The SCJ is generally located on
the ectocervix at variable distances from the os in reproductive-aged women, as the cervix, and
particularly the endocervical canal elongates under the influence of estrogen. The high estrogen
levels of pregnancy and oral contraceptive use promote further eversion of the SCJ. Eversion is
usually more pronounced on the anterior and posterior lips of the ectocervix and less so at the 3 and
9 o'clock positions. Eversion of the columnar epithelium onto the ectocervix may not be
symmetrical. The resulting asymmetric appearance may cause confusion and prompt a referral for a
possible cervical lesion. An eversion of the SCJ onto the ectocervix is sometimes referred to as an
ectropion or erosion. The latter term is a misnomer and should not be used. Occasionally, the
SCJ is located in part or entirely on the vaginal fornices. The process of squamous epithelialization
of the vaginal tube begins at the dorsal urogenital sinus and vaginal plate, spreading upwards along
the vaginal tube. This process proceeds most rapidly along the lateral walls. If the epithelialization
proceeds normally, the SCJ is located at near the external os of the cervix. If the epithelialization is
arrested before completion, the SCJ will be located on the vaginal walls, usually involving the
anterior and posterior vaginal fornices, as epithelialization in these locations occurs later than
laterally. This type of variant in SCJ location are most striking in in-utero DES-exposed women. In
some cases the entire cervical portio will be covered with columnar epithelium. From the
perimenopause on, or with prolonged exposure to strong progestational agents which cause atrophy,
the SCJ recedes up the endocervical canal. This makes cytologic sampling less reliable and
colposcopic examination of the SCJ impossible in many cases. [2, 3, 4]
2.4. Transformation Zone
An understanding of the cervical transformation zone (TZ) is essential to the identification
and management of cervical intraepithelial neoplasia. It lies between the original and new
squamocolumnar junctions. The SCJ discussed above is the visible border between the squamous
and columnar epithelia of the cervix and represents the new squamocolumnar junction. It is adjacent
to the new SCJ that the dynamic process of squamous metaplasia occurs throughout the reproductive
10
years. This is a normal process during which columnar epithelium is replaced by squamous. The
trigger for this process is thought to be the eversion of the columnar epithelium under the influence
of estrogen and its subsequent exposure to the acidic vaginal pH. In response to the insult of
vaginal acidity, the process of metaplasia replaces the more fragile columnar epithelium with the
more sturdy squamous type. This process is thought to occur by two mechanisms. One is by reserve
cell hyperplasia. Reserve cells proliferate around the exposed endocervical glands and eventually
obliterate and replace them. The columnar epithelium is replaced, not changed into another type of
epithelium.
Colposcopically, this process is seen as a flattening out and merging of the villous structures
of the glandular tissue, with replacement by a smoother, milky coating. It is also thought that some
metaplasia occurs by the ingrowth of squamous epithelium centripetally from the squamous
epithelium of the ectocervix. This ingrowth undermines and replaces the overlying columnar
epithelium. The net result is a zone of squamous metaplasia of variable width distal (caudal) to the
columnar epithelium and proximal (cephalad) to the original squamous epithelium laid down
during embyogenesis.
The border between the metaplastic epithelium arising during the reproductive years and the
original squamous epithelium is called the original SCJ. The TZ is the area of metaplastic
epithelium between the original and new SCJs. During the process of metaplasia, still-functioning
endocervical glands may become covered and blocked, giving rise to Nabothian cysts.
The metaplastic epithelium adjacent to the new SCJ is the newest and the least mature
squamous epithelium on the cervix. As new metaplastic epithelium arises, the older metaplastic
epithelium is moved outward toward the original SCJ, with the newest and least mature metaplasia
adjacent to the new SCJ. With time, the metaplastic epithelium matures to the point where its
thickness and glycogenation is indistinguishable from the original squamous epithelium. This makes
the colposcopic identification of the original SCJ, and therefore the outer limits of the TZ,
impossible in many cases. The location of Nabothian cysts, always formed within the TZ, is useful
in identifying its limits.
The identification of the TZ is of utmost importance to the colposcopist. It is within the
metaplastic epithelium, i.e. the TZ, that essentially all cervical neoplasia arises. Metaplasia is
particularly active during the peripubertal years and during the first pregnancy. Perhaps this
11
accounts for the fact that early first sexual intercourse and early age at first pregnancy are risk
factors for cervical cancer. It is hypothesized that the reserve cells in adolescent and young women
are especially vulnerable to the oncogenic potential of human papillomavirus infection. The size and
location of the TZ will influence selection of treat modality if neoplasia is present. [2, 3, 4]
2.5. Colposcopic and Neoplastic significance of the transformation zone
Nearly all cervical neoplasia occurs in the TZ. This is even true of the adenocarcinomas,
which are often associated with adjacent high-grade squamous disease, although they may rarely
occur higher up in the endocervical canal. This is because it is the reserve cells undergoing
metaplasia that are vulnerable to various carcinogens such as HPV. Since metaplasia is at peak
activity during adolescence and first pregnancy, it is understandable that early age on sexual activity
and first pregnancy are known risk factors for cervical cancer. It is therefore of great importance that
the colposcopist be able to identify and evaluate the TZ. Given a particular lesion, the more severe
disease tends to be cephalad in the TZ, where the epithelium is least mature. In order that a
colposcopic exam may be deemed satisfactory or adequate, the TZ must be seen in its entirety,
all the way up to the columnar epithelium, 360, which means that all areas involved in squamous
metaplasia have been visualized. If this is not possible, because the new SCJ or abnormalities are up
inside the canal beyond view, then one cannot be sure that a high-grade lesion or cancer has been
ruled out.
The importance of the TZ to cervical neoplasia explains why it is desirable to see both
columnar (endocervical) and squamous metaplastic cells on Pap smears. Their presence indicates
that the area at risk has indeed been sampled. [2, 3, 4]
2.6. Histology and colposcopy of the transformation zone
As reserve cell hyperplasia progresses to several layers of thickness, the columnar epithelium
is pushed off and replaced. This proliferation of reserve cells is seen as the flattening and fusing of
columnar villi. The areas of metaplasia are paler than the one-cell-thick columnar epithelium as the
underlying blood vessels are now viewed through several cell layers. Metaplasia is usually seen as
numerous small, glassy islands overlying the columnar epithelium and also as pale, translucent
ingrowths of metaplasia from the original squamous epithelium. These islands and tongues of
metaplasia can be irregularly shaped and distributed around the TZ, and coalesce into sheets of
metaplasia, often with a thin acetowhite line at the advancing border. Immature metaplasia can turn
12
acetowhite, causing striking frosting of these areas. As the epithelium matures and pushes
outward relative to the external os of the cervix, it shows a gradient of maturity. The most mature
epithelium is densest with at most a trivial, fine vascular pattern. It does not turn acetowhite. It also
has the highest level of glycogenation and therefore iodine uptake. Less mature metaplasia may be a
pale acetowhite and may show fine vascular patterns that are can both be confused with low-grade
lesions. When the crypts of the mucin-secreting columnar epithelium become covered up by
metaplastic epithelium, they become blocked, and Nabothian cysts are formed. Therefore, these
cysts are by definition located within the TZ. The vessel overlying Nabothian cysts can be large and
alarming to the novice colposcopist. However, close inspection will reveal their benign, arborizing
character.
The most mature metaplastic epithelium probably has little neoplastic potential, like that of
the original squamous epithelium.
Some women have a large area of acetowhite, iodine-variable epithelium which extends onto
the anterior and / or posterior vaginal fornices. There may also be a very fine mosaic pattern. This is
called a congenital TZ and is caused by squamous epithelium of arrested maturation and variable
glycogenation, probably laid down during fetal development. This epithelium is of low neoplastic
potential and can be very confusing to the colposcopist. [2, 3, 4]
13
Chapter 2
Cervical Cancer
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.
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) Smear, which permits detection and treatment of preinvasive disease. [5]
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. However, women who have symptoms, abnormal screening test results, or a gross
lesion of the cervix are best evaluated with colposcopy and biopsy.
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.
1. Pathophysiology
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
squeal, 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.
14
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. [6]
1.1. 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 (4, 5). 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, TNF-572, TNF-857, TNF-863, and TNF G-308A have been associated with a
higher incidence of cervical cancer [9, 10, 11, 12]. 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. [13, 14, 15, 16, 17]
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 (15,
16), others with a protective effect [17, 18]. The chemokine receptor-2 (CCR2) gene on
15
chromosome 3p21 [22, 23] and the Fas gene on chromosome 10q24 [19, 24]. may also influence
genetic susceptibility to cervical cancer, perhaps by disrupting the immune response to HPV.
TheCASP8 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. [25]
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. [26, 27]
1.2. Human papillomavirus
HPV comprises a heterogeneous group of viruses that contain closed circular doublestranded 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 [28]. 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. [29]
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 (Table 1). [29]
16
Table 1
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.
1.3. 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.
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. [30]
17
2. Etiology
With rare exceptions, cervical cancer results from genital infection with HPV, which is a
known human carcinogen [31, 32, 33, 29, 34].
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 [30]. Exposure to diethylstilbestrol in
utero has been associated with an increased risk of CIN grade 2 or higher. [35]
3. 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 estimates that 4220 women will die of cervical cancer in the United States in 2012.
[36] This represents 1.3% of all cancer deaths and 6.5% of deaths from gynecologic cancers.
4. 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
18
countries [36]. 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.
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 [34]. This trend has been attributed to mass screening with Pap
smears [38]. Cervical cancer rates continue to rise in many developing countries, however.
The American Cancer Society (ACS) estimates that in the United States, 12,170 new cases
of cervical cancer will be diagnosed in 2012 [37]. 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 [39].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.[40]
4.1 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.[41] 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.[42] These cases are less easily detected with Pap smear screening, and survivorship is low
19
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. [43,
44]
5. 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
postcoital. 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.
6. 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.
7. Diagnosis and Evaluation
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
20
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: [45]
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.
8. Screening Recommendations
The American Cancer Society (ACS), the American Society for Colposcopy and Cervical
Pathology, and the American Society for Clinical Pathology have issued joint guidelines for cervical
cancer screening [46]. In addition, the US Preventive Services Task Force (USPSTF) has issued
updated 2012 guidelines whose recommendations are consistent with those of these other groups.
[47]
Screening recommendations for specific patient age groups are as follows: [46, 47]
< 21 years No screening recommended

21
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
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. [47]
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 12month 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. [46]
8.1. Papanicolaou Smear Testing
For many years, the Pap smear has been the standard method for cervical cancer screening.
Retrospective data have shown that screening with a PAP Smear reduces the incidence of cervical
cancer by 60-90% and the death rate by 90%.
Because of false negatives, the best that a PAP Smear 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.
22
The limitations of the conventional PAP Smear include limited sensitivity (51%) and a
significant proportion of inadequate specimens. In addition, accurate interpretation of conventional
PAP Smears is often compromised by the presence of artifacts (eg, blood, mucus, obscuring
inflammation, scant cellular material, or air-drying artifact).
Newer liquid-based PAP Smear 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. [48]
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. [48]
8.2. ThinPrep Papanicolaou test
Test samples for the ThinPrep PAP Smear are collected the same way as those for the
conventional PAP Smear. 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.
8.3. 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 Smear. If a
woman has a PAP Smear result showing ASCUS but a subsequent HPV test is negative, she can be
rescreened with PAP Smearing 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 Smear can be delayed for 5 years.
23
8.4. 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. [49]
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. [49]
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. [50]
9. 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.
10. Histologic Findings
Precancerous lesions of the cervix usually are detected via a PAP Smear. The PAP Smear
classification system has evolved over the years. Standardized PAP Smear reporting emerged from a
1988 workshop sponsored by the National Cancer Institute. Currently, cervical cytology results are
reported according to the 2001 Bethesda System. [51]
10.1. 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:
24
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 (Fig. 3)
HSIL
Encompassing moderate and severe dysplasia, carcinoma in situ, CIN 2, and CIN 3 (Fig.4)
Squamous cell carcinoma (Fig. 5)
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)

25
Endometrial cells in a woman aged 40 years or older
Figure 3
Figure 4
26
Figure 5
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. [51, 52, 53, 54, 55]
27
Chapter 3
Conization
Conization of the cervix (Fig. 6) is defined as excision of a cone-shaped or cylindrical wedge
from the cervix uteri that includes the transformation zone and all or a portion of the endocervical
canal. It is used for the definitive diagnosis of squamous or glandular intraepithelial lesions, for
excluding microinvasive carcinomas, and for conservative treatment of cervical intraepithelial
neoplasia (CIN). [59]
While no recent changes have occurred in the technique of conization, a quadrivalent human
papillomavirus (types 6, 11, 16, 18) recombinant vaccine (Gardasil) was introduced in 2006. Its
widespread use is expected to reduce the number of cervical neoplasias, and, consequently the need
for surgical interventions.
Conization can be performed with a scalpel (cold-knife conization), laser, or electrosurgical
loop. The latter is called the loop electrosurgical excision procedure (LEEP) or large loop excision
of the transformation zone (LLETZ). Combined conization usually refers to a procedure started with
a laser and completed with a cold-knife technique. Laser conization can be excisional or destructive
(by vaporization). Techniques for diagnostic and therapeutic conization are virtually identical. The
extent of excision must be adjusted according to individual needs.
Each of these approaches has distinct benefits and disadvantages. Cold-knife conization
provides the cleanest specimen margins for further histologic study, but it is typically associated
with more bleeding than laser or LEEP, and it requires general anesthesia in most cases. Laser
procedures are of longer duration and, especially if low-power density is used, may "burn" the
margins, thus interfering with histologic diagnosis. The main advantage with this procedure is that
dots produced by the laser energy can be used to accurately outline the exocervical margins.
However, overall, the benefit of using laser for conization may not justify the high cost of the
procedure.
LEEP procedures have several advantages, including rapidity, preservation of the margins
for histologic evaluation, and virtual bloodlessness. Moreover, one can perform LEEP procedures in
the office or in other outpatient settings.
28
Figure 6
1. History of conization:
Procedures similar to conization were used in the early 19th century in an attempt to excise
gross cervical tumors per vaginam. During the second half of the 20th century, conization evolved
as an important tool for diagnosing the cause of positive cervical cytology in women without visible
lesions and, later, as treatment of CIN. The diagnostic application of cold-knife conization was
reduced following the widespread use of colposcopically directed cervical biopsies combined with
endocervical curettage. However, conization remains an important diagnostic tool in selected
situations. Therapeutic conization for CIN became an accepted modality in the management of CIN
following publication of rigorous studies by Scandinavian and Austrian researchers. The precise
origin of cold-knife conization is historically uncertain. [59]
29
2. Techniques:
2.1. Cold-Knife Conization
Surgical Steps:
A) Anesthesia and Patient Positioning: For most women, cold-knife conization is a day-surgery
procedure performed under general or regional anesthesia. Following administration of anesthesia,
the patient is placed in the dorsal lithotomy position. The vagina is surgically prepared, the bladder
is drained, and vaginal sidewalls are retracted to reveal the cervix. Areas of planned excision may be
identified more easily following Lugol solution application.
B) Injection of Vasoconstrictors: Bleeding during cold-knife conization can be a risk and obscure
the operating field. Accordingly, preventative steps can be taken both before and during surgery.
First, vasoconstrictors are injected circumferentially into the cervix. Additionally, descending
cervical branches of the uterine arteries can be ligated with figure-of-eight sutures using a
nonpermanent material placed along the lateral aspects of the cervix at 3 and 9 o'clock. After these
knots are secured, the sutures are kept long and held by hemostats to manipulate the cervix.
C) Conization: A uterine sound or small-caliber uterine dilator is placed into the endocervical canal
to orient the surgeon as to the depth and direction of the canal. Using a Beaver blade or a no. 11
blade, the surgeon initiates the incision on the lower lip of the cervix. This limits blood from
obscuring the operative field. A Beaver blade is a triangular-shaped knife blade with a 45-degree
bend and is useful for creating incisions at an angle. A circumscribing incision creates a 2- to 3-mm
border around the entire lesion (Fig. 7). The 45-degree angle of the blade is directed centrally and
cephalad to excise a conical specimen. Toothed forceps or tissue hooks may be used to retract the
ectocervix during creation of the cone. Scalpel or Mayo scissors may be used to cut the tip of the
cone and release the specimen. Following excision, an orienting suture is placed on the site of the
specimen that corresponds to the 12 o'clock position in situ. This orientation is noted on a pathology
requisition form.
D) Endocervical Curettage: Following removal of the cone specimen, endocervical curettage is
performed to screen for residual disease distal to the excised cone apex.
E) Hemostasis: Following excision of the specimen, bleeding is common and can be controlled with
individual suturing of isolated vessels, with electrosurgical coagulation, or with Sturmdorf sutures.
In addition, a topical absorbable hemostat mesh (Surgicel Nu-knit, Johnson and Johnson,
30
Piscataway, NJ) can be placed in the cone bed. Sturmdorf suturing is a running locked suture line
that closes the cone bed by circumferentially folding the cut ectocervical edge inward toward the
endocervix. This technique is less favored because of increased rates of postoperative
dysmenorrhea, inadequate postoperative surveillance PAP smears, and concerns that the flap might
conceal residual disease. [56, 57, 58, 59]
Figure 7
2.2. Loop Electrosurgical Excision Procedure (LEEP)

Loop electrosurgical excision procedure (LEEP) (Fig.8), also known as large loop excision of
the transformation zone (LLETZ), uses electric current to generate energy waveforms through a
metal electrode that either cuts or desiccates cervical tissues. These thin wire semicircular electrodes
allow clinicians to excise cervical lesions in an office setting with minimal patient discomfort, cost,
and complications. In addition, LEEP permits submission of a surgical specimen for additional
evaluation. [56, 57, 58, 59]
2.2.1. Preoperative Patient Evaluation
Ideally, LEEP is performed after completion of menstruation. This decreases the chances of
pregnancy and allows cervical healing prior to the next menses. If it is performed prior to menses,
postoperative swelling can block menstrual flow and intensify cramping. Before LEEP, a normal
31
bimanual examination should be confirmed. If there is a possibility of pregnancy, -hCG level testing
should precede treatment.
This procedure is associated with low morbidity, and overall complication rates approximate 10
percent. Major complications are rare (0.5 percent) and may include bowel or bladder injury and
hemorrhage. Short term complications such as abdominal pain, vaginal bleeding, vaginal discharge,
and bladder spasm may be treated symptomatically.
Long-term complications include failure to treat the cervical lesion completely and cervical
stenosis. Persistent disease typically is noted in initial surveillance PAP smear testing following
LEEP. However, such treatment failure rates are low (approximately 5 percent) and are positively
correlated with initial excised lesion size. Cervical stenosis is estimated to complicate less than 6
percent of cases, and risk factors include the presence of an endocervical lesion and excision of a
large tissue volume.
The effects of LEEP and obstetric outcomes are unclear. Several studies have shown that
pregnancy does not appear to be adversely affected by LEEP, whereas meta-analysis reviews by
others have noted increased risks of premature labor and premature rupture of the membranes. [56,
57, 58, 59]
Figure 8
32
2.2.2. Intraoperative Instruments

Tissue excision during LEEP requires an electrosurgical unit, wire loop electrodes, insulated
speculum, and smoke evacuation system. Electrosurgical units used in LEEP procedures generate
high-frequency (350 to 1200 kHz), low-voltage (200 to 500 V) electric current. Because of the risk
for electrical burns to the patient from stray current, grounding pads should contact patients on
conductive tissue that is close to the operative site.
Similarly, an insulated speculum is used in LEEP procedures to limit the risk of stray current
conductance to the patient. The insulated speculum should have a port for smoke evacuation tubing,
which assists in clearing smoke from the operating field to improve visualization.
Surgical smoke plumes have contents including carbon monoxide, polyaromatic hydrocarbons, and
a variety of trace toxic gases. Although there has been no documented transmission of infectious
disease through surgical smoke, the potential for generating infectious viral fragments may exist.
For these reasons, local smoke evacuation systems are recommended. Electric current is directed to
tissue via a 0.2-mm stainless steel or tungsten wire electrode that comes in a variety of sizes
customized to treat lesions of various sizes (Fig.9). These instruments are disposable and are
discarded after each patient procedure. [59]
Figure 9
33
Surgical Steps
2.2.3. Anesthesia and Patient Positioning:
The patient is placed in the dorsal lithotomy position, and the electrosurgical grounding pad
is placed on the upper thigh or buttock. The insulated speculum is inserted into the vagina, and
smoke evacuation tubing is attached. The application of Lugol solution outlines lesion margins
before starting the procedure. For most patients, LEEP is an office procedure, typically
performed under local analgesia.Vasoconstricting solutions of either pitressin and 1-percent
lidocaine solution (10 units pitressin in 30 mL of lidocaine) or 1- percent lidocaine and
epinephrine (1:100,000 dilution) may be used. A 25- to 27-gauge needle is used to
circumferentially inject 5 to 10 mL of either solution 1 to 2 cm deep into the cervix outside the
area to be excised. Cervical blanching should be seen.
1. Single-Pass Excision. Ideally, the lesion should be excised in one pass, and the appropriately
sized loop is selected for thisgoal. If colposcopy is satisfactory, the correct loop diameter
should incorporate the entire lesion diameter to a depth of 5 to 8 mm. The electrosurgical
unit is set to cutting mode, and typically 30 to 50 W is used depending on loop size. Larger
loops require higher wattage. To excise the lesion, a loop is positioned 3 to 5 mm outside the
lateral perimeter of the lesion (Fig. 9). Current through the loop is activated prior to tissue
contact, during which electric sparks at the loop tip may be seen. The loop is introduced to
the cervix at a right angle to its surface. The loop is drawn parallel to the surface until a point
3 to 5 mm outside the opposite border of the lesion is reached. The loop then is withdrawn
slowly, positioning it at right angles to the surface. Current is stopped as soon as the loop
exits the tissue.
2. Following excision, the specimen is placed in formalin for pathologic evaluation.
34
Figure 10
Multiple-Pass Excision. Less commonly, bulky lesions may require multiple passes using a
combination of loop electrode sizes (Fig. 11).
Figure 11
35
Control of Bleeding Sites Despite use of vasoconstrictors, bleeding following LEEP is common.
Sites of active bleeding may be controlled using a 3- or 5-mm ball electrode and the electrosurgical
unit switched to coagulation mode. Alternatively, Monsel solution can be applied with direct
pressure to bleeding sites. [59]
2.2.4. Postoperative
Copious watery vaginal discharge that develops after treatment usually requires sanitary pad use,
and tampons are discouraged. Although some advocate dbridement of the necrotic eschar to
decrease the amount of discharge, Harper and colleagues (2000) reported no affect in the amount or
duration of this discharge with such dbridement. Vaginal spotting is expected and can persist for
weeks, but hemorrhage is rare. During the first few days following cryotherapy, patients may
complain of diffuse mild lower abdominal pain or cramping, for which NSAIDs typically provide
relief. Infrequently, severe pain and cramping may result from necrotic tissue obstructing the
endocervical canal and is termed necrotic plug syndrome. Removal of the obstructing tissue
typically resolves symptoms. Because a large area of the cervix is denuded after cryotherapy, there
is an increased potential for infection. Accordingly, patients should abstain from intercourse during
the 4 weeks following surgery. If abstinence is not feasible, then condom use is encouraged.
Depending on patient symptoms, work and exercise may resume following treatment. [59]
2.3. Laser Conization
Excision of a laser cone-biopsy specimen uses similar techniques as those described for laser
ablation (Surgical Steps). However, rather than ablating the involved tissue, laser energy is directed
to cut and remove a cone-biopsy specimen. A higher wattage of 800 to 1200 W/cm2 combined with
a smaller laser spot size is used to create a cutting effect. A cone-shaped specimen then is excised.
During excision of the cone specimen, nonreflective tissue hooks may be needed to retract the
ectocervical edge away from the laser beam path and to create tissue tension along the plane of
incision. [59]
36
Part 2
1. Introduction
Cervical cancer is a major risk and concern in Romania and the rest of the world, and efforts
are made everywhere to stop it, especially when we have the tools to prevent and treat, while the
problem that remains is logistic.
Cervical cancer is diagnosed in about 500,000 women each year in the world, every year
more than 270,000 deaths occur from cervical cancer, every 2 minutes one woman dies because of
cervical cancer, over 80% of the death cases happen in the developing world. [63]
Epidemiological data show that 86.6% of genital cancers are localized to the cervix, ovaries
4.9%, 4.2% in the endometrium and myometrium, 2.5% at vulvar, 1.7% the vagina and only 0.1% in
the tubes. [63]
Conization as a method for preventing cervical cancer has proved itself as efficient in
preventing Cervical Intraepithelial Neoplasias (CIN), and being performed in more than one
technique in Romania.
It is estimated that up to 90% of the cases of CIN treated by conization are met with success,
however exceptions still exist. It is not clear yet, how the precursors of cervical cancer evolve. It is
believed that any form of CIN can result in invasive cancer. It is known now that the majority of
forms of CIN 1 will regress without treatment, thought there is no scientific prove for why this
phenomenon happen. The one certain fact is that CIN 3 that remains untreated leads to invasive
cancer and death. In present, conization is the preferable method of treatment in case of females
diagnosed with CIN 2 and 3. Conclusion of some studies that followed the percentage of the
Cervical Intraepithelial Neoplasia residuals showed that only age and neoplastic grade can be
considered as predictive factors. [61, 63]
37
2. Material and methods
In this thesis a prospective statistical study is used, based on admitted cases in the period of
1/1/2012-30/6/2012, in the Obstetrics-Gynecology II Clinic Dominic Stanca in Cluj-Napoca, who
underwent conization, with complete histopathological results based on the Bethesda 2001 reporting
system.
The study was performed over 31 patients ranging from 22 years old to 61 years old, with
the average age of 34.9 years.
In this study the following parameters were used:
Age of patient at admission
Biopsy and cytological diagnosis
Environment of accommodation
Type of conization performed
Method used for post conization hemostasis
Smoking
The information was obtained through medical files and personal interviews.
38
3. Results
3.1. Incidence in Age Groups
The group age in incidence of cervical cancer is a major risk factor. (Fig. 11)
Age Group
14
12
Nr. of Cases
10
8
6
4
2
0
20-25
26-30
31-35
36-40
above 40
Age Groups
Figure 12
Table 2 Age Groups Distribution
Age Group
Nr. Of Cases
20-25
26-30
1
31-35
10
above
40
36-40
13
The study was performed over 31 cases, with ranging age of 22- 61 years old, and average
age of 34.93 years.
39
Ages 26-30
7
6
5
4
Ages 26-30
3
2
1
0
HSIL
LSIL
AGC
Figure 13
Table 3 Cytological results Age group of 26-30 y.
Cytology
HSIL
LSIL
AGC
Nr. Of cases -Ages 26-30
In this age group the most frequent cytological result was HSIL with 7 cases, 2 cases with
LSIL, and one case of AGC.
40
Ages 31-35
9
8
7
6
5
Ages 31-35
4
3
2
1
0
HSIL
LSIL
AGC
ASCUS
Figure 14
Cytology
HSIL
Nr. Of cases Ages 31-35
LSIL
AGC
ASCUS
In this age group the most frequent cytological result was HSIL with 9 cases, 2 cases with
LSIL, one case of AGC, and 1 case with ASCUS.
41
Ages 36-40
3
2
Ages 36-40
0
HSIL
LSIL
Cocbacili
ASCUS
Figure 15
Cytology
Nr. Of cases Ages 36-40
HSIL
LSIL
Cocbacili
ASCUS
In this age group the most frequent cytological result was HSIL with 3 cases, 1 case with
LSIL, and one case of ASCUS..
42
Above 40
4
3
Above 40
2
1
0
HSIL
LSIL
AGC
ASCUS
Table 6 Cytological results in age group of above 40 years old.
Cytology
HSIL
Nr. Of cases Above 40
LSIL
4
AGC
1
ASCUS
1
Cervical cancer incidence is related to age but it is unusual as it does not follow the same
pattern of increasing incidence with age seen for most cancers. There are two peaks in the agespecific incidence rates: the first in women aged 30-34 (at 21.2 per 100,000 women) and the second
in women aged 80-84 (at 14 per 100,000 women). The earlier peak is related to many women
becoming sexually active in their late teens/early 20s, giving rise to the increase of the Human
Papilloma Virus. The second peak is due to increasing cancer incidence with age.
In this study, the results were not far from other studies, and show that most cases occur in
the age group of 31-35 years old patients, while also neighboring groups also show an up rise when
getting to this group age, and a down fall when getting older, which emphasizes the claim of this age
group being a risk factor of cervical cancer.
Its also observed that HSIL is the most frequent cytological finding in all age groups,
because it is more prone to cause invasive cancerous cells, while LSIL lesion tend to regress
spontaneously sometimes, and can be monitored in regular checkups for further measures if needed.
43
3.2. Smoking
19%
Non Smoker
58%
23%
<10 Cig./day
>10 Cig./day
Figure 16
Table 7 Smoking habits
Non Smoker
<10 Cig./day
>10 Cig./day
18
7
6
Smoking is considered to be a risk factor for cervical cancer, in my study 48% of the patients
were smokers, with the category of ( >10 cig./day) answering as I dont finish the whole pack.., or
..a pack a day.., and the category of (<10 cig./day) answering as occasional smoker, or one or
two cigarettes a day...
The results were not conclusive for establishing a relationship between smoking and CIN.
44
3.3. Cytology and Biopsy results
Cytology Results
3%
8%
17%
8%
LSIL
HSIL
AGC
COCBACILI
ASCUS
64%
Figure 17
Table 8 Distribution of Cytological results
Cytological Result
Nr. Of cases
LSIL
HSIL
23
AGC
COCBACILI
ASCUS
Histological evaluation remains the basis for treatment and follow-up of women with cervical
intraepithelial neoplasia (CIN). The fundamental premise for treating or following young women
with CIN hinges on the risk of an eventual outcome of CIN2 or CIN3 (high-grade squamous
intraepithelial lesion or HSIL).
45
In contrast to low grade squamous epithelial abnormalities, women who have any glandular
cytologic abnormality are recommended to have colposcopic assessment.
My results show 64% of patients being treated for HSIL, which is more prone to cause cervical
cancer (Table 9) [68], as for LSIL there are indications that these lesions are 60% likely to regress.
Example of cytological findings in the study group:

HSIL Smear:
Figure 18
46
LSIL Smear:
Figure 19
AGC Smear:
Figure 20
47
3.3. Environmental background
Environment of patients
32%
URBAN
RURAL
68%
Figure 21
Table 9
URBAN RURAL
21
10
While 21 of the cases admitted to conization were from an urban environment, only 10 cases
were from a rural one.
48
3.4. Method of Conization
Method of Conization
48%
CKC
52%
LEEP
Figure 22
Table 10
CKC
LEEP
16
15
Although the LEEP technique was introduced in the hospital about a year ago (late 2011),
we already have 15 cases performed with it, while 16 were performed with CKC.
49
3.5. Hemostasis Method

After Cold Knife Conization bleeding is a common scene, and there for two hemostasis
techniques (Fig. 15) are used in the hospital:
Hemostasis Method (for CKC)
38%
Sturmdurf
Green
62%
Figure 23
Table 11
Sturmdurf
10
Green
6
There was no difference in both indication and results using any of the techniques.
Out of 16 conizations performed in the Cold Knife Conization technique, the Green suturing
technique for hemostasis was used in 6 cases, and the Sturmdurf in 10 cases.
50
4. Discussion
Romania has the highest cervical cancer mortality and third highest cervical cancer incidence
in Europe according to the latest data from the WHO. Cervical cancer ranks as the 2nd most
frequent cancer among women in Romania, and the 1st most frequent cancer among women
between 15 and 44 years of age. [62]
Awareness, education and knowledge are the main factor of these results, as the medical
facilities dont lack the expertise or the equipment to handle this pathology, where early detection
can be of a major role in reducing the incidence of developing malignancy.
Age groups at risk according to studies, are between 15-44 years old [60, 62], and in this
study it shows that more than 90% of the patients are 26-40 years old, which strengthens the claim,
and approves of it.
A study performed in 2008 showed that Romanian women have a low level of awareness
about cervical cancer with only 2% mentioning HPV as the cause of cervical cancer and 58% not
knowing of any method to prevent cervical cancer, 33% mentioning the PAP Smear and 15%
mentioning vaccination. The lowest level of awareness was found for women in rural areas, those
with low educational levels, housewives and those aged over 60. [62]
Past trials of a national program for screening has been done to reduce these numbers, it
encountered major difficulties and was stopped.
According to the 2004 Reproductive Health Survey in Romania less than 20% of the women
aged 15-44 has ever had a PAP smear test, while in rural areas the percentage drops to 11%. [62]
51
A national school-based HPV immunization program was started in 2008 but was stopped
due to very poor uptake (3%). The main cause for this was considered to be the lack of a proper
health educational campaign to prepare the public with accurate information in advance of the
implementation of the program. [62]
Environmental aspects seen in the study, such as providence play a major role in screening,
and there for getting the proper treatment and my results support this claim by showing that only
32% of the patients treated are from a rural environment.
The conization techniques used in the hospital are almost equally used, and no report of
different was observed, which by far supports the global researches on the subjects, because
according to many studies, Cold-knife conization and loop-excision conization yield similar
diagnostic and therapeutic results [63], even though the LEEP technique was only initiated about a
year ago.
The cytological findings of this research show more cases of HSIL treated than any other
finding or all of them together, as the HSIL (moderate and severe dysplasia) is considered true premalignant lesions with a progression rate to invasive cancer of 30% to 50% over time [68].
It is estimated that up to 90% of the cases of CIN treated by conization are met with success,
however exceptions still exist. It is not clear yet, how the precursors of cervical cancer evolve. It is
believed that any form of CIN can result in invasive cancer. It is known now that the majority of
forms of CIN 1 will regress without treatment, thought there is no scientific prove for why this
phenomenon happen. The one certain fact is that CIN 3 that remains untreated leads to invasive
cancer and death. In present, conization is the preferable method of treatment in case of females
diagnosed with CIN 2 and 3. Conclusion of some studies that followed the percentage of the
52
Cervical Intraepithelial Neoplasia residuals showed that only age and neoplastic grade can be
considered as predictive factors. [61, 63]
The small part that remains is treated with hysterectomy, because this maneuver is often
unnecessary and that the patient can be followed up just by cytological and colposcopical exams.
[59]
However hysterectomy was proven as a better option in cases of patients of old age, with a
diameter more than possible for conization. [65, 66, 67]
In long term prognosis the study showed that conization with negative margins, is the ideal
way for treatment in cases of CIN 3. [66, 67]
However hysterectomy was proven as a better option in cases of patients of old age, with a
diameter more than possible for conization. [65, 66, 67]
The hemostasis phase of the Cold Knife Conization showed no complications, in either two
methods that are in hands, and were used both without a preferable method to be mentioned.
No conclusive information were obtained about the relationship of smoking with cervical
cancer or other aspects of this research.
53
5. Conclusion
1. Women in ages of 25-40 years are most prevalent for cervical cancer.
2. Romania still lacks the tools and infrastructure for screening for HPV.
3. Surgical skills available for diagnosed patients meet the standards of the developed world.
4. No method of conization is superior to another, in methods used in the Obstetrics-Gynecology II
Clinic Dominic Stanca in Cluj-Napoca.
5. The progress in importing new surgical techniques for treatment is in progress, and performed in
high standards.
54
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Universitatea de Medicin i Farmacie

Iuliu Haieganu Cluj-Napoca

Squamous Epithelium ............................................................................................................ 8

Glandular Epithelium ............................................................................................................ 9

Squamocolumnar Junction .................................................................................................. 10

Transformation Zone ........................................................................................................... 10

Colposcopic and Neoplastic significance of the transformation zone ................................. 12

Histology and colposcopy of the transformation zone ........................................................ 12

Genetic susceptibility ....................................................................................................... 15

Human papillomavirus ..................................................................................................... 16

Human immunodeficiency virus ...................................................................................... 17

Papanicolaou Smear Testing ............................................................................................ 22

ThinPrep Papanicolaou test.............................................................................................. 23

Human Papillomavirus Testing........................................................................................ 23

Imaging Studies for Metastasis ........................................................................................ 24

9. Surgical Staging ...................................................................................................................... 24

2001 Bethesda System for reporting cervical cytologic diagnoses .............................. 24

Cold-Knife Conization ..................................................................................................... 30

Loop Electrosurgical Excision Procedure (LEEP)........................................................... 31

Laser Conization .............................................................................................................. 36

Material and methods ................................................................................................................. 38

Incidence in Age Groups ..................................................................................................... 39

Cytology and Biopsy results ................................................................................................ 45

Method of Conization .......................................................................................................... 49

Hemostasis Method ............................................................................................................. 50

2.2. Glandular Epithelium

2.3. Squamocolumnar Junction

Environmental factors (eg, smoking and vitamin deficiencies)

Lack of access to routine cytology screening

Sex at a young age

Multiple sexual partners

Promiscuous male partners

History of sexually transmitted diseases

Stage I - Greater than 90%

Stage III - Approximately 50%

Stage IV - Less than 30%

< 21 years No screening recommended

21-29 years Cytology (Pap smear) alone every 3 years

Women who had a hysterectomy without removal of the cervix

Women who have had cervical carcinoma at any time

8.4. Imaging Studies for Metastasis

Satisfactory for evaluation (note presence/absence of endocervical/transformation zone

Unsatisfactory for evaluation (specify reason)

Specimen rejected/not processed (specify reason)

Negative for intraepithelial lesion or malignancy

Epithelial cell abnormality

Negative for intraepithelial lesion or malignancy

Reporting other nonneoplastic findings (ie, inflammation and atrophy) is optional

Epithelial cell abnormalities

Atypical squamous cells (ASC)

Low-grade squamous intraepithelial lesion (LSIL)

Encompassing HPV, mild dysplasia, and CIN 1 (Fig. 3)

Squamous cell carcinoma (Fig. 5)

AGC favoring neoplastic (specify endocervical or not otherwise specified)

Endocervical adenocarcinoma in situ (AIS)

Other (list not comprehensive)

Endometrial cells in a woman aged 40 years or older

2.2. Loop Electrosurgical Excision Procedure (LEEP)

2.2.2. Intraoperative Instruments

2. Material and methods

Age of patient at admission

Biopsy and cytological diagnosis

Type of conization performed