Anatomy of the cervix

The cervix means in Latin, 'neck'. The cervix is the lower part of
the uterus in the female reproductive system. The cervix is about 2 to
3 cm long (~1 inch) and roughly cylindrical in shape, which changes
during pregnancy (Ovalle et al, 2013).

The cervical canal connects the uterine cavity and the lumen of
the vagina. The opening into the uterus is called the internal os, and the
opening into the vagina is called the external os. The lower part of the
cervix is known as ectocervix, bulges into the upper part of the vagina
(Reich et al, 2014).

Embryology of the cervix

The cervix is originated from the two Müllerian ducts, which

develop around the 6th week of fetal growth. During development, the
outer parts of the two ducts fuse, forming a single urogenital canal that
will become the vagina, cervix and uterus (Schoenwolf et al, 2009).

The cervix grows in size at a smaller rate than the body of the
uterus. The size of the cervix decreases compared to the uterine body,
starts of being larger than the uterine body during fetal life, being double
the body size during childhood and ends by being half the size of uterine
body after puberty (Beckmann et al, 2013).

Histology of the cervix

1
 The endocervical mucosa is thick and lined with a single layer of
columnar mucous cells containing numerous tubular mucous glands,
which drains viscous alkaline mucus into the lumen (Lowe et al, 2005).

In contrast, the ectocervix is covered with non-keratinized stratified

squamous epithelium, which resembles the squamous epithelium lining
the vagina. The junction between these two types of epithelia is called the
squamocolumnar junction (Beckmann et al, 2013).

Beneath both types of epithelium, there is a tough layer

of collagen. The mucosa of the endocervix is not shed during
menstruation. The cervix has more fibrous tissue, including collagen
and elastin, than the rest of the uterus (Daftary 2011).

Transformation zone of the cervix

In prepubertal girls, the functional squamocolumnar junction is

present just within the cervical canal. Due to hormonal influence that
occurs upon puberty and during pregnancy, the columnar epithelium
extends outward over the ectocervix as the cervix everts. Hence, this also
causes the squamocolumnar junction to move outwards onto the vaginal
portion of the cervix, where it is exposed to the acidity of vaginal
secretions (McLean and John 2006).

The exposed columnar epithelium will undergo

physiological metaplasia and will change to tougher metaplastic
squamous epithelium within days or weeks. The new squamocolumnar
junction is therefore internal to the original squamocolumnar junction,
and the zone of unstable epithelium between the two junctions is called

2
the transformation zone of the cervix. Infection with the human
papillomavirus (HPV) can cause changes in the epithelium, which can
lead to cancer of the cervix (Beckmann et al, 2013).

Figure ( ): Female
reproductive system

Figure ( ): Transformation zone of the cervix

Epidemiology of cancer cervix

3
 Cervical cancer continues to be a major public health problem
affecting middle-aged women, particularly in less-resourced countries.
The worldwide scale-up of HPV vaccination and HPV-based screening
(including self-sampling) has an effect to make cervical cancer a rare
disease in the nearest decades (Arbyn et al, 2019).

Ten years ago, cervical cancer ranked as the third most common
cancer among women worldwide. However, in forty-two low-resources
countries, it was the most common cancer in women (Arbyn et al, 2008).

According to the latest data from GLOBOCAN 2018, cervical

cancer is the fourth most common cancer in women worldwide, and it
was the second most common in low-and middle-income countries
(LMICs). Thus, it is a major cause of morbidity and mortality from
cancer. In 2018, there were about 569 847 new cases and 311 365 deaths
worldwide annually (Bray et al, 2018).

In Egypt, cervical cancer was ranked as the 21 st regarding the

incidence and the 18th regarding the death rate among other cancers
according to Globocan 2018 (Arbyn et al, 2019).

According to cervical cancer incidence rates at national and

regional level of Egypt regarding to National Cancer Registry Program
(NCRP), that stratified Egypt into 3 geographical strata: lower, middle,
and upper. The incidence rates (/ 100,000 populations) were 1.26%,
1.06% and 0.48% in the 3 regions respectively (Amal et al, 2018).

Factors Influencing the Risk of Cervical Cancer

4
 Human papillomavirus is a key causative agent in the
development of cervical cancer. Approximately all cases of cervical
cancer can be due to HPV infection with the prevalence of HPV infection
in cervical cancer as high as 99%. HPV infection is sexually transmitted
and is often asymptomatic. The lifetime cumulative risk of HPV infection
is larger than 80%. The peak time for acquiring the infection is shortly
after becoming sexually active. Penetrative sex is not essential for
transmission, and skin-to-skin genital contact is enough for getting the
infection (WHO 2016).

Most genital HPV infections are transient and will spontaneously

resolve within about 8 months of acquisition, especially in women under
the age of 30 years old. Viral load is usually undetectable by 2 years in
90% of women. Persistent infection is reported to occur in less than 10%
and is defined as the presence of high-risk HPV for longer than 2 years.
Persistent infection with HPV increases the risk of cervical cancer
(Goodman 2015).

There is convincing evidence that tobacco smoking is an

independent risk factor for cervical cancer. As in the two large
collaborative studies on cervical cancer, there was about doubling in risk
of cervical cancer among smokers compared to non-smokers; and this
risk was further increased with younger age at starting smoking and the
number of cigarettes smoked per day. In these studies, the effect of
smoking appeared to be limited to squamous cell carcinoma of the cervix.
Some recent studies approved an increased risk of cervical cancer in
women exposed to passive smoking (Kapeu et al, 2008).

HIV increases the risk of developing CIN and invasive cervical

cancer in the presence of HPV. The prevalence of HPV is greater in HIV-

5
positive people than HIV-negative people (37.2% vs 13.7%,
respectively). Furthermore, persistent infection with HPV-16 or HPV-18
is relatively more common in HIV- positive people compared to those
who are HIV-negative (20% vs 3%). However, despite treatment of HIV
with antiretroviral therapy, the risk of developing cervical cancer remains
substantially higher than in the HIV-negative population (Rohner et al.,
2017).

Co-infection of HPV with Chlamydia trachomatis has been

associated with an increased risk of developing cervical cancer especially
squamous cell carcinoma in several studies. In a pooled analysis of the
International Agency for Research on Cancer (IARC) multi-centered
case-control studies, there was a 2fold increased risk in HPV DNA-
positive women who were also C. trachomatis seropositive compared to
those who were seronegative (Dahlstrom 2011).

Currently there is a good epidemiological evidence to support an

association between multiparity and invasive cervical cancer. Most
studies show that multiparity is common and associated with an increased
risk of cervical cancer among both HPV-positive and HPV-negative
women (Munoz et al., 2011).

It has long been recognized that sexual behavior played an

important role in the etiology of cervical cancer. It is now well
established that an early age at first intercourse and increased number of
lifetime sexual partners are associated with an increased risk of cervical
cancer and its precursor lesions. In a recent study that demonstrated a
protective effect of condom use, the incidence rates of both genital HPV
infection and cervical intraepithelial lesions were reduced in condom
users compared to nonusers (Winer et al., 2006).

6
 There is some evidence to suggest that obesity, particularly weight
gain since age 18, may be a risk factor for adenocarcinoma of the cervix
(Lee et al., 2013).

It is plausible that certain foods and nutrients could have a

protective effect against the development of cervical cancer. There is
some evidence to suggest that high dietary consumption of carotenoids,
retinol, vitamins C and E, folate and fruits and vegetables may reduce the
risk of CIN and cervical cancer (Garcia et al., 2005).

Pathogenesis of cervical cancer

The natural history of cervical carcinogenesis as a result of HPV
infection is a fourfold process beginning with the virus infecting the
metaplastic epithelium of the cervix in the transformation zone.
Following initial infection, over 90% of women will go on to clear the
virus; however, a small number of women will continue to have viral
persistence. This viral persistence can then cause the metaplastic cells to
become precancerous cervical intraepithelial neoplasia (CIN) which is
graded CIN-I, CIN-II and CIN-III depending upon the extent of the
neoplastic change. Invasive cervical cancer develops when these
neoplastic cells invade the basement membrane of the cervix (Castle et
al., 2009).

There are many different types of HPV, some of which are low risk
and some high risk for developing cervical cancer. HPV-16, HPV-18,
HPV-31, HPV-33, HPV-35, HPV-45, HPV-52 and HPV-58 are the high-
risk HPV types. Out of these high-risk types, HPV-16 and HPV-18 are
accountable for about 70% of cervical cancers, and 32% of people with

7
an HPV infection are infected with these phenotypes (Crosbie et al.,
2013).

Regarding smoking, it has been suggested that cigarette smoking

may promote carcinogenicity by affecting local cell-mediated immune
response, inducing genetic damage and causing localized immune
suppression which may promote HPV persistence (International Agency
for Research on Cancer 2012).

It is believed that there is a synergistic interaction between HIV

and oncogenic HPV-16 – HIV infection compromises the immune system
and predisposes sexually active women to co-infection by HPV-16 and its
persistence. (Rohner et al., 2017).

It has been hypothesized that concomitant genital infections may

induce chronic irritation/inflammation of the cervix which could promote
HPV-related oncogenic processes (Dahlstrom et al., 2011).

Several hypotheses have been suggested to explain possible

biological mechanisms that may influence the risk, including hormonal,
nutritional and immunological changes during pregnancy and/or trauma
to the cervix that occurs during parturition (Munoz et al., 2002).

8
 Figure ( ): Shows the pathogenesis of cervical cancer.

Histopathological types of cervical cancer

9
 The most frequent types of cervical cancer are squamous-cell
carcinoma and adenocarcinoma, which develop from the distinctive
precursor lesions cervical intraepithelial neoplasia (CIN) / squamous
intraepithelial lesion (SIL), and adenocarcinoma in situ (AIS),
respectively (Sigurd 2011).

Squamous cell carcinoma (SCC) is by far the most common tumor

of the cervix. SCC most commonly affects women in their mid-30s to
mid-40s, but can affect women over a wide age range, from <20 to >80
years of age. The vast majority of these tumors (>99% worldwide) are
related to infection with HPV (Kurman et al., 2014).

Microscopically, invasive SCC is characterized by infiltrating nests

of neoplastic squamous epithelium in the stroma. These nests typically
display an irregular, angulated shape, and may demonstrate increased
cytoplasmic keratinization (so-called paradoxical maturation (Kurman et
al., 2014).

Various subtypes of cervical SCC have been described. In 1958 Wentz

and Reagan divided cervical SCC into three cell types: large cell
keratinizing, large cell nonkeratinizing, and small cell. With the advent of
electron microscopy and immunohistochemistry, it became apparent that
what had been termed small cell SCC really represents a heterogeneous
group of tumors, including basaloid SCC and small cell neuroendocrine
carcinoma (Diaz et al., 2013).

10
The histopathological types, as described in the World Health
Organization’s 2014 "Tumors of the Female Reproductive Organs" are:
1. Squamous cell carcinoma (keratinizing; non-keratinizing; papillary,
basaloid, warty, verrucous, squamotransitional, lymphoepithelioma-like)
2.Adenocarcinoma (endocervical; mucinous, villoglandular,
endometrioid)
3. Clear cell adenocarcinoma
4. Serous carcinoma
5. Adenosquamous carcinoma
6. Glassy cell carcinoma
7. Adenoid cystic carcinoma
8. Adenoid basal carcinoma
9. Small cell carcinoma
10. Undifferentiated carcinoma (Kurman et al., 2014).

Prognostic factors.

Lymph node metastases significantly worsen the prognosis in

cervical carcinoma and assessment of lymph node involvement is
therefore important for preoperative therapy planning. Nevertheless,
preoperative lymph node staging has now been included in the
International Federation of Gynecology and Obstetrics (FIGO) staging
guidelines for the first time (Widschwendter et al., 2019).

Several factors like large clinical tumor size, deep cervical stroma
invasion, histopathological type, grading and lymph vascular space
invasion (LVSI) are associated with an increased risk of recurrence and
poor overall survival in early and advanced stages of cervical cancer. The
presence of lymph node metastases has also negative prognostic impact,

11
while parametrial infiltration alone without lymph node involvement does
not always worsen the prognosis (Rotman et al., 2006).

Novel markers for cervical cancer prognosis.

Maspin is known to be a tumor suppressor and anti‐angiogenic

protein, and its prognostic significance in patients with several types of
cancer has been reported in the literature. Related to its function as a
suppressor, however, a paradoxical increase of maspin expression has
been identified in several malignant cell types compared to their normal
cells of origin, including those from lung, bladder and ovarian tissues.
Maspin expression is also related to the advanced stages of several types
of tumors, including cervical, endometrial and pancreatic cancers
(Nosaka et al., 2015)

Nuclear maspin staining was found to be significantly related to a

higher overall survival (Bostanci et al., 2020).

HPV expresses two viral oncoproteins: E6 and E7. These proteins

bind to and inactivate the tumor suppressor proteins p53 and pRb,
respectively, causing deregulation of the cell cycle. It was found that a
high level of HPV 16 and HPV 18 E6/E7 mRNA expression was an
independent predictor of unfavorable prognosis in cervical cancer,
whereas the number of HPV DNA copies per cell was not. Importantly,
when the analysis was limited to lymph node –negative patients, HPV
E6/E7 mRNA expression was still of significant prognostic value
(Marjon et al. 2007).

12
 Tumor cell differentiation, apoptosis, and oncogenesis are
associated with prostaglandins as (PGE2). PGE2 signaling is well-known
for apoptosis inhibition, angiogenesis, metastatic formation, and tumor
progression. The membrane-bound EP receptors specific for PGE 2 are
classified into four subtypes: EP1, EP2, EP3, and EP4. It was showed that
up-regulated expressions of PGE2, EP2 and EP4 in cervical cancer tissues
compared to in normal cervical tissues, indicating that PGE 2 may regulate
neoplastic cell function in cervical carcinoma via EP2 and EP4 receptors.
Additionally, it was reported that the EP3 receptor is an independent
negative prognosticator for cervical cancer patients (Heideggeret al.,
2017).

EP2 receptor is a prognostic factor for the overall survival in the

subgroup of negative EP3 and high galectin-3 expressed cervical cancer
patients. EP2 in combination with EP3 or galectin-3 might act as
prognostic indicators of cervical cancer. EP2, EP3, and galectin-3 could
be targeted for clinical diagnosis or endocrine treatment in cervical cancer
patients, which demands future investigations (Dietlmeier et al. 2020).

Cervical cancer spreads by direct extension into the parametrium,

vagina, uterus and adjacent organs, i.e., bladder and rectum. It also
spreads along the lymphatic channels to the regional lymph nodes,
namely, obturator, external iliac and internal iliac, and thence to the
common iliac and para-aortic nodes. Distant metastasis to lungs, liver,
and skeleton by the hematogenous route is a late phenomenon. Until now,
the FIGO staging was based mainly on clinical examination with the
addition of certain procedures that were allowed by FIGO to change the
staging (Bhatla et al., 2018).

13
 Figure ( ) FIGO 2018 of cervical cancer staging

The hallmark of a good staging system is the ability to define

anatomical extent of disease and differentiate survival outcomes. The
staging system also allows comparison of patients and their outcomes
between centers. Cancer staging is an evolving process that responds to
developments in technology that improve diagnosis and treatment, new
information about prognostic factors, and outcomes data (Bhatla et al.,
2019).

Since publication of the last FIGO cervical cancer staging in 2009,

considerable progress has been made in the use of imaging modalities to

14
evaluate women with cervical cancer. Although FIGO moved to a
surgico-pathological system of staging for ovarian and endometrial
cancer, this was not as simple for cervical cancer, a disease mainly of
under-resourced regions (Bhatla et al., 2018).

Diagnosis of cervical cancer.

A punch biopsy may generally suffice, but if not satisfactory a

small loop biopsy or cone may be required. Clinical assessment is the
first step in allocation of staging. Imaging evaluation may now be used in
addition to clinical examination where resources permit. The revised
staging permits the use of any of the imaging modalities according to
available resources, i.e. ultrasound, CT, MRI, positron emission
tomography (PET), to provide information on tumor size, nodal status,
and local or systemic spread. The accuracy of various methods depends
on the skill of the operator. MRI is the best method of radiologic
assessment of primary tumors greater than 10 mm (Fischerova et al.,
2008).

However, ultrasound has also been shown to have good diagnostic

accuracy in expert hands. Imaging has the advantage of the ability to
identify additional prognostic factors, which can guide the choice of
treatment modality (Clare et al., 2016).

For detection of nodal metastasis greater than 10 mm, PET-CT is

more accurate than CT and MRI, with false-negative results in 4%–15%
of cases (Sakurai et al., 2006).

This is especially true in advanced stages, where surgical

assessment of para-aortic lymph nodes may be used to tailor treatment
according to extent of disease. They can be accessed by minimally

15
invasive surgery or laparotomy. Surgical exclusion of para-aortic lymph
node involvement has been reported to have a better prognosis than
radiographic exclusion alone (Smits et al., 2014).

FIGO no longer mandates any biochemical investigations or

investigative procedures; however, in patients with frank invasive
carcinoma, a chest X-ray, and assessment of hydronephrosis (with renal
ultrasound, intravenous pyelography, CT, or MRI) should be done. The
bladder and rectum are evaluated by cystoscopy and sigmoidoscopy only
if the patient is clinically symptomatic (Bhatla et al., 2018).

Cystoscopy is also recommended in cases of a barrel-shaped

endocervical growth and in cases where the growth has extended to the
anterior vaginal wall. Suspected bladder or rectal involvement should be
confirmed by biopsy and histologic evidence. Bullous edema alone does
not warrant a case to be allocated to Stage IV (Bhatla et al., 2018).

The revised staging system does not mandate the use of a specific
imaging technique, lymph node biopsy, or surgical assessment of the
extent of tumor. In low-resourced conditions, clinicians can continue to
assess the patient clinically as before (Bhatla et al., 2019).

16
 Management of cervical cancer
Early detection and prevention of cervical cancer

It is now recognized that cervical cancer is a rare long-term

outcome of persistent infection of the lower genital tract by one of about
15 high-risk HPV types. HPV 16 and HPV 18 account for about 71% of
cases; while HPV types 31, 33, 45, 52, and 58 account for another 19% of
cervical cancer cases (Bruni et al., 2010).

It is well documented that nearly 90% of incident HPV infections

are not detectable within a period of 2 years from the acquisition of
infection and persist only in a small proportion. It is debatable whether
the virus is completely cleared or whether it remains latent in basal cells
with the potential for reactivation in some cases (International Agency
for Research on Cancer 2007).

Persistent HPV infection denotes the presence of the same type-

specific HPV DNA on repeated sampling after 6–12 months. Only one-
tenth of all infections become persistent, and these women could develop
cervical precancerous lesions (Bhatla et al., 2018).

This knowledge has resulted in the development of new initiatives

for prevention and early detection. The two major approaches for control
of cervical cancer involve:
(1) Prevention of invasive cancer by HPV vaccination.
(2) Screening for precancerous lesions.

17
 Prevention and elimination are potential possibilities but the
tragedy is that it is not yet prevented on a large scale in many LMICs due
to lack of efficient and effective intervention programs
(Sankaranarayanan et al., 2018).

Primary prevention of cervical cancer with HPV vaccination

Age-specific cross-sectional HPV prevalence peaks at 25% in

women aged less than 25 years, which suggests that the infection is
predominantly transmitted through the sexual route following sexual
debut. Thus, prophylactic HPV vaccination as a preventive strategy
should target women before initiation of sexual activity, focusing on girls
aged 10–14 years (WHO 2017).

Three prophylactic HPV vaccines are currently available in many

countries for use in females and males from the age of 9 years for the
prevention of premalignant lesions and cancers affecting the cervix,
vulva, vagina, and anus caused by high-risk HPV types: a bivalent
vaccine targeting HPV16 and HPV18; a quadrivalent vaccine targeting
HPV6 and HPV11 in addition to HPV16 and HPV18; and a nonvalent
vaccine targeting HPV types 31, 33, 45, 52, and 58 in addition to HPV 6,
11, 16, and 18. The last two vaccines target anogenital warts caused by
HPV 6 and 11 in addition to the above-mentioned malignant and
premalignant lesions (Garland et al., 2016).

All the vaccines are recombinant vaccines composed of virus-like

particles (VLPs) and are not infectious since they do not contain viral
DNA. For girls and boys aged 9–14 years, a two-dose schedule (0.5 mL
at 0 and 5–13 months) is recommended. If the second vaccine dose is
administered earlier than 5 months after the first dose, a third dose is
18
recommended. For those aged 15 years and above, and for
immunocompromised patients irrespective of age, the recommendation is
for three doses (0.5 mL at 0, 1, 6 months). There is evidence for the
effectiveness of vaccination at the population level in terms of reduced
prevalence of high-risk HPV types, and reduction in anogenital warts and
high-grade cervical abnormalities caused by the vaccine types among
young women; there is some evidence of cross-protection from non-
vaccine types also (Kreimer et al., 2018).

Secondary prevention of cervical cancer by early detection and

treatment of precancerous lesions.

Even with the advent of effective vaccines, screening will remain a

priority for cervical cancer prevention for several decades. Cervical
cancer screening has been successful in preventing cancer by detection
and treatment of precursor lesions, namely, high-grade cervical
intraepithelial neoplasia (CIN 2 and 3) and adenocarcinoma in-situ (AIS)
(Sankaranarayanan et al., 2014).

Several cervical screening strategies have been found to be

effective in varied settings. The tests used widely include conventional
cytology (Pap smear), in recent years liquid-based cytology and HPV
testing, and, in LMICs, visual inspection with acetic acid (VIA). While
the Pap smear is still the major workhorse of screening and is associated
with substantial declines in cervical cancer risk in high-income countries,
it is a challenging and resource intensive technology that is not feasible in
low-resource settings where poor organization, coverage, and lack of
quality assurance result in suboptimal outcomes (Shiferaw et al ., 2016).

19
 In the context of declining HPV infections after the introduction of
HPV vaccines a decade ago, many healthcare systems are considering
switching to primary HPV screening, which has higher sensitivity and
negative predictive value, and allows extended screening intervals or
even a single lifetime screening in low-resource settings (Ronco et at.
2010).

VIA involves detection of acetowhite lesions on the cervix 1

minute after application of 3%–5% freshly prepared acetic acid. In view
of its feasibility, VIA screening has been widely implemented in
opportunistic settings in many low-income countries. A single-visit
approach (SVA) for screening with rapid diagnosis and treatment
improves coverage, eliminates follow-up visits, and makes screening
more time and cost-efficient in low-resource settings (Msyamboza et al .,
2016).

VIA screening is particularly suitable for SVA and WHO has

issued guidelines for implementing SVA in public health settings. A
single screening modality will never be universally applicable, but it is
possible to adapt cost-effective means of cervical cancer screening to
each country. The screening strategy chosen must be feasible, simple,
safe, accurate, acceptable, and easily accessible to highest-risk women. A
judicious combination of HPV vaccination and screening has enormous
potential to eliminate cervical cancer in the foreseeable future (Parham
et al., 2015).

20
Cervical cancer screening methods in low- and middle-income
countries (LMICs):

Every year 445000 women in LMICs develop cervical cancer

compared to 83,000 women in high income countries (HICs). This
disparity is largely attributed to the absence of organized screening
programs in LMICs. Although HPV vaccination programs are being
scaled up globally, implementation has been slow in LMICs. The vaccine
is targeted at adolescents before sexual debut and will not help women
already infected with HPV. Therefore screening programs will continue
to be necessary for cervical cancer prevention (Bruni et al., 2016).

However, cytology based screening programs (i.e., Pap smears)

have been successful in reducing incidence of cervical cancer in high
income countries (HICs), evidence suggests that it may not be the most
effective screening method in LMICs due to complex infrastructure
requirements and quality assurance issues(Jeronimo et al., 2014).

Instead, the WHO recommends either human papillomavirus

(HPV) testing or visual inspection with acetic acid (VIA) for screening
programs (WHO 2013).

A systematic review evaluated the efficacy and the cost benefit of

screening tests for cervical cancer and the results indicate that cytology is
the least efficient screening method to implement in developing countries.
The sensitivity of cytology was estimated to be 58.4%. This is
substantially lower than the established sensitivity of HPV testing
(Perkins et al., 2010).

21
 The requirement of three visits to complete a full course of
cytology screening leads to greater loss to follow-up compared to VIA
and HPV testing, which can be conducted in one or two visits. In LMICs,
the requirement of three visits to receive a full course of screening
appears to represent a significant barrier to care (Shi et al., 2011).

Comparing HPV testing and VIA, it demonstrates that HPV testing

was generally more effective, yet also more costly than VIA. This is
likely explained by the higher direct cost of HPV testing, as well as its
greater sensitivity to detect precancerous conditions. It was concluded
that HPV testing and VIA are more cost-effective screening methods than
cytology in LMICs (Mezei et al., 2017).

22
 Management of cervical cancer
Treatment of invasive cervical caner

Treatment of cervical cancer is based on stage of the disease, age,

and fertility status, menopausal status of the patient and associated
comorbid conditions and histopathological type. Treatment requires
multidisciplinary approach involving a gynecologic oncologist, radiation
oncologist and medical oncologist (NCCN 2015).

Management of cervical cancer is primarily by surgery or radiation

therapy, with chemotherapy a valuable adjunct (Bhatla et al., 2018)

After careful clinical evaluation and staging, the primary treatment

of early stage cervical cancer is either surgery or radiotherapy. The
treatment approach is determined by the FIGO stage 2018 and whether
fertility preservation is desired (De Juan et al., 2019).

Nodal metastasis is 1% with stromal invasion <1 mm while stromal

invasion 1-3 mm has 1.5% risks in stage IA1 cervical cancer. In Stage
IA1 with LVSI, lymph node metastasis & cancer recurrence rate is 5%.
Lymph node metastasis is 7% and risk of disease recurrence is 4% in
Stage 1A2 cancer (Sahu 2015).

For the Stage 1A1: the treatment is completed with cervical

conization unless there is lympho-vascular space invasion (LVSI) or
tumor cells are present at the surgical margin. In women who have
completed childbearing or elderly women, total extrafascial hysterectomy
may also be recommended (Lee et al., 2009).

23
 Any route can be chosen, i.e. abdominal, vaginal, or laparoscopic.
When LVSI is evident, pelvic lymphadenectomy should be considered,
along with modified radical hysterectomy. If fertility is desired, cervical
conization with close follow-up will be adequate (Elliott et al., 2000).

Regarding Stage 1A2, there is a small risk of lymph node

metastases in these cases; pelvic lymphadenectomy is performed in
addition to type B radical hysterectomy or more radical surgery. In low
risk cases, simple hysterectomy or trachelectomy, with either pelvic
lymphadenectomy or sentinel lymph node assessment, may be adequate
surgical treatment. When the patient desires fertility, she may be offered a
choice of the following:
 Cervical conization with laparoscopic (or extraperitoneal) pelvic
lymphadenectomy.
 Radical abdominal, vaginal, or laparoscopic trachelectomy with
pelvic lymphadenectomy (Bouchard-Fortier et al. 2014).

Follow-up with 3-monthly Pap smears for 2 years, and then 6-

monthly for the next 3 years is recommended after treatment of micro
invasive carcinoma. With normal follow-up at 5 years, the patient can
return to the routine screening schedule according to the national
guidelines (Lee et al., 2009).

Surgical treatment is the preferred modality for the treatment of

Stage IB1, IB2, and IIA1 lesions. It would usually consist of type C
radical hysterectomy with pelvic lymphadenectomy. The routes of
surgery may be open or minimally invasive, i.e. laparoscopic or robotic
(Roh et al., 2015).

24
 FIGO Stage IB1 is considered as low risk as the largest tumor
diameter less than 2 cm, cervical stromal invasion less than 50%, and no
suspicious lymph nodes on imaging. So, the standard management is a
type C radical hysterectomy, also modified radical hysterectomy may be
considered in these cases. Pelvic lymphadenectomy should always be
included on account of the high frequency of lymph node involvement
(Kato et al., 2015).

In young women desiring fertility sparing, a radical trachelectomy

may be performed, indicated for Stage IA2–IB1 tumors measuring less
than or equal to 2 cm in largest diameter. The cervix along with the
parametrium is removed followed by anastomosis of the uterus with the
vaginal end. Trachelectomy can be done by open abdominal, vaginal, or
by minimally invasive routes. When a vaginal approach is planned, the
pelvic nodes are first removed laparoscopically and sent for frozen
section to confirm node negativity and then proceed with the radical
trachelectomy vaginally. Alternatively, the nodes may be first be assessed
by conventional pathologic methods and the radical trachelectomy done
as a second surgery after 1 week (Abu-Rustum et al., 2006).

In FIGO Stage IB2 and IIA1 cervical cancer, surgery or

radiotherapy can be chosen as the primary treatment depending on other
patient factors and local resources, as both have similar outcomes. The
advantages of surgical treatment are:
 That it is feasible to determine the postoperative stage precisely on
the basis of histopathologic findings, thereby enabling
individualization of postoperative treatment for each patient.

25
  That it is possible to treat cancers that are likely to be resistant to
radiotherapy.
 That it is possible to conserve ovarian function (Bhatla et al., 2018).

In Stage IB3 and IIA2, the tumors are larger and the likelihood of
high risk factors such as positive lymph nodes, positive parametria, or
positive surgical margins that increase the risk of recurrence and require
adjuvant radiation after surgery are high. Other risk factors that increase
the risk of pelvic recurrence even when nodes are not involved include:
largest tumor diameter greater than 4 cm, LVSI, and invasion of outer
one-third of the cervical stroma. In such cases, adjuvant whole pelvic
irradiation reduces the local failure rate and improves progression-free
survival compared with patients treated with surgery alone (Rotman et
al., 2006).

However, the dual modality treatment increases the risk of major

morbidity to the patient. The treatment modality must, therefore, be
determined based on the availability of resources and tumor-and patient-
related factors (Bhatla et al., 2018).

Concurrent platinum-based chemoradiation (CCRT) is the

preferred treatment option for Stage IB3 to IIA2 lesions. It has been
demonstrated that the prognosis is more favorable with CCRT, rather
than radiotherapy alone, as postoperative adjuvant therapy as well in
terms of overall survival, progression-free survival, and local and distant
recurrences (Rose et al., 2007).

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 In areas where radiotherapy facilities are scarce, neoadjuvant
chemotherapy (NACT) has been used with the goal of:
 Down-staging of the tumor to improve the radical curability and safety
of surgery.
 Inhibition of micrometastasis and distant metastasis.
There is no unanimity of view as to whether it improves prognosis
compared with the standard treatment (Moss et al., 2010).

The extent of surgery after NACT remains the same, i.e. radical
hysterectomy and pelvic lymphadenectomy. The greater difficulty is in
determining the indications for adjuvant therapy which are often kept the
same as those after primary surgery (Rose et al., 2007).

However, it must be remembered that NACT may give a false

sense of security by masking the pathologic findings and thus affecting
evaluation of indications for adjuvant radiotherapy/CCRT. NACT surgery
is best reserved for research settings or those areas where radiotherapy is
unavailable. This is especially true in patients with very large tumors or
adenocarcinomas, which have lower response rates (Dastidar et al.,
2016).

Rarely, patients with Stage IVA disease may have only central
disease without involvement to the pelvic sidewall or distant spread. Such
cases, or in case of such a recurrence, pelvic exenteration can be
considered but usually has a poor prognosis (Benn et al., 2011).

27
Nerve sparing in radical hysterectomy

A pelvic nerve-sparing surgical procedure is recommended in

patients undergoing radical hysterectomy, in so far as radical curability is
maintained, as intrapelvic injuries to the autonomic nerves (i.e.
hypogastric nerve, splanchnic nerve, and pelvic plexus) often lead to
impairment of urination, defecation, and sexual function, and consequent
deterioration of the postoperative quality of life (Roh et al., 2015).

The results of both surgery and radiotherapy are comparable for the
treatment of the early stages of cervical cancer, but surgical treatment is
the favored modality, especially in young women. Neoadjuvant and
adjuvant chemotherapy are used in individual cases based on the stage of
cervical cancer. High curability rates in women in the early stages of this
disease (88–97%), which are based on individualized therapy, currently
emphasize the increase in the quality of life of treated women. Morbidity
related to the treatment of cervical cancer is specifically linked to the
radical nature of the surgery (Siegel et al., 2017).

Bladder dysfunction is one of the most common long-term

complications after radical abdominal hysterectomy (RAH) and has an
incidence of 8–85% (Zullo et al., 2003).

The most common disorders of RAH include loss of sensation,

hypertonic urinary bladder, hypo-/acontractile bladder, urgency and stress
urinary incontinence (Benedetti-Panici et al., 2004).

Voiding disorders have been related to damage of the hypogastric

nerves and of the inferior hypogastric plexus due to radical resection of
the parametrial tissue (Maneschi 2014).

28
 The autonomic fibers innervating the bladder can be disrupted at
several stages during RAH, e.g., during dissection of the presacral or
superior gluteal nodes, during vaginal dissection and mobilization of the
bladder, and during resection of the cardinal ligaments (Zullo et al.,
2003).

After radical hysterectomy, changes usually occur in two phases.

The initial phase is hypertonic and is characterized by a small, usually
transient, spastic bladder. During the early postoperative stage, both
surgical trauma and selective denervation result in the dominance of the
parasympathetic nervous system, which leads to hyperexcitability of the
smooth muscle (Jackson and Naik 2006).

The nature of the surgical damage seems to be decentralization of

nerve stimuli rather than complete denervation. The second phase is
hypotonic, which is characterized by an over distended bladder. Nerve-
sparing radical hysterectomy (NSRH) has emerged for reducing surgery-
related dysfunctions without compromising oncological outcomes (Van
Gent et al., 2017).

The nerve-sparing technique includes four main steps:

 The preservation of the superior hypogastric plexus at the level
of the presacral area during presacral lymphadenectomy.
 The preservation of the hypogastric nerve dorsal to the ureter
and lateral to the utero-sacral ligament during resection of the
utero-sacral ligaments;
 The preservation of the inferior hypogastric plexus during
resection of the cardinal ligament, as the plexus lies dorsal to
the parametrial vessels at the level of the deep uterine vein; a

29
  The preservation of the bladder branch during resection of the
deep layer of the cervico-vesical ligament (Maneschi 2014).

Comparative studies of RAH and NSRH support the current

opinion that the nerve-sparing technique is associated with faster
postoperative restitution of lower urinary tract function. Similarly,
laparoscopic NSRH should be related to shorter catheterization time and a
lower rate of voiding dysfunctions compared with laparoscopic radical
hysterectomy (Van Gent et al., 2017).

Sentinel lymph node (SLN) concept in cervical cancer

Sentinel lymph node (SLN) biopsy, instead of systematic pelvic

lymph node dissection (PLND), is increasingly being used in the standard
management of early-stage cervical cancer. The benefit for the patient is
obvious. Less-radical lymph node (LN) dissection diminishes the risk of
lower-leg lymphoedema, which is a severe morbidity that persists for life.
New ESGO/ESTRO/ESP (European Society of Gynaecological
Oncology/European Society for Radiotherapy and Oncology/European
Society of Pathology) guidelines recommend performing SLN biopsy as
the first step of the primary surgical management in all early stages of
cervical cancer (except T1a1) and submitting the SLNs for intraoperative
assessment to triage patients towards radical surgery or definitive
chemoradiotherapy (Dostalek et al., 2018).

These guidelines even accept SLN biopsy without additional

PLND as a preferred method of LN staging in stage T1a cervical cancer.
The National Comprehensive Cancer Network (NCCN) guidelines also
recommended performing SLN biopsy in addition to PLND as an

30
alternative option for LN staging in the early stages of cervical cancer
(NCCN 2016).

SLN biopsy is considered to be more accurate in the assessment of

pelvic LN involvement than a complete PLND. Higher accuracy,
manifested as more frequent detection of positive LNs, is a result of an
intensive pathological assessment of a small number of SLNs. This
pathological ultrastaging increases the probability of finding smaller
metastases. For the pathologist (and pathology department), this is a
demanding and time-consuming technique, which cannot be applied to all
pelvic LNs in systematic PLNDs (Brar and Hogen, 2017).

Dual labeling using blue dye and radiocolloid increases the

accuracy of sentinel lymph nodes can be performed with. Indocyanine
green dye with near infrared technique has been used in robotic surgery
and laparoscopy. Pelvic lymphadenectomy needs to be considered if
LVSI is present (Hauspy et al., 2007).

Clinical practice has been shifting towards the acceptance of the

replacement of full PLND by SLN biopsy in the management of cervical
cancer patients. Besides decreasing morbidity due to the abandonment of
PLND, SLN biopsy offers other benefits. It enables intraoperative
assessment of key pelvic LNs and tailoring of patient management in one
step. It also improves LN staging by detecting up to 15% of additional
patients with LN involvement secondary to intensive pathological
utrastaging (David and McCluggage, 2018).

31
Neoadjuvant chemotherapy in cervical cancer

Treating cervical cancer with radical surgery alone usually leads to

high recurrence rate and greatly affects the patient quality of life
(Shepherd 2009).

The mechanism of chemotherapy is to prevent the proliferation

infiltration and metastasis of cancer cells (Wagner et al., 2005).

Clinically, postoperative chemotherapy is often adopted to

eliminate microscopic cancer lesions remaining after surgery and improve
the efficacy of surgery (Sun et al., 2018).

Mahmoud et al. demonstrated in their study that neoadjuvant

chemotherapy can improve the quality of life of patients with cervical
cancer (Mahmoud and Einstein, 2018).

Whether preoperative neoadjuvant chemotherapy combined with

radical surgery can significantly improve the efficacy of traditional
radical treatment and the survival of patients is very worthy of
exploration (Meng et al., 2020).

Cisplatin, one of the most widely used chemotherapeutic agents in

oncology, which is commonly used in the treatment of reproductive sys-
tem tumors, is one of the most typical drugs in combination
chemotherapy. Cisplatin mainly achieves its anti-tumor effect by
inhibiting DNA replication. Its inhibition on the human hematopoietic
system usually occurs after around 3 weeks of chemotherapy. Scandurra
et al found that the combination of paclitaxel-ifosfamide-cisplatin (TIP
chemotherapy), was highly efficient in treating advanced or recurrent
cervical cancer with low toxicity (Scandurra et al., 2015).

32
 Paclitaxel is a taxane with anticancer activity, which has good
efficacy in ovarian cancer when combined with cisplatin. Therefore,
paclitaxel and cisplatin were selected as drugs of the preoperative
neoadjuvant chemotherapy in this study (Kinjyo et al., 2017).

Patients received neoadjuvant chemotherapy before surgery:

liposomal Paclitaxel for injection was intravenously injected at a dose of
135 mg/m2, Cisplatin injection was intravenously injected at a dose of
100 mg/m2. The second chemotherapy cycle followed after three weeks
of the first chemotherapy. After 2 to 3 cycles of chemotherapy, patients
who met the surgical conditions were radically operated for cervical
cancer (Meng et al., 2020).

On the one hand, the application of preoperative neoadjuvant

chemotherapy in patients with cervical cancer can significantly improve
the treatment efficacy and reduce metastasis to the lymph nodes; while on
the other hand, it can increase the incidence of adverse reactions, impact
the patient quality of life and create worries about complications (Meng
et al., 2020).

33
 Non-surgical management of cervical cancer

In LMICs, the majority of patients present with locally advanced

disease, where surgery plays a limited role, and radiotherapy has an
important role. Over the last two decades, development of sophisticated
planning and delivery techniques, and introduction of computer
technology and imaging have galvanized the practice of radiotherapy,
resulting in improved clinical outcome and reduced toxicity (Dutta et al.,
2015).

Although surgery is preferred for early stage disease, in cases with

contraindications for surgery or anesthesia, radiotherapy provides equally
good results in terms of local control and survival. Patients with
microinvasive disease have been treated by intracavitary radiation therapy
(ICRT) alone with good results if surgery is contraindicated owing to
medical problems. Selected patients with very small Stage IB1 disease
(less than 1 cm) may also be treated with ICRT alone, particularly if there
are relative contraindications to external beam radiation therapy (EBRT).
A dose of 60–65 Gy equivalents is usually prescribed to Point A.
Combination of EBRT and ICRT is also an option for such patients
(Landoni et al., 2017).

Following radical hysterectomy, postoperative radiotherapy with or

without chemotherapy is indicated for patients with adverse pathologic
factors such as positive pelvic nodes, parametrial infiltration, positive
margins, deep stromal invasion, etc. According to various prognostic
factors, patients may be categorized into high-risk, intermediate-risk, or
low-risk disease (Landoni et al., 2017).

34
 High-risk disease includes patients with either positive surgical
margins or lymph node metastases or parametrial spread, and such
patients should be offered PORT with chemotherapy. Intermediate-risk
patients with any two of three factors (tumor size more than 4 cm,
lymphovascular invasion, deep stromal invasion) require PORT and no
chemotherapy should be offered to these patients. All other patients
following radical hysterectomy are termed as low-risk disease patients
and do not need any adjuvant therapy (Harkenride et al., 2015).

PORT consists of whole pelvic EBRT to cover the tumor bed and
draining lymph node areas. A dose of 45–50 Gy is usually prescribed.
Intensity modulated radiation therapy (IMRT); an advanced and refined
technique of irradiation has been explored in the postoperative setting to
reduce the toxicity (Klopp et al., 2016).

Although feasible, surgery as initial treatment is not encouraged for

patients with Stage IB3 and IIA2 disease since 80% of them require
PORT or CCRT. It is well known that the addition of adjuvant
radiotherapy to surgery increases morbidity and thus compromises the
quality of life. Additionally, combined modality treatment will
unnecessarily overburden the surgical and radiation facilities, which are
already inadequate in low-resource countries. Therefore, CCRT is the
standard of care for Stage IB3 and IIA2 disease. CCRT includes external
radiation and intracavitary brachytherapy (Minig et al., 2014).

Concurrent chemoradiation is considered the standard treatment for

patients with locally advanced cervical cancer (LACC). The
chemotherapy regimen is intravenous administration of weekly cisplatin
during the course of EBRT (Vale et al., 2008).

35
 A once-weekly infusion of Cisplatin (40 mg/m2 weekly with
appropriate hydration) for 5–6 cycles during external beam therapy is a
commonly used concurrent chemotherapy regimen. For patients who are
unable to receive platinum chemotherapy, 5–fluorouracil-based regimens
are an acceptable alternative. Data on the toxicity associated with
concurrent chemotherapy and extended field irradiation are limited (Kim
et al., 2008).

The combination of EBRT and ICRT maximizes the likelihood of

locoregional control while minimizing the risk of treatment
complications. The primary goal of EBRT is to sterilize local disease and
to shrink the tumor to facilitate subsequent ICRT. Standard EBRT should
deliver a dose of 45–50 Gy to the whole pelvis encompassing uterus,
cervix, adnexal structures, parametria, and pelvic lymph nodes. Although
EBRT is commonly delivered by a Cobalt-60 teletherapy machine in
several low-resource countries, linear accelerators are preferred nowadays
as they provide higher energy beams resulting in more homogeneous dose
delivery to deep tissues with relative sparing of superficial tissues.
Recently, conformal radiotherapy techniques like 3D-CRT and IMRT are
increasingly being used with encouraging results in terms of reduced
toxicity owing to relative sparing of normal tissues (Bhatla et al .2018).

36