Cervical intraepithelial neoplasia

• Cervical intraepithelial neoplasia (CIN)

is a premalignant condition of the cervix.

• It is usually asymptomatic and is detected

by routine cytological screening.
Risk factors :
1. Behavioral :
• Early coitarche
• Multiple sexual partners
• Male partner who has multiple sexual partners.
1. Human papilloma virus (HPV)
2. Smoking
3. Imunosuppression
4. Dietary deficiencies
5. Oral contraceptive pills
6. Poor uptake of screening programs.
7. Indirect risk factors
• High parity
• Low socioeconomic status
• Ethnicity: Black races
 Pathophysiology
• The ectocervix is covered by stratified squamous
epithelium.
• The canal of the cervix is lined by columnar
epithelium .
• point where these two epithelia meet is called the
squamocolumnar Junction .
• It lies just at the external os, but as the cervix increases
in volume during puberty and also pregnancy, the SCJ is
said to roll out onto the ectocervix.
• The delicate columnar epithelium exposed to the acid
environment of the vagina undergoes a process of
metaplasia whereby it becomes squamous epithelium.
Cont.Pathophysiology:
• The transformation zone
is that part of the cervix that
extends from the widest
part of skin that was
originally columnar
epithelium into the current
SCJ.
:Cont.Pathophysiology
 Dysplasia occurs in the stratifies squamous epithelium
leading to disordered squamous epithelium.
 HPV is a factor in the dysplastic changes.
 Smoking and immune suppression appear to be
additional factors .
 Dysplastic epithelium lacks the normal maturation of
cells .
 Dysplasias are now usually referred to as cervical
intraepithelial neoplasia (CIN).
 :Dysplastic changes
• Architectural changes:
– Loss of stratification of cells
– Loss of differentiation of cells
• Nuclear changes:
– Hyperchromasia
– Increase N\C ratio
– Anisonucleosis
– Presence of mitotic figures
Grades of CIN
They are graded as mild, moderate or severe,
depending on:
– The degree of cytological atypia
– The thickness of the epithelium involved.

 CIN I.
 CIN II.
 CIN III.
 CIS .

CIN I is considered as ' low-grade squamous intraepithelial

lesions (LSIL) ' and CIN II and III as 'high-grade SIL
(HSIL)'.
Grading
:Prognosis
• Without treatment, 30 - 50% of cases of severe
cervical dysplasia may lead to invasive cancer.
• Progression to cancer typically takes 15 (3 to 40)
years.
• Evidence suggests that cancer can occur
without first detectably progressing through
these stages and that a high grade
intraepithelial neoplasia can occur without first
existing as a lower grade.
:Diagnosis
1. Cytology - cervical smears(Pap
smear):
 Cont.diagnosis :
1. Cytology - cervical smears(Pap
smear):

:Three components of Pap smear

).V. Posterior vaginal fornix: (by blunt end of spatula
C. Exocervical (TZ) by 360o rotation of bifurcated end of spatula into
.external os
E. Endocervical: by mopping endocervical secretions using cotton-tipped
.rod
Cont.diagnosis :
1. Cytology - cervical smears(Pap
smear):

Results:
• Normal (negative) smear: with no dyskaryosis
at all-women having negative smears are
assured and advised for annual smear later.
• Abnormal (positive) smear: with variable
degrees of dyskaryosis: mild, moderate or
severe.
 Cont.diagnosis :
2.Colposcopy
• The cervix is first examined
for abnormal vessel patterns
• premalignant and malignant
lesions of the cervix
abnormal findings includes:
1-Leukoplakia: white lesions without
adding acetic acid.
2-Aceto white lesions: white lesions
on adding acetic acid.
3- Abnormal blood vessels:
punctate,mosaicism,cork
skrew,spagetti like.
:Cont.diagnosis
2.Colposcopy
Findings may be:
-Normal colposcopy.
-Abnormal colposcopy.
-Unsatisfactory colposcopy: can't visualize
T-zone.
:Cont.diagnosis
3.Schiller's iodine test
Normal, mature squamous epithelium contains
abundant glycogen that stains dark brown with
iodine, and the test involves the application of
Lugol's iodine solution to the ectocervix.
Results:
• Negative: The normal squamous epithelium
will stain dark brown
• Positive: Abnormal squamous epithelium will
not.
:Cont.diagnosis
4.Cervical biopsy

• Biopsy will be taken from the most abnormal

areas of the epithelium to confirm the
diagnosis.
• Types:
1. Directed Biopsy: by Colposcopy or Schiller's test
2. Endocervical curettage (ECC): in unsatisfactory
colposcopy.
3. Cone Biopsy: (Diagnostic conization).
Cont.diagnosis
4.Cervical biopsy

Cone Biopsy:
Conization is both a diagnostic and therapeutic
procedure
Indicated in:
• Unsatisfactory colposcopy/+ve ECC
• Multifocal lesion
• Suspicion of microinvasion
• Discrepancy between Pap smear, colposcopy and biopsy.
Treatment of CIN
• CIN has the potential to be an invasive
malignancy but does not have malignant
properties so treatment involves completely
removing the abnormal epithelium. This can be
done either by an excisional technique or by
destroying the abnormal epithelium.
,(:Treatment of CIN (cont
Ablative therapy is appropriate when the following
conditions exist:
• There is no evidence of microinvasive or
invasive cancer on cytology, colposcopy,
• endocervical curettage, or biopsy.
• The lesion is located on the ectocervix and can
be seen entirely.
• There is no involvement of the endocervix with
high-grade dysplasia as determined by
• colposcopy and endocervical curettage.
,(:Treatment of CIN (cont
• Cryotherapy
• Laser Ablation
• Loop Electrosurgical Excision
• Conization
• Hysterectomy
:Invasive Cervical cancer
• Cervical cancer is the second most common
malignancy in women worldwide.
• Internationally, 500,000 new cases are
diagnosed each year.
• Cervical cancer is more common in Hispanic,
African American, and Native American women
than in white women.
• Cervical cancers usually affect women 40 – 50
years old, but it may be diagnosed in any
reproductive-aged woman.
Causes & Risk factors
• HPV infection
• Lack of regular Pap tests
• Smoking
• Weakened immune system
• Sexual history
• Using birth control pills for a long time:
• Having many children
• DES (diethylstilbestrol) in utero exposure
Having an HPV infection or other risk factors does not mean that
a woman will develop cervical cancer. Most women who have
risk factors for cervical cancer never develop it.
Clinical
Symptoms:
• Clinically, the first symptom is abnormal vaginal
bleeding, usually postcoital.
• Vaginal discomfort, malodorous discharge, and
dysuria are common.
• tumor growth:
constipation, fistula, and ureteral obstruction frequency, dysuria and
hematuria, leg edema, pain, and hydronephrosis, back aches
Somatic pain Deeply seated pelvic pain, loin pain
• Pelviabdominal mass
Clinical
• Signs:
 General:
• Cachexia in advanced cases
• Ureamia if the ureter is compressed
• Leg edema suggests lymphatic/vascular obstruction from tumor.
 Abdominal:
• Kidneys may be enlarged if hydronephrosis occurred,
Pelviabdominal mass may be felt in case of pyometria with tender
uterus & high fever.
• If the disease involves the liver, hepatomegaly may develop.
•
 Clinical
 Vaginal:

• 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 examination findings often reveal pelvic metastasis.
Staging
Tumor spread

• LYMPHATIC SPREAD

• LOCAL TUMOR EXTENSION

• DISTANT METASTASIS: lungs, ovaries, liver, and bone are the

most frequently affected organs.

• DIRECT IMPLANTATION
into lower part of vagina or vulva may occur during operation
Workup
• Cytology - cervical smears

• Colposcopy

• Schiller's test

• After the diagnosis is established, a complete blood cell

count and serum chemistry for renal and hepatic
functions should be ordered to look for abnormalities
from possible metastatic disease.
Imaging Studies
• A routine CXR should be obtained to help rule out pulmonary
metastasis.
• CT scan & MRI of the abdomen and pelvis is performed to
look for metastasis in the liver, lymph nodes, or others
• In patients with bulky primary tumor, barium enema studies
can be used to evaluate extrinsic rectal compression from the
cervical mass.
• IV pyelography to detect ureteric obstruction or presence of
non functioning kidney.
• The use of positron emission tomography (PET) scan is
recommended for patients with stage IB2 disease or higher
• US of the abdomen and pelvis to detect local extension to
adjacent organs, hepatic metastasis, & lymph node
enlargement.
CT scan of a large,
lobulated mass that is Transverse
replacing the cervix TVUS shows a
and circumscribed
MRI of stage IIb
cervical cancer with hypoechoic
anterior parametrial tumor in the left
and anterior vaginal posterior aspect
fornix invasion of the cervix
Treatment
• Preventive measures:
A. Vaccination
Human Papillomavirus (HPV) vaccine:
:Human Papillomavirus (HPV( vaccine
• Is a vaccine that prevents infection with certain species
of human Papillomavirus associated with the
development of cervical cancer, genital warts, and some
less common cancers. Two HPV vaccines are currently
on the market: Gardasil and Cervarix. Both vaccines
protect against two of the HPV types (HPV-16 and HPV-
18) that can cause cervical cancer.
• Both gardasil and cervarix have shown a nearly 100%
efficacy in preventing development of cervical cancer for
the HPV strains that they are targeted
• This effect has lasted 4 years after vaccination for
gardasil and more than 6 years for cervarix.
Safety
• Studies found that the HPV vaccine was safe and
caused no serious side effects. The most common
adverse event was injection site pain. This reaction was
common but mild.
• There have been reports of syncope after vaccination.
Syncope after any vaccination is more common in
adolescents
• Guillain-Barré Syndrome (GBS)has been rarely reported
after vaccination
 Targeted populations
• It’s recommended for women who are 9 to 25 years old
who have not been exposed to HPV
• Currently the vaccine is not recommended for pregnant
women. The long-term effects of the vaccine on fertility
are not known, but no effects are anticipated.

• In the UK, HPV vaccines are licensed for boys aged 9–15 & they
have been FDA approved for use in males age 9 to 26 for
prevention of genital warts and precancerous lesions caused by
HPV.
 Mechanism of action
• The latest generation of preventive HPV vaccines is
based on hollow virus-like particles assembled from
recombinant HPV coat proteins. The vaccines target the
two most common high-risk HPVs, types 16 and 18.
Together, these two HPV types currently cause about 70
percent of all cervical cancer. Gardasil also targets HPV
types 6 and 11, which together currently cause about 90
percent of all cases of genital warts.
• Gardasil and Cervarix are designed to elicit virus-
neutralizing antibody responses that prevent initial
infection with the HPV types represented in the vaccine.
:Administration
• The vaccine should be delivered through a
series of three intra-muscular injections over a
six-month period. The second and third doses
should be given two and six months after the
first dose.
• The vaccine can be administered at the same
visit as other age-appropriate vaccines.
• Providers should consider a 15-minute waiting
period for vaccine recipients following
vaccination.
,(:Preventive measures (cont

B. Screening & proper treatment of CIN

• Cervical cancer screening recommendations have not
changed for females who receive the HPV vaccine
• Cytological & colposcopical screening

C. Others
• Male circumcision
• Penile hygiene
• Use of condoms to prevent STDs
Active treatment
 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.
:Surgical treatment
i. Extended hysterectomy
• It's indicated in stage I A. It involves removal of the uterus – adnexa –
upper vagina – parametrium & pelvic lymph nodes all in one mass.

ii. Werthiem hysterectomy (radical abdominal hysterectomy & bilateral

dissection of pelvic lymph nodes)
• It's indicated in stages I B & II A. It involves removal of uterus – adnexa –
upper vagina – parametrium - & pelvic lymph nodes all in one mass
• The ovaries may be preserved in young females to avoid post
menopausal manifestations as they are rarely involved in cervical
carcinoma

iii. Radical vaginal hysterectomy ( schuata operation ) :

• This operation include removal of uterus – adnexa – vagina –
parametrium without removal of pelvic lymph nodes
 ,(:Surgical treatment (cont
iv. Pelvic exentration (ultra radical surgery):
• Indicated in stage IV A. It includes:
i. Anterior Pelvic exentration
• It's indicated if there is extension to urinary bladder. It consists of radical
abdominal hysterectomy & removal of urinary bladder with implantation
of ureters into an ileal loop
ii. Posterior pelvic exentration
• It's indicated in case of rectal involvement. It consists of radical
abdominal hysterectomy & removal of the rectum with aterminal
colostomy
iii. Total pelvic exentration
• It's indicated in case of spread to both rectum & urinary bladder. It It
consists of radical abdominal hysterectomy & removal of both the
bladder and rectum with implantation of the ureters into an ileal loop &
a terminal colostomy is performed.
Pelvic exentration Werthiem hysterectomy
:Radiotherapy
 It's recommended in:
• All stages of invasive cervical carcinoma.
• Combined with surgery.
• Palliative treatment.

 It has a lethal effect on cancer cells as well as indirect

effect through fibrosis of stroma and devascularization .
 A carcinocidal dose of cervical carcinoma is about 8000
rad fractionated over a period 4-5 weeks
,(:Radiotherapy (cont
 2 methods are used to deliver that dose:

• Teletherapy ( external beam whole pelvic

irradiation ):
• It aims at:
• Shrinkage of primary cervical tumor mass to make the
subsequent intra cavitery radiation more effective
• Treat pelvic lymph node involvement
,(:Radiotherapy (cont
• Brachytherapy (intra cavitary radiation ):
• Using caesium or radium deliver a lethal dose of
irradiation to primary cervical tumor & adjacent
parametrium. Three techniques are used: Stockholm,
Paris & Manchester techniques.
• The radium contained in tubes is introduced into cervical
canal & uterine cavity after gentle dilatation of the cervix
under anesthesia. Radium contained in ovoids is placed
in the vault of vagina. The vaginal fornices are packed
with gauze to keep radium containers in place.
,(:Radiotherapy (cont
 Contraindications of radiotherapy:
• Radio resistant adenocarcinoma
• Recurrence after irradiation
• Stage IV B (distant metastasis)
• Bladder or rectal involvement
• Pelvic sepsis
• Vaginal stenosis
• Associated fibromyoma or ovarian cyst
• Late pregnancy
,(:Radiotherapy (cont
Complications of radiotherapy:
• Radiation sickness
• Cystitis, proctitis, urinary or rectal fistula
• Sepsis
• Vaginal stenosis
• Menopausal symptoms
• Avascular necrosis & spontaneous
fracture of neck of femur
:Combined surgery and radiotherapy
 It aims at preventing recurrence & improving the 5
years survival rate and include using different
combinations
i. Preoperative intracavitary radium followed by a radical
surgery
ii. External pelvic irradiation followed by a radical
surgery,
iii. Full irradiation with intracavitary radium followed by
pelvic lymphadenectomy,
iv. Radical surgery followed by post operative external
pelvic irradiation for pelvic lymph nodes.
:Palliative treatment
Pain relief:
• Analgesics & narcotics e.g. Pethidine or
morphia
• Intrathecal injection of phenol
• Lateral cordotomy (cutting spinothalamic
tract which is the pain pathway to higher
cortical centers)
• Posterior rhizotomy (cutting post. Roots of
of spinal nerves to relieve somatic pain)
,(:Palliative treatment (cont
 Control bleeding:
• Packing the vagina with gauze
• Ligation of cervical branch of uterine artery
• Electrocautery or cryosurgery
• Ligation of internal iliac artery
 Palliative radiotherapy: to deal with recurrence after
surgery or to relieve pain of secondaries
 Palliative chemotherapy: may be used tin advanced
cases or to treat recurrence after surgical or
radiological treatment or in case of secondaries
Treatment of cervical cancer In
:pregnancy
 Depends on duration of pregnancy and stage of
disease:
• In early pregnancy: Radical hysterectomy in
operable cases (stages I & II A) or radiotherapy
after evacuation of uterus irrespective of stage of
the disease
• In late pregnancy: C-section is performed
followed by: Radical hysterectomy in operable
cases (stages I & II A) or radiotherapy
irrespective of stage of the disease.