CIN and Cervical Cancer
Henok k.
Introduction and epidemiology
• Cancer of the cervix is the third most common type of cancer
in women after cancer of the breast and the endometrium
• About 2% of all women over age 40 will develop cervical
cancer
• Average age at diagnosis- 45 years
• Cervical intraepithelial neoplasia (CIN) is most commonly
detected in women in their 20s
• The peak incidence of carcinoma in situ is in women ages
25–35 years, whereas
• The incidence of cervical cancer rises most significantly after
the age of 40 years.
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prevalence
• Prevalence figures for CIN vary according to
the socioeconomic characteristics and
geographic area of the population studied,
• Low as 1.05% in some FP clinic
• High as 13.7% in women attending sexually
transmitted disease (STD) clinics
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• Cure with early detection of CIN & cervical
cancer > 95%
– long preinvasive state
– treatment of preinvasive lesions is effective
• In third world countries, where limited health
care resources exist,cervical carcinoma
remains a significant cause of mortality
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Etiology
Causal agent- HPV
Cofactors- herpes virus and Chlamydia trachomatis
Risk factors
• Young age at first coitus (<20 yr)
• Multiple sexual partners
• Young age at first pregnancy
• Lower socioeconomic status
Multiparty & long-term oral contraceptive pill use
Human papillomavirus (HPV 16, 18, 31) infection
80% for CIN and 99.7 for invasive cx ca
Cigarette smoking 2-4X with HPV
Immunosuppressant ( HIV /AIDS)
Post-menopause
Based on their malignant potential, HPV subtypes
are categorized into low-risk and high-risk types.
• Low-risk HPV types (eg, types 6, 11, 42, 43, and
44) are associated with condylomata and low-
grade lesions (CIN I)
• High-risk HPV (such as types 16, 18, 31, 33, 35,
39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) is, in
addition to high-grade lesions (CIN II and CIN III),
found in invasive cancer.
Among the more than 40 genital mucosal HPV types identified,
approximately 15 are known to be oncogenic .
Subtypes HPV 16 and 18 are found in over 70 percent of all cervical
cancers.
The infection is considered necessary for development of cervical
neoplasia, but HPV alone is not sufficient to cause these disorders .
The two major factors associated with development of high grade
lesions and cervical cancer are HPV subtype and persistence.
Anatomy and transformation of the cervix
• The cervix is composed of
– columnar epithelium, which lines the endocervical
canal, and
– squamous epithelium, which covers the exocervix .
• The point at which they meet is called the
squamocolumnar junction (SCJ)
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squamocolumnar junction (SCJ)
• dynamic point that changes in response to
puberty, pregnancy, menopause, and
hormonal stimulation
• Under certain circumstances the ectocervix
will be changed to columnar epi.
• Over a period of time ectocervix is again
replaced….......squamous epi.
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transformation zone and the SCJ during a
woman's lifetime
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• Metaplasia advances from the original SCJ inward,
toward the external os and over the columnar villi.
• This process establishes an area called the
transformation zone which extends from the
original SCJ to the physiologically active SCJ.
• Cervical intraepithelial neoplasia (CIN) arises in an
area of metaplasia in the transformation zone at the
advancing squamocolumnar junction (SCJ) in most
cases.
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The cervix and the transformation zone.
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CIN is most likely to begin either during menarche
or after pregnancy, when metaplasia is most active
after menopause, metaplasia is less active and a
woman has a lower risk of developing CIN.
In most cases, CIN is believed to originate as a
single focus in the transformation zone at the
advancing SCJ.
early metaplastic cells is susceptible to oncogenic
factors
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Columnar epithelium
low PH
Physiologic well differentiated Atypical metaplasia due to effect
sqaumous epithelium of env. Factor- HPV
Only dysplasia
Beyond dysplasia
16
Inadequate host response
dysplasia
Carcinoma in situ
Invasive carcinoma
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Cervical intraepithelial neoplesia (CIN)
Cervical intraepithelial neoplesia (CIN) is a premalignant cervical
disease that is also called cervical dysplasia
Disordered growth and development of cervical epithelium.
Pre-invasive conditions of the cervix which has various degrees
It takes 10-17 years to change into malignant cervical disease
Cont...
But as the women get older, this SCJ averts outward onto the
ectocervix.
The exposure of the columnar epithelium to this low pH stimulates
squamous metaplasia, the conversion of one type of normal epithelium
(columnar) into another (squamous).
This creates a zone of metaplastic epithelium termed the transformation
zone (TZ), between the original SCJ and the columnar epithelium
Cont…
Once this meta plastic epithelium is infected, the virus can either
persist in the cytoplasm or integrate into the host genome.
When HPV remains in an episomal nonintegrated state, the result is a
low grade lesion.
When the virus becomes integrated into the human genome, Viral
integration results in the disabling of two major tumor suppressor
genes, p53 and retinoblastoma protein , thus high grade lesions and
cancer may develop.
Upregulation of the viral oncogenes E6 and E7
E7 protein binds to the pRB protein production of
proteins required for cellular DNA synthesis
◦ ordinarily lead to activation of epithelial cell p53
protein, an important protector of the normal cell cycle
However, the HPV E6 protein targets p53 for
proteolytic degradation, allowing oncogenic HPV
types to bypass this key cellular control
mechanism.
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Histological Degree of CIN
• CIN=Dysplasia= pre-invasive lesion
– abnormal maturation
CIN I, Mild dysplasia ,defined as disordered growth of the lower third
of the epithelial lining.
CIN II ,moderate dysplasia ,the dysplasia involves the lower two-thirds
of the epithelial lining.
CIN III ,Severe dysplasia encompasses full-thickness of the epithelial
thickness, this is called carcinoma in situ (CIS)
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Clinical Findings of CIN
There are usually no symptoms or signs of CIN.
The diagnosis is most often based on biopsy findings following an
abnormal routine cervical cytology smear.
Special Examinations
Pap smears
VIA
Biopsy
Schiller test ,Colpos copy and HPV testing
Initiation of Screening
Screening should begin approximately 3 years after coitarche or by age 21
Annually.
After age 30, women at average risk for cervical cancer can be screened at 2-
to 3-year intervals if three consecutive, annual negative Pap tests have been
documented.
Cervical cytology screening may be discontinued at age 70 years
if the patient had 3 or more consecutive normal smears in the
preceding 10 years.
Screening cytology smears may also be discontinued if the
patient has undergone a total hysterectomy, unless it was done for
the treatment of cervical dysplasia or cancer.
NB Women with high-risk factors should be screened annually at least once.
Visual Inspection
simple visual inspection of the cervix after
application of acetic acid
Areas of cervical dysplasia turn white after
application of acetic acid
Although visual inspection with acetic acid is not as
specific as cytology, it is almost as sensitive ,Cheaper,
faster and simpler than colposcopy.
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HPV testing
Testing for high-risk HPV types has been investigated
as an intermediary test for patients with minimally
abnormal cervical cytology smears
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Colposcopic Examination
• Colposcopy is the primary technique for the evaluation of an
abnormal cervical cytology smear
• after the application of 3–5% aqueous acetic acid solution
• If the new squamocolumnar junction is visualized in its entirety,
the colposcopic examination is called satisfactory; if it cannot be
fully visualized, the examination is called unsatisfactory ECC
for this
• Indications for colposcopy are:
1. Abnormal cervical cytology smear or HPV testing;
2. Clinically abnormal or suspicious-looking cervix;
3. Unexplained intermenstrual or postcoital bleeding;
4. Vulvar or vaginal neoplasia; or
5. History of in utero diethylstilbestrol (DES) exposure.
Diagnostic conization
Following expert colposcopic evaluation, diagnostic
conization of the cervix is indicated:
if colposcopy is unsatisfactory,
if the lesion extends into the cervical canal beyond the
view afforded by the colposcope,
if there is dysplasia on the endocervical curettage,
if adenocarcinoma in situ is suspected, or
if microinvasive carcinoma is suspected.
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Diagnosis steps
• PAP SMEAR (cytology)
Hist
ologi • HPV testing
cal
visu • Visual Inspection/colposcopy
alize
• punch biopsy
• endocervical curettage (ECC)
invas
ive • Diagnostic Conization
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Papanicolaou smear (Pap smear)
Preparation
Patients should abstain from intercourse and douching for a minimum
of 24 to 48 hours before a test
Sampling Tools
Bivalve Speculum
Over head light
Spatula
Cotton tipped applicator
Two slide
Cytological interpretation of result
Bethesda System Cytology Report Components
1. ASC-US Atypical squamous cells undetermined significance
2. ASC-H Atypical squamous cells high grade lesion cannot be
excluded
3. LSIL Low-grade squamous intraepithelial lesion consistent with
CIN I
4. HSIL High-grade squamous intraepithelial lesion corresponding to
CIN II and CIN III
The Schiller
Lugol's solution is an aqueous iodine preparation and is commonly used
for the Schiller test.
The Schiller test is based on the principle that normal mature squamous
epithelium of the cervix contains glycogen, which combines with iodine
to produce a deep mahogany-brown color.
Non staining, therefore, indicates abnormal squamous (or columnar)
epithelium, scarring, cyst formation, or immature metaplastic
epithelium, and constitutes a positive Schiller test.
Natural History
• expectantly follow the compliant patient with
CIN I using surveillance with serial cervical
cytology smears at 6-month intervals or an HPV
test at 12 months.
• The majority of high-grade lesions will persist
or progress so immediate treatment is generally
warranted.
• patient's age, the inciting HPV type, the patient's
immune competence, and smoking habits
Natural History
VIA
Treatment
1. Cryotherapy
2. Carbon Dioxide Laser
3. Loop Electrosurgical Excision Procedure
4. Conization
Cryotherapy
Nitrous oxide or carbon dioxide is used as the refrigerant for a super
cooled probe.
The cryoprobe is positioned on the ectocervix where it must cover the
entire lesion
It is then activated until blanching of the cervix extends at least 7 mm
beyond the probe in all directions
Carbon Dioxide Laser
Carbon dioxide (CO2) laser can be used to ablate the transformation zone
The laser destroys tissue with a very narrow zone of injury around the
treated tissue.
The tissue is vaporized to a depth of at least 7 mm.
Loop Electrosurgical Excision Procedure(LEEP)
LEEP uses a small, fine, wire loop attached to an electrosurgical
generator to excise the tissue of interest and is the procedure of choice for
treating CIN II and CIN III.
Conization:
Refers to the excision of a cone-shaped portion of the cervix using a
scalpel.
This technique can be individualized to accommodate the cervical
anatomy and the size and shape of the lesion
Cervical cancer
Introduction
Cervical cancer is the most common gynecologic malignancy in the
world.
The third most frequently diagnosed cancer in women worldwide after
breast and colo-rectal cancer.
But number one killer
The majority of cases occur in developing countries
Have declined in most developed countries
Cont...
This decrease is mostly attributed to .
1. Introduction of effective screening techniques.(18.9 ????
2. Effective treatment at intraepithelial neoplesia
3. Many years needed for the malignancy to develop since CIN
Clinical Presentation
Symptoms and signs
Enlarged lymph nodes supraclavicular or inguinal lymphadenopathy
Abnormal vaginal bleeding (post examination post coital bleeding, or
postmenopausal bleeding)
Abnormal vaginal discharge (Yellowish vaginal discharge, at times foul
smelling, may occur particularly in large tumors)
Fistula (Bladder or rectal invasion by advanced-stage disease may produce
urinary or rectal symptoms ( vaginal passage of stool or urine, hematuria,
urinary frequency, hematochezia).
Other patients may present with symptomatic anemia or pelvic pain
Cont...
Fungated cervix ,cauliflower like lesion of the portio vaginalis.
A watery, purulent, or bloody discharge may also be present.
lower extremity edema, ascites, or decreased breath sounds with
lung auscultation may indicate metastases.
Spread of Disease
1. Direct Extension
2. Lymphatic Spread.
3. Blood-Borne Metastasis
Stages of cervical cancer
Has five stages – 0 to 4
1. Stage 0 Carcinoma in situ
2. Stage 1 Invaded cervix, but has not spread.
3. Stage 2 Has spread to nearby areas, not leaving pelvic area.
4. Stage 3 Cancer has spread to the lower part of the vagina.
5. Stage 4 Cancer has spread to nearby organs; metastasis.
Diagnosis - history
asymptomatic women
◦ cervical cancer is most commonly identified through
evaluation of abnormal cytologic screening tests.
Abnormal vaginal bleeding is the most common
symptom
◦ Irregular or heavy vaginal bleeding
◦ Post coital bleeding
Leukorrhea, usually purulent, odorous,
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…
advanced disease
– Pelvic pain, often unilateral and radiating to the
hip or thigh
– involuntary loss of urine or feces through the
vagina, a sign of fistula formation.
late stages of the disease
– Weakness, weight loss, and anemia
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Physical examination
enlargement, irregularity, and a firm
consistency of the cervix
growth pattern can be endophytic/ exophytic
barrel-shaped enlargement bleeding, flower
like lesion
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Investigations
Biopsy
Colposcopy - abnormal blood vessels, irregular
surface contour with loss of surface epithelium,
and color tone change.
Conization
Radiologic – CXR , CT ,MRI
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Treatment
Radical abdominal or hysterectomy
Primary radiation therapy can be used for all stages of disease and
for most patients
Chemotherapy. Single-agent chemotherapy is used to treat patients
with extra pelvic metastases
Adjuvant chemotherapy is referred to the administration of
chemotherapeutic agents before or after radical hysterectomy
Prevention
• How can we prevent cervical ca
prevention
– Avoid multiple sexual partner (1-to-1)
– Avoid early sex
– Avoid smoking
– Screening
– Stop smoking
– ART drugs
– HPV vaccines
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• Education of young women and men about risk factors and
the necessity for regular screening
• Universal cytologic screening of all postpubertal women
• Women with preinvasive cervical neoplasia should be
treated and followed up closely
• Sexual abstinence is an effective but impractical
prophylactic measure
• Information about the association. HIV infection and
smoking with the development of cervical cancers, is
crucial
• Several HPV vaccines are currently in advanced stages of
development
• Nearly 60% of women who develop cervical cancer in developed
countries either never had been screened
• must be continued on a regular basis until better, more sensitive and
specific means of screening are found, and outreach into underserved
areas is improved .
• It is important to remember that cervical cytology smears are of limited
value in detecting frankly invasive disease, with some studies finding
false-negative rates up to 50, as well as
• Gardasil a quadrivalent vaccine against HPV 16/18/6/11 received FDA
approval in the United States in June 2006 for use in girls and women 9–
26 years old. To date, large trials have demonstrated that the vaccines are
generally safe, well tolerated and highly immunogenic with excellent
efficacy in the prevention of persistent HPV infection and against the
development of cytologic abnormalities.
