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BY PROF. DR. AHMED EL TAGY Prof. of Obst. & Gyn. AL AZHAR UNIVERSITY E-mail: Tagy_5@hotmail.com
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I.L.O.
PRECANCEROUS LESIONS (CIN)
Definition Epidemiology Etiology & pathogenesis (Carcinogenesis) Morphology & clinical picture Grades Treatment

Cervical carcinoma was once the most frequent form of cancer in women around the world only 50 years ago.
Over 80% of women newly diagnosed live in developing countries; most are diagnosed when they have advanced disease. An estimated 95% of women in developing countries have never been screened for cervical cancer.

The widespread use of Papanicolaou (cytologic) screening has:

Dramatically lowered the incidence of invasive tumors Decreased cervical carcinoma by 50% to 85% in Western countries.

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** mortality rate has fallen by 70%.

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By contrast, the incidence of precursor cervical intraepithelial neoplasia (CIN) has increased (this being in part attributable to better case finding) to its present level of over 50,000 cases annually.
Cytologic examination can detect CIN (SIL) long before any abnormality can be seen grossly.

CERVICAL CANCER SCREENING IN THE USA

* Approximately 50 million Pap tests

done annually.

3.5 million ( 7%) interpreted as abnormal.

* 800,000 LSIL (1.6%); ~

1600 women with LSIL have invasive cervical carcinoma (0.2 %)

* 250,000 interpreted as HSIL; ~

2500 women with HSIL have invasive cervical carcinoma (1.0-2.0%)
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CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN), SQUAMOUS INTRAEPITHELIAL LESION (SIL)

On the basis of histology, precancerous changes are graded as follows: CIN I : Mild dysplasia CIN II : Moderate dysplasia CIN III : Severe dysplasia and carcinoma in situ
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In cytologic smears : The precancerous lesions are separated into only two groups: A. Low-grade, correspond to CIN I Regression is 50% to 60%. Persistence is 30%. Progression to CIN III, 20%. Only 1% to 5% become invasive.
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B.

High-grade SIL, correspond to CIN II or III. Regression Progression only 33% 6% to 74% (in various studies).

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Dysplasia

It is a loss in the uniformity of the individual cells and a loss in their architectural orientation.

Dysplastic cells exhibit considerable pleomorphism (variation in size and shape) and often possess deeply stained (hyperchromatic) nuclei that are abnormally large for the size of the cell.
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Mitotic figures are more abundant than usual. Frequently the mitoses appear in abnormal locations within the epithelium.
In dysplastic stratified squamous epithelium, mitoses are not confined to the basal layers, where they normally occur, but may appear at all levels and even in surface cells.
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Carcinoma in situ is characterized by highly atypical cells at all levels of the epithelium but not break through the basement membrane.

When these cells break through the basement membrane, the process has become invasive carcinoma

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Physiological and neoplastic changes in the cervical transformation zone:

Before puberty, the squamo-columnar junction lies within the endocervical canal .

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With the onset of puberty and in pregnancy, there is eversion of the columnar epithelium of the endocervix so that the squamo-columnar junction comes to lie beyond and on the vaginal aspect of the external os.
This produces the clinical appearance of a cervical 'erosion', an unfortunate term, as the change is physiological. The term ectopy is more appropriate.
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The cervical transformation zone extends from the endocervical margin of the original squamous epithelium of the ectocervix to the identified squamo-columnar junction. Over 95% of all cervical intraepithelial neoplasias (CIN) arise within the transformation zone of the cervix.

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The columnar epithelium is then exposed to the low pH of the vaginal mucus and undergoes Squamous metaplasia. This is a physiological phenomenon, and takes place through the stages of reserve cell hyperplasia and immature squamous metaplasia.

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Reserve cells, which may be derived from the cervical stroma, undermine the columnar mucus-secreting cells multiply. This labile epithelium is called the transformation zone.

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Epidemiology
The mean age at which women develop CIN is:

24 to 27 yrs. 35 to 42 yrs.

for CIN-1 and CIN-2 for CIN-3.

45 yrs.

for invasive carcinoma.

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Although invasive tumors are occasionally seen in women in their early 20s, precancerous changes usually take many years, perhaps decades, to evolve into overt carcinomas.

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Pathogenesis
Prominent risk factors for the development of CIN and invasive carcinoma. In virtually all cases, CIN and SIL arise because of infection with HPV. HPV can be detected by molecular methods in nearly all precancerous lesions and invasive neoplasms.
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HPV High Risk Types (N=13)

16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68
Solomon D, et al, 2001, JNCI 93(4):293-99
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High-risk types, including 16, 18, 31, 33, 35, 39, 45, 52, 56, 58, and 59. By contrast, condylomas, which are benign lesions, are associated with infection by low-risk types (i.e., 6, 11, 42, and 44)

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Early age at first intercourse

Multiple sexual partners

A male partner with multiple previous sexual partners. Smoking: Twice as likely as nonsmokers

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Human immunodeficiency virus (HIV) infection

Chlamydia infection: Past or present infection Diet: Low in fruits and vegetables

Oral contraceptives: Long term use

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Multiple pregnancies Low socio-economic standard (SES)

Family history of cervical cancer; mothers or sisters

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MECHANISM OF VIRAL ONCOGENESIS

The viral DNA may integrate into the host cell DNA; results in:

Neoplastic transformation of the host cell, as a result of DNA alteration or damage.

Can cause 2ry rearrangements of chromosomes, including multiple deletions.

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e.g. HPV types 16 and 18 possess genes that, after integration into the cellular genome, encode proteins that block or inactivate tumor suppressor genes

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The result is a transformed cell phenotype, capable of autonomous growth and susceptible to the acquisition of further mutations.

The recently introduced HPV vaccine is very effective in preventing HPV infections and hence cervical cancers.

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DIAGNOSIS

Clinical picture Direct visualization test. Cytology.

Colposcopy.
Biopsy.

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Diagnosis of CIN: Early diagnosis of cervical cancer

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Clinical picture:

Usually asymptomatic On examination N.A.D. Bleeds easily on contact Ectropion

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** Visual inspection :
Washing the cervix with acetic acid (VIA), either without or with a simple device to magnify the cervix e.g. a hand lens.

Suspicious areas include white patches, raised areas, areas bleeding on contact and areas of superficial ulceration.
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** Schillers iodine test:

* Grams iodine solution, consisting of one part of iodine and two parts of potassium iodine in 300 parts of water.
* Normally, the squamous epithelium homogenous deep mahogany brown stain due to formation of glycogen iodine complex.
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* The columnar, metaplastic,

dysplastic epithelium or uncovered due to ulceration will be much lighter and appear dirty yellow.

* Endocervical curettage (ECC) is

needed to cover for the possibility of the presence of endocervical lesion.

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** Cytological screening

Historical success in developed countries. High specificity, meaning women with no cervical abnormalities are correctly identified by the test with normal test results. A well characterized screening approach. May have the potential to be costeffective in middle-income countries.
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Test performance: Sensitivity and specificity

Sensitivity: The proportion of all those with disease that the test correctly identifies as positive.
Specificity: The proportion of all those without disease (normal) that the test correctly identifies as negative.
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Pap test performance:

Sensitivity = 51% for CIN I or higher

Range

of 37% to 84%

Specificity = 98% for CIN I or higher

Range of 86% to 100%

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Limitations of cytology:

Moderate to low sensitivity: High rate of false-negative test results. Women must be screened frequently.
Rater dependent.

Requires complex infrastructure.

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Results are not immediately available.. Requires multiple visits.

Likely to be less accurate among postmenopausal women.

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ALTERNATIVE PROGRAMMATIC APPROACHES:

Reduced frequency of screening:

once or twice a life time

Reducing the number of visits and

improving adherence to treatment

screen and treat (1 or 2 visits) screen, see (colposcopy), and treat

(1 to 2 visits)
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Accuracy of screening tests in developing countries: range in sensitivity and specificity

Test Cytology HPV testing VIA VILI Sensitivity 31-78% 61-90% 50-96% 44-93% Specificity 91-99% 62-94% 44-97% 75-85%

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** Colposcopy

Stereoscopic binocular microscope 6x to 40x magnification. Concentration is made on transformation zone

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Colposcopy is not a screening tool, and again it does not give a final diagnosis. It point to the site from which a biopsy can be taken in cases with abnormal cervical smear.

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Colposcopy mainly evaluates the terminal vascular network of the surface epithelium, which closely corresponds to histological changes.

In routine colposcopy a magnification of 16x is used and a green filter allows better color differentiation.

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The cervix is moistened with normal saline. 5% acetic acid is applied to the cervix. Acetic acid helps to coagulate mucus that can be easily mobbed away.
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The abnormal colposcopic findings include:

a) Atypical transformation zone 1- Leukoplakia: heavy thick white lesion, seen by the naked eye. 2- Aceto-white epithelium. 3- Punctation pattern. 4- Mosaicism. 5- Atypical vessels, comma-like, spagheti-like, corkscrew & hair-pin vessels.
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b) Suspect or frank invasive cancer.

c) Unsatisfactory colposcopic findings, the squamocolumnar junction is not visible; often in postmenopausal women.
d) Other colposcopic findings inflammatory changes, atrophic epithelium, true erosion, condylomata or papilloma.
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Colposcopic examination is frequently followed by endocervical curettage (ECC), especially in cases of unsatisfactory colposcopic findings.

C) Biopsy:
After ECC, a punch biopsy is taken under colposcopic guide

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A cone biopsy is needed if the colposcopic examination is unsatisfactory or if the ECC proves positive in malignant material.
The cone is excised using a cold fine knife.

Diathermy knife is not suitable because it will destroy a good part of the specimen.
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Large Loop Excision of the Transformation zone (LLE)

Electrified thin wire loop is used to remove the transformation zone under colposcopic guide (or after iodine staining).
The procedure combines the diagnosis and treatment.
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CAUSES OF NON-CORRELATION BETWEEN CYTOLOGY AND COLPOSCOPY

* Cervical lesion is in the endocervical

canal, or not in the cervix.

* Colposcopic findings are not apparent to

the examiner, although the lesion is present. (eg. Severe atrophy ,obscures the colposcopic findings).
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* The biopsies performed did not include

the visualized lesion.

* The laboratory did not identify the

lesion within the submitted biopsies. (Orientation of the biopsy, initial sections of the paraffin embedded tissue did not include the lesion.)

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* The cervical cytologic sample was

classified as HSIL, but only contained immature metaplastic, or atrophic squamous cells (interpretative cytology issue).

* Other issues.

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Treatment of CIN depends on :

Degree of CIN. Age 40 ys. Parity. Type of pt. I Q. Compliance for follow up. Pt. preference.

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Treatment of CIN

Wait & See. Excision:

Localized Total

Hysterectomy.
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1- Observation:
CIN I , in a young pt. who can be kept under close observation.

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MANAGEMENT OF CIN 1
Risk of follow up of CIN 1

Invasive cancer already exists and was missed by Pap, colpo and biopsy. Invasive cancer develops between follow up visits. Patient lost to follow up and develops invasive cancer.
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FOLLOW-UP: OBSERVATION VS. THERAPY

Should the Pap return as ASCUS, LSIL or HSIL, the patient should have colposcopy done, with directed biopsies if needed. If colposcopy is performed, and a lesion is identified, Colposcopic directed biopsies are indicated to establish the diagnosis.
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OBSERVATIONAL FOLLOW-UP, CIN 1

If the patient has a follow-up Pap smear that is within normal, or benign cellular changes, repeat follow-up at 4 to 6 month intervals should continue. If the smears remain within normal, or benign cellular changes, the patient may return to annual yearly screening if four consecutive smears remain unremarkable.

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The see and treat approach using electro- loop excision of any visible lesion is generally not recommended due to common treatment of non CIN lesions, and the potential unnecessary excision of part of the cervix.

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METHODS TO TREAT CIN

There are a variety of accepted methods of therapy to treat CIN, including:

* Cryosurgery ablation, * Laser ablation or excision, * Electro-loop excision, * Cone biopsy.

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Treatment of CIN:
2- Electrocautary: eradicate early CIN with a success rate of about 90%.
Cytological and colposcopic followup is required.

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3- Cryosurgery: Less painful than electrocautary and less likely to cause secondary hemorrhage.

Freon, carbon dioxide or better liquid nitrogen. Recurrence rate of only about 1%.

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4- Laser surgery: Carbon dioxide laser.

Bleeding is limited The base of destruction is clean, with little necrotic tissue and rapid healing. The depth of destruction should be 5 to 7 mm.
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5- Conization of the cervix: If the dysplasia is marked and the limits of the lesion could not be defined by colposcopy.

6- LLE of the transformation zone. 7- Total hysterectomy: Major grades of CIN in completed childbearing.
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RESULTS OF TREATMENT OF CIN

Treatment
Cryotherapy
LEEP

Total number
562
422

Cured (%)
477 (85%)
357 (85%)

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RISK OF SIGNIFICANT HEMORRHAGE ASSOCIATED WITH TREATMENT FOR CIN

Treatment No. %

Cone biopsy Laser ablation Electro-loop Cryotherapy Total

627 1419 635 1130 3811

4.6% 1.75% 1.35% 0.00%

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Prof. Dr. Ahmed El Tagy E-mail: Tagy_5@hotmail.com

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CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN):

Mild Dysplasia / CIN 1: Dysplasia confined to the lowest third of the epithelium.
Moderate Dysplasia / CIN 2: Dysplasia involving the lower two thirds of the epithelium.

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Severe Dysplasia / CIN 3: Dysplasia extending into the upper third of the epithelium, but not involving the full thickness.

Carcinoma In Situ / CIN 3: A squamous intraepithelial lesion in which nuclear abnormalities involve the full thickness of the epithelium.

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Micro Invasive Squamous Cell Carcinoma

It is the Earliest Stage (Ia) of Invasive Cervical Cancer

Microinvasive cancer features neoplastic cells that invade the stroma minimally by small clusters of malignant cells.

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Invasion to a depth of (below the basement membrane): * Less than 3 mm (stage 1a1) * 5 mm (stage 1a2) * 7 mm maximum lateral extension. About 7% of specimens removed for CIS show foci of microinvasive cancer.

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Natural history of CIN

Regress Persist

Progress Progress to CIS to invasion

CIN 1 CIN 2 CIN 3

57% 43% 32%

32% 35% < 56%

11% 22% --

1% 5% >12%

64 studies, 274 carcinomas, 15,473 CIN cases Follow up <1-12 years

str AG, Int J Gyne Path 1993;12:186-192
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There is considerable architectural anarchy. For example, the usual progressive maturation of tall cells in the basal layer to flattened squamous on the surface may be lost and replaced by a disordered scrambling of dark basal-appearing cells .

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When dysplastic changes are marked and involve the entire thickness of the epithelium, the lesion is referred to as carcinoma in situ, a preinvasive stage of cancer .

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* Protein E6, binds to and induces

degradation of p53

* Protein E7, binds to and inhibits RB

Allowing cells to escape normal regulation growth and activate cell cycle-related genes such as cyclin E, thus permitting uncontrolled cellular proliferation --------78