CIN & Cervical Screening

Plan

• Part 1: Incidence, pathogenesis, and prevention

• Part 2: Cervical Screening• Part 3: Grading, treatment, and Follow up

Part 1: Incidence, pathogenesis, and prevention

Introduction

• Premalignant condition of uterine cervix• Ectocervix is covered by squamous epitheiam• Endocervix including cervical canal covered by

glandular epithelium– CIN refers to squamous abnormality• Adenocarcinoma in situ, and adenocarcinoma

• CIN can be low grade or high grade. – Women with low grade CIN have minimal

potential for developing cervical malignancy

Incidence

• 4 % in US for CIN 1, 5% for CIN2, 3• High grade lesion are typically diagnosed in

women 25-35 years old• Invasive cancer is commonly after age of 40– Typically 8-13 years afer a diagnosis of a high

grade lesion

Premalignant disease of the cervix

HPV infection

CIN I

CIN II

CIN III

Cervicalcancer

Normal cervix

Pathogenesis

• Role of human papillomavirus (HPV)– Major etiologic agent– Strong association– Necessary for development of neoplasia– Not sufficient alone to cause such disorders cause

many HPV infected women do not develop it– HPV subtype, and persistence of virus

• Enviromental (eg, cigarette smoking) • Immunlogic influences

HPV Subtype

• Over 100 subtype– 40 types specific for anogenital epithelium– Distribution varies by geographic region– Infection with more than one subtype is common– Acquisition of one subtype and clearance of

another are independent events• Subtype determines manifestation of infection

and oncogenic potential of virus

Oncogenic HPV

Low Risk & High Risk Subtypes

• Low risk – e.g., HPV 6 and 11– do not integrate into host genome– Only cause CIN 1 (10%)– benign condylomatous genital warts (90%)

• High risk – e.g., HPV 16 and 18– Associated with CIN 2, 3, persistence, and invasive

cancer, can also cause low grade– Low grade (25%), high grade (50-60%)Cancer(70%)

Persistence

• HPV is transient and occur in young women– Persistency is a key factor for development of high

grade– Unknown why it persists– The likelihood of persistence• Older age - > 55 years of age (50%)• Duration of infection – long infection = long clearance• High oncogenic HPV subtype – the longer it persists

Sexual transmission

• HPV transmitted sexually• Endemic amongst sexually experienced

individuals• At least 75-85% of sexually active women will

have acquired genital HPV by age 50

Cervical Transformation Zone

• Transformation Zone vs SCJ– SCJ – where the squamous epithelium meets the cervical

of ectocervix meets columnar epithelium of endocervix.– Transformation zone is dynamic entity of metaplasia

throughout a women’s life, which is the area of glandular epithelium has been replaced by squamous epithelium

– Transformation zone comprises SCJ + larger area• Primary site of carcinogenic HPV-related CIN& CN– Cuboidal cells at Squamouscolumnar Junction

Molecular Mechanism

• Epitheliotropic, once epithelium is infected, the virus can either persist in cytoplasm or integrate into the host genome– Remains episomal nonintegrated state

• Low-grade cervical lesion

– Becomes integrate into human genome• High grade lesion and cancer may develop

• Integration into host cell – disruptions of viral regulatory oncoproteins, where E6 binds to p53, and E7 binds to Retinoblastoma, and suppress their function, the latter activates IL5&IL6 which are important in progression of CN 2,3 to over malignancy..

Co-factor in Pathogenesis

• Immunosupression – cervical cancer is one of AIDS related malignancy in women

• Cigarette smoking – with HPV have synergistic effects on development of CIN and CN– Breakdown products of nicotine cotinine and NNK are

concentrated in cervical mucus and cause cellular abnormalities

• HSV and Chlamydia – surrogate marker for exposure of HPV rather than a causal factor

• OCP – long term use, as a surrogate marker

Prevention

• Primary – HPV vaccination• Secondary – for cervical cancer rather than

CIN, through appropriate treatment and prevent progression to malignant disease

Part 2Cervical Screening

Cervical screening

• Prevention of cervical cancer• Early detection by:– Pap smear– HPV test

Pap Smear

• George Papanicolaou (1883-1962)• The Pap test aims to identify abnormal cells

sampled from the transformation zone, the junction of the ecto- and endocervix, where cervical dysplasia and cancers arise.

Guidelines

• ACOG• Start at 21 years• 21-29: Pap smear every 3 years • 30-65: Pap smear every 3 years OR HPV co-

test every 5 years• Stop at 65 years• Annual screening not recommended

How to prepare?

• Before the pap test, patient should avoid:– Having intercourse– Using tampon– Douching

• Preferably not during menstruation

Speculum

• Insert lubricated speculum

Methods Of Interpretation

• For conventional Pap smears, cervical samples obtained by brush and spatula are plated on a microscope slide and preserved with fixative.

• Thin layer (or liquid-based) cytology, an alternative to conventional cytologic sampling, has been widely implemented in the US.– Testing involves transferring samples from the brush

and spatula into a liquid fixative solution; the cytology lab subsequently traps the loose cells onto a filter from which they are plated in a monolayer onto a glass slide

Spatula

• Insert spatula and rotate• Smear on a slide

Cytobrush

• Insert brush and rotate• Smear on slide

Fixation

• Alcohol

Liquid Media

Bethesda

• Specimen type (conventional, liquid-based, etc)• Specimen adequacy– Satisfactory for evaluation (note presence/absence of

endocervical/transformation zone component)– Unsatisfactory for evaluation (specify reason)• Specimen rejected/not processed (specify reason)• Specimen processed and examined, but unsatisfactory

for evaluation of epithelial abnormality because of (specify reason)

Bethesda

• General Categorization (Optional)– Negative for intraepithelial lesion or malignancy– Epithelial cell abnormality– Other

• Interpretation/result– Negative for intraepithelial lesion or malignancy

• Organisms (e.g. trichomonasvaginalis)• Reactive cellular changes associated with inflammation,

radiation, intrauterine contraceptive device• Atrophy

Bethesda

• Epithelial cell abnormalities– Squamous• Atypical squamous cells

– ASC-US (undetermined significance)– ASC-H (cannot exclude HSIL)

• Low grade squamous intraepithelial lesion (LSIL) - mild dysplasia/CIN I• High grade squamous intraepithelial lesion (HSIL) –

moderate and severe dysplasia/CIN II/III• Squamous cell carcinoma

Bethesda

• Epithelial cell abnormalities– Glandular• Atypical

– Endocervical– Endometrial– NOS

• Atypical favor neoplastic– Endocervical– NOS

• Endocervical adenocarcinoma in situ (AIS)• Adenocarcinoma

Part 3Classification and Treatment

CIN Classification

• Low-grade squamous intraepithelial lesion (LSIL)– CIN I (Mild dysplasia) 50%, 30%, 20%, 1-5%

• High-grade squamous intraepithelial lesion (HSIL– CIN II (Moderate dysplasia)– CIN III (Severe dysplasia) 33%, 60-74%

CIN Classification

Diagnosis:

• Pap tests• Colposcopy• Endocervical curettage• Cone biopsy or loop electrosurgical excision

procedure (LEEP) which are performed to rule out invasive cancer

Adequacy of Colposcopy

• Must evaluate the entirety of the lesion

• Must evaluate the entirety of the SCJ

Failure of either criteria is an inadequate colposcopy and leads to changes

TREATMENT

• Mainstays of treatment of high-grade cervical intraepithelial neoplasia (CIN) are excision or ablation

• Excisional treatments are:– referred to as cone biopsies or cervical conization

• Ablative treatments– use an energy source (eg, cryotherapy, laser) to

destroy the transformation zone

Laser

TREATMENT

What to choose• Factors affect:

– Efficacy: the efficacy rate for both ablation and excision is approximately 90 to 95 percent

– Diagnostic specimen: no specimen is removed in ablative. For this reason, an excisional procedure is required for diagnostic purposes in the following situations:• High risk of invasive disease • Glandular disease is present• Diagnostic uncertainty

– Future obstetric risks — Excision has been associated with an increased risk of adverse obstetric outcomes

– Morbidity — Excisional methods are typically thought to be associated with greater morbidity than ablative therapy. However, the meta-analysis of randomized trials found no significant difference in adverse effects

What to choose?

• For women with CIN 2,3 and an adequate colposcopy, either an excisional treatment or an ablative treatment is appropriate.

• For women with an inadequate colposcopy, recurrent CIN 2,3, an excisional procedure is preferred

What to choose?

• For young women with CIN 2,3 and an adequate colposcopy, either observation or treatment is acceptable. If treatment is performed, either excision or ablation may be used.

What to choose?

• Women with CIN 1 — Most women with CIN 1 are managed with follow-up testing, and treatment is only indicated if CIN 1 persists for longer than two years.

Hysterectomy for:

1. CIN 2,3 with a positive conization margin2. who have completed childbearing3. who would benefit from a definitive

procedure4. women who are not willing or able to comply

with long-term follow-up

Outcome:

• The rate of recurrent or persistent CIN is 5 to 17 percent despite therapy with any of the excisional or ablative techniques

• Higher rates of persistent disease are associated with:– Large lesion size (eg, greater than two thirds of the surface of the

cervix)– Endocervical gland involvement– Positive margin status– Continuing human papillomavirus (HPV) DNA positivity (especially

with HPV 16) six months or more post-treatment

• The prognosis after treatment of CIN differs based upon the presence of CIN at the margin of a conization specime

FOLLOW-UP AFTER TREATMENT:• After treatment with excision or ablation, women with

CIN 2,3 should be followed with:– Human papillomavirus (HPV)/cervical cytology co-testing in

12 and 24 months.• If both co-tests are negative, co-testing should be repeated in

three years. • If there is abnormal cytology or a positive HPV test during follow-

up, colposcopy with endocervical sampling should be performed.

• If CIN 2,3 is identified at the margins of an excisional procedure or post-procedure endocervical curettage (ECC), cytology and ECC at four to six months is preferred.