Cervical Intraepithelial Neoplasia (CIN)

Cervical Intraepithelial Neoplasia Essentials

• The cervix may appear normal during examination.
• Human papillomavirus infection is generally present.
• Cytologic tests show dysplastic or carcinoma in situ cells(traditional Pap smear or liquid-based cytology)
• Colposcopy reveals an atypical transformation zone with thickened acetowhite epithelium, coarse punctate, or mosaic surface capillaries.
• Squamous epithelium typically includes an iodine-nonstaining (Schiller-positive) area.
• Biopsy confirms cervical intraepithelial neoplasia (dysplasia or carcinoma in situ).

General Considerations

• Lower genital tract squamous intraepithelial neoplasia is often multicentric, affecting multiple sites derived from the same anogenital epithelium.
• Multicentricity includes cervical intraepithelial neoplasia (CIN), vaginal (VAIN), vulvar (VIN), and perianal intraepithelial neoplasia (PAIN).
• 10% of women with CIN have concomitant preinvasive neoplasia of the vulva, vagina, or anus.
• 40-60% of patients with VIN or VAIN have synchronous or metachronous CIN.
• 2012 Lower Anogenital Squamous Terminology(LAST) project changes use the same terminology for histologic and cytologic results.
• CIN I is referred to as a low-grade squamous intraepithelial lesion (LSIL); CIN II is subdivided according to p16 staining
• CIN II classified as LSIL if p16 negative, and as a high-grade squamous intraepithelial lesion (HSIL) if p16 positive.
• CIN III is referred to as HSIL and CIN terminology is used for histologic results because of the American Society for Colposcopy and Cervical Pathology guidelines.
• CIN (formerly dysplasia), describes disordered growth and development of the cervical epithelial lining.
• Degrees of CIN: Mild dysplasia (CIN I) involves disordered growth in the lower third of the lining; Moderate dysplasia (CIN II) affects the lower two-thirds; Severe dysplasia (CIN III) covers more than two-thirds of the thickness.
• Carcinoma in situ (CIS) represents full-thickness dysmaturity.
• Cytologic tests use the Bethesda System revised in 2014, atypical squamous cells divided into undetermined significance (ASC-US) and those where a high-grade lesion is not excluded (ASC-H).
• LSIL covers changes matching koilocytic atypia or CIN I
• HSIL denotes findings corresponding to CIN II and CIN III.
• Glandular cell abnormalities: atypical glandular cells not otherwise specified (AGC-NOS) or favoring neoplasia (AGC-FN), endocervical adenocarcinoma in situ, or adenocarcinoma.
• Abnormal cytology test suggests CIN, diagnosis is established by cervical biopsy.
• Spontaneous regression, especially of CIN I, occurs frequently, allowing expectant management with serial cytologic tests in reliable patients.
• Untreated high-grade lesions can progress to invasive cancer; predicting progression is unreliable, needing treatment for CIN II and CIN III.
• Young women with CIN II can be monitored due to substantial spontaneous regression and almost no cancer risk, pregnant women delaying until after postpartum.

Pathogenesis

• CIN prevalence varies by socioeconomic status and location, from 1.05% in family planning clinics to 13.7% in STI clinics.
• CIN typically appears in women in their 20s; CIS peaks at 25-35 years; Cervical cancer increases significantly after 40 years.
• Risk factors for CIN are like those for cervical cancer: multiple sexual partners, early sexual activity, a high-risk partner (multiple partners, HPV, genital neoplasia, prior exposure to cervical neoplasia), STIs, smoking, HIV, AIDS, immunosuppression, multiparity, and long-term oral contraceptive use.
• HPV is a key factor in CIN and cervical cancer, negating other behavioral/sexual risk factors when adjusted.
• HPV presence: >80% of all CIN lesions and 99.7% of invasive cervical cancers.
• HPV-16 occurs in 50-70% of cervical cancers, HPV-18 in 7-20% of cervical cancers.
• In the United States, HPV prevalence rises from 1% in newborns to 20% in teenagers, 40% in women aged 20-29, then declines to 5% in women over 50.
• 50-80% lifetime risk of HPV infection for women.
• Condoms provide 60% protection against HPV but transmission occurs from labial-scrotal contact.
• Types: ~130 HPV types, 30-40 infecting the anogenital epithelium.
• Low-risk HPV types (e.g., 6, 11, 42, 43, 44) linked to condylomata and low-grade lesions (CIN I).
• High-risk HPV types (e.g., 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) are associated with invasive cancer and high-grade lesions (CIN II & CIN III).

• 90% of immunocompetent women spontaneously resolve HPV infection in 2 years, with ~5% having detectable CIN.

• 10% of women have persistent high-risk HPV infection, increasing the risk for CIN II/III and cervical cancer.
• Most women with HPV do not develop CIN or cervical cancer, suggesting HPV alone is insufficient and underscoring the importance of cofactors.
• Synergistic effects: Smoking and HPV on CIN development, smoking associating with a 2-4 fold increased risk of cervical cancer.
• Cigarette smoke carcinogens are found in cervical mucus, pack-years correlating with CIN/CIS risk.
• HIV-infected women have an increased incidence of cervical neoplasia, studies showing 20-30% colposcopically confirmed CIN.
• Worsening immunosuppression increases risk of new and persistent HPV infection, as well as progressive cervical neoplasia and invasive cervical cancer included as AIDS-defining illness since 1993.

Prevention

• Three FDA-approved HPV vaccines: quadrivalent (Gardasil, HPV-16, -18, -6, -11), bivalent (Cervarix, HPV-16 & -18), and 9-valent (Gardasil 9, HPV-6, -11, -16, -18, -31, -33, -45, -52, -58).
• Trials showed 93-100% efficacy in preventing CIN II or worse from vaccine HPV types in HPV-naïve populations.
• Entire study cohorts showed 30-44% efficacy for preventing CIN II or worse and 20-50% protection against nonvaccine HPV types.
• The 9-valent vaccine showed high efficacy (96%) in preventing CIN II or worse from its 5 additional HPV strains and noninferiority for HPV-6, -11, -16, or -18.
• CDC’s ACIP recommends HPV vaccination for children (male/female) aged 11-12, starting as early as age 9 and extending to age 26 for females/21 for males (catch-up).
• Males having sex with men/immunocompromised males should be vaccinated through age 26.
• HPV vaccines are prophylactic, not therapeutic, so most effective before HPV infection (e.g., before sexual debut).
• HPV vaccination is not altered by current abnormal Pap or positive HPV test because 25% of women aged 20+ are + for 1 of the 4 HPV types in the quadrivalent vaccine, 1% for HPV-16 and -18, and 0.1% for all 4 HPV types.
• The bivalent, quadrivalent, or nine-valent HPV vaccine should offer benefit to almost all individuals in the indicated age range.
• There is no evidence that the HPV vaccine is harmful during pregnancy, but HPV vaccination is not recommended for safety reasons.
• Women becoming pregnant mid-series, or unknowingly vaccinated while pregnant, should continue series postpartum. It is safe to offer during lactation.
• Population-based screening programs and early treatment have reduced cervical cancer incidence and mortality by 75% in developed countries.

• Half of women developing cervical cancer never had cytology, had sporadic screening, or lacked screening in the last 5 years. Therefore, following screening guidelines is critical for vaccinated/unvaccinated women.

• 2012 guidelines were released by the US Preventive Services Task Force (USPSTF) and the American Cancer Society/American Society for Colposcopy and Cervical Pathology/American Society for Clinical Pathology (ACS/ASCCP/ASCP).
• 3 primary, acceptable cervical cancer screening methods: cytology alone, HPV testing alone, or combined cytology and HPV cotesting.

Cervical Cytology Screening

• Using liquid-based cytology is preferable, though conventional Pap smears are acceptable.
• Screening should begin at age 21, regardless of sexual activity onset due to the rarity of cervical cancer in women <21 years of age
• Invasive cancer is rare in women under 21, and there is likely significant potential for adverse effects associated with follow-up of abnormalities
• High HPV prevalence in young women after intercourse is linked to abnormal cervical cytology and high clearance rates for both HPV and dysplasia.
• Screening frequency recommended every 3 years for women aged 21-29; for women 30 or older, cytology and HPV cotesting every 5 years or cytology alone every 3 years.
• Screening discontinued after age 65 with negative consecutive screening in the past 10 years.
• Screening should not be resumed unless posttreatment surveillance (CIN II/III or worse), in which case routine screening should continue at least 20 years, even if it extends past age 65.

Special Population Deviations

• Screenings discontinued following hysterectomy (total) without CIN (grade II/III or worse) history, if no adequate prior screening.
• For HIV+ women, initial Pap tests are done within 1 year of diagnosis at 6- or 12-month intervals based on AIDSinfo guidelines, with cytology every 3 years after 3 normal results.
• American College of Obstetricians and Gynecologists (ACOG) guidelines suggest annual screening for immunosuppressed women or those with in utero diethylstilbestrol (DES) exposure.
• Pap test results are reported using the 2014 Bethesda nomenclature.

HPV Testing

• There are 4 US FDA-approved HPV tests that test for 1+ of 13 or 14 high-risk HPV types.
• High-risk HPV testing now triages ASC-US cervical cytology in women ≥21 years, using liquid-based cytology’sresidual preservative.
• It is also a triage test for LSIL in postmenopausal women and a follow-up test after CIN I or negative colposcopy in women with ASC-US, ASC-H, LSIL, or atypical glandular cells (AGCs).
• Approved as an adjunct to cytology for women older than 30 years. If HPV testing combined with cytology are both negative, screening shouldn’t be repeated for 5 years.
• Cytology and HPV testing (+): colposcopy; cytology normal, HPV +: repeat tests at 12 months, colposcopy if either is abnormal, also type-specific testing for HPV-16/18.
• Primary screening in patients aged ≥25 years, using Cobas HPV test approved in 2014, screening for HPV-16, HPV-18, and 12 other high-risk HPV types every 3 years.

Visual Screening

• Visual inspection of the cervix is a screening tool for low-resource settings lacking HPV testing or cytology screenings, economical but w/ limited specificity.
• It can be performed through direct visual inspection or cervicoscopy using acetic acid, toluidine blue, or Lugol’s iodine as an adjunct.

Clinical Findings

• There are usually no symptoms/signs of CIN, and often the diagnosis is based on biopsy following an abnormal, routine cervical cytology test.
• Detection relying on screening guidelines is vital, high-grade dysplasia is a phase in the pathogenesis of many cervical cancers.
• Cervical lesion seen during pelvic exam: biopsy is prompted.

Pathology

• Anaplasia is present on cytologic exams, increased nuclear-to-cytoplasmic ratios (ie, larger nucleus), hyperchromatism with changes in nuclear with chromatin, multinucleation, differentiation abnormalities.
• Histologically, stratified squamous epithelium thickness is typical of dysplasia, with anaplastic/hyperchromatic cells and loss of polarity in deeper layers and with abnormal mitotic figures.
• Benign epithelial alterations (inflammatory), HPV cytopathic effects, and technical artifacts can be mistaken for CIN I/II.
• Endocervical glands’ columnar epithelium can undergo neoplastic transformation in situ (ACIS), defined as the presence of endocervical glands lined by atypical columnar epithelium resembling cells of endocervical adenocarcinoma in its cells by lining, and lacking invasion.

Diagnosis

• Diagnosis of microinvasive carcinoma and ACIS can be made only by cone biopsy.
• Further evaluation needed for abnormal cervical cytology: visual inspection, repeat cytology, HPV testing, Lugol staining, or toluidine blue, colposcopy, directed biopsy, endocervical sampling, or diagnostic conization. Exclusion objective includes presence of invasive carcinoma, to determine CIN (degree/extent)
• Acceptable initial evaluation for minimal abnorms, accelerate serial cytology tests, testing+ HPV for colpopscopy. All H+, premono L, HSILS referral for colposcopy.
• For repeat cytology test for ASC-US, treat infectious vaginal results. Pap @ 12m. import, neg ASC-us @ hsil 33% biposy- prooven HSILs. Asc colpsocy

Treatment

• Testing for low-risk HPV has no role in cervical cancer prevention. Hi-risk testing @ ACS- US postmeno L. Reflex HPV is Preffer. Concur collxn pap/ hpv

Examination

• It is based on normal squamo-cell of the cervix contains glycol, iodine + magogwny
• Test limits bec 85% hpx positive.

Colposcopy

• Evaluates abnorm cervical tissue w/low-power magnf. Normal collp, orig s,j, and sqma-cln.
• Indic collp is an abnormal cervix or suspected.
• Abnorm collp (Leukopaia/hyperceratiosis is wite, thick epith)

Progression And Action

• The course of Dysplsia is influenced by HPV type, immunity, and habits. Failure to have HPV means increase cancer dev
• CIN I spontanetaly regresses without treatment. CIN 1 9–16% dig CIN II/III over 2 yr folow. Cin I overall regresses overall (60%) 81% young w
• CINI follow compliant for spont resol, a myority. Tx is warranted
• test all (bxs and such)
• Expectant for for CINI when low grade test results(AS)-us or LSIL(
• CIN 1 @ ASC-H has H (prv > Asc H) is followd clls.
• The choice can depend colopsy + excis.

Methods For The Management Of Abnormal Cytologic Testing

• If it;s non visible, try coloposcy then do dirrected biposis
• Lesion extends into cannal, so do a conzinization. 5 commmon technics: cryo and lap + CO excision, & knife.
• Most CINS is ablative methods ( cryo or laser).

Other factors

• Most test F- because the inability to visualize.

Other Tx Factors

• Cryo : not an office procefure. Nitorus oixde + proge set cervix 7 mm so ice goes beyond depth.
• Freezinng beyond depth with 2 cycle thar. easy and cheap
• LEEP is for CINS II + III and more. Small wire elctrodes
• Cold kniffe- remove shapred, used when on EC for 12–15 or 10 % and to find dysplasia