cervical%20cancer%20-%20prevention%20-and-%20screening
CERVICAL CANCER - PREVENTION & SCREENING
Mortality due to cervical cancer can be reduced by prevention, early detection & treatment.
Vaccination may be started as early as 9 years old.
Vaccination may reduce the incidence of HPV-related disease.
Screening for cervical cancer after vaccination is still recommended because only 70% of the virus types associated w/ invasive cervical cancer consist of HPV 16 & 18 types & women may not be entirely protected if they have been infected w/ other HPV types prior to vaccination.

Prevention

Informed Consent

  • Vaccination is anticipated to reduce the lifetime risk of cervical cancer by 70-83% as long as Papanicolaou (Pap) screening is continued
  • Patients and guardians should be informed regarding:
    • Benefits of the human papilloma virus (HPV) vaccine
    • The risk of cervical cancer associated with HPV
    • The sexual transmission of HPV

Vaccination

Goals of Prophylactic Vaccination

  • Vaccination may reduce the incidence of HPV-related disease (eg cervical, penile, vulvar, vaginal, anal and oropharyngeal cancer and precancerous lesions)
    • It is recommended to vaccinate girls before the start of sexual activity because vaccines do not treat existing HPV infection or HPV-related disease
  • HPV vaccines are composed of virus-like particles made up of L1 major capsid proteins and are identical to HPV capsids
  • These virus-like particles pose no infectious or oncologic risk because they do not have any viral DNA
    • They also do not have RNA, mercury or egg products
  • Clinical trials have shown high efficacy rates for the HPV vaccines

Vaccines

9-valent Human Papilloma Virus (HPV) Vaccine

  • Contains HPV types 6, 11, 16, and 18 similar to the quadrivalent HPV vaccine but also targets 5 additional cancer causing types 31, 33, 45, 52, and 58
  • Protects against genital warts and premalignant lesions and cancers of the cervix, vulva, vagina, and anus
    • Epidemiology studies show that 9-valent HPV vaccine is expected to protect against HPV types that cause about 90% of cervical cancers, >95% of adenocarcinoma in situ, and 75-85% of high-grade cervical intraepithelial neoplasia (CIN 2/3)
  • A randomized trial showed noninferior immunogenicity for the HPV types common among the quadrivalent and 9-valent vaccines and high efficacy for the 5 additional HPV types
    • An active comparator-controlled, double-blind, randomized clinical study showed efficacy in preventing HPV 31, 33, 45, 52 and 58-related persistent infection and disease and reduction in the incidence of related Pap test abnormalities, cervical and external genital procedures and cervical definitive therapy procedures
  • Individuals who previously received a 3-dose quadrivalent vaccination series may receive 3 doses of 9-valent HPV vaccination; however, there is no Advisory Committee on Immunization Practices (ACIP) recommendation for routine additional 9-valent HPV vaccination of individuals who had completed a bivalent or quadrivalent vaccination series
  • According to ACIP, the 9-valent HPV vaccine may be used to continue or complete the vaccination series began wih a different HPV vaccine product; however, there is no recommendation for additional doses of 9-valent HPV vaccine for individuals who began the series with a bivalent or quadrivalent HPV vaccine and had finished the series with the 9-valent HPV vaccine
  • Available data demonstrate no serious safety concerns in individuals who, after completing a 3-dose series of quadrivalent HPV vaccine, were vaccinated with 9-valent HPV vaccine
    • On receiving the 9-valent vaccine, safety profiles are generally similar between the HPV naive person and a person who had completed a 3-dose series

Quadrivalent Human Papilloma Virus (HPV) Vaccine

  • Contains HPV capsids of type 6, 11, 16 and 18
  • Recommended for prevention of cervical cancers and precancers, and genital warts
  • Demonstrated to protect against vulvar, vaginal and anal cancers and precancers
  • Amorphous aluminum hydroxyphosphate sulfate is the vaccine adjuvant which helps evoke higher immune response
  • Studies show 100% efficacy in preventing type-specific HPV infection and cervical intraepithelial neoplasia or CIN 2/3
    • At least 5 years follow-up data is available and strong immune memory has been demonstrated
    • Data show cross-protection efficacy in reducing incidence of CIN 2/3 or adenocarcinoma in situ (AIS) caused by 10 other oncogenic types (HPV 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59)
    • Results of 3 clinical trials suggest that the vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types among sexually active women
    • Safety and clinical efficacy have been confirmed in women 24-45 years of age based on a randomized double-blind trial

Bivalent Human Papilloma Virus (HPV) Vaccine

  • Contains virus-like particles for HPV types 16 and 18
  • Formulated with a novel, proprietary ASO4 adjuvant system that consists of aluminum and 3-o-desacyl-4-monophosphoryl lipid A (MPL)
    • Adjuvant system boosts antibody level by at least 11-fold higher than those from natural infection
  • Data from a clinical trial translated to 95.1% efficacy for prevention of persistent cervical HPV infection and follow-up studies showed 100% efficacy for prevention of CIN lesions associated with HPV types 16 and 18
    • At the end of 64 months follow-up, data revealed that >98% of patients were seropositive for HPV types 16 and 18
    • Vaccine efficacy against CIN2+ after 8.4 years follow-up was 100% for lesions associated with HPV 16/18; antibody concentrations remained ≥10-fold higher than after natural infection
  • Based on a randomized controlled study, data showed cross-protection against CIN2+ caused by 12 non-vaccine oncogenic HPV types (HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68)
    • Individual cross-protection against HPV types 31, 33 and 45 as supported by virological and lesion endpoints
    • Reduced number of colposcopy referrals of 26.3% and cervical excision procedures of 68.8% among subjects with no evidence of previous HPV infection
  • Vaccine efficacy against CIN3+ irrespective of HPV DNA in lesions was 93.2% in the total vaccinated cohort (TVC)-naive as showed in the end-of-study results from a double-blind, randomized, efficacy study

Screening

  • Mortality due to cervical cancer can be reduced by prevention, early detection and treatment
    • Patients with early changes of pre-cancer are asymptomatic; screening is needed to diagnose a pre-cancerous lesion
  • Cervical cancer screening should be done at least once in women 30-49 years old; <30 years old if high risk for CIN2+
  • More frequent cervical cancer screening may be required in patients with risk factors: Immunocompromised, infected with HIV, in utero diethylstilbestrol exposure, prior treatment for CIN2, CIN3 or cancer 
  • Screening is unnecessary in patients who had total hysterectomy 
  • Visual inspection techniques are less specific than Pap smear but are more sensitive in detecting pre-invasive lesions
    • Can be used as cervical cancer screening tools in low-resource settings or even in well-equipped health centers and cancer centers

 Papanicolaou (Pap) Smear Test

  • Consists of microscopic exam of exfoliated cervical cells
  • Cytology screening with the Pap smear test is still the most effective strategy to detect cervical cancer and precursor lesions
    • Conventional cytology and liquid-based cytology showed similar sensitivity and specificity in detecting CIN 2 or more severe diagnoses (CIN2+)
    • Effectiveness is increased when part of an organized screening program
  • Reported sensitivity and specificity vary widely
    •  Factors influencing accuracy include small lesion size, inadequate sampling and obscuring blood and debris
  •  Liquid-based preparations are now available
    •  Improve specimen adequacy and cellular sampling, distribute cells evenly on the slide, decrease cell overlapping and obscuring background, and provide residual material for HPV DNA testing
  •  The majority of women developing invasive cervical cancer have never been screened or have not been screened adequately
  •  Specific recommendations on target populations and screening frequency will differ between countries
    •  The recommendations attempt to balance the risk of false-negative results against potential for over-treatment of clinically insignificant lesions that occur in transient disease

Human Papilloma Virus (HPV) DNA Testing

  • A molecular test for high-risk HPV
    • Greater sensitivity but lower specificity in detecting CIN 2/3
  • Addition of HPV testing in cervical cancer screening guidelines may increase disease detection as well as length of screening intervals
    • Less specific when used alone and may identify clinically insignificant disease which may regress spontaneously
    • Routine HPV testing and cytology screening should be discontinued and not restarted in patients with total hysterectomy and had never developed CIN2 or higher
  • As a primary screening test, it can be considered as an alternative to cytology screening in patients >25 years old

Visual Inspection with Acetic Acid (VIA)

  • Naked-eye inspection of the cervix washed with 3-5% acetic acid
  • Test is positive after detecting any acetowhite areas (low-threshold) or well-defined, opaque, acetowhite lesions close to or touching the squamocolumnar junction (high-threshold)
  • Has a positive predictive value comparable to Pap smear but is more likely to achieve earlier diagnosis, follow-up, and treatment than cytology-based screening

Visual Inspection with Lugol’s Iodine (VILI)

  • Naked-eye inspection of the cervix with Lugol’s iodine test is positive upon detection of yellow iodine nonuptake areas in the transformation zone close to or touching the squamocolumnar junction

Follow Up

  • Screening for cervical cancer is still recommended because:
    • Only 70% of the virus types associated with invasive cervical cancer consist of HPV 16 and 18 types
    • Women may not be entirely protected if they have been infected with other HPV types prior to vaccination
    • Duration of protection has not been established and ongoing studies are still being monitored for HPV vaccines
  • Similar screening guidelines are used in patients who have been vaccinated and in those who have not
  • Screening services should be tied up with treatment and post-treatment follow-up
    • Monitoring and evaluation are significant for cervical cancer prevention
  • An alteration in prevalence of disease probably will not be evident for another decade or more after the institution of regular prophylactic vaccine
    • At which time, screening recommendations may change

Management of Atypical Squamous Cells of Undetermined Significance

Human Papilloma Virus (HPV) DNA Testing

  • Test for high-risk viruses only
  • Can easily be done as reflex testing after liquid-based cytology
  • Resumption of screening protocol after a negative result
    • Patients with ASC-US cytology and negative HPV test are recommended to have cotesting in 3 years
  • Refer patient for colposcopy and biopsy after a positive result

Repeat Cytology

  • Repeat cervical cytology (Pap smear) after 12 months
  • If repeat smear is negative, repeat cytology in 3 years
  • If positive for ≥ atypical squamous cells of undetermined significance (ASCUS), refer for colposcopy

Management of Cervical Intraepithelial Neoplasia (CIN) 1, 2/3, and Adenocarcinoma In Situ (AIS)

Cervical Intraepithelial Neoplasia (CIN) 1 Preceded by Atypical Squamous Cells of Undetermined Significance (ASCUS), Atypical Squamous Cells-Cannot Exclude High-grade Squamous Intraepithelial Lesion (ASC-H) or Low-grade Squamous Intraepithelial Lesion (LSIL) Cytology

  • Repeat cervical cytology every 6-12 months
    • After 2 negative smears, proceed with normal screening interval
    • If cytology is ≥ASCUS, colposcopy is recommended
  • Do human papilloma virus (HPV) DNA testing for high-risk types after 12 months
    •  If negative, resume normal screening interval
    •  If positive, colposcopy is recommended

Follow-up

  • If CIN 1 persists for at least 2 years, continued follow-up or treatment is recommended
  • If treatment is selected, may proceed with either excision or ablation
    • Diagnostic excision is recommended for the following cases:
      • Colposcopic examination is found to be unsatisfactory
      • Endocervical sampling contains CIN
      • Previously-treated patient

Cervical Intraepithelial Neoplasia (CIN) 1 Preceded by High-grade Squamous Intraepithelial Lesion (HSIL) or Atypical Glandular Cells-Not Otherwise Specified (AGC-NOS) Cytology

  • The following are recommended for CIN 1 preceded by HSIL or AGC-NOS cytology (with satisfactory colposcopic examination and negative endocervical sampling):
    • Diagnostic excisional procedure
    • Observation with colposcopy and cytology at 6-month intervals for 1 year
  • Review the histological, cytological, and colposcopy findings
  •  Do recommended treatment for revised interpretation

Observation

  • For patients with repeated HSIL or AGC-NOS cytology results at 6- or 12-months visit, diagnostic excision is preferred
  • Routine cytological screening is recommended if after 1 year of observation it resulted to 2 consecutive negative findings for intraepithelial lesion or malignancy

Diagnostic Excisional Procedure

  • Recommended for patients with unsatisfactory colposcopic examination

Cervical Intraepithelial Neoplasia (CIN) 2/3

  • For patients with satisfactory colposcopy, excisional procedure and ablation are acceptable
  • For patients with unsatisfactory colposcopy, excisional procedure is recommended
  • For patients with recurrent CIN 2/3, diagnostic excisional procedure is an option

Follow-up

  • May include cytology alone, combined cytology and colposcopy at 6 months, HPV DNA testing at 6- to 12-month intervals, or cotesting at 12 and 24 months
  • For patients with positive HPV DNA or repeat cytology result of ≥ASCUS, colposcopy with endocervical sampling is recommended
  • For patients with negative HPV DNA or if 2 repeat cytology results are negative for intraepithelial lesion or malignancy, proceed with routine screening
  • If CIN 2/3 is identified at the margins after diagnostic excisional procedure or present in endocervical sample, reassessment after 4-6 months posttreatment is recommended using cytology with endocervical sampling
    • Repeat diagnostic excisional procedure is adequate while hysterectomy is preferred if excision is not possible
  • For recurrent or persistent CIN 2/3, either repeat diagnostic excisional procedure or hysterectomy is recommended

Adenocarcinoma In Situ (AIS)

  • Prior to any subsequent treatments, excisional biopsy is required in all patients with AIS
  • Studies have shown that in majority of AIS patients, diagnostic excisional procedure is curative
    • Failure rate ranges from 0-9%
  • One of the most useful predictors of residual disease is the margin status
    •  Another predictor is endocervical sampling at the time of biopsy
  •  If family is complete, total hysterectomy can be an option
  •  If future fertility is desired, conservative management is recommended
    •  If the margins of the specimen or endocervical sampling contains CIN or AIS, re-excision is preferred to increase the probability of complete excision
      •  Reevaluation is recommended at 6 months using a combination of cytology, HPV DNA testing, and colposcopy with endocervical sampling
    •  Long-term follow-up is strongly suggested with negative margins

Microinvasion/Cancer

  • Refer to Cervical Cancer - Treatment Disease Management Chart
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