Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses

hrHPV testing with an appropriate assay offers a promising new strategy that could increase population coverage substantially

What is already known on this topic

  • Tests performed on self samples are less sensitive and less specific than tests performed on clinician samples when using a high-risk human papillomavirus (hrHPV) assay based on signal amplification
  • Response rates for hrHPV testing are higher for self sampling kits than for conventional invitations

What this study adds

  • Tests performed on self samples are similarly sensitive and slightly less specific than tests performed on clinician samples when using a hrHPV assay based on polymerase chain reaction
  • Response rates for hrHPV testing continue to be higher for self sampling kits than for conventional invitations

2018 Study Abstract

Objective
To evaluate the diagnostic accuracy of high-risk human papillomavirus (hrHPV) assays on self samples and the efficacy of self sampling strategies to reach underscreened women.

Design
Updated meta-analysis.

Data sources
Medline (PubMed), Embase, and CENTRAL from 1 January 2013 to 15 April 2018 (accuracy review), and 1 January 2014 to 15 April 2018 (participation review).

Review methods
Accuracy review: hrHPV assay on a vaginal self sample and a clinician sample; and verification of the presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by colposcopy and biopsy in all enrolled women or in women with positive tests. Participation review: study population included women who were irregularly or never screened; women in the self sampling arm (intervention arm) were invited to collect a self sample for hrHPV testing; women in the control arm were invited or reminded to undergo a screening test on a clinician sample; participation in both arms was documented; and a population minimum of 400 women.

Results
56 accuracy studies and 25 participation trials were included. hrHPV assays based on polymerase chain reaction were as sensitive on self samples as on clinician samples to detect CIN2+ or CIN3+ (pooled ratio 0.99, 95% confidence interval 0.97 to 1.02). However, hrHPV assays based on signal amplification were less sensitive on self samples (pooled ratio 0.85, 95% confidence interval 0.80 to 0.89). The specificity to exclude CIN2+ was 2% or 4% lower on self samples than on clinician samples, for hrHPV assays based on polymerase chain reaction or signal amplification, respectively. Mailing self sample kits to the woman’s home address generated higher response rates to have a sample taken by a clinician than invitation or reminder letters (pooled relative participation in intention-to-treat-analysis of 2.33, 95% confidence interval 1.86 to 2.91). Opt-in strategies where women had to request a self sampling kit were generally not more effective than invitation letters (relative participation of 1.22, 95% confidence interval 0.93 to 1.61). Direct offer of self sampling devices to women in communities that were underscreened generated high participation rates (>75%). Substantial interstudy heterogeneity was noted (I2>95%).

Conclusions
When used with hrHPV assays based on polymerase chain reaction, testing on self samples was similarly accurate as on clinician samples. Offering self sampling kits generally is more effective in reaching underscreened women than sending invitations. However, since response rates are highly variable among settings, pilots should be set up before regional or national roll out of self sampling strategies.

Whereas accuracy of new combinations of assays and self sampling devices can be evaluated in a diagnostic setting, acceptance and participation should be shown locally in a screening setting before general roll out.

Screening for Cervical Cancer – US Preventive Services Task Force Recommendation Statement

New Cervical Cancer Screening Guidelines: What You Need to Know

Some women have a new option for cervical cancer screening — and it doesn’t necessarily involve a Pap test — according to updated guidelines from a government-appointed panel of experts, livescience reports.

Key Points

  • Women under age 21 should not be screened for cervical cancer.
  • Women ages 21 to 29 should undergo screening every three years using a Pap test, also called “cervical cytology.” (HPV testing isn’t recommended for women ages 21 to 29 because, in this age group, HPV infection is common and is often cleared by the immune system.)
  • Women over age 65 do not need to be screened for cervical cancer if they are up to date on their screening, their tests in the previous 10 years were negative and they don’t have other risk factors for cervical cancer.

Abstract

Importance
The number of deaths from cervical cancer in the United States has decreased substantially since the implementation of widespread cervical cancer screening and has declined from 2.8 to 2.3 deaths per 100 000 women from 2000 to 2015.

Objective
To update the US Preventive Services Task Force (USPSTF) 2012 recommendation on screening for cervical cancer.

Evidence Review
The USPSTF reviewed the evidence on screening for cervical cancer, with a focus on clinical trials and cohort studies that evaluated screening with high-risk human papillomavirus (hrHPV) testing alone or hrHPV and cytology together (cotesting) compared with cervical cytology alone. The USPSTF also commissioned a decision analysis model to evaluate the age at which to begin and end screening, the optimal interval for screening, the effectiveness of different screening strategies, and related benefits and harms of different screening strategies.

Findings
Screening with cervical cytology alone, primary hrHPV testing alone, or cotesting can detect high-grade precancerous cervical lesions and cervical cancer. Screening women aged 21 to 65 years substantially reduces cervical cancer incidence and mortality. The harms of screening for cervical cancer in women aged 30 to 65 years are moderate. The USPSTF concludes with high certainty that the benefits of screening every 3 years with cytology alone in women aged 21 to 29 years substantially outweigh the harms. The USPSTF concludes with high certainty that the benefits of screening every 3 years with cytology alone, every 5 years with hrHPV testing alone, or every 5 years with both tests (cotesting) in women aged 30 to 65 years outweigh the harms. Screening women older than 65 years who have had adequate prior screening and women younger than 21 years does not provide significant benefit. Screening women who have had a hysterectomy with removal of the cervix for indications other than a high-grade precancerous lesion or cervical cancer provides no benefit. The USPSTF concludes with moderate to high certainty that screening women older than 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer, screening women younger than 21 years, and screening women who have had a hysterectomy with removal of the cervix for indications other than a high-grade precancerous lesion or cervical cancer does not result in a positive net benefit.

Conclusions and Recommendation
The USPSTF recommends screening for cervical cancer every 3 years with cervical cytology alone in women aged 21 to 29 years. (A recommendation) The USPSTF recommends screening every 3 years with cervical cytology alone, every 5 years with hrHPV testing alone, or every 5 years with hrHPV testing in combination with cytology (cotesting) in women aged 30 to 65 years. (A recommendation) The USPSTF recommends against screening for cervical cancer in women younger than 21 years. (D recommendation) The USPSTF recommends against screening for cervical cancer in women older than 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer. (D recommendation) The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and do not have a history of a high-grade precancerous lesion or cervical cancer.

Recommendations of Others

… “Women at increased risk of cervical cancer (ie, women with a history of cervical cancer, a compromised immune system, or diethylstilbestrol exposure) may need to be screened more often.” …

Reference. US Preventive Services Task Force, August 21, 2018.

USPSTF Draft Recommendation Statement Cervical Cancer : Screening

The US Preventive Services Task Force has New Draft Guidance for Cervical Cancer Screening

These recommendations do NOT apply to women with in utero exposure to diethylstilbestrol or women who have a compromised immune system (e.g., women living with HIV).

The major change from the US Preventive Services Task Force (USPSTF) 2012 recommendation is that testing for high-risk strains of human papillomavirus (hrHPV) alone is now recommended as an alternative to cytology or Papanicolaou (Pap) screening alone beginning at age 30 years; cotesting is no longer recommended.

As in the 2012 recommendation, the USPSTF continues to recommend that women aged 21 to 29 years undergo Pap screening every 3 years.

The USPSTF recommend against screening in women younger than age 21 years because there is adequate evidence that regardless of sexual history, screening younger women does not reduce cervical cancer incidence or mortality.

The USPSTF also continues to give a thumbs down to screening in women older than age 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer, as well as in women who have had a hysterectomy and their cervix removed and do not have a history of a high-grade precancerous lesions or cervical cancer.

More Information

Could a pap smear done early in pregnancy help doctors diagnose babies with genetic diseases?

Fetal genome profiling at 5 weeks of gestation after noninvasive isolation of trophoblast cells from the endocervical canal

Noninvasive peek at fetal DNA

Single-gene mutations are responsible for a large number of diseases and contribute to a sizeable fraction of pediatric hospitalizations and deaths. Current methods for prenatal diagnosis of such mutations are limited because they are invasive (except for detection of circulating fetal DNA, which is safe but can be difficult to perform accurately) and most cannot be performed early in pregnancy.

Pap Smear Early in Pregnancy Could Reveal Genetic Disorders Earlier, livescience, November 2, 2016.

Jain et al. now demonstrate a way to isolate and analyze trophoblast cells, which carry fetal DNA, by noninvasively obtained Papanicolaou smears. The authors show that analysis of the DNA in these cells presents an accurate reflection of the fetal genotype as early as 5 weeks of gestation, without the risk posed by invasive procedures.

Abstract

Fetal genome profiling at 5 weeks of gestation after noninvasive isolation of trophoblast cells from the endocervical canal, sciencemag, 02 Nov 2016.

Single-gene mutations account for more than 6000 diseases, 10% of all pediatric hospital admissions, and 20% of infant deaths. Down syndrome and other aneuploidies occur in more than 0.2% of births worldwide and are on the rise because of advanced reproductive age. Birth defects of genetic origin can be diagnosed in utero after invasive extraction of fetal tissues. Noninvasive testing with circulating cell-free fetal DNA is limited by a low fetal DNA fraction. Both modalities are unavailable until the end of the first trimester. We have isolated intact trophoblast cells from Papanicolaou smears collected noninvasively at 5 to 19 weeks of gestation for next-generation sequencing of fetal DNA. Consecutive matched maternal, placental, and fetal samples (n = 20) were profiled by multiplex targeted DNA sequencing of 59 short tandem repeat and 94 single-nucleotide variant sites across all 24 chromosomes. The data revealed fetal DNA fractions of 85 to 99.9%, with 100% correct fetal haplotyping. This noninvasive platform has the potential to provide comprehensive fetal genomic profiling as early as 5 weeks of gestation.

Are you Too Young for a Pap Test? Become aware of the Cervical Cancer Symptoms

Heather – now cance-free – was diagnosed with cervical cancer a year before she became eligible for smear tests… she shares her tips

image of too-young-for-pap-test
Heather wants to share her story so that there is more awareness around cervical cancer.

I want to share my story, to help others be more aware of the symptoms of cervical cancer. So that girls under 25 that are not entitled to a free smear know what to look out for and for those who are over 25 be more aware of the importance of going for your smear.

Symptoms

  • Abnormal bleeding
    • heavy or longer periods
    • between periods
    • after sex
    • after menopause
  • Foul smelling discharge
  • Pain or discomfort in the pelvis or during sex

Sources

Depression and diethylstilbestrol exposure in women

The Journal of Reproductive Medicine, 1987

image of Mental-Illness
In this 1987 study, there were significant differences between DES-exposed women and their unexposed sisters (sister controls) in major depression and major recurrent depression. Mental Illness.

1987 Study Abstract

Fifty women exposed to diethylstilbestrol (DES) in utero, 50 of their unexposed sisters (sister controls) and 43 women with abnormal Papanicolaou smears (population controls) were tested using the Diagnostic Interview Schedule to assess differences in depression and other kinds of psychologic impairment possibly associated with DES exposure.

There were significant differences between DES-exposed women and their sisters in major depression and major recurrent depression. Papanicolaou controls were more depressed in comparison to sister controls. However, there were no significant differences in depression between Papanicolaou controls and the DES exposed, suggesting that major and recurrent depressions are more likely to result from concern about reproductive and other gynecologic problems than from the hormonal effects of intrauterine exposure to DES. Differences in amphetamine abuse/dependence were also noted between the DES exposed and the sister controls.

Sources and more information
  • Depression and diethylstilbestrol exposure in women, The Journal of reproductive medicine, NCBI PMID: 3430493, 1987 Nov;32(11):847-50.
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Management of females exposed to DES-type drugs ; 1977 recommendations

Vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones

woman-at-hospital
1977 study and recommendations about vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones. all you’ve been through.

1977 Study Abstract

All asymptomatic girls who wore exposed to diethylstilbestrol in utero should receive a thorough pelvic examination at menarche or if they have reached 14 years of age. Younger girls should be examined if they develop abnormal bleeding or discharge. Whenever prenatal exposure is probable and theme are symptoms of discharge, further investigation is imperative, regardless of the patient’s age. This investigation should not be concluded until it is certain that no lesion is present.

Before the examination is undertaken, the entire procedure should be thoroughly discussed with the patient (and her mother on father if she is a minor).

The examination should include inspection and palpation, Papanicolaou smear (cervix and vagina), and an iodine staining test of the entire cervix and vagina. Abnormal areas, including those that do not stain with iodine, should be biopsied.  This procedure can be performed in the physician’s office with small biopsy instruments and without significant discomfort.

For the very young patient who has symptoms that require investigation, anesthesia may occasionally be required be fore an examination. A small speculum permits adequate visualization of the vagina without undue discomfort in younger patients.

With asymptomatic females, if adequate examination is not possible at the initial visit, vaginal tampons should be used for a few months to allow an adequate examination later without discomfort. Colposcopy is a useful adjunct to this examination, but it is not essential. Utilizing its low power magnification to examine the vagina and cervix, the physician can identify areas of glandular tissue (adenosis) in the vagina on on the cervix. This identification permits directed rather than “blind” biopsies. When used in con junction with the iodine staining test and selected biopsy, colposcopy permits precise recording of observed abnormalities and their appraisal at fixed intervals.

The patient exposed to DES-type drugs should be followed on a regular basis. After a normal initial examination, annual pelvic examinations with cervical and vaginal cytology and iodine staining are probably adequate. If any abnormalities are noted during the initial evaluation, more frequent follow-up examinations are suggested (every 3 to 6 months, depending on the severity of the findings).

Locally destructive measures such as cauterization, cryosurgery, or excision can be utilized if atypical changes such as marked squamous dysplasia on carcinoma in situ of the vagina or cervix are found on biopsy.

Sources and more information
  • Vaginal and cervical cancers and other abnormalities associated with exposure in utero to diethylstilbestrol and related synthetic hormones, Cancer Research, 1977 Apr.
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Development of DES-associated clear-cell carcinoma: the importance of regular screening

Regular and frequent PAP smears are needed for DES-affected women

pap-smear image
This 1979 study underscores the necessity for frequent vaginal cytologic smears and pelvic examinations at intervals no greater than 6 months for the DES-affected women.

1979 Study Abstract

Because the rate of malignancies in young women exposed in utero to diethylstilbestrol (DES) is low, appropriate population screening methods have not been established. A case is presented that is believed to represent the first reported instance of a DES-exposed daughter who developed clear cell adenocarcinoma of the vagina after initially negative examinations. The patient was followed with Papanicolaou smears, pelvic examinations, and colposcopy every 6 months for 2 years prior to the discovery of malignancy. Initially negative, Papanicolaou smears successfully predicted the presence of an early adenocarcinoma. Palpation aided by colposcopy allowed directed biopsy of the small asymptomatic lesion.

This case underscores the necessity for frequent vaginal cytologic smears and pelvic examinations at intervals no greater than 6 months. Colposcopy is indicated to direct biopsies when an abnormal cytologic smears is reported or when abnormal bleeding or discharge occurs. Biopsy of any palpable lesion is mandatory.

Sources and more information
  • Development of DES-associated clear-cell carcinoma: the importance of regular screening, Obstetrics and Gynecology 1979 Mar;53(3):293-9, NCBI PMID: 424100.
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Cervical intraepithelial neoplasia associated with exposure to diethylstilbestrol in utero

Obstetical Gynecology, Clinical and Pathologic Study 1981

intraepithelial-neoplasia image
Orr JW Jr, Shingleton HM, Gore H, Austin JM Jr, Hatch KD, Soong SJ., Obstetrics and Gynecology 1981.

1981 Study Abstract

The anatomic, colposcopic, cytologic, and histologic findings of the cervix in 300 women exposed to diethylstilbestrol (DES) in utero are reported.

Structural cervical abnormalities were found in 51.7% of these patients and an abnormal colposcopic examination was present in 50.6%. The initial interpretation of the pathologic specimens revealed that 26.6% of patients had cytologic or histologic evidence of cervical dysplasia. A uniform pathologic review demonstrated that 10.8% of the cytologic specimens and 37.5% of the histologic specimens had been overread by the initial pathologist. A correlation of the review cytology and histology revealed that the Papanicolaou smear sensitivity for the prediction of abnormal histology was 83.9% and specificity was 86.3%. The probability of an atypical cytologic finding predicting an abnormal histologic pattern was highly significant (P less than .00001). Colposcopic and structural cervical abnormalities were not predictive of an abnormal histologic diagnosis. Of the 18 patients (6%) with histologic evidence of mild-moderate dysplasia, 12 have been followed with no treatment, and cytologic and colposcopic examination has been normal. Marked dysplasia-carcinoma in situ was found in 14 patients (4.7%). Their therapy is summarized.

These data strongly suggest that women exposed to DES may be followed safely with Papanicolaou smears and colposcopic examinations provided that both cytopathologists and colposcopists are cognizant of the metaplastic changes in the DES progeny that distinguish them from patients with cervical intraepithelial neoplasia (CIN) who were not exposed to DES. Biopsy should be performed only if indicated by cytologic atypia, colposcopic evidence of advanced CIN, or the presence of an invasive lesion.

Sources and more information
  • Cervical intraepithelial neoplasia associated with exposure to diethylstilbestrol in utero: a clinical and pathologic study, Obstet Gynecol. 1981 Jul;58(1):75-82, NCBI PMID: 7195532.
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Increased Incidence of Cervical and Vaginal Dysplasia in Diethylstilbestrol-Exposed Young Women

A DES Experience of the National Collaborative Diethylstilbestrol Adenosis Project.

Cervical-Dysplasia-Testing image
In this 1984 study, the incidence rate for dysplasia and carcinoma in situ was significantly higher in the women exposed to diethylstilbestrol.

1984 Study Abstract

The incidence rates of dysplasia and carcinoma in situ (CIS) of the cervix and vagina were determined in 3,980 young women exposed prenatally to diethylstilbestrol. Strict criteria were developed to minimize selection bias among the subset of 744 pairs of matched exposed and unexposed (control) cohort participants, all of whom were identified through review of prenatal obstetrical records. A high degree of compliance was achieved throughout the seven-year study period since in each group about 90% of the women remained as active participants, kept 77% of the annual anniversary examinations, and had separate Papanicolaou smears of the cervix and vagina performed in 99% of the anniversary examinations. The incidence rate for dysplasia and CIS was significantly higher in the women exposed to diethylstilbestrol than in those not exposed in the matched cohort (15.7 v 7.9 cases per 1,000 person-years of follow-up). The rates were higher in the exposed women if squamous metaplasia extended to the outer half of the cervix or onto the vagina. In other respects, the matched cohorts were strikingly similar.

Sources and more information
  • Increased incidence of cervical and vaginal dysplasia in 3,980 diethylstilbestrol-exposed young women. Experience of the National Collaborative Diethylstilbestrol Adenosis Project, NCBI PMID: 6502858, JAMA. 1984 Dec 7;252(21):2979-83.
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